Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:7]=1[C:8]([OH:10])=O>C1C=CC=CC=1>[NH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:7]=1[C:8]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:7]=1)=[O:10]
Reactant: Cc1cccc(N)c1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1cccc(N)c1C(=O)Nc1ccccc1
Reaction time: 8 h

Procedure:
Thionyl chloride (14.5 mL, 198 mmol) was added to a solution of 2-amino-6-methylbenzoic acid (10.0 g, 66.1 mmol) in benzene (250 mL). The resulting suspension was heated to reflux and stirred overnight. After cooling, the reaction was concentrated in vacuo, and the resulting residue was dissolved in chloroform (300 mL). Aniline (15, mL, 165 mmol) was added, and the mixture heated to reflux. After three hours, the reaction was allowed to cool and the resulting suspension was filtered. The filtrate was subjected to flash chromatography, and the Crude product recrystallized from isopropanol to provide compound 15 as a yellow crystalline solid. MS (ES): m/z 227 (M+H), 134. 1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.75 (d, 2H, J=7.9 Hz), 7.32 (t, 2H, J=7.8 Hz), 7.07 (t, 1H, J=7.3 Hz), 7.00 (t, 1H, J=7.8 Hz), 6.58 (d, 1H, J=8.1 Hz); 6.46 (d, 1H, J=7.4 Hz), 4.98 (br. s, 2H), 2.21 (s, 3H). The reaction described above and compound 15 are shown below.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:11][C:10]2[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=2[CH:4]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:1][CH2:2][C:3]1[S:11][C:10]2[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=2[CH:4]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2sc(CO)cc2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2sc(COS(C)(=O)=O)cc2C1
Reaction time: 2 h

Procedure:
To a dichloromethane solution (22 ml) of tert-butyl 2-(hydroxymethyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (5.3 mmol) was added triethylamine (21.2 mmol) and methane sulfonyl chloride (7.95 mmol) at 0° C. and the resulting reaction mixture was stirred at same temperature for 2 h (monitored by TLC). The reaction was diluted with dichloromethane, successively washed with water and brine and finally dried over sodium sulfate. Evaporation of the organic layer under reduced pressure gave the crude product which was used directly in the next step. Yield: quantitative
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:12]2)=[O:10])[CH2:4][CH2:3]1.[N:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:20]1([S:17]([N:13]2[CH2:14][CH2:15][CH2:16][C@H:11]([C:9]([NH:8][CH:5]3[CH2:6][CH2:7][CH:2]([O:1][C:29]4[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=4)[CH2:3][CH2:4]3)=[O:10])[CH2:12]2)(=[O:19])=[O:18])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)[C@H]1CCCN(S(=O)(=O)c2ccccc2)C1
Reactant: Oc1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NC1CCC(Oc2ccncc2)CC1)[C@H]1CCCN(S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.3 %

Procedure:
Under a nitrogen atmosphere, to a mixture of (3S)—N-(trans-4-hydroxycyclohexyl)-1-(phenylsulfonyl)piperidine-3-carboxamide (25 mg, 0.068 mmol), 4-pyridinol (9.7 mg, 0.10 mmol), and triphenylphosphine (26.8 mg, 0.10 mmol) in tetrahydrofuran (0.5 mL) was added a solution of diethyl azodicarboxylate (16 μL, 0.10 mmol) in tetrahydrofuran (0.1 mL). The mixture was stirred at r.t. overnight. The product was purified with prep. HPLC. 1.9 mg product was obtained, yield: 6.3%. LCMS: m/z 444.2 (M+H)+; 887.2 (2M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=2[Cl:16])=[N:6][CH:5]=[C:4](Cl)[N:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=2[Cl:16])=[N:6][CH:5]=[C:4]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)[N:3]=1
Reactant: Nc1nc(Cl)cnc1-c1cc(Cl)cc(Cl)c1Cl
Reactant: CN1CCNCC1
Product: CN1CCN(c2cnc(-c3cc(Cl)cc(Cl)c3Cl)c(N)n2)CC1
Temperature: 140 °C

Procedure:
2-Amino-6-chloro-3-(2,3,5-trichlorophenyl)pyrazine (0.215 g ,7.0×10−3 mole) Example I Route A and 1-methylpiperazine (5 ml, Aldrich), were heated at 140° C. for 1 hr. The mixture was evaporated in vacuo and the residue was purified by ‘flash chromatography’ eluting with ethanol:dichloromethane, 0-4%. The product was dissolved in the minimum of dichloromethane and hexane (10 ml), added slowly to give yellow needles. Yield 0.247 g (95%), M.p. 185° C.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[C:42]([CH3:43])=[C:41]([CH3:44])[N:40]([CH3:45])[C:39](=[O:46])[CH:38]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[C:42]([CH3:43])=[C:41]([CH3:44])[N:40]([CH3:45])[C:39](=[O:46])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1c(Br)cc(=O)n(C)c1C
Product: Cc1c(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc(=O)n(C)c1C

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-1,5,6-trimethylpyridin-2(1H)-one following a procedure analogous to that described in Example 6 Step 1. LC-MS Method 2 tR=1.187 min, m/z=489.2; 1H NMR (CDCl3) 1.10 (s, 3H), 1.15 (s, 3H), 1.32 (m, 3H), 1.52 (m, 3H), 1.72 (s, 1H),2.18 (m, 3H), 2.19 (m, 1H), 2.42 (m, 4H), 2.86 (m, 1H), 4.12 (m, 2H), 5.66 (m, 1H), 6.16 (s, 1H), 6.53 (s, 1H), 6.98 (m, 2H), 7.23-7.34 (m, 7H).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[C:3]=1[C:14]([NH2:16])=[O:15].C(N(CC)C(C)C)(C)C.[C:26]1([CH3:35])[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>C(Cl)Cl>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([CH3:35])=[CH:27][CH:28]=3)=[O:34])=[CH:11][CH:12]=2)[C:3]=1[C:14]([NH2:16])=[O:15]
Reactant: NC(=O)c1c(-c2ccc(N)cc2)nsc1N
Reactant: Cc1ccc(N=C=O)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)Nc2ccc(-c3nsc(N)c3C(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 69.3 %

Procedure:
A mixture of 5-amino-3-(4-aminophenyl)isothiazole-4-carboxamide (25 mg, 0.11 mmol), N,N-diisopropylethylamine (0.047 mL, 0.27 mmol), and para-tolyl isocyanate (0.016 mL, 0.13 mmol) in 0.9 mL DCM was reacted at room temperature. After 1 hour an additional 0.006 mL para-tolyl isocyanate was added, and then 0.004 mL at 3.5 hrs. At 21 hours the reaction was quenched with 1 mL MeOH, stirred 10 min at rt, and then evaporated. The residue was triturated with EtOAc which afforded the title compound as a pale yellow solid (28 mg, 72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:11]=[CH2:10]
Reactant: C=CCBr
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
Into a 1 L round-bottomed flask containing 500 ml of acetonitrile was added 4-fluorophenol (30.0 g, 267.6 mmol), 3-bromoprop-1-ene (41.7 g, 344.7 mmol, 1.3 eq), and potassium carbonate (55 g, 398 mmol, 1.5 eq). The mixture was stirred for 3.5 hours at 60° C. (oil bath).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][CH:32]=1)[CH2:7][NH:8][C:9]([C:11]1[NH:12][C:13]2[C:18]([C:19]=1[S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])=[CH:17][C:16]([Cl:29])=[CH:15][CH:14]=2)=[O:10])([O-])=O.[H][H]>O1CCCC1.CO.[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][CH:32]=1)[CH2:7][NH:8][C:9]([C:11]1[NH:12][C:13]2[C:18]([C:19]=1[S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:21])=[O:22])=[CH:17][C:16]([Cl:29])=[CH:15][CH:14]=2)=[O:10]
Reactant: [H][H]
Reactant: O=C(NCc1cccc([N+](=O)[O-])c1)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Agent: O=[Pt]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cccc(CNC(=O)c2[nH]c3ccc(Cl)cc3c2S(=O)(=O)c2ccccc2)c1

Procedure:
A solution of N-(3-nitrobenzyl) 3-phenylsulfonyl-5-chloroindole-2-carboxamide (353 mg, 0.75 mmol) in tetrahydrofuran (25 mL) and methanol (10 mL) containing platinum oxide (70 mg) was hydrogenated with an atmospheric pressure of hydrogen for 3 hours. The degassed solution was filtered to remove catalyst and the solvents evaporated. The residue was triturated with diethyl ether to give the product. Crystallization from acetonitrile gave analytically pure product, mp 247°-249° C.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([SH:16])[CH:11]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:10]1([CH3:9])[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[CH:11]=1
Reactant: Cc1cccc(S)c1
Reactant: Nc1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: Cc1cccc(Sc2ccc(N)cc2)c1
Yield: 90.1 %

Procedure:
The general procedure in example 39 was followed. 4-Iodoaniline (219 mg, 1.0 mmol), m-thiocresol (119 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 4-(3-tolyl)sulfanylaniline (194 mg, 90% yield) as pale yellow liquid. Column chromatographic solvent (hexane/ethyl acetate=4/1). Rf=0.4 (hexane/ethyl acetate=4/1). 1H NMR (CDCl3, 300 MHz) δ 7.28 (dt, 2 H, J=7.5 Hz, 0.9 Hz), 7.08 (t, 1 H, J=7.8 Hz), 6.91 (t, 3 H, J=7.5 Hz), 3.71 (brs, 2 H), 2.26 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 138.8, 138.1, 136.2, 128.9, 128.1, 126.4, 124.6, 117.5, 116.1, 100.0, 21.8. IR (neat, cm−1) 3460 (broad), 3377 (broad), 3211, 3051, 3027, 2919. MS (EI) m/z (relative intensity) 219 (100), 92 (80). HRMS (EI), Cald. for C13H13NS 215.0769. Found 215.0766.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.S(Cl)([Cl:14])=O>ClC1C=CC=CC=1Cl.CN(C=O)C>[Cl:14][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Oc1ccnc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: Clc1ccccc1Cl
Product: FC(F)(F)c1cc(Cl)ccn1
Temperature: 75 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
4-Hydroxy-2-trifluoromethylpyridine (6.4 g, 39 mmol) was dissolved in 1,2-dichlorobenzene (64 g). Thionylchloride (23.2 g, 195 mmol) and DMF (10 drops) were added to the reaction mixture which was then heated to 70 to 80° C. After about 2 hours the reaction was completed and excess thionyl chloride was removed at an elevated temperature. The desired product was distilled under reduced pressure (50° C., 15 mbar) to yield 4-chloro-2-trifluoromethyl-pyridine (6.5 g, 36 mmol, yield: 92%). If required, remaining DMF was removed using an aqueous work-up.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=O.[N+:5]([C:8]1[CH:26]=[CH:25][C:11]2[O:12][C:13]([CH:19]([Cl:24])[C:20]([F:23])([F:22])[F:21])([C:15]([F:18])([F:17])[F:16])[O:14][C:10]=2[CH:9]=1)([O-:7])=[O:6]>S(=O)(=O)(O)O>[N+:1]([C:26]1[C:8]([N+:5]([O-:7])=[O:6])=[CH:9][C:10]2[O:14][C:13]([CH:19]([Cl:24])[C:20]([F:21])([F:22])[F:23])([C:15]([F:17])([F:16])[F:18])[O:12][C:11]=2[CH:25]=1)([O-:4])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1ccc2c(c1)OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 250 ml of 100% strength by weight nitric acid and 350 ml of concentrated sulphuric acid was added to an initial charge of 352 g of 5-nitro-2-(1-chloro-2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole from Example 16a. The mixture was stirred at 60° C. for 2 hours. It was cooled, poured into ice-water and extracted with methylene chloride. After washing the mixture with sodium hydrogen carbonate solution, and drying, it was concentrated on a rotary evaporator. The yield was 392 g (91% of theory) and the melting point was 125° C. The NMR spectra showed the following characteristic absorptions: 19F-NMR: -68.5 and -81.0 ppm; 1H-NMR: 4.86 ppm.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[CH2:5][S:6][CH2:7][C:8]1([OH:26])[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([O:15][CH3:16])[CH:9]1[C:17]1([CH3:25])[O:24][CH:18]1[CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22].[Cl:31][CH2:32][C:33]([N:35]=[C:36]=[O:37])=[O:34].O>ClCCl>[Cl:31][CH2:32][C:33]([NH:35][C:36]([O:14][CH:11]1[CH2:12][CH2:13][C:8]([CH2:7][S:6][CH2:5][C:4]2[CH:27]=[CH:28][CH:29]=[CH:30][C:3]=2[CH2:2][Cl:1])([OH:26])[CH:9]([C:17]2([CH3:25])[O:24][CH:18]2[CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[CH:10]1[O:15][CH3:16])=[O:37])=[O:34]
Reactant: COC1C(O)CCC(O)(CSCc2ccccc2CCl)C1C1(C)OC1CC=C(C)C
Reactant: O=C=NC(=O)CCl
Solvent: O
Solvent: ClCCl
Product: COC1C(OC(=O)NC(=O)CCl)CCC(O)(CSCc2ccccc2CCl)C1C1(C)OC1CC=C(C)C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
In dichloromethane (1.5 ml) was dissolved 1-(2-chloromethylbenzyl)thiomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1,4-cyclohexanediol (300 mg). To the solution was added dropwise, under ice-cooling, chloroacetylisocyanate (84 μl). The mixture was stirred for 15 minutes, to which was added water to suspend the reaction. The product was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 30 g, developing solvent : methyl acetate - hexane=1:2) to give 4-(N-chloroacetylcarbamoyloxy)-1-(2-chloromethylbenzyl)thiomethyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxycyclohexanol (302 mg: yield 79%) as colorless powder.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]([CH3:10])=[N:3]1.C1COCC1.[C:16]([C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)#[CH:17]>CCN(CC)CC>[C:16]([C:18]1[CH:19]=[C:20]([NH:24][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH:5]=2)=[O:8])[CH:21]=[CH:22][CH:23]=1)#[CH:17]
Reactant: C#Cc1cccc(N)c1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#Cc1cccc(NC(=O)c2cc(C)nn2C)c1
Temperature: 55 °C
Yield: 71.9 %

Procedure:
A dry 25 mL flask was charged with 2,5-dimethyl-2H-pyrazole-3-carbonyl chloride (0.135 g, 0.854 mmol) and THF (5 mL) was added. 3-Ethynyl-phenylamine (0.100 g, 0.854 mmol) was added to the THF solution of the acid chloride followed by NEt3, and the mixture was allowed to stir at 55° C. The reaction mixture was then allowed to cool to room temperature. The reaction was extracted twice with EtOAc (˜5 mL) and water (˜10 mL) followed by saturated aqueous NaHCO3(˜10 mL). The combined organic layers were dried over anhydrous Na2SO4 (s) and then concentrated. The crude residue was purified by chromatography (silica gel, gradient elution EtOAc/Hexanes 0 to 60%). The product containing fractions were concentrated to give the title compound as a tan solid (147 mg. 72%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C@H:18]([NH:20][C:21]([C:23]3([NH:27]C(OCC4C5C=CC=CC=5C5C4=CC=CC=5)=O)[CH2:26][O:25][CH2:24]3)=[O:22])[CH3:19])=[C:14]([F:45])[CH:13]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[O:4].N1CCCCC1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C@H:18]([NH:20][C:21]([C:23]3([NH2:27])[CH2:24][O:25][CH2:26]3)=[O:22])[CH3:19])=[C:14]([F:45])[CH:13]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[O:4]
Reactant: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)C2(NC(=O)OCC3c4ccccc4-c4ccccc43)COC2)c(F)c1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)C2(N)COC2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-chloro-4′-((R)-1-{[3-(9H-fluoren-9-ylmethoxycarbonylamino)-oxetane-3-carbonyl]-amino}-ethyl)-3′-fluoro-biphenyl-2-carboxylic acid methyl ester (100 mg, 159 μmol, step C) in dry DMF (1.8 ml) was added piperidine (0.2 ml) and the solution was stirred at room temperature for 2 h. The brown solution was concentrated to dryness under high vacuum. The remaining residue was purified by chromatography (silica gel; DCM/MeOH 98:2) and the title compound was obtained as white solid (60 mg, 92%). MS: 407.2 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:12]([O:36][CH3:37])=[CH:13][C:14]2[C:15]3[C:16]4[C:33](=[O:34])[NH:32][C:31](=[O:35])[C:17]=4[C:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])=[CH:19][C:20]=3[NH:21][C:22]=2[CH:23]=1)(=O)=O.[I-:40].[Na+]>C(OCC)(=O)C>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:18]1[C:17]2[C:31](=[O:35])[NH:32][C:33](=[O:34])[C:16]=2[C:15]2[C:14]3[CH:13]=[C:12]([O:36][CH3:37])[C:11]([CH2:10][CH2:9][CH2:8][CH2:7][I:40])=[CH:23][C:22]=3[NH:21][C:20]=2[CH:19]=1
Reactant: COc1cc2c(cc1CCCCOS(=O)(=O)C(F)(F)F)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Reactant: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1CCCCI)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O

Procedure:
A mixture of the mesylate (172) 0.12 g, 0.21 mmol) prepared as described in example 311 and sodium iodide (1 g) in ethyl acetate (50 mL) was refluxed for 4 h. The cooled solution was washed with water and worked up to give the iodide (173) which crystallised from tetrahydrofuran/petroleum ether as an orange powder (0.10 g, 85%), mp 142–144° C. 1H NMR δ [(CD3)2SO] 11.86 (s, 1H), 11.05 (s, 1H), 8.43 (s, 1H), 7.58 (m, 1H), 7.55 (s, 1H), 7.52–7.43 (m, 3H), 7.42 (s, 1H), 3.94 (s, 3H). EIMS found M+=558.0212, 560.0178. C25H20ClN2O3 requires 558.0207, 560.0178.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([NH2:15])=[O:14])=[N:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:4][CH:3]=1.[H-].[Na+].[F:26][C:27]([F:33])([F:32])[CH2:28][CH2:29][CH2:30]Br>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]([NH:15][CH2:30][CH2:29][CH2:28][C:27]([F:33])([F:32])[F:26])=[O:14])=[N:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:6][CH:7]=1
Reactant: FC(F)(F)CCCBr
Reactant: NC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCCCC(F)(F)F)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Part B: To a cooled (0° C.) stirred solution of 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxamide (1.16 gram, 3.02 mmol) in anhydrous DMF (20 mL) is added NaH (0.13 gram of a 60% dispersion) in a nitrogen atmosphere. The resulting mixture is stirred for 1 hour and excess 4,4,4-trifluoro-1-bromobutane (0.7 mL) is added. The resulting solution is stirred at room temperature for 1 hour, poured onto ice/water and extracted twice with diethyl ether. The collected diethyl ether layers are twice washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The residue is further purified by column chromatography (silica gel: eluant: dichloromethane) to give 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-N-(4,4,4-trifluorobutyl)thiazole-2-carboxamide. Melting point: 99-101° C.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:21]=1[OH:29].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[OH:29][C:21]1[C:22]([N+:26]([O-:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccc([N+](=O)[O-])c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc([N+](=O)[O-])c1O
Yield: 67.9 %

Procedure:
The product is prepared according to the procedure described in example 5, using 1 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 590 mg of 2-amino-6-nitrophenol, and 734 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 5 ml of pyridine and 6 ml of N,N-dimethylformamide. 976 mg of N-(2-hydroxy-3-nitrophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a yellow solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([Si:4]([Cl:7])(Cl)Cl)[CH:2]=[CH2:3].N12CCCN=C1CCCCC2.[OH:19][C:20]([C:23]([OH:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[CH2:1]([Si:4]1([Cl:7])[O:26][C:23]([CH3:25])([CH3:24])[C:20]([CH3:22])([CH3:21])[O:19]1)[CH:2]=[CH2:3]
Reactant: CC(C)(O)C(C)(C)O
Reactant: C=CC[Si](Cl)(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C=CC[Si]1(Cl)OC(C)(C)C(C)(C)O1
Reaction time: 12 h
Yield: 69.3 %

Procedure:
To a cooled (0° C.) solution of allyltrichlorosilane (4.9 mL; 34 mmol) in CH2Cl2 (50 mL) was added 1,8-Diazabicyclo[5.4.0]undec-7-ene (13 mL; 84 mmol). A solution of pinacol (4.0 g; 34 mmol) in CH2Cl2 (50 mL) was then added slowly and the resultant solution was warmed to room temperature and stirred for 12 hours. The solution was concentrated and the residue was treated with diethylether (100 mL). The mixture was stirred for 1 hour during which time the formation of a precipitate was observed. The mixture was then filtered and the filtrate was concentrated. The residue was distilled under reduced pressure to give 5.2 g (72%) of 2-allyl-2-chloro-4,4,5,5-tetramethyl-[1,3,2]dioxasilolane as a clear, colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH2:21][CH2:22][C@@H:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][C:36]3=[O:41])=[CH:31][CH:30]=2)[CH2:24]1.O>CN(C1C=CN=CC=1)C.ClCCl>[CH:33]1[C:32]([N:35]2[C:36](=[O:41])[CH2:37][O:38][CH2:39][CH2:40]2)=[CH:31][CH:30]=[C:29]([N:25]2[C:26](=[O:28])[O:27][C@@H:23]([CH2:22][NH:21][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:9])[CH2:24]2)[CH:34]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: ClCCl
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Reaction time: 0.17 h
Yield: 85.6 %

Procedure:
4-(N,N-dimethylamino)pyridine (36.6 g, 0.3 mol) was added to a stirred suspension of 5-chlorothiophene-2-carboxylic acid (16.25 g, 0.1 mol) in dichloromethane (162 ml) at 0-5° C. and the resulting solution was stirred for 10 minutes. A mixture of p-toluenesulfonyl chloride (19.05 g, 0.1 mol) and dichloromethane (50 ml) was added to the above solution at −5° C. The resulting solution was stirred for 1 hour at −5° C. to produce a reaction mass containing the sulfonyl ester intermediate, followed by portion wise addition of 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (29.1 g, 0.1 mol, chiral purity: 99.9%). The reaction mixture was stirred for 2 hours at 25-30° C., followed by the addition of water (162 ml) and then stirring for 15 minutes. The separated solid was filtered, washed with dichloromethane (50 ml) and water (100 ml), and the resulting wet material was dried at 80-85° C. for 3 to 5 hours to produce 37.3 g of pure rivaroxaban as a white crystalline solid (Theoretical Yield: 85.6%; Purity by HPLC: 99.9%; and Chiral Purity by HPLC: 99.9%).