Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][CH:11]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[C@H:2]([C:4](O)=[O:5])[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.[F:39][C:40]1[CH:45]=[C:44]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=2)[C:43]([NH2:54])=[CH:42][CH:41]=1.[NH4+].[Cl-]>C(Cl)Cl>[F:39][C:40]1[CH:41]=[CH:42][C:43]([NH:54][C:4](=[O:5])[C@@H:2]([NH:1][C:7](=[O:8])[O:9][CH2:10][CH:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]3[C:23]2=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:3])=[C:44]([NH:46][C:47]2[CH:48]=[CH:49][C:50]([F:53])=[CH:51][CH:52]=2)[CH:45]=1
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: Nc1ccc(F)cc1Nc1ccc(F)cc1
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Nc1ccc(F)cc1Nc1ccc(F)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a −10° C. solution (NaCl-ice bath) of Fmoc-L-Ala-OH (4.45 g, 14.30 mmol) and N-methylmorpholine (1.573 mL, 14.30 mmol) in DCM (34.1 mL) was added isobutyl chloroformate (1.782 mL, 13.62 mmol). The resulting cloudy colorless mixture was stirred at −10° C. for 30 min. To the mixture was then added a solution of 5-fluoro-N1-(4-fluorophenyl)benzene-1,2-diamine (1.500 g, 6.81 mmol) in DCM (12.75 mL). The resulting mixture was stirred at −10° C. for 1 h, to which the cold mixture was added satd. aq. NH4Cl solution (100 mL). The precipitate was collected by filtration and washed with water (100 mL) to give (S)-(9H-fluoren-9-yl)methyl 1-(4-fluoro-2-(4-fluorophenylamino)phenylamino)-1-oxopropan-2-ylcarbamate as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.42 (1H, s), 7.89 (2H, d, J=7.6 Hz), 7.63-7.78 (3H, m), 7.22-7.46 (6H, m), 6.96-7.14 (4H, m), 6.83 (1H, dd, J=11.2, 2.7 Hz), 6.67 (1H, td, J=8.5, 2.8 Hz), 4.11-4.33 (4H, m), 1.28 (3H, d, J=7.0 Hz); LC-MS (ESI) m/z 514.2 [M+H]+. The off-white solid was carried on crude without purification.
Reaction SMILES: [NH2:1][C:2]1[N:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)=[CH:10][CH:9]=1)=[O:5].[Cl-].[NH4+]>C(O)C.O1CCCC1.O.[Fe]>[NH2:1][C:2]1[N:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])=[CH:10][CH:9]=1)=[O:5]
Reactant: Nc1ncccc1C(=O)NCc1ccc(OCc2ccccc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccccc1COc1ccc(CNC(=O)c2cccnc2N)cc1
Reaction time: 8 h
Yield: 98 %

Procedure:
2-Amino-N-(4-(2-nitrobenzyloxy)-benzyl)-nicotinamide described in Example A-15 was dissolved in a mixture solvent of ethanol-tetrahydrofuran-water (3:1:1.5), iron powder (4 mg) and ammonium chloride (85 mg) were added thereto, and the solution was stirred overnight under reflux. In addition, iron powder (10 mg) and ammonium chloride (20 mg) were added, and the solution was stirred under reflux for 2 hours. The reaction solution was allowed to room temperature, filtered through Celite pad to remove insoluble matter, and the filtrate was concentrated in vacuo. The residue was purified by NH silica gel chromatography (hexane:ethyl acetate), and the title compound (9 mg, 98%) was obtained as a pale brown solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]([CH3:15])[CH3:14])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[C:16]([Mg]Br)#[CH:17]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]([OH:9])[C:16]#[CH:17])[CH:10]=[CH:11][C:12]=1[N:13]([CH3:15])[CH3:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#C[Mg]Br
Reactant: CN(C)c1ccc(C=O)cc1C(C)(C)C
Product: C#CC(O)c1ccc(N(C)C)c(C(C)(C)C)c1

Procedure:
In a manner analogous to example 1 e, the process is carried out by a reaction of 1 g (4.9 mmol) of 3-tert-butyl-4-dimethylaminobenzaldehyde with 12 ml (6 mmol) of a 0.5M solution of ethynylmagnesium bromide. 900 mg of 1-(3-tert-butyl-4-dimethylaminophenyl)prop-2-yn-1-ol are obtained in the form of a colourless oil (yield=79%).
Reaction SMILES: C([O:3][C:4](=[O:8])[C@@H:5]([OH:7])[CH3:6])C.N1C=CC=CC=1.[C:15]1([C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)Cl)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C1C=CN=CC=1.C(#N)C>[C:21]([O:7][C@@H:5]([CH3:6])[C:4]([OH:3])=[O:8])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)[C@H](C)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CC#N
Product: C[C@H](OC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reaction time: 16 h
Yield: 51.6 %

Procedure:
To a solution of 38.6 g of (S)-2-hydroxy-propionic acid ethyl ester, 8.21 g of 4-dimethylamino-pyridine and 25.9 g of pyridine in 97 g of acetonitrile were added 92.0 g of triphenylchloromethane, and the mixture was heated at reflux for 16 h. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was successively washed with 1M potassium hydrogensulfate solution, saturated potassium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residual oil was taken up in a solution of 22 g of sodium hydroxide in 200 ml of methanol, and the mixture was stirred for 16 h. The reaction mixture was filtered and the filtrate was diluted with 0.5 l of water. The resulting mixture was first concentrated in vacuo to a volume of about 0.5 l and then extracted with tert-butyl methyl ether and the organic phase was discarded. The pH of the aqueous phase was adjusted to 3 by the addition of 2N potassium hydrogensulfate solution and again extracted with tert-butyl methyl ether. The organic phase was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residual oil was taken up in hexane to afford 56.0 g of (S)-2-trityloxy-propionic acid as off white crystals, m.p. 100°-106° C. Recrystallization from hexane/tert-butyl methyl ether afforded white crystals, m.p. 117.5°-119° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)(=O)=O)=CC=1.[CH3:30][C:31]1[C:32]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[N:33][CH:34]=[C:35]([N+:37]([O-:39])=[O:38])[CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:29][C:26]1[CH:27]=[N:28][C:23]([N:20]2[CH2:19][CH2:18][CH:17]([C@H:15]3[CH2:16][C@H:14]3[CH2:13][CH2:12][N:40]([C:32]3[C:31]([CH3:30])=[CH:36][C:35]([N+:37]([O-:39])=[O:38])=[CH:34][N:33]=3)[C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:45])[CH3:46])[CH2:22][CH2:21]2)=[N:24][CH:25]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cnc1N(CC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1)C(=O)OC(C)(C)C
Temperature: 50 °C

Procedure:
2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate (95 mg, 0.22 mmol) from Step 1 of Example 2 and tert-butyl (3-methyl-5-nitropyridin-2-yl)carbamate (55 mg, 0.22 mmol) were added in DMF (2.2 mL), then cesium carbonate (212 mg, 0.65=101) was added and the reaction was heated to 50° C. overnight. The reaction was cooled to room temperature, water (20 mL) was added and extracted with ethyl acetate (50 mL), second wash with brine (20 mL). The organic phase was dried by magnesium sulfate, filtered, concentrated and purified by column chromatography through a 25 gram Biotage SNAP KP-Sil™ silica gel cartridge eluting with 6.3% ethyl acetate/hexanes to give the title compound as a pale yellow sticky solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[C:30]([NH2:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21]1>>[NH2:31][C:30]1[C:25]([CH:22]2[CH2:23][CH2:24][N:20]([C:11]3[CH:12]=[C:13]4[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:10]=3[F:15])[CH2:21]2)=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: Nc1cccnc1C1CCNC1
Product: Nc1cccnc1C1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Yield: 91 %

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.81 g, 3.1 mmol) and 2-(3-pyrrolidinyl)-3-pyridinamine, a procedure analogous to that given in Example 1 provided the title compound (1.15 g, 91%) as an off-white solid, mp >270° C.
Reaction SMILES: [Cl:1][C:2]1[C:14]([CH:15]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[OH:16])=[C:13]([Cl:22])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[H-].[Na+].I[CH3:26]>O1CCCC1.[Cl-].[Na+]>[Cl:1][C:2]1[C:14]([CH:15]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[O:16][CH3:26])=[C:13]([Cl:22])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)c(C(O)c2ccco2)c1Cl
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(c1ccco1)c1c(Cl)ccc(C(=O)OC(C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At room temperature, 3.0 g (8.8 mmol) of tert-butyl 2,4-dichloro-3-((2-furyl)(hydroxymethyl))benzoate in 40 ml of tetrahydrofuran are stirred for 1 h with 0.4 g (16.6 mmol) of sodium hydride. 6.3 g (43.8 mmol) of iodomethane are added dropwise and the mixture is stirred at room temperature for a further 3 h. The reaction mixture is taken up in 100 ml of saturated aqueous sodium chloride solution, extracted with methyl tert-butyl ether, dried over sodium sulfate, filtered and freed from the solvent under reduced pressure. The crude product is purified by silica gel chromatography using cyclohexane/ethyl acetate. Yield: 2.7 g; 1H NMR, δ [ppm], (CDCl3): 1.6 (s), 3.5 (s), 6.2 (m), 6.3 (m), 7.4 (m), 7.5 (d)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[F:12][C:13]([F:26])([F:25])[O:14][C:15]1[CH:16]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>CN(C1C=CN=CC=1)C>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:13]([F:12])([F:25])[F:26])[CH:16]=2)(=[O:23])=[O:22])[CH:7]=[CH:8][CH:9]=1
Reactant: O=S(=O)(Cl)c1cccc(OC(F)(F)F)c1
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1cccc(OC(F)(F)F)c1
Yield: 59 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.69 mmol), 3-trifluoromethoxybenzenesulfonyl chloride (200 mg, 0.69 mmol) and DMAP (cat.) gave the title compound (150 mg, 60%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: C[O:2][C:3]1[C:12]([O:13]C)=[C:11]2[C:6]([CH:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([O:23]C)[CH:16]=3)[CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.[BrH:25]>>[BrH:25].[OH:2][C:3]1[C:12]([OH:13])=[C:11]2[C:6]([CH:7]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([OH:23])[CH:16]=3)[CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2CNCc3c2ccc(OC)c3OC)cc1OC
Agent: Br
Product: Oc1ccc(C2CNCc3c2ccc(O)c3O)cc1O

Procedure:
To 700 mg of 7,8-dimethoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline, was added 14 ml of 48% hydrobromic acid, and the mixture was heated under reflux for 3 hours under an argon gas stream. The reaction mixture was cooled, and the crystals which separated out were collected by filtration, giving 540 mg of 7,8-dihydroxy-4(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline hydrobromide.
Reaction SMILES: [C:1](Cl)(=O)C.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=[CH:13][C:14](=[O:18])[C:15]([OH:17])=[O:16]>CO>[CH3:1][O:16][C:15](=[O:17])[C:14](=[O:18])[CH:13]=[CH:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[Cl:5]
Reactant: CC(=O)Cl
Reactant: O=C(O)C(=O)C=Cc1ccccc1Cl
Solvent: CO
Product: COC(=O)C(=O)C=Cc1ccccc1Cl
Yield: 39.7 %

Procedure:
Acetyl chloride (19.4 mL, 274.4 mmol) was slowly added at 0° C. to methanol (120.0 mL) under stirring. A solution of 4-(2-chloro-phenyl)-2-oxo-3-butenoic acid (17.0 g, 80.7 mmol) prepared in Step 1 in methanol (80.0 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 1 hour, additionally at 80° C. for 16 hours. The reaction mixture was concentrated under reduced pressure and then ethyl acetate was added thereto. The reaction mixture was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/8) to give 7.2 g of the titled compound as a yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1.[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O.[OH-].[Na+]>CO>[Br:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[CH:9][CH:10]=2)=[O:16])[CH:23]=[CH:24][CH:25]=1
Reactant: CC(=O)c1ccc(OC2CCCCO2)cc1
Reactant: O=Cc1cccc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1cccc(Br)c1)c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55 %

Procedure:
4′-Tetrahydropyranyloxy-acetophenone (1.1 g, 5.0 mmol, synthesized according to our previously reported method),ii 3-bromobenzaldehyde (650 μL, 5.5 mmol), and MeOH (20 mL) were combined in a 50 mL round bottom flask with a stir bar. After all of the reactants were dissolved, 50% (w/v) aq. NaOH (1.5 mL, 27.5 mmol) was added. The flask was stoppered and stirred at room temperature for 5 h. The resulting precipitate was filtered, washed with EtOH (1 mL, 3×), and allowed to air dry to afford 1.06 g of THP-4Ae as a white powder (55% yield). The product was used without further purification. TLC: Rf=0.23 (hexane/EtOAc 4:1); Melting point: 166-168° C.; 1H NMR: (300 MHz, CDCl3) δ 8.01, 7.14 (AA′XX′ peak, Jaa′=Jxx′=2.5, Jax=8.5, Jax′=0.3 Hz, 2H), 7.78 (t, J=1.7 Hz, 1H), 7.70 (d, J=15.5 Hz, 1H), 7.54 (bs, 1H), 7.51 (m, 2H), 7.29 (d, J=7.9 Hz, 1H), 5.54 (t, J=3 Hz, 1H), 3.87 (ddd, J=11.3, 8.5, 3 Hz, 1H), 3.63 (dtd, J=11.3, 44.0, 1.4 Hz, 1H), 2.03 (m, 1H), 1.70 (m, 1H); 13C NMR: (75 MHz, CDCl3) δ 188.60, 161.35, 142.33, 137.48, 133.24, 131.64, 130.93, 130.63, 127.38, 123.45, 123.28, 116.39, 96.32, 62.27, 30.32, 25.28, 18.70; IR (ATR): 2946, 1660, 1607, 1595, 1576, 1557, 1509, 1480, 1420, 1357, 1331, 1314, 1284, 1224, 1202, 1175, 1112, 1076, 1038, 1022, 1010, 965 cm−1; ESI-MS: expected, 386.1; observed, m/z 387.0 [M+H+].
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.Cl.C1(C(C2C=CC=CC=2)=CC[N:41]2[CH2:46][CH2:45][CH:44]([N:47]3[CH2:55][C:54]4[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:48]3=[O:56])[CH2:43][CH2:42]2)C=CC=CC=1>CN(C=O)C.ClCCl>[O:11]=[C:9]([N:41]1[CH2:46][CH2:45][CH:44]([N:47]2[CH2:55][C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:48]2=[O:56])[CH2:43][CH2:42]1)[CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1c2ccccc2CN1C1CCN(CC=C(c2ccccc2)c2ccccc2)CC1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CC(c1ccccc1)c1ccccc1)N1CCC(N2Cc3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
To a solution of 3,3-diphenylpropionic acid (500 mg, 2.21 mmol) and DMF (1 drop) in dichloromethane (5 mL) at RT was added dropwise a solution of oxalyl chloride in dichloromethane (2.0M, 1.66 mL, 3.32 mmol). Bubbling of escaping gasses continued for 10 min after addition. The reaction was stirred at RT for 60 min, then concentrated in vacuo to give a crude oil. To a solution of crude acid chloride and triethylamine (1.4 mL, 10.0 mmol) in dichloromethane (10 mL) at 0° C. under argon was added dropwise a solution of Example 2 Part A compound (434 mg, 2.00 mmol) in dichloromethane (2 mL). The reaction was stirred at 0° C. for 10 min. Dichloromethane (100 mL) was added to dilute the reaction and the resulting solution was washed with H2O (40 mL), saturated sodium bicarbonate solution (40 mL), brine (40 mL) and dried over MgSO4. Evaporation gave a crude gum. Purification was performed by flash chromatography on silica gel (100 g), loaded and eluted with 2.5% methanol in dichloromethane. Pure fractions were combined and evaporated to give title compound (610 mg, 72%) as a off-white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([C:16]([O:18]CC)=[O:17])[C:11]([O:13]CC)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)C.O>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([C:16]([OH:18])=[O:17])[C:11]([OH:13])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(CCCc1ccccc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(CCCc1ccccc1)C(=O)O
Yield: 97.9 %

Procedure:
A mixture of diethyl 3-phenylpropylmalonate (5.5 g) and potassium hydroxide (2.8 g, 2.5 eq) in ethanol (20 ml) and water (30 ml) was refluxed for 5 hours. Work-up as described in Example 37b) gave the title compound (4.3 g, 98%); νmax (CH2Cl2) 2940 (br), 1727 and 1413cm-1 ; δH (CDCl3) 1.73 (2H, m, CH2), 2.00 (2H, m, CH2), 2.66 (2H, t, J 7.5 Hz, CH2), 3.44 (1H, t, J 6.8 Hz, CH), 6.84 (2H, bs, 2×CO2H), 7.26 (5H, m, Ph). EIMS M+ 222, DCIMS MNH4+ 240.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[C:12]2[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=1[O:29][CH3:30])=[O:8].CN(C)C=O>ClCCl>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[C:12]2[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([Cl:3])=[O:25])=[CH:22][C:21]=1[O:29][CH3:30])=[O:8]
Reactant: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)O)cc1OC)cn2C
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)Cl)cc1OC)cn2C
Reaction time: 2 h

Procedure:
A solution of thionyl chloride (2.42 ml, 33 mmole) in dichloromethane (10 ml) was added dropwise over 5 minutes to a suspension of the product of step b) (10.59 g, 30 mmole) in dichloromethane (90 ml) containing N,N-dimethylformamide (0.2 ml), stirred at reflux under an atmosphere of nitrogen. After 2 hours, solvent was removed from the resulting yellow solution by distillation, approximately 85 ml distillate being collected. Dilution of the residue with methyl t-butyl ether was followed by stirring at 15° C. for 30 minutes prior to collection of the solid precipitate by filtration. After washing with methyl t-butyl ether (2×20 ml), 4-(5-methoxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxybenzoyl chloride was obtained as an off-white solid, 10.10 g (90.6%); m.p. 147°-149° C.; NMR (250 MHz, DMSO-d6): 3.76, 3.92, 3.97 (each s, 3H, NCH3 plus OCH3 plus CO2CH3), 4.16 (s, 2H, ArCH2Ar'), 6.87 (s, 1H), 7.20 (d, 1H), 7.29 (d, 1H), 7.54 (d, 1H), 7.66 (dd, 1H), 7.92 (dd, 1H), 8.32 (d, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl.Cl[CH2:24][C:25]1[N:26]=[CH:27][NH:28][CH:29]=1>CN(C)C=O>[NH:28]1[CH:29]=[C:25]([CH2:24][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)[C:8]#[N:9])[N:26]=[CH:27]1
Reactant: ClCc1c[nH]cn1
Reactant: N#CC(c1ccccc1)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(Cc1c[nH]cn1)(c1ccccc1)c1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A 3.84 g. portion of 2-phenyl-2-(4-trifluoromethylphenyl)acetonitrile was reacted with 1.42 g. of 50% sodium hydride and 2.25 g. of 4-chloromethylimidazole hydrochloride in 50 ml. of dimethylformamide, as described in Example 1. The mixture was stirred for 2 hours at 60° C., and for 20 hours at ambient temperature. The reaction mixture was then worked up as described in Example 1 to obtain 3.6 g. of the desired product as the free base, a sample of which was analyzed as follows.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)=[C:15]([CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14]=1[CH3:33])=[S:11])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:29]([O:28][C:26]([NH:25][CH2:24][C:15]1[C:14]([CH3:33])=[C:13]([NH:12][C:10]([NH2:9])=[S:11])[CH:18]=[CH:17][C:16]=1[N:19]1[CH:23]=[CH:22][CH:21]=[N:20]1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1c(NC(=S)NC(=O)c2ccccc2)ccc(-n2cccn2)c1CNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1c(NC(N)=S)ccc(-n2cccn2)c1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the compound (163 mg) obtained in Example 7d, 10% palladium-carbon (20 mg) and methanol (10 ml) was stirred at room temperature for 6 hours under a hydrogen atmosphere. The reaction mixture was filtered to remove the palladium-carbon and the resulting filtrate was concentrated at reduced pressure. Acetone (10 ml) was added to the resulting residue and benzoyl isothiocyanate (0.064 ml) was then added dropwise at room temperature. The reaction mixture was stirred at room temperature for 16 hours and then water was added, followed by extraction with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and then concentrated at reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:3) to give N-benzoyl-N′-(3-((tert-butoxycarbonyl)aminomethyl)-2-methyl-4-(pyrazol-1-yl)phenyl)thiourea (yield, 78%). A mixture of the resulting thiourea compound (143 mg), potassium carbonate (64 mg) and methanol (4 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated at reduced pressure and water was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried with anhydrous magnesium sulfate and then concentrated at reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:2) to give the titled compound quantitatively.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.O[CH:14]1[CH2:19]SC(O)C[S:15]1.C(N(CC)CC)C>C(O)C>[NH2:10][C:9]1[S:15][CH:14]=[CH:19][C:8]=1[C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=1
Reactant: OC1CSC(O)CS1
Reactant: N#CCC(=O)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1sccc1C(=O)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 116.6 %

Procedure:
A mixture of 4-fluorobenzoylacetonitrile (2.84 g), 2,5-dihydroxy-1,4-dithian (1.31 g), triethylamine (2.2 ml) and ethanol (15 ml) was stirred for 40 minutes at 50° C. The reaction mixture was cooled to give 2-amino-3-(4-fluorobenzoyl)thiophene as yellow crystals (2.22 g).