Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:7]2O.[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([CH:24](O)[N:25]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:26]2=[O:29])=[CH:22][CH:21]=1.O.C[O:37][CH2:38][CH2:39]OC>C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10]([C:9](=[O:13])[N:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:7]2[CH2:39][C:38]([O:29][CH2:26][CH3:27])=[O:37])=[CH:11][CH:12]=1.[Cl:19][C:20]1[CH:28]=[C:27]2[C:23](=[CH:22][CH:21]=1)[CH:24]([CH2:39][C:38]([O:13][CH2:9][CH3:10])=[O:37])[N:25]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:26]2=[O:29]
Reactant: CC(C)CN1C(=O)c2ccc(Cl)cc2C1O
Reactant: CC(C)CN1C(=O)c2cc(Cl)ccc2C1O
Reactant: COCCOC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CC1c2cc(Cl)ccc2C(=O)N1CC(C)C
Product: CCOC(=O)CC1c2ccc(Cl)cc2C(=O)N1CC(C)C
Temperature: 20 °C

Procedure:
Ethyl (5-chloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate and ethyl (6-chloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate are prepared as described in Example 2, starting with 4 g of 60% sodium hydride in 200 cm3 of 1,2-dimethoxyethane, 20.3 cm3 of triethyl phosphonoacetate and 12 g of 5-chloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-chloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one. The mixture is refluxed for 18 hours and is then cooled to a temperature in the region of 20° C. The reaction mixture is treated with 200 cm3 of water and then with 100 cm3 of ethyl acetate. After separation of the phases by settling, the aqueous phase is extracted twice with 200 cm3 of ethyl acetate. The organic extracts are combined, washed with 100 cm3 of brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is purified by chromatography under argon pressure (60 kPa) on a cartridge of silica gel (particle size 32-63 μm), eluting with successive mixtures of cyclohexane/ethyl acetate (90/10 and then 80/20 by volume). The fractions comprising the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 3.1 g of ethyl (5-chloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate and ethyl (6-chloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate are thus obtained in the form of a viscous yellow oil. (Rf=0.34, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:47]CCCl>>[ClH:47].[O:18]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][N:14]1[CH2:13][CH2:12][C:11]2([N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][NH:9][C:10]2=[O:17])[CH2:16][CH2:15]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClCCCl
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=Cc1ccccc1Oc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cl
Product: O=C1NCN(c2ccccc2)C12CCN(Cc1ccccc1Oc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (291 mg, 1.26 mmol) and 2-phenoxybenzaldehyde (299 mg, 1.50 mmol) in 1,2-dichloroethane (25 mL) was added sodium triacetoxyborohydride (454 mg, 2.14 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 20 h. The reaction mixture was then quenched with 1N aqueous NaHCO3 and extracted with CHCl3 (100 mL). The combined extracts were dried over Na2SO4, filtered and concentrated. The isolated solid was purified by flash chromatography on silica gel to yield the title compound as a free base.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.C(N(CC)CC)C.C1COCC1.[C:23](#[N:26])[CH:24]=[CH2:25]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH2:25][CH2:24][C:23]#[N:26])[CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: C=CC#N
Reactant: OCc1cc(Cl)nc(Cl)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#CCCOCc1cc(Cl)nc(Cl)c1
Reaction time: 2 h
Yield: 49.2 %

Procedure:
0.36 g of 2,6-dichloro-4-pyridinemethanol and 0.1 g of triethylamine were dissolved into 2 ml of THF, 0.12 g of acrylonitrile were added to the solution at room temperature, and stirring was conducted for 2 hours. After the reacted solution was left overnight at room temperature, ethyl acetate was added. The organic phase was washed with water, and was dried by adding sodium sulfate. The solvent was removed by evaporation, and the residue was purified by silica gel column chromatography to obtain 0.23 g of 2,6-dichloro-4-(2-cyanoethoxymethyl)pyridine (Compound No. 6).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]([CH2:14][CH3:15])[CH2:12][CH2:11][NH:10][C:9]2=[O:16])=[CH:4][CH:3]=1.Br[C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])[N:23]=1.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O>C(O)(C)C>[Br:24][C:22]1[N:23]=[C:18]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[C:9](=[O:16])[NH:10][CH2:11][CH2:12][N:13]3[CH2:14][CH3:15])=[CH:6][CH:7]=2)[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=1
Reactant: CCN1CCNC(=O)C1c1ccc(N)cc1
Reactant: Cn1cc(Br)nc(Br)c1=O
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CCN1CCNC(=O)C1c1ccc(Nc2nc(Br)cn(C)c2=O)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 33 (450 mg, 2.05 mmol), isopropanol (5 mL), 13 (603 mg, 2.26 mmol) and DL-10-camphorsulfonic acid (813 mg, 3.50 mmol), and the reaction mixture was then stirred at reflux for 16 h. After this time, the reaction mixture was cooled to room temperature, filtered and the filter cake washed with isopropanol (10 mL). The resulting solid was dissolved in methylene chloride/methanol (3:1), absorbed onto silica gel and purified by flash chromatography to afford 34 in 79% yield (654 mg) as an orange solid: mp 152-153° C.; 1H NMR (500 MHz, CDCl3) δ8.28 (bs, 1H7.73 (d, 2H, J=8.5 Hz), 7.43 (d, 2H, J=8.5 Hz), 6.74 (s, 1H), 5.90 (d, 1H, J=3.5 Hz), 4.12 (s, 1H), 3.60 (m, 1H), 3.52 (s, 3H), 3.36 (m, 1H), 3.12 (m, 1H), 2.60 (m, 2H), 2.28 (m, 1H), 1.00 (t, 3H, J=7.0 Hz); MS (ESI+) m/z 406.0 (M+H).
Reaction SMILES: [O:1]=[C:2]([CH3:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:18])OCC(Cl)(Cl)Cl)=[CH:6][CH:5]=1.[C:20]1([C:26]2[N:27]=[C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[O:1]=[C:2]([CH3:19])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([N:34]2[CH2:35][CH2:36][N:31]([C:28]3[S:29][CH:30]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:27]=3)[CH2:32][CH2:33]2)=[O:18])=[CH:8][CH:9]=1
Reactant: CC(=O)Cc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Cc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)cs3)CC2)cc1

Procedure:
A solution of 2,2,2-trichloroethyl [4-(2-oxopropyl)phenyl]carbamate (200 mg, 0.616 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (151 mg, 0.616 mmol), diisopropylethylamine (0.107 ml, 0.616 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (47.0 mg, 18.2%) as a solid.
Reaction SMILES: N[C@@:2]12[C@H:19]3[C@@H:10]([C@:11]4([CH3:21])[C@H:16]([CH2:17][CH2:18]3)[CH2:15][C@@H:14](O)[CH2:13][CH2:12]4)[CH2:9][CH2:8][C@:6]1([CH3:7])[C@@H:5]([C:22]([O:24][CH3:25])=[O:23])[CH2:4][CH2:3]2.C(N1C=CN=C1)(N1C=CN=C1)=O.OCCN1CCNCC1.C(Cl)[Cl:48]>>[ClH:48].[ClH:48].[CH3:7][C@:6]12[CH2:8][CH2:9][C@H:10]3[C@@H:19]([CH2:18][CH2:17][CH:16]4[C@:11]3([CH3:21])[CH2:12][CH2:13][CH2:14][CH2:15]4)[C@@H:2]1[CH2:3][CH2:4][CH:5]2[C:22]([O:24][CH3:25])=[O:23]
Reactant: ClCCl
Reactant: COC(=O)[C@H]1CC[C@]2(N)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: OCCN1CCNCC1
Product: COC(=O)C1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C
Product: Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A stirred solution of (3β,5β,14β,17β)-14-Amino-3-hydroxyandrostane-17-carboxylic Acid, Methyl Ester, prepared according to the procedure described in U.S. Pat. No. 4,885,280, incorporated by reference herein, (1.03 g, 2.95 mmole) in 25 ml of CH2Cl2 under a N2 blanket is treated with 1,1'-carbonyldiimidazole (0.58 g, 3.55 mmole). The mixture is stirred at room temperature for 24 hours and then treated with 4-hydroxyethyl-piperazine (1.92 g, 14.75 mmole). The reaction is continued to be stirred at room temperature under nitrogen overnight. The reaction solution is concentrated under reduced pressure and the residue is taken up in fresh CH2Cl2. The CH2Cl2 solution is washed with 4×25 ml portions of water. The organic layer is dried over anhydrous Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to leave an oily residue weighing 0.94 g. The crude free base is purified by chromatography on silica gel packed column with an eluent of 5% MeOH/95% CH2Cl2 containing 1% NH4OH. The pure free base is dissolved in absolute alcohol and then treated with saturated ethanolic/HCl to yield (3β,5β,14β,17β)-14-Amino-3-[[[4-2-hydroxyethyl)-1-piperazinyl)carbonyl]oxy]androstane-17-carboxylic Acid, Methyl Ester Dihydrochloride Final Product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]2[C:29]3[C:24](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=3)[CH2:23][N:22]([CH3:32])[CH2:21]2)[CH:15]=1)(=[O:13])=[O:12].[CH2:33]([N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])C.[O:40]([CH2:52][C:53]([O:55]N1C(=O)CCC1=O)=O)[CH2:41][C:42]([O:44]N1C(=O)CCC1=O)=O>CN(C=O)C>[O:40]([CH2:41][C:42]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:37]2[C:29]3[C:39](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=3)[CH2:38][N:35]([CH3:33])[CH2:36]2)[CH:15]=1)(=[O:13])=[O:12])=[O:44])[CH2:52][C:53]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]2[C:29]3[C:24](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=3)[CH2:23][N:22]([CH3:32])[CH2:21]2)[CH:15]=1)(=[O:13])=[O:12])=[O:55]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCN)c2)C1
Reactant: CCN(CC)CC
Reactant: O=C(COCC(=O)ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCNC(=O)COCC(=O)NCCOCCOCCNS(=O)(=O)c3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1
Reaction time: 8 h
Yield: 26.8 %

Procedure:
To a solution of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (150 mg, 0.30 mmol) in DMF (2 mL) was added triethylamine (60 mg, 0.59 mmol) and bis(2,5-dioxopyrrolidin-1-yl) 2,2′-oxydiacetate (intermediate 178.1) (49 mg, 0.15 mmol) and the resulting solution was stirred overnight. After removal of the solvent, the crude product (150 mg) was purified by Flash-Prep-HPLC (C18 silica gel; methanol/water=0.05/100 increasing to methanol/water=90/100 within 25 min) to give 44.4 mg (27%) of the title compound as a TFA salt. 1H-NMR (300 MHz, CD3CD, ppm): 7.79˜7.76 (m, 2H), 7.70 (s, 2H), 7.57-7.50 (m, 4H), 7.36 (d, J=Hz, 2H), 4.89-4.41 (m, 2H), 4.06 (m, 4H), 3.81-3.62 (m, 5H), 3.59-3.42 (m, 11H), 3.33-3.31 (m, 8H), 3.07-3.01 (m, 6H), 2.71-2.64 (m, 2H), 2.48 (s, 6H). LCMS (ES, m/z): 1103[M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5](O)=[O:6].Cl.[CH3:13][NH:14][O:15][CH3:16].C(N=[N+]=[N-])C.O>O=S(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([N:14]([O:15][CH3:16])[CH3:13])=[O:6]
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Reactant: CNOC
Agent: CCN=[N+]=[N-]
Agent: Cl
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The solution of 3,5-dibromobenzoic acid (26 g, 93 mmol) in SOCl2 (100 mL) was heated at reflux for 2 h, concentrated, diluted with dry DCM (300 mL) and added slowly to a stirred solution of N,O-dimethylhydroxylamine hydrochloride (9.75 g, 100 mmol) and EtN3 (28 g, 277 mmol) in dry DCM (300 mL) at 0° C. The solution was stirred for 1 h at rt, poured into water and the organic layer was separated. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated to give crude compound P37a (28 g, 93%) as an oil.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(OCC)C>O1CCCC1>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccc(Oc2ccccc2)c1
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
After stirring the reaction mixture for an additional 0.5 hour at 0°-5°C, a solution of 3860 grams (18 moles) of m-phenoxybenzoic acid in tetrahydrofuran was added dropwise over a 4 hour period while maintaining a reaction temperature of 0°-10°C. When the addition was complete, the reaction mixture was stirred for 12 hours at 20°C followed by 2 hours at 40°C. The reaction mixture was then transferred to a 10 gallon bottle containing 6 liters of water and 8 liters of diethyl ether. After mixing thoroughly, the aqueous layer was removed and the organic layer was extracted with water (1 × 4 liters), extracted with aqueous saturated sodium bicarbonate solution (1 × 4 liters), extracted with aqueous saturated sodium chloride solution (1 × 4 liters), dried over anhydrous potassium carbonate, filtered, and concentrated on a rotary evaporator. Short-path distillation gave 3000 grams (83% yield) of m-phenoxybenzyl alcohol, bp 135°-140°C/0.10 mm, n20D 1.5935.
Reaction SMILES: [CH:1]1([C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I.[P]>C(O)(=O)C>[CH:1]1([CH:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OC(c1ccncc1)(c1ccc(F)cc1)C1CCCCC1
Agent: I
Agent: [P]
Solvent: CC(=O)O
Product: Fc1ccc(C(c2ccncc2)C2CCCCC2)cc1
Yield: 33.9 %

Procedure:
A mixture of the free base of α-cyclohexyl-α-(4-fluorophenyl) -4-pyridinemethanol (16.54 g, 0.058 mole), 57% hydrogen iodide (250 ml), glacial acetic acid (250 ml), and phosphorus (50.0 g) was heated overnight at reflux. The reaction mixture was cooled and filtered with Celite®. The volume of the filtrate was concentrated to 100 ml. Ice/50% sodium hydroxide was added and the aqueous phase was extracted with chloroform. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a green oil. A 4 g portion of this oil was subjected to flask chromatography on silica gel using 20% ethyl acetate-hexanes for elution. Fractions of similar purity were combined and solvent removed to give an oil. This oil was dried in vacuo overnight at 80° C. The oil crystallized to give 2.95 g (33.9% yield) of white, crystalline solid, m.p. 78°-81° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]Cl)=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2].[CH2:16]([SH:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][S:28][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Reactant: CCCCCCCCCCCCS
Product: CCCCCCCCCCCCSSc1ccc([N+](=O)[O-])cc1C(Cl)(Cl)Cl
Yield: 85.6 %

Procedure:
As in Example 1, 61.4 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride is reacted with 40.5 g of dodecyl-mercaptan. There is obtained 81 g (86% of theory) of (4-nitro-2-trichloromethylphenyl)-dodecyl disulfide.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.N1C=CC=CC=1.Cl.Cl.Cl.[NH:50]1[CH2:54][CH2:53][CH:52]([C:55]2[CH:60]=[N:59][CH:58]=[CH:57][N:56]=2)[CH2:51]1>C(#N)C>[F:17][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([N:50]2[CH2:54][CH2:53][CH:52]([C:55]3[CH:60]=[N:59][CH:58]=[CH:57][N:56]=3)[CH2:51]2)=[O:16])=[CH:7][CH:8]=1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Reactant: c1cnc(C2CCNC2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCC(c2cnccn2)C1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
5-[4-(Trifluoromethyl)phenyl]isoxazole-4-carboxylic acid (30 mg, 0.12 mmol) was dissolved in acetonitrile (1.5 mL) followed by the addition of o-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (52 mg, 0.16 mmol), pyridine (60 μL, 0.72 mmol) and 2-pyrrolidin-3-yl-pyrazine trihydrochloride (36 mg, 0.14 mmol), and stirred at 60° C. for 30 min. The residue was purified on reversed phase HPLC to yield the title compound (26 mg). HRMS (ESI, pos. ion) m/z calcd for C19H15F3N4O2: 388.1147, found 388.1152.
Reaction SMILES: C(O[C@H]1C2C(=CC(OCCC)=CC=2)[C@@H](N)C1)C=C.[CH3:19][O:20][C:21]([CH:23](P(OC)(OC)=O)[NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:22].CN(C)C(=N)N(C)C.[Cl:49][C:50]1[CH:51]=[C:52]([CH:55]=[C:56]([Cl:58])[CH:57]=1)[CH:53]=O>C1COCC1>[CH2:28]([O:27][C:25]([NH:24]/[C:23](=[CH:53]\[C:52]1[CH:51]=[C:50]([Cl:49])[CH:57]=[C:56]([Cl:58])[CH:55]=1)/[C:21]([O:20][CH3:19])=[O:22])=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: C=CCO[C@@H]1C[C@H](N)c2cc(OCCC)ccc21
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1cc(Cl)cc(Cl)c1)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 85.6 %

Procedure:
Step BF (1): To a slurry of N-(Benzyloxycarbonyl)-alpha-phosphonoglycine trimethyl ester (76.37 g, 230.5 mmol) in THF (210 mL) just thawed from a −78° C. bath was added tetramethylguanidine (28.85 mL, 230.0 mmol) dropwise. A cold solution of 3,5-dichlorobenzaldehyde (36.70 g, 209.7 mmol) in THF (52.5 mL) was added via cannula. The cold yellow solution was stirred for 1 hour, at which time TLC revealed no aldehyde remained. The THF was removed in vacuo, and EtOAc and 1M HCl was added. The mixture was extracted three times into EtOAc, and the combined organic layers were washed with water, brine, and then dried over MgSO4. Concentration in vacuo followed by recrystallization of the desired olefin isomer from EtOAc/hexane yielded pure product. Concentration of the mother liquor and recrystallization of the residue yielded, over 4 crops, 68.22 g (86% yield) of (Z)-methyl 2-(benzyloxycarbonylamino)-3-(3,5-dichlorophenyl)acrylate. 1H NMR (500 MHz, CDCl3) δ 7.28-7.42 (m, 7H) 7.16 (s, 2H) 6.55 (s, 1H) 5.10 (s, 2H) 3.79-3.90 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16](O)=[O:17])[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11]([CH3:30])=[C:10]2[C:31]([C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)=[O:32])=[CH:5][CH:4]=1)#[N:2].[F:38][C:39]([F:46])([F:45])[CH2:40][S:41]([NH2:44])(=[O:43])=[O:42].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]([NH:44][S:41]([CH2:40][C:39]([F:46])([F:45])[F:38])(=[O:43])=[O:42])=[O:17])[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=3)[C:11]([CH3:30])=[C:10]2[C:31]([C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)=[O:32])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC1=C(C(=O)c2ccco2)C(c2ccc(C#N)cc2)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: NS(=O)(=O)CC(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1=C(C(=O)c2ccco2)C(c2ccc(C#N)cc2)N(CC(=O)NS(=O)(=O)CC(F)(F)F)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
A solution of [6-(4-cyanophenyl)-5-(2-furoyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phen-yl]-3,6-dihydropyrimidin-1(2H)-yl]acetic acid (Example 29A) (75 mg, 0.15 mmol), 2,2,2-trifluoroethane-sulfonamide (23 mg, 0.16 mmol), 1,3-dicyclohexylcarbodiimide (33 mg, 0.16 mmol) and 4-dimethylaminopyridine (20 mg, 0.16 mmol) in dichloromethane (4 ml) is stirred at room temperature for 4 days. The product is extracted with dichloromethane (100 ml), washed with 2 N hydrochloric acid and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by preparative HPLC(RP18 column; eluent: acetonitrile/0.1% aq. formic acid 30:70→90:10). The title compound is isolated as a colourless solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=S)[S-:12].C([NH+](CC)CC)C.ClC(OCC)=O.C(Cl)(Cl)Cl.C(Cl)Cl>C(N(CC)CC)C>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N:10]=[C:11]=[S:12]
Reactant: Fc1ccc(NC(=S)[S-])c(F)c1F
Agent: CCOC(=O)Cl
Agent: CC[NH+](CC)CC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc(N=C=S)c(F)c1F

Procedure:
That is, first 2,3,4-trifluoroaniline (V) is reacted with carbon disulfide in the presence of triethylamine to produce triethylammonium N-(2,3,4-trifluorophenyl)dithiocarbamate (VI). Then the compound (VI) is reacted with ethyl chloroformate in an organic solvent such as chloroform or methylene chloride in the presence of triethylamine to give 2,3,4-trifluorophenylisothiocyanate (VII). The compound (VII) is then reacted with di(lower alkyl) malonate sodium salt, which is prepared from di(lower alkyl) malonate and sodium hydride, in an organic solvent such as tetrahydrofuran or dioxane to give di(lower alkyl) [(2,3,4-trifluoroanilino)(mercapto)methylene]malonate sodium salt (VIII). The compound (VIII) is then reacted with 1-acetoxy-3-halogenoacetone in an organic solvent such as N,N-dimethylformamide, dimethylsulfoxide or acetonitrile to give di(lower alkyl) [(2,3,4-trifluoroanilino)(3-acetoxy-2-oxopropylthio)methylene]malonate (IX). The compound (IX) is then reacted with sulfuric acid to give di(lower alkyl) [3-(2,3,4-trifluorophenyl)-4-hydroxymethyl-2-thiazolidene]malonate (X). The compound (X) is then reacted with sodium hydride in an organic solvent such as dioxane, tetrahydrofuran or N,N-dimethylformamide to give di(lower alkyl) (6,7-difluoro-1H,4H-thiazolo[4,3-c][1,4]benzoxazin-1-ylidene)malonate (XI).