Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si]([C:35]#[N:36])(C)C.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([C:35]#[N:36])=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C[Si](C)(C)C#N
Reactant: CCCCCCCc1ccc(C(=O)Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: CCCCCCCc1ccc(C(=O)C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Heptylbenzoyl cyanide was synthesized according to the general procedure reported by G. A. Olah et al [supra]. Under dry conditions, 2.5518 g of 4-heptylbenzoyl chloride (99%, Aldrich) (10.69 mmol), 30 mL of methylene chloride, freshly distilled from phosphorus pentoxide under nitrogen, and 1.65 mL of trimethylsilyl cyanide (12 mmol) were added to a 100-mL round bottom flask. To this solution 0.27 mL of tin (IV) chloride (2.3 mmol) was added. The reaction mixture was stirred for 2 hr at room temperature. During the 2 hr, the color of the solution changed from a pale yellow to dark brown. After 2 hr of stirring, the reaction was quenched with 81 mL of ice-cold water and then extracted with two 81-mL portions of methylene chloride. The methylene chloride extracts were combined, washed with two 81-mL portions of ice-cold water, dried with MgSO4, and filtered. The methylene chloride was removed by rotary evaporation to yield 2.097 g of a dark brown oil. This oil was distilled at 106°-109.5° C. (0.2 mm) to yield 1.214 g (50%) of 4-heptylbenzoyl cyanide as a colorless oil that solidified on standing in the freezer: IR (CCl4) (partial) 2930, 2860, 2220, 1680, 1610 cm-1.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH3:15])[CH2:3][CH2:2]1.[CH:16]1([CH2:19][C@H:20]([NH2:27])[C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)[CH2:18][CH2:17]1>>[CH:16]1([CH2:19][C@H:20]([NH:27][C:12]([C:10]2[CH:9]=[CH:8][C:7]([CH3:15])=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)[CH2:18][CH2:17]1
Reactant: Cc1nc([C@@H](N)CC2CC2)no1
Reactant: Cc1ccc(C(=O)O)nc1OCC1CC1
Product: Cc1nc([C@H](CC2CC2)NC(=O)c2ccc(C)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (Example 36 d) and (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38 e) as starting materials, MS (EI): m/e 357.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>C(Cl)Cl>[NH2:21][C:20]1[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=1[C:2]#[C:1][C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Nc1ccccc1I
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccccc1N)O2

Procedure:
This compound was obtained by reacting rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 2-iodoaniline under the conditions described in Example 26. The product was isolated by chromatography over the 40 fold amount of silica gel using methylene chloride. Crystallization from ether/hexane and recrystallization from cyclohexane gave pale yellow crystals with m.p. 110°-112°.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([C:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=2)[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:10]([CH3:27])[NH:9][C:8]=1[CH3:28])=[O:6])[CH3:3].[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33]Cl>C(O)C>[CH2:2]([O:4][C:5]([C:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:33][CH2:32][CH2:31][N:30]([CH3:35])[CH3:29])=[C:15]([O:20][CH3:21])[CH:14]=2)[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:10]([CH3:27])[NH:9][C:8]=1[CH3:28])=[O:6])[CH3:3]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccc(O)c(OC)c1
Reactant: CN(C)CCCCl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccc(OCCCN(C)C)c(OC)c1
Yield: 75 %

Procedure:
A solution of 2.3 g of sodium in 100 ml of ethanol is added to a warm solution of 37.5 g of 2,6-dimethyl-4-(3-methoxy-4-hydroxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (melting point 172°C) in 300 ml of ethanol. The mixture is heated at reflux and 15 g of 3-dimethylaminopropyl chloride are added dropwise. After refluxing for several hours, the mixture is filtered hot, the residue being washed with alcohol, and the filtrate is evaporated in vacuo to yield yellow crystals of melting point 62°C after recrystallization from ligroin-petroleum ether. Yield: 75% of theory.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].Cl.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:20]([C:21]([C:23]3[CH:40]=[CH:39][C:26]([CH2:27][NH:28][C:29](=[O:38])[CH2:30][CH2:31][CH:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)=[CH:25][C:24]=3[CH3:41])=[O:22])[CH2:19][C:18]3[CH:17]=[N:16][N:15]([CH3:42])[C:14]=3[NH:13][C:12]=2[CH:43]=1>ClCCl.C(N(CC)CC)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:20]([C:21]([C:23]3[CH:40]=[CH:39][C:26]([CH2:27][NH:28][C:29](=[O:38])[CH2:30][CH2:31][CH:32]4[CH2:37][CH2:36][N:35]([C:1](=[O:4])[CH2:2][CH3:3])[CH2:34][CH2:33]4)=[CH:25][C:24]=3[CH3:41])=[O:22])[CH2:19][C:18]3[CH:17]=[N:16][N:15]([CH3:42])[C:14]=3[NH:13][C:12]=2[CH:43]=1
Reactant: Cc1cc(CNC(=O)CCC2CCNCC2)ccc1C(=O)N1Cc2cnn(C)c2Nc2cc(Cl)ccc21
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCC(CCC(=O)NCc2ccc(C(=O)N3Cc4cnn(C)c4Nc4cc(Cl)ccc43)c(C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of propionyl chloride (0.46 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of N-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methyl-benzyl]-3-piperidin-4-yl-propionamide hydrochloride (Compound number 1108) (2.97 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=577.4
Reaction SMILES: C(O)C.[Na].[C:5](=[N:8][OH:9])([NH2:7])[CH3:6].[Br:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13](OC)=O>O>[Br:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]1[O:9][N:8]=[C:5]([CH3:6])[N:7]=1
Reactant: COC(=O)c1ccccc1Br
Reactant: CC(N)=NO
Agent: [Na]
Solvent: O
Solvent: CCO
Product: Cc1noc(-c2ccccc2Br)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.5 %

Procedure:
To activated molecular sieves (2.0 g, 4 Å powdered) was added ethanol (20 ml) followed by sodium metal (0.435 g, 18.9 mmol), and the mixture heated at reflux for 15 min. After cooling to ambient temperature, acetamide oxime (1.4 g, 18.9 mmol) was added and the suspension stirred for 15 min. Methyl 2-bromobenzoate (1.32 ml, 9.5 mmol) was added and the mixture heated at reflux for 2 h. The reaction was poured into water and extracted with ethyl acetate. The organic phase was separated, dried over magnesium sulfate, filtered and evaporated to give a white solid. The crude product was purified by crystallisation from ethyl acetatelisohexane to give 5-(2-bromophenyl)-3-methyl-[1,2,4]oxadiazole as a white solid (0.76 g): δH (400 MHz, CDCl3) 2.52 (3H, s), 7.45 (2H, m), 7.76 (1H, dd, J 7.8 and 1.2), 7.97 (1H, dd, J 7.8 and 1.2); m/z (ES+) 239:241 (1:1) (M++H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH:9]([CH3:11])[CH3:10])[C:6]=1[CH:7]=[O:8].[BH4-].[Na+].O>CO>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH:9]([CH3:11])[CH3:10])[C:6]=1[CH2:7][OH:8]
Reactant: Cc1ncn(C(C)C)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ncn(C(C)C)c1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
To a 0° C. solution of 4-methyl-1-(propan-2-yl)-1H-imidazole-5-carbaldehyde (924 mg, 6.1 mmol) in anhydrous methanol (75 mL) was added sodium borohydride (425 mg, 11.2 mmol). The reaction mixture was stirred at room temperature for 3 hours. Water (20 mL) was added. Methanol was evaporated. The resultant mixture was extracted with EtOAc (1×20 mL) and 2-butanol (2×20 mL). The solution was dried over MgSO4, filtered, evaporated, and dried in vacuo, affording [4-methyl-1-(propan-2-yl)-1H-imidazol-5-yl]methanol (703 mg, 75% yield). The product was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH2:8][CH2:9][N:10]=[CH:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[CH:7]=1.[BH4-].[Na+].O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH2:8][CH2:9][NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(C=NCCc2cc(F)ccc2OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(CNCCc2cc(F)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.30 g (16.8 mmol) of methyl 4-({[2-(5-fluoro-2-methoxyphenyl)ethyl]imino}-methyl)benzoate are dissolved in 48.4 ml of methanol, and 1.27 g (33.6 mmol) of sodium borohydride are added. The solution is stirred at RT for 2 hours, and water is then added and the solution is extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is taken up in ethyl acetate and extracted with diluted HCl. The aqueous phase is made alkaline and extracted with ethyl acetate, and the extract is dried over magnesium sulphate, filtered and concentrated under reduced pressure.
Reaction SMILES: Br.C([N:9]1[C:13]2=[C:14]([N+:29]([O-:31])=[O:30])[C:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=3[F:28])=[C:16]([CH3:19])[C:17](=[O:18])[N:12]2[CH2:11][CH2:10]1)C1C=CC=CC=1.C(OC(=O)C)C.C([O-])(O)=O.[Na+]>C(O)(=O)C>[F:28][C:22]1[CH:23]=[C:24]([I:27])[CH:25]=[CH:26][C:21]=1[NH:20][C:15]1[C:14]([N+:29]([O-:31])=[O:30])=[C:13]2[NH:9][CH2:10][CH2:11][N:12]2[C:17](=[O:18])[C:16]=1[CH3:19]
Reactant: Cc1c(Nc2ccc(I)cc2F)c([N+](=O)[O-])c2n(c1=O)CCN2Cc1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1c(Nc2ccc(I)cc2F)c([N+](=O)[O-])c2n(c1=O)CCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
HBr in acetic acid (30 mL) was added to 1-benzyl-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-8-nitro-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one (I-3b: 2.5 g) and the resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was basified with NaHCO3 solution and partitioned between ice water and ethyl acetate. The organic layer was concentrated to afford the crude product. Purification by column chromatography on silica gel (60% ethylacetate in hexane) afforded 1.5 g of the product (75% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[CH2:4]NC(=O)C.P(Cl)(Cl)([Cl:18])=O.CN(C)C=O>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[CH2:4][Cl:18]
Reactant: CC(=O)NCc1cc([N+](=O)[O-])ccc1C
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])cc1CCl
Yield: 85 %

Procedure:
A solution of N-(2-methyl-5-nitrobenzyl)acetamide (3.12 g; 0.015 mol), phosphorus oxychloride (5.12 g; 0.032 mol) and dimethylformamide (2.19 g; 0.03 mol) in xylene (50 ml) is refluxed for one hour. The reaction mixture is then washed with water and the solvent evaporated. This treatment produces 2.36 g (i.e., 85% yield) of product having a melting point of 56° to 62° C.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[CH2:8]([C:12]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([C:30]([OH:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[C:15]2[C:33](O)=[CH:34][CH:35]=[C:36]([CH3:37])[C:14]=2[N:13]=1)[CH2:9][CH2:10][CH3:11].C(Cl)(=O)C>N1C=CC=CC=1>[C:3]([O:5][C:33]1[C:15]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]([OH:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[C:12]([CH2:8][CH2:9][CH2:10][CH3:11])=[N:13][C:14]=2[C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:4])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCc1nc2c(C)ccc(O)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Solvent: c1ccncc1
Solvent: CC(=O)Cl
Product: CCCCc1nc2c(C)ccc(OC(C)=O)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 2 h

Procedure:
0.55 g (1 mmol) of 4'-[(2-n-butyl-7-hydroxy-4-methyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid trifluoroacetate is dissolved in 20 ml of pyridine. 0.5 ml (7 mmol) of acetyl chloride is added dropwise to the mixture at 5° C. with stirring. The mixture is stirred for 1 hour at 5° C. and then for 2 hours at ambient temperature. The pyridine is distilled off in vacuum on a rotary evaporator. The residue is mixed with water and filtered under suction. After washing with water, it is dried at 50° C. in vacuum.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:22]1[O:23][CH:24]=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]C(C)(C)C.[Cl:32]N1C(=O)CCC1=O>C1COCC1.CCOC(C)=O>[Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([Cl:32])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncco1
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(Cl)o1
Temperature: -78 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazole (116 mg, 0.310 mmol) was dissolved in anhydrous THF (5 mL), cooled to −78° C. and t-BuLi (1.7 M in pentane, 1.3 equiv) was added dropwise under Ar. The reaction mixture was stirred for 2 h at −40° C., cooled to −78° C. and N-chlorosuccinimide (1.5 equiv) in THF (3 mL) was added dropwise. The reaction mixture was warmed to room temperature, diluted with EtOAc, washed with saturated aqueous NaCl and dried over Na2SO4. Evaporation in vacuo yielded the crude aryl chloride, which was purified by flash chromatography (0-2% EtOAc/hexanes) to afford the title compound as a clear oil (73 mg, 57%): 1H NMR (CDCl3, 600 MHz) 7.29-7.26 (m, 2H), 7.18-7.17 (m, 3H), 6.82 (s, 1H), 4.71 (t, 1H, J=7.2 Hz), 2.60 (t, 2H, J=7.8 Hz), 1.88-1.80 (m, 2H), 1.62-1.60 (m, 2H), 1.43-1.35 (m, 6H), 0.89 (s, 9H), 0.09 (s, 3H), −0.01 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 165.6, 143.6, 136.9, 129.3, 129.1, 126.5, 122.9, 69.5, 37.0, 36.8, 32.3, 29.9, 29.9, 26.6, 19.1, −4.2, −4.3.
Reaction SMILES: C(O)(=O)C(O)=[O:3].[C:7]([CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C:20]=2[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:31][CH:30]=2)=[CH:15][CH:14]=1)#[N:8].[ClH:43]>>[ClH:43].[NH2:8][C:7](=[O:3])[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C:20]=2[CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][N:38]3[CH2:39][CH2:40][CH2:41][CH2:42]3)=[CH:33][CH:34]=2)=[CH:17][CH:18]=1
Reactant: N#CCCCOc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: NC(=O)CCCOc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
The free base of the above nitrile (Example 34, Part D) (0.15 g; 0.3 mmol) was combined with 7 mL of conc HCl and stirred at room temperature for 3 days. The mixture was concentrated under reduced pressure, and the product (0.16 g; 100% yield) was dried in vacuo overnight.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH:18]([CH2:23][CH:24]=[CH2:25])[C:19]([O:21][CH3:22])=[O:20])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([NH:17][CH:18]([CH2:23][CH:24]3[O:35][CH2:25]3)[C:19]([O:21][CH3:22])=[O:20])(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: C=CCC(NS(=O)(=O)c1ccc(-c2ccc(Br)cc2)cc1)C(=O)OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 72 h

Procedure:
To a solution of methyl 2-[(4′-bromo[1,1′-biphenyl]-4-yl)-sulfonylamino]-pent-4-eneoate 13c (10.2 g, 24.1mmol) in CH2Cl2 (150 mL), NaHCO3 (11.0 g, 50 mmol) and water (140 mL) at 0° C., is slowly added m-chloroperbenzoic acid (57-86%) (19.4 g, ˜80 mmol). The reaction is stirred for 72 hours. The mixture is diluted with aqueous NaHCO3 and this mixture is extracted with ethyl acetate (3×250 mL). The combined ethyl acetate layer is washed with brine, dried over MgSO4, filtered and concentrated to an oil. Purification of this compound is accomplished by column chromatography with 40% ethyl acetate in hexanes as the eluent to give the desired product.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([OH:22])=O)[CH2:3][CH2:2]1.O.[NH:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:24]2[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)=[O:22])[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)O
Solvent: O
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(=O)CC1

Procedure:
The title compound was prepared analogously to intermediate 15 from 5-cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid and 4-piperidone hydrate. MS: 392.2 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17]([S:20][CH3:21])=[N:18]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:33])C=1.C([O-])(O)=O.[Na+]>>[CH3:21][S:20]([C:17]1[N:16]=[CH:15][C:14]2=[CH:13][CH:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=3)[N:19]2[N:18]=1)=[O:33]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a Round bottom flask, 7-(4-Methanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.630 g, 0.00197 mol) and Methylene chloride (50 mL, 0.8 mol) were added. m-Chloroperbenzoic acid (0.464 g, 0.00207 mol) was added portion wise. The reaction was stirred at room temperature for 30 minutes. Saturated NaHCO3 was added. The organic layer was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The organic was removed under vacuum. to give 2-Methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine a yellow solid (0.63 g, 93%). NMR 1H (DSMO-d6)-9.40 (s, 1H), 8.54 (d, 2H, J=8.60 Hz), 8.09 (d, 2H, J=7.56 Hz), 7.85 (d, 1H, J=4.84 Hz), 7.39 (d, 1H, J=4.88 Hz), 3.29 (s, 3H), 3.00 (s, 3H)
Reaction SMILES: C([Mg]Br)C.[Br:5][C:6]1[CH:20]=[CH:19][C:9]2[C:10]3[N:11]([CH:15]=[C:16](I)[N:17]=3)[CH2:12][CH2:13][O:14][C:8]=2[CH:7]=1.CN(C)[CH:23]=[O:24]>C(OCC)C.O1CCCC1>[Br:5][C:6]1[CH:20]=[CH:19][C:9]2[C:10]3[N:11]([CH:15]=[C:16]([CH:23]=[O:24])[N:17]=3)[CH2:12][CH2:13][O:14][C:8]=2[CH:7]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc2c(c1)OCCn1cc(I)nc1-2
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 15 °C
Reaction time: 0.33 h

Procedure:
Ethylmagnesium bromide in ethyl ether (3.0 M, 3.472 mL) was added dropwise to a solution of 9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (1173 mg, 3.000 mmol) in 20 ml of tetrahydrofuran at −30° C. The mixture was stirred at this temperature for 20 min and allowed to warm to 15° C. The mixture was cooled to −25° C. again and N,N-dimethylformamide (929.2 uL, 12.00 mmol) was added. The mixture was left for 18 hours. The mixture was quenched with sat. aq. NH4Cl and extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over mgSO4 and concentrated in vacuum. Yield 0.92 g. MS: 293.1
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]3[N:17]([C:31]4[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=4)[C:34]#[N:35])[C:18](=[O:30])[N:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH:20]([CH3:21])[C:14]3=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl>[C:34]([C:33]1[CH:32]=[C:31]([N:17]2[C:15]3[N:16]=[C:11]([NH:10][C:6]4[CH:5]=[C:4]([CH2:3][CH2:2][O:1][S:47]([CH3:46])(=[O:49])=[O:48])[CH:9]=[CH:8][CH:7]=4)[N:12]=[CH:13][C:14]=3[CH:20]([CH3:21])[N:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:18]2=[O:30])[CH:38]=[CH:37][CH:36]=1)#[N:35]
Reactant: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4cccc(CCO)c4)ncc3C2C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4cccc(CCOS(C)(=O)=O)c4)ncc3C2C)cc1
Reaction time: 0.75 h

Procedure:
(±)-3-[7-[3-(2-Hydroxy-ethyl)-phenylamino]-3-(4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile (0.67 mg; 1.27 mmol) (from Example 4 supra) was suspended in dichloromethane (13 mL). The mixture was treated with triethylamine (0.23 mL; 1.65 mmol) and methane-sulfonyl chloride (0.13 mL; 1.68 mmol) (Aldrich). The solid went into solution as the methanesulfonyl chloride was added. After 45 minutes, the reaction was shown by thin layer chromatography to be complete. The reaction was diluted with additional dichloromethane and washed with water and then brine. The organic phase was dried over anhydrous sodium sulfate, concentrated and dried under high vacuum to give crude (±)-methanesulfonic acid (2-{3-[8-(3-cyano-phenyl)-6-(4-methoxy-phenyl)-5-methyl-7-oxo-5,6,7,8-tetrahydro-pyrimido[4,5-d]pyrimidin-2-ylamino]-phenyl}-ethyl)-ester as a foam. This material was used in the next step without further purification. (Yield: 0.76 g, 95.4%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][O:5][C:6]1[CH:15]=[C:14]([CH:16]=[C:17]([CH2:20][O:21][CH3:22])[C:18]#[N:19])[C:9]2[CH:10]=[CH:11][CH2:12][O:13][C:8]=2[C:7]=1[O:23][CH3:24]>CO.O>[CH3:4][O:5][C:6]1[CH:15]=[C:14]([CH2:16][CH:17]([CH:20]([O:2][CH3:1])[O:21][CH3:22])[C:18]#[N:19])[C:9]2[CH:10]=[CH:11][CH2:12][O:13][C:8]=2[C:7]=1[O:23][CH3:24]
Reactant: COCC(C#N)=Cc1cc(OC)c(OC)c2c1C=CCO2
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(CC(C#N)C(OC)OC)c2c(c1OC)OCC=C2
Yield: 62.2 %

Procedure:
A mixture of sodium methoxide (8.86 g, 0.164 mole), and 3-(7,8-dimethoxy-2H-1-benzopyran-5-yl)-2-methoxymethylpropenenitrile (Example 37A, 23.1 g, 0.080 mole) in methanol (60 mL) was heated at reflux for 24 hr, allowed to cool and diluted with water (200 mL). The resultant mixture was extracted with toluene (1×200 mL and 2×100 mL). The combined toluene portions were extracted with water (3×100 mL) and dried over magnesium sulfate. The toluene solution was concentrated leaving a brown oil which was distilled under reduced pressure to give 15.9 g (62%) of a yellow oil which was used without further purification.