Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:23]1([CH2:29][O:30][CH2:31][CH2:32][Br:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC#N>[Br-:33].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:32][CH2:31][O:30][CH2:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: BrCCOCc1ccccc1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCOCc3ccccc3)(CC1)CC2
Product: [Br-]
Temperature: 60 °C
Reaction time: 16 h
Yield: 43.4 %

Procedure:
To a solution of 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (3.30 g, 11.2 mmol) in 2 CH3CN/3 CHCl3 (200 mL) was added 2-bromoethyl phenylmethyl ether (2.31 mL, 14.6 mmol). The solution was stirred at 60° C. for 16 h. The reaction was cooled down to room temperature and concentrated. EtOAc (200 mL) was added to the solid, and the mixture was allowed to stir for 1 hour then filtered. The resulting solid was taken up in MeOH (125 mL) and heated to 60° C. The solution was filtered hot, and then cooled back to room temperature. The reaction was concentrated to a low volume of MeOH (˜20 mL) and filtered. Water (75 mL) was then added and the resulting mixture was heated at 55° C. with brisk stirring for 40 min. After cooling to room temperature, the solid was filtered off, washed with water (20 mL) and dried in a vacuum oven at 45° C. for 16 hours to give the title compound (2.47 g, 43.3%). EI-MS m/z 428 (M+) Rt (1.90 min) 1H NMR (DMSO-d6) δ 7.56 (d, 4H, J=1.2), 7.28 (m, 11H), 5.95 (s, 1H), 4.50 (s, 2H), 3.81 (d, 2H, J=4.0), 3.48 (t, 6H, J=7.2), 3.38 (d, 2H, J=4.0), 2.01 (t, 6H, J=7.2); Elemental analysis (C29H34NO2Br) C, H, N: calculated, 68.50, 6.74, 2.75. found, 68.28, 6.68, 2.73.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:17]([NH2:27])(=[O:26])([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)=[O:18]>CO>[NH2:27][S:17]([C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:14]([C:10]2[CH:9]=[C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[N:13]=[CH:12][N:11]=2)=[O:16])=[CH:23][CH:24]=1)(=[O:18])=[O:26]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Solvent: CO
Product: NS(=O)(=O)c1ccc(NC(=O)c2cc(NC3CCCCC3)ncn2)cc1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and sulfanilamide (Acros), the title compound was obtained as a white solid after trituration in methanol.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[NH:15][C:16]3[CH:22]=[C:21]([C:23]([OH:25])=O)[CH:20]=[CH:19][C:17]=3[N:18]=2)=[C:9]([CH3:26])[CH:8]=1)=[O:4].[C:27](NC1C=CC=CC=1)([CH3:30])([CH3:29])[CH3:28].CCN=C=NCCCN(C)C.[CH:49]1[CH:50]=[CH:51][C:52]2N(O)N=[N:55][C:53]=2[CH:54]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:4])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:26])[C:10]([C:14]2[NH:15][C:16]3[CH:22]=[C:21]([C:23](=[O:25])[NH:55][C:53]4[CH:54]=[CH:49][C:50]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:51][CH:52]=4)[CH:20]=[CH:19][C:17]=3[N:18]=2)=[C:11]([CH3:13])[CH:12]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)Nc1ccccc1
Reactant: COC(=O)COc1cc(C)c(-c2nc3ccc(C(=O)O)cc3[nH]2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(C)c(-c2nc3ccc(C(=O)Nc4ccc(C(C)(C)C)cc4)cc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(4-methoxycarbonylmethoxy-2,6-dimethylphenyl)-3H-benzoimidazole-5-carboxylic acid (0.3 g, 0.847 mmol) in DMF (6 mL) was added t-butylaniline (0.1338 mL, 0.847 mmol), EDCI (0.1953 g, 1.02 mmol) and HOBt (0.1374 g, 1.02 mmol). The brown solution was stirred at ambient temperature for 18 h. The mixture was extracted with EtOAc, then washed with water, brine, and dried with Na2SO4. The solvent was removed under reduced pressure and the residue purified on silica gel using MeCN/methylene chloride (1:1) to give {4-[6-(4-tert-butylphenylcarbamoyl)-1H-benzoimidazol-2-yl]-3,5-dimethylphenoxy}-acetic acid methyl ester.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C:14]([N:16]1[CH2:20][C@H:19]([OH:21])[CH2:18][C@H:17]1[CH2:22][O:23][CH2:24][C:25]([OH:27])=[O:26])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl>O1CCCC1.O>[CH2:6]([O:13][C:14]([N:16]1[CH2:20][C@H:19]([O:21][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:18][C@H:17]1[CH2:22][O:23][CH2:24][C:25]([OH:27])=[O:26])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)COC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)O)N(C(=O)OCc2ccccc2)C1
Reaction time: 1 h

Procedure:
A solution of methanesulfonyl chloride (10 ml) in tetrahydrofuran (20 ml) was dropwise added to a solution of (2S,4R)-1-benzyloxycarbonyl-2-carboxymethyloxymethyl-4-hydroxypyrrolidine (19.95 g) and triethylamine (27 ml) in tetrahydrofuran (200 ml) at -10°~5° C. and the mixture was stirred at the same temperature for 1 hour The mixture was poured into water (200 ml), adjusted to pH 2.5 with 6N hydrochloric acid and extracted with ethyl acetate (150 ml×2). The organic layer was washed with brine (200 ml×2), dried over magnesium sulfate and concentrated under reduced pressure to give (2S,4R)-1-benzyloxycarbonyl-2-carboxymethyloxymethyl-4methanesulfonyloxypyrrolidine (24.85 g).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([C:7]([C@H:9]2[CH2:11][C@H:10]2[C:12](O)=[O:13])=O)=[CH:3][CH:2]=1.O.[NH2:17][NH2:18]>C(O)C>[C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([C:7]2[CH:9]3[CH:10]([C:12](=[O:13])[NH:17][N:18]=2)[CH2:11]3)=[CH:3][CH:2]=1
Reactant: NN
Reactant: Cc1ccc(C(=O)[C@H]2C[C@H]2C(=O)O)cc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(C2=NNC(=O)C3CC23)cc1
Yield: 79.8 %

Procedure:
5.5 g (26.9 millimoles) of cis-2-(p-toluoyl)-cyclopropanecarboxylic acid, 1.5 g (30.0 millimoles) of hydrazine hydrate and 100 ml of ethanol are refluxed for 6 hours. The mixture is then concentrated and the residue is recrystallized from ethyl acetate. 4.3 g (80% of theory) of 2-(p-tolyl)-3,4-diaza-bicyclo[4.1.0]-hept-2-en-5-one are obtained as colorless crystals of melting point 162°-163.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1Br.C(O[C:16]([S-:18])=[S:17])C.[K+].O>CN1CCCC1=O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:16]([SH:18])[S:17][C:3]=2[CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: FC(F)(F)c1ccc2nc(S)sc2c1
Temperature: 160 °C
Reaction time: 3 h
Yield: 25.8 %

Procedure:
4-Amino-3-bromobenzotrifluoride (2.40 g) was dissolved in N-methyl-2-pyrrolidone (10 mL), and potassium ethylxanthate (3.52 g) was added thereto. The mixture was stirred at 160° C. for 3 hr with heating. Water (300 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and brine, and concentrated under reduced pressure to give 6-trifluoromethyl-2-mercaptobenzothiazole (607 mg) as an orange powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]([CH3:18])[C:14]([O:16]C)=[O:15])[CH2:8][CH2:7]1.O.[OH-].[Li+].CO>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]([CH3:18])[C:14]([OH:16])=[O:15])[CH2:8][CH2:7]1
Reactant: COC(=O)C(C)CN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(CN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1)C(=O)O
Reaction time: 21 h
Yield: 98.6 %

Procedure:
Methyl 2-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]propionate (470 mg, 1.36 mmol) and lithium hydroxide monohydrate (185 mg, 4.41 mmol) were dissolved in water (5 ml) and methanol (15 ml) and stirred at room temperature. After 21 h, the solvents were removed under reduced pressure. The resulting residue was taken up in a mixture of methylene chloride and water, and the aqueous layer was made acidic (˜pH 4) with 1M HCl. The layers were separated and the aqueous phase was extracted with several portions of methylene chloride. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford 2-(RS)-[4-(3,4-dichloro-benzyl)piperazin-1-ylmethyl]propionic acid (444 mg) as a pale-yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[NH2:12][CH:13]1[C:17](=[O:18])[N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH:14]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:12][C@H:13]2[C:17](=[O:18])[N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][C@H:14]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:6])[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C1CN(c2ccccc2)C(=O)C1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NC(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.3 %

Procedure:
To a solution of 3,4-dichlorobenzoyl chloride (295 mg, 1.41 mmol) in CH2Cl2 (4 ml) was added a solution of aminopyrrolidinone of Example S (350 mg, 1.41 mmol) and triethylamine (0.4 ml, 2.82 mmol) in CH2Cl2 (4 ml) and the resulting solution was stirred for 18 h at room temperature. Concentration in vacuo gave an oil which was chromatographed on silica gel eluting with 2% EtOH/CH2Cl2 to give the title compound (400 mg, 67%) as a colorless solid. Anal calcd for C20H18N2O4Cl2 : C, 57.02; H, 4.31; N, 6.65. Found: C, 57.05; H, 4.39; N, 6.50. MS M+1 calcd for C20H18N2O4Cl2 422, found 422.
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:5]2[N:6]=[C:7]([NH:15][C:16]3[C:21]([Cl:22])=[CH:20][C:19]([C:23]4[NH:27][N:26]=[CH:25][CH:24]=4)=[CH:18][C:17]=3[Cl:28])[C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:38][C:39]([OH:43])([C:41]#[CH:42])[CH3:40]>CN(C=O)C.C(OCC)(=O)C.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.[Cu]I>[Cl:28][C:17]1[CH:18]=[C:19]([C:23]2[NH:27][N:26]=[CH:25][CH:24]=2)[CH:20]=[C:21]([Cl:22])[C:16]=1[NH:15][C:7]1[C:8]2[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=2[C:4]2[CH:3]=[C:2]([C:42]#[C:41][C:39]([OH:43])([CH3:40])[CH3:38])[CH:30]=[CH:29][C:5]=2[N:6]=1
Reactant: C#CC(C)(C)O
Reactant: O=c1[nH]ccc2c(Nc3c(Cl)cc(-c4ccn[nH]4)cc3Cl)nc3ccc(Br)cc3c12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ccc2nc(Nc3c(Cl)cc(-c4ccn[nH]4)cc3Cl)c3cc[nH]c(=O)c3c2c1
Temperature: 75 °C

Procedure:
A solution of 9-bromo-5-{[2,6-dichloro-4-(1H-pyrazol-5-yl)phenyl]amino}benzo[c]-2,6-naphthyridin-1(2H)-one (125 mg, 0.25 mmol) in DMF (3 mL) was degassed with nitrogen. Triethylamine (0.07 ml, 0.50 mmol), 2-methylbut-3-yn-2-ol (42.0 mg, 0.499 mmol), Pd(Ph3P)4 (28.8 mg, 0.025 mmol) and copper(I) iodide (9.50 mg, 0.050 mmol) were added and the reaction was heated to 75° C. for 16 h. After cooling to room temperature, the reaction was diluted with ethyl acetate and extracted with water. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in THF/MeOH, filtered and purified by reverse phase HPLC to afford the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]#[CH:13])[CH:9]=[CH:10][CH:11]=1.C(N(CC)CC)C.[NH2:21][C:22]1[C:27](Br)=[CH:26][C:25]([N+:29]([O-:31])=[O:30])=[CH:24][N:23]=1>O1CCCC1.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>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]#[C:13][C:27]2[C:22]([NH2:21])=[N:23][CH:24]=[C:25]([N+:29]([O-:31])=[O:30])[CH:26]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: C#Cc1cccc(OCCOC)c1
Reactant: Nc1ncc([N+](=O)[O-])cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCOc1cccc(C#Cc2cc([N+](=O)[O-])cnc2N)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.5 %

Procedure:
3-(2-Methoxy-ethoxy)-phenylacetylene (6.3 g, 36 mmol) was added to a solution of triethylamine (1.92 mL, 14 mmol), 2-amino-3-bromo-5-nitropyridine (4 g, 18 mmol), PdCl2(PPh3)2 (966 mg, 1.38 mmol) and CuI (262 mg, 1.38 mmol) in anhydrous tetrahydrofuran (80 mL) in the dark. The mixture was stirred at room temperature for 48 hours then concentrated in vacuo and resolvated in dichloromethane (150 mL). The organic solution was washed with water (25 mL), dried over MgSO4, filtered and concentrated in vacuo to 20% of its original volume and heptane (20 mL) was then added. The resultant yellow solid was filtered and dried to give 3-[3-(2-methoxy-ethoxy)-phenylethynyl]-5-nitro-pyridin-2-ylamine (4.2 g, 74% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>C(OCC)(=O)C.C1CCCCC1.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>[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[C:29]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(Br)cn2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)cn2)CC1

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.3.). Starting with 3 g (8.06 mmol) of 2-(ethyloxy)-2-oxoethyl 4-(5-bromo-2-pyridyl)-1-piperazine-carboxylate, obtained in step 3.3., 4.59 g (24.17 mmol) of 3-(trifluoromethyl)phenylboronic acid, 6.84 g (32.23 mmol) of hydrated potassium phosphate and 0.93 g (0.806 mmol) of tetrakis(triphenylphosphine)palladium, and after chromatography on silica gel, eluting with a 30/70 mixture of ethyl acetate and cyclohexane, 2.22 g of product are obtained in the form of a white solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.F[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[CH2:13][CH2:12][N:11]([C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:7]1
Reactant: C[C@H]1CC[C@@H](N2CCNCC2)CC1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCN([C@H]3CC[C@@H](C)CC3)CC2)cc1
Temperature: 140 °C
Reaction time: 9 h

Procedure:
A mixture of cis-1-(4-methylcyclohexyl)piperazine (29.6 g), ethyl 4-fluorobenzoate (41.0 g) and potassium carbonate (67.3 g) in DMSO (300 ml) was stirred at 140° C. for 9 hours. The reaction mixture was poured into water (1.2 l) and extracted twice with ethyl acetate (400 ml). The extracts were collected, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (1 l) eluting with a mixture of n-hexane and ethyl acetate (2:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give ethyl 4-[cis-4-(4-methylcyclohexyl)-1-piperazinyl]benzoate (37.64 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH2:12]([O:14][C:15]([C:17]1([NH2:26])[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:16])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:12]([O:14][C:15]([C:17]1([NH:26][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=2[OH:11])[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1cccc(Cl)c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(Cl)c2O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
To a solution of 3-chloro-2-hydroxy-benzoic acid (413 mg, 2.4 mmol), 2-Amino-indan-2-carboxylic acid ethyl ester (500 mg, 2.4 mmol), HATU (1.1 g, 2.9 mmol) in anhydrous DMF (10 mL) is added DIPEA (0.88 ml, 5.3 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (50 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 10%-80% EtOAc in heptane) to give a pure product (14) as white solid (420 mg, 49%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[NH:13][C:12]3=[C:14](C)[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=4)=[N:16][C:11]3=[CH:10][N:9]=2)[CH2:5][CH2:4][NH:3]1.B(Br)(Br)Br.CCN(CC)CC>C(Cl)Cl>[CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[NH:13][C:12]3=[CH:14][C:15]([C:17]4[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=4)=[N:16][C:11]3=[CH:10][N:9]=2)[CH2:5][CH2:4][NH:3]1
Reactant: COc1cccc(-c2nc3cnc(C4CCNC(C)C4)[nH]c-3c2C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CC(c2ncc3nc(-c4cccc(O)c4)cc-3[nH]2)CCN1
Temperature: 25 °C
Reaction time: 20 h
Yield: 105.7 %

Procedure:
To a −78° C. solution of 1-[2,7-dimethyl-4-piperidylpyrrolo[4,5-d]pyrimidin-6-yl]-3-methoxybenzene (Example 139) (0.89 g, 2.76 mmol) in CH2Cl2 (40 mL) under a N2 atmosphere was added 1 M BBr3 (5.50 mL, 5.50 mmol). The reaction mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for an additional 20 h. The reaction mixture was then poured onto ice-water (200 mL) and the pH of the aqueous solution was adjusted to pH 9 with the addition of NEt3 (2 mL). CH2Cl2 (60 mL) added and the resulting mixture was stirred at room temperature for 2 h. The mixture was transferred to a separatory funnel. The organic solution was separated, washed with H2O (100 mL), saturated NaCl (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure to afford 0.90 g (100%) of 3-[2-methyl-4-piperidylpyrrolo[4,5-d]pyrimidin-6-yl]phenol as a beige colored solid. This compound (0.90 mg, 5.00 mmol) was dissolved in 5:1:1 EtOAc/MeOH/CH2Cl2 (40 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (5.00 mL, 5.00 mmol). The solution was allowed to cool to room temperature. The resulting solid was collected by filtration, washed with EtOAc (2×10 mL), Et2O (3×5 mL) and dried under vacuum at 60° C. to give 525 mg (55%) of the title compound as white colored crystals. Mp: >280° C. 1H HMR (DMSO-d6; 400 MHz): δ 1.63 (br s, 6), 2.48 (s, 3), 3.97 (br s, 4), 6.73 (s, 1), 6.84-6.87 (m, 1), 7.24 (br s, 1), 7.27-7.28 (m, 2), 9.75 (s, 1), 11.61 (s, 1), 13.87 (s, 1). MS m/z: 309 (M+1 for free base). Anal. Calcd for C18H20N4O.HCl.1.3H2O: C, 58.70; H, 6.46; N, 15.22; Cl, 9.63. Found: C, 59.09; H, 6.11; N, 14.91; Cl, 9.30.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([N:8]2[CH2:17][C:16]3[C:11](=[N:12][C:13]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH3:27])[CH3:26])[CH:20]=4)=[N:14][CH:15]=3)[N:10]([CH3:28])[C:9]2=[O:29])[CH:7]=1.[CH3:31][C:32]1[N:33]=[CH:34][N:35]([C:37]2[CH:38]=[C:39]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=2)[C:40](O)=[O:41])[CH:36]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:27][N:25]([CH3:26])[C:21]1[CH:20]=[C:19]([NH:18][C:13]2[N:12]=[C:11]3[N:10]([CH3:28])[C:9](=[O:29])[N:8]([C:6]4[CH:7]=[C:2]([NH:1][C:40](=[O:41])[C:39]5[CH:43]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:45]=[C:37]([N:35]6[CH:36]=[C:32]([CH3:31])[N:33]=[CH:34]6)[CH:38]=5)[CH:3]=[CH:4][C:5]=4[CH3:30])[CH2:17][C:16]3=[CH:15][N:14]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cn(-c2cc(C(=O)O)cc(C(F)(F)F)c2)cn1
Reactant: Cc1ccc(N)cc1N1Cc2cnc(Nc3cccc(N(C)C)c3)nc2N(C)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(-c2cc(C(=O)Nc3ccc(C)c(N4Cc5cnc(Nc6cccc(N(C)C)c6)nc5N(C)C4=O)c3)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.3 %

Procedure:
To a solution of 3-(5-amino-2-methyl-phenyl)-7-(3-dimethylamino-phenylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (52 mg, 0.13 mmol), 3-(4-methyl-imidazol-1-yl)-5-trifluoromethylbenzoic acid (42 mg, 0.15 mmol), and DIEA (78 μL, 0.45 mmol) in DMF is added HATU (59 mg, 0.15 mmol), and the mixture is stirred for 1 hour at room temperature. The reaction mixture is diluted with EtOAc and washed with 5% aqueous Na2S2O3 solution, saturated aqueous NaHCO3 solution, and brine. The organic layer is dried over MgSO4 and concentrated in reduced pressure. The residue is purified by recrystallization from methanol to give N-{3-[7-(3-dimethylamino-phenylamino)-1-methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl]-4-methyl-phenyl}-3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzamide (25 mg, 30%) as a yellowish solid; 1H NMR 400 MHz (DMSO-d6) δ 9.34 (s, 1H), 8.43 (s, 1H), 8.38 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 8.13 (s, 1H), 7.74 (s, 1H), 7.69 (s, 1H), 7.65 (d, 1H), 7.34-7.30 (m, 2H), 7.08-7.03 (m, 2H), 6.33 (d, 1H), 4.68 (d, 1H), 4.51 (d, 1H), 3.35 (s, 3H), 2.88 (s, 6H), 2.17 (s, 3H), 2.14 (s, 3H); MS m/z 656.3 (M+1).
Reaction SMILES: [O:1]=[O+][O-].[CH:4]([C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]=2[N:23]=1)=C.CSC>C(Cl)Cl.O>[CH:4]([C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]=2[N:23]=1)=[O:1]
Reactant: O=[O+][O-]
Reactant: C=Cc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCCC2
Solvent: CSC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCCc2ccc(C=O)nc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ozone was bubbled through a mixture of tert-butyl 2-vinyl-7,8-dihydro-5H-pyrido[2,3-b]azepine-9(6H)-carboxylate (intermediate 239, 470 mg, 1.66 mmol) in DCM (6.5 ml) at −78° C. After 15 minutes, the intermediate ozonide was treated with dimethyl sulfide (0.86 ml, 11.62 mmol) and then the reaction mixture was slowly warmed to room temperature. After 1.5 h, the mixture was diluted with H2O and extracted with DCM (3×). The combined organic layers were washed with sat. aq. NaHCO3 and brine, dried over Na2SO4 and evaporated to give the crude title compound as a light brown solid. (UPLC-MS 6) tR 1.04; ESI-MS 277.1 [M+H]+.