Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1.[Br:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>CCC(=O)CC>[Br:17][CH2:18][CH2:19][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(-c2cc3ccccc3o2)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(=O)CC
Product: BrCCOc1ccc(-c2cc3ccccc3o2)cc1

Procedure:
A mixture of 10.5 g. (0.05 mol.) of 2-p-hydroxyphenylbenzofuran and 47 g. (0.25 mol.) of 1,2-dibromoethane in 200 ml. of 3-pentanone containing 46 g. (0.3 mol.) of potassium carbonate was heated at 100° for 12 hours. The mixture was filtered while hot and the solid remaining was washed with hot acetone. The combined filtrate and washings were concentrated to give 2-[4'-(2-bromoethoxy)phenyl]benzofuran.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[CH3:16][N:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[CH3:16][N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:11]([C:6]1[C:5]([Cl:13])=[C:4]([Cl:14])[C:3]([Cl:15])=[C:2]([Cl:1])[C:7]=1[C:8]([OH:10])=[O:9])=[O:12].[C:16]1([N:17]2[CH:21]=[CH:20][CH:19]=[C:18]2[C:8]([C:7]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[C:11]([OH:10])=[O:12])=[O:9])[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: Cn1cccc1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Cn1cccc1C(=O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)O
Product: O=C(O)c1ccccc1C(=O)c1cccn1-c1ccccc1

Procedure:
Proceeding in a similar fashion to the one described in part A of Example 17, 28.6 g (0.01 mole) of tetrachlorophthalic anhydride, 16.2 g (0.2 mole) of N-methylpyrrole and 40 g (0.3 mole) of aluminum chloride were interacted in 50 ml of dry chlorobenzene to obtain 2-[(1-methyl-2-pyrrolyl)carbonyl]-3,4,5,6-tetrachlorobenzoic acid (Formula IX: R°=R1 =R2 =R3 =Cl; R7 =CH3) having a melting point of 203°-205° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[C:11]([CH3:12])=[C:10]([C:13](=[O:15])[CH3:14])[CH:9]=[N:8]1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.[ClH:29].[CH2:30](O)C.C=O>C(O)C>[ClH:29].[CH3:12][C:11]1[N:7]([C:2]2[N:1]=[CH:6][CH:5]=[CH:4][N:3]=2)[N:8]=[CH:9][C:10]=1[C:13](=[O:15])[CH2:14][CH2:30][N:26]1[CH2:27][CH2:28][N:23]([C:20]2[CH:19]=[CH:18][C:17]([OH:16])=[CH:22][CH:21]=2)[CH2:24][CH2:25]1
Reactant: CCO
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: CC(=O)c1cnn(-c2ncccn2)c1C
Agent: C=O
Agent: Cl
Product: Cc1c(C(=O)CCN2CCN(c3ccc(O)cc3)CC2)cnn1-c1ncccn1

Procedure:
2.0 g of 1-(2-pyrimidinyl)-4-acetyl-5-methylpyrazole was dissolved in 50 ml of ethanol. After adding 2.6 g of 1-(4-hydroxyphenyl)piperazine, 10 ml of a 1N hydrochloric acid/ethanol solution and 1.6 g of paraformaldehyde, the mixture was heated under reflux for 24 hours. Further, 3.2 g of paraformaldehyde was added and the resulting mixture was heated under reflux for additional 48 hours. Then the reaction mixture was concentrated and neutralized by adding a saturated aqueous solution of sodium hydrogencarbonate. After extracting with chloroform, the extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue thus obtained was purified by silica gel column chromatography (chloroform:methanol=20:1), converted into hydrochloride by adding a 1N hydrochloric acid/ethanol solution and then recrystallized from ethanol. Thus 946 mg of the title compound was obtained in the form of a pale brown powder.
Reaction SMILES: [C:1]1(=[O:7])[CH2:5][CH2:4][C:3](=[O:6])[CH2:2]1.[CH2:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:8]([O:6][C:3]1[CH2:4][CH2:5][C:1](=[O:7])[CH:2]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCC(=O)C1
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C=C(OCc2ccccc2)CC1

Procedure:
A mixture of cyclopentane-1,3-dione (2.00 g, 20.4 mmol), benzyl alcohol (2.11 mL, 20.4 mmoL) and para-toluenesulfonic acid (35 mg, 0.20 mmol) in toluene (10.0 mL) is heated at reflux over night. Water is added, and the mixture is extracted with dichloromethane. The organic layer is concentrated, and the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 9:1 to cyclohexane/ethyl acetate 1:4). Yield: 1.66 g; ESI mass spectrum: [M+H]+=189; Retention time HPLC: 0.51 min (X012_S01).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[C:8]([Cl:11])[C:9]=1[O:10][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1cc(Cl)c(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1c(Cl)cc(C=O)cc1Cl
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a solution of 3,5-dichloro-4-hydroxybenzaldehyde (302 mg, 1.6 mmol) in acetone (15 mL) was added cesium carbonate (700 mg, 2.15 mmol), followed by ethyl bromoacetate (0.27 mL, 2.43 mmol). The mixture was refluxed in acetone under stirring for 1 hour. After evaporation of acetone under reduced pressure, 100 ml, of water were added and the mixture was extracted with dichloromethane (200 mL). The organic phase was washed with brine (100 mL), dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent: dichloromethane) to give 264 mg of an oil (59% yield). 1H NMR (500 MHz, CDCl3): δ 1.29 (t, J=7.2 Hz, 3H), 4.26 (q, J=7.2 Hz, 2H), 4.85 (s, 2H), 7.96 (s, 2H), 9.98 (s, 1H). 13C NMR (126 MHz, CD3COCD3): δ 15.0, 62.3, 70.8, 131.2, 131.4, 135.4, 156.4, 168.4, 190.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:12]=3[O:11]2)=[CH:5][CH:4]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20][C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][C:12]=3[O:11]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(C=C2Oc3cc(OC(=O)c4ccccc4)ccc3C2=O)cc1
Temperature: 25 °C

Procedure:
After 2-[(4-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, benzoyl chloride 0.282 ml was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml and with saturated sodium bicarbonate solution 50 ml. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 200.5 mg.
Reaction SMILES: [CH2:1]([OH:7])[C@@H:2]([OH:6])[CH2:3][CH2:4]O.N1C=CC=CC=1.[S:14](Cl)(Cl)=[O:15].[ClH:18]>C(#N)C.C(OCC)(=O)C>[Cl:18][CH2:4][CH2:3][C@H:2]1[CH2:1][O:7][S:14](=[O:15])[O:6]1
Reactant: OCC[C@H](O)CO
Reactant: Cl
Reactant: O=S(Cl)Cl
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=S1OC[C@H](CCCl)O1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (2S)-butane-1,2,4-triol (10.0 g) and pyridine (15.2 mL) in acetonitrile (100 mL) was added thionyl chloride (34.4 mL) at 0° C., and the mixture was stirred at room temperature for 15 hr. Ethyl acetate (20 mL) and 0.1M hydrochloric acid (10 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with brine (20 mL) and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the object fraction was concentrated under reduced pressure to give (4S)-4-(2-chloroethyl)-1,3,2-dioxathiolane 2-oxide as a brown oil. A mixture of (4S)-4-(2-chloroethyl)-1,3,2-dioxathiolane 2-oxide produced above, sodium periodate (19.6 g), ruthenium chloride monohydrate (172 mg), acetonitrile (200 mL) and water (40 mL) was stirred at room temperature for 15 hr. Acetonitrile was evaporated under reduced pressure, and the aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with brine (20 mL) and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the object fraction was concentrated under reduced pressure to give the title compound (14.2 g) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9])#[CH:2].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1I.C(N(CC)CC)C>C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]#[C:1][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: C#Cc1cncc(C#N)c1
Reactant: Clc1ccccc1I
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1cncc(C#Cc2ccccc2Cl)c1
Temperature: 70 °C

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (63.2 mg, 0.090 mmol), copper (I) iodide (34.3 mg, 0.180 mmol), and 5-ethynylnicotinonitrile (242 mg, 1.89 mmol), (prepared essentially as described in PREPARATION 4), to a solution of 1-chloro-2-iodobenzene (0.22 mL, 1.77 mmol) in triethylamine (3.60 mL, 25.8 mmol) and heat to 70° C. in a sealed tube for 1.5 h. Cool to room temperature and dilute with ethyl acetate. Wash with a saturated aqueous solution of sodium chloride, dry (sodium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with a gradient from 95:5 to 80:20 (90:10 hexanes:ethyl acetate):dichloromethane, to give the title compound as a yellow solid. Further purify the title compound by recrystallizing from cyclohexane (20 mL) to give a white solid (95 mg, 22%).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[C:12]([NH:14][CH:15]2[C:25](=[O:26])[N:17]3[C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=O.C([O-])(=O)C.[Na+].O>O1CCCC1>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[C:12]([NH:14][CH:15]2[C:25](=[O:26])[N:17]3[C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: Cc1ccc(CON=C(C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)c2csc(NC(=O)C(F)(F)F)n2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(CON=C(C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)c2csc(N)n2)cc1
Yield: 22.5 %

Procedure:
A mixture of 7-[2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]-2-(4-methylbenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 4.5 g.), sodium acetate 3 hydrate (12.5 g.), water (250 ml.) and tetrahydrofuran (20 ml.) was treated in a similar manner to that of Example 16-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-(4-methylbenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.84 g.),
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])[CH:11]=2)[NH:6][CH:5]=1.CN1C(N)=N[C:24](=[O:25])[CH2:23]1.S(=O)(=O)(O)O.O.[CH2:35]([OH:37])C>>[N:15]1([C:13]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[NH:6][CH:5]=[C:4]3[CH2:3][CH2:2][NH:1][C:35](=[O:37])[O:25][CH2:24][C:23]2[CH:11]=[CH:12][CH:4]=[CH:3][CH:2]=2)=[O:14])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: NCCc1c[nH]c2ccc(C(=O)N3CCOCC3)cc12
Reactant: CCO
Reactant: CN1CC(=O)N=C1N
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(C(=O)N3CCOCC3)cc12)OCc1ccccc1

Procedure:
(ii)c [2-[5-[(4-Morpholinyl)carbonyl]-1H-indol-3-yl]ethyl]carbamic acid, phenylmethyl ester (1.5 g) gave 4-[[3-(2-aminoethyl)-1H-indol-5-yl]carbonyl] morpholine, compound with creatinine, sulphuric acid and water (1:1:1:1) (0.65 g) as a white crystalline solid m.p. 178°-181° C. (from aqueous ethanol)
Reaction SMILES: [CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([OH:7])=O)[CH3:2].CCOC(OC(OCC)=O)=O.[CH:30]([O:33][C:34]1[CH:39]=[C:38]([CH2:40][NH2:41])[CH:37]=[C:36]([C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=2)[N:35]=1)([CH3:32])[CH3:31]>C1COCC1>[CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([NH:41][CH2:40][C:38]1[CH:37]=[C:36]([C:42]2[CH:43]=[CH:44][C:45]([C:48]([F:49])([F:50])[F:51])=[CH:46][CH:47]=2)[N:35]=[C:34]([O:33][CH:30]([CH3:32])[CH3:31])[CH:39]=1)=[O:7])[CH3:2]
Reactant: C=C(C(=O)O)N(CC)S(=O)(=O)c1ccc(F)cc1
Reactant: CC(C)Oc1cc(CN)cc(-c2ccc(C(F)(F)F)cc2)n1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1cc(OC(C)C)nc(-c2ccc(C(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 16.2 %

Procedure:
A solution of acid 4B (300 g, 1.09 mmol) in THF (15 mL) was added with DEPC (0.21 mL, 1.3 mol eq) and the mixture was stirred at room temperature several minutes. Then [2-isopropoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27M (370 mg, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, water was added to the residue that is extracted with EtOAc (3×30 mL) and washed with brine (1×40 mL). The separated organic phase was dried over Na2SO4, evaporated to dryness and the residue was purified by flash chromatography (3/7 EtOAc/Petroleum ether) to afford a white solid (100 mg) after crystallization from ethyl ether. Yield=18%. 1HNMR (DMSO, 400 MHz) δ 1.08 (t, 3H, J=7.4), 1.26 (d, 6H, J=6.2), 3.39 (q, 2H), 4.40 (d, 2H, J=7.9), 5.13 (s, 1H), 5.39 (m, 1H), 6.12 (s, 1H), 6.65 (s, 1H), 7.42 (t, 3H, J=4), 7.56 (s, 1H), 7.86 (m, 4H), 8.23 (d, 2H, J=8), 8.79 (t, 1H). [M+1] 565.02 (C27H27F4N3O4S requires 565.58).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([C:27]3[N:32]=[C:31](S(C)(=O)=O)[N:30]=[C:29]([N:37]4[CH2:42][CH2:41][CH:40]([NH:43]C(=O)OC(C)(C)C)[CH2:39][CH2:38]4)[CH:28]=3)=[CH:15][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[C:11]2=[CH:10][CH:9]=1.[OH-].[Na+].C(O)(C(F)(F)F)=[O:54]>O1CCOCC1.C(Cl)(Cl)Cl.CC(O)C>[NH2:43][CH:40]1[CH2:39][CH2:38][N:37]([C:29]2[CH:28]=[C:27]([C:14]3[C:12]4=[N:13][C:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])=[CH:9][CH:10]=[C:11]4[NH:16][CH:15]=3)[N:32]=[C:31]([OH:54])[N:30]=2)[CH2:42][CH2:41]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N4CCC(NC(=O)OC(C)(C)C)CC4)nc(S(C)(=O)=O)n3)c3nc(-c4ccccc4F)ccc32)cc1
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: NC1CCN(c2cc(-c3c[nH]c4ccc(-c5ccccc5F)nc34)nc(O)n2)CC1
Temperature: 100 °C
Yield: 64 %

Procedure:
A glass microwave reaction vessel was charged with tert-butyl 1-(6-(5-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-2-(methylsulfonyl)pyrimidin-4-yl)piperidin-4-ylcarbamate (100 mg, 0.139 mmol) and NaOH (0.3 mL, 0.600 mmol) in p-dioxane (2 mL). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 1 h. The mixture was diluted with CHCl3/iPrOH (4:1) and washed with water. The organic layer was dried, filtered and concentrated. The residue was dissolved in DCM (1 mL) and TFA (200 μL, 2.60 mmol) was added. The reaction was stirred at RT for 15 min, then the solvent was removed. The residue was purified with preparative HPLC (eluting with 5-30% ACN in water in 30 min) to give 4-(4-aminopiperidin-1-yl)-6-(5-(2-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyrimidin-2-ol (36.0 mg, 0.089 mmol, 64.2% yield) as a TFA salt. MS (ESI, pos. ion) m/z: 405.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 12.51 (1 H, br. s.), 8.79 (1 H, d, J=3.1 Hz), 8.12 (1 H, d, J=8.6 Hz), 7.85-8.05 (4 H, m), 7.76 (1 H, dd, J=8.5, 1.9 Hz), 7.46-7.61 (2 H, m), 7.32-7.44 (2 H, m), 4.19-4.55 (2 H, m), 3.37-3.52 (2 H, m), 3.10-3.33 (2 H, m), 2.04 (2 H, d, J=11.2 Hz), 1.47-1.68 (2 H, m).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[F:49][C:50]([F:64])([F:63])[C:51]1[CH:52]=[C:53]([CH:60]=[CH:61][CH:62]=1)[O:54][CH:55]1[CH2:59][CH2:58][NH:57][CH2:56]1>CN(C=O)C.O>[O:27]=[C:25]([N:57]1[CH2:58][CH2:59][CH:55]([O:54][C:53]2[CH:60]=[CH:61][CH:62]=[C:51]([C:50]([F:49])([F:64])[F:63])[CH:52]=2)[CH2:56]1)[CH2:24][NH:23][C:21]([C:18]1[CH:17]=[C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:20][N:19]=1)=[O:22]
Reactant: FC(F)(F)c1cccc(OC2CCNC2)c1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)C1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 0.03 h
Yield: 61.9 %

Procedure:
DIPEA (167.7 mg, 1.29 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (106 mg, 0.43 mmol) in DMF (4 mL) followed by HOBt (70.13 mg, 0.52 mmol) and EDCI (99.5 mg, 0.52 mmol). After 2 minutes of stirring, 3-(3-trifluoromethyl-phenoxy)-pyrrolidine (100 mg, 0.43 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was added and the precipitate was collected to afford 122 mg (61.5% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[3-(3-trifluoromethyl-phenoxy)-pyrrolidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 459.16, 96.52%. 1H NMR (300 MHz, DMSO-d6): δ 13.8 (s, 1H), 8.05 (bs, 1H), 7.8 (db, 2H), 7.7-7.6 (m, 7H), 7.05 (bs, 1H), 5.4 (s, 1H), 5.3 (s, 1H), 4.1 (m, 2H), 3.9 (m, 1H), 3.8-3.6 (m, 3H), 3.4 (m, 1H), 2.3-2.0 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:36]([NH2:38])[CH3:37]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:38][CH2:36][CH3:37])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: CCN
Product: CCNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (750 mg, 1.48 mmol) and ethylamine (2M in THF, 2.22 ml, 4.4 mmol) as starting materials.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][NH2:10])=[C:4]([F:11])[CH:3]=1.[C:12]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=O)(=O)[CH3:13].C(O)(=O)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:12]([CH3:13])=[C:15]3[C:16]([CH2:17][CH2:18][CH2:19][CH2:20]3)=[N:10]2)=[C:4]([F:11])[CH:3]=1
Reactant: CC(=O)C1CCCCC1=O
Reactant: NNc1cc(O)c(Cl)cc1F
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: Cc1c2c(nn1-c1cc(O)c(Cl)cc1F)CCCC2
Yield: 88.1 %

Procedure:
4-Chloro-2-fluoro-5-hydroxyphenylhydrazine (0.5 g), 2-acetylcyclohexanone (0.4 g) and a catalytic amount of acetic acid were admixed with xylene (15 ml), and the resultant mixture was heated under reflux for 5 hours while removing water. After cooling, the mixture was concentrated, and the residue was purified by silica gel column chromatography to obtain 0.7 g of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole. m.p., 188.5°-190° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]([NH2:17])=O)=[N:8][C:7]=3[C:6]=2[CH:18]=1.[CH3:19]OC(OC)N(C)C.CC(O)=O.Cl.[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[NH:40][NH2:41]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:40]([C:34]5[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=5[F:32])[N:41]=[CH:19][N:17]=4)=[N:8][C:7]=3[C:6]=2[CH:18]=1
Reactant: NNc1ccc(F)cc1F
Reactant: NC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc(-n2ncnc2-c2nc3c(s2)CCOc2ccc(Br)cc2-3)c(F)c1
Temperature: 100 °C
Yield: 31 %

Procedure:
A stirred suspension of 9-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (0.70 g; 2.2 mmol) and dimethylformamide dimethylacetal (DMF DMA, 6 ml) in toluene (5 ml) was heated at 100° C. overnight (16 h) upon which time the reaction mixture was concentrated. To the resulting residue was added AcOH (5 ml), water (0.5 ml) and 2,4-difluorophenylhydrazine hydrochloride (0.56 g; 3.1 mmol) and the resulting solution heated at 100° C. for 3 h. The reaction mixture was concentrated, the residue was dissolved in CH2Cl2 (50 ml) and washed with satd. NaHCO3 (50 ml). The organic layer was separated (hydrophobic frit), concentrated and purified by ISCO to give 399 as a cream-coloured solid (0.31 g; 31%). δH (400 MHz, CDCl3) 3.41 (t, J=5.2, 2H), 4.36 (t, J=5.2, 2H), 6.89 (d, J=8.8, 1H), 7.14-7.20 (m, 2H), 7.27-7.30 (m, 1H), 7.55-7.61 (m, 1H), 7.69 (d, J=2.8, 1H), 8.16 (s, 1H). [M+H]+: 462
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH2:10][C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][O:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][C@@H:14]23)[CH:19]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:10][C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][O:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][NH:26][CH2:27][C@@H:14]23)[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Reactant: O=Cc1cccc(F)c1
Product: Fc1cccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)c1

Procedure:
Using 3-fluorobenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 132. LRMS (ES)+: 354.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:9]([C:19]#[N:20])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:21]([O:23]CC)=[O:22].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[C:9]([C:19]#[N:20])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1cnn(-c2ccc(OCC(C)(C)C)c(C#N)c2)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)COc1ccc(-n2ncc(C(=O)O)c2N)cc1C#N
Yield: 41 %

Procedure:
To a solution (17 ml) of ethyl 5-amino-1-(3-cyano-4-neopentyloxyphenyl)pyrazole-4-carboxylate (1.7 g) in ethanol was added 2 N aqueous sodium hydroxide solution (3 ml) with stirring, and the mixture was refluxed under heating for 2 hours. After the completion of the reaction, the reaction mixture was poured into water and neutralized with acetic acid. The precipitated crystals were recrystallized from a mixed solvent of dioxane and water to give 0.64 g of 5-amino-1-(3-cyano-4-neopentyloxyphenyl)pyrazole-4-carboxylic acid, melting point 212° C. (decomposition).