Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][C@@H:3]([OH:5])[CH3:4].C(N(CC)CC)C.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>ClCCl>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:6][CH2:1][CH2:2][C@@H:3]([OH:5])[CH3:4])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: C[C@H](O)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC[C@H](C)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
To a solution of (S)-1,3-butanediol (1.0 g) and triethylamine (1.12 g) in dichloromethane (30 ml) was added portionwise p-toluenesulfonyl chloride (2.12 g) at 0° C., and then the mixture was stirred at ambient temperature for 3hours and stand overnight. The resulting solution was dilueted with dichloromethane (30 ml) and the organic layer was washed successively with 1 N hydrochloric acid, saturated sodium bicarbonate aqueous solution and brine. Drying, filtering and removal of solvents afforded (S)-3-hyrdoxybutyl p-toluenesulfonate (2.26 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[I:14]I>C(Cl)Cl.O>[I:14][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Cc1ccc(N)cc1
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
To a stirred solution of p-toluidine (50 g, 467 mmol) in methylene chloride (250 mL) was added a solution of sodium bicarbonate (47 g, 560 mmol) in water (750 mL). Then it was added iodine (118.6 g, 467 mmol) in small portions and the mixture was stirred for 16 h at room temperature. The reaction was quenched with saturated NaHSO3 and the product was extracted with methylene chloride. The methylene chloride layer was washed with brine, dried over Na2SO4, and evaporated in vacuum to give the crude product (100 g, yield 92%). 1H NMR (300 MHz, CDCl3): δ 7.46 (s, 1H), 7.13-6.95 (d, 1H), 6.68-6.64 (d, 1H), 4.00 (br, 2H), 2.21 (s, 3H). MS: m/z 234 [M+1]+.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[C:7]([NH:17][C@H:18]([C:22](O)=[O:23])[CH:19]([CH3:21])[CH3:20])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[Br:1][CH2:2][CH:3]([OH:6])[CH2:4][O:5][C:22](=[O:23])[C@H:18]([CH:19]([CH3:20])[CH3:21])[NH:17][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: OCC(O)CBr
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(O)CBr
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 3-bromo-1,2-propanediol (10.85 g, 70 mmole), N-CBz-L-valine (10.05 g, 40 mmole) and DMAP (0.49 g, 4 mmol) in 250 ml dichloromethane was added dropwise a solution of DCC (9.1 g, 44 mmol) in 50 ml dichloromethane at about 10° C. The mixture was stirred for two days at room temperature and then cooled to 5° C. The urethane was filtered and the solution was evaporated under reduced pressure. The product was isolated by silica gel column chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[N:32]1C=CC=CC=1.N>C(#N)C>[NH2:32][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH:14]1[CH2:16][CH2:15]1
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CC1)C(=O)O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: N
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CC1CC1)C(N)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
A mixture of (S)-2-(tert-butoxycarbonylamino)-3-cyclopropylpropanoic acid (CAN 89483-06-7, 10 g, 44 mmol), di-tert-butyl dicarbonate (CAN:24424-99-5, 14.28 g, 66 mmol) and pyridine (2.4 mL) in acetonitrile (200 mL) was stirred at room temperature for 20 min. Ammonia (10 mL) was added dropwise for 20 min. The resulting reaction mixture was stirred for 4 h. During removal of most of the solvent under reduced pressure the product precipitated and the solid was filtered off and washed with acetonitrile (20 mL). The solid was dried under reduced pressure to give the title compound (7.73 g, 78%) as white solid; MS (EI): m/e 251.2 [M+Na]+.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][S:5][C:4]1=[C:8]1[C:13](=[O:14])[CH2:12][CH2:11][NH:10][C:9]1=[O:15].[CH3:16]I>CN(C)C=O>[CH3:16][N:10]1[CH2:11][CH2:12][C:13](=[O:14])[C:8](=[C:4]2[S:5][CH:6]=[CH:7][S:3]2)[C:9]1=[O:15]
Reactant: O=C1CCNC(=O)C1=C1SC=CS1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(=O)C(=C2SC=CS2)C1=O
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
Sodium hydride (60% dispersion in oil) (226 mg) is suspended in N,N-dimethylformamide (10 ml), and to the suspension is added dropwise a solution of 3-(1,3-dithiol-2-ylidene)-2,4-dioxopiperidine (1.0 g) (which is prepared in Example 13) in N,N-dimethylformamide (100 ml) while cooling at 0° to 5° C. The mixture is stirred for 10 minutes at the same temperature, and to the mixture is added dropwise methyl iodide (861 mg), and the mixture is stirred at 0° to 2° C. for 1.5 hour. After distilling off the solvent under reduced pressure, the residue is purified by silica gel column chromatography (solvent, n-hexane:ethyl acetate=1:1), and recrystallized from ethyl acetate-isopropyl ether to give 1-methyl-3-(1,3-dithiol-2-ylidene)-2,4-dioxopiperidine (634 mg, 59.5%) as pale yellow needles. m.p. 148.5°-153° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][C@H:18]([CH3:22])[CH2:17]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[CH:25]1([CH2:28][NH:29][C:30](=[O:41])[NH:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:25]1([CH2:28][NH:29][C:30]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([N:19]3[CH2:20][CH2:21][N:16]([CH2:15][C:12]4[CH:11]=[CH:10][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:23])([F:1])[F:24])=[CH:14][CH:13]=4)[CH2:17][C@H:18]3[CH3:22])=[O:37])=[CH:39][CH:40]=2)=[O:41])[CH2:27][CH2:26]1
Reactant: C[C@@H]1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1C(=O)c1ccc(NC(=O)NCC2CC2)cc1
Temperature: 25 °C
Yield: 15.5 %

Procedure:
(R)-1,1,1,3,3,3-Hexafluoro-2-(4-((3-methylpiperazin-1-yl)methyl)phenyl)propan-2-ol (0.427 mmol, 0.152 g), 4-(3-(cyclopropylmethyl)ureido)benzoic acid (0.427 mmol, 0.1 g) and triethylamine (1.281 mmol, 0.178 mL, 0.130 g) were combined in dichloromethane and stirred at room temperature. 1-Propanephosphonic acid cyclic anhydride (0.640 mmol, 0.381 mL, 0.407 g; 50% solution in ethyl acetate) was added and the reaction allowed to stir for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 5% methanol/dichloromethane) to afford the title compound (38 mg).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([C:12]3[N:13]=[CH:14][C:15]4[NH:16][C:17]5[C:22]([C:23]=4[CH:24]=3)=[CH:21][CH:20]=[CH:19][CH:18]=5)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:26][CH2:27][CH2:28][Cl:29].[H-].[Na+]>CN(C=O)C>[Cl:29][CH2:28][CH2:27][CH2:26][N:16]1[C:15]2[CH:14]=[N:13][C:12]([C:10]3[O:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2
Reactant: c1ccc(-c2noc(-c3cc4c(cn3)[nH]c3ccccc34)n2)cc1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ClCCCn1c2ccccc2c2cc(-c3nc(-c4ccccc4)no3)ncc21
Yield: 97 %

Procedure:
The compound was synthesized by mixing (Compound 8) (0.6 g, 1.9 mmol), 1-bromo-3-chloropropane (0.45 g, 2.9 mmol), NaH (0.09 g, 2.3 mmol) in DMF, in the same manner as illustrated in example 3 to give the title compound (0.72 g, 97%). M.p. 192°-195° C. (and 235.5°-236° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.[Cl:33][C:34]1[C:35]([CH2:41][CH2:42][NH2:43])=[N:36][CH:37]=[C:38]([Cl:40])[CH:39]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:18])[NH:43][CH2:42][CH2:41][C:35]3[C:34]([Cl:33])=[CH:39][C:38]([Cl:40])=[CH:37][N:36]=3)=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: NCCc1ncc(Cl)cc1Cl
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ncc(Cl)cc4Cl)cc3)c(Cl)cc21
Reaction time: 0.17 h
Yield: 45.6 %

Procedure:
4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation B; 60 mg, 0.16 mmol) was diluted with DCM (1 mL) followed by the addition of oxalyl chloride in DCM (2M) (88 μl, 0.18 mmol) and DMF (1 drop). After stirring for 10 minutes, 2-(3,5-dichloropyridin-2-yl)ethanamine (30 mg, 0.16 mmol) and DIEA (111 μl, 0.64 mmol) were added. The reaction was stirred for 2 hours. The reaction was loaded onto silica gel and eluted with a gradient of 5%-75% ethyl acetate/hexanes to yield the desired compound (40 mg, 0.073 mmol, 46% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([F:14])=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=3)[CH:11]=[C:10]([CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])[N:9]=2)=[CH:4][CH:3]=1.[Cl:31]N1C(C)(C)C(=O)N(Cl)C1=O>C(#N)C.O>[Cl:31][C:11]1[C:10]([CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[N:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:13]([F:14])[C:12]=1[N:15]=[C:16]1[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: CCOC(OCC)c1cc(Nc2ccc(OC)cc2)c(F)c(-c2ccc(Cl)cc2)n1
Solvent: CC#N
Solvent: O
Product: CCOC(OCC)c1nc(-c2ccc(Cl)cc2)c(F)c(N=C2C=CC(=O)C=C2)c1Cl
Temperature: 25 °C

Procedure:
In a typical reaction, crude 2-(4-chlorophenyl)-6-(diethoxymethyl)-3-fluoro-N-(4-methoxyphenyl)pyridin-4-amine is treated with two equivalents of 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione in an acetonitrile/water mixture. The mixture is stirred at ambient temperature until the reaction is complete. The solid product is collected by filtration, washed with additional acetonitrile/water mixture and dried, providing crude 4-((3-chloro-6-(4-chlorophenyl)-2-(diethoxymethyl)-5-fluoropyridin-4-yl)imino)cyclohexa-2,5-dienone.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl.[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][NH:10]1.[OH-].[Na+]>CCOC(C)=O.O>[N:5]1[CH:6]=[CH:7][C:2]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)=[CH:3][CH:4]=1
Reactant: Clc1ccncc1
Reactant: c1ccc2c(c1)CCNC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)CCN(c1ccncc1)C2
Temperature: 150 °C

Procedure:
A mixture of 4-chloro-pyridine 1:1 hydrochloride (24.5 g, 163 mmol) and 1,2,3,4-tetrahydro-isoquinoline (65.3 g, 490 mmol) was slowly heated to 150° C. After 30 min the reaction mixture was cooled to rt, H2O (700 ml) and 2N NaOH (82 ml) was added followed by extraction with AcOEt (5 times 300 ml). The combined organic phases were dried (Na2SO4), and the solvent was evaporated. After trituration with pentane and recrystallization the title compound (30.2 g, 88%) was obtained as a light brown crystalline material. Mp. 95-96° C. (AcOEt), MS: m/e=210 (M+).
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[CH3:13][O:14][C:15]([CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16].BrC=CCC>C1COCC1.CCCCCC.CN(P(N(C)C)(N(C)C)=O)C>[CH3:13][O:14][C:15]([C:17]1([CH2:11][CH2:10][CH:9]=[CH2:8])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]
Reactant: [Li]CCCC
Reactant: COC(=O)C1CCOCC1
Agent: CCC=CBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: C=CCCC1(C(=O)OC)CCOCC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
In a 250 mL round bottom flask was weighed 6.1 g (60 mmol) of diisopropylamine and dissolved in THF (100 mL). This solution was cooled to −78° C. To this solution was added 24 mL of 2 M butyllithium in hexane and stirred for 15 min, warmed up to 0° C. for 20 min, re-cooled to −78° C. To this mixture was added tetrahydro-pyran-4-carboxylic acid methyl ester (7.2 g, 50 mmol) in THF (10 mL). There was almost no color change (light a little bit). This was stirred at −78° C. for 45 min. Then, a mixture of 5 g of HMPA and bromo-butene (8.78 g, 65 mmol) was added slowly via cannula at −78° C. There was no noticeable change. When about half of this mixture was added, the dry ice-acetone bath was removed. When the addition was complete, the flask was submerged into an ice-water bath, stirred for 20 min; then at rt for 2 h. TLC (EtOAc/Heptane 1:1, paraldehyde visualization) showed the reaction was complete. The reaction mixture was poured into ice-water (100 mL) and ether (50 mL). The two layers were separated; the aqueous layer was extracted with ether (3×50 mL). The combined organic layers were washed with brine, dried (K2CO3), filtered, and concentrated in vacuo to obtain 10.4 g (87%) of the title product as a slightly yellow liquid. The material is pure enough to be used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:32])[NH:21][C:22]([CH3:31])=[CH:23][C:24]=1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(O)(C(F)(F)F)=O.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][CH2:18][C:19]2[C:20](=[O:32])[NH:21][C:22]([CH3:31])=[CH:23][C:24]=2[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:16])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(Br)cc21
Reactant: Cc1cc(C2CCCCC2)c(CN)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: On1nnc2cccnc21
Agent: [K+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Cc1cc(C2CCCCC2)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-bromo-1-(1-methylethyl)-1H-indazole-4-carboxylic acid (237 mg, 0.84 mmol) and 3-(aminomethyl)-4-cyclohexyl-6-methyl-2(1H)-pyridinone.TFA (434 mg, 1.3 mmol) in DMSO (10 mL). 1-hydroxy-7-azabenzotriazole (194 mg, 1.42 mmol) was added and the resulting mixture was degassed with nitrogen for 10 minutes. N-methylmorpholine (0.39 mL, 3.52 mmol) and EDC (273 mg, 1.42 mmol) were added, the vessel was sealed, and the mixture was stirred at room temperature for 2 days. The mixture was poured into 10 mL of ice-water and beige solids crashed out. K2CO3 (10%) was added to adjust the pH˜8-9 and the mixture stirred for 30 min and let stand for another 30 min. Solids were filtered off and air-dried. DMF was added, it was heated and sonicated and some water was added. Solids that precipitated were filtered, washed with water and dried to afford the title compound (307 mg, 73%) as a light beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (s, 1H) 8.63 (t, J=4.80 Hz, 1H) 8.37 (s, 1H) 8.20 (s, 1H) 7.68 (d, J=1.26 Hz, 1H) 6.01 (s, 1H) 5.05 (dt, J=13.14, 6.57 Hz, 1H) 4.43 (d, J=4.80 Hz, 2H) 2.84 (t, J=11.24 Hz, 1H) 2.15 (s, 3H) 1.70 (d, J=13.39 Hz, 2H) 1.60 (d, J=12.13 Hz, 3H) 1.47 (s, 3H) 1.45 (s, 3H) 1.42 (br. s., 1H) 1.17-1.39 (m, 4H). MS(ES) [M+H]+ 485.2, 487.2.
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]3[S:19][C:20]([C:23]#[N:24])=[CH:21][N:22]=3)[CH:13]=2)[O:8]1>O1CCCC1.[Ni]>[C:1]1([CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]3[S:19][C:20]([CH2:23][NH2:24])=[CH:21][N:22]=3)[CH:13]=2)[O:8]1
Reactant: Cc1ccccc1C1CCc2cc(Oc3ncc(C#N)s3)ccc2O1
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1ccccc1C1CCc2cc(Oc3ncc(CN)s3)ccc2O1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5-carbonitrile (2.3 g, 6.6 mmol) in tetrahydrofuran (100 ml) an aqueous suspension of Raney nickel (approximately 500 mg) was added and the resulting suspension was vigorously stirred under an hydrogen atmosphere (atmospheric pressure) for 1 h (TLC control) at 45° C. The suspension was filtered through a celite plug and the filter cake washed with ethyl acetate. The organic layer was dried over sodium sulfate and filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate/methanol gradient). [2-(2-o-Tolyl-chroman-6-yloxy)-thiazol-5-ylmethyl]amine was obtained as pale yellow oil (834 mg, 36%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]=[CH:11][N+:12]([O-])=O.Cl[Si](C)(C)C.[Li+].[BH4-]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][NH2:12]
Reactant: COc1ccc(F)c(C=C[N+](=O)[O-])c1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(CCN)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 101 %

Procedure:
1-Fluoro-4-methoxy-2-(2-nitro-vinyl)-benzene (3 g, 15.22 mmol) was reacted with chlorotrimethylsilane (13.2 g, 121.51 mmol) and LiBH4 (1.32 g, 60.91 mmol) in dry THF (50 mL) at 0° C. The resulting mixture was stirred for 72 hours at room temperature to afford 2.6 g of the crude product which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13]>CS(C)=O>[Cl:8][C:4]1[N+:3]([O-:9])=[C:2]([NH:14][CH2:10][CH2:11][CH2:12][CH3:13])[CH:7]=[CH:6][CH:5]=1
Reactant: CCCCN
Reactant: [O-][n+]1c(Cl)cccc1Cl
Solvent: CS(C)=O
Product: CCCCNc1cccc(Cl)[n+]1[O-]
Temperature: 120 °C

Procedure:
To a solution consisting of 9.9 grams (0.055 mole) of 2,6-dichloropyridine-N-oxide in 50 milliliters of dimethylsulfoxide was slowly added 8.4 grams (0.115 mole) of n-butylamine. The temperature of the mixture was 75°C. at the start of the reaction and was allowed to increase to 120°C. After a total reaction time of ~21/2 hours, 3/4 of the dimethyl sulfoxide was removed by evaporation and the reaction mixture poured into cold water. The solid 6-chloro-2-(n-butylamino)pyridine-N-oxide product which precipitated was recovered by filtration in the yield of 6.0 grams. The product melted was 103°-104°C. and was found upon analysis to have carbon, hydrogen, chlorine and contents of 54.1, 6.9, 17.9 and 13.8 percent, respectively, as compared with the theoretical contents of 54.0, 6.5, 17.8 and 14.0 percent, respectively, calculated for the above named compound.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:17]=[C:18]([CH2:22][CH2:23][CH2:24][OH:25])[CH:19]=[CH:20][CH:21]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[CH3:26][S:27]([O:25][CH2:24][CH2:23][CH2:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH2:14][C:12]2[N:13]=[C:9](/[CH:8]=[CH:7]/[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:10][CH:11]=2)[CH:17]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1cccc(OCc2coc(/C=C/c3ccccc3)n2)c1
Product: CS(=O)(=O)OCCCc1cccc(OCc2coc(/C=C/c3ccccc3)n2)c1
Yield: 78 %

Procedure:
In substantially the same manner as in Reference Example 12, 3-[3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol was allowed to react with methanesulfonyl chloride to give 3-[3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate. The yield was 78%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 75-76° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1.Cl>CN(C=O)C>[Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18][C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)[CH:3]=1
Reactant: Clc1cnccn1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(Cl)c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(Cl)c21
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 17.1 %

Procedure:
To a solution of ethyl 2-(4-chloro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (500 mg, 1.85 mmol) in DMF (5 mL) was added Cs2CO3 (1.51 g, 4.62 mmol) at room temperature, followed by 2-chloropyrazine (254 mg, 2.22 mL). The resulting mixture was stirred at 90° C. for 40 min. The mixture was poured into ice-water and acidified to pH=2 with diluted hydrochloric acid. The resulting mixture was extracted with EtOAc (2×25 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by HPLC to give the product (110 mg, yield: 32%). MS (ESI) m/z=349 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[Br:35]Br>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([OH:30])=[C:28]([Br:35])[CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(O)cc1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(O)c(Br)c1

Procedure:
To a mixture of 6-bromo-2-(4-hydroxybenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (290 mg), aluminum chloride (82 mg) and dichloromethane (5.7 ml) was added bromine (39 μl) at 0° C. with stirring, and the mixture was stirred for 1 hr. After the completion of the reaction, the reaction mixture was washed with water, dried and concentrated. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=4/1-1/1) to give the title compound (180 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][S:20]([CH2:23][C@@H:24]([NH2:27])[CH2:25][OH:26])(=[O:22])=[O:21])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]>>[OH:26][CH2:25][C@H:24]([NH:27][C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:9])[CH2:23][S:20](=[O:21])(=[O:22])[NH:19][CH:16]1[CH2:17][CH2:18][N:13]([CH:10]([CH3:11])[CH3:12])[CH2:14][CH2:15]1
Reactant: CC(C)N1CCC(NS(=O)(=O)C[C@@H](N)CO)CC1
Reactant: O=C(O)c1ccc(Cl)s1
Product: CC(C)N1CCC(NS(=O)(=O)C[C@H](CO)NC(=O)c2ccc(Cl)s2)CC1

Procedure:
5-Chloro-thiophene-2-carboxylic acid [(S)-1-hydroxymethyl-2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide was prepared by an analogous procedure as described in example 26 viii) starting from 28 mg (1.1 equiv.) 5-chloro-thiophene-2-carboxylic acid and 44 mg (0.16 mmol) (S)-2-amino-3-hydroxy-propane-1-sulfonic acid (1-isopropyl-piperidin-4-yl)-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-thiophene-2-carboxylic acid [(S)-1-hydroxymethyl-2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material.