Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([Br:8])[CH:5]=[N:6][CH:7]=1.N(OCCC(C)C)=O.[CH3:17][CH:18]([OH:20])[CH3:19]>Cl>[CH:18]([O:20][C:2]1[CH:3]=[C:4]([Br:8])[CH:5]=[N:6][CH:7]=1)([CH3:19])[CH3:17]
Reactant: Nc1cncc(Br)c1
Reactant: CC(C)O
Agent: CC(C)CCON=O
Agent: Cl
Product: CC(C)Oc1cncc(Br)c1

Procedure:
A slurry of 5-amino-3-bromopyridine (1.29 g, 7.46 mmol) in 6M HCl solution (5 mL) was stirred 30 min at ambient temperature. The mixture was concentrated under high vacuum, and the residue was vacuum dried for 15 h at 50° C., affording a tan solid. The solid was slurried in 2-propanol (25 mL), and treated with isoamyl nitrite (1.70 g, 15.00 mmol). The mixture was stirred and heated under reflux for 1.5 h. The solution was concentrated by rotary evaporation, and the residue was partitioned between diethyl ether and 1M NaOH solution. The aqueous layer was separated and extracted with ether. The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation producing an orange oil (2.03 g). The oil was purified by vacuum distillation, collecting the fraction with bp 105–115° C. at 9 mm Hg. The distilled product was further purified by column chromatography on silica gel, eluting with 10–20% (v/v) diethyl ether in hexane. Selected fractions, based upon TLC analysis (Rf 0.40 in hexane-ether, (4:1, v/v)) were combined and concentrated by rotary evaporation to give 566.0 mg (35.2%) of a clear, colorless oil.
Reaction SMILES: C([N:5]1[C:13]2[N:12]=[CH:11][N:10](CCCCC(=O)C)[C:9]=2[C:8](=[O:21])[NH:7][C:6]1=[O:22])CCC.[OH-].[Na+].CI>CO.O>[NH:7]1[C:8](=[O:21])[C:9]2[NH:10][CH:11]=[N:12][C:13]=2[NH:5][C:6]1=[O:22]
Reactant: CCCCn1c(=O)[nH]c(=O)c2c1ncn2CCCCC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CI
Product: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Temperature: 48 °C
Reaction time: 24 h
Yield: 77.2 %

Procedure:
60 g of 3-n-butyl-7-(5'-oxohexyl)-xanthine are added to a solution of 8 g of sodium hydroxide in 160 ml of a methanol/water mixture (1:1). 28 g of methyl iodide are dropwise added to the clear solution having a temperature of 40° C. and the mixture is stirred at 48° C. for 24 hours. After concentration under reduced pressure the residue is diluted with 300 ml of diethylether and the unreacted 3-(n-butyl)-7-(5'-oxohexyl)-xanthine is removed by shaking with 1 N sodium hydroxide. After neutralisation, drying, concentration under reduced pressure and distillation at 140° C. temperature of the mixture and 0.02 mmHg 48.5 g of 1-methyl-3-(n-butyl)-7-(5'-oxohexyl)-xanthine are obtained from the ether phase as a viscous oil (nD20 =1.5320; yield 77.2%, referred to reacted starting xanthine). Analysis: C16H24N4O3 =320.396
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10][C:11]1[NH:15][CH:14]=[C:13]([C:16]([O:18]C)=[O:17])[CH:12]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10][C:11]1[NH:15][CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=1
Reactant: COC(=O)c1c[nH]c(Sc2cc(Cl)c(Cl)cc2Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(Sc2cc(Cl)c(Cl)cc2Cl)c1
Reaction time: 2.5 h

Procedure:
Methyl 5-(2,4,5-trichlorophenylthio)pyrrole-3-carboxylate (2.1 g.) was combined with 20 ml. of methanol and 20 ml. of 1N sodium hydroxide and heated to reflux. Additional 1N sodium hydroxide was added in an amount sufficient to obtain a solution. Reflux was continued for 2.5 hours, the methanol was then allowed to evaporate, and the aqueous residue was diluted with approximately one volume of water and extracted twice with ether. The aqueous phase was cooled in an ice-water bath and acidified with conc. hydrochloric acid. Crude product (1.65 g., m.p. 210°-215° C.) was recovered by filtration. Recrystallization from methanol/water afforded purified 5-(2,4,5-trichlorophenylthio)pyrrole-3-carboxylic acid (1.01 g., m.p. 215°-217° C.).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].[H-].[Na+].[Cl:8][C:9]1[CH:14]=[CH:13][C:12](F)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1>C1COCC1>[CH2:1]([O:5][C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][C:11]=1[N+:16]([O-:18])=[O:17])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCO
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCOc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a solution of 3-butene-ol (1.08 mL, 12.53 mmol) in THF (30 mL) at 0° C. was added NaH (60%, 592 mg, 14.81 mmol). The mixture was stirred for 30 minutes, and 4-chloro-1-fluoro-2-nitrobenzene (2 g, 11.39 mmol) in THF (5 mL) was added dropwise. The reaction mixture was further stirred at 0° C. for 2 hours, poured into ice-water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated to give the desired product (2.5 g, 97%). MS (DCI/NH3) m/z: 244.95 (M+H)+; 1H NMR (400 MHz, DMSO-D6) δ ppm 2.47 (q, J=6.55 Hz, 2 H) 4.22 (t, J=6.60 Hz, 2 H) 5.08 (d, J=10.13 Hz, 1 H) 5.15 (dd, J=17.18, 1.84 Hz, 1 H) 5.80–5.91 (m, 1 H) 7.42 (d, J=9.21 Hz, 1 H) 7.70 (dd, J=9.21, 2.76 Hz, 1 H) 8.00 (d, J=2.76 Hz, 1 H)
Reaction SMILES: [S:1]1[C:5]2=[C:6]3[C:10](=[CH:11][CH:12]=[C:4]2[N:3]=[CH:2]1)[NH:9][C:8](=[O:13])[C:7]13[C:25]2[C:16](=[CH:17][C:18]3[O:23][CH2:22][CH2:21][O:20][C:19]=3[CH:24]=2)[O:15][CH2:14]1.[NH:26]1[C:34]2[C:29](=CC=C[CH:33]=2)[C@@:28]2([C:46]3[C:37](=CC4OCCOC=4C=3)OC2)C1=O.Br.BrCC1C=CC=CN=1.BrCCOCCOC>>[N:26]1[CH:37]=[CH:46][CH:28]=[CH:29][C:34]=1[CH2:33][N:9]1[C:10]2[C:6](=[C:5]3[S:1][CH:2]=[N:3][C:4]3=[CH:12][CH:11]=2)[C:7]2([C:25]3[C:16](=[CH:17][C:18]4[O:23][CH2:22][CH2:21][O:20][C:19]=4[CH:24]=3)[O:15][CH2:14]2)[C:8]1=[O:13]
Reactant: O=C1Nc2ccc3ncsc3c2C12COc1cc3c(cc12)OCCO3
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Agent: Br
Agent: BrCc1ccccn1
Agent: COCCOCCBr
Product: O=C1N(Cc2ccccn2)c2ccc3ncsc3c2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 9.70 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one to replace (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 1-bromo-2-(2-methoxyethoxy)ethane, 6′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one was obtained (41%) as a colorless solid: mp 156-158° C.; 1H NMR (300 MHz, CDCl3) δ8.75 (s, 1H), 8.60-8.53 (m, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.69-7.61 (m, 1H), 7.32-7.26 (m, 1H), 7.23-7.17 (m, 1H), 7.13 (d, J=8.2 Hz, 1H), 6.56 (s, 1H), 6.30 (s, 1H), 5.17 (ABq, 2H), 4.87 (ABq, 2H), 4.24-4.03 (m, 4H); MS (ES+) m/z 444.1 (M+1).
Reaction SMILES: Cl.Cl.Cl.[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH2:22])[O:18][C:17]3=[O:23])=[N:14][CH:15]=2)[CH:5]=1.CN(C=O)C.[N+:29]([C:32]([CH3:41])=[CH:33]NC1C=CC=CN=1)([O-:31])=[O:30]>O>[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:20][C@@H:19]([CH:21]([CH:33]=[C:32]([N+:29]([O-:31])=[O:30])[CH3:41])[NH2:22])[O:18][C:17]3=[O:23])=[N:14][CH:15]=2)[CH:5]=1
Reactant: CC(=CNc1ccccn1)[N+](=O)[O-]
Reactant: NC[C@H]1CN(c2ccc(-c3cccnc3)cn2)C(=O)O1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=CC(N)[C@@H]1CN(c2ccc(-c3cccnc3)cn2)C(=O)O1)[N+](=O)[O-]
Reaction time: 8 h

Procedure:
100 mg (0.37 mmol) of the compound from Example XXVIII (free base; prepared by dissolving in water, NH3(aq) addition to pH 11, extraction with CH2Cl2, drying over MgSO4 and concentrating) are initially introduced into 1 ml of DMF under argon and 200 mg (1.11 mmol) of 2-(2-nitro-prop-1-en-1-yl-amino)-pyridine are added and the mixture is stirred overnight. It is treated with water, extracted 3× with ethyl acetate, and the organic phase is washed with satd. NaCl solution and dried over MgSO4. It is concentrated and the residue is purified by column chromatography on silica gel (eluent CH2Cl2 :MeOH=100:5). 126 mg (96% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:39][C:40]([F:63])([F:62])[C:41]1[CH:46]=[CH:45][C:44]([CH:47]2[CH2:52][NH:51][CH2:50][CH:49]([NH:53][C:54](=[O:61])[C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH2:48]2)=[CH:43][CH:42]=1>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:55]1([C:54]([NH:53][CH:49]2[CH2:48][CH:47]([C:44]3[CH:43]=[CH:42][C:41]([C:40]([F:63])([F:39])[F:62])=[CH:46][CH:45]=3)[CH2:52][N:51]([C:12]([C:9]3([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11]3)=[O:14])[CH2:50]2)=[O:61])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: O=C(NC1CNCC(c2ccc(C(F)(F)F)cc2)C1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C(=O)N2CC(NC(=O)c3ccccc3)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
125 mg (0.62 mmol) of 1-[(tert-butoxycarbonyl)amino]cyclopropanecarboxylic acid together with 295 mg (0.78 mmol) of HATU and 127 mg (1.03 mmol) of 4-dimethylaminopyridine were initially charged in 8 ml of DMF, and 180 mg (0.52 mmol) of N-{5-[4-(trifluoromethyl)phenyl]piperidin-3-yl}benzamide were added. The reaction mixture was stirred overnight at RT and then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 179 mg (65% of theory)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@@H:26]([OH:28])[CH2:27][C@H:21]2[C:20](=[O:29])[NH:19][C@:18]2([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][C@H:17]2[CH2:16][C:15]([F:37])([F:36])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:39]1[CH:48]=[N:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>ClCCl.O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:39]3[CH:48]=[N:47][C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:40]=3)[CH2:27][C@H:21]2[C:20](=[O:29])[NH:19][C@:18]2([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][C@H:17]2[CH2:16][C:15]([F:36])([F:37])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)[C@@]12C[C@H]1CC(F)(F)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H](O)C[C@H]1C(=O)N2
Reactant: Oc1cnc2ccccc2n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)[C@@]12C[C@H]1CC(F)(F)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3cnc4ccccc4n3)C[C@H]1C(=O)N2
Temperature: 0 °C
Reaction time: 20 h
Yield: 61.5 %

Procedure:
To (2S,6S,13aS,14aR,16aS)-ethyl 6-(tert-butoxycarbonylamino)-12,12-difluoro-2-hydroxy-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (Example 1e, 19 mg, 0.036 mmol) was added 2-hydroxyquinoxaline (8.06 mg, 0.055 mmol) followed by tetrahydrofuran (357 μl). Triphenylphosphine (15.23 mg, 0.058 mmol) was added and the solution was cooled to 0° C. DIAD (10.5 μl, 0.054 mmol) was added dropwise and the mixture was stirred at 0° C. for 15 min and at room temperature for 20 hr. The reaction mixture was diluted with dichloromethane and filtered through Celite. The solvent was evaporated under reduced pressure and the residue was purified by prep-TLC (dichloromethane/ethyl acetate=3/2, 2×) to provide the title compound (2R,6S,13aS,14aR,16aS)-ethyl 6-(tert-butoxycarbonylamino)-12,12-difluoro-5,16-dioxo-2-(quinoxalin-2-yloxy)octadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (14.6 mg, 61.8% yield).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7](SC)[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].O.[NH2:30][NH2:31]>C(O)CCC>[CH2:1]([C:5]1[N:6]=[C:7]([NH:30][NH2:31])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NN
Reactant: CCCCc1nc(SC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: CCCCO
Solvent: O
Product: CCCCc1nc(NN)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
A mixture of 4′-{[4-butyl-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (3.5 g), hydrazine hydrate (10 mL) and n-butanol (100 mL) was stirred at 120° C. for 6 hr. The reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration. The obtained solid was washed with methanol to give the title compound as a colorless solid (2.6 g, 77%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]#[N:14])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH:21]1(Br)[CH2:24][CH2:23][CH2:22]1>CN(C=O)C>[CH:21]1([N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:12]=3)[C:8]([C:13]#[N:14])=[CH:9]2)[CH2:24][CH2:23][CH2:22]1
Reactant: CCOc1ccc2c(C#N)c[nH]c2c1
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1ccc2c(C#N)cn(C3CCC3)c2c1
Temperature: 80 °C
Yield: 83.2 %

Procedure:
6-Ethoxy-1H-indole-3-carbonitrile (2.8 g, 15 mmol), prepared as shown in example 1A, step A, is combined with Cs2CO3 (11.6 g, 35.6 mmol), DMF (21 mL), and cyclobutyl bromide (1.73 mL, 17.9 mmol) in a capped tube. The reaction mixture is heated at 80° C. for 8 h. This is then quenched with H2O (200 mL) and is extracted with EtOAc. The EtOAc layer is backwashed with H2O, and then with brine. The organic phase is dried and concentrated. Purification by silica gel chromatography (hexanes/CH2Cl2, 50-100%) yields 1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile (3.00 g, 83%) as a white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([C:12]1([CH3:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11].[C:19]([O:23][C:24]1[C:25]([CH:30]=O)=[N:26][CH:27]=[CH:28][N:29]=1)([CH3:22])([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[C:19]([O:23][C:24]1[C:25]([CH2:30][N:15]2[CH2:14][CH2:13][C:12]([C:10](=[O:11])[CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[F:2])([CH3:18])[CH2:17][CH2:16]2)=[N:26][CH:27]=[CH:28][N:29]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC1(C(=O)Cc2ccccc2F)CCNCC1
Reactant: CC(C)(C)Oc1nccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1nccnc1CN1CCC(C)(C(=O)Cc2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
After suspending 126 mg of 2-(2-fluorophenyl)-1-(4-methylpiperidin-4-yl)ethanone hydrochloride in 3 ml of dichloromethane, 100 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 146 mg of sodium triacetoxyborohydride were added and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, saturated aqueous sodium bicarbonate solution was added and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (135 mg, 69% yield).
Reaction SMILES: [N:1]12CCCN=C1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.C([NH:22][C@H:23]([C:26]([OH:28])=O)[CH2:24][OH:25])(OCC1C=CC=CC=1)=O.N1C=CC=CC=1.CC(C)(C)C(Cl)=O.CCCCCN.P(=O)(O)(O)O.O.O.C(O)(=O)C(O)=O>C(O)C.O.C(OCC)(=O)C>[CH2:2]([NH:1][C:26](=[O:28])[C@H:23]([CH2:24][OH:25])[NH2:22])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C(O)C(=O)O
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCNC(=O)[C@@H](N)CO
Temperature: 50 °C

Procedure:
Under an inert atmosphere, 1,8-diazabicyclo[5.4.0]undec-7-ene (5.10 g, 33.5 mmol) was added to a suspension of Part A carbobenzyloxy-L-serine (7.50 g, 31.4 mmol) in ethanol. Ethyl acetate was added and the mixture was agitated (optionally, with heating up to about 50° C.) to obtain a clear solution. Pyridine (0.25 g, 3.2 mmol) was added and the mixture was cooled to about -30° C. Trimethylacetyl chloride (4.12 g, 34.2 mmol) was added and the mixture was maintained at about -30° C. With cooling, n-amylamine (3.00 g, 34.4 mmol) was added and the mixture was stirred at about -10° C. for about 2 hours. Cooling was discontinued and aqueous phosphoric acid was added. The mixture was warmed to about 10° C. and the phases were separated. The organic solution was washed sequentially with aqueous phosphoric acid, aqueous potassium carbonate, and brine. Throughout these extractions, the aqueous phase was back extracted with ethyl acetate. The combined organic solution was distilled under vacuum at about 25° C. while ethanol was added until all of the ethyl acetate was removed. Under an inert atmosphere, 10% palladium on carbon (50% water, 0.75 g) was added. The resulting mixture was purged with nitrogen and then stirred in the presence of hydrogen at about 25° C. for about 6 hours. The catalyst was removed by filtration, and the clear filtrate was partially concentrated under vacuum at about 30° C. The concentrated filtrate was added to a solution of oxalic acid dihydrate (4.35 g, 34.5 mmol) in ethanol and water and a thick precipitate was formed. The suspension was heated to reflux to obtain a clear solution. Water was added at the reflux temperature until a slight turbidity was observed. The mixture was cooled to about 0° C. and stirred until crystallization was complete (about 1 hour). The product was collected and the cake was washed with ethanol. The product was dried under vacuum at about 25° C. to afford title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][CH:7]([NH2:14])[CH2:6]2.C(=O)(O)[O-].[Na+].Cl[CH2:21][C:22]([NH2:24])=[O:23]>C(O)C>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH2:6][CH:7]([NH:14][CH2:21][C:22]([NH2:24])=[O:23])[CH2:8]2
Reactant: NC(=O)CCl
Reactant: COc1cc2c(cc1OC)CC(N)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1cc2c(cc1OC)CC(NCC(N)=O)C2

Procedure:
5,6-Dimethoxy-2-indanylamine (0.024 moles, 4.6 g) and sodium bicarbonate (0.026 moles, 2.2 g) are added to a solution of chloroacetamide (0.024 moles, 2.2 g) in absolute ethanol (100 ml) and refluxed for 10 hours. The mixture is filtered at r.t. and the solution is evaporated to dryness. The resulting oil is chromatographed under medium pressure through silica gel (eluent: methylene chloride/methanol=90/10) Yield: 1.95 g (32.7%)--m.p.=135-138° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.C1C(=O)N([Br:22])C(=O)C1>CC#N.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:22][CH2:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([Cl:1])=[CH:3][C:4]([C:13]#[N:14])=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1ccc2c(Cl)cc(C#N)nc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Product: N#Cc1cc(Cl)c2ccc(CBr)cc2n1
Reaction time: 16 h
Yield: 57.6 %

Procedure:
4-Chloro-7-methyl-2-quinolinecarbonitrile (1-5, 57 g, 0.37 mol, 1.0 equiv.), NBS (75 g, 0.42 mol, 1.14 equiv.) and benzoyl peroxide (0.8 g, 3.3 mmol, 0.01 equiv.) were stirred in CH3CN (30 ml, 12.3 M) at room temperature. After 16 h, the solvent was removed and the residue was partitioned between AcOEt and water, the organic layer was washed with water, dried over MgSO4 and filtered. After removal of the solvent, the residue was recrystallized from methanol to give 60 g of desired 7-(bromomethyl)-4-chloroquinoline-2-carbonitrile (2-4). LRMS m/z (M+H)+ 283.1 found, 282.9 required.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][CH3:14])[CH:8]=2)[N:3]=1.[NH3:15].O>CO.C(Cl)(Cl)Cl>[NH2:15][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][CH3:14])[CH:8]=2)[N:3]=[C:2]([Cl:1])[N:11]=1
Reactant: CCc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: N
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCc1ccc2nc(Cl)nc(N)c2c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of 2,4-dichloro-6-ethylquinazoline (10.8 g) in methanol and chloroform (70 ml) was cooled with ice-water. Ammonia was passed through the reaction mixture for 20 minutes and the mixture was allowed to stand for 18 hours at ambient temperature. The resultant mixture was concentrated under reduced pressure to give a residue, to which was added water and heated to 50°-60° C. with stirring. The precipitates was separated by filtration, washed with hot water and recrystallized from dioxane to give crystalline 4-amino-2-chloro-6-ethylquinazoline (8.3 g). Crystals (0.7 g) of the same compound were obtained by treating the mother liquor in substantially the same manner as mentioned above.
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:27])[C:10]2[CH:11]=[C:12]([O:25]C)[CH:13]=[C:14]3[C:22]=2[N:21]([CH:23]=1)[C:20]1[CH:19]=[C:18]([Br:24])[CH:17]=[CH:16][C:15]3=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C(O)(=O)C.Br>[CH2:1]([C:8]1[C:9](=[O:27])[C:10]2[CH:11]=[C:12]([OH:25])[CH:13]=[C:14]3[C:22]=2[N:21]([CH:23]=1)[C:20]1[CH:19]=[C:18]([Br:24])[CH:17]=[CH:16][C:15]3=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(=O)c(Cc3ccccc3)cn3c4cc(Br)ccc4c(c1)c23
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=c1c(Cc2ccccc2)cn2c3cc(Br)ccc3c3cc(O)cc1c32
Yield: 58.2 %

Procedure:
5-benzyl-9-bromo-2-methoxy-4H-pyrido[3,2,1-jk]carbazole-4-one (137 mg) produced in Example 121 was dissolved in acetic acid (7 ml) and 48% HBr (7 ml), and the solution was stirred at room temperature for 30 hours. The reaction mixture was poured into water and the crystals precipitated were recovered by filtration, and washed with water, ethanol and ether in succession to obtain the title compound (77 mg, 58%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([NH2:13])[CH:7]=1)[CH3:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])=[CH:7][C:8]=1[NH:13][S:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=1)(=[O:25])=[O:24]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)Cc1ccc(O)c(N)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1ccc(O)c(NS(=O)(=O)c2ccc(OC)cc2)c1

Procedure:
Ethyl(3-amino-4-hydroxyphenyl)acetate is reacted with 4-methoxybenzene sulfonyl chloride in chloroform in the presence of triethylamine, to give ethyl 2-[4-hydroxy-3-[[(4-methoxyphenyl)sulfonyl]amino]phenyl]acetate.