Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:16]([F:19])([F:18])[F:17])[C:4]=1[CH3:20].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:16]([F:17])([F:18])[F:19])[C:4]=1[CH3:20]
Reactant: CCOC(=O)CCc1ccc(OC)c(C)c1C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(O)c(C)c1C(F)(F)F
Temperature: -78 °C

Procedure:
Into a 50-mL round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 3-[4-methoxy-3-methyl-2-(trifluoromethyl)phenyl]propanoate (210 mg, 0.72 mmol, 1.00 equiv), dichloromethane (2.0 mL). This was followed by the addition of BBr3 (1N in dichloromethane) (1.45 mL, 2.00 equiv) dropwise with stirring at −78° C. The resulting solution was warmed to room temperature (30° C.) and stirred for 2 h. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×10 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by TLC-Plate with petroleum ether/EtOAc=4:1. This resulted in 0.130 g (65%) of ethyl 3-[4-hydroxy-3-methyl-2-(trifluoromethyl)phenyl]propanoate as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C13H15P3O3, 275.1 (M−H). found 275.1.
Reaction SMILES: Cl[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:12][C:8]1[N:7]2[C:2]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:3]([OH:4])[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(NC(=O)C(Cl)c2ccccc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Solvent: C1CCOC1
Product: Cc1cccc2nc(O)c(-c3ccccc3)n12
Temperature: 25 °C

Procedure:
2-Chloro-N-(6-methylpyridin-2-yl)-2-phenylacetamide (11.5 g, ˜80%, see step 1) was dissolved in 167 mL anhydrous THF. After addition of tetra-n-butyl ammonium iodide (700 mg, 1.90 mmol) the reaction mixture was cooled with ice-water. 2.5 Equivalents potassium bis(trimethylsilyl)amide as a 0.5M solution in THF (95 mL, 47.4 mmol) were added dropwise. The reaction mixture was stirred for 10 min at room temperature and for additional 2h at reflux. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and an 1M aqueous solution of citric acid. The organic phase was washed with brine and dried with sodium sulphate. LC-MS analysis showed that the predominant portion of the title compound was still remaining in the aqueous phase. The aqueous phase was therefore neutralized with 1M sodium hydroxide solution. After extraction with dichloromethane (2×) the combined organic phases were washed with brine and dried with sodium sulphate. The residue was triturated with hot ethyl acetate and was filtered while being hot. The filtrate was concentrated in vacuo. After drying under high vacuum 2.70 g (26%) of the title compound were observed.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:30])[C:12]3[S:19][C:18]([CH2:20]O)=[C:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS([Cl:46])(=O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:30])[C:12]3[S:19][C:18]([CH2:20][Cl:46])=[C:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:31][CH:32]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CO)c(COCC[Si](C)(C)C)c21
Reactant: CS(=O)(=O)Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)c(COCC[Si](C)(C)C)c21
Reaction time: 18 h

Procedure:
To a cold (0° C.), stirred solution of 426 mg of N-(4-chlorobenzyl)-2-(hydroxymethyl)-4-methyl-7-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide and 0.46 mL of 2,4,6-collidine in 4 mL of dry DMF is added 0.17 mL of methanesulfonyl chloride. The ice bath is removed and the mixture is allowed to stir for 18 h, then is diluted slowly with water to a volume of 25 mL. The resulting solid is filtered, washed well with water, and dried in vacuo to furnish 429 mg of the title compound as a brown solid.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[F:10][C:11]1[CH:24]=[CH:23][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=2)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:24]=[CH:23][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:1][CH:2]3[CH:7]4[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]4)[CH2:3]3)=[CH:18][CH:17]=2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(Oc2ccc(F)cc2)cc1
Reactant: OC1CN2CCC1CC2
Product: Fc1ccc(Oc2ccc(OC3CN4CCC3CC4)cc2)cc1

Procedure:
3-Hydroxy quinuclidine (Aldrich, 254 mg, 2 mmol) was treated with 4-(4-fluoro-phenoxy)-phenol (Aldrich, 205 mg, 1 mmol) according to the procedure of Example 1A. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.45) as oil (230 mg, yield, 73%). 1H NMR (MeOH-d4, 300 MHz) δ 1.40–1.52 (m, 1H), 1.64–1.87 (m, 2H), 1.98–2.15 (m, 1H), 2.20–2.25 (m, 1H), 2.66–3.00 (m, 5H), 3.30–3.40 (m, 1H), 4.48(m, 1H), 6.61 (dt, J=10.5, 2.4 Hz, 1H), 6.71(dd, J=8.1, 2.3 Hz, 1H), 6.76 (tdd, J=8.4, 2.3, 1.0 Hz, 1H), 6.87–7.00 (m, 3H), 7.22–7.32 (m, 2H) ppm. MS (DCl/NH3) m/z 314 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[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[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([CH3:43])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[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:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[C:38]([CH3:43])[N:39]=[C:40]([CH3:42])[CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(C(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J24) (311 mg, 1.0 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (325 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow oil (356 mg, 63%).
Reaction SMILES: COC(=O)[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([C:16](=[N:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=2)[C:17]2[NH:21][C:20](=[O:22])[N:19]([C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:18]=2)[C:9]=1[F:38].C([BH3-])#N.[Na+].C(O)(=O)C.[OH-].[Na+]>O.O1CCCC1.CO>[F:38][C:9]1[C:8]([O:7][CH2:6][CH2:5][OH:4])=[CH:13][C:12]([O:14][CH3:15])=[CH:11][C:10]=1[CH:16]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]#[N:37])=[CH:34][CH:35]=1)[C:17]1[NH:21][C:20](=[O:22])[N:19]([C:23]2[N:24]=[CH:25][CH:26]=[CH:27][N:28]=2)[N:18]=1
Reactant: COC(=O)OCCOc1cc(OC)cc(C(=Nc2ccc(C#N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1F
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C#N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 15 °C
Reaction time: 28 h
Yield: 93.8 %

Procedure:
A suspension of carbonic acid 2-{3-[(4-cyanophenylimino)-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]-triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxy}ethyl ester methyl ester (25.0 g, 47.1 mmol) and methanol (90 mL) was cooled to 15° C. Sodium cyanoborohydride (5.45 g, 87 mmol) was added thereto, and was rinsed with methanol (10 mL). Acetic acid (21.5 mL, 375 mmol) was added dropwise thereto, and the resulting mixture was stirred at room temperature for 28 hours. The mixture was cooled in an ice-water bath, and tetrahydrofuran (100 mL) and a 5 N aqueous sodium hydroxide solution (113 mL, 565 mmol) were added thereto. After stirring the resulting mixture for 18 hours, the mixture was cooled to 15° C. or below, and acetic acid (81 mL, 1.410 mol) was added thereto. To the solution obtained, a seed crystal (5.0 mg) of the captioned compound was added at room temperature, and water (250 mL) was added dropwise to the resulting mixture, after which the resulting mixture was stirred at 4° C. for 21.5 hours. The suspension obtained was filtered and was washed with 25% aqueous methanol (100 mL) and dried at 40° C. under reduced pressure to obtain the captioned compound (21.1 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:16]=1[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH:12]=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.9 %

Procedure:
To a solution of 3,4,5-tribenzyloxy-benzyl alcohol 5 (8.9 g, 21 mmol) in methylene chloride (200 mL) at 0° C. was added pyridinium chlorochromate (5.43 g, 25 mmol) in small portions with vigorous stirring. The cooling was discontinued and reaction stirred at room temperature for 4 h. The dark brown suspension was filtered over a long pad of silica gel in a sintered glass funnel, and eluted with CH2Cl2, until all the pure product eluted out. The organic filtrate was evaporated down to give the pure product 6 as a soft white solid (8.1 g, 91.5% yield). 1H NMR (300 MHz, CDCl3): δ 5.16 (s, 6H, OCH2), 7.18 (s, 2H, 2,6-Ar—H), 7.26-7.41 (m, 15H, Ar—H), 9.80 (s, 1H, CHO).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[C:17]([F:20])([F:19])[F:18])[NH2:13]>C(O)(=O)C.CCOCC>[F:9][C:10]1[C:16]([C:17]([F:18])([F:19])[F:20])=[CH:15][C:14]([I:1])=[C:12]([CH:11]=1)[NH2:13]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ccc(C(F)(F)F)c(F)c1
Solvent: CCOCC
Solvent: CC(=O)O
Product: Nc1cc(F)c(C(F)(F)F)cc1I
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
6.16 g of N-iodosuccinimide (27 mmol) were slowly added to a solution of 4.9 g of 3-fluoro-4-(trifluoromethyl)-aniline (27 mmol) in 20 ml acetic acid. After the reaction mixture had been stirred for 1.5 h at rt it was diluted with ether and washed with a 2 molar solution of Na2S2O3 and with brine. The ether layer was then dried with magnesium sulfate, filtered and the solvent was evaporated. 5-Fluoro-2-iodo-4-trifluoromethyl-aniline was isolated from the remaining residue by chromatography (silica gel; cyclohexane/EtOAc 4:1). This yielded 3.27 g (39%) of 5-fluoro-2-iodo-4-trifluoromethyl-aniline as a dark red liquid. 1H-NMR (CDCl3, 300 MHz): δ 4.52 (br s, 2H), 6.49 (d, J=12 Hz, 1H), 7.79 (d, J=8 Hz, 1H).
Reaction SMILES: C(OC([N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:9][CH2:10][C:11]1[NH:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=1)=O)(C)(C)C.Br[CH2:30][CH:31]1[CH2:33][CH2:32]1>>[CH:31]1([CH2:30][N:15]2[C:11]([CH2:10][CH2:9][NH:8][C:22](=[O:23])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[N:12][C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:14]2)[CH2:33][CH2:32]1
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N(CCc1nc(-c2ccccc2)n[nH]1)C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NCCc1nc(-c2ccccc2)nn1CC1CC1

Procedure:
The product was obtained starting from 5-[2-bis(tert-butoxycarbonyl)aminoethyl]-3-phenyl-[1,2,4]triazole (250 mg, 644 μmol, example 22, step 1) and (bromomethyl)cyclopropane (104 mg, 73.9 μL, 772 μmol) according to the method described in example 34, step 1 as colorless oil (69 mg, 201 μmol, 31.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[CH:13]=2)=[CH:5][CH:4]=1.Cl.[CH2:19]([N:21]([CH2:35][CH3:36])[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)[CH3:20]>>[CH2:35]([N:21]([CH2:19][CH3:20])[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([C:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:31])=[CH:33][CH:34]=1)[CH3:36]
Reactant: CCN(CC)CCCOc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(-c2cc3ccccc3o2)cc1
Agent: Cl
Product: CCN(CC)CCCOc1ccc(C(=O)c2c(-c3ccc(OC)cc3)oc3ccccc23)cc1

Procedure:
Acylation of 2-(p-methoxyphenyl)benzofuran with 4-(3-diethylaminopropoxy)benzoyl chloride hydrochloride by the procedure described in Example 6 gives the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1.[Cl:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:15][C:9]1[C:10]([CH:13]=[O:14])=[CH:11][NH:12][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1c[nH]c(-c2ccccc2F)c1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
To a solution (15 mL) of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (1.0 g) in N,N-dimethylformamide was added N-chlorosuccinimide (0.71 g) at 0° C., and the mixture was stirred at 60° C. for 2 hr. The mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=8:1→3:1) to give the title compound as a yellow powder (yield 0.55 g, 46%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].N[C@H]1COC2C=C(C)C=CC=2NC1=O.[CH3:22][C@@H:23]1[O:29][C:28]2[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:27]=2[NH:26][C:25](=[O:35])[C@H:24]1[NH:36]C(=O)OC(C)(C)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:36][C@H:24]1[C@H:23]([CH3:22])[O:29][C:28]2[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:27]=2[NH:26][C:25]1=[O:35]
Reactant: Cc1ccc2c(c1)O[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N2
Agent: Cc1ccc2c(c1)OC[C@H](N)C(=O)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)O[C@@H](C)[C@H](N)C(=O)N2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 112 %

Procedure:
In a similar manner to that described for the preparation of (S)-3-amino-8-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one trifluoroacetate except the reaction mixture was stirred at 0° C. for 30 min. and at RT for 20 min., tert-butyl (2S,3S)-2,8-dimethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate was converted to the title compound (175 mg, 112%) which was used without purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([C:14]2[N:18]([CH3:19])[N:17]=[N:16][N:15]=2)[CH:6]=1)[CH3:2]>CCOC(C)=O.C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:6]=[C:7]([C:14]2[N:18]([CH3:19])[N:17]=[N:16][N:15]=2)[CH:8]=[C:9]([NH2:11])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(-c2nnnn2C)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc(N)cc(-c2nnnn2C)c1
Yield: 72.5 %

Procedure:
A solution of 3-(1-Methyl-1H-tetrazol-5-yl)-5-nitro-benzoic acid ethyl ester (6.5 g) in EtOAc:ethanol (1:1, 320 ml) was hydrogenated at 20° C. and 50 psi with 10% Pd/C (750 mg). After reaction completion, the mixture was filtered and the filtrate concentrated in vacuum to give the title compound (4.2 g). Rt=1.21 min (method D).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13](=[O:15])[NH2:14])=[CH:8][C:7]=1[CH3:16].CS(C)=O.OO.C(=O)([O-])[O-].[K+].[K+]>O>[C:21]([O:20][C:18]([NH:17][CH:4]([CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13](=[O:15])[NH2:14])=[CH:8][C:7]=1[CH3:16])[C:3]([OH:25])=[O:2])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)C(Cc1c(C)cc(C(N)=O)cc1C)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C(N)=O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 43.5 °C
Reaction time: 3 h

Procedure:
2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionic acid methyl ester (250 g, 0.713 mol), DMSO (750 mL) and 30% H2O2 (250 mL), were added to a 5 L three-necked round bottom flask equipped with addition funnel, mechanical stirrer, heating mantel, reflux condenser, thermocouple and nitrogen inlet. Potassium carbonate (158 g, 1.14 mol, 1.6 eq) was dissolved in water (750 mL) and added dropwise over 30 minutes. During the addition, a temperature increase was observed (from 23° C. to 34° C.). The resulting mixture was warmed up to about 42-45° C. and the progress of the reaction monitored by HPLC. After 3 hours, to the warm mixture was added activated carbon (ECOSORB-941) (37.5 g, 15% by weight). The resulting slurry was refluxed for 1 hour, and then filtered hot through CELITE®. The CELITE® pad was rinsed with H2O (1.5 L). The resulting mixture was cooled to about 10° C. and quenched with 2.0N HCl (pH 2, 1.22 L), to yield a mixture comprising a white solid precipitated. The mixture was aged under agitation for a period of about 4 hours in an ice bath and then filtered and dried for 48 hours in a vacuum oven to yield the title compound as a white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9]Br)=[CH:4][N:3]=1.[CH2:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[C:14]=1[OH:21])[CH3:12]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:17]2[CH:16]=[C:15]([CH2:19][CH3:20])[C:14]([OH:21])=[C:13]([CH2:11][CH3:12])[CH:18]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(CBr)c(N)n1
Reactant: CCc1cccc(CC)c1O
Product: CCc1cc(Cc2cnc(N)nc2N)cc(CC)c1O
Yield: 65 %

Procedure:
2,4-diamino-5-bromomethylpyrimidine was reacted with 2,6-diethylphenol using the experimental conditions described in Example 1. 2,4-diamino-5-(3,5-diethyl-4-hydroxybenzyl)pyrimidine was obtained in a yield of approximately 65%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=3)[CH2:13][NH:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9].[CH2:23]=O>[Ni].CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=3)[CH2:13][N:12]([CH3:23])[CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: C=O
Reactant: COc1cc2c(cc1O)CNCC2c1ccc(Cl)c(Cl)c1
Agent: [Ni]
Agent: Cl
Solvent: CO
Product: COc1cc2c(cc1O)CN(C)CC2c1ccc(Cl)c(Cl)c1

Procedure:
The free base prepared from 3.7 g. of rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-6-methoxy-7-isoquinolinol hydrochloride is treated with 100 ml. of methanol and 5 ml. of 35% formaldehyde solution and, after standing at room temperature for 2 hours, hydrogenated with 5 g. of Raney nickel. After filtration, evaporation and acidification with ethanolic hydrogen chloride, a crystallized product is obtained. Recrystallization from methanol-ether gives rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-6-methoxy-2-methyl-7-isoquinolinol hydrochloride, m.p. 253°-254°C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([Cl:15])=[N:10][C:9]([C:16]([OH:18])=O)=[C:8]2[OH:19])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[O:45][C:46](=[O:50])[C@H:47]([CH3:49])[NH2:48].[OH-].[Na+].Cl>CO.O>[CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([Cl:15])=[N:10][C:9]([C:16]([NH:48][C@@H:47]([CH3:49])[C:46]([OH:50])=[O:45])=[O:18])=[C:8]2[OH:19])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc2c(Cl)nc(C(=O)O)c(O)c2c1
Reactant: COC(=O)[C@H](C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CO
Product: CC(C)Oc1ccc2c(Cl)nc(C(=O)N[C@@H](C)C(=O)O)c(O)c2c1
Yield: 61.2 %

Procedure:
0.030 g of 6-isopropoxy-1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid and 0.046 g of HATU were allowed to react with 0.017 g of L-Alanine methyl ester under analogous conditions to Example A-1 a). Treatment of the crude product ester with 0.014 g of NaOH in 0.1 ml of 1:1 methanol-water at room temperature for 2 days, followed by acidification to pH=˜2 with 1M hydrochloric acid, gave a solid product. The product was collected by filtration, washed with water, and dried to give 0.023 g of an off-white solid: MS-(−)-ion, M−1=353.0 amu.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[CH:10][C:11]([C:14]#[C:15][CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)=[N:12][CH:13]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](OB(O)O)=[CH:35][CH:34]=1>O1CCOCC1>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][CH2:16][N:17]3[C:25]4[C:20](=[CH:21][C:22]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:23][CH:24]=4)[CH:19]=[CH:18]3)=[N:12][CH:13]=2)=[CH:35][CH:34]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: Brc1ccc(C#CCn2ccc3cc(CN4CCCC4)ccc32)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc(-c2ccc(C#CCn3ccc4cc(CN5CCCC5)ccc43)nc2)cc1
Temperature: 110 °C
Reaction time: 2.5 h

Procedure:
Under an argon atmosphere 0.5 mL 2 M Na2CO3 solution and 10 mg (0.01 mmol) tetrakis-triphenylphosphane-palladium are added to a solution of 59 mg (0.15 mmol) 1-[3-(5-bromo-pyridin-2-yl)-prop-2-ynyl]-5-pyrrolidin-1-ylmethyl-1H-indole and 50 mg (0.32 mmol) 4-chlorophenyl-boric acid in 5 mL 1,4-dioxane and the reaction mixture is stirred for 2.5 h at 110° C. The mixture is evaporated down i.vac., the residue is combined with 3 mL water, extracted with 5 mL EtOAc, the organic phase is washed with saturated NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1.C(N(CC)CC)C.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:26]=[O:28])=[CH:12][CH:11]=1
Reactant: COC(=O)CCCCCOc1ccc(N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCOc1ccc(N=C=O)cc1
Temperature: 75 °C
Yield: 72.3 %

Procedure:
To 6-(4-aminophenoxy)-hexanoic acid methyl ester 17 (26 g, 109.7 mmol) and tri-ethylamine (29.2 g, 288.56 mmol) in toluene (390 ml) under nitrogen atmosphere was added triphosgene (15.6 g, 52.56 mmol) in one lot. The reaction was exothermic and internal temperature rose to 60° C. Later the reaction mixture was heated to 75° C. over a period of one hour and maintained at this temperature for 26 hours. The reaction mixture was cooled to room temperature, the solids filtered off, and toluene distilled off under vacuum to get crude 18, which was vacuum distilled to get pure 18 (10 g, 34.7%) with an m.p between 47-50° C.