Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[K+].Cl[C:7]1[N:12]=[CH:11][N:10]=[C:9]2[NH:13][N:14]=[CH:15][C:8]=12.[F:16][C:17]1[C:22](B(O)O)=[CH:21][CH:20]=[CH:19][N:18]=1.O>CCO>[F:16][C:17]1[C:22]([C:7]2[N:12]=[CH:11][N:10]=[C:9]3[NH:13][N:14]=[CH:15][C:8]=23)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: Clc1ncnc2[nH]ncc12
Reactant: OB(O)c1cccnc1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Fc1ncccc1-c1ncnc2[nH]ncc12
Temperature: 25 °C
Yield: 40 %

Procedure:
A degassed mixture of potassium acetate (1.9 g, 19 mmol), PdCl2(PtBu2Ph)2 (0.16 g, 0.26 mmol), 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (1.00 g, 6.5 mmol) and 2-fluoropyridin-3-ylboronic acid (1.1 g, 7.8 mmol) in EtOH (30 mL)-water (10 mL) was sonicated until the solid became a fine powder. The mixture was refluxed under N2 overnight. After cooling to rt, solvent was removed in vacuo and water (50 mL) and NaHCO3 (sat. 100 mL) were added to the residue. The mixture was extracted with EtOAc (3×100 mL). The solid was filtered and washed with water. The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered through celite and concentrated in vacuo to give 4-(2-fluoropyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (0.56 g). The previous solid was dissolved in MeOH-DCM and preloaded on silica gel and purified by flash column chromatography eluting with MeOH/DCM (1-5%) to give give 4-(2-fluoropyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (3.4 g). The two product crops were combined (65% overall). MS (ESI, pos. ion) m/z: 216 [M+H]+
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C.[OH:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.C1(C)C=CC(S(O[CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)(=O)=O)=CC=1>O>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][CH2:34][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[CH:37][CH:38]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(Cl)cc2)cc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(OCCc2ccc(Cl)cc2)cc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 90.1 %

Procedure:
Potassium carbonate (54.9 g, 397 mmol) was added to a N,N-dimethylacetamide (330 mL) solution of methyl 4-hydroxybenzoate (25.2 g, 165 mmol) and 2-(4-chlorophenyl)ethyl p-toluenesulfonate (compound described in J. Am. Chem. Soc., (1978), 100, 228-246, 61.7 g, 199 mmol) at room temperature. The mixture was stirred at 120° C. for 1.5 hours. The reaction solution was cooled to room temperature, and water (1 L) was added thereto. The resulting mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with water (three times) and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate, 10:1, V/V) to give 43.2 g of methyl 4-[2-(4-chlorophenyl)ethoxy]benzoate (white solid). All this solid was dissolved in ethanol (430 mL), and a 2 M lithium hydroxide aqueous solution (148 mL, 297 mmol) was added thereto. The mixture was stirred at 60° C. for 2 hours, and the solvents (mainly ethanol) were evaporated. The residue was suspended in water (300 mL), and 2 N hydrochloric acid (160 mL) was added thereto under ice-cooling with stirring. The precipitated white solid was collected by filtration, washed with water and n-hexane, and dried under reduced pressure to give 41.0 g of the title compound (white solid, yield: 90%).
Reaction SMILES: [NH2:1][CH:2]([C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:8])[C:3]([O:5][CH3:6])=[O:4].CCN(CC)CC.[C:24](Cl)([CH3:26])=[O:25]>C(Cl)Cl>[C:24]([NH:1][CH:2]([C:7]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)=[O:8])[C:3]([O:5][CH3:6])=[O:4])(=[O:25])[CH3:26]
Reactant: COC(=O)C(N)C(=O)c1ccc(OC)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(NC(C)=O)C(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 60.5 %

Procedure:
To a solution of methyl 2-amino-3-(4-methoxyphenyl)-3-oxopropanoate (35.5 g, 137 mmol) and Et3N (57.2 mL, 411 mmol) in DCM (120 mL) at 0° C. was added AcCl (12.9 g, 164 mmol) dropwise. The reaction mixture was stirred at 0° C. for 40 min and then quenched with water (500 mL). The resulting mixture was extracted with DCM (300 mL×2) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was washed with petroleum ether/EtOAc (300 mL, 100:1) to methyl 2-acetamido-3-(4-methoxyphenyl)-3-oxopropanoate (22.0 g, 61% yield) as a colorless solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH:9]([CH3:12])[S:8][CH2:7]1.Cl.[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:15]1.[Na+].[I-]>C(#N)C>[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([N:23]2[CH2:24][CH2:25][N:26]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[CH:9]([CH3:12])[S:8][CH2:7]3)[CH2:27][CH2:28]2)=[N:15]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: CC1SCN(CCCCBr)C1=O
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC1SCN(CCCCN2CCN(c3nsc4ccccc34)CC2)C1=O
Yield: 58.8 %

Procedure:
A mixture of 3-(4-bromobutyl)-5-methyl-4-thiazolidinone (4.00 g), 1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride (4.46 g), K2 CO3 (8.00 g) and NaI (300 mg) in acetonitrile (210 ml) was heated at 40°-45° C. for 64 hours and the product was processed in substantially the same manner as in Example 10 to afford 3.64 g of crystals, m.p. 113°-115° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH3:19])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:20]O>O=S(Cl)Cl>[CH3:20][O:10][C:9](=[O:11])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH2:12][CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][N:15]1[CH3:19]
Reactant: CO
Reactant: CN1CCCC1CCC(C(=O)O)c1ccc(Br)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(CCC1CCCN1C)c1ccc(Br)cc1

Procedure:
To the solution of 2-(4-bromo-phenyl)-4-(1-methyl-pyrrolidin-2-yl)-butyric acid in MeOH (60 mL), SOCl2 (2 mL) was added at 0 degrees Celsius, then the mixture refluxed for 5 h. After cooling, the solution was evaporated to dryness under reduced pressure, then EtOAc was added, the organic layer was washed with aq. NaHCO3, dried with MgSO4, and evaporated to give an oil. MS: calc'd 340 (MH+), exp 340 (MH+).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[CH3:5][N:6]1[C:10]([C:11](=[O:34])[NH:12][C:13]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:16]3[CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:27]=[C:15]3[CH:14]=2)=[C:9]([C:35](O)=[O:36])[CH:8]=[N:7]1>>[N:19]1([C:17]2[N:16]3[CH:25]=[C:26]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:27]=[C:15]3[CH:14]=[C:13]([NH:12][C:11]([C:10]3[N:6]([CH3:5])[N:7]=[CH:8][C:9]=3[C:35]([N:1]3[CH2:4][CH2:3][CH2:2]3)=[O:36])=[O:34])[N:18]=2)[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1
Reactant: C1CNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2c(N2CCOCC2)n1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2c(N2CCOCC2)n1

Procedure:
The title compound was prepared in analogy to Example 13, Step 2, using azetidine and 1-methyl-5-(5-morpholin-4-yl-2-phenyl-imidazo[1,2-c]pyrimidin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (Example 73, Step 1). MS (m/e)=487.2 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[CH2:6]1)=[O:4].[NH2:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:24]3[CH:25]=[CH:26][C:21]([NH2:20])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[O:19])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCCC(C(=O)c2ccc(Br)cc2)C1
Reactant: Nc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COC(=O)C1CCCC(C(=O)c2ccc(-c3ccc(N)cc3)cc2)C1
Temperature: 80 °C

Procedure:
To a solution of 3-(4-bromo-benzoyl)-cyclohexanecarboxylic acid methyl ester (500 mg, 1.54 mmol) and 4-aminophenyl boronic acid (252 mg, 1.85 mmol) in toluene (40 mL) and dioxane (10 mL), 2 N aqueous Na2CO3 (10 mL) was added, and the mixture was degassed by bubbling with a flow of argon for 45 minutes. (1,1-Bis(diphenylphosphino)ferrocene)-dichloropalladium (63 mg, 0.08 mmol) was added to the mixture, which was then heated at 80° C. overnight. The reaction mixture was cooled to rt, and then filtered through a pad of Celite®, rinsing with ethyl acetate. The organic layer was separated, washed with water and brine, and dried (Na2SO4). The solvent was removed by rotary evaporation, and the solid residue was purified by using a Biotage QuadUV flash chromatography system (eluant: 3:1 hexane/EtOAc). The product 3-(4′-amino-biphenyl-4-carbonyl)-cyclohexanecarboxylic acid methyl ester was obtained as a brown solid (200 mg, yield 38.5%). 1H NMR (300 MHz, DMSO) δ 7.90 (d, 2H), 7.60 (d, 2H), 7.45 (d, 2 H), 6.80 (d, 2H), 3.70 (s, 3H), 3.25 (m, 1H), 2.50 (m, 1H), 2.20-1.90 (m, 4 H), 1.70-1.50 (m, 4H); LC-MS ret. time 3.80 min (method 2), m/z 338.17 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:17]=2)=[C:10]([CH3:32])[CH:9]=1)=[O:6]>CCO.CCOC(C)=O.[Ni]>[CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH3:32])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[OH:31])[CH:17]=2)=[C:12]([CH3:14])[CH:13]=1)=[O:6]
Reactant: COC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(O)c(C(=O)c3ccc(F)cc3)c2)c(C)c1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(O)c(C(O)c3ccc(F)cc3)c2)c(C)c1
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a solution of N-{4-[3-(4-fluoro-benzoyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-malonamic acid methyl ester (222 mg, 0.49 mmol) in a mixture of EtOH/EtOAc (4:1, 25 mL) was added nickel catalyst (2 mL, water and methanol washed). The mixture was hydrogenated under 50 psi at room temperature for 1 h. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by preparative TLC to give the title compound of Step A (159 mg) as a white solid. MS (APCl−) Calc.: 453.2. Found: 452.2 (M−1).
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].Cl.[F:51][C:52]1([F:58])[CH2:56][NH:55][CH2:54][C@H:53]1[OH:57]>>[C:28]([C:32]1[N:33]=[C:34]([N:55]2[CH2:56][C:52]([F:58])([F:51])[C@H:53]([OH:57])[CH2:54]2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: O[C@@H]1CNCC1(F)F
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2C[C@@H](O)C(F)(F)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (R)-4,4-difluoropyrrolidin-3-ol hydrochloride and isolated as white solid. MS(m/e): 423.3 (MH+).
Reaction SMILES: CS[C:3]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[N:4]=1.[N+:14]([CH3:17])([O-:16])=[O:15]>>[N+:14](/[CH:17]=[C:3]1\[NH:4][C:5]2[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=2[CH2:7][CH2:8][CH2:9]\1)([O-:16])=[O:15]
Reactant: C[N+](=O)[O-]
Reactant: CSC1=Nc2ccccc2CCC1
Product: O=[N+]([O-])/C=C1/CCCc2ccccc2N1

Procedure:
A mixture of Example 182C (2.481 g, 12.97 mmol) and nitromethane (13.99 mL, 259 mmol) was heated with an oil bath at 120° C. for 48 hours. The nitromethane was evaporated and the crude mixture was purified by silica gel chromatography (Analogix IntelliFlash™ 280, SF25-80) eluting with 15-30% ethyl acetate/hexanes to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.15 (s, 1H), 7.34-7.25 (m, 3H), 7.25-7.15 (m, 1H), 6.87 (s, 1H), 2.77-2.64 (m, 2H), 2.22 (m, 2H), 2.14 (m, 2H); MS (ESI+) m/z 205.3 (M+H)+.
Reaction SMILES: [N:1]1([CH:10]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([P:21](=[O:32])([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([F:20])[F:19])=[CH:14][CH:13]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Li]CCCC.[CH:44]([O:47][C:48]1[CH:60]=[C:59]([C:61]2[CH:66]=[CH:65][C:64]([CH2:67]Br)=[CH:63][CH:62]=2)[CH:58]=[CH:57][C:49]=1[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])([CH3:46])[CH3:45]>CCCCCC.C1COCC1>[N:1]1([C:10]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([P:21]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:32])([F:19])[F:20])=[CH:16][CH:17]=2)[CH2:67][C:64]2[CH:63]=[CH:62][C:61]([C:59]3[CH:58]=[CH:57][C:49]([C:50]([O:52][C:53]([CH3:54])([CH3:56])[CH3:55])=[O:51])=[C:48]([O:47][CH:44]([CH3:46])[CH3:45])[CH:60]=3)=[CH:66][CH:65]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CC(c2ccccc2)n2nnc3ccccc32)cc1
Reactant: CC(C)Oc1cc(-c2ccc(CBr)cc2)ccc1C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)Oc1cc(-c2ccc(CC(Cc3ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc3)(c3ccccc3)n3nnc4ccccc43)cc2)ccc1C(=O)OC(C)(C)C

Procedure:
To a solution of di(tert-butyl) {4-[2-(1H-1,2,3-benzotriazol-1-yl)-2-phenylethyl]phenyl}(difluoro)methylphosphonate (0.060 g, 0.110 mmol) in TRF (1.0 mL) were added n-BuLi 1.6 M in hexane (0.086 mL) and the bromide of Example 11, Step 1 (0.045 g, 0.111 mmol) in THF (1.0 mL). Then using the same protocol as described for Example 14 Step 1 the title compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH:20]([NH2:23])([CH3:22])[CH3:21]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:23][CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: CC(C)N
Product: CCOC(=O)c1cnc2c(N)cccc2c1NC(C)C
Yield: 80 %

Procedure:
The compound prepared in Example 3 was reacted with isopropylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 80%).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].Cl.[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18]([N:21]2[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:24][C:23]([C:32]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[O:33])=[N:22]2)=[CH:17][CH:16]=1>C(Cl)Cl>[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18]([N:21]2[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:24][C:23]([C:32]([N:34]3[CH2:39][CH2:38][N:37]([C:8](=[O:10])[CH3:9])[CH2:36][CH2:35]3)=[O:33])=[N:22]2)=[CH:17][CH:16]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(-n2nc(C(=O)N3CCNCC3)cc2-c2ccccn2)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(=O)N3CCN(C(C)=O)CC3)cc2-c2ccccn2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At 0° C., triethylamine (0.205 mL) and acetyl chloride (0.0447 mL) were added to a solution of 4-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]piperazine hydrochloride (0.185 g) obtained in Example 81 in methylene chloride (5.0 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between water and chloroform. The aqueous layer was further extracted with chloroform, and the organic layers were combined, followed by washing with saturated brine and drying over sodium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as an amorphous product (0.147 g, 87%).
Reaction SMILES: CN(C=O)C.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[C:15](=O)[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>O>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]2[O:6][C:25]([C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[C:15]([CH3:16])[C:8]=2[CH:9]=1
Reactant: COc1ccc(O)c(C(C)=O)c1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2oc(C(=O)C(C)(C)C)c(C)c2c1
Temperature: 85 °C

Procedure:
DMF (4 mL) was added to a mixture of 166 mg 1-(2-hydroxy-5-methoxyphenyl)ethanone and 370 mg cesium carbonate followed by 188 mg 1-bromopinacolone. After heating this mixture in an 85° C. oil bath for 3 hours, it was poured into cold water and extracted with ether. The combined ether extract was washed with water, 1.5 N NaOH, water, and saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product. It was purified on silica gel (9:1 hexanes and EtOAc) to give the title compound as a colorless solid. 1H NMR (CDCl3, 500 MHz) δ 7.41 (d, J=9.0 Hz, 1H), 7.11 (dd, J=2.5 & 9.0 Hz, 1H), 7.04 (d, J=2.5 Hz, 1H), 3.90 (s, 3H), 2.59 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [CH2:1]1N2CCN(CC2)C1.[CH3:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:33]=[C:32]4[C:28]([C:29]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:30][NH:31]4)=[CH:27][CH:26]=3)[N:21]=2)[CH:13]=[N:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18]>C(=O)(OC)OC.CN(C=O)C>[CH3:1][N:31]1[C:32]2[C:28](=[CH:27][CH:26]=[C:25]([C:22]3[N:21]=[C:20]([C:12]4[CH:13]=[N:14][C:15]([O:16][CH:17]([CH3:19])[CH3:18])=[C:10]([CH3:9])[CH:11]=4)[O:24][N:23]=3)[CH:33]=2)[C:29]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:30]1
Reactant: C1CN2CCN1CC2
Reactant: Cc1cc(-c2nc(-c3ccc4c(CCC(=O)O)c[nH]c4c3)no2)cnc1OC(C)C
Solvent: CN(C)C=O
Solvent: COC(=O)OC
Product: Cc1cc(-c2nc(-c3ccc4c(CCC(=O)O)cn(C)c4c3)no2)cnc1OC(C)C
Temperature: 90 °C
Yield: 53.2 %

Procedure:
DABCO (110 mg) was added to a solution of 3-[6-(5-{5-methyl-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E85) (100 mg) in dimethyl carbonate (3 mL) and DMF (2 mL). The resulting mixture was heated at reflux for 5 days. After cooling, the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was dissolved in iPrOH (3 mL) and water (3 mL). Sodium hydroxide (30 mg) was added to the mixture. The resulting mixture was heated at 90° C. for 1 hour. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[1-methyl-6-(5-{5-methyl-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E86) (55 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 2.24 (3H, s), 2.60 (2H, t), 2.95 (2H, t), 3.83 (3H, s), 5.41 (1H, m), 7.31 (1H, s), 7.74 (2H, m), 8.10 (1H, s), 8.29 (1H, d), 8.82 (1H, d), 12.10 (1H, br s). MS (ES): C23H24N4O4 requires 420; found 421.2 (M+H+).
Reaction SMILES: CO[C:3]1[CH:19]=[C:18]([NH:20][CH3:21])[C:17]([N+:22]([O-])=O)=[CH:16][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][CH3:15])=[O:13])[CH:7]=1.[Br:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1>O1CCOCC1>[CH3:15][NH:14][C:12]([C:8]1[CH:7]=[C:6]([O:5][C:4]2[CH:3]=[CH:19][C:18]3[N:20]([CH3:21])[C:30]([C:29]4[CH:32]=[CH:33][C:26]([Br:25])=[CH:27][CH:28]=4)=[N:22][C:17]=3[CH:16]=2)[CH:11]=[CH:10][N:9]=1)=[O:13]
Reactant: CNC(=O)c1cc(Oc2cc([N+](=O)[O-])c(NC)cc2OC)ccn1
Reactant: O=Cc1ccc(Br)cc1
Solvent: C1COCCO1
Product: CNC(=O)c1cc(Oc2ccc3c(c2)nc(-c2ccc(Br)cc2)n3C)ccn1
Temperature: 100 °C

Procedure:
A mixture of diamine 1 (137 mg, 0.36 mmol) and 4-bromobenzaldehyde (66 mg, 0.50 mmol) in dry dioxane (2 mL) was heated to 100° C. for 16 h. The reaction mixture was allowed to cool to rt and was then concentrated. The resulting residue was purified by reverse phase HPLC to finish 2 as the TFA salt: LCMS m/z 437.1, tR=2.16 min.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[Br:23][C:24]1[CH:25]=[C:26]([F:34])[CH:27]=[C:28]2[C:32]=1[NH:31][C:30](=[O:33])[CH2:29]2>>[Br:23][C:24]1[CH:25]=[C:26]([F:34])[CH:27]=[C:28]2[C:32]=1[NH:31][C:30](=[O:33])/[C:29]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C1Cc2cc(F)cc(Br)c2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3c(Br)cc(F)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Yield: 76.44 %

Procedure:
The title compound was prepared under the same conditions as described in step 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d obtained from step 4 of Example 32 and 7-bromo-5-fluoro-1,3-dihydro-indol-2-one 4b obtained from step 1 of Example 4 as starting materials to obtain (Z)-2-(7-bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 56 (63 mg, yield 76.44%) as a yellow solid.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][C:4]1[N:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:9]([O-])=[CH:8][C:7]=2[N:17]=1.C1(S(Cl)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O>[CH3:3][C:4]1[N:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:2])[C:7]=2[N:17]=1
Reactant: [NH4+]
Reactant: Cc1nc2c[n+]([O-])c3cccnc3c2n1CC(C)C
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc2c(N)nc3cccnc3c2n1CC(C)C
Temperature: 11 °C
Reaction time: 0.08 h

Procedure:
Aqueous ammonium hydroxide (5.07 kg of 30% w/w) was added over a period of ten minutes to a suspension of 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-5-oxide (6.00 kg, 23.4 mol) in ethanol (23.2 kg) at 22° C. The reaction was stirred for five minutes. Benzenesulfonyl chloride (8.80 kg, 49.8 mol) was added over a period of 30 minutes. The reaction was stirred for one hour at 22° C. A solution of aqueous sodium hydroxide (15.0 kg of 25% w/w) and water (34.0 kg) was added to the reaction mixture over a period of 30 minutes at 22° C. to adjust the mixture to pH 13. The resulting mixture was cooled to 11° C. and stirred at that temperature for three hours and then separated by centrifugation. A solid was collected, washed with demineralized water (105.0 kg) at 22° C. until the filtrate was pH 7, and dried under vacuum (2×103 Pa, 0.02 bar) at 45° C. for 24 hours to provide 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine.