Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]2[C:11]([C:25]([NH2:27])=[O:26])=[N:12][C:13]([CH:22]([CH3:24])[CH3:23])=[C:14]([O:16][C@@H:17]3[CH2:21][CH2:20][NH:19][CH2:18]3)[N:15]=2)[CH:6]=[N:5]1.C(N(C(C)C)CC)(C)C.[C:37](Cl)(=[O:40])[CH:38]=[CH2:39]>C(Cl)(Cl)Cl>[C:37]([N:19]1[CH2:20][CH2:21][C@@H:17]([O:16][C:14]2[N:15]=[C:10]([NH:9][C:7]3[CH:6]=[N:5][N:4]([CH2:3][CH2:2][OH:1])[CH:8]=3)[C:11]([C:25]([NH2:27])=[O:26])=[N:12][C:13]=2[CH:22]([CH3:23])[CH3:24])[CH2:18]1)(=[O:40])[CH:38]=[CH2:39]
Reactant: CC(C)c1nc(C(N)=O)c(Nc2cnn(CCO)c2)nc1O[C@@H]1CCNC1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: C=CC(=O)N1CC[C@@H](Oc2nc(Nc3cnn(CCO)c3)c(C(N)=O)nc2C(C)C)C1
Reaction time: 1 h

Procedure:
To a mixture of 3-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-6-isopropyl-5-[(3R)-pyrrolidin-3-yloxy]pyrazine-2-carboxamide (476 mg), chloroform (5 mL), and diisopropylethylamine (867 μL) was added acryloyl chloride (226 μL) at 0° C., followed by stirring at the same temperature for 1 hour. The solvent of the reactant was evaporated, and then to the obtained residue were added tetrahydrofuran (5 mL) and a 1 M aqueous sodium hydroxide solution (5 mL), followed by stirring at 50° C. for 4 hours. After leaving to be cooled, the mixture was extracted by the addition of chloroform, and the organic phase was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=980:18:2-90:9:1), and then washed with diisopropyl ether to obtain 5-{[(3R)-1-acryloylpyrrolidin-3-yl]oxy}-3-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-6-isopropylpyrazine-2-carboxamide (343 mg) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[C:20]([C:21]#[N:22])=[CH:19][C:6]2[N:7](CCC)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:9][C:5]=2[CH:4]=1)#[N:2].[CH2:23]([C:26](C1C=CC(C=O)=CC=1)([CH2:30][CH:31]=[CH2:32])[CH2:27][CH:28]=[CH2:29])[CH:24]=[CH2:25]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH2:23]([C:26]([C:13]1[CH:14]=[CH:15][C:10]([C:8]2[NH:7][C:6]3[CH:19]=[C:20]([C:21]#[N:22])[C:3]([C:1]#[N:2])=[CH:4][C:5]=3[N:9]=2)=[CH:11][CH:12]=1)([CH2:30][CH:31]=[CH2:32])[CH2:27][CH:28]=[CH2:29])[CH:24]=[CH2:25]
Reactant: CCCn1c(-c2ccccc2)nc2cc(C#N)c(C#N)cc21
Reactant: C=CCC(CC=C)(CC=C)c1ccc(C=O)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C=CCC(CC=C)(CC=C)c1ccc(-c2nc3cc(C#N)c(C#N)cc3[nH]2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
A solution of 1 (198 mg, 1.25 mmol) in NMP (2.5 mL) and a solution of 2 (300 mg, 1.25 mmol) in NMP (3.5 mL) were combined in a flask fitted with a Hickman still. The mixture was heated at 120° C. and stirred for 2 h. Then FeCl3.6H2O (17 mg, 63 μmol) was added and oxygen was bubbled through the mixture with continued heating and stirring for 20 h. The cooled reaction mixture was diluted with ethyl acetate. The organic solution was washed with water and brine. The organic layer was dried (Na2SO4), filtered, concentrated, and chromatographed (silica, CH2Cl2 w/ethyl acetate gradient of 0-5%). Fractions containing the desired compound were concentrated to give a reddish solid, which was chromatographed over a short plug of alumina (CH2Cl2 w/ethyl acetate gradient of 10-100%) yielding a colorless solid (268 mg, 57%): mp 264-266° C.; 1H NMR (do-acetone) δ 2.57 (d, J=7.2 Hz, 6H), 4.88-5.11 (m, 6H), 5.56-5.69 (m, 3H), 7.65 (d, J=8.8 Hz, 2H), 8.26 (d, J=8.8 Hz, 2H), 12.89 (brs, 1H); 13C NMR (d6-acetone) δ 41.6, 44.0, 108.2, 116.9, 117.7, 126.4, 127.3, 128.0, 134.4, 150.2; FABMS obsd 379.1909, calcd 379.1923 (C25H22N4).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:11]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21]S(C2C=CC(C)=CC=2)(=O)=O)[C:14]([C:32]2[CH:36]=[CH:35][O:34][C:33]=2[CH2:37][OH:38])=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO>[C:42]([O:41][C:39]([N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[C:11]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([OH:21])[C:14]([C:32]2[CH:36]=[CH:35][O:34][C:33]=2[CH2:37][OH:38])=[CH:13][CH:12]=1)=[O:40])([CH3:44])([CH3:45])[CH3:43]
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(-c2ccoc2CO)c1OS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(-c2ccoc2CO)c1O
Temperature: 45 °C
Yield: 92.4 %

Procedure:
1M aqueous sodium hydroxide (50 mL) was added to a solution of methyl 6-[bis-(tert-butoxycarbonyl)amino]-3-(2-hydroxymethylfuran-3-yl)-2-(4-methylbenzene-sulfonyloxy)benzoate (Intermediate 5, 3.82 g) in methanol (100 mL) and the mixture was stirred and heated at 45° C. for 1.5 hours. The mixture was evaporated to dryness and the residue was dissolved in ethyl acetate and acidified with acetic acid. The organic layer was separated, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 10-50% to give methyl 6-[bis-(tert-butoxycarbonyl)amino]-2-hydroxy-3-(2-hydroxymethylfuran-3-yl)benzoate (2.65 g) as a white foam.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[C:5]#[N:6].Cl[CH2:13][CH2:14][CH2:15][C:16]#[CH:17]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[O:10][CH2:17][CH2:16][CH2:15][C:14]#[CH:13])[C:5]#[N:6]
Reactant: Cc1cc(C#N)cc(C)c1O
Reactant: C#CCCCCl
Product: C#CCCCOc1c(C)cc(C#N)cc1C
Yield: 99.4 %

Procedure:
Following the procedure of Example 1c and using 14.7 g (100 mmol) of 3,5-dimethyl-4-hydroxybenzonitrile and substituting 5-chloro-1-pentyne (12.7 mL, 120 mmol) for the product of Example 1b, there was obtained a red-brown oil which was purified by chromatography (Silica Gel 60, 15% ethyl acetate in hexanes) to give pure title compound (21.2 g, 99.4%) as a pale yellow oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][CH:5]=[C:6]([CH2:11][CH2:12][CH2:13][CH3:14])[C:7]=1[N+:8]([O-:10])=[O:9].[OH:15]O>C(O)(=O)C>[CH3:1][S:2]([C:3]1[NH:4][CH:5]=[C:6]([CH2:11][CH2:12][CH2:13][CH3:14])[C:7]=1[N+:8]([O-:10])=[O:9])=[O:15]
Reactant: CCCCc1c[nH]c(SC)c1[N+](=O)[O-]
Reactant: OO
Solvent: CC(=O)O
Product: CCCCc1c[nH]c(S(C)=O)c1[N+](=O)[O-]
Yield: 40.2 %

Procedure:
2-Methylthio-3-nitro-4-n-butylpyrrole (3.7g) was suspended in glacial acetic acid (50 ml) and 30% hydrogen peroxide (1.62g) was added. The mixture was heated to 80° for 7 hours, and it was then evaporated to a brown oil. The crude product was purified by column chromatography using silica gel, eluted with benzene and chloroform, to give an oil which crystallized on standing. This was recrystallised from 2-propanol to give 2-methylsulphinyl-3-nitro-4-butyl-pyrrole (1.6g), m.p. 133-4°.
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=[O:12])[CH:2]=[CH2:3].[CH2:16]([CH2:18][NH2:19])[OH:17]>>[OH:17][CH2:16][CH2:18][N:19]=[C:14]([CH:5]1[CH:6]([C:11]([OH:13])=[O:12])[CH:7]2[CH2:10][C:4]1([CH2:1][CH:2]=[CH2:3])[CH:9]=[CH:8]2)[OH:15]
Reactant: NCCO
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=NCCO

Procedure:
760 g of allylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride (isomeric mixture) are placed into the reaction vessel, and 227.55 g of monoethanolamine are added dropwise with stirring. The mixture is refluxed for 2 hours, and water and some excess monoethanolamine are distilled off until a temperature of 175° C. is reached. The pressure is then decreased to 2670 Pa. The temperature is lowered to 100° C. and the product is rectified at 4.9 Pa. At between 170° and 174° C., there distil over 712.4 g (77.3% of theory) of a pale yellow oil having the following characteristic values:
Reaction SMILES: [CH3:1][NH2:2].[CH:3]12[O:8][CH:7]1[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]2>C(OC(C)C)(C)C>[OH:8][CH:3]1[CH:7]([NH:2][CH3:1])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Reactant: CN
Solvent: CC(C)OC(C)C
Product: CNC1CN(C(=O)OC(C)(C)C)CC1O
Yield: 96 %

Procedure:
Aqueous methylamine solution (40% solution, 812 mL, 3.8 mol) was added to the epoxide 3 (140 g, 0.65 mol) at room temperature and the reaction was stirred until complete. The excess methylamine was removed by distillation under reduced pressure. To the residue obtained, diisopropyl ether (800 mL) was added and the mixture stirred for about 30 min. The solid was filtered, washed with diisopropyl ether (200 mL), then dried to give compound 4 (135 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[O:15][C:16]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:17][N:18]=3)[CH:5]=[CH:4][C:3]1=2.[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=O>>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[O:15][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][OH:26])[CH2:21][CH2:20]4)=[CH:17][N:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: O=CCCCCO
Reactant: CC1(C)CCC(C)(C)c2cc(-c3ncc(C4CCNCC4)o3)ccc21
Product: CC1(C)CCC(C)(C)c2cc(-c3ncc(C4CCN(CCCCCO)CC4)o3)ccc21

Procedure:
The preparation was carried out as already described via a reductive amination starting from 150 mg (0.44 mmol) of 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxazol-5-yl]piperidine and 91 mg (0.89 mmol) of 5-hydroxypentanal. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[O:5][C:4]([CH3:16])([CH3:15])[CH2:3]1.S(=O)(=O)(O)O.[C:22](=O)([O-])[O-].[K+].[K+]>CO>[NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:22])=[O:13])[CH:10]=2)[O:5][C:4]([CH3:16])([CH3:15])[CH2:3]1
Reactant: CC1(C)CC(N)c2cc(C(=O)O)ccc2O1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)C(N)CC(C)(C)O2

Procedure:
0.05 mol of 4-amino-6-carboxy-2,2-dimethylchroman is treated with 9.5 ml of conc. sulfuric acid in 200 ml of methanol and the dark solution is heated to reflux for 6 hours. The reaction mixture is adjusted to pH 9 with ice cooling by addition in portions of saturated aqueous potassium carbonate solution and the precipitated salt is filtered off. The solvent is distilled off on a rotary evaporator, the oily residue is treated with water and the mixture is extracted several times with diethyl ether. After removing the solvent by distillation, the oily amorphous residue is crystallized under n-heptane.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[S:23]1[CH:27]=[CH:26][N:25]=[C:24]1[CH:28]=O>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:28][C:24]4[S:23][CH:27]=[CH:26][N:25]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1nccs1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4nccs4)c23)c1

Procedure:
Analogously to Example 32, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 180 mg of acetic acid are dissolved in 26 ml of methanol and reacted with 170 mg (1.5 mmol) of thiazole-2-carbaldehyde to form 4-(3-chloro-phenylamino)-3-[(thiazol-2-yl)-methyleneamino]-1H-pyrazolo[3,4-d)pyrimidine. Reduction of the above intermediate in 15 ml of DMEU with 8 ml (8 mmol) of DIBAL-H, analogous working-up and digestion in DIPE yield 4-(3-chloro-phenylamino)3[(thiazol-2-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine; HPLC:tRet(grad20-100/20)=9.8; FAB-MS: (M+H)+=358.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]S(C)(=O)=O)[C:8]1=[O:25].[F:33][C:34]1[CH:56]=[CH:55][C:37]([CH2:38][N:39]2[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[N:41]=[C:40]2[C:48]2([OH:54])[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)=[CH:36][CH:35]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:51]2[CH2:52][CH2:53][C:48]([C:40]3[N:39]([CH2:38][C:37]4[CH:55]=[CH:56][C:34]([F:33])=[CH:35][CH:36]=4)[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)([OH:54])[CH2:49][CH2:50]2)([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]1=[O:25]
Reactant: COc1cc(CN2CCC(CCS(C)(=O)=O)(Cc3ccccc3)C2=O)cc(OC)c1OC
Reactant: OC1(c2nc3ccccc3n2Cc2ccc(F)cc2)CCNCC1
Product: COc1cc(CN2CCC(CCN3CCC(O)(c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(Cc3ccccc3)C2=O)cc(OC)c1OC

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzyl)-3-(phenylmethyl)-3-(2-methanesulfonyl-ethyl)-2-oxo-pyrrolidine and 4-[1-(4-fluoro-benzyl)-1H-benzoimidazol-2-yl]-4-hydroxy-piperidine to give the title compound: Rf=0.42 (silica gel, 30% methanol/ethyl acetate)
Reaction SMILES: [SH:1][CH2:2][C@H:3]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([C:13]([OH:15])=[O:14])[NH:5][C:4]1=[O:16].[C:17](Cl)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([S:1][CH2:2][C@H:3]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([C:13]([OH:15])=[O:14])[NH:5][C:4]1=[O:16])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: O=C1N[C@@H](C(=O)O)CCCCCC[C@@H]1CS
Solvent: c1ccncc1
Product: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)O)NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trans 3-mercaptomethyl-2-oxo-1-azacyclodecane-10-carboxylic acid (0.75 g, 3.06 mmol) is dissolved in pyridine (20 mL). Acetyl chloride (0.26 g, 3.37 mmol) is added, and the reaction is stirred at room temperature overnight. The reaction is quenched by cooling to 0° C., adding concentrated hydrochloric acid (20 mL), diluting with water, and extracting several times with ethyl acetate. The combined organic layers are dried (MgSO4), and the solvent is evaporated to give trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid, MS: M+1=288.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]=2[C:20]([F:23])([F:22])[F:21])[CH2:4][CH2:3]1.[OH-].[Na+]>O.CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[C:20]([F:23])([F:21])[F:22])[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(CN2CCN(C)CC2)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CCN(Cc2ccc(C(=O)O)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of ethyl 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzoate (330 mg, 0.96 mmol) and sodium hydroxide solution (1.5 M) in water/methanol (15/5 mL) were stirred at room temperature for 5 hours. The mixture was concentrated and acidified with aqueous hydrochloric acid until a white solid formed. The mixture was lyophilized to give a white solid (600 mg, contains salt).
Reaction SMILES: [SH:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[NH2:7][CH2:8][CH2:9][CH2:10]O.[BrH:12]>>[BrH:12].[BrH:12].[NH2:7][CH2:8][CH2:9][CH2:10][S:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1
Reactant: Sc1nc[nH]n1
Reactant: NCCCO
Agent: Br
Product: NCCCSc1nc[nH]n1

Procedure:
A solution of 3-mercapto-1,2,4-triazole and 3-aminopropanol in hydrobromic acid is heated under reflux for 24 hours. The reaction mixture is evaporated to dryness and the residue recrystallised from ethanol/ether to give 3-(3-aminopropylthio)-1,2,4-triazole dihydrobromide.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[OH:20])=[O:11])[N:5]=[CH:4][C:3]=1[NH:21][C@@H:22]1[CH2:27][C@@H:26]2[CH2:28][C@@H:24]([C:25]2([CH3:30])[CH3:29])[C@H:23]1[CH3:31].[CH3:32][CH:33](O)[CH3:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[O:20][CH:33]([CH3:34])[CH3:32])=[O:11])[N:5]=[CH:4][C:3]=1[NH:21][C@@H:22]1[CH2:27][C@@H:26]2[CH2:28][C@@H:24]([C:25]2([CH3:30])[CH3:29])[C@H:23]1[CH3:31]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3O)c(=O)c1Cl)C2(C)C
Reactant: CC(C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)Oc1cnccc1CNC(=O)Cn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 15.3 %

Procedure:
2-[5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-[(3-hydroxypyridin-4-yl)methyl]acetamide (26.6 mg, 0.06 mmol) in tetrahydrofuran (1 mL) was mixed with 2-propanol (10.9 mg, 0.18 mmol), triphenylphosphine (23.6 mg, 0.09 mmol) and diethyl azodicarboxylate in toluene (2.2 M, 0.04 mL, 0.09 mmol) at 0° C. and stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel chromatography (ethyl acetate/methanol 20/1) to give the desired product (4.48 mg, 15%).
Reaction SMILES: [C:1]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[N:14]=[C:10]2[CH:9]=[C:8]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:7]=1)(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH3:28][O:29][NH2:30].O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[CH2:19]([NH:18][C:16]([NH:15][C:13]1[N:14]=[C:10]2[CH:9]=[C:8]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:7]=[C:6]([C:1](=[N:30][O:29][CH3:28])[CH2:2][CH2:3][CH3:4])[N:11]2[N:12]=1)=[O:17])[CH3:20]
Reactant: CCCC(=O)c1cc(-c2cccnc2)cc2nc(NC(=O)NCC)nn12
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCC(=NOC)c1cc(-c2cccnc2)cc2nc(NC(=O)NCC)nn12

Procedure:
1-(5-Butyryl-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-3-ethyl-urea, which may be produced as in Example 108 (46.0 mg, 0.13 mmol) and O-methylhydroxylamine HCl (18.0 mg, 0.22 mmol) in ethanol (1.0 mL) were charged with sodium acetate trihydrate (55.0 mg, 0.41 mmol). After 24 h the reaction was concentrated then taken up in ethyl acetate and washed with saturated sodium bicarbonate. The organic was concentrated and the resulting oil chromatographed (0-10% isopropanol/CH2Cl2) to afford 1-ethyl-3-[5-(1-methoxyimino-butyl)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridine-2-yl]-urea. MS (APCI+): m/z 382.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[C:5]([NH2:14])=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:23](=[O:29])[C:24](OCC)=[O:25]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:14][C:24](=[O:25])[C:23](=[O:29])[N:8]([CH2:9][CH2:10][CH:11]([CH3:12])[CH3:13])[C:6]=2[N:7]=1
Reactant: CC(C)CCNc1nc(Cl)ncc1N
Reactant: CCOC(=O)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)CCn1c(=O)c(=O)[nH]c2cnc(Cl)nc21
Temperature: 25 °C
Yield: 59.8 %

Procedure:
To a stirred solution of 2-chloro-N4-(3-methylbutyl)pyrimidine-4,5-diamine (2.8 g, 13.08 mmol) in toluene (40 mL) was added triethylamine (4.23 g, 41.88 mmol) and ethyl chlorooxoacetate (1.95 g, 14.33). The mixture was then heated to reflux for 16 h. It was then cooled to rt, the bulk of solvent was removed under reduced pressure to give a crude residue, which was purified by silica gel column chromatography (eluent: 70% ethyl acetate in hexane) afforded the desired product (2.1 g). 1H NMR (CDCl3, 300 MHz) δ 1.01 (d, J=6.6 Hz, 6H), 1.60-1.82 (m, 3H), 4.20-4.35 (m, 2H), 8.35 (s, 1H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:16])[CH2:14]Br)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([O-])(=[O:19])C.[Na+].CCO.[OH-].[Na+]>O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:16])[CH2:14][OH:19])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CC(=O)N1CCc2cc(C(=O)CBr)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)N1CCc2cc(C(=O)CO)ccc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
To a solid mixture of 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-2-bromoethanone (1.0 g, 3.54 mmol) and sodium acetate (1.45 g, 17.71 mmol, 5 equiv) in a 40 mL vial was added EtOH (8 mL) and water (8 mL). The resulting suspension was heated in an oil bath at 70° C. for 3.5 hours. The mixture was cooled in an ice bath, to which was added 0.7 mL of 6 N NaOH. After 2 h, the cold mixture was quenched with 2 ml of 1N HCl, and then concentrated in vacuo. The residue was partitioned between 10% MeOH in DCM and water. The organic was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was taken up between DCM and ether to give a suspension, which was filtered. The yellow solids collected were washed with ether and dried under vacuum to give 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-2-hydroxyethanone (534 mg) as a light yellowish solid, which was used without further purification.
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:4][CH2:3]1.CCN(CC)CC.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>CN(C=O)C>[CH:2]1([NH:5][C:6](=[O:7])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][N:22]([C:41]([N:40]([CH3:44])[CH3:39])=[O:42])[CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)[CH2:3][CH2:4]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CN(C(=O)N(C)C)C2
Temperature: 20 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
To a stirring solution of (S)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (Example 149) (115 mg, 0.279 mmol) and NEt3 (43 μL, 0.307 mmol) in DMF (2 ml) was added dimethylcarbamoyl chloride (35 μL, 0.307 mmol). Reaction mixture was stirred at room temperature (20° C.) overnight before being concentrated in vacuo and purified by prep. HPLC at high pH to afford a white solid (75 mg, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[CH:17]=[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)=[CH:4][C:3]=1[OH:18].[Cl:19]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:17]([Cl:19])=[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)=[CH:4][C:3]=1[OH:18]
Reactant: Oc1cc(-c2cc3n(n2)CCCC3)c(F)cc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Oc1cc(-c2nn3c(c2Cl)CCCC3)c(F)cc1Cl
Temperature: 65 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
A mixture of 2-chloro-4-fluoro-5-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)-phenol (5.0 g) and N-chlorosuccinimide (2.65 g) in N,N-dimethylformamide (30 ml) was stirred at 65° C. for 2 hours. The resulting mixture was poured into water and the precipitate was collected by filtration and dried. 2-Chloro-5-(3-chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)-4-fluorophenol (5.50 g) was obtained as a white solid.
Reaction SMILES: [CH3:1]I.[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8](=[N:24][OH:25])[C:9]1[CH:23]=[CH:22][C:12]([O:13][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1>CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8](=[N:24][O:25][CH3:1])[C:9]1[CH:23]=[CH:22][C:12]([O:13][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1
Reactant: CI
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(=NO)c2cccs2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C(=NOC)c2cccs2)cc1

Procedure:
This oily compound, which consists of a mixture of both isomers Z/E, is obtained by reacting methyl iodide with ethyl 2-[4-(2-thienyl-hydroxyiminomethyl)-phenoxy]-2-methyl-propionate dissolved in dimethyl formamide and in the presence of potassium carbonate.