Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:33]=[C:32]([I:34])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH2:35].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:24][C:25]1[CH:33]=[C:32]([I:34])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH:35][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)cc(I)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1

Procedure:
N-(5-chloro-7-iodo-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholin-4ylpropoxy)quinazolin-4-amine was prepared using the method described in example 4 using 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (1.0 g, 2.96 mmol), 5-chloro-7-iodo-1,3-benzodioxol-4-amine (0.97 g, 3.26 mmol) and sodium bis(trimethylsilyl)amide (1.0M in THF, 6.2 ml) in DMF (15 ml). The crude product was obtained as a pale bown solid (1.71 g, 97%) by quenching the reaction mixture with dilute aqueous ammonium chloride solution; Mass Spectrum: M+H+ 599/601.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:22](=[O:23])[C:21]([CH2:24][C:25]5[CH:30]=[CH:29][C:28]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=6[C:37]6[NH:41][C:40](=[O:42])[O:39][N:38]=6)=[CH:27][CH:26]=5)=[C:20]([CH2:43][CH2:44][CH3:45])[N:19]=[C:18]4[CH2:46][CH3:47])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1>O1CCCC1.C(OCC)(=O)C>[CH2:46]([C:18]1[N:17]([C:14]2[CH:13]=[CH:12][C:11]([N:8]3[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]3)=[CH:16][CH:15]=2)[C:22](=[O:23])[C:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][C:40](=[O:42])[O:39][N:38]=3)=[CH:27][CH:26]=2)=[C:20]([CH2:43][CH2:44][CH3:45])[N:19]=1)[CH3:47]
Reactant: CCCc1nc(CC)n(-c2ccc(N3CCC4(CC3)OCCO4)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(N3CCC(=O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Yield: 107.5 %

Procedure:
A solution of 3-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.45 g) in tetrahydrofuran (10 mL)-1 M hydrochloric acid (10 mL) was stirred at 60° C. for 2 days. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.45 g, 38%).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH:20]1([C@@H:26]([NH2:29])[CH2:27][OH:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>>[CH:20]1([C@@H:26]([NH:29][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH2:27][OH:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: N[C@@H](CO)C1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@@H](CO)C2CCCCC2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (R)-1-cyclohexyl-2-hydroxy-ethylamine and DIEA to give 2-((R)-1-cyclohexyl-2-hydroxy-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 382 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:20]=[C:21]([NH2:22])[C:4]=2[N:3]=1.CCN(CC)CC.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:20]=[C:21]([NH:22][S:37]([CH3:36])(=[O:39])=[O:38])[C:4]=2[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc2c(N)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2c(NS(C)(=O)=O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 2-methyl-6-morpholino-1-(naphthalen-1-ylmethyl)-1H-benzo[d]imidazol-4-amine (186 mg), Et3N (0.15 mL) and DCM (20 mL) was added a solution of methanesulfonyl chloride (69 mg) in DCM at 0° C. and then the mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM and washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in-vacuo. The residue was then purified by silica gel chromatography eluted with MeOH:DCM=1:30 to afford the desired product as a solid (180 mg, 80%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.40 (s, 3H), 2.98 (t, 4H, J=4.8 Hz), 3.21 (s, 3H), 3.68 (t, 4H, J=4.8 Hz), 5.96 (s, 2H), 6.37 (d, 1H, J=8.1 Hz), 6.80 (s, 2H), 7.35 (t, 1H, J=8.1 Hz), 7.60-7.71 (m, 2H), 7.85 (d, 1H, J=8.1 Hz), 8.01 (d, 1H, J=8.1 Hz), 8.24 (d, 1H, J=8.1 Hz), 9.49 (br s, 1H); LC-MS: m/e=451 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.S(Cl)([Cl:18])=O>>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([Cl:18])=[O:15]
Reactant: O=C(O)c1cnc2c(Cl)cccc2c1O
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cnc2c(Cl)cccc2c1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 9.2 g of 4-hydroxy-8-chloro-3-quinoline-carboxylic acid in 100ml of thionyl chloride was stirred at room temperature for 24 hours and wasthen vacuum filtered. The recovered precipitate was washed to obtain 0.4 g of 4 -hydroxy-8-chloro-3-quinoline-carboxylic acid chloride melting at 258° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:39])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[NH2:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:39])[C:5]([C:3]([NH:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:33][CH:34]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 51 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-8-pyridin-3-yl-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (32 mg, 0.060 mmol), β-alanine (537 mg, 6.0 mmol) and NaOMe solution (9.6 mL, 4.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (10-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 18 mg of the title compound. MS: (+) m/z 589.36 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([NH2:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[C:12]([C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)(=O)[CH3:13]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[CH:12]([NH:11][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:10])[CH3:13]
Reactant: CC(=O)c1ccc2ccccc2c1
Reactant: COc1cccc(C(C)N)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: COc1cccc(C(C)NC(C)c2ccc3ccccc3c2)c1

Procedure:
In a similar fashion equal molar amounts 1-(3-methoxyphenyl)ethylamine (1.51 g, 10 mmol), 2′-acetonaphthone (1.70 g, 10 mmol) and 1.25 equivalents of titanium(IV) isopropoxide (3.55 g, 12.5 mmol) were treated as above. Work-up yielded N-[1-(2-naphthyl)ethyl]-1-(3-methoxyphenyl)ethylamine, 6F, as a clear, colorless oil; m/z (rel. int.) 305 (M+, 1), 290 (35), 170 (49), 155 (100), 135 (55), 115 (8), 105 (10), 91 (9), 77 (10).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[CH2:8])[CH3:7])(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:1]([O:4][CH2:5][C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:7])[CH3:8])(=[O:3])[CH3:2]
Reactant: c1ccccc1
Reactant: C=C(C)COC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)OCC(C)(C)c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Mix methallyl acetate (228 g, 2.0 mol) and benzene (1L) and cool to 5° C. Add aluminum chloride (266 g, 2.0 mol) over approximately 30 minutes while maintaining the temperature below 10° C. Add, in portions of 50 mL to 80 mL each, to a 5° C. mixture of aluminum chloride (15 g) in benzene (600 mL). After addition is complete, stir at 0-3° C. for ½ hour, pour onto ice (2 kg) and separate the organic layer. Wash with water (2×300 mL), dry (Na2SO4), and distill to give neophyl acetate.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH:25](=O)[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: O=Cc1ccncc1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=Cc1ccncc1
Temperature: 25 °C
Yield: 76.3 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with isonicotinaldehyde (0.5 g, 4.7 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.093 g, 76%).
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9](=[O:14])[CH2:10][CH2:11][O:12][CH3:13])([CH3:7])[CH2:3][C:4](=O)[CH3:5].[CH3:15][NH:16][CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>[Pt]=O>[CH3:1][C:2]([NH:8][C:9](=[O:14])[CH2:10][CH2:11][O:12][CH3:13])([CH3:7])[CH2:3][CH:4]([N:16]([CH3:17])[CH3:15])[CH3:5]
Reactant: COCCC(=O)NC(C)(C)CC(C)=O
Reactant: CNC
Agent: O=[Pt]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COCCC(=O)NC(C)(C)CC(C)N(C)C
Reaction time: 12 h

Procedure:
To a mixture of 201 parts (1 mole) of N-(1,1-dimethyl-3-oxobutyl)-3-methoxypropionamide and 91 parts (2 moles) of dimethylamine are added 0.5 part of platinum oxide and 3 parts of p-toluenesulfonic acid. The liquid mixture is poured into a hydrogenation bottle, flushed with hydrogen and pressurized with hydrogen on a Parr hydrogenation apparatus at 69 psi. and hydrogenated for about 12 hours, with hydrogen pressure being replenished to 70 psi. when it has dropped to 27 psi. The mixture is then stripped on a rotary evaporator and the residue, a yellow liquid, is dissolved in 16% aqueous hydrochloric acid and extracted with four 100-ml. portions of chloroform. The aqueous solution is then made alkaline by the addition of a solution of 30 parts of sodium hydroxide in 75 parts of water, the alkaline solution is again extracted with four 100-ml. portions of chloroform and the chloroform extracts are stripped and distilled. The desired product, N-(1,1-dimethyl-3-dimethylaminobutyl)-3-methoxypropionamide, is obtained boiling at 87°-95° C./0.5 mm. It contains 12.1% nitrogen, as compared with 12.2% theoretical.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[N:12]([CH3:20])[C:13]([Br:19])=[C:14]([Br:18])[C:15]=1[C:16]#[N:17].[SH2:21]>N1C=CC=CC=1>[Br:10][C:11]1[N:12]([CH3:20])[C:13]([Br:19])=[C:14]([Br:18])[C:15]=1[C:16](=[S:21])[NH2:17]
Reactant: S
Reactant: Cn1c(Br)c(Br)c(C#N)c1Br
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Br)c(Br)c(C(N)=S)c1Br
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Diisopropylethylamine (1.1 mL, 6 mmol), 2,4,5-Tribromo-1-methylpyrrole-3-carbonitrile (2.16 g, 6 mmol) and pyridine (10 mL) are added to condensed hydrogen sulfide in a pressure tube at -78° C. The tube is sealed and the reaction mixture is stirred for 5 days at room temperature. The reaction mixture is then concentrated in vacuo to obtain a residue. Chromatography of the residue using silica gel and a 4:1 hexanes/ethyl acetate mixture gives the title product as a yellow solid (0.47 g, mp 100.5°-102° C. dec.).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[N:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.CC(O)=O>[Si:1]([O:8][C@H:9]1[CH2:10][NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CN=C(c2cccc(F)c2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CN[C@@H](c2cccc(F)c2)C1
Temperature: -78 °C
Yield: 76.9 %

Procedure:
(R)-3-(tert-butyldimethylsilyloxy)-5-(3-fluorophenyl)-3,4-dihydro-2H-pyrrole (6.21 g, 21.2 mmol) was dissolved in methanol (100 mL) and AcOH (10 mL). The reaction was cooled to −78° C. and the sodium borohydride (2.00 g, 52.9 mmol) was slowly added in small portions. The reaction was allowed to warm to ambient temperature overnight. The reaction mixture was concentrated and the residue was diluted with EtOAc and 1N NaOH. Additional NaOH pellets were added to basify the aqueous layer. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered and concentrated. The residual oil was purified by silica chromatography eluting with 5% MeOH/EtOAc to afford (2R,4R)-4-(tert-butyldimethylsilyloxy)-2-(3-fluorophenyl)pyrrolidine (4.82 g, 77.1%) as a brown oil. MS (apci) m/z=296.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:8]=[C:7]([CH3:21])[C:3]=1[C:4]([OH:6])=O.[N:22]1([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[C:3]([C:4]([N:30]2[CH2:31][CH2:32][CH:27]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:28][CH2:29]2)=[O:6])=[C:7]([CH3:21])[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:10]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)nc(C)c1C(=O)O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedures described for example 1, for intermediate 5B and for intermediate 1, the title compound has been prepared by the following reaction sequence: i) 6-chloro-2,4-dimethyl-nicotinic acid ethyl ester [Zhou, Y.; Bridger, G. J.; Skerlj, R. T.; Bogucki, D.; Yang, W.; Bourque, E.; Langille, J.; Li, T.-S.; Metz, M. U.S. Pat. Appl. Publ. (2005), US 2005277668 A1] was reacted with 3-trifluoromethyl-phenyl boronic acid to give 2,4-dimethyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid ethyl ester; ii) 2,4-dimethyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid ethyl ester has been saponified to give 2,4-dimethyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid; iii) 2,4-dimethyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid was converted into its acid chloride and reacted with 4-pyrrolidin-1-yl-piperidine to give the title compound as colorless solid. MS: 432.3 (MH+).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)[C:3]([O:5]C(C)(C)C)=O.[C:45]1([CH2:51]C(Cl)=O)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)[C:3]([CH2:51][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:5]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)Cc3ccccc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 29, Step H in Step A and phenylacetyl chloride in Step B, the title compound was prepared.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)=O.C(O)C.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>CCOCC>[N:20]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=2)=[CH:2][N:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=12
Reactant: CCOC(=O)Cc1ccc(C(=O)CCl)cc1
Reactant: Nc1ccccn1
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)Cc1ccc(-c2cn3ccccc3n2)cc1
Yield: 39.4 %

Procedure:
A mixture of 96 g of ethyl 4-(chloroacetyl)phenylacetate, 200 ml of ethanol and 64 g of 2-aminopyridine is heated under reflux for 2 hours. The ethanol is distilled off under reduced pressure, and water is added to the residue. The mixture is extracted with benzene, and the extract is washed with water, dried and concentrated to give a brown oil. To the oil is added ether, and the crystalline precipitate is filtered off and recrystallized from a mixture of benzene and petroleum ether to give 44 g of ethyl 4-(imidazo[1,2-a]pyridin-2-yl)phenylacetate as pale brown crystals melting at 92°-93°C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[C:23]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1[nH]c2ccccc2c1NC(=O)c1ccccc1

Procedure:
To a mixture of 3-Amino-2-carboethoxyindole (572 mg) and triethylamine (400 mg) in methylene chloride (100 mL) was added benzoyl chloride (450 mg). After 30 min at room temperature the reaction mixture was washed with 0.1N HCl, dried over magnesium sulfate and the solvent was removed in vacuo. The residue was triturated with ether to afford 3-Benzamido-2-carboethoxyindole as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28](OC)=[O:29])=[CH:25][C:24]=4[CH:32]=3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26](=[CH:28][OH:29])[CH2:25][C:24]=4[CH:32]=3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(C(C)(C)C)c4)n3)ccc2o1
Agent: CC(C)C[AlH]CC(C)C
Product: CC(C)(C)c1cccc(Nc2nc(Nc3ccc4c(c3)CC(=CO)O4)ncc2F)c1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine, N4-(3-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine reacted with DIBALH to give N4-(3-tert-butylphenyl)-5-fluoro-N2-[2-(hydroxymethylene)benzofur-5-yl]-2,4-pyrimidinediamine. LCMS: retn, time: 23.15 min.; purity: 99%; MS (m/e): 407 (MH+); 1□□□ (DMSO-d6): δ 9.34 (1H, s), 9.22 (1H, s), 8.18 (1H, d, J=3.9 Hz), 8.04 (1H, s), 8.00 (1H, d, J=8.7 Hz), 7.60 (1H, t, J=2.1 Hz), 7.47 (2H, m), 7.34 (1H, t, J=7.8 Hz), 7.21 (1H, d, J=8.7 Hz), 6.69 (1H, s), 5.54 (1H, t, J=5.8 Hz), 4.63 (2H, d, J=5.8 Hz), 1.35 (9H, s).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[N:30]([CH:33]([CH3:35])[CH3:34])=[C:31]=[O:32]>C(Cl)Cl>[CH:33]([NH:30][C:31]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=1)=[O:32])([CH3:35])[CH3:34]
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Reactant: CC(C)N=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)NC(=O)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (70 mg, 0.252 mmol, example 9 (step 3) and DIEA (44 μL, 0.252 mmol) in DCM (1.6 mL) was added 2-isocyanatopropane (25 μL, 0.252 mmol). The resulting mixture was reacted under the same conditions as described for example 10 to give the title compound as a white solid. MS (ESI, positive ion) m/z: 363 (M+H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([OH:14])[CH2:10][C@@H:9]1[CH2:15][CH3:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[C:1]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][N:18]2[C:22](=[O:23])[C:21]3[C:20](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19]2=[O:28])[CH2:10][C@@H:9]1[CH2:15][CH3:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC[C@H]1C[C@H](O)CCN1C(=O)OC(C)(C)C
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC[C@H]1C[C@@H](ON2C(=O)c3ccccc3C2=O)CCN1C(=O)OC(C)(C)C

Procedure:
A suspension of 0.74 g (0.003227 mol) of trans-N-BOC-2-ethyl-4-hydroxypiperidine (cf. Example 3b), 0.526 g (0.003227 mol) of N-hydroxyphthalimide and 0.846 g (0.003227 mol) of triphenylphosphine in 10 ml of benzene is reacted in accordance with the general procedure of Example 3a with a solution of 0.566 ml (0.003385 mol) of diethyl azodicarboxylate (93%) in 2 ml of benzene, to give the title compound as a colourless resin; Rf =0.60 (silica gel/ethyl acetate:hexane (2:1)).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([Cl:15])=[C:7]([O:16][CH2:17][C:18]#[CH:19])[N:6]=1>>[Cl:15][C:8]1[C:7]([O:16][CH2:17][C:18]#[CH:19])=[N:6][C:5]([NH:2][NH2:3])=[C:10]([C:11]([F:14])([F:13])[F:12])[CH:9]=1
Reactant: NN
Reactant: C#CCOc1nc(Cl)c(C(F)(F)F)cc1Cl
Solvent: O
Product: C#CCOc1nc(NN)c(C(F)(F)F)cc1Cl

Procedure:
Starting from 7.8 g (0.155 mol) of hydrazine hydrate and 20 g (0.074 mol) of 2,5-dichloro-6-propargyloxy-3-trifluoromethylpyridine, 11.0 g (56% of theory) of the title compound were obtained as a colorless powder of m.p. 98°-102° C. (Table II, No. 2.036) under the conditions of Example III.4.