Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[N:2]1.C(N(C(C)C)CC)(C)C.[CH2:18]([O:25][C:26](=[O:47])[C@H:27]([CH3:46])[CH2:28][C@H:29]([N:43]=[C:44]=[O:45])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:33][CH:32]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:25][C:26]([C@H:27]([CH3:46])[CH2:28][C@H:29]([NH:43][C:44]([N:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[N:2]1)=[O:45])[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:35][CH:36]=1)=[O:47])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)N=C=O)C(=O)OCc1ccccc1
Reactant: O=C(O)c1cc[nH]n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)n1ccc(C(=O)O)n1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Next, to a solution of 1H-pyrazole-3-carboxylic acid (20.5 mg, 0.183 mmol) in DMF (1 mL) is added diisopropylethylamine (0.032 mL, 0.183 mmol). After 15 min a solution of the above (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid benzyl ester in DMF (1 mL) is added dropwise and the mixture is stirred at room temperature for 18 hours. The mixture is purified by preparative HPLC using a gradient of 10% MeCN to 100% MeCN (0.1% TFA). Lyophilization of the appropriate fractions furnishes 1-((1S,3R)-3-benzyloxycarbonyl-1-biphenyl-4-ylmethyl-butylcarbamoyl)-1H-pyrazole-3-carboxylic acid. Next, a solution of 1-((1S,3R)-3-benzyloxycarbonyl-1-biphenyl-4-ylmethyl-butylcarbamoyl)-1H-pyrazole-3-carboxylic acid (60 mg, 0.117 mmol) in EtOAc (10 mL) is hydrogenated over 10% Pd/C (40 mg) at 1 atm for 5 hours. The catalyst is filtered through Celite and the filtrate evaporated under reduced pressure. The residue is purified by preparative HPLC using a gradient of 10% MeCN to 100% MeCN (0.1% TFA). Lyophilization of the appropriate fractions furnishes 1-((1S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butylcarbamoyl)-1H-pyrazole-3-carboxylic acid. HPLC Retention time 0.96 minutes (condition A); MS 422.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (d, J=7.07Hz, 3H), 1.78 (m, 1H), 1.88 (m, 1H), 2.45 (m, 1H), 2.86 (m, 1H), 2.98 (m, 1H), 4.14 (m, 1H), 6.84 (d, J=2.65Hz, 1H), 7.28 (d, J=8.34Hz, 2H), 7.33 (t, 1H), 7.43 (t, 2H), 7.56 (d, J=8.34Hz, 2H), 7.63 (d, J=7.07Hz, 2H), 8.29 (d, J=2.78Hz, 1H), 8.58 (d, J=9.09Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](=[O:28])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.[BH4-].[Na+]>O1CCCC1.CO.[Cl-].[Na+].O>[CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH:14]([OH:28])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][CH:22]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(OCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(C(O)COc3ccc(C(=O)O)cc3)ccc21
Yield: 76 %

Procedure:
2.1 g (5 mmol) of 1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-(4-ethoxycarbonylphenoxy)ethanone (from Example 5) in 100 ml of tetrahydrofuran/methanol (2:1) were stirred with 0.4 g (10 mmol) of sodium borohydride at room temperature for 30 min; the reaction solution was poured into saturated brine and extracted with ethyl acetate; the extracts were washed with water, dried over magnesium sulfate and evaporated to provide an oily residue which was subjected to alkaline hydrolysis as described in Example 6 and yielded after appropriate working up 1.4 g of the title compound; melting point (cyclohexane): 160°-162° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([N:11]1[CH2:14][C:13](=O)[CH2:12]1)([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]>O1CCCC1.C(O)(=O)C.CO.[C].[Pd]>[CH3:1][N:2]([CH3:3])[CH:13]1[CH2:14][N:11]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH2:12]1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 101 %

Procedure:
After adding a 2 M solution of dimethylamine in tetrahydrofuran (21.9 ml), acetic acid (1.73 ml) and 10% palladium-carbon (2.15 g) to a solution of 1-Boc-azetidin-3-one (3.45 g) in methanol (175 ml), the mixture was stirred for 14 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The combined organic layers were dried over anhydrous sodium sulfate. This was followed by concentration to provide the title compound (4.07 g, 101%) as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.[OH-].[K+].[C:13](=[S:15])=[S:14].Cl[CH2:17][C:18](O)=[O:19]>O>[O:19]=[C:18]1[CH2:17][S:14][C:13](=[S:15])[N:1]1[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1
Reactant: NC1CCCC(C(=O)O)C1
Reactant: S=C=S
Reactant: O=C(O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCCC(N2C(=O)CSC2=S)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21.2 %

Procedure:
To a round bottom flask containing 3-amino-cyclohexanecarboxylic acid (3.80 g, 26.54 mmol) was added aqueous potassium hydroxide (3 g, 53.08 mmol) in water (20 mL). The reaction mixture was stirred at room temperature for 15 minutes. Carbon disulfide (1.60 mL, 26.54 mmol) was added drop-wise to the reaction mixture and stirred at room temperature for 1.5 h. The reaction mixture was then cooled to 0° C. and an aqueous solution of chloroacetic acid (2.5 g, 26.54 mmol) and potassium hydroxide (1.5 g, 26.54 mmol) in water (15 mL) was added slowly to the reaction mixture. The cooling bath was removed and the reaction mixture stirred at room temperature for 1.5 h. The reaction mixture was cooled to 0° C. and acidified with concentrated sulfuric acid (3 mL). The cooling bath was removed and the reaction mixture was heated at 100° C. for 8 h and then allowed to cool to room temperature overnight. The solid was filtered, washed with water (15 mL), 1:1 hexanes/ether (100 mL) and hexanes (100 mL). The solid was dried in a vacuum oven at 55-60° C. for 5 h to afford 3-(4-oxo-2-thioxo-thiazolidin-3-yl)-cyclohexanecarboxylic acid (1.46 g, 21%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 1.16-1.39 (2H, m), 1.57 (1H, m), 1.79-1.89 (3H, m), 1.96-2.36 (3H, m), 4.12 (2H, s), 4.79 (1H, m), 12.18 (1H, s); APCI-MS: 258.31
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17]CC)=O)[C:11](=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:21][C:22]([NH2:24])=[S:23].[CH3:25][O-].[Na+].IC>CO>[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]2[C:11](=[N:21][C:22]([S:23][CH3:25])=[N:24][C:15]2=[O:17])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CSC1=NC(=O)C2CCN(Cc3ccccc3)CC2=N1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A suspension of ethyl N-benzyl-3-oxo-4-piperidine-carboxylate hydrochloride (8.9 g, 30 mmol) and thiourea (4.56 g, 60 mmol) in a solution of sodium methoxide in methanol (34 mL, 25% wt/wt) was stirred at 100° C. in a sealed tube overnight. Iodomethane (5.1 g, 42 mmol) was added dropwise to the reaction mixture after cooling to room temperature and stirred at room temperature for 1 hr. Solvent was removed in vacuo and the residue was dissolved in water (100 mL), extracted by CHCl3 and i-PrOH (3:1, 10×40 mL) and dried over sodium sulfate. Solvent was removed in vacuo, product was obtained as a beige powder (7.6 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([OH:7])=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1O>>[Br:11][C:9]1[CH:8]=[C:4]([C:5]2[O:7][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=2)[CH:3]=[C:2]([Br:1])[CH:10]=1
Reactant: Nc1ccccc1O
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Product: Brc1cc(Br)cc(-c2nc3ccccc3o2)c1

Procedure:
3,5-Dibromo-benzoic acid and 2-aminophenol were condensed to give 2-(3,5-dibromo-phenyl)-benzoxazole, which was converted to N-[3-benzoxazol-2-yl-5-(1H-indol-4-yl)-phenyl]-acetamide as described in Example 106. 1H NMR (400 MHz, DMSO-d6): δ 11.35 (s, 1H), 10.36 (s, 1H), 8.57 (t, J=1.6 Hz, 1H), 8.13 (d, J=1.6 Hz, 2H), 7.77-7.84 (m, 2H), 7.44-7.48 (m, 2H), 7.39-7.43 (m, 2H), 7.21 (t, J=7.5 Hz, 1H), 7.17 (dd, J=7.2, 1.0 Hz, 1H), 6.64-6.67 (m, 1H), 2.11 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:39](=[O:40])[C:38]2[CH:42]=[CH:43][C:35]([C:34]([F:33])([F:44])[F:45])=[CH:36][CH:37]=2)=[CH:22][CH:23]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc(NC(=O)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl{2-[(4-aminophenyl)ethynyl]-4-chlorophenoxy}acetate (Intermediate 222; 72 mg; 0.20 mmol) and triethylamine (83 μl; 0.60 mmol) in DCM (2 ml) was treated with 4-(trifluoromethyl)-benzoyl chloride (30 μl; 0.20 mmol). After stirring at RT for 1 hour, the reaction was quenched with a saturated aqueous ammonia solution (1 mL). EtOAc and a saturated NH4Cl solution in water were added, the phases separated and the organic phase was dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([N:21]=[C:22]=[O:23])[CH:19]=[CH2:20]>>[CH2:18]([NH:21][C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23])[CH:19]=[CH2:20]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: C=CCN=C=O
Product: C=CCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 96 %

Procedure:
Beginning with 15.0 mg 0.0655 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 11.1 mg (0.131 mMol) allyl isocyanate, 19.6 mg (96%) of the title compound were recovered.
Reaction SMILES: Cl.Cl.Cl.[N:4]1([CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:13]=[C:12]2[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:8][CH2:7][CH2:6][CH2:5]1.Cl[C:29]1[C:30]2[C@H:38]([CH3:39])[CH2:37][C:36](=[O:40])[NH:35][C:31]=2[N:32]=[CH:33][N:34]=1.N12CCCN=C1CCCCC2.C>C(O)CC.C(OCCCC)(=O)C>[CH3:39][C@H:38]1[C:30]2[C:29]([N:25]3[CH2:24][CH2:23][CH:22]([C:12]4[N:11]([CH2:10][CH2:9][N:4]5[CH2:5][CH2:6][CH2:7][CH2:8]5)[CH:15]=[C:14]([CH:16]5[CH2:21][CH2:20][O:19][CH2:18][CH2:17]5)[N:13]=4)[CH2:27][CH2:26]3)=[N:34][CH:33]=[N:32][C:31]=2[NH:35][C:36](=[O:40])[CH2:37]1
Reactant: c1c(C2CCOCC2)nc(C2CCNCC2)n1CCN1CCCC1
Reactant: C[C@@H]1CC(=O)Nc2ncnc(Cl)c21
Agent: Cl
Solvent: CCCCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCCO
Product: C[C@@H]1CC(=O)Nc2ncnc(N3CCC(c4nc(C5CCOCC5)cn4CCN4CCCC4)CC3)c21
Temperature: 25 °C
Yield: 109 %

Procedure:
Charge 4-(1-(2-(Pyrrolidin-1-yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidine trihydrochloride (300 g, 1.0 equiv), (R)-4-Chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (146.2 g, 1.0 equiv) and n-propanol (3.0 L) to a 12-L reaction flask. Stir the reaction mixture and add 1,8-diazabicyclo[5.4.0]undec-7-ene (394.3 g, 3.5 equiv) over ten minutes. Heat the reaction to 90° C. for 8 hours, and allow to cool to room temperature over 12 hours. Displace the n-propanol with n-butyl acetate to a total volume of 3-L and a residual n-propanol content of 11% (w/w). Heat the organic solution to 50-60° C. and wash with brine (2.25 L). Back-extract the aqueous phase with nButyl acetate (1.5 L) and combine the organic layers. Wash the combined organic layers with water (2×450 mL) at 50-60° C. Separate the organic layer and add activated charcoal (75 g, 0.25 equiv) and stir at 50-60° C. for 30 min. Filter the slurry and rinse the solids with n butyl acetate (1.5 L). Wash with water (1 L), separate the organic phase and azeotropically dry the organic phase to remove water. At 50-60° C., add heptanes (3.0 L) cool to 40° C. and add seed crystals. Allow the slurry to cool to room temperature over ˜12 h. Cool to 0-5° C., filter the slurry and wash with heptanes (2×900 mL). Dry in vacuo and isolate (R)-5-Methyl-4-(4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one as a white solid (365.3 g, 64%). MS (ES) m/z=494 [M]+.
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)#[N:15].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:2]2[CH2:3][CH2:4][C:5]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6]=3[CH2:1]2)=[O:21])=[CH:18][CH:17]=1)#[N:15]
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C(=O)N2CCc3c([nH]c4ccccc34)C2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of 175 mg of 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole, 5 ml of dimethylformamide, 0.2 g of 4-cyano-benzoic acid, 0.35 g of diphenylphosphoryl azide and 0.4 ml of diisopropylethylamine was stirred at room temperature over night. The solvent was removed under reduced pressure and the residue was partitioned between methylene chloride and 10% aqueous sodium carbonate solution. The organic phase was washed with 1 N hydrochloric acid, dried over magnesium sulfate and evaporated. Crystallization of the residue from methylene chloride/ether yielded 245 mg of 2-(4-cyano-benzoyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole with m.p. 228-232° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][C:19](=[O:21])[N:18]([N:22]([CH3:35])[CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)[CH:17]([C:36]([OH:38])=O)[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>CN(C=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:16][CH:17]([C:36]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:38])[N:18]([N:22]([CH3:35])[CH:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=4)[CH2:27][CH2:28]3)[C:19](=[O:21])[CH2:20]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CN(C1CCN(c2ccncc2)CC1)N1C(=O)CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1C(=O)O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CN(C1CCN(c2ccncc2)CC1)N1C(=O)CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1C(=O)N1CCOCC1
Product: Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
A mixture of 4-[(6-chloro-2-naphthyl)sulfonyl)-1-[methyl[1-(4-pyridinyl)-4-piperidinyl]amino]-6-oxo-2-piperazinecarboxylic acid (0.22 g) obtained in Example 110, morpholine (0.048 g) and 1-hydroxy-1H-benzotriazole monohydrate (0.085 g) in DMF (4.4 ml) was combined with WSC (0.12 g) and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and partitioned between saturated aqueous sodium bicarbonate and methylene chloride. The organic phase was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified on a CHP-20 column (water→1% 1N hydrochloric acid-containing 30% aqueous solution of acetonitrile) to obtain the title compound (0.13 g) as a colorless powder.
Reaction SMILES: [CH3:1][CH:2]1[O:17][C:5]2=[C:6]([O:15][CH3:16])[C:7]3[O:12][C:11](=[O:13])[CH:10]=[CH:9][C:8]=3[CH:14]=[C:4]2[CH2:3]1.C1(OC2C=CC=CC=2)C=CC=CC=1>[Pd]>[CH3:16][O:15][C:6]1[C:7]2[O:12][C:11](=[O:13])[CH:10]=[CH:9][C:8]=2[CH:14]=[C:4]2[CH:3]=[C:2]([CH3:1])[O:17][C:5]=12
Reactant: COc1c2c(cc3ccc(=O)oc13)CC(C)O2
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1c2oc(C)cc2cc2ccc(=O)oc12
Reaction time: 8 h

Procedure:
To a solution of 0.70g. (3.02 mmoles) of 2-methyl-9-methoxy-2,3-dihydro-7H-furo[3,2-g][1]benzopyran-7-one in 15 ml. of diphenyl ether was added 0.70 g. of 10% Pd/C. The mixture was heated under reflux for 6.0 hours, cooled, and filtered over Celite (washing with methanol). The methanol was removed from the filtrate by rotary evaporation, and the remaining solution of the product in diphenyl ether was diluted with 200 ml. of pet. ether. After standing overnight, the solid which separated was filtered off and washed with pet. ether to yield 9-methoxy-2-methyl-7H-furo[3,2-g][1]benzopyran-7-one. Recrystallization from ethanol afforded an analytical sample, mp 149°-150°.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[C:14]#[CH:15])=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1.O1CCCC1>O>[NH2:13][C:9]1[C:8]([C:14]#[CH:15])=[C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([NH:1][C:26]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=3)=[O:27])=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: C#Cc1c(Oc2ccc(N)cc2)ccnc1N
Reactant: O=C=Nc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1c(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccnc1N

Procedure:
4-(4-Aminophenoxy)-3-(1-ethynyl)-2-pyridinamine (260 mg), para-fluorophenyl isocyanate (0.13 ml) and tetrahydrofuran (5 ml) were stirred at room temperature for 20 hours. Water was added to the reaction solution, the tetrahydrofuran was distilled off, and then a small amount of ethyl acetate was added and the precipitated solid was filtered off to obtain 20 mg of a light brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[C:18]([CH3:20])[N:17]=[C:16](Cl)[C:15]=2[N+:22]([O-:24])=[O:23])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38].C(OCC)(=O)C>CN1CCCC1=O>[C:1]([O:5][C:6](=[O:25])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH:38][CH2:37][C:36]3[CH:39]=[CH:40][C:41]([O:43][CH3:44])=[CH:42][C:35]=3[O:34][CH3:33])[C:15]=2[N+:22]([O-:24])=[O:23])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Cc1cc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)c([N+](=O)[O-])c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2nc(C)cc(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c2[N+](=O)[O-])c(OC)c1
Reaction time: 24 h
Yield: 73 %

Procedure:
1.85 g (R)-1-(2-chloro-6-methyl-3-nitropyridin-4-yl)piperidine-3-carbamic acid tert-butyl ester (5 mmol) was dissolved in 10 mL N-methylpyrrolidone, to which 1.4 mL triethylamine (10 mmol) was added, and 1.25 g 2,4-dimethoxybenzylamine (7.5 mmoL) was added. The reaction was continued for 24 h at 80° C. The reaction solution was exacted three times with ethyl acetate. The ethyl acetate phase was combined, washed three times with water, dried, and evaporated to dryness. The resultant crude product was purified through a column chromatography (ethyl acetate:petroleum ether=1:8) to afford 1.83 g titled product with a yield of 73.1%.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][NH:36][CH3:37].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][N:36]([CH2:27][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]2)[CH:26]=[CH:25][CH:24]=1)[CH3:37]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: CNCCN(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN(C)CCN(C)C)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (45.0 mg, 0.101 mmol) in DCM (2 mL) was added N,N,N′-trimethyl-1,2-ethanediamine (116 ul, 0.90 mmol). The reaction solution was stirred at ambient temperature for 1 hr prior to addition of NaBH(OAc)3 (69 mg, 0.326 mmol). The resulting mixture was stirred overnight at ambient temperature, and additional NaBH(OAc)3 (128 mg, 0.606 mmol) was added. The reaction was stirred for another 2 h, after which time the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound
Reaction SMILES: [OH2:1].[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[C:13](=O)(O)[O-].[Na+]>C(Cl)Cl.COCOC>[CH3:13][CH2:3][C:4](=[O:1])[CH2:5][CH2:6][CH2:7][CH2:2][CH3:12]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: COCOC
Solvent: ClCCl
Product: CCCCCC(=O)CC

Procedure:
To a solution of 6(7)-hydroxy-2-methoxycarbonyl-8-azabicyclo(3.2.1)octane-3-one (18 g, 84.5 mmol) in 200 ml of CH2Cl2, 70 ml of dimethoxymethane was added, followed by (18 g, 93 mmol) of p-toluene sulfonic acid monohydrate. The round-bottom flask was fitted with a soxhiet extractor containing 3-4 A molecular sieves. The reaction mixture was heated to reflux with stirring until the starting material had disappeared (TLC). The mixture was cooled and treated with sat. sodium bicarbonate solution and extracted with CH2Cl2. The combined organics were dried over K2CO3 removed in vacuo and applied to column (silica gel, 10% Et3N, 30% EtOAc/hexane). 6-Methoxymethoxy-2-methoxy-carbonyl-8-azabicyclo(3.2.1))octane-3-one (2.2 g) was obtained as a yellow oil. Rf 0.3 (10% Et3N, 30% EtOAc in hexane).
Reaction SMILES: COC(=O)[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](OC)=[O:13])Br.COC(=O)C(C1C=CC(Cl)=CC=1C(OC)=O)Br.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([OH:43])=[C:39]([CH:42]=1)[C:40]#[N:41].OC1C=CC=CC=1C#N>>[OH:13][C:12]1[C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]2[O:43][C:38]3[CH:37]=[CH:36][C:35]([Cl:34])=[CH:42][C:39]=3[C:40]=2[N:41]=1
Reactant: COC(=O)c1ccccc1C(Br)C(=O)OC
Reactant: N#Cc1cc(Cl)ccc1O
Agent: COC(=O)c1cc(Cl)ccc1C(Br)C(=O)OC
Agent: N#Cc1ccccc1O
Product: Oc1nc2c3cc(Cl)ccc3oc2c2ccccc12

Procedure:
The procedure was similar to step S19B, while the starting material was 24A in stead of 19A, and used 5-chloro-2-hydroxy-benzonitrile in stead of 2-hydroxy-benzonitrile.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[C:11]([C:17]([OH:19])=O)[NH:12]3)[CH:2]=1.Cl.Cl.Cl.[N:24]1([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:31][CH2:32][N:33]2[CH2:34][CH2:35][CH:36]([NH:39][C:17]([C:11]3[NH:12][C:13]4[C:9]([CH:10]=3)=[C:8]([O:7][C:3]3[CH:2]=[C:1]([CH3:20])[CH:6]=[CH:5][CH:4]=3)[CH:16]=[CH:15][CH:14]=4)=[O:19])[CH2:37][CH2:38]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1cccc(Oc2cccc3[nH]c(C(=O)O)cc23)c1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Agent: Cl
Product: Cc1cccc(Oc2cccc3[nH]c(C(=O)NC4CCN(CCN5CCCCCC5)CC4)cc23)c1

Procedure:
This compound is synthesized analogously to Example 1 from 4-m-tolyloxy-1H-indole-2-carboxylic acid 133 (preparation see below) and amine 5.