Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:27][CH3:28])[C:9]3[CH:14]=[C:13]([CH2:15][C:16]4[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=4)[C:19]([O:21]C)=[O:20])[N:12]=[CH:11][C:10]=3[N:26]=2)=[N:4][O:5][N:6]=1.[Li+].[OH-]>CO.O>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:27][CH3:28])[C:9]3[CH:14]=[C:13]([CH2:15][C:16]4[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=4)[C:19]([OH:21])=[O:20])[N:12]=[CH:11][C:10]=3[N:26]=2)=[N:4][O:5][N:6]=1
Reactant: CCn1c(-c2nonc2N)nc2cnc(Cc3cccc(C(=O)OC)c3)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCn1c(-c2nonc2N)nc2cnc(Cc3cccc(C(=O)O)c3)cc21
Temperature: 80 °C
Yield: 83.6 %

Procedure:
To a solution of the product from Step 1 (85 mg, 0.22 mmol) in MeOH (12 ml) and water (4 ml), was added LiOH (40 mg, 0.95 mmol). This mixture was then heated to 80° C. for 2 h. Reaction mixture was concentrated, dissolved in 10 ml water, acidified with 1 N HCl to pH=5, then filtered and washed with water to afford a pale yellow solid (67 mg, 82%). MS (ES+) m/e 365 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH2:13][N:14]2[CH:18]=[C:17]([I:19])[CH:16]=[C:15]2[CH:20]=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH2:13][N:14]2[CH:18]=[C:17]([I:19])[CH:16]=[C:15]2[CH2:20][OH:21])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCn2cc(I)cc2C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)OCCn2cc(I)cc2CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
2-(2-Formyl-4-iodo-pyrrol-1-yl)ethyl 4-methylbenzenesulfonate (2.1 g, 5.01 mmol) in ethanol (25 mL) was cooled to 0° C. and sodium borohydride (95 mg, 2.50 mmol) was added. After 30 min, the reaction mixture was allowed to warm to ambient temperature and stirred for a further 1 h, after which time acetic acid was added and the mixture was concentrated in vacuo. The residue was partitioned between water and dichloromethane and the organic phase was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 2-[2-(hydroxymethyl)-4-iodo-pyrrol-1-yl]ethyl 4-methylbenzenesulfonate (2.0 g, 95%) as a brownish crystalline solid.
Reaction SMILES: C([Li])CCC.C(OP([CH2:14][C:15]([OH:17])=[O:16])(OCC)=O)C.[C:18]1([CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O1CCCC1.O>[C:18]1([CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=[CH:14][C:15]([OH:17])=[O:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=CC=CC=Cc1ccccc1
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C=CC=CC=Cc1ccccc1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
Butyllithium (12.8 mL of 2.5 N solution) was added to 65 mL of anhydrous tetrahydrofuran (THF) at −65° C. A solution of diethylphosphonoacetic acid (2.92 g) in 25 mL of anhydrous THF was added dropwise to the stirred solution at −65° C. The resulting solution was stirred at −65° C. for an additional 30 minutes and then a solution of 5-phenyl-2,4-pentadienal (2.4 g) in 15 mL of anhydrous THF was added to the reaction at −65° C. The reaction was stirred for one hour, allowed to warm to room temperature and then stirred overnight. To the reaction was added 30 mL of water, acidified with 5% hydrochloric acid (14 mL) to a pH of 4.7 and then added an additional 20 mL of water. The aqueous layer was extracted with 10 mL of ether twice and with 10 mL of ethyl acetate once. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude material was dissolved in 50 mL of hot methanol and then refrigerated overnight. The crystals formed were filtered and dried under vacuum to afford 2.4 g of the desired 7-phenyl-2,4,6-heptatrienoic acid. 1H NMR (DMSO-d6, 300 MHz), δ (ppm) 7.52 (m, 2H), 7.33 (m, 4H), 7.06 (m, 1H), 6.86 (m, 2H), 6.58 (m, 1H), 5.95 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([S:13]([CH3:16])(=[O:15])=[O:14])=[N:10][C:9]=2[C:17]([NH:19][C:20]2[CH:36]=[CH:35][C:23]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:31]([NH:33][CH3:34])=[O:32])[CH:26]=3)=[CH:22][CH:21]=2)=[O:18])=[CH:4][CH:3]=1.[C:37]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:37])[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])=[N:10][C:9]=2[C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:31]([NH:33][CH3:34])=[O:32])[CH:26]=3)=[CH:35][CH:36]=2)=[O:18])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1cc(Oc2ccc(NC(=O)c3nc(S(C)(=O)=O)[nH]c3-c3ccc(F)cc3)cc2)ccn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)c3nc(S(C)(=O)=O)n(C)c3-c3ccc(F)cc3)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a chilled solution of 4-(4-(5-(4-fluorophenyl)-2-(methylsulfonyl)-1H-imidazole-4-carboxamido)phenoxy)-N-methylpicolinamide (200 mg, 0.39 mmol) and K2CO3 (119 mg, 0.86 mmol) in DMF (3.9 mL), was added methyl iodide (29 μL, 67 mg, 0.47 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. TLC indicates completion of reaction with a single major product. Solvent was removed under reduced pressure and the crude material was dissolved in H2O (20 mL) and extracted with EtOAc (3×10 mL). The organic fractions were dried over Na2SO4 and concentrated. The crude material was purified by SiO2 chromatography (DCM/MeOH from 100% DCM to 94% DCM/6% MeOH, the desired product elutes in 97% DCM/3% MeOH) to yield a white solid (149 mg, 72% yield). 1HNMR (400 MHz, CDCl3): δ 8.88 (s, 1H), 8.33 (d, 1H, J=6.0 Hz), 7.97 (m, 1H), 7.66 (m, 3H), 7.50 (m, 1H), 7.43 (m, 2H), 7.22 (t, 2H, J=8.4 Hz), 7.03 (d, 2H, J=9.2 Hz), 3.79 (s, 3H), 3.50 (s, 3H), 2.98 (d, 3H, J=5.2 Hz). MS (ESI): m/z 524.0 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:8]([OH:10])=O)=[O:5])[CH3:2].Cl.[CH2:18]([O:25][C:26](=[O:32])[C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26]([C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:8](=[O:10])[C@H:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:32])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)N[C@@H](C(=O)O)C1CCCCC1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Product: CCOC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C1CCCCC1
Yield: 75.1 %

Procedure:
Reaction of 1.1 g of (R)-ethoxycarbonylamino-cyclohexyl-acetic acid and 1.16 g of (L)-proline benzyl ester hydrochloride according to the procedure described in example 91b gave 1.50 g (75%) of the title compound as a colorless oil. (+)-APCI-MS: 417 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:20][CH2:19][CH2:18]1)=[O:15].[F:21][C:22]1[CH:23]=[CH:24][C:25]([O:31][CH3:32])=[C:26](B(O)O)[CH:27]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:23]=[C:22]([F:21])[CH:27]=[CH:26][C:25]=3[O:31][CH3:32])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:20][CH2:19][CH2:18]1)=[O:15]
Reactant: Nc1c(C(=O)NC2CCC2)nnc2c(Br)c(F)ccc12
Reactant: COc1ccc(F)cc1B(O)O
Product: COc1ccc(F)cc1-c1c(F)ccc2c(N)c(C(=O)NC3CCC3)nnc12
Yield: 71.1 %

Procedure:
Using Method A, 4-amino-8-bromo-7-fluoro-N-cyclobutyl-cinnoline-3-carboxamide (175 mg) and 5-fluoro-2-methoxy-phenyl boronic acid (191 mg) were reacted to afford the title compound (141 mg) as white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.21 (d, 1H), 8.53 (m, 1H), 7.74 (m, 1H), 7.28 (m, 1H), 7.17 (m, 2H), 4.49 (m, 1H), 3.64 (s, 3H), 2.26-2.10(m, 4H), 1.72-1.62 (m, 2H). MS APCI, m/z=385 (M+H).
Reaction SMILES: C(P([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(CC)=O)C.[H-].[Na+].[CH:15]([C:17]1[CH:18]=[C:19]([CH3:36])[C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[N:21][CH:22]=1)=O.O>C1COCC1>[CH2:11]([O:10][C:8](=[O:9])/[CH:7]=[CH:15]/[C:17]1[CH:18]=[C:19]([CH3:36])[C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:25][CH2:24]2)=[N:21][CH:22]=1)[CH3:12]
Reactant: Cc1cc(C=O)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCOC(=O)CP(=O)(CC)CC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
Ethyl (diethylphosphoryl)acetate (471 mg) was dissolved in THF (15 ml), and NaH (98 mg) was added thereto, followed by stirring at room temperature for 30 minutes. A solution of tert-butyl 4-(5-formyl-3-methylpyridin-2-yl)piperazine-1-carboxylate (493 mg) in THF (5 ml) was added thereto, followed by stirring at room temperature for 3 hours. To the reaction mixture was added water, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain tert-butyl 4-{5-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-3-methylpyridin-2-yl}piperazine-1-carboxylate (305 mg).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][CH:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:10][CH:11]1[NH:12][CH2:13][CH2:14][N:15]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:16]1
Reactant: CC1CNCCN1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CN(c2ccc(C=O)cc2)CCN1
Temperature: 120 °C
Yield: 69.9 %

Procedure:
To a solution of 4-fluorobenzaldehyde (2.0 g, 16.1 mmol) in DMF (10 mL) was added 2-methylpiperazine (1.9 g, 19.3 mmol) and K2CO3 (2.7 g, 19.3 mmol). The reaction was heated at 120° C. for 6 hours, diluted with H2O, and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo, to afford 4-(3-methylpiperazin-1-yl)benzaldehyde (2.3 g, 69%): 1H NMR (300 MHz, CDCl3): δ 9.77 (s, 1H), 7.75 (d, J=9.0 Hz, 2H), 6.90 (d, J=9.0 Hz, 2H), 3.67-3.83 (m, 2H), 3.07-3.18 (m, 1H), 2.81-3.06 (m, 3H), 2.50-2.62 (m, 1H), 1.46-1.73 (br s, 1H), 1.15 (d, J=6.3 Hz, 3H). ESI MS m/z 205 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:9]=1)=[CH2:6])[CH3:2].C(N(CC)CC)C.[C:30]([OH:33])(=[S:32])[CH3:31]>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH2:6][S:32][C:30](=[O:33])[CH3:31])[CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:9]=1)[CH3:2]
Reactant: C=C(Cc1ccnc(NC(=O)OC(C)(C)C)c1)C(=O)OCC
Reactant: CC(O)=S
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CSC(C)=O)Cc1ccnc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A solution of 2-(2-tert-butoxycarbonylamino-pyridin-4-ylmethyl)-acrylic acid ethyl ester (0.48 g, 1.57 mmol) and triethylamine (0.17 g, 1.64 mmol) was added to thioacetic acid (3 mL) at 0° C. under nitrogen. The mixture was stirred at room temperature for 4 h. The mixture was poured onto ice-water and extracted with CH2Cl2. The organic phase was washed with saturated NaHCO3 (aq) and dried. The crude product was purified by flash chromatography (2.5% MeOH in CH2Cl2) to give 2-acetylsulfanylmethyl-3-(2-tert-butoxycarbonylamino-pyridin-4-yl)-propionic acid ethyl ester (0.60 g, 100%).
Reaction SMILES: [C@H:1]12[CH2:49][C@H:4]([N:5]([CH2:7][CH2:8][NH:9][C@:10]34[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:11]3[C@@H:12]3[C@@:25]([CH3:28])([CH2:26][CH2:27]4)[C@@:24]4([CH3:29])[C@@H:15]([C@:16]5([CH3:42])[C@@H:21]([CH2:22][CH2:23]4)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]4[CH:41]=[CH:40][C:35]([C:36]([O:38]C)=[O:37])=[CH:34][CH:33]=4)=[CH:18][CH2:17]5)[CH2:14][CH2:13]3)[CH2:6]1)[CH2:3][O:2]2.[OH-].[Li+]>C1COCC1.CO>[C@H:1]12[CH2:49][C@H:4]([N:5]([CH2:7][CH2:8][NH:9][C@:10]34[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:11]3[C@@H:12]3[C@@:25]([CH3:28])([CH2:26][CH2:27]4)[C@@:24]4([CH3:29])[C@@H:15]([C@:16]5([CH3:42])[C@@H:21]([CH2:22][CH2:23]4)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]4[CH:33]=[CH:34][C:35]([C:36]([OH:38])=[O:37])=[CH:40][CH:41]=4)=[CH:18][CH2:17]5)[CH2:14][CH2:13]3)[CH2:6]1)[CH2:3][O:2]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CO4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CO4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Reaction time: 3.5 h
Yield: 59.5 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (99 mg, 0.148 mmol) in THF (2 mL) and MeOH (0.5 mL) was added 3N lithium hydroxide (0.197 mL, 0.592 mmol). The reaction mixture was stirred at 75° C. After 3.5 h, the reaction was cooled to rt and concentrated to a white paste which was purified by reverse phase prep-HPLC using prep method 6 and dried under vacuum to give the title compound (81.4 mg, 0.088 mmol, 59.2% yield) as a white solid. LC/MS: m/e 655.5 (M+H)+, 3.76 min (method 8). 1H NMR (400 MHz, 1:1 CHLOROFORM-d:METHANOL-d4) δ 7.90 (d, J=8.3 Hz, 2H), 7.18 (d, J=8.3 Hz, 2H), 5.35-5.23 (m, 1H), 4.79 (s, 1H), 4.70 (s, 1H), 4.58 (br. s., 1H), 4.08 (d, J=9.0 Hz, 1H), 4.02 (br. s., 1H), 3.76 (dd, J=9.3, 1.5 Hz, 1H), 3.30-3.21 (m, 2H), 3.16 (d, J=10.3 Hz, 2H), 3.00 (br. s., 1H), 2.74 (td, J=11.1, 5.5 Hz, 1H), 2.18-1.94 (m, 7H), 1.91-1.84 (m, 1H), 1.82-1.75 (m, 1H), 1.71 (s, 3H), 1.70-1.63 (m, 2H), 1.63-1.30 (m, 11H), 1.28-1.17 (m, 2H), 1.14 (s, 3H), 1.07 (s, 3H), 1.00 (s, 3H), 0.93 (s, 3H), 0.92 (br. s., 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][C:25]1[CH:33]=[CH:32][C:28]2=[N:29][S:30][N:31]=[C:27]2[CH:26]=1.O>CN(C=O)C>[N:29]1[S:30][N:31]=[C:27]2[CH:26]=[C:25]([CH2:24][N:14]3[C:13](=[O:16])[CH:12]=[CH:11][C:10]([C:4]4[CH:5]=[C:6]([F:9])[C:7]([F:8])=[C:2]([F:1])[CH:3]=4)=[N:15]3)[CH:33]=[CH:32][C:28]=12
Reactant: BrCc1ccc2nsnc2c1
Reactant: O=c1ccc(-c2cc(F)c(F)c(F)c2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccc(-c2cc(F)c(F)c(F)c2)nn1Cc1ccc2nsnc2c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3.0 g (13.3 mmol) of 6-(3,4,5-trifluorophenyl)-2H-pyridazin-3-one and 4.8 g (14.4 mmol) of caesium carbonate are suspended in 250 ml of DMF, 3.0 g (13.3 mmol) of 5-(bromomethyl)2,1,3-benzothiadiazole are added, and the mixture is stirred at room temperature. After 15 h, 110 ml of water are added to the reaction mixture, which is then stirred at room temperature for 2 h. The resultant precipitate is filtered off with suction and washed with water and dried in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=3)[S:13][C:6]=12.[NH4+].[Cl-].O>CCO.[Fe]>[F:1][C:2]1[CH:24]=[C:23]([CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=3)[S:13][C:6]=12)[NH2:25]
Reactant: CN1CC=C(c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CN1CC=C(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Reaction time: 0.67 h
Yield: 66.7 %

Procedure:
To a mixture of 4-(7-(2-fluoro-4-nitrophenoxy)benzo[b]thiophen-2-yl)-1-methyl-1,2,3,6-tetrahydropyridine 259 (279 mg, 0.72 mmol) and NH4Cl (33 mg, 0.612 mmol) in EtOH (7.2 mL)/water (3.6 mL) at 100° C. Fe (342 mg, 6.2 mmol) was added in one portion and the mixture heated to reflux with vigorous stirring for 40 min. The mixture was filtered through Celite®, the Celite® washed with EtOH and the combined organic solutions concentrated under reduced pressure. The residue was dissolved in MeOH and purified by flash chromatography (DCM/MeOH 5:1) giving 260 (171.3 mg, 0.48 mmol, 67% yield) as a yellow solid. MS (m/z): (M+1) 356.0 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1.Cl.[CH:23](O)([CH3:25])[CH3:24]>>[CH:23]([O:12][C:11](=[O:13])[CH:10]([O:9][C:8]1[CH:15]=[CH:16][C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:2]=2[Cl:1])=[CH:6][CH:7]=1)[CH3:14])([CH3:25])[CH3:24]
Reactant: CC(Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1)C(=O)O
Reactant: CC(C)O
Agent: Cl
Product: CC(C)OC(=O)C(C)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Reaction time: 8 h

Procedure:
55 g of 4-(2',4'-dichlorophenoxy)-α-phenoxy-propionic acid were suspended in 500 ml of isopropanol. While stirring, hydrogen chloride was fed in, whereupon the temperature rose to about 50° C. While the feed of hydrogen chloride was continued, the suspension was refluxed for 5 hours and the reaction mixture was then allowed to stand overnight. After the excess alcohol had been distilled off, the solution was poured on water and then extracted with methylene chloride. The methylene chloride extract was washed with dilute bicarbonate solution and then twice with water and dried over sodium sulfate. After filtration the solution was concentrated and then distilled under greatly reduced pressure. 34 g of 4-(2',4'-dichlorophenoxy)-α-phenoxy-propionic acid isopropyl ester were obtained, boiling point 182°-185° C. under a pressure of 0.04 mm mercury.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.B.C1COCC1.[NH4+].[OH-]>Cl>[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: N#Cc1ccc(N)nc1
Agent: B
Agent: Cl
Agent: [NH4+]
Solvent: C1CCOC1
Product: NCc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a solution of 6-aminonicotinonitrile 117-A (5.0 g, 42 mmol) was added a solution of 1 M BH3-THF (294 mL, 294 mmol) at 0° C. (prepared as in J.Org. Chem., Vol. 38, No. 5, 1973). The reaction was stirred at room temperature for 1 hour. The reaction mixture was then slowly pored into ice water. 100 mL 4N HCl was added and stirred for 20 min. The solution was basified with NH4OH to pH of about 11, and then concentrated. THF (300mL×2) was added to the mixture followed by addition of solid KOH (excess). The suspension was stirred. The THF layer was collected by filtration and concentrated to give 5-(aminomethyl)pyridin-2-amine 117-B (4.3 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([Cl:13])=[C:4]([C:8]([Cl:12])=[CH:9][C:10]=1[Cl:11])[C:5]([NH2:7])=[O:6].[Na].C([O:17][C:18](=[O:21])[CH2:19]Br)C>CO>[C:5]([C:4]1[C:3]([Cl:13])=[C:2]([C:10]([Cl:11])=[CH:9][C:8]=1[Cl:12])[O:1][CH2:19][C:18]([OH:21])=[O:17])(=[O:6])[NH2:7]
Reactant: NC(=O)c1c(Cl)cc(Cl)c(O)c1Cl
Reactant: CCOC(=O)CBr
Agent: [Na]
Solvent: CO
Product: NC(=O)c1c(Cl)cc(Cl)c(OCC(=O)O)c1Cl
Temperature: 60 °C
Yield: 84.1 %

Procedure:
16 g (66.9 mmol) of 3-hydroxy-2,4,6-trichlorobenzamide is suspended in 100 ml of methanol and dissolved by adding 1.54 g (66.9 mmol) of sodium. After the addition of 16.8 g (66.9 mmol) of bromoacetic acid ethyl ester, the mixture is maintained under reflux until the reaction is complete (TLC control). The product is then concentrated to dryness under vacuum and the resultant 3-carbamoyl-2,4,6-trichlorophenoxyacetic acid methyl ester is suspended in 100 ml of water. The mixture is combined with 20 ml of concentrated sodium hydroxide solution and maintained for 3 hours at 60° C. for saponifying. The solution is filtered over active carbon, brought to pH 2 by adding concentrated hydrochloric acid, and the precipitate is vacuum-filtered after several hours of stirring in an ice bath. After washing with water and drying, 16.8 g (84% of theory) of 3-carbamoyl-2,4,6-trichlorophenoxyacetic acid is obtained as a white powder, mp 261°-262° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:18][N:19]1[CH2:24][C:23](=[O:25])[N:22]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([N:35]=C(C3C=CC=CC=3)C3C=CC=CC=3)[CH:28]=2)[CH:21]([C:49]([O:51][CH3:52])=[O:50])[CH2:20]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>Cl.CO>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:18][N:19]1[CH2:24][C:23](=[O:25])[N:22]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([NH2:35])[CH:28]=2)[CH:21]([C:49]([O:51][CH3:52])=[O:50])[CH2:20]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1CN(Cc2cc3cc(Cl)ccc3n2C(=O)OC(C)(C)C)CC(=O)N1Cc1ccc(C#N)c(N=C(c2ccccc2)c2ccccc2)c1
Agent: Cl
Solvent: CO
Product: COC(=O)C1CN(Cc2cc3cc(Cl)ccc3n2C(=O)OC(C)(C)C)CC(=O)N1Cc1ccc(C#N)c(N)c1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
Partially-purified (±)-2-{4-[3-(benzhydrylidene-amino)-4-cyano-benzyl]-3-methoxycarbonyl-5-oxo-piperazin-1-ylmethyl}-5-chloro-indole-1-carboxylic acid tert-butyl ester (550 mg, 0.76 mmol) is suspended in reagent grade MeOH (20 mL). To the heterogeneous mixture is added 12M HCl (5 drops) and the reaction mixture is maintained at ambient temperature until homogeneous (˜30 min). The reaction mixture is partitioned between diethyl ether and water containing excess NaHCO3 (500 mL). The layers are separated and the organic phase is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue is chromatographed on silica gel (CH2Cl2 to 2% MeOH/CH2Cl2) to provide 400 mg (94%) of the title compound which is used directly in the next reaction. MS (ISP loop): 532 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH2:4]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:31]>C(OCC)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH2:4][Br:31]
Reactant: OCc1cc(Br)ccc1F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Fc1ccc(Br)cc1CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
In a 250 ml round bottom flask, under a nitrogen atmosphere, 2-fluoro-5-bromobenzyl alcohol (5.85 g, 28.5 mmol) was dissolved in diethy ether (125 ml). To this solution triphenylphosphine (9.73 g, 37.1 mmol) and carbon tetrabromide (12.30 g, 37.1 mmol) were added. The resulting mixture was stirred at ambient temperature for about three hours. The progress of the reaction was monitored by thin layer chromatography. The mixture was then stirred at ambient temperature for about 19 additional hours. The reaction mixture was filtered and washed with cold diethyl ether. The filtrate was evaporated, yielding a light yellow oil. The oil was further purified by chromatography on a silica gel with hexanes. The desired fractions were purified by evaporation to yield 5.8 grams of the desired title intermediate. The material slowly crystallized upon standing.