Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][C:21]([C:24]2[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[N:25]=2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Ca+2].CN(C)C=O>C(OCC)(=O)C>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][C:18]4[CH:19]=[CH:20][C:21]([C:24]5[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[N:25]=5)=[CH:22][N:23]=4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(OC)nc(-c2ccc(Cl)nc2)n1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(OC)nc(-c2ccc(Oc3ccc4c(c3)CCN(C3CCC3)CC4)nc2)n1

Procedure:
3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (125 mg, 0.58 mmol), 2-(6-chloro-pyridin-3-yl)-4,6-dimethoxy-pyrimidine (145 mg, 0.58 mmol), calcium carbonate (720 mg, 2.2 mmol) and dimethylformamide (4 ml) were heated in a microwave reactor at 180° C. for 900 seconds at 300 W. The mixture was diluted with ethyl acetate, washed with water, then brine and dried over sodium sulphate. The residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.2:1.8:98) to afford the title product. MS (ES+) m/e 433 [M+H]+.
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1.CSC.B.CCN(C(C)C)C(C)C.II>C1COCC1.CO>[NH2:1][CH2:2][CH2:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CC(CC(N)=O)C1
Agent: B
Agent: II
Solvent: CSC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CCN)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
tert-Butyl 3-(2-amino-2-oxoethyl)azetidine-1-carboxylate (70 mg, 0.327 mmol) was dissolved in THF (2 mL) and cooled on an ice-bath. Borane dimethyl sulfide complex (0.41 mL, 2M in THF) was added dropwise, whereafter the mixture was refluxed for 6 h. The reaction mixture was allowed to attain rt and a mixture of DIPEA:MeOH (0.6 mL, 1:2) and iodine (166 mg, 0.654 mmol) was added. The mixture was stirred at rt overnight and then evaporated to dryness. Water (5 mL) and EtOAc (5 mL) were added to the residue an the two phases were separated. Saturated, aqueous NaHCO3 (1 mL) was added into the water phase, and it was extracted with EtOAc (5 mL×4). NaOH (1M, ca 1 mL) was added into the water phase and it was extracted with EtOAc (5 mL×2). The extracts were combined, dried (Na2SO4) and evaporated, and the residue was purified by using an ion exchange column (ISOLUTE PRS, 2 g/15 mL), eluting with MeOH and DCM (10:90), then MeOH and then MeOH (saturated with NH3) to give the title compound (35 mg, 53.5%). 1H NMR (400 MHz, CDCl3): 1.41 (s, 9H), 1.71 (dt, 2H), 2.49-2.60 (m, 1H), 2.64 (t, 2H), 3.54 (dd, 2H), 3.99 (t, 2H); 13C NMR (100 MHz, CDCl3): 26.6, 28.3, 38.3, 39.8, 54.3 (br), 79.1, 156.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[C:6]([O:15][CH3:16])=[C:5]([CH2:17][CH:18]2[CH2:23][CH2:22][C:21]([CH:25](O)[CH3:26])([OH:24])[CH2:20][CH:19]2[C:28]([O:30]CC2C=CC=CC=2)=O)[CH:4]=1.C(OC(=O)C)(=O)C.N1C=CC=CC=1.[K+].[Br-].[OH2:53]>CN(C)C1C=CN=CC=1>[OH:53][CH:25]([C:21]1([OH:24])[CH2:22][CH2:23][CH:18]2[CH:19]([C:28](=[O:30])[C:4]3[C:5]([CH2:17]2)=[C:6]([O:15][CH3:16])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[C:3]=3[O:2][CH3:1])[CH2:20]1)[CH3:26]
Reactant: COc1cc(CC2CCC(O)(C(C)O)CC2C(=O)OCc2ccccc2)c(OC)c2c(OC)cccc12
Reactant: O
Agent: CN(C)c1ccncc1
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1c2c(c(OC)c3c(OC)cccc13)CC1CCC(O)(C(C)O)CC1C2=O
Yield: 49 %

Procedure:
0.48 g of 1-(1,4,5-trimethoxy-3-naphthylmethyl)-2- benzyloxycarbonyl-4-(1-hydroxyethyl)-4-hydroxy-cyclohexane, prepared as described in Example 5, was treated with acetic anhydride and pyridine in the presence of 4-dimethylamino-pyridine. After a night at room temperature the reaction mixture was poured into iced water and extracted with ethyl acetate. The organic layer was washed with water and concentrated. The crude product was dissolved in methanol and refluxed with cyclohexene in the presence of 10% by weight palladium-on-carbon. The catalyst was then filtered off and the solution, concentrated to a small volume, was treated at 0° C for 60 minutes with trifluoroacetic anhydride and trifluoroacetic acid. Then the solution was diluted with ethyl acetate, washed with an aqueous saturated solution of sodium bicarbonate and with water, dried and concentrated to dryness under vacuum. The residue was dissolved in methanol in the presence of catalytic amount of sodium methylate. After conventional work-up and purification by chromatography 0.18 g of the title compound was obtained (yield 49%): m/z 400 (M+.); IR (KBr) : 3450 cm-1 (OH), 1675 cm-1 (C=O benzylic ketone); PMR (CDCL3): inter alia δ(1.2 (d, CH3 -CH), 3.7-3.9 (s, three OCH3) and 6.4-8.0 (m, three aromatic hydrogen).
Reaction SMILES: [I:1]/[CH:2]=[CH:3]/[C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(O)C.[BH4-].[Na+]>O>[I:1]/[CH:2]=[CH:3]/[CH:4]([OH:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC(=O)/C=C/I
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCC(O)/C=C/I
Reaction time: 2 h

Procedure:
A solution of 78.2 g. (0.310 moles) of 1-iodo-trans-1-octen-3-one (Example 724) in 150 ml. of absolute ethanol is added dropwise over 2 hours to a slurry of 6.49 g. (0.172 moles) of sodium borohydride in 50 ml. of absolute ethanol cooled in an ice bath. After the addition is complete, the mixture is stirred for 2 hours with ice cooling and is then poured into 1 l. of water. The mixture is extracted into benzene and the organic phase is washed with saturated brine, dried (Na2SO4) and evaporated. The resulting oil is dissolved into 400 ml. of absolute ethanol and treated with 5 mole percent of p-carboxyphenylhydrazine at 70°C. for 1.5 hours to remove residual ketone. The mixture is cooled and evaporated and the residue is dissolved into 400 ml. of ether and is filtered. The filtrate is washed with dilute sodium bicarbonate solution and saturated brine, dried (Na2SO4), and evaporated to an oil. This oil chromatographyed upon 2 Kg. of Florisil packed in hexane and the product is obtained upon elution with benzene Distillation of the product yields a colorless oil, b.p. 74°-76°C. (0.005 tor.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2O.P(Cl)(Cl)([Cl:18])=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(O)c2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ncnc(Cl)c2cc1OC
Yield: 77.1 %

Procedure:
6,7-Dimethoxy-quinazolin-4-ol (1.00 g, 4.85 mmol, 1 eq.), phosphorous oxychloride (4.07 mL, 43.6 mmol, 9.00 eq.) and triethylamine (6.08 mL, 43.6 mmol, 9 eq.) were refluxed for 2 hours. Stripped then restripped 3× from methylene chloride then dissolved in methylene chloride and rinsed 3× with saturated sodium bicarbonate, 1× with brine. Dried and stripped in vacuo to give an amber oil. Purified over silica gel in 9:1 to 3:1 Hexanes/EtOAc. Obtained 0.84 g of off-white solids as product. LCMS detects (M+H)+=225.
Reaction SMILES: C1C=CC2OC(=O)NC(=O)C=2C=1.C([O:15][C:16](=[O:32])[CH:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)C(OCC)=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CC(N(C)C)=O>[C:16]([OH:32])(=[O:15])[CH2:17][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCOC(=O)C(CCCCCCCCBr)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: O=c1[nH]c(=O)c2ccccc2o1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCC(=O)O
Temperature: 45 °C
Reaction time: 9 h

Procedure:
20 g (0.123 mole) carsalam (available from Sigma-Aldrich of Shiboygan Falls, Wis.), 43.16 g (0.123 mole) 2-(8-bromooctyl)malonic acid diethyl ester (available from Allied Signal, Inc. of Morristown, N.J.), 15.52 g (0.137 mole) sodium carbonate (available from Sigma-Aldrich of St. Louis, Mo.) and 100 mL dimethylacetamide (DMA) (available from Sigma-Aldrich) were heated to about 75° C. for about 5 hours. The solids were filtered off and the filtrate was stirred in 2N sodium hydroxide at 45° C. for a total of about 9 hours to form N-(2-hydroxybenzoyl)-10-amino)-decanoic acid. Formation of the decanoic acid was evident. It was then heated to about 100° C. to determine if the decanoic acid was indeed forming. HPLC of the reaction showed the 9.09 peak transforms to 8.79, 7.23, 5.78 min. Last HPLC showed 49.6 area % of peak 5.78 min, indicating formation of about 50% (w/w) of the decanoic acid.
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2]2.[Cl-].[NH4+].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C)C=O>[N:15]([CH:1]1[CH:6]([OH:7])[CH2:5][CH2:4][CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2]1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C1CCC2OC2C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(O)C(N=[N+]=[N-])C1
Temperature: 76 °C
Reaction time: 13 h

Procedure:
A mixture of Racemate-ethyl 7-oxa-bicyclo[4.1.0]heptane-3-carboxylate (24.0 g, 140 mmol), ammonium chloride (13.6 g, 210 mmol) and sodium azide (13.7 g, 210 mmol) in N,N-dimethylformamide (120 mL) was stirred at 76° C. for 13 hours. After any insoluble matter was collected by filtration, the filtrate was concentrated under reduced pressure while not allowing the solvent to evaporate to dryness. The residue was combined with the solid matter collected by the previous filtration, and the thus-obtained mixture was dissolved in water (500 mL). The solution was extracted with ethyl acetate (500 mL). The extract was washed with water (500 mL×5) and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the tile compound (28 g, crude) as an yellow oil. MS (ES+) C9H15N3O3 requires: 213, found: 214 [M+H]+, 236 [M+Na]+.
Reaction SMILES: C(C1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2)#N.[C:14]([OH:17])(=[O:16])[CH3:15]>Cl>[O:13]=[C:9]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:4]=[C:15]([C:14]([OH:17])=[O:16])[CH:12]=[CH:11][C:10]1=2
Reactant: N#Cc1ccc2c(c1)CCCC2=O
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)c1ccc2c(c1)CCCC2=O
Temperature: 120 °C
Reaction time: 16 h

Procedure:
6-Cyano-1-tetralone (1.30 g, 7.59 mmol) synthesized by a known literature method (Synthetic Communications, 23(21), 2965 (1993)) was dissolved in a mixed solution of concentrated hydrochloric acid (10 ml) and acetic acid (20 ml), which was stirred at 120° C. for 16 hours. The reaction mixture was concentrated. Ethyl acetate and water were added to the residue, and extraction was conducted. The organic layer was washed with water, and concentrated. The residue was washed with ethyl acetate-n-hexane (1:1), to give 5-oxo-5,6,7,8-tetrahydro-2-naphthalenecarboxylic acid (1.10 g) as a white powder.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:5]([C:19]([O:21]C)=[O:20])=[C:6]2[N:11]([C:12]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:10][CH2:9][CH2:8][CH2:7]2>O.C(O)C>[CH3:3][C:4]1[C:5]([C:19]([OH:21])=[O:20])=[C:6]2[N:11]([C:12]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:10][CH2:9][CH2:8][CH2:7]2
Reactant: COC(=O)c1c(C)c(-c2cccnc2)n2c1CCCC2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)c2n(c1-c1cccnc1)CCCC2
Yield: 62.4 %

Procedure:
1.46 g of potassium hydroxide pellets in 20 cm3 of water are added to a solution of 1.2 g of methyl 2-methyl-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylate in 20 cm3 of ethanol. The mixture is heated to reflux for 20 hours. The mixture is then concentrated at reduced pressure (2.7 kPa). The oily residue is taken up with 100 cm3 of water and washed with 4×20 cm3 of dichloromethane. The aqueous phase is filtered and then cooled and acidified with a 1N aqueous solution of hydrochloric acid to pH˜3-4. The solid is filtered off on a No. 4 glass sinter and washed with 4×30 cm3 of water. The solid obtained is recrystallized from 95 cm3 of a 60/40 ethanol/water mixture. 0.71 g of 2-methyl-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylic acid are thus obtained in the form of a white powder melting at 250° C.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([C@H:26]([NH2:28])[CH3:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C([BH3-])#N.[Na+]>CO>[C:16]1([C@H:26]([NH:28][CH2:12][C:11]2[CH:14]=[CH:15][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[CH3:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: C[C@@H](N)c1cccc2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: C[C@@H](NCc1ccc(Oc2ccccc2)cc1)c1cccc2ccccc12
Reaction time: 48 h
Yield: 77 %

Procedure:
4-Phenoxybenzaldehyde (2.34 g, 11.8 mmol) and (2R)-2-(1-naphthyl)eth-2-ylamine (2.02 g, 11.8 mmol) were dissolved in methanol (39 mL) under a nitrogen at room temperature. Sodium cyanoborohydride (742 mg, 11.8 mmol) was added, and stirring was continued for 48 hours. The solvent was evaporated and the residue was suspended in ether, washed with brine, and dried over Na2SO4. The ether was evaporated, and the crude product was chromatographed on silica gel eluting with 3% methanol in methylene chloride to provide 3.21 g (77%) of the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz), δ 1.52 (d, J=6 Hz, 3H), 1.64 (s, 1H), 3.7 (dd, J=13.5 Hz, 7.5 Hz, 2H), 4.7 (q, J=7.5 Hz, 1H), 6.95 (m, 4H), 7.08 (m, 1H), 7.3 (m, 4H), 7.5 (m, 3H), 7.75 (m, 2H), 7.9 (m, 1H), 8.15 (m, 1H). MS (DCl/NH3) m/e 354 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:21])=[CH:4][C:5]([O:15][CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]2)[CH:7]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][C@@H:30]2[CH2:38][C@H:37]3[N:33]([CH2:34][CH2:35][CH2:36]3)[C:32]([CH3:40])([CH3:39])[CH2:31]2)[C:26]([C:41]#[N:42])=[CH:25][N:24]=1.C1(S(O)(=O)=O)C=CC=CC=1>CC(O)C>[CH3:39][C:32]1([CH3:40])[CH2:31][C@H:30]([NH:29][C:27]2[C:26]([C:41]#[N:42])=[CH:25][N:24]=[C:23]([NH:1][C:2]3[CH:7]=[C:6]([N:8]4[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]4)[C:5]([O:15][CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])=[CH:4][C:3]=3[F:21])[N:28]=2)[CH2:38][C@H:37]2[N:33]1[CH2:34][CH2:35][CH2:36]2
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2C#N)C[C@@H]2CCCN21
Reactant: Cn1nnn(-c2cc(N)c(F)cc2OCC(C)(C)O)c1=O
Agent: O=S(=O)(O)c1ccccc1
Solvent: CC(C)O
Product: Cn1nnn(-c2cc(Nc3ncc(C#N)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)c(F)cc2OCC(C)(C)O)c1=O
Temperature: 80 °C
Yield: 79.5 %

Procedure:
A mixture of 1-(5-amino-2-(2-hydroxy-2-methylpropoxy)-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one (305 mg), (7R,8aS)—N-(2-chloro-5-cyanopyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine (262 mg), and benzenesulfonic acid (160 mg) in IPA (2 mL) were heated to 80° C. overnight. After cooling to ambient temperature, the crude mixture was concentrated to dryness. The crude product was absorbed onto silica gel and purified by CombiFlash chromatography (2N NH3 in MeOH/CH2Cl2=0-30%) to give desired product (386 mg, 80%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1([S:22][CH3:23])[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[S:11]1.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][O:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1([S:22][CH3:23])[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[S:11]1
Reactant: BrCCCCBr
Reactant: COc1ccc(O)c(C2(SC)Sc3ccccc3N(C)C2=O)c1
Product: COc1ccc(OCCCCBr)c(C2(SC)Sc3ccccc3N(C)C2=O)c1
Yield: 80 %

Procedure:
3,4-Dihydro-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-2-methylthio-3-oxo-2H-1,4-benzothiazine (3.5 g, compound No. 8) and 1,4-dibromobutane (3.6 ml) are treated by the similar method as in Example 15 to give 3.9 g (80.0%) of the titled compound.
Reaction SMILES: S([N:11]1[C:15]2[N:16]=[CH:17][N:18]=[CH:19][C:14]=2[C:13]([C:20]#[N:21])=[CH:12]1)(C1C=CC(C)=CC=1)(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-]>O1CCCC1>[N:16]1[C:15]2[NH:11][CH:12]=[C:13]([C:20]#[N:21])[C:14]=2[CH:19]=[N:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C#N)c3cncnc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1c[nH]c2ncncc12
Reaction time: 3 h
Yield: 64.6 %

Procedure:
In a 15 mL round-bottomed flask, 7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (1 g, 3.35 mmol, Eq: 1.00) and TBAF (13.4 ml, 13.4 mmol, Eq: 4.00) were combined with Tetrahydrofuran to give an off-white solution. The reaction mixture was stirred for 3 h. The reaction mixture was poured into 20 mL sat NH4Cl and extracted with EtOAc (3×25 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was triturated with diethyl ether (1×20 mL) to obtain 7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (312 mg, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([CH2:7][CH2:8][C:9]([OH:11])=O)=[O:6].[NH:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([CH2:7][CH2:8][C:9]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:11])=[O:6]
Reactant: O=C(O)CCC(=O)c1cccc(Cl)c1
Reactant: O=C(O)[C@@H]1CCCN1
Product: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1cccc(Cl)c1

Procedure:
The preceding compound is converted to 3-[3-chlorobenzoyl]propionic acid, hydroxysuccinimide ester as described in Example 15 and coupled with L-proline as described in Example 16 to give 1-[3-(3-chlorobenzoyl)propionyl]-L-proline. The preceding compound is reacted with bromine in acetic acid as described in Example 20 to give 1-[3-bromo-3-(3-chlorobenzoyl)propionyl]-L-proline. The preceding compound in a mixture of ethanol-water (1:1) is reacted with potassium thioacetate as in Example 21 to give the product of the Example as a glass.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1.O>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:24]2[CH:25]=[CH:26][C:22]([CH3:21])=[N:23]2)=[C:6]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[CH:7]=1
Reactant: O=C(c1cc(Br)ccc1F)C(F)(F)F
Reactant: Cc1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccn(-c2ccc(Br)cc2C(=O)C(F)(F)F)n1
Temperature: 110 °C

Procedure:
1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone (2.20 g, 8.12 mmol) from Step 1, K2CO3 (1.68 g, 12.2 mmol), and 3-methyl-1H-pyrazole (1.33 g, 16.2 mmol) were stirred in toluene (10 mL). The reaction was then heated to 110° C. for 16 h. The reaction was cooled, and water and EtOAc were added. The toluene-EtOAc layer is removed in vacuo, and then the reaction is extracted with water and EtOAc, washed with brine, and dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided 1-[5-bromo-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-trifluoroethanone.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([O:12][CH3:13])[CH:4]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:13][O:12][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[N+:9]([O-:11])=[O:10])[CH2:2][N:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1
Reactant: OC1CCNCC1
Reactant: COc1cc(CBr)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(CN2CCC(O)CC2)ccc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
Into a 8-dram vial, 4-Bromomethyl-2-methoxy-1-nitro-benzene (2.44 g, 9.93 mmol), Piperidin-4-ol (2.01 g, 19.9 mmol), Potassium carbonate (5.49 g, 39.7 mmol), and N,N-Dimethylformamide (25 ml) were added. The reaction mixture was heated at 80° C. overnight. The reaction was partitioned with water and EtOAc. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with hexane and EtOAc as eluant (0 to 100% EtOAc). The collected fractions afforded 1-(3-Methoxy-4-nitro-benzyl)-piperidin-4-ol as a yellow solid.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][NH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([CH:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)#[N:17].C1CCN2C(=NCCC2)CC1>C(#N)C.O>[C:13]([C:12]1[C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:9][N:10]([C:19]2([CH2:18][C:16]#[N:17])[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:23][CH2:24]2)[CH:11]=1)(=[O:14])[NH2:15]
Reactant: NC(=O)c1c[nH]nc1Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Solvent: O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccccc3)n2)CC1
Temperature: 25 °C

Procedure:
To a mixture of 3-(phenylamino)-1H-pyrazole-4-carboxamide, Intermediate 31-1, (1.4 g, 6.9 mmol) and tert-butyl 4-(cyanomethylidene)piperidine-1-carboxylate, Intermediate 19-1 (3.1 g, 13.8 mmol) in acetonitrile (23 mL) was added DBU (1.0 mL, 6.9 mmol), and maintained at ambient temperature for 18 hours. The mixture was diluted with water, extracted with EtOAc, and the combined organics were washed with brine, dried over anhydrous MgSO4, and filtered. The filtrate was adsorbed onto silica gel in vacuo and then purified by MPLC on silica gel (using a gradient elution of 0-80% EtOAc/DCM) to afford the title compound, Example #2-1.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][CH:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12]([OH:14])=[O:13].[OH-].[Na+].[BH4-].[Na+].[ClH:25]>CO.O1CCOCC1>[ClH:25].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:10][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: NC(C(=O)O)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)C(NCc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Fluorobenzaldehyde (0.25 mL, 2.38 mmol), 2-amino-2-phenylacetic acid (300 mg, 1.98 mmol) and NaOH (79 mg, 1.98 mmol) are dissolved in MeOH (20 mL) and stirred at RT overnight. The reaction is cooled at 0° C. and NaBH4 (150 mg, 3.97 mmol) is added. After being stirred at 0° C. for 30 minutes, the reaction is judged complete by UPLC-MS analysis. 4M HCl in dioxane is added dropwise till pH 5 and the precipitate is collected by suction filtration, washed with Et2O and dried under vacuum at 40° C. to obtain intermediate I129 as a white solid (587 mg, quantitative yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:12]=[CH:13][C:14](O)=[O:15]>C1COCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:12]=[CH:13][CH2:14][OH:15]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C=CCO)cc1OC
Yield: 61.8 %

Procedure:
A solution of lithium aluminum hydride (0.1 mol) in THF (100 ml) was added dropwise to a stirred suspension of 3,4-dimethoxycinnamic acid (41.6 g, 0.2 mol) in THF (150 ml) at room temperature. After the addition, the mixture was stirred for 2 hous, and the solution was evaporated in vacuo to a residue, which was partitioned between dichloromethane and aqueous sodium hydroxide. The organic layer was washed three times with water, dried, and evaporated to an oil. Crystallization from ethyl acetate-hexane gave 3,4-dimethoxycinnamyl alcohol (24 g, 62%), m.p. 76°-77° C.