Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([CH2:26][CH2:27][C:28]([O:30][CH2:31]C)=[O:29])=[CH:20]4)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[C:33](=O)(OC)OC.C1N2CCN(CC2)C1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH3:33])[C:21]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:20]4)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCc1cc2cc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)ccc2[nH]1
Reactant: COC(=O)OC
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCc1cc2cc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)ccc2n1C
Temperature: 25 °C

Procedure:
A solution of ethyl 3-[5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]propanoate (D115) (112 mg), dimethyl carbonate (2.0 mL) and DABCO (33 mg) in N,N-dimethylformamide (2 mL) was stirred at 90° C. for 2 days. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate. The organic solution was washed with water. The organic solution was dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography to afford methyl 3-[5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-2-yl]propanoate (D116) (72 mg). The crude product was used directly in the next step without further identification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=1.[OH-].[Na+]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(OCCc2cc3ccccc3[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCCc2cc3ccccc3[nH]2)cc1

Procedure:
Ester 4-3 (150 mg, 0.51 mmol) and 1N NaOH (1.3 mL, 1.3 mmol) were combined in 10 mL MeOH. After 16 h additional 1N NaOH (5 mL, 5 mmol) was added, and 7 h later, 5 mL more 1N NaOH. After a total of 2 d the mixture was heated at 50° for 1 h, then concentrated, redissolved in H2O, washed with EtOAc, and the pH of the aqueous layer was adjusted to 1 with 20% KHSO4. This was extracted with EtOAc, and this organic layer was washed with brine, dried (MgSO4) and concentrated, providing 4-4 as a gray solid. Rf 0.48 (silica, EtOAc).
Reaction SMILES: C1(O[C:8](=[O:20])[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[OH:21][C:22]1[CH:23]=[C:24]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:24]3[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([OH:21])[CH:23]=3)[CH2:35][CH2:34]2)=[O:20])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Reactant: COc1ccc(N2CCNCC2)cc1O
Product: COc1ccc(N2CCN(C(=O)Nc3cc(C)c(C)nc3OC)CC2)cc1O
Yield: 69 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(3-hydroxy-4-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: C([O:5][C:6]([N:8](C)[C@H:9]([C:22]([NH:24][C@@H:25]([C:30]([NH:32][CH2:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:31])[CH2:26][CH2:27][S:28][CH3:29])=[O:23])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]C(C)(C)C)=[CH:13][CH:12]=1)=O)(C)(C)C.CCOCC.[ClH:48].O1CCOCC1>>[OH2:5].[ClH:48].[CH3:6][NH:8][C@H:9]([C:22]([NH:24][C@H:25]([C:30]([NH:32][CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:31])[CH2:26][CH2:27][S:28][CH3:29])=[O:23])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)N(C)C(=O)OC(C)(C)C)C(=O)NCCCc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CCSC)C(=O)NCCCc1ccccc1
Product: O

Procedure:
A solution of [N-(tert-butyloxycarbonyl)-O-(tert-butyl)-N-methyl-L-tyrosyl]-N-(3-phenylpropyl)-D-methioninamide (1.9 g.) in hydrogen chloride-dioxane (3.9 N, 25 ml.) was stirred for 75 minutes at room temperature, then stripped of volatiles. Trituration of the residue with ether gave a white powder (1.308 g.), an aqueous solution of which was lyophilized, affording as an amorphous solid N-methyl-L-tyrosyl-N-(3-phenylpropyl)-L-methioninamide monohydrochloride hydrate (4:1) (1.260 g.; [α]D25 +68.0°, c=1, methanol), whose free base is the compound of Formula II wherein Q is Met, R1 is methyl, R2 and R5 are each hydrogen and R4 is (CH2)nY wherein n is 3 and Y is phenyl.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13]C)=[CH:4][N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([OH:13])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)c2cc(F)ccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cnc(Cl)c2cc(F)ccc12
Yield: 92.9 %

Procedure:
A solution of 1-chloro-7-fluoro-4-methoxyisoquinoline (0.75 g, 3.54 mmol) in DCM (10 ml) was added BBr3 (6.22 g, 24.81 mmol) at 0° C. drop wise. The reaction mass was refluxed for 5 h. The residue was cooled and quenched with methanol. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The precipitated solid was filtered, washed with water to get crude compound (0.65 g, 93%) as pale yellow solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.36-8.33 (m, 1H), 7.89-7.86 (d, J=12 Hz, 1H), 7.76 (s, 1H), 7.64 (t, J=10 Hz, 1H); MS: MS m/z 198.0 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:28])([CH3:27])[CH2:9][NH:10][C:11]2[N:16]=[N:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][N:21]=[C:20]4[NH2:26])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:29](Cl)(=[O:31])[CH3:30]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:28])([CH3:27])[CH2:9][NH:10][C:11]2[N:16]=[N:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][N:21]=[C:20]4[NH:26][C:29](=[O:31])[CH3:30])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(CNc1ccc(-c2ccc3[nH]nc(N)c3c2)nn1)c1ccc(F)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1n[nH]c2ccc(-c3ccc(NCC(C)(C)c4ccc(F)cc4)nn3)cc12
Reaction time: 0.25 h
Yield: 44.9 %

Procedure:
To a solution of 5-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)-1H-indazol-3-amine (50 mg, 133 μmol) in pyridine (1 mL) was added acetyl chloride (9.5 μL, 133 μmol). The mixture was stirred for 15 min, concentrated, purified by reverse phase chromatography using a CH3CN/water gradient to afford 25 mg of white solid, m/z=419.9 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][CH:18]1[O:20][CH2:19]1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:17][CH:18]1[O:20][CH2:19]1
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc(OCC2CO2)c(Cl)c1

Procedure:
A mixture containing 81.5 g of 2,4-dichlorophenol in 120 g of 1-chloro-2,3-epoxypropane and 138 g of potassium carbonate is refluxed for 10 hours.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1.[BH4-].[Na+]>CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1
Reactant: COc1cccc(CC(=O)c2ccco2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(CC(O)c2ccco2)c1

Procedure:
1-(Furan-2-yl)-2-(3-methoxyphenyl)ethan-1-one (20 g, 92.56 mmol) was dissolved in MeOH (200 mL), and NaBH4 (3.5 g, 92.52 mmol) was slowly added to the solution at 5° C. After the reaction was completed, the solution was quenched with H2O, and the MeOH was evaporated. The residue was extracted with EtOAc and the organic layer was washed with brine, dried over MgSO4, and evaporated to give the 1-(furan-2-yl)-2-(3-methoxyphenyl)ethan-1-ol as yellow oil: 20 g (crude yield: 98%)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[CH2:12][N:13]([CH:27]([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)(=[NH:3])[NH2:2].[ClH:34].[C:35](=[NH:40])(OCC)[CH3:36].C(N(CC)CC)C.Cl>CO.O1CCOCC1>[ClH:34].[ClH:34].[ClH:34].[C:35]([N:24]1[CH2:25][CH2:26][CH:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([N:13]([CH:27]([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:12]/[CH:11]=[CH:10]/[C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[NH:2])[NH2:3])[CH:5]=3)=[CH:15][CH:16]=2)[CH2:22][CH2:23]1)(=[NH:40])[CH3:36]
Reactant: CCOC(C)=N
Reactant: CCOC(=O)C(C)N(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCNCC2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)N(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCN(C(C)=N)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47 %

Procedure:
To a solution of a mixture (544 mg) containing ethyl 2-[N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[4-(piperidin-4-yloxy)phenyl]amino]propionate in methanol (30 ml) were added ethyl acetimidate hydrochloride (360 mg) and triethylamine (0.81 ml) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. To the reaction mixture was added a 4M solution of hydrogen chloride in dioxane (1 ml) and the solution was concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 25% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in methanol (10 ml) was added a 4M solution of hydrogen chloride in dioxane (0.5 ml) and the mixture was concentrated to dryness in vacuo. A solution of the residual solid in water (about 10 ml) was lyophilized to give the title compound (468 mg, yield of two steps 47%) as a pale brown amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:24])[C:7](=[O:23])[NH:8][N:9]=1.N[CH:26]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]1.C([BH3-])#N.[Na+]>CO.CC(O)=O>[C:33]([O:32][C:30]([N:28]1[CH2:29][CH:26]([NH:1][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:24])[C:7](=[O:23])[NH:8][N:9]=2)[CH2:27]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC1C(=O)NN=C2COc3cc(Oc4ccccc4)c(N)cc3N21
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1C(=O)NN=C2COc3cc(Oc4ccccc4)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 11.3 %

Procedure:
A mixture of 6-amino-4-methyl-7-phenoxy-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.090 g, crude from previous step), tert-butyl 3-aminoazetidine-1-carboxylate (0.087 g, 0.51 mmol) and sodium cyanoborohydride (0.00032 g, 0.51 mmol) in MeOH (2.7 mL) and AcOH (0.3 mL) was heated at reflux overnight. The reaction mixture was cooled to ambient temperature and diluted with MeOH (10 mL). The solution was purified by preparative HPLC (Table 3, Method 3) to give 3-(4-methyl-3-oxo-7-phenoxy-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.015 g, 12% over 2 steps) as a colorless oil. LC/MS (Table 1, Method 2) Rt=1.188 min; MS m/z: 502 [M+23]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([NH:27][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=3[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:15])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCCCC1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NC1CCCCC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and cyclohexylamine (49 mg, 0.39 mmol). The title compound was obtained as a solid (60 mg, 34% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, s), 8.62 (1H, m), 8.50 (1H, s), 3.63 (1H, m), 1.71 (4H, m), 1.59 (1H, m), 1.24 (4H, m), 1.09 (1H, m). MS m/z: 430.13, 432.07 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:16][NH:17][C:18]2[C:19]([F:32])=[C:20]([CH:28]=[CH:29][C:30]=2[F:31])[O:21][CH2:22][C:23]([O:25]CC)=[O:24])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH:8]=1)#[N:2].C([O-])([O-])=[O:34].[K+].[K+].OO.Cl>CS(C)=O.O>[C:1]([C:3]1[CH:4]=[C:5]([CH2:16][NH:17][C:18]2[C:19]([F:32])=[C:20]([CH:28]=[CH:29][C:30]=2[F:31])[O:21][CH2:22][C:23]([OH:25])=[O:24])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH:8]=1)(=[O:34])[NH2:2]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(C#N)cc(-c3cccc(F)c3)c2)c1F
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cc(CNc2c(F)ccc(OCC(=O)O)c2F)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.5 %

Procedure:
To a mixture of ethyl 2-[3-[[3-cyano-5-(3-fluorophenyl)phenyl]methylamino]-2,4-difluoro-phenoxy]acetate (see example 24) (200 mg, 0.45 mmol, 1 eq) and K2CO3 (310 mg, 2.3 mmol, 5 eq) in DMSO (10 mL) at 40° C. was added H2O2 (30% aqueous solution, 10 mL) dropwise. The mixture was stirred for 20 min then cooled to room temperature. Water was added, and the reaction neutralised by addition of diluted HCl. The solid precipitate that formed was collected by filtration, washed with water and dried to give the title compound as white solid (90 mg, 46%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][N:16]([C:18]([N:20]2[CH2:25][CH2:24][S:23][CH2:22][CH2:21]2)=[O:19])[CH2:15][CH:14]([C:26]([O:28]C)=[O:27])[CH2:13]1.CC(C)([O-])C.[K+]>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][N:16]([C:18]([N:20]2[CH2:25][CH2:24][S:23][CH2:22][CH2:21]2)=[O:19])[CH2:15][CH:14]([C:26]([OH:28])=[O:27])[CH2:13]1
Reactant: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2F)CN(C(=O)N2CCSCC2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2F)CN(C(=O)N2CCSCC2)C1

Procedure:
According to General Method 4A, 945 mg (1.56 mmol) of the compound from Example 89A were reacted with 1.74 g (15.5 mmol) of potassium tert-butoxide. This gave 762 mg of crude product in 69% purity (LC-MS), which was reacted without any further purification steps.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH:27][CH3:28])=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19].[CH2:29](N)C>>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][CH3:29])=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19]
Reactant: CNC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Reactant: CCN
Product: CCNC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1

Procedure:
Compound 19 was prepared in a manner similar to that of compound 16 using ethylamine instead of methylamine, MS 405.35 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH:4]([OH:6])[CH3:5].C(N(CC)CC)C.Cl.CN(C)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>CC#N>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:6][C@H:4]([CH3:5])[C:3]([O:2][CH3:1])=[O:7])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C(C)O
Agent: CN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)OS(=O)(=O)c1ccc(C)cc1
Temperature: 5 °C

Procedure:
2-Hydroxy-propanoic acid methyl ester (6.66 g) was dissolved in MeCN (34 mL) and the solution cooled to 5° C. Triethylamine (9.8 mL) was added followed by trimethylamine hydrochloride (0.62 g). A solution of p-toluenesulfonyl chloride (11.6 g) in MeCN (34 mL) (sonicated to complete dissolution) was added over 20 min maintaining the temperature of the reaction below 5° C. The reaction was filtered through Celite and washed through with further MeCN. The filtrate was concentrated almost to dryness (bath 30° C.) and partitioned between diethyl ether and water. The organic layer was separated, dried (MgSO4) and the solvents removed to give the sub titled product as a yellow oil that solidified in the freezer (13.71g).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:35])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23](OCC2C=CC=CC=2)[CH:22]=1.[H][H].[CH3:38][OH:39]>[Pd]>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:14][CH2:15]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:35])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:38][OH:39])[CH:22]=1
Reactant: [H][H]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(OCc3ccccc3)c2)c1N
Reactant: CO
Agent: [Pd]
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(CO)c2)c1N

Procedure:
3-[5-Amino-4-(3-benzyloxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide 6 (200 mg, 0.43 mmol) was dissolved in MeOH (10 mL). Catalyst 10% palladium on activated carbon (dry) was added and was stirred in an atmosphere of hydrogen for 2 h. The catalyst was removed by filtration and solvent was removed in vacuo. Product 3-[5-amino-4-(3-hydroxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide 7 was obtained as a light yellow solid (140 mg, 87%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[C:9]=2[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1.[C:22]1(C)C=CC(S(O)(=O)=O)=C[CH:23]=1>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[C:9]=2[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CCc1c(-c2ccc(O)cc2)[nH]c2nccnc12
Solvent: CCO
Product: CCOC(=O)CCc1c(-c2ccc(O)cc2)[nH]c2nccnc12

Procedure:
A solution of 3-{6-(4-hydroxyphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl}propionic acid (0.02 g) [Example 30] in ethanol (2 mL) was treated with a catalytic amount of para-toluenesulfonic acid. The mixture was refluxed for 4 hours, the solvent removed by evaporation and the precipitate filtered. The solid was then taken in ethyl acetate, the organic layer washed with water, brine, dried over magnesium sulfate and evaporated to give a yellow solid which was subjected to flash chromatography on silica, eluting with ethyl acetate) to give the title compound. MS: 298 (MH+). HPLC (Method C): RT=2.58 minutes.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:26])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:17])=[C:11]([F:27])[CH:10]=1)C1C=CC=CC=1>CO.[C].[Pd]>[F:27][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[N:15]([CH3:26])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:17]
Reactant: CN(C(=O)Nc1ccc(F)cc1)c1ccc(OCc2ccccc2)cc1F
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)Nc1ccc(F)cc1)c1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71.1 %

Procedure:
After dissolving N-(4-benzyloxy-2-fluorophenyl)-N′-(4-fluorophenyl)-N-methylurea (105 mg, 0.2881 mmol) in methanol (10 ml), 10% palladium carbon (20 mg) was added and the mixture was stirred for 45 minutes at room temperature under a hydrogen atmosphere. The catalyst was filtered off, and then was washed with ethanol, and the solvent of the filtrate was distilled off under reduced pressure. The precipitated crystals were suspended in diethyl ether, and then filtered out, washed with diethyl ether and dried by aspiration to obtain the title compound (57 mg, 0.2048 mmol, 71.10%) as colorless crystals.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([C:15]([O:17]C)=[O:16])=[N:8]1.[OH-].[Li+]>CO.C1COCC1.O.O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([C:15]([OH:17])=[O:16])=[N:8]1
Reactant: COC(=O)c1cc([N+](=O)[O-])n(C2CCCCO2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc([N+](=O)[O-])n(C2CCCCO2)n1
Reaction time: 16 h
Yield: 177.7 %

Procedure:
Methyl 1-(tetrahydro-2H-pyran-2-yl)-5-nitro-1H-pyrazole-3-carboxylate (500 mg, 0.70 mmol) was dissolved in a mixture of MeOH/THF/H2O (1:2:1, 20 mL). Lithium hydroxide (56.3 mg, 2.35 mmol) was added and the reaction mixture was stirred for 16 hrs. The reaction mixture was diluted with water and washed with DCM. The aqueous phase was evaporated which gave 1-(tetrahydro-2H-pyran-2-yl)-5-nitro-1H-pyrazole-3-carboxylic acid (300 mg, 64%) as a white solid which was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].Cl.[NH2:31][CH2:32][C:33]1([OH:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:31][CH2:32][C:33]2([OH:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: NCC1(O)CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCC3(O)CCCCC3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 1-aminomethyl-1-cyclohexanol hydrochloride (13 mg, 0.10 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[(1-hydroxycyclohexyl)methylaminomethyl]indol-2-yl}isoindolinone.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[OH:15].[CH2:16]([O:18][C:19](=[O:24])[CH:20]=[C:21](Cl)[CH3:22])[CH3:17]>O1CCCC1>[CH2:16]([O:18][C:19](=[O:24])/[CH:20]=[C:21](/[O:15][C:9]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[Cl:7])\[CH3:22])[CH3:17]
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: CCOC(=O)C=C(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cc(Cl)ccc1Cl
Temperature: 23 °C
Yield: 38 %

Procedure:
Potassium t-butoxide (7.50 g, 0.067 mol) was added to a stirred solution of 2,5-dichloro-phenol (5.46 g, 0.033 mol) in tetrahydrofuran (35 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 5.00 g, 0.034 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(2,5-dichloro-phenoxy)-but-2-enoic acid ethyl ester (3.45 g, 37%) as a yellow oil.