Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[CH2:4][NH:5][NH2:6].C([O:14][C:15](=O)[CH:16]=[C:17]([NH2:21])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:21][C:17]1[NH:6][N:5]([CH2:4][C:3]2[C:2]([F:1])=[CH:10][CH:9]=[C:8]([Cl:11])[CH:7]=2)[C:15](=[O:14])[CH:16]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1cc(Cl)ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2cc(Cl)ccc2F)[nH]1
Reaction time: 2 h

Procedure:
21.6 g of 2-fluoro-5-chlorobenzylhydrazine were added dropwise under nitrogen to a solution of 19.8 g of β-amino-β-ethoxyacrylic acid ethyl ester and 0.5 g of p-toluenesulphonic acid in 100 ml of ethanol, in the course of which the temperature rose from 20° to 30°. After stirring for two hours, the mixture was left to stand overnight and the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 160°, 17 g (57%).
Reaction SMILES: C(S[C:4]1[S:5][C:6](=[CH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[C:29]([F:32])([F:31])[F:30])[N:15]=[CH:14]3)[C:7](=[O:9])[N:8]=1)C.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][C@@H:41]1[CH2:46][OH:47])=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][N:43]([C:4]2[S:5][C:6](=[CH:10][C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[C:29]([F:30])([F:32])[F:31])[N:15]=[CH:14]4)[C:7](=[O:9])[N:8]=2)[CH2:42][C@@H:41]1[CH2:46][OH:47])=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(OC)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CO
Product: COc1ccc(Cn2ncc3cc(C=C4SC(N5CCN(C(=O)OC(C)(C)C)[C@@H](CO)C5)=NC4=O)ccc32)c(C(F)(F)F)c1

Procedure:
(2R)2-Hydroxymethyl-4-{5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazine-1-carboxylic acid tert-butyl ester was prepared from 2-Ethylsulfanyl-5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one and (2R)2-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH3:17][C:18]1[C:22](/[CH:23]=[CH:24]/[C:25](O)=[O:26])=[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:20][N:19]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:25](=[O:26])/[CH:24]=[CH:23]/[C:22]2[C:18]([CH3:17])=[N:19][O:20][C:21]=2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: Cc1noc(-c2ccccc2)c1/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(NC(=O)/C=C/c2c(C)noc2-c2ccccc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (0.43 g), (E)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenoic acid (0.50 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.38 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 (E)-N-(4-diethylphosphonomethylphenyl)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenamide (0.71 g, yield 83%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 155–156° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][C:9](OC)=[C:8]([Cl:14])[CH:7]=1)[OH:5].[K+].[Br-:16]>>[ClH:14].[NH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:16])[CH:7]=1)[OH:5]
Reactant: COc1ccc([C@H](O)CN)cc1Cl
Reactant: [Br-]
Agent: Cl
Agent: [K+]
Product: NC[C@@H](O)c1cccc(Br)c1

Procedure:
The title material was prepared according to the general procedure outlined for the synthesis of (S)-2-amino-1-[3-chloro-4-methoxyphenyl]ethanol hydrochloride. LRMS [M+H]+ 217.9; IR (KBr, cm−1) 3025, 3443, 2891; 1H NMR (500 MHz, DMSO-d6) δ 7.93 (b s, 2H), 7.60 (s, 1H), 7.52 (d, 1H), 7.41 (s, 1H), 7.35 (d, J=7.7 Hz, 1H) 6.17 (s, 1H), 4.82 (m, 1H), 3.08 (ddd, J=2.6, 12.7, 9.6 Hz, 2H); 13C NMR (DMSO-d6, 75.5 MHz) δ 144.4, 130.5, 128.7, 125.0, 121.6, 68.3, 45.1.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2O.FC1C([O:17][C:18](=O)[O:19]C2C(F)=C(F)C(F)=C(F)C=2F)=C(F)C(F)=C(F)C=1F.[C:36]1([C@H:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH2:45][CH2:44][NH:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[C:52]([OH:59])(=[O:58])[CH2:53][CH2:54][C:55]([OH:57])=[O:56]>ClCCl.CC(C)=O.C(O)(C)C>[CH:39]1[CH:40]=[CH:41][C:36]([C@@H:42]2[N:43]([C:18]([O:19][C@@H:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[O:17])[CH2:44][CH2:45][C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:51]2=3)=[CH:37][CH:38]=1.[CH2:53]([C:52]([OH:59])=[O:58])[CH2:54][C:55]([OH:57])=[O:56]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O[C@@H]1CC2CCN1CC2
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Agent: O=C(O)CCC(=O)O
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C(O[C@H]1CN2CCC1CC2)N1CCc2ccccc2[C@@H]1c1ccccc1
Reaction time: 0.33 h
Yield: 80.4 %

Procedure:
127.2 g (1.0 mol) of (R)-quinuclidinol was dissolved in 1270 mL of dichloromethane and then stirred at 25˜30° C. for 20 minutes to obtain a reaction solution. Subsequently, 472.9 g (1.2 mol) of bis(pentafluorophenyl)carbonate was added to the reaction solution to form a suspended reaction solution, and then the suspended reaction solution was stirred at 25˜30° C. for 3˜4 hours. After confirming the completion of a reaction using thin layer chromatography (TLC), the reaction solution was concentrated under reduced pressure. Subsequently, oily matter obtained by adding 1270 mL of isopropanol to the reaction solution was dissolved, and then 209.3 g (1.0 mol) of (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline was added to the reaction solution and stirred at 25˜30° C. for 4˜5 hours. After confirming the completion of a reaction using high performance liquid chromatography (HPLC), the reaction solution was concentrated under reduced pressure. Subsequently, 1270 mL water was added to the reaction solution, and concentrated hydrochloric acid was added dropwise into the reaction solution to adjust the pH of the reaction solution to 1˜2. Then, the reaction solution was washed with 1270 mL of toluene to remove pentafluorophenol (a by-product formed during the reaction) from the reaction product. Then, an aqueous layer was extracted from the reaction solution using 1270 mL of dichloromethane, and then the reaction solution was concentrated under reduced pressure. Then, 1270 mL of water was added to the reaction solution, the pH of the reaction solution was adjusted to 9˜10 using ammonium hydroxide, and then an aqueous layer was further extracted from the reaction solution using 1270 mL of toluene. Subsequently, 1270 mL of acetone and 118.1 g (1.0 mol) of succinic acid were added to the reaction solution, stirred at 55˜60° C. for 30 minutes, further stirred at 10˜15° C. for 2 hours, and then filtered to obtain a reaction product. Finally, the reaction product was washed with 640 mL of toluene and 640 mL of acetone, and then dried in vacuum at 40° C. to obtain 386.4 g (80.4%) of solifenacin succinate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[CH:35]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[N:50]1[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)([CH3:37])[CH3:36]>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:53]2[CH2:54][CH2:55][CH2:56][N:50]([C:42]3[N:41]([CH2:40][CH2:39][O:38][CH:35]([CH3:37])[CH3:36])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:51][CH2:52]2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)=[O:6]
Reactant: CC(C)OCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Agent: I
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCN2CCCN(c3nc4ccccc4n3CCOC(C)C)CC2)(c2ccccc2)C1

Procedure:
Prepare by the method of Example 102.1.2 using 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt)(0.52 g, 1.10 mmol) and 4-(1-(2-(isopropoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.60 g, 1.08 mmol) to give the title compound: Rf=0.28 (silica gel, dichloromethane/methanol/concentrated aqueous ammonia 90/10/0.1).
Reaction SMILES: [OH:1]O.C(O[C:10]([C:12](F)(F)F)=[O:11])(C(F)(F)F)=O.[O-:16][N+:17]1[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][C:21]=2[N:20]=C(CCCO)N=1)[CH2:27][CH2:26][CH2:25]3.N>C(Cl)Cl>[N+:17]([C:22]1[CH:23]=[C:24]2[C:28]([CH2:27][CH2:26][CH2:25]2)=[CH:29][C:21]=1[NH:20][C:10](=[O:11])[CH3:12])([O-:16])=[O:1]
Reactant: [O-][n+]1nc(CCCO)nc2cc3c(cc21)CCC3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: OO
Agent: N
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
H2O2 (70%, 1.6 mL, ca. 33 mmol) was added dropwise to a stirred solution of TFAA (4.6 mL, 33 mmol) in DCM (30 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. The solution was added to a solution of 1-oxide 70 (0.86 g, 3.3 mmol) in DCM (50 mL) at 0° C. and the solution was stirred at 20° C. for 16 h. Dilute aqueous NH3 solution (30 mL) was added and the mixture stirred vigorously for 30 min and then extracted with DCM (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give (i) starting material 70 (283 mg, 33%) and (ii) 1,4-dioxide 71 (347 mg, 40%) as a yellow solid: mp (MeOH/EtOAc) 153-155° C.; 1H NMR δ 8.33 (s, 1H, H-9), 8.26 (s, 1H, H-5), 3.68 (br dt, J=6.1, 5.7 Hz, 2H, CH2O), 3.33 (t, J=6.9 Hz, 2H, CH2), 3.13-3.20 (m, 4H, H-6, H-8), 3.09 (br t, J=6.1 Hz, 1H, OH), 2.26 (p, J=7.5 Hz, 2H, H-7), 2.10-2.18 (m, 2H, CH2); 13C NMR δ 155.5, 155.0, 150.9, 138.8, 134.0, 115.8, 114.1, 61.2, 33.4, 32.9, 29.6, 26.8, 25.6. Anal. calcd for C13H15N3O3: C, 59.8; H, 5.8; N, 16.1. Found: C, 60.0; H, 5.7; N, 16.1%.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([OH:7])[CH2:5][OH:6].[S:8](Cl)(Cl)=[O:9].I([O-])(=O)(=O)=[O:13].[Na+].O>C(Cl)Cl.C(OCC)C.[Ru](Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][C@H:4]1[CH2:5][O:6][S:8](=[O:9])(=[O:13])[O:7]1
Reactant: COC[C@H](O)CO
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=S(Cl)Cl
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: COC[C@H]1COS(=O)(=O)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of crude (R)-3-methoxypropane-1,2-diol (7.66 g, 72.2 mmol) in DCM (100 mL) was slowly (˜10 min) added thionyl chloride (6.32 mL, 87 mmol) at rt. When the addition was completed, the dark brown solution was heated to reflux for 1 h before concentrating it to ˜10-20 mL under vacuum. Then, the cyclic sulfite was dissolved in DCM (80 mL) and acetonitrile (80 mL) and cooled to 0° C. Ruthenium(III) chloride (0.075 g, 0.361 mmol) and sodium periodate (23.16 g, 108 mmol) were added followed by water (100 mL). The biphasic reaction was vigorously stirred at 0° C. for 1 h. The reaction was finally diluted with diethyl ether (600 mL) and the product was sequentially washed with water, a saturated solution of sodium bicarbonate (repeated twice) and brine. The organic layer was dried over Na2SO4, filtered through a pad of silica gel (the pad was rinsed with diethyl ether) and concentrated under vacuum. The turbid liquid was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18]OC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.CN([Si](C)(C)C)C(=O)C(F)(F)F.[I:43][Si](C)(C)C>C(Cl)Cl>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18][I:43])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C[Si](C)(C)I
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: ClCCl
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CI)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7β-[(Z)-2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid (977 mg) was suspended in methylene chloride (16 ml), followed by an addition of N-methyl-N-(trimethylsilyl)trifluoroacetamide (1350 μl). The resulting mixture was stirred at room temperature for 1 hour. After ice-cooling, iodotrimethylsilane (810 μl) was added and the resulting mixture was stirred for 15 minutes. The reaction mixture was concentrated under reduced pressure to obtain the silylated derivative of 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-iodomethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:16]([C:18]2[CH:23]=[C:22]([C:24]3([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[O:28][CH2:27][CH2:26][O:25]3)[CH:21]=[CH:20][C:19]=2[NH2:36])=[O:17])[CH:13]=[CH:14][CH:15]=1>C1(C)C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[C:16]([C:18]1[CH:23]=[C:22]([C:24]2([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)[O:28][CH2:27][CH2:26][O:25]2)[CH:21]=[CH:20][C:19]=1[NH:36][C:1](=[O:3])[CH3:2])=[O:17]
Reactant: COc1cccc(C(=O)c2cc(C3(c4ccc(Cl)cc4)OCCO3)ccc2N)c1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: COc1cccc(C(=O)c2cc(C3(c4ccc(Cl)cc4)OCCO3)ccc2NC(C)=O)c1
Yield: 100 %

Procedure:
Acetic anhydride (13.9 ml) was added to a solution of interm. (5-c) (31.2 g) in toluene (300 ml) and the mixture was stirred and refluxed for 2 hours. The mixture was evaporated till dryness and the product was used without further purification, yielding 36.4 g (100%) of N-[2-(3-methoxybenzoyl)-4-[2-(4-chlorophenyl)1,3-dioxolan-2-yl]phenyl]acetamide (interm. 5-d).
Reaction SMILES: [NH2:1][C:2]([CH2:9][CH3:10])=[C:3]([Cl:8])[C:4](OC)=O.[CH:11]([NH2:13])=O.C[O-].[Na+].[ClH:17]>CO>[Cl:17][C:4]1[C:3]([Cl:8])=[C:2]([CH2:9][CH3:10])[N:1]=[CH:11][N:13]=1
Reactant: CCC(N)=C(Cl)C(=O)OC
Reactant: Cl
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1ncnc(Cl)c1Cl
Reaction time: 10 h

Procedure:
134.0 g (0.82 mol) of methyl 3-amino-2-chloro-2-pentenoate and 125.3 g of formamide, dissolved in 150 ml of methanol, are simultaneously added dropwise with stirring to 357.8 ml of a 30% strength sodium methylate solution in methanol at room temperature. The mixture is heated to the reflux temperature over the course of 5 h and is then left at this for 10 h. After cooling, dry HCl gas is passed through until the pH reaches 3. The solvent and the excess formamide are removed by distillation and subsequently 100 ml of toluene are added and removed by distillation twice. 145.3 ml of POCl3 are added to the mixture, which is heated at 70°-80° C. with stirring for 5 h. The excess POCl3 is then removed by distillation, the mixture is added to ice water and neutralized with K2CO3. The residue after extraction with ethyl acetate and evaporation of the solvent is distilled at 110°-112° C. under 25 mbar. Yield: 114.0 g (78.5%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[S:24][C:14]=2[N:15]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-dichlorobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH:4]([OH:7])[CH2:5][OH:6].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>ClCCl>[Si:14]([O:6][CH2:5][CH:4]([OH:7])[CH2:3][N:2]([CH3:8])[CH3:1])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)CC(O)CO
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CN(C)CC(O)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A dry dichloromethane (10 mL) solution of 3-(dimethylamino)-1,2-propanediol (98%, 1.00 g, 8.39 mmol, 1.0 equiv) and imidazole (0.57 g, 8.39 mmol, 1.0 equiv) was stirred at 0° C. under argon for 15 minutes. Solid tert-butyldimethylsilyl chloride (1.26 g, 8.39 mmol, 1.0 equiv) was added to the mixture and the resultant was stirred for 2 hours at 0° C. The mixture was then diluted with 20 mL of dichloromethane and poured into deionized water (15 mL). The organic layer was separated and the aqueous layer was extracted with two additional portions of dichloromethane (20 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to afford crude 1-(tert-butyldimethylsilyloxy)-3-(dimethylamino)propan-2-ol, a thick clear oil, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH:31]=[CH2:32])(=[O:30])=[O:29])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:33]([CH3:35])[CH3:34])[NH:11]1.[CH2:36]([NH:38][CH2:39]C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH:27][S:28]([CH:31]=[CH:32][N:38]([CH3:39])[CH3:36])(=[O:30])=[O:29])=[CH:25][CH:26]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:33]([CH3:35])[CH3:34])[NH:11]1
Reactant: C=CS(=O)(=O)Nc1ccc(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(C(C)C)c-3c(=O)n2)cc1
Reactant: CCNCC
Solvent: C1CCOC1
Product: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(NS(=O)(=O)C=CN(C)C)cc3)nc(=O)c1-2
Reaction time: 3 h
Yield: 100 %

Procedure:
To a stirred, solution of 23 mg(0.042 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(ethenesulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one in 1 mL of THF was added 1 mL of 2M diethylamine in THF. The solution was stirred 3 h and concentrated under reduced pressure. The product was dissolved in 1 mL of benzene and 0.05 mL of MeOH, frozen, and lyophilized to afford 25 mg (100%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-(dimethylamino)ethenesulfonamido) benzyl)pyrazolo[3,4-d]pyrimidin-4-one as an amorphous white solid. 1H NMR (300 MHz, DMSO) δ 7.96(s, 2H); 7.19(d, 2H, J=8.5 Hz); 7.08(d, 2H, J=8.8 Hz); 3.79(s, 2H); 3.18-3.32(m, 1H); 3.13(t, 2H, J=7.5 Hz); 2.53(t, 2H, J=7.5 Hz); 1.99(s, 6H); 1.28(d, 6H, J=7.0 Hz).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.Br[CH2:8][CH2:9][CH2:10][Cl:11]>CC(C)=O.[OH-].[Na+]>[Cl:11][CH2:10][CH2:9][CH2:8][N:3]1[CH2:4][CH2:5][CH2:6][C@H:2]1[CH3:1]
Reactant: ClCCCBr
Reactant: C[C@@H]1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C[C@@H]1CCCN1CCCCl
Temperature: 80 °C
Reaction time: 4 h
Yield: 52.1 %

Procedure:
To a solution of (R)-2-methylpyrrolidine (18.0 g) and 1-bromo-3-chloropropane (100.0 g) in acetone (360 mL), aqueous sodium hydroxide (5 M, 50 mL) was added dropwise in an ice bath and the mixture was heated to 80° C., at which it was stirred for 4 hours. The reaction mixture was extracted with diethyl ether, and the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=4:1 to 1:1) and silica gel column chromatography (eluting solvent: chloroform:methanol=9:1) to give the titled compound (17.8 g, 52%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10](I)=[CH:9][N:8]([C:12]([CH3:17])([CH3:16])[CH2:13][O:14][CH3:15])[C:6]=2[N:7]=1.[Br:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([CH:30]=1)[C:24](N(OC)C)=[O:25]>>[Br:18][C:19]1[CH:30]=[C:23]([C:24]([C:10]2[C:5]3[CH:4]=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[N:8]([C:12]([CH3:17])([CH3:16])[CH2:13][O:14][CH3:15])[CH:9]=2)=[O:25])[CH:22]=[N:21][CH:20]=1
Reactant: COCC(C)(C)n1cc(I)c2cnc(Cl)nc21
Reactant: CON(C)C(=O)c1cncc(Br)c1
Product: COCC(C)(C)n1cc(C(=O)c2cncc(Br)c2)c2cnc(Cl)nc21

Procedure:
The title compound was prepared according to the method described for Preparation 64 using 2-Chloro-5-iodo-7-(2-methoxy-1,1-dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine (Preparation 259) and 5-Bromo-N-methoxy-N-methyl-nicotinamide to afford the title compound as yellow gum in 34% yield, 900 mg.
Reaction SMILES: [Cl:1][C:2]1C=CC(C[C@@H](NC(=O)C2C=CC(I)=CC=2NS(C2C3N=CC=NC=3C=CC=2)(=O)=O)C(O)=O)=CC=1.C(OC([NH:44][C@H:45]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=1)[C:46]([OH:48])=[O:47])=O)(C)(C)C>>[ClH:1].[CH3:2][O:48][C:46](=[O:47])[C@H:45]([NH2:44])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=1
Reactant: O=C(N[C@H](Cc1ccc(Cl)cc1)C(=O)O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Product: COC(=O)[C@H](N)Cc1ccc(Cl)cc1
Product: Cl

Procedure:
(R)-3-(4-Chloro-phenyl)-2-[4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionic acid. (R)-2-(tert-Butoxycarbonylamino)-3-(4-chloro-phenyl)-propionic acid was treated as in EXAMPLE 2, Part A, to produce (R)-2-amino-3-(4-chloro-phenyl)-propionic acid methyl ester hydrochloride as a white solid. This ester was coupled with 4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoic acid as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E. HPLC: RT=9.74 min. MS (ESI−): mass calcd. for C24H18ClIN4O5S, 635.97; m/z found, 635/637 [M−H]−. 1H NMR (500 MHz, CDCl3): 10.93 (d, J=12.8, 1H), 8.99 (d, J=1.6, 1H), 8.92 (s, 1H), 8.54 (d, J=7.4, 1H), 8.31 (d, J=8.5, 1H), 8.10 (s, 1H), 7.90-7.87 (m, 1H), 7.30-7.22 (m, 3H), 7.05 (d, J=8.4, 2H), 6.84 (d, J=8.2, 1H), 6.29 (d, J=7.9, 1H), 4.93-4.80 (m, 1H), 3.24 (dd, J=14.3, 5.8, 1H), 3.16 (dd, J=14.2, 5.9, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[S:9][CH2:10][C:11](=[O:13])[N:12]=1.[N:14]1[C:23]2[C:18](=[N:19][C:20]([CH:24]=O)=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[N:19]1[C:18]2[C:23](=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:22]=[CH:21][C:20]=1[CH:24]=[C:10]1[S:9][C:8]([NH:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:12][C:11]1=[O:13]
Reactant: O=Cc1ccc2ncccc2n1
Reactant: O=C1CSC(NCc2cccs2)=N1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C1N=C(NCc2cccs2)SC1=Cc1ccc2ncccc2n1
Temperature: 120 °C
Yield: 34.9 %

Procedure:
To a suspension of 2-[(thiophen-2-ylmethyl)-amino]-thiazol-4-one (34.0 mg, 0.16 mmol), and 1,5-naphthyridine-6-carboxaldehyde (31.6 mg, 0.2 mmol) in toluene (1 mL) in a microwave tube were added benzoic acid (2.0 mg, 0.02 mmol) and piperidine (1.7 uM, 0.02 mmol). The reaction mixture was heated to 120° C. with microwave for 5 min, then cooled to r.t. and diluted with toluene. The solid was collected by filtration and washed with toluene, MeOH and ether to give 5-[1,5]naphthyridin-2-ylmethylene-2-[(thiophen-2-ylmethyl)-amino]-thiazol-4-one as a light brown solid (19.7 mg, 34.9%). HR-ES (+) m/e calcd. for C17H12N4OS2: (M+H)+ 353.0526. Found: 353.0526.