Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:10])[N:5]([CH2:7][CH2:8][NH2:9])[CH:6]=1.[F:11][C:12]1[CH:13]=[C:14]([CH2:22][CH2:23][CH:24]=O)[CH:15]=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19]>>[F:11][C:12]1[CH:13]=[C:14]([CH2:22][CH2:23][CH:24]2[NH:9][CH2:8][CH2:7][N:5]3[C:4]([CH3:10])=[N:3][C:2]([I:1])=[C:6]23)[CH:15]=[CH:16][C:17]=1[C:18]([F:19])([F:20])[F:21]
Reactant: Cc1nc(I)cn1CCN
Reactant: O=CCCc1ccc(C(F)(F)F)c(F)c1
Product: Cc1nc(I)c2n1CCNC2CCc1ccc(C(F)(F)F)c(F)c1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(4-iodo-2-methyl-imidazol-1-yl)-ethylamine (51.840 mmol) and 3-(3-fluoro-4-trifluoromethyl-phenyl)-propionaldehyde (13.125 g; 59.616 mmol) afforded 8-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-1-iodo-3-methyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.76 min.; [M+H]+=453.93 g/mol. Subsequent protection of the secondary amine, and purification by FC (DCM/MeOH=20/1) allowed the isolation of the pure product 8-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-1-iodo-3-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a pale yellow solid (15.450 g; 54%). LC-MS: tR=0.97 min.; [M+H]+=554.84 g/mol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:12])=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(C(C)C)CC)(C)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>CC#N.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)c1ccc(Br)cc1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)o1
Reaction time: 12 h
Yield: 63.3 %

Procedure:
To a solution of the product of Step 1 (1.00 g, 2.43 mmol), PPh3 (1.00 g, 3.71 mmol) and diisopropylethylamine (1.3 mL, 7.28 mmol) in CH3CN (30 mL) was added hexachloroethane (0.812 g, 3.43 mmol) as a solid, portion-wise. The mixture was allowed to stir for 12 hours. TLC (3:1 hexanes:ethyl acetate) indicated the presence of starting material. Therefore, additional PPh3 (0.65 g, 2.43 mmol) and hexachloroethane (0.575 g, 2.43 mmol) were added and stirring continued for 4 hours. The solvent was removed in vacuo, the residue diluted with ethyl acetate-H2O and the layers separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed (H2O, brine), dried (Na2SO4), and filtered. The solvent was removed in vacuo and the residue purified by flash column chromatography (3:1 hexanes:ethyl acetate) to provide (S)-tert-butyl 2-(5-(4-bromophenyl)oxazol-2-yl)pyrrolidine-1-carboxylate (0.605 g, 63%). 1HNMR (400 MHz, DMSO-d6) δ 7.60-7.68 (m, 5H), 4.80-4.91 (m, 1H), 3.46-3.51 (m, 1H), 3.33-3.39 (m, 1H), 2.18-2.31 (m, 1H), 1.84-1.99 (m, 3H), 1.36 (s, 4H), 1.15 (s, 5H). LCMS: Anal. Calcd. for C18H21BrN2O3: 392. found: 393 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][NH:9][CH2:10][C:5]2=[CH:4][CH:3]=1.[CH3:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:24][C@@H:25]([CH3:30])[C:26]([F:29])([F:28])[F:27])=[C:19]([CH:23]=1)[C:20](O)=[O:21])(=[O:14])=[O:13]>>[Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][N:9]([C:20]([C:19]3[CH:23]=[C:15]([S:12]([CH3:11])(=[O:13])=[O:14])[CH:16]=[CH:17][C:18]=3[O:24][C@@H:25]([CH3:30])[C:26]([F:28])([F:29])[F:27])=[O:21])[CH2:10][C:5]2=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(n1)CNC2
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(Cl)nc2C1)C(F)(F)F

Procedure:
Prepared in analogy to Example 1 from 2-chloro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (Example A8(b)) and 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example B3). Yellow foam. MS (m/e): 451.0 ({37Cl}[M+H]+, 41%), 449.2 ({35Cl}[M+H]+, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][OH:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:20]2[S:33][CH:32]=[CH:31][C:21]=2[N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[N:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O.C(OCC)(=O)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:20]2[S:33][CH:32]=[CH:31][C:21]=2[N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[N:23]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(CO)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
To a solution of 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester [373 mg, 0.794 mmol Intermediate (10)] in Dichloromethane (20 mL) is added Dess-Martin Periodinane (407 mg, 0.959 mmol). Stirred at room temperature for 30 minutes. Water (10 mL) is added and stirred for 30 minutes at room temperature. The reaction mixture is dissolved with ethyl acetate (30 mL) and washed twice with a mixture of 10% Na2S2O3/saturated NaHCO3 (4 mL) solution. The ethyl acetate phase is washed with water, NaHCO3, brine and dried over sodium sulfate. The residue is chromatographed on 10 g silica gel cartridge eluting with 30 to 40% ethyl acetate gradient in heptane to afford 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-formyl-indole-1-carboxylic acid tert-butyl ester [300 mg, 81%, Intermediate (11)] as a white solid; 1H NMR [(CD3)2SO)]: δ 10.079 (1H, s, CHO), 8.323 (1H, s), 8.318 (1H, d), 8.017 (1H, s), 7.978 (1H, d), 7.391 (1H, d), 7.345 (1H, s), 1.660 (9H, s), 1.341 (9H, s); TLC data Rf=0.37 (30% ethyl acetate in heptane).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([CH3:36])[C:34]=1[NH2:35])[O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:31])[CH2:14][CH2:13]2)[CH:7]=1.[F:37][C:38]([F:44])([F:43])[CH2:39][C:40](O)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O)(=O)C>CN(C=O)C>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:21]2[NH:20][C:19](=[O:31])[N:18]([CH:15]3[CH2:14][CH2:13][N:12]([C:8]4[CH:7]=[C:6]([O:5][C:4]5[CH:32]=[C:33]([CH3:36])[C:34]6[N:35]=[C:40]([CH2:39][C:38]([F:44])([F:43])[F:37])[NH:1][C:2]=6[CH:3]=5)[N:11]=[CH:10][N:9]=4)[CH2:17][CH2:16]3)[CH2:24][CH2:23][C:22]=2[CH:25]=1
Reactant: O=C(O)CC(F)(F)F
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c(N)c(N)c4)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5nc(CC(F)(F)F)[nH]c5c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.20 g (0.42 mmol) 3-{1-[6-(3,4-diamino-5-methyl-phenoxy)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one, 60 mg (0.46 mmol) 3,3,3-tri-fluoropropionic acid, 0.15 g (0.47 mmol) TBTU and 0.14 mL (1.0 mmol) TEA in 2.0 mL DMF were stirred for 4 h at RT. Then 2.0 mL glacial acetic acid was added and the mixture was stirred overnight at RT. In addition the reaction mixture was stirred for 1 h at 100° C., then cooled and purified by preparative HPLC-MS. The product-containing fractions were combined and the acetonitrile was evaporated down. The residue was made alkaline with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13]([OH:15])=O)=[C:5]2[C:16]([OH:18])=[O:17].CC(OC(C)=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]1[C:13]([O:18][C:16](=[O:17])[C:5]2=1)=[O:15]
Reactant: Cc1nc2ccc(Br)cc2c(C(=O)O)c1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2ccc(Br)cc2c2c1C(=O)OC2=O

Procedure:
A 1 liter round-bottom flask with a magnetic stirring bar, reflux condenser and drying tube was charged with 16 g (0.0516 mole) of (viii) and 250 ml of reagent grade Ac2O. The mixture was stirred and refluxed for 18 hours.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12](O)=[O:13])=[C:10](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][N:8]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+].[OH-].[Na+]>C1COCC1.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][OH:13])=[C:10](/[CH:15]=[CH:16]/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:9][N:8]=1
Reactant: O=C(O)c1c(-c2ccccn2)noc1/C=C/c1ccccc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: OCc1c(-c2ccccn2)noc1/C=C/c1ccccc1
Yield: 68.3 %

Procedure:
To a solution of 3-pyridin-2-yl-5-([E]-styryl)-isoxazole-4-carboxylic acid (1.1 g, 4 mmol) and triethylamine (0.53 mL, 4 mmol) in THF (15 mL) was added dropwise at room temperature a solution of ethyl chloroformate (0.36 mL, 4 mmol) in THF (15 mL). After 1 h the triethylamine hydrochloride salt was filtered off and washed with a small amount of THF. The filtrate was added to a solution of sodium borohydride (0.36 g, 10 mmol) in water (10 mL). After stirring for 1 h at 5° C. aqueous sodium hydroxide (2 M, 22 mL) was added. Extraction with ethyl acetate, drying over sodium sulfate, filtering and evaporation of the solvent followed by trituration with diisopropylether afforded the title compound (0.76 g, 72%) as a white solid. MS: m/e=279.2 [M+H]+.
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:34][C@H:35]([CH2:39][OH:40])[CH:36]([CH3:38])[CH3:37]>C1COCC1>[C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@@H:12]1[C:13]([NH:34][C@H:35]([CH2:39][OH:40])[CH:36]([CH3:38])[CH3:37])=[O:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)[C@H](N)CO
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)[C@@H](CO)NC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Yield: 71 %

Procedure:
2.49 g (10 mmol) N-carbobenzoxy-D-proline, 1.37 g (10 mmol) isobutyl chloroformate, 1.01 g (10 mmol) N-methylmorpholine, and 1.03 g (10 mmol) L-valinol were contacted and reacted in THF substantially according to the procedure described in Example 1. Crude product (2.82 g) was recrystallized from a mixture of 20 mL ethyl acetate and 15 mL n-hexane, to give 2.37 g (7.1 mmol, 71%) of colorless crystalline N-carbobenzoxy-D-prolyl-L-valinol; m.p. 117.5°-118.6°, α25D=+26.7° (C=1.02 g/100 mL in acetone).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=1)=[O:10].[F:18][C:19]([F:32])([F:31])[O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:31])[F:32])=[CH:26][CH:25]=2)(=[O:29])=[O:28])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=2)=[O:10])[CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1cc(C(=O)c2cc(Cl)ccc2N)ccn1
Product: Cc1cc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)ccn1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and 4-trifluoromethoxy-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3) δ 10.17 (s, 1H) 8.63 (d, J=4 Hz, 1H) 7.78 (m, 3H) 7.51 (s, 1H) 7.30 (s, 1H) 7.17 (s, 1H) 7.09 (s, 1H) 6.97 (d, J=4 Hz, 2H) 2.64 (s, 3H). MS (ES) m/z=471.0 (M++1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:23][C:24]([F:27])([F:26])[F:25])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].CC1(C)C(C)(C)OB([C:42]2[CH:54]=[CH:53][C:45]([CH2:46][N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[CH:44][CH:43]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:42]2[CH:43]=[CH:44][C:45]([CH2:46][N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[CH:53][CH:54]=2)[CH:3]=[C:4]([N:22]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:23][C:24]([F:27])([F:26])[F:25])[C:5]=1[CH3:21])=[O:8]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(CC(F)(F)F)C3CCOCC3)c2C)c(=O)[nH]1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc(N(CC(F)(F)F)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 81 %

Procedure:
In a 2 necked RBF, 5-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2-methyl-3-[(oxan-4-yl)(2,2,2-trifluoroethyl)amino]benzamide (200 mg, 0.38 mmol), 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine (126 mg, 0.41 mmol) in 1,4-dioxane (3.0 ml) was treated with a solution containing Na2CO3 (140 mg, 1.3 mmol) in water (1.0 ml). Nitrogen was bubbled through the mixture using a long needle for 5 minutes before the addition of palladium-triphenylphosphane (1:4) (44 mg, 0.04 mmol). Nitrogen was bubbled through the yellow suspension for a further 5 minutes before heating the reaction mixture to 100° C. for 5.5 hours. The reaction mixture was diluted with water (10 ml) and 10% MeOH in CH2Cl2 (10 ml). The layers were separated and the aqueous phase was extracted with 10% MeOH in CH2Cl2 (3×15 ml). The combined organic extracts were washed with brine (40 ml), dried over MgSO4, filtered and concentrated in-vacuo. The crude residue was purified by column chromatography (10 g SNAP cartridge, Isolera, 0-4% MeOH:CH2Cl2) to give the title compound (193 mg, 82%) as an off white powder. LC-MS 100%, 3.34 min (7 minute LC-MS method), m/z=627.5; 1H NMR (500 MHz, Acetone) δ 10.76 (s, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.60 (d, J=8.2 Hz, 2H), 7.57 (t, J=5.6 Hz, 1H), 7.43 (d, J=1.5 Hz, 1H), 7.39 (d, J=8.1 Hz, 2H), 5.91 (s, 1H), 4.44 (d, J=5.5 Hz, 2H), 3.97 (s, 2H), 3.90 (dd, J=11.4, 4.1 Hz, 2H), 3.61 (t, J=4.6 Hz, 4H), 3.50 (s, 2H), 3.29 (t, J=11.5 Hz, 2H), 3.06 (tt, J=11.4, 3.8 Hz, 1H), 2.39 (d, J=5.0 Hz, 7H), 2.34 (s, 3H), 2.22 (s, 3H), 1.82 (dd, J=12.3, 1.7 Hz, 2H), 1.70-1.56 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1.[H][H]>[C].[Pd].CC(O)C>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]([CH3:12])[CH2:3]1
Reactant: [H][H]
Reactant: C[C@@H]1CC(C)(C)c2cccc(N)c21
Agent: [Pd]
Solvent: CC(C)O
Product: CC1CC(C)(C)c2cccc(N)c21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Into a reaction vessel were charged 6.00 parts by weight of (3R)-1,1,3-trimethyl-4-aminoindane (optical purity of 96.5% ee), 0.81 part by weight of 5% palladium-carbon (STD-type, manufactured by N. E. Chemcat Corporation), and 12 parts by weight of 2-propanol, thereby obtaining a mixture. The reaction vessel was sealed and the gas in the reaction vessel was replaced with nitrogen. While stirring the mixture at room temperature, into the reaction vessel was charged hydrogen until the internal pressure of hydrogen in the reaction vessel reached 0.5 MPa. After 15 minutes, hydrogen was removed to normal pressure, and the mixture was stirred at an internal temperature of 130° C. and an internal pressure of 0.45 MPa for 7 hours while the inside of the reaction vessel was replaced with hydrogen, thereby obtaining a reaction mixture. The obtained reaction mixture was cooled and filtered. The obtained solid was washed with 20 parts by weight of 2-propanol. The washing liquid recovered after washing and the filtrate obtained by filtration were combined. The combined mixture was concentrated under reduced pressure to obtain 5.55 parts by weight of 1,1,3-trimethyl-4-aminoindane. The obtained 1,1,3-trimethyl-4-aminoindane had an optical purity of 1.2% ee and a recovery rate of 92.5%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[C:5]([C:10]#[N:11])=[C:4]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.C1(C2[O:25]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:9])=[O:25])[C:5]([C:10]#[N:11])=[C:4]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1nc(N)nc(-c2cccs2)c1C#N
Solvent: ClCCl
Product: CS(=O)c1nc(N)nc(-c2cccs2)c1C#N
Reaction time: 16 h
Yield: 54.4 %

Procedure:
To a stirred suspension of 2.65 g (10.7 mmol) 2-amino-4-(methylthio)-6-(2-thienyl)-pyrimidine-5-carbonitrile in 200 ml dichloromethane was added 2.79 g (10.7 mmol) 3-phenyl-2-(phenylsulfonyl)oxaziridine and stirring continued for 16 hours at room temperature. The resulting crystals were collected by filtration and washed with 30 ml dichloromethane to afford 1.54 g (55%) 2-amino-4-methanesulfinyl-6-thiophen-2-yl-pyrimidine-5-carbonitrile as a white crystalline solid. EI-MS m/e (%): 264 (M+, 20), 218 (32), 201 (20), 159 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]([C:18](=[O:21])[CH2:19]Cl)[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[Cl:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:11]2[C:16](=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH2:19][C:18]1=[O:21]
Reactant: Cc1ccc(N(C(=O)CCl)c2c(Cl)cc(C)cc2Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(Cl)c(N2C(=O)Cc3cc(C)ccc32)c(Cl)c1
Temperature: 165 °C
Reaction time: 3.5 h

Procedure:
A mixture of 6.85 g (20 mmol) of N-(2′,6′-dichloro-4′-methylphenyl)-N-chloroacetyl-4-methylaniline and 3.36 g (26 mmol) of aluminium chloride was heated slowly to 160-170° C. and held at this temperature for 3-4 h. During this time, nitrogen was continuously bubbled into the melt. The mixture was diluted with 20 ml of toluene and added on 20 ml of warm water. The organic layer was separated, washed with water and evaporated. The residue was crystallised from 20 ml of 2-propanol giving N-(2′,6′-dichloro-4′-methylphenyl)-5-methyloxindole. Mp: 153-154° C.
Reaction SMILES: F[C:2]1(F)[C:10]2[C:5](=[C:6]([F:14])[C:7]([F:13])=[C:8]([F:12])[C:9]=2[F:11])[C:4](=[O:15])[O:3]1.C(O)(=[O:19])C>>[F:11][C:9]1[C:8]([F:12])=[C:7]([F:13])[C:6]([F:14])=[C:5]2[C:4](=[O:15])[O:3][C:2](=[O:19])[C:10]=12
Reactant: CC(=O)O
Reactant: O=C1OC(F)(F)c2c(F)c(F)c(F)c(F)c21
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Yield: 87.5 %

Procedure:
Into a 300 ml glass reactor equipped with a reflux condenser and a stirrer, 100 g (0.413 mol) of the 3,3,4,5,6,7-hexafluoro-1-[3H]-isobenzofuranone obtained in Example 2, and 100 ml of acetic acid were charged, and the mixture was reacted for 48 hours under reflux. Then, the reaction mixture was separated by distillation to obtain 79.5 g of tetrafluorophthalic anhydride. The yield was 87.5%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2N=C(C(F)(F)F)[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C([OH:27])C.O.OOS([O-])=O.[K+]>C1COCC1>[OH:11][CH:12]([C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1)[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:27]
Reactant: CCO
Reactant: CSc1ccc(-c2oc(C(F)(F)F)nc2-c2ccc(C)cc2)cc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc(C(O)C(=O)c2ccc(C)cc2)cc1
Reaction time: 3 h

Procedure:
4-(4-Methylphenyl)-5-(4-methylthiophenyl)-2-trifluoromethyloxazole from Step 2 (350 mg, 1.0 mmol) was dissolved in THF (20 mL), ethanol (20 mL) and water (20 mL). Oxone® (1.2 g, 2 mmol) was added and the reaction stirred for 3 hours. The reaction mixture was filtered and concentrated to dryness. The residue was dissolved in ethyl acetate (200 mL), washed with water, NaHCO3 and brine, dried and concentrated to yield a white crystalline product (350 mg) which was recrystallized from ethanol and water to yield 4-(4-methylphenyl)-5-(4-methylsulfonylphenyl)-2-trifluoromethyl-oxazole (300 mg, 79%): mp 141-142° C. Anal. Calc'd. for C18H14NO3SF3 : C, 56.69; H, 3.70; N, 3.67. Found: C, 56.47; H, 3.79; N, 3.57.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:23])=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2)(=O)=O.[H-].[Na+]>CN(C)C=O>[CH3:23][C:12]1[C:13]2[CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]3[CH2:6][CH2:7][O:8][C:9]([C:17]=23)=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1cc2c(C)ccc(OCCOS(C)(=O)=O)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C)ccc3c2n1CCO3
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
A mixture of ethyl 7-(2-methanesulfonyloxy-ethoxy)-4-methyl-1H-indole-2-carboxylate (1.30 g, 3.81 mmol), 60% sodium hydride (0.15 g, 3.81 mmol) and N,N-dimethylformamide (65 ml) was stirred at room temperature for 8 hours. The reaction mixture was poured into ice water and extracted three times with ethyl acetate, and the extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/98) to obtain ethyl 2,3-dihydro-7-methyl-pyrrolo[1,2,3-de]-1,4-benzoxazine-5-carboxylate (0.87 g).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2[nH]1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 65.4 %

Procedure:
To a mixture of 4-(4-bromo-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine (0.7 g, 2.364 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)-3-chlorobenzene (0.583 g, 2.84 mmol) and potassium carbonate (0.980 g, 7.09 mmol). The resulting reaction mixture was stirred at 90° C. for 4 h. It was cooled to room temperature and poured into water (100 mL). The aqueous mixture was extracted with DCM (100 mL×2). The combined organic phases were washed with Brine (100 mL) and concentrated. The crude material was purified on silica column (20˜70% EtOAc in Hexane) to give the product as solid (0.65 g, 65%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.57 (s, 3H) 2.90-3.16 (m, 4H) 3.69-3.95 (m, 4H) 5.25 (s, 2H) 6.60 (d, J=2.02 Hz, 1H) 6.88 (d, J=7.07 Hz, 1H) 7.07 (s, 1H) 7.16 (d, J=2.02 Hz, 1H) 7.20-7.37 (m, 2H); MS (ES+) m/e 420.0 [M+H]+.