Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)[CH3:2].[CH3:14][N:15]1CCCC1=O.[Cu]C#N>CCOC(C)=O.[NH4+].[OH-]>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:14]#[N:15])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Br)c1
Reactant: CN1CCCC1=O
Agent: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cccc(C#N)c1
Temperature: 190 °C
Reaction time: 1 h

Procedure:
To a mixture of of (3-bromo-phenyl)-acetic acid ethyl ester (15.3 g, 62.9 mmol) and 1-methyl-2-pyrrolidinone (125 mL) was added copper (I) cyanide (8.46 g, 94.4 mmol). The reaction mixture was stirred in an oil bath at 190° C. for 1 h. The reaction was cooled to room temperature and was diluted with EtOAc and 2:1H2O/NH4OH. The mixture was stirred for 10 minutes and was filtered through Celite. The aqueous layer was washed with EtOAc (2×). The organic solution was washed with 2:1H2O/NH4OH until the aqueous extracts were no longer blue. The organic solution was dried over MgSO4, filtered and concentrated to afford (3-cyano-phenyl)-acetic acid ethyl ester (11.95 g). 1H NMR (400 MHz, CDCl3) δ 7.51-7.58 (m, 3H), 7.43 (t, 1H), 4.16 (q, 2H), 3.63 (s, 2H), 1.25 (t, 3H).
Reaction SMILES: N#N.Cl[C:4]1[N:9]=[N:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:12]([CH3:23])[CH2:11]2)=[C:6]([CH3:24])[C:5]=1[CH3:25].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[F-].[Cs+]>O1CCOCC1>[CH3:24][C:6]1[C:5]([CH3:25])=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:9]=[N:8][C:7]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:12]([CH3:23])[CH2:11]1
Reactant: OB(O)c1ccccc1
Reactant: Cc1c(Cl)nnc(N2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c1C
Agent: N#N
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2)nnc(N2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c1C
Temperature: 95 °C
Yield: 86.4 %

Procedure:
Treat a N2 degassed mixture of (S)-tert-butyl 4-(6-chloro-4,5-dimethylpyridazin-3-yl)-2-methylpiperazine-1-carboxylate (3.03 g, 8.87 mmol), phenylboronic acid (1.62 g, 13.3 mmol), and CsF (4.09 g, 26.9 mmol) in 1,4-dioxane (120 mL) with (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) chloride (1.08 g, 1.32 mmol). Heat the reaction mixture at 95° C. overnight. Cool the reaction, and partition between EtOAc and H2O. Wash the organic layer with brine, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography (gradient of 15 to 85% EtOAc in hexanes) to afford the title compound as a white solid (2.93 g, 86%). ES/MS m/z 383.0 (M+1).
Reaction SMILES: Br[CH:2]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[O:4].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K].C(OCC)(=O)C>O>[CH3:14][CH:13]([CH3:15])[CH2:12][CH:2]([N:20]1[C:16](=[O:26])[C:17]2[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:19]1=[O:21])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[O:4]
Reactant: Cc1ccc(C(=O)C(Br)CC(C)C)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)C(CC(C)C)N2C(=O)c3ccccc3C2=O)cc1
Temperature: 160 °C
Yield: 72.7 %

Procedure:
2-Bromo-4-methyl-1-(4-methylphenyl)pentan-1-one (13.5 g, 50 mmol) and potassium phthalimide (9.26 g, 50 mmol) were thoroughly mixed and heated at 160° C. for 2 hours. After cooling, to the reaction mixture were added ethyl acetate (100 ml) and water (50 ml). The resulting organic layer was separated and washed with brine. The organic solution was then dried over sodium sulfate and evaporated under reduced pressure. The residue was crystallized by treatment with hexane and the crystals were recrystallized from hexane to obtain 12.2 g of the title compound as white crystals (yield: 73%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[O-]S(C(F)(F)[F:16])(=O)=O.F[N+]1C=CC=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCCl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([F:16])[C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: F[n+]1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cc(O)c(F)c(C)c1Br
Yield: 36.2 %

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (2.00 g, 9.95 mmol) in 1,2-dichloroethane (20 mL) was added N-fluoropyridinium triflate (6.15 g, 24.9 mmol), and the mixture was heated under reflux for 7 hr. The reaction mixture was treated with 1 M aqueous sodium thiosulfate solution, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-30:70) to give the title compound (0.790 g, yield 36%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#N)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:13].[Na+].CC[OH:17]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:17])=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CCO
Reactant: N#CC1(c2ccc(Br)cc2)CC1
Agent: [Na+]
Product: O=C(O)C1(c2ccc(Br)cc2)CC1
Temperature: 100 °C

Procedure:
A mixture of nitrile (1 eq) from step 1, NaOH 25% (12 eq) in EtOH (0.5M) was heated to 100° C. for 5 h. The mixture was cooled to rt, quenched with AcOH and diluted with ether. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (hexane:EtOAc, 90:10 to 50:50) afforded the title compound.
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:7]([C:9]3[CH:10]=[C:11]([C:20]([OH:23])([CH3:22])[CH3:21])[CH:12]=[CH:13][C:14]=3[N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)=[N:8][C:4]=2[CH:3]=1.[NH2:30][C:31]1[N:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:30][C:31]1[N:36]=[CH:35][C:34]([C:2]2[CH:29]=[CH:28][C:5]3[N:6]([C:24]([CH3:26])([CH3:25])[CH3:27])[C:7]([C:9]4[CH:10]=[C:11]([C:20]([OH:23])([CH3:22])[CH3:21])[CH:12]=[CH:13][C:14]=4[N:15]4[CH:19]=[N:18][CH:17]=[N:16]4)=[N:8][C:4]=3[CH:3]=2)=[CH:33][N:32]=1
Reactant: CC(C)(O)c1ccc(-n2cncn2)c(-c2nc3cc(Br)ccc3n2C(C)(C)C)c1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccc(-n2cncn2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Temperature: 110 °C
Yield: 69 %

Procedure:
To a sealed vial is added 2-[3-(5-bromo-1-tert-butyl-1H-benzoimidazol-2-yl)-4-[1,2,4]triazol-1-yl-phenyl]propan-2-ol (60 mg, 0.13 mmol) in DMF (2 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (35 mg, 0.16 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) and 2M aqueous Na2CO3 (0.3 mL, 0.6 mmol). The reaction mixture is heated under Ar at 110° C. for 2 hours. The residue is diluted with EtOAc (20 mL), washed with brine (10 mL), dried under anhydrous Na2SO4 (500 mg). The mixture is filtered and concentrated. The residue is purified by silica gel flash chromatography with 0-7% 2M NH3 in MeOH/CH2Cl2 as the eluent. The product fractions are collected and concentrated to afford the title compound (42 mg, 68%). LCMS (ESMS): m/z 469.50 (M++1)
Reaction SMILES: NC12CC3CC(CC(N[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=4)=[O:14])(C3)C1)C2.Cl.[CH3:23][O:24][C:25]([C:27]12[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][C:29]([NH2:37])([CH2:30]3)[CH2:28]1)[CH2:34]2)=[O:26].CC1N=C(C(O)=O)C=CC=1>>[CH3:23][O:24][C:25]([C:27]12[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][C:29]([NH:37][C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=4)=[O:14])([CH2:30]3)[CH2:28]1)[CH2:34]2)=[O:26]
Reactant: Cc1cccc(C(=O)NC23CC4CC(CC(N)(C4)C2)C3)n1
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1)C2
Agent: Cc1cccc(C(=O)O)n1
Agent: Cl
Product: COC(=O)C12CC3CC(CC(NC(=O)c4cccc(C)n4)(C3)C1)C2
Yield: 75 %

Procedure:
Intermediate 1 was also made via the same synthetic procedures for Intermediate 2 (see below). Starting from 3-amino-adamantane-1-carboxylic acid methyl ester hydrochloride (14.9 g, 60.8 mmol), coupling with 6-methyl-pyridine-2-carboxylic acid afforded 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid methyl ester (14.9 g, 75%). The methyl ester was then hydrolyzed to give 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid (12.2 g, 86%). Finally; the Curtius rearrangement of 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid (10.0 g, 31.8 mmol) yielded Intermediate 1 (8.48 g, 93%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][C:15]=2[CH2:24][N:25]([C:32]([CH:29]2[CH2:31][CH2:30]2)=[O:33])[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1ccc(C(F)(F)F)cc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc(C(F)(F)F)ccc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-5′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: C([O:8][C:9]1[C:10]([F:22])=[C:11]([CH2:18][C:19](=[O:21])[CH3:20])[C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)C1C=CC=CC=1.Br>C(OC(=O)C)(=O)C.C(O)(=O)C>[F:22][C:10]1[C:9]([OH:8])=[CH:14][CH:13]=[C:12]([N+:15]([O-:17])=[O:16])[C:11]=1[CH2:18][C:19](=[O:21])[CH3:20]
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1F
Agent: Br
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(O)c1F
Temperature: 100 °C
Yield: 79.8 %

Procedure:
Method G-1: To a solution of 1-(3-benzyloxy-2-fluoro-6-nitrophenyl)-propan-2-one (3.03 g, 10 mmol) in acetic anhydride (5 mL) and acetic acid (5 mL) at room temperature was added hydrobromic acid (48% aqueous solution, 3 mL). After addition, the reaction was heated at 100° C. for 30 min and then cooled to room temperature. To this mixture was added 10 mL of hexanes with stirring. The solution was decanted and concentrated. The residue was diluted with ethyl acetate (50 mL) and washed with brine (3×20 mL). The organic layer was dried and concentrated in vacuo to provide 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (1.7 g, 80%) as a brown solid, which was used in the next step without further purification. LC/MS; (M+H)+=213.2 Method G-2: A mixture of 1-(3-benzyloxy-2-fluoro-6-nitrophenyl)-propan-2-one (65.0 g, 0.214 mol) and pyridinium chloride (60.74 g, 0.526 mol) was stirred at 180° C. for 1 hr. The reaction mixture was cooled to room temperature, diluted with 3N HCl (100 mL) and ethyl acetate (500 mL) and filtered. The aqueous layer was extracted with ethyl acetate (2×) and the combined organic layers were washed with brine, dried (MgSO4),s filtered through a pad of silica gel and concentrated in vacuo. The residue was decolorized with charcoal in methanol, filtered and concentrated in vacuo to afford 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (37 g, 81%) as a brown solid. LC/MS; (M+H)+=213.2
Reaction SMILES: [N+]([O-])([O-])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([NH:17][C:18]([NH2:20])=[NH2+:19])[CH:10]=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14].[C:21]([O:25][C:26]([NH:28][C:29]([C:32]1[CH:37]=[CH:36][C:35]([C:38](=O)[C:39]([C:44]#N)=[CH:40][N:41](C)C)=[CH:34][CH:33]=1)([CH3:31])[CH3:30])=[O:27])([CH3:24])([CH3:23])[CH3:22].[OH-].[Na+].C(OCC)(=O)C>CCCCCC>[NH2:28][C:29]([C:32]1[CH:33]=[CH:34][C:35]([C:38]2[C:39]([C:40]#[N:41])=[CH:44][N:20]=[C:18]([NH:17][C:9]3[CH:10]=[C:11]([O:15][CH3:16])[C:12]([O:13][CH3:14])=[C:7]([O:6][CH3:5])[CH:8]=3)[N:19]=2)=[CH:36][CH:37]=1)([CH3:31])[CH3:30].[C:21]([O:25][C:26]([NH:28][C:29]([C:32]1[CH:37]=[CH:36][C:35]([C:38]2[C:39]([C:40]#[N:41])=[CH:44][N:20]=[C:18]([NH:17][C:9]3[CH:10]=[C:11]([O:15][CH3:16])[C:12]([O:13][CH3:14])=[C:7]([O:6][CH3:5])[CH:8]=3)[N:19]=2)=[CH:34][CH:33]=1)([CH3:31])[CH3:30])=[O:27])([CH3:23])([CH3:22])[CH3:24]
Reactant: CN(C)C=C(C#N)C(=O)c1ccc(C(C)(C)NC(=O)OC(C)(C)C)cc1
Reactant: COc1cc(NC(N)=[NH2+])cc(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(Nc2ncc(C#N)c(-c3ccc(C(C)(C)N)cc3)n2)cc(OC)c1OC
Product: COc1cc(Nc2ncc(C#N)c(-c3ccc(C(C)(C)NC(=O)OC(C)(C)C)cc3)n2)cc(OC)c1OC
Yield: 164.4 %

Procedure:
The title compound was prepared from 3,4,5-trimethoxyphenylguanidinium nitrate (576 mg, 2.0 mmol), 1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethylaminopropen-1-one (660 mg, 1.8 mmol) and powdered sodium hydroxide (89 mg, 2.2 mmol) following the method described for the compound of Example 8. This gave the intermediate 4-[4-(1-tert-butoxycabonylamino-1methylethyl)phenyl]-5-cyano-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine as a yellow solid (769 mg) after column chromatography (silica, 40% ethyl acetate in hexane). This compound was treated with TFA acid in CH2Cl2 as descibed for the analogous compound of Example 8 to give the title compound as a pale yellow solid (597 mg) m.p. 167-168°. δH (d6 DMSO) 10.34 (1H, bs), 8.90 (1H, s), 7.96 (2H, bd, J 7.8 Hz), 7.73 (2H, d, J 8.2 Hz), 7.24 (2H, bs), 3.76 (6H, s), 3.63 (3H, s), 3.18 (2H, bs), 1.42 (6H, s). MS (ESI) 442 (MNa+, 16%), 420 (MH+, 57%), 403 (100%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[C:14]([NH2:27])[CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2.N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(Cl)Cl>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[C:14]([NH:27][C:34](=[O:36])[CH3:35])[CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(C(=O)NC2CN3CCC2CC3)c2nc(-c3ccccc3)oc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(C(=O)NC2CN3CCC2CC3)c2nc(-c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
To a solution of N-(1-azabicyclo[2.2.2]oct-3-yl)-6-amino-2-phenylbenzoxazole-4-carboxamide (35 mg, 0.09 mmol) in methylene chloride (1 mL) was added pyridine (11 μL, 0.14 mmol) and acetic anhydride (11 μL, 0.10 mmol) at 0° C. and stirred for 30 min, then allowed to warm to room temperature for 1 h. The reaction mixture was quenched with saturated solution of sodium bicarbonate and concentrated under reduced pressure. The crude was purified by semi-preparative HPLC to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-6-acetylamino-2-phenylbenzoxazole-4-carboxamide (13 mg, 44%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.58 (d, J=7.4 Hz, 1H), 8.73 (d, J=1.9 Hz, 1H), 8.20 (d, J=6.8 Hz, 1H), 8.13 (s, 1H), 7.81 (d, J=1.7 Hz, 1H), 7.55-7.50 (m, 4H), 4.35-4.27 (m, 1H), 3.57-3.48 (m, 1H), 3.16-3.03 (m, 2H), 2.97-2.82 (m, 2H), 2.27 (s, 3H), 2.17-2.05 (m, 2H), 1.85-1.60 (m, 3H); MS (ESI+) m/z 405 (M+H); HPLC>99% (AUC), tR=23.81 min.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([S:10][CH2:11][CH2:12][CH3:13])[N:3]=1.[NH2:14][CH:15]1[CH2:19][CH:18]([CH2:20][OH:21])[CH:17]([OH:22])[CH:16]1[OH:23].C(N(CC)CC)C>C(O)CCC>[NH2:8][C:7]1[C:2]([NH:14][CH:15]2[CH2:19][CH:18]([CH2:20][OH:21])[CH:17]([OH:22])[CH:16]2[OH:23])=[N:3][C:4]([S:10][CH2:11][CH2:12][CH3:13])=[N:5][C:6]=1[Cl:9]
Reactant: NC1CC(CO)C(O)C1O
Reactant: CCCSc1nc(Cl)c(N)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CCCSc1nc(Cl)c(N)c(NC2CC(CO)C(O)C2O)n1

Procedure:
The product of step iv) (4.6 g) was added to a solution of 3-amino-5-(hydroxymethyl)-cyclopentane-1,2-diol (1.41 g) in butan-1-ol (200 ml) containing triethylamine (10 ml) and the whole heated to reflux for 48 hours. Evaporation gave a dark residue which was chromatographed (SiO2, 10% ethanol/dichloromethane) to afford the sub-title compound (2.8 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1.[C:18]([N:25]1[CH:29]=[CH:28]N=C1)(N1C=CN=C1)=[O:19].C(N)[C:31]1[CH:36]=[CH:35]C=[CH:33][CH:32]=1.N12CCCN=C1CCCCC2>C1COCC1.C(OCC)(=O)C>[CH2:29]([NH:25][C:18]([O:1][CH2:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1)=[O:19])[C:28]1[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1sc(CO)cc1-c1ccccc1
Reactant: NCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(COC(=O)NCc2ccccc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.8 %

Procedure:
To a solution of 169 (0.900 g, 3.62 mmol) in THF was added 1,1′-carbonyldiimidazole (0.588 g, 3.62 mmol) and stirred at room temperature for 90 min. Then BnNH2 (0.396 mL, 3.62 mmol), TEA (0.505 mL, 3.62 mmol) and 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.546 mL, 3.62 mmol) were added and stirred at room temperature for an additional 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by ISCO (40 g column, 0-45% ethyl acetate in hexanes) to yield in 82% (1.13 g) compound 170 as a pink solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:23][NH:24][CH2:25][CH2:26][OH:27]>>[Br:1][C:2]1[C:3]([N:24]([CH2:25][CH2:26][OH:27])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: CNCCO
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1Br

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 22.1 using 5-bromo-6-chloro-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 25.2) and 2-methylamino-ethanol to afford an off-white crystalline solid. HPLC (Condition 4) tR=5.97 min, UPLC-MS (Condition 3) tR=1.18 min, m/z=450.2 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[CH3:5][S:6]([C:8](SC)=[CH:9][N+:10]([O-:12])=[O:11])=O>CO>[CH3:5][S:6][C:8]([NH:4][CH2:1][C:2]#[CH:3])=[CH:9][N+:10]([O-:12])=[O:11]
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: C#CCN
Solvent: CO
Product: C#CCNC(=C[N+](=O)[O-])SC
Reaction time: 1 h

Procedure:
A solution of propargylamine (1.10 g, 0.02 mole) in 22 ml of methanol was added dropwise to a stirred suspension of 1-methylsulfinyl-1-methylthio-2-nitroethylene [prepared according to the procedure described in Belgian Pat. No. 841,526] at 25°. After 1 hour at ambient temperature, the solution was evaporated under reduced pressure, triturated under 20 ml of cold isopropyl alcohol and filtered to give product. Recrystallization from isopropyl alcohol gave 1-methylthio-1-(2-propynylamino)-2-nitroethylene; mp 131°-132°.
Reaction SMILES: [CH3:1][C:2]([O-:5])([CH3:4])[CH3:3].[Na+].CN(C=O)C.F[C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1>CN(P(N(C)C)(N(C)C)=O)C.O>[C:2]([O:5][C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1)([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1ccc(F)cn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)Oc1ccc(C#N)nc1
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To NaOtBu (1.57 g, 16.4 mmol) in HMPA (6 mL) was added DMF (6 mL) (to facilitate stirring). 5-Fluoropyridine-2-carbonitrile (1.00 g, 8.19 mmol) was added and the dark mixture was stirred overnight. The mixture was diluted with water (100 mL), extracted with DCM (3×50 mL) and the organics were washed with water (50 mL) and sat. aq. NaHCO3 (50 mL), dried over MgSO4, evaporated and purified by column chromatography (0-50% EtOAc/hex) to give 5-tert-butoxypyridine-2-carbonitrile (0.90 g, 62%) as a yellow solid. ESI-MS m/z calc. 211.1, found 211.9 (M+1)+; Retention time: 0.97 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 8.38 (dd, J=2.7, 0.5 Hz, 1H), 7.67-7.56 (m, 1H), 7.41-7.31 (m, 1H), 1.52-1.38 (m, 10H).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2.N1CCCCC1>C(O)C>[CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][CH:9]2[NH:13][C:14](/[CH:17]=[C:26]3\[C:27](=[O:32])[NH:28][C:29]4[C:25]\3=[CH:24][C:23]([F:22])=[CH:31][CH:30]=4)=[C:15]([CH3:16])[CH:8]2[C:7]1=[O:19])[CH3:2]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCN1CCCC2NC(/C=C3\C(=O)Nc4ccc(F)cc43)=C(C)C2C1=O
Temperature: 25 °C
Yield: 80.4 %

Procedure:
5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j (0.271 g, 0.93 mmol) and 5-fluoro-1,3-dihydro-indol-2-one (0.127 g, 0.84 mmol) were dissolved in 1.4 ml of anhydrous ethanol under stirring at room temperature, the resulting mixture was stirred for 10 minutes in dark, and added with piperidine (0.15 ml, 1.49 mmol). The mixture was refluxed at 70° C. for about 1.5 hours in an oil bath under an argon atmosphere and lots of orange precipitates were formed. After thin lay chromatography showed the disappearance of starting materials, the ice-salt bath was removed, and the reaction mixture was naturally cooled to room temperature, filtered and dried to obtain the title compound (Z)-5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-3 a,5,6,7,8,8a-hexahydro-1H-pyrrolo[3,2-c]azepin-4-one 1 (0.288 g, yield 80.76%) as an orange solid.