Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br.[N:3]1([C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.O.C(=O)([O-])O.[Na+].[C:22](OC(=O)C)(=[O:24])[CH3:23]>ClC(Cl)Cl>[C:22]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:8][CH2:7]1)(=[O:24])[CH3:23]
Reactant: Oc1cccc(N2CCNCC2)c1
Reactant: CC(=O)OC(C)=O
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCN(c2cccc(O)c2)CC1
Temperature: 10 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a stirred solution of 80 parts of 3-(1-piperazinyl)phenol dihydrobromide in 360 parts of water and 180 parts of trichloromethane are added portionwise 42 parts of sodium hydrogen carbonate at 10° C. Then there are added dropwise, during a 15 minutes-period, 26 parts of acetic acid anhydride while cooling at 10° C. Upon completion, stirring is continued for 3 hours at room temperature. The precipitated product is filtered off, washed with water and crystallized from 2-propanol, yielding 37 parts (70%) of 1-acetyl-4-(3-hydroxyphenyl)piperazine; mp. 186.1° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]([OH:19])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([S:27]([NH2:30])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1>>[S:27]([C:23]1[CH:22]=[C:21]([NH:20][C:17]([C:16]2[CH:15]=[N:14][N:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][C:10]=23)=[O:19])[CH:26]=[CH:25][CH:24]=1)(=[O:28])(=[O:29])[NH2:30]
Reactant: O=C(O)c1cnn2ccc(-c3ccc(Cl)cc3)nc12
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3ccc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.22) and 3-amino-benzenesulfonamide according to general procedure II. Pale-yellow solid. MS (ISP) 428.3 [(M+H)+]; mp 345° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([C:18](=S)[NH2:19])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1.[NH2:21][OH:22]>O1CCOCC1.C1COCC1>[OH:22][NH:21][C:18]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([C:10]2[CH:9]=[N:8][N:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:11]=2)[N:17]=1)=[NH:19]
Reactant: NO
Reactant: NC(=S)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: N=C(NO)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
With heating, 0.4 g (1.4 mmol) of 6-(1-pyridin-3-yl-1H-pyrazol-4-yl)pyridine-2-carbothioamide were dissolved in 40 ml of dioxane-THF 1:3, 0.4 ml of hydroxylamine (50% strength aqueous solution, corresponds to 6.8 mmol) was added and the mixture was stirred at 60° C. for 1 h and then concentrated by evaporation. The crude product obtained in this manner was not purified any further.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)[N:3]=1.C1C(=O)N([Br:33])C(=O)C1.OS([O-])=O.[Na+]>C(#N)C.C(OCC)(=O)C>[Br:33][C:10]1[C:2]([Cl:1])=[N:3][C:4]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[O:19])=[CH:16][CH:17]=2)=[C:5]([CH:9]=1)[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1ccc(Cl)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(Br)c(Cl)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reaction time: 8 h
Yield: 38.6 %

Procedure:
A suspension of 6-chloro-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (500 mg, 1.385 mmol) and NBS (250 mg, 1.4 mmol) in acetonitrile (10 mL) was stirred at overnight. The reaction mixture was treated with 1M NaHSO3 and stirred at rt for 2 h. Next, the reaction mixture was diluted with ethyl acetate and the precipitate filtered to give a solid. The organic layer of the filtrate was separated and concentrated to an additional amount of solid. The above solids were combined and triturated with 250 mL of MeOH/CH2Cl2 (˜1:1 ratio) to give 235 mg of 5-bromo-6-chloro-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide as a grey solid. LCMS: (M+H)+=338.80, 440.83, 442.87 (Br, Cl pattern). 1H NMR (400 MHz, methanol-d3-MIX) δ ppm 8.38 (1H, s), 7.77 (2H, d, J=8.35 Hz), 7.42 (2H, d, J=8.79 Hz), 3.69 (8H, br. s.).
Reaction SMILES: Cl[C:2]1[C:7]([C:8](OCC)=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>>[CH:14]1([NH:17][C:2]2[C:7]([CH:8]=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=2)[CH2:16][CH2:15]1
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Reactant: NC1CC1
Product: Cc1ncc(C=S)c(NC2CC2)n1

Procedure:
4-cyclopropylamino-2-methylthiopyrimidine-5-carboxaldehyde was prepared as described in Example 1 (steps A through C) starting with ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (Aldrich Chemical Co.) and cyclopropyl amine (Aldrich Chemical Co.).
Reaction SMILES: [O:1]([C:8]1[CH:21]=[CH:20][C:11]([CH2:12][NH:13][C:14]([CH:16]2[CH2:19][CH2:18][CH2:17]2)=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:16]1([CH2:14][NH:13][CH2:12][C:11]2[CH:20]=[CH:21][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: O=C(NCc1ccc(Oc2ccccc2)cc1)C1CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(Oc2ccc(CNCC3CCC3)cc2)cc1
Temperature: 0 °C
Yield: 99.7 %

Procedure:
A cooled (0° C.) solution of N-(4-phenoxybenzyl)cyclobutanecarboxamide (0.60 g, 2.1 mmol) in THF (7 mL) was treated with 1M solution of LAH in THF (2.1 mL). The solution was refluxed for 2 hours then cooled to 0° C. and quenched with Na2SO4 ·10 H2O. The suspension was diluted with THF and filtered through a pad of celite. Evaporation of the solvent provided 0.56 g (99%) of the title compound as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 1.15 (br s, 1H), 1.62-1.70 (m, 2H), 1.80-1.98 (m, 3H), 2.02-2.10 (m, 2H), 2.50 (p, J=7.5 Hz, 1H), 2.65 (d, J=7.5 Hz, 2H), 3.75 (s, 2H), 6.95-7.02 (m, 4H) 7.05-7.10 (tt, J=7.5, 1.5 Hz, 1H), 7.25-7.35 (m, 4H). MS (DCl/NH3) m/e 268 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].C=O.[C:14]1(B(O)O)C=CC=CC=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[CH2:14])[C:6]2=[O:11]
Reactant: O=C1CCc2c(F)cccc21
Reactant: OB(O)c1ccccc1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=C1Cc2c(F)cccc2C1=O
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a 1000 mL round bottle flask were charged 4-fluoro-2,3-dihydro-1H-inden-1-one (249a) (5.04 g, 33.6 mmol), paraformaldehyde (10.08 g, 336 mmol), phenylboronic acid (4.92 g, 40.3 mmol) followed by toluene (235 mL), to the suspension was added TFA 2.6 mL, 33.6 mmol), and the resulting suspension was refluxed for 4 hrs, which resulted a clear yellowish solution. The solution was cooled to room temperature, and the pH was adjusted to 7-8 by adding saturated NaHCO3. After extracting with ethyl acetate, the organic layers were combined, and evaporated. The residue was purified by flash chromatography (0 to 30% EtOAc/Hexane) to give 4-fluoro-2-methylene-2,3-dihydro-1H-inden-1-one (249b) (3.91 g, 72%). LC-MS tR=1.49 min in 3 min chromatography, MS (ESI) m/z 163 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[S:23]1[CH2:29][C:27](=[O:28])[NH:26][C:24]1=[S:25]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[C:29]3[S:23][C:24](=[S:25])[NH:26][C:27]3=[O:28])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccc(OCc2ccc(Cl)cc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc(OCc2ccc(Cl)cc2)cc1

Procedure:
Under a nitrogen atmosphere in a round bottom flask 4-[(4-chlorophenyl)methoxy]benzaldehyde (0.40 g, 1.62 mmol) was dissolved in acetic acid (8.1 ml) while stirring. To this solution was added sodium acetate (0.47 g, 5.7 mmol) followed by the addition of rhodanine (0.22 g, 1.65 mmol). The reaction mixture was heated to the reflux temperature and maintained at this temperature. The progress of the reaction was monitored by thin layer chromatography.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:7]2)([O-])=O>CO.O=[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:7]2
Reactant: COC(=O)Cn1ccc2cc([N+](=O)[O-])ccc21
Agent: O=[Pt]=O
Solvent: CO
Product: COC(=O)Cn1ccc2cc(N)ccc21

Procedure:
To a solution of methyl 2-(5-nitro-1H-indol-1-yl)acetate (830 mg, 3.54 mmol) in MeOH (50 ml), a catalytic amount of PtO2 was added, and the mixture was reacted under H2 atmosphere in a Parr apparatus at 30 psi for 15 minutes. The catalyst was filtered off, the solvent was removed and crude methyl 2-(5-amino-1H-indol-1-yl)acetate was obtained and was used in the next step without any additional purification (730 mg, 3.54 mmol, quantitative yield). MS/ESI+ 205.2 [MH]+.
Reaction SMILES: C([Li])CCC.C(P([CH2:12][S:13]([O:16][CH2:17][CH3:18])(=[O:15])=[O:14])(CC)=O)C.[CH3:19][C:20]1[S:24][C:23]([CH:25]=O)=[CH:22][CH:21]=1>C1COCC1>[CH3:25][C:23]1[S:24][C:20]([CH:19]=[CH:12][S:13]([O:16][CH2:17][CH3:18])(=[O:14])=[O:15])=[CH:21][CH:22]=1
Reactant: CCOS(=O)(=O)CP(=O)(CC)CC
Reactant: Cc1ccc(C=O)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOS(=O)(=O)C=Cc1ccc(C)s1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
n-Butyl lithium (1.6 mL of a 2.5 M solution in hexanes, 4.0 mmol) was added dropwise to a solution of ethyl diethylphosphorylmethanesulfonate (1.0 g, 3.8 mmol), prepared as described in Tetrahedron, 1987, 43(21), 5125, at −78° C. in THF (15 mL). The mixture was stirred for 20 min. then 5-methyl-2-thiophenecarboxaldehyde (460 mg, 4.2 mmol) was slowly added. The mixture was stirred at −78° C. for 1 h. then allowed to warm to room temperature overnight. The bulk of the solvents were evaporated and the residue was treated with water (2 mL) and extracted with CH2CL2. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography eluting with CH2CL2 to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][CH:22]([F:32])[C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29](=[O:30])[C:26]3[CH:25]=[CH:24][C:23]([CH:22]([F:32])[F:21])=[CH:28][N:27]=3)[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: O=C(O)c1ccc(C(F)F)cn1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(C(F)F)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1) and 5-(difluoromethyl)picolinic acid [J. D. Scott et al. WO2011044181 (2011)] following General Procedure G yielded the title compound as a colorless amorphous solid. MS: m/z=447.5 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J6) (160 mg, 0.5 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (201 mg, 0.5 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (247 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:9][O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=2)[CH:13]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: Brc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Oc2cccc(Br)n2)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
A solution of 2.37 g of 2,6-dibromopyridine and 1.52 g of 3-hydroxybenzoic acid methyl ester in 10 ml of dimethylformamide is mixed with 6.6 g of cesium carbonate and heated to 120° C. with stirring for 3 hours. The reaction mixture is filtered on diatomaceous earth, rewashed with dichloromethane and the filtrate is concentrated by evaporation in a vacuum. The residue is distilled on a bulb tube at 140°-150° C. and 0.04 mbar. 2.98 g of 3-(6-bromo-2-pyridyloxy)-benzoic acid methyl ester of melting point 68°-69° C. is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]2[N:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]1=[O:17].[H-].[Na+].[CH3:20][N:21]([CH3:36])[CH2:22][CH2:23][CH2:24]OS(C1C=CC(C)=CC=1)(=O)=O>C1(C)C(C)=CC=CC=1>[CH3:20][N:21]([CH3:36])[CH2:22][CH2:23][CH2:24][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:17])[C:4]2[CH:16]=[CH:15][CH:14]=[N:13][C:5]1=2
Reactant: CN1C(=O)c2cccnc2Nc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)OCCCN(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CN(C)CCCN1c2ccccc2N(C)C(=O)c2cccnc21
Yield: 38.7 %

Procedure:
A mixture of 4.5 gm of 6,11-dihydro-6-methyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, 0.83 gm of 55% sodium hydride in mineral oil, and 100 ml of absolute xylene was refluxed for two hours. Thereafter, 7 gm of p-toluenesulfonic acid 3-dimethylamino-n-propyl ester were added, and the resulting mixture was refluxed for 14 hours more. After cooling, the reaction mixture was suction-filtered, and the filtrate was extracted with dilute acetic acid. From the acidic aqueous phase, the base was precipitated as an oil with concentrated ammonia and taken up in ether. After evaporation of the ether solution, the residue was distilled, yielding 2.4 gm of 11(3'-dimethylamino-n-propyl)-6,11-dihydro-6-methyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, b.p. 180°-183° C. at 0.03 mm Hg, which melted at 98.5°-100° C. after crystallization from cyclohexane and recrystallization from petroleum ether.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:11]2[C:6]([CH:7]=[CH:8][C@H:9]([CH3:29])[C@@H:10]2[CH2:12][CH2:13][C@H:14]2[O:19][C:18](=[O:20])[CH2:17][C@H:16]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:15]2)=[CH:5][CH2:4][CH2:3]1.[CH2:30]([C:32]([CH3:38])([CH2:36][CH3:37])[C:33](Cl)=[O:34])[CH3:31]>>[CH2:30]([C:32]([CH3:38])([CH2:36][CH3:37])[C:33]([O:1][C@@H:2]1[C@H:11]2[C:6]([CH:7]=[CH:8][C@H:9]([CH3:29])[C@@H:10]2[CH2:12][CH2:13][C@H:14]2[O:19][C:18](=[O:20])[CH2:17][C@H:16]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[CH2:15]2)=[CH:5][CH2:4][CH2:3]1)=[O:34])[CH3:31]
Reactant: CCC(C)(CC)C(=O)Cl
Reactant: C[C@H]1C=CC2=CCC[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCC(C)(CC)C(=O)O[C@H]1CCC=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 74.4 %

Procedure:
A procedure similar to that described in Example 4, above, was followed, but using 1.0 g (2.4 mmol) of (4R,6R)-6-{2-[(1S,2S,8S,8aR)-1,2,6,7,8,8a-hexahydro-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Japanese Patent Kokai Application No. Sho 59-175450] and 1.4 g (9.4 mmol) of 2-ethyl-2-methylbutyryl chloride, to provide 951 mg of the title compound.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1)[NH2:2].[C:22]([O:26][C:27]([N:29]1[CH2:33][C@H:32]([CH2:34][CH3:35])[C@H:31]([C:36](O)=[O:37])[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:34]([C@H:32]1[C@@H:31]([C:36]([NH:2][NH:1][C:3]2[N:4]=[C:5]3[CH:11]=[CH:10][N:9]([S:12]([C:15]4[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=4)(=[O:13])=[O:14])[C:6]3=[N:7][CH:8]=2)=[O:37])[CH2:30][N:29]([C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:28])[CH2:33]1)[CH3:35]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (5.00 g, 16.48 mmol, Example 1, Step D) and (cis)-1-(tert-butoxycarbonyl)-4-ethylpyrrolidine-3-carboxylic acid (4.01 g, 16.48 mmol) in DCM (70 mL) were added TEA (5.75 mL, 41.2 mmol) and HATU (6.90 g, 18.15 mmol, Novabiochem). The resulting suspension was stirred at about 25° C. for about 2 h. The reaction mixture was transferred to a separatory funnel and washed with saturated aqueous NaHCO3 (4×30 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concd in vacuo to give a brown foam. The crude material was purified via flash chromatography on silica gel by dry loading the compound onto the column and eluting with 50-100% EtOAc in DCM/petroleum ether (1:1) to afford (cis)-tert-butyl 3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)pyrrolidine-1-carboxylate with EtOAc as an excipient (9.41 g, 100%) as a tan foam: LC/MS (Table 1, Method a) Rt=2.45 min; MS m/z: 529 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:9][C:10]1[S:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:12][CH:11]=1>CN(C=O)C>[N:3]1([CH2:9][C:10]2[S:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:12][CH:11]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CCOC(=O)c1ncc(CBr)s1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc(Cn2ccnc2)s1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 44 %

Procedure:
To a cooled (0 C) suspension of sodium hydride (60% in oil, 82 mg, 2.05 mmol) in dry DMF (2 ml) was added imidazole (93 mg, 1.37 mmol) as a solution in dry DMF (0.5 ml). Mixture was stirred at RT 45 min, cooled to 0° C. followed by addition of ethyl 5-(bromomethyl)thiazole-2-carboxylate (342 mg, 1.37 mmol) dissolved in dry DMF (2 ml). After being stirred at RT for 20 h, the reaction mixture was evaporated and the residue was taken up in DCM and washed twice with saturated NaCl solution. Thus, 143 mg (44%) of the title compound was obtained. 1H-NMR (400 MHz; d6-DMSO): δ 1.32 (t, 3H), 4.37 (q, 2H), 5.39 (s, 2H), 6.91 (s, 1H), 7.20 (s, 1H), 7.75 (s, 1H), 7.93 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([N:20]([CH3:25])[CH2:21][CH2:22][CH2:23]O)=[O:19])[N:9]=1.CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([N:20]([CH3:25])[CH2:21][CH2:22][CH2:23][S:34]([CH3:33])(=[O:36])=[O:35])=[O:19])[N:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCCO)C(=O)c1cc2ccccc2c(-c2ccccc2I)n1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCCS(C)(=O)=O)C(=O)c1cc2ccccc2c(-c2ccccc2I)n1
Temperature: 0 °C
Yield: 69.9 %

Procedure:
To a solution of 1-(2-iodophenyl)-N-methyl-N-(3-hydroxypropyl)-3-isoquinolinecarbo-xamide (20 mg, 0.045 mmol), DMAP (5.5 mg, 0.045 mmol), and Et3N (0.02 mL, 0.14 mmol) in CH2Cl2 (2 mL) at 0° C. was added dropwise MsCl (0.006 mL, 0.77 mmol). The resulting mixture was stirred at 0° C. and monitored by TLC. After stirring at 0° C. for 4 h, TLC showed that no starting material left. Then, it was transferred into separatory funnel and washed with H2O (15 mL) The organic layer was dried (MgSO4), and filtered. The filtrate was concentrated in vacuo. The residue was purified on column (silica gel, 2% MeOH/CH2Cl2, 0.1% Et3N), thereby affording an oil (16 mg, 68%). 1H NMR (CDCl3) d 2.12-2.22 (m, 2 H, CH2), 2.77, 3.06 (two s, total 3 H, --SO2Me), 3.17, 3.20 (two s, total 3 H, N--Me), 3.62-3.82 (m, 2 H, N--CH2), 4.15 (t, J=6.0 Hz, 1 H, CH2O), 4.39 (t, J=6.0 Hz, 1 H, CH2O), 7.19-7.27 (m, 1 H, aromatic), 7.39-7.41 (m, 1 H, aromatic), 7.48-7.64 (m, 3 H, aromatic), 7.73-7.79 (m, 1 H, aromatic), 7.96-8.05 (m, 2 H, aromatic), 8.12, 8.24 (two s, total 1 H, aromatic). HRFABMS Cacld. for C21H21ILiN2O4S: 531.0427 (M+Li)+. Found: 531.0443.
Reaction SMILES: O.[C:2]1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]([F:22])([C:18]([OH:21])([CH3:20])[CH3:19])[C:15]([OH:17])=[O:16].C(=O)([O-])O.[Na+]>CO>[F:13][C:14]([F:22])([C:18]([OH:21])([CH3:20])[CH3:19])[C:15]([O:17][CH3:2])=[O:16]
Reactant: CC(C)(O)C(F)(F)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(F)(F)C(C)(C)O
Yield: 65 %

Procedure:
A catalytic amount of p-toluenesulfonic acid monohydrate was added to a mixture of 73.3 g of Intermediate 3 in Example 3 and 300 g of methanol. With stirring in a nitrogen atmosphere, the reaction mixture was heated under reflux for 12 hours. After cooling, the reaction mixture was poured into a saturated sodium hydrogen carbonate aqueous solution and extracted with ethyl acetate. The ethyl acetate solution was washed, dried and concentrated. The residue was distilled in vacuum, obtaining 52.0 g (yield 65%) of methyl 2,2-difluoro-3-hydroxy-3-methylbutanoate.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[CH:3]=1.[F:11][C:12]([F:19])([F:18])[C:13](=O)[CH2:14][C:15]#[N:16]>>[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:15]([NH2:16])=[CH:14][C:13]([C:12]([F:19])([F:18])[F:11])=[N:9]2)[CH:3]=1
Reactant: Cc1cccc(NN)c1
Reactant: N#CCC(=O)C(F)(F)F
Agent: Cl
Product: Cc1cccc(-n2nc(C(F)(F)F)cc2N)c1
Yield: 21.5 %

Procedure:
Following the procedure in Example 161A Step 3, m-tolylhydrazine hydrochloride (1.15 g, 7.30 mmol) and 4,4,4-trifluoro-3-oxobutanenitrile (1.0 g, 7.30 mmol) were reacted to give 1-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (380 mg, 1.57 mmol, 22%). 1H NMR (300 MHz, DMSO-d6) δ 7.60-7.20 (m, 4H), 5.82-5.61 (m, 3H), 2.59 (s, 3H); LC-MS (ESI) m/z 242 (M+H)+.
Reaction SMILES: C(OC([N:6]1[CH2:10][CH2:9][C:8]([OH:21])([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH2:7]1)=O)C.[OH-].[K+]>O1CCOCC1.C(O)CCC>[F:20][C:17]([F:18])([F:19])[C:14]1[CH:13]=[CH:12][C:11]([C:8]2([OH:21])[CH2:9][CH2:10][NH:6][CH2:7]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)N1CCC(O)(c2ccc(C(F)(F)F)cc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCCCO
Product: OC1(c2ccc(C(F)(F)F)cc2)CCNC1
Yield: 57 %

Procedure:
To a solution of 1.98 mmol rac-3-Hydroxy-3-(4-trifluoromethyl-phenyl)-pyrrolidine-1-carboxylic acid ethyl ester in 15 ml dioxane., was added 8 ml of a 2.5N solution of KOH in butanol. The solution was stirred under reflux for 2 hours. The solvent was removed in vacuo and the residue was taken in water. The aqueous phase was extracted 3 times with dichloromethane. The combined organic phases were dried over Na2SO4, evaporated and dried. The compound was suspended in hexane/ether (˜2:1), filtered and rinsed with hexane to yield the title compound (57%) as a light brown solid MS (m/e): 232.1 ([M+1], 100%).