Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5]OCC1.[Se](=O)=O.[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[N:19]([CH3:34])[C:20]3[C:29]4[C:28](=[O:30])[NH:27][C:26](C)=[C:25](C)[C:24]=4[CH:23]=[CH:22][C:21]=3[N:33]=2)=[C:13]([CH3:35])[CH:12]=1.[Se]>CO.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[N:19]([CH3:34])[C:20]3[C:29]4[C:28](=[O:30])[NH:27][C:5]([CH:6]=[O:1])=[C:25]([CH3:26])[C:24]=4[CH:23]=[CH:22][C:21]=3[N:33]=2)=[C:13]([CH3:35])[CH:12]=1
Reactant: C1COCCO1
Reactant: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C)[nH]c(=O)c3c2n1C
Agent: O=[Se]=O
Agent: [Se]
Solvent: CO
Solvent: O
Product: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C=O)[nH]c(=O)c3c2n1C
Temperature: 55 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
To a 1 L round-bottom flask equipped with a magnetic stir-bar was added dioxane (500 mL) and water (16.5 mL). The solution was heated to 55° C., and selenium dioxide (8.6 g, 77 mmole) was added. The mixture was stirred at 55° C. for one hour, over which time all the selenium dioxide had dissolved. To the solution was then added 2-(4-fluoro-2-methyl-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one. The flask was fitted with a reflux condenser and the resulting slurry heated to a bath temperature of 115° C. After 18 hours, additional selenium dioxide (4.0 g, 36 mmole) was added and stirring continued for 6 hours. The reaction mixture was dark red, with gray metallic selenium lining the sides of the flask. The reaction mixture was cooled to room temperature then filtered through a pad of celite and washed with 10% MeOH/DCM. The filtrate was concentrated in vacuo to produce a gummy red solid. Methanol (50 mL) was added, and the mixture stirred over an ice bath, during which time a flocculent yellow precipitate formed. The solid was isolated by filtration, and washed sparingly with cold methanol to give 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde (3.90 g, 61%) as a bright yellow solid. 1H NMR (400 MHz, DMSO-d6+TFA) δ 10.80 (br s, 1H), 10.70 (br s, 1H), 10.25 (s, 1H), 8.02 (d, 1H, J=8.8 Hz), 7.80 (d, 1H, J=8.8 Hz), 7.57 (dd, 1H, J1=5.5 Hz, J2=8.6 Hz), 7.35 (dd, 1H, J1=3.1 Hz, J2=9.8 Hz), 7.26 (td, 1H, J1=3.1 Hz, J2=8.6 Hz), 4.14 (s, 3H), 2.69 (s, 3H), 2.31 (s, 3H); ESMS (m/z): 365 (M+1)+.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([N+:15]([O-])=O)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].CO>O>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[NH2:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1cccc(C#Cc2ccccc2)c1
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CO
Product: Nc1cccc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.8 %

Procedure:
To a 5-liter multi-necked flask fitted with a mechanical stirrer, reflux condenser, and thermometer was charged 215.6 g (0.96 mol) of 3-phenylethynylnitrobenzene obtained as described above, 600.2 g (2.5 mol) of sodium sulfide nonahydrate, 2 liters of methanol, and 500 ml of distilled water. The system is brought to 70° C. for 3 hours at which point the reduction is complete by thin layer chromatography. The reaction mixture is cooled to room temperature and the methanol removed by a rotary evaporator. The concentrate is added to a separatory funnel along with 1 liter of toluene. The toluene layer is separated and washed with distilled water until neutral to pH paper. Concentration of the toluene solution followed by vacuum distillation gave 131 g (0.68 mol, 71% yield) of 3-phenylethynylaniline.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH:18]3[CH2:23][CH2:22][C:21](=[CH:24][C:25](O)=[O:26])[CH2:20][CH2:19]3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.Cl.[CH3:60][NH:61][O:62][CH3:63]>ClCCl>[CH3:63][O:62][N:61]([CH3:60])[C:25](=[O:26])[CH:24]=[C:21]1[CH2:22][CH2:23][CH:18]([CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:28])([F:29])[F:2])[CH:5]=3)[CH2:15][CH2:14]2)[CH2:19][CH2:20]1
Reactant: O=C(O)C=C1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C=C1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
To a solution of 200 mg (0.46 mmol) of (4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexylidene)acetic acid, hydrochloride in 5 mL of dichloromethane stabilized on amylene are successively added 63 mg (0.46 mmol) of 1-hydroxybenzotriazole, 88 mg (0.46 mmol) of 3-ethyl-1-(3-dimethylaminopropyl)carbodiimide hydrochloride and 140 mg (1.4 mmol) of triethylamine. The mixture is stirred for 15 minutes then 45 mg (0.46 mmol) of N,O-dimethylhydroxylamine hydrochloride are added. The mixture is stirred overnight at room temperature, then evaporated under reduced pressure. The residue is dissolved in ethyl acetate and washed twice with water. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified over 10 g of silica gel (eluant dichloromethane/methanol 98/2) to give 143 mg (71%) of N-methoxy-N-methyl-2-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexylidene)acetamide as an oil.
Reaction SMILES: FC1C=C(F)C=CC=1NC1C=CC(C(C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=O)=C(C)C=1.Br[C:35]1[CH:40]=[CH:39][C:38]([C:41]([C:43]2[CH:48]=[C:47]([N:49]3[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]3)[CH:46]=[CH:45][C:44]=2[CH3:57])=[O:42])=[C:37]([CH3:58])[CH:36]=1.[NH2:59][C:60]1[CH:61]=[C:62]([CH:65]=[CH:66][CH:67]=1)[C:63]#[N:64]>>[OH:56][CH2:55][CH2:54][C:52]1[N:51]=[N:50][N:49]([C:47]2[CH:46]=[CH:45][C:44]([CH3:57])=[C:43]([CH:48]=2)[C:41]([C:38]2[CH:39]=[CH:40][C:35]([NH:59][C:60]3[CH:61]=[C:62]([CH:65]=[CH:66][CH:67]=3)[C:63]#[N:64])=[CH:36][C:37]=2[CH3:58])=[O:42])[CH:53]=1
Reactant: Cc1cc(Br)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Reactant: N#Cc1cccc(N)c1
Agent: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Product: Cc1cc(Nc2cccc(C#N)c2)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 452 (0.13 mmol) and 3-amino-benzonitrile (0.13 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM/petroleum ether (40-60) 0:50:50, 0:100:0 and 5:95:0 as the eluent to afford the title compound as yellow solid. 13C NMR (DMSO-d6) δ 196.5, 146.5, 145.7, 142.4, 142.1, 142.1, 135.4, 135.0, 134.5, 132.2, 130.7, 127.7, 124.9, 123.3, 121.1, 120.7, 120.6, 118.8, 118.6, 118.5, 112.2, 60.2, 29.2, 21.9, 18.9
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Li]CCCC.Cl[Si:15]([CH3:26])([CH3:25])[CH:16]1[C:20]([CH3:21])=[C:19]([CH3:22])[C:18]([CH3:23])=[C:17]1[CH3:24]>C1COCC1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][Si:15]([CH3:25])([CH3:26])[CH:16]2[C:20]([CH3:21])=[C:19]([CH3:22])[C:18]([CH3:23])=[C:17]2[CH3:24])=[CH:4][CH:3]=1
Reactant: CC1=C(C)C([Si](C)(C)Cl)C(C)=C1C
Reactant: Nc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)Nc2ccc(Br)cc2)C(C)=C1C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, to a solution of 14.8 g (86.0 mmol) of 4-bromoaniline in 250 ml of THF, 34.0 ml of 2.5 M (86.0 mmol) nBuLi in hexanes were added at −80° C. This mixture was stirred for 30 minutes at this temperature and then warmed for ca. 1 hour to ambient temperature. The resulting solution was added dropwise over ca. 1 hour, while vigorous stirring, to a solution of 18.4 g (86.0 mmol) of chloro(dimethyl)(2,3,4,5-tetramethyl-2,4-cyclopentadien-1-yl)silane in 100 ml of THF. The resulting mixture was stirred overnight at ambient temperature, then, evaporated to dryness. To the residue 100 ml of toluene were added. This mixture was filtered through a glass frit (G4). The filtrate was evaporated to dryness. Fractional distillation gave a yellow liquid, bp 170° C./0.4 mm Hg. The product crystallizes slowly at ambient temperature. Yield 21.3 g (70%).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)=[O:5])#[N:2].[C:26]1(=O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.N1CCOCC1>C1(C)C=CC=CC=1>[C:1]([C:3](=[C:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=2)=[CH:11][CH:12]=1)=[O:5])#[N:2]
Reactant: COC(=O)c1ccc(CCCc2ccc(NC(=O)CC#N)cc2)cc1
Reactant: O=C1CCCCC1
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CCCc2ccc(NC(=O)C(C#N)=C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 19.3 g of methyl 4-(3-{4-[(cyanoacetyl)amino]phenyl}propyl)benzoate, 18 mL of cyclohexanone, and 100 mL of toluene was added dropwise 5.0 mL of morpholine at room temperature. In a reaction device in which a Dean-Stark type dehydration tube was installed, the reaction mixture was stirred for 8 hours under heating and refluxing. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-chloroform and ethyl acetate-chloroform) to obtain methyl 4-[3-(4-{[cyano(cyclohexylidene)acetyl]amino}phenyl)propyl]benzoate in the form of a reddish brown amorphous substance as a crude product. ESI+: 417
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24].C1(=O)C=CC(=O)C=C1.CCOCC>C(O)C>[O:13]=[C:11]1[NH:10][C:9](=[O:14])[C:8](=[CH:7][C:6]2[CH:15]=[CH:16][C:3]([C:1]3[S:24][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[N:17]=3)=[CH:4][CH:5]=2)[S:12]1
Reactant: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Reactant: Nc1ccccc1S
Agent: O=C1C=CC(=O)C=C1
Solvent: CCOCC
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2ccc(-c3nc4ccccc4s3)cc2)S1
Temperature: 25 °C
Yield: 74.6 %

Procedure:
To a suspension of 5-(4-formylbenzylidene)-2,4-thiazolidinedione (50 mg, 0.21 mmol) and 2-aminothiophenol (0.025 mL, 0.23 mmol) in ethanol (7 mL) was heated to reflux for 10 h. 1,4-Benzoquinone (24 mg, 0.22 mmol) was added, and the mixture was heated additional 1 h. The mixture was cooled to room temperature, ether (3 mL) was added, and the precipitated product was collected by filtration to afford 2-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenyl]benzothiazole (53 mg, 75%).
Reaction SMILES: [C:1]([Si:5]([CH3:33])([CH3:32])[O:6][C@H:7]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([CH2:30][OH:31])[CH:24]=1)[CH2:8][NH:9][C:10]([CH3:22])([CH3:21])[CH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([O:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[CH2:40][CH2:41][NH2:42])[CH3:35]>>[Si:5]([O:6][C@H:7]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([CH2:30][OH:31])[CH:24]=1)[CH2:8][NH:9][C:10]([CH3:22])([CH3:21])[CH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH:42][CH2:41][CH2:40][C:39]1[CH:43]=[CH:44][CH:45]=[C:37]([O:36][CH2:34][CH3:35])[CH:38]=1)=[O:16])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:32])[CH3:33]
Reactant: CCOc1cccc(CCN)c1
Reactant: CC(C)(Cc1cccc(C(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Product: CCOc1cccc(CCNC(=O)c2cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)c2)c1
Yield: 67 %

Procedure:
The title compound was prepared from 3-{2-[(2R)-2-(tert-butyldimethyl silanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid (preparation 37) and 3-ethoxyphenethylamine, using a similar method to that of preparation 158, in 67% yield.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12](SC)[N:13]=[N:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:6][CH:5]=1.[CH3:26][OH:27]>C(OCC)C>[CH3:26][O:27][C:12]1[N:13]=[N:14][C:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[N:11]=1
Reactant: CO
Reactant: COc1ccc(-c2nnc(SC)nc2-c2ccc(OC)cc2)cc1
Agent: [Na]
Solvent: CCOCC
Product: COc1ccc(-c2nnc(OC)nc2-c2ccc(OC)cc2)cc1

Procedure:
Sodium, 3.0 g. (0.13 mole), was added piecewise under a nitrogen atmosphere to 100 ml. of dry methanol, followed by the addition of a slurry of 31.6 g. (0.1 mole) of 5,6-bis(4-methoxyphenyl)-3-methylthio-1,2,4-triazine in methanol. The reaction mixture was heated at reflux overnight. The reaction mixture was cooled and filtered. The filter cake and filtrate were extracted with diethyl ether. The diethyl ether was concentrated, giving a solid, m.p. >220° C. The solid was taken up in diethyl ether and the insoluble material was removed by filtration. The filtrate was dried over anhydrous sodium sulfate and concentrated to give a solid residue which was recrystallized from petroleum ether to give 3-methoxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine, m.p. about 105°-108° C.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:22]([NH:29][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([C:12]([N:9]2[CH2:10][CH2:11][N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:7][CH2:8]2)=[O:13])=[CH:15][CH:16]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: CCC(CC)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC(CC)N1CCN(C(=O)c2ccc(CNCc3ccccc3)cc2)CC1

Procedure:
To a solution of the product of Example 12 (150 mg) and benzylamine (0.062 mL) in DCM (5 mL) was added acetic acid (0.03 mL) and sodium triacetoxyborohydride (165 mg). After 16 h the reaction was treated with 1 N NaOH (20 mL) and extracted with DCM (3×20 mL). The organic layers were dried (Na2SO4), concentrated, and chromatographed (2-3% 2 M methanolic ammonia-DCM) to give the title compound as an oil (150 mg).
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[CH:10][C:11]=2[CH3:13])[NH:6][C:5]=1[C:15]([O:17][CH3:18])=[O:16].CI.[C:21](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:21][O:1][N:2]=[CH:3][C:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[CH:10][C:11]=2[CH3:13])[NH:6][C:5]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1[nH]c2c(C)ccc(C)c2c1C=NO
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CON=Cc1c(C(=O)OC)[nH]c2c(C)ccc(C)c12
Yield: 24.8 %

Procedure:
A mixture of 0.8 g (3.25 mmol) of methyl 3-(hydroxyiminomethyl)-4,7-dimethylindole-2-carboxylate, 0.60 g (4.23 mmol) of methyl iodide, 0.59 g (4.23 mmol) of potassium carbonate and 20 ml of acetonitrile was refluxed for 19 hours. After potassium carbonate was removed by filtration, acetonitrile was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with water three times and dried over anhydrous magnesium sulfate. The crude crystals were purified by silica gel column chromatography to provide 210 mg of light yellow crystals. Yield: 25%
Reaction SMILES: [C:1]1([CH:7]([N:14]2[CH2:17][CH:16]([CH2:18][OH:19])[CH2:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[C:1]1([CH:7]([N:14]2[CH2:17][CH:16]([CH2:18][O:19][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Yield: 99 %

Procedure:
The title compound from Step B above (1.7 g, 6.72 mmoles) and triethylamine (1.1 g, 10.87 mmoles) were dissolved in CH2Cl2 (20 mL) and the mixture was stirred under nitrogen at 0° C. Methanesulfonylchloride (1.1 g, 9.6 mmoles) was added and the solution was stirred at room temperature for 2 h. The solution was diluted with CH2Cl2 and washed with saturated aqueous sodium bicarbonate, water and dried (MgSO4), filtered and evaporated to dryness to give the title compound (2.32 g, 99%). FABMS (M+1)=332.
Reaction SMILES: [I-:1].[Na+].CS(O[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)(=O)=O>CC(C)=O>[I:1][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1
Reactant: [I-]
Reactant: CS(=O)(=O)OCCCCc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCCCc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Yield: 100.4 %

Procedure:
Sodium iodide (29.25 g) was dissolved in acetone (195 ml); 4-[4-(benzyloxy)phenyl]butyl methanesulfonate (13 g) was added, followed by refluxing at 80° C. for 1.5 hours. After cooling, the solvent was distilled off; to the residue, ethyl acetate (750 ml) was added; the mixture was washed sequentially with water, an aqueous solution of sodium thiosulfate, and saturated saline. The organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure to yield the titled compound (14.29 g) as an oily substance. This product was used for the next process without purification.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]([F:20])([F:19])[F:18])=[C:15]([C:21]([NH:23][C:24]3[CH:25]=[C:26]([S:30](F)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=3)=[O:22])[CH:14]=[N:13]2)=[CH:8][CH:7]=1>C(Cl)Cl>[CH:1]1([NH:4][S:30]([C:26]2[CH:25]=[C:24]([NH:23][C:21]([C:15]3[CH:14]=[N:13][N:12]([C:9]4[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][CH:10]=4)[C:16]=3[C:17]([F:20])([F:18])[F:19])=[O:22])[CH:29]=[CH:28][CH:27]=2)(=[O:31])=[O:32])[CH2:3][CH2:2]1
Reactant: O=C(Nc1cccc(S(=O)(=O)F)c1)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Reactant: NC1CC1
Solvent: ClCCl
Product: O=C(Nc1cccc(S(=O)(=O)NC2CC2)c1)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
Cyclopropyl amine (0.012 mL, 0.167 mmol) was added to 3-{[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-benzenesulfonyl fluoride (0.025 g, 0.055 mmol) in CH2Cl2 (10 ml). Reaction mixture stirred overnight at room temperature, concentrated under reduced pressure and crude product purified by column chromatography to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-cyclopropylsulfamoyl-phenyl)-amide (0.015 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][CH2:7][CH:8]=[CH:9][CH2:10][CH2:11]CC.[Cl:17][CH:18]([Cl:22])[C:19](Cl)=[O:20]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]([CH2:7][CH:8]=[CH:9][CH2:10][CH3:11])[C:19](=[O:20])[CH:18]([Cl:22])[Cl:17]
Reactant: CCCCC=CCNCc1cccc(Cl)c1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: Cc1ccccc1
Product: CCC=CCN(Cc1cccc(Cl)c1)C(=O)C(Cl)Cl
Temperature: 25 °C

Procedure:
2 g of N-(3-chlorobenzyl)-N-(2-heptenyl)amine was dissolved in 40 ml of toluene, to which 1.7 g of 2,2-dichloroacetyl chloride was dropped under stirring gradually at a room temperature. After stirring for 20 min, deposited insoluble matters were filtered and then 50 ml of toluene was added. The toluene solution was washed with an aqueous saturated solution of sodium hydrogen carbonate and with a saturated solution of sodium chloride respectively each by twice. After dying with anhydrous sodium sulfate, it was concentrated in an evaporated to obtain an aimed oily product quantitatively.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([C:8]2([CH2:11][C:12]([C:27]([F:30])([F:29])[F:28])([OH:26])[CH:13]=[N:14][C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][C:19]([CH3:25])=[N:20]4)[CH2:10][CH2:9]2)[CH:7]=1.[BH4-].[Na+]>CO.O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([C:8]2([CH2:11][C:12]([C:27]([F:28])([F:29])[F:30])([OH:26])[CH2:13][NH:14][C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][C:19]([CH3:25])=[N:20]4)[CH2:9][CH2:10]2)[CH:7]=1
Reactant: COc1ccc(F)cc1C1(CC(O)(C=Nc2cccc3nc(C)ccc23)C(F)(F)F)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C1(CC(O)(CNc2cccc3nc(C)ccc23)C(F)(F)F)CC1

Procedure:
870 mg (1.95 mmol) of 3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-1-(2-methylquinolin-5-ylimino)-2-(trifluoromethyl)propan-2-ol is reacted analogously to Example 37 with 96 mg (2.53 mmol) of sodium borohydride in 6.0 ml of methanol and 3.0 ml of tetrahydrofuran. After recrystallization from hexane and ethyl acetate, 790 mg (90% of theory) of the product is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][C:3]=1[O:24][CH3:25].N1C=CC=CC=1.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34](Cl)=[O:35]>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[CH3:32])=[C:3]([O:24][CH3:25])[CH:4]=3)=[CH:9][N:10]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1N
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
5-(4-Amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.147 mmol) was dissolved in dichloromethane (1.5 mL). Pyridine (1.5 mL) was added followed by 2,2-dimethylpropanoyl chloride (31 mg, 0.221 mmol). After stirring at room temperature for 2 hours, the solvent was removed and the residue was dissolved in 1 ml DMSO, methanol (1 mL) was added and precipitate was formed. The solid was collected by filtration to give N1-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-2,2-dimethylpropanamide (27 mg, 0.064 mmol). 1H NMR (CDCl3-d) δ 1.35 (s, 9H), 2.09 (m, 4H), 3.66 (m, 2H), 3.96 (s, 3H), 4.13(m, 2H), 4.97 (m, 1H), 5.46(bs, 2H), 6.98 (s, 1H), 7.04 (s, 1H), 7.07 (d, J=8.2 Hz, 1H), 8.15 (s, 1H), 8.29 (s, 1H), 8.49 (d, J=8.2 Hz, 1H). LC/MS: MH+=424.
Reaction SMILES: C([O:3][C:4](=[O:22])[C@@H:5]([O:20][CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][NH2:32].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][NH:32][C:17]([C:14]([CH3:15])([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH3:21])[C:4]([OH:3])=[O:22])=[CH:12][CH:11]=1)[CH3:16])=[O:19]
Reactant: NCCc1ccccc1F
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCCc2ccccc2F)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (PREPARATION 5, step 2) and 2-(2-fluoro-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C22H26FNO5 [M−H]−: 402.