Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH:8]=[CH2:9].[OH:11][C:12]1[CH:21]=[C:20]([NH:22][C:23]([CH3:25])=[O:24])[CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.C(#N)C>[CH2:7]([O:11][C:12]1[CH:21]=[C:20]([NH:22][C:23]([CH3:25])=[O:24])[CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH2:9]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(NC(C)=O)cc1O
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: C=CCOc1cc(NC(C)=O)ccc1C(=O)OC

Procedure:
138 g of potassium carbonate, 16.5 g of benzyltributylammonium chloride, 650 ml of acetonitrile and 133 g of allyl bromide were introduced into a 2-liter round-bottomed flask and 209 g of ground methyl 2-hydroxy-4-acetaminobenzoate were then added in small amounts. The contents were heated under reflux for 11 hours, a part of the acetonitrile was then distilled off and the residue was taken up with water. The precipitate formed was drained, washed with water and dried in an oven at 50° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH3:37])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:11]1[C:12]([C:14]([F:17])([F:15])[F:16])=[CH:13][C:8]2[N:7]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH3:37])[CH:31]=4)[CH:25]=3)[CH2:21][C:20](=[O:38])[NH:19][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(C(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(C(F)(F)F)c(Cl)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from (4-chloro-2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M113) (0.32 g, 0.57 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (170 mg, 67%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1.C1COCC1>CN(C1C=CN=CC=1)C.C(O)C>[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][C:2]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:21][CH:20]=1
Reactant: Clc1cc(-c2ccccc2)c2ccccc2n1
Reactant: Nc1ccc(S)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(Sc2cc(-c3ccccc3)c3ccccc3n2)cc1
Yield: 451.6 %

Procedure:
2-Chloro-4-phenylquinoline (4.18 mmoles, 10.0 g), 4-aminothiophenol (41.8 mmoles, 5.2 g) and DMAP (41.8 mmoles, 5.0 g) were stirred in 200 ml ethanol and 50 ml THF for 3 days. The solution was concentrated, ethyl acetate added, washed with water, dried over sodium sulfate and the solvent removed. The product was purified by HPLC over silica gel eluted with 30% ethyl acetate in hexane to yield 2-(4-aminophenylthio)-4-phenylquinoline 6.2 g, 45%. Mass Spec (FD) 328. Calculated for C21H16N2S: C, 76.80; H, 4.91N, 8.53. Found: C, 77.04; H, 5.00; N, 8.55.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([CH2:14][NH:15][CH2:16][CH3:17])([OH:13])[CH2:9]1)C1C=CC=CC=1.[CH2:18]=O>C(O)=O>[CH2:16]([N:15]([CH2:14][C:10]1([OH:13])[CH2:11][CH2:12][NH:8][CH2:9]1)[CH3:18])[CH3:17]
Reactant: C=O
Reactant: CCNCC1(O)CCN(Cc2ccccc2)C1
Solvent: O=CO
Product: CCN(C)CC1(O)CCNC1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
1.8 g (93 mmol) 1-benzyl-3-ethylaminomethyl-3-hydroxy-pyrrolidine (according to example Ca) are dissolved in a mixture of 9.5 g formic acid and 8.5 g 37% proof aqueous formaldehyde solution. The mixture is stirred at 80° C. for 4 hours. The solvents are removed in vacuo, the residue is taken up in water, and the pH is adjusted alkaline with potassium carbonate. The reaction mixture is then extracted with chloroforme, and the organic phase is dried with potassium carbonate. After filtration the organic solvent is removed in vacuo and the residue is destilled.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][O:11][C:10]2=[O:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].I[CH3:18].[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:18])[CH2:13][CH2:12][O:11][C:10]2=[O:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CI
Reactant: O=C1OCCC1c1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(c2ccc(Cl)c(Cl)c2)CCOC1=O
Temperature: 25 °C
Reaction time: 64 h
Yield: 81.6 %

Procedure:
A mixture of 18.5 g (80 mmol) 3-(3,4-dichloro-phenyl)-dihydro-furan-2-one, 3.84 g (88 mmol) NaH (55% suspension) and 14.2 g (100 mmol) iodomethane in 300 mL THF was stirred for 64 h at room temperature. NH4Cl aq. sat. was added and the mixture was extracted with ethyl acetate. The organic phases were washed with NaCl aq. sat. dried with Na2SO4, filtered and evaporated to dryness. The residue was purified by flash column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane. The product containing fractions were evaporated to yield 16 g (82%) of the title compound as yellow oil. MS(m/e): 246.0 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:10][OH:11])([C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:4][SH:5].CO[C:14](OC)(OC)[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1>>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]23[S:5][CH2:4][C:3]([C:6]([CH3:7])([CH3:8])[CH3:9])([CH2:10][O:11]2)[CH2:2][O:1]3)=[CH:16][CH:17]=1
Reactant: CC(C)(C)C(CO)(CO)CS
Reactant: COC(OC)(OC)c1ccc(Br)cc1
Product: CC(C)(C)C12COC(c3ccc(Br)cc3)(OC1)SC2

Procedure:
From 2,2-di-hydroxymethyl-3,3-dimethyl-butan-1-thiol and trimethyl 4-bromo-orthobenzoate, trimethyl 4-chloro-orthobenzoate, trimethyl orthocyclohexylcarboxylate and trimethyl ortho-cycloheptylcarboxylate in the manner described previously, the following compounds were prepared:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Mg].[Cl:11][C:12]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=1[CH:14]=[O:15].Cl>CCOCC.O1CCCC1>[Cl:11][C:12]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=1[CH:14]([OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: COc1ccccc1Br
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccccc1C(O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C

Procedure:
A solution of 2-bromoanisole (50.0 g, 0.267 mol) in ether is added portionwise to a mixture of magnesium (7.10 g, 0.293 mol) in ether. After the addition is complete, the reaction mixture is heated at reflux for one hour, diluted with ether, cooled to 0° C., treated with a solution of 2-chloro-5-nitrobenzaldehyde (39.0 g, 0.210 mol) in tetrahydrofuran, warmed to room temperature, and diluted with an ice-water mixture. After acidifying the aqueous mixture with hydrochloric acid (pH2-pH3), the organic phase is separated and the aqueous phase is extracted with ether. The organic extracts are combined, washed sequentially with 10% sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a brown gum.
Reaction SMILES: ClC(Cl)C.[NH2:5][N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1.C([C@@H]1COC(=O)N1[C:26](=[O:48])[C@H:27]([CH2:31][C:32]1[C:37]([Cl:38])=[CH:36][C:35]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:34][C:33]=1[Cl:47])[CH2:28][CH:29]=O)C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:40]([O:39][C:35]1[CH:34]=[C:33]([Cl:47])[C:32]([CH2:31][C@@H:27]2[CH2:28][CH2:29][N:5]([N:6]3[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]3)[C:26]2=[O:48])=[C:37]([Cl:38])[CH:36]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: NN1CCC(O)CC1
Reactant: O=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1N1CCC(O)CC1
Yield: 87.2 %

Procedure:
Stir a mixture of dichloroethane (500 mL), N-amino-4-hydroxypiperidine (10.66 g, 91.88 mmol), (R)-4-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde (40.2 g, 76.57 mmol) and sodium triacetoxyborohydride (48.47 g, 229.71 mmol) at room temperature for 21 hours. Bring the reaction to 55° C. and is stir for 1 hour. Cool the reaction, dilute with dichloromethane, and wash with water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica with a 100% ethyl acetate and 10% methanol in methylene chloride to afford 30 g (90%) of the titled product. MS (m/z): 449 (M+).
Reaction SMILES: COC1C=CC(CC2C=CC(OC)=CC=2)=C(C=1)OC1C=CC(O)=CC=1.Cl.ClCCN1CCCCC1.C[O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:60][C:61]2[CH:66]=[CH:65][C:64]([O:67]C)=[CH:63][CH:62]=2)=[C:42]([CH:59]=1)[O:43][C:44]1[CH:58]=[CH:57][C:47]([O:48][CH2:49][CH2:50][N:51]2[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)=[CH:46][CH:45]=1>>[OH:67][C:64]1[CH:65]=[CH:66][C:61]([CH2:60][C:41]2[CH:40]=[CH:39][C:38]([OH:37])=[CH:59][C:42]=2[O:43][C:44]2[CH:58]=[CH:57][C:47]([O:48][CH2:49][CH2:50][N:51]3[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]3)=[CH:46][CH:45]=2)=[CH:62][CH:63]=1
Reactant: COc1ccc(Cc2ccc(OC)cc2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Agent: COc1ccc(Cc2ccc(OC)cc2Oc2ccc(O)cc2)cc1
Agent: Cl
Agent: ClCCN1CCCCC1
Product: Oc1ccc(Cc2ccc(O)cc2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Yield: 28.2 %

Procedure:
Synthesized from 4-[5-methoxy-2-(4-methoxybenzyl)phenoxy]phenol and 1-(2-chloroethyl)piperidine hydrochloride according to an analogous synthetic method to Preparation Example 40, 1-{2-{4-[5-methoxy-2-(4-methoxybenzyl)phenoxy]phenoxy}ethyl}piperidine (223 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (59 mg).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][C:13]2[O:12][CH2:11][O:10][C:9]=2[CH:8]=1)(=[O:3])[CH3:2].C=O.Cl.C(Cl)[CH2:20][Cl:21]>>[Cl:21][CH2:20][C:15]1[C:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[CH:8][C:9]2[O:10][CH2:11][O:12][C:13]=2[CH:14]=1
Reactant: ClCCCl
Reactant: CC(=O)NCCc1ccc2c(c1)OCO2
Agent: C=O
Agent: Cl
Product: CC(=O)NCCc1cc2c(cc1CCl)OCO2
Temperature: 0 °C

Procedure:
In a 100 ml round-bottom flask provided with a stirrer, thermometer, gas inlet tube, and a condenser were placed 4.12 g of N-acetyl-homopiperonylamine (0.02 mole), 2.1 g of 37% formaldehyde solution, and 50 ml of ethylene chloride. The mixture was cooled to 3° and hydrogen chloride passed into the stirred mixture. After about 15 minutes a thick paste of crystals had formed. At this point, another 2.1 g of 37% formaldehyde was added and the mixture allowed to stir until all the solid had dissolved. The solution was then poured into ice water and the lower ethylene chloride layer separated, washed three times with water, then dried. The clear ethylene chloride solution was freed of solvent in the rotary evaporator, leaving the above-named product as a crystalline solid. After recrystallization from acetone, the solid melted at 116.5°-122°.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.CN1C(=O)N(C)CCC1.[CH2:18]([O:20][C:21](=[O:33])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)[CH3:19].[O:34]1[CH2:39][CH2:38][CH:37]([CH:40]=O)[CH2:36][CH2:35]1>CCCCCCC.C1COCC1.C1(CC)C=CC=CC=1.C1COCC1>[CH3:32][S:29]([C:26]1[CH:27]=[CH:28][C:23](/[C:22](=[CH:40]\[CH:37]2[CH2:38][CH2:39][O:34][CH2:35][CH2:36]2)/[C:21]([O:20][CH2:18][CH3:19])=[O:33])=[CH:24][CH:25]=1)(=[O:31])=[O:30]
Reactant: O=CC1CCOCC1
Reactant: CCOC(=O)Cc1ccc(S(C)(=O)=O)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: CCOC(=O)/C(=C/C1CCOCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
LDA (24 mL of a 1.8M solution in n-C7H16-THF-PhEt, 43.3 mmol) was added dropwise to a stirred solution of DMPU (19 mL, 153.0 mmol) in anhydrous THF (100 mL) at −78° C. After 30 min, a solution of ethyl(4-methanesulfonylphenyl)acetate (Preparation 15, 5.00 g, 20.6 mmol) in anhydrous THF (42 mL) was added dropwise. The mixture was stirred further for 1 h, before being treated dropwise with a solution of tetrahydropyran-4-carboxaldehyde (2.36 g, 20.6 mmol) in anhydrous THF (25 mL). After being allowed to warm up to 20° C. over 16 h, the reaction was quenched with saturated aqueous NH4Cl (210 mL). The THF was removed under reduced pressure, then the remainder was extracted with EtOAc (3×250 mL). The combined EtOAc extracts were dried (MgSO4), filtered, and concentrated. Column chromatography (IH-EtOAc, 7:3) furnished (E)-ethyl 2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)acrylate: m/z (ES+)=356.2 [M+NH4]+. A solution of this ester (6.46 g, 19.1 mmol) in MeOH (30 mL) and 1M NaOH (40 mL, 40.0 mmol) was heated under reflux for 1 h. On cooling, the mixture was washed with EtOAc. The aqueous phase was acidified with 1M HCl, before being extracted with EtOAc. The combined organic extracts were dried (MgSO4). Filtration and solvent evaporation afforded the title compound: m/z (ES+)=621.3 [2M+H]+.
Reaction SMILES: [Br:1][C:2]1[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[C:11](O)=[O:12]>O1CCCC1>[Br:1][C:2]1[S:6][N:5]=[C:4]([C:7]([F:9])([F:10])[F:8])[C:3]=1[CH2:11][OH:12]
Reactant: O=C(O)c1c(C(F)(F)F)nsc1Br
Solvent: C1CCOC1
Product: OCc1c(C(F)(F)F)nsc1Br
Temperature: 0 °C

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 5-bromo-3-(trifluoromethyl)-1,2-thiazole-4-carboxylic acid (800 mg, 2.90 mmol, 1.00 equiv), tetrahydrofuran (3 mL). This was followed by the addition of BH3 (14.5 mL, 5.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred overnight at 25° C. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:5). The reaction was then quenched by the addition of 20 mL of methanol. The reaction mixture was heated to reflux for 1 h. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 200 mg (25%) of [5-bromo-3-(trifluoromethyl)-1,2-thiazol-4-yl]methanol as yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][C:18]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:38]=3)[CH:33]=[C:32]2C(OCC)=O)([CH2:21][NH:22][C:23]([O:25]C(C)(C)C)=O)[CH2:17][CH2:16]1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[O:25]=[C:23]1[C:32]2=[CH:33][C:34]3[CH:35]=[CH:36][C:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][C:39]=3[N:31]2[CH2:30][C:18]2([CH2:17][CH2:16][NH:15][CH2:20][CH2:19]2)[CH2:21][NH:22]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC3(CNC(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)CC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2cc3n(c2c1)CC1(CCNCC1)CNC3=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.6 %

Procedure:
Trifluoroacetic acid (13.4 mL, 173.8 mmol) is added dropwise to the solution of diethyl 1-{[1-(tert-butoxycarbonyl)-4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-4-yl]methyl}-1H-indole-2,6-dicarboxylate (17 g, 29.0 mmol) in CH2Cl2 (200 mL) at 0° C. The reaction mixture is stirred for 3 h at room temperature and then is basified with aqueous K2CO3 solution until the pH is 8. The aqueous layer is separated and extracted with CH2Cl2 (2×250 mL). The organic layers are combined, washed with brine, dried (Na2SO4) and concentrated. The crude material is recrystallized using diethyl ether to afford the title compound (6 g, 61%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([O:36][CH:37]2[CH2:42][CH2:41][N:40]([C:43]3([CH3:47])[CH2:46][O:45][CH2:44]3)[CH2:39][CH2:38]2)[C:34]=1[Cl:35])[C:30]#[N:31].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:35][C:34]1[C:33]([O:36][CH:37]2[CH2:42][CH2:41][N:40]([C:43]3([CH3:47])[CH2:44][O:45][CH2:46]3)[CH2:39][CH2:38]2)=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=1[NH:26][C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:19][CH2:20]2)[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1
Reactant: CC1(N2CCC(Oc3cc(C#N)cc(N)c3Cl)CC2)COC1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(OC4CCN(C5(C)COC5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 80 °C
Yield: 40.8 %

Procedure:
A mixture of 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 9) (47.4 mg, 0.134 mmol), 3-amino-4-chloro-5-((1-(3-methyloxetan-3-yl)piperidin-4-yl)oxy)benzonitrile (43 mg, 0.134 mmol), palladium(II) acetate (7.95 mg, 0.035 mmol), xantphos (7.73 mg, 0.013 mmol), DPPF (7.41 mg, 0.013 mmol) and cesium carbonate (113 mg, 0.347 mmol) in dioxane (2 ml) was evacuated and back filled with nitrogen three time and was heated at 80° C. for 6 h. The reaction mixture was filtered through a pad of celite, the filtrate was concentrated and the crude was purified by prep-HPLC. 2-((2-chloro-5-cyano-3-((1-(3-methyloxetan-3-yl)piperidin-4-yl)oxy)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (35 mg) was obtained.
Reaction SMILES: [ClH:1].CC([N:6]([CH:10]1[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][CH2:11]1)C(=O)[O-])(C)C>O1CCOCC1>[ClH:1].[F:16][C:13]1([F:17])[CH2:14][CH2:15][CH:10]([NH2:6])[CH2:11][CH2:12]1
Reactant: CC(C)(C)N(C(=O)[O-])C1CCC(F)(F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCC(F)(F)CC1
Reaction time: 3 h

Procedure:
A solution of hydrogen chloride in dioxane (4M, 1.6 ml) was added at 20° C. to a stirred solution of Intermediate 146 (140 mg, 0.6 mmol), in dioxane (1.6 ml). After 3 h, the reaction mixture was concentrated in vacuo to afford Intermediate 147 (96.5 mg) containing 4-fluoro-3-cyclohexen-1-amine. 1H NMR (400 MHz in d6-DMSO, 27° C., δ ppm) Minor component: δ8.22 (br, 3H excess), 5.18 (dm, 16 Hz, 1H), 3.28-3.13 (m, 1H excess), 2.41-1.53 (m's, 6H excess). Major component: δ8.22 (br, 3H excess), 3.28-3.13 (m, 1H excess), 2.41-1.53 (m's, 8H excess). Impurities are also present.
Reaction SMILES: Cl.C([O:4][C:5](=O)[C@@H:6]([CH2:24][CH2:25][S:26][CH3:27])[NH:7][C:8](=[O:23])[C@H:9]([NH2:22])[C@@H:10]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[CH3:11])C.N>C(O)C>[CH3:27][S:26][CH2:25][CH2:24][C@H:6]1[NH:7][C:8](=[O:23])[C@@H:9]([C@@H:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[CH3:11])[NH:22][C:5]1=[O:4]
Reactant: CCOC(=O)[C@@H](CCSC)NC(=O)[C@H](N)[C@H](C)c1cccc2ccccc12
Agent: Cl
Agent: N
Solvent: CCO
Product: CSCC[C@H]1NC(=O)[C@@H]([C@H](C)c2cccc3ccccc23)NC1=O
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a solution of hydrochloric acid salt of N-[(2R,3R)-2-amino-3-(1-naphthyl)butyryl]-D-methionine ethyl ester (1.60 g) in ethanol (30 ml) was added a saturated solution of ammonia in ethanol (30 ml) and the mixture was set aside overnight at ambient temperature, and precipitated mass was collected, washed with ethanol, and dried to give (3R,6R)-3-(2-methylthioethyl)-6-[(R)-1-(1-naphthyl)ethyl]piperazine-2,5-dione (0.68 g).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[C:11]([OH:22])[CH:12]=[CH:13][C:14]=3[NH:18]C(=O)[O-])[C:9]2=[O:23])[CH2:6][CH2:5][C:4](=[O:24])[NH:3]1.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[NH2:18][C:14]1[CH:13]=[CH:12][C:11]([OH:22])=[C:10]2[C:15]=1[C:16](=[O:17])[N:8]([CH:7]1[CH2:6][CH2:5][C:4](=[O:24])[NH:3][C:2]1=[O:1])[C:9]2=[O:23]
Reactant: O=C([O-])Nc1ccc(O)c2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Nc1ccc(O)c2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 2-(2,6-dioxopiperidin-3-yl)-7-hydroxy-1,3-dioxoisoindolin-4-ylcarbamate C3-4 (6.73 g, 17.2 mmol) in DCM (200 mL) was added TFA (20 mL) slowly. The mixture was stirred at room temperature overnight. Water (20 mL) was added to quench the reaction. The mixture was extracted with EA (100 mL×3). The combined organic layers were collected and dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, DCM:MeOH:PE) to give 4-amino-2-(2,6-dioxopiperidin-3-yl)-7-hydroxyisoindoline-1,3-dione 3 as a yellow solid (4.05 g, yield: 81%). 1H NMR (DMSOd6, 400 MHz) δ: 1.95-1.98 (m, 1H), 2.52-2.58 (m, 2H), 2.83-2.92 (m, 1H), 4.98 (dd, J=12.6, 5.4 Hz, 1H), 6.06 (s, 2H), 6.95 (d, J=8.8 Hz, 1H), 7.06 (d, J=9.2 Hz, 1H), 10.17 (s, 1H), 11.05 (s, 1H); MS (ESI+): m/z 290 (M+1); Elem. Anal. Calcd. for C13H11N3O5: C, 53.98; H, 3.83; N, 14.53. Found C, 53.96; H, 3.74; N, 14.45.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:5]=[C:4]([N+:19]([O-])=O)[CH:3]=1>C(O)(=O)C.[Fe]>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[CH:12]=[CH:11][N:10]=2)[CH:5]=[C:4]([NH2:19])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)nc(Nc2cc(C(F)(F)F)ccn2)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cc(Br)nc(Nc2cc(C(F)(F)F)ccn2)c1
Temperature: 50 °C

Procedure:
A suspension of 6-bromo-4-nitro-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine (586 mg, 1.614 mmol) and iron (361 mg, 6.46 mmol) in acetic acid (7 mL) was heated to 50° C. for 1 hour. The reaction mixture was partitioned between ethyl acetate (70 mL) and water (70 mL). The aqueous layer was further extracted with ethyl acetate (70 mL), and the combined organic layers were washed with water (70 mL), saturated aqueous sodium bicarbonate solution (2×70 mL), brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (10-60% ethyl acetate/hexanes) to afford 6-bromo-N2-[4-(trifluoromethyl)pyridin-2-yl]pyridine-2,4-diamine. MS ESI calcd. for C11H9BrF3N4 [M+H]+ 333 and 335. found 333 and 335. 1H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.63 (s, 1H), 8.59 (d, J=5.4 Hz, 1H), 7.85 (s, 1H), 7.83-7.76 (m, 2H), 7.48-7.42 (m, 1H), 7.37-7.32 (m, 1H).