Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[C:7]([O:13][CH3:14])[CH:6]=2.C(O)(=O)C(O)=O.CO>O>[OH:2][C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[C:4]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C1C(OC)=CCc2ccc(OC)cc21
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O
Product: COC(=O)C1=C(O)CCc2ccc(OC)cc21
Temperature: 20 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of II (0.124 mole), oxalic acid (0.124 mole), 400 ml. methanol and 120 ml. water was warmed until solution occurred. This solution was then stirred at 20° C. for 18 hours. The resultant mixture was warmed again to solution and then concentrated. The residue was treated with dilute potassium carbonate and extracted with methylene chloride. The extracts were dried (MgSO4), filtered and concentrated to give III (~100%). Two recrystallizations of a small sample from methanol gave an analytical sample; mp 48.0°-48.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=1)[CH3:2].[H-].[Na+].I[CH3:28]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([C:6]1[CH:11]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:9]=[C:8]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=1)[CH3:28])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)Cc1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (3-benzyloxy-5-trifluoromethyl-phenyl)-acetic acid ethyl ester (5.0 g, 14.8 mmol) in DMF (50 mL) at 0° C. under N2 was added sodium hydride (60% in mineral oil; 0.65 g, 16.3 mmol), and the mixture was stirred at room temperature for 15 minutes. Iodomethane (1 mL, 16.3 mmol) was added, and the reaction was monitored by analytical LCMS and tlc. After work-up with EtOAc and H2O, the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Br:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1.[ClH:63]>C(Cl)Cl.C(Cl)Cl.CO>[ClH:63].[Br:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:55][CH2:56][N:57]4[CH2:62][CH2:61][O:60][CH2:59][CH2:58]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: OCCN1CCOCC1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
Diethyl azodicarboxylate (209 mg, 1.2 mmol) was added dropwise to a suspension of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (146 mg, 0.4 mmol), (prepared as described for the starting material in Example 24), triphenylphosphine (314 mg, 1.2 mmol) and 4-(2-hydroxyethyl)morpholine (79 mg, 0.6 mmol) in methylene chloride (5 ml). The mixture was stirred for 1 hour at ambient temperature and purified by column flash chromatography eluting with methylene chloride/methanol (95/5 followed by 90/10) to give a white solid. The solid was dissolved in methylene chloride/methanol and 2M ethereal hydrogen chloride (0.5 ml) was added. The mixture was concentrated by evaporation and the resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-morpholinoethoxy)quinazoline hydrochloride (155 mg, 70%).
Reaction SMILES: [C:1]([C:6]1[O:7][C:8]2[C:16]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=4)=[CH:21][CH:20]=3)=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[CH:11]=1)([O:3]CC)=[O:2].C(=O)(O)[O-].[Na+]>C(O)C.O>[C:1]([C:6]1[O:7][C:8]2[C:16]([CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=4)=[CH:23][CH:24]=3)=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[CH:11]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)c1cc(=O)c2cccc(COc3ccc(OCc4ccc5ccccc5n4)cc3)c2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(=O)c2cccc(COc3ccc(OCc4ccc5ccccc5n4)cc3)c2o1
Yield: 61.7 %

Procedure:
0.74 g of 2-carboethoxy-8-(4-(quinoline-2-ylmethoxy)phenoxymethyl)-4-oxo-4H-1-benzopyran and 0.7 g sodium bicarbonate are combined in 50 ml of ethanol and 5 ml of water. After refluxing for 1.5 hours the mixture is concentrated and the residue diluted with ether. The resulting solid is collected, suspended in water and the pH adjusted to 6 with 1 molar hydrochloric acid. The resulting solid is crystallized from aqueous acetic acid, then tetrahydrofuran/hexane to give 0.43 g 2-carboxy-8-(4- (quinolin-2-ylmethoxy)phenoxymethyl)-4-oxo-4H-1-benzopyran; m.p. 221°-24° C.
Reaction SMILES: C(Cl)(Cl)Cl.CCCCCC.C1CO[C:13]2([C:19]3[CH:20]=[CH:21][C:22]([CH2:24][C:25](N)=[O:26])=[CH:23][C:18]=3[CH:17]=[CH:16][C:15]3[CH:28]=[CH:29][CH:30]=[CH:31][C:14]2=3)[O:12]1.CC(C)=[O:36].CCCCCC>>[CH:21]1[C:20]2[CH:17]=[CH:16][C:15]3[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=3[C:13](=[O:12])[C:19]=2[CH:18]=[CH:23][C:22]=1[CH2:24][C:25]([OH:36])=[O:26]
Reactant: CC(C)=O
Reactant: NC(=O)Cc1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: O=C(O)Cc1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
11.0 Gm. of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionamide is refluxed for 2 hours in 70 ml. of acetic acid and 105 ml. of concentrated hydrochloric acid. The mixture is cooled and diluted, then extracted with ether. The ethereal solution is extracted with aqueous sodium carbonate and the extract acidified and extracted with ethyl acetate to afford a 70% yield of 2-(5H-dibenzo[a,d] cyclohepten-5-on-2-yl)propionic acid., m.p. (chloroform-hexane) 138°-139°C.; m.p. (acetone-hexane) 113°-115°C. Use of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)acetamide gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid, m.p. (acetone-hexane) 148°-149.5°C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1>>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C:16]2[CH:17]=[C:12]([N:8]3[CH2:7][CH2:6][C:5]4[C:10](=[CH:11][C:2]([C:30]5[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=5)=[CH:3][CH:4]=4)[CH2:9]3)[N:13]=[C:14]([NH2:25])[N:15]=2)[CH2:19][CH2:20]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Product: CN1CCN(c2cc(N3CCc4ccc(-c5cnn(C)c5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Aldrich, Cat. No. 595214). LCMS (M+H)+: m/z=405.4.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(=O)[CH3:9].Cl.[NH2:21][OH:22]>C(O)C>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([C:8](=[N:21][OH:22])[CH3:9])=[CH:12]1
Reactant: NO
Reactant: CC(=O)c1c[nH]c2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=NO)c1c[nH]c2ccccc12
Temperature: 90 °C
Yield: 96.9 %

Procedure:
Triethylamine (3.93 mL) was added to a solution of 3-acetylindole (500 mg) and hydroxylamine hydrochloride (981 mg) in ethanol (20 mL), and the reaction solution was heated to reflux at 90° C. for 14 hours. The reaction solution was allowed to be cooled to room temperature, the solvent was concentrated under reduced pressure, and ethyl acetate and water were added to the resulting residue and the organic layer was partitioned. The resulting organic layer was washed with brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate) to obtain 0.53 g of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Li])CCC.O1CCN([C:20](=[O:30])[C@H:21]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH3:22])CC1>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:20](=[O:30])[C@H:21]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH3:22])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C[C@@H](OC1CCCCO1)C(=O)N1CCOCC1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: C[C@@H](OC1CCCCO1)C(=O)c1ccc(Br)cn1
Temperature: 25 °C
Yield: 61.8 %

Procedure:
2,5-dibromopyridine (5 g, 21.1 mmol) was dissolved in dried toluene (100 mL), cooled to −78° C., to which n-butyl lithium (9 mL, 22.5 mmol, 2.5 M solution in n-hexane) was added dropwise. The mixture was allowed to react at −78° C. for 2 hrs, and then the solution of (2R)-1-morpholino-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-one (7.7 g, 31.6 mmol) in toluene was added dropwise and allowed to react at −78° C. for 5 hrs. The reaction was monitored by TLC (petroleum ether). After the reaction completed, the reaction was quenched by adding saturated solution of ammonium chloride. The mixture was raised to room temperature and diluted with water. The toluene layer was separated and extracted with ethyl acetate. The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then dried by rotary dryer. Column chromatography (petroleum ether) afforded 4.1 g of pale yellow solid (compound 1a), yield 62%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.I[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])(=O)C.[K+]>CN(C)C(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:7]1([C:5]2[S:1][CH:2]=[N:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Ic1ccccc1
Reactant: c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: c1ccc(-c2cncs2)cc1
Temperature: 100 °C

Procedure:
A solution of thiazole (10.0 g), iodobenzene (2.63 ml), tetrakis(triphenylphosphine)palladium (0) (1.36 g) and potassium acetate (3.46 g) in N,N-dimethylacetamide (100 ml) was stirred under heating at 100° C. overnight. The solvent was evaporated under reduced pressure, and added to the residue was ethyl acetate. The mixture was washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-90:10) to give 5-phenylthiazole (1.50 g) as a pale yellow solid. APCI-Mass m/Z 162 (M+H). (2) The above 5-phenylthiazole and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 100 to give 5-bromo-2-chloro-1-(5-phenyl-2-thiazolylmethyl)benzene as a yellow solid. APCI-Mass m/Z 364/366 (M+H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.[OH-].[Na+]>O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1
Reactant: OCCOCCc1ccccn1
Reactant: BrCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCOCCc1ccccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.5 %

Procedure:
A mixture of 2-[2-(2-pyridinyl)ethoxy]ethanol hydrochloride (1.55 g), 1,6-dibromohexane (5.94 g), TAB (0.5 g) and 50% sodium hydroxide (15 ml) was stirred at room temperature under nitrogen for 5 h. The mixture was diluted with water (100 ml), extracted with diethyl ether (2×150 ml) and evaporated in vacuo to give an oil. The residual oil was partitioned between 2N hydrochloric acid (100 ml) and hexane (2×100 ml). The aqueous phase was basified to pH12 with 50% sodium hydroxide, extracted with diethyl ether (2×150 ml), dried and evaporated in vacuo to give an oil. Purification by FCC eluting with System F (2:1→1:1) gave the title compound (1.62 g) as a colourless oil. T.l.c. (diethyl ether) Rf 0.40
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([F:24])[C:15]=1[O:25][C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=1.Cl>C(OCC)(=O)C>[CH2:8]([NH:10][C:11]([N:28]1[C:29]([CH3:31])=[CH:30][C:26]([O:25][C:15]2[C:16]([F:24])=[CH:17][C:18]([C:20]([F:23])([F:21])[F:22])=[CH:19][C:14]=2[Cl:13])=[N:27]1)=[O:12])[CH3:9]
Reactant: CCN=C=O
Reactant: Cc1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)n[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2c(F)cc(C(F)(F)F)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
Triethylamine (2.02 g, 20.0 mmol) and ethyl isocyanate (1.42 g, 20.0 mmol) were added to an ethyl acetate (50 mL) solution of 3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole (5.33 g, 18.0 mmol), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into 2 mol/L hydrochloric acid, followed by extraction with ethyl acetate (50 mL×3 times). The organic layer was washed with water and dried over anhydrous magnesium sulfate. Then, the desiccant was removed by filtering and the solvent was distilled off the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane= 1/10) to give a white solid of N-ethyl-3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (5.37 g, yield: 81.6%). Melting point: 84˜86° C., 1H-NMR (Acetone-d6, Acetone, ppm): δ1.10 (t, J=7.2 Hz, 3H), 2.55 (d, J=0.9 Hz, 3H), 3.26 (dq, J=6.1 and 7.2 Hz, 2H), 5.98 (q, J=0.9 Hz, 1H), 7.39˜7.48 (brt, J=6.1 Hz, 1H), 7.75 (ddq, J=2.1 and JHF=0.7 and 9.7 Hz, 1H), 7.82 (dq, 1H, J=2.1 and JHF=0.7 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[CH:15]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])([CH3:17])[CH3:16].O>C(O)C>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][N:8]=1)[N:5]=[CH:4][C:3]([C:13]#[N:14])=[C:2]2[NH:21][C:20]1[CH:22]=[CH:23][CH:24]=[C:18]([CH:15]([CH3:17])[CH3:16])[CH:19]=1
Reactant: CC(C)c1cccc(N)c1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Solvent: CCO
Solvent: O
Product: CC(C)c1cccc(Nc2c(C#N)cnc3cnc(F)cc23)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.4 %

Procedure:
A solution of 4-chloro-6-fluoro-[1,7]naphthyridine-3-carbonitrile (0.75 g, 3.62 mmol) and 3-isopropylaniline (0.82 mL, 5.79 mmol) in ethanol (11 mL) was heated to 80° C. for 10 hours. The reaction was cooled to 0° C., water was added and the mixture was stirred for 15 minutes. The product was filtered, washed with water and dried in the vacuum oven to provide pure 6-fluoro-4-[(3-isopropylphenyl)amino]-1,7-naphthyridine-3-carbonitrile (0.88 g, 80%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.2 (d, J=7.1 Hz, 6 H) 2.9 (dq, J=6.9 Hz, 1 H) 7.2 (m, 3 H) 7.4 (t, J=7.8 Hz, 1 H) 8.2 (s, 1 H) 8.6 (s, 1 H) 9.1 (s, 1 H) 10.1 (s, 1 H).
Reaction SMILES: [Br-].C([P+](CCCC)(CCCC)[CH:7]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=2[C:9](=[O:16])[O:8]1)CCC.[F:25][C:26]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][C:27]=1[C:28]#[N:29].C(N(CC)CC)C>ClCCl>[F:25][C:26]1[CH:33]=[CH:32][C:31]([CH:34]=[C:7]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[C:9](=[O:16])[O:8]2)=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: CCCC[P+](CCCC)(CCCC)C1OC(=O)C2=C1CCCC2
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(C=C2OC(=O)C3=C2CCCC3)ccc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of EXAMPLE 1B (3.05 g) in dichloromethane (30 mL) was added 2-fluoro-5-formylbenzonitrile (1.08 g) and triethylamine (1.02 mL). The mixture was stirred at ambient temperature for 16 hours and concentrated. The concentrate was partitioned between ethyl acetate and brine. The organic layer was washed with brine and concentrated. The concentrate was purified by flash chromatography on silica gel with 50% ethyl acetate in hexane.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Brc1cccnc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(C#Cc4cccnc4)c3n2)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 3-bromopyridine [CAS 626-55-1; commercially available] (158 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (94 mg, 22%). MS (ISP) 433.3 [(M+H)+]; mp 187–188° C.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16].C(OCC)C>C1(C)C=CC=CC=1.[OH-].[Na+]>[CH2:1]([O:8][C:9]([NH:12][CH2:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CN)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(CNC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 41.7 ml of chloroformic acid benzyl ester (90%) in toluene is added to 25 g of 3-amino-2(R,S)-methylpropionic acid in 533 ml of 1N sodium hydroxide at 0° C. The reaction mixture is then stirred for 30 minutes at 0° C. After the addition of 400 ml of diethyl ether, the aqueous phase is removed and 140 ml of 4N hydrochloric acid are added. The crude title compound is obtained from the organic phase by extraction with diethyl ether: Rf (dichloromethane/methanol=8:2)=0.41.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=1[OH:14])(=[O:5])=[O:4].[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[O:25]>CN(C)C=O.C(OCC)(=O)C>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([NH:13][C:8]1[CH:9]=[CH:10][C:11]([Cl:12])=[C:6]([S:3]([N:2]([CH3:15])[CH3:1])(=[O:5])=[O:4])[C:7]=1[OH:14])=[O:25]
Reactant: O=C=Nc1ccccc1Br
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Br)c1O
Yield: 61.3 %

Procedure:
A solution of N,N-dimethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (80 mg, 0.32 mmol) and 2-bromophenylisocyanate (47 μL, 0.38 mmol) in 2 mL of N,N-dimethylformamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (20/80, v/v), followed by recrystallization from ethyl acetate and hexane, gave the desired product (88 mg, 62%). EI-MS (m/z) 446.2, 448.3, 450.3 (M−).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>O1CCOCC1>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([C:28]3[NH:27][CH:31]=[CH:30][N:29]=3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccccc4)ncnc23)CC1
Reactant: c1c[nH]cn1
Solvent: C1COCCO1
Product: O=S1CCN(c2nc(-c3ncc[nH]3)nc3c(SCc4ccccc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 8-benzylthio-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido[5,4-d]pyrimidine and imidazole by refluxing for six hours in dioxane.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[C@@H:31](O)[CH2:32][N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[C@H:31]([O:1][C:2]1[C:3]([CH2:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2)[CH2:32][N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1
Reactant: O=C1CCCc2c1ccc(O)c2CS(=O)(=O)c1ccccn1
Reactant: O[C@@H](Cn1ccnc1)c1ccc(F)cc1F
Product: O=C1CCCc2c1ccc(O[C@H](Cn1ccnc1)c1ccc(F)cc1F)c2CS(=O)(=O)c1ccccn1

Procedure:
The title compound was prepared using the procedure of Example 10, step (b) using 6-Hydroxy-5-(pyridine-2-sulfonylmethyl)-3,4-dihydro-2H-naphthalen-1-one and (R)-1-(2,4-difluoro-phenyl)-2-Imidazol-1-yl-ethanol.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][C:7]([C:11]1[CH:12]=[C:13]([CH:21]3[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]3)[N:14]3[C:19]=1[C:18]([NH2:20])=[N:17][CH:16]=[N:15]3)=[CH:6]2.[C:38](Cl)(=[O:40])[CH3:39]>ClCCCl.N1C=CC=CC=1>[NH2:20][C:18]1[C:19]2=[C:11]([C:7]3[CH:8]=[CH:9][C:10]4[C:5]([CH:6]=3)=[N:4][N:3]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:2]=4[NH:1][C:38](=[O:40])[CH3:39])[CH:12]=[C:13]([CH:21]3[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]3)[N:14]2[N:15]=[CH:16][N:17]=1
Reactant: CC(=O)Cl
Reactant: CS(=O)(=O)N1CCC(c2cc(-c3ccc4c(N)n(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1c2ccc(-c3cc(C4CCN(S(C)(=O)=O)CC4)n4ncnc(N)c34)cc2nn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.6 %

Procedure:
To a suspension of 5-(3-Amino-2-benzyl-2H-indazol-6-yl)-7-(1-methanesulfonyl-piperidin-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (150 mg, 0.29 mmol) in DCE (2.9 mL) and pyridine (0.29 mL) was added acetyl chloride (20 μl, 0.38 mmol, 1.3 mmol), and the reaction mixture was stirred at rt under N2 for 18 h. The mixture was partitioned between EtOAc and water. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified via preparative HPLC. The product containing fractions were collected, and the TFA from the eluent was removed via filtration through an acidic resin followed by washing with acetonitrile. The product was then eluted with 2M NH3 in MeOH. The MeOH was removed and the residue was crystallized from DCM-hexane to provide the title compound (14 mg, 9%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.91 (s, 1H), 7.58 (d, 1H), 7.51 (s, 1H), 7.35 to 7.22 (m, 5H), 7.14 (dd, 1H), 6.65 (s, 1H), 5.49 (s, 2H), 3.68 to 3.64 (m, 2H), 3.26 (dt, 1H), 2.92 to 2.86 (m, 5H), 2.16 to 2.07 (m, 5H), 1.77 to 1.73 (m, 2H); ES-MS m/z 559.4 [M+H]+, RT (min) 2.39.