Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:17])[CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)[CH2:2][CH2:3][CH3:4].[H-].[Na+].I[CH3:21]>CN(C)C=O>[CH2:1]([NH:5][C:6](=[O:17])[CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:21])[CH:12]=[CH:11]2)[CH2:2][CH2:3][CH3:4]
Reactant: CI
Reactant: CCCCNC(=O)Cc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCNC(=O)Cc1ccc2c(ccn2C)c1
Reaction time: 1 h
Yield: 43 %

Procedure:
A solution of N-butylindole-5-acetamide (1.0 g) in dimethylformamide (15 ml) was added to a slurry of sodium hydride (0.11 g) in dimethylformamide (7 ml) at 0° under a nitrogen atmosphere, stirred for 1 hr at 0° and treated with iodomethane (0.3 ml). The reaction was quenched with saturated ammonium chloride solution and diluted with water. The precipitate that formed was collected by filtration, washed with water, and dried under vaccum to give N-butyl-1-methyl-indole-5-acetamide (0.46 g, 43%) as a pale yellow powder: NMR (250 MHz, CDCl3): 0.84(t, 3H, N(CH2)3CH3), 1.38-1.17(m, 4H, NCH2 (CH2)2), 3.16(q, 2H, NCH2), 3.67(s, 2H, ArCH2), 3.80(s, 3H, NCH3), 5.43(br, 1H, NH), 6.45(d, 1H, H2 -indole).
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[OH-].[K+].O.[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Br>CN(C=O)C>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[F:14])[N:6]=[C:7]([OH:9])[CH:8]=1
Reactant: Fc1ccccc1CBr
Reactant: Nc1cc(O)nc(S)n1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(O)nc(SCc2ccccc2F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a stirred suspension of 4-Amino-6-hydroxy-2-mercaptopyrimidine monohydrate (25 g) in DMF (300 ml) was added potassium hydroxide (10.2 g) and water (50 ml). After a clear solution was obtained, 2-fluorobenzyl bromide (29.3 g) was added and the reaction stirred at room temperature for 30 min. The mixture was poured into water (21) and the resulting precipitate isolated by filtration, washing with isopropanol and diethyl ether, affording the subtitled compound as a white solid (34.7 g).
Reaction SMILES: [Cl-].[CH3:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([CH3:10])[N+:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:18]>C(O)C>[Cl-:9].[CH3:2][C:3]1[CH:8]=[C:7]([N:19]([CH2:17][CH3:18])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[C:5]([CH3:10])[N+:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(Cl)cc(C)[n+]1-c1ccccc1
Reactant: CCNc1ccccc1
Agent: [Cl-]
Solvent: CCO
Product: CCN(c1ccccc1)c1cc(C)[n+](-c2ccccc2)c(C)c1
Yield: 56 %

Procedure:
A mixture of 2,6-dimethyl-N-phenyl-4-chloropyridinium chloride (previously reported in Annalen, 1958, 617, 181-202) (2.19 g, 10 mM), N-ethylaniline (3.6 g, 30 mM) and ethanol (100 ml) was heated under reflux for 30 minutes. The solvent was removed by evaporation and the resultant syrup was purified by flash chromatography (Merck 9385 silica column, 180 g) using a 1:19 v/v mixture of methanol/methylene chloride as eluant. The resultant syrup was further purified by flash column chromatography using a neutral alumina column (ICN type N32-63, 150 g) and eluting with an increasing gradient (0-5% v/v) of methanol in dichloromethane. There was thus obtained 2,6-dimethyl-4-(N-ethylanilino)-N-phenylpyridinium chloride (1.9, 56% yield) as a pale orange glass; microanalysis, found: C,70.7; H,6.5; N,7.6; Cl,9.7%; C21H23N2Cl .H2O requires: C,70.7; H,7.0; N,7.85; Cl, 9.93%; NMR: 1.2-1.3(3H, t,CH2CH3), 2.1(6H,5 pyridine-CH3), 3.9-4.05(2H,q,CH2CH3), 6.7-7.1(2H,br, pyridine-3H and -5H), 7.35-7.7 (10H, complex, aromatic).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([NH:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CO.O>[C:10]([O:14][C:15]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([NH:22][C:2]2[N:7]=[C:6]([NH:22][C:21]3[CH:20]=[CH:19][C:18]([NH:17][C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])=[CH:24][CH:23]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:23][CH:24]=1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2ncc(F)c(Nc3ccc(NC(=O)OC(C)(C)C)cc3)n2)cc1
Temperature: 70 °C

Procedure:
2,4-Dichloro-5-fluoropyrimidine (75 mg, 0.45 mmol) was dissolved in a mixture of MeOH (2 ml) and H2O (0.2 ml). 4-tert-butoxycarbonylaminoaniline (374 mg, 1.8 mmol) was added and the mixture was refluxed for 24 hours (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 9:1) to give N2,N4-bis[4-(tert-butoxycarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6+CD3OD): δ 7.96 (d, 1H, J=3.5 Hz), 7.63 (d, 2H, J=8.8 Hz), 7.49 (d, 2H, J=8.8 Hz), 7.37 (d, 2H, J=8.8 Hz), 7.24 (d, 2H, J=8.8 Hz), 1.45 (s, 9H), 1.43 (s, 9H); LCMS: purity: 97.9%; MS (m/e): 511.04 (M+, 100).
Reaction SMILES: [CH:1]([OH:3])=O.N#N.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:38])[C:24]=1[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][CH:34]=2)[CH2:29][NH:28][N:27]=1.C(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1>[Cl:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:38])[C:24]=1[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][CH:34]=2)[CH2:29][N:28]([CH:1]=[O:3])[N:27]=1
Reactant: O=CO
Reactant: COc1ccc2c(c1)CNN=C2Cc1c(Cl)cncc1Cl
Agent: N#N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CN(C=O)N=C2Cc1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
A solution of formic acid (0.123 ml, 3.255 mmoles) in dry THF (40 ml), under stirring and dry N2 at room temperature, was added with 1,1′-carbonyldiimidazole (0.53 g, 3.255 mmoles) and the mixture was left to stand for 1 hour. Then 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-1,2-dihydro-phthalazine (1 g, 3.1 mmoles), prepared as described in example 22, was portionwise added. After 6.5 hours another portion of a mixture of formic acid/carbonyldiimidazole (about ⅓ of the previous one) was added and the mixture was stirred at room temperature for 1 hour, then left to stand overnight. The mixture was poured into water/ice, THF was evaporated, and the solution was extracted more times with CH2Cl2. The organic phase was washed with KHSO4, then with NaHCO3 and with water, anhydrified and concentrated. The residue was crystallised from acetonitrile (40 ml) to give 1 g of the title compound (yield: 92.6%). m.p.: 165-167° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:27][CH2:28][CH2:29][CH3:30])[C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:31][CH2:32][CH2:33][NH2:34]>>[CH2:1]([N:8]([CH2:27][CH2:28][CH2:29][CH3:30])[C:9]1[C:14]2[N:15]=[C:16]([NH:34][CH2:33][CH2:32][OH:31])[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCN(Cc1ccccc1)c1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Reactant: NCCO
Product: CCCCN(Cc1ccccc1)c1ncnc2c(N3CCS(=O)CC3)nc(NCCO)nc12

Procedure:
This compound was prepared analogous to Example 2 from 8-(N-benzyl-butylamino)-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido[5,4-d]pyrimidine (melting point: 153°-155° C.) and 2-hydroxyethyl-amine.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[N:11]=[C:10]([NH:12][C:13]2[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=[C:17]([Br:19])[CH:18]=2)[CH:9]=[CH:8][CH:7]=1.CCN(CC)CC.[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>C(Cl)Cl>[Br:19][C:17]1[CH:18]=[C:13]([NH:12][C:10]2[N:11]=[C:6]([O:5][CH2:4][CH2:3][NH:2][C:29](=[O:32])[CH2:30][CH3:31])[CH:7]=[CH:8][CH:9]=2)[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=1
Reactant: Cn1cc(Br)cc(Nc2cccc(OCCN)n2)c1=O
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NCCOc1cccc(Nc2cc(Br)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.7 %

Procedure:
A mixture of 3-(6-(2-aminoethoxyl)pyridin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one hydrochloride 103a (250 mg, 0.66 mmol) and Et3N (0.23 mL, 6.0 mmol) in DCM (15 mL) was added propionyl chloride (70 uL, 0.79 mmol). The mixture was stirred at RT for 2 h. The mixture was washed with water (20 mL*2). The organic layer was dried and concentrated to give N-(2-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-2-yloxy)ethyl)propionamide 119a (140 mg, 54%) as a light yellow solid. ESI-LCMS: m/z=395.1.
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:18]S(C)(=O)=C>>[O:3]1[C:2]([CH3:18])([CH2:4][CH:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:1]1
Reactant: CC(=O)CC(c1ccccc1)c1ccccc1
Reactant: C=S(C)(C)=O
Product: CC1(CC(c2ccccc2)c2ccccc2)CO1

Procedure:
The 1,2-epoxy-4,4-diarylbutane starting materials can alternatively be prepared by reaction of dimethylsulfonium methylide or dimethyloxosulfonium methylide with an appropriate diarylalkyl aldehyde or a diarylalkyl ketone. For example, reaction of an aldehyde such as 3,3-diphenylpropanal with either dimethylsulfonium methylide or dimethyloxosulfonium methylide in approximately equimolar amounts provides 1,2-epoxy-4,4-diphenylbutane. Similarly, reaction of a diarylalkyl ketone such as methyl-(2,2-diphenylethyl) ketone with either dimethylsulfonium methylide or dimethyloxosulfonium methylide provides 1,2-epoxy-4,4-diphenyl-2-methylbutane. Such reactions typically are carried out in a solvent such as dimethyl sulfoxide or tetrahydrofuran, and normally at a reduced temperature of about 0° C. Dimethylsulfonium methylide is prepared by reaction of trimethylsulfonium iodide with methylsulfinylcarbanion, while demethyloxosulfonium methylide is prepared by reaction of trimethyloxosulfonium iodide with sodium hydride. Such reactions are more fully discussed by Corey et al., J. Am. Chem. Soc., 84, 867(1962) and J. Am. Chem. Soc., 84, 3782 (1962).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH:21]([N:24]1[C:28]([C:29]2[N:38]=[C:37]3[N:31]([CH2:32][CH2:33][O:34][C:35]4[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][C:36]=43)[CH:30]=2)=[N:27][CH:26]=[N:25]1)([CH3:23])[CH3:22]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:43]([C:40]2[CH:41]=[CH:42][C:35]3[O:34][CH2:33][CH2:32][N:31]4[C:37](=[N:38][C:29]([C:28]5[N:24]([CH:21]([CH3:22])[CH3:23])[N:25]=[CH:26][N:27]=5)=[CH:30]4)[C:36]=3[CH:39]=2)(=[O:45])=[O:44])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)Cl)ccc1OCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)N3CCN(C(=O)OC(C)(C)C)CC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (216 mg, 1.16 mmol) and NEt3 (272 μL, 1.93 mmol) in DCM (30 mL) at 0° C. was added a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride from Example 121 (270 mg, 0.39 mmol) in DCM (20 mL) and the resulting mixture warmed to RT after 10 min then stirred for 30 min. The reaction mixture was diluted with DCM, washed with a saturated aqueous NaHCO3 solution then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-5% MeOH in DCM) affording 4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl]piperazine-1-carboxylic acid tert-butyl ester (196 mg, 93%) as a white solid. LCMS: RT 4.72 min [M+H]+ 544.3. 1H NMR (DMSO, 400 MHz): δ 8.77 (1H, d, J=2.43 Hz), 8.01 (1H, s), 7.94 (1H, d, J=0.61 Hz), 7.63 (1H, dd, J=8.64, 2.44 Hz), 7.28 (1H, d, J=8.64 Hz), 5.75-5.71 (1H, m), 4.67-4.57 (4H, m), 3.44-3.38 (4H, m), 2.91 (4H, t, J=4.83 Hz), 1.50 (6H, d, J=6.62 Hz), 1.32 (9H, s)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][C:36]2[CH:37]=[C:38]([CH:41]=[C:42]([CH:44]=[CH:45][C:46]3[CH:51]=[C:50]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:49]=[C:48]([C:56]([CH3:59])([CH3:58])[CH3:57])[CH:47]=3)[CH:43]=2)[CH:39]=O)[CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1)([CH3:23])([CH3:22])[CH3:21].[C:60]([Br:64])(Br)(Br)[Br:61]>ClCCl>[Br:61][C:60]([Br:64])=[CH:39][C:38]1[CH:41]=[C:42]([CH:44]=[CH:45][C:46]2[CH:51]=[C:50]([C:52]([CH3:53])([CH3:54])[CH3:55])[CH:49]=[C:48]([C:56]([CH3:59])([CH3:57])[CH3:58])[CH:47]=2)[CH:43]=[C:36]([CH:35]=[CH:34][C:26]2[CH:25]=[C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=2)[CH:37]=1
Reactant: CC(C)(C)c1cc(C=Cc2cc(C=O)cc(C=Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)c2)cc(C(C)(C)C)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(C=Cc2cc(C=Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc(C=C(Br)Br)c2)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 94.9 %

Procedure:
Triphenylphosphine (3.92 g, 14.96 mmol) was added in one portion to a stirred solution of -3,5-bis[2-(3,5-di-tert-butylphenyl)vinyl]benzaldehyde (1) (2.00 g, 3.74 mmol) and carbon tetrabromide (2.48 g, 7.38 mmol) in dichloromethane (20 mL). Heat was evolved and the mixture stirred at room temperature for 75 min. The resultant orange suspension was washed with water (2×50 mL), dried over anhydrous magnesium sulphate, filtered and the solvent removed to leave an orange-brown residue, which was purified by passing through a plug of silica with dichloromethane—light petroleum (2:3) as eluent. The solvent was removed to give 2-{3,5-bis[2-(3,5-di-tert-butylphenyl)vinyl]phenyl}-1,1-dibromoethene (2) as a white foam (2.45 g, 95%) mp 148-150° C. (Found: C, 69.5; H, 7.3; C40H50Br2 requires C, 69.6; H, 7.3%); νmax(KBr)/cm−1 1595 (C═C) and 958 (C═C—H trans); λmax(CH2Cl2)/nm 306 (log(ε/dm3 mol−1 cm−1)4.85), 317 (4.85) and 329sh (4.73); −δH(400 MHz, CDCl3) 1.40 (36 H, s, t-butyl), 7.14 and 7.24 (4 H, d, J 16, vinyl H) 7.40 (2 H, dd, J 1.5, sp H),7.42(4 H, d, J 1.5, sp H), 7.56 (1 H, s, CHCBr2), 7.60 (2 H, s, cp H) and 7.69 (1 H, s, cp H); m/z (CI+) 692.2 (MH+, 100%), 613.2 (M−79Br, 96%), 611.2 (M−81Br, 90%) and 533.3 (M−279Br, 74%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH3:17])[C:13](SC)=[N:12]3)[CH2:10][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:28].[I-].N.CCO>>[NH2:28][C:13]1[N:14]([CH3:17])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[CH2:10]2)[N:12]=1
Reactant: [NH4+]
Reactant: COc1cccc(C2CC3(N=C(SC)N(C)C3=O)c3cc(Br)ccc3O2)c1
Agent: N
Agent: [I-]
Solvent: CCO
Product: COc1cccc(C2CC3(N=C(N)N(C)C3=O)c3cc(Br)ccc3O2)c1
Yield: 17.9 %

Procedure:
A solution of 6-bromo-2-(3-methoxyphenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (13 mg) and NH4I (10 mg) in a solution of NH3/EtOH (2 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-2-(3-methoxyphenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (2.17 mg, 22%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(N(CC)CC)C.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([F:18])([F:30])[F:31])(=[O:28])=[O:27])[N:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: Brc1n[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1C(F)(F)F)n1nc(Br)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.9 %

Procedure:
To a suspension of 3-bromoindazole (500 mg, 2.54 mmol) in 8 ml CH2Cl2 was added triethyl amine (1.06 ml, 7.61 mmol) at room temperature. To this yellow solution was added 2-(trifluoromethyl)benzenesulfonyl chloride (0.392 ml, 2.54 mmol) and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified on SiO2 using 5% to 20% ethyl acetate in heptane to give 3-bromo-1-(2-(trifluoromethyl)phenylsulfonyl)-1H-indazole (894 mg)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].[Cl:15][C:16]([Cl:21])([Cl:20])[C:17](Cl)=[O:18]>CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]2[C:12]([C:17](=[O:18])[C:16]([Cl:21])([Cl:20])[Cl:15])=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc2nccn12
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Product: CCOC(=O)c1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Yield: 74.2 %

Procedure:
To a solution of 25.22 g (0.133 mol) of 5-ethoxycarbonylimidazo[1,2-a]pyridine and 48.60 g (0.398 mol) of 4-dimethylaminopyridine was added dropwise 72.33 g (0.398 mol) of trichloroacetyl chloride. The mixture was heated for 63 hours under reflux. After cooling, the reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate/n-hexane=1:1) to give 33.10 g of the desired compound (77.4%, yellow solid).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]([Cl:9])=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=2)[C:6]([C:18]([O:20][CH3:21])=[O:19])=[CH:5]1.Cl.[CH2:23]=O.N>CO.O>[Cl:9][C:8]1[N:4]2[CH2:3][CH2:2][NH:1][CH2:23][C:5]2=[C:6]([C:18]([O:20][CH3:21])=[O:19])[C:7]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1
Reactant: COC(=O)c1cn(CCN)c(Cl)c1-c1cccc(C#N)c1
Reactant: C=O
Agent: Cl
Agent: N
Solvent: O
Solvent: CO
Product: COC(=O)c1c(-c2cccc(C#N)c2)c(Cl)n2c1CNCC2
Temperature: 90 °C
Reaction time: 4 h
Yield: 224.9 %

Procedure:
To a solution of 8.41 g (27.7 mmol) of methyl 1-(2-amino-ethyl)-5-chloro-4-(3-cyanophenyl)-1H-pyrrole-3-carboxylate in 20 ml of methanol are added 84 ml (340 mmol) of aqueous 4N hydrochloric acid solution. The formation of a white precipitate is rapidly observed and the medium then becomes clear, while the mixture is heated to 90° C. and 0.92 g (10 mmol) of paraformaldehyde is added. Heating is continued at 90° C. for 4 hours. After cooling, the reaction medium is poured into 200 ml of water and the solution is basified by adding aqueous ammonia. The product is extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give an orange-coloured oil, which is chromatographed on a column of 80 g of silica gel, eluting with a mixture of 2% methanol in dichloromethane, to give 7.1 g of methyl 6-chloro-7-(3-cyanophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylate in the form of a yellow oil.
Reaction SMILES: [O:1]1[C@@H:3]2[CH:4]=[C:5]3[C@@H:21]([C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C@@:2]124)[CH2:20][CH2:19][C@@:18]1([CH3:29])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]>[K]>[CH3:16][CH:14]([CH2:13][CH2:12][CH2:11][C@H:10]([C@@H:9]1[C@:18]2([CH3:29])[C@H:6]([C:5]3[C@H:21]([CH2:20][CH2:19]2)[C@:22]2([CH3:28])[C@@:2]([OH:1])([CH2:26][C@@H:25]([OH:27])[CH2:24][CH2:23]2)[CH2:3][CH:4]=3)[CH2:7][CH2:8]1)[CH3:17])[CH3:15]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C[C@H]4O[C@]45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Agent: [K]
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC[C@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 35.8 %

Procedure:
5,6βEpoxy-5β-cholest-7-en-3β-ol [J. Org. Chem. 50(1985), 1835] (150 mg) is dissolved in 2.5 ml of a potassium hydroxyde solution (5% in methanol). The reaction mixture is refluxed for one hour. Aqueous work-up, extraction with ethylacetate and column chromatography yields 5βcholest-7-ene-3β,5β-diol (54 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:7]=[O:8])=[CH:4][S:5][CH:6]=1.[C:9]1([CH2:15][CH2:16][CH2:17][Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:1][C:2]1[C:3]([CH:7]([OH:8])[CH2:17][CH2:16][CH2:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][S:5][CH:6]=1
Reactant: Br[Mg]CCCc1ccccc1
Reactant: O=Cc1cscc1Br
Product: OC(CCCc1ccccc1)c1cscc1Br

Procedure:
Prepared according to the procedure described in Example 5, Step 1, using the following starting materials: 4-bromo-thiophene-3-carbaldehyde and 3-phenyl-propyl magnesium bromide.
Reaction SMILES: [OH:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[C:29](Cl)=[O:30].CC#N>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[C:29]([O:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19])=[O:30]
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Reactant: O=C1Nc2ccccc2C(c2ccccc2)=NC1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC#N
Product: O=C(OC1N=C(c2ccccc2)c2ccccc2NC1=O)c1cc2ccccc2[nH]1
Reaction time: 16 h
Yield: 63.5 %

Procedure:
1,3-Dihydro-3-(RS)-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one (100 mg, 0.398 mmol) was dissolved in CH2Cl2 (10 ml), treated with indole-2-carbonyl chloride (78.6 mg, 0.438 mmol) and 4-dimethylaminopyridine (DMAP, 53.5 mg, 0.438 mmol) and stirred 16 hrs. at 25° C. A second portion of indole-2-carbonylchloride (78.6 mg, 0.438 mmol and DMAP (53.5 mg, 0.438 mmol) was added and the reaction stirred an additional 24 hrs. Chromatography of the reaction mixture on silica gel (1% MeOH in CH2Cl2) gave the title compound (100 mg) as a white solid from MeCN: (m.p. 271°-273°).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH2:14][CH2:13][C:8]3[N:9]([CH3:12])[N:10]=[CH:11][C:7]=3[C:4]=2[NH:5][N:6]=1.[H-].[Na+].I[CH3:18].[ClH:19]>CN(C)C=O.C(OCC)C>[ClH:19].[CH3:18][N:5]1[C:4]2[C:7]3[CH:11]=[N:10][N:9]([CH3:12])[C:8]=3[CH2:13][CH2:14][C:3]=2[C:2]([CH3:1])=[N:6]1
Reactant: Cc1n[nH]c2c1CCc1c-2cnn1C
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1nn(C)c2c1CCc1c-2cnn1C
Temperature: 0 °C
Yield: 20 %

Procedure:
A solution of 14.5 g of 1,4,5,6-tetrahydro-3,6-dimethylbenzo[1,2-c:3,4-c']dipyrazole in 50 ml of dimethylformamide was added to an ice-cold stirred suspension of 2.4 g of sodium hydride in 50 ml of dimethylformamide. The reaction was stirred at 0° C. for 20 minutes and then a solution of 6.3 ml of iodomethane in 15 ml of dimethylformamide was added dropwise. The mixture was allowed to come to room temperature and stirred for 2 hours. The solvent was evaporated under reduced pressure and the residue partitioned between dichloromethane and water. The aqueous layer was extracted exhaustively with dichloromethane and the combined dichloromethane extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was flash chromatographed (7.5% 2-propanol in dichloromethane) to give crude product. This crude mixture was dissolved in ethyl ether and acidified with ethereal hydrogen chloride. The cream color precipitate which formed was recrystallized from 2-butanol to give 1,4,5,6- tetrahydro-1,3,6-trimethylbenzo[1,2-c:3,4-c']dipyrazole monohydrochloride as light-yellow granules (20% yield) melting at about 252°-254° C.