Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH:19]=[CH:20][CH:21]=2)=[O:13])[NH:3]1.C1COCC1.CO.C(OCC)(=O)C.[ClH:48]>C(OCC)(=O)C.C(OCC)C>[ClH:48].[ClH:48].[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)[CH:17]=2)=[O:13])[NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)CC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCc1cccc(N2CCNCC2)c1)c1nc2ccccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a suspension of 1,1-dimethylethyl 4-[3-({[(4-oxo-3,4-dihydroquinazolin-2-yl)carbonyl]amino}methyl)phenyl]piperazine-1-carboxylate obtained in Reference Example 115 (2.40 g, 6.86 mmol) in ethyl acetate (10 mL)-THF (50 ml)-methanol (40 mL) was added 4N hydrogen chloride-ethyl acetate (10.4 mL), and the mixture was stirred at room temperature for 4 hr, and then at 50° C. for 2 hr. Diethyl ether (about 100 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration to give the title compound as a white powder (2.18 g, 97%).
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2B2OC(C)(C)C(C)(C)O2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:36]1[CH:37]=[N:38][C:39]([CH:42]2[CH2:44][CH2:43]2)=[N:40][CH:41]=1>>[CH2:28]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:36]2[CH:37]=[N:38][C:39]([CH:42]3[CH2:44][CH2:43]3)=[N:40][CH:41]=2)[O:11][CH2:10]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC1(C)OB(c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)OC1(C)C
Reactant: Brc1cnc(C2CC2)nc1
Product: c1ccc(CN(Cc2ccccc2)[C@@H]2COc3cccc(-c4cnc(C5CC5)nc4)c3C2)cc1
Yield: 53 %

Procedure:
The title compound was synthesized as described for Intermediate example I-28 in 53% yield, starting from (3S)-N,N-dibenzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-3-amine and 5-bromo-2-cyclopropylpyrimidine (1.1 equiv); 1H NMR (400 MHz, CDCl3) δ ppm 8.55 (s, 2 H), 7.27-7.36 (m, 8 H), 7.13-7.26 (m, 3 H), 6.86 (dd, 1 H), 6.75 (dd, 1 H), 4.32-4.41 (m, 1 H), 4.02 (t, 1 H), 3.70 (s, 4 H), 3.14-3.25 (m, 1 H), 2.76-2.89 (m, 1 H), 2.59-2.69 (m, 1 H), 2.30-2.40 (m, 1 H), 1.22-1.28 (m, 2 H), 1.13-1.21 (m, 2 H); MS (ESI) m/z 448[M+H+].
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])=[C:4]([F:15])[CH:3]=1.[NH2:16][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19].C([O-])([O-])=O.[K+].[K+].C(C1CCCCC1=O)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.[Cu]I.O>[CH2:9]([NH:8][C:6]([C:5]1[CH:13]=[CH:14][C:2]([NH:16][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19])=[CH:3][C:4]=1[F:15])=[O:7])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCNC(=O)c1ccc(Br)cc1F
Reactant: CC(C)(N)C(=O)O
Agent: [Cu]I
Agent: CC(=O)C1CCCCC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCNC(=O)c1ccc(NC(C)(C)C(=O)O)cc1F
Temperature: 100 °C
Yield: 94.3 %

Procedure:
The title compound was prepared according to General Method 7. 4-bromo-N-butyl-2-fluorobenzamide (950 mg, 3.22 mmol), 2-aminoisobutyric acid (450 mg, 4.36 mmol), CuI (100 mg, 0.5 mmol), TEA (0.1 mL) and K2CO3 (1.0 g, 7.2 mmol) were charged in DMF (8 ml) and water (2 ml) and stirred at RT for 5 min. 2-acetylcyclohexanone (100 mg, 0.7 mmol) was added and the reaction mixture was heated at 100° C. for 18 h. The reaction mixture was acidified with 1 M citric acid (pH 4) and extracted with ethyl acetate (50 mL, 2 times). The combined organic layer was dried over Na2SO4 and concentrated to obtain 900 mg of 2-(4-(butylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH:8]2O)([O-:3])=[O:2].S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[Cl:16][CH:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: O=[N+]([O-])c1cccc2c1CCC2O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc2c1CCC2Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 4-nitro-2,3-dihydro-1H-inden-1-ol (252 mg, 1.41 mmol, 1.0 equiv) in dry toluene (2.5 mL) was added thionyl chloride (160 μL, 2.11 mmol, 1.5 equiv) dropwise by syringe. After stirring at 0° C. for 30 min, the reaction mixture was heated to 55° C. for 2 h. The reaction was allowed to cool to room temperature, washed twice with water, dried over sodium sulfate, filtered and concentrated in vacuo. The unpurified alkyl chloride (221 mg, 79%) was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][N:9]2[CH:15]2[CH2:17][CH2:16]2)=[CH:4][C:3]=1[F:24].[C:25]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])#[N:26].CC(C)([O-])C.[K+].Cl>O1CCOCC1>[C:25]([CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][N:9]2[CH:15]2[CH2:16][CH2:17]2)=[CH:4][C:3]=1[F:24])#[N:26]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)c1cn(C2CC2)c2c([N+](=O)[O-])c(Cl)c(F)cc2c1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CC2)c2c([N+](=O)[O-])c(C(C#N)C(=O)OCC)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.0 g of ethyl 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-8-nitro-4-oxo-3-quinoline-carboxylate and 1.92 g of ethyl cyanoacetate are initially introduced into 30 ml of dioxane. 1.91 g of potassium tert-butoxide are added in portions at room temperature. The mixture is stirred overnight and then heated to 50° for a further 4 hours. After cooling to room temperature, the mixture is diluted using ice-water and rendered acidic using HCl. The mixture is extracted using methylene chloride, and the organic phase is dried and concentrated. The residue is recrystallized from isopropanol.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:12]1.[C:23](Cl)(=O)[CH2:24][CH3:25].C(N(CC)CC)C>ClCCl>[CH2:24]([C:25]1[N:15]([C@H:13]2[CH2:12][C@H:11]([NH:10][C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)[CH2:14]2)[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[N:22]=1)[CH3:23]
Reactant: CCC(=O)Cl
Reactant: Nc1cccnc1N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2cccnc2n1[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
N2-(Trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)pyridine-2,3-diamine (0.075 g, 0.241 mmol) was suspended in dichloromethane (20 mL) and treated with propionyl chloride (0.03 ml, 0.357 mmol). Triethylamine (0.050 ml, 0.359 mmol) was added and the reaction stirred for 1 hour. The mixture was evaporated to dryness under reduced pressure and the crude redissolved in propionic acid (5 mL). The solution was heated at 100° C. for 16 hours. The mixture was evaporated to dryness under reduced pressure and purified using silica chromatography (0-10% methanol in dichloromethane gradient) followed by reverse phase HPLC gave the desired N-(trans-3-(2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)cyclobutyl)benzo[d]thiazol-2-amine (0.045 g, 0.129 mmol, 53.5% yield). M+1: 350.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.31 (t, J=7.53 Hz, 3 H) 2.46 (br. s., 1 H) 2.52-2.68 (m, 2 H) 2.79 (q, J=7.63 Hz, 2 H) 3.61-3.84 (m, 2 H) 4.47-4.68 (m, 1 H) 5.12 (quin, J=8.20 Hz, 1 H) 7.03 (t, J=7.53 Hz, 1 H) 7.12 (dd, J=7.92, 4.79 Hz, 1 H) 7.18-7.32 (m, 1 H) 7.52 (dd, J=21.91, 8.00 Hz. 2 H) 7.88 (dd, J=8.02, 1.37 Hz. 1 H) 8.26 (dd, J=4.69, 1.37 Hz. 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)O.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([Cl:19])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: OC(c1ccc(Cl)cc1)c1ccccc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Clc1ccc(C(Cl)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.3 %

Procedure:
A stirred solution of 9.0 grams (0.036 mole) of (2-chlorophenyl)(4-chlorophenyl)methanol in 90 mL of chloroform was cooled to 0° C., and 5.3 mL (0.072 mole) of thionyl chloride was added. Upon completion of the addition the reaction mixture was allowed to warm to ambient temperature, where it stirred for about 18 hours. After this time the reaction mixture was filtered and concentrated under reduced pressure. The filtrate was taken up in hexane and subjected to column chromatography on silica gel with hexane as eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 10.0 grams of (2-chlorophenyl)(4-chlorophenyl)methyl chloride. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[C:24]([CH3:40])[N:23]=[C:22](SC)[N:21]=3)[C@H:14]2[CH3:43])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[F:57][C:58]1([F:62])[CH2:61][NH:60][CH2:59]1.CCN(CC)CC>C(Cl)Cl.C1COCC1>[F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[C:24]([CH3:40])[N:23]=[C:22]([N:60]4[CH2:61][C:58]([F:62])([F:57])[CH2:59]4)[N:21]=3)[C@H:14]2[CH3:43])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: FC1(F)CNC1
Reactant: COC(=O)CCc1ccc(OC)c(-c2c(C)nc(SC)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCc1ccc(OC)c(-c2c(C)nc(N3CC(F)(F)C3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the title compound from Step A (20 mg, 0.030 mmol) and mCPBA (10.50 mg, 0.061 mmol) in CH2Cl2 (2 mL) was stirred at room temperature for 1 h. TLC showed no SM. The mixture was diluted with CH2Cl2 (10 mL) and washed with Na2S2O3 and Na2HCO3, and dried over Na2SO4. The solvent was removed. A mixture of the residue, 3,3-difluoro-azetidine (19.70 mg, 0.152 mmol) and Et3N (3.08 mg, 0.030 mmol) in THF was heated at 140° C. under microwave for 4 h. The solvent was removed and the title compound was purified by preparative TLC plate as a white solid using EtOAc/hexane as the elute (2/8). LCMS=703.4 (M+H)+. The final compound was a mixture of two separable atropisomers, which could be separated by chiral OD column using EtOH/heptane as the elute.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:33]=3[CH:43]=2)=[CH:7][CH:6]=1.[F:44][C:45]1[CH:50]=[CH:49][C:48]([CH2:51][CH:52]=O)=[CH:47][CH:46]=1.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.CO>[F:44][C:45]1[CH:50]=[CH:49][C:48]([CH2:51][CH2:52][NH:1][CH2:2][CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:13][CH:12]3[O:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]4[O:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:33]=4[CH:43]=3)=[CH:9][CH:10]=2)=[CH:47][CH:46]=1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCN)cc3)cc21
Reactant: O=CCc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CO
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCNCCc4ccc(F)cc4)cc3)cc21
Temperature: 20 °C
Reaction time: 2 h

Procedure:
0.361 g of benzyl 4-[4-(2-aminoethoxy]phenyl]-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 184) is dissolved under argon in tetrahydrofuran. 2 g of 4 Å molecular sieve are added, followed by a solution of (4-fluorophenyl)acetaldehyde in 1 ml of tetrahydrofuran. The reaction mixture is stirred at 20° C. for 2 hours. 3 ml of methanol and 0.078 g of sodium acetate are added to the mixture. A solution of 0.055 g of sodium cyanoborohydride in 3 ml of methanol is added dropwise at 0° C. and the mixture is subsequently stirred at 0° C. over 1 hour. 10 ml of saturated aqueous sodium hydrogencarbonate solution are added and the mixture is subsequently filtered through Hyflo. The filtrate is extracted with ethyl acetate (2×20 ml)—the combined organic phases are washed with 20 ml of brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (200:5:1 dichloromethane-methanol-25% conc. ammonia); Rt=4.74.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[CH:10][N:11]=[C:6]2[C:5]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:4]1)[CH3:2].[CH3:19][N:20]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[N:22]=[C:21]1S(C)(=O)=O.[H-].[Na+].O>CN(C=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[CH:10][N:11]=[C:6]2[C:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:21]3[N:20]([CH3:19])[C:24]4=[N:25][CH:26]=[CH:27][CH:28]=[C:23]4[N:22]=3)=[CH:14][CH:13]=2)=[N:4]1)[CH3:2]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CCn1nc(-c2ccc(O)cc2)c2nccnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2nccnc21
Temperature: 150 °C
Yield: 63.4 %

Procedure:
To a solution of 4-(1-ethyl-1H-pyrazolo[3,4-b]pyrazin-3-yl)phenol (100 mg) and 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (88 mg) in DMF (3 mL) was added NaH (60% in oil, 17 mg) at room temperature, and the mixture was heated at 150° C. for 1.5 h under microwave irradiation. The mixture was poured into water and extracted with AcOEt. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane) and recrystallized from AcOEt/hexane to give the title compound (98 mg).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:17][NH2:18]>C(O)C>[NH:17]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)[NH2:18]
Reactant: NN
Reactant: CS(=O)(=O)c1nccc(-c2ccccc2)n1
Solvent: CCO
Product: NNc1nccc(-c2ccccc2)n1

Procedure:
A solution of 1.0 g. of 2-methylsulfonyl-4-phenylpyrimidine in 25 ml. of absolute ethanol is treated with 0.34 g. of 95% hydrazine. The reaction mixture is refluxed for 6 hours and then cooled and the desired product is obtained by filtration, m.p. 116°-118° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[CH2:13]([N:15]1[CH2:19][CH2:18][C@@H:17]([NH2:20])[CH2:16]1)[CH3:14].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>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][C@@H:17]2[CH2:18][CH2:19][N:15]([CH2:13][CH3:14])[CH2:16]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CCN1CC[C@@H](N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CC[C@@H](NC(=O)c2ccc(N)c(OC)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-3-methoxybenzoic acid (Aldrich; 424 mg, 2.54 mmol) and (3R)-1-ethylpyrrolidin-3-amine (Intermediate 246; 312 mg, 2.73 mmol) in DMF (10 mL) was added DIPEA (1.4 ml, 8.04 mmol). The resultant solution was treated with HATU (1.21 g, 3.18 mmol) and stirred, under nitrogen, at ambient temperature overnight.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:8][C:9]2[CH:10]=[C:11]([CH2:15]O)[CH:12]=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:19])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:19][CH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Cc1cccnc1Oc1cccc(CO)c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1Oc1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.7 %

Procedure:
(3-(3-Methylpyridin-2-yloxy)phenyl)methanol from Step 1 (3.3 g, 15 mmol), in dichloromethane (50 mL), was cooled to 0° C., and treated dropwise with thionyl chloride (1.34 mL, 18.4 mmol). The reaction mixture was allowed to warm to ambient temperature and was stirred for 3 h. Saturated aqueous sodium bicarbonate (20 mL) was added and the mixture was stirred at RT for 5 min. The organic layer was separated, dried over sodium sulfate, filtered and concentrated by evaporation to afford the title compound (3.6 g, 99% yield) as an oil.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[S:24][CH:25]=1>>[CH:1]1([C:4]2[N:5]([CH2:20][C:21]3[N:22]=[C:23]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=4)[S:24][CH:25]=3)[C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:14])([F:15])[F:16])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:2][CH2:3]1
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Reactant: FC(F)(F)c1ccc(-c2nc(CCl)cs2)cc1
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2csc(-c3ccc(C(F)(F)F)cc3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 4 using 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 165A) and 4-(chloromethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole: MS (ES) m/z 492 (M+1).
Reaction SMILES: [CH2:1]=[O:2].[N+:3]([CH:6]([CH2:8][CH3:9])[CH3:7])([O-:5])=[O:4]>C(N(CC)CC)C>[CH3:7][C:6]([N+:3]([O-:5])=[O:4])([CH2:8][CH3:9])[CH2:1][OH:2]
Reactant: C=O
Reactant: CCC(C)[N+](=O)[O-]
Solvent: CCN(CC)CC
Product: CCC(C)(CO)[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A 2-liter 3-neck flask is equipped with a mechanical stirrer, a reflux condenser with a nitrogen bubbler, an addition funnel and a temperature controller with heating mantle and thermocouple. The flask is charged with aqueous formaldehyde solution (420 mL, 37% active, 5.64 mol) and 4 mL triethylamine catalyst. The addition funnel is charged with 2-nitrobutane (554.1 g, 5.37 mol). The 2-nitrobutane is added dropwise, over a period of 7 hours to the formaldehyde solution, which is being stirred under nitrogen. The reaction is maintained at 40° C. during the addition. After all the 2-nitrobutane is added, the turbid mixture is warmed to 45° C. for 30 min, and then heating and stirring are discontinued overnight. If a GC analysis indicates the reaction is not yet complete; an additional 10.9 g aqueous formaldehyde is added and the mixture stirred at 45° C. for 2.5 hours. Upon cooling to room temperature, the reaction mass separates into an oil layer with a smaller, separate water layer. The oil layer is collected (1022.8 g, 97.9% of theory) and GC indicates 94.8% purity. The oil is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]2[CH2:18][CH2:17][CH:16]([N:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.NC1C=CC(C2CCC(=O)CC2)=C2[C:31]=1[C:30](=[O:32])[N:29]([CH3:33])[CH2:28]2.C(N1CCNCC1)(=O)C>>[C:30]([N:29]1[CH2:33][CH2:21][N:19]([CH:16]2[CH2:17][CH2:18][CH:13]([C:5]3[CH:4]=[CH:3][C:2]([NH2:1])=[C:10]4[C:6]=3[CH2:7][N:8]([CH3:12])[C:9]4=[O:11])[CH2:14][CH2:15]2)[CH2:20][CH2:28]1)(=[O:32])[CH3:31]
Reactant: CN1Cc2c(C3CCC(N(C)C)CC3)ccc(N)c2C1=O
Reactant: CN1Cc2c(C3CCC(=O)CC3)ccc(N)c2C1=O
Agent: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(C2CCC(c3ccc(N)c4c3CN(C)C4=O)CC2)CC1

Procedure:
The title product was prepared according to the procedure for Compound 233A using 7-amino-2-methyl-4-(4-oxocyclohexyl)-2,3-dihydro-1H-isoindol-1-one and 1-acetylpiperazine. 1H NMR (CDCl3, 400 MHz): δ=1.80-1.98 (m, 3H), 2.01-2.14 (m, 6H), 2.25 (d, J=19.20 Hz, 1H), 2.42-2.62 (m, 5H), 3.12-3.17 (m, 3H), 3.45-3.70 (m, 4H), 4.28-4.33 (m, 2H), 5.10 (br. s., 2H), 6.58 (d, J=8.08 Hz, 1H), 7.17 (d, J=8.34 Hz, 1H). MS (ES+): m/z 371.26 [MH+] (TOF, polar).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[N:19][N:20]3[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[N:19][N:20]3[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C(=O)NCc2cccc3c2cnn3C2CCCCO2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCc1cccc2c1cnn2C1CCCCO1)c1ccc(C(=O)O)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A suspension of 2-chloro-4-[[[[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methyl]amino]carbonyl]benzoic acid, methyl ester (87.8 mg, 0.206 mmol) in methanol (1 mL) was cooled to ˜0° C. and 1 M sodium hydroxide (0.206 mL, 0.206 mmol) was added. The cooling bath was removed and the reaction mixture was allowed to stir overnight. A further portion of sodium hydroxide (1 M; 0.2 mL, 0.2 mmol) was added and the mixture was stirred at room temperature for 7 h. The solvent was evaporated and the residue was dissolved in water (25 mL) and washed with ethyl acetate (2×10 mL). The aqueous layer was made acidic with 1 M HCl and extracted with ethyl acetate (2×20 mL). These extracts were combined, washed with brine (10 mL), dried (MgSO4), filtered, and concentrated to give 2-chloro-4-[[[[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methyl]amino]carbonyl]benzoic acid (77.3 mg, 91%) as a white solid.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[CH2:24]([O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH2:25][CH2:26][CH2:27][CH3:28]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:34][C:33]4[CH:32]=[CH:31][C:30]([O:29][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:36][CH:35]=4)=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CCCCCOc1ccc(N)cc1
Product: CCCCCOc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 50.2 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-pentyloxyaniline (61.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-pentyloxyphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (37.6 mg).