Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[NH:4][N:3]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].O>N1C=CC=CC=1>[OH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[N:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:3]=1
Reactant: COC(=O)c1ccc2[nH]nc(O)c2c1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)n1nc(O)c2cc(C(=O)OC)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
Methyl 3-hydroxy-1H-indazole-5-carboxylate (1.60 g, 8.33 mmol) was suspended in pyridine (10 mL). Ethyl chloroformate (0.90 mL, 9.3 mmol) was added slowly and the reaction was stirred at room temperature for 1 hour. Additional ethyl chloroformate (0.30 mL, 3.1 mmol) was added and the reaction was stirred for another 30 minutes. The reaction was poured into water (65 mL) and cooled in a refrigerator for 3 hours. The brown solid was collected by filtration, rinsed with water, and dried under vacuum to give the title compound (1.75 g, 80%). +ESI (M+H) 265.1; 1H NMR (400 MHz, CDCl3, δ): 8.56 (s, 1H), 8.29 (d, J=7.8 Hz, 1H), 8.13 (br. s., 1H), 4.59 (q, J=7.0 Hz, 2H), 3.97 (s, 3H), 1.56 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][C:6]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:7]1([F:10])[F:9].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C@H:29]([C@@H:33]([CH3:38])[C:34]([F:37])([F:36])[F:35])[C:30](O)=[O:31])=[CH:25][CH:24]=1.N1C=CC=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[Cl:21][C:20]1[CH:19]=[CH:18][C:4]([CH2:5][C:6]2([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:8][C:7]2([F:10])[F:9])=[CH:3][C:2]=1[NH:1][C:30](=[O:31])[C@H:29]([C:26]1[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=1)[C@@H:33]([CH3:38])[C:34]([F:35])([F:36])[F:37]
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(Cl)c(N)c2)CC1(F)F
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C[C@H]([C@H](C(=O)Nc1cc(CC2(C(=O)OC(C)(C)C)CC2(F)F)ccc1Cl)c1ccc(Cl)cc1)C(F)(F)F
Temperature: 40 °C
Reaction time: 8 h

Procedure:
1.15 g (3.62 mmol) of (+/−)-tert-butyl 1-(3-amino-4-chlorobenzyl)-2,2-difluorocyclopropane-carboxylate were dissolved in 5 ml of DMF, and 1.49 g (5.43 mmol) of (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid, 2.5 ml of pyridine and 1.79 g (4.71 mmol) of HATU were added at RT. The reaction mixture was then stirred at 40° C. overnight. After cooling, the mixture was diluted with ethyl acetate and the solution was washed with 1 N hydrochloric acid and saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 30:1). This gave 1.82 g of the title compound (88.8% of theory).
Reaction SMILES: [C:1]([N:4]([CH2:25][C@@H:26]1[O:30][C:29](=[O:31])[N:28]([C:32]2[CH:37]=[CH:36][C:35]([CH:38]3[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]3)=[C:34]([F:46])[CH:33]=2)[CH2:27]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:24])[C@@H:11]([NH:16]C(OC(C)(C)C)=O)[C@@H:12]([CH3:15])[CH2:13][CH3:14])=[O:6])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.[ClH:55]>C1COCC1>[ClH:55].[C:1]([N:4]([CH2:25][C@@H:26]1[O:30][C:29](=[O:31])[N:28]([C:32]2[CH:37]=[CH:36][C:35]([CH:38]3[CH2:39][CH2:40][S:41](=[O:44])(=[O:45])[CH2:42][CH2:43]3)=[C:34]([F:46])[CH:33]=2)[CH2:27]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:24])[C@@H:11]([NH2:16])[C@@H:12]([CH3:15])[CH2:13][CH3:14])=[O:6])(=[O:3])[CH3:2]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCOC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Agent: Cl
Solvent: COc1ccccc1
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](N)C(=O)OCOC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
2(S)-tert-Butoxycarbonylamino-3(S)-methyl-pentanoic acid (acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5(R)-ylmethyl}-carbamoyloxy)-methyl ester (12f) (0.82 g, 1.23 mmol), anisole (0.2 mL) and THF (25 mL) are cooled to 0° C. Hydrogen chloride (4 M in dioxane, 9 mL, 36.8 mmol) is added in a dropwise manner. After complete addition, the ice-bath is removed and the mixture is stirred at RT overnight. Under reduced pressure, the mixture is concentrated to one-third of its original volume. Ether is then added dropwise to the mixture while stirring, resulting in the formation of a solid. The solid is collected via filtration, rinsed with ether, and dried under vacuum to give the title compound in 52% yield (0.39 g). 1H NMR (400 MHz, CD3OD): δ 7.51 (d, 1H), 7.36 (t, 1H), 7.26 (d, 1H), 6.05 (d, 1H), 6.00 (d, 1H), 4.87 (m, 1H), 4.20 (m, 3H), 4.09 (dd, 1H), 3.84 (dd, 1H), 3.37 (m, 2H), 3.23 (tt, 1H), 3.11 (m, 2H), 2.54 (s, 3H), 2.34 (m, 2H), 2.17 (m, 2H), 2.06 (m, 1H), 1.56 (m, 1H), 1.39 (m, 1H), 1.06 (d, 3H), 1.00 (t, 3H). MS-APCI (m/z+): 341, 385, 572.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])=[N:11][C:12]([N:16]([CH3:18])[CH3:17])=[N:13][C:14]=1[CH3:15])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:18][N:16]([CH3:17])[C:12]1[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[C:9]([OH:8])=[C:14]([CH3:15])[N:13]=1
Reactant: Cc1nc(N(C)C)nc(CCCCCCCCCCO)c1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(N(C)C)nc(CCCCCCCCCCO)c1O
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution containing 44.0 mg (0.11 mmol) of 10-(5-(benzyloxy)-2-(dimethylamino)-6-methylpyrimidin-4-yl)decan-1-ol in 3 mL of methanol was added 3 mg of 20% palladium hydroxide on carbon (Degussa type E101 NE/N). The reaction mixture was stirred at 23° C. under a hydrogen atmosphere for 15 min. The reaction mixture was filtered through Celite and the filtrate was concentrated under diminished pressure to afford 2-(dimethylamino)-4-(10-hydroxydecyl)-6-methylpyrimidin-5-ol as a colorless oil: yield 33 mg (100%). An analytical sample was obtained by chromatography on a silica gel column (10×1 cm). Elution with 2:1 toluene-ethyl acetate afforded the purified product as a colorless oil; silica gel TLC Rf 0.25 (2:1 toluene-ethyl acetate); 1H NMR (methanol-d4) δ1.29-1.35 (m, 12H), 1.49 (m, 2H), 1.65 (m, 2H), 2.26 (s, 3H), 2.62 (dd, 2H, J=7.2, 7.2 Hz), 3.06 (s, 6H) and 3.51 (t, 2H, J=6.4 Hz); 13C NMR (methanol-d4) δ 17.8, 25.5, 27.3, 29.13, 29.15, 29.15, 29.18, 29.3, 31.2, 32.2, 36.5, 36.5, 61.6, 138.0, 155.6, 157.3 and 159.4; mass spectrum (APCI), m/z 310.2490 (M+H)+ (C17H32N3O2 requires 310.2495).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[C:7]([CH3:13])=[CH:6][N:5]=1.[NH3:14].CO>>[NH2:14][CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[C:7]([CH3:13])=[CH:6][N:5]=1
Reactant: N
Reactant: COc1c(C)cnc(CCl)c1C
Agent: Cl
Solvent: CO
Product: COc1c(C)cnc(CN)c1C
Yield: 76 %

Procedure:
A solution of 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine HCl (Aldrich 3.7 g, 16.6 mmole) in 7N NH3/MeOH (Aldrich, 200 mLs) was refluxed in a steel bomb for 15 hours. Removed the solvent under reduced pressure, the residue was taken into 5% MeOH/CH2Cl2 and filtering it through a thin layer of silica gel afforded the product at 76% yield. HPLC RT was 2.850 min. 1HNMR (CDCl3) δ 8.18 (s, 1H), 4.32 (s, 2H), 3.76 (s, 3H), 2.23 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([C@H:13](N)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:21]([OH:23])=[O:22].ClC1C=CC(Cl)=CC=1C(N(C)C(Cl)=O)=O>>[CH3:1][C:2]1([CH3:24])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:21]([OH:23])=[O:22]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: CN(C(=O)Cl)C(=O)c1cc(Cl)ccc1Cl
Product: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Yield: 32 %

Procedure:
This penicilling was prepared from 28 parts by weight of ampicillin and 18.7 parts by weight of N-(2,5-dichlorobenzoyl)-N-methylcarbamic acid chloride, in the manner described in Example 107.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[Br:4][C:5]1[N:14]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]2[CH:9]=[N:10][NH:11][C:12](=[O:13])[C:7]=2[C:6]=1[CH2:23]Br.C(O)C.[O-]CC.[Na+]>O>[Br:4][C:5]1[N:14]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]2[CH:9]=[N:10][NH:11][C:12](=[O:13])[C:7]=2[C:6]=1[CH2:23][O:3][CH2:1][CH3:2]
Reactant: CCO
Reactant: C[Si](C)(C)CCOCn1c(Br)c(CBr)c2c(=O)[nH]ncc21
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: CCOCc1c(Br)n(COCC[Si](C)(C)C)c2cn[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To 23 ml of ethanol solution containing 1.06 g (2.42 mmol) of 2-bromo-3-bromomethyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 24-(f) was added 3.33 g (9.78 mmol) of 20% sodium ethoxide ethanol solution, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=2:1→1:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 549 mg of the title compound as a white solid. (Yield: 56%)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[NH:14][C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)=[C:12]([CH3:23])[C:10]3=2)[NH:5][C:4](=[O:24])[CH:3]=1.[F:25][C:26]([F:31])([F:30])[C:27](O)=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[N:14]([CH2:27][C:26]([F:31])([F:30])[F:25])[CH:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[CH:12]([CH3:23])[C:10]3=2)[NH:5][C:4](=[O:24])[CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1c(-c2ccc(Cl)c(Cl)c2)[nH]c2ccc3[nH]c(=O)cc(Cl)c3c12
Product: CC1c2c(ccc3[nH]c(=O)cc(Cl)c23)N(CC(F)(F)F)C1c1ccc(Cl)c(Cl)c1

Procedure:
This compound was prepared using the method described in Example 23 from 9-chloro-2-(3,4-dichlorophenyl)-1-methyl-3,6-dihydro-pyrrolo[3,2-f]quinolin-7-one, and trifluoroacetic acid. Spectral data for compound 157: 1H NMR (500 MHz, DMSO-d6) δ 11.91 (s, 1H), 7.75 (d, J=1.9 Hz, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.49 (dd, J=8.3, 1.9 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 6.78 (d, J=1.7 Hz, 1H), 5.02 (d, J=7.0 Hz, 1H), 4.30 (qn, J=7.0 Hz, 1H), 4.25 (dq, J=16.5, 10.2 Hz, 1H), 3.71 (dq, J=16.5, 9.2 Hz, 1H), 0.76 (d, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17]1[O:18][C:19]2[C:24]([N:25]=1)=[CH:23][CH:22]=[CH:21][N:20]=2.[CH3:26][N:27]1[CH2:32]CO[CH2:29][CH2:28]1.C[N:34]1C(=O)CCC1>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:34][CH2:29][CH2:28][N:27]([CH3:32])[CH3:26])=[O:14])=[CH:15][CH:16]=2)=[CH:4][C:3]=1[C:17]1[O:18][C:19]2[C:24]([N:25]=1)=[CH:23][CH:22]=[CH:21][N:20]=2
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1-c1nc2cccnc2o1
Reactant: CN1CCCC1=O
Reactant: CN1CCOCC1
Product: CN(C)CCNC(=O)c1ccc(-c2cnc(N)c(-c3nc4cccnc4o3)c2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 4-(6-amino-5-oxazolo[5,4-b]pyridin-2-yl-3-pyridyl)benzoic acid (100 mg) N,N-dimethylethane-1,2-diamine (0.036 ml), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (145 mg) and 4-methylmorpholine (0.066 ml) in NMP (1 ml) was stirred at room temperature for 15 hours. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford the title compound (38 mg) as a solid; NMR Spectrum: (DMSOd6) 2.19 (s, 6H), 2.42 (t, 2H), 3.35-3.42 (m, 2H), 7.54 (dd, 1H), 7.86 (d, 2H), 7.93 (bs, 2H), 7.95 (d, 2H), 8.30 (dd, 1H), 8.41 (dd, 1H), 8.45 (t, 1H), 8.59 (d, 1H), 8.71 (d, 1H); Mass spectrum: M+H+: 403. RT: 1.73
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.CC(C)([O-])C.[K+].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1ncnc2[nH]ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2c(Cl)ncnc21
Reaction time: 3 h

Procedure:
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (10 g, 0.065 mol) in THF (300 mL) was added potassium tert-butoxide (9.15 g, 0.082 mol) at r.t. over 5 min. A slight exotherm was noticed and suspension was cooled with the aid of a water bath. Benzenesulfonyl chloride (10.5 mL, 0.082 mol) was then added drop-wise over a period of 10 min and the resulting suspension stirred for a further 3 h. Then water (20 mL) was added drop-wise and the solution was then stirred for 15 min. The solvent was evaporated under reduced pressure and the reaction mixture was eluted with ethyl acetate (1.2 l), washed with brine (2×100 mL), dried and concentrated. The resulting solid was triturated with ethyl acetate (50 mL) to afford 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 6.75 (1H, d), 7.55-7.625 (2H, t), 7.70 (1H, t), 7.82 (1H, d), 8.25 (1H, d) and 8.80 (1H, s).
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH2:3][C@H:4]([N:8]1[CH2:12][C:11]([O:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[N:17][N:18]3[CH3:23])=[CH:10][C:9]1=[O:24])[C:5](O)=[O:6].[CH3:26][C:27]1([CH3:39])[O:31][C@H:30]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]2)[CH2:29][O:28]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl.O>[CH3:26][C:27]1([CH3:39])[O:31][C@H:30]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH:38][C:5](=[O:6])[C@@H:4]([N:8]3[CH2:12][C:11]([O:13][C:14]4[CH:22]=[CH:21][CH:20]=[C:19]5[C:15]=4[CH:16]=[N:17][N:18]5[CH3:23])=[CH:10][C:9]3=[O:24])[CH2:3][CH:2]([CH3:25])[CH3:1])=[N:34]2)[CH2:29][O:28]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc3c2cnn3C)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc3c2cnn3C)=CC1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 57 %

Procedure:
A solution of (S)-4-methyl-2-[4-(1-methyl-1H-indazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester (30 mg, 0.08 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was treated with lithium hydroxide monohydrate (3.6 mg 0.08 mmol). The mixture was stirred at room temperature for 3.5 h and then partitioned between ethyl acetate and water. The aqueous phase was acidified with 1N aqueous hydrochloric acid (pH=1), and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford (S)-4-methyl-2-[4-(1-methyl-1H-indazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid as an off-white solid. A mixture of (S)-4-methyl-2-[4-(1-methyl-1H-indazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid in dichloromethane (5 mL) was treated with 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.025 g, 0.13 mmol), N,N-diisopropylethylamine (0.033 g, 0.26 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.056 g, 0.13 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 3.5 h. The mixture was partioned between dichloromethane and water. The organic layer was collected and concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 20% to 100% ethyl acetate/hexanes) which afforded (S)-4-Methyl-2-[4-(1-methyl-1H-indazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (0.025 g, 57%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.II.O=[C:13]([CH:15]=[C:16]([CH3:18])[CH3:17])[CH3:14]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:16]([CH3:18])([CH3:17])[CH:15]=[C:13]2[CH3:14]
Reactant: COc1ccc(N)cc1
Reactant: CC(=O)C=C(C)C
Agent: II
Product: COc1ccc2c(c1)C(C)=CC(C)(C)N2

Procedure:
Skraup reaction of 4-anisidine (5.0 g) and iodine (1.7 g) in mesityl oxide (25 ml) was performed according to the method described in example 1.
Reaction SMILES: O=[C:2]1[CH:10]([C:11]#[N:12])[CH2:9][CH2:8][C:3]21[S:7][CH2:6][CH2:5][S:4]2.[C:13]1([C:19]2[N:24]=[CH:23][C:22]([C:25]3[CH:26]=[N:27][NH:28][C:29]=3[NH2:30])=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[C:13]1([C:19]2[N:24]=[CH:23][C:22]([C:25]3[CH:26]=[N:27][N:28]4[C:11]([NH2:12])=[C:10]5[CH2:9][CH2:8][C:3]6([S:7][CH2:6][CH2:5][S:4]6)[C:2]5=[N:30][C:29]=34)=[CH:21][CH:20]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1[nH]ncc1-c1ccc(-c2ccccc2)nc1
Reactant: N#CC1CCC2(SCCS2)C1=O
Solvent: Cc1ccccc1
Product: Nc1c2c(nc3c(-c4ccc(-c5ccccc5)nc4)cnn13)C1(CC2)SCCS1
Temperature: 115 °C

Procedure:
A mixture of 6-oxo-1,4-dithiaspiro[4.4]nonane-7-carbonitrile (485 mg, 2.27 mmol) and 4-(6-phenylpyridin-3-yl)-1H-pyrazol-5-amine (537 mg, 2.27 mmol) in toluene (10 mL) was heated at 115° C. overnight. Concentration afforded crude 3-(6-phenylpyridin-3-yl)-6,7-dihydrospiro[cyclopenta[d]pyrazolo[1,5-a]pyrimidine-5,2′-[1,3]dithiolan]-8-amine, which was converted to 8-amino-3-(6-phenylpyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidin-5-one applying Stork's procedure (G. Stork, K. Zhao, Tetrahedron Letter, 1989, 30, 287) by treating with PhI(OCF3)2. LCMS tR=1.07 Min (5 min run, UV254nm), Mass calculated for, M+341.1, observed LC/MS m/z 342.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH2:11])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21]Br>CN(C)C=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:21][CH2:20][NH:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: BrCCBr
Reactant: COC(=O)c1ccc(O)c(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)NCCO2
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A solution of 3-amino-4-hydroxy-benzoic acid methyl ester (4.2 g, 25.4 mmol) in dimethylformamide (85 mL) was treated with K2CO3 (14.2 g, 102.9 mmol, 4 equiv.) and 1,2-dibromoethane (19.3 g, 102.9 mmol, 4 equiv.). The mixture was stirred at 70° C. overnight, then filtered to remove the solids. The filtrate was removed under vacuo, and the residue was purified by flash chromatography (heptane/ethyl acetate gradient) to yield 3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, 3.65 g (73%) as a light yellow solid, MS (ISP): m/e=235.1 (M+CH3CN+.); δH (300 MHz; CDCl3) 7.36 (1H, dd, J=8.5, 2.0), 7.30 (1H, d, J=2.0), 6.78 (1H, d, J=8.5), 4.30 (2H, m); 3.85 (3H, s), 3.43 (2H, m).
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]1([C:9]([NH2:11])=[O:10])[CH2:8][NH:7][CH2:6]1)[CH3:3].C(N(C(C)C)CC)(C)C.Cl[C:22]1[N:27]2[N:28]=[C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[C:30]([I:31])=[C:26]2[N:25]=[CH:24][CH:23]=1.N1CCC1>CC(C)=O>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:29]1[C:30]([I:31])=[C:26]2[N:25]=[CH:24][CH:23]=[C:22]([N:7]3[CH2:8][C:5]([NH:4][CH2:2][CH3:3])([C:9]([NH2:11])=[O:10])[CH2:6]3)[N:27]2[N:28]=1
Reactant: Clc1ccccc1-c1nn2c(Cl)ccnc2c1I
Reactant: CCNC1(C(N)=O)CNC1
Agent: C1CNC1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC1(C(N)=O)CN(c2ccnc3c(I)c(-c4ccccc4Cl)nn23)C1
Temperature: 50 °C

Procedure:
To a slurry of 3-ethylaminoazetidine-3-carboxylic acid amide, hydrochloride salt (I-1A-3e; 1.13 g, 5.2 mmol) and diisopropylethylamine (3.2 ml, 18 mmol) in acetone (60 ml) was added 7-chloro-2-(2-chlorophenyl)-3-iodopyrazolo[1,5-a]pyrimidine (I-1A-1d; 1.36 g, 3.48 mmol). The mixture was heated to 50° C. overnight. Additional azetidine and diisopropylethylamine were added in portions until the reaction was judged complete by LCMS. A pale yellow precipitate formed and was isolated by vacuum filtration. The filtrate was concentrated to 20 ml and then diluted with diethyl ether to precipitate additional material that was collected by vacuum filtration. The combined solids were triturated from ether to afford product I-2A-1a as a pale yellow solid (1.3 g, 76%): +ESI MS (M+1) 497.0; 1H NMR (400 MHz, DMSO-D6) δ 8.27 (d, J=5.4 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.52–7.44 (m, 3H), 7.35 (br s, 1H), 7.30 (br s, 1H), 5.98 (d, J=5.0 Hz, 1H), 2.40–2.30 (m, 2H), 0.99 (t, J=7.1 Hz, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]1[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=1)[C:9]([C:26](=[O:37])[NH:27][CH:28]1[CH2:33][CH2:32][N:31]([CH:34]([CH3:36])[CH3:35])[CH2:30][CH2:29]1)=[CH:8]2)=[O:4].[Li+].[OH-]>C1COCC1.CO>[Cl:25][C:22]1[S:21][C:20]([C:18]2[O:17][N:16]=[C:15]([CH2:14][N:10]3[C:11]4[C:7](=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:13][CH:12]=4)[CH:8]=[C:9]3[C:26](=[O:37])[NH:27][CH:28]3[CH2:33][CH2:32][N:31]([CH:34]([CH3:35])[CH3:36])[CH2:30][CH2:29]3)[CH:19]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc2c(c1)cc(C(=O)NC1CCN(C(C)C)CC1)n2Cc1cc(-c2ccc(Cl)s2)on1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)N1CCC(NC(=O)c2cc3cc(C(=O)O)ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 70 °C

Procedure:
To a solution of 8.8 g 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-indole-5-carboxylic acid methyl ester in 200 ml THF and 100 ml methanol 58.5 ml of a 1 M aqueous LiOH solution were added and the mixture was heated to 70° C. for 4 h. After cooling to RT the organic solvents were removed under reduced pressure and the remaining aqueous solution was acidified with half concentrated HCl to pH 2. The precipitated product was collected by filtration. Yield: 7.9 g.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][NH:10][C:6]=2[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][N:3]=1.[H-].[Na+].[CH2:18](I)[CH3:19]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH2:18][CH3:19])[C:6]=2[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][N:3]=1
Reactant: CCI
Reactant: CCOC(=O)c1cnc(Cl)c2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Cl)c2ccn(CC)c12
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Ethyl 4-chloro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (0.10 g) was dissolved in dimethylformamide (2 ml), cooled to 0° C. and sodium hydride (60% dispersion in oil) (0.027 g) added. The reaction mixture was stirred for 45 minutes at 0° C., allowed to warm to room temperature and stirred for a further 45 minutes. The reaction mixture was cooled to 0° C., ethyl iodide (0.039 ml) added, the reaction mixture allowed to warm to room temperature, and stirred for 1 hour. The reaction mixture was partitioned between ethyl acetate and water, the aqueous was separated and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to afford the title compound as a yellow oil (0.095 g).