Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[CH2:12]([S-:15])[CH2:13][CH3:14].[Na+].O>CN(C=O)C>[N+:9]([C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][S:15][CH2:12][CH2:13][CH3:14])([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: CCC[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCSCc1cccc([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
A solution of 1-(chloromethyl)-3-nitrobenzene (10.0 g, 58.1 mmol) in DMF (30 mL) was stirred at room temperature, then sodium propane-1-thiolate (5.7 g, 58.1 mmol) was added, followed by stirring at 60° C. overnight. After water was added, the aqueous layer was extracted with ethyl acetate 3 times. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated to give (3-nitrobenzyl)(propyl)sulfane (11.2 g, yield 91%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:12]([O:11][C:9]([CH:8]([O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)=[O:10])[CH3:13]
Reactant: OCc1ccc(O)cc1
Reactant: CCOC(=O)Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Oc1ccc(CO)cc1)c1ccccc1

Procedure:
41.8 g (0.172 mol) of ethyl 2-bromo-phenylacetate and 21.3 g (0.172 mol) of 4-hydroxybenzyl alcohol are dissolved in 850 ml of acetone and 24.8 g (0.18 mol) of potassium carbonate and 5.0 g (0.03 mol) of potassium iodide are added thereto. The reaction mixture is refluxed for 60 hours with stirring. Then the inorganic salts are filtered off and the residue is washed with hot acetone. The filtrate is evaporated down and the residue is purified over a silica gel column (particle size: 0.063-0.02 mm), initially using petroleum ether as eluant and then using mixtures of petroleum ether and ethyl acetate of increasing polarity (9:1, 8:2 and 7:3). The unified fractions are evaporated down in vacuo.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[CH:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[N+:15]([O-:17])=[O:16])=[CH:9][CH:8]=1.C1(C=CC(O)=CC=1)O>CC1C=CC=CC=1C>[N+:15]([CH:14]1[CH:13]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:10]2[CH2:9][CH2:8][CH:7]1[CH:12]=[CH:11]2)([O-:17])=[O:16]
Reactant: C1=CCCC=C1
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])C1C2C=CC(CC2)C1c1ccccc1

Procedure:
45.1 g of 1,3-cyclohexadiene (EMKA), 41.9 g of ω-nitrostyrene, 60 g of o-xylene and 1 pinch of hydroquinone are treated in an autoclave at 200° C. and under a nitrogen pressure of 60 bar for 24 hours. The solvent is stripped off and the residue is distilled under a high vacuum. Boiling point 0.05 =120°-160° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][N:19]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([C:40]3([C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[O:44])[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)O1>>[CH3:13][C:10]1[C:9]([NH:14][C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][N:19]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]3[CH:35]=[CH:36][C:37]([C:40]4([C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[O:44])[CH2:42][CH2:41]4)=[CH:38][CH:39]=3)=[CH:3][CH:4]=2)[O:12][N:11]=1
Reactant: CC1(C)OB(c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)OC1(C)C
Reactant: Cc1noc(-c2ccc(Br)cc2)c1Nc1nnc(-c2ccccc2)o1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1Nc1nnc(-c2ccccc2)o1

Procedure:
Prepared according to the procedure described in Example 166, Step 3, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(5-phenyl-[1,3,4]oxadiazol-2-yl)-amine and N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonyl}-methanesulfonamide.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=2)=[N:4][N:3]=1.[C:22](=[N:24]S(Cl)(=O)=O)=[O:23].O>CCOCC>[CH3:16][C:13]([C:11]1[CH:12]=[C:7]([C:5]2[S:6][C:2]([NH:1][C:22]([NH2:24])=[O:23])=[N:3][N:4]=2)[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[OH:17])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(-c2nnc(N)s2)cc(C(C)(C)C)c1O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)c1cc(-c2nnc(NC(N)=O)s2)cc(C(C)(C)C)c1O
Yield: 53.8 %

Procedure:
A suspension of 4-(5-amino-1,3,4-thiadiazol-2-yl)-2,6-bis(1,1-dimethylethyl)-phenol (1.0 g, 0.0032 mole) in ether (5 ml) is added to a 0° C. solution of N-carbonylsulfamyl chloride (0.46 g, 0.0032 mole) in ether (5 ml). The resulting mixture is stirred 15 minutes before water (10 ml) is added. The mixture is diluted with ether and washed with 2M HCl and saturated aqueous NaCl. Extract with aqueous 1M NaOH (3×). The combined aqueous layers are made acidic with aqueous 2M HCl. The resulting precipitate is filtered and washed with water to provide 0.6 g (1.2 g theor., 53%) of N-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-yl]-urea after drying in vacuo at 50° C.; mp >270° C.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]1([C:18]2[NH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C(C)=CC=CC=1>[C:12]1([C:18]2[NH:19][C:20]3[C:25]([C:26]=2[C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1C
Product: O=C(O)c1ccccc1C(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Temperature: 110 °C
Yield: 62.1 %

Procedure:
A suspension of 14.8 g (0.10 mole) of phthalic anhydride, 10.5 g (0.05 mole) of 2-phenylindole and 82 ml of xylene was heated to 110° C. briefly, cooled to and maintained at 95° C. for approximately two hours. The solution was cooled to ambient temperature and the solid which separated was collected by filtration and dried to obtain 10.6 g of 2-[(2-phenyl-3-indolyl)carbonyl]benzoic acid (Formula VIII: R°=R1 =R2 =R3 =R6 =Y1 =H; R5 =C6H5) which melted at 106°-107° C. and had a nuclear magnetic resonance spectrum consistent with the assigned structure.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16](O)=[S:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:20][NH:21][O:22][CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH3:23][O:22][N:21]([CH3:20])[C:16]([C:8]1[NH:9][C:10]2[C:15]([C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[S:17]
Reactant: OC(=S)c1[nH]c2ccccc2c1-c1ccccc1
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CON(C)C(=S)c1[nH]c2ccccc2c1-c1ccccc1

Procedure:
The title compound was prepared from 3-phenylthioindole-2-carboxylic acid (1.0 g, 3.7 mmol), N,O-dimethylhydroxylamine hydrochloride (0.54 g, 5.5 mmol), triethylamine (1.5 mL, 11 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorphosphate (1.64 g, 3.7 mmol) according to the procedure described in Example 1 for N-(3-pyridylmethyl)-5-chloro-3-phenylthio-2-carboxamide.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH2:11][CH2:10]1)(=O)=O.[NH2:23][C:24]1[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=1[C:26]([N:28]([CH3:30])[CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:12]1[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][CH2:6][NH:23][C:24]2[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=2[C:26]([N:28]([CH3:30])[CH3:29])=[O:27])[CH2:10][CH2:11]1
Reactant: CN(C)C(=O)c1ccccc1N
Reactant: COc1ccccc1N1CCN(CCCOS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccccc1N1CCN(CCCNc2ccccc2C(=O)N(C)C)CC1
Yield: 62.4 %

Procedure:
A mixture of 3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl methanesulfonate (2 g, 6.06 mmol), 2-amino-N,N-dimethylbenzamide (1 g, 6.06 mmol), prepared as in Example 22, and potassium carbonate (2.1 g, 15 mmol) in 50 mL of acetonitrile was heated at reflux for 30 hours. The mixture was poured into water and extracted with ethyl acetate. The organic phase was dried (K2CO3) and concentrated. The residue was purified on silica gel by flash chromatography eluting with 6% methanol/methylene chloride to give 2-{3-[4-(2-methoxyphenyl)-piperazin-1-yl]propylamino}-N,N-dimethylbenzamide (1.5 g, 3.78 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][OH:20]>>[OH:20][CH2:19][CH2:18][CH2:17][N:10]1[CH2:9][CH2:8][C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:15][CH:14]=2)([OH:13])[CH2:12][CH2:11]1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Reactant: OCCCBr
Product: Cc1ccc(CC2(O)CCN(CCCO)CC2)cc1

Procedure:
The title compound, MS: m/e=263.3 (M+) was prepared from 4-(4-methyl-benzyl)-piperidin-4-ol and 3-bromo-1-propanol.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13](=[O:15])[CH3:14].Br[CH2:17][CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:19][CH2:18][CH2:17][O:1][CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13](=[O:15])[CH3:14])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCCOCc1ccccc1
Reactant: CC(=O)N1Cc2ccccc2C[C@H]1CO
Product: CC(=O)N1Cc2ccccc2C[C@H]1COCCOCc1ccccc1
Yield: 63.3 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 116B, (S)-1-(3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (Intermediate 116A, 40.0 mg, 0.20 mmol) and ((2-bromoethoxy)methyl)benzene (92 μl, 0.58 mmol) were converted to the title compound (43 mg, 65%) after purification by flash column chromatography (gradient from 0% to 50% EtOAc/hexanes). 1H NMR (CDCl3, 2:1 mixture of amide rotamers) δ 7.41-7.25 (m, 5H), 7.24-7.06 (m, 4H), 5.10 (d, J=18.0 Hz, 1H), 4.66-4.44 (m, 3H), 4.39 (q, J=5.9 Hz, 0.5H), 4.26 (d, J=17.8 Hz, 0.5H), 3.68-3.47 (m, 5H), 3.44-3.27 (m, 1.5H), 3.10 (dd, J=5.8, 16.0 Hz, 0.5H), 3.01-2.80 (m, 1H), 2.24 (s, 2H), 2.19 (s, 1H); MS(ESI+) m/z 340.2 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7]Br)=[CH:3][CH:2]=1.[CH:9]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([F:22])=[CH:19][C:20]=2[F:21])=[CH:13][C:12]([C:23]([OH:25])=[O:24])=[C:11]([OH:26])[CH:10]=1.O>CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[F:21][C:20]1[CH:19]=[C:18]([F:22])[CH:17]=[CH:16][C:15]=1[C:14]1[CH:9]=[CH:10][C:11]([OH:26])=[C:12]([C:23]([O:25][CH2:7][C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)=[O:24])[CH:13]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: O=C(OCc1ccccc1)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.9 %

Procedure:
BnBr (1.35 mL, 11.286 mmol) was added to a solution of diflunisal (2.0 g, 7.99 mmol) in TBAF (10 mL, 1 M solution in THF) and the reaction mixture was stirred at r.t. overnight (18 h). The organic layer was poured into H2O (15 mL) and extracted with EtOAc (40 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (hexanes) to furnish 2.09 g of benzyl 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate (white solid, yield: 77%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH2:36][CH2:37][O:38][CH3:39])=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH2:36][CH2:37][O:38][CH3:39])=[N:22][C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=3)=[N:24][CH:25]=2)=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CCl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2CCOC)cc1C

Procedure:
In analogy to the procedures described in example 101A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 110B]) to give the title compound as light yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:28])[CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32](=[O:49])[CH2:33][C:34]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=1)[CH3:30]>>[CH2:29]([O:31][C:32](=[O:49])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]([OH:28])[CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=3)=[CH:6][CH:7]=2)=[CH:36][CH:35]=1)[CH3:30]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)COCc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3C(O)COCc3cccc(C(F)(F)F)c3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-(3-trifluoromethyl-benzyloxy)-ethanol and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>N1C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:29])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CN=C(c2ccccn2)c2cc(Cl)ccc2N1
Solvent: c1ccncc1
Product: S=C1CN=C(c2ccccn2)c2cc(Cl)ccc2N1
Temperature: 100 °C
Reaction time: 2 h
Yield: 185.1 %

Procedure:
A solution of 18.5 g of 7-chloro-5-(2-pyridyl)-3H-1,4-benzodiazepin-2(1H)-one (N. Ch. Hindley, T. M. McClymont & G. O. Chase; F. Hoffmann La Roche and Co., A. G., German Offenlegungsschrift 2,233,483, 1973) in 150 ml of pyridine was treated with 14.2 g of Lawesson reagent and the mixture was stirred at 100° C. for 2 h. After the addition of 1.0 g of Lawesson reagent the mixture was stirred at 100° C. for a further 0.5 h. and then evaporated in a vacuum. The residue was poured into 500 ml of saturated aqueous sodium hydrogen carbonate solution and the precipitate was filtered off (22 g). The red crystals were suspended in 100 ml of boiling methanol. After cooling 100 ml of diethyl ether were added and the crystals were filtered off. There were obtained 18.7 g of 7-chloro-5-(2-pyridyl)-3H-1,4-benzodiazepine-2(1H)-thione of m.p. 217-218° C.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([Br:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:16](OC(=O)C)(=[O:18])[CH3:17].S(=O)(=O)(O)O>>[C:16]([O:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([Br:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCc1c(Br)ccc(C(=O)OC)c1O
Agent: O=S(=O)(O)O
Product: C=CCc1c(Br)ccc(C(=O)OC)c1OC(C)=O

Procedure:
254 g of methyl 2-hydroxy-3-allyl-4-bromobenzoate and 191 g of acetic anhydride were introduced into a 1-liter round-bottomed flask and 2 ml of sulphuric acid were then added.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8]2[C:9]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([CH3:24])([CH3:23])[CH3:22])=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:4][C:3]=1[C:25]([F:28])([F:27])[F:26].[O:29](C(OC(C)(C)C)=O)[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=O.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[Br:1][C:2]1[S:6][C:5]([N:7]([C:8]2[C:9]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([CH3:24])([CH3:22])[CH3:23])=[N:10][CH:11]=[CH:12][CH:13]=2)[C:30](=[O:29])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[N:4][C:3]=1[C:25]([F:27])([F:26])[F:28]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc(C(F)(F)F)c(Br)s1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1nc(C(F)(F)F)c(Br)s1)c1cccnc1Oc1ccccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of N-(5-bromo-4-(trifluoromethyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine (Example 323a, 135 mg, 0.29 mmol), BOC2O (75 mg, 0.34 mmol), DMAP (5 mg) and DIPEA (59 μL, 0.34 mmol) in THF (5 mL) was stirred at rt for 5 h. The solvent was removed and the residue was purified by flash chromatography (silica, 0-50% EtOAc/hexane gradient) provided Example A125a (149 mg) as a white foam. (M+H)+=574.2.
Reaction SMILES: [OH-:1].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([C:10](N)=[O:11])[CH:7]=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14].Cl>O>[NH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:1])=[O:11])[CH:7]=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14]
Reactant: [OH-]
Reactant: NC(=O)c1ccc(C(F)(F)F)c(N)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1cc(C(=O)O)ccc1C(F)(F)F

Procedure:
Into 160 ml. of water containing 9.6 g. of sodium hydroxide is suspended 16 g. of 2-amino-α,α,α-trifluoro-p-toluamide. The solution is refluxed 5 hours, then cooled, poured onto ice and acidified to a pH of 6 with concentrated hydrochloric acid. The resultant precipitate is filtered, washed with water and dried in vacuo to yield 2-amino-α,α,α-trifluoro-p-toluic acid (4-trifluoromethylanthranilic acid), m.p. 175°-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH2:26])=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH:26][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: Cc1nc(NC(=O)c2cccc(Cl)c2)sc1C(=O)NCc1ccccc1
Yield: 32 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 3-chlorobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 32% yield; m.p. 178-179° C.; 1H NMR (CDCl3, 300 MHz) δ 8.05 (t, J=1.6 Hz, 1H), 7.86 (ddd, J=1.1, 1.6, and 7.8 Hz, 1H), 7.59-7.27 (m, 7H), 5.98 (t, J=5.3 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H), 2.57 (s, 3H); MS (ES+) m/z 386 (M+1).
Reaction SMILES: [BrH:1].[Br:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].[NH2:10][C:11]([NH2:13])=[S:12]>CCO>[BrH:2].[BrH:1].[CH3:9][C:8]1[N:7]=[CH:6][NH:5][C:4]=1[CH2:3][S:12][C:11](=[NH:10])[NH2:13]
Reactant: Cc1[nH]cnc1CBr
Reactant: NC(N)=S
Agent: Br
Solvent: CCO
Product: Cc1nc[nH]c1CSC(=N)N

Procedure:
A mixture of 12.8 g of 4-bromomethyl-5-methyl imidazole hydrobromide and 4 g. of thiourea in 200 ml. of EtOH is heated at reflux for 3 hr., cooled and the product is filtered off to give the title compound, m.p. 130°-132° C. (dec.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[NH2:24])=[O:20]>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:24][C:23]2[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:21]([C:19]([O:18][CH3:17])=[O:20])[CH:22]=2)=[N:3][CH:4]=1
Reactant: COC(=O)c1cc(N)ccc1OC
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: COC(=O)c1cc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)ccc1OC

Procedure:
In like manner to the preparation of 5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 3-methyloxycarbonyl-4-methoxyaniline were reacted to yield 5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-methyloxycarbonyl-4-methoxyphenyl)-2,4-pyrimidinediamine R940301. 1H NMR (DMSO-d6): δ 9.93 (1H, s), 9.79 (1H, s), 9.54 (1H, s), 8.26 (1H, s, J=4.5 Hz), 7.92 (1H, s), 7.81 (1H, dd, J=9.3 Hz, J=2.7 Hz), 7.32 (1H, d, J=8.1 Hz), 7.20-7.13 (3H, m), 6.64 (1H, d, J=8.1 Hz), 3.89 (3H, s), 3.84 (3H, s); purity: 97%; MS (m/e): 385 (MH+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:15]O>CCOC(C)=O>[CH3:15][O:11][C:10](=[O:12])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: CO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 89 %

Procedure:
Into a solution of 3-trifluoromethylphenylacetic acid (20.0 g. 98 mmol) in MeOH (100 mL), cooled in an ice-water bath, was bubbled HCl (g) for 15 min. The mixture was allowed to warm to room temperature and was then concentrated in vacuo to furnish a clear, yellow-green liquid which was diluted with EtOAc (0.25L) and washed with saturated aqueous NaHCO3 (2×0.25L), brine (0.25L), and dried (Na2SO4). Concentration in vacuo provided the crude ester which was purified by chromatography on a column of silica gel(230-400 mesh, 600 g, 70 mm o.d., ethyl acetate-hexanes 10:90, 400 mL fractions) using the flash technique. Fractions 6-9 provided 19.08 g (89%) of methyl-3-trifluoromethylphenylacetate as a clear colorless liquid.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)(=O)C.CCOCC>C(Cl)Cl>[C:37]([O:36][C:34]([N:31]1[CH2:32][CH2:33][CH:28]([CH:25]=[C:1]([Br:5])[Br:2])[CH2:29][CH2:30]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: BrC(Br)(Br)Br
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(C=C(Br)Br)CC1
Reaction time: 0.67 h
Yield: 79.8 %

Procedure:
A solution of 48.615 g (146.6 mmole) carbon tetrabromide in 150 mL DCM was added dropwise with stirring to a solution of 76.895 g (293.2 mmole) triphenylphosphine in 150 mL DCM in a 1-L rb flask with ice bath cooling over 1.75 hours. After 40 minutes, a solution of 15.631 g (73.29 mmole) 1-(t-butoxycarbonyl)-4-formyl-piperidine (from Step 2 above) in 100 mL DCM was added to the resulting brown suspension with stirring and cooling over 40 minutes. After one hour, 200 mL ether and 400 mL hexanes was added. The top suspension was filtered through Celite, and the residue was resuspended in 150 mL DCM and treated with 300 mL ether. The mixture was filtered, and the solid was washed with hexanes till total filtrate was 2 L. The filtrate was filtered again through Celite and washed with hexanes. The filtrate was washed with 100 mL 5% NaHCO3, 300 mL water (2×), and 150 mL brine. The organic layer was dried over Na2SO4 and concentrated under vacuum to give 53.458 g crude product as a yellowish solid. Flash chromatography (PC) on 250 g silica gel (0-15% EtOAc in hexanes) gave 21.595 g title compound as a white solid. RF: 0.57 (15% EtOAc in hexanes); 1H NMR (500 MHz) δ 6.25 (d, J=8.9 Hz, 1H), 4.04-4.12 (m, 2H), 2.75-2.83 (m, 2H), 2.42-2.50 (m, 1H), 1.69-1.75 (m, 2H), 1.47 (s, 9H), 1.29-1.37 (m, 2H).