Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[S:3]([N:6]1[C:11]2([CH2:13][CH2:12]2)[CH2:10][N:9]([C:14]2[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4].CCN(C(C)C)C(C)C.[OH:38][CH2:39][CH2:40][C:41](O)=[O:42].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O>[OH:42][CH2:41][CH2:40][C:39]([N:26]1[CH2:27][CH2:28][CH:24]([CH2:23][N:2]([CH3:1])[S:3]([N:6]2[C:11]3([CH2:13][CH2:12]3)[CH2:10][N:9]([C:14]3[C:15]4[CH:22]=[CH:21][NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:8][CH2:7]2)(=[O:4])=[O:5])[CH2:25]1)=[O:38]
Reactant: O=C(O)CCO
Reactant: CN(CC1CCNC1)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC1CCN(C(=O)CCO)C1)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 40 °C
Reaction time: 1 h

Procedure:
N-methyl-N-(pyrrolidin-3-ylmethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8-diazaspiro[2.5]octane-8-sulfonamide (intermediate 25) (0.042 mmol) was dissolved in dry DMSO (0.5 mL), added DIPEA (0.25 mL), 3-hydroxypropanoic acid (0.050 mmol) and Pybrop (0.050 mmol) then stirred at 40° C. for 1 h. The pure compound was obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15](=[O:17])[CH3:16])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Br:18]Br.C([O-])(O)=O.[Na+]>C1C=CC=CC=1.Br.C(O)(=O)C>[Br:18][CH2:16][C:15]([C:5]1[CH:6]=[CH:7][C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:17]
Reactant: COc1cc(C(C)=O)ccc1-c1ccccn1
Reactant: BrBr
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COc1cc(C(=O)CBr)ccc1-c1ccccn1
Reaction time: 0.5 h

Procedure:
A solution of 1-(3-methoxy-4-pyridin-2-ylphenyl)ethanone (400 mg, 1.7 mmol) in benzene (6 mL) and 30% HBr/Acetic acid (6 mL) was cooled to 0° C. and was treated with a solution of bromine (0.086 mL, 1.67 mmol) in benzene (1 mL) over 1 h. The reaction was stirred for an additional 30 min, then poured into an iced solution of saturated aqueous NaHCO3 (100 mL), and the product was extracted into ethyl acetate (3×50 mL). The combined organic layers were dried (MgSO4) and concentrated to afford 2-bromo-1-(3-methoxy-4-pyridin-2-ylphenyl)ethanone.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25]C(=O)C)=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1>[CH2:31]([NH:38][C:2]1[O:3][C:4]2[C:24]([OH:25])=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7]([C:8]1[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=1)=[O:20])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCc1ccccc1
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Solvent: c1ccncc1
Product: COc1cc(C(=O)c2c(NCc3ccccc3)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran (140 mg, 0.29 mmol) was dissolved in dry pyridine (2 mL) and benzylamine (500 μL, excess) was added to it and the reaction mixture was stirred at 80° C. for 1 hour. Solvent was distilled and the crude product was purified over silica gel column to afford the title compound as light yellow solid (112 mg, 83%); 1H NMR (300 MHz, CDCl3) δ: 9.27 (b, 1H, NH), 7.39-7.32 (m, 5Hs, Ar Hs), 6.96 (s, 2H, benzoyl Hs), 6.61 (d, 1H, J=8.47 Hz), 6.50 (d, 1H, J=8.10 Hz), 4.83 (d, 2H, J=4.95 Hz, Benzyl Hs), 3.91 (s, 3H, OMe), 3.85 (s, 3H, OMe), 3.84 (s, 6H, 2×OMe).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]#[N:11])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:24][CH2:25][CH2:26][CH2:27][OH:28]>>[Br-:24].[C:10]([C:9]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:25][CH2:26][CH2:27][OH:28])([CH2:2][CH2:3]1)[CH2:8][CH2:7]2)#[N:11]
Reactant: OCCCBr
Reactant: N#CC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Product: N#CC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCO)(CC1)CC2
Product: [Br-]
Yield: 64.5 %

Procedure:
Following the general procedure outlined in Example 7, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)acetonitrile (0.0495 g, 0.164 mmol) and 3-bromo-1-propanol (0.030 mL, 0.343 mmol) in 2CH3CN/3CHCl3 (4.0 mL) were reacted to give the desired product (0.0467 g, 64.9%). EI-MS m/z 361 (M+) Rt (1.98 min).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19](=[O:41])[NH:20][CH2:21][C:22](=[O:40])[N:23]3[CH2:28][CH2:27][CH:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=4)[CH2:25][CH2:24]3)[N:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(N1CCC(N)CC1)(OC(C)(C)C)=O.[ClH:56]>O1CCOCC1>[ClH:56].[O:40]=[C:22]([N:23]1[CH2:24][CH2:25][CH:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=2)[CH2:27][CH2:28]1)[CH2:21][NH:20][C:19]([C:17]1[N:16]=[N:15][N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:18]=1)=[O:41]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)NCC(=O)N3CCC(Oc4cccc(C(F)(F)F)c4)CC3)nn2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cn(C2CCNCC2)nn1
Yield: 73.9 %

Procedure:
A mixture of 4-(4-{2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethylcarbamoyl}-[1,2,3]triazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (prepared by the method used for the synthesis of Example 136, starting from 1-Boc-4-aminopiperidine) (380 mg, 0.65 mmol) in dioxane.HCl (5 mL) was stirred at ambient temperature for 1 hr. The reaction mixture was concentrated under reduced pressure to get the crude solid which was purified by recrystallisation from a mixture of MeOH and diethyl ether to afford 252 mg (73.9% Yield) of 1-piperidin-4-yl-1H-[1,2,3]triazole-4-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide hydrochloride.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O.[NH:27]1[CH2:33][C:31](=[O:32])[NH:30][C:28]1=S.[NH:34]1CCCCC1>C(O)C.O>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[CH:10]([O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[C:33]1[NH:27][C:28](=[NH:34])[NH:30][C:31]1=[O:32]
Reactant: C1CCNCC1
Reactant: O=C1CNC(=S)N1
Reactant: CN1CCC(OC(c2cccc(C=O)c2)c2nc3ccccc3[nH]2)CC1
Solvent: CCO
Solvent: O
Product: CN1CCC(OC(c2cccc(C=C3NC(=N)NC3=O)c2)c2nc3ccccc3[nH]2)CC1
Temperature: 55 °C
Reaction time: 48 h

Procedure:
To a solution of 3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-benzaldehyde (example 505C, 200 mg) in a mixture of ethanol-water (8:2) (3 mL) is added thiohydantoin (70 mg) and piperidine (57 μL). The reaction mixture is heated at 55° C. for 5 h. Ethanol is removed under reduced pressure. Water is added and the reaction mixture is extracted by ethyl acetate. The organic phase is washed by water, then dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel (gradient dichloromethane/methanol from 95/5 to 90/10). The residue is dissolved in methanol (6 mL) and 30% solution of aqueous ammonia (1.1 mL) and tert-butylhydroperoxide (90 μL) are added. The reaction mixture is stirred at room temperature for two days. The reaction mixture is evaporated to dryness. The residue is purified by chromatography on silica gel (gradient dichloromethane/methanol/ammonia from 90/10/0.1 to 70/30/0.1) to give 5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzylidene}-2-iminoimidazolidin-4-one. MS, [M+H]+=431.1; [M+Na]+=453.1
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][CH2:14][C:15]1[S:16][C:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:34](=[O:36])[CH3:35])[CH2:30][CH2:29]3)=[CH:24][N:23]=2)=[CH:18][CH:19]=1)=[O:11])[NH:2]C(OC(C)(C)C)=O.O1CCOCC1.Cl.Cl>CC(O)C.C(O)C>[NH:1]([C:10]([O:12][CH2:13][CH2:14][C:15]1[S:16][C:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:34](=[O:36])[CH3:35])[CH2:32][CH2:33]3)=[CH:24][N:23]=2)=[CH:18][CH:19]=1)=[O:11])[NH2:2]
Reactant: CC(=O)N1CCN(c2ccc(CCc3ccc(CCOC(=O)NNC(=O)OC(C)(C)C)s3)nc2)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Solvent: CCO
Product: CC(=O)N1CCN(c2ccc(CCc3ccc(CCOC(=O)NN)s3)nc2)CC1
Yield: 86.1 %

Procedure:
By a method similar to Production Example 108, step 8, 2-(5-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}thiophen-2-yl)ethyl tert-butyl hydrazine-1,2-dicarboxylate (corresponding to 0.974 mmol) was treated with 4M hydrogen chloride dioxane solution. The obtained hydrochloride was dissolved in 2-propanol-ethanol (9:1) mixture, and filtered through aminopropylated silica gel. The aminopropylated silica gel was washed with 2-propanol-dichloromethane (1:9), the filtrate and the washing solution were combined and concentrated under reduced pressure to about 20 ml. Hexane (200 ml) was added, and the mixture was concentrated again under reduced pressure to about 40 ml. Hexane (200 ml) was added to the residue and the mixture was stirred. The resulting solid was collected by filtration, washed with hexane and dried under reduced pressure to give the title compound (350.1 mg, yield 86.1%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7]([NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])=[O:8].BrC1SC=CC=1.[C-:21]#[N:22].[Na+]>CN(C)C=O>[C:21]([C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7]([NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])=[O:8])#[N:22]
Reactant: CC(C)(C)NS(=O)(=O)c1sccc1Br
Reactant: [C-]#N
Agent: Brc1cccs1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)NS(=O)(=O)c1sccc1C#N
Temperature: 25 °C

Procedure:
A mixture of 197.7 g of 3-bromo-N-(1,1-dimethylethyl)thiophene-2-sulfonamide, 195.9 g of cuprous cyanide and 500 mL of dimethylformamide was heated to 150° for two one half hours at which time none of the bromothiophene remained as indicated by thin layer chromatography. The reaction was cooled to room temperature and poured into 1500 mL of 10% aqueous sodium cyanide. The aqueous mixture was extracted with five, 200 mL portions of ethyl ether and the combined extracts were washed with five, 150 mL portions of water followed by one, 200 mL aqueous sodium chloride wash. After drying over magnesium sulfate, filtration and evaporation of the solvent 140.8 g of the desired product was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1.[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1cccc(C(=C/C=C/C(=O)O)c2cccc(OC)c2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccc(OC)c2)c1
Reaction time: 1 h

Procedure:
As in Example 115, (E)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid (49.6) and 4-nitrophenol (25 g) in dichloromethane (600 mL) was treated with 1,3-dicyclohexylcarbodiimide (33 g). The mixture was stirred at 0°-5° C. for 1 hour, then at room temperature for 2 hours. After the usual work up, the crude product (67 g) was crystallized from 2-propanol-ether-hexane to give 61.0 g of (E)-5,5-bis (3-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester mp 95°-97° C. Recrystallization of a portion from dichloromethane-hexane yielded the analytical sample, mp 99°-100° C. Anal. Calculated for C25H21NO6 : C, 69.60; H, 4.91; N, 3.23 Found: C, 69.62; H, 5.04; N, 3.23.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([C:25](O)=[O:26])=[C:17]2[CH3:28])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:30][CH2:31][C:32]1[C:33](=[O:41])[NH:34][C:35]([CH3:40])=[CH:36][C:37]=1[O:38][CH3:39].CN(C=O)C.CCN(C(C)C)C(C)C.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F>O>[CH3:39][O:38][C:37]1[CH:36]=[C:35]([CH3:40])[NH:34][C:33](=[O:41])[C:32]=1[CH2:31][NH:30][C:25]([C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]([CH:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH2:12]2)[CH3:15])[C:17]=1[CH3:28])=[O:26]
Reactant: Cc1c(C(=O)O)c2ccccc2n1C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1cc(C)[nH]c(=O)c1CN
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc12
Temperature: 0 °C
Yield: 65.1 %

Procedure:
A 250 mL round bottom flask was charged with a magnetic stir bar, (R or S)-1-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)-2-methyl-1H-indole-3-carboxylic acid (1.950 g, 5.05 mmol), 3-(aminomethyl)-4-methoxy-6-methylpyridin-2(1H)-one hydrochloride (2.065 g, 10.09 mmol), DMF (25.2 ml, 5.05 mmol). Hunig's base (3.52 ml, 20.18 mmol). The reaction mixture was cooled to 0° C. and COMU (2.16 g, 5.05 mmol) was added. The reaction was allowed to stir overnight to room temperature. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extract was washed with brine, dried with MgSO4, filtered and conc. in vacuo to afford the crude material which was purified via silica gel chromatography (120 g) using MeOH/ethyl acetate (1:5) as eluent to afford the title compound (1.86 g, 3.29 mmol, 65.3% yield). LCMS 537 (M+1)+ 1H NMR (400 MHz, DMSO-d6) δ=11.83-11.71 (m, 1 H), 7.80 (br. s., 1 H), 7.73 (d, J=7.6 Hz, 1 H), 7.62 (d, J=7.8 Hz, 1 H), 7.06 (td, J=7.1, 14.4 Hz, 2 H), 6.21 (s, 1 H), 4.32 (br. s., 2 H), 4.16 (br. s., 1 H), 4.02 (br. s., 1 H), 3.85 (s, 3 H), 3.75 (br. s., 1 H), 2.70 (br. s., 1 H), 2.58 (s, 3 H), 2.37 (br. s., 1 H), 2.21 (s, 3 H), 1.90 (d, J=12.9 Hz, 1 H), 1.53 (d, J=6.9 Hz, 3 H), 1.35 (s, 10H), 1.21 (br. s., 1 H), 0.89 (d, J=8.7 Hz, 1 H), 0.67 (d, J=11.8 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH:24]4[CH:14]3[CH2:15][CH:16]3[N:21]([CH3:22])[C:20](=O)[CH2:19][O:18][CH:17]34)[N:10]([CH:25]([CH3:27])[CH3:26])[N:9]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].CO>O1CCCC1>[CH:25]([N:10]1[C:11]([CH:13]2[CH:24]3[CH:14]2[CH2:15][CH:16]2[N:21]([CH3:22])[CH2:20][CH2:19][O:18][CH:17]23)=[CH:12][C:8]([C:5]2[CH:4]=[C:3]([C:28]([F:30])([F:31])[F:29])[C:2]([NH2:1])=[N:7][CH:6]=2)=[N:9]1)([CH3:27])[CH3:26]
Reactant: CC(C)n1nc(-c2cnc(N)c(C(F)(F)F)c2)cc1C1C2CC3C(OCC(=O)N3C)C21
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)n1nc(-c2cnc(N)c(C(F)(F)F)c2)cc1C1C2CC3C(OCCN3C)C21
Temperature: 70 °C

Procedure:
To a stirred solution of (±)-6-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)-4-methylhexahydro-2H-cyclopropa[4,5]cyclopenta[1,2-b][1,4]oxazin-3(6bH)-one (0.040 g, 0.092 mmol) in tetrahydrofuran (5 mL) was added borane tetrahydrofuran complex (5 mL, 5 mmol). The reaction mixture was heated at 70° C. for 2 h under nitrogen. Methanol was added and the resulting solution was concentrated in vacuo. Purification by preparative HPLC afforded a 1.5:1 mixture of diastereomers (15 mg, 39%). LCMS (ESI): [MH]+=401.9 1H NMR (400 MHz, Methanol-d4) δ: 8.52 (d, J=3.6 Hz, 1 H), 8.32 (s, 1 H), 8.13 (s, 1 H), 6.31 (s, 0.6 H), 6.22 (s, 0.4 H), 4.85-4.82 (m, 1H), 4.06-4.02 (m, 1 H), 3.85-3.70 (m, 1.6 H), 3.50-3.45 (m, 0.4 H), 3.40-3.30 (m, 0.6 H), 3.20-3.17 (m, 0.4 H), 2.90-2.85 (m, 0.6 H), 2.79-2.65 (m, 3.4 H), 2.60 (s, 1 H), 2.37-2.36 (m, 1 H), 2.05-1.95 (m, 2 H), 1.90-1.80 (m, 1 H), 1.55-1.52 (m, 6 H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH:6]([O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([OH:22])=O)=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:11]=1)([CH3:8])[CH3:7].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([N:3]([CH2:4][CH3:5])[C:20]([C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[C:10]([O:9][CH:6]([CH3:7])[CH3:8])=[N:11][C:12]([NH:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1)=[CH:13]2)=[O:22])[CH3:2]
Reactant: CCNCC
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
Diethylamine (14 ul) and triethylamine (17 ul) in CH2Cl2 (5 ml) was added to 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid (33 mg), HOBt (18 mg), EDCI (25 mg) at 0° C. in order. The mixture was stirred at room temperature for 3 hrs and washed with 8% NaOH, water and brine, dried with anhydrous sodium sulfate and concentrated. The residue was purified by preparative LC-MS to give 31 mg of product as yellow solid. (80% yield). LC-MS: m/e 382 (MH+).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:24])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26]O>>[C:1]([NH:5][CH2:6][CH:7]([OH:24])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][CH:18]=[C:19]([C:21]([O:23][CH3:26])=[O:22])[N:20]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CO
Reactant: CC(C)(C)NCC(O)COc1ccc(-c2nc(C(=O)O)c[nH]2)cc1
Agent: Cl
Product: COC(=O)c1c[nH]c(-c2ccc(OCC(O)CNC(C)(C)C)cc2)n1
Reaction time: 2 h

Procedure:
A solution of crude 2-[4-(3-tert-butylamino-2-hydroxypropoxy)phenyl]-4-carboxyimidazole (30 g.) in methanol (600 ml.) is heated to reflux, and then heating is discontinued as hydrogen chloride is bubbled rapidly through the solution with stirring for a half hour, followed by two and a half hours at reflux. Bubbling of hydrogebn chloride is continued for another two hours followed by another hour at reflux and then the reaction mixture is stirred at room temperature overnight. The mixture is filtered and the filtrate is then concentrated to dryness under reduced pressure. The residue is dissolved in water (150 ml.) and the pH is adjusted to 8 with saturated sodium carbonate solution. The basic mixture is extracted with ethyl acetate and the extracts are dried, filtered, and concentrated under reduced pressure to yield a solid which is recrystallized from acetonitrile to yield the methyl 2-[4-(3-tert.butylamino-2-hydroxypropoxy)phenyl]-imidazole-4-carboxylate as a cream-colored solid, m.p. 168-172° C.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]#[N:14])[C:9]([C:15]#[N:16])=[CH:8][CH:7]=2)[CH2:2][CH3:3].[Br:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([C:24]2[O:25][C:26]([CH2:29]Cl)=[N:27][N:28]=2)[CH:23]=1>>[Br:17][C:18]1[CH:23]=[C:22]([C:24]2[O:25][C:26]([CH2:29][N:5]3[C:6]4[C:11](=[C:10]([C:13]#[N:14])[C:9]([C:15]#[N:16])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:1][CH2:2][CH3:3])=[N:27][N:28]=2)[CH:21]=[N:20][CH:19]=1
Reactant: CCCc1cc2c(C#N)c(C#N)ccc2[nH]1
Reactant: ClCc1nnc(-c2cncc(Br)c2)o1
Product: CCCc1cc2c(C#N)c(C#N)ccc2n1Cc1nnc(-c2cncc(Br)c2)o1

Procedure:
Synthesized as described in Example 4 from 2-propyl-1H-indole-4,5-dicarbonitrile and 3-bromo-5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyridine: 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J=1.7 Hz, 1 H), 8.95 (d, J=2.1 Hz, 1 H), 8.48 (s, 1 H), 8.16 (s, 1 H), 7.91 (d, J=8.7 Hz, 1 H), 7.57 (d, J=8.7 Hz, 1 H), 6.05 (s, 2 H), 3.07 (t, J=7.6 Hz, 2 H), 1.78-1.67 (m, 2 H), 0.96 (t, J=7.6 Hz, 3 H); MS (ES) m/z 448 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1.CC1(C)[O:33][CH2:32][CH:31]([CH2:34]O)[CH2:30][O:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N=C=NN=NN=C=NCC)C.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:34][CH:31]([CH2:32][OH:33])[CH2:30][OH:29])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1
Reactant: CC1(C)OCC(CO)CO1
Reactant: COc1cc2c(Oc3ccc(C)nc3-c3nccs3)ccnc2cc1O
Agent: CCN=C=NN=NN=C=NCC
Agent: O=S(=O)(O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(Oc3ccc(C)nc3-c3nccs3)ccnc2cc1OCC(CO)CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.9 %

Procedure:
Toluene (0.4 ml) was added to 6-methoxy-4-(6-methyl-2-thiazol-2-yl-pyridin-3-yloxy)-quinolin-7-ol (compound 329) (20 mg) and (2,2-dimethyl[1,3]dioxan-5-yl)-methanol (24 mg). Triphenylphosphine (43 mg) and a solution of diethylazocarbodiimide (29 mg) in toluene (0.2 ml) were added in that order to the mixture, and the mixture was stirred at room temperature for 4 hr. A 1 N aqueous sulfuric acid solution (1 ml) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, the mixture was washed with ethyl acetate, and the ethyl acetate layer was extracted with 1 N hydrochloric acid. Aqueous layers were combined, the combined aqueous layers were made alkaline by the addition of potassium carbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (4.7 mg, yield 19%).
Reaction SMILES: [CH:1]1([CH:7]=[CH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[C:25]([F:28])([F:27])[F:26])=[CH:14][C:13]=2[N+:29]([O-])=O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCO.CC(O)=O.[Fe]>[CH:1]1([CH:7]=[CH:8][C:9]2[NH:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:25]([F:28])([F:27])[F:26])=[CH:20][CH:21]=[CH:22][C:23]=4[F:24])=[CH:14][C:13]=3[N:29]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(C=CC1CCCCC1)Nc1ccc(-c2c(F)cccc2C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Fc1cccc(C(F)(F)F)c1-c1ccc2[nH]c(C=CC3CCCCC3)nc2c1
Temperature: 25 °C

Procedure:
To a solution of 3-cyclohexyl-N-(6′-fluoro-3-nitro-2′-trifluoromethyl-biphenyl-4-yl)-acrylamide (135 mg, 0.309 mmol, prepared as in STEP B above) in EtOH (4 mL) and HOAc (2 mL) was added Fe powder (86.3 mg, 1.54 mmol). The resulting mixture was heated at reflux overnight. The resulting mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated. The residue was dissolved in DCM with heating and sonication. The DCM layer was washed with 10 mL saturated aqueous NaHCO3, separated, dried over Na2SO4 and concentrated. The residue obtained was purified on silica (EtOAc/hexane, 0:100 to 100:0, v/v) to yield 2-(2-Cyclohexyl-vinyl)-5-(2-fluoro-6-trifluoromethyl-phenyl)-1H-benzimidazole.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5](Cl)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C=CC=CC=1>O>[C:5]([NH:4][CH2:3][CH2:1][OH:2])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCO
Solvent: O
Solvent: c1ccncc1
Product: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of ethanolamine, trityl chloride and pyridine was refluxed for 15 h. Water was added slowly to the cooled reaction and the precipitate collected by filtration. The crude product recrystallized from a 1:1 mixture of ethanol and water.