Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH3:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3([CH2:28]OS(C)(=O)=O)[CH2:27][CH2:26]3)[O:16][N:15]=2)=[CH:10][CH:9]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[C:17]([C:25]3([CH2:28][S:2][CH3:1])[CH2:26][CH2:27]3)[O:16][N:15]=2)=[CH:12][CH:13]=1
Reactant: C[S-]
Reactant: COCOc1ccc(-c2noc(C3(COS(C)(=O)=O)CC3)c2-c2ccccc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOc1ccc(-c2noc(C3(CSC)CC3)c2-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
To a mixture consisting of sodium thiomethoxide (0.33 g) in N,N-dimethylformamide (3 mL) is added a mixture consisting of methanesulfonic acid 1-[3-(4-methoxymethoxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropylmethyl ester (synthetic intermediate prepared in Example 11, Step iv, 1 g) in N,N-dimethylformamide at 0° C. The mixture is stirred at 80° C. for four hours and is cooled to room temperature. The mixture is then diluted with ethyl acetate (50 mL) and is sequentially washed with 1 N hydrochloric acid solution (3×15 mL), water (15 mL), and brine solution (15 mL.) The mixture is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the synthetic intermediate 3-(4-methoxymethoxy-phenyl)-5-(1-methylsulfanylmethyl-cyclopropyl)-4-phenyl-isoxazole (0.89 g.)
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][C:38](O)=[O:39]>>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][C:38]([N:16]([C:13]1[CH:14]=[N:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)=[O:39]
Reactant: COc1ccc(NCCc2ccc(C(F)(F)F)cc2)cn1
Reactant: COc1ccccc1CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N(CCc2ccc(C(F)(F)F)cc2)C(=O)Cc2ccccc2OC)cn1

Procedure:
In analogy to example 33, step 2, without TFA addition, (6-methoxy-pyridin-3-yl)-[2-(4-trifluoromethyl-phenyl)-ethyl]-amine, prepared in example 33, step 1) was coupled to (2-methoxy-phenyl)-acetic acid (commercially available) to give the title compound. MS m/e: 445.3 [M+H]+.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:16][CH2:17][C:18]([CH:20]=[CH2:21])=[O:19]>C(O)C>[C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:21][CH2:20][CH:18]([C:17]([CH:1]([OH:8])[CH2:2][CH2:3][N:13]2[CH2:14][CH2:15][CH:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:12]2)=[O:16])[OH:19])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: C=CC(=O)CO
Solvent: CCO
Product: O=C(NC1CCN(CCC(O)C(=O)C(O)CCN2CCC(NC(=O)c3ccccc3)CC2)CC1)c1ccccc1

Procedure:
4-Benzamidopiperidine (2.4 g.) in ethanol (15 ml.) was added to hydroxymethylvinyl ketone (2.0 g.). An exothermic reaction occured and crystallisation occurred on cooling to give 2-(4-benzamidopiperidino)ethylhydroxymethyl ketone, m.p. 154°-155° C. (Found: C, 65.9; H, 7.7; N, 9.5; C16H22N2O3 requires C, 66.2; H, 7.6; N, 9.65%).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[C:8]2[N:13]([C:14](=[O:18])[C:15]=1[O:16][CH3:17])[CH2:12][CH2:11][O:10][C:9]2([CH3:20])[CH3:19])=[O:5].[CH3:22][Mg+].[Br-]>C1COCC1.CCOCC>[C:4]([C:6]1[N:7]=[C:8]2[N:13]([C:14](=[O:18])[C:15]=1[O:16][CH3:17])[CH2:12][CH2:11][O:10][C:9]2([CH3:19])[CH3:20])(=[O:5])[CH3:22]
Reactant: COc1c(C(=O)N(C)OC)nc2n(c1=O)CCOC2(C)C
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1c(C(C)=O)nc2n(c1=O)CCOC2(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
To a solution of N,3-dimethoxy-N,9,9-trimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.40 g, 1.35 mmol, 1.0 equiv) in THF (13 mL) at 0° C. (ice/water bath) under a nitrogen atmosphere, was added CH3MgBr (0.63 mL of a 3 M solution in ether, 1.88 mmol, 1.4 equiv). After stirring 3 h, the reaction was cautiously quenched by addition of 1N HCl (10 mL). After stirring 1 h, the reaction was poured into water and extracted with CH2Cl2 (×5). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo. The crude product was purified by silica gel chromatography (20-100% ethyl acetate/hexane) to provide the title compound (0.054 g, 16% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.98 (s, 3H), 3.96-4.05 (m, 4H), 2.52 (s, 3H), 1.61 (s, 6H); LCMS (ES+, (M+H)+) m/z 253.23.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C:9]=2[S:8][C:7]=1[NH2:22])=O)C.C(O)(=O)C.[CH:27](N)=[NH:28]>CN(C=O)C>[C:18]([O:17][C:15]([N:11]1[CH2:10][C:9]2[S:8][C:7]3[N:22]=[CH:27][NH:28][C:4](=[O:3])[C:6]=3[C:14]=2[CH2:13][CH2:12]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: N=CN
Reactant: CCOC(=O)c1c(N)sc2c1CCN(C(=O)OC(C)(C)C)C2
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCc2c(sc3nc[nH]c(=O)c23)C1
Temperature: 100 °C
Yield: 90.7 %

Procedure:
A mixture of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-dicarboxylic acid 6-tert-butyl ester 3-ethyl ester (18.5 g) and formamidine acetate (8.85 g) in DMF (100 mL) were heated at 100° C. for 16 h. The reaction mixture was cooled and concentrated. The residues was partitioned between water and ethyl acetate. The organic layer was washed with water 3 times and concentrated to give the title compound (15.8 g, 90%). 1H NMR (400 MHz, CDCl3): δ 7.88 (s, 1H), 4.56-4.62 (brs, 2H), 3.62-3.70 (brs, 2H), 3.02-3.08 (brs, 2H), 1.42 (s, 9H). LC-MS (ESI) m/z 308.1 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.[CH:19]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25](O)=[O:26])([CH3:21])[CH3:20].C(OCC)(=O)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:14][CH2:15][N:16]([C:25]([C:24]3[CH:28]=[C:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:30]=[CH:31][C:23]=3[O:22][CH:19]([CH3:21])[CH3:20])=[O:26])[CH2:17][CH2:18]1)[CH:7]=[CH:6]2
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1

Procedure:
Prepared in analogy to example 1.1 (b) from 6-chloro-2-piperazin-1-yl-quinoline hydrochloride and 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a yellowish foam.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[NH2:16][C:17]1[CH:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>O>[F:24][C:23]([F:25])([F:26])[C:19]1[CH:18]=[C:17]([NH:16][CH2:2][CH2:3][NH:4][C:5]2[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1ccccc1NCCBr
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1ccccc1NCCNc1cccc(C(F)(F)F)c1
Temperature: 110 °C
Yield: 37.8 %

Procedure:
Ethyl N-(2-bromoethyl)aminobenzoate (3.3 g, 12 mmol), 3-aminobenzotriflouride (1.5 mL, 12 mmol) and triethylamine (2 mL, 14 mmol) were mixed in dimethyltormamide (25 mL). The reaction mixture was heated at 110° C. for five hours. The cooled reaction mixture was poured into water and extracted with diethyl ether. Purification by column chromatography on silica gel using dichloromethane as eluent gave 1.6 g of the desired material.
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)(C1C=CC(C)=CC=1)(=O)=O.[CH3:23][N:24](C=O)C.[C-]#N.[K+]>O>[C:23]([CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)#[N:24]
Reactant: COc1cccc(CCCOS(=O)(=O)c2ccc(C)cc2)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: COc1cccc(CCCC#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A solution of 1-tosyloxy-3-(3-methoxyphenyl)propane (125 g, 0.39 mole) and DMF (400 mL) was stirred at 0° as a solution of KCN (30 g, 0.46 mole) and water (70 mL) was added dropwise. The reaction mixture was stirred at 65°-70° for 1 hour, was cooled to room temperature and poured onto ice water. The solution was extracted with ether. The extracts were washed with water, saturated aqueous NaCl, dried (MgSO4), filtered, and evaporated to yield 62 g yellow oil, (91%), M+ 175.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9]COC)[CH:6]=[CH:5][C:4]=1[C:13]1[C:14]([CH2:26][O:27][C:28](=[O:36])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([CH3:24])([CH3:23])[CH:17]=[C:16]2[CH3:25].Cl.O1CCOCC1>O1CCOCC1.C(OCC)(=O)C>[OH:9][C:7]1[CH:6]=[CH:5][C:4]([C:13]2[C:14]([CH2:26][O:27][C:28](=[O:36])[C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([CH3:24])([CH3:23])[CH:17]=[C:16]3[CH3:25])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COCOc1ccc(-c2ccc3c(c2COC(=O)c2ccc(C)cc2)C(C)=CC(C)(C)N3)c(OC)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(O)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)cc1)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
6-(2-Methoxy-4-methoxymethoxyphenyl)-5-(4-methylbenzoyloxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 2-1, 943 mg, mmol) was dissolved in 1,4-dioxane (9 mL), 4N HCl/1,4-dioxane solution (980 μL) was added thereto, and then the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (100 mL). The mixture was washed with water (80 mL)-saturated aqueous sodium hydrogen carbonate solution (20 mL), and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (687 mg) as a colorless amorphous product. (Yield 80%)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:10][CH3:11])[C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21]>>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[S:20]([NH:9][C:5]1[C:4]([O:10][CH3:11])=[N:3][C:2]([Cl:1])=[C:7]([Cl:8])[N:6]=1)(=[O:22])=[O:21]
Reactant: COc1nc(Cl)c(Cl)nc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Product: COc1nc(Cl)c(Cl)nc1NS(=O)(=O)c1ccc(Cl)cc1Cl

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5,6-dichloro-3-methoxy-2-pyrazinamine (0.1 g) and 2,4-dichlorobenzenesulphonyl chloride (0.15 g). Yield 0.076 g.
Reaction SMILES: [NH2:1]/[C:2](/[CH2:10][F:11])=[C:3](/[F:9])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[Cl:14][C:15]1[CH:26]=[C:25]([F:27])[C:24]([N:28]=[C:29]=[O:30])=[CH:23][C:16]=1[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18]>CN(C)C=O>[Cl:14][C:15]1[CH:26]=[C:25]([F:27])[C:24]([NH:28][C:29]([NH:1][C:2]([CH2:10][F:11])=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[F:9])=[O:30])=[CH:23][C:16]=1[C:17]([O:19][CH:20]([CH3:21])[CH3:22])=[O:18]
Reactant: CC(C)OC(=O)c1cc(N=C=O)c(F)cc1Cl
Reactant: CCOC(=O)/C(F)=C(\N)CF
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(F)=C(CF)NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F
Reaction time: 0.25 h

Procedure:
A solution of 1.80 g of ethyl 3-amino-2,4-difluorocrotonate in 20 ml of absolute dimethylformamide is added dropwise with stirring during 10 minutes to 0.48 g of a 55% sodium hydride dispersion in 25 ml of dimethylformamide at room temperature, and the mixture is stirred for a further 15 minutes. Thereafter 2.81 g of isopropyl 2-chloro-4-fluoro-5-isocyanatobenzoate are added, with the result that the temperature of the reaction mixture rises to 35° C. Then the mixture is stirred for a further two hours at room temperature. The isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-2-fluoro-1-fluoromethyl-vinyl]ureido}-benzoate formed as an intermediate is not isolated.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6](N)[CH:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:8][O:9][C:4]=2[CH:3]=1.[C:19]1(=O)[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[CH2:20]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:18]=[C:17]2[C:5]3=[C:4]([O:9][CH2:8][CH:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[N:6]3[C:19]3[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[C:20]2=3)[CH:3]=1
Reactant: O=C1CCCC(=O)C1
Reactant: Cc1ccc2c(c1)OCC(c1ccccc1)N2N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc2c3c(c1)c1c(n3C(c3ccccc3)CO2)CCCC1=O
Temperature: 106 °C
Yield: 51.6 %

Procedure:
To a mixture of 7-methyl-3-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-amine (5.95 g, 24.8 mmol) in toluene (175 mL) is added while stirring 1,3 cyclohexandione (2.86 g, 25.5 mmol). The mixture is heated to 95° C. for 20 min, at which time p-toluenesulfonic acid monohydrate (4.71 g, 24.8 mmol) is added and the temperature is increased to 106° C. for 1 h. The mixture is refluxed for 12 h, then cooled to room temperature and concentrated. The residue is partitioned between CH2Cl2/1N NaOH. The organic layer is washed with brine, dried over magnesium sulfate and concentrated to dryness. Column chromatography (100 g silica gel) using acetone/hexane (25/75) as eluent gave 4.06 g (51%) of 5-methyl-1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one; mp 171° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[OH:28])[CH:23]=O>>[F:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:15][C:14]([C:12]2[S:13][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[O:16])[CH:25]=[CH:26][C:27]=1[OH:28]
Reactant: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: O=Cc1ccc(O)c(F)c1
Product: O=C(C=Cc1ccc(O)c(F)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
3-(3-Fluoro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)ethanone and 3-fluoro-4-hydroxybenzaldehyde according to general procedure B. The residue is crystallized from acetonitrile.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=2)[N:5]=[C:4]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)[N:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(O)CCC>[CH3:17][S:14]([C:10]1[CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[N:3]=[C:4]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[N:5]=2)[CH:13]=[CH:12][CH:11]=1)(=[O:16])=[O:15]
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1cccc(-c2cc(Cl)nc(Nc3ccc(OC(F)(F)F)cc3)n2)c1
Solvent: CCCCO
Product: CS(=O)(=O)c1cccc(-c2cc(N3CCOCC3)nc(Nc3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
[4-Chloro-6-(3-methanesulfonyl-phenyl)-pyrimidin-2-yl]-(4-trifluoromethoxy-phenyl)-amine (0.14 g, 0.3 mmol) was reacted with morpholine (0.09 mL) in a solvent n-butanol (7 mL) at reflux temperature for 12 hours. Solid was filtered and dried to afford the desired compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH:5]([NH2:10])[C:6]([F:9])([F:8])[F:7])[CH3:2].[C:12]1([CH3:24])[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[S:20](Cl)(=[O:22])=[O:21].S(Cl)(Cl)(=O)=O>N1C=CC=CC=1.Cl>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([NH:10][S:20]([C:13]1[C:14]([CH3:19])=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[CH3:24])(=[O:22])=[O:21])[C:6]([F:7])([F:8])[F:9])[CH3:2]
Reactant: CCOC(=O)C(N)C(F)(F)F
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: Cl
Solvent: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(NS(=O)(=O)c1c(C)cc(C)cc1C)C(F)(F)F
Temperature: 70 °C
Reaction time: 3 h
Yield: 25.3 %

Procedure:
A mixture of 2.10 g (12.3 mmol) of 2-amino-3,3,3-trifluoropropionic acid ethyl ester and 2.80 g (12.8 mmol) of 2-mesitylenesulfonyl chloride in 10 mL of pyridine was warmed at 70° C. After 3 hours, TLC (ethyl acetate-hexanes (2:8)) indicated a new product (PMA stain) that was more polar then sulfonyl chloride. The mixture was then diluted with 1 N aqueous HCl and extracted with three 30 mL portions of ethyl acetate. The combined organic layers were washed with three 30 mL portions of 1 N aqueous HCl, 20 mL of brine, and three 20 mL portions of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate-hexanes (2-6% gradient) to afford 1.1 g (25%) of 3,3,3-trifluoro-2-(2,4,6-trimethylbenzenesulfonylamino)propionic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][CH3:21])[C@H:10]([OH:16])[C:11]([O:13]CC)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].OO.O.[OH-].[Li+]>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][CH3:21])[C@H:10]([OH:16])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC(CC)[C@@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)OCC
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(CC)[C@@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)O

Procedure:
A solution of Example 236B (0.168 g, 0.51 mmol), 30% hydrogen peroxide (0.25 mL, 2.2 mmol), and lithium hydroxide monohydrate (0.042 g, 1.0 mmol) in 3:1 tetrahydrofuran/water (7 mL) was stirred in an ice bath for 3 hours, then concentrated. The residues were taken up in water and the pH adjusted to 10 with NaOH. The solution was washed twice with ether, adjusted to pH 2 with HCl, then extracted twice with ethyl acetate. The ethyl acetate extracts were dried (MgSO4), filtered, then concentrated to provide the desired product.
Reaction SMILES: [OH-].[Na+].[C:3]([O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[S:18])[CH3:17])=[CH:11][CH:10]=1)(=[O:5])[CH3:4]>O.ClCCl>[CH3:17][C:16]1[S:18][C:13]2[CH:14]=[C:9]([CH2:8][CH2:7][O:6][C:3](=[O:5])[CH3:4])[CH:10]=[CH:11][C:12]=2[N:15]=1
Reactant: CC(=O)OCCc1ccc(NC(C)=S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCCc1ccc2nc(C)sc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
K3Fe(CN)6 (7.6 g, 23.1 mmol) was dissolved in water (18 ml) and then mixed with 50 ml 2% NaOH aqueous solution. 4-Thioacetamidophenethyl acetate (1.0 g, 4.1 mmol) was dissolved in dichloromethane (50 ml) and then added to the K3Fe(CN)6 solution. The reaction mixture was stirred at room temperature for 1 hr. The organic layer was separated by a separatory funnel, washed with water, and then dried over anhydrous sodium sulfate. The dried solution was concentrated and then purified by flash silica gel chromatography. Yield: 0.6 g (61%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=2)[CH:3]=1.CCN(C(C)C)C(C)C.[NH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1>C1COCC1>[OH:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][NH:37][C:2]2[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]3[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:3]=2)=[CH:40][CH:41]=1
Reactant: NCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2cc(Cl)nc(OCC(F)(F)F)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1ccc(Nc2cc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Yield: 45.9 %

Procedure:
To a solution of tert-butyl 4-((6-chloro-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzoate (210 mg, 0.52 mmol), and Hunig's Base (0.18 mL, 1.04 mmol) in THF (3 mL) was added 4-(aminomethyl)phenol (96 mg, 0.78 mmol). The resulting mixture was refluxed for 1 hour. After cooling to rt, the solvent was removed and the crude product was purified by silica gel chromatography using 20-40% EtOAc/Hexanes to give tert-butyl 4-((6-((4-hydroxybenzyl)amino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzoate (117 mg, 46%) as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:12]2[C:13]([O:19]C)=[N:14][CH:15]=[CH:16][C:17]=2I)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].Cl.C(N(CC)CC)C.[NH2:29][CH2:30][C@H:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=1)[OH:32]>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:12]2[C:13](=[O:19])[NH:14][CH:15]=[CH:16][C:17]=2[NH:29][CH2:30][CH:31]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)[OH:32])=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(-c2c(I)ccnc2OC)nc1C
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c(-c2c(NCC(O)c3cccc(Cl)c3)cc[nH]c2=O)nc1C
Temperature: 65 °C
Yield: 13.8 %

Procedure:
2-(4-Iodo-2-methoxy-pyridin-3-yl)-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester (0.020 g, 0.052 mmol) was dissolved in acetic acid (1 mL) and concentrated hydrochloric acid (1 mL) and this mixture was stirred at reflux for 2 hours. The mixture was then evaporated and the residue was dissolved in N,N-dimethylformamide (2 mL) and treated with triethylamine (˜22 μL, 0.155 mmol) and the hydrochloric acid salt of (S)-2-amino-1-[3-chlorophenyl]ethanol (0.020 g, 0.096 mmol). The mixture was heated at 65° C. overnight, then the solvent was evaporated and the residue was purified by Prep HPLC (ammonium acetate/acetonitrile/water) to give the title compound (0.003 g, 14%) as a white solid. HPLC 100% (220 nm), LCMS (+ESI, M+H+) m/z 417; 1H NMR (400 MHz, methanol-d4) δ (ppm) (mixture of tautomers): 1.40 and 1.43 (3H, 2t, J=7.1 Hz), 2.49 and 2.61 (3H, 2s), 3.61-3.72 (2H, m), 4.35 and 4.39 (2H, q, J=7.1 Hz), 4.95-4.97 (1H, m), 6.21 and 6.23 (1H, 2d, J=7.6 Hz), 7.19-7.55 (5H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([C:18]1([NH2:37])[N:24]=[C:23]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=2[N:20]([CH3:35])[C:19]1=[O:36])=[O:17])[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([C:18]2([NH2:37])[N:24]=[C:23]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:22]3[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=3[N:20]([CH3:35])[C:19]2=[O:36])=[O:17])[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)C1(N)N=C(C2CCCCC2)c2ccccc2N(C)C1=O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)N=C(C2CCCCC2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one (Example 8-G), the title compound was prepared as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[I:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]I>>[I:9][CH:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: ICCCCCI
Reactant: Oc1ccc(Br)cc1
Product: CCCCC(I)Oc1ccc(Br)cc1

Procedure:
To 4-bromophenol was reacted 1,5-diiodopentane in the presence of an alkali, to obtain 1-(1-iodopentyloxy)-4-bromobenzene {compound (A)}.