Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:23])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]#[N:13])=[CH:9][C:8]([C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([F:22])[CH:15]=1)=[CH:7]2.Cl.[NH+]1C=CC=CC=1>>[Cl:1][C:2]1[C:3]([OH:23])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]#[N:13])=[CH:9][C:8]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:22])[CH:15]=1)=[CH:7]2
Reactant: COc1ccc(-c2cc(C#N)c3c(Cl)c(O)ccc3c2)cc1F
Agent: Cl
Agent: c1cc[nH+]cc1
Product: N#Cc1cc(-c2ccc(O)c(F)c2)cc2ccc(O)c(Cl)c12

Procedure:
The title compound was prepared by reacting 8-chloro-3-(3-fluoro-4-methoxyphenyl)-7-hydroxy-1-naphthonitrile (0.042 g, 0.13 mmol) with pyridinium HCl (1.8 g) according to method D to yield 0.033 g (78%) of a tan solid. This material was further purified by preparative reverse phase HPLC to yield the title compound as a white solid: mp 246–252° C.; 1H NMR (DMSO-d6): δ 7.04–7.10 (1H, m), 7.44 91H, d, J=8.94 Hz), 7.56 (1H, dd, J=1.66 Hz, J=8.37 Hz), 7.76 (1H, dd, J=2.20 Hz, J=12.88 Hz), 7.99 (1H, d, J=9.09 Hz), 8.43 (1H, d, J=1.98 Hz), 8.52 (1H, d, J=1.94 Hz), 10.19 (1H, bs), 11.05 (1H, bs); MS (ESI) m/z 312/314 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[O:11][CH2:12][C:13](=[O:20])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.N1CCCCC1>C(O)C>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:12]2[O:11][C:10]([NH:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]2=[O:20])=[CH:22]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccccc2OC)OCC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccccc2OC)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of ethyl 2-[(2-methoxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.28 g, 1.0 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.15 g, 1.2 mmol) in ethanol (4.0 mL), piperidine (0.12 mL, 1.2 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.30 g, y. 74%).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[S:15][C:16]([NH:18][C:19]3[O:20][C@:21]4([CH2:29][N:30]=3)[CH:26]3[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]3)[CH2:22]4)=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>>[N:23]12[CH2:24][CH2:25][CH:26]([CH2:27][CH2:28]1)[C@@:21]1([O:20][C:19]([NH:18][C:16]3[S:15][C:13]4[NH:14][C:9](=[O:8])[CH:10]=[CH:11][C:12]=4[N:17]=3)=[N:30][CH2:29]1)[CH2:22]2.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]
Reactant: c1ccc(COc2ccc3nc(NC4=NC[C@@]5(CN6CCC5CC6)O4)sc3n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1ccc2nc(NC3=NC[C@@]4(CN5CCC4CC5)O3)sc2[nH]1

Procedure:
(R)—N-(5-(benzyloxy)thiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (390 mg, 0.925 mmol) was dissolved in TFA and allowed to react for 4 hours at ambient temperature, at which time LCMS and TLC showed the starting material to be mostly consumed. The TFA was removed in vacuo and the crude mixture was purified by preparative HPLC. The combined product fractions were concentrated in vacuo and triturated with ether to afford (R)-2-(4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)thiazolo[5,4-b]pyridin-5(4H)-one, TFA (164 mg, 0.368 mmol, 39.8% yield). M.P. 245 (dec). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.99 (br. s., 1H) 9.05 (br. s., 1H) 7.81 (d, J=8.53 Hz, 1H) 6.65 (d, J=8.78 Hz, 1H) 3.96 (d, J=10.29 Hz, 1H) 3.82 (d, J=10.54 Hz, 1H) 3.63-3.78 (m, 2H) 3.36-3.47 (m, 1H) 3.16-3.34 (m, 3H) 2.43 (br. s., 1H) 2.16 (br. s., 1H) 1.76-2.07 (m, 3H). MS (LC/MS) R.T.=0.50; [M+H]+=332.15.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:22][CH2:23][N:24]3[C@H:29]4[CH2:30][CH2:31][C@@H:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)[CH2:13][CH2:12][N:11]([C:14](=[O:21])[CH:15]([NH2:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:42][CH2:43][C:44](Cl)=[O:45].CCN(C(C)C)C(C)C>>[Cl:42][CH2:43][C:44]([NH:20][C@H:15]([C:14]([N:11]1[CH2:12][CH2:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)([CH2:22][CH2:23][N:24]2[C@H:29]3[CH2:30][CH2:31][C@@H:25]2[CH2:26][CH:27]([N:32]2[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[N:34]=[C:33]2[CH3:41])[CH2:28]3)[CH2:9][CH2:10]1)=[O:21])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:45]
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(N)C(C)(C)C)CC1
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H](NC(=O)CCl)C(C)(C)C)CC1

Procedure:
2-chloro-N-{(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2,2-dimethylpropyl}acetamide was obtained from treating 1,1-dimethylethyl {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl)-}-piperidinyl)carbonyl]-2,2-dimethylpropyl}carbamate (0.591 g, 0.90 mmol) with HCl as outlined in the procedure for Example 890 to form (2S)-1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-3,3-dimethyl-1-oxo-2-butanamine (0.500 g, 99%). 2S)-1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-3,3-dimethyl-1-oxo-2-butanamine (0.050 g, 0.09 mmol), Chloro-acetyl chloride (0.011 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2-chloro-N-(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2,2-dimethylpropyl}acetamide (0.038 g, 66%) as an oil. ES-LCMS m/z 636 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:43])[CH2:3][CH2:4][NH:5][C:6]([C@@H:8]([NH:20][C:21]([C:23]1[CH:42]=[CH:41][C:26]2[N:27]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:28]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[NH:12][CH:11]=1)=[O:7].NCCN1C[CH2:51][O:50][CH2:49]C1>>[OH:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:9][C@H:8]([NH:20][C:21]([C:23]1[CH:42]=[CH:41][C:26]2[N:27]([CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]3)[C:28]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[C:6](=[O:7])[NH:5][CH2:4][CH2:3][N:2]1[CH2:1][CH2:51][O:50][CH2:49][CH2:43]1
Reactant: NCCN1CCOCC1
Reactant: CN(C)CCNC(=O)[C@H](Cc1c[nH]c2ccc(O)cc12)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Product: O=C(N[C@@H](Cc1c[nH]c2ccc(O)cc12)C(=O)NCCN1CCOCC1)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1

Procedure:
The carboxylic acid of example 133 was coupled to aminoethylmorpholine under standard TBTU conditions to yield the title compound of example 135.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:28][C:29]1[CH:30]=[C:31]([CH3:37])[C:32]([CH:35]=O)=[N:33][CH:34]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:35][C:32]1[C:31]([CH3:37])=[CH:30][C:29]([Cl:28])=[CH:34][N:33]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Cl)cnc1C=O
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)cnc1CNCCCCNC(=O)OC(C)(C)C

Procedure:
Using General Procedure B: Reaction of (4-amino-butyl)-carbamic acid tert-butyl ester in CH2Cl2 and 5-chloro-3-methyl-pyridine-2-carbaldehyde with NaBH(OAc)3 gave {4-[(5-chloro-3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as a colorless oil. 1H NMR (CDCl3) δ 1.41 (s, 9H), 1.54 (m, 4H), 2.13 (s, 1H), 2.28 (s, 3H), 2.68 (t, 2H, J=6.0 Hz), 3.11 (d, 2H, J=6.0 Hz), 3.81 (s, 2H), 4.77 (br s, 1H), 7.41 (s, 1H), 8.31 (s, 1H).
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7]([O:9][CH2:10][CH3:11])[CH:6]=[C:5]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:4]=1.[Cl-].[NH4+].[CH2:18]([OH:20])[CH3:19]>O>[CH2:10]([O:9][C:7]1[CH:6]=[C:5]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:4]=[C:3]([O:20][CH2:18][CH3:19])[N:8]=1)[CH3:11]
Reactant: CCOc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Reactant: CCO
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: O
Product: CCOc1cc(C(Cl)(Cl)Cl)cc(OCC)n1
Reaction time: 72 h

Procedure:
A solution was prepared by dissolving 17.24 grams (0.75 mole) of sodium metal in 400 ml of ethanol. To this solution was rapidly added a solution prepared by dissolving 137.48 grams (0.5 mole) of 6-chloro-2-ethoxy-4-(trichloromethyl)pyridine in 300 ml of ethanol at 35° C. The mixture was heated to reflux at 72° for ~42 hours and thereafter a solution of 8.62 grams of sodium metal dissolved in 200 ml of ethanol was added thereto and the mixture refluxed for about an additional 5 hours. The mixture was diluted with 500 ml of water after first removing 500 ml of ethanol. The mixture was extracted twice with methylene chloride and the methylene chloride layers combined and washed with water (an emulsion formed and ammonium chloride was added thereto and the mixture allowed to set 3 days (week-end) for the emulsion to break). The methylene chloride layer was dried over sodium sulfate, treated with activated charcoal and filtered. The methylene chloride was removed by evaporation and 150 ml of methanol was added thereto. The mixture was chilled and the 2,6-diethoxy-4-(trichloromethyl)pyridine product which precipitated was separated. The product was recrystallized from 150 ml of methanol and dried over methylene chloride. The product melted at 45.5°-47.0° C. and was recovered in a yield of 46 grams (32 percent of theoretical). The product was found by analysis to have carbon, hydrogen, and nitrogen contents of 42.12, 4.17 and 4.92 percent, respectively, as compared with the theoretical contents of 42.20, 4.25 and 4.92 percent, respectively, as calculated for the above-named compound. The structure of the compound was confirmed by NMR.
Reaction SMILES: [CH3:1][C:2]1[CH:7]([CH2:8][CH2:9][C:10]([CH3:12])=[O:11])[C:6]([CH3:14])([CH3:13])[CH2:5][CH2:4][CH:3]=1.[CH:15](OC)(OC)OC.B(F)(F)F.CCOCC.[OH-].[K+]>C(Cl)Cl>[CH3:15][O:11][C:10]1([CH3:12])[CH2:9][CH2:8][CH:7]2[C:2](=[CH2:1])[CH:3]1[CH2:4][CH2:5][C:6]2([CH3:14])[CH3:13]
Reactant: COC(OC)OC
Reactant: CC(=O)CCC1C(C)=CCCC1(C)C
Agent: FB(F)F
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: C=C1C2CCC(C)(OC)C1CCC2(C)C
Yield: 85.4 %

Procedure:
120 g (0.563 mol) of dihydro-α-ionone, 65 g (0.612 mol) of trimethyl orthoformate and 200 ml of methylene chloride are treated dropwise while stirring during 15 minutes with a solution of 8 g of boron trifluoride etherate in 60 ml of methylene chloride and the mixture is subsequently held under reflux for 105 minutes. The reaction mixture is cooled and poured into 500 ml of a 5% aqueous potassium hydroxide solution. After the addition of 500 ml of methylene chloride and vigorous intermixing the phases are separated, the organic phase is washed with water and the solvent is distilled off. The residue (197.1 g) is fractionated in a vacuum over a 15 cm Widmer column. There are obtained 100.2 g of product of b.p. 44°-47° /0.06-0.07 mbar (yield 87% of theory based on pure dihydro-α-ionone) as a colorless liquid which contains 72.3% of exo isomer and 20.1% of endo isomer of the desired bicyclo-nonane.
Reaction SMILES: O.[CH3:2][N:3]([CH3:23])[C@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[N+:20]([O-])=O)[CH2:5]1>CO.[Pd]>[NH2:20][C:11]1[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=1[N:6]1[CH2:7][CH2:8][CH2:9][C@H:4]([N:3]([CH3:23])[CH3:2])[CH2:5]1
Reactant: CN(C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CN(C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2N)C1
Reaction time: 8 h

Procedure:
A 500 mL parr pressure bottle was charged with palladium, 10 wt. % on activated carbon, 50% water wet (9.1 g, 8.6 mmol) under nitrogen. (S)—N,N-dimethyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-amine (13.6 g, 43 mmol) was added as a solution in methanol via syringe, rinsing in with multiple methanol washes until the final volume was approximately 100 mL. The vessel was placed in a parr shaker, and treated with 2 atm H2 and shaken overnight. The reaction was flushed with nitrogen, and filtered through a pad of celite rinsing with 1.3 L of methanol and concentrated in vacuo. The oil was taken up in CH2Cl2, dried over Na2SO4, filtered, and concentrated in vacuo to give (S)-1-(2-amino-4-(trifluoromethyl)phenyl)-N,N-dimethylpiperidin-3-amine as a red oil. MS m/z=288 [M+H]+. Calc'd for C14H20F3N3: 287.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH:11]1([NH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+]>O.CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:14]([CH:11]2[CH2:12][CH2:13]2)[CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: CC(C)(C)OC(=O)CCCNC1CC1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CCCN(c1ccc(Br)cc1C=O)C1CC1
Yield: 23 %

Procedure:
5-bromo-2-fluorobenzaldehyde (20 g), t-butyl N-cyclopropyl-4-aminobutyrate (14.5 g), sodium carbonate (13.8 g), water (70 ml) and DMSO (70 ml) were heated at 80° C. for 5 days and at 110° C. for 3 days, which was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give t-butyl N-(4-bromo-2-formylphenyl)-N-cyclopropyl-4-aminobutyrate (6.4 g) as red oil.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=3[O:17][CH3:18])[NH:9][C:5]=2[CH:4]=1)#[N:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[C:1]([C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:12][C:11]=3[O:17][CH3:18])[NH:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COc1cc(O)ccc1-c1nc2ccc(C#N)cc2[nH]1
Reactant: CS(=O)(=O)Cl
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(C#N)cc2[nH]1

Procedure:
Prepared analogously to Example 1 from 5-cyano-2-(2'-methoxy-4'-hydroxy-phenyl)-benzimidazole and methanesulfonic acid chloride.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:13][C:14]3[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=3)[N:8]=[C:9]2O)=[CH:4][C:3]=1[O:20][CH3:21].O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:20][CH3:21])=[C:2]([F:1])[CH:11]=2)[CH:6]=[C:7]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(O)c2cc1F
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1F
Temperature: 150 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
7-Fluoro-6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ol (1.9 g), POCl3 (15 ml), were sealed in a process vial (20 ml). The mixture was heated at 150° C. for 30 minutes under microwave irradiation. The mixture was concentrated, and the residue was treated with 5 ml MeOH. The mixture was stirred for 2 hours at room temperature, and the solid was collected and dried to give desired product (1.3 g, 64% yield). LC-MS: m/e 307 (MH+)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[C:35]([CH2:36][O:37]C3CCCCO3)=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[C:35]([CH2:36][OH:37])=[CH:34][N:33]=[N:32]4)[CH:26]=3)[CH2:23][C:22](=[O:45])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-(isobutyl-methyl-amino)-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M88) (0.32 g, 0.49 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (107 mg, 48%).
Reaction SMILES: [CH:1]1([NH:8][C:9]([C:11]2[C:23]3[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[CH:14]=[CH:13][CH:12]=2)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1COCC1.Cl.[OH-].[Na+]>CO>[CH:1]1([NH:8][CH2:9][C:11]2[C:23]3[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1CCCCCC1)c1cccc2c1Cc1ccccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc2c(c1)Cc1c(CNC3CCCCCC3)cccc1-2
Temperature: 60 °C
Yield: 94.2 %

Procedure:
To N-cycloheptyl-1-fluorenecarboxamide (1.00 g, 3.28 mmol) was added a 1M solution of borane-tetrahydrofuran complex in THF (13 ml, 13 mmol) and the mixture was heated at 60° C. for 7.5 hrs. To this reaction mixture were added methanol (0.4 ml) and concentrated hydrochloric acid (3 ml) and the mixture was heated at 60° C. for 0.5 hr. Then, 1N aqueous sodium hydroxide solution (50 ml) was added at room temperature and the mixture was extracted with chloroform (80 ml×2 times). The organic layer was taken, dried and concentrated. To the residue were added ether (30 ml) and 4N hydrogen chloride in ethyl acetate (2 ml) and the resulting white solid was collected by filtration. This solid was dissolved in chloroform (80 ml) and washed with 1N aqueous sodium hydroxide solution (80 ml×1). The organic layer was dried and concentrated to give 0.90 g of a pale yellow solid.
Reaction SMILES: [C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH2:22]([Cl:24])Cl>>[C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][C:4]2[CH:11]=[CH:12][C:22]([Cl:24])=[CH:6][CH:5]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Reactant: ClCCl
Product: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCc2ccc(Cl)cc2)C1

Procedure:
A similar procedure starting with 3-(S)-(-)-(1-carbamoyl1,1-diphenylmethyl)pyrrolidine (0.64 g--see Preparation 10B) gave 3-(S)-(-)-(1-carbamoyl-1,1-diphenylmethyl)-l-(4-chlorophenethyl)pyrrolidine, yield 0.2 g, [α]25D -7.4° (c 1.0, CH2Cl2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([I:26])=[N:9]2)=[CH:5][CH:4]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:41](=[O:42])[C:40]([C:43](O)=[O:44])=[CH:39][CH:38]=[N:37]2)=[CH:32][CH:31]=1.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C>CN(C=O)C>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:43]([C:40]2[C:41](=[O:42])[N:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[N:37]=[CH:38][CH:39]=2)=[O:44])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=3)[N:9]=[C:10]([I:26])[C:11]=12
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(I)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (1.50 g, 3.06 mmol; prepared as in Example 7, Step B), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (1.43 g, 6.12 mmol; prepared as in Example 19, Step C), and HOBT-H2O (2.81 g, 18.4 mmol) dissolved in dry DMF (30 mL) was added EDCI (3.52 g, 18.4 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was then partitioned between ethyl acetate (60 mL) and aqueous NH4Cl (100 mL). The organic layer was separated, washed with saturated NaHCO3, dried over NaSO4, and evaporated to dryness. The crude material was triturated with MeOH and the solid removed by filtration, dried to afford the title compound as yellow solid. Yield: 1.93 g, 89%. LRMS (APCI pos) m/e 707.0 (M+H).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7](O)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.S(Cl)([Cl:18])=O>>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7]([Cl:18])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccccc1-c1ccccc1

Procedure:
A mixture of 5.6 g of 2-biphenylcarboxylic acid and 29 ml of thionyl chloride is heated on a steam bath for 0.5 hour and the volatiles removed under vacuum. Toluene (40 ml) is added (twice) and the solvent removed under vacuum to give 6.8 g of a yellow oil.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([CH2:11][NH2:12])=[CH:3]1.F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([CH2:11][NH:12][C:19]2[CH:20]=[N:21][CH:22]=[CH:14][C:15]=2[C:16]([OH:18])=[O:17])=[CH:3]1
Reactant: NCc1coc2ccccc12
Reactant: O=C(O)c1ccncc1F
Agent: Cl
Product: O=C(O)c1ccncc1NCc1coc2ccccc12
Yield: 8 %

Procedure:
The title compound was prepared in 8% yield from (1-benzofuran-3-yl)methylamine hydrochloride and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ 13.39 (br s, 1H), 8.33 (s, 1H), 7.97 (s, 1H), 7.77 (d, 1H, J=5.0 Hz), 7.68 (br s, 1H), 7.57 (d, 1H, J=7.6 Hz), 7.48-7.52 (m, 2H), 7.17-7.28 (m, 2H), 4.64 (s, 2H). [M+H] calc'd for C15H12N2O3, 267. Found 267.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH2:12].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=1)(=[O:24])=[O:23]
Reactant: COC(=O)c1cc(Br)cc(C)c1N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)c1cc(Br)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Temperature: 80 °C
Yield: 84.5 %

Procedure:
To a stirred solution of 24.5 g (100 mmol) of the product of Example 133 in 100 mL of pyrdine was added 21.0 g (100 mmol) of p-methoxybenzenesulfonyl chloride and the resulting mixture was heated to 80° C. for 24 h. The reaction mixture was then quenched with ice cold water and acidified with concentrated HCl. The resulting mixture was extracted with chloroform, washed with water, dried over MgSO4, filtered and concentrated in vacuo. The residue was triteretd with diethyl ether, filtered and dried to provide 35 g (84%) of the desired product as a brown solid. Electrospray Mass Spec 416, (M+H).