Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH:17]([C:19]1[S:23][C:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:21][CH:20]=1)=O>CCCCCC.O1CCCC1.C(OCC)C>[CH2:15]([O:14][C:12](/[CH:11]=[CH:17]/[C:19]1[S:23][C:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:21][CH:20]=1)=[O:13])[CH3:16]
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)s1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(C(=O)OC(C)(C)C)s1

Procedure:
Sodium hydride (min 60% paraffinic dispersion, 1.88 g, about 47 mmol) was washed with anhydrous hexane in a nitrogen stream and suspended in anhydrous tetrahydrofuran. The obtained suspension was stirred under cooling with ice, followed by the gradual dropwise addition of a solution of ethyl diethylphosphonoacetate (10.53 g, 47 mmol) in anhydrous tetrahydrofuran. The obtained mixture was stirred at room temperature for 15 minutes. A solution of the t-butyl 5-formyl-2-thiophenecarboxylate (6.65 g, 31.3 mmol) prepared above in anhydrous tetrahydrofuran was gradually dropped into the resulting mixture under cooling with ice. The obtained mixture was stirred at room temperature for 30 minutes, diluted with diethyl ether, washed with a dilute alkali, diluted hydrochloric acid and an aqueous solution of common salt, dehydrated and evaporated in a vacuum to dryness. The residue was purified by silica gel column chromatography (developer: n-hexane/ethyl acetate=8:1) to give the objective compound. yield: 7.58 g
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:16]3[NH:15][C:14]4[CH2:19][CH:20]5[NH:24][CH:23]([C:13]=4[C:12]=3[C:11]=2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:21]5)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:35][CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1OCCOCCOCCOCCOCCOC1>[C:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:16]3[N:15]([CH2:35][CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[C:14]4[CH2:19][CH:20]5[NH:24][CH:23]([C:13]=4[C:12]=3[C:11]=2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:21]5)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)c1c(S(=O)(=O)c2ccccc2)ccc2[nH]c3c(c12)C1CCC(C3)N1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1c(S(=O)(=O)c2ccccc2)ccc2c1c1c(n2CCO[Si](C)(C)C(C)(C)C)CC2CCC1N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.3 %

Procedure:
To a solution of the product of Example 88, step C (120 mg, 0.27 mmol) in anhydrous DMF (3 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 22 mg, 0.54 mmol), tetrabutylammonium iodide (51 mg, 0.13 mmol) and 18-crown-6 (7 mg, 0.02 mmol). The resulting mixture was stirred for 30 min before 2-bromoethoxy-tert-butyldimethylsilane (0.07 ml, 0.32 mmol) was added. The reaction mixture was stirred at room temperature for 4 h, quenched with water and extracted with ethyl acetate. The organic extract was dried over sodium sulfate, filtered, and concentrated to give tert-butyl 2-phenylsulfonyl-5-[2-(tert-butyldimethylsilyloxy)]ethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (160 mg, quant) as a yellow-brown solid: 1H NMR (CDCl3, 300 MHz), δ 8.39 (s, 1H), 8.14-8.18 (m, 2H), 7.86 (d, J=8.4 Hz, 1H), 7.63-7.71 (m, 3H), 7.56 (d, J=8.7 Hz, 1H), 5.47 (br s, 1H), 4.91 (br s, 1H), 4.25-4.38 (m, 2H), 4.03 (t, J=5.4 Hz, 2H), 2.76 (d, J=16.2 Hz, 1H), 2.34-2.57 (m, 2H), 2.10-2.22 (m, 1H), 1.79-1.86 (m, 2H), 1.58 (s, 9H), 0.93 (s, 9H), 0.04 (s, 3H), 0.01 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH2:16][C:17]([O:19]CC)=O)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1>C(N)CC>[CH3:1][C:2]1[N:3]([CH2:15][CH2:16][C:17]([NH:3][CH2:4][CH2:5][CH3:6])=[O:19])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1
Reactant: CCOC(=O)CCn1c(C)nc2cnc3ccccc3c21
Solvent: CCCN
Product: CCCNC(=O)CCn1c(C)nc2cnc3ccccc3c21
Temperature: 25 °C
Yield: 198.5 %

Procedure:
Propylamine (20 mL) and ethyl 3-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate (5.77 g, 20.4 mmol) were heated overnight at 100° C. in a sealed vessel. The reaction was allowed to cool to ambient temperature and concentrated under reduced pressure to provide 6.0 g of 3-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-propylpropanamide.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1([CH2:18][CH2:17][CH2:16]1)[CH2:5][CH2:6][N:7]2[CH2:12][C:13]([NH2:15])=O.CSC.B>O1CCCC1>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1([CH2:16][CH2:17][CH2:18]1)[CH2:5][CH2:6][N:7]2[CH2:12][CH2:13][NH2:15]
Reactant: NC(=O)CN1CCC2(CCC2)c2c(F)cccc21
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: NCCN1CCC2(CCC2)c2c(F)cccc21
Temperature: 70 °C
Yield: 26.7 %

Procedure:
A solution of 40 mg (0.16 mmol) of 2-(5′-fluoro-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-quinolin]-1′-yl)-acetamide obtained in step 31.4 in 1 ml of tetrahydrofurane was treated with 38 μl (0.40 mmol) of borane dimethylsulfide and heated to 70° C. for two hours. The mixture was quenched with water and hydrochloric acid, diluted with dichloromethane and extracted twice with water. The combined aqueous phases were set to pH 10 with sodium hydroxide solution and extracted 3× with dichloromethane. The combined organic phases were dried and evaporated to yield 10 mg of the title compound as an oil.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH2:5]1COC[CH2:6]1.C([Mg]Cl)C.[F:14][C:15]1[CH:29]=[CH:28][C:18]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1>C(O)(=O)C>[F:14][C:15]1[CH:29]=[CH:28][C:18]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([OH:20])[CH2:5][CH3:6])=[CH:17][CH:16]=1
Reactant: C1CCOC1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC[Mg]Cl
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCC(O)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78 %

Procedure:
Into a reactor were introduced 10.0 g (40.6 mmol) of cerium chloride and 80 mL of THF under a nitrogen atmosphere. This mixture was stirred at room temperature for 20 hours and then cooled to 0° C. Thereto was added dropwise 25.1 mL (24.3 mmol; 0.97 M THF solution) of ethylmagnesium chloride over 30 minutes. Subsequently, a solution prepared by mixing 3.54 g (16.2 mmol) of 4,4′-difluorobenzophenone with 20 mL of THF was added dropwise thereto over 40 minutes, and this mixture was stirred for 1 hour. To the resultant reaction mixture was added 10% aqueous acetic acid solution. Thereafter, the mixture was extracted with ethyl acetate, and the resultant organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, subsequently dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain 3.12 g (78%) of the target compound as a light-yellow oily substance.
Reaction SMILES: [CH:1]([NH2:3])=[O:2].C([N-]C=O)=O.[Na+].Cl[CH2:11][C:12]1[CH:25]=[CH:24][C:15]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C[O-].[Na+]>[CH:1]([NH:3][CH2:11][C:12]1[CH:25]=[CH:24][C:15]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[CH:14][CH:13]=1)=[O:2]
Reactant: O=C(c1ccccc1)c1ccc(CCl)cc1
Reactant: NC=O
Agent: C[O-]
Agent: O=C([O-])[O-]
Agent: O=C[N-]C=O
Product: O=CNCc1ccc(C(=O)c2ccccc2)cc1
Reaction time: 15 h

Procedure:
150 g of formamide are stirred together with 90 mL of 30%ig sodium methylate solution for 8 hours under slight vacuum at 80° C. To the resulting solution of sodium diformylamide there are added 150 g of 4-chloromethylbenzophenone. After 15 hours the suspension originally present has changed to a clear solution which is added to 1l of 10%ig sodium carbonate solution. A solid material precipitates, which is filtered off in vacuo and dried.
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]1[CH:7]=[C:8]([N:13]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:14]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][C@H:17]2[C:22]([OH:24])=[O:23])=[O:15])[CH:9]=[C:10]([CH3:12])[CH:11]=1.[CH2:31]([N:36]([CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:37](Cl)=[O:38])[CH2:32][CH2:33][CH2:34][CH3:35].C(N(CC)CC)C>C1COCC1.O>[CH3:5][C:6]1[CH:7]=[C:8]([N:13]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:37](=[O:38])[N:36]([CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:18][C@H:17]2[C:22]([OH:24])=[O:23])=[O:15])[CH:9]=[C:10]([CH3:12])[CH:11]=1
Reactant: CCCCCN(CCCCC)C(=O)Cl
Reactant: Cc1cc(C)cc(N(C(=O)N2CCNC[C@H]2C(=O)O)c2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)O
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2cc(C)cc(C)c2)[C@H](C(=O)O)C1
Temperature: 55 °C
Reaction time: 72 h
Yield: 68.2 %

Procedure:
A mixture of 220 mg (0.53 mmole) of 1-[N-(3,5-dimethylphenyl)-N-phenylcarbamoyl]piperazine-2-(S)-carboxylic acid acetate salt (from Step E above), 175 mg (0.80 mmole) of N,N-di-n-pentylcarbamoyl chloride (from Example 1, Step C-2) and 188 mg (1.86 mmole) of triethylamine in 6 mL of THF and 3 mL of water was stirred at 55° C. for 72 hours. To the mixture was added an additional 6 mL of THF, 175 mg of N,N-di-n-pentylcarbamoyl chloride, and 187 mg of triethylamine and the mixture again heated at 55° C. for 48 hours. To the mixture was added an additional 120 mg N,N-di-n-pentylcarbamoyl chloride and the reaction mixture heated for an additional 24 hours. The mixture was cooled and was partitioned between 16 mL of 0.5N aqueous HCl and 30 mL of EtOAc. The layers were separated and the aqueous layer extracted with 2×40 mL of EtOAc. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on 68 g of silica gel eluting with 100:4:0.1 CH2Cl2 :MeOH:HOAc to give 194 mg (68%) of an oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([C:20]#[N:21])=[CH:17][CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[O:22]=[C:11]1[CH:12]=[N:13][C:14]2[C:19](=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[N:10]1[CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH2:34][C:32]2[CH:31]=[CH:30][C:27]3[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=3[N:33]=2)[CH2:3][CH2:4]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: N#Cc1ccc2c(c1)ncc(=O)n2CCN1CCC(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: N#Cc1ccc2c(c1)ncc(=O)n2CCN1CCC(NCc2ccc3c(n2)NC(=O)CO3)CC1
Yield: 65.7 %

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-2-oxo-1,2-dihydroquinoxaline-6-carbonitrile (Intermediate 197, 0.125 g) was reacted with 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (0.17 g) and NaBH(OAc)3 (0.27 g) as described for Example 107. The residue was purified by reverse phase HPLC with acetonitrile in water containing 0.1% TFA. Fractions containing product were concentrated to remove acetonitrile, neutralized with Na2CO3 solid, extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated. The residue was suspended in diethyl ether and filtered to yield 127 mg of a colorless solid.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:8])=[N:4][O:5][C:6]=1[CH3:7].O[CH2:10][C@@H:11]([N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23])[CH3:12]>>[F:1][C:2]1[C:3]([O:8][CH2:12][C@@H:11]([N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])[CH3:10])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: C[C@@H](CO)N1C(=O)c2ccccc2C1=O
Reactant: Cc1onc(O)c1F
Product: Cc1onc(OC[C@H](C)N2C(=O)c3ccccc3C2=O)c1F

Procedure:
Using 4-fluoro-5-methylisoxazol-3-ol and 2-[(1S)-2-hydroxy-1-methylethyl]-1H-isoindole-1,3(2H)-dione, and in the same manner as in Example 1, step B, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[Br:10][C:11]1[S:15][C:14]2=[N:16][C:17]([C:19](O)=[O:20])=[CH:18][N:13]2[CH:12]=1>>[Br:10][C:11]1[S:15][C:14]2=[N:16][C:17]([C:19]([NH:5][C:4]3[CH:6]=[CH:7][C:8]([F:9])=[C:2]([Cl:1])[CH:3]=3)=[O:20])=[CH:18][N:13]2[CH:12]=1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Product: O=C(Nc1ccc(F)c(Cl)c1)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using 3-chloro-4-fluoroaniline and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].[Na]>C(OCCO)C>[Cl:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: ClCCCBr
Reactant: O=C1COc2cc(O)ccc2N1
Agent: [Na]
Solvent: CCOCCO
Product: O=C1COc2cc(OCCCCl)ccc2N1
Yield: 65 %

Procedure:
7-Hydroxy-2H-1,4-benzoxazin-3(4H)-one was treated with 3-bromo-1-chloro-propane and sodium metal in ethyleneglycol monoethyl ether to give the desired product in 65% yield, mp 95° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][N:9]2[N:12]=[CH:13][C:14]([CH:15]=O)=[C:8]2[N:7]=1)[CH:2]([CH3:4])[CH3:3].[NH:17]1[CH2:23][C:21](=[O:22])[NH:20][C:18]1=[O:19].N1CCCCC1>C(#N)C>[CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][N:9]2[N:12]=[CH:13][C:14]([CH:15]=[C:23]3[NH:17][C:18](=[O:19])[NH:20][C:21]3=[O:22])=[C:8]2[N:7]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)CNc1ccn2ncc(C=O)c2n1
Reactant: O=C1CNC(=O)N1
Solvent: CC#N
Solvent: C1CCNCC1
Product: CC(C)CNc1ccn2ncc(C=C3NC(=O)NC3=O)c2n1
Temperature: 70 °C

Procedure:
To 5-(isobutylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (24 mg, 0.110 mmol) in acetonitrile was added hydantoin (11 mg, 0.110 mmol) and piperidine (11 μL, 0.110 mmol). The reaction was heated at 70° C. for 48 hr. The reaction was cooled to room temperature and the solid formed was isolated by filtration to yield 5-((5-(isobutylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=301)
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[CH2:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH:22]1[C:30]([O:32][CH3:33])=[O:31].[CH3:34][C:35]([CH3:37])=[O:36]>C1COCC1>[OH:36][C:35]([C:22]1([C:30]([O:32][CH3:33])=[O:31])[CH2:21][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)([CH3:37])[CH3:34]
Reactant: COC(=O)C1Cc2ccccc2C1
Reactant: CC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(C(C)(C)O)Cc2ccccc2C1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a dried THF solution of lithiumdiisopropylamide prepared from 107.3 ml (0.149 mole) of n-butyllithium and 15.81 g (0.156 mole) of diisopropylamine, was added dropwise at -50° C. a solution of 25.0 g (0.142 mole) of methyl indane-2-carboxylate in 50 ml of dried THF over a period of 10 minutes. To the resulting mixture, which had been stirred for 30 minutes at -50° C., was added dropwise over a period of 10 minutes a solution of 9.88 g (0.17 mole) of dried acetone in 10 ml of dried THF. After the addition, stirring was continued for further 10 minutes. The reaction mixture was poured into ice water and extracted with ether. The aqueous layer was extracted twice with ether. The ether layers were combined, washed successively with 3% aqueous hydrochloric acid solution, saturated aqueous hydrogen-carbonate solution, and saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the intended product as a oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:19][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH3:18])[CH2:9]2)=[CH:7][C:2]=1[CH3:1])=[O:24]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Cc1cc(N2CCC(N3CCC[C@H]3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCC[C@H]3C)C2)ccc1NC(=O)c1ccccc1F

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-(2-(R)-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 2-fluorobenzoyl chloride. LCMS: RT=1.70 minutes, MS: 382 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([NH:6][C:7]2[C:12]([Cl:13])=[CH:11][N:10]=[C:9]([Cl:14])[N:8]=2)=[CH:4][CH:3]=1.[F:17][C:18]([F:24])([F:23])[CH2:19][CH2:20][CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([N:6]([C:7]2[C:12]([Cl:13])=[CH:11][N:10]=[C:9]([Cl:14])[N:8]=2)[CH2:21][CH2:20][CH2:19][C:18]([F:24])([F:23])[F:17])=[CH:4][CH:3]=1
Reactant: FC(F)(F)CCCBr
Reactant: Clc1ncc(Cl)c(Nc2ccc(Br)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)CCCN(c1ccc(Br)cc1)c1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.6 %

Procedure:
A mixture of 4-(4-bromoanilino)-2,5-dichloropyrimidine (Method 24; 315 mg, 1.0 mmol), 4,4,4-trifluoro-1-bromobutane (228 mg, 1.20 mmol) and potassium carbonate (165 mg, 1.20 mmol) in DMF (3 ml) was stirred at room temperature for 12 hours. Silica (2.5 g) was added and volatile material was removed by evaporation. The residue was purified by column chromatography, eluting with 0-40% ethyl acetate in isohexane, to give the product (187 mg). NMR: (373K); 1.84 (m, 2H), 2.28 (m, 2H), 3.99 (t, 2H), 7.22 (d, 2H), 7.58 (d, 2H), 8.23 (s, 1H); MS (MH+): 428.2, 430.2, 432.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)[CH3:12].[NH2:22][N:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:22][N:23]2[CH:27]=[CH:26][CH:25]=[CH:24]2)[CH3:20])[N:14]=1)[CH3:12]
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Reactant: Nn1cccc1
Solvent: Cc1ccccc1
Product: CC(=Nc1c(C)cc(C)cc1C)c1cccc(C(C)=Nn2cccc2)n1
Reaction time: 40 h

Procedure:
Monoimine ((1), 3.0 g, 10.7 mmol) and 1-aminopyrrole (1.0 g, 12.18 mmol) were dissolved in 50 ml of toluene. To this solution, molecular sieves (4 Å) were added. After standing for 40 hours the mixture was filtered. The solvent was removed in vacuo. The residue was recrystallised from ethanol. Yield 1.85 g (50%) of mixed diimine (16).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[N:15]4[C:16]5[C:21]([NH:22][C:23](=[O:24])[C:14]4=[CH:13][N:12]=3)=[CH:20][C:19]([C:25]([O:27][CH3:28])=[O:26])=[C:18]([CH3:29])[CH:17]=5)[CH2:7][CH2:6]2)[O:4]CC1.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:29][C:18]1[CH:17]=[C:16]2[C:21]([NH:22][C:23](=[O:24])[C:14]3[N:15]2[C:11]([CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)=[N:12][CH:13]=3)=[CH:20][C:19]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1cc2[nH]c(=O)c3cnc(C4CCC5(CC4)OCCO5)n3c2cc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc2[nH]c(=O)c3cnc(C4CCC(=O)CC4)n3c2cc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 125.4 %

Procedure:
270 mg of methyl 1-(1,4-dioxaspiro[4.5]decan-8-yl)-8-methyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylate was added to 10 mL of tetrahydrofuran, and 2 mL of 1 M hydrochloric acid was added thereto under ice-cooling, followed by stirring at room temperature for 3 days. To the reaction mixture were added a saturated aqueous sodium hydrogen carbonate solution to adjust the pH to about 7, followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 301 mg of methyl 8-methyl-4-oxo-1-(4-oxocyclohexyl)-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylate as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[NH2:12].[CH:13]1([CH2:18][C:19](Cl)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]1>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[NH:12][C:19](=[O:20])[CH2:18][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: Cc1cc([N+](=O)[O-])cc(Cl)c1N
Solvent: CC#N
Product: Cc1cc([N+](=O)[O-])cc(Cl)c1NC(=O)CC1CCCC1
Temperature: 150 °C
Yield: 57.6 %

Procedure:
2-Chloro-6-methyl-4-nitro-phenylamine (6.0 g) and cyclopentylacetyl chloride (5.1 g) were dissolved in acetonitrile (45 mL) and heated to 150° C. for 20 minutes in a sealed microwave process vessel. The reaction mixture was cooled to 0° C. and the precipitated product collected by filtration and washed with cold acetonitrile to furnish 5.5 g (58%) of the title compound as a yellow solid. 1H NMR (500 MHz, DMSO-d6): 1.24 (m, 2H), 1.58 (m, 4H), 1.78 (m, 2H), 2.27 (m, 1H), 2.30 (s, 3H), 2.38 (d, 2H), 8.15 (d, 1H), 8.18 (d, 1H), 9.83 (s, 1H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[CH:37][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:36]=[CH:35][C:28]5[N:29]([CH3:34])[C:30](=[O:33])[N:31]([CH3:32])[C:27]=5[CH:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1OS(C(F)(F)F)(=O)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:48][C:49]1[CH:54]=[CH:53][C:52](B(O)O)=[CH:51][CH:50]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[CH:37][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:36]=[CH:35][C:28]5[N:29]([CH3:34])[C:30](=[O:33])[N:31]([CH3:32])[C:27]=5[CH:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:52]1[CH:53]=[CH:54][C:49]([Cl:48])=[CH:50][CH:51]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(c4)n(C)c(=O)n5C)c3)sc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(c4)n(C)c(=O)n5C)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(2-(2-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pyridin-4-yl)-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)acetate (15.3 mg, 0.022 mmol), 4-chlorophenylboronic acid (4.0 mg, 0.026 mmol) and K2CO3 (9.0 mg, 0.066 mmol) in DME (0.5 mL) was added Pd(PPh3)4 (2.0 mg, 1.73×10−3 mmol). The reaction was degassed for 5 minutes with N2 and then heated at 120° C. for 6 h. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C36H36ClN4O4S: 655.2; found: 655.3.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]2=[N:5][N:4]=1>CO.[Pd]>[F:12][CH:2]([F:1])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[N:5][N:4]=1
Reactant: FC(F)c1nnc2cnccn12
Agent: [Pd]
Solvent: CO
Product: FC(F)c1nnc2n1CCNC2
Reaction time: 3 h
Yield: 85.1 %

Procedure:
3-(Difluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine 23c (460 mg, 2.70 mmol) was dissolved in 10 mL of methanol, followed by addition of Pd—C (10%, 46 mg), and the reactor was purged with hydrogen for three times. After stirring for 3 hours, the reaction mixture was filtered and the filter cake was washed with methanol (10 mL). The filtrate was concentrated under reduced pressure to obtain crude 3-(difluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 23d (400 mg) as a light yellow oil. The product was used directly in the next reaction without purification.