Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]12[CH2:15][CH:11]3[CH2:12][CH:13]([CH2:14]1)[C:9](C(O)=O)([CH2:10]3)[CH2:8]2.OS(O)(=O)=O.[N-:24]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl.O>[NH2:24][C:9]12[CH2:10][CH:11]3[CH2:15][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][C:2]4=[O:1])([CH2:14][CH:13]1[CH2:12]3)[CH2:8]2
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCCN1C12CC3CC(C1)C(C(=O)O)(C3)C2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: NC12CC3CC1CC(N1CCCC1=O)(C3)C2
Temperature: 45 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
To a stirred solution of the acid obtained in step II (0.5 g, 2.0 mmol) in CHCl3 (21 mL) at room temperature was added conc. H2SO4 (1.0 mL, 20 mmol) followed by NaN3 (0.39 g, 6.0 mmol) in portions over a period of 30 min., so that the temperature of the reaction did not rise above 40° C. The reaction was warmed to 45° C. and stirred for 2 h, then cooled to ice bath temperature, diluted with water and extracted with EtOAc. The aqueous layer was basified by adding 50% NaOH solution and extracted with CHCl3. The combined organic layer was washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure to obtain 1-(3-aminotricyclo[3.3.1.03,7]non-1-yl) pyrrolidin-2-one as an off-white solid (0.25 g) in 74% yield. m/z (M+1) 221; 1H NMR (CDCl3) 300 MHz δ 3.41 (t, J=7.0 Hz, 2H), 2.46 (dd, J=2.4, 10.3 Hz, 1H), 2.38-2.28 (m, 1H), 2.30 (t, J=8.3 Hz, 2H), 2.16-1.82 (m, 9H), 1.78 (dd J=2.6, 10.8 Hz, 1H), 1.66-1.58 (m, 1H), 1.51 (dd, J=2.5, 10.8 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:3]([C:31]#[N:32])=[C:4]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:26]=2)[C:5]([O:18][CH2:19][CH3:20])=[C:6]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH:7]=1.[CH3:33]B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[C:31]([C:3]1[C:2]([CH3:33])=[CH:7][C:6]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[C:5]([O:18][CH2:19][CH3:20])[C:4]=1[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:26]=1)#[N:32]
Reactant: CCOc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C#N)c1-c1cncc(S(C)(=O)=O)c1
Reactant: CB(O)O
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1c(C(C)NC(=O)OC(C)(C)C)cc(C)c(C#N)c1-c1cncc(S(C)(=O)=O)c1
Temperature: 90 °C
Yield: 65.3 %

Procedure:
To tert-butyl (1-{5-chloro-4-cyano-2-ethoxy-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)carbamate (60 mg, 0.1 mmol) and methylboronic acid (6.4 mg, 0.11 mmol) in 1,4-dioxane (4 mL) was added sodium carbonate (20 mg, 0.2 mmol) in water (2 mL). The reaction was degassed with N2. Dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (4 mg, 0.005 mmol) was added and degassed again with N2. The reaction was heated at 90° C. overnight. The reaction was allowed to cool to room temperature and was partitioned between EtOAc and water. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give crude product. The product was purified by chromatography on silica gel eluting with a hexane: EtOAc gradient to give tert-butyl (1-{4-cyano-2-ethoxy-5-methyl-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)carbamate as a yellow oil (0.030 g, 50%). LCMS calculated for C23H30N3O5S (M+H)+: m/z=460.1. found: 460.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].O>CN(C)C=O>[CH3:18][C:10]([N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)([CH3:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)n1cc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 4-nitro-1H-pyrazole (3.0 g) in N,N-dimethylformamide (50 mL) was added tert-butyl 2-bromo-2-methylpropanoate (15 mL), and the mixture was stirred at 80° C. for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (7.0 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:11](C(O)=O)=[C:10]([C:15]([F:18])([F:17])[F:16])[NH:9][C:6]2=[N:7][CH:8]=1)#[N:2]>O.CN1CCCC1=O>[F:18][C:15]([F:16])([F:17])[C:10]1[NH:9][C:6]2=[N:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[C:5]2[CH:11]=1
Reactant: N#Cc1cnc2[nH]c(C(F)(F)F)c(C(=O)O)c2c1
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cnc2[nH]c(C(F)(F)F)cc2c1
Temperature: 120 °C
Yield: 61.1 %

Procedure:
5-Cyano-2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (Intermediate 3, 2.49 g, 9.76 mmol) was dissolved in water (36 mL) and N-methyl-2-pyrrolidone (48 mL). The resulting mixture was heated at 120° C. for 18 hours. The reaction mixture was allowed to cool to room temperature and diluted with water. The resulting precipitate was collected by filtration, washed with water and dried under high vacuum at 40° C. for 5 hours to give the title compound as a white solid (1.26 g);
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]3[C:19]([CH:22]=O)=[N:20][N:21]=[C:10]3[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[NH3:30]>CCOCC>[C:1]1([C:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]3[C:19]([C:22]#[N:30])=[N:20][N:21]=[C:10]3[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: N
Solvent: CCOCC
Solvent: c1ccccc1
Product: N#Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 24 h

Procedure:
A solution of 4.8 g (0.015 mole) of 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxaldehyde [see Example 1 a)] in abs. benzene is saturated with ammonia. After cooling of the solution to 0°, an addition is made portionwise, with a light flow of ammonia gas and in the course of 45 minutes, of 14.0 g (0.030 mole) of lead tetraactetate. The reaction mixture is then stirred for a further 24 hours at 25°; it is subsequently diluted with ether and filtered through kieselguhr. The filtrate is washed with 1N hydrochloric acid, water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The residue is chromatographed through silica gel with the use of ethyl acetate as eluant. The fractions containing the desired nitrile [Rf = 0.63 in the eluant system ethyl acetate/isopropanol (7:1)] are combined, and concentrated by evaporation. The residue is crystallised from ethyl acetate/petroleum ether to obtain 6-phenyl-8-chloro-4H-s-triazolo [4,3-a][1,4]benzodiazepine-1-carbonitrile, M.P. 191°-192°.
Reaction SMILES: [N:1]1([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][C@@H:14]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][N:23]=2)=[O:21])[CH2:13][CH2:12]3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH2:34]OS(C)(=O)=O>>[N:1]1([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][C@@H:14]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:34][C@@H:30]4[CH2:31][CH2:32][CH2:33][O:29]4)=[CH:24][N:23]=2)=[O:21])[CH2:13][CH2:12]3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N[C@H]1CCc2cc(CN3CCCCCC3)ccc2C1)c1ccc(O)cn1
Reactant: CS(=O)(=O)OC[C@@H]1CCCO1
Product: O=C(N[C@H]1CCc2cc(CN3CCCCCC3)ccc2C1)c1ccc(OC[C@@H]2CCCO2)cn1

Procedure:
According to method F, 5-hydroxypyridine-2-carboxylic acid ((S)-6-azepan-1-ylmethyl-1,2,3,4-tetrahydronaphthalen-2-yl)amide was alkylated with methanesulfonic acid (S)-1-(tetrahydrofuran-2-yl)methyl ester (DMF, 12 h, 80° C.). The product was thus obtained with the molecular weight of 463.63 (C28H37N3O3); MS (ESI): 464 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:16]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]([CH2:12][NH2:16])([OH:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: N
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(O)(CN)CC1
Reaction time: 8 h
Yield: 60.5 %

Procedure:
A stirred solution of 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (9.0 g, 42.2 mmol) in ethanol (60 ml) was added with ammonia (160 ml). The resulting mixture was stirred under a nitrogen atmosphere overnight. The mixture was concentrated under reduced pressure. The residue was added with Water (50 ml) and extracted with ethyl acetate (150 ml×3). The Combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane:methanol (20:1) as eluents to give 4-aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (5.87 g, 60.5%) as a white solid.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]3[C:25]4[CH:26]=[CH:27][CH2:28][CH2:29][C:30]=4[C:31](=[O:32])[C:16]=23)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[C:9]1([C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]3[C:25]4[C:30]([C:31]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)([OH:32])[C:16]=23)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1C2=C(C=CCC2)c2nc3ccccc3c(-c3ccccc3)c21
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: OC1(c2ccccc2)c2ccccc2-c2nc3ccccc3c(-c3ccccc3)c21
Yield: 90 %

Procedure:
After dripping 1M phenylmagnesium bromide (20 ml, 20.0 mmol) into the starting material 10-phenyl-1H-indeno[1,2-b]quinolin-11-one (3.07 g, 10.0 mmol) which is dissolved in pure tetrahydrofuran, the mixed solution undergoes reaction for 24 hours at room temperature. Then, the reaction is terminated by adding ammonium chloride solution therein. Finally, 3.47 g of 10,11-diphenyl-11H-indeno[1,2-b]quinolin-11-ol is obtained by filtering the mixed solution to remove precipitates. The percentage yield is 90.0%. 10-diphenyl-11H-indeno[1,2-b]quinolin-11-ol obtained here can be also used as starting materials to produce other 6H-indeno[2,1-b]quinoline derivatives.
Reaction SMILES: [N:1]1([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:47][CH2:46][CH2:45][C@H:2]1[C:3]([NH:5][C@H:6]([C:13]([N:15]1[CH2:44][CH2:43][CH2:42][C@H:16]1[C:17]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:38]([O:40]C)=[O:39])[CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])=[O:14])[CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)=[O:4].[OH-].[Na+].Cl.C(O)CCC.O>CO.O>[N:1]1([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:47][CH2:46][CH2:45][C@H:2]1[C:3]([NH:5][C@H:6]([C:13]([N:15]1[CH2:44][CH2:43][CH2:42][C@H:16]1[C:17]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:38]([OH:40])=[O:39])[CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])=[O:14])[CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)=[O:4]
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reaction time: 0.25 h

Procedure:
17.2 g of crude Boc-Pro-His-Pro-Phe-His-OMe are dissolved in 54 ml of MeOH, 650 ml of 0.1N NaOH are added, the whole is left to stand for 15 minutes at 25°, neutralised by the addition of 650 ml of 0.1N HCl concentratod to dryness. The residue is dissolved in 120 ml of H2O, the pH value is adjusted exactly to 6.8 and this solution is subjected in the system n-butanol/H2O to Craig partitioning over 500 stages; (K=2.8). The fractions that are pure according to thin layer chromagotraphy analysis are combined, concentrated to dryness, dissolved in H2O and lyophilised, yielding Boc-Pro-His-Pro-Phe-His-OH in amorphous form; Rf (A)=0,15; Rf (C)=0.42; Rf (E)=0.25.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:28])[C:5]2[N:6]=[CH:7][N:8]([CH2:11][O:12][C@H:13]([CH2:19][O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][O:15]C(=O)C)[C:9]=2[N:10]=1>N.CO>[NH2:1][C:2]1[NH:3][C:4](=[O:28])[C:5]2[N:6]=[CH:7][N:8]([CH2:11][O:12][C@@H:13]([CH2:14][OH:15])[CH2:19][O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:9]=2[N:10]=1
Reactant: CC(=O)OC[C@@H](COCc1ccccc1)OCn1cnc2c(=O)[nH]c(N)nc21
Agent: N
Solvent: CO
Product: Nc1nc2c(ncn2CO[C@@H](CO)COCc2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (R)-2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1-acetoxy-3-benzyloxy-propane in 30% ammonia/methanol (1:2) was stirred at ambient temperature for 18 hours. The solvent was evaporated and the residue was triturated with a small amount of methanol. The pale yellow solid was collected to give (S)-2-(2-Amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1-benzyloxy-propan-3-ol. The mother liquor was concentrated and the residue recrystallized from hot methanol to give a second crop of the product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5](/[CH:14]=[CH:15]\OCC)=[CH:4][N:3]=1.Cl>CCO>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:14]=[CH:15][N:8]([CH:9]([CH2:10][CH3:11])[CH2:12][CH3:13])[C:6]=2[N:7]=1
Reactant: CCO/C=C\c1cnc(Cl)nc1NC(CC)CC
Agent: Cl
Solvent: CCO
Product: CCC(CC)n1ccc2cnc(Cl)nc21
Temperature: 100 °C

Procedure:
To a solution of [2-chloro-5-((Z)-2-ethoxy-vinyl)-pyrimidin-4-yl]-(1-ethylpropyl)-amine (1.1 g, 4.07 mmol) in EtOH (8 mL) is added concentrated HCl (0.1 mL) at ambient temperature. The reaction mixture is sealed in a microwave reactor and heated at 100° C. for 10 min. After cooling to room temperature, the mixture is concentrated in vacuo to provide 2-chloro-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine. The crude product is used as it is. The crude product can be purified by flash chromatography (SiO2, EtOAc/Hexane 1:5).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl[Si:22](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([Si:22]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCC[Mg]Br
Product: CCCCCCCCCCCCCCCCCC[Si](CCCCCCCCCCCCCCCCCC)(c1ccccc1)c1ccccc1
Yield: 78 %

Procedure:
The first portion of the octadecylmagnesium bromide was cooled to 0° and cuprous cyanide (0.12 g 1.34 mmoles) was added with stirring. Then dichlorodiphenylsilane (1.95 ml, 9.27 mmoles) was added. The reaction mixture was stirred at 10° for 140 minutes. Gas chromatographic analysis showed that most of the dichlorodiphenylsilane had disappeared during the first hour of reaction. The mixture was then stirred at room temperature for about 16 hours (i.e. overnight). The reaction mixture was then filtered, quenched with water, and acidified slightly with HCl. After extraction with diethylether, drying (with MgSO4) and removal of solvent, a solid was obtained. Extraction with hot heptane and crystallization provided 4.96 g of dioctadecyldiphenylsilane. The yield was about 78%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:21]3[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)=[CH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4]>[Pd].CO>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([CH:14]([C:21]3[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)[CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)nc3)cc2c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)nc3)cc2c1
Temperature: 50 °C
Yield: 73.5 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(6-methanesulfonyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (150 mg, 0.35 mmol) and 10% palladium on activated carbon (45 mg) in methanol (300 mL) was heated at 50° C. under hydrogen (50 bar) for 5 h. The mixture was cooled to room temperature. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo to afford 2-[2-cyclopentyl-1-(6-methanesulfonyl-pyridin-3-yl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (110 mg, 73%) which was used in the next step without further purification: LC/MS m/e calcd for C22H25N3O4S [M+H]+ 428.53, observed 427.9.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][N:9]=1.O>CC(O)(C)C>[N:1]1([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Clc1nsc2ccccc12
Solvent: O
Solvent: CC(C)(C)O
Product: c1ccc2c(N3CCNCC3)nsc2c1
Temperature: 2.5 °C

Procedure:
A mixture of piperazine (10.2 g, 0.118 mmol) and 3-chloro-1,2-benzisothiazole (4.0 g, 0.024 mmol) in t-BuOH (4 mL) was refluxed overnight. The reaction mixture was poured into water (100 mL) and extracted with toluene (200 mL). The organic phase was dried over MgSO4 and evaporated until about 20 mL remained, under vacuum. The resulting suspension was cooled at 0-5° C. overnight. The precipitate was filtered and dried under vacuum to provide 3-(piperazin-1-yl)benzo[d]isothiazole as an intermediate (3.36 g, 15.4 mmol, 65%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:31]([CH3:32])=[CH:30][C:12]([C:13]([NH:15][CH2:16][C:17]([C:19]2[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH:26][CH:27]([CH3:29])[CH3:28])[N:20]=2)=[O:18])=O)=[CH:11][C:10]=1[CH2:33][CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH2:1]([O:8][C:9]1[C:31]([CH3:32])=[CH:30][C:12]([C:13]2[O:18][C:17]([C:19]3[CH:29]=[C:27]([CH3:28])[N:26]=[C:21]([NH:22][CH:23]([CH3:25])[CH3:24])[N:20]=3)=[CH:16][N:15]=2)=[CH:11][C:10]=1[CH2:33][CH3:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(C(=O)NCC(=O)c2cc(C)nc(NC(C)C)n2)cc(C)c1OCc1ccccc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: CCc1cc(-c2ncc(-c3cc(C)nc(NC(C)C)n3)o2)cc(C)c1OCc1ccccc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 9.4 %

Procedure:
To a solution of crude 4-benzyloxy-3-ethyl-N-[2-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-2-oxo-ethyl]-5-methyl-benzamide (300 mg, 0.65 mmol) in THF (10 mL), Burgess reagent (775 mg, 3.3 mmol) is added. The mixture is stirred at 80° C. for 18 h before it is concentrated. The crude product is purified on prep. TLC plates with Heptane/EA 1:1 to give {4-[2-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-oxazol-5-yl]-6-methyl-pyrimidin-2-yl}-isopropyl-amine (27 mg) as a yellow solid; LC-MS: tR=1.05 min, [M+H]+=442.81.
Reaction SMILES: [N:1]([CH:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:5]([NH:7][C:8]1([O:17][CH3:18])[CH2:11][N:10]([S:12]([OH:15])(=[O:14])=[O:13])[C:9]1=[O:16])=[O:6])=[N+]=[N-].[K].FC(F)(F)C(O)=O>CO.[Pd]>[NH2:1][CH:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:5]([NH:7][C:8]1([O:17][CH3:18])[CH2:11][N:10]([S:12]([OH:15])(=[O:13])=[O:14])[C:9]1=[O:16])=[O:6]
Reactant: COC1(NC(=O)C(N=[N+]=[N-])c2ccccc2)CN(S(=O)(=O)O)C1=O
Agent: [Pd]
Agent: [K]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COC1(NC(=O)C(N)c2ccccc2)CN(S(=O)(=O)O)C1=O
Reaction time: 1 h

Procedure:
(±)-3-[(Azidophenylacetyl)amino]-3-methoxy-2-oxo-1-azetidinesulfonic acid, potassium salt (209 mg; see Example 88) is dissolved in 60 ml of dry methanol. Anhydrous trifluoroacetic acid (0.6 ml) and 10% palladium on carbon (105 mg) are added and the mixture is hydrogenated for 1 hour. The catalyst is removed by filtration and the filtrate is evaporated in vacuo to yield 271 mg of crude product.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:5](=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:13]>C(Cl)Cl.O=[Mn]=O>[CH3:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[C:5](=[O:14])[N:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[C:3]([CH:2]=[O:1])=[CH:12]2
Reactant: Cc1ccccc1-n1c(CO)cc2cccc(C)c2c1=O
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1ccccc1-n1c(C=O)cc2cccc(C)c2c1=O
Temperature: 25 °C
Yield: 90.1 %

Procedure:
To a stirred solution of 3-(hydroxymethyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one 1609 (2.79 g, 10 mmol) in CH2Cl2 (200 mL), MnO2 (5 g) was added and the resulting mixture was stirred at reflux for 3 h. The mixture was allowed to cool to RT, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10-50% EA/PE) to afford the product, 8-methyl-1-oxo-2-o-tolyl-1,2-dihydroisoquinoline-3-carbaldehyde 4101 (2.5 g, 90% yield) as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH3:5].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32]I)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32][C:6]([CH2:3][CH2:4][CH3:5])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCC(C(=O)OCC)C(=O)OCC
Reactant: ICCc1ccccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CCc1ccccc1OCc1ccccc1)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a suspension of sodium hydride (1.3 g) in dimethylformamide (15 ml), a solution of diethyl propylmalonate (6.6 g) in dimethylformamide (45 ml) was added under ice-cooling and the mixture was stirred at room temperature for an hour. To the solution was added a solution of 2-(2-benzyloxyphenyl)ethyl iodide (10 g) in dimethylformamide (30 ml), the mixture was stirred at the same temperature for an hour and left standing overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and a saturated brine and dried over magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was subjected to silica gel chromatography (eluent; hexane-ethyl acetate=8:1) to give the subject compound (10 g).
Reaction SMILES: O=[C:2]1[C:15]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.BrN1C(=[O:22])CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH:2]1[C:15]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[C:5]([OH:22])=[CH:4][CH:3]=1
Reactant: O=C1CCCc2c1ccc1ccccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1cccc2ccc3ccccc3c12
Temperature: 25 °C

Procedure:
In a 1000 ml 3-neck flask equipped with magnetic stirrer and reflux condenser with nitrogen inlet, 400 ml of carbon tetrachloride was added followed by 26 gms of 4 oxo-1,2,3,4-tetrahydrophenanthrene and 26.5 gm of N-bromo succinimide. The reaction was illuminated with a 600 watt Quartzlite lamp for 6 hours. Then an additional 2.0 gms of N-bromosuccinimide was added and the reaction refluxed for 1 hour. The reaction was cooled to room temperature and the solids filtered off and washed with carbon tetrachloride and air dried. The solids were recrystallized from 220 ml of ethyl acetate, filtered and washed with several portions of warm water, dried in vacuo in the presence of P2O5 to yield 8.3 gms (32.25% by weight) of 4-phenanthrol. m.p. 114°-116° C. m/e 194.