Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:9].[H-].[Na+].[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17]>C1COCC1.O>[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([NH:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:9])=[O:17]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1c(Cl)cncc1Cl)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-amino 3,5-dichloro pyridine in THF (0.5M) at 0° C. was added NaH (1.5 eq). The mixture was stirred at 0° C. for 30 min then 3-bromo benzoyl chloride (2.0 eq.) was added dropwise. The resulting mixture was stirred 12 hours at room temperature, poured in water and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2 SO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 1:1) afforded the desired compound a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[CH:15][C:16]([CH:17]=[C:18]3S[C:21](=[O:23])[NH:20][C:19]3=[O:24])=[C:10]2[N:9]=1.[NH:25]1CC(=O)NC1=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[CH:15][C:16]([CH:17]=[C:18]3[NH:25][C:21](=[O:23])[NH:20][C:19]3=[O:24])=[C:10]2[N:9]=1
Reactant: O=C1NC(=O)C(=Cc2cnn3ccc(-c4ccccc4F)nc23)S1
Reactant: O=C1CNC(=O)N1
Product: O=C1NC(=O)C(=Cc2cnn3ccc(-c4ccccc4F)nc23)N1

Procedure:
5-((5-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione was prepared using the same procedure as for the synthesis of 5-((5-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione using hydantoin instead of thiazolidine-2,4-dione.
Reaction SMILES: C1(C(C)C([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH:12]([NH2:20])[C@@H:11]2[OH:21])=O)C=CC=CC=1.[ClH:23]>>[ClH:23].[NH2:20][C@@H:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][C@H:11]1[OH:21]
Reactant: CC(C(=O)C1c2ccccc2CC(N)[C@@H]1O)c1ccccc1
Agent: Cl
Product: N[C@@H]1Cc2ccccc2C[C@H]1O

Procedure:
Trans-N-[(2R)-2-phenylpropanoyl-3-amino-1,2,3,4-tetrahydro-2-naphthalenol, diastereoisomer A (183 mg) was refluxed in 6N aqueous hydrochloric acid (20 ml) for 4 hours. The reaction mixture was evaporated in vacuo and the residue taken up in water. The aqueous solution was washed with ethyl acetate and evaporated to give a white solid which was recrystallized from a methanol/ethyl acetate mixture to yield the title compound (99 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([CH2:14][CH2:15][CH:16]=O)[CH:10]=[C:9]([Cl:18])[CH:8]=2)=[O:4].[C:19]1([CH3:25])[CH:24]=CC=C[CH:20]=1>>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([CH2:14][CH2:15][CH:16]=[CH:5][C:3]([O:4][C:19]([CH3:20])([CH3:24])[CH3:25])=[O:2])[CH:10]=[C:9]([Cl:18])[CH:8]=2)=[O:4]
Reactant: Cc1ccccc1
Reactant: COC(=O)c1cc2c(CCC=O)cc(Cl)cc2[nH]1
Product: COC(=O)c1cc2c(CCC=CC(=O)OC(C)(C)C)cc(Cl)cc2[nH]1
Yield: 82 %

Procedure:
A mixture of 6-chloro-4-(3-oxopropyl)indole-2-carboxylic acid methyl ester (12.0 g, 45.2 mmol) and (tert-butoxycarbonylmethylene)triphenylenephosphorane (18.7 g, 49.7 mmol)in toluene (500 mL) was refluxed for 1 h and concentrated. The residue was purified by silica gel column chromatography with 5:1 hexane/toluene to give 12.21 g of the title compound (82%): 1H NMR (CDCl3) δ9.03 (bs, 1H), 7.29 (d, 1H, J=1.7 Hz), 7.20 (d, 1H, J=2.0 Hz), 6.95 (d, 1H, J=2.0 Hz), 6.92 (dt, 1H, J=15.5, 6.6 Hz), 5.80 (dt, 1H, J=15.5, 1.7 Hz), 3.96 (s, 3H), 3.01 (dd, 2H, J=8.6, 7.3 Hz), 2.59 (dd, 2H, J=14.5, 6.6 Hz), 1.49 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:27])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]([CH3:26])=[CH2:25])[C:5]2=[CH:4][CH:3]=1.[CH3:28][O:29][CH:30]([Si:32]([CH3:35])([CH3:34])[CH3:33])[CH3:31].[C:36]([O:40][C:41](=[O:44])[CH2:42]Br)([CH3:39])([CH3:38])[CH3:37].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:27])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:42][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:44])[CH:11]3[C:24]([CH3:26])=[CH2:25])[C:5]2=[CH:4][CH:3]=1.[CH3:28][O:29][CH:30]([Si:32]([CH3:35])([CH3:34])[CH3:33])[CH3:31]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C=C(C)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: COC(C)[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=C(C)C1N(CC(=O)OC(C)(C)C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 79 %

Procedure:
In a manner similar to the method described in example 55c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (3 g, 5.64 mmol) prepared in example 116a was reacted with bromo-acetic acid tert-butyl ester and cesium carbonate in N,N-dimethyl-formamide to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-1′-[(tert-butoxycarbonyl)methyl]-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white foam (Yield: 2.98 g, 79%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([CH:19]=[CH:20][CH:21]=1)[CH2:10][N:11]1[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]1.[N:22]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1COCC1>[F:17][C:14]1([F:18])[CH2:15][CH2:16][N:11]([CH2:10][C:9]2[CH:8]=[C:7]([N:22]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH:21]=[CH:20][CH:19]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: FC1(F)CCN(Cc2cccc(Br)c2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1cccc(CN2CCC(F)(F)CC2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 43.2 %

Procedure:
n-Butyllithium (1.6 M in hexanes, 4.5 mL, 7.28 mmol) was added dropwise to a stirred solution of Intermediate 12a (1.98 g, 6.82 mmol) in dry THF (15 mL) at −78° C. under nitrogen. The mixture was stirred at −78° C. for 10 min, then di-tert-butyl azodicarboxylate (1.73 g, 7.51 mmol) was added in one portion. The mixture was stirred at −78° C. for 20 min, then allowed to warm to RT over 20 min. The mixture was then partitioned between saturated ammonium chloride solution (15 mL) and ethyl acetate (3×20 mL). The combined organic extracts were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and the residue purified by FCC, eluting with 0-100% EtOAc in pentane, to give the title compound as a pale yellow oil (1.30 g, 43%). LCMS (Method 1): Rt 2.54 min, m/z 442 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](C1CCCCO1)[N:13]=[C:12]2[C:24]1[CH:29]=[N:28][CH:27]=[C:26]([O:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[N:25]=1.Cl>CO>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[C:24]1[CH:29]=[N:28][CH:27]=[C:26]([O:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[N:25]=1
Reactant: Fc1cccc(F)c1-c1ccc2c(c1)c(-c1cncc(Oc3cccnc3)n1)nn2C1CCCCO1
Agent: Cl
Solvent: CO
Product: Fc1cccc(F)c1-c1ccc2[nH]nc(-c3cncc(Oc4cccnc4)n3)c2c1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A solution of 5-(2,6-difluorophenyl)-3-(6-(pyridin-3-yloxy)pyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (74 mg, 0.15 mmol) and HCl (5-6 M in IPA, 3.0 mL, 15.2 mmol) in 4 mL of MeOH was heated at 80° C. for 90 min. The reaction was cooled to RT and concentrated. The residue was diluted with CH2Cl2 and saturated NaHCO3 (aq.) was added slowly. The mixture was extracted with CH2Cl2 (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (55 mg, 0.14 mmol, 90% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 402.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.77 (s, 1H), 9.15 (s, 1H), 8.60 (s, 1H), 8.56 (d, J=2.15 Hz, 1H), 7.99 (d, J=4.30 Hz, 1H), 7.82 (dd, J=8.22, 1.37 Hz, 1H), 7.69 (d, J=8.61 Hz, 1H), 7.53-7.62 (m, 1H), 7.49 (s, 1H), 7.37 (d, J=8.61 Hz, 1H), 7.25-7.33 (m, 2H), 7.23 (dd, J=8.41, 4.69 Hz, 1H).
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:33]=[C:32]([O:34]CC2C=CC=CC=2)[CH:31]=[CH:30][C:11]=1[C:12]([NH:14][C@H:15]([C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22])[CH2:16][CH2:17][C:18](=[O:20])[NH2:19])=[O:13])C1C=CC=CC=1>[H][H].[C].[Pd]>[ClH:1].[OH:9][C:10]1[CH:33]=[C:32]([OH:34])[CH:31]=[CH:30][C:11]=1[C:12]([NH:14][C@H:15]([C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22])[CH2:16][CH2:17][C:18](=[O:20])[NH2:19])=[O:13]
Reactant: CN1CCN(C(=O)[C@H](CCC(N)=O)NC(=O)c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Product: CN1CCN(C(=O)[C@H](CCC(N)=O)NC(=O)c2ccc(O)cc2O)CC1
Yield: 85.9 %

Procedure:
10% Palladium-carbon (200 mg) was added to an ethanolic solution (50 ml) of 1-(2,4-dibenzyloxybenzoyl-L-glutaminyl)-4-methylpiperazine.hydrochloride (270 mg) obtained above and catalytic reduction was carried out at room temperature and under atmospheric pressure in hydrogen stream. Thereafter, treatments were conducted in the same manner as in Example 5 (ii) to obtain colorless crystalline powder 1-(2,4-dihydroxybenzoyl-L-glutaminyl)-4-methylpiperazine.hydrochloride (160 mg). Melting point: 144°-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].FC(F)(F)C(O)=O.[CH2:42]([N:49]1[C:53](=[O:54])[C:52]2([CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[N:51]([C:60]2[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=2)[CH2:50]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH2:42]([N:49]1[C:53](=[O:54])[C:52]2([CH2:59][CH2:58][N:57]([CH2:29][CH2:28][C:9]3([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]4[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=4)[CH2:10]3)[CH2:56][CH2:55]2)[N:51]([C:60]2[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=2)[CH2:50]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C1N(Cc2ccccc2)CN(c2ccc(F)cc2)C12CCNCC2
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N2CCC(CCN3CCC4(CC3)C(=O)N(Cc3ccccc3)CN4c3ccc(F)cc3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 3-benzyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one trifluoroacetate (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [Cl-].[CH:2]1([NH2+:9][CH2:10][CH2:11]Cl)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[N:23]=[C:24]=[S:25]>>[CH3:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[N:23]=[C:24]1[N:9]([CH:2]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:10][CH2:11][S:25]1
Reactant: ClCC[NH2+]C1CCCCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCN1C1CCCCCC1

Procedure:
2-Hydroxyethylamine was reacted with cycloheptyl bromide according to Method B2a to give N-cycloheptyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cycloheptyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-cycloheptyl-1,3-thiazolidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:20]([O:22]CC)=[O:21])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[K+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:20]([OH:22])=[O:21])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccc(C)cc2)n(-c2ccc(F)cc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)O)nn2-c2ccc(F)cc2)cc1
Yield: 85.1 %

Procedure:
A mixture of ethyl 1-(4-fluorophenyl)-5-(4-tolyl)pyrazole-3-carboxylate (2.7 g) and potassium hydroxide (1.1 g) in methanol (40 ml) was refluxed for 30 minutes. The solvent was evaporated, and the residue was dissolved in water and washed with ethyl acetate. The aqueous layer was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated, giving crystals of 1-(4-fluorophenyl)-5-(4-tolyl)pyrazole-3-carboxylic acid (2.1 g).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[C:26](O)(=[O:29])[CH2:27][CH3:28]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: CCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (17.9 mg, 57.9%), MS (ISP) m/z=387.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (29.4 mg, 0.080 mmol) and propionic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12](=O)[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:14])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[NH2:23]C1C=CC=CC=1O>>[OH:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13](=[O:14])[O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[N:23]=2)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8]
Reactant: CCCCCCOC(=O)C(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1O
Product: O=c1oc2ccccc2nc1-c1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A mixture of 3.93 g of n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 1.38 g of 2-aminophenol is melted at 120° while stirring. The melt crystallizes after 5 minutes. After 2 hours it is cooled and recrystallized from methanol. There is obtained 3-(3,4-dihydroxy-5-nitrophenyl)-2H-1,4-benzoxazin-2-one of m.p. 202°-204°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>O>[CH2:17]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:2]=1[Cl:1])[CH3:18]
Reactant: CCO
Reactant: O=C(O)c1ccc(O)cc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1ccc(O)cc1Cl

Procedure:
A solution consisting of 34.5 g (200 mmol) of 2-chloro-4-hydroxy-benzoic acid, 5 mL of concentrated sulfuric acid and 400 mL of ethanol was refluxed for 18 hours. 1.2 L of water were added to the resulting mixture followed by extraction with 1.5 L of methylene chloride. The mixture was then washed with aqueous sodium bicarbonate solution and water and dried with magnesium sulfate followed by distilling off the solvent. The residue was recrystallized from hexane/ethyl acetate to obtain 20.4 g of a light orange solid.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:25]N(C=O)C>ClC(Cl)C>[C:1]1([S:7][C:8]2[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[CH:13][C:9]=2[C:10]([O:12][CH3:25])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1Sc1ccccc1
Reactant: CN(C)C=O
Solvent: CC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(F)(F)F)cc1Sc1ccccc1

Procedure:
A solution of 2-(phenylsulphenyl)-4-trifluoromethylbenzoic acid (11.5 g) and thionyl chloride (11.4 g) in dichloroethane containing a few drops of DMF was heated at reflux for 1.5 hours. The mixture was evaporated to dryness and methanol was added. The mixture was heated at reflux for 1 hour and evaporated to dryness. It was treated with water and extracted with ether, washed with sodium carbonate solution (2M), water, dried (Na2SO4) and filtered. The flitrate was evaporated to dryness and the residue was triturated with cyclohexane and filtered to give methyl 2-(phenylsulphenyl)-4-trifluoromethylbenzoate (10.5g) as a white solid, m.p. 55°-60° C.
Reaction SMILES: [NH2:1][CH2:2][C@@:3]1([CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:9][C@@:8]2([CH3:10])[C@@H:4]1[CH:5]=[CH:6][CH2:7]2>Cl.C(OCC)(=O)C>[NH2:1][CH2:2][C@@:3]1([CH2:11][C:12]([OH:14])=[O:13])[CH2:9][C@@:8]2([CH3:10])[C@H:4]1[CH:5]=[CH:6][CH2:7]2
Reactant: CC(C)(C)OC(=O)C[C@]1(CN)C[C@]2(C)CC=C[C@@H]21
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@]12CC=C[C@H]1[C@](CN)(CC(=O)O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
Tert-butyl(±)-[(1S,5S,6R)-6-(aminomethyl)-1-methylbicyclo[3.2.0]hept-3-en-6-yl]acetate (0.90 g, 3.6 mmol) was dissolved in a 4 N hydrochloric acid-ethyl acetate solution (20 mL), and the solution was stirred at room temperature for 2 hours. Then, the solvent was distilled off under reduced pressure. The residue was suspended by the addition of dichloromethane. To the suspension, triethylamine was then added dropwise, and the resulting powder was collected by filtration. The obtained powder was washed with dichloromethane to obtain the compound of interest as a white powder (0.33 g, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([C:13]([O:15]C)=[O:14])[C:4]=1[C:17]1[C:22]([C:23]([O:25]C)=[O:24])=[CH:21][C:20]2[O:27][CH2:28][O:29][C:19]=2[C:18]=1[O:30][CH3:31].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([C:13]([OH:15])=[O:14])[C:4]=1[C:17]1[C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]2[O:27][CH2:28][O:29][C:19]=2[C:18]=1[O:30][CH3:31]
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1-c1c(C(=O)OC)cc2c(c1OC)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)O)c(-c2c(C(=O)O)cc3c(c2OC)OCO3)c(OC)c1OC
Yield: 79.4 %

Procedure:
In 20 ml of methanol was dissolved 1.75 g of dimethyl 2,2',3,4-tetramethoxy-3',4'-methylenedioxy-1,1'- biphenyl-6,6'-dicarboxylate obtained in Example 2, and 1 ml of a 10% aqueous solution of sodium hydroxide was added to the solution and the mixture was heated and refluxed for 16 hours. After termination of the reaction, the reaction mixture was cooled and the precipitated crystals were recovered by filtration and recrystallized from methanol to obtain 1.3 g of 2,2',3,4-tetramethoxy-3',4'-methylenedioxy-1,1' -biphenyl-6,6'-dicarboxylic acid (the yield was 81%).
Reaction SMILES: C([O:8][C:9]1[CH2:13][N:12]([CH2:14][C:15]([NH2:17])=[O:16])[C:11](=[O:18])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd].[Pt]=O>[OH:8][CH:9]1[CH2:13][N:12]([CH2:14][C:15]([NH2:17])=[O:16])[C:11](=[O:18])[CH2:10]1
Reactant: [H][H]
Reactant: NC(=O)CN1CC(OCc2ccccc2)=CC1=O
Agent: O=[Pt]
Agent: [Pd]
Solvent: CC(=O)O
Product: NC(=O)CN1CC(O)CC1=O

Procedure:
3.00 g of 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide was dissolved in 30 ml of concentrated acetic acid and mixed with 240 mg of palladium 5 percent on activated carbon and 24 mg of platinum oxide. Hydrogenolysis and hydrogenation at 15 bars of hydrogen pressure and room temperature were performed for 65 hours. Then filtering off from the catalyst and evaporation of the solvent were performed. The residue was picked up in H2O and allowed to run over 5.0 g of weakly basic ion exchanger. The water was distilled off and the residue mixed with 10 ml of acetone. 1.53 g of nearly white 4-hydroxypyrrolidin-2-on-1-yl acetamide with a melting point of 163.5° to 165.7° C. was obtained.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:45])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([N:26]4[C:34]5[C:29](=[CH:30][C:31]([Cl:36])=[C:32]([Cl:35])[CH:33]=5)[CH:28]=[N:27]4)[N:24]=3)[N:19](COCC[Si](C)(C)C)[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:45])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([N:26]4[C:34]5[C:29](=[CH:30][C:31]([Cl:36])=[C:32]([Cl:35])[CH:33]=5)[CH:28]=[N:27]4)[N:24]=3)[NH:19][CH:18]=2)=[O:16])[CH:11]2[CH2:12][CH2:13]2)[CH2:5][CH2:4]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(-n3ncc4cc(Cl)c(Cl)cc43)cnc21
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: N#CC1CCN(C(=O)[C@H](NC(=O)c2c[nH]c3ncc(-n4ncc5cc(Cl)c(Cl)cc54)nc23)C2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.6 %

Procedure:
To a solution of 2-(5,6-dichloro-indazol-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (220 mg, 0.33 mmol) in CH2Cl2 (4 mL) was added TFA (2.0 mL, 26.0 mmol). The yellow reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in CH2Cl2 (4 mL) and ethylenediamine (0.4 mL, 5.92 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 h then quenched with water and extracted with CH2Cl2 (3×). The combined organics were concentrated and the residue was purified by silica gel chromatography with 0% to 5% MeOH/CH2Cl2 (0.5% NH4OH) then triturated with Et2O to afford 95 mg (54%) of 2-(5,6-dichloro-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a light yellow solid. MS: (M+Na)+=559; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.91 (br. s., 1H), 8.91 (s, 1H), 8.79 (s, 1H), 8.44 (s, 1H), 8.41 (d, J=7.9 Hz, 1H), 8.29 (d, J=7.9 Hz, 1H), 8.18 (s, 1H), 4.77 (t, J=7.6 Hz, 1H), 3.59-3.86 (m, 2H), 3.32-3.46 (m, 1H), 2.95-3.05 (m, 2H), 1.45-1.92 (m, 4H), 1.24 (br. s., 1H), 0.32-0.48 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11](C(O)=O)=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1>N1C2C(=CC=CC=2)C=CC=1.C(OCC)(=O)C.[Cu]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][CH:11]=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2ccc([N+](=O)[O-])cc2)c(-c2ccc(F)cc2)s1
Agent: [Cu]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: O=[N+]([O-])c1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Yield: 57.4 %

Procedure:
A mixture of 5-(4-fluorophenyl)-4-(4-nitrophenyl)thiophene-2-carboxylic acid (7.6 g) and copper powder (1.6 g) in quinoline (12 ml) was stirred and refluxed for 7 hours. The reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water, brine, dilute hydrochloric acid and brine, successively, dried and evaporated. The residue (7.3 g) was purified by column chromatography on silica gel (80 g) eluting with a mixture of hexane and toluene (2:1) to give yellow orange crystals of 2-(4-fluorophenyl)-3-(4-nitrophenyl)thiophene (3.8 g).