Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.[CH3:29][C@H:30]1[O:35][C@@H:34]([CH3:36])[CH2:33][NH:32][CH2:31]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:11]([C:4]2[C:5]([C:8]([N:32]3[CH2:31][C@H:30]([CH3:29])[O:35][C@H:34]([CH3:36])[CH2:33]3)=[O:9])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:12][O:13][CH3:14])(=[O:17])=[O:16])=[CH:19][C:20]=1[C:25]([F:28])([F:27])[F:26]
Reactant: COCN(c1cc(Cl)cnc1C(=O)Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: C[C@@H]1CNC[C@H](C)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCN(c1cc(Cl)cnc1C(=O)N1C[C@@H](C)O[C@@H](C)C1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl chloride (50 mg, 0.11 mmol), cis-2,6-dimethylmorpholine (50 mg, 0.40 mmol) and di-isopropylethylamine (DIEA, 0.07 mL, 0.40 mmol) in CH2Cl2 (1.5 mL) was stirred at room temperature overnight. The mixture was concentrated to provide 4-chloro-N-[5-chloro-2-(cis-2,6-dimethyl-morpholine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide, which was directly used in the next step without any purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH:20]2[CH2:24][CH2:23][O:22][CH2:21]2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.C(N(CC)CC)C.[F:32][CH2:33][CH2:34][S:35](Cl)(=[O:37])=[O:36].[Cl-].[NH4+]>ClCCl>[F:32][CH2:33][CH2:34][S:35]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH:20]2[CH2:24][CH2:23][O:22][CH2:21]2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1)(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)CCF
Reactant: Cn1cc(-c2cc(N)ccc2OC2CCOC2)c2cc[nH]c2c1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(-c2cc(NS(=O)(=O)CCF)ccc2OC2CCOC2)c2cc[nH]c2c1=O
Reaction time: 1 h
Yield: 6.5 %

Procedure:
To a mixture of Example 91b (80.0 mg, 0.246 mmol) and triethylamine (74.6 mg, 0.738 mmol) in dichloromethane (4 mL) was added dropwise 2-fluoroethanesulfonyl chloride (144 mg, 0.984 mmol), and the reaction mixture was stirred at about ambient temperature for about 1 hour. The reaction mixture was neutralized with saturated aqueous ammonium chloride solution (50 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried (anhydrous magnesium sulfate), filtered, and concentrated. The residue was purified by preparative HPLC (C18, 10-80% acetonitrile in 0.1% TFA/water) to provide the title compound (7.0 mg, 6.5% yield). 1H NMR (300 MHz, CDCl3) ppm 11.54 (bs, 1H), 7.45 (t, J=2.8 Hz, 1H), 7.19 (s, 1H), 6.88 (d, J=8.7 Hz, 1H), 6.73 (d, J=2.7 Hz, 1H) 6.67 (dd, J=3.1, 8.8 Hz, 1H), 6.40 (dd, J=2.0, 2.7 Hz, 1H), 4.76 (m, 1H), 3.82 (s, 3H), 3.85-3.62 (m, 8H), 2.97 (bs, 1H), 2.24-1.85 (m, 2H). MS (ESI+) m/z 436.2 (M+H)+.
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:13][CH2:14][CH:15]1[CH:24]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:23]2[C:18](=[C:19]([F:36])[CH:20]=[CH:21][C:22]=2[F:35])[O:17][CH2:16]1)[CH2:10][CH:11]=C)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[O:37]=[O+][O-].[BH4-].[Na+]>CO.C(Cl)Cl>[C:1]([Si:5]([CH3:6])([CH3:7])[O:8][CH:9]([CH2:13][CH2:14][CH:15]1[CH:24]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[C:23]2[C:18](=[C:19]([F:36])[CH:20]=[CH:21][C:22]=2[F:35])[O:17][CH2:16]1)[CH2:10][CH2:11][OH:37])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=[O+][O-]
Reactant: C=CCC(CCC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1)O[Si](C)(C)C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(CCO)CCC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of tert-butyl-(1-{2-[4-(4-chloro-benzenesulfonyl)-5,8-difluoro-chroman-3-yl]-ethyl}-but-3-enyloxy)-dimethyl-silane (1.45 g, 2.60 mmol) in 1:1 MeOH/CH2Cl2 (25 mL) at −78° C. was purged with ozone until the blue color persisted. The reaction mixture was then purged with N2 for 5 min, treated with NaBH4 (300 mg, 7.8 mmol) portionwise and slowly warmed to ambient temperature. Over the next 4.5 h, 2 additional portions of NaBH4 (500 mg each) were added, and the reaction mixture was quenched with saturated aqueous NH4Cl and concentrated in vacuo. The residue was extracted with CH2Cl2 (3×). The combined organic extracts were washed saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo. Flash chromatography (5→40% EtOAc/Hex) afforded the title compound (730 mg, 50%): 1H NMR (CDCl3 400 MHz) δ 7.72 (dd, J=8.8, 1.5 Hz, 2H), 7.52 (dd, J=8.8, 1.5 Hz, 2H), 7.02 (m, 1H), 6.38 (m, 1H), 4.90 (dd, J=11.7, 2.2 Hz, 1H), 4.33 (d, J=12.4 Hz, 1H), 4.28 (s, 1H), 3.85 (m, 1H), 3.73-3.64 (m, 2H), 2.76 (m, 1H), 1.91 (br s, 1H), 1.71-1.22 (m, 6H), 0.80 (s, 4.5H), 0.79 (s, 4.5H), 0.03 (s, 3H), −0.04 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:20][CH:21]([OH:28])[CH2:22][NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:9]([CH:18]=1)[C:10]([CH2:12][CH2:13][C:14](OC)=[O:15])=O)(=[O:3])[CH3:2].O.[NH2:30][NH2:31].[OH-].[Na+]>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:20][CH:21]([OH:28])[CH2:22][NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:9]([C:10]2[CH2:12][CH2:13][C:14](=[O:15])[NH:30][N:31]=2)[CH:18]=1)(=[O:3])[CH3:2]
Reactant: NN
Reactant: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1OCC(O)CNC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(OCC(O)CNC(C)(C)C)c(C2=NNC(=O)CC2)c1

Procedure:
A solution of methyl 3-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)benzoyl]propionate (0.21g) and hydrazine hydrate (0.12 ml) in glacial acetic acid (5 ml) was heated under reflux of 16 hours. Evaporation of the reaction mixture under reduced pressure gave a glassy residue to which was added sodium hydroxide solution (2N, 10 ml). The resulting solution was extracted well with chloroform, the combined organic phases washed with water, dried and evaporated to give a white brittle residue which was recrystallised from isopropanol/ether to give 6-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone as a white solid (0.16g, 80% m.p. 102°-109° C; M+, 376, M 376).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:10]=[C:11]=[S:12])[CH:8]=2)[CH:3]=[N:2]1.Cl.[CH2:14]([O:16][C:17](=[O:21])[CH2:18][CH2:19][NH2:20])[CH3:15].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:14]([O:16][C:17](=[O:21])[CH2:18][CH2:19][NH:20][C:11](=[S:12])[NH:10][C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[N:2][NH:1]2)=[CH:5][CH:6]=1)[CH3:15]
Reactant: CCOC(=O)CCN
Reactant: S=C=Nc1ccc2cn[nH]c2c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=S)Nc1ccc2cn[nH]c2c1
Yield: 37.1 %

Procedure:
A solution of 5 g (28.6 mmol) of lH-indazol-6-yl isothiocyanate, 5.3 g (34.3 mmol) of beta-alanine ethyl ester hydrochloride and 4.8 ml (34.3 mmol) of triethylamine in 50 ml of chloroform is left at room temperature under agitation for one hour. The chloroform phase is washed with water (2 × 10 ml) and with a 1 N hydrochloric acid solution (2 × 10 ml). It is dried and concentrated to dryness. The residue (8 g) is triturated in ethyl ether (3 × 20 ml). There is obtained 3.1 g of (lH-indazol-6-yl)thiocarbamoyl-beta-alanine ethyl ester (yield 28%, melting point 145° C.).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].C1(C)C=CC=CC=1.[C:12]([O:16][C:17]([NH:19][C@@H:20]([CH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C@@H:21]([O:24][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH:22]=[O:23])=[O:18])([CH3:15])([CH3:14])[CH3:13].[NH4+].[Cl-]>C(OCC)C.Cl[Hg]Cl>[C:12]([O:16][C:17]([NH:19][C@@H:20]([CH2:35][CH:36]1[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1)[C@@H:21]([O:24][Si:25]([CH:26]([CH3:27])[CH3:28])([CH:29]([CH3:30])[CH3:31])[CH:32]([CH3:33])[CH3:34])[C@@H:22]([OH:23])[CH2:3][C:2]#[CH:1])=[O:18])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)[Si](O[C@@H](C=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Reactant: C#CCBr
Agent: Cl[Hg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C#CC[C@H](O)[C@H](O[Si](C(C)C)(C(C)C)C(C)C)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 10 °C
Reaction time: 0.75 h

Procedure:
To a dry flask under an N2 atmosphere was added Mg (0.40 g, 6.4 mmol), HgCl2 (0.03 g) and anhydrous diethyl ether (4 mL). A solution of 80% propargyl bromide in toluene (1.83 mL, 16.4 mmol) was added to an addition funnel and several drops were added to the reaction mixture. After the reaction was initiated, anhydrous diethyl ether (10 mL) was added to the reaction flask and anhydrous diethyl ether (10 mL) was added to the funnel solution. The funnel solution was added dropwise while the reaction solution was cooled with a 10° C. bath. The white, opaque mixture was stirred at room temperature for 45 minutes and then a solution of aldehyde of Step 4 (2.05 g, 4.64 mmol) in anhydrous diethyl ether (10 mL) was added dropwise. The yellow, opaque mixture was stirred at room temperature for 2 hours. The mixture was cooled to about 0° C. with an ice-water bath and a saturated NH4Cl solution (25 mL) was added dropwise. The organic layer was collected and the aqueous layer was extracted with diethyl ether (10mL). The combined organic layers were washed with H2O (10 mL) and brine and then dried over MgSO4. The filtrate was concentrated and purified by medium pressure column chromatography (10% EtOH in hexane, silica gel, Rf 0.20) to give the title compound as a clear, pale yellow liquid (1.49 g, 65% yield). The 1H and 13C NMR spectral data were consistent with the proposed structure.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].Cl[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[O:36][CH3:37].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:23]=[CH:22][C:6]2[N:7]([CH2:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][C:27]=3[O:36][CH3:37])[C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2]
Reactant: C[C@@H]1Nc2cc(C#N)ccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: COc1ccc2ccccc2c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)Nc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
To a rt solution of tert-butyl(3S,4S)-7-cyano-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (406 mg, 1.28 mmol) in DMF (3.21 ml) was added 1-(chloromethyl)-2-methoxynaphthalene (318 mg, 1.54 mmol) and cesium carbonate (1.25 g, 3.85 mmol). The reaction was stirred at rt for 16 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(3S,4S)-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (448 mg, 72%) as an off-white solid. MS m/z 509 (MNa)+.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-:5]C(C)C)C.[F:9][C:10]([F:17])([F:16])[C:11]([O:13]CC)=O.C(#N)C>C1COCC1>[F:17][C:10]([F:9])([F:16])[C:11](=[O:13])[CH2:2][C:3]#[N:5]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC#N
Product: N#CCC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 56.7 %

Procedure:
To a cooled (−78° C.) solution of LDA (2M, 15 g, 39 mmol) in anhydrous THF (50 mL) was added drop-wise a solution of ethyl trifluoroacetate (2.5 g, 18 mmol) and acetonitrile (1.4 g, 35 mmol) in 15 ml THF. The reaction was kept at −78° C. for 45 min, warmed up to room temperature over 1 hour period and quenched with ice water. The reaction was concentrated under vacuum, the residue extracted with ethyl ether, the pH brought to 1 with concentrated HCl, extracted with dichloromethane. The aqueous solution was extracted with ethyl ether, the combined organic layers dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to afford 1.4 g of 4,4,4-trifluoro-3-oxobutanenitrile as a yellow oil, which was used as such in the next step.
Reaction SMILES: [C-:1]#[N:2].[Na+].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17](Br)[CH3:18])=[CH:13][CH:12]=1)=[O:10]>CS(C)=O>[C:5]1([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:18])[C:1]#[N:2])=[CH:13][CH:12]=2)=[O:10])[S:4][CH:8]=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: CC(Br)c1ccc(C(=O)c2cccs2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C#N)c1ccc(C(=O)c2cccs2)cc1
Temperature: 60 °C

Procedure:
A suspension of 4.9 parts of sodium cyanide in 55 parts of dimethyl sulfoxide is stirred while heating to 60° C. Then there are added at once 10 parts of α-bromo-α-methyl-p-tolyl 2-thienyl ketone and stirring at 60° C is continued for 4h.30. The reaction mixture is poured onto water and the products ae extracted with ether. The organic layer is washed with water, dried, filtered and evaporated, yielding p-(2-thenoyl)hydratroponitrile as a residue.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[C:21]([C:23]4O[C:25]([CH3:28])=[N:26][N:27]=4)[CH:20]=[CH:19][C:18]=3[CH3:29])[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.[CH2:30]([CH2:32][NH2:33])[OH:31]>CS(C)=O>[OH:31][CH2:30][CH2:32][NH:33][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[C:21]([C:23]4[N:33]([CH2:32][CH2:30][OH:31])[C:25]([CH3:28])=[N:26][N:27]=4)[CH:20]=[CH:19][C:18]=3[CH3:29])[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5]
Reactant: NCCO
Reactant: CCOC(=O)c1cncc2c(COc3cc(-c4nnc(C)o4)ccc3C)csc12
Solvent: CS(C)=O
Product: Cc1ccc(-c2nnc(C)n2CCO)cc1OCc1csc2c(C(=O)NCCO)cncc12
Temperature: 160 °C

Procedure:
A mixture of 3-[2-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester and 3-[2-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid methyl ester (0.08 g, 0.20 mmol) (from Example 36 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160° C. for 2 hours in a microwave reactor. The reaction mixture was purified by C18 column chromatography eluting with acetonitrile/water to give 3-{5-[4-(2-hydroxy-ethyl)-5-methyl-4H-[1,2,4]triazol-3-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white solid. (Yield: 37.0 mg, 39%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]2[O:22][C:21]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:20]=3[O:19][CH2:18]2)[CH2:12][CH2:11]1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[S:36](Cl)(=[O:38])=[O:37]>ClCCl>[Cl:27][C:24]1[CH:25]=[CH:26][C:20]2[O:19][CH2:18][C@H:17]([CH2:16][N:13]3[CH2:14][CH2:15][CH:10]([CH2:9][NH:8][S:36]([C:30]4[C:31]([F:35])=[CH:32][CH:33]=[CH:34][C:29]=4[F:28])(=[O:38])=[O:37])[CH2:11][CH2:12]3)[O:22][C:21]=2[CH:23]=1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: NCC1CCN(C[C@H]2COc3ccc(Cl)cc3O2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCC1CCN(C[C@H]2COc3ccc(Cl)cc3O2)CC1)c1c(F)cccc1F
Reaction time: 20 h
Yield: 41.4 %

Procedure:
Triethylamine (0.62 ml) was added to a solution of (S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)piperidine (0.44 g) and 2,6-difluorobenzene-sulphonyl chloride (0.62 g) in dichloromethane (22 ml), under nitrogen, and stirred for 20 hours. The reaction was diluted with dichloromethane (100 ml), washed with water (100 ml) and brine (100 ml), dried over anhydrous magnesium sulphate and concentrated under reduced pressure to afford an orange oil. Purification by flash chromatography on silica gel eluting with a 20:1 mixture of dichloromethane and methanol gave an orange gum. Trituration with petroleum ether (b.p. 40-60° C.) yielded (S)-(-)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,6-difluorobenzenesulphonamide as an off-white solid (0.29 g); m.p. 122-124° C., [α]D22.5 -22.1° (c=1.0, CH2Cl2).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:26][O:27][NH:28][CH3:29].O>C1COCC1>[CH3:26][O:27][N:28]([CH3:29])[C:10]([C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1)=[O:12]
Reactant: CNOC
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred brown solution of 1H-indole-6-carboxylic acid (2.68 g, 16.6 mmol) in THF (25 mL) was added CDI (2.97 g, 18.3 mmol) and stirred at room temperature for 2 hours. The mixture was then cooled to 0° C. and O,N-dimethyl-hydroxylamine hydrochloride (1.95 g, 20.0 mmol) was added and stirred at room temperature over night. Water (50 mL) was added to the reaction and extracted with EtOAc (2×100 mL). The combined organic phases were washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo to give 1H-indole-6-carboxylic acid methoxy-methyl-amide as an oil (3.87 g, 114% crude yield): 1H NMR (CDCl3) δ 3.40 (s, 3H, NCH3), 3.59 (s, 3H, OCH3), 6.57-6.59 (m, 1H, Ar), 7.31-7.33 (m, 1H, Ar), 7.46-7.50 (m, 1H, Ar), 7.64 (d, J=8 Hz, 1H, Ar), 7.84 (s, 1H, Ar), 8.60 (brs, 1H, NH). The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[CH:5][C:4]([C:10]([OH:12])=O)=[CH:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:46][C:47]1[CH:48]=[C:49]2[C:53](=[CH:54][C:55]=1[NH:56][C@@H:57]([CH3:61])[CH2:58][O:59][CH3:60])[N:52]([CH3:62])[C:51](=[O:63])[C:50]2([CH3:65])[CH3:64]>CN1C(=O)CCC1>[CH3:60][O:59][CH2:58][C@@H:57]([NH:56][C:55]1[CH:54]=[C:53]2[C:49]([C:50]([CH3:65])([CH3:64])[C:51](=[O:63])[N:52]2[CH3:62])=[CH:48][C:47]=1[NH:46][C:10]([C:4]1[CH:5]=[C:6]([CH3:9])[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)=[O:12])[CH3:61]
Reactant: COC[C@H](C)Nc1cc2c(cc1N)C(C)(C)C(=O)N2C
Reactant: Cc1cc(C(=O)O)cn(C)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC[C@H](C)Nc1cc2c(cc1NC(=O)c1cc(C)c(=O)n(C)c1)C(C)(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid D1 (47 mg; 0.28 mmol), is dissolved in NMP (500 μl) and DIPEA (135 μl; 0.85 mmol) and HATU (111 mg; 0.29 mmol) is added. The reaction mixture is stirred at ambient temperature for 15 min. 5-Amino-6-((S)-2-methoxy-1-methyl-ethylamino)-1,3,3-trimethyl-1,3-dihydro-indol-2-one E-1.1 (85 mg; 0.31 mmol) dissolved in NMP (500 μl) is added and stirring is continued for 12 h at ambient temperature. The reaction mixture is poured on water and extracted with DCM once. The organic phase is dried with MgSO4 and concentrated under reduced pressure.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][C:9]1([CH3:16])[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[O:10]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[CH3:8][C:9]1([CH3:16])[C:13](=[O:14])[CH:12]=[C:11]([CH:15]=[CH:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[O:10]1
Reactant: O=Cc1cccs1
Reactant: CC1=CC(=O)C(C)(C)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2cccs2)=CC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
To a solution of 2-thiophenecarboxaldehyde (2.1 g, 19 mM) and 2,2,5-trimethyl-3(2H)-furanone (2.0 g, 15.9 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.6 mL, 1.6 mM). The reaction solution was stirred at room temperature for one day. After saturated aqueous sodium chloride (400 mL) was added, the aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a yellow solid. The product was recrystallized from hexane to afford a yellow crystalline solid (1.5 g, 43% yield), m.p. 75°-77° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14]>C(N(CC)CC)C.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:14]
Reactant: Nc1ccccc1
Reactant: COc1cccc(C(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)Nc2ccccc2)c1
Yield: 94.6 %

Procedure:
A solution of 13.4 mL (147 mmol) of aniline in 30.7 mL of triethylamine was slowly added to a solution containing 25.1 g (147 mmol) of 3-methoxybenzoyl chloride in methylene chloride. The resulting reaction mixture was reacted for approximately thirty minutes and then diluted with 1N sodium bicarbonate. The resultant layers were separated and the organic layer was washed sequentially with water, 1M sodium hydroxide and then brine, dried over sodium sulfate, filtered and then reduced to dryness under reduced pressure to provide 31.6 g of an off-white solid. Yield: 95%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[CH:30]=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([Br:28])[CH:30]=2)[C:19]2[N:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][N:24]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Reactant: BrCc1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2cccc(Br)c2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
2-[(4-{2-[(5-Ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (5.5 g) synthesized in Example 265-1 and 1-bromo-3-(bromomethyl)benzene (4.04 g) were dissolved in N,N-dimethylformamide (55 mL), potassium tert-butoxide (1.82 g) was added thereto, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1) to give the title compound (6.3 g) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]([C:10]1[CH:15]=[CH:14][N:13]=[N:12][CH:11]=1)[CH2:3]P(=O)(OC)OC.C(N(CC)CC)C.[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C1COCC1>[Br:23][C:24]1[CH:31]=[CH:30][C:27](/[CH:28]=[CH:3]/[C:2]([C:10]2[CH:15]=[CH:14][N:13]=[N:12][CH:11]=2)=[O:1])=[CH:26][CH:25]=1
Reactant: COP(=O)(CC(=O)c1ccnnc1)OC
Reactant: O=Cc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(Br)cc1)c1ccnnc1
Yield: 7 %

Procedure:
To a solution of dimethyl 2-oxo-2-(pyridazin-4-yl)ethylphosphonate (1.83 g, 7.95 mmol) in THF (18 mL) was added triethylamine (885 mg, 8.75 mmol) and 4-bromobenzaldehyde (1.49 g, 7.95 mmol) at 0° C. After 6 h the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. The residue was suspended in ethyl acetate and the title compound (824 mg, 36%) collected by filtration. Chromatography of the mother liquor (SiO2; ethyl acetate) produced a second crop of product (160 mg, 7%). Light yellow solid, MS: 288.9 [M+H]+.