Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]12[CH2:14][CH2:13][CH2:12][CH:11]1[C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([F:15])[C:5]=1[NH:4][C:3]2=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1COCC1>[F:1][C:2]12[CH2:14][CH2:13][CH2:12][CH:11]1[C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([F:15])[C:5]=1[NH:4][C:3]2=[S:26]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1Nc2c(F)cccc2C2CCCC12F
Solvent: C1CCOC1
Product: Fc1cccc2c1NC(=S)C1(F)CCCC21

Procedure:
A solution of 60 mg (0.27 mmol) of 3a,6-difluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one in 15 ml of THF is mixed with 288 mg (0.71 mmol) of Lawesson's reagent and refluxed for 1.5 hours. Then, the reaction mixture is concentrated by evaporation, and the residue is purified by column chromatography on silica gel (eluant: hexane-ethyl acetate): 50 mg of product.
Reaction SMILES: C([C:8]([NH2:12])([OH:11])[CH2:9][CH3:10])(OC(C)(C)C)=O.[OH:13][C:14]([CH2:16][C:17]1[CH:28]=[CH:27][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][CH:18]=1)=[O:15].[ClH:29].C(OCC)(=O)C.C(OCC)C>ClCCl>[NH2:12][CH:8]([OH:11])[CH2:9][CH3:10].[ClH:29].[OH:15][C:14]([CH2:16][C:17]1[CH:28]=[CH:27][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][CH:18]=1)=[O:13]
Reactant: CCC(N)(O)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C(O)Cc1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(N)O
Reaction time: 2 h

Procedure:
The Boc-aminopropanol-felbinac obtained above (1.69 mmol) was dissolved in dichloromethane (1 ml), and 4 N hydrochloric acid/ethyl acetate (3 ml) was added thereto under ice-cooling. The mixture was returned to room temperature, followed by stirring for 2 hours. After confirming disappearance of Boc-aminopropanol-felbinac by TLC, diethyl ether was added thereto and the thus formed precipitate was centrifuged. The thus obtained precipitate was subjected to three times of decantation with diethyl ether and then dried under reduced pressure to give the titled compound (511.7 mg, yield 99%). The structure was identified by 1H-NMR (CDCl3:CD3OD=1:1).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12](O)=[O:13])=[CH:10][C:9]([C:15]([F:18])([F:17])[F:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:22])=O.CN(C)C=O>C(Cl)Cl.CN(C)C=O>[C:1]1([N:7]2[C:11]([C:12]([Cl:22])=[O:13])=[CH:10][C:9]([C:15]([F:18])([F:17])[F:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ccccc1
Reaction time: 0.33 h

Procedure:
A sample of crude 1-phenyl-3-(trifluoromethyl)pyrazole-5-carboxylic acid (i.e. the product of Step B) (4.13 g, 16.1 mmol) was dissolved in methylene chloride (45 mL). The solution was treated with oxalyl chloride (1.80 mL, 20.6 mmol), followed by N,N-dimethylformamide (0.010 mL, 0.13 mmol). Off-gassing began shortly after adding the N,N-dimethylformamide catalyst. The reaction mixture was stirred for ˜20 minutes under ambient conditions, then was heated to reflux for a period of 35 minutes. Volatiles were removed by stripping the reaction mixture on a rotary evaporator at a bath temperature of 55° C. The product consisted of 4.43 g of a light-yellow oil. The only imparity observed by 1H NMR was N,N-dimethylformamide.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:37][CH2:38][C:39](Cl)=[O:40]>C1COCC1>[CH2:1]([N:8]([CH2:9][CH:10]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[OH:12])[C:39](=[O:40])[CH2:38][Cl:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(CNCc1ccccc1)C(O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(CN(Cc1ccccc1)C(=O)CCl)C(O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of (1RS,2RS)-3-(benzylamino)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-(3,4-dichlorophenyl)propan-1-ol (2.98 g) and triethylamine (1.10 mL) in THF (30 mL) was added chloroacetyl chloride (0.526 mL) under ice-cooling, and the mixture was stirred at 0° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (2.95 g).
Reaction SMILES: [CH2:1]1[C:6]2[S:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[CH2:4][CH2:3][O:2]1.[CH2:14](Cl)[CH3:15].[CH3:17][NH:18][CH3:19]>O1CCOCC1>[CH3:17][N:18]([CH3:19])[CH2:14][CH2:15][CH:1]1[C:6]2[S:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[CH2:4][CH2:3][O:2]1
Reactant: c1ccc2c3c(sc2c1)COCC3
Reactant: CCCl
Reactant: CNC
Solvent: C1COCCO1
Product: CN(C)CCC1OCCc2c1sc1ccccc21

Procedure:
A mixture of 3,4-dihydro-1H-[1]benzothieno[2,3-c]-pyran-1-ethyl chloride (6.0 g), described in Example 35, dioxane (50 ml), and 40% aqueous dimethylamine (50 ml) is heated on a steam bath for 3 hr. The mixture is evaporated, diluted with 10% hydrochloric acid and washed with ether. The free base is then liberated from the aqueous phase by the addition of 5% sodium hydroxide soln. and taken up in ether. The ether phase is dried and concentrated to yield the title compound, nmr (CDCl3) δ 2.80 and 4.13.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=O)[CH3:10].[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]([CH:32]1[C:41]2[N:40]=[CH:39][CH:38]=[CH:37][C:36]=2[CH2:35][CH2:34][CH2:33]1)[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH3:10])=[CH:26][CH:25]=1)[CH:32]1[C:41]2[N:40]=[CH:39][CH:38]=[CH:37][C:36]=2[CH2:35][CH2:34][CH2:33]1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: COc1ccccc1C(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccccc1C(C)NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.2 %

Procedure:
Using General Procedure B: To a stirred solution of 1-(2-methoxy-phenyl)-ethanone (69 uL, 0.50 mmol), N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (200 mg, 0.50 mmol) and AcOH (0.10 mL, 1.4 mmol) in THF (5 mL) was added NaBH(OAc)3 and the mixture was stirred at room temperature for 48 hours. Purification of the crude light yellow foam (267 mg) by column chromatography on silica gel (100:1:1—CH2Cl2:MeOH:NH4OH) followed by radial chromatography on silica gel (100:1:1—CH2Cl2:MeOH:NH4OH) afforded the desired product (83 mg, 27%) as a white foam.
Reaction SMILES: [NH2:1][C:2]([CH:4]1[N:9]([CH2:10][CH2:11][CH2:12][CH:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:8][CH2:7][N:6]([CH2:28][C:29]([NH:31][C:32]2[C:37]([CH3:38])=[CH:36][C:35]([NH2:39])=[CH:34][C:33]=2[CH3:40])=[O:30])[CH2:5]1)=[O:3].C(O)(=O)C.[N-:45]=[C:46]=[O:47].[K+]>O>[NH2:1][C:2]([CH:4]1[N:9]([CH2:10][CH2:11][CH2:12][CH:13]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH2:8][CH2:7][N:6]([CH2:28][C:29]([NH:31][C:32]2[C:33]([CH3:40])=[CH:34][C:35]([NH:39][C:46]([NH2:45])=[O:47])=[CH:36][C:37]=2[CH3:38])=[O:30])[CH2:5]1)=[O:3]
Reactant: Cc1cc(N)cc(C)c1NC(=O)CN1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)C(C(N)=O)C1
Reactant: [N-]=C=O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(NC(N)=O)cc(C)c1NC(=O)CN1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)C(C(N)=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5.5 parts of 3-(aminocarbonyl)-N-(4-amino-2,6-dimethylphenyl)-4-[4,4-bis(4-fluorophenyl)butyl]-1-piperazineacetamide in 70 parts of acetic acid was added dropwise a solution of 1.62 parts of potassium isocyanate in 20 parts of water. Upon completion, stirring at room temperature was continued for 30 minutes. Upon standing overnight at room temperature, the reaction mixture was evaporated. Water was added to the residue and the product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 2.55 parts of 3-(aminocarbonyl)-N-[4-[(aminocarbonyl)amino]-2,6-dimethylphenyl]-4-[4,4-bis(4-fluorophenyl)butyl]-1-piperazineacetamide; mp. 142.5° C. (compound 168).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:22](=[O:23])[CH:21]2[CH:19]([CH2:20]2)[C:18]1=[O:24].O>ClCCl>[F:7][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:22](=[O:23])[CH:21]2[CH:19]([CH2:20]2)[C:18]1=[O:24]
Reactant: O=C1C2CC2C(=O)N1CCCCCCO
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C1C2CC2C(=O)N1CCCCCCF
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethylaminosulfurtrifluoride (76mg) was added dropwise to a stirred solution of 3-(6-hydroxyhex-1-yl)-3-azabicyclo[3.1.0]hexane-2,4-dione (from step (b), 100mg) in dichloromethane (2.0 ml) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature and water (3 ml) was then added. The reaction mixture was extracted with ether (2×10 ml) and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by chromatography on silica (5 g) using 40% ethyl acetate/hexane as eluant to give the title compound as a pale yellow oil.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][SH:13].C(N(CC)CC)C>CS(C)=O>[F:10][C:8]1[CH:7]=[CH:6][C:3]2[CH:4]=[C:12]([C:11]([O:15][CH3:16])=[O:14])[S:13][C:2]=2[CH:9]=1
Reactant: COC(=O)CS
Reactant: O=Cc1ccc(F)cc1F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2ccc(F)cc2s1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4-difluorobenzaldehyde (5.0 g) in dimethylsulfoxide (100 ml) were added methyl thioglycolate (3.45 ml) and triethylamine (10 ml), and the mixture was stirred at 80° C. overnight. The reaction mixture was poured into ice-cold water. The mixture was extracted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1) to give 6-fluoro-2-methoxycarbonylbenzo[b]thiophene (1.32 g) as colorless powder. GC-EI-Mass m/Z 210 (M). (2) The above 6-fluoro-2-methoxycarbonylbenzo[b]thiophene was treated in a manner similar to Reference Example 4-(1) to give 6-fluorobenzo[b]thiophen-2-ylcarboxylic acid as colorless powder. ESI-Mass m/Z 195 (M−H). (3) The above 6-fluorobenzo[b]thiophen-2-ylcarboxylic acid was treated in a manner similar to Reference Example 4-(2) to give 6-fluoro-2-(N-methoxy-N-methylcarbamoyl)benzo[b]thiophene as colorless powder. APCI-Mass m/Z 240 (M+H). (4) A solution of 1,3-dibromobenzene (493 mg) in tetrahydrofuran (10 ml) was cooled to −78° C. under argon atmosphere, and thereto was added dropwise n-butyl lithium (2.44 M hexane solution, 0.86 ml). The reaction mixture was stirred at the same temperature for 30 minutes, and thereto was added dropwise a solution of the above 6-fluoro-2-(N-methoxy-N-methylcarbamoyl)benzo[b]thiophene (500 mg) in tetrahydrofuran (3 ml). The mixture was warmed to room temperature, and added thereto was a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5-85:15) to give 3-bromophenyl 6-fluorobenzo[b]thiophen-2-yl ketone (479 mg) as a pale yellow solid. APCI-Mass m/Z 335/337 (M+NH4). (5) The above 3-bromophenyl 6-fluorobenzo[b]thiophen-2-yl ketone was treated in a manner similar to Reference Example 5-(2) to give 3-bromo-1-(6-fluorobenzo[b]thiophen-2-ylmethyl)benzene as a colorless solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:28][CH3:29])[CH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:39][C:40]1[C:59]([F:60])=[CH:58][CH:57]=[CH:56][C:41]=1[CH2:42][NH:43][C:44](=[O:55])OC1C=CC([N+]([O-])=O)=CC=1>C1COCC1>[Si:1]([O:8][CH2:9][C@@H:10]([N:28]([CH3:29])[C:44]([NH:43][CH2:42][C:41]1[CH:56]=[CH:57][CH:58]=[C:59]([F:60])[C:40]=1[Cl:39])=[O:55])[CH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN[C@@H](CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)CO[Si](C)(C)C(C)(C)C
Reactant: O=C(NCc1cccc(F)c1Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a solution of (S)-tert-butyl 4-(5-(tert-butyldimethylsilyloxy)-4-(methylamino)pentanoyl)piperazine-1-carboxylate (16 g, 37.3 mmol) and DIEA (1.3 mL, 7.46 mmol) in THF (180 mL) was added 4-nitrophenyl 2-chloro-3-fluorobenzylcarbamate (12 g, 37.3 mmol). The reaction mixture was stirred at RT for 2 h and concentrated. The residue was purified on silica gel using a mixture of EtOAc and hexanes to give (S)-tert-butyl 4-(5-(tert-butyldimethylsilyloxy)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentanoyl)piperazine-1-carboxylate (14.3 g, 62.4% for three steps). LRMS (M+H) m/z 615.3.
Reaction SMILES: I[C:2]1[N:7]2[N:8]=[C:9]([S:19][CH3:20])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25](OB(O)O)=[C:24]([O:33][CH3:34])[CH:23]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(OCC)(=O)C>COCCOC.O.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>[CH3:34][O:33][C:24]1[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[C:23]=1[C:2]1[N:7]2[N:8]=[C:9]([S:19][CH3:20])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C)cc(C)c1OB(O)O
Reactant: CSc1nn2c(I)cccc2c1NC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C)cc(C)c1-c1cccc2c(NC(=O)OC(C)(C)C)c(SC)nn12
Temperature: 80 °C
Reaction time: 3 h
Yield: 102.9 %

Procedure:
After dissolving tert-butyl N-[7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate (2.0 g) in 1,2-dimethoxyethane (60 mL) and water (30 mL), 4,6-dimethyl-2-methoxyphenylboric acid (1.33 g), tetrakis(triphenylphosphine)palladium (0) complex (865 mg) and barium hydroxide octahydrate (2.34 g) were added and the mixture was heated and stirred at 80° C. for 3 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (2.1 g) was obtained from the n-hexane:ethyl acetate (20:1) fraction as yellow amorphous.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].I[CH2:14][CH2:15][F:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:14][CH2:15][F:16])[C:8](=[O:11])[C:7]2=[O:12]
Reactant: O=C1Nc2c(F)cccc2C1=O
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C(=O)N(CCF)c2c(F)cccc21

Procedure:
7-Fluoro-1H-indole-2,3-dione (prepared according to the method of Gassman as described in U.S. Pat. No. 4,188,325 (2.00 g, 12.1 mmol), 1-iodo-2-fluoroethane (4.21 g, 24.2 mmol) and potassium carbonate (3.30 g, 24.2 mmol) in DMF (20 ml) are stirred at room temperature for 20 hours. The reaction mixture is diluted with cold water and the resulting precipitate filtered and dried to give the title compound as an orange solid. HPLC r.t. 4.18 min; MS for C10H7F2NO2 m/z 212.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.[NH:28]1[CH2:31][CH:30]([CH2:32][OH:33])[CH2:29]1>>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:28]3[CH2:31][CH:30]([CH2:32][OH:33])[CH2:29]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Reactant: OCC1CNC1
Agent: Cl
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC(CO)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 63 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1) and 3-azetidinemethanol hydrochloride to afford a yellow foam. HPLC (Condition 7) tR=5.51 min, UPLC-MS (Condition 3) tR=0.89 min, m/z=450.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.55-2.68 (m, 1H) 3.43-3.49 (m, 2H) 3.49-3.56 (m, 2H) 3.73-3.82 (m, 2H) 4.66-4.73 (m, 1H) 6.42 (br.s, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.79-7.91 (m, 3H) 8.04 (d, J=2.35 Hz, 1H) 8.75 (br.s, 1H) 10.21 (s, 1H) 13.02 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:24][CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=4)[N:27]=3)[CH2:18]2)[N:3]=1.[NH2:36][NH2:37]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:36][NH:37]3)=[CH:14][CH:15]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:24][CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=4)[N:27]=3)[CH2:18]2)[N:3]=1
Reactant: COc1cccc(-c2c[nH]c(C3CN(c4cc(-c5ccc(C#N)c(F)c5)nc(N)n4)CCO3)n2)c1
Reactant: NN
Solvent: CCO
Product: COc1cccc(-c2c[nH]c(C3CN(c4cc(-c5ccc6c(N)n[nH]c6c5)nc(N)n4)CCO3)n2)c1
Reaction time: 1 h
Yield: 3.5 %

Procedure:
A mixture of 4-[2-amino-6-(2-{4-[3-(methyloxy)phenyl]-1H-imidazol-2-yl}-4-morpholinyl)-4-pyrimidinyl]-2-fluorobenzonitrile (700 mg, 1.485 mmol) and hydrazine (2.35 mL, 74.2 mmol) in ethanol (8.0 mL) was heated under microwave conditions with stirring for 1 hour. The mixture was concentrated, and water (20 mL) was added. The resulting mixture was filtered to afford the crude title compound (725 mg) as a yellow solid. This material was combined with another sample of the title compound (25 mg). The combined material was washed with CH2Cl2 (2×25 mL) and EtOAc (2×20 mL), and dried under high vacuum to afford the title compound (216 mg) as a yellow solid. LC-MS (ES) m/z=484 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 3.08-3.15 (m, 1H), 3.23 (d, J=8.8 Hz, 1H), 3.69-3.76 (m, 1H), 3.79 (s, 3H), 4.05 (d, J=11.2 Hz, 1H), 4.33 (d, J=9.6 Hz, 1H), 4.62 (dd, J=10.0 Hz, 2.4 Hz, 1H), 4.73 (s, 1H), 5.38 (s, 2H), 6.21 (s, 2H), 6.71 (s, 1H), 6.76 (d, J=8.2 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 7.35-7.37 (m, 2H), 7.54-7.63 (m, 2H), 7.71 (d, J=8.4 Hz, 1H), 7.97 (s, 1H), 11.52 (s, 1H), 12.34 (s, 1H).
Reaction SMILES: [N:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[C:4](=O)[CH2:3][CH2:2]2.C1(C)C=CC(S([CH2:20][N+:21]#[C-])(=O)=O)=CC=1.C(O)C.CC(C)([O-])C.[K+]>C(COC)OC>[N:1]12[CH2:9][C@H:5]([CH2:6][CH2:7][CH2:8]1)[C@H:4]([C:20]#[N:21])[CH2:3][CH2:2]2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CCN2CCCC1C2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: N#C[C@@H]1CCN2CCC[C@H]1C2
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
To a solution of 2.00 g of 1-azabicyclo[3.3.1]nonan-4-one in 100 ml of dimethoxyethane, 3.65 g of p-toluenesulfonylmethylisocyanide and 1.13 g of ethanol were added, followed by cooling to 5° C. Then, 4.00 g of potassium tert-butoxide was added while keeping the internal temperature below 10° C. The mixture was stirred at room temperature for 30 minutes, followed by further stirring at 40° C. for 30 minutes. The precipitate thus formed was removed by filtration. The residue obtained by evaporation of the solvent was purified by an alumina column chromatography (eluent: chloroform:hexane=1:1). The resulting crude product was then purified by silica gel column chromatography (eluent: chloroform:methanol=20:1), whereby 1.01 g of (4R*,5R*)-1-azabicyclo[3.3.1]nonane-4-carbonitrile was obtained.
Reaction SMILES: [C@H:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH2:28][C:29]([OH:31])=O)[C:20]3=[O:32])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.Cl.CN.C[CH2:37][N:38]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C.O>[C@H:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH2:28][C:29]([NH:38][CH3:37])=[O:31])[C:20]3=[O:32])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)Cn1c(=O)n(C2CCN([C@@H]3Cc4cccc5cccc3c45)CC2)c2ccccc21
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)Cn1c(=O)n(C2CCN([C@@H]3Cc4cccc5cccc3c45)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.1 %

Procedure:
(R)-2-{3-[1-(Acenaphthen-1-yl)piperidin-4-yl]-2,3-dihydro-2-oxo-benzoimidazol-1-yl}acetic acid (1 g, 2.3 mmol) was dissolved in DMF (10 ml). Methylamine hydrochloride (0.17 g, 2.5 mmol), WSC•HCl (0.53 g, 2.7 mmol), HOBt (0.43 g, 2.8 mmol) and triethylamine (0.7 ml, 5 mmol) were added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (0.7 g) as pale-yellow crystals.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2>C(Cl)Cl.N1C=CC=CC=1>[CH3:5][O:4][C:2]([NH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:3]
Reactant: Nc1cnc2ccccc2c1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Nc1cnc2ccccc2c1
Reaction time: 0.5 h

Procedure:
3.2 ml of methyl chloroformate am added dropwise to 5.0 g of 3-aminoquinoline in 30 ml of methylene chloride and 15 ml of pyridine at 0° C. in the course of 30 min. The mixture is subsequently stirred for a further 30 min and then worked up in the customary manner. The title compound is obtained as a crystalline solid: Rf (H)=0.41.