Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:35])=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:19]1[C:20]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18])[CH:10]=2)=[O:5])C.CO.O.O.[OH-].[Li+]>O1CCCC1>[CH3:35][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:15][C:14]2[C:9](=[CH:10][C:11]([NH:16][C:17]([C:19]3[C:20]([C:25]4[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:29][CH:30]=4)=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:18])=[CH:12][CH:13]=2)[N:8]=1
Reactant: CCOC(=O)c1cc2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2cc1C(=O)O
Reaction time: 3 h
Yield: 100.5 %

Procedure:
2-Methyl-7-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid ethyl ester (345 mg, 0.72 mmol) was dissolved in 3 ml of tetrahydrofuran, 1 ml of methanol and 1 ml of water, and lithium hydroxide monohydrate was added (61 mg, 1.44 mmol). After 3 h at room temperature, the volatiles were evaporated and the resulting mixture diluted with 10 ml of water before being brought to pH 1 with 1N HCl. Filtration of the resulting solid followed by air drying afforded 326 mg of the title compound as a yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[H-].[Na+].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>CS(C)=O.C(OCC)(=O)C.[NH4+].[Cl-]>[CH3:14][S:15]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1c[nH]c2ccccc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)n1cc(C=O)c2ccccc21
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a solution of 1H-indole-3-carboxaldehyde (300 mg, 2.07 mmol) in 4.1 mL of dry dimethylsulfoxide was added sodium hydride (108 mg, 55%, 2.5 mmol) under nitrogen at 0° C. After the reaction mixture was stirred for 30 min, methylsulfonyl chloride (0.19 mL, 2.5 mmol) was added with additional stirring for 1 h. The reaction mixture was diluted with 10 mL of ethyl acetate and 10 mL of saturated NH4Cl aqueous solution at 0° C., successively, and the solution was extracted with 100 mL of ethyl acetate. The extract was washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the solution was concentrated in vacuo. The residue was purified by recrystallization (chloroform/hexane) to obtain the title compound as a pale red solid (300 mg, 65%).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:3]=1.FC(F)(F)C(O)=O.[NH2:26][C:27]1[N:28]=[C:29]([NH:34][CH2:35][CH2:36][NH2:37])[S:30][C:31]=1[C:32]#[N:33].CCN(C(C)C)C(C)C.Cl>O.CS(C)=O>[NH2:26][C:27]1[N:28]=[C:29]([NH:34][CH2:35][CH2:36][NH:37][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[N:3]=2)[S:30][C:31]=1[C:32]#[N:33]
Reactant: N#Cc1sc(NCCN)nc1N
Reactant: Clc1ccc(-c2cc3nccn3c(Cl)n2)c(Cl)c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1sc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nccn23)nc1N
Temperature: 120 °C

Procedure:
214.27 mg (0.72 mmol) of chloropyrimidine (Example 6A) are introduced into 28 ml of dry DMSO, 320 mg (1.08 mmol) of 4-amino-2-[(2-aminoethyl)amino]-1,3-thiazole-5-carbonitrile trifluoroacetate (Example 20A) and 742 mg (5.74 mmol) of DIPEA are added, and the mixture is heated at 120° C. under argon for 16 h. Water is added, and the mixture is neutralized with 1N hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases are freed of solvent, and the residue is purified by preparative HPLC. 48.4 mg (14% of theory) of the product are obtained as a solid.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH:19]([CH2:25][N+:26]([O-])=O)[CH2:20][C:21](OC)=[O:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+]>CO>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH:19]2[CH2:25][NH:26][C:21](=[O:22])[CH2:20]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)CC(C[N+](=O)[O-])c1ccc(OC)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(C2CNC(=O)C2)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a mixture of 8.3 g (34.8 mmol) of NiCl2-6H2O in 750 mL of MeOH was slowly added 14 g (104.5 mmol) of NaBH4. This mixture was stirred for 30 minutes at 0° C. and a solution of 25 g of methyl 3-(3-benzyloxy-4-methoxyphenyl)-4-nitrobutanoate in 500 mL of MeOH was added. Then, 8.3 g (34.8 mmol) of NiCl2-6H2O was added to the reaction mixture, followed by the slow portion-wise addition of 9.2 g (243 mmol) of NaBH4. The mixture stirred at 0° C. for 1 hour and then 150 g of K2CO3 was added in one portion. The mixture was allowed to warm to ambient temperature and stirring continued for 18 hours. The suspension was filtered through a pad of celite, washed with 2×1000 mL of MeOH and concentrated. The residue was taken up in 2000 mL of EtOAc and the organic fraction was successively washed with 200 mL of H2O, 250 mL of brine, dried (Na2SO4) and concentrated to a solid. Trituration with hexanes/EtOAc provided 13 g of the desired product. An additional 2.3 g of product was obtained by extracting the aqueous fractions with EtOAc and combining this with the trituration solvent, concentrating and triturating with EtOAc/hexanes. Total yield was 15.3 g (74% yield). 1H NMR (400 MHz, CDCl3) δ 7.44-7.26 (m, 5H), 6.87-6.70 (m, 3H), 5.75 (bs, 1H), 5.14 (s, 2H), 3.87 (s, 3H), 3.70-3.50 (m, 2H), 3.28 (t, 1H), 2.70-2.63 (m, 1H), 2.42-2.35 (m,1H).
Reaction SMILES: [C:1](#[N:3])[CH3:2].CC(C)(C)C[O-].[K+].C([O:13][C:14]([CH:16]1[CH2:18][CH:17]1[CH3:19])=O)C>C1COCC1>[CH3:19][CH:17]1[CH2:18][CH:16]1[C:14](=[O:13])[CH2:2][C:1]#[N:3]
Reactant: CCOC(=O)C1CC1C
Reactant: CC#N
Agent: CC(C)(C)C[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1CC1C(=O)CC#N
Reaction time: 0.08 h

Procedure:
Acetonitrile (0.102 mL, 1.95 mmol) was dissolved in THF. Potassium 2,2-dimethylpropan-1-olate (3.44 mL, 5.85 mmol) was added, followed by addition of ethyl-2-methylcyclopropanecarboxylate (1.0 g, 7.80 mmol). After five minutes, the reaction mixture was quenched with 1N HCl and then partitioned with EtOAc. The organic layer was washed with water (3×), brine, dried over Na2SO4 and concentrated to give 3-(2-methylcyclopropyl)-3-oxopropanenitrile as an oil, which was used in the next step without further purification.
Reaction SMILES: C([C:4]1([CH:8]([O:10][CH:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:22](=[O:23])[C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]5[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=5)=[CH:27][C:26]=4[F:39])=[C:20]([CH2:40][CH2:41][CH3:42])[N:19]4[N:43]=[CH:44][N:45]=[C:18]34)[CH2:13][CH2:12]2)[CH3:9])[CH2:7][CH2:6][CH2:5]1)(=O)C.OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:51].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:39][C:26]1[CH:27]=[C:28]([C:31]2[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:29]=[CH:30][C:25]=1[CH2:24][C:21]1[C:22](=[O:23])[N:17]([C@H:14]2[CH2:13][CH2:12][C@H:11]([O:10][CH:8]([C:4]3([OH:51])[CH2:7][CH2:6][CH2:5]3)[CH3:9])[CH2:16][CH2:15]2)[C:18]2[N:19]([N:43]=[CH:44][N:45]=2)[C:20]=1[CH2:40][CH2:41][CH3:42]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC(OC(C)C3(C(C)=O)CCC3)CC2)c2ncnn12
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: OO
Solvent: ClC(Cl)Cl
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C3(O)CCC3)CC2)c2ncnn12
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a mixture of 4′-[(4-{4-[1-(1-acetylcyclobutyl)ethoxy]cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl}-3′-fluorobiphenyl-2-carbonitrile (11 g), 30% hydrogen peroxide (157 mL) and chloroform (150 mL) was gradually added dropwise trifluoroacetic acid anhydride (105 mL), and the mixture was stirred at 60° C. for 24 hr and then at room temperature for 40 hr. Saturated aqueous sodium hydrogen carbonate solution and aqueous sodium thiosulfate solution were gradually added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was mixed with tetrahydrofuran (100 mL), methanol (100 mL) and 1 M aqueous sodium hydroxide solution (100 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid. After evaporation of the solvent under reduced pressure, the residue was extracted with ethyl acetate. The organic layer was washed with 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 to give the title compound as a colorless solid (1.3 g, 12%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14](C4CC5C(=CC=CC=5)C4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.S(C1C=CC(C)=CC=1)(OC1CC2C(=CC=CC=2)C1)(=O)=O>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CC(N1CCN(c3cccc4c3OCCO4)CC1)C2
Agent: Cc1ccc(S(=O)(=O)OC2Cc3ccccc3C2)cc1
Product: c1cc2c(c(N3CCNCC3)c1)OCCO2
Yield: 11 %

Procedure:
4-(benzodioxan-5-yl)-1-(indan-2-yl)-piperazine, m.p. (M.K): 168°-171° C., from indan-2-yl tosylate [cf. Bull. Soc. Chem. (1962), p. 51] and N-(benzodioxan-5-yl)piperazine (yield: 11%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:30]=[CH:29][C:15]([O:16][CH2:17][C:18]([N:20]2[C@@H:24]([CH:25]([CH3:27])[CH3:26])[CH2:23][O:22][C:21]2=[O:28])=[O:19])=[CH:14][C:13]=1[CH3:31].[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:40][CH2:41][CH:42]=[CH:43][CH2:44]I)=[CH:35][C:34]=1[CH3:46].[NH4+].[Cl-]>C1COCC1>[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:40][CH2:41][CH:42]=[CH:43][CH2:44][C@@H:17]([O:16][C:15]2[CH:29]=[CH:30][C:12]([F:11])=[C:13]([CH3:31])[CH:14]=2)[C:18]([N:20]2[C@@H:24]([CH:25]([CH3:26])[CH3:27])[CH2:23][O:22][C:21]2=[O:28])=[O:19])=[CH:35][C:34]=1[CH3:46]
Reactant: Cc1cc(OCC(=O)N2C(=O)OC[C@@H]2C(C)C)ccc1F
Reactant: Cc1cc(COCC=CCI)ccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(COCC=CC[C@@H](Oc2ccc(F)c(C)c2)C(=O)N2C(=O)OC[C@@H]2C(C)C)ccc1F
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
To the solution of lithium bis(trimethylsilyl)amide (1.9 mL, 1.29 mmol, 1M in THF) in anhydrous 30 mL THF at −70° C. was slowly added over 15 minutes (S)-3-(2-(4-fluoro-3-methylphenoxy)acetyl)-4-isopropyloxazolidin-2-one (480 mg, 1.6 mmol) as a solution in 4.0 mL THF. The reaction mixture was stirred for 30 min at −70° C. and then was slowly added a pre-cooled solution of 1-Fluoro-4-((4-iodobut-2-enyloxy)methyl)-2-methylbenzene (1.0 g, 3.2 mmol) in 4 mL of THF. The resulting mixture was stirred at −70° C. for 1 h and the temperature was slowly raised over a period of 2 h. The mixture was poured into 40 mL saturated NH4Cl and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine (2×30 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the product isolated by Flash column chromatography eluting with 0% to 50% ethyl acetate/hexane to give 430 mg of the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]3[CH2:17][CH2:16]3)=[C:10]([N+:18]([O-])=O)[CH:9]=2)=[N:6][NH:5][C:4](=[O:21])[CH2:3]1.C(O)C.[H][H]>[Pd].C(O)(=O)C>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]3[CH2:16][CH2:17]3)=[C:10]([NH2:18])[CH:9]=2)=[N:6][NH:5][C:4](=[O:21])[CH2:3]1
Reactant: CC1CC(=O)NN=C1c1ccc(NC2CC2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc(NC2CC2)c(N)c1

Procedure:
5.8 gm of 5-methyl-6-(3-nitro-4-cyclopropylamino-phenyl)-3-oxo-4,5-dihydro-2H-pyridazine were hydrogenated in a mixture consisting of 100 ml of ethanol and of 20 ml of glacial acetic acid in the presence of 0.5 gm of 10% palladium charcoal at a hydrogen pressure of 5 bar. 120 ml of glacial acetic acid were added, the catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was reacted further without further purification.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C(N(CC)CC)C>[C:9]1([C:15]#[C:16][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccc(I)cc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Nc1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C

Procedure:
More particularly, 4-iodoaniline (17.38 g), phenyl acetylene (10.4 g), and triphenyl phosphine (193 mg) are added to a three-necked 500 mL flask, which is fitted with a reflux condenser, nitrogen blanket, and an overhead mechanical stirrer. Bis(triphenylphosphine)-palladium(II)dichloride (“Pd(PPH3)2Cl2]”) (94 mg) and CuI (38 mg) are then added with 100 mL of triethylamine (“Et3N”). The flask is maintained at room temperature overnight under a nitrogen atmosphere. Afterwards, the reaction mixture is cooled and filtered to remove the precipitate. The precipitate is washed with methylene chloride and the soluble portions are recombined with the filtrate. The solvent is then evaporated to yield 4-phenylethynyl aniline (“Compound E”) as a yellowish solid. Further purification, typically involves repeated re-crystallization from hexanes to give the final product as a pale yellow colored solid.
Reaction SMILES: Cl.[C:2]1([C:8]2[O:12][N:11]=[C:10]([CH:13]3[O:18][CH2:17][CH2:16][NH:15][CH2:14]3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1C=CC([C@H]2CO2)=CC=1.[CH3:29][N:30]1[C:35](=[O:36])[CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][N:38]=2)[N:32]=[C:31]1N1CCOC(C2ON=C(C3C=CC=CC=3)N=2)C1.C(N(CC)CC)C>O1CCCC1>[CH3:29][N:30]1[C:35](=[O:36])[CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][N:38]=2)[N:32]=[C:31]1[N:15]1[CH2:16][CH2:17][O:18][CH:13]([C:10]2[N:9]=[C:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[O:12][N:11]=2)[CH2:14]1
Reactant: Cn1c(N2CCOC(c3nc(-c4ccccc4)no3)C2)nc(-c2ccncn2)cc1=O
Reactant: c1ccc(-c2nc(C3CNCCO3)no2)cc1
Agent: Brc1ccc([C@H]2CO2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCOC(c3noc(-c4ccccc4)n3)C2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A solution of the resulting 2-(5-phenyl-[1,2,4]oxadiazol-3-yl)-morpholine hydrochloride (intermediate 10 in tetrahydrofuran (6.0 ml) was added with 2-chloro-3-methyl-6-(pyrimidine-4-yl)pyrimidin-4-one (intermediate 1, 260 mg, 2.34 mmol) and triethylamine (1.81 ml, 13.0 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The solution was partitioned between water and chloroform, and the organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (eluent; 5% methanol in chloroform) to afford 1-methyl-2-[2-(5-phenyl-[1,2,4]oxadiazol-3-yl)-morpholin-4-yl]-1H-[4,4′]bipyrimidinyl-6-one (compound 2 in Table 1, 749 mg, 64%, 2 steps) as solid
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11]C)[CH:8]=[CH:7][C:6]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[BrH:21]>>[BrH:21].[F:20][C:2]([F:1])([F:19])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[N:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1
Reactant: COc1ccc(N2CCNCC2)c(OCC(F)(F)F)c1
Agent: Br
Product: Oc1ccc(N2CCNCC2)c(OCC(F)(F)F)c1
Temperature: 0 °C

Procedure:
A mixture of 1-[2-(2,2,2-trifluoroethoxy)-4-methoxyphenyl]piperazine (1.87 g, 6.4 mmol) and 48% aqueous hydrobromic acid (5 mL) was heated 17 hours at reflux. The reaction mixture was allowed lo cool and then concentrated in vacuo. The residue was dissolved in ethanol (10 mL) at approximately 55° C. and the solution was cooled to 0° C. The solids were collected, washed with cold ethanol (3×10 mL) and dried in vacuo at approximately 80° C. to give 1-[2-(2,2,2-trifluoroethoxy)-4-hydroxyphenyl]piperazine hydrobromide, m.p. 190-194. Anal.: Calcd. for C12H14F3N2O2.(HBr)0.5. H2O: C, 43.00; H, 5.27; N, 8.37%; Found: C, 43.41; H, 4.97; N, 8.36%.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:5]([CH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:16]1)[C:6]1[C:7]([CH:12]=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:4]>CCO.O>[CH2:3]([N:5]([CH2:14][C@H:15]1[CH2:16][CH2:17][C@H:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][CH2:20]1)[C:6]1[C:7]([CH2:12][OH:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:4]
Reactant: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2cccnc2C=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2cccnc2CO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (62.3 mg, 1.65 mmol) was added to a stirred solution of ethyl (trans-4-{[ethyl(2-formylpyridin-3-yl)amino]methyl}cyclohexyl)acetate (136.9 mg, 0.412 mmol) in EtOH (10 mL) at room temperature. The reaction was stirred at room temperature for 1 h, then diluted with water and most of the EtOH was removed in vacuo. The resulting aqueous slurry was extracted with EtOAc (3×20 mL) and the combined extracts were washed with brine (5 mL), dried (Na2SO4) and concentrated in vacuo to afford ethyl [trans-4-({ethyl[2-(hydroxymethyl)pyridin-3-yl]amino}methyl)cyclohexyl]acetate. LCMS calc.=335.2; found=335.3 (M+1)+.
Reaction SMILES: C([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:11][C@H:10]1[OH:26])C1C=CC=CC=1.[ClH:27]>C(O)C.[Pd]>[ClH:27].[NH2:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:11][C@H:10]1[OH:26]
Reactant: CCOC(=O)COc1cccc2c1C[C@@H](NCc1ccccc1)[C@H](O)C2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)COc1cccc2c1C[C@@H](N)[C@H](O)C2
Reaction time: 24 h

Procedure:
To a solution of trans 3-benzylamino-5-carboethoxymethoxy-2-hydroxy-1,2,3,4-tetrahydronaphthalene (10 g) in 95% aqueous ethanol (200 mL) was added dropwise concentrated aqueous hydrochloric acid solution to bring the pH to 6. Addition of 5% palladium on carbon was followed by hydrogenation on a Parr apparatus at 50 psi for 1 day. The mixture was filtered, rinsing the catalyst with 95% aqueous ethanol and methanol. The filtrate was evaporated to yield a residue. The residue was recrystallized from a mixture of methanol and absolute ethanol to provide the title product (5.2 g, m.p. 210-211° C.).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:27])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C@H:23]([CH3:26])[CH2:24][OH:25])[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:30][C@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]1[C:37]1[N:41]2[CH:42]=[C:43]([O:46][C@H:47]3[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C@@H:50]([NH2:57])[CH2:49][CH2:48]3)[CH:44]=[CH:45][C:40]2=[N:39][N:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:57][C@@H:50]2[C:51]3[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=3)[C@H:47]([O:46][C:43]3[CH:44]=[CH:45][C:40]4[N:41]([C:37]([N:32]5[CH2:33][CH2:34][CH2:35][CH2:36][C@@H:31]5[CH3:30])=[N:38][N:39]=4)[CH:42]=3)[CH2:48][CH2:49]2)=[O:27])[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C@H:23]([CH3:26])[CH2:24][OH:25])[CH:17]=2)[N:9]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: C[C@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)c1
Temperature: 70 °C
Reaction time: 7.5 h
Yield: 60.6 %

Procedure:
A solution of Intermediate 151c (102 mg, 0.22 mmol) in 1,4-dioxane (2.0 mL) was treated with Intermediate 81d (75 mg, 0.20 mmol) and DIPEA (0.043 mL, 0.25 mmol) and the mixture was stirred at 70° C. for 7.5 h then at 50° C. for 64 h. The cooled solution was concentrated in vacuo, and the residue was partitioned between DCM and water. The phases were separated and the aqueous layer was extracted with DCM (×2). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo to a brown gum. The gum was purified by FCC, using 0-10% MeOH in DCM to give the title compound as a yellow glass (84 mg, 61%). LCMS (Method 3): Rt 3.75 min, m/z 693.5 [MH+].
Reaction SMILES: [Li][CH2:2]CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[C:21]([Cl:24])[CH:20]=[CH:19]2.CI>C1COCC1.O>[Br:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[C:21]([Cl:24])[C:20]([CH3:2])=[CH:19]2
Reactant: Clc1ccc2cccc(Br)c2n1
Reactant: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cc2cccc(Br)c2nc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 65.4 %

Procedure:
nBuLi (1.86 M in hexanes; 6.10 mL, 11.34 mmol) was added to a solution of diisopropylamine (1.600 mL, 11.34 mmol) in THF (20 mL) at 78° C., and the resulting solution was warmed to 0° C., stirred for 5 min, then cooled to 78° C. After 5 min, a solution of 8-bromo-2-chloroquinoline (Biofine International, Vancouver, BC; 2.5 g, 10.31 mmol) in THF (20.0 mL) was added (dropwise over 10 min) The resulting solution was stirred at 78° C. for 50 min and added (dropwise over 10 min) to a solution of MeI (1.925 mL, 30.9 mmol) in THF (20.0 mL) at 78° C. The resulting solution was stirred at 78° C. for 1 h. The mixture was then transferred to an ice bath, and water (1 mL) was added. The resulting mixture was warmed to RT and concentrated onto silica gel. Chromatographic purification (silica gel, 0-25% EtOAc/hexanes) furnished 8-bromo-2-chloro-3-methylquinoline (104b; 1.73 g, 6.74 mmol, 65% yield) as a light-yellow solid (64% pure), which was used without further purification in the subsequent step: m/z (ESI, +ve) 255.9 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][CH2:28][OH:29]>CN(C)C=O.C(OCC)(=O)C.O.[Cl-].[Cs+]>[C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:26][CH2:27][CH2:28][OH:29])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCc1ccccc1O)C(=O)OC(C)(C)C
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCc1ccccc1OCCCO)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 16 h
Yield: 70.2 %

Procedure:
N-(2-(2-Hydroxyphenyl)ethyl)-N-methylcarbamic acid tert-butyl ester (702 mg, 2.79 mmol) was dissolved in N,N-dimethylformamide (6 ml). Potassium carbonate (1.93 g, 13.97 mmol) and cesium chloride (24 mg, 0.14 mmol) were added. 3-bromo-1-propanol (0.28 ml, 3.07 mmol) was added. The reaction mixture was stirred at 80° C. for 16 h. It was cooled to room temperature and diluted with ethyl acetate (75 ml) and water (75 ml). The phases were separated. The aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with a 10% aqueous solution of sodium hydrogen sulfate solution (70 ml) and a saturated aqueous solution of sodium hydrogen carbonate (70 ml). They were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using ethyl acetate/heptane (1:1) as eluent, to give 606 mg of {2-[2-(3-hydroxypropoxy)phenyl]ethyl}-N-methylcarbamic acid tert-butyl ester.