Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl.[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][NH:10]1.[OH-].[Na+]>CCOC(C)=O.O>[N:5]1[CH:6]=[CH:7][C:2]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)=[CH:3][CH:4]=1
Reactant: Clc1ccncc1
Reactant: c1ccc2c(c1)CCNC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc2c(c1)CCN(c1ccncc1)C2
Temperature: 150 °C

Procedure:
A mixture of 4-chloro-pyridine 1:1 hydrochloride (24.5 g, 163 mmol) and 1,2,3,4-tetrahydro-isoquinoline (65.3 g, 490 mmol) was slowly heated to 150° C. After 30 min the reaction mixture was cooled to rt, H2O (700 ml) and 2N NaOH (82 ml) was added followed by extraction with AcOEt (5 times 300 ml). The combined organic phases were dried (Na2SO4), and the solvent was evaporated. After trituration with pentane and recrystallization the title compound (30.2 g, 88%) was obtained as a light brown crystalline material. Mp. 95-96° C. (AcOEt), MS: m/e=210 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH2:12][NH:11][CH2:10][CH2:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17](F)=[C:18]([CH:21]=1)[C:19]#[N:20].N12CCCN=C1CCCCC2>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N:11]2[CH2:10][CH2:9][C:5]3[N:6]=[CH:7][N:8]=[C:3]([O:2][CH3:1])[C:4]=3[CH2:12]2)=[C:18]([CH:21]=1)[C:19]#[N:20]
Reactant: COc1ncnc2c1CNCC2
Reactant: N#Cc1cc(Cl)ccc1F
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ncnc2c1CN(c1ccc(Cl)cc1C#N)CC2
Temperature: 80 °C
Yield: 82.4 %

Procedure:
A mixture of 4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (12.88 g, 0.078 mol), 5-chloro-2-fluorobenzonitrile (40 g, 0.2 mol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (60 mL, 0.4 mol) was heated at 80° C. for 3 hours. After cooling the mixture was diluted with CH2Cl2 (300 mL), washed with water, dried, and concentrated to afford a brown solid which was purified by silica gel chromatography (0-50% EtOAc/hexane) to afford a solid (19.33 g, 78.3%).
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:19]4[C:18]([NH2:20])=[N:17][CH:16]=[N:15][C:14]=4[N:13]([CH3:21])[CH:12]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([N:2]2[C:10]3[C:5](=[CH:6][C:7]([C:11]4[C:19]5[C:18]([NH2:20])=[N:17][CH:16]=[N:15][C:14]=5[N:13]([CH3:21])[CH:12]=4)=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)=[O:31])=[CH:25][CH:24]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2ccc(F)cc2)c2c(N)ncnc21
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to a solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine HCl (70 mg, 0.232 mmol), (4-fluorophenyl)acetic acid (37.5 mg, 0.244 mmol), and HATU (93 mg, 0.244 mmol) in DMF (2 mL) was added Hunig's base (0.162 mL, 0.928 mmol). The mixture was stirred at overnight. The reaction was poured into water (100 mL), and an off-white solid was formed. The solid was filtered, washed with water (10 mL), and dried to afford the title compound as an off-white solid. LC-MS (ES) m/z=402.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.23 (t, J=8.34 Hz, 2H), 3.73 (s, 3H), 3.88 (s, 2H), 4.23 (t, J=8.46 Hz, 2H), 7.15-7.20 (m, 2H), 7.21-7.26 (m, 2H), 7.30-7.37 (m, 3H), 8.13 (d, J=8.34 Hz, 1H), 8.15 (s, 1H).
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[N:3]=1.[OH-].[Na+].CN1C[CH2:16][C:15](=O)[CH2:14]1.ICCC.Cl>O>[CH2:14]([S:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[N:3]=1)[CH2:15][CH3:16]
Reactant: CN1CCC(=O)C1
Reactant: Oc1cc(O)nc(S)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCI
Product: CCCSc1nc(O)cc(O)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2-mercaptopyrimidine-4,6-diol (25 g, 173.61 mmol, 1.00 equiv.), sodium hydroxide (15.8 g, 395.00 mmol, 2.27 equiv.), 1-methylpyrrolidin-3-one (50 mL), and 1-iodopropane (30.6 g, 180.00 mmol, 1.05 equiv.) dissolved in water (60 mL) was stirred at ambient temperature for about 48 hours. The pH value of the solution was adjusted to 2-3 by adding hydrochloric acid. The solids were then collected by filtration to give the product as an off-white solid (35 g; (crude)). 1H NMR (300 MHz, DMSO-d6) δ: 11.78 (b, 1H), 10.30 (b, 1H), 5.13 (s, 1H), 3.07 (t, J=7.2 Hz, 2H), 1.58-1.70 (m, 2H), 0.96 (t, J=7.2 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5](C)[N:4]([C:8]([NH2:10])=[NH:9])N=1.C(N(CC)C(C)C)(C)C.NCCCC[CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29]>O1CCOCC1.O>[NH:4]([CH2:5][CH2:6][CH2:2][CH2:1][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:8]([NH2:10])=[NH:9]
Reactant: NCCCCCCCC(=O)O
Reactant: Cc1cc(C)n(C(=N)N)n1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)NCCCCCCCC(=O)O

Procedure:
3,5-dimethyl-pyrazole-1-carboxamidine (Aldrich) (100 g; 0.5 Mole) and N,N-diisopropylethyl amine (DIEA) (65 g; 0.5 Mole) were suspended in dioxane (300 ml) and water (115 ml). 8-Amino-octanoic acid (48 g; 0.3 Mole) was added to the mixture with stirring. The colorless solution was then refluxed for 2 days. The product was filtered and washed with water (3×50 ml).
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3]1.[C:19]([OH:23])([CH3:22])([CH3:21])[CH3:20].OC1CC(=O)C(CCCCCCC(OCC)=O)=C1>C(=O)([O-])[O-].[Ag+2].CO>[C:19]([O:23][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)O
Reactant: CCOC(=O)CCCCCCC1=CC(Br)CC1=O
Agent: [Ag+2]
Agent: CCOC(=O)CCCCCCC1=CC(O)CC1=O
Agent: O=C([O-])[O-]
Solvent: CO
Product: CCOC(=O)CCCCCCC1=CC(OC(C)(C)C)CC1=O

Procedure:
A stirred mixture of 6.35 g. (20 mmoles) of 4-bromo-2-(carbethoxyhexyl)cyclopent-2-en-1-one (Example 94), 3.01 g. (11 moles) of silver carbonate, and 40 ml. of t-butanol is heated at 70°C. for 17 hours. The mixture is cooled and filtered. After evaporation of t-butanol the residue is treated with aq. sodium chloride and extracted with 3:1 ether-hexane. The extract is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product is purified by chromatography on silica gel to give, in order of elution: the subject compound as an oil; λ max.MeOH = 219 mμ (8860); ν max. = 1735 (ester carbonyl group), 1725 ketone carbonyl group), and 1365 cm-1 (tert.-butyl group); and 4-hydroxy-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one also as an oil.
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl.CCN(C(C)C)C(C)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:39])[C:27]2[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[C:30]([NH:36][CH3:37])=[CH:29][C:28]=2F)=[CH:21][C:20]=1[Cl:40]>CC#N>[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:39])[C:27]2[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[C:30]([NH:36][CH3:37])=[CH:29][C:28]=2[N:5]2[CH2:6][CH2:7][CH:2]([F:1])[CH2:3][CH2:4]2)=[CH:21][C:20]=1[Cl:40]
Reactant: FC1CCNCC1
Reactant: CNc1cc(F)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(N2CCC(F)CC2)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]
Reaction time: 6 h

Procedure:
A mixture of 4-fluoropiperidine×HCl (67 mg, 0.48 mmol), DIPEA (0.64 ml, 3.73 mmol), N-(4-fluoro-3-chloro-phenyl)-2-fluoro-4-methylamino-5-nitro-benzoic acid amide (150 mg, 0.44 mmol) and MeCN (5 mL) is stirred for 6 h at reflux. Then the mixture is concentrated, diluted with EtOAc, washed with water and concentrated.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:9])[CH:4]([CH3:8])[O:5][C:6]=1[CH3:7].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.O>N1C=CC=CC=1.ClCCl>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([O:9][C:3]2[C:2](=[O:1])[CH:6]([CH3:7])[O:5][C:4]=2[CH3:8])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: CC1=C(O)C(=O)C(C)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC1=C(OS(=O)(=O)c2ccc(C)cc2)C(=O)C(C)O1
Temperature: -10 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
12.8 grams (0.1 m) of 4-hydroxy-2,5-dimethyl-2,3-dihydrofuran-3-one were dissolved in 70 ml of dry pyridine. The solution was stirred and cooled to -10° C. in an ice-salt bath. With stirring a cold solution of 22.9 grams (0.12 m) of p-toluene sulfonylchloride in 50 ml of dry dichloromethane was added dropwise (temp. below -5° C.). After completion of the addition (1 hour), stirring at 0° C. was continued for 3 hours, and water (10 ml) was added in portions at intervals of 5 min., with stirring and cooling, so that the temperature did not rise above 5° C. The solution was then poured into 250 ml of ice-water. The mixture was extracted four times with dichloromethane, and the combined extracts were successively washed with portions of ice-cold dilute sulphuric acid, water, sodium hydrogen carbonate solution and water. The dichloromethane solution was then dried with anhydrous sodium sulphate and evaporated to dryness. Crystallization from ethanol yielded 21.3 grams = 75.5% of the pure 4-p-toluenesulfonyloxy-2,5-dimethyl-2,3-dihydrofuran-3-one with m.p. 70°-72° C. 3.5 grams (12.4 mmol) of the tosylate thus obtained were dissolved in a mixture of 15 ml of ethanol and 5 ml of water at 40° C. To this solution was added a solution of 1.68 grams (30 mmol) of sodium hydrogen sulphide in 20 ml of ethanol, while a gentle stream of hydrogen sulphide was passed through the reaction mixture. After completion of the addition, which took one hour, stirring and passing of H2S into the solution were continued for 6 hours at 40° C. and the reaction mixture was diluted with 200 ml of water, acidified with aqueous dilute hydrochloric acid (pH 5.5) and continuously extracted with ether for 18 hours. The extract was dried over anhydrous sodium sulphate and evaporated to dryness. From the residue the title compound was isolated in a quantity of 3 grams by preparative gaschromatography, using a column of 600 × 0.4 cm, a support of Diatoport S (a silanated silicagel) ex Hewlett Packard, loaded with 1% Carbowax 20 M (a polyethylene glycol ether with a molecular weight above 20,000) ex Hewlett Packard and 10% Apiezon (a mixture of stable alkanes) ex Shell Comp. Nitrogen was used as a carrier gas at a velocity of 40 ml per minute. The temperature was programmed; starting temperature 60° C.; increase in temperature 4° per minute. The retention time found for 4-mercapto-2,5-dimethyl-2,3-dihydrothiophene-3-one was 40.1 minutes.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.[CH2:16]([N:18](CC)CC)[CH3:17].C(N)C>C(O)C>[CH2:16]([NH:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1)[CH3:17]
Reactant: O=[N+]([O-])c1c(Cl)nc(C(F)(F)F)nc1Cl
Reactant: CCN(CC)CC
Agent: CCN
Solvent: CCO
Product: CCNc1nc(C(F)(F)F)nc(Cl)c1[N+](=O)[O-]
Reaction time: 4 h
Yield: 97.9 %

Procedure:
5.25 g (0.02 mol) of 4,6-dichloro-5-nitro-2-trifluoromethyl-pyrimidine are dissolved in 100 ml of abs. ethanol and the solution is cooled to -30° C. At this temperature, 2.0 g (0.02 mol) of triethylamine and 0.9 g (0.2 mol) of ethylamine are added. The mixture is stirred first for 4 hours at -20° C to -30° C and then for 6 hours at 0° C. After it has been left to stand overnight at 20° C, the reaction mixture is concentrated to dryness. The residue is taken up in ether and the solution washed with water. The ethereal phase is dried and concentrated to yield 5.3 g of 4-ethylamino-6-chloro-5-nitro-2-trifluoromethyl-pyrimidine as a pale yellow oil; nD20 = 1.4985.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[C:2]([N:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[CH:3]=4)[CH:9]=3)=[CH:16][CH:17]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: C1CCNC1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-pyrrolidin-1- ylisonicotinamide was prepared from 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide and pyrrolidine using method A. NMR; δH [2H6]—DMSO 10.28,(1H. s), 8.62,(1H, t), 8.19,(1H, d), 7.93,(2H, d), 7.71,(1H, dd), 7.66,(1H, d), 7.44,(2H, d), 7.30,(1H, d), 6.97,(1H, d), 6.86,(1H, s), 3.43,(4H, m), 3.16,(2H, t), 2.20,(3H, s), 1.95,(4H, m), 1.04,(1H, b), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 2.85 min, M+455.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:35])=[C:13]([C:15]3[CH:16]=[CH:17][C:18]4[O:22][C:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)=[C:20]([C:30]([NH:32][CH3:33])=[O:31])[C:19]=4[CH:34]=3)[CH:14]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2].Cl.[NH2:37][OH:38].CCN(CC)CC>C(O)C>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:21]2[O:22][C:18]3[CH:17]=[CH:16][C:15]([C:13]4[CH:14]=[C:9]([C:7](=[O:8])[NH:6][C:3]5([C:1](=[NH:2])[NH:37][OH:38])[CH2:4][CH2:5]5)[CH:10]=[CH:11][C:12]=4[CH3:35])=[CH:34][C:19]=3[C:20]=2[C:30]([NH:32][CH3:33])=[O:31])=[CH:28][CH:27]=1
Reactant: NO
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(C#N)CC4)ccc3C)cc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(C(=N)NO)CC4)ccc3C)cc12
Temperature: 115 °C

Procedure:
To a mixture of 5-(5-(1-cyanocyclopropylcarbamoyl)-2-methylphenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (43.5 mg, 0.093 mmol) in ethanol (1.5 mL) at r.t. under N2 was added hydroxylamine hydrochloride (12.93 mg, 0.186 mmol), followed by Et3N (0.039 mL, 0.279 mmol). The mixture was stirred at reflux (115° C.) for about 4 hours. The mixture was cooled to r.t. and evaporated. The residue was used for the next step without further purification. LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters MICROMASS®. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: PHENOMENEX® Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=501.13, HPLC Rt=1.385 min.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11](=[O:34])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[C:27](\[O:32][CH3:33])/[C:28]([O:30]C)=[O:29])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(O)(=O)C>O1CCCC1>[CH2:3]([NH:10][C:11](=[O:34])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:21]=[CH:22][C:23](/[CH:26]=[C:27](\[O:32][CH3:33])/[C:28]([OH:30])=[O:29])=[CH:24][CH:25]=2)[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)O)cc2)c1
Temperature: 68 °C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
3.3 mL (3.3 mmol) of aqueous 1 N sodium hydroxide solution are added to a solution of 1 g (2.2 mmol) of methyl (Z)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]-2-methoxyacrylate in 16 mL of tetrahydrofuran. The reaction medium is heated at 68° C. and stirred for 4 hours. The reaction medium is acidified with 3.5 mL of 1 N acetic acid solution and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is recrystallized from a hot heptane/ethyl acetate mixture. 800 mg (86%) of (Z)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]-2-methoxyacrylic acid are obtained in the form of a white solid with a melting point of 114° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:31][CH3:32])[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C@H:10]([O:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C@H:9]2[O:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:4][C:3]=1[CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(Cl)Cl.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:31][CH3:32])[O:13][C@H:12]([CH:14]=[O:15])[C@@H:11]([O:16][Si:17]([CH3:20])([CH3:18])[CH3:19])[C@H:10]([O:21][Si:22]([CH3:23])([CH3:24])[CH3:25])[C@H:9]2[O:26][Si:27]([CH3:28])([CH3:29])[CH3:30])=[CH:4][C:3]=1[CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(COc3ccccc3)c2)O[C@H](CO)[C@@H](O[Si](C)(C)C)[C@H](O[Si](C)(C)C)[C@H]1O[Si](C)(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@@]1(c2ccc(Cl)c(COc3ccccc3)c2)O[C@H](C=O)[C@@H](O[Si](C)(C)C)[C@H](O[Si](C)(C)C)[C@H]1O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a suspension of ((2R,3R,4S,5R,6S)-6-(4-chloro-3-(phenoxymethyl)phenyl)-6-methoxy-3,4, 5-tris((trimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)methanol (23.0 g, 36.7 mmol) in DMSO (250 mL) was added DCM (20 mL) to make a clear solution. The solution was cooled to 0° C. followed by addition of triethyl amine (122.4 ml, 881.0 mmol) and sulphur trioxide pyridine complex (87.5 g, 550.6 mmol). The reaction mixture was stirred at 0 to 10° C. for 3 h under nitrogen atmosphere. After completion of the reaction as confirmed by TLC, the crude compound was extracted with diethyl ether (1 L). The organic layer was separated, washed with water (2×500 mL), dried over Na2SO4, concentrated in vacuo to afford crude title compound (22.9 g, 100%) as a viscous oil which was used for next step without any purification.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([Br:7])[N:6]=1.[CH3:11]N(C)CCCN=C=NCC>CO>[CH3:11][O:9][C:8]([C:4]1[S:3][C:2]([Br:1])=[N:6][C:5]=1[Br:7])=[O:10]
Reactant: O=C(O)c1sc(Br)nc1Br
Reactant: CCN=C=NCCCN(C)C
Solvent: CO
Product: COC(=O)c1sc(Br)nc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
A solution of 2,4-dibromo-thiazole-5-carboxylic acid (1.7 g, 5.92 mmol) in methanol (20 ml) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (920 mg, 5.92 mmol). The mixture was stirred at ambient temperature overnight. The solvent was evaporated and water (30 ml) was added. The mixture was then extracted with 3×30 ml of EtOAc. The combined organics were washed with brine, dried with MgSO4 and concentrated in vacuo. The crude was purified by flash chromatography (0 to 5% EtOAc/Hexanes) to afford 2,4-Dibromo-thiazole-5-carboxylic acid methyl ester (1.4 g, 78%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 3.91 (s, 3H).
Reaction SMILES: Cl.[OH:2][CH:3]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH:4]([NH2:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[OH:2][CH:3]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH:4]([NH:16][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][C:29]([C:28]([F:27])([F:38])[F:39])=[CH:30][CH:31]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a solution of (1RS,2SR)-1-hydroxy-1-(1-naphthalenyl)-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.39 mmol) in ethyl acetate (5 ml) were added 4-trifluoromethylbenzoyl chloride (87.5 ml, 0.59 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (178 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Cl.[CH3:11][C:12]([CH3:15])([O-:14])[CH3:13].[Na+].C1(C)C=CC=CC=1.Cl>C1OCCOCCOCCOCCOC1.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][O:14][C:12]([CH3:15])([CH3:13])[CH3:11]
Reactant: Fc1cccc(Cl)c1CCl
Reactant: CC(C)(C)[O-]
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OCc1c(F)cccc1Cl
Temperature: 45 °C
Yield: 89.9 %

Procedure:
A mixture of 200 g (1.117 mole) of 2-chloro-6 fluorobenzyl chloride, 118 g (1.23 mole) of sodium t-butoxide, 2.2 mL (11 mmole) of 15-crown-5 (15-C-5) and 1.2 L of toluene was heated at reflux temperature for four hours. After allowing the reaction mixture to cool to 45° C., 600 mL of water was added followed by 90 mL of 2N HCl. After separation, the organic phase was concentrated in vacuo to give a dark oil. Distillation using a 5-tray Oldershaw column, sand bath to 155° C., gave 217.5 g of 1-chloro-3-fluoro-2-[(1,1-dimethylethoxy)methyl]-benzene as a clear liquid (bp 60-64° C./0.6 mm Hg.).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:13]CN)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:20]([O:23]C(=O)C)(=O)[CH3:21].[N:27]1C=CC=C[CH:28]=1>>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:13][N:27]([CH3:28])[C:20](=[O:23])[CH3:21])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CCN)ccc1Cl
Reactant: c1ccncc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N(C)Cc1ccc(Cl)c(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-chlorobenzyl]methylamine from the previous step (1 eq.) in pyridine (0.09 M) was added acetic anhydride (1.1 eq.) The resulting reaction mixture was stirred at RT for 3 h. After quenching the reaction with H2O, the mixture was extracted with EtOAc. The combined organic extracts were washed with 10% aq. HCl, sat. aq. NaHCO3, and brine. Drying over Na2SO4, filtration and concentration of the filtrate in vacuo afforded the crude product as a brown oil. Purification by way of flash chromatography (SiO2, 7:3 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:4][C:5]2[C:15]([N:16]=1)=[CH:14][C:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][C:7]=1[CH:6]=2.[Cl:19][CH2:20][CH2:21][CH2:22][S:23][C:24]1[N:25]([CH3:40])[C:26]([C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][C:33]([CH3:39])=[N:34]3)=[N:27][N:28]=1>>[ClH:19].[CH3:40][N:25]1[C:26]([C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][C:33]([CH3:39])=[N:34]3)=[N:27][N:28]=[C:24]1[S:23][CH2:22][CH2:21][CH2:20][N:11]1[CH2:10][CH2:9][C:8]2[CH:14]=[C:15]3[N:16]=[C:3]([C:2]([F:17])([F:1])[F:18])[O:4][C:5]3=[CH:6][C:7]=2[CH2:13][CH2:12]1
Reactant: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Reactant: FC(F)(F)c1nc2cc3c(cc2o1)CCNCC3
Product: Cc1ccc2c(-c3nnc(SCCCN4CCc5cc6nc(C(F)(F)F)oc6cc5CC4)n3C)cccc2n1
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (0.14 μmol) and 5-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline and was obtained as a colourless solid (97 μmol).