Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].[N:34]1([CH2:39][CH2:40][CH2:41][NH2:42])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[N:34]1([CH2:39][CH2:40][CH2:41][NH:42][C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:31])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: NCCCN1CCCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCCN1CCCC1

Procedure:
5-[5-(2,6-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid was coupled with 3-pyrrolidin-1-yl-propylamine to give the titled compound.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][CH:6]([C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([CH3:9])=O)C.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C(O)CCC>[CH3:9][C:7]1[C:6]([CH2:5][C:4]([OH:3])=[O:18])=[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:26]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)CC(C(C)=O)C(=O)c1ccccc1
Agent: Cl
Solvent: CCCCO
Product: Cc1nn(-c2ccccc2)c(-c2ccccc2)c1CC(=O)O
Yield: 93.9 %

Procedure:
3.0 grams 3-benzoyl-levulinic acid-ethyl ester, 1.3 gram phenyl-hydrazine, 0.15 milliliter 2N aqueous hydrochloric acid and 25 milliliters n-butanol were mixed and the mixture heated to boiling temperature under reflux for 1.5 hour. The reaction mixture was evaporated in vacuo and benzene added to the residue. The benzene solution was adjusted to a pH of 4 and extracted with water. The benzene was evaporated from the solution, and 15 milliliters ethanol and 20 milliliters 1N aqueous sodium hydroxide were added to the residue and the mixture heated to the boiling temperature. The mixture was then worked up and the free acid recovered in accordance with the procedure set out in Example (1b). 3.3 grams 3-methyl-1,5-diphenyl-pyrazol-4-acetic acid, melting at 159°-161° C., were obtained representing a yield of 93%.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][C:12](=O)[C:13](F)([F:15])[F:14])[CH:3]=1.FC(F)(F)S(OCC(F)F)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][CH2:12][CH:13]([F:15])[F:14])[CH:3]=1
Reactant: COC(=O)c1sc(Br)cc1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1sc(Br)cc1NCC(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of methyl 5-bromo-3-[(trifluoroacetyl)amino]thiophene-2-carboxylate (500 mg, 1.51 mmol), 2,2-difluoroethyl trifluoromethanesulfonate (441 mg, 2.06 mmol), cesium carbonate (1.23 g, 3.78 mmol) and DMF (10 mL) was microwave-irradiated at 90° C. for 1 h. Then, water was added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was dissolved in MeOH (3 mL). To the solution were added potassium carbonate (100 mg) and water (1.5 mL). The mixture was stirred at room temperature for 0.5 h. After removal of the solvent at reduced pressure, the organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, hexane to 85:15 hexane/EtOAc) to give the title compound (290 mg, 64%) as a yellow solid:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[CH3:6][NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13]Cl)[N:12]=1>Cl>[CH3:6][NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][S:5][CH2:4][CH2:3][NH2:2])[N:12]=1
Reactant: NCCS
Reactant: CNc1nc(CCl)cs1
Agent: Cl
Product: CNc1nc(CSCCN)cs1
Yield: 35 %

Procedure:
Cysteamine hydrochloride (2.8 g; 24.6 mmoles) and 2-methylamino-4-chloromethylthiazole (4.0 g; 24.6 mmoles) [prepared from N-methylthiourea and 1,3-dichloro-2-propane] were dissolved in 20 ml of concentrated hydrochloric acid and the solution was heated at an oil bath temperature of 100°. After 30 hours of heating, the reaction mixture was evaporated under reduced pressure and the residue made basic with 40% aqueous NaOH solution. The aqueous phase was extracted with methyl acetate, dried, filtered and evaporated to give 1.75 g of the title compound as an oil which was used without further purification in Step B.
Reaction SMILES: [C:1]1([CH:7]([CH3:17])[CH2:8][C:9]([C:13]([F:16])([F:15])[F:14])([OH:12])[CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[OH:12][C:9]([C:13]([F:14])([F:15])[F:16])([CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:17])[CH2:10][O:11][S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(CC(O)(CO)C(F)(F)F)c1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(O)(CC(C)c2ccccc2)C(F)(F)F)cc1
Reaction time: 16 h

Procedure:
4.25 g of 4-phenyl-2-trifluoromethyl-1,2-pentanediol in 30 ml of pyridine is mixed at 0° C. with 3.8 g of 4-toluenesulfonic acid chloride. After 16 hours at 0° C., it is concentrated by evaporation in a vacuum, mixed with ethyl acetate, washed with water, dried (Na2SO4) and concentrated by evaporation. By crystallization from ethyl acetate/hexane, 4.9 g of 4-toluenesulfonic acid-(2-hydroxy-4-phenyl-2-trifluoromethyl-pentyl)ester, melting point 95-96° C., is obtained.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([O:26][CH:27]([CH3:29])[CH3:28])=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[CH:15][C:14]([Cl:25])=[CH:13][CH:12]=2)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:25][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([O:26][CH:27]([CH3:28])[CH3:29])[C:8]([C:6]([OH:7])=[O:5])=[C:17]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1
Reactant: CC(C)Oc1nc2ccc(Cl)cc2c(-c2cccc(Cl)c2)c1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1nc2ccc(Cl)cc2c(-c2cccc(Cl)c2)c1C(=O)O
Yield: 16.2 %

Procedure:
To the stirred solution of 6-chloro-4-(3-chloro-phenyl)-2-isopropoxy-quinoline-3-carboxylic acid tert-butyl ester (100 mg, 0.23 mmol) in DCM (4 ml) was added 0.2 ml TFA and reaction mixture was refluxed for 16 h. After cooling, the volatiles were removed under vacuum and the reaction mixture was diluted with ethyl acetate (40 ml) and washed with NaHCO3 solution (10 ml). The separated organic layer was washed with brine (7 ml), dried over sodium sulfate and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (100% ethyl acetate) to afford 6-chloro-4-(3-chloro-phenyl)-2-isopropoxy-quinoline-3-carboxylic acid (14 mg, 16%) as an off white solid. LC-MS (ESI): 374 (M−H)−.
Reaction SMILES: C(N(CC)C(C1C=CC=CC=1S([C:14]1[C@H:15]([CH3:45])[C@@H:16]2[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]2[C:18]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])=O)=O)C.[N+:48]([C:51]1[CH:64]=[CH:63][C:54]([CH2:55][O:56][C:57]([NH:59][CH2:60][CH2:61][SH:62])=[O:58])=[CH:53][CH:52]=1)([O-:50])=[O:49]>>[Si:37]([O:36][C@@H:34]([C@H:33]1[C:32](=[O:44])[N:17]2[C:18]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])=[C:14]([S:62][CH2:61][CH2:60][NH:59][C:57]([O:56][CH2:55][C:54]3[CH:63]=[CH:64][C:51]([N+:48]([O-:50])=[O:49])=[CH:52][CH:53]=3)=[O:58])[C@H:15]([CH3:45])[C@H:16]12)[CH3:35])([C:40]([CH3:41])([CH3:42])[CH3:43])([CH3:39])[CH3:38]
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2[C@H]1C
Reactant: O=C(NCCS)OCc1ccc([N+](=O)[O-])cc1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H](C)[C@H]12
Yield: 83 %

Procedure:
Following a procedure similar to that described in Example 21(b), but using 4-nitrobenzyl (1R, 5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 39) and 2-(4-nitrobenzyloxycarbonyl)aminoethylmercaptan as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 83%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:22][CH2:23][CH2:24][CH2:25][C:26]([NH:28][C@H:29]([C:45]([O:47][CH3:48])=[O:46])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34]C(OCC3C=CC=CC=3)=O)=[O:27])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[BrH:49]>C(O)(=O)C.C(OCC)C>[BrH:49].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([S:22][CH2:23][CH2:24][CH2:25][C:26]([NH:28][C@H:29]([C:45]([O:47][CH3:48])=[O:46])[CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])=[O:27])[NH:12][C:13]=2[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)CCCSc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)[nH]1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)[C@H](CCCCN)NC(=O)CCCSc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)[nH]1
Reaction time: 1 h
Yield: 95 %

Procedure:
The N2-[4-[4,5-bis(4-methoxyphenyl)-1H-imidazol-2-ylthio]-1-oxobutyl]-N6-[(phenylmethoxy)carbonyl]-L-lysine, methyl ester (1.60 g, 0.0023 mol) was dissolved in hydrogen bromide 30 wt. % solution in acetic acid (20 ml) under a nitrogen atmosphere at ambient temperature. The reaction mixture was stirred for 1 hour, and diluted with ethyl ether to precipitate a gum. This residue was triturated with ethyl ether to give the title compound (1.58 g, 0.00224 mol, 95% yield) as an off white powder, mp 165°-70°. 1H NMR (DMSO-d6) δ8.38 (d, 1H), 7.80-7.70(bs, 3H), 7.39(d, 4H), 7.03(d, 4H), 4.26-4.23(m, 1H), 3.79(s, 6H), 3.6(s, 3H), 3.30-3.26(t, 2H), 2.79-2.73(m, 2H), 2.36-2.31(t, 2H), 1.93-1.86(m, 2H), 1.70-1.31(m, 6H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([C:37]([O:39][CH3:40])=[O:38])[S:35][CH:36]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([N:9]1[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=2[C:7]([C:32]2[CH:33]=[C:34]([C:37]([O:39][CH3:40])=[O:38])[S:35][CH:36]=2)=[N:8]1)([CH3:19])([CH3:20])[CH3:21]
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C(C)(C)C
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2nn(C(C)(C)C)c3ccnc(OC)c23)cs1
Temperature: 100 °C
Reaction time: 8 h
Yield: 120.2 %

Procedure:
To a solution of 1-tert-butyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (1.60 g) obtained in Step C of Example 86 in DME (100 mL) were added methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (1.46 g) and 2M aqueous sodium carbonate solution (11.3 mL), and then tetrakis(triphenylphosphine)palladium(0) (523 mg) was added thereto under nitrogen atmosphere. The reaction mixture was stirred overnight under nitrogen atmosphere at 100° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.88 g).
Reaction SMILES: COC[O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[O:14][C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:12](C(O)=O)[C:11]2=[O:25].C1(P([N:40]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.Cl.O1CCOCC1>C(O)(C)(C)C>[NH2:40][C:12]1[C:11](=[O:25])[C:10]2[C:15](=[C:6]([CH2:5][OH:4])[CH:7]=[CH:8][CH:9]=2)[O:14][C:13]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COCOCc1cccc2c(=O)c(C(=O)O)c(-c3ccccc3)oc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: Nc1c(-c2ccccc2)oc2c(CO)cccc2c1=O

Procedure:
8-Methoxymethoxymethylflavone-3-carboxylic acid was reacted with diphenylphosphoryl azide and then with t-butanol. The resultant product was hydrolyzed with aqueous hydrochloric acid-dioxane to give 3-aminoflavone-8-methanol.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:20])[CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH2:11][C:4]=2[CH:3]=1.C(O)(=O)/C=C\C(O)=O.ClC1[N:35]=[N:34]C2CCNCC=2C=1.C(C(CCC)C(Cl)=O)CC>>[NH:34]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:20])[CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH2:11][C:4]=2[CH:3]=1)[NH2:35]
Reactant: CCCC(CCC)C(=O)N1CCc2nnc(Cl)cc2C1
Reactant: Clc1cc2c(nn1)CCNC2
Agent: CCCC(CCC)C(=O)Cl
Agent: O=C(O)/C=C\C(=O)O
Product: CCCC(CCC)C(=O)N1CCc2nnc(NN)cc2C1

Procedure:
The 3-chloro-5,6,7,8-tetrahydro-6-(2-n-propylvaleroyl)pyrido[4,3-c]pyridazine, required as starting material, is produced in a manner analogous to that described in Example 8 (g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and 2-n-propylvaleroyl chloride. The organic phase is concentrated, and the crude product is extracted from the resulting solid residue with a Soxhlet extraction apparatus, and is recrystallized from cyclohexane. M.P. 94°-95°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[N:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:16][C:14]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[N:15]=1
Reactant: C1CNCCN1
Reactant: Cc1ccc(C#N)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)c(N2CCNCC2)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
Piperazine (1.13 g) and 2-chloro-6-methylnicotinonitrile (500 mg) were dissolved in DMF (15 ml), and K2CO3 (1.36 g) was added thereto, followed by stirring at 60° C. overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 6-methyl-2-piperazin-1-ylnicotinonitrile (628 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:21](=[CH:22][CH:23]=1)[O:20][C:7]1([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:24].[CH3:25][N:26](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]([C:2]1[CH:3]=[C:4]2[C:21](=[CH:22][CH:23]=1)[O:20][C:7]1([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:24])#[N:26]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(C#N)ccc1O2
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 6-bromo-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (6593 g, 16.6 mol) and DMF (33 L) was added Zn(CN)2 (1947 g, 16.6 mol) and Pd(PPh3)4 (192 g, 0.17 mol). The slurry was heated to 90° C. for 3 hours, then cooled to room temperature and filtered. Water (16 L) was added to the filtrate. The resulting slurry was cooled to 5° C., stirred for 1 hour and filtered. The solid was washed with DMF/water (2:1) and dried under vacuum to give tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate.
Reaction SMILES: C(N(CC)CC)C.[S:8](Cl)([CH3:11])(=[O:10])=[O:9].[OH:13][CH:14]1[CH2:17][C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]2)[CH2:15]1>ClCCl>[CH3:11][S:8]([O:13][CH:14]1[CH2:15][C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]2)[CH2:17]1)(=[O:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(O)C2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CC(OS(C)(=O)=O)C2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.76 mL (5.49 mmol) of triethylamine and then 0.43 mL (5.49 mmol) of mesyl chloride are added to a solution of 1.52 g (4.99 mmol) of tert-butyl 2-hydroxy-6-azaspiro[3.4]octane-6-carboxylate, obtained in step 6.1., in 45 mL of dichloromethane. The reaction medium is stirred at room temperature for 1 hour 30 minutes. After evaporating off the solvent, water is added to the reaction medium, the aqueous phase is separated out and extracted several times with dichloromethane, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. After evaporating off the solvent, 1.90 g of product are obtained in the form of a brown oil, which is used without further purification in the following step.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[N:15]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:2].Cl[CH:23]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CCN(CC)CC>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[N:15]1[CH2:21][CH2:20][CH2:19][N:18]([CH:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[CH2:17][CH2:16]1)[CH3:2]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: Clc1ccc(C(Cl)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCCn1c(N2CCCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)nc2ccccc21

Procedure:
A solution of compound 15 (2 mmols) and 21 (2 mmols) in methylene chloride (10 mL) and Et3N (0.3 mL) is stirred under an inert atmosphere. The solution is warmed and the course of the reaction is followed by TLC. When the reaction is complete, dil. aq. Na2CO3 is added to the solution, shaken, and the layers are separated. The aqueous layer is extracted with additional CH2Cl2, the combined organic extracts are washed with half-saturated brine, dried (Na2SO4), filtered and concentrated under reduced pressure giving the crude product. The desired compound 1-(2-ethoxyethyl)-2-[hexahydro-4-(4-chlorobenzhydryl)-1H-1,4-diazepin-1-yl]-1H-benzimidazole 25 is obtained by purification of the crude product with the use of HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].CS(O)(=O)=O.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH:5]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: [H][H]
Reactant: CCOC(=O)Cc1c[nH]c2ccc(F)cc12
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CCO
Product: CCOC(=O)CC1CNc2ccc(F)cc21

Procedure:
A mixture of ethyl (5-fluoro-1H-indol-3-yl)acetate (Bullock et al. J. Am. Chem. Soc. 1951, 73, 5155-5157) (72.5 g, 0.33 mol), 70% methane sulfonic acid (aq) (50 mL) and palladium (5 wt %, dry basis) on activated carbon (20 g) in ethanol (700 mL) was treated with hydrogen at 3 bar and 50° C. for 48 h. The mixture was filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate, and aqueous ammonia was added. The phases were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo (55 g, 75%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[NH2:17][C:18]1[N:19]=[CH:20][C:21]2[C:27](=[O:28])[N:26]([C:29]3[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:30]=3[CH3:38])[CH2:25][CH2:24][C:22]=2[N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:38][C:30]1[CH:31]=[CH:32][C:33]([N+:35]([O-:37])=[O:36])=[CH:34][C:29]=1[N:26]1[CH2:25][CH2:24][C:22]2[N:23]=[C:18]([NH:17][C:2]3[CH:7]=[CH:6][C:5]([C:8]([N:10]4[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]4)=[O:9])=[CH:4][CH:3]=3)[N:19]=[CH:20][C:21]=2[C:27]1=[O:28]
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CCc2nc(N)ncc2C1=O
Reactant: CN1CCN(C(=O)c2ccc(I)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ccc([N+](=O)[O-])cc1N1CCc2nc(Nc3ccc(C(=O)N4CCN(C)CC4)cc3)ncc2C1=O

Procedure:
A mixture of 4,5-Bis(diphenylphos-phino)-9,9-dimethylxanthene(xanthopos)(8.6 mg, 0.0148 mmol) and Tris(dibenzylideneacetone)dipalladium(0)[Pd2(dba)3] (6.81 mg, 0.0074 mmol) in dry 1,4-dioxane (5 ml) was stirred vigorously and nitrogen was bubbled through the suspension for 30 minutes. (4-Iodo-phenyl)-(4-methyl-piperazin-1-yl)-methanone (41.1 mg, 0.1247 mmol), 2-Amino-6-(2-methyl-5-nitro-phenyl)-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one (37.3 mg, 0.1247 mmol) and dry cesium carbonate (100 mg, 0.31 mmol) was added. Nitrogen was bubbled through for another 30 minutes; the mixture was allowed to reflux overnight. The mixture was cooled, diluted with ethylacetate, water was added and the layers were separated. The aqueous layer was extracted with ethyl acetate and the two organic extracts were combined. The organics were washed with brine, then dried (sodium sulfate), filtered and concentrated. Silica gel chromatography using 5-10% ethyl acetate/hexane as eluent provided 6-(2-Methyl-5-nitro-phenyl)-2-[4-(4-methyl-piperazine-1-carbonyl)phenylamino]-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one [22] as a yellow solid [Yield: 12.3 mg, 19.7%]
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])=[O:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.I[CH:26]([CH3:28])[CH3:27]>C(OCC)(=O)C>[CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:26]([CH3:28])[CH3:27])[C:6]([O:8][CH3:9])=[O:7])=[O:2]
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(C=O)c1
Temperature: 60 °C
Yield: 98.9 %

Procedure:
To a mixture of methyl 3-formyl-4-hydroxy-benzoate (10.0 g, 55.5 mmol), potassium carbonate (30.7 g, 222.0 mmol) and N,N-dimethylformamide (62.5 mL) was added 2-iodopropane (18.9 g, 11.1 mL, 111.0 mmol) and the reaction mixture was heated at 60° C. for 18 hours. The reaction mixture was filtered, the filtrate was concentrated in vacuo to give a residue which was dissolved in ethyl acetate (150 mL) and washed sequentially with water (3×75 mL) and brine solution (1×75 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield methyl 3-formyl-4-isopropoxy-benzoate (12.2 g, 99%) as a yellow viscous liquid. ESI-MS m/z calc. 222.2. Found 223.3 (M+1)+; Retention time: 1.51 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 8.23 (d, J=2.3 Hz, 1H), 8.17 (dd, J=8.8, 2.3 Hz, 1H), 7.39 (d, J=8.9 Hz, 1H), 4.98-4.83 (m, 1H), 3.85 (s, 3H), 1.38 (d, J=6.0 Hz, 6H).