Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][SH:19])[CH:15]=[N:14]1.[OH-].[Na+].O.[CH2:23]([N:26]1[C:30]([C:31]#[N:32])=[C:29]([C:33]#[N:34])[N:28]=[C:27]1Br)[CH:24]=[CH2:25]>O1CCOCC1>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][S:19][C:27]2[N:26]([CH2:23][CH:24]=[CH2:25])[C:30]([C:31]#[N:32])=[C:29]([C:33]#[N:34])[N:28]=2)[CH:15]=[N:14]1
Reactant: C=CCn1c(Br)nc(C#N)c1C#N
Reactant: FC(F)(F)c1cc(Cl)c(-n2ncc(CS)n2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=CCn1c(SCc2cnn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)n2)nc(C#N)c1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(2,6-Dichloro-4-trifluoromethylphenyl)-4-mercaptomethyl-2H-1,2,3-triazole, prepared as in EP 350 237, (0.33 g) and sodium hydroxide (0.04 g) were stirred in dioxane (2 ml) and water (1 ml) at ice bath temperature. 1-Allyl-2-bromo-4,5-dicyanoimidazole (0.24 g) in dioxane was added and the mixture stirred at room temperature for 2 hours. Aqueous work up and silica gel column chromatography gave 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-[(4,5-dicyano-1-allyl-1H-imidazol-2-ylthio)methyl]-2H-1,2,3-triazole, m.p. 125°-127°. (Compound 24a)
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH:19]([NH2:21])=O.CN(C)C=O>O>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=2)[N:1]=[CH:19][N:21]=1
Reactant: NC=O
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2ccc([N+](=O)[O-])cc12
Temperature: 150 °C
Reaction time: 0.83 h

Procedure:
A mixture of 2-amino-5-nitrobenzonitrile (48.9 g), anhydrous potassium carbonate (45.6 g), formamide (240 ml) and N,N-dimethylformamide (200 ml) was stirred for 50 minutes at 150° C. and then cooled to ambient temperature. To the resultant mixture was added a small volume of water with stirring. Precipitated crystals were separated by filtration, washed three times with water and dried under reduced pressure to give crystalline 4-amino-6-nitroquinazoline (50.1 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.P(Cl)(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7].[Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: c1ccccc1
Agent: Cl
Agent: O=C(O)CCCBr
Agent: [Al+3]
Solvent: ClP(Cl)Cl
Product: O=C(CCCBr)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
In this Example, 8.35 g of 4-bromobutyric acid (50 mmol) was dissolved in 10 g of benzene (128mmol) and, after the temperature was raised to 60° C., 3.43 g of phosphorus trichloride (24 mmol) was dropwise added. Thereafter, the mixture was stirred at that temperature for one hour. Then, after the mixture was cooled to 20° C., the reaction solution was dropwise added into a suspension solution of 20 g containing benzene (256 mmol) and 6.7 g of aluminum chloride (50 mmol) at 10° C. After stirring the mixture at that temperature for one hour, the temperature was raised to 20° C. and the mixture was further stirred for 30 minutes and added into a 10% aqueous solution of hydrochloric acid that had been cooled to 10° C. Then, the aqueous phase was extracted with benzene, and the organic phase was washed with diluted hydrochloric acid, an aqueous solution of sodium hydrogencarbonate, and brine, followed by removing the solvent by distillation under reduced pressure to give 4-bromobutyrophenone in a 73.9% yield from 4-bromobutyric acid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([F:19])[C:11]([F:18])=[C:12]([F:17])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])C.[C:20](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[F:17][C:12]1[CH:13]=[C:14]2[C:9](=[C:10]([F:19])[C:11]=1[F:18])[N:8]([CH3:20])[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[C:15]2=[O:16]
Reactant: CCOC(=O)c1c[nH]c2c(F)c(F)c(F)cc2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reaction time: 10 h
Yield: 77.3 %

Procedure:
A mixture of 6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (0.3 g), anhydrous potassium carbonate (0.8 g), methyl iodide (1.6 g), and N,N-dimethyl-formamide (DMF) (10 ml) was heated with stirring at 90°-100° C. for 10 hours. The mixture was evaporated to dryness. The residue was treated with water, extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was added to a mixture of 18% hydrochloric acid (5 ml) and ethanol (2.5 ml) and the mixture was refluxed for 2.5 hours. After water (5 ml) and ethanol (5 ml) added and cooled, the resulting precipitate was filtered off and recrystallized from a mixture of DMF and ethanol to give 6,7,8-trifluoro-1,4-dihydro-1-methyl-4-oxoquinoline-3-carboxylic acid (0.22 g), mp 255°-258° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](Br)=[C:7]([O:12][CH2:13][CH2:14][O:15][CH3:16])[N:6]=1)=[O:4].Cl.[F:18][C:19]1([F:23])[CH2:22][NH:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:21]2[CH2:22][C:19]([F:23])([F:18])[CH2:20]2)=[C:7]([O:12][CH2:13][CH2:14][O:15][CH3:16])[N:6]=1)=[O:4]
Reactant: COCCOc1nc(C(=O)OC)ccc1Br
Reactant: FC1(F)CNC1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COCCOc1nc(C(=O)OC)ccc1N1CC(F)(F)C1
Temperature: 110 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
Under a nitrogen atmosphere a mixture of 5-bromo-6-(2-methoxyethoxy)-pyridine-2-carboxylic acid methyl ester (Example 142 b, 0.42 g, 1.45 mmol), 3,3-difluoroazetidine hydrochloride (0.22 g, 1.74 mmol), tris(dibenzylideneacetone)dipalladium (CAN 51364-51-3, 27 mg, 0.03 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (CAN 76189-55-4, 36 mg, 0.06 mmol) and cesium carbonate (1.4 g, 4.35 mmol) in toluene (50 mL) was stirred at 110° C. overnight. After evaporation of solvents the residue was partitioned between water (30 mL) and ethyl acetate (30 mL) and the aqueous phase was extracted with ethyl acetate (2×30 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue which was purified by column chromatography (silica gel, 8 g, 15% ethyl acetate in petroleum ether) to give the title compound (0.3 g, 68%) as white solid; MS (EI): m/e=303.1 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](OS(C(F)(F)F)(=O)=O)=[C:6]([CH3:18])[CH:5]=1)(=[O:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:24]1[O:25][CH:26]=[CH:27][CH:28]=1)CCC.[Cl-].[Li+]>O1CCOCC1.O.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>[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][C:6]=1[CH3:18]
Reactant: CC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2ccco2)c(C)c1
Temperature: 25 °C
Yield: 100.5 %

Procedure:
To a stirred solution of trifluoromethanesulfonic acid 4-acetyl-2methylphenyl ester (1.19 g, 4.2 mmol) in 1,4-dioxane (40 mL) was added 2-(tributylstannyl)furan (1.81 g, 5.05 mmol), lithium chloride (0.45 g, 10.5 mmol) and tetrakis(triphenylphosphine)palladium (0.49 g, 0.42 mmol) under nitrogen. The mixture was heated at reflex temperature for 2 hours, and cooled down to room temperature. The reaction mixture was diluted with water and the whole was extracted with diethylether. The organic layer was washed with saturated NaHCO3 aqueous solution, brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate/hexane (1/10) to give title compound (0.845 g, quant).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)([OH:25])[C:19]4[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=4)[CH:16]=3)[N:11]=[C:10]([NH:33]C(C3OC=CC=3)=O)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([OH:48])=O)=[CH:44][CH:43]=1.Cl.C(C(NCCCN(C)C)=N)C.ON1C2C=CC=CC=2N=N1.CCN(CC)CC>C1COCC1.O.CCOC(C)=O>[Br:41][C:42]1[CH:43]=[CH:44][C:45]([C:46]([NH:33][C:10]2[CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=4)([OH:25])[C:19]4[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=4)[CH:16]=3)[N:11]=2)=[O:48])=[CH:49][CH:50]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(NC(=O)c3ccco3)cc(-c3cccc(Cl)c3)c2c1
Agent: CCC(=N)NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(NC(=O)c3ccc(Br)cc3)cc(-c3cccc(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47 %

Procedure:
A mixture of (±)-2-amino-4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinolinemethanol (0.000210 mol) (see Example B8), 4-bromo-benzoic acid (0.000252 mol), N′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine monohydrochloride (0.000315 mol), 1-hydroxy-1H-benzotriazole (0.000315 mol; 1.5 equiv) and Et3N (0.000315 mol) in THF (2 ml) was stirred for 18 hours at room temperature, then taken up into EtOAc and H2O. The organic layer was separated and the solvent evaporated. The residue was purified by HPLC. The product fractions were collected and the solvent was evaporated, yielding 0.065 g (41%) of (±)-4-bromo-N-[4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-2-quinolinyl]benzamide, MS (ESI) m/z: 657 659 661 663.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17]C)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:19][CH3:20]>B(Br)(Br)Br.C(Cl)Cl>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:19][CH3:20]
Reactant: CCc1cc2c(OC)cccc2n1Cc1ccccc1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1cc2c(O)cccc2n1Cc1ccccc1-c1ccccc1
Yield: 69.3 %

Procedure:
By the method used in Example 1, Part D, 911 mg (2.6 mmol) of 1-([1,1′-biphenyl]-2-ylmethyl)-2-ethyl-4-methoxy-1H-indole was O-demethylated by treating it with 10 mL of 1M BBr3/CH2Cl2. The crude product was chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 590 mg (69% yield) of 1-([1,1′-biphenyl]-2-ylmethyl)-2-ethyl-4-hydroxy-1H-indole as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([NH:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]3[S:28][CH2:27][C:26](=[O:29])[NH:25][C:24]=3[CH:30]=2)([C:14]([F:17])([F:16])[F:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:16][C:14]([F:15])([F:17])[C:11]1([NH:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]3[S:28][CH2:27][C:26](=[O:29])[NH:25][C:24]=3[CH:30]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccc3c(c2)NC(=O)CS3)(C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CSc2ccc(CNC3(C(F)(F)F)CCNCC3)cc2N1

Procedure:
A solution of 6-[{1-(tert-butoxycarbonyl)-4-(trifluoromethyl)piperidin-4-ylamino}methyl]-4H-benzo[1,4]thiazin-3-one (3f) in 1:1 TFA/CH2Cl2 is stirred at room temperature until the starting material is consumed, then is concentrated to dryness in vacuo. The residue is partitioned between dilute NaOH and CH2Cl2, and the layers are separated. The aqueous layer is extracted with CH2Cl2, and the combined organic extracts are dried (Na2SO4) and concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][CH:6]=[CH2:7])[CH2:3][OH:4].[H-].[Na+].IC.[CH2:13](OCC)C>CN(C)C=O.O>[CH3:1][C:2]([CH3:8])([CH2:3][O:4][CH3:13])[CH2:5][CH:6]=[CH2:7]
Reactant: C=CCC(C)(C)CO
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: C=CCC(C)(C)COC
Reaction time: 1 h

Procedure:
2,2-Dimethylpent-4-en-1-ol (4.0 g.) was added dropwise to a suspension of sodium hydride (1.13 g. 80% dispersion in oil, washed with hexane) in dry dimethylformamide (80 ml.) under nitrogen. After stirring for 1 hour, iodomethane (5.3 g.) was added dropwise and the mixture stirred for a further hour. Diethyl ether (100 ml.) was added and was followed by slow addition of water (100 ml.). The ethereal extracts were evaporated in vacuo and the residue was dissolved in hexane (50 ml.). The hexane solution was washed with water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and 4,4-dimethyl-5-methoxypent-1-ene was obtained as a colourless oil (1.9 g.).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[F:9][C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[C:13]([NH:15][CH2:16][CH2:17][C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[Na+].[Cl-].[Li+]>CN(C)C=O.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:9][C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[C:13]([NH:15][CH2:16][CH2:17][C:18]1[C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[NH:8][C:19]=1[Si:20]([CH3:22])([CH3:21])[CH3:23])=[O:14]
Reactant: C[Si](C)(C)C#CCCNC(=O)c1cccc(F)c1
Reactant: Nc1ccncc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: C[Si](C)(C)c1[nH]c2ccncc2c1CCNC(=O)c1cccc(F)c1

Procedure:
A suspension of 3-iodo-4-pyridineamine (594 mg), 3-fluoro-N-[4-(trimethylsilyl)-3-butynyl]benzamide (710 mg), palladium acetate (61 mg), triphenylphosphine (142 mg), sodium acetate (443 mg) and lithium chloride (115 mg) in N,N-dimethylformamide (6 mL) and acetonitrile (3 mL) was irradiated with microwave (100 W) for 30 minutes, poured into water and then extracted with ethyl acetate. The organic layer was washed in turn with an aqueous saturated sodium hydrogen carbonate solution and saturated saline, dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (parallel separation purification system) to obtain the titled compound having the following physical properties (404.8 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([CH2:36][CH2:37][CH2:38][OH:39])[CH2:15][CH2:14][CH2:13][CH:12]([O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][C:26]=2[Cl:27])[C:23]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:22][CH:21]=[CH:20]3)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:44].CO>C1COCC1>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([CH2:36][CH2:37][CH2:38][O:39][CH3:44])[CH2:9][CH2:10][CH2:11][CH:12]([O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][C:26]=2[Cl:27])[C:23]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:22][CH:21]=[CH:20]3)[CH2:13][CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1(CCCO)CCCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COCCCC1(NC(=O)OC(C)(C)C)CCCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
A solution of 405 mg (0.71 mmol) of [5-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-1-(3-hydroxy-propyl)-cyclooctyl]-carbamic acid tert-butyl ester (59) in 5 mL of THF was dropped into a suspension of 31.3 mg (0.78 mmol) of sodium hydride (60%) in 5 mL THF at 0° C. 88.6 μL (1.42 mmol) of iodomethane were added, and after stirring for 1 h at room temperature another 88.6 μL (1.42 mmol). The reaction mixture was stirred at room temperature until LCMS indicated complete conversion, then 5 mL of methanol were added and the volatiles removed in vacuo. The crude material was purified by silica gel chromatography. 196 mg of [5-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-1-(3-methoxy-propyl)-cyclooctyl]-carbamic acid tert-butyl ester (61) as diastereomeric mixture could be isolated. Rt=1.89 min, 2.02 min (Method I). Detected mass: 583.3 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[C:5]([C:19]#[N:20])=[CH:4][N:3]=1.[CH:21]([C:24]1[C:29]([N:30]2[CH:34]=[N:33][N:32]=[N:31]2)=[CH:28][C:27]([NH2:35])=[C:26]([F:36])[CH:25]=1)([CH3:23])[CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.FC1C(NC2CC(C)(C)NC(C)(C)C2)=NC(OC(C)C)=NC=1>CC(O)C>[CH3:15][C:13]1([CH3:16])[CH2:14][CH:9]([NH:8][C:6]2[C:5]([C:19]#[N:20])=[CH:4][N:3]=[C:2]([NH:35][C:27]3[CH:28]=[C:29]([N:30]4[CH:34]=[N:33][N:32]=[N:31]4)[C:24]([CH:21]([CH3:22])[CH3:23])=[CH:25][C:26]=3[F:36])[N:7]=2)[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12]1
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2C#N)CC(C)(C)N1
Reactant: CC(C)c1cc(F)c(N)cc1-n1cnnn1
Agent: CC(C)Oc1ncc(F)c(NC2CC(C)(C)NC(C)(C)C2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CC(C)c1cc(F)c(Nc2ncc(C#N)c(NC3CC(C)(C)NC(C)(C)C3)n2)cc1-n1cnnn1
Temperature: 80 °C

Procedure:
A mixture of 2-chloro-5-cyano-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine (0.05 g, 0.17 mmol, 1 equiv), 4-isopropyl-2-fluoro-5-(1H-tetrazol-1-yl)benzenamine (0.045 g, 0.204 mmol, 1.2 equiv), and para-toluenesulfonic acid monohydrate (0.025 g, 0.136 mmol, 0.8 equiv) in IPA (5 mL) were heated to 80° C. overnight. LCMS indicated desired product plus approximately 10% of 5-fluoro-2-isopropoxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine byproduct. After cooling to ambient temperature, the crude mixture was quenched with 2M NH3/MeOH followed by concentrating to dryness and repeating once. The crude product was purified by flash chromatography and eluted with DCM:2M NH3/MeOH (100:0 to 95:5 using 1% 2M NH3/MeOH increments) to provide the desired product which was recrystallized with DCM/IPA to give the title compound (45 mg, 55%) as a solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][N:12]2[S:15]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=2[O:25][CH3:26])(=[O:17])=[O:16])=[CH:7][CH:6]=1)=[O:4].[OH-].[K+].O>CO.O1CCCC1>[CH3:26][O:25][C:19]1[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=1[S:15]([N:12]1[C:13]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=2)[CH2:9][CH2:10][CH2:11]1)(=[O:16])=[O:17]
Reactant: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(C)ccc1OC)CCC2
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(C)cc1S(=O)(=O)N1CCCc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (35.09 g, 0.09 mol) in methanol (0.27 L) and tetrahydrofuran (95.00 mL) was treated with a 3N solution of KOH in water (93.00 mL, 0.28 mol) and stirred at room temperature for 18 hours, then at 45° C. for 2 hours. The organic solvents were evaporated and the residual aqueous slurry diluted with water (0.45 L) and cooled to 0° C. The mixture was set to pH 1 with HCl 3N (85.00 mL) and the precipitated solid was filtered and dried under vacuum. 1-(2-Methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid was obtained as an off-white solid, 34.08 g (100%), MS (ISP): m/e=360.1 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][C:23]2[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=2)[O:26][CH2:27][C:28]([O:30]CC)=[O:29])=[N:14][C:15]=1[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].[OH-].[Na+].Cl>C1COCC1.CO>[CH3:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]1[N:14]=[C:13]([O:21][CH2:22][C:23]2[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=2)[O:26][CH2:27][C:28]([OH:30])=[O:29])[CH:12]=[CH:11][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CCOC(=O)COc1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(OCC(=O)O)c3)nc2CC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a solution of ethyl 2-(3-(((5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)oxy)methyl)phenoxy)acetate (77 mg) in THF (3.0 mL) and methanol (3.0 mL) was added 1N aqueous sodium hydroxide solution (1.0 mL), and the mixture was stirred at 50° C. for 30 min. To the reaction mixture was added 1N hydrochloric acid (1.0 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (63 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].C(Cl)(=O)C(Cl)=O.Cl.[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([C@@H:32]2[C@H:37]([NH2:38])[CH2:36][CH2:35][S:34][CH2:33]2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH3:22].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([C@@H:32]2[C@H:37]([NH:38][C:9]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=3)=[O:11])[CH2:36][CH2:35][S:34][CH2:33]2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH3:22]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CCOc1cc([C@H]2CSCC[C@H]2N)ccc1OC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1cc([C@H]2CSCC[C@H]2NC(=O)c2ccc(C(=O)OC)cc2)ccc1OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 4-(methoxycarbonyl)benzoic acid (11.35 g) in DCM (300 ml) are added 5 drops of DMF and the reaction mixture is stirred for 20 min at RT under a nitrogen atmosphere. To this suspension oxalyl chloride (5.67 ml) dissolved in DCM (60 ml) is slowly added at 0° C. (ice bath The ice bath is removed and the mixture is stirred for 4 h at RT. DCM (3×200 ml) is added to the reaction mixture and the volatiles are co-evaporated under reduced pressure (three times). Finally all volatiles are removed under vacuo to obtain an oil, which is dissolved in DCM (200 ml) and added dropwise to a solution of (3R,4R)-3-(3-ethoxy-4-methoxyphenyl)tetrahydro-2H-thiopyran-4-amine hydrochloride (18.23 g; compound C13) and DIPEA (41.1 ml) in DCM (200 ml) at 0° C. under nitrogen atmosphere. After stirring for 12 h at RT the reaction is quenched by addition of a saturated aqueous solution of sodium hydrogen carbonate. The organic phase is separated, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The resulting residue is suspended in DIP (300 ml) and heated under reflux for 3.5 h. The suspension is stirred for 2 d at RT and subsequently cooled to 0° (ice bath). The suspension is filtered and the filter cake is washed with little amounts of DIP and dried in vacuo for 12 h at 60° C. to give the title compound as a solid.