Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20](/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)=[C:19]([O:38][CH3:39])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20](/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH:25]4[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]4)=[C:19]([O:38][CH3:39])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1/C=C\CCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2c(c1/C=C\CCC1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
A solution of tert-butyl 4-((Z)-4-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}but-3-enyl)piperidine-1-carboxylate (0.0293 g, 0.0553 mmol) in methylene chloride (3 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the precipitated solid was collected by filtration. The solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[(Z)-4-(piperidin-4-yl)but-1-enyl]benzofuran-3(2H)-one (0.0173 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14](I)[CH:13]=[CH:12][C:3]=1[N:4]([CH3:11])[C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].[SH:17][C:18]1[CH:19]=[C:20]([C:24]2([O:30][CH3:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1>>[Cl:1][C:2]1[CH:15]=[C:14]([S:17][C:18]2[CH:19]=[C:20]([C:24]3([O:30][CH3:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:21]=[CH:22][CH:23]=2)[CH:13]=[CH:12][C:3]=1[N:4]([CH3:11])[C:5](=[O:10])[C:6]([F:9])([F:8])[F:7]
Reactant: COC1(c2cccc(S)c2)CCOCC1
Reactant: CN(C(=O)C(F)(F)F)c1ccc(I)cc1Cl
Product: COC1(c2cccc(Sc3ccc(N(C)C(=O)C(F)(F)F)c(Cl)c3)c2)CCOCC1
Yield: 8 %

Procedure:
Using a similar procedure to that described in Example 12, 2'-chloro-4'-iodo-2,2,2-trifluoro-N-methylacetanilide was reacted with 4-(3-mercaptophenyl)-4-methoxytetrahydropyran to give 4-[3-(3-chloro-4-(N-methyltrifluoroacetamido)phenylthio)phenyl]-4-methoxytetrahydropyran in 8% yield as a gum.
Reaction SMILES: [F:1][CH2:2][O:3][C:4]1[CH:33]=[CH:32][C:7]2[CH2:8][CH2:9][CH2:10][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C@H:15]([OH:24])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][C:6]=2[CH:5]=1.Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[F:1][CH2:2][O:3][C:4]1[CH:33]=[CH:32][C:7]2[CH2:8][CH2:9][CH2:10][CH:11]([NH:13][CH2:14][C@H:15]([OH:24])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][C:6]=2[CH:5]=1
Reactant: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccccc1)C1CCCc2ccc(OCF)cc2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O[C@@H](CNC1CCCc2ccc(OCF)cc2C1)COc1ccccc1
Reaction time: 5.5 h
Yield: 71.7 %

Procedure:
To a solution of N-(3-fluoromethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-2-hydroxy-3-phenoxypropyl]-tert-butoxycarbonylamine (41 mg) in ethyl acetate (2 ml) was added 4N hydrogen chloride in ethyl acetate (0.45 ml) at room temperature, and the mixture was stirred at the same temperature for 5.5 hours. The mixture was poured into a mixture of saturated aqueous sodium hydrogencarbonate and ethyl acetate, followed by being made basic with saturated aqueous sodium hydrogencarbonate. After separation, the organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (silica gel, chloroform:methanol=10:1) to give (2S)-1-(3-fluoromethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanol (23 mg).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[C:6]([O:10][C:11](=[O:41])[N:12]([CH2:21][C:22]1[CH:23]=[N:24][C:25]([CH3:40])=[C:26]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[N:39])[CH:33]=2)[C:27]=1[CH:28]=[O:29])[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][C:11](=[O:41])[N:12]([CH2:21][C:22]1[CH:23]=[N:24][C:25]([CH3:40])=[C:26]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[N:39])[CH:33]=2)[C:27]=1[CH:28]([CH:1]1[CH2:3][CH2:2]1)[OH:29])[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: Br[Mg]C1CC1
Reactant: Cc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)c(C=O)c1OCc1cccc(C#N)c1
Product: Cc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)c(C(O)C2CC2)c1OCc1cccc(C#N)c1
Yield: 62.1 %

Procedure:
The addition of cyclopropyl magnesium bromide (2.8 mL, 0.5 M, 1.4 mmol) to 5-(3-cyano-benzyloxy)-4-formyl-6-methyl-pyridin-3-ylmethyl]-(4-cyano-phenyl)-carbamic acid tert-butyl ester (109) (474 mg, 0.9 mmol), was carried out as described in Example 104, gave [5-(3-cyano-benzyloxy)-4-(cyclopropyl-hydroxy-methyl)-6-methyl-pyridin-3-ylmethyl]-(4-cyano-phenyl)-carbamic acid tert-butyl ester (117) (293 mg, 57% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:16][CH2:15]2)=[CH:10][C:9]=1[NH2:17])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:25][C:24]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=2)=[CH:23][C:22](=O)[O:21]1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:16][CH2:15]2)=[CH:10][C:9]=1[NH:17][C:22](=[O:21])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CC2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2ccnc(C#N)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(C2CC2)cc1NC(=O)CC(=O)c1ccnc(C#N)c1

Procedure:
Prepared from (2-amino-4-cyclopropyl-phenyl)-carbamic acid tert.-butyl ester (Example G48) and 4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-pyridine-2-carbonitrile (Example J16) according to the general procedure K. Obtained as a light brown solid (148 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([S:11][CH2:12][C:13]#[N:14])[N:3]=1.[CH2:15]([NH2:25])[C:16]1[CH:24]=[CH:23][C:22]2[O:21][CH2:20][O:19][C:18]=2[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[O:21]1[C:22]2[CH:23]=[CH:24][C:16]([CH2:15][NH:25][C:2]3[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([S:11][CH2:12][C:13]#[N:14])[N:3]=3)=[CH:17][C:18]=2[O:19][CH2:20]1
Reactant: CCCc1cc(Cl)nc(SCC#N)n1
Reactant: NCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCc1cc(NCc2ccc3c(c2)OCO3)nc(SCC#N)n1

Procedure:
A stirred suspension of 13.50 g. (0.06 mole) of (4-chloro-6-propyl-2-pyrimidinylthio)acetonitrile, 9.00 g. (0.06 mole) of piperonylamine and 6.36 g. (0.06 mole) of sodium carbonate was heated under reflux for six hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was dissolved in ethyl acetate, diluted with petroleum ether and was cooled in ice. The precipitate which formed was collected and recrystallized from a mixture of ethanol-petroleum ether to give 3.0 g. of product, m.p. 92°-94°.
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([CH3:11])=[N:5][CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1.[C:12]1([C:17](Cl)=[O:18])[S:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[OH:10][CH2:9][C:7]1[CH:8]=[C:3]([O:2][C:17](=[O:18])[C:12]2[S:16][CH:15]=[CH:14][CH:13]=2)[C:4]([CH3:11])=[N:5][CH:6]=1
Reactant: Cc1ncc(CO)cc1O
Reactant: O=C(Cl)c1cccs1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ncc(CO)cc1OC(=O)c1cccs1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 0.9 g of 3-hydroxy-5-hydroxymethyl-2-methylpyridine hydrochloride in 5 ml. of pyridine was added dropwise 0.7 g. of 2-thenoyl chloride under cooling. The resulting mixture was stirred overnight, poured into ice-water and then extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off to give an oily substance. This substance was purified by silica gel chromatography to give 0.75 g. of the desired product. m.p. 59° - 61°C.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([CH2:11][NH2:12])[OH:10]>[Cl-].[Na+].O>[CH2:1]([NH:12][CH2:11][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: NCCO
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: OCCNCc1ccccc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
A mixture of benzyl bromide (15 g, 0.0872 mol) and ethanol amine (26.5 g, 0.436 mol) was stirred at 120° C. for 3 h. The reaction mixture was diluted with brine and extracted with dichloromethane. The organic layer was washed with water and brine and dried over sodium sulfate. Solvent evaporated under reduced pressure and the residue was purified by column chromatography over silica gel using 4% methanol in dichloromethane as eluent to give N-benzyl ethanolamine (12 g) as a liquid.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([Cl:7])[C:4]([Cl:8])=[C:3]([C:9]2[N:14]=[N:13][C:12]([NH2:15])=[N:11][C:10]=2[NH2:16])[CH:2]=1.[Cl:17][C:18]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>N1C=CC=CC=1>[NH2:16][C:10]1[N:11]=[C:12]([NH:15][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:18]=2[Cl:17])[N:13]=[N:14][C:9]=1[C:3]1[CH:2]=[CH:1][CH:6]=[C:5]([Cl:7])[C:4]=1[Cl:8]
Reactant: Nc1nnc(-c2cccc(Cl)c2Cl)c(N)n1
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Solvent: c1ccncc1
Product: Nc1nc(NC(=O)c2cccc(Cl)c2Cl)nnc1-c1cccc(Cl)c1Cl

Procedure:
Lamotrigine (512.00 g, 2.00 moles) was dissolved in pyridine (3 I) and 2,3-dichlorobenzoyl chloride (873.00 g, 96% pure, equivalent to 838.10 g, 4.00 moles) was added below 35° C. with stirring under anhydrous conditions. The acid chloride was added in two equal portions. The second portion of acid chloride was added after 30 minutes from the start of the reaction and stirred below 35° C. for a further 30 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([N:65]([CH2:73][CH3:74])[CH2:66][CH:67]1[CH2:72][CH2:71][CH2:70][CH2:69][NH:68]1)[CH3:64]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:68]1[CH2:69][CH2:70][CH2:71][CH2:72][CH:67]1[CH2:66][N:65]([CH2:73][CH3:74])[CH2:63][CH3:64])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CCN(CC)CC1CCCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CC1CCCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and N,N-diethyl-N-(piperidin-2-ylmethyl)-amine in DMSO at ambient temperature.
Reaction SMILES: [CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[Na+].[CH3:8][N:9]([C:11]([N:14]([CH3:16])[CH3:15])(Cl)[Cl:12])[CH3:10]>C(#N)C>[CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[CH3:8][N:9]([C+:11]([N:14]([CH3:16])[CH3:15])[Cl:12])[CH3:10]
Reactant: CN(C)C(Cl)(Cl)N(C)C
Agent: COS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN(C)[C+](Cl)N(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.3 %

Procedure:
1.54 g (11.48 mmol) of sodium methylsulfate and 10 ml of dry acetonitrile are added under an inert-gas atmosphere to 1.96 g (11.46 mmol) of bis(dimethylamino)dichloromethane. The reaction mixture is stirred for 5 hours at room temperature, and the precipitate of NaCl is filtered off. The solvent of the filtrate is subsequently distilled off, and the residue obtained is dried for 1 hour at an oil-bath temperature of 50° C. under reduced pressure at 7.0 Pa, giving 2.78 g of bis(dimethylamino)chlorocarbenium methylsulfate as a viscous liquid, corresponding to a yield of 98.3%.
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([NH2:26])=[NH:25])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.CN(C)[CH:29]=[C:30]([C:36](=O)[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:31]([O:33][CH2:34][CH3:35])=[O:32].C(N(CC)CC)C>C(O)C.C(OCC)(=O)C>[Cl:43][C:40]1[CH:39]=[CH:38][C:37]([C:36]2[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][N:26]=[C:24]([NH:23][C:13]3[CH:14]=[CH:15][C:16]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:11]([O:10][CH3:9])[CH:12]=3)[N:25]=2)=[CH:42][CH:41]=1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: O=[N+]([O-])O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc1-c1ccc(Cl)cc1
Yield: 67.7 %

Procedure:
A mixture of N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (185 mg, 0.5 mmol), crude ethyl 3-dimethylamino-2-(4-chloro-benzoyl)-acrylate (292 mg, 1.0 mmol), and triethylamine (0.66 mL, 4.7 mmol) in ethanol (2 mL) was heated at reflux for 15 h. The mixture was cooled and diluted with ethyl acetate (50 mL). The solution was washed with sat. sodium carbonate solution (5 mL) and with brine (5 mL), dried over sodium sulfate and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using dichloromethane/0-20% methanol as eluent to give the title compound (157 mg, 68%) as a pale-yellow solid. Mp 216-218° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:32]([OH:34])=O)=[N:11][C:12]([CH2:16][C:17]2([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Si:44]([O:51][CH2:52][CH2:53][NH2:54])([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[Si:44]([O:51][CH2:52][CH2:53][NH:54][C:32]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)[N:11]=1)=[O:34])([C:47]([CH3:49])([CH3:50])[CH3:48])([CH3:46])[CH3:45]
Reactant: CC(C)(C)[Si](C)(C)OCCN
Reactant: O=C(O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCNC(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Yield: 93.6 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (345) (250 mg, 0.55 mmol) in dimethylformamide (7.5 mL) were added N,N-diisopropylethylamine (0.27 mL, 1.65 mmol), 2-(tert-butyl-dimethylsilanyloxy)-ethylamine (8c) (145 mg, 0.83 mmol) and HATU (251 mg, 0.66 mmol) and the reaction mixture was stirred at room temperature for 1.5 h (silica TLC, 50% ethyl acetate in hexane, Rf=0.5). The reaction mass was diluted with ethyl acetate (60 ml) and washed with brine (3×30 mL). The organic phase was thereafter dried and concentrated in vacuo to get a crude mass which was purified by CombiFlash using a gradient eluent mixture of ethyl acetate and hexane to get pure 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-amide (346) (315 mg, 94%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1CC[CH2:14][N:13]1[CH3:17].C(OC(N1C2C(=CC(Br)=CC=2)C=C1C(C1CCCN1)=O)=O)C1C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:14])[CH3:17]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Agent: O=C(c1cc2cc(Br)ccc2n1C(=O)OCc1ccccc1)C1CCCN1
Product: CN(C)CCc1c[nH]c2ccc(Br)cc12

Procedure:
(R)-5-Bromo-3-[(N-methylpyrrolidin-2-yl)methyl]-1H-indole: (63%) from (R)-3-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl5-bromo-1H-indole (Example 2a).
Reaction SMILES: C([Li])(C)(C)C.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[C:22](=[O:24])=[O:23].O>O1CCCC1>[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[C:15]=1[C:22]([OH:24])=[O:23])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c(F)c1
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(F)c(F)c1C(=O)O
Yield: 76.1 %

Procedure:
400 ml (600 mmol) of tert.butyllithium (1.5M in pentane) were added dropwise within 1 hour to a solution, cooled to -70°, of 57.2 g (250 mmol) of N-(tert.butoxycarbonyl)-3,4-difluoroaniline in 500 ml of tetrahydrofuran. Subsequently, 160 g of dry ice were added in small portions to the yellow suspension, the mixture was left to warm to 0° and 400 ml of water were added dropwise. The tetrahydrofuran and the pentane were distilled off and the aqueous phase was washed twice with ether and subsequently adjusted to pH=1 with conc. hydrochloric acid. The acidic aqueous phase was extracted three times with methylene chloride; the organic phase was dried over sodium sulfate, filtered and evaporated. The beige solid obtained was recrystallized from ethylene chloride and there were obtained 52 g (76%) of 2-(tert.-butoxycarbonyl)amino-5,6-difluorobenzoic acid as colourless needles of m.p. 159.5°-160.5°.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[S:9][C:10]3[N:11]=[CH:12][N:13]=[C:14](SC)[C:15]=3[N:16]=2)=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]=[CH:4]1)[CH3:2].C([N:27]1C(C2SC3N=CN=C(SC)C=3C=2)=C(C2C=CC=CC=2)N=C1)C>>[CH2:1]([N:3]1[C:7]([C:8]2[S:9][C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:27])[C:15]=3[N:16]=2)=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cnc(-c2ccccc2)c1-c1nc2c(SC)ncnc2s1
Reactant: CCn1cnc(-c2ccccc2)c1-c1cc2c(SC)ncnc2s1
Product: CCn1cnc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Example 56 but using 2-(1-ethyl-4-phenyl-1H-imidazol-5-yl)-7-(methylthio)[1,3]thiazolo[5,4-d]pyrimidine (Intermediate 78) in place of 6-(1-ethyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno-[2,3-d]pyrimidine (Intermediate 70). Yellow solid (60 mg, 64%);
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.[NH2:29][CH2:30][CH2:31][OH:32]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:29][CH2:30][CH2:31][OH:32])=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1
Reactant: NCCO
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)NCCO)cc3C)cc12

Procedure:
4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-3-methylbenzamide was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116/Step 2) and 2-aminoethanol following the procedures described for Example 117. 1H NMR (CDCl3): δ 8.59 (s, 1H), 8.34 (s, 1H), 8.04 (d, 1H), 7.50-7.62 (m, 3H), 7.08-7.25 (m, 2H), 3.80 (t, 2H), 3.63 (t, 2H), 3.07-3.16 (m, 4H), 2.51 (s, 3H), 2.32 (s, 3H). LRMS [M+H]=415.2
Reaction SMILES: O[CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:9].[CH3:26][C@H:27]1[CH2:31][CH2:30][C@H:29]([CH3:32])[NH:28]1>>[CH3:26][C@H:27]1[CH2:31][CH2:30][C@@H:29]([CH3:32])[N:28]1[CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:9]
Reactant: O=C(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)N1CCC[C@H]1CO
Reactant: C[C@H]1CC[C@H](C)N1
Product: C[C@@H]1CC[C@H](C)N1CC1CCCN1C(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure RR starting from (2-(S)-Hydroxymethyl-pyrrolidin-1-yl)-(4′-trifluoromethyl-biphenyl-4-yl)-methanone and mixture of cis and trans-2,5-dimethyl-pyrrolidine. MS (M+H) 431.2
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]([O:15][C:16](=[O:38])[CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:35][CH2:36][CH3:37])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:11]([O:15][C:16](=[O:38])[CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([N:27]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:35][CH2:36][CH3:37])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3ccc(Cl)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-benzoyl chloride (46 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C30H32ClN3O3+H: 518, observed: 518.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][CH2:9][C:10]1[C:11]([NH:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[C:12]2[CH:20]=[N:19][N:18]([CH2:21][CH3:22])[C:13]2=[N:14][C:15]=1[CH2:16][CH3:17])=[O:7].[Br:33][C:34]1[CH:35]=[C:36]([CH2:41][NH:42][CH3:43])[CH:37]=[CH:38][C:39]=1[F:40].CCOC(C)=O>CN(C=O)C>[Br:33][C:34]1[CH:35]=[C:36]([CH2:41][N:42]([CH2:2][C:3]2[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=2)[C:6]([NH:8][CH2:9][C:10]2[C:11]([NH:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[C:12]3[CH:20]=[N:19][N:18]([CH2:21][CH3:22])[C:13]3=[N:14][C:15]=2[CH2:16][CH3:17])=[O:7])[CH3:43])[CH:37]=[CH:38][C:39]=1[F:40]
Reactant: CNCc1ccc(F)c(Br)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CCl)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CN(C)Cc2ccc(F)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 66 h
Yield: 93.4 %

Procedure:
To a solution of 3-(chloromethyl)-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (0.284 g, 0.623 mmol) in DMF (2.5 mL) was added [(3-bromo-4-fluorophenyl)methyl]methylamine (0.436 g, 2.0 mmol). This mixture was stirred at room temperature for 66 h. Then EtOAc (50 mL) was added and that solution washed with H2O (7.5+2×5 mL), brine (5 mL), dried over Na2SO4. The dried organic solution was filtered, concentrated and purified by CombiFlash chromatograph to afford the title compound 0.371 g (93%). LC-MS m/z 637 (M+H)+.