Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[N:19]([C:31]4[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=4)[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[N:22]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:38][C@H:39]([C:43]([OH:45])=[O:44])[CH2:40][CH2:41][CH3:42]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[N:19]([C:31]4[CH:36]=[CH:35][C:34]([NH:38][C@@H:39]([CH2:40][CH2:41][CH3:42])[C:43]([OH:45])=[O:44])=[CH:33][CH:32]=4)[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[N:22]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC[C@H](N)C(=O)O
Reactant: CC(C)(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(I)cc3)cc2)cc1
Product: CCC[C@H](Nc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1)C(=O)O

Procedure:
2-(4′-tert-Butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-1-(4-iodo-phenyl)-1H-imidazole (191 mg, 0.3 mmol) was treated as described in general procedure R using L-norvaline (352 mg, 3 mmol) to give (S)-2-{-4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-pentanoic acid, which was then treated as described in general procedure F to give (4S)-5-{-4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-4-propyl-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: F[C:2](F)(F)[C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])=[CH:6][NH:5][CH:4]=1.[NH3:18]>O1CCOCC1>[Cl:15][C:9]1[C:10]([Cl:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[C:3]([C:2]#[N:18])=[CH:4][NH:5][CH:6]=1
Reactant: N
Reactant: FC(F)(F)c1c[nH]cc1-c1cccc(Cl)c1Cl
Solvent: C1COCCO1
Product: N#Cc1c[nH]cc1-c1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
4.0 g of 3-trifluoromethyl-4-(2,3-dichlorophenyl)pyrrole, 21 ml of 25% aqueous ammonia and 40 ml of dioxane are stirred for 26 hours at 180° C. in an autoclave. After cooling to room temperature, the reaction mixture is filtered, and the clear filtrate is concentrated by evaporation. The residue is taken up in ethyl acetate, washed with water and subsequently with diluted sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated by evaporation. The residue is caused to crystallise by the addition of hexane; it is then filtered off and dried to thus obtained 3.4 g (100% of theory) of 4-(2,3-dichlorophenyl)-3-cyanopyrrole having a melting point of 150° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:14]=3[O:15][C@H:16]([CH3:22])[C:17]([O:19]CC)=[O:18])=[N:7][CH:8]=[N:9]2)=[C:4]([F:28])[CH:3]=1.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:14]=3[O:15][C@H:16]([CH3:22])[C:17]([OH:19])=[O:18])=[N:7][CH:8]=[N:9]2)=[C:4]([F:28])[CH:3]=1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(F)ccc1Nc1ncnc2cc(Br)cc(F)c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](Oc1cc(F)ccc1Nc1ncnc2cc(Br)cc(F)c12)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 34 g (75 mmol) of ethyl (2R)-2-[2-[(7-bromo-5-fluoro-quinazolin-4-yl)amino]-5-fluoro-phenoxy]propanoate and 225.5 ml 1 mol/l aq. NaOH solution in THF are stirred for 2 h at RT. The solvent is evaporated and water is added. The mixture is neutralized with 1 mol/l aq. HCl and the precipitate is filtered off and dried yielding (2R)-2-[2-[(7-bromo-5-fluoro-quinazolin-4-yl)amino]-5-fluoro-phenoxy]propanoic acid.
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:21]([O-:23])=[O:22])[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[CH3:25]N(C)P(=O)(N(C)C)N(C)C.IC>CC1C=CC=CC=1>[C:1]1([NH:7][C:8]2([C:21]([O:23][CH3:25])=[O:22])[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CI
Product: COC(=O)C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 70 °C
Reaction time: 21 h

Procedure:
A mixture of 66.4 parts of sodium 4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylate in 375 parts of hexamethylphosphoric triamide is heated to 70° C. After cooling to 10° C, 31.2 parts of iodomethane are added (slightly exothermic reaction). The whole is stirred for 21 hours at room temperature. The reaction mixture is diluted with 360 parts of methylbenzene. The whole is washed with water and the layers are separated. The aqueous phase is washed with methylbenzene. The combined organic layers are washed successively once with 300 parts of a 10% sodium hydroxide solution and twice with 300 parts of water, dried, filtered and evaporated, yielding methyl 4-(phenylamino)-1 (phenylmethyl)-4-piperidinecarboxylate as a residue.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]([C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:10]([CH3:12])[CH:11]=1)=[O:6]>C(O)(=O)C>[Br:1][C:17]1[CH:18]=[C:13]([C:9]2[S:8][C:7]([C:5]([O:4][CH3:3])=[O:6])=[CH:11][C:10]=2[CH3:12])[CH:14]=[CH:15][C:16]=1[O:19][CH3:20]
Reactant: BrBr
Reactant: COC(=O)c1cc(C)c(-c2ccc(OC)cc2)s1
Solvent: CC(=O)O
Product: COC(=O)c1cc(C)c(-c2ccc(OC)c(Br)c2)s1
Reaction time: 16 h
Yield: 90 %

Procedure:
Liquid bromine (1.8 g, 0.57 ml, 11.43 mmol) was added drop wise to a stirred solution of methyl-5-(4-methoxyphenyl)-4-methylthiophene-2-carboxylate (prepared according to the procedure reported in WO 2007/092751, 2.0 g, 7.62 mmol) in acetic acid (20 ml) at a temperature of about 25° C. The resulting mixture was stirred at the same temperature for 16 hours. The progress of reaction was monitored by TLC. The reaction mixture was poured onto ice water (100 ml). The mixture so obtained was extracted with ethyl acetate (3×100 ml). The separated combined organic layer was washed with 10% aqueous sodium bicarbonate solution (2×50 ml). The organic layer was then dried over anhydrous Na2SO4. The solvent was evaporated form the organic layer under reduced pressure to obtain a crude product. The crude product was further purified by flash chromatography using 15-25% ethyl acetate in hexanes as an eluent to obtain the title compound (2.35 g, 90%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH2:8][C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N+:10]=1[CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Br:23]>C(O)CC>[NH:8]=[C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]1[CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Br:23]
Reactant: Nc1nccc[n+]1CSc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCCO
Product: N=c1ncccn1CSc1ccccc1Br
Temperature: 25 °C
Yield: 97.4 %

Procedure:
To a suspension of 13.8 g of anhydrous potassium carbonate in 150 ml of anhydrous n-propanol is added 33.1 g of 2-amino-1-[[(o-bromophenyl)thio]methyl]pyrimidinium chloride, portionwise, under nitrogen, at room temperature, with stirring. Subsequently, the mixture is stirred and heated under reflux for 2 hours, filtered hot, and the filtrate concentrated in vacuo. The residue is partitioned between 200 ml each of water and ether, the ether layer is separated, dried, and concentrated to give about 28.7 g of the named compound, after recrystallization from pentane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:14]=3[CH:20]=2)=O)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23].C(O)(=O)C>C(O)C>[CH3:18][C:16]1([CH3:19])[CH2:15][C:14]2[CH:20]=[C:10]([C:8](=[N:22][NH2:23])[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:11]=[CH:12][C:13]=2[O:17]1
Reactant: CC1(C)Cc2cc(C(=O)c3ccc(Cl)cc3)ccc2O1
Reactant: NN
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)Cc2cc(C(=NN)c3ccc(Cl)cc3)ccc2O1

Procedure:
This compound was prepared in a manner analogous to that of Example 1, Step D, using 1.4 grams (0.005 mole) of (4-chlorophenyl) (2,3-dihydro-2,2-dimethylbenzofuran-5-yl)ketone, 0.4 mL (0.008 mole) of hydrazine hydrate, and 0.3 mL of acetic acid in 50 mL of ethanol. The yield of (4-chlorophenyl) (2,3-dihydro-2,2-(dimethyl- benzofuran-5-yl) ketone hydrazone was 1.23 grams. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: NCC#N.Br[C:6]1[C:7]([NH:11][C@H:12]([C:17]([NH:19][CH2:20][C:21]#[N:22])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[N:8][S:9][CH:10]=1.C(OC([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=O)(C)(C)C>>[C:21]([CH2:20][NH:19][C:17](=[O:18])[C@H:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH:11][C:7]1[C:6]([C:39]2[CH:38]=[CH:37][C:36]([N:33]3[CH2:32][CH2:31][NH:30][CH2:35][CH2:34]3)=[CH:41][CH:40]=2)=[CH:10][S:9][N:8]=1)#[N:22]
Reactant: CC(C)C[C@H](Nc1nscc1Br)C(=O)NCC#N
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Agent: N#CCN
Product: CC(C)C[C@H](Nc1nscc1-c1ccc(N2CCNCC2)cc1)C(=O)NCC#N

Procedure:
Ester hydrolysis and coupling with aminoacetonitrile as described in example 4 provided N2-(4-bromoisothiazol-3-yl)-N1-(cyanomethyl)-L-leucinamide. N2-(4-bromoisothiazol-3-yl)-N1-(cyanomethyl)-L-leucinamide was then treated with 4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenylboronic acid (prepared as described in Example 1) as described in Example 1 to afford, after BOC removal with methanesulfonic acid as described in Example 10, N1-(cyanomethyl)-N2-[4-(4-piperazin-1-ylphenyl)isothiazol-3-yl]-L-leucinamide. MS (+ESI): 413.2 [M+1]+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]4)=[C:24]([O:27][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15]>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:33][CH2:34][CH2:35][N:36]4[CH2:37][CH2:38][NH:39][CH2:40][CH2:41]4)=[C:24]([O:27][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2cc3ncnc(Nc4ccc(F)c(Cl)c4)c3cc2OC2CCCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(Nc2ncnc3cc(OCCN4CCNCC4)c(OC4CCCC4)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.00 ml trifluoroacetic acid are added dropwise to 740 mg of 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-{2-[4-(tert.butyloxycarbonyl)-piperazin-1-yl]-ethoxy}-quinazoline in 10 ml of methylene chloride. The reaction solution is stirred overnight at ambient temperature. For working up the reaction mixture is concentrated by evaporation, combined with 20 ml of water and made alkaline with concentrated aqueous ammonia solution. The aqueous phase is extracted with ethyl acetate. The combined extracts are washed with saturated sodium carbonate solution and saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. A light yellow solid remains.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6]([N:8]([CH3:25])[C@H:9]([C:22]([NH2:24])=[O:23])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].N[C@H](C(N(C)[C@H](C(N)=O)CC1C=CC(O)=C(C(C)(C)C)C=1)=O)C(C)C.[CH:58]1[CH:63]=[CH:62][C:61]([CH2:64][C@H:65]([NH:78][C:79]([O:81][CH2:82][C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)=[O:80])[C:66](OC2C=CC([N+]([O-])=O)=CC=2)=[O:67])=[CH:60][CH:59]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O.CN(C=O)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH:78]([C:79]([O:81][CH2:82][C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1)=[O:80])[C@H:65]([C:66]([NH:1][C@H:2]([C:6]([N:8]([CH3:25])[C@H:9]([C:22]([NH2:24])=[O:23])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:18]([CH3:21])([CH3:19])[CH3:20])[CH:12]=1)=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:67])[CH2:64][C:61]1[CH:60]=[CH:59][CH:58]=[CH:63][CH:62]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O
Agent: CC(C)[C@H](N)C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 146 mg (0.325 mmol) of Boc-Val-N-Me-Tyr(3-tBu)-NH2 in 2 ml of methylene chloride, 1 ml of TFA was added and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure. To a solution of the resulting TFA salt of Val-N-Me-Tyr(3-tBu)-NH2 in 2 ml of DMF, 0.1 ml of TEA, 219 mg (0.348 mmol) of Z-Phe-ONp and 93.5 mg (0.765 mmol) of DMAP were added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed first with saturated aqueous NaHCO3, then with water and finally with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane=1:1) to give Z-Phe-Val-N-Me-Tyr(3-tBu)-NH2 in the amount of 189 mg (92%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[CH:25]=[CH:26][C:27]4[C:31]([CH:32]=3)=[N:30][N:29]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:28]=4)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[ClH:40]>CO.O1CCOCC1>[ClH:40].[CH2:33]([N:29]1[CH:28]=[C:27]2[C:31]([CH:32]=[C:24]([C:8]3[CH:9]=[C:10]([CH:11]4[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:25]=[CH:26]2)=[N:30]1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ncnn2c(C3CCCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 100 %

Procedure:
To a suspension of tert-butyl 3-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]piperidine-1-carboxylate in MeOH (8 mL) was added 4M HCl in dioxane (4 mL). The mixture was stirred at rt for 17 h. The mixture was concentrated to dryness to afford 1.5 g (100%) of the desired product. ES-MS m/z 424.21 [M+H]+, HPLC RT (min) 2.21.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)=O)(C)(C)C.[C:17]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([O:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][C:35](O)=[O:36])[CH2:29][CH2:28]1)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:14][C:35]([CH2:34][CH2:33][N:30]2[CH2:29][CH2:28][CH:27]([O:26][C:24](=[O:25])[NH:23][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:32][CH2:31]2)=[O:36])=[CH:15][CH:16]=1
Reactant: O=C(O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NCc1ccc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
To a stirred solution of 4-(N-tert-butoxycarbonylaminomethyl)aniline (756 mg, 3.4 mmol), 3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionic acid (1.5 g, 4.08 mmol; prepared as described in Preparation 3) and HATU (1.55 g, 4.08 mmol) in DMF (6.8 mL), was added DIPEA (770 μL, 4.42 mmol). The reaction mixture was stirred at 50° C. overnight, and then the solvent was removed under reduced pressure. The resulting residue was dissolved in DCM (20 mL) and washed with saturated aqueous sodium bicarbonate solution (10 mL). The organic phase was then dried (magnesium sulfate) and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (5-10% MeOH/DCM) to give a solid, which was dissolved in TFA/DCM (25%, 30 mL) and stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure and the crude residue was dissolved in DCM (30 mL) and washed with 1N NaOH (15 mL). The organic phase was separated, dried (magnesium sulfate), filtered and the solvent was removed under reduced pressure to give 1.5 g of the title intermediate (94% yield over 2 steps).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[CH3:18].[H-].[Na+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CN(C=O)C>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:16]=[CH:17][C:2]([O:1][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:3]([CH3:18])[CH:4]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: COC(=O)CBr
Reactant: COc1ccc(C(=O)c2ccc(O)c(C)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(=O)c2ccc(OC)cc2)cc1C
Reaction time: 8 h

Procedure:
50 g of 4-hydroxy-3-methyl-4'-methoxybenzophenone (R. Martin et al. Monatsh. Chemie 110, 1057-1066 (1979)) are dissolved in 200 ml of dry DMF and, under N2, 9 g of a 55% dispersion of sodium hydride in mineral oil are cautiously added. Then, while stirring, 19.5 ml of methyl bromoacetate are added dropwise, and the mixture is left to stand at room temperature overnight. The precipitated salt is filtered off with suction, and the filtrate is concentrated in vacuo. The residue is taken up in ethyl acetate, and the solution is washed with sodium bicarbonate solution and water. The organic phase is dried over magnesium sulfate, and the solvent is removed in vacuo. The residue is triturated with ether, filtered off with suction and dried.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH2:17][C:18]3[N:19]([CH2:34][C:35]([F:38])([F:37])[F:36])[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=4)[CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[F:37][C:35]([F:36])([F:38])[CH2:34][N:19]1[C:18]([CH2:17][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:39])=[O:3])=[CH:10][CH:11]=2)=[CH:22][C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=2)=[N:20]1
Reactant: CCOC(=O)Cn1ccc2ccc(OCCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3CC(F)(F)F)cc21
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2ccc(OCCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3CC(F)(F)F)cc21

Procedure:
In analogy to the procedure described in example 1 f], (6-{2-[2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-ethoxy}-indol-1-yl)-acetic acid ethyl ester was treated with LiOH to obtain (6-{2-[2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-ethoxy}-indol-1-yl)-acetic acid as off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14][S:15]([C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[CH:22]=1)(=[O:17])=[O:16].[C:30](Cl)(=[O:32])[CH3:31].N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C.Cl>[O:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[CH:22]=[C:18]1[S:15]([NH:14][C:8]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[S:6][CH2:5][C:4]1[CH:3]=[C:2]([NH:1][C:30](=[O:32])[CH3:31])[CH:29]=[CH:28][CH:27]=1)(=[O:17])=[O:16]
Reactant: CC(=O)Cl
Reactant: Nc1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a solution of N-{2-[(3-aminobenzyl)sulfanyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide (440 mg, 0.90 mmol) in CH2Cl2 (10 ml) was added acetyl chloride (71 μl, 0.99 mmol), pyridine (180 μl, 2.25 mmol), and catalytic amount of DMAP. The reaction was stirred at room temperature for 2 hours, diluted with 1M HCl, and extracted with CH2Cl2. The organic layer was dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5-10% EtOAc in hexane) to yield the title compound (330 mg, 68%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[NH:37][CH3:38].C(#N)C>CO.C(Cl)Cl.O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=4[NH:37][CH3:38])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CNc1cc(C(C)=O)ccc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CNc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Yield: 47.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.3 g, 10.3 mmol), K2CO3 (1.4 g, 10.3 mmol), 1-[4-(3-chloropropoxy)-3-(methylamino)phenyl]ethanone (2.5 g, 10.3 mmol), KI (0.10 g), and acetonitrile (100 ml) was stirred at reflux under nitrogen for 23 hours. The reaction was cooled to ambient temperature, poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed twice with water, dried with MgSO4 and was concentrated to yield 4.8 g of a damp, brown solid. The compound was isolated by preparative HPLC (Waters Associates prep LC/System 500, utilizing 2 silica gel columns and 4% methanol-methylene chloride as eluent). Concentration of appropriate fractions afforded 2.4 g. Recrystallization from ethanol gave 2.1 g of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-(methylamino)phenyl]ethanone as a beige solid, m.p.=151°-153° C.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][S:8][C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]1=2.[CH:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=1)=O.CC[O-].[Na+].Cl>C1COCC1>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])/[C:9](=[CH:20]/[C:22]2[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)/[S:8][C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]1=2
Reactant: O=C1CSc2ccccc2N1Cc1ccccc1F
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(/C=C2\Sc3ccccc3N(Cc3ccccc3F)C2=O)cc1
Temperature: 70 °C
Yield: 76.1 %

Procedure:
4-(2-fluorobenzyl)-2H-benzo[b][1,4]thiazin-3(4H)-one (1 g, 3.66 mmole) and methyl 4-formylbenzoate (1.2 g) were dissolved in THF (20 mL) and to the solution was added NaOEt (1 g). The reaction solution was heated at 70 ° C. overnight and aqueous HCl (5%, 10 mL) was added to quench the reaction. The mixture was extracted with EtOAc (50 mL) twice and combined organic layers were dried over anhydrous magnisum sulfate. After filtration, the solvent was removed under vacuum to give 4-((Z)-(4-(2-fluorobenzyl)-3,4-dihydro-3-oxobenzo[b][1,4]thiazin-2-ylidene)methyl)benzoic acid (1.13 g, 71%).