Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[S:13]([NH:16][CH2:17][CH2:18][OH:19])(=[O:15])=[O:14].[H-].[Na+].[Na].[C:25]1(C)C=CC(S(OC)(=O)=O)=CC=1>CN(C=O)C.C(Cl)CCC.CCOC(C)=O>[CH3:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[S:13]([N:16]([CH2:17][CH2:18][OH:19])[CH3:25])(=[O:15])=[O:14]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CN(C)C(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCO
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CCCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)N(C)CCO
Reaction time: 20 h

Procedure:
A solution of N,N-Dimethyl-2-[N-(2-hydroxyethyl)aminosulfonyl]-6-nitrobenzamide (3.97 g, 12.5 mmol) in dry DMF (40 ml) was added slowly to a stirred suspension of 50% NaH (0.60 g, 12.5 mmol) in dry DMF (10 ml) under N2 at 20-25°. After formation of the sodium salt was complete, a solution of methyl p-toluenesulfonate (2.40 g, 12.9 mmol) in DMF (4 ml) was added and the reaction mixture stirred at 20-25° for 20 hours and then at 60° for 23 hours. The orange solution was mixed with EtOAc (400 ml) and the white solid which formed was filtered off. This precipitate was washed with EtOAc (100 ml). The combined EtOAc solutions were washed with a saturated aqueous NaCl solution, dried (Na2SO4), filtered and concentrated under reduced pressure. Pure produced, mp 107-08°, 2.5 g (60%) was obtained by flash chromatography over silica gel and elution with a 65% n-butylchloride-35% acetonitrile solvent mixture.
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:7][O:6][CH2:5][CH2:4]1.[CH3:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OCCBr)C>C(OCC)(=O)C.O>[CH2:5]([O:6][CH2:7][CH2:3][N:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:8])[CH3:4]
Reactant: C1CCOC1
Reactant: CNCc1ccccc1
Agent: CCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOCCN(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Process 1) NaH (washed with hexane in advance, 8.78 g, 0.305×1.2 mol) was added to a dry THF (300 mL) solution of N-methylbenzylamine (39 mL, 0.305 mol) under an argon atmosphere at room temperature. After stirring at room temperature for 30 minutes, a dry THF (100 mL) solution of bromoethyl ethyl ether (51 mL, 0.305×1.5 mol) was added dropwise, and further heated under reflux under an argon atmosphere for 24 hours. After cooling to room temperature, water (350 mL) was carefully added for dissolution of insoluble materials, followed by adding ethyl acetate (350 mL). The organic layer was separated, further washed with brine (200 mL) and then concentrated to dryness. Since insoluble materials precipitated in the residual fraction, they were filtered off and washed with ethyl acetate, and the filtrate was again concentrated to dryness. The residue was purified by vacuum distillation (fraction at 1.0 to 1.1 kpa and 95° C. to 110° C. collected), and BnEO (49.73 g, 0.257 mol, 84%) was obtained as a colorless transparent liquid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)=[CH:6][N:5]=[C:4]([N:21]2[CH2:26][C@@H:25]3[C@@H:23]([CH2:24]3)[CH:22]2[C:27]([OH:29])=O)[N:3]=1.[NH4+].[Cl-].C[N:33](C([O:39]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.CN([CH:66]=[O:67])C>>[C:66]([OH:67])([C:17]([F:20])([F:19])[F:18])=[O:39].[CH3:1][C:2]1[C:7]([C:8]2[CH:16]=[C:15]([C:17]([F:19])([F:18])[F:20])[CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)=[CH:6][N:5]=[C:4]([N:21]2[CH2:26][C@@H:25]3[C@@H:23]([CH2:24]3)[CH:22]2[C:27]([NH2:33])=[O:29])[N:3]=1
Reactant: CN(C)C=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1nc(N2C[C@H]3C[C@H]3C2C(=O)O)ncc1-c1cc(C(F)(F)F)cc2[nH]ncc12
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Product: Cc1nc(N2C[C@H]3C[C@H]3C2C(N)=O)ncc1-c1cc(C(F)(F)F)cc2[nH]ncc12
Product: O=C(O)C(F)(F)F
Reaction time: 8 h
Yield: 3.2 %

Procedure:
In a 4 mL vial equipped with a magnetic stir bar were mixed (1R,5S)-3-(4-methyl-5-(6-(trifluoromethyl)-1H-indazol-4-yl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (80 mg, 0.198 mmol), NH4Cl (21.22 mg, 0.397 mmol), HATU (90 mg, 0.238 mmol) and Et3N (0.083 mL, 0.595 mmol) in DMF (2 mL). The resulting brown solution was stirred overnight. The product was purified by preparative HPLC, eluting with a gradient of 25-50% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA). The pure fractions were lyophilized to give a TFA salt of the title compound as a white solid (3.3 mg, 3.2%). 1H NMR (400 MHz, CD3OD) δ ppm 0.78-0.86 (m, 2H), 1.88 (ddd, J=12.06, 7.26, 4.67 Hz, 1H), 2.09-2.15 (m, 1H), 2.25-2.29 (m, 3H), 3.82 (dd, J=10.61, 5.05 Hz, 1H), 3.92-3.96 (m, 1H), 4.61 (d, J=5.31 Hz, 1H), 7.28 (d, J=1.01 Hz, 1H), 7.93-7.95 (m, 2H), 8.27 (s, 1H); ESI-MS m/z [M+H]+ calc'd for C19H17F3N6O, 403.2. found 403.4.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C([Li])CCC.[Cl:18][C:19]1[CH:30]=[CH:29][C:22]([C:23](N(OC)C)=[O:24])=[CH:21][C:20]=1[S:31](=[O:34])(=[O:33])[NH2:32]>O1CCCC1>[Cl:18][C:19]1[CH:30]=[CH:29][C:22]([C:23](=[O:24])[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=2)=[CH:21][C:20]=1[S:31]([NH2:32])(=[O:34])=[O:33]
Reactant: CC(C)COc1ccc(Br)cc1
Reactant: CON(C)C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)COc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Temperature: -78 °C
Reaction time: 18 h
Yield: 35.8 %

Procedure:
1-Bromo-4-isobutoxy-benzene (625 mg, 2.73 mmol) is dissolved in tetrahydrofuran (2 mL) and cooled to −78° C. The solution is treated with a solution of n-butyllithium (1.6 M in hexanes, 1.7 mL, 2.73 mmol) and stirred 30 minutes after which a solution of 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide (250 mg, 0.91 mmol) in tetrahydrofuran (2 mL) is added. The reaction is allowed to stir for 18 hours while warming to ambient temperature. The reaction is quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase is separated and concentrated in vacuo. The residue is purified by column chromatography (gradient of ethyl acetate in hexanes 10-50%) affording 120 mg (37% yield) of the title compound. 1H NMR (DMSO) δ 1.00 (d, 6H, J=6.56 Hz), 2.01-2.10 (m, 1H), 3.88 (d, 2H, J=6.57 Hz), 7.11 (d, 2H, J=8.85 Hz), 7.76 (d, 2H, J=8.85 Hz), 7.81-7.84 (m, 3H), 7.89 (dd, 1H, J=2.02, 8.08), 8.24 (d, 1H, J=2.02). MS (m/z): 366 (M−1). CHN Calc C, 55.51; H, 4.93; N, 3.81. Found C, 55.38; H, 4.74; N, 3.77.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[C:4]2[C:9]([C:10]=1[C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.CN1CCOCC1.F[B-](F)(F)F.C(OC(C(=NOC(N(C)C)=[N+](C)C)C#N)=O)C.[N:55]1([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1>CN(C=O)C>[C:64]([O:63][C:61]([N:55]1[CH2:60][CH2:59][N:58]([C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[C:2]=2[Cl:1])=[O:13])[CH2:57][CH2:56]1)=[O:62])([CH3:67])([CH3:65])[CH3:66]
Reactant: COCCCOc1ccccc1-n1c(Cl)c(C(=O)O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCCCOc1ccccc1-n1c(Cl)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a solution of 200 mg (556 μmol) of the compound of step 5 in DMF (5 ml) and NMM (122 μl, 1.11 mmol) was added O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N′,N′-tetramethyluronium tetrafluoroborate (201 mg, 612 μmol), and the mixture was stirred at room temperature for 30 min. tert-Butyl 1-piperazinecarboxylate (114 mg, 612 μmol) was then added and the reaction mixture was stirred for 3 h. The mixture was quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography (EA/HEP 2:5). 285 mg of the title compound were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(O)cc(OC)c1
Yield: 37 %

Procedure:
A suspension of methyl 3,5-dihydroxybenzoate (2.0 g, 11.9 mmol), K2CO3 (1.6 g, 11.9 mmol), and iodomethane (1.7 g, 11.9 mmol) in acetone (100 mL) was stirred at reflux. After stirring for three hours the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography to yield the title compound as a white solid (0.813 g, 4.4 mmol). 1H NMR (400 MHz, CDCl3) δ7.16 (m, 1H), 7.12 (m, 1H), 6.61 (m, 1H), 5.04 (s. 1H), 3.91 (s, 3H) 3.82 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1)C(O)=O.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:35])C=CC=CC=1.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:35])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1
Reactant: CSc1ccc(C=C(C(=O)O)c2ccccc2F)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CSc1ccc(CC(=O)c2ccccc2F)cc1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 64.7 %

Procedure:
A solution of 2-(2-fluorophenyl)-3-(4-methylthiophenyl)propenoic acid from Step 1 (7.86 g, 27.3 mmol) and triethylamine (2.80 g, 27.7 mmol) in 22 mL of anhydrous toluene was cooled to 0° C. and treated with diphenylphosphoryl azide (7.73 g, 28.1 mmol). The solution was stirred at 0° C. for 20 minutes and at room temperature for 3.50 hours. The reaction was poured into water, extracted with ether, dried over magnesium sulfate, and concentrated in vacuo to remove the ether. The remaining toluene solution was heated to reflux and a vigorous evolution of gas occurred. After 0.75 hours, 11 mL of tert-butyl alcohol was added to the reaction. After an additional twenty minutes, concentrated hydrochloric acid (5 mL) was added slowly and the reaction was heated at 90 ° C. overnight (14 hours). The solution was cooled to room temperature and diluted with ethyl acetate, washed with saturated aqueous NaHCO3, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide a brown solid that was purified by crystallization from ether to afford 1-(2-fluorophenyl)-2-(4-methylthiophenyl)ethanone as a yellow solid (4.60 g, 65%): mp 58°-59.5° C. 1H NMR (CDCl3) 300 MHz 7.84 (m, 1H), 7.52 (m, 1H), 7.23-7.08 (m, 6H), 4.25 (d, J=2.6Hz, 2H), 2.46 (s, 3H). 19F NMR (CDCl3) -108.51 (m). Mass spectrum M+H+ =261.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:21][CH3:22])=[CH:12][C:13]2[O:18][C:17](=[O:19])[CH:16]=[CH:15][C:14]=2[CH:20]=1)(=O)=O.[C:23]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])(=O)/C=C/C([O-])=O>C(O)C>[CH3:22][O:21][C:11]1[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:32]2[CH2:33][CH2:34][N:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:30][CH2:31]2)=[CH:20][C:14]2[CH:15]=[CH:16][C:17](=[O:19])[O:18][C:13]=2[CH:12]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1cc2oc(=O)ccc2cc1OCCCOS(C)(=O)=O
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Product: COc1cc2oc(=O)ccc2cc1OCCCN1CCN(c2ccccc2)CC1
Yield: 55 %

Procedure:
Method A (23 h at 60° C.); starting materials: 6-[3-(methanesulfonyloxy)propoxy]-7-methoxy-2H-1-benzopyran-2-one (see example 67) and 1-phenylpiperazine; yield 55%; fusion point 124° to 125° C. (from ethanol). Fumarate: method E; yield 88%; fusion point 172° to 173° C. (from ethanol).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[C:8](=O)[O:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)(=O)C>C1COCC1>[CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][O:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(n1)C(=O)OC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc2c(n1)COC2=O
Temperature: 15 °C
Reaction time: 4 h
Yield: 65.8 %

Procedure:
A suspension of 2-methyl-furo[3,4-b]pyridine-5,7-dione (15 g, 92 mmol) in THF (100 mL) is treated with sodium borohydride (3.75 g, 99 mmol) at 15° C. under an argon atmosphere. The reaction mixture is then treated dropwise with acetic acid (12 g, 200 mmol) at 15° C. During this addition gas evolution is observed. The reaction mixture is stirred at 15° C. for 4 h and is then concentrated. The residue is treated with acetic acid (40 mL) and acetic anhydride (40 mL). The resulting solution is stirred at 100° C. for 3 h. The brown solution is cooled to room temperature and concentrated. The residue is treated with a 20% aqueous NaCl solution and extracted with chloroform. The organic extract is washed with saturated aqueous NaCl solution, dried over Na2SO4 and concentrated. The residue is purified by chromatography (silica gel, gradient elution, 5:1 hexane/ethyl acetate to 2:1 hexane/ethyl acetate). The product containing fractions are concentrated to give the title compound as a white solid (9.03 g, 44%)
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH2:17][CH2:18][CH2:19][OH:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.[OH-].[Na+]>ClCCl.O>[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:20][CH2:19][CH2:18][CH2:17][C:9]1[N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: BrCCCCCBr
Reactant: OCCCc1nc2ccccc2n1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: BrCCCCCOCCCc1nc2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 20.9 %

Procedure:
A mixture of 1-(phenylmethyl)-2-benzimidazolepropanol (3.0 g), 1,5-dibromopentane (7.77 g), TAB (0.5 g) and 40% sodium hydroxide (5 ml) in dichloromethane (10 ml) was stirred at room temperature for 6 h under nitrogen. The mixture was diluted with water (100 ml) and extracted with dichloromethane (2×100 ml). The dried extracts were evaporated in vacuo to give an oil. Purification by FCC eluting with hexane-ether (10:0→0:10) gave the title compound as a colourless oil (0.98 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:33])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[N:16]2[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:11][C:10]=1[O:34][CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:38]1COCC1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([O:33][CH3:38])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[N:16]2[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:11][C:10]=1[O:34][CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C2(O)c3ccccc3C(=O)N2CCc2ccccn2)ccc1OCc1ccccc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COc1cc(C2(OC)c3ccccc3C(=O)N2CCc2ccccn2)ccc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of 6 (0.20 g, 0.43 mmol) in dry THF (3 mL) at 0° C., NaH (60%, 0.021 g, 0.86 mmol) was added. After the mixture was stirred for 30 min, Mel (54 μL, 0.86 mmol) was added and stirring was continued overnight at room temperature. The reaction was quenched by the addition of saturated aqueous NH4Cl (0.5 mL). Solvent was evaporated under reduced pressure and the residue was extracted with CH2Cl2 (2×10 mL). The combined organic layer was washed with H20 (3 mL), brine (3 mL) and then dried over anhydrous Na2SO4. Solvent was evaporated under reduced pressure and the residual red syrup was purified by column chromatography using 35% acetone/hexane as the eluent to provide 7 (0.16 g, 75%) as a light yellow syrup.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:21]=[C:20]([CH:22]5[CH2:25][C:24](=[O:26])[CH2:23]5)[N:19]([CH3:27])[C:18]=4[CH:28]=3)[C:10](=[O:29])[CH:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:21]=[C:20]([CH:22]5[CH2:25][CH:24]([OH:26])[CH2:23]5)[N:19]([CH3:27])[C:18]=4[CH:28]=3)[C:10](=[O:29])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(C2CC(=O)C2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(C2CC(O)C2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
To a stirred solution of 4-((4-fluorobenzyl)oxy)-1-(1-methyl-2-(3-oxocyclobutyl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one (80 mg) in a mixture of THF (10 ml) and MeOH (3 ml) was added NaBH4 (15 mg) at 0° C. The mixture was then allowed to warm to room temperature, and stirred for 3 h. The reaction mixture was then quenched with saturated NH4Cl (5 ml), and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (50 mg) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]([CH:5]([NH2:10])[C:6]([O:8][CH3:9])=[O:7])([CH3:4])[CH3:3].C(N(C(C)C)C(C)C)C.[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[N:30]=[C:31]=[O:32])[CH2:27]2>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C@@H:5]([NH:10][C:31]([NH:30][CH:21]1[CH:20]2[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]1[CH2:23]3)[CH2:27]2)=[O:32])[C:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: O=C=NC1C2CC3CC(C2)CC1C3
Reactant: COC(=O)C(N)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)NC1C2CC3CC(C2)CC1C3)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
L-(+)-Methyl-tert-leucinate hydrochloride (564 mg) was dissolved in abs. DMF and then N-ethyl-diisopropylamine (0.68 mL) was added drop by drop. The mixture was allowed to stir for 30 minutes at RT and then 2-adamantyl isocyanate (500 mg) was added in one portion. Stirring was continued over night at RT. The reaction mixture was evaporated to dryness and residual DMF was removed by co-evaporation with toluene. The residue was purified by flash chromatography using 5% methanol in DCM as an eluent to give (S)-2-(3-adamantan-2-yl-ureido)-3,3-dimethyl-butyric acid methyl ester (834 mg) as a white solid. MS (EI): 322.4 (M+).
Reaction SMILES: [CH2:1]([C:5]1[C:6]([NH:8][C:9](=[O:11])[CH:10]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C(O)(=O)C.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:1]([C:5]1([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C:9](=[O:11])[NH:8][C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1=CC(=O)NC1=O
Reactant: Nc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CCCCC1(Nc2ccccc2)CC(=O)NC1=O
Temperature: 120 °C
Yield: 58.1 %

Procedure:
Maleic anhydride is reacted with n-butylamine under the conditions reported by L. E. Coleman et al., in J. Org. Chem., 24: 135, (1959). A mixture containing the thus-formed n-butylmaleamic acid (12.0 g, 0.07 mol), anhydrous sodium acetate (2.7 g) and acetic anhydride (29 mL) is heated at 85° C. to 90° C. for 30 minutes. The solution is cooled to 40° C. and poured into 55 mL of water. The layers are stirred at room temperature for 15 minutes, the diluted to 275 mL. A dark oil precipitates. Extraction with 100 mL of CH2Cl2, then another 25 mL of CH2Cl2, and evaporation of solvent gives 9.9 g of n-butylmaleimide as an oil, ir, 1735 (sh) and 1700 cm-1. A solution of 9.9 g (0.065 mol) of the n-butylmaleimide and 35 mL of acetic acid is treated with 6.51 g (0.07 mol) of aniline, with the resulting solution heated at 120° C. for 30 minutes. The solution is cooled and poured into 280 mL of water. The amorphous material is collected and recrystallized from isopropyl alcohol to give 9.3 g of n-butyl anilinosuccinimide as off-white crystals, m.p. 97°-100° C., ir, 3350, 1720 (sh), 1680, 1600 cm-1; mass spec, (ci) m/e 247. Anal. Calcd. for C14H18N202: C, 68.29; H, 7.32; N, 11.38. Found: C, 68.46; H, 7.28; N, 11.25.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:26](=[O:30])[N:27]([CH3:29])[CH3:28])([CH3:25])[CH3:24])[CH:17]=1)[C:10]([CH3:32])([CH3:31])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:29][N:27]([CH3:28])[C:26]([C:23]([NH:22][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:31])([CH3:32])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1)([CH3:24])[CH3:25])=[O:30]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)N(C)C)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)C(C)(C)Nc1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 6.1 %

Procedure:
A mixture of 2-[3-(1-dimethylcarbamoyl-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.8 g, 1.8 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (10 mL) was stirred at 50° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(1-dimethylcarbamoyl-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (45 mg, 6%) as a white solid: LC/MS m/e calcd for C24H31N3O3 (M+H)+: 410.53, observed: 410.1.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:17][C:18]#[N:19].[NH4+]>BrC1C=CC=CC=1>[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][NH:10][C:18]([NH2:19])=[S:17])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#C[S-]
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: [NH4+]
Solvent: Brc1ccccc1
Product: NC(=S)NCCC(c1ccccc1)c1ccccc1
Yield: 58.7 %

Procedure:
A solution of 3,3-diphenylpropylamine (4.00 g, 18.9 mmol) and ammonium thiocyanate (1.60 g, 20.8 mmol) in bromobenzene (30 mL) was refluxed for 1 hour. After cooling, the solid precipitate was recovered, rinsed with diethyl ether, water, and ethanol, and dried to provide 3.00 g (yield 59%) of the title compound. Amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([O:23][CH3:24])[CH:5]=1.[CH3:26][C:27]1[N:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=1.CCOC(C)=O>CN1C(=O)CCC1>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:33][C:30]2[CH:29]=[N:28][C:27]([CH3:26])=[CH:32][N:31]=2)=[O:13])=[C:6]([O:23][CH3:24])[CH:5]=1
Reactant: COC(=O)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c(OC)c1
Reactant: Cc1cnc(N)cn1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(NC(=O)Nc2cnc(C)cn2)c(OC)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 3-methoxy-4-(4-nitro-phenoxycarbonylamino)-benzoic acid methyl ester (11.7 g, 33.8 mmol) in 34 mL NMP at room temperature under nitrogen was added 5-methyl-2-aminopyrazine (3.69 g, 33.8 mmol) and the reaction was immersed in an 85° C. oil bath. After 6 hours the reaction was allowed to cool to room temperature and a precipitate formed. EtOAc (200 mL) was added and the precipitate was isolated by filtration (4.7 g, 44%). 1H-NMR (400 MHz, d6-DMSO) δ 8.79 (br s, 1H), 8.36 (d, 1H), 8.23 (s, 1H), 7.60 (d, 1H), 7.52 (s, 1H), 3.98 (s, 3H), 3.81 (s, 3H), 2.42 (s, 3H).