Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.C[O-].[Na+]>C(OCC)(=O)C>[OH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=Cc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 54 %

Procedure:
100.00 parts by mass of p-acetoxystyrene was dissolved in 400 parts by mass of ethyl acetate and cooled to 0° C., and 47.60 parts by mass of sodium methoxide (28% methanol solution) was added dropwise to the cooled solution over a period of 30 minutes, followed by stirring at room temperature for 5 hours. Ethyl acetate was added thereto and the organic layer was washed with distilled water three times. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 131.70 parts by mass of p-hydroxystyrene (54% ethyl acetate solution). 18.52 parts by mass of the p-hydroxystyrene (54% ethyl acetate solution) was dissolved in 56.00 parts by mass of ethyl acetate, and 31.58 parts by mass of 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl difluoride was added thereto, followed by cooling to 0° C. A solution obtained by dissolving 12.63 parts by mass of triethylamine in 25.00 parts by mass of ethyl acetate was added dropwise to the mixture over a period of 30 minutes, followed by stirring while cooling at 0° C. for 4 hours. Ethyl acetate was added thereto, the organic layer was washed with saturated saline three times, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and then the residue was dissolved in 315 parts by mass of methanol, followed by cooling to 0° C. 245 parts by mass of a 1 N aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for 2 hours. The solvent was evaporated, followed by addition of ethyl acetate. The organic layer was washed with saturated saline three times, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and then the residue was dissolved in 200 parts by mass of methanol. 27.22 parts by mass of triphenylsulfonium bromide was added thereto, followed by stirring at room temperature for 3 hours. The solvent was evaporated, followed by extraction with chloroform three times. The resultant organic layer was washed with saturated saline three times and then the solvent was evaporated to obtain 50.55 parts by mass of a desired compound (M-I-1).
Reaction SMILES: C(O[CH2:4][CH:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[OH:13][C:11]1[C:22]2[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=2)[N:16]=[CH:4][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: Cc1cccc(N)c1
Reactant: CCOCC(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(C)ccc2c1O
Temperature: 100 °C
Yield: 76.3 %

Procedure:
Diethyl ethoxymethylmalonate (37.8 mL, 187 mmol) and m-toluidine (20.0 mL, 187 mmol) were combined and heated at 100° C. for about 3 hours. The reaction mixture was allowed to cool to ambient temperature and it solidified. Dowtherm A (350 mL) was added and the reaction mixture was heated at reflux for about 30 minutes. The reaction mixture was allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration, rinsed with acetone and dried to provide 33 g of ethyl 4-hydroxy-7-methyl-3-quinolinecarboxylate as a tan powder.
Reaction SMILES: COC1C=CC(C(=O)C(Br)C)=CC=1.[N-]=[N+]=[N-].[Na+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:32])[CH:27]([N:29]=[N+]=[N-])[CH3:28])=[CH:22][CH:21]=1.[ClH:33]>C1COCC1.O.[Pd].CCOCC>[ClH:33].[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](=[O:32])[CH:27]([NH2:29])[CH3:28])=[CH:24][CH:25]=1
Reactant: COc1ccc(C(=O)C(C)N=[N+]=[N-])cc1
Agent: [Pd]
Agent: COc1ccc(C(=O)C(C)Br)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COc1ccc(C(=O)C(C)N)cc1
Reaction time: 5 h
Yield: 100 %

Procedure:
4′-Methoxy-2-bromopropiophenone (10 g, 41 mmol.) was dissolved in a mixture of THF (100 mL) and water (20 mL), followed by addition of sodium azide (6.5 g, 0.1 mole). The slurry was vigorously stirred for 5 hours and TLC indicated a completed conversion to 4′-methoxy-2-azidopropiophenone. The aqueous layer was then removed and the organic layer was further diluted with ethanol (200 mL). Concentrated hydrochloride (5 mL, about 60 mmol.) and palladium on carbon (10%, 2 g) were added and hydrogenation was performed using Parr apparatus at 20 psi for 1 hour. The product precipitated during the hydrogenation was re-dissolved by addition of methanol (100 mL). After filtration to remove the catalyst, the solution was concentrated to form a solid. It was stirred with ether (300 mL) and solids were filtered and dried under vacuum at 50° C. overnight to give the titled compound (8.8 g, 100%) MS: 180 (MH+), 162 (M-NH3). Proton NMR (DMSO-d6) δ: 7.96(2H, brs), 7.79(2H, d, J=8.4 Hz), 6.87(2H, d, J=8.4 Hz), 4.49(1H,brs), 1.17(2H, d, J=6.9 Hz).
Reaction SMILES: Br[C:2](Br)([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:3][O:4][C:5]1[C:12]([C:13]23[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]4)[CH2:14]2)[CH2:20]3)=[CH:11][C:8]([CH:9]=[CH2:10])=[C:7]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:6]=1.C1COCC1.C([Li])CCC>O>[CH2:24]([O:23][C:7]1[CH:6]=[C:5]([O:4][CH2:3][CH2:2][CH2:30][CH2:31][CH2:32][CH3:33])[C:12]([C:13]23[CH2:14][CH:15]4[CH2:21][CH:19]([CH2:18][CH:17]([CH2:16]4)[CH2:22]2)[CH2:20]3)=[CH:11][C:8]=1[C:9]#[CH:10])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: C=Cc1cc(C23CC4CC(CC(C4)C2)C3)c(OCC(Br)(Br)CCCC)cc1OCCCCCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cc(C23CC4CC(CC(C4)C2)C3)c(OCCCCCC)cc1OCCCCCC
Temperature: 25 °C

Procedure:
3 g (5 mmol) of 2',2'-dibromo-2,4-dihexyloxy-5-(1-adamantyl)styrene and 50 ml of THF were introduced into a three-necked flask under a stream of nitrogen. 4 ml (10 mmol) of an n-butyllithium solution (2.5M in hexane) were added dropwise at -78° C. and the temperature was permitted to increase to room temperature for one hour. The reaction mixture was poured into water and extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][O:6][C:5](=[O:8])[N:4]1[CH2:9][CH2:10][S:11][C:12]1[S:13][CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=1.C(OCC)(=O)C.C(N(CC)CC)C.Cl>CS(C)=O>[CH:2]([C@H:3]1[CH2:7][O:6][C:5](=[O:8])[N:4]1[CH2:9][CH2:10][S:11][C:12]1[S:13][CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=1)=[O:1]
Reactant: CCOC(=O)c1csc(SCCN2C(=O)OC[C@@H]2CO)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1csc(SCCN2C(=O)OC[C@@H]2C=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of the compound 4 (338 mg) in dimethylsulfoxide (3.40 mL)/ethyl acetate (6.80 mL) were added triethylamine (1.00 mL) and sulfur trioxide-pyridine complex (650 mg) at 10° C. and the solution was stirred at room temperature for 1 hour. To the reaction solution was added 1N hydrochloric acid and the solution was extracted with ethyl acetate. The organic layer was washed water and brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (336 mg) having the following physical data. The compound was used in the next reaction without purification.
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].[CH3:16]I>>[CH3:16][S:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Sc1nccc(-c2ccccc2)n1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Product: CSc1nccc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.5 g. of 2-mercapto-4-phenylpyrimidine in 50 ml. of 1 N sodium hydroxide is cooled to near 0° C. and 2.94 g. of methyl iodide is added. After stirring at room temperature for 2 hours, the product is recovered by filtration. Recrystallization from methylene chloride-hexane affords the desired compound, m.p. 87°-89° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([NH:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][C@@H:4]1[OH:28].OC[C@]1(O)CC[C@H](NC(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C1.C(N(CC)CC)C.[CH:64]([Si:67](Cl)([CH:71]([CH3:73])[CH3:72])[CH:68]([CH3:70])[CH3:69])([CH3:66])[CH3:65]>C(OCC)(=O)C.CCCCCCC.C(Cl)Cl>[CH:64]([Si:67]([CH:71]([CH3:73])[CH3:72])([CH:68]([CH3:70])[CH3:69])[O:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([NH:8][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:5][C@@H:4]1[OH:28])([CH3:66])[CH3:65]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OC[C@@H]1C[C@@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@@H]1O
Agent: OC[C@]1(O)CC[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](OC[C@@H]1C[C@@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@@H]1O)(C(C)C)C(C)C
Temperature: 7.5 °C
Reaction time: 48 h

Procedure:
A reactor was charged with the mixture of (1S,2S,4R)-2-(hydroxymethyl)-4-(tritylamino)cyclopentanol and (1S,3S)-1-(hydroxymethyl)-3-(tritylamino)cyclopentanol (1.87 kg total, ˜280 g of (1S,2S,4R)-2-(hydroxymethyl)-4-(tritylamino)cyclopentanol, 0.75 mol). The reactor was charged with methylene chloride (7.4 L) and the agitation started. While maintaining the temperature less than 25° C., triethylamine (210 mL, 1.5 mol) was added. While maintaining the temperature less than 25° C., triisopropylsilyl chloride (402 mL, 1.9 mol) was slowly added. The reaction mixture was allowed to stir at 20° C. to 22° C., for ˜48 hours. The reaction mixture was analyzed by TLC (50% ethyl acetate/heptane, UV visualization), which indicated the formation of the product (Rf 0.70) and the presence of unreacted (1S,3S)-1-(hydroxymethyl)-3-(tritylamino)cyclopentanol (Rf 0.15). The clear pale yellow solution was cooled to 5 to 10° C., slowly quenched with DI water (7.5 L), and the resulting layers separated. The aqueous phase was extracted with methylene chloride (3 L) and the combined organic phases were dried over anhydrous magnesium sulfate, filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give a brown oil (4.06 kg), which was purified by silica gel chromatography using multiple columns. Each column was performed as follows. A 20 cm diameter glass column was loaded with a slurry of silica gel (4.5 kg) in 10% ethyl acetate/heptane. The oil (˜1.2 kg) was loaded on the column. Combined purified material from all columns afforded the title compound (2.94 kg) as a clear oil which was used without further purification. 1H NMR (300 MHz, CDCl3, δ): 7.56-7.54 (m, 5H), 7.34-7.13 (m, 10H), 4.26 (bs, 1H), 3.86-3.81 (dd, J=10.0, 4.5 Hz, 1H), 3.65-3.60 (dd, J=10.1, 7.2 Hz, 1H), 3.41-3.37 (m, 1H), 3.07 (bs, 1H), 2.16-2.07 (m, 1H), 1.69-1.63 (m, 3H), 1.47-1.20 (m, 4H) and 1.08-1.03 (2 s, 18H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4]([C:8](Cl)=[O:9])=[N:3]1.[C:11]1([S:17]([N:20]2[C:28]3[CH:27]=[C:26]([Sn:29]([CH3:32])([CH3:31])[CH3:30])[CH:25]=[C:24]([NH2:33])[C:23]=3[CH:22]=[N:21]2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4]([C:8]([NH:33][C:24]2[CH:25]=[C:26]([Sn:29]([CH3:32])([CH3:31])[CH3:30])[CH:27]=[C:28]3[C:23]=2[CH:22]=[N:21][N:20]3[S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:19])=[O:18])=[O:9])=[N:3]1
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Reactant: Cc1cn(C)nc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cn(C)nc1C(=O)Nc1cc([Sn](C)(C)C)cc2c1cnn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,4-Dimethyl-1H-pyrazole-3-carbonyl chloride (46 mg) in DCM (2.5 ml) was added over 5 min to 1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (100 mg) in DCM (2.5 ml) and pyridine (0.023 ml). The reaction was stirred at room temperature for 2 h. Separately, 1,4-dimethyl-1H-pyrazole-3-carbonyl chloride (273 mg) in DCM (5 ml) was added over 10 min to 1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (600 mg) in DCM (25 ml) and pyridine (0.2 ml). The reaction was stirred at room temperature for 1 h. The reactions were combined and separated between saturated sodium bicarbonate (aq) and DCM. The DCM was passed through a hydrophobic frit then dried. The residue was dissolved in DCM and purified using a silica cartridge, preconditioned with cyclohexane. The cartridge was eluted with cyclohexane:diethyl ether (1:1, v/v) then diethyl ether, then 10% methanol in diethyl ether and finally with 50% methanol in diethyl ether. Pure fractions were combined and dried to give title compound, 753 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[C:16]([C:19]#[N:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:29][C:30]([NH:32][CH3:33])=[O:31].C=O.[C:36]([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.CO.C(OCC)(=O)C.O.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]4[CH2:24][CH2:25][N:26]([CH3:36])[CH2:27][CH2:28]4)=[C:16]([C:19]#[N:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:29][C:30]([NH:32][CH3:33])=[O:31]
Reactant: CNC(=O)Nc1ccc(Oc2ccnc3cc(OCC4CCNCC4)c(C#N)cc23)cc1Cl
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OCC4CCN(C)CC4)c(C#N)cc23)cc1Cl
Reaction time: 1 h
Yield: 64.7 %

Procedure:
After dissolving N-(2-chloro-4-((6-cyano-7-(4-piperidylmethoxy)-4-quinolyl)oxy)phenyl)-N′-methylurea (15 mg) in tetrahydrofuran (0.5 ml) and methanol (0.5 ml), there were added 37% aqueous formaldehyde (0.03 ml), acetic acid (0.06 ml) and sodium cyanoborohydride (5.0 mg) at room temperature, and the mixture was stirred for 1 hour. Water was added to the reaction solution, saturated aqueous sodium bicarbonate was added for neutralization, and extraction was performed with ethyl acetate. The organic layer was washed with water and the solvent was distilled off to obtain a crude product. This was recrystallized with ethyl acetate to obtain the title compound (10 mg) as white crystals.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9][C@H:8]1[CH2:17][CH2:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH2:24][OH:25])=[O:6])[CH:2]=[CH2:3].[C:26]([SH:29])(=[O:28])[CH3:27]>>[C:26]([S:29][C@@H:10]1[CH2:11][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C@H:8]([CH2:17][CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[C:20]2[CH2:24][OH:25])[CH2:9]1)(=[O:28])[CH3:27]
Reactant: CC(=O)S
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1ccnc1CO
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CCn1ccnc1CO

Procedure:
(2R,4R)-1-Allyloxycarbonyl-2-[2-(2-hydroxymethyl-imidazol-1-yl) ethyl]-4-methanesulfonyloxypyrrolidine (15.7 g) was reacted with thioacetic S-acid (6.30 ml) in substantially the same manner as that of Preparation 4-12) to give (2R,4S)-4-acetylthio-1-allyloxycarbonyl-2-[2-(2-hydroxymethylimidazol-1-yl) ethyl]pyrrolidine (5.93 g) as an orange paste.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.[CH:17]1[N:21]=[CH:20][N:19]([C:22](N2C=NC=C2)=[O:23])[CH:18]=1>C1COCC1.C(Cl)Cl>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:4]2[S:3][C:2]([NH:1][C:22]([N:19]3[CH:18]=[CH:17][N:21]=[CH:20]3)=[O:23])=[N:6][C:5]=2[CH3:7])=[CH:9][CH:10]=1)(=[O:16])[CH3:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)c1ccc(-c2sc(N)nc2C)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(-c2sc(NC(=O)n3ccnc3)nc2C)cc1
Temperature: 50 °C

Procedure:
A solution of 1-[4-(2-amino-4-methyl-thiazol-5-yl)-phenyl]-ethanone (0.57 g, 2.45 mmol) is dissolved in a mixture of THF (10 ml) and DCM (20 ml) and heated in an oil bath set to 50° C. CDI is added (0.64 g, 3.92 mmol) and the reaction mixture heated at 50° C. for a further 2 hours in which a pale yellow precipitate forms. After cooling to room temperature the precipitate is filtered, washed with DCM and dried under high vacuum to yield the title compound.
Reaction SMILES: [H-].[Na+].CN(C)P(=O)(N(C)C)N(C)C.[O:14]=[C:15]1[C@@H:21]([N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])[CH2:20][S:19][CH2:18][C@@H:17]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:16]1.Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CN(C)C=O.C(OCC)(=O)C>[O:14]=[C:15]1[C@@H:21]([N:22]2[C:23](=[O:32])[C:24]3=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]3[C:26]2=[O:27])[CH2:20][S:19][CH2:18][C@@H:17]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:16]1[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1N[C@H](c2ccccc2)CSC[C@@H]1N1C(=O)c2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N2C(=O)c3ccccc3C2=O)CSC[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.6 %

Procedure:
270 mg of a 50% w/w suspension of sodium hydride in mineral oil were added to a solution containing 5 ml of hexamethylphosphoric triamide and 1.9 g of 5-oxo-3(R)-phenyl-6(R)-phthalimidoperhydro-1,4-thiazepine [prepared as described in step (e) above] dissolved in 20 ml of dimethylformamide, and the mixture was stirred for 5 minutes at room temperature, 1.8 g of t-butyl bromoacetate was then added to the mixture. The resulting mixture was stirred for 1 hour at room temperature, after which a further 0.2 g of a 55% w/w suspension of sodium hydride in oil and 1 g of t-butyl bromoacetate were added. The mixture was stirred for a further 1 hour at room temperature. Ethyl acetate was then added to the mixture, and the mixture was washed with an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate, after which the solvent was distilled off. The residue was subjected to silica gel column chromatography, using a 1:40 by volume mixture of ethyl acetate and methylene chloride as eluent, to give 1.65 g of the title compound as an amorphous substance.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:25][N:26]([CH3:36])[S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:25][N:26]([CH3:36])[S:27]([N:30]1[CH2:35][CH2:34][N:33]([CH2:16][C:13]2[S:12][C:11]([NH:10][C:8]([N:7]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:9])=[N:15][CH:14]=2)[CH2:32][CH2:31]1)(=[O:28])=[O:29]
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: CN(C)S(=O)(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: CN(C)S(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1
Yield: 42.1 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (84 mg, 0.25 mmol), piperazine-1-sulfonic acid dimethyl amide hydrochloride (115 mg, 0.50 mmol) and sodium triacetoxyborohydride (70 mg, 0.33 mmol) to afford 54 mg (42%) of the desired product after purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][C@H:19]2[C@H:11]([C:12](=O)[C:13]3[C:18]2=[CH:17][C:16]([Br:21])=[CH:15][C:14]=3[CH3:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)CO>[CH2:1]([N:8]1[CH2:20][C:19]2[C:18]3[C:13](=[C:14]([CH3:22])[CH:15]=[C:16]([Br:21])[CH:17]=3)[CH2:12][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Br)cc2c1C(=O)[C@@H]1CCN(Cc3ccccc3)C[C@H]21
Agent: NN
Solvent: O
Solvent: OCCO
Product: Cc1cc(Br)cc2c1CC1=C2CN(Cc2ccccc2)CC1
Temperature: 180 °C
Yield: 6.7 %

Procedure:
To a solution of cis-3-benzyl-6-bromo-8-methyl-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one (680 mg, 1.8 mmol) in ethylene glycol (9.0 mL) was added hydrazine hydrate (1.8 mL). The reaction mixture was heated at 120° C. for 2 h and at 180° C. for additional 15 h. The reaction was cooled to 20° C., quenched by addition of brine and extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed in silica gel column (hexane/EtOAc 9/1) to give the title compound (42 mg, 0.12 mmol): MS (ES) 354.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][NH2:21].Cl>N1C=CC=CC=1>[S:8]([NH:12][CH2:13][CH2:14][N:15]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH2:16][CH2:17][N:18]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH2:19][CH2:20][NH:21][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCNCCNCCN
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NCCN(CCN(CCNS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 24 h

Procedure:
Procedure 3 is further illustrated by the preparation of racemic 6e'. A solution of 80 g of p-tosyl chloride in 300 ml. of dry pyridine was cooled to 0° and added to a cooled, stirred solution of triethylenetetramine (MCB, technical) in 50 ml. of dry pyridine over a period of 3 hr. The solution was kept at 0° during addition. The solution was allowed to stand at 0° for 24 hrs, and mixed with 100 ml. of concentrated hydrochloric acid and 1 kg. of crushed ice. The resulting aqueous solution was decanted, and the oily residue was triturated with methanol, filtered, and recrystallized twice from 50 ml. of dimethyl formamide and 300 ml. of 95% ethanol to give N,N',N",N'"-tetratosyltriethylenetetramine, 28.8 g. (38%), m.p. 211°-213°. The analytical sample was dried at 180° for 14 hrs at 10μ.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21]O)[CH:17]=3)[N:12]([CH3:23])[N:11]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS(Cl)(=O)=O.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[CH:17]=3)[N:12]([CH3:23])[N:11]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: C1COCCN1
Reactant: Cn1nc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)ccc21
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
To a solution of N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide [Example 4] (0.062 g), DMAP (0.015 g) and collidine (0.030 mL) in 5 mL anhydrous DMF in a flame-dried flask is added methanesulfonyl chloride (0.015 mL) in one portion. The reaction is stirred at room temperature for 18 h. Morpholine (0.16 mL) is then added in one portion and the reaction is stirred at room temperature for 5 h. The reaction is poured into 50 mL water. The aqueous solution is extracted 3× with CH2Cl2, then 2× with EtOAc. The organics are combined, dried over Na2SO4, filtered and concentrated. The residue is dissolved in CH2Cl2 and adsorbed onto silica. Purification by Biotage Flash 40S (eluent CH2Cl2 (1L), 1% MeOH/CH2Cl2 (1L), 2% MeOH/CH2Cl2 (1L), 3.5% MeOH/CH2Cl2 (1L), 5% MeOH/CH2Cl2 (1L)) affords the desired product as a pale yellow solid (0.034 g, 46%). Physical characteristics are as follows: m.p. 190-192° C.; 1H NMR (300 MHz, DMSO-d6) δ8.17, 7.94, 7.40, 4.56, 4.26, 3.66, 3.58, 2.39; MS (ESI) m/z 427.0 (M+H)+; HRMS (FAB) calcd for C22H23ClN4O3+H1 427.1537, found 427.1544. An alternate synthesis route for Example 5 is as follows: