Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.CCOCC>C(Cl)Cl>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3]2=[O:19])=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,3-Dihydro-3-(RS)-amino-5-phenyl-2H-1,4-benzodiazepin-2-one (500 mg, 1.98 mmole) and p-chlorobenzoyl chloride (255 μl, 2.00 mmole) were combined at room temperature in 30 ml of methylene chloride. The resulting solution was protected from moisture and stirred at room temperature overnight. The reaction mixture was diluted with 70 ml of methylene chloride and washed with sodium bicarbonate solution (sat.) and brine. The organic extracts were dried (MgSO4) and concentrated to give the crude product. Trituration with ether afforded the analytical sample as a white solid.
Reaction SMILES: Br[C@H:2]([CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][CH3:8])[C:3]([OH:5])=[O:4].[C:15]([OH:18])(=[S:17])[CH3:16].[H-].[Na+]>CN(C)C=O>[C:15]([S:17][C@@H:2]([CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][CH3:8])[C:3]([OH:5])=[O:4])(=[O:18])[CH3:16]
Reactant: CCC(c1ccccc1)[C@@H](Br)C(=O)O
Reactant: CC(O)=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(c1ccccc1)[C@H](SC(C)=O)C(=O)O
Reaction time: 3 h
Yield: 78 %

Procedure:
A solution of (R)-2-bromo-3-phenylpentanoic acid in dimethylformamide is added to a solution of thioacetic acid (1.5 equivalents) and sodium hydride (2.5 equivalents) in anhydrous dimethylformamide. The mixture is stirred for 3 hours at a temperature close to 20° C. After customary treatment, (S)-2-acetylthio-3-phenylpentanoic acid is obtained with a yield of 78% in the form of a yellow oil having the following characteristics: Rf =0.44 [methylene chloride/methanol (9:1 by volume)].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15](=O)[CH2:14][CH2:13][CH2:12][CH2:11][C:8]=2[NH:9][CH:10]=1)=[O:5])[CH3:2].[NH2:17][CH:18]=[CH:19][CH:20]=O.C([O-])(=O)C.[NH4+]>C(N(CC)CC)C.ClCCl.C([O-])(O)=O.[Na+]>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]3[N:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH2:13][CH2:12][CH2:11][C:8]=2[NH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: NC=CC=O
Reactant: CCOC(=O)c1c[nH]c2c1C(=O)CCCC2
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1c[nH]c2c1-c1ncccc1CCC2
Temperature: 110 °C
Yield: 19.7 %

Procedure:
A mixture of 4-oxo-1,4,5,6,7,8-hexahydrocyclohepta(b)pyrrole-3-carboxylic acid ethyl ester (7.0 g, 31.67 mmol), 3-amino-prop-2-enal (3.37 g, 47.5 mmol) and ammonium acetate (365 mg, 4.75 mmol) in triethylamine (7 mL) is heated at 110° C. for 4 h. It is cooled to room temperature and the solid residue is dissolved in 100 mL dichloromethane and 100 mL sat. NaHCO3 solution. Layers are separated and the aqueous phase is extracted with 4:1 DCM/2-propanol (4×100 mL). Combined organic layers are dried (Na2SO4) and evaporated. Flash Chromatography on silica gel, eluting with EtOAc:triethylamine (20:1), provides 3,4,5,6-tetrahydro-3,10-diaza-benzo[e]azulene-1-carboxylic acid ethyl ester (1.6 g, 20%) as off-white solid. 1H NMR (400 MHz, CD3OD) δ 1.247 (3H, t), 2.227 (2H, m), 2.631 (4H, m), 4.197 (2H, q), 7.170 (1H, m), 7.405 (1H, s), 7.686 (1H, d), 8.375 (1H, d). MS (ES+) 257 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1.[CH2:12](O)[CH3:13].O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:3]2[C:4]([CH3:9])=[CH:5][CH:6]=[CH:7][C:12]=2[CH3:13])=[C:6]([CH3:10])[CH:5]=1)=[O:11]
Reactant: CCO
Reactant: COC(=O)c1cccc(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2c(C)cccc2C)c(C)c1
Yield: 83 %

Procedure:
2,6-Dimethyl boronic acid (13.7 g, 91 mmol) and 3-methyl benzoic acid methyl ester (20.9 g, 91 mmol) were dissolved in toluene (425 mL). Then ethanol (250 mL) and water (250 mL) were added followed by sodium carbonate (38.7 g, 365 mmol). The system was purged with nitrogen and then tetrakis triphenylphospine palladium(0) catalyst (10.5 g, 9 mmol) was added. The mixture was heated under nitrogen for 21 hours and filtered through celite. The cake was washed with a large amount of ethyl acetate, the combined filtrate was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated to give a solid. Flash chromatography of the residue over silica gel Merck-60 using a gradient of 0-20% ethyl acetate in hexane as the eluant, gave the title compound as a white solid (19.2 g, 83%).
Reaction SMILES: [C:1](=O)([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[O:2]CC1C=CC=C(Br)C=1.BrC1C=C(CO)C=CC=1.[Br:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][OH:39])=[N:36][CH:37]=1>>[C:1](=[O:2])([O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1)[O:39][CH2:38][C:35]1[CH:34]=[CH:33][C:32]([Br:31])=[CH:37][N:36]=1
Reactant: OCc1ccc(Br)cn1
Reactant: O=C(OCc1cccc(Br)c1)Oc1ccc([N+](=O)[O-])cc1
Agent: OCc1cccc(Br)c1
Product: O=C(OCc1ccc(Br)cn1)Oc1ccc([N+](=O)[O-])cc1

Procedure:
The title compound was prepared using a procedure analogous to 3-bromobenzyl 4-nitrophenyl carbonate except that (3-bromophenyl)methanol was replaced with (5-bromopyridin-2-yl)methanol. LCMS, [M+H]+=352.9.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.[OH-].[Na+]>C(Cl)(Cl)Cl.O.ClCCl>[CH3:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[O:15])=[CH:12][CH:11]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Oc2ccc(Cl)cc2)cc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 131.5 %

Procedure:
Triethylamine (6 mL) and a solution of 4.0 g of 4-methoxybenzoyl chloride (supplied from Tokyo Chemical industry) in 40 mL of chloroform were added to a solution of 6.0 g of 4-chlorophenol (supplied from Tokyo Chemical industry) in 60 mL of chloroform, and stirred at 55° C. for one hour. Then, 100 mL of dichloromethane, 200 mL of water and 25 mL of an aqueous solution of 1 N sodium hydroxide were added to the reaction solution, and the mixture was separated into two liquid phases. The organic layer was dried on sodium sulfate anhydrate and subsequently concentrated, to yield 8.1 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]([CH2:11][CH:12]2[CH2:14][CH2:13]2)[C:9]#[N:10])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:20]([O:22][CH2:23][CH3:24])=[CH2:21])CCC>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:12]1([CH2:11][CH:8]([C:5]2[CH:6]=[N:7][C:2]([C:20]([O:22][CH2:23][CH3:24])=[CH2:21])=[CH:3][CH:4]=2)[C:9]#[N:10])[CH2:14][CH2:13]1
Reactant: N#CC(CC1CC1)c1ccc(Cl)nc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: C=C(OCC)c1ccc(C(C#N)CC2CC2)cn1
Temperature: 120 °C
Yield: 169.8 %

Procedure:
A solution of 2-(6-chloropyridin-3-yl)-3-cyclopropylpropanenitrile (1.0 g, 4.86 mmol), tributyl(1-ethoxyvinyl)stannane (3.4 g, 9.72 mmol), Lid (0.612 g, 14.58 mmol) and Pd(PPh3)4 (0.282 mg, 0.243 mmol) in 1,4-dioxane (20 mL) was degassed and heated to 120° C. under N2 overnight. The reaction mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4 and concentrated to give 3-cyclopropyl-2-(6-(1-ethoxyvinyl)pyridin-3-yl)propanenitrile (2 g), which was used for the next step without further purification.
Reaction SMILES: [Si:1]([N:8]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][C:9]1=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:20][C:21]([CH2:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=[CH2:22]>C1COCC1>[Si:1]([N:8]1[C@@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:10]([CH2:22][C:21]([CH2:23][O:24][C:25](=[O:34])[C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)=[CH2:20])[C:9]1=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=C(CBr)COC(=O)c1ccc(OC)cc1
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1c1ccccc1
Solvent: C1CCOC1
Product: C=C(COC(=O)c1ccc(OC)cc1)C[C@@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@H]1c1ccccc1
Reaction time: 0.5 h
Yield: 112.4 %

Procedure:
Under an atmosphere of N2, a 1.5M solution of LiN(Pri)2THF in c-C6H6 (Aldrich; 43.9 ml, 65.9 mmol) was added dropwise to a stirred solution of 1-tert-butyldimethylsilyl-4-phenyl-2-azetidinone (13.24 g, 50.64 mmol) in dry THF (230 ml) at an inner temperature between -78 and -73 C. After stirring at -78 C for 30 minutes, the reaction mixture became a white slurry. A solution of 3-bromo-2-[(4-methoxybenzoyloxy)methyl]propene (14.69 g, 54.18 mmol) in dry THF (30.0 ml) was added dropwise at an inner temperature between -78 and -71 C. After the addition was complete, the dropping funnel used was rinsed with dry THF (5 ml×2). The resultant homogeneous reaction mixture was stirred at -78 C. for an hour, and then at -10 C. for 50 minutes. The reaction was quenched by adding sat. NH4Cl aq. solution (30.0 ml) below 0 C. The mixture was taken up in AcOEt (500 ml). The AcOEt solution separated was washed with sat. NaCl aq. solution (100 ml×2), dried (MgSO4), and concentrated in vacuo to give a heterogeneous yellow oil (26.51 g). This was, then, diluted with Et2O (250 ml), washed with H2O (×2), and sat. NaCl aq. solution (×1), dried (MgSO4), and concentrated in vacuo to give a homogeneous yellow oil (24.91 g). This was flash chromatographed over SiO2 (Merck Kieselgel 60, 250 g). Elution with n-hexane-AcOEt (40:1/30:1/20:1/10:1) gave title compound (19.73 g, 86.3%) as a viscous pale yellow oil. IRmax (film): 1745(s), 1645(m), 1610(m), 1510(m), 990(shoulder, m), 910(m), 775(m), 745(w), 700(m), 680(m) cm-1 ; 1H-NMR δ: 7.40-7.25(m, 5H), 7.20(d, J=8.8 Hz, 2H), 6.85(d, J=8.8 Hz, 2H), 5.05(s, 1H), 4.84(s, 1H), 4.35(s, 2H), 4.20(d, J=2.6 Hz, 1H), 3.86(s, 2H), 3.80(s, 3H), 3.25(ddd, J=10.5, 5.1, 2.6 Hz, 1H), 2.70(dd, J=15.7, 5.1 Hz, lH), 2.48(dd, J=15.7, 10.7 Hz, 1H), 0.92(s, 9H), 0.21(s, 3H), -0.21(s, 3H) ppm.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[C:25]([CH3:31])[CH:24]=2)([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][C:13]=1[CH3:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[Si:1]([O:8][CH:9]([C:33]([CH3:34])([CH3:35])[CH3:36])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[C:25]([CH3:31])[CH:24]=2)([CH2:19][CH3:20])[CH2:21][CH3:22])=[CH:14][C:13]=1[CH3:32])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CCC(CC)(c1ccc(CO)c(C)c1)c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCC(CC)(c1ccc(C=O)c(C)c1)c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
To a solution of [4-(1-{4-[2-(t-butyldimethylsilanyloxy)-3,3-dimethylbutoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylphenyl]methanol (0.25 g, 0.48 mmol) in CH2Cl2 (4 mL) is added powdered 4 Å molecular sieves (250 mg) followed by the addition of NMO (84 mg, 0.72 mmol), and TPAP (8.4 mg, 0.02 mmol). The resulting mixture is stirred at RT for 5 m, filtered through silica gel, washed with EtOAc, and the combined filtrate is concentrated to give the title compound (0.20 g, 83%).
Reaction SMILES: [ClH:1].C(N(CC)CC)C.S(F)(O[C:13]([F:20])([F:19])[C:14]([F:18])=[C:15]([F:17])[F:16])(=O)=O>COCCOCCOC>[F:19][C:13]([Cl:1])([F:20])[C:14]([F:18])=[C:15]([F:17])[F:16]
Reactant: Cl
Reactant: O=S(=O)(F)OC(F)(F)C(F)=C(F)F
Solvent: COCCOCCOC
Solvent: CCN(CC)CC
Product: FC(F)=C(F)C(F)(F)Cl
Temperature: 0 °C
Yield: 93 %

Procedure:
A 300-mL four-neck flask provided with a Dimroth condenser, a dropping funnel, and a thermometer was charged with triethylamine hydrochloride (97 g, 703 mmol) and 50 mL of diglyme, and the mixture was stirred by a magnetic stirrer. The Dimroth condenser was cooled using a −20° C. refrigerant, and the reaction flask was cooled to 0° C. in an ice bath. With the dropping funnel, perfluoroallyl fluorosulfate (135 g, 586 mmol) was dropped over about one hour in such a manner that the temperature in the flask was maintained at 10° C. or lower. After the dropping, the mixture was stirred for one hour. The Dimroth condenser was replaced by a Liebig distillation apparatus. The flask was allowed to reach room temperature (25° C.), and the resulting product (having a boiling point of 12° C.) was distilled. An amount of 100 mL of water was added to the flask to terminate the reaction. As a result, 90.7 g of the target perfluoroallyl chloride (purity: 99 GC %) was obtained as a distilled component (yield: 93%). The distillation residue was determined by NMR analysis to include carboxylic acids and ammonium fluorosulfate which were probably generated from hydrolysis of unreacted perfluoroallyl fluorosulfate in terminating the reaction, and an excess amount of triethylamine hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27]([NH2:29])=[O:28])[C:19]([C:33]([F:36])([F:35])[F:34])=[CH:18][N:17]=1.C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH3:39])[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27]([NH2:29])=[O:28])[C:19]([C:33]([F:34])([F:35])[F:36])=[CH:18][N:17]=1
Reactant: COc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2cccc(C(N)=O)c2)n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COc1cc(C2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2cccc(C(N)=O)c2)n1
Reaction time: 1.5 h
Yield: 74.2 %

Procedure:
To a solution of 3-(2-(2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)benzamide (5) (0.021 g, 0.042 mmol) in anhydrous methanol (2.00 mL) was added 37% aqueous formaldehyde (0.012 mL, 0.16 mmol) and sodium triacetoxyborohydride (0.044 g, 0.21 mmol) under a N2 atmosphere. The mixture was then stirred for 1.5 hours. The resulting mixture was concentrated under reduced pressure and diluted with EtOAc (10 mL) and washed with sat. aqueous NaHCO3 (10 mL). The Aqueous was further extracted with EtOAc (10 mL) and the combined organic layers were washed with brine (10 mL) and water (10 mL) then dried using a phase separation cartridge. The organics were concentrated under reduced pressure and purified using silica gel column chromatography (0-30% MeOH/EtOAc+1% 2 M ethanolic NH3). The product was then taken up in minimal hot acetonitrile and water and freeze dried to give the title compound (6) (0.016 g, 74%) as a white solid; 1H NMR (400 MHz, d6-Acetone) δ 8.62 (s, 1H), 8.27 (dd, J=8.3, 4.1 Hz, 1H), 8:15 (s, 1H), 7.90 (s, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.41 (m, 3H), 6.99 (d, J=1.7 Hz, 1H), 6.89 (dd, J=8.2, 1.6 Hz, 1H), 6.55 (s, 1H), 3.98 (s, 3H), 3.20 (m, 4H), 2.90 (m, 2H), 2.57 (m, 1H), 2.22 (s, 3H), 1.98 (td, J=11.2, 3.8 Hz, 2H), 1.78 (m, 4H). LCMS Method C: rt 4.97 min; m/z 514.2 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([C:9]([NH2:11])=[NH:10])[S:7][CH:8]=2)[CH2:3][CH2:2]1.BrCC(=O)C(C)C>>[CH:1]([C:4]1[N:5]=[C:6]([C:9]([NH2:11])=[NH:10])[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: N=C(N)c1nc(C2CC2)cs1
Agent: CC(C)C(=O)CBr
Product: CC(C)c1csc(C(=N)N)n1

Procedure:
4-Isopropyl-thiazole-2-carboxamidine (Compound V) was prepared in analogy to Compound M with procedure shown in Example 10 by using 1-bromo-3-methyl-butan-2-one instead of 2-bromo-1-cyclopropyl-ethanone. MS: calc'd (MH+) 170, measured (MH+) 170.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:11]([CH2:15][CH3:16])[C:12]([OH:14])=O)[CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.C(Cl)(=O)C(Cl)=O.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:38]3[CH2:37][CH2:36][CH2:35][NH:34][C:33]=3[CH:32]=[N:31]2)=[CH:26][CH:25]=1.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.O.CN(C)C=O>[F:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[C:38]3[CH2:37][CH2:36][CH2:35][N:34]([C:12](=[O:14])[CH:11]([N:3]4[CH:4]=[C:5]([C:7]([F:8])([F:9])[F:10])[N:6]=[C:2]4[CH3:1])[CH2:15][CH3:16])[C:33]=3[CH:32]=[N:31]2)=[CH:28][CH:29]=1
Reactant: CCC(C(=O)O)n1cc(C(F)(F)F)nc1C
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCC(C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1)n1cc(C(F)(F)F)nc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[2-Methyl-4-(trifluoromethyl)imidazol-1-yl]butyric acid (149 mg, 0.632 mmol) was dissolved in dichloromethane (2 mL) at room temperature. Oxalyl chloride (110 μL, 1.26 mmol) and a catalytic amount of dimethylformamide (1 μL) was added and the reaction was stirred at room temperature for 2 h. Solvent was removed under reduced pressure and the acid chloride was dried under vacuum. The crude acid chloride was dissolved in acetonitrile (1.5 mL). To a portion of this solution (0.5 mL, 0.21 mmol) was added 1-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-b]pyridine (38.7 mg, 0.178 mmol) and pyridine (55 μL, 0.68 mmol) at room temperature and the reaction mixture was stirred for 2 h. Water and ethyl acetate were then added and the layers were separated. The aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 50˜80% ethyl acetate in hexanes with 0.1% aqueous ammonium hydroxide) to afford the desired product contaminated with some 2-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]butyric acid. The product was dissolved in ethyl acetate and washed once with 1N aqueous sodium hydroxide solution. Drying over anhydrous sodium sulfate followed by filtration and removal of solvent under reduced pressure and drying under vacuum afforded the desired product as a white solid (60.4 mg, 0.139 mmol, 78%). 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.84 (d, J=1.2 Hz, 1H), 7.58 (ddd, J=9.2, 5.2, 2.0 Hz, 2H), 7.35 (ddd, J=9.2, 8.4, 0.8 Hz, 2H), 5.47 (dd, J=9.2, 5.6 Hz, 1H), 3.81-3.98 (m, 2H), 2.84 (t, J=6.2 Hz, 2H), 2.34 (s, 3H), 2.03-2.11 (m, 2H), 1.96-2.01 (m, 2H), 0.85 (t, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C21H21N5OF4 [M+H]+ 436, found 436.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:60][C:61]1([CH3:73])[O:65][C@H:64]([CH2:66][N:67]2[CH:71]=[CH:70][C:69]([NH2:72])=[N:68]2)[CH2:63][O:62]1>CN(C)C=O.C(OCC)(=O)C>[CH3:60][C:61]1([CH3:73])[O:65][C@H:64]([CH2:66][N:67]2[CH:71]=[CH:70][C:69]([NH:72][C:11](=[O:13])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:2]=4[F:1])=[CH:6][C:7]3=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:68]2)[CH2:63][O:62]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2ccc(F)cc2F)=CC1=O
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: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccc(F)cc2F)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
A solution of (S)-2-[4-(2,4-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.49 g, 1.53 mmol) in N,N-dimethylformamide (5.9 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.76 mL, 4.59 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1.01 g, 2.29 mmol) and a solution of 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.31 g, 1.60 mmol) in N,N-dimethylformamide (0.5 mL). The reaction was stirred at 25° C. overnight. At this time, the reaction was diluted with ethyl acetate (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×150 mL) and a saturated aqueous sodium chloride solution (1×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 50-75% ethyl acetate/hexanes) afforded (S)-2-[4-(2,4-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.63 g, 81%) as a light orange foam: HR-ES-MS m/z calculated for C25H30N4O5F2 [M+H]+ 505.2257, observed 505.2257; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.4 Hz, 3H), 0.91 (d, J=6.4 Hz, 3H), 1.23 (s, 3H), 1.28 (s, 3H), 1.43 (br. s., 1H), 1.48-1.63 (m, 1H), 1.66-1.81 (m, 1H), 3.71 (dd, J=8.5, 5.7 Hz, 1H), 3.94-4.13 (m, 3H), 4.19 (d, J=18.4 Hz, 1H), 4.27-4.38 (m, 1H), 4.57 (d, J=18.4 Hz, 1H), 4.86 (dd, J=10.9, 4.8 Hz, 1H), 4.90 (s, 1H), 6.41 (d, J=2.1 Hz, 1H), 7.12-7.23 (m, 1H), 7.48-7.62 (m, 3H), 10.79 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:3]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](B2OC(C)(C)C(C)(C)O2)=[N:20]1>>[NH:19]1[C:27]2[C:22](=[C:23]([C:2]3[N:7]=[C:6]4[N:8]([CH3:11])[N:9]=[CH:10][C:5]4=[C:4]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[N:3]=3)[CH:24]=[CH:25][CH:26]=2)[CH:21]=[N:20]1
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Reactant: Cn1ncc2c(NC3CCOCC3)nc(Cl)nc21
Product: Cn1ncc2c(NC3CCOCC3)nc(-c3cccc4[nH]ncc34)nc21

Procedure:
(6-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(tetrahydro-pyran-4-yl)-amine was reacted with indazole boronic acid pinacol ester in General Procedure A. Purification on silica yielded 154. NMR (CDCl3) 1.70-1.80 (m, 2H, CH2), 2.24-2.27 (m, 2H, CH2), 3.67-3.73 (m, 2H, CH2), 4.11-4.14 (m, 2H, CH2), 4.18 (s, 3H, CH3), 4.55 (m, H, CH), 5.32 (sbr, H, NH), 7.55 (t, H, ArH, J=7.76 Hz), 7.63 (d, H, ArH, J=8.27 Hz), 7.92 (s, H, ArH), 8.40 (d, H, ArH, J=7.23 Hz), 9.16 (s, H, ArH), 10.22 (sbr, H, NH). MS: (ESI+) MH+=350.16