Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1F.[F:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[CH:20][NH:21]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[N:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([F:14])[CH:23]=2)[CH:19]=[CH:20]1
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc2ccn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (34.5 g) in dimethylformamide (250 ml) was added 6-fluoroindole (34.5 g) and potassium carbonate (20.4 g). The mixture was heated at 90° C. for 6 hours and then left to stir for 16 hours at room temperature. The reaction was diluted with water (1000 ml) and extracted with hexane (1000 ml). The organic fraction was separated and evaporated to dryness to give the title compound as a colourless liquid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([S:19]([CH3:22])(=O)=O)[N:3]=1.C(S)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([S:19][CH2:22][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1
Reactant: SCc1ccccc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(SCc2ccccc2)nc(N)nc1-c1ccc2c(c1)OCO2

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, benzyl mercaptan and DBU in DME. ES-MS m/e (%): 401 (M+K+, 30), 385 (M+Na+, 24), 363 (M+H+, 100).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH3:27]
Reactant: CCOC(=O)CCCCCCBr
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CCCCCCn1c2ccccc2c2ccccc21
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 66.3 %

Procedure:
A RB flask fitted with reflux condenser containing carbazole (0.60 g, 3.59 mmol) and sodium hydride (60 wt. % in mineral oil, 0.22 g, 5.38 mmol) was vacuum purged and filled with argon, followed by addition of DMF (16 mL). After stirring at 50° C. for 20 min, ethyl 7-bromo-heptanoate (0.85 g, 3.59 mmol) was added and the mixture stirred at 80° C. overnight. The reaction was quenched by addition of 5% aqueous NH4Cl (75 mL), transferred to a separatory funnel and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (2×20 L), dried (Na2SO4) and concentrated. Purification by MPCC (0-50% gradient of ethyl acetate in hexane) afforded the title compound (0.77 g, 66%). 1H NMR (300 MHz, CDCl3): δ 8.15 (d, 2H, J=7.8 Hz), 7.52 (t, 2H, J=7.3 Hz), 7.44 (d, 2H, J=8.1 Hz), 7.28 (t, 2H, J=7.7 Hz), 4.32 (t, 2H, J=7.2 Hz), 4.16 (q, 2H, J=7.1 Hz), 2.30 (t, 2H, J=7.4 Hz), 1.91 (m, 2H), 1.64 (m, 2H), 1.41 (m, 4H), 1.30 (t, 3H, J=7.2 Hz). 13C NMR APT (100 MHz, CDCl3): 173.7 (up), 140.5 (up), 125.6 (down), 122.9 (up), 120.4 (down), 118.8 (down), 108.7 (down), 60.3 (up), 43.0 (up), 34.3 (up), 28.9 (up), 27.0 (up), 24.8 (up), 14.3 (down). ESI-HRMS (m/z): [M+H]+ calcd. for C21H25NO2, 324.1958. found, 324.1957
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:24][C:25](=[O:27])[CH3:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccccc2)c1O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccccc2)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 120(a) from 1-benzyl-7-cyano-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, acetic anhydride, and triethylamine. The title compound, ESI MS (m/z): 364 (M+H)+.
Reaction SMILES: [OH-].[Li+:2].[C:3]([O:7][C:8]([NH:10][C:11]1([C:26]([NH:28][CH:29]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH2:30][C:31]([O:33]C)=[O:32])=[O:27])[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[CH:25]=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.C1COCC1>[C:3]([O:7][C:8]([NH:10][C:11]1([C:26]([NH:28][CH:29]([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[CH2:30][C:31]([O-:33])=[O:32])=[O:27])[CH2:12][CH2:13][N:14]([C:17]2[C:18]3[CH:25]=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:15][CH2:16]1)=[O:9])([CH3:6])([CH3:4])[CH3:5].[Li+:2]
Reactant: COC(=O)CC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CC(=O)[O-])c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
Lithium hydroxide (1.436 mL, 2.87 mmol) 2N in water was added to a stirred suspension of methyl 3-(4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamido)-3-(4-chlorophenyl)propanoate (Intermediate 35) (400 mg, 0.72 mmol) in THF (40 mL) at room temperature. The resulting suspension quickly went into solution and was then stirred at RT overnight. The following morning a white precipitate had formed. This was filtered and dried in vacuo to give lithium 3-(4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamido)-3-(4-chlorophenyl)propanoate (396 mg, 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:19][CH:20]1[O:25][CH2:24][CH2:23][NH:22][CH2:21]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(N(CC)CC)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:22]2[CH2:23][CH2:24][O:25][CH:20]([CH3:19])[CH2:21]2)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1CNCCO1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1CN(c2cccc([C@H](C)NC(=O)OC(C)(C)C)c2)CCO1
Yield: 58.1 %

Procedure:
The solution of (S)-[1-(3-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (4.36 g, 14.5 mmol), 2-Methyl-morpholine hydrochloric acid salt (4 g. 2eq.), palladium acetate (20 mol %, 652 mg), 2-(di-t-butylphosphino) biphenyl (40 mol %, 1.73 g), triethylamine (4.45 ml, 2.2eq.), and sodium tert-butoxide (1.54 g, 1.1eq) in toluene (26 ml) was stirred at 80° C. for 2 days. The solution was filtered through Celite Pad and washed with ethyl acetate. The filtrate was washed with saturated sodium bicarbonate solution and the organic layer was separated. The aqueous layer was extracted with ethyl acetate three times. The combined organic layer was dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography with 25% ethyl acetate/hexane. Yellow sticky oil was obtained as the product (2.7 g, 58% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[C:32]([Cu])#[N:33].O.Cl>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:32]#[N:33])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: N#C[Cu]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1nc(C#N)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 51.9 %

Procedure:
A mixture of 1,3-dibenzyl-8-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (114 mg, 0.24 mmol) and CuCN (43 mg, 0.48 mmol) in 5 mL of DMF was refluxed for 40 min. After the mixture was cooled to r.t., it was poured into a mixture of water and CH2Cl2. 4M HCl was added with vigorous stirring until both layers became homogeneous. The aqueous layer was extracted with additional CH2Cl2, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (0-50% EtOAc/hexanes+2% AcOH) to give 53 mg of the title compound. MS: (+) m/z 426.14 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[NH3:17]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([NH:8][C:9]([NH2:17])=[S:10])[CH:7]=1
Reactant: Cc1ccc(N2CCOCC2)c(N=C=S)c1
Reactant: N
Product: Cc1ccc(N2CCOCC2)c(NC(N)=S)c1

Procedure:
Reaction of 5-methyl-2-morpholinophenyl isothiocyanate (15 g) with 33% ethanolic ammonia solution for 48 hours at room temperature gave 1-(5-methyl-2-morpholinophenyl)thiourea as a pale yellow solid (m.p. 181°-182° C.).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl.Cl.[CH3:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[CH2:19][CH2:20][NH2:21].[CH3:22][N:23]1[CH:28]=[C:27]([CH2:29]Cl)[C:26]([C:31](OC)=[O:32])=[C:25]([Cl:35])[C:24]1=[O:36]>CO.CC#N>[Cl:35][C:25]1[C:24](=[O:36])[N:23]([CH3:22])[CH:28]=[C:27]2[CH2:29][N:21]([CH2:20][CH2:19][C:11]3[N:10]([CH3:9])[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[N:12]=3)[C:31](=[O:32])[C:26]=12
Reactant: Cn1c(CCN)nc2ccccc21
Reactant: COC(=O)c1c(CCl)cn(C)c(=O)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1nc3ccccc3n1C)C2
Temperature: 90 °C
Reaction time: 5 h
Yield: 54.2 %

Procedure:
K2CO3 (8.35 g, 60.4 mmol) was added rapidly to a suspension of 2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethanamine dihydrochloride (5 g, 20.15 mmol) in MeOH (50 ml) and the reaction was stirred for about 5 h. The mixture was filtered and the filtrate was concentrated. The residue and TEA (28.1 ml, 201 mmol) were added to a solution of 1-methyl-2-oxo-1,2-dihydro-3-chloro-4-methoxycarbonyl-5-chloromethyl-pyridine (5.04 g, 20.15 mmol, see compound (6) of Example b1)) in MeCN (100 ml). The mixture was heated at about 90° C. overnight. The reaction was cooled to r.t. and the mixture was filtered through a sintered glass funnel. The solid was washed with water and dried to afford the title compound (3.9 g, 10.93 mmol, 54.2% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10]Br.[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CC#N>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10][N:16]1[C:12](=[O:22])[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15]1=[O:17]
Reactant: Clc1cc(Cl)c(CBr)c(Br)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1Cc1c(Cl)cc(Cl)cc1Br
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a solution of 1-bromo-2-(bromomethyl)-3,5-dichlorobenzene (1.98 mmol) [J. Med. Chem., 35 (22), 4221 (1992)] in 10 mL CH3CN were added phthalimide (1.98 mmol) and K2CO3 (5.93 mmol). The reaction mixture was stirred at 50° C. for 6 h and then at RT overnight. Sat. aq. NaHCO3 solution was added and the mixture was extracted 3 times with DCM. The combined organic phases were dried over MgSO4 and concentrated in vacuo to obtain the desired product as beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([C:17](=[O:19])[NH:26][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: NC1CCCCC1
Product: O=C(NC1CCCCC1)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 91 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxy-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (300 mg, 0.92 mmol) and cyclohexylamine (100 mg, 1.0 mmol) to give 340 mg of the title compound (91%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.14 (s, 1H), 8.03 (d, 1H, J=7.9 Hz), 7.16 (bs, 1H), 7.14 (bs, 1H), 5.08~5.13 (m, 1H), 3.42~3.59 (m, 1H), 2.79 (dm, 1H, J=16.8 Hz), 2.45~2.63 (m, 1H), 2.36 (dm, 1H, J=13.5 Hz), 1.85~2.02 (m, 1H), 1.63~1.74 (m, 4H), 1.05~1.33 (m, 6H).
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][N:8]1[C:12]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[N:16]=[CH:15][CH:14]=2)=[C:11]([CH3:26])[N:10]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[C:9]1=[O:37])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([N:17]2[C:13]([C:12]3[N:8]([CH2:7][C:6]([OH:38])=[O:5])[C:9](=[O:37])[N:10]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)[C:11]=3[CH3:26])=[CH:14][CH:15]=[N:16]2)=[CH:19][CH:20]=1)#[N:25]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)n(CC(=O)OC(C)(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)n(CC(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
tert-Butyl-{5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-1-yl}acetate (Example 20) (75 mg, 0.143 mmol) was stirred in DCM (3 mL) and water (0.03 mL). To this mixture was added TFA (0.1 mL) and the mixture stirred overnight. Reaction was incomplete so further TFA (0.5 mL) was added and after 1 h 30 minutes, a further 1 ml was added. After 4 h reaction was complete, solvents were evaporated and the residue partitioned between EtOAc and water. The organic phase was separated, dried over Na2SO4 and evaporated to give the title compound as a gum.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C:15]2=[O:21])[C:3]=1[CH3:22].[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31]([NH2:35])[CH:32]=[N:33][CH:34]=2)[CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:35][C:31]1[CH:32]=[N:33][CH:34]=[C:29]([N:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)[CH:30]=1)=[C:3]([CH3:22])[C:4]([N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C:15]1=[O:21])=[N:5]2
Reactant: Cc1c(N2CCN(C)CC2=O)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cncc(N2CCOCC2)c1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCN(C)CC2=O)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure H using 1-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-4-methylpiperazin-2-one (25.0 mg, 0.077 mmol) and 5-morpholinopyridin-3-amine in toluene to give 1-(5,7-difluoro-3-methyl-4-((5-(4-morpholinyl)-3-pyridinyl)amino)-2-quinolinyl)-4-methyl-2-piperazinone. 1H NMR (400 MHz, chloroform-d) δ ppm 7.92 (1H, br. s.), 7.88 (1H, br. s.), 7.47 (1H, ddd, J=9.6, 2.5, 1.4 Hz), 7.23 (1H, d, J=14.9 Hz), 7.01 (1H, ddd, J=13.9, 8.6, 2.5 Hz), 6.53 (1H, t, J=2.1 Hz), 4.41 (1H, ddd, J=11.8, 5.2, 5.1 Hz), 3.75-3.89 (4H, m), 3.53-3.67 (1H, m), 3.29-3.43 (1H, m), 3.11-3.27 (5H, m), 2.82-2.96 (2H, m), 2.44 (3H, s), 1.95 (3H, s). Mass Spectrum (ESI) m/e=326.0 (M+1).
Reaction SMILES: Cl[CH:2]([F:4])[F:3].C([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:15][CH2:16][F:17])=O.[OH-].[K+]>O1CCCC1.O.[OH-].[Na+].C1OCCOCCOCCOCCOCCOC1>[F:3][CH:2]([F:4])[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:15][CH2:16][F:17]
Reactant: O=COc1ccccc1OCCF
Reactant: FC(F)Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: FCCOc1ccccc1OC(F)F

Procedure:
Chlorodifluoromethane was bubbled into a stirred solution of 6.6 grams (0.036 mole) of 2-(2-fluoroethoxy)phenyl formate, 12.0 grams (0.215 mole) of potassium hydroxide, and 0.1 gram (0.00038 mole) of 18-crown-6 in 150 ml of tetrahydrofuran for 10 minutes. The resultant solution was heated at reflux for approximately 18 hours. The reaction mixture was cooled and was diluted with water. Evaporization of most of the solvent under reduced pressure left a solid residue. This residue was dissolved in a 3 N aqueous sodium hydroxide solution. The basic solution was extracted with three 100 ml portions of methylene chloride, and the extracts were combined. The extract was washed with an aqueous saturated sodium chloride solution. The washed extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving a residue. This residue was purified by column chromatography on silica gel, eluting with diethyl ether:n-hexane(1:1), to yield 3.3 grams of 2-fluoroethyl 2-difluoromethoxyphenyl ether.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[N:19]=[C:18](Cl)[N:17]=[C:16]4[C:12]=3[N:13]=[CH:14][N:15]4[CH2:21][CH3:22])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[N:19]=[C:18]([N:25]4[C:24]([CH3:23])=[CH:28][C:27]([CH3:29])=[N:26]4)[N:17]=[C:16]4[C:12]=3[N:13]=[CH:14][N:15]4[CH2:21][CH3:22])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1cc(C)[nH]n1
Reactant: CCn1cnc2c(Nc3ccc4c(c3)OCO4)nc(Cl)nc21
Product: CCn1cnc2c(Nc3ccc4c(c3)OCO4)nc(-n3nc(C)cc3C)nc21

Procedure:
Was prepared according to Example 6 from benzo[1,3]dioxol-5-yl-(2-chloro-9-ethyl-9H-purin-6-yl)-amine and 3,5-dimethylpyrazole.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[N:26][N:27]([CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:28]=2)O1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:31]1([CH2:30][CH2:29][N:27]2[CH:28]=[C:24]([C:2]3[CH:3]=[N:4][C:5]([C:8]4[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=4)=[N:6][CH:7]=3)[CH:25]=[N:26]2)[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1
Reactant: OCc1cccc(-c2ncc(Br)cn2)c1
Reactant: CC1(C)OB(c2cnn(CCN3CCOCC3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: OCc1cccc(-c2ncc(-c3cnn(CCN4CCOCC4)c3)cn2)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Under an argon atmosphere, 2.82 g (10 mmol) of [3-(5-bromopyrimidin-2-yl)-phenyl]methanol are dissolved in 100 ml of ethylene glycol dimethyl ether, 3.38 g (10 mmol) of 4-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]ethyl}morpholine and 4.25 g (20 mmol) of tripotassium phosphate trihydrate are added. The reaction mixture is evacuated twice and flushed with argon. 840 mg (1.2 mmol) of bis(triphenylphosphine)palladium(II) chloride are added, the mixture is again evacuated and flushed argon. The reaction mixture is stirred at 80° C. for 16 hours. The reaction mixture is diluted with dichloromethane and water and filtered through Celite. The organic phase is separated off, washed with water again, the organic phase is dried over sodium sulfate and evaporated to dryness. The residue is recrystallised from isopropanol; yield: 2.74 g, LCMS: 366 (M+H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2F)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[Cl:39]C1C=CC=CC=1CC(=O)C(OCC)=O.[H-].[Na+].[Br-].C(O[C@@H]1[C@@H](OC(=O)C)[C@@H](OC(=O)C)[C@@H](COC(=O)C)O[C@@H]1O)(=O)C>>[C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:39])[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1ccccc1Cl
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Br-]
Agent: [H-]
Product: CCOC(=O)/C(=C/c1ccccc1Cl)O[C@H]1O[C@@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 36 %

Procedure:
The title compound was prepared as described for C4 using ethyl 3-(2-chlorophenyl)-2-oxopropanoate B11 (100 mg, 0.441 mmol), sodium hydride (11.65 mg, 0.485 mmol) and 2,3,4,6 tetra-O-acetyl-α-D-galactose bromide (181 mg, 0.441 mmol). The resulting compound was isolated in the form of white solid in 36% yield.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C1(C)C=CC=CC=1>CCOCC>[N:20]1([CH2:2][CH2:3][O:4][CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:13])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: C1CNCCN1
Reactant: O=C(c1ccccc1)C(OCCCl)c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)C(OCCN1CCNCC1)c1ccccc1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
27 g (0.1 mole) of benzoin 2-chloroethyl ether and 34 g (0.4 mole) of piperazine are heated to 70° C. After 11/2 hours, 5 ml of toluene are added in order to prevent the piperazine from subliming and the mixture is heated to 140° C. and kept for 2 hours at reflux temperature. After cooling, the reaction mixture is diluted with ether and extracted with dilute hydrochlorid acid. The hydrochloric acid solution is freed from ether and neutralised with K2CO3. The alkaline solution is extracted with ether and then with toluene. The toluene solution is dried over Na2SO4 and concentrated. The residual oil is dried in a high vacuum at 60° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].I[C:22]1[NH:23][CH:24]=[CH:25][N:26]=1>>[NH:23]1[CH:24]=[CH:25][N:26]=[C:22]1[C:2]#[C:1][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Reactant: Ic1ncc[nH]1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ncc[nH]2)c1)c1ccccc1
Yield: 29 %

Procedure:
In a manner similar to that describe in Example 434, a mixture of (S)-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 2-iodo-1H-imidazole were reacted to give the title compound as a white solid (15 mg, 29%).