Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[N+:13]([O-])([OH:15])=[O:14]>C(OC(=O)C)(=O)C.C(O)(=O)C>[N+:13]([C:11]1[CH:10]=[CH:9][C:3]2[C:4]([C:6]([OH:8])=[O:7])=[CH:5][S:1][C:2]=2[CH:12]=1)([O-:15])=[O:14]
Reactant: O=C(O)c1csc2ccccc12
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1csc2cc([N+](=O)[O-])ccc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
2 g benzo[b]thiophene-3-carboxylic acid are dissolved in 11 ml acetic anhydride and cooled to 0° C. A solution of 4.4 ml concentrated nitric acid in 10 ml acetic acid is added dropwise, while not allowing the temperature to rise above 5° C. Then the mixture is stirred for 1.5 hours and then combined with 200 ml ice water. The solid is suction filtered and dried in vacuo. Then it is dissolved in hot ethanol. After cooling to ambient temperature the solid (5-nitro-benzo[b]thiophene-3-carboxylic acid, approximately 80%) is suction filtered. By elimination of the solvent in vacuo, 6-nitro-benzo[b]thiophene-3-carboxylic acid (approx. 66%) is obtained from the mother liquor.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.O.[OH-].[Li+].Br[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:34]=[CH:33][CH:32]=[CH:31][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27]>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:34]=[CH:33][CH:32]=[CH:31][C:21]=2[O:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[C:4]([CH2:10][CH3:11])[N:3]=1
Reactant: CCc1nc(N)nc(N)c1O
Reactant: CCOC(=O)CCCOc1ccccc1OCCCBr
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc(N)nc(N)c1OCCCOc1ccccc1OCCCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
2,4-Diamino-6-ethyl-5-hydroxypyrimidine (0.4625 g, 3 mmol) was added to a stirred solution of lithium hydroxide monohydrate (0.4406 g, 10.5 mmol) in DMF (4 mL) and the reaction mixture was stirred at 25° C. for 1 hour. A solution of ethyl 4-(2-(3-bromopropoxy)phenoxy)butanoate (1.0357 g, 3 mmol) in DMF (1 mL) was added and the reaction mixture was left stirring at 25° C. overnight. DMF was partially removed under reduced pressure to give residue. The residue was diluted with water and extracted with dichloromethane. The aqueous layer was neutralized with dilute HCl to give white solid. Recrystallization with acetone afforded the desired diaminopyrimidine as white solid (0.6911 g, 59%, m.p. 204-206° C.). 1H NMR (400 MHz, DMSO-d6): 1.10 (3H, t, J=7.5 Hz), 1.91 (2H, m), 2.14 (2H, m), 2.31-2.39 (4H, m), 3.78 (2H, t, J=6.1 Hz), 3.96 (2H, t, J=6.4 Hz), 4.13 (2H, t, J=6.1 Hz), 5.60 (2H, s), 6.09 (2H, s), 6.86-6.90 (2H, m), 6.95-7.01 (2H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[C:15]([N:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CCOCC>[OH:27][C:24]1([C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH2:25][CH2:26][N:22]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)C2)cn1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
5-bromo-2-methoxypyridine (324 μL, 2.50 mmol) was added dropwise to a stirred suspension of n-butyllithium (1.72 mL of a 1.6 M hexanes solution, 2.75 mmol) in ether (10.0 mL) at −78° C. After 10 min, a solution of N-Boc-3-pyrrolidinone (463 mg, 2.50 mmol) in ether (2.00 mL) was added dropwise, and the reaction mixture was allowed to stir at −78° C. After 2 h, the reaction was quenched with satd. aq. NH4Cl and extracted with EtOAc. The combined organics were washed with brine, dried (sodium sulfate) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 10%-80% EtOAc/hexanes as eluent) afforded the title compound i-5a. m/z (ES) 295 (MH)+. 1H NMR (500 MHz, CDCl3): δ 8.31 (s, 1H), 7.71 (d, 1H, 7.1 Hz), 6.79 (dd, 1H, J=2.2, 8.6 Hz), 3.97 (s, 3H), 3.40-3.80 (m, 4H), 2.25 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:8]([NH2:9])=[CH:7][S:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[CH3:19][C:20]1[C:21]([N:25]=[C:26]=[S:27])=[CH:22][S:23][CH:24]=1>O1CCCC1>[NH2:3][C:4]1[C:8]([NH:9][C:26]([NH:25][C:21]2[C:20]([CH3:19])=[CH:24][S:23][CH:22]=2)=[S:27])=[CH:7][S:6][CH:5]=1
Reactant: Nc1cscc1N
Reactant: Cc1cscc1N=C=S
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cscc1NC(=S)Nc1cscc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1.87 g of 3,4-diaminothiophene dihydrochloride, 60 ml of anhydrous tetrahydrofuran (THF) and 2.58 g of N-ethyl-N,N-diisopropylamine was stirred at room temperature for 30 minutes and then admixed with 1.5 g of 4-methyl-3-thienyl isothiocyanate. After stirring over approx. 18 hours, the solvent was distilled off, the residue admixed with water and extracted repeatedly with ethyl acetate. After the combined organic phases had been treated with activated carbon, they were dried over sodium sulfate and the solvent was once again distilled off. The N-(3-amino-4-thienyl)-N′-(4-methyl-3-thienyl)thiourea was obtained as an amorphous foamy solid.
Reaction SMILES: COC[O:4][C@@H:5]1[CH2:28][C@@H:9]2[C:10](=[O:27])[O:11][C:12]3[C@@H:13]4[CH2:20][CH2:19][C@H:18]([C@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[C@@:14]4([CH3:26])[CH2:15][CH2:16][C:17]=3[C@@:8]2([CH3:29])[CH2:7][CH2:6]1.CC1C=CC(S(O)(=O)=O)=CC=1.[Cl-].[NH4+]>C(O)(C)(C)C>[OH:4][C@@H:5]1[CH2:28][C@@H:9]2[C:10](=[O:27])[O:11][C:12]3[C@@H:13]4[CH2:20][CH2:19][C@H:18]([C@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[C@@:14]4([CH3:26])[CH2:15][CH2:16][C:17]=3[C@@:8]2([CH3:29])[CH2:7][CH2:6]1
Reactant: COCO[C@H]1CC[C@]2(C)C3=C(OC(=O)[C@H]2C1)[C@@H]1CC[C@H]([C@H](C)COC)[C@@]1(C)CC3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)(C)O
Product: COC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C[C@@H]1C(=O)O3
Temperature: 105 °C
Reaction time: 4 h
Yield: 28.9 %

Procedure:
Compound 67 (581.6 mg, 1.431 mmol) obtained in Example 63 was dissolved in tert-butanol (48 mL), and pyrimidium p-toluenesulfonate (3.6 g; 14 mmol) was added thereto, followed by stirring at 105° C. for 4 hours. The reaction mixture was cooled to 0° C., a saturated aqueous ammonium chloride solution was added, followed by extraction with ethyl acetate (50 mL×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to yield a residue. The residue was purified by silica gel column chromatography, followed by purification by high-speed liquid chromatography (60 to 100% acetonitrile/water) to obtain the title compound (150 mg, 29%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:10]2[CH2:11][CH:12]=[C:13]([CH2:14][OH:15])[C@H:9]2[C@H:8]([OH:16])[O:7][CH:6]=1)=[O:4].FB(F)F.[CH2:21](OCC)C.C(=O)(O)[O-].[Na+]>CO>[OH:15][CH2:14][C:13]1[C@@H:9]2[C@@H:10]([C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][O:7][CH:8]2[O:16][CH3:21])[CH2:11][CH:12]=1
Reactant: CCOCC
Reactant: COC(=O)C1=CO[C@@H](O)[C@@H]2C(CO)=CC[C@H]12
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1=COC(OC)[C@@H]2C(CO)=CC[C@H]12
Reaction time: 3 h

Procedure:
Genipin (5 g, 22.1 mmol) was dissolved with 250 ml of methanol and catalytic amount of trifluoroboron diethylether was added, and stirred for 3 hours, then saturated sodium bicarbonate solution was added to finish the reaction. Under reduce pressure, methanol was removed and extracted with ethylacetate, and dried, filtered and concentrated with anhydous magnesium sulfate. Oily phase of methyl (3aS,7aS)-1-hydroxymethyl-7-methoxy-3,7,3a,7a-tetrahydro-6-oxaindene-4-carboxylate (5.26 g, 7S:7R=1:3) was obtained.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([C:21](O)=[O:22])[CH:20]=1)[NH:17][CH:16]([C:24]1[CH:25]=[C:26]([C:30]3[CH:35]=[CH:34][C:33]([N:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=3)[CH:27]=[CH:28][CH:29]=1)[C:15]([CH3:40])([CH3:39])[CH2:14]2.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:20]=1)[NH:17][CH:16]([C:24]1[CH:25]=[C:26]([C:30]3[CH:31]=[CH:32][C:33]([N:36]([CH3:38])[CH3:37])=[CH:34][CH:35]=3)[CH:27]=[CH:28][CH:29]=1)[C:15]([CH3:40])([CH3:39])[CH2:14]2
Reactant: CN(C)c1ccc(-c2cccc(C3Nc4c(cc(Cl)cc4C(=O)O)CC3(C)C)c2)cc1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2cccc(C3Nc4c(cc(Cl)cc4C(=O)NS(=O)(=O)C4CC4)CC3(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.6 %

Procedure:
To a suspension of 60% sodium hydride (91 mg, 2.2 mmol) in N,N-dimethylformamide (1.5 mL) was added cyclopropanesulfonamide (280 mg, 2.3 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 6-chloro-2-(4′-dimethylamino-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (100 mg, 0.23 mmol) and 1,1′-carbonyldiimidazole (94 mg, 0.58 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [6-chloro-2-(4′-dimethylamino-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-amide (49 mg, 40%) as a white solid: LC/MS m/e calcd for C29H32ClN3O3S (M+H)+: 539.11, observed: 538.1.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]=1[C:18]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH3:26])[N:25]=1)=[O:19]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:26][C:24]1[N:25]=[C:21]([NH:20][C:18]([C:3]2[C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:4]=2)=[O:19])[S:22][CH:23]=1
Reactant: Cc1csc(NC(=O)C2=C(O)c3ccccc3N(c3ccccc3)C2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: Cc1csc(NC(=O)c2cn(-c3ccccc3)c3ccccc3c2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of 9.0 g of 1,2-dihydro-4-hydroxy-N-(4-methyl-2-thiazolyl)-1-phenyl-3-quinolinecarboxamide in 250 ml of hot toluene was treated with 36.0 g of activated manganese dioxide and stirred for two hours at ambient temperature. The slurry was filtered and evaporated. Recrystallization of the residue from chloroform yielded 6.0 g (66%) of 1,4-dihydro-N-(4-methyl-2-thiazolyl)-4-oxo-1-phenyl-3-quinolinecarboxamide, m.p. 252°-254° C.
Reaction SMILES: C(O[C@H](C)[C:10]([NH:12][C@H:13]1[CH2:17][C@@H:16]([N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][C:21]([N:42]2[CH2:46][CH2:45][C@@H:44]([NH:47][C:48]([NH:50][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=4)=[O:49])[CH2:43]2)=[N:22][C:23]=3[NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:15]([OH:57])[C@@H:14]1[OH:58])=[O:11])C1C=CC=CC=1.N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](N[C:81](=O)[C@H:82]([O:84]CC4C=CC=CC=4)C)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1>>[C:36]1([CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][NH:27][C:23]2[N:22]=[C:21]([N:42]3[CH2:46][CH2:45][C@@H:44]([NH:47][C:48]([NH:50][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=4)=[O:49])[CH2:43]3)[N:20]=[C:19]3[C:24]=2[N:25]=[CH:26][N:18]3[C@@H:16]2[CH2:17][C@H:13]([NH:12][C:10](=[O:11])[CH2:81][CH2:82][OH:84])[C@@H:14]([OH:58])[C@H:15]2[OH:57])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Product: O=C(CCO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to (R)-2-benzyloxy-N-((1S,2R,3S,4R)-4-{6-(2,2-diphenyl-ethylamino)-2[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide (Example 181, step 5), by substituting N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-3-hydroxy-propionamide (Intermediate ZG) for (R)—N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-propionamide (Example 181, step 4).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:8][CH:9]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[OH:8][CH:9]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC(O)c1cccc(CBr)c1
Reactant: Nc1ccccc1
Product: CCCCCC(O)c1cccc(CNc2ccccc2)c1

Procedure:
For compounds in which X is --NR2 --(CHR1)n --, the corresponding amino starting compounds are employed to form the desired amino compound. Thus, aniline is condensed with 3-(1-hydroxyhexyl)benzylbromide to form 2-[3-(1-hydroxyhexyl)benzylamino]benzene. Alternatively, benzyl bromide is condensed with 3-(1-hydroxyhexyl)aniline to form 2-[3-(1-hydroxyhexyl)anilinomethyl]benzene.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[C:23]([O:25][CH3:26])=[O:24].O>C(Cl)Cl>[C:5]([C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[CH2:14][CH:15]([C:23]([O:25][CH3:26])=[O:24])[CH2:16]2)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C1Cc2ccccc2C1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1Cc2ccc(C(=O)c3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 250 cm3 reaction vessel fitted with a stirrer, a cooler, a dropping funnel and a thermometer, is placed 23.2 g (0.173 mole) of anhydrous aluminum chloride in suspension in 40 ml of methylene chloride. 35.3 g (0.252 mole) of benzoyl chloride dissolved in 40 cm3 of methylene chloride is then slowly added at ambient temperature. The aluminum chloride tends to pass into solution while the temperature gradually rises several degrees. The mixture is cooled to hold the temperature close to 20° C. and a solution of 11.1 g (0.063 mole) of methyl indane-2-carboxylate dissolved in 50 cm3 of methylene chloride is added. The temperature gradually rises during the course of the addition and the mixture turns a light brown color. The mixture is stirred for one hour at ambient temperature and is then heated to reflux for 3 hours. After cooling, the mixture is poured into acidified iced water and the resulting mixture is extracted with chloroform. The chloroform extract is then washed with water containing caustic soda, then with slightly acidified water and finally with water. It is dried over anhydrous sodium sulphate. The product is then filtered and the filtrate concentrated to an oily residue which is distilled and a fraction is collected boiling at 178°-184° C. at 0.6 to 0.8 torr.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)=[CH:11][C:10]([C:23]([O:25]CC)=[O:24])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)=[CH:11][C:10]([C:23]([OH:25])=[O:24])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)c(OC)c2)n(-c2cccc(Cl)c2)n1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(-c2cc(C(=O)O)nn2-c2cccc(Cl)c2)cc1OC
Yield: 94 %

Procedure:
Starting from 500 mg (1.29 mmol) of ethyl 1-(3-chlorophenyl)-5-(3,4-dimethoxy-phenyl)-1H-pyrazole-3-carboxylate from example 17A and 725.2 mg (12.9 mmol) of potassium hydroxide, 434.1 mg (1.2 mmol, 94% yield of theory) are obtained as crystals according to the method described in example 7A.
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]3[CH:18]=[CH:19][C:20]([NH:22][C:14]=3[CH:13]=2)=[O:21])[CH2:5][CH2:4][N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[Cl:30])[CH2:2]1.CC(C)([O-])C.[K+].CC1CCCO1.Cl[C:44]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:45]>O>[C:44](=[O:45])([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[O:21][C:20]1[CH:19]=[CH:18][C:15]2[C:14](=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]3[CH2:5][CH2:4][N:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=4[Cl:30])[CH2:2][CH2:1]3)=[CH:17][CH:16]=2)[N:22]=1
Reactant: CCCCCCOC(=O)Cl
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC1CCCO1
Product: CCCCCCOC(=O)Oc1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of dehydro-aripiprazole (1.5 g, 3.4 mmol), potassium tert-butoxide (0.75 g, 6.7 mmol) and 2-methyltetrahydrofuran (30 mL) at 0° C. was added hexyl chloroformate (1.32 mL, 8.1 mmol). The reaction mixture was stirred for 2 h, allowed to self warm to room temperature and stirred for a further 4 h. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and evaporated. The residue was further purified on silica eluting with ethyl acetate/tetrahydrofuran and the major product containing fractions evaporated to give a yellow solid. This was triturated in heptane (30 mL) for 2.5 h, filtered and dried to give Compound-328 (1.55 g) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.Br[C:7]1([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:17]>ClCCl>[Cl:16][C:12]1[CH:11]=[C:10]2[C:15]([C:7]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([NH:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:8](=[O:17])[NH:9]2)=[CH:14][CH:13]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Reactant: NCC1CC1
Solvent: ClCCl
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)NCC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of cyclopropanemethylamine (142 mg, 2.0 mmol) in dichloromethane (20 mL) was added rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (0.37 g, 0.99 mmol). After the mixture was stirred at room temperature for 1 h, another portion of dichloromethane (20 mL) was added. The mixture was washed with water (20 mL×2). The organic layer was separated, dried over Na2SO4 and concentrated to give 0.34 g of rac-6-chloro-3-(3-chloro-benzyl)-3-(cyclopropylmethyl-amino)-1,3-dihydro-indol-2-one as a white solid. MS: [M+H]+=361
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:8]([O:14][CH3:15])[O:9][CH:10]([O:12][CH3:13])[CH:11]=2)=[CH:3][CH:2]=1>CCO.CCOC(C)=O.[Pd]>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:2]=[CH:3][C:4]([CH:7]2[CH2:11][CH:10]([O:12][CH3:13])[O:9][CH:8]2[O:14][CH3:15])=[CH:5][CH:6]=1
Reactant: COC1C=C(c2ccc(-c3ccccc3)cc2)C(OC)O1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Reaction time: 1.75 h
Yield: 96.1 %

Procedure:
A mixture of 3-biphenyl-4-yl-2,5-dihydro-2,5-dimethoxyfuran (1.00 g, 3.55 mmol) and 5% Pd/C (300 mg) in EtOH:EtOAc (1:2) was stirred under H2 atmosphere for 1.75 hours. The catalyst was filtered onto Celite. The filtrate was concentrated to provide 0.97 g (97%) of a diastereomeric mixture of 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydro-furan as a colorless oil which was typically used without purification. 1H NMR: δ 7.60-7.53 (m, 4H), 7.45-7.28 (m, 5H), 5.26 (t, 1H, J=5.5 Hz), 5.02 (d, 1H, J=4.4 Hz), 3.54 (s, 3H), 3.36 (s, 3H), 2.63-2.53 (m, 1H), 2.41-2.30 (m, 1H). Anal. calculated for C18H20O3: C, 76.03; H, 7.09. Found: C, 75.74; H, 6.92.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[N:18]([CH:33]([F:35])[F:34])[N:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=4)[CH:21]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[F:35][CH:33]([F:34])[N:18]1[C:17]([CH2:16][O:15][C:12]2[CH:13]=[C:14]3[C:9]([CH:8]=[CH:7][N:6]3[CH2:5][C:4]([OH:36])=[O:3])=[CH:10][CH:11]=2)=[CH:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:24][CH:23]=2)=[N:19]1
Reactant: CCOC(=O)Cn1ccc2ccc(OCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3C(F)F)cc21
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2ccc(OCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3C(F)F)cc21

Procedure:
In analogy to the procedure described in example 1 f], {6-[2-difluoromethyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain {6-[2-difluoromethyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid as colorless crystals.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]1[O:25][N:24]=[C:23]([CH2:26]OS(C)(=O)=O)[CH:22]=1>CC#N.O>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:26][C:23]2[CH:22]=[C:21]([CH3:20])[O:25][N:24]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(COS(C)(=O)=O)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)no1
Yield: 89.1 %

Procedure:
To a solution of N-BOC-piperazine (300 mg) in MeCN (5 mL) was added potassium carbonate (289 mg) followed by methanesulfonic acid 5-methyl-isoxazol-3-ylmethyl ester (369 mg). The reaction mixture was heated to reflux for 24 h. After cooling the reaction mixture was diluted with water, extracted into ethyl acetate, dried (MgSO4) and the solvent was removed in vacuo to yield 4-(5-methyl-isoxazol-3-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (404 mg).