Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]([S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:10][CH2:11][C@H:12]([NH:20][C:21](=[O:26])[CH2:22][CH2:23][CH:24]=[CH2:25])[C:13]([O:15][C:16](C)(C)[CH3:17])=[O:14].C([N:36](C(C)C)C(C)C)C.O>ClCCl.BrCC#N>[O:8]=[C:9]([S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:10][CH2:11][C@H:12]([NH:20][C:21](=[O:26])[CH2:22][CH2:23][CH:24]=[CH2:25])[C:13]([O:15][CH2:16][C:17]#[N:36])=[O:14]
Reactant: C=CCCC(=O)N[C@@H](CCC(=O)Sc1ccccc1)C(=O)OC(C)(C)C
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: C=CCCC(=O)N[C@@H](CCC(=O)Sc1ccccc1)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
Trifluoroacetic acid (3.85 ml, 51.8 mmol) was added to a solution of (S)-tert-butyl 5-oxo-2-(pent-4-enamido)-5-(phenylthio)pentanoate (Compound 1e-IIF) (978 mg, 2.59 mmol) in dichloromethane (6.74 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then concentrated under reduced pressure. N-Ethyl-N-isopropylpropan-2-amine (1.30 ml, 7.47 mmol) was added to a solution of the resulting residue in 2-bromoacetonitrile (8 ml), and the mixture was stirred at room temperature for 30 minutes. After adding water to the reaction mixture, purification by reverse phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=60/40→20/80) afforded (S)-cyanomethyl 5-oxo-2-(pent-4-enamido)-5-(phenylthio)pentanoate (Compound 1g-IIF) (722 mg, 64%).
Reaction SMILES: N#N.[C:3]1([CH2:9][C:10]([NH:12][C@H:13]([C:16]([NH:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:17])[CH2:14]O)=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:3]1([CH2:9][C:10]([NH:12][C@H:13]2[CH2:14][N:18]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16]2=[O:17])=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cc1ccccc1)N[C@@H](CO)C(=O)NOCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)N[C@H]1CN(OCc2ccccc2)C1=O
Temperature: 26 °C

Procedure:
To a cold solution (0° C.) of N2 -(phenylacetyl)-N-[(phenylmethyl)oxy]-L-serinamide (6.88 g) in distilled tetrahydrofuran (300 ml), under nitrogen, is added triphenylphosphine (11.20 g) followed by diethylazodicarboxylate (6.60 ml). The solution is allowed to warm to 26° C. and stirred for twelve hours. After removal of solvent under reduced pressure the resulting residue is applied to a silica gel column (eluant ether/hexane→ether). Combination of fractions gives two batches; 1.0 g (pure) and 2.5 g (ca. 60% pure) (total yield ca. 2.2 g). The pure material is recrystallized from ethyl acetate/hexane to give solids; melting point 130°-131° C.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1.[OH-].[Na+]>C(O)C>[I:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:13]2[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=2)=[CH:18][CH:19]=1
Reactant: O=C(Oc1ccc(Oc2ccc(I)cc2)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1ccc(Oc2ccc(I)cc2)cc1
Yield: 89.3 %

Procedure:
300 g of p-(p-iodophenoxy)phenyl benzoate are suspended in 2800 ml of 96% ethanol, treated with 700 g of 20% sodium hydroxide solution and heated on a boiling water-bath for 90 minutes. Subsequently, the alcohol is distilled off as an azeotropic mixture and the residue is treated with 1500 ml of deionized water. After the addition of 380 ml of concentrated hydrochloric acid, the mixture is extracted three times with 1500 ml of dichloromethane each time. The dichloromethane extract is washed twice with 500 ml of saturated sodium hydrogen carbonate solution, twice with 500 ml of 2 N hydrochloric acid and twice with 500 ml of water. After drying over sodium sulphate, the solution is evaporated to 500 ml under reduced pressure and 500 ml of hot n-hexane is added to the mixture. 201 g of p-(p-iodophenoxy)phenol melting point 119° C.-121° C. is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:58]1([CH2:63][C@@H:64]2[CH2:69][CH2:68][CH2:67][NH:66][CH2:65]2)[CH2:62][CH2:61][CH2:60][CH2:59]1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:66]2[CH2:67][CH2:68][CH2:69][C@@H:64]([CH2:63][N:58]3[CH2:59][CH2:60][CH2:61][CH2:62]3)[CH2:65]2)=[O:32])[C:25]=1[CH3:33])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(F)cccc4F)cc32)c(C)c1C(=O)O
Reactant: C1CNC[C@H](CN2CCCC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(F)cccc4F)cc32)c(C)c1C(=O)N1CCC[C@@H](CN2CCCC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-[5-(2,6-difluoro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (236 mg), HATU (1.2 eq.), (R)-3-pyrrolidin-1-ylmethyl-piperidine (2×) in DMF (2.5 mL) was stirred at rt for 2 hours. The reaction was concentrated, diluted with DCM, washed with water (2×), sodium carbonate (2×), dried and concentrated. The residue was purified on a silica gel column to give 120 mg of the titled compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]([F:6])=[C:3]([F:5])[F:4].[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8]>>[Cl:1][CH:2]([F:6])[C:3]([N:9]([CH2:10][CH3:11])[CH2:7][CH3:8])([F:5])[F:4]
Reactant: FC(F)=C(F)Cl
Reactant: CCNCC
Product: CCN(CC)C(F)(F)C(F)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
Chlorotrifluoroethylene (454 g; 3.91 mole) is bubbled into diethylamine (350 g; 4.8 mole) over about 6 hours while the temperature is maintained at 30°-45° C. by use of an ice bath. The mixture is stirred overnight at room temperature and then distilled in vacuo to give 415 g (2.2M) of N-(2-chloro-1,1,2-trifluoroethyl)-diethylamine.
Reaction SMILES: [NH2:1][C:2]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[F:15])([CH:5]1[CH2:7][CH2:6]1)[CH2:3][OH:4].C(=O)([O-])O.[Na+].[Cl:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Br:14][C:12]1[CH:11]=[CH:10][C:9]([F:15])=[C:8]([C:2]([NH:1][C:23](=[O:24])[CH2:22][Cl:21])([CH:5]2[CH2:7][CH2:6]2)[CH2:3][OH:4])[CH:13]=1
Reactant: O=C(Cl)CCl
Reactant: NC(CO)(c1cc(Br)ccc1F)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCl)NC(CO)(c1cc(Br)ccc1F)C1CC1
Temperature: 25 °C

Procedure:
(RS)-2-Amino-2-(5-bromo-2-fluoro-phenyl)-2-cyclopropyl-ethanol (2.27 g, 8 mmol) was dissolved in a mixture of dichloromethane (85 ml) and a saturated aqueous solution of sodium hydrogen-carbonate (85 ml). The biphasic mixture was then treated with a solution of chloroacetylchloride (0.69 ml, 8.7 mmol) in dichloromethane. The reaction mixture was stirred at room temperature and the progress of the transformation checked by chromatography. After completion, the reaction mixture was diluted with dichloromethane, the organic layer separated and washed with water, then dried over sodium sulfate and evaporated. The (RS)-N-[1-(5-bromo-2-fluoro-phenyl)-1-cyclopropyl-2-hydroxy-ethyl]-2-chloro-acetamide was obtained as a yellow oil (2.73 g, 94.0% of theory). Mass (calculated) C13H14BrClFNO2 [350.614]; (found) [M+H]+=350, [M+2-H]+=352, [M+4-H]+=354.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[OH:14])([CH3:6])([CH3:5])[CH3:4].[C:15](=[O:17])=[O:16]>COCCOC>[C:3]([C:7]1[CH:12]=[C:11]([CH:10]=[C:9]([CH3:13])[C:8]=1[OH:14])[C:15]([OH:17])=[O:16])([CH3:6])([CH3:5])[CH3:4]
Reactant: O=C=O
Reactant: Cc1cccc(C(C)(C)C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cc(C(=O)O)cc(C(C)(C)C)c1O
Temperature: 5 °C

Procedure:
Charge a reaction vessel with a suspension of sodium hydride (4.74 g, 0.198 mol) in anhydrous ethylene glycol dimethyl ether (150 mL). Add, by dropwise addition, a solution of 2-t-butyl-6-methylphenol (0.1 mol) in ethylene glycol dimethyl ether (150 mL). Warm to 50°-60° C. for 1.5 hours then introduce carbon dioxide through a gas-disparging tube below the surface of the reaction mixture for 20 hours. Cool to 5° C. and destroy the excess sodium hydride carefully with methyl alcohol (30 mL). After hydrogen evolution ceases, adjust the pH of the reaction mixture to 2 with 1N hydrochloric acid. Dilute with water (1.6 L) and collect the title compound by filtration.
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([F:11])=[CH:4][N:3]=1.Cl.[F:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][O:22][CH2:23][C:24]([NH2:26])=[NH:25])[CH:17]=[CH:18][CH:19]=1>>[F:11][C:5]1[CH:4]=[N:3][C:2]2[N:25]=[C:24]([CH2:23][O:22][CH2:21][CH2:20][C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=3)[NH:26][C:8](=[O:10])[C:7]=2[CH:6]=1
Reactant: N=C(N)COCCc1cccc(F)c1
Reactant: O=C(O)c1cc(F)cnc1F
Agent: Cl
Product: O=c1[nH]c(COCCc2cccc(F)c2)nc2ncc(F)cc12

Procedure:
The title compound was prepared in analogy to example 85 from 2,5-difluoropyridine-3-carboxylic acid and 2-[2-(3-fluoro-phenyl)-ethoxy]-acetamidine hydrochloride (example 101). Light brown solid. MS: m/e=318.2 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([O:27][CH3:28])=[C:19]([O:25]C)[CH:20]=3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N[C@H](C(O)=O)CCSC>CS(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([O:27][CH3:28])=[C:19]([OH:25])[CH:20]=3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)[nH]c(=O)c2cc1OC
Agent: CS(=O)(=O)O
Agent: CSCC[C@H](N)C(=O)O
Product: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)[nH]c(=O)c2cc1O
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 86.6 %

Procedure:
A mixture of 2-(3-fluoro-4-(phenyl)phenyl)-6,7-dimethoxyquinazolin-4(3H)-one (3.83 g, 10.2 mmol) and methionine (2.1 g, 14.1 mmol) in methanesulfonic acid was heated 110° C. for 4 h. Additional methionine (0.75 g) was added and heating was continued for another 1.5 h. The mixture was allowed to cool to RT and was poured into ice-water (300 mL). A solid separated out, which was collected via filtration. The solid was suspended in sat. NaHCO3 and the after the effervescence subsided the solid was again collected via filtration. The solid was washed with water and EtOH to give the desired product 2-(3-fluoro-4-(phenyl)phenyl)-6-hydroxy-7-methoxyquinazolin-4(3H)-one (3.2 g, 8.83 mmol, 87%). HPLC retention time 7.06 mins.
Reaction SMILES: CC([CH:5]1[C@@H:10]([NH2:11])[CH2:9][CH2:8][CH2:7][N:6]1[C:12]([O-:14])=[O:13])(C)C.[O:15]1[CH2:19][CH2:18][CH:17]([CH:20]=O)[CH2:16]1>[Pd].C(O)C>[O:15]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:11][C@H:10]2[CH2:9][CH2:8][CH2:7][N:6]([C:12]([O:14][C:17]([CH3:20])([CH3:18])[CH3:16])=[O:13])[CH2:5]2)[CH2:16]1
Reactant: CC(C)(C)C1[C@@H](N)CCCN1C(=O)[O-]
Reactant: O=CC1CCOC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H](NCC2CCOC2)C1
Reaction time: 8 h

Procedure:
To 5% palladium on carbon (0.05 g) under nitrogen was added a solution of 1,1-dimethylethyl-(3S)-3-aminopiperidine-1-carboxylate (0.50 g, 2.5 mmol) and tetrahydrofuran-3-carboxaldehyde (50% w/w in water) (0.50 g, 2.5 mmol) in ethanol (20 mL). The reaction mixture was hydrogenated overnight at 60 psi in a Parr hydrogenator. The catalyst was removed by filtration through Celite and the solvent removed in vacuo to give 1,1-dimethylethyl (3S)-3-[(tetrahydrofuran-3-ylmethyl)amino]piperidine-1-carboxylate as a colourless, slightly cloudy oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C@@H:4]2[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].[F:24][C:25]([F:37])([F:36])[C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>CN(C)C=O.ClCCl>[F:37][C:25]([F:24])([F:36])[C:26]1[CH:27]=[C:28]([S:32]([NH:1][C@@H:2]2[CH2:17][N:5]3[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:9][C@@H:4]3[CH2:3]2)(=[O:33])=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@@H](N)C[C@H]2C1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN2C[C@@H](NS(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (7S,8aS)-tert-butyl 7-aminohexahydropyrrolo[1,2-a]-pyrazine-2(1H)-carboxylate (0.22 g, 0.92 mmol) in dimethylformamide/dichloromethane (1:5, 5 mL) was added sodium carbonate (0.166 g, 1.56 mmol) and 3-(trifluoromethyl)-benzene-1-sulfonyl chloride (0.315 g, 1.29 mmol). The mixture was stirred at room temperature for 18 hours and then concentrated. The residue was purified by chromatography on silica gel (dichloromethane/methanol=15:1) to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.19 (m, 1H), 1.38 (s, 9H), 1.40 (m, 2H), 1.70 (m, 1H), 1.84 (m, 1H), 2.00 (m, 1H), 2.18 (m, 1H), 2.64 (m, 1H), 2.79 (m, 1H), 3.70 (m, 1H), 3.80-3.95 (m, 2H), 7.83 (m, 1H), 8.05 (m, 1H), 8.11 (m, 2H), 8.15 (m, 1H); MS (ESI) m/z 450 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH2:33][CH2:34][C:35](OCC)=[O:36])=[CH:20][CH:19]=3)[N:15]=2)=[CH:5][CH:4]=1.[CH3:42][NH2:43]>C(O)C>[CH3:42][NH:43][C:35](=[O:36])[CH2:34][CH2:33][C:29]1[N:28]([CH2:27][CH2:26][CH2:25][CH2:24][C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][C:14]3[N:15]=[C:11](/[CH:10]=[CH:9]/[C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:40])([F:41])[F:1])=[CH:8][CH:7]=4)[O:12][CH:13]=3)=[CH:23][CH:22]=2)[CH:32]=[CH:31][N:30]=1
Reactant: CN
Reactant: CCOC(=O)CCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Solvent: CCO
Product: CNC(=O)CCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1

Procedure:
A mixture of ethyl 3-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]propionate (180 mg) and a solution (3 ml) of 30% methylamine in ethanol in sealed tube was heated at 120° C. for 12 hr. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent; dichloromethane to dichloromethane:methanol=30:1) and recrystallized from ethyl acetate-hexane to give the titled compound (43 mg) as a colorless crystal powder.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:12]=[C:11]([Cl:20])[C:10]=1[F:21])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:12]=[C:11]([Cl:20])[C:10]=1[F:21]
Reactant: CCN(CC)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)c1cc(Cl)c(F)c(CN)c1

Procedure:
was prepared according to Scheme C1 (step B) from (3-chloro-5-diethylamino-2-fluoro-benzyl)-carbamic acid tert-butyl ester and TFA in CH2Cl2. MS (LC-MS): 231.0 [M]+; tR (HPLC conditions c): 2.29 min.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([O:8][CH3:9])=[O:7].C[Si](C)(C)[N-][SiH3].C[Si](C)(C)[N-][SiH3].[Na+].[Na+].[CH:24]([C:26]1[CH:27]=[CH:28][C:29]([O:41][CH3:42])=[C:30]([CH:40]=1)[CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:25].[Cl-].[NH4+]>O1CCCC1>[C:35]([O:34][C:33]([NH:32][CH2:31][C:30]1[CH:40]=[C:26]([CH:24]([OH:25])[C:2]2([C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:4][CH2:5][O:1]2)[CH:27]=[CH:28][C:29]=1[O:41][CH3:42])=[O:39])([CH3:38])([CH3:36])[CH3:37]
Reactant: COc1ccc(C=O)cc1CNC(=O)OC(C)(C)C
Reactant: COC(=O)C1CCCO1
Agent: C[Si](C)(C)[N-][SiH3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C1(C(O)c2ccc(OC)c(CNC(=O)OC(C)(C)C)c2)CCCO1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
A solution of 2.60 g of methyl tetrahydro-2-furancarboxylate in 10 ml of tetrahydrofuran was added dropwise to 20 ml of sodium bis(trimethyldisilylamide) (1 M solution in tetrahydrofuran) cooled to −75° C. under an atmosphere of nitrogen gas, and the reaction mixture was stirred for 30 minutes. A solution of 2.65 g of t-butyl N-(5-formyl-2-methoxybenzyl)carbamate in 20 ml of tetrahydrofuran was added dropwise, and the mixture was stirred further for 1 hour. 200 ml of saturated aqueous ammonium chloride was added, and the mixture was extracted with 200 ml of ethyl acetate. The organic layer washed with 100 ml of brine, dried over magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography, to give 1.934 g of the title compound as a colorless powder.
Reaction SMILES: [CH:1]1([C:4]([CH:6]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH:1]1([C:4]([CH:6]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:16][CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])=[O:5])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(C1CC1)C(c1ccccc1F)N1CCC(O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(C(C(=O)C2CC2)c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 50 ml of dichloromethane, 8.0 g (28.9 mmol) of 1-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4-hydroxypiperidine were dissolved, followed by the addition of 2.92 g (28.9 mmol) of triethylamine. To the resulting mixture, a solution of 3.31 g (28.9 mmol) of methanesulfonyl chloride in 10 ml of dichloromethane was added dropwise under ice cooling, followed by stirring at room temperature for 1 hour. The solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue and triethylamine hydrochloride so precipitated was filtered off. The filtrate was concentrated by evaporation under reduced pressure, whereby crude 1-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4-methylsulfonyloxypiperidine was obtained. To the crude product, 50 ml of dimethylsulfoxide (DMSO) and 19.8 g (170 mmol) of potassium thioacetate were added and the resulting mixture was stirred at 50° C. for 4 hours. After the addition of water, the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to chromatography on a silica gel column (eluting solvent: toluene/ethylacetate=19/1), whereby a reddish brown oil was obtained. The resulting oil was crystallized from hexane, whereby 3.6 g of the title compound were obtained as light brown crystals (yield: 37%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@H:10]([CH:14]2[CH2:17][NH:16][CH2:15]2)[CH:11]([CH3:13])[CH3:12])[CH:6]=[C:7]([F:9])[CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:25]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30]>C(#N)C>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([C@H:25]([N:16]2[CH2:15][CH:14]([C@@H:10]([C:5]3[CH:6]=[C:7]([F:9])[CH:8]=[C:3]([F:2])[CH:4]=3)[CH:11]([CH3:13])[CH3:12])[CH2:17]2)[C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[C:29]#[N:30])=[CH:39][CH:38]=1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Reactant: CC(C)[C@H](c1cc(F)cc(F)c1)C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)[C@H](c1cc(F)cc(F)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 106 mg (0.5 mmole) of 3-[(1S)-1-(3,5-difluorophenyl)-2-methylpropyl]azetidine hydrochloride from Step 3 and 0.650 g (2 mmole) of Cs2CO3 in 5 mL dry acetonitrile was stirred at rt in a flask fitted with a small Dean-Stark trap. After 15 minutes, 0.306 g (1 mmole) of 3-[bromo(4-chlorophenyl)methyl]benzonitrile was added and the mixture was heated at 60° C. After 18 h, the solution was partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over Na2SO4. The solution was filtered and the filtrate was concentrated to an oil. The residue was purified by chromatography on a ChralPak AD column using 4% isopropanol-heptane to afford two enantiomers. Fractions containing the slower product diastereomer were pooled and concentrated to afford the title compound; Mass Spectrum: m/e=451 (M+1, 35Cl) and 453 (M+1, 37Cl).
Reaction SMILES: [CH:1]([N:4]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:5](=[O:28])[CH2:6][N:7]1[C:16](=[O:17])[CH2:15][C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]1=2)([CH3:3])[CH3:2].N1CCCCC1.[NH:41]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]([CH:50]=O)=[CH:42]1>C1(C)C=CC=CC=1>[NH:41]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]([CH:50]=[C:15]2[C:14]3[N:10]([C:11]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:12][N:13]=3)[C:9]3[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=3[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:28])[C:16]2=[O:17])=[CH:42]1
Reactant: CC(C)N(C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CC(C)N(C(=O)CN1C(=O)C(=Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Temperature: 110 °C
Yield: 96 %

Procedure:
To a solution of N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-phenyl-acetamide (Preparation 7(A)) (1.2 g, 2.7 mmol) and piperidine (0.4 mL, 1.33 mmol) in toluene was added 1H-indole-3-carbaldehyde (0.46 g, 3.2 mmol). The reaction mixture was heated at 110° C. for 31 hours. Activated 4 Å molecular sieves (2 g) were added. The reaction mixture was heated for 24 hours at 110° C. The reaction was cooled to room temperature and the molecular sieves were filtered with the aid of toluene. The filtrate was concentrated and the residue was purified by chromatography (12%-20% acetone/methylene chloride) to give 1.5 g of 2-[4-(1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide as a solid. MS 579.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.[Pd](Cl)Cl.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:1][C:2]1[N:7]=[C:6]([C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: Clc1nccc(-c2cccnc2)n1
Temperature: 60 °C

Procedure:
Nitrogen was bubbled through a solution of 2,4-dichloropyrimidine (1 eq) in tetrahydrofuran and water (3:1) for 0.5 h. Bis(diphenylphosphino)ferrocene Palladium(II)chloride (0.05 eq) followed by pyridine-3-boronic acid (1 eq) and sodium carbonate (3 eq) was added and the mixture was heated to 60° C. for 16 h under nitrogen. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried with sodium sulfate and concentrated. Purification on silica gel gave 2-chloro-4-(3-pyridyl)pyrimidine. MS: MH+=190.