Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[CH3:13][C:14]1[CH:45]=[CH:44][CH:43]=[CH:42][C:15]=1[CH2:16][NH:17][C:18]([C@@H:20]1[C:24]([CH3:26])([CH3:25])[S:23][CH2:22][N:21]1[C:27](=[O:41])[C@@H:28]([OH:40])[C@@H:29]([NH2:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)=[O:19].[NH2:46][C:47]1[C:48]([CH3:56])=[C:49]([CH:53]=[CH:54][CH:55]=1)[C:50](O)=[O:51].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[CH3:13][C:14]1[CH:45]=[CH:44][CH:43]=[CH:42][C:15]=1[CH2:16][NH:17][C:18]([C@@H:20]1[C:24]([CH3:26])([CH3:25])[S:23][CH2:22][N:21]1[C:27](=[O:41])[C@@H:28]([OH:40])[C@@H:29]([NH:39][C:50](=[O:51])[C:49]1[CH:53]=[CH:54][CH:55]=[C:47]([NH2:46])[C:48]=1[CH3:56])[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=1)=[O:19]
Reactant: Cc1c(N)cccc1C(=O)O
Reactant: COc1ccc(C[C@H](N)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NCc2ccccc2C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](NC(=O)c2cccc(N)c2C)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NCc2ccccc2C)cc1
Reaction time: 8 h
Yield: 64.2 %

Procedure:
EDC.HCl (42 mg) was added to a solution of the compound obtained in Step 2 of Example 1 (94 mg), 3-amino-2-methylbenzoic acid (30 mg), and HOBt (27 mg) in DMF while cooling with ice, and the mixture was stirred overnight. EtOAc was added and the mixture was washed with 5% Na2CO3 (×2) and 5% NaCl, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2—MeOH) and reprecipitated from a mixture of CH2Cl2 and n-hexane to obtain the title compound (77 mg, 64%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH:11](Br)[CH3:12])[CH:5]=1.[CH:16]([NH2:18])=[S:17]>CCO>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:18]=[CH:16][S:17][C:11]=2[CH3:12])[CH:5]=1
Reactant: NC=S
Reactant: COC(=O)c1cccc(C(=O)C(C)Br)c1
Solvent: CCO
Product: COC(=O)c1cccc(-c2ncsc2C)c1
Yield: 103.3 %

Procedure:
A solution of crude rac-3-(2-bromo-propionyl)-benzoic acid methyl ester (2.71 g) and thioformamide (1.83 g) in EtOH (20 ml) was heated at reflux for 1 h. The mixture was partitioned between AcOEt and brine, the organic layer was dried and evaporated and the residual oil was chromatographed on silica gel using AcOEt/hexane (1:4) as eluent to give 3-(5-methyl-thiazol-4-yl)-benzoic acid methyl ester (2.41 g) as white solid.
Reaction SMILES: C([O:5][C:6](=O)[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:22])[F:21])[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:25]([O:27][C:28](=[O:40])[CH:29](C(OCC)=O)[C:30](OCC)=[O:31])[CH3:26]>>[CH2:25]([O:27][C:28]([C:29]1[C:6](=[O:5])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:22])([F:23])[F:21])[N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:30]=1[OH:31])=[O:40])[CH3:26]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1C(F)(F)F)n1cccc1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2ccccc2C(F)(F)F)c1=O

Procedure:
Prepared according to the thermal cyclization condition used in Example 1 step c) from (2-trifluoromethyl-benzyl)-pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.0 eq.). ESI (m/z): 381 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:11][CH3:12])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:30][CH2:31][O:32][C:33]([CH2:35]Br)=[O:34]>CN(C=O)C>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH2:35][C:33]([O:32][CH2:31][CH3:30])=[O:34])=[CH:15][CH:14]=2)[CH2:11][CH3:12])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: CCC(=NOCc1ccc(C(F)(F)F)cc1)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccc(C(CC)=NOCc2ccc(C(F)(F)F)cc2)cc1
Yield: 55.5 %

Procedure:
To a solution of the product of step 2 (3.5 g, 0.0097 moles) in DMF (35 mL), potassium carbonate (4 gm, 0.0291 moles) and Ethyl bromo acetate (1.8 gm, 0.0107 moles) were added and reaction mixture was srirred at 100° C. for over night. The reaction mixture was poured into ice cold water and extracted by ethyl acetate. The combined ethyl acetate extract was washed with water and brine, dried over sodium sulphate and evapourated under reduced pressure to yield 2.2 gm (55%) of product as solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH:22]=O)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl-].C[NH3+].[C:27]([BH3-])#[N:28].[Na+].C(=O)([O-])O.[Na+]>CO>[CH3:27][NH:28][CH2:22][C:13]1[CH:14]=[C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[CH:12]=1
Reactant: [BH3-]C#N
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2)cc1
Agent: C[NH3+]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.2 %

Procedure:
To a solution (10 mL) of 1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (200 mg) in methanol were added methylammonium chloride (207 mg) and sodium cyanoborohydride (39 mg), and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→1:1) to give the title compound as a brown oil (yield 15 mg, 7%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[CH:41]=[CH:42][C:43](=[O:47])[N:44]([CH3:46])[CH:45]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.O.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[CH:41]=[CH:42][C:43](=[O:47])[N:44]([CH3:46])[CH:45]=5)=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cn1cc(Br)ccc1=O
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
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: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Cn1cc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)ccc1=O
Temperature: 25 °C
Yield: 74.9 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 5-bromo-1-methylpyridine-2(1H)-one (284 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (402 mg, 75%) as a light yellow oily substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])=[C:13]([CH:17]=1)[C:14](O)=[O:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1Cl
Reactant: Nc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccccc1Cl
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Solid pyridin-3-amine (212 mg, 2.25 mmol) was added in one charge to a stirred solution of 5-bromo-2-{[(2-chlorophenyl)methyl]oxy}benzoic acid (may be prepared as described in Description 28; 350 mg, 1.03 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (236 mg, 1.23 mmol) and 1-Hydroxybenzotriazole (166 mg, 1.23 mmol) in DMF (20 ml) under nitrogen at 20° C. The reaction mixture was stirred at 20° C. for 16 h. Water (50 ml) was added to the mixture and the mixture was filtered to yield the title compound as a white solid. 400 mg.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[S:11](Cl)(=[O:13])=[O:12])[CH2:2][CH3:3].[Cl:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([S:33]([N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)(=[O:35])=[O:34])=[CH:29][CH:28]=3)=[CH:21][CH:22]=[N:23]2)=[CH:18][CH:17]=1>>[CH2:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[S:11]([N:39]1[CH2:40][CH2:41][N:36]([S:33]([C:30]2[CH:31]=[CH:32][C:27]([NH:26][C:20]3[C:19]4[C:24](=[CH:25][C:16]([Cl:15])=[CH:17][CH:18]=4)[N:23]=[CH:22][CH:21]=3)=[CH:28][CH:29]=2)(=[O:34])=[O:35])[CH2:37][CH2:38]1)(=[O:13])=[O:12])[CH2:2][CH3:3]
Reactant: O=S(=O)(c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1)N1CCNCC1
Reactant: CCCc1cc(Br)ccc1S(=O)(=O)Cl
Product: CCCc1cc(Br)ccc1S(=O)(=O)N1CCN(S(=O)(=O)c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2)CC1

Procedure:
In the manner given in Example 13 but using 2-propyl-4-bromophenylsulfonyl chloride in place of sulfamoyl chloride and [[4-[(7-chloro-4-quinolinyl)amino]phenyl]sulfonyl]piperazine in place of [[4-[(7-trifluoromethyl-4-quinolinyl]amino]sulfonyl] -piperazine, 1-[(2-propyl-4-bromophenyl)sulfonyl]-4 -[[4-[[7-chloro-4-quinolinyl]amino]phenyl]sulfonyl]-piperazine is obtained.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)=[N:10][N:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl:34][CH2:35][CH2:36][CH2:37][C:38](Cl)=[O:39]>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:34][CH2:35][CH2:36][CH2:37][C:38]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([O:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]3[N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[N:8]=[N:9][N:10]=3)=[CH:26][CH:25]=2)[CH2:20][CH2:21][C:22]1=[O:27])=[O:39]
Reactant: O=C(Cl)CCCCl
Reactant: O=C1CCc2cc(OCCCCc3nnnn3C3CCCCC3)ccc2N1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCCCl)N1C(=O)CCc2cc(OCCCCc3nnnn3C3CCCCC3)ccc21
Temperature: 70 °C
Reaction time: 20 h
Yield: 42 %

Procedure:
To a solution of 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydroquinolin-2(1H)-one (cilostazol, 1, A=H, 15.00 g, 40.6 mmol), pyridine (6.42 g, 81.2 mmol) and 4-dimethyl-aminopyridine (DMAP, 6.45 g, 52.8 mmol) in 135 mL chloroform at room temperature is added slowly 4-chlorobutanoyl chloride (7.45 g, 52.8 mmol). The mixture is stirred at 70° C. for 20 hours. The reaction mixture is diluted with 1000 mL CH2Cl2, and washed with 1N HCl, saturated NaHCO3 solution and brine. The organic phase is dried over sodium sulphate, and concentrated. The residue is purified by flash chromatography (silica gel, CH2Cl2/tert-butyl methyl ether 90:10) to give the title compound in 42% yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:29][CH2:30][CH3:31])[CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C@H:19]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:17]3)=[N:7][CH:8]=1)#[N:2].[SH2:32].C(NCC)C>CN(C=O)C>[NH2:2][C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:29][CH2:30][CH3:31])[CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C@H:19]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:17]3)=[N:7][CH:8]=1)=[S:32]
Reactant: S
Reactant: CCCN(CCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC)c1ccc(C#N)cn1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCCN(CCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC)c1ccc(C(N)=S)cn1
Temperature: 60 °C
Yield: 95 %

Procedure:
Through a solution of ethyl ((1S)-5-{3-[(5-cyano-2-yridinyl)(propyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 265) (0.62 g, 1.47 mmol) in DMF (7 mL) at rt for 20 min was gently passed H2S. Diethylamine (0.23 mL, 2.21 mmol) was added in one portion, and the resultant light green solution was heated at 60° C. for 3 h. Upon completion of the reaction, the dark green solution was purged with a strong flow of argon, and then concentrated under reduced pressure. The product (0.63 g, 95%) was isolated after silica gel column chromatography (1:1 hexanes/EtOAc) as a yellow solid. 1H NMR (400 MHz, CD2Cl2) δ 8.68 (d, 1H), 8.02 (dd, 1H), 7.30 (b, 1H), 7.15-7.02 (m, 2H), 6.79 (d, 1H), 6.71 (dd, 1H), 6.49 (d, 1H), 4.16 (q, 2H), 4.00 (t, 2H), 3.75 (t, 2H), 3.56-3.45 (m, 3H), 2.96-2.78 (m, 2H), 2.75-2.68 (m, 1H), 2.48-2.34 (m, 2H), 2.11 (qt, 2H), 1.82-1.60 (m, 3H), 1.28 (t, 3H), 0.97 (t, 3H).
Reaction SMILES: C([Sn](CCCC)=O)CCC.[N:11]([Si](C)(C)C)=[N+:12]=[N-:13].[CH2:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH:19]1[NH:27][C:28]1[N:29]=[CH:30][C:31]2[CH2:36][N:35]([C:37](=[O:44])[CH2:38][CH2:39][CH2:40][CH2:41][C:42]#[N:43])[CH2:34][C:32]=2[N:33]=1>C1(C)C=CC=CC=1>[CH2:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH:19]1[NH:27][C:28]1[N:29]=[CH:30][C:31]2[CH2:36][N:35]([C:37](=[O:44])[CH2:38][CH2:39][CH2:40][CH2:41][C:42]3[NH:43][N:13]=[N:12][N:11]=3)[CH2:34][C:32]=2[N:33]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CCCCCC(=O)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=C(CCCCc1nnn[nH]1)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Temperature: 105 °C
Yield: 30.8 %

Procedure:
Add dibutyloxostannane (0.071 g; 1.33 equiv; 0.29 mmoles) and azidotrimethylsilane (1.6 mL; 56 equiv; 12.01 mmoles) to a stirred solution of 6-[2-(indan-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]-6-oxo-hexanenitrile (0.077 g; 1.0 equiv; 0.213 mmoles) in toluene (6 mL). Heat the resulting solution to 105° C. for 16 hours. Cool the reaction mixture to ambient temperature and concentrate. Dissolve the residue in methanol (5 mL) and load the solution on an SCX column (eluting with methanol to 7N ammonia in methanol) to afford the crude product, which is purified by reverse phase chromatography to give 1-[2-(2,3-dihydro-1H-inden-2-ylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl]-5-(1H-tetrazol-5-yl)pentan-1-one (0.0265 g; 31%): MS (m/z): 405(M+1).
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[N:6][N:7]=1.[CH3:15][O-:16].[Na+]>CO>[CH3:15][O:16][C:2]1[C:3]2[S:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[N:6][N:7]=1
Reactant: C[O-]
Reactant: Clc1nnnc2c1sc1ccccc12
Agent: [Na+]
Solvent: CO
Product: COc1nnnc2c1sc1ccccc12

Procedure:
A 2.2 g. portion of the product of Example 1 was stirred at reflux temperature in 100 ml. of methanol with 0.7 g. of sodium methoxide for one hour. When the reaction mixture was cooled, the product, 1.9 g. of 4-methoxy[1]-benzothieno[3,2-d]-v-triazine, m.p. 165°-167° C., crystallized and needed no further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][NH2:14]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:14][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CN
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(OC)cc1
Reaction time: 1.33 h
Yield: 74.1 %

Procedure:
4-Methoxybenzene-1-sulfonyl chloride (688.1 mg, 3.331 mmol) was suspended in DCM (10 mL) and methylamine (6.5 mL, 2.0 M in THF, 13 mmol) was added. The reaction was stirred under nitrogen for about 80 minutes. The mixture was filtered, and the solid was washed with DCM. The filtrate was concentrated and dried under high vacuum to provide 4-methoxy-N-methylbenzenesulfonamide (497 mg, 74% yield). MS (ESI pos. ion) m/z: 202 (MH+). Calculated exact mass for C8H, NO3S: 201.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][OH:6])=[CH2:2].[CH2:7](Br)[CH:8]=[CH2:9].[OH-].[Na+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].C1(C)C=CC=CC=1>[CH2:7]([O:6][CH2:5][CH2:4][O:3][CH:1]=[CH2:2])[CH:8]=[CH2:9]
Reactant: C=CCBr
Reactant: C=COCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCOCCOC=C
Temperature: 65 °C

Procedure:
A 100 ml round bottom flask fitted with a reflux condenser and a magnetic stirrer was charged with 8.8 grams (0.1 mol) of ethylene glycol monovinyl ether, 14.5 grams (0.12 mol) of allyl bromide, 4.8 grams (0-12 mol) of NaOH, 0.9 grams (3 mol %) of (n-Bu)4NBr, and 20 ml of dried toluene. The white suspension was stirred and heated at 65 ° C. for 12 hours. After cooling the reaction mixture, the resulting light yellow solution was separated from the white solids by decantation and washed with four times with 50 ml portions of water in a separatory funnel. Removal of the solvent under reduced pressure followed by vacuum distillation (b.p. 30° C./0.15 mm Hg gave the desired 1-allyloxy-2-vinyloxyethane as a colorless liquid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1>[OH-].[Na+]>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH:6]([C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)[OH:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: Oc1ccc(C(O)C(O)c2ccc(O)cc2)cc1
Temperature: 45 °C
Yield: 74 %

Procedure:
The electrolysis cell was charged with 400 grams (3.28 moles) of 4-hydroxybenzaldehyde and 3500 milliliters 2.0 molar aqueous sodium hydroxide. The mixture was warmed on a stirrer-hotplate to about 45° C to effect complete dissolution. Then a small amount of Union Carbide SAG 470 silicone antifoam agent was added. The electrolysis was conducted at a constant current of 25 amperes and a temperature range between about 44° C and about 49° C over an 8-hour period. The cathode potential was -2.0 to about -2.1 volts versus the saturated calomel electrode. Upon completion of the electrolysis, the product solution was allowed to cool to ambient temperatures and removed from the cell. The cell was washed with water and the washings added to the product solution. The volume of the combined product solution and washings was reduced to approximately 1,500 milliliters by evaporation in vacuo. The remaining solution was acidified to about pH 6.3 by the dropwise addition of acetic acid at the rate of 20 milliliters per minute. A total of 450 milliliters of acetic acid was added. The solution was cooled in an ice-water bath to induce crystallization. The precipitate was collected by suction filtration, washed with cold water, and dried to yield 299.0 grams (74.1 percent) of 1,2-bis(4-hydroxyphenyl)-ethane-1,2-diol.
Reaction SMILES: Cl.[CH2:2]([S:4]([CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1)(=[O:6])=[O:5])[CH3:3].[CH:24]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH2:25].C(N(CC)CC)C>CN(C)C(=O)C>[CH2:2]([S:4]([CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH2:25][CH2:24][S:26]([CH3:29])(=[O:28])=[O:27])(=[O:6])=[O:5])[CH3:3]
Reactant: CCS(=O)(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Reactant: C=CS(C)(=O)=O
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3CCS(C)(=O)=O)c2c1
Temperature: 100 °C
Yield: 54.4 %

Procedure:
5-(2-Ethylsulphonylethyl)-3-(2(R)-pyrrolidinylmethyl)-1H-indole hydrochloride (Preparation 5; 200 mg, 0.56 mmol) was dissolved in N,N-dimethylacetamide (4 ml) under nitrogen at room temperature, then methyl vinyl sulphone (0.06 ml, 0.69 mmol) and triethylamine (0.2 ml) were added. The resulting mixture was heated at 100° C. for 18 hours, allowed to cool, then partitioned between ethyl acetate and water. The organic phase was separated, washed with water, dried (Na2SO4) and evaporated under reduced pressure. The resulting crude material was purified by column chromatography on silica gel, eluting with a gradient of ethanol in dichloromethane (0 to 5% ethanol), to afford the title compound as a gum (130 mg). Rf 0.70 (SS 4). [α]D25 +43° (c=0.1, CH3OH). Found: C,55.38; H,7.12; N,6.50. C20H30N2O4S2 ; 0.10 CH2Cl2 requires C,55.48; H,7.00; N,6.44%. δ(CDCl3): 1.38(3H,t), 1.50-1.90(5H,m), 2.22(1H,m), 2.60-2.80(3H,m), 2.90-3.35(12H,m), 3.48(1H,m), 5.30(0.20H,s,CH2Cl2), 6.98-7.10(2H,m), 7.30(1H,d), 7.44(1H,s), 8.22(1H,br s).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10](Br)[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1.[F:17][CH:18]([F:32])[O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH:29]([F:31])[F:30])[CH:23]=[O:24]>C1COCC1>[F:17][CH:18]([F:32])[O:19][C:20]1[CH:21]=[C:22]([CH:23]([C:10]2[CH:9]=[C:8]([O:7][CH3:6])[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=2)[OH:24])[CH:25]=[CH:26][C:27]=1[O:28][CH:29]([F:30])[F:31]
Reactant: O=Cc1ccc(OC(F)F)c(OC(F)F)c1
Reactant: COc1cc(Br)cc(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(O)c2ccc(OC(F)F)c(OC(F)F)c2)c1
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
n-Butyl lithium (2.5 M, 3.7 mL) was added to s stirred solution of 3,5-dimethoxy-bromobenzene (2.0 g, 9.2 mmol) in THF (15 mL) at −65° C. After stirring for 30 min, a solution of 3,4-bis-difluoromethoxy-benzaldehyde (2.0 g, 8.4 mmol) in THF (15 mL) was added slowly. The resulting mixture was stirred at −65° C. for 6 h and then quenched with isopropanol (5 mL). Water (40 mL) was added and the mixture was extracted with ether (3×60 mL). The combined organic layers were washed with water (2×40 mL), brine (40 mL), and dried (MgSO4). Solvent was removed and the residue was purified by flash chromatography (Silica gel, Hexane:EtOAc 7:3) to afford (3,4-bis-difluoromethoxy-phenyl)-(3,5-dimethoxy-phenyl)-methanol (1.3 g, 42%): 1H NMR (CDCl3) δ 7.32 (m, 1H), 7.19 (m, 2H), 6.86-6.19 (m 5H), 5.69 (d, J=2 Hz, 1H), 3.76 (s, 6H), 2.47 (d, J=2 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([NH:26][CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=2)[N:4]=1)[CH3:2].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:44](C)=O.[Na+]>C(Cl)Cl.CO>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([NH:26][CH:27]4[CH2:31][CH2:30][N:29]([CH3:44])[CH2:28]4)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)NC5CCNC5)ccn34)c12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)NC5CCN(C)C5)ccn34)c12
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To N3-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-N7-(pyrrolidin-3-yl)imidazo[1,2-a]pyridine-3,7-dicarboxamide (5 mg, 0.0096 mmol; prepared as in Example 46) in DCM/MeOH (1 mL/1 mL) was added HCHO as a 35% aqueous solution (16 mg, 0.19 mmol) and NaBH(OAc)3 (10 mg, 0.048 mmol). The reaction mixture was stirred for one hour, concentrated under reduced pressure and the residue was purified by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) to provide the final product (4 mg). MS (ES+APCI) m/z=537 (M+H).