Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>S(=O)(=O)(O)O>[C:12]([O:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:14])[CH3:13]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)O
Temperature: 40 °C

Procedure:
A mixture of 86 g (0.5 mole) of 5-chloro salicylic acid and 102 g (1.0 mole) of acetic anhydride are warmed to 40° C. With stirring, 5 drops of conc. sulfuric acid are added, which causes an exothermic reaction. The mixture is stirred for 1/2 hour at 60° C. then poured into ice. The solid is filtered, washed with water and air dried, mp 146°-8° C, and is used as is for the next step. ##STR5##
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[C:7]([CH3:9])[CH:8]=1.[Br:16][C:17]1[CH:18]=[N:19][C:20]([C:23](O)=[O:24])=[N:21][CH:22]=1>>[Br:16][C:17]1[CH:18]=[N:19][C:20]([C:23]([N:13]2[CH2:12][CH2:11][N:10]([C:4]3[C:3]([CH3:2])=[CH:8][C:7]([CH3:9])=[CH:6][N:5]=3)[CH2:15][CH2:14]2)=[O:24])=[N:21][CH:22]=1
Reactant: O=C(O)c1ncc(Br)cn1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ncc(Br)cn3)CC2)c(C)c1
Yield: 99.7 %

Procedure:
Using 1-(3,5-dimethylpyridin-2-yl)piperazine hydrochloride (528 mg) described in Preparation Example 80 and 5-bromopyrimidine-2-carboxylic acid (406 mg) and by the reaction and treatment in the same manner as in Example 97, (5-bromopyrimidin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (750 mg) was obtained. Using this compound (750 mg) and (R)-4-methyl-2-oxazolidinone (303 mg) and by the reaction and treatment in the same manner as in Example 1, (R)-3-[2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyrimidin-5-yl]-4-methyloxazolidin-2-one was obtained. The obtained (R)-3-[2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyrimidin-5-yl]-4-methyloxazolidin-2-one was dissolved in ethyl acetate, 4N hydrogen chloride/ethyl acetate (0.4 mL) was added, and the precipitate was collected by filtration to give the title compound (509 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[C:9](Cl)=[N:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[C:13]=1[CH3:14].O.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29]>CC(CC)=O>[Br:7][C:8]1[C:9]([O:27][C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:28]([F:31])([F:29])[F:30])[CH:23]=2)=[N:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[C:13]=1[CH3:14]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1c([N+](=O)[O-])cnc(Cl)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: Cc1c([N+](=O)[O-])cnc(Oc2ccc(Cl)c(C(F)(F)F)c2)c1Br
Temperature: 80 °C
Reaction time: 3 h

Procedure:
In a 250 ml three-necked round-bottomed flask, 4.00 g 4-chloro-3-trifluoromethyl-phenol is dissolved in 80 ml of dry methyl-ethyl-ketone. 3.85 g potassium carbonate followed by 4.70 g of 3-bromo-2-chloro-4-methyl-5-nitro-pyridine are added. The resulting brown suspension is heated to 80° C. under stirring for 3 hours. Afterwards, the green suspension is allowed to reach an ambient temperature and it then poured into water. The mixture is extracted with ethyl actetate (3×50 ml). The combined organic phases are washed with brine, dried over sodium sulfate, filtered and the solvent removed in vacuo. After purification of the raw product on silica gel with cyclohexane/ethyl actetae 19:1 (v:v) 7.36 g of the title compound are obtained as a light yellow gum that solidifies upon standing (MP: 73-74° C.).
Reaction SMILES: CC(C)([O-])C.[K+].C(OP([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)(=O)OCC)C.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][CH:40]=O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].O>O1CCCC1>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39]/[CH:40]=[CH:15]/[C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Reactant: CCOP(=O)(Cc1ccc(C(F)(F)F)cc1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C/C=C/c2ccc(C(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
Potassium tert-butoxide (5.78 g, 50.0 mmol) was added to a solution of 4-(trifluoromethyl)benzylphosphonic acid diethyl ester (14.8 g, 50.0 mmol) in tetrahydrofuran solution (40 ml) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. Subsequently, a tetrahydrofuran solution (10 ml) of 4-(2-oxoethyl)piperidine-1-carboxylic acid tert-butyl ester (11.4 g, 50.0 mmol) was added thereto dropwise at 0° C., warmed to room temperature, and then stirred overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=86:14) to afford the title compound as a colorless oil (8.6 g, yield 47%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[OH:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:18]2[C:19]([O:21][C:22](=O)[C:17]=12)=[O:20]>>[OH:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:18]2[C:17]=1[C:22](=[O:21])[N:1]([CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:19]2=[O:20]
Reactant: O=C1OC(=O)c2c(O)cccc21
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Product: CCOC(=O)C(CN1C(=O)c2cccc(O)c2C1=O)C1(C)OCCO1

Procedure:
Ethyl 3-(4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.46 g, 67%) in the same manner as described in the above example 5 (20) from ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.40 g, 1.96 mmol) and 3-hydroxyphthalic anhydride (0.42 g, 2.16 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.NCC[C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1.[CH2:29]([N:31](CC)CC)[CH3:30]>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([N:31]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH2:29][CH3:30])[N:3]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: CCN(CC)CC
Product: CCN(c1c[nH]c2ccccc12)c1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[(3-indolyl)-2-ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, tryptamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C.O>ClCCl.CN(C)C1C=CN=CC=1>[Cl:11][C:8]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([NH:6][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 34.5 %

Procedure:
A mixture of 2-nitro-5-chloroaniline (Tokyo Kasei Kogyo Co., Ltd., 3 g, 17.4 mmol), pivaloyl chloride (2.1 mL, 17.4 mmol) and N,N-diisopropylethylamine (3.1 mL, 17.4 mmol) in dichloromethane (80 mL) was stirred at room temperature for 20 h. 4-Dimethylaminopyridine (531 mg, 4.4 mmol) was added and the stirring was continued for 3 days. The mixture was poured into water (30 mL) and the mixture was extracted with dichloromethane (30 mL). After removal of solvent, the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:20 as eluent) to afford the title compound (1.54 g, 34%) as a pale yellow solid.
Reaction SMILES: CS[C:3]([C:13]1[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[NH2:12])[CH3:4].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:12][C:6]1[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:5]=1[CH:3]([C:13]1[N:14]=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[N:18]=1)[CH3:4]
Reactant: COc1cc(OC)nc(C(C)(SC)c2cccc(Cl)c2N)n1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(OC)nc(C(C)c2cccc(Cl)c2N)n1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of 2-{1-methylthio-1-(2-amino-3-chlorophenyl)ethyl}-4,6-dimethoxypyrimidine 3 g (8.8 mmol) in 100 ml methanol, nickel (II) chloride hexahydrate 4.2 g (17.7 mmol) was added at 0° C. and the mixture was stirred for 30 minutes. Then, at the same temperature, sodium borohydride 1.35 g (35 mmol) was added little by little thereto. The solution was stirred at room temperature for 1 hour and then the solvent was distilled off. 2N-hydrochloric acid was added to the residue and then 28% aqueous ammonia was added and the mixture was extracted with ethyl acetate. The organic layer washed with an aqueous solution of sodium hydroxide and the solvent was distilled off. After washing with hexane, the deposited crystals were filtered to obtain 2-{1-(2-amino-3-chlorophenyl)ethyl}-4,6-dimethoxypyrimidine 2.12 g (82%).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.B(F)(F)F.[NH:31]1[CH:35]=[CH:34][N:33]=[CH:32]1>CN(C)C=O>[NH:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH2:2][C:3]1([OH:1])[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:7][CH2:8]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: c1c[nH]cn1
Agent: FB(F)F
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(Cc4ncc[nH]4)CC3)c(F)c2)C(=O)O1
Yield: 66 %

Procedure:
The compound was obtained by reacting (S)—N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.40 mmol), BF3 etherate (catalytic) and imidazole (1.80 mmol) in dimethylformamide (10 ml) at 80° C. for 8 hours, followed by silica gel column chromatographic separation to provide title compound in 66% yield. M.P. 130-132° C. and MS (M+1)=432 (MH+, 100%) for M.F.=C21H26FN5O4.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:7](Cl)=[O:8])([O-:3])=[O:2].N1C=CC=CC=1.[CH:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:7]([O:26][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:8])([O-:3])=[O:2]
Reactant: OC1CCCCC1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(OC1CCCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Yield: 88 %

Procedure:
Twelve grams (0.055 mole) fo crude 3-nitro-4-chlorobenzoyl chloride was dissolved in 200 ml. of benzene. Eight milliliters of pyridine were added to the reaction mixture. Six milliliters of cyclohexanol were dissolved in 50 ml. of benzene and the solution was added dropwise to the acid chloride-pyridine mixture. The reaction mixture was refluxed for 4 hours and filtered. The benzene filtrate was washed successively with dilute acid, dilute base and water. The washed benzene solution was dried and evaporated in vacuo to yield 12.5 g (88 percent) of cyclohexyl 3-nitro-4-chlorobenzoate, mp 57°-58° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:31]([NH:33][CH:34]([CH3:36])[CH3:35])[CH3:32]>>[CH2:31]([N:33]([CH:34]([CH3:36])[CH3:35])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)[CH3:32]
Reactant: CCNC(C)C
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Product: CCN(CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1)C(C)C

Procedure:
The product from Example 44E and ethyl(isopropyl)amine were processed as described in Example 1D to provide the titled compound. 1HNMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.25 (d, J=1.8 Hz, 1H), 7.98 (m, 3H), 7.59 (d, J=8.7 Hz, 1H), 6.85 (s, 1H), 3.3-3.8 (m, 15H), 1.4 (m, 9H); MS (DCI) m/z 422 (M+H)+;
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[S:7][CH:8]=[CH:9][C:10]=2[NH2:11])[N:3]=[CH:2]1.[N:12]1([CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][C:29]([NH:11][C:10]3[CH:9]=[CH:8][S:7][C:6]=3[C:4]3[N:3]=[CH:2][S:1][CH:5]=3)=[O:30])=[CH:26][CH:27]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)Cc1ccc(OCCCN2CCCCC2)cc1
Reactant: Nc1ccsc1-c1cscn1
Product: O=C(Cc1ccc(OCCCN2CCCCC2)cc1)Nc1ccsc1-c1cscn1

Procedure:
The title compound was prepared from 2-(thiazol-4-yl)thiophen-3-amine and 2-(4-(3-(piperidin-1-yl)propoxy)phenyl)acetic acid using protocol X. Method[7], MS(ESI) 442.1 [M+H], Retention time=3.586 min; 1H-NMR (300 MHz, CDCl3) δ 10.8 (s, 1H), 8.54-8.53 (m, 1H), 8.13-8.11 (m, 1H), 7.33-7.30 (m, 2H), 7.25-7.17 (m, 2H), 6.90 (d, J=8.8 Hz, 2H), 4.08 (t, J=4.95 Hz, 2H), 3.74 (m, 3H), 3.28-3.21 (m, 2H), 2.72-2.61 (m, 2H), 2.40-2.20 (m, 6H), 2.05-1.91 (m, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:9][C:10]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:11]=1[CH:12]=[CH:13][CH2:14]Cl.[O:23]1CCCC1>C(OCC)(=O)C>[CH3:1][N:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:14](=[O:23])[CH:13]=[CH:12][C:11]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:10]=1[Cl:9]
Reactant: C1CCOC1
Reactant: CCCCCCNC
Reactant: O=[N+]([O-])c1ccc(Cl)c(C=CCCl)c1
Solvent: CCOC(C)=O
Product: CCCCCCN(C)C(=O)C=Cc1cc([N+](=O)[O-])ccc1Cl
Reaction time: 2 h
Yield: 81 %

Procedure:
At 0° to 5° C., 11.5 g (0.10 mol) of N-methylhexylamine in 100 ml of tetrahydrofuran was added to a solution of 12.3 g (0.05 mol) of 2-chloro5-nitrocinnamyl chloride in 40 ml of tetrahydrofuran. After the mixture had been stirred for 2 hours, the solvent was removed, and the residue thus obtained was dissolved in ethyl acetate and extracted with 5% strength sodium hydroxide solution. The organic phase was washed with water, followed by separation and drying, to give 13.3 g (81% of theory) of 2-chloro-5-nitrocinnamic acid-N-methyl-N-hexylamide.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][N:9]1[C:13]([S:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)=[N:12][N:11]=[N:10]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:8][N:9]1[C:13]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[N:12][N:11]=[N:10]1
Reactant: Sc1ccccn1
Reactant: Cn1nnnc1SCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCCSc1ccccn1
Yield: 75.9 %

Procedure:
2-Mercaptopyridine (1.3 g) and 1-methyl-5-(4-bromobutyl)thio-1,2,3,4-tetrazole (2 g) are dissolved in acetone (50 ml). To the mixture is added potassium carbonate (1.4 g), and the mixture is refluxed for 2 hours. After acetone is distilled off, water is added to the residue, and the precipitated crystals are separated by filtration and recrystallized from ethanol-water to give 1-methyl-5-[4-(2-pyridyl)thiobutyl]thio-1,2,3,4-tetrazole (1.7 g) as pale yellow prisms, m.p. 49°-51.5° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[C:27](=[O:31])[N:26]([CH2:32][C:33]([OH:35])=[O:34])[C:25]3=[O:36])[S:18]([CH3:21])(=[O:20])=[O:19])[CH2:11][CH2:10]1.[Cl:37][C:38]1[CH:39]=[N+:40]([O-:63])[CH:41]=[C:42]([Cl:62])[C:43]=1[CH2:44][C@@H:45]([C:47]1[CH:52]=[CH:51][C:50]([O:53][CH:54]([F:56])[F:55])=[C:49]([O:57][CH2:58][CH:59]2[CH2:61][CH2:60]2)[CH:48]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:37][C:38]1[CH:39]=[N+:40]([O-:63])[CH:41]=[C:42]([Cl:62])[C:43]=1[CH2:44][C@@H:45]([C:47]1[CH:52]=[CH:51][C:50]([O:53][CH:54]([F:56])[F:55])=[C:49]([O:57][CH2:58][CH:59]2[CH2:61][CH2:60]2)[CH:48]=1)[O:34][C:33](=[O:35])[CH2:32][N:26]1[C:25](=[O:36])[C:24]2[C:28](=[CH:29][CH:30]=[C:22]([N:17]([CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][N:9]([CH3:8])[CH2:14][CH2:13]3)[S:18]([CH3:21])(=[O:20])=[O:19])[CH:23]=2)[C:27]1=[O:31]
Reactant: CN1CCN(CCN(c2ccc3c(c2)C(=O)N(CC(=O)O)C3=O)S(C)(=O)=O)CC1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1CCN(CCN(c2ccc3c(c2)C(=O)N(CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC4CC4)c2)C3=O)S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.76 %

Procedure:
A mixture of 2-(5-(N-(2-(4-methylpiperazin-1-yl)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetic acid 2,2,2-trifluoroacetic acid salt (128 mg, 0.237 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (83 mg, 0.198 mmol), EDC (53.0 mg, 0.277 mmol) and DMAP (48.3 mg, 0.395 mmol) in DCM (4 ml) was stirred at room temperature overnight. Additional EDC (18.93 mg, 0.099 mmol) was added, and the reaction was stirred at the same temperature for further 4 hours. The mixture was diluted with DCM and washed with 1N HCl and brine. The organic phase was dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography on silica gel (DCM/MeOH 96/4, then DCM/MeOH 92/8) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(N-(2-(4-methylpiperazin-1-yl)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetoxy)-ethyl)pyridine 1-oxide as a white solid (29 mg, 0.035 mmol, 17.76% yield, MS/ESI+ 826.03 [MH]+, [αD]=−23.91, c=0.466, MeOH). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.44 (s, 2H), 7.92-7.99 (m, 2H), 7.88 (dd, 1H), 7.19 (d, 1H), 7.09 (d, 1H), 6.97 (dd, 1H), 7.08 (t, 1H), 6.02 (dd, 1H), 4.43 (s, 2H), 3.95 (dd, 2H), 3.80-3.92 (m, 2H), 3.32-3.45 (m, 1H), 3.17-3.24 (m, 1H), 3.15 (s, 3H), 2.39 (t, 2H), 2.25-2.34 (m, 4H), 2.12-2.22 (m, 4H), 2.07 (s, 3H), 1.15-1.32 (m, 1H), 0.53-0.67 (m, 2H), 0.31-0.45 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]2[C:27](=[O:28])[NH:26][N:25]=[CH:24][C:13]3=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[NH:15][C:16]([CH:17]=1)=[C:12]23.[CH3:29][CH:30]1[CH2:32][CH:31]1[C:33](O)=[O:34].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:28]=[C:27]1[C:11]2[C:12]3[C:13](=[C:14]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:15][C:16]=3[CH:17]=[C:9]([NH:8][C:33]([CH:31]3[CH2:32][CH:30]3[CH3:29])=[O:34])[CH:10]=2)[CH:24]=[N:25][NH:26]1
Reactant: CC1CC1C(=O)O
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1CC1C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reaction time: 8 h
Yield: 37 %

Procedure:
Triethylamine (0.030 mL, 0.22 mmol), the title compound of Example 7 (15mg, 0.054 mmol) and 2-methyl-cyclopropanecarboxylic acid (6 mg, 0.062 mmol) were stirred in N,N-dimethylformamide (1.0 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) was added and the reaction was stirred overnight at which point the volatile components were removed under vacuum. The resulting mixture was purified on silica gel, eluting with 3:2 hexane:ethyl acetate. The purest fractions were combined and after solvent removal, the resulting solids were triturated with diethyl ether to give the title compound (7 mg, 0.020 mmol) as yellow powder in 36% yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14]2)[CH:3]=1.[CH2:24](B1OC(C)(C)C(C)(C)O1)[CH:25]=[CH2:26].C(=O)([O-])[O-].[K+].[K+].COCCOC>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:13]1[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14]1)[CH:3]=[C:2]2[CH2:26][CH:25]=[CH2:24].[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:13]1[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14]1)[CH:3]=[CH:2]2
Reactant: Clc1ccc2nc(N3CCCc4ccccc4C3)cc(Cl)c2c1
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: C=CCc1cc(N2CCCc3ccccc3C2)nc2ccc(Cl)cc12
Product: Clc1ccc2nc(N3CCCc4ccccc4C3)ccc2c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
The mixture of 2-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine (200 mg, 0.58 mmol), 2-allyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.164 mL, 0.87 mmol), tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.058 mmol), potassium carbonate (241 mg, 1.74 mmol), 1,2-dimethoxyethane (3 mL) and water (1 mL) was heated with stirring in a 10 mL of microwave process vial for 3 hours at 120° C. under microwave irradiation. The resulting mixture was diluted with ethyl acetate (20 mL), and then washed with water (20 mL). The ethyl acetate fraction was dried over sodium sulfate, and then concentrated under reduced pressure to give a residue which was separated by column chromatography on silica gel (ethyl acetate/petroleum ether, 0.1:5) to afford 2-[6-chloro-4-(prop-2-en-1-yl)quinolin-2-yl]-2,3,4,5-tetrahydro-1H-2-benzazepine (20 mg) and 2-(6-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine (50 mg).
Reaction SMILES: [Cl:1]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[N:25]=[C:24]2[O:26][CH2:27][CH2:28][C:23]2=[CH:22][CH:21]=1>ClCCCl.C(Cl)Cl>[Cl:1][C:21]1[CH:22]=[C:23]2[CH2:28][CH2:27][O:26][C:24]2=[N:25][C:20]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Br:13]
Reactant: Brc1ccccc1-c1ccc2c(n1)OCC2
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: Clc1cc2c(nc1-c1ccccc1Br)OCC2
Reaction time: 8 h
Yield: 206.3 %

Procedure:
Trichloroisocyanuric acid (0.63 g, 2.7 mmol) was added as a solid to a solution of 6-(2-bromophenyl)-2,3-dihydrofuro[2,3-b]pyridine (1.5 g, 5.4 mmol) in 1,2-dichloroethane (30 ml). The mixture was allowed to stir overnight and then a small additional amount of the chlorinating agent was added and the solution refluxed for 1.5 h. The mixture was diluted with methylene chloride and washed with water, brine (sat.), dried (over MgSO4), filtered and concentrated to afford 1.73 grams of the desired product, m.p. 106°-117° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:14]([O:23][CH3:24])(=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH2:17]>C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>[C:9]([C:8]1[CH:12]=[CH:13][C:5]([S:2]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[C:14]([O:23][CH3:24])=[O:22])(=[O:4])=[O:3])=[CH:6][CH:7]=1)([OH:11])=[O:10]
Reactant: COC(=O)c1ccccc1N
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(C(=O)O)cc1
Reaction time: 16 h

Procedure:
4-Chlorosulfonylbenzoic acid (2.21 g, 10 mmol) is added to a solution of the methyl anthranilate (1.51 g, 10 mmol) in 20 mL of DCM at RT. The reaction is stirred 16 h and then filtered to give a white solid. The solid is dissolved in diluted aqueous potassium carbonate and extracted with EtOAc. The aqueous phase is added slowly to an excess (25 mL) of 1 N aqueous HCl. A white solid precipitates and is collected by filtration, washed with water, and dried under vacuum to give methyl 2-(4-carboxybenzene-sulfonylamino)-benzoate.