Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:15]2[CH2:17][CH2:16]2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=O)C.CC(C[AlH]CC(C)C)C.Cl>C1(C)C=CC=CC=1>[CH:15]1([N:9]2[C:10]([C:11]([F:13])([F:12])[F:14])=[C:6]([CH2:4][OH:3])[CH:7]=[N:8]2)[CH2:16][CH2:17]1
Reactant: CCOC(=O)c1cnn(C2CC2)c1C(F)(F)F
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: OCc1cnn(C2CC2)c1C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 1-Cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (Preparation 135, 1.4 g, 5.64 mmol) in dry toluene (25 mL) was cooled to −78° C. and DIBAL-H (11.8 mL of 1.2 M solution in toluene, 14.1 mmol) was added dropwise to it. The reaction mixture was stirred at −78° C. for 2 hours and poured into 2N HCl (10 mL). This was stirred for a further 4 hours at room temperature followed by extraction with EtOAc (2×25 mL) and the combined organic layers were washed with water (2×10 mL), brine (10 mL) dried (Na2SO4) and evaporated in vacuo to afford the title compound as off white solid in 100% yield, 1.2 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[C:5]2[O:10][CH2:9][O:8][CH2:7][C:6]=2[CH:11]=1.[CH2:15]([O:17][C:18]([C:20]1([NH2:29])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:19])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:15]([O:17][C:18]([C:20]1([NH:29][C:12]([C:4]2[C:5]3[O:10][CH2:9][O:8][CH2:7][C:6]=3[CH:11]=[C:2]([F:1])[CH:3]=2)=[O:14])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: O=C(O)c1cc(F)cc2c1OCOC2
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cc(F)cc3c2OCOC3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of 6-fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid (386 mg, 1.95 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (400 mg, 1.95 mmol), HATU (1.11 g, 2.93 mmol) in anhydrous DMF (8 mL) is added DIPEA (484 μL, 2.93 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (70 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (61) as white solid (720 mg, 6%).
Reaction SMILES: O=[C:2]1[CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH2:9][CH2:8][C:3]21[CH2:7][CH2:6][CH2:5][CH2:4]2.C([O-])(=O)C.[NH4+].[BH3-]C#[N:23].[Na+]>CO>[NH2:23][CH:2]1[CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH2:9][CH2:8][C:3]21[CH2:7][CH2:6][CH2:5][CH2:4]2
Reactant: COC(=O)C1CCCC2(CCCC2)C1=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCCC2(CCCC2)C1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a flask containing methyl 6-oxospiro[4.5]decane-7-carboxylate, 60, (4.10 g, 19.50 mmol) in MeOH (35 mL) was added ammonium acetate (10.52 g, 136.50 mmol) and NaCNBH3 (1.47 g, 23.40 mmol). The mixture was stirred at room temperature for 24 hrs. GCMS showed conversion to product SM (Rt=12.3 min, E+=211), product (Rt=12.6 min, ES+=212 [major] and Rt=12.45 min, ES+=212 [minor]). The solvent was evaporated, HCl (1N) was added and the aqueous phase was extracted with EtOAc. The organic phase was neutralized with NaOH (6N) to pH ˜10. The aqueous phase was extracted three times with EtOAc and twice with dichloromethane, dried over Na2SO4 to yield 1.6 g of product.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([C:21]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([BH3-])#N.[Na+]>C(O)C>[CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([CH2:13][N:24]2[CH2:25][CH2:26][C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:22][CH2:23]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: O=Cc1ccn(Cc2ccccc2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: c1ccc(Cn2ccc(CN3CCC(c4ccccc4)(c4ccccc4)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product from step (a) (0.17 g) was dissolved in ethanol (3 ml) and a solution of 4,4-diphenylpiperidine (0.118 g) in ethanol (1 ml) added. A solution of sodium cyanoborohydride (1.0 M in tetrahydrofuran, 3.0 ml) was added and the solution stirred at room temperature for 16 hours. Silica gel was added, the solvent removed by evaporation and the crude material purified by chromatography (dichloromethane:methanol, 100:0 to 95:5) to give the product as an oil. Further purification by supercritical fluid chromatography gave the product as a solid (0.010 g), m.p. 167-168° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:11]#[N:12])[C:6](=[CH:9][CH:10]=1)[C:7]#[N:8].[Cl:13][C:14]1[CH:15]=[CH:16][C:17](=[O:51])[N:18]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]3[N:28]=[CH:29][N:30](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:31]=3)=[CH:22][N:21]=2)[CH:19]=1>CC#N>[Cl:13][C:14]1[CH:15]=[CH:16][C:17](=[O:51])[N:18]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]3[N:28]([CH2:2][C:3]4[CH:4]=[C:5]([C:11]#[N:12])[C:6](=[CH:9][CH:10]=4)[C:7]#[N:8])[CH:29]=[N:30][CH:31]=3)=[CH:22][N:21]=2)[CH:19]=1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Reactant: N#Cc1ccc(CBr)cc1C#N
Solvent: CC#N
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1C#N
Temperature: 60 °C

Procedure:
4-Bromomethyl-phthalonitrile from step 3 (50 mg, 0.28 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (150 mg, 0.28 mmol) were dissolved in CH3CN (1.4 ml) and heated to 60° C. for 16 hours. The solvent was removed in vacuo and redissolved in MeOH (1.4 ml). The reaction mixture was heated to 60° C. for several hours. Solvent was removed in vacuo and the resulting residue was purified by flash chromatography [4% MeOH(5% NH4OH)/CH2Cl2 ] to yield the final product.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:15])=[N:6][C:7]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:16]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:16][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([NH2:15])=[N:6][C:7]=1[C:10]1[O:11][CH:12]=[CH:13][N:14]=1
Reactant: Nc1nc(-c2ncco2)ccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(-c2ncco2)c(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 101.8 %

Procedure:
To a stirred solution of 3-nitro-6-(1,3-oxazol-2-yl)pyridin-2-amine (0.127 g, 0.62 mmol) in dimethylformamide (3 mL) at 0° C. was added N-bromosuccinimide (0.115 g, 0.65 mmol) and the mixture was warmed to room temperature. After 3 days, further N-bromosuccinimide (0.058 g, 0.33 mmol) was added and stirring was continued for 3 hours. The solution was poured into water and the precipitate was filtered, washed with water and dried to give the title compound (0.18 g, 70%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[C:4]2[N:3]=1.[C:17]1([S:23]([NH2:26])(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[CH:14]([NH:13][C:11]([C:10]1[CH:9]=[N:8][N:5]2[CH:6]=[CH:7][C:2]([NH:26][S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])=[N:3][C:4]=12)=[O:12])([CH3:16])[CH3:15]
Reactant: CC(C)NC(=O)c1cnn2ccc(Cl)nc12
Reactant: NS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CC(C)NC(=O)c1cnn2ccc(NS(=O)(=O)c3ccccc3)nc12
Temperature: 85 °C
Yield: 39.6 %

Procedure:
A mixture of 5-chloro-N-isopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide (95.5 mg, 0.40 mmol, 1.0 equiv), benzenesulfonamide (62.0 mg, 0.40 mmol, 1.0 equiv) and cesium carbonate (312 mg, 0.96 mmol, 2.4 equiv) in 1,2-dimethoxyethane (8 mL) was heated to 85° C. for 72 hours. The solvent was removed in vacuo, and the resultant residue dissolved in water. The pH of the solution was then adjusted to about 5 by the addition of 1M HCl aqueous solution and extracted with dichloromethane (2×30 mL). The organic extracts were concentrated under vacuum and the residue purified by flash column chromatography on silica gel (gradient: 0 to 10% methanol in dichloromethane) to afford 57.0 mg (40%) of 5-benzenesulfonylamino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid isopropylamide as a solid. LCMS (ESI) m+H=360.3; 1H NMR (400 MHz, DMSO-d6) δ: 12.2 (s, 1H), 8.97 (d, 1H), 8.30 (s, 1H), 8.01 (d, 2H), 7.64 (m, 4H), 6.64 (m, 1H), 4.13 (m, 1H), 1.21 (d, 6H).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].Cl[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][CH3:21]>C(Cl)(Cl)Cl>[CH2:10]([O:9][C:7](=[O:8])[C:6]([C:18]1[CH:17]=[CH:16][C:15]([S:20][CH3:21])=[C:14]([Cl:13])[CH:19]=1)=[O:12])[CH3:11]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CSc1ccccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=O)c1ccc(SC)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
A solution of aluminum trichloride (34.8 g, 261.4 mmol) in chloroform (120 mL) cooled to 0° C. was treated with a solution of ethyl chlorooxoacetate (18.7 mL, 167.5 mmol) in chloroform (120 mL). The mixture was stirred at 0° C. for 30 min. At this time, a solution of 2-chlorothioanisole (25.0 g, 156.5 mmol) in chloroform (120 mL) was added dropwise to the reaction mixture. It was then allowed to warm to 25° C. and stirred for an additional 3.5 h at 25° C. At this time, the reaction was quenched by the slow addition of water (500 mL) and extracted with chloroform (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded (3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (31.37 g, 77%) as a yellow oil: EI-HRMS m/e calcd for C18H24Cl2N2O3 (M+) 386.1164, found 386.1154.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][CH:22]([CH:26]1[CH2:28][CH2:27]1)[C:23]([NH2:25])=[O:24].CO>CCCCCCC>[C:23]([CH:22]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH:26]1[CH2:28][CH2:27]1)(=[O:24])[NH2:25]
Reactant: NC(=O)C(N)C1CC1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Solvent: CO
Solvent: CCCCCCC
Product: NC(=O)C(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethyloxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and α-amino-cyclopropaneacetamide (CAN 1100749-41-4) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/40% ethanol as eluent. The (−)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 381.1734 (M+H)+, αD20 (MeOH)=−23.5°.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.S(Cl)([Cl:29])=O>C(Cl)(Cl)Cl>[Cl:29][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product from Step F is dissolved in chloroform and cooled to 0° C. under nitrogen. Thionyl chloride (molar equivalent) is added slowly via syringe. The reaction is stirred for 30 min, and extracted with sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, filtered and concentrated to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:24])[C:5]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH2:17])[CH2:12][CH2:11]3)[CH:7]=1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:36](O)=[O:37])[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:31])[NH:32][C:33]1([C:36](=[O:37])[NH:17][C@@H:13]2[C:14]3[C:10](=[CH:9][C:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([F:24])[C:5]=4[C:18]4[N:22]=[C:21]([CH3:23])[O:20][N:19]=4)=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)[CH2:34][CH2:35]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3N)no1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(NC(=O)OC(C)(C)C)CC2)no1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], (S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-ylamine (intermediate A-11) was coupled with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid to yield the title compound as light yellow amorphous solid. MS: 527.2 (MH+, 1Cl).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[NH2:11][CH2:12][C:13]1[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=1>CCCCO>[Cl:9][C:6]1[N:5]=[C:4]([NH2:10])[N:3]=[C:2]([NH:11][CH2:12][C:13]2[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=2)[C:7]=1[NH2:8]
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Reactant: COc1c(C)cnc(CN)c1C
Solvent: CCCCO
Product: COc1c(C)cnc(CNc2nc(N)nc(Cl)c2N)c1C

Procedure:
A mixture of 4,6-dichloro-pyrimidine-2,5-diamine and 2-aminomethyl-4-methoxy-3,5-dimethyl-pyridine was heated to reflux in n-BuOH for 3 h, following the general procedure 1. HPLC RT was 3.597 min. 1HNMR (CDCl3) δ 8.22 (s, 1H), 7.12 (br. t, 1H), 4.61 (s, 2H), 4.56–4.55 (d, 2H), 3.80 (s, 3H), 3.00 (s, 2H), 2.29 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: Cl.[F:2][CH:3]([F:13])[O:4][C:5]1[CH:6]=[C:7]([NH:11][NH2:12])[CH:8]=[CH:9][CH:10]=1.[CH:14]([CH:16]([CH:22]=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=O>C(O)C.CCCCC>[F:2][CH:3]([F:13])[O:4][C:5]1[CH:6]=[C:7]([N:11]2[CH:22]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:14]=[N:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(C=O)C=O
Reactant: NNc1cccc(OC(F)F)c1
Agent: Cl
Solvent: CCCCC
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2cccc(OC(F)F)c2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(3-(Difluoromethoxy)phenyl)hydrazine hydrochloride (4.2 g, 19.9 mmol; CAS 479581-64-1) was suspended in ethanol (80 ml) and cooled to 0° C. A solution of ethyl 2-formyl-3-oxopropanoate (2.87 g, 19.9 mmol; CAS 80370-42-9) in ethanol (40 ml) was added, and the reaction was stirred overnight. The solvent was removed under reduced pressure and the residue partitioned between sodium bicarbonate solution and ethyl acetate. The organic layers were combined, dried (MgSO4) and evaporated to yield an orange solid. The solid was suspended in pentane (50 ml) and stirred at 35° C. for 90 min. The suspension was cooled in an ice bath for one hour and the solid was filtered and washed with pentane. After drying 5.12 g (91%) of a yellow solid was obtained MS (ISP): 283.1 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]=[O:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][Mg]Br>O1CCCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([OH:23])[CH3:24])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(C=O)nc3N21
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10.00 g (4R,9aR)-6-Formyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 100 ml tetrahydrofuran was added drop wise at 0° C. 20 ml of a ca 3M solution of methyl magnesium bromide solution in ether. The mixture was stirred at 0° C. for 30 min. The reaction mixture was quenched with 10% aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed with 105 aqueous citric acid, 10% aqueous sodium bicarbonate and brine, dried over sodium sulfate, evaporated and dried to constant weight under high vacuum to yield 10.0 g of the title compound as colorless oil (MS: 334.5 (M+H+)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:13][C:12](=O)[CH:11]=[C:10]([CH2:15][CH3:16])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)[Cl:19].C([O-])(O)=O.[Na+].[OH-].[Na+]>>[Cl:19][C:12]1[CH:11]=[C:10]([CH2:15][CH3:16])[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1
Reactant: CCc1cc(=O)[nH]c(-c2cccc(Cl)c2)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Temperature: 100 °C
Reaction time: 5 h
Yield: 92.3 %

Procedure:
A 250-mL round bottom flask was charged with 2-(3-chlorophenyl)-6-ethylpyrimidin-4(3H)-one (9.3 g, 39.8 mmol, 1 eq.). POCl3 (50 mL, 536 mmol, 13.4 eq.) was cautiously added at 0° C. The resulting mixture was stirred at 100° C. for 5 hr. After cooling to room temperature, the mixture was added slowly dropwise to cold aq. NaHCO3. NaOH was added to keep the pH˜0.7 during quenching. The mixture was extracted with ethyl acetate. The organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography using dichloromethane/ethyl acetate as eluent afforded 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (9.3 g, 99% yield) as a white solid. 1H NMR (CD3OD, 500 MHz) δ 8.32 (s, 1H), 8.28 (d, J=7.5 Hz, 1H), 7.50-7.46 (m, 1H), 7.45-7.40 (m, 1H), 7.27 (s, 1H), 2.83 (q, J=7.5 Hz, 2H), 1.34 (t, J=7.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=1>CN(C)C=O>[F:29][C:26]([F:27])([F:28])[C:23]1[N:22]=[CH:21][C:20]([CH2:19][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(C(F)(F)F)nc1
Yield: 79.1 %

Procedure:
By using (3,3,3-trifluoropropyl)malononitrile (83 mg), N,N-dimethylformamide (10 ml), potassium carbonate (71 mg) and 3-(chloromethyl)-6-(trifluoromethyl)pyridine (100 mg) according to the similar method described in Production Example 4 was obtained 130 mg of 2-((6-(trifluoromethyl)-3-pyridyl)methyl)-2-(3,3,3-trifluoropropyl)malononitrile represented by the following formula (hereinafter referred to as the present invention compound (9)).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[CH2:20].CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1/[CH:19]=[CH:20]/[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1
Reactant: C=Cc1ccccn1
Reactant: O=Cc1ccc2c(I)nn(C3CCCCO3)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=Cc1ccc2c(/C=C/c3ccccn3)nn(C3CCCCO3)c2c1
Temperature: 100 °C
Yield: 75.8 %

Procedure:
In a scintillation vial a solution of 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carbaldehyde (24 mg, 0.0673 mmol), 2-vinylpyridine (9.4 uL, 0.0875 mmol), DIPEA (24 uL, 0.135 mmol) and DMF (1.0 mL) was purged with Ar for 20 min. Pd(OAc)2 (1.5 mg, 0.0067 mmol) and P(o-tolyl)3 (6.1 mg, 0.0202 mmol) were then added and the vial was capped and heated to 100° C. overnight. The solution was cooled to room temperature and extracted with EtOAc, washing with NH4Cl(sat.), H2O, and brine. The organic layer was dried over MgSO4, the solvent removed in vacuo, and the residue purified by column chromatography (silica gel, 96:4 CH2Cl2/MeOH) to give 17 mg, 77% of a yellow oil which was 70% pure by NMR. This crude material was used for the subsequent synthetic step. 1H NMR (400 MHz, CD3OD) δ 10.16 (s, 1H), 8.59 (s, 1H), 8.34 (s, 1H), 8.27 (d, J=8.4 Hz, 1H), 7.95-7.83 (m, 4H), 7.75 (m, 1H), 7.68 (d, J=16.0 Hz, 1H), 6.00 (d, J=9.6 Hz, 1H), 4.05-4.01 (m, 1H), 3.93-3.86 (m, 1H), 2.65-2.56 (m, 1H), 2.27-2.10 (m, 2H), 1.92-1.66 (m, 3H); MS ESI 334.1 [M+H]+, calcd for [C20H19N3O2+H]+ 334.16.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5](I)=[CH:4][N:3]=1.[CH3:10][CH:11]([CH3:14])[C:12]#[CH:13]>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([C:13]#[C:12][CH:11]([CH3:14])[CH3:10])=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)ncc1I
Reactant: C#CC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)C#Cc1cnc(Cl)cc1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-chloro-5-iodopyridin-4-amine (Compound 11, 2.55 g, 10.0 mmol) in Et3N (35 ml) was added Pd(PPh3)2Cl2 (70 mg, 0.10 mmol), CuI (19 mg, 0.10 mmol), and 3-methyl-1-butyne (1.2 ml, 12 mmol). The reaction was stirred at room temperature for 20 h and was quenched with H2O, extracted with EtOAc (×2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][N:3]=1.[CH3:10][O:11]C1C=CC(Br)=CN=1.C([Li])CCC>O1CCCC1>[CH3:10][O:11][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][N:3]=1
Reactant: CSc1ccc(Br)nc1
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(SC)cn1

Procedure:
For example, 2-bromo-5-methylthiopyridine may be prepared by the treatment of 2-methoxy-5-bromopyridine (Shiao. M. J. et. al. Syn. Comm. 20(19), 2971, 1990) with n-butyllithium in anhydrous tetrahydrofuran at -78 ° C. followed by quenching the reaction with dimethyldisulfide to afford 2-methoxy-5-methylthiopyridine. Demethylation provides 2-hydroxy-5-methylthiopyridine which upon reaction with phosphorousoxybromide yields the desired 2-bromo-5-methylthiopyridine starting material. (Scheme 7) ##STR19##
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>CCO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)C1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@H](Oc2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Palladium (10 wt. %) on carbon (50 mg) was added in one portion to a solution of crude ethyl 4-(4-nitrophenoxy)cyclohexanecarboxylate in a mixture of EtOH (15 mL) and THF (10 mL). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 16 h then filtered and concentrated in vacuo to give a solid that was purified by chromatography, using 30-60% EtOAc in isohexane as eluent, to give the title compound (127 mg, 4% over 2 steps) as a solid; 1H NMR (CDCl3) δ1.16-1.20 (3H, t), 1.31-1.42 (2H, m), 1.43-1.52 (2H, m), 1.96-2.01 (2H, m), 2.05-2.10 (2H, m), 2.20-2.28 (1H, m), 3.35 (2H, br s), 3.89-3.96 (1H, m), 4.05 (2H, q), 6.53-6.57 (2H, d), 6.65-6.69 (2H, d); MS m/e MH+ 264.