Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(/[C:3](=[CH:7]\[C:8]1[N:18]([CH:19]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]2=[N:12][C:13]([CH3:17])=[CH:14][C:15]([CH3:16])=[C:10]2[C:9]=1[C:33]#[N:34])/[C:4]([OH:6])=[O:5])C.[OH-].[Na+].O.Cl>C(O)C.C1COCC1>[C:33]([C:9]1[C:10]2[C:11](=[N:12][C:13]([CH3:17])=[CH:14][C:15]=2[CH3:16])[N:18]([CH:19]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]=1/[CH:7]=[CH:3]/[C:4]([OH:6])=[O:5])#[N:34]
Reactant: CC/C(=C\c1c(C#N)c2c(C)cc(C)nc2n1C(c1ccccc1)c1ccc(F)cc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n(C(c3ccccc3)c3ccc(F)cc3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (2E)-3-{3-cyano-1-[(4-fluorophenyl)(phenyl)methyl]-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (7.40 g, 17.0 mmol) in ethanol (70 ml) and THF (80 ml) was added a 1 N aqueous sodium hydroxide solution (34ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water, neutralized with 1 N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give the objective product as a solid material. The product was recrystallized from ethyl acetate and hexane.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:4][NH:3]1.[N+]([NH:20][C:21](N)=[O:22])([O-])=O>CC(C)=O.O>[CH3:1][C@H:2]1[C@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)[CH2:4][N:3]1[C:21]([NH2:20])=[O:22]
Reactant: C[C@@H]1NC[C@H]1Oc1cccc(C(F)(F)F)c1
Reactant: NC(=O)N[N+](=O)[O-]
Solvent: O
Solvent: CC(C)=O
Product: C[C@H]1[C@H](Oc2cccc(C(F)(F)F)c2)CN1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A mixture of 6 g (0.015 mole) of crude trans-2-methyl-3-[3-(trifluoromethyl)phenoxy]azetidine (purity 56.6% contains diphenylmethane) and 2.4 g (0.0225 mole) of nitrourea in 40 ml of acetone was treated with 4 ml of water, then heated until a clear homogenous solution was obtained. The reaction mixture was stirred overnight as it cooled to ambient temperature and diluted with water until an oil separated. The oil solidified and was recrystallized from ethanol/water, yielding 4.3 g of white plate-like crystals; m.p. 117°-118° C. The product was recrystallized from benzene, yielding 3.35 g (96.8%) of crystals, m.p. 118°-119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH:13](Cl)Cl.Cl.[NH2:17]O.C([O-])=O.[Na+]>C(O)=O.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[C:13]#[N:17]
Reactant: Clc1cnc2c(C(Cl)Cl)c(Cl)ccc2c1
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: N#Cc1c(Cl)ccc2cc(Cl)cnc12
Yield: 78.5 %

Procedure:
28.1 parts by weight of the 3,7-dichloro-8-dichloromethylquinoline thus obtained, 6.95 parts by weight of hydroxylamine hydrochloride and 13.6 parts by weight of sodium formate in 200 ml of formic acid and 60 ml of water were stirred for 12 hours at 100° C., the reaction solution was poured onto ice, the precipitated solid was filtered off under suction, washed neutral with water and dried. 19 parts by weight of 3,7-dichloro-8-cyanoquinoline of melting point 222° C. were obtained. Yield: 78.5% of theory.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4](S)[N:3]=1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[N:3]=1
Reactant: Cc1cc(C)nc(S)n1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(C)nc(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
A solution of 25.0 grams (g) 4,6-dimethyl-2-mercaptopyrimidine, 25.1 g 4-fluoronitrobenzene and 24.6 g potassium carbonate in 750 milliliters (ml) acetonitrile was refluxed for 16 hours. The solution was then filtered hot through a pad of dicalite. The dicalite was washed with 300 ml hot acetonitrile. The solvent was evaporated from the combined filtrates giving a waxy yellow solid. This solid was triturated with hexanes giving 42.5 g yellow solid.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH2:4][O:3]1.Cl>C1COCC1>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20]
Reactant: CC1(C)OCC(CCCN2C(=O)c3ccccc3C2=O)O1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCC(O)CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-[3-(2,2-dimethyl[1,3]dioxolan-4-yl)propyl]isoindole-1,3-dione (1.65 g, 5.70 mmol) in THF (20 mL) at room temperature was added 2N HCl solution (15 mL, 30 mmol) in one portion and the resulting mixture was stirred at room temperature for two hours and then evaporated in vacuo to half of the initial volume. The residue was saturated with NaCl and extracted with ethyl acetate. The organic phase was dried by anhydrous magnesium sulfate. Filtration and concentration in vacuo afforded a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[CH:14]([C:16]1[C:17]([O:24][CH3:25])=[N:18][CH:19]=[C:20]([Br:23])[C:21]=1[Cl:22])[OH:15]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[C:14]([C:16]1[C:17]([O:24][CH3:25])=[N:18][CH:19]=[C:20]([Br:23])[C:21]=1[Cl:22])=[O:15]
Reactant: COc1cc(C)c(C(O)c2c(OC)ncc(Br)c2Cl)c(OC)c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C(=O)c2c(OC)ncc(Br)c2Cl)c(OC)c1OC
Temperature: 25 °C
Yield: 86.5 %

Procedure:
4.55 g of manganese dioxide (88%, 46 mmol) was added to a solution having 2.21 g (5.1 mmol) of (2,3,4-trimethoxy-6-methylphenyl)(5-bromo-4-chloro-2-methoxy-3-pyridyl)methanol dissolved in 70 ml of toluene, followed by reflux with heating for 1 hour. 4.55 g of manganese dioxide (88%, 46 mmol) was further added, followed by reflux with heating for 1 hours. The reaction mixture was cooled to room temperature, manganese dioxide was removed by filtration on the pad of celite, and toluene was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography to obtain 1.90 g (yield: 87%) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-5-bromo-4-chloro-2-methoxypyridine (melting point 84 to 87° C.).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:26]([O:28][C:29](=[O:41])[NH:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:32]=1O)[CH3:27].CCOC(/N=N/C(OCC)=O)=O>>[CH2:26]([O:28][C:29](=[O:41])[NH:30][C:31]1[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][C:36]=1[O:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:27]
Reactant: CCOC(=O)Nc1ccc([N+](=O)[O-])cc1O
Reactant: OC1CCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)Nc1ccc([N+](=O)[O-])cc1OC1CCCC1
Temperature: 25 °C

Procedure:
Cyclopentanol (7.24 mL, 376 mM in dry tetrahydrofuran) was added to triphenylphosphine (1.44 g, polystyrene bound, 1.89 mMol/g) under argon, followed by the addition of a solution of (2-Hydroxy-4-nitrophenyl)-carbamic acid ethyl ester (25.6 mL, 62 mM in dry tetrahydrofuran) and a solution of diethylazodicarboxylate (7.24 mL, 376 mM in dry tetrahydrofuran). The reaction mixture was shaken at room temperature over night. The resin was filtered and washed with tetrahydrofuran (THF) (35 mL) and methanol (35 mL). The combined organic phase was evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, heptane/ethyl acetate, gradient) to yield the title compound as slightly yellow solid (294 mg, 64%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3(O)[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)=[C:11]3[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:4][C:3]=2[O:2]1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)=[C:11]3[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.3 %

Procedure:
To a solution of ethyl (1RS)-1,3-di-(3,4-methylenedioxyphenyl)-1-hydroxyindene-2-carboxylate (0.29 g, 0.65 mmol) in CH2Cl2 (3 ml) at 0° C. under an argon atmosphere was added triethylsilane (91 mg, 0.78 mmol), followed by boron trifluoride etherate (0.3 ml, 2.4 mmol). The reaction mixture was stirred for 10 min, at which time was added ice-cold 1M HCl, and the mixture was extracted with EtOAc. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was placed on a small pad of silica gel, eluting with CH2Cl2 to provide the title compound (257 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH:11]C(O)=O)=[CH:4][CH:3]=1.C(O)C1C=CC=CC=1.CN(C=O)C>C(OCC)(=O)C>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)Nc1ccc(Cl)cc1C(=O)O
Solvent: OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)cc1C(=O)O
Yield: 59 %

Procedure:
1.0 g (5.1 mmol) of 5-chloroisatoic acid was heated under stirring in a mixed solvent of benzyl alcohol (5 mL) and DMF (5 mL) at 100° C. for 5 hours. After cooling, the reaction mixture was diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was separated and purified using silica gel column chromatography to give 0.516 g of 2-amino-5-chlorobenzoic acid.benzylester (yield: 39%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:26][C:27]1[N:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:26][C:27]3[N:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccnc(S)n1
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: Cc1ccnc(SCCCC(=O)NC/C=C\COc2cc(CN3CCCCC3)ccn2)n1
Yield: 70 %

Procedure:
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 2-mercapto-4-methylpyrimidine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 70% yield.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([NH2:13])=[C:9]([CH:12]=1)[CH2:10][NH2:11])([O-:4])=[O:3].[C:14](Cl)(=O)[C:15]1[CH:23]=[CH:22][C:21]2[O:20][CH2:19][O:18][C:17]=2[CH:16]=1.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[N+:2]([C:5]1[CH:12]=[C:9]2[C:8](=[CH:7][CH:6]=1)[N:13]=[C:14]([C:15]1[CH:23]=[CH:22][C:21]3[O:20][CH2:19][O:18][C:17]=3[CH:16]=1)[N:11]=[CH:10]2)([O-:4])=[O:3]
Reactant: NCc1cc([N+](=O)[O-])ccc1N
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Agent: Cl
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2nc(-c3ccc4c(c3)OCO4)ncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
To a suspension of 5-nitro-2-amino-benzylamine hydrochloride (31 g, 0.152 mol) in DCM (450 ml) was added at 0° C. TEA (52.6 ml, 0.38 mol) and a solution of piperonyloyl chloride (27.3 g, 0.16 mol) in DCM (80 ml). The mixture was stirred for 2 hours at r.t. The solvent was removed i.v. and the residue triturated with ethanol/water 1/9, then with diisopropyl ether. The obtained solid was dried and suspended in toluene (900 ml) and POCl3 (670 ml). The mixture was heated at reflux for 2 hours, then the solvent was removed i.v. and the residue was triturated with water/ammonia, washed with water, dried over P2O5. A mixture of the obtained product and chloranil (32.7 g, 0.129 mol) in toluene (500 ml) was heated at reflux for 2 hours. The mixture was concentrated i.v. and the residue was triturated with NaOH 1M, washed with water and with methanol. The obtained solid was dried i.v. (37 g, 82.5% yield). C15H9N3O4, MW: 295.26, mp 220-222° C.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:29][C:30](=[N:36][OH:37])[CH2:31][NH:32][C:33](=[O:35])[O-:34]>>[C:11]([O:35][C:33](=[O:34])[NH:32][CH2:31][C:30]1[N:29]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:37][N:36]=1)([CH3:26])([CH3:12])[CH3:10]
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(CNC(=O)[O-])=NO
Product: CC(C)(C)OC(=O)NCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
161 mg (0.40 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 83 mg (0.44 mmol, 1.1 eq.) of tert-butyl[(2-amino-2-(hydroxyimino)ethyl]carbamate were reacted according to the General Method 1. Yield: 127 mg (57% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[N:11]=[C:10]2SC)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]([NH2:29])=[NH:28])[CH:22]=[CH:23][C:24]=1[Cl:25]>C(Cl)(Cl)Cl>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]([N:29]=[C:10]2[NH:11][C:12](=[O:15])[C:13](=[O:14])[N:9]2[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[NH:28])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: CSC1=NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1
Reactant: N=C(N)Nc1ccc(Cl)c(Cl)c1
Solvent: ClC(Cl)Cl
Product: N=C(N=C1NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1)Nc1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Yield: 67.5 %

Procedure:
To the solution of the crude dione 15 (0.551 g, 1.907 mmol) in 25 ml of dry CHCl3 was added N-(3,4-dichlorophenyl)guanidine (14) (0.389 g, 1.907 mmol) at room temperature. The reaction mixture was heated at 50° C. overnight. The solid was collected and washed sequentially with CHCl3 and H2O to afford the compound 19 as a light yellow solid (0.573 g, 1.288 mmol, 68%), mp 220° C. 1H NMR (300 MHz, DMSO-d6): δ 7.75(d, J=8.3 Hz, 1H), 7.69 (s, 1H), 7.55–7.40 (m, 3H), 7.15 (d, 7.9 Hz, 1H); 13C NMR: δ 170.54, 169.33, 160.26, 156.74, 136.75, 132.72, 131.15, 131.00, 130.73, 130.52, 129.64, 128.04. MS (m/z) 444 (MH+), 256, 227, 185. Anal. (C16H9Cl4N5O2) C, H, Cl, N.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[SH:7][CH2:8][CH2:9][OH:10].[CH3:11][C:12]1[CH:13]=[C:14]([C:29]2[S:33][C:32]([N:34]3[CH2:40][CH2:39][CH2:38][NH:37][C:36](=[O:41])[CH2:35]3)=[N:31][CH:30]=2)[CH:15]=[C:16]([NH:18][C:19]2[N:24]=[C:23](S(C)(=O)=O)[CH:22]=[CH:21][N:20]=2)[CH:17]=1>CN(C=O)C.C(OCC)(=O)C>[OH:10][CH2:9][CH2:8][S:7][C:21]1[CH:22]=[CH:23][N:24]=[C:19]([NH:18][C:16]2[CH:15]=[C:14]([C:29]3[S:33][C:32]([N:34]4[CH2:40][CH2:39][CH2:38][NH:37][C:36](=[O:41])[CH2:35]4)=[N:31][CH:30]=3)[CH:13]=[C:12]([CH3:11])[CH:17]=2)[N:20]=1
Reactant: OCCS
Reactant: Cc1cc(Nc2nccc(S(C)(=O)=O)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(SCCO)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Reaction time: 0.25 h
Yield: 27.7 %

Procedure:
Potassium carbonate (9.95 mg, 0.072 mmol) was added to a solution of 2-mercaptoethanol (18.34 μL, 0.262 mmol) stirring in DMF (327 μL) at room temperature in an oven-dried vial. Stirred for 15 minutes, then added 4-[5-(3-methyl-5-{[4-(methylsulfonyl)-2-pyrimidinyl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (30 mg, 0.065 mmol). Stirred at room temperature for 30 minutes, diluted with ethyl acetate (10 mL), and washed with 1:1 water:brine (10 mL). The organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purified by CombiFlash (100:0 to 0:20 dichloromethane:methanol) to afford 4-{5-[3-({4-[(2-hydroxyethyl)sulfanyl]pyrimidin-2-yl}amino)-5-methylphenyl]-1,3-thiazol-2-yl}-1,4-diazepan-2-one (8.4 mg, 0.018 mmol, 28.1% yield) as a yellow solid. MS APCI: [M+H]+ m/z 457.1. 1H NMR (500 MHz, DMSO) δ 9.52 (s, 1H), 8.14 (d, J=5.3 Hz, 1H), 7.58 (d, J=12.2 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 6.92 (s, 1H), 6.75 (d, J=5.4 Hz, 1H), 4.97 (t, J=5.4 Hz, 1H), 4.16 (s, 2H), 3.79 (s, 2H), 3.64 (dd, J=6.3 Hz, 11.9 Hz, 2H), 3.29 (s, 1H), 3.21 (s, 2H), 3.15 (d, J=5.2 Hz, 1H), 2.27 (s, 3H), 1.78 (s, 2H). rhSYK activity=+++.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:40][CH3:41])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH2:13][CH3:14])[CH:8]=[C:7]2[O:15][CH:16]1[CH2:33][CH:32]2[CH:18]([C:19](=[O:39])[N:20]([CH3:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]3[C:29]([C:35](O)=[O:36])([NH:30][C:31]2=[O:34])[CH2:28]3)[CH2:17]1.C(OC1C=C(OC2CC3C(C(=O)N(C)CCCCC=CC4C(C([NH:77][S:78]([CH:81]5[CH2:83][CH2:82]5)(=[O:80])=[O:79])=O)(NC3=O)C4)C2)C2C(=C(C)C(OC)=CC=2)N=1)C>>[Br:1][C:2]1[C:3]([O:40][CH3:41])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH2:13][CH3:14])[CH:8]=[C:7]2[O:15][CH:16]1[CH2:33][CH:32]2[CH:18]([C:19](=[O:39])[N:20]([CH3:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]3[C:29]([C:35]([NH:77][S:78]([CH:81]4[CH2:83][CH2:82]4)(=[O:80])=[O:79])=[O:36])([NH:30][C:31]2=[O:34])[CH2:28]3)[CH2:17]1
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(Br)c2n1
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(Br)c2n1

Procedure:
The title compound (7) was prepared from 17-[8-bromo-2-ethoxy-7-methoxyquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (6) following the procedure reported for synthesis of N-[17-[2-ethoxy-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (3): m/z=734 (M+H)+.
Reaction SMILES: [CH3:1][O-].[Na+].[C:4]([O:13][CH3:14])(=[O:12])[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[SH:7].IC>CO>[CH3:14][O:13][C:4](=[O:12])[C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[S:7][CH3:1]
Reactant: COC(=O)c1ccccc1S
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: COC(=O)c1ccccc1SC
Yield: 388 %

Procedure:
To a solution of 160 mg (2.97 mmol) of sodium methoxide in 10 mL of methanol was added at 0°, 0.4 mL (2.97 mmol) of methyl thiosalicylate, 0.37 mL (5.97 mmol) of iodomethane and stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, taken up in ethyl acetate, washed with water, brine, dried over sodium sulfate, and concentrated in vacuo to give 2.10 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:26])=[C:4]([C:9]2[C:10]([OH:25])=[N:11][C:12]3[C:17]([C:18]=2[O:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=[CH:14][N:13]=3)[C:5]([F:8])=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[F:36][CH:37]([F:47])[CH2:38]OS(C(F)(F)F)(=O)=O>C(#N)C>[Br:1][C:2]1[C:3]([Cl:26])=[C:4]([C:9]2[C:10](=[O:25])[N:11]([CH2:38][CH:37]([F:47])[F:36])[C:12]3[C:17]([C:18]=2[O:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=[CH:14][N:13]=3)[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Oc1c(-c2c(F)ccc(Br)c2Cl)c(O)nc2ncccc12
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)Oc1c(-c2c(F)ccc(Br)c2Cl)c(=O)n(CC(F)F)c2ncccc12
Reaction time: 8 h

Procedure:
To a solution of Isobutyric acid 3-(3-bromo-2-chloro-6-fluoro-phenyl)-2-hydroxy-[1,8]naphthyridin-4-yl ester (1.749 g) in acetonitrile (17 ml) was added N,N-diisopropylethylamine (“Hunig's base”) (0.83 ml) at ambient temperature. The mixture was stirred for 5 minutes at ambient temperature before drop wise addition of a solution of 2,2-difluoroethyltrifluoromethanesulfonate (1.022 g) at ambient temperature. The reaction mixture was stirred at ambient temperature for 7 hours when further 2,2-difluoroethyltrifluoromethanesulfonate (0.5 g) and the reaction was stirred overnight. A further portion of 2,2-difluoroethyltrifluoromethanesulfonate (0.5 g) and N,N-diisopropylethylamine (“Hunig's base”) (0.83 ml) was added and the reaction was stirred for 5 hours then left to stand overnight. The reaction was concentrated and partitioned between ethyl acetate and 2M hydrochloric acid. The organic layer was dried and concentrated and the oily residue was purified by column chromatography on silica (eluent: 4:1 hexane:ethyl acetate) to give Compound No. D23 of Table D as a light yellow solid (1.56 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C@@:18]([OH:30])([CH3:29])[CH2:19][N:20]2[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[N:22]=[C:21]2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C@:18]2([CH3:29])[O:30][C:21]3=[N:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][N:20]3[CH2:19]2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC[C@](C)(O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To the solution of (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-tertbutoxycarbonylpiperazine-1-carboxylate prepared in Example 87 (4.12 g, 9.20 mmol) in DMF (30 ml), sodium hydride (0.44 g, 11.04 mmol) was added followed by stirring for 1 hour with cooling on ice-bath. Ice-water was added to the reaction mixture, and the precipitates were filtered off, purified by silica gel column chromatography (ethyl acetate) and then washed with isopropanol to afford (R)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl 4-tertbutoxycarbonylpiperazine-1-carboxylate (2.24 g, yield 59%) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=O)[CH2:15]Br)C.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH2:26])=[O:25]>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:18])=[C:8]([C:14]2[N:26]=[C:24]([C:23]3[CH:27]=[CH:28][CH:29]=[C:21]([O:20][CH3:19])[CH:22]=3)[O:25][CH:15]=2)[CH:9]=1
Reactant: COc1cccc(C(N)=O)c1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)CBr
Product: COc1cccc(-c2nc(-c3cc(Br)ccc3OCC(=O)O)co2)c1

Procedure:
Title compound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and 3-methoxybenzamide according to GP5 and GP3: LC/MS (an10p8) Rt 2.68 min, m/z 404 [M+H]+; 1H NMR (CDCl3): δ 3.87 (s, 1H), 4.89 (s, 2H), 7.09 (m, 2H), 7.4-7.7 (m, 4H), 8.22 (s, 1H), 8.89 (s, 1H), 13.3 (br s, 1H).