Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[CH2:5][N:6]([CH3:28])[C:7](=[O:27])[C@@H:8]([N:16]([CH2:24][CH:25]=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([CH2:43][C@H:44]([NH2:49])[CH2:45][C:46]([OH:48])=[O:47])=[CH:35]1>>[CH3:1][O:2][C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[CH2:5][N:6]([CH3:28])[C:7](=[O:27])[C@@H:8]([N:16]([CH2:24][CH2:25][NH:49][C@H:44]([CH2:45][C:46]([OH:48])=[O:47])[CH2:43][C:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[NH:34][CH:35]=1)[C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N[C@H](CC(=O)O)Cc1c[nH]c2ccccc12
Reactant: COc1ccccc1CN(C)C(=O)[C@H](Cc1ccccc1)N(CC=O)C(=O)OC(C)(C)C
Agent: Cl
Product: COc1ccccc1CN(C)C(=O)[C@H](Cc1ccccc1)N(CCN[C@H](CC(=O)O)Cc1c[nH]c2ccccc12)C(=O)OC(C)(C)C

Procedure:
Prepare by the method of Example 1 using (S)-N-(2-methoxybenzyl)-N-methyl-2-[N'-(t-butoxycarbonyl)-2-oxo-ethylamino]-3-phenyl-propionamide (0.71 g, 1.6 mmol) and (S)-2-(1H-indol-3-yl)-1-carboxymethyl-ethylamine hydrochloride salt ((S)-tryptophan methyl ester hydrochloride salt) (0.45 g, 1.76 mmol). Purify by chromatography eluting with 50% ethyl acetate/hexane to give the title compound: TLC Rf =0.56 (silica gel, 50% ethyl acetate/hexane)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[CH2:10]([OH:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[Na]>CS(C)=O>[OH-:9].[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:18][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N+:3]=1[O-:9]
Reactant: CCCCCCCCO
Reactant: [O-][n+]1c(Cl)cccc1Cl
Agent: [Na]
Solvent: CS(C)=O
Product: CCCCCCCCOc1cccc(Cl)[n+]1[O-]
Product: [OH-]

Procedure:
The 0.82 g (0.0050 moles) of 2,6-dichloropyridine N-oxide and 0.658 g (99%) (0.0050 moles) of 1-octanol was reacted with 0.200 g (0.0050 moles) of ground sodium. hydroxide in 8.2 ml of DMSO at 80° C. for 4.5 hours to give 2-chloro-6-octyloxypyridine N-oxide. It was reacted with 0.600 g (0.015 moles) of ground sodium hydroxide at 80° C. for 2.5 hours to give 1-hydroxy-6-octyoxypyridine-2(1H)-one. After cooling, it was added 74 ml of water and was adjusted with 6N HCL to pH 3. The precipitate was filtered and washed with water to give 0.577 g (48%). It was recrystallized from ethanol and hexanes: mp 119°-120° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][C:5]=1[NH:11][CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)([O-])=O.[CH:25](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH:15]1[CH2:14][CH2:13][CH:12]([N:11]2[C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[N:1]=[CH:25]2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c[n+]([O-])ccc2[N+](=O)[O-])CC1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1cc2ncn(C3CCNCC3)c2cn1
Temperature: 105 °C

Procedure:
To tert-butyl 4-[(4-nitro-1-oxidopyridin-3-yl)amino]piperidine-1-carboxylate (1.6 g) in toluene (3 ml) was added trimethyl orthoformate (3.6 ml) followed by p-toluenesulfonic acid (105 mg) and the resulting mixture was heated to 105° C. for 4 hours. The mixture was cooled and partitioned between ethyl acetate (75 ml) and water (75 ml). The organic layer was washed with brine, dried and evaporated to dryness to give the title compound as a solid. Yield 1.18 g. NMR (CDCl3) 1.5 (s, 9H), 2.1 (m, 2H), 2.25 (m, 2H), 3.0 (m, 2H), 4.4 (m, 3H), 7.7 (dd, 1H), 8.1 (s, 1H), 8.5 (d, 1H), 8.9 (s, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[OH:13].CN([CH:17]=[O:18])C.N1[CH2:23][CH2:22][CH2:21][CH2:20]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]2[O:13][C:21]([C:22]3[CH:23]=[CH:4][C:3]([O:18][CH3:17])=[CH:2][CH:7]=3)=[CH:20][C:2]=2[CH:7]=1
Reactant: CN(C)C=O
Reactant: C1CCNC1
Reactant: COc1cc(I)c(O)c([N+](=O)[O-])c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: COc1ccc(-c2cc3cc(OC)cc([N+](=O)[O-])c3o2)cc1
Temperature: 60 °C

Procedure:
The 2-Iodo-4-methoxy-6-nitro-phenol 97 (1 g, 2.25 mmol based on 0.67 molar purity) in DMF/pyrrolidine (3 mL/3 mL) was treated with 4-methoxystyryne (0.45 g, 3.4 mmol), catalytic PdCl2(PPh3)2 and catalytic Cul was heated at 60° C. until reaction was adjudged complete by TLC analysis (<1 h to completion). The reaction was worked up by partitioning between EtOAc and 2 N HCl aq. The EtOAc was washed with saturated NaHCO3 aq, brine and dried over MgSO4. After filtering and concentrating, the product was purified by trituration with MeOH to give 0.57 g: Mp=141° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=1)=[O:8]
Reactant: O[C@@H]1CCNC1
Reactant: O=C(Nc1ccc(SC(F)(F)F)nc1)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(SC(F)(F)F)nc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 8.1 using 5-bromo-6-chloro-N-(6-((trifluoromethyl)thio)pyridin-3-yl)nicotinamide (Stage 32.2) and (R)-pyrrolidin-3-ol to afford an off-white powder. HPLC (Condition 4) tR=5.53 min, UPLC-MS (Condition 3) tR=1.01 min, m/z=463.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[F:15][C:16]([F:29])([F:28])[CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O.[BH4-].[Na+]>CCO>[CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6](=[CH:5][CH:4]=1)[NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH:12][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([O:19][CH2:18][CH2:17][C:16]([F:15])([F:29])[F:28])[CH:21]=1
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Reactant: O=Cc1cccc(OCCC(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2[nH]cc(CCNCc3cccc(OCCC(F)(F)F)c3)c2c1

Procedure:
Combine 350 mg (1.8 mmol) 5-methoxytryptamine, 401 mg 3-trifluoropropoxybenzaldehyde (1.8 mmol) and 4 g 4A molecular sieves in 35 mL EtOH and reflux overnight. Decant the liquid into a separate flask and treat with 209 mg (5.5 mmol) NaBH4. Stir the reaction at ambient temperature for 1 hour. Concentrate under vacuum, and partition between 50 mL 1 N NaOH and 25 mL dichloromethane. Extract the aqueous layer with 25 ml dichloromethane and combine the organic layers and concentrate to dryness. Purify the resulting oil by radial chromatography (SiO2; 1% MeOH in CHCl3 mixed with conc. NH4OH) to afford 705 mg (1.8 mmol; 100%) of the desired compound as an oil. Conversion to it's HCl salt by stirring a solution of the compound in 50 mL 50/50 THF/EtOH with 1 g polyvinyl pyridine hydrochloride overnight, filtering and concentrating to a solid. Recrystallize the product from EtOAc: Analysis for C21H23F3N2O2.HCl: calcd: C, 58.81; H, 5.64; N, 6.53. found: C, 58.42; H, 5.44; N, 6.51. ISMS 393 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=O)[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:15][CH2:16][N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2(CC(=O)N(C)C)CC=CCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C2(CCN(C)C)C=CCCC2)c1

Procedure:
A solution of 1.0 g of 1-(m-methoxyphenyl)-N,N-dimethyl-3-cyclohexene-1-acetamide in 10 ml of absolute tetrahydrofuran is added to a suspension of 1 g of lithium aluminum hydride in 50 ml of absolute tetrahydrofuran, and the mixture is boiled at reflux overnight. After the addition of water, the separated precipitate is removed by filtration under suction and washed well with tetrahydrofuran, whereupon the filtrate is evaporated. The oil remaining behind is treated with 1 N hydrochloric acid. The neutral portion is taken up in ether. The acidic phase is made alkaline by the addition of concentrated ammonia and the liberated rac. 1-(m-methoxyphenyl)-N,N-dimethyl-2-cyclohexene-1-ethylamine is taken up in methylene chloride. The hydrochloride of this compound melts at 161°-162° C. (after recrystallization from ethyl acetate/ethanol).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][C:7](=[O:19])[NH:8][C:9]3[CH:16]=[C:15]([Cl:17])[C:14](I)=[CH:13][C:10]=3[C:11]=2[N:12]=1.[CH2:20]([N:23]([CH3:25])[CH3:24])[C:21]#[CH:22].O>C(N(CC)CC)C.CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][C:7](=[O:19])[NH:8][C:9]3[CH:16]=[C:15]([Cl:17])[C:14]([C:22]#[C:21][CH2:20][N:23]([CH3:25])[CH3:24])=[CH:13][C:10]=3[C:11]=2[N:12]=1
Reactant: C#CCN(C)C
Reactant: Nc1ncc2c(n1)-c1cc(I)c(Cl)cc1NC(=O)C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)CC#Cc1cc2c(cc1Cl)NC(=O)Cc1cnc(N)nc1-2
Temperature: 75 °C
Reaction time: 8 h
Yield: 109.8 %

Procedure:
A solution of 2-amino-9-chloro-10-iodo-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (1.66 g, 4.29 mmol) and propargyl(dimethylamine) (0.74 mL, 6.89 mmol) in triethylamine (7 mL) and DMF (7 mL) was degassed with argon. To this solution was added bis(triphenylphosphine)palladium(II) chloride (0.30 g, 0.43 mmol) and copper iodide (0.163 g, 0.86 mmol). The reaction mixture was allowed to stir at 75° C. overnight. After the reaction mixture was allowed to cool to rt, water was added. The precipitate that formed was filtered and dried to give 2-amino-9-chloro-10-[3-(dimethylamino)prop-1-yn-1-yl]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (1.61 g, 98%) as a brown solid. LCMS (FA): m/z=342 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)#[N:14].C(=O)([O-])[O-].[Na+].[Na+].O>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:12][CH2:11][CH2:10][CH2:9][S:8][C:4]1[CH:5]=[CH:6][C:7]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13]#[N:14])=[CH:2][CH:3]=1
Reactant: OCCCSc1cccc(Br)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccccc1-c1ccc(SCCCO)cc1
Temperature: 80 °C
Reaction time: 7 h
Yield: 71.2 %

Procedure:
3-(3-Bromophenylsulfanyl)propane-1-ol (0.49 g) was suspended in acetonitrile (8.5 mL), 4-cyanophenylboronic acid (0.34 g), sodium carbonate (0.42 g), water (1.7 mL) and tetrakis(triphenylphosphine)palladium(0) (0.12 g) were added, and the resulting mixture was stirred at 80° C. for 7 hours. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate (35 mL) and water (10 mL). The organic layer was washed successively with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1) to give the title compound (0.38 g).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([F:32])[C:24]=1[F:33].[C:34](=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:34][O:28][C:27](=[O:29])[C:26]1[CH:30]=[CH:31][C:23]([NH:22][C:2]2[N:3]=[CH:4][C:5]3[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[C:6]=3[N:21]=2)=[C:24]([F:33])[C:25]=1[F:32]
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: Nc1ccc(C(=O)O)c(F)c1F
Reactant: O=C([O-])[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)c(F)c1F
Yield: 76.6 %

Procedure:
To a mixture of 0.4997 g (1.578 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20), 0.3539 g (1.891 mmole) of 4-amino-2,3-difluorobenzoic acid, and 25 mL of dioxane, was added 1.028 g (3.152 mmole) of cesium carbonate and 0.0367 g (0.163 mmole) of palladium acetate. The mixture was deoxygenated with argon, 0.2044 g (0.318 mmole) of 1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenyl phosphine was added and the reaction mixture was heated at 100 degrees for 4 hrs. The cooled mixture was concentrated under reduced pressure, dissolved in ethyl acetate, made slightly acidic by the addition of 1M hydrochloric acid, washed with water, brine, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.565 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,3-difluoro-benzoic acid methyl ester (I-242) as off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:24]=3[NH:23][CH:22]=[C:21]4[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>O1CCCC1.CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:24]=3[NH:23][CH:22]=[C:21]4[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC)c(OC)c4)n3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1OC
Temperature: 20 °C
Reaction time: 4 h
Yield: 77.1 %

Procedure:
To a solution of ethyl 3-(7-{5-[3,4-bis(methyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D67) (100 mg) in tetrahydrofuran (10 mL) and methanol (10 mL) stirred at 20° C. was added a solution of sodium hydroxide (48 mg) in water (10 mL) in one charge. The reaction mixture was stirred at 20° C. for 4 h. The organic solvent was evaporated off and the mixture was acidified with HCl (1 M) solution to pH around 1. The solid was filtered and recrystallized from acetonitrile/EtOAc to afford 3-(7-{5-[3,4-bis(methyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoic acid (E43) (72 mg). δH (DMSO-d6, 400 MHz): 2.61 (2H, t), 2.99 (2H, t), 3.90 (3H, s), 3.93 (3H, s), 7.21 (1H, t), 7.23 (1H, d), 7.26 (1H, d), 7.75 (1H, d), 7.81 (1H, d), 7.90 (1H, dd), 7.95 (1H, dd), 10.74 (1H, s). MS (ES): C21H19N3O6 requires 393; found 394.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([NH:15][C:16]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]([C@H:28]([CH3:43])[CH2:29][N:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]2)[C:21]3=[O:27])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CO.Cl.O1CCOCC1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([NH:15][C:16]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]([C@H:28]([CH3:43])[CH2:29][N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:21]3=[O:27])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:9])[F:11]
Reactant: Cc1ccc2c(=O)n([C@H](C)CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc2c(=O)n([C@H](C)CN3CCNCC3)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-tert-butyl 4-(2-(5-(2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamido)-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl)piperazine-1-carboxylate (100 mg, 0.0002 mol) in methanol (6 mL, 0.1 mol) was added 4M hydrogen chloride in 1,4-dioxane(6 mL, 0.02 mol) at 0° C. The mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was purified by reverse phase preparative HPLC to afford the desired product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH:17]=[CH2:18].O>CC(C)=O>[CH2:18]([O:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1])[CH:17]=[CH2:16]
Reactant: Oc1cc(F)ccc1F
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1cc(F)ccc1F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2,5-Difluorophenol (10 g) was dissolved in dimethylformaldehyde (120 ml). At room temperature, potassium carbonate (21 g) and allyl bromide (8.57 ml) were successively added to the mixture and it was stirred at 80° C. for 1 hr. After adding water to the liquid reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: 5% ethyl acetate/n-hexane) to give 2,5-difluorophenol allyl ether (13 g) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[C:6](=[CH:10][C:11]([CH3:19])=[C:12]([C:14](=[O:18])[CH2:15][CH2:16][CH3:17])[CH:13]=1)[NH:7][CH2:8][CH3:9])[CH3:2].C(N(C(C)C)C(C)C)C.[CH2:30]([O:32][C:33](=[O:38])[CH2:34][C:35](Cl)=[O:36])[CH3:31]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[C:6](=[CH:10][C:11]([CH3:19])=[C:12]([C:14](=[O:18])[CH2:15][CH2:16][CH3:17])[CH:13]=1)[N:7]([CH2:8][CH3:9])[C:35](=[O:36])[CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:38])[CH3:2]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CCCC(=O)c1cc(C(=O)OCC)c(NCC)cc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCCC(=O)c1cc(C(=O)OCC)c(N(CC)C(=O)CC(=O)OCC)cc1C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
13.86 g of the above anthranilic acid ethyl ester are dissolved in 140 ml of absolute toluene and 6.45 g of ethyl diisopropylamine are added. A solution of 7.6 g of chlorocarbonylacetic acid ethyl ester in 75 ml of absolute toluene is added dropwise at room temperature to this solution over a period of 30 minutes. After stirring for 10 hours at room temperature, a further 7.6 g of chlorocarbonylacetic acid ethyl ester in toluene are added dropwise in the course of 15 minutes and the mixture is stirred for a further 15 hours at room temperature. The reaction mixture is washed with water, sodium bicarbonate solution and water, dried over anhydrous sodium sulphate, filtered and concentrated to dryness by evaporation in vacuo. In this manner N-ethyl-5-butyryl-4-methyl-N-(1'-oxo-2'-ethoxycarbonylethyl)-anthranilic acid ethyl ester is obtained in the form of a pale yellow oil, which is further processed without further purification.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[C:18]([CH2:20][N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:19]=2)=[CH:11][CH:10]=1.[F:27][C:28]([F:44])([F:43])[C:29]1[O:33][N:32]=[C:31]([C:34]2[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=2)[C:37](O)=[O:38])[N:30]=1>>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[C:18]([CH2:20][N:21]3[CH2:22][CH2:23][N:24]([C:37]([C:36]4[CH:40]=[CH:41][CH:42]=[C:34]([C:31]5[N:30]=[C:29]([C:28]([F:43])([F:27])[F:44])[O:33][N:32]=5)[CH:35]=4)=[O:38])[CH2:25][CH2:26]3)[N:19]=2)=[CH:11][CH:10]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: Fc1ccc(-c2nc(CN3CCNCC3)cs2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCN(Cc2csc(-c3ccc(F)cc3)n2)CC1
Yield: 34 %

Procedure:
This compound was synthesized from 2-(4-fluorophenyl)-4-(piperazin-1-ylmethyl)thiazole TFA salt and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (26 mg, yield 34%). 1H NMR (400 MHz, CDCl3) δ 8.20-8.17 (m, 2H), 7.95-7.92 (dd, J=8.8 Hz, 5.1 Hz, 2H), 7.64-7.59 (m, 2H), 7.16-7.11 (m, 3H), 3.89 (m, 2H), 3.80 (s, 2H), 3.51 (m, 2H), 2.72 (m, 2H), 2.57 (m, 2H). MS (ESI) m/z: Calculated for C24H19F4N5O2S: 517.12. found: 518.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[S:16][CH2:15][CH2:14][CH2:13][S:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([Li])CCC.[Cl:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:44])[CH2:27][C:28]1([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:42][CH3:43])[CH:35]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.Cl>CCCCCC.O1CCOCC1.O1CCCC1>[ClH:22].[CH3:43][O:42][C:36]1[CH:35]=[C:34]([C:28]2([CH2:27][N:26]([CH3:44])[CH2:25][CH2:24][CH2:23][C:11]3([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[S:12][CH2:13][CH2:14][CH2:15][S:16]3)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[CH:39]=[CH:38][C:37]=1[O:40][CH3:41]
Reactant: COc1ccc(C2SCCCS2)cc1OC
Reactant: COc1ccc(C2(CN(C)CCCCl)CCCCC2)cc1OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C2(CN(C)CCCC3(c4ccc(OC)c(OC)c4)SCCCS3)CCCCC2)cc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 2.56 g (0.01 mol) of 2-(3,4-dimethoxyphenyl)-m-dithiane in 20 ml of abs. tetrahydrofuran was cooled to -60° in a sulphonation flask while gassing with dry argon and treated dropwise within 15 minutes with 4.68 ml (0.0075 mol) of a solution of butyllithium in hexane, whereby the temperature was held at -60°. Thereafter, the solution was stirred at -20° for 2 hours, then again cooled to -60° and treated dropwise with a solution of 1.70 g (0.005 mol) of N-(3-chloropropyl)-1-(3,4-dimethoxyphenyl)-N-methylcyclohexanemethanamine in 20 ml of abs. tetrahydrofuran. After 16 hours at -20° and 4 hours at room temperature the solution was poured on to ice-water and the mixture was washed three times with ether. The ethereal extracts were dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residual oil was chromatographed on silica gel 60 with toluene/ethyl acetate (8:2 ). After evaporation of the solvent there was obtained a colourless oil which was dissolved in a small amount of abs. dioxan and treated with an excess of hydrogen chloride in abs. dioxan, whereby N-[[1-(3,4-dimethoxyphenyl)cyclohexyl]methyl]-2-(3,4-dimethoxyphenyl)-N-methyl-m-dithiane-2-propanamine hydrochloride was obtained as solid white foam.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.[N:13]([C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[CH:19][NH:20]2)=[C:14]=[O:15].C(N(CC)CC)C>C1COCC1>[NH:20]1[C:21]2[C:17](=[C:16]([NH:13][C:14](=[O:15])[O:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][CH:7]=3)[CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19]1
Reactant: O=C=Nc1cccc2[nH]ccc12
Reactant: OCc1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc2[nH]ccc12)OCc1ccc(C(F)(F)F)cc1
Yield: 53.8 %

Procedure:
[4-(Trifluoromethyl)phenyl]methanol (0.09 g, 0.55 mmol) and the product of Example 80A (0.08 g, 0.5 mmol) in THF (5 mL) were heated at reflux for 16 hours with a catalytic amount of triethylamine. The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography on silica gel eluting with 50% hexane:ethylacetate to provide the title compound as an oil (0.09 g). 1H NMR (300 MHz, DMSO-d6) δ 5.32 (s, 2H), 6.73 (s, 1H), 7.0 (t, 1H), 7.11 (d, 1H), 7.23 (t, 1H), 7.38 (d, 1H), 7.66 (d, 2H), 7.78 (d, 2H), 9.52 (s, 1H), 11.08 (s, 1H). Anal. Calcd. for C17H13N2F3O2: C, 61.08; H, 3.92; N, 8.38. Found: C, 60.97; H, 4.21; N, 8.17.