Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[CH:41]=[C:42]([CH2:46][C:47]([NH:49][CH3:50])=[O:48])[CH:43]=[CH:44][CH:45]=1>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>[OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:44]2[CH:45]=[CH:40][CH:41]=[C:42]([CH2:46][C:47]([NH:49][CH3:50])=[O:48])[CH:43]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CNC(=O)Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CNC(=O)Cc1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Yield: 23.5 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.47 g), 2-(3-bromophenyl)-N-methylacetamide (0.93 g) and tetrakis(triphenylphosphine)palladium(0) (0.21 g), the title compound (580 mg) was obtained as colorless powder crystals.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].O>CS(C)=O>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)c([N+](=O)[O-])c2)CC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 169 %

Procedure:
A solution of 4-fluoro-2-nitrobenzaldehyde (0.50 g, 3.0 mmol) in DMSO (5.0 mL) was added with 1-(tert-butoxycarbonyl)piperazine (1.7 g, 8.9 mmol), followed by stirring at 80° C. for 5 hours. The reaction mixture was added with water and the precipitated solid was collected by filtration to obtain 4-(4-formyl-3-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (1.7 g, 100%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:22][CH2:23][O:24][CH3:25])[C:12]=1[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:8]=[O:9].[OH-:26].[Na+]>CO.O.[N+]([O-])([O-])=O.[Ag+]>[CH3:25][O:24][CH2:23][O:22][C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:12]=1[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:8]([OH:26])=[O:9]
Reactant: COCOc1cc(C=O)cc(OCOC)c1C/C=C/c1ccccc1
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCOc1cc(C(=O)O)cc(OCOC)c1C/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution of 3,5-bis-methoxymethoxy-4-((E)-3-phenyl-allyl)-benzaldehyde (220f) (42 g, 0.12 mol) in MeOH/H2O (500 mL) was added AgNO3 (21 g, 0.12 mol), followed by NaOH (15 g, 0.36 mol) in one portion at room temperature. The mixture was stirred at room temperature overnight and then filtered. The filtrate was concentrated under vacuum to remove MeOH. The residue was extracted with Et2O (2×100 mL) to remove impurities. The aqueous layer was acidified with conc. HCl to pH 4. The resulting white solid was filtered and dried under vacuum to give the title compound (31 g, 62% yield) as white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1nc(Nc2cc(C)[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2-methoxy-phenylboronic acid to give [1-(2-methoxy-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 331(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH2:15])=[CH:5][C:4]=1[O:16][CH3:17].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](Cl)=[O:33])=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl.C(N(CC)CC)C>[CH3:17][O:16][C:4]1[CH:5]=[C:6]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:29]([C:27]([NH:26][C:23]3[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=3)=[O:28])[CH:30]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc([C@@H]2CCCC[C@@H]2N)cc1OC
Reactant: COc1ccc(NC(=O)c2cccc(C(=O)Cl)c2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2cccc(C(=O)N[C@@H]3CCCC[C@@H]3c3ccc(OC)c(OC)c3)c2)cc1
Reaction time: 8 h

Procedure:
4.0 g of (−)-cis-1,2-dimethoxy-4-(2-aminocyclohexyl)benzene (compound C2) are dissolved in 100 ml of methylene chloride and 5.0 ml of triethylamine. The solution is added dropwise at RT to 4.95 g of 3-(4-methoxyphenylcarbamoyl)benzoyl chloride in 50 ml of methylene chloride and the mixture is extracted with 100 ml each of water, 2N hydrochloric acid, satd. sodium hydrogencarbonate solution and water again after stirring overnight. The organic phase is dried using sodium sulfate and concentrated. The residue is taken up in petroleum ether (low)/ethyl acetate in the ratio 2/1, filtered off with suction and dried. 7.14 g of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)=[CH:14][CH:15]=2)(=[O:10])=[O:9])[O:4][N:3]=1.[Br:25]NC(=O)CCC(N)=O>>[Br:25][C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[NH:7][S:8]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[CH:14][CH:15]=1)(=[O:9])=[O:10]
Reactant: Cc1cc(NS(=O)(=O)c2ccc(-c3cccc([N+](=O)[O-])c3)s2)on1
Reactant: NC(=O)CCC(=O)NBr
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3cccc([N+](=O)[O-])c3)s2)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-nitrophenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 136C. Reaction of N-(3-methyl-5-isoxazolyl)-5-(3-nitrophenyl)thiophene-2-sulfonamide (328 g, 0.90 mmol) with N-bromosuccinamide (160 mg, 0.90 mmol) gave the final product. A fraction of this material was further purified by preparative HPLC to give the pure sulfonamide as a brown solid, m.p. 132° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:38]=[CH:37][C:27]2[N:28]([CH3:36])[C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:34])([CH3:33])[C:26]=2[CH:25]=1>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)=[N:7][C:2]([NH:23][C:24]2[CH:38]=[CH:37][C:27]3[N:28]([CH3:36])[C:29](=[O:35])[CH2:30][CH2:31][C:32]([CH3:34])([CH3:33])[C:26]=3[CH:25]=2)=[N:3][CH:4]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2Cl)c(-n2cccn2)c1
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Product: COc1ccc(Nc2nc(Nc3ccc4c(c3)C(C)(C)CCC(=O)N4C)ncc2Cl)c(-n2cccn2)c1

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(4-methoxy-2-pyrazol-1-yl-phenyl)-amine, of Example 611c, was reacted with 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one, in a similar manner as Example 601b, to yield desired product 7-[5-Chloro-4-(4-methoxy-2-pyrazol-1-yl-phenylamino)-pyrimidin-2-ylamino]-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a lyophylate (60%); 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 9.48 (s, 1H), 8.26 (s, 1H), 8.14 (s, 1H), 8.04 (d, J=9.26 Hz, 1H), 7.84 (s, 1H), 7.65 (d, J=8.20 Hz, 1H), 7.41 (s, 1H), 7.22 (s, 1H), 7.13 (d, J=8.65 Hz, 1H), 7.00 (m, 1H), 6.55 (s, 1H), 3.85 (s, 3H), 3.17 (s, 3H), 2.12 (m, 2H), 1.90 (m, 2H), 1.16 (s, 6H); MS (m/e)
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C@H:22]([CH2:23]O)[CH2:21][N:20]3[N:25]=[C:26]([CH2:28][O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:27]=[C:19]3[C:18]2=[O:36])=[CH:13][CH:12]=1>C(Cl)Cl>[F:7][CH2:23][C@@H:22]1[CH2:21][N:20]2[N:25]=[C:26]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]=[C:19]2[C:18](=[O:36])[N:17]1[C:14]1[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=1
Reactant: O=C1c2cc(COc3ccccc3)nn2C[C@@H](CO)N1c1ccc(F)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=C1c2cc(COc3ccccc3)nn2C[C@@H](CF)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.3 %

Procedure:
DAST (0.067 mL, 0.55 mmol) was added to a solution of (S)-5-(4-fluoro-phenyl)-6-hydroxymethyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (135 mg, 0.37 mmol) in DCM (2 mL) at −10° C. The mixture was stirred at room temperature for 15 minutes. Then quenched with a 1N solution of HCl and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was purified by flash column chromatography (silica; AcOEt in heptane 20/80 to 80/20). Desired fractions were collected and the solvents evaporated in vacuo. The residue was triturated with DIPE to yield (S)-6-fluoromethyl-5-(4-fluoro-phenyl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (81 mg, 60% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.32-4.37 (m, 1H), 4.37-4.42 (m, 0.5H), 4.42-4.52 (m, 1H), 4.59 (dd, J=9.4, 4.5 Hz, 0.5H), 4.66-4.77 (m, 2H), 5.13 (s, 2H), 6.95-7.03 (m, 3H), 7.03 (s, 1H), 7.13-7.20 (m, 2H), 7.27-7.35 (m, 4H).
Reaction SMILES: CO.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:12]([N+:23]([O-])=O)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1>[C].[Pd].C(OCC)(=O)C>[NH2:23][C:12]1[CH:11]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=2)[CH:22]=[CH:21][C:13]=1[C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.33 g of 10% palladium-carbon was added to a mixed solution of 11 mL of methanol and 11 mL of ethyl acetate containing 1.1 g of tert-butyl 4-(3-chlorophenyl)-2-nitrobenzoate and stirred under hydrogen atmosphere at room temperature for 3 hours. After insoluble were removed by filtration, the solvent was evaporated under reduced pressure. 11 mL of acetic acid, 11 mL of methanol and 0.33 g of 10% palladium-carbon were added to the obtained residue sequentially and stirred under hydrogen atmosphere at room temperature for 2 hours. After insoluble were removed by filtration, the solvent was evaporated under reduced pressure to obtain 0.70 g of tert-butyl 2-amino-4-(3-chlorophenyl)benzoate as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2=[CH:15][N:16]([CH3:18])C)=[O:4].NC1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2=[CH:15][NH:16][C:18]1[CH:25]=[CH:24][C:23]([S:26](=[O:28])(=[O:27])[NH2:29])=[CH:22][CH:21]=1)=[O:4]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: COC(=O)c1ccc2c(c1)C(=CN(C)C)C(=O)N2
Product: COC(=O)c1ccc2c(c1)C(=CNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Yield: 41 %

Procedure:
A solution of 2.66 g (20.0 mmol) of ethyl (methylthio)acetate dissolved in 200 mL of dichioromethane was cooled with stirring to −70° C. and 2.7 g (20.0 mmol) of sulfuryl chloride was added. The reaction was stirred for 30 min. at −70° C., and a solution of 3.0 g (20 mol) of methyl 4-aminobenzoate and 4.3 g (20 mmol) of Proton Sponge® in 250 mL of dichloromethane was added dropwise over 1 h. The resulting pink slurry was treated with 2.3 9 (23 mmol) of TEA in one portion, and the solution was allowed to warm to rt. The solution was washed with three 250-mL portions of water, dried over MgSO4, and concentrated to give an oil. This was chromatographed on silica gel eluting with hexane:EtOAc (1:1) to yield 2.0 g (42% yield) of 3-methylthio-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester: 1H NMR (DMSO-d6): δ 1.97 (s, 3H), 3.35 (s, 3H), 4.67 (s, 1H), 6.97 (d, J=8.2 Hz, 1H), 7.84 (s, 1H), 7.91 (d, J=8.2 Hz, 1H), 10.97 (s, 1H), solution of 2.0 g (8.4 mmol) of 3-methylthio-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester in 20 mL of acetic acid was treated with 10 g of zinc powder. The reaction mixture was stirred for 2 h at rt, filtered through celite and concentrated to dryness. The residue was chromatographed on silica gel eluting with hexane:EtOAc (1:1) to yield 1.6 g (99% yield) of 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester as a pink solid: 1H NMR (DMSO-d6): δ 3.52 (s, 2H), 3.77 (s, 3H), 6.87 (d, J=8.2 Hz, 1H), 7.74 (s, J=1H), 7.80 (d, J=8.2 Hz, 1H), 10.72 (br s, 1H). Conversion to the 3-dimethylaminomethylene-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester (mixture of E and Z isomers) was carried out via Procedure G in 49% yield: 1H NMR (DMSO-d6): δ 3.29 Z (s, 6H), 3.31 E (s, 6H), 3.76 Z (s, 3H), 3.76 E (s, 3H), 6.74 Z (d, J=8.1 Hz, 1H), 6.81 E (d, J=8.2 Hz, 1H), 7.47-7.50 Z (m, 1H), 7.50-7.52 E (m, 1H), 7.57 E (dd, J=1.3, 8.2 Hz, 1H), 7.74 Z (s, 1H), 7.89 Z (s, 1H), 7.94 E (s, 1H), 10.33 Z (bs, 1H), 10.43 E (bs, 1H). The title compound was prepared in 41% yield from 3-[(dimethylamino)methylene]oxindole-5-carboxylic acid methyl ester and 4-aminobenzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ 3.81 (s, 3H), 6.92 (d, J=8.2 Hz, 1H), 7.26 (s, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.2 Hz, 1H), 7.75 (d, J=8.4 Hz, 2H), 8.29 (s, 1H), 8.86 (d, J=12.4 Hz, 1H), 10.80 (d, J=12.4 Hz, 1H), 10.94 (s, 1H); APCI−MS m/z 372 (M−1)−. Anal. Calcd for C17H15N3O5S: C, 54.68, H, 4.05; N, 11.25; S, 8.59. Found C, 54.65, H, 4.12; N, 11.17; S. 8.49.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:14]#[N:15])[CH2:13][CH:12]=[CH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].B.C1C[O:20]CC1>>[NH2:15][CH2:14][C:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:12][CH:11]([OH:20])[CH2:10]1
Reactant: N#CC1(c2ccc(Cl)c(Cl)c2)CC=CC1
Reactant: C1CCOC1
Agent: B
Product: NCC1(c2ccc(Cl)c(Cl)c2)CCC(O)C1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(3,4-dichlorophenyl)cyclopent-3-enecarbonitrile (119 mg, 0.500 mmol) and borane-THF (2 mL, 1M in THF, 2 eq) was heated at 65° C. for 2 hours. The reaction was cautiously quenched with ethanol (0.5 mL), sodium hydroxide (lmL, 5M aqueous) and stirred for two hours. It was then extracted with MTBE and evaporated. The residue was purified by HPLC to give cis 167 and trans 167.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[N:11]1[N:15]2[CH2:16][CH2:17][CH2:18][NH:19][C:14]2=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH:5]([N:19]1[CH2:18][CH2:17][CH2:16][N:15]2[N:11]=[CH:12][CH:13]=[C:14]12)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: c1cc2n(n1)CCCN2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=CO
Product: O=CN1CCCn2nccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To acetic anhydride (0.153 ml) was added formic acid (0.077 ml) at 15°-20° C. The mixture was stirred at ambient temperature for 30 minutes. To this solution was added 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (100 mg) under ice-cooling and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was added to a mixture of dichloromethane and aqueous sodium bicarbonate solution. The separated organic layer was dried over magnesium sulfate and evaporated in vacuo to give 4-formyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (79.9 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:12][C:13](=[O:24])[C@@H:14]([OH:23])[C@@H:15]([N:20]=[N+]=[N-])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[C].[Pd].CO>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:12][C:13](=[O:24])[C@@H:14]([OH:23])[C@@H:15]([NH2:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCCC[C@H](N=[N+]=[N-])[C@H](O)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCCC[C@H](N)[C@H](O)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Reaction time: 18 h
Yield: 94 %

Procedure:
To 30 ml of a methanol solution containing 442 mg (1.27 mmol) of (2S,3S)-N-[(2S)-1-methoxy-1-oxo-3-phenyl-2-propyl]-3-azido-2-hydroxyheptanamide was added 45 mg of 5% palladium carbon, and the mixture was stirred under hydrogen atmosphere for 18 hours. Insoluble materials were filtered off, and the filtrate was distilled under reduced pressure to obtain 385 mg (Yield: 94%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].Br[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[O:14]([CH2:13][CH2:12][O:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1sccc1O
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1sccc1OCCOc1ccccc1
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 93 %

Procedure:
To a solution of methyl 3-hydroxythiophene-2-carboxylate (0.992 g, 6.27 mmol) in N,N-dimethylformamide (12 ml) were added β-bromophenetole (1.268 g, 6.31 mmol) and potassium carbonate (1.059 g, 7.66 mmol), and the mixture was stirred at 80° C. for 4.5 hr. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give methyl 3-(2-phenoxyethoxy)thiophene-2-carboxylate (1.624 g, 5.83 mmol, yield 93%). This was dissolved in methanol (12 ml), 1N-aqueous sodium hydroxide solution (12 ml) was added at room temperature, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure and neutralized with 1N-aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give a carboxylic acid compound 3-(2-phenoxyethoxy)thiophene-2-carboxylic acid (1.491 g, 5.64 mmol, yield 97%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:16][CH3:17])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13](=[S:15])[NH2:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2].Cl[CH2:19][C:20](=O)[CH3:21]>C(O)C>[CH2:1]([C:3]1[C:4]([O:16][CH3:17])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]3[S:15][CH:19]=[C:20]([CH3:21])[N:14]=3)[N:12]=2)[C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1c(OC)nc2nc(C(N)=S)cn2c1C
Reactant: CC(=O)CCl
Solvent: CCO
Product: CCc1c(OC)nc2nc(-c3nc(C)cs3)cn2c1C
Reaction time: 5 h
Yield: 68.7 %

Procedure:
A mixture of 4.30 g (0.017 mol) of 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-thiocarboxamide and 3.18 g (0.0344 mol; 2 eq) of chloroacetone in 300 ml of ethanol was heated under reflux. After 5 hours, 3.18 g of more chloroacetone were added. After 29 hours, the solvent was evaporated, and the residue was dissolved in 2000 ml of water. The solution was made alkaline with concentrated ammonia and was extracted 3 times with chloroform. The chloroform extracts were dried over MgSO4, filtered and evaporated to dryness. The residue was purified by flash chromatography using chloroform as eluent and the resulting solid was recrystallized from ethyl acetate to obtain 3.37 g (68%) of 6-ethyl-7-methoxy-5-methyl-2-(4-methylthiazol-2-yl)-imidazo[1,2-a]pyrimidine as a buff powder melting at 184°-186° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]2)=[CH:5][C:4]=1[C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=2[N:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:52][NH:53][CH:54]1[CH2:58][CH2:57][N:56]([CH3:59])[CH2:55]1>>[CH3:52][N:53]([CH:54]1[CH2:58][CH2:57][N:56]([CH3:59])[CH2:55]1)[C:15]([CH:12]1[CH2:11][CH2:10][N:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([C:18]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=4[N:19]=3)[CH:5]=2)[CH2:14][CH2:13]1)=[O:17]
Reactant: CNC1CCN(C)C1
Reactant: Cc1ccc2[nH]c(-c3cc(N4CCC(C(=O)O)CC4)ccc3Cl)nc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1ccc2[nH]c(-c3cc(N4CCC(C(=O)N(C)C5CCN(C)C5)CC4)ccc3Cl)nc2c1
Temperature: 35 °C
Yield: 34.3 %

Procedure:
Method Q—Step a To a mixture of 1-[4-chloro-3-(5-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidine-4-carboxylic acid hydrochloride (obtained as described in general method 3,4, step e) (0.01 g, 0.25 mmol) in dcm (2 mL), HATU (0.10 g, 0.26 mmol), TEA (0.07 mL, 0.53 mmol) and methyl-(1-methyl-pyrrolidin-3-yl)-amine (0.03 g, 0.31 mmol) were added. The reaction mixture was heated at 35° C. overnight, cooled to room temperature, washed with ammonium chloride solution (2 mL), filtered through a phase separator and organic phase was filtered by SCX column (eluent: first dcm:MeOH/1:1 then NH3 in MeOH (2N)). This work up was done using the Zinsser Speedy (version 6.1.3). The crude was then purified by flash chromatography (eluent: gradient from EtOAc to EtOAc:NH3 in MeOH (2N)/10:1) to obtain 0.04 g of the title compound (37%). 1H-NMR (400 MHz, CD3OD): δ 1.76-1.93 (5H, m), 2.08-2.23 (2H, m), 2.36-2.48 (6H, m), 2.51-3.09 (9H, m), 3.83-3.86 (2H, m), 5.13-5.20 (1H, m), 7.09-7.13 (2H, m), 7.38-7.40 (3H, m), 7.51 (1H, bs); m/z 466 (M+H)+, retention time (method b)=2.30 (10 min run)
Reaction SMILES: [OH-].[K+].[CH2:3]([C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=1)[O:21][CH2:22][C:23]([O:25]C)=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CO>[CH2:3]([C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=1)[O:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCc1cccc(OCC(=O)O)c1
Reaction time: 2 h
Yield: 91.6 %

Procedure:
A 2-L round bottom flask equipped with a magnetic stirring bar and a reflux condenser was charged with potassium hydroxide (28 g, 0.5 mol) and methanol (1-L). To this vigorously stirred mixture, methyl (3-pentadecylphenoxy)acetate (93 g, 0.247 mol) was added and the resulting slurry was brought to a gentle reflux (2 hr). The ester was not completely soluble. The reaction was monitored by TLC. The hydrolysis was complete in 2 hr. The mixture was cooled and poured into crushed ice-water-hydrochloric acid mixture to precipitate the acid as white solid. The acid was dried and further purified by trituration from hot methanol to afford 82 g (92% yield) of the acid, mp 96° C.