Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[OH:27])[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=1)=[O:6].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[O:27][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=1)=[O:6]
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(O)c(O)c2)c2ccccc21
Reactant: Cc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(OCc3ccc(C)cc3)c(O)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.9 %

Procedure:
Ethyl 4-[3-(3,4-dihydroxybenzoyl)indol-1-yl]butanoate (5.70 g) was dissolved in N,N-dimethylformamide (40 ml). α-bromo-p-xylene (3.72 g) and potassium carbonate (2.57 g) were added to the resultant solution and stirred for 3 hours at room temperature. The reaction mixture was poured into 2N HCl and extracted with ethyl acetate. The resultant extract was sequentially washed with saturated sodium bicarbonate solution and brine, and then dried. The solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), obtaining 2.77 g of ethyl 4-{3-[3-hydroxy-4-(4-methylphenylmethoxy)benzoyl]indol-1-yl}butanoate (2.77 g) as light brown crystals.
Reaction SMILES: [Mg].[CH3:2][C:3]1[CH2:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2Br.BrCCBr.[Cl:17][Si:18](Cl)([CH3:20])[CH3:19]>C1COCC1>[Cl:17][Si:18]([CH3:20])([CH3:19])[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][C:3]([CH3:2])=[CH:11]2
Reactant: C[Si](C)(Cl)Cl
Reactant: CC1=Cc2cccc(Br)c2C1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC1=Cc2cccc([Si](C)(C)Cl)c2C1

Procedure:
To 11.9 g (0.496 mol) of magnesium turnings in 80 mL of dry THF a solution of 50.0 g (0.239 mol) of 2-methyl-7-bromo-1H-indene and 45.0 g (0.239 mol) of 1,2-dibromoethane in 620 mL of THF was added dropwise by vigorous stirring in such rate that the mixture is refluxed. Then, this mixture was additionally refluxed for 30 minutes. Further on, to a solution of 110 g (0.853 mol) of dichlorodimethylsilane in 100 mL of THF the above-obtained solution of the Grignard reagent was added dropwise with vigorous stirring at room temperature using water bath to cool the reaction mixture. The resulting mixture was additionally stirred for 12 hours at ambient temperature, evaporated to dryness, and then 200 mL of dry ether was added. The obtained suspension was stirred for 20 minutes at room temperature and then filtered through glass frit (G3). The precipitate was additionally washed with 2×200 mL of ether. The combined filtrate was evaporated to dryness, and the residue was rectificated in vacuum, b.p. 105° C.-110° C./1 mm Hg. Yield 42.5 g (80%) of the title product. 1H NMR (CD2Cl2): δ 7.37-7.41 (m, 2H, 4,6-H), 7.30 (m, 1H, 5-H), 6.57 (m, 1H, 3-H), 3.51 (m, 2H, 1,1′-H), 2.23 (m, 3H, 2-Me), 0.81 (s, 6H, SiMe2). Anal. Calc. for C12H15ClSi: C, 64.69; H, 6.79%. Found: C, 64.56; H, 6.85%.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]1[CH2:21][CH2:22][CH2:23][CH:24]([NH2:25])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:15])([CH3:18])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)C(N)CCC[C@H]1CNCCN1C(=O)OC(C)(C)C
Yield: 5 %

Procedure:
The title compound was prepared according to the procedure described in Example 2, Step C except using 4-benzyl-1-tert-butoxycarbonyl-2(S)-(4-tert-butoxycarbonylaminobutyl)-piperazine (3.74 g, 8.36 mmol), 10% palladium on carbon (0.50 g) in methanol (50 mL) for 48 h at 60 psi hydrogen. The title compound (Rf 0.3 in 5% methanol in chloroform) was obtained as an oil (3.14 g). NMR (300 MHz, CDCl3) d 4.59 (1H, m), 4.00 (1H, m), 3.83 (1H, br d J=12 Hz), 3.12 (2H, m), 2.90 (4H, m), 2.70 (1H, dt, J=4, 13 Hz), 1.0-1.9 (25H, m).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.Cl.[N:12]1([NH:21][CH2:22][CH2:23][CH3:24])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.C([O-])([O-])=O.[Na+].[Na+]>CN1CCCC1=O.O>[N:12]1([N:21]([CH2:22][CH2:23][CH3:24])[C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CCCNn1ccc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCN(c1ncnc2[nH]cnc12)n1ccc2ccccc21
Temperature: 120 °C
Reaction time: 6 h
Yield: 25.1 %

Procedure:
To a solution of 6-chloropurine (5.0 g, 0.032 mole) in 50 ml 1-methyl-2-pyrrolidinone, was added 1 ml ethereal-HCl; followed by a solution of N-(1H-indol-1-yl)-N-propylamine (5.2 g, 0.030 mole) in 50 ml 1-methyl-2-pyrrolidinone. After stirring at 120° C. for six hours, the mixture was cooled, poured into 500 ml water and stirred for five minutes, pH adjusted to 10 with Na2CO3 ; then extracted with ethyl acetate. The organic layer was washed with water, then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solution was evaporated to an oil, about 8 g, which was eluted on a silica gel column with ethyl acetate via high pressure liquid chromatography. The desired fractions were combined, then evaporated to yield 2.2 g (25%) of N-(1H-indol-1-yl)-N-propyl-9H-purin-6-amine, m.p. 90°-5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])[O:10][C:8](=O)[C:7]=12.[CH2:14]1[C@@H:18](C(O)=O)[NH:17][CH2:16][C@@H:15]1[OH:22]>CS(C)=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:10])[N:17]3[CH2:16][C@H:15]([OH:22])[CH2:14][C@H:18]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Solvent: CS(C)=O
Product: O=C1Nc2cccc(Cl)c2C(=O)N2C[C@H](O)C[C@@H]12

Procedure:
37.0 g (187.3 mmol) of 6-chloroisatoic acid anhydride and 24.6 g (187.3 mmol) of L-4-hydroxyproline in 180 ml of dimethyl sulphoxide is heated to 100° for 2 hours, evaporated to dryness in a high vacuum and the residue obtained is heated to 130° for 2 hours. By recrystallization from ethanol there is obtained (2R,11aS)-6-chloro-1,2,3,11a-tetrahydro-2-hydroxy-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione of melting point 284°-287°.
Reaction SMILES: [BrH:1].C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][NH:16][CH:17]2[C:20]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[CH2:22][CH2:21]2)=[CH:12][C:11]=1[O:30][CH3:31])C1C=CC=CC=1.[CH2:32]=O.[Na].Cl.Br>CO>[BrH:1].[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:20]1([CH:17]2[C:18]3[C:13](=[CH:12][C:11]([O:30][CH3:31])=[C:10]([OH:9])[CH:19]=3)[CH2:14][CH2:15][N:16]2[CH3:32])[CH2:22][CH2:21]1
Reactant: C=O
Reactant: COc1cc2c(cc1OCc1ccccc1)C(C1(c3ccccc3Cl)CC1)NCC2
Agent: Br
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COc1cc2c(cc1O)C(C1(c3ccccc3Cl)CC1)N(C)CC2
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A mixture of 7-benzyloxy-1-[1-(2-chlorophenyl)cyclopropyl]-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (5 g prepared as described in Example RC14), methanol (100 ml) and 37% aqueous formaldehyde solution (5 ml) was cooled to 10° C. Sodium borohyride (2.5 g) was added and the mixture stirred at ambient temperature for 2 hours. The methanol was evaporated in vacuo and the residue partitioned between dilute aqueous sodium hydroxide solution (100 ml) and ether (2×100 ml). The organic layer yielded an oil which was dissolved in methanol (25 ml) and concentrated hydrochloric acid (25 ml) and heated under reflux for 2 hours. The solvent was removed in vacuo and the residue dissolved in hot ethanol, decolorised, filtered and the solvent evaporated. The resulting solid was washed in ether, dried and then partitioned between ethyl acetate and concentrated aqueous ammonia solution. The organic layer yielded an oil which was dissolved in methanol. 48% Aqueous hydrobromic acid was added and the mixture heated under reflux for 2 hours. The solvents were removed by evaporation to yield a solid which was recrystallised from ethanol. The solid residue was washed with ether and dried in vacuo at 50° C. to give 1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide, m.p. 150°-153° C. Yield 2.95 g.
Reaction SMILES: [H-].[Na+].[OH:3][NH:4][C:5](=[NH:7])[CH3:6].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH:27]3[CH2:28][CH:29]([C:31](OCC)=O)[CH2:30][CH:19]2[CH2:20][C:21]2([CH2:26]3)[O:25][CH2:24][CH2:23][O:22]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C1COCC1.CCOC(C)=O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH:27]3[CH2:28][CH:29]([C:31]4[O:3][N:4]=[C:5]([CH3:6])[N:7]=4)[CH2:30][CH:19]2[CH2:20][C:21]2([CH2:26]3)[O:25][CH2:24][CH2:23][O:22]2)(=[O:16])=[O:17])=[CH:11][CH:10]=1
Reactant: CCOC(=O)C1CC2CC3(CC(C1)N2S(=O)(=O)c1ccc(Cl)cc1)OCCO3
Reactant: CC(=N)NO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1noc(C2CC3CC4(CC(C2)N3S(=O)(=O)c2ccc(Cl)cc2)OCCO4)n1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% dispersion, 43 mg, 1.09 mmol) was added to a solution of N-hydroxy acetamidine (81 mg, 1.09 mmol) in THF (2 mL) and the resulting mixture was stirred at 50° C. for 15 minutes. Ethyl 9-[(4-chlorophenyl)sulfonyl]spiro[9-azabicyclo[3.3.1]nonane-3,2′-[1,3]dioxolane]-7-carboxylate (50) (0.394 g, 0.916 mmol) in THF (2 mL) was added to the reaction mixture and the resulting solution was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc and washed with H2O. The organic phase was dried (Na2SO4), filtered and concentrated under vacuum to yield 0.40 g (quant.) of compound 51. MS (ESI) 440.1 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=C(C#N)[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=2.O.S(=O)(=O)(O)O.[C:24]([OH:27])(=[O:26])[CH3:25]>O>[O:1]=[C:2]1[C:15]2[CH:14]=[C:25]([C:24]([OH:27])=[O:26])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=2
Reactant: CC(=O)O
Reactant: N#Cc1ccc2oc3c(c(=O)c2c1)CCCC3
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc2oc3c(c(=O)c2c1)CCCC3
Yield: 88.5 %

Procedure:
To 88.0 g of 5,6,7,8-tetrahydro-9-oxo-xanthene-2-carbonitrile obtained in Example 12 was added 1.5 l of a mixed solution of water-sulfuric acid-acetic acid (1:1:1), and the mixture was heated for 2 hours under refluxing and stirring conditions. After being cooled, the reaction mixture was combined with 1.5 l of water and then ice-cooled for 2 hours. The resulting crystal deposit was collected by filtration, washed with water and then air-dried. The deposit was recrystallized from acetic acid to obtain 84.9 g (yield: 88.5%) of 5,6,7,8-tetrahydro-9-oxo-xanthene-2-carboxylic acid as light yellowish prism-like crystals having a melting point of 253° to 255° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][NH:22][C:23]([C:25]1[N:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=1)=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:31]([C:28]3[CH:27]=[CH:26][C:25]([C:23]([NH:22][CH3:21])=[O:24])=[N:30][CH:29]=3)=[O:32])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: CNC(=O)c1ccc(C(=O)O)cn1
Product: CNC(=O)c1ccc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)cn1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 6-[(methylamino)-carbonyl]-3-pyridinecarboxylic acid (CAN 170464-32-1) as starting materials; MS (EI) 465.2(M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([NH:8][C:9]([C:11]2[NH:12][C:13]([CH2:17][CH3:18])=[C:14]([Cl:16])[N:15]=2)=[O:10])[CH2:6][CH2:5][N:4]([C:19]2[S:20][C:21]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:3]1.[CH3:33][CH:34]([CH3:38])[CH2:35][CH:36]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:16][C:14]1[N:15]=[C:11]([C:9]([NH:8][C@H:7]2[CH2:6][CH2:5][N:4]([C:19]3[S:20][C:21]4[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)[CH2:3][C@H:2]2[NH:1][CH2:36][CH2:35][CH:34]([CH3:38])[CH3:33])=[O:10])[NH:12][C:13]=1[CH2:17][CH3:18]
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](N)C3)sc12
Reactant: CC(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](NCCC(C)C)C3)sc12

Procedure:
The same operation as in Example (77d) was performed using ethyl cis(±)-2-(3-amino-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained by the method described in Example (81e) (30 mg, 0.063 mmol), 3-methylbutanal (10.8 μL, 0.010 mmol) and sodium (triacetoxy)borohydride (87 mg, 0.41 mmol), to obtain 34.2 mg of the title compound as a colorless oily substance (99%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[Br:18][C:19]1[CH:20]=[C:21]([SH:27])[CH:22]=[C:23]([Br:26])[C:24]=1[NH2:25]>>[Br:18][C:19]1[CH:20]=[C:21]([S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)[CH:22]=[C:23]([Br:26])[C:24]=1[NH2:25]
Reactant: O=c1ccc2cc(OCCCCBr)ccc2[nH]1
Reactant: Nc1c(Br)cc(S)cc1Br
Product: Nc1c(Br)cc(SCCCCOc2ccc3[nH]c(=O)ccc3c2)cc1Br

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p. 198°-199° C.) and 3,5-dibromo-4-amino-thiophenol.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[O:8][C:9]1[CH:14]=[N:13][NH:12][C:11](=[O:15])[CH:10]=1)(=[O:5])[CH3:4].CN(C)C=O.[CH3:25][O:26][C:27](=[O:36])[CH:28](Br)[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1>[CH3:25][O:26][C:27](=[O:36])[CH:28]([N:12]1[C:11](=[O:15])[CH:10]=[C:9]([O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[C:3](=[O:5])[CH3:4])[CH:14]=[N:13]1)[CH2:29][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: CC(=O)c1ccccc1Oc1cn[nH]c(=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)n1ncc(Oc2ccccc2C(C)=O)cc1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
Sodium hydride in mineral oil (3.65 g) was added to a solution of 5-(2-acetyl-phenoxy)-2H-pyridazin-3-one (16.3 g, 0.07 mol) in tetrahydrofuran (340 mL) at 0° C. The resulting mixture was stirred at 0° C. for 10 min and then was warmed to 20° C., where it stirred for 50 min. After this time, N,N-dimethylformamide (45 mL) and 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 25 g, 0.11 mol) were added to the reaction. The reaction was then warmed to 50° C. overnight. After this time, the reaction was concentrated in vacuo. Silica gel column chromatography afforded 2-[4-(2-acetyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid methyl ester (23.4 g, 86%); ESI-MS 385 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:9]/[CH2:10][OH:11])=[CH:4][CH:3]=1.O[C:23]1[CH:34]=[CH:33][C:26]([O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:25]([CH3:35])[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)=[CH:9]/[CH2:10][O:11][C:23]2[CH:34]=[CH:33][C:26]([O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:25]([CH3:35])[CH:24]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)COc1ccc(O)cc1C
Reactant: OC/C=C(/c1ccc(Br)cc1)c1ccc(C(F)(F)F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Br)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 0 °C

Procedure:
The above allyl alcohol (0.77 g, 2.16 mmol), methyl (4-hydroxy-2-methylphenoxy)acetate (0.47 g, 2.37 mmol) and triphenylphosphine (0.68 g, 2.59 mmol) were dissolved in a mixture of anhydrous toluene (10 mL) and tetrahydrofuran (3 mL). The mixture was degassed, cooled to 0° C. and a degassed solution of diisopropyl azodicarboxylate (0.525 g, 2.60 mmol) in anhydrous tetrahydrofuran (3 mL) was added dropwise under nitrogen. The reaction mixture was stirred at ambient temperature over night. The solvents were evaporated in vacuo and the residue was submitted to column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 95: 5-90:10) affording methyl (E)-[4-[3-(4-bromophenyl)-3-[4-trifluoromethyl phenyl]allyloxy]-2-methylphenoxy]acetate.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:26])[CH2:6][CH2:7][C:8]1[N:9]=[C:10]([N:21]([CH:23]2[CH2:25][CH2:24]2)[CH3:22])[C:11]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:12]=2[N:13]=1.Cl>O.C1COCC1>[CH:23]1([N:21]([CH3:22])[C:10]2[C:11]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=4[S:14][C:12]=3[N:13]=[C:8]([CH2:7][CH2:6][C:5]([OH:26])=[O:4])[N:9]=2)[CH2:24][CH2:25]1
Reactant: COC(=O)CCc1nc(N(C)C2CC2)c2c3c(sc2n1)CCCC3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(c1nc(CCC(=O)O)nc2sc3c(c12)CCCC3)C1CC1
Reaction time: 3 h
Yield: 53.9 %

Procedure:
The LiOH (0.047 g, 0.0018 mol) dissolved in water (2 ml) was added to a solution of 3-[4-(cyclopropyl-methyl-amino)-5,6,7,8-tetrahydro-[1]benzothiopheno[2,3-d]pyrimidin-2-yl]-propionic acid methyl ester (0.5 g, 0.0014 mol) in THF (3 ml), and the resulting solution was stirred at R.T for 3 hrs. The reaction mixture was diluted with water, acidified with dilute HCl (up to pH 5) and extracted with ethyl acetate (3×15 ml). The combined organic layers were dried over Na2SO4, concentrated, and the crude was purified by preparative HPLC to give 0.25 g (54%) of 3-[4-(cyclopropyl-methyl-amino)-5,6,7,8-tetrahydro-[1]benzothiopheno[2,3-d]pyrimidin-2-yl]-propionic acid. 1H NMR (400 MHz, CDCl3) δ ppm=0.53 (m, 2H), 0.87 (m, 2H), 1.76 (m, 2H), 1.92 (m, 2H), 2.84 (m, 7H), 3.1 (s, 3H), 3.22 (t, 2H), 14.75 (s, 1H). LC-MS: [M+H]=331.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH:5]([NH:12]S(C(C)(C)C)=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[ClH:20]>CO.O1CCOCC1>[ClH:20].[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH:5]([NH2:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)CC(NS(=O)C(C)(C)C)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CC(N)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3-(2-Methyl-propane-2-sulfinylamino)-3-phenyl-propionic acid methyl ester (1.73 mmol, 1 eq) is dissolved in 10 mL methanol (J. Org. Chem., 2002, 67, 7819-7832). A solution of HCl in dioxane (4 M, 10 mL) is added. The solution is stirred at room temperature for 45 min and concentrated in vacuo. 3-Amino-3-phenyl-propionic acid methyl ester hydrochloride is obtained as yellow viscous oil (135% crude product); ES-MS (MH+)=181.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[S:6][C:5]2=[CH:7][C:8]3[S:9][C:10]([CH3:15])([CH3:14])[O:11][C:12]=3[CH:13]=[C:4]2[O:3]1.C([Li])CCC.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[CH3:24][Si:23]([CH3:26])([CH3:25])[C:13]1[C:4]2[O:3][C:2]([CH3:16])([CH3:1])[S:6][C:5]=2[CH:7]=[C:8]2[S:9][C:10]([CH3:15])([CH3:14])[O:11][C:12]=12
Reactant: C[Si](C)(C)Cl
Reactant: CC1(C)Oc2cc3c(cc2S1)SC(C)(C)O3
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)Oc2c(cc3c(c2[Si](C)(C)C)OC(C)(C)S3)S1
Reaction time: 0.25 h

Procedure:
The reaction was performed under an argon atmosphere using deoxygenated solvents. 2,2,6,6-tetramethylbenzo[1,2-d:5,4-d']-bis(1,3)oxathiole (6.0 g, 23.6 mmol) was dissolved in dry THF (120 mL). The mixture was cooled on an ice-bath and n-butyllithium (10.8 mL, 2.5M in hexane) was added dropwise over 10 min. After 15 min, chlorotrimethylsilane (6.0 mL, 47.2 mmol) was added dropwise over 5 min. After another 15 min, the reaction mixture was quenched with dietyl ether/aq. NaHCO3, the aqueous layer was extracted with ether and the combined organic layers were washed with water and dried (Na2SO4). After evaporation and chromatography (silica gel, chloroform) essentially pure product (6.3 g, 92%) could be collected.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)=[O:12])[CH2:7][CH2:6]1.[CH3:23][C:24]1[O:28][C:27](=[O:29])[NH:26][C:25]=1[C:30](O)=[O:31]>>[CH3:1][N:2]([CH2:3][CH2:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[C:17]([Cl:22])[CH:18]=[C:19]([Cl:21])[CH:20]=2)=[O:12])[CH2:9][CH2:10]1)[C:30]([C:25]1[NH:26][C:27](=[O:29])[O:28][C:24]=1[CH3:23])=[O:31]
Reactant: Cc1oc(=O)[nH]c1C(=O)O
Reactant: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Product: Cc1oc(=O)[nH]c1C(=O)N(C)CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1

Procedure:
The title compound was prepared from 3,5-dichlorobenzyl 4-(2-methylamino)ethyl)piperidine-1-carboxylate (Example 1, step 3) and 5-methyl-2-oxo-2,3-dihydrooxazole-4-carboxylic acid analogously to Example 6;
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:18]O>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reaction time: 8 h
Yield: 98 %

Procedure:
To a stirred solution of 2-chloro-3-nitrobenzoic acid (1.0 g, 5.0 mmol) in anhydrous methanol (10 mL) at 0° C. was added thionyl chloride (0.5 mL, 7.4 mmol) dropwise and the reaction mixture was stirred overnight at reflux. The mixture was diluted with methanol and concentrated under reduced pressure to remove the excess thionyl chloride. The residue was then re-dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, re-extracted with ethyl acetate, dried (Na2SO4), filtered, and concentrated under reduced pressure to give methyl 2-chloro-3-nitrobenzoate (1.1 g, 98%) as a white foam that was used in the next step without further purification: 1H NMR (300 MHz, DMSO-d6) δ 8.21 (d, J=1.5 Hz, 1H), 8.07 (dd, J=7.8, 1.5 Hz, 1H), 7.73 (t, J=8.1 Hz, 1H), 3.91 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12](O)=[O:13])=[CH:4][CH:3]=1.C(OC(=O)[NH:36][CH2:37][CH2:38][NH2:39])(C)(C)C.Cl>>[ClH:1].[NH2:36][CH2:37][CH2:38][NH:39][C:12](=[O:13])[CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:15]([N:17]2[CH2:18][CH2:19][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[CH2:21][CH2:22]2)=[O:16])=[CH:7]1
Reactant: O=C(O)Cn1cc(C(=O)N2CCC(c3ccccc3F)CC2)c2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)NCCN
Agent: Cl
Product: NCCNC(=O)Cn1cc(C(=O)N2CCC(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure I, the coupling of {6-chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (preparation described herein), with (commercially available) (2-amino-ethyl)-carbamic acid tert-butyl ester gave, after treatment with HCl the title compound.