Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[CH2:13])[CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8].N1C=CN=C1.[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20].O>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9](=[CH2:13])[CH2:10][CH2:11][O:12][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:25])[CH3:24])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C(CCO)c1ccc(F)c(Br)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(CCO[Si](C)(C)C(C)(C)C)c1ccc(F)c(Br)c1
Yield: 95 %

Procedure:
The compound (2.17 g, 8.85 mmol) obtained in Example 91b was dissolved in methylene chloride (33 mL), imidazole (0.90 g, 13.3 mmol) and tert-butyl(chloro)dimethylsilane (1.60 g, 10.6 mmol) were added with stirring under ice cooling, and the mixture was stirred at room temperature under a nitrogen atmosphere for 20 hours. After the reaction was completed, water was added, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1, v/v) to give the title compound (3.02 g; yield, 95%) as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([NH:15]C(=O)C(C)(C)C)[NH:9][C:8](=[O:22])[C:7]=3[C:6]=2[CH:23]=1.[OH-].[Na+]>>[NH2:15][C:10]1[NH:9][C:8](=[O:22])[C:7]2[C:6]3[CH:23]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=3[CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CC(C)(C)C(=O)Nc1nc2ccc3ccc(N)cc3c2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc2ccc3nc(N)[nH]c(=O)c3c2c1

Procedure:
N-(9-Amino-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.065 g, 0.2 mmole) was reacted with aqueous sodium hydroxide in the same manner as in example 2. The product was precipitated from the basic reaction mixture with acetic acid, filtered and washed with water to give 3,9-diaminobenzo[f]quinazolin-1(2H)-one as a tan solid. (0.04 g, 84%) 1H NMR (DMSO-d6, 300 MHz) δ: 5.54 (br s, 2H, NH2); 6.35 (br s, 2H, NH2); 6.80 (dd, J=8.5, 2.3 Hz, 1H, Ar); 6.87 (d, J=8.6 Hz, 1H, Ar); 7.52 (d, J=8.6 Hz, 1H, Ar); 7.73 (d, J=8.6 Hz, 1H, Ar); 8.73 (s, 1H, Ar); 10.91 (br s, 1H, NH).
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]([C@@H:8]2[CH2:12][C@H:11]([S:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:10][N:9]2[CH3:23])=[O:7])[CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=[O:35]>C(Cl)Cl.C(OCC)(=O)C>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][S:13][C@@H:11]2[CH2:10][N:9]([CH3:23])[C@H:8]([C:6]([N:4]3[CH2:5][CH:2]([NH:1][C:34]([O:36][CH2:37][C:38]4[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=4)=[O:35])[CH2:3]3)=[O:7])[CH2:12]2)=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(N)C3)N(C)C2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C)C2)cc1
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
0.60 g of (2S, 4S)-2-(3-aminoazetidin-1-ylcarbonyl]-4-(4-methoxybenzylthio)-1-methylpyrrolidine [prepared as described in step (a) above] was dissolved in 18 ml of methylene chloride, and 0.38 ml of diisopropylethylamine and 0.46 g of p-nitrobenzyl chloroformate were added to the resulting solution, whilst ice-cooling, after which the mixture was stirred at the same temperature for 30 minutes. At the end of this time, the reaction mixture was diluted with ethyl acetate and washed with water and with an aqueous solution of sodium chloride, in that order. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography (silica gel 60 9385, manufactured by Merck, 40 g), to give 0.85 g of the title compound, in the form of an amorphous powder, from the fraction obtained by elution with a 95:5 by volume mixture of ethyl acetate and methanol.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)[CH:8]=[O:9].[Si]([O:18][CH:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)(C(C)(C)C)(C)C>C(OCC)(=O)C>[Cl:3][C:22]1[CH2:23][CH2:24][CH:19]([OH:18])[CH2:20][C:21]=1[CH:8]=[O:9]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=CC1=C(Cl)CCC(O)C1

Procedure:
Phosphorus oxychloride (4.08 mL) was added to cooled (−10° C.) N,N-dimethylformamide (20 mL). The temperature was maintained below 0° C. Stirring was continued for another 30 minutes before the addition of 4-(tert-butyldimethylsilyloxy)cyclohexanone (10 g). The mixture was then stirred at room temperature for 2 hours before it was diluted with ethyl acetate (300 mL) and washed with water (3×), brine and dried over Na2SO4. After filtration and concentration, the crude product was used directly in the next reaction without further purification.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:36].[C:37](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.C(OCC)(=O)C>[C:31]([O:30][C:29](=[O:35])[NH:28][C:24]1([C:21]2[CH:22]=[CH:23][C:18]([C:9]3[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][C:5]4[N:4]([CH3:37])[C:3](=[O:36])[CH:2]([CH3:1])[O:7][C:6]=4[N:8]=3)=[CH:19][CH:20]=2)[CH2:25][CH2:26][CH2:27]1)([CH3:32])([CH3:34])[CH3:33]
Reactant: O=C([O-])[O-]
Reactant: CC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2NC1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N(C)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.6 %

Procedure:
A solution of tert-butyl 1-(4-(3-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (50 mg, 0.103 mmol) in DMF (2 ml) was added potassium carbonate (42.7 mg) and iodomethane (7.69 μl, 0.124 mmol). The reaction mixture was stirred at room temperature for 48 h then was diluted with ethyl acetate (20 ml). Washed with water, brine, and dried with Na2SO4, filtered and concentrated to give product 43 mg. 1H NMR (500 MHz, CDCl3): 7.19-7.32 (m, 10H), 4.96 (q, 1H), 3.39 (s, 3H), 2.43-2.48 (m, 4H), 2.04 (m, 1H), 1.79 (m, 1H), 1.70 (d, 3H), 1.24-1.36 (m, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10](I)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]2[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1)#[CH:15].CN.C(O)C>CC(N(C)C)=O.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.[Cu]I.O>[OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:15]#[C:14][C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:25][C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=3)(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C#Cc1ccc(S(=O)(=O)Nc2ncccc2C)cc1
Reactant: CCOC(=O)c1cc(I)ccc1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CN
Solvent: O
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3ncccc3C)cc2)ccc1O
Yield: 77.9 %

Procedure:
Dichlorobis(triphenylphosphine)palladium (0.07 g, 0.1 mmol) and copper(I)iodide (0.04 g, 0.2 mmol) were added to a solution of ethyl 2-hydroxy-5-iodobenzoate (14.9 g, 50 mmol) and 4-ethynyl-N-(3-methyl-2-pyridinyl)benzenesulfonamide (14.3 g, 50 mmol) in methylamine (10 g, 0.1 mol) and dimethylacetamide (60 ml) at 65° C. Hot ethanol was added after 1 h and then hot water (100 ml) with stirring. The solid was filtered off after cooling in the refrigerator and recrystallized from formic acid and water to yield 17.0 g (77%) product.
Reaction SMILES: N1(C(C2CCCCC2C(O)=O)=O)CCOCC1.[Cl:18][C:19]1[CH:34]=[CH:33][C:22]2[NH:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=3)=[N:25][C:21]=2[CH:20]=1.[CH3:35][O:36][C:37](=[O:50])[C@H:38]([CH2:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)[CH2:39][C:40](O)=[O:41]>>[CH3:35][O:36][C:37](=[O:50])[CH:38]([CH2:43][CH:44]1[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1)[CH2:39][C:40]([NH:32][C:29]1[CH:28]=[CH:27][C:26]([C:24]2[NH:23][C:22]3[CH:33]=[CH:34][C:19]([Cl:18])=[CH:20][C:21]=3[N:25]=2)=[CH:31][CH:30]=1)=[O:41]
Reactant: Nc1ccc(-c2nc3cc(Cl)ccc3[nH]2)cc1
Reactant: COC(=O)[C@@H](CC(=O)O)CC1CCCCC1
Agent: O=C(O)C1CCCCC1C(=O)N1CCOCC1
Product: COC(=O)C(CC(=O)Nc1ccc(-c2nc3cc(Cl)ccc3[nH]2)cc1)CC1CCCCC1
Yield: 51 %

Procedure:
This compound was prepared by the procedure described in Example 1 part (a) from 4-(5-Chloro-1H-benzoimidazol-2-yl)-phenylamine and (R)-2-(Cyclohexylmethyl) succinic acid 1-methyl ester to give the crude product (2.0 g, 51%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.C(N(CC)C(C)C)(C)C.[C:40]1([S:46](Cl)(=[O:48])=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([OH:30])[CH2:25][CH2:26][N:27]([S:46]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)(=[O:48])=[O:47])[CH2:28][CH2:29]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCNCC3)s2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCN(S(=O)(=O)c4ccccc4)CC3)s2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[5-(3-Methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-4-ol (Example 46, 50 mg, 0.115 mmol) was dissolved in CH2Cl2 (1 mL). N,N-diisopropylethyl-amine (50 μL, 0.287 mmol) and benzenesulfonyl chloride (29 μL, 0.230 mmol) were added sequentially. The solution was stirred overnight at room temperature, then concentrated in vacuo on a Genevac. The resultant residue was dissolved in DMSO and purified via HPLC (48-82% CH3CN:H2O) to provide 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1-(phenylsulfonyl)piperidin-4-ol. MS ESI: [M+H]+ m/z 576.1. 1H NMR (600 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.80 (d, J=5.2 Hz, 1H), 7.93 (d, J=9.2 Hz, 2H), 7.75 (dd, J=8.7, 10.3 Hz, 2H), 7.73 (s, 1H), 7.65 (t, J=8.1 Hz, 1H), 7.43 (s, 1H), 7.25 (d, J=5.1 Hz, 1H), 7.12 (s, 1H), 6.10 (s, 1H), 3.54 (d, J=12.3 Hz, 1H), 2.58 (t, J=12.3 Hz, 2H), 2.54-2.37 (m, 1H), 2.28 (s, 3H), 2.08 (t, J=16.1 Hz, 2H), 1.80 (d, J=14.6 Hz, 2H). rhSYK activity=++
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[CH2:15]([NH2:18])[CH:16]=C.C=O>C(O)C>[O:7]1[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH:16]=[CH:15][NH:18]1
Reactant: Oc1ccccc1
Reactant: C=CCN
Agent: C=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2ON1
Yield: 75.5 %

Procedure:
At room temperature, phenol was dissolved in anhydrous ethanol; the pH was adjusted to 8-10; toluene, allyl amine and paraformaldehyde were added according to the molar ratio of phenolic hydroxyl group:amine group:aldehyde group of 1:0.8:1.5. After being homogeneously stirred, the mixture was heated and refluxed, reacted for 4 h to vacuum distill off ethanol, toluene, and placed in a cooling unit. Butanone was added to obtain a yellowish, translucent viscous body. The viscous body was washed, purified and dried to obtain a benzoxazine intermediate having the following structural formula, wherein the yield is 75.5%.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:14][CH:13]=2)[CH:8]=[C:7]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[N:6]=1)(=O)=O.CCN(C(C)C)C(C)C.[NH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=1>C1COCC1>[OH:48][C:45]1[CH:46]=[CH:47][C:42]([CH2:41][NH:40][C:5]2[N:10]=[C:9]([NH:11][C:12]3[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:14][CH:13]=3)[CH:8]=[C:7]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[N:6]=2)=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2cc(OCC(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Reactant: NCc1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(Nc2cc(OCC(F)(F)F)nc(NCc3ccc(O)cc3)n2)cc1
Yield: 81.6 %

Procedure:
To a solution of tert-butyl 4-((2-(methylsulfonyl)-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzoate (80 mg, 0.18 mmol), and Hunig's Base (0.062 mL, 0.36 mmol) in THF (1 mL) was added 4-(aminomethyl)phenol (44 mg, 0.36 mmol). The resulting mixture was stirred at r.t for 16 hs. The solvent was removed and the crude product was purified by silica gel chromatography using 40-70%-100% EtOAc/Hexanes to give tert-butyl 4-((2-((4-hydroxybenzyl)amino)-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzoate (72 mg, 83%) as white solid.
Reaction SMILES: [F:1][CH:2]([F:18])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[Cl:19][CH2:20][C:21](Cl)=[O:22].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Cl:19][CH2:20][C:21]([C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:8]=[CH:7][C:6]([S:3]([CH:2]([F:1])[F:18])(=[O:5])=[O:4])=[CH:11][CH:10]=2)=[CH:13][CH:14]=1)=[O:22]
Reactant: O=C(Cl)CCl
Reactant: O=S(=O)(c1ccc(-c2ccccc2)cc1)C(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCl)c1ccc(-c2ccc(S(=O)(=O)C(F)F)cc2)cc1
Temperature: 27.5 °C
Reaction time: 13 h
Yield: 82 %

Procedure:
To a 500-mL sidearm flask equipped with a vented addition funnel, overhead stirrer, thermometer, and nitrogen bubbler connected to a caustic scrubber was charged 26.8 g (0.098 mol, assay=98%) 4-[(difluoromethyl)sulfonyl]-1,1'-biphenyl, of 13.4 g (0.20 mol) of chloroacetyl chloride, and 150 mL of dichloromethane. Granular anhydrous aluminum chloride (28.0 g, 0.210 mol) was added in portions over 20 minutes, and the mixture was allowed to stir at 25-30° C. for 8-18 h. The violet solution was poured onto 300 g of ice with efficient stirring, 300 mL of dichloromethane was added to the resulting yellow slurry, and the mixture was filtered to remove undissolved 4'-(chloroacetyl)[1,1'-biphenyl]-4-sulfinic acid. After phase separation, the dichloromethane solution was washed with aqueous HCl, aqueous NaHCO3, dried with MgSO4, filtered, and concentrated to dryness. The residue was slurried in 200 mL of isopropanol, filtered, and washed with 50 mL of isopropanol to afford 27.7 g (ca. 79%) of crude 2-chloro-1-[4'-[(difluoromethyl)sulfonyl][1,1'-biphenyl]-4-yl]ethanone as a pale yellow solid assaying at 96% by gc-area. A 98%-pure sample was obtained by chromatography on silica-gel and crystallization from EtOAc/hexane, m.p. 157-159° C. IR(KBr) 1696, 1604, 1594, 1397, 1344, 1308, 1210, 1168, 1118, 1081, 999, 816, 750, 631 cm-1. UV (CH2Cl2): λmax =287 nm (ε=33.1×103) 1H-NMR (CDCl3): δ4.75 (s, 2H), 6.25 (t, 1H, J=60 Hz), 7.77 (d, 2H), 7.89 (d, 2H), 8.10 (2 d, 4H). 13C-NMR (DMSO-d6): δ47.6, 114.7 (t, JCF =283 Hz), 191.3 ppm. 19F-NMR (CDCl3): δ-121.6 ppm (d, JHF =53 Hz). Mass spectrum m/z=344 (M+), 295 (M+ --CH2Cl, base peak), 245, 229, 180, 165, 152 amu.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)N.[I-:14].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([I:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Reactant: [I-]
Agent: [K+]
Product: COc1cc(I)cc(C(F)(F)F)c1

Procedure:
Using conventional procedures 3-methoxy-5-trifluoromethylaniline (J. Chem. Soc., 1951, 2013) was diazotised and reacted with potassium iodide to give 3-methoxy-5-trifluoromethyliodobenzene, as an oil. The product so obtained was reacted with boro tribromide using the conditions described in Note b. above to give 3-hydroxy-5-trifluoromethyliodobenzene in 95% yield, as an oil. The product so obtained was reacted with 2-bromomethylnaphthalene using the conditions described in Example 1 to give 3-(naphth-2-ylmethoxy)-5-trifluoromethyliodobenzene in 62% yield, m.p. 65°-66° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][NH:11][C:12](=[O:31])[C@H:13]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:14][N:15]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:16]=[O:17])[C:3]=1[F:32].Cl.[NH:34]1[CH2:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>CS(C)=O>[N:34]1([C:2]2[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][NH:11][C:12](=[O:31])[C@H:13]([CH2:25][CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:14][N:15]([O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH:16]=[O:17])[C:3]=2[F:32])[CH2:37][CH2:36][CH2:35]1
Reactant: CSc1nc(Cl)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)n1
Reactant: C1CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CSc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c(F)c(N2CCC2)n1
Temperature: 67.5 °C
Reaction time: 72 h
Yield: 65.3 %

Procedure:
To a pressure tube was added [(2R)-3-{2-[6-chloro-5-fluoro-2-(methylthio)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.100 g, 0.204 mmol), azetidine hydrochloride (19.1 mg, 0.204 mmol), DIPEA (71.2 μL, 0.408 mmol) and DMSO (2 mL). The tube was sealed and was heated to 65-70° C. with stirring for 3 days. The reaction mixture was then cooled to RT and purified by RP-HPLC to afford [(2R)-3-{2-[6-(1-azetidinyl)-5-fluoro-2-(methylthio)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (68 mg, 65%). LCMS: (M+H)+: 511.2.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[C:37]([C:38]([F:39])([F:41])[F:40])[C:30]=3[F:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1F
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Fc1c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cccc1C(F)(F)F

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2-fluoro-3-trifluoromethyl benzaldehyde. MS (ESI) m/z 555.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]([NH2:10])[C@H:2]1O.[OH-:12].[K+].[C:14](OCC)(=O)C.CCCCCC>CC(O)C.[Ru](Cl)Cl.C1C=CC=CC=1.[Ru]>[NH2:10][C:3]1[CH:2]=[CH:14][CH:1]=[C:9]2[C:4]=1[CH2:5][C@@H:6]([OH:12])[CH2:7][CH2:8]2
Reactant: CCOC(C)=O
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: [OH-]
Agent: Cl[Ru]Cl
Agent: [Ru]
Agent: [K+]
Solvent: CC(C)O
Solvent: c1ccccc1
Solvent: CCCCCC
Product: Nc1cccc2c1C[C@@H](O)CC2
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
Benzene ruthenium(II)chloride dimmer (0.17 g, 0.0008 mol, 0.02 eq), (1R,2S)-(+)-cis-1-Amino-2-indanol (0.207 g, 0.0013 mol, 0.08 eq) were taken in nitrogen bubbled IPA (50 ml). This solution was heated at 80° C. for 20 min and cooled back to RT. Step-a product (2.8 g, 0.017 mol) was taken in nitrogen bubbled IPA (78 ml), a solution of KOH (0.19 g, 0.0034 mol, 0.2 eq) in IPA (40 ml) and the earlier prepared ruthenium solution were added drop wise simultaneously at RT. The overall reaction mixture was heated to 50° C. and stirred for 30 min at the same temperature. Progress of the reaction was monitored by TLC (50% ethyl acetate/hexane, Rf˜0.2). On completion of the reaction, cooled the reaction contents to rt, filtered on a silica gel bed and the bed was washed with ethyl acetate (2×30 ml). Filtrate was concentrated under reduced pressure, residue was taken in DCM (75 ml) and treated with charcoal. Filtered the contents over a silica gel bed and the bed washed with DCM (4×30 ml). DCM was distilled off completely and the crude obtained was purified by column chromatography (silica gel, 20% ethyl acetate/hexane) to yield the titled product as a red colored solid (1.8 g, 63% yield, mp 89-94° C.).
Reaction SMILES: N1C=CC=CC=1.[C:7]([CH2:10][C:11]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])([OH:9])=O.[CH3:22][CH2:23][O:24]CC>C(OC(=O)C)(=O)C>[C:23]([CH:10]1[C:11]2[C:12](=[CH:16][CH:17]=[C:18]([O:20][CH3:21])[CH:19]=2)[C:13](=[O:14])[O:15][C:7]1=[O:9])(=[O:24])[CH3:22]
Reactant: CCOCC
Reactant: COc1ccc(C(=O)O)c(CC(=O)O)c1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)C(C(C)=O)C(=O)OC2=O
Reaction time: 16 h

Procedure:
Pyridine (5.0 ml, 62 mmol) is added slowly to suspension of 2-carboxymethyl-4-methoxy-benzoic acid (10 g, 48 mmol) in acetic anhydride (80 ml) at 0° C. After stirring for 16 h, ether (100 ml) is added. The resulting solid is collected and dried to give 10 g of 4-acetyl-6-methoxy-isochroman-1,3-dione.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[S:5](=[O:15])(=[O:14])[N:4]([CH3:16])[C:3]=1[C:17]([O:19]C)=O.[NH2:21][C:22]1[S:23][C:24]([CH3:27])=[CH:25][N:26]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[S:5](=[O:14])(=[O:15])[N:4]([CH3:16])[C:3]=1[C:17]([NH:21][C:22]1[S:23][C:24]([CH3:27])=[CH:25][N:26]=1)=[O:19]
Reactant: COC(=O)C1=C(O)c2cc(OC)ccc2S(=O)(=O)N1C
Reactant: Cc1cnc(N)s1
Solvent: Cc1ccccc1C
Product: COc1ccc2c(c1)C(O)=C(C(=O)Nc1ncc(C)s1)N(C)S2(=O)=O
Yield: 89.4 %

Procedure:
5.2 gm (0.017 mol) of methyl 4-hydroxy-6-methoxy-2-methyl-2H-1,2-benzothiazine-3-caboxylate-1,1-dioxide and 2.2 gm (0.019 mol) of 2-amino-5-methyl-thiazole were refluxed in 200 ml of xylene for 24 hours. After cooling, the precipitated crystals were filtered off and recrystallized from tetrahydrofuran. 5.8 gm (89% of theory) of 4-hydroxy-6-methoxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-caboxamide-1,1-dioxide were obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:2]1=2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:46]([O:48][C:49]([C:51]1([NH2:60])[CH2:59][C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52]1)=[O:50])[CH3:47]>CO.C(Cl)Cl.C(Cl)Cl>[CH2:46]([O:48][C:49]([C:51]1([NH:60][C:10]([C:7]2[CH:8]=[CH:9][C:2]3[S:1][CH:5]=[CH:4][C:3]=3[CH:6]=2)=[O:12])[CH2:59][C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52]1)=[O:50])[CH3:47]
Reactant: O=C(O)c1ccc2sccc2c1
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2ccc3sccc3c2)Cc2ccccc2C1
Yield: 88.6 %

Procedure:
To a 40 mL vial containing a stirring bar, benzo[b]thiophene-5-carboxylic acid (434 g, 2.44 mmol) is charged with dry DCM (7 mL). Stirring is initiated. HBTU (922 mg, 2.43 mmol) and DIPEA (0.95 mL, 8 mmol) are added. The 2-aminoindane-2-carboxylic acid ethyl ester (500 mg, 2.44 mmol) is added. The reaction is allowed to stir for 64 h. Analysis by tlc of the reaction mixture (silica, 10% MeOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are diluted with EtOAc (50 mL) and transferred to a separatory funnel. This is washed consecutively with dilute aqueous NaHCO3 (25 mL) and brine (25 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 1.4 g of an off white solid. This material is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 10% EtOAc in heptanes over 3 column volumes followed by a linear gradient to 50% over 8 column volumes and then 90% EtOAc for 2 column volumes with a ramp of 1 column volume. 25 mL fractions are collected. Fractions 4 through 16 are combined and evaporated in vacuo. Pumping to a constant weight gives amorphous white solid 0.79 g.