Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[CH2:19]1[O:27][C:26]2[CH:25]=[CH:24][C:23]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:22][C:21]=2[O:20]1.[C:34]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl>C1COCC1>[C:42]1([C:34]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([OH:41])[CH:29]([CH2:28][C:23]2[CH:24]=[CH:25][C:26]3[O:27][CH2:19][O:20][C:21]=3[CH:22]=2)[C:30]([O:32][CH3:33])=[O:31])[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: COC(=O)CCc1ccc2c(c1)OCO2
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccc2c(c1)OCO2)C(O)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 75.3 %

Procedure:
To a solution of di-isopropylamine (0.52 ml, 3.69 mmol) in dry THF (3 ml) at 0° C. under argon was added n-BuLi in hexane (1.36 ml, 2.5 M, 3.4 mmol). After stirring for 40 min the solution was cooled to -78° C. and a solution of methyl 3-(3,4-methylenedioxyphenyl)-propanoate (0.592 g, 2.84 mmol) in dry THF (2 ml) was added dropwise over 7 min. After a further 2 min a solution of benzophenone (0.517 g, 2.84 mmol) in dry THF (2 ml) was added dropwise. After a further 30 min at -78° C. the mixture was warmed to 0° C. over 30 min and poured into 1M aqueous HCl. The product was extracted with EtOAc (3X). The combined organic extract was washed with water (2X) then brine. After drying (Na2SO4 anhydrous), filtration and evaporation gave an off-white solid. Recrystallization from hot hexane gave the title compound (0.835 g, 76% yield) as a colorless solid.
Reaction SMILES: O1CCCC1.[C:6]([C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1)#[CH:7].[O:15]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[N:30][OH:31])=[CH:24][N:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>O>[O:15]([C:22]1[N:23]=[CH:24][C:25]([CH2:28][C:29]2[CH:7]=[C:6]([C:8]3[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=3)[O:31][N:30]=2)=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: ON=C(Cl)Cc1ccc(Oc2ccccc2)nc1
Reactant: C#Cc1ccc(N)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4ccccc4)nc3)no2)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
To a tetrahydrofuran (2 mL) solution of 5-ethynyl-pyridin-2-ylamine (30 mg, 0.25 mmol) described in Manufacturing Example 28-1-3 were added (2-phenoxy-pyridin-5-yl)-acetohydroximoyl chloride (100 mg, 0.381 mmol) described in Manufacturing Example 40-1-4 and triethylamine (70.8 μL, 0.508 mmol), which was stirred for 8 hours at 50° C. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (26 mg, 30%).
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([NH:27][N:28]2[NH:32][CH:31]=[CH:30][S:29]2)=[O:26])=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1>>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:18]=[CH:19][C:2]([C:22]2[CH:23]=[C:24]([C:25](=[O:26])[NH:27][N:28]3[NH:32][CH:31]=[CH:30][S:29]3)[CH:33]=[CH:34][C:21]=2[CH3:20])=[N:3][CH:4]=1
Reactant: Cc1ccc(C(=O)NN2NC=CS2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Product: COc1cccc(CNC(=O)c2ccc(-c3cc(C(=O)NN4NC=CS4)ccc3C)nc2)c1

Procedure:
N-(3-Methoxybenzyl)-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B. LCMS: retention time 3.02 min, MH+ 460. NMR: δH [2H6]-DMSO 13.14,(1H, b), 9.32, (1H, t), 9.24,(1H, s), 9.18,(1H, d), 8.40,(1H, dd), 8.26,(1H, s), 8.10,(1H, d), 7.84,(1H, d), 7.55,(1H, d), 7.27,(1H, t), 6.94,(2H, m), 6.84,(1H, d), 4.53,(2H, d), 3.75, (3H, s), 2.46,(3H, s).
Reaction SMILES: [CH2:1](OC(ON1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=C1.[CH3:28][NH:29][CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([N:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]([CH2:30][NH:29][CH3:28])=[CH:32]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCc1c[nH]c2ccccc12
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: c1ccc2[nH]ccc2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNCc1cn(Cc2ccccc2)c2ccccc12
Reaction time: 8 h
Yield: 86 %

Procedure:
3-IN-(Benzyloxycarbonyl)-N-methylaminomethyl]-1H-indole N-(Benzyloxycarbonyloxy)succinimide (8.9 g, 35.7 mmole) was added to a solution of 3-(methylaminomethyl)-1H-indole (5.2 g, 32.5 mmole) and triethylamine (5.0 mL, 65.7 mmole) in DMF (100 mL) at RT. The reaction was stirred overnight then was concentrated in vacuo. The residue was diluted with water and the mixture was extracted with ethyl acetate. The combined extracts were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (33% ethyl acetate/hexanes) gave the title compound (7.0 g, 74%) as an off-white solid: MS (ES) m/e 295 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24]C(C#N)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:10][N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-:28].[Na+].Cl.C(O)CO[CH2:34][CH2:35][OH:36]>>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:34]([C:35]([OH:36])=[O:28])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:10][N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: [OH-]
Reactant: OCCOCCO
Reactant: CCCCCCCc1ccc(-c2ccc(-c3ccc(C#N)cc3)cc2)cn1
Agent: Cl
Agent: [Na+]
Product: CCCCCCCc1ccc(-c2ccc(-c3ccc(C(=O)O)cc3)cc2)cn1

Procedure:
0.5 g (1.4 mmol) of 4'-(2-heptylpyridin-5-yl)-4-cyanobiphenyl and 0.5 g of sodium hydroxide were added to 20 ml of diethylene glycol and refluxed for 12 hours. By adding 200 ml of a 3% aqueous hydrochloric acid solution to the reaction solution, crystals were precipitated, separated by filtration and dried with air. The solid was recrystallized from acetic acid, to obtain 0.5 g of 4'-(2-heptylpyridin-5-yl)-4-biphenyl carboxylic acid. The melting thereof was above 250° C.
Reaction SMILES: [CH2:1]([C:8]1O[C:10]([O:14]CC)=[C:11]([CH3:13])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:17]1[CH2:23][CH:22]=[CH:21][CH2:20][O:19][CH2:18]1>>[CH2:1]([C:8]1[C:22]2[CH2:23][O:17][CH2:18][O:19][CH2:20][C:21]=2[C:10]([OH:14])=[C:11]([CH3:13])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=CCOCOC1
Reactant: CCOc1oc(Cc2ccccc2)nc1C
Product: Cc1nc(Cc2ccccc2)c2c(c1O)COCOC2
Temperature: 180 °C

Procedure:
A mixture of 8.4 g (40 millimoles) of 2-benzyl-4-methyl-5-ethoxyoxazole and 20 g (200 millimoles) of 4,7-dihydro-1,3-dioxepine is heated for 4 hours at 180° C. in an autoclave. Unconverted 4,7-dihydro-1,3-dioxepine is distilled off under reduced pressure. The residue is taken up in methylene chloride and extracted with 10% strength sodium hydroxide solution. On neutralizing the alkaline solution, 5.2 g of 6-benzyl-8-methyl-1,5-dihydro-[1,3]dioxepino[5,6-c]pyridin-9-ol precipitate and these are extracted with methylene chloride.
Reaction SMILES: C1([NH2:7])C=CC=CC=1.C([CH:15](Br)[C:16]([O-:18])=[O:17])C1C=CC=CC=1.CN(C)[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2N(C)C)C=CC=1.[I-].[Na+]>C(#N)C.CN(C=O)C>[C:31]1([CH2:22][O:18][C:16](=[O:17])[CH2:15][NH2:7])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ccccc1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: O=C([O-])C(Br)Cc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: NCC(=O)OCc1ccccc1

Procedure:
A mixture of 0.36 g (0.67 mmol) of 3-(octadecyloxy)-5-[(tricyclo[3.3.1.1/3,7/]dec-1-ylcarbonyl)oxy]benzenamine, 0.31 mL (2.0 mmol) of benzylbromoacetate, 0.44 g (2.0 mmol) of 1,8-bis(dimethylamino)naphthalene and 0.11 g (0.7 mmol) of sodium iodide in 10 mL of acetonitrile and 13 mL of DMF was stirred and refluxed under argon for 72 hours. The solvents were removed at reduced pressure, ethyl acetate was added to the residue and the extract was washed with 0.01 N HCl, with NaHCO3 solution, dried and concentrated at reduced pressure to an oil. Purification by chromatography on 75 g of silica gel using 15% ethyl acetate-hexane gave 0.177 g of N-[[3-(octadecyloxy)-5-(tricyclo[3.3.1.1/3,7/]dec-1-ylcarbonyl)oxy]phenyl]glycine phenylmethyl ester as an oil. The nmr and mass spectra were consistent with the structure. A mixture of 0.17 g of N-[[3-(octadecyloxy)-5-tricyclo[3.3.1.1/3,7/]dec-1-ylcarbonyl)oxy]phenyl]glycine phenylmethyl ester and 0.1 g of 10% palladium on carbon was shaken under an initial hydrogen pressure of 54 psi on a Parr Hydrogenator for 2.5 hours. The catalyst was removed at reduced pressure and the filtrate was concentrated at reduced pressure to 0.12 g of N-[[3-(octadecyloxy)-5-(tricyclo[3.3.1.1/3,7/]dec-1-ylcarbonyl)oxy]phenyl]glycine as a semisolid. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]#[CH:22].CN(C)C=O>O>[CH3:1][O:2][N:3]=[C:4]([O:13][CH2:22][C:21]#[CH:20])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12]
Reactant: CONC(=O)c1ccc(Cl)cc1Cl
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOC(=NOC)c1ccc(Cl)cc1Cl
Reaction time: 3 h
Yield: 29.8 %

Procedure:
1.0 g of N-methoxy-2,4-dichlorobenzamide, 0.75 g of potassium carbonate and 0.65 g of propargyl bromide were added to 10 ml of N,N-dimethylformamide, and the mixture was stirred for 3 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried, concentrated and purified by silica gel column chromatography to obtain 0.35 g of propargyl N-methoxy-2,4-dichlorobenzimidate.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:18]=[CH:17][C:12]3[NH:13][C:14](=[S:16])[NH:15][C:11]=3[CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([Cl:22])[CH:20]=[CH2:21]>C(O)C>[ClH:22].[C:1]1([S:7]([C:9]2[CH:18]=[CH:17][C:12]3[N:13]=[C:14]([S:16][CH2:21][CH:20]=[CH2:19])[NH:15][C:11]=3[CH:10]=2)=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CCCl
Reactant: O=S(c1ccccc1)c1ccc2[nH]c(=S)[nH]c2c1
Solvent: CCO
Product: C=CCSc1nc2ccc(S(=O)c3ccccc3)cc2[nH]1
Product: Cl

Procedure:
6.86 g (25 mmoles) of 5-phenylsulfinyl-benzimidazoline-2-thione and 4.9 ml (60 mmoles) of allylchloride are refluxed in 50 ml of ethanol for 24 hours. Then the reaction mixture is concentrated and the residue is crystallized from acetonitrile. The weight of the filtered endproduct is 7.68 g (87.55%). After recrystallization from ethanol it melts at 168° C.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]=[C:6]=[O:7])=[O:4].[NH2:8][C:9]1[S:10][C:11]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:12]=2[N:13]=1.C(Cl)Cl>C(OCC)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:11]2[S:10][C:9]([NH:8][C:6](=[O:7])[NH:5][C:3]([O:2][CH3:1])=[O:4])=[N:13][C:12]=2[CH:14]=1
Reactant: Nc1nc2cc(Cl)ccc2s1
Reactant: COC(=O)N=C=O
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)NC(=O)Nc1nc2cc(Cl)ccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
One part by weight of methoxycarbonyl isocyanate was added gradually with stirring to a solution of 2 parts by weight of 2-amino-5-chlorobenzothiazole in 100 parts by weight of methylene chloride and 50 parts by weight of ethyl ether. After stirring the reaction mixture at room temperature overnight, a product was isolated by filtration giving an 85% yield of methyl 4-(5-chlorobenzothiazol-2-yl)allophanate having a melting point of 395°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH:5]2[OH:20].[H-].[Na+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>O1CCCC1>[CH3:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[CH3:1])[C:5](=[O:20])[N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH:7]2[O:12][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc2c(cc1C)C(O)N(c1cccc(F)c1)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COC1c2cc(C)c(C)cc2C(=O)N1c1cccc(F)c1
Reaction time: 0.17 h
Yield: 96.7 %

Procedure:
To a solution of 5,6-dimethyl-2-(3-fluorophenyl)-3-hydroxyisoindolin-1-one (0.15 g, 0.55 mmol) in anhydrous tetrahydrofuran (5 ml) was added 60% sodium hydride (24 mg, 0.60 mmol), and stirred on ice for 10 minutes. Then, ethyl bromoacetate (67 ml, 0.60 mmol) was added thereto, and stirred at 25° C. overnight. The reaction solution was concentrated under reduced pressure, and water was added to the residue, followed by extracting with ethyl acetate. The extract was washed with saturated brine, dried, and concentrated under reduced pressure to give 0.19 g of 5,6-dimethyl-2-(3-fluorophenyl)-3-ethoxycarbonylmethyloxy-isoindolin-1-one [IUPAC name: ethyl 2-{[2-(3-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}-acetate].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[Mg].[CH3:13][N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].S(=O)(=O)(O)O>C1C=CC=CC=1.C(OCC)C>[OH:19][C:18]1([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=2)[N:14]([CH3:13])[C:15](=[O:20])[CH2:16][CH2:17]1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: CN1C(=O)CCC1=O
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CN1C(=O)CCC1(O)c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
To a Grignard prepared from 37 g. (0.16 mole) of 3-bromobenzotrifluoride and 3.7 g. (0.16 mole) of magnesium turnings in 100 ml. of dry diethylether, there is added dropwise over a period of about 10 minutes 12.2 g. (0.11 mole) of N-methylsuccinimide in 100 ml. of dry benzene. The resulting mixture is stirred and refluxed for about 4 hours and then allowed to stand overnight at room temperature. Stirring is resumed and 40 ml. of 50% sulfuric acid is added dropwise at such a rate to maintain a gentle reflux. After an additional 0.5 hours, the water layer is separated and washed twice with 50 ml. of benzene. The organic layers are combined and washed with 50 ml. of sodium carbonate and then twice more with 50 ml. of water. The resulting layer is dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resulting residue is crystallized from methylene chloride/hexane to give 5-hydroxy-1-methyl-5-(m-trifluoromethylphenyl)pyrrolidone; m.p. 137°- 139°C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[C:9]1[N:13]2[CH:14]=[C:15]([O:18][C@H:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:22]([NH2:29])[CH2:21][CH2:20]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.[CH:30]1([NH:33][C:34](=[O:45])[O:35]C2C=CC([N+]([O-])=O)=CC=2)[CH2:32][CH2:31]1>>[CH:34]([OH:45])=[O:35].[CH:30]1([NH:33][C:34]([NH:29][C@@H:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([N:3]5[C@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][C@@H:4]5[CH3:8])=[N:10][N:11]=4)[CH:14]=3)[CH2:20][CH2:21]2)=[O:35])[CH2:32][CH2:31]1
Reactant: O=C(NC1CC1)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)NC4CC4)c4ccccc43)cn12
Product: O=CO

Procedure:
The title compound was prepared starting from Intermediate 96c and 4-nitrophenyl cyclopropylcarbamate (for reference procedure see WO 2007/72158, which is incorporated herein by reference in its entirety) using analogous procedures to those described in Example 99. LCMS (Method 5): Rt 4.70 min, m/z 614 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.31-0.35 (2H, m), 0.52-0.60 (8H, m), 1.33-1.56 (3H, m), 1.63-1.70 (2H, m), 1.73-1.88 (3H, m), 1.94-2.11 (2H, m), 3.08-3.20 (2H, m), 4.78 (1H, td, J=8.6, 6.8 Hz), 5.47 (1H, t, J=3.8 Hz), 6.07 (1H, d, J=2.1 Hz), 6.24 (1H, d, J=8.9 Hz), 7.15-7.22 (2H, m), 7.27-7.32 (3H, m), 7.62 (1H, d, J=9.8 Hz), 7.84 (1H, d, J=1.7 Hz), 8.12 (0.6H, br s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13]C)=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([OH:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1Cl)C(=O)NCC2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C1NCCc2ccc(O)c(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 902.6 %

Procedure:
To a 0° C. solution of 8-chloro-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (1d, 7.8 g, 3.7 mmol) in dry CH2Cl2 (120 mL) was added dropwise BBr3 (11 mL, 111 mmol). After the addition, the mixture was stirred at room temperature overnight. To the reaction mixture was added dropwise H2O (200 mL). The mixture was extracted with EtOAc (8×200 mL), dried over Na2SO4 and concentrated under vacuum. To the residue was added EtOAc (20 mL) and petroleum ether (40 mL). The mixture was filtered and the solids were dried under vacuum to give 8-chloro-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (1e, 6.6 g, 91%) as a brown solid.
Reaction SMILES: C([O:8][C:9]1[CH:35]=[CH:34][C:33]([CH:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)=[CH:32][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12])C1C=CC=CC=1.C(Cl)(Cl)Cl>CO.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:35]=[CH:34][C:33]([CH:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)=[CH:32][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12]
Reactant: COC(=O)c1ccc(-c2cccc(OC)c2)cc1NC(=O)c1cc(C2CCN(C)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(-c2cccc(OC)c2)cc1NC(=O)c1cc(C2CCN(C)CC2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
To a solution mixture of the obtained methyl 2-(2-(benzyloxy)-5-(1-methylpiperidin-4-yl)benzamido)-4-(3-methoxyphenyl)benzoate (0.093 g) in methanol (2.0 mL) and ethyl acetate (2.0 mL), 10% palladium-carbon (0.050 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. Chloroform was added to the reaction mixture. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-92% chloroform/methanol] to obtain 0.026 g of methyl 2-(2-hydroxy-5-(1-methylpiperidin-4-yl)benzamido)-4-(3-methoxyphenyl)benzoate as a white solid.
Reaction SMILES: CN1CCCC1=O.[OH:8][C@H:9]1[C@H:13]([CH3:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1.[H-].[Na+].Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]([Cl:35])[N:26]=1>O>[Cl:35][C:27]1[N:26]=[C:25]([O:8][C@H:9]2[C@H:13]([CH3:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:10]2)[C:34]2[C:29]([CH:28]=1)=[CH:30][CH:31]=[CH:32][CH:33]=2
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1O
Reactant: Clc1cc2ccccc2c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Oc1nc(Cl)cc2ccccc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 58.2 %

Procedure:
To a 25 mL microwave vial was added N-methyl-2-pyrrolidinone (10.00 mL) and tert-butyl trans-3-hydroxy-4-methylpyrrolidine-1-carboxylate (1.118 g, 5.55 mmol). The mixture was cooled to 0° C. under a nitrogen atmosphere. To this mixture was added portion-wise NaH (60% suspension in mineral oil, 0.202 g, 5.05 mmol). After 5 minutes the mixture was allowed to warm to RT and was stirred for 10 minutes. Next, 1,3-dichloroisoquinoline (1 g, 5.05 mmol) was added and the reaction mixture was heated in a microwave reactor at 135° C. for 30 minutes. The reaction mixture was subsequently diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated onto silica. The crude product was purified by flash column chromatography (SiO2) eluting with a gradient of 5-50% heptane in EtOAc to give the title compound as a white solid (1.066 g, 58.2%). 1H NMR (500 MHz, CDCl3) δ ppm 1.16 (d, 3H), 1.48 (s, 9H), 2.60 (br s, 1H), 3.23 (br s, 1H), 3.49 (br s, 1H), 3.74 (br s, 1H), 3.94 (br s, 1H), 5.38 (br s, 1H), 7.23-7.32 (m, 1H), 7.51 (ddd, 1H), 7.61-7.71 (m, 2H), 8.17 (d, 1H); ESI-MS m/z [M+H]+ 307.6.
Reaction SMILES: C1(N([C@H]2CC[C@H](OC)CC2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11](SCC(O)=O)=[CH:12][N:13]=2)CCCC1.[CH:28]1([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C([O:43][C:44](=[O:55])[CH2:45][CH2:46][S:47][CH2:48]C1N=C(N)SC=1)C>>[CH:35]1([N:34]([CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:48][S:47][CH2:46][CH2:45][C:44]([OH:55])=[O:43])[N:13]=2)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: CO[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Reactant: CCOC(=O)CCSCc1csc(N)n1
Reactant: C1CCC(NC2CCCCC2)CC1
Product: O=C(O)CCSCc1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1

Procedure:
Prepared in accordance with the procedure for the synthesis of {2-[3-cyclopentyl-3-(trans-4-methoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using dicyclohexylamine and 3-(2-amino-thiazol-4-ylmethylsulfanyl)-propionic acid ethyl ester prepared in analogy to the methyl ester described in WO 2004/002481).
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:29])[CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C>C(O)CC(C)C.C(#N)C>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:29])[CH2:22][N:23]1[CH2:24][CH2:25][N:26]([C:3]2[NH:12][C:11](=[O:13])[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[N:4]=2)[CH2:27][CH2:28]1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Reactant: O=C(CN1CCNCC1)Nc1ccccn1
Solvent: CC#N
Solvent: CC(C)CCO
Solvent: CCN(CC)CC
Product: O=C(CN1CCN(c2nc3c(c(=O)[nH]2)CCCC3)CC1)Nc1ccccn1

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol), N-(2-pyridyl)-2-(piperazin-1-yl)acetamide * 3HCl * 2H2O (279.5 mg; 0.76 mmol) and triethylamine (282.5 μl; 2.04 mmol) are reacted in isoamyl alcohol (2 ml) in accordance with the procedure for Example 9 (reaction time 8 h) and worked up. The crystals obtained are dissolved in acetonitrile and water and freeze-dried; yield: 19 mg (10%), crystals;
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].Cl[CH2:13][CH:14]=O>O>[CH3:10][C:8]1[N:9]2[CH:13]=[CH:14][N:1]=[C:2]2[C:3]([C:4]#[N:5])=[C:6]([CH3:11])[CH:7]=1
Reactant: Cc1cc(C)c(C#N)c(N)n1
Reactant: O=CCCl
Solvent: O
Product: Cc1cc(C)n2ccnc2c1C#N
Yield: 75 %

Procedure:
To a stirred solution of compound 2-amino-4,6-dimethylnicotinonitrile (1 equiv.) in water was added chloroacetaldehyde (55% aq. solution) (1.2 equiv.) and reaction was heated at 80 oC for 16 h. On completion, it was quenched by 1N NaOH till pH 8. Solid precipitated was filtered and vacuum dried to afford the title compound (75% yield).