Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]3[CH2:21][CH2:20]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][C:4]=1Br.[CH3:23][C:24]1([CH3:44])[C:33]2[C:28](=[CH:29][CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[C:27](=[O:43])[NH:26][CH2:25]1>>[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]3[CH2:21][CH2:20]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:43])[NH:26][CH2:25][C:24]2([CH3:44])[CH3:23]
Reactant: Nc1ncc(-c2ccc(S(=O)(=O)NC3CC3)cc2)cc1Br
Reactant: CC1(C)CNC(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: Br
Product: CC1(C)CNC(=O)c2ccc(-c3cc(-c4ccc(S(=O)(=O)NC5CC5)cc4)cnc3N)cc21
Yield: 37.2 %

Procedure:
General method C was applied to 4-(6-amino-5-bromopyridin-3-yl)-N-cyclopropylbenzenesulfonamide hydrobromide (92 mg, 0.25 mmol) and 4,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (75 mg, 0.25 mmol) to give 4-(6-amino-5-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)-N-cyclopropylbenzenesulfonamide (43 mg, 37% yield) as a white solid after purification by flash chromatography over silica gel (2-5% MeOH/DCM eluent). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.61 (s, 1H), 8.06 (d, J=8.5 Hz, 2H), 7.96-8.02 (m, 2H), 7.80 (d, J=1.5 Hz, 1H), 7.75 (dd, J=7.5, 1.5 Hz, 1H), 7.62 (d, J=8.5 Hz, 2H), 6.00 (s, 2H), 3.20 (d, J=2.0 Hz, 2H), 2.06-2.18 (m, 1H), 1.33 (s, 6H), 0.33-0.55 (m, 4H); MS (EI) m/z=463.6 [M+1]+.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[C:13](=[O:17])[CH2:14][O:15][CH2:16][C:10]3=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C[AlH]CC(C)C)C>ClCCl>[C:1]1([C:7]2[N:12]=[C:11]3[C:13]([OH:17])=[CH:14][O:15][CH2:16][C:10]3=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1COCc2ccc(-c3ccccc3)nc21
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OC1=COCc2ccc(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To a cooled solution (-70° C.) of 2-phenyl-8-oxopyrano[4,3-b]pyridine (1.09 g, 4.84 mmol) in dichloromethane (25 ml) was added DIBAL (1M in dichloromethane, 9 ml) keeping the temperature below -65° C. The reaction mixture was held at -70° C. for 4 hours. The reaction mixture was quenched by adding MeOH/dichloromethane (5 ml) (1/1), allowed to warm to ambient temperature and poured onto a slurry of SiO2 and dichloromethane. The silica slurry was applied to the top of a chromatography column which was eluted with methanol/dichloromethane to give 2-phenyl-8-hydroxypyrano[4,3-b]pyridine as a pale yellow solid (0.89 g, 81%). (It was used immediately in the following step)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[NH:12][N:11]=2)[CH:6]=[CH:7][C:8]=1[Cl:9].[I:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[I:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:12]2[CH:13]([CH3:16])[CH2:14][CH2:15][C:10]([C:5]3[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([C:2]([F:17])([F:1])[F:18])[CH:4]=3)=[N:11]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CC1CCC(c2ccc(Cl)c(C(F)(F)F)c2)=NN1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: ClCCl
Product: CC1CCC(c2ccc(Cl)c(C(F)(F)F)c2)=NN1S(=O)(=O)c1ccc(I)cc1
Temperature: 105 °C
Yield: 14.8 %

Procedure:
3-(3-trifluoromethyl-4-chlorophenyl)-6-methyl-1,4,5,6-tetrahydropyridazine (700 mg) was combined with 4-iodobenzenesulfonyl chloride (558 mg) and heated to 105° C. for 3 h. Dichloromethane was added and the solution washed with water, 10% HCl, sat'd NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered and solvent removed at reduced pressure to give a residue which was recrystallized from acetone/hexane to give 148 mg of the title compound with mp 157°-158° C.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[CH2:21]([NH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][NH:28][CH2:27]2)[CH3:22].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH2:21]([NH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:27]2)[CH3:22]
Reactant: CCNc1ccc2c(c1)CNC2
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCNc1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn4c3c1OCC4C)C2
Yield: 51.3 %

Procedure:
141 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 97 mg of 5-ethylaminoisoindoline, 152 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 1 to produce 109 mg of the target compound.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][CH:13]=[N:14][CH:15]=2)[NH:10][C:9](=O)[CH:8]1[CH3:18])=[O:6])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][CH:13]=[N:14][CH:15]=2)[NH:10][C:9](=[S:28])[CH:8]1[CH3:18])=[O:6])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)OC(=O)N1c2cncnc2NC(=O)C1C
Product: CC(C)OC(=O)N1c2cncnc2NC(=S)C1C
Yield: 28 %

Procedure:
100 mg of (2RS)-1-(isopropoxycarbonyl)-2-methyl-1,2-dihydro-1,4,5,7-tetraazanaphthalen-3(4H)-one from Example 24 were reacted with Lawesson's reagent in analogy to Example 20. The crude product after concentration was chromatographed (silica gel; ethyl acetate/heptane=1:1). 30 mg (28%) of the desired compound, of melting point 203°-204° C., were obtained.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:26])=[CH:10][CH2:11][CH2:12][C:13]([CH3:25])=[CH:14][CH2:15][CH2:16][C:17]([CH3:24])=[CH:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[C:3]([OH:5])=O.[CH2:27]([NH2:29])[CH3:28]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:26])=[CH:10][CH2:11][CH2:12][C:13]([CH3:25])=[CH:14][CH2:15][CH2:16][C:17]([CH3:24])=[CH:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[C:3]([NH:29][CH2:27][CH3:28])=[O:5]
Reactant: CCN
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: CCNC(=O)C(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=O

Procedure:
Starting materials: 2,6,10,14-tetramethyl-18-oxo-2,6,10,14-nonadecatetraenoic acid and a 70% aqueous ethylamine solution
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:28]([O:30]C)=[O:29])[CH2:7][CH2:6]1)(=[O:4])=[O:3].[OH-].[Na+]>CO.C1COCC1>[CH3:1][S:2]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:20][CH:21]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:28]([OH:30])=[O:29])[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2N(S(C)(=O)=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(C(=O)O)=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
In methanol (100 ml) and THF (100 ml) was dissolved methyl 1-methanesulfonyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.4 g). To the solution was added 1N sodium hydroxide solution (10 ml), and the mixture was stirred at room temperature overnight. To the mixture was added 1N sodium hydroxide solution (5 ml), and the mixture was stirred at 60° C. for 1.5 hours and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 1-methanesulfonyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.36 g) as pale yellow crystals.
Reaction SMILES: Cl.[F:2][C:3]1[NH:4][CH:5]=[CH:6][N:7]=1.[OH-].[K+].[CH2:10](Br)/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(C)=O>[CH2:10]([N:4]1[CH:5]=[CH:6][N:7]=[C:3]1[F:2])/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrC/C=C/c1ccccc1
Reactant: Fc1ncc[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Fc1nccn1C/C=C/c1ccccc1
Reaction time: 0.17 h

Procedure:
2-Fluoroimidazole hydrochloride was added to a suspension of powdered KOH in acetone, stirred for 10 minutes, and E-cinnamyl bromide added. After stirring 1 hour, the mixture was worked up by extraction and chromatography to give E-1-cinnamyl-2-fluoro-imidazole, having the following n.m.r. in CDCl3 : 4.6 (d, 2H); 6.1-6.4 (d of t, 1H); 6.6 (d, 1H); 6.6-6.8 (m, 2H); 7.2-7.5 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH3:15])[N:5]2[S:6](=[O:12])(=[O:11])[NH:7][C:8](=[O:10])[N:9]=[C:4]2[N:3]=1.[CH3:16][O:17][NH:18][CH3:19]>C(Cl)Cl>[CH3:16][O:17][N:18]([S:6]([NH:7][C:8]([NH:9][C:4]1[N:3]=[C:2]([CH3:1])[CH:14]=[C:13]([CH3:15])[N:5]=1)=[O:10])(=[O:12])=[O:11])[CH3:19]
Reactant: CNOC
Reactant: CC1=CC(C)=NC2=NC(=O)NS(=O)(=O)N12
Solvent: ClCCl
Product: CON(C)S(=O)(=O)NC(=O)Nc1nc(C)cc(C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.7 %

Procedure:
5.7 g (0.025 mol) of 2,3-dihydro-6,8-dimethyl-3-oxopyrimidino-[1,2-b][1,2,4,6]-thiatriazine 1,1-dioxide (cf. Example 1) are suspended in 100 ml of methylene dichloride, and 3.05 g (0.05 mol) of O,N-dimethylhydroxylamine--dissolved in 50 ml of methylene dichloride--are added at -40° C. in the course of one hour. The mixture is stirred for a further 18 hours at room temperature and evaporated to dryness, and the residue is taken up in water and acidified to pH 4-5 with 0.5 N HCl. After extraction with methylene dichloride, the mixture is worked up as under Example 17. 4.9 g (67.8% of theory) of 1-[(N-methoxy-N-methylamino)-sulfonyl]-3-(4,6-dimethyl-2-pyrimidinyl)-urea of melting point 152° C. are obtained.
Reaction SMILES: [C:1]1([CH3:22])[C:2]([S:7]([N:10]([CH2:18][C:19]([OH:21])=O)[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:23]([NH:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH3:24]>>[CH2:23]([N:25]([CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[C:19](=[O:21])[CH2:18][N:10]([S:7]([C:2]1[C:1]([CH3:22])=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])=[O:9])[C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[CH3:24]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cc1
Reactant: CCNCc1cccnc1
Product: CCN(Cc1cccnc1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(toluene-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-pyridin-3-ylmethyl-amine
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[C:10](=[O:29])[N:11]([CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[N:12]([CH2:15][C:16]#[N:17])[C:13](=[O:14])[C:8]=2[N:7]=[C:6]1Cl)[C:2]#[C:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[C:37]([O:41][C:42]([NH:44][C@@H:45]1[CH2:50][CH2:49][CH2:48][NH:47][CH2:46]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].O>CS(C)=O>[CH2:1]([N:5]1[C:9]2[C:10](=[O:29])[N:11]([CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[N:12]([CH2:15][C:16]#[N:17])[C:13](=[O:14])[C:8]=2[N:7]=[C:6]1[N:47]1[CH2:48][CH2:49][CH2:50][C@@H:45]([NH:44][C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:43])[CH2:46]1)[C:2]#[C:3][CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CC#CCn1c(Cl)nc2c(=O)n(CC#N)n(Cc3ccc4ccccc4n3)c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c(=O)n(CC#N)n(Cc3ccc4ccccc4n3)c(=O)c21

Procedure:
A solution of 0.14 g 1-(but-2-ynyl)-2-chloro-5-cyanomethyl-6-(quinolin-2-ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione, 0.15 g potassium carbonate and 0.07 g (R)-3-tert-butoxycarbonylaminopiperidine in 2 ml dimethylsulphoxide is stirred for 5 h at 60° C. Then water is added and the mixture is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulphate, and then the solvent is removed. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:1).
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1C(O)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:27]([O:29][CH3:30])=[O:28])#[C:22][C:23]([O:25][CH3:26])=[O:24]>C(OC(=O)C)(=O)C>[CH3:26][O:25][C:23]([C:22]1[C:21]([C:27]([O:29][CH3:30])=[O:28])=[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:9]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11][C:10]=12)=[O:24]
Reactant: O=C(O)C1Cc2ccccc2N1C(=O)c1ccccc1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1c(C(=O)OC)c(-c2ccccc2)n2c1Cc1ccccc1-2
Temperature: 120 °C

Procedure:
A mixture of 1-benzoyl-2,3-dihydro-1H-indole-2-carboxylic acid (7.48 g, 28 mmol) and dimethyl acetylenedicarboxylate (4.55 g, 32 mmol) in acetic anhydride (40 mL) was heated for 4.5 h at 120° C. until no gas was eliminated. The dark solution was concentrated in vacuo to dryness and the solid residue was recrystallized from methanol to yield 3-phenyl-8H-3a-azacyclopenta[a]indene-1,2-dicarboxylic acid dimethyl ester, 7.5 g (77%): mp 149-151° C.; 1H NMR (DMSO-d6) δ 3.62 (3H, s, OMe), 3.79 (3H, s, OMe), 4.15 (2H, s, CH2), 6.60-6.67 (1H, m, ArH), 7.18-7.23 (2H, m, 2×ArH), 7.51-7.67 (6H, m, 6×ArH). Anal. Calcd for C21H17NO4: C, 69.40; H, 5.21; N, 3.85. Found: C, 69.42; H, 4.65; N, 3.83.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:24][CH3:25])=[C:5]([CH3:26])[O:4][N:3]=1.[N:27]([CH2:30][CH2:31][O:32][CH3:33])=[C:28]=S>>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:24][CH3:25])=[CH:9][C:10]3[C:11]4[N:18]([CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[C:28]([NH:27][CH2:30][CH2:31][O:32][CH3:33])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: COCC(C)Nc1c(N)cnc2cc(-c3c(C)noc3C)c(OC)cc12
Reactant: COCCN=C=S
Product: COCCNc1nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c2n1C(C)COC
Yield: 47 %

Procedure:
From 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(1-methoxypropan-2-yl)quinoline-3,4-diamine (for a preparation see Intermediate 19) (70 mg) and 1-isothiocyanato-2-(methyloxy)ethane (50 mg) to give the title compound as beige solid (41 mg, 47%). LCMS (formate) Rt 0.56 min, MH+ 440.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.CCN(C(C)C)C(C)C.[CH:42]1([CH2:45][N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:44][CH2:43]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:49]3[CH2:50][CH2:51][N:46]([CH2:45][CH:42]4[CH2:44][CH2:43]4)[CH2:47][CH2:48]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: C1CN(CC2CC2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cn(CC(=O)N2CCN(CC3CC3)CC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (10 mL) was added DIEA (83 mg, 0.64 mmol), 1-(cyclopropylmethyl)piperazine (60.6 mg, 0.43 mmol) and HATU. The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The crude product (120 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, CH3CN:H2O=5:95 increasing to CH3CN:H2O=24:40 within 14 min; Detector, UV 254 nm. This resulted in 47.6 mg (38%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(cyclopropylmethyl)piperazin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (Method 20) [M+H]+=585.2, RT=2.40 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz), 7.02 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 3.51-3.49 (m, 4H), 2.49-2.41 (m, 4H), 2.23-2.21 (m, 2H), 0.87-0.82 (m, 1H), 0.50-0.44 (m, 2H), 0.13-0.08 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([CH3:12])[N:3]=1.C(N(CC)CC)C.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([NH:27][C:6]1[CH:5]=[C:4]([CH3:12])[N:3]=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(NCc2ccccc2)c([N+](=O)[O-])c(Cl)n1
Temperature: 25 °C
Yield: 26.6 %

Procedure:
2,4-Dichloro-6-methyl-3-nitro-pyridine (2 g, 9.7 mmol) and triethylamine (1.35 mL, 9.7 mmol) were dissolved in 40 mL THF and cooled (ice/water) to ˜5° C. A solution of benzylamine (1.04 g, 9.7 mmol) in 10 mL THF was added dropwise and the mixture was then allowed to warm gradually to room temperature overnight. The mixture was evaporated in vacuo, partitioned between EtOAc (50 mL) and water (20 mL). The organic layer was washed with saturated aqueous NaHCO3 (10 mL), dried (MgSO4) and evaporated in vacuo to an orange gum. This gum was preabsorbed onto silica gel and then purified by column chromatography, eluting with DCM:pentane 3:1. Appropriate fractions combined and evaporated in vacuo to yield the title compound as a yellow solid (716 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH2:20]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][N:21]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:26]2[CH2:27][CH2:28][C:23]3([CH2:22][N:21]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH2:20]3)[CH2:24][CH2:25]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC2(CCN(c3ccc([N+](=O)[O-])cc3)CC2)C1
Temperature: 100 °C

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (0.155 ml, 1.458 mmol) in DMSO was added N,N-diisopropylethylamine (0.926 ml, 5.30 mmol) followed by tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (300 mg, 1.326 mmol). The reaction mixture was heated to 100° C. overnight, and cooled to room temperature. The reaction mixture was quenched with 75 mL water, filtered, washed with water and dried over high-vac to provide the title compound. MS (ESI+) m/z 348.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[CH2:36]=O>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][CH2:26][N:25]([CH3:36])[CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C1CCCNC1
Reactant: C=O
Product: CN1CCCC(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(1-methylpiperidin-3-yl)-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperidin-3-yl-1,3-thiazolidine-2,4-dione (Example 124) and formaldehyde following General Procedure R.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].C([Li])CCC.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C>C1COCC1>[NH:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([B:18]([OH:23])[OH:19])=[C:3]2[CH:10]=[CH:9]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccnc2[nH]ccc12
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: OB(O)c1ccnc2[nH]ccc12
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 76.1 %

Procedure:
4-Bromo-1H-pyrrolo[2,3-b]pyridine (0.944 g, 4.79 mmol) in THF (10 ml) was added dropwise to sodium hydride (0.240 g, 5.99 mmol) in THF (10 ml) at 20° C. under nitrogen. The resulting mixture was stirred at 20° C. for 10 minutes. The reaction mixture was cooled to −78° C. and n-butyllithium in hexanes (2.396 mL, 5.99 mmol) was added dropwise over 10 minutes and stirred at −78° C. for 10 minutes. Triisopropyl borate (3.32 mL, 14.37 mmol) was added dropwise over 2 minutes and the reaction mixture allowed to warm to RT over 1.5 hours. The reaction mixture was quenched with water (10 ml) and C18 silica gel was added (10 g) and the mixture was concentrated in vacuo. The resultant solid was purified by reverse phase flash silica chromatography, eluting with a gradient of 5 to 40% acetonitrile in water. Pure fractions were evaporated to afford 1H-pyrrolo[2,3-b]pyridin-4-ylboronic acid (0.590 g, 76%); m/z: (ES+) MH+, 162.88.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[O-]CC.[Na+].[C:15]([Si:19]([CH3:28])([CH3:27])[O:20][CH2:21][CH2:22][CH2:23][C:24](=[O:26])[CH3:25])([CH3:18])([CH3:17])[CH3:16]>>[CH2:9]([O:8][C:1](=[O:7])[C:2](=[O:4])[CH2:25][C:24](=[O:26])[CH2:23][CH2:22][CH2:21][O:20][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:27])[CH3:28])[CH3:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)CCCO[Si](C)(C)C(C)(C)C
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)CC(=O)CCCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 16.6 %

Procedure:
Diethyl oxalate (4.048 g, 37.7 mmol) was added to solid sodium ethoxide (0.472 g, 69.3 mmol) at 0° C. followed by slow addition of 5-(tert-butyl-dimethyl-silanyloxy)-pentan-2-one (1.500 g, 69.3 mmol). The resulting orange solution was stirred at 0° C. for 10 minutes and at room temperature for 3 h. Purification by flash chromatography (19:1 hexanes:EtOAc to 9:1 EtOAc:MeOH) provided the title compound (1.982 g); MS 317 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11]([OH:13])[CH2:10][N:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11]([O:13][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:10][N:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1c1cccc(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@@H]1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2R,4R)-tert-butyl 2-(3-fluorophenyl)-4-hydroxypyrrolidine-1-carboxylate (I-4A) (253 mg, 0.9 mmol) in DCM (6 mL) at 0° C. was added triethylamine (0.25 mL, 1.8 mmol) followed by dropwise addition of methanesulfonyl chloride (95 μL, 1.3 mmol). After stirring 2 hours at room temperature the reaction mixture was concentrated under reduced pressure and the resulting solid was extracted with Et2O (2×20 mL). The combined extracts were washed sequentially with 1% aqueous citric acid and brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford (2R,4R)-tert-butyl 2-(3-fluorophenyl)-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (I-29) as a colorless oil. MS m/z 382.1 (M+23)+.