Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH3:21])=[C:11]([CH2:13][OH:14])[CH:12]=1.[CH3:22]CN(C(C)C)C(C)C.CCOCC>C(Cl)Cl.CO>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH3:21])=[C:11]([CH2:13][O:14][CH3:22])[CH:12]=1
Reactant: CC1CCCCN1c1ccc(Br)cc1CO
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: COCc1cc(Br)ccc1N1CCCCC1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
Methanesulfonyl chloride (4.0 mL, 51.6 mmol) was added into a solution of [5-bromo-2-(2-methylpiperidin-1-yl)phenyl]methanol (13.43 g, 47.3 mmol) and DIEA (17.7 mL, 104 mmol) in anhydrous DCM (130 mL) cooled at 0° C. After 1 hour, the reaction mixture was diluted with MeOH (150 mL) and heated at 50° C. for 3 hours. The solvents were removed under reduced pressure to give a brown oil. The residue was taken up with Et2O (450 mL), and then washed with water (150 mL, pH 8 adjusted with a 5N aqueous solution of NaOH), saturated aqueous solution of NH4Cl (2×150 mL) and brine (150 mL). The aqueous layers were extracted with Et2O (150 mL). The combined organic layers were dried (MgSO4) and the solvent was removed under reduced pressure to give the title compound as a brown yellow oil (13.0 g, 92%) used without further purification in the next step. HPLC (Method A), Rt 2.9 min (Purity: 97.1%). HPLC/MS, M+(ESI): 298.1, 300.1. 1H NMR (CDCl3, 300 MHz) δ 7.59 (d, J=2.5 Hz, 1H), 7.36 (dd, J=8.5, 2.5 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 4.60 (d, J=12.8 Hz, 1H), 4.52 (d, J=12.8 Hz, 1H), 3.44 (s, 3H), 2.96-2.81 (m, 2H), 2.51 (m, 1H), 1.77 (m, 2H), 1.64 (m, 2H), 1.50-1.30 (m, 2H), 0.79 (d, J=6.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C[Si](C)(C)[O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C1COCC1.C(Cl)Cl>[N:9]1([CH2:8][CH2:7][O:6][C:5]2[CH:14]=[CH:15][C:2]([CH2:23][C:22]3[CH:25]=[CH:26][C:19]([OH:18])=[CH:20][CH:21]=3)=[CH:3][CH:4]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Reactant: C[Si](C)(C)Oc1ccc(C=O)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: Oc1ccc(Cc2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
To a stirred solution of 1-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine (2.89 g, 10.7 mmol) in THF (30 mL) was added dropwise 1.6 M solution in hexanes n-BuLi (7 mL, 10.2 mmol) over a 5-min period at −78° C. The mixture was stirred at −78° C. for 15 min before 4-trimethylsilyloxybenzaldehyde (2.08 g, 10.7 mmol) was added. The mixture was allowed to warm to rt during 20 min and quenched with water. Extraction with CH2Cl2, drying (MgSO4), filtration and evaporation provided the crude diarylmethanol which was dissolved in CH2Cl2 (30 mL) and stirred with triethylsilane (4 mL) and TFA (5 mL) for 16 h at rt. Evaporation gave 3.0 g (84%) 4-[4-(2-pyrrolidin-1-yl-ethoxy)-benzyl]-phenol. This was carbamoylated using general procedure 1 (CH2Cl2 was used as solvent) to give the title product after purification by preparative HPLC (Gilson) (35%, oil).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:22]=[CH:21][C:12]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1.[CH2:23]([N:26]=[C:27]=[O:28])[CH2:24][CH3:25]>C1(C)C=CC=CC=1>[C:13]([C:12]1[CH:21]=[CH:22][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:27]([NH:26][CH2:23][CH2:24][CH3:25])=[O:28])=[CH:10][CH:11]=1)(=[O:14])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCCN=C=O
Reactant: Nc1ccccc1Nc1ccc(C(=O)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCNC(=O)Nc1ccccc1Nc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-(2-aminophenylamino)benzophenone (Compound 101, 0.58 g, 2 mmol) in toluene (10 ml) was added n-propylisocyanate (0.23 ml, 2.4 mmol). The reaction mixture was heated for 4 hours on a steam bath. After cooling the reaction mixture to room temperature the resulting precipitate was collected by filtration and washed with toluene. The crude product was dissolved in hot isopropanol and crystallized on cooling to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:21][C:5]2[NH:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.[CH2:22]([O:24][C:25](=[O:36])[C:26](=[CH2:35])[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH3:23]>CCO>[C:28]([NH:27][CH:26]([CH2:35][N:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:4]3[CH:3]=[C:2]([CH3:1])[S:21][C:5]=3[NH:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[N:9]=2)[CH2:12][CH2:13]1)[C:25]([O:24][CH2:22][CH3:23])=[O:36])([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29]
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCNCC1
Reactant: C=C(NC(=O)OC(C)(C)C)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(CN1CCN(C2=Nc3ccccc3Nc3sc(C)cc32)CC1)NC(=O)OC(C)(C)C

Procedure:
A mixture of 2-methyl-4-(1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine, compound D above, (0.14 g, 0.46 mmol, 1 eq) and N-Boc-dehydroalanine ethyl ester (G, 0.1 g, 0.46 mmol, 1 eq) in 4 ml of anhydrous EtOH was refluxed at 60-65° C. overnight. The solvent was evaporated to dryness and the crude product was purified by flash chromatography (eluent—40% EtOAc in Hexanes). Yield—0.15 g (65%)
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:23])=[C:4]([C:13]([NH:15][C:16]([CH2:21][OH:22])([CH2:19][OH:20])[CH2:17][OH:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8].[C:24]([OH:27])(=O)[CH3:25].S(=O)(=O)(O)O.Cl>O>[NH2:1][C:2]1[C:3]([I:23])=[C:4]([C:13]([NH:15][C:16]([CH2:17][O:18][C:24](=[O:27])[CH3:25])([CH2:19][O:20][C:13](=[O:14])[CH3:4])[CH2:21][O:22][C:7](=[O:8])[CH3:6])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8]
Reactant: CC(=O)O
Reactant: Nc1c(I)c(C(=O)O)c(I)c(C(=O)NC(CO)(CO)CO)c1I
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)OCC(COC(C)=O)(COC(C)=O)NC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I

Procedure:
A mixture of 5-amino-2,4,6-triiodo-N-[tris(hydroxymethyl) methyl]isophthalamic acid and glacial acetic acid is heated in the presence of a catalytic amount of mineral acid (such as sulfuric acid or dry hydrogen chloride) or a dry cation exchange resin (strong acid form). Molecular sieves may be used to act as a water scavenger. After the reaction is complete the acid catalyst is neutralized, or in the case of use of molecular sieves and the cation-exchange resin, the reaction mixture is filtered. The solution is then concentrated in high vacuum to provide the desired 5-amino-2,4,6-triiodo-N-[tris(acetoxymethyl)methyl]isophthalamic acid in sufficient purity for use as an intermediate.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=O.[C:12](#[N:15])[CH:13]=C.C(N1CCOCC1)C>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:7]([C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[CH:13][C:12]#[N:15])=[CH:4][CH:5]=1)=[O:8]
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCN1CCOCC1
Solvent: Cc1ccc(C)cc1
Product: N#CC=Cc1ccc(C=O)cc1

Procedure:
The amounts of palladium acetate shown in Table 2 below, 6.74 g (40 millimols) of 4-formylbenzoyl chloride, 2.63 ml (40 millimols) of acrylonitrile and 5.12 ml (40 millimols) of N-ethylmorpholine, in 80 ml of p-xylene, are stirred for 5 hours at 120° C. The yields of 4-formylcinnamonitrile are shown in Table 2.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]2[C:11]([O:13][C:14](=[O:15])[C:2]=12)=[O:12].[NH2:16][C:17]([CH3:24])([CH:21]([CH3:23])[CH3:22])[C:18]([NH2:20])=[O:19]>O1CCCC1>[C:18]([C:17]([NH:16][C:14]([C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:15])([CH3:24])[CH:21]([CH3:23])[CH3:22])(=[O:19])[NH2:20]
Reactant: CC(C)C(C)(N)C(N)=O
Reactant: O=C1OC(=O)c2nc3ccccc3cc21
Solvent: C1CCOC1
Product: CC(C)C(C)(NC(=O)c1nc2ccccc2cc1C(=O)O)C(N)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2,3-quinolinedicarboxylic anhydride (0.037 mol) in tetrahydrofuran (THF, 250 ml) is stirred at 5° C. under a drying tube, and a solution of 2-amino-2,3-dimethylbutyramide (0.037 mol) in THF (50 ml) added thereto, in small increments, over a 15 minute period. The reaction mixture is allowed to warm slowly to room temperature for an extended period of time, i.e. about 17 hours. The solvent is evaporated in vacuo to afford a gummy residue, which is triturated with hot ethyl acetate (400 ml) and then filtered to afford the desired 2-[(1-carbamoyl-1,2-dimethylpropyl)carbamoyl]-3-quinolinecarboxylic acid, mp 172.5°-173.5° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>N1CCNCC1.O>[CH2:24]([O:23][C:21]([N:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)C1CNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Reaction time: 0.5 h

Procedure:
To azetidine-3-carboxylic acid (0.50 g), potassium carbonate (0.82 g), dioxan (5 mL), water (10 mL) was added benzyl chloroformate (0.74 mL) at room temperature for 6 h under nitrogen. Piperazine (5 drops) was then added. After ½ h, the dioxan was removed in vacuo and the residue diluted with 2M hydrochloric acid (25 mL). After extracting with ethyl acetate (35 mL), the organic layer was washed with brine (10 mL) and dried (MgSO4). Solvent removal in vacuo gave Intermediate 13 as a colourless oil (1.07 g).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:9](=[O:25])[N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=1[CH3:24])(=[O:5])[CH2:2][CH2:3][CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]([C:6]1[CH2:7][CH:8]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:9](=[O:25])[N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]1[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=1[CH3:22])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cc(C(=O)OCC)c(=O)n2c(-c3c(C)cc(C)cc3C)cccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC(=O)C1=C2C=CC=C(c3c(C)cc(C)cc3C)N2C(=O)C(C(=O)OCC)C1
Reaction time: 0.25 h
Yield: 40.9 %

Procedure:
Ethyl 1-butyryl-6-mesityl-4-oxo-4H-quinolizine-3-carboxylate (0.034 g, 0.084 mmol) was dissolved in tetrahydrofuran (1 mL). Lithium aluminum hydride (0.007 g, 0.17 mmol) was added at 0° C. After 15 minutes, the reaction was quenched with Glauber's salt. The solution was filtered, concentrated, and flash chromatographed (15% ethyl acetate/hexanes) to give the title compound (0.014 g, 41% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]([C:25](=[O:48])[C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:47])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)=[CH:28][CH:27]=2)[CH2:17][CH2:16][C:15]1=[O:49].C(N(CC)CC)C>ClCCl>[CH:12]([CH2:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]([C:25](=[O:48])[C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:33](=[O:47])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)=[CH:30][CH:31]=2)[CH2:17][CH2:16][C:15]1=[O:49])=[O:11]
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CCC(=O)N(CCO)c4ccccc43)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CCC(=O)N(CC=O)c4ccccc43)cc2)cc1
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
To a solution of oxalyl chloride (0.134 ml) in dichloromethane (10 ml) was added dimethyl sulfoxide (0.109 ml) at -78° C. and the mixture was stirred at the same temperature. After 10 minutes, 1-(2-hydroxyethyl) -5-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (400 mg) in dichloromethane (10 ml) was added dropwise at -78° C. and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added triethylamine (0.537 ml) and the mixture was allowed to ambient temperature. The solution was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo to give 1-formylmethyl-5-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (301 mg) as an unstable oil. The oil was used for next step without further purification.
Reaction SMILES: C(OC([C:8]1([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]#[C:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH:20]=[CH:19][C:11]([C:12](N2C=CN=C2)=[O:13])=[CH:10][CH2:9]1)=O)(C)(C)C.[OH-].[Na+].[NH2:44][CH2:45][CH:46]([OH:49])[CH2:47][OH:48]>C(Cl)(Cl)Cl>[OH:49][CH:46]([CH2:47][OH:48])[CH2:45][NH:44][C:12](=[O:13])[C:11]1[CH:10]=[CH:9][C:8]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]#[C:34][C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)=[CH:20][CH:19]=1
Reactant: NCC(O)CO
Reactant: CC(C)(C)OC(=O)C1(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)C=CC(C(=O)n2ccnc2)=CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(NCC(O)CO)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a mixture containing 4.3 g. of 1-{4-(tert-butyloxycarbonyl)-4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl}imidazole, 50 ml. of chloroform, and 50 ml. of 5N sodium hydroxide is added 1.1 g. of 3-amino-1,2-propanediol. The solution is vigorously stirred for 24 hours, the layers are separated, and the chloroform solution is washed once with 50 ml. of 1 N sodium hydroxide. The solvent is evaporated and the residue is heated for 30 minutes at 40° C. in 50 ml. of anhydrous trifluoroacetic acid. The solvent is again evaporated and the oil is crystallized from acetone to yield light yellow crystals of N-(2,3-dihydroxypropyl)-4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzamide.
Reaction SMILES: C1C=CC(Cl)=C(C[N:8]2[CH2:16][C:12]3[CH:13]=[CH:14][S:15][C:11]=3[CH2:10][CH2:9]2)C=1.NCCC1SC=CC=1>>[S:15]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:16][C:12]=2[CH:13]=[CH:14]1
Reactant: Clc1ccccc1CN1CCc2sccc2C1
Agent: NCCc1cccs1
Product: c1cc2c(s1)CCNC2

Procedure:
Alternatively, ticlopidine of formula (1a) may also be synthesized by directly cyclizing 2-(2-aminoethyl)thiophene of formula (a) with a formylating agent to obtain 4,5,6,7-tetrahydrothieno[3,2-c]pyridine of formula (f), and then reacting the compound (f) with a compound of formula (b).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](O)=[O:8].C(N(CC)CC)C.C(Cl)(=O)OCC.O.[NH2:29][NH2:30]>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:13][CH3:14])[C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:29][NH2:30])=[O:8]
Reactant: COC(OC)c1cccc(C(=O)O)c1
Reactant: NN
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(OC)c1cccc(C(=O)NN)c1
Temperature: -55 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
3.92 g of 3-dimethoxymethylbenzoic acid and 2.22 g of triethylamine were dissolved in 40 ml of methylene chloride. To the solution was dropwise added 2.28 g of ethyl chlorocarbonate at -30° to -20° C. The mixture was stirred for 30 minutes at the same temperature. The mixture was then cooled to -55° C., and 5.00 g of hydrazine hydrate was added thereto. The temperature of the mixture was elevated to room temperature. The methylene chloride layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: chloroform/ethanol=30/1) to obtain 4.13 g of colorless oily 3-dimethoxymethylbenzhydrazide.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH2:14][C:15]2[C:16]([CH3:21])=[N:17][O:18][C:19]=2[CH3:20])[CH:13]=1)=[O:7].[H-].[Na+]>CN(C=O)C>[CH3:21][C:16]1[C:15]([CH2:14][N:12]2[CH:13]=[C:9]([N:8]3[CH2:2][CH2:3][CH2:4][NH:5][C:6]3=[O:7])[CH:10]=[N:11]2)=[C:19]([CH3:20])[O:18][N:17]=1
Reactant: Cc1noc(C)c1Cn1cc(NC(=O)NCCCCl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc(N2CCCNC2=O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.7 %

Procedure:
1-(3-chloropropyl)-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)1H-pyrazol-4-yl)urea (example 9-5b) (200 mg, 0.64 mmol) and 60% sodium hydride (28 mg, 0.71 mmol) in DMF (2 mL) were stirred at 0° C. for 15 minutes then allowed to warm up to room temperature and stir for 2 hours. The reaction was quenched with methanol and concentrated. The reaction was diluted with brine (50 mL) and extracted with dichloromethane (2×, 50 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. The residue was taken up in dichloromethane (5 mL) and purified by silica column chromotography (100% to 90% dichloromethane in methanol: 30 minute gradient) to afford 1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)tetrahydropyrimidin-2(1H)-one (84 mg, 48%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ1.85-1.91 (m, 2H), 2.10 (s, 3H), 2.37 (s, 3H), 3.12 (m, 2H), 3.48 (t, J=6.0 Hz, 2H), 5.05 (s, 2H), 6.57 (s, 1H), 7.46 (s, 1H), 7.80 (s, 1H). LC/MS; [M+H] calculated for C13H17N5O2; expected 276.14. Found 276.10.
Reaction SMILES: C(C1C=CC=CN=1)#N.[C:9]([NH2:17])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:19]>>[Cl:19][C:11]1[C:10]([C:9]#[N:17])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: NC(=O)c1cccnc1
Solvent: N#Cc1ccccn1
Product: N#Cc1cccnc1Cl
Yield: 30 %

Procedure:
For production of a cyanopyridine, there has been known, for example, a process which comprises reacting nicotinamide with phosphorus pentachloride to obtain 2-chloro-3-cyano-pyridine at a yield of 30% [Org. Syn., Coll., Vol. IV, p. 166 (1963)]. In this process, however, use of phosphorus pentachloride makes the operation troublesome; the conversion of acid amide group into nitrile group and the chlorination of ring proceed simultaneously, perchlorides are formed, and various side reactions take place; thus, the yield of intended product is not sufficient. Hence, the process has not been satisfactory for selective production of an intended cyanopyridine.
Reaction SMILES: [OH:1][N:2]=[CH:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1C(=O)N(Cl)C(=O)C1.[CH2:24]([O:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)[C:25]#[CH:26].C(=O)(O)[O-].[Na+]>C1COCC1.CCN(CC)CC.CN(C=O)C>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([O:27][CH2:24][C:25]2[O:1][N:2]=[C:3]([C@@H:4]3[CH2:8][CH2:7][CH2:6][N:5]3[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:26]=2)[CH:29]=1
Reactant: C#CCOc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=NO
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc(COc2cccnc2)on1
Temperature: 25 °C
Yield: 55.2 %

Procedure:
To a DMF (60 mL) solution of the compound (8.57 g) obtained in Example 2-(1), NCS (5.341 g) was added in small portions at 0° C. and the mixture was stirred at room temperature for an hour. The reaction mixture was cooled to 0° C. and after adding a solution of 3-(prop-2-yn-1-yloxy)pyridine (2.663 g) in THF (5 mL) and a solution of Et3N (5.6 mL) in THF (15 mL), the resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was added to saturated aqueous sodium bicarbonate (200 mL), followed by extraction with AcOEt (200 mL). The resulting organic layer was washed with brine (200 mL), dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by neutral silica gel chromatography (AcOEt/hexane) to give the titled compound (3.81 g, pale yellow solid.)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[F:36][C:37]1[C:38]([CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[CH:39][C:40]([O:44][CH3:45])=[C:41]([CH:43]=1)[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[C:37]([F:36])[C:38]([CH2:46][CH2:47][N:48]4[CH2:53][CH2:52][O:51][CH2:50][CH2:49]4)=[CH:39][C:40]=3[O:44][CH3:45])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1cc(CCN2CCOCC2)c(F)cc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(CCN2CCOCC2)c(F)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 47.8 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 5-fluoro-2-(methyloxy)-4-[2-(4-morpholinyl)ethyl]aniline (46 mg, 0.18 mmol), and p-toluenesulfonic acid (92 mg, 0.49 mmol) were weighed into a 10 mL microwave vial. 5 mL of iPrOH was added and the mixture was heated in the microwave to 180° C. for 17 min. The mixture was transferred to a 50 mL round bottom and neutralized with 1 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography, followed by MeOH re-crystallization to give the title compound (61 mg, 0.086 mmol, 47%). 1H NMR (400 MHz, CDCl3) δ ppm 9.51 (d, J=6.97 Hz, 1H), 9.28 (s, 1H), 8.61 (d, J=2.20 Hz, 1H), 8.24-8.32 (m, 2H), 7.88 (dd, J=8.62, 2.38 Hz, 1H), 7.78 (s, 1H), 7.71 (d, J=8.80 Hz, 1H), 7.32-7.39 (m, 1H), 7.16-7.23 (m, 1H), 7.14 (d, J=8.80 Hz, 1H), 6.90-7.00 (m, 3H), 6.74 (d, J=6.60 Hz, 1H), 6.69 (d, J=5.13 Hz, 1H), 4.12 (s, 3H), 3.91 (s, 3H), 3.73-3.80 (m, 4H), 2.78-2.86 (m, 2H), 2.58-2.65 (m, 2H), 2.52-2.58 (m, 4H). MS (ESI): 710 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[C:3]=1[NH2:4].[CH3:13][N:14](C)C=O>CCOCC>[C:13]([C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[C:3]=1[NH2:4])#[N:14]
Reactant: CN(C)C=O
Reactant: Nc1c(Br)cccc1C(F)(F)F
Solvent: CCOCC
Product: N#Cc1cccc(C(F)(F)F)c1N

Procedure:
2-Bromo-6-trifluoromethylaniline (12.0 g., 0.05 mol.) and 4.5 g. (0.05 mol.) of cuprous cyanide in 100 ml. of dimethylformamide is refluxed for 12 hours. The reaction mixture is decomposed by addition of aqueous ferrous sulfate solution, ether is added, the layers are separated and the ethereal phase is washed with water, dried (MgSO4) and concentrated to give 2-cyano-6-trifluoromethylaniline.