Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([OH:41])=O)=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:42][CH2:43][C:44]1[CH:49]=[N:48][C:47]([CH3:50])=[CH:46][N:45]=1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([NH:42][CH2:43][C:44]4[CH:49]=[N:48][C:47]([CH3:50])=[CH:46][N:45]=4)=[O:41])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Reactant: Cc1cnc(CN)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cnc(CNC(=O)c2ccc3c(C4CCCCC4)c4n(c3c2)CC(C(=O)N2CCC(N3CCOCC3)CC2)=Cc2ccccc2-4)cn1
Yield: 93.2 %

Procedure:
A solution of 13-cyclohexyl-6-[[4-(4-morpholinyl)-1-piperidinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (40 mg, 0.07 mmol), 2-(aminomethyl)-5-methylpyrazine (12 mg, 0.1 mmol), N,N-diisopropylethylamine (60 μL, 0.34 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (19 mg, 0.1 mmol), and 1-hydroxybenzotriazole (14 mg, 0.1 mmol) in CH2Cl2 (1.5 mL) was stirred at r.t. for 20 h, at which point it was introduced directly to silica gel and chromatographed (gradient elution: 0%→10% MeOH in CH2Cl2) to afford a yellow foam, which was triturated with Et2O and dried to give the title compound as a pale yellow solid (43 mg, 90% yield). LC/MS (ESI) retention time: 1.69 min, m/z 659 (MH+); 1H NMR (400 MHz, CDCl3) δ 1.28-1.44 (m, 3 H) 1.46-1.59 (m, 1 H) 1.61-1.70 (m, 1 H) 1.71-1.81 (m, 2 H) 1.85-1.96 (m, 1 H) 1.97-2.13 (m, 3 H) 2.29 (t, J=10.45 Hz, 1 H) 2.35-2.46 (m, 4 H) 2.55 (s, 3 H) 2.61-2.77 (m, 2 H) 2.77-2.89 (m, 2 H) 3.62 (s, 4 H) 4.38 (s, 1 H) 4.78 (d, J=5.04 Hz, 2 H) 5.00-5.18 (m, 1 H) 6.81 (s, 1 H) 7.32-7.40 (m, 2 H) 7.40-7.50 (m, 3 H) 7.51-7.59 (m, 1 H) 7.88 (d, J=8.56 Hz, 1 H) 8.01 (s, 1 H) 8.39 (s, 1 H) 8.56 (d, J=1.01 Hz, 1 H); 13C NMR (101 MHz, CDCl3) δ 21.18, 26.21, 27.03, 28.08, 33.26, 36.73, 41.91, 42.60, 49.52, 61.59, 67.07, 108.98, 116.90, 120.03, 121.21, 126.98, 127.94, 128.21, 129.27, 130.96, 131.23, 133.27, 134.01, 135.18, 135.25, 136.39, 142.94, 143.40, 149.41, 152.50, 168.10, 168.87.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][N:5]([CH2:17][C@@H:18]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:19]([CH3:22])[CH2:20][CH3:21])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[C:27]([O:26][C:24]([NH:23][C@@H:18]([C@@H:19]([CH3:22])[CH2:20][CH3:21])[CH2:17][N:5]([CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH2:4][C:3]([OH:31])=[O:2])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC[C@H](C)[C@@H](CN(CC(=O)OC)Cc1cccc2ccccc12)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](C)[C@@H](CN(CC(=O)O)Cc1cccc2ccccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-[2(S)-(t-Butoxycarbonylamino)-3(S)-methylpentyl]-N-(1-naphthylmethyl)glycine methyl ester (7, 2.61 g, 6.10 mmol) was dissolved in MeOH (50 ml) and 1N NaOH (24.4 ml, 24.4 mmol) was added. The mixture was stirred at ambient temperature for 4 h and concentrated. The resulting residue was dissolved in water (25 ml) and neutralized with 1N HCl (24.4 ml). The aqueous layer was washed with EtOAc (3×50 ml). The organic layers were combined, dried with Na2SO4, filtered, and concentrated to give the product. 1H NMR (CD3OD) δ 8.43 (1H, d, J=6 Hz), 7.97 (2H, t, J=6 Hz) 7.75-7.48 (4H, m), 4.96 (1H, d, J=12 Hz), 4.72 (1H, d, J=12 Hz), 3.80-3.58 (3H, m), 3.49-3.40 (1H, dd,, J=3 and 12 Hz), 3.03 (1H, dd, J=3 and 12 Hz), 1.42 (9H, s,), 1.37-1.28 (2H, m), 1.80-1.00 (1H, m), 0.94-0.78 (6H, m,) ppm.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]1[C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=2[NH:9][C:10]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:11]=2[N:12]=1.S(=O)(=O)(O)O>>[Cl:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]3[CH:3]=[CH:4][N:5]=[C:6]3[C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[NH:9][C:10]=2[CH:16]=1
Reactant: COC(CNC1=Nc2ccc(Cl)cc2Nc2ccccc21)OC
Agent: O=S(=O)(O)O
Product: Clc1ccc2c(c1)Nc1ccccc1-c1nccn1-2

Procedure:
In the manner given in Example 2, 7-chloro-[(5H-dibenzo[b,e][1,4]diazepin-11-yl)amino]acetaldehyde dimethyl acetal is treated with concentrated sulfuric acid to give 7-chloro-9H-dibenzo[b,f]imidazo[1,2-d][1,4]diazepine.
Reaction SMILES: C([N:5]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]2[C:7]([C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)=[N:6]1)(C)(C)C>C(O)=O.Cl>[C:17]1([CH3:21])[CH:18]=[CH:19][CH:20]=[C:15]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[N:12][C:13]=3[NH2:14])[NH:5][N:6]=2)[CH:16]=1
Reactant: Cc1cccc(-c2nn(C(C)(C)C)c3ncnc(N)c23)c1
Agent: Cl
Solvent: O=CO
Product: Cc1cccc(-c2n[nH]c3ncnc(N)c23)c1

Procedure:
1-tert-butyl-3-m-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (23 mg, 0.1 mmol) was dissolved in a solution of formic acid (1 mL) and conc. HCl (0.3 mL) and heated to reflux for 2.5 hours. Reaction was concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA). ESI-MS (M+H)+ m/z calcd 226.1, found 226.3.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:7]1([C@H:13]([NH2:15])[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>CCOC(C)=O>[C:7]1([C@H:13]([NH:15][CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)CBr
Reactant: C[C@@H](N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)CN[C@H](C)c1ccccc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
Methyl 2-bromoacetate (621 g, 4.1 mol) was added dropwise to a mixture of (1R)-1-phenylethanamine (410 g, 3.4 mol) and triethylamine (377 g, 3.7 mol) in EtOAc (4.5 L) at r.t. The mixture was then stirred at 50-60° C. overnight then cooled to r.t. The mixture was then washed with water (800 mL) and brine (100 mL), dried (Na2SO4) and concentrated in vacuo to give the title compound (587 g, 90%) as yellow oil; 1H NMR: (CDCl3) 1.29 (3H, d), 3.13-3.24 (2H, m), 3.60 (3H, s), 3.68-3.71 (1H, m), 7.13-7.26 (5H, m).
Reaction SMILES: ClCl.CC(C)([O-])C.[K+].[C:9]([CH:12]([CH:14]([C:16]([OH:18])=[O:17])[OH:15])[OH:13])([OH:11])=[O:10].[CH2:19]([S:23][C:24]1[C:28]([C@@H:29]2[CH2:35][N:34]3[CH2:36][C@H:30]2[CH2:31][CH2:32][CH2:33]3)=[N:27][S:26][N:25]=1)[CH2:20][CH2:21][CH3:22]>C1(C)C=CC=CC=1>[C:9]([C@@H:12]([C@H:14]([C:16]([OH:18])=[O:17])[OH:15])[OH:13])([OH:11])=[O:10].[CH2:19]([S:23][C:24]1[C:28]([C@@H:29]2[CH2:35][N:34]3[CH2:36][C@H:30]2[CH2:31][CH2:32][CH2:33]3)=[N:27][S:26][N:25]=1)[CH2:20][CH2:21][CH3:22]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: CC(C)(C)[O-]
Agent: CCCCSc1nsnc1[C@@H]1CN2CCC[C@@H]1C2
Agent: ClCl
Solvent: Cc1ccccc1
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O

Procedure:
Starting from a mixture of (5S,6S)- and (5S,6R)-6-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane described in example 63C, the chlorine was substituted with butylthio as described in example 14. A 1:9 mixture of (5S,6S)- and (5S,6R)-6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane (10 g, 35 mmol) was dissolved in toluene (40 ml) and treated with potassium tertbutoxide (0.5 g) at reflux for 1 hour. The toluene solution was washed with water (15 ml) dried and evaporated. The residue crystallized with (+) L-tartaric acid giving the optical pure title compound in 12.5 g yield. (Compound 111). M.p. 128-129° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8](C(C(OCC)=O)C(OCC)=O)[CH3:9])[CH:2]=1.[C:21](=[O:24])(O)[O-:22].[Na+]>Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]([CH3:9])[C:21]([OH:22])=[O:24])[CH:2]=1
Reactant: O=C([O-])O
Reactant: CCOC(=O)C(C(=O)OCC)C(C)Cc1cccnc1
Agent: Cl
Agent: [Na+]
Product: CC(Cc1cccnc1)C(=O)O
Yield: 46.4 %

Procedure:
Diethyl 2-(1-(pyridin-3-yl)propan-2-yl)malonate (2.00 g, 7.55 mmol) was refluxed in conc. HCl (30 ml) for 16 h. The reaction mixture was neutralized using solid sodium bicarbonate (pH˜7) and extracted with ethyl acetate. The combined ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 580 mg (46.4%) of 2-((pyridin-3-yl)methyl)propanoic acid as a brown semi solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=1.[CH2:18]([O:22][C:23]1[C:28]([CH:29]=[CH:30][C:31](O)=[O:32])=[CH:27][CH:26]=[C:25]([C:34]([F:37])([F:36])[F:35])[N:24]=1)[CH2:19][CH2:20][CH3:21]>>[CH2:18]([O:22][C:23]1[C:28]([CH:29]=[CH:30][C:31]([NH:2][CH2:3][C:4]2[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=2)=[O:32])=[CH:27][CH:26]=[C:25]([C:34]([F:37])([F:35])[F:36])[N:24]=1)[CH2:19][CH2:20][CH3:21]
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Reactant: CCCCOc1nc(C(F)(F)F)ccc1C=CC(=O)O
Agent: Cl
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2OCCCC)cc(F)c1NS(C)(=O)=O
Yield: 53.7 %

Procedure:
N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (25 mg, 0.087 mmol) was reacted with 3-(2-butoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (21 mg, 0.73 mmol) to give the title compound (24 mg, 54%).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=O)[CH2:4][CH2:3][C:2]1=[O:13].Cl.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22]N)=[CH:18][CH:17]=1.C([O-])(=O)C.[Na+].S(=O)(=O)(O)O>C(O)(=O)C>[Br:15][C:16]1[CH:17]=[C:18]2[C:4]3[CH2:3][C:2](=[O:13])[NH:1][C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[C:5]=3[NH:22][C:19]2=[CH:20][CH:21]=1
Reactant: O=C1CCC(=O)c2ccccc2N1
Reactant: NNc1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C1Cc2c([nH]c3ccc(Br)cc23)-c2ccccc2N1
Temperature: 70 °C
Yield: 86.3 %

Procedure:
To a suspension of 1H-[1]benzazepin-2,5(3H, 4H)-dione (0.247 g, 1.3 mmol) in acetic acid (5 ml) was added 4-bromophenylhydrazine hydrochloride (0.532 g, 2.3 mmol) and sodium acetate (0.195 g, 2.3 mmol) and stirred under argon. The mixture was heated at 70° C. for 3 hours, then cooled and concentrated sulfuric acid (0.5 ml) added, before heating at 70° C. for a further 3 hours. The slurry was poured into 10% sodium acetate aqueous solution (20 ml) and the precipitate filtered to give the title compound as a cream solid (0.367 g, yield 79.6%), mp>300° C.; 1H-NMR (DMSO-d6, 300 MHz): δ (ppm)=11.82 (s; 1 H), 10.1 (s; 1H), 7.89 (d; 1H), 7.74 (dd; 1H), 7.41-7.36 (m; 2H), 7.30-7.21 (m; 3H), 3.51 (s; 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]=[C:9]=[S:10])=[O:7])=[CH:4][CH:3]=1.[NH2:13][C:14]([NH2:16])=[O:15]>C1COCC1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([NH:8][C:9]([NH:13][C:14](=[O:15])[NH2:16])=[S:10])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccc(Cl)cc1
Reactant: NC(N)=O
Solvent: C1CCOC1
Product: NC(=O)NC(=S)NC(=O)c1ccc(Cl)cc1
Yield: 51.2 %

Procedure:
A solution of 4-Chlorobenzoylisothiocyanate (152.4 g) in THF (500 ml) is added dropwise to a stirred suspension of urea (46.3 g) in THF (750 ml). The reaction mixture is stirred over the weekend. The precipitate is filtered, washed with ether and dried leaving 101.7 g of a white solid, m.p. 155°-158° C. The filtrate is evaporated, filtered, the solid washed with ether and recrystallized from dioxane to give 7.8 g of additional white solid.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.CON(C)[C:11]([C:13]1[S:17][C:16]([CH3:18])=[N:15][C:14]=1[CH3:19])=[O:12]>C1COCC1>[CH3:18][C:16]1[S:17][C:13]([C:11]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=2)=[O:12])=[C:14]([CH3:19])[N:15]=1
Reactant: CON(C)C(=O)c1sc(C)nc1C
Reactant: Cn1cncc1Br
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(=O)c2cncn2C)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a flask containing 5-bromo-1-methyl-1H-imidazole (390 mg, 2.42 mmol) was added THF (8 mL) and the solution was cooled to 0° C. To this solution was added isopropylmagnesium chloride-LiC1 complex (1.3 M in THF, 2.5 mL, 3.25 mmol) which resulted in a white suspension. The reaction mixture was stirred in a 0° C. bath for 30 minutes, then a THF (2 mL) solution of N-methoxy-N,2,4-trimethylthiazole-5-carboxamide (550 mg, 2.75 mmol, Intermediate 17: step a) was introduced. The reaction mixture was stirred at 50° C. for 18 hours, cooled to room temperature and quenched with aqueous NH4Cl solution. The aqueous portion was extracted with DCM (4×50 mL) and the combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. Chromatography on silica gel (25% EtOAc-DCM increasing to 5% MeOH-DCM) afforded the title compound as an amber solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[N:40]1([C:46](Cl)=[O:47])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>C1COCC1>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH:35][C:46]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[O:47])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=C(Cl)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.9 %

Procedure:
To a solution of 51.1 mg (0.0964 mmole) of 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]- 2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 16, Step C) in 0.2 ml of dry THF was added 4.6 mg (0.116 mmole) of sodium hydride (60% in oil), and the mixture was allowed to stir at room temperature under N2 for 4 hours. Next, 17 μl (21.6 mg, 0.145 mmole) of 4-morpholinecarbonyl chloride was added, and the solution was stirred under N2 at room temperature overnight. The reaction was quenched by addition of 2 ml of H2O followed by extraction with 3×5 ml of ethyl acetate. The combined organic extracts were washed with 2×5 ml of H2O and then with 5 ml of brine. After co-evaporation twice from toluene, the crude product was flash chromatographed on silica gel (gradient elution with 0.3-10% MeOH in CH2Cl2) to give 16.1 mg of the title compound as a whitish glass; satisfactory purity by TLC in 19:1 and 9:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 682 (M+K)+.
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH:6]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=O)[CH:21]=[CH:22][CH:23]=[CH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[O:33][CH3:34])[CH2:16][CH2:15]2)[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH:21]=[CH:22][CH:23]=[CH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[O:33][CH3:34])[CH2:16][CH2:15]2)[C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)=[CH:36][CH:37]=1
Reactant: COc1ccc(C=CC=CC(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: COc1ccc(C=CC=CCN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(OC)c1
Yield: 84.3 %

Procedure:
To 11.6 g (23.0 mmol) of said 1-(4,4'-difluorobenzhydryl)-4-(5-(2,4-dimethoxyphenyl)-2,4-pentadienoyl)piperazine was added 250 ml of dry ether, and the mixture was stirred. After slow addition of 870 mg (23.0 mmol) of lithium aluminum hydride, the mixture was heated for 1 hour under reflux. To the reaction mixture was added saturated aqueous solution of ammonium chloride, and the mixture was extracted with ether. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. There was obtained a residue, which was subjected to column chromatography on silica gel and eluted with chloroform-methanol (40:1) to give 9.50 g (19.4 mmol) of 1-(4,4'-difluorobenzhydryl)-4-(5-(2,4-dimethoxyphenyl)-2,4-pentadienyl)piperazine. Spectrophotometric data of the product support the structure (VII). ##STR7##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]3[C:15](=[O:19])[CH2:16][CH2:17][CH2:18][C:13]=3[N:12]=[C:11]2[CH:20]([CH3:22])[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8].ClCCl.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]3[CH:15]([OH:19])[CH2:16][CH2:17][CH2:18][C:13]=3[N:12]=[C:11]2[CH:20]([CH3:22])[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(=O)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(O)CCC2
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To Intermediate 80 (131.02 g, combination of two batches) under nitrogen in methanol (1000 mL) and dichloromethane (DCM) (1000 mL) was added sodium borohydride (29.4 g) slowly in portions over 10 min and the mixture stirred at room temperature under nitrogen. Temp rose from 19° C. to 23° C. Gas evolution still visible for 20-30 mins and temp rose over 40 mins to 26° C. Temp still going up after 1 hr20 min—now 26.2° C. After 2.5 hr water was added carefully and the mixture was partitioned between ethyl acetate and water (should have given the mixture more time to quench before extracting—gas evolution during extraction seen) and the aqueous layer extracted well with ethyl acetate. The combined organics were washed with water, brine, dried (MgSO4), filtered and evaporated. This gave the title compound, a white solid, 133.3 gm. LC/MS MH+ 339, 341, Rt 0.76 min (2 min run).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]2(O)[CH2:10][CH2:9][CH2:8]2)=[CH:5][N:6]=1>FC(F)(F)C(O)=O.[OH-].[OH-].[Pd+2]>[CH:7]1([C:4]2[S:3][C:2]([NH2:1])=[N:6][CH:5]=2)[CH2:10][CH2:9][CH2:8]1
Reactant: Nc1ncc(C2(O)CCC2)s1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(C2CCC2)s1
Yield: 59.7 %

Procedure:
Hydrogenate 1-(2-amino-thiazol-5-yl)-cyclobutanol (0.94 g, 5.52 mmol, 1.0 eq.) in trifluoroacetic acid (16 mL) in the presence of Pearlman's catalyst (0.16 g) under H2 (52 psi) for over night. Filter off the catalyst. Wash with methanol. Concentrate in vacuo. Add dichloromethane (100 mL) to the residue. Wash the organic layer with sodium bicarbonate (sat. 2×30 mL), aqueous saturated sodium chloride (2×20 mL) and water (2×30 mL). Dry the organic phase over MgSO4 and filter the drying reagent off. Concentrate in vacuo. Purify by column chromatography (0%→5% methanol in dichloromethane) to afford product (0.508 g, 60%). MS(ES), m/z 155 (M+1).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])=[C:8]1[CH:34]([CH3:36])[CH3:35])C.Cl>CC(C)=O>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]2[N:7]([CH2:6][CH2:5][CH:4]=[O:3])[C:8]([CH:34]([CH3:36])[CH3:35])=[C:9]([C:25]([NH:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:26])[C:10]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][CH:16]=1
Reactant: CCOC(CCn1c(-c2ccc(F)cc2)c(-c2ccccc2)c(C(=O)Nc2ccccc2)c1C(C)C)OCC
Agent: Cl
Solvent: CC(C)=O
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CCC=O
Yield: 94.3 %

Procedure:
To a nitrogen purged flask fitted with an overhead stirrer, a thermometer, and a condenser is added 20 kg (37.8 mol) of 1-(3,3-diethoxypropyl)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl- 1H-pyrrole-3-carboxamide along with 200 L of acetone. The solution is stirred and 100 L of 2N hydrochloric acid solution is added. The mixture is heated to reflux for four hours then cooled to 50° C.±5° C., seeded, and cooled to 0° C.±5° C. The product is collected by filtration, washed with 100 L 2-propanol-water (1:1) and dried in vacuo at 50° C. for 64 hours to yield 16.2 kg of 5-(4-fluorophenyl)-2-(1-methylethyl)-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[S:7][C:8]([CH:10]=O)=[CH:9][C:5]=2[CH:4]=1.[C:16]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:17]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[S:7][C:8](/[CH:10]=[CH:18]/[C:16]#[N:17])=[CH:9][C:5]=2[CH:4]=1
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc2cc(C=O)sc2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2cc(/C=C/C#N)sc2cc1OC
Yield: 84.2 %

Procedure:
A mixture of 5,6-dimethoxybenzo[b]thiophene-2-carboxaldehyde (8.14 g) and cyanomethylene triphenylphosphorane (22.06 g) in dry toluene (270 ml) was stirred and heated to reflux for 1 hour. The reaction mixture was then evaporated to dryness and the residue was dissolved in a mixture of dichloromethane (50 ml) and toluene (50 ml) and passed through a column of coarse silica (0.2-0.5 mm, Merck, 600 g). The column eluted with toluene:ethyl acetate (4:1 v/v). The appropriate fractions were combined and evaporated to dryness and the residue was crystallised from dichloromethane:diethyl ether to give pure (E)-3-(5,6-dimethoxy-benzo[b]thiophene-2-yl)-2-propenenitrile (7.56 g), m.p. 154°-158° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:22]=[CH:21][C:11]([O:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:24][CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:15]1([CH2:14][CH2:13][O:12][C:11]2[CH:21]=[CH:22][C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:24][CH2:25][C:26]4[CH:27]=[CH:28][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:34][CH:35]=4)[N:7]=3)=[CH:9][CH:10]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: Clc1nccc(-c2ccc(OCCN3CCOCC3)cc2)n1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CNc2nccc(-c3ccc(OCCN4CCOCC4)cc3)n2)cc1
Temperature: 100 °C
Yield: 50 %

Procedure:
To a solution of 19 (2.7 g, 8.4 mmol) and methyl 4-(aminomethyl)benzoate hydrochloride (2.7 g, 13.5 mmol) in dry toluene (33 mL) was added cesium carbonate (8.2 g, 25.3 mmol) followed by Pd2(dba)3 (464 mg, 0.51 mmol) and rac-BINAP (473 mg, 0.76 mmol). The solution was degassed and heated at 100° C. for 16 h. The reaction mixture was partitioned between water and EtOAc and the phases were separated. The organic layer was successively washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to form a residue which was purified by flash chromatography on silica gel (MeOH/CH2Cl2: 2/98) to afford the title compound 20 (1.9 g, 4.2 mmol, 50% yield).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][C:15]([F:18])([F:17])[F:16])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7])=O.Cl.[NH2:20]O>C(O)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][C:15]([F:18])([F:17])[F:16])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7])#[N:20]
Reactant: NO
Reactant: COc1c(C=O)cc(C(=O)O)cc1OC(F)(F)F
Agent: Cl
Solvent: O=CO
Product: COc1c(C#N)cc(C(=O)O)cc1OC(F)(F)F
Yield: 95.2 %

Procedure:
3-formyl-4-methoxy-5-trifluoromethoxybenzoic acid (4.22 g) was dissolved in formic acid (20 mL), and hydroxylamine hydrochloride (1.22 g) was added to the solution, and then the mixture was refluxed for 16 hours. The solvent was distilled off under reduced pressure and 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (3.97 g) as a brown solid.