Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH2:8][CH:9]([P:16]([O:20]C)(=[O:19])[O:17]C)[P:10]([O:14]C)(=[S:13])[O:11]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](Br)(C)C>C(Cl)(Cl)Cl>[CH2:1]([CH2:8][CH:9]([P:16]([OH:20])(=[O:17])[OH:19])[P:10]([OH:14])(=[S:13])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COP(=O)(OC)C(CCc1ccccc1)P(=S)(OC)OC
Agent: C[Si](C)(C)Br
Solvent: ClC(Cl)Cl
Product: O=P(O)(O)C(CCc1ccccc1)P(O)(O)=S
Reaction time: 0.25 h

Procedure:
Tetramethyl 2-benzylthioethane-1,1-diphosphonate (2.45 g) in chloroform (5 cm3) was treated with an excess of trimethylsilyl bromide (5.1 g) at room temperature. The formation of the trimethylsilyl esters was monitored by 31P n.m.r. and was complete after 15 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Cl.O=[C:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH:13]1[C:18](OC)=[O:19]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]=3[C:18](=[O:19])[O:9][C:5]=2[CH:4]=1
Reactant: COC(=O)C1CNCCC1=O
Reactant: COc1cccc(O)c1
Agent: Cl
Product: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Yield: 35.8 %

Procedure:
Prepared by the method described for Example 1 from 3-methoxyphenol (16 g, 0.126 moles) and methyl 4-oxo-3-piperidinecarboxylate hydrochloride (25 g, 0.129 moles). Recrystallization from ethanol gave the product (10.43 g), mp 179°-183° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[Cl:9][CH2:10][C:11](=O)[CH2:12][C:13](OCC)=[O:14]>>[Cl:9][CH2:10][C:11]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]2[C:13](=[O:14])[CH:12]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Cc1cccc(N)n1
Product: Cc1cccc2nc(CCl)cc(=O)n12
Temperature: 125 °C
Reaction time: 5.5 h

Procedure:
A mixture of 2-amino-6-methylpyridine (10.00 g, 92.47 mmol), ethyl 4-chloro-acetoacetate (16.24 mL, 120.2 mmol), and polyphosphoric acid (50.00 g) was stirred at 125° C. After 5.5 h, the mixture was removed from the heat. To the cooled mixture was added ice-water (200 mL) and neutralized with 2 N NaOH (400 mL) to pH 6-7. The resulting precipitate was collected by filtration, washed with water (˜400 mL), and dried to give 2-(chloromethyl)-6-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one as a dark brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.68 (1 H, dd, J=9.0, 7.0 Hz), 7.40 (1 H, dd, J=9.0, 0.8 Hz), 6.93 (1 H, d, J=6.7 Hz), 6.36 (1 H, s), 4.58 (2 H, s), 2.93 (3 H, s); Mass Spectrum (ESI) m/e=208.9 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[NH:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][NH:25]C(=O)OCC)[CH2:19][CH2:18]2)[N:3]=[CH:2]1.[BrH:31]>O>[BrH:31].[BrH:31].[BrH:31].[NH2:25][CH2:24][CH2:23][N:20]1[CH2:19][CH2:18][CH:17]([NH:16][C:8]2[N:7]([CH2:6][C:4]3[N:3]=[CH:2][S:1][CH:5]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH2:22][CH2:21]1
Reactant: CCOC(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2cscn2)CC1
Agent: Br
Solvent: O
Product: NCCN1CCC(Nc2nc3ccccc3n2Cc2cscn2)CC1

Procedure:
A mixture of 14 parts of ethyl [2-[4-[[1-(4-thiazolylmethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]carbamate and 300 parts of a hydrobromic acid solution 48% in water was stirred and refluxed for 30 minutes. The reaction mixture was evaporated. The sticky residue solidified in a mixture of ethanol and acetonitrile. The product was filtered off and dried, yielding 14 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-(4-thiazolylmethyl)-1H-benzimidazol-2-amine trihydrobromide (intermediate 134).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[N:3][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2ncc(Br)cc2[N+](=O)[O-])cc1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
A stirred mixture of 2,5-dibromo-3-nitropyridine (0.2563 g, 0.909 mmol), 4-methoxyphenylboronic acid (0.14 g, 0.93 mmol), tetrakis(triphenylphosphine)-palladium (0.072 g, 0.062 mmol), and 2.0M sodium carbonate (2.3 mL, 4.60 mmol) in toluene (3.0 mL) and ethanol (1.0 mL) was heated to 70° C. After 2.5 h, the reaction was cooled to rt then diluted with water. After extraction with EtOAc, the organic extraction was dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified on silica gel (0-15% EtOAc in hexanes) to afford a yellow solid as 5-bromo-2-(4-methoxyphenyl)-3-nitropyridine. 1H NMR (400 MHz, CDCl3) δ ppm 8.88 (1H, d, J=2.0 Hz), 8.23 (1H, d, J=2.2 Hz), 7.53 (2H, m), 6.99 (2H, m), 3.87 (3H, s).
Reaction SMILES: C(OCC)C.C([Mg]Br)C.[C:10]1([S:16]([N:19]2[C:27]3[C:22](=[CH:23][C:24]([F:29])=[CH:25][C:26]=3[F:28])[C:21](I)=[CH:20]2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:31]([N:38]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@@H:39]([CH3:42])[CH:40]=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[CH2:43]([N:38]([CH:39]([CH3:42])[CH:40]([C:21]1[C:22]2[C:27](=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[N:19]([S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[CH:20]=1)[OH:41])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: C[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(F)cc(F)c21
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C(O)c1cn(S(=O)(=O)c2ccccc2)c2c(F)cc(F)cc12)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 76.8 %

Procedure:
A 3.0 M diethyl ether solution of ethylmagnesium bromide (7.3 ml, 21.8 mmol) is added under N2 at 0° C. to a 95 ml tetrahydrofuran solution of N-benzenesulfonyl-3-iodo-5,7-difluoro-indole (8.4 g, 20 mmol). The resulting mixture is stirred for 20 minutes at 0° C., allowed to warm to room temperature over 20 minutes, then recooled to 0° C. A 20 ml tetrahydrofuran solution of (S)N,N dibenzyl-2-aminopropanal (Syn. Lett., 1997,2, 223-224, 5.1 g, 22 mmol) is added to the reaction mixture and the resulting mixture is stirred 1 hour as it warmed to room temp. The reaction is quenched with aqueous NH4Cl, extracted with ethyl acetate, washed with brine, dried (Na2SO4), filtered, concentrated, and the residue is purified by flash chromatography (SiO2, ethyl acetate/hexane gradient) to yield 8.4 g of 2-(N,N-dibenzylamino)-1-(1-benzenesulfonyl-5,7-difluoro-1H-indol-3-yl)-propan-1-ol. (77%)
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2Cl)=[O:8])[N:5]=[C:4]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.N[C:25]1N(C(NC2C=CC=C(Cl)C=2)=O)N=C(NC2C=NC=CC=2)N=1.NC1N=C(NC2C=NC=CC=2)N(C(NC2C=CC=CC=2Cl)=O)N=1.NC1N(C(NC2C=CC(C)=CC=2)=O)N=C(NC2C=NC=CC=2)N=1>>[NH2:1][C:2]1[N:6]([C:7]([NH:9][CH2:10][C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:25]=2)=[O:8])[N:5]=[C:4]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1
Reactant: Nc1nc(Nc2cccnc2)nn1C(=O)Nc1ccccc1Cl
Reactant: Nc1nc(Nc2cccnc2)nn1C(=O)Nc1cccc(Cl)c1
Agent: Cc1ccc(NC(=O)n2nc(Nc3cccnc3)nc2N)cc1
Agent: Nc1nc(Nc2cccnc2)n(C(=O)Nc2ccccc2Cl)n1
Product: Nc1nc(Nc2cccnc2)nn1C(=O)NCc1ccccc1

Procedure:
5-amino-N-(2-chlorophenyl)-3-(pyridin-3-ylamino)-1H-1,2,4-triazole-1-carboxamide; 5-amino-N-(3-chlorophenyl)-3-(pyridin-3-ylamino)-1H-1,2,4-triazole-1-carboxamide; 3-amino-N-(2-chlorophenyl)-5-(pyridin-3-ylamino)-1H-1,2,4-triazole-1-carboxamide; and 5-amino-N-(4-methylphenyl)-3-(pyridin-3-ylamino)-1H-1,2,4-triazole-1-carboxamide.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[CH:23]([CH3:25])[CH3:24].[CH:26]1([NH2:29])[CH2:28][CH2:27]1>>[CH:26]1([NH:29][C:6]2[C:5]3[C:10](=[CH:11][C:2]([F:1])=[C:3]([CH:23]([CH3:25])[CH3:24])[CH:4]=3)[N:9]=[C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)[N:7]=2)[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(C(C)C)cc3c(=O)[nH]2)c1
Reactant: NC1CC1
Product: CC(C)c1cc2c(NC3CC3)nc(-n3cc(C(=O)O)cn3)nc2cc1F

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-6-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropyl amine in step E. MS (ESI): predicted mass calcd. for C18H18FN5O2, 355.1
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:10](=[O:17])[C:9]([F:19])([F:18])[CH2:8][N:7]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:6]=2[N:25]=1.[NH2:26][C:27]1[CH:42]=[CH:41][C:30]([C:31]([NH:33][CH:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)=[O:32])=[CH:29][C:28]=1[O:43][CH3:44].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(O)(C)C>[CH:20]1([N:7]2[CH2:8][C:9]([F:19])([F:18])[C:10](=[O:17])[N:11]([CH2:12][C:13]([F:14])([F:15])[F:16])[C:5]3[CH:4]=[N:3][C:2]([NH:26][C:27]4[CH:42]=[CH:41][C:30]([C:31]([NH:33][CH:34]5[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]5)=[O:32])=[CH:29][C:28]=4[O:43][CH3:44])=[N:25][C:6]2=3)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: O=C1N(CC(F)(F)F)c2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2CC(F)(F)F
Yield: 47.2 %

Procedure:
A mixture of 0.10 g (0.26 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-(2,2,2-trifluoro-ethyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-150), 0.072 g (0.27 mmole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.074 g (0.39 mmole) of p-toluenesulfonic acid monohydrate and 4 mL of isopropanol was heated in a pressure tube at 140 degrees overnight. After cooling, dichloromethane and saturated sodium carbonate were added. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (100:0-70:30) gave 0.075 g of 4-[9-cyclopentyl-7,7-difluoro-6-oxo-5-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-150) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:11][C:12](=[O:15])[CH2:13]Cl)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[I-:17].[Na+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:11][C:12](=[O:15])[CH2:13][I:17])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: [I-]
Reactant: CCOC(=O)C(NC(=O)CCl)C(=O)OCC
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C(NC(=O)CI)C(=O)OCC

Procedure:
A solution of 5.02 g (0.02 mole) of (2-chloroacetamido)-malonic acid diethyl ester [see Ajay Kumar Bose, J.Indian Chem. Soc. 31, 108-110 (1954)] and 4.50 g (0.03 mole) of sodium iodide in 100 ml of acetone is refluxed for 30 minutes. The reaction mixture is thereupon concentrated in vacuo. Water is added to the residue, and extraction is performed twice with methylene chloride. The organic phase is washed once with diluted aqueous sodium bisulphite solution and twice with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo. The residue is recrystallised from methylene chloride/hexane. After filtration with suction and drying in vacuo, there is obtained (2-iodoacetamido)-malonic acid diethyl ester, m.p. 95°-97°.
Reaction SMILES: [CH2:1]([C:11]1[C:15]2[S:16][C:17]3[C:21]4[S:22][C:23](C(O)=O)=[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:20]=4[S:19][C:18]=3[C:14]=2[S:13][C:12]=1C(O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(=O)=O.CCCCCC>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[CH2:25]([C:24]1[C:20]2[S:19][C:18]3[C:14]4[S:13][CH:12]=[C:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:15]=4[S:16][C:17]=3[C:21]=2[S:22][CH:23]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCc1c(C(=O)O)sc2c1sc1c3sc(C(=O)O)c(CCCCCCCCCC)c3sc21
Agent: [Cu]
Agent: O=C=O
Solvent: c1ccc2ncccc2c1
Solvent: CCCCCC
Product: CCCCCCCCCCc1csc2c1sc1c3scc(CCCCCCCCCC)c3sc21
Temperature: 255 °C
Yield: 62.5 %

Procedure:
Compound 75 (13.5 g, 0.021 mol) is mixed with copper powder (0.9 g) in quinoline (80 mL), and the mixture is heated to 250-260° C. in a Woods metal bath. When no further bubbles of carbon dioxide gas could be detected (about 2 hours), the mixture is allowed to cool to room temperature and hot hexane (400 mL) is added. This mixture is then repeatedly washed in HCl (2N, 4×50 mL). The hexane is partially removed by evaporation, and the resultant solid is collected by filtration and re-crystallized from hexane to afford compound 70 (7.0 g, 60.6% yield). M.P.: 111.0-113.3° C. 1H NMR (C6D6): δ 6.53 (s, 2H), 2.51 (t, 4H), 1.64 (m, 4H), 1.27 (m, 28H), 0.89 (t, 6H). 13C NMR: 141.26, 136.42, 133.17, 132.04, 120.73, 32.31, 30.03, 29.96, 29.90, 29.79, 29.66, 29.04, 23.07, 14.28.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.Cl.[Cl:18][C:19]1[CH:35]=[CH:34][C:22](/[CH:23]=[CH:24]/[S:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[ClH:18].[Cl:18][C:19]1[CH:20]=[CH:21][C:22](/[CH:23]=[CH:24]/[S:25]([N:28]2[CH2:33][CH2:32][N:31]([C:12](=[O:14])[C:11]3[CH:10]=[CH:9][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=4)=[CH:16][CH:15]=3)[CH2:30][CH2:29]2)(=[O:26])=[O:27])=[CH:34][CH:35]=1
Reactant: O=S(=O)(/C=C/c1ccc(Cl)cc1)N1CCNCC1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Agent: Cl
Product: O=C(c1ccc(-c2ccccn2)cc1)N1CCN(S(=O)(=O)/C=C/c2ccc(Cl)cc2)CC1

Procedure:
In the same manner as in Example A-17, a reaction was conducted using 4-(2-pyridyl)benzoic acid hydrochloride and 1-[(E)-4-chlorostyrylsulfonyl]piperazine hydrochloride as starting materials, whereby the title compound was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Li]CCCC.Cl[Si](CC)(CC)CC.[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:37]([C:39]4[N:43]([CH3:44])[CH:42]=[N:41][CH:40]=4)=[O:38])[CH:35]=3)[N:30]([CH3:45])[C:29](=[O:46])[CH:28]=2)[CH:24]=[CH:25][CH:26]=1>C1COCC1>[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:37]([OH:38])([C:3]4[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=4)[C:39]4[N:43]([CH3:44])[CH:42]=[N:41][CH:40]=4)[CH:35]=3)[N:30]([CH3:45])[C:29](=[O:46])[CH:28]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Cn1ccnc1
Reactant: Cn1cncc1C(=O)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C)c1nccn1C
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
A mixture of 1-methyl-1H-imidazole (0.0054 mol) in THF (10 ml) was cooled to −70° C. BuLi 1.6M (3.4 ml) was added dropwise and the mixture stood at −70° C. for 30 min. Chlorotriethylsilane (0.0054 mol) was added. The mixture was allowed to warm to 10° C. and then cooled to −70° C. BuLi 1.6M (3.4 ml) was added dropwise. The mixture stood at −70° C. for 1 hour, brought quickly to −15° C. and cooled to −70° C. THF (20 ml) and then intermediate 29) (0.0045 mol) were added. The mixture was allowed to warm to room temperature, stirred at room temperature overnight, stirred and refluxed for 24 hours, then hydrolized and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (2.7 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.5; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone/DIPE. The precipitate was filtered off and dried, yielding 0.6 g (28%) of 4-(3-chlorophenyl)-6-[hydroxy(1-methyl-1H-imidazol-2-yl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone, melting point 130° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:32]#[N:33])[C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25]>ClCCl.C(N(CC)CC)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:32]#[N:33])[C:29]=1[O:30][CH3:31])[C:24]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:25]
Reactant: COc1c(Cl)cc(C(=O)Cl)cc1C#N
Reactant: c1ccc2c(c1)NCS2
Agent: C=O
Agent: Nc1ccccc1S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Cl)cc(C(=O)N2CSc3ccccc32)cc1C#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (810 mg) and 37% formalin (0.53 mL) in the same manner as in the synthesis of Example 1 was dissolved in dichloromethane (15 mL), and triethylamine (1.90 mL) and 3-chloro-5-cyano-4-methoxybenzoyl chloride (993 mg) were added to the solution, and then the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain the title compound (580 mg) as a yellow oily substance.
Reaction SMILES: C1(C)C=CC=CC=1.C(O)C.[F:11][CH:12]([F:39])[C:13]([N:15]1[C@H:19]([CH2:20][F:21])[C@@H:18]([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[O:17][C:16]1([CH3:38])[CH3:37])=[O:14].[Cl-].Br[C:42]1[CH:43]=[CH:44][C:45]([C:48]2([NH3+:52])[CH2:51][O:50][CH2:49]2)=[N:46][CH:47]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:52][C:48]1([C:45]2[N:46]=[CH:47][C:42]([C:25]3[CH:24]=[CH:23][C:22]([C@H:18]4[O:17][C:16]([CH3:38])([CH3:37])[N:15]([C:13](=[O:14])[CH:12]([F:39])[F:11])[C@@H:19]4[CH2:20][F:21])=[CH:27][CH:26]=3)=[CH:43][CH:44]=2)[CH2:51][O:50][CH2:49]1
Reactant: [NH3+]C1(c2ccc(Br)cn2)COC1
Reactant: CC1(C)O[C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@@H](CF)N1C(=O)C(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)O[C@H](c2ccc(-c3ccc(C4(N)COC4)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
To a toluene/ethanol (15 ml toluene, 12 ml ethanol) solution of 2,2-difluoro-1-((4S,5R)-4-(fluoromethyl)-2,2-dimethyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazolidin-3-yl)ethanone (594 mg, 1.44 mmol) is added 3-(5-bromopyridin-2-yl)oxetan-3-aminium chloride (434 mg, 1.44 mmols), sodium bicarbonate (3 mL of a 2M solution) and Pd(dppf)2Cl2 (150 mg, 0.2 mmol)). The reaction mixture is heated to 80° C. while stirring under nitrogen for two hours. The reaction is cooled to room temperature and diluted with ethyl acetate (60 ml). The mixture is washed water (2×10 ml). The organic phase is dried over sodium sulfate and concentrated. The residual material is purified on silica gel (mobile phase 6% methanol in methylene chloride) to give the title compound (436 mg, 70%): m/z (Cl) 436 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][N:18]=[CH:17][C:16]=2[CH2:20][CH2:21][C:22](O)=[O:23])=[CH:11][CH:10]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:22](=[O:23])[CH2:21][CH2:20][C:16]2[CH:17]=[N:18][O:19][C:15]=2[C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[CH:3]=1
Reactant: Nc1cccnc1
Reactant: O=C(O)CCc1cnoc1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1cnoc1-c1ccc(Cl)cc1)Nc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
A mixture of 3-aminopyridine (0.18 g), 3-[5-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.50 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.35 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.45 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(3-pyridyl)-3-[5-(4-chlorophenyl)-4-isoxazolyl]propionamide (0.60 g, yield 96%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from acetone-hexane. melting point: 197–198° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[C:11]([Cl:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH2:19]C)[C:7]([O:15][CH2:16]C)=[N:8]2.[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.C(OCC)(=O)C>[Cl:13][C:12]1[C:3]([CH2:2][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:14])[N:8]=[C:7]([O:15][CH3:16])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOc1nc2cc(Cl)c(Cl)c(CBr)c2nc1OCC
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1nc2cc(Cl)c(Cl)c(Cn3cncn3)c2nc1OC
Temperature: 50 °C
Reaction time: 18 h
Yield: 58.2 %

Procedure:
A mixture of 5-bromomethyl-6,7-dichloro-2,3-diethoxyquinoxaline (Preparation 1,176 mg, 0.5 mmol), 1,2,4-triazole (69 mg, 1.0 mmol) and anhydrous potassium carbonate (138 mg, 1.0 mmol) in dry N,N-dimethylacetamide (2 mL) was heated at 50° C. with stirring for 18 hours. The mixture was diluted with ethyl acetate, washed with water, and concentrated under reduced pressure. The residue was purified by flash chromatography using a hexane:ethyl acetate:methanol gradient to give 6,7-dichloro-2,3-dimethoxy-5-(1,2,4-triazol-1-ylmethyl)quinoxaline (99 mg, 58%).
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH:20]=[O:21])[N:11]([C:13]2[C:14]([Cl:19])=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:12]=1.CC(C)=[O:24].[OH-].[Na+]>O>[Br:7][C:8]1[CH:9]=[C:10]([C:20]([OH:24])=[O:21])[N:11]([C:13]2[C:14]([Cl:19])=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:12]=1
Reactant: O=Cc1cc(Br)cn1-c1cccnc1Cl
Reactant: CC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Br)cn1-c1cccnc1Cl
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of 4.43 g of potassium permanganate in 15 ml of water was added dropwise to a mixture of 4.22 g of 4-bromo-1-(2-chloro-3-pyridinyl)-1H-pyrrole-2-carbaldehyde and 30 ml of acetone while the mixture was maintained at 40° C. The resulting mixture was stirred at 40° C. for 2 hours. A precipitate was filtered off to obtain a filtrate. The filtrate was adjusted to pH 10-12 by an addition of a 2N aqueous sodium hydroxide solution, and then washed with chloroform two times. The aqueous layer was adjusted to around pH 3 by an addition of 2N hydrochloric acid, and then extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3.02 g of 4-bromo-1-(2-chloro-3-pyridinyl)-1H-pyrrole-2-carboxylic acid of the formula: