Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][C:7]1[CH:61]=[CH:60][C:10]([CH2:11][C:12]2[CH:13]=[C:14]([C@@:19]3(OC)[C@H:24]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:23]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C@H:22]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[O:20]3)[CH:15]=[CH:16][C:17]=2[Cl:18])=[CH:9][CH:8]=1)[CH:2]=[CH2:3].C([SiH](CC)CC)C.B(F)(F)F.O>C(Cl)Cl>[CH2:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][C:12]2[CH:13]=[C:14]([C@H:19]3[C@H:24]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:23]([O:33][CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C@H:22]([O:41][CH2:42][C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[O:20]3)[CH:15]=[CH:16][C:17]=2[Cl:18])=[CH:60][CH:61]=1)[CH:2]=[CH2:3]
Reactant: C=CCOCCc1ccc(Cc2cc([C@]3(OC)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: O
Product: C=CCOCCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Reaction time: 3 h
Yield: 60 %

Procedure:
(2S,3R,4S,5R,6R)-2-(3-(4-(2-(allyloxy)ethyl)benzyl)-4-chlorophenyl)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-methoxytetrahydro-2H-pyran (intermediate BJ) (55 mg, 0.065 mmol) was taken up in 1 mL anhydrous DCM kept under argon, and triethylsilane (31.4 μL, 0.197 mmol) was added. The mixture was brought to −20° C. and borontrifluoride diethyletherate (20.1 μL, 0.164 mmol) was added. The mixture was allowed to warm and stirred at −5° C. to 0° C. for 3 h. Water (0.5 mL) was added to quench the reaction and the organic layer was separated. The aqueous layer was extracted with DCM (1 mL), and the combined organic solution was washed with brine (1 mL), dried (Na2SO4), filtered and evaporated. Preparative TLC using 10:1 hexane:EtOAc gave intermediate BK (39.5 mg, yield 60%). 1H NMR (300 MHz, CDCl3): δ 7.30-7.03 (m, 27H), 5.90 (m, 1H), 5.22 (m, 2H), 4.88-4.70 (m, 3H), 4.65-4.38 (m, 5H), 4.16-4.08 (m, 3H), 4.05-3.88 (m, 4H), 3.82-3.72 (m, 5H), 3.60-3.52 (m, 3H); LC-ESI-MS (m/z): 808 (M+H).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[Br:14][CH2:15][CH2:16][CH2:17]Br.C(N(CC)CC)C>CN(C)C=O>[Br:14][CH2:15][CH2:16][CH2:17][N:10]1[C:11]2[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=2[N:8]=[CH:9]1
Reactant: BrCCCBr
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(ncn2CCCBr)n(C)c1=O
Reaction time: 24 h
Yield: 76.6 %

Procedure:
A solution of theophylline (10.0 g, 0.0555 mol), 1,3-dibromopropane (11.6 ml, 23.1 g, 0.114 mol) and triethylamine (10.5 ml, 7.62 g, 0.0753 mol) in N,N-dimethylformamide (250 ml) was stirred at 60° C. overnight. The stirring was continued one day at room temperature. The solvent was evaporated under reduced pressure. The residue was suspended in CH2Cl2 and water. An emulsion was caused by a fine solid suspended in the mixture. The solid was filtered out and discarded. The aqueous layer was extracted three times with CHCl3. The combined organic layers were dried with MgSO4. Evaporation of the solvent under reduced pressure gave 7-(3-bromopropyl)-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione (12.8 g, 77% yield).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1.[OH:27][C@@H:28]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:29](O)=[O:30].F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[OH:27][C@H:28]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:29]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1)=[O:30]
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Reactant: NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1)[C@H](O)Cc1ccccc1
Yield: 46.3 %

Procedure:
A mixture comprising 50 mg (130 μmol) (RS)-6-{[7-(aminomethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]amino}-1,3-benzothiazol-2(3H)-one (prepared according to example 20), 4 mL N,N-dimethylforamide, 17.5 mg N,N-dimethylpyridin-4-amine, 21.7 mg (2S)-2-hydroxy-3-phenylpropanoic acid and 54.5 mg N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphate was stirred at 23° C. overnight. The solvent was removed and the residue purified by chromatography to give 32 mg (45%) of the title compound.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:21]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[O:21]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:33])=[CH:35][CH:36]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1ccc(Oc2ccccc2)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and p-phenoxybenzoyl chloride, there is obtained ethyl N-(p-phenoxybenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a foam, mass spectrum m/e: M+ 462 (8), 433 (5), 197 (30), 194 (100);
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:5]([C:21]([OH:23])=O)=[N:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9].[NH2:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:37]1[CH:38]=[CH:39][CH:40]=[C:35]([NH:34][C:21]([C:5]2[C:4]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=3)=[CH:3][C:2]([CH3:1])=[C:7]([C:8]([N:10]3[CH2:15][CH2:14][CH:13]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[CH2:12][CH2:11]3)=[O:9])[N:6]=2)=[O:23])[CH:36]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)O)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: Nc1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)Nc2cccnc2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of example 1, 5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (example 47) was reacted with 3-aminopyridine, Et3N and HATU in DMF to give the title compound as light yellow solid. MS: 538.2 (MH+).
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=1)#[CH:25]>>[OH:35][C:32]([C:29]1[CH:28]=[CH:27][C:26]([C:24]2[N:3]=[N:2][N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[CH:25]=2)=[CH:31][CH:30]=1)([CH3:34])[CH3:33]
Reactant: C#Cc1ccc(C(C)(C)O)cc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Product: CC(C)(O)c1ccc(-c2cn(C3CCc4c(CC(=O)O)c5ccccc5n4C3)nn2)cc1

Procedure:
The title compound was prepared using procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate and 2-(4-ethynylphenyl)propan-2-ol. MS (+ESI) m/z: 431.2.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:15]=3[O:14][C:13]2([CH3:23])[CH3:22])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1.O>CN(C)C=O>[CH:3]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[C:16]3[CH:17]=[CH:18][C:19]([O:21][CH2:30][C:29]4[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=4)=[CH:20][C:15]=3[O:14][C:13]2([CH3:23])[CH3:22])=[CH:10][CH:11]=1)([CH3:5])[CH3:4]
Reactant: CC(C)c1ccc(C2c3ccc(O)cc3OC2(C)C)cc1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2ccc3c(c2)OC(C)(C)C3c2ccc(C(C)C)cc2)cc1
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
Sodium hydride (60% liquid paraffin dispersion, 179.0 mg, 4.48 mmol) was added to a solution of 3-(4-isopropylphenyl)-2,2-dimethyl-2,3-dihydrobenzofuran-6-ol (1.12 g, 4.00 mmol) in N,N-dimethylformamide (15 mL) at 0° C., and the mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was added 4-methoxybenzyl chloride (636.8 mg, 4.07 mmol) and the mixture was stirred for further 30 minutes at room temperature. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain the title compound (1.19 g, yield 74%).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]2[CH2:6][CH:7]([CH3:25])[N:8](C(OCC)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:27]=[CH:26][C:5]2[CH2:6][CH:7]([CH3:25])[NH:8][N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: CCOC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc(Br)ccc2CC1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1Cc2ccc(Br)cc2C(c2ccc([N+](=O)[O-])cc2)=NN1
Yield: 92.3 %

Procedure:
5.20 g (12 mmoles) of 8-bromo-3-ethoxycarbonyl-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 32) are boiled in 104 ml of methanol with 6 ml of 10N sodium hydroxide solution for 2 hours. After cooling, the reaction mixture is diluted with 104 ml of water, and the precipitated crystals are filtered. Thus, 3.99 g (92%) of the title compound are obtained. M.p.: 125°-130° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]=2)=[O:7])[N:3]=[CH:2]1.[CH:20]([Mg]Cl)([CH3:22])[CH3:21].[Cl-].[NH4+]>C1COCC1.O>[NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]=2)([OH:7])[CH:20]([CH3:22])[CH3:21])[N:3]=[CH:2]1
Reactant: CC(C)[Mg]Cl
Reactant: COc1ccc2cc(C(=O)c3c[nH]cn3)ccc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
(1H-Imidazol-4-yl)-(6-methoxynaphthalen-2-yl)ketone (6.50 g) was dissolved in THF (120 ml) and the mixture was cooled to −10° C. A solution (2.0 M; 38.7 ml) of isopropyl magnesium chloride in THF was slowly added dropwise and the mixture was stirred for 30 min. To the reaction mixture was added saturated aqueous solution of ammonium chloride and the mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, and after drying, concentrated. The obtained residue was purified by silica gel column chromatography (eluate, chloroform:methanol=20:1→10:1) and recrystallized from ethyl acetate to give the title compound (5.04 g) as a colorless crystalline powder.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH:20](OCC)=[O:21]>>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH:17][CH:20]=[O:21])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: NCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: CCOC=O
Product: O=CNCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 94 %

Procedure:
A mixture of 2-[4-(4-trifluoromethylphenyl)piperazin-1-yl]ethylamine (906 mg, 3.32 mmol) prepared in Reference Example 154 and ethyl formate (10 ml) was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford N-{2-[4-(4-trifluoromethylphenyl)piperazin-1-yl]ethyl}formamide (942 mg, yield 94%) as a white powder.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=2[C:4]([OH:6])=[O:5])=[CH:15][CH:14]=1
Reactant: Oc1ccc(F)cc1
Reactant: Cc1cccc(Cl)c1C(=O)O
Product: Cc1cccc(Oc2ccc(F)cc2)c1C(=O)O

Procedure:
The title compound was synthesized from 2-chloro-6-methyl-benzoic acid and 4-fluorophenol in analogy to example 18a; MS-(−)-ion: M−1=245.5.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H].[OH-].[Na+]>[C].[Pd].O>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
A 1-liter electromagnetically stirred glass reactor was charged with 2.53 g (0.01 mole) of 1-nitroanthraquinone (roughly purified product with no impurity detected by thin-layer chromatography), 52 g of water and 0.051 g of 5% palladium-carbon. The inside of the reactor was purged with nitrogen, and with stirring at room temperature, the 1-nitroanthraquinone was hydrogenated. In 4.5 hours when 0.03 mole of hydrogen was absorbed, the hydrogen inside the reactor was replaced by nitrogen, and 2.1 g (0.052 mole) of sodium hydroxide was added. The inside of the reactor was purged with hydrogen, and the hydrogenation was continued at room temperature. In 1 hour, the absorption of hydrogen was stopped. The amount of hydrogen absorbed until then was 0.01 mole. The reaction mixture completely dissolved. The inside of the reactor was purged with nitrogen, and the reaction mixture was filtered in an atmosphere of nitrogen to separate the catalyst. The filtrate was oxidized with air at 20° to 30° C. for 2 hours with stirring to afford 2.08 g of 1-aminoanthraquinone having a purity of 98% by weight in a yield of 93% of theory. By a thin-layer chromatographic analysis, no impurity was detected.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[NH2:12].[CH3:14][C:15]1[CH:19]=[C:18]([CH2:20][C:21](O)=[O:22])[O:17][N:16]=1.CCOC(C)=O>O=P(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[NH:12][C:21](=[O:22])[CH2:20][C:18]1[O:17][N:16]=[C:15]([CH3:14])[CH:19]=1
Reactant: COC(=O)c1cc(C#N)ccc1N
Reactant: Cc1cc(CC(=O)O)on1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C#N)ccc1NC(=O)Cc1cc(C)no1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A solution of 2-amino-5-cyano-benzoic acid methyl ester (1.50 g, 8.51 mmol) and (3-methyl-isoxazol-5-yl)-acetic acid (1.32 g, 9.36 mmol) in 40 ml of POCl3 was heated at 80° C. for 2 hr and then cooled to RT. Treated with 50 mL of EtOAc, the mixture was washed with H2O (3×40 ml), sat. NaHCO3 (40 ml), brine (40 ml) and dried (Na2SO4). Removal of the solvent under reduced pressure gave 2.31 g (91%) of product as a light yellow solid: 1H-NMR (CDCl3; 400 MHz) δ 11.49 (s, 1H), 8.85 (d, 1H, J=8.8 Hz), 8.35 (d, 1H, J=2.0 Hz), 7.79 (dd, 1H, J=8.8, 2.0 Hz), 6.20 (s, 1H), 3.97 (s, 3H), 3.95 (s, 2H), 2.33 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C15H13N3O4, 300.1 (M+H), found 299.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](C#N)=[N:6][CH:7]=1.C[Mg]Br.[CH2:13]1[CH2:17][O:16]CC1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:17](=[O:16])[CH3:13])=[N:6][CH:7]=1
Reactant: N#Cc1ncc(Br)cn1
Reactant: C1CCOC1
Agent: C[Mg]Br
Product: CC(=O)c1ncc(Br)cn1
Temperature: -78 °C
Reaction time: 3.5 h

Procedure:
To a solution of 5-bromopyrimidine-2-carbonitrile (221 mg, 1.2 mmol) in THF (10 ml) was added methylmagnesium bromide (3.0 ml, 4.20 mmol, 1.4 molar, THF) at −78 CC under nitrogen. The solution was stirred at −78° C. for 3.5 hours, and then quenched with satd aq NH2Cl, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The reaction was purified by column chromatography on silica gel (petroleum ether: EtOAc=1:0 to 0:1) to afford 1-(5-bromopyrimidin-2-yl)ethanone (1.55 mg, 61.% yield). 1H NMR (CDCl3 500 MHz): δ 9.00 (s, 2H), 2.80 (s, 3H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:8][C:9]([C:11]1[C:15]([C:16]2[C:21]([NH:22][C:23](OCC3C=CC=CC=3)=O)=[CH:20][CH:19]=[C:18]([O:33][CH3:34])N=2)=[CH:14][NH:13][CH:12]=1)=[O:10])[CH3:7].[C:35](=O)(O)[O-].[Na+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:6]([O:8][C:9]([C:11]1[C:15]2[C:16]3[CH:35]=[C:18]([O:33][CH3:34])[CH:19]=[CH:20][C:21]=3[N:22]=[CH:23][C:14]=2[NH:13][CH:12]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1c[nH]cc1-c1nc(OC)ccc1NC(=O)OCc1ccccc1
Reactant: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c2cnc3ccc(OC)cc3c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 10 mL aliquot DMF is cooled to 5° C. To this is added 2.26 mL (0.024 mol) of phosphorous oxychloride. The mixture is warmed to room temperature, stirred for 15 minutes and cooked to 5° C. To this solution is added dropwise a solution 3.2 g (0.08 mol) of 4-(benzyloxycarbonylamino-6-methoxy-pyridin-2-yl)-1H-pyrrole-3-carboxylic acid ethyl ester dissolved in 15 mL of DMF. The reaction mixture is warmed to room temperature and stirred for 3 hours. The reaction mixture is carefully poured into 100 mL of saturated sodium bicarbonate. The pH is adjusted to 8 with solid K2CO3 and the mixture extracted with ethyl acetate. The organic extracts are dried (Na2SO4) and evaporated. The residue is chromatographed on 150 g of silica gel using ethyl acetate followed by 10/1 chloroform/methanol as the eluant. Appropriate fractions are combined to yield 1.46 grams of 8-methoxy-3H-pyrrolo [2,3-c]quinoline-1-carboxylic acid ethyl ester. 1H NMR (CDCl3) δ9.10 (s, 1H), 8.35 (d, 1H), 8.10 (s, 1H, 7.2 (s, 1H), 7.05 (d, 1H), 4.4 (q, 2H), 4.10 (s, 3H), 1.40 (t, 3H). Mass spectrum: m/e=260 (p+1). TLC (ethyl acetate) Rf=0.3.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([O:21]C)=[O:20])=[CH:14][CH:13]=3)[CH:5]=[CH:4][N:3]=1.[Li+].[OH-]>C1COCC1.O>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=3)[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc2cnc(Nc3ccnc(C)c3)cc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Nc2cc3cc(C(=O)O)ccc3cn2)ccn1
Reaction time: 3 h

Procedure:
A slurry of 96 (132 mg, 0.45 mmol) in THF (2.19 mL) and water (0.324 mL) was treated with solid LiOH (24 mg, 0.99 mmol) and stirred for 3 h. THF was removed in vacuo, and the mixture was suspended in water (6.0 mL) and treated with aqueous HCl (10 M, 0.27 mL). A yellow-brown precipitate was collected by vacuum filtration to afford 3-(2-methylpyridin-4-ylamino)isoquinoline-6-carboxylic acid (98) as a yellow solid, which was used in subsequent steps without further purification.
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:41][CH3:42])([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[C:27]([CH3:40])[CH:26]=2)[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:43])[C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH2:44]([O:46][C:47](=[O:56])[CH2:48][C:49]1[CH:50]=[CH:51][C:52](Cl)=[N:53][CH:54]=1)[CH3:45].O>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:44]([O:46][C:47](=[O:56])[CH2:48][C:49]1[CH:54]=[N:53][C:52]([C:28]2[CH:29]=[CH:30][C:25]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:17]([CH3:43])[CH:18]=3)([CH2:23][CH3:24])[CH2:41][CH3:42])=[CH:26][C:27]=2[CH3:40])=[CH:51][CH:50]=1)[CH3:45]
Reactant: CCOC(=O)Cc1ccc(Cl)nc1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2ccc(C(CC)(CC)c3ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c3)cc2C)nc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 15.5 %

Procedure:
A solution of t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 23-(1); 13 mg, 0.021 mmol) in N,N-dimethylformamide (0.2 mL) was added to 2-chloropyridine-5-acetic acid ethyl ester (7.4 mg, 0.037 mmol) and a [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex (1:1) (2.0 mg, 0.0024 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 76 to 84° C. for seven hours and 30 minutes. Water was added to the reaction mixture, followed by extraction with ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=10/1) to give the title compound (2.1 mg, 16%).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[C:22](=[O:37])[N:23]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][C:28]=2[CH3:36])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:33][C:30]1[CH:31]=[CH:32][C:27]([N:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:22]2=[O:37])=[C:28]([CH3:36])[CH:29]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(N)ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
62 g (121 mmol) of the compound from Example 25A are dissolved in 2 l of a 1:1 mixture of ethanol and ethyl acetate, and 46 g (726 mmol) of ammonium formate and 0.6 g of palladium on carbon are added. The mixture is heated at 80° C. After 45 min, the mixture is allowed to cool and filtered through silica gel. The filter cake is washed with ethyl acetate and the filtrate is evaporated to dryness under reduced pressure. This gives 36 g (61% of theory) of the desired product.