Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[C:10]([O:12]C)[CH:9]=[CH:8][C:7]=1[C:14]1[N:18]([CH3:19])[C:17]([C:20]23[CH2:27][CH2:26][C:23]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([CH2:24][CH2:25]2)[CH2:22][CH2:21]3)=[N:16][N:15]=1>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:7]=1[C:14]1[N:18]([CH3:19])[C:17]([C:20]23[CH2:27][CH2:26][C:23]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([CH2:24][CH2:25]2)[CH2:22][CH2:21]3)=[N:16][N:15]=1
Reactant: CCCCCC12CCC(c3nnc(-c4ccc(OC)cc4Cl)n3C)(CC1)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCC12CCC(c3nnc(-c4ccc(O)cc4Cl)n3C)(CC1)CC2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Boron tribromide (135 μL, 1.43 mmol) was added dropwise to a solution of 3-(2-chloro-4-methoxyphenyl)-4-methyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazole (3-F) (287 mg, 0.714 mmol) in methylene chloride (5 mL) at 0° C. The mixture was stirred at room temperature for 2.5 h. The solution was washed with water, 10% NaHCO3, dried (MgSO4) and concentrated in vacuo and the residue purified by column chromatography (silica gel, 5% MeOH/methylene chloride) to provide 3-chloro-4-[4-methyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazol-3-yl]phenol (3-G). Mass spectrum: 388 (M+1); 1H NMR (500 MHz, CDCl3); δ 0.93 (t, 3H); 1.26 (m, 8H); 1.56 (m, 6H); 2.13 (m, 6H); 3.58 (s, 3H); 6.69 (dd, 1H); 6.92 (d, 1H); 7.09 (d 1H) ppm.
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.CN([CH:28]=[O:29])C>ClC(Cl)C.Cl>[C:1]1([N:7]2[C:8]3[CH:9]=[CH:10][C:11]([CH:28]=[O:29])=[CH:12][C:13]=3[C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-n2c3ccccc3c3ccccc32)cc1
Reactant: CN(C)C=O
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To 0.49 g of N-phenylcarbazole in 2 mL of dichloroethane is added 0.19 mL of phosphorus oxychloride and 0.5 mL of DMF. The resulting mixture is stirred at 40° C. overnight. After stirring, 1 mL of 1 M HCl is added. After 5 additional minutes, the mixture is diluted with 1 M HCl and extracted with ethyl acetate. The crude product is purified by column chromatography on silica gel to give 60 mg of Compound 7.
Reaction SMILES: [OH:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[N:5]([CH3:14])[C:4](=[O:15])[C:3]=1[C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=1[CH3:24].C(N(CC)CC)C.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C)C1C=CN=CC=1.O1CCCC1.C(OCC)(=O)C.O>[CH3:13][O:12][N:9]1[CH2:10][CH2:11][C:6]2([N:5]([CH3:14])[C:4](=[O:15])[C:3]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=3[CH3:24])=[C:2]2[O:1][C:33](=[O:34])[O:35][CH2:36][CH3:37])[CH2:7][CH2:8]1
Reactant: CCOC(=O)Cl
Reactant: CON1CCC2(CC1)C(O)=C(c1c(C)cc(C)cc1C)C(=O)N2C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)N(C)C12CCN(OC)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-hydroxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (238 mg, 0.72 mmol), triethylamine (0.15 ml, 109 mg, 1.08 mmol) and 4-dimethylaminopyridine (2 mg) in tetrahydrofuran (10 ml) at 0° C. was added ethyl chloroformate (0.075 ml, 85 mg, 0.79 mmol) dropwise. The suspension was stirred at 0° C. for one hour. The reaction mixture was diluted with ethyl acetate and water, the layers separated, the aqueous phase extracted with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/heptane 5:1). Yield: 145 mg of carbonic acid ethyl ester 8-methoxy-1-methyl-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester (title compound P1.2) as a white solid, mp 134-136° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18](I)[N:17]=[CH:16]3)[N:9]=2)=[CH:4][C:3]=1[CH3:21].[C:22]([NH:26][S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([NH:26][S:27]([C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([C:18]2[N:17]=[CH:16][N:15]([C:10]3[N:11]=[C:12]([CH3:14])[CH:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:21])[CH:4]=4)[N:9]=3)[CH:19]=2)[CH:35]=1)(=[O:29])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-n2cnc(I)c2)n1
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-n2cnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
N-tert-Butyl-3-{1-[6-(4-chloro-3-methyl-phenyl)-4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(4-chloro-3-methyl-phenyl)-2-(4-iodo-imidazol-1-yl)-6-methyl-pyrimidine (example E.76) (0.41 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as a light grey solid (0.53 g) which was subsequently deprotected.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[CH2:7][CH:8]([CH3:12])[O:9]2)=[CH:4][CH:3]=1.[N+:14]([O-])([OH:16])=[O:15].O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[CH2:7][CH:8]([CH3:12])[O:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: CC1CC(=O)c2ccc(Cl)cc2O1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1CC(=O)c2cc([N+](=O)[O-])c(Cl)cc2O1
Temperature: 0 °C

Procedure:
7-Chloro-2-methylchroman-4-one (4.56 g, 23.2 mmol) was dissolved in 7 ml concentrated sulfuric acid at 0°-5° C. and cooled in an acetone-ice bath. Nitric acid (1.41 ml, s.g. 1.5, 90%) in 3 ml concentrated sulfuric acid was added dropwise over 20 minutes. The resulting viscous mixture was poured into 150 ml ice and water and extracted with 200 ml ethyl acetate. The organic layer was separated, washed 4×50 ml water and then brine, dried over magnesium sulfate, and stripped to a tan solid, 5.8 g. The latter was chromatographed on 500 cc silica gel, initially eluting with 5 liters 1:10 diethyl ether:hexane to remove starting material and then with 5 liters of 1:5 diethyl ether:hexane to obtain title product as a white solid, 2 g (36%); m/e 241(P+), 226, 199, 183, 169, 154, 141. 1H-NMR indicates contamination with about 44% of the 7-chloro-8-nitro isomer.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[O:6][CH2:7][CH:8]3[N:13]([C:14]=2[N:15]=1)[CH2:12][CH2:11][O:10][CH2:9]3.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][C:33]([NH2:36])=[N:34][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:16]1([C:4]2[C:5]3[O:6][CH2:7][CH:8]4[N:13]([CH2:12][CH2:11][O:10][CH2:9]4)[C:14]=3[N:15]=[C:2]([C:30]3[CH:31]=[N:32][C:33]([NH2:36])=[N:34][CH:35]=3)[N:3]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2c(n1)N1CCOCC1CO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1ncc(-c2nc(N3CCOCC3)c3c(n2)N2CCOCC2CO3)cn1
Temperature: 120 °C
Yield: 5.6 %

Procedure:
A mixture of 3-chloro-1-morpholin-4-yl-5,6,8a,9-tetrahydro-8H-7,10-dioxa-2,4,4b-triaza-phenanthrene (45 mg, 0.144 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (60 mg, 0.271 mmol), PdCl2(PPh3)2 (10 mg, 0.014 mmol) and sodium carbonate (460 μL, 0.46 mmol, 1M aqueous solution) in acetonitrile (2 mL) was degassed and heated at 120° C. for 30 mins in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient acetonitrile 5-98%) affording 121 as a white solid (3 mg, 6%). LCMS (method B): RT=3.08 min, [M+H]+=372. 1H NMR (400 MHz, CDCl3): δ 9.11 (2H, s), 5.18 (2H, broad s), 4.55 (1H, dd, J=13.5, 2.4 Hz), 4.22 (1H, dd, J=10.8, 3.1 Hz), 4.05 (1H, dd, J=11.5, 3.5 Hz), 3.88 (2H, m), 3.81 (4H, m), 3.69-3.56 (6H, m), 3.29 (1H, t, J=11.5 Hz), 3.02 (1H, m).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[C:9]([Cl:12])[CH:10]=2)[N:5]([C@@H:14]2[O:28][C@H:27]([CH2:29][O:30]C(C3C=CC(C)=CC=3)=O)[C@@H:16]([O:17]C(C3C=CC(C)=CC=3)=O)[CH2:15]2)[C:4]=1Cl)=[O:2].[CH3:41][O-:42].[Na+].CO.C(Cl)(Cl)Cl>CO>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[Cl:13])[N:5]([C@@H:14]1[O:28][C@H:27]([CH2:16][OH:17])[C@@H:29]([OH:30])[CH2:15]1)[C:4]([O:42][CH3:41])=[C:3]2[CH:1]=[O:2]
Reactant: C[O-]
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3c(Cl)c(C=O)c4cc(Cl)c(Cl)cc43)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1c(C=O)c2cc(Cl)c(Cl)cc2n1[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
3-Formyl-2,5,6-trichloro-1-[3,5-di-O-(p-toluoyl)-2-deoxy-β-D-ribofuranosyl]indole (4.113, 198 mg, 0.33 mmol) was suspended in dry MeOH (10 mL) to which was added sodium methoxide (75 mg, 1.4 mmol). The suspension was stirred at room temperature for 16 h, after which time the solution clarified. The solvent was then removed under vacuum, and the residue was suspended in water (50 mL), and extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine (25 mL), dried over MgSO4, filtered and evaporated to yield a damp solid. The crude material was dissolved in MeOH (1 mL) and subjected to column chromatography (40×350 mm) on silica gel with 10% MeOH/CHCl3. Fractions containing product were pooled and evaporated to yield a white solid. The solid was recrystallized from warm MeOH to yield 82 mg (68%) of 4.114 as a white crystalline solid: mp 186-187° C.; Rf 0.3 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 10.21 (s, 1H), 8.29 (s, 1H), 8.22 (s, 1H), 6.32 (dd, 1H), 5.37 (b, 1H, D2O exch.), 5.15 (b, 1H, D2O exch.), 4.43 (s, 3H), 4.41 (m, 1H), 3.83 (d, 1H), 3.68 (m, 2H), 2.53 (m, 1H), 2.11 (m, 1H). 13C-NMR (125 MHz, DMSO-d6): δ 183.22, 159.16, 129.40, 125.04, 124.73, 124.66, 121.11, 114.24, 100.02, 87.29, 82.99, 70.07, 64.16, 61.03, 38.43. HRMS (EI) m/z calcd. for C15H15Cl2NO5 359.0327. found 359.0320. Anal calcd for C15H15Cl2NO5.½H2O: C, 48.80; H, 4.37; N, 3.79. Found: C, 48.48; H, 4.61; N, 3.61.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:19].[Na+].Cl>CO>[NH2:19][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:12])([CH3:1])[CH2:3]1
Reactant: [BH3-]C#N
Reactant: CC1(C)CC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: CC1(C)CC(N)c2ccccc21
Yield: 40.9 %

Procedure:
3,3-Dimethyl-1-(N-methyl-N-methylsulfonyl)aminoindan ##STR18## a) A solution of 25.0 g (0.156 mol) of 3,3-dimethylindan-1-one (Chem. Ber. 64, 1931, 1493) in 700 ml of methanol was stirred with 120.2 g (1.56 mol) of ammonium acetate and 69.1 g (1.1 mol) of sodium cyanoborohydride at 60° C. for 8 h. The reaction mixture was adjusted to pH<2 using dilute hydrochloric acid and concentrated using a rotary evaporator. The residue was taken up in dilute hydrochloric acid and extracted with EA, and the aqueous phase was then made alkaline using potassium carbonate solution and extracted with EA. The organic phase was dried with magnesium sulfate and concentrated under reduced pressure, giving 10.3 g of 1-amino-3,3-dimethylindan.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.Cl[C:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:17](=[O:25])(=[O:24])[N:16]=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[S:17](=[O:24])(=[O:25])[N:16]=2)=[N:6][CH:7]=1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: Cc1cc(Br)cnc1CCCCN
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)cnc1CCCCNC1=NS(=O)(=O)c2ccccc21
Reaction time: 0.25 h

Procedure:
To a refluxing solution of 4-(5-bromo-3-methyl-2-pyridinyl)butylamine (1.87 g, 7.69 mmol) in chloroform (80 ml, freed of EtOH by passage through Woelm Grade I neutral alumina) was added over 50 minutes a solution of 3-chloro-1,2-benzisothiazole-1,1-dioxide (U.S. Pat. No. 4,490,527) (1.55 g, 7.69 mmol) in chloroform (50 ml, purified as above) while maintaining reflux. After the addition was complete, reflux was continued for another 15 minutes. Evaporation in vacuo gave a yellow orange foam. Crystallization from 2-propanol and recrystallization from methanol/methylene chloride/2-propanol (Norite) gave 2.07 g of the title compound as a tan solid hydrochloride: m.p. 232°-244° C., IR(KBr) 3070, 1610, 1578, 1508, 1280, 1140 cm-1. 1H NMR (Me2SO d6) 9.85 (1H, t), 8.70 (1H, s), 8.33 (1H, m), 8.27 (1H, s), 7.88 (3H, m) 3.40 (2H, m), 2.90 (2H, m), 2.37 (3H, s), 1.70 (4H, m).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2([C:29]([CH:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:32](OCC)=[O:33])=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:19]=[CH:20][C:21]=1[F:22]>OS(O)(=O)=O.C(OCC)C>[Cl:15][C:16]1[CH:17]=[C:18]2[C:19]([C:32]([OH:33])=[C:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:29](=[O:30])[C:23]32[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[CH:20][C:21]=1[F:22]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccc(F)c(Cl)c2)CCOCC1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCOC(=O)C1=C(O)c2cc(F)c(Cl)cc2C2(CCOCC2)C1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 75.8 %

Procedure:
P2O5 (1.4 g) was suspended in H2SO4 (3.34 mL), and the mixture was cooled to 0° C. Diethyl 2-(4-(3-chloro-4-fluorophenyl)-tetrahydro-pyran-4-carbonyl)malonate (1.43 g, 3.57 mmol) was then added dropwise, and the resulting mixture was stirred for 1.5 hours. The reaction mixture was allowed to warm to ambient temperature and stirred for 5 hours. The reaction mixture was then poured into a beaker of ice, diluted with 200 mL of diethyl ether, added to a separatory funnel, partitioned with water, washed with water (2×75 mL), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (0.96 g) as a colorless oil after flash chromatography. MS m/e=355 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O.O>[CH2:15]([O:14][C:12]([C:11]1[CH:17]=[CH:18][C:8]([N:7]([CH2:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:21](=[O:23])[CH3:22])=[CH:9][CH:10]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1ccc(NCc2ccc(Cl)cc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(N(Cc2ccc(Cl)cc2)C(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Ethyl 4-(4-chlorobenzylamino)-benzoate (11.56 g; 0.04 M), acetic anhydride (40 ml) and concentrated sulphuric acid (5 drops) were mixed and heated with stirring on a steam-bath for 1 hour. The mixture was cooled to room temperature, added to iced water (100 ml) and neutralised with solid sodium bicarbonate. The product was extracted into dichloromethane (2×100 ml), washed with water (1×100 ml) and evaporated to give an oil from which N-(4-ethoxycarbonylphenyl)-N-(4-chlorobenzyl)-acetamide (8.32 g; 63%) was obtained by chromatography on silica-gel in dichloromethane then 2% methanol-dichloromethane followed by crystallisation from ethanol. M.p. 65°-6° C.
Reaction SMILES: OO.Cl.[CH3:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:12][NH:13][C:14]1[S:15][CH2:16][CH2:17][N:18]=1.[OH-].[Na+]>C(Cl)Cl>[CH3:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[N:12]=[N:13][C:14]1[S:15][CH2:16][CH2:17][N:18]=1
Reactant: Cc1cccc(NNC2=NCCS2)c1C
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc(N=NC2=NCCS2)c1C
Reaction time: 18 h

Procedure:
3.5 ml of 30% strength perhydrol were added to a mixture of 6.5 g (0.025 mol) of 2-[2-(2,3-dimethylphenyl)-hydrazino]-2-thiazoline hydrochloride, 60 ml of methylene chloride and 50 ml of 2N sodium hydroxide solution. The mixture was stirred for 18 hours under reflux, and a further 2 ml of perhydrol were added after 6 hours, and another 1 ml of perhydrol after 12 hours. The organic phase was separated off, dried over potassium carbonate and evaporated down, and the residue was recrystallised from hexane/diethyl ether. Mp. 74° to 79°, yield 4.1 g (74% of theory).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([NH2:17])=[O:16].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]([N:13]1[CH2:20][CH2:19][CH2:18][CH:14]1[C:15](=[O:16])[NH2:17])=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)N1CCCC1C(N)=O
Temperature: 25 °C
Yield: 96 %

Procedure:
N-tert-butyloxycarbonyl glycine 1a (5 g, 28.56 mmol) and L-prolinamide (3.25 g, 28.50 mmol) were dissolved in 75 mL of N,N-dimethylformamide, the resulting solution was cooled down to 0° C. (centigrade), and 1-hydroxybenzotriazole (11.8 g, 87.3 mmol), N-ethyl-N′-(dimethylaminopropyl)-carbodiimide (11.3 g, 59 mmol) and triethylamine (12.1 mL, 87.3 mmol) were then added with stirring. Upon completion of the addition, the reaction mixture was allowed to increase to room temperature, and stirred overnight. After thin lay chromatography showed the starting material disappeared, N,N-dimethylformamide was evaporated below 50° C., and the reaction solution was extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by recrystallization with ethyl acetate to obtain the title compound [2-(2-carbamoyl-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1b (7.42 g, yield 95.8%) as a white powder.
Reaction SMILES: [CH3:1][C:2](=[CH:4][C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[CH3:8])[CH3:3].[C:11]([O:15][OH:16])([CH3:14])([CH3:13])[CH3:12]>>[CH3:1][C:2]([O:16][O:15][C:11]([CH3:14])([CH3:13])[CH3:12])([CH2:4][C:5](=[O:10])[CH2:6][C:7]([CH3:9])([O:16][O:15][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:8])[CH3:3]
Reactant: CC(C)=CC(=O)C=C(C)C
Reactant: CC(C)(C)OO
Product: CC(C)(C)OOC(C)(C)CC(=O)CC(C)(C)OOC(C)(C)C

Procedure:
A mixture of 47.0 g. (0.34 mole) of phorone and 157 g (1.36 mole) of 78% t-butyl hydroperoxide was stirred with 34 g. of dry Amberlyst 15® sulfonic acid type ion exchange resin in a 500 ml flask equipped with a condenser and thermometer for forty-eight hours at 40° C. and one hour at 50° C. The ion exchange resin was separated by filtration and the product diluted with pentane. The pentane solution was washed with water, sodium bisulfite solution, 5% sodium hydroxide solution and water. After drying over anhydrous magnesium sulfate, the pentane was removed under reduced pressure. The recovered product weighed 74.2 g. (68.5% of the calculated amount). A GLC scan showed a large major peak for the expected product. In the infrared spectrum, small bands for hydroxyl and olefin were observed but the band in the 880 cm-1 region usually associated with t-butyl peroxy groups was strong. By active oxygen assay, the purity of the product was estimated at 83%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C[N:15](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])ccc1C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 2-methyl-4-nitrobenzoic acid suspended in CH2Cl2 under Ar was added DMF then oxalyl chloride. The reaction was stirred at room temperature 1.5 hours then the solvent was evaporated. The residue was dissolved in THF and ammonia gas was bubbled through the reaction for 15 minutes. The solvent was evaporated and the residue partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The extracts were dried (MgSO4), filtered and evaporated. Column chromatography (SiO2, 0-100% EtOAc/Hex) gave pure 2-methyl-4-nitrobenzamide (E111).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]3[CH:19]=[C:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:17](=[O:27])[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]([C:15]=2[CH:16]=1)[C:9]3=4)(=[O:3])[CH3:2].B.[Na].C(=O)([O-])O.[Na+]>CO.[OH-].[Na+]>[CH2:20]([C:18]1[C:17](=[O:27])[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[N:8]([CH:19]=1)[C:7]1[CH:6]=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[CH:16][C:15]3=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)c1ccc2c(c1)c1cccc3c(=O)c(Cc4ccccc4)cn2c31
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc2c(c1)c1cccc3c(=O)c(Cc4ccccc4)cn2c31
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
10-acetyl-5-benzyl-4H-pyrido[3,2,1-jk]carbazole-4-one (150 mg) produced in Example 196 was suspended in methanol (15 ml), and 1N sodium hydroxide (1 drop) was added. The mixture was cooled in an ice bath, and sodium boron hydride (161 mg) was gradually added. After stirring the mixture at room temperature for 1 hour, a small amount of saturated sodium hydrogencarbonate was added to the reaction mixture, and the solution was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residual crude crystals were washed with a mixed solvent of ether and hexane to obtain the title compound (126 mg, 83%).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=2)[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])=[O:38])=[CH:29][CH:28]=1
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(Cl)c1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(Cl)c1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol (300 mg, 0.79 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (151 mg, 0.79 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (228 mg, 1.19 mmol) and 1-hydroxybenzotriazole hydrate (122 mg, 0.79 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-ethyl acetate). Recrystallization from ethyl acetate-hexane gave the objective substance (163 mg, 37%).