Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:31])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([C:18]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[O:19])[CH:15]=[C:14]([C:27]([O:29]C)=[O:28])[CH:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH3:32]O>[OH-].[Na+].O>[CH3:32][C:13]1[C:14]([C:27]([OH:29])=[O:28])=[CH:15][C:16]([C:18]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[O:19])=[CH:17][C:12]=1[C:9]1[CH:8]=[CH:7][C:6]([S:3]([N:2]([CH3:31])[CH3:1])(=[O:4])=[O:5])=[CH:11][CH:10]=1
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2ccc(S(=O)(=O)N(C)C)cc2)c1
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCN(CCC)C(=O)c1cc(C(=O)O)c(C)c(-c2ccc(S(=O)(=O)N(C)C)cc2)c1
Temperature: 22.5 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 4′-[(dimethylamino)sulfonyl]-5-[(dipropylamino)carbonyl][1,1′-biphenyl]-3-carboxylate (XXXVIII, step 2, 555 mg, 1.24 mmol) in methanol (6 mL) and sodium hydroxide (2 mL of a 6.0 M mixture in water, 12 mmol) is stirred at 20-25 degrees C. for 4 hours. The reaction mixture is partitioned between ethyl acetate (40 mL) and water (40 mL). The aqueous phase is acidified to pH=4 with hydrochloric acid (1N), extracted with ether (3×100 mL), and the combined organic phases are concentrated under reduced pressure to give methyl 4′-[(dimethylamino)sulfonyl]-5-[(dipropylamino)carbonyl][1,1′-biphenyl]-3-carboxylic acid (IX-XXXIX), NMR (300 MHz, CDCl3) □ 8.37, 8.12, 7.89, 7.80, 3.51, 3.22, 2.76, 1.74, 1.59, 1.02 and 0.79.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([C:13]2[N:14]=[CH:15][S:16][CH:17]=2)[C:5]([O:11][CH3:12])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:25].[Na+].C1COCC1>CO.C(#N)C>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([C:13]2[N:14]=[CH:15][S:16][CH:17]=2)[C:5]([O:11][CH3:12])=[C:6]([CH:8]([NH2:25])[CH3:9])[CH:7]=1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1-c1cscn1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C(C)N)cc(Cl)c(C)c1-c1cscn1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-2-methoxy-4-methyl-3-(1,3-thiazol-4-yl)phenyl]ethanone (6.0 mg, 0.021 mmol), ammonium acetate (20 mg, 0.2 mmol) and 1.0 M sodium cyanoborohydride in THF (0.053 mL, 0.053 mmol) in methanol (0.05 mL)/acetonitrile (0.05 mL) was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the crude product, which was used in the next step directly. LCMS calculated for C13H13ClNOS (M−NH2)+: m/z=266.1. found: 266.0.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]1[O:8][C@@H:7]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[C:10]2[CH3:19])[C@H:6]([OH:20])[C@@H:5]1[OH:21].Cl[CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].CCN(C(C)C)C(C)C>CN(C=O)C>[C:25]([CH2:24][CH2:23][N:2]([CH3:1])[CH2:3][C@H:4]1[O:8][C@@H:7]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[C:10]2[CH3:19])[C@H:6]([OH:20])[C@@H:5]1[OH:21])([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CNC[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reactant: CCOC(=O)CCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Temperature: 60 °C

Procedure:
A mixture of 4a (500 mg, 1.69 mmol), ethyl 3-chloropropionate (270 mg, 1.97 mmol), DIEA (109 mg, 0.14 mL, 0.84 mmol), and DMF (5 mL) was heated at 60° C. for 2 days. Starting material remained but since the solution was getting darker, heating was stopped. The reaction mixture was concentrated to dryness. The product was purified by column chromatography (7:1:0.1 chloroform:methanol:NH4OH) to give a sticky solid: yield 210 mg (31%); MS m/z 395 (M+H)+; 1HNMR (DMSO-d6) δ 8.08 (s, 1H, H-2), 7.11 (bs, 2H, 6-NH2), 5.74 (d, 1H, H-1′, J1′,2′=5.6 Hz), 5.33 (bd, 1H, OH-2′), 5.16 (bd, 111, OH-3′), 5.12 (bdd, 1H, H-2′, J1′,2′=5.6 Hz, J2′,3′=5.5 Hz), 4.21 (bdd, 1H, H-3′, J2′,3′=5.5 Hz, J3′,4′=4.3 Hz), 4.01 (q, 2H, OCH2CH3), 3.91-4.00 (m, 1H, H-4′), 2.70-2.77 (m, 1H, 5′-CH2), 2.54-2.66 (m, 3H, 5′-CH2, CO—CH2), 2.53 (s, 3H, 8-CH3), 2.38 (t, 2H, N(CH3)—CH2), 2.16 (bs, 3H, N—CH3), 1.15 (t, 3H, OCH2CH3).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:4][CH2:3]1.[C:44](Cl)(Cl)=[O:45].[CH3:48][NH:49][CH3:50]>>[C:40]([C:34]1[N:33]=[CH:32][C:31]([C:11]2[N:10]([C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:44](=[O:45])[N:49]([CH3:50])[CH3:48])[CH2:7][CH2:6]3)=[O:9])[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=2)=[C:36]([O:37][CH2:38][CH3:39])[CH:35]=1)([CH3:42])([CH3:41])[CH3:43]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)CC1
Reactant: O=C(Cl)Cl
Reactant: CNC
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NC(=O)N(C)C)CC1

Procedure:
(4-Amino-piperidin-1-yl)-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-methanone (example 204) was reacted with phosgene (Fluka) and dimethylamine (Aldrich) to give the title product. LC-MS (ES+) 693 [(M+H)+].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[C:9](OC(=O)C)(=[O:11])C.O>C(O)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][CH:9]=[O:11]
Reactant: NCCc1cccs1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: O=CO
Product: O=CNCCc1cccs1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
##STR108## 2-(2-thienyl)ethylamine (15.0 g, 118 mmol) was dissolved in formic acid (120 ml) while cooling with an water bath. The solution was cooled to 0° C. Acetic acid anhydride (45 ml) was added dropwise. The reaction mixture was stirred at room temperature for 3 h. It was cooled to 0° C., and water (45 ml) was added dropwise. The mixture was stirred for 16 h, while it was warming up to room temperature. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (300 ml). The solution was washed with water (2×150 ml) and saturated sodium hydrogen carbonate solution (200 ml). It was dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (180 g), using ethyl acetate/heptane (2:1) as eluent to give 14.30 g of N-(2-(2-thienyl)ethyl)formamide.
Reaction SMILES: [O-:1]CC.[Mg+2].[O-]CC.[Mg].[CH3:9][C:10](=[O:15])[CH2:11][CH2:12][CH:13]=O.[N+:16]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22])([O-:18])=[O:17].Cl>C1(C)C=CC=CC=1.C(O)C>[N+:16]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([CH:11]([C:10](=[O:15])[CH3:9])[C:12](=[O:1])[CH3:13])=[O:22])([O-:18])=[O:17]
Reactant: CC[O-]
Reactant: CC(=O)CCC=O
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [Mg+2]
Agent: [Mg]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)C(C(C)=O)C(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Magnesium ethoxide was generated by refluxing ethanol (50 mL) with 1.2 g (50 mmol) Magnesium turnings for 3 days. The ethanol was removed under reduced 10 pressure, and 50 mL of toluene was added, followed by dropwise addition of 5 g (50 mmol) of 2,5-pentanedione. The reaction mixture was stirred at room temperature for two hours and then at 70° C. for one hour, and then cooled to −10° C. A solution of 9.27 g (50 mmol) of 2-nitrobenzoyl chloride in 20 mL of toluene was added dropwise, and the solution was stirred at ambient temperature for 18 hours. The reaction mixture was 15 poured into a mixture of ice and 1N HCl, and the resulting solution was extracted with ethyl acetate. The organic layert was washed with brine, dried (MgSO4) filtered and concentrated to dryness under reduced pressure to afford 12.23 g of 3-(2-nitro-benzoyl)-pentane-2,4-dione
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[N+:9]([C:12]1[CH:13]=[C:14]([C:22](Cl)=[O:23])[C:15]2[O:20][CH2:19][CH2:18][O:17][C:16]=2[CH:21]=1)([O-:11])=[O:10].O>C(C(C)=O)C>[CH3:8][N:5]1[CH2:6][CH2:7][N:2]([NH:1][C:22]([C:14]2[C:15]3[O:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=2)=[O:23])[CH2:3][CH2:4]1
Reactant: CN1CCN(N)CC1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc2c1OCCO2
Solvent: O
Solvent: CCC(C)=O
Product: CN1CCN(NC(=O)c2cc([N+](=O)[O-])cc3c2OCCO3)CC1
Temperature: 10 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
33 g of 1-amino-4-methylpiperazine were dissolved in 630 ml of methyl ethyl ketone. The mixture was cooled to 10° C. and 61 g of 7-nitro-1,4-benzodioxane-5-carbonyl chloride were introduced by portions. The mixture was stirred for two hours and then the solid was filtered off and washed with 150 ml of methyl ethyl ketone. The obtained product was purified by transformation into the base (M.P.: 212° C.) and recrystallized by treatment with hydrochloric ethanol. 45 g of N-(4-methyl-1-piperazinyl)-7-nitro-1,4-benzodioxane-5-carboxamide were obtained (M.P.: 210° C. with one mole of water). The structue was confirmed by nuclear magnetic resonance and infrared analyses.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:4][N:5]([S:14]([C:17]2[O:18][C:19]([CH2:22]O)=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(N(S(F)(F)[F:40])CC)C.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]1[C:3]([CH2:24][N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[CH:4][N:5]([S:14]([C:17]2[O:18][C:19]([CH2:22][F:40])=[CH:20][CH:21]=2)(=[O:15])=[O:16])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CN(Cc1cn(S(=O)(=O)c2ccc(CO)o2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(Cc1cn(S(=O)(=O)c2ccc(CF)o2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.1 %

Procedure:
To a solution of tert-butyl [(4-fluoro-5-(2-fluoropyridin-3-yl)-1-{[5-(hydroxymethyl)-2-furyl]sulfonyl}-1H-pyrrol-3-yl)methyl]methylcarbamate (223 mg) in dichloromethane (5 mL) was added diethylaminosulfur trifluoride (78.7 mg) under ice-cooling, and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:1) to give the title compound as a pale-yellow oil (yield 166 mg, 57%).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=2[C:29]([F:32])([F:31])[F:30])=[N:18][CH:19]=1.Cl.[CH3:34][C:35]([C:38]([O:40][CH3:41])=[O:39])([CH3:37])[NH2:36]>CCOC(C)=O.C(N(CC)CC)C>[C:25]([C:24]1[CH:27]=[CH:28][C:21]([O:20][C:17]2[N:18]=[CH:19][C:14]([NH:13][C:2]([NH:36][C:35]([CH3:37])([C:38]([O:40][CH3:41])=[O:39])[CH3:34])=[O:4])=[CH:15][CH:16]=2)=[C:22]([C:29]([F:32])([F:30])[F:31])[CH:23]=1)#[N:26]
Reactant: COC(=O)C(C)(C)N
Reactant: N#Cc1ccc(Oc2ccc(N)cn2)c(C(F)(F)F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)NC(=O)Nc1ccc(Oc2ccc(C#N)cc2C(F)(F)F)nc1
Reaction time: 1 h
Yield: 105.5 %

Procedure:
To a solution of triphosgene (32 mg, 0.11 mmol) in EtOAc (1 ml) at 0° C. was added dropwise a solution of 4-[(5-amino-2-pyridinyl)oxy]-3-(trifluoromethyl)benzonitrile (Intermediate 143, 69.8 mg) in triethylamine (60 μL)/EtOAc (4 mL) and then a suspension of methyl 2-methylalaninate hydrochloride (Intermediate 107, 46 mg) in triethylamine (120 μL)/EtOAc (4 mL). The resulting reaction mixture was stirred for 1 hour. An aqueous pH 3 buffer solution was added to the reaction mixture and the two phases were separated. The aqueous phase was extracted 3 times with EtOAc and the combined organic phases were dried over sodium sulphate and evaporated to dryness to give the title compound (49 mg) as crude. This crude was used in the next step without further purification.
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C@H:18]([C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:19][C:20]([O:22]CC)=[O:21])=[O:16].[Li+].[OH-].Cl>CCO>[N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[C:25]([C@@H:18]([NH:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][CH2:7][CH2:8][NH:9][C:10]=3[N:1]=2)[CH2:19][C:20]([OH:22])=[O:21])[CH:26]=1
Reactant: CCOC(=O)C[C@H](NC(=O)CCCCc1ccc2c(n1)NCCC2)c1cnc2ccccc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C[C@H](NC(=O)CCCCc1ccc2c(n1)NCCC2)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ester 5-8 (145 mg, 0.320 mmol) was dissolved in 1 mL EtOH and treated with 1N LiOH (352 mL, 0.35 mmol) and stirred at room temperature overnight. The reaction solution was neutralized with 1N HCl (352 mL), evaporated, and purified by chromatography on silica gel (60% 20:1:1 EtOH/NH4OH/H2O-40% EtOAc) to afford 5-9 as a white solid.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH3:26][CH:27]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[N:29]1[CH2:30][CH2:31][CH2:32][CH:27]([CH3:26])[CH2:28]1)=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Reactant: CC1CCCNC1
Product: CC1CCCN(c2c(C(=O)NC3C4CC5CC(C4)CC3C5)cnn2-c2ccccc2)C1

Procedure:
5-(3-Methyl-piperidin-1-y1)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and 3-methylpiperidine. Mass spectrum (ES) MH+=419.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[C:11]([Cl:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH2:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:20]1([C:16](=[O:18])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[Cl:19])[CH2:23][CH2:22][CH2:21]1
Reactant: C1CNC1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(OCc2ccccc2)cc1Cl)N1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[4-(Benzyloxy)-2-chlorophenyl]acetic acid (0.52 g, 1.88 mmol) was dissolved in DMF (1 ml) and azetidine (0.161 g, 2.82 mmol), DIEA (0.99 ml, 5.64 mmol), and HATU (1.43 g, 3.76 mmol) added. The mixture was stirred at RT for 1 hr. The solution was loaded directly onto a Biotage RP C18 cartridge (30 g) and purified using a gradient eluant of 10-100% water:acetonitrile+0.05% formic acid. The volatiles were removed in vacuo to afford the title compound. LC/MS (m/z): 316 (M+H)+.
Reaction SMILES: [Cl-:1].[NH3+:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[NH+:11][CH:12]=[CH:13][CH:14]=1)=O.[Cl-].[CH:16]([C:18]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:20][CH:19]=1)=O>C(O)(C)C>[ClH:1].[ClH:1].[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:7]2[C:6](=[CH:16][C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[O:20][CH:19]=3)[CH2:5][CH2:4][CH2:3][N:2]=2)[CH:10]=1
Reactant: [NH3+]CCCCC(=O)c1ccc[nH+]c1
Reactant: [Cl-]
Reactant: O=Cc1coc2ccccc2c1=O
Solvent: CC(C)O
Product: Cl
Product: O=c1c(C=C2CCCN=C2c2cccnc2)coc2ccccc12
Temperature: 85 °C
Yield: 144.7 %

Procedure:
3-(5-Ammoniopentanoyl)pyridinium chloride (219 mg, 0.87 mmol) and 3-formylchromone (228 mg, 1.31 mmol) were combined and suspended in a reaction vessel with i-propanol (30 mL). The reaction vessel was sealed and the reaction heated to 85 ° C. overnight then cooled to room temperature. The precipitate was recovered by vacuum filtration, washed with a 20% i-propanol in hexane solution, then dried under vacuum giving 245 mg (72%) of a powdery brown solid. LC-MS: RT=4.20 min, [M+H]+=317.1.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH3:4].[CH3:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1>>[Br-:1].[CH2:2]([N+:6]1([CH3:5])[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:3][CH3:4]
Reactant: CCCBr
Reactant: CN1CCCC1
Product: CCC[N+]1(C)CCCC1
Product: [Br-]

Procedure:
(Propyl)(methyl)pyrrolidinium bromide is prepared by reaction of 12.4 g of 1-bromopropane with 8.5 g of N-methylpyrrolidine at normal temperature.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:8]=[CH:7][C:6]=1[NH2:14])[CH3:3].C[Al](C)C.C1(C)C=CC=CC=1.CO[C:28](=O)[CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[C:35]1[S:36][CH:37]=[CH:38][N:39]=1>C(Cl)Cl>[CH2:2]([N:4]1[C:5]2[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:8]=[CH:7][C:6]=2[N:14]=[C:28]1[CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[C:35]1[S:36][CH:37]=[CH:38][N:39]=1)[CH3:3]
Reactant: CCNc1cc(C(C)C)ncc1N
Reactant: COC(=O)Cn1ccnc1-c1nccs1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCn1c(Cn2ccnc2-c2nccs2)nc2cnc(C(C)C)cc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of N4-ethyl-6-isopropyl-pyridine-3,4-diamine hydrochloride (126 mg, 0.582 mmol) in CH2Cl2 (5 mL) at room temperature under N2 is added 2.0 M AlMe3 in toluene (0.35 mL, 0.728 mmol). The dark solution is then stirred at room temperature for 45 min. Next, a solution of (2-Thiazol-2-yl-imidazol-1-yl)-acetic acid methyl ester (65 mg, 0.291 mmol) in CH2Cl2 (2 mL) is added via cannula followed by a 1 mL rinse. The reaction mixture is stirred at reflux overnight. After cooling, it is treated with MeOH (˜0.5 mL) and then diluted with 0.5 N NaOH and additional CH2Cl2. The mixture is stirred vigorously for 15 min and then extracted thrice with CH2Cl2 containing some (˜5%) MeOH. The combined extracts are dried over K2CO3 and concentrated to 156 mg of a crude mixture of the desired 1-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine and N-(4-amino-6-isopropyl-pyridin-3-yl)-2-(2-thiazol-2-yl-imidazol-1-yl)-acetamide. This material is then dissolved in AcOH (6 mL), and the resulting solution is stirred at reflux for 5 h. After cooling, the reaction mixture is concentrated in vacuo. The residue is dissolved in CH2Cl2 and washed with 0.5 N NaOH. The aqueous layer is reextracted twice with CH2Cl2, and the combined extracts are dried over K2CO3 and concentrated. The crude material is purified by preparative TLC. Developing with 15:1 CHCl3 yields 1-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine. 1H NMR (CDCl3, 400 MHz) δ 9.01 (s, 1H), 7.83 (d, J=3.2 Hz, 1H), 7.38 (d, J=3.2 Hz, 1H), 7.15 (s, 1H), 7.12 (s, 1H), 7.09 (s, 1H), 6.32 (s, 2H), 4.21 (q, J=7.2 Hz, 2H), 3.17 (sept, J=6.8 Hz, 1H), 1.34 (d, J=6.8 Hz, 6H), 1.10 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([F:18])=[CH:16][C:15]([Br:19])=[C:14]2[C:10]=1[C:11]([CH2:21][C:22]([OH:24])=[O:23])=[CH:12][N:13]2C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(F)=CC(Br)=C2C=1C=CN2)C1C=CC=CC=1>ClCCl.CO>[CH2:1]([O:8][C:9]1[C:17]([F:18])=[CH:16][C:15]([Br:19])=[C:14]2[C:10]=1[C:11]([CH2:21][C:22]([OH:24])=[O:23])=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cc(CC(=O)O)c2c(OCc3ccccc3)c(F)cc(Br)c21
Agent: Fc1cc(Br)c2[nH]ccc2c1OCc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: O=C(O)Cc1c[nH]c2c(Br)cc(F)c(OCc3ccccc3)c12
Yield: 58 %

Procedure:
Following the procedure (step 3, scheme 33) used to prepare compound 33-4, compound 17-1 gave compound 34-2 in 58% yield as a yellow solid after column chromatography on silica gel eluting with dichloromethane/methanol (5:1). LRMS: calc 377.0 and found: 378.0 [M+1].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([N+:18]([O-])=O)[CH:17]=1)[O:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](=[O:14])[CH3:13])[CH2:7]1.FC1C=C(C=C(F)C=1)O[C@@H]1CCCN(C(=O)C)C1.C([O-])=O.[NH4+].CC(C)=O>CO.O>[NH2:18][C:16]1[CH:15]=[C:4]([CH:3]=[C:2]([F:1])[CH:17]=1)[O:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](=[O:14])[CH3:13])[CH2:7]1
Reactant: CC(=O)N1CCC[C@@H](Oc2cc(F)cc([N+](=O)[O-])c2)C1
Agent: CC(=O)N1CCC[C@@H](Oc2cc(F)cc(F)c2)C1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: CO
Solvent: O
Product: CC(=O)N1CCC[C@@H](Oc2cc(N)cc(F)c2)C1
Yield: 75 %

Procedure:
Three 22 L 3-neck RBFs equipped with heating mantles, mechanical stirrers, thermowells, condensers, and nitrogen bubblers were purged under nitrogen for at least ten minutes. The flasks were charged with 0.454 kg (10 wt %) Pd/C, and 13.62 L (3 vol) methanol. A solution of 4.54 kg (˜16.1 mol) of a mixture of 1-[(R)-3-(3-fluoro-5-nitro-phenoxy) -piperidin-1-yl]-ethanone and 1-[(R)-3-(3,5-difluoro-phenoxy)-piperidin-1-yl]-ethanone in 4.54 L (1 vol) methanol was then charged to the flasks, and an additional 4.54 L (1 vol) methanol was added to the flasks. The solutions were warmed to a gentle reflux, and a solution of 5.07 kg (80.4 mol) ammonium formate in 3.63 L water was then added drop-wise for 10 hours. The reactions were deemed complete by TLC (1:1 hexanes:acetone/PMA stain) and HPLC, and were filtered through celite and concentrated. The concentrate was transferred to two 50 L extractors, and was partitioned between 47.2 L MTBE and 17.7 L 3N HCl. The layers were separated, and the organics were extracted with 6 L (2×) 3N HCl. The aqueous layers were neutralized with 3.54 kg NaOH to pH ˜7, then 9.6 L saturated sodium bicarbonate was added. The aqueous layers were then extracted with 6 L (3×) DCM. The combined organics were washed with 18 L brine, dried over sodium sulfate, filtered and concentrated to yield 3.06 kg of 1-[(R)-3-(3-amino-5-fluoro-phenoxy)-piperidin-1-yl]-ethanone in 75% yield as a thick brown oil (theoretical yield=4.06 kg, purity=90.7% and 95.4% ee).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[OH-].[Li+].C([N:21]=[C:22]=[S:23])(=O)C1C=CC=CC=1.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1)=O>C1COCC1>[C:34]([C:31]1[CH:32]=[CH:33][C:28]([C:26]2[N:21]=[C:22]([NH:1][CH:2]3[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]3)[S:23][CH:25]=2)=[CH:29][CH:30]=1)#[N:35]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2csc(NC3CCC(C(=O)O)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.7 %

Procedure:
cis-4-Amino-1-cyclohexanecarboxylic acid (1.5 g, 10.5 mmol) was suspended in THF (40 mL), lithium hydroxide (1N aqueous solution, 10.5 mL, 10.5 mmol) was added, followed by benzoylisothiocyanate (1.42 mL, 10.5 mmol). The mixture was stirred for 30 min, lithium hydroxide (1N aqueous solution, 10.5 mL, 10.5 mmol) was added, and the mixture was heated to reflux for 1 h. Additional lithium hydroxide (1N aqueous solution, 0.3 mL, 0.3 mmol) was added, heating was continued for 30 min, and then the mixture was cooled to 25° C. 2-Bromo-1-(4-cyanophenyl)-ethanone (2.35 g, 10.5 mmol) was added, the mixture was heated to reflux for 1 h, and then concentrated. The crude product was chromatographed with 25% acetone in hexane with 0.5% acetic acid. Further chromatography with 20% acetone:20% ethyl acetate:60% hexane provided the intermediate 4-[4-(4-cyano-phenyl)-thiazol-2-ylamino]-cyclohexanecarboxylic acid (0.196 g, 0.609) that was dissolved in dioxane (30 mL). Carbonyl diimidazole (118 mg, 0.73 mmol) was added and the mixture was heated to 100° C. for 16 h. The mixture was concentrated and flashed with 10% acetone in hexane to give 105 mg of 4-[2-(3-oxo-2-azabicyclo[2.2.2]oct-2-yl)-1,3-thiazol-4-yl]benzonitrile.