Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:15]2[C:14]([Cl:16])=[N:13][CH:12]=[N:11][C:10]=2[N:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:8]=1.[N+:22]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29])([O-:24])=[O:23]>C1COCC1>[Cl:16][C:14]1[C:15]2[C:7]([C:28]([C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=3)=[O:29])=[CH:8][N:9]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Clc1ncnc2c1c(Br)cn2C1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1cccc([N+](=O)[O-])c1)c1cn(C2CCCC2)c2ncnc(Cl)c12
Temperature: 25 °C
Yield: 65 %

Procedure:
n-BuLi (22 mL, 2.5 M in Hexane, 55.0 mmol) was added dropwise to a solution of 5-Bromo-4-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine (15.0 g, 50.0 mmol) in THF (200 mL) at −78° C. After 1 h the resulting solution was added via cannula to a solution of 3-Nitrobenzoyl Chloride in THF (100 mL) at −78° C. After 30 min the reaction was quenched with saturated aqueous NH4Cl and warmed to room temperature. The layers were separated and the aqueous layer was extracted with EtOAc (1×200 mL). The THF was concentrated off under reduced pressure and the resulting organic layer was diluted with EtOAc. The organic layer was washed with 1N NaOH (2×) and water (1×) then dried over Na2SO4 and concentrated. Recrystallization from EtOAc afforded the title compound as a white solid (12.1 g, 65%). MS: 371.2/373.1 (MH+); HPLC Rf: 6.59 min. (HPLC method 4).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[CH:18]1([NH2:25])[CH2:23][CH2:22][CH2:21][CH:20]([NH2:24])[CH2:19]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[Cl:17][C:13]1[CH:12]=[C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:24][CH:20]4[CH2:21][CH2:22][CH2:23][CH:18]([NH2:25])[CH2:19]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Clc1cccc(-c2cnc3ccc(Cl)nn23)c1
Reactant: NC1CCCC(N)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: NC1CCCC(Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)C1
Temperature: 180 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
To a solution of 6-chloro-3-(3-chlorophenyl)imidazo[1,2-b]pyridazine (100 mg, 0.38 mmol) and cyclohexane-1,3-diamine (43 mg, 0.38 mmol) in NMP (1.0 mL) was added NaHCO3 (32 mg, 0.38 mmol), the mixture was stirred at 180° C. for 60 mins under microwave irridation. The mixture was purified by flash chromatograph to give N1-(3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)cyclohexane-1,3-diamine (30 mg, 0.088 mmol, 23%) as a pale yellow solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][C@@H:4]1[CH3:36].[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:40])[CH2:38][CH3:39])[C@@H:4]([CH3:36])[CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)[C@@H](C)C1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1C

Procedure:
Starting from N-[(1S*,3S*,4S*)-4-amino-3-methylcyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f65) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9]2[S:13][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[N:11][C:10]=2[CH3:18])[N:8]=1)#[N:2].Cl.[NH2:20][OH:21].C(N(CC)CC)C>O1CCOCC1>[NH2:2]/[C:1](=[N:20]/[OH:21])/[CH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9]2[S:13][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[N:11][C:10]=2[CH3:18])[N:8]=1
Reactant: NO
Reactant: CC(=O)Nc1nc(C)c(-c2csc(CC#N)n2)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(C)c(-c2csc(C/C(N)=N\O)n2)s1
Temperature: 80 °C
Yield: 95 %

Procedure:
N-[2-(cyanomethyl)-4′-methyl-4,5′-bi-1,3-thiazol-2′-yl]acetamide, Compound (3) (50 mg; 0.18 mmol; 1 eq.), is dissolved in dioxane (10 ml). Hydroxylamine hydrochloride (15 mg; 0.22 mmol; 1.20 eq.) and N,N-diethylethanamine (0.03 ml; 0.22 mmol; 1.20 eq.) are added and reaction mixture is heated at 80° C. overnight. Reaction mixture is cooled down and dioxane evaporated. The residue is taken up in EtOAc and washed several times with water (3×10 mL). The organic phases are dried over MgSO4, filtrated and evaporated. Crude material is purified by flash chromatography on silica gel (cyclohexane/ethylacetate, 50/50), affording the title compound as an oil (50 mg; 95%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH:19]([CH3:22])[CH2:20][Cl:21])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].Cl>C1(C)C=CC=CC=1>[C:14]([C:13](=[CH:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:12]([O:18][CH:19]([CH3:22])[CH2:20][Cl:21])=[O:17])(=[O:15])[CH3:16]
Reactant: CC(=O)CC(=O)OC(C)CCl
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC(C)CCl
Reaction time: 48 h
Yield: 82.9 %

Procedure:
A solution containing 12.2 g of 3-nitrobenzaldehyde and 14.3 g of 1-methyl-2-chloroethyl acetoacetate in 80 ml of toluene, maintained at 0°-5° C., was saturated with hydrogen chloride gas. After two days at 20°-25° C., the residual hydrogen chloride was removed by bubbling nitrogen through the solution. The toluene was then evaporated off in vacuo. The residual oil was dissolved in dichloromethane and the solution thus obtained was washed with water until it was neutral. The organic phase which was separated and dried, was then evaporated to dryness under vacuum at 20° C. The residue was crystallized from 200 ml of isopropanol to give 20.70 g of the title compound, melting at 95°-96° C.
Reaction SMILES: ClCCCl.[CH3:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[O:8][N:7]=1.[I:20]N1C(=O)CCC1=O.OS(O)(=O)=O>O>[I:20][C:10]1[C:6]([CH3:5])=[N:7][O:8][C:9]=1[C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(-c2ccc([N+](=O)[O-])cc2)on1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCCl
Product: Cc1noc(-c2ccc([N+](=O)[O-])cc2)c1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.7 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged with 10 mL of 1,2-dichloroethane. To the stirring solution were added 3-methyl-5-(4-nitrophenyl)-1,2-oxazole (0.27 g, 1.30 mmol), N-iodosuccinimide (0.28 g, 1.24 mmol), followed by concentrated H2SO4 (0.2 mL) at 0° C. and stirred at room temperature for 4 h. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with sodium thiosulphate solution (30 mL), water (30 mL) and saturated brine solution (10 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as yellow solid (0.40 g, yield: 93.7%). 1H NMR (300 MHz, CDCl3): δ 8.29-8.32 (dd, 2H), 8.18-8.21 (dd, 2H), 2.33 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][C:39]([CH3:49])([CH3:48])[C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:45]3[CH2:46][CH2:47][N:42]([C:40](=[O:41])[C:39]([CH3:49])([CH3:48])[CH3:38])[CH2:43][CH2:44]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(C)(C)C(=O)N1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)C(C)(C)C)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 2,2-dimethyl-1-piperazin-1-yl-propan-1-one (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C38H48Cl2N5O3 [(M+H)+] 692.3129, observed 692.3129.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[CH3:7][C:5]1[N:6]=[C:2]([C:11]#[C:10][CH2:9][CH2:8][N:12]2[N:13]=[C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]3=[N:16]2)[S:3][CH:4]=1
Reactant: Cc1csc(Br)n1
Reactant: C#CCCn1nc2ccccc2n1
Product: Cc1csc(C#CCCn2nc3ccccc3n2)n1
Yield: 26.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-4-methylthiazole (100 mg, 0.56 mmol) and 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (96 mg, 0.56 mmol, Example 109(D)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 40 mg (0.15 mmol, 27%) of 2-(4-(4-methylthiazol-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a white solid (M.P.=78-80° C.).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][NH:14][C:13]2[CH:18]=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:12]1=2)[C:8](=[O:10])[CH3:9].[Br:35]Br>CC(O)=O>[F:30][C:29]([F:31])([F:32])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][NH:14][C:13]2[C:18]([Br:35])=[CH:19][C:20]([C:22]([F:23])([F:24])[F:25])=[CH:21][C:12]1=2)[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2ccc(C(F)(F)F)cc21
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2c(Br)cc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a solution of crude N-(3,5-Bis-trifluoromethyl-benzyl)-N-(7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-acetamide (0.0980 mg, 0.197 mmol) in HOAc (2.00 ml), was added bromine (0.0106 ml, 0.207 mmol) dropwise. The reaction mixture was stirred at room temperature overnight. Remove the solvent on a rotary evaporator. Purification by silica gel chromatography (eluent, 0-40% ethyl acetate in hexane) provided the titled compound (0.0850 mg, 75%). MS (ES+): 577, 579 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[C:25]1([CH3:34])[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.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>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:23]([CH3:24])=[C:12]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[C:2]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH3:34])=[N:3][N:4]=[CH:5]4)[CH:13]=2)[CH2:20][CH2:19]1
Reactant: Cc1ccccc1B(O)O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(Cl)nncc2c1
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: COCCOC
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(-c3ccccc3C)nncc2c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(1-chlorophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide (100 mg, 296 μmol), o-tolylboronic acid (40 mg, 296 μmol) and tetrakis(triphenylphosphine)palladium (17 mg, 15 μmol) in 5 mL DME/EtOH (4:1) was treated with 2M potassium carbonate (444 μl, 888 μmol). The mixture was stirred at 90° C. for 2 h. The mixture was cooled to RT and purified directly without work-up, via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia in MeOH/DCM to give the title compound in (65 mg) as a pale yellow solid. Found MS (ES+): 394(M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[C@H:22]12[CH2:28][C@H:25]([NH:26][CH2:27]1)[CH2:24][S:23]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][C@@H:22]4[CH2:28][C@H:25]3[CH2:24][S:23]4)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: C1S[C@@H]2CN[C@H]1C2
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1C[C@@H]2C[C@H]1CS2

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (1S,4S)-2-thia-5-azabicyclo[2.2.1]heptane hydrochloride (125136-43-8) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=382.5 [MH+].
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]3[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:24]=3[N:23]=[CH:22]2)=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][CH:34]([CH3:39])[CH2:35][CH:36]([NH2:38])[CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:33][CH:34]([CH3:39])[CH2:35][CH:36]([NH:38][C:30]([C:28]1[CH:27]=[CH:26][C:25]2[N:21]([CH2:20][C:17]3[CH:16]=[CH:15][C:14]([C:9]4[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:19][CH:18]=3)[CH:22]=[N:23][C:24]=2[CH:29]=1)=[O:31])[CH3:37]
Reactant: CC(C)CC(C)N
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(Cn2cnc3cc(C(=O)O)ccc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(C)NC(=O)c1ccc2c(c1)ncn2Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
The mixture of 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-5-carboxylic acid (45 mg, 0.105 mmol), 4-methylpentan-2-amine (12.7 mg, 0.126 mmol), HATU (78 mg, 0.315 mmol) and DIPEA (27 mg, 0.315 mmol) in 10 mL of DCM was stirred at RTovernight. Then the solvent was removed under the reduced pressure to give the residue which was purified with prep-TLC (hexane/EtOAc=1/1, silica gel) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=3[CH3:26])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[OH:36].[C:37]([O:41][CH2:42][CH3:43])(=[O:40])[CH2:38]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=3[CH3:26])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:36][CH2:38][C:37]([O:41][CH2:42][CH3:43])=[O:40]
Reactant: CCOC(=O)CO
Reactant: Cc1c(N(Cc2ccc(Oc3ccc(Cl)c(O)c3)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Product: CCOC(=O)COc1cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)ccc1Cl

Procedure:
The product from Example 91F and ethyl glycolate were processed as described in Example 62A to provide the title compound. MS (ESI+) m/z 597 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:25])([CH3:24])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:22][CH:10]2[CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH2:14][N:9]2[C:8]1=[O:23].C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][CH2:2][C:3]([CH3:25])([CH3:24])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:22][CH:10]2[CH2:11][NH:12][CH2:13][CH2:14][N:9]2[C:8]1=[O:23]
Reactant: CC(C)(CO)CCCN1CC2CN(C(=O)OC(C)(C)C)CCN2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CO)CCCN1CC2CNCCN2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-(5-hydroxy-4,4-dimethyl-pentyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate (Compound 69-B) (1 mmol) was dissolved in CH2Cl2 (3 mL) followed by the slow addition of TFA (1 mL) at 0° C. The reaction mixture was stirred at rt for 1 hour and then the solvent was removed under vacuum to give the crude product 69-A, which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:7][CH2:6][CH:5]([N+:8]([O-])=O)[CH2:4][O:3]1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][C:2]1([CH3:11])[O:7][CH2:6][CH:5]([NH2:8])[CH2:4][O:3]1
Reactant: CC1(C)OCC([N+](=O)[O-])CO1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC1(C)OCC(N)CO1
Yield: 70.3 %

Procedure:
220 mg 5% Pd/C was added to a solution of 500 mg 2,2-dimethyl-5-nitro-1,3-dioxane (3.1 mmoles) in 30 ml methanol. Ammonium formate (985 mg, 15.6 mmoles) was then added, and the mixture was refluxed for three hours. The reaction solution was then filtered, and the filtrate concentrated in vacuo to yield 286 mg 2,2-dimethyl-5-amino-1,3-dioxane (70% yield).
Reaction SMILES: [F-:1].[Cs+].[C:3]1([S:9][CH2:10]Cl)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(#N)C>[C:3]1([S:9][CH2:10][F:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [F-]
Reactant: ClCSc1ccccc1
Agent: [Cs+]
Solvent: CC#N
Product: FCSc1ccccc1
Yield: 58.5 %

Procedure:
Cesium fluoride (191.50 g, 2 eq) was added to a mixture of PEG400 (100 mL) and acetonitrile (600 mL). The mixture was stirred for a few minutes under an argon atmosphere and then acetonitrile (100 mL) was removed by distillation. Chloromethyl phenyl sulfide (100 g, 630.32 mmol) was added and the resulting mixture was stirred for 6 hours at a temperature between 80° C. and 85° C. The mixture was filtered and the filtrate was concentrated. The crude product was purified by distillation to give 52.46 g (58.5%) of the desired product as slightly yellow oil (bp: 43° C. at 40 Pa).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:8]2)[CH2:4][CH2:3]1.O1CCC[CH2:23]1.C([Li])CCC.COS(OC)(=O)=O>CCCCCC>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH3:23])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:8]2)[CH2:4][CH2:3]1
Reactant: CN1CCC2(CC1)OC(c1ccccc1)c1ccccc12
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: COS(=O)(=O)OC
Solvent: CCCCCC
Product: CN1CCC2(CC1)OC(C)(c1ccccc1)c1ccccc12
Reaction time: 0.5 h

Procedure:
A solution of 1.4 g. of 1,3-dihydro-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidine], (Example 2), in 20 ml. of tetrahydrofuran is cooled to -50° and treated dropwise with 4 ml. of butyllithium in hexane. Stirring is continued for 30 minutes under nitrogen. To the solution is slowly added 900 mg. of dimethylsulfate in 10 ml. of tetrahydrofuran. The mixture is stirred at -10° for 1 hour and overnight at ambient temperature. Ice is added, the mixture is extracted with ether, and the organic solution is concentrated to an oil. The oil is converted to the hydrobromide salt and recrystallized from ethyl acetate to give crystals, m.p. 122°-125°.
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[C:8]([O:12][C:13]([N:15]([CH2:32][CH:33]=O)[CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>ClC(Cl)C>[C:8]([O:12][C:13]([N:15]([CH2:32]/[CH:33]=[N:7]/[S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH:16]1[CH2:17][CH2:18][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:20][CH2:21]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N(CC=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)S(N)=O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N(C/C=N/S(=O)C(C)(C)C)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
2-Methyl-2-propanesulfinamide (212 mg, 1.753 mmol) and cupric sulfate monohydrate (849 mg, 4.78 mmol) were added to a solution of benzyl 4-[(tert-butoxycarbonyl)(2-oxoethyl)amino]piperidine-1-carboxylate (600 mg, 1.59 mmol) in dichloroethane (15 mL) and was heated at 50° C. After 18 h, the reaction was filtered, concentrated, and purified by silica gel chromatography chromatography (75%-95% ethyl acetate/hexanes) to give the title compound (400 ing). MS 380.24 (M+1-boc group)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.OC1C2N=NNC=2C=CC=1.C(N=C=NC(C)C)(C)C.[S:32]([NH2:42])(=[O:41])([C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1)=[O:33]>CN(C=O)C>[S:32]([C:34]1[CH:35]=[CH:36][C:37]([NH:40][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:12])=[CH:38][CH:39]=1)(=[O:33])(=[O:41])[NH2:42]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(NC(=O)c2n[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.2 %

Procedure:
A mixture of indazole-3-carboxylic acid (324 mg, 2 mmol), hydroxybenzotriazole (297 mg, 2.2 mmol) and diisopropylcarbodiimide (344 μl, 2.2 mmol) in DMF (10 ml) is stirred for 30 min at room temperature. Sulphanilamide (380 mg, 2.2 mmol) is added. The reaction mixture is stirred overnight at room temperature and then filtered. The filtrate is evaporated and is then extracted with AcOEt/H2O. The organic phase is dried over MgSO4, filtered and evaporated under vacuum to give a yellow solid (640 mg). This compound is recrystallized successively from AcOEt/CH2Cl2 and AcOEt/MeOH.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:32]#[N:33])=[CH:4][N:3]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[C:37]([O:44][CH3:45])[CH:36]=1>>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]4[S:17][CH:18]=[CH:19][N:20]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[C:5]([C:32]#[N:33])=[CH:4][N:3]=2)=[C:37]([O:44][CH3:45])[CH:36]=1
Reactant: COc1cc(Cl)ccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncc(C#N)c3c2)c(OC)c1
Product: COc1cc(Cl)ccc1-c1ncc(C#N)c2cc(S(=O)(=O)Nc3nccs3)ccc12

Procedure:
Example 241 was synthesized in a similar manner to Example 228, except that 1-chloro-4-cyano-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide and (4-chloro-2-methoxyphenyl)boronic acid were used as the coupling partners. The final compound was purified via column chromatography (12 g silica gel column, gradient elution 25 to 100% EtOAc:Heptane) to afford 1-(4-chloro-2-methoxyphenyl)-4-cyano-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=13.06 (s, 1H), 9.26 (s, 1H), 8.58-8.43 (m, 1H), 8.06 (dd, J=1.8, 8.9 Hz, 1H), 7.94 (dd, J=0.6, 8.9 Hz, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.37 (d, J=1.9 Hz, 1H), 7.32 (d, J=4.6 Hz, 1H), 7.24 (dd, J=1.9, 8.1 Hz, 1H), 6.92 (d, J=4.6 Hz, 1H), 3.69 (s, 3H). m/z (ESI) 457.2 (M+H)+.