Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:10]([CH2:20][C:21]2[N:26]=[C:25]([C:27](=[N:29][OH:30])[NH2:28])[CH:24]=[CH:23][CH:22]=2)[C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2.[C:31](N1C=CN=C1)(N1C=CN=C1)=[S:32].N12CCCN=C1CCCCC2.Cl>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:10]([CH2:20][C:21]2[N:26]=[C:25]([C:27]3[NH:28][C:31](=[S:32])[O:30][N:29]=3)[CH:24]=[CH:23][CH:22]=2)[C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2
Reactant: COc1ccc2c(c1)cc(-c1cc(F)ccc1F)n2Cc1cccc(C(N)=NO)n1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(c1)cc(-c1cc(F)ccc1F)n2Cc1cccc(-c2noc(=S)[nH]2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
To a suspension of 6-[2-(2,5-difluorophenyl)-5-methoxyindol-1-ylmethyl]pyridine-2-carboxamidoxime (63 mg) in acetonitrile (1.54 mL) were successively added 1,1′-thiocarbonyldiimidazole (41 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.092 mL), followed by stirring at room temperature for 3 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-methanol) to obtain the title compound (70 mg). 1H-NMR (DMSO-d6) δ ppm: 3.77 (3H, s), 5.41 (2H, s), 6.50-6.60 (1H, m), 6.67 (1H, s), 6.80 (1H, dd, J=2.4, 9.0 Hz), 7.15 (1H, d, J=2.4 Hz), 7.25-7.45 (3H, m), 7.50-7.60 (1H, m), 7.65-7.80 (2H, m). ESI-MS (m/z): 451 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=[N:34][NH2:35])[NH:23][CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:37](OCC)(OCC)OCC>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24]5=[N:34][N:35]=[CH:37][N:23]5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=NN)NCC4)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3nncn3CC4)cc2)CCC1
Yield: 22 %

Procedure:
A solution of tert-butyl(1-(4-(5-hydrazono-3-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)phenyl)cyclobutyl)carbamate (40 mg, 0.08 mmol) in triethyl orthoformate (1 mL) was heated at 150° C. for 1.5 h under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by preparative HPLC (method G, gradient 5 to 95% 0.1% FA/ACN in 0.1% FA/H2O) to give the title compound (9 mg, 22%). 1H NMR (500 MHz, CDCl3): 8.47 (1H, s), 8.29 (1H, s), 7.37 (2H, d), 7.31 (2H, d), 7.28-7.26 (3H, m), 7.23-7.21 (2H, m), 5.07 (1H, br s), 4.42 (2H, t), 3.50 (2H, t), 2.55-2.25 (4H, m), 2.10-2.02 (1H, m), 1.85-1.76 (1H, m), 1.45-1.20 (9H, br).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][C:45]=3[F:48])[C:40]2=[O:49])[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.Cl.[NH2:51][C:52]1[S:53][C:54]([Cl:57])=[CH:55][N:56]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[Cl:57][C:54]1[S:53][C:52]([NH:51][C:36](=[O:38])[C@@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][C:45]=3[F:48])[C:40]2=[O:49])[CH2:34][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[N:56][CH:55]=1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2c(F)cccc2C1=O
Reactant: Nc1ncc(Cl)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(Nc1ncc(Cl)s1)[C@H](CC1CCCCC1)N1Cc2c(F)cccc2C1=O
Yield: 28 %

Procedure:
BOP coupling of (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (ca. 1:1 mixture of regioisomers, prepared in Step C; 501 mg; 1.64 mmol) and 2-amino-5-chlorothiazole hydrochloride (643 mg; 3.64 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as outlined in Example 9, Step B) provided after normal phase HPLC (Waters Prep. 500, loaded on column with methylene chloride, eluent: 20% ethyl acetate/hexanes) 194 mg of (S)-N-(5-Chloro-thiazol-2-yl)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide: EI-HRMS m/e calcd for C20H21ClFN3O2S (M+) 421.1027, found 421.1024; and 173 mg of regioisomeric (S)-N-(5-Chloro-thiazol-2-yl)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide: EI-HRMS m/e calcd for C20H21ClFN3O2S (M+) 421.1027, found 421.1031.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:34])[C@@H:16]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:25]([CH3:33])[CH:24]=2)[CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:10]1)(C)(C)C.C(O)C>Cl.C(OCC)(=O)C>[CH:18]1([CH2:17][C@H:16]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[C:25]([CH3:33])[CH:24]=2)[C:15]([NH:14][C:11]2[CH:12]=[CH:13][N:9]([CH2:8][CH2:7][OH:6])[N:10]=2)=[O:34])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1cc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)n2)ccc1S(C)(=O)=O
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCO)n2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
In a flask containing N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionamide (300 mg, 0.56 mmol) was added ethanol (10 mL) and concentrated hydrochloric acid (seven drops) and was stirred at 25° C. for 2 h. It was then diluted with ethyl acetate (100 mL) and washed with water (1×30 mL) and saturated aqueous brine solution (1×30 mL). The organic layer was then dried over sodium sulfate and absorbed onto silica gel (2.5 g) and purified on Biotage Flash chromatography system (40S column, silica gel, 5% methanol/ethyl acetate) afforded 3-cyclopentyl-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionamide (194 mg, 83%) as a white foam: [α]28589=−19.0° (c=0.20, methanol); ES-HRMS m/e calcd for C21H29N3O4S (M+H)+ 420.1952, observed 420.1949; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.18 (m, 2H, CH2), 1.37-1.80 (m, 8H, 4×CH2), 2.06-2.17 (m, 1H, CH) ArCH3), 3.16 (s, 3H, SO2CH3), 3.66 (q, J=5.6 Hz, 2H, OCH2), 3.85 (dd, J=8.8 Hz, J=5.7 Hz, 1H, ArCH), 3.98 (t, J=5.6 Hz, 2H, NCH2), 4.82 (t, J=5.6 Hz, 1H, OH), 6.40 (d, J=2.2 Hz, 1H, Ar), 7.41-7.46 (m, 2H, Ar), 7.52 (d, J=2.2 Hz, 1H, Ar), 7.83 (d, Jo=8.5 Hz, 1H, Ar), 10.72 (s, 1H, NH).
Reaction SMILES: Cl.[Cl-].[NH4+].[N+:4]([C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][CH:28]=1)[CH2:10][S:11][C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=1)([O-])=O>C(O)C.O.[Fe]>[NH2:4][C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][CH:28]=1)[CH2:10][S:11][C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:22])[CH3:23])[CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(SCc2cccc([N+](=O)[O-])c2)c1
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(SCc2cccc(N)c2)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
A mixture of iron (0.62 g, 11 mmol) in ethanol (22 mL) was treated with 1 M HCl in water (1.1 mL) and heated at 60° C. for 2 h. The reaction mixture was cooled to 55-60° C. and treated with 5 M ammonium chloride in water (1.9 mL). The reaction mixture was then treated with a solution of tert-butyl {3-[(3-nitrobenzyl)thio]phenyl}carbamate (0.80 g, 2.2 mmol) in ethanol (2.5 mL) while the temperature was kept at 60° C. The resulting suspension was stirred at 60-65° C. for 30 min. The reaction mixture was cooled to 40° C., diluted with ethanol, treated with celite, filtered over a pad of celite, and washed with ethanol. The filtrate was concentrated to a tan solid that was diluted with ethyl acetate (50 mL) and saturated sodium bicarbonate (50 mL). The organic layer was separated and washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude tan oil. This material was purified by flash column chromatography to give the desired product (0.63 g, 85%). LCMS for C18H23N2O2S (M+H)+: m/z=331.1.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH3:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:14][CH2:13][CH2:12][C:11]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([CH3:16])[CH:10]=2)[CH2:26][CH2:25]1
Reactant: Cc1cc(CCC=O)n(-c2ccccc2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccccc2)n1

Procedure:
85 mg (83%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-methyl-1H-pyrazol-5-yl)propanal (58 mg, 0.268 mmol), 1-(2-fluorophenyl)piperazine (52 mg, 0.289 mmol), DIPEA (0.070 mL, 0.403 mmol) and NaBH(OAc)3 (171 mg, 0.805 mmol).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:11][CH:5]2[C:4](=O)[N:3]=1.P(Cl)(Cl)(Cl)=O.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:5]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][C:6]=2[N:7]=1
Reactant: C1CCNCC1
Reactant: CC1=NC(=O)C2CCN(Cc3ccccc3)CC2=N1
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2c(c(N3CCCCC3)n1)CCN(Cc1ccccc1)C2
Reaction time: 72 h

Procedure:
2-methyl-7-(phenylmethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(4aH)-one (Preparation 85, 19 g) and phosphorous oxychloride (150 ml) was heated for 1.5 h. The reaction mixture was concentrated and poured onto ice. Sodium carbonate was added to adjust pH to 10, and the product was extracted with chloroform. The organic extracts were concentrated and then purified by passing through a thick pad of florisil (5 cm diameter) the product was eluted with chloroform. Evaporation gave a dark red oil which was dissolved in ethanol (100 ml) and piperidine (25 ml) was added. After 72 h, the reaction mixture was concentrated in vacuo then dissolved in chloroform and basified with sodium hydroxide (2 M solution). The reaction mixture was dried and concentrated before purifying by flash chromatography on florisil eluting the product with petroleum ether (30-40) to give the title compound (12.5 g)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[CH2:8][C:9]([C:11]1[C:16]2[CH:17]=[C:18]([C:20]([OH:22])=O)[O:19][C:15]=2[C:14]([O:23][CH3:24])=[CH:13][CH:12]=1)=[O:10].O.ON1C2C=CC=CC=2N=N1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[CH2:8][C:9]([C:11]1[C:16]2[CH:17]=[C:18]([C:20]([N:41]3[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]3)=[O:22])[O:19][C:15]=2[C:14]([O:23][CH3:24])=[CH:13][CH:12]=1)=[O:10]
Reactant: CN1CCNCC1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2cc(C(=O)O)oc12
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2cc(C(=O)N3CCN(C)CC3)oc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
4-[2-(3,5-Dichloro-4-pyridyl)-1-oxoethyl]-7-methoxybenzofuran-2-carboxylic acid (Compound M, 5.8 g) obtained in Reference Example 3 was dissolved in DMF (700 ml), and 1-hydroxybenzotriazole monohydrate (8.4 g), N-ethyl-N′-3-dimethylaminopropylcarbodiimide monohydrochloride (11.6 g) and 1-methylpiperazine (6.8 ml) were added thereto, and the mixture was stirred at room temperature for 5 hours. After the solvent was distilled off under reduced pressure, the residue was extracted with chloroform, washed with a saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol 80:1 to 20:1) and then recrystallized from ethanol to give Compound 13 (5.5 g, 79%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:28])=[C:23]([CH2:25][CH2:26][OH:27])[CH:24]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>O1CCOCC1>[F:16][CH:15]([F:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[N:3][C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH3:28])=[C:23]([CH2:25][CH2:26][OH:27])[CH:24]=3)=[N:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: Cc1ccc(N)cc1CCO
Reactant: FC(F)Oc1ccc(-c2cnc(Cl)nc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1CCO
Temperature: 25 °C

Procedure:
A solution of 2-chloro-5-(4-difluoromethoxy-phenyl)-pyrimidine 30 (1.3 mmol), 2-(5-Amino-2-methyl-phenyl)-ethanol 50 (1.3 mmol) and p-TSA (0.24 g, 1.3 mmol) in dioxane (10 mL) is heated at 100° C. for 12 h then cooled to rt. The reaction mixture is slowly added to water (100 mL) with stirring. The resulting precipitate is collected by filtration, washed with water and air dried. The crude precipitate is purified by column chromatography on silica with hexanes:EtOAc=1:1 as eluant to yield 2-{5-[5-(4-difluoromethoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-phenyl}-ethanol 51a as solid. MS (m/z) (M+1)+: 372.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[H-].[Na+].[Br:12][C:13]1[N:17]2[N:18]=[C:19](Cl)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.[Cl-].[NH4+]>CN(C)C=O>[Br:12][C:13]1[N:17]2[N:18]=[C:19]([O:6][CH2:5][C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: OCc1cccc(F)c1
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Fc1cccc(COc2ccc3ncc(Br)n3n2)c1
Reaction time: 0.17 h
Yield: 86.6 %

Procedure:
To a solution of 3-fluorobenzyl alcohol (0.59 g) in N,N-dimethylformamide (20 ml), sodium hydride (55% oil, 0.26 g) was added under ice cooling, and the mixture was stirred at the same temperature as above for 10 minutes. 3-Bromo-6-chloroimidazo[1,2-b]pyridazine (1 g) was added to the reaction solution, and the mixture was stirred at the same temperature as above for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was washed with n-hexane to obtain the title compound (1.2 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3]1.[S:13]([NH2:17])([NH2:16])(=[O:15])=[O:14].[BH4-].[Na+]>C(O)C.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:16][S:13]([NH2:17])(=[O:15])=[O:14])=[CH:3]1
Reactant: Cn1cc(C=O)c2ccccc21
Reactant: NS(N)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1cc(CNS(N)(=O)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Methylindole-3-carboxaldehyde (1.66 g, 10.4 mmol) was dissolved in anhydrous ethanol (50 mL). Sulfamide (4.5 g, 47 mmol) was added and the mixture was heated to reflux for 16 hours. Additional sulfamide (1.0 g, 10.4 mmol) was added and the mixture was heated to reflux for 24 hours. The mixture was cooled to room temperature. Sodium borohydride (0.722 g, 12.5 mmol) was added and the mixture was stirred at room temperature for one hour. The reaction was diluted with water (50 mL) and extracted with DCM (3×75 mL). The extracts were concentrated and about 1 mL of methanol was added to create a slurry which was filtered to yield the title compound as a white powder.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][C:15]3([CH3:20])[CH3:19])[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33].C(O)C>Cl.O>[CH3:33][O:32][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:23]=1[NH:22][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][C:15]3([CH3:20])[CH3:19])[C:6]=2[N:21]=1)[C:27]([OH:29])=[O:28]
Reactant: CN1C(=O)CCN(C2CCCC2(C)C)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1(C)C)CCC(=O)N2C
Yield: 66 %

Procedure:
A mixture of 0.09 g (0.0003 mole) of (rac)-2-chloro-5-methyl-9-(2,2-dimethyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-59), 0.06 g (0.00036 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.087 g of (rac)-3-methoxy-4-[5-methyl-9-(2,2-dimethyl-cyclopentyl)-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-benzoic acid (I-59a) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]([O:4][C@@H:5]1[CH2:6][O:7][C:8](/[C:10]/1=[CH:11]/[CH2:12][C@H:13]1[C@:19]2([CH3:31])[CH2:20][CH2:21][C@H:22]3[O:27]C(C)(C)[O:25][CH2:24][C@@:23]3([CH3:30])[C@H:18]2[CH2:17][CH2:16][C:14]1=[CH2:15])=[O:9])=[O:3].C(O)(=O)C>ClCCl>[CH3:1][C:2]([O:4][CH:5]1[CH2:6][O:7][C:8](/[C:10]/1=[CH:11]\[CH2:12][CH:13]1[C:19]2([CH3:31])[CH2:20][CH2:21][CH:22]([OH:27])[C:23]([CH2:24][OH:25])([CH3:30])[CH:18]2[CH2:17][CH2:16][C:14]1=[CH2:15])=[O:9])=[O:3]
Reactant: C=C1CC[C@@H]2[C@]3(C)COC(C)(C)O[C@@H]3CC[C@@]2(C)[C@@H]1C/C=C1/C(=O)OC[C@H]1OC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: C=C1CCC2C(C)(CO)C(O)CCC2(C)C1C/C=C1\C(=O)OCC1OC(C)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
14-Acetyl-3,19-isopropylidene andrographolide (13 g) obtained in step 2 was treated with 75 ml of aq. acetic acid (aceticacid:water=7:3) and the contents stirred for 10 min at room temperature till a clear solution was obtained. The contents were diluted with dichloromethane (500 ml) and washed with water (3×300 ml) followed by aq sodium bicarbonate (2×300 ml). The organic layer was separated, dried over Na2SO4 and concentrated to get crude 14-acetyl andrographolide as a pale yellow coloured solid which was purified by crystallising in ethyl acetate/light petrol (11.2 g). m.p.169° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][CH2:48][CH2:49][CH2:50][NH2:51]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:51][CH2:50][CH2:49][CH2:48][F:47])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: NCCCF
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCCCF)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with 3-fluoro-propylamine (Astatech) to give the title compound. HR-MS (ES, m/z) calculated for C39H49Cl2FN5O3 [(M+H)+] 724.3191, observed 724.3190.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7](N)=[CH:6][C:5]=1[O:11][CH3:12].S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:23].[K+].II>O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([I:23])=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: [I-]
Agent: II
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(I)cc1OC
Reaction time: 1 h
Yield: 55.7 %

Procedure:
4-Amino-2-methoxybenzoic acid methyl ester (3.0 g, 16.6 mmol) was suspended in water (40 mL) and concentrated sulfuric acid (10 mL) was added. The suspension was cooled in an ice/salt water bath, and an aqueous solution (10 mL) of sodium nitrite (1.26 g, 18.3 mmol) was added dropwise so that the temperature remained close to 0° C. After the addition, a homogeneous, yellow-green solution was obtained. An aqueous solution (60 mL) of potassium iodide (3.02 g, 18.2 mmol) and iodine (2.31 g, 9.1 mmol) was then added dropwise, and the reaction stirred for an additional 1 hour. The reaction mixture was then extracted with ethyl acetate, the organic extracts were combined and washed with 1 N sodium thiosulfate, 1 N sodium hydroxide and brine. After drying over anhydrous sodium sulfate the solution was filtered and concentrated in vacuo to give 2.7 g of the title product as an orange oil which was used in the next step.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.C(=O)=O.CC(C)=O.[Li]CCCC.[B:23](OC)([O:26]C)[O:24]C>C1COCC1>[S:1]1[C:5]([B:23]([OH:26])[OH:24])=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1
Reactant: c1csc(-c2cccs2)c1
Reactant: COB(OC)OC
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: OB(O)c1ccc(-c2cccs2)s1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
In a flame-dried, 3-neck, 250 mL rbf, 2,2′-bithiophene (5.0 g, 30.1 mmol) was dissolved in anhydrous THF (100 mL) and cooled to −78° C. (dry ice/acetone). A solution of n-BuLi in hexanes (2.5 M, 12.6 mL, 31.6 mmol) was added slowly over a period of ˜5 minutes. The reaction mixture was allowed to stir at −78° C. for 15 minutes, and then trimethyl borate (10.1 mL, 90 mmol) was added dropwise over a period of 5 minutes. The reaction was allowed to stir at −78° C. for 2 hours, then warm to RT and stir for a further 1 hour. The yellow reaction mixture was quenched by pouring it into a 10% HCl solution (250 mL). The mixture was extracted with ether (2×100 mL) and the combined organic portions were washed with water (500 mL), dried over MgSO4, filtered and solvent removed by rotary evaporation. The resulting yellow solid was washed with water, filtered and air dried to afford (109) (6.15 g, 97%). The material was used in the next step without further purification.