Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH2:11])[CH2:7]1)([CH3:5])[CH3:4].[CH2:30]([O:32][CH:33]1[C:38](=O)[CH2:37][CH2:36][O:35][CH2:34]1)[CH3:31].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH2:30]([O:32][CH:33]1[CH:38]([NH:11][C@@H:8]2[CH2:9][CH2:10][C@:6]([CH:3]([CH3:5])[CH3:4])([C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=4)[CH2:16][CH2:15]3)=[O:13])[CH2:7]2)[CH2:37][CH2:36][O:35][CH2:34]1)[CH3:31]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)CC[C@@H](N)C1
Reactant: CCOC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.6 %

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)cyclopentanamine dihydrochloride (200 mg, 0.438 mmol), 3-ethoxytetrahydro-4H-pyran-4-one (130 mg, 0.88 mmol) and triethylamine (0.18 mL, 1.3 mmol) in methylene chloride (10 mL) was added sodium triacetoxyborohydride (180 mg, 0.88 mmol). After being stirred at room temperature overnight, the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried (MgSO4), concentrated and purified on silica gel (EtOAc to 1% Et3N/EtOAc to 5% Et3N/EtOAc) affording 230 mg of product. The product was separated by chiral HPLC to give two major isomers: isomer 1 (110 mg) and isomer 2 (77 mg). MS calculated for C27H40F3N3O3: (M+H) 512; found 512.2.
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].C([O-])(=O)C.[Na+].N[C@H](C(O)=O)CS.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>C(O)C.O>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]2[NH:3][CH:4]([C:7]([OH:9])=[O:8])[CH2:5][S:6]2)=[CH:26][CH:25]=1
Reactant: N[C@@H](CS)C(=O)O
Agent: CC(=O)[O-]
Agent: COc1ccc(C=O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(C2NC(C(=O)O)CS2)cc1
Reaction time: 0.5 h

Procedure:
A 22 L three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with L-cysteine hydrochloride monohydrate (500.0 g, 2.85 mol), sodium acetate (260.0 g, 3.17 mol) and 4.00 L of water. The mixture was stirred until all of the L-cysteine dissolved. A solution of p-methoxybenzaldehyde (426.0 g, 3.13 mol) in 3.50 L of ethanol was prepared and added to the reaction such that the internal reaction temperature was kept below 30° C. The reaction becomes a thick white slurry during the addition of the p-methoxybenzaldehyde solution. After 30 minutes, 3.50 L of ethanol was added to the reaction. Stirring was continued for 1 hour and then the solid was isolated by filtration. A 1.50 L portion of ethanol was used to wash the solid. The solid was dried in a vacuum oven at 50° C. for 48 hours. Approximately 610 g of 2-(4-methoxy-phenyl)thiazolidine-4-carboxylic acid was obtained (90% yield). 1H NMR (300 MHz, DMSO) δ 7.41-7.31 (m, 4H), 6.93-6.83 (m, 4H), 5.56 (s, 1H), 5.42 (s, 1H), 4.23 (dd, J=6.7, 4.4 Hz, 1H), 3.84 (dd, J=7.6, 7.1 Hz, 1H), 3.73 (s, 3H), 3.71 (s, 3H), 3.37-3.23 (m, 2H), 3.16-3.00 (m, 2H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[F:22][C:23]([F:35])([F:34])[C:24]1[CH:25]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=1>>[O:21]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])=[N:11][N:2]1[NH:1][C:31](=[O:32])[CH2:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:34])([F:22])[F:35])[CH:25]=1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O
Product: O=C(Cc1cccc(C(F)(F)F)c1)Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O

Procedure:
The product from Example 68B and 2-(3-(trifluoromethyl)phenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.93-11.95 (bs, 1H), 8.55-8.57 (m, 1H), 8.37-8.40 (m, 1H), 8.09-8.13 (m, 1H), 7.98-8.03 (m, 3H), 7.77-7.82 (m, 1H), 7.59-7.71 (m, 6H), 3.83 (s, 2H); MS (ESI−) M/Z 486 (M−H)−.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([NH:22][CH2:23][CH2:24][C:25]([CH2:31][CH:32]2[CH2:34][CH2:33]2)([OH:30])[CH2:26][C:27]([CH3:29])=[CH2:28])[CH3:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([C@@H:20]([N:22]2[CH2:23][CH2:24][C:25]([CH2:31][CH:32]3[CH2:34][CH2:33]3)([CH2:26][C:27]([CH3:29])=[CH2:28])[O:30][C:2]2=[O:4])[CH3:21])=[CH:18][CH:19]=1
Reactant: C=C(C)CC(O)(CCN[C@@H](C)c1ccc(Br)cc1)CC1CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)CC1(CC2CC2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triphosgene (653 mg) was added to a solution of 1-[(S)-1-(4-bromophenyl)ethylamino]-3-(cyclopropylmethyl)-5-methylhex-5-en-3-ol (800 mg) and triethylamine (667 mg) in CH2Cl2 (15 mL) at 0° C. The mixture was stirred at room temperature overnight and the reaction was then quenched with water. The resulting mixture was extracted with CH2Cl2 and the combined organic layer was washed with brine and dried (Na2SO4). The solvent was evaporated and the residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate 3:1) to afford the title compound. Yield 670 mg (78% of theory).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:40][CH2:41][CH3:42])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N:47]=[C:48]=[O:49])(C)C>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][N:37]([C:48]([NH2:47])=[O:49])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:40][CH2:41][CH3:42])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1
Reactant: C[Si](C)(C)N=C=O
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 160, [(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (example 185) was reacted with trimethylsilyl isocyanate (TCI-US) to give the title compound. HR-MS (ES, m/z) calculated for C34H41Cl2N6O3 [(M+H)+] 651.2612, observed 651.2608.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[C:11]1([N:17]=[C:18]=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC=CC=1.C(N(CC)CC)C.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[C:11]1([NH:17][C:18]([O:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=2)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C=Nc1ccccc1
Reactant: Oc1ccc(N=C=S)cc1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(Nc1ccccc1)Oc1ccc(N=C=S)cc1

Procedure:
By a procedure similar to that of Example I, the above compound (5.2 g., m.p. 139°-142° C.) was prepared from 7.6 g. (0.05 m.) of p-hydroxyphenylisothiocyanate and 6.0 g. (0.05 m.) of phenyl isocyanate, using 35 mls. of benzene as a solvent and 2 drops each of triethylamine and dibutyltin dilaurate as catalysts.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]([CH2:27][CH3:28])[C:8]1[CH:26]=[CH:25][C:11]([NH:12][CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17]CC)=O)=[CH:10][CH:9]=1)(=[O:3])[CH3:2].C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[C:1]([O:4][CH2:5][CH2:6][N:7]([CH2:27][CH3:28])[C:8]1[CH:9]=[C:10]2[C:11](=[CH:25][CH:26]=1)[N:12]=[CH:13][C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:15]2[OH:17])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=CNc1ccc(N(CC)CCOC(C)=O)cc1)C(=O)OCC
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(N(CC)CCOC(C)=O)cc2c1O
Yield: 35 %

Procedure:
To a flask containing crude diethyl 2-({4-[[2-(acetyloxy)ethyl](ethyl)amino]-anilino}methylene)malonate (2.2 g) is added diphenyl ether (15 mL). The reaction mixture is heated from room temperature to 260° C. over 45 minutes under a flow of argon gas. After 1 hour at 260° C. the hot reaction is slowly and carefully added to stirred diethyl ether (150 mL). The resulting precipitate is filtered and washed repeatedly with heptane. The residue is adsorbed onto silica and chromatographed on silica eluting with 3% to 10% methanol in dichloromethane. The product-containing fractions are evaporated to give 0.68 g of ethyl 6-[[2-(acetyloxy)ethyl](ethyl)amino]-4-hydroxy-3-quinolinecarboxylate as a brown solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[NH:10][CH2:9][CH2:8][N:7]([S:11]([C:14]2[S:18][C:17]3[CH:19]=[C:20]([C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=[CH:22][C:16]=3[CH:15]=2)(=[O:13])=[O:12])[CH2:6]1)=[O:4].[CH3:29][CH:30]1[NH:35][CH2:34][C:33]2[S:36][C:37]([C:39]([O-])=[O:40])=[N:38][C:32]=2[CH2:31]1.[Li+].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(Cl)Cl>[CH3:1][NH:2][C:3]([CH:5]1[CH2:6][N:7]([S:11]([C:14]2[S:18][C:17]3[CH:19]=[C:20]([C:23]#[C:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[CH:21]=[CH:22][C:16]=3[CH:15]=2)(=[O:13])=[O:12])[CH2:8][CH2:9][N:10]1[C:39]([C:37]1[S:36][C:33]2[CH2:34][NH:35][CH:30]([CH3:29])[CH2:31][C:32]=2[N:38]=1)=[O:40])=[O:4]
Reactant: CNC(=O)C1CN(S(=O)(=O)c2cc3ccc(C#C[Si](C)(C)C)cc3s2)CCN1
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)C1CN(S(=O)(=O)c2cc3ccc(C#C[Si](C)(C)C)cc3s2)CCN1C(=O)c1nc2c(s1)CNC(C)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In N,N-dimethylformamide (5 ml) was dissolved 3-(N-methylcarbamoyl)-1-[(6-trimethylsilylethynylbenzo[b]thien-2-yl)sulfonyl]piperazine (218 mg), followed by the addition of lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (188 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (240 mg) and 1-hyroxybenzotriazole (68 mg). The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with methylene chloride, washed with water (twice) and then with a saturated aqueous solution of sodium bicarbonate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (methanol:methylene chloride=3:97→5:95→7:93), whereby the title compound (90 mg) was obtained. MS (FAB) m/z: 616 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[O:18][CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]([NH:14][C:11]2[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:26]=[CH:25][C:9]=3[N:10]=2)[CH2:16][CH2:17]1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(NC1CCOc3ccccc31)=N2
Reactant: C1COCCN1
Product: O=C(CN1CCOCC1)Nc1ccc2c(c1)COC(NC1CCOc3ccccc31)=N2
Yield: 102.7 %

Procedure:
Prepared from rac-2-chloro-N-[2-(chroman-4-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 120, step A) (186 mg, 0.50 mmol; HPLC 1.092 min) and morpholine (0.87 ml, 10 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (217 mg, 100%; HPLC 0.504 min), MS (ISP) m/e=423.2 [(M+H)+].
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[O:29]1[CH2:33][CH2:32][CH:31]([CH2:34][NH2:35])[CH2:30]1>>[CH3:28][N:4]1[C:3]([CH2:2][NH:35][CH2:34][CH:31]2[CH2:32][CH2:33][O:29][CH2:30]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: NCC1CCOC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNCC3CCOC3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with (tetrahydrofuran-3-yl)methanamine via General Procedure E to give 6.9 mg of 297 following reverse phase purification. MS (Q1) 463.2 (M)+
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)=[O:29])=[CH:24][CH:23]=1.[OH-].[Na+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:21][C:22]2[CH:23]=[CH:24][C:25]([C:28](=[O:29])[C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)=[CH:26][CH:27]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: Cc1ccc(C(=O)c2ccc(O)cc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccc(C)cc3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with (4Hydroxy-phenyl)-p-tolyl-methanone from Srep A under the Standar Procedure J. The compound thus obtained was allowed to react under Standar hydrolysis procedure C (NaOH) to give the title compound. Ms(ES) for C27H28O6 [M+NH4]+: 471 [M+H]+: 449.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=3)[CH2:26][CH2:25]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47].[OH-].[Na+]>O1CCCC1>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([NH:37][S:46]([CH3:45])(=[O:48])=[O:47])=[CH:35][CH:36]=3)[CH2:28][CH2:29]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccc(N)cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccc(NS(C)(=O)=O)cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
1-Acetyl-N-{3-[4-(4-aminobenzyl)-1-piperidinyl]propyl}-N-(3,4-dichlorophenyl)-4-piperidinecarboxamide (Example 303) (18 mg, 0.033 mmol) was dissolved in tetrahydrofuran (0.3 mL). To the solution were added triethylamine (5.0 mg, 0.050 mmol) and methanesulfonyl chloride (4.9 mg, 0.043 mmol), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added aqueous solution of 1N-sodium hydroxide (5 mL), and the mixture was extracted with ethyl acetate (5 mL×2). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to alumina column chromatography (alumina 2 g, ethyl acetate), and the desired fraction was concentrated under reduced pressure to give the titled compound (16 mg, 0.026 mmol, Yield 78%) as a colorless oily substance.
Reaction SMILES: [N:1]([CH2:4][CH:5]([OH:12])[CH2:6][C:7]([CH3:11])([CH3:10])[CH2:8][CH3:9])=[N+]=[N-]>[Pd].C(O)C>[NH2:1][CH2:4][CH:5]([OH:12])[CH2:6][C:7]([CH3:11])([CH3:10])[CH2:8][CH3:9]
Reactant: CCC(C)(C)CC(O)CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: CCC(C)(C)CC(O)CN
Reaction time: 48 h

Procedure:
A mixture of 1-azido-4,4-dimethylhexan-2-ol (54.8 g, 320 mmol), 5% Pd/C (4 g) and ethanol (500 mL) were stirred under hydrogen (40 psi) for 2 days. The reaction mixture was filtered through Celite and the filtrate was concentrated to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 3.61 (m, 1H), 2.77 (dd, J=12.5 Hz, J=3.4 Hz, 1H), 2.49 (dd, J=12.5 Hz, J=8.9 Hz, 1H), 2.00 (brs, 2H), 1.30 (m, 3H), 1.24 (dd, J=14.5 Hz, J=2.6 Hz, 1H), 0.92 (s, 3H), 0.90 (s, 3H), 0.83 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[C:10]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[CH:9]=2)[CH2:4][CH2:3]1.C([O-])=O.[NH4+]>CCO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[C:12]([CH:11]=[C:10]([N:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[CH:9]=2)[NH2:14])[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cc(N3CCN(C)CC3)cc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CN1CCN(c2cc(N)cc(N3CCN(C)CC3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
1-methyl-4-[3-(4-methylpiperazin-1-yl)-5-nitrophenyl]piperazine (258 mg, 0.81 mmol) was hydrogenated using ammonium formate (0.51 g, 10 eq) and Pd/C (10% Pd, 85 mg, 0.1 eq) in 8 mL of EtOH. The mixture was stirred overnight at room temperature and then filtered through a celite pad. The filtrate was evaporated and the residue was dissolved in DCM and washed with a saturated aqueous solution of Na2CO3. The aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated to yield expected compound as a brown powder (212 mg, 90% yield). m/z (MALDI-TOF) 290.2 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:32])/[CH:10]=[CH:11]/[C:12]1[CH:16]=[CH:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[C:27][Si](C)(C)C)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:13]=1.[F-].[K+]>CO>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([S:17]([N:14]2[CH:15]=[CH:16][C:12](/[CH:11]=[CH:10]/[C:9]([NH:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[O:32])=[CH:13]2)(=[O:19])=[O:18])=[CH:21][CH:22]=1)#[CH:27]
Reactant: C[Si](C)(C)C#Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NOC3CCCCO3)c2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NOC3CCCCO3)c2)cc1

Procedure:
To a stirred solution of (E)-N-(Tetrahydro-pyran-2-yloxy)-3-[1-(4-trimethylsilanylethynyl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylamide (0.139 mmol) in methanol (1.2 ml) is added KF (0.26 mmol). After 15 min the solvent is evaporated and the residue is taken up in DCM and filtered over alumina (1 g, neutral, activity II-III) using DCM as eluent. After evaporation of the solvent 0.0801 mmol of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]([NH2:18])([CH3:17])[CH3:16]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:18][CH:15]([CH3:17])[CH3:16])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
4-Chloro-3-nitrobenzenesulfonyl chloride (2 g) and isopropylamine (2.1 ml) in dichloromethane (30 ml) was stirred at room temperature for 2 h. The mixture was washed with water, 2M hydrochloric acid, water, dried and evaporated under reduced pressure. Yield 2.2 g.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:4]1.[NH2:19][C:20]1[CH:25]=[C:24]([C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)[CH:23]=[CH:22][C:21]=1[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>N1C=CC=CC=1>[CH3:18][N:2]([CH3:1])[C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)[CH:23]=[CH:22][C:21]=3[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:15])=[CH:16][CH:17]=2)[CH2:4]1
Reactant: CN(C)[C@@H]1CCN(Cc2ccc(C(=O)O)cc2)C1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Product: CN(C)[C@@H]1CCN(Cc2ccc(C(=O)Nc3cc(-c4cccs4)ccc3NC(=O)OC(C)(C)C)cc2)C1
Yield: 67.9 %

Procedure:
A solution of acid 7 (0.20 g, 0.62 mmol), amine 4 (0.164 g, 0.56 mmol) and BOP reagent (0.30 g, 0.68 mmol) in pyridine (4 mL) was stirred for 18 h, concentrated, diluted with AcOEt, washed with aqueous sodium bicarbonate (NaHCO3), brine, dried over MgSO4, filtered and concentrated. Flash chromatography purification of the residue (eluent: 1:1 MeOH:AcOEt with 1% triethylamine) gave compound 8 (0.198 g, 67% yield).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[C:29]1(OB(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:16][C:6]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:2]([CH3:1])[N:3]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:23][CH2:24][N:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26][CH2:27]2)=[O:20])[N:5]=1
Reactant: OB(O)Oc1ccccc1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: Cc1nc(OCC(=O)N(C)C2CCN(c3ccccc3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31, phenylboric acid, copper (II) acetate and pyridine in the same manner as in Example 32.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[O:8]=[C:9]([N:28]1[CH2:33][CH2:32][C:31]([CH2:34][C:35]2[S:36][CH:37]=[CH:38][N:39]=2)=[CH:30][CH2:29]1)/[CH:10]=[CH:11]/[C:12]1[CH:13]=[C:14]2[C:24](=[N:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:16]1([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH2:15]2.C=O.C(N(CC)CC)C.[BH4-].[Na+]>CO>[CH3:2][N:19]1[CH2:20][CH2:21][C:16]2([CH2:15][C:14]3[C:24](=[N:25][CH:26]=[C:12](/[CH:11]=[CH:10]/[C:9](=[O:8])[N:28]4[CH2:33][CH2:32][C:31]([CH2:34][C:35]5[S:36][CH:37]=[CH:38][N:39]=5)=[CH:30][CH2:29]4)[CH:13]=3)[NH:23][C:22]2=[O:27])[CH2:17][CH2:18]1
Reactant: O=C(/C=C/c1cnc2c(c1)CC1(CCNCC1)C(=O)N2)N1CC=C(Cc2nccs2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CN1CCC2(CC1)Cc1cc(/C=C/C(=O)N3CC=C(Cc4nccs4)CC3)cnc1NC2=O
Temperature: 27.5 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To a stirred solution of (E)-β-methyl-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one (Compound 34) (200 mg, 0.35 mmol) in methanol (3 mL) was added 37% formaldehyde solution (0.086 mL, 1.07 mmol), followed by triethylamine (0.15 mL, 1.07 mmol) at 20-35° C. and the mixture was continued stirring at 20-35° C. for 30 minutes. Then NaBH4 (20 mg, 0.53 mmol) was added slowly portionwise at 0° C. and the reaction mixture was allowed to stir at 20-35° C. for 16 h. The reaction mixture was rotary evaporated under vacuum to get residue which was purified by preparative HPLC to get the desired compound as an off-white solid (25 mg, 15%); 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.34 (s, 1H), 8.15 (s, 1H), 7.71 (d, J=2.9 Hz, 1H), 7.61 (d, J=2.5 Hz, 1H), 7.45 (d, J=15.6 Hz, 1H), 7.30-7.14 (m, 1H), 5.68-5.64 (m, 1H), 4.26-4.22 (m, 1H), 4.06-4.02 (m, 1H), 3.80-3.72 (m, 3H), 3.68-3.62 (m, 1H), 2.90 (s, 2H), 2.62-2.54 (m, 2H), 2.28-2.04 (m, 4H), 2.19 (s, 3H), 1.90-1.78 (m, 2H), 1.42-1.28 (m, 2H); LC-MS: 464.3 (M+1)+. Preparative HPLC conditions: Column-Phenomenex Luna C18 (2) (250×21.1 mm, 5μ), Mobile Phase: (A) 0.1% TFA(Aq); (B) ACN; Flow rate: 15 ml/min.