Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[CH:5][N:4]=1>C(O)C>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7]([CH:6]=[CH:5][N:4]=[C:3]2[NH2:1])=[CH:8][CH:9]=1
Reactant: N
Reactant: COc1ccc2ccnc(Cl)c2c1
Solvent: CCO
Product: COc1ccc2ccnc(N)c2c1
Temperature: 170 °C

Procedure:
Liquid ammonia (220 mL) was added to a solution of 32.8 g of 1-chloro-7-methoxy-isoquinoline in 420 mL of ethanol in a steel vessel. Nitrogen was pressed upon until an initial pressure of 20 atm. was obtained. This reaction mixture was heated for 2 days at 170° C. The solvent was removed in vacuo and the residue dissolved in water. The pH value was adjusted to pH 10 by adding aqueous sodium carbonate solution, followed by extraction with ethyl acetate. The organic extract was washed with brine and dried (Na2SO4). Evaporation of the solvent in vacuo gave pure 7-methoxy-isoquinolin-1-ylamine as a white solid. Yield 24.0 g (81%); m.p. 128-130° C.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[CH:9]=C([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH:19]1[CH2:21][CH2:20]1)C(O)=O.CN(C)C=O>ClCCl>[Cl:7][C:8]1[CH:9]=[C:1]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH:19]1[CH2:21][CH2:20]1)[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(OCC2CC2)c(Cl)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(OCC2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.8 %

Procedure:
Oxalyl chloride (0.053 mL, 0.6 mmol) was added to a stirred solution of 3-chloro-4-[(cyclopropylmethyl)oxy]benzoic acid (WO 2005058848; 68 mg, 0.3 mmol) in dichloromethane (DCM) (2 ml) containing N,N-dimethylformamide (DMF) (0.02 ml) at 0° under nitrogen, and the mixture was allowed to warm to room temperature with stirring overnight. The solvent was evaporated to give the title compound as a yellow oil (ca 80 mg) which was used crude in the subsequent reaction (D46).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([S:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)(=[O:23])=[O:22])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[C:24]1([S:21]([N:17]2[CH2:16][C:15]3[CH:14]=[N:13][C:12]4[NH:8][N:9]=[CH:10][C:11]=4[C:20]=3[CH2:19][CH2:18]2)(=[O:23])=[O:22])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CN(S(=O)(=O)c2ccccc2)CC4)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1)N1CCc2c(cnc3[nH]ncc23)C1
Temperature: 65 °C
Yield: 5.4 %

Procedure:
To 3-(4-methoxybenzyl)-7-(phenylsulfonyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.109 g, 2.51 mmol) was added trifluoroacetic acid (2 mL). The reaction mixture was heated at 65° C. for 16 hours. On completion of the reaction, toluene (5 mL) was added. The reaction mixture was evaporated to dryness under reduced pressure to yield a dark brown solid. The crude product was purified using reverse phase HPLC chromatography to give the desired product, 7-(phenylsulfonyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine as a white solid (0.043 g, 54%). M.p.=270-271° C.; 400 MHz 1H NMR (DMSO-d6) δ: 13.59 (s, 1H), 8.33 (s, 1H), 8.1 (d, J=1.2 Hz, 1H), 7.88-7.84 (m, 2H), 7.73-7.61 (m, 3H), 4.35 (s, 2H), 3.43 (t, J=5.6 Hz, 2H), 3.14 (t, J=6.4 Hz, 2H); LCMS [M+H]: 315.
Reaction SMILES: [C:1]([O:10][CH2:11][CH2:12][CH:13]1[O:18][CH2:17][CH2:16][CH2:15][O:14]1)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23](S(C)(=O)=O)[N:22]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([O:10][CH2:11][CH2:12][CH:13]2[O:14][CH2:15][CH2:16][CH2:17][O:18]2)=[O:9])[N:22]=1
Reactant: O=C(OCCC1OCCCO1)c1ccccc1O
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)nc(Oc2ccccc2C(=O)OCCC2OCCCO2)n1
Reaction time: 1 h

Procedure:
0.84 Gram of 2-(1,3-dioxan-2-yl)ethyl salicylate and 0.73 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine was dissolved in 10 ml of N,N-dimethylformamide, and 0.51 g of anhydrous potassium carbonate was added thereto. The resulting solution was stirred at 100° to 110° C. for 1 hour. The reaction solution was allowed to cool, poured into diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer separated from the aqueous layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (mfd. by Merck & Co., Inc., solvent: chloroform) to obtain 0.50 g of 2-(1,3-dioxan-2-yl)ethyl 2-(4,6-dimethoxypyrimidin-2-yl)oxybenzoate [present compound (V-1)].
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]([O:18]C)=[O:17])[CH:12]=3)[CH2:7]2)[CH2:5][CH2:4][NH:3]1.[OH-].[Li+].Cl>C1COCC1.O>[O:1]=[C:2]1[C:6]2([CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]([OH:18])=[O:17])[CH:12]=3)[CH2:7]2)[CH2:5][CH2:4][NH:3]1
Reactant: COC(=O)c1ccc2c(c1)CCC1(CCNC1=O)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(c1)CCC1(CCNC1=O)C2

Procedure:
A stirred solution of (±)-methyl 2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate from Step F (50 mg, 0.193 mmol) and lithium hydroxide (24 mg, 0.578 mmol) in THF (3 mL) and H2O (1 mL) was heated at reflux for 5 h, then allowed to cool. The mixture was poured into 10% aqueous HCl (10 mL) and extracted with EtOAc (3×20 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with CH2Cl2 to give the title compound. MS: m/z=246 (M+1).
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[C:16]([C:17]4[C:22]([C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][C:14](B(O)O)=[C:13]1[C:8]=3[CH:9]=[CH:10][CH:11]=[CH:12]1.[Br:26][C:27]1[CH:28]=[C:29](I)[CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:26][C:27]1[CH:28]=[C:29]([C:14]2[CH:15]=[C:16]3[C:7](=[C:8]4[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]4)[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:22]2[C:17]3=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: OB(O)c1cc2c3ccccc3c3ccccc3c2c2ccccc12
Reactant: Brc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2cc3c4ccccc4c4ccccc4c3c3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Under an argon atmosphere, 3.86 g of the benzo[g]chrysene-10-boronic acid which had been prepared in Synthesis Example 3, 2.83 g of 3-bromoiodobenzene, 0.231 g of tetraxis(triphenylphosphine)palladium(0), 40 mL of toluene and 20 mL of a 2M aqueous solution of sodium carbonate were placed in a flask. The resultant was refluxed with stirring for 8 hours. After cooling to room temperature, the reaction solution was extracted with toluene. An aqueous phase was removed, and an organic phase which had been separated was washed with water and then with saturated brine, and dried with magnesium sulfate. After the magnesium sulfate was filtered out, the organic phase was concentrated. The resulting residue was purified by a silica gel column chromatography, whereby 4.12 g (yield: 95%) of 10-(3-bromophenyl)benzo[g]chrysene was obtained.
Reaction SMILES: C(OC([C:11]1[NH:12][C:13]2[CH2:14][CH2:15][C:16]([CH3:23])([CH3:22])[C:17](=[O:21])[C:18]=2[C:19]=1[CH3:20])=O)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:20][C:19]1[C:18]2[C:17](=[O:21])[C:16]([CH3:23])([CH3:22])[CH2:15][CH2:14][C:13]=2[NH:12][CH:11]=1
Reactant: [H][H]
Reactant: Cc1c(C(=O)OCc2ccccc2)[nH]c2c1C(=O)C(C)(C)CC2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c[nH]c2c1C(=O)C(C)(C)CC2
Reaction time: 0.5 h

Procedure:
3,5,5-trimethyl-4-oxo-4,5,6,7-tetrahydroindole-2-carboxylic acid benzyl ester from the previous step, 6.60 g (21.20 mmol) and 2.0 g of 10% Pd—C was suspended in ethyl acetate 150 mL and hydrogenated under balloon of hydrogen for 3 hours. The reaction mixture was diluted with methanol 0.5 L and the mixture was stirred under Ar for 30 min to dissolve the precipitated carboxylic acid intermediate. The catalyst was then removed by filtration and the filtrates were evaporated to dryness and dried on highvac. The residue was dissolved in trifluoroacetic acid 40 mL, the solution was stirred on a 45° C. bath for 30 min, then evaporated to dryness. The residue was dried on highvac. The crude material was applied onto a column of silica (60 g) in dichloromethane and eluted with 10:1 dichloromethane-ethyl acetate mixture. Y=3.17 g (84% overall) of 3,5,5-trimethyl-4-oxo-4,5,6,7-tetrahydroindole as a white solid that gradually turns pink on air and light. 1H-NMR (d6-DMSO, 400 MHz): 10.89 (br s, 1H), 6.44 (s, 1H), 2.72 (t, 6.3 Hz, 2H), 2.12 (s, 3H), 1.85 (t, 6.3 Hz, 2H), 1.04 (s, 6H)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C1COCC1.[CH3:11][N:12]([CH2:14][CH:15]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH2:16]1)[CH3:13].C(N(CC)CC)C>C(=O)(O)[O-].[K+]>[CH3:13][N:12]([CH2:14][CH:15]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:16]1)[CH3:11]
Reactant: CN(C)CC1CNc2ccccc2C1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CC1Cc2ccccc2N(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.1 %

Procedure:
Methanesulfonyl chloride (0.6 g) was added to a THF (20 ml) solution of 3-(N,N-dimethylamino)methyl-1,2,3,4-tetrahydroquinoline (Reference Example 44; 1 g) under ice-cooling. The reaction mixture was stirred at room temperature for 10 minutes, to which was added triethylamine (2 ml), and the mixture was further stirred at room temperature for 3 hours. The reaction mixture was diluted with a saturated aqueous potassium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, then dried and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate) and recrystallized from IPE to obtain the entitled compound (1 g).
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[CH3:24][C:25]1[O:29][N:28]=[C:27]([C@:30]([OH:34])([C:32]#[CH:33])[CH3:31])[N:26]=1>>[F:23][C:3]1[C:2]([C:33]#[C:32][C@@:30]([OH:34])([C:27]2[N:26]=[C:25]([CH3:24])[O:29][N:28]=2)[CH3:31])=[CH:22][C:6]2[C:7]3[N:8]([C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(C#C[C@@](C)(O)c3noc(C)n3)cc1-2

Procedure:
10-Bromo-9-fluoro-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide (0.08 g) was reacted with (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol similar to as described in Procedure E to afford 8.6 mg of 9-fluoro-10-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 455 (M)+. 1H NMR (400 MHz, DMSO) δ 11.09 (q, J=4.4 Hz, 1H), 8.65 (d, J=8.3 Hz, 1H), 8.38 (s, 1H), 7.86 (s, 1H), 7.06 (d, J=10.5 Hz, 1H), 6.76 (s, 1H), 6.59 (s, 1H), 5.08-4.94 (m, 2H), 4.63-4.41 (m, 2H), 2.80 (d, J=4.5 Hz, 3H), 2.62 (s, 3H), 1.86 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][CH:8]([CH2:14][CH2:15][CH2:16][CH2:17][B:18]2[O:22]C(C)(C)C(C)(C)[O:19]2)[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1>Cl>[ClH:1].[B:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH:8]([NH:7][CH2:6][C:5]1[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:9]([OH:11])=[O:10])([OH:19])[OH:22]
Reactant: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)NCc1ccc(Cl)cc1
Agent: Cl
Product: O=C(O)C(CCCCB(O)O)NCc1ccc(Cl)cc1
Yield: 148.8 %

Procedure:
A solution of ethyl 2-(4-chlorobenzylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (59 mg) in aq 6 M HCl was heated to reflux for 16 h, concentrated to dryness and purified by preparative HPLC. The residue was redissolved in 2 N HCl and evaporated to give 6-borono-2-(4-chlorobenzylamino)hexanoic acid hydrochloride (36 mg, 83%). 1H NMR (CD3OD, 300 MHz) δ 7.56-7.46 (m, 4H), 4.23 (s, 2H), 4.09-3.98 (m, 1H), 2.02-1.91 (m, 2H), 1.52-1.37 (m, 4H), 0.81 (t, J=7.0 Hz, 2H). ESI MS found for C13H19B1Cl1N1O4 m/z [300.2 (M+1)].
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH:24][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:4][CH3:5])[CH3:2]
Reactant: O=C1CCC(=O)O1
Reactant: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1NC(=O)CCC(=O)O
Temperature: 25 °C

Procedure:
A mixture of 4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylamine (100 mg, 0.304 mmol), succinic anhydride 31 mg,0.304 mmol) and triethylamine in methylene chloride was stirred at rt. overnight. The mixture was quenched with water, and extracted with methylene chloride. The organic layer was separated, dried and concentrated to give a solid. The title compound was isolated as a white crystal after silica gel column chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](O)=[O:8].S(Cl)([Cl:21])=O>ClCCCl>[NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([Cl:21])=[O:8]
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)Cl)c1I
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-Amino-3-acetoxymethyl-2,4,6-triiodobenzoic acid (43.9 g, 0.075 mol) was suspended in 1,2-dichloroethane (40 ml) and thionyl chloride (24.9 ml, 0.34 mol) was added. The mixture was heated to reflux temperature for 3 h. After evaporation to dryness, the residue was dissolved in tetrahydrofuran (50 ml). Sodium hydrogen carbonate (15 g) and crystalline sodium carbonate (5 g) were added to the solution and the mixture was stirred at room temperature for 3 h. The mixture was filtered and the filtrate evaporated to dryness. After pump-drying, a foam was formed, yield 44.6 g (98%). This material was used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:25][CH3:26])=[C:13]([C:16]3([C:21](OC)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:14]=2)[C@H:9]([N:27]([CH2:32][C:33]2[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=2)[C:28]([O:30][CH3:31])=[O:29])[CH2:8][C@@H:7]1[CH3:47])=[O:5])[CH3:2].B.CSC>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:25][CH3:26])=[C:13]([C:16]3([CH2:21][OH:22])[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:14]=2)[C@H:9]([N:27]([CH2:32][C:33]2[CH:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[C:35]([C:43]([F:45])([F:44])[F:46])[CH:34]=2)[C:28]([O:30][CH3:31])=[O:29])[CH2:8][C@@H:7]1[CH3:47])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(C3(C(=O)OC)CCCC3)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CCOC(=O)N1c2cc(C3(CO)CCCC3)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Yield: 3 %

Procedure:
To a solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methoxy-7-(1-methoxycarbonyl-cyclopentyl)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 27) (700 mg; 1.04 mmol) in 20 mL anhydrous tetrahydrofuran was added borane-dimethylsulfide complex (1M THF; 2.28 mL) and the reaction was heated to reflux for 3 hours. The reaction was quenched with H2O and extracted with 50 mL of ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated. The residue was chromatographed (25% ethyl acetate-hexane) to afford the title product (20 mg). MS m/z 664 (M+ +18); 1H NMR (CDCl3) δ 1.1 (d, 3H), 3.6 (s, 2H), 3.7 (s, 3H), 3.8 (s, 3H), 6.3 (s, 1H), 7.3 (S, 1H), 7.7 (S, 2H), 7.8 (S, 1H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[OH-].[Na+].[S:12]1(=[O:18])(=[O:17])[CH2:16][CH2:15][CH2:14][NH:13]1>O>[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:13]2[CH2:14][CH2:15][CH2:16][S:12]2(=[O:18])=[O:17])=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCN1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S1(=O)CCCN1Cc1ccncc1
Reaction time: 2 h

Procedure:
A mixture of 4-picolylchloride hydrochloride (2.7 g) was stirred in water (10 cm3) with sodium hydroxide (1.3 g) during the addition of isothiazolidine-1,1-dioxide (2.0 g) in water (5 cm3). After stirring for 2 hours the mixture was extracted with chloroform (3×15 cm3) and the dried (MgSO4) extracts were evaporated in vacuo to give an oil which was chromatographed on silica (MK 60. 9385) eluting with ethyl acetate to give an oil which crystallised from ethyl acetate affording 2-(4-pyridylmethyl)isothiazolidine-1,1-dioxide as white crystals, m.p. 82° (3.5 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5]=[CH:6][C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[C:23]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[O:14])[S:10][CH:11]=1)[CH3:2]>[Pd]>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[C:23]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[O:14])[S:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Agent: [Pd]
Product: CCOC(=O)CCc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Yield: 93.1 %

Procedure:
3-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-propionic acid ethyl ester (48 mg, 96%) was prepared by hydrogenation of 3-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acrylic acid ethyl ester (0.05 g, 0.12 mmol) with Pd/C.
Reaction SMILES: [NH2:1][C@H:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][CH2:4][NH:5][C:6]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:8]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:7]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>CO>[C:33]([NH:1][C@H:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][CH2:4][NH:5][C:6]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[C:8]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:7]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(NCC[C@H](N)c2ccccc2)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Solvent: CO
Product: CC(=O)N[C@@H](CCNc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c(=O)n1C)c1ccccc1

Procedure:
A solution of 2-(((S)-3-amino-3-phenylpropyl) -amino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone (23.8 mg, 0.055 mmol) and acetic anhydride (20 μl, 0.21 mmol) in methanol(1 ml) was kept for 30 min at room temperature. Evaporation was followed by column chromatography (dichloromethane-methanol-ammonium hydroxide=93:7:0.7) to provide the title compound. MS (m/z): 472.2 (M+H)+; C27H26FN5O2requir. 471.5.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[I:15]Cl.O>C(O)(=O)C>[OH:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[I:15]
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: ClI
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(I)c(O)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 91075.4 %

Procedure:
To a solution of methyl 4-hydroxy-3-nitrobenzoate (2.0 g) in acetic acid (15 mL) was added iodine monochloride (1.65 mg) in acetic acid, and the mixture was stirred at 100° C. for 1.5 h. After cooling to room temperature, the mixture was poured into water (200 mL), and stirred for 30 min. The mixture was filtered and washed with water and hexanes. The yellow powder was collected by filtration and dried in vacuum oven overnight to give 2.99 g of the title compound: 1H NMR (300 MHz, CDCl3) δ 11.68, 8.81, 8.72, 3.96.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH3:47])[C:4](=[O:48])[CH:3]=1.[CH3:49][CH2:50][O:51][C:52]([CH2:54][SH:55])=[O:53].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:50]([O:51][C:52]([CH2:54][S:55][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH3:47])[C:4](=[O:48])[CH:3]=1)=[O:53])[CH3:49]
Reactant: CCOC(=O)CS
Reactant: CCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CSc1cc(=O)n(CC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 33 %

Procedure:
A mixture of 6-chloro-3-ethyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.6 g), ethyl thioglycollate (0.13 ml) and potassium carbonate (0.19 g) in acetonitrile (10 ml) was heated under reflux for 10 hours with stirring. The reaction mixture was allowed to cool and the precipitate was removed by filtration. The filtrate was concentrated to dryness. The resulting residue was dissolved in methanol (15 ml) and 1N hydrochloric acid (1.5 ml), followed by stirring at room temperature for 7 hours. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give pale yellow amorphous powders (0.15 g, 33%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[CH2:13]([Mg]Cl)[CH2:14][CH3:15]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:11])[CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1
Reactant: CCC[Mg]Cl
Reactant: COC(=O)c1ccc(C=O)cc1
Product: CCCC(O)c1ccc(C(=O)OC)cc1

Procedure:
This compound is made from 4-formyl-benzoic acid methyl ester and n-propylmagnesium chloride following the general method exemplified in Preparation 1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][O:17]2)=[CH:4][CH:3]=1.[CH3:23][NH:24][CH3:25]>O1CCCC1>[CH3:23][N:24]([CH3:25])[CH2:18][CH:16]([OH:17])[CH2:15][O:14][C:13]1[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(CCCCc2ccccc2OCC2CO2)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: Cc1ccc(CCCCc2ccccc2OCC(O)CN(C)C)cc1
Yield: 89 %

Procedure:
Following a procedure similar to that described in Example 1(b), a solution of 0.63 g of 2-{2-[4-(4-methylphenyl)butyl]phenoxymethyl}oxirane [prepared as described in step (a) above] in 10 ml of tetrahydrofuran was treated with 2 ml of 50% by volume aqueous dimethylamine. The crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 0.65 g (yield 89%) of the title compound as a colorless oil.