Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1N=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5](=[O:8])[NH:6][CH:7]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[CH:15]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]cc(Br)nc1N1CCOCC1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: O=c1[nH]cc(Br)cc1N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of 5-bromo-3-morpholinopyrazin-2(1H)-one (1.0 equiv.) in DMF (0.1 M) was added potassium carbonate (2.0 equiv.) and iodomethane (1.0 equiv.) at 0° C. and the solution was allowed to warm to room temperature and stirred for 2 hours. Upon completion, the reaction was partitioned between water and ethyl acetate, the organic phase was washed with brine, dried with sodium sulfate, filtered and concentrated. The crude material was used for the next step without further purification. Isolated 5-bromo-1-methyl-3-morpholinopyrazin-2(1H)-one in 91% yield. LCMS m/z (M+H)=274/276, Rt=0.60 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 3.42 (s, 3H) 3.66-3.83 (m, 4H) 3.85-4.00 (m, 4H), 6.77 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:14]=[N:15][N:16]4[C:21]([NH2:22])=[C:20]5[CH2:23][NH:24][CH2:25][C:19]5=[N:18][C:17]=34)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](O)(=[O:30])[C@@H:27]([CH3:29])[OH:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:22][C:21]1[N:16]2[N:15]=[CH:14][C:13]([C:10]3[CH:11]=[N:12][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)=[C:17]2[N:18]=[C:19]2[CH2:25][N:24]([C:26](=[O:30])[C@H:27]([OH:28])[CH3:29])[CH2:23][C:20]=12
Reactant: C[C@@H](O)C(=O)O
Reactant: Nc1c2c(nc3c(-c4ccc(-c5ccccc5)nc4)cnn13)CNC2
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C[C@@H](O)C(=O)N1Cc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of crude 3-(6-phenylpyridin-3-yl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidin-8-amine (0.28 mmol), D-(−)-lactic acid (33.6 mg, 0.37 mmol), EDC (109.7 mg, 0.57 mmol), HOBt (77.6 mg, 0.57 mmol) and DIEA (299.7 uL, 1.72 mmol) in DMF (4 mL) was stirred at room temperature overnight. Purification with prep-LC provided (R)-1-(8-amino-3-(6-phenylpyridin-3-yl)-5H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidin-6(7H)-yl)-2-hydroxypropan-1-one: LCMS tR=2.65 Min (10 min run, UV254nm), Mass calculated for, M+400.1, observed LC/MS m/z 401.1 (M+H).
Reaction SMILES: [C:1]([NH:9][C@@H:10]1[C:16](=[O:17])[N:15]2[C@H:18](C(O)=O)[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:25])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:30]([NH:32][CH:33]([C:42](=[O:53])[CH2:43][O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[Cl:52])[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:31])C=C.C(NC1C(=O)N2C(C(NC(C(=O)CSCC3C=CC=CC=3Cl)CC(OC(C)(C)C)=O)=O)CCCN2C(=O)CC1)(=O)C1C=CC=CC=1>>[C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:30]([NH:32][CH:33]([C:42](=[O:53])[CH2:43][O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[Cl:52])[CH2:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[O:31])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:25])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(=O)COCc1ccccc1Cl
Reactant: O=C(N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)O)N2C1=O)c1ccccc1
Agent: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(=O)CSCc1ccccc1Cl
Product: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(=O)COCc1ccccc1Cl
Yield: 23 %

Procedure:
was prepared from acid 212e and (3S) t-butyl N-(allyloxycarbonyl)-3-amino-5-(2-chorophenylmethyloxy)-4-oxopentanoate (201) using a method similar to that used for compound 224e, to afford 40 mg (23%) of a glassy solid: 1H NMR (CDCl3) δ7.83-7.73 (2H, m), 7.67-7.10 (9H, m), 5.23-5.09 (2H, m), 4.59 (1H, m), 4.45-4.22 (2H, m), 3.7-3.19, 3.08-2.72, 2.71-2.47, 2.05-1.85, 1.72-1.61, 1.45-1.26 (20H, 6 m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=[N:19][C:18]1[CH:20]=[CH:21][C:15]([Br:14])=[CH:16][CH:17]=1
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: Nc1ccc(Br)cc1
Solvent: CO
Product: COc1cc(C=Nc2ccc(Br)cc2)cc(OC)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
3,5-Dimethoxy-4-hydroxybenzaldehyde (1 g, 5.46 mmol) was dissolved in methanol (50 ml) and 4-bromoaniline (939 mg, 5.46 mmol) was added. The resultant reaction solution was stirred overnight at room temperature under nitrogen to give a precipitate that was collected by filtration to yield light yellow fine crystals (860 mg) of the title product: 1H NMR (300 MHz, CDCl3); δ 8.30 (S, 1H) , 7.49 (d, J=9 Hz, 2H) , 7.16 (S, 2H), 7.07 (d, J=9 Hz, 2H), 5.86 (S, 1H), 3.98 (S, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](=O)[CH2:8][C:9](=O)[C:10]([F:14])([F:13])[CH2:11][CH3:12])[O:5][CH:6]=1.[C:17]([CH2:19][C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31])=[O:21])#[N:18].CCCCCCC=CCCC>C1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:7]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[C:20](=[O:21])[C:19]([C:17]#[N:18])=[C:9]([C:10]([F:14])([F:13])[CH2:11][CH3:12])[CH:8]=2)[O:5][CH:6]=1
Reactant: CCC(F)(F)C(=O)CC(=O)c1cc(Br)co1
Reactant: N#CCC(=O)NCc1ccc(F)cc1F
Agent: CCCC=CCCCCCC
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCC(F)(F)c1cc(-c2cc(Br)co2)n(Cc2ccc(F)cc2F)c(=O)c1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.4 %

Procedure:
To a solution of 1-(4-bromo-furan-2-yl)-4,4-difluoro-hexane-1,3-dione (220 mg, 0.75 mmol), and 2-cyano-N-(2,4-difluoro-benzyl)-acetamide (300 mg, 1.4 mmol) in benzene (4 mL) was added 1,8-diaza-bicycle-[5.4.0]-undec-7-ene (60 μL, 0.4 mmol). The red reaction mixture was then heated to reflux. After 3 hours, heating was discontinued and the reaction was allowed to cool to ambient temperature. After stirring at ambient temperature for 16 hours the reaction mixture was diluted with CH2Cl2 and purified by adsorbing the material onto silica gel, loading the resulting solid onto the column and eluting with a gradient from 0% to 30% ethyl acetate/hexane to afford 6-(4-bromo-furan-2-yl)-1-(2,4-difluoro-benzyl)-4-(1,1-difluoro-propyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (188 mg, 54% yield) as a yellow oil. 1H-NMR (400 MHz, CDCl3): δ 7.62 (1H, s), 7.1-7.03 (1H, m), 6.86-6.78 (2H, m), 6.76 (1H, s), 6.64 (1H, s), 5.46 (2H, s), 2.31 (2H, t of q, JH-H=7.6 Hz, JH-F=16.9 Hz), 1.11 (3H, t, J=7.6 Hz).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:10]=1.[OH-].[Na+].C(OCC)(=O)C>C(#N)C>[Br:1][C:14]1[N:9]=[CH:10][C:11]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:12][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccnc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)nc2)CC1
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
2.70 g (15.19 mmol) of N-bromosuccinimide (NBS) are added portionwise to a solution of 4 g (15.19 mmol) of 1,1-dimethylethyl 4-(3-pyridyl)-1-piperazinecarboxylate, obtained in step 7.1., in 50 ml of acetonitrile, cooled to about 0° C. Stirring is continued at 0° C. for 15 minutes and then at room temperature for 2 hours. 100 ml of aqueous sodium hydroxide solution (1M) and 100 ml of ethyl acetate are added to the reaction medium. The aqueous phase is separated out and extracted twice with ethyl acetate, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. 5.16 g of product are thus obtained in the form of an orange-yellow solid, and are used without further purification in the following step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1>C(O)C>[CH3:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CN1CCN(CCCN)CC1
Solvent: CCO
Product: CN1CCN(CCCNc2ncccc2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
In a two liter, three-necked flask fitted with condenser, dropping funnel, thermometer, magnetic stirrer and nitrogen inlet was placed 71.8 g. (0.456 mole) 1-(3-aminopropyl)-4-methyl piperazine and 150 ml. of ethanol. The solution was heated at reflux and a solution of 65.0 g. 2-chloro-3-nitropyridine dissolved in 500 ml. of warm ethanol was added dropwise over 90 minutes. The dark yellow reaction mixture was maintained at reflux of an additional hour then cooled to ambient temperature. The solvent was then removed in vacuo to obtain a yellow-brown semi-solid residue. The residue was partitioned between 200 ml. each of aqueous 1N HCl and methylene chloride, and aqueous phase washed with 100 ml. CH2Cl2. The aqueous portion was made basic with 6N NaOH and extracted with 3 × 250 ml. CH2Cl2. The combined organic layers were dried over Na2SO4 and the solvent evaporated to afford 2-[3-(4-methyl-1-piperazinyl)-propylamino]-3-nitropyridine as a red-yellow oil which crystallized on standing at room temperature; yield 82.9 g. (72%).
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.CN(C)C=O.[CH3:16][O:17][CH2:18][CH2:19][O:20][C:21](Cl)=[O:22]>C(N(CC)CC)C>[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][C:21]([O:20][CH2:19][CH2:18][O:17][CH3:16])=[O:22])[CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: COCCOC(=O)Cl
Reactant: Nc1cc(Cl)nc(N)[n+]1[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCOC(=O)Nc1cc(Cl)nc(N)[n+]1[O-]

Procedure:
5 G. of 2,4-diamino-6-chloropyrimidine-3-oxide are suspended in 50 ml. of dimethylformamide and 5 ml. of triethylamine and cooled to 0° C. while stirring. 4.3 G. of chloroformic acid 2-methoxyethyl ester are added dropwise to the cold suspension in the course of 15 minutes. The mixture is cooled for 2 hours and then stirred at room temperature for 16 hours. The solvent is distilled off at 25° C. in a high vacuum and the residue is digested with methylene chloride. The precipitate obtained is filtered off and washed with methylene chloride, methanol and water. The filtrate is washed with water and dried over sodium sulfate. By concentrating the solvent, there is obtained pure 2-methoxyethyl 2-amino-6-chloro-4-pyrimidinecarbamate-3-oxide having a melting point of 176°-178° C. Additional material is obtained by subjecting the mother liquor to chromatographical separation on silica gel.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[O:3].[O:13]1[CH2:17][CH2:16][O:15][CH:14]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C@H:24]1[C@@H:27]([NH:28][C:29](=[O:38])[CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26](=[O:39])[NH:25]1.C(N(CC)CC)C>O1CCCC1>[OH:3][CH:2]([N:25]1[C:26](=[O:39])[C@H:27]([NH:28][C:29](=[O:38])[CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:24]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:14]1[O:13][CH2:17][CH2:16][O:15]1)[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: O=C(COc1ccccc1)N[C@H]1C(=O)N[C@H]1c1ccccc1C1OCCO1
Reactant: O=CC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(COc1ccccc1)N[C@H]1C(=O)N(C(O)C(=O)OCc2ccccc2)[C@H]1c1ccccc1C1OCCO1
Reaction time: 1.5 h

Procedure:
Freshly distilled benzyl glyoxylate (312 mg, 1.9 mmol) and freshly distilled tetrahydrofuran (15 ml) were stirred with 4A molecular sieves for one hour and then cooled in ice. To this solution was added the solid product from Example 5 (437 mg, 1.19 mmol) followed by the dropwise addition of triethylamine (240 mg, 2.37 mmol). The ice bath was removed and the reaction was stirred for 1.5 hours. The solution was filtered and the filtrate was evaporated to dryness. The residue was dissolved in chloroform and chromatographed on a silica gel column with a chloroform-ethyl acetate gradient as eluant to give the title product, 525 mg (83%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][C:10]=1[N+:21]([O-])=O)C1C=CC=CC=1>ClCCl.C(O)C.[Pd]>[NH2:21][C:10]1[CH:11]=[C:12]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: O=[N+]([O-])c1cc(N2CCOCC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Nc1cc(N2CCOCC2)ccc1O
Yield: 96 %

Procedure:
Catalytic hydrogenation of 4-(4-benzyloxy-3-nitro-phenyl)-morpholine (5 g, 16 mmol) in dichloromethane (500 ml) and ethanol (500 ml) using palladium on carbon (500 mg, 10%) afforded the title compound as a grey solid (96%), MS: m/e=194(M+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)(O)[O-].[Na+].Br[CH2:15][C:16](=O)[C:17]([O:19][CH3:20])=[O:18].O>C(#N)C>[Cl:1][C:2]1[C:3]2[N:4]([CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[N:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccnc1Cl
Reactant: COC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cn2ccnc(Cl)c2n1
Temperature: 80 °C
Yield: 70.7 %

Procedure:
To a solution of 3-chloropyrazin-2-amine (52 g, 401 mmol) in acetonitrile (750 mL) under N2 was added sodium bicarbonate (67.4 g, 803 mmol), and then methyl bromopyruvate (97 mL, 803 mmol). The mixture was then heated to 80° C. for 4 hours and then cooled to r.t. The reaction was then diluted water (2200 mL) and stirred for 30 minutes. The resulting solids were filtered, azeotroped with EtOAc (2 L), and dried overnight at 40° C. under vacuum and nitrogen sweep to give the title compound (60 g). LRMS (ESI) calc (M+H)+=212.0. found 212.0
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19](=[S:21])[NH2:20])=[CH:15]2)(=[O:8])=[O:7].Cl[CH2:23][C:24](=O)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(O)C.CN(C)C(=O)C>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:21][CH:23]=[C:24]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:20]=1)=[CH:15]2)(=[O:7])=[O:8]
Reactant: NC(=S)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)Cc1csc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
A mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.30 g), ethyl 4-chloro-3-oxobutyrate (0.22 g), ethanol (6 mL) and N,N-dimethylacetamide (6 mL) was stirred at 80° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.25 g, yield 63%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 161-162° C.
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3](O)=O.[NH2:14][C:15]1[C:23]([Br:24])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.Cl.[NH2:48]CCC(OCC)=O>N1C=CC=CC=1>[Br:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:16]2[C:15]=1[N:14]=[C:3]([C:2]([F:13])([F:1])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[N:48]=[C:17]2[OH:18]
Reactant: O=C(O)C(F)(F)c1ccc(F)cn1
Reactant: CCOC(=O)CCN
Reactant: Nc1c(Br)cccc1C(=O)O
Agent: Cl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: c1ccncc1
Product: Oc1nc(C(F)(F)c2ccc(F)cn2)nc2c(Br)cccc12
Temperature: 150 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
To 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetic acid from Example 33 step A (440 mg, 2.31 mmol) and 2-amino-3-bromobenzoic acid (0.5 g, 2.31 mmol) in pyridine (8 mL) was added triphenyl phosphite (0.667 mL, 2.54 mmol) and the mixture was heated in a microwave synthesizer at 150° C. for 10 min. The mixture was cooled to rt and then ethyl 3-aminopropanoate hydrochloride (396 mg, 2.54 mmol) was added and the mixture was heated in a microwave synthesizer at 180° C. for 3 min. The mixture was concentrated under reduced pressure. THF (10 mL) was added followed by sodium ethoxide (21% in EtOH, 3.2 mL) and the mixture was stirred at 50° C. for 2 h. An additional amount of sodium ethoxide (21% in EtOH, 1 mL) was added and the mixture stirred at 50° C. for 4 h. The mixture was allowed to cool and was partitioned between EtOAc and 1 N HCl. The organic layer was washed (3×) with 1 N HCl, dried over sodium sulfate, and concentrated under reduced pressure. The residue was triturated with DCM and collected by filtration to afford 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-ol (444 mg, 52%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.52 (t, J=7.91 Hz, 1H) 7.99-8.12 (m, 2H) 8.13-8.23 (m, 2H) 8.69 (d, J=2.45 Hz, 1H) 13.39 (br s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([O:17][CH3:18])=[C:5]([C:13]([O:15]C)=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].O[Li].O.O.CO>C(=O)(O)[O-].[Na+]>[C:1]([C:3]1[C:4]([O:17][CH3:18])=[C:5]([C:13]([OH:15])=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2]
Reactant: COC(=O)c1c(OC)c(C#N)cc2ccccc12
Agent: O=C([O-])O
Agent: [Li]O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c(C#N)cc2ccccc2c1C(=O)O

Procedure:
A solution of methyl 3-cyano-2-methoxy-1-naphthoate (0.113 g) and LiOH·H2O (0.0196 g) THF (3 mL), water (1 mL) and methanol (1 mL) was stirred overnight at room temperature. The solution was diluted with saturated sodium bicarbonate and extracted with Et2O. The aqueous layer was acidified to pH 2 by addition of 1N HCl and extracted with Et2O. The organic layer was washed with water (30 mL) and brine (40 mL), dried (sodium sulfate), filtered, and concentrated to a white solid. 1H NMR (DMSO-d6): δ 14.06 (broad, 1 H), 8.08-8.02 (m, 1 H), 7.83-7.76 (m, 2H), 7.69-7.63 (m, 1 H), 4.02 (s, 3 H); MS m/z: 226 (M−1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]=[C:8]1[C:14]2[CH:15]=[CH:16][C:17]([CH:19]([CH3:23])[C:20](O)=[O:21])=[CH:18][C:13]=2[CH:12]=[CH:11][C:10]2[CH:24]=[CH:25][CH:26]=[CH:27][C:9]1=2>CCOCC>[O:7]=[C:8]1[C:14]2[CH:15]=[CH:16][C:17]([CH:19]([CH3:23])[CH2:20][OH:21])=[CH:18][C:13]=2[CH:12]=[CH:11][C:10]2[CH:24]=[CH:25][CH:26]=[CH:27][C:9]1=2
Reactant: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(CO)c1ccc2c(=O)c3ccccc3ccc2c1
Reaction time: 2 h

Procedure:
0.5 G. of lithium aluminum hydride is added to a solution of 2.78 g. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid in 200 ml. of anhydrous ether. The mixture is stirred for 2 hours and then excess hydride is destroyed by sequential addition of ethyl acetate, methanol and water. The ethereal solution is separated and filtered and to it is added 15 g. of activated manganese dioxide. The mixture is stirred for 8 hours, then filtered through 10 g. of silica gel and the eluate evaporated to afford 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propan-1-ol (m.p. 63°-66°C).
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:55]([CH:63]1[C:70]2[CH:69]=[C:68]([C:71]([O:73]C)=[O:72])[NH:67][C:66]=2[CH2:65][CH2:64]1)[CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>C(#N)C.O>[Br:1][C:69]1[C:70]2[CH:63]([CH2:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH2:64][CH2:65][C:66]=2[NH:67][C:68]=1[C:71]([OH:73])=[O:72]
Reactant: COC(=O)c1cc2c([nH]1)CCC2CCc1ccccc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: O
Product: O=C(O)c1[nH]c2c(c1Br)C(CCc1ccccc1)CC2
Reaction time: 8 h

Procedure:
Tetrabutylammonium tribromide (114 mg, 0.24 mmol) was added to a solution of methyl 4-phenethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (53 mg, 0.2 mmol) in 5 mL of acetonitrile at room temperature. After reacting overnight, the reaction was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated with silica gel. Purification by column chromatography (Isco CombiFlash) eluting with a gradient of 0-30% EtOAc/heptane gave the title compound. 54.2 mg. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.69-1.80 (m, 1H), 2.10-2.22 (m, 2H), 2.56-2.71 (m, 4H), 2.72-2.83 (m, 1H), 3.00-3.09 (m, 1H), 3.80 (s, 3H), 7.11-7.16 (m, 1H), 7.17-7.21 (m, 2H), 7.22-7.27 (m, 2H); LCMS-MS (ESI+) 372.0 (M+Na).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([NH2:11])[CH2:3][CH2:2]1.[CH3:12][CH2:13][O:14]C(C)=O.[NH4+].[OH-]>C(Cl)Cl.CO>[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[C@H:4]([NH:11][C:13](=[O:14])[CH3:12])[CH2:3][CH2:2]1
Reactant: NC1CCOc2cccnc21
Reactant: CCOC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N[C@@H]1CCOc2cccnc21
Reaction time: 2 h

Procedure:
Following the general procedure, 3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-ylamine (243 mg, 1.62 mmol), CALB (73 mg) and EtOAc (6.0 mL) were stirred for 2 hours. The conversion determined from 1H NMR by integration of the peaks at 7.93 ppm and 8.16 ppm was 50% (CHNH2 and CHNHAc signals were not distinct). Flash chromatography of the material on silica gel using 1:10 MeOH:CH2Cl2 followed by 1:1:10 NH4OH:MeOH:CH2Cl2 furnished the (R)-N-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)acetamide ((145 mg, 47%) in 98% ee (chiral GC method: 140° C. for 16 min, ramp rate 5° C./min to 160° C., hold at 160° C. for 50 min, (S)-enantiomorrt=41.5 min, (R)-enantiomerrt=40.9 min); [α]D=−69° (c 1.45, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 1.91-2.00 (m, 1H), 1.97 (s, 3H), 2.47-2.57 (m, 1H), 4.18-4.22 (m, 2H), 4.85-4.92 (m, 1H), 6.97 (m, 2H), 7.24 (br s, 1H), 7.93-7.95 (dd, 1H, J=1.8, 3.9 Hz); 13C NMR (CDCl3) δ 23.3, 28.9,47.2, 64.4, 124.3, 124.7, 141.3, 141.7, 152.0, 170.9; MS m/z: 215 (M+Na+). The unreacted (S)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-ylamine (was isolated in 43% yield (104 mg) and 99% ee ((S)-enantiomerrt=14.7 min, (R)-enantiomerrt=15.6 min); [α]D=−13° (c 0.72, CHCl3); 1H NMR (CDCl3, 300 MHz): δ 1.84 (br s, 2H), 1.90-2.01 (m, 1H), 2.24-2.34 (m, 1H), 4.12 (dd, 1H, J=5.7, 6.9 Hz), 4.18-4.26 (m, 1H), 4.28-4.36 (m, 1H), 7.06-7.13 (m, 2H), 8.15 (dd, 1H, J=1.8, 3.6 Hz); 13C NMR (CDCl3) δ 31.5, 47.8, 64.2, 123.8, 124.5, 142.1, 147.0, 151.1; MS m/z: 151.0 (M+H+), 134.0 (M−NH2); Anal. Calc. for C8H10N2O.0.1H2O: C; 63.22; H, 6.76; N, 18.43. Found: C, 62.99; H, 6.81; N, 18.22.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][NH2:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][NH:12][C:13](=[O:15])[CH3:14])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(CN)c[nH]c2c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCc1c[nH]c2cc(C)ccc12
Reaction time: 0.33 h

Procedure:
To a solution of C-(6-methyl-1H-indol-3-yl)-methylamine (0.24 g) in dichloromethane (4 ml) was added acetic anhydride (0.14 ml) and pyridine (0.13 ml) and stirring was continued at 22° C. for 20 min. The mixture was washed with aqueous HCl (1N), the organic layer was dried and evaporated. The residue was chromatographed on silica using dichloromethane/methanol (70:1) to give N-(6-methyl-1H-indol-3-ylmethyl)-acetamide as colorless foam (0.15 g). MS: 203.1 ([M+H]+).