Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][CH2:10][S:11]([NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][N:31]([CH2:39][C@H:40]([OH:50])[C:41]3[CH:46]=[CH:45][C:44]([N+:47]([O-])=O)=[CH:43][CH:42]=3)[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:25][CH:24]=2)=[CH:19][C:18]=1[O:51][CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1)=[O:16])(=[O:13])=[O:12])C1C=CC=CC=1.C([O-])=O.[NH4+].CO>[Pd].O>[NH2:47][C:44]1[CH:45]=[CH:46][C:41]([C@@H:40]([OH:50])[CH2:39][N:31]([CH2:30][CH2:29][C:26]2[CH:27]=[CH:28][C:23]([C:20]3[CH:21]=[CH:22][C:17]([C:15]([NH:14][S:11]([CH2:10][CH2:9][OH:8])(=[O:13])=[O:12])=[O:16])=[C:18]([O:51][CH:52]4[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]4)[CH:19]=3)=[CH:24][CH:25]=2)[C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C(=O)NS(=O)(=O)CCOCc3ccccc3)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C(=O)NS(=O)(=O)CCO)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1ccc(N)cc1
Temperature: 25 °C
Yield: 67.3 %

Procedure:
A mixture of tert-butyl [2-[4′-[[[[2-(benzyloxy)-ethyl]sulfonyl]amino]carbonyl]-3′-(cyclohexyloxy)-4-biphenylyl]ethyl][(2R)-2-hydroxy-2-(4-nitrophenyl)ethyl]-carbamate (215 mg), 10% palladium on activated carbon (50% wet, 645 mg), ammonium formate (845 mg), methanol (6.45 ml) and water (0.65 ml) was refluxed for 20 minutes. After cooling to room temperature, the catalyst was removed by filtration and washed with methanol. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel (eluent: hexane/ethyl acetate) to give tert-butyl [(2R)-2-(4-aminophenyl)-2-hydroxyethyl][2-[3′-(cyclohexyloxy)-4′-[[[(2-hydroxyethyl)sulfonyl]amino]carbonyl]-4-biphenylyl]ethyl]-carbamate (123 mg) as a pale-yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8].Cl[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].ClCCl.CO>C(N(CC)CC)C>[CH2:23]([NH:9][C:5]1[C:4]([NH2:10])=[CH:3][C:2]([CH3:1])=[C:7]([CH3:8])[CH:6]=1)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: Cc1cc(N)c(N)cc1C
Reactant: CCCCCCCCCCCCCl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCCCCCNc1cc(C)c(C)cc1N
Temperature: 130 °C
Reaction time: 6 h
Yield: 59.1 %

Procedure:
A mixture of 4.08 g (30 millimoles (mmol)) of 4,5-dimethyl-benzene-1,2-diamine (hereinafter compound “1”) and 2.04 grams (g) (10 mmol) of 1-chloro-dodecane in 20 milliliters (mL) of triethylamine was stirred at 130° C. for 6 hrs under argon. After cooling and addition of dichloromethane (100 mL), the organic solution was washed with aqueous Na2CO3 solution (10%, 40 mL). The aqueous layer was extracted twice with dichloromethane (2×100 mL). The combined organic extracts were dried over MgSO4 and rotary evaporated to dryness. The thin-layer chromatography retention factor (Rf) of the target compound (2) was 0.55 with dichloromethane (MC):methanol (MeOH) (95:5) mixture. Compound (2) was purified by flash chromatography on silica gel in MC:MeOH (95:5) to produce 1.8 g of reddish crystals (60% yield); mp 53-54° C.; 1H NMR (400 MHz, CDCl3) δ 6.56 (1H, s), 6.50 (1H, s), 3.20 (3H, broad s), 3.1 (2H, t, J=8 Hz), 2.26 (3H, s), 2.21 (3H, s), 1.68 (2H, q, J=7 Hz), 1.46 (2H, m), 1.34 (16H, s), 0.92 (3H, t, J=8 Hz); 13C NMR (100 MHz, CDCl3) δ 136.0, 131.8, 128.1, 125.9, 118.4, 113.93, 44.7, 31.9, 29.9, 29.69, 29.65, 29.5, 29.4; Anal. Calcd. for C20H36N2 (MW=304.51): C, 78.88; H, 11.92; N, 9.20. Found: C, 78.95; H, 12.16; N, 9.32.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:71]=[CH:70][C:13]([O:14][CH2:15][C@@H:16]([CH2:43][O:44][C:45](=[O:69])[C@H:46]([CH3:68])[NH:47][C:48](=[O:67])[CH2:49][CH2:50][C@H:51]([NH:59]C(OC(C)(C)C)=O)[C:52]([O:54]C(C)(C)C)=[O:53])[O:17][C:18](=[O:42])[C@H:19]([CH3:41])[NH:20][C:21](=[O:40])[CH2:22][CH2:23][C@H:24]([NH:32]C(OC(C)(C)C)=O)[C:25]([O:27]C(C)(C)C)=[O:26])=[CH:12][CH:11]=2)[C:5]([C:72]#[N:73])=[C:4]([S:74][CH2:75][C:76]2[N:77]=[C:78]([C:81]3[CH:86]=[CH:85][C:84]([Cl:87])=[CH:83][CH:82]=3)[O:79][CH:80]=2)[N:3]=1.[F:88][C:89]([F:94])([F:93])[C:90]([OH:92])=[O:91]>ClCCl>[F:88][C:89]([F:94])([F:93])[C:90]([OH:92])=[O:91].[F:88][C:89]([F:94])([F:93])[C:90]([OH:92])=[O:91].[NH2:32][C@@H:24]([CH2:23][CH2:22][C:21](=[O:40])[NH:20][C@@H:19]([CH3:41])[C:18](=[O:42])[O:17][C@@H:16]([CH2:15][O:14][C:13]1[CH:12]=[CH:11][C:10]([C:6]2[C:5]([C:72]#[N:73])=[C:4]([S:74][CH2:75][C:76]3[N:77]=[C:78]([C:81]4[CH:82]=[CH:83][C:84]([Cl:87])=[CH:85][CH:86]=4)[O:79][CH:80]=3)[N:3]=[C:2]([NH2:1])[C:7]=2[C:8]#[N:9])=[CH:71][CH:70]=1)[CH2:43][O:44][C:45](=[O:69])[C@H:46]([CH3:68])[NH:47][C:48](=[O:67])[CH2:49][CH2:50][C@H:51]([NH2:59])[C:52]([OH:54])=[O:53])[C:25]([OH:27])=[O:26]
Reactant: C[C@H](NC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC[C@H](COc1ccc(-c2c(C#N)c(N)nc(SCc3coc(-c4ccc(Cl)cc4)n3)c2C#N)cc1)OC(=O)[C@H](C)NC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)OC[C@H](COc1ccc(-c2c(C#N)c(N)nc(SCc3coc(-c4ccc(Cl)cc4)n3)c2C#N)cc1)OC(=O)[C@H](C)NC(=O)CC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An amount of 120 mg (0.096 mmol) of the compound from example 27A was introduced in 1 ml of dichloromethane, admixed with 0.074 ml (0962 mmol) of trifluoroacetic acid and stirred at RT overnight. The reaction mixture was then concentrated and the residue was purified by means of preparative HPLC (eluent gradient: acetonitrile/water 10:90→95:5 with addition of 0.1% TFA). This gave 20 mg (18% of theory) of the target compound.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[CH:18]1[C:23]([C:24]2[C:29](=[O:30])[C:28]3[CH:31]=[CH:32][C:33]([OH:35])=[CH:34][C:27]=3[O:26][CH:25]=2)=[CH:22][CH:21]=[C:20]([OH:36])[CH:19]=1.[OH-].[K+].CO>CC(C)=O>[OH:36][C:20]1[CH:21]=[CH:22][C:23]([C:24]2[C:29](=[O:30])[C:28]3[C:27](=[CH:34][C:33]([O:35][CH2:2][CH2:3][N:4]4[CH2:9][CH2:8][N:7]([C:10]5[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=5)[CH2:6][CH2:5]4)=[CH:32][CH:31]=3)[O:26][CH:25]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(N2CCN(CCCl)CC2)cc1
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Product: COc1ccc(N2CCN(CCOc3ccc4c(=O)c(-c5ccc(O)cc5)coc4c3)CC2)cc1

Procedure:
To a solution of 1-[4-(2-chloroethyl)piperazinyl]-4-methoxybenzene (0.929 mmol) and 4,7-dihydroxyisoflavone (0,929 mmol) in acetone (10 ml)was added 11% potassium hydroxide (0.5 ml), and the mixture stirred at reflux temperature for 48 hours. Sufficient methanol was added to precipitate unreacted starting material, which was filtered off, and solvent was removed from the filtrate under reduced pressure. The residue was purified by biotage column chromatography, eluting with 5% methanol/methylene chloride, to provide pure 3-(4-hydroxyphenyl)-7-{2-[4-(4-methoxyphenyl)piperazinyl]ethoxy}chromen-4-one.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:25])[C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[C:22](Br)[N:23]=[C:17]3[CH:16]=2)=[O:13])=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[N:31][CH:32]=1>>[CH3:26][C:27]1[CH:28]=[C:29]([C:22]2[N:23]=[C:17]3[CH:16]=[C:15]([NH:14][C:12]([C:11]4[N:10]([CH3:25])[N:9]=[CH:8][C:7]=4[C:5]([N:1]4[CH2:4][CH2:3][CH2:2]4)=[O:6])=[O:13])[CH:20]=[CH:19][N:18]3[N:21]=2)[CH:30]=[N:31][CH:32]=1
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(Br)nc2c1
Reactant: Cc1cncc(B(O)O)c1
Product: Cc1cncc(-c2nc3cc(NC(=O)c4c(C(=O)N5CCC5)cnn4C)ccn3n2)c1
Yield: 58.3 %

Procedure:
The product was prepared in the same manner as described in example 66 using 4-(azetidine-1-carbonyl)-N-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide (150 mg, 371 μmol) and 5-methylpyridin-3-ylboronic acid (76.2 mg, 557 μmol) as starting materials. The crude material was applied on silicagel and purified by flash chromatography over a 50 g NH2-silicagel column using heptane/ethyl acetate 20-100% as eluent affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid [2-(5-methyl-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (90 mg, 19.4%) as a light brown solid. mp: 262-264° C., MS: m/z=417.3 (M+H+)
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH:18]=[O:19])=[C:5]([OH:17])[C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1)[CH3:2].[OH-].[K+].S(OC)(O[CH3:26])(=O)=O.Cl>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[C:4]([CH:18]=[O:19])=[C:5]([O:17][CH3:26])[C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1)[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CCc1cc2c(c(O)c1C=O)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCc1cc2c(c(OC)c1C=O)C(C)(C)CCC2(C)C
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Methylation. 3-Ethyl-2-formyl-1-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (48.2 g, 0.185 mol) was stirred with toluene (650 mL), and potassium hydroxide 85% (19.5 g, 0.296 mol) was added in one portion. The mixture was heated to 45° C. and dimethyl sulfate (35 g, 0.278 mol) was added during 0.5 h at 45°-50° C. The heating was continued for an additional 0.5 h at 50° C. The mixture was cooled to 20° C., neutralized with 5% hydrochloric acid, washed with water (50 mL), and then finally washed with brine (30 mL). Solvent was removed by distillation and the residue distilled to give 3-ethyl-2-formyl-1-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (40.6 g), GLC purity 98%. Crystallization from hexane gave 27 g material, GLC purity 99%. 1H-NMR (CDCl3) δ10.38 (1H, s), 6.97 (1H, s), 3.85 (3H, s), 2.89 (2H, q), 1.64 (4H, s), 1.40 (6H, s), 1.28 (6H, s), 1.20 (3H, t). 13C-NMR (CDCl3) δ192.0 (1C, d), 165.3 (1C, s), 153.6 (1C, s), 144.4 (1C, s), 135.7 (1C, s), 125.3 (1C, s), 124.1 (1C, d), 66.0 (1C, q), 38.1 (1C, t), 35.4 (1C, s), 34.8 (1C, t), 34.3 (1C, s), 31.8 (2C, q), 29.8 (2C, q), 26.6 (1C, t), 15.7 (1C, q). IR (KBr) 1275, 1263 cm-1, MS (M/e) 274.2 (M+, 17.1), 258.1 (100.0), 260.3 (20.3), 128.1 (15.1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH2:4]Br.C([O-])(=[O:14])C.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH2:4][OH:14]
Reactant: CC(=O)[O-]
Reactant: Clc1cc(Cl)c(CBr)c(Br)c1
Agent: [Na+]
Solvent: CC(=O)O
Product: OCc1c(Cl)cc(Cl)cc1Br
Yield: 56.6 %

Procedure:
Heat a mixture of 22 g of 2-bromo-4,6-dichlorobenzyl bromide, 30 g anhydrous sodium acetate and 80 mL of glacial acetic acid for 18 hr at 100° C. Evaporate the mixture to a dry residue. Treat the residue with 200 mL of ethanol and 200 mL of 2N NaOH. Stir the mixture at reflux for 3 hr. Cool the mixture and concentrate the cooled mixture to 50 mL. Extract the cooled concentrate with Et2O. Dry the extract over anhydrous K2CO3 and evaporate it to a dry residue. Recrystallize the residue from toluene-hexane to give 10 g of 2-bromo-4,6-dichlorobenzyl alcohol, mp 111°-112° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:6](=[O:18])[N:7]([CH2:16][CH3:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([OH:15])[CH:9]=2.COC(=O)C.[C:25]([O:29][C:30](=[O:36])[NH:31][CH2:32][CH2:33][CH2:34]Br)([CH3:28])([CH3:27])[CH3:26]>>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:6](=[O:18])[N:7]([CH2:16][CH3:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH2:34][CH2:33][CH2:32][NH:31][C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:36])[CH:9]=2
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: CCn1c(=O)c(CC(=O)OC)cc2ccc(O)cc21
Solvent: COC(C)=O
Product: CCn1c(=O)c(CC(=O)OC)cc2ccc(OCCCNC(=O)OC(C)(C)C)cc21

Procedure:
The title compound is prepared using the procedure of Example 75 and (1-ethyl-7-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl)-acetic acid methyl ester in place of 7-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)acetic acid methyl ester and (3-bromo-propyl)carbamic acid tert-butyl ester in place of (2-bromoethyl)carbamic acid tert-butyl ester.
Reaction SMILES: Cl.[F:2][C:3]1([F:9])[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>CN(C=O)C.C(OCC)(=O)C>[Si:21]([O:20][CH2:19][CH2:18][CH2:17][N:5]1[CH2:6][CH2:7][CH2:8][C:3]([F:9])([F:2])[CH2:4]1)([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: FC1(F)CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCN1CCCC(F)(F)C1
Temperature: 50 °C

Procedure:
To a solution of 3,3-difluoropiperidine hydrochloride (518 mg) in DMF (15 mL) was added cesium carbonate (3.21 g) and (3-bromopropoxy)-tert-butyldimethylsilane (0.838 mL). The resulting reaction mixture was heated to 50° C. for 1.5 hours before cooling back to room temperature. Water and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate (2×). The combined organics were washed with water (2×), brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (ISCO, 0 to 40% ethyl acetate in hexanes with 1% triethylamine) gave the desired product (612 mg). 1H NMR (400 MHz, CDCl3): δ (ppm) 4.20 (t, 1H), 3.71-3.64 (m, 2H), 3.46 (t, 1H), 2.62 (t, 1H), 2.50-2.47 (m, 1H), 2.44-2.42 (m, 1H), 2.05-1.98 (m, 1H), 1.91-1.82 (m, 2H), 1.77-1.67 (m, 4H), 0.89 (d, 9H), 0.05 (s, 3H), 0.04 (s, 3H).
Reaction SMILES: [CH:1]1([NH:6][S:7]([C:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[N:15][C:16]=3[CH:17]=[C:18]([C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:19]=2)(=[O:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C([Cl:33])C=C(C(OO)=O)C=1>ClCCl.C(OCC)(=O)C>[Cl:33][C:14]1[CH:13]=[CH:12][C:11]2[C:10]([S:7]([NH:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)(=[O:9])=[O:8])=[CH:19][C:18]([C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])=[CH:17][C:16]=2[N:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2cccnc2c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2ccc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamide (272 mg, 0.73 mmol) and mCPBA (max 77% by weight, 364 mg) in dichloromethane (5 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium sulfite solution followed by brine. The organic layer was dried over sodium sulfate and concentrated. The residue was dissolved in POCl3 and heated at 80° C. for 1 hour. The reaction mixture was concentrated before being partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate and purified on silica gel (rf=0.42 in 2:1 hexanes:ethyl acetate) to give 2-chloro-N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[S:13])[NH:8][C:7]([CH3:14])=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+].I[CH3:24].[NH4+].[Cl-]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([S:13][CH3:24])=[N:8][C:7]([CH3:14])=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc2c(=S)[nH]c(C)c(-c3ccccc3)c2c1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc2c(SC)nc(C)c(-c3ccccc3)c2c1
Reaction time: 0.5 h

Procedure:
6-methoxy-3-methyl-4-phenylisoquinoline-1(2H)-thione (0.9 g) was combined with 20 mL DMF and 0.33 g of NaH (60% dispersion in mineral oil). The reaction was heated to 60 C and stirred for 30 min. Iodomethane (0.33 mL) was added, and the reaction was stirred overnight at 60 C, then poured into saturated aqueous NH4Cl. The mixture was extracted with EtOAc (3×), then the combined organic solutions were washed with water (1×) and brine (1×), dried (Na2SO4) and concentrated to give 6-methoxy-3-methyl-1-(methylthio)-4phenylisoquinoline, which was used directly in the next step.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[NH:3]1.Br[C:20]1[S:21][CH:22]=[C:23]([Br:25])[N:24]=1>>[Br:25][C:23]1[N:24]=[C:20]([N:3]2[C:4]3[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=3[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:2]2=[O:1])[S:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Reactant: Brc1csc(Br)n1
Product: CC(C)(C)OC(=O)Cn1c(=O)n(-c2nc(Br)cs2)c2ccccc21

Procedure:
Essentially following the procedures described for Intermediate 7, but using 2,4-dibromothiazole in place of 2-bromopyridine, the title compound was prepared. MS: m/z=412 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[C:11](=[O:20])[C:10]=2[CH:21]=1)(=[O:5])=[O:4].CO.[BH4-].[K+].[OH-].[K+]>O>[CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH:11]([OH:20])[C:10]=2[CH:21]=1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)c1ccc2ccc3ccccc3c(=O)c2c1
Agent: [BH4-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(O)c1ccccc1C=C2

Procedure:
3-Dimethylsulfamoyl-5H-dibenzo[a,d]cyclohepten-5-one (6.9 g., 0.022 mole) and 100 ml. of absolute methanol are stirred and heated to refluxing. A solution of 1.6 g. (0.0296 mole) of potassium borohydride in 12 ml. of water containing one pellet of potassium hydroxide is added dropwise at a rate such that reflux is maintained without external heating. After another 11/2 hours at reflux, the solution is evaporated to dryness under reduced pressure. The residual white solid is suspended in water, collected, and crystallized from 95% ethanol. The yield of 3-dimethylsulfamoyl-5H-dibenzo[a,d]cyclohepten-5-ol is 6.05 g. (87%), m.p. 150°-152°C. The melting point is unchanged by further recrystallization.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:68])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:66])[C:57]4[C:62]([CH3:63])=[CH:61][C:60]([CH3:64])=[CH:59][C:58]=4[CH3:65])=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:67])[C:36]([O:38]C)=[O:37]>>[CH3:33][CH:34]([CH3:68])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:50]=[CH:51][C:52]([NH:55][C:56](=[O:66])[C:57]4[C:58]([CH3:65])=[CH:59][C:60]([CH3:64])=[CH:61][C:62]=4[CH3:63])=[CH:53][CH:54]=3)=[CH:45][CH:46]=2)[C:41]1=[O:67])[C:36]([OH:38])=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4c(C)cc(C)cc4C)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: Cc1cc(C)c(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2)c(C)c1
Yield: 81 %

Procedure:
The compound of example 154 was prepared analogous to compound of example 98 by hydrolysis of compound of example 153.
Reaction SMILES: [O:1]1[CH:7]2[C:2]1([CH3:11])[CH2:3][CH:4]1[C:8]([CH3:10])([CH3:9])[CH:5]1[CH2:6]2.C([OH:14])C>>[C:4]12[C:8]([CH3:10])([CH3:9])[CH:5]1[CH2:6][CH:7]([OH:1])[C:2]([OH:14])([CH3:11])[CH:3]=2
Reactant: CCO
Reactant: CC12CC3C(CC1O2)C3(C)C
Product: CC1(O)C=C2C(CC1O)C2(C)C

Procedure:
subjecting 3,4-epoxycarane to hydration reaction in the presence of a base catalyst in aqueous ethanol under pressure to obtain 3,4-carenediol of the formula [I].
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[Cl:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]=1[NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:30]3[CH:29]=[CH:28][C:27]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[C:26]([Cl:25])[CH:31]=3)[C:10]=12
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(NC(=O)OC(C)(C)C)c(Cl)c4)c4c(N)ncnc43)CC2)CC1

Procedure:
A mixture of trans 3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.20 g, 0.00498 mol), tert-butyl N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (1.93 g, 0.00548 mol), sodium carbonate (1.32 g, 0.01245 mol) in 1,2-dimethoxyethane (50 mL) and water (100 mL) was stirred rapidly and tetrakis(triphenylphosphine)palladium(O) (0.345 g, 0.00030 mol) was added. The reaction mixture was stirred 6 hours at 80° C., after which time additional tetrakis(triphenylphosphine)palladium(0) (0.345 g, 0.00030 mol) was added. The reaction mixture was stirred an additional 16 hours at 80° C. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (200 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3×75 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The product was purified by flash column chromatography on silica using dichloromethane/methanol/ammonium hydroxide (90:10:0.5). The solvent was removed in vacuo to give trans tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)carbamate as a white solid (1.993 g, 0.00368 mol):
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH2:7][CH2:6][N:5]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[BH4-].[Na+].[OH-].[Na+]>CO>[N:17]1([CH2:3][CH:4]2[C:16]3[NH:15][C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8]=3[CH2:7][CH2:6][NH:5]2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: C1COCCN1
Reactant: ClCC1=NCCc2c1[nH]c1ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1ccc2c3c([nH]c2c1)C(CN1CCOCC1)NCC3
Temperature: 25 °C
Reaction time: 6 h
Yield: 83 %

Procedure:
Under ice-cooling, 1-chloromethyl-4,9-dihydro-3H-β-carboline hydrochloride (synthesized according to the method described in J. Med. Chem., 34, 8, 1991, 2624-2633, 400 mg) was added to a mixture of morpholine (684 mg) and methanol (4.5 ml), and the mixture was stirred at room temperature for 6 hr. Under ice-cooling, sodium borohydride (119 mg) was added, and the mixture was stirred at room temperature for 16.5 hr. The reaction mixture was alkalified with a 1N aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a brown oil. The oil was purified by silica gel column chromatography (elution solvent: chloroform-methanol (20:1)) to give 1-(morpholine-4-ylmethyl)-2,3,4,9-tetrahydro-1H-β-carboline (353 mg, yield 83%).