Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][C:18]([NH:20][CH:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:19])[CH:14]=[CH:13][C:5]=1[CH:6]=[CH:7][C:8]([O:10]CC)=[O:9])[CH3:2].[OH-].[Na+].Cl>C(O)C.O>[CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][C:18]([NH:20][CH:21]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:19])[CH:14]=[CH:13][C:5]=1[CH:6]=[CH:7][C:8]([OH:10])=[O:9])[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(CC(=O)NC(c2ccccc2)c2ccccc2N2CCCCC2)cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1cc(CC(=O)NC(c2ccccc2)c2ccccc2N2CCCCC2)ccc1C=CC(=O)O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Ethyl 2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-cinnamate (330 mg, 0.62 mmol) is dissolved in ethanol (10 ml) and, after the addition of 4N sodium hydroxide solution (4 ml), stirred for 3 hours at 50° C. Then the mixture is neutralized with 4N hydrochloric acid (4 ml), diluted with water and, filtered off from the precipitate. It is then recrystallized from aqueous ethanol.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=O)=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH:24]=1>>[C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][C:11]([CH3:16])([CH3:15])[C:12]([NH:33][CH2:32][CH2:31][CH2:30][CH2:29][C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)=[O:14])=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCC(C)(C)C(=O)O)ccc(C(C)=O)c1O
Reactant: NCCCCc1cccnc1
Product: CCCc1c(OCCC(C)(C)C(=O)NCCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
4(4-Acetyl-3-hydroxy-2-propylphenoxy)-2,2-dimethyl butanoic acid was allowed to react with 3-pyridine butanamine according to procedure A and the product was purified by HPLC to give 4-(4-acetyl-3-hydroxy-2-propylphenoxy)-2,2-dimethyl-N-[4-(3-pyridinyl)butyl]-butanamide, the title compound, mp 80°-83° (from hexane) in 83% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[NH2:17][CH2:18][CH2:19][C@H:20]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C:21]([OH:23])=[O:22].[BH3-]C#N.[Na+]>C1COCC1.O>[CH2:28]([O:27][C:25]([NH:24][C@@H:20]([CH2:19][CH2:18][NH:17][CH:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C:2]1([CH3:16])[CH3:1])[C:21]([OH:23])=[O:22])=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(NCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)C(C)(C)C1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To a 0° C. solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (1.76 g, 7.74 mmol) and (S)-4-amino-2-(benzyloxycarbonylamino)butanoic acid (1.95 g, 7.74 mmol) in THF (20 mL) and water (3 mL) was added NaCNBH3 (0.48 g, 7.7 mmol). This mixture was stirred at 60° C. for 2 days. The reaction was then evaporated to a solid to give the crude (2S)-2-(benzyloxycarbonylamino)-4-(1-(tert-butoxycarbonyl)-3,3-dimethylpiperidin-4-ylamino)butanoic acid. This material was taken on directly to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28]([NH:19][C:4]1[CH:5]=[N:6][C:7]([O:8][C:9]2[N:10]=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([Cl:1])[CH:3]=1)(=[O:30])=[O:29]
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Product: O=S(=O)(Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1)c1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per the procedure described in preparation 2) and 2,4-dichloro benzenesulfonylchloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:13][C:3]1[C:2]([NH:1][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:11][C:10]([Cl:12])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCCC1
Reactant: COC(=O)c1cc(Cl)cc(N)c1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Cl)cc(NC2CCCC2)c1Cl
Reaction time: 3 h
Yield: 8.3 %

Procedure:
To a stirred solution of methyl 3-amino-2,5-dichlorobenzoate (2.5 g, 11.5 mmol) and cyclopentanone (4.8 g, 57.1 mmol) in methanol (5 mL) was added acetic acid (0.6 g, 11.3 mmol) and stirring was continued at room temperature for 3 h. Then sodium cyanoborohydride (1.4 g, 22.2 mmol) was added and the reaction stirred overnight. On completion, the solvent was removed under reduced pressure and the product was purified by column chromatography to afford methyl 2,5-dichloro-3-(cyclopentylamino)benzoate (0.275 g, 8%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH2:27]([NH2:29])[CH3:28]>C(#N)C>[CH3:26][S:23]([C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][CH:13]([CH2:12][NH:29][CH2:27][CH3:28])[O:14]2)=[CH:19][CH:18]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCN
Solvent: CC#N
Product: CCNCC1CCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), ethanamine (2.0 M in MeOH, 0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 269 (M+, 5), 131 (6), 77 (6), 58 (bp), 56 (4).
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[CH:4]([C:11](Cl)=[O:12])[C:3]2=O.C(N(CC)CC)C.C(OC([N:29]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl>[CH2:41]([N:29]1[C:3]2[C@:2]3([CH3:1])[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]3)[C:4]=2[C:11](=[O:12])[N:30]1[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)Cl
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)Nc1ccc2ccccc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCCl
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccc3ccccc3c2)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30.4 %

Procedure:
A solution of (1 S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 25; 240 mg, 1.12 mmol) in 1,2-dichloroethane (8 mL) was added to a cooled (0° C.) solution of triethylamine (210 μL, 1.5 mmol) and N-benzyl-N′-naphthalen-2-yl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 37; 260 mg, 0.75 mmol) in 1,2-dichloroethane (4 mL) over 1 min. The reaction mixture was stirred at room temperature for 15 min, and then in an oil bath at 50° C. for 30 min. A solution of HCl in dioxane (4 M; 4 mL, 16 mmol) was added and the reaction mixture was heated at reflux for 1 h, and allowed to cool. Silica gel was added and the solvent was evaporated. The residue was purified using an ISCO 40 g column, eluting with 50-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated and the residue was co-evaporated with diethyl ether and dried under high vacuum to give (4R,7S)-1-benzyl-7,8,8-trimethyl-2-naphthalen-2-yl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (93 mg, 30%) as an off-white solid. ES(+)-MS (M+H) 409.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[C:17]2[C:18](F)=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:5][CH:4]=1.[NH2:26][C:27]1[C:28]([CH3:46])=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][N:33]=[C:32]2[NH:37][C:38]1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CC(O)=O>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[C:17]2[C:18]([NH:26][C:27]3[C:28]([CH3:46])=[CH:29][CH:30]=[C:31]4[C:36]=3[N:35]=[CH:34][N:33]=[C:32]4[NH:37][C:38]3[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2cnc3c(-c4cccnc4F)ncnc32)cc1
Reactant: Cc1ccc2c(Nc3ccc(C#N)cc3)ncnc2c1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cn2cnc3c(-c4cccnc4Nc4c(C)ccc5c(Nc6ccc(C#N)cc6)ncnc45)ncnc32)cc1
Temperature: 140 °C

Procedure:
A mixture of 9-(4-methoxybenzyl)-6-(2-fluoropyridin-3-yl)-9H-purine (146 mg, 436 μmol) and 4-(8-amino-7-methylquinazolin-4-ylamino)benzonitrile (120 mg, 436 μmol) in THF (4 mL) was sonicated until all solids became a fine powder. Lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 1.53 mL, 1.53 mmol) was added dropwise with stirring (all solids dissolved and then some solid appeared again). The mixture was stirred at rt for 10 min and then heated in a microwave at 140° C. for 30 min. The mixture was poured into AcOH (0.5 mL) in MeOH (20 mL) and the mixture was stirred for 10 min. Solvent was removed and the product was purified by flash chromatography eluting with MeOH/DCM (2-5%) to give 4-(8-(3-(9-(4-methoxybenzyl)-9H-purin-6-yl)pyridin-2-ylamino)-7-methylquinazolin-4-ylamino)benzonitrile. MS (ESI, pos. ion) m/z: 591.2 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[C:14]([NH2:20])=[N:15][CH:16]=[C:17]([CH3:19])[N:18]=1>>[CH3:1][C:2]1[S:6][C:5]([S:7]([NH:20][C:14]2[C:13]([O:12][CH3:11])=[N:18][C:17]([CH3:19])=[CH:16][N:15]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: COc1nc(C)cnc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)s1
Product: COc1nc(C)cnc1NS(=O)(=O)c1ccc(C)s1

Procedure:
Prepared by the method of Example 1 using 5-methylthiophenesulphonyl chloride and 3-methoxy-5-methyl-2-pyrazinamine.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].Cl[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: Clc1ccccn1
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCO[C@@H]1CN(c2ccccn2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 3.5 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (100 mg, 0.297 mmol), 2-chloropyridine (0.035 mL, 0.37 mmol) and sodium carbonate (157 mg, 1.48 mmol) were suspended in DMF (1 mL), and the suspension was heated using a microwave reactor at 180° C. for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=7/3→1/0) to obtain 3.9 mg of the title compound as a white amorphous solid (3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH:14]1[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[N:8]([CH:14]1[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(Cl)cc2c1=O
Reactant: C1CNCCN1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNCC3)c(Cl)cc2c1=O
Yield: 84.1 %

Procedure:
12 g (40 mmol) of the product from Example A in 100 ml of pyridine are heated with 17.2 g (0.2 mole) of piperazine under reflux for 5 hours. The mixture is concentrated in vacuo, the residue is stirred with 120 ml of water and the pH is adjusted to 5 with 2N hydrochloric acid. The precipitate is filtered off with suction, washed with water and methanol, boiled in 80 ml of methanol and dried. 12.3 g (84% of theory) 6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro- 4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid of melting point 295°-298° (with decomposition) are obtained.
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[S:12][C:11]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[C:17]([CH2:23][OH:24])[CH:16]=3)=[CH:10][CH:9]=2)OCC[O:4]1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[OH:24][CH2:23][C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][C:11]2[S:12][C:8]([C:3](=[O:4])[CH2:1][CH3:2])=[CH:9][CH:10]=2)[CH:20]=[CH:19][C:18]=1[CH2:21][OH:22]
Reactant: CCC1(c2ccc(CCc3ccc(CO)c(CO)c3)s2)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CCC(=O)c1ccc(CCc2ccc(CO)c(CO)c2)s1

Procedure:
In a manner similar to that of Example 6(g), by reaction of 8.7 g (23 mmol) of (4-{2-[5-(2-ethyl-[1,3]dioxolan-2-yl)-2-thienyl]ethyl}-2-hydroxymethylphenyl)methanol with a solution of para-toluenesulphonic acid in an acetone/water mixture, the desired product is obtained in the form of a white powder (m=5.41 g; Y=71%).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][N:4]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:4]2[C:3](=[O:2])[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5]2)=[CH:14][CH:13]=1
Reactant: COc1ccc(C=O)cn1
Reactant: Clc1ccc(CBr)cc1
Product: O=Cc1ccc(=O)n(Cc2ccc(Cl)cc2)c1
Yield: 67.8 %

Procedure:
According to Scheme 2: The title compound was prepared from 6-methoxynicotinaldehyde (1 eq, 13.4 mmol, 1.83 g) and 4-chloro-benzylbromide (2 eq, 26.8 mmol, 5.50 g) according to the procedure described for Example 6 Step 2. Reaction conditions: 17 hours under reflux. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/AcOEt 95/5 as eluent to afford 1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridine-3-carbaldehyde (9.08 mmol, 2.25 g, 68%) as an orange solid.
Reaction SMILES: CN([SiH3])[Si:3]([CH3:6])(C)[CH3:4].[F:8][C:9]([F:22])([F:21])[S:10]([O:13]S(C(F)(F)F)(=O)=O)(=[O:12])=[O:11]>>[F:8][C:9]([F:22])([F:21])[S:10]([O:13][SiH:3]([CH3:6])[CH3:4])(=[O:12])=[O:11]
Reactant: CN([SiH3])[Si](C)(C)C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: C[SiH](C)OS(=O)(=O)C(F)(F)F

Procedure:
Additionally, for example when mixing tetramethyldisilazane as the silicon compound D with trifluoromethanesulfonic anhydride as the acid D, the trifluoromethanesulfonic anhydride immediately reacts therewith to form dimethylsilyl trifluoromethanesulfonate as the silicon compound B.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11][CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][C@@H:5]23)[CH:10]=1.[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.[C:36]([O-:39])([O-])=[O:37].[Na+].[Na+]>C1C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11][CH2:12][CH:13]([C:36]([O:39][C:4]([CH3:8])([CH3:5])[CH3:3])=[O:37])[N:7]3[C@H:6]3[CH2:14][CH2:15][N:16]=[CH:17][C@H:5]23)[CH:10]=1
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCS3
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)C1CSc2cc(-c3cccc(Cl)c3Cl)cc3c2N1[C@H]1CCN=C[C@H]31
Temperature: 20 °C
Yield: 159.2 %

Procedure:
A solution of tert-butyl(6bR,10aS)-5-bromo-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate (150 mg, 0.37 mmol) and 2,3-dichlorophenylboronic acid (143 mg, 0.75 mmol) in benzene (10 mL) and 2M Na2CO3 aqueous solution (0.74 mL, 1.48 mmol) was degassed at 20° C. Pd(PPh3)2Cl2 (7.8 mg, 0.01 mmol) was added, and the reaction mixture was degassed one more time. The reaction mixture was refluxed for 15 h then cooled to 20° C. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3 and brine. The combined organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed (silica gel; Hexane:EtOAc 3:1) to give tert-butyl(6bR,10aS)-5-(2,3-dichlorophenyl)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole carboxylate as a light yellow solid (140 mg, 81%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.Cl[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[N:2]2)=[CH:13][CH:14]=1.[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:2]2[N:3]=[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[N:1]2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: c1ccc2[nH]nnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(Cn2nc3ccccc3n2)cc1
Product: Fc1ccc(Cn2nnc3ccccc32)cc1

Procedure:
In a procedure as in Example 2 but using 1H-benzotriazole (23.8 g, 0.200 mol), 1-(chloromethyl)-4-fluorobenzene (29.0 g,0.200 mol) and K2CO3 (70 g) in CH3CN (300 mL) for 1 hour gave the title compound and (4-fluorophenyl)methyl-2H-benzotriazole. Workup and recrystallization gave the mixture of the 1H and 2H-isomers (75% yield) which was used in the subsequent reactions. A sample (5 g) was chromatographed (PE/EtOAc 9:1) eluting first the 2H isomer and then the title compound: mp 92°-94° C. (cyclohexane); 1H NMR (300 MHz, CDCl3) δ5.82 (s, 2H, CH2), 7.00-7.06 (m, 2H), 7.25-7.46 (m, 5H), 8.08 (d, J=8.9 Hz, 1H); IR (CDCl3) 3052 (w), 2938 (w), 1609, 1513, 1451 (w), 1351 (w), 1315 (w), 1269 (w), 1230 (s), 1159, 1084 cm-1. MS (EI) m/e 227 (M+, 52.6), 198 (100), 109 (96.9); Anal. Calcd for C13H10N3F (227.24): C, 68.71; H, 4.44; F, 8.36; N, 18.49; Found: C, 68.44; H. 4.44; F, 8.40; N, 18.57.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Br[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=1.O>CN(C)C(=O)C>[I:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][S:3][C:1](=[O:4])[CH3:2])=[CH:9][CH:10]=1
Reactant: BrCc1ccc(I)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)SCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following a general procedure (Zheng et al. (1999) Tetrahedron Lett. 40: 603–606), potassium thioacetate (2.20 g, 19.3 mmol) was added to a solution of 4-(bromomethyl)-1-iodobenzene (4.80 g, 16.2 mmol) in anhydrous N,N-dimethylacetamide (15 mL). The mixture was stirred overnight at rt, poured into water, and extracted with CH2Cl2. The combined organic extracts were washed with water, dried (Na2SO4) and evaporated. The resulting brown oil was distilled (90° C., 0.005 mmHg) to obtain a pale-yellow solid which solidified after a few days (4.68 g, 99%). mp 40–41° C.; 1H NMR δ 2.37 (s, 3H), 4.07 (s, 2H), 7.07, 7.64 (AA′BB′, 2×2H); 13C NMR δ 31.09, 33.6, 93.5, 131.6, 138.2, 138.4, 195.5; FAB-MS obsd 291.9425, calcd exact mass 291.9419; Anal. Calcd. for C9H9IOS: C, 37.00; H, 3.11; I, 43.44; S, 10.98; Found: C, 37.39; H, 3.13; 1,43.04; S, 11.26.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:19]=[C:18]([C:20](O)=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[OH:24][C:25]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][CH2:30]2>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:19]=[C:18]([C:20]([N:29]3[CH2:28][CH2:27][C:26]4[C:31](=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:25]=4[OH:24])[CH2:30]3)=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1nc(-c2ccc([N+](=O)[O-])cc2)nc2ccccc12
Reactant: COc1ccc2c(c1O)CCNC2
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc([N+](=O)[O-])cc3)nc3ccccc13)C2
Yield: 99.5 %

Procedure:
Reaction of 2-(4-nitrophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 95 (99.5% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.62 and 2.91 (2t, 2H), 3.50 and 4.04 (2t, 2H), 3.74-3.80 (2s, 3H), 4.41 and 4.93 (2s, 2H), 6.31 and 6.78 (2d, 1H), 6.71 and 6.91 (2d, 1H), 7.75-7.84 (m, 1H), 7.87-8.03 (2d, 1H), 8.16-8.26 (m, 2H), 8.41-8.46 (m, 2H), 8.72-8.79 (m, 3H); MS (ESI) m/z 457 ([M+H]+).
Reaction SMILES: [OH:1][CH:2]([CH2:23]O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH3:21])[CH:16]=[N:15][C:14]=2[N:13]([CH3:22])[C:11]1=[O:12].[BrH:25].[C:26]([OH:29])(=O)[CH3:27].C(=O)(O)[O-].[Na+]>ClCCl.O>[C:26]([O:1][CH:2]([CH2:23][Br:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH3:21])[CH:16]=[N:15][C:14]=2[N:13]([CH3:22])[C:11]1=[O:12])(=[O:29])[CH3:27]
Reactant: Br
Reactant: CC(=O)O
Reactant: Cn1cnc2c1c(=O)n(CCCCCCCC(O)CO)c(=O)n2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)OC(CBr)CCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 1.5 h
Yield: 96 %

Procedure:
A mixture of 1-(8,9-dihydroxynonyl)-3,7-dimethylxanthine, prepared above, and 30% hydrogen bromide in acetic acid (0.8 ml, 3.90 mmol) was stirred for 90 minutes. The solution was poured into a mixture of water (10 ml), sodium bicarbonate (1.35 g, and dichloromethane (10 ml). After 10 minutes of vigorous stirring, the layers were separated and the aqueous portion was extracted with three 15 ml aliquots of dichloromethane. The combined organic phases were dried over sodium sulfate and the solvent was evaporated under vacuum, leaving 550 mg of a yellow oil, 1-(8-acetoxy-9-bromononyl)-3,7-dimethylxanthine (96% yield). Without further purification, the oil was dissolved in methanol (5 ml), to which a 1 M solution of sodium methoxide in methanol (4.1 ml, 4.1 mmol) was added. After 30 minutes, the reaction mixture was poured into water (30 ml) was extracted with three 40 ml aliquots of dichloromethane. The combined organic layers were dried over sodium sulfate. Evaporating the solvents under vacuum left a solid residue. Recrystallization in dichloromethane-petroleum ether yielded 380 mg of 1-(8,9-oxidononyl)-3,7-dimethylxanthine (91% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH:8]([CH3:15])[N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33].C(O)C>Cl.O>[CH:16]1([N:7]2[CH:8]([CH3:15])[CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CC1C(=O)N(C)c2cnc(Cl)nc2N(C2CCCC2)C1C
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)C(C)C(C)C(=O)N2C
Yield: 72.1 %

Procedure:
A mixture of 0.092 g (0.0003 mole) of (rac)-2-chloro-9-cyclopentyl-5,7,8-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-41), 0.1 g (0.00036 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.095 g of (rac)-4-(9-cyclopentyl-5,7,8-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-41a) as an off-white solid.