Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:17][NH:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.[SiH](CC)(CC)CC>C(O)(C(F)(F)F)=O>[CH:1]1[C:10]2[C@H:11]3[CH2:17][NH:16][CH2:15][CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: c1cc2c3c(c1)c1c(n3CCC2)CCCNC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: c1cc2c3c(c1)[C@H]1CNCCC[C@H]1N3CCC2
Reaction time: 72 h
Yield: 82.6 %

Procedure:
To a solution of 5,6,9,10,11,12-hexahydro-4H,8H-azepino[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (240 mg, 1.06 mmol) in TFA (4.0 mL) was added Et3SiH (2.0 mL). The mixture was stirred for 3 days then concentrated in vacuo. The residue was dissolved in dilute AcOH and washed with Et2O. The aqueous solution was basified with 1N NaOH. A white solid was precipitated and filtered to yield the title compound as a pale yellow viscous oil (200 mg, 83%). MS (CI, NH3): 229.4 (base, M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3([C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[O:22])[CH2:20][CH2:19]3)=[O:17])=[C:11]([F:31])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:40](OC1C=CC=CC=1)=[O:41].FC(F)(F)C(O)=O.[CH3:56][O:57][CH:58]1[CH2:61][NH:60][CH2:59]1>O1CCCC1>[F:31][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:40]([N:60]3[CH2:61][CH:58]([O:57][CH3:56])[CH2:59]3)=[O:41])[CH:7]=2)[CH:14]=[CH:13][C:12]=1[NH:15][C:16]([C:18]1([C:21]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)=[O:22])[CH2:20][CH2:19]1)=[O:17]
Reactant: COC1CNC1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC1CN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)c(F)c3)ccn2)C1
Reaction time: 1 h
Yield: 48.9 %

Procedure:
N-{4-[(2-Aminopyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (75 mg) was dissolved in tetrahydrofuran (1.8 ml) under a nitrogen atmosphere, and triethylamine (0.074 ml) and phenyl chloroformate (0.0488 ml) were added dropwise in this order at room temperature, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a 1N aqueous solution of sodium hydroxide, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (1.8 ml). This solution was added to a mixture of a crude product of 3-methoxyazetidine trifluoroacetate (209.8 mg, corresponds to 0.671 mmol) and triethylamine (0.450 ml), followed by stirring at room temperature for 13 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a 1N aqueous solution of sodium hydroxide, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:2, ethyl acetate, ethyl acetate:methanol=50:1, then 20:1). Fractions containing the target compound were concentrated. To the resultant residue was added diethyl ether:heptane=1:2 to suspend a solid. The solid was collected by filtration and washed with heptane. This was dried under aeration to provide the titled compound as white powder (46.5 mg, 48.9%).
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:13]=4[N:14]=[CH:15][C:10]3=[N:9][CH:8]=2)[CH2:5][CH:4]([NH2:27])[CH2:3]1.CCN(C(C)C)C(C)C.[CH:37]1([S:40](Cl)(=[O:42])=[O:41])[CH2:39][CH2:38]1.CO>C(Cl)Cl>[CH3:1][CH:2]1[CH:6]([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:13]=4[N:14]=[CH:15][C:10]3=[N:9][CH:8]=2)[CH2:5][CH:4]([NH:27][S:40]([CH:37]2[CH2:39][CH2:38]2)(=[O:42])=[O:41])[CH2:3]1
Reactant: CC1CC(N)CC1c1cnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CC(NS(=O)(=O)C2CC2)CC1c1cnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
To a solution of 3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine (0.27 g, 0.7 mmol) and DIEA (0.18 mL, 1.05 mmol) in DCM (5 mL) was added cyclopropanesulfonyl chloride (0.098 g, 0.7 mmol) drop-wise. The resulting mixture was stirred at ambient temperature for about 1 h. Another 0.18 mL of DIEA and 0.098 g of cyclopropanesulfonyl chloride were added and the reaction was continued for about 3 h. The solvent was removed and the residue was partitioned between saturated aqueous ammonium chloride and EtOAc (20 mL each). The organic layer was washed with brine (10 mL), dried over anhydrous MgSO4, filtered and concd. The residue was purified by silica gel chromatography (100% DCM for 5 min, then to 6% MeOH in DCM over next 30 min) to yield N-(3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)cyclopropanesulfonamide (0.18 g, 52% yield) as an off-white solid. LC/MS (Table 1, Method a) Rt=2.45 min; MS m/z 490 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH2:11][CH3:12])[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])(C)C.S(=O)(=O)(O)O.COC[O:26][CH3:27]>>[CH2:1]([C:4]1[CH:1]=[C:5]([CH2:10][CH3:9])[CH:6]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:27]=1[OH:26])[C:5]1[CH:10]=[C:9]([CH2:11][CH3:12])[CH:8]=[C:7]([C:13]([CH3:14])([CH3:15])[CH3:16])[C:6]=1[OH:17]
Reactant: CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: COCOC
Agent: O=S(=O)(O)O
Product: CCc1cc(Cc2cc(CC)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Yield: 57 %

Procedure:
Into the reactor described in Example 1 hereinbefore there are charged 58.5 g (0.25 g-mol) of 2,6-ditert.butyl4-ethylphenol, 1 g of a concentrated sulfuric acid and 19 g (0.25 g-mol) of methylal are added into the reactor at the temperature of 130° C. over 30 minutes. The reaction mass is treated and 26.2 g of 2,2'-methylene-bis-(4-ethyl-6-tert.butylphenol) are thus obtained which corresponds to 98.9% of the theoretical yield calculated for the reacted 2,6-ditert.butyl-4-ethylphenol (conversion of the latter is 57.5).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13](/[CH:16]=[CH:17]/[C:18]([NH2:20])=[O:19])[CH:14]=2)[C:9](=[O:21])[N:8]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:7]=1[CH2:27][NH:28]C(OC(C)(C)C)=O)[CH2:2][CH2:3][CH3:4].[ClH:36]>C(OCC)(=O)C>[ClH:36].[NH2:28][CH2:27][C:7]1[N:8]([CH2:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:9](=[O:21])[C:10]2[C:15]([C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH2:20])=[O:19])=[CH:12][CH:11]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(/C=C/C(N)=O)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC(C)(C)C)c(=O)c2ccc(/C=C/C(N)=O)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of (E)-3-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide (0.24 g, 0.5 mmol) in ethyl acetate (5 mL) was added a solution of 4N hydrogen chloride in ethyl acetate (5 mL) and the obtained solution was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were recrystallized from methanol-diethyl ether to give (E)-3-[3-(aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide hydrochloride (0.19 g, 90.5%) as crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#[N:7].C(N(C(C)C)C(C)C)C.[CH3:20][O:21][CH2:22]Cl.O>CN(C=O)C>[CH3:20][O:21][CH2:22][O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#[N:7]
Reactant: N#Cc1ccnc(CO)c1
Reactant: COCCl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCOCc1cc(C#N)ccn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under a nitrogen atmosphere, to a solution of 2-(hydroxymethyl)isonicotinonitrile (5.08 g) and N-ethyldiisopropylamine (26.5 mL) in DMF (76 mL) was added chloromethyl methyl ether (8.63 mL) at room temperature, and the mixture was stirred at room temperature for 20 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.87 g) as an orange oil.
Reaction SMILES: [C:1]([C:5]([C:8]([O:11][C:12]([C:18](F)=[O:19])([C:14]([F:17])([F:16])[F:15])[F:13])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].[CH:21]([CH2:26][OH:27])([CH2:24][Br:25])[CH2:22][Br:23]>>[CH:21]([CH2:26][O:27][C:18]([C:12]([O:11][C:8]([C:5]([C:1]([F:2])([F:3])[F:4])([F:6])[F:7])([F:10])[F:9])([C:14]([F:16])([F:17])[F:15])[F:13])=[O:19])([CH2:24][Br:25])[CH2:22][Br:23]
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: OCC(CBr)CBr
Product: O=C(OCC(CBr)CBr)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F

Procedure:
CF3CF2CF2OCF(CF3)COF obtained in Example 1-7 is reacted with (BrCH2)2CHCH2OH under the same conditions as the above esterification reaction to obtain (BrCH2)2CHCH2OCOCF(CF3)OCF2CF2CF3. Employing the obtained (BrCH2)2CHCH2OCOCF(CF3)OCF2CF2CF3, the same reactions as in Example 1-3 to 1-7 are carried out to obtain (FSO2CF2)2CFCOF and CF3CF2CF2OCF(CF3)COF.
Reaction SMILES: [NH2:1][CH:2]([CH3:5])[CH2:3][OH:4].C[O:7][C:8]([C:10]1[C:14]([NH:15][C:16]([C:18]2[C:23]([NH:24][C:25]3[CH:26]=[N:27][CH:28]=[N:29][CH:30]=3)=[CH:22][CH:21]=[C:20]([CH:31]3[CH2:33][CH2:32]3)[N:19]=2)=[O:17])=[CH:13][N:12]([CH3:34])[N:11]=1)=O>>[OH:4][CH2:3][CH:2]([NH:1][C:8]([C:10]1[C:14]([NH:15][C:16]([C:18]2[C:23]([NH:24][C:25]3[CH:26]=[N:27][CH:28]=[N:29][CH:30]=3)=[CH:22][CH:21]=[C:20]([CH:31]3[CH2:33][CH2:32]3)[N:19]=2)=[O:17])=[CH:13][N:12]([CH3:34])[N:11]=1)=[O:7])[CH3:5]
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: CC(N)CO
Product: CC(CO)NC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 14 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 2-amino-propan-1-ol with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (14%) as sticky yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[N+:9]([O-])=O>CO.[Ni]>[NH2:9][C:3]1[C:4]([CH3:8])=[N:5][CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Cc1nccc(N)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: Cc1nccc(N)c1N
Yield: 90.2 %

Procedure:
4-Amino-3-nitro-2-picoline (5.5 g, 0.036 mole) was hydrogenated in methanol (250 mL) at 5 psi and 25° for 1.25 hr using Raney Nickel as catalyst. The catalyst was filtered, the filtrate stripped in vacuo and the residue triturated with cyclohexane to give a solid. The solid was filtered and air dried to give 4.0 g (88%) of the title compound, m. pt. 170-171°.
Reaction SMILES: [CH2:1]([C@H:8]([NH:23]C(=O)C1C=CC(F)=C(Br)C=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])NCCC(C)(C)C)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:34]([O:37][C:38]1[CH:39]=[C:40]([CH:44]=[C:45]([N:47]2[CH2:51][CH2:50][CH2:49][C:48]2=[O:52])[CH:46]=1)[C:41]([OH:43])=O)([CH3:36])[CH3:35].N[C@H]([C@H]1OC(=O)[C@H](C)C1)CC1C=CC=CC=1>>[CH:34]([O:37][C:38]1[CH:39]=[C:40]([CH:44]=[C:45]([N:47]2[CH2:51][CH2:50][CH2:49][C:48]2=[O:52])[CH:46]=1)[C:41]([NH:23][C@H:8]([C@@H:9]1[CH2:10][C@@H:11]([CH3:12])[C:13](=[O:21])[O:22]1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:43])([CH3:35])[CH3:36]
Reactant: CC(C)Oc1cc(C(=O)O)cc(N2CCCC2=O)c1
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1ccc(F)c(Br)c1)C(=O)NCCC(C)(C)C
Agent: C[C@@H]1C[C@@H]([C@@H](N)Cc2ccccc2)OC1=O
Product: CC(C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H]2C[C@@H](C)C(=O)O2)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to D3 from 3-isopropoxy-5-(2-oxopyrrolidin-1-yl)benzoic acid (D16) and (3R,5S)-5-((S)-1-amino-2-phenylethyl)-3-methyldihydrofuran-2-one (D48).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:12]([O-])=O)[CH:9]=2)[CH2:4]1.[H][H]>CO.[Pd]>[NH2:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH2:4][CH:3]([N:2]([CH3:15])[CH3:1])[CH2:11]2
Reactant: [H][H]
Reactant: CN(C)C1Cc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CO
Product: CN(C)C1Cc2ccc(N)cc2C1
Yield: 93.3 %

Procedure:
Dimethyl(5-nitro-2,3-dihydro-1H-inden-2-yl)amine (1.5 g, 7.3 mmol)) was dissolved in MeOH and stirred vigorously with of 5% Pd/C (250 mg) under a 55 PSI atmosphere of hydrogen for 15 h. The reaction was filtered through celite and the solvent was removed under vacuum. The reaction produced 1.2 g (94%) of the white powder (5-amino-2,3-dihydro-1H-inden-2-yl)dimethylamine. 1H NMR (400 MHz, DMSO-d6) δ 6.84 (d, J=8.2 Hz, 1H), 6.41 (s, 1H), 6.38-6.36 (m, 1H), 4.88 (s, 2H), 3.86 (quint, J=8.8 Hz, 1H), 3.16-2.88 (m, 4H), 2.60 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C:20]2[N:29]=[C:28]3[C:23]([CH:24]=[C:25]([CH3:31])[C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10]1>C1COCC1.CCO.[Ni]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[N:29]=[C:28]3[C:23]([CH:24]=[C:25]([CH3:31])[C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10]1
Reactant: Cc1cc2ccc(C=CCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2[nH]c1=O
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc2ccc(CCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2[nH]c1=O
Reaction time: 4 h
Yield: 50.9 %

Procedure:
A solution of 7-{5-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3-methyl-1H-[1,8]naphthyridin-2-one (0.43 g, 0.94 mmol) in THF was added to a slurry of Raney Ni in EtOH. The mixture was hydrogentated for 4 h at 40 psi. The reaction mixture was filtered through a small celite bed and rinsed with CH2Cl2 and mMeOH. The filtrate was concentrated and purified by column chromatography on silica (10% MeOH/EtOAc) to afford the title compound as a pale yellow solid (0.22 g, 51.4%). mp: 157–158° C.; 1H NMR (400 MHz, CDCl3) δ 9.00 (br s, 1H), 7.75 (d, 1H), 7.50 (s, 1H), 7.15 (m, 2H), 7.00–6.90 (m, 2H), 3.10 (br s, 4H), 2.80 (t, 2H), 2.60 (br s, 4H), 2.42–2.38 (m, 2H), 2.20 (s, 3H), 1.82–1.80 (m, 2H), 1.70–1.60 (m, 4H); MS: ES+: 459.01 (M+H)+, 460.97 (Exact mass: 458.16).
Reaction SMILES: [CH3:1][O:2][C:3](=O)[C@H:4]([CH2:9][CH:10]([CH3:12])[CH3:11])[NH:5][C:6](=O)[CH3:7].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:15].[OH-].[K+]>C(Cl)(Cl)Cl>[CH3:7][C:6]1[S:15][C:3]([O:2][CH3:1])=[C:4]([CH2:9][CH:10]([CH3:12])[CH3:11])[N:5]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(C)=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COc1sc(C)nc1CC(C)C

Procedure:
A one-liter three necked flash equipped with a stirrer, condenser, and heating mantle is charged with 10 g (0.052 mole) of N-acetylleucine methyl ester and 14.5 g (0.062 mole) of phosphorus pentasulfide in 250 ml of chloroform, and the reaction mixture is refluxed for 24 hours while care is taken to exclude moisture. The reaction mixture is then cooled and made basic with 200 ml of 10% potassium hydroxide.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9](O)=[O:10]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:9]=[O:10])=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: Nc1ccc(F)cc1
Product: O=CNc1ccc(F)cc1

Procedure:
Was prepared according to Example 2 from 4-fluoroaniline and formic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14]([NH:20][C@H:21]2[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22]2)=[N:15]3)=O)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C(=O)([O-])[O-].[Na+].[Na+].O>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14]([NH:20][C@H:21]2[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22]2)=[N:15]3)=[N:31][OH:32])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(c1ccc(F)cc1)c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C(c1ccc(F)cc1)c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Yield: 32.9 %

Procedure:
A stirred suspension of (4-fluoro-phenyl)-[2-((R)-indan-1-ylamino)-quinolin-5-yl]-methanone (example 83) (100 mg, 0.26 mmol), hydroxylamine hydrochloride (55 mg, 0.79 mmol) and sodium carbonate (83 mg, 0.78 mmol) in EtOH (2 ml) was heated under reflux conditions for 18 hours, the reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/ethyl acetate) and crystallization (diethyl ether/heptane) to yield the title compound as off-white solid (34 mg, 33%).
Reaction SMILES: [CH:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15]1([P:21](Cl)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][O:12][P:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc(C2CCCCC2)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=P(OCc1ccc(C2CCCCC2)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
To a stirred solution of 4-cyclohexylbenzyl alcohol (1 g, 5.26 mmol) in 45 ml of dry dichloromethane, 5 ml of triethylamine and 41 mg of dimethylaminopyridine was added 1.05 ml (1.25 g) of diphenylphosphinic chloride. The mixture was stirred at room temperature for 3 h after which it was concentrated to approximately 10 ml. The mixture was diluted with dichloromethane, washed with cold 10% sodium bicarbonate, water, dried (sodium sulfate), filtered and concentrated to approximately 10 ml. The resulting solution was chromatographed on silica gel, eluting with ethyl acetate/heptane to provide 1.92 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[CH:11]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])([CH3:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:14]([CH:11]([CH3:13])[CH3:12])[CH:15]=1)=[O:7]
Reactant: CC(C)c1cccc(N)c1
Reactant: O=C(O)c1ccnc(Br)c1
Product: CC(C)c1cccc(NC(=O)c2ccnc(Br)c2)c1

Procedure:
In a manner similar to that described in Preparation 17, 2-bromoisonicotinic acid and 3-isopropylaniline were converted to the title compound
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[CH:34][NH:33][C:32]3=[O:36])=[CH:27][CH:26]=2)[N:21]=[CH:22][CH:23]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:33]1[CH:34]=[CH:35][N:31]([C:28]2[CH:27]=[CH:26][C:25]([CH2:24][N:20]3[N:21]=[CH:22][CH:23]=[N:19]3)=[CH:30][CH:29]=2)[C:32]1=[O:36])[CH3:12]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=c1[nH]ccn1-c1ccc(Cn2nccn2)cc1
Product: C[C@@H](n1ccn(-c2ccc(Cn3nccn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 1-[4-(2H-1,2,3-triazol-2-ylmethyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-1,2,3-triazol-2-ylmethyl)phenyl]-2(1H,3H)-imidazolone (Compound 20).
Reaction SMILES: C([C:8]([S:10][C:11]1[C:16]2=[N:17][CH:18]=[C:19]([C:22]([O:24]CC3C=CC(OC)=CC=3)=[O:23])[C:20](=[O:21])[N:15]2[CH:14]=[CH:13][CH:12]=1)=[O:9])C1C=CC=CC=1.[C:34]1(OC)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.FC(F)(F)[C:44](O)=[O:45]>C(Cl)Cl>[CH2:44]([O:45][C:8]([S:10][C:11]1[C:16]2=[N:17][CH:18]=[C:19]([C:22]([OH:24])=[O:23])[C:20](=[O:21])[N:15]2[CH:14]=[CH:13][CH:12]=1)=[O:9])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COc1ccccc1
Reactant: COc1ccc(COC(=O)c2cnc3c(SC(=O)Cc4ccccc4)cccn3c2=O)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)Sc1cccn2c(=O)c(C(=O)O)cnc12
Temperature: 0 °C

Procedure:
A mixture of 0.872 g of 9-(benzylcarbonyl)thio-3-(4-methoxybenzyloxycarbonyl)-4H-pyrido[1,2-a]pyrimidin-4-one Ie-79, 2.5 g of anisole and 10 ml of dry methylene chloride is cooled with ice water, mixed with 5 ml of trifluoroacetic acid and stirred under cooling with ice water for 3 hours. The reaction mixture is concentrated to dryness in vacuo, and the residue is recrystallized from ethyl acetate to give the titled compound Ie-80.
Reaction SMILES: ClC1C=C(NC2C3C(=CC(OCCOC)=C(N)C=3)N=CN=2)C=CC=1F.Cl[C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:40][CH3:41])=[C:34]([N+:37]([O-])=O)[CH:35]=2)[N:30]=[CH:29][N:28]=1.[Br:42][C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[C:45]([F:50])[CH:44]=1>>[Br:42][C:43]1[CH:49]=[CH:48][C:46]([NH:47][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:40][CH3:41])=[C:34]([NH2:37])[CH:35]=3)[N:30]=[CH:29][N:28]=2)=[C:45]([F:50])[CH:44]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: COc1cc2ncnc(Cl)c2cc1[N+](=O)[O-]
Agent: COCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N
Product: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1N

Procedure:
Starting material: N4-(4-bromo-2-fluorophenyl)-7-methoxyquinazoline-4,6-diamine was prepared according to the same method of preparation of N4-(3-chloro-4-fluorophenyl)-7-(2-methoxy)ethoxyquinazoline-4,6-diamine in WO2008/33747, but the starting materials were 4-chloro-7-methoxy-6-nitro-quinazoline and 4-bromo-2-fluoro-aniline; other starting materials were prepared as example 1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:17][CH3:18])[C:11]=1[C:19]#[N:20])([CH3:9])[C:6](=[O:8])[CH3:7])[CH3:2].[Br:22]Br>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:21])[C:5]([C:10]1[CH:15]=[C:14]([Br:22])[C:13]([NH2:16])=[C:12]([NH:17][CH3:18])[C:11]=1[C:19]#[N:20])([CH3:9])[C:6](=[O:8])[CH3:7])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)C(C)(C(C)=O)c1ccc(N)c(NC)c1C#N
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C)(C(C)=O)c1cc(Br)c(N)c(NC)c1C#N
Yield: 52.7 %

Procedure:
To a solution of 2-(4-amino-2-cyano-3-methylaminophenyl)-2-methyl-3-oxobutyric acid ethyl ester from Example 4 (9.02 g, 31.2 mmol) in CHCl3 (90 mL) was added bromine (4.98 g, 31.2 mmol) dropwise at ambient temperature. After the addition of bromine, the reaction mixture was diluted with ethyl acetate (800 mL). This solution was washed successively with sat. NaHCO3 solution and brine and dried. The residue after evaporation was purified by flash chromatography in hexanes/EtOAc 2:1 to yield 2-(4-amino-5-bromo-2-cyano-3-methylaminophenyl)-2-methyl-3-oxobutyric acid ethyl ester as an oil (6.06 g, 53%).