Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].N1C=CC=CC=1.[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[Cl-].[NH4+]>C(Cl)Cl>[C:42]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:23])(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
188 mg (0.40 mmol) of (−)-2-amino-2′-diphenylphosphinyl-1,1′-binaphthyl (the formula (1-1a-1)) was dissolved in 8 ml of methylene chloride, followed by the addition of 39 μl (0.48 mmol) of pyridine and 51 μl (0.44 mmol) of benzoyl chloride under 0° C. The reaction mixture was stirred at room temperature for 1.5 hours. To the reaction solution, 10 ml of saturated aqueous solution of ammonium chloride was added and extracted with 50 ml of methylene chloride. The extract was washed with 20 ml of brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified using a silica gel column chromatography (eluent: 1:1 mixture of ethyl acetate and hexane) to obtain 228 mg of the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][C:11]2([CH:13]([C:14](O)=[O:15])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:20](C)C=O.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[C:14]([CH:13]1[C:11]2([CH2:17][CH2:18][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH2:12]1)(=[O:15])[NH2:20]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC2C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC2C(N)=O
Temperature: 15 °C
Reaction time: 2.5 h
Yield: 65 %

Procedure:
To a mixture of 165d (400 mg, 1.57 mmol) and N,N-dimethylformamide (0.1 mL) in DCM (5 mL) was added oxalyl chloride (397 mg, 3.13 mmol) dropwise. See FIG. 6. The reaction mixture was stirred at 15° C. for 2.5 h and then concentrated. The residue was dissolved in tetrahydrofuran (20 mL) and added dropwise to aqueous ammonia (10 mL, 28%). The mixture was stirred at 15° C. for 4 h and then diluted with water (15 mL). The reaction mixture was extracted with EtOAc (15 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford tert-butyl 1-carbamoyl-6-azaspiro[2.5]octane-6-carboxylate 165e (260 mg, 65%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 5.58 (s, 1H), 5.34 (s, 1H), 3.48-3.39 (m, 4H), 1.73-1.70 (m, 2H), 1.48 (s, 9H), 1.47-1.41 (m, 2H), 1.40-1.22 (m, 2H), 0.89-0.87 (m, 1H).
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)[C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1.C[Si](C)(C)C1C=C(C(NC2C=CC(C=CC(OCC)=O)=CC=2)=S)C=C([Si](C)(C)C)C=1>>[CH3:1][Si:2]([CH3:30])([CH3:29])[C:3]1[CH:4]=[C:5]([C:6]([NH:8][C:9]2[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=2)=[S:40])[CH:22]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1
Reactant: CCOC(=O)/C=C/c1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)nc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: CCOC(=O)C=Cc1ccc(NC(=S)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1
Product: CCOC(=O)/C=C/c1ccc(NC(=S)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)nc1
Yield: 92.6 %

Procedure:
Using Compound 18a (135 mg) and Lawesson's reagent (86.7 mg), Compound 18b (90.7 mg, 65%) was obtained as a yellow solid in the same manner as Compound 17b was synthesized.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:17].[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]2[C:29]3[CH2:36][C:35](=[O:37])[NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH:23]=[CH:24][C:25]=1[F:26]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]2[C:29]3[C:36](=[CH:15][C:12]4[NH:11][C:8]5[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][N:2]([CH3:18])[CH3:1])[C:6](=[O:17])[C:7]=5[C:13]=4[CH3:14])[C:35](=[O:37])[NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CC2
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Product: Cc1c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)[nH]c2c1C(=O)N(CCN(C)C)CC2
Yield: 61.5 %

Procedure:
The title compound was prepared under the same conditions as described in Example 102 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (prepared according to Bioorganic & Medicinal Chemistry Letters, 12 (16), 2153-2157, 2002) as starting materials to give 4-(3-chloro-4-fluoro-phenylamino)-5-[5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (240 mg, 61.5%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[OH:12].P(=O)(O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([N+:18]([O-:20])=[O:19])[C:3]=1[OH:12]
Reactant: CC(=O)Nc1ccc(Cl)c(O)c1
Reactant: O=[N+]([O-])O
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1ccc(Cl)c(O)c1[N+](=O)[O-]
Temperature: -30 °C

Procedure:
0.23 mole (43 g) of 2-chloro-5-acetylamino phenol is dissolved, with agitation, in 500 cc of sulfuric acid (d=1.83) at a temperature of about +5° C. There are then added 15 cc of phosphoric acid and the resulting reaction medium is cooled to -30° C. There are then slowly added, over a 35 minute period, while vigorously agitating, 9.7 cc of nitric acid (d=1.52) in 1.5 cc of sulfuric acid (d=1.83). The reaction mixture is then poured over 3 kgs of shaved ice to precipitate the desired product which is separated by filtration, washed with water and dried, yielding 47 g of product.
Reaction SMILES: [CH:1]1([CH:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1>>[CH:9]1([CH:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[O:8][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: OC(C1CCCCC1)C1CCCCC1
Product: CCOC(=O)c1ccc(OC(C2CCCCC2)C2CCCCC2)cc1

Procedure:
Dicyclohexylmethanol (8-1) (4.91 g, 25 mmol) and ethyl 4-hydroxybenzoate (8-2) (4.15 g, 25 mmol) were reacted, as in Example 6, Step B, to obtain a colorless oil 8-3 after chromatography. 1H NMR (CDCl3): δ 0.98-1.3 (11H, m), 1.36 (3H, t), 1.58-1.86 (11H, m), 4.02 (1H, t), 4.33 (2H, q), 6.92 (2H, d), 7.94 (2H, d).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17].[CH2:19]([CH:23]1[CH2:29][CH:28]2[NH:30][CH:25]([CH2:26][CH2:27]2)[CH2:24]1)[CH2:20][CH2:21][CH3:22]>CCCCCCC.CCOC(C)=O>[CH2:19]([CH:23]1[CH2:24][CH:25]2[N:30]([CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]3[C:10]4[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=4[O:8][CH2:7][C:6]3=[O:17])[CH:28]([CH2:27][CH2:26]2)[CH2:29]1)[CH2:20][CH2:21][CH3:22]
Reactant: COc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Reactant: CCCCC1CC2CCC(C1)N2
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccc(OC)cc21
Yield: 67.8 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one (111MF36) (0.239 g, 0.66 mmol) and 3-Butyl-8-aza-bicyclo[3.2.1]octane (0.100 g, 0.60 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF40) (0.163 g, 61%). 1H NMR (CDCl3) d 6.88 (d, J=8.8 Hz, 1H), 6.85 (d, J=2.8 Hz, 1H), 6.49 (dd, J=8.8 Hz, J=2.8 Hz, 1H), 4.61-4.47 (m, 2H), 4.01-3.99 (m, 2H), 3.77 (s, 3H), 3.17-3.04 (m, 2.35-2.29 (m, 1H), 2.14-1.79 (m, 3H), 1.57-1.13 (m, 6H), 0.88 (m, 3H); 13C NMR (CDCl3) d 165.4, 155.6, 139.8, 129.8, 117.1, 107.0, 103.8, 68.0, 61.6, 60.2, 58.1, 56.0, 45.4, 38.5, 38.4, 36.9, 31.6, 29.4, 28.2, 27.3, 26.5, 23.9, 14.3; HPLC-MS (ammonium acetate) [M+H]+=401.3.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].[O:12]=[CH:13]C(Cl)(Cl)Cl>>[CH2:1]([N:3]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:13]=[O:12])[CH3:2]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: CCNCCc1ccccc1
Product: CCN(C=O)CCc1ccccc1

Procedure:
N-Ethyl-N-phenethylformamide was prepared from N-ethylphenethylamine and chloral. The boiling point was 107°-108°C/0.4 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].Cl.Cl[CH2:14][CH2:15][N:16]([CH2:18][CH2:19]Cl)[CH3:17]>ClC1C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[CH2:19][CH2:18][N:16]([CH3:17])[CH2:15][CH2:14]1
Reactant: CN(CCCl)CCCl
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Solvent: Clc1ccccc1
Solvent: ClCCl
Product: CN1CCN(c2cc([N+](=O)[O-])ccc2Cl)CC1
Yield: 66.5 %

Procedure:
A mixture of 2-chloro-5-nitrobenzenamine (7.95 g) and 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (8.86 g) in chlorobenzene (40 ml) under nitrogen was heated to reflux for 3 days before cooling and diluting with dichloromethane (60 ml). The reaction mixture was then extracted with water (2×500 ml), the aqueous layers combined and basified with 2N sodium hydroxide, then extracted with dichloromethane (4×400 ml). The combined, dried extracts were concentrated in vacuo to give a dark brown oil (7.82 g) which was purified by FCC eluting with ether to give a dark brown oil which crystallised upon standing. This material was dissolved in ethanol (40 ml) and boiled up with some charcoal (300 mg). The hot ethanolic suspension was filtered through a pad of hyflo and concentrated in vacuo to give the title compound as a yellow oil which crystallised on standing (5.25 g) m.p.63°-64° C.
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[CH:8]=[N:7]1)C.O[Li].O.Cl>C1COCC1.O>[N:6]1([CH2:5][C:4]([OH:15])=[O:3])[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[CH:8]=[N:7]1
Reactant: CCOC(=O)Cn1ncc2cccnc21
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cn1ncc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a stirred solution of pyrazolo[3,4-b]pyridin-1-yl-acetic acid ethyl ester (210 mg, 1.02 mmol) (Preparation 133) in THF (4 mL) and water (1 mL) at 0° C. was added LiOH.H2O (129 mg, 3.06 mmol). The reaction mixture was stirred at room temperature for 2 hours. The pH was of the mixture was adjusted to pH 4 with 2 N aqueous hydrochoric acid and extracted with 20% isopropanol in dichloromethane (8×5 mL). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as an off-white solid in 40% yield, 70 mg.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH-].[K+].[SH2:13]>CO>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[SH:13])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: S
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])c1cnccc1S
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-chloro-3-nitropyridine (18 g, 0.114M) was added to a cooled solution of 10 g of potassium hydroxide and 70 mL of methanol saturated with hydrogen sulfide. The reaction stirred for 2 hours at 25° C. and the solvents were removed by vacuum. The residue was acidified and filtered. (mp. 132° C.)
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([CH3:21])[CH:17]=[C:16]2Cl)([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:28][NH2:29]>CS(C)=O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([CH3:21])[CH:17]=[C:16]2[NH:29][CH2:28][C:27]1[CH:30]=[CH:31][C:32]([Cl:33])=[C:25]([Cl:24])[CH:26]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Cl)c2cccc(OCCNC(=O)OC(C)(C)C)c2n1
Reactant: NCc1ccc(Cl)c(Cl)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCNC(=O)OC(C)(C)C)c2n1
Yield: 12.5 %

Procedure:
[2-(4-Chloro-2-methylquinolin-8-yloxy)-ethyl]-carbamate tert-butyl ester (1.30 g, 3.86 mmole), 3,4-dichlorobenzylamine (1.36 g, 7.72 mmole) and a catalytic effective amount of copper(II)sulphate pentahydrate in dimethylsulfoxide (0.2 mL) were stirred at 155° C. for 30 min in a microwave oven. The organic phases were washed with water and saturated NaCl solution, dried and the solvent was removed. The residue thus obtained was purified using silica gel chromatography, eluting with dichloromethane:water 90:10. Precipitation in ethyl acetate gave a brownish solid (230 mg, 13%).
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>CN(C=O)C.O>[O:24]=[C:21]1[N:20]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:10]2=[N:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:25])=[CH:6][CH:5]=3)[N:8]=[C:9]2[CH2:23][CH2:22]1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NC(=O)CC3)cc1
Reactant: CCOC(=O)CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCCCN1C(=O)CCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one ((prepared according to the preparation procedures disclosed in PCT patent application PCT/EP2011/062028, Example 12.1 step 1) (500 mg, 1.518 mmol) and potassium carbonate (1049 mg, 7.59 mmol) in DMF (15 ml) under N2 was treated with ethyl 9-bromononanoate (805 mg, 3.04 mmol) and stirred at RT overnight. A further portion of ethyl 9-bromononanoate (805 mg, 3.04 mmol) was added and stirring continued at RT for 3 days. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine (×3), dried (MgSO4) and the solvent was removed under reduced pressure to afford the titled compound as a yellow oil;
Reaction SMILES: [OH-:1].[Na+].[CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH:17]=[N:18][CH:19]=3)[CH:12]=2)[N:7]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[N:6]=1)=[O:4]>O.O1CCOCC1.[N+]([O-])([O-])=O.[Ag+]>[CH3:23][N:22]([CH3:24])[C:21](=[O:25])[NH:20][C:16]1[CH:15]=[C:14]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[N:6]=[C:5]3[C:3]([OH:1])=[O:4])[CH:19]=[N:18][CH:17]=1
Reactant: [OH-]
Reactant: CN(C)C(=O)Nc1cncc(-c2ccc3c(c2)c(C=O)nn3C2CCCCO2)c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)C(=O)Nc1cncc(-c2ccc3c(c2)c(C(=O)O)nn3C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
A solution of sodium hydroxide (0.173 g, 4.33 mmol) in water (5 mL) was added to a solution of silver nitrate (0.367 g, 2.16 mmol) in water (5 mL) to give a brown precipitate. 3-(5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-1,1-dimethylurea (CXXIII) (0.340 g, 0.86 mmol) was dissolved in 1,4-dioxane (10 mL) and added to the reaction which was stirred overnight at room temperature. The solution was diluted with water and then extracted with diethyl ether. The aqueous layer was separated and carefully brought to pH=3 with aqueous HCl. The aqueous layer was then extracted with 10% iPrOH/chloroform. The combined organic layers were then dried (Na2SO4), filtered and concentrated to give 5-(5-(3,3-dimethylureido)pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (CXXIV) as a brownish white solid (246 mg, 0.60 mmol, 70% yield). 1H NMR (DMSO-d6) δ ppm 13.26 (br. s, 1H), 8.87 (s, 1H), 8.63 (s, 1H), 8.41 (s, 1H), 8.34 (s, 1H), 8.03 (d, J=7.1 Hz, 1H), 7.86 (dd, J=7.2, 1.3 Hz, 1H), 6.06 (dd, J=8.0, 4.0 Hz, 1H), 3.92 (m, 1H), 3.80 (m, 1H), 2.98 (s, 6H), 2.42-2.39 (m, 1H), 2.03-2.02 (m, 2H), 1.79-1.77 (m, 1H) 1.61 (m, 2H); ESIMS found for C21H23N5O4 m/z 410.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:11]([N+:20]([O-:22])=[O:21])=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:19])=[CH:13]2.IC.[C:31](=O)([O-])[O-].[Cs+].[Cs+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:31][N:15]1[C:16]2[C:12](=[C:11]([N+:20]([O-:22])=[O:21])[C:10]([O:9][C:8]3[CH:7]=[CH:6][C:5]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][C:3]=3[O:2][CH3:1])=[CH:18][CH:17]=2)[CH:13]=[C:14]1[CH3:19]
Reactant: CCOC(=O)Cc1ccc(Oc2ccc3[nH]c(C)cc3c2[N+](=O)[O-])c(OC)c1
Reactant: O=C([O-])[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)Cc1ccc(Oc2ccc3c(cc(C)n3C)c2[N+](=O)[O-])c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a room temperature solution of 3.1 (38 mg, 0.099 mmol) and iodomethane (6.8 μL, 0.11 mmol) dissolved in N,N-dimethylformamide (1 mL) was added cesium carbonate (35 mg, 0.11 mmol). The resulting intense red solution was stirred at room temperature overnight. After 19 h, the color had dissipated to a faint pink and HPLC indicated no 3.1 remained. Several drops of aqueous 20% citric acid solution were added and the mixture partitioned between ethyl acetate and water. The separated aqueous layer was extracted again with ethyl acetate. The combined organic extracts were washed with water twice then brine. The organic separation was stirred over magnesium sulfate, filtered and the filtrate concentrated in vacuo on a rotary evaporator to afford a yellow solid. The product was used without further purification. 1H NMR (400 MHz) (CDCl3) δ 7.35 (d, J=8.8 Hz, 1H); 6.95 (s, 1H); 6.83-6.76 (m, 3H); 6.71 (s, 1H); 4.16 (q, J=9.6 Hz, 2H); 3.88 (s, 3H); 3.70 (s, 3H); 2.48 (s, 3H); 1.27 (t, J=9.6 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([OH:14])=[C:12]([CH:15]=O)[C:11]([CH3:17])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH:18][C:19]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:20]=1[C:21]([NH:23][NH2:24])=[O:22]>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[CH:15][NH:24][NH:23][C:21](=[O:22])[C:20]3[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:19]=3[OH:18])[C:11]([CH3:17])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-n2nc(C)c(C=O)c2O)cc1C
Reactant: NNC(=O)c1ccc(O)cc1O
Solvent: CCO
Product: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=CNNC(=O)c1ccc(O)cc1O
Yield: 69.7 %

Procedure:
46 mg (0.2 mmol) of the 1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-carbaldehyde synthesized in 1) and 34 mg (0.20 mmol) of 2,4-dihydroxybenzoic hydrazide were stirred in 1 ml of ethanol at room temperature for 96 hours. The precipitated solid was collected by filtration and washed with 1 ml of ethanol, 1 ml of ether and 1 ml of methanol successively to obtain 53 mg of the desired product (yield 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].O>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[CH:8]=[CH:7][C:3]=1[C:4]([N:19]([CH2:20][CH3:21])[CH2:17][CH3:18])=[O:5]
Reactant: CC(C)C(=O)Nc1ccc(C(=O)Cl)c(Cl)c1
Reactant: CCNCC
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(NC(=O)C(C)C)cc1Cl
Reaction time: 8 h

Procedure:
The crude 2-chloro-4-(2'-methylpropionamido)benzoyl chloride from the preceding reaction in dry THF (10 ml) was added dropwise with stirring over 10-15 minutes to a solution of diethylamine (1.46 g) in dry THF (10 ml), at 0°-5° C. After stirring at 0°-10° C. the reaction mixture was stood overnight at room temperature, poured into cold water and extracted with ethyl acetate. This extract was dried and evaporated to give a viscous gum which crystallised slowly and was then recrystallised from ethyl acetate to give 2-chloro-4-(2'-methylpropionamido)-N,N-diethylbenzamide as white crystals (0.507 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]1[NH:23][N:22]=[CH:21][CH:20]=1.[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]1[CH:20]=[CH:21][N:22]([CH2:29][CH2:28][C:27]([O:31][CH3:32])=[O:30])[N:23]=1
Reactant: C=CC(=O)OC
Reactant: Cc1nnc2ccc3c(cc(-c4ccn[nH]4)n3Cc3cccc(Cl)c3)n12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)CCn1ccc(-c2cc3c(ccc4nnc(C)n43)n2Cc2cccc(Cl)c2)n1
Reaction time: 1.17 h

Procedure:
6-(3-Chlorobenzyl)-1-methyl-7-(1H-pyrazol-5-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (25 mg, 0.069 mmol, from Example 103, Step 5) in acetonitrile (0.90 mL) was treated with methyl acrylate (19 μL, 0.21 mmol, Aldrich) and 1,8-diazabicyclo[5.4.0]undec-7-ene (10. μL, 0.069 mmol, Aldrich) and stirred for 70 minutes. Purification via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) followed by evaporation of eluent afforded methyl 3-(3-(6-(3-chlorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrazol-1-yl)propanoate. The ester intermediate was dissolved in THF (0.45 mL) and was treated with 1.0 M NaOH in water (0.45 mL, 0.45 mmol). After 25 minutes, the reaction was acidified to pH 3-4 by the addition of 1 N HCl. Water was added (3 mL), and the precipitated product was isolated by filtration and air dried. Yield: (21 mg, 70%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].[N-:10]=[N+:11]=[N-:12].[Na+].[Cl-].[NH4+]>CN(C)C=O>[N:2]1[NH:10][N:11]=[N:12][C:1]=1[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(O)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1cccc(-c2nn[nH]n2)c1
Temperature: 160 °C

Procedure:
A mixture of 3-cyanophenol (4.14 g, 34.75 mmol) (Aldrich), sodium azide (2.49 g, 38.23 mmol) (Aldrich) and ammonium chloride (2.05 g, 38.23 mmol) in N,N-dimethylformamide (30 mL) were heated to 160° C. for 18 hours. The reaction mixture was concentrated. The residue was purified by C18 column eluting with acetonitrile-water to give 3-(2H-tetrazol-5-yl)-phenol. (Yield 0.9 g, 16%).