Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9]Br.[C-:11]#[N:12].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:11]#[N:12]
Reactant: [C-]#N
Reactant: Clc1ccc(CBr)c(Br)c1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(Cl)cc1Br
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
A mixture of 2-bromo-1-(bromomethyl)-4-chlorobenzene (9.8 g; 34.5 mmol) and sodium cyanide (2.0 g; 41.4 mmol) in 15 mL of 95% ethanol and 2.5 mL water was stirred and heated to reflux. After 30 minutes, the solvent was evaporated and the residue was partitioned between 100 mL ether and 50 mL water. The organic layer was dried over sodium sulfate and evaporated. The residual solid was washed out of the flask with hexane and collected by filtration, washed with hexane, and air-dried on the filter to give 4.82 g of 2-(2-bromo-4-chlorophenyl)acetonitrile as a light yellow solid.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]=O)[C:4]([S:9]([O-:12])(=[O:11])=[O:10])=[CH:3][CH:2]=1.[Na+:13].[CH3:14][C:15]1[CH2:19][C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:16]=1.C(N(CC)CC)C>C(O)C>[CH3:14][C:15]1[C:19](=[CH:7][C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[S:9]([O-:12])(=[O:11])=[O:10])[C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:16]=1.[Na+:13]
Reactant: O=Cc1ccccc1S(=O)(=O)[O-]
Reactant: CC1=NN(c2ccccc2)C(=O)C1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1=NN(c2ccccc2)C(=O)C1=Cc1ccccc1S(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
2.1 g of sodium benzaldehyde-2-sulfonate, 1.75 g of 3-methyl-1-phenyl-2-pyrazolin-5-one and 1 g of triethylamine in 20 mL of ethanol were allowed to reflux 5 hours. After cooling to room temperature, the precipitate was filtered off and dried.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:36])[CH:12]([C:19]2[N:20]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:21]=[C:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]=23)[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:6]([F:37])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([N:20]2[C:19]([CH:12]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:38])=[O:2])=[CH:5][C:6]=3[F:37])=[O:36])=[C:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:22]3=[N:21]2)=[CH:34][CH:33]=1
Reactant: COC(=O)c1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCCC3)C2CCCCC2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCCC3)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 2, 4-{2-[2-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazol-3-yl]-2-cyclohexyl-acetylamino}-3-fluoro-benzoic acid methyl ester (example 12) was hydrolysed using aqueous lithium hydroxide solution in THF and MeOH to give the title compound as white solid. MS: m/e=524.2 [M+H+].
Reaction SMILES: C[O:2][C:3](=[O:48])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH:7]=[C:6]([O:29][CH2:30][CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:36][CH:35]=2)[CH:5]=1.[OH-].[Na+]>CO.O1CCOCC1>[C:42]1([CH2:41][O:40][C:37]2[CH:38]=[CH:39][C:34]([O:33][CH2:32][CH2:31][CH2:30][O:29][C:6]3[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]4[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[CH:19][CH:20]=4)[CH:7]=3)[C:3]([OH:48])=[O:2])=[CH:35][CH:36]=2)[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: COC(=O)c1cc(OCCCOc2ccc(OCc3ccccc3)cc2)cc(OCCCOc2ccc(OCc3ccccc3)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)c1cc(OCCCOc2ccc(OCc3ccccc3)cc2)cc(OCCCOc2ccc(OCc3ccccc3)cc2)c1
Yield: 93.8 %

Procedure:
A solution of 1.5 g (2.3 mmol) of 3,5-bis[3-[4-(phenylmethoxy) phenoxy]propoxy]benzoic acid methyl ester (prepared in Example 46) and 1.2 ml (7.2 mmol) of 6N NaOH in 25 ml of methanol and 10 ml of dioxane was stirred at reflux under argon for 19 hours. The solvents were removed at reduced pressure, the residue was acidified and the product was extracted with ethyl acetate. The dried extract was concentrated to a solid which was recrystallized from acetone-hexane to give 1.37 g (93% yield, mp 139°-140°) of 3,5-bis[3-[4-(phenylmethoxy)phenoxy]propoxy]benzoic acid.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH2:15])[O:7][CH2:6]1)[CH2:2][CH3:3].CO[CH:21]1[CH2:25][CH2:24][CH:23](OC)O1.[OH-].[Na+]>C(O)(=O)C>[CH2:16]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N:15]2[CH:21]=[CH:25][CH:24]=[CH:23]2)[O:7][CH2:6]1)[CH2:17][CH3:18]
Reactant: CCCN(CCC)C1COc2cccc(N)c2C1
Reactant: COC1CCC(OC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCCN(CCC)C1COc2cccc(-n3cccc3)c2C1

Procedure:
3-Dipropylamino-5-aminochroman (Example 14; 0.60 g, 2.42 mmol) was dissolved in acetic acid (10 ml) and 2,5-dimethoxytetrahydrofuran (0.40 g, 3.0 mmol) was added. The solution was refluxed for 1 hour. The solution was neutralized with NaOH (aq.) and extracted with toluene. The organic phase was dried with sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel by elution with ethyl acetate/hexane 1:9 to give the title compound. 13C-NMR: 111.75 21.89 24.81 52.69 53.15 67.94 108.93 115.67 118.22 118.44 121.87 127.22 141.47 155.27
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:4][C:3]=1[NH2:16].O.O.[C:19](O)(=[O:23])[C:20](O)=[O:21]>Cl>[OH:21][C:20]1[C:19]([OH:23])=[N:16][C:3]2[CH:4]=[C:5]([S:12](=[O:15])(=[O:14])[NH2:13])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[N:1]=1
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc(S(N)(=O)=O)c2ccccc2c1N
Agent: Cl
Solvent: O
Product: NS(=O)(=O)c1cc2nc(O)c(O)nc2c2ccccc12
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of 1.0 g (3.4 mmol) 1,2-diamino-4-sulphamoyl-naphtalene and 1.0 (7.9 mmol) oxalic acid dihydrate in 20 ml 2N HCl was refluxed for 2 hours. After cooling to room temperature the precipitate was filtered off and washed with water. The crude product was recrystallized from dimethylformamide/water to give 0.6 g (50%) of the title compound.
Reaction SMILES: [CH:1]([N:4]1[C:8]([NH:9][C:10]2[C:11](=[CH:15][C:16]([S:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[C:12](O)=O)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:31]>>[CH:1]([N:4]1[C:8]2=[N:9][C:10]3[C:11]([C:12]([Cl:31])=[C:7]2[CH:6]=[N:5]1)=[CH:15][C:16]([S:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])(=[O:21])=[O:20])=[CH:17][CH:18]=3)([CH3:3])[CH3:2]
Reactant: CCN(CC)S(=O)(=O)c1ccc(Nc2ccnn2C(C)C)c(C(=O)O)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCN(CC)S(=O)(=O)c1ccc2nc3c(cnn3C(C)C)c(Cl)c2c1
Temperature: 25 °C

Procedure:
A mixture of N-(1-isopropylpyrazol-5-yl)-5-(diethylaminosulfonyl) anthranilic acid (12.0 g, 0.031 mol) and POCl3 (80 mL) was refluxed for 6 hours. The reaction mixture was cooled to room temperature and then was poured into ice-water and neutralized with concentrated NH4OH. The mixture was extracted with CH2Cl2 and the CH2Cl2 layer was dried over MgSO4 and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with CH2Cl2 /ether (9/1) to afford 10 g of crude 1-isopropyl-6-(diethylaminosulfonyl)-4-chloro-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[N:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:19]2[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2OCc2ccncc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cnc(N2CCNCC2)c(OCc2ccncc2)c1
Reaction time: 3 h

Procedure:
The crude 4-[3-(Pyridin-4-ylmethoxy)-pyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (˜500 mg) was dissolved in 10 mL of 30% trifluoroacetic acid in dichloromethane. The reaction mixture was stirred for 3 hr and then the solvent was removed under vacuum. The impure material was used without purification.
Reaction SMILES: C(OC([N:8]1[C:12]2=[CH:13][N:14]=[CH:15][C:16]([C:17]3[CH:22]=[C:21]([C:23]([C:25]4[NH:52][C:28]5=[N:29][C:30]([N:33]6[CH2:38][CH2:37][CH:36]([O:39][P:40]([O:47]C(C)(C)C)([O:42]C(C)(C)C)=[O:41])[CH2:35][CH2:34]6)=[CH:31][CH:32]=[C:27]5[N:26]=4)=[O:24])[CH:20]=[CH:19][C:18]=3[C:53]#[N:54])=[C:11]2[CH:10]=[CH:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[C:53]([C:18]1[CH:19]=[CH:20][C:21]([C:23]([C:25]2[NH:52][C:28]3=[N:29][C:30]([N:33]4[CH2:38][CH2:37][CH:36]([O:39][P:40](=[O:41])([OH:42])[OH:47])[CH2:35][CH2:34]4)=[CH:31][CH:32]=[C:27]3[N:26]=2)=[O:24])=[CH:22][C:17]=1[C:16]1[CH:15]=[N:14][CH:13]=[C:12]2[NH:8][CH:9]=[CH:10][C:11]=12)#[N:54]
Reactant: CC(C)(C)OC(=O)n1ccc2c(-c3cc(C(=O)c4nc5ccc(N6CCC(OP(=O)(OC(C)(C)C)OC(C)(C)C)CC6)nc5[nH]4)ccc3C#N)cncc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)c2nc3ccc(N4CCC(OP(=O)(O)O)CC4)nc3[nH]2)cc1-c1cncc2[nH]ccc12
Temperature: 23 °C
Reaction time: 16 h
Yield: 92.4 %

Procedure:
To a solution of 4-(2-Cyano-5-{5-[4-(di-tert-butoxy-phosphoryloxy)-piperidin-1-yl]-3H-imidazo[4,5-b]pyridine-2-carbonyl}-phenyl)-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (100 mg, 0.132 mmol) (Step 1) in anhydrous CH2Cl2 (5 mL) at 0° C. was added 4M HCl in Dioxane (0.331 mL, 1.32 mmol, 10 eq) and the solution warmed to 23° C. and stirred for 16 hr. The resulting suspension was concentrated under reduced pressure to afford Phosphoric-acid-mono-(1-{2-[4-cyano-3-(1H-pyrrolo[2,3-c]pyridin-4-yl)-benzoyl]-3H-imidazo-[4,5-b]pyridin-5-yl}-piperidin-4-yl)ester as a red-orange solid (75 mg, 0.122 mmol, 92%). HRMS m/z 544.1523 (M+H)+. 1H NMR (400 MHz, MeOD) δ: 9.24 (1H, s), 8.90 (s, 1H), 8.81 (d, J=8 Hz, 1H), 8.58 (s, 1H), 8.34 (d, J=3 Hz, 1H), 8.23 (d, J=8 Hz, 1H), 8.11 (d, J=9 Hz, 1H), 7.29 (d, J=9.5 Hz, 1H), 6.98 (d, J=2.5 Hz, 1H), 4.63 (m, 1H), 3.98 (m, 2H), 3.77 (m, 2H), 2.08 (m, 2H), 1.94 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][CH:13]=2)[C:9]#N)=[CH:4][CH:3]=1.[CH:22]([CH:24]=C)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][CH:13]=3)[CH:22]=[CH:24][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C=CC=O
Reactant: N#CC(Nc1ccc(S(N)(=O)=O)cc1)c1ccc(F)cc1
Product: NS(=O)(=O)c1ccc(-n2cccc2-c2ccc(F)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-fluorophenyl)-α-(4-sulfamoylanilino)acetonitrile [prepared as described in step (ii) above] and acrolein as starting materials, the title compound was obtained as a brown powder (yield 11%), melting at 198-199° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:20][CH2:19]1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([O:45][CH3:46])[C:31]=1[OH:47]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[CH2:20][CH2:19]2)[CH:33]=[C:32]([O:45][CH3:46])[C:31]=1[OH:47]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CCN(CC)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: CCN(CC)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(OC)c4)cc23)CC1

Procedure:
Following general procedure D, {6-bromo-4-[trans-4-(diethylamino)cyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (31 mg, 0.070 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.015 mmol) to afford the desired product (19.7 mg, 54%) as an orange-brown solid: 1H NMR (500 MHz, CD3OD) δ 9.15 (s, 1H), 8.34 (d, J=1.8 Hz, 1H), 8.04 (dd, J=8.7, 1.9 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.31 (d, J=2.1 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 4.20 (s, 1H), 3.99 (s, 3H), 3.12 (q, J=7.2 Hz, 4H), 2.89-2.80 (m, 1H), 2.41 (d, J=10.4 Hz, 2H), 2.15 (d, J=9.8 Hz, 2H), 1.82-1.62 (m, 4H), 1.30 (t, J=7.3 Hz, 6H), 1.23-1.16 (m, 2H), 1.15-1.04 (m, 2H); ESI MS m/z 522 [C30H36ClN3O3+H]+; HPLC 98.5% (AUC), tR=11.05 min.
Reaction SMILES: [Cl:1][CH:2]=[C:3]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][O:4]1.[CH:10]([OH:12])=[O:11]>>[Cl:1][CH2:2][C:3](=[O:4])[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][O:11][CH:10]=[O:12]
Reactant: O=CO
Reactant: CC1(C)CCOC1=CCl
Product: CC(C)(CCOC=O)C(=O)CCl
Yield: 87 %

Procedure:
29.2 g (0.2 mol) of 2-chloromethylene-3,3-dimethyltetrahydrofuran, in 100 ml of formic acid, are heated at 60° for 5 hours. Fractional distillation produces 34 g (0.174 mol, 87%) of 1-chloro-3,3-dimethyl-5-formyloxypentan-2-one with a boiling point of 110°/0.2.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.C[Al](C)C.[NH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23](OC)=[O:24].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:23]([C:19]2[S:20][CH:21]=[CH:22][C:18]=2[NH2:17])=[O:24])=[CH:6][CH:5]=1
Reactant: COC(=O)c1sccc1N
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Nc1ccsc1C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-trifluoromethoxyaniline (7.8 g, 44.5 mmol) in toluene (50 mL) under nitrogen was added trimethylaluminum (2M in toluene, 26.7 mL, 53.4 mmol). The mixture was stirred at RT for 16 h. Methyl 3-amino-2-thiophenecarboxylate (7 g, 44.5 mmol) was added and the resulting solution was stirred at reflux (oil bath temperature: 130° C.) under nitrogen for 24 h. After cooling to RT, saturated sodium bicarbonate solution (100 mL) was added dropwise with caution and the mixture was stirred at RT for 30 min. The product was extracted into dichloromethane (3×100 mL), and the organic layer was dried over Na2SO4, and concentrated to yield a thick oil, which was then triturated with a mixture of hexane/ethyl acetate to afford N-(4-trifluoromethoxyphenyl) 3-Aminothiophene-2-carboxamide as a brown solid. 1H-NMR (400 MHz/CD3OD): δ=6.65 (d, J=5.6 Hz, 1 H), 7.23 (d, J=8.4 Hz, 2 H), 7.39 (d, J=5.2 Hz, 1 H), 7.67 (d, J=9.2 Hz, 2 H). MS (ES+): 303 [MH+].
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[C:18]2[C:13](=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:10]=1>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[C:11]([NH:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1)[N:10]=[C:9]2[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Product: COc1cccc2c(Oc3ccccc3)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 10 was used, starting from phenol and (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methoxy-1-phenoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 337(MH+).
Reaction SMILES: IC.[C:3]([O:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])=[O:14])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:22](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:3]([O:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][CH3:22])=[O:14])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccccc1C(=O)COC(=O)c1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNc1ccccc1C(=O)COC(=O)c1ccccc1
Reaction time: 21 h

Procedure:
Iodomethane (55.8 ml) was added to a stirred suspension of 2-(2-aminophenyl)-2-oxoethyl benzoate (109 g) and potassium carbonate (1 )8 g) in dry dimethylformamide (400 ml) at ambient temperature. The mixture was stirred at this temperature for 21hours and then at 40° for 5 hours. The solvent was removed under reduced pressure at 60°, water (100 ml) was added and the mixture extracted with dichloromethane (3×200 ml). The combined extracts were dried over sodium sulphate and the solvent was removed by evaporation to leave a dark oil. The oil was purified by flash chromatography on a silica gel column eluted with dichloromethane to give the novel compound 2-[2(methylamino)phenyl]-2-oxoethyl benzoate, m.p. 85°-87°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]#[N:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([OH:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1>COCCO.[Pd]>[S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)([OH:24])(=[O:23])=[O:22].[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1)[CH2:12][CH2:13][NH2:14]
Reactant: N#CCc1cc(F)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCO
Product: NCCc1cc(F)cc(C(F)(F)F)c1

Procedure:
A solution of 2.5 g of 3-fluoro-5-trifluoromethylphenylacetonitrile and 2.34 g (12.3 mmol) of p-toluenesulfonic acid in 75 ml of ethylene glycol monomethyl ether is hydrogenated for 3 hours at room temperature at 40 psi, using 200 mg 10% palladium on carbon catalyst. The catalyst is filtered off and the solvent evaporated to half the volume. Upon standing, the p-toluenesulfonic acid salt of the desired 3-fluoro-5-trifluoromethylphenethylamine crystallizes. The white crystals, 4.26 g (91%) are collected by filtration.
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([C:14](Cl)=[O:15])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([N:27]2[CH2:31][CH:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:29][NH:28]2)=[O:26])=[CH:20][CH:19]=1.[OH-].[Na+]>C(Cl)Cl.O.C(Cl)Cl>[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([N:27]2[CH2:31][CH:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:29][N:28]2[C:14]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:13]=2)=[O:15])=[O:26])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccnc(Oc2ccccc2)n1
Reactant: O=C(Cc1ccc(F)cc1)N1CC(N2CCOCC2)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1ccc(F)cc1)N1CC(N2CCOCC2)CN1C(=O)c1ccnc(Oc2ccccc2)n1
Reaction time: 18 h
Yield: 23 %

Procedure:
2-Phenoxypyrimidine-4-carbonyl chloride, 18, (0.07 g, 0.28 mmol) in methylene chloride (1.5 mL) is added dropwise to a suspension of 2-(4-fluorophenyl)-1-(4-morpholin-4-yl-pyrazolidin-1-yl)ethanone, 13, (0.06 g, 0.18 mmol) in a 2:5 water/CH2Cl2 solution (7 mL) containing NaOH (0.0112 g, 0.28 mmol) at room temperature. The solution is stirred 18 hours and diluted with additional 2:5 water/CH2Cl2. The layers are allowed to separate and the aqueous phase extracted with additional methylene chloride. The organic layers are combined, dried, filtered and concentrated in vacuo to afford a tan solid which is purified by preparative HPLC to provide 0.021 g (23% yield) of the desired product as an oily solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10]([N:26]2[CH2:27][CH2:28][N:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=3)[CH2:24][CH2:25]2)=[O:11])[CH2:7]1
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(N1CCN(c2ccccn2)CC1)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
A stirred solution of 2.8 g (0.01 mole) of 3-(3,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 25 ml of tetrahydrofuran was treated in turn with 1.6 g (0.01 mole) of 1-(2-pyridyl)piperazine and 1.4 g (0.01 mole) of potassium carbonate. After 30 min, a solid had precipitated which dissolved when approximately 2 g of ice was added. After stirring for 18 hr, the reaction mixture was diluted with 200 ml of water and a paste-like solid separated which was filtered to yield 3.3 g of crude product. After several attempts to recrystallization from methyl isobutyl ketone, it was recrystallized from acetonitrile to yield 1.25 g (30.7%) of fine white crystals, m.p. 153.5°-154.5° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][N:26]1[CH:30]=[CH:29][N:28]=[C:27]1[SH:31]>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:31][C:27]3[N:26]([CH3:25])[CH:30]=[CH:29][N:28]=3)=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cn1ccnc1S
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3nccn3C)s2)c(C(=O)C2CCCC2)c1
Yield: 31.9 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(1-methyl-1H-imidazol-2-ylsulfanyl)-thiazol-2-yl]-urea (141 mg, 32%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 1-methyl-1H-imidazole-2-thiol (228 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:14]([CH2:30][CH2:31][N:32]=3)[C:15]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=3)=[N:16][C:17]=2[C:18]=1[O:19][CH3:20])C1C=CC=CC=1.C(O)(C(F)(F)F)=O>CO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:14]([CH2:30][CH2:31][N:32]=3)[C:15]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=3)=[N:16][C:17]=2[C:18]=1[O:19][CH3:20]
Reactant: COc1c(OCc2ccccc2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1c(O)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 60 °C
Reaction time: 17 h
Yield: 113.7 %

Procedure:
N-[8-(Benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide (20 g, 45.1 mmol) was added portionwise over 1 h to a round bottom flask containing TFA (400 mL) precooled with an ice bath. The reaction mixture was heated to 60° C. and allowed to stir at this temperature for 17 h at which time it was cooled to room temperature. The reaction mixture was then concentrated under reduced pressure. The resulting residue was dissolved in CH2Cl2 and hexane and concentrated under reduced pressure. The material thus obtained was dissolved in MeOH and CH2Cl2 (250 mL, 1:1) and concentrated under reduced pressure. The resulting solids were dried overnight under vacuum with low heat to give N-(8-hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (17.3 g, 66%): 1H NMR (DMSO-d6+2 drops TFA-d) δ: 13.41 (1H, s), 12.21 (1H, br s), 9.38 (1H, s), 8.78 (1H, d), 8.53 (1H, d), 7.85 (1H, d), 7.59 (1H, m), 7.17 (1H, d), 4.54 (2H, m), 4.21 (2H, m), 3.98 (3H, s); mass spectrum m/z 481 ((M+1)+).