Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:62])=[O:61])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6].Cl.[C:64](Cl)(=[O:71])[C:65]1[CH:70]=[CH:69][CH:68]=[N:67][CH:66]=1>N1C=CC=CC=1.ClCCl>[C:60]([O:59][C@@H:4]1[C:3]2[C:15]([CH3:16])([CH3:17])[C@@:14]([OH:41])([CH2:18][C@H:19]([O:20][C:21](=[O:22])[C@H:23]([O:40][C:64](=[O:71])[C:65]3[CH:70]=[CH:69][CH:68]=[N:67][CH:66]=3)[C@@H:24]([NH:31][C:32](=[O:33])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:2]=2[CH3:1])[C@@H:13]([O:42][C:43](=[O:44])[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@@H:12]2[C@:11]3([O:53][C:54](=[O:55])[CH3:56])[CH2:51][O:52][C@@H:10]3[CH2:9][C@H:8]([OH:57])[C@@:7]2([CH3:58])[C:5]1=[O:6])(=[O:61])[CH3:62]
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](OC(=O)c4cccnc4)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.6 %

Procedure:
4 drops of pyridine were added to a solution of paclitaxel [4114] (0.10 g, 0.117 mmol 1.0 eq) of in dry dichloromethane under argon atmosphere. At 0° C., nicotinoyl chloride hydrochloride [296] (0.17 g, 1.17 mmol 10.0 eq) was added. The reaction mixture was stirred at room temperature for 24 hours. After 24 hours, the mixture was diluted with dichloromethane (25 ml) and washed with a 10% solution of NaHCO3 (15 ml) and brine (10 ml) followed by drying over anhydrous sodium sulfate. Evaporation of the solvents provided residual yellow solid which was purified by silica gel column chromatography (30% ethyl acetate: cyclohexane, 100-200 mesh silica) to get a white solid [310], (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-benzamido-2-(nicotinoyloxy)-3-phenylpropanoyl)oxy)-12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxete-6,12b-diyl diacetate, (0.05 g, 45%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O[NH:18][C:19](=[NH:28])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:10][N:28]=[C:19]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=3)[N:18]=2)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)c(Cl)c1
Reactant: N=C(NO)c1ccc(CO)cc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: OCc1ccc(-c2noc(-c3ccc(-c4ccccc4)c(Cl)c3)n2)cc1
Temperature: 122.5 °C

Procedure:
N,N-Dicyclohexylcarbodiimide (4 g, 0.019 mol) is added to a solution of 2-chlorobiphenyl-4-carboxylic acid (3 g, 0.013 mol), N-hydroxy-4-hydroxymethyl benzamidine (2.9 g, 0.017 mol) and N-hydroxybenzotriazole monohydrate (2.9 g, 0.019 mol) in N,N-dimethylformamide (40 mL). The reaction mixture is heated at 120-125° C. for 3 hrs. It is then cooled to 0-5° C., filtered and washed with dichloromethane (2×15 mL). The filtrate is evaporated under reduced pressure and the residue is treated with demineralized water (20 mL). It is extracted with ethyl acetate (2×20 mL) and the combined extract is dried over sodium sulfate. Removal of solvent under reduced pressure gives a crude residue which is purified by column chromatography (silica gel 230-400, ethyl acetate:toluene, 1:9) to give {4-[5-(2-chlorobiphenyl-4-yl)-[1,2,4]-oxadiazol-3-yl]-phenyl}-methanol.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])[O:4][N:3]=1.[C:14](Cl)([Cl:16])=[O:15]>ClCCl>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([Cl:16])=[O:15])[O:4][N:3]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1noc(-c2ccccc2N)n1
Solvent: ClCCl
Product: Cc1noc(-c2ccccc2NC(=O)Cl)n1
Reaction time: 4 h

Procedure:
A solution of 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzenamine (1.0 g) in dry dichloromethane (20 ml) was added dropwise to a 0° solution of phosgene (14.1 ml, 20% in toluene) in dry dichloromethane (50 ml) under a nitrogen atmosphere. After addition the reaction mixture was allowed to slowly attain room temperature and stirred for 4 h. Nitrogen, was bubbled through the resulting mixture for 16 h. Dichloromethane was added to the resultant precipitate and the solution was evaporated to give the title compound (1.322 g), max (Nujol) 2800-2500, 1782 (NCO-Cl), 1631 (C=N), 1501 (NH), 769 (aromatic) cm-1.
Reaction SMILES: N[C@@:2]1(/[CH:15]=[N:16]\[O:17][C:18](=O)[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][CH:22]=2)[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[N:30]1C=CC=CC=1>>[OH:28][CH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:18]2[O:17][N:16]=[C:15]([C@@H:2]3[CH2:7][CH2:6][CH2:5][CH2:4][N:3]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[N:30]=2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@]1(N)/C=N\OC(=O)COc1ccc(CO)cc1
Reactant: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1c1noc(COc2ccc(CO)cc2)n1

Procedure:
tert-Butyl (Z)-(2S)-2-amino[(2-[4-(hydroxymethyl)phenoxy]acetyloxy)imino]methyl-1-piperidinecarboxylate (see Preparation 12] (2.94 g) was dissolved in pyridine (30 ml) and heated under reflux for 18 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate and water, the organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 50:50 changing to 0:100 (in 10% increments), by volume, hexane:ethyl acetate to afford tert-butyl (2S)-2-(5-[4-(hydroxymethyl)phenoxymethyl]-1,2,4-oxadiazol-3-yl)-1-piperidinecarboxylate (1.06 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[K+].[CH2:13]([N:15]1[C:19]([CH:20]=[O:21])=[CH:18][C:17]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[N:16]1)[CH3:14]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:20]([C:19]3[N:15]([CH2:13][CH3:14])[N:16]=[C:17]([NH:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[CH:18]=3)=[O:21])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCn1nc(NCc2ccc(F)cc2)cc1C=O
Reactant: Clc1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCn1nc(NCc2ccc(F)cc2)cc1C(=O)c1c[nH]c2ncc(Cl)cc12
Reaction time: 0.83 h
Yield: 2.1 %

Procedure:
5-Chloro-1H-pyrrolo[2,3-b]pyridine (532, 0.068 g, 0.44 mmol) was combined with methanol (10 mL) and potassium hydroxide (0.16 g, 2.8 mmol). The mixture was stirred for 50 minutes, then 2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carbaldehyde (530, 0.100 g, 0.40 mmol, prepared as described in Example 47, Scheme 162, Step 5) was added and the reaction was stirred overnight at room temperature and then concentrated. Ethyl acetate was added and the mixture was washed with sodium bicarbonate saturated solution and brine. After drying over anhydrous sodium sulfate the solvent was removed under reduced pressure. Purification with silica gel column chromatography eluting with a gradient of ethyl acetate (10-100%) in hexanes provided the desired compound (0.0033 g, 2%). MS (ESI) [M+H+]+=398.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].[CH3:25][C:26]1([CH3:36])[O:31][CH2:30][C:29]([C:33](O)=[O:34])([CH3:32])[CH2:28][O:27]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>CN(C)C=O>[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([C:5]2([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9][N:8]([C:33]([C:29]3([CH3:32])[CH2:28][O:27][C:26]([CH3:36])([CH3:25])[O:31][CH2:30]3)=[O:34])[CH2:7][CH2:6]2)(=[O:13])=[O:12])=[CH:19][CH:18]=1)[C:22]#[C:23][CH3:24]
Reactant: CC1(C)OCC(C)(C(=O)O)CO1
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)C3(C)COC(C)(C)OC3)CC2)cc1

Procedure:
Methyl 4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxylate was prepared following the procedure Example 64 (step 6). Starting from 4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (500 mg, 1.29 mmol) in dimethylformamide (10 ml), (2,2,5-trimethyl-1,3-dioxan-5-yl)carboxylic acid (224 mg, 1.29 mmol), 1-hydroxybenzotriazole (209 mg, 1.56 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (346 mg, 1.81 mmol), and N-methylmorpholine (0.212 ml, 1.94 mmol), to obtain 385 mg (59%) of the product as a solid. HR-MS: m/z Calculated for C25H33NO8S 508.2000; Found 508.1998.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[N:32]=[C:31]([C:33]([OH:35])=O)[CH:30]=[CH:29][C:28]=1[N+:36]([O-:38])=[O:37].CCN(C(C)C)C(C)C.CN>C1COCC1>[CH3:25][O:26][C:27]1[N:32]=[C:31]([C:33]([NH:2][CH3:1])=[O:35])[CH:30]=[CH:29][C:28]=1[N+:36]([O-:38])=[O:37]
Reactant: COc1nc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1ccc([N+](=O)[O-])c(OC)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
HATU (0.606 g, 1.594 mmol) was added to a solution of 6-methoxy-5-nitropicolinic acid (Preparation 190, 0.243 g, 1.226 mmol), DIPEA (0.320 mL, 1.840 mmol) and 2M methylamine solution in THF (1.2 mL, 2.453 mmol) in THF (3.3 mL). The reaction mixture was stirred at room temperature for 3 hours. Further methylamine (0.6 mL) was added and the mixture was stirred for 18 hours. The reaction was quenched with water and concentrated in vacuo. The aqueous phase was extracted with EtOAc (×2) and the combined organic layers were washed twice with water, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by Biotage silica gel column chromatography eluting with DCM/EtOAc 99/1 to 90/10 to afford the title compound as a yellow solid (182 mg, 70%).
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[C:5]([OH:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:7]=[CH:8][CH:9]=1.Br[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].FC(F)OC1C(OCC(C)(C)C)=C(/C=C/C2N=C3N(C=2C(O)=O)C=CS3)C=CC=1>CN(C)C=O>[F:27][CH:2]([F:1])[O:3][C:4]1[C:5]([O:26][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)CCBr
Reactant: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2O)nc2ccccn12
Agent: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2OCCC(C)C)nc2ccccn12
Yield: 101 %

Procedure:
Alkylation of Intermediate 12 (400 mg, 1.069 mmol) with 1-bromo-3-methylbutane (193.8 mg, 1.283 mmol) in presence of potassium carbonate (163 mg, 1.175 mmol) in anhydrous N,N-dimethylformamide (4 mL) as described in Intermediate 7A, Step 1 gave 480 mg of the compound as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.94 (d, J=6.9, 6H), 1.40-1.47 (m, 3H), 1.64-1.71 (m, 2H), 1.88-1.95 (m, 1H), 3.97-4.03 (m, 2H), 4.40-4.48 (m, 2H), 7.12-7.20 (m, 2H), 7.21 (t, J=74.7 Hz, 1H), 7.22-7.28 (m, 1H), 7.53-7.62 (m, 2H), 7.74 (d, J=8.4 Hz, 1H), 7.94 (d, J=15.9 Hz, 1H), 8.04 (d, J=16.2 Hz, 1H), 9.23 (d, J=6.3 Hz, 1H); ESI-MS (m/z) 445.25 (M)+.
Reaction SMILES: [I:1][C:2]1[C:3]([NH2:13])=[N:4][CH:5]=[C:6]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:7]=1.Br[CH2:15][CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Si:19]([O:18][CH2:17][CH2:16][CH2:15][N:10]1[N:11]=[N:12][C:8]([C:6]2[CH:7]=[C:2]([I:1])[C:3]([NH2:13])=[N:4][CH:5]=2)=[N:9]1)([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20]
Reactant: Nc1ncc(-c2nn[nH]n2)cc1I
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCn1nnc(-c2cnc(N)c(I)c2)n1
Temperature: 80 °C

Procedure:
The reaction mixture of 3-iodo-5-(2H-tetrazol-5-yl)pyridin-2-amine (0.61 g, 2.12 mmol, 1 eq), (3-bromopropoxy)-tert-butyldimethylsilane (0.66 mL, 1.3 eq), and potassium carbonate (0.44 g, 1.5 eq) in anhydrous dimethylformamide (8 mL) was stirred and heated at 80° C. under nitrogen atmosphere for 2 hours. It was then diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted and concentrated under reduced pressure with silica gel. A gradient column chromatography [Hexane to EtOAc-Hex (1:2)] rendered 5-(2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-tetrazol-5-yl)-3-iodopyridin-2-amine as a white solid in the amount of 797 mg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1F.[NH4+:13].[OH-]>CCOC(C)=O>[NH2:13][C:7]1[C:6]([F:9])=[C:5]([F:10])[N:4]=[C:3]([C:11]#[N:12])[C:2]=1[Cl:1]
Reactant: N#Cc1nc(F)c(F)c(F)c1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: N#Cc1nc(F)c(F)c(N)c1Cl
Yield: 88.3 %

Procedure:
A solution of 3-chloro-4,5,6-trifluoropicolinonitrile (200 g) in EtOAc (3 L) was cooled to 10° C. To this was slowly added 14% aq NH4OH (1296 g) keeping the temperature between 18-23° C. The aqueous solution was separated from the organic solution. The organic phase was washed sequentially with a 50/50 solution of aqueous saturated NaCl and water (500 mL) and satd NaC1 solution (250 mL). The organic phase was concentrated under vacuum at 50° C. to about 500 mL volume as the product crystallized out. To this slurry was added heptane (1 L), and the mixture was concentrated under vacuum. The solids were collected by filtration. This solid was washed with pentane and dried under vacuum to give 4-amino-3-chloro-5,6-difluoropicolinonitrile (173.8 g, 90%, 99.6% purity) as a white crystalline solid: mp 190-191.5° C.; 13CNMR (101 MHz, DMSO-d6) δ 150.03 (dd, J=232.4, 12.5 Hz, C6), 144.29 (dd, J=11.4, 6.9 Hz, C4), 133.72 (dd, J=257.9, 30.8 Hz, C5), 122.14 (dd, J=19.6, 4.9 Hz, C2), 119.31 (s, C3), 114.25 (s, CN); 19F NMR (376 MHz, DMSO-d6) δ −91.24 (d, J=24.2 Hz), −154.97 (d, J=24.2 Hz); EIMS m/z 189 ([M]+). Anal. Calcd for C6H2C1F2N3: C, 38.02; H, 1.06; N, 22.17. Found: C. 37.91; H.1.00; 22.02.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].B(F)(F)F.[CH2:10]([CH:12]1[O:14][CH2:13]1)Cl.[OH-].[Na+]>CCOCC.O>[CH2:1]([O:5][CH2:10][CH:12]1[O:14][CH2:13]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: ClCC1CO1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCCCOCC1CO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
370 g (5 mol) of n-butanol and 3 ml of BF3.(C2H5)2O catalyst were heated to 45° C. and stirred for 4 h. An amount of 466 g (5 mol) of epichlorohydrin was added dropwise at 40°-50° C. The mixture was cooled down to room temperature and 6.25 mol of a 50% aqueous solution of sodium hydroxide (250 g of sodium hydroxide dissolved in 250 ml of water) was added dropwise. The mixture was stirred for 1 h. Water was added until complete dissolution of the inorganic salt. The organic phase was separated and 0.5 l of ethyl acetate was added thereto. The organic phase was rinsed twice with water, dried over sodium sulphate, filtered, and concentrated by evaporation. Fractionation was carried out then at normal pressure. Yield: 290 g of 1-butoxy-2,3-epoxypropane boiling at 170°-174° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:11][C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCc2ccc(F)cc2)cc1
Yield: 96.1 %

Procedure:
A mixture of methyl p-hydroxybenzoate (4.38 g, 28.8 mmol), p-fluorobenzyl chloride (5.0 g, 34.6 mmol) and anhydrous potassium carbonate (10 g) in acetone (250 ml) was heated under reflux for 24 h. The solid was then filtered and the filtrate was evaporated under reduced pressure. Crystallization of the residue from hexane gave 7.20 g (96%) of the title ester as white plates: mp 93-94° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.9 (3H, s, OCH3), 5.1 (2H, s, CH2), 7.0 (2H, d, J=8.8 Hz, aromatics), 7.11 (2H, m, aromatics), 7.43 (2 H, m, aromatics), 8.02 (2H, d, J=8.8 Hz, aromatics). Anal. Calcd for C15H13FO3: C, 69.22; H, 5.03. Found: C, 68.89; H, 4.69.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)/[C:12]([OH:14])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Cl[CH2:30][C:31]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)/[C:12]([O:14][CH2:30][C:31]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:32])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccccc1Cl
Reactant: CCN(CC)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)OCC(=O)N(CC)CC)n1Cc1ccccc1Cl
Temperature: 70 °C

Procedure:
A solution of (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid (Example 1) (5 mmol) in dry dimethylformamide (10 mL) was treated with 2-chloro-N,N-diethyl-acetamide (5.51 mmol) followed by powdered potassium carbonate. This mixture was heated at 70° C. for 7 hours, diluted with water and extracted with ethyl acetate. The water-washed, dried, concentrated product solidifies and after trituration with ether/hexane affords the title ester; mp 139°-140° C.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.[NH2:25][C@H:26]([CH3:36])[C@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Br:35])[CH:30]=1)[OH:28]>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:25][C@H:26]([CH3:36])[C@H:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Br:35])[CH:30]=3)[OH:28])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: C[C@@H](N)[C@@H](O)c1cccc(Br)c1
Agent: Cl
Product: C[C@@H](NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)[C@@H](O)c1cccc(Br)c1
Yield: 12 %

Procedure:
The title compound (7 mg, 12%) was obtained from 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid and (1S,2R)-2-amino-1-(3-bromo-phenyl)-propan-1-ol hydrochloride salt as in Example 1, Part C. HPLC: RT=10.08 min. MS (ESI−): mass calcd. for C22H18BrClN4O4S2, 581.89; m/z found, 579/581 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.58 (s, 1H), 8.38 (dd, J=7.0, 0.9, 1H), 8.22 (dd, J=8.8, 0.9, 1H), 7.74-7.71 (m, 2H), 7.55-7.53 (m, 1H), 7.47-7.43 (m, 1H), 7.31-7.22 (m, 2H), 6.95 (dd, J=8.4, 2.0, 1H), 6.19 (d, J=8.5, 1H), 4.95 (d, J=2.7, 1H), 4.48-4.39 (m, 1H), 2.61 (s, 1H), 1.04 (d, J=6.9, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(O)C.[CH3:27][C:28]1[CH:29]=[C:30]([C:34]([N:36]=[C:37]=[S:38])=[O:35])[CH:31]=[CH:32][CH:33]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:36][C:34](=[O:35])[C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([CH3:27])[CH:29]=2)=[S:38])=[CH:18][C:17]=1[F:23]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: Cc1cccc(C(=O)N=C=S)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 3-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (64 mg, yield 82%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:16])[CH3:2].[CH:18]1([S:24]([C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[CH:29]=O)(=[O:26])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH:18]1([S:24]([C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[CH2:29][C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=3)[N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])[C:7]=2[CH3:16])(=[O:25])=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CCOC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1ccccc1S(=O)(=O)C1CCCCC1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)C2CCCCC2)c2cc(F)ccc21
Reaction time: 2 h
Yield: 51.4 %

Procedure:
To a stirred solution of [5-fluoro-2-methyl-1H-indol-1-yl]acetic acid ethyl ester (0.85 g, 3.62 mmol) at room temperature in dichloromethane (20 mL) was added 2-(cyclohexylsulfonyl)benzaldehyde (1.00 g, 3.97 mmol) followed by triethylsilane (2.9 mL, 18.3 mmol). TFA (0.85 mL, 11.0 mmol) was then added dropwise over 15 minutes, and after the addition was complete, the resulting mixture was stirred for 2 hours. Saturated aqueous NaHCO3 was then added to the solution, and the separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resulting solid was purified by trituration with light petroleum then recrystallised from an ethyl acetate/hexanes mixture to afford ethyl 2-(3-(2-(cyclohexylsulfonyl)benzyl)-5-fluoro-2-methyl-1H-indol-1-yl)acetate (0.875 g, 1.86 mmol, 51%).