Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].CN(C)C=O.Br[CH2:13][C:14]1[CH:18]=[CH:17][S:16][CH:15]=1>O1CCCC1>[S:16]1[CH:17]=[CH:18][C:14]([CH2:13][O:3][CH2:2][CH2:1][OH:4])=[CH:15]1
Reactant: OCCO
Reactant: BrCc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: OCCOCc1ccsc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 101.3 %

Procedure:
621 mg of ethylene glycol was dissolved in 1 ml of tetrahydrofuran, and 88 mg of 60% oily sodium hydride and 0.5 ml of dimethylformamide were added. After the mixture was stirred at room temperature for 5 minutes, a tetrahydrofuran solution(1 ml) of 200 mg of 3-bromomethylthiophene was added. The mixture was stirred at 60 ° C. for 2 hours, and then the solvent was evaporated. The residue was worked up in a customary manner to give 181 mg of the captioned compound as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][N:14]1[C:19](=[O:20])[CH:18]=[CH:17][C:16]([C:21](O)=[O:22])=[N:15]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:21]([C:16]3[CH:17]=[CH:18][C:19](=[O:20])[N:14]([CH3:13])[N:15]=3)=[O:22])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cn1nc(C(=O)O)ccc1=O
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cn1nc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)ccc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
TEA (0.61 mL, 4.35 mmol) was added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.20 g, 0.87 mmol, Example 1, Step H), 1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (0.16 g, 1.04 mmol) and BOP-Cl (0.29 g, 1.13 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 1 hour, and then a LiOH solution (3 mL, 2N) was added. The mixture was stirred for 30 minutes, and water (10 mL) was added. The solid formed was collected by filtration, washed with DCM (5 mL) and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (0.223 g, 70% yield) as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br>CO>[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:10]2[CH:9]=[C:8]([C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)[O:12][N:11]=2)=[CH:15][CH:16]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Reactant: Fc1ccccc1CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccccc3F)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
To a mixture of 4-(5-(2-amino-pyridin-3-yl)isoxazol-3-ylmethyl)-phenol (4.2 mg, 0.016 mmol) described in Manufacturing Example 5-1-1 and methanol (0.4 mL) was added 1 N aqueous sodium hydroxide solution (16 μL, 0.016 mmol). This mixture was concentrated under a reduced pressure. To a mixture of the residue and N,N-dimethylformamide (0.5 mL) was added 2-fluorobenzyl bromide (2.3 μL, 0.019 mmol), which was stirred for 1 hour at room temperature. The reaction mixture was then purified directly by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (3.3 mg, 43%) as a trifluoroacetic acid salt.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[N:9]2[CH:24]=[CH:25][CH:26]=[C:8]2[C:7]=1[OH:27])=[O:5])C.[NH2:28][CH2:29][C:30]([O-:32])=[O:31].[Na+]>>[F:23][C:20]([F:22])([F:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:10]1[C:11](=[O:12])[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])=[C:7]([OH:27])[C:8]2=[CH:26][CH:25]=[CH:24][N:9]12
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2ccccc2C(F)(F)F)c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cccn2n(Cc2ccccc2C(F)(F)F)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 1-(2-trifluoromethyl-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 410 (M+H)+.
Reaction SMILES: O[C:2]1([CH:5]=[CH2:6])[CH2:4][CH2:3]1.[C:7]1([C:13]2(O)[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:7]1([C:13]2([C:2]3([CH:5]=[CH2:6])[CH2:4][CH2:3]3)[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=CC1(O)CC1
Reactant: OC1(c2ccccc2)c2ccccc2-c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=CC1(C2(c3ccccc3)c3ccccc3-c3ccccc32)CC1
Temperature: 90 °C

Procedure:
1-Hydroxy-1-vinylcyclopropane is added to a suspension of 9-phenyl-9-fluorenol (1eq) and AW-300 molecular sieves in anhydrous toluene under an argon atmosphere. p-Toluenesulfonic acid (catalytic amount) is added in one portion. The resulting suspension is heated at 90° C. until the disappearance of starting material is observed by thin layer chromatography. The mixture is filtered to remove the sieves. The resulting filtrate is concentrated in vacuo and the concentrate is purified by flash chromatography on silica gel using hexanes-ethyl acetate as eluent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=O)=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ClS(O)(=O)=O.Cl>O>[CH:14]1[C:13]([F:12])=[CH:18][CH:17]=[C:16]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)(=[O:10])=[O:11])[CH:15]=1
Reactant: Fc1ccccc1
Reactant: O=S(=O)(O)c1ccc(F)cc1
Agent: Cl
Agent: O=S(=O)(O)Cl
Solvent: O
Product: O=S(=O)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 3 h
Yield: 58 %

Procedure:
A 194 g (1.1 moles) quantity of 4-fluorobenzenesulfonic acid was added to 96 g (1 mole) of fluorobenzene and the mixture was cooled with water while 123 g (1.1 moles) of chlorosulfonic acid was added at about 10° to about 20° C. over a period of 1 hour. After the addition, the reaction mixture was stirred for 3 hours while being maintained at 20° to 30° C. The hydrochloric acid gas evolved during the reaction was continuously removed from the reaction system. After the completion of the reaction, about 400 ml of water was added to the reaction mixture, and 9.6 g (0.1 mole) of the unreacted fluorobenzene was recovered by distillation. Separation of the precipitate by filtration gave 65 g of 4,4'-difluorodiphenylsulfone in 58% yield. M.P. 97° to 98° C. Purity of 99.7%.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][CH2:5]1.[C:19]([O:23][C:24]([N:26]([CH:39]([CH3:41])[CH3:40])[CH2:27][CH:28]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:29](O)=[O:30])=[O:25])([CH3:22])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(N(CC)CC)C>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH:28]([C:29]([N:16]2[CH2:17][CH2:18][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][CH2:6][C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:14][CH2:15]2)=[O:30])[CH2:27][N:26]([CH:39]([CH3:40])[CH3:41])[C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[CH:33][CH:34]=1
Reactant: CC(C)N(CC(C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: C[C@@H]1CCc2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(CC(C(=O)N1CCN(c2ncnc3c2[C@H](C)CC3)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.1 %

Procedure:
To a solution of (R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (30 mg, 0.1 mmol) in DCM (10 mL) and triethylamine (1 mL) were added 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (35 mg, 0.1 mmol) and HBTU (39 mg, 0.1 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed and the residue was purified by silica gel chromatography, eluting with ethyl acetate to give tert-butyl 2-(4-chlorophenyl)-3-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (25 mg, 44%). 1H NMR (CDCl3, 400 MHz) δ 8.44 (s, 1H), 7.30-7.20 (m, 4H), 3.90-3.18 (m, 9H), 3.18-2.70 (m, 4H), 2.28 (m, 1H), 1.83 (m, 1H), 1.65 (m, 1H), 1.47 (s, 9H), 1.12 (m, 3H), 0.98 (m, 3H), 0.68 (m, 3H). MS (APCI+) [M+H] +542.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:15]3[S:16][C:17]([C:19]([N:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])[CH3:22])=[O:20])=[CH:18][C:14]=3[CH2:13][CH2:12][O:11][C:10]=2[CH:30]=1)=[O:4].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:21]([CH3:22])[C:19]([C:17]1[S:16][C:15]2[C:9]3[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)=[CH:30][C:10]=3[O:11][CH2:12][CH2:13][C:14]=2[CH:18]=1)=[O:20]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(NC(=O)CCl)cc1OCC2)c1ccccc1Cl
Reactant: CN1CCNCC1
Product: CN1CCN(CC(=O)Nc2ccc3c(c2)OCCc2cc(C(=O)N(C)c4ccccc4Cl)sc2-3)CC1

Procedure:
Following the procedure in Example 147 for 237, 8-(2-chloroacetamido)-N-(2-chlorophenyl)-N-methyl-4,5-dihydro-benzo[b]thieno[2,3-d]oxepine-2-carboxamide and N-methylpiperazine were reacted to give 171. MS: (ESI+) 525.3
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:18])=[C:4]2[NH:10][C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1.[C:19]([C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)#[N:20]>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:18])=[C:4]2[NH:10][C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH:15][S:27]([C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([C:19]#[N:20])[CH:22]=4)(=[O:29])=[O:28])=[CH:13][CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1c(Br)cnc2nc(-c3ccc(N)cc3)[nH]c12
Solvent: c1ccncc1
Product: Cc1c(Br)cnc2nc(-c3ccc(NS(=O)(=O)c4cccc(C#N)c4)cc3)[nH]c12
Temperature: 60 °C

Procedure:
4-(6-Bromo-7-methyl-1H-imidazo[4,5-b]pyridin-2-yl)aniline (Example 260) (0.020 g, 0.07 mmol) was dissolved in pyridine and 3-cyanobenzenesulfonyl chloride (0.013 g, 0.07 mmol) was added. The mixture was heated to 60° C. for 3 h. Thereafter the solvent was removed in vacuo and the residue was submitted to HPLC-C18 purification. Yield: 0.006 g (15%) of the title compound as the trifluoroacetate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:10][CH:9]=2)[CH:7]=1.O.[NH2:22][NH2:23]>>[OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH2:15][CH2:16][C:17](=[O:19])[NH:22][N:23]=3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc(-n2cnc(CO)c2)cc1
Solvent: O
Product: O=C1CCC(c2ccc(-n3cnc(CO)c3)cc2)=NN1

Procedure:
Similarly, the reaction of 4-(4-hydroxymethyl-1H-imidazol-1-yl)-γ-oxobenzenebutanoic acid with hydrazine hydrate according to the procedure of this Example gives 4,5-dihydro-6-[4-(4-hydroxymethyl-1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone (3g), mp 213.5°-215° C.
Reaction SMILES: [CH3:1][C@@:2]12[C@H:12]3[C@@H](O)[CH2:14][C@:15]4([CH2:24]O)[C@@H:19]([C:20]([CH2:22][OH:23])=[O:21])[CH2:18][CH2:17][C@H:16]4[C@@H:11]3[CH2:10][CH2:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2.C[C@@]12[C@H]3[C@@H](O)C[C@]4(C=O)[C@@H](C(CO)=O)CC[C@H]4[C@@H]3CCC1=CC(=O)CC2.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC(=O)C)(=O)C.[CH:71](N)=[O:72]>ClCCCl.CC1CCCCC1.C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH3:1][C@@:2]12[C@H:12]3[C@H:71]4[O:72][CH2:24][C:15]5([C@@H:19]([C:20]([CH2:22][OH:23])=[O:21])[CH2:18][CH2:17][C@H:16]5[C@@H:11]3[CH2:10][CH2:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2)[CH2:14]4
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(CO)[C@@H](C(=O)CO)CC[C@@H]12
Reactant: NC=O
Agent: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C=O)[C@@H](C(=O)CO)CC[C@@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCCl
Solvent: CC1CCCCC1
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H]2CC3(CO2)[C@@H](C(=O)CO)CC[C@@H]13

Procedure:
18-deoxyaldosterone was prepared by acid-catalyzed dehydration of 18-hydroxycorticosterone, the latter having been, in turn, prepared biosynthetically employing slices of aldosterone-producing adrenal tissue [Ulick et al, Methods in Enzymology, 36, p. 503 (1975)]. The 11,18-diol (1.0 mg.) in 10 ml 1,2-dichloroethane saturated with p-toluenesulfonic acid was heated under reflux for 30 minutes. The solvent was washed with dilute sodium carbonate and water, dried and evaporated. Chromatographic analysis of the residue revealed 18-deoxyaldosterone as the major product of 18-hydroxycorticosterone along with small amounts of starting material and its etiolactone derivative. 18-deoxyaldosterone migrated at 1.06 (±0.02) the rate of 11-dehydrocorticosterone in the toluene/formamide or methylcyclohexane:toluene (1:1)/formamde paper chromatographic systems. Its properties agreed with those of reference samples prepared by a published method [Kondo et al, JACS 87, 4655 (1965)]. Its 21-acetylated derivative prepared in the usual way with acetic anhydride:pyridine migrated at a slightly faster rate (1.05 ±0.02) than 21-acetoxy-11-dehydrocorticosterone in methylcyclohexane:toluene (1:1)/formamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13]([Cl:14])=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].C1C(=O)N([Br:26])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:18][Br:26])=[C:8]2[C:13]([Cl:14])=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1CBr
Temperature: 77 °C
Yield: 99.2 %

Procedure:
A suspension of compound 1D (79 mg, 0.30 mmol), NBS (59 mg, 0.33 mmol) and benzoyl peroxide (5 mg, 0.02 mmol) in CCl4 (2 mL) was heated at 77° C. for 3 hours. After cooling to room temperature, the reaction was purified by a short silica gel column (eluted with CH2Cl2) to give compound 16A as a yellow solid (102 mg, 99%). B. 4-Chloro-3-cyano-5-hydroxymethyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester (16B)
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:7]=[C:8]=[O:9]>C(#N)C>[C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Reactant: [N-]=C=O
Solvent: CC#N
Product: O=C=Nc1ccccc1

Procedure:
In the present invention, benzene is oxidized in acetonitrile to form a radical cation. The isocyanate anion (solubilized by the 18-crown-6 polyether) then attacks the activated ring to give a phenyl isocyanate radical which then loses a proton to give phenyl isocyanate. The 18-crown-6 acts as a solid to liquid phase transfer catalyst bringing the insoluble KOCN into the acetonitrile solution. A schematic is shown below.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[SH:6].[CH:7](O)([CH3:9])[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:7]([S:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)([CH3:9])[CH3:8]
Reactant: Sc1nccs1
Reactant: CC(C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)Sc1nccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.8 %

Procedure:
To a solution of thiazole-2-thiol (300 mg, 2.56 mmol), isopropanol (154 mg, 2.56 mmol) and triphenylphosphine (671.5 mg, 2.56 mmol) in THF (5 mL) was added DEAD (445.8 mg, 2.56 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 3 hours. Reaction was completed according to t.l.c. The reaction mixture was allowed to stir over the weekend then concentrated and the residue was subjected to flash column chromatography using 10% ethyl acetate/hexane as solvent to give a colorless oil (260 mg, 64% yield).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH2:10])[CH:6]=[C:7]([NH2:9])[CH:8]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1.C(Cl)Cl>[NH2:9][C:7]1[CH:6]=[C:5]([NH:10][S:14]([CH3:13])(=[O:16])=[O:15])[CH:4]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:8]=1
Reactant: Nc1cc(N)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(N)cc(C(F)(F)F)c1
Temperature: 8 °C

Procedure:
A solution of 5-trifluoromethyl-benzene-1,3-diamine (250 mg, 1.42 mmol) in pyridine (0.52 mL) and CH2Cl2 (6.5 mL) was cooled to 0° C. Methanesulfonyl chloride (171 mg, 1.49 mmol) was slowly added at such a rate that the temperature of the solution remained below 10° C. The mixture was stirred at ˜8° C. and then allowed to warm to room temperature after 30 min. After stirring at room temperature for 4 h, reaction was almost complete as indicated by LCMS analysis. The reaction mixture was quenched with sat. aq. NH4Cl (10 mL) solution, extracted with CH2Cl2 (4×10 mL), dried over Na2SO4, filtered, and concentrated to yield N-(3-amino-5-trifluoromethyl-phenyl)-methanesulfonamide (D-19) as a reddish semisolid (0.35 g, 97%), which was used without further purification. 1H-NMR (CDCl3, 300 MHz) δ 6.76 (m, 1H), 6.70 (m, 1H), 6.66 (s, 1H), 3.02 (s, 3H); ESI-MS 255.3 m/z (MH+).
Reaction SMILES: Cl.[C:2]1([CH:8]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:9][CH2:10][NH:11][CH:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[CH2:13][OH:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41].C(OCC)(=O)C>O1CCOCC1>[C:44]1([CH2:43][O:42][C:40]([N:11]([CH2:10][CH2:9][CH:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[CH2:13][OH:14])=[O:41])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc(CC(CO)NCCC(c2ccccc2)c2ccccc2)cc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(CC(CO)N(CCC(c2ccccc2)c2ccccc2)C(=O)OCc2ccccc2)cc1OC
Reaction time: 4 h
Yield: 54 %

Procedure:
To a magnetically stirred solution of β-[(3,3-diphenylpropyl)amino]-3,4-dimethoxybenzenepropanol, monohydrochloride (3.66 mole, 1.62 g; see example 2) and triethylamine (7.32 mmole, 1.02 ml) in p-dioxane (14 ml) at room temperature under nitrogen was added benzyl chloroformate (4.39 mmole, 0.63 ml). The reaction was complete in 4 hours. The mixture was filtered and the filtrate reduced in vacuo to yield an oil. The oily residue was taken into ethyl acetate and washed with 1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate, filtered and evaporated. Flash chromatography (160 g of LPS-1 silica, 1:1 ethyl acetate:hexane, eluted ~50 ml/min.) afforded 1.28 g of the title compound as an oil.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:19](/B(O)O)=[CH:20]\[CH2:21][CH2:22][CH2:23][CH3:24]>>[CH:19](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:20]\[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCC/C=C/B(O)O
Reactant: Brc1cnc2ccc(NCc3ccncc3)nn12
Product: CCCC/C=C/c1cnc2ccc(NCc3ccncc3)nn12
Yield: 53 %

Procedure:
Prepared from the product of step A and (E)-1-hexeneboronic acid according to general procedure 2 providing the title compound (47 mg, 53%) as a brown solid; 1H NMR (500 MHz, CD3OD) δ 8.46-8.44 (m, 2H), 7.61 (d, J=9.1 Hz, 1H), 7.46 (d, J=7.1 Hz, 2H), 7.38 (s, 1H), 6.75 (d, J=9.7 Hz, 1H), 6.56-6.37 (m, 2H), 4.62 (s, 2H), 2.18-2.11 (q, J=6.5 Hz, 2H), 1.39-1.28 (m, 4H), 0.92 (t, J=7.1 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 154.8, 152.0, 150.0, 138.0, 133.1, 129.4, 128.6, 125.9, 123.9, 116.6, 113.0, 45.5, 34.3, 32.7, 23.3, 14.3; HPLC tR=10.9 min (Luna), 97.4%; ES-MS: (M+H)=308 m/z.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[CH2:23]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH:24]=[CH2:25].C(=O)([O-])[O-].[Cs+].[Cs+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH:26]1([CH2:23]/[CH:24]=[CH:25]/[C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:3]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Reactant: C=CCC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(/C=C/CC2CCCCC2)cc1Nc1ccc(F)cc1
Temperature: 110 °C
Reaction time: 22 h

Procedure:
To toluene 3.0 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 0.20 g were added allylcyclohexane 0.17 mL, cesium carbonate 0.36 g, tetrabutylammonium bromide 53 mg and polymer-carried bis(acetato)triphenylphosphine palladium(II) 86 mg at room temperature, and it was stirred at 110° C. for 22 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution, saturated sodium thiosulfate aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 4-((E)-3-cyclohexyl-1-propenyl)-2-(4-fluoroanilino)benzoate.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18]/[CH:19]=[C:20](/[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)\[CH3:21])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+]>>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18]/[CH:19]=[C:20](/[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)=[CH:24][CH:23]=2)\[CH3:21])=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(F)cc3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(F)cc3)cc2)cc1)C(=O)O
Yield: 52.7 %

Procedure:
The title compound was prepared from (E)-(S)-ethyl 2-ethoxy-3-{4-[3-(4′-fluoro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate (example 153) (463 mg, 1.0 mmol) and sodium hydroxide (1M, 1.5 ml , 1.5 mmol) by a procedure analogous to that described in example 51, yielding (E)-(S)-2-ethoxy-3-{4-[3-(4′-fluoro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionic acid (229 mg, 53%) as a colourless solid containing a trace of water.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]([C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([CH3:34])[CH:21]=3)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:8]=2[C:9]=1[CH3:10])=[O:4].[BH4-].[Na+]>>[CH3:35][N:2]([CH3:1])[C:3]([C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([C:15]([CH2:16][CH3:17])([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28]([OH:33])[C:29]([CH3:31])([CH3:32])[CH3:30])=[C:22]([CH3:34])[CH:21]=3)[CH2:18][CH3:19])=[CH:11][C:8]=2[C:9]=1[CH3:10])=[O:4]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2oc(C(=O)N(C)C)c(C)c2c1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc2oc(C(=O)N(C)C)c(C)c2c1
Yield: 99.6 %

Procedure:
5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-benzofuran-2-carboxylic acid dimethylamide (109 mg, 0.228) is reduced with NaBH4 (17 mg, 0.457 mmol) analogous to Example 3 to give the title product (109 mg, 100%).