Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=[O:11])[CH2:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)(C)C.C1C=CC=CC=1.C1C=CC=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[C:1]1([CH:7]([OH:11])[C:8]#[C:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(=O)c1ccccc1
Agent: Cl[Ru]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CC(C)O
Product: CC#CC(O)c1ccccc1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Benzeneruthenium(II) chloride dimer (1.0 mg, 2 μmol, 0.5 mol %) and a chiral ligand (M=Ru, R=t-Bu, Ar=3,5-t-Bu2C6H3—, 2.6 μmol, 0.65 mol %) were dissolved in i-propanol (3 mL) under nitrogen atmosphere, and then heated and stirred for 1 h at 85° C. After the mixture was cooled to room temperature, 1-phenylbutan-1-one (0.4 mmol), i-propanol (2 mL) and a solution of sodium hydroxide in i-propanol (0.4 mL, 0.4 M) were added thereto. Thereafter, the reaction system were placed in an autoclave, and stirred for 12 h under H2 (10 atm) at 40° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent:ethyl acetate/petroleum ether=1/8). Accordingly, pure 1-phenylbutynol was obtained and the ee value (ee=99.2%) was measured by GC analysis.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[N:7]2.[N+:18]([O-])([OH:20])=[O:19]>OS(O)(=O)=O.[OH-].[Na+]>[Br:1][C:2]1[C:11]([N+:18]([O-:20])=[O:19])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([N:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)=[N:7]2
Reactant: O=[N+]([O-])O
Reactant: Brc1cccc2nc(N3CCNCC3)ccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc2nc(N3CCNCC3)ccc2c1Br
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a -10° C. solution of 10 (300 mg, 1.03 mmol) in H2SO4 (10 ml) was added dropwise HNO3 (0.25 ml). The mixture was stirred 15 min. at -10° -0° C., poured onto ice, and diluted with 1M NaOH until basic. The mixture was then extracted with CH2Cl2 (3×), and the combined organic layers were dried (MgSO4). Concentration yielded 2a (240 mg, 70%) as a yellowish solid which was utilized in the next step without further purification. (m.p.>230° C., dec. ). 1H NMR d (ppm): 1.79 s (NH), 3.00 dd (CH2), 3.80 dd (CH2), 7.07 d (CH arom), 7.57 d (CH arom), 7.81 d (CH arom), 8.37 d (CH arom).
Reaction SMILES: Cl.Br[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[O:23])=[CH:17][CH:16]=1.[CH2:25]([NH:27][CH2:28][CH2:29][OH:30])[CH3:26]>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([N:11]2[CH2:12][CH2:13][CH:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][N:27]([CH2:25][CH3:26])[CH2:28][CH2:29][OH:30])[CH2:9][CH2:10]2)=[O:23])=[CH:17][CH:16]=1
Reactant: BrCCCCOC1CCNCC1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CCNCCO
Agent: Cl
Product: CCN(CCO)CCCCOC1CCN(C(=O)Cc2ccc(Cl)cc2)CC1

Procedure:
In analogy to example 1.4 and 1.5, reaction of 4-(4-Brom-butoxy)-piperidine hydrogen chloride with (4-chloro-phenyl)-acetyl chloride and 2-ethylamino-ethanol yielded 2-(4-Chloro-phenyl)-1-(4-{4-[ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-piperidin-1-yl)-ethanone, MS: 397 (MH+).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[H-].[Na+].[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([Cl:17])=[CH:12][N:11]=1>CN(C=O)C>[Cl:9][C:10]1[N:15]=[C:14]([O:1][CH:2]2[CH2:6][CH2:5][O:4][CH2:3]2)[C:13]([Cl:17])=[CH:12][N:11]=1
Reactant: OC1CCOC1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ncc(Cl)c(OC2CCOC2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-hydroxy-tetrahydrofurane (115 mg, 1.31 mmol) in DMF (4 ml) at 0° C. was treated with NaH (60% dispersion in mineral oil, 45.8 mg, 1.145 mmol), the resulting suspension was allowed to warm to room temperature, stirred for 15 min and then added to a solution of 2,4,5-trichloropyrimidine (200 mg, 1.09 mmol) in DMF (4 ml) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h. The reaction mixture was quenched by addition of sat. aq. NH4Cl and extracted with EtOAc. The org. layer was washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a colorless liquid. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 5.67-5.62 (m, 1H), 3.91-3.84 (m, 3H), 3.81-3.74 (m, 1H), 2.36-2.25 (m, 1H), 2.14-2.06 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][C:3]=1[O:11][CH3:12].[CH2:13]([S:15]([NH:18][C@@H:19]([CH:23]([CH3:25])[CH3:24])[C:20](O)=[O:21])(=[O:17])=[O:16])[CH3:14].F[P-](F)(F)(F)(F)F.N1([P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:20](=[O:21])[C@@H:19]([NH:18][S:15]([CH2:13][CH3:14])(=[O:17])=[O:16])[CH:23]([CH3:25])[CH3:24])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: CCS(=O)(=O)N[C@H](C(=O)O)C(C)C
Reactant: COc1cc(CCN)ccc1O
Agent: CN(C)[P+](N(C)C)(N(C)C)n1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(O)c(OC)c1)C(C)C

Procedure:
1.7 g of 2-(4-hydroxy-3-methoxy-phenyl)-ethylamine and 2.1 g of (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid are stirred at room temperature for 2 hours together with 4.6 g of (benzotriazol-1-yl)-tris(dimethylamino)phosphonium hexafluorophosphate and 4.5 ml of diisopropylethylamine in 40 ml of dimethylformamide. The reaction mixture is then introduced into 600 ml of water. Extraction is carried out twice using 400 ml of ethyl acetate each time. The organic phases are washed twice using 300 ml of water each time and once with 200 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated, yielding (S)-2-(ethylsulfonylamino)3-methyl-butyric acid N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-amide in the form of a brown oil, which can be purified by chromatography on silica gel with ethyl acetate.
Reaction SMILES: [F:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.C(C1NC=CN=1)(C1NC=CN=1)=O.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=1>C(Cl)Cl>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:5]([C:2]2([F:1])[CH2:4][CH2:3]2)=[O:7])=[CH:26][N:25]=1
Reactant: COc1ccc(N)cn1
Reactant: O=C(O)C1(F)CC1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: COc1ccc(NC(=O)C2(F)CC2)cn1
Reaction time: 1 h
Yield: 29.4 %

Procedure:
1-Fluorocyclopropanecarboxylic acid (crude) (0.84 g, 0.0081 moles) was added in two portions to a solution of methylene chloride (50 ml ) and carbonyl di-imidazole (1.31 g, 0.0081 moles). The reaction was allowed to stand for 1 hour and then 5-amino-2-methoxypyridine (0.83 ml , 0.0081 moles) was added to it in one portion. The reaction mixture was allowed to stand at room temperature for 1 hour. The reaction mixture was then washed with saturated sodium bicarbonate (50 ml ), 5% hydrochloric acid (20 ml ) and saturated sodium bicarbonate solution (25 ml ); dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give 0.5 g of crude N-(2-methoxy-5-pyridyl)-1-fluorocyclopropanecarboxamide.
Reaction SMILES: [NH3:1].C(Cl)(Cl)Cl.[C:6]([N:11]=[C:12]=[O:13])(=[O:10])[C:7]([CH3:9])=[CH2:8]>ClCCCl>[C:6]([NH:11][C:12]([NH2:1])=[O:13])(=[O:10])[C:7]([CH3:9])=[CH2:8]
Reactant: N
Reactant: C=C(C)C(=O)N=C=O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(N)=O

Procedure:
Gaseous ammonia was blown into dry chloroform (50 g) to prepare a chloroform solution containing ammonia (0.18 g; 10.5 mmol). To the resultant solution, a solution of methacryloyl isocyanate (1.11 g; 10 mmol) in 1,2-dichloroethane (2 ml) was dropwise added under nitrogen stream while cooling with ice. After completion of the addition, chloroform and 1,2-dichloroethane were evaporated under reduced pressure to give 1-methacryloylurea (1.28 g), which was recrystallized from a mixture of benzene and hexane to give colorless needles. M.P., 137°-138° C.
Reaction SMILES: COC(OC)CN.C(OC(=O)C)(=O)C.COC(OC)[CH2:18][NH:19][C:20](=[O:22])[CH3:21].[F:25][C:26]1[CH:27]=[C:28]([S:32]([C:35]2[CH:36]=[CH:37][C:38]3[O:42][CH:41]=[C:40]([CH2:43][CH2:44][NH:45][C:46](=O)OC(C)(C)C)[C:39]=3[CH:53]=2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>ClCCCl.ClCCCl.C(O)(C(F)(F)F)=O>[F:25][C:26]1[CH:27]=[C:28]([S:32]([C:35]2[CH:36]=[CH:37][C:38]3[O:42][C:41]4[CH:46]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[NH:45][CH2:44][CH2:43][C:40]=4[C:39]=3[CH:53]=2)(=[O:33])=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)NCCc1coc2ccc(S(=O)(=O)c3cccc(F)c3)cc12
Reactant: COC(CNC(C)=O)OC
Agent: COC(CN)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NCC1NCCc2c1oc1ccc(S(=O)(=O)c3cccc(F)c3)cc21
Reaction time: 0.17 h

Procedure:
2,2-Dimethoxyethylamine (16 μL, 1.5 eq) was dissolved in DCE (400 μL), acetic anhydride (15 μL, 1.5 eq) was added and the solution was shaken for 10 min. The resulting solution of N-(2,2-dimethoxyethyl)acetamide in DCE was added to a solution of tert-butyl (2-{5-[(3-fluorophenyl)sulfonyl]-1-benzofuran-3-yl}ethyl)carbamate (800 μL, 0.125 M) in DCE:TFA 1:1. The reaction mixture was shaken at 100° C. for 16 h and the solvent was evaporated. The crude product was purified by preparative LC/MS and concentrated to afford the product as a trifluoroacetic acid salt. MS m/z 403 [M+H]+.
Reaction SMILES: C([Li])CCC.[C:6]([NH-:10])([CH3:9])([CH3:8])[CH3:7].[CH3:11][C:12]1[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[O:14][N:13]=1.Cl.[O:21]1CCC[CH2:22]1>O.CN(C)C=O>[C:6]([NH-:10])([CH3:9])([CH3:8])[CH3:7].[CH:22]([C:16]1[C:12]([CH3:11])=[N:13][O:14][C:15]=1[C:17]([OH:19])=[O:18])=[O:21]
Reactant: C1CCOC1
Reactant: Cc1cc(C(=O)O)on1
Agent: CC(C)(C)[NH-]
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(C(=O)O)c1C=O
Reaction time: 1 h

Procedure:
56 ml of butyllithium (1.6 molar solution in n-hexane) are added dropwise, at -78° C., to 8 g of the tertbutylamide of 3-methylisoxazole-5-carboxylic acid in 150 ml of tetrahydrofuran. The mixture is stirred for 1 hour, after which 22 ml of dimethylformamide are slowly added dropwise. The mixture is allowed to reach room temperature overnight and is hydrolyzed with water, neutralized with concentrated hydrochloric acid and extracted with ether. The oil which remains after evaporation is chromatographed over silica gel sing cyclohexane/ethyl acetate. The tert-butylamide of 4-formyl-3-methylisoxazole-5-carboxylic acid is obtained as the first fraction, in the form of pale yellow crystals of melting point 36°-38° C. (compound No. 2).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccccc4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 76 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4.08 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, benzoyl chloride (0.31 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAC 6:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}benzamide (0.55 g, 76%) as a white solid: mp 227-229° C.; 1H NMR (DMSO-d6) δ 11.16 (s, 1H), 9.16 (t, J=5.7 Hz, 1H), 7.95-7.72 (m, 5H), 7.60-7.46 (m, 3H), 5.22-5.12 (dd, J=5.4 and 12.8 Hz, 1H), 4.96 (d, J=5.7 Hz, 2H), 2.98-2.85 (m, 1H), 2.65-2.50 (m, 2H), 2.11-2.06 (m, 1H); 13C NMR (DMSO-d6) δ 172.72, 169.80, 167.54, 166.96, 166.60, 139.34, 134.77, 133.92, 133.02, 131.52, 131.42, 128.34, 127.28, 127.12, 121.83, 48.88, 38.32, 30.93, 21.98; Anal. Calcd. For C21H17N3O5: C, 64.45; H, 4.38; N, 10.74. Found: C, 64.47; H, 4.50; N, 10.34.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[CH3:10][C@H:11]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([CH3:20])=[CH:16][CH:17]=2)[C@@H:12]1[NH2:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[Br:8][C:7]1[C:2]([NH2:1])=[N:3][C:4]([NH:21][C@H:12]2[C:13]3[C:18](=[CH:17][CH:16]=[C:15]([CH3:20])[CH:14]=3)[CH2:19][C@@H:11]2[CH3:10])=[N:5][CH:6]=1
Reactant: Nc1nc(Cl)ncc1Br
Reactant: Cc1ccc2c(c1)[C@H](N)[C@@H](C)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc2c(c1)[C@H](Nc1ncc(Br)c(N)n1)[C@@H](C)C2
Yield: 40.6 %

Procedure:
0.2 g (0.96 mmol) of 4-amino-5-bromo-2-chloropyrimidine, 0.196 g (1.15 mmol) of (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine and 0.399 g of potassium carbonate are heated in 1.5 ml of N,N-dimethylacetamide at 170° C. in a closed cell in a microwave for 60 minutes (Biotage initiator, http://www.biotage.com/DynPage.aspx?id=22001). The resulting crude mixture is absorbed on silica gel and purified by means of column chromatography using heptane/ethyl acetate as eluent. Following concentration by evaporation, 0.13 g of 5-bromo-N2-[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-yl]pyrimidine-2,4-diamine is obtained (yield 37% at 95% purity).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:20]=[CH:19][C:8]2[C:9]([CH2:13]/[CH:14]=[CH:15]/[CH2:16][CH2:17][CH3:18])([CH3:12])[CH2:10][O:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].C(O)C.Cl>O1CCCC1.O>[CH2:13]([C:9]1([CH3:12])[C:8]2[CH:19]=[CH:20][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[O:11][CH2:10]1)/[CH:14]=[CH:15]/[CH2:16][CH2:17][CH3:18]
Reactant: CCC/C=C/CC1(C)COc2cc(C(=O)OC)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCC/C=C/CC1(C)COc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3-((E)-Hex-2-enyl)-3-methyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (200 mg, 0.73 mmol), sodium hydroxide (200 mg, 5 mmol), ethanol (7 ml) and water (1 ml) in tetrahydrofuran (7 ml), was stirred for 12 h at room temperature. The reaction medium was acidified by adding a 1.2 M hydrochloric acid solution and extracted with ethyl acetate. The organic phase was washed with water, dried (Na2SO4), and concentrated in a rotary evaporator. The product was obtained as colorless oil which crystallized (M: 155 mg, 82%).
Reaction SMILES: [OH:1][C@H:2]([C@H:9]([CH3:16])[C:10]([O:12]C(C)C)=[O:11])[C:3]([O:5]C(C)C)=[O:4].[OH-].[K+]>C1COCC1.O>[OH:1][C@H:2]([C@H:9]([CH3:16])[C:10]([OH:12])=[O:11])[C:3]([OH:5])=[O:4]
Reactant: CC(C)OC(=O)[C@@H](C)[C@@H](O)C(=O)OC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](C(=O)O)[C@@H](O)C(=O)O
Temperature: 0 °C
Reaction time: 48 h
Yield: 40 %

Procedure:
Diisopropyl (2R,3S)-2-hydroxy-3-methylsuccinate (9.75 g; 42.0 mmol; 1.00 eq.) was taken in THF (146 mL), cooled to 0° C. and was treated with KOH (14.1 g, 152 mmol) in water (49 mL). The resulting mixture was stirred at RT for 48 h. THF was removed and the residue was taken in water. The aqueous layer was washed with ether (100 mL) and was acidified with an aqueous solution of HCl (1.5 N), then was extracted with EtOAc (continuous extraction during 20 hours). The organic phase was dried over Na2SO4 and then concentrated to give the title product (mixture of diastereoisomers) as a pale yellow oil (2.49 g).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].CCCC=O.[C:13]([OH:22])(=[O:21])[C@@H:14]([C@H:16]([C:18]([OH:20])=[O:19])[OH:17])[OH:15]>C(O)=O>[NH:1]1[CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[C:18]([C@@H:16]([C@H:14]([C:13]([O-:22])=[O:21])[OH:15])[OH:17])([O-:20])=[O:19]
Reactant: O=C(O)[C@@H]1CCN1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: O=CO
Solvent: CCCC=O
Product: O=C(O)[C@H]1CCN1
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Temperature: 90 °C
Yield: 18.1 %

Procedure:
L-AzeOH (99% e.e.; 1.01 g; 10 mmol) was dissolved in formic acid (4 mL) at 80° C. Butyric aldehyde (0.072 g; 1.0 mmol) was added and the mixture heated at 90° C. for 3 hours. The solvent was subsequently distilled (45° C.; 4 mbar) and the residue dried under vacuum. The residue was subsequently dissolved in a mixture of ethanol:water (35.6: 29.1) at 76° C. L-Tartaric acid (1.5 g; 10 mmol) was added, the insoluble compounds were filtered off and the solution was cooled to 0° C. The crystalline product was filtered, washed and dried under vacuum to yield 0.45 g of D-AzeOH-L-tartrate with a d.e. of 75%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.N1C=CC=CC=1.[Cl:16][CH2:17][C:18](Cl)=[O:19]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:16][CH2:17][C:18]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:19]
Reactant: O=C(Cl)CCl
Reactant: c1ccc2[nH]ccc2c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(CCl)c1c[nH]c2ccccc12
Temperature: 55 °C
Reaction time: 2 h

Procedure:
According to the method of J. Bergman et al. Tet. 29, 971-976 (1973), combine indole (11.7 g, 100 mmol), pyridine (8.1 mL, 100 mmol), and toluene (250 mL). Heat to 55° C. Add dropwise a solution of chloroacetyl chloride (8 mL, 100 mmol) in toluene (10 mL). After 2 hours, cool to ambient temperature. Dilute the reaction mixture with ethyl acetate and extract with water. Dry the organic layer over MgSO4, filter and evaporate in vacuo to give a residue. Recrystallize the residue from ethanol to give the title compound.
Reaction SMILES: S(C)C.[CH3:4][O:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:15]=[CH:16][C:17]3[N:23]([CH3:24])[C:22](=O)[CH2:21][CH2:20][N:19]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[C:18]=3[N:31]=2)=[C:9]([O:32][CH3:33])[CH:8]=1.Cl>C1COCC1.O>[CH3:4][O:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:15]=[CH:16][C:17]3[N:23]([CH3:24])[CH2:22][CH2:21][CH2:20][N:19]([CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)[C:18]=3[N:31]=2)=[C:9]([O:32][CH3:33])[CH:8]=1
Reactant: COC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CCC(=O)N3C)c(OC)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Solvent: O
Product: COC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CCCN3C)c(OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.3 %

Procedure:
BH3.SMe2 (1.36 mL, 5.0 M in Et2O, 6.8 mmol) was added to solution of methyl4-[(9-cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxybenzoate (Intermediate 8; 290 mg, 0.68 mmol) in THF (4 mL) and stirred for 5 h at ambient temperature under an atmosphere of nitrogen. HCl (10 mL, concentrated aqueous) was added and the resulting solution was stirred at ambient temperature for 16 h. The HCl solution was then diluted with water (50 mL), and loaded onto an SCX-2 column. The SCX-2 column was then washed with water (50 mL) and MeOH (50 mL). The product was then eluted from the SCX-2 column with NH3 (50 mL, 7M in MeOH). The volatiles were then removed under reduced pressure to afford the title compound (250 mg, 89%) as a solid.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[CH3:13][C:14]1[CH:45]=[CH:44][CH:43]=[CH:42][C:15]=1[CH2:16][NH:17][C:18]([C@@H:20]1[C:24]([CH3:26])([CH3:25])[S:23][CH2:22][N:21]1[C:27](=[O:41])[C@@H:28]([OH:40])[C@@H:29]([NH2:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)=[O:19].[NH2:46][C:47]1[C:48]([CH3:56])=[C:49]([CH:53]=[CH:54][CH:55]=1)[C:50](O)=[O:51].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[CH3:13][C:14]1[CH:45]=[CH:44][CH:43]=[CH:42][C:15]=1[CH2:16][NH:17][C:18]([C@@H:20]1[C:24]([CH3:26])([CH3:25])[S:23][CH2:22][N:21]1[C:27](=[O:41])[C@@H:28]([OH:40])[C@@H:29]([NH:39][C:50](=[O:51])[C:49]1[CH:53]=[CH:54][CH:55]=[C:47]([NH2:46])[C:48]=1[CH3:56])[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=1)=[O:19]
Reactant: COc1ccc(C[C@H](N)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NCc2ccccc2C)cc1
Reactant: Cc1c(N)cccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](NC(=O)c2cccc(N)c2C)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NCc2ccccc2C)cc1
Reaction time: 8 h
Yield: 64.2 %

Procedure:
EDC.HCl (42 mg) was added to a solution of the compound obtained in Step 2 of Example 1 (94 mg), 3-amino-2-methylbenzoic acid (30 mg), and HOBt (27 mg) in DMF while cooling with ice, and the mixture was stirred overnight. EtOAc was added and the mixture was washed with 5% Na2CO3 (×2) and 5% NaCl, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2—MeOH) and reprecipitated from a mixture of CH2Cl2 and n-hexane to obtain the title compound (77 mg, 64%).
Reaction SMILES: C(O[C:9]1[C:21]([C:22]([N:24]2[CH2:28][CH2:27]SC2=S)=[O:23])=[CH:20][C:12]([C:13]([NH:15][CH2:16][CH2:17][O:18][CH3:19])=[O:14])=[CH:11][C:10]=1[C:30]([N:32]1[CH2:36][CH2:35][S:34][C:33]1=[S:37])=[O:31])C1C=CC=CC=1.[CH2:38]([O:45]C1C(C(N2CCSC2=S)=O)=CC(C(N2CCSC2=S)=O)=CC=1C(N1CCSC1=S)=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[CH3:76][O:77]CCN>>[CH2:38]([O:45][C:11]1[C:10]([C:30]([N:32]2[CH2:36][CH2:35][S:34][C:33]2=[S:37])=[O:31])=[CH:9][C:21]([C:22]([NH:24][CH2:28][CH2:27][O:77][CH3:76])=[O:23])=[CH:20][C:12]=1[C:13]([NH:15][CH2:16][CH2:17][O:18][CH3:19])=[O:14])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COCCNC(=O)c1cc(C(=O)N2CCSC2=S)c(OCc2ccccc2)c(C(=O)N2CCSC2=S)c1
Reactant: COCCN
Reactant: O=C(c1cc(C(=O)N2CCSC2=S)c(OCc2ccccc2)c(C(=O)N2CCSC2=S)c1)N1CCSC1=S
Product: COCCNC(=O)c1cc(C(=O)NCCOC)c(OCc2ccccc2)c(C(=O)N2CCSC2=S)c1
Yield: 73 %

Procedure:
This compound was prepared by the same procedure as compound 18A except the molar ratio of compound 17 and 2-methoxyethylamine was 1:2 instead of compound 17 in large excess. Separation and purification were performed as described for compound 18A. Pure material was obtained as thick, bright, yellow oil; yield: 73%.
Reaction SMILES: C([N:4]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([O:25][CH3:26])[C:19]([S:21]([Cl:24])(=[O:23])=[O:22])=[CH:20][C:7]=2[CH2:6][CH2:5]1)(=O)C.[CH3:27][NH2:28]>>[ClH:24].[ClH:24].[CH3:26][O:25][C:18]1[C:19]([S:21](=[O:23])(=[O:22])[NH:28][CH3:27])=[CH:20][C:7]2[CH2:6][CH2:5][NH:4][CH2:10][CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]=2[CH:17]=1
Reactant: CN
Reactant: COc1cc2c(cc1S(=O)(=O)Cl)CCN(C(C)=O)CC2c1ccccc1
Product: CNS(=O)(=O)c1cc2c(cc1OC)C(c1ccccc1)CNCC2
Product: Cl

Procedure:
Following the general procedure of Example 2, 3-acetyl-7-chlorosulfonyl-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine is treated with methylamine and then with refluxing hydrochloric acid to give 8-methoxy-7-(N-methylsulfamoyl)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride. By the procedure of Example 2, the methoxy compound is treated with hydrobromic acid to afford 8-hydroxy-7 (N-methylsulfamoyl)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.