Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][O:10][C:11](=[O:20])[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1F>>[CH3:9][O:10][C:11](=[O:20])[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[S:8]/[C:3](=[CH:4]/[CH3:5])/[C:2](/[NH2:1])=[CH:7]\[CH3:6]
Reactant: COC(=O)c1cc(F)ccc1F
Reactant: Nc1ccccc1S
Product: C/C=C(N)\C(=C/C)Sc1ccc(F)cc1C(=O)OC

Procedure:
Thus, 2-aminobenzenethiol may be reacted with 2,5-difluoro-benzoic acid methyl ester to form a 2-[(E)-2-amino-1-eth-(E)-ylidene-but-2-enylsulfanyl]-5-fluoro-benzoic acid methyl ester intermediate that can be converted by treatment with alkali to 2-[(E)-2-amino-1-eth-(E)-ylidene-but-2-enylsulfanyl]-5-fluoro-benzoic acid. The benzoic acid can be cyclized to form 2-fluoro-10H-dibenzo[b,f][1,4]thiazepin-11-one, that may be converted to 11-chloro-2-fluoro-dibenzo[b,f][1,4]thiazepine, that may be further reacted with piperazine to form the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:13]=[O:14]>>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][OH:14])=[N:11][CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: Fc1cccc(-n2cncn2)c1
Product: OCc1ncnn1-c1cccc(F)c1
Temperature: 150 °C

Procedure:
A mixture of the crude 1-(3-Fluorophenyl)-1,2,4-triazole and formaldehyde (10 mL of 37 wt % in water) is heated at 150° C. in a sealed tube for 48 h. After cooling the reaction vessel, the reaction mixture is extracted with dichloromethane, dried (MgSO4), concentrated, and the residue purified using silica gel chromatography to afford 1-(3-Fluorophenyl)-5-hydroxymethyl-1,2,4-triazole. 1H NMR (CDCl3): δ 8.02 (s, 1H), 7.42-7.53 (m, 3H), 7.22-7.29 (m, 1H), 4.81 (s, 2H). LCMS 194.2 (MH−).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH2:29][C:30](=O)[CH3:31])(=[O:28])=[O:27])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[N:16]=[C:30]([CH3:31])[CH2:29][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=1)(=[O:28])=[O:27])=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Reactant: CC(=O)CS(=O)(=O)c1ccc(C)cc1
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CS(=O)(=O)c1ccc(C)cc1
Reaction time: 6 h
Yield: 124.4 %

Procedure:
To a 25 ml volume three-necked flask with Dean-Stark, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39) (500 mg), toluene (1.75 ml), and 1-(4-methylphenylsulfonyl)-2-propanone (7-2-4) (470 mg) were added. Water was removed by azeotropic distillation at 45-50° C. under 100 mmHg for 1.5 hours. To the mixture, toluene (1.75 ml) was added, and water was removed by azeotropic distillation at 60° c. under 120 mmHg for 6 hours. The reaction mixture was concentrated under reduced pressure to give 1.109 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-[1-(4-methylphenylsulfonyl)-2-propylidene]hydrazine ((4-36)-(1)-39).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:37][CH3:38])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21](CC4C=CC(OC)=CC=4)[C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:11](=[O:36])[NH:10][N:9]=2)[CH:7]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:37][CH3:38])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:11](=[O:36])[NH:10][N:9]=2)[CH:7]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4cc(Cl)ccc4OC)n[nH]c(=O)c3c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)cc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Nc3nccs3)ccc12
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
In a vial, 1-(5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-4-oxo-N-(thiazol-2-yl)-3,4-dihydrophthalazine-6-sulfonamide (56 mg, 0.098 mmol) was dissolved in DCM (984 μl, 0.098 mmol) and then TFA (37.9 μl, 0.492 mmol) was added. After 30 min at rt, LCMS showed product. The reaction was quenched with saturated aqueous NaHCO3 (1 mL). White solid precipitated out of the solution and was filtered off with the aid of water. The solid was washed with 3 mL of water and dried to afford 1-(5-chloro-2-methoxyphenyl)-4-oxo-N-(thiazol-2-yl)-3,4-dihydrophthalazine-6-sulfonamide (32 mg, 72.4% yield). m/z (ESI) 449.0 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1([NH2:12])[CH2:9][CH:8]1[CH:10]=[CH2:11])=[O:6])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:37]([N:43]([CH3:55])[C:44]([CH:46]1[CH2:50][CH:49]([OH:51])[CH2:48][CH:47]1[C:52](O)=[O:53])=[O:45])[CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:2]([O:4][C:5]([C:7]1([NH:12][C:52]([CH:47]2[CH2:48][CH:49]([OH:51])[CH2:50][CH:46]2[C:44](=[O:45])[N:43]([CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])[CH3:55])=[O:53])[CH2:9][CH:8]1[CH:10]=[CH2:11])=[O:6])[CH3:3]
Reactant: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)O
Reactant: C=CC1CC1(N)C(=O)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
1-(Amino)-2-(vinyl)cyclopropanecarboxylic acid ethyl ester hydrochloride (4.92 g, 31.7 mmol) and HATU (12.6 g, 33.2 mmol) were added to the acid (142) (8.14 g, 30.2 mmol). The mixture was cooled in an ice bath under argon, and then DMF (100 mL) and DIPEA (12.5 mL, 11.5 mmol) were added. After 30 min at 0° C., the solution was stirred at room temperature for an additional 3 h. Then, the reaction mixture was partitioned between EtOAc and water, washed successively with 0.5 N HCl (20 mL) and saturated NaCl (2×20 mL), and dried (Na2SO4). Purification by flash chromatography (EtOAc/CH2Cl2/Petroleum ether, 1:1:1) afforded the title compound (7.41, g 60%) as a colorless oil, m/z=407 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4]/[CH:5]=[CH:6]\[Sn:7]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2].BrC/C=C\[Sn](CCCC)(CCCC)CCCC.N1CC[C@H]([O:44][C:45](=[O:47])[CH3:46])C1>>[CH2:8]([Sn:7]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12][CH2:13][CH2:14][CH3:15])/[CH:6]=[CH:5]\[CH2:4][N:3]1[CH2:1][CH2:2][C@H:21]([O:47][C:45](=[O:44])[CH3:46])[CH2:20]1)[CH2:9][CH2:10][CH3:11]
Reactant: CC(=O)O[C@H]1CCNC1
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Agent: CCCC[Sn](/C=C\CBr)(CCCC)CCCC
Product: CCCC[Sn](/C=C\CN1CC[C@H](OC(C)=O)C1)(CCCC)CCCC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 3, starting from ((Z)-3-bromoprop-1-en-1-yl)-tributyl-stannane (Intermediate 2) and acetic acid (S)-pyrrolidin-3-yl ester.
Reaction SMILES: [F:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.CN(C)C=O.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[F:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:19])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CF)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(CF)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
4-(Fluoromethyl)benzoic acid (6.20 g) was dissolved in 30 ml of benzene, and 0.3 ml of N,N-dimethylformamide was added and then 4.4 ml of thionyl chloride was added dropwise. The mixture was stirred for 1 hour at 40° C. and then heated to reflux for another 1 hour. The solvent was distilled off under reduced pressure to provide 6.70 g of the objective compound as pale yellow oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([O:9][CH:10](C)[CH3:11])=[CH:7][CH:6]=1)[CH2:2][CH3:3].C(Cl)(=[O:17])C.C(Cl)(C)C>>[C:10]([O:9][C:8]1[CH:13]=[CH:14][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[CH:6][CH:7]=1)(=[O:17])[CH3:11]
Reactant: CC(=O)Cl
Reactant: CCCOc1ccc(OC(C)C)cc1
Agent: CC(C)Cl
Product: CCCOc1ccc(OC(C)=O)cc1
Yield: 98 %

Procedure:
Hydroquinone isopropyl n-propylether was reacted with acetyl chloride for 3 hours (RT) to give 4-n-propoxyphenyl acetate (yield >98%) together with isopropyl chloride.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23])[C:17]=3[CH:27]=2)[C:3]1=[O:28].[CH2:29](Cl)Cl.C(Cl)(=O)C(Cl)=O.[Cl-].C[Zn+]>CN(C)C=O.O1CCCC1>[CH3:26][C:21]([C:18]1[C:17]2[CH:27]=[C:13]([N:4]3[C:5](=[O:12])[CH:6]=[C:7]([C:8]([F:10])([F:11])[F:9])[N:2]([CH3:1])[C:3]3=[O:28])[CH:14]=[CH:15][C:16]=2[S:20][N:19]=1)([CH3:25])[C:22](=[O:23])[CH3:29]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(C)(C)C(=O)O)c3c2)c1=O
Reactant: ClCCl
Agent: C[Zn+]
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)C(C)(C)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Yield: 65.7 %

Procedure:
N,N-Dimethylformamide (8 drops) is added to a mixture of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-α,α-dimethyl-1,2-benzisothiazole-3-acetic acid (0.800 g, 0.00194 mol) and methylene chloride. The mixture is cooled on an ice bath and oxalyl chloride (2.0 M in methylene chloride, 2.42 ml, 0.00484 mol) is added. The resultant mixture is stirred one hour on an ice bath and concentrated in vacuo. The residue is taken up in tetrahydrofuran. The resultant solution is added dropwise to a mixture of methyl zinc chloride (2.0 M, 0.970 ml, 0.00194 mol) in tetrahydrofuran, followed by addition of palladium tetrakistriphenylphosphine (0.220 g, 0.000190 mol). The resultant mixture is stirred overnight at room temperature, quenched with 10% hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to an orange solid. The solid is chromatographed on silica gel to afford the title compound as an off-white solid (0.270 g, 65.7%, mp 195-196° C.).
Reaction SMILES: Cl[P:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[O:3]1.[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1>CC1C=CC=CC=1C.O1CCCC1>[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([P:2]([C:20]2[CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=[C:18]([C:17]([F:16])([F:31])[F:30])[CH:19]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[OH:3])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1
Reactant: ClP1Oc2ccccc2-c2ccccc21
Reactant: FC(F)(F)c1cc([Mg]Br)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: Cc1ccccc1C
Product: Oc1ccccc1-c1ccccc1P(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 120 °C
Yield: 97.4 %

Procedure:
23.5 g (0.1 mol) of 6-chloro-6H-dibenz[c,e][1,2]oxaphosphorine in 200 ml of anhydrous o-xylene at 80° C. are introduced, in an argon atmosphere with stirring, and a solution of 0.23 mol of 3,5-di(trifluoromethyl)phenylmagnesium bromide in 300 ml of tetrahydrofuran is added dropwise. Tetrahydrofuran is distilled off and the temperature is slowly increased to 120° C. in the course of this. The mixture is then stirred for 3 hours at 120° C., cooled to room temperature, and 100 ml of water are added. The mixture is neutralized with dilute hydrochloric acid, the organic phase is separated off, dried with sodium sulfate and concentrated under reduced pressure. 61.0 g of black solid are obtained. By recrystallization from heptane, with addition of activated carbon, and subsequent hot filtration, 37.2 g (59%) of pale yellow crystals having melting point 120° to 121° C. are obtained.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][C:16]([N:18]1[CH:31]2[C:22]([S:34]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])([C:23]3[C:28]([O:29][CH2:30]2)=[C:27]([F:32])[CH:26]=[CH:25][C:24]=3[F:33])[CH2:21][CH2:20][CH2:19]1)=[O:17])(C)(C)C>ClCCl>[NH2:14][CH2:15][C:16]([N:18]1[CH:31]2[C:22]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=3)(=[O:35])=[O:36])([C:23]3[C:28]([O:29][CH2:30]2)=[C:27]([F:32])[CH:26]=[CH:25][C:24]=3[F:33])[CH2:21][CH2:20][CH2:19]1)=[O:17]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)N1CCCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (2 mL, 27.0 mmol) was dissolved in 16 ml of dichloromethane. The solution was added to {2-[4a-(4-Chloro-benzenesulfonyl)-5,8-difluoro-2,3,4,4a,10,10a-hexahydro-9-oxa-1-aza-phenanthren-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (260 mg, 0.467 mmol). The solution was stirred at room temperature overnight. The reaction was quenched by washing with Sat. sodium carbonate solution. The organic layer was dried over sodium sulfate and concentrated. Yield: 20.0 mg, 9%. %. 1H NMR (CDCl3 400 MHz) δ 7.62 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H), 7.06 (td, J=8.8, 4.4 Hz, 1H), 6.61-6.52 (m, 1H), 5.41 (bs, 1H), 4.52 (dd, J=11.0, 3.7 Hz, 1H), 4.21 (dd, J=11.7, 5.1 Hz, 1H), 3.53 (bs, 2H), 2.86 (bs, 1H), 2.70-2.61 (m, 1H), 2.55-2.45 (m, 1H), 2.15-2.03 (m, 1H), 1.75-1.44 (m, 4H).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH:22]([CH3:24])[CH3:23])[N:13]=[C:12]([NH:25][CH3:26])[N:11]=2)[CH:7]=[C:6]([O:27][CH3:28])[C:3]=1[C:4]#[N:5].O.[NH2:30][NH2:31]>C(O)C>[CH3:26][NH:25][C:12]1[N:11]=[C:10]([C:8]2[CH:9]=[C:2]3[C:3]([C:4]([NH2:5])=[N:30][NH:31]3)=[C:6]([O:27][CH3:28])[CH:7]=2)[CH:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[CH:22]([CH3:23])[CH3:24])[N:13]=1
Reactant: CNc1nc(-c2cc(F)c(C#N)c(OC)c2)cc(N2CCOC[C@H]2C(C)C)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CNc1nc(-c2cc(OC)c3c(N)n[nH]c3c2)cc(N2CCOC[C@H]2C(C)C)n1
Temperature: 100 °C

Procedure:
To a solution of 2-fluoro-4-{2-(methylamino)-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-6-(methyloxy)benzonitrile (350 mg, 0.91 mmol) in ethanol (10 mL) was added hydrazine monohydrate (2.5 mL) in one portion. The mixture was heated at 100° C. for 20 hours, cooled to room temperature and concentrated in vacuo. The residue was taken up in water (10 mL) as a suspension. The solids were collected by filtration, washed with water (2×2 mL), and dried under vacuum at room temperature over P2O5 for 20 hours. The solids were washed with hexane (2×3 mL). Drying under vacuum at 65° C. for 20 hours afforded the title compound (302 mg) as a cream-colored solid. LC-MS (ES) m/z=398 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 0.89 (d, J=6.8 Hz, 3H), 1.11 (d, J=6.6 Hz, 3H), 2.45-2.55 (m, 1H), 2.96 (s, 3H), 3.25-3.35 (m, 1H), 3.53-3.61 (m, 2H), 3.94 (dd, J=11.1, 3.5 Hz, 1H), 4.04 (s, 3H), 4.11 (d, J=11.9 Hz, 1H), 6.38 (s, 1H), 6.89 (s, 1H), 7.35 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][NH:11][CH2:10][C@H:9]2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Br[C:27]1[S:28][CH:29]=[CH:30][N:31]=1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:27]3[S:28][CH:29]=[CH:30][N:31]=3)[CH2:10][C@H:9]2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: Brc1nccs1
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CN(c2nccs2)C[C@H]1c1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 24.2 %

Procedure:
The product of Step A in Preparation 17, methyl (3S,4R)-4-(4-chlorophenyl)pyrrolidine-3-carboxylate (0.46 g, 1.92 mmol) was dissolved in 1,4-dioxane (2 ml). DIPEA (1.34 ml, 7.67 mmol) and 2-bromo-1,3-thiazole (1.57 g, 9 6 mmol) were added. The reaction was conducted at 180° C. for 20 minutes with microwave. Then, the reaction mixture was concentrated in vacuo. The obtained residue was diluted with EtOAc, washed with water and purified by column chromatography (eluent: EtOAc/Hex=1/3) to give the title compound (0.15 g, 25%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:36](O)[CH2:37][CH2:38][OH:39].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:5]=[C:6]([CH:7]=1)[O:8][CH2:36][CH2:37][CH2:38][OH:39]
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc3ccccc23)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a solution of 5-methyl-3-(1-naphthalenylsulfonyloxy)phenol (620 g, 2.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol) and 1,3-propanediol (760 mg, 10 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1,1'-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (50 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (1:1 hexane/ethyl acetate) to give the title compound as a yellow oil (650 mg, 87%). 1H-NMR (300 MHz, CDCl3) δ 8.80 (d, J=8.6 Hz, 1H), 8.14 (d, J=7.3 Hz, 2H), 7.98 (d, J=8.2 Hz, 1H), 7.78 (t, J=8.5 Hz, 1H), 7.67 (t, J=8.1 Hz, 1H), 7.49 (t, J=8.1 Hz, 1H), 6.54 (s, 1H), 6.33 (s, 1H), 6.22 (s, 1H), 3.84 (t, J=6.0 Hz, 2H), 3.75 (t, J=6.0 Hz, 2H), 2.15 (s, 3H), 1.90 (m, 2H), 1.59 (s, 1H).
Reaction SMILES: [Na].C(O)C.[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8][CH2:9][CH3:10])=O.C([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])C.Cl>C1(C)C=CC=CC=1>[CH2:9]([O:8][CH:6]([C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:17])[C:5]([O:12][CH2:13][CH3:14])=[O:11])[CH3:10]
Reactant: CCOCC(=O)OCC
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(=O)C(OCC)C(=O)OCC
Temperature: 45 °C
Yield: 87 %

Procedure:
A stirred mixture of molten sodium metal (24.15 g, 1.05 mol) in toluene is treated with ethanol (55.2 g, 1.2 mol) over a 1 hr period at 100° C.-110° C., heated at reflux temperatures for 0.5 hr, cooled to 45° C., treated with a mixture of diethyl oxalate (160.6 g, 1.1 mol) and ethyl ethoxyacetate (132 g, 98%, 0.98 mol) over a 1 hr period at 45° C.-50° C., heated at 55° C.-60° C. for 1.5 hr and poured into 328 g of 14% HCl with cooling. The resultant mixture is separated. The title product is obtained as a 32% solution in the organic phase, identified by HRGC analysis, total yield is 198.2 g (87% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9][CH3:10].[C:11](=[O:13])=[O:12]>CCCCCC.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]([OH:13])=[O:12])=[C:4]([F:8])[C:3]=1[S:9][CH3:10]
Reactant: O=C=O
Reactant: CSc1c(F)cccc1Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1c(Cl)ccc(C(=O)O)c1F
Temperature: -78 °C
Reaction time: 3.5 h

Procedure:
n-Butylithium (2.5M in hexane, 140 ml) was added to a stirred, cooled solution of crude 2-chloro-6-fluorothioanisole (60.0 g) in dry tetrahydrofuran while maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 3.5 hours then poured onto solid carbon dioxide pellets. It was stirred and allowed to warm to room temperature. It was evaporated to dryness and the residue was dissolved in water and washed with ether. The aqueous layer was acidified to pH1 and extracted with ether, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with hexane and filtered to give 4-chloro-2-fluoro-3-(methylsulphenyl)benzoic acid as a white solid, m.p. 183°-185° C.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH:14]=[O:15])([O-:3])=[O:2].I[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH:14]([C:5]2[CH:6]=[CH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]=2[N+:1]([O-:3])=[O:2])[OH:15])=[CH:18][CH:19]=1
Reactant: O=Cc1ccc2ccccc2c1[N+](=O)[O-]
Reactant: COc1ccc(I)cc1
Product: COc1ccc(C(O)c2ccc3ccccc3c2[N+](=O)[O-])cc1

Procedure:
The titled compound was prepared from 1-nitro-2-naphthaldehyde and 4-iodoanisole in a procedure similar to that of example 1 (1).
Reaction SMILES: C(N(C(C)C)CC)(C)C.C([Li])CCC.[O:15]1[C:19]2([CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1.[C:30]1([Se:36]Br)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[C:30]1([Se:36][C:22]2([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:24][C:19]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:20][CH2:21]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Reactant: Br[Se]c1ccccc1
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1([Se]c2ccccc2)CCC2(CC1)OCCO2
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of diisopropylethyl amine (5.59 g, 55.30 mmol) in anhydrous tetrahydrofuran (150 mL) was added a solution of butyllithium (1.6 M in hexanes, 34.5 mL, 55.30 mmol) at 0° C. The reaction solution was stirred at the same temperature for 1 hour, then added a solution of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (10.80 g, 50.00 mmol) in anhydrous tetrahydrofuran (20 mL) at −78° C. The reaction mixture was stirred at the same temperature for 1 h then added phenylselenium bromide (11.90 g, 50.70 mmol). The mixture was continued to stir at −78° C. for 5 hour, then at ambient temperature for 16 hour. The reaction was quenched with saturated sodium hydrogencarbonate (200 mL), diluted with ethyl acetate (200 mL), saturated ammonium chloride (3×150 mL), brine (3×100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate in hexanes (10%) to afford the title compound as a viscous liquid (14.10 g, 76%): 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J=7.6 Hz, 1H), 7.37-7.32 (m, 1H), 7.26 (dd, J=7.0, 7.0 Hz, 2H), 4.05 (dd, J=7.1 Hz, 2H), 3.90 (d, J=3.4 Hz, 4H), 2.20-2.12 (m, 2H), 2.00-1.88 (m, 2H), 1.82-1.70 (m, 2H), 1.57-1.46 (m, 2H), 1.14 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:11]([O:13][CH3:14])=[O:12])[NH:4][N:3]=1.[CH3:19]C1C=C(C)C(B2OC(C)(C)C(C)(C)O2)=CC=1C(OC)=O.CC1C=CC(C(OC)=O)=CC=1B1OC(C)(C)C(C)(C)O1>>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[C:10]([CH:9]=2)[C:11]([O:13][CH3:14])=[O:12])[NH:4][N:3]=1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C
Reactant: COC(=O)c1ccc(C)c(-c2[nH]nc(C)c2C)c1
Agent: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)c1cc(-c2[nH]nc(C)c2C)c(C)cc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 59.2, except methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) was used in place of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4). m/z (ES+) 259 (M+H)+.