Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH:8]=[CH:7]2)([O-])=O.O.NN>CO.[Ni]>[N:15]1([CH2:14][CH2:13][N:9]2[C:10]3[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=3)[CH:7]=[CH:8]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc2c(ccn2CCN2CCCCC2)c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccc2c(ccn2CCN2CCCCC2)c1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
A suspension of compound 94 (250 mg, 0.915 mmol) in dry methanol (10 mL) was treated with Ra—Ni (˜0.05 g) followed by hydrazine hydrate (0.33 mL, 10.7 mmol) and the resulting mixture was refluxed for 20 min. The dark green reaction was cooled to room temperature, filtered through a celite pad, washed with methanol (2×10 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) to obtain compound 95 (215 mg, 97%) as a yellow oil. 1H NMR (CDCl3) δ 7.16 (d, J=8.7 Hz, 1H), 7.05 (d, J=3.0 Hz, 1H), 6.92 (d, J=2.1 Hz, 1H), 6.67 (dd, J=2.1, 8.7 Hz, 1H), 6.29 (d, J=3.0 Hz, 1H), 4.18 (t, J=7.2 Hz, 2H), 2.67 (t, J=7.5 Hz, 2H), 2.45 (m, 4H), 1.59 (m, 4H); ESI-MS (m/z, %): 244 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](Cl)=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C(C([O-])=O)=NN=N1)C1C=CC=CC=1.[K+].[CH3:32][C:33]1[CH:38]=[C:37]([C:39]([CH3:41])=[O:40])[C:36]([OH:42])=[C:35]([NH2:43])[CH:34]=1.N1C=CC=CC=1>C(Cl)Cl>[C:39]([C:37]1[C:36]([OH:42])=[C:35]([CH:34]=[C:33]([CH3:32])[CH:38]=1)[NH:43][C:13]([C:12]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=[N:10][N:11]=1)=[O:14])(=[O:40])[CH3:41]
Reactant: O=C(Cl)c1nnnn1Cc1ccccc1
Reactant: CC(=O)c1cc(C)cc(N)c1O
Agent: O=C([O-])c1nnnn1Cc1ccccc1
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1cc(C)cc(NC(=O)c2nnnn2Cc2ccccc2)c1O
Reaction time: 8 h

Procedure:
A solution of crude 1-benzyl-1H-tetrazole-5-carbonyl chloride (prepared from 0.73 g of potassium 1-benzyl-1H-tetrazole-5-carboxylate in the manner hereinbefore described in Reference Example 3) in dry methylene chloride (14 ml) was added to a stirred mixture of 3-amino-2-hydroxy-5-methylacetophenone (0.5 g) and pyridine (0.27 g) in dry methylene chloride (12 ml) at between 5° and 10° C. Stirring was maintained for 2 hours, allowing the temperature to rise to room temperature, and then the mixture was left to stand overnight. A further portion of methylene chloride (20 ml) was then added and the mixture was washed with water. The organic phase was dried over magnesium sulphate, and evaporated in vacuo to give a solid, which was recrystallised from ethanol, to give 3'-acetyl-1-benzyl-2'-hydroxy-5'-methyl-1H-tetrazole-5-carboxanilide (1.0 g), m.p. 183°-184° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)[CH:10]=[CH:9][C:8]=2[OH:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([O-])([O-])=O.[Cs+].[Cs+].C1(Br)CCCC1.C1(O)C=CC=CC=1.ClCl>CN(C=O)C>[CH:1]1([O:6][C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)[CH:10]=[CH:9][C:8]=2[O:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cccc(-c2ccc(O)c(OC3CCCC3)c2)c1
Agent: BrC1CCCC1
Agent: ClCl
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Product: COc1ccc(-c2cccc([N+](=O)[O-])c2)cc1OC1CCCC1
Yield: 53.9 %

Procedure:
2-Cyclopentyloxy-4-(3-nitrophenyl)phenol (600 mg, 2.45 mmol) was dissolved in DMF (40 ml) and treated with Cs2CO3 (730 mg, 2.24 mmol) and cyclopentyl bromide (0.32 ml, 2.94 mmol). After stirring overnight at RT some of the phenol remained (SiO2 :t.l.c, CH2 Cl2). Cs2CO3 (870 mg, 2.67 mmol) and cyclopentyl bromide (0.32 ml, 2.94 mmol) were added. After stirring at RT for 3 h the phenol had been consumed. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in Et2O (50 ml), filtered, and concentrated in vacuo to give a yellow solid which was recrystallised from dichloromethane/hexane to afford the title compound (378 mg) as yellow needles. δH (CDCl3 ; 80 mHz) 1.5-2.1 (8H, br m, (CH2)4), 3.87 (3H, s, OMe), 4.84 (1H, br m, OCHCH2), 6.91 (1H, d, J9.1 Hz, ArH ortho to OMe), 7.0-7.2 (2H, m, ArH meta to OMe), 7.54 (1H, d, J 7.5 Hz, ArH meta to NO2), 7.80 (1 H, ca. dt, J ca 7.5, 1.5 Hz, ArH para to NO2), 8.09 (1H, ca. dt, J ca.8, 1.5 Hz, ArH para to aryl), 8.33 (1H, ca. t, J ca 2 Hz, ArH ortho to NO2 and aryl); m/z 313 (M+, 7%), 246 (17), 245 (M+ -cyclopentyl, 100), 230 (41), 202 (8), and 139 (9).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:14]([Cl:25])[CH:13]=2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][C:37]([C:38]([NH2:40])=[O:39])=[CH:36][CH:35]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.CN(C=O)C.O1CCOCC1>[Cl:25][C:14]1[CH:13]=[C:12]([NH:11][C:5]2[C:6]3[N:7]([CH:8]=[CH:9][N:10]=3)[C:2]([C:34]3[CH:42]=[CH:41][C:37]([C:38]([NH2:40])=[O:39])=[CH:36][CH:35]=3)=[CH:3][N:4]=2)[CH:17]=[CH:16][C:15]=1[N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1
Reactant: CC1(C)OB(c2ccc(C(N)=O)cc2)OC1(C)C
Reactant: CN1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2Cl)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(Nc3ncc(-c4ccc(C(N)=O)cc4)n4ccnc34)cc2Cl)CC1

Procedure:
In the same way as described for Compound 178, step 4, using (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-[3-chloro-4-(4-methyl-piperazin-1-yl)-phenyl]-amine (60.0 mg, 0.14 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (46.0 mg, 0.28 mmol), Pd(PPh3)4 (40.0 mg, 0.035 mmol) and 1.5 M Na2CO3 (0.75 mL, 1.12 mmol) in 2:1 DMF-dioxane (3 mL). The crude residue is triturated with DCM and then the title compound is crystallised from EtOH (4 mg, 6%). LCMS: Rt 2.01 min (96%) m/z (APCI) 462 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.27 (3H, s), 2.49-2.54 (4H, t), 2.99 (4H, m), 7.19 (1H, d), 7.53 (1H, br s), 7.60 (1H, s), 7.76 (1H, s), 7.84 (2H, d), 7.98 (1H, dd), 8.04 (1H, s), 8.09 (2H, d), 8.13 (1H, br s), 8.35 (1H, s), 9.86 (1H, s).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][C:11]([OH:15])([CH3:14])[C:12]#[CH:13].O1CCCC1>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)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:13]#[C:12][C:11]([OH:15])([CH3:14])[CH3:10])=[CH:3][CH:4]=1)#[N:7]
Reactant: C#CC(C)(C)O
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(O)C#Cc1ccc(C#N)cc1
Yield: 105.3 %

Procedure:
50 g (274.7 mmol) 4-bromobenzonitrile, 46.2 g (550 mmol) 3-methyl-1-butyne-3-ol, 0.97 g (1.38 mmol) bis(triphenylphosphine) dichloropalladium, 0.26 g (1.38 mmol) copper iodide and 2 g (7.6 mmol) triphenyl phosphine were added in a nitrogen stream, and 100 ml tetrahydrofuran (THF) and 20 ml triethylamine were added thereto, and the mixture was reacted at 80 ° C. for 15 hours. The reaction solution was concentrated and partitioned by adding 300 ml ethyl acetate and 300 ml water, and the organic layer was washed twice with 100 ml water and dried over magnesium sulfate anhydride. The solvent was distilled away, and about 250 ml heptane was added to the residual paste and stirred for a while, and the precipitated crystals were filtered to give 53.6 g crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[N:5].CCN(CC)CC.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:13]([Si:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[O:1][CH2:2][CH2:3][C:4]#[N:5])([CH3:16])([CH3:14])[CH3:15]
Reactant: N#CCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCCC#N)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxypropanenitrile (7.1 g, 0.1 mol) and DMAP (1.22 g, 0.01 mmol) in 30 mL of dry DCM at room temperature was added NEt3 (30.3 g, 0.3 mol), followed by tert-butyldiphenyl-silylchloride (27.5 g, 0.1 mol). A lot of white solid appeared. After stirring at room temperature overnight, the reaction mixture was quenched with Sat. NH4Cl solution, extracted with DCM, dried over Na2SO4, and evaporated in vaco. Flash chromatography (SiO2, hexane/EtOAc=100:2 to 100:5 to 100:10) gave the title compound as a white solid. B. Preparation 3-(tert-butyldiphenylsilyloxy)propanamidine. To a suspension of NH4Cl (5.35 g, 0.1 mol) in 60 mL of dry benzend at 0 C was slowly added 50 mL of 2 M solution of trimethylaluminum in toluene. After the addition was complete, the reaction mixture was allowed to warm up to room temperature and was stirred for 2 h until gas evolution had ceased. A solution of the above nitrile in 20 mL of dry benzene was added to the aluminum amide reagent and the resulting mixture was heated up to 80 C for 20 h. The reaction mixture was slowly cooled to room temperature and then carefully poured into a slurry of 300 mL of DCM and 200 g of silica gel. It was then filtered and washed thoroughly with MeOH/DCM (1:2). After concentration, flash chromatography (SiO2, EtOAc to EtOAc/MeOH=100:20 to 100:30 to EtOAc/2 m NH3 in MeOH=100:30) gave the product as a white solid. C. Preparation of 3-(tert-butyldiphenylsilyloxy)propanamidine2-(2-(tert-butyldiphenylsilyloxy)ethyl)-7,8-dihydroquinazolin-5(6H)-one.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].N1C=CC=CC=1.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl>[C:19]([O:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[CH2:12])=[CH:9][CH:10]=1)([CH3:4])[CH3:3])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: C=Cc1ccc(C(C)(C)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=Cc1ccc(C(C)(C)OC(C)=O)cc1
Yield: 48 %

Procedure:
A mixture of 6.7 g of 1-(1-hydroxy-1-methylethyl)-4-ethenyl-benzene and 4.0 g of pyridine in 100 ml of dichloromethane was stirred while 4.0 g of acetyl chloride in 20 ml of dichloromethane was added dropwise. After the addition was complete, the mixture was refluxed gently overnight. After cooling, an additional 30 ml of dichloromethane was added and the mixture was then washed with 50 m) of cold 5% aqueous HCl, and then several times with 30 ml portions of water. After drying over magnesium sulfate, filtering, and concentrating, the crude product was purified by HPLO using ethyl/acetate hexane as eluent. This method affords 4.05 g (47.5% yield) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](#[N:12])[CH:10]=[CH2:11].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:10][C:9]#[N:12])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: C=CC#N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#CCCOc1ccc(Cl)cc1

Procedure:
A mixture of p-chlorophenol (25 g), acrylonitrile (30 ml) and a solution of benzyltrimethylammonium hydroxide (8 ml of a 40 wt % solution in methanol) were heated at reflux over the weekend. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extract was dried and evaporated to give 3-(4-chlorophenoxy)propionitrile.
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[C:7]([NH2:14])[C:8]([O:12][CH3:13])=[C:9]([NH2:11])[CH:10]=1)([CH2:3][CH3:4])[CH3:2].N1C=CC=CC=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[NH2:14][C:7]1[C:8]([O:12][CH3:13])=[C:9]([NH:11][S:22]([CH3:21])(=[O:24])=[O:23])[CH:10]=[C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(C)c1cc(N)c(OC)c(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(C)c1cc(N)c(OC)c(NS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.46 g of 5-sec-butyl-2-methoxy-1,3-diamino-benzene are dissolved in 20 ml dichloromethane, combined with 1.21 ml of pyridine and cooled to 0° C. 600 μl of methanesulphonic acid chloride are added, the mixture is allowed to come up to ambient temperature and stirred for 2 hours. The solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20 to 20:80).
Reaction SMILES: [CH2:1]([C:3]1([CH2:10][O:11][C:12](=[O:15])[CH:13]=[CH2:14])[CH2:8][O:7][C:6](=[O:9])[O:5][CH2:4]1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:27][OH:28]>>[CH2:1]([C:3]([CH2:10][O:11][C:12](=[O:15])[CH:13]=[CH2:14])([CH2:8][O:7][C:6]([O:5][CH3:4])=[O:9])[CH2:27][OH:28])[CH3:2]
Reactant: CO
Reactant: C=CC(=O)OCC1(CC)COC(=O)OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CC(=O)OCC(CC)(CO)COC(=O)OC

Procedure:
Analogous to Example 1, the title compound was synthesized using 21.4 g of 5-ethyl-5-acryloyloxymethyl-2-oxo-1,3-dioxane, 96 g of methanol and 0.1 g of p-toluenesulfonic acid.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][NH2:15])=[C:10]([CH3:16])[CH:9]=1.[C:17](OCC)(=[O:20])[C:18]#[CH:19]>O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:19]=[CH:18][C:17]([OH:20])=[N:15]2)=[C:10]([CH3:16])[CH:9]=1
Reactant: Cc1cc(Br)ccc1NN
Reactant: C#CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(Br)ccc1-n1ccc(O)n1
Yield: 24.3 %

Procedure:
Potassium tert-butoxide (20 ml, 1M in tert-butanol, 20.0 mmol) was added to 1-(4-bromo-2-methylphenyl)hydrazine (J. Chem. Soc. 109; 1916; 582)(2.01 g, 10.0 mmol) to give a dark brown suspension. Ethyl propiolate (1.02 ml, 10 mmol) was then added dropwise over 10 minutes, with cooling, and once addition was complete, the reaction was heated under reflux for 4 hours. The reaction was diluted with water (200 ml) and this mixture washed with dichloromethane (2×50 ml). The aqueous phase was acidified using hydrochloric acid (2N), extracted with dichloromethane (5×100 ml), these combined organic extracts dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol (98:2) as eluant, and triturated with ether/di-isopropyl ether to give the title compound (615 mg, 24%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.[H-].[Na+]>C1COCC1>[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]2[N:22]=[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]3[C:2](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:1]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(C#N)cc1
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A 7.9 g portion of 2-aminobenzophenone, 4.7 g of 4-methylbenzonitrile and 2.0 g of 60% sodium hydride were suspended in 40 ml of THF and heated at 60° C. with stirring for 2 hours. After completion of the reaction, the reaction mixture was allowed to cool and the precipitate was collected by filtration, thus giving 5.7 g of 2-(4-methylphenyl)-4-phenylquinazoline as a crude product. Then 4.4 g of the compound thus obtained, 2.7 g of NBS and 0.2 g of benzoyl peroxide were suspended in 50 ml of carbon tetrachloride and refluxed with heating for 2 hours. The reaction mixture was allowed to cool and 20 ml of diethyl ether was added thereto. The crystals precipitated were separated by filtration. The filtrate was concentrated under reduced pressure. The residue was recrystallized from chloroform-n-hexane to provide 1.9 g of 2-(4-bromomethylphenyl)-4-phenylquinazoline as colorless needles. Then 1.9 g of the crystals thus obtained were suspended in 10 ml of triethyl phosphite and heated with stirring at 130° C. for 2 hours. After completion of the reaction, an excess of triethyl phosphite was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: chloroform: n-hexane=1:1) and recrystallized from diethyl ether-n-hexane to provide 0.2 g of the objective compound as colorless needles. Table 1 shows the structure and physical property (melting point) of the compound.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[CH:8][CH:7]=1.[S:25]1(=[O:33])(=[O:32])[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1.C(O)(=O)C.C(=O)([O-])O.[Na+]>CO>[ClH:1].[O:32]=[S:25]1(=[O:33])[CH2:30][CH2:29][CH:28]([NH:2][C@@H:3]2[CH2:5][C@H:4]2[C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=3)=[CH:10][CH:11]=2)[CH2:27][CH2:26]1
Reactant: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1
Reactant: O=C1CCS(=O)(=O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(Nc1ccc([C@@H]2C[C@H]2NC2CCS(=O)(=O)CC2)cc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (75 mg), tetrahydro-4H-thiopyran-4-one 1,1-dioxide (37.4 mg) and acetic acid (0.2 mL) in methanol (2 mL) was added 2-picoline-borane complex (38.2 mg). The mixture was stirred at room temperature overnight, and saturated aqueous sodium hydrogen carbonate solution was added under ice-cooling. The mixture was m extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate, ethyl acetate/methanol) and 10% hydrochloric acid methanol solution was added. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (32.0 mg).
Reaction SMILES: N1(C(Cl)=O)CCCC1.[N:9]1([C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][C:28]1[C:37]2[C:32](=[CH:33][C:34]([O:40][CH3:41])=[C:35]([O:38][CH3:39])[CH:36]=2)[N:31]=[CH:30][CH:29]=1)[NH2:23].C1(C)C=CC=CC=1>C(O)C>[N:9]1([C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:17]([NH:16][C:14]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:15])=[S:18])[CH:24]=[CH:25][C:26]=1[O:27][C:28]1[C:37]2[C:32](=[CH:33][C:34]([O:40][CH3:41])=[C:35]([O:38][CH3:39])[CH:36]=2)[N:31]=[CH:30][CH:29]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)N1CCCC1
Agent: O=C(N=C=S)N1CCCC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)N4CCCC4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
1-Pyrrolidinecarbonyl isothiocyanate was prepared using commercially available 1-pyrrolidinecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 1-Pyrrolidinecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (52 mg, yield 70%).
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])([C:6]#[CH:7])[CH3:5].[Li]CCCC.CON(C)[C:19]([C:21]1[CH:29]=[CH:28][C:24]2=[N:25][O:26][N:27]=[C:23]2[CH:22]=1)=[O:20]>C1COCC1>[N:25]1[O:26][N:27]=[C:23]2[CH:22]=[C:21]([C:19](=[O:20])[C:7]#[C:6][C:4]([CH3:8])([O:3][Si:2]([CH3:10])([CH3:9])[CH3:1])[CH3:5])[CH:29]=[CH:28][C:24]=12
Reactant: CON(C)C(=O)c1ccc2nonc2c1
Reactant: C#CC(C)(C)O[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C#CC(=O)c1ccc2nonc2c1)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
To a −78° C. stirred solution of trimethyl(2-methylbut-3-yn-2-yloxy)silane (0.49 g, 2.367 mmol) in dry THF (20 mL), n-BuLi (3.70 mL, 5.917 mmol, 1.6 M in hexane) was added dropwise over 10 minutes under an inert atmosphere. The reaction mixture was stirred for 30 min at −78° C., and then a solution of N-methoxy-N-methylbenzo[c][1,2,5]oxadiazole-5-carboxamide (0.557 g, 3.550 mmol) in dry THF (10 mL) was added to reaction mixture and stirring was continued for an additional 3 h at −78° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 5% EtOAc in hexanes to afford 1-(benzo[c][1,2,5]oxadiazol-5-yl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-1-one (0.45 g, 63%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1(C)C=CC(S(O)=O)=CC=1.[Na].[C-:22]#[N:23].[K+]>CS(C)=O.O>[N:5]1[C:4]2[NH:8][CH:9]=[CH:10][C:3]=2[C:2]([C:22]#[N:23])=[N:7][CH:6]=1
Reactant: [C-]#N
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cc1ccc(S(=O)O)cc1
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ncnc2[nH]ccc12
Temperature: 100 °C

Procedure:
Commercially available 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1 g, 6.51 mmol) was dissolved in DMSO (15 mL) then p-toluenesulfinic acid, sodium salt (1.16 g, 6.51 mmol) and KCN (635 mg, 9.76 mmol) were added. The reaction mixture was heated at 100° C. for 17 h, cooled to RT and diluted with water. The mixture was extracted with EtOAc. The organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give 7H-pyrrolo[2,3-d]pyrimidine-4-carbonitrile as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[CH:4][N:3]=1.[CH3:11][Mg]Br>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([OH:10])[CH3:11])=[CH:4][N:3]=1
Reactant: C[Mg]Br
Reactant: O=Cc1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Product: CC(O)c1cnc(Cl)nc1Cl
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2,4-dichloro-pyrimidine-5-carbaldehyde (Example 17, 1.01 g, 5.7 mmol) in THF (10 mL), methyl magnesium bromide (Aldrich, 3 M in ether, 6.27 mmol, 2.1 mL) was added slowly at −78° C. The mixture was stirred for an additional 2 hours at −78° C. and the reaction was quenched with 1N HCl (10 mL). The resulting mixture was extracted with EtOAc and the extract was dried with sodium sulfate. Removal of solvent gave a brown solid. 1.07 g, 97%. MS (M+H)+, 193.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16][CH2:17]O>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([O:7][CH2:16][CH3:17])=[O:6]
Reactant: O=C(O)c1ccc(F)c(Br)c1
Reactant: CCO
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(F)c(Br)c1
Yield: 90.3 %

Procedure:
To a solution of compound 3-bromo-4-fluoro-benzoic acid (430 g, 1.97 mol, 1 eq) in EtOH (2.3 L) was added dropwise thionyl chloride (287 mL, 3.94 mol, 2 eq) at 10° C. Then the mixture was heated to reflux overnight. The mixture was concentrated in vacuum to give a residue. The residue was dissolved in ethyl acetate (800 mL), washed with aqueous sodium hydrogen carbonate, brine (300 mL) and water (200 mL), then concentrated in vacuo to give title compound as a white solid (440 g, 1.78 mol, 90.3%).