Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6](=[S:8])[NH2:7].Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH2:15]([O:14][C:12]([C:11]1[N:7]=[C:6]([C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[S:8][CH:10]=1)=[O:13])[CH3:16]
Reactant: NC(=S)c1ncc[nH]1
Reactant: CCOC(=O)C(=O)CBr
Product: CCOC(=O)c1csc(-c2ncc[nH]2)n1
Temperature: 75 °C
Yield: 57.1 %

Procedure:
A mixture of 1H-Imidazole-2-carbothioic acid amide (200 mg, 1.57 mmol) and Ethyl bromopyruvate (340 mg, 1.57 mmol) is heated at 75° C. for about 5 hours. After the volatiles are evaporated in vacuo, the residue is partitioned between Ethyl acetate (40 mL) and aqueous NaHCO3 (10 mL). The organic layer is separated, washed with water, dried and concentrated. The residue is purified on a silica gel column with 3% MeOH in CH2Cl2 as eluent to give 200 mg of the titled compound. 1H NMR (CDCl3): δ 8.15 (s, 1H), 7.20 (br, 1H), 7.10 (br, 1H), 4.33 (q, 2H), 1.23 (t, 3H). LRMS calcd 223. found 224 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9]Br.C([O-])([O-])=O.[K+].[K+].[CH3:17][O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][O:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][O:18][CH3:17])=[CH:27][CH:26]=1
Reactant: COCCOc1ccc(O)cc1
Reactant: Clc1ccc(Br)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCOc1ccc(OCc2cc(Cl)ccc2Br)cc1
Yield: 94.7 %

Procedure:
1.42 g (5 mmol) of the compound obtained in Step 1 was dissolved in 20 ml of acetonitrile, 1.38 g (10 mmol) of K2CO3 and 0.84 g (5 mmol) of 4-(2-methoxyethoxy)phenol were added thereto, which was refluxed for 15 hours. The reaction mixture was distilled under a reduced pressure to remove the solvent, and 20 ml of ethyl acetate was added thereto. The resulting mixture was washed twice with water, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The concentrate was subjected to column chromatography using 20% ethyl acetate/hexane to obtain 1.76 g (yield 95%) of 1-(2-bromo-5-chlorobenzyloxy)-4-(2-methoxyethoxy)benzene.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:28])[C:4]([C:6]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([CH3:27])=[CH:8][N:7]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:35][O:36][CH2:37]Cl.CON(C)C(C1C(N(COC)S(C2C=CC(Cl)=C(C(F)(F)F)C=2)(=O)=O)=CC(Cl)=CN=1)=O>C1COCC1>[CH3:1][O:2][N:3]([CH3:28])[C:4]([C:6]1[C:11]([N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:24])[F:25])[CH:17]=2)(=[O:15])=[O:14])[CH2:35][O:36][CH3:37])=[CH:10][C:9]([CH3:27])=[CH:8][N:7]=1)=[O:5]
Reactant: COCCl
Reactant: CON(C)C(=O)c1ncc(C)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: COCN(c1cc(Cl)cnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cc(C)cnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Prepared from 223 mg (0.51 mmol) of 3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-5-methyl-pyridine-2-carboxylic acid methoxy-methyl-amide, 352 mg of potassium carbonate and 116 μL of methoxymethyl chloride in 1 mL THF using the procedure used to prepare Intermediate 12. Yield: 200 mg of a white solid. LC-MSD, m/z for C18H19ClF3N3O5S [M+H]+=482.0, 484.0; HPLC retention time: 2.5 minutes.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([S:14][C:15]2[C:23]([N:24]([CH3:26])[CH3:25])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:27].C(N(CC)CC)C.[CH:35]1([S:38](Cl)(=[O:40])=[O:39])[CH2:37][CH2:36]1>C(Cl)Cl>[NH2:27][C:10]1[N:9]=[CH:8][N:7]=[C:6]2[C:11]=1[N:12]=[C:13]([S:14][C:15]1[C:23]([N:24]([CH3:26])[CH3:25])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=1)[N:5]2[CH2:4][CH2:3][CH2:2][NH:1][S:38]([CH:35]1[CH2:37][CH2:36]1)(=[O:40])=[O:39]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CN(C)c1cc2c(cc1Sc1nc3c(N)ncnc3n1CCCN)OCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1cc2c(cc1Sc1nc3c(N)ncnc3n1CCCNS(=O)(=O)C1CC1)OCO2

Procedure:
9-(3-Aminopropyl)-8-(6-(dimethylamino)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine (61 mg, 0.158 mmol), triethylamine (18 mg, 24 μL, 0.174 mmol), cyclopropane sulfonyl chloride (22 mg, 17 μL, 0.158 mmol) in CH2Cl2 (3 mL) was stirred for 2 h at rt. The mixture was dried under reduced pressure and the residue purified by preparatory TLC (CH2Cl2:MeOH—NH3(7N), 20:1) to give MRP-I-31 (55 mg, 71%). 1H NMR (600 MHz, CDCl3): δ 8.30 (s, 1H), 6.78 (s, 1H), 6.66 (t, J=6.8 Hz, 1H), 6.51 (s, 1H), 6.29 (br s, 2H), 5.91 (s, 2H), 4.31 (t, J=6.0 Hz, 2H), 3.02 (q, J=6.1 Hz, 2H), 2.70 (s, 6H), 2.34-2.38 (m, 1H), 1.95-1.99 (m, 2H), 1.15-1.17 (m, 2H), 0.93-0.96 (m, 2H); 13C NMR (150 MHz, CDCl3): δ 154.9, 153.1, 151.7, 148.4, 147.6, 146.3, 144.8, 119.8, 119.4, 109.6, 102.4, 101.8, 45.4, 40.0, 39.0, 30.4, 30.2, 5.26; HRMS (ESI) m/z [M+H]+ calcd. for C20H26N7O4S2, 492.1488. found 492.1468.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([NH:8]C(OC(C)(C)C)=O)[C:5](O)=[O:6])[CH3:3].CN1CCOCC1.[NH2:23][C@H:24]([C:29]([N:31]1[CH2:45][CH2:44][CH2:43][C@H:32]1[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CCOC(C)=O>[NH2:8][C@H:4]([C:5]([NH:23][C@H:24]([C:29]([N:31]1[CH2:45][CH2:44][CH2:43][C@H:32]1[C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])=[O:30])[CH2:25][CH:26]([CH3:27])[CH3:28])=[O:6])[CH:2]([CH3:3])[CH3:1]
Reactant: CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@@H](N)C(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
To a flask containing Boc-Valine-OH (652 mg, 3 mmol) in DCM (6 ml) at 0° C. was added NMM (0.35 ml, 3.15 mmol). After stirring for 15 min, A5 (1.065 g, 3 mmol), HOBt (405 mg, 3.0 mmol) and DCC (650 mg, 3.15 mmol) were added in portions, The reaction mixture was allowed to warm to 23° C. and stirred for 14 h. The suspension was diluted with DCM (25 ml) and washed successively with aq KHSO4 (2×10 ml, 10%), aq NaHCO3 (2×10 ml, sat) and brine (10 ml) dried over Na2SO4 filtered and concentrated under reduced pressure. The residue was purified by flash LC (silica, gradient hex-EtOAc 2:1 to 1:1) to give SVPLA4 (1.48 g, 93%) as a white solid. Rf==0.57 (hex-EtOAc 1:2).
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:11][CH3:12])=[CH:7][CH:8]=2)[C:3]1=[O:13].[O:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:18]=2[O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([N:24]3[CH2:29][CH2:28][N:27]([CH:2]4[CH2:10][C:9]5[C:4](=[CH:5][C:6]([O:11][CH3:12])=[CH:7][CH:8]=5)[C:3]4=[O:13])[CH2:26][CH2:25]3)[C:18]=2[O:17][CH2:16][CH2:15]1
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCO2
Reactant: COc1ccc2c(c1)C(=O)C(Br)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=O)C(N1CCN(c3cccc4c3OCCO4)CC1)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 73.9 %

Procedure:
A suspension prepared from 25.3 g (100 mmol) of the compound obtained in Step 1, 22.0 g (100 mmol) of (2,3-dihydro[1,4]benzodioxin-5-yl)piperazine, 13.8 g (100 mmol) of potassium carbonate and 140 ml of dimethylformamide is stirred at room temperature for 20 hours. The mixture is then poured into 1.5 liters of water, and the solid that forms (violet) is filtered off, rinsed with water and dried in vacuo to obtain 28.1 g of the expected product.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([Br:24])[C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Product: Cc1nc(N2CCCC(Br)C2=O)sc1C(=O)NCc1ccccc1
Yield: 56 %

Procedure:
Following the procedure as described in Example 4, making variations as required to use N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide to react with N-bromosuccinimide, the title compound was obtained as a yellow oil in 56% yield: MS (ES+) m/z 408.2 (M+1), 410.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH2:11]/[C:12](/[CH3:31])=[CH:13]\[C:14]([O:16][CH2:17][C:18]([CH3:30])([CH3:29])[CH2:19][N:20]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:21])=[O:15].[C:32]([O:38][CH3:39])(=[O:37])[CH2:33][C:34]([CH3:36])=O>>[CH3:31][C:12]1[NH:11][C:34]([CH3:36])=[C:33]([C:32]([O:38][CH3:39])=[O:37])[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[C:3]=2[F:10])[C:13]=1[C:14]([O:16][CH2:17][C:18]([CH3:30])([CH3:29])[CH2:19][N:20]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:21])=[O:15]
Reactant: O=Cc1cccc(Cl)c1F
Reactant: COC(=O)CC(C)=O
Reactant: C/C(N)=C/C(=O)OCC(C)(C)CN(C)Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)(C)CN(C)Cc2ccccc2)C1c1cccc(Cl)c1F

Procedure:
To a solution of 158.5 mg of 3-chloro-2-fluorobenzaldehyde were adde 291 mg or 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl 3-aminocrotonate and 116 mg of methyl acetoacetate. The mixture was refluxed overnight. The solvent was distilled off in vacuo to give a residue. The reaction was treated in the same ways as the Example 18-(iii) to give the desired product (156) which has the identical physical properties with those of the compound of the Example 18-(i).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7]P(=O)(OCC)OCC.O=[C:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22][CH2:21]1>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH:7]=[C:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[CH2:22][CH2:21]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCOP(=O)(Cc1cccc(F)c1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(=Cc2cccc(F)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
Sodium hydride (0.245 g) was added portionwise to a solution of diethyl (3-fluorobenzyl)phosphonate (Intermediate 182, 1 g) in THF (40 mL) at 0° C. The mixture was stirred for 30 minutes then benzyl 4-oxopiperidine-1-carboxylate (0.947 g) was added at 0° C. The mixture was allowed to warm to room temperature and stirred for 21.5 hours. The mixture was partitioned between water and ethyl acetate and the organic layer was washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25% to give benzyl 4-(3-fluorobenzylidene)piperidine-1-carboxylate (1.05 g)
Reaction SMILES: N1C=CC=NC=1.Cl[C:8]1[N:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[C:9]=1[N+:25]([O-:27])=[O:26].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:8]2[C:9]([N+:25]([O-:27])=[O:26])=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[N:11]=[CH:12][N:13]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(Cl)c2[N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1cncnc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
General Procedure for the Addition of Amine to pyrimidine: (6-Chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (132 mg, 0.4 mmole), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.4 mmole, 1 eq) and K2CO3 (0.4 mmole, 1 eq) were dissolved in DMF, and the mixture was stirred at 60° C. for 1 hour. Final product was precipitated out with water to provide Compound B1 as a yellow solid (152 mg, 77%). 1H NMR (400 MHz CDCl3) δ (ppm): 10.8 (s, 1H), 9.18 (d,1H), 8.17 (s,1H), 7.90 (d,2H), 7.85 (d,2H), 4.39-4.32 (m,1H), 4.02 (m,2H), 3.01 (s,3H), 2.95-2.90 (m, 2H), 2.00 (m,2H), 1.57-1.50 (m,2H), 1.46 (s, 9H). Exact mass calculated for C21H28N6O6S 492.18, LCMS (ESI) m/z 493.4 (M+H+, 100%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:28](O)=[O:29]>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:28]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:29]
Reactant: COc1ccccc1CC(=O)O
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: COc1ccccc1CC(=O)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(2-methoxyphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.32 (dd, J=7.9, 1.3 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.91 (td, J=7.5, 1.3 Hz, 1H), 7.33 (dd, J=7.4, 1.7 Hz, 1H), 7.27 (td, J=7.8, 1.7 Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 6.93 (td, J=7.4, 1.1 Hz, 1H), 3.85-3.82 (m, 4H), 3.82 (s, 3H), 3.62 (s, 2H), 3.09-3.11 (m, 4H); MS (ESI+) M/Z 395 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.CS(C)=O.[CH3:13][NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(OCC)(=O)C>[Cl:8][C:4]1[N:3]=[C:2]([N:14]([CH3:13])[CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:7]=[N:6][CH:5]=1
Reactant: CNCC1CCOCC1
Reactant: Clc1cncc(Cl)n1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(CC1CCOCC1)c1cncc(Cl)n1
Temperature: 70 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
A mixture of 2,6-dichloropyrazine (298 mg, 2.000 mmol), DMSO (6 ml), TEA (0.418 ml, 3.00 mmol) and N-methyl-1-(tetrahydro-2H-pyran-4-yl)methanamine (264 mg, 2.040 mmol) was stirred at 70° C. for 16 hours, and the reaction progress was followed by LCMS. The crude reaction mixture was let cool to room temperature, diluted with 150 ml of ethyl acetate, washed with 1M NaOH soln. (1×), water (2×), saturated salt soln. (1×), dried with sodium sulfate, filtered, and concentrated to constant mass, giving 475 mg of the title compound as free base, which was used without further purification. LCMS (m/z): 242.0 (MH+), retention time=0.85 min.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:6]=1[Cl:14])[CH:2]=[CH2:3].O.O.[Sn](Cl)Cl>C(OCC)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>[CH2:1]([O:4][C:5]1[C:6]([Cl:14])=[C:7]([CH:8]=[CH:9][CH:10]=1)[NH2:11])[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc([N+](=O)[O-])c1Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOc1cccc(N)c1Cl
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 278A (2 g, 10.35 mmol) in ethyl acetate (60 ml) added tin(II) chloride dihydrate (8.18 g, 36.2 mmol), and the mixture was heated at 65° C. overnight. The reaction mixture was cooled to room temperature, diluted with 100 mL ethyl acetate, and 1M aqueous Na2CO3 was added until precipitation stopped. The solid was filtered through a pad of diatomaceous earth. The filter pad was suspended in ethyl acetate, stirred for a few minutes, and rinsed with ethyl acetate. The filtrate was washed with saturated aqueous Na2CO3, water, and brine, dried over MgSO4, filtered, and concentrated. Chromatography was performed with an Analogix 280 with an SF 40-80 column, 0% to 5% methanol/dichloromethane gradient over 30 minutes to provide the title compound. MS (DCI+) m/z 164.1 (M+H)+.
Reaction SMILES: [Cl-].[C:2]([C:5]1([NH3+:8])[CH2:7][CH2:6]1)([OH:4])=[O:3].C(N(CC)CC)C.[F:16][C:17]([F:24])([F:23])[C:18](OCC)=[O:19]>CO>[F:16][C:17]([F:24])([F:23])[C:18]([NH:8][C:5]1([C:2]([OH:4])=[O:3])[CH2:7][CH2:6]1)=[O:19]
Reactant: CCOC(=O)C(F)(F)F
Reactant: [NH3+]C1(C(=O)O)CC1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(NC1(C(=O)O)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Carboxycyclopropanaminium chloride (0.980 g, 7.124 mmol) was suspended in methanol (14 mL) and triethylamine (1.514 g, 14.960 mmol) was subsequently added. To this suspension was then added ethyl trifluoroacetate (1.113 g, 7.836 mmol) and allowed to stir at 25° C. After 16 hours, the reaction was quenched with 1N hydrochloric acid and extracted with ethyl acetate. The organic extract was dried with sodium sulfate, filtered and concentrated under reduced pressure to produce the title compound as a white solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.76 (s, 1H), 9.94 (s, 1H), 1.38-1.44 (m, 2H), 1.08-1.14 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[N:20]=[N:19][C:18]([CH2:21][CH3:22])=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].C1(C(C2C=CC=CC=2)CNC2N=C(NCCN3CCCCC3)N=C3C=2N=CN3[C@@H]2C[C@H](N3C=C(CO)C=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.[C:94]([NH:101][C@@H:102]1[CH2:106][CH2:105][NH:104][CH2:103]1)([O:96][C:97]([CH3:100])([CH3:99])[CH3:98])=[O:95]>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[C:97]([O:96][C:94](=[O:95])[NH:101][C@@H:102]1[CH2:106][CH2:105][N:104]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@@H:11]3[CH2:15][C@H:14]([N:16]4[N:20]=[N:19][C:18]([CH2:21][CH3:22])=[N:17]4)[C@@H:13]([OH:23])[C@H:12]3[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:3]=2)[CH2:103]1)([CH3:100])([CH3:98])[CH3:99]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Agent: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)OC(C)(C)C)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (BA6) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 46) replacing 1-(2-amino-ethyl)piperidine with (3R)-(+)-3-(BOC-amino)pyrrolidine. MS (ES+) m/e 696 (MH+).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27].O>C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:27][CH2:26][C:25]([O:29][CH3:30])=[O:28])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C=CC(=O)OC
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Solvent: CCO
Solvent: O
Product: COC(=O)CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Yield: 69.5 %

Procedure:
A mixture of 3.31 g (0.01 mole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid and 5 g (0.058 mole) of methyl acrylate in 50 ml of ethanol is heated under reflux for 2 hours. The solution is poured into 10 ml of water and the precipitate is filtered off with suction, washed with methanol and recrystallised from glycol monomethyl ether. 2.9 g (70% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[4-(2-methoxycarbonylethyl)-1-piperazinyl]-3-quinolinecarboxylic acid of decomposition point 192° to 194° C. are obtained.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.C[O:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][N:28]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:30]4[CH:29]=[N:28][C:27]([OH:26])=[N:32][CH:31]=4)=[C:4]([CH:9]=3)[C:3]([OH:2])=[O:24])[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COc1ncc(B(O)O)cn1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cnc(O)nc1
Yield: 76.5 %

Procedure:
Using the conditions of General Procedure C for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2-methoxypyrimidine-5-boronic acid (available from Combi-Blocks Inc.; 77 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2-(2-hydroxy-pyrimidin-5-yl)-benzoic acid (85 mg, 76%). 1H NMR (400 MHz, DMSO-d6) δ 13.40 (br s, 1H), 8.42-8.62 (m, 2H), 8.20-8.38 (m, 2H), 8.04-8.14 (m, 1H), 7.76 (d, J=8.3 Hz, 2H), 7.61 (d, J=7.5 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:20][CH3:21])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:22]N(C=NC=[N+](C)C)C.[Cl-].C([O-])(=O)C.[Na+].C(O)(=O)C>O1CCOCC1>[CH2:12]([O:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:6][CH:22]=[N:1]2)=[CH:7][C:8]=1[O:20][CH3:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)C=NC=[N+](C)C
Reactant: COc1cc(C(N)=O)c(N)cc1OC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Yield: 77 %

Procedure:
A mixture of 2-amino-4-benzoyloxy-5-methoxybenzamide (10 g, 0.04 mol), (prepared according to J. Med. Chem. 1977, 20, 146–149), and Gold's reagent (7.4 g, 0.05 mol) in dioxane (100 ml) was stirred and heated at reflux for 24 hours. Sodium acetate (3.02 g, 0.037 mol) and acetic acid (1.65 ml, 0.029 mol) were added to the reaction mixture and it was heated for a further 3 hours. The volatiles were removed by evaporation, water was added to the residue, the solid was collected by filtration, washed with water and dried. Recrystallisation from acetic acid yielded 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.7 g, 84% yield) as a white solid.