Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH:14]3[CH:20]([CH3:22])[CH3:21])[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH2:29]([C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:29]([C:31]1[N:32]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH:14]4[CH:20]([CH3:21])[CH3:22])[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:3]=2)[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30]
Reactant: CC(C)C1C(=O)NCCN1Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C
Reactant: CCc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCNC(=O)C3C(C)C)n(C)c2n1
Temperature: 110 °C
Yield: 77.3 %

Procedure:
A mixture of 4-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl)-3-isopropylpiperazin-2-one (198 mg, 0.49 mmol), 2-ethylbenzimidazole (78 mg, 0.53 mmol), Pd2(dba)3 (11.1 mg, 2.5 mol %), Xphos (23.1 mg, 10 mol %) and Cs2CO3 (237 mg, 0.16 mmol) in dioxane (4 mL) was purged with argon gas then heated at 110° C., for 17 h, in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by column chromatography (Si—PCC, 0-10% MeOH in EtOAc) to give 648 (196 mg, 78%) as a white solid. LCMS: (Method I): RT 3.37 min, [M+H]+ 518.2 1H NMR (400 MHz, CDCl3d): δ 8.05-8.00 (m, 1 H), 7.79-7.75 (m, 1 H), 7.30-7.23 (m, 2 H), 6.02 (s, 1 H), 4.50-3.96 (m, 4 H), 4.09 (d, J=13.6 Hz, 1 H), 3.94 (d, J=13.6 Hz, 1 H), 3.89 (s, 3 H), 3.87 (t, J=4.80 Hz, 4 H), 3.63-3.54 (m, 1 H), 3.37 (q, J=7.5 Hz, 2 H), 3.34-3.28 (m, 1 H), 3.13-3.04 (m, 1 H), 3.03 (d, J=5.5 Hz, 1 H), 2.74-2.66 (m, 1 H), 2.25-2.14 (m, 1 H), 1.46 (t, J=7.5 Hz, 3 H), 1.11 (d, J=6.8 Hz, 3 H), 1.03 (d, J=6.8 Hz, 3 H)
Reaction SMILES: Cl.[C:2]([CH:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:17]1[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:18]=1.C(N(CC)CC)C.O>O1CCCC1>[C:2]([CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:17]2[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[N:18]=2)[CH2:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: O=C(c1ccccc1)C1CCCNC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCCC(C(=O)c3ccccc3)C2)nc(-c2ccncc2)cc1=O
Yield: 121.5 %

Procedure:
A solution of 3-benzoylpiperidine hydrochloride (109 mg, 0.60 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (118 mg, 0.40 mmol) and triethylamine (0.50 ml, 4.00 mmol) in tetrahydrofuran (6 ml) was stirred at room temperature for several hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and evaporated in vacuo. Purification of the residue by silica gel column chromatography (ethyl acetate) gave the title compound (182 mg, 61%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[Br:14][C:15]1[C:16]([I:24])=[C:17]2[CH:23]=[CH:22][NH:21][C:18]2=[N:19][CH:20]=1.[Cl-].[NH4+]>CN(C)C=O>[Br:14][C:15]1[C:16]([I:24])=[C:17]2[CH:23]=[CH:22][N:21]([S:10]([C:7]3[CH:8]=[CH:9][C:4]([CH3:3])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[C:18]2=[N:19][CH:20]=1
Reactant: Brc1cnc2[nH]ccc2c1I
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(I)c(Br)cnc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
55% Sodium hydride (170 mg) and 4-methylbenzenesulfonyl chloride (740 mg) were added to a solution of 5-bromo-4-iodo-1H-pyrrolo[2,3-b]pyridine obtained by the method described in WO 2008/150914 (1.14 g) in N,N-dimethylformamide (12 ml) in an ice bath, and the mixture was stirred at room temperature for 3 hours. An aqueous ammonium chloride solution was added to the reaction solution, and the precipitated solid was collected by filtration and washed with water. This was dissolved in dichloromethane and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1.68 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.Cl[C:19]1[CH:20]=[C:21]2[N:28](C(OC(C)(C)C)=O)[C@@H:27]([CH3:36])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[CH2:16][O:17][C:19]1[CH:20]=[C:21]2[NH:28][C@@H:27]([CH3:36])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C(=O)OC(C)(C)C
Reactant: OCc1ccc(Oc2cccc(F)c2)c(F)c1
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4cccc(F)c4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-(3-fluorophenoxy)phenyl)methanol and (S)-tert-butyl 7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH:10]=[CH2:11])/[CH:4]=[CH:5]/[C:6]([OH:8])=O)[CH3:2].C(OC(=O)C)(=O)C.C(N(CC)CC)C.O>CN(C)C(=O)C>[CH2:1]([C:3]1[CH2:9][CH:10]2[CH:5]([CH:4]=1)[C:6](=[O:8])[CH2:11]2)[CH3:2]
Reactant: C=CCC(/C=C/C(=O)O)CC
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCC1=CC2C(=O)CC2C1
Temperature: 110 °C
Reaction time: 6.5 h
Yield: 73.5 %

Procedure:
(2E)-4-Ethylhepta-2,6-dienoic acid (34.0 g, purity: 90.7%) was dissolved in N,N-dimethylacetamide (100 mL) under the nitrogen atmosphere. To the solution, acetic anhydride (37.8 mL, 0.40 mol) and triethylamine (28 mL, 0.20 mol) were added. The reaction mixture was warmed and stirred at 105 to 115° C. for 6.5 hours. The reaction mixture was cooled to room temperature, and water (200 mL) was added thereto, followed by four extractions with n-hexane (150 mL×2 and 50 mL×2). All the extracted organic layers were combined and then washed with a saturated aqueous solution of sodium bicarbonate (50 mL) and water (50 mL) in this order. The obtained organic layer was concentrated under reduced pressure, and the residue was distilled under reduced pressure (93-102° C., approximately 25 mmHg) to obtain the title compound (22.06 g, colorless oil substance) (yield: 81%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[NH:25]1[CH2:30][CH2:29][O:28][CH:27]([CH2:31][CH2:32][C:33]2([C:38](O)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:26]1>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:11][CH:12]=1)[NH:5][C:38]([C:33]1([CH2:32][CH2:31][CH:27]2[O:28][CH2:29][CH2:30][NH:25][CH2:26]2)[CH2:34][CH2:35][CH2:36][CH2:37]1)=[O:39]
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reactant: O=C(O)C1(CCC2CNCCO2)CCCC1
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)C1(CCC2CNCCO2)CCCC1
Yield: 62 %

Procedure:
4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[[1-[(2-morpholinyl)ethyl]cyclopentyl]carbonyl]-L-phenylalanine methyl ester was prepared from 4-[[(2,6-Dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester and 1-[(2-morpholinyl)ethyl]cyclopentane carboxylic acid using the general coupling procedure described in example 46 to provide a 62% yield. HRMS (C29H35Cl2B3O5): Obs. mass, 576.2531. Calcd. mass, 576.2582. (M+H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[NH2:6][C@H:7]1[CH2:11][N:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:9]([C:16]([NH:18][CH2:19][C@@H:20]([OH:48])[C@@H:21]([NH:29][C:30](=[O:47])[C@H:31]([CH2:43][C:44](=[O:46])[NH2:45])[NH:32][C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:17])[CH2:8]1.C(=O)(O)[O-].[Na+]>O.CN(C)C=O>[C:1]([NH:6][C@H:7]1[CH2:11][N:10]([C:12]([CH3:14])([CH3:13])[CH3:15])[C@H:9]([C:16]([NH:18][CH2:19][C@@H:20]([OH:48])[C@@H:21]([NH:29][C:30](=[O:47])[C@H:31]([CH2:43][C:44](=[O:46])[NH2:45])[NH:32][C:33]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:17])[CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)N1C[C@H](N)C[C@H]1C(=O)NC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N[C@@H]1C[C@@H](C(=O)NC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(N)=O)NC(=O)OCc2ccccc2)N(C(C)(C)C)C1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
15 mg of freshly distilled acetyl chloride were added to a solution, which was cooled to 0° C. and stirred, of 12 mg of 4(R)-amino-N2 -[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide hydrochloride and 21 mg of sodium bicarbonate in 0.5 ml of water and 0.25 ml of dimethylformamide. The mixture was stirred vigorously at 0° C. for 5 hours and then left to stand at room temperature overnight. The mixture was diluted with water and extracted with dichloromethane. The combined dichloromethane extracts were evaporated to give a gum which was purified by flash chromatography on silica gel using 20% methanol in dichloromethane for the elution. There were obtained 2 mg of 4(R)-acetylamino-N2 -[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide as a semi-solid; MS: m/e 639 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:11](=[O:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH:16]2[CH2:17][CH2:18]2)[C:11](=[O:19])[C:10]=1[Br:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1cc(OCc2ccccc2)ccn1CC1CC1
Solvent: ClCCl
Product: O=c1c(Br)c(OCc2ccccc2)ccn1CC1CC1

Procedure:
A solution of intermediate D1 (3.0 g, 11.7 mmol) and N-bromosuccinimide (2.09 g, 11.7 mmol) in DCM (100 ml) was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo and the crude residue was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo yielding D33 (3.56 g, 91%).
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.Cl.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([OH:41])[CH:28]([NH2:40])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH:27]([OH:41])[CH:28]([NH:40][C:10]([C:6]2[C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=[CH:8][CH:7]=2)=[O:12])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)=[CH:25][CH:26]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1cccc2c1OCC2
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of 2,3-dihydro-1-benzofuran-7-carboxylic acid (106 mg, 0.64 mmol) in tetrahydrofuran (5 ml) were added oxalyl chloride (0.11 ml, 1.72 mmol) and N,N-dimethylformamide (0.01 ml) and the mixture was stirred at room temperature for 30 min. The reaction solution was evaporated under reduced pressure. To a solution of the residue in ethyl acetate (5 ml) were added (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (160 mg, 81%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:14]([CH3:19])([CH3:18])[CH2:13][CH2:12][C:11]([CH3:21])([CH3:20])[C:10]=3[CH:9]=2)[N:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC.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>[C:22]([O:26][C:27]([N:29]1[CH2:30][CH:31]=[C:32]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH:17]=[CH:16][C:15]4[C:14]([CH3:19])([CH3:18])[CH2:13][CH2:12][C:11]([CH3:21])([CH3:20])[C:10]=4[CH:9]=3)[N:3]=2)[CH2:33][CH2:34]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(Br)n3)ccc21
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: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1

Procedure:
100 mg (0.29 mmol) of 2-bromo-6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridine and 135 mg (0.44 mmol) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester are dissolved in 2 ml of 2M sodium carbonate solution and in 2 ml of dimethoxyethane. The reaction mixture is degassed a number of times, 34 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium are added under nitrogen atmosphere, and the mixture is irradiated in the microwave for 30 min, subsequently evaporated, and saturated sodium hydrogencarbonate solution is added. This mixture is extracted three times with ethyl acetate, the combined organic phases are dried over Na2SO4 and evaporated. The crude product is purified by column chromatography on silica gel.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[S:7][C:8]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)=[CH:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26]>>[CH:19]([N:18]1[C:14]([C:8]2[S:7][C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:32]5[CH:31]=[CH:30][CH:29]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:33]=5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][C:10]=3[CH:9]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)n1ncnc1-c1cc2c(s1)-c1ccc(-c3cccc(S(C)(=O)=O)c3)cc1OCC2

Procedure:
Following the procedure for 114, 5 5-(8-Bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazole was reacted with 3-methylsulfonylphenylboronic acid to give 146. MS (ESI+) 466.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:10][S:11]([O-:13])=[O:12].[Na+].N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:8][C:6]1[CH:5]=[C:4]([OH:9])[CH:3]=[C:2]([S:11]([CH3:10])(=[O:13])=[O:12])[CH:7]=1
Reactant: Oc1cc(Cl)cc(Br)c1
Reactant: CS(=O)[O-]
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1cc(O)cc(Cl)c1

Procedure:
Preparation according to Preparation 1: 3-bromo-5-chlorophenol (4.0 g, 19.3 mmol), sodium methanesulfinate (3.1 g, 28.9 mmol), cupper(I)iodide (2.2 g, 11.5 mmol), L-proline (2.7 g, 23.1 mmol), potassium carbonate (1.6 g, 11.6 mmol), dry dimethyl sulfoxide (70 ml). Yield: 3.7 g (92%). MS m/z (relative intensity, 70 eV) 206 (M+, 88), 191 (36), 144 (58), 127 (bp), 99 (76).
Reaction SMILES: N([O-])=O.[Na+].[Br:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][C:7]=1[CH3:13].CC([O-])=O.[Na+].[CH2:19]([CH:21](C(=O)C)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:20].[OH-].[K+].BrC1C(C)=C2C(=CC=1)NC(C(OCC)=O)=C2C>O.CCO>[Br:5][C:6]1[CH:12]=[C:11]2[C:9](=[CH:8][C:7]=1[CH3:13])[NH:10][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:19]2[CH3:20]
Reactant: Cc1cc(N)ccc1Br
Reactant: CCOC(=O)C(CC)C(C)=O
Agent: CC(=O)[O-]
Agent: CCOC(=O)c1[nH]c2ccc(Br)c(C)c2c1C
Agent: O=N[O-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1[nH]c2cc(C)c(Br)cc2c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of NaNO2 (1.52 g, 22 mmol) in water (4 mL) was added to a vigorously stirred mixture of 4-bromo-3-methylaniline (3.72 g, 20 mmol) at −5° C. After 30 min stirring, the solution was adjusted to pH 5 with NaOAc (1.40 g). A cold solution of ethyl 2-ethyl-3-oxobutanoate (4.0 g, 22 mmol) and KOH (1.36 g, 22 mmol) in EtOH (16 mL) were added followed by crushed ice (˜30 g). NaOAc was added if necessary to adjust the pH to 5. The mixture was stirred for 5 h at 0° C. then kept at this temperature overnight. The solution was extracted with EtOAc, washed with brine, dried and evaporated to 8 mL. This solution was added to a solution of HCl (25 mL, 7M in EtOH). It was further refluxed for 3 h. Upon cooling in an ice bath, water (200 mL) was added slowly. The precipitate was filtered, washed with water and dried to afford 5.36 g (91%) as a 1:1 mixture of the title compound and its ethyl 5-bromo-3,4-dimethyl-1H-indole-2-carboxylate isomer. 1H NMR (300 MHz, CDCl3), 8, mix 8.66 and 8.54 (2s, br, 1H), 7.83 and 7.23 (2s, 2×0.5H), 7.42 and 7.05 (2d, J=8.7 Hz, 2×0.5H), 4.41 (q, J=7.2 Hz, 2H), 2.81, 2.79, 2.53 and 2.49 (4s, 4×1.5H), 1.42 (t, J=7.2 Hz, 3H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[C:13]([N+:30]([O-:32])=[O:31])[CH:12]=3)[CH:9]=2)[N:4]([S:33]([C:36]2[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH:3]=1.[F:43][C:44]1[CH:45]=[C:46]([CH:62]=[CH:63][CH:64]=1)[CH2:47][N:48]1[CH:52]=[C:51](B2OC(C)(C)C(C)(C)O2)[CH:50]=[N:49]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:43][C:44]1[CH:45]=[C:46]([CH:62]=[CH:63][CH:64]=1)[CH2:47][N:48]1[CH:52]=[C:51]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[C:13]([N+:30]([O-:32])=[O:31])[CH:12]=4)[CH:9]=3)[N:4]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:3]=2)[CH:50]=[N:49]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)c([N+](=O)[O-])c4)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(Cc3cccc(F)c3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)c([N+](=O)[O-])c4)cnc32)cc1
Yield: 33.05 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-nitrophenyl)piperazine-1-carboxylate (intermediate 66J) (340 mg, 0.48 mmol) was coupled with 1-(3-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 11) (189 mg, 0.628 mmol) using Pd(dppf)Cl2 (18 mg, 0.024 mol) and sodium carbonate (152 mg, 1.44 mmol) in toluene/ethanol/water (20/10/5 ml) to afford 120 mg (33.05% yield) of the titled. MS: m/z=752.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][CH2:9][CH2:10][C:11]2[N:12]([CH3:22])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)=[C:5]([C:24]([O:26]C)=[O:25])[N:4]=[N:3]1.[Li+].[OH-].Cl.ClCCl>C1COCC1.CO>[CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][CH2:9][CH2:10][C:11]2[N:12]([CH3:22])[CH:13]=[C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:15]=2)=[C:5]([C:24]([OH:26])=[O:25])[N:4]=[N:3]1
Reactant: COC(=O)c1nnn(C)c1C(=O)NCCc1nc(-c2ccccc2)cn1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(-c2ccccc2)nc1CCNC(=O)c1c(C(=O)O)nnn1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.3 %

Procedure:
To a solution of methyl 1-methyl-5-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethylcarbamoyl)-1H-1,2,3-triazole-4-carboxylate (77 mg, 209 μmol) in THF (0.9 mL) and MeOH (0.3 mL) was added LiOH (1M aqueous solution, 418 μL, 418 μmol) at 0-5° C. The ice bath was removed and the mixture was stirred at RT for 4 h. HCl (1M aqueous solution, 0.42 mL, 0.42 mmol) was added and the solution was poured into dichloromethane (40 mL) to result in a suspension. The solid precipitate was filtered, washed with THF/water 4:1 and dried in vacuo to give the product as colorless solid (52 mg, 147 μmol, 70.2%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:33])[C:23]=1[N:24]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[N:25]1)[O:5][C@H:6]([C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9].O.O1CCCC1.O.[OH-].[Li+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:33])[C:23]=1[N:24]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[N:25]1)[O:5][C@H:6]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:19][CH:20]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCC[C@H](Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCC[C@H](Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.3 %

Procedure:
To a flask containing (S)-ethyl 4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzoate (11.8 g, 25.6 mmol) was added water (32.0 mL), tetrahydrofuran (32.0 mL), and methanol (32.0 mL). Lithium hydroxide monohydrate (2.15 g, 51.2 mmol) was then added. The suspension was stirred at room temperature. After 1.5 h, another (1.07 g, 25.6 mmol) of lithium hydroxide monohydrate was added. After 2 h, the reaction was concentrated. The crude residue was dissolved in water and the solution was acidified to pH=3 with 1N hydrochloric acid. A white precipitate formed. The solid was filtered, rinsed with water, and dried under vacuum to give (S)-4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzoic acid (11.1 g, 100%) as a white gum. 1H NMR (400 MHz, CDCl3, δ): 8.07 (d, J=8.4 Hz, 2H), 7.88 (s, 1H), 7.65 (s, 1H), 7.45 (d, J=8.2 Hz, 2H), 6.58 (s, 2H), 5.18 (dd, J=8.0, 4.9 Hz, 1H), 2.04-1.92 (m, 1H), 1.89 (s, 6H), 1.87-1.75 (m, 1H), 1.61-1.36 (m, 2H), 0.97 (t, J=7.4 Hz, 3H). MS (M+1): 433.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]1[O:16][CH:17]=[CH:18][N:19]=1)[N:9]=[CH:8]2)([O-])=O.Cl[Sn]Cl.[OH-].[Na+]>C(O)C>[O:16]1[CH:17]=[CH:18][N:19]=[C:15]1[CH2:14][N:10]1[C:11]2[C:7](=[CH:6][C:5]([NH2:2])=[CH:13][CH:12]=2)[CH:8]=[N:9]1
Reactant: O=[N+]([O-])c1ccc2c(cnn2Cc2ncco2)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc2c(cnn2Cc2ncco2)c1
Temperature: 50 °C
Yield: 45.4 %

Procedure:
Concentrated HCl (2.5 mL) was added to a solution of 5-nitro-1-(1,3-oxazol-2-ylmethyl)-1H-indazole (456 mg, 1.87 mmol) and SnCl2 (1.42 g, 7.47 mmol) in ethanol (10 mL) and the mixture was heated at 50° C. for 4 hours. The mixture was cooled down, neutralized to pH 8 with 2N sodium hydroxide and extracted with ethyl acetate. The residue is purified on silica gel (EtOAc) to give 1-(1,3-oxazol-2-ylmethyl)-1H-indazol-5-amine (182 mg, 46%); NMR spectrum (CDCl3) 5.55 (s, 2H), 6.79 (d, 1H), 6.86 (s, 1H), 7.00 (s, 1H), 7.24 (d, 1H), 7.50 (s, 1H), 7.77 (s, 1H); Mass spectrum MH+ 215.