Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:18]=[C:17]([NH:19][CH3:20])[CH:16]=[C:15]([CH3:21])[C:14]=1[CH2:22][CH2:23][S:24]([N:27]1[CH2:44][CH2:43][C:30]2([N:34]=[C:33]([CH:35]3[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]3)[NH:32][C:31]2=[O:42])[CH2:29][CH2:28]1)(=[O:26])=[O:25]>CC(C)=O>[C:1]([NH:9][C:10](=[S:11])[N:19]([C:17]1[CH:18]=[C:13]([CH3:12])[C:14]([CH2:22][CH2:23][S:24]([N:27]2[CH2:28][CH2:29][C:30]3([N:34]=[C:33]([CH:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[NH:32][C:31]3=[O:42])[CH2:43][CH2:44]2)(=[O:26])=[O:25])=[C:15]([CH3:21])[CH:16]=1)[CH3:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNc1cc(C)c(CCS(=O)(=O)N2CCC3(CC2)N=C(C2CCC(C)CC2)NC3=O)c(C)c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: Cc1cc(N(C)C(=S)NC(=O)c2ccccc2)cc(C)c1CCS(=O)(=O)N1CCC2(CC1)N=C(C1CCC(C)CC1)NC2=O
Yield: 104.5 %

Procedure:
Benzoyl isothiocyanate (37.8 mg, 0.23 mmol) was added to a solution of 8-[2-(2,6-dimethyl-4-methylamino-phenyl)-ethanesulfonyl]-2-(4-methyl-cyclohexyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (100 mg, 0.21 mmol) in acetone (3 ml) in a nitrogen stream. The mixture was heated under reflux for one hour and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to give 3-benzoyl-1-(3,5-dimethyl-4-{2-[2-(4-methyl-cyclohexyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-phenyl)-1-methyl-thiourea (140 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]([N:15]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[N:17]=[CH:16]1)([CH3:14])[C:9](OCC)=[O:10].O.[OH-].[Na+]>O1CCCC1>[CH3:14][C:8]([N:15]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[N:17]=[CH:16]1)([CH3:7])[CH2:9][OH:10]
Reactant: CCOC(=O)C(C)(C)n1cnc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CO)n1cnc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
To a solution of lithium aluminium hydride (400 mg) in tetrahydrofuran (50 mL) was added a solution of ethyl 2-methyl-2-(4-nitro-1H-imidazol-1-yl)propanoate (2.0 g) obtained in Step A of Example 306 in tetrahydrofuran (20 mL) in an ice bath, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture were added water and 2M aqueous sodium hydroxide solution, the insoluble substance was removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (260 mg).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5].[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([C:29](O)=[O:30])=[CH:23]2>>[OH:12][CH:9]1[CH2:8][CH2:7][N:6]([C:4](=[O:5])[C@@H:3]([NH:2][C:29]([C:24]2[NH:25][C:26]3[C:22]([CH:23]=2)=[CH:21][C:20]([Cl:19])=[CH:28][CH:27]=3)=[O:30])[CH2:13][C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)[CH2:11][CH2:10]1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC(O)CC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Product: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
(S)-2-Amino-1-(4-hydroxy-piperidin-1-yl)-3-(1H-imidazol-4-yl)-propan-1-one hydrochloride (0.7 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0.7 mmol) were coupled according to Procedure A (120 hour reaction time, acid wash omitted). The crude product was triturated twice with ether, with 1:1 ether-hexanes and the residue purified by chromatography on silica gel eluted with 5-20% ethanol in dichloromethane containing 0.5% ammonium hydroxide. Yield 232 mg, 81%; HPLC (40/60) 2.57 minutes (98%); PBMS 416/418 (MH+, 100%);
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:21][C:22]([F:25])([F:24])[F:23])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2.IC.[C:28]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH3:28][O:1][C:2]1[CH:3]=[C:4]([O:21][C:22]([F:25])([F:23])[F:24])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:13])([F:14])[F:15])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(O)c2OC1C(F)(F)F
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(OC)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of ethyl 8-hydroxy-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 621w, Step 2 (165 mg, 0.442 mmole), iodomethane (82.8 uL, 1.33 mmole), KI (7.34 mg, 0.0442 mmole), K2CO3 (184 mg, 1.33 mmole) in anhydrous DMF (5.0 mL) was stirred at room temperature for 17 hrs. The mixture was then poured into brine (100 mL) and extracted with EtOAc (2×100 mL). The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give a tan solid. The crude product was purified by silica chromatography (0%-25% EtOAc in hexanes) to give an assumed quantitative yield of the product as an off-white crystalline solid: EIHRMS m/z 386.0593 (M+, C15H12F6O5, Calc'd 386.0589).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[C:5]#[N:6].[CH3:12][C:13]1([CH3:20])[O:17][CH:16]([CH2:18]O)[CH2:15][O:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C1(C)C=CC=CC=1>[CH3:12][C:13]1([CH3:20])[O:17][CH:16]([CH2:18][O:10][C:9]2[C:8]([CH3:11])=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[CH3:1])[CH2:15][O:14]1
Reactant: Cc1cc(C#N)cc(C)c1O
Reactant: CC1(C)OCC(CO)O1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C)c1OCC1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of 3,5-dimethyl-4-hydroxy-benzonitrile (5.0 g, 34.0 mmol) in THF (40 mL), rac-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (4.49 g, 34.0 mmol) followed by triphenylphosphine (13.4 g, 50.9 mmol) is added. The mixture is cooled with an ice-bath before DEAD (8.87 g, 50.9 mmol, 23.4 mL of a 40% solution in toluene) is added dropwise. The mixture is stirred at rt for 1 h, the solvent is removed in vacuo and the residue is purified by CC on silica gel eluting with heptane:EA 99:1 to 92:8 to give rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,5-dimethyl-benzonitrile (7.20 g) as a pale yellow oil; LC-MS: tR=0.99 min, [M+1]+=not detected.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:13][N:14]2[CH2:30][CH2:29][C:17]3([N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][NH:19][C:18]3=[O:28])[CH2:16][CH2:15]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br>CCCCCCC.CN(C)C=O.O>[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][N:19]1[C:18](=[O:28])[C:17]2([CH2:29][CH2:30][N:14]([CH2:13][C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:6]=[CH:5][CH:4]=3)[CH2:15][CH2:16]2)[N:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:20]1
Reactant: BrCCCCCCCBr
Reactant: O=C1NCN(c2ccccc2)C12CCN(Cc1cccc3ccccc13)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCCC
Product: O=C1N(CCCCCCCBr)CN(c2ccccc2)C12CCN(Cc1cccc3ccccc13)CC2
Reaction time: 0.08 h
Yield: 72.4 %

Procedure:
Sodium hydride, 60% (0.156 g, 3.9 mmol) was suspended in dry heptane (5 ml) and stirred under nitrogen for 5 minutes. The solvent was decanted and dry dimethyl formamide (4 ml) was added. 8-Naphthalen-1-ylmethyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (1.115 g, 3.0 mmol), dissolved in dry dimethyl formamide (11 ml) was added dropwise under cooling in an ice bath. The mixture was stirred at 0° C. for 1 h. The resulting solution of deprotonated 1-phenyl-8-naphthalen-1-ylmethyl-1,3,8-triazaspiro[4.5]decan-4-one was added dropwise to a stirred solution of 1,7-dibromoheptane (3.88 g, 15 mmol) in dimethyl formamide (3 ml) at room temperature and stirring was continued for 1 h. The mixture was then diluted with water (50 ml) and extracted with ethyl acetate (2×30 ml). The combined organic phases were successively washed with water (2×20 ml) and brine (2×20 ml), dried over MgSO4 and evaporated In vacuo. The residue was dissolved in a mixture of tetrahydrofuran (10 ml) and ether (10 ml) and the hydrochloride was precipitated by the dropwise addition of a solution of hydrogen chloride in ether in excess. The precipitate was washed with a 1:1 mixture of tetrahydrofuran and ether and dried, affording 3-(7-bromo-heptyl)-8-naphthalen-1-ylmethyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (1.192 g, 68% yield) as a powder.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].[F:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>O1CCOCC1.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.C(OCC)(=O)C>[CH:9]1([C:7]2[O:8][C:4]3[C:5](=[C:12]([C:15]#[N:16])[C:13]([CH3:14])=[C:2]([C:23]4[CH:22]=[CH:21][CH:20]=[C:19]([F:18])[C:24]=4[F:25])[C:3]=3[F:17])[N:6]=2)[CH2:11][CH2:10]1
Reactant: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: OB(O)c1cccc(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1c(-c2cccc(F)c2F)c(F)c2oc(C3CC3)nc2c1C#N
Temperature: 95 °C
Reaction time: 86 h
Yield: 52.8 %

Procedure:
6-Bromo-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-77) (190 mg, 0.64 mmol), 2,3-difluorophenylboronic acid (407 mg, 2.58 mmol) and tripotassium phosphate (274 mg, 1.29 mmol) were dissolved in 1,4-dioxane (6 ml), then at room temperature, tetrakis(triphenylphosphine)palladium(0) (149 mg, 0.13 mmol) was added. The suspension was stirred under nitrogen atmosphere at 95° C. for 86 hours. After cooling to room temperature, the solution was fractionated with ethyl acetate and aqueous saturated ammonium chloride solution. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, hexane:ethyl acetate=9:1) to obtain the entitled compound (111 mg, 53%) as a white solid.
Reaction SMILES: C(OC([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:31])[CH:14]([NH:16][C:17](=[O:30])[C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([O:25][CH2:26][CH:27]=[CH2:28])=[C:20]([CH3:29])[CH:19]=1)[CH3:15])=O)(C)(C)C.[O:32]=[C:33]1[O:37][CH:36]([O:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43]C=2)[CH:35]([NH:47][C:48](C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=[O:49])[CH2:34]1>>[CH2:39]([O:38][CH:36]1[CH:35]([NH:47][C:48]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:31])[CH:14]([NH:16][C:17](=[O:30])[C:18]2[CH:19]=[C:20]([CH3:29])[C:21]([O:25][CH2:26][CH:27]=[CH2:28])=[C:22]([CH3:24])[CH:23]=2)[CH3:15])=[O:49])[CH2:34][C:33](=[O:32])[O:37]1)[C:40]1[CH:41]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Reactant: C=CCOc1c(C)cc(C(=O)NC(C)C(=O)N2CCCC2C(=O)OC(C)(C)C)cc1C
Product: C=CCOc1c(C)cc(C(=O)NC(C)C(=O)N2CCCC2C(=O)NC2CC(=O)OC2OCc2ccccc2)cc1C
Yield: 46 %

Procedure:
Prepared from 1-[2-(4-allyloxy-3,5-dimethyl-benzoylamino)-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester and 40 according to the procedure used to prepare 98a to afford 264 mg (yield 46%) of the title compound. 1H-NMR (500 MHz, CDCl3): δ 1.09-1.43 (m, 3H), 1.90-2.20 (m, 3H), 2.20-2.38 (m, 7H), 2.38-2.52 (m, H), 2.80-2.95 (m, H), 3.52-3.67 (m, H), 3.70-3.80 (m, H), 4.10-4.40 (m, 2H), 4.40-4.95 (m, 5H), 5.26-5.55 (m, 3H), 6.00-6.14 (m, H), 6.87 (d, H), 7.10-7.70 (m, 8H); retention time on analytical HPLC: 18.56 and 18.92 min1; LC-MS: m/z=564 (M+H+)
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH3:45][C:46]([O:49][C:50]([NH:52][C@@H:53]([C:65](O)=[O:66])[CH2:54][C:55]1[C:60]([C:61]([F:64])([F:63])[F:62])=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:51])([CH3:48])[CH3:47]>ClCCl.O>[C:46]([O:49][C:50](=[O:51])[NH:52][C@@H:53]([C:65](=[O:66])[NH:1][CH:2]1[C:3](=[O:13])[NH:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH2:7][CH2:8]1)[CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][C:60]=1[C:61]([F:64])([F:63])[F:62])([CH3:45])([CH3:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1C(F)(F)F)C(=O)O
Reactant: NC1CCc2ccccc2NC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1C(F)(F)F)C(=O)NC1CCc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of racemic 3-amino-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one (0.100 g, 0.57 mmol) in dichloromethane (5.0 mL) were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.218 g, 1.13 mmol), 1-hydroxybenzotriazole (0.153 g, 1.13 mmol), diisopropylethylamine (0.20 mL, 1.13 mmol) and N-Boc-D-2-trifluoromethyl phenylalanine (0.189 g, 0.57 mmol). The resulting mixture was stirred at room temperature for 18 hours, then diluted with H2O and extracted with ethyl acetate. The organic extracts were combined, dried over MgSO4, filtered and concentrated in vacuo to give an oil that was purified via prepatory thin-layer chromatography on silica gel (50% ethyl acetate/hexanes) to give the desired product.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[S:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH:13]=[N:14][C:15]([C:16]3[O:17][CH2:18][C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=3)=[C:4]2[CH2:3]1.[Br-].C1C(C(OOC(C)(C)C)=O)=CC=CC=1.O>C1C=CC=CC=1>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[S:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH:13]=[N:14][C:15]([C:16]3[O:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=3)=[C:4]2[CH2:3]1
Reactant: COC(=O)[C@@H]1COC(c2ncn3c2CN(C)C(=O)c2sccc2-3)=N1
Agent: CC(C)(C)OOC(=O)c1ccccc1
Agent: [Br-]
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1coc(-c2ncn3c2CN(C)C(=O)c2sccc2-3)n1
Yield: 25.1 %

Procedure:
A solution of 5.92 g (0.0171 mol) of methyl (S)-2-(5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]-diazepin-3-yl)-4,5-dihydro-oxazole-4-carboxylate in 300 ml of benzene was treated with 2.69 g (0.0188 mol) of copperl bromide and 4.97 ml (0.0256 mol) of tert-butyl perbenzoate according to the method described in Tetr. Letters 1994, 35, 2481. The mixture was boiled at reflux for 1 hr., cooled and treated with 100 ml of water. The mixture was filtered, extracted with benzene and chromatographed over silica gel with ethyl acetate as the eluent. There were obtained 1.48 g (25%) of methyl 2-(5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]-diazepin-3-yl)-oxazole-4-carboxylate as a yellowish solid. An analytical sample was recrystallized from hot ethyl acetate and gave white crystals; m.p. 254°-255°.
Reaction SMILES: [C:1]([C:9]1[CH:28]=[CH:27][C:12]([CH2:13][O:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:30][NH2:31]>CO>[N:30](=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:28]=[CH:27][C:12]([CH2:13][O:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[CH:11][CH:10]=1)[NH2:31]
Reactant: NN
Reactant: O=C(NCCOCc1ccc(C(=O)c2ccccc2)cc1)Nc1ccccc1
Solvent: CO
Solvent: O
Product: NN=C(c1ccccc1)c1ccc(COCCNC(=O)Nc2ccccc2)cc1
Yield: 94.8 %

Procedure:
A solution of (XI) (0.7 g, 1.9 mmol) in methanol (10 ml) was treated with hydrazine hydrate (1.9 g, 38 mmol). The resulting solution was heated to a gentle reflux for 16 h., cooled and concentrated in vacuo. The residue was partitioned between DCM and water and the organic layer was collected, washed with water and dried over MgSO4. Concentration in vacuo yielded (XII) (0.7 g, 99%) as a thick cloudy white oil; δH (CDCl3, 200 MHz) 3.47 (m, 2H, N(H)CH2CH2), 3.61 (m, 2H, OCH2CH2), 4.43, 4.52 (s, 2H, ArCH2O), 5.49 (s, 2H, NNH2), 6.55 (m, 1H, CH2NHC(O)), 6.99 (m, 1H, 4″-H), 7.22 (m, 7H, 3-, 3′-, 3″-, 4′-, 5-, 5′-, 5″-H), 7.46 (m, 6H, 2-, 2′-, 2″-, 6-, 6′-, 6″-H), 7.80 (m, 1H, ArNHC(O)) ppm; υmax 3435 (N—Hstr), 1734 ((R(H)N)2C═Ostr) cm−1; m/z 389 [M+H]+ (15%), 447 [M+MeCN+NH4]+ (100%); found 389.1973, C23H25N4O2 requires 389.1978.
Reaction SMILES: ClC1C(C(C2[CH:11]=[N:12][N:13](C)C=2C2C=CC(C)=CC=2)=O)=C(Cl)N=CN=1.C(N(CC)C(C)C)(C)C.N1CC[C@H](N2CCCCC2)C1.Cl[C:45]1[C:50]([C:51]([C:53]2[CH:54]=[N:55][N:56]([CH3:65])[C:57]=2[C:58]2[CH:63]=[CH:62][C:61]([CH3:64])=[CH:60][CH:59]=2)=O)=[C:49]([N:66]2[CH2:70][CH2:69][C@H:68]([N:71]3[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]3)[CH2:67]2)[N:48]=[CH:47][N:46]=1.CNN>C(#N)C>[CH3:11][N:12]1[C:45]2=[N:46][CH:47]=[N:48][C:49]([N:66]3[CH2:70][CH2:69][C@H:68]([N:71]4[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76]4)[CH2:67]3)=[C:50]2[C:51]([C:53]2[CH:54]=[N:55][N:56]([CH3:65])[C:57]=2[C:58]2[CH:59]=[CH:60][C:61]([CH3:64])=[CH:62][CH:63]=2)=[N:13]1
Reactant: Cc1ccc(-c2c(C(=O)c3c(Cl)ncnc3Cl)cnn2C)cc1
Reactant: Cc1ccc(-c2c(C(=O)c3c(Cl)ncnc3N3CC[C@H](N4CCCCC4)C3)cnn2C)cc1
Agent: C1CCN([C@H]2CCNC2)CC1
Agent: CNN
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2c(-c3nn(C)c4ncnc(N5CC[C@H](N6CCCCC6)C5)c34)cnn2C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a mixture of (4,6-dichloropyrimidin-5-yl)[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]methanone (C5) (7.3 g, 21 mmol) and N,N-diisopropylethylamine (13.56 g, 104.9 mmol) in acetonitrile (100 mL) was added 1-[(3S)-pyrrolidin-3-yl]piperidine (4.8 g, 31 mmol), and the resulting reaction mixture was stirred at room temperature for 3 hours. To this solution of {4-chloro-6-[(3S)-3-(piperidin-1-yl)pyrrolidin-1-yl]pyrimidin-5-yl}[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]methanone (C7) was added drop-wise a solution of methylhydrazine (12.1 g, 262 mol) in acetonitrile (20 mL). After being stirred overnight at room temperature, the reaction mixture was concentrated in vacuo and partitioned between dichloromethane (100 mL) and water (100 mL). The aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated; purification via silica gel chromatography (Gradient: 10% to 50% ethyl acetate in petroleum ether) afforded the product as a white solid. Yield: 8.64 g, 18.9 mmol, 90% yield. LCMS m/z 457.3 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.39-1.49 (br m, 2H), 1.53-1.73 and 2.00-2.25 (br multiplets, presumed 8H), 2.31 (s, 3H), 2.32-2.45 (br m, 2H), 2.56-2.68 (br m, 1H), 2.90-3.16 (v br m, 1H), 3.26-3.78 (br m, 3H), 3.87 (s, 3H), 4.00 (s, 3H), 7.16 (br AB quartet, JAB=8 Hz, ΔνAB=26 Hz, 4H), 7.66 (s, 1H), 8.29 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[CH:3]=1.[OH-].[Na+].[N:19]([O-])=[O:20].[Na+].C(O)(=O)C>O>[NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[C:3]=1[N:19]=[O:20]
Reactant: O=N[O-]
Reactant: Cn1c(=O)cc(N)n(-c2ccccc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(=O)c(N=O)c(N)n(-c2ccccc2)c1=O
Reaction time: 2 h
Yield: 99.3 %

Procedure:
The obtained 6-amino-3-methyl-1-phenyluracil (24 g, 0.11M) and NaOH (2.8 g, 70 mM) were dissolved in 110 ml of water. To the resulting solution was added dropwise an aqueous solution of sodium nitrite (9.5 g/80 ml). Acetic acid (13 ml) was then added dropwise at 0° C. and the mixture was brought to room temperature, followed by stirring for 2 hours. A precipitated solid product was obtained by filtration. The solid product was washed successively with water and methanol and dried to yield 6-amino-3-methyl-5-nitroso-1-phenyluracil (yield: 27 g, or 99% based on 6-amino-3-methyl-1-phenyluracil).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[C:23](=[O:25])[CH3:24])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCC(=O)C1)C1C=CC=CC=1.C(N1C2C(=CC=C(N)C=2)CC1)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O.[C:70](Cl)(=[O:79])[CH:71]=[CH:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1>ClCCCl>[C:23]([N:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]([N:13]([CH:10]3[CH2:11][CH2:12][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9]3)[C:70](=[O:79])/[CH:71]=[CH:72]/[C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[CH:22]=2)[CH2:18][CH2:19]1)(=[O:25])[CH3:24]
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CC(=O)N1CCc2ccc(NC3CCN(Cc4ccccc4)C3)cc21
Agent: CC(=O)N1CCc2ccc(N)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C1CCN(Cc2ccccc2)C1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(=O)N1CCc2ccc(N(C(=O)/C=C/c3ccccc3)C3CCN(Cc4ccccc4)C3)cc21
Yield: 74 %

Procedure:
1-[6-(1-benzyl-pyrrolidin-3-ylamino)-2,3-dihydro-indol-1-yl]-ethanone. The desired intermediate (84 mg, 44%) was prepared as in Example 39, Step A, using 1-benzyl-3-pyrrolidinone (0.20 g, 1.1 mmol), 1-acetyl-6-aminoindoline (0.10 g, 0.57 mmol), Na(OAc)3BH (360 mg, 1.7 mmol), and AcOH (171 μL, 3.0 mmol) in 1,2-dichloroethane (10 mL). 1H NMR (500 MHz, CDCl3): 7.61 (s, 1H), 7.35-7.28 (m, 4H), 7.28-7.20 (m, 1H), 6.93 (d, J=8.1 Hz,1H), 6.24 (dd, J=8.2, 1.9 Hz, 1H), 4.05-3.96 (m, 3H), 3.68-3.56 (m, 2H), 3.10-3.01 (m, 2H), 2.80-2.71 (m, 2H), 2.59-2.51 (m, 1H), 2.48-2.39 (m, 1H), 2.38-2.22 (m, 1H), 2.20 (s, 3H), 1.71-1.56 (m, 1H). MS: exact mass calculated for C21H25N3O, 335.20; m/z found, 336.1 [M+H]+. Step B. The above intermediate (49 mg, 0.29 mmol) was reacted with with cinnamoyl chloride (2 76 mg, 0.2 mmol) as in Example 2, Step C to provide 79 mg (74%) of the desired product. 1H NMR (500 MHz, CDCl3): 8.09 (s, 1H), 7.62 (d, J=15.5 Hz, 1H), 7.30-7.15 (m, 1H), 6.78 (d, J=7.0 Hz, 1H), 6.17 (d, J=15.5 Hz, 1H), 5.15-5.05 (br m, 1H), 4.19-4.08 (m, 2H), 3.70-3.51 (m, 2H), 3.29-3.20 (m, 2H), 3.07-2.95 (br m, 1H), 2.76-2.57 (br m, 3H), 2.30-2.22 (m, 1H), 2.21 (s, 3H), 1.98-1.83 (m, 1H). MS: exact mass calculated for C30H31N3O2, 465.24; m/z found, 466.2 [M+H]+.
Reaction SMILES: [OH-].[K+].Cl.[OH:4][C:5]1[C:6]([CH2:11][OH:12])=[N:7][CH:8]=[CH:9][CH:10]=1.[CH:13]1([CH2:16]Br)[CH2:15][CH2:14]1.Cl>O.CS(C)=O>[CH:13]1([CH2:16][O:4][C:5]2[C:6]([CH2:11][OH:12])=[N:7][CH:8]=[CH:9][CH:10]=2)[CH2:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: OCc1ncccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: OCc1ncccc1OCC1CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43.2 %

Procedure:
Potassium hydroxide (5.2 g, 0.093 mol) was ground to a powder under nitrogen, added to DMSO (30 ml) and stirred for 20 min under nitrogen at room temperature. The mixture was cooled to 0° C. and 3-hydroxy-2-hydroxymethyl pyridine hydrochloride (5.0 g, 0.031 mol) was added. The slurry was stirred at 0° C. for 1 h before the addition of cyclopropylmethyl bromide (3.01 ml, 4.2 g, 0.031 mol). The mixture was allowed to warm to room temperature and stirred under nitrogen overnight. Water (100 ml) was added, and the resultant solution was acidified to pH 1 with hydrochloric acid (5 N). The solution was washed with dichloromethane (3×100 ml), basified to pH 14 with sodium hydroxide solution (4 N), and washed again with dichloromethane (3×100 ml). The organic layers from the second extraction were combined, washed with water (1×100 ml) and saturated sodium chloride solution (1×100 ml), dried over magnesium sulfate and concentrated in vacuo to give 3-cyclopropylmethyloxy-2-hydroxymethyl pyridine as a dark brown solid (2.40 g). 1H NMR (250 MHz, CDCl3) δ 0.35 (2H, m), 0.65 (2H, m), 1.26 (1H, m), 3.85 (2H, d, J=6.8 Hz), 4.33 (1H, br s), 4.77 (2H, s), 7.13 (2H, m), 8.13 (2H, m); MS (ES+) m/e 180 [MH]+.