Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.[H-].[Na+].[Cl:15][C:16]1[C:21]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:19]([N:26]=[C:27]=[O:28])=[C:18]([F:29])[CH:17]=1.Cl>C1(C)C=CC=CC=1.CN(C)C=O.O>[Cl:15][C:16]1[C:21]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:20][C:19]([N:26]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:27]2=[O:28])=[C:18]([F:29])[CH:17]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CC(C)Oc1cc(N=C=O)c(F)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 1.0 g of ethyl 3-amino-4,4,4-trifluorocrotonate in 10 ml of absolute toluene is added dropwise while stirring at 0° C. during 15 minutes to a suspension of 0.24 g of a 55% sodium hydride dispersion in 20 ml of absolute dimethylformamide and the mixture is stirred at 0° C. for 15 minutes. The reaction mixture is subsequently cooled to -30° C. and treated with a solution of 1.26 g of 4-chloro-2-fluoro-5-isopropoxyphenyl isocyanate in 10 ml of absolute toluene. The temperature rises rapidly to -10° C. and the reaction mixture is thereafter stirred at room temperature for 2 hours. The reaction mixture is poured into a solution of 3 ml of 2N hydrochloric acid and 500 ml of water and the aqueous mixture is extracted twice with 100 ml of ethyl acetate each time, and the organic phases are washed twice with 50 ml of water each time, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystalized from diethyl ether/n-hexane. There is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 195°-197° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:10][CH2:9]2)[CH:3]=1.[Li]CCCC.C(OCC)C.[S:21](Cl)([Cl:24])(=[O:23])=[O:22]>C1COCC1.C(OCC)C.CCCCCC>[CH:8]1([C:4]2[CH:3]=[C:2]([S:21]([Cl:24])(=[O:23])=[O:22])[CH:7]=[CH:6][CH:5]=2)[CH2:10][CH2:9]1
Reactant: O=S(=O)(Cl)Cl
Reactant: Brc1cccc(C2CC2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: O=S(=O)(Cl)c1cccc(C2CC2)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Bromo-3-cyclopropyl-benzene (1.0 g, 5.1 mmol) [prep.: J. Org. Chem. vol. 41, 2262-6 (1976)] was dissolved in dry THF/diethyl ether (1:1, 30 ml) under an argon atmosphere and cooled to −78° C. BuLi (1.6 M in hexanes, 3.2 ml, 5.1 mmol) was added dropwise and the reaction mixture was further stirred at low temperature for 15 min. This reaction mixture was added via cannula to a SO2 gas saturated solution of diethyl ether (20 ml) precooled to −78° C. The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure. The crude intermediate was suspended in n-hexane (4A sieves dried, 20 ml) and chilled (ice-water). A solution of sulfuryl chloride (0.3 ml, 3.6 mmol) in dry hexane (8 ml) was added dropwise to the stirred suspension and then the cold bath was removed. After 90 min at room temperature the reaction mixture was filtered (Speedex pad) and the filtrate was concentrated under reduced pressure to yield a yellow oil: 0.6 g, (67%) GC-MS: M=216.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:19][CH:20]([F:24])[C:21](O)=O>C1(C)C=CC=CC=1>[F:19][CH:20]([F:24])[C:21]1[NH:1][C:2]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][C:9]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:10][C:11]=2[N:12]=1
Reactant: O=C(O)C(F)F
Reactant: COC(=O)c1cc(N2CCOCC2)cc(N)c1N
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(N2CCOCC2)cc2nc(C(F)F)[nH]c12
Temperature: 25 °C

Procedure:
A mixture of methyl 2,3-diamino-5-morpholinobenzoate (40.16 g, 160 mmol) and 2,2-difluoroacetic acid (46.08 g, 480 mmol) in toluene (500 mL) was stirred at reflux temperature for 15 h. Then the mixture was cooled to room temperature and the solvent was removed in vacuum. The residue was purified by silica gel chromatography eluted with petroleum ether:EtOAc=2:1 to afford the desired product. Then, it was dissolved with EtOAc (2 L) and washed with aqueous NaHCO3 (1 L) and brine (1 L). The organic layer was dried over anhydrous Na2SO4 and concentrated to give the desired product (40.9 g, 82%) as a yellow solid. 1H NMR showed this compound is in a form of tautomeric mixture (major tautomer/minor tautomer=5/1) 1H NMR of the major tautomer (300 MHz, DMSO-d6): δ ppm 3.14 (t, 4H, J=4.8 Hz), 3.78 (t, 4H, J=4.8 Hz), 3.96 (s, 3H), 7.21 (t, 1H, J=52.8 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.65 (d, 1H, J=2.4 Hz), 12.92 (s, 1H); LC-MS: m/e=312 [M+1]+
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].CC(N(C)C)=O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2ccc(C=O)cc2)nc1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
Combine 4-Hydroxybenzaldehyde (8.0 g, 65.5 mmol), 6-Chloronicotinonitrile (9.07 g, 65.5 mmol), powdered K2CO3 (13.6 g, 98.3 mmol), and DMA/Toluene (80/240 mL) in a 500 mL RB flask equipped with a stir, reflux condenser, and a Dean Stark Trap. Reflux the reaction mixture for several hours under a Nitrogen atmosphere then cool to room temperature and quench with sat NH4Cl (aq). Add Ethyl acetate to extract the product and wash several times with water and then brine. Dry the organic layer over Na2SO4. Concentrate and flash chromatograph using 2:1 Hexanes:Ethyl acetate to give 13.2 g (88% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 7.1 (1H, d), 7.3-7.4 (2H, m), 7.9-8.0 (3H, m), 8.5 (1H, d), 10.0 (1H, s); MS m/z 225 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH2:5][CH:4]([CH2:7]O)[CH2:3]1.C(Br)(Br)(Br)[Br:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:11][CH2:7][CH:4]1[CH2:5][O:6][C:2]([CH3:9])([CH3:1])[CH2:3]1
Reactant: BrC(Br)(Br)Br
Reactant: CC1(C)CC(CO)CO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(C)CC(CBr)CO1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.9 %

Procedure:
To a solution of (5,5-dimethyltetrahydrofuran-3-yl)methanol (2.00 g) in dichloromethane (30 ml) were added carbon tetrabromide (6.10 g) and triphenylphosphine (4.80 g) at room temperature. The reaction mixture was stirred at room temperature for 20 hr, and extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (2.40 g) as a colorless oil.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH:18]=[N:17][NH:16][C:15]3=[O:19])[CH2:10][CH2:9]2)C=CC=CC=1.C1CC=CCC=1.C(O)C>[OH-].[Pd+2].[OH-].O>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[N:17][NH:16][C:15]2=[O:19])[CH2:12][CH2:13]1
Reactant: O=c1[nH]ncn1C1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1=CCC=CC1
Product: O=c1[nH]ncn1C1CCNCC1
Temperature: 100 °C
Yield: 50.3 %

Procedure:
2,4-Dihydro-4-[1-(phenylmethyl)-4-piperidinyl]-3H-1,2,4-triazol-3-one (Example 64(b)) (2.2 g) was divided between 2, 10 mL vials. 1,4-Cyclohexadiene (5 mL) and palladium hydroxide (270 mg, 20 wt. % on carbon) were added to each vial and the reactions were heated at 100° C. for 30 minutes within a microwave. The reaction mixtures were combined, ethanol (50 mL) and water (50 mL) were added and the mixture was filtered through diatomaceous earth and evaporated to give the sub-title compound as a solid (720 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([O:14][C:10]2[CH:9]=[N:8][CH:13]=[CH:12][CH:11]=2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCCC(Oc2cccnc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cncc(OC2CCCNC2)c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 99.7 %

Procedure:
To 130 mg of 3-(1-t-butoxycarbonyl-3-piperidinyloxy)-pyridine was added 10 mL of solution containing 5 mL of TFA and 5 mL of CH2Cl2 at ice-bath temperature. The reaction solution was slowly warmed to room temperature and allowed to stir 50 min at room temperature. After 50 min, solvents were removed in vacuo and the crude product was purified by flash chromatography (9:1:0.05, CHCl3:MeOH:conc. NH4OH) to obtain 83 mg (quantitative yield) of a clear oil: 1H NMR (300 MHz, CD3OD) δ8.27 (1H, d, J=2.7 Hz), 8.13 (1H, d, J=4.0 Hz), 7.49-7.34 (2H, m), 4.52 (1H, m), 3.20-2.80 (4H, m), 2.05-1.55 (4H, m); Mass spectrum (ESI) m/z 179.6 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:23](=[O:28])N(OC)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH:23]=[O:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CS[C@@H]2C[C@@H](C(=O)N(C)OC)N(C(=O)OC(C)(C)C)C2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CS[C@@H]2C[C@@H](C=O)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
A solution of 1.5 g (3.5 mmol) (2S,4R)-4-(4-methoxy-benzylsulfanyl)-2-(methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester dissolved in 15 ml was added to 4.2 ml (4.2 mmol, 1M THF solution) of LAH in 50 ml THF at −78° C. The reaction was was warmed up to −30° C., cooled to −78° C. and quenched with a suspension of 1.2 g silica gel/1.2 g MgSO4.7H2O in 5 ml aqueous 10% KHSO4. The suspension was stirred for 15 min at room temperature, filtered and washed with THF. After evaporation of the THF, the residue was taken up in CH2Cl2, dried over Na2SO4 and evaporated to give 1.2 g (98%) of (2S,4R)-2-formyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, MS: 351 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]#[N:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:14](Cl)(Cl)=[O:15].C1(C)C=CC=CC=1.[OH-].[Na+]>C(OCC)(=O)C>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([C:12]#[N:13])=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1)=[C:14]=[O:15]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N=C=O)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-amino-2-cyanobenzotrifluoride (1a) (2.0 g, 10.7 mmol) in ethyl acetate (6 mL) at 0° C. under argon, was added dropwise a 2.0 M solution of phosgene in toluene (6.5 mL, 12.9 mmol). The solution was stirred 30 min at 0° C. and allowed to return at room temperature. Toluene (3 mL) was then added to the ethyl acetate and the resulting solution was refluxed for 3 hrs using a Dean-Stark apparatus, equipped with an HCl trap (solid NaOH). The first 6 mL of distilled solvent was removed and replaced by toluene (6 mL). The solution was then filtrated and evaporated to give compound 8a (1.6 g) as an orange oil which was directly used for the next step. IR: 2268 (strong), 2232 (weak) cm−1.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:18])[CH:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].[CH3:19][O:20][C:21]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Cl.O>CN(C)C=O>[CH2:3]([O:5][C:6](=[O:18])[C:7]([CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:28]([O:29][CH3:30])[C:21]=1[O:20][CH3:19])([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4]
Reactant: CCCCCC(C(=O)OCC)C(=O)OCC
Reactant: COc1cccc(CCl)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCC(Cc1cccc(OC)c1OC)(C(=O)OCC)C(=O)OCC
Yield: 73.1 %

Procedure:
To a suspension of 60% sodium hydride (440 mg, 11 mmol) in 5 ml of dimethylformamide was added a solution of 2.30 g (10 mmol) of n-pentylmalonic acid diethyl ester in 5 m of dimethylformamide under stirring and ice cooling, and the resultant mixture was stirred for 30 minutes. A solution of 1.86 g (10 mmol) of 2, 3-dimethoxybenzyl chloride in 5 ml of dimethylformamide was dropwise added to the mixture, which was stirred at 70° C. for 1 hour. After cooling, the reaction mixture was mixed with water and extracted with ethyl acetate. The organic layers were combined, washed with water and saturated saline in this order, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The residue was chromatographed on a silica gel column, eluting with ethyl acetate/hexane (1/12) to give 2.78 g of 2, 3-dimethoxybenzyl-n-pentylmalonic acid diethyl ester as a colorless oil. Yield, 73%.
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.Cl.[CH2:7]([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:22]3[CH2:28][CH2:27][NH:26][CH:25]([CH3:29])[C:23]=3[N:24]=2)=[CH:15][CH:14]=1)=[O:11])[CH3:8].C(N(CC)C(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:7]([NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[C:21]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[C:22]3[CH2:28][CH2:27][N:26]([CH:3]4[CH2:2][O:1][CH2:4]4)[CH:25]([CH3:29])[C:23]=3[N:24]=2)=[CH:17][CH:18]=1)=[O:11])[CH3:8]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3C)cc1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C2COC2)C3C)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
3-oxetanone (0.38 mL, 5.2 mmol) and 1-ethyl-3-(4-(8-methyl-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride salt (451 mg, 1.04 mmol) were mixed in 1,2-Dichloroethane (6.2 mL) and N,N-Diisopropylethylamine (0.73 mL, 4.2 mmol). The reaction was stirred at 70° C. for 1 h and at 80° C. for 30 minutes. Sodium triacetoxyborohydride (0.71 g, 3.3 mmol) was added to the reaction, and the mixture was stirred at 80° C. for 30 minutes. The reaction mixture was quenched with NaHCO3 and water, which was extracted by CHCl3. The organic layers were combined, washed by water and brine (final pH ˜9), dried over Magnesium sulfate and evaporated. The residue was purified to give the desired product sk (269 mg, 57% yield) as white powder: 1H NMR (400 MHz, DMSO) δ 8.62 (s, 1H), 8.18 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 6.14 (t, J=5.5 Hz, 1H), 4.62 (m, 3H), 4.53 (t, J=6.2 Hz, 1H), 4.04 (p, J=6.7 Hz, 1H), 3.81-3.64 (m, 5H), 3.54-3.35 (m, 4H), 3.17-3.03 (m, 2H), 2.67 (m, 4H), 1.29 (d, J=6.8 Hz, 3H), 1.06 (t, J=7.2 Hz, 3H); LC-MS m/z=453 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[NH2:9][C:10]1[CH:14]=[CH:13][N:12]([CH3:15])[N:11]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([OH:27])[CH:25]=2)[N:20]=[CH:19][N:18]=1>>[F:8][C:4]1[N:3]=[C:2]([O:27][C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:9][C:10]2[CH:14]=[CH:13][N:12]([CH3:15])[N:11]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Cn1ccc(N)n1
Reactant: Fc1cccc(F)n1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4cccc(F)n4)cc23)n1

Procedure:
The compound of Example 128 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2,6-difluoropyridine, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: N[C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@@H:3]1[C:15]([O:17][CH3:18])=[O:16].C(N([CH2:24][CH3:25])CC)C>ClCCl>[CH2:11]([O:10][C:8]([C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[C:15]([O:17][CH3:18])=[O:16])=[O:9])[C:25]1[CH:24]=[CH:4][CH:3]=[CH:2][CH:7]=1
Reactant: CCN(CC)CC
Reactant: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 184.6 %

Procedure:
A solution of 260B (0.75 g, 2.90 mmol) in dichloromethane (30 mL) at 0° C. was treated with triethylamine (0.35 g, 3.48 mmol) and N-(benzyloxycarbonyoxy)succinimide (0.72 g, 2.90 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. The reaction mixture was diluted with dichloromethane, washed with 10% citric acid (2×50 mL), then saturated NaHCO3 (2×50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give 1.01 g (yield: 89%) of Compound 260C as an oil. It was used in the next step without further purification.
Reaction SMILES: CO[C:3](=[O:16])[C:4]([CH2:9][NH:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)([CH2:7][CH3:8])[CH2:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27]([N+:31]([O-])=O)=[CH:26][N:25]=1>CC(C)=O.C(O)(=O)C.[Fe]>[Cl:23][C:24]1[N:29]=[C:28]2[C:27]([NH:31][C:3](=[O:16])[C:4]([CH2:5][CH3:6])([CH2:7][CH3:8])[CH2:9][N:10]2[CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)=[CH:26][N:25]=1
Reactant: CCC(CC)(CNC1CCCC1)C(=O)OC
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CCC1(CC)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.2 %

Procedure:
To a solution of methyl2-[(cyclopentylamino)methyl]-2-ethyl-butanoate (Intermediate 252; 7.1 g, 31.3 mmol) in acetone (150 mL) was added potassium carbonate (5.3 g, 38.0 mmol) followed by 2,4-dichloro-5-nitropyrimidine (Aldrich; 6.1 g, 31.3 mmol). The black mixture was stirred at room temperature for 18 hours. The reaction was filtered and the solvent removed in vacuo to yield a black gum, which was dissolved in acetic acid (175 mL) and iron (7.0 g, 125 mmol) added and the reaction heated at 80° C. overnight. The resulting solution was filtered and the solvent removed in vacuo, the black solid/gum was quenched with water (75 mL) and to this was added sodium carbonate until basic, the resultant black emulsion was filtered through a pad of celite. The obtained mixture was extracted with DCM (3×150 mL), dried and the solvent removed in vacuo to yield a black solid. This was passed through a bond elute column (50 g) eluting with 0-1% MeOH in DCM to afford a brown solid, which was triturated with diethyl ether to yield the title compound as a white solid (3.05 g, 30%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=2[O:16][CH3:17])[CH2:9][CH2:8][NH:7]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][CH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1>>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=2[O:16][CH3:17])[CH2:9][CH2:8][N:7]1[CH2:27][C:28]([NH:31][CH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1)=[O:29]
Reactant: NC1CCc2ccccc21
Reactant: O=C(Br)CBr
Reactant: COc1ccc(OC)c(CC2NCCc3c(OC)ccc(OC)c32)c1
Product: COc1ccc(OC)c(CC2c3c(OC)ccc(OC)c3CCN2CC(=O)NC2CCc3ccccc32)c1

Procedure:
prepared by reaction of 1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-indane
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[S:10]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)(=[O:13])(=[O:12])[NH2:11]>>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:18][C:17]2[CH:19]=[CH:20][C:14]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: Cc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-methylbenzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a white powder (yield 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.[C:24]([N:31](C)[CH2:32][C:33](O)=[O:34])(OC(C)(C)C)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:33](=[O:34])[CH2:32][NH:31][CH3:24])[CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Cl)ccc21
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Product: CNCC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Examples 19 and 20, with the exceptions that 5-chloro-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide was used instead of 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide, and that N-Boc-N-methyl glycine was used instead of N-Boc glycine.
Reaction SMILES: [C:1]([BH3-])#N.[Na+].Cl.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:38][C:16]3[C:17](=[O:37])[N:18]([C:21]4[CH:22]=[N:23][C:24]([N:27]5[CH2:31][CH2:30][C@@H:29]([NH:32][CH2:33][CH:34]([F:36])[F:35])[CH2:28]5)=[CH:25][CH:26]=4)[CH:19]=[CH:20][C:15]=3[CH:14]=2)=[CH:9][CH:8]=1.C(O)(=O)C.C=O>CO>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:38][C:16]3[C:17](=[O:37])[N:18]([C:21]4[CH:22]=[N:23][C:24]([N:27]5[CH2:31][CH2:30][C@@H:29]([N:32]([CH2:33][CH:34]([F:36])[F:35])[CH3:1])[CH2:28]5)=[CH:25][CH:26]=4)[CH:19]=[CH:20][C:15]=3[CH:14]=2)=[CH:9][CH:8]=1
Reactant: O=c1c2sc(-c3ccc(Cl)cc3)cc2ccn1-c1ccc(N2CC[C@@H](NCC(F)F)C2)nc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(CC(F)F)[C@@H]1CCN(c2ccc(-n3ccc4cc(-c5ccc(Cl)cc5)sc4c3=O)cn2)C1
Reaction time: 18 h
Yield: 80.7 %

Procedure:
Add sodium cyanoborohydride (716 μmol, 45 mg) to a room temperature mixture of 2-(4-chloro-phenyl)-6-{6-[(R)-3-(2,2-difluoro-ethylamino)-pyrrolidin-1-yl]-pyridin-3-yl}-6H-thieno[2,3-c]pyridin-7-one, hydrochloride (150 mg, 287 μmol), acetic acid (49 μL, 360 μmol,) and formaldehyde (115 μL, 1.53 mmol, 37% aqueous solution) in methanol (9 mL) and stir the mixture for 18 h. Concentrate the mixture and partition between CH2Cl2 (5 mL) and 1N NaOH (5 mL). Separate the organic portion and extract the aqueous portion with CH2Cl2 (3×). Dry the combined organics over Na2SO4, filter, and concentrate to dryness. Purify by chromatography 0% to 5% MeOH (2M NH3)/CH2Cl2 to afford 116 mg (80%) of 2-(4-chloro-phenyl)-6-(6-{(R)-3-[(2,2-difluoro-ethyl)-methyl-amino]-pyrrolidin-1-yl}-pyridin-3-yl)-6H-thieno[2,3-c]pyridin-7-one. Add 1M hydrogen chloride in ethanol (232 μL, 232 μmol) to a solution of 2-(4-chloro-phenyl)-6-(6-{(R)-3-[(2,2-difluoro-ethyl)-methyl-amino]-pyrrolidin-1-yl}-pyridin-3-yl)-6H-thieno[2,3-c]pyridin-7-one (232 μmol, 116 mg) in dichloromethane (2 mL) and stir the mixture at room temperature for 5 min. Dilute the mixture with of Et2O (8 mL) and filter. Rinse the solid with Et2O (2×) and dry under vacuum at 80° C. to afford 100 mg (80%) of the title compound. LC-MS/ES m/z (35Cl) 501.0 [M+H]+.