Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:5]([C:10]([F:13])([F:12])[F:11])[C:6]=1[C:7]([NH2:9])=[O:8].ClC(Cl)(Cl)[C:22]([N:24]=C=O)=[O:23].N>O1CCCC1.CO>[NH2:24][C:22]([NH:1][C:2]1[S:3][C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:5]([C:10]([F:11])([F:13])[F:12])[C:6]=1[C:7]([NH2:9])=[O:8])=[O:23]
Reactant: NC(=O)c1c(N)sc(-c2ccccc2)c1C(F)(F)F
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)Nc1sc(-c2ccccc2)c(C(F)(F)F)c1C(N)=O
Reaction time: 0.08 h
Yield: 36.1 %

Procedure:
2-Amino-4-trifluoromethyl-5-phenyl-3-thiophenecarboxamide (0.35 g) was suspended in tetrahydrofuran (10 ml) and trichloroacetylisocyanate (0.19 g) was added dropwise with stirring over 5 minutes. Stirring was continued for 1 h at room temperature and then a 2M solution of ammonia in methanol (10 ml) was added and stirring continued for a further 12 h. A precipitate formed and was filtered off and washed with ethyl acetate (5 ml) to give the title urea (0.12 g).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH:5]1[CH2:10][NH:9][C@H:8]([C:11]([N:13]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14]2)=[O:12])[C@@H:7]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:6]1.[OH-].[Li+]>C1COCC1>[C:27]([O:26][C:24]([C@@H:7]1[C@@H:8]([C:11]([N:13]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:14]2)=[O:12])[NH:9][CH2:10][CH:5]([CH2:4][C:3]([OH:31])=[O:2])[CH2:6]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)CC1CN[C@H](C(=O)N2CCC(c3ccccc3)C2)[C@@H](C(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H]1CC(CC(=O)O)CN[C@@H]1C(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A solution of tert-butyl(2S,3S)-5-(2-methoxy-2-oxoethyl)-2-[(3-phenylpyrrolidin-1-yl)carbonyl]piperidine-3-carboxylate in THF (3 mL) was cooled to 0° C. prior to the addition of lithium hydroxide (7 mg, 0.16 mmol). After warming to ambient temperature, the reaction mixture was stirred overnight. The volatiles were removed in-vacuo to afford 60 mg (87%) of {(5S,6S)-5-(tert-butoxycarbonyl)-6-[(3-phenylpyrrolidin-1-yl)carbonyl]piperidin-3-yl}acetic acid as an off-white solid that was used without neutralization and purification in the following coupling reaction. MS (ESI): 417 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1)(=[O:9])=[O:8].[C:20]1([Mg]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[C:20]1([S:16]([C:13]2[CH:14]=[CH:15][C:10]([S:7]([NH:6][C:2]3[S:1][CH:5]=[CH:4][N:3]=3)(=[O:9])=[O:8])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=S(=O)(Nc1nccs1)c1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 4.1 %

Procedure:
4-(N-thiazol-2-ylsulfamoyl)benzene-1-sulfonyl chloride (0.339 g, 0.00100 mol) was mixed in tetrahydrofuran (15 mL) and cooled to −78° C. Phenylmagnesium bromide (0.363 g, 0.002 mol) solution in THF (1M) was added to the reaction in a dropwise manner. The reaction was allowed to stir 1 hour while warming to room temperature. A second portion of phenyl magnesium bromide solution (0.181 g, 0.001 mol) was added to the reaction mixture. The reaction mixture was then stirred for 18 hours then quenched with saturated ammonium chloride solution. The organic phase was separated and dried over magnesium sulfate. The organic phase was evaporated to a residue and purified by column chromatography (12 g silica gel ISCO column, hexanes to ethyl acetate gradient elution). Product fractions were combined and rotary evaporated to give 15.7 mg of product as white crystals. LCMS: Rt=1.30 min, MS m/z 380.6 [MH]+.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](OS(C)(=O)=O)([CH3:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>C(O)C>[CH:1]([N:14]1[CH2:17][C:16]([NH:27][CH:24]2[CH2:26][CH2:25]2)([CH3:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCO
Product: CC1(NC2CC2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 20 °C
Reaction time: 96 h

Procedure:
A suspension of 16.6 g of 1-benzhydryl-3-methane-sulphonyloxy-3-methylazetidine and 28.84 g of of cyclopropylamine in 250 cm3 of ethanol is stirred for 96 hours at approximately 20° C. The reaction mixture is concentrated under reduced pressure (20 kPa) at approximately 30° C. The dry extract is taken up with 50 cm3 of water and 8.8 g of methanesulphonic acid. The aqueous phase is washed with 3 times 25 cm3 of dichloromethane, treated with 12 cm3 of 35% aqueous sodium hydroxide and extracted with 3 times 50 cm3 of ethyl acetate. The combined organic phases are washed with twice 50 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 kPa) at approximately 25° C. 14.6 g of 1-benzhydryl-3-cyclopropylamino-3-methylazetidine are obtained in the form of a yellow oil, which is used without further purification for the subsequent steps.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].[CH3:18][Mg]Br>O1CCCC1>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH3:18])=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(Cl)c(S(C)(=O)=O)c1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Cl)c(S(C)(=O)=O)c1
Reaction time: 3 h

Procedure:
A round bottom flask was charged with 4-chloro-N-methoxy-N-methyl-3-(methylsulfonyl)benzamide (18.0 g, 64.9 mmol) and tetrahydrofuran (200 mL) at 0° C. Methylmagnesiumbromide (1M solution in THF, 78 mL, 78 mmol) was added slowly and the reaction was stirred for 3 h at that temperature. The reaction was then quenched with aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layers were concentrated under reduced pressure and the residue was purified by flash chromatography to get the title compound.
Reaction SMILES: [CH:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:18]([NH2:21])[CH2:19][CH3:20]>>[CH2:18]([NH:21][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([CH:1]=[CH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:17][CH:16]=1)[CH2:19][CH3:20]
Reactant: O=C(O)c1ccc(C=Cc2ccccc2)cc1
Reactant: CCCN
Product: CCCNC(=O)c1ccc(C=Cc2ccccc2)cc1

Procedure:
Using preparation method 1, 73B (67 mg, 0.3 mmol) was reacted with n-propylamine (27 μL, 19.5 mg, 0.33 mmol). The product was purified by flash chromatography on SiO2 using CH2Cl2/EtOAc 80:20. White crystals were obtained (48 mg, 61%). NMR 1H (ppm, CDCl3): 7.74 (d, J3=8.4 Hz, 2H), 7.53 (d, J3 8.1 Hz, 2H), 7.51 (d, J3=6.4 Hz, 2H), 7.35 (t, J3=7.1 Hz, 2H), 7.27 (tt, J3=7.2 Hz, J4=2.4 Hz, 1H), 7.17 (d, J3=16 Hz, 1H), 7.09 (d, J3=16 Hz, 1H), 6.21 (br. s, 1H), 3.45-3.38 (m, 2H), 1.64 (sext., J3=7.3 Hz, 2H), 0.98 (t, J3=7.4 Hz, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][N:10]2[N:13]=[C:14]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:15]([C:16](=[O:19])[NH:17][CH3:18])=[C:9]2[CH:8]=1)(=O)=O.B([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([OH:37])=[O:36])(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:14]2[C:15]([C:16](=[O:19])[NH:17][CH3:18])=[C:9]3[CH:8]=[C:7]([C:32]4[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=4)[C:35]([OH:37])=[O:36])[CH:12]=[CH:11][N:10]3[N:13]=2)=[CH:25][CH:24]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cccc(C(=O)O)c3)cc12
Temperature: 95 °C

Procedure:
To a degassed solution containing 2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl trifluoromethanesulfonate (0.19 g, 0.44 mmol), 3-boronobenzoic acid (0.11 g, 0.67 mmol), cesium carbonate (0.22 g, 0.67 mmol), dioxane (3.7 mL) and water (0.74 mL) was added tetrakis(tiphenylphosphine)palladium(0) (0.0090 g, 0.010 mmol). The solution was maintained at 95° C. for 7 h. The solution was cooled to room temperature, concentrated and dissolved in a solution containing water and methanol (1.8/1, 14 mL). The solution was filtered to remove fine particulates and washed with dichloromethane (3×5 mL). The aqueous portion was concentrated to dryness to afford 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl)benzoic acid as a pale grey solid which was used without further purification. LCMS: retention time: 1.830 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 u, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 390 (MH+).
Reaction SMILES: [O:1]=[S:2]1(=[O:21])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([OH:20])=[O:19])[CH:8]=1.C(OC(C1C=C(N)N(C2C=CC=CC=2[F:39])N=1)=O)C>>[O:21]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:39])[N:10]=[C:9]([C:18]([OH:20])=[O:19])[CH:8]=1
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2F)n1
Reactant: O=C(O)c1cc(N2CCCS2(=O)=O)n(-c2ccccc2)n1
Product: O=C(O)c1cc(N2CCCS2(=O)=O)n(-c2ccccc2F)n1

Procedure:
According to this procedure 5-(1,1-Dioxo-1lambda*6*-isothiazolidin-2-yl)-1-phenyl-1H-pyrazole-3-carboxylic acid is prepared starting from 5-Amino-1-(2-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester.
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[S:16](Cl)(=[O:19])(=[O:18])[NH2:17].C(N(C(C)C)CC)(C)C>C(#N)C>[N:2]1[N:1]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][O:13][S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][CH:15]=2)[CH:5]=[N:4][CH:3]=1
Reactant: NS(=O)(=O)Cl
Reactant: OCCOc1ccc(-n2cncn2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)OCCOc1ccc(-n2cncn2)cc1
Reaction time: 2 h
Yield: 55 %

Procedure:
A solution of 8.2 g (0.04 mole) of 2-[4-(1H-1,2,4-triazol-1-yl)phenoxy]ethanol in 100 ml of acetonitrile was treated with a solution of 1.3 equivalents of sulfamoyl chloride in 19 ml of acetonitrile. One equivalent, 5.2 g (0.04 mole), of diisopropylethylamine was also added in one portion. The mixture was stirred for 2 hr. The precipitate was collected and partitioned between ethyl acetate and a dilute potassium carbonate solution. The organic layer was separated and concentrated to a white powder. The powder was triturated with ethyl ether, collected and dried to give 6.3 g (55%) of white powder, mp 134°-136° C.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:10]([N:11]3[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]3=[O:23])=[C:9]([F:24])[CH:8]=[C:7]([Cl:25])[C:5]=2[N:6]=1.[C:26](Cl)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([NH:1][C:2]1[O:3][C:4]2[C:10]([N:11]3[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[N:13]([CH3:22])[C:12]3=[O:23])=[C:9]([F:24])[CH:8]=[C:7]([Cl:25])[C:5]=2[N:6]=1)(=[O:28])[CH3:27]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3nc(N)oc23)c1=O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1

Procedure:
A solution of 3.8 grams (10 mmole) of 3-(2-amino-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione and 1.0 gram (15 mmole) of acetyl chloride in 20 mL of pyridine is stirred at ambient temperature for about 18 hours. The reaction mixture is concentrated under reduced pressure, yielding 3-(2-acetylamino-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][CH2:38][C:39]#[N:40])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[C:39]([CH2:38][CH2:37][NH:36][S:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=1)(=[O:34])=[O:35])#[N:40]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: N#CCCNS(=O)(=O)c1cccc(Br)c1
Product: N#CCCNS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 3-Bromo-N-(2-cyano-ethyl)-benzenesulfonamide (example B.21) (376 mg, 1.3 mmol) according to general procedure II. Obtained as a yellow solid (254 mg, 45%). MS (ISP) 564.3 [(M+H)+]; mp 174-182° C.
Reaction SMILES: [C:1]([CH:4]=[N:5][C:6]1[C:7](=[C:11]([F:15])[CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9])([OH:3])=[O:2].S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[C:1]([CH:4]=[N:5][C:6]1[C:7](=[C:11]([F:15])[CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9])([O:3][CH2:21][CH3:22])=[O:2]
Reactant: O=C(O)C=Nc1cccc(F)c1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=Nc1cccc(F)c1C(=O)O
Temperature: 25 °C

Procedure:
10.6 g of N-carboxymethylene-6-fluoro-anthranilic acid having a purity of 73% (corresponding to 39.6 mmol) are suspended in 25 ml of ethanol, 0.98 g (9.6 mmol) of concentrated sulfuric acid are added and the reaction mixture is heated under reflux for 6 hours. It is cooled to room temperature and the product which has precipitated out is filtered off with suction, washed with ethanol and dried.
Reaction SMILES: [CH:1]1([N:7]([C@H:18]2[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:26][N:27]([CH3:37])[S:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])=[O:29]>>[CH3:26][N:27]([CH3:37])[S:28]([N:31]1[CH2:36][CH2:35][N:34]([CH2:16][C:13]2[S:12][C:11]([NH:10][C:8]([N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C@H:18]3[CH2:19][CH2:20][C@H:21]([CH3:24])[CH2:22][CH2:23]3)=[O:9])=[N:15][CH:14]=2)[CH2:33][CH2:32]1)(=[O:29])=[O:30]
Reactant: CN(C)S(=O)(=O)N1CCNCC1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(C=O)s2)C2CCCCC2)CC1
Agent: Cl
Product: CN(C)S(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)[C@H]3CC[C@H](C)CC3)s2)CC1

Procedure:
Prepared in 62% (326 mg) yield as described in general procedure (B) from trans-1-cyclohexyl-3-(5-formyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-urea (349 mg, 1.0 mmol) and piperazine-1-sulfonic acid dimethylamide hydrochloride (230 mg, 1 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][S:17]([CH3:16])(=[O:19])=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CCCCO)cc1OC
Product: COc1ccc(CCCCOS(C)(=O)=O)cc1OC
Yield: 78 %

Procedure:
Ester 24 was prepared following procedure E from alcohol 23 (12.0 g, 57 mmol) and methanesulfonyl chloride (8.4 g, 74 mmol) in 78% yield. 1H NMR (300 MHz, CDCl3) δ 1.65 (m, 4H), 2.62 (m, 2H),3.05 (s, 3H), 3.88 (br s, 6H), 4.38 (m, 2H) 6.70–6.88 (m, 3H).
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C@@H:20]([OH:32])[CH2:21][C@@H:22]([C:28]([OH:31])([CH3:30])[CH3:29])[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=O)(C)(C)C.[CH2:40]([C@H:47]([CH2:51][C:52]([N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1)=[O:53])C(O)=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>>[CH2:40]([C@H:47]([CH2:51][C:52]([N:54]1[CH2:55][CH2:56][O:57][CH2:58][CH2:59]1)=[O:53])[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:33][CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)[C@@H:20]([OH:32])[CH2:21][C@@H:22]([C:28]([OH:31])([CH3:30])[CH3:29])[C:23]([N:25]([CH3:26])[CH3:27])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:5])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1
Reactant: CN(C)C(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1)C(C)(C)O
Yield: 35.1 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 100 mg (0.176 mmoles) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N,N-dimethylhexanamide [prepared as described in Example 15(a)], 50 mg (0.18 mmoles) of 2(R)-benzyl-3-(morpholinocarbonyl)propionic acid, 0.28 ml (2 mmoles) of triethylamine, and 0.029 ml (0.18 mmoles) of diethyl cyanophosphate were used, to obtain 45 mg of the title compound as a white powder.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:36])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:35])=[C:25]([C:27]([NH:29][CH2:30][C:31]([O:33]C)=[O:32])=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1.O>[CH2:1]([O:8][NH:9][C:10](=[O:36])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:35])=[C:25]([C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CNC(=O)c1nc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1oc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)nc1C(=O)NCC(=O)O
Reaction time: 1 h
Yield: 39.3 %

Procedure:
A solution of methyl ({[2-((1R)-1-{2-[(benzyloxy)amino]-2-oxoethyl}-4-cyclohexylbutyl)-5-methyl-1,3-oxazol-4-yl]carbonyl}amino)acetate (Preparation 99) (158 mg, 0.32 mmol) in 1,4-dioxan (5 ml) was treated with sodium hydroxide solution (1M) (470 l, 0.47 mmol). The mixture was stirred for 1 hour under a nitrogen atmosphere. The reaction mixture was diluted in water and washed with ethyl acetate. The aqueous layer was acidified with solid citric acid and extracted with ethyl acetate. The organic layers were dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound (61 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:3]=1.C(O)C>[Pd].C(N(CC)CC)C>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[CH:3][C:4]=1[CH:13]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CCCCCC(c1ccccc1)c1cc(Cl)c2ccccc2c1O
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCC(c1ccccc1)c1ccc2ccccc2c1O
Reaction time: 16 h
Yield: 92.6 %

Procedure:
Using ethyl 7-(4-chloro-1-hydroxy-2-naphthyl)-7-phenylheptanoate (4.3 g), 10% palladium-on-carbon (0.4 g), ethanol (90 ml), and triethylamine (10 ml), a catalytic hydrogenation reaction was carried out at 50° C. and atmospheric pressure for 16 hours. The reaction mixture was then filtered and the filtrate was concentrated and applied to a silica gel column (hexane-ethyl acetate) to provide the title compound (3.65 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:16][CH3:17]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:16][CH3:17])[CH:3]=1
Reactant: CCI
Reactant: Oc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cncc(Br)c1
Yield: 54.2 %

Procedure:
A solution of 5-bromopyridin-3-ol (70 g, 402 mmol), K2CO3 (111 g, 805 mmol), iodoethane (69.0 g, 443 mmol) in DMF (900 mL) was stirred for 16 h at 25° C. Then the mixture was concentrated and water (100 mL) was added, the mixture was extracted with DCM (400 mL×2), the combined organic phase were dried over Na2SO4, filtered, and concentrated to give 3-bromo-5-ethoxypyridine (53 g, 218 mmol, 54% yield): 1H NMR (400 MHz, CD3OD) δ 8.19-8.17 (m, 2H), 7.60-7.59 (m, 1H), 4.13-4.07 (m, 2H), 1.40 (t, J=7.0 Hz, 3H); ES-LCMS m/z 202 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[S:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+].S(=O)(=O)(O)O>O1CCOCC1.O>[N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[S:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH:11]([OH:13])[CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2Sc2ccccc21
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)CC(O)c1ccccc1S2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
165.3 g of 10,11-dihydro-2-nitro-dibenzo[b,f]thiepin-10-one are suspended in 6 litres of dioxane and treated with a solution of 63 g of sodium borohydride in 300 ml of dioxane and 300 ml of water. The mixture is stirred overnight at room temperature, then diluted with water, made neutral with sulphuric acid and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and evaporated under reduced pressure. The 10,11-dihydro-2-nitro-dibenzo[b,f]thiepin-10-ol obtained is recrystallised from ethyl acetate; melting point 144°-146° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][Br:18])=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
Heat a mixture of 4′-methylacetophenone (5 g, 37.26 mmol), NBS (6.964 g, 39.12 mmol), and AIBN (153 mg, 0.93 mmol) in carbon tetrachloride (120 mL) for 14 h at reflux. Cool to ambient temperature and wash sequentially with water (100 mL), 1M aqueous HCl (100 mL), 5% aqueous NaHCO3 (100 mL) and brine (100 mL). Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting sequentially with hexane and hexane/EtOAc (19:1, 9:1) to provide the title compound as oil (5.191 g, 65%). GC-MS m/z: 213 (M+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[H][H]>C(O)C.C1COCC1.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCC(c2ccc(N)cc2)CC1

Procedure:
4.3 g (19.5 mmol) 1-methyl-4-(4-nitro-phenyl)-piperidine are dissolved in a mixture of 60 ml of ethanol and 60 ml THF, combined with 2 g palladium/charcoal (10%) and hydrogenated at 1 bar hydrogen. Then the reaction mixture is suction filtered and the filtrate is concentrated by evaporation. Yield: 3.5 g