Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[NH:11][CH2:12][C:13]1[S:17][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:15][CH:14]=1.[CH:25]1([CH2:28][NH2:29])[CH2:27][CH2:26]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH:25]1([CH2:28][NH:29][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]([NH:11][CH2:12][C:13]3[S:17][C:16]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[N:15][CH:14]=3)[CH:4]=2)[CH2:27][CH2:26]1
Reactant: O=C(O)c1ccc(F)c(NCc2cnc(Nc3ccccn3)s2)c1
Reactant: NCC1CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCC1CC1)c1ccc(F)c(NCc2cnc(Nc3ccccn3)s2)c1
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 4-fluoro-3-{[2-(pyridin-2-ylamino)-thiazol-5-ylmethyl]-amino}-benzoic acid (35 mg, 0.10 mmol) in DMF (1 mL) at RT, cyclopropylmethyl amine (14 mg 0.20 mmol) was added followed by the addition of BOP reagent (53 mg, 0.12 mmol). The above reaction mixture was stirred for 2 h, diluted with EtOAc (10 mL), washed with 10% NaHCO3 (3×5 mL), and 10% LiCl (5 mL). The organic layer was dried over Na2SO4, concentrated and the residue was purified by preparative HPLC to give the title compound as a off-white solid (33 mg, 83%). (M+H)+=398.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1>P(Cl)(Cl)(Cl)=O.C(OCC)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1
Reactant: C1=COCCC1
Reactant: OCCCCCBr
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: BrCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 36 g of 5-bromopentan-1-ol were added 24.72 ml of 2,3-dihydropyran and 3 drops of phosphorus oxychloride under cooling in an ice bath, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with diethyl ether, washed with 5% aqueous potassium hydroxide, water, a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (1:19) as eluent to give 49.5 g of the subtitle compound having the following physical characteristics:
Reaction SMILES: [Br:1][C:2]([OH:12])([CH3:11])[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>>[Br:1][C:2]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])([CH3:11])[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1
Reactant: CC(O)(Br)CCC1CCC(=O)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CC(Br)(CCC1CCC(=O)N1)O[Si](C)(C)C(C)(C)C
Yield: 98.4 %

Procedure:
Analogous to the procedure described for Compound 1A, Step C, 5-(3-bromo-3-hydroxy-butyl)-pyrrolidin-2-one (6.76 g, 21.6 mmol) was reacted with tert-butyldimethylsilyl chloride (3.59 g, 23.8 mmol). Purification by medium pressure chromatography using a solvent gradient (CH2Cl2 to 1% MeOH in CH2Cl2 to 3% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2 to 8% MeOH in CH2Cl2) provided 5-[3-bromo-3-(tert-butyl-dimethyl-silanyloxy)-butyl]-pyrrolidin-2-one (7.45 g). 1H NMR (CDCl3) δ 7.30 (m, 2H), 7.12 (m, 1H), 7.04 (m, 1H), 5.71 (m, 1H), 3.81 (m, 1H), 3.56 (m, 1H), 2.66 (m, 2H), 2.32-2.17 (m, 3H), 1.70-1.35 (m, 5H), 0.82 (s, 9H), −0.06 (d, 3H), −0.24 (d, 3H); MS 426.2, 428.2 (M+).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][C:13]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:8][CH:7]=1.[OH-].[K+]>CO.C1COCC1>[C:23]1([C:13]2[CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:12]=2[C:9]2[CH:8]=[CH:7][C:6]([CH:5]=[CH:4][C:3]([OH:29])=[O:2])=[CH:11][CH:10]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of ester (2d) (4.2 g, 11.0 mmol) in methanol (370 mL) and THF (225 mL) was added 1N KOH (188 mL). After stirring overnight the mixture was heated to 50° C. for 0.5 h and was allowed to cool to rt. After stirring 2 h the solvent was partially removed under reduced pressure, the mixture was acidified with 1N HCl, and was extracted with EtOAc. The combined organic layers were washed with water, brine and were dried (MgSO4). The solvent was removed under reduced pressure and the residue was triturated (EtOAc) to give the acid (2e) as a white solid (3.86 g, 96%): 1H NMR (CD3OD) δ 7.54 (d, J=15.7 Hz, 1H), 6.28 (d, J=8.1 Hz, 2H), 7.27-7.08 (m, 8H), 6.89 (d, J=8.1 Hz, 2H), 6.76 (dd, J=7.3, 1.1 Hz, 1H), 6.34 (d, J=15.7 Hz, 1H), 2.83 (t, J=7.0 Hz, 2H), 2.37 (t, J=7.0 Hz, 2H), 2.14 (m, 2H); ESI m/z: 365 (M−H−, 100%).
Reaction SMILES: [CH2:1]([O:5][N:6]=[C:7]([C:13](=[O:15])[CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:19])(=O)=O.C(O)(=O)C>O>[CH2:1]([O:5][N:6]=[C:7]([C:13](=[O:15])[CH2:14][Cl:19])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCON=C(C(C)=O)C(=O)OCC
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: CCCCON=C(C(=O)CCl)C(=O)OCC
Yield: 92 %

Procedure:
A solution of ethyl 2-n-butoxyimino-3-oxobutyrate (syn isomer, 48.8 g.), sulfuryl chloride (31.5 g.) and acetic acid (48.8 ml.) was stirred at 40° C. for 10 minutes and further at room temperature for 5.5 hours. After water (300 ml.) was added to the resultant solution under ice cooling, the solution was extracted with methylene chloride three times. The extract was washed with water, an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, and dried over magnesium sulfate. The solution was concentrated in vacuo to give ethyl 2-n-butoxyimino-4-chloro-3-oxobutyrate (syn isomer, 52.1 g.), oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:23]=[N:22][C:10]3[S:11][CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[C:9]=3[CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:14]1[CH2:13][CH2:12][S:11][C:10]2[N:22]=[CH:23][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:8][C:9]1=2
Reactant: CC(C)(C)OC(=O)N1CCSc2ncc(N3CCOCC3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1nc2c(cc1N1CCOCC1)NCCS2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl 7-morpholino-2,3-dihydro-1H-pyrido[2,3-b]-[1,4]thiazine-1-carboxylate (280 mg, 0.83 mmol) in DCM (2.0 mL) was added TFA (3.2 mL, 41.5 mmol). The reaction was stirred at rt for 2 h and evaporated in vacuo. The resulting residue was dissolved in DCM (40 mL) and washed with NaHCO3 (20 mL, saturated aqueous solution). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo to give 4-(2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl)morpholine as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.62 (1H, d, J=2.5 Hz), 6.26 (1H, d, J=2.5 Hz), 3.82-3.87 (4H, m), 3.59-3.63 (2H, m), 3.13-3.17 (2H, m), 3.06-3.10 (4H, m). Mass Spectrum (ESI) m/e=238.2 (M+1).
Reaction SMILES: [NH2:1][CH:2]([CH2:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=1)[CH:3]([OH:18])[CH2:4][NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C.[C:35]1(=[O:42])[O:41][C:39](=[O:40])[CH2:38][CH2:37][CH2:36]1>C(Cl)(Cl)Cl>[F:27][C:22]1[CH:21]=[C:20]([CH:25]=[C:24]([F:26])[CH:23]=1)[CH2:19][C@H:2]([NH:1][C:35](=[O:42])[CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])[C@H:3]([OH:18])[CH2:4][NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: O=C1CCCC(=O)O1
Reactant: CCc1ccc2c(c1)C(NCC(O)C(N)Cc1cc(F)cc(F)c1)CCC2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1ccc2c(c1)[C@@H](NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)CCCC(=O)O)CCC2
Temperature: 60 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of 3-amino-4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-butan-2-ol (0.240 g, 0.64 mmol), triethylamine (0.268 mL, 1.92 mmol), and chloroform (3 mL) was added glutaric anhydride (0.073 g, 0.64 mmol) and reaction was stirred overnight at 60° C. Reaction was washed with 1N HCl, 10% NaHCO3, brine, dried over MgSO4, filtered, concentrated in vacuo to give 5-[((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-7-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-hydroxypropyl)amino]-5-oxopentanoic acid (100 mg). Purified via prep-HPLC. 1H NMR (400 MHz, CD3OD) δ 1.26 (t, J=8 Hz, 3H), 1.73 (m, 2H), 1.89 (m, 1H), 2.01 (m, 1H), 2.17 (m, 6H), 2.68 (d, J=8 Hz, 2H), 2.93 (d, J=6 Hz, 1H), 3.02 (m, 1H), 3.30 (m, 2H), 3.88 (m, 1H), 4.09 (m, 1H), 4.57 (m, 1H), 6.79 (m, 1H), 6.88 (m, 3H), 6.93 (d, J=6 Hz, 1H), 7.20 (m, 2H), 7.31 (s, 1H); OAMS: ES+ 488.9 ES− 486.9
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH3:10])[CH:3]=1
Reactant: CCC(=O)c1cccc(Br)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 18.7 %

Procedure:
To a solution of 1-(3-bromophenyl)propan-1-one (2.00 g, 9.39 mmol) in 10 mL TFA, was added triethylsilane (4.50 mL, 28.2 mmol). The mixture was stirred at rt for 20 h, then concentrated. The crude material was purified by flash chromatography to afford 350 mg of Intermediate 214.1 as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][N:3]=1.[NH:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CCOC(C)=O>[N:13]1([C:2]2[C:6]3[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=3[O:4][N:3]=2)[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: C1CNCCNC1
Reactant: COc1ccc2c(Cl)noc2c1
Solvent: CCOC(C)=O
Product: COc1ccc2c(N3CCCNCC3)noc2c1
Temperature: 140 °C
Reaction time: 0.75 h

Procedure:
3-Chloro-6-methoxy-1,2-benzisoxazole (5.0 g, 27.2 mml) and homopiperazine (8.2 g, 81.6 mmol) were combined and mechanically stirred under N2 at 140° C. for 45 minutes. The reaction mixture was cooled to room temperature, dissolved with EtOAc (500 ml), and the solution was washed with water, brine, dried over MgSO4, and concentrated in vacuo. Flash column chromatography (silica gel, 20% MeOH/CH2Cl2) provided the product (2.0 g, m.p. 74-75° C.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5][CH2:4]1)[CH3:2].O.NN>[Pd].C(O)C>[CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCCOc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CCN1CCCOc2ccc(N)cc21
Reaction time: 4 h

Procedure:
9-Ethyl-2-nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (486 mg, 2.19), 10% Palladium on Carbon (50% Wet) (302 mg) and Hydrazine monohydrate (1.00 g, 20.0 mmol) in Ethanol (20 mL) was heated at 60° C. After 4 h, the mixture was filtered and conc. in vacuo. After azeotroping with toluene and drying, 9-Ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-ylamine was isolated in quantitative yield.
Reaction SMILES: Cl.[OH:2][C:3]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:28])([CH3:27])[C:22]([O:24]CC)=[O:23])=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5]1.[OH-].[Na+]>CO>[OH:2][C:3]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:28])([CH3:27])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C(=O)O)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
A mixture of 1 g of ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate hydrochloride, 25 ml of methanol and 5 ml of 25% sodium hydroxide solution is stirred and refluxed for 2 hours then concentrated to a solid, neutralized with dilute hydrochloric acid and extracted with hot toluene. The toluene extract is filtered and concentrated to a residue which is recrystallized from chloroform/toluene to give 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetic acid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]([C@H:10]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][N:11]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=O.B.C1COCC1.C1COCC1>CO>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[CH2:8][C@H:10]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:13][CH2:12][N:11]1[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24]
Reactant: C[C@H]1COCCN1C(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 15 h
Yield: 101.4 %

Procedure:
A 250-mL round-bottomed flask was charged with di-tert-butyl (2R)-2-(((3S)-3-methyl-4-morpholinyl)carbonyl)-1,4-piperazinedicarboxylate (2.55 g, 6.17 mmol, step 1), BH3.THF (1.0 M in THF, 19.0 mL, 19.0 mmol, Sigma-Aldrich, St. Louis, Mo.) and THF (100 mL). The mixture was stirred at 50° C. for 15 h. The mixture was allowed to cool to room temperature and then additional BH3.THF complex (1.0 M in THF, 5.0 mL, 5.0 mmol) was added. The reaction mixture was heated at 50° C. for 1 h. The mixture was allowed to cool to room temperature and then MeOH was added slowly until bubbling ceased. The reaction mixture was concentrated to give di-tert-butyl (2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1,4-piperazinedicarboxylate (2.5 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:38]1[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[N:43]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:34])[CH3:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:38]4[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[N:43]=4)=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Reactant: Cn1nc(Cl)ccc1=O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 6-chloro-2-methylpyridazin-3(2H)-one following a procedure analogous to that described in Example 1 Step 3. LC-MS Method 2 tR=1.179 min, m/z=422.1; 1H NMR (CDCl3) 1.08 (d, 6H), 1.49 (d, 3H), 2.10 (s, 3H), 2.18 (m, 1H), 2.32-2.41 (m, 1H), 2.83 (m, 1H), 3.79 (s, 3H), 5.63 (m, 1H), 6.90-7.03 (m, 5H), 7.23 (m, 2H), 7.46-7.59 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br.Br[CH2:18][C:19]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][N:22]=1)=[O:20]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:18]=1[C:19]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][N:22]=1)=[O:20]
Reactant: O=C(CBr)c1cc(Cl)ccn1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Agent: Br
Product: CCOC(=O)n1c(C(=O)c2cc(Cl)ccn2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-[(ethoxycarbonyl)amino]benzonitrile (Example 1, step 1) and 2-(bromoacetyl)4-chloropyridine hydrobromide*.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:10]([NH2:11])[CH2:9][CH2:8][O:7][CH2:6]1)=[O:4].Cl.[CH3:13][C:14]1[CH:23]=[C:22]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]([CH:5]1[CH:10]([NH:11][S:32]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:24][C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:14]([CH3:13])[CH:23]=3)=[CH:27][CH:28]=2)(=[O:33])=[O:34])[CH2:9][CH2:8][O:7][CH2:6]1)=[O:4]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Reactant: COC(=O)C1COCCC1N
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1COCCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
To a mixture of 0.5 g (2.79 mmol) of 4-amino-tetrahydro-pyran-3-carboxylic acid methyl ester [WO 01/70673, Example 207] and 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride (1.0 g, 2.94 mmol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (1.02 mL, 5.88 mmol) at 0° C. The solution was allowed to warm to 25° C. over 19 h. The DMF was removed in vacuo and the resulting solid was partitioned between ethyl acetate (100 mL) and water (30 mL). The aqueous layer was washed with ethyl acetate (2×50 mL). ). The organic layer was dried over MgSO4, filtered and concentrated to obtain a crude oil (1.48 g). The crude product was purified by Biotage Flash 40M chromatography, eluting with 1:4 ethyl acetate-hexanes, to afford 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylic acid methyl ester as a white solid (1.08 g, 78%). MS: 471 (M+H)+
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21](=[O:23])[NH2:22])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:28]1([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)[CH2:30][CH2:29]1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:24][C:25](=[O:27])[N:31]([CH:28]2[CH2:30][CH2:29]2)[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([NH2:22])=[O:23])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccccc2C(N)=O)cc1
Reactant: Cc1cccc(CNC2CC2)c1
Product: Cc1cccc(CN(C(=O)CN(c2ccccc2C(N)=O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)C2CC2)c1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(2-carbamoyl-phenyl)-amino]-acetic acid with cyclopropyl-(3-methyl-benzyl)-amine
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:8]([CH3:20])[CH:7]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>O1CCCC1>[CH3:1][N:2]([CH3:21])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:29](=[O:31])[CH3:30])[S:13]([C:16]([F:19])([F:17])[F:18])(=[O:15])=[O:14])=[C:8]([CH3:20])[CH:7]=1)(=[O:4])=[O:5]
Reactant: Cc1cc(S(=O)(=O)N(C)C)ccc1NS(=O)(=O)C(F)(F)F
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N(c1ccc(S(=O)(=O)N(C)C)cc1C)S(=O)(=O)C(F)(F)F
Yield: 76.7 %

Procedure:
To a solution of N,N-dimethyl-3-methyl-4-(trifluoromethanesulfonamido)benzenesulfonamide (1.5 g) and triethylamine (0.65 g) in tetrahydrofuran (40 ml), acetyl chloride (0.51 g) was added, and the resultant mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and solidified with water. The solidified product was recrystallized from a mixture of ethanol and toluene to give 1.29 g of N,N-dimethyl-3-methyl-4-(N-acetyl-N-trifluoromethanesulfonylamino)benzenesulfonamide (Compound No. 86). M.P., 148°-148.5° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5](=O)[CH2:6][CH3:7])[CH3:4].F[B-](F)(F)F.[NH:14]=[C:15](SC)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH2:6]([C:5]1[NH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:2][C:3]=1[CH3:4])[CH3:7]
Reactant: CCC(=O)C(C)N
Reactant: CCOC(=O)C(=N)SC
Agent: Cl
Agent: F[B-](F)(F)F
Product: CCOC(=O)c1nc(C)c(CC)[nH]1
Yield: 60 %

Procedure:
The same operation as in Example (lb) was performed using 2-amino-pentan-3-one hydrochloride obtained in Example (15c) (about 10 mmol) and ethyl imino(methylthio)acetate tetrafluoroborate obtained according to a method known in the literature (J. Med. Chem., 38, 1995, 2196-2201) (about 10 mmol), to obtain 1.1 g of the title compound as a yellow solid (60%).
Reaction SMILES: N#N.[Br:3][C:4]1[S:5][C:6]([C:9](=[O:11])[CH3:10])=[CH:7][N:8]=1.[CH2:12](O)[CH2:13][OH:14].COC(OC)OC>C([O-])(O)=O.[Na+]>[Br:3][C:4]1[S:5][C:6]([C:9]2([CH3:10])[O:14][CH2:13][CH2:12][O:11]2)=[CH:7][N:8]=1
Reactant: OCCO
Reactant: CC(=O)c1cnc(Br)s1
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(OC)OC
Product: CC1(c2cnc(Br)s2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a condenser under inert atmosphere (N2), a solution of 1-(2-bromo-thiazol-5-yl)-ethanone (2.20 g, 10.68 mmol) in ethylene glycol (11.46 mL, 205.53 mmol) was treated with trimethylorthoformate (2.39 mL, 21.76 mmol) followed by LiBF4 (204 mg, 2.14 mmol). The reaction mixture was heated at 95° C. for 2 days. Sat. aq. NaHCO3 (50 mL) was added and the mixture was extracted with EA (50 mL). The org. extracts were washed with brine (2×50 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1 to 3:1 hept-EA) gave the title compound as a yellow oil. TLC:rf (1:1 hept-EA)=0.80. LC-MS-conditions 01: tR=0.84 min; [M+H]+=251.85.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([CH:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:26](O)=[O:27])=[C:13]([C:15]2[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=2[F:25])[N:14]=1)=[O:8].CN.O.O[N:35]1[C:39]2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([CH:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:26]([NH:35][CH3:39])=[O:27])=[C:13]([C:15]2[C:16]([F:25])=[C:17]([F:24])[C:18]([F:23])=[C:19]([F:22])[C:20]=2[F:21])[N:14]=1)=[O:8]
Reactant: On1nnc2ccccc21
Reactant: O=C(Nc1nc(-c2c(F)c(F)c(F)c(F)c2F)c(C(=O)O)s1)c1cc(Br)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1sc(NC(=O)c2cc(Br)ccc2O)nc1-c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.1 %

Procedure:
A mixture of 2-(5-bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)-thiazole-5-carboxylic acid (0.20 g, 0.48 mmol), methylamine 40% methanol solution (0.2 ml), 1-hydroxybenzotriazole hydrate (96.7 mg, 0.72 mmol), WSC.HCl (137.2 mg, 0.72 mmol) and tetrahydrofuran (15 mL) was stirred at room temperature for 18 hours. The reaction mixture was poured into 2 N hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=1:2), and crystallized (dichloromethane/n-hexane) to give the title compound (87.9 mg, 42.6%) as a white powder.