Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][CH2:40][N:41]1[CH:45]=[CH:44][N:43]=[CH:42]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:39][CH2:40][N:41]4[CH:45]=[CH:44][N:43]=[CH:42]4)=[CH:27][CH:28]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: BrCCn1ccnc1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCn3ccnc3)cc2)c2ccccc21
Temperature: 80 °C
Yield: 75.6 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.065 g, 0.15 mmol) was dissolved in DMF at room temperature and K2CO3 (0.12 g, 0.87 mmol) was added. 1-(2-Bromo-ethyl)-1H-imidazole (0.08 g, 0.45 mmol) was added and the reaction was allowed to heat to 80° C. overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (10% methanol/90% dichloromethane) to afford the product (0.06 g, 76%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([N+:22]([O-])=O)=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[Cl:21])[C:8]([F:12])=[C:9]([F:11])[CH:10]=1)[CH:2]=[CH2:3].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C.O>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[Cl:21])[C:6]=1[NH2:22])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(F)c(F)c(Nc2ccc(I)cc2Cl)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCOc1cc(F)c(F)c(Nc2ccc(I)cc2Cl)c1N
Temperature: 70 °C
Yield: 72.5 %

Procedure:
A suspension of (3-allyloxy-5,6-difluoro-2-nitro-phenyl)-(2-chloro-4-iodo-phenyl)-amine (Intermediate 10, 0.823 g, 1.8 mmol) in ethanol (12 mL) was stirred at 70° C. to obtain a clear solution. To this hot solution, was added a freshly prepared solution of Na2S2O4 (0.920 g, 5.3 mmol) in water (2.4 mL) and stirred the reaction mixture at 90° C. for 1 h. The progress of reaction was monitored by TLC. After completion, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, and the organic phase was dried over anhydrous Na2SO4 and concentrated to yield 6-allyloxy-N2-(2-chloro-4-iodo-phenyl)-3,4-difluoro-benzene-1,2-diamine as an off-white solid (570 mg). 1H-NMR (400 MHz, CDCl3): δ 3.86 (2H, bs), 4.54 (2H, d, J=5.2), 5.34 (1H, d, J=10.8), 5.42 (1H, d, J=17.2), 5.66 (1H, bs), 6.02-6.09 (1H, m), 6.20 (1H, d, J=8.4), 6.62-6.66 (1H, m), 7.33 (1H, dd, J=2, 8.4), 7.63 (1H, d, J=2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH:14]2[CH2:18][NH:17][CH:16]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH2:23][CH2:22]3)=[O:20])[CH2:15]2)[N:13]=1.[CH:35]1([CH:41]=O)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH:35]1([CH2:41][N:17]2[CH2:18][C@@H:14]([N:12]3[N:11]=[N:10][C:9]([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])=[N:13]3)[CH2:15][C@H:16]2[C:19]([N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=3[C:29]#[N:30])[CH2:25][CH2:26]2)=[O:20])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(n3nnc(-c4ccc(F)cc4F)n3)CN2)CC1
Reactant: O=CC1CCCCC1
Product: N#Cc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](n3nnc(-c4ccc(F)cc4F)n3)CN2CC2CCCCC2)CC1
Yield: 11.7 %

Procedure:
As described for Example 1e, 2-(4-{4-[5-(2,4-difluoro-phenyl)-tetrazol-2-yl]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile (60 mg, 0.13 mmol) was converted, using cyclohexanecarbaldehyde (16 mg, 0.14 mmol) instead of benzaldehyde, to the title compound (8.5 mg, 11.7%) as light yellow oil. MS m/e=561.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][N:11]=2)[C:5]([C:20]#[N:21])=[C:4]([SH:22])[N:3]=1.Cl[CH2:24][C:25]1[N:26]=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[S:28][CH:29]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][N:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:24][C:25]2[N:26]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[S:28][CH:29]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(OCCO)cn1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
23 mg of the crude product from example 29A are dissolved in 0.7 ml of dry DMF, and 11 mg (0.04 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 12 mg (0.14 mmol) of sodium bicarbonate are added. The reaction mixture is stirred at RT for 8 h. The mixture is then poured into 2 ml of saturated aqueous sodium bicarbonate solution, and the aqueous phase is extracted three times with in each case 4 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate, and the solvent is removed on a rotary evaporator. The residue is purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [O:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]2)=[C:18]([CH:21]=1)[C:19]#[N:20]>>[C:19]([C:18]1[CH:21]=[C:14]([NH:13][C:6]([C:5]2[O:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[O:8])[CH:15]=[CH:16][C:17]=1[N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]1)#[N:20]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: N#Cc1cc(N)ccc1N1CCC(CCO)CC1
Product: N#Cc1cc(NC(=O)c2cc3ccccc3o2)ccc1N1CCC(CCO)CC1
Yield: 10.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 7 using benzo[b]furan-2-carboxylic acid (2 g) and 5-amino-2-[4-(2-hydroxyethyl)piperidin-1-yl]benzonitrile (3 g), the title compound (0.5 g) was obtained. melting point: 214° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH:16][C:17]1[C:26]([C:27]([O:29]C)=[O:28])=[C:25]2[C:20]([CH:21]3[CH2:31][CH:22]3[CH2:23][O:24]2)=[CH:19][CH:18]=1)(=[O:15])=[O:14])[CH3:2].O.[OH-].[Li+].O>O1CCOCC1>[CH2:32]([N:3]([CH2:1][CH3:2])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH:16][C:17]1[C:26]([C:27]([OH:29])=[O:28])=[C:25]2[C:20]([CH:21]3[CH2:31][CH:22]3[CH2:23][O:24]2)=[CH:19][CH:18]=1)(=[O:15])=[O:14])[CH3:33]
Reactant: CCN(CC)C/C=C\c1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)C/C=C\c1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Temperature: 80 °C
Yield: 30.6 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 153, 0.495 g) and lithium hydroxide monohydrate (0.442 g) was suspended in dioxane (20 mL) and water (5 mL) and the mixture was stirred and heated at 80° C. for 12.5 hours. After cooling, the volatiles were removed in vacuo and the residue was acidified by addition of aqueous citric acid solution (10%) and extracted with DCM. The organic layer was dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by preparative HPLC (C18) eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 35-70% to give (1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.147 g) as a white solid.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)O.[NH2:20][C:21]1[N:26]([CH2:27][CH3:28])[C:25](=[O:29])[CH:24]=[C:23]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Br:36])[CH:31]=2)[CH:22]=1.[CH3:37][C:38](=O)[CH2:39][C:40](=O)[CH2:41][CH3:42].[OH-].[Na+]>>[Br:36][C:32]1[CH:31]=[C:30]([C:23]2[C:22]3[C:21](=[N:20][C:40]([CH2:41][CH3:42])=[CH:39][C:38]=3[CH3:37])[N:26]([CH2:27][CH3:28])[C:25](=[O:29])[CH:24]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: CCn1c(N)cc(-c2cccc(Br)c2)cc1=O
Reactant: CCC(=O)CC(C)=O
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Product: CCc1cc(C)c2c(-c3cccc(Br)c3)cc(=O)n(CC)c2n1
Temperature: 140 °C
Yield: 73 %

Procedure:
A mixture of diphosphorus pentoxide (10.4 g) and phosphoric acid (5 ml) was stirred at 140° C. until it became transparent. Then, 6-amino-4-(3-bromophenyl)-1-ethyl-2(1H) -pyridone (2.5 g, 8.5 mmol) and 2,4-hexanedione (1.1 ml) were added to this solution, and the mixture was stirred at 140° C. for 3 hours. The reaction solution was poured into ice water, made alkaline by adding 1N sodium hydroxide aqueous solution and then extracted with ethyl acetate. After drying the organic layer with anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography (benzene-ethyl acetate) to give 4-(3-bromophenyl)-1,7-diethyl-5-methyl-1,8-naphthyridin-2(1H)-one (2.3 g, 73%).
Reaction SMILES: O[CH:2]([N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[CH3:3].[C:10]([O:16]CC)(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13].[Na]>>[C:10]([O:16][CH2:3][CH2:2][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(O)N1CCCC1=O
Agent: [Na]
Product: CC(=O)CC(=O)OCCN1CCCC1=O
Yield: 4 %

Procedure:
A mixture of 20 g (0.16 mol) of 1-hydroxyethyl-2-oxo-pyrrolidine, 40 g (0.31 mole) of ethyl acetoacetate and 100 mg of sodium was heated at 140°-150° C. for six hours. Residual ethanol was removed in vacuo and the resultant oil was kugelrohr distilled (200° C./1 mm) to give 1.38 g (40%) of the product. NMR (CDCl3) δ 2.1 (7H, m), 3.4 (6H, m) 4.1 (2H, t)
Reaction SMILES: C(OC(=O)C[N:8]1[C:12]([C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)=[C:11]([C:20]2[CH:33]=[CH:32][C:23]3[N:24]([CH2:30][CH3:31])[C:25](=[O:29])[N:26]([CH2:27][CH3:28])[C:22]=3[CH:21]=2)[CH:10]=[N:9]1)(C)(C)C.Br[CH2:36][C:37](OC(C)(C)C)=[O:38].O.I([O-])(=O)(=O)=O.[Na+]>C(O)(C)(C)C.C(OC(=O)C)C.C(=O)(O)[O-].[Na+].[Os](=O)(=O)(=O)=O>[CH2:30]([N:24]1[C:23]2[CH:32]=[CH:33][C:20]([C:11]3[C:12]([C:13]4[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=4)=[N:8][N:9]([CH2:36][CH:37]=[O:38])[CH:10]=3)=[CH:21][C:22]=2[N:26]([CH2:27][CH3:28])[C:25]1=[O:29])[CH3:31]
Reactant: CCn1c(=O)n(CC)c2cc(-c3cnn(CC(=O)OC(C)(C)C)c3-c3cccc(C)c3)ccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CCn1c(=O)n(CC)c2cc(-c3cn(CC=O)nc3-c3cccc(C)c3)ccc21
Temperature: 23 °C
Reaction time: 2 h

Procedure:
5-(1-Allyl-3-m-tolyl-1H-pyrazol-4-yl)-1,3-diethyl-1,3-dihydro-benzoimidazol-2-one (obtained in the using the same procedure as utilized for the preparation of [4-(1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-5-m-tolyl-pyrazol-1-yl]-acetic acid tert-butyl ester (0.135 g), substituting allyl iodide for t-butyl bromoacetate) (0.107 g) was diluted with t-butanol (3 mL). To this solution was added water (3 mL), sodium periodate (0.120 g) and catalytic osmium tetroxide (0.1 mL, 2.5% solution in t-butanol). The mixture was stirred at 23° C. for 2 hours then was diluted with ethylacetate and saturated sodium bicarbonate and extracted. The organic layer was dried over sodium sulfate and concentrated. Subsequent chromatography on silica gel gave [4-(1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-3-m-tolyl-pyrazol-1-yl]-acetaldehyde (0.06 g).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.Cl.[NH2:19][OH:20]>O>[O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[N:19][OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1Oc1ccccc1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CO
Product: ON=Cc1ccccc1Oc1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 61.7 %

Procedure:
To 2-phenoxybenzaldehyde (4.96 g, 0,025 mole) were added anhydrous methanol (50 ml) and hydroxylamine hydrochloride (2.08 g, 0.03 mole), and the mixture was stirred at 60° C. for 3 hours. After completion of the reaction, water (200 ml) was added to the reaction mixture, which was extracted with methylene chloride and dried over magnesium sulfate. The crude product obtained by concentration under reduced pressure was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain 2-phenoxybenzaldoxime (3.95 g, yield: 74.1%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:15]([N:16]=[C:17]=[S:18])=[C:14]([Cl:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[NH2:20][C:21]1[C:22]([NH2:45])=[N:23][C:24]([O:40][CH2:41][CH:42]([F:44])[F:43])=[C:25]([CH:39]=1)[C:26]([NH:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([C:35]([F:38])([F:37])[F:36])[CH2:31][CH2:30]1)=[O:27]>CN(C=O)C.O>[Cl:1][C:2]1[C:15]([NH:16][C:17]([NH:20][C:21]2[CH:39]=[C:25]([C:26](=[O:27])[NH:28][C@H:29]3[CH2:30][CH2:31][C@H:32]([C:35]([F:38])([F:36])[F:37])[CH2:33][CH2:34]3)[C:24]([O:40][CH2:41][CH:42]([F:43])[F:44])=[N:23][C:22]=2[NH2:45])=[S:18])=[C:14]([Cl:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(OCC(F)F)nc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(NC(=S)Nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(OCC(F)F)nc2N)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(2,4-Dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (100 mg, 0.30 mmol) is added to 5,6-diamino-2-(2,2-difluoro-ethoxy)-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (120 mg, 0.30 mmol) in DMF (5 mL) and it is stirred at rt overnight. The reaction mixture is diluted with water, extracted with EtOAc, the organic layer is washed with water, dried and concentrated to give the sub-title compound.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[N+:12]([O-])([OH:14])=[O:13]>>[N+:12]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:3]=1[CH2:2][Br:1])[C:9]([OH:11])=[O:10])([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(CBr)cc1
Product: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 85 %

Procedure:
The bromoacid 3 (11.8 g) was added in portions over 0.5 hour to 100 ml of 90% HNO3 (white fumming) at -10° C. The suspension was stirred at -10° for an additional 2 hours when the solution became clear orange. This solution was poured onto crushed ice. The product was collected by filtration, washed with ice cold H2O (3 × 50 ml) until the washings were neutral. Drying in vacuo followed by crystallization twice from CH2Cl2 /hexane gave pure nitro acid 4 (11.02 g, 85%): m.p. 125-126, i.r. (Nujol) 2800-2300, 1690, 1610 (COOH), 1600 (Aromatic), 1540, 1300 cm-1 (NO2); nmr (CDCl3, DMSO-d6) 4.9 (S,2), 7.8 (d,1), 8.2 (dd,1), 8.6 (d,1) 10.8 (s,1); Rf(5) 0.55; Rf (1) 0.82; UVmax (CH3OH) 227 mμ (t = 2.13 104) 305 mμ (t 4.1 × 103).
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:12][O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[N:3]=1.C(OCC)(=[O:21])C>[OH-].[Na+]>[F:16][C:15]([F:18])([F:17])[CH2:14][O:13][CH2:12][C:4]1[NH:3][C:2](=[O:21])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=1
Reactant: CCOC(C)=O
Reactant: Nc1nc(COCC(F)(F)F)nc2nccnc12
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c(COCC(F)(F)F)nc2nccnc12

Procedure:
Obtained using the procedure described in section d of Example 2, starting with 5.0 g (0.0193 mole) of 4-amino-2-[(2,2,2-trifluoroethoxy)methyl]pteridine in 105 ml of 5% aqueous sodium hydroxide. Heating time: 1 hour 30 minutes at 80° C. Yld: 2.5 g (50%), m.p. 165°-167° C. (ethyl acetate).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][C@H:8]([N:12]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:7][C:6]=2[C:5]([O:27][CH3:28])=[CH:4][CH:3]=1.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:44])(=O)=O)=CC=1.[NH4+].[Cl-].NO.Cl.C([O-])([O-])=O.[Na+].[Na+].N>C1COCC1.O>[CH2:13]([N:12]([C@@H:8]1[CH2:7][C:6]2[C:5]([O:27][CH3:28])=[CH:4][CH:3]=[C:2]([F:44])[C:11]=2[O:10][CH2:9]1)[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(Br)c2c1C[C@@H](N(Cc1ccccc1)Cc1ccccc1)CO2
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: Cl
Agent: N
Agent: NO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)c2c1C[C@@H](N(Cc1ccccc1)Cc1ccccc1)CO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
(R)-8-Bromo-3-(N,N-dibenzylamino)-5-methoxy-3,4-dihydro-2H-1-benzopyran (4.35 g, 9.9 mmol) was dissolved in 45 mL of anhydrous THF and cooled to -78° C. To this was a 1.6M n-BuLi solution (6.8 mL, 10.9 mmol) added dropwise and the mixture was allowed to stir at -78° C. for 1 h. N-Fluorobenzenesulfonimide (3.8 g, 11.9 mmol), dissolved in 30 mL anhydrous THF, was added dropwise over 45 min and allowed to stir at -78° C. for 1 h. The reaction was stopped by adding 3 mL saturated NH4Cl followed by 9 mL of a solution comprised of 2 g of NH2OH×HCl and 8 g of Na2CO3 in 100 mL of H2O and allowing the reaction to warm to room temperature. A 2M NH3 solution was added and the reaction was extracted twice with ether, treated with brine, dried (Na2SO4), filtered, and evaporated in vacuo to give the crude product. Purification of the 8-fluoro (desired) from the 8-hydrogen (15 %) compound was carried out by a crude chromatography (eluent: 25% CH2Cl2 /hexane) to give 1.78 g. The crude product was rechromatographed on silica (eluent: 3% acetone/hexane) to give 1.50 g (40% yield) of the title compound as a clear oil. [α]21D =-112.1° (C=0.1, CHCl3). GC-MS (70 eV) M=377 (37%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])[C:12]3[CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](OC)=[O:30])[CH:21]=[CH:22][C:11]=3[N:10]=2)=[CH:5][CH:4]=1)#[N:2].[CH3:33][O:34][CH2:35][CH2:36][CH2:37][NH2:38]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])[C:12]3[CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:38][CH2:37][CH2:36][CH2:35][O:34][CH3:33])=[O:30])[CH:21]=[CH:22][C:11]=3[N:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COCCCN
Reactant: COCCCn1c(-c2ccc(C#N)cc2)nc2ccc(OCCCCCC(=O)OC)cc21
Product: COCCCNC(=O)CCCCCOc1ccc2nc(-c3ccc(C#N)cc3)n(CCCOC)c2c1

Procedure:
2-(4-Cyano-phenyl)-6-[(5-(methoxycarbonyl)pentyl)oxy]-1-(3-methoxypropyl)-benzimidazole is reacted with 3-methoxypropylamine according to general operating instructions 7. 2-(4-Cyano-phenyl)-1-(3-methoxy-propyl)-6-[(5-((3-methoxy-propyl)aminocarbonyl)-pentyl)oxy]-benzimidazole is obtained as a yellow solid.
Reaction SMILES: [C:1]1(C2(C(O)=O)CCCC2)[CH:6]=CC=C[CH:2]=1.[CH3:15][CH:16]([CH3:46])[CH:17]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:18]([NH:20][C@@H:21]1[C@H:28]2[C@H:24]([CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH2:27]2)[CH2:23][CH2:22]1)=[O:19].C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[C:40]1([CH:17]([C:16]2[CH:46]=[CH:6][CH:1]=[CH:2][CH:15]=2)[C:18]([NH:20][C@@H:21]2[C@H:28]3[C@H:24]([CH2:25][N:26]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=4)[CH2:27]3)[CH2:23][CH2:22]2)=[O:19])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: O=C(N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)C(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared by substituting 2,2-diphenylacetic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4S*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 1: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.50 (s, 1H), 7.71 (d, J=7.5, 2H), 7.63 (d, J=7.2, 2H), 7.45 (d, J=7.4, 2H), 7.39-7.28 (m, 5H), 7.25 (dd, J=5.8, 8.9, 3H), 4.51-4.42 (m, 1H), 3.44 (d, J=13.3, 1H), 3.25 (d, J=13.3, 1H), 2.85 (qd, J=3.2, 7.9, 1H), 2.59 (dd, J=3.4, 9.5, 1H), 2.47-2.37 (m, 1H), 2.26 (t, J=8.3, 1H), 2.21-2.13 (m, 2H), 1.85-1.76 (m, 1H), 1.67-1.52 (m, 3H), 1.27-1.18 (m, 1H); MS (ESI+) m/z 479 (M+H)+.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[CH3:9][O:10][C:11]1[S:15][C:14]([C:16]([O:18]C)=[O:17])=[CH:13][C:12]=1[C:20]1[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=1.[OH-].[Na+]>O1CCCC1>[Cl:8][C:21]1[CH:22]=[N:23][N:24]([CH3:25])[C:20]=1[C:12]1[CH:13]=[C:14]([C:16]([OH:18])=[O:17])[S:15][C:11]=1[O:10][CH3:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc(-c2ccnn2C)c(OC)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Temperature: 70 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
NCS (382 mg, 2.80 mmol) was added in portions to a 50 mL sealed tube reactor containing methyl 5-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (642 mg, 2.54 mmol) [prepared according to the procedure of Example 185] in Tetrahydrofuran (THF) (12 mL) at room temperature. The mixture was heated to 70° C. for 1 hour. The reaction was cooled to room temperature, 6N NaOH (10 mL, 60.0 mmol) was added and the mixture stirred an additional 3 h at 70° C. The mixture was partitioned between CHCl3 and H2O and the aqueous layer was made acidic with 6N HCl. The organic layer was dried over Na2SO4 and concentrated affording the title compound (759 mg, 2.51 mmol, 98%) which was used without further purification: LC-MS (ES) m/z=273 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([SH:15])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[Cl:18][C:19]1[CH:24]=[C:23]([N+]([O-])=O)[CH:22]=[CH:21][N:20]=1>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:23]2[CH:22]=[CH:21][N:20]=[C:19]([Cl:18])[CH:24]=2)[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(S)c1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)Oc1cccc(Sc2ccnc(Cl)c2)c1
Yield: 64.4 %

Procedure:
Using the method of Example 3, Step A, 3-(tert-butyldimethylsilyloxy)benzenethiol (1.52 g, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to provide 4-(3-(tert-butyldimethylsilyloxy)phenylthio)-2-chloropyridine (1.43 g, 64% yield) as an oil. 1H NMR (CDCl3) δ 8.11 (d, 1H), 7.34 (t, 1H), 7.16 (d, 1H) 7.02 (s, 1H), 6.97 (d, 1H), 6.90 (s, 1H), 6.87 (d, 1H).