Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N)C1C=CC=CC=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]3)[CH2:11][CH2:10]1.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1.Cl.O1CCOCC1>>[ClH:29].[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]4)[CH2:11][CH2:10]2)=[CH:32][CH:31]=1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Reactant: Clc1ccc(CBr)cc1
Agent: Cl
Solvent: NCc1ccccc1
Solvent: C1COCCO1
Product: Nc1nc(N)c2c(OCC3CCN(Cc4ccc(Cl)cc4)CC3)cccc2n1
Yield: 56 %

Procedure:
The benzylamine was obtained by reacting 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (75 mg; 0.27 mmol) and 4-chlorobenzyl bromide (66 mg; 0.32 mmol) via Method BB to a solid, which was stirred in the presence of 4M HCl in dioxane (4 eq). Solids were filtered and rinsed once with ether to give title compound. (66 mg; 56% yield). 1HNMR (400 MHz, DMSO-d6) δ 12.9 (s, 1H), 11.3 (s, 1H), 8.82 (s, 1H), 8.23 (s, 1H), 7.7 (m, 4H), 7.52 (d, J=6.8 Hz, 2H), 7.02 (m, 2H), 4.66 (br s, 3H), 4.26 (d, J=4.8 Hz, 2H), 4.17 (d, J=6.4 Hz, 2H), 3.34 (br d, J=11.6 Hz, 2H), 2.87 (m, 2H), 2.2 (m, 1H), 1.81 (m, 4H). MS m/z (ESI) 398 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][CH2:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][NH:16][C:17]3[N:26]=[C:25]([N:27]([CH3:29])[CH3:28])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)[CH2:11][CH2:10]2)=[C:4]([O:32][C:33]([F:36])([F:35])[F:34])[CH:3]=1.C=O.[C:39](O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([CH2:8][C@H:9]2[CH2:10][CH2:11][C@H:12]([CH2:15][NH:16][C:17]3[N:26]=[C:25]([N:27]([CH3:29])[CH3:28])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)[CH2:13][CH2:14]2)[CH3:39])=[C:4]([O:32][C:33]([F:35])([F:36])[F:34])[CH:3]=1
Reactant: CN(C)c1nc(NC[C@H]2CC[C@H](CNCc3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(Cc1ccc(Br)cc1OC(F)(F)F)C[C@H]1CC[C@H](CNc2nc(N(C)C)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of trans-N2-{4-[(4-bromo-2-trifluoromethoxy-benzylamino)-methyl]-cyclohexylmethyl}-N4,N4-dimethyl-quinazoline-2,4-diamine obtained in step B of example 15 (290 mg, 0.52 mmol) in CH2Cl2 (3 mL) were added 37% aqueous formaldehyde (42 mg, 0.52 mmol), acetic acid (31 mg, 0.52 mmol), and NaBH(OAc)3 (165 mg, 0.78 mmol). The reaction mixture was stirred at ambient temperature for 19 hr. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 25% EtOAc in hexane) to give trans-N2-(4-{[(4-bromo-2-trifluoromethoxy-benzyl)-methyl-amino]-methyl}-cyclohexylmethyl)-N4,N4-dimethyl-quinazoline-2,4-diamine (153 mg, 51%) as a pale yellow solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[C:5]([O:12][CH3:13])[C:4]=1OC.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(O)C.[C:27](=[O:30])([O-])[O-].[K+].[K+]>O>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([O:12][CH3:13])[C:6]([O:30][CH3:27])=[CH:7][C:8]=1[NH2:9]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc([N+](=O)[O-])c(SC)c1OC
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(N)c(SC)cc1OC

Procedure:
A reaction mixture was prepared containing 68.7 g. of 3-methylthio-4-nitroveratrole, 261 g. sodium dithionite (Na2S2O4), 1500 ml. of ethanol and 2250 ml. of water. The reaction mixture was heated at reflux temperature for about 1 hour and then cooled. The reaction mixture was then made basic with potassium carbonate and the resulting alkaline solution concentrated in vacuo to one-half its original volume. The aqueous solution was extracted twice with 2 l. portions of ether. The ether extracts were combined, dried, and the ether removed therefrom by evaporation in vacuo. The solid residue, comprising 2-methylthio-4,5-dimethoxy aniline formed in the above reaction, was recrystallized from a benzene-hexane solvent mixture to yield 33.6 g. of crystalline material melting at 69°-72° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:31])=[C:6]([CH:30]=1)[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C@H:15]([C:19]([O:21][CH3:22])=[O:20])[N:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][CH2:12]2.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:31])=[C:6]([CH:30]=1)[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C@H:15]([C:19]([O:21][CH3:22])=[O:20])[N:14]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:13][CH2:12]2)(=[O:34])[CH3:33]
Reactant: COC(=O)[C@H]1c2ccc(OCc3cc(N)ccc3Cl)cc2CCN1C(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: COC(=O)[C@H]1c2ccc(OCc3cc(NC(C)=O)ccc3Cl)cc2CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.4 %

Procedure:
To a solution of (R)-2-tert-butyl 1-methyl 6-(5-amino-2-chlorobenzyloxy)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (15 mg, 0.033 mmol) in CH2Cl2 (1 mL) was added TEA (200 μl, 1.43 mmol) followed by the addition of acetyl chloride (10 μl, 0.05 mmol). The reaction was stirred at room temperature for 2 h. It was concentrated and purified by preparative HPLC (Phenomenex 20×100 mm eluting with 0-100% MeOH/H2O (90% in H2O, 0.1% TFA) gradient over 8 min with flow rate 25 mL/min) to yield (R)-2-tert-butyl 1-methyl 6-(5-acetamido-2-chlorobenzyloxy)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate as a colorless oil (2 mg, 13%). HPLC retention time (Method C)=3.86 min. LC/MS (ESI) (M+H)+=489.12. 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (s, 5H), 1.50 (s, 4H), 2.19 (s, 3H), 2.80-2.90 (m, 2H), 3.64-3.83 (m, 5H), 3.88 (s, 1H), 5.10 (s, 2H), 5.38 (s, 0.5H), 5.55 (s, 0.5H), 6.72-6.79 (m, 1H), 6.81-6.89 (m, 1H), 7.31-7.68 (m, 4H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7]/[C:6]/1=[N:12]\[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COCCn1c(C)c(C)sc1=N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1ccccc1
Yield: 34.5 %

Procedure:
The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.45 mL, 3.2 mmol) and benzoyl chloride (Aldrich, 0.16 mL, 1.4 mmol) in 15 mL THF were processed using the method described in Example 129 to afford the title compound (0.11 g, 0.38 mmol, 35% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.24 (s, 3H), 2.27 (d, J=0.7 Hz, 3H), 3.32 (s, 3H), 3.82 (t, J=5.3 Hz, 2H), 4.41 (t, J=5.3 Hz, 2H), 7.38-7.51 (m, 3H), 8.27-8.34 (m, 2H); MS (DCI/NH3) m/z 291 (M+H)+; Anal: calculated for C15H18N2O2S: C, 62.04; H, 6.25; N, 9.65. Found: C, 62.02; H, 6.05; N, 9.56.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:12])[NH:11][C:5]=2[CH:4]=1.[H-].[Na+].I[CH2:18][CH3:19]>CN(C=O)C>[CH2:18]([N:11]1[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:14]=[CH:13][C:6]=2[CH2:7][CH2:8][CH2:9][C:10]1=[O:12])[CH3:19]
Reactant: COc1ccc2c(c1)NC(=O)CCC2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)CCCc2ccc(OC)cc21
Temperature: 100 °C
Yield: 73.8 %

Procedure:
A mixture of 8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (2.6 g, 13.6 mmol), NaH (648 mg, 27 mmol) and iodoethane (3 ml, 37 mmol) in anhydrous DMF (50 ml) was vigorously stirred and heated at 100° C. for one hour. The reaction mixture was evaporated under reduced pressure to dryness and the residue dissolved in 100 ml ice-cold water. The resulting brown emulsion was extracted three times with chloroform, the combined extracts were washed with 2% solution of HCl and brine. The organic phase was treated with decolorizing carbon, stirred at room temperature for an hour and filtered through Celite. After drying over anhydrous magnesium sulfate the filtrate was evaporated to dryness. The residual oil was purified by gravity column chromatography on silica gel using 30% THF in n-hexane as an eluent to yield 2.2 g (74%) of the desired compound as a pale yellow oil.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@H:19]([O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:18]([O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:17]([CH3:38])[O:16][C@H:11]1[O:12][CH2:13][CH:14]=C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:43]CC1>CC(C)=O.O.O=[Os](=O)(=O)=O>[C:1]([O:9][C@H:10]1[C@H:19]([O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:18]([O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:17]([CH3:38])[O:16][C@H:11]1[O:12][CH2:13][CH:14]=[O:43])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCO[C@@H]1O[C@@H](C)[C@@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CC(C)=O
Product: C[C@@H]1O[C@@H](OCC=O)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of prop-2-en-1-yl 2,3,4-tri-O-benzoyl-α-L-fucopyranoside (6.06 g, 11.73 mmol) in acetone (94 mL) and water (23.5 mL) was added 4-methylmorpholine 4-oxide (2.75 g, 23.46 mmol) followed by the addition of 2.5% OsO4 in water (5.97 g, 0.587 mmol). The mixture was allowed to stir at rt for 16 hr. To the resulting mixture was then added a solution of NaIO4 (5.40 g, 23.46 mmol) in water (100 mL). After stirring for additional 6 hr, the precipitate was filtered and washed with acetone (200 mL). The volume of the filtrate was reduced to approximately ⅓ of the initial volume and then extracted with EtOAc (200 mL). The organic phase was separated, washed with sat. NaHCO3 (200 mL). The aqueous phase was extracted with EtOAc (3×100 mL). The organic phases were combined and washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (220 g), eluting with 0-100% EtOAc in hexanes to give the title compound. 1H NMR (CDCl3) δ 1.33-1.29 (3H, m), 3.27 (1H, s), 3.41 (1H, s), 4.35-4.31 (1H, m), 5.51-5.45 (1H, m), 5.75-5.69 (1H, m), 5.81 (1H, dd, J=13.91, 3.57), 6.05-5.98 (1H, m), 7.42 (2H, d, J=7.76), 7.53 (5H, d, J=8.61), 7.67-7.63 (2H, m), 7.84-7.81 (2H, m), 8.01 (2H, t, J=8.82), 8.14-8.12 (2H, m), 9.77-9.77 (1H, m).
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=1)(=[O:3])[NH2:2].[NH2:20][C@@H:21]([CH3:37])[CH2:22][N:23]1[CH:27]=[CH:26][C:25]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([Cl:36])[CH:29]=2)=[N:24]1>>[Cl:36][C:30]1[CH:29]=[C:28]([C:25]2[CH:26]=[CH:27][N:23]([CH2:22][C@@H:21]([NH:20][C:9]([C:7]3[N:8]=[C:4]([C:1]([NH2:2])=[O:3])[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=3)=[O:11])[CH3:37])[N:24]=2)[CH:35]=[CH:34][C:31]=1[C:32]#[N:33]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)nc1C(N)=O
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn(COCC[Si](C)(C)C)c(C(N)=O)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-carbamoyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (400 mg, 1.4 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (366 mg, 1.4 mmol). The product was purified with flash-chromatography. Yield 410 mg. LC-MS: [M+1]=528.24.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].C([O:13][CH2:14][CH3:15])(=O)C>>[C:14]([O:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5])(=[O:13])[C:15]1[CH:7]=[CH:6][CH:2]=[CH:3][CH:4]=1
Reactant: C#CCC(O)CCCC
Reactant: CCOC(C)=O
Product: C#CCC(CCCC)OC(=O)c1ccccc1

Procedure:
From fractions 13-20 is obtained 75 mg of colorless oil, identical to 4-hydroxy-1-octyne, [α]D25 = -17 ± 1.0° (C=0.77, ethyl acetate). This compound has the (R)-configuration.
Reaction SMILES: C([O:8]C1C=CC(C(O)=O)=CC=1)CCCCCC.ON1C2C=CC=CC=2N=N1.[CH:28]1([N:34]=[C:35]=[N:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.NC1C=CC=CC=1O>O1CCCC1>[CH:37]1([NH:36][C:35]([NH:34][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[O:8])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Nc1ccccc1O
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4.7 g of p-heptyloxybenzoic acid, 2.7 g of 1-hydroxybenztriazole (HOBT) and 50 ml of tetrahydrofuran was added 4.2 g of dicyclohexylcarbodiimide (DCC) under ice cooling. After stirring at room temperature for 1 hour, 9 g of o-aminophenol was added to the mixture. The resulting mixture was stirred at room temperature overnight. Dicyclohexyl urea formed was filtered off and the filtrate was concentrated. The residue was dissolved in 500 ml of ethyl acetate. The solution was washed subsequently with diluted hydrochloric acid, a diluted sodium hydrogen carbonate solution and then water, dried over anhydrous magensium sulfate and the concentrated under reduced pressure. The residue was applied to silica gel column chromatography (using 500 ml of silica gel), eluted with a toluene-ethyl acetate (1:1) mixture and further recrystallized from ethanol to obtain 5.6 g of p-heptyloxy-N-(o-hydroxyphenyl)benzamide.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C@H:18]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:21][CH2:20][S:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[C:29]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:30]=[CH:31][C:26]([S:23]([N:22]2[CH2:21][CH2:20][S:19][CH:18]2[C:16]([NH:15][CH:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:6][N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[O:17])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)OCC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Reactant: C1COCCN1
Product: O=C(NC(CCN1CCOCC1)c1ccccc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method A as outlined in Example 16, starting from 3-({[3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and morpholine, the title compound was obtained in 99.3% purity by HPLC.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:23])=[C:7]([CH3:22])[C:8]2[O:12][C:11]([CH3:13])=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]=2[C:20]=1[CH3:21])(=O)C.[OH-].[Na+]>O1CCCC1.CO>[CH3:13][C:11]1[O:12][C:8]2[C:7]([CH3:22])=[C:6]([CH3:23])[C:5]([OH:4])=[C:20]([CH3:21])[C:9]=2[C:10]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)Oc1c(C)c(C)c2oc(C)c(-c3ccccc3)c2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc2c(C)c(C)c(O)c(C)c2c1-c1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of 2,4,6,7-tetramethyl-3-phenylbenzofuran-5-yl acetate (4.00 g, 13.0 mmol) in a mixture of tetrahydrofuran (32 mL) and methanol (8 mL) was added 8N sodium hydroxide solution (2.0 mL) dropwise and the mixture was stirred at 40° C. for 1 hour. The solvent was then distilled off under reduced pressure. To the residue was added 2N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from isopropyl ether-hexane to obtain the title compound (3.0 g, yield 87%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH:17]=[C:18]([Cl:20])[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:21].C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]([F:35])([F:34])[S:30](Cl)(=[O:32])=[O:31]>CN(C)C=O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH:17]=[C:18]([Cl:20])[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[O:21][S:30]([C:29]([F:35])([F:34])[F:28])(=[O:32])=[O:31]
Reactant: CCCC1(CC=C(C)Cl)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC1(CC=C(C)Cl)Cc2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c(Cl)c2C1=O
Temperature: 10 °C
Yield: 98.1 %

Procedure:
6,7-Dichloro-2-(3-chloro-2-butenyl)-2,3-dihydro-5-hydroxy-2-propyl-1H-inden-1-one (24.5 g, 0.0716 mole) was stirred for 11/4 hours at 25° C. in a mixture of potassium carbonate (29.7 g, 0.215 mole) in dimethylformamide (85 ml). The suspension was cooled to 10° C. and trifluoromethanesulfonyl chloride (14.6 g, 0.087 mole) was added. The mixture was stirred 1/3 hour at 10° C., 11/2 hours at 25° C. and then poured over ice and extracted with diethyl ether. The organic extracts were washed with water, dried over MgSO4 and concentrated under vacuum to obtain 33.7 g of the product as an oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6](Cl)=[O:7])=[CH:2]1.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[O:17][CH3:18].[Al+3].[Cl-].[Cl-].[Cl-].CCCCCC>C(=S)=S>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([C:14]2[CH:13]=[CH:12][C:11]([O:17][CH3:18])=[C:10]([Cl:9])[C:15]=2[Cl:16])=[O:7])=[CH:2]1
Reactant: O=C(Cl)c1ccoc1
Reactant: COc1cccc(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: S=C=S
Product: COc1ccc(C(=O)c2ccoc2)c(Cl)c1Cl

Procedure:
3-Furoyl chloride (18.0 g) and 2,3-dichloro anisole (24.7 g) are dissolved in 125 ml of CS2 and treated with AlCl3 (18.7 g), first at 5° C. and then at room temperature. After five hours the reaction is quenched with ice/HCl an extracted with CH2Cl2. Drying and evaporation gives a crystalline product that is titurated with hexane to yield 4-(3-furoyl)-2,3-dichloroanisole, mp 118°-122° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@H:13]([NH:29][CH3:30])[CH2:14][O:15][C:16](=[O:28])[NH:17][C:18]1[N:19]=[CH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31][C:32]1[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:33]=1[CH2:34][NH:35][C:36](=[O:47])OC1C=CC([N+]([O-])=O)=CC=1.CCN(C(C)C)C(C)C>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C@H:13]([N:29]([CH3:30])[C:36]([NH:35][CH2:34][C:33]1[CH:48]=[CH:49][CH:50]=[C:51]([F:52])[C:32]=1[Cl:31])=[O:47])[CH2:14][O:15][C:16](=[O:28])[NH:17][C:18]1[N:19]=[CH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN[C@@H](CNC(=O)OCc1ccccc1)COC(=O)Nc1cc2ccccc2cn1
Reactant: O=C(NCc1cccc(F)c1Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CNC(=O)OCc1ccccc1)COC(=O)Nc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
To a solution of the crude isoquinolin-3-yl-carbamic acid (S)-3-benzyloxycarbonylamino-2-methylamino-propyl ester (9.0 mmol) in THF (35 mL) were added 4-nitrophenyl 2-chloro-3-fluorobenzylcarbamate (2.85 g, 8.79 mmol) and DIEA (2.3 mL, 13.2 mmol) at RT. The reaction mixture was stirred at RT for 30 min. The solvent was removed and the residue was dissolved in EtOAc (400 mL). The organic mixture was washed with NaOH (1 N, 50 mL×3), HCl (0.5 N, 50 mL), saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of EtOAC and hexanes to give Isoquinolin-3-yl-carbamic acid (S)-3-benzyloxycarbonylamino-2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-propyl ester (3.8 g, 71% for two steps) as white foam. LRMS (M+H+) m/z 594.2.
Reaction SMILES: [N:1]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][C@H:2]1C(OC)=O.C([Mg]Br)C.[CH2:29]1[CH2:33][O:32]C[CH2:30]1>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[OH:32][C:33]1([C@@H:2]2[CH2:3][N:4]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:5][CH2:6][N:1]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:30][CH2:29]1
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CC[Mg]Br
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@H](C2(O)CC2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-1,4-di-tert-butyl 2-methyl piperazine-1,2,4-tricarboxylate (3 g; 8.7 mmol) and titanium tetraisopropoxide (0.77 ml; 2.6 mmol), cooled to 0° C. under N2, a 3M solution of ethyl magnesium bromide in THF (8.7 ml; 26 mmol) was added dropwise over 45 minutes. The reaction mixture was left to warm up to room temperature and stirred for 18 hours. The reaction mixture was quenched with a 1M hydrochloric acid aqueous solution. The reaction mixture was diluted with water. Extractions were carried out with ethyl acetate. The combined organics were backwashed with a saturated sodium bicarbonate aqueous solution and brine. The organic was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel (40 g), eluting with petrol/ethyl acetate (0 to 40%). The product was obtained as colourless oil (1.4 g; 50%). 1H NMR (CDCl3) 1.37-1.41 (18H, m), 1.52 (4H, s), 2.80-2.90 (1H, m), 3.10-3.40 (2H, m), 3.50-3.70 (2H, m), 3.80-4.20 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27](Cl)(=[O:29])=[O:28]>>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27]([NH:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=2)[N:14]=1)(=[O:29])=[O:28]
Reactant: Nc1cccc(COCc2ccc(F)cc2)n1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1cccc(COCc2ccc(F)cc2)n1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.07 g) and 2,4-dichloro-6-methyl-benzenesulfonyl chloride (0.086 g) as a light yellow solid (0.11 g). MS (ESI−): 453.1 ([M−H]−).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1>>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:28])=[CH:22][CH:21]=1
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: Cc1ccc(CC(=O)Nn2nc(N3CCOCC3)c3ccccc3c2=O)cc1

Procedure:
The product of Example 1B and 2-(4-methylphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ 8.30 (dd, J=7.9, 0.8, 1H), 8.04-8.02 (m, 1H), 8.01-7.96 (m, 1H), 7.94-7.88 (m, 1H), 7.26 (d, J=8.0, 2H), 7.16 (d, J=7.9, 2H), 3.87-3.78 (m, 4H), 3.61 (s, 2H), 3.13-3.05 (m, 4H), 2.30 (s, 3H); MS (ESI+) M/Z 379 (M+H)+.