Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:40]=[CH:39][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][F:38])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:41][CH3:42].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.ClCCl>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:40]=[CH:39][C:26]([C:27]([NH:29][CH:30]5[CH2:31][CH2:32][N:33]([CH2:36][CH2:37][F:38])[CH2:34][CH2:35]5)=[O:28])=[CH:25][C:24]=4[O:41][CH3:42])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)NC2CCN(CCF)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(C(=O)NC2CCN(CCF)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
A mixture of 0.08 g (0.25 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20) and 0.075 g (0.25 mmole) of 4-amino-N-[1-(2-fluoro-ethyl)-piperidin-4-yl]-3-methoxy-benzamide and 0.072 g (0.38 mmole) of p-toluenesulfonic acid monohydrate in 3 mL of isopropanol was stirred in a sealed tube at 140 degrees overnight. The mixture was cooled, and dichloromethane and saturated sodium carbonate were added. The mixture was extracted twice with dichloromethane. The combined organic layers were washed three times with sodium carbonate three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.080 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-[1-(2-fluoro-ethyl)-piperidin-4-yl]-3-methoxy-benzamide (I-75).
Reaction SMILES: [CH2:1](N(CC)CC)C.IC.[OH:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[N:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)[NH:23][C:24]3=[O:27])=[CH:19][CH:18]=2)[CH2:12]1>C(#N)C>[OH:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[N:34]4[CH2:39][CH2:38][N:37]([CH3:1])[CH2:36][CH2:35]4)[NH:23][C:24]3=[O:27])=[CH:19][CH:18]=2)[CH2:12]1
Reactant: O=c1[nH]c(-c2ccccc2N2CCNCC2)cc2ccc(N3CCCC(O)C3)cc12
Reactant: CCN(CC)CC
Solvent: CC#N
Solvent: CI
Product: CN1CCN(c2ccccc2-c2cc3ccc(N4CCCC(O)C4)cc3c(=O)[nH]2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.3 %

Procedure:
0.0185 ml (0.133 mmol) of triethylamine and 0.00665 ml (0.107 mmol) of iodomethane were added to an acetonitrile solution (0.4 ml) containing 3.6 mg (0.0089 mmol) of the 7-(3-hydroxypiperidin-1-yl)-3-(2-piperazin-1-ylphenyl)-2H-isoquinolin-1-one obtained in Example 102. The obtained mixture was stirred at a room temperature for 4 hours. Thereafter, the solvent was distilled away under reduced pressure. The obtained residue was developed and purified by thin-layer chromatography (NH2 F254s, Merck, developing solvent; dichloromethane:methanol=10:1, Rf value: 0.8), so as to obtain 1.8 mg (48%) of 7-(3-hydroxypiperidin-1-yl)-3-[2-(4-methylpiperazin-1-yl)phenyl]-2H-isoquinolin-1-one in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2.[CH:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19](O)=[O:20])([CH3:15])[CH3:14]>>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:19]([C:18]1[CH:22]=[C:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:24]=[CH:25][C:17]=1[O:16][CH:13]([CH3:15])[CH3:14])=[O:20])[CH2:7]2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Clc1cc(Cl)c2c(c1)CNCC2
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2c(Cl)cc(Cl)cc2C1

Procedure:
Prepared in analogy to example 1.1 from 5,7-dichloro-1,2,3,4-tetrahydro-isoquinoline (CA [89315-56-0]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.[CH3:35][C:36]1[N:40]([CH2:41][CH2:42]O)[C:39]([CH3:44])=[N:38][N:37]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:42][CH2:41][N:40]4[C:39]([CH3:44])=[N:38][N:37]=[C:36]4[CH3:35])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: Cc1nnc(C)n1CCO
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCn1c(C)nnc1C
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 123.8 %

Procedure:
Diethyl azodicarboxylate (295 μl, 1. 8 mmol) was added dropwise to a suspension of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (200 mg, 0.62 mmol), (prepared as described for the starting material in Example 24), 2-(3,5-dimethyl-[1,2,4]-triazol-4-yl)ethanol (114 mg, 0.81mmol), (EP 0329357 A1), and triphenylphosphine (492 mg, 1.8 mmol) in methylene chloride (4 ml) and the mixture stirred for 1 hour at ambient temperature. The precipitated solid was collected by filtration, washed with ether and dried under vacuum. The solid was dissolved in methylene chloride/methanol and ethereal hydrogen chloride (2 ml of 4.5M solution) was added. The volatiles were removed by evaporation, the residue was suspended in ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-7-(2-(3,5-dimethyl-[1,2,4]-triazol-4-yl)ethoxy)-6-methoxyquinazoline hydrochloride (184 mg, 54%).
Reaction SMILES: CN(C)C=O.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:15]=[CH:14][C:13]1=[O:24].[Br:25]N1C(=O)CCC1=O>O>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:15]=[C:14]([Br:25])[C:13]1=[O:24]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1ccc(-c2ccccn2)cn1-c1ccccn1
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccn1
Yield: 54.3 %

Procedure:
2 ml of a dimethylformamide solution containing 0.07 g of 1-(2-pyridyl)-5-(2-pyridyl)-1,2-dihydropyridin-2-one was incorporated with 0.07 g of N-bromosuccinic acid imide, under stirring and ice-cooling. After stirring the mixture at room temperature for 2 hours, it was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl acetate/hexane=3:1), to give 0.05 g of the title compound as a pale brown powder.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH2:17][CH:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)[C:6]=3[C:5]1=2)#[N:2].[OH:31][Li].O.OO>CO.C(OCC)(=O)C>[NH:21]1[CH2:20][CH2:19][CH:18]([CH2:17][O:16][C:7]2[N:8]=[CH:9][N:10]=[C:11]3[C:6]=2[C:5]2[C@@H:4]([CH2:3][C:1]([NH2:2])=[O:31])[CH2:15][CH2:14][C:13]=2[S:12]3)[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ncnc3sc4c(c23)[C@@H](CC#N)CC4)CC1
Reactant: [Li]O
Agent: OO
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: NC(=O)C[C@H]1CCc2sc3ncnc(OCC4CCNCC4)c3c21
Temperature: 0 °C

Procedure:
To a solution of tert-butyl 4-([[(3R)-3-(cyanomethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]methyl)piperidine-1-carboxylate (290 mg, 0.68 mmol, 1.00 equiv) in methanol (20 mL) were added LiOH.H2O (114 mg, 2.71 mmol, 4.01 equiv). This was followed by the addition of H2O2 (30%) (114 mg, 4.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 4 h at room temperature. The resulting solution was diluted with 50 mL of ethyl acetate. The resulting mixture was washed with 3×20 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. This resulted in 220 mg (73%) of tert-butyl 4-([[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]methyl)piperidine-1-carboxylate as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[C:15]([OH:17])=O)[CH:5]=[CH:6][C:7]=1[CH3:8].[NH:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25]([C:27]2[N:34]3[C:30]([S:31][CH:32]=[CH:33]3)=[N:29][C:28]=2[CH3:35])=[O:26])[CH2:19]1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[C:15]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25]([C:27]3[N:34]4[C:30]([S:31][CH:32]=[CH:33]4)=[N:29][C:28]=3[CH3:35])=[O:26])[CH2:19]2)=[O:17])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(C)c(C)c2)s1
Product: Cc1nc(C(=O)N2CCC[C@@H](NC(=O)c3c(C)nc4sccn34)C2)c(-c2ccc(C)c(C)c2)s1

Procedure:
prepared by reaction of 5-(3,4-dimethyl-phenyl)-2-methyl-thiazole-4-carboxylic acid with (R)-6-methyl-imidazo[2,1-b]-thiazole-5-carboxylic acid-piperidin-3-ylamide.
Reaction SMILES: Cl.C(OCC)(=O)C.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[C:17]([C:36]([C:38]1[CH:43]=[CH:42][N:41]=[C:40]([O:44]C)[CH:39]=1)=[O:37])[C:18]([C:20]1[CH:21]=[C:22]([S:26]([NH:29][C:30](=[NH:35])[C:31]([OH:34])([CH3:33])[CH3:32])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)=[O:19]>CCO.O1CCOCC1>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[C:17]([C:36](=[O:37])[C:38]1[CH:43]=[CH:42][NH:41][C:40](=[O:44])[CH:39]=1)[C:18]([C:20]1[CH:21]=[C:22]([S:26]([NH:29][C:30](=[NH:35])[C:31]([OH:34])([CH3:32])[CH3:33])(=[O:27])=[O:28])[CH:23]=[CH:24][CH:25]=1)=[O:19]
Reactant: COc1cc(C(=O)C(C(=O)c2cccc(S(=O)(=O)NC(=N)C(C)(C)O)c2)=C2Nc3ccccc3N2)ccn1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(O)C(=N)NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc[nH]c(=O)c2)=C2Nc3ccccc3N2)c1
Reaction time: 1 h
Yield: 14.6 %

Procedure:
Under ice cooling, 4 N—HCl/ethyl acetate (0.09 mL) was added to an EtOH/dioxane (2/1) mixed solution (4 mL) of N-({3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(2-methoxypyridin-4-yl)-3-oxopropanoyl]phenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide (127 mg), followed by stirring for 1 hour. The reaction mixture was concentrated under reduced pressure. An aqueous sodium hydrogencarbonate solution was added to the resulting residue, followed by extraction with ethyl acetate and concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to obtain N-({3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxo-3-(2-oxo-1,2-dihydropyridin-4-yl)propanoyl]phenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide (18 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:3]=1.Cl.Cl[C:21]1C=CC(C(O)=O)=C(NC2C=CC(OC)=CC=2)C=1.S(OC)(OC)(=O)=O.ClC1C=CC(C(OC)=O)=C(NC2C=CC(OC)=CC=2)C=1.B(Br)(Br)Br>CO>[CH3:21][C:3]1[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[C:5]([CH:9]=[CH:10][C:2]=1[Cl:1])[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(Cl)cc1Nc1ccc(O)cc1
Reactant: COc1ccc(Nc2cc(Cl)ccc2C(=O)O)cc1
Agent: BrB(Br)Br
Agent: COC(=O)c1ccc(Cl)cc1Nc1ccc(OC)cc1
Agent: Cl
Solvent: COS(=O)(=O)OC
Solvent: CO
Product: Cc1c(Cl)ccc(C(=O)O)c1Nc1ccc(O)cc1

Procedure:
[I; R=4-Cl, R' and R"=H, Alk=CH3, OH at 4-position] is obtainable by esterification of 4-chloro-2-(4-hydroxyphenylamino)benzoic acid with methanol and hydrochloric acid; or by esterification of 4-chloro-2-(4-methoxyphenylamino)benzoic acid with dimethyl sulfate, followed by de-etherification of the resulting methyl 4-chloro-2-(4-methoxyphenylamino)benzoate with boron tribromide.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])#[N:24].[H-].[Na+].Cl>O.O1CCOCC1>[C:23]([CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:11]1[C:12]([F:14])=[C:13]2[C:8]([C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][N:4]2[CH:1]2[CH2:2][CH2:3]2)=[CH:9][C:10]=1[F:16])#[N:24]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CCOC(=O)CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(C(C#N)C(=O)OCC)c(F)cc2c1=O

Procedure:
86.2 g of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylate and 63.3 g of ethyl cyanoacetate are initially introduced into 1,000 ml of dioxane. 15.8 g of NaH are added in portions. The mixture is then heated to reflux for 4 hours. The completeness of the reaction is checked using thin-layer chromatography. After completion of the reaction, water is added dropwise. The mixture is then rendered acidic using dilute HCl and extracted using methylene chloride. The organic phase is dried and evaporated. The residue is recrystallized from isopropanol.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[O:6]=[C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[C:13]([OH:15])=O.[Br:16]Br>C(OCC)C>[CH2:1]([N:3]([CH2:4][CH3:5])[C:13]([CH:8]1[CH2:9][CH2:10][CH2:11][CH:12]([Br:16])[C:7]1=[O:6])=[O:15])[CH3:2]
Reactant: O=C(O)C1CCCCC1=O
Reactant: BrBr
Reactant: CCNCC
Solvent: CCOCC
Product: CCN(CC)C(=O)C1CCCC(Br)C1=O
Temperature: 0 °C
Yield: 109.8 %

Procedure:
2-oxo-cyclohexanecarboxylic acid diethylamine (3.56 mL, 19.3 mmol) was dissolved in diethyl ether (5 mL) and cooled with stirred to 0° C. under N2. Bromine (0.99 mL, 19.3 mmol) was added drop wise over 15 minutes and the reaction mixture was allowed to warm to room temperature over 3 hours. A solid had precipitated out of the reaction. It was collected by filtration and washed with ether to give 5.85 g (109%) of 3-Bromo-2-oxo-cyclohexanecarboxylic acid diethylamide (35) as a pale yellow solid. The structure was confirmed by 13C NMR (CDCl3) 811.2, 12.8, 22.7, 28.8, 37.6, 37.9, 39.4, 51.0, 55.7, 165.5, 197.2
Reaction SMILES: [CH:1]([N:4]([CH:16]([CH3:18])[CH3:17])[C:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2].[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([C@@H:30]2[C@H:35]([NH2:36])[CH2:34][CH2:33][O:32][CH2:31]2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH3:20].C(N(CC)CC)C>ClCCl>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([C@@H:30]2[C@H:35]([NH:36][C:11](=[O:12])[C:10]3[CH:14]=[CH:15][C:7]([C:5]([N:4]([CH:16]([CH3:18])[CH3:17])[CH:1]([CH3:3])[CH3:2])=[O:6])=[CH:8][CH:9]=3)[CH2:34][CH2:33][O:32][CH2:31]2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH3:20]
Reactant: CCOc1cc([C@H]2COCC[C@H]2N)ccc1OC
Reactant: CC(C)N(C(=O)c1ccc(C(=O)Cl)cc1)C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc([C@H]2COCC[C@H]2NC(=O)c2ccc(C(=O)N(C(C)C)C(C)C)cc2)ccc1OC
Reaction time: 2 h

Procedure:
A solution of 1 equivalent 4-diisopropylcarbamoyl-benzoyl chloride (prepared from N,N-diisopropyl-terephthalamic acid and thionyl chloride) in dichloromethane is added dropwise at RT in the course of 10 min. to a solution of 1 equivalent of (3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-tetrahydro-pyran-4-ylamine in dichloromethane and 1.1 equivalents of triethylamine. After stirring for about 2 h, the mixture is extracted with saturated sodium hydrogencarbonate solution, and the organic phase is washed a further two times with water and dried over sodium sulfate. The viscous residue remaining after concentration is purified by column chromatography on SiO2 (dichloromethane/ethyl acetate 85/15 vol/vol). The main product fraction concentrated in vacuo affords a brownish solid foaming residue which is used for the next reaction step without further treatment.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 31.8 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (60 mg, 0.16 mmol), 5-aminovaleric acid (909 mg, 7.8 mmol), and NaOMe solution (12 mL, 6.2 mmol) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-60% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 24 mg of the title compound as a pale yellow solid. MS: (+) m/z 472.34 (M+1).
Reaction SMILES: I.I[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[C:12]([CH3:24])[CH:11]=2)[C:4]=1[NH2:25].[C:26]([C:28]1[CH:29]=[C:30]([CH:40]=[CH:41][CH:42]=1)[CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])#[CH:27]>C(#N)C.C(N(CC)CC)C.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.[Cu]I>[NH2:25][C:4]1[C:3]([C:27]#[C:26][C:28]2[CH:29]=[C:30]([CH:40]=[CH:41][CH:42]=2)[CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[N:8][CH:7]=[N:6][C:5]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[C:12]([CH3:24])[CH:11]=1
Reactant: C#Cc1cccc(CNC(=O)OC(C)(C)C)c1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc(I)c3N)cc2C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2ccc(Nc3ncnc(C#Cc4cccc(CNC(=O)OC(C)(C)C)c4)c3N)cc2C)cn1
Yield: 78.6 %

Procedure:
6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine hydroiodide (500 mg) was dissolved in a mixed solvent of acetonitrile (14.8 mL)/triethylamine (11.0 mL), and tert-butyl 3-ethynylbenzylcarbamate (247 mg), trans-dichlorobis(triphenylphosphine)palladium(II) (31.3 mg) and copper(I) iodide (10.2 mg) were sequentially added. The title compound (376 mg) was obtained as a powder by the reaction in the same manner as in Example 9 (iv).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[NH:12][C:13]([CH:16]=[O:17])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C=O)C>[CH:16]([C:13]1[N:12]([CH3:18])[C:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[CH:15][CH:14]=1)=[O:17]
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)[nH]1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(C=O)ccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-formyl-1H-pyrrole-2-carboxylic acid benzyl ester (from the preparation of Intermediate 18) (400 mg, 1.75 mmol) in DMF (10 mL) is added cesium carbonate (853 mg, 2.62 mmol) and MeI (297 mg, 2.09 mmol). The mixture is stirred at room temperature for 2 hours then water is added and the mixture is extracted with ethyl acetate (3×). The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure to give benzyl 5-formyl-1-methyl-1H-pyrrole-2-carboxylate; HPLC Retention time 1.26 minutes (condition C): MS 244.3 (M+1).
Reaction SMILES: [Na+].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH2:16][S:17]([O-:20])(=O)=[O:18])[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN(C)C=O.C(Cl)(=O)C([Cl:29])=O>C1COCC1.C(OCC)C>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH2:16][S:17]([Cl:29])(=[O:20])=[O:18])[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)([O-])Cc1cccc(OCc2ccccc2)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=S(=O)(Cl)Cc1cccc(OCc2ccccc2)c1
Reaction time: 0.25 h

Procedure:
Under inert gas, 2.36 g of (3-benzyloxyphenyl)methanesulfonic acid sodium salt and 0.61 ml of N,N-dimethylformamide were initially charged in 45 ml of THF, then, at a temperature of −20° C., 4.1.73 ml of oxalyl chloride were added dropwise and the reaction solution was allowed to come to 0° C. within 15 minutes. The reaction solution was diluted with 100 ml of diethyl ether and washed with water, dilute aqueous sodium hydrogencarbonate solution and saturated sodium chloride solution. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. The residue (2.30 g) was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=2F)=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O-:24].[Na+]>C(Cl)Cl.CO>[CH2:1]([N:8]1[C:12]([C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=2[O:24][CH3:23])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc(F)c1-c1nnnn1Cc1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cccc([N+](=O)[O-])c1-c1nnnn1Cc1ccccc1
Reaction time: 4 h

Procedure:
1-Benzyl-5-(2-fluoro-6-nitrophenyl)-1H-tetrazole (Intermediate 18, 0.3 g) was dissolved in DCM (4 mL) and a solution of sodium methoxide in methanol (20%; 2 mL) was added. The mixture was stirred for 4 hours and then the solvent was removed by evaporation under vacuum. The residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid and then brine. The organic solution was dried with sodium sulfate, filtered and the solvent was removed by evaporation under vacuum. The residue was purified by flash chromatography on silica, eluting with a mixture of DCM and methanol. The fractions containing the desired product were combined and evaporated to give the title compound as a pale yellow solid (0.14 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[CH:4][C:3]=1[NH2:16].[CH3:17][O:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>>[CH3:17][O:18][CH2:19][CH2:20][C:21]([NH:16][C:3]1[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH:6]=[CH:7][C:2]=1[CH3:1])=[O:22]
Reactant: Cc1ccc(COC2CCCCO2)cc1N
Reactant: COCCC(=O)Cl
Product: COCCC(=O)Nc1cc(COC2CCCCO2)ccc1C

Procedure:
Analogously to Example 116b, 4.95 g of 2-methyl-5-(tetrahydropyran-2-yloxymethyl)phenylamine and 3.27 g of 3-methoxypropionyl chloride are reacted. The title compound is obtained as a white solid. Rf=0.33 (2:1 EtOAc-heptane); Rt=3.60.