Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:41]=2[Cl:47])[C:5](=[O:38])[CH:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][C:29]3[C:34]([Cl:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=3[Cl:37])=[CH:21][CH:20]=2)[CH2:7][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]C)=[O:15])[CH2:3][CH2:2]1.CO.[OH-].[Na+]>C1COCC1>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:41]=2[Cl:47])[C:5](=[O:38])[CH:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][C:29]3[C:34]([Cl:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=3[Cl:37])=[CH:21][CH:20]=2)[CH2:7][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:2][CH2:3]1
Reactant: COC(=O)CCCCCNCC(Cc1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1)C(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(CNCCCCCC(=O)O)C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)cc2)c(Cl)c1

Procedure:
Methyl 6-[(3-[cyclopropyl(2,3-dichlorobenzyl)amino]-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)amino]hexanoate (Example 20, 1 eq.) was dissolved in a 2:1 (v/v) THF:MeOH solution (0.01 M). To this was then added sodium hydroxide (1.0 M aqueous solution, 3 eq.) and the resulting solution was stirred at RT for 18 h. The volatiles were then removed in vacuo. Following careful acidification of the resulting residue to a pH of ˜4 with 10% aq. HCl, the mixture was saturated with sodium chloride and extracted with EtOAc. The combined organic extracts were concentrated in vacuo. The resulting solid residue was then azeotroped with toluene to give the title compound as a white solid. MS (ESI+): 709.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C@H:8]([C:17]1[CH:22]=[CH:21][C:20]([O:23][Si](C(C)(C)C)(C)C)=[CH:19][CH:18]=1)[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOCC>[C:1]([O:5][C:6](=[O:31])[NH:7][C@H:8]([C:17]1[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=1)[CH2:9][N:10]1[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCN(C[C@H](NC(=O)OC(C)(C)C)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1CCN(C[C@H](NC(=O)OC(C)(C)C)c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [(R)-1-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-(4-methyl-piperazin-1-yl)-ethyl]-carbamic acid tert-butyl ester (370 mg, 0.82 mmol) in THF (3 ml) was added TBAF (1M in THF, 1 ml, 1 mmol). The resulting mixture was stirred at rt for 3 h. The reaction mixture was diluted with ether and quenched with aq. NH4Cl. The organic layer was washed with water and brine, and then dried over MgSO4. Removal of the solvent provided the titled compound.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[S:26][C:25]([S:27](Cl)(=[O:29])=[O:28])=[N:24][N:23]=1)([O-:15])=[O:14]>>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:27]([C:25]1[S:26][C:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])=[N:23][N:24]=1)(=[O:28])=[O:29])[CH3:4]
Reactant: O=[N+]([O-])c1ccccc1-c1nnc(S(=O)(=O)Cl)s1
Reactant: CCOC(=O)CNCCN
Agent: Cl
Product: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccccc2[N+](=O)[O-])s1

Procedure:
The title compound was synthesized by the reaction of N-(2-aminoethyl)-glycine ethyl ester 2HCl with 5-(2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonyl chloride as per the procedure of example 1. 1H NMR (MHz; DMSO-d6) δ 8.16 (d, 1H), 7.81–7.78 (m, 3H), 4.02 (q, 2H), 3.34 (s, 2H), 3.21 (t, 2H), 2.70 (t, 2H), 1.15 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[CH:27]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH:29]1[C:30]2[C:26](=[CH:25][C:24]([O:23][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[N:4][CH:3]=3)=[CH:32][CH:31]=2)[CH:27]=[CH:28]1
Reactant: COc1cc2c(Cl)cnnc2cc1OCCCN1CCCC1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)cnnc2cc1OCCCN1CCCC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 15.4 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)cinnoline (200 mg, 0.62 mmol), (prepared as described for the starting material in Example 1), 5-hydroxyindole (100 mg, 0.75 mmol) and potassium carbonate (129 mg, 0.93 mmol) in DMF (3 ml) was stirred at 100° C. for 6 hours. After cooling, the volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methylene chloride/methanol saturated with ammonia (98/2 to 90/10). The fractions containing the expected product were combined and evaporated to give 4-(indol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)cinnoline (40 mg, 15%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][C:16]3[C:15](=[O:25])[NH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:5][CH:4]=1>C(Cl)(Cl)Cl.C(#N)C.[O-2].[O-2].[Mn+4]>[O:25]=[C:15]1[NH:14][CH:13]=[CH:12][C:11]2[N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=3)[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][C:16]1=2
Reactant: O=c1[nH]ccc2nc(-c3ccc(CO)cc3)c(-c3ccccc3)cc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=Cc1ccc(-c2nc3cc[nH]c(=O)c3cc2-c2ccccc2)cc1
Temperature: 60 °C

Procedure:
To a solution of 2-[4-(hydroxymethyl)phenyl]-3-phenyl-1,6-naphthyridin-5(6H)-one (316 mg, 0.96 mmol) in chloroform (15 mL) and acetonitrile (15 mL) was added activated manganese dioxide (903 mg, 10 mmol) which was warmed at 60° C. for three hours. The warm suspension was filtered, rinsed with chloroform and the solvents removed in vacuo. The residue was triturated with diethyl ether and the suspension filtered to give the title compound as a pinkish solid. 1H-NMR (500 MHz, CDCl3): δ 10.20 (1H, s), 9.89 (1H, br s), 8.73 (1H, s), 7.81 (2H, d, J=8 Hz), 7.61 (2H, d, J=8 Hz), 7.35-7.38 (1H, m), 7.30-7.32 (2H, m), 7.21-7.22 (2H, m), 6.91 (1H, d, J=7.3 Hz). m/e (m+1): 327.2.
Reaction SMILES: [N+]([O-])([O-])=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[NH4+].[NH4+].[NH4+].[NH4+].C[O:30][C:31]1[C:36]2[CH:37]=[CH:38][O:39][C:35]=2[C:34]([O:40]C)=[C:33]([O:42][CH2:43][N:44]2[C:54](=[O:55])[C:53]3[C:48](=[CH:49][C:50]([O:59][CH3:60])=[CH:51][C:52]=3[CH:56]([CH3:58])[CH3:57])[S:45]2(=[O:47])=[O:46])[C:32]=1[C:61](=[O:63])[CH3:62]>O.C(#N)C>[C:61]([C:32]1[C:31](=[O:30])[C:36]2[CH:37]=[CH:38][O:39][C:35]=2[C:34](=[O:40])[C:33]=1[O:42][CH2:43][N:44]1[C:54](=[O:55])[C:53]2[C:48](=[CH:49][C:50]([O:59][CH3:60])=[CH:51][C:52]=2[CH:56]([CH3:58])[CH3:57])[S:45]1(=[O:47])=[O:46])(=[O:63])[CH3:62]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1c(C(C)=O)c(OC)c3ccoc3c1OC)C2=O
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Solvent: O=[N+]([O-])O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COC1=C(C(C)=O)C(=O)c3ccoc3C1=O)C2=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.1 %

Procedure:
A solution of triceric tetraammonium hexanitrate (0.98 g) in water (3 mL) was added dropwise to a solution of 2-(4,7-dimethoxy-5-acetylbenzofuran-6-yl)oxymethyl-4-isopropyl-6-methoxysaccharin (0.3 g) in acetonitrile (5 mL). The mixture was stirred at room temperature for 15 minutes and poured into ice-water. The resulting gold colored solid was purified by rapid chromatography on silica gel with dichloromethane-ether (95:5) as eluant and crystallization with sonication from ethanol affording 2-(5-acetyl-4,7-dihydro-4,7-dioxobenzofuran-6-yl)oxymethyl-4-isopropyl-6-methoxysaccharin (0.13 g, 46.6% yield, m.r. 193°-195° C. with decomposition).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[F:5][C:6]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:7]=1[CH:8]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:5][C:6]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:7]=1[CH:8]1[O:4][CH2:1][CH2:2][O:3]1
Reactant: OCCO
Reactant: O=Cc1ccc(F)c(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(C2OCCO2)c(F)c1F
Reaction time: 24 h

Procedure:
Ethylene glycol (348.7 g, 5.62 mol) was added in one portion to a stirred mixture of 2,3,4-trifluorobenzaldehyde (300.0 g, 1.87 mol) and p-toluenesulfonic acid monohydrate (35.6 g, 0.18 mol) in toluene (4.5 L) at ambient temperature. The resulting mixture was heated at reflux with azeotropic removal of water using a Dean-Stark apparatus. The water was removed from time to time (3 hour intervals). After 24 hours, the toluene was removed and the residue was diluted with ethyl acetate (1.5 L) and washed with saturated aqueous NaHCO3 (2×750 mL), water (2×500 mL) and brine solution (500 mL). The organic layers were dried over sodium sulphate and the solvent was removed under vacuum. The crude product was subjected to distillation at 60-70° C. in high vacuum (0.1 mm of Hg) to remove the starting material and impurities. The fraction obtained at 75-85° C. (0.1 mm of Hg) is consistent the title compound. Yield: 300.0 g (78%). 1H NMR (400 MHz, DMSO-d6) δ: 3.9-4.1 (m, 4H), 6.0 (s, 1H), 7.3-7.4 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18]([OH:20])[C:17]([F:21])=[CH:16][C:11]=1[C:12]([O:14]C)=[O:13].[OH-].[Na+].C(OCC)(=O)C.O>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18]([OH:20])[C:17]([F:21])=[CH:16][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(F)c(O)nc1Nc1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1cc(F)c(O)nc1Nc1ccc(F)cc1F
Yield: 93.7 %

Procedure:
In 30 ml of methanol was suspended 3.00 g of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinate, and 16.1 ml of 2N aqueous sodium hydroxide solution was added thereto at room temperature, after which the resulting mixture was subjected to reaction under reflux for 4 hours. Subsequently, the reaction mixture was added to a mixture of 60 ml of ethyl acetate and 60 ml of water, and the aqueous layer was separated. The aqueous layer was adjusted to pH 1.0 with 6N hydrochloric acid, and the crystals thus deposited were collected by filtration, washed successively with 15 ml of water and 25 ml of isopropyl alcohol to obtain 2.68 g (yield 93.7%) of 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinic acid having a melting point of 213°-216° C.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[C:7]=1[OH:14])(=[O:5])[CH3:4].Cl[CH:16]([F:18])[F:17]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[F:17][CH:16]([F:18])[O:14][C:7]1[C:8]([CH3:13])=[CH:9][C:10]([CH3:12])=[CH:11][C:6]=1[C:3](=[O:5])[CH3:4]
Reactant: FC(F)Cl
Reactant: CC(=O)c1cc(C)cc(C)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)c1cc(C)cc(C)c1OC(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 21 %

Procedure:
10 ml of a 30% aqueous sodium hydroxide solution and 8.5 g (0.025 mol) of tetrabutylammonium hydrogensulphate are added to a solution of 8.2 g (0.05 mol) of 2-acetyl-4,6-dimethylphenol, obtained above in Example XXX, in dichloromethane. A stream of chlorodifluoromethane is then passed into the reaction mixture for 30 minutes and the latter is then stirred at room temperature for 4 hours. The reaction mixture is then extracted with dichloromethane and the extract is washed with water. After drying the organic phase over MgSO4 and evaporation, the residue obtained is purified by passing through a silica column (dichloromethane) to lead to the production of a liquid: (2-difluoromethoxy-3,5-dimethylphenyl)ethanone: yield 21%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.CN(C)CCCN=C=NCC.ON1C(=O)CCC1=O.[CH2:31]([NH:34][CH2:35][CH2:36][CH3:37])[CH2:32][CH3:33].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([N:34]([CH2:35][CH2:36][CH3:37])[CH2:31][CH2:32][CH3:33])=[O:7]
Reactant: O=C(O)c1ccc(F)c(Br)c1
Reactant: CCCNCCC
Agent: CCN=C=NCCCN(C)C
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)c1ccc(F)c(Br)c1

Procedure:
Combine 3-bromo-4-fluorobenzoic acid (5.0 g, 22.8 mmol) with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (4.4 g, 22.8 mmol) and N-hydroxy-succinimide (2.6 g, 22.8 mmol) in dichloromethane (75 mL) and stir at room temperature for 30 min. Add N,N-dipropylamine (4.7 mL, 34.3 mmol) and triethylamine (8.0 mL, 57.1 mol) and stir at room temperature overnight. Dilute with ethyl acetate and wash with 1 N HCl, saturated aqueous potassium carbonate, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 30:70 ethyl acetate:hexanes) to give the title compound.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[C:11]([O:13][C@H:14]2[CH2:19][CH2:18][C@@H:17]([N:20]3[CH2:23][C:22]([CH2:46][C:47]#[N:48])([N:24]4[CH:28]=[C:27]([C:29]5[C:30]6[CH:37]=[CH:36][N:35]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:31]=6[N:32]=[CH:33][N:34]=5)[CH:26]=[N:25]4)[CH2:21]3)[CH2:16][CH2:15]2)[N:10]=[C:9]([C:49]([F:52])([F:51])[F:50])[N:8]=1)(=O)=O.[CH3:53][NH:54][CH3:55]>O1CCCC1>[CH3:53][N:54]([CH2:6][C:7]1[N:8]=[C:9]([C:49]([F:51])([F:52])[F:50])[N:10]=[C:11]([O:13][C@@H:14]2[CH2:19][CH2:18][C@H:17]([N:20]3[CH2:21][C:22]([CH2:46][C:47]#[N:48])([N:24]4[CH:28]=[C:27]([C:29]5[C:30]6[CH:37]=[CH:36][N:35]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:44])([CH3:45])[CH3:43])[C:31]=6[N:32]=[CH:33][N:34]=5)[CH:26]=[N:25]4)[CH2:23]3)[CH2:16][CH2:15]2)[CH:12]=1)[CH3:55]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN([C@H]5CC[C@@H](Oc6cc(COS(C)(=O)=O)nc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)Cc1cc(O[C@H]2CC[C@@H](N3CC(CC#N)(n4cc(-c5ncnc6c5ccn6COCC[Si](C)(C)C)cn4)C3)CC2)nc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[6-[(cis-4-{3-(Cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}cyclohexyl)oxy]-2-(trifluoromethyl)pyrimidin-4-yl]methyl methanesulfonate (450.0 mg, 0.5906 mmol) was dissolved in tetrahydrofuran (10.00 mL) and 2.0 M dimethylamine in tetrahydrofuran (4.00 mL, 8.00 mmol) was added. The reaction were stirred at 25° C. for 16 hours at which time LCMS analysis showed that the reaction was completed. The solvent was then removed and the product was used in the next reaction without purification. MS (ES): 711(M+1).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][NH:13][C:14](=O)[CH3:15])[C:5]=2[O:4][CH2:3][CH2:2]1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH3:15][C:14]1[C:9]2[C:10](=[C:5]3[C:6](=[CH:7][CH:8]=2)[O:1][CH2:2][CH2:3][O:4]3)[CH2:11][CH2:12][N:13]=1
Reactant: CC(=O)NCCc1cccc2c1OCCO2
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1=NCCc2c1ccc1c2OCCO1

Procedure:
In close analogy to the procedure described above, N-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
Reaction SMILES: Br[CH:2]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=O.[C:20]([NH2:23])(=[S:22])[CH3:21]>C(O)C>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:2]2[S:22][C:20]([CH3:21])=[N:23][C:3]=2[C:5]2[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: CSc1ccc(C(=O)C(Br)c2ccc(Br)cc2)cc1
Reactant: CC(N)=S
Solvent: CCO
Product: CSc1ccc(-c2nc(C)sc2-c2ccc(Br)cc2)cc1
Yield: 56.1 %

Procedure:
A mixture of 2-bromo2-(4-bromophenyl)-1-(4-methylthiophenyl)ethanone (7.6 g, 0.018 mol) and thioacetamide 1.4 g, 0.018 mol) in ethanol (150 mL) was refluxed for 1 day. The mixture was concentrated and the solid was purified by flash chromatography eluting with CH2Cl2/hexane (2/1) to give title compound (3.8 g, 56%).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:6]([NH2:8])=[O:7])[CH2:5][CH2:4]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:20]([O:22][C:23]([CH3:25])=[CH2:24])=[O:21]>C1COCC1>[CH3:1][O:2][C:3]1([C:6]([NH:8][C:20](=[O:21])[O:22][C:23]([CH3:25])=[CH2:24])=[O:7])[CH2:5][CH2:4]1
Reactant: C=C(C)OC(=O)Cl
Reactant: COC1(C(N)=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)OC(=O)NC(=O)C1(OC)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.3 %

Procedure:
A −78° C. solution of 1-methoxycyclopropane-1-carboxamide (0.23 g, 1.998 mmol) in THF (6 mL) was treated drop-wise with lithium bis(trimethylsilyl)amide (1M THF, 2.80 mL, 2.80 mmol), stirred for 0.5 h, treated drop-wise with a solution of isopropenyl chloroformate (0.262 mL, 2.397 mmol) in dry THF (1 mL), stirred for 1 h at −78° C., allowed to slowly warm to RT and stirred for 1 h. The mixture was quenched with satd. NaHCO3), extracted with EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford prop-1-en-2-yl (1-methoxycyclopropane-1-carbonyl)carbamate (0.423 g, 106%). MS(ESI) m/z: 222.1 (M+Na+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C1([Mg]Br)C=CC=CC=1.C[O:22][B:23](OC)[O:24]C.C(Cl)Cl>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:23]([OH:24])[OH:22])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COB(OC)OC
Reactant: COc1ccc(I)c([N+](=O)[O-])c1
Agent: Br[Mg]c1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)c([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
To a solution of 1-iodo-4-methoxy-2-nitrobenzene (5 g, 17.9 mmol) in THF (50 mL) cooled to −60° C. was added phenylmagnesium bromide (10.4 mL, 25 wt %, 19.7 mmol) which gave a dark red solution. Trimethylborate (2.4 mL, 21.5 mmol) was then added dropwise. After 30 min, the reaction was quenched with 1 N HCl (40 mL) and extracted with ether. The organic layer was then dried over Na2SO4 and the solvent was removed in vacuo to give a dark brown oil which was tritrated with DCM to yield (4-methoxy-2-nitrophenyl)boronic acid as grey solid. A portion of this material (1.57 g, 8 mmol) was then taken up in DME (1 mL) and 1-bromo-4-iodo-2-methoxybenzene (C1, step 1) (2.5 g, 8 mmol), CsF (2.73 g, 18 mmol), and tetrakistriphenylphosphine palladium (0.92 g, 0.8 mmol) under nitrogen. The mixture was then heated to 100° C. for 18 h. The mixture was then extracted with water and EtOAc. The organic layer was then dried over Na2SO4 and the solvent was removed in vacuo. The crude material was then purified on silica (gradient elution, 3-50% EtOAc/hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:29]2[C:24](=[C:25]([NH:30][C:31](=[O:40])[C:32]3[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:39])[CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][C:21]=1[C:41](=[O:46])N(OC)C)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[Si:1]([O:18][CH2:19][C:20]1[C:29]2[C:24](=[C:25]([NH:30][C:31](=[O:40])[C:32]3[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:39])[CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][C:21]=1[CH:41]=[O:46])([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCc1c(C=O)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12)(c1ccccc1)c1ccccc1
Temperature: -52.5 °C
Reaction time: 0.83 h
Yield: 86.1 %

Procedure:
To a solution of 4-(tert-butyldiphenylsilyloxymethyl)-8-(2,6-dichlorobenzoylamino)-3-(N-methoxy-N-methylcarbamoyl)quinoline (1.03 g) in tetrahydrofuran (10 ml) was dropwise added 1M solution of diisobutylaluminum hydride in tetrahydrofuran (15 ml) at -55° C., and the mixture was stirred for 50 minutes at -60 to -45° C. The mixture was quenched by saturated ammonium chloride solution and 101, aqueous solution of potassium sodium tartrate. Diethyl ether (50 ml) was added to the mixture, and the mixture was stirred for 1.5 hours at ambient temperature. The separated aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate-n-hexane) to give 4-(tert-butyldiphenylsilyloxymethyl)-8-(2,6-dichlorobenzoylamino)-3-formylquinoline (809 mg).
Reaction SMILES: Cl.O(C([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[C:15]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[O:25])=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)C(C)(C)C>C1COCC1>[ClH:33].[NH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[C:15]([C:24]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[O:25])=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: CC(C)(C)OC(=O)NCCCOc1cc2ccccc2cc1C(=O)Nc1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Product: NCCCOc1cc2ccccc2cc1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111 %

Procedure:
An aqueous solution of HCl (4 N, 2 mL) was added to a stirred solution of 19 (134 mg, 0.29 mmol) in THF (2 mL) at room temperature. The resulting mixture was stirred at room temperature for overnight. The solvent was removed under reduced pressure and the residue was treated with Et2O (2 mL). The precipitate was collected by filtration and washed with dichloromethane to give a white solid (63 mg, 55%): 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.17 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.89 (brs, 3H), 7.88 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 2H), 7.56 (t, J=7.2 Hz, 1H), 7.50 (s, 1H), 7.43 (t, J=6.8 Hz, 1H), 7.43 (d, J=8.8 Hz, 2H), 4.29 (t, J=5.6 Hz, 2H), 2.95-3.03 (m, 2H), 2.10 (quintet, J=6.4 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 165.1. 152.9, 138.0, 134.8, 129.5, 128.7, 128.2, 127.8, 127.5, 127.2, 127.1, 126.5, 124.5, 121.2, 107.2, 65.5, 36.6, 26.5.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].Cl[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[OH-].[Na+]>>[OH:4][CH2:3][CH2:2][NH:1][C:6](=[O:7])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCCO
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCO)OCc1ccccc1

Procedure:
It has already been disclosed that alkyl N-(hydroxy-alkyl)-carbamates can be obtained by reacting amino alcohols with chloroformates. This reaction is customarily carried out in an inert organic solvent in the presence of an acid acceptor at temperatures from -20° C. to +20° C. Examples which may be mentioned are the reaction of 2-methylamino-ethanol with benzyl chloroformate and triethylamine in chloroform at 20° C. (DE-A 3,239,390), of 2-(2-hydroxyethyl)-piperidine with butyl chloroformate and triethylamine in tetrahydrofuran at -20° C. (EP-A 289,842) and the reaction of 2,2-diethyl-3-hydroxypropylamine with ethyl chloroformate and triethylamine in benzene, with cooling, followed by refluxing for 2.5 hours (German Patent Specification 1,150,973). It is also known that 2-(2-hydroxyethyl)-piperidine can be reacted with methyl chloroformate at 0° to 20° C. in the presence of an aqueous sodium hydrogen carbonate solution to give methyl 2-(2-hydroxyethyl)-piperidinyl-carbamate (J. Chem. Soc. Perkin Trans. I 1988, 2251 to 2253). It is furthermore known that 2-aminoethanol can be reacted with benzyl chloroformate at 0° C. using 4N sodium hydroxide solution as acid acceptor to give benzyl N-(2-hydroxy-ethyl)-carbamate [J. Am. Chem. Soc. 69, 1384 (1947)].