Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li].[H-].[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+]>C1COCC1.O>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH2:16])=[CH:17][CH:18]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Li]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.4 %

Procedure:
To a stirred suspension of lithium alminium hydride (1.75 g, 0.46 mol) in THF (800 ml) at 0° was added 4-benzyloxybenzonitrile (43.0 g, 0.23 mol) in THF (600 ml), dropwise over 4 h. The reaction mixture was allowed to warm to room temperature and stirred for 16 h and then cooled to 0°. Water (30 ml) was added and 2M sodium hydroxide solution (80 ml) was then added dropwise with stirring. The resulting precipitate was filtered off washed with diethyl ether (100 ml) and toluene (200 ml). The fltrate was washed with sodium chloride solution, dried over sodium sulphate and the solvent removed by evaporation in vacuo, to give a waxy solid. The two soilds were combined to give the title compound (48.26 g, 110%). 1H NMR (CDCl3) δ 7.46-7.25 (5H, br m), 7.23 (2H, d, J 8.75 Hz), 6.95 (2H, d, J 8.7 Hz), 5.07 (2H, s), 3.81 (2H, s) and 1.50 (2H, br s). MS (ES) m/e 197 [M+NH4]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:12][CH:11]=1.[C:32](Cl)(=[O:41])[C:33]1[C:34]([O:39][CH3:40])=[CH:35][CH:36]=[CH:37][CH:38]=1.O>O1CCCC1.[H-].[Na+]>[CH3:40][O:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:32]([N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9](=[O:31])[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:14][CH:15]=1)=[O:41]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)NCc2ccccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(=O)c2ccccc2OC)cc1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a solution of 1 g of product from Example 4 in 15 ml of dry tetrahydrofuran is added in one portion 0.0622 g of sodium hydride. The mixture is heated at reflux temperature for 2 hours, cooled to room temperature and 0.442 g o-anisoyl chloride is added. The reaction is then heated at reflux for 1.5 hours, cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:35% ethyl acetate/hexane) to give 1.27 g of the desired product.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH:33]1([CH2:36][N:37]([CH2:45]OC)[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:35][CH2:34]1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[C@@H:15]([C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[CH2:45][N:37]([CH2:36][CH:33]1[CH2:34][CH2:35]1)[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:41])[CH3:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: COCN(CC1CC1)C(=O)OC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(CC1CC1)C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86.8 %

Procedure:
(R)-4-Benzyl-3-(2-(4-chlorophenyl)acetyl)oxazolidin-2-one (2.0 g, 6.06 mmol) was added to a flask in DCM (75 ml) followed by TiCl4 (1.38 g, 7.28 mmol) and DIEA (0.823 g, 6.37 mmol). The reaction was allowed to stir for about 15 to about 20 minutes at −78° C. at which point tert-butyl cyclopropylmethyl(methoxymethyl)carbamate (1.57 g, 7.28 mmol) was added. The reaction allowed to stir for 5 minutes, and the −78° C. bath was replaced with a 0° C. bath. The reaction was then allowed to stir for 3 hours at room temperature. After the reaction was determined to be complete by HPLC, the reaction was cooled to 0° C. and quenched by the slow addition of aqueous NaHCO3 while stirring for 10 minutes. The organic layer was separated, and the aqueous layer was re-extracted (3×EtOAc). The combined organics were dried with MgSO4, filtered and concentrated. The crude residue was purified by column chromatography, eluting 6:1 to 2:1 hexane/EtOAc to give tert-butyl (S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropyl(cyclopropylmethyl)carbamate (2.70 g, 87%) as light brown oil. (LCMS (APCI+) [M−Boc+H]+ 412.9; Rt: 4.42 min)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][N:3]=1.[N+:10]([CH2:13][C:14](=O)[CH2:15][CH3:16])([O-:12])=[O:11]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:14]([CH2:15][CH3:16])=[CH:13][N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1
Reactant: CCC(=O)C[N+](=O)[O-]
Reactant: NCc1ccc(Cl)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCC(=C[N+](=O)[O-])NCc1ccc(Cl)nc1
Yield: 57.6 %

Procedure:
In 50 ml of toluene, 4.2 g of 2-chloro-5-pyridylmethylamine, 3.5 g of 1-nitro-2-butanone and 0.1 g of p-toluene sulfonic acid were mixed and the mixture was refluxed for 2 hours. The solvent was then distilled off and the residue was purified by column chromatography on silica gel to afford 4.1 g of compound No. 368. m.p. 95°-98° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH2:3][CH:4]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][N:22]=1)[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[N:12]2)=[CH:7][CH:6]=1.Cl.[NH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36].C(N(C(C)C)CC)(C)C>CN(C)C=O.[Cl-].[NH4+]>[CH3:30][CH:2]([CH3:1])[CH2:3][CH:4]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[O:27])=[CH:23][N:22]=1)[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[N:12]2)=[CH:9][CH:10]=1
Reactant: CC(C)CC(Nc1ccc(C(=O)O)cn1)c1ccc(-n2cc(C(F)(F)F)cn2)cc1
Reactant: COC(=O)CCN
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)c1ccc(NC(CC(C)C)c2ccc(-n3cc(C(F)(F)F)cn3)cc2)nc1
Reaction time: 0.75 h
Yield: 82.8 %

Procedure:
To a solution of (+/−)-6-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)butylamino)nicotinic acid (50 mg, 0.12 mmol) in N,N-dimethylformamide (5 mL) was added O-(7-Azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (67.7 mg, 0.178 mmol). The mixture was stirred for 45 minutes. Methyl 3-aminopropionate hydrochloride (24.6 mg, 0.178 mmol) and diisopropylethylamine (61.5 mg, 0.476 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with saturated ammonium chloride. The solution was extracted three times with ethyl acetate. The combined organics were washed with water, dried over sodium sulfate, filtered and concentrated to give methyl 3-(6-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)butylamino)nicotinamido)propanoate (50 mg, 83%) as a brown oil. MS (M+1): 504.1.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:19])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2].[CH2:24]([O:26][C:27](=[O:30])[CH2:28]Cl)[CH3:25].C(N(CC)CC)C>CN(C=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:19])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:30])[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)CCl
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCNCC3)cc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCN(c2cc3c(cc2Cl)c(=O)c(C(=O)O)cn3CC)CC1
Yield: 49.8 %

Procedure:
A mixture of 1-ethyl-6-chloro-7-(1-piperazinyl)-4-oxo-1,4-dihydoquinoline-3-carboxylic acid 1.7 g (0.01 mole), ethylchloroacetate 1.2 g (0.01 mole), triethylamine 1.0 g (0.01 mole) and DMF 10 ml was heated at 90°-100° C. for 3 hours under stirring. The reaction mixture was cooled, evaporated under vacuum, the residue was dissolved in dichloromethane, washed with water, dried with anhydrous Na2SO4, and the solvent was distilled off. The residue was recrystallized from a mixed solvent of DMF and ethanol to obtain 2.1 g (quantitative) of 1-ethyl-6-chloro-7-(4-ethoxycarbonylmethyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. Colorless powders.
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[C:8]([CH:11]=[C:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:15])=[O:14])=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5].[CH2:28]([Li])CCC>CO.[Pt]=O>[ClH:27].[CH2:2]([C:6]1[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[C:8]([CH2:11][CH:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([O:15][CH3:28])=[O:14])=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: [Li]CCCC
Reactant: CCCCC(=Cc1cnc(CCCC)n1Cc1ccccc1Cl)C(=O)O
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: CCCCc1ncc(CC(CCCC)C(=O)OC)n1Cc1ccccc1Cl
Yield: 74 %

Procedure:
A mixture of methyl (E and Z)-3-[2-n-butyl-1-{(2chlorophenyl)methyl}-1H-imidazol-5-yl]-2-n-butyl-propenoate hydrochloride salt (prepared by the method in Example 6, replacing methyl lithium with butyl lithium) (245 mg, 0.578 mmol) in methanol (15 mL) and platinum oxide (30 mg) was stirred under an atmosphere of hydrogen for 0.5 hours. The catalyst was filtered, the filtrate was concentrated, and the residue was triturated with diethyl ether to afford 181 mg (74%) of methyl 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-n-butylpropanoate hydrochloride; mp 123°-125° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17]>C1COCC1.C(OCC)(=O)C>[CH2:1]([NH:8][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1NCc1ccccc1
Reaction time: 8 h

Procedure:
Benzylamine, (3.1 ml, 28 mmol) was added to 2-fluoronitrobenzene (3 ml, 28.5 mmol) in 20 ml dry THF and the reaction stirred overnight. The crude was diluted with ethyl acetate and washed with said. Bicarbonate and then purified by silica gel chromotography eluting with 10-50% Ethyl acetate in hexanes.
Reaction SMILES: Cl.C(OC1C=CC(C(N)=N)=CC=1)CCC.C(OC(=O)C(=COCC)C#N)C.CC[O-].[Na+].[OH-].[Na+].[C:34]([C:36]1[C:37](O)=[N:38][C:39]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:44][CH:43]=2)=[N:40][CH:41]=1)#[N:35].P(Cl)(Cl)([Cl:56])=O>C(O)C>[Cl:56][C:37]1[C:36]([C:34]#[N:35])=[CH:41][N:40]=[C:39]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:44][CH:43]=2)[N:38]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCOc1ccc(-c2ncc(C#N)c(O)n2)cc1
Agent: CCCCOc1ccc(C(=N)N)cc1
Agent: CCOC=C(C#N)C(=O)OCC
Agent: CC[O-]
Solvent: CCO
Product: CCCCOc1ccc(-c2ncc(C#N)c(Cl)n2)cc1

Procedure:
The starting material can be obtained according to the procedure of A. R. Todd and F. Bergel, J. Chem. Soc. 1937, 365 by reaction of p-n-butoxybenzamidine hydrochloride with α-ethoxymethylene-α-cyanoacetic acid ethyl ester and sodium ethylate in ethanol and then with sodium hydroxide solution. The resulting 5-cyano-4-hydroxy-2-(4-n-butyoxyphenyl)-pyrimidine (melting point 223.2°-229.5° C) is treated with phosphorus oxychloride to give 4-chloro-5-cyano-2-(4-n-butoxyphenyl)-pyrimidine having a melting point of 169.7°-170.2° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[OH:18][C:19]([CH3:32])([C:23]([NH:25][CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[O:24])[C:20](O)=[O:21].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.Cl>O1CCCC1>[OH:18][C:19]([CH3:32])([C:23]([NH:25][CH2:26][CH2:27][C:28]([F:29])([F:30])[F:31])=[O:24])[C:20]([NH:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2)=[O:21]
Reactant: CC(O)(C(=O)O)C(=O)NCCC(F)(F)F
Reactant: N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(O)(C(=O)NCCC(F)(F)F)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 36.7 %

Procedure:
A solution of 210 mg (0.94 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one and 215 mg (0.94 mmol) (RS)-2-hydroxy-2-methyl-N-(3,3,3-trifluoro-propyl)-malonamic acid in 50 ml tetrahydrofuran were cooled to 0° C. and 129 mg (0.94 mmol) 1-hydroxy-benzotriazole hydrate, 327 μl (1.87 mmol) diisopropylethylamine and 183 mg (0.94 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued overnight at room temperature. The mixture was poured on ice/water and 1 N aqueous hydrochloric acid was added until pH=1 was reached. Extraction with first diethylether and second with ethylacetate, washing with saturated aqueous sodium hydrogen carbonate solution and brine and chromatography on silicagel with ethylacetate/heptane 2/1 yielded 150 mg (41%) (R/S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(3,3,3-trifluoro-propyl)-malonamide as a white solid, MS (m/e): 436.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([CH3:13])[N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1.C(N(C(C)C)C(C)C)C>CC#N.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:13])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:6]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:7]=1
Reactant: Cc1cccc(N)c1
Reactant: COC(=O)c1c(C)nc(Cl)nc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)nc(Cl)nc1Nc1cccc(C)c1
Yield: 96.8 %

Procedure:
A mixture of methyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate (940 mg, 4.25 mmol), m-toluidine (0.461 mL, 4.25 mmol) and N-ethyldiisopropylamine (1.481 mL, 8.51 mmol) in CH3CN (30 mL) was heated under reflux for 3 h. The mixture was diluted with EtOAc, and was washed with brine and water. The organic extract was dried and concentrated under reduced pressure to give the title compound as a light yellow solid (1.2 g, 97%). [M+H] calc'd for C14H14N3ClO2, 292. found, 292.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]([CH3:13])[CH3:12])=[N:5][NH:6]2.[BH:14]([OH:16])[OH:15]>>[CH:11]([C:4]1[C:3]2[C:2]([B:14]([OH:16])[OH:15])=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6][N:5]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1n[nH]c2cccc(Br)c12
Reactant: OBO
Product: CC(C)c1n[nH]c2cccc(B(O)O)c12

Procedure:
4-Bromo-3-isopropyl-1H-indazole is converted to the corresponding boronic acid following analogous procedures to that given in the preceding example. 1H NMR (CD3OD) 7.44(d, 1H), 7.32 (t, 1H), 7.05 (d, 1H), 3.56 (m, 1H), 1.38 (d, 6H). LCMS (m/z): 205.45 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]#[N:10])[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[CH:3]=1.[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:17][SH:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:10][C:9]1[CH2:8][N:7]2[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[CH:3]=[C:2]2[S:18][C:17]=1[C:16]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CS
Reactant: CCCn1c(=O)cc(Cl)n(CC#N)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCn1c(=O)cc2n(c1=O)CC(N)=C(C(=O)OCC)S2

Procedure:
A solution of 6-chloro-1-cyanomethyl-3-propylpyrimidine-2,4(1H,3H)-dione (1.5 g), ethyl thioglycolate (0.88 g) and potassium carbonate (1 g) in ethanol (30 ml) was refluxed for 15 hours. The reaction solution was concentrated to dryness, and the resulting residue was purified by column chlomatography on silica gel. The resulting crude crystals were recrystalized from ethyl acetate-hexane to give colorless plates (0.23 g, 11%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[C:24]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])#[N:25].[H-].[Na+].Cl>O.O1CCOCC1>[C:24]([CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:11]1[C:12]([F:14])=[C:13]2[C:8]([C:7](=[O:18])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][N:4]2[CH:1]2[CH2:3][CH2:2]2)=[C:9]([F:17])[C:10]=1[F:16])#[N:25]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(C(C#N)C(=O)OCC)c(F)c(F)c2c1=O

Procedure:
6.6 of ethyl 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylate and 3.4 g of ethyl cyanoacetate are initially introduced into 100 ml of dioxane. 1.16 g of NaH are added in portions at room temperature. The mixture is heated to reflux for 6 hours and then diluted using water. After acidification using HCl, 9.4 g of the title compound can be isolated.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:16]([CH2:18][CH3:19])[N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:16]([CH2:18][CH3:19])[N:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: CCc1nc(N)sc1-c1ccccc1
Product: CCc1nc(NC(=O)c2cc(Br)ccc2O)sc1-c1ccccc1
Yield: 17.4 %

Procedure:
Using 5-bromosalicylic acid and 2-amino-4-ethyl-5-phenylthiazole as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[H-].[Na+].[CH2:11]([O:13][C:14]([C:16]1[C:20](CBr)=[C:19]([S:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)[N:18]([CH:32]([CH3:34])[CH3:33])[N:17]=1)=[O:15])[CH3:12].O>CN(C=O)C>[CH2:11]([O:13][C:14]([C:16]1[C:20]([CH2:2][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[C:19]([S:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)[N:18]([CH:32]([CH3:33])[CH3:34])[N:17]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)c1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1CBr
Reactant: OCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1Cc1ccncc1
Yield: 35.2 %

Procedure:
To a solution of 55 mg of 4-(hydroxymethyl)pyridine in DMF at 0° C. was added 20 mg sodium hydride (60% in oil). To the mixture was added dropwise a solution of 229 mg of 4-bromomethyl-5-(3,5-dichlorophenylthio)-1-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester in 2 ml of N,N-dimethylformamide. After 15 min water was added and the mixture was extracted with dichloromethane (×3). The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography using ethyl acetate/iso-hexane for the elution to give 80 mg of 5-(3,5-dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methyl]-1H-pyrazole-3carboxylic acid ethyl ester as a colourless gum. Mass spectrum (ESI) m/z 480 [M]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]2[N:7](S(C3C=CC(C)=CC=3)(=O)=O)[CH:6]=[CH:5][C:4]=2[C:3]=1[C:22]([C:24]1[N:28](COCC[Si](C)(C)C)[C:27]2[CH:37]=[CH:38][C:39]([C:41]#[N:42])=[CH:40][C:26]=2[N:25]=1)=[O:23].CC1C=C(C)C2N(S(C3C=CC(C)=CC=3)(=O)=O)C=CC=2C=1C(C1N(COCC[Si](C)(C)C)C2C=C(C#N)C=CC=2N=1)=O>>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]2[NH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:22]([C:24]1[NH:28][C:27]2[CH:37]=[CH:38][C:39]([C:41]#[N:42])=[CH:40][C:26]=2[N:25]=1)=[O:23]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(=O)c4nc5cc(C#N)ccc5n4COCC[Si](C)(C)C)c(C)cc(C)c32)cc1
Agent: Cc1ccc(S(=O)(=O)n2ccc3c(C(=O)c4nc5ccc(C#N)cc5n4COCC[Si](C)(C)C)c(C)cc(C)c32)cc1
Product: Cc1cc(C)c2[nH]ccc2c1C(=O)c1nc2cc(C#N)ccc2[nH]1

Procedure:
The title compound was synthesized from a mixture of 2-(5,7-dimethyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-(5,7-dimethyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 75-A) analogously to Example 64-B and 64-C. MS (ESI+) m/z 315.1 (M+H).
Reaction SMILES: Cl.Cl[CH:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[F:25])[CH3:4].[CH3:26][NH:27][C@@H:28]([C:30]([NH2:32])=[O:31])[CH3:29]>>[Cl:24][C:20]1[C:19]([F:25])=[C:18]([NH:17][C:8]2[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([CH:3]([N:27]([CH3:26])[C@@H:28]([C:30]([NH2:32])=[O:31])[CH3:29])[CH3:4])[CH:6]=3)[N:11]=[CH:10][N:9]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C(C)Cl
Reactant: CN[C@H](C)C(N)=O
Agent: Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C(C)N(C)[C@H](C)C(N)=O

Procedure:
6-(1-Chloroethyl)-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine hydrochloride (described in Example 91) was coupled with N2-methyl-D-alaninamide using an analogous method to that described for the equivalent step in Example 62 to give N2-(1-{4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}ethyl)-N2-methyl-D-alaninamide as a 1:1 mixture of diastereoisomers; 1H NMR Spectrum: (DMSO d6) 1.03 and 1.08 (both d, 1.5H); 1.38 (d, 3H); 2.06 and 2.22 (both s, 1.5H); 3.13 and 3.51 (both q, 0.5H); 3.97 (s, 3H); 4.31 (m, 1H); 7.07 (s, 1H); 7.22 (m, 1H); 7.23 (m, 1.5H); 7.44 (s, 0.5H); 7.53 (m, 2H); 8.44 (m, 1.5H); 8.60 (s, 0.5H); 9.77 and 9.80 (both s, 0.5H). Mass Spectrum: (M+H)+ 432.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([O:18]C)[N:8]2[CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:4]([NH2:20])[N:3]=1>CC(CC)CN>[NH2:20][C:4]1[N:3]=[C:2]([NH:8][CH2:11][CH:12]([CH3:17])[CH2:13][CH3:14])[N:10]=[C:9]2[C:5]=1[NH:6][C:7](=[O:18])[N:8]2[CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COc1nc2c(N)nc(Cl)nc2n1CC1CCOCC1
Agent: CCC(C)CN
Product: CCC(C)CNc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1
Temperature: 170 °C
Yield: 40.1 %

Procedure:
A mixture of 2-chloro-8-methoxy-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (40 mg) in 2-methyl-1-butylamine (117 mg) was heated in a microwave at 170° C. for 15 mins. The mixture was concentrated in vacuo to give a green oily residue which was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (20-60%) to give the title compound as an off-white solid (9 mg).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[CH3:27][C:28]1[N:29]=[CH:30][N:31]2[CH:35]=[CH:34][S:33][C:32]=12>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:29]3[C:28]([CH3:27])=[C:32]4[S:33][CH:34]=[CH:35][N+:31]4=[CH:30]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: Cc1ncn2ccsc12
Product: Cc1c2scc[n+]2cn1CC1=C(C(=O)[O-])N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Yield: 7.7 %

Procedure:
The same procedure as in Example 1 was repeated except that 103 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 117 mg of 7-methylimidazo[5,1-b]thiazole were used, thereby obtaining 7.8 mg of the title compound.