Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]([OH:14])=[N:5]1)(=O)C.[C:15](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CN(C=O)C>[CH3:15][O:14][C:6]1[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:8][NH:4][N:5]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cn(C(C)=O)nc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)c1c[nH]nc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 1-acetyl-3-hydroxy-1H-pyrazole-4-carboxylate (2.1 g, 10.6 mmol) and potassium carbonate (1.5 g, 10.6 mmol) in 45 mL of DMF is stirred at RT for 30 minutes. Dimethyl sulfate (1.0 mL, 10.6 mmol) in 25 mL of DMF is then added dropwise over 10 min, and the resulting reaction mixture is heated to 70° C. for 4 h. The solvent is evaporated in vacuo, and the residue is dissolved in water and extracted with CH2Cl2 (2×30 mL). The combined organic extracts are dried (Na2SO4), filtered, and evaporated in vacuo to give a yellow/brown oil. Purification by silica gel column chromatography (gradient from 50% EtOAc/hexane to 80% EtOAc/hexane) affords the title compound as a clear, viscous oil which slowly solidifies on standing.
Reaction SMILES: [C:1]1([C:6]2[CH:30]=[CH:29][C:9]([C:10]([NH:12][CH2:13][C:14]3[C:15]([CH2:20][NH:21]C(=O)OC(C)(C)C)=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:11])=[C:8]([NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.O1CCOCC1>CO>[NH2:21][CH2:20][C:15]1[C:14]([CH2:13][NH:12][C:10](=[O:11])[C:9]2[CH:29]=[CH:30][C:6]([C:1]3[CH2:5][CH2:4][CH2:3][CH:2]=3)=[N:7][C:8]=2[NH:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=2)=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)OC(=O)NCc1ncccc1CNC(=O)c1ccc(C2=CCCC2)nc1NCCc1cccc(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCc1ncccc1CNC(=O)c1ccc(C2=CCCC2)nc1NCCc1cccc(F)c1
Temperature: 25 °C
Yield: 25 %

Procedure:
tert-butyl (3-((6-cyclopentenyl-2-(3-fluorophenethylamino)nicotinamido)methyl)pyridin-2-yl)methylcarbamate was dissolved in MeOH (1 mL) and allowed to stir at room temperature. HCl/dioxane (4M, 2 mL) was added dropwise and stirred until complete. The reaction mixture was concentrated, diluted with EtOAc, washed with saturated sodium bicarbonate, brine and dried (Na2SO4). The organics were concentrated and purified by RP-HPLC with a mixture of acetonitrile and H2O to give N-((2-(aminomethyl)pyridin-3-yl)methyl)-6-cyclopentenyl-2-(3-fluorophenethylamino)nicotinamide as a solid (0.026 g, 25%). LC/MS (M+H+) m/z 446.2.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH3:33])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:30]([O:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[CH2:10][CH2:11]2)(=[O:21])=[O:22])=[CH:24][CH:25]=1)[C:31]#[C:32][CH3:33]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(F)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(F)cc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-fluoro-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-but-2-ynyloxy-benzenesulfonyl)-1-(4-fluoro-benzyl)-piperidine-4-carboxylic acid ethyl ester (9.5 g, 20 mmol) dissolved in THF:methanol 3:1 (100 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 5.7 g (63%); white solid; mp 106-106° C.; MS: 447 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[OH-].[Na+].Cl[C:20]([O:22][CH3:23])=[O:21].Cl>O1CCOCC1.CCOC(C)=O>[CH3:23][O:22][C:20]([N:14]1[CH2:15][CH2:16][N:11]([C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[F:1])[CH2:12][CH2:13]1)=[O:21]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)c(F)c1
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a solution of Example 119A (4.0 g, 17.76 mmol) in dioxane (40 mL) at 0° C. was added 2 M NaOH (29.3 mL, 58.6 mmol) followed by dropwise addition of methyl chloroformate (2.75 mL, 35.5 mmol). The solution was warmed to room temperature and stirred for 2 h. Diluted with EtOAc and added 1 N HCl until all solid had dissolved, separated the phases and washed the organic phase with 1 N HCl, H2O, brine, dried (Na2SO4), filtered and removed solvent in vacuo to give the title compound (4.69 g, 16.56 mmol, 93%). 1H NMR (400 MHz, CDCl3) δ ppm 3.20-3.31 (m, 4H) 3.62-3.71 (m, 4H) 3.75 (s, 3H) 6.92 (t, J=8.8 Hz, 1H) 7.93 (dd, J=12.9, 2.6 Hz, 1H) 7.98-8.02 (m, 1H). MS (ESI) m/z 284 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[C:9]([CH2:15][OH:16])=[N:10][CH:11]=[CH:12][C:13]=1Cl>C(O)C>[O:4]1[CH2:5][CH2:6][N:1]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([CH2:15][OH:16])[C:8]=2[Cl:7])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: OCc1nccc(Cl)c1Cl
Solvent: CCO
Product: OCc1nccc(N2CCOCC2)c1Cl

Procedure:
Morpholine (7.34 ml) and 3.4 -dichloro-2 -hydroxymethylpyridine (3.0 g) were heated together in a bomb at 180 ° for 4 hours. After cooling, the mixture was taken up in ethanol and evaporated under reduced pressure to remove excess amine. The residue was taken up in water and extracted with chloroform. After drying (K2CO3 ) and removal of solvent, the residue was chromatographed (silica gel, CHCl3) to give an oil which was crystallised from petroleum ether (60/80 ) to give 4 -morpholino-3 -chloro-2 -hydroxymethylpyridine, 3.24 g, m.p. 80°-2°.
Reaction SMILES: C([O:8][C:9](=[O:31])/[C:10](/[O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([O:18]CC2C=CC=CC=2)=[CH:14][CH:13]=1)C1C=CC=CC=1>CO.[Pd]>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH:10]([O:26][CH2:27][CH2:28][O:29][CH3:30])[C:9]([OH:31])=[O:8])=[CH:13][CH:14]=1
Reactant: COCCO/C(=C\c1ccc(OCc2ccccc2)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COCCOC(Cc1ccc(O)cc1)C(=O)O
Yield: 82.3 %

Procedure:
(Z)-3-[4-(Benzyloxy)phenyl]-2-(2-methoxyethoxy)-2-propenoic acid benzyl ester (1.75 g; 4.2 mmole) was hydrogenated in methanol (50 ml) at atmospheric pressure using Pd/C (5%) as catalyst. The mixture was filtered through celite and evaporated in vacuo to give 3-(4-hydroxyphenyl)-2-(2-methoxyethoxy)propanoic acid 0.83 g (88% yield).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[S:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][NH:10][CH2:9][CH2:8]1>ClCCl>[CH2:1]([S:3]([N:10]1[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:7][CH2:8][CH2:9]1)(=[O:5])=[O:4])[CH3:2]
Reactant: c1ccc2c(c1)CNCCS2
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCSc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ethanesulphonyl chloride (3.8 g) in dichloromethane (50 ml) was added dropwise at room temperature to a stirred solution of 2,3,4,5-tetrahydro-1,4-benzothiazepine (4.29 g, prepared as described in the first paragraph of Example 6 above) in dichloromethane (100 ml). The reaction mixture was stirred at room temperature for one hour, washed with water, dried and the solvent was removed by evaporation. Purification of the residue by flash chromatography using trichloromethane as eluent gave 4-ethylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from hexane. Yield 4.25 g (m.p. 78°-80° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](Cl)=[N:13][CH:12]=1.[CH2:19]([NH2:22])[CH2:20][NH2:21]>>[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([NH:21][CH2:20][CH2:19][NH2:22])=[N:13][CH:12]=1
Reactant: NCCN
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)c(N)c1
Product: Cc1ccc(NC(=O)c2ccc(NCCN)nc2)c(N)c1
Yield: 51 %

Procedure:
N-(2-Amino-4-methyl-phenyl)-6-chloronicotinamide (261 mg, 1 mmol) and 5 ml of ethylenediamine were heated to 80° C. for 3 hours. The excess ethylenediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (145 mg, 51% yield) as a brown solid. LC-MS (m/z) 286 (M+1).
Reaction SMILES: [CH:1]([O-:3])=O.[Na+].C(Br)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]>C(O)C>[CH2:1]([OH:3])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(CO)c1ccccc1
Temperature: 105 °C

Procedure:
This procedure was adapted from the one developed by Pirkle and Simmons (Pirkle, W. H. and Simmons, K A., J. Org. Chem. 48:2520-2527 (1983)). 11.62 g (0.1706 moles) sodium formate was stirred in 50 ml ethanol for about 15 minutes. 5.31 g (26.7 mmol) phenacyl bromide was added to it and the mixture was refluxed under nitrogen at 105° C. for nearly 20 h. The reaction mixture was cooled and complete conversion of the starting material was confirmed by TLC. The solvent was evaporated and about 50 ml of boiling water was added and the solution was filtered hot. The filtrate was then cooled to precipitate out the alcohol. Yield 3.11 g (86%) from 5.31 g phenacyl bromide, white crystalline solid: mp 82-84° C. (lit. mp 84-85° C. (Pirkle, W. H. and Simmons, K A., J. Org. Chem. 48:2520-2527 (1983)); 1H NMR (CDCl3) δ6 3.49 (t, J=4.5), 4.87 (d, J=4.5), 7.44-7.65 (m, 3H), 7.91 (dd, J1=8, J21.3, 2H); 13C NMR (CDCl3) δ198.4, 134.3, 133.5, 129.0, 127.7, 65.5; EI-MS, m/z (rel. intensity) 136 (M+, 6), 105 (100), 77 (81), 52 (29).
Reaction SMILES: O[CH:2]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:3]([Cl:6])([Cl:5])[Cl:4].[Cl:17]CCl.S(Cl)(Cl)=O>CN(C)C=O>[Cl:17][CH:2]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:3]([Cl:6])([Cl:5])[Cl:4]
Reactant: ClCCl
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1ccccc1O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(NC(Cl)C(Cl)(Cl)Cl)c1ccccc1O

Procedure:
14.2 g of N-(1-hydroxy-2,2,2-trichloroethyl)-2-hydroxybenzamide was mixed with 100 ml of dichloromethane, 7.2 g of thionyl chloride and 0.1 g of N,N-dimethylformamide and the reaction was effected while stirring under reflux for three hours. The solvent was distilled off to obtain N-(1,2,2,2-tetrachloroethyl)-2-hydroxybenzamide (m.p.: 113°-113.5° C.). Without taking this out, 100 ml of dichloromethane and 3.8 g of iso-propyl mercaptan were added thereto and then 4.0 g of pyridine was also added dropwise. After effecting the reaction at room temperature for one hour, water was added thereto, the dichloromethane layer was separated out, dried and concentrated to obtain 16.2 g of N-(1-iso-propylthio-2,2,2-trichloroethyl)-2-hydroxybenzamide as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][O:27][C:28](=[O:40])[C@H:29]([CH2:38][SH:39])[NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[CH3:26][O:27][C:28](=[O:40])[CH:29]([NH:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:38][S:39][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH:3]=1
Reactant: COC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Reactant: CN1CCC(OC(c2cccc(Br)c2)c2nc3ccccc3[nH]2)CC1
Product: COC(=O)C(CSc1cccc(C(OC2CCN(C)CC2)c2nc3ccccc3[nH]2)c1)NC(=O)OC(C)(C)C

Procedure:
The compound is synthesized from 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (example 72A) and N-Boc-Cysteine methyl ester using the method described in example 150; mixture of diastereomers. 1H NMR: 10.66 and 9.83 (sl, 1H), 7.90-7.70 (m, 2H), 7.50-7.35 (m, 2H), 7.35-7.18 (m, 5H), 5.87 and 5.85 (s, 1H), 5.58-5.30 (m, 1H), 4.65-4.40 (m, 1H), 3.70-3.20 (m, 6H), 2.82-2.62 (m, 2H), 2.28 and 2.26 (s, 3H), 2.22-1.65 (m, 6H), 1.53 and 1.45 (s, 9H).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH:9]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[S:8](=[O:17])(=[O:16])[C:7]2[S:18][C:19]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:20][C:6]1=2)(=O)[CH3:2].B.CSC.CSC>O1CCCC1>[CH2:14]([O:13][CH2:12][CH2:11][CH:9]1[S:8](=[O:16])(=[O:17])[C:7]2[S:18][C:19]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:20][C:6]=2[CH:5]([NH:4][CH2:1][CH3:2])[CH2:10]1)[CH3:15]
Reactant: CCOCCC1CC(NC(C)=O)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CCNC1CC(CCOCC)S(=O)(=O)c2sc(S(N)(=O)=O)cc21

Procedure:
To a stirred solution of 4-acetamido-5,6-dihydro-6-(2-ethoxyethyl)-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide (6.8 g, 0.017 mol) in tetrahydrofuran (20 ml) heated under nitrogen to reflux was added borane-methyl sulfide (17 ml, 0.170 mol) dropwise over 1/2 hr. The reaction was heated at reflux for 2 hr. while allowing the methyl sulfide to distill off. Then the mixture was concentrated in vacuo to a yellow gum. Then 6N HCl (30 ml) was added followed by water (30 ml) and the mixture was heated on the steam bath for 1/4 hour. The solution was basified with excess sodium bicarbonate and was extracted with ethyl acetate (300 ml). The aqueous solution was again extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried, filtered and concentrated in vacuo to obtain a white foam (5.3 g) mixture of cis and trans isomers. Chromatography on silica gel gave 2.28 g of the a-isomer and 0.17 g of the β -isomer.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:19]=[CH:18][N:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[N:21]=3)[N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:23]=[C:22]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=2)[N:21]=[C:20]([N:17]2[CH:18]=[N:19][C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)=[N:16]2)[CH:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ncn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2ncn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)n2)c1
Yield: 26.8 %

Procedure:
To a cooled and stirred solution of the above prepared N-tert-butyl-3-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-1H-[1,2,4]triazol-3-yl}-benzenesulfonamide (0.090 g, 0.16 mmol) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield the title compound as a white solid (0.022 g, 27%). MS (ISP) 514.3 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH3:20])[C:6](=[O:21])[NH:5][C:4]=2[N:3]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:23]([N:5]1[C:4]2[N:3]=[C:2]([Cl:1])[N:10]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[C:9]=2[C:8](=[O:19])[N:7]([CH3:20])[C:6]1=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cn1c(=O)[nH]c2nc(Cl)n(Cc3ccc(Cl)cc3)c2c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccc(Cl)cc2)n(Cc2ccccc2)c1=O
Temperature: 40 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a solution of 8-chloro-7-(4-chlorobenzyl)-1-methyl-1H-purine-2,6(3H,7H)-dione (50 mg, 0.154 mmol, intermediate 10) in DMF (3 mL) was added (bromomethyl)benzene (50 mg, 0.29 mmol) followed by potassium carbonate (40 mg, 0.29 mmol). The mixture was stirred at 40° C. overnight. The mixture was diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography eluting with petroleum/ethyl acetate (5:1 to 3:1) to give 3-benzyl-8-chloro-7-(4-chlorobenzyl)-1-methyl-1H-purine-2,6(3H,7H)-dione (60 mg, 93.6% yield) as white solid. LCMS retention time 1.893 min; LCMS MH+ 415.
Reaction SMILES: [NH2:1][CH:2]([CH:5]([C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2)[CH3:6])[C:3]#[N:4].C(N)CN>CO.[Ni]>[N:12]1[C:13]2[C:8](=[C:7]([CH:5]([CH3:6])[CH:2]([NH2:1])[CH2:3][NH2:4])[CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(c1cccc2ncccc12)C(N)C#N
Agent: [Ni]
Solvent: NCCN
Solvent: CO
Product: CC(c1cccc2ncccc12)C(N)CN
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71.3 %

Procedure:
In a Parr bottle, a mixture of 2-amino-3-quinolin-5-yl-butyronitrile (Intermediate-E2) (5.38 g, 25.4 mmol) in MeOH (100 mL) and ethylene diamine (3.2 mL, 47.8 mmol) was reacted with Raney 2800 nickel (18.9 g) and bubbled with ammonia gas for 10 m. The Parr bottle was pressurized with hydrogen at 50 psi and shaken on a Parr apparatus for 2.5 h at rt. The mixture was filtered through celite, washed with MeOH (3×) and evaporated to leave a residue. This material was placed onto a column and eluted with a gradient of 1% to 5% sat. NH3-MeOH:CH2Cl2 to give 3-quinolin-5-yl-butane-1,2-diamine (Intermediate E3) 3.9 g (71%).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([O:61][CH3:62])=[C:53]([C:58](=[O:60])[NH2:59])[CH:54]=4)[O:49][C:48]=3[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([O:61][CH3:62])=[C:53]([C:58]([NH2:59])=[O:60])[CH:54]=4)[O:49][C:48]=3[C:63]3[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: COc1cc2oc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(=O)c2cc1C(N)=O
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1cc2oc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)c(=O)c2cc1C(N)=O
Yield: 58.3 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(6-carbamoyl-7-methoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butylester (40 mg, 0.074 mmol) was reacted to give the title compound (19 mg, 58%). LCMS (Method E): RT=3.15 min, [M+H]+=441. 1H NMR (400 MHz, DMSO-d6): δ 8.44 (s, 1H), 7.68 (d, J=7.7 Hz, 2H), 7.41-7.26 (m, 8H), 7.10 (d, J=8.3 Hz, 2H), 3.98 (s, 3H), 3.27 (s, 2H), 2.39-2.29 (m, 2H), 2.11-2.02 (m, 2H), 2.00-1.89 (m, 1H), 1.67-1.55 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=2)[CH:3]=1.[NH2:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>CN1CCCC1=O.C(OCC)(=O)C.O>[C:28]([O:27][C:26](=[O:32])[NH:25][C@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]1[NH:18][C:2]1[N:7]=[N:6][C:5]([C:8](=[O:9])[NH2:10])=[C:4]([NH:11][C:12]2[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=2)[CH:3]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: Cn1ccc(Nc2cc(Cl)nnc2C(N)=O)n1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: Cn1ccc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Temperature: 150 °C
Yield: 17.6 %

Procedure:
6-Chloro-4-(1-methyl-1H-pyrazol-3-ylamino)-pyridazine-3-carboxylic acid amide (60 mg, 0.237 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (102 mg, 0.475 mmol) were dissolved in N-methylpyrrolidinone (1.5 mL). The reaction mixture was heated at 150° C. for 16 h, then additional tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (100 mg, 0.47 mmol total) was added in three portions over 6 d. The reaction mixture was cooled, diluted with ethyl acetate and water, and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, and then dried (sodium sulfate), filtered, and concentrated in vacuo. The residue obtained was purified by chromatography (silica, 0 to 7% methanol in dichloromethane) to give {(1S,2R)-2-[6-carbamoyl-5-(1-methyl-1H-pyrazol-3-ylamino)-pyridazin-3-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (18 mg, 17%) as a brown amorphous residue. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 10.68-10.80 (m, 1H) 7.89-8.06 (m, 1H) 7.34-7.37 (m, 1H) 7.25 (d, J=2.3 Hz, 1H) 5.93 (d, J=2.3 Hz, 1H) 5.56-5.64 (m, 1H) 5.02-5.14 (m, 1H) 3.91-4.01 (m, 1H) 3.86 (s, 3H) 1.55 (br. s., 8H) 1.40 (s, 9H); LCMS (EI/CI) m/z: 431 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=1.Cl[C:30]([O:32][CH3:33])=[O:31].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:30]([O:32][CH3:33])=[O:31])[CH:6]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CNCc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN(Cc2ccccc2)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To {3-[2-(benzylamino-methyl)-4-bromo-phenoxy]-phenyl}-acetic acid methyl ester (0.076, 0.17 mmol) and methyl chloroformate (0.01 mL, 0.18 mmol) in CH2Cl2 (2 mL) was added triethylamine (0.02 mL, 0.18 mmol), and the reaction was stirred at room temperature for 3 hours. Some starting material was still observed by analytical LCMS, so additional methyl chloroformate (0.02 mL) and triethylamine (0.03 mL) was added, and the reaction was stirred overnight. The mixture was concentrated and purified by silica gel chromatography (10-30% EtOAc in hexanes) to give the title compound.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].[Cl-].C[Zn+].[CH2:15](N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(C)c(C#N)c(Cl)n1
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Zn+]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cc1cc(C)c(C#N)c(C)n1
Temperature: 0 °C
Yield: 87 %

Procedure:
2-chloro-4,6-dimethyl-nicotinonitrile (700 mg, 4.201 mmol) and Pd(PPh3)4 (243 mg, 0.210 mmol) were dissolved in 20 mL of anhydrous THF, added with methylzinc chloride (2M CH3ZnCl/THF, 12.6 mL, 25.21 mmol) and refluxed for about 40 hours under the nitrogen atmosphere. The mixture was added to a saturated EDTA solution (50 mL), and neutralized with potassium carbonate while stirring at 0° C. and then extracted twice with 150 mL of methylene chloride. The resulting organic layer was dried using anhydrous sodium sulfate, filtered and concentrated. A silica gel column chromatography (25% EtOAc/Hexanes) was performed on the resulting residue and 535 mg (87%) of 2,4,6-trimethyl-nicotinonitrile was obtained in white solid.