Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(OC)[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([F:12])=[CH:5][C:4]=1[Cl:13].[OH-].[Na+]>O>[Cl:13][C:4]1[CH:5]=[C:6]([F:12])[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[OH:2]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Yield: 98 %

Procedure:
A mixture of 2-chloro-4-fluoro-5-nitrophenyl methyl carbonate (120g 0.48 mol) and sodium hydroxide (22.7 g, 0.57 mol) in water (300 mL) was refluxed for 4 h. The insoluble solids were removed by filtration and the filtrate was acidified with dilute HCl. The precipitated solid was collected by filtration and washed with water to give 2-chloro-4-fluoro-5-nitrophenol (90g, 98% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.10 (d, J=10.4 Hz, 1H), 7.62 (d, J=7.2 Hz, 1H); MS (ESI) m/z: 192.1 (M+H+)
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22].[OH-].[K+].O>ClCCl>[CH3:12][O:13][CH:14]([S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCOCCOCCO
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC(COCCOCCO)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C

Procedure:
200 g of p-toluenesulfonyl chloride and 172.4 g of triethylene glycol monomethyl ether are dissolved in 1 liter of dichloromethane and cooled to 0° C. With vigorous stirring, 236.3 g of freshly powdered potassium hydroxide are metered in at a rate such that the temperature does not exceed 5° C. The mixture is maintained at 0° C. for 3 hours. 1 liter of dichloromethane and 1.2 liters of iced water are added. If more solids form, a further 0.5 liter of iced water are added. The organic phase is separated off and washed with 0.3 liter of saturated sodium chloride solution. It is dried over Na2SO4 and evaporated to dryness under reduced pressure.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1.[C:24]1(=[O:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]([C:24]2([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: O=C1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)C(c1cccc(Cl)c1)C1(O)CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
A solution of Diisopropylamine (7.87 mL, 56.2 mmol) in dry tetrahydrofuran (50 mL) under nitrogen was cooled to −78° C. and treated dropwise with a solution of n-butyllithium (2.5 M in hexanes, 22 mL, 55.0 mmol). The resulting solution was warmed to 0° C. and stirred for 15 min. The solution was re-cooled to −78° C. and treated, via cannula, with a solution of 3-chlorophenylacetic acid (4.0 g, 23.4 mmol) in tetrahydrofuran (20 mL). The reaction was then allowed to warm to 25° C. where it was stirred for 45 minutes and was then re-cooled to −78° C. A solution of cyclohexanone (3.65 mL, 35.3 mL) in tetrahydrofuran (10 mL) was then added via cannula, and the resulting mixture was stirred at −78° C. for 1.5 h. The reaction was then quenched by the addition of a saturated aqueous solution of ammonium chloride, and the tetrahydrofuran was removed in vacuo. The resulting residue was dissolved in a 2N aqueous solution of sodium hydroxide (30 mL) and washed with ethyl acetate (1×30 mL). The aqueous layer was then acidified to pH=1 with the addition of a 2 N aqueous solution of hydrochloric acid. The product was extracted with ethyl acetate (3×30 mL), and the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to yield 6.05 g (96%) of pure (3-chlorophenyl)(1-hydroxycyclohexyl)acetic acid as a white solid. HRMS: calcd for C14H17ClO3, 268.0866; found (ESI_FT), 291.0748.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][OH:30])[CH2:25][CH2:24]1>>[OH:30][CH2:29][CH:26]1[CH2:27][CH2:28][N:23]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:24][CH2:25]1
Reactant: OCC1CCNCC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCC(CO)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with piperidin-4-ylmethanol (1.2 equiv) to give 183 (15.9 mg, M+1 411.1)
Reaction SMILES: [N:1]([C:4]12[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:8][O:7][C:6]1[CH:14]=[CH:15][CH:16]=[CH:17][C:5]2=1)=[C:2]=[O:3].[CH3:18][OH:19]>>[CH3:18][O:19][C:2](=[O:3])[NH:1][C:4]12[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:8][O:7][C:6]1[CH:14]=[CH:15][CH:16]=[CH:17][C:5]2=1
Reactant: O=C=NC12CCCCC1COc1ccccc12
Reactant: CO
Product: COC(=O)NC12CCCCC1COc1ccccc12

Procedure:
A solution of the product from Example 71 (0.66 g, 2.88 mmol) in 20 ml methanol was refluxed 18 hours. Evaporation and chromatography gave the title compound (0.75 g).
Reaction SMILES: C(O[C:6]([N:8]([C:10]1[CH:37]=[CH:36][C:13]([CH2:14][N:15]2[C:19]3=[N:20][C:21]([C:24](=[O:34])[NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:28])=[O:27])=[CH:22][CH:23]=[C:18]3[N:17]=[C:16]2[CH3:35])=[C:12]([Cl:38])[CH:11]=1)C)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:38][C:12]1[CH:11]=[C:10]([NH:8][CH3:6])[CH:37]=[CH:36][C:13]=1[CH2:14][N:15]1[C:19]2=[N:20][C:21]([C:24](=[O:34])[NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:28])=[O:27])=[CH:22][CH:23]=[C:18]2[N:17]=[C:16]1[CH3:35]
Reactant: CCCCCS(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(N(C)C(=O)OC(C)(C)C)cc3Cl)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCS(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(NC)cc3Cl)c2n1
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a solution of 3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (1.91 g) in dichloromethane (19 ml) was added trifluoroacetic acid (14.5 ml) under ice-cooling, and the mixture was stirred for 1 hr. The solvent was evaporated and methanol (19 ml) was added to the residue for re-dissolution. Water (9.5 ml) was added and 1N aqueous sodium hydroxide solution was added dropwise under ice-cooling to adjust to about pH 4. The resulting precipitate was collected by filtration and dried under reduced pressure to give 3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (1.53 g) as a white powder.
Reaction SMILES: CO[C:3](=O)[CH2:4][CH2:5][NH:6][CH2:7][CH3:8].[CH2:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C:11]1=[O:19]>C1(C)C=CC=CC=1>[CH2:7]([N:6]1[C:11](=[O:19])[CH2:10][CH2:18][C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=3[CH2:4][C:5]1=2)[CH3:8]
Reactant: O=C1Cc2ccccc2C1
Reactant: CCNCCC(=O)OC
Solvent: Cc1ccccc1
Product: CCN1C(=O)CCC2=C1Cc1ccccc12
Temperature: 25 °C
Yield: 27.1 %

Procedure:
3-Ethylamino-propionic acid methyl ester (2.41 g, 18.4 mmol) is added to a solution of 2-indanone (2.3 g, 17.33 mmol) in toluene (27 mL), and the reaction is brought to reflux for 2 hours. Toluene is removed in vacuo and the residue is dissolved in ethylene glycol (23 mL) and the resulting solution is heated to reflux for 8 hours. The reaction is allowed to cool to ambient temperature and is poured over water and extracted with dichloromethane. The organic phase is dried over magnesium sulfate and concentrated in vacuo to afford the crude title compound. The crude product is purified by silica gel chromatography (gradient of ethyl acetate in hexanes 10-100%) affording 1 g (27% yield) of the title compound. MS (m/z): 213.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:6]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=3)[C:13]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1
Reactant: CCn1cc(Br)cn1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(CC)c3)c3c(F)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: Cl[CH:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3]1[CH:16]=[CH:15][C:6]2[NH:7][C:8]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[N:9][C:5]=2[CH:4]=1.[OH-].[NH4+:24]>O1CCCC1>[NH2:24][CH:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3]1[CH:16]=[CH:15][C:6]2[NH:7][C:8]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[N:9][C:5]=2[CH:4]=1
Reactant: COC(=O)Nc1nc2cc(C(Cl)c3ccccc3)ccc2[nH]1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)Nc1nc2cc(C(N)c3ccccc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 22 %

Procedure:
The above hydrochloride salt of methyl (±)-[5- [chloro (phenyl)methyl]-1H-benzimidazol-2-yl]carbamate was then suspended in dry tetrahydrofuran (30 mL) and excess ammonium hydroxide was added to this suspension. The resulting reaction mixture was stirred at room temperature for 12 hours. The solvent was then removed and the residue was chromatographed on silica gel 60F254 (40 g, 70-230 mesh, column size 1'×1") using CHCl3 :CH3OH (95:5) as eluant. Fractions 3 through 12 (20 mL each) upon concentrating on a steam bath under vacuum afforded the title product, yield 22%; mp>232° C.; IR (KBr): 3340, 1718, 1630, 1600, 870, 750, 721, 695 cm-1. 1H-NMR (DMSO-d6): δ 3.75 (2, 3H, --OCH3); 5.23 (2, 1H, CH--N), 5.60-6.87 (m, 2H, NH2 [exchangeable with D2O]), 6.90-7.83 (m, 9H, Ar--H and NHCO [exchangeable with D2O]). Analysis calculated for C16H16N4O2 : C, 64.85; H, 5.44; N, 18.91 and found: C, 65.03; H, 5.53; N, 18.67.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29](Cl)(=[O:31])=[O:30]>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:3]([OH:10])([CH2:2][NH:1][S:29]([C:20]1[CH:21]=[CH:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=1)(=[O:31])=[O:30])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Product: O=S(=O)(NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl)c1ccc2ccccc2c1

Procedure:
Following the procedure described in the preceeding examples but using 3-amino-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and 2-naphtalenesulfonylchloride, the title compound was obtained in a similar yield:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].[Cl:12][S:13](O)(=[O:15])=[O:14]>C(Cl)Cl>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH3:9])[C:6]([S:13]([Cl:12])(=[O:15])=[O:14])=[C:7]([CH3:8])[C:2]=1[CH3:1]
Reactant: COc1cc(C)cc(C)c1C
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Temperature: 0 °C

Procedure:
In 500 ml of methylenchloride was dissolved 4.5 g of 2,3,5-trimethylanisole, and after cooling at -5°~-10° C., a solution (400 ml) of 6.0 ml of chlorosulfonic acid in methylene chloride was added dropwise to the mixture. The reaction mixture was kept at room temperature and then poured into ice-5% aqueous NaHCO3. The methylene chloride layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was crystallized from n-hexane and filtered.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>>[O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=C(O)CN1C(=O)C=CC1=O
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CN1C(=O)C=CC1=O

Procedure:
A suspension of 2,5-dihydro-2,5-dioxopyrrol-1-ylacetic acid (821 mg) in thionyl chloride (15.9 ml) was heated under reflux for 0.5 hours and the excess thionyl chloride was removed under vacuum. The residue was evaporated twice with dry toluene to afford 2,5-dihydro-2,5-dioxopyrrol-1-ylacetyl chloride [(5) where m=1] as a colourless, readily hydrolysed liquid. (The compound has been prepared previously by a less convenient route5). The crude acid chloride was dissolved in dry ether (25 ml) and added dropwise to an ice-cold solution of the hydrazinecarboxylate [(4) where n=1, 1.30 g] and triethylamine (588 mg) in dry ether (25 ml). The mixture was stirred in an ice bath for 1 hour then diluted with ethyl acetate and washed with water, dilute HCl, saturated NaHCO3 and brine, dried and evaporated. The residue was crystallised from ethyl acetate--petroleum ether to give the compound (6) as colourless plates (1.67 g; 82%) m.p. 157°-9° C. (Found: C, 53.1; H, 6.7; N, 10.8. C17H25N3O7 requires C, 53.25; H, 6.6; N, 11.0%).
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[CH2:16]1[O:24][C:23]2[CH:22]=[CH:21][C:20]([CH2:25][CH2:26][C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:28])=[CH:19][C:18]=2[O:17]1>CCCCCC.O1CCCC1>[O:24]1[C:23]2[CH:22]=[CH:21][C:20]([CH2:25][CH2:26][C:27]3([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:28][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]3)=[CH:19][C:18]=2[O:17][CH2:16]1
Reactant: O=C(CCc1ccc2c(c1)OCO2)c1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=C(O)CC(CCc2ccc3c(c2)OCO3)(c2ccccc2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 0.22 mL of methyl acetoacetate, 90 mg of NaH 60% dispersion in oil, 1 mL of 2.1M n-butyl lithium in hexane, 500 mg of 3-(3,4-methylenedioxyphenyl)propiophenone and 15 mL of tetrahydrofuran. After addition of the ketone, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature and stirred for 2 hours. The crude product was triturated from diethyl ether to afford a solid (m.p. 112°-114° C.). 1H NMR (CDCl3) δ2.20-2.28 (m, 2H), 2.37-2.44 (m, 1H), 2.61-2.69 (m, 1H), 2.95 (dd, 2H), 3.32 (dd, 2H), 5.90 (s, 2H), 6.52-6.70 (m, 3H), 7.33-7.44 (m, 5H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[N:5]1[CH:6]=[CH:7][C:2]([C:11]#[C:10][CH2:9][CH2:8][C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[N:3][CH:4]=1
Reactant: C#CCCc1nc2ccccc2o1
Reactant: Clc1ccncn1
Product: C(#Cc1ccncn1)CCc1nc2ccccc2o1
Yield: 17.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 4-chloropyrimidine (85 mg, 0.74 mmol) and 2-(but-3-ynyl)benzo[d]oxazole (127 mg, 0.74 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 32 mg (128 μmol, 17%) of 2-(4-(pyrimidin-4-yl)but-3-ynyl)benzo[d]oxazole as a white solid.
Reaction SMILES: [O:1]=[C:2]=[N:3][S:4]([Cl:7])(=[O:6])=[O:5].[CH3:8][C:9]([OH:12])([CH3:11])[CH3:10].CCCCCC>C1C=CC=CC=1>[Cl:7][S:4]([NH:3][C:2](=[O:1])[O:12][C:9]([CH3:11])([CH3:10])[CH3:8])(=[O:6])=[O:5]
Reactant: CC(C)(C)O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCCCCC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(oxomethylene)sulfamoyl chloride (13.4 mmol) was dissolved in dry benzene (5 mL) and dropwise added t-BuOH (13.4 mmol) while the temperature was kept below 25° C. The reaction mixture was stirred at 25° C. for 2 h, added hexane (5 mL) and cooled to 0° C. Precipitate was collected by filtration, washed with hexane affording tert-butyl N-chlorosulfonylcarbamate as white crystals. 4-(4,7-diaza-spiro[2.5]oct-7-yl)-7H-pyrrolo[2,3-d]pyrimidine (4.6 mmol) (intermediate 21) was suspended in dry DCM (25 mL) and added triethylamine (6.9 mmol). To this suspension was slowly added tert-butyl N-chlorosulfonylcarbamate (4.6 mmol) at rt. After 15 min all starting material has been consumed. The obtained reaction mixture was concentrated in vacuo on celite. The product was purified by flash chromatography on silica using EtOAc:MeOH in heptane as eluent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.4 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (42.8 mg, 36%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CCc1cc2c(NCc3ccc(OC)c(Cl)c3)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc(OC)c(Cl)c3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-ethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-ethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[CH:7]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C1COCC1>O>[Br:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)[C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nc(Br)cn2cnnc12
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Br)cn3cnnc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
A 100 mL round bottom flask was charged with 6-bromo-8-chloro-[1,2,4]triazolo[4,3-a]pyrazine (1.11 g, 4.73 mmol), tert-butyl piperazine-1-carboxylate (2.64 g, 14.2 mmol) and THF (50 mL). The resulting mixture was stirred at room temperature for 0.5 h. Reaction progress was monitored by TLC (EtOAc/petroleum ether=1:2). Work-up: the reaction mixture was diluted with water and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 20% EtOAc in petroleum ether, to afford 1.62 g (89%) of the product as a yellow solid.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]=[C:6]([C:15]([F:18])([F:17])[F:16])[C:5]=1[CH:19]=[O:20].O>CS(C)=O>[F:1][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]=[C:6]([C:15]([F:18])([F:17])[F:16])[C:5]=1[CH:19]=[O:20]
Reactant: O=Cc1c(C(F)(F)F)nn(-c2ccccc2)c1Cl
Reactant: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1c(C(F)(F)F)nn(-c2ccccc2)c1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
10.5 g (180.2 mmoles) of potassium fluoride was added to a solution of 33.0 g (120.1 mmoles) of 5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 500 ml of dimethyl sulfoxide. The mixture was stirred at 100° C. for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 26.5 g (yield: 85.0%) of 5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde.
Reaction SMILES: O[CH:2]([CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:19][CH:2]([CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(O)CCCCCc1nc2ccccc2[nH]1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Br)CCCCCc1nc2ccccc2[nH]1
Yield: 75.8 %

Procedure:
2.18 g of the compound obtained in Example 19a, 4.97g of carbon tetrabromide and 3.93 g of triphenylphosphine were added to 30 ml of tetrahydrofuran and the mixture was reacted overnight at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 2.10 g of the title compound as pale yellow solid (yield: 75%).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH2:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23]O)=[C:19]([F:25])[CH:18]=1)[CH3:16]>>[CH2:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:19]([F:25])[CH:18]=1)[CH3:16]
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: CCc1ccc(CO)c(F)c1
Product: CCc1ccc(COc2ccnn2-c2cc(C#N)ccn2)c(F)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-ethyl-2-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.23 (3H, t, J=7.6 Hz), 2.66 (2H, q, J=7.6 Hz), 5.26 (2H, s), 5.81 (1H, d, J=2.0 Hz), 6.95 (1H, d, J=11.2 Hz), 7.00 (1H, d, J=7.6 Hz), 7.35 (1H, d, J=8.0 Hz), 7.38 (1H, dd, J=1.6 Hz, 5.2 Hz), 7.57 (1H, d, J=1.6 Hz), 8.00-8.01 (1H, m), 8.69 (1H, d, J=0.8 Hz, 5.2 Hz). [M+H] Calc'd for C18H15FN4O, 323. Found, 323.