Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[C@H:13]([N:17]2[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:18]2=[O:24])[O:12][C@@:11]1([F:34])[CH2:25]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.N.C[OH:37]>>[F:16][C@:14]1([CH3:15])[C@H:10]([OH:9])[C@@:11]([F:34])([CH2:25][OH:37])[O:12][C@H:13]1[N:17]1[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:18]1=[O:24]
Reactant: C[C@]1(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@@](F)(CC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: CO
Agent: N
Product: C[C@]1(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@](F)(CO)[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
Chiral (2R,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,4-difluor-O-2-benzoylmethyl-4-methyl-tetrahydrofuran-3-yl benzoate (0.34 g, 0.7 mmol) was dissolved into methanol, and a solution of ammonia in methanol (7 N, 20 mL) was added. The reaction mixture was stirred at room temperature for overnight. The mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM:MeOH=20:1) and pre-HPLC to afford the title compound as a white solid (0.074 g, 38%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH2:5])[CH3:2].[C:10]([C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])[C:17](O)=[O:18])([CH3:13])([CH3:12])[CH3:11]>>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH:5][C:17](=[O:18])[C:16]1[CH:20]=[C:21]([C:24]([CH3:25])([CH3:26])[CH3:27])[C:22]([OH:23])=[C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:15]=1)[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: CCCCC(CC)CN
Product: CCCCC(CC)CNC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
In the manner of Example 7, 2-ethylhexylamine was reacted with 3,5-di-t-butyl-4-hydroxybenzoic acid to produce N-(2-ethylhexyl)-3,5-di-t-butyl-4-hydroxybenzamide; melting point 136°-140°C. When tested by the procedure of Example 2, this compound lasted 1000 hours, about 3.3 times as long as the control.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].[H-].[Na+].Cl[CH2:13][CH2:14][N:15]([CH2:17][CH2:18]Cl)[CH3:16]>CS(C)=O.Cl>[CH3:16][N:15]1[CH2:17][CH2:18][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)([C:8]#[N:9])[CH2:13][CH2:14]1
Reactant: CN(CCCl)CCCl
Reactant: N#CCc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN1CCC(C#N)(c2ccccn2)CC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
A solution of 2-pyridyl acetonitrile (1.0 g, 8.54 mmol) in DMSO (8 mL) was treated with sodium hydride (1.195 g, 29.88 mmol) portionwise. The resulting brown suspension was stirred at 23° C. for 30 minutes. 2-Chloro-N-(2-chloroethyl)-N-methylethanamine (1.81 g, 9.39 mmol) was then slowly added over 5 minutes, then the suspension was heated at 65° C. overnight. The reaction was then diluted with 1N hydrochloric acid and washed with ethyl acetate (2×). The aqueous phase was basified with 1N sodium hydroxide and extracted with ethyl acetate (3×). The combined extracts were washed with water (5×) and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil. This was purified on Biotage silica gel column (1% to 10% (methanol+1% ammonia) in dichloromethane) to give the desired product as an oil (0.583 g, 34%). 1H NMR (400 MHz, CDCl3) δ ppm: 2.14-2.25 (2H, m), 2.30-2.38 (2H, m), 2.40 (3H, s), 2.51 (td, J=12.25 and 2.27 Hz), 2.99 (2H, d, J=12.13 Hz), 7.25-7.36 (1H, m), 7.56 (1H, d, J=8.08 Hz), 7.75 (1H, td, J=7.71 and 1.77 Hz), 8.64 (1H, d, J=4.80 Hz). LC/MS (M+H)+: 202. HPLC ret. time (Condition E): 1.025 min.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH:11]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:12]([O:14]CC)=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[Li+].[OH-].OP(O)(O)=O>CO.O>[C:21]([O:20][C:18](=[O:19])[CH2:17][CH:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]=[CH:1]2)[C:12]([OH:14])=[O:13])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)c1cccc2cnccc12
Agent: O=P(O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CC(C(=O)O)c1cccc2cnccc12

Procedure:
4-Tert-butyl 1-ethyl 2-(5-isoquinolinyl)succinate (1.00 g, 3.04 mmol) and LiOH (0.29 g) were stirred in MeOH:H2O (3:1, 20 mL) at room temperature for 5 hours. The solution was poured into aqueous H3PO4 (0.1M, 30 mL) and extracted with CHCl3:IPA (3:1, 30 mL×3). The extracts were combined, dried (MgSO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound. MS (ESI+) m/z 302 (M+H)+; MS (ESI−) m/z 300 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.28 (s, 9H), 2.74 (dd, J1 16.7, J2 6.1, 1H), 3.10 (dd, J1 9.5, J2 6.1, 1H), 4.68 (dd, J1 16.7, J2 9.5, 1H), 7.70 (m, 2H), 8.05 (m, 2H), 8.57 (d, J 6.1, 1H), 9.33 (s, 1H); Anal. Calcd for C17H19NO4+1.25 H2O: C, 63.05; H, 6.69. Found: C, 63.27; H, 6.95.
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH3:23])[C:16]=2[F:24])=[CH:11][C:10]1=[O:25])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1>[CH2:22]([O:21][C:17]1[C:16]([F:24])=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:26])=[O:2])[C:10](=[O:25])[CH:11]=1)[CH3:23]
Reactant: CCOc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)OC)C2)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Temperature: 25 °C
Yield: 81.3 %

Procedure:
To a solution containing (S)-2-[4-(3-ethoxy-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (2.40 g, 0.007 mol) in tetrahydrofuran (40 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 30 mL, 0.015 mol). The mixture was stirred at room temperature for 2H, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-2-[4-(3-ethoxy-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (2.00 g, 87%) as a white solid after triturating with diethyl ether.
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[N:22]=[C:21]([CH3:23])[C:20](=[O:24])[N:19]([CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:18][C:17]=3[CH:33]=2)=[O:11])=[CH:6][CH:5]=1.FC(F)(F)C([O-])=O>>[NH2:1][N:2]=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:22][CH:21]([CH3:23])[C:20](=[O:24])[N:19]([CH2:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:18][C:17]=3[CH:33]=2)=[O:11])=[CH:8][CH:9]=1
Reactant: CC1=Nc2ccc(NC(=O)c3ccc(C=NN)cc3)cc2CN(CCc2ccccc2)C1=O
Agent: O=C([O-])C(F)(F)F
Product: CC1Nc2ccc(NC(=O)c3ccc(C=NN)cc3)cc2CN(CCc2ccccc2)C1=O

Procedure:
7-[[[4-(aminoiminomethyl)phenyl]carbonyl]-amino]-2-methyl-3-oxo-4-(2-phenylethyl)-4,5-dihydro-3H-1,4-benzodiazepine, trifluoroacetate;
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[C:32]([Cl:34])[CH:33]=1)[CH2:30][C:29](=O)[CH2:28][CH2:27]2>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:29]2[CH2:28][CH2:27][C:26]3[C:31](=[C:32]([Cl:34])[CH:33]=[C:24]([Cl:23])[CH:25]=3)[CH2:30]2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=C1CCc2cc(Cl)cc(Cl)c2C1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Product: CCCC(NC1CCc2cc(Cl)cc(Cl)c2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 6,8-dichloro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 19.6, 24.3, 26.6, 26.6, 26.7, 28.5, 29.5, 34.0, 34.7, 36.6, 52.5, 53.2, 56.0, 59.1, 59.2, 60.1, 60.8, 67.3, 104.8, 126.7, 127.2, 127.3, 131.1, 131.5, 131.7, 131.8, 131.9, 135.3, 137.3, 139.7, 140.0, 172.2, 172.4; MS m/z 506.4, 508.4 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:29]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:30])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: O=C(Cl)N1CCOCC1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)N1CCOCC1
Yield: 77.4 %

Procedure:
Using the general method of Example 143, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 5.01 mmol) was reacted with 4-morpholinecarbonyl chloride (830 mg, 5.51 mmol) to provide 1.6 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}morpholine-4-carboxamide as a white powder, m.p. 194-196° C. Analysis: Calculated for C21H28N6O3: %C, 61.15; %H, 6.84; %N, 20.37; Found: %C, 60.82; %H, 6.94; %N, 20.34.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[C:22]([CH2:24][OH:25])[CH:23]=1>>[O:16]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:11]([N:29]2[CH2:28][CH2:27][N:26]([C:21]3[CH:20]=[CH:19][C:18]([CH3:17])=[CH:23][C:22]=3[CH2:24][OH:25])[CH2:31][CH2:30]2)=[O:13])=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Reactant: Cc1ccc(N2CCNCC2)c(CO)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3)CC2)c(CO)c1
Yield: 27 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (550 mg) described in Preparation Example 16 and [5-methyl-2-(piperazin-1-yl)phenyl]methanol (470 mg) described in Preparation Example 99 and by the reaction and treatment in the same manner as in Example 87, the title compound (264 mg) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=4)[N:13]([CH3:24])[CH:12]=3)=[CH:10][C:3]=12.[CH3:35][N:36](C)C(=O)C>[Zn].[C-]#N.[Zn+2].[C-]#N>[C:35]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=4)[N:13]([CH3:24])[CH:12]=3)=[CH:10][C:3]=12)#[N:36]
Reactant: CC(=O)N(C)C
Reactant: COC(=O)c1ccc2c(c1)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Product: COC(=O)c1ccc2c(c1)c(-c1cc3c(C#N)ccnc3[nH]1)cn2C
Temperature: 140 °C

Procedure:
A mixture of 3-[4-chloro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-yl]-1-methyl-1H-indole-5-carboxylic acid, methyl ester [0.4 g, Reference Example 2(r)], zinc powder (0.05 g), zinc cyanide (0.117 g), [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium (II) complex with dichlroromethane (catalytic) and N,N-dimethylacetamide (8 mL) was heated at 130-150° C. for 5 hours. The reaction mixture was cooled, filtered and the precipitated washed with dimethylformamide (2 mL). The filtrate was diluted with ethyl acetate (120 mL) and the solution extracted with water (2×20 mL). The combined organic layer was evaporated and the residue subjected to flash column chromatography on silica gel eluting with a mixture of heptane and ethyl acetate (7:3 v/v) moving to neat ethyl acetate to give the title compound (0.12 g) as a bright yellow solid. MS: 331(MH+). HPLC(Method C): RT=4.01 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][NH:12][CH2:13]2.C(N(CC)CC)C.[C:28](Cl)(=[O:32])[CH2:29][CH2:30][CH3:31]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][N:12]([C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH2:13]2
Reactant: CCCC(=O)Cl
Reactant: O=[N+]([O-])c1cc2c(c(-c3ccccc3Cl)c1)CCNC2
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCc2c(cc([N+](=O)[O-])cc2-c2ccccc2Cl)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 47 %

Procedure:
5-(2-chlorophenyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline (0.065 g, 0.2 mmoles) was dissolved in anhydrous dimethylacetamide (1 ml) followed by the addition of triethylamine (0.068 mls) and butyryl chloride (0.0253 mls, 0.24 mmoles) followed finally by N,N-dimethylamino pyridine (catalytic amount). The reaction was left stirring at room temperature for 2.5 hours and the solution purified by automated C18 HPLC purification (0.0336 g, 47% yield, 100% pure, CO-AAW00017).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([OH:18])([CH3:17])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](F)(=[O:15])=[O:14])=[CH:9][CH:8]=1)=[O:5].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C)C1C=CN=CC=1.C(#N)C.O>[F:1][C:2]([F:20])([F:19])[C:3]([OH:18])([CH3:17])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)=[O:5]
Reactant: CC(O)(C(=O)Nc1ccc(S(=O)(=O)F)cc1)C(F)(F)F
Reactant: C1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC#N
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)N2CCCCC2)cc1)C(F)(F)F
Temperature: 22 °C
Yield: 82.9 %

Procedure:
A solution of 3,3,3-trifluoro-N-[4-(fluorosulfonyl)phenyl]-2-hydroxy-2-methylpropanamide (0.2 g), piperidine (0.1 g), and 4-dimethylaminopyridine (5 mg) in dry acetonitrile (4 ml) was heated at reflux for 3 hours. After cooling to 22° C., the reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with 1N HCl, brine, dried (Na2SO4), and the solvent evaporated under reduced pressure. Recrystallization from methyl-t-butyl ether/hexane gave the title compound as a colourless crystalline solid, (0.2 g); mp 164°-166° C.; MS: m/z=381(M+1); NMR (250 MHz, CDCl3): 1.42 (m, 2), 1.64 (m, 4), 1.77 (s,3), 2.97 (t,4), 3.79 (s,1), 7.73 (s), 8.67 (s,1). Analysis for C15H19F3N2 04S: Calculated: C, 47.36; H, 5.03; N, 7.37. Found: C, 47.38; H, 5.16; N, 7.30.
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[C:28]([CH3:33])=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH3:33][C:28]1[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:32][CH:31]=[CH:30][N:29]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1ncccc1Br
Product: Cc1ncccc1C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

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-bromo-2-methyl-pyridine [CAS 38749-79-0; commercially available] (252 mg, 1.3 mmol) according to general procedure II. Obtained as a light brown solid (270 mg, 60%). MS (ISP) 447.0 [(M+H)+]; mp 198° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([NH2:24])[CH:22]=2)[CH2:17][CH2:16]1.N1C=CC=CC=1.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([NH:24][C:31](=[O:33])[CH3:32])[CH:22]=2)[CH2:17][CH2:16]1
Reactant: CC(=O)Cl
Reactant: COc1cc2ncnc(N3CCc4ccc(N)cc43)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc2ncnc(N3CCc4ccc(NC(C)=O)cc43)c2cc1OC
Yield: 68.8 %

Procedure:
To 1-(6,7-dimethoxy-quinazolin-4-yl)-2,3-dihydro-1H-indol-6-ylamine (99 mg, 0.307 mmol; from Example 30) and pyridine (32 μL, 0.620 mmol) in CHCl3 (5 mL) was added acetyl chloride (33 μL, 0.455 mmol). The mixture was refluxed 2 hours, diluted with CHCl3 (15 mL), and the organic solution was washed with saturated aqueous NaHCO3, dried over Na2SO4(s), filtered and concentrated in vacuo. Flash chromatography on silica (5% MeOH/CHCl3) afforded 77 mg of product. (M.P. 223°-229° C. (dec); GC-MS: 364 (M+); anal. RP18-HPLC RT: 3.42 min.).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][CH2:25][C:26]([F:38])([F:37])[C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])[CH:6]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:47])C=1>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16]([CH2:17][C:18]([F:21])([F:20])[F:19])=[O:47])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][CH2:25][C:26]([F:37])([F:38])[C:27]([F:35])([F:36])[C:28]([F:34])([F:33])[C:29]([F:30])([F:31])[F:32])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)Nc1cc(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)F)c(C)cc1F
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
0.2 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,4,4,5,5,5-nonafluoropentyloxy)pyrazole was dissolved in 10 mL of chloroform, and 77 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 30 minutes under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous potassium carbonate solution, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.19 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-(2,2,3,3,4,4,5,5,5-nonafluoropentyloxy)pyrazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=1[C:24](=O)[CH3:25].Cl.[NH2:28][OH:29].C(N(CC)CC)C>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=1[C:24](=[N:28][OH:29])[CH3:25]
Reactant: NO
Reactant: COc1cc2nccc(Oc3cc(C)c(C)cc3C(C)=O)c2cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2nccc(Oc3cc(C)c(C)cc3C(C)=NO)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-4,5-dimethylphenyl]-1-ethanone (compound 38) (30 mg) was dissolved in ethanol (1 ml) to prepare a solution. Hydroxylamine hydrochloride (12 mg) and triethylamine (27 mg) were added to the solution, and the mixture was stirred at room temperature overnight. Further, hydroxylamine hydrochloride (12 mg) and triethylamine (27 mg) were then added to the reaction solution, and the mixture was stirred at room temperature for 5 hr. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (10 mg, yield 31%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[I:7][C:8]1[CH:9]=[C:10]([OH:18])[C:11](=[CH:16][CH:17]=1)[C:12]([O:14][CH3:15])=[O:13].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC#N>[CH2:19]([O:18][C:10]1[CH:9]=[C:8]([I:7])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(I)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(I)cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
Solid K2CO3 (76.1 g, 0.55 mol) was added to a solution of methyl 4-iodosalicylate (1) (76.5 g, 0.28 mol) in MeCN (550 mL) at RT. Benzyl bromide (32.7 mL, 0.28 mol) was added via syringe, and the resulting reaction mixture was warmed to 80° C. and stirred overnight. The reaction mixture was then cooled to RT and filtered subsequently to remove insoluble salts, which were washed further with EtOAc. The filtrate was concentrated in vacuo, before re-dissolving the residue in fresh EtOAc and filtering a second time. The filtrate was concentrated in vacuo to provide an oil which solidified upon standing to yield 2 (99%, 100.5 g) as a beige solid that required no further purification. 1H NMR (500 MHz, CDCl3, 25° C.): δ=7.54 (d, J=8.0 Hz, 1H), 7.49 (d, J=7.5 Hz, 2H), 7.43-7.35 (m, 4H), 7.33 (t, J=7.5 Hz, 1H), 5.15 (s, 2H), 3.89 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3, 25° C.): δ=166.3, 158.4, 136.2, 133.1, 130.1, 128.8, 128.1, 127.0, 123.3, 120.3, 100.0, 71.0, 52.3 ppm. HRMS (ESI) calculated for C15H14IO3: m/z=367.9909 ([M+H]+); Found m/z=367.9893.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24]C)=[O:23])=[C:16]3[O:26][CH2:27][O:28][C:15]=13)=[CH:10][C:9]([O:29][CH3:30])=[C:8]([O:31][CH3:32])[CH:7]=2)#[N:2].[OH-].[Na+]>CO>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[C:16]3[O:26][CH2:27][O:28][C:15]=13)=[CH:10][C:9]([O:29][CH3:30])=[C:8]([O:31][CH3:32])[CH:7]=2)#[N:2]
Reactant: COC(=O)/C=C/c1ccc(Nc2c(C#N)cnc3cc(OC)c(OC)cc23)c2c1OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2ncc(C#N)c(Nc3ccc(/C=C/C(=O)O)c4c3OCO4)c2cc1OC
Temperature: 40 °C

Procedure:
A mixture of methyl (2E)-3-[4(3-cyano-6,7-dimethoxyquinolin-4-ylamino)-2,3-methylenedioxyphenyl]acrylate (0.75 g), a 1N aqueous sodium hydroxide solution (12 ml) and methanol (45 ml) was stirred and warmed to 40° C. for 12 hours. The reaction mixture was evaporated. Water was added and the mixture was acidified by the addition of 2N aqueous hydrochloric acid solution. The resultant precipitate was isolated and dried. There was thus obtained the title compound as a solid (0.703 g); NMR Spectrum: (DMSOd6) 3.98 (s, 6H), 6.19 (s, 2H), 6.59 (d, 1H), 7.02 (d, 1H), 7.28 (d, 1H), 7.48 (s, 1H), 7.55 (d, 1H), 8.09 (s, 1H), 8.95 (s, 1H); Mass Spectrum: M+H+ 420.
Reaction SMILES: [BH4-].[Na+].[Br-].[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][C:16]1[CH:17]=[N+:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:20][CH:21]=1>CO>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][C:16]1[CH2:17][N:18]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:20][CH:21]=1
Reactant: COc1ccc2[nH]cc(Cc3ccc[n+](Cc4ccccc4)c3)c2c1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2[nH]cc(CC3=CCCN(Cc4ccccc4)C3)c2c1

Procedure:
Sodium borohydride in pellets (1.5 g; 0.0396 mol) was added to a cold (0° C.) stirring mixture of 3[(5-methoxy-1H-indol-3-yl)methyl]-1-benzyl-pyridinium bromide (5.8 g; 0,0141 mol) in methanol (130 ml). The reaction mixture was stirred at 0° C. for 2 hours. The product precipitated as a whitepink solid was filtered and washed with cold methanol and dried under vacuum.