Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][S:13]([OH:16])(=O)=[O:14].[Na].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][S:13]([Cl:19])(=[O:16])=[O:14]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)Cc1cc(C(F)(F)F)ccc1Cl
Agent: [Na]
Product: O=S(=O)(Cl)Cc1cc(C(F)(F)F)ccc1Cl
Temperature: 85 °C
Yield: 91.6 %

Procedure:
A mixture of sodium (2-chloro-5-trifluoromethyl-phenyl)-methanesulfonic acid (Example 1.1) (9.4 g) and phosphorous pentachloride (13.5 g) was heated to 80-90° C. for 4 hours. The reaction mixture was concentrated. The residue was poured onto a mixture of ice and water and the mixture extracted twice with dichloromethane. The combined organic extracts were washed with water and brine, dried over magnesium sulfate and concentrated to give (2-chloro-5-trifluoromethyl-phenyl)-methanesulfonyl chloride as an off-white solid (8.480 g). 1H-NMR (400 MHz, CDCl3): 7.87 (m, 1H), 7.68 (m, 2H), 5.15 (s, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[CH3:11][C:12](O)=[O:13]>CC(OC(C)=O)=O>[C:12]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1)(=[O:13])[CH3:11]
Reactant: CC(=O)O
Reactant: Nc1ccc2c(c1)CCO2
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2c(c1)CCO2
Yield: 88 %

Procedure:
The product (5.2 g, 38.5 mmol) obtained in Step 2 was dissolved in AcOH (20 mL) and Ac2O (5 mL), heated to 60° C., reacted for 12 h, and concentrated to obtain a crude product (6 g, 88.0%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[NH2:19][CH2:20][C:21]1[CH:22]=[C:23]([CH:53]=[CH:54][CH:55]=1)[CH2:24][N:25]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)=[CH:41][CH:40]=1)[S:26]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[C:30]=1[OH:37])(=[O:28])=[O:27]>C(Cl)Cl>[Cl:36][C:31]1[C:30]([OH:37])=[C:29]([S:26]([N:25]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][C:46]3[CH:47]=[CH:48][C:49]([F:52])=[CH:50][CH:51]=3)=[CH:41][CH:40]=2)[CH2:24][C:23]2[CH:53]=[CH:54][CH:55]=[C:21]([CH2:20][NH:19][S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:22]=2)(=[O:28])=[O:27])[CH:34]=[C:33]([Cl:35])[CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1cccc(CN(Cc2ccc(Oc3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NCc2cccc(CN(Cc3ccc(Oc4ccc(F)cc4)cc3)S(=O)(=O)c3cc(Cl)cc(Cl)c3O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
To a suspension of 4-methylbenzene-1-sulfonyl chloride (25 mg, 0.13 mmol) in CH2Cl2 (3 mL) were added Et3N (0.10 ml, 075 mmol) and N-(3-(aminomethyl)benzyl)-3,5-dichloro-N-(4-(4-fluorophenoxy)benzyl)-2-hydroxybenzenesulfonamide (70 mg, 0.13 mmol). The reaction mixture was stirred at rt. under nitrogen for 2 h. The mixture was concentrated and dissolved in MeOH, purified by preparative HPLC. The fractions containing the desired product were combined, concentrated and lyophilized to give white solid (52 mg, 58%).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:14]=[CH:13][C:9]2=[N:10][O:11][N:12]=[C:8]2[CH:7]=1)=[O:5].[CH3:16][Li]>C1COCC1>[N:10]1[O:11][N:12]=[C:8]2[CH:7]=[C:6]([C:4](=[O:5])[CH3:16])[CH:14]=[CH:13][C:9]=12
Reactant: CON(C)C(=O)c1ccc2nonc2c1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(=O)c1ccc2nonc2c1
Reaction time: 1 h

Procedure:
To a solution of N-Methoxy-N-methyl-2,1,3-benzoxadiazole-5-carboxamide (630 mg, 3.04 mmol) in THF (5 mL) cooled to −40° C. was added methyl lithium solution (1.6M, 2.28 mL, 3.65 mmol). The reaction mixture was stirred at the same temperature for 1 h, then was quenched by addition of 1M HCl. The mixture was extracted with ethyl acetate and the organic layer was dried over MgSO4. Purification my flash chromatography afforded the title compound. 1H-NMR (500 MHz, CDCl3) δ ppm 8.48 (s, 1H), 8.02 (d, 1H), 7.91 (d, 1H), 2.72 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4]=1[O:18][CH3:19].[C-:20]#[N:21].[K+].O>CN(C=O)C.[Cl-].[Na+].O>[F:9][C:7]1[CH:6]=[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4]([O:18][CH3:19])=[C:3]([CH2:2][C:20]#[N:21])[CH:8]=1
Reactant: COc1c(CCl)cc(F)cc1OCc1ccccc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(CC#N)cc(F)cc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 80.2 %

Procedure:
To a solution of 1-(chloromethyl)-5-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]benzene (6.82 g, 24.3 mmol) in DMF (60 mL) was added potassium cyanide (3.2 g, 48.6 mmol), and the resulting mixture was stirred at 50° C. for 2 h 20 min before cooling to rt. Water and brine were added, and the resulting aqueous mixture was extracted with ethyl acetate. The organic phase was washed twice with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (80% hexanes, 20% ethyl acetate) to afford {5-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]phenyl}acetonitrile (5.3 g, 19.5 mmol, 80% yield) as a colorless oil which eventually solidified. 1H NMR (400 MHz, CDCl3): δ 7.42-7.32 (m, 5H), 6.69-6.67 (m, 2H), 5.08 (s, 2H), 3.89 (s, 3H), 3.70 (s, 2H).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:5][N:4]([CH:6]2[CH2:23][CH2:22][C:9]3([CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]3)[CH2:8][CH2:7]2)[CH2:3]1.[ClH:25]>CO>[ClH:25].[ClH:25].[F:24][C:2]1([F:1])[CH2:5][N:4]([CH:6]2[CH2:7][CH2:8][C:9]3([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[CH2:22][CH2:23]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(N3CC(F)(F)C3)CC2)CC1
Agent: Cl
Solvent: CO
Product: FC1(F)CN(C2CCC3(CCNCC3)CC2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl 9-(3,3-difluoroazetidin-1-yl)-3-azaspiro[5.5]undecane-3-carboxylate (1.26 g, 3.66 mmol) was dissolved in hydrogen chloride in methanol (1.25 mol/l, 29 ml) and refluxed for 45 min. The solvent was removed under vacuum and the residue was dissolved in a small amount of ethanol. A solid was then precipitated by addition of acetone. The mixture was stirred for 10 min at room temperature, then diethyl ether was added and stirring was carried out for a further 30 min at room temperature. The resulting precipitate was filtered out with suction, washed with diethyl ether and dried under vacuum. Yield: 1.1 g (95%)
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11]O)[OH:10])[OH:8])[OH:6])[OH:4].O.[NH2:14][NH2:15]>CO>[CH:11](=[N:14][NH2:15])[C@@H:9]([C@H:7]([C@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: NN
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Solvent: O
Solvent: CO
Product: NN=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reaction time: 8 h

Procedure:
A 2.0 g portion of D-galactose was dissolved in a mixture of 5 ml of methanol and 5 ml of hydrazine hydrate and stirred overnight, then evaporated to dryness in vacuo. About 5 ml of methanol was added, the mixture was stirred for 48 hours and the solid was collected giving 1.9 g of D-galactose hydrazone.
Reaction SMILES: [F:1][C:2](=[CH2:6])[C:3](Cl)=[O:4].[C:7]1([O-:18])[C:12]([Cl:13])=[C:11]([Cl:14])[C:10]([Cl:15])=[C:9]([Cl:16])[C:8]=1[Cl:17].[K+]>C(#N)C>[F:1][C:2](=[CH2:6])[C:3]([O:18][C:7]1[C:8]([Cl:17])=[C:9]([Cl:16])[C:10]([Cl:15])=[C:11]([Cl:14])[C:12]=1[Cl:13])=[O:4]
Reactant: C=C(F)C(=O)Cl
Reactant: [O-]c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [K+]
Solvent: CC#N
Product: C=C(F)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reaction time: 1.5 h
Yield: 51 %

Procedure:
13.9 g (0.128 mol) of α-fluoroacryloyl chloride (obtained in accordance with example 1c) were added dropwise, at a temperature of 25° C., with stirring and in the course of 30 minutes, to a solution of 30 g (0.0985 mol) of potassium pentachlorophenate in 400 ml of anhydrous acetonitrile, and the reaction mixture was then stirred for a further 90 minutes at the same temperature. The solid formed was filtered off and washed with 20 ml of anhydrous acetonitrile. After 0.01 g of hydroquinone monomethyl ether had been added, the volatile constituents in the mixture of filtrate and washing liquor were distilled off and the residue was recrystallized from boiling n-hexane. 17 g (51% of theory) of pentachlorophenyl α-fluoroacrylate were obtained, melting point 90° to 92° C.
Reaction SMILES: [NH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=1)[NH2:2].BrC1C=CC2N([C:18]([S:21][C:22]3[CH:23]=[CH:24][C:25]4[N:26]([CH:28]=[C:29]([NH:31][C:32]([CH:34]5[CH2:36][CH2:35]5)=[O:33])[N:30]=4)[N:27]=3)=NN=2)C=1>>[C:7]([C:6]1[CH:9]=[CH:10][C:3]2[N:4]([C:18]([S:21][C:22]3[CH:23]=[CH:24][C:25]4[N:26]([CH:28]=[C:29]([NH:31][C:32]([CH:34]5[CH2:36][CH2:35]5)=[O:33])[N:30]=4)[N:27]=3)=[N:2][N:1]=2)[CH:5]=1)#[N:8]
Reactant: O=C(Nc1cn2nc(Sc3nnc4ccc(Br)cn34)ccc2n1)C1CC1
Reactant: N#Cc1ccc(NN)nc1
Product: N#Cc1ccc2nnc(Sc3ccc4nc(NC(=O)C5CC5)cn4n3)n2c1

Procedure:
To a suspended mixture of 6-chloronicotinonitrile (7 g, 50.8 mmol) in EtOH (50 mL), was added NH2NH2 (10 g, 310.2 mmol). The mixture was stirred at room temperature for 10 min, and then 60° C. for 5 h. The mixture was cooled to room temperature. The solids were filtered out, washed with water and dried under high vacuum to give 6-hydrazinylnicotinonitrile (3.5 g). Compound 6 was prepared from 6-hydrazinylnicotinonitrile following the procedure of the synthesis of compound 4. 1H NMR (400 MHz, CDCl3-CD3OD 10:1) δ ppm 11.37 (s, 1H), 8.70 (t, J=1.2 Hz, 1 H), 8.14 (s, 1 H), 8.11(dd, J=1.04 and 9.52 Hz, 1 H), 7.96 (dd, J=1.12 and 9.52 Hz, 1 H), 7.61 (dd, J=1.52 and 9.48 Hz, 1 H), 7.38 (d, J=9.0 Hz, 1 H), 1.77 (m, 1 H), 1.06 (m, 2 H), 0.90 (m, 2H) ESI-MS:m/z 377.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([Cl:14])[N:3]=1.[O:15]1[CH2:18][C:17](=O)[CH2:16]1.C([BH3-])#N.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10][N:11]([CH:17]3[CH2:18][O:15][CH2:16]3)[CH2:12][CH2:13]2)[CH:5]=[C:4]([Cl:14])[N:3]=1
Reactant: O=C1COC1
Reactant: Clc1cc(C2CCNCC2)cc(Cl)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc(C2CCN(C3COC3)CC2)cc(Cl)n1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
A solution of 2,6-dichloro-4-(piperidin-4-yl)pyridine (2 g, 8.7 mmol) and oxetan-3-one (6.26 g, 87 mmol) in THF (50 mL) was stirred at 70° C. for 30 min and then sodium cyanoborohydride (2.74 g, 43.5 mmol) was added to the mixture and the mixture solution was stirred at 70° C. for additional 30 min. The reaction solution was filtered and the filtrate was concentrated to give crude product which was purified by flash column chromatography on silica gel (30% ethyl acetate in petroleum ether) to afford 2,6-dichloro-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridine. (2 g, 88.7% yield). LCMS (ESI) [MH]+=286.7.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N+]([O-])=O)=[CH:5][C:4]=1[C:12]#[N:13])#[N:2].[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24])([CH3:17])([CH3:16])[CH3:15]>>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]=1[C:12]#[N:13])#[N:2]
Reactant: CC(C)(C)c1ccccc1S
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Product: CC(C)(C)c1ccccc1Sc1cccc(C#N)c1C#N
Yield: 50 %

Procedure:
As in Synthesis Example 1 but using 1.73 grams of 1,2-dicyano-4-nitrobenzene and 4.9 grams of 2-t-butylbenzenethiol, there was obtained 1.46 grams of 1,2-dicyano-3-(2-t-butylphenylthio)benzene (yield of 50%). Next, as in Synthesis Example 1 but using 1.46 grams of this benzene compound and 0.42 gram of BBr3 l there was obtained 0.73 gram of the end product (yield 45%, mp 160°-161° C.).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:4][CH2:3]1.[C:26](Cl)(=[O:28])[CH3:27]>CN(C)C1C=CN=CC=1>[C:26]([N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:6][CH2:7]1)(=[O:28])[CH3:27]
Reactant: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CC(=O)N1CCC(c2[nH]nc(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Reaction time: 3 h

Procedure:
To a stirred suspension of 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole hydrochloride (Example C-74) (1 g, 2.4 mmol) in 24 mL of CH2Cl, was added 4-dimethylamino pyridine (0.88 g, 7.2 mmol) and acetyl chloride (0.21 g, 2.6 mmol). The solution was stirred for 3 h and the solvent was removed under reduced pressure. The residue was treated with saturated NH2OH (20 mL) and the suspension was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine (1×50 mL), dried over MgSO4, filtered and concentrated to leave a solid. The solid was triturated with ether and was filtered to leave the title compound: MS (M+H): 381 (base peak).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[C:12](N)=[CH:11][C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[CH3:19][S:20](Cl)(=[O:22])=[O:21].N1C=CC=CC=1.Cl>C(Cl)Cl>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:11][C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCc1cc(F)c(N)cc1F
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCc1cc(F)c(S(C)(=O)=O)cc1F
Temperature: 0 °C
Yield: 76.9 %

Procedure:
A dried 25 ml of two-neck round bottom flask was filled with argon gas. The solution of (4-amino-2,5-difluorobenzyl)-carbamic acid t-butyl ester (0.43 g, 1.66 mmol) in methylenechloride was put into the flask and then cooled to 0° C. To the solution were added methanesulfonylchloride (1.2 eq, 1.99 mmol, 0.16 ml) and pyridine (excess, 0.5 ml) slowly, the mixture solution was refluxed for 12 hours. After confirming the completion of the reaction with TLC, the reaction solution was acidified by 10% HCl, extracted with methylenechloride, washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was purified with column chromatography (n-hexane/ethyl acetate=2/1) to yield a white solid (0.41 g, 73.5%).
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:12])[CH2:4]/[CH:5]=[CH:6]\[CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9].C1COCC1.[OH-].[K+]>O>[CH3:9][Si:8]([CH3:11])([CH3:10])[CH2:7]/[CH:6]=[CH:5]\[CH2:4][C@@H:3]1[CH2:2][O:12]1
Reactant: C[Si](C)(C)C/C=C\C[C@@H](O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)C/C=C\C[C@@H]1CO1
Yield: 98.3 %

Procedure:
12.97 g (62.7 mmol) of (Z)-(R)-1-Chloro-6-trimethylsilanyl-hex-4-en-2-ol was dissolved in 215 ml of abs. THF. A solution of 60.34 g (1.08 mol) of KOH in 61 g of water was added ant the heterogeneous mixture stirred at 30° for 24h, until GC analysis indicated the disappearance of the starting chlorohydrine. The reaction mixture was then poured onto crushed ice/NH4Cl, extracted with ether, dried over sodium sulfate, and the solvents removed i.V. Thereby, 10.5 g of (Z)-(R)-trimethyl-(4-oxiranyl-but-2-enyl)-silane was isolated, 93% pure according to GC, which was used as such for the next step.
Reaction SMILES: [C:1]([CH:3]([CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:4][CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])#N.CC(C[AlH]CC(C)C)C.[OH2:33].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH:1]([CH:3]([CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:4][CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[O:33]
Reactant: CC(C)(C)[Si](C)(C)OCCC(C#N)CCO[Si](C)(C)C(C)(C)C
Reactant: O
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCC(C=O)CCO[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 73 %

Procedure:
Following a published procedure,24 a solution of 3 (3.65 g, 10.2 mmol) in dry toluene (52 mL) at −78° C. under argon was treated with DIBALH (12 mmol, 8.3 mL, 1.5 M solution in toluene), and the reaction was allowed to proceed for 1 h. Water (2.6 mL) was added, and the mixture was allowed to reach room temperature. Aqueous NaOH (2.6 mL, 4.0 M solution) was added, and stirring was continued for 15 min. Water (7.8 mL) was added and the suspension was stirred for a further 15 min. The sample was dried (Na2SO4), concentrated at reduced pressure, and chromatographed [silica, petroleum ether/diethyl ether (20:1)], affording a colorless liquid (2.70 g, 73%): IR (film, νmax cm−1) 2955, 2859, 1729, 1708, 1472; 1H NMR δ 0.01 (s, 12H), 0.87 (s, 18H), 1.64-1.74 (m, 2H), 1.85-1.96 (m, 2H), 2.50 (m, 1H), 3.57-3.68 (m, 4H), 9.65 (d, J=2.4 Hz, 1H); 13C NMR δ −5.27, 18.45, 26.09, 32.15, 46.40, 60.80, 204.74; EI-MS 171/172, 141, 97, 75, calcd 360.2516 (C18H40O3Si2); Anal. Calcd C, 59.94; H, 11.18. Found: C, 58.15; H, 11.16.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[C:9]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:26])=[C:21](F)[C:22]=3[Cl:24])[C:17](=[O:27])[C:16]([C:28]([OH:30])=[O:29])=[CH:15]2)[CH:8]=1.Cl.Cl.[NH2:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:33][CH:34]1[CH2:37][N:36]([C:21]2[C:22]([Cl:24])=[C:23]3[C:18]([C:17](=[O:27])[C:16]([C:28]([OH:30])=[O:29])=[CH:15][N:14]3[C:9]3[CH:8]=[C:7]([NH2:6])[C:12]([F:13])=[CH:11][N:10]=3)=[CH:19][C:20]=2[F:26])[CH2:35]1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)ncc1F
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)ncc1F
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 87.6 %

Procedure:
To 110 mg of N,N-dimethylformamide were added 23 mg of 1-(4-amino-5-fluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 20 mg of 3-aminoazetidine dihydrochloride, and 50 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 20 minutes. After adding 500 mg of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 23 mg of the title compound as a colorless powder.
Reaction SMILES: O[C@H:2]1[CH2:7][C@@H:6]([CH3:8])[S:5](=[O:10])(=[O:9])[C:4]2[S:11][CH:12]=[CH:13][C:3]1=2.[CH2:14]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>C(Cl)Cl>[CH2:14]([N:16]([C@H:2]1[CH2:7][C@H:6]([CH3:8])[S:5](=[O:10])(=[O:9])[C:4]2[S:11][CH:12]=[CH:13][C:3]1=2)[S:17]([C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1)(=[O:18])=[O:19])[CH3:15]
Reactant: CCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H]1C[C@H](O)c2ccsc2S1(=O)=O
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCN([C@H]1C[C@H](C)S(=O)(=O)c2sccc21)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: -20 °C
Yield: 50.4 %

Procedure:
Methylene chloride (60 mL), cis-4-hydroxy-5,6-dihydro-6-methyl-4-H-thieno-[2,3-b]-thiopyran-7,7-dioxide (5 g), N-ethyl-4-nitrobenzene-sulfonamide (6.86 g) and triphenyl-phosphine (8.42 g) are mixed under nitrogen atmosphere. The mixture is cooled to under −20° C. and diisopropyl azadicarboxylate (5.9 mL) is added, maintaining the temperature under −20° C. The temperature is allowed to rise to 20-25° C. The obtained mixture is treated with 5% NaOH (125 mL) and the resulting organic phase is vacuum distilled to dryness. The residue is chromatographed in a column (ethyl acetate/heptane, 2/1), obtaining 4.97 g of trans-4-[N-ethyl-N-(4-nitrobenzenesulfonyl)amino]-5,6-dihydro-6-methyl-4-H-thieno-[2,3-b]-thiopyran-7,7-dioxide.
Reaction SMILES: O1CCOCC1.Cl.C([N:11]([C:16]1[C:32]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:31][C:19]2[C:20](=[O:30])[C:21]([C:25]([O:27]CC)=[O:26])=[C:22]([CH3:24])[O:23][C:18]=2[CH:17]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(=O)C>O>[C:25]([C:21]1[C:20](=[O:30])[C:19]2[CH:31]=[C:32]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:16]([NH:11][S:12]([CH3:15])(=[O:13])=[O:14])=[CH:17][C:18]=2[O:23][C:22]=1[CH3:24])([OH:27])=[O:26]
Reactant: CCOC(=O)c1c(C)oc2cc(N(C(C)=O)S(C)(=O)=O)c(Oc3ccccc3)cc2c1=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1oc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c(=O)c1C(=O)O
Yield: 94.4 %

Procedure:
10 ml of dioxane and 10 ml of 6N hydrochloric acid were added to 500 mg of 7-(N-acetyl-N-methylsulfonylamino)-3-ethoxycarbonyl-2-methyl-6-phenoxy-4H-1-benzopyran-4-one. The mixture was refluxed for 20 minutes. The reaction mixture was cooled to 5°-10° C. 30 ml of water was added thereto. The resulting crystal was collected by filtration and recrystallized from acetic acid to obtain 400 mg (yield: 95.2%) of 3-carboxy-2-methyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 238°-241° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:12])[N:10]([CH3:11])[C:6]=2[CH:5]=[C:4]([N:13]([CH3:17])[C:14](=[O:16])[CH3:15])[C:3]=1[CH2:18][CH2:19][CH:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>>[CH3:12][C:9]1[N:10]([CH3:11])[C:6]2[CH:5]=[C:4]([N:13]([CH3:17])[C:14](=[O:16])[CH3:15])[C:3]3[CH2:18][CH2:19][CH:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:1][C:2]=3[C:7]=2[N:8]=1
Reactant: CC(=O)N(C)c1cc2c(nc(C)n2C)c(O)c1CCC(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N(C)c1cc2c(nc(C)n2C)c2c1CCC(c1ccccc1)O2
Temperature: 80 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
A suspension of 0.75 g (2.0 mmol) N-[7-hydroxy-6-(3-hydroxy-3-phenyl-propyl)-2,3-dimethyl-3H-benzoimidazol-5-yl]-N-methyl-acetamide in 8 ml 85% orthcphosphodc acid was heated to 80° C. After 2 h stirring, the reaction was cooled to room temperature, neutralized with 6M sodium hydroxide and extracted with ethyl acetate (3×20 ml). The organic layers were dried over magnesium sulphate and concentrated in vacuo. The residue was crystallized from ethyl acetate/disopropyl ether (1:10) to afford the title compound (57%) as a beige solid. m.p. 214°-216° C.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Br:15][C:16]1[C:21](=[O:22])[N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[NH:19][C:18](=[O:32])[CH:17]=1.[CH3:33][O:34][C:35]1[CH:36]=[CH:37][C:38]([C@H:41]2[CH2:43][C@@H:42]2[CH2:44]O)=[N:39][CH:40]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Br:15][C:16]1[C:21](=[O:22])[N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[N:19]=[C:18]([O:32][CH2:44][C@H:42]2[CH2:43][C@@H:41]2[C:38]2[CH:37]=[CH:36][C:35]([O:34][CH3:33])=[CH:40][N:39]=2)[CH:17]=1
Reactant: COc1ccc([C@H]2C[C@@H]2CO)nc1
Reactant: COc1ccc(Cn2[nH]c(=O)cc(Br)c2=O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(OC[C@H]3C[C@@H]3c3ccc(OC)cn3)cc(Br)c2=O)cc1

Procedure:
DIAD (0.625 ml, 3.21 mmol) was added to a mixture of 5-bromo-1-(4-methoxybenzyl)-1,2-dihydropyridazine-3,6-dione (500 mg, 1.607 mmol), ((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methanol (288 mg, 1.607 mmol) and PPh3 (843 mg, 3.21 mmol) in THF (15 ml) at 0° C.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30](O)=[O:31])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>>[CH:37]1([NH:40][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=2[S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:39][CH2:38]1
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 80 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and cyclopropylamine (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 43 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 538 [M+H]+.