Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:8]1(O)[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH3:21][O:22]C1C=CC(C2C=CC=CC=2)=CC=1.C1(=O)OC(=O)CC1.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:21][O:22][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:2](=[O:1])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[CH:9][CH:10]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)CCC(O)C1(O)C=CC(c2ccccc2)=CC1
Reactant: COc1ccc(-c2ccccc2)cc1
Agent: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1

Procedure:
γ,4-dihydroxy-4-biphenylbutyric acid may be prepared by treating p-methoxybiphenyl with succinic anhydride in nitrobenzene. The mixture is treated with aluminum chloride at reduced temperature. The solid is dissolved in aqueous base with heat, chilled to reprecipitate and acidified giving 4'-methoxy-γ-oxo-4-biphenylbutyric acid. This intermediate is refluxed with hydrogen bromide for several hours, diluted with water and cooled. The precipitate is 4'-hydroxy-γ-oxo-biphenylbutyric acid. This intermediate is treated with sodium borohydride in an alkaline medium and then acidified giving the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2([C:11]#N)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.CC(C[AlH]CC(C)C)C.C(OCC)(=[O:24])C.OS(O)(=O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2([CH:11]=[O:24])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(C)=O
Reactant: N#CC1(c2ccnc(Br)c2)CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: O=CC1(c2ccnc(Br)c2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-bromo-pyridin-4-yl)-cyclopropanecarbonitrile (1.16 g, 5.20 mmol) in toluene (30 mL) is added DIBAL-H (10.4 mL, 1M in toluene) at −78° C. The mixture is stirred 1 hour at −78° C. and warmed to room temperature. After 1 hour, ethyl acetate (30 mL) is added, followed by 1M aqueous solution of H2SO4 (30 mL). Phases are separated and the aqueous layer is extracted with ethyl acetate (3×50 mL). The combined organic layers are dried over MgSO4, filtered and concentrated to afford crude 1-(2-bromo-pyridin-4-yl)-cyclopropanecarbaldehyde (ES+ m/z 226.48; 228.47), which is used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].Cl>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(-c2ccccc2)ccc1OC
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)cc1C(=O)O

Procedure:
0.84 g (3.33 mmol) of methyl 2-Methoxy-5-phenylbenzoate was stirred under heating at 80° C. in a solvent mixture of dioxane/water containing 4 M of hydrogen chloride for 7 hours. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6](=[O:20])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[C:14]1[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=1)[CH3:3].[Cl:27][C:28]1[N:33]=[C:32](Cl)[C:31]([I:35])=[CH:30][N:29]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:27][C:28]1[N:33]=[C:32]([NH:1][C@H:2]([C:4]2[N:5]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:6](=[O:20])[C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)[CH3:3])[C:31]([I:35])=[CH:30][N:29]=1
Reactant: C[C@H](N)c1cc2cccc(-c3cnn(C)c3)c2c(=O)n1-c1ccccc1
Reactant: Clc1ncc(I)c(Cl)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(Cl)ncc1I)c1cc2cccc(-c3cnn(C)c3)c2c(=O)n1-c1ccccc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
(S)-3-(1-Aminoethyl)-8-(1-methyl-1H-pyrazol-4-yl)-2-phenylisoquinolin-1(2H)-one (63) (570 mg, 1.66 mmol), 2,4-dichloro-5-iodopyrimidine (455 mg, 1.66 mmol) and DIEA (0.27 mL, 1.66 mmol) were dissolved in n-butanol (12 mL) in a sealed tube, and the resulting mixture was stirred at 100° C. for 16 h. The mixture was allowed to cool to RT, quenched with water and extracted with ethyl acetate (150 mL×2). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the product (S)-3-(1-((2-chloro-5-iodopyrimidin-4-yl)amino)ethyl)-8-(1-methyl-1H-pyrazol-4-yl)-2-phenylisoquinolin-1(2H)-one (64) as an oil. The product obtained was used in the next step without purification. ESI-MS m/z: 583.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[CH:4][C:3]=1[O:18][CH2:19][O:20][CH3:21].[Li]CCCC.[I:27]I.S([O-])(O)=O.[Na+]>C1COCC1.CC(OC)(C)C>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[C:4]([I:27])[C:3]=1[O:18][CH2:19][O:20][CH3:21]
Reactant: II
Reactant: CCCCCC1CCc2cc(OCOC)c(F)c(F)c2O1
Agent: O=S([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCCCCC1CCc2c(I)c(OCOC)c(F)c(F)c2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
17.7 g (58.9 mmol) of 7,8-difluoro-6-methoxymethoxy-2-pentylchroman are initially introduced in 370 ml of THF, and 47.7 ml (75.9 mmol) of n-BuLi (15% soln. in hexane) are added dropwise at −78° C. When the addition is complete, the mixture is stirred at this temperature for 30 min and subsequently at room temperature for 1 h. The solution is re-cooled to −78° C., and a solution of 17.9 g (70.7 mol) of iodine in 100 ml of THF is added dropwise. The reaction mixture is stirred at room temperature for 90 min and subsequently diluted with MTBE. Sat. sodium hydrogensulfite soln. is added to the mixture, which is subsequently washed with water and sat. sodium chloride soln. The crude product remaining after drying using sodium sulfate and removal of the solvents is purified by column chromatography (SiO2, n-heptane:MTBE=3:1), giving 7,8-difluoro-5-iodo-6-methoxymethoxy-2-pentylchroman as a brown oil.
Reaction SMILES: [F:1][C:2]1[C:3]([O:9][C@@H:10]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]2)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.O1CCOCC1.[ClH:28]>>[F:1][C:2]1[C:3]([O:9][C@@H:10]2[CH2:14][CH2:13][NH:12][CH2:11]2)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[ClH:28]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ncc(F)cc2F)C1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1cnc(O[C@@H]2CCNC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-tert-butyl 3-(3,5-difluoropyridin-2-yloxy)pyrrolidine-1-carboxylate (0.83 g, 2.75 mmol) was dissolved in 4M HCl in dioxane (5 mL, 200 mmol) and stirred overnight at rt. The mixture was concentrated to leave (R)-3,5-difluoro-2-(pyrrolidin-3-yloxy)pyridine as its HCl salt (722 mg, quant). LC-MS Method 1 tR=0.58 min, m/z=201.
Reaction SMILES: ClC1C(Cl)=C(OCC(OCC)=O)C=C2C=1C1C(CC)(C2)CCCC=1.[Cl:25][C:26]1[C:38]([Cl:39])=[C:37]([O:40][C:41]2([C:46]([O:48]CC)=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42]2)[CH:36]=[C:35]2[C:27]=1[C:28]1[C:33]([CH3:51])([CH2:34]2)[CH2:32][CH2:31][C:30](=[O:52])[CH:29]=1>>[Cl:25][C:26]1[C:38]([Cl:39])=[C:37]([O:40][C:41]2([C:46]([OH:48])=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42]2)[CH:36]=[C:35]2[C:27]=1[C:28]1[C:33]([CH3:51])([CH2:34]2)[CH2:32][CH2:31][C:30](=[O:52])[CH:29]=1
Reactant: CCOC(=O)C1(Oc2cc3c(c(Cl)c2Cl)C2=CC(=O)CCC2(C)C3)CCCC1
Agent: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C1=CCCCC1(CC)C2
Product: CC12CCC(=O)C=C1c1c(cc(OC3(C(=O)O)CCCC3)c(Cl)c1Cl)C2

Procedure:
Carrying out a reaction as described in Example 1, Step E, except that the ethyl [(5,6-dichloro-9a-ethyl-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetate is replaced by an equimolar quantity of ethyl 1-[(5,6-dichloro-9a-methyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]cyclopentane-1-carboxylate, to give 1-[(5,6-dichloro-9a-methyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]cyclopentane-1-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[CH2:25]([OH:28])[C:26]#[CH:27]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:27]#[C:26][CH2:25][OH:28])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Oc1ccc2c(ccn2-c2ccc(F)cc2)c1)C(F)(F)F
Reactant: C#CCO
Product: OCC#Cc1ccc2c(ccn2-c2ccc(F)cc2)c1

Procedure:
In analogy to example 5.2, Trifluoro-methanesulfonic acid 1-(4-fluoro-phenyl)-1H-indol -5-yl ester and propargylalcohol were converted to yield 3-[1-(4-Fluoro-phenyl)-1H-indol -5-yl]-prop-2-yn-1-ol as light brown solid, 85-88° C., MS: 265 (M).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:32][C@H:33]5[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]5)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN[C@H]5CC[C@H](O)CC5)c4)cc23)CC1

Procedure:
Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol), trans-4-aminocyclohexanol (10 mg, 0.087 mmol) and NaBH(OAc)3 (58 mg, 0.261 mmol) were reacted to give the title compound (6.0 mg, 9.8%).
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([N+:19]([O-])=O)[CH:16]=[CH:17][CH:18]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[O:27][CH3:28])(=[O:3])[CH3:2]>[Ni].O1CCCC1>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[NH2:19])=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[O:27][CH3:28])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2cccc([N+](=O)[O-])c2)ccc(C(C)=O)c1OC
Agent: [Ni]
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2cccc(N)c2)ccc(C(C)=O)c1OC

Procedure:
2.0 g of Raney nickel are added to a solution of 10 g of 3-[3-(4-acetyl-3-methoxy-2-n-propylphenoxy)-propoxy]-nitrobenzene in 100 ml of tetrahydrofuran and the whole is hydrogenated at room temperature. The catalyst is filtered off and washed with tetrahydrofuran. After concentration of the filtrate by evaporation under reduced pressure, 3-[3-(4-acetyl-3-methoxy-2-n-propylphenoxy)-propoxy]-aniline is obtained in the form of a colourless oil.
Reaction SMILES: BrCC(N[C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])=O.Cl.NC(C)CO.C(N(CC)CC)C>C(O)C>[ClH:20].[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])[C:7]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:6]=1
Reactant: O=C(CBr)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: CC(N)CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
A mixture of 79.4 g. (225 mmole) of 2-(2-bromoacetamido)-5-chlorobenzophenone, 25 g. of 2-aminopropanol hydrochloride, 95 ml. of triethylamine and 500 ml. of ethanol was stirred overnight at room temperature, and then at reflux for 5 hours. The solution was concentrated under reduced pressure to a residue which was partitioned between ether and water. The organic layer was washed with water, dried and treated with hydrogen chloride to give 18 g. of a colorless solid. Recrystallizations from ethanol-ether gave prisms of 5-chloro-2-[2-hydroxy-2-propylamino)acetimido]-benzophenone, hydrochloride, m.p. 183°-186°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([C:15]3[N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:17]=[CH:18][CH:19]=3)[CH:14]=1)[O:11][C:10]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[CH:9][C:8]2=[O:33])=[O:4]>CO.[Rh]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([CH:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH:14]=1)[O:11][C:10]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[CH:9][C:8]2=[O:33])=[O:4]
Reactant: COC(=O)c1cc(-c2cccn2C(=O)OC(C)(C)C)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: [Rh]
Solvent: CO
Product: COC(=O)c1cc(C2CCCN2C(=O)OC(C)(C)C)c2oc(N3CCOCC3)cc(=O)c2c1
Yield: 83.5 %

Procedure:
tert-butyl 2-(6-(methoxycarbonyl)-2-morpholino-4-oxo-4H-chromen-8-yl)-1H-pyrrole-1-carboxylate (17.1 g, 37.63 mmol) and 5% Rhodium on Alumina (50% wet) (3.4 g, 0.80 mmol) in MeOH (175 mL) were stirred under an atmosphere of hydrogen at 5 bars and 65° C. for 7 h. The catalyst was removed from the reaction by filtration on a pad of Celite and washed with MeOH. The celite and catalyst were slurried in 500 mL of 10% MeOH in DCM and filtered again. The organic solutions were combined and evaporated to give tert-butyl 2-(6-(methoxycarbonyl)-2-morpholino-4-oxo-4H-chromen-8-yl)pyrrolidine-1-carboxylate (14.4 g, 83%) as a fawn solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:12]([N:28]=1)=[CH:13][C:14]1[CH2:15][N:16]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:17](=[O:20])[C:18]=1[CH:19]=2.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[CH2:37][C@@H:38]([NH2:40])[CH3:39].CCN(C(C)C)C(C)C>CCO>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[CH2:37][C@@H:38]([NH:40][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:12]([N:28]=1)=[CH:13][C:14]1[CH2:15][N:16]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:17](=[O:20])[C:18]=1[CH:19]=2)[CH3:39]
Reactant: C[C@H](N)Cc1cc(F)ccc1Cl
Reactant: O=C1c2cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc3cc2CN1CCN1CCCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cc1cc(F)ccc1Cl)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(CCN1CCCC1)C3
Yield: 36.1 %

Procedure:
A solution of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one (50 mg, 0.126 mmol), (1S)-2-(2-chloro-5-fluorophenyl)-1-methylethylamine (30 mg, 0.164 mmol) and DIEA (66 uL, 0.38 mmol) in 2 mL of EtOH was heated at 80° C. for 24 h. Then the solvent was evaporated and the residue was purified by column (silica gel, DCM:MeOH 9:1) to give 2-(4-((1S)-2-(2-chloro-5-fluorophenyl)-1-methylethylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one (25 mg, 36%) as pale yellow oil. ESI-MS: m/z (MH+) 549.5. 1H NMR (300 MHz, CD3OD): δ 8.0 (d, J=60.6 Hz, 1H), 7.67 (d, J=52.5 Hz, 1H), 7.33 (m, 1H), 7.15 (m, 2H), 6.89 (m, 1H), 6.09 (m, 1H), 4.66 (m, 2H), 3.98 (m, 2H), 3.68 (m, 1H), 3.30 (m, 2H), 3.15 (m, 6H), 2.02 (m, 4H), 1.43 (d, J=6.60 Hz, 3H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:26])[CH2:21][S:22][CH2:23][CH2:24][OH:25])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][CH:28]([CH3:32])[C:29](Cl)=[O:30]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:26])[CH2:21][S:22][CH2:23][CH2:24][O:25][C:29](=[O:30])[CH:28]([CH3:32])[CH3:27])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)OCCSCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 73 %

Procedure:
Following a procedure similar to that described in Example 7, but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) and 2-methylpropionyl chloride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a 73% yield.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]1[N:16]=[C:15]([Cl:17])[N:14]=[C:13]([NH:18][C:19]2[NH:23][N:22]=[C:21]([CH:24]3[CH2:26][CH2:25]3)[CH:20]=2)[N:12]=1.[F:27][C:28]1[N:33]=[CH:32][C:31]([NH:34][C:35]([C@:37]2([CH3:42])[CH2:41][CH2:40][CH2:39][NH:38]2)=[O:36])=[CH:30][CH:29]=1>C1COCC1>[Cl:17][C:15]1[N:14]=[C:13]([NH:18][C:19]2[NH:23][N:22]=[C:21]([CH:24]3[CH2:26][CH2:25]3)[CH:20]=2)[N:12]=[C:11]([N:38]2[CH2:39][CH2:40][CH2:41][C@@:37]2([CH3:42])[C:35]([NH:34][C:31]2[CH:32]=[N:33][C:28]([F:27])=[CH:29][CH:30]=2)=[O:36])[N:16]=1
Reactant: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
Diisopropylethylamine (0.77 mL, 4.42 mmol) was added to a mixture of 4,6-dichloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-1,3,5-triazin-2-amine (800 mg, 2.95 mmol) and (S)—N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide (625 mg, 2.8 mmol) in THF (20 mL). The reaction mixture was stirred at room temperature overnight and the product was separated by preparative HPLC. Removal of the solvents furnished 1C (860 mg, 64%) as a TFA salt. LC/MS [M+H]+: 458; Ret time (Method F): 2.70 min.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:12])=[N:9][C:10]=1[CH3:11])[CH3:2].[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20]([NH:12][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][O:3][CH2:1][CH3:2])=[C:10]([CH3:11])[N:9]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: CCOCc1ccc(N)nc1C
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: CCOCc1ccc(NS(=O)(=O)c2cccc(Cl)c2C)nc1C

Procedure:
This material was prepared in analogy to example 1 from 5-ethoxymethyl-6-methyl-pyridin-2-ylamine (0.066 g) and 3-chloro-2-methyl-benzenesulfonyl chloride (0.099 g) as an off-white solid (0.08 g). MS (ESI−): 351.3 ([M−H]−)
Reaction SMILES: C[C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18]C2C=CC=CC=2)=[O:15])=[N:10][CH:9]=1)(C)[C:3]([OH:5])=[O:4].ClCC[S:35]([C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=1)(=[O:37])=[O:36].C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([N:16]([CH2:17][CH2:18][S:35]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)(=[O:37])=[O:36])[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:2][C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)[CH2:26][CH2:27]1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)CCCl)cc1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: Cc1ccc(S(=O)(=O)CCN(C(=O)Nc2ncc(SCC(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 1-(2-chloro-ethanesulfonyl)-4-methyl-benzene and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[CH:21][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=O.[C:29]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])(=[O:34])[CH2:30][C:31]([CH3:33])=O>C(O)(=O)C>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([C:9]2[C:8]3[C:7](=[CH:24][C:23]([O:25][CH3:26])=[C:22]([O:27][CH3:28])[CH:21]=3)[N:6]=[C:31]([CH3:33])[C:30]=2[C:29]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:34])[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Reactant: CCCCOC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCCCOC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 53 %

Procedure:
Conc. sulfuric acid was added to a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone, butyl acetoacetate and acetic acid. The mixture was treated according to the same manner as in Reference Example 1 to give butyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-methylquinoline-3-carboxylate (53%). This compound was recrystallized from ethyl acetatehexane. Colorless prisms, mp. 119°-120° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.Cl[C:35]([O:37][CH3:38])=[O:36].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:26][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:35]([O:37][CH3:38])=[O:36])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2ccc(F)c(Cl)c2)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)NCCO[C@@H](c1ccc(F)c(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 4.3 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chloro-4-fluorophenyl)methyl)piperidine-1-carboxylate (1 g, 2.6 mmol) and DMAP (79 mg, 0.62 mmol) in dry CH2Cl2 (20 mL), Et3N (657 mg, 6.5 mmol) was added. The resulting mixture was cooled to 0-5° C. under ice-water bath, a solution of methyl chloroformate (1.22 g, 13 mmol, 5 eq) was added dropwise. After addition, the reaction mixture was stirred for 1-2 hr at rt. Water (20 mL) was added to quench the reaction. The aqueous layer was extracted with CH2Cl2 (3×20 mL), the combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative HPLC to afford (R)-tert-butyl 3-((R)-(3-chloro-4-fluorophenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (50 mg, yield 4.3%). 1H NMR (CDCl3, 400 MHz) δ 7.27 (m, 1H), 7.12 (m, 2H), 4.30 (s, 1H), 3.91 (d, 2H), 3.66 (s, 3H), 3.10-3.40 (m, 5H), 2.90 (m, 1H), 1.75 (s, 1H), 1.55 (d, 1H), 1.46 (s, 9H), 1.33 (m, 2H), 1.04 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[CH:12][N:11]([Si](C(C)C)(C(C)C)C(C)C)[C:8]2=[N:9][CH:10]=1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.7 %

Procedure:
To 1-Triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester (531, 0.950 g, 2.9 mmol) in tetrahydrofuran (20.0 mL) was added tetrabutyl-ammonium fluoride, trihydrate (1.20 g, 3.8 mmol). The reaction was stirred at room temperature for 10 minutes. The reaction was concentrated and purified with silica gel column chromatography eluting with 4% methanol in methylene chloride to give the compound as a white solid (532, 300 mg, 60%). MS (ESI) [M+H+]+=177.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH2:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:50][CH:49]([C:57]([NH2:59])=[O:58])[NH:48]1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:48]2[CH:49]([C:57]([NH2:59])=[O:58])[CH2:50][C:51]3[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH2:47]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: NC(=O)C1Cc2ccccc2CN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2oncc2C(=O)N2Cc3ccccc3CC2C(N)=O)cc1
Reaction time: 2 h
Yield: 22.1 %

Procedure:
A solution of 5-(4-methylphenyl)isoxazole-4-carboxylic acid (20 mg, 0.1 mmol), TBTU (39 mg, 0.12 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (35 μL, 0.2 mmol, 2 equ) in DMF (1 mL) was added to 1,2,3,4-tetrahydroisoquinoline-3-carboxamide (18 mg, 0.1 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (8 mg). MS (ESI, pos. ion) m/z calcd for C21H19N3O3: 361.1426, found 361.1418.