Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[C:24](=[O:31])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[NH2:25].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C(Cl)Cl.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]>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([NH:25][C:24](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(NC(=O)OC(C)(C)C)cc1OCC2
Temperature: 110 °C
Yield: 61.8 %

Procedure:
A mixture of 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 194 (250 mg, 0.67 mmol), t-butyl carbamate (390 mg, 3.3 mmol), cesium carbonate (440 mg, 1.3 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (58 mg, 0.10 mmol), and tris(dibenzylideneacetone)dipalladium(0) (46 mg, 0.05 mmol) was suspended in 1,4-dioxane (5.2 mL) and heated at 110° C. for 24 hr. The reaction mixture was cooled to ambient temperature, diluted with DCM, and filtered to remove solids. The crude mixture was absorbed onto celite for purification by flash chromatography to afford tert-butyl 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-ylcarbamate as a yellow crystalline solid (170 mg, 61%). 1H NMR (400 MHz, DMSO) δ 9.56 (d, J=12.5 Hz, 1H), 8.27 (d, J=8.8 Hz, 1H), 7.89 (s, 1H), 7.85 (s, 1H), 7.26 (t, J=5.8 Hz, 1H), 7.23-7.14 (m, 1H), 5.89 (hept, J=6.6 Hz, 1H), 4.52-4.42 (m, 4H), 1.47 (d, J=6.6 Hz, 6H)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[NH:22]1[CH2:25][CH:24]([CH2:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]3[NH:34][C:35]4[N:51]=[C:39]([NH:40][C:41]5[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=5)[CH2:46][CH2:47][C:48]=2[CH:49]=3)[N:38]=[CH:37][C:36]=4[Cl:52])=[O:28])[CH2:23]1.[O:53]1[C:57]([C:58](Cl)=[O:59])=[CH:56][CH:55]=[N:54]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:52][C:36]1[CH:37]=[N:38][C:39]2[NH:40][C:41]3[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=3)[CH2:46][CH2:47][C:48]3[CH:49]=[C:33]([NH:34][C:35]=1[N:51]=2)[CH:32]=[CH:31][C:30]=3[NH:29][C:27](=[O:28])[CH2:26][CH:24]1[CH2:23][N:22]([C:58]([C:57]2[O:53][N:54]=[CH:55][CH:56]=2)=[O:59])[CH2:25]1
Reactant: O=C(Cl)c1ccno1
Reactant: O=C(CC1CNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CN(C(=O)c2ccno2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 68 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 2-azetidin-3-yl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide tris(trifluoroacetate) and isoxazole-5-carbonyl chloride as the starting materials in 68% yield. LCMS for C26H24ClN8O3 (M+H)+: m/z=531.0.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH:11]([CH2:18][N+:19]([O-])=O)[CH2:12][C:13](OCC)=[O:14])=[CH:5][C:4]=1[O:22][CH3:23])[CH3:2]>C(O)C>[CH2:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH:11]2[CH2:18][NH:19][C:13](=[O:14])[CH2:12]2)=[CH:5][C:4]=1[O:22][CH3:23])[CH3:2]
Reactant: CCOC(=O)CC(C[N+](=O)[O-])c1cc(OC)c(CC)c(OC)c1
Solvent: CCO
Product: CCc1c(OC)cc(C2CNC(=O)C2)cc1OC
Reaction time: 2.5 h
Yield: 76.5 %

Procedure:
15.1 g (46.4 mmol) of ethyl 3-(4-ethyl-3,5-dimethoxy-phenyl)-4-nitro-butanoate dissolved in 300 ml of ethanol were hydrogenated on Raney-nickel while stirring over a period of 2.5 hours. The catalyst was filtered off, washed several times with ethanol and the combined ethanol phases were concentrated in a vacuum to a volume of 200 ml. The reaction mixture was treated with 1.7 g of sodium acetate and 50 mg of p-toluenesulphonic acid and heated under reflux over 24 hours. Subsequently, the mixture was concentrated in a vacuum and the residue was purified by column chromatography on silica gel (methylene chloride/methanol 19:1). 8.85 g (76%) of 4-(4-ethyl-3,5-dimethoxy-phenyl)-pyrrolidin-2-one were obtained as a beige solid with m.p. 156°.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Cl>ClCCl.CN(C1C=CC=CN=1)C>[C:18]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.2 %

Procedure:
13.8 Grams (0.1 mol) of 4-hydroxybenzoic acid was dissolved in 140 ml of dichloromethane. To this mixture were consecutively added 16 ml of triethylamine, 20.1 g (0.11 mol) of n-decanoic acid chloride and 0.97 g (0.0079 mol) dimethylaminopyridine, and the mixture was stirred at room temperature over 1 day and night. To this reaction mixture was added 50 ml of 10% hydrochloric acid, and the mixture was extracted with 100 ml of ether three times. An organic layer was washed with 100 ml of sodium chloride aqueous solution three times, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was washed with 400 ml of hexane to give 25.5 g (yield 82%) of 4-decanoyloxybenzoic acid as an end product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: C1CCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Product: COc1cc(N2CCCCC2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared according to the method described for Preparation 78 using 4-fluoro-2-methoxy-1-nitrobenzene and piperidine. The residue was purified using silica gel column chromatography eluting with 50-80% DCM in cyclohexanes.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:31])[C:7]([NH:9][O:10][CH:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1)=[O:8])C>O1CCCC1CO>[F:30][C:27]([F:28])([F:29])[O:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([N:14]2[CH2:15][CH2:16][CH:11]([O:10][NH:9][C:7](=[O:8])[C:6]([OH:31])=[O:5])[CH2:12][CH2:13]2)(=[O:19])=[O:18])=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(=O)NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: O=C(O)C(=O)NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Aqueous 1 N NaOH solution (5 ml) was added to a solution of N-[1-(4-trifluoromethoxybenzenesulfonyl)piperidin-4-yloxy]oxalamic acid ethyl ester in tetrahydrofuran-methanol (1:1, 10 ml) and stirred at room temperature for 1 hour. The reaction was quenched with aqueous 1 N HCl solution (6 ml). The resulting precipitation was collected and washed with H2O to give N-[1-(4-trifluoromethoxybenzenesulfonyl)piperidin-4-yloxy]oxalamic acid (422 mg).
Reaction SMILES: [CH:1]([N:4]([CH:35]([CH3:37])[CH3:36])[C:5]([NH:7][C:8]1[C:9]([C:19]2[NH:23][C:22]3[CH:24]=[C:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)[CH:26]=[CH:27][C:21]=3[N:20]=2)=[N:10][N:11](C2CCCCO2)[CH:12]=1)=[O:6])([CH3:3])[CH3:2].Cl>O1CCOCC1>[CH:35]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([NH:7][C:8]1[C:9]([C:19]2[NH:23][C:22]3[CH:24]=[C:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)[CH:26]=[CH:27][C:21]=3[N:20]=2)=[N:10][NH:11][CH:12]=1)=[O:6])([CH3:37])[CH3:36]
Reactant: CC(C)N(C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2ccc(N3CCN(C)CC3)cc2[nH]1)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)N(C(=O)Nc1c[nH]nc1-c1nc2ccc(N3CCN(C)CC3)cc2[nH]1)C(C)C
Yield: 51.6 %

Procedure:
A solution of 230 mg of 1,1-diisopropyl-3-[3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]urea in solution in 40 eq of a 4N solution of hydrochloric acid in dioxane is stirred at 22° C. for approximately 4 hours, and precipitation occurs. The suspension is filtered through sintered glass and the solid is rinsed with dioxane and with isopropyl ether. The precipitate is dried in an oven. The precipitate is dissolved in 5 mL of 2N NaOH, and then extracted with 2 times 5 mL of ethyl acetate then 2 times 10 mL of ethyl acetate. The organic phases are dried over MgSO4, filtered and concentrated under vacuum in a rotary evaporator. The concentrate is purified by preparative HPLC with, as eluent, a gradient of water/acetonitrile containing respectively 0.07% of trifluoroacetic acid. 99 mg of 1,1-diisopropyl-3-{3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}urea are isolated in the form of a pale yellow powder. 1H NMR (400 MHz, DMSO-d6, δ in ppm): 1.25 (d, J=7.0 Hz, 12H); 2.90 (s, 3H); 3.03 (m, 2H); 3.23 (m, 2H); 3.58 (m, 2H); 3.87 (m, 4H); 7.12 (d, J=2.0 Hz, 1H); 7.24 (dd, J=2.0 and 9.0 Hz, 1H); 7.58 (d, J=9.0 Hz, 1H); 7.98 (s, 1H).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH:21]1([C:27]#[CH:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C1(CC#C)CCCC1>>[CH:25]1([CH2:24][C:23]#[C:22][C:2]2[N:3]=[C:4]([NH2:20])[C:5]3[N:6]=[CH:7][N:8]([C:18]=3[N:19]=2)[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH2:26][CH2:21][CH2:27][CH2:28]1
Reactant: C#CC1CCCCC1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: C#CCC1CCCC1
Product: Nc1nc(C#CCC2CCCC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 70.3 %

Procedure:
The procedure of Example 1 was repeated except that 1.56 g (3.98 mmol) of 2-iodoadenosine was used as the starting compound and that the cyclohexylacetylene was replaced by 3-cyclopentylpropyne, whereby 1.05 g (2.8 mmol) of crystalline 2-(3-cyclopentyl-1-propynyl)adenosine was obtained (yield: 70.3%).
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][C:13]([O:15]CC)=[O:14])=[CH:10][N:9]([CH2:18][C:19]3[CH:20]=[N:21][C:22]([O:25][CH2:26][C:27]4[N:28]=[C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[S:30][CH:31]=4)=[CH:23][CH:24]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:11]([CH2:12][C:13]([OH:15])=[O:14])=[CH:10][N:9]([CH2:18][C:19]3[CH:20]=[N:21][C:22]([O:25][CH2:26][C:27]4[N:28]=[C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[S:30][CH:31]=4)=[CH:23][CH:24]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)nc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)Cc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)nc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
After a mixture of ethyl [3-phenyl-1-(6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]acetate (536 mg), 1N sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml), and ethanol (4 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (2 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain [3-phenyl-1-[6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]acetic acid (459 mg, yield: 91%). This was recrystallized from ethanol-hexane. Melting point: 118–119° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([O:17]CC)=[O:16])[N:12]=[C:11]2[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[OH-].[Na+].Cl>O1CCCC1.O.CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[N:12]=[C:11]2[C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)c1cn(-c2cccc(OCC)c2)c(-c2ccc(C)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cccc(-n2cc(C(=O)O)nc2-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.75 g (2.1 mmol) of ethyl 1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazole-4-carboxylate in 10 mL of tetrahydrofuran, 5 mL of water and 5 mL of methanol was added 0.80 mL (4.0 mmol) of 5.0 M NaOH solution. The reaction mixture was stirred at ambient temperature overnight. Next, hydrochloric acid (2.0 M) was added to neutralize the reaction mixture. After removal of the organic solvents in vacuo, dichloromethane (20 mL) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (10 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a yellow foam. LC/MS 323.3 (M+1).
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[F:29][C:30]1([F:34])[CH2:33][NH:32][CH2:31]1>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:25])([CH3:26])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([N:32]2[CH2:33][C:30]([F:34])([F:29])[CH2:31]2)=[O:20])[C:14]1([CH3:21])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: FC1(F)CNC1
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)O)C1(C)C
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)N2CC(F)(F)C2)C1(C)C

Procedure:
The product from Example 173 and 3,3-difluoroazetidine hydrochloride (Oakwood) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.51 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.22 (s, 3H), 1.25 (s, 3H), 1.26-1.36 (m, 2H), 1.39-1.48 (m, 1H), 1.57 (s, 9H), 1.57-1.78 (m, 3H), 1.93-2.05 (m, 1H), 2.62-2.67 (m, 2H), 2.73-2.83 (m, 1H), 2.88-2.94 (m, 1H), 4.14-4.37 (m, 2H), 4.41-4.53 (m, 1H), 4.74-4.86 (m, 1H), 8.51 (s, 1H). (ESI+) m/z 470 (M+H)+.
Reaction SMILES: S.[Na].Cl.[Cl:4][C:5]1[C:6]([C:18]2[CH:23]=[C:22]([S:24]([CH3:26])=O)[N:21]=[C:20]([NH2:27])[N:19]=2)=[C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]2=[C:9]([CH:17]=1)[CH2:10][O:11][CH2:12]3.C(N(CC)C(C)C)(C)C.ClC[CH2:39][NH:40][C:41]([NH2:43])=[O:42]>CN(C)C=O.C(OC(=O)C)C>[NH2:27][C:20]1[N:21]=[C:22]([S:24][CH2:26][CH2:39][NH:40][C:41]([NH2:43])=[O:42])[CH:23]=[C:18]([C:6]2[C:5]([Cl:4])=[CH:17][C:9]3[CH2:10][O:11][CH2:12][C:13]4[C:8]=3[C:7]=2[CH:16]=[CH:15][CH:14]=4)[N:19]=1
Reactant: CS(=O)c1cc(-c2c(Cl)cc3c4c(cccc24)COC3)nc(N)n1
Reactant: NC(=O)NCCCl
Agent: Cl
Agent: S
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)NCCSc1cc(-c2c(Cl)cc3c4c(cccc24)COC3)nc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
Sodium hydrogen sulfide (1.07 g) was dissolved in N,N-dimethylformamide (25 ml). To the mixture was added 4N hydrogen chloride in ethylacetate (13.3 ml) at room temperature. After stirring for approximately 30 minutes at the same temperature, to the resulting mixture were added 4-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-6-methanesulfinyl-pyrimidin-2-ylamine (1.20 g) obtained in Step 5 of Example 314 and N,N-diisopropylethylamine (2.9 ml) successively. The mixture was stirred at 80° C. for four hours, and then the mixture was allowed to cool to room temperature. To the mixture were added to 2-chloro-ethylurea (3.20 g), N,N-diisopropylethylamine (5.8 ml) and N,N-dimethylformamide (15 ml) successively. The reaction mixture was stirred at 80° C. for 14 hours and then allowed to cool to room temperature. The reaction was quenched by adding water and extracted with ethyl acetate. The organic layer was separated, washed with water and brine subsequently, dried over anhydrous sodium sulfate. After removal of inorganic salts, the solution was concentrated by evaporation. The resulting residue was purified by HPLC (column; ODS, mobile phase; 0.05% TFA in water: 0.05% TFA in acetonitrile=65:35) to give {2-[2-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-pyrimidin-4-ylsulfanyl]-ethyl}-urea (0.93 g).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[N:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.Cl.[NH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[C:8]([C:9]([NH:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=3)=[O:10])=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][N:15]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1Oc1ccc(F)cc1
Agent: Cl
Product: COC(=O)c1ccc(CNC(=O)c2cc(C(F)(F)F)cnc2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2-(4-fluorophenoxy)-5-(trifluoromethyl)nicotinic acid (step 3) and methyl 4-(aminomethyl)benzoate hydrochloride: 1H-NMR (CDCl3) δ 8.90 (1H, d, J=2.7 Hz), 8.45 (1H, s), 8.01 (2H, d, J=8.2 Hz), 7.43 (2H, d, J=8.2 Hz), 4.78 (2H, d, J=5.9 Hz), 3.90 (3H, s); MS (ESI) m/z 449 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C@H:7]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:8][C:9](=[O:24])[CH:10]([C:21](O)=[O:22])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:41]([O:48][NH2:49])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CN1CCOCC1>CN(C=O)C>[C:1]([O:5][C:6](=[O:29])[C@H:7]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:8][C:9](=[O:24])[CH:10]([C:21](=[O:22])[NH:49][O:48][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C[C@H](NC(=O)C(Cc1ccc(C(C)C)cc1)C(=O)O)C(=O)OC(C)(C)C
Reactant: NOCc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)C(Cc1ccc(C(C)C)cc1)C(=O)NOCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 48 h

Procedure:
The residue from stage (d) was stirred in DMF at -15° C. for 1 hour with HOBT (2 equiv) and DCCl (1 equiv). To the mixture was added a precooled solution of O-benzylhydroxylamine hydrochloride (1 equiv) and NMM (1 equiv) in DMF and stirring continued for 48 hour at +4° C. The product was filtered, the filtrate concentrated in vacuo, dissolved in ethyl acetate and acid/base washed in the normal manner. The solution was dried (MgSO4), evaporated in vacuo and the residue used the next stage without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-])=O)=[C:9]([CH3:14])[C:8]([Cl:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O-]S(S([O-])=O)=O.[Na+].[Na+].Cl.C([O-])([O-])=O.[Na+].[Na+]>COCCO.O>[NH2:11][C:10]1[C:2]([Cl:1])=[C:3]([CH:7]=[C:8]([Cl:15])[C:9]=1[CH3:14])[C:4]([OH:6])=[O:5]
Reactant: Cc1c(Cl)cc(C(=O)O)c(Cl)c1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: O
Solvent: COCCO
Product: Cc1c(Cl)cc(C(=O)O)c(Cl)c1N
Temperature: 25 °C

Procedure:
43 g of 2,5-dichloro-4-methyl-3-nitrobenzoic acid and 108.8 g of Na2S2O4 are boiled in a mixture of 340 ml of glycol monomethyl ether and 340 ml of water for 3 hours. 480 ml of 1/2-concentrated HCl are added to the still warm solution and the mixture is then boiled up once again. After cooling to room temperature, the mixture is poured into 1 l of ice-water and the strongly acid solution is buffered with Na2CO3 (pH 5). The solid which has precipitated is isolated and dried. Melting point: 218°-21°, yield: 32.5 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][C@H:8]([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].I[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[C:1]([O:5][C:6](=[O:16])[C@@H:7]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@@H:8]([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCCI
Reactant: CCCCCC[C@@H](O)CC(=O)OC(C)(C)C
Product: CCCCCC[C@H](O)[C@H](CCCCC)C(=O)OC(C)(C)C

Procedure:
The target compound (2.00 g, 31%) was obtained in the same manner as in Production Example C-1, except that the (R)-3-hydroxynonanoic acid t-butyl ester (5.00 g, 21.7 mmol) obtained in Production Example B-3 and 1-iodopentane (5.59 g, 28.2 mmol) were used.
Reaction SMILES: [OH-].[Na+].[C:3]([OH:13])(=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[Cl-].[Zn+2:15].[Cl-]>O>[C:3]([O-:13])(=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[Zn+2:15].[C:3]([O-:13])(=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: O=C(O)C(O)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])C(O)c1ccccc1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 60.9 %

Procedure:
A solution of 47% (w/w) sodium hydroxide (5.5 g) is added to slurry of mandelic acid (7.6 g, 0.05 mol) in water (100 mL) at 70° C. to give a clear slightly alkaline solution. A solution of zinc chloride (3.4 g, 0.025 mol) in water (50 mL) is added and a precipitate is formed immediately. The mixture is stirred at 70° C. for further 2.5 hours. The precipitate is then filtered and dried to yield 5.6 g (61%) zinc mandelate as a fine white powder. IR absorption bands: 1592, 1404 and 1361 cm−1.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH3:22])=[CH:16][CH:17]=4)[CH:12]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=4[O:31][CH2:32][CH2:33][OH:34])[CH:11]3[C:35]([O:37]C)=[O:36])=[CH:9][C:4]=2[O:3][CH2:2]1.C1COCC1.O[Li].O.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CCOC(C)=O.CO>[OH:34][CH2:33][CH2:32][O:31][C:24]1[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:23]=1[C@@H:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH3:22])[CH:14]=2)[C@H:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)[C@H:11]1[C:35]([OH:37])=[O:36]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCCO)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCCO)[C@H](C(=O)O)[C@H]2c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A 10 mL three-necked flask equipped with reflux condenser was charged with [1S -(1α, 2α, 3α)]-methyl 1-(1,3-benzodioxol-5-yl)-2,3-dihydro-3-[2-(2-hydroxyethoxy)-4-methoxyphenyl]-5-propoxy-1H-indene-2-carboxylate (34 mg, 0.071 mmol), THF (1 mL), MeOH (0.5 mL) and LiOH—H2O (15 mg, 0.355 mmol). The solution was heated to reflux for 12 h, cooled to room temperature and acidified with citric acid monohydrate (40 mg, 0.19 mmol) to pH 3.0. Upon complete hydrolysis, EtOAc (20 mL) and H2O (20 mL) was added, the organic phase washed with brine (15 mL), dried (MgSO4) and concentrated in vacuo affording (+) (1S, 2R, 3S)-3-[2-(2-hydroxyeth-1-yloxy)-4methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid as a white solid (30 mg, 81%).