Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]2[N:7]3[CH2:15][CH2:16][N:17]=[C:18]([CH3:19])[C:6]3=[CH:5][C:4]=2[CH2:3]1.[BH4-].[Na+].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>CO.O.C(O)C>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[CH3:1][CH:2]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]2[N:7]3[CH2:15][CH2:16][NH:17][CH:18]([CH3:19])[C:6]3=[CH:5][C:4]=2[CH2:3]1
Reactant: CC1=NCCn2c1cc1c2-c2ccccc2C(C)C1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: CC1Cc2cc3n(c2-c2ccccc21)CCNC3C
Yield: 81 %

Procedure:
5,6,10,11-Tetrahydro-5,8-dimethylbenzo[g]pyrazino[1,2-a]indole (2.0 g) was dissolved in a mixture of 80 ml of methanol and 8 ml of water under argon. The solution was treated portionwise with 0.9 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the solvent was removed in a vacuum, the residue was taken up in 100 ml of methylene chloride and washed with 100 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 50 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 2.0 g of yellow-brown oil, was dissolved in a 25-fold amount of hot ethanol and treated with 1.1 equivalents of a hot saturated solution of fumaric acid in ethanol. There were obtained 2.4 g (81%) of 5,6,8,9,10,11-hexahydro-5,8-dimethylbenzo[g]pyrazino[1,2-a]indole fumarate (1:1); m.pt.: 196°-199° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.Cl.[Cl:16][CH:17](Cl)C>>[C:1]([O:9][CH2:10][CH2:11][O:12][CH2:17][Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Cl)Cl
Reactant: O=C(OCCO)c1ccccc1
Agent: C=O
Agent: Cl
Product: O=C(OCCOCCl)c1ccccc1
Reaction time: 3 h

Procedure:
A cold (0° C.) mixture of ethylene glycol monobenzoate (166g) and paraformaldehyde (30g) in dry dichloroethane was saturated with dry HCl with stirring for 3 hours. The pinkish red li1uid was dried over calcium chloride and the volatile components removed on a rotary evaporator at 30° C. to give 1-benzoyloxy-2-chloromethoxyethane (215g). The Infra-Red spectrum indicated the absence of a hydroxyl group.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)(=[O:4])=[O:3].[CH2:15]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)[CH2:16][CH2:17][CH3:18]>>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[C:22]1[CH2:23][CH2:24][N:19]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:20][CH:21]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1ccc2[nH]ccc2c1
Reactant: CCCCN1CCC(=O)CC1
Product: CCCCN1CC=C(c2c[nH]c3ccc(NS(C)(=O)=O)cc23)CC1
Yield: 84.6 %

Procedure:
Beginning with 1.0 gm (4.76 mMol) 5-methanesulfonylamino-1H-indole and 0.96 gm (6.2 mMol) 1-butyl-4-piperidone, 1.4 gm (84.8%) of the title compound were recovered as a yellow powder.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:8]([C:12]([NH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[N:21]3[CH2:26][C@H:25]([CH3:27])[CH2:24][C@H:23]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:22]3)=[O:13])=[N:9]2)=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1.CC1(C)C(C)(C)OB([C:69]2[CH2:70][CH2:71][O:72][CH2:73][CH:74]=2)O1>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl.O>[C:32]([O:31][C:29]([NH:28][C@H:23]1[CH2:24][C@@H:25]([CH3:27])[CH2:26][N:21]([C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[NH:14][C:12]([C:8]2[C:7]([NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:6][C:5]3[C:10](=[CH:11][C:2]([C:69]4[CH2:74][CH2:73][O:72][CH2:71][CH:70]=4)=[CH:3][CH:4]=3)[N:9]=2)=[O:13])[CH2:22]1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(C4=CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 80 °C
Yield: 57.1 %

Procedure:
A pressure vial was charged with benzyl (7-bromo-2-{[(4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}pyridin-3-yl)amino]carbonyl}quinolin-3-yl)carbamate (0.029 g, 0.043 mmol), K3PO4 (0.0181 g, 0.0852 mmol), 1,4-dioxane (0.55 mL), water (0.092 mL) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (0.013 g, 0.063 mmol). The mixture was deoxygenated with nitrogen for 10 min. Dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.0022 g, 0.0028 mmol) was added. The mixture was sealed with screw cap, then heated at 80° C. for 1 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic extracts were dried and concentrated. The residue was purified by flash chromatography on 20 g silica gel, eluting with 0-100% EtOAc in hexanes, to yield benzyl [2-{[(4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-(3,6-dihydro-2H-pyran-4-yl)quinolin-3-yl]carbamate (0.017 g, 57%), LCMS calc. for C39H45N6O6 [M+H]+: m/z=639.3. found: 693.3; and the corresponding benzyl carbamate deprotected product tert-butyl {(3S,5R)-1-[3-({[3-amino-7-(3,6-dihydro-2H-pyran-4-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate (0.010, 42%). LCMS calc. for C31H39N6O4 [M+H]+: m/z=559.3. found: 559.3.
Reaction SMILES: F[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH:8]1([C:11]#[N:12])[CH2:10][CH2:9]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[C:8]1([C:11]#[N:12])[CH2:10][CH2:9]1
Reactant: N#CC1CC1
Reactant: Fc1cnccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC1(c2cnccn2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 8.4 %

Procedure:
A mixture of 2-fluoropyrazine (2.0 g, 20.4 mmol, 1 eq) and cyclopropanecarbonitrile (1.5 ml, 20.4 mmol, 1 eq) In a dry flask under an argon atmosphere were dissolved in dry toluene (50 ml). The solution was cooled to 0° C. and potassium bis(trimethylsilyl)amide (0.5 M in toluene, 40.9 ml, 20.45 mmol, 1 eq) was added slowly over 5 min via syringe. The black, opaque reaction mixture was allowed to warm to room temperature and stirred for 4 h. The reaction was diluted with water (200 ml) and ethyl acetate (200 ml), and the layers were separated. The aqueous layer was back extracted with ethyl acetate (2×100 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated to give a black oil. The crude was purified by silica gel (60-120) column chromatography using 20% ethyl acetate in hexane as eluent to give 0.25 g of the product as light a yellow oil. Yield: 0.25 g (8.4%). 1H NMR (400 MHz, CD3OD): δ1.84-1.86 (m, 4H), 8.51-8.55 (q, 2H), 8.89 (s, 1H). LCMS: (ES+) m/z=146.2 (M)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](Br)[C:3]=1[F:10].C(=[NH:24])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl>CCOCC.C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Pd]>[Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[NH2:24]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Fc1cc(Br)c(F)c(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: Nc1cc(F)cc(Br)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55.8 %

Procedure:
A mixture of 1,3-dibromo-2,5-difluorobenzene (4 g, 14.7 mmol), benzophenone imine (2.6 mL, 15.5 mmol), sodium tert-butoxide (2.1 g, 22.1 mmol), (S)-BINAP (1.4 g, 2.2 mmol), in toluene (15 mL) was sparged with Argon and charged with Pd2(dba)3 (0.67 g, 0.74 mmol). The reaction was then sealed and irradiated at 100° C. for 30 minutes in a microwave reactor. The reaction mixture was diluted with Et2O and stirred for 2 hours with a palladium scavenger (Siliabond DMT). The mixture was filtered through a plug of Celite and the collected filtrate was partitioned between diethyl ether and water, and the resulting layers separated. The organic portion was washed with water, brine, dried (MgSO4), and concentrated to afford a brown red solid. The solid was dissolved in THF (40 mL) and treated with aqueous 6.0 N HCl solution (25 ml, 150 mmol). The reaction was stirred for 1.5 hours at room temperature was partitioned between water and Et2O. The layers were separated and the aqueous portion was brought to a pH of 9 with aqueous 1.0 M NaOH solution. The basic aqueous layer was extracted diethyl ether (3×30 mL) the combined diethyl ether layers were washed with aqueous 1.0 M NaOH solution, water, brine, dried (MgSO4), concentrated. Purification by flash chromatography (SiO2, 0-10% EtOAc in heptane) afforded 3-bromo-2,5-difluoroaniline (1.7 g, 8.2 mmol, 56%, trace benzophenone) as an orange solid: 1H NMR (400 MHz, CDCl3) δ 3.93 (br s, 2H) 6.43 (m, 1H) 6.62 (m, 1 H).
Reaction SMILES: CC[N:3](CCCC(NC1C=C(/C=C/C2C=CC=CC=2Cl)N=C2C=C(Cl)C=CC=12)C)CC.Cl[C:33]1[C:34]2[CH2:42][CH2:41][N:40](C3C=CC=CN=3)[CH2:39][C:35]=2[N:36]=[CH:37][N:38]=1>>[N:36]1[C:35]2[CH:39]=[N:40][CH:41]=[CH:42][C:34]=2[C:33]([NH2:3])=[N:38][CH:37]=1
Reactant: CCN(CC)CCCC(C)Nc1cc(/C=C/c2ccccc2Cl)nc2cc(Cl)ccc12
Reactant: Clc1ncnc2c1CCN(c1ccccn1)C2
Product: Nc1ncnc2cnccc12

Procedure:
Appropriate 7-(pyridin-2-yl)-5,6,7,8-tetrahydro-N-(1,2,3,4-tetrahydro-4,4-dimethyl-1-substituted)quinolin-7- yl)pyrido[3,4-d]pyrimidin-4-amine derivatives are prepared starting from 1,2,3,4-tetrahydro-4,4-dimethyl-7-nitroquinoline. The nitroquinoline derivate is reacted with appropriate alkylating agent to give the N-substituted nitroquinoline, which is reduced using standard procedures known in the art to yield 7-aminoquinoline derivative. The resulting aminoquinoline derivated is then condensed with the appropriate 4-chloro-7-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine to give the desired 7-(pyridin-2-yl)-5,6,7,8-tetrahydro-N-(1,2,3,4-tetrahydro-4,4-dimethyl-1-substituted)quinolin-7-yl)pyrido[3,4-d]pyrimidin-4-amine derivative. As a representative example, preparation of the N-morpholionethyl derivative is depicted in Scheme 6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]3([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)OCC(C)(C)C[O:16]3)[C@H:9]2[C:30]2[CH:44]=[CH:43][C:33]([O:34][CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])=[CH:32][CH:31]=2)=[CH:4][CH:3]=1>C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)=[O:16])[C@H:9]2[C:30]2[CH:44]=[CH:43][C:33]([O:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:32][CH:31]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)COC(CS[C@H]2C(=O)N(c3ccc(Cl)cc3)[C@@H]2c2ccc(OCC(=O)OC(C)(C)C)cc2)(c2ccc(Cl)cc2)OC1
Solvent: O=CO
Product: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(Cl)cc3)C(=O)N2c2ccc(Cl)cc2)cc1
Reaction time: 2 h
Yield: 81.4 %

Procedure:
tert-Butyl {4-[(2R,3R)-1-(4-chlorophenyl)-3-({[2-(4-chlorophenyl)-5,5-dimethyl-1,3-dioxan-2-yl]methyl}thio)-4-oxoazetidin-2-yl]phenoxy}acetate (1.69 g, 2.57 mmol) was dissolved in formic acid (25 ml) and stirred for two hours. The mixture was concentrated under reduced pressure (temperature <30° C.) and the crude oil was purified by flash-chromatography (hexane:acetone:formic acid 60:40:0.1) to afford 1.08 g (81%) of the title compound as a pale yellow solid. 1H-NMR (CDCl3, 200 MHz): δ 4.0-4.2 (m, 3H), 4.7 (s, 2H), 4.9 (d, 1H), 6.9 (d, 2H), 7.2-7.4 (m, 6H), 7.5 (d, 2H), 7.9 (d, 2H). MS (CI) M/z: 514.2 (NT), 515.2 (30), 516.1 (70), 517.2 (20).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][NH:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[CH:20][CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C=O.[CH3:38]CN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>O.ClCCCl.CC(O)=O.C(Cl)Cl>[F:34][C:31]1[CH:32]=[CH:33][C:28]([N:27]([CH3:38])[CH2:26][CH2:25][CH2:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][C:8]3([NH:7][C:6](=[O:35])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]3)=[CH:19][CH:20]=2)=[CH:29][CH:30]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(CCCNc3ccc(F)cc3)cc2)COC(C)(C)OC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(CCCc1ccc(CCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the product of Step C (0.04 g, 0.08 mmol), formaldehyde solution in H2O (0.25 ml) in 1,2-dichloroethane (5 ml) 4 drops of DIPEA was added at room temperature, followed by 5 drops of AcOH and NaBH(OAc)3 (0.04 g, 0.19 mmol). The mixture was stirred overnight at room temperature and diluted to 20 ml with CH2Cl2. The organic layer was washed with aqueous NaHCO3, H2O, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2) to give the product (0.035 g), as creamy paste. 1H-NMR (CDCl3) 1.40 (s, 3H); 1.42 (s, 3H); 1.46 (s, 9H); 1.84-1.99 (m, 4H); 2.5-2.61 (m, 4H); 2.85 (s, 3H); 3.25 (tr, 2H, J=7.41 Hz); 3.66 (d, 2H, J=11.8 Hz); 3.88 (d, 2H, J=11.7 Hz); 4.85 (s, 1H); 6.54-6.59 (m, 2H); 6.86-6.92 (m, 2H); 7.07 (s, 4H).
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:7][C:8](=[O:13])[C:9]([CH2:11]O)=[CH2:10])[CH3:6].O>CCOCC>[CH2:5]([O:7][C:8](=[O:13])[C:9]([CH2:11][Br:2])=[CH2:10])[CH3:6]
Reactant: C=C(CO)C(=O)OCC
Reactant: BrP(Br)Br
Solvent: O
Solvent: CCOCC
Product: C=C(CBr)C(=O)OCC
Reaction time: 3 h
Yield: 123.1 %

Procedure:
Phosphorus tribromide (17.16 g, 63.41 mmol) was added to a stirred solution of the compound of example 30 (17.92 g, 138.1 mmol) in dry ether (132 mL) at −10° C. The temperature was allowed to rise to 20° C. and stirring was continued for 3 h. Water (80 mL) was then added at −10° C. and the mixture was extracted with hexane (3×45 mL). The organic extracts were washed with saturated sodium chloride solution (2×45 mL) and dried with anhydrous MgSO4. Evaporation of solvent under vacuum gave 15.07 g (yield 56.6%) of the crude product, which was used directly in the next reaction without any further purification. 1H NMR (CDCl3, 400 MHz) δ 6.25 (s, 1H), 5.88 (s, 1H), 4.2 (q, 2H), 4.11 (s, 2H), 1.25 (t, 3H); 13C NMR (CDCl3, 400 MHz) 166.7, 140.1, 125.3, 61.1, 53.9, 14.4.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=[CH:9][CH:10]=[C:11]([C:17]1C=C[CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[S:5].F[B-](F)(F)F.CN(C(C(OCC)=O)=CC=[N+](C)C)C.CC[O-].[Na+]>C(O)C>[CH3:23][N:2]([CH3:1])[C:3](=[CH:9][CH:10]=[C:11]([CH2:17][CH2:18][CH2:19][CH3:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[S:5]
Reactant: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Agent: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: CC[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: CCCCC(=CC=C(C(=S)OCC)N(C)C)C(=O)OCC

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (10 g), a 2M ethanolic solution of sodium ethylate (17.5 cc) and ethyl (n-butyolthio)acetate (6.16 g) in ethanol (60 cc). Diethyl 2-dimethylamino-5-n-butylthio-2,4-hexadienedioate (10 g) is thereby obtained in the form of an orange-red oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [OH-].[Na+].[CH3:3][C@@H:4]1[CH2:9][N:8]([C:10]2[O:11][C:12]3[C:17]([C:18](=[O:20])[CH:19]=2)=[CH:16][C:15]([C:21]([O:23]C)=[O:22])=[CH:14][C:13]=3[CH:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:7][CH2:6][O:5]1.O>CO>[CH3:3][C@@H:4]1[CH2:9][N:8]([C:10]2[O:11][C:12]3[C:17]([C:18](=[O:20])[CH:19]=2)=[CH:16][C:15]([C:21]([OH:23])=[O:22])=[CH:14][C:13]=3[CH:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:7][CH2:6][O:5]1
Reactant: COC(=O)c1cc(C2CCCN2c2ccccc2)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@@H]1CN(c2cc(=O)c3cc(C(=O)O)cc(C4CCCN4c4ccccc4)c3o2)CCO1
Yield: 87.1 %

Procedure:
Sodium hydroxide (2N in water) (0.293 mL, 0.59 mmol) was added to a stirred suspension of methyl 2-((R)-2-methylmorpholino)-4-oxo-8-(1-phenylpyrrolidin-2-yl)-4H-chromene-6-carboxylate (105 mg, 0.23 mmol) in MeOH (2 mL)/water (2 mL) as described in example 3.00 to afford 2-((R)-2-methylmorpholino)-4-oxo-8-(1-phenylpyrrolidin-2-yl)-4H-chromene-6-carboxylic acid (87 mg, 86%) which was used without further purification. Mass Spectrum: m/z [M+H]+=435.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:9])[O:8][CH2:7][CH2:6][NH:5][CH2:4]1.[OH-].[Na+].[O:12]1[C@H:14]2[CH2:15][C@H:16]3[C@:29]([CH3:31])([CH2:30][C@@H:13]12)[C@@H:28]1[C@H:19]([C@H:20]2[C@@:24]([CH2:26][C:27]1=[O:32])([CH3:25])[C@@H:23]([C:33]#[N:34])[CH2:22][CH2:21]2)[CH2:18][CH2:17]3.O>C(O)CO>[OH:12][C@@H:14]1[C@@H:13]([N:5]2[CH2:6][CH2:7][O:8][C:3]([CH3:9])([CH3:2])[CH2:4]2)[CH2:30][C@@:29]2([CH3:31])[C@@H:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:28]2[C:27](=[O:32])[CH2:26][C@@:24]2([CH3:25])[C@H:20]3[CH2:21][CH2:22][C@@H:23]2[C:33]#[N:34])[CH2:15]1
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C#N)[C@@]3(C)CC(=O)[C@@H]12
Reactant: CC1(C)CNCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@H]4[C@@H]5CC[C@H](C#N)[C@@]5(C)CC(=O)[C@@H]43)C[C@@H]2O)CCO1
Temperature: 120 °C
Reaction time: 4.5 h

Procedure:
2,2-Dimethylmorpholine hydrochloride (9.67 g) and sodium hydroxide (2.55 g) were added to a mixture (4:1) of (2α,3α,5α,17β)-2,3-epoxyandrostan-11-one-17-carbonitrile and its 3α,4α-epoxy isomer (5.0 g) (British patent 1,434,919) in 1,2-ethanediol (50 ml) and the mixture was heated in an atmosphere of nitrogen at 120° C. for 19 h and then at 150° C. for 4.5 h. The reaction mixture was poured into water (500 ml) and the precipitated solid was filtered off and dissolved in dichloromethane. After washing the solution with water and drying over sodium sulfate, the solvent was removed under reduced pressure and the residue (6.9 g) was chromatographed on silica gel. The purified product (4.3 g) was sequentially crystallised from ethanol and acetone-diethyl ether to give (2β,3α,5α,17β)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)androstan-11-one-17-carbonitrile (2.37 g). m.p. 206°-210° C.; [α]D +122.9° (c 0.8).
Reaction SMILES: [CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH3:21]O>>[CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:5][C:6]([O:8][CH3:21])=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(O)CC(c1cccc(O)c1)C1CC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CC(c1cccc(O)c1)C1CC1
Temperature: 25 °C

Procedure:
To a solution of 3-cyclopropyl-3-(3-hydroxyphenyl)propanoic acid (longer retention time: 2.47 g) in methanol (60 mL) was added conc. sulfuric acid (64 μL), and the mixture was heated under reflux for 12 hr. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate (30 mL), and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound (2.53 g) as a colorless oil. This compound was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1.[CH2:18]([S:22](Cl)(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([S:22]([NH:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1)(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21]
Reactant: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Reactant: CCCCS(=O)(=O)Cl
Product: CCCCS(=O)(=O)Nc1ccc(C)n(CC(=O)OC(C)(C)C)c1=O

Procedure:
The title compound was prepared from tert-butyl 2-[3-amino-6-methyl-2-oxo-1(2H)-pyridinyl]acetate (EXAMPLE 1, STEP 1-3), and 1-butanesulfonyl chloride using the procedure of EXAMPLE 9 (STEP 2). The product was recrystallized from ethylacetate to give a white crystalline solid compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][N:21]=[C:20]3[C:15]=2[C:16]2[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=2[C:18](=[O:24])[NH:19]3)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.CO>[N:11]1([C:14]2[CH:23]=[CH:22][N:21]=[C:20]3[C:15]=2[C:16]2[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=2[C:18](=[O:24])[NH:19]3)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc3[nH]c(=O)c4ccccc4c23)CC1
Agent: Cl
Solvent: CO
Product: O=c1[nH]c2nccc(N3CCNCC3)c2c2ccccc12
Temperature: 60 °C
Reaction time: 4 h
Yield: 118.9 %

Procedure:
Compound 178 (70 mg, 0.18 mmol) was dissolved in 1.5 M HCl/MeOH (5 mL), and stirred for 4 h at 60° C. The reaction solution was concentrated, and the resulting precipitate was dried under vacuum to provide 179 (60 mg, 92% yield) as a white solid. LC-MS (M+H=281, obsd.=281).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]3[CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH2:15][O:16][C:17]=3[N:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:26].C(OCC)(=O)C>>[ClH:26].[CH:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]3[CH2:12][NH:13][CH2:14][CH2:15][O:16][C:17]=3[N:18]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(OC3CCCCC3)ccc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc2c(nc1OC1CCCCC1)OCCNC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A mixture of the compound obtained in step 1 (0.40 g) and 4N hydrogen chloride/ethyl acetate (3 mL) was stirred at room temperature for 3 hr. The precipitate was collected by filtration, and the aqueous layer was basified and extracted with ethyl acetate and aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and 4N hydrogen chloride/ethyl acetate was added. The precipitate was collected by filtration and recrystallized from ethanol-diisopropyl ether to give the title compound (0.25 g, 50%) as a white powder.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27]([OH:29])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([NH2:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>>[C:33]([C:32]1[N:37]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]3)=[O:10])[CH2:12]2)[O:29][N:31]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Reactant: CC(C)(C)C(N)=NO
Product: CC(C)(C)c1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 31.2 mg (0.269 mmol) of N′-hydroxy-2,2-dimethylpropanimidamide were reacted according to the General Method 1. Yield: 79.1 mg (66% of theory).