Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10](O)=[O:11])(=[O:4])=[O:3].C(Cl)(C(Cl)=O)=O.[CH3:22][NH:23][CH3:24].C1COCC1>C(Cl)Cl.CN(C=O)C>[CH3:22][N:23]([CH3:24])[C:10]([C:9]1[CH:13]=[C:5]([S:2]([Cl:1])(=[O:4])=[O:3])[CH:6]=[CH:7][C:8]=1[O:14][CH3:15])=[O:11]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Reactant: CNC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)Cl)cc1C(=O)N(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-(chlorosulfonyl)-2-methoxybenzoic acid (1.243 g, 4.96 mmol) in dry DCM (20 ml) cooled to 0° C., (COCl)2 (1.302 ml, 14.88 mmol) was added drop-wise followed by few drops of dry DMF and the reaction was stirred at RT for 1 hour. The mixture was concentrated under reduced pressure, treated with dry toluene (30 ml×2) and evaporated to dryness. The residue was suspended in dry toluene (20 ml) and the resulting suspension was cooled to 0° C.; a solution of dimethylamine 2.0 M in THF (4.96 ml, 9.92 mmol) was added drop-wise and the reaction was stirred at RT overnight. The mixture was diluted with DCM and washed with brine; the organic phase was dried over sodium sulfate and the solvent was removed. The crude was purified by flash chromatography on silica gel (EtOAc/petroleum ether=60/40) to give 3-(dimethylcarbamoyl)-4-methoxybenzene-1-sulfonyl chloride (Int. 9) (400 mg, 1.440 mmol, MS/ESI+278.0 [MH]+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1.Cl.CO>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (±) methyl 1-benzyl-2-oxo-4-pyrrolidylcarboxylate (D16, 35.4 g, 0.18 mole) in dry THF (135 ml) was added dropwise over 30 mins to 1 M borane-THF solution (228 ml, 0.23 mole) at 0° C. under nitrogen, and when addition was complete the solution was heated under reflux for 1 h. The solution was cooled to room temperature, then treated dropwise with 8% hydrogen chloride/methanol (114 ml, 0.25 mole HCl) and stirred for 18 h, followed by 3 h at reflux. The mixture was then concentrated in vacuo and the residue treated with water (40 ml), washed with ether (2×50 ml), basified with 40% sodium hydroxide solution, saturated with potassium carbonate and extracted with ether (3×70 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a yellow oil, which was purified by distillation (b.p. 146° C./0.7 mmHg) to give the title compound (D17) as a colorless oil (19.8 g, 50%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:32])[CH:10]2[NH:14][C:15](=[O:31])[CH:16]([C:22]2[CH:23]=[CH:24][C:25]3[O:29][CH2:28][CH2:27][C:26]=3[CH:30]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]=1[C:33]([OH:35])=[O:34])(=[O:3])[CH3:2].[Na].[C:37]([O:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45]O)=[CH:43][CH:42]=1)(=[O:39])[CH3:38].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:37]([O:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][O:34][C:33]([C:7]2[N:8]3[CH:11]([S:12][CH2:13][C:6]=2[CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:10]([NH:14][C:15](=[O:31])[CH:16]([C:22]2[CH:23]=[CH:24][C:25]4[O:29][CH2:28][CH2:27][C:26]=4[CH:30]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9]3=[O:32])=[O:35])=[CH:43][CH:42]=1)(=[O:39])[CH3:38]
Reactant: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CSC12)c1ccc2c(c1)CCO2
Reactant: CC(=O)Oc1ccc(CO)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc(OC(C)=O)cc3)=C(COC(C)=O)CSC12)c1ccc2c(c1)CCO2

Procedure:
To a suspension of 6 mmole of 3-[(acetyloxy)methyl]-7-[[3-ethoxy-1,3-dioxo-2-(2,3-dihydro-5-benzofuranyl)-propyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt in 40 ml of dimethylformamide (DMF) is added 2 equivalents of p-(acetyloxy)-benzyl alcohol. The mixture is cooled to 0° C. after which 6.8 mM of dicyclohexylcarbodiimide in 10 ml of DMF is added dropwise with stirring. The mixture is stirred at 0° C. for 1 hour and an addition 4 hours at room temperature. Dicyclohexylurea is removed by filtration. The filtrate is diluted with chloroform, washed with water, dried over magnesium sulfate, filtered and evaporated in vacuo to give the title compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].[CH2:11](O)[CH2:12][CH2:13][OH:14].CO>C(Cl)Cl.C1C(=O)N(Br)C(=O)C1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2([CH3:1])[O:14][CH2:13][CH2:12][CH2:11][O:3]2)=[CH:5][CH:6]=1
Reactant: OCCCO
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: ClCCl
Product: CC1(c2ccc(Cl)cc2)OCCCO1
Temperature: 25 °C
Reaction time: 70 h
Yield: 51.7 %

Procedure:
To a stirred mixture of 4-chloroacetophenone (1.3 mL, 10 mmol), triethylformate (2.0 mL, 12 mmol), 1,3-propanediol (2.2 mL, 30 mmol) and dry methanol (1.2 mL) in dry CH2Cl2 (50 mL) was added NBS (53 mg, 0.30 mmol). The mixture was protected from light and stirred at room temperature under an inert atmosphere of nitrogen for 70 h. After the mixture was washed with saturated aqueous sodium bicarbonate solution (20 mL), the aqueous phase was extracted with dichloromethane (3×30 mL). The combined organic solution was washed with water (2×20 mL), brine (1×20 mL), then dried (Na2SO4) and concentrated under reduced pressure. Flash column chromatography of the residue, eluting with 37% aqueous ammonia:ether:hexane (0.02:1:6) afforded 2-(4-chlorophenyl)-2-methyl-1,3-dioxane (20) as a colourless oil (1.1 g, 52%). 1H nmr (200 MHz, CDCl3) 1.49 (s, 3H, CH3), 1.98-2.25 (m, 2H, OCH2CH2CH2O), 3.65-4.10 (m, 4H, OCH2CH2CH2O), 7.30-7.50 (m, 4H, 4×ArH).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:29])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][C:18]=2[Cl:27])[C:8]=1[CH3:28]>C1COCC1.CO>[Cl:27][C:18]1[CH:19]=[C:20]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=[CH:22][C:17]=1[CH2:16][N:9]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:15]2[C:7]([CH2:6][C:5]([OH:29])=[O:4])=[C:8]1[CH3:28]
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2Cl)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc(S(C)(=O)=O)cc1Cl
Temperature: 45 °C
Reaction time: 1 h

Procedure:
1M Aqueous NaOH (15 ml) is added to a stirring suspension of [1-(2-chloro-4-methanesulfonyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (2.6 g, 6.39 mmol) in 1:1 THF/MeOH (40 ml). After stirring at 45° C. for 1 hour, the reaction mixture is filtered to remove any undissolved material and is evaporated to dryness. The resulting solid is dissolved in water (30 ml) and acidified to pH 2-3 using concentrated HCl. The resulting suspension is collected by filtration and dried in vacuo at 50° C. to yield a solid which is purified by recrystallisation from IPA/water (1:3) to afford the titled product. (MH+ 393)
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[C:13]([CH3:14])=[CH:12][C:7]2[NH:8][C:9]([SH:11])=[N:10][C:6]=2[C:5]=1[CH3:15].Cl.Cl[CH2:19][C:20]1[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][N:21]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CC(O)C>[F:16][CH:2]([F:1])[O:3][C:4]1[C:13]([CH3:14])=[CH:12][C:7]2[NH:8][C:9]([S:11][CH2:19][C:20]3[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][N:21]=3)=[N:10][C:6]=2[C:5]=1[CH3:15]
Reactant: Cc1cc2[nH]c(S)nc2c(C)c1OC(F)F
Reactant: COc1ccnc(CCl)c1C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CC(C)O
Product: COc1ccnc(CSc2nc3c(C)c(OC(F)F)c(C)cc3[nH]2)c1C

Procedure:
2.0 g of 5-difluoromethoxy-4,6-dimethyl-1H-benzimidazole-2-thiol and 1.72 g of 2-chloromethyl-4-methoxy-3-methylpyridine hydrochloride are heated in 30 ml of 2-propanol for 4 h to the boil. This gives 3.6 g of the dihydrochloride of the title compound. This is dissolved in water and concentrated hydrochloric acid, the solution is clarified with activated charcoal, the product is precipitated with dilute sodium hydroxide solution and the precipitate is recrystallised from butanol. This gives 2.6 g (85%) of the title compound (m.p. 190°-191° C.).
Reaction SMILES: COCCOC[O:7][C:8]1[C:9]([Se:22][C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=2)=[CH:10][C:11]2[C:12]([CH3:21])([CH3:20])[CH2:13][CH2:14][C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1.S(=O)(=O)(O)O.CO>C1COCC1>[OH:7][C:8]1[C:9]([Se:22][C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=2)=[CH:10][C:11]2[C:12]([CH3:20])([CH3:21])[CH2:13][CH2:14][C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1
Reactant: CCOC(=O)c1ccc([Se]c2cc3c(cc2OCOCCOC)C(C)(C)CCC3(C)C)cc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1ccc([Se]c2cc3c(cc2O)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 108.5 %

Procedure:
A mixture of ethyl 4-(3-methoxyethoxymethoxy5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanyl)benzoate (2.3 g, 4.4 mmol), concentrated sulphuric acid (475 μl), methanol (40 ml) and THF (20 ml)is stirred for 48 h at room temperature. The reaction medium is extracted with ethyl ether. The organic phase is washed twice with water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum. The product is purified by crystallization from heptane. 2.06 g (97%) of the expected compound are obtained in the form of an orange-coloured powder. m.p.=113° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([S:13]([NH2:16])(=[O:15])=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:17]1[CH:21]=[C:20]([CH:22]=O)[C:19]2[CH:24]=[CH:25][CH:26]=[CH:27][C:18]1=2.[BH4-].[Na+]>C(O)C>[S:17]1[CH:21]=[C:20]([CH2:22][NH:16][S:13]([N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)(=[O:15])=[O:14])[C:19]2[CH:24]=[CH:25][CH:26]=[CH:27][C:18]1=2
Reactant: O=Cc1csc2ccccc12
Reactant: NS(=O)(=O)N1CCC(c2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(NCc1csc2ccccc12)N1CCC(c2ccccc2)CC1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
4-Phenyl-piperidine-1-sulfonic acid amide (1.5 g, 6.24 mmol) was dissolved in ethanol (20 mL). Benzo[b]thiophene-3-carbaldehyde (1.0 g, 6.24 mmol) was then added and the reaction mixture was warmed to 45° C. overnight. The reaction mixture was cooled to room temperature and then treated with sodium borohydride (0.2 g, 5.29 mmol). The reaction was then quenched by addition of 1N HCl. The reaction mixture was stirred overnight. The product precipitated from solution and was removed by vacuum filtration to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[NH2:16]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:14]=[C:13]([Cl:12])[CH:19]=[C:18]([Cl:20])[CH:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1cc(Cl)cc(Cl)c1
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1cc(Cl)ccc1O
Yield: 41.2 %

Procedure:
Using 5-chlorosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the Example 1(1) gave the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12]2[C:13]3[CH:18]=[CH:17][S:16][C:14]=3[CH2:15][C:11]=2[CH:10]=[N:9]1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C)C=O>[N:19]([CH2:6][CH2:7][N:8]1[C:12]2[C:13]3[CH:18]=[CH:17][S:16][C:14]=3[CH2:15][C:11]=2[CH:10]=[N:9]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCn1ncc2c1-c1ccsc1C2
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCn1ncc2c1-c1ccsc1C2
Temperature: 70 °C
Reaction time: 17 h
Yield: 91.8 %

Procedure:
A 0.75 g of 2-(1,4-dihydrothieno[2′,3′:4,5]cyclopenta[1,2-c]pyrazol-1-yl)ethyl methanesulfonate was dissolved in 10 ml of dimethylformamide, 0.47 g of sodium azide was added, and the mixture was stirred at 70° C. for 17 hours. After cooling, the reaction solution was poured into ice water and extracted with ether. The organic layers were combined, washed with brine and then dried with anhydrous magnesium sulfate. After removal of the drying agent, the solvent was concentrated under a reduced pressure to give 0.56 g of 1-(2-azidoethyl)-1,4-dihydrothieno[2′,3′:4,5]cyclopenta[1,2-c]pyrazole.
Reaction SMILES: [I:1]I.[F:3][C:4]([F:13])([F:12])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][N:6]=1.C([O-])([O-])=O.[K+].[K+]>CO>[I:1][C:8]1[C:9]([OH:11])=[CH:10][C:5]([C:4]([F:3])([F:12])[F:13])=[N:6][CH:7]=1
Reactant: II
Reactant: Oc1ccnc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Oc1cc(C(F)(F)F)ncc1I
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.6 %

Procedure:
Iodine (8.16 g, 32.1 mmol) was added in five portions to a solution of 2-(trifluoromethyl)pyridin-4-ol (5 g, 30.65 mmol) and K2CO3 (4.66 g, 33.7 mmol) in methanol (34 mL) at 0° C. and the resulting mixture was stirred at room temperature for 20 h. The solution was washed with saturated aqueous sodium sulfite then acetic acid (10 mL) was added and the solution was extracted with ethyl acetate, dried (Na2SO4), filtered, concentrated under vacuum and the residue was purified on a silica gel column to give 5-iodo-2-(trifluoromethyl)pyridin-4-ol (5.1 g, 57%). Retention time (min)=1.761, method [1], MS (ESI) 290.9 (M+H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](O)([CH3:13])[CH3:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>>[N:15]([C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)([CH3:13])[CH3:12])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(O)c1ccc2ncccc2c1
Agent: [Na+]
Product: CC(C)(N=[N+]=[N-])c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
2-(Quinolin-6-yl)propan-2-ol (0.50 g, 2.67 mmol) and sodium azide (1.73 g, 26.70 mmol) were added successively to ice-cold trifluoroacetic acid (20 ml) and warmed to room temperature. After 12 h, the reaction mixture was cooled to 0° C., quenched with water and basified with sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as brown liquid (0.340 g, 60%). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ8.90 (dd J=4.1, 1.6 Hz, 1H), 8.41 (d, J=7.6 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 8.04 (d, J=9.0 Hz, 1H), 7.88 (dd, J=8.1, 2.2 Hz, 1H), 7.56 (q, J=4.2 Hz, 1H), 1.71 (s, 6H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]([CH3:4])[CH3:3].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:17][CH2:18][C@H:19]2[O:21][CH2:20]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1>O1CCCC1>[OH:21][C@@H:19]([CH2:20][CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:18][O:17][S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: CC(C)C[Mg]Br
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)CCC(C)C)cc1
Temperature: 2.5 °C
Yield: 75.5 %

Procedure:
Add dropwise over 5 minutes isobutylmagnesium bromide (4.4 mL, 8.8 mmol, 2 M in diethyl ether) to a solution of lithium tetrachlorocuprate (4.4 mL, 0.44 mmol, 0.1 M in tetrahydrofuran) cooled to −35-40° C. Dissolve (2S)-(+)-glycidyl tosylate (1.674 g, 7.73 mmol) in tetrahydrofuran (8 mL), cool to −40° C. and cannulate into the stirring Grignard reaction flask. Quench with saturated aqueous ammonium chloride (25 mL), pour supernate into saturated aqueous ammonium chloride (25 mL) and water and shake well. Wash with saturated aqueous sodium chloride, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 10:90 to 25:75 ethyl acetate:hexanes) to give the desired compound (1.6711 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17](=O)[CH2:18][C:19](=[O:21])[CH3:20])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17](=[S:32])[CH2:18][C:19](=[O:21])[CH3:20])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1C(=O)CC(C)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1C(=S)CC(C)=O

Procedure:
In analogy to the procedure described in example 192 g, (2S,4R)-4-cyclopropylmethanesulfonyl-1-(3-oxo-butyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with Lawesson's reagent to give the title compound as brown solid. MS (ESI): m/z=348.4 [M+H]+.
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:11]([O:13][C:14]([C:16]1[CH2:21][CH2:20][CH2:19][CH:18](Br)[C:17]=1O)=[O:15])[CH3:12]>CC(O)C.[Cl-].[Zn+2].[Cl-]>[CH2:11]([O:13][C:14]([CH:16]1[C:17]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:3][CH2:2][F:1])[C:18]=2[CH2:19][CH2:20][CH2:21]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)C1=C(O)C(Br)CCC1
Reactant: FCCNc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Product: CCOC(=O)C1CCCc2c1c1ccccc1n2CCF
Temperature: 50 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
A mixture of (2-fluoro-ethyl)-phenyl-amine (24; prepared according to Example 4(a)) (560 mg, 4.0 mmol) and 3-bromo-2-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester (29) (500 mg, 2.0 mmol) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (4 mL) and dry zinc chloride (820 mg, 6 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The product was dissolved in ethyl acetate/ether (30 mL/150 mL) and washed with 2 N HCl (40 mL), water (2×100 mL) and aqueous potassium carbonate solution (2×100 mL) then dried and concentrated to afford 447 mg (91%) of 9-(2-fluoro-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid ethyl ester (30) as a yellow oil which was used in the next step without purification. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 14.3, 20.4, 21.7, 26.4, 38.5, 43.1 (d, JCF=15 Hz), 60.6, 76.6, 77.0, 77.4, 82.1 (d, JCF=173 Hz), 106.9, 108.5, 118.9, 119.4, 121.1, 127.1, 136.2, 136.7, 174.9.
Reaction SMILES: ClC(OCC)=O.Cl.[Br:8][C:9]1[N:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[C:18]([OH:20])=O)=[CH:11][CH:10]=1.CCN(CC)CC.[N-:28]=[N+:29]=[N-:30].[Na+]>CC(C)=O.O>[Br:8][C:9]1[N:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[C:18]([N:28]=[N+:29]=[N-:30])=[O:20])=[CH:11][CH:10]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(Br)nc1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(=O)[C@@H]1C[C@H]1c1ccc(Br)nc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
Ethyl chloroformate (5.8 mL, 62 mmol) was added to a solution of (trans)-2-(6-bromopyridin-3-yl)cyclopropanecarboxylic acid hydrochloride (Intermediate C, 5 g, 20.7 mmol) and Et3N (14.2 mL, 103.7 mmol) in Acetone (100 mL) at −5° C., then reaction mixture was stirred at −5° C. for 1 h, then a solution of NaN3 (2.7 g, 41.4 mmol) in water (10 mL) was added and stirred for 30 mins at RT. After completion the solvent was evaporated under vacuum. The crude residue was dissolved in ethyl acetate (200 mL), washed with water (80 mL), brine (80 mL), dried over anhydrous Na2SO4, filtered and evaporated to get (trans)-2-(6-bromopyridin-3-yl)cyclopropanecarbonyl azide (2.5 g, 45.5%) as a brown color gummy liquid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[C:4]#[N:5].[CH3:11][NH:12]N.C[N:15](C)C(=O)C>>[I:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]2[C:3]=1[C:4]([NH2:15])=[N:5][N:12]2[CH3:11]
Reactant: N#Cc1c(F)cccc1I
Reactant: CC(=O)N(C)C
Reactant: CNN
Product: Cn1nc(N)c2c(I)cccc21
Temperature: 120 °C

Procedure:
To a 330 mL pressure vessel equipped with a magnetic stir bar was added 2-fluoro-6-iodobenzonitrile (4.5 g, 18.2 mmol), N,N-dimethylacetamide (45 mL), and methylhydrazine (1.2 mL 23.7 mmol). The vessel was flushed with N2 gas, sealed and heated at 87° C. overnight and at 120° C. for 5 h. The reaction mixture was cooled, diluted with EtOAc (300 mL, and washed with water. The aqueous layer was extracted and the combined EtOAc extracts were washed with water (3×150 mL), brine, dried (Na2SO4), filtered and concentrated to a brown solid. The solid was triturated with EtOAc/hexanes (1:1, 10 mL), filtered, washed with EtOAc/hexanes (1:1) and dried to give 4.04 g (81%) of I-216 as a beige solid. 1H NMR (400 MHz, DMSO-d6)
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:24]([NH:26][C@@H:27]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH3:28])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13]C(OCC1C=CC=CC=1)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H][H]>CO.[Pd]>[C:1]([NH:8][C@@H:9]([C:24]([NH:26][C@@H:27]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH3:28])=[O:25])[CH2:10][CH2:11][CH2:12][NH2:13])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: [H][H]
Reactant: C[C@@H](NC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccc(O)cc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](NC(=O)[C@@H](CCCN)NC(=O)OC(C)(C)C)c1ccc(O)cc1
Yield: 88.5 %

Procedure:
To a solution of (R)-N2 -(Boc)-N5 -(Cbz)-(R)-N-[1-(4-hydroxyphenyl)-ethyl]ornithine amide (66.26 g; 139 mmol; see Example 4(b) above) in methanol (400 mL) was added 10% Pd/C (w/w; 3.53 g). After stirring for 18 h under 1 atmosphere of hydrogen the reaction was filtered through Celite to remove the catalyst and the filtrate was concentrated under reduced pressure to afford the sub-title compound as a white foam (43.2 g, 123 mmol).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH:20]3[CH2:22][CH2:21]3)=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=[CH:27][C:26]=1[OH:35].[H-].[Na+]>CS(C)=O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH:20]3[CH2:22][CH2:21]3)=[C:18]([O:35][C:26]3[CH:27]=[CH:28][C:29]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:30][C:25]=3[F:24])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(O)c(F)c1
Reactant: CC(C)OC(=O)N1CCC(Oc2ncnc(Cl)c2C2CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)OC(=O)N1CCC(Oc2ncnc(Oc3ccc(S(C)(=O)=O)cc3F)c2C2CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(6-Chloro-5-cyclopropyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (200 mg, 0.588 mmol), 2-fluoro-4-methanesulfonyl-phenol (168 mg, 0.883 mmol) and sodium hydride (60% dispersion in mineral oil, 53 mg, 1.325 mmol) were dissolved in DMSO (2 mL) and the mixture stirred under Nitrogen for 10 min at rt. The mixture was then heated under microwave irradiation for 1 h at 150° C. The crude was quenched with water and extracted with EtOAc (3×). The organic layer was concentrated and the residue was purified by HPLC to afford Compound C44 (51 mg, 14.3%) as oil. 1H NMR (CDCl3, 400 MHz) δ 0.90-0.97 (m, 2H), 1.01-1.06 (m, 2H), 1.23-1.27 (d, J=6.06 Hz, 6H), 1.76-1.91 (m, 2H), 1.92-2.02 (m, 2H), 3.08 (s, 3H), 3.46-3.55 (m, 2H), 3.63-3.72 (m, 2H), 4.87-4.98 (m, 1H), 5.32-5.39 (m, 1H), 7.36-7.42 (m, 1H), 7.73-7.80 (m, 2H), 8.17 (s, 1H). Exact mass calculated for C23H28FN3O6S 493.17, found 494.5 (MH+).