Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)C1C=CC=CC=1>C(O)C.[Pd]>[F:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH:14]([O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])=[CH:22][CH:21]=1
Reactant: COCCOCOC(CCCCCOCc1ccccc1)COc1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: COCCOCOC(CCCCCO)COc1ccc(F)cc1
Reaction time: 3 h
Yield: 90.9 %

Procedure:
(±)-7-benzyloxy-1-(4-fluorophenoxy)-2-(2-methoxyethoxy-methoxy)-heptane 43 (11 g, 26.3 mmol) in 30 ml of ethanol is added to a 50 ml round bottom flask. Palladium on activated carbon (10% Pd/C, 150 mg) is added and the reaction mixture is stirred under an atmosphere of hydrogen. After 3 hours, the reaction mixture was filtered through celite, washed with ethanol and concentrated. The crude product was purified on silica gel (ethyl acetate:hexane 1:1) to give (±)-7-(4-fluorophenoxy)-6-(2-methoxyethoxymethoxy)heptan-1-ol 44 (7.9 g, 91%). The structure was confirmed by 1H-NMR.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:28][C:29]([C:31]1[CH:35]=[C:34]([OH:36])[N:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:32]=1)=[O:30])[C:10](=[O:27])[N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:50][O:51][C:52]([C:54]1[O:55][C:56]([CH2:59]Cl)=[CH:57][CH:58]=1)=[O:53]>CN(C=O)C.C(OCC)(=O)C>[CH3:50][O:51][C:52]([C:54]1[O:55][C:56]([CH2:59][O:36][C:34]2[N:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:32]=[C:31]([C:29](=[O:30])[NH:28][C@H:9]([C:10]([N:11]3[CH2:12][CH2:13][N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=4)[CH2:15][CH2:16]3)=[O:27])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:43])[CH:35]=2)=[CH:57][CH:58]=1)=[O:53]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(O)n(-c2ccccc2)n1)C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: COC(=O)c1ccc(CCl)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(COc2cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N3CCN(c4cccc(C(F)(F)F)c4)CC3)nn2-c2ccccc2)o1

Procedure:
180 mg of (S)-4-[(5-Hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-5-oxo-5-[4-(3-trifluoromethyl-phenyl)piperazin-1-yl]-pentanoic acid tert-butyl ester dissolved in 4 ml DMF was treated with 293 mg of cesium carbonate and 78 mg of Methyl-5-(chlormethyl)furan-2-carboxylate. After 3 h at 70° C. the mixture was diluted with ethyl acetate and washed with saturated sodium hydrogen carbonate solution. Drying of the organic layer over sodium sulfate gave crude 5-(5-{(S)-3-tert-Butoxycarbonyl-1-[4-(3-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-propylcarbamoyl}-2-phenyl-2H-pyrazol-3-yloxymethyl)-furan-2-carboxylic acid methyl ester which was used for the subsequent reaction.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].CN1CCOCC1.Cl[C:28]([O:30][CH:31]([Cl:33])[CH3:32])=[O:29]>ClCCl>[Cl:33][CH:31]([O:30][C:28]([NH:2][CH2:3][CH:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])=[O:29])[CH3:32]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CC(C)CC(CN)CC(=O)OCc1ccccc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)CC(CNC(=O)OC(C)Cl)CC(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
To a stirred solution of (39) (428 mg, 1.51 mmol) in dichloromethane at 0° C. was added N-methylmorpholine (0.33 mL, 3.02 mmol) and 1-chloroethyl chloroformate (0.164 mL, 1.51 mmol). The resulting solution was stirred at 0° C. until the reaction was complete (˜30 min, as monitored by TLC) and then was diluted with dichloromethane, washed successively with cold 1N HCl solution, water and brine, then dried over anhydrous Na2SO4. Filtration and removal of the solvent in vacuo afforded the title compound (40) as a mixture of two diastereomers (530 mg, 100%), which was used without further purification in the following example. 1H-NMR (CDCl3, 400 MHz): δ 0.87 (m, 6H), 1.13 (m, 2H), 1.63 (m, 1H), 1.76 (m, 3H), 2.15 (m, 1H), 2.34 (m, 2H), 3.10 (m, 1H), 3.27 (m, 1H), 5.11 (br.s, 3H), 6.53 (q, 1H), 7.33 (m, 5H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:12](=[O:30])[CH2:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][CH:17]([CH2:16][N:13]2[CH2:14][CH2:15][N:10]([S:7]([C:5]3[S:6][C:2]([C:35]4[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=4)=[CH:3][CH:4]=3)(=[O:9])=[O:8])[CH2:11][C:12]2=[O:30])[CH2:18][CH2:19]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(Br)s3)CC2=O)CC1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(-c4ccc(Cl)cc4)s3)CC2=O)CC1
Yield: 92.6 %

Procedure:
A mixture of 4-(5-bromo-2-thiophenesulfonyl)-1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-piperazinone (115 mg), 4-chlorophenylboronic acid (52 mg), tetrakistriphenylphosphine palladium (25 mg), 2M sodium carbonate solution (0.25 ml) and dimethoxyethane (10 ml) was refluxed for 15 hours. The reaction solution was concentrated, and to the residue was sodium bicarbonate solution. The mixture was extracted with ethyl acetate, washed with brine, dried, and concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:3) to give colorless solid of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-[5-(4-chlorophenyl)-2-thiophenesulfonyl]-2-piperazinone (113 mg).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([NH:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=O)=[O:11])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:36]=[C:37]([N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)[NH2:38]>CN1C(=O)CCC1>[CH3:22][C:21]1[CH:20]=[CH:19][C:15]([C:16]2[O:18][N:38]=[C:37]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[N:36]=2)=[CH:14][C:13]=1[NH:12][C:10]([C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1)=[O:11]
Reactant: Cc1ccc(C(=O)O)cc1NC(=O)c1cnc2ccccn12
Reactant: NC(=NO)N1CCOCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2nc(N3CCOCC3)no2)cc1NC(=O)c1cnc2ccccn12
Temperature: 105 °C
Reaction time: 0.25 h

Procedure:
A stirring suspension of 3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylbenzoic acid (4) (41 mg, 0.138 mmol) in anhydrous NMP (1 mL) was heated in the microwave at 105° C. for 2 minutes to dissolve all solid. Then, 1,1′-carbonyldiimidazole (22 mg, 0.138 mmol) was added and the reaction was stirred at room temperature for 15 minutes. N′-hydroxymorpholine-4-carboximidamide (20 mg, 0.138 mmol) was added and the reaction was stirred for 30 minutes. The reaction was heated in the microwave at 130° C. for 15 minutes. The crude product was purified by reverse phase preparative HPLC to give N-(2-methyl-5-(3-morpholino-1,2,4-oxadiazol-5-yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (F75). 1H NMR (400 MHz, d6-DMSO) δ 10.18 (s, 1H), 9.52-9.48 (m, 1H), 8.68 (s, 1H), 8.11 (d, J=2.0 Hz, 1H), 7.88-7.83 (m, 2H), 7.68-7.63 (m, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.31-7.27 (m, 1H), 3.72-3.69 (m, 4H), 3.41-3.38 (m, 4H), 2.39 (s, 3H). MS m/z 405.16 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([CH2:17][CH2:18][CH3:19])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[BH4-].[Na+]>CO.ClCCl>[F:1][C:2]([F:20])([F:21])[C:3]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[C:11]([CH2:17][CH2:18][CH3:19])[CH:10]=1)([OH:8])[C:4]([F:5])([F:7])[F:6]
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
4-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)-2-propylbenzaldehyde (0.636 mmol, 200 mg) was dissolved in methanol (4 mL)/dichloromethane (1 mL) and sodium borohydride (1.909 mmol, 72.2 mg) was added. The mixture was stirred at room temperature for 90 minutes then was concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL) and washed with a saturated solution of sodium bicarbonate (25 mL). The organic phase was filtered through a hydrophobic frit and concentrated to afford the title compound (161 mg). MS (ESI) m/z 315.1 [M−H]
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[N:12]1([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]1
Reactant: CCOC(=O)C1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
Benzyl chloroformate (Aldrich, cat #:119938) (191 mL, 1.34 mol) was slowly added to a cooled (at 0° C.) mixture of ethyl piperidine-3-carboxylate (Aldrich, cat #:194360) (200 g, 1.27 mol) and triethylamine (266 mL, 1.91 mol) in methylene chloride (1000 mL). The reaction mixture was allowed to gradually warm to ambient temperature and stirred for 3 h. The reaction was quenched by the addition of 1N HCl aq. solution and the product was extracted several times with methylene chloride. The combined extracts were washed with water, saturated aq. NaHCO3, water, brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product as oil (359.8 g, 97%). LC/MS 292.2 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[CH2:18][CH:17]([NH2:29])[CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[N:30]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[CH2:18][CH:17]([NH:29][C:35]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:36])[CH2:16]2)=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Reactant: O=C(Cl)N1CCCC1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)N3CCCC3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
57 mg (0.12 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 7A) and 20 mg (0.15 mmol, 1.3 eq.) of pyrrolidine-N-carbonyl chloride were reacted according to General Method 3. Yield: 24 mg (52% of theory)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH2:19])[C:9]([NH2:18])=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.Cl.[C:21](Cl)(=O)[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1.O>N1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]2[NH:19][C:21]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[N:18][C:9]2=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: Nc1nc(-c2ccncc2)c(-c2ccco2)nc1N
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: c1cncc(-c2nc3nc(-c4ccncc4)c(-c4ccco4)nc3[nH]2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.5 %

Procedure:
A mixture of 5-(2-furyl)-6-pyridin-4-ylpyrazine-2,3-diamine (Example 87, 146 mg, 0.58 mmol) and nicotinoyl chloride hydrochloride (516 mg, 2.9 mmol) in pyridine (5 mL) was stirred and heated at reflux for 24 h. Then polyphosphoric acid was added and the stirring was continued at the same temperature for 24 h. The reaction was allowed to cool to room temperature and was poured into water and extracted with ethyl acetate. The organic phase was dried (MgSO4), evaporated and the residue was purified by silica gel chromatography (CH2Cl2/MeOH/NH3 50:8:1). The appropriate fractions were concentrated to leave a solid which upon washing with diethyl ether give the title compound as a light brown solid (82 mg, 61%).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])=[CH:23][C:22]=3[F:36])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][C:29]([OH:31])=[O:30])=[CH:23][C:22]=3[F:36])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CC(=O)OC(C)(C)C)cc3F)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CC(=O)O)cc3F)CC2)CC1
Yield: 91.6 %

Procedure:
4-[1-(4-tert-Butoxycarbonylmethyl-2,5-difluoro-phenyl)-piperidin-4-ylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester 75a (368 mg) was dissolved in DCM (5 mL) and TFA (3 mL) and stirred at r.t. for 4 h. The solvent was removed in vacuo, DCM and water were added and the organic phase was dried over MgSO4 and concentrated to give 4-[1-(4-carboxymethyl-2,5-difluoro-phenyl)-piperidin-4-ylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester 75b (300 mg).
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.I[C:30]1SC2C=CC=C(C)C=2N=1>>[CH3:30][C:27]1[C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=[CH:2][CH:28]=1
Reactant: Cc1cccc2sc(I)nc12
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Product: Cc1cccc2sc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)nc12

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 2-iodo-4-methyl-1,3-benzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.10-2.31 (m, 4H), 2.74 (s, 3H), 3.05-3.18 (m, 2H), 3.41 (d, J=13.2 Hz, 2H), 4.49-4.57 (m, 1H), 7.41-7.48 (m, 2H), 8.02 (dd, J=6.4, 2.7 Hz, 1H), 8.09 (s, 1H), 8.45 (s, 1H), 8.49 (br. s., 1H), 8.56 (d, J=1.8 Hz, 1H). MS (ES+): m/z=391.14 [MH+]. HPLC: tR=2.11 min (ZQ2, polar—5 min).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]1([C:11]2[C:2]([C:23]3[CH:24]=[CH:25][C:20]([CH:18]=[O:19])=[CH:21][CH:22]=3)=[N:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][N:5]=3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Clc1nc2ncccc2cc1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2nc3ncccc3cc2-c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
2-Chloro-3-phenyl-1,8-naphthyridine (Rani, H. S.; Mogilaiah, K.; Sreenivasulu, B. Indian J. Chem. Sect. B. 1996, 35, 106; 154 mg, 0.64 mmole), 4-formylphenylboronic acid (144 mg, 0.96 mmole), 2 M Na2CO3 (0.64 mL, 1.28 mmole), and Pd(PPh3)4 (37 mg, 0.03 mmole) were combined in dioxane (3 mL) in a sealed microwave vessel. The mixture was degassed (3× vacuum/N2) then microwave irridiated at 150° C. for 30 min. The mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column (60% EtOAc/hexanes) gave the title compound as a yellow foam (10-1): 1H-NMR (500 MHz, CDCl3) δ 10.02 (s, 1 H), 9.19 (dd, J=1.95, 2.20 Hz, 1 H), 8.28 (dd, J=1.95, 6.35 Hz, 1 H), 8.26 (s, 1 H), 7.79 (d, J=8.30 Hz, 2 H), 7.73 (d, J=8.05 Hz, 2 H), 7.57 (m, 1H), 7.35 (m, 2H), 7.27 (m, 3 H).
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:17]([CH:20]=[C:21]1[CH2:24][O:23][CH2:22]1)([O-:19])=[O:18].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]1[CH2:9][CH:20]([N+:17]([O-:19])=[O:18])[C:21]2([CH2:24][O:23][CH2:22]2)[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=[N+]([O-])C=C1COC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])C1CN(Cc2ccccc2)CC12COC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To a solution of benzyl-methoxymethyl-trimethylsilanylmethyl-amine (3.0 g, 12.6 mmol) and 3-nitromethylene-oxetane (1.38 g, 12.0 mmol) in dichloromethane (60 mL) was added trifluoroacetic acid (0.93 mL, 12.6 mmol) dropwise. The mixture was stirred at room temperature for 2 hours, quenched with sodium carbonate, extracted with dichloromethane. The organic layer was dried over sodium sulfate, concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 2 g of product as colorless oil. It was used for next step without further purification.
Reaction SMILES: O=S(Cl)[Cl:3].[NH2:5][C:6]1[N:11]=[C:10]([OH:12])[C:9]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=2)=[C:8]([CH3:22])[N:7]=1>C(Cl)Cl>[NH2:5][C:6]1[N:11]=[C:10]([OH:12])[C:9]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][Cl:3])=[CH:16][CH:15]=2)=[C:8]([CH3:22])[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(N)nc(O)c1Sc1ccc(CO)cc1
Solvent: ClCCl
Product: Cc1nc(N)nc(O)c1Sc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
SOCl2 (20 ml) was added slowly to a stirred mixture of the product from step (i) (6.7 g) in DCM (50 ml) and stirred at rt for 24 h. The solvent was evaporated under reduced pressure to give the title compound, 8.7 g.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([CH2:25][CH3:26])=[C:18]3[N:23]([CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:27][C:28](=[O:31])[C:29]#[CH:30]>>[C:28]([C:29]1[CH:30]=[C:24]2[N:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=13)[C:17]([CH2:25][CH3:26])=[C:16]2[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])=[CH:11][CH:12]=1)(=[O:31])[CH3:27]
Reactant: C#CC(C)=O
Reactant: CCc1c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)cn2ccccc12
Product: CCc1c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)c2cc(C(C)=O)c3cccc1n32
Yield: 45 %

Procedure:
2-(4-(tert-Butyldimethylsilanyloxymethyl)phenyl)-1-ethylindolizine was reacted with 3-butyn-2-one by the general synthetic principles outlined in example 73, step 1, to afford 4-acetyl-2-(4-(tert-butyldimethylsilanyloxymethyl)phenyl)-1-ethylpyrrolo[2,1,5-cd]indolizine in 45% yield. 1H-NMR (CDCl3, 200 MHz) δ: 0.17 (s, 6H); 0.99 (s, 9H); 1.47 (t, 3H); 2.72 (s, 3H); 3.22 (q, 2H); 4.86 (s, 2H); 7.51 (d, 2H); 7.74 (d, 2H); 7.80-7.96 (m, 3H); 8.48 (dd, 1H).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[CH2:21]([NH:29][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCc1ccccc1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3NCCc2ccccc2)nc1
Yield: 87.8 %

Procedure:
Using a method similar to Example 14, using 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 805 mg, 3.00 mmol), phenethylamine (436 mg, 3.60 mmol), Ti(iPrO)4 (1.70 g, 6.00 mmol), TiCl4 (1.0M/DCM, 6.00 ml, 6.00 mmol), and NaBH3CN (377 mg, 6.00 mmol) gives the title compound (984 mg) as a light yellow solid. Mass spectrum (ion spray): m/z=374 (M+1); 1HNMR (CDCl3): 8.59 (s, 1H), 8.15 (d, 1H), 7.33-7.19 (m, 6H), 6.98 (s, 1H), 6.95-6.91 (m, 2H), 5.99 (br. s, 2H), 4.26 (t, 1H), 3.04-2.94 (m, 3H), 2.88-2.74 (m, 3H), 2.44 (m, 1H), 1.84 (m, 1H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].O.[NH2:18][NH2:19].O>CO>[NH:18]([C:3](=[O:2])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])[NH2:19]
Reactant: COC(=O)COc1cccc(C(=O)OC)c1
Reactant: NN
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc(OCC(=O)NN)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a suspension of methyl 3-(2-methoxy-2-oxoethoxy)benzoate (887 mg, 3.96 mmol) in MeOH (50 mL) was added hydrazine hydrate (1.92 mL). After stirring for 0.5 h at rt, water (50 mL) was added and the reaction mixture was filtered. Washing with water (3×5 mL) and drying under vacuo at 70° C. overnight gave 713 mg of the title compound (80%) as a white solid in 98.3% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[NH4+:34].[OH-]>>[NH2:34][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: CN(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Agent: [OH-]
Product: CN(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(N)n2)s1
Temperature: 140 °C
Yield: 31 %

Procedure:
N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(dimethylamino)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (0.1 g, 0.2 mmol) was taken up in 2 mL 30% NH4OH (aq) and heated to 140° C. for 20 min in a microwave reactor. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed with 2 mL of 0.1 N HCl (aq). The organic layer was dried over Na2SO4 and evaporated onto silica gel. Purification by flash chromatography (0 to 40% EtOAC/DCM) afforded the title compound (30 mg, 0.061 mmol, 31% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.98 (s, 1H), 7.59-7.70 (m, 2H), 7.26-7.35 (m, 1H), 7.15-7.25 (m, 4H), 7.09 (d, J=7.5 Hz, 1H), 6.48 (s, 2H), 5.68 (d, J=5.3 Hz, 1H), 3.03 (s, 6H)). MS (ESI): 489 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([O:15]C)=O)[CH2:11][C@H:10]([NH:17][C:18]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:19]=2[C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:41][NH2:42]>CO>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13](=[O:15])[NH:42][CH3:41])[CH2:11][C@H:10]([NH:17][C:18]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:19]=2[C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)=[O:21])[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN
Reactant: COC(=O)[C@@H]1C[C@H](Nc2ccc([N+](=O)[O-])cc2C(=O)NCc2ccc(OC)c(OC)c2)CN1C(=O)OC(C)(C)C
Solvent: CO
Product: CNC(=O)[C@@H]1C[C@H](Nc2ccc([N+](=O)[O-])cc2C(=O)NCc2ccc(OC)c(OC)c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-[(3S,5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin-3-ylamino]-N-(3,4-dimethoxylbenzyl)-5-nitrobenzamide (143 mg) and 30% methanol solution of methylamine (4 mL) was stirred for one day at ambient temperature. After evaporation of the solvent, the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine and dried over magnesium sulfate. The residue was subjected to a silica gel column chromatography eluting with ethyl acetate to give 2-[(3S,5S)-1-(tert-butoxycarbonyl)-5-(methylcarbamoyl)pyrrolidin-3-ylamino]-N-(3,4-dimethoxylbenzyl)-5-nitrobenzamide (149 mg).