Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[CH3:20])=[O:11])=[CH:5][CH:4]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Br[CH2:32][CH:33]=[CH2:34]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:34][CH:33]=[CH2:32])[C:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[CH3:20])=[O:11])=[CH:7][CH:8]=1
Reactant: C=CCBr
Reactant: COc1ccc(CC(=O)c2ccc(C#N)cc2C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(C(=O)c1ccc(C#N)cc1C)c1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
To a solution of A-7 (4-(2-(4-methoxyphenyl)acetyl)-3-methylbenzonitrile) (19 g, 71.6 mmol) in anhydrous tetrahydrofuran (200 mL) was added dropwise lithium hexamethyldisilazide (LiHMDS) (86 mL, 1 mol/L in THF) at −78° C. under nitrogen, and the reaction mixture was stirred at −78° C. for 30 min. A solution of 3-bromo-propene (10.4 g, 86 mmol) in anhydrous tetrahydrofuran (70 mL) was added dropwise into the mixture, and the resulting mixture was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (200 mL), and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate (10 g), evaporated, and purified on silica gel column (petroleum ether/ethyl acetate=25:1) to give A-8 (4-(2-(4-methoxyphenyl)pent-4-enoyl)-3-methylbenzonitrile) (7.7 g, yield 35.2%) as an oil. 1H NMR (CDCl3 400 MHZ): δ 7.36 (m, 3H), 7.01 (d, J=8.4 Hz, 2H), 6.74 (d, J=8.4 Hz, 2H), 5.72-5.62 (m, 1H), 5.04-4.93 (m, 2H), 4.20-4.17 (m, 1H), 3.69 (s, 3H), 2.92-2.85 (m, 1H), 2.52-2.40 (m, 1H), 2.16 (s, 3H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[N:11]=[C:12]([C:14]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]3[NH:23][C:24]([C:26]3[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([Cl:35])=[CH:30][CH:29]=4)=[O:25])=[O:15])[S:13][C:7]=2[CH2:6]1.C(N(CC)CC)C.[C:43](OC(=O)C)(=[O:45])[CH3:44]>CN(C)C=O.Cl>[ClH:35].[C:43]([NH:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[N:11]=[C:12]([C:14]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]3[NH:23][C:24]([C:26]3[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([Cl:35])=[CH:30][CH:29]=4)=[O:25])=[O:15])[S:13][C:7]=2[CH2:6]1)(=[O:45])[CH3:44]
Reactant: CC(=O)OC(C)=O
Reactant: NCCN1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NCCN1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-cis-N1-[[5-(2-Aminoethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-N2-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine hydrochloride (90 mg) was dissolved in N,N-dimethylformamide (3 ml), triethylamine (65 μl) and acetic anhydride (22 μl) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and dichloromethane and a 0.3N aqueous solution of sodium hydroxide were added to the residue to conduct liquid separation. The resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol=100:3) to obtain a colorless foamy substance. This product was suspended in 1N hydrochloric acid (0.3 ml), and the suspension was concentrated under reduced pressure to obtain the title compound (73 mg) as a pale yellow foamy substance.
Reaction SMILES: [N:1]#[C:2]Br.[O:4]=[C:5]1[NH:14][C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([O:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:22][CH2:21]1>>[O:4]=[C:5]1[N:14]([C:2]#[N:1])[C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([O:26][CH:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:22][CH2:21]1
Reactant: N#CBr
Reactant: O=c1[nH]c(=O)n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c2ccccc12
Product: N#Cn1c(=O)c2ccccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Yield: 64.3 %

Procedure:
Using the method similar to that in Example 61 and cyanogen bromide (657 mg, 6.20 mmol) instead of benzyl bromide and starting from 2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydroquinazoline (2.50 g, 5.17 mmol) obtained in Example 2, the title compound (1.69 g, 64%) was synthesized. Recrystallization from ethyl acetate yielded a colorless crystal having a melting point of 106 to 107° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]3[CH:14]=[CH:15][N:16]=[CH:17][C:12]3=[N:11][C:10]=2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:13]3[CH2:14][CH2:15][NH:16][CH2:17][C:12]3=[N:11][C:10]=2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(Nc2c(-c3ccc(F)cc3)nc3cnccn23)cc1
Agent: [Pd]
Solvent: CO
Product: Fc1ccc(Nc2c(-c3ccc(F)cc3)nc3n2CCNC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Example 28 was synthesized by the following way: to a stirred solution of Example 26 (761 mg, 2.36 mmol) in 10 mL of MeOH was added Pd/C (258 mg, 0.24 mmol). The reaction mixture was evacuated and back filled with H2. The reaction mixture was stirred at room temperature overnight. The solid was filtered off and solvent was removed. The product was subjected to mass-triggered HPLC purification. The obtained MeCN/water solution was combined and concentrated to give the final product as yellow oil after neutralization.
Reaction SMILES: C([Mg]Cl)(C)C.[Cl:6][C:7]1[N:17]=[CH:16][C:15]2[O:14][CH2:13][CH2:12][N:11]3[C:18](I)=[C:19]([I:21])[N:20]=[C:10]3[C:9]=2[CH:8]=1.[NH4+].[Cl-]>O1CCCC1>[Cl:6][C:7]1[N:17]=[CH:16][C:15]2[O:14][CH2:13][CH2:12][N:11]3[CH:18]=[C:19]([I:21])[N:20]=[C:10]3[C:9]=2[CH:8]=1
Reactant: Clc1cc2c(cn1)OCCn1c-2nc(I)c1I
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1cc2c(cn1)OCCn1cc(I)nc1-2
Temperature: 10 °C
Yield: 98.5 %

Procedure:
Isopropylmagnesium chloride in tetrahydrofuran (2.0 M, 3.311 mL) was added dropwise to a solution of 10-chloro-2,3-diiodo-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine (2.850 g, 6.020 mmol) in 110 ml of tetrahydrofuran at −10° C. The mixture was allowed to warm to 10° C. in 45 min and then mixed with 250 ml of cold 10% NH4Cl. The organic layer was washed with brine and dried over Na2SO4. Concentration in vacuum afforded 2.06 g of 10-chloro-2-iodo-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine (98.5%). MS: 348.0. 1H NMR (500 MHz, CDCl3) δ 8.33 (d, J=10.1, 1H), 8.18 (s, 1H), 7.18 (s, 1H), 4.46 (q, J=5.8, 4H).
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[CH2:24][CH2:25][NH2:26]>C(O)C>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]2[C:7](=[O:17])[C:6](=[O:18])[C:5]=2[NH:26][CH2:25][CH2:24][C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=2)=[CH:14][CH:13]=1
Reactant: NCCc1cccc(C(F)(F)F)c1
Reactant: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Solvent: CCO
Product: COc1ccc(-c2c(NCCc3cccc(C(F)(F)F)c3)c(=O)c2=O)cc1
Yield: 67.8 %

Procedure:
In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) and 3-trifluoromethylphenethyl-amine (0.23 g, 1.22 mmol) in ethanol (3 mL) were converted to the title compound (0.155 g, 68%) m.p. 220.2-222.3° C.; 1H NMR (DMSO-d6) δ9.05(br t,1H), 7.95(ABq, 2H), 7.60-7.45(m,4H), 7.08(ABq,2H), 3.94(br t,2H), 3.83(s,3H), 3.04(t,3H); IR (KBr) 3210, 3170, 1775, 1780, 1575, 1360, 1325, 1175, 1125, 1070, 1020, 840, 800, 695 cm−1; MS (m/z) 375 [M+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]([N:16]3[CH2:19][CH:18]([O:20][C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH2:17]3)=[O:15])=[N:11][N:10]=2)=[CH:5][CH:4]=1.Cl.[NH:30]1[CH2:36][CH2:35][CH2:34][CH:33]([OH:37])[CH2:32][CH2:31]1.[Na].C([O-])(O)=O.[Na+]>ClCCl>[OH:37][CH:33]1[CH2:34][CH2:35][CH2:36][N:30]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH:18]3[CH2:19][N:16]([C:14]([C:12]4[O:13][C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)=[N:10][N:11]=4)=[O:15])[CH2:17]3)=[CH:28][CH:27]=2)[CH2:31][CH2:32]1
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4)C3)o2)cc1
Reactant: OC1CCCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CCCC(O)CC5)cc4)C3)o2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Intermediate 55A (0.10 g, 0.26 mmol), azepan-4-ol hydrochloride (0.052 g, 0.34 mmol, see WO 2011019090) and TEA (0.146 mL, 1.05 mmol) were mixed in dichloromethane (4 mL). The mixture was stirred at RT for 1 h and then sodium triacetoxyhydroborate (0.112 g, 0.53 mmol) was added and the mixture was stirred at RT overnight. Aqueous NaHCO3 (sat., 3 mL) and dichloromethane (3 mL) were added and the mixture was filtered through a phase separator and the solvent was removed by evaporation. The product was purified by preparative reverse-phase HPLC at pH 10 to give 88 mg (70%). 1H NMR (600 MHz, DMSO) δ 1.38-1.85 (m, 7H), 2.37-2.65 (m, 3H), 3.53 (s, 2H), 3.71-3.77 (m, 1H), 3.88 (s, 3H), 4.05-4.14 (m, 1H), 4.31-4.46 (m, 1H), 4.5-4.67 (m, 2H), 5.05-5.2 (m, 2H), 6.85 (d, 2H), 7.17-7.29 (m, 4H), 8-8.05 (m, 2H), LC purity: 94%.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:14]([C:15](OCC)=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([CH3:21])=[C:10]1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[F:29][C:30]([F:47])([F:46])[C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38](Cl)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:33][CH:32]=1>>[CH3:21][C:11]1[NH:12][C:13]2[CH:20]=[C:38]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:37]([C:34]3[CH:35]=[CH:36][C:31]([C:30]([F:47])([F:46])[F:29])=[CH:32][CH:33]=3)[C:15](=[O:16])[C:14]=2[CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:28])([F:1])[F:27])[C:10]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: FC(F)(F)c1ccc(N=C(Cl)c2ccccc2)cc1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Product: CCOC(=O)C1=C(C)Nc2cc(-c3ccccc3)n(-c3ccc(C(F)(F)F)cc3)c(=O)c2C1c1ccccc1C(F)(F)F

Procedure:
This product is obtained using the procedure of Example 1 from diethyl 1,4-dihydro-4-(2-trifluoromethylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate and N-(4-trifluoromethylphenyl)-benzimidoyl chloride (1.7 g, 5.6%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15].C(N(CC)CC)C>CN(C=O)C>[CH3:15][N:14]([CH3:16])[CH:13]=[C:8]([C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1)[C:9]#[N:10]
Reactant: COC(OC)N(C)C
Reactant: N#CCc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C=C(C#N)c1ccncc1
Temperature: 110 °C

Procedure:
To a solution of 4-pyridylacetonitrile hydrochloride (155 mg, 1 mmol) in DMF (0.5 mL) was added dimethylformamide dimethylacetal (2 mL) and triethylamine (0.15 mL, 1.1 eq). The mixture was heated at 110° C. for 9 hours and then concentrated to give 3-dimethylamino-2-pyridin-4-ylacrylonitrile (3, Ar=4-Py) as dark brown crystals and used for the next step without further purification.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:8]=[C:9]([CH:35]=[CH:36][C:37]=1[CH3:38])[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH2:24][C:25]3[N:29]([CH3:30])[C:28]4[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=4[N:26]=3)=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1)(=O)C.[ClH:39]>CO.C(Cl)Cl>[ClH:39].[OH:6][C:7]1[CH:8]=[C:9]([CH:35]=[CH:36][C:37]=1[CH3:38])[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH2:24][C:25]3[N:29]([CH3:30])[C:28]4[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=4[N:26]=3)=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1nc2ccccc2n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(Nc3ccc(C)c(O)c3)ncnc2cc1OCc1nc2ccccc2n1C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 37 %

Procedure:
2M Aqueous sodium hydroxide solution (900 μl) was added to a solution of 4-(3-acetoxy-4-methylanilino)-6-methoxy-7-((1 -methylbenzimidazol-2-yl)methoxy)quinazoline (290 mg, 0.6 mmol) in methanol (15 ml) and methylene chloride (12 ml) and the mixture stirred for 25 minutes at ambient temperature. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The solid residue was purified by column chromatography eluting with methylene chloride/methanol (97/3 and 95/5). The purified white solid was suspended in methanol (20 ml) and a solution of 7.5M hydrochloric acid in methanol (2 equivalents) was added. The solid was collected by filtration, washed with methanol and then pentane and dried under vacuum at 50° C. to give 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-((1-methylbenzimidazol-2-yl)methoxy)quinazoline hydrochloride (106 mg, 37%).
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:35]([CH3:37])[CH3:36])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]2[CH2:2][CH2:3][N:4]([CH:35]([CH3:37])[CH3:36])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(CC2(c3ccc(Br)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)N1CCn2c(CC3(c4ccc(Br)cc4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a mixture of 5-benzyloxy-2-[1-(4-bromophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (233) (0.7 g, 1.23 mmol) and triphenyl phosphine (0.807 g, 3.08 mmol) in dr y dichloromethane (10 mL) was added diethyl azidocarboxylate (0.58 mL, 3.69 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. After completion, the solvent was evaporated and the crude product was purified by 100-200 silica gel column chromatography using 2% methanol in dichloromethane as the eluent to give 9-benzyloxy-6-[1-(4-bromophenyl)-cyclopentylmethyl]-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (234) (0.40 g, 59%) as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][CH2:7][OH:8])[CH3:5].N#N.F[C:12]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:22]1[C:26]2=[N:27][CH:28]=[N:29][C:30]([OH:31])=[C:25]2[CH:24]=[N:23]1>O1CCOCC1>[CH3:3][N:4]([CH3:5])[CH2:6][CH2:7][O:8][C:12]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:22]1[C:26]2=[N:27][CH:28]=[N:29][C:30]([OH:31])=[C:25]2[CH:24]=[N:23]1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(O)ncnc32)c(F)c1
Reactant: CN(C)CCO
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C)CCOc1cc(S(C)(=O)=O)ccc1-n1ncc2c(O)ncnc21
Temperature: 70 °C

Procedure:
In a reaction vial was placed a stir bar and NaH (60% in oil, 90 mg). Dimethylaminoethanol (200 mg) was dissolved in dioxane (1.5 mL) and added to the reaction vial under N2. The mixture was stirred at room temperature for 1 hour before 1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (50 mg) was added. The reaction mixture was heated at 70° C. for 60 hours. The resulting solution was concentrated under vacuum and 1-[2-(2-dimethylamino-ethoxy)-4-methanesulfonyl-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-ol was purified by preparative HPLC. 1H NMR (DMSO-d6, 400 MHz) δ 2.68 (s, 6H), 3.36 (s, 3H), 3.40 (m, 2H), 4.54 (m, 2H), 7.74 (m, 1H), 7.78 (m, 1H), 7.85 (m, 1H), 8.10 (s, 1H), 8.37 (s, 1H), 9.75 (s, 1H), 12.5 (s, 1H). Exact mass calculated for C16H19N5O4S 377.12, found 377.9 (MH+).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[S:17]([O-:20])(=[O:19])=[O:18])[CH2:2][CH3:3].[Na+].[Cl-].[NH4+].C(O)(C)C>O>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH3:3])=[C:9]([S:17]([OH:20])(=[O:19])=[O:18])[CH:10]=1
Reactant: CCCOCCOc1ccc([N+](=O)[O-])cc1S(=O)(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCCOCCOc1ccc(N)cc1S(=O)(=O)O
Temperature: 77 °C
Reaction time: 2 h

Procedure:
A mixture of 10 g of sodium 2-(2-propoxyethoxy)-5-nitrobenzenesulfonate, 5 g of reduced iron, 0.2 g of ammonium chloride, 20 ml of isopropyl alcohol and 20 ml of water was stirred at 77° C. for 2 hours. After the reaction was completed, the reaction solution was filtered to remove insoluble products. After addition of 10 ml of concentrated hydrochloric acid (36%), the filtrate was cooled. Precipitated crystals were collected by filtration and dried by air. Yield: 7.1 g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][N:23]([C:25]2([CH2:29][OH:30])[CH2:28][CH2:27][CH2:26]2)[CH:24]=1.C(O)(=O)C>CC(O)C>[CH:15]1([C@:10]2([C:13]#[N:14])[CH2:11][CH2:12][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]4[CH:21]=[N:22][N:23]([C:25]5([CH2:29][OH:30])[CH2:28][CH2:27][CH2:26]5)[CH:24]=4)[N:7]=3)[C:9]2=[O:18])[CH2:17][CH2:16]1
Reactant: Nc1cnn(C2(CO)CCC2)c1
Reactant: N#C[C@@]1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O
Solvent: CC(=O)O
Solvent: CC(C)O
Product: N#C[C@@]1(C2CC2)CCN(c2ccnc(Nc3cnn(C4(CO)CCC4)c3)n2)C1=O
Yield: 62.6 %

Procedure:
A solution of (3S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (150 mg) obtained in Step E of Example 103, (1-(4-amino-1H-pyrazol-1-yl)cyclobutyl)methanol (95 mg) obtained in Step C of Example 127 and acetic acid (34 mg) in propan-2-ol (4.0 mL) was stirred in a microwave reactor at 160° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate), and recrystallized (diisopropyl ether/ethyl acetate) to give the title compound (140 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17](CCC(O)=O)=[CH:16][CH:15]=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4]([O:31][CH2:32]C2CCCC2)[CH:3]=1.ClC1C=CC(C2N(CC3C=C(C=CC=3)C(O)=O)C3C=C(F)C(F)=CC=3N=2)=C(OCC2CCCC2)C=1.[CH3:73][O:74][C:75](=[O:86])[CH2:76][O:77]C1C=CC(CBr)=CC=1>>[CH3:73][O:74][C:75](=[O:86])[CH2:76][O:77][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:12]2[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[O:31][CH3:32])=[CH:15][CH:16]=1
Reactant: COC(=O)COc1ccc(CBr)cc1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Agent: O=C(O)c1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1
Product: COC(=O)COc1ccc(Cn2c(-c3ccc(Cl)cc3OC)nc3cc(F)c(F)cc32)cc1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and (4-bromomethyl-phenoxy)-acetic acid methyl ester (CAS Reg. No. 104508-23-8). Brown sticky solid (50%). MS (Turbo Spray): m/z=472.7 (M+H).
Reaction SMILES: Br[C:2](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:20])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:27]([O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)[CH3:28].O>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:27]([O:29][C:30]1[CH:35]=[C:34]([C:5]2[C:6]([O:9][CH3:10])=[CH:7][CH:8]=[C:3]([CH:2]=[C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:12]3=[O:20])[CH:4]=2)[CH:33]=[CH:32][CH:31]=1)[CH3:28]
Reactant: COc1ccc(C(Br)=C2C(=O)Nc3ccccc32)cc1
Reactant: CCOc1cccc(B(O)O)c1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCOc1cccc(-c2cc(C=C3C(=O)Nc4ccccc43)ccc2OC)c1
Reaction time: 12 h
Yield: 397.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.02 mmol) was added to a solution of 3-(bromo-4-methoxybenzylidene)-1,3-dihydroindol-2-one (0.2 g, 0.61 mmol) in toluene (1 ml) and ethanol (1 ml), followed by addition of 2M aqueous sodium carbonate (1.2 ml, 2.4 mmol). To this mixture was added 3-ethoxyphenylboronic acid (0.11 g, 0.67 mmol), and the mixture was held at 100° C. in a sealed tube for 12 hours. The reaction mixture was added to water (40 ml) and extracted with ethyl acetate (75 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate (50 ml) and brine (50 ml). The organic layer was dried over magnesium sulfate and concentrated. The resulting solid was triturated with dichloromethane/hexanes to afford 0.9 g (39%) of 3-(3′-ethoxy-6-methoxybiphenyl-3-ylmethylene)-1,3-dihydroindol-2-one as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=[O:7].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([Mg]Cl)[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1>C1COCC1>[CH3:12][O:11][C:9]1[CH:8]=[C:5]([CH:6]([C:17]2[CH:16]=[C:15]([O:14][CH3:13])[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=2)[OH:7])[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: COc1cc(OC)cc([Mg]Cl)c1
Reactant: COc1cc(C=O)cc(OC)c1
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(O)c2cc(OC)cc(OC)c2)c1
Temperature: 40 °C

Procedure:
3,5-Dimethoxybenzaldehyde (5.0 g, 30 mmol) was dissolved in 150 mL THF in a 500 mL round bottom flask. 3,5-Dimethoxyphenyl magnesium chloride (1 M in THF, 45 mL) was added slowly. The reaction was heated at 40° C. for 4 hours then quenched with saturated ammonium chloride. The mixture was extracted with 3 portions of ether and the combined organic layers washed with brine, dried over anhydrous MgSO4, then concentrated to a crude pale yellow solid which was carried forward to the next step: 1H NMR (250 MHz, C6D6): δ 3.29 (d, J=5.0 Hz, 12H), 6.46 (m, 2H), 6.56 (m, 1H), 6.76 (m, 2H), 7.04 (t, J=8.2 Hz, 1H).
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([NH:14]C(OC(C)(C)C)=O)[C:5]1=[O:22])[CH2:2][CH3:3].[OH-].[Na+]>CO.Cl>[CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([NH2:14])[C:5]1=[O:22])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c(NC(=O)OC(C)(C)C)nc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCn1c(=O)c(N)nc2ccccc21
Yield: 95.7 %

Procedure:
A solution of 7.12 grams (0.0234 mol) of carbamate 3 in 50 ml of methanol and 35 ml of 6N hydrochloric acid is stirred at room temperature for 4 hours. The solution is neutralized, with cooling, by addition of 6N sodium hydroxide. The crystals formed are filtered off, washed with water and dried at 50° C. 4.55 g (yield 95%) of compound 4 are thus obtained in the form of a white powder.