Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[S:5][C:6]2[CH:32]=[CH:31][CH:30]=[CH:29][C:7]=2[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])=[CH:15][CH:14]=2)[C:9](=[O:11])[CH:10]=1.[CH3:33][O:34][C:35]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:36]=1[CH:37]=O.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH3:33][O:34][C:35]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:36]=1[CH2:37][NH:1][CH2:2][CH2:3][C:4]1[S:5][C:6]2[CH:32]=[CH:31][CH:30]=[CH:29][C:7]=2[N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:28])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])=[CH:17][CH:18]=2)[C:9](=[O:11])[CH:10]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(CN2C(=O)C=C(CCN)Sc3ccccc32)cc1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CNCCC2=CC(=O)N(Cc3ccc(NC(=O)c4ccccc4C)cc3)c3ccccc3S2)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of Compound 7 as prepared in Example 31 (0.105 g, 0.24 mM), 2,4-dimethoxybenzaldehyde (0.040 g, 0.240 mM) and acetic acid (0.05 ml) in methanol was stirred at room temperature for three hours and 2.5 equivalence of sodium cyanoborohydride was added. The mixture was stirred at room temperature for an additional 4 hours and a 6N NaOH (0.5 ml; adjusted to pH8) was added. The methanol was removed under reduced pressure and the residue diluted with water (50 ml) and extracted with ethyl acetate (2×5 ml). The ethyl acetate extracts were dried (MgSO4), evaporated in vacuo and purified by flash column chromatography (EM silica gel 60; 5% MeOH in CH2Cl2) to give a white solid product. m/z (MH+) 596.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[O:5][CH:6]([CH2:10][CH3:11])[C:7](O)=[O:8].C1(C)C=CC=CC=1.C(Cl)([Cl:25])=O.C(=O)=O>O.CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[O:5][CH:6]([CH2:10][CH3:11])[C:7]([Cl:25])=[O:8]
Reactant: O=C(Cl)Cl
Reactant: CCC(Oc1cc(C)cc(C)c1)C(=O)O
Agent: O=C=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(Oc1cc(C)cc(C)c1)C(=O)Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
A mixture of 2-(3,5-dimethylphenoxy)-butyric acid [849 g (4.1 moles)], 1075 ml toluene, and 8 ml dimethylformamide was heated to 60° C. in a 5-liter flask fitted with a gas inlet tube, a stirrer, a thermometer and a dry ice condenser. Phosgene, 472 g (4.8 moles), was passed into the solution at 60°-70° C. The mixture was then heated at 60°-70° C. for thirty minutes. The dry ice condenser was then replaced with a water-cooled condenser and the solution was purged with nitrogen to remove excess phosgene and HCl. After 2 hours, purging was discontinued and the solution was vacuum stripped to leave 2-(3,5-dimethylphenoxy)butyryl chloride, 931 g (101% yield), nD30 1.5050.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[CH:7][N:6]=1)=O.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[CH3:21][N:18]1[CH2:19][CH2:20][CH:15]([CH2:14][CH2:13][CH2:12][NH:11][C:8]2[N:9]=[CH:10][C:5]([CH:3]=[O:2])=[N:6][CH:7]=2)[CH2:16][CH2:17]1
Reactant: COC(=O)c1cnc(NCCCC2CCN(C)CC2)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CN1CCC(CCCNc2cnc(C=O)cn2)CC1

Procedure:
A −78° C. solution of 5-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrazine-2-carboxylic acid methyl ester in DCM (0.1 M) was treated with diisobutylaluminum hydride (1 M in hexanes; 1 equiv.) dropwise. The reaction was quenched with 1 M H2SO4, neutralized with satd. aq. NaHCO3, and diluted with MeOH, CHCl3, and satd. aq. sodium potassium tartrate. The mixture was stirred vigourously until the layers separated. The organic layer was dried (Na2SO4) and concentrated to give the crude product, which was used in the next step without further purification.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:30]([OH:32])=O)[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:41]>ClCCl>[C:1]([NH:18][C@H:19]([C:30]([F:41])=[O:32])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)F)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 6.5 h

Procedure:
FMOC-L-Tryptophan (5 g, 11.72 mmol) (Bachem) was dissolved in dichloromethane (60 mL). Pyridine (0.95 mL, 11.72 mmol) (Aldrich) and cyanuric fluoride (1.58 g, 11.72 mmol) (Aldrich) were successively added at room temperature and the mixture was stirred for 6.5 hours. Ice cold water (100 mL) was added and the resulting slurry was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford FMOC-L-tryptophanyl fluoride as a beige powder. (Yield 4.36 g, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([CH3:20])=[CH:6]2.[H-].[Na+].F[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>CN(C=O)C>[CH3:20][C:7]1[C:8]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:9]([O:13][C:24]2[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=2)[C:10]2[C:5]([CH:6]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1ccc2c(O)c(-c3ccccc3)c(C)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(C)cc2c1
Temperature: 70 °C
Yield: 40.8 %

Procedure:
A solution of crude 3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenol (7) (1.83 g) in DMF (8 mL) was slowly added dropwise to an ice-water cooled suspension of NaH (60% dispersion in oil) (0.179 g, 4.48 mmol) in DMF (8 mL) with stirring under N2. The ice-water bath was removed and the reaction mixture was allowed to stir at RT for 10 min. To the reaction mixture was added a solution of 4-fluorobenzaldehyde (0.9 mL, 1.04 g, 8.39 mmol) in DMF (3 mL). The reaction mixture was heated at 70° C. for 18 h. The reaction mixture was partially concentrated and the crude product was partitioned between CH2Cl2 and H2O. The organic phase was separated, dried over MgSO4, filtered, and the filtrate was concentrated to give the crude title compound. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (9:1) to give 1.04 g (66%) of compound (8) as a yellow amorphous solid. 1H NMR (400 MHz; DMSO-d6): δ 2.19 (s, 3H), 3.88 (s, 3H), 6.78 (d, J=8.6 Hz, 2H), 7.09 (dd, J=2.6 Hz, 9.1 Hz, 1H), 7.19 (m, 2H), 7.24 (m, 1H), 7.30 (m, 2H), 7.38 (d, J=2.4 Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.70 (d, J=8.7 Hz, 2H), 7.75 (s, 1H), 9.78 (s, 1H). AP LRMS m/z 369 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[NH:5][C:4](=[O:13])[C:3]=1[C:14]#[N:15].[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]>>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[N:7][CH:8]=1)[NH:5][C:4](=[O:13])[C:3]([C:14]#[N:15])=[C:2]2[N:26]1[CH2:27][CH2:28][N:23]([C:21]([C:17]2[O:16][CH:20]=[CH:19][CH:18]=2)=[O:22])[CH2:24][CH2:25]1
Reactant: N#Cc1c(Cl)c2cc(Cl)cnc2[nH]c1=O
Reactant: O=C(c1ccco1)N1CCNCC1
Product: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(Cl)cnc2[nH]c1=O
Yield: 71 %

Procedure:
This compound was prepared from 4,6-dichloro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (97) and 2-furoyl piperazine according to general procedure E to yield 2.27 g (71%) of 6-chloro-2-oxo-4-[4-(furan-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (101) as yellow solids. MP 303° C.; 1H-NMR (DMSO-d6): δ 3.76 (m, 4H), 3.93 (m, 4H), 6.65 (dd, J=1.6, 3.6 Hz, 1H), 7.09 (d, J=3.6 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.66 (d, J=2.4 Hz, 1H), 12.36 (s, 1H); EIMS: 384 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][C:8]([F:11])([F:10])[F:9])[N:6]=1.[CH:12]1[C:25]2[CH:24]([C:26](Cl)=[O:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:17][C:16]=2[CH:15]=[CH:14][CH:13]=1>>[F:10][C:8]([F:9])([F:11])[CH2:7][N:5]1[N:4]=[N:3][C:2]([NH:1][C:26]([CH:24]2[C:25]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[C:23]2=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:27])=[N:6]1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Reactant: Nc1nnn(CC(F)(F)F)n1
Product: O=C(Nc1nnn(CC(F)(F)F)n1)C1c2ccccc2Oc2ccccc21

Procedure:
The title compound, white solid, m.p. 209-210 and MS: (neg. ions): m/e=374.1 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-(2,2,2-trifluoroethyl)-2H-tetrazole and 9H-xanthene-9-carbonyl chloride.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:23])[NH:18][CH2:19][C:20]([OH:22])=O)[CH:12]=[C:13]([Cl:15])[CH:14]=1.Cl.[CH:25]([N:28]=[C:29]=[O:30])([CH3:27])[CH3:26]>ClC1C=CC=CC=1>[CH:25]([NH:28][C:29]([N:18]1[CH2:19][C:20](=[O:22])[N:16]([C:11]2[CH:12]=[C:13]([Cl:15])[CH:14]=[C:9]([Cl:8])[CH:10]=2)[C:17]1=[O:23])=[O:30])([CH3:27])[CH3:26]
Reactant: O=C(O)CNC(=O)Nc1cc(Cl)cc(Cl)c1
Reactant: CC(C)N=C=O
Agent: Cl
Solvent: Clc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)N1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 100.6 %

Procedure:
101 g of triethylamine are added to a suspension of 263 g of 2-[3-(3,5-dichlorophenyl)-ureido]-acetic acid in 2,000 cm3 of chlorobenzene and 300 g of isopropyl isocyanate, which has been heated to 50° C, and the mixture is stirred for 4 hours at 80°-90°. After cooling, the reaction mixture is stirred for 30 minutes with 500 cm3 of a 7% strength (weight/volume) aqueous solution of hydrochloric acid. The organic solution is decanted, dried and concentrated under reduced pressure. 332 g of 1-isopropylcarbamoyl-3-(3,5-dichlorophenyl)-hydantoin melting at 130° C are thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([N:10]([CH2:14][CH3:15])[CH2:11][CH2:12]O)[CH3:9].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[CH2:8]([N:10]([CH2:14][CH3:15])[CH2:11][CH2:12][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:9]
Reactant: Nc1ccccc1
Reactant: CCN(CC)CCO
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: CCN(CC)CCNc1ccccc1
Yield: 75 %

Procedure:
93 parts of aniline, 180 parts of 2-diethylaminoethanol and 10 parts of triphenyl phosphite are heated for 20 hours at 210° C in a stirred autoclave. The autoclave is then let down and the water of reaction formed, the excess aniline and the unconverted aminoalcohol are distilled under reduced pressure. 144 parts of N-(β-diethylaminoethyl)-aniline, corresponding to a yield of 75% of theory, distil at a boiling point of 185° - 187° C/15 mm Hg.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:50]=[CH:49][CH:48]=[CH:47][C:14]=1[C:15]([NH:17][C:18]1[CH:44]=[CH:43][C:21]([C:22]([N:24]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=2)[CH3:25])=[O:23])=[CH:20][C:19]=1[O:45][CH3:46])=[O:16])=O)(C)(C)C.C[Sn]([N:55]=[N+:56]=[N-:57])(C)C.Cl.[Sn].N1C=NN=N1.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:50]=[CH:49][CH:48]=[CH:47][C:14]=1[C:15]([NH:17][C:18]1[CH:44]=[CH:43][C:21]([C:22]([N:24]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=2[O:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[NH:42][N:57]=[N:56][N:55]=3)=[CH:39][CH:40]=2)[CH3:25])=[O:23])=[CH:20][C:19]=1[O:45][CH3:46])=[O:16]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCc2ccc(C#N)cc2)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCc2ccc(-c3nnn[nH]3)cc2)ccc1NC(=O)c1ccccc1OCCCN
Temperature: 120 °C
Reaction time: 72 h
Yield: 68.8 %

Procedure:
To a solution of 4-[2-[3-(tert-butoxycarbonyl)aminoprop-1-yl]oxybenzoyl]amino-3-methoxy-N-[2-(4-cyanophenylmethyl)oxy-4-methylphenyl]-N-methylbenzamide (360 mg) in xylene (8 ml) was added trimethyltin azide (218 mg) and the solution was stirred at 120° C. for 3 days. The solution was cooled to ambient temperature and 12N hydrochloric acid (10 ml) was added to the solution to decompose tin salt of the tetrazole compound and the excess reagent. Then the solution was adjusted to pH 7 with saturated aqueous sodium hydroxide at 0° C., and the solution was extracted with ethyl acetate (50 ml×3). The organic layer was washed with brine, and dried over magnesium sulfate. The solvent was evaporated to give a crude product. The crude product was purified by silica gel column chromatography (SiO2 30 g, 2-25% methanol in chloroform) to give 4-[2-(3-aminoprop-1-yl)oxybenzoyl]amino-3-methoxy-N-[2-[4-(tetrazol-5-yl)phenylmethyl]oxy-4-methylphenyl]-N-methylbenzamide (227 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=[O:13])[C:10]=1[F:11])[N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=[O:13])[C:10]=1[F:11])[NH:7][CH2:6][CH2:5]2
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Br)c(F)c(C(=O)O)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1c(F)c(Br)cc2c1NCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
To a stirred solution of 5-bromo-1-{[(1,1-dimethylethyl)oxy]carbonyl}-6-fluoro-2,3-dihydro-1H-indole-7-carboxylic acid (8.3 g, 0.023 mol) in DCM (90 mL) was added TFA (90 mL). The reaction mixture was stirred at room temperature for 3 h and then concentrated. The residue was partitioned between EtOAc (100 mL) and water (100 mL), and the aqueous fraction was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (1×50 mL) and brine (1×50 mL). dried (Na2SO4) and concentrated under reduced pressure, giving 5.9 g (99%) of the title compound.
Reaction SMILES: [H-].[Na+].[N:3]1[NH:4][N:5]=[N:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([C:36]([F:39])([F:38])[F:37])=[O:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.Cl>CN(C)C=O.O>[F:39][C:36]([F:37])([F:38])[S:34]([C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][C:7]4[N:6]=[N:5][NH:4][N:3]=4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1)=[O:35]
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Reactant: Oc1ccc(CCCCc2nn[nH]n2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(c1ccc(/C=C/c2nc(COc3ccc(CCCCc4nn[nH]n4)cc3)co2)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 16.9 %

Procedure:
47.5 mg (1.88 mmol) 95% sodium hydride were given at 0° C. to a solution of 200 mg (0.916 mmol) 4-(4-2H-tetrazol-5-yl-butyl)-phenol in 5.0 ml N,N-dimethylformamide and stirred for 15 min. 308 mg (0.916 mmol) 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole were added and stirring continued at 25° C. for 2 h. The reaction mixture was neutralized with HCl, poured into water and the resulting precipitate washed with little methanol and diethyl ether. The obtained material (180 mg) was purified by chromatography on silica gel (dichloromethane/methanol 100:4) to give 80 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][Mg+].[Br-]>C1COCC1>[Cl:1][C:2]1[C:11]([CH:12]([OH:13])[CH3:15])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[Mg+]
Reactant: O=Cc1cc2ccc(F)cc2nc1Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)c1cc2ccc(F)cc2nc1Cl
Reaction time: 8 h

Procedure:
A suspension of 2-chloro-7-fluoroquinoline-3-carbaldehyde (44.7 g, 213 mmol) in THF (600 mL) was treated with MeMgBr (78.0 mL, 234 mmol 1.1 eq) at −20° C. After stirring overnight, the reaction was quenched with NH4Cl solution and extracted with Et2O (300 mL and 100 mL). The organic layers were washed with water, brine, dried over Na2SO4, concentrated and recrystallized from EtOAc (100 mL) and hexane (1 L). A pale yellow solid of 1-(2-chloro-7-fluoroquinolin-3-yl)-ethanol was obtained (41 g, 85%). Mass Spectrum (ESI) m/e=226 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]12[CH2:13][CH2:12][C:9]([C:14]3[NH:22][C:21]4[C:20](=[S:23])[NH:19][C:18](=[O:24])[N:17]([CH2:25][CH2:26][CH3:27])[C:16]=4[N:15]=3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2.[OH-].[Na+].[CH3:31]I>CCO.O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]12[CH2:7][CH2:8][C:9]([C:14]3[NH:22][C:21]4[C:20]([S:23][CH3:31])=[N:19][C:18](=[O:24])[N:17]([CH2:25][CH2:26][CH3:27])[C:16]=4[N:15]=3)([CH2:10][CH2:11]1)[CH2:12][CH2:13]2
Reactant: CCCn1c(=O)[nH]c(=S)c2[nH]c(C34CCC(CCC(=O)OC)(CC3)CC4)nc21
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCn1c(=O)nc(SC)c2[nH]c(C34CCC(CCC(=O)OC)(CC3)CC4)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-[4-(2-Oxo-3-propyl-6-thioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionic acid methyl ester (100 mg) was dissolved in 2 mL of EtOH and 1 mL of H2O. NaOH (20 mg) was added as a solution in 1 mL of H2O, followed by MeI (23 uL, 1.5 eq). The resulting reaction mixture was stirred at rt for 30 min. It was then extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to afford 105 mg of the titled compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[CH:19]=[C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[N:21]=[CH:22][C:15]=2[N:14]([CH3:31])[C:13]1=[O:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[Cl:41][C:42]1[CH:49]=[CH:48][C:45]([CH:46]=[O:47])=[CH:44][CH:43]=1>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:46]([C:45]3[CH:48]=[CH:49][C:42]([Cl:41])=[CH:43][CH:44]=3)[OH:47])=[C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[N:21]=[CH:22][C:15]=2[N:14]([CH3:31])[C:13]1=[O:32])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2cc(Oc3cccc(Cl)c3)ncc21
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cccc(Cl)c3)ncc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 28.8 %

Procedure:
To a solution of 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-(3-chlorophenoxy)-1-methyl pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (150 mg, 0.315 mmol) in THF (4 mL) at −78° C. was added LDA (2.0 M in THF, 0.79 mL, 1.58 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then a solution of 4-chlorobenzaldehyde (88 mg, 0.625 mmol) in THF (1 mL) was added. The reaction was stirred at −78° C. for 30 min, quenched with aq. NH4Cl (3 mL) then diluted EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography PE/EA (2:1) to give 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-(3-chlorophenoxy)-5-((4-chlorophenyl)(hydroxy)methyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (56 mg, 29% yield) as a solid. LCMS: (M+-OH) 598 and TR=2.221 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C@H:13]1[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12]1)[N:7]=[C:6]2[C:19]1[CH:24]=[CH:23][C:22]([C:25]([O:27]C)=O)=[CH:21][CH:20]=1.[C-:29]#[N:30].[Na+]>CN.C(O)C>[CH3:29][NH:30][C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:6]2[C:5]3[C:14](=[CH:15][C:16]([O:17][CH3:18])=[C:3]([O:2][CH3:1])[CH:4]=3)[C@H:13]3[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12]3)[N:7]=2)=[CH:24][CH:23]=1)=[O:27]
Reactant: COC(=O)c1ccc(C2=N[C@H]3CCCC[C@H]3c3cc(OC)c(OC)cc32)cc1
Reactant: [C-]#N
Agent: CN
Agent: [Na+]
Solvent: CCO
Product: CNC(=O)c1ccc(C2=N[C@H]3CCCC[C@H]3c3cc(OC)c(OC)cc32)cc1

Procedure:
680 mg of (+/−)-cis-8,9-dimethoxy-6-[4-(methoxycarbonyl)phenyl]-1,2,3,4,4a,10b-hexahydrophenanthridine with 25 mg of sodium cyanide in 13 ml of 9 molar methylamine solution in ethanol are heated to 90° C. in an autoclave for 10 h. The solution is concentrated under reduced pressure and the residue is taken up in methylene chloride and extracted with water. The organic phase is dried with sodium sulfate, the solvent is removed under reduced pressure and the residue is treated with diethyl ether, filtered off with suction and dried. This gives 380 mg (56.1 % of Th.) of the title compound of m.p. 209-211° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5](O)=[O:6].P(Cl)(Cl)(Cl)(Cl)[Cl:13]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([Cl:13])=[O:6]
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: O=C(Cl)c1cc(Br)cc(Br)c1
Yield: 70.4 %

Procedure:
In a flask equipped with a reflux condenser, 84 g (0.3 mole) of 3,5-dibromobenzoic acid and 68 g (0.33 mole) of phosphorus pentachloride were reacted under reflux for one hour. After removal of phosphorus oxychloride under reduced pressure by means of an aspirator, the reaction product was subjected to vacuum distillation under 8 mm Hg to obtain 63 g of 3,5-dibromobenzoic acid chloride, melting at 125° to 130° C.; in the form of a colorless transparent liquid (yield: 70%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]3[C:16]([C:19]([O-:21])=O)=[CH:17][N:18]=[C:12]3[CH:11]=2)[CH2:3][CH2:2]1.[Li+].C(Cl)(=O)C(Cl)=O.[CH2:29]([N:36]1[C:44]2[CH:43]=[CH:42][CH:41]=[C:40]([NH2:45])[C:39]=2[CH:38]=[N:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:29]([N:36]1[C:44]2[C:39](=[C:40]([NH:45][C:19]([C:16]3[N:13]4[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:11][C:12]4=[N:18][CH:17]=3)=[O:21])[CH:41]=[CH:42][CH:43]=2)[CH:38]=[N:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Nc1cccc2c1cnn2Cc1ccccc1
Reactant: O=C([O-])c1cnc2cc(OCCN3CCOCC3)ccn12
Agent: O=C(Cl)C(=O)Cl
Agent: [Li+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2c1cnn2Cc1ccccc1)c1cnc2cc(OCCN3CCOCC3)ccn12
Yield: 12.2 %

Procedure:
To a suspension of lithium 7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxylate (42 mg, 0.142 mmol) in DCM were added oxalyl chloride (1.1 equivalents) and a drop of DMF. The mixture was stirred until gas evolution stopped. To the reaction mixture were then added 1-benzyl-1H-indazol-4-amine (31.6 mg, 0.142 mmol) and Hunig's base (1.2 equivalents). The reaction was stirred at ambient temperature for two hours and then concentrated. The residue was triturated with diethyl ether followed by chromatographic purification on silica with 10% MeOH/DCM as eluent to provide 8.6 mg of the desired product as a white solid. MS (ES+APCI) m/z=497 (M+H) detected.