Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][N:17]=1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26]1>>[Cl:15][C:16]1[N:17]=[CH:18][C:19]([C:20]([N:6]2[CH:7]([C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[NH:25][CH:26]=3)[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:21])=[CH:23][CH:24]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: c1ccc2[nH]ccc2c1
Reactant: c1ccc2c(c1)cnc1ccccc12
Product: O=C(c1ccc(Cl)nc1)N1c2ccccc2-c2ccccc2C1c1c[nH]c2ccccc12

Procedure:
(6-Chloro-pyridin-3-yl)-[6-(1H-indol-3-yl)-6H-phenanthridin-5-yl]-methanone was prepared from phenanthridine, 6-chloronicotinoyl chloride, and indole according to GP 2. Yield, 55%. 1H-NMR (DMSO-d6): δ=6.24 (d, J=1.7 Hz, 1H), 6.46 (s, br., 1H), 6.90 (t, J=7.5 Hz, 1H), 6.99-7.09 (m, 2H), 7.15-7.28 (m, 3H), 7.40-7.48 (m, 2H), 7.51-7.59 (m, 2H), 7.64 (d, J=8.2 Hz, 1H), 7.85 (d, J≈7 Hz, 1H), 8.01 (d, J=7.6 Hz, 1H), 8.12 (d, J=7.6 Hz, 1H), 8.23 (s, 1H), 10.73 (s, 1H); (+)-ESI-MS: m/z=436 [M(35Cl)+H]+, 319 [M(35Cl)-indole+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: CCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Product: CCCCCCCCCCCC(=O)NCCn1cc(CCCCCc2cn(C(=O)OC(C)(C)C)c(N)n2)nn1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.107 g, 0.387 mmol) was reacted with N-(2-azidoethyl)dodecanamide (0.104 g, 0.387 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-dodecanamidoethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.36 (s, 1H), δ 6.94 (s, 1H), δ 6.49 (s, 1H), δ 6.23 (s, 2H), δ 4.46 (t, 2H), δ 3.74 (q, 2H), δ 2.68 (t, 2H0, δ 2.34 (t, 2H), δ 2.16 (t, 2H), δ 1.54 (m, 13H), δ 1.47 (m, 2H), δ 1.24 (m, 18H), δ 0.87 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 174.3, 150.4, 149.5, 148.3, 138.5, 121.9, 106.5, 84.9, 49.5, 39.5, 36.6, 34.1, 32.1, 29.8, 29.8, 29.7, 29.6, 29.5, 29.3, 28.9, 28.2, 28.1, 29.0, 26.9. 25.6, 22.9, 14.3 ppm; HRMS (ESI) calcd for C29H51N7O3 (M+) 545.4053, found 545.4053, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)dodecanamide hydrochloride (0.155 g, 83% yield). 1H NMR (400 MHz, CD3OD) δ 8.31 (s, 1H), δ 6.49 (s, 1H), δ 4.63 (s, 2H), δ 3.97 (s, 2H), δ 2.81 (s, 2H), δ 2.51 (t, 2H), δ 2.14 (t, 2H), δ 1.76 (s, 2H), δ 1.67 (s, 2H), δ 1.51 (s, 2H), δ 1.44 (s, 2H), δ 1.26 (bs, 16H), δ 0.71 (s, 3H) ppm; 13C NMR (100 MHz, CD3OD) δ 175.6, 159.4, 147.3, 127.6, 108.5, 51.3, 48.6, 38.8, 35.8, 31.9, 29.6, 29.5, 29.4, 29.3, 29.2, 28.2, 28.1, 27.7, 24.8, 24.2, 23.9, 22.6, 22.5, 13.4, 13.3 ppm; HRMS (ESI) calcd for C24H43N7O (M+) 445.3429, found 445.3524.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:3][CH2:2]1.C1(C2C=CC(C(O)=O)=NC=2OCC2CCCO2)CC1.Cl.[NH2:41][C:42]([CH2:50][CH3:51])([CH2:48][CH3:49])[C:43]([O:45][CH2:46][CH3:47])=[O:44]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([NH:41][C:42]([CH2:48][CH3:49])([CH2:50][CH3:51])[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:20])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(N)(CC)CC
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCOCC2)n1
Agent: Cl
Agent: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Product: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(C2CC2)c(OCC2CCOCC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (which can e.g. be prepared in a similar manner than 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 b)) and ethyl 2-amino-2-ethylbutanoate hydrochloride (CAN 1135219-29-2) as starting materials. MS (EI): m/e=419.3 [M+H]+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11]([O-])([O-])=[O:12].[K+].[K+].C(OC)=O>O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][CH:11]=[O:12])=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Agent: [K+]
Solvent: COC=O
Solvent: O
Product: O=CNNc1ccc(Br)cc1
Reaction time: 12 h
Yield: 109.1 %

Procedure:
10.0 g of 4-bromophenylhydrazine hydrochloride are dissolved in 30 ml of water. 6.2 g of K2CO3 and 36 ml of methyl formate are added and then the mixture is heated at reflux for one hour and then at ambient temperature for 12 hours. The precipitate formed is filtered off and washed with an isopropanol/petroleum ether (v/v; 50/50) mixture. 10.5 g of the expected product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=O)[C:11](=[C:15](O)[CH2:16][O:17][CH3:18])[C:10](=[O:20])[CH2:9]1.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12]2[NH:23][N:22]=[C:15]([CH2:16][O:17][CH3:18])[C:11]=2[C:10](=[O:20])[CH2:9]1
Reactant: COCC(O)=C1C(=O)CC(c2ccccc2Cl)CC1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: COCc1n[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Yield: 25.3 %

Procedure:
A solution of 5-(2-chlorophenyl)-2-(1-hydroxy-2-methoxyethylidene)cyclohexane-1,3-dione (0.4 g) and hydrazine hydrate (0.072 g) in ethanol (15 ml) was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography to give 6-(2-chlorophenyl)-3-methoxymethyl-4,5,6,7-tetrahydroindazol-4-one (0.1 g) as oil.
Reaction SMILES: [F:1][CH2:2][C:3]1[N:4]=[CH:5][C:6]([C:9]([O:11]C)=[O:10])=[N:7][CH:8]=1.O.O.[OH-].[Li+].CCOCC>O1CCOCC1>[F:1][CH2:2][C:3]1[N:4]=[CH:5][C:6]([C:9]([OH:11])=[O:10])=[N:7][CH:8]=1
Reactant: COC(=O)c1cnc(CF)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cnc(CF)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.3 %

Procedure:
Methyl 5-(fluoromethyl)pyrazine-2-carboxylate (94 mg) was dissolved in dioxan (1 mL) and water (1 mL) was added, followed by lithium hydroxide monohydrate (60 mg). After stirring at RT for 18 h, Et2O (20 mL) was added and the mixture was then extracted with NaOH (1 N, aq., 2×20 mL). The aqueous portions were acidified with 6N HCl to pH 1, extracted with EtOAc (2×40 mL), the combined organic portions dried over MgSO4 and evaporated to afford the title compound as a white solid (71 mg). 1H NMR (400 MHz, CDCl3) δ ppm 5.70 (d, J=46.2 Hz, 2H), 8.85 (s, 1H), 9.40 (s, 1H)
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC2C=CC=CC=2)=[O:18])=[CH:4][C:3]1=[O:27]>C(OCC)(=O)C.CCOCC.[Pd]>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:4][C:3]1=[O:27]
Reactant: O=C(CCCCOC1=CC(=O)C(=O)c2ccccc21)OCc1ccccc1
Agent: [Pd]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(O)CCCCOC1=CC(=O)C(=O)c2ccccc21
Reaction time: 10 h
Yield: 37 %

Procedure:
Benzyl ester 502 (1.90 g, 5.22 mmol) was hydrogenated at 30 psi with Pd (400 mg) in ethyl acetate (120 mL) for 6 h. The catalyst was removed by filtration through celite, the solvent was evaporated in vacuo and the residue was oxidized with Ag2O (1.45 g, 6.25 mmol) in Et2O by stirring for 10 h. Following filtration and evaporation of the solvent the product was crystallized from benzene to afford 0.53 g of pure material. The mother liquor was purified by flash chromatography (CH2Cl2/MeOH 15:1), the product dissolved in CH2Cl2, extracted with aqueous NaHCO3 solution, acidified to pH 1 with 3% HCl and extracted back with CH2Cl2 to give additional 0.25 g of pure material (total yield 55%), mp 134-136° C.; 1H NMR (CDCl3) 8.12 (d, J=7.0 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.70 (t, J=7.5 H), 7.59 (t, J=7.4 Hz, 1H), 7.27 (s, 1H), 4.18 (t, J=5.9 Hz, 2H), 2.51 (t, J=7.0 Hz, 2H), 1.75-2.15 (m, 4H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH:14]([CH3:16])[CH3:15])[C:8](O)=[O:9])(=[O:4])=[O:3].S(Cl)([Cl:19])=O>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH:14]([CH3:16])[CH3:15])[C:8]([Cl:19])=[O:9])(=[O:4])=[O:3]
Reactant: CC(C)c1ccc(C(=O)O)cc1S(C)(=O)=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(C(=O)Cl)cc1S(C)(=O)=O

Procedure:
4.0 g of 3-methylsulfonyl-4-i-propylbenzoic acid, 1.5 ml of thionyl chloride and 3 drops of DMF are heated under reflux for 10 h in 30 ml of toluene. The solvent is subsequently removed in vacuo and the product is taken for further use without purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=O.[P:8]([OH:11])([OH:10])[OH:9].P(Cl)(Cl)Cl>CCCCCCCC>[CH2:3]([CH2:2][NH2:1])[CH2:4][C:5]([P:8]([OH:11])([OH:10])=[O:9])([P:8]([OH:11])([OH:10])=[O:9])[OH:7]
Reactant: NCCCC(=O)O
Reactant: OP(O)O
Solvent: ClP(Cl)Cl
Solvent: CCCCCCCC
Product: NCCCC(O)(P(=O)(O)O)P(=O)(O)O
Temperature: 92.5 °C
Yield: 43.1 %

Procedure:
4-Aminobutyric acid (50 gm), phosphorous acid (140 gm) and n-octane (1000 mL) was taken in a four necked round bottom flask fitted with an addition funnel, mechanical stirrer, condenser and thermometer pocket and allowed to stir at 90-95° C. Phosphorus trichloride (240 gm) was then added to the reaction mixture and allowed to heat at 90-95° C. The reaction mixture was cooled and distilled water (500 mL) was added to it. The reaction mixture was further heated to 90-95° C. It was then cooled and ethanol (1000 mL) was added to it. The solution was further cooled to 0-5° C. and stirred for 4-5 hrs. The precipitated solid was filtered and washed with ethanol and dried under vacuum to yield 52.0 gm product.
Reaction SMILES: C[O-].[Na+].I.[NH:5]=[C:6]1[N:10]([CH3:11])[CH:9]=[CH:8][S:7]1.[C:12]1([N:18]=[C:19]=[S:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:11][N:10]1[CH:9]=[CH:8][S:7][C:6]1=[N:5][C:19]([NH:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[S:20]
Reactant: Cn1ccsc1=N
Reactant: S=C=Nc1ccccc1
Agent: C[O-]
Agent: I
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cn1ccsc1=NC(=S)Nc1ccccc1

Procedure:
Sodium methoxide (5.40 g) was added to a stirred mixture of 2-imino-3-methylthiazoline hydroiodide (24.95 g) in ethanol (100 ml) and the mixture brought to reflux. Phenyl isothiocyanate (16.35 g) in toluene (50 ml) was added over 30 minutes and reflux continued for a further hour then cooled in ice. The solid obtained on filtration and washing with ethanol and water was dried to give the product, mpt 172.5°-173.5°. Recrystallisation from iso-propanol gave analytically pure product, mpt 173.5°-174°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]O)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(Cl)(=O)=O.C([N:30]([CH2:33][CH3:34])[CH2:31]C)C.[CH2:35](CN)C=C>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:30]([CH2:33][CH:34]=[CH2:35])[CH3:31])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCc2cc(CCCCCO)ccc21
Reactant: C=CCCN
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCN(C)CCCCCc1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 77.5 %

Procedure:
To 2.75 g (9 mmol) 5-(5-Hydroxy-pentyl)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester in 100 ml CH2Cl2, 0.87 ml (11 mmol) methanesulfonyl chloride and 3.8 ml (27 mmol) triethylamine were added at 0° C. The solution was concentrated in vacuo to yield crude 5-(5-Methanesulfonyloxy-pentyl)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as yellow viscous oil, MS: 384 (MH+). The crude material was dissolved in 5 ml DMF and 5 ml (50 mmol) N-allylmethylamine. The mixture was heated to 80° C. for 3 h, concentrated and the residue was dissolved in water and ether, 2M NaOH was added and the inorganic phase was extacted with ether. The combined organic phases were washed with water and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2:MeOH 9:1 yielded 2.5 g (72%) 5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as colorless liquid, MS: 359 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[CH2:11]([O:13][C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH3:12].CCCCCC>C(Cl)(Cl)Cl.CCOCC>[CH2:11]([O:13][C:14]([NH:16][C:17]([NH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8])=[S:18])=[O:15])[CH3:12]
Reactant: COC(=O)c1sccc1N
Reactant: CCOC(=O)N=C=S
Solvent: CCOCC
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NC(=S)Nc1ccsc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Methyl 3-amino-2-thiophenecarboxylate (5.0 g (32 mmol) was dissolved in 16 mL of chloroform and to this solution 4.17 g (32 mmol) of ethoxycarbonyl isothiocyanate was added slowly with stirring at ambient temperature. A precipitate began to appear after a few minutes and after 20 min the volatile components were removed by evaporation under reduced pressure. The tan solid residue obtained was diluted with 20 mL of ether and allowed to stir for about 20 min and then 100 mL of hexane was added. The insoluble solids were recovered by filtration and dried to obtain 8.51 g of the title compound as a tan solid melting at 165°-167° C.
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:35][CH3:36])=[C:25]([NH:28][C:29](=[O:34])[CH:30]=[CH:31][CH2:32]Cl)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:13]=[CH:14][C:15]=1[F:16].CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:35][CH3:36])=[C:25]([NH:28][C:29](=[O:34])[CH:30]=[CH:31][CH2:32][N:5]4[CH2:6][CH2:7][CH2:8][CH:3]([F:2])[CH2:4]4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCCl
Reactant: FC1CCCNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCCC(F)C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
99 mg 3-Fluoro-piperidine hydrochloride, 300 mg 4-Chloro-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide and 0.37 ml of DIEA were dissolved in 5 ml THF stirred at 70° C. overnight. The mixture was then diluted with ethyl acetate, washed with water and brine and dried over Na2SO4. The resulting solids were flash chromatographed with 0-4% methanol in chloroform to give 275 mg of 4-(3-Fluoro-piperidin-1-yl)-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][CH2:6][CH2:7][NH2:8])C.[CH:12]([C:14]([CH3:16])=O)=[CH2:13].Cl.Cl.[Br:19][C:20]1[CH:21]=[C:22]([N:26]([CH3:28])N)[CH:23]=[CH:24][CH:25]=1>CCOCC.CCO>[Br:19][C:20]1[CH:25]=[CH:24][C:23]2[C:13]3[CH:4]4[N:8]([CH2:7][CH2:6][CH2:5]4)[CH2:16][CH2:14][C:12]=3[N:26]([CH3:28])[C:22]=2[CH:21]=1
Reactant: CN(N)c1cccc(Br)c1
Reactant: CCOC(CCCN)OCC
Reactant: C=CC(C)=O
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: Cn1c2c(c3ccc(Br)cc31)C1CCCN1CC2
Temperature: 100 °C
Reaction time: 1 h
Yield: 19.6 %

Procedure:
To a solution of 4-aminobutyraldehyde diethyl acetal (12.5 mL, 63.3 mmol) in Et2O (25 mL) was added methyl vinyl ketone (6.70 mL, 82.3 mmol). After 1 h, concentrated HCl (35 mL) was added, and the reaction mixture was heated at 100° C. for 3 h. After the mixture was concentrated, the residue was diluted with EtOH (25 mL), and 1-(3-bromophenyl)-1-methylhydrazine hydrochloride (3.90 g, 15.9 mmol) was added followed by concentrated HCl (25 mL). The reaction was heated at reflux overnight. After the mixture was concentrated, the residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) to give 9-bromo-7-methyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (0.95 g, 39%) as an orange solid. 9-Bromo-7-methyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (0.15 g, 0.49 mmol) was reacted according to the procedure of Example 2 (step b) to give a yellow oil in 20% (46 mg). The yellow oil was dissolved in CH3OH (1 mL) and was treated with 2 N HCl in Et2O (1 mL). The resulting solid was isolated by filtration and dried under vacuum to give the title compound (49 mg, 99%) as a yellow powder: mp 235-240° C.; 1H NMR (500 MHz, CD3OD) δ 9.10 (d, J=2.0 Hz, 1H), 8.41 (dd, J=8.5, 2.5 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.85 (d, J=7.5 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 7.16 (dd, J=8.5, 2.0 Hz, 1H), 7.03 (d, J=1.5 Hz, 1H), 6.89 (dd, J=7.0, 2.0 Hz, 1H), 5.15 (t, J=7.0 Hz, 1H), 3.77 (s, 3H), 3.77-3.71 (m, 4H), 3.49-3.44 (m, 1H), 3.28-3.25 (m, 1H), 2.76-2.72 (m, 1H), 2.31-2.19 (m, 3H); ESI MS m/z 465 [M+H]+; HPLC (Method A) 97.2% (AUC), tR=12.8 min.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][CH:11]([F:36])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:33](O)=[O:34])[O:30][C:31]=3[CH3:32])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.[CH3:37][C:38]1[C:42]([S:43]([NH2:46])(=[O:45])=[O:44])=[C:41]([CH3:47])[O:40][N:39]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[F:10][CH:11]([F:36])[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:33]([NH:46][S:43]([C:42]4[C:38]([CH3:37])=[N:39][O:40][C:41]=4[CH3:47])(=[O:44])=[O:45])=[O:34])[O:30][C:31]=3[CH3:32])=[CH:23][CH:24]=2)=[CH:17][CH:18]=1
Reactant: Cc1noc(C)c1S(N)(=O)=O
Reactant: Cc1oc(C(=O)O)cc1CNc1ccc(-c2ccc(OC(F)F)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1noc(C)c1S(=O)(=O)NC(=O)c1cc(CNc2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 3.7 %

Procedure:
Diisopropylethylamine (60 μL, 0.339 mmoles) and a solution of 4-(4′-difluoromethoxy-biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acid (171) (50 mg, 0.103 mmoles) in N,N-dimethylformamide (1.0 ml) were added to a stirred solution of 3,5-dimethyl-isoxazole-4-sulphonic acid amide (55 mg, 0.308 mmoles) in N,N-dimethylformamide (5.0 ml). A solution of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (46 mg, 0.124 mmoles) in N,N-dimethylformamide (1.0 ml) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to afford compound 174 (2 mg) as a solid. LC/MS System D; Rt=10.35 mins, m/z (ES+)=532 (M+H for C25H23F2N3O6S).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6]([C:7]2[CH:12]=[C:11]([CH2:13]O)[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[CH:5][CH2:4][CH2:3]1.CN(C=O)C.S(Cl)([Cl:32])=O>C(Cl)Cl>[Cl:32][CH2:13][C:11]1[CH:10]=[CH:9][C:8]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[C:7]([C:6]2[C:2]([CH3:24])([CH3:1])[CH2:3][CH2:4][CH:5]=2)[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2=CCCC2(C)C)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ccc(CCl)cc2C2=CCCC2(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound T1.7 (1.10 g, 3.37 mmol) and a catalytic amount of DMF (0.10 mL) in DCM (12.0 mL), was slowly added thionyl chloride (0.802 g, 6.74 mmol) at 0° C. After addition, the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the resulting residue was purified by CombiFlash® chromatography (silica gel column eluted with hexane/EtOAc, 100/0 to 95/5) to give the title compound T1 (1.15 g). 1H NMR (400 MHz, CDCl3) δ ppm. 7.32-7.39 (m, 2H), 7.28-7.29 (m, 1H), 6.88 (t, 1H), 6.80-6.82 (m, 2H), 5.56 (s, 1H), 4.66 (s, 2H), 3.78 (s, 3H), 2.27-2.29 (m, 2H), 1.69 (t, 2H), 0.89 (s, 6H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.[C:18]([O-:21])([O-:20])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]([NH:37][C:38](=[O:40])[CH3:39])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]>CN(C)C=O.C(#N)C.C(O)C>[C:5]([OH:28])(=[O:9])/[CH:6]=[CH:16]/[C:18]([OH:21])=[O:20].[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:30]=[C:31]([NH:37][C:38](=[O:40])[CH3:39])[CH:32]=[CH:33][C:34]=4[O:35][CH3:36])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:30]=[C:31]([NH:37][C:38](=[O:40])[CH3:39])[CH:32]=[CH:33][C:34]=4[O:35][CH3:36])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(NC(C)=O)cc1OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc(NC(C)=O)cc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Product: O=C(O)/C=C/C(=O)O
Temperature: 100 °C

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (3.94 g, 15.4 mmol), K2CO3 (3.67 g, 26.6 mmole), N-[3-(3-bromopropoxy)-4-methoxyphenyl]acetamide (5.56 g, 18.6 mmol) in dimethylformamide (75 ml) and acetonitrile (100 ml) was heated at 100° C. for 3 hours. At the end of the reaction, the solvent was concentrated and the mixture was extracted into dichloromethane (500 ml). The organic solution was washed with water (500 ml) and brine (400 ml), dried, then concentrated to a crude oil. The purification was effected by flash chromatography over a silica gel column (SiO2, 65 g, eluted with 1% CH3OH:dichloromethane, 1.2 l; and 3% CH3OH:dichloromethane, 500 ml). The material thus obtained weighed 2.33 g (34.3%) as an oil. This material was dissolved in ethanol and treated with a solution of fumatic acid (661 mg) in ethanol. The N-[3-[3-[4-(6-fluoro-1,2 benzisoxazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyphenyl]acetamide hemifumarate was obtained as off-white crystals weighing 2.17 g, m.p.=205°-206° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[F:16][C:17]([F:38])([F:37])[C:18]1[CH:19]=[C:20]([C:28]2([C:33]([F:36])([F:35])[F:34])[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[F:26][C:24]([F:25])([F:27])[C:22]1[CH:21]=[C:20]([C:28]2([C:33]([F:36])([F:34])[F:35])[CH2:32][CH2:31][N:30]([C:2]3[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=3)[CH2:29]2)[CH:19]=[C:18]([C:17]([F:16])([F:37])[F:38])[CH:23]=1
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Reactant: FC(F)(F)c1cc(C(F)(F)F)cc(C2(C(F)(F)F)CCNC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 80 °C
Yield: 65.3 %

Procedure:
Methyl 6-chloro-4-(trifluoromethyl)nicotinate (2.39 g), 3-[3,5-bis(trifluoromethyl)-phenyl]-3-(tri-fluoromethyl)pyrrolidine (2.98 g) and potassium carbonate (1.8 g) were suspended in dimethylformamide (50 ml). The reaction mixture was heated for 8 hours at 80° C. Water and ethyl acetate were added and the extraction was carried out. The extract was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The target compound (3.07 g) was obtained by purification with silica gel column chromatography.