Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[C:16]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:17]=3[S:18][C:19]=2C(O)=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N1C2C(=CC=CC=2)C=CC=1>[F:27][C:24]1[CH:25]=[CH:26][C:16]2[C:15]([CH:12]3[CH2:13][CH2:14][N:9]([C:1]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:8])[CH2:10][CH2:11]3)=[CH:19][S:18][C:17]=2[CH:23]=1
Reactant: O=C(O)c1sc2cc(F)ccc2c1C1CCN(C(=O)c2ccccc2)CC1
Solvent: c1ccc2ncccc2c1
Product: O=C(c1ccccc1)N1CCC(c2csc3cc(F)ccc23)CC1
Temperature: 200 °C
Reaction time: 1 h
Yield: 56.7 %

Procedure:
3-(1-Benzoylpiperidin-4-yl)-6-fluorobenzo[b]thiophene-2-carboxylic acid (10 g, 26 mmol) was suspended in quinoline (100 mL) and cupper powder (0.5 g) was added. After stirring at 200° C. for 1 h, the mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography eluting hexane/ethyl acetate to give (4-(6-fluorobenzo[b]thiophen-3-yl)piperidin-1-yl)phenylmethanone (5.0 g, 48%) as yellow crystals.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7](/[C:9](=[N:13]/[O:14][C:15](=[O:17])[CH3:16])/[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].[Cl:18]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[Cl:18][C:6]1[S:5][C:4]([NH:3][CH:1]=[O:2])=[N:8][C:7]=1/[C:9](=[N:13]/[O:14][C:15](=[O:17])[CH3:16])/[C:10]([OH:12])=[O:11]
Reactant: CC(=O)O/N=C(\C(=O)O)c1csc(NC=O)n1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)O/N=C(\C(=O)O)c1nc(NC=O)sc1Cl
Temperature: 25 °C
Reaction time: 0.47 h
Yield: 70.9 %

Procedure:
To a suspension of 2-(2-formylaminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetic acid (5 g) in tetrahydrofuran (50 ml) was added N-chlorosuccinimide (3.89 g) at room temperature. After the mixture was stirred at room temperature for 5 hours 28 minutes, the reaction mixture was poured into a mixture of 5% aqueous sodium thiosulfate solution (25 ml) and ethyl acetate (50 ml) under ice-cooling. The mixture was adjusted to pH 3.0 with 30% aqueous potassium carbonate solution under ice-cooling, stirred for 1 hour at the same temperature, and the resulting precipitate was collected by filtration to give 2-(5-chloro-2-formylaminothiazol-4-yl)-2-(Z)-(acetoxyimino)-acetic acid (4.02 g).
Reaction SMILES: [C:1]1([C@@H:7]([OH:11])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].N1C=CC=CC=1>ClCCl>[C:12]([O:10][CH2:9][CH2:8][C@H:7]([OH:11])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: OCC[C@H](O)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (S)-1-phenyl-1,3-propanediol (8.0 g, 52.6 mmol) in dichloromethane (80 ml) were added at 0° C. acetic anhydride (5.5 ml) and pyridine (4.7 ml). The mixture was stirred for 6 hours at the same temperature range and for 1.5 hour at room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous saline solution, successively. The solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography to give 4.8 g of (S)-3-hydroxy-3-phenylpropyl acetate. Physico-chemical properties and spectral data of these products are shown in [Table 7].
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]([O:11][C:12]([N:14]1[CH:19]([CH2:20][CH3:21])[CH2:18][CH:17]([NH:22][CH2:23][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)[C:16]2[S:38][CH:39]=[CH:40][C:15]1=2)=[O:13])([CH3:10])[CH3:9].N1C=CC=CC=1>ClCCl>[CH:8]([O:11][C:12]([N:14]1[CH:19]([CH2:20][CH3:21])[CH2:18][CH:17]([N:22]([C:1](=[O:3])[CH3:2])[CH2:23][C:24]2[CH:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:27]=[C:26]([C:34]([F:35])([F:36])[F:37])[CH:25]=2)[C:16]2[S:38][CH:39]=[CH:40][C:15]1=2)=[O:13])([CH3:9])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CCC1CC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2sccc2N1C(=O)OC(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC1CC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)c2sccc2N1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.2 %

Procedure:
Inject acetic anhydride (0.250 ml, 2.65 mmol) dropwise to a solution of crude 7-(3,5-bis-trifluoromethyl-benzylamino)-5-ethyl-6,7-dihydro-5H-thieno[3,2-b]pyridine-4-carboxylic acid isopropyl ester (0.120 g, 0.243 mmol) and pyridine (0.250 ml, 3.10 mmol) in dichloromethane (1 ml) at room temperature. Stir the mixture at room temperature for 16 h. Evaporate the solvents and purify the resulting reside using silica gel column chromatography (gradient eluent, 0-35% ethyl acetate in hexane) to provide the title compound (0.0290 g, 22%). MS (ES+): 559 (M+Na); (ES−): 535 (M−H). cl Example 2
Reaction SMILES: C1N=[C:5]2[N:7]([C@@H:10]3O[C@H:13](COP(OP(OP(O)(O)=O)(O)=O)(O)=O)[C@@H:12](O)[CH2:11]3)C=N[C:4]2=[C:3](N)[N:2]=1.P(OC[C@H]1O[C@@H]([N:50]2C=CC(N)=NC2=O)C[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.P(OC[C@H]1O[C@@H](N2C3N=C(N)NC(=O)C=3N=C2)C[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O>>[NH2:50][CH2:13][CH2:12][CH2:11][CH2:10][NH:7][CH2:5][CH2:4][CH2:3][NH2:2]
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O1
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)n1
Agent: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]1
Product: NCCCCNCCCN

Procedure:
1 mM for each dATP, dCTP, dGTP
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[Br:12][C:13]1[N:18]=[CH:17][C:16]([NH2:19])=[C:15]([CH3:20])[CH:14]=1.N1C=CC=CC=1.O>C(Cl)Cl>[Br:12][C:13]1[N:18]=[CH:17][C:16]([NH:19][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=2[F:11])=[C:15]([CH3:20])[CH:14]=1
Reactant: Cc1cc(Br)ncc1N
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(Br)ncc1NC(=O)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a (0° C.) cooled and stirred solution of 2,6-difluorobenzoyl chloride (357 μL, 2.83 mmol) in DCM (5 mL) was added 6-bromo-4-methylpyridin-3-amine (583 mg, 3.12 mmol) followed by the addition of pyridine (344 μL, 4.25 mmol). The resulting mixture was then stirred at room temperature overnight. Water (5 mL) was added to the above mixture and then extracted with DCM (3×10 mL). The combined organic layers were washed with 10% aq.HCl (10 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum to afford 650 mg (70%) of the title compound as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H, D2O exchangeable), 8.41 (s, 1H), 7.66 (s, 1H), 7.65-7.58 (m, 1H), 7.27 (t, J=7.0 Hz, 2H), 2.27 (m, 3H); (ESI-MS (m/z) 327, 329 [(MH)+, Br79, 81].
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[S:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[S:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccccc2Sc2ccccc21
Solvent: CO
Product: Nc1ccc(C(=O)N2Cc3ccccc3Sc3ccccc32)cc1
Yield: 89.2 %

Procedure:
A mixture of 2.2 g of 10,11-dihydro-10-(4-nitrobenzoyl)dibenz[b,f][1,4]thiazepine in 150 ml of methanol is shaken in a Parr hydrogenator under 50 pounds per square inch of hydrogen for 72 hours. The mixture is filtered through diatomaceous earth and the filtrate evaporated in vacuo. The residue is recrystallized from chloroform-hexane to give 1.8 g of crystals, m.p. 52°-55° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([CH2:2][C:1]([O:4][CH2:5][CH3:6])=[O:3])([OH:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Ethyl acetate (1.95 ml, 20 mmol) was added dropwise at −78° C. to 1M solution of LiHMDS in THF (20 ml, 20 mmol). After stirring for 10 min at −78° C., 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (3.98 g, 20 mmol) in 8 ml of THF was added dropwise at −78° C. and the dry ice/acetone bath was removed to allow the temperature to slowly reach 0° C. At this temperature, the reaction mixture was quenched by addition of 25 ml of H2O and the mixture was extracted twice with Et2O, the organic layers were washed with brine, dried over Na2 SO4 and concentrated on vacuum to give the product as an yellow oil.
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH2:21][C:22]3[N:23]=[C:24]([CH3:27])[S:25][CH:26]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:28][C:29]1[C:34]([C:35](O)=[O:36])=[C:33]([CH3:38])[N:32]=[C:31]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:30]=1>>[CH3:38][C:33]1[C:34]([C:35]([N:5]2[CH2:6][CH2:7][C:2]([CH3:1])([N:8]3[CH2:9][CH2:10][CH:11]([N:14]([CH2:21][C:22]4[N:23]=[C:24]([CH3:27])[S:25][CH:26]=4)[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:12][CH2:13]3)[CH2:3][CH2:4]2)=[O:36])=[C:29]([CH3:28])[N:30]=[C:31]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:32]=1
Reactant: Cc1nc(-c2ccccc2)nc(C)c1C(=O)O
Reactant: Cc1nc(CN(c2ccccc2)C2CCN(C3(C)CCNCC3)CC2)cs1
Product: Cc1nc(CN(c2ccccc2)C2CCN(C3(C)CCN(C(=O)c4c(C)nc(-c5ccccc5)nc4C)CC3)CC2)cs1

Procedure:
It is prepared from (4′-methyl-[1,4′]bipiperidinyl-4-yl)-(2-methyl-thiazol-4-ylmethyl)-phenyl-amine and 4,6-dimethyl-2-phenyl-pyrimidine-5-carboxylic acid using a procedure as described for Example 1 of PCT/EP02/03871. MS/ESI 595 [M+H]+. (4′-Methyl-[1,4′]bipiperidinyl-4-yl)-(2-methyl-thiazol-4-ylmethyl)-phenyl-amine used as a starting material may be prepared using procedures described in example 83 of PCT/EP02/03871. MS/ESI 385 [M+H]+
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH2:30][CH2:31][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:33][CH:34]=3)=[CH:25][CH:24]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.[OH-].[Na+]>ClCCl>[CH3:38][S:35]([N:32]1[CH2:31][CH:30]=[C:29]([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)=[CH:24][CH:25]=2)[CH2:34][CH2:33]1)(=[O:36])=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(C3=CCN(S(C)(=O)=O)CC3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CC=C(c2ccc(OCC3CCNCC3)cc2)CC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
Trifluoroacetic acid (2.98 g, 1.97 mL, 26.10 mmol) is added to a solution of 4-[4-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenoxymethyl]-piperidine-1-carboxylic acid tert-butyl ester (1.20 g, 2.61 mmol) in dichloromethane (13 mL). The mixture is stirred at 23° C. for 30 min. 2 M aq. sodium hydroxide is added. The resulting white precipitate is filtered and washed with water. The mother liquor is extracted with dichloromethane. The combined organic layers are dried over anhydrous sodium sulfate, filtered, and the solvent is removed to obtain a white solid which is combined with the initial precipitate and dried under high vacuum for 16 h. Diethyl ether is added and the solid is filtered and washed with ethyl acetate to obtain 0.810 g of an off-white solid. MS (m/z) 351 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH:5]([CH3:36])[CH:6]([C:17]1[C:25]2[C:20](=[C:21]([CH2:26][S:27][CH3:28])[CH:22]=[CH:23][CH:24]=2)[N:19](C(OC(C)(C)C)=O)[CH:18]=1)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH3:2].FC(F)(F)C(O)=O.O>ClCCl>[CH3:36][CH:5]([CH:6]([C:17]1[C:25]2[C:20](=[C:21]([CH2:26][S:27][CH3:28])[CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:15])([F:14])[F:16])=[CH:9][CH:8]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:37]
Reactant: CCOC(=O)C(C)C(c1ccc(C(F)(F)F)cc1)c1cn(C(=O)OC(C)(C)C)c2c(CSC)cccc12
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)C(c1ccc(C(F)(F)F)cc1)c1c[nH]c2c(CSC)cccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.52 g (4.71 mmol) of the compound from Example 27A were dissolved in 70 ml of dichloromethane, and 14.5 ml (188.56 mmol) of trifluoroacetic acid were added. After stirring at RT for 3 h, the reaction solution was mixed with water, the phases were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and dried over sodium sulfate, the solid was filtered off and the solvents were removed in vacuo. Purification of the crude product by flash chromatography on silica gel (mobile phase: dichloromethane/methanol 95/5) and preparative HPLC (mobile phase: acetonitrile-water gradient) resulted in 1.01 g (48% of theory) of the title compound as mixture of diasteromers.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C@:7]12[CH2:13][CH:12]([CH3:14])[CH:11]1[CH2:10][N:9]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:8]2)=[O:6].Cl>O1CCCC1.CO>[CH2:18]([O:17][C:15]([N:9]1[CH2:10][CH:11]2[C@:7]([C:5]([OH:6])=[O:4])([CH2:13][CH:12]2[CH3:14])[CH2:8]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@]12CC(C)C1CN(C(=O)OCc1ccccc1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1C[C@]2(C(=O)O)CN(C(=O)OCc3ccccc3)CC12
Reaction time: 0.5 h

Procedure:
A 1N sodium hydroxide solution (23 mL) was added dropwise to a mixed solution of (R)-6-methyl-3-azabicyclo[3.2.0]heptane-1,3-dicarboxylic acid 3-benzyl ester 1-methyl ester (3.5 g, 11.5 mmol) in tetrahydrofuran (60 mL) and methanol (20 mL) under ice-cooling, and the mixture was stirred for 30 minutes. The reaction solution was neutralized with 1N hydrochloric acid, followed by extraction with ethyl acetate. The extract was dried over magnesium sulfate and filtered. The solvent was evaporated under reduced pressure to give 3.4 g (quantitative) of the diastereomer mixture title compound as a colorless oil. The diastereomers were used for the next step without separation.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([CH3:8])=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:17]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([CH:26]=1)[C:24]#[N:25])#[CH:18]>C(#N)C.C(OCC)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:9][C:4]1[CH:3]=[C:2]([C:18]#[C:17][C:19]2[CH:20]=[N:21][CH:22]=[C:23]([CH:26]=2)[C:24]#[N:25])[CH:7]=[CH:6][C:5]=1[CH3:8]
Reactant: Cc1ccc(I)cc1C
Reactant: C#Cc1cncc(C#N)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CC#N
Product: Cc1ccc(C#Cc2cncc(C#N)c2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
Combine 4-iodo-o-xylene (0.362 g, 1.561 mmol), bis(triphenylphosphine)palladium (II) dichloride (55 mg, 0.078 mmol), and copper (I) iodide (30 mg, 0.156 mmol) in triethylamine (0.653 mL, 4.683 mmol) and stir under nitrogen for 5 min at 80° C. Add a solution of 5-ethynylnicotinonitrile, (prepared essentially as described in PREPARATION 4), (200 mg, 1.561 mmol) in anhydrous acetonitrile (2.50 mL), and stir under nitrogen overnight. Cool to room temperature and dilute with diethyl ether. Wash with a saturated aqueous solution of sodium bicarbonate, dry (sodium sulfate), filter, and concentrate. Purify the residue by silica gel chromatography, eluting with 95:5 to 50:50 dichloromethane:ethyl acetate, to give the title compound as a yellow solid (225 mg, 62%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[N:10]2[CH:11]=[C:12]([CH:15]=O)[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)[CH3:2].[CH3:18][NH:19][CH3:20].C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.CO.C(O)(=O)C.O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[N:10]2[CH:11]=[C:12]([CH2:15][N:19]([CH3:20])[CH3:18])[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)Cc1cnc2ccc(C=O)cn12
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1cnc2ccc(CN(C)C)cn12
Temperature: 60 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
(6-Formyl-imidazo[1,2-a]pyridin-3-yl)-acetic acid ethyl ester (770 mg, 3.15 mmol) is dissolved in THF (10 ml) and treated with an excess of dimethylamine. The reaction mixture is stirred for 16 hours at room temperature in a stainless steel autoclave. A solution of sodium cyanoborohydride (229 mg, 3.46 mmol, 1.1 equiv) in MeOH (1.0 ml) and glacial acetic acid (1.1 ml) are added, and the solution is stirred for 1 hour at 60° C. The reaction mixture is diluted with water and adjusted to pH 8-9 by the addition of concentrated aqueous NaHCO3 solution. Extraction with EtOAc, washing with brine, drying over Na2SO4 and removal of solvent affords the crude reaction product. Purification via flash chromatography (EtOAc/cyclohexane 4:1, +0.2% NEt3) yields the title compound (242 mg, 29%). 1H NMR (400 MHz, CDCl3): δ=7.76-7.74 (m, 1H), 7.35 (dd, J=9.3/1.0 Hz, 1H), 7.31 (s, 1H), 6.99 (dd, J=9.1/1.7 Hz, 1H), 3.95 (q, J=7.1 Hz, 2H), 3.71 (s, 2H), 3.23 (s, 2H), 2.06 (s, 6H), 1.03 (t, J=7.1 Hz, 3H). MS (ES+): 262 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:18])[NH:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C([O-])([O-])=O.[K+].[K+].[Br:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Br)[C:28]=1[F:35]>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:18])[N:4]([CH2:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([CH2:26][Br:25])[C:28]=2[F:35])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Fc1c(CBr)cccc1CBr
Reactant: O=c1[nH]ccc(OCc2ccc(F)cc2F)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c(Br)c(OCc2ccc(F)cc2F)ccn1Cc1cccc(CBr)c1F
Temperature: 110 °C
Reaction time: 3 h
Yield: 48.9 %

Procedure:
To a solution of 3-bromo-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one (from Step 3, Example 74) (0.3 g, 0.95 mmol) in DMF (26 mL) was added K2CO3 (0.26 g, 1.9 mmol) and 2,6-bis(bromomethyl)fluorobenzene (1.6 g, 5.7 mmol), and the reaction mixture was stirred at 110° C. for 3 h. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was diluted with a 50% aqueous solution of brine, and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organics were washed with water, dried (Na2SO4), filtered, and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, eluent 99:1 to 95:5 methylene chloride/methanol) afforded 3-bromo-1-(3-bromomethyl-2-fluorobenzyl)-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one as an off-white solid (0.24 g, 49%): 1H NMR (300 MHz, CDCl3) δ 7.55-7.40 (m, 3H), 7.35-7.25 (m, 1H), 7.10-7.05 (m, 1H), 7.00-6.80 (m, 2H), 6.14 (d, J=6 Hz, 1H), 5.22 (s, 2H), 5.19 (s, 2H), 4.50 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:24].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:24]
Reactant: Cc1ccccc1Cn1c2cccc(O)c2c2c(C(N)=O)cccc21
Reactant: COC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1C
Reaction time: 0.05 h
Yield: 82.1 %

Procedure:
40% Methanolic Triton B (0.45 mL, 0.99 mM) was added to a solution of the 9-[(2-methylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (80 mg, 0.24 mM) in 8 mL DMF at room temperature. After 3 minutes, methyl bromoacetate (115 mg, 0.72 mM) was added and the resultant mixture stirred at room temperature for 48 hours. The mixture was diluted with ethyl acetate, washed with H2O, 1 N HCl, H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 80 mg (82%) of the {9-[(2-methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (DMSO-d6) δ7.56 (br s, 1H), 7.5-7.1 (m, 9H), 6.9 (t, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.65 (s, 2H), 4.9 (s, 2H), 3.8 (s, 3H), and 2.5 (s, 3H). IR (KBr, cm−1) 3367, 3153, 1760, 1740, 1672, 1644, 1619, 1591, 1578, 1498, 1456, 1425, 1327, 1200, 1153, 1109, 1100, and 777. MS (FD) m/e 402.
Reaction SMILES: [C:1]([CH:3]1[CH2:12][CH2:11][C:6]2(OCC[O:7]2)[CH2:5][CH:4]1[N:13]1[CH:17]=[C:16]([C:18]([NH2:20])=[O:19])[C:15]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:14]1)#[N:2].C1COCC1.Cl>CCOC(C)=O>[C:1]([CH:3]1[CH2:12][CH2:11][C:6](=[O:7])[CH2:5][CH:4]1[N:13]1[CH:17]=[C:16]([C:18]([NH2:20])=[O:19])[C:15]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:14]1)#[N:2]
Reactant: N#CC1CCC2(CC1n1cc(C(N)=O)c(Nc3ccccc3)n1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CC1CCC(=O)CC1n1cc(C(N)=O)c(Nc2ccccc2)n1
Temperature: 75 °C

Procedure:
To a vial containing 1-(8-cyano-1,4-dioxaspiro[4.5]dec-7-yl)-3-(phenylamino)-1H-pyrazole-4-carboxamide (Example #2-4, 37 mg, 0.10 mmol) was added THF (0.38 mL), and 1N aqueous HCl (0.13 mL). The resulting mixture was heated to 75° C. for 5.5 hours. The reaction mixture was allowed to cool to ambient temperature and was diluted with EtOAc. The layers were separated and the organic layer was washed with water, saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was dissolved in DMSO and purified by reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, and lyophilized to afford the title compound as a 1:1 mixture of cis and trans isomers.
Reaction SMILES: [ClH:1].Br[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[ClH:1].[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(Nc1ccc(Br)cc1)C1CN2CCC1CC2
Reactant: OB(O)c1cccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: O=C(Nc1ccc(-c2cccs2)cc1)C1CN2CCC1CC2

Procedure:
90 mg (0.26 mmol) of N-(4-bromophenyl)-1-azabicyclo[2.2.2]octane-3-carboxamide hydrochloride, 40 mg (0.31 mmol) of 2-thiopheneboronic acid, 190 mg (0.57 mmol) of cesium carbonate and 20 mg (0.03 mmol) of bis(diphenylphosphino)ferrocenepalladium(II) chloride are reacted in 1 ml of 1,2-dimethoxyethane by the general method. 14.1 mg (15% of theory) of the title compound are obtained.