Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(OC([NH:9][C@@H:10]([CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=1)[C:11]([N:13]1[CH2:18][CH2:17][C:16]2([CH2:23][C:22](=[O:24])[C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[O:19]2)[CH2:15][CH2:14]1)=[O:12])=O)(C)(C)C.C(N(CC)CC)C.[CH:47](=O)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.S([O-])([O-])(=O)=O.[Mg+2].C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.O.ClCCl>[ClH:38].[CH2:47]([NH:9][C@@H:10]([CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=1)[C:11]([N:13]1[CH2:14][CH2:15][C:16]2([CH2:23][C:22](=[O:24])[C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[O:19]2)[CH2:17][CH2:18]1)=[O:12])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccc(Cl)c(Cl)c1)C(=O)N1CCC2(CC1)CC(=O)c1ccccc1O2
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C1CC2(CCN(C(=O)[C@H](COCc3ccc(Cl)c(Cl)c3)NCc3ccccc3)CC2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.3 %

Procedure:
Methanolic hydrogen chloride (4M, 2 mL) was added to a stirred, cooled (0° C.) solution of (S)-1'-[2-t-butoxycarbonylamino-3-(3,4-dichlorobenzyloxy)propionyl]spiro[2H-1-benzopyran-2,4'-piperidine]-4-(3H)-one (243 mg, 0.43 mmol) in methanol (2 mL) and the mixture was stirred at room temperature for 5 h. The solvent was evaporated under reduced pressure, dichloromethane (5 mL), triethylamine (0.120 mL, 87 mg, 0.86 mmol), benzaldehyde (0.052 mL, 55 mg, 0.52 mmol) and magnesium sulfate (300 mg) were added. The mixture was stirred at room temperature for 4 h., filtered and the solvent was evaporated under reduced pressure. Methanol (5 mL) and sodium cyanoborohydride (54 mg, 0.86 mmol) were added. The mixture was stirred at room temperature for 1 h., aqueous sodium hydrogen carbonate (saturated, 20 mL) and water (10 mL) were added and the mixture was extracted with dichloromethane (3×20 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. Methanol (25 mL) was added and the volume was reduced to 10 mL by distillation. The remaining solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH/NH3 (Aq.) (99:1:0.1 increasing to 97:3:0.3). The residue was dissolved in methanol (5 mL), cooled to 0° C. and methanolic hydrogen chloride (1M, 0.23 mL) was added. The solvent was evaporated under reduced pressure and the residue was triturated with ether (5 mL). The solid was collected and dried in vacuo to give the title compound as a colorless solid (126 mg, 50%), mp. 173°-175° C. Found: C, 59.92; H, 5.14; N, 4.32. C30H30Cl2N2O4.HCl.0.5H2O requires: C, 60.16; H, 5.39; N, 4.68%. m/e (ES+) 553 (MH+).
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.[CH2:23]([O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH:34]=[O:35])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCOC(C)=O.C1COCC1>[Cl:16][C:17]1[C:22]([CH:34]([C:33]2[CH:36]=[CH:37][CH:38]=[C:31]([O:30][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:32]=2)[OH:35])=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: Clc1cnccn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl
Temperature: 0 °C

Procedure:
A THF (20 mL) solution of 2M n-BuLi in cyclohexanes was cooled to −78° C. and charged with 2,2,6,6-tetramethylpiperidine (1.8 mL, 10.48 mmol). The reaction vessel was removed from the cooling bath and allowed to warm to 0° C. for 15 min, then cooled back to −78° C. and charged with 2-chloropyrazine (1.0 g, 8.73 mmol) dropwise. The reaction was allowed to react for 15 min, and charged with a 10.0 mL THF solution of 3-benzyloxybenzaldehyde (2.0 g, 9.60 mmol) slowly at −78° C. The reaction was allowed to react for 2 h (TLC analysis (30% EtOAc:Hex)) and quenched with HClconc. (2.0 mL), and H2O (30.0 mL). The crude product was extracted from the aqueous/THF layer 4× with CH2Cl2. The organic layers were combined and washed 1× with H2O, 1×brine, dried over Na2SO4 and concentrated in vacuo, to yield the crude product as a brown oil. High performance flash chromatography (HPFC) with a 70 g Jones silica gel column (30% EtOAc:Hex) was applied to yield the desired product as a pale yellow solid; 1H NMR (CDCl3, 400 MHz) δ 5.01 (s, 3H), 6.00 (s, 2H), 6.90-6.96 (m, 3H), 7.23-7.41 (m, 6H), 8.36 (d, 1H, J=2.4 Hz), 8.54 (d, 1H, J=2.5 Hz); MS (ES) 327.16 (M+1), 329.16 (M+3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([C@:8]2([CH3:14])[CH2:12][O:11]C(=O)[NH:9]2)[CH:7]=1.C(O)C.O.[OH-].[Li+]>O>[NH2:9][C@@:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:15])([CH3:14])[CH2:12][OH:11]
Reactant: C[C@@]1(c2cc(Br)ccc2F)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@](N)(CO)c1cc(Br)ccc1F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of the (R)-4-(5-bromo-2-fluoro-phenyl)-4-methyl-oxazolidin-2-one (8.94 g, 33 mmol) in a 1:1-mixture of ethanol and water (120 ml) was treated with lithium hydroxide monohydrate (6.85 g, 163 mmol) and the reaction mixture was stirred at 100° C. overnight. For the workup, the reaction mixture was evaporated at reduced pressure and the residue dissolved in ethyl acetate (90 ml), then extracted with hydrochloric acid (2N, 90 ml). The aqueous layer was treated with a solution of sodium hydroxide (2N, 100 ml) and solid sodium chloride was added until saturation. The following extraction with ethyl acetate (3×200 ml) and the evaporation of the combined organic layers after drying over sodium sulphate yielded the (R)-2-amino-2-(5-bromo-2-fluoro-phenyl)-propan-1-ol as a white crystalline solid (7.90 g, 98% of theory, e.e.>98%).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[C:4]([CH3:11])[C:3]=1[CH3:12].C([Li])(C)(C)C.FC(F)(F)S(O[C:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])(=O)=O.C(OCC)C>O1CCCC1.CCCCC.[Cl-].[Zn+2].[Cl-].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:10][O:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([C:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:3]([CH3:12])[C:4]=1[CH3:11]
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCCC1
Reactant: COc1cc(C)c(Br)c(C)c1C
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCOC(=O)C1=C(c2c(C)cc(OC)c(C)c2C)CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-bromo-4-methoxy-2,3,6-trimethylbenzene in anhydrous tetrahydrofuran at -78° C. is added 1.7M tert-butyllithium in pentane, followed by the addition of zinc chloride, 0.5M in tetrahydrofuran. The mixture is allowed to warm to room temperature, tetrakis (triphenylphosphine) palladium(0) and ethyl 2-trifluoromethanesulfonyloxycyclohexen-1-ylcarboxylate in tetrahydrofuran is added and the resulting solution is stirred for 2 hours at the reflux temperature of the solvent. The reaction is cooled to room temperature, 50 ml of diethyl ether is added and the layers are separated. The organic layer is washed with water, aqueous sodium bicarbonate, saturated sodium chloride, and dried over sodium sulfate. Evaporation of the solution, followed by chromatography (silica gel: hexane/diethyl ether 4:1) gives 2-(4-methoxy-2,3,6-trimethylphenyl)-1-cyclohexene-1-carboxylic acid, ethyl ester.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[Na+].[CH2:12]([O:19][C:20](=[O:23])[CH2:21]Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH4+].[Cl-]>CN(C=O)C>[CH2:12]([O:19][C:20](=[O:23])[CH2:21][N:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: c1cc2cc[nH]c2cn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(Cn1ccc2ccncc21)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
To a stirred solution of 1H-pyrrolo[2,3-c]pyridine (1 g, 8.46 mmol) in DMF (10 mL) under nitrogen atmosphere NaH (0.504 g, 12.6 mmol) is added in portions at ice-cold conditions. The reaction mixture is allowed to stir for 30 min at room temperature. It is then cooled in an ice-bath and bromoacetic acid benzyl ester (1.46 mL, 9.31 mmol) in DMF (10 mL) is added dropwise. The reaction mixture is stirred at room temperature for 5 h. Saturated aqueous NH4Cl solution is added to quench the reaction mixture at ice-cold conditions, then diluted with water (200 mL) and extracted with EtOAc (3×100 mL). Combined organic layer is washed with water followed by brine. It is then dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography (silica-gel, 100-200 mesh, eluent; EtOAc to 2% MeOH in EtOAc) to afford pyrrolo[2,3-c]pyridin-1-yl-acetic acid benzyl ester (1.4 g) as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH:6]=[CH:7][C:8]=1[N:9]=[CH:10][N:11](C)C)#[N:2].Cl.Cl.[CH3:22][N:23]([CH3:31])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26](N)[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.C(#N)C>[CH3:22][N:23]([CH3:31])[C:24]1[CH:25]=[C:26]([NH:2][C:1]2[C:3]3[C:8](=[CH:7][CH:6]=[C:5]([NH:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH:4]=3)[N:9]=[CH:10][N:11]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: CN(C)c1cccc(N)c1
Reactant: CC#CC(=O)Nc1ccc(N=CN(C)C)c(C#N)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC#CC(=O)Nc1ccc2ncnc(Nc3cccc(N(C)C)c3)c2c1
Yield: 58.5 %

Procedure:
A mixture of 2.54 grams (0.01 moles) of but-2-ynoic acid [3-cyano-4-(dimethylamino-methyleneamino)-phenyl]-amide, 2.40 grams (0.0115 moles) of N, N-dimethyl-1,3-phenylenediamine dihydrochloride, and 1.59 grams (0.0115 moles) of potassium carbonate in 2.5 mL of glacial acetic acid and 5 mL of acetonitrile was refluxed for an hour. On cooling the solid was filtered and recrystallized from methyl cellusolve to give 2.02 grams (58%) of the desired product, which melted at 252-254° C. MS M+H=346.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][NH:6][C:7]=1[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:11]([OH:13])=[O:12])#[N:2].I[C:19]1NN=C(C)C=1C#N.IC1C(C#N)=CNN=1>>[C:1]([C:3]1[C:4]([CH3:19])=[N:5][NH:6][C:7]=1[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:11]([OH:13])=[O:12])#[N:2]
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]ncc1C#N
Reactant: Cc1n[nH]c(I)c1C#N
Agent: N#Cc1c[nH]nc1I
Product: Cc1ccc(C(=O)O)cc1-c1[nH]nc(C)c1C#N

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 256.5, except 5-iodo-3-methyl-1H-pyrazole-4-carbonitrile (compound 257.4) was used in place 3-iodo-1H-pyrazole-4-carbonitrile (compound 256.1).
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([CH3:8])[CH2:6][CH2:5][N:4]([CH:9]2[CH2:12][N:11](C(OCC3C=CC=CC=3)=O)[CH2:10]2)[CH2:3]1>[C].[Pd].CO>[NH:11]1[CH2:12][CH:9]([N:4]2[CH2:5][CH2:6][N:7]([CH3:8])[C@@H:2]([CH3:1])[CH2:3]2)[CH2:10]1
Reactant: C[C@H]1CN(C2CN(C(=O)OCc3ccccc3)C2)CCN1C
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN(C2CNC2)CCN1C
Yield: 132.8 %

Procedure:
To a mixed solution of benzyl 3-((3S)-3,4-dimethylpiperazin-1-yl)azetidine-1-carboxylate (28.6 g, 94.3 mmol) described in Production Example 4-2 and methanol (150 mL) was added 10% palladium-carbon (50% aqueous, 10.0 g) at room temperature. The resultant mixture was stirred under a hydrogen atmosphere at room temperature and at 0.35 MPa to 0.40 MPa for 1 hour and 45 minutes. The reaction mixture was purged with a nitrogen atmosphere, and then filtrated using Celite. A filtrate was concentrated under a reduced pressure to give the title compound (21.2 g, yield: quantitative). The product was used in the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23](Cl)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[NH2:32].CN1C=CN=C1>CC#N>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([NH:32][C:28]3[S:27][CH:31]=[CH:30][N:29]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc(C(F)(F)F)ccc1-c1ncnc2cc(S(=O)(=O)Cl)ccc12
Reactant: Nc1nccs1
Agent: Cn1ccnc1
Solvent: CC#N
Product: COc1cc(C(F)(F)F)ccc1-c1ncnc2cc(S(=O)(=O)Nc3nccs3)ccc12
Reaction time: 1 h
Yield: 52.2 %

Procedure:
A solution of 4-(2-methoxy-4-(trifluoromethyl)phenyl)quinazoline-7-sulfonyl chloride (Intermediate DDDD; 2.040 g, 5.06 mmol) and thiazol-2-amine (2.54 g, 25.3 mmol) in 40 mL of MeCN was treated with 1-methylimidazole (0.496 ml, 5.06 mmol) and was heated to reflux with a heat gun, and then allowed to stir at room one hour. The reaction mixture was concentrated and the material was purified by silica gel column chromatography (0 to 100% EtOAc/heptane) to yield 4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide (1.230 g, 2.64 mmol, 52.1% yield). 1H NMR (acetonitrile-d3) δ ppm: 9.42 (s, 1H), 8.52 (s, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.58 (d, J=7.4 Hz, 1H), 7.45-7.51 (m, 2H), 7.01 (d, J=4.8 Hz, 1H), 6.64 (d, J=4.7 Hz, 1H), 3.76 (s, 3H). m/z (ESI) 467.0 (M+H)+
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20](O)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CN1CCOCC1.C(OC(Cl)=O)C.[NH2:43][C@H:44]([C:52]([OH:54])=[O:53])[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.FC(F)(F)C(O)=O.[NH2:62][C@H:63]([CH2:68][OH:69])[CH2:64][CH2:65][S:66][CH3:67]>O1CCCC1.CN(C=O)C>[NH:1]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:43][C@H:44]([C:52]([OH:54])=[O:53])[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:62][C@H:63]([CH2:68][OH:69])[CH2:64][CH2:65][S:66][CH3:67]
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: CSCC[C@H](N)CO
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.08 h

Procedure:
4.1 g of Boc-Tyr-(D)Ala-Gly-OH and 1.1 ml of N-methyl-morpholine are dissolved in 50 ml of absolute tetrahydrofuran and 1.0 ml of chloroformic acid ethyl ester added dropwise at -15°. After 5 minutes, a solution of 4.0 g of H-Phe-methioninol trifluoroacetate and 1.2 ml of N-methylmorpholine in 50 ml of DMF is added. After 1 hour's stirring at 0°, the reaction mixture is evaporated and the residue taken up in acetic acid. The solution is repeatedly washed with 10% phosphoric acid and 1 N sodium bicarbonate. After evaporation of the acetic esters, the residue is crystallised from methanol/ether. M.P. 158°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:18](O)=O)=[CH:11][N:12]([CH3:17])[C:13](=[O:16])[C:14]=2[F:15])=[C:4]([F:21])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:43][NH:44][C:45]([NH2:47])=[S:46].CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)(Cl)(Cl)Cl>CN(C=O)C.[NH4+].[Cl-].C(OCC)(=O)C.CC#N.C(Cl)Cl>[NH2:47][C:45]1[S:46][C:18]([C:10]2[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[F:21])=[C:14]([F:15])[C:13](=[O:16])[N:12]([CH3:17])[CH:11]=2)=[N:43][N:44]=1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)c(F)c1=O
Reactant: NNC(N)=S
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cc(-c2nnc(N)s2)c(Nc2ccc(Br)cc2F)c(F)c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 4.3 %

Procedure:
A mixture of 4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (200 mg, 0.557 mmol), EDCI (214 mg, 1.11 mmol) and HOBt (151 mg, 1.11 mol) were stirred in DMF (10 mL) for 30 minutes. Thiosemicarbazide (51 mg, 0.562 mmol) and Et3N (0.116 mL, 1.5 mmol) were added. After 1 hour, the reaction mixture was diluted with saturated aqueous NH4Cl, and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography (5% to 10% MeOH in methylene chloride) gave 70 mg partially pure intermediate adduct. PPh3 (78 mg, 0.30 mmol), Et3N (0.10 mL, 0.74 mmol), and CCl4 (0.029 mL, 0.30 mmol) were added to a stirred suspension of intermediate adduct (40 mg, 0.093 mmol) in 1:1 methylene chloride:MeCN (4 mL). The reaction mixture was heated to 50° C. for 5 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water, dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography (twice) (4% MeOH in methylene chloride) gave clean desired product (10 mg, 33%); MS APCI (+) m/z 414, 416 (M+, Br pattern) detected; 1H NMR (400 mHz, CD3OD) δ 7.80 (s, 1H), 7.31 (dd, 1H), 7.25 (d, 1H), 7.02 (td, 1H), 3.64 (s, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([N:24]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26])[C:11]1[S:12][CH:13]=[C:14]([CH2:16][NH:17]S(C(C)(C)C)=O)[CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl>CO.O1CCOCC1>[NH2:17][CH2:16][C:14]1[CH:15]=[C:11]([CH:10]([N:24]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[S:12][CH:13]=1
Reactant: CC(C)CCN(C(CO[Si](C)(C)C(C)(C)C)c1cc(CNS(=O)C(C)(C)C)cs1)S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)CCN(C(CO[Si](C)(C)C(C)(C)C)c1cc(CN)cs1)S(=O)(=O)c1ccccc1
Reaction time: 2 h

Procedure:
N-[2-{[tert-butyl(dimethyl)silyl]oxy}-1-(4-{[(tert-butylsulfinyl)amino]-methyl}thiophen-2-yl)ethyl]-N-(3-methylbutyl)benzenesulfonamide (127 mg, 0.211 mmol) was dissolved in 2.1 mL MeOH. The mixture was cooled to 0° C. before the addition of HCl (0.264 mL of a 4 M solution in dioxane, 1.06 mmol). The mixture was stirred for 120 minutes and the solvents were removed by co-evaporation with toluene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:21]=[CH:20][N:19]([CH2:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[N:18]=4)=[CH:15][N:14]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[C:40]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:41]=1>[N+](C1C=C(C=CC=1)CN1C=C(B2OC(C)(C)C(C)(C)O2)C=N1)([O-])=O.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:21]=[CH:20][N:19]([CH2:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[N:18]=4)=[CH:15][N:14]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:31])=[O:32])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:40]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccn(CCc4ccccc4)n3)c3cc(-c4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Agent: [Pd+2]
Agent: CC1(C)OB(c2cnn(Cc3cccc([N+](=O)[O-])c3)c2)OC1(C)C
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccn(CCc4ccccc4)n3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Yield: 82.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-82, tert-butyl 4-(2-fluoro-4-(3-(1-phenethyl-1H-pyrazol-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (125 mg, 0.174 mmol) was reduced with palladium hydroxide (90 mg) in ethyl acetate/ethanol 10/20 mL to afford 103 mg (81.6% yield) of the titled compound. MS: m/z=720.7 (M+1).
Reaction SMILES: N1C=CC=C(CN)C=1.[CH3:9][C:10]1[O:14][N:13]=[C:12]([CH2:15][NH2:16])[CH:11]=1.FC1C=CC(CN2[C@@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1.[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[C:63]([F:65])[CH:64]=1)[CH2:45][N:46]1[C@H:50]([CH3:51])[CH2:49][N:48]([C:52]2[S:53][C:54]([C:58](O)=[O:59])=[C:55]([CH3:57])[N:56]=2)[C:47]1=[O:61]>>[F:65][C:63]1[CH:62]=[C:44]([CH:43]=[C:42]([F:41])[CH:64]=1)[CH2:45][N:46]1[C@H:50]([CH3:51])[CH2:49][N:48]([C:52]2[S:53][C:54]([C:58]([NH:16][CH2:15][C:12]3[CH:11]=[C:10]([CH3:9])[O:14][N:13]=3)=[O:59])=[C:55]([CH3:57])[N:56]=2)[C:47]1=[O:61]
Reactant: Cc1cc(CN)no1
Reactant: Cc1nc(N2C[C@@H](C)N(Cc3cc(F)cc(F)c3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1cc(CNC(=O)c2sc(N3C[C@@H](C)N(Cc4cc(F)cc(F)c4)C3=O)nc2C)no1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with (5-methylisoxazol-3-yl)methanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (R)-2-(3-(3,5-difluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white solid: mp 63-66° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 8.50 (t, J=5.4 Hz, 1H), 7.17-7.08 (m, 3H), 6.14 (s, 1H), 4.57 (d, J=16.2 Hz, 1H), 4.42-4.36 (m, 3H), 4.25-4.21 (m, 1H), 3.88-3.81 (m, 1H), 3.62-3.57 (m, 1H), 2.48 (s, 3H), 2.37 (s, 3H), 1.23 (d, J=5.9 Hz, 3H); MS (ES+) m/z 462.0 (M+1).
Reaction SMILES: [C@H:1]1([O:12][C@@H:13]2[C@@H:26]([CH2:27][OH:28])[O:25][C@@H:16]([S:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[C@H:15]([OH:29])[C@H:14]2[OH:30])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[C:31](OC(=O)C)(=[O:33])[CH3:32]>O>[C@H:1]1([O:12][C@@H:13]2[C@@H:26]([CH2:27][OH:28])[O:25][C@@H:16]([S:17][C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:31](=[O:33])[CH3:32])=[CH:22][CH:23]=3)[C@H:15]([OH:29])[C@H:14]2[OH:30])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(S[C@@H]2O[C@H](CO)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)cc1
Solvent: O
Product: CC(=O)Nc1ccc(S[C@@H]2O[C@H](CO)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)cc1
Reaction time: 0.17 h

Procedure:
A 1.0 g portion of 4-aminophenyl 4-O-(α-D-glucopyranosyl)-1-thio-β-D-glucopyranoside was dissolved in 5 ml of water and 0.340 ml of acetic anhydride was added with vigorous stirring. After stirring 10 minutes the reaction was concentrated, reconcentrated from toluene, dissolved in ethanol and precipitated with ether, giving 836 mg of the desired intermediate.
Reaction SMILES: [C:1]1([C:7]2[CH:20]=[CH:19][C:10]([C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:22][CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1.C(N(CC)CC)C>CN(C)C=O>[C:1]1([C:7]2[CH:20]=[CH:19][C:10]([C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:22][CH2:23][C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[NH:26][CH:25]=4)[CH2:15][CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: O=C(c1ccc(-c2ccccc2)cc1)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccccc2)cc1)C1CCN(CCc2c[nH]c3ccccc23)CC1

Procedure:
A solution of 10.4 g of 4-(4-phenylbenzoyl)piperidine, 8.8 g of 3-(2-bromoethyl)indole and 4.5 g of triethylamine in 300 ml of dimethylformamide is treated according to the manipulative procedure outlined in Example 3(b) to produce 3-{2-[4-(4-phenylbenzoyl)piperidyl]ethyl}indole. The indole is recrystallized twice from an ethanol-water mixture (one charcoal treatment), thrice from a pyridine-water mixture, and twice from an actetone-water mixture to give the product, mp 189°-192° C.