Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:3]([N:5]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([CH3:25])[CH:19]=1)[CH2:6][CH2:7][C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)=[O:4].[O:32]1[CH2:35][C:34](=O)[CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:25][C:20]1[CH:19]=[C:18]([N:5]([CH2:6][CH2:7][C:8]2[CH:9]=[N:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)[C:3](=[O:4])[C@@H:2]([NH:1][CH:34]2[CH2:35][O:32][CH2:33]2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=[CH:22][C:21]=1[CH3:24]
Reactant: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](N)c2ccccc2)cc1C
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](NC2COC2)c2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 25 mg (S)-2-Amino-N-(3,4-dimethyl-phenyl)-2-phenyl-N-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-acetamide (from example 1) in 1.5 ml dry CH2Cl2 under argon in a sealed tube was added 1.1 eq. oxetan-3-one. The reaction mixture was stirred at RT for 20 min, followed by the addition of 3.0 eq., Sodium triacetoxyborohydride and the reaction stirred for 16 h at RT. The reaction mixture diluted with 10 ml CH2Cl2 and washed with 2M aq. Na2CO3 2M, dried and concentrated then chromatographed on silica gel (EtOAc/Heptane, gradient elution) to give the desired compound. MS(m/e): 484.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][C:21]4[NH:26][CH2:25][CH2:24][O:23][C:22]=4[N:27]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:20][C:21]4[N:26]([C:42](=[O:44])[CH3:43])[CH2:25][CH2:24][O:23][C:22]=4[N:27]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NCCO4)cc2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCOc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a solution of tert-butyl(1-(4-(7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (22 mg, 0.05 mmol) in dry DCM (1 ml) was added triethyl amine (10 μl, 0.07 mmol) and acetyl chloride (5 μl, 0.07 mmol) under nitrogen. The resulting mixture was stirred for 1 h at room temperature. A saturated solution of NaHCO3 was added and the mixture was extracted with dichloromethane (3×10 ml) using a phase separator (Isolute® SPE). The combined organic phases were concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 80% EtOAc in cyclohexane) to give the title compound (20 mg, 83%). 1H NMR (500 MHz, CDCl3): 8.50 (1H, br s), 7.25 (2H, d), 7.19-7.17 (5H, m), 7.11-7.10 (2H,m), 4.95 (1H, s), 4.43 (2H, t), 3.94 (2H, br s), 2.55-2.25 (7H, m), 2.06-1.98 (1H, m), 1.82-1.73 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[C:4]=1[C:13]1[C:14](=[O:27])[N:15]([CH3:26])[N:16]=[C:17]([C:22]([F:25])([F:24])[F:23])[C:18]=1S(C)=O)[CH3:2].CN1CCCC1=[O:34].[OH-].[Na+].Cl>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[C:4]=1[C:13]1[C:14](=[O:27])[N:15]([CH3:26])[N:16]=[C:17]([C:22]([F:25])([F:24])[F:23])[C:18]=1[OH:34])[CH3:2]
Reactant: CCc1cc(CC)c(-c2c(S(C)=O)c(C(F)(F)F)nn(C)c2=O)c(CC)c1
Reactant: CN1CCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cc(CC)c(-c2c(O)c(C(F)(F)F)nn(C)c2=O)c(CC)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 54.1 %

Procedure:
To a 50 ml volume three-necked flask, 4-(2,4,6-triethylphenyl)-2-methyl-5-methylsulfinyl-6-trifluoromethyl-2,3-dihydro-3-pyridazinone ((2-49)-(1)-40) (0.692 g), N-methylpyrrolidone (6.40 g), water (3.11 g), and sodium hydroxide (0.626 g) were added at room temperature. The resulting mixture was stirred at 50° C. for 4 hours. The reaction mixture was cooled to room temperature, added 12N hydrochloric acid (3 ml) and water (15 ml), and extracted with ethyl acetate (30 ml) 3 times. The combined organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (hexane: ethyl acetate=8:1 to hexane: ethyl acetate=5:1 to hexane: ethyl acetate=3:1). Then, the resulting fraction was concentrated under reduced pressure, recrystallized from hexane to give 0.331 g of 4-(2,4,6-triethylphenyl)-5-hydroxy-2-methyl-6-trifluoromethyl-2,3-dihydro-3-pyridazinone ((1-16)-(1)-40) on the filter paper.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:30]([O:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:29][CH:28]=[CH:27][C:26]=2[F:38])[C:21]([Cl:39])=[CH:20][N:19]=1>>[Cl:39][C:21]1[C:22]([NH:24][C:25]2[C:30]([O:31][CH:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:29][CH:28]=[CH:27][C:26]=2[F:38])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: Fc1cccc(OC2CCOCC2)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4OC4CCOCC4)n3)cc2CC1

Procedure:
Title compound was prepared from 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(tetrahydro-pyran-4-yloxy)-phenyl]-amine in an analogous manner to Example 1221d. Title compound was isolated as a white solid (70 mg, 48%). LCMS 542.26 (M+H), HPLC purity 99%, 1H-NMR (DMSO-d6, 400 MHz) δ 9.71 (bs, 1H), 9.35 (s, 1H), 8.57 (s, 1H), 8.13 (s, 1H), 7.39-7.36 (m, 1H), 7.25 (s, 1H), 7.12 (d, J=7.9 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 6.95 (dd, J=8.6 Hz, 1H), 6.85 (d, J=8.2 Hz, 1H), 4.64-4.60 (m, 1H), 3.71-3.69 (m, 2H), 3.60-3.58 (m, 2H), 3.36-3.33 (m, 4H), 3.33 (s, 3H), 3.15-2.85 (m, 6H), 1.84-1.80 (m, 2H), 1.51-1.47 (m, 2H).
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4]([NH:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:5].Cl[C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26].Cl>C(=O)([O-])O.[Na+].O1CCCC1>[CH2:28]([O:27][C:25]([S:1][CH2:2][CH:3]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4]([NH:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:5])=[O:26])[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)COC(=O)Cl
Reactant: Cc1c(NC(=O)C(CS)Cc2ccccc2)cccc1C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)C(CSC(=O)OCC(C)C)Cc2ccccc2)cccc1C(=O)O
Yield: 36 %

Procedure:
3-[(2-Mercaptomethyl-3-phenylpropionyl)amino]-2-methylbenzoic acid (compound of Example 7) (0.66 g) is dissolved in a mixture of saturated aqueous sodium hydrogen carbonate solution and tetrahydrofuran (1 ml), and to the mixture is added a solution of isobutyl chloroformate (0.33 g) in tetrahydrofuran (5 ml) with stirring under ice cooling, and the mixture is stirred under ice cooling for 30 minutes and further at room temperature for one hour. The reaction mixture is acidified with 4N hydrochloric acid and extracted with ethyl acetate. The extract is washed with water and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected and concentrated under reduced pressure, and the precipitates are separated by filtration to give the title compound (0.31 g).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][OH:13])[CH:6]=[CH:5]2.[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15]>C(N(CC)CC)C.C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][Si:16]([C:14]#[C:15][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][OH:13])[CH:6]=[CH:5]2)([CH3:19])[CH3:18]
Reactant: C#C[Si](C)(C)C
Reactant: OCCn1ccc2cc(I)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc2c(ccn2CCO)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
398 mg (2.1 mmol) CuI and 1.47 g (2.1 mmol) Pd(PPh3)2Cl2 are added to a solution, cooled to 0° C., of 30 g (104 mmol) 2-(5-iodo-indol-1-yl)-ethanol and 18 mL (125 mmol) ethynyl-trimethyl-silane in 480 mL triethylamine and 120 mL THF and stirred for 30 min at 0° C. and 2 h at RT. The mixture is evaporated down i. vac., the residue is taken up in 300 mL EtOAc, the organic phase is washed with 150 mL water and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, gradient: cyc/EtOAc 4:1 to 2:1).
Reaction SMILES: N#N.[Br:3][C:4]1[CH:5]=[C:6]([CH2:9][OH:10])[S:7][CH:8]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>C(Cl)Cl.O>[Br:3][C:4]1[CH:5]=[C:6]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[S:7][CH:8]=1
Reactant: OCc1cc(Br)cs1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: N#N
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), (4-bromo-thiophen-2-yl)-methanol (3.97 g, 20.57 mmol) was dissolved in dry CH2Cl2 (50 mL). tert-Butyldimethylsilyl chloride (3.59 g, 22.63 mmol) was added at rt followed by imidazole (1.56 g, 22.63 mmol). The reaction mixture was stirred at rt for 1 h. Water was added, the layers were separated and the org. layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (hept) gave the title compound as a colorless oil. TLC: rf (100:1 hept-EA)=0.44. LC-MS-conditions 02: tR=1.21 min.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=O)C(F)(F)F)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21].O>CN(C)C=O>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH3:11])[CH:5]=1)=[O:3]
Reactant: CC(=O)c1cccc(NC(=O)C(F)(F)F)c1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CNc1cccc(C(=O)C=CN(C)C)c1
Temperature: 150 °C
Yield: 55 %

Procedure:
8.37 g (36.21 mmol) de N-(3-acetylphenyl)-2,2,2-trifluoro-acetamide were dissolved in 80 ml of N,N-dimethyl formamide. To the resultant solution 24.23 ml (181.02 mmol) of N,N-dimethylformamide dimethyl acetal were added and heated at 150° C. for 2 h. The solvent was removed by reduced pressure distillation to yield an oil which was treated with 50 ml of water and extract with 3×100 ml of dichloromethane. The organic layers were washed with 2×200 ml of a saturated solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness by reduced pressure distillation. A solid was obtained, which precipitated from a mixture of ethanol-ethyl ether to give 4.1 g (yield=55%) of 3-(dimethylamino)-1-[3-(methylamino)phenyl]prop-2-en-1-one.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]#[N:14])[CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+].CO>O1CCOCC1>[C:13]([C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][CH2:5][NH:4]2)=[CH:8][CH:9]=1)#[N:14]
Reactant: CC(=O)N1CCc2ccc(C#N)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: N#Cc1ccc2c(c1)NCC2
Temperature: 25 °C
Yield: 51.1 %

Procedure:
1-Acetyl-6-cyanoindoline (2.4 g, 12.9 mmol, Tetrahedron, 1967, 23, 3823) was stirred in a solution containing 5 N NaOH (20 mL), MeOH (60 mL) and dioxane (60 mL). The mixture was stirred at RT over the weekend. Solvent was removed under reduced pressure and the residue was partitioned between water (100 mL) and DCM (100 mL). Aqueous layer was extracted with DCM (2×75 mL). Combined organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. Chromatography (10-30% EtOAc/hexanes) provided 6-cyanoindoline (0.95 g, 51%) which was then converted to 12A in a manner similar to that found in Example 4, Step 1.
Reaction SMILES: [C:1]([C:5]([OH:23])([CH:9]([N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:6][C:7]#[CH:8])([CH3:4])([CH3:3])[CH3:2].[I:24]I.[OH-].[K+]>CO>[C:1]([C:5]([OH:23])([CH:9]([N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[CH2:6][C:7]#[C:8][I:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: II
Reactant: C#CCC(O)(C(Cc1ccc(Cl)cc1)n1cncn1)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)C(O)(CC#CI)C(Cc1ccc(Cl)cc1)n1cncn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.9 %

Procedure:
9.9 g (0.03 mol) of 4-tert.-butyl-6-(4-chlorophenyl)-5-(1,2,4-triazol-1-yl)-hex-1-in-4-ol are dissolved in 100 ml of methanol, and 9.2 g (0.036 mol) of iodine are introduced into the ice-cooled solution at the same time as 14.5 ml of 50% strength potassium hydroxide solution are being added dropwise. The mixture is stirred for a further 4 hours at room temperature, and the crystalline precipitate is filtered off under suction, washed with water and dried. 10.7 g (78% of theory) of 4-tert.-butyl-6-(4-chlorophenyl)-1-iodo-5-(1,2,4-triazol-1-yl)-hex-1-in-4-ol of melting point 155° C. are obtained.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:23]([C:24](=[O:27])[NH:25][CH3:26])=[C:22]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)[O:21][C:5]2=[N:6][C:7]=1[N:8]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[S:9]([CH3:12])(=[O:11])=[O:10].[C:35]1([CH3:41])C=CC=C[CH:36]=1>>[CH:41]1([C:2]2[CH:3]=[C:4]3[C:23]([C:24](=[O:27])[NH:25][CH3:26])=[C:22]([C:28]4[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=4)[O:21][C:5]3=[N:6][C:7]=2[N:8]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[S:9]([CH3:12])(=[O:11])=[O:10])[CH2:35][CH2:36]1
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCCC(=O)OC)S(C)(=O)=O)c(I)cc12
Reactant: Cc1ccccc1
Product: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCCC(=O)OC)S(C)(=O)=O)c(C3CC3)cc12
Yield: 67 %

Procedure:
The methyl 5-(N-(5-iodo-3-(methylcarbamoyl)-2-p-tolylfuro[2,3-b]pyridin-6-yl)methylsulfonamido)pentanoate (35 mg, 0.058 mmol) was suspended/dissolved in 1 mL toluene and added to 2. 1 was added to 2. The biphasic mixture was degassed for 5 min, then microwaved at 122° C. for 10 min. The mixture was then heated again at the same temperature for another 2×10 min. HPLC purification yielded methyl 5-(N-(5-cyclopropyl-3-(methylcarbamoyl)-2-p-tolylfuro[2,3-b]pyridin-6-yl)methylsulfonamido)pentanoate (20 mg, 0.039 mmol, 67%) MS-ES [M+H]+=513.9, LC RT=1.60 min, Method A.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=[O:8])[N:3]=[CH:2]1.[CH2:10](I)[CH3:11]>>[S:1]1[CH:5]=[C:4]([CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=[O:8])[N:3]=[CH:2]1
Reactant: CCI
Reactant: O=C(O)Cc1cscn1
Product: CCC(C(=O)O)c1cscn1

Procedure:
2-(1,3-Thiazol-4-yl)butanoic acid was prepared from commercially available 1,3-thiazol-4-ylacetic acid and ethyl iodide using a procedure analogous to that used to prepare Intermediate 26. 1H NMR (500 MHz, CDCl3) δ: 0.95 (t, J=7.3, 3H), 1.25 (t, J=7.3, 3H), 1.95-2.05 (m, 1H), 2.08-2.17 (m, 1H), 3.88 (t, J=7.6, 1H), 4.15-4.23 (m, 2H), 7.22 (d, J=1.8, 1H), 8.77 (d, J=1.8, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[CH:10]1([CH:16]=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH:5][CH2:16][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=CC1CCCCC1
Reactant: Cc1ccc(N)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(NCC2CCCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a solution of 3-chloro-4-methylaniline (7.08 g) in methanol (35 ml) were added cyclohexanecarbaldehyde (5.33 g) and sodium cyanoborohydride (3.78 g) under ice-cooling and the mixture was stirred at room temperature. After one hour, the reaction mixture was concentrated and water and saturated brine were added. The mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=15/1) to give 3-chloro-N-cyclohexylmethyl-4-methylaniline as a pale-yellow oil (9.64 g).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:31])=[C:14]2[C:18]=1[CH:17]([NH:19][C:20]1[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH2:30])[CH:26]=3)[N:21]=1)[CH2:16][CH2:15]2>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:31])=[C:14]2[C:18]=1[CH:17]([NH:19][C:20]1[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:30][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[CH:26]=3)[N:21]=1)[CH2:16][CH2:15]2
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1ccc(C)c2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Product: COc1ccc(C)c2c1C(Nc1ccc3cc(NS(=O)(=O)N(C)C)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method described in example 66 from dimethylsulfamoylchloride and rac-N2-(7-methoxy-4-methyl-indan-1-yl)-quinoline-2,6-diamine; MS: m/e=427.6 (M+H+).
Reaction SMILES: [CH2:1]([C:8]1([NH2:11])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C1O[N:15]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C(Cl)Cl>[CH2:1]([C:8]1([NH:11][NH:15][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1OC1C(Cl)(Cl)Cl
Reactant: NC1(Cc2ccccc2)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC1(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10.6 g (72.0 mmol) of 1-benzylcyclopropanamine was dissolved in 90 mL of methylene chloride, mixed with 14.3 g (54.5 mmol) of separately prepared t-butyl 3-(trichloromethyl)-1,2-oxaziridine-2-carboxylate under cooling with ice, and stirred at room temperature for 30 minutes. After completion of the reaction, methylene chloride was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel 350 g, ethyl acetate:hexane=1:20) to give 4.6 g of the desired product as a brown solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[CH:12]=2)[CH:7]=[N:6]1.[NH:19]1[CH2:23]C=C[CH2:20]1>>[CH3:20][N:19]([CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[CH:12]=2)[CH:7]=[N:6]1)[CH3:23]
Reactant: ClCCCn1ncc2ccc(-c3ccsc3)cc21
Reactant: C1=CCNC1
Product: CN(C)CCCn1ncc2ccc(-c3ccsc3)cc21

Procedure:
1-(3-(N-pyrrolin-3-yl)propyl)-6-(3-thienyl)-1H-indazole: (20.2 mg, 82%); from 1-(3-chloropropyl)-6-(3-thienyl)-1H-indazole (22.0 mg, 0.08 mmol) and neat 3-pyrroline (250 mg, 3.6 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[CH3:8].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:26][CH2:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[C:30](=[O:47])[N:31]([CH:39]1[CH2:44][CH2:43][C:42](=[O:45])[NH:41][C:40]1=[O:46])[C:32]([CH3:38])=[N:33]2>CN(C=O)C>[O:46]=[C:40]1[CH:39]([N:31]2[C:30](=[O:47])[C:29]3[C:34](=[CH:35][CH:36]=[CH:37][C:28]=3[CH2:27][NH:26][C:10](=[O:12])[CH2:9][C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([F:1])[CH:3]=3)[N:33]=[C:32]2[CH3:38])[CH2:44][CH2:43][C:42](=[O:45])[NH:41]1
Reactant: Cc1ccc(CC(=O)O)cc1F
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1ccc(CC(=O)NCc2cccc3nc(C)n(C4CCC(=O)NC4=O)c(=O)c23)cc1F
Reaction time: 1 h
Yield: 74 %

Procedure:
To a stirred solution of (3-fluoro-4-methyl-phenyl)-acetic acid (0.25 g, 1.5 mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1.1′ carbonyldiimidazole (0.27 g, 1.6 mmol) and stirred for one hour. To the mixture, 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.50 g, 1.5 mmol) was added, and the mixture was stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-Dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-2-(3-fluoro-4-methyl-phenyl)-acetamide as a yellow solid (500 mg, 74% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.10 min (99.3%); mp, 264-266° C.; 1HNMR (DMSO-d6) 2.15-2.20 (m, 4H, CHH and CH3Ar), 2.57-2.91 (m, 6H, CHCH2, CH3), 3.51 (s, 2H, ArCH2), 4.73-4.78 (m, 2H, CH2NH), 5.23 (dd, J=6, 11 Hz, 1H, CH), 6.99-7.72 (m, 6H, Ar), 8.34 (t, J=6 Hz, 1H, CH2NH), 11.01 (s, 1H, NH; 13C NMR (DMSO-d6) δ 13.76 (d, JC-F=3 Hz), 20.73, 23.27, 30.59, 41.60, 41.72, 56.48, 115.43 (d, JC-F=22 Hz), 117.69, 121.98 (d, JC-F=17 Hz), 124.82 (d, JC-F=7 Hz), 124.83, 125.59, 131.23 (d, JC-F=5 Hz), 133.80, 136.12 (d, JC-F=8 Hz), 140.64, 148.44, 154.80, 160.38 (d, JC-F=242 Hz), 160.91, 169.49, 169.90, 172.58. LCMS MH=451; Anal Calcd For C24H23N4O4F: C, 63.99; H, 5.15; N, 12.44; F, 4.22. Found: C, 63.61; H, 5.19; N, 12.33; F, 4.20.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10](=O)[C:9]2[C:4](=[C:5]([CH3:14])[C:6]([CH3:13])=[CH:7][C:8]=2[CH3:12])[C:3]1=O.C1C=CC=CC=1>Cl.C(O)C>[CH3:1][C:2]1([CH3:16])[CH2:10][C:9]2[C:4](=[C:5]([CH3:14])[C:6]([CH3:13])=[CH:7][C:8]=2[CH3:12])[CH2:3]1
Reactant: Cc1cc(C)c2c(c1C)C(=O)C(C)(C)C2=O
Agent: Cl
Solvent: c1ccccc1
Solvent: CCO
Product: Cc1cc(C)c2c(c1C)CC(C)(C)C2
Temperature: 25 °C
Yield: 80.6 %

Procedure:
To a mixture of 100 g of 7% Zn/Hg in 200 ml of 20% hydrochloric acid and 70 ml of ethanol was added 22.32 g of the 2,2,4,6,7-pentamethylindan-1,3-dione with stirring. After refluxing for 6 hours, the reaction mixture was added 100 ml of benzene and refluxed for 1 hour. The reaction mixture was cooled to room temperature and extracted with diethyl ether. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 15.67 g of the title compound as yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[O:6][C:5]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([O:24]CC4C=CC=CC=4)=[CH:19][C:18]=3[Cl:32])=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1>[Pd].CO>[CH3:1][C:2]1([CH3:33])[O:6][C:5]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([OH:24])=[CH:19][C:18]=3[Cl:32])=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1
Reactant: CC1(C)Cc2cccc(OCCCCOc3c(Cl)cc(OCc4ccccc4)cc3Cl)c2O1
Agent: [Pd]
Solvent: CO
Product: CC1(C)Cc2cccc(OCCCCOc3c(Cl)cc(O)cc3Cl)c2O1

Procedure:
A mixture of 0.67 gram (0.0014 mole) of, 2-[4-(2,2-dimethyl(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-1,3-dichloro-5-(phenylmethoxy)benzene and 0.01 gram (catalyst) of 10% palladium on carbon in 75 mL of methanol was subjected to hydrogenation conditions using a Parr Hydrogenator, yielding 0.55 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.