Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.[Br:24][C:25]1[C:26](=[O:39])[N:27]([C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[N:28]=[CH:29][C:30]=1[Br:31]>ClCCl>[Br:24][C:25]1[C:26](=[O:39])[N:27]([C:32]2[CH:33]=[CH:34][C:35]([O:38][CH:23]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:36][CH:37]=2)[N:28]=[CH:29][C:30]=1[Br:31]
Reactant: O=c1c(Br)c(Br)cnn1-c1ccc(O)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=c1c(Br)c(Br)cnn1-c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A catalytic amount of pyridinium p-toluenesulfonate and 3,4-dihydro-2H-pyrane (0.8 mL, 8.89 mmols) were added to a dichloromethane (30 mL) solution of 4,5-dibromo-2-(4-hydroxyphenyl)-2H-pyridazin-3-one (1.03 g, 2.98 mmols), and stirred at room temperature for 2 hours, washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous potassium carbonate. Concentrating the solvent under reduced pressure, the resulting residue was crystallized from mixed solvent of ethyl acetate and hexane to provide the title compound (1.1 g, 86%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:4]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[N:27]=[C:28]=[O:29].CO>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[NH:27][C:28](=[O:29])[N:2]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH:4]=1)[CH3:1]
Reactant: Cc1ccc([N+](=O)[O-])cc1N=C=O
Reactant: CNc1cc(NC(=O)OC(C)(C)C)ncn1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])cc1NC(=O)N(C)c1cc(NC(=O)OC(C)(C)C)ncn1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
A solution of tert-butyl (6-Methylamino-pyrimidin-4-yl)-carbamate (240 mg, 1.07 mmol, 1.0 eq.), commercially available 2-methyl-5-nitrophenylisocyanate (210 mg, 1.18 mmol, 1.1 eq.), and DMAP (26 mg, 0.21 mmol, 0.2 eq.) in toluene (10 ml) is stirred at 80° C. for 24 h. After cooling to room temperature methanol (10 ml) is added and the suspension formed is stirred for 10 min at 50° C. The precipitate is filtered off and washed with methanol (2×10 ml). After drying in vacuo an extremely insoluble colorless powder is obtained: HPLC: tR=8.09 min (purity: 85%, gradient A), ESI-MS: 403.5 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C[N:13]1CCOCC1.ClC(OC(C)C)=O>ClCCl>[Cl:1][C:2]1[C:7]([C:8]([NH2:13])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: CN1CCOCC1
Agent: CC(C)OC(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1ccc(Cl)nc1Cl
Reaction time: 0.08 h
Yield: 109.9 %

Procedure:
A mixture of 2,6-dichloro-3-carboxypyridine (5.73 g, 30 mmole) and N-methylmorpholine (3.6 ml, 33 mmole) in dichloromethane (100 ml) was stirred in an ice-bath for 5 min. Isopropyl chloroformate (4.28 ml, 33 mmole) was added the reaction mixture at 0° C. The reaction mixture was stirred for 30 min and then bubbled with pure ammonia gas for 2 min. and stirred overnight at room temperature. The crude was concentrated under reduced pressure and sodium bisulfate (0.5M, 35 ml) was added with stirring. The aqueous solution was extracted with ethyl acetate (3×40 ml). The organics was washed with water and brine and dried with sodium sulfate to give yellow crude product (6.3 g, 50% pure).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH2:11][CH2:12][C:13]([CH3:16])([Cl:15])[CH3:14])[N:5]([S:7]([NH2:10])(=[O:9])=[O:8])[CH3:6].C[O-].[Na+]>CO>[CH3:14][C:13]([Cl:15])([CH3:16])[CH2:12][CH2:11][CH:4]1[N:5]([CH3:6])[S:7](=[O:9])(=[O:8])[NH:10][C:3]1=[O:2]
Reactant: COC(=O)C(CCC(C)(C)Cl)N(C)S(N)(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN1C(CCC(C)(C)Cl)C(=O)NS1(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.4 %

Procedure:
A solution of N-(aminosulfonyl)-2-(3-methyl-3-chlorobutyl) sarcosine methyl ester (14.5 g, 50.56 mmol) in methanol (150 ml) was added to a solution of sodium methoxide (Na=2.4 g) in 150 ml of ice-cold methanol. The resulting reaction mixture was stirred at room temperature under nitrogen for 1.5 hours, and the mixture was treated with 25 g of ion-exchange resin (BIO-RAD® 50W- x8 H+) for 40 minutes and filtered. The filtrate was concentrated in vacuo to afford 12.54 g (97.4%) of 4-(3-methyl-3-chlorobutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1 -dioxide (Formula IV: R1 =H; R2 =(CH2)2C(Cl) (CH3)2 ; R3 =CH3) as a solid.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.C(OC([CH:21]1[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]1)=O)C.Cl[C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=[CH:37][CH:36]=1.[OH-].[K+].Cl.[OH-].[Na+]>C1COCC1.O1CCOCC1>[NH:24]1[CH2:25][CH2:26][CH:21]([C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=[CH:37][CH:36]=2)[CH2:22][CH2:23]1
Reactant: Clc1ccnc2ccccc12
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: c1ccc2c(C3CCNCC3)ccnc2c1
Temperature: 25 °C

Procedure:
A solution of 1.03 M LiHMDS/THF (11.5 mL, 11.8 mmol) was treated dropwise with a solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (2.79 g, 10.9 mmol) (WO 2003064413) in THF (6 mL) over 5 min at 0° C. with stirring under argon. After stirring 30 min at 0° C., the dark yellow homogeneous solution was treated dropwise with a solution of 4-chloroquinoline (1.615 g, 9.88 mmol) in THF (5 mL) over 1-2 min at 0° C. with stirring. The ice bath was then removed and the reaction was stirred at rt overnight, then refluxed for two hours. After cooling to rt, 1 M KOH (aq) (44 mL, 44 mmol) was added and the reaction refluxed for 30 min. Dioxane (22 mL) was added to the bilayer, and the reaction was refluxed an additional 30 min. After cooling to rt, the bilayer was treated dropwise with 12 N HCl (7.4 mL, 89 mmol HCl) (Caution: exotherm) and then refluxed for 30 min under air. The light amber bilayer was allowed to cool to rt, made basic by the addition of 2.5 M NaOH (50 mL), and extracted with DCM (1×50 mL) and 4:1 DCM/MeOH (1×50 mL). The organic layers were combined, dried (Na2SO4), and concentrated to give a residue that was shown by LC/MS to contain the title compound as a minor component and the ethyl ester intermediate as the major component. The ethyl ester intermediate was stirred with KOH pellets (2.4 g, 37 mmol) in MeOH (10 mL) at 100° C. (oil bath) for 3 h, allowed to cool to rt, treated cautiously with 6 M HCl (aq) (10 mL) and water (10 mL), and stirred at 100° C. for 20 min. After cooling to rt, the homogeneous solution was brought to pH >12 with 2.5 M NaOH and extracted with 9:1 DCM/MeOH (2×50 mL). The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure. Flash chromatography (85:15 DCM/MeOH saturated with NH3) afforded the title compound as a white semisolid (702 mg, 34%). 1H-NMR (300 MHz, CDCl3) δ 8.86 (d, 1H), 8.11 (m, 2H), 7.70 (m, 1H), 7.56 (m, 1H), 7.30 (d, 1H), 3.46 (tt, 1H), 3.27 (m, 2H), 2.91 (td, 2H), 2.02-1.92 (m, 2H), 1.87 (br s, 1H), 1.85-1.69 (m, 2H). LC/MS (ESI): calcd mass 212.1, found 213.1 (MH)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:20]2[CH2:25][C@@H:24]([C:26](=[O:31])N(OC)C)[CH2:23][N:22]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:43][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[C:26]([C@@H:24]1[CH2:25][C@H:20]([N:19]([C:17]([C:8]2[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])=[N:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][CH:7]=2)=[O:18])[CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:21][N:22]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[CH2:23]1)(=[O:31])[CH3:43]
Reactant: C[Mg]Br
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N(C)OC)CN(C(=O)OC(C)(C)C)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(C)=O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
tert-Butyl (3S,5R)-3-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (75 mg) was dissolved in tetrahydrofuran (10 ml), 1 M methylmagnesium bromide in THF solution (1.3 ml) was added at 0° C., and the mixture was stirred at room temperature for 10 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (0:1-1:1) was concentrated under reduced pressure to give the object compound (38 mg).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[K].[CH3:11][C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][C:31]=1[CH3:32])[C:15]([C:17]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH3:28])[N:24]=2)[NH:19][CH:18]=1)=[O:16].[Br:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40]Br)[N:35]=1.O>O1CCCC1.C(OCC)(=O)C>[Br:33][C:34]1[N:35]=[C:36]([CH2:40][N:19]2[C:20]3[C:25](=[N:24][C:23]([CH3:28])=[CH:22][CH:21]=3)[C:26](=[O:27])[C:17]([C:15](=[O:16])[C:14]3[CH:29]=[CH:30][C:31]([CH3:32])=[C:12]([CH3:11])[CH:13]=3)=[CH:18]2)[CH:37]=[CH:38][CH:39]=1
Reactant: BrCc1cccc(Br)n1
Reactant: Cc1ccc2[nH]cc(C(=O)c3ccc(C)c(C)c3)c(=O)c2n1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc2c(n1)c(=O)c(C(=O)c1ccc(C)c(C)c1)cn2Cc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium hexamethyldisilazane (0.49 mL, 0.246 mmol, 0.5 M in THF) was added to a solution of 3-(3,4-Dimethyl-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one (60 mg, 0.205) in 2 mL of tetrahydrofuran. After the reaction was stirred at room temperature for 20 minutes 2-bromo-6-bromomethyl-pyridine (61.8 mg, 0.246 mmol) was added and stirred overnight at room temperature. Water and ethyl acetate were added and the two phases were separated. The aqueous phase was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried with magnesium sulfate, filtered and concentrated in vacuo. The crude brown solid was purified by reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 1-(6-Bromo-pyridin-2-ylmethyl)-3-(3,4-dimethyl-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one as an off white solid. LC-MSD, m/z for C24H20BrN3O2 [M+H]: 462.07 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.3 min.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH:15]=[C:14]([S:17](Cl)(=[O:19])=[O:18])[CH:13]=[CH:12]2)(=[O:3])[CH3:2].C([N:23](CC)CC)C.[OH-].[NH4+]>C(Cl)Cl>[NH2:23][S:17]([C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][CH:8]=[C:7]2[CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: CCN(CC)CC
Reactant: CC(=O)NCCc1cccc2ccc(S(=O)(=O)Cl)cc12
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)NCCc1cccc2ccc(S(N)(=O)=O)cc12
Reaction time: 2 h

Procedure:
0.8 mmol of the compound obtained in Step B is dissolved in 10 ml of CH2Cl2 and then 1.2 mmol of triethylamine are added. The mixture is cooled with the aid of an ice bath and 1.2 mmol of ammonium hydroxide solution are added dropwise. After stirring for 2 hours, the mixture is evaporated and the residue obtained is recrystallised.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:24]=[CH:25]/[C:26](O)=[O:27]>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:24]=[CH:25]/[C:26]([NH:16][C:14]1[CH:13]=[N:12][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[CH:15]=1)=[O:27]
Reactant: O=C(O)/C=C/c1ccccc1Cl
Reactant: CC1(CCCCn2cc(N)cn2)OCCO1
Product: CC(=O)CCCCn1cc(NC(=O)/C=C/c2ccccc2Cl)cn1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-4-ylamine and (E)-3-(2-chloro-phenyl)-acrylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:28])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][O:24]C(C)(C)[O:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:28])=[CH:8][C:9]=1[N:10]([CH:20]([CH2:25][OH:24])[CH2:21][OH:22])[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1COC(C)(C)OC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C(CO)CO

Procedure:
A mixture of 5-bromo-3-[(2,2-dimethyl-[1,3]dioxan-5-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (35 mg) contaminated with a small impurity in THF (1.1 mL) and 3N HCl (0.75 mL) was stirred at room temperature for 16 h. It was neutralized with solid NaHCO3 and evaporated down to dryness. The residue was triturated with ethyl acetate (3×8 mL). The ethyl acetate extracts were combined, evaporated and chromatographed over silica gel (hexane:EtOAc—1:1) yielding pure 5-bromo-3-[(2-hydroxy-1-hydroxymethyl-ethyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (18 mg; 7.2% in two steps).
Reaction SMILES: [F:1][C:2]1([CH2:26][N:27]=[N+]=[N-])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[F:1][C:2]1([CH2:26][NH2:27])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(CN=[N+]=[N-])CC3)c(F)c2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(CN)CC3)c(F)c2)C(=O)O1
Yield: 67 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(4-fluoro-4-azidomethylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.73 mmol) with triphenylphosphine (1.27 mmol) in tetrahydrofuran (10 ml) at a temperature 25° C. for six hours and then refluxing for overnight after addition of drop of water followed by purification using silica gel column chromatography in 67% yield.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C.C(OCC)C>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH3:7])[CH3:23])[CH3:22]
Reactant: CCOC(=O)C(C)Br
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C(C)Oc1ccccc1OC
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 91.6 %

Procedure:
Cesium carbonate (53.86 g, 165.3 mmol) was added to a solution of 2-methoxyphenol (10.26 g, 82.6 mmol) in anhydrous DMF (500 mL) at room temperature under an atmosphere of nitrogen. After five minutes, ethyl 2-bromopropionate (10.7 mL, 82.6 mmol, d=1.394) was added rapidly dropwise and the resultant mixture was allowed to stir at 90° C. for 18 h. The reaction mixture was diluted with diethyl ether, then extracted twice with 1N HCl and twice with water. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (25% ether in hexanes) to provide the titled compound (16.97 g, 92%) as a light yellow oil.1H NMR (400 MHz, CDCl3): δ 6.96–6.80 (m, 4H), 4.73 (q, 1H, J=7.04 Hz), 4.23–4.12 (m, 2H), 3.82 (s, 3H), 1.62 (d, 3H, J=6.65 Hz), 1.21(t, 3H, J=7.04 Hz). MS [ES+] m/z exact mass calcd for C12H17O4 225.1127, found 225.1110. Rf=0.19 in 25% ether in hexanes.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:20]2[CH2:25][C@@H:24]([C:26]([N:28]3[CH2:33][CH2:32][C:31]([OH:35])([CH3:34])[CH2:30][CH2:29]3)=[O:27])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:47].CO>>[ClH:47].[ClH:47].[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([C@H:20]2[CH2:25][C@@H:24]([C:26]([N:28]3[CH2:33][CH2:32][C:31]([OH:35])([CH3:34])[CH2:30][CH2:29]3)=[O:27])[CH2:23][NH:22][CH2:21]2)[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:18])=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCC(C)(O)CC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@@H]1CNC[C@H](C(=O)N2CCC(C)(O)CC2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl (3S,5R)-3-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-[(4-hydroxy-4-methylpiperidin-1-yl)carbonyl]piperidine-1-carboxylate (113 mg) was dissolved in 10% hydrogen chloride-methanol solution (4.5 ml), and the mixture was stirred at room temperature for 18 hr. The solvent was evaporated under reduced pressure, and the residue was dried under reduced pressure to give the object compound (82 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][CH:8]([C:14]([F:17])([F:16])[F:15])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6]2)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([S:36][CH3:37])[N:31]=1>[Cl-].[Na+].O>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([S:36][CH3:37])[N:31]=1)[O:9][CH:8]([C:14]([F:15])([F:16])[F:17])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6]2)[CH3:2]
Reactant: CCOC(=O)C1=Cc2cc(CC)c(O)cc2OC1C(F)(F)F
Reactant: CSc1nccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)C1=Cc2cc(CC)c(Oc3ccnc(SC)n3)cc2OC1C(F)(F)F
Temperature: 130 °C
Yield: 42.9 %

Procedure:
To the mixture of 172 mg (0.54 mmol) of Ethyl 6-ethyl-7-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate and 320 mg (1.95 mmol) of potassium carbonate in 3 mL of anhydrous dimethylformmamide was added 270 uL (2.3 mmol) of 4-chloro-2-methylthiopyrimidine. The mixture was heated at 130° C. for half an hour. After cooling to room temperature, the reaction was dumped into 50 mL of brine, the product was extracted with ethyl acetate. The combined organic phases were washed with brine, and dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was purified by silica chromatography with 1:9 EtOAc/Hexane (1:9) to afford 102 mg (43%) of a yellow solid: 1H NMR (CDCl3/400 MHz) 8.35(d, 5.2 Hz, 1H), 7.72(s, 1H), 7.13(s, 1H), 6.74(s, 1H), 6.54(d, J=5.6 Hz, 1H), 5.66(q, J=6.8 Hz, 1H), 4.30(m, 2H), 2.45(q, J=7.6 Hz, 2H), 2.27(s, 3H), 1.33(t, J=7.2 Hz, 3H), 1.12(t, J=7.6 Hz, 3H); MS (ESI+) 441 (M+1, 100).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]([CH3:32])[NH:11][C:12]([C@H:14]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:15][N:16]([O:19]CC3C=CC=CC=3)[CH:17]=[O:18])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1>CCO.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]([CH3:32])[NH:11][C:12]([C@H:14]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:15][N:16]([OH:19])[CH:17]=[O:18])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)NN(C)c1ccc2c(c1)OCO2
Agent: [Pd]
Solvent: CCO
Product: CCCCC[C@H](CN(O)C=O)C(=O)NN(C)c1ccc2c(c1)OCO2
Reaction time: 5 h
Yield: 56.8 %

Procedure:
To a solution of N-[(R)-2-(N′-Benzo[1,3]dioxol-5-yl-methyl-hydrazinocarbonyl)-heptyl]-N-benzyloxy-formamide (0.221 g, 0.501 mmol) in EtOH (10 mL) was added 10% Pd/C (50 mg). The mixture was subjected to hydrogenation for 5 h at room temperature. The mixture was filtered through Celite. The filtrate was evaporated and purified by HPLC to afford the title compound (0.10 g, 57%) in a white solid. MH+352.
Reaction SMILES: [CH:1]([C:5]([CH2:12][CH3:13])([CH2:8][CH2:9][C:10]#[N:11])[CH:6]=O)=[CH:2][CH2:3][CH3:4].N.O=[Si]=O.[H][H]>>[CH2:1]([C:5]1([CH2:12][CH3:13])[CH2:8][CH2:9][CH2:10][NH:11][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCC=CC(C=O)(CC)CCC#N
Reactant: [H][H]
Agent: N
Agent: O=[Si]=O
Product: CCCCC1(CC)CCCNC1
Reaction time: 23.9 h
Yield: 754.6 %

Procedure:
45.1 g per hour of 2-butenyl-2-ethyl-4-cyanobutanal (purity 64.0%, 28.9 g, 0.161 mol) and 950 ml (570 g, 33.5 mol) per hour of liquid ammonia were pumped at 250 bar and 50° C. through a tubular reactor (diameter 16 mm, fill level 50 cm, oil-heated twin jacket) upstream of the hydrogenation reactor and filled with 43.3 g (96 ml) of a Y-zeolite pelleted with Aerosil 200 (HY-zeolite: Aerosil 200=9:1, SiO2 :Al2O3 =6:1). The product stream was subsequently passed through the hydrogenation reactor from bottom to top at 250 bar and 120° C. while simultaneously passing 100 l(S.T.P.)/h (4.5 mol) of hydrogen through the reactor. The product stream was decompressed to atmospheric pressure and NH3 was removed by distillation. From the product from 23.9 hours, 205.7 g of 3-butyl-3-ethylpiperidine and 438.4 g of a mixture of 2-butyl- and 2-butenyl-2-ethylpentane-1,5-diamine (8:1), corresponding to a diamine yield of 61.9% of theory, were isolated by fractional distillation on a 30 cm packed column (3 mm glass rings).
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11](O)=[O:12])=[C:9]2[C:4]([N:5]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[CH2:6][CH2:7][CH2:8]2)=[N:3]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:49][CH2:48][NH:47]1>ClCCl.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:49][CH2:48][N:47]1[C:11]([C:10]1[N:2]([CH3:1])[N:3]=[C:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][N:5]2[C:14]1[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=1[CH3:20])=[O:12]
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3C(=O)O)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(N2CCCc3c2nn(C)c3C(=O)N2CCc3ccccc3C2)c(C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A suspension of 125 mg of 2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine-3-carboxylic acid in 5 mL of dichloromethane was treated with 116 μL of triethylamine, 56 mg of 1-hydroxybenzotriazole hydrate, 88 mg of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, and 52 μL of 1,2,3,4-tetrahydroisoquinoline and stirred under an atmosphere of nitrogen at room temperature for 20 h. The mixture was diluted with 50 mL of ethyl acetate, washed with 30 mL of 0.5M HCl, washed with 30 mL of saturated sodium bicarbonate solution, dried over magnesium sulfate, and evaporated to dryness yielding 149 mg of (3,4-dihydro-1H-isoquinolin-2-yl)[2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]methanone, mp 80.3-87.7° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>[Ni].C(O)C>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ni]
Solvent: CCO
Product: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reaction time: 18 h

Procedure:
A suspension of 4-acetyl-1-(4-nitrophenyl)piperazine [C. A., 67, P101031Z] (30 g, 0.12 mole) and Raney nickel (2.5 g) in ethanol (500 ml) was hydrogenated at 60 psi (414 kPa) and 40° for 6 hours followed by 18 hours at room temperature. The catalyst was subsequently removed by filtration, the solvent removed under reduced pressure and the residue crystallized from ethyl acetate to yield the title compound, m.p. 129°-130° (18.4 g, 71%), which was used directly in the next stage.