Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].CN([Si:17]([CH3:20])([CH3:19])[CH3:18])C(=O)C(F)(F)F>ClCCl>[CH3:18][Si:17]([N:6]([Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]1[CH:7]=[CH:8][NH:1][C:2](=[O:3])[N:4]=1)([CH3:20])[CH3:19]
Reactant: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Reactant: Nc1cc[nH]c(=O)n1
Solvent: ClCCl
Product: C[Si](C)(C)N(c1cc[nH]c(=O)n1)[Si](C)(C)C
Temperature: 0 °C

Procedure:
A bis-trimethylsilylcytosine solution was prepared by suspending 5.78 g of cytosine in 20 ml of dichloromethane and adding 20.57 ml of N-methyl-N-trimethylsilyltrifluoroacetamide in 10 ml of dichloromethane and cooling the resulting solution to 0° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][C:14]4[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:15]=4[N:11]3[CH2:10][CH2:9]2)=[C:4]([Cl:26])[CH:3]=1.C([Li])CCC.CN(C)[CH:34]=[O:35]>O1CCCC1>[Cl:26][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[N:8]1[C:12]2=[N:13][C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:15]=3[N:11]2[CH2:10][CH2:9]1)[CH:34]=[O:35]
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(Br)cc1Cl
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(C=O)cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-bromo-2-chlorophenyl)-8-chloro-5-(1-ethylpropyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (204.6 mg, 0.451 mmol) in tetrahydrofuran (3.0 mL) was added n-butyllithium (1.60 M solution in n-hexane, 0.34 mL, 0.542 mmol) at −78° C. The reaction mixture was stirred at same temperature for 1 hr, to the mixture was added N,N-dimethylformamide (0.17 mL, 2.255 mmol). The reaction mixture was allowed to warm to 0° C. and stirred for 1 hr. The reaction mixture was quenched with aqueous saturated ammonium chloride at 0° C. and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-15% ethyl acetate/n-hexane gradient mixture to give the title compound as a yellow amorphous (89.5 mg, 0.156 mmol, 49%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([CH2:18][F:19])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.C(OCC)(=O)C.[Pd]>[F:19][CH2:18][C:10]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CCOC(=O)C1(CF)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(CF)CCNC1
Yield: 50 %

Procedure:
To a solution of 1.27 g (4.8 mmol) of ethyl 1-benzyl-3-(fluoromethyl)pyrrolidine-3-carboxylate in 20 mL of methanol was added 500 mg of Pd/C (10% on carbon) and 1.5 g (24 mmol) of HCOONH4. The reaction mixture was refluxed for 1 h, filtered through celite pad and evaporated to give a residue. The residue was then dissolved in ethyl acetate, the resulting solution was washed with saturated NaHCO3 aqueous solution, brine, dried over Na2SO4, evaporated to give the final crude product (426 mg, 2,4 mmol, yield: 50%): MS (m/e): 176 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][NH:4][CH2:3]1.[C:8]([N:15]1[CH2:18][C:17](=O)[CH2:16]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CC(O)=O>[C:11]([O:10][C:8]([N:15]1[CH2:18][CH:17]([N:4]2[CH2:5][CH2:6][NH:7][C:2](=[O:1])[CH2:3]2)[CH2:16]1)=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: O=C1CNCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2CCNC(=O)C2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
To a mixture of 3-oxopiperazine 4a (490 mg, 4.89 mmol) and N-Boc-azetidin-3-one 1a (922 mg, 5.38 mmol) in 1,2-dichloroethane (10 mL) and HOAc (0.5 mL) was added Na(OAc)3BH (1141, 5.38 mmol). The reaction was stirred at room temperature overnight. Additional 1a (335 mg, 1.96 mmol) and Na(OAc)3BH (415 mg, 1.96 mmol) was added. The reaction was stirred for another 24 h before it was quenched with aq. NaHCO3. The resulting mixture was extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 4% MeOH/CH2Cl2) gave intermediate 4b as white solid (860 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])=[O:17])[CH2:12][CH2:11]2)[N:3]=1.[C:30]1([C@@H:36]([CH3:39])[CH2:37][NH2:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:9][NH:8][C:6]1[N:7]=[C:2]([NH:38][CH2:37][C@@H:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:39])[N:3]=[C:4]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:27])[F:28])=[O:17])[CH2:14][CH2:15]2)[N:5]=1
Reactant: C[C@@H](CN)c1ccccc1
Reactant: CNc1nc(Cl)nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)n1
Product: CNc1nc(NC[C@H](C)c2ccccc2)nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)n1
Temperature: 80 °C

Procedure:
Approximately half of the suspension prepared in step c was treated with (2R)-2-phenylpropylamine (1.16 mL, 8.14 mmol, 10.0 equiv). After heating to 80° C., the solvents were removed in vacuo, and the residue was purified by reverse-phase HPLC (Sunfire, 35-60% CH3CN/H2O, 0.1% TFA, 12 min) to afford 156 mg of the title compound. MS (ES+): m/e 528.1 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl>[OH:4][CH2:3][CH:2]([NH:1][S:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=1)(=[O:26])=[O:25])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(N)CO
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(CO)NS(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 53.8 %

Procedure:
To a mixture of 5.0 g (32.14 mmol) of D,L-serine, methyl ester and 15.7 ml (0.012 mol) of triethylamine in 100 ml of CH2Cl2, cooled to 0° C., was added portionwise 6.64 g (32.14 mmol) of 4-methoxybenzenesulfonyl chloride. The mixture was then stirred under argon at room temperature for 2 days. The mixture was diluted with 100 ml of CH2Cl2 and then washed with 60 ml each of H2O, 2 N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give a solid. Crystallization from ethyl acetate gave 5.0 g (54%) of white crystals, m.p. 92-94° C. Anal. for C11H15NO6S: Calc'd: C, 45.7; H, 5.2; N, 4.8; S, 11.1; Found: C, 45.6; H, 5.2; N, 4.8; S, 11.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C@H:18]2[C:31]([O:33][CH3:34])=[O:32])[C:13]1=[O:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C@@H:18]2[C:31]([O:33][CH3:34])=[O:32])[C:13]1=[O:35])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
To a solution of (1R,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)-cyclohexanecarboxylate (281 mg, 0.573 mmol, see Example 12a, Step 3) in anhydrous DMF was added cesium carbonate (747 mg, 2.29 mmol), and the mixture was stirred for 16 h at rt. At the end of the stirring the mixture was poured into water, and extracted with EtOAc (3×). The combined extracts were washed with water, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with elution by EtOAc to afford pure trans isomer, (1S,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonyl)amino-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonyl)amino-cyclohexanecarboxylate (214 mg) as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:13]=[CH:12][C:11]2[NH:10][C:9]3[N:14]=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24][N:25]5[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:20][CH:19]=4)=[CH:17][C:8]=3[C:7]=2[CH:6]=1)=O.[NH3:31]>CO>[N:25]1([CH2:24][C:21]2[CH:22]=[CH:23][C:18]([C:16]3[CH:15]=[N:14][C:9]4[NH:10][C:11]5[CH:12]=[N:13][C:5]([C:3]([NH2:31])=[O:2])=[CH:6][C:7]=5[C:8]=4[CH:17]=3)=[CH:19][CH:20]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: N
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Solvent: CO
Product: NC(=O)c1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Yield: 16 %

Procedure:
A solution of 3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester (67.3 mg, 0.168 mmol) in 7M ammonia in methanol (8.0 mL) was heated to 70° C. for 24 h in a sealed tube. The mixture was allowed to cool and concentrated in vacuo. The residue was dissolved in DMSO and purified by preparative HPLC (2-60% MeCN/water modified with 0.1% ammonium hydroxide) to afford a light-yellow fluffy solid (10.3 mg, 16%). 1H NMR (DMSO-D6, 500 MHz): 12.56 (s, 1H), 9.18 (d, J=2.2 Hz, 1H), 9.00 (s, 1H), 8.96 (d, J=2.1 Hz, 1H), 8.90 (s, 1H), 8.10 (s, 1H), 7.79 (d, J=8.1 Hz, 2H), 7.53 (s, 1H), 7.44 (d, J=8.1 Hz, 2H), 3.49 (s, 2H), 2.36 (m, 4H), 1.56-1.47 (m, 4H), 1.40 (m, 2H). LCMS (Method D): RT=5.88 min, M+H+=386.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:8]([C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[CH2:7][CH:6]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:4].[N:32]([C:35]1[CH:36]=[C:37]([CH:43]=[CH:44][CH:45]=1)[C:38]([O:40][CH2:41][CH3:42])=[O:39])=[C:33]=[O:34]>O1CCCC1>[CH2:41]([O:40][C:38]([C:37]1[CH:36]=[C:35]([NH:32][C:33](=[O:34])[NH:1][CH2:2][C:3]([N:5]2[CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[CH:8]([C:17]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[O:18])[CH2:7][CH:6]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:4])[CH:45]=[CH:44][CH:43]=1)=[O:39])[CH3:42]
Reactant: CC(C)(C)OC(=O)C1CC(C(=O)N2CCOCC2)C(c2ccccc2F)N1C(=O)CN
Reactant: CCOC(=O)c1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(C(=O)N3CCOCC3)C2c2ccccc2F)c1
Yield: 61.3 %

Procedure:
B tert-Butyl (2RS,4SR,5SR)-1-{2-[3-(3-(ethoxycarbomyl)phenyl)ureido]acetyl}-5-(2-fluorophenyl)-4-(morpholinocarbonyl)pyrrolidine-2-carboxylate can be prepared as described in Example 17B, but from 1.7 g of tert-butyl (2RS,4SR,5SR)-1-(2-aminoacetyl)-5-(2-fluorophenyl)-4-(morpholinocarbonyl)pyrrolidine-2-carboxylate and 0.75 g of ethyl 3-isocyanatobenzoate in 80 cm3 of tetrahydrofuran. After treatment, there are obtained 1.5 g of tert-butyl (2RS,4SR,5SR)-1-{2-[3-(3-(ethoxycarbonyl)phenyl)ureido]acetyl}-5-(2-fluorophenyl)-4-(morpholinocarbonyl)pyrrolidine-2-carboxylate in the form of a foam used as is in the subsequent syntheses.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:18])[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:19]=O.S(=O)(=O)(O)O>O1CCOCC1>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([C:11](=[O:18])[C:12]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)=[CH2:19])[CH:4]=[CH:5][C:6]=1[O:9][CH3:10]
Reactant: C=O
Reactant: COc1ccc(C(=O)CC2CCCC2)c(Cl)c1Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: C=C(C(=O)c1ccc(OC)c(Cl)c1Cl)C1CCCC1

Procedure:
2',3'-Dichloro-4'-methoxy-2-cyclopentyl-acetophenone (51.6 g., 0.18 mole) is dissolved in dioxane (460 ml.) and paraformaldehyde (21.6 g., 0.72 mole) and concentrated sulfuric acid (9.65 g.) are added. The mixture is heated at 80°-85°C. for 20 hours. The dioxane is evaporated at reduced pressure. Water is added to the residual gum which then is extracted into ether. The ether extract is washed with water and dried over magnesium sulfate. The ether is evaporated and upon triturating the residue with hexane (5 ml.) there is obtained a solid that is crystallized from ligroin to obtain (33.3 g.), m.p. 59°-63°C. Crystallization from butyl chloride affords a sample (m.p. 66°-67.5°C.) for analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]3=[CH:12][CH:13]=[N:14][N:7]3[CH:6]=[CH:5][C:4]=2[C:3]=1[C:15]([O:17][CH3:18])=[O:16].[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1.C(Cl)Cl>[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]3=[CH:12][CH:13]=[N:14][N:7]3[CH:6]=[CH:5][C:4]=2[C:3]=1[C:15]([O:17][CH3:18])=[O:16])(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: COC(=O)c1c(N)ccc2c1ccn1nccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1ccn1nccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
A mixture of methyl 8-aminopyrazolo[5,1-a]isoquinoline-7-carboxylate (Intermediate 6, 0.140 g) and 2-bromo-4-fluorobenzenesulfonyl chloride (0.190 g) in pyridine (4 mL) and DCM (3 mL) was stirred at room temperature overnight. The resultant mixture was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-60%. The resultant glass was triturated with ether to give methyl 8-(2-bromo-4-fluorobenzenesulfonylamino]-pyrazolo[5,1-a]isoquinoline-7-carboxylate (0.103 g) as an off-white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]=[O:10])[C:4]=1[NH:11][C:12](=[O:28])[CH2:13][CH:14]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:21][C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:2].[CH2:29]([Mg]Br)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([OH:10])[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:4]=1[NH:11][C:12](=[O:28])[CH2:13][CH:14]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[O:21][C:22]2[C:27]1=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:2]
Reactant: CCc1cccc(C=O)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: Br[Mg]CCc1ccccc1
Product: CCc1cccc(C(O)CCc2ccccc2)c1NC(=O)CC1c2ccccc2Oc2ccccc21

Procedure:
Following a procedure similar to that described in Example 14, but using N-(2-ethyl-6-formylphenyl)-2-(9H-xanthen-9-yl)acetamide (prepared by a procedure similar to that described in Preparation 29) and phenethylmagnesium bromide as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as crystals, melting at 128°-129° C. (after recrystallization from a mixture of ethyl acetate and hexane).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:26]4[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=4)[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br>C(Cl)Cl>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:26]4[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=4)[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)ccc32)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)ccc32)cc1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
3,6-Diphenyl-9-(4-methoxyphenyl)carbazole (4.20 g, 9.9 mmol) was dissolved in methylene chloride (30 mL). Then, 1M methylene chloride solution of boron tribromide (10 mL) was added dropwise to the resultant solution at −10° C., followed by stirring at room temperature. Next, the mixture was washed with water and dried and the solvent was evaporated, to thereby obtain 3.98 g of 3,6-diphenyl-9-(4-hydroxyphenyl)carbazole.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH2:10])[CH3:2].O.[Br:12]Br>Cl>[Br:12][C:7]1[CH:6]=[C:5]([CH3:9])[C:4]([NH2:10])=[C:3]([CH2:1][CH3:2])[CH:8]=1
Reactant: BrBr
Reactant: CCc1cccc(C)c1N
Agent: Cl
Solvent: O
Product: CCc1cc(Br)cc(C)c1N

Procedure:
2-Ethyl-6-methyl-phenylamine (14 mL, 100 mmol) was dissolved in concentrated hydrochloric acid (30 mL) and water (220 mL) and cooled to 0° C. To this was added bromine (5.1 mL, 1 equiv.) dropwise. There was rapid formation of a white precipitate. The precipitate was filtered and washed with diethyl ether. The precipitate was suspended in water and neutralized with aqueous potassium carbonate. An oil formed which was extracted into diethyl ether. The ethereal was dried over potassium carbonate, filtered, and concentrated to give 7.0 g (33%) as a purple oil which was used without purification. Mass spec.: 214.01 (MH)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([NH:10][CH2:11][C:12]1([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)(=O)[CH3:8].O>O1CCCC1>[CH2:7]([NH:10][CH2:11][C:12]1([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH3:8]
Reactant: CC(=O)NCC1(N2CCN(C)CC2)CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCNCC1(N2CCN(C)CC2)CCCCC1
Reaction time: 8 h

Procedure:
To a stirred solution of lithium aluminium hydride (3 g.,) in dry tetrahydrofuran (40 ml) was added a solution of 1-[1-(Acetamidomethyl)cyclohexyl]-4-methyl piperazine (3 g.,) in dry tetrahydrofuran (40 ml) dropwise. The stirring was continued overnight, the suspension was heated under reflux for a further 6 hrs. and the excess LiAlH4 neutralised with water. The mixture was filtered and the filtrate was dried (anhyd. Na2SO4) and evaporated to an oil, which was micro distilled to give 1-[1-(Ethylaminomethyl)cyclohexyl]-4-methyl piperazine as a colourless oil. b.p. 35mm 105°-109° (1.96 g., 69%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:20]=[C:14]2[C:15](=[O:19])[NH:16][CH2:17][CH:18]=[C:13]2[N:12]=1.C([O-])(=[O:23])C.[Na+].BrBr>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:10])=[O:23])[CH:6]=[CH:5][C:4]=1[C:11]1[N:20]=[C:14]2[C:15](=[O:19])[NH:16][CH2:17][CH:18]=[C:13]2[N:12]=1
Reactant: COc1cc(SC)ccc1C1=NC2=CCNC(=O)C2=N1
Reactant: CC(=O)[O-]
Agent: BrBr
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(S(C)=O)ccc1C1=NC2=CCNC(=O)C2=N1

Procedure:
0.3 g of 2-(2-methoxy-4-methylmercapto-phenyl)-5H-imidazo[4,5-c]pyridin-4-one were suspended in 10 ml of 50% acetic acid, and 0.2 g of anhydrous sodium acetate were added thereto. 0.15 g of bromine, dissolved in 2 ml of glacial acetic acid, was added dropwise to the mixture, while stirring. After the reaction had ended the mixture was poured over ice, and the precipitate thus obtained was recrystallized from ethanol. Melting point: 267°-272° C. (decomposition).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[O:7][C:8]([CH3:11])([CH3:10])[O:9][C@H:5]2[C@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:3]1.[H-].[Na+].CC1C=CC(S(O[CH2:33][CH2:34][O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=O)=O)=CC=1>CN(C=O)C>[C:36]([O:35][CH2:34][CH2:33][O:1][C@@H:2]1[C@H:6]2[O:7][C:8]([CH3:10])([CH3:11])[O:9][C@H:5]2[C@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:3]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: Cc1ccc(S(=O)(=O)OCCOC(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](O)[C@H]2OC(C)(C)O[C@H]21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OCCO[C@H]1C[C@@H](NC(=O)OC(C)(C)C)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl ((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta-[d][1,3]dioxol-4-yl)carbamate (7.0 g, 25.6 mmol) in dry DMF (70 mL) under nitrogen atmosphere was cooled at 0° C. followed by addition of NaH (60%, 1.3 g, 30.7 mmol). After stirring for 30 min at 0° C., 2-(tert-butoxy)ethyl 4-methylbenzenesulfonate (7.0 g, 25.6 mmol) was added and the reaction mixture was allowed to warm at room temperature. After stirring for 4 hours, the reaction mixture was quenched with water (70 mL). To the mixture was extracted 3×100 mL of n-hexane. The combined organic phases were dried over MgSO4, filtered and evaporated to the dryness. The pure IIId was isolated from reaction mixture by chromatography on silica gel column (mobile phase: n-hexane/EtOAc).
Reaction SMILES: [CH3:1][C:2](=[O:23])[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([C:18](=[O:22])[CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11][CH:12]=[CH:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[CH2:24](O)[CH2:25][OH:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:24]1[CH2:25][O:26][C:2]([C@@H:3]2[C@:20]3([CH3:21])[C@H:6]([C@H:7]4[C@H:17]([C:18](=[O:22])[CH2:19]3)[C@:15]3([CH3:16])[C@H:10]([CH2:11][CH:12]=[CH:13][CH2:14]3)[CH2:9][CH2:8]4)[CH2:5][CH2:4]2)([CH3:1])[O:23]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5CC=CC[C@]5(C)[C@H]4C(=O)C[C@]23C)OCCO1
Reaction time: 8 h

Procedure:
5α-Pregn-2-ene-11,20-dione (10 g) in benzene (300 ml) was treated with ethylene glycol (30 ml) and toluene-4-sulphonic acid (100 mg), and the vigorously stirred mixture was refluxed through a Dean and Stark separator for 8 hours. The reaction mixture was partitioned between ether/ethyl acetate and dilute sodium bicarbonate solution. The organic layer was washed with water (3 times), dried over sodium sulphate and evaporated to a solidifying oil which was triturated with petrol to give title compound (9.42 g) as an off-white solid, m.p. 130°-135°, [α]D +111°.
Reaction SMILES: [OH:1][C@@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].ClC(Cl)(Cl)C(=N)O[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.FC(F)(F)S(O)(=O)=O>C1CCCCC1.C(Cl)Cl>[CH2:13]([O:1][C@@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: COC(=O)C[C@H](C)O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: COC(=O)C[C@H](C)OCc1ccccc1
Reaction time: 1 h

Procedure:
Methyl (S)-(+)-3-hydroxybutyrate (17) (2.223 g, 18.82 mmol) and benzyl 2,2,2-trichloroacetimidate (4.2 mL) were dissolved into 37.5 mL of cyclohexane/methylene chloride (2:1). After the addition of 0.2 mL of trifluoromethane sulfonic acid the reaction was stirred under nitrogen for one hour. The reaction was diluted with 75 mL of cyclohexane/methylene chloride (2:1) and filtered. The organic layer was washed with 50 mL of saturated sodium bicarbonate and 50 mL of distilled water. After drying with anhydrous sodium sulfate the solution was filtered and the solvents were removed on a rotovap. The resulting solid was purified using silica gel and elution with ether/hexane (1:4).
Reaction SMILES: [C:1]1([NH:7][C:8]([C@@H:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[Cl:25][C:26]1[CH:31]=[C:30](Cl)[N:29]=[C:28]([NH2:33])[N:27]=1>CC#N>[NH2:33][C:28]1[N:29]=[C:30]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:10]([C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:9])[CH2:11]2)[CH:31]=[C:26]([Cl:25])[N:27]=1
Reactant: O=C(Nc1ccccc1)[C@@H]1CCCNC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Cl)cc(N2CCC[C@@H](C(=O)Nc3ccccc3)C2)n1
Temperature: 160 °C
Yield: 43.4 %

Procedure:
To a solution of (3R)—N-phenyl-3-piperidinecarboxamide (339 mg, 1.66 mmol) in CH3CN (3 mL) in a 5 mL microwave vial, was added Hunig's base (0.87 mL, 4.98 mmol) and 4,6-dichloro-2-pyrimidinamine (299 mg, 1.83 mmol), and the reaction mixture was heated at 160° C. under microwave conditions for 0.5 hours. A solid formed upon cooling of the reaction mixture. The solid was then isolated by filtration, washing with CH3CN to afford the crude title compound (239 mg) as a light brown solid. LC-MS (ES) m/z=332 [M+H]+.