Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=1>>[Br:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Br
Reactant: Cc1cccc(Br)n1
Product: Cc1cccc(-c2cc(C)c(Br)c(C)c2)n1

Procedure:
The title compound is prepared from 2-bromo-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-bromo-6-methyl-pyridine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 7): tR=0.88 min; Mass spectrum (ESI+): m/z=276/278 (Br) [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH3:6])[OH:4])[CH3:2].[C:7]1([N:13]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]2=[O:19])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([N:13]2[C:17](=[O:18])[CH2:16][CH:15]([O:4][N:3]([CH2:5][CH3:6])[CH2:1][CH3:2])[C:14]2=[O:19])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCN(O)CC
Reactant: O=C1C=CC(=O)N1c1ccccc1
Product: CCN(CC)OC1CC(=O)N(c2ccccc2)C1=O

Procedure:
The procedure of Example 1 is repeated using 4.46 g (50 mmole) of N,N-diethylhydroxylamine and 8.66 g (50 mmole) of N-phenylmaleimide.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].CN(C)C=O.[H-].[Na+]>O.C(OCC)(=O)C>[CH3:33][C:32]([CH3:35])([CH3:34])[C:31](=[O:36])[CH2:30][N:9]1[C:10](=[O:11])[C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[S:28][C:6]=2[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[C:8]1=[O:12]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)C(C)(C)C)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 1-bromo-3,3-dimethylbutan-2-one (0.52 mL) and N,N-dimethylformamide (8 mL) was added 60% sodium hydride (0.16 g), and the mixture was stirred at room temperature for 24 hr. To the reaction mixture was added ethyl acetate and water, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.76 g, 61%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:32].[CH2:33]([N:35]([CH2:40][CH3:41])[CH2:36][CH2:37][CH2:38][NH2:39])[CH3:34]>ClCCl>[CH2:33]([N:35]([CH2:40][CH3:41])[CH2:36][CH2:37][CH2:38][NH:39][C:16]1[N:17]=[C:18]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[CH3:28])[C:22]([OH:24])=[O:23])[C:13]2[CH:12]=[CH:11][C:10](=[O:32])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1)[CH3:34]
Reactant: CCN(CC)CCCN
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: ClCCl
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (600 mg, 1.32 mmol) in dichloromethane (30 mL) was added N,N-diethyl-1,3-propanediamine (0.624 mL, 4.0 mol). The mixture was stirred at room temperature overnight. Solvent was removed by rotovap. Separation by HPLC with TFA afforded the title compound (695 mg, 85%). LC-MS m/z 522 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([S:18]Cl)[CH:14]=[CH:15][C:16]=1[Cl:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([S:18][C:5]2[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: COC(=O)c1cc[nH]c1
Reactant: ClSc1ccc(Cl)c(Cl)c1
Product: COC(=O)c1c[nH]c(Sc2ccc(Cl)c(Cl)c2)c1
Yield: 104.2 %

Procedure:
By the procedure of Example 23, methyl pyrrole-3-carboxylate (2.5 g., 20 mmoles) was reacted with 3,4-dichlorobenzenesulfenyl chloride (4.24 g., 20 mmoles) to yield crude product (6.3 g., oil). The crude was chromatographed on 250 g. of silica gel, with 125 ml. fractions of the ethyl acetate-1/hexane-5/5% acetic acid eluant collected. Fractions 2 to 6 were combined and evaporated to dryness to afford purified methyl 5-(3,4-dichlorophenylthio)pyrrole-3-carboxylate (2.76 g., m.p. 93°-96° C.).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][C:15]=1[N:24]1[N+:28]([O-])=[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]2=[N:25]1.C1C2C(=O)C3C(=CC=CC=3)CC=2C=CC=1.S(=O)(=O)(O)O>C1C2C(=O)C3C(=CC=CC=3)C=2C=CC=1>[OH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][C:15]=1[N:24]1[N:28]=[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]2=[N:25]1
Reactant: CC(C)(C)c1ccc(O)c(-n2nc3ccccc3[n+]2[O-])c1
Agent: O=C1c2ccccc2-c2ccccc21
Agent: O=C1c2ccccc2Cc2ccccc21
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CC(C)(C)c1ccc(O)c(-n2nc3ccccc3n2)c1
Reaction time: 6 h

Procedure:
9-fluorenone 0.7 g was then added to the reaction liquor thus obtained, and the liquor was heated to 55°~60° C. Thereafter, glucose 6.0 g was added to the reaction liquor over 30 minutes, and the reaction was conducted at 75° C. (boiling point) for 6 hours. As this result, the N-oxide disappeared, thus Process (c) being completed. Thereafter, pH of the reaction liquor was made to 8 with 62% sulfuric acid 19.0 g to precipitate a crystal. The precipitated crystal was separated by filtration, and the separated crystal was fully washed with water and further with methanol. The washed crystal was then dried, thus obtaining 11.6 g of 2-(2'-hydroxy-5'-t-butylphenyl)benzotriazole.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[CH:4][N:3]=1.[C:11]1([NH2:18])[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1>CN1CCCC1=O.O>[N+:8]([C:7]1[C:2]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([NH2:18])=[CH:12][CH:13]=2)=[N:3][CH:4]=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Nc1ccc(N)cc1
Reactant: O=[N+]([O-])c1cncnc1Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1ccc(Nc2ncncc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
A mixture of 4-chloro-5-nitropyrimidine (380 mg) and benzene-1,4-diamine (257 mg) in N-methylpyrrolidone (5 mL) was stirred overnight at ambient temperature. After this time, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated sodium bicarbonate (50 mL) then brine (50 mL), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 3:97 methanol/methylene chloride) to afford N-(5-nitropyrimidin-4-yl)benzene-1,4-diamine (260 mg) as a brown oil.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[C:5]=2[CH:6]=1.[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.ClCCl.O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:11][C:8]1([CH3:12])[C:7](=[O:13])[C:5]2[CH:6]=[C:2]([C:17]3[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=3)[S:3][C:4]=2[CH2:10][CH2:9]1
Reactant: CC1(C)CCc2sc(Br)cc2C1=O
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(C)CCc2sc(-c3ccncc3)cc2C1=O
Temperature: 120 °C
Reaction time: 16 h
Yield: 77.7 %

Procedure:
In a 100 ml round bottomed flask, were placed 2-bromo-5,5-dimethyl-6,7-dihydro-1-benzothiophen-4(5H)-one (550 mg, 2.1 mmol), pyridine-4-boronic acid (326 mg, 2.65 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, dichloromethane (96 mg, 0.12 mmol) and then suspended in 1,4-dioxane (30 mL, 400 mmol). To the mixture were added cesium carbonate (3.08 g, 9.45 mmol) and water (20 mL). The mixture was stirred for 16 h at 120° C. The mixture was allowed to cool to rt and then diluted with EtOAc (100 mL), which was washed with water (50 mL×2). The combined aqueous phase was extracted with EtOAc (50 mL×2). The combined organic phase was dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by pre-packed silica gel (40 g) column chromatography eluted with a 30% to 100% EtOAc/hexane to obtain title compound (420 mg, 77%) as a colorless crystalline solid. LCMS: (FA) ES+ 258; 1H NMR (400 MHz, d-chloroform) δ ppm 8.60 (dd, 2H), 7.77 (s, 1H), 7.43 (dd, 2H), 3.09 (t, 2H), 2.10 (t, 2H), 1.24 (s, 6H).
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([S:8][C:9]1[C:10]([S:17]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])=[O:18])=[C:11]([C:14]([OH:16])=[O:15])[S:12][CH:13]=1)[CH2:6][CH3:7].[CH3:25]O>>[CH2:5]([S:8][C:9]1[C:10]([S:17]([NH:20][C:21]([CH3:23])([CH3:22])[CH3:24])(=[O:19])=[O:18])=[C:11]([C:14]([O:16][CH3:25])=[O:15])[S:12][CH:13]=1)[CH2:6][CH3:7]
Reactant: CO
Reactant: CCCSc1csc(C(=O)O)c1S(=O)(=O)NC(C)(C)C
Solvent: O=S(Cl)Cl
Product: CCCSc1csc(C(=O)OC)c1S(=O)(=O)NC(C)(C)C
Temperature: -10 °C

Procedure:
Thionyl chloride (2.3 mL) was added dropwise to 110 mL methanol cooled to -10° C. Next 10.4 g 4-propylthio-3-(N-(1,1-dimethylethyl)aminosulfonyl)-2-thiophenecarboxylic acid was added in one portion. The solution was warmed to reflux for 6 hours, then cooled to -45° C., and the product precipitated in sufficiently pure form for the purposes of this invention; yield 8.45 g; m.p. 93°-98° C.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:35])[C@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](OC2C=CC([N+]([O-])=O)=CC=2)=[O:24])=[CH:18][CH:17]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:2]=[CH2:3].[C:36]([O:40][C:41]([NH:43][C@H:44]([C:49]([OH:51])=[O:50])[CH2:45][CH2:46][CH2:47][NH2:48])=[O:42])([CH3:39])([CH3:38])[CH3:37]>ClCCl>[CH2:1]([O:4][C:5](=[O:35])[C@@H:6]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([NH:48][CH2:47][CH2:46][CH2:45][C@@H:44]([C:49]([OH:51])=[O:50])[NH:43][C:41]([O:40][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:42])=[O:24])=[CH:18][CH:17]=1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)O
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Temperature: 75 °C

Procedure:
6.00 g (12.33 mmol) of the compound from example 1A was dissolved in 120 ml dichloromethane. 2.57 g (12.33 mmol) N2-(tert-Butoxycarbonyl)-L-ornithine was added. The reaction mixture was split into 6 portions. The portions were heated for 90 min in a sealed tube at 75° C. in a microwave synthesizer. The combined reaction mixture was extracted with approx. 100 ml saturated ammonium chloride solution. The aqueous phase was twice back extracted with approx. 30 ml dichloromethane each. The combined organic phases were extracted with approx. 50 ml brine and dried over sodium sulfate. The solvent was removed under reduced pressure. The raw product was dissolved in dichloromethane and chromatographed over approx. 600 ml silica gel. Solvents used were dichloromethane, dichloromethane/methanol 40/1 to dichloromethane/methanol 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 2.63 g (4.06 mmol, 33% of theory, 89% purity) of the desired product.
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:22]1[CH:26]=[C:25]([C:27]2[C:28]3[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:29]=3[N:30]=[CH:31][N:32]=2)[CH:24]=[N:23]1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH:7]1[CH2:19][O:20][CH3:21])#[N:2].[ClH:44]>O1CCOCC1>[ClH:44].[CH3:21][O:20][CH2:19][CH:7]1[CH2:8][NH:9][CH2:10][CH2:11][N:6]1[CH2:5][CH:4]([N:22]1[CH:26]=[C:25]([C:27]2[C:28]3[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:42])([CH3:41])[CH3:43])[C:29]=3[N:30]=[CH:31][N:32]=2)[CH:24]=[N:23]1)[CH2:3][C:1]#[N:2]
Reactant: COCC1CN(C(=O)OC(C)(C)C)CCN1CC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: Cl
Solvent: C1COCCO1
Product: COCC1CNCCN1CC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
A solution of tert-butyl 4-{3-cyano-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-(methoxymethyl)piperazine-1-carboxylate (91 mg, 0.10 mmol, as a mixture of diastereomers from Step 3) in 1,4-dioxane (0.6 mL) was treated with 4.0 M of hydrogen chloride in p-dioxane (0.50 mL, 2.0 mmol). After the mixture was stirred at RT for 80 min, solvent was removed in vacuo to afford product which was used without purification in Step 5. LCMS (M+H)+: 511.2.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]([NH:11][C:12]3[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=[C:16](Br)[CH:17]=3)=[N:9][CH:10]=2)[CH2:2]1.[C:21]([O:24][CH2:25][C:26]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=[CH:28][C:27]=1[N:41]1[CH2:53][CH2:52][N:44]2[C:45]3[CH2:46][CH2:47][CH2:48][CH2:49][C:50]=3[CH:51]=[C:43]2[C:42]1=[O:54])(=[O:23])[CH3:22].O1CCOCC1>C([O-])([O-])=O.[Na+].[Na+].COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([O:24][CH2:25][C:26]1[C:27]([N:41]2[CH2:53][CH2:52][N:44]3[C:45]4[CH2:46][CH2:47][CH2:48][CH2:49][C:50]=4[CH:51]=[C:43]3[C:42]2=[O:54])=[CH:28][CH:29]=[CH:30][C:31]=1[C:16]1[CH:17]=[C:12]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([CH:3]3[CH2:4][NH:1][CH2:2]3)=[CH:10][N:9]=2)[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=1)(=[O:23])[CH3:22]
Reactant: Cn1cc(Br)cc(Nc2ccc(C3CNC3)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CNC4)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 100 °C
Reaction time: 14 h
Yield: 37.5 %

Procedure:
In a 44-mL sealed tube equipped with a magnetic stirring bar were placed 3-(5-(azetidin-3-yl)pyridin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one 155n (60 mg, 0.18 mmol), 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a (110 mg, 0.23 mmol), Pd(PPh3)4 (21 mg, 0.0.18 mmol) in 2 N Na2CO3 (3 mL), DME (2 mL), and dioxane (3 mL). After the reaction mixture was stirred at 100° C. for 14 h., it was partitioned between dichloromethane (5 mL) and water (5 mL), and the organic phase was extracted with dichloromethane (5 mL×3). The combined organic phases were washed with water (5 mL×2) and brine (5 mL×1), dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography (dichloromethane:MeOH, 85:15) to give 40% (40 mg) of 2-(5-(5-(azetidin-3-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzyl acetate 151a as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12].C(O)(C(F)(F)F)=O.CC#N.O>C(O)C.[Pd]>[CH3:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: COc1cccc([N+](=O)[O-])c1C
Agent: [Pd]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cccc(N)c1C
Yield: 98 %

Procedure:
To a solution of 2-methyl-3-nitro anisole which is commercially available (2a1) (5.1 g 30.33 mmol; requires ˜30 min. to dissolve) in absolute ethanol (85 mL) was added 10% Pd/C catalyst (500 mg). The solution was hydrogenated under a hydrogen filled balloon at atmospheric pressure and room temperature for 19 hrs. The reaction mixture was filtered through a Celite pad, rinsed and evaporated to dryness to obtain the compound 2a2 as a deep mauve oil (4.1 g; 29.81 mmol; 98% yield). MS 137 (MH)+. Reverse Phase HPLC Homogeneity @ 220 nm (0.06% TFA; CH3CN; H2O): 99%.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40](OC)=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].Cl.O[C:48](C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)([C:52]1[N:53]=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:56]=1)C(C)C.C(N)(C)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>C1COCC1.O.CO>[OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]([NH:53][CH:52]([CH3:56])[CH3:48])=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Reaction time: 2 h

Procedure:
To a solution of methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (16.4 g) in THF (160 mL) was added methanol (35 mL) and 4N-NaOH (35 mL) at 60° C. The mixture was stirred for 2 h, neutralized with conc.HCl. The mixture was concentrated, diluted with water and extracted with ethyl acetate. The extract was concentrated to give crude mixture of 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid. To a solution of the crude mixture was added isopropylamine (3.95 mL), 1-hydroxybenzotriazole (5.33 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.67 g) and diisopropylethylamine (6.0 mL) under ice cooling. The mixture was stirred at room temperature for 14 h, diluted with water and extracted with ethyl acetate. The extract was washed with brine, concentrated. The residue was crystallized from ethyl acetate to give the titled compound (16.7 g) as a colorless powder.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:15]>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:15])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Solvent: c1ccccc1
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Yield: 104.3 %

Procedure:
10 g of p-acetyloxybenzoic acid was added to 45 ml of benzene, and 11.8 g of PCl5 was added little by little under stirring at room temperature. After 8.5 hours of heat-refluxing thereafter, the solvent was distilled off to obtain 11.5 g of p-acetyloxybenzoic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:31]([O:35][CH3:36])(=[O:34])[CH2:32]O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:32][C:31]([O:35][CH3:36])=[O:34])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Reactant: COC(=O)CO
Product: COC(=O)COC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and methyl glycolate according to Method E. 1H NMR (400 MHz, CDCl3) δ ppm 1.20-1.69 (m, 7H), 1.72-1.84 (m, 1H), 1.89-2.03 (m, 1H), 2.06-2.20 (m, 1H), 2.26-2.36 (m, 1H), 2.86-2.99 (m, 1H), 3.07-3.18 (m, 1H), 3.49 (ddd, J=13.70, 9.40, 4.83 Hz, 1H), 3.82 (s, 3H), 4.65 (dd, J=9.53, 5.50 Hz, 1H), 4.89 (s, 2H) 7.03 (dd, J=8.73, 2.01 Hz, 1H), 7.31 (d, J=1.88 Hz, 1H), 7.46 (d, J=8.86 Hz, 1H), 7.95-8.01 (m, 2H), 8.17 (d, J=8.86 Hz, 1H). ES-MS m/z 492 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[OH:24])[CH:19]=O.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[Cl:15][C:16]1[CH:17]=[C:18]([C:19]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:21]=[CH:22][C:23]=1[OH:24]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(O)c(Cl)c3)nc2c1
Yield: 30 %

Procedure:
2-(3-Chloro-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 3-chloro-4-hydroxybenzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(3-Chloro-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (75 mg, 30%) was isolated as a yellow solid. Selected data: MS (m/z): 333.03; MP 279-281° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:9]1[CH:10]=[C:11]([CH:15]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[NH:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[CH3:18])[CH:12]=[CH:13][CH:14]=1)#[N:8].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[NH2:8][CH2:7][C:9]1[CH:10]=[C:11]([CH:15]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[NH:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[CH3:18])[CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2cccc(C#N)c2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2cccc(CN)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
A solution of lithium aluminum hydride in tetrahydrofuran (1N, 15 ml) was added to a solution of N-[(3-cyanophenyl)-(4-methoxyphenyl)methyl]-N-[1-(3,4-difluorophenyl)ethyl]amine (1.65 g) [prepared as described in step (a) above] in anhydrous tetrahydrofuran (20 ml) in an ice bath. The mixture was stirred at ambient temperature for 4 hours. Sodium sulfate decahydrate (15 g) was added to the reaction mixture and the insoluble material was removed by filtration using a Celite (trade mark) filter aid. The filtrate was concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column using 20:1 by volume mixture of methylene chloride and methanol as the eluant, to afford a mixture of diastereoisomers of the title compound (1.59 g) as a yellow oil.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[C:7]([CH2:12][O:13]C3CCCCO3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>O1CCCC1>[OH:13][CH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[C:4]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:3]2[CH3:2]
Reactant: CCOC(=O)c1cc2c(COC3CCCCO3)cccc2n1C
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(CO)cccc2n1C
Temperature: 50 °C
Yield: 98.7 %

Procedure:
In a solvent mixture of 20 ml of 2N hydrochloric acid and 60 ml of tetrahydrofuran was dissolved 4.00 g (12.6 mmol) of ethyl 1-methyl-4-(2-tetrahydropyranyl)oxymethyl-2-indolecarboxylate. The solution was stirred at 50° C. for an hour. The reaction mixture was poured onto ice water and the aqueous layer was extracted three times with ethyl acetate. The combined extracts were washed with saturated sodium hydrogen-carbonate solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 2.90 g (99%) of ethyl 4-hydroxymethyl-1-methyl-2-indolecarboxylate.