Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]([F:7])([F:6])[F:5].[Cl:9][C:10]1[CH:15]=[C:14]([CH2:16]Cl)[CH:13]=[C:12]([F:18])[CH:11]=1.O>CN(C)C=O>[Cl:9][C:10]1[CH:15]=[C:14]([CH2:16][O:8][CH2:3][C:4]([F:7])([F:6])[F:5])[CH:13]=[C:12]([F:18])[CH:11]=1
Reactant: OCC(F)(F)F
Reactant: Fc1cc(Cl)cc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cc(Cl)cc(COCC(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
Under argon stream, to a suspension of sodium hydride (601 mg, 60 wt. % oil dispersion) in dimethylformamide (13 ml) was added dropwise trifluoroethanol (1.08 ml) at 0° C., and the mixture was stirred for 15 minutes. To this reaction solution was added dropwise a solution of 1-chloro-3-fluoro-5-chloromethylbenzene (2.23 g) in dimethylformamide (9 ml), and then the mixture was stirred at room temperature for 1 hour. To this reaction mixture was added water, and the mixture was extracted with a mixed solvent of n-hexane/ethyl acetate=1/1. This organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 9/1) to give the titled compound (2.85 g).
Reaction SMILES: [CH2:1]([C@H:8]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@H:9]([OH:22])[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1([CH3:21])[O:20][CH2:19][CH2:18][O:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=1>ClCCl>[CH2:1]([C@H:8]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:9]([OH:22])[CH:10]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1([CH3:21])[O:20][CH2:19][CH2:18][O:17]1)[S:48]([C:45]1[CH:44]=[CH:43][C:42]([O:41][CH3:40])=[CH:47][CH:46]=1)(=[O:50])=[O:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNCCCCC1(C)OCCO1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)C(NCCCCC2(C)OCCO2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1

Procedure:
To a solution of the product of Step 2 (0.63 g, 1.49 mmol) in anhydrous dichloromethane (7 mL) at 0° C. was added N-ethyldiisopropylamine (0.38 g, 0.51 mL, 2.98 mmol) and a solution of 4-methoxybenzenesulfonyl chloride (0.32 g, 1.56 mmol) in anhydrous dichloromethane (2 mL) and the mixture was stirred at ambient temperature under nitrogen atmosphere for 18 hours. The mixture was washed sequentially with 1M hydrochloric acid, sodium bicarbonate/water, brine, dried (sodium sulfate) and concentrated. The residue was chromatographed (silica gel, dichloromethane/methanol, 97:3) to provide the title compound as a thick oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.S(Cl)([Cl:23])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([Cl:23])=[O:7])#[N:2]
Reactant: COc1ccc(C(=O)O)cc1C#N
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Cl)cc1C#N
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-cyano-4-methoxybenzoic acid (1.78 g), toluene (20 mL), N,N-dimethylformamide (3 droplets) and thionyl chloride (1.14 mL) were added, and then the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and used for the synthesis of (d).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10][CH2:9]1)C1C=CC=CC=1.[OH-:25].[OH-:26].[Pd+2]>C(O)C>[C:14]1([C@H:12]2[C@@H:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10][CH2:9][N:8]([C:1]([O:26][C:11]([CH3:20])([CH3:12])[CH3:10])=[O:25])[CH2:13]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C1=C(c2ccccc2)CN(Cc2ccccc2)CC1
Reactant: [OH-]
Agent: [Pd+2]
Solvent: CCO
Product: CCOC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 152.6 %

Procedure:
A solution of the compound (10.5 g) obtained in step 1 in 20% palladium hydroxide on carbon (50% wet, 2.63 g) in ethanol (250 mL) was stirred under a hydrogen atmosphere (1 atm) at room temperature for 14 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. To a solution of the obtained residue in acetonitrile (50 mL) were added triethylamine (4.6 mL) and Boc2O (7.14 g), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (solvent gradient; 10→20% ethyl acetate/hexane) to give 4-ethyl 1-tert-butyl (3R*,4S*)-3-phenylpiperidine-1,4-dicarboxylate (8.31 g, 76%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([N:5]([CH3:15])[C:6](=[O:14])[N:7]([CH3:13])[C:8]2=[O:12])=[N:3]1.[H-].[Na+].[CH3:18][O:19][C:20](=O)[O:21]C>>[CH3:1][N:2]1[C:10]([CH2:11][C:20]([O:19][CH3:18])=[O:21])=[C:9]2[C:4]([N:5]([CH3:15])[C:6](=[O:14])[N:7]([CH3:13])[C:8]2=[O:12])=[N:3]1
Reactant: Cc1c2c(=O)n(C)c(=O)n(C)c2nn1C
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Product: COC(=O)Cc1c2c(=O)n(C)c(=O)n(C)c2nn1C
Temperature: 25 °C

Procedure:
To a stirred solution of Step 5 intermediate (3.8 g, 18.24 mmol) in dimethylcarbonate (91 ml) was added sodium hydride (60% dispersion in mineral oil, 4.5 g, 187.5 mmol) at room temperature. The reaction mixture was heated to reflux for overnight. The reaction mixture was cooled to room temperature, quenched into 1N HCl (200 ml), extracted with ethyl acetate (2×250 ml) and the combined organic layers were washed with water (2×250 ml), dried over Na2SO4 and concentrated. The residue obtained was triturated in hexane, solid obtained was filtered to give 5.5 g of the product as a white solid; 1H NMR (300 MHz, DMSO-d6): δ 3.37 (s, 3H), 3.50 (s, 3H), 3.82 (s, 5H), 3.90 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH2:10][C:11]([O:13]CC)=O)=[O:8].CC(C)([O-])C.[K+].O.Cl>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[C:11](=[O:13])[CH2:10][NH:9][C:7]1=[O:8]
Reactant: CCOC(=O)CNC(=O)Cc1cccs1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CNC(=O)C1c1cccs1
Yield: 94 %

Procedure:
To a solution of ethyl 2-thiopheneacetylaminoacetate (31.77 g, 140 mmol) in anhydrous toluene (190 mL) was added potassium tert-butoxide (20.95 g, 187 mmol). The mixture was heated to reflux for 2 hours. After cooling, it was poured into water (190 mL) and the water phase was isolated and acidified with dilute HCl to about pH 1 (˜70 mL 10% HCl). The pale brown precipitate was filtered, washed with water and dried. Finally, a pale brown solid with some dark brown chunks was obtained (23.8 g, yield 94%). 1H NMR (d6-DMSO, 500 MHz), δ=7.55 (dd, J=3.5, 1.0 Hz, 1H), 7.48 (s, 1H), 7.30 (dd, J=5.0 1.0 Hz, 1H), 7.01 (dd, J=5.0, 4.0 Hz, 1H), 3.88 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1[N:20]([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[N:33][NH:32][C:31]3=[O:35])=[CH:26][CH:25]=2)[N:21]=[N:22][CH:23]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:32]1[C:31](=[O:35])[N:30]([C:27]2[CH:26]=[CH:25][C:24]([N:20]3[N:21]=[N:22][CH:23]=[N:19]3)=[CH:29][CH:28]=2)[CH:34]=[N:33]1)[CH3:12]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=c1[nH]ncn1-c1ccc(-n2ncnn2)cc1
Product: C[C@@H](n1ncn(-c2ccc(-n3ncnn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 4-[4-(2H-2-tetrazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone in the same manner as in Working Example 11 to give 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2H-2-tetrazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 25).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][CH2:22][CH2:23][NH:24][CH3:25].CCN(CC)CC>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:24]([CH2:23][CH2:22][O:21][CH3:20])[CH3:25])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCCOC
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COCCN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl

Procedure:
The title compound was prepared from (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B2) (3.07 g, 10 mmol), N-(2-methoxyethyl)methylamine (2.43 mL, 23 mmol) and Et3N (4.2 mL, 30 mmol) in DMSO (20 mL) at 23° C. according to the general procedure C. Obtained as a brown oil (3.57 g).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[C:6]([OH:9])(=[O:8])[CH3:7]>>[C:6]([O:9][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])(=[O:8])[CH3:7]
Reactant: ClCC1CO1
Reactant: CC(=O)O
Product: CC(=O)OCC(O)CCl
Temperature: 65 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
Epichlorohydrin (92.5 g, 1.0 mol) was dissolved in 61.2 g (1.0 mol) of glacial acetic acid and 0.35 g of ferric chloride was added. The mixture was stirred at 65° C. overnight. Another 0.35 g of ferric chloride was added and the mixture was stirred another day. It was then concentrated by evaporation under reduced pressure to obtain 153 g 3-chloro-2-hydroxypropyl acetate as an oil. A few crystals of p-toluenesulfonic acid were added and then 81.5 g (1.13 mol) of ethyl vinyl ether was added dropwise with stirring and cooling with an ice bath to keep the temperature below about 35° C. When the addition was complete, the mixture was stirred overnight at 40° C. The dark oily product was presumed to be 3-chloro-2-(1-ethoxyethoxy)propyl acetate. This oil was added dropwise with stirring to a mixture of 110 g (2.75 mol) of sodium hydroxide in 110 mL of water heated to 105° C. When the addition was complete, the mixture was heated at 105° C. with stirring for 4 hours. It was then cooled and poured into 500 mL of water. The resulting mixture was extracted with 2×500 mL of diethyl ether and the ethereal extract was washed with concentrated aqueous sodium chloride, dried over sodium sulfate, and concentrated by evaporation under reduced pressure at 30° C. to obtain a dark oil. This oil was distilled at 5 mm Hg (665 pascals) pressure. The 40 g portion boiling at 60-68° C., which was 3-(1-ethoxyethoxy)oxetane, was collected. This fraction was dissolved in 100 mL of methanol and 25 mg of p-toluenesulfonic acid was added with stirring at about 10° C. The mixture was stirred for 2 hours at ambient temperature and then 1.0 g of solid sodium bicarbonate was added with stirring. After 5 min, the mixture was filtered and concentrated by evaporation under reduce pressure. The colorless oil residue was distilled at 5 mm Hg (665 pascals) pressure and the 1.9 g fraction boiling at 50-56° C., which was the title compound, a colorless liquid, was collected.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:24][N:23]=[CH:22][CH:21]=1)=[CH:16][CH:15]=3.Cl[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:21]=[CH:22][N:23]([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:24]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Reactant: ClCCN1CCOCC1
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(CCN5CCOCC5)n4)ccc3n(C)c21

Procedure:
The process is carried out as in Example 36, using compound 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(1H-pyrazol-5-yl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one from Example 39 above and chloroethylmorpholine
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:10])[CH2:7][C:8]#[N:9].[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[C:19]=1[OH:20])[CH:15]=O>>[OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:10])[C:7]([C:8]#[N:9])=[CH:15][C:14]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[C:19]([OH:20])=[C:12]([OH:11])[CH:13]=1
Reactant: N#CCC(=O)NCCCO
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Product: N#CC(=Cc1cc(O)c(O)c([N+](=O)[O-])c1)C(=O)NCCCO
Yield: 52 %

Procedure:
The procedure described in Example 99 was repeated using N-(3-hydroxypropyl)cyanoacetamide and 3,4-dihydroxy-5-nitrobenzaldehyde. Yield 52%, m.p. 223°-228° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]([CH3:12])=O)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[CH3:13][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:15]>C(O)C.C(O)(=O)C>[CH3:1][O:2][N:3]=[C:4]([C:10](=[N:15][N:14]([CH3:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:12])[C:5]([N:7]([CH3:9])[CH3:8])=[O:6]
Reactant: CON=C(C(C)=O)C(=O)N(C)C
Reactant: CN(N)c1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: CON=C(C(=O)N(C)C)C(C)=NN(C)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.1 %

Procedure:
1.0 g (5.8 mmol) of 2-methoxyimino-N,N-dimethylacetoacetamide was dissolved in 15 ml of ethanol and 0.5 ml of acetic acid, and 0.78 g (6.4 mmol) of N-methyl-N-phenylhydrazine was added and the mixture was stirred for 24 hours at room temperature. After distilling the solvent off, water was added and the mixture was extracted three times with 20 ml of diethylether. After washing with a dilute hydrochloric acid, water and a saturated aqueous sodium chloride, the mixture was dried over with anhydrous magnesium sulfate, and the solvent was distilled off, and finally the residue thus obtained was purified by a column chromatography on a silica gel (n-hexane/ethyl acetate) to obtain 1.38 g (yield: 86%) of 2-methoxyimino-N,N-dimethy-3-(N-methyl-N-phenylhydrazono)butyramide as a yellow oil. 1H-NMR(CDCl3) δ ppm:2.13(3H, s), 2.90(3H,s), 3.07(3H, s), 3.29(3H, s), 3.99(3H,s), 6.90-7.02(3H, m), 7.33-7.29(2H, m).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([OH:12])[CH:10]=[CH2:11].[H-].[Na+]>CS(C)=O>[CH2:9]([O:12][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1)[CH:10]=[CH2:11]
Reactant: Clc1nccnc1Cl
Reactant: C=CCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C=CCOc1nccnc1Cl
Temperature: 0 °C

Procedure:
59.6 g of 2,3-dichloropyrazine and 92.8 g of allyl alcohol are dissolved in 400 ml of dimethylsulphoxide. 9.6 g of sodium hydride are introduced into this solution over the course of 30 minutes at 0°-5° C., whilst stirring. The mixture is then stirred for 15 hours at room temperature. Thereafter the reaction mixture is poured into 2 liters of ice water and extracted by shaking with ether. The ether extracts are washed with water, dried over sodium sulphate and evaporated in a waterpump vacuum. The residue is distilled in a high vacuum. 2-Allyloxy-3-chloro-pyrazine, boiling point 42°-44° C./0.03 mm Hg, is thus obtained.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH:17]3[C:22](=[O:23])[NH:21][C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[S:18]3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:30]I>CN(C)C=O>[CH3:30][N:21]1[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[S:18][CH:17]([CH2:16][CH2:15][CH2:14][CH2:13][N:10]2[CH2:9][CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)[C:22]1=[O:23]
Reactant: O=C1Nc2ccccc2SC1CCCCN1CC=C(c2ccccc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)C(CCCCN2CC=C(c3ccccc3)CC2)Sc2ccccc21
Temperature: 25 °C
Yield: 32.7 %

Procedure:
1.77 g (=0.004 m) of 2-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl]-2H-1,4-benzothiazine-3(4H)one (see Example 10) prepared analogously to Example were dissolved in 20 ml of anhydrous dimethylformamide with stirring. 0.121 g of sodium hydride was added under a nitrogen atmosphere, and the resulting suspension was maintained at room temperature for 10 minutes. 0.70 g of methyl iodide was then added all at once, and the reaction mixture was stirred for 2.5 hours at room temperature. The reaction mixture was worked up by distilling off the solvent, adding 100 ml of water to the residue, and extracting the mixture with 100 ml of ethyl acetate. The organic phase was concentrated by evaporating the solvent, and the crude title compound which remained as a residue was purified by column chromatography. 0.6 g of 4-methyl-2-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl]-2H-1,4-benzothiazine-3(4H)-one was obtained as beige-colored powder.
Reaction SMILES: [Br:1][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]=[O:15])=[CH:4][CH:3]=1.[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=1)[CH2:21][C:22]1[O:23][CH:24]=[N:25][N:26]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:24]2[O:23][C:22]([CH2:21][C:20]3[CH:27]=[CH:28][CH:29]=[C:18]([C:17]([F:30])([F:31])[F:16])[CH:19]=3)=[N:26][N:25]=2)[OH:15])=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cccc(Cc2nnco2)c1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1nnc(Cc2cccc(C(F)(F)F)c2)o1

Procedure:
Prepared according to the procedure described in Example 30, Step 1, using 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2-(3-trifluoromethyl-benzyl)-[1,3,4]oxadiazole.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[C:7]([NH2:17])([C:13]([F:16])([F:15])[F:14])([C:9]([F:12])([F:11])[F:10])[Cl:8].[N-]=C=O>N1C=CC=CC=1>[Cl:8][C:7]([N:17]=[C:2]=[O:3])([C:9]([F:12])([F:11])[F:10])[C:13]([F:14])([F:15])[F:16]
Reactant: NC(Cl)(C(F)(F)F)C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Agent: [N-]=C=O
Solvent: c1ccncc1
Product: O=C=NC(Cl)(C(F)(F)F)C(F)(F)F
Reaction time: 4 h

Procedure:
A mixture of 127 g (1 mole) of oxalyl chloride, 165 g (1 mole) of perfluoropropyliden-2-imine, and 5 ml of pyridine was heated in a 600 ml Hastelloy tube at 100° for 4 hrs, 150° for 4 hrs, and 200° for 4 hrs. The bomb was cooled and vented, and the contents were filtered to remove suspended solid. Distillation gave 102.3 g of a 25:75 mixture of (CF3)2CClNH2 and the isocyanate, bp 46.0°-46.5°, and 29.3 g of pure isocyanate as a colorless liquid: bp 50.5°-51.0°; 19F nmr (CCl3F) δ 78.0 (s); ir (liquid) 4.40 μ.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:3][CH2:2]1.Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:21]([CH3:23])[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:15]=23)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(OC)ccc3OCC3CC3)ccnc12
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(OC)ccc3OCC3CC3)ccnc12

Procedure:
Starting from ethyl 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (example D.a5) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is prepared as pale yellow viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]2Cl.[CH3:19][O:20][C:21]1[C:22]([NH2:26])=[CH:23][S:24][CH:25]=1>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]2[NH:26][C:22]1[C:21]([O:20][CH3:19])=[CH:25][S:24][CH:23]=1
Reactant: COc1cscc1N
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2c(OC)cccc2c1Nc1cscc1OC
Yield: 76.2 %

Procedure:
Ethyl 8-methoxy-4-chloroquinoline-3-carboxylate (1.5 g, 0.0056 mol) and 4-methoxy-3-aminothiophene (1.46 g, 0.0112 mol) in 1,4 dioxan (20 ml) were heated under reflux for 4 hours. The solid which had formed was collected by filtration and dried. The solid was dissolved in chloroform, washed with sodium carbonate solution (50 ml), then water, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a yellow solid. Recrystallization from ethyl acetate gave the title compound, (1.53 g) m.p. 176°-178°.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]2[CH2:11][CH:12]([CH2:14]OS(C3C=CC(C)=CC=3)(=O)=O)[O:13][C:9]=2[CH:8]=[C:7]([C:26](=[O:34])[NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH3:33])[N:29]=2)[CH:6]=1)([CH3:3])[CH3:2].[NH2:35][CH2:36][CH2:37][CH3:38]>C1COCC1>[CH3:33][N:30]1[CH:31]=[CH:32][C:28]([NH:27][C:26]([C:7]2[CH:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[C:10]3[CH2:11][CH:12]([CH2:14][NH:35][CH:36]4[CH2:38][CH2:37]4)[O:13][C:9]=3[CH:8]=2)=[O:34])=[N:29]1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(OC(C)C)cc(C(=O)Nc4ccn(C)n4)cc3O2)cc1
Reactant: CCCN
Solvent: C1CCOC1
Product: CC(C)Oc1cc(C(=O)Nc2ccn(C)n2)cc2c1CC(CNC1CC1)O2
Temperature: 50 °C
Yield: 16 %

Procedure:
To a solution of toluene-4-sulfonic acid 4-isopropoxy-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-2-ylmethyl ester (216a) (84 mg, 0.17 mmol) in THF (2 mL) was added aminopropane (0.5 mL). The mixture was heated at 50° C. for 2 days, then concentrated, and purified by reverse phase HPLC to give a white solid (10 mg, 16% yield). 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1 H) 7.26-7.34 (m, 1 H) 7.01 (s, 1 H) 6.80-6.87 (m, 1 H) 4.98-5.07 (m, 1 H) 4.59-4.69 (m, 1 H) 3.81 (s, 3 H) 3.23 (dd, J=16.42, 9.35 Hz, 1 H) 2.93-3.05 (m, 2 H) 2.86 (dd, J=16.42, 7.07 Hz, 1 H) 2.20-2.27 (m, 1 H) 1.34 (dd, J=5.94, 1.14 Hz, 6 H) 0.36-0.54 (m, 4 H); LCMS for C20H26N4O3 m/z 371.20 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:44]=[CH:45][CH:46]=1)[CH2:12][C@@H:13]1[C@@H:17](/[CH:18]=[CH:19]/[C@@H:20]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:16]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:15][C@@H:14]1[CH2:42][OH:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:54][S:55](Cl)(=[O:57])=[O:56].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:54][S:55]([O:43][CH2:42][C@H:14]1[CH2:15][C@@H:16]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C@H:17](/[CH:18]=[CH:19]/[C@@H:20]([O:26][Si:27]([C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:28])[CH3:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:13]1[CH2:12][C:11]1[CH:44]=[CH:45][CH:46]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)(=[O:57])=[O:56]
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](Cc2cccc(OCc3ccccc3)c2)[C@@H](CO)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](Cc2cccc(OCc3ccccc3)c2)[C@@H](COS(C)(=O)=O)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A solution of ((1S,2S,3R,4R)-2-(3-(benzyloxy)benzyl)-4-(tert-butyldimethysilyoxy)-3-((S,E)-3-(tert-butyldimethylsilyoxy)oct-1-enyl)cyclopentyl)methanol (50 g, 0.075 mol) in dry CH2Cl2 (500 ml) was cooled to 0° C. under nitrogen and treated with triethylamine (31.3 ml, 0.225 mol), then with methanesulfonyl chloride (11.6 ml, 0.15 mol). The mixture was poured to saturated sodium bicarbonate aqueous and stirred for 30 minutes. The reaction mixture was phase separated and the aqueous layer was extracted with 500 ml ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. Yield: 81%.