Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH2:8][C:9]([NH2:12])([CH3:11])[CH3:10])[CH:6]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([OH:33])[CH:28](OCC)O)=[CH:23][C:22]=1[NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([OH:33])[CH2:28][NH:12][C:9]([CH3:10])([CH3:11])[CH2:8][CH2:7][N:5]2[CH:6]=[C:2]([I:1])[N:3]=[CH:4]2)=[CH:23][C:22]=1[NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:36])=[O:37])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(O)C(O)c1ccc(OCc2ccccc2)c(NS(=O)(=O)c2ccccc2)c1
Reactant: CC(C)(N)CCn1cnc(I)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(CCn1cnc(I)c1)NCC(O)c1ccc(OCc2ccccc2)c(NS(=O)(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
2.1 g (7.7 mmol) of 3-(4-iodimidazol-1-yl)-1,1-dimethyl-propylamine and 3.4 g (7.7 mmol) of N-[2-benzyloxy-5-(2-ethoxy-1,2-dihydroxy-ethyl)-phenyl]-phenylsulphonamide in 25 mL ethanol were refluxed for 18 h. The reaction mixture was cooled to 0° C. and then combined with 0.3 g (7.7 mmol) sodium borohydride. The mixture was stirred for a further 3 h at ambient temperature and then combined with glacial acetic acid. The solvent was removed using the rotary evaporator and the residue was dissolved in 300 mL ethyl acetate/water (1:2). The aqueous phase was made alkaline with conc. ammonia and separated from the organic phase. The organic phase was washed twice with 100 mL water and once with 100 mL of saturated aqueous sodium chloride solution, dried over sodium sulphate and freed from solvent using the rotary evaporator. The residue was purified by flash column chromatography [methylene chloride/methanol/ammonia (90:10:1)]. 3.5 g (5.0 mmol, 69%) N-(2-benzyloxy-5-{1-hydroxy-2-[3-(4-iodo-imidazol-1-yl)-1,1-dimethyl-propylamino]-ethyl}-phenyl)-phenylsulphonamide were obtained as a yellowish solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].CS([CH2:27][CH:28]1[O:33][C:32]2[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=2[O:30][CH2:29]1)(=O)=O>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:27][CH:28]4[O:33][C:32]5[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=5[O:30][CH2:29]4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CS(=O)(=O)CC1COc2ccccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CC4COc5ccccc5O4)CC3)noc2c1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), K2CO3 (2.45 g, 17.7 mmol), 2-methanesulfonylmethyl-1,4-benzodioxan (3.35 g, 13.7 mmole) in acetonitrile (100 ml) was heated at reflux for 12 hours. At the end of the reaction, the insolubles were filtered and rinsed with dichloromethane. The organic solution was concentrated. The crude oil was purified by flash chromatography on a silica gel column. The fractions containing the pure product were pooled and concentrated to a light yellow oil (3.94 g, 74%). Crystallization from ethanol and petroleum ether gave 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl-1,4-benzodioxan as off-white crystals, 2.22 g, m.p.=86°-87° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].B(Cl)(Cl)Cl.C(Cl)Cl.Cl[CH2:18][C:19]#N.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[F:9][C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([Br:1])[CH:8]=1)[NH:4][CH:19]=[CH:18]2
Reactant: N#CCCl
Reactant: Nc1ccc(F)cc1Br
Agent: ClB(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClCCCl
Product: Fc1cc(Br)c2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
2-Bromo-4-fluoro-aniline (13.8 g, 72.6 mmol) was added dropwise to a solution of boron trichloride in methylene chloride (1.0 M, 81.1 mL, 81.1 mmol) cooled with ice water. The reaction mixture was warmed to room temperature, stirred for 30 min, and chloroacetonitrile (13.5 mL, 87.1 mmol) and aluminum chloride (13.5 g, 98.4 mmol) added, followed by 1,2-dichloroethane (95 mL). The reaction mixture was heated to 70° C. to distill off methylene chloride, and then refluxed for 24 h. After cooling to 0–5° C., the mixture was treated with 2.5 M HCl (130 mL) carefully, and then heated to 80° C. for 1 h until all solids dissolved. The aqueous layer was separated and extracted with methylene chloride. The combined organic solutions were washed with water and brine, dried (sodium sulfate) and concentrated to a yellow solid (11, 56.9%), which was used without further purification. The crude product was taken into dioxane (68 mL) and water (7.6 mL), and treated with sodium borohydride (1.64 g) in portions. After 30 min at room temperature, all the starting material was consumed, and the reaction mixture was heated to reflux for 18 h. The mixture was cooled to room temperature, treated with 0.1 N HCl (70 mL), 2N HCl (20 mL) and concentrated HCl (15 mL), and extracted with ethyl acetate. The organic layer was separated and washed with water and brine, dried (sodium sulfate), and concentrated. Column chromatography on silica gel (hexanes/ethyl acetate) gave 5-fluoro-7-bromoindole (4.4 g, 52.2%). 1H NMR (400 MHz, CDCl3) 6.49, (dd, J1=2.35 Hz, J2=3.13 Hz, 1H), 7.06 (d, J1=2.35 Hz, J2=8.60 Hz, 1H), 7.14˜7.17 (m, 2H), 8.18 (br, 1H); MS (ES, m/z): C8H5BrFN: 211.9 (M+(79Br)−1), 214.0 (M+(81Br)−1).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[Cl-].[NH4+]>O1CCCC1>[OH:18][CH:17]([C:16]1[CH:19]=[CH:20][C:13]([CH3:12])=[CH:14][CH:15]=1)[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: C#CC(=O)OC
Reactant: Cc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)c1ccc(C)cc1
Reaction time: 0.17 h

Procedure:
A solution of 8.4 ml (0.1 mol) of methyl propiolate in 100 ml of tetrahydrofuran was treated at -78° under argon with 68.8 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 11.8 ml (0.1 mol) of 4-methylbenzaldehyde in 100 ml of tetrahydrofuran was added within 40 minutes. The reaction mixture was stirred at -78° for a further 20 minutes, then brought to room temperature and treated with 100 ml of saturated ammonium chloride solution The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 1000 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained methyl 4-hydroxy-4-(4-methylphenyl)-2-butynoate as a yellow oil.
Reaction SMILES: [Na].Cl[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N:9]2[C:13]3=[N:14][CH:15]=[CH:16][N:17]=[C:12]3[CH:11]=[N:10]2)[CH:8]=1.[CH:18]([OH:22])([CH2:20][CH3:21])[CH3:19]>>[CH:18]([O:22][C:16]1[N:17]=[C:12]2[CH:11]=[N:10][N:9]([C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:8]=3)[C:13]2=[N:14][CH:15]=1)([CH2:20][CH3:21])[CH3:19]
Reactant: Clc1cccc(-n2ncc3nccnc32)c1
Reactant: CCC(C)O
Agent: [Na]
Product: CCC(C)Oc1cnc2c(cnn2-c2ccccc2)n1
Yield: 53 %

Procedure:
In 50 ml of sec.-butanol was dissolved 2.1 g (0.091 mole) of metallic sodium, and then, 10.0 g (0.043 mole) of 5-chloro-phenyl-1H-pyrazolo[3,4-b]pyrazine was added to the solution. The mixture was heated under reflux for 2 hours. After completion of the reaction, the excessive amount of sec.-butanol was removed by distillation under a reduced pressure. The residue was washed with water, dried and then recrystallized from hexane to obtain 6.2 g (the yield was 53%) of 5-sec.-butoxy-1-phenyl-1H-pyrazolo[3,4-b]pyrazine in the form of a colorless needle crystal.
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15](O)=[O:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH:29]1[C:33]([NH2:34])=[N:32][N:31]=[N:30]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([NH:34][C:33]2[NH:32][N:31]=[N:30][N:29]=2)=[O:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1nnn[nH]1
Reactant: CC(C)(C)c1ccccc1OC1CCN(C(=O)C(=O)O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccccc1OC1CCN(C(=O)C(=O)Nc2nnn[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
A solution of [4-(2-tert-butylphenoxy)piperidin-1-yl](oxo)acetic acid (300 mg, 0.98 mmol) obtained in Example 52 and oxalyl chloride (126 μL, 1.47 mmol) in toluene (5 ml) was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and DMF (1 mL) was added to the residue. The mixture was added to a solution of 1H-tetrazole-5-amine (255 mg, 3.0 mmol) and triethylamine (205 μL, 1.47 mmol) in toluene (10 ml) under ice-cooling, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was partitioned between ethyl acetate-1N hydrochloric acid, and the ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (317 mg, 87%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:4]2[N:3]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C>[C:15]1([C:14]2[N:4]3[N:3]=[C:2]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[C:11]4[C:6]([C:5]3=[N:12][N:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C1CCNC1
Reactant: Clc1nn2c(-c3ccccc3)nnc2c2ccccc12
Solvent: CCO
Product: c1ccc(-c2nnc3c4ccccc4c(N4CCCC4)nn23)cc1
Temperature: 100 °C
Yield: 82 %

Procedure:
A mixture of 6-chloro-3-phenyl-1,2,4-triazolo[3,4-a]phthalazine (5 g), pyrrolidine (5 ml), ethanol (35 ml) and catalytic amounts of KI, is poured in a pressure resistant vessell and heated to 100° C. for 8 hours. The reaction mixture is then cooled, the solvent is evaporated off and the residue is thoroughly washed with a small amount of water and crystallized from ethanol yielding the compound of the title in 82% yield. M.p. 208°-09° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(CBr)cc1

Procedure:
38.1 g (0.2 mol) of 4-methylbenzenesulphonyl chloride are dissolved in 300 ml of carbon tetrachloride, 35.6 g (0.2 mol) of N-bromosuccinimide are added and, after addition of 0.2 g (1.2 mmol) of azobisisobutyronitrile (AIBN),the mixture is heated under reflux for 4 hours. After cooling, the solids are filtered off and the filtrate is freed from the solvent. Flash chromatography (petroleum ether/toluene 4:1, 50 μm particle size) and subsequent recrystallisation from 100 ml of cyclohexane give 24.0 g (45% of theory) of the title compound. Rf =0.75 (toluene).
Reaction SMILES: [NH:1]([CH2:5][C:6]#[N:7])[CH2:2][C:3]#[N:4].[N:8]1[C:15]([Cl:16])=[N:14][C:12](Cl)=[N:11][C:9]=1[Cl:10]>O1CCOCC1>[Cl:10][C:9]1[N:8]=[C:15]([Cl:16])[N:14]=[C:12]([N:1]([CH2:5][C:6]#[N:7])[CH2:2][C:3]#[N:4])[N:11]=1
Reactant: N#CCNCC#N
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: C1COCCO1
Product: N#CCN(CC#N)c1nc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of 9.5 g. (0.1 mole) of iminodiacetonitrile in 100 ml. dioxane was added to a stirred solution of 9.2 g. (0.05 mole) of cyanuric chloride in 100 ml. dioxane. The suspension was stirred at ambient temperature for 1 hour. An additional 100 ml. dioxane was added and mixture heated to 50°C. for 1 hour and filtered. The filtrate was diluted with 500 ml. ice/water and the solid filtered and dried to give 9.6 g. (80% yield), m.p. 154°-158°C.
Reaction SMILES: [CH3:1][CH:2]([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21](COCC[Si](C)(C)C)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[Cl:32][C:33]1[S:37][C:36]([S:38](Cl)(=[O:40])=[O:39])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[S:37][C:36]([S:38]([N:7]2[CH2:6][CH2:5][N:4]([CH2:3][CH:2]([N:10]3[CH:14]=[C:13]([C:15]4[C:16]5[CH:23]=[CH:22][NH:21][C:17]=5[N:18]=[CH:19][N:20]=4)[CH:12]=[N:11]3)[CH3:1])[CH2:9][CH2:8]2)(=[O:40])=[O:39])=[CH:35][CH:34]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CC(CN1CCNCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Product: CC(CN1CCN(S(=O)(=O)c2ccc(Cl)s2)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1

Procedure:
This compound was prepared according to the procedure of Example 92, using 4-[1-(1-methyl-2-piperazin-1-ylethyl)-1H-pyrazol-4-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine and 5-chlorothiophene-2-sulfonyl chloride as the starting materials. 1H NMR (300 MHz, DMSO-D6): δ 12.05 (s, 1H); 8.62 (s, 1H); 8.60 (s, 1H); 8.22 (s, 1H); 7.54 (d, 1H); 7.48 (d, 1H); 7.28 (d, 1H); 6.90 (d, 1H); 4.63 (m, 1H); 2.85 (m, 5H); 2.61 (m, 3H); 2.41 (m, 2H); 1.41 (d, 3H); LCMS calculated for C20H23CIN7O2S2(M+H)+: m/z=492.0.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[C:16]([C:26]([O:28]CC)=O)[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:34][CH:33]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[C:16]([C:26]([N:41]3[CH2:42][CH2:43][CH:38]([C:35]4[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=4)[CH2:39][CH2:40]3)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1ccccc1Cl
Reactant: Fc1ccc(C2CCNCC2)cc1
Product: CC(C)(C)NS(=O)(=O)c1cnn2c(Nc3ccccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 46.9 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(2-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (4.25 g, 8.82 mmol) obtained in Example 6 step 3 and 4-(4-fluorophenyl)piperidine (1.87 g, 10.46 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (2.42 g, 59%) was obtained.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[C@H:20]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([C:30]4[N:31]=[C:32]5[C:37](=[CH:38][CH:39]=4)[N:36]=[C:35]([C:40]4[CH:61]=[CH:60][C:43]6[NH:44][C:45]([C@@H:47]7[CH2:52][C@@H:51]8[C@@H:49]([CH2:50]8)[N:48]7C(OC(C)(C)C)=O)=[N:46][C:42]=6[CH:41]=4)[CH:34]=[CH:33]5)[CH:28]=[CH:29][C:23]=3[N:22]=2)[CH2:19][C@@H:18]2[C@H:16]1[CH2:17]2)=O)(C)(C)C>C(Cl)Cl>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[C@@H:16]12[CH2:17][C@@H:18]1[CH2:19][C@@H:20]([C:21]1[NH:25][C:24]3[CH:26]=[C:27]([C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[C:35]([C:40]6[CH:61]=[CH:60][C:43]7[N:44]=[C:45]([C@@H:47]8[CH2:52][C@@H:51]9[C@@H:49]([CH2:50]9)[NH:48]8)[NH:46][C:42]=7[CH:41]=6)[N:36]=5)[N:31]=4)[CH:28]=[CH:29][C:23]=3[N:22]=1)[NH:15]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2cc(-c3ccc4nc(-c5ccc6nc([C@@H]7C[C@H]8C[C@H]8N7C(=O)OC(C)(C)C)[nH]c6c5)ccc4n3)ccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc2nc([C@@H]3C[C@H]4C[C@H]4N3)[nH]c2cc1-c1ccc2nc(-c3ccc4nc([C@@H]5C[C@H]6C[C@H]6N5)[nH]c4c3)ccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.6 %

Procedure:
TFA (0.25 mL, 3.2 mmol) was added to a solution of tert-butyl (1R,3S,5R)-3-(5-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-b enzimidazol-6-yl)-1,5-naphthyridin-2-yl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (20 mg, 0.028 mmol) in DCM (0.5 mL) and the mixture was stirred at rt for 16 h. The volatile were removed under vacuum and the residue was triturated with Et2O. The resulting solid was collected via filtration and rinsed with Et2O to yield a TFA salt of 2,6-bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridine (26 mg, 0.022 mmol, 78% yield) as a yellow solid. LC-MS retention time 1.41 min; m/z 525 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water: 10% methanol: 0.1% TFA. Solvent B=10% water: 90% methanol: 0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220). 1H NMR (400 MHz, MeOD) δ ppm 8.61 (2H, d, J=8.8 Hz), 8.51 (2H, s), 8.40 (2H, d, J=9.0 Hz), 8.23 (2H, dd, J=8.5, 1.5 Hz), 7.81 (2H, d, J=8.5 Hz), 4.74-4.97 (2H, m), 3.47-3.57 (2H, m), 2.78-2.88 (2H, m), 2.52-2.65 (2H, m), 2.04-2.15 (2H, m), 1.22-1.33 (2H, m), 0.99-1.11 (2H, m).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[CH3:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCN(C)CC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 31.7 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 69, 100 mg, 0.240 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (50.53 mg, 0.264 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was dissolved in EtOAc. The resulting solution was diluted with Hexanes to initiate the precipitation of the product. The solid precipitate that formed was filtered then washed with ˜1 mL of i-prOH yielding 32% (45 mg, 0.076 mmol) of the title compound.
Reaction SMILES: C[O-].[Na+].[Cl:4][CH2:5][C:6]1([CH3:24])[O:10][N:9]=[C:8]([S:11][CH2:12][C:13]2[C:14]([C:20]([F:23])([F:22])[F:21])=[N:15][N:16]([CH3:19])[C:17]=2F)[CH2:7]1.O.[C:26](OCC)(=[O:28])C>CO>[Cl:4][CH2:5][C:6]1([CH3:24])[O:10][N:9]=[C:8]([S:11][CH2:12][C:13]2[C:14]([C:20]([F:23])([F:22])[F:21])=[N:15][N:16]([CH3:19])[C:17]=2[O:28][CH3:26])[CH2:7]1
Reactant: CCOC(C)=O
Reactant: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1F
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(CSC2=NOC(C)(CCl)C2)c(C(F)(F)F)nn1C

Procedure:
0.9 g (4.4 mmoles) of sodium methoxide (in the form of a 28% methanol solution) was added, at room temperature, into a solution of 1.0 g (2.9 mmoles) of 5-chloromethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline dissolved in 10 ml of methanol. The mixture was heated for refluxing for 5 hours, to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order, and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 3.3 g (yield: quantitative) of 5-chloromethyl-3-(5-methoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmeth-ylthio)-5-methyl-2-isoxazoline.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[C:14]([C:29]#[N:30])=[N:15][CH:16]=[C:17]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][C:22]([F:27])([F:26])[C@@H:21]4[NH2:28])[N:18]=3)[CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:4][CH:5]=1.[OH-].[Na+].OO.CC(O)=[O:37]>CCO.CS(C)=O>[N:1]1[N:2]([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[C:14]([C:29]([NH2:30])=[O:37])=[N:15][CH:16]=[C:17]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][C:22]([F:27])([F:26])[C@@H:21]4[NH2:28])[N:18]=3)[CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:4][CH:5]=1
Reactant: CC(=O)O
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1cccc(-n2nccn2)c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1cccc(-n2nccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound 3-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)pyrazine-2-carbonitrile (41 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (38 mg). MS 430.3 (M+H); UV 202.3, 262.1, 299.7, 358.5 nm; t 0.488 min.
Reaction SMILES: O.[C:2]([O-])(=[O:4])C.[NH4+].C=O.[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:14]=1[OH:23])([CH3:12])([CH3:11])[CH3:10]>C(O)(=O)C>[C:19]([C:15]1[CH:16]=[C:17]([CH:18]=[C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:14]=1[OH:23])[CH:2]=[O:4])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: C=O
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Temperature: 25 °C
Yield: 67.4 %

Procedure:
A 500 ml reaction flask fitted with a mechanical stirrer, heating mantle, thermometer and water-cooled condenser was charged with 200 ml of glacial acetic acid, and 61.7 g (0.8 mole) of ammonium acetate. To the stirred mixture there were slowly added 97 g of 37% formalin (1.2 moles of formaldehyde) and 20.6 g (0.1 mole) of 2,6-ditert.-butylphenol. The reaction flask was equipped with a take-off head to remove the methanol which is present in commercially available formalin. The mixture was refluxed (107°-9°) for 6 hours. After cooling to ambient temperature, the mixture was poured on a vacuum filter and the product cake was washed with water. After drying, there was obtained 15.8 g of crystalline 3,5-ditert.butyl-4-hydroxybenzaldehyde, m.p. 184°-86° (67.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:15]=1)[C:7](=[NH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)C.Cl.[CH2:21]([O:23][C:24](=[O:32])[CH:25](N)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:22]>N1C=CC=CC=1>[CH2:21]([O:23][C:24](=[O:32])[CH:25]([N:14]=[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:6]1[CH:15]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:16])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:22]
Reactant: N=C(c1ccccc1)c1cc(Cl)ccc1O
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)C(N=C(c1ccccc1)c1cc(Cl)ccc1O)C(=O)OCC

Procedure:
A suspension of 9.2 g. of 5-chloro-2-hydroxy-benzophenone imine in 60 ml. of ethanol is treated with 12.6 g. of aminomalonic acid diethyl ester hydrochloride and 5.0 ml. of pyridine and the mixture boiled at reflux for 1 hour while stirring. The mixture is then concentrated to dryness under reduced pressure and the residue partitioned between toluene and water. The organic phase is washed with water, briefly dried over sodium sulfate and evaporated to dryness. The residual oily residue crystallizes upon trituration with hexane. There is obtained [(5-chloro-2-hydroxy-α-phenylbenzyliden)amino] malonic acid diethyl ester, having a melting point of 55°-56° C. Recrystallization from ethanol yields gold-yellowish leaflets having the same melting point.