Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:11]([CH3:21])[C:12]=2[S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[Li]CCCC.[I:33]I>C1COCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][C:12]2[N:11]([CH3:21])[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([I:33])=[CH:3][CH:4]=2)=[CH:15][CH:16]=1
Reactant: II
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(Br)cc2)c1Sc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(-c2ccccn2)nc(-c2ccc(I)cc2)c1Sc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To 2-{4-(4-bromophenyl)-5-[(4-chlorophenyl)thio]-1-methyl-1H-imidazol-2-yl}pyridine (Example 15, 150 mg, 0.33 mmol) in THF (1 mL) was added BuLi (2.5 M in hexanes, 0.17 mL, 0.427 mmol) at −78° C. After stirring at −78° C. for 0.5 h, I2 (167 mg, 0.657 mmol) was added and the reaction was allowed to warm up to rt overnight. The reaction was quenched with aq NH4Cl, extracted with EtOAc. The combined extracts were washed with aq Na2S2O3, water, and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (1-20% EtOAc in hexanes) to give the title compound. 1H NMR (500 MHz, (CDCl3): 8.64 (d, 1H), 8.38 (d, 1H), 7.87 (d, 2H), 7.85 (t, 1H), 7.78 (d, 2H), 7.38 (t, 1H), 7.25 (d, 2H), 7.03 (d, 2H), 4.11). LCMS: [M+1]=504.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:17]=[CH:18]/[C:19]([O:21]CC)=[O:20])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+].Cl>O1CCCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)/C=C/c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 476.1 %

Procedure:
To a solution of ethyl (2E)-3-[3-(4-fluorophenyl)-1H-indazol-5-yl]prop-2-enoate (0.10 g, 0.32 mmol) in tetrahydrofuran (10 mL) was added a solution of lithium hydroxide (0.032 mg, 1.6 mmol) in water (5 mL) and the mixture was stirred at ambient temperature overnight. The reaction mixture was acidified with 6 N hydrochloric acid solution to give a white solid. It was then purified by HPLC to provide the title compound (0.43 g, 48% yield): 1H NMR (DMSO-d6) δ 13.45 (br s, 1H), 12.28 (br s, 1H), 8.39 (s, 1H), 8.11 (d, 1H), 8.10 (d, 1H), 7.83 (d, 1H), 7.79 (d, 1H), 7.60 (d, 1H), 7.35 (t, 2H), 6.57 (d, 1H); ES-MS (m/z) 283 [M+1]+.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[Br:21][CH:22]([CH3:26])[C:23](Br)=[O:24]>C1(C)C=CC=CC=1>[Br:21][CH:22]([CH3:26])[C:23]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:24]
Reactant: CC(Br)C(=O)Br
Reactant: CCCCCCCCCCCCO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOC(=O)C(C)Br
Temperature: 57.5 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
To a stirred solution of 1-decanol 2 (10 g, 53.7 mmol) in toluene (100 mL) was added triethylamine (7.5 mL, 53.7 mmol)) followed by 2-bromo propionyl bromide 58 (12.7 g, 59.1 mmol) at 5-10° C. The reaction mixture was stirred for 3 hours at 55-60° C.; the reaction was monitored by TLC. The reaction mixture was quenched with saturated sodium bicarbonate solution and stirred for 15 minutes at 25-35° C. The aqueous and organic layers were separated, the organic layer was washed with brine, and the combined organic layers were washed with brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford crude 59 (16.2 g, yield: 94%) as a liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:19](Cl)(=[O:21])=[O:20])[C:5]([C:8]2[C:9]([S:15](Cl)(=[O:17])=[O:16])=[CH:10][C:11]([Br:14])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>[N+](C)([O-])=O>[C:27]1([S:19]([C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=2[C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=2[S:15]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:17])=[O:16])(=[O:21])=[O:20])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccccc1
Reactant: O=S(=O)(Cl)c1cc(Br)ccc1-c1ccc(Br)cc1S(=O)(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: O=S(=O)(c1ccccc1)c1cc(Br)ccc1-c1ccc(Br)cc1S(=O)(=O)c1ccccc1
Temperature: 100 °C
Yield: 74 %

Procedure:
Inside a glove box, a 125 mL round-bottom flask equipped with a stirring bar, reflux condenser, and gas inlet was charged with 4,4′-dibromobiphenyl-2,2′-disulfonyl dichloride (10.18 g, 20 mmoles) and aluminum chloride (5.87 g, 44 mmoles). Benzene (14 mL) and anhydrous nitromethane (40 mL) were added and the mixture stirred until dissolved. The solution was heated to 100° C. for about 8 hours. The solution was cooled to room temperature and poured onto 200 g ice mixed with 100 mL hydrochloric acid. The mixture was extracted several times with dichloromethane. The organic extracts were washed twice with water, dried with sodium carbonate, filtered, and evaporated to give 11.75 g (99%). The mixture was purified by column chromatography using silica gel and dichloromethane (Rf 0.32) to give 8.73 g (74% yield) of 2,2′-bis-benzenesulfonyl-4,4′-dibromobiphenyl.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])(=O)=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C@H:10]([O:14][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCC/C=C\CCCCCCCCOS(C)(=O)=O
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Product: CCCCCCCC/C=C\CCCCCCCCO[C@@H]1CN(Cc2ccccc2)C[C@H]1OCCCCCCCC/C=C\CCCCCCCC

Procedure:
Compound VI-4 (507 mg, 56.4%) was obtained in the same manner as that in Reference Example 1, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 250 mg, 1.29 mmol) and (Z)-octadec-9-enyl methanesulfonate (Nu-Chek Prep, Inc; 1.79 g, 5.17 mmol).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:34]>>[ClH:34].[ClH:34].[CH3:33][O:32][C:30]([CH2:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:21][CH2:20]2)=[CH:23][CH:24]=1)=[O:31]
Reactant: COC(=O)COc1ccc(C2CCN(CCC3CCN(C(=O)OC(C)(C)C)CC3)CC2)cc1
Agent: Cl
Product: COC(=O)COc1ccc(C2CCN(CCC3CCNCC3)CC2)cc1

Procedure:
Prepared from 1-[2-(1-tert-butyloxycarbonylpiperidin-4-yl)ethyl]-4-(4-methoxycarbonylmethyloxyphenyl)piperidine and ethereal hydrochloric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([OH:23])=[O:22])[CH2:9]2)=[CH:4][CH:3]=1.[CH2:24](O)[CH3:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:24]([O:22][C:21]([C:10]1[CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:11]=1)=[O:23])[CH3:25]
Reactant: CCO
Reactant: O=C(O)C1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Temperature: 80 °C

Procedure:
5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid (0.55 g, 1.50 mmol) was dissolved in 20 mL of toluene and (2 mL) ethanol and (0.05 g) of p-toluenesulfonic acid monohydrate were added. The mixture was heated at 80° C. for 72 hours. After cooling to room temperature, the reaction mixture washed with sodium hydrogen carbonate solution and water, dried over sodium sulphate and evaporated to dryness to give the title compound in form of oil.
Reaction SMILES: [OH:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:7]([CH2:15]CC(O)=O)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1.[H-].[Na+].O.[CH3:31]N(C)C=O>C1(C)C=CC=CC=1>[CH3:31][O:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:7]([CH3:15])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: O=C(O)CCC1=C(c2ccccc2)c2ccc(O)cc2Sc2ccccc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)Sc1ccccc1C(C)=C2c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
7-hydroxy-11-[(2-carboxy)ethyl]-10-phenyldibenzo[b,f]thiepin (1.87 g) in dry dimethylformamide (25 ml) was treated with sodium hydride (0.4 g of 75%) and stirred, first at room temperature and then at 50° C. until effervescence ceased. A solution of 1-chloro-2-NN-dimethylamino-ethane in toluene (15 ml of 1 M) was added and the mixture was heated with stirring under argon to 100° C. After 1.5 hours the mixture was allowed to cool, treated with water and extracted three times with ethyl acetate. The ethyl acetate solution was evaporated and the residue dissolved in methanol (10 ml) and 10% aqueous sodium hydroxide (5 ml) and refluxed for 20 minutes. The solvent was mostly removed and the sodium salt was dissolved in 200 ml of boiling water. Carbon dioxide was passed through the boiling solution until the pH fell to 8. This was extracted three times into ethyl acetate with a little methanol. The solution was dried and evaporated.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].[Cl:13][C:14]1[CH:15]=[C:16]2[NH:22][C:21](=[O:23])[S:20][C:17]2=[N:18][CH:19]=1.O>CN(C)C=O>[Cl:13][C:14]1[CH:15]=[C:16]2[N:22]([CH2:2][C:3]([O:5][CH3:6])=[O:4])[C:21](=[O:23])[S:20][C:17]2=[N:18][CH:19]=1
Reactant: O=c1[nH]c2cc(Cl)cnc2s1
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)sc2ncc(Cl)cc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
Methyl chloroacetate (9.6 g) and potassium carbonate (11.1 g) were added to a solution of 6-chloro-2-oxo-1,2-dihydrothiazolo[5,4-b]pyridine (15.0 g) in dry N,N-dimethylformamide (50 ml). The mixture was stirred for 30 minutes at 80° C. and then poured into cold water. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide to give white power of 6-chloro-1-methoxycarbonylmethyl-2-oxo-1,2-dihydrothiazolo[5,4-b]pyridine (20.52 g).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.C1CCCCC1>[Pd].CO>[CH3:17][S:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: C1CCCCC1
Solvent: CO
Product: CS(=O)(=O)N1CCNCC1

Procedure:
A mixture of N-benzyl-N'-methanesulphonylpiperazine (12.4 g), cyclohexane (5.1 ml), 10% Pd/C (2 g) and methanol (120 ml) was heated under reflux for 7 hours to give 1-methanesulphonylpiperazine (m.p. 90°-91° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[C:6]([O:8][CH3:9])=[O:7]>CCO.C1COCC1.[Pd]>[NH2:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N)c(OC)c1
Reaction time: 8 h
Yield: 77.9 %

Procedure:
A stirred mixture of methyl 3-methoxy-4-nitrobenzoate (1.20 g, 5.7 mmol) and 5% Pd-C (1.0 g) in EtOH (30 mL) and THF (20 mL) was hydrogenated overnight at 1 atm. The mixture was filtered and the filtrate was evaporated. The residue was chromatographed on silica-gel with CHCl3 as eluent, and the solid obtained was further purified by recrystallization from CHCl3-n-hexane to give 805 mg (78%) methyl 4-amino-3-methoxybenzoate as white plates. mp 126-128; IR (KBr) 3475, 1700 cm−1; 1H-NMR (CDCl3) δ3.86 (3H, s), 3.89 (3H, s), 4.21 (2H, br s), 6.66 (1H, d, J=8.3 Hz), 7.45 (1H, d, J=1.9 Hz), 7.54 (1H, dd, J=1.9 and 8.3 Hz); MS (FAB) m/z 182 (M++1); Anal. Calcd. for C9H11NO3: C, 59.66; H, 6.12; N, 7.73. Found: C, 59.65; H, 6.15; N, 7.65.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.O>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([C:33]5[CH:32]=[N:31][C:30]([F:29])=[CH:35][CH:34]=5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: CC1(C)OB(c2ccc(F)nc2)OC1(C)C
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Temperature: 80 °C
Yield: 83.8 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (4.16 g, 10 mmol), 2-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (2.67 g, 12 mmol), Cs2CO3 (6.50 g, 20 mmol) Pd(dppf)Cl2 (730 mg, 1.0 mmol) and CH3CN—H2O (1 1, 40 mL) were added in a 50 mL of sealed tube, and the mixture was heated at 80° C. for 60 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (50 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative TLC to give 2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (4.0 g, yield: 84%). 1HNMR (DMSO-d6, 400 MHz): δ8.68 (s, 1H), 8.43 (t, J=4.8 Hz, 2H), 8.12-8.01 (m, 1H), 8.00-7.92 (m, 1H), 7.84 (t, J=2.8 Hz, 1H), 7.58-7.50 (m, 2H), 7.26 (s, 2H), 4.39 (s, 2H), 3.24 (s, 2H), 2.23 (s, 3H). ESI-MS: m/z=478 [M+H+]
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[CH:10][C:9]([CH3:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:16])[NH:7]2.[Br:17]N1C(=O)CCC1=O.CCCCCC>C(Cl)(Cl)Cl>[Br:17][CH2:14][CH:13]1[O:1][C:2]2=[C:3]3[C:8](=[C:9]([CH3:15])[CH:10]=[C:11]2[CH2:12]1)[NH:7][C:6](=[O:16])[CH:5]=[CH:4]3
Reactant: C=CCc1cc(C)c2[nH]c(=O)ccc2c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CBr)C2
Yield: 103.6 %

Procedure:
A suspension of 5-hydroxy-8-methyl-6-(2-propenyl) carbostyril (64.57 g) in chloroform (2000 ml) was combined with N-bromosuccinimide (56.47 g) and refluxed with heat for 3 hours while stirring. The reaction mixture became yellow uniform solution. The reaction solution was washed with water, dried and condensed. n-Hexane was added to the concentrate, and crystallized. 91.40 g of the title compound was obtained as white powder.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:14])[CH:5]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25]O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[CH3:1][S:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:14][CH2:25][CH2:24][CH2:23][NH:22][C:20]([O:19][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:21])[CH:5]=1
Reactant: COC(=O)c1ccc(CSC)cc1O
Reactant: CC(C)(C)OC(=O)NCCCO
Product: COC(=O)c1ccc(CSC)cc1OCCCNC(=O)OC(C)(C)C
Yield: 76 %

Procedure:
Using a procedure analogous to Example 1-D, methyl 4-(methylthiomethyl)-2-hydroxybenzoate and 3-(t-butoxy-carbonylamino)propanol gave the title compound as a white solid (2.70 g, 76%).
Reaction SMILES: [H-].[Na+].[Br-].[C:4]([O:8]C(C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)(C)(C)C.C([C:33]1[NH:37][C:36]([C:38]([O:40][CH3:41])=[O:39])=[CH:35][CH:34]=1)=O>C1COCC1>[CH:4]([C:34]1[CH:35]=[C:36]([C:38]([O:40][CH3:41])=[O:39])[NH:37][CH:33]=1)=[O:8]
Reactant: COC(=O)c1ccc(C=O)[nH]1
Reactant: CC(C)(C)OC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C=O)c[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (5.74 g, 143.5 mmol; 60% in oil) in THF (200 mL) at 0° C. was added (tert-butoxycarbonylmethyl)triphenylphosphonium bromide (66 g, 143.5 mmol) as a solid in three portions. Cooling was removed and the mixture was stirred at rt for 30 min. It was then cooled to 0° C. and methyl 5-formyl-1H-pyrrole-2-carboxylate (16.9 g, 110.4 mmol) in THF (60 mL) was added dropwise over 40 min. The reaction mixture was allowed to warm to rt and was stirred overnight. Silica was added and the solvent was removed. The crude product was purified by flash chromatography (0-20% EtOAc/Heptane) to afford two isomeric compounds:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:25])[C:9]([OH:24])([C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][N:18]=[CH:19]2)[C:10]([F:13])([F:12])[F:11].[F:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:40]=1[C:41]([O:43][CH3:44])=[O:42].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:44][O:43][C:41]([C:40]1[CH:39]=[CH:38][C:37]([C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:25])[C:9]([OH:24])([C:14]3[CH:23]=[CH:22][CH:21]=[C:16]4[C:15]=3[CH:20]=[CH:19][N:18]=[CH:17]4)[C:10]([F:12])([F:13])[F:11])=[C:2]([Cl:1])[CH:3]=2)=[CH:36][C:35]=1[F:34])=[O:42]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: CC(c1ccc(OS(=O)(=O)C(F)(F)F)cc1Cl)C(O)(c1cccc2cnccc12)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3cccc4cnccc34)C(F)(F)F)c(Cl)c2)cc1F
Temperature: 80 °C
Reaction time: 5 h
Yield: 13.8 %

Procedure:
To a suspension of trifluoromethanesulfonic acid 3-chloro-4-(3,3,3-trifluoro-2-hydroxy-2-isoquinolin-5-yl-1-methyl-propyl)-phenyl ester (86 mg), 3-fluoro-4-methoxycarbonylphenyl-boronic acid (50 mg) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]dichloromethane adduct (7 mg) in dioxane (0.5 ml) under argon were added water (0.4 ml) and a 2 M aqueous sodium carbonate solution (0.25 ml). The mixture was stirred at 80° C. for 5 h. The mixture was filtered and to the filtrate was added water. The mixture was extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>2:3) to give the title compound (12 mg) as a colorless solid.
Reaction SMILES: [N:1]([CH:4]1[CH2:13][C:12]2[C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5]1)=[N+:2]=[N-:3].[Br:18]Br>C(O)(=O)C>[N:1]([CH:4]1[CH2:13][C:12]2[C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=[C:8]([Br:18])[C:7]=2[CH2:6][CH2:5]1)=[N+:2]=[N-:3]
Reactant: CC(=O)Nc1cccc2c1CC(N=[N+]=[N-])CC2
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Br)c2c1CC(N=[N+]=[N-])CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 112.8 %

Procedure:
A solution of N-(7-azido-5,6,7,8-tetrahydronaphthalen-1-yl)-acetamide (1 g, 4.3 mmol) in acetic acid (40 mL) was treated dropwise with bromine (1 g, 6.5 mmol) and stirred at room temperature for 3 h. The solvent was evaporated and the solid residue was washed with ether, collected by filtration and dried to give the product (1.5 g) in 89% yield.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:16][C:17]([OH:19])=O)([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.[S:40]1[C:44]2([CH2:48][CH:47]([C:49]([OH:51])=[O:50])[NH:46][CH2:45]2)[S:43][CH2:42][CH2:41]1>C(#N)C>[CH2:1]([O:3][P:4]([CH2:16][C:17]([N:46]1[C@H:47]([C:49]([OH:51])=[O:50])[CH2:48][C:44]2([S:40][CH2:41][CH2:42][S:43]2)[CH2:45]1)=[O:19])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)O
Reactant: O=C(O)C1CC2(CN1)SCCS2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1CC2(C[C@H]1C(=O)O)SCCS2
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A mixture of 2.0 g of [ethoxy(4-phenylbutyl)phosphinyl]acetic acid and 1.1 g of carbonyldiimidazole in acetonitrile is stirred under argon at 0° C. for 1 hour and then treated with 1.9 g of triethylamine and 1.7 g of 1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, hydrochloride. After 4.5 hours the acetonitrile is stripped and the residue is partitioned between ethyl acetate and 1 N HCl. The organic phase is washed with brine, dried (MgSO4), and the solvent is stripped to give 3.2 g of the title compound as an oil.
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:15]=[N:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:16]O>>[CH3:16][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][N:14]=[CH:15][C:7]=1[Br:6]
Reactant: CO
Reactant: O=C(O)c1ccncc1Br
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccncc1Br
Temperature: 25 °C
Reaction time: 14 h

Procedure:
H2SO4 (2.5 mL, 48.3 mmol, 1.0 eq.) was added to a solution of 3-bromoisonicotinic acid (9.7 g, 48.3 mmol, 1.0 eq.) in MeOH (150 mL). The resulting solution was stirred for 14 hours while the temperature was maintained at reflux in an oil bath. The mixture was then cooled to room temperature and concentrated under vacuum. The residue was dissolved in EtOAc (200 mL). The pH of the solution was adjusted to 10 with Na2CO3. The resulting solution was extracted with EtOAc (100 mL). The organic layer was washed with water (1×200 mL) and saturated aqueous NaCl (2×100 mL). The mixture was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:20) to yield 3-bromoisonicotinic acid methyl ester (4.4 g) as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[C:30](=[O:31])[O:29][N:28]=[C:27]([CH3:32])[C:26]=2[CH:33]=1.CN1CCCN(C)C1=O>O1CCCC1>[OH:11][C:10]([C:13]([F:16])([F:15])[F:14])([CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:19][CH3:20])([CH3:18])[CH3:17])[CH2:12][NH:21][C:22]1[CH:23]=[CH:24][C:25]2[C:30](=[O:31])[O:29][N:28]=[C:27]([CH3:32])[C:26]=2[CH:33]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: Cc1noc(=O)c2ccc(N)cc12
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1ccc2c(=O)onc(C)c2c1)C(F)(F)F

Procedure:
584 mg of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methyl-propyl]-2-trifluoromethyl-oxiran, 282 mg of 6-amino-4-methyl-2,3-benzoxazin-1-one and 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2[1H]-pyrimidinone are heated to 120° C. for 6 hours. After 1 ml of tetrahydrofuran is added, it is chromatographed on silica gel, and the title compound is eluted with hexane/ethyl acetate/tetrahydrofuran (55:40:5), flash point 178-179° C.