Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][O:11]2)=[CH:4][CH:3]=1.[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1.[OH-].[Na+].O>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH2:12][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)([OH:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1
Reactant: CCCCCC1(CCc2ccc(Cl)cc2)CO1
Reactant: c1nc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCCCC(O)(CCc1ccc(Cl)cc1)Cn1cncn1
Temperature: 25 °C
Yield: 47 %

Procedure:
A solution of 89 g (0.352 mol) of 2-(4-chlorophenylethyl)-2-pentyl-oxirane, 26.5 g (0.384 mol) of 1,2,4-triazole, 3.5 g (0.0875 mol) of sodium hydroxide, 1.2 ml of water and a spatula tipful of α,α'-azoisobutyronitrile in 175 ml of N-methylpyrrolidone is heated at 120° C. for 4 hours. After this the mixture is cooled to room temperature and concentrated by stripping off the solvent under reduced pressure, the remaining residue is dissolved in ethyl acetate and washed three times with water, the organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure. The residue is purified by column chromatography (silica gel; dichloromethane:ethyl acetate=1:1). In this manner 53.2 g (47.0% of theory) of 1-(4-chlorophenyl)-3-(1,2,4-triazol-1-yl-methyl)-3-octanol are obtained in the form of a yellow oil.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]=[N+:18]=[N-:19])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].O[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[NH:34][C:35](=[O:45])[C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[C:38]([O:43][CH3:44])[CH:37]=3)=[CH:29][CH:28]=1.O>CN(C=O)C>[N:17]([CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[NH:34][C:35](=[O:45])[C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[C:38]([O:43][CH3:44])[CH:37]=3)=[CH:31][CH:32]=1)=[N+:18]=[N-:19]
Reactant: CS(=O)(=O)OCCOCCOCCOCCN=[N+]=[N-]
Reactant: COc1ccc2cc(-c3ccc(O)cc3)[nH]c(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2cc(-c3ccc(OCCOCCOCCOCCN=[N+]=[N-])cc3)[nH]c(=O)c2c1
Temperature: 80 °C
Yield: 23.1 %

Procedure:
2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl methanesulphonate (175 mg, 0.58 mmol) and Cs2CO3 (190 mg, 0.58 mmol) are added to a mixture of 3-(4-hydroxyphenyl)-7-methoxyisoquinolin-1(2H)-one (compound 45) (130 mg, 0.48 mmol) in DMF (6 mL). The reaction mixture is heated at 80° C. for 24 hours. Then the solvent is evaporated off, the reaction crude is added to water (100 mL) and extracted with CH2Cl2 (3×100 mL). The organic phase is dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on a silica column using a gradient of EtOH (1 to 3%) in CH2Cl2 as eluents. Intermediate 3-(4-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)phenyl)-7-methoxyisoquinolin-1(2H)-one (52 mg, 23%) is obtained, which is used directly in the following stage.
Reaction SMILES: [CH2:1]([SH:5])[CH:2]([SH:4])[CH3:3].Cl[CH:7]([CH3:11])[C:8](=O)[CH3:9]>>[CH3:3][CH:2]1[CH2:1][S:5][C:8]([CH3:9])=[C:7]([CH3:11])[S:4]1
Reactant: CC(S)CS
Reactant: CC(=O)C(C)Cl
Product: CC1=C(C)SC(C)CS1
Yield: 36.5 %

Procedure:
The procedure of Example 1(a) is repeated, using 1,2-propanedithiol and 3-chloro-2-butanone to give 2,3-dihydro-2,5,6-trimethyl-1,4-dithiin as a clear green liquid, bp 49.5°-51°/0.7 mm, yield 36.5% NMR 1.36 (3d), 1.88 (6s), 2.4-3.6 (3m) (CDCl3). IR, 2905 (sh); 1605, 1410 (broad); 1250, 1155 (sh); 1065 (br); 730, 705.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH:26]=[O:27])=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH2:26][OH:27])=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C=O)c2cnnc(OCc3ccc(F)cc3)c2n1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1c(CO)c2cnnc(OCc3ccc(F)cc3)c2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
A solution of 780 mg (2.08 mmol) of 1-benzyl-7-(4-fluorobenzyloxy) 3-formyl-2 -methylpyrrolo [2,3-d]pyridazine in 50 ml of ethanol is treated with 80 mg (2.1 mmol) of sodium borohydride and stirred at room temperature for 30 min. After addition of 100 ml of water, the mixture is concentrated on a rotary evaporator to half the volume. The precipitate is filtered off, washed with 50 ml of water and dried in a high vacuum over potassium hydroxide. 670 mg (85%) of the title compound are isolated. M.p.: 122°-124° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[N:9]/[S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.C[Si](C)(C)[C:18]([F:21])([F:20])[F:19]>C1COCC1.[Cl-].[NH4+]>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([NH:9][S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[C:18]([F:21])([F:20])[F:19])=[CH:4][CH:3]=1
Reactant: CC(C)(C)S(=O)/N=C/c1ccc(Br)nc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC(c1ccc(Br)nc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a chilled (−20° C.) solution of 2-methyl-propane-2-sulfinic acid 1-(6-bromo-pyridin-3-yl)-meth-(E)-ylideneamide (1.25 g, 4.32 mmol) and tetrabutylammonium triphenyldifluorosilicate (2.6 g, 4.82 mmol) in THF (20 mL) was added a solution of trimethyl(trifluoromethyl)silane (1 g, 7.0 mmol) in THF (10 mL) in several portions. After 30 minutes, the mixture was warmed to room temperature. The reaction was monitored by TLC (ethyl acetate-hexanes 2:8). The mixture was diluted with saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (2×20 mL), dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography eluting with a gradient of 0-20% ethyl acetate in hexanes. The material from the column was triturated with ether-hexanes to afford 2-methyl-propane-2-sulfinic acid [1-(6-bromo-pyridin-3-yl)-2,2,2-trifluoro-ethyl]-amide.
Reaction SMILES: Br[C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[OH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1B(O)O>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:13]([C:3]1[C:2]([C:24]2[CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=[CH:28][C:23]=2[OH:22])=[CH:6][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[N:4]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1nn(C2CCCCO2)cc1Br
Reactant: OB(O)c1cc(C(F)(F)F)ccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=[N+]([O-])c1nn(C2CCCCO2)cc1-c1cc(C(F)(F)F)ccc1O
Temperature: 75 °C
Yield: 53.8 %

Procedure:
To a solution of 4-bromo-3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (Preparation 869, 18.95 g, 0.06864 mol) in 1,2-dimethoxyethane (175 mL) was added aqueous potassium carbonate (2M in water, 68.0 mL, 0.123 mol) and tetrakis(triphenylphosphine)palladium(0) (6.34 g, 0.00549 mol). The reaction was sparged 3 times with Argon and heated to 75° C. To this, [2-hydroxy-5-(trifluoromethyl)phenyl]boronic acid (Preparation 871, 21.22 g, 0.103 mol) was added in four portions over six hours. The reaction solution was heated for an additional 12 hours and then allowed to cool. The mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification by automated flash column chromatography using a 0-50% ethyl acetate/hexanes gradient and a 80 g column gave the title compound (13.2 g, 54%) as a yellow oil.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[CH2:16][C:17](Cl)=[O:18]>C(OCC)(=O)C>[Cl:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[CH2:16][C:17]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:18]
Reactant: CCNCC
Reactant: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1Cl
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)Cc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.67 mL (54.0 mmol) of diethylamine is dissolved in 50 mL of ethyl acetate and 3.20 g (13.7 mmol) of (2-chloro-4-nitrophenyl)acetic acid chloride (VI.1.a) in 50 mL of ethyl acetate is slowly added dropwise at 0° C. Then the mixture is stirred for another 2 hours at ambient temperature. After this time, some more ethyl acetate is added and the mixture is washed twice with water and twice with saturated saline solution. The organic phase is dried over sodium sulfate, the solvent is eliminated and the residue is dried in vacuo. Yield: 3.70 g (100% of theory); Rf value: 0.45 (silica gel, petroleum ether/ethyl acetate=1:1); C12H15ClN2O3; EII mass spectrum: m/z=271/273 [M+H]+.
Reaction SMILES: [CH:1]1([C:5]2[C:6]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:20][S:21]([CH2:24][C:25]([NH2:33])([CH3:32])[C:26]1[N:30]=[C:29]([CH3:31])[O:28][N:27]=1)(=[O:23])=[O:22]>>[CH3:20][S:21]([CH2:24][C:25]([NH:33][C:11]([C:8]1[CH:7]=[C:6]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)=[CH:10][N:9]=1)=[O:13])([CH3:32])[C:26]1[N:30]=[C:29]([CH3:31])[O:28][N:27]=1)(=[O:22])=[O:23]
Reactant: Cc1nc(C(C)(N)CS(C)(=O)=O)no1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CCC2)cn1
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(OCC(F)(F)F)c(C3CCC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 23b, using 5-Cyclobutyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 108f) and 2-Methanesulfonyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 109d) as starting materials and isolated (62 mg, 45%) as colorless oil; MS (ESI, m/z): 477.6 (M+H+).
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14]>C1COCC1>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][NH:2][CH3:1])=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CCBr
Solvent: C1CCOC1
Product: CNCCc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of methyl amine in THF (2 M, 200 mL) was added 1-(2-bromo-ethyl)-4-chloro-2-nitro-benzene (17.5 g, 0.066 mole) in a pressure bottle, the reaction mixture was stirred at 60° C. overnight and the solvent was removed. The solid residue was treated with sodium hydroxide (1 N, 100 mL) and the aqueous extracted with methylene chloride (2×100 mL). The combined organic layers were washed with water (100 mL), saturated sodium chloride (100 mL), dried (sodium sulfate) and concentrated to provide 14.9 g of the title compound as a brown oil. 1H NMR (DMSO-d6): 7.95 δ (d, 1H); 7.67 δ (dd, 1H); 7.50 δ (t, 1H); 3.28 δ (broad, 1H); 2.85 δ (t, 2H); 2.64 δ (t, 2H); 2.20 δ (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][NH2:11])=[CH:4][C:3]=1[CH3:12].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21]>ClCCl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][NH:11][C:20](=[O:22])[CH3:21])=[CH:4][C:3]=1[CH3:12]
Reactant: CC(=O)Cl
Reactant: Cc1cc(CCN)cc(C)c1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCc1cc(C)c(Br)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) solution of 2-(4-bromo-3,5-dimethylphenyl)ethanamine (100 mg) and triethylamine (68 μL) in dichloromethane (3 mL) is added acetyl chloride (31 μL). The mixture is stirred for 2 hours at 0° C. Then the mixture is partitioned between dichloromethane and water. The organic phase is separated and dried (MgSO4). The solvent is evaporated and the residue is purified by HPLC on reversed phase to give the title compound. Yield: 25 mg; LC (method 7): tR=0.98 min; Mass spectrum (ESI+): m/z=270 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[C:3]#[N:4].C#C.[CH:8]1[CH:13]=CC=[CH:10][CH:9]=1>[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Co+2]>[CH3:1][N:2]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:13][N:4]=1)[CH3:5]
Reactant: c1ccccc1
Reactant: CN(C)C#N
Agent: [Co+2]
Agent: C#C
Agent: c1cc[cH-]c1
Product: CN(C)c1ccccn1
Temperature: 70 °C

Procedure:
3.1 gm. of cobaltocene (0.016 mole) under nitrogen was dissolved in 44.0 gm. of benzol. The solution mixed with 164 gm. of anhydrous N,N-dimethylcyanamide (2.3 moles). The reaction mixture was saturated with 12 atm. of acetylene at 20° C. in a 1-liter autoclave (with stirring). The reaction mixture was heated to 70° C. Then at the beginning of the exothermal reaction, the heating was carefully increased so that a temperature of 160° C. prevailed in the autoclave. After a drop in pressure in the autoclave to below 12 atm., acetylene was repressed on. After 10 hours of reaction time, the autoclave was cooled down and expansion allowed. As a result of fractional distillation, 238 gm. of 2-(N,N-dimethylamino)-pyridine (boiling point: 92° C., 21 torr) was obtained, after benzol and a small quantity of N,N-dimethylcyanamide had been obtained. The 2-(N,N-dimethylamino)-pyridine had a purity of 99.8 percent--this corresponded to a yield of 84.5 percent.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]([NH2:14])=[NH:13].O=[C:16]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH2:17][C:18](OCC)=[O:19]>CN1CCCC1=O.C(O)C>[OH:19][C:18]1[N:14]=[C:12]([NH:11][C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[CH3:1])[N:13]=[C:16]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH:17]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=N)N
Reactant: CCOC(=O)CC(=O)c1cccnc1
Solvent: CN1CCCC1=O
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nc(O)cc(-c2cccnc2)n1
Temperature: 150 °C

Procedure:
40 g (2-methyl-5-nitrophenyl)guanidine in 160 mL N-methyl pyrrolidone is dissolved. The mixture is heated to 150° C. and ethyl β-oxo-3-pyridine propionate is added portionwise, to 50 g total in a time period of 5 hours, distillating about 15 g of by-products under a nitrogen flow. At the end of the reaction, the mixture is cooled and diluted with ethanol. The precipitate is filtrated, yielding, upon drying, 46.4 g of product with HPLC purity of 99% (A %), identified through LC-MS and 1H-NMR.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@H:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:30][C:31]1[CH:36]=[C:35]([NH:37][C:38]2[N:43]=[C:42](Cl)[N:41]=[C:40](Cl)[N:39]=2)[CH:34]=[CH:33][C:32]=1[NH:46][C:47](=[O:49])[CH3:48])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([O:30][C:31]1[CH:36]=[C:35]([NH:37][C:38]2[N:43]=[C:42]([N:11]3[CH2:12][C@@H:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10]3)[N:41]=[C:40]([N:11]3[CH2:12][C@@H:13]([NH:15][C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:14][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10]3)[N:39]=2)[CH:34]=[CH:33][C:32]=1[NH:46][C:47](=[O:49])[CH3:48])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)Nc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](NC(=O)OC(C)(C)C)C1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Nc2nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)n2)cc1OCc1ccccc1
Temperature: 80 °C
Yield: 95 %

Procedure:
(3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidine (4) (1.68 g, 5.33 mmol) was suspended in DMF (20 mL), sonicated for 2 minutes and added to the crude reaction mixture containing N-[2-benzyloxy-4-(4,6-dichloro-[1,3,5]triazin-2-ylamino)-phenyl]-acetamide (400). The mixture was heated to 80° C. for 8 h. LC-MS indicated complete reaction at this point. The mixture was concentrated to a volume of 50 mL and poured into ice-water. A white solid precipitated immediately and was collected by filtration under reduced pressure followed by drying under high vacuum for 16 h to give the desired product (401) as a white powder (2.32 g, 2.4 mmol, 95% total yield for two steps). LC-MS (ESI): (exact mass: 961.54) m/e=962.7 [M+1]+ (100%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13]/[C:14](=[N:17]/[H])/[NH:15][OH:16].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Cl:40][C:41]1[N:45]([CH3:46])[N:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[C:42]=1[C:51](O)=O.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13][C:14]1[N:17]=[C:51]([C:42]2[C:43]([C:47]([F:50])([F:48])[F:49])=[N:44][N:45]([CH3:46])[C:41]=2[Cl:40])[O:16][N:15]=1
Reactant: Cn1nc(C(F)(F)F)c(C(=O)O)c1Cl
Reactant: [H]/N=C(/Cn1c(CCC)cc2c(Cl)c(C#N)ccc21)NO
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2c(C(F)(F)F)nn(C)c2Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Synthesized as described in Example 32A and Example 33 using (1Z)-2-(4-chloro-5-cyano-2-propyl-1H-indol-1-yl)-N-hydroxyethanimidamide (0.030 g, 0.1 mmol) in anhydrous THF (5 mL) with propanephosphonic acid cyclic anhydride (T3P) (0.034 g, 0.12 mmol), 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (0.023 g, 0.1 mmol) and DIEA (0.016 g, 0.12 mmol) and stirred at rt for 1 h and then heated at 120° C. for 2 h in the microwave: 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=8.6 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.31 (s, 1H), 4.99 (s, 2H), 3.95 (s, 3H), 2.87 (t, 2H), 1.80-1.58 (m, 2H), 1.01 (t, 3H); MS (ES) m/z 484 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH3:16])[CH:9]=2)[C:3]=1[CH:17]=O.FC(F)(F)C(O)=O.C[SiH](C)C>O>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH3:16])[CH:9]=2)[C:3]=1[CH3:17]
Reactant: COc1ccc(-c2nn(C)c(Cl)c2C=O)cc1C
Agent: C[SiH](C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(-c2nn(C)c(Cl)c2C)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
At 0° C., a mixture of 5-chloro-4-formyl-3-(4-methoxy-3-methyl-phenyl)-1-methyl-1H-pyrazole (described in Reference Preparation example 91) 0.3 g and trifluoroacetic acid 10 ml was added trimethylsilane 0.27 g. The resulting mixture was stirred at room temperature for three hours, and thereto was added water 5 ml. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 5-chloro-3-(4-methoxy-3-methyl-phenyl)-1,4-dimethyl-1H-pyrazole 0.28 g.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[CH:7]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14]>CN1C(=O)CCC1.O>[Br:1][C:2]1[N:3]=[C:4]([NH:16][CH:13]([CH3:15])[CH3:14])[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[CH:7]=1
Reactant: Cc1nnc2c(Cl)nc(Br)cn12
Reactant: CC(C)N
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nnc2c(NC(C)C)nc(Br)cn12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
6-bromo-8-chloro-3-methyl-[1,2,4]triazolo[4,3-a]pyrazine J-1 (30.00 g; 121.2 mmol), isopropylamine (14.30 g; 242.44 mmol) and hünigbase (17.20 g; 133.33 mmol) are dissolved in 150 ml NMP and are stirred for 2 hours at 80° C. The reaction mixture is diluted with water and extracted with EtOAc. The organic layer is separated and dried over MgSO4 and evaporated to dryness.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Cl[CH2:12][C:13]([OH:15])=[O:14].Cl>C1(C)C=CC=CC=1.O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1
Reactant: O=C(O)CCl
Reactant: Sc1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)CSc1ccc(Br)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To water (600 mL) solution of 88.9 g of sodium hydroxide was added 200 g of 4-bromothiophenol and dropwise added water (300 mL) solution of 105 g of chloroacetic acid, which was then stirred at 60 to 70° C. for 1 hour. After cooling the reaction mixture to 40° C., thereto were added 140 mL of hydrochloric acid and 600 mL of toluene, which was then heated to 80° C. The organic layer was separated and slowly cooled to 5° C. After stirring at the same temperature for 1 hour, the crystals precipitate was collected by filtration to provide 243 g of (4-bromophenylthio)acetic acid as white solid form.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:17])=[CH:16][C:3]=12.CC(C)([O-])C.[Na+].[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.CN(C=O)C>[Br:17][C:15]1[S:14][C:4]2=[N:5][C:6]([CH3:13])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([NH:1][S:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:32])=[O:31])=[C:3]2[CH:16]=1
Reactant: CCOC(=O)c1c(C)nc2sc(Br)cc2c1N
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)nc2sc(Br)cc2c1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
To a stirring mixture of ethyl 4-amino-2-bromo-6-methylthieno[2,3-b]pyridine-5-carboxylate (Description 66) (5.84 g, 18.53 mmol) in THF (110 mL) and DMF (55 mL) was added sodium tert-butoxide (4.45 g, 46.3 mmol) and benzenesulfonyl chloride (4.75 mL, 37.1 mmol). The resulting mixture was stirred at RT for 30 min. The reaction mixture was quenched with saturated ammonium chloride solution (ca. 150 mL) and extracted with DCM (80 mL×3). The combined organic layers were dried and concentrated. The residue was purified via normal phase chromatography, eluting with 0-30% ethyl acetate in DCM, to give the title compound (6.27 g). LCMS (A) m/z: 455/457 [M+1]+, Rt 1.35 min (acidic).
Reaction SMILES: [CH3:1][N:2]1[CH2:29][CH2:28][CH2:27][C@:3]1([CH3:30])[C:4]([NH:6][C@H:7]([C:11]([N:13]([C@@H:15]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C@H:16]([O:21][CH3:22])[CH2:17][C:18]([OH:20])=[O:19])[CH3:14])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5].N1C=CC=CC=1.FC(F)(F)C(O[C:42]1[C:47]([F:48])=[C:46]([F:49])[C:45]([F:50])=[C:44]([F:51])[C:43]=1[F:52])=O>ClCCl>[CH3:1][N:2]1[CH2:29][CH2:28][CH2:27][C@:3]1([CH3:30])[C:4]([NH:6][C@H:7]([C:11]([N:13]([C@@H:15]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C@H:16]([O:21][CH3:22])[CH2:17][C:18](=[O:20])[O:19][C:42]1[C:43]([F:52])=[C:44]([F:51])[C:45]([F:50])=[C:46]([F:49])[C:47]=1[F:48])[CH3:14])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(C)CCCN1C)C(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(C)CCCN1C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled solution (0° C.) of #196 (4.0 g, 9.4 mmol, 1 eq.) in dichloromethane (40 mL) was added dropwise pyridine (2.95 g, 37.6 mmol, 4 eq.) followed by a solution of pentafluorophenyl trifluoroacetate (3.9 g, 13.6 mmol, 1.4 eq.) in dichloromethane (5 mL). The mixture was stirred at room temperature for one hour, and the solvent was concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 1 to 10% methanol in dichloromethane) to afford compound #197 (4.5 g, 81.2% (over three steps) as white solid.