Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[Cl:29][C:30]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:31]=1[NH:32][CH3:33]>>[Cl:29][C:30]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:31]=1[N:32]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:27])([F:26])[F:28])(=[O:17])=[O:18])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1)[CH3:33]
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Reactant: CNc1ccc(Cl)cc1Cl
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)cc1)c1ccc(Cl)cc1Cl
Yield: 69 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 2,4-dichloro-N-methylaniline, the title compound was isolated as a yellow solid in 69% yield (96% purity by HPLC).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[C:20](=[O:37])[N:19]([CH2:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[N:18]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:3][C:4](=[O:7])[O:5][N:36]=3)=[CH:25][CH:24]=2)[C:20](=[O:37])[N:19]([CH2:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[N:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nn(CC(=O)C(C)(C)C)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nn(CC(=O)C(C)(C)C)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
A mixture of hydroxylammonium chloride (1.12 g), sodium hydrogen carbonate (1.69 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[3-butyl-1-(3,3-dimethyl-2-oxobutyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-carbonitrile (0.58 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL). N,N′-carbonyldiimidazole (0.24 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.42 g, 63%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(CC)CC)C.O>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(N2CCC(O)C2)c1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1cccc(N2CCC(=O)C2)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 53.7 %

Procedure:
A solution of 1-(3-cyanophenyl)-3-pyrrolidinol (0.65 g, 4.1 mmol) in triethyl amine (5.72 ml, 41 mmol) and DMSO (15 ml) was cooled to 0° C. and pyridine-SO3 (1.96 g, 12.3 mmol) was added. The mixture was stirred at 0° C. for 1 hr and at room temperature for 18 hr. The reaction mixture was poured into water (100 ml) and extracted three times with methylene chloride. The methylene chloride extracts were dried over magnesium sulfate and concentrated in vacuo to give 1-(3-cyanophenyl)-3-pyrrolidinone (0.41 g, 54%) that was used without purification.
Reaction SMILES: C(O)(=O)CCCC.NC1C=CN(CC(=O)N(C)C)C(=O)C=1NCC1C=CC([C:30]2[CH:34]=[CH:33][S:32][C:31]=2[C:35]2[NH:39][N:38]=[N:37][N:36]=2)=CC=1.N[C:41]1[C:42](=[O:61])[N:43](CC(=O)N(C)C)[CH:44]=[CH:45][C:46]=1NCC1C=CC=CC=1.[CH2:62]([NH:69][CH:70]1[CH:75]=[CH:74][N:73]([CH2:76][C:77](=[O:81])[N:78]([CH3:80])[CH3:79])[CH2:72][C:71]1=O)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.C[Sn](N=[N+]=[N-])(C)C>>[NH:36]1[C:35]([C:31]2[S:32][CH:33]=[CH:34][C:30]=2[N:69]([CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:70]2([NH:43][C:42](=[O:61])[CH2:41][CH2:46][CH2:45][CH3:44])[CH:75]=[CH:74][N:73]([CH2:76][C:77](=[O:81])[N:78]([CH3:80])[CH3:79])[CH:72]=[CH:71]2)=[N:39][N:38]=[N:37]1
Reactant: CN(C)C(=O)CN1C=CC(NCc2ccccc2)C(=O)C1
Reactant: CN(C)C(=O)Cn1ccc(N)c(NCc2ccc(-c3ccsc3-c3nnn[nH]3)cc2)c1=O
Reactant: CN(C)C(=O)Cn1ccc(NCc2ccccc2)c(N)c1=O
Agent: C[Sn](C)(C)N=[N+]=[N-]
Solvent: CCCCC(=O)O
Product: CCCCC(=O)NC1(N(Cc2ccccc2)c2ccsc2-c2nnn[nH]2)C=CN(CC(=O)N(C)C)C=C1

Procedure:
A mixture of 1.02 g of valeric acid, 4.50 g of 4-amino-1,2-dihydro-2-oxo-3-(4-(2-(1H-5-tetrazolyl)-3-thienyl)benzylamino)-1-(N,N-dimethylcarbamoylmethyl)pyridine [obtainable by reaction of 3-amino-4-benzylamino-1,2-dihydro-2-oxo-1-(N,N-dimethylcarbamoylmethyl)pyridin with IIa to give 4-benzylamino-3-oxo-1-(N,N-dimethylcarbamoylmethyl)pyridine, reaction with trimethyltin azide to give 4-benzylamino-1,2-dihydro-2-oxo-3-(4-(2-(1H-5-tetrazolyl)-3-thienyl)benzylamino)-1-(N,N-dimethylcarbamoylmethyl)pyridine and hydrogenolytic removal of the benzyl group] and 50 g of polyphosphoric acid is heated for 5 hours at 140°. 4-Amino-1,2-dihydro-2-oxo-3-(N-4-(2-(1H-5-tetrazolyl)-3-thienyl)benzyl-N-valerylamino)-1-(N,N-dimethylcarbamoylmethyl)pyridine and 1,2-dihydro-2-oxo-3-(4-(2-(1H-5-tetrazolyl)-3-thienylbenzylamino)-1-(N,N-dimethylcarbamoylmethyl)-4-valerylaminopyridine are formed in situ as intermediates. The mixture is cooled, poured onto ice, rendered alkaline with sodium hydroxide solution and worked up in the conventional manner, and gives 2-butyl-3-(4-(2-(1H-5 -tetrazolyl)-3-thienyl)benzyl-4,5-dihydro-4-oxo-5-(N,N-dimethylcarbamoylmethyl)-3H-IP.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][N:18]=2)[C:15]([NH2:19])=[N:14][CH:13]=[CH:12]3)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:48])[C:39]1[C:40](=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:41](Cl)=[O:42]>ClCCl>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:30][CH:29]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][N:18]=2)[C:15]([N:19]2[C:41](=[O:42])[C:40]4[C:39](=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:38]2=[O:48])=[N:14][CH:13]=[CH:12]3)=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc3ccnc(N)c3cn2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc3ccnc(N4C(=O)c5ccccc5C4=O)c3cn2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred mixture of crude 4-5 (10.9 g, <19.3 mmol), triethylamine (8.05 mL, 57.8 mmol), and dichloromethane (75.0 mL) at 0° C. under an atmosphere of nitrogen gas was added phthaloyl dichloride (90%; 3.75 mL, 23.4 mmol). The resulting mixture was stirred at ambient temperature for 15 hours under an atmosphere of nitrogen gas. The reaction mixture was quenched with saturated aqueous NH4Cl (200 mL) and the resulting mixture was extracted with dichloromethane (1000 mL, 500 mL×2). The combined organic extracts were washed with brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel 200 g, step gradient eluting with 50:1, 40:1, 30:1, 20:1, 10:1, and 5:1 dichloromethane/ethyl acetate) followed by recrystallization from dichloromethane to give 3.94 g (39% in 3 steps) of 4-6 as yellow crystals: 1H NMR (400 MHz, CDCl3) δ 8.94 (1H, br s), 8.33 (1H, d, J=6.0 Hz), 8.02 (2H, m), 7.84 (2H, m), 7.31 (1H, dd, J=6.0, 0.8 Hz), 7.15 (4H, m), 6.85 (4H, m), 6.52 (1H, br s), 4.81 (4H, br s), 3.79 (6H, s); ESI-MS m/z 531 [C32H26N4O4+H]+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:15][CH:14]=1)=[N+:2]=[N-:3].[I:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]#[CH:37])=[CH:30][CH:29]=1.O>C1COCC1.[O-]S([O-])(=O)=O.[Cu+2]>[I:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[N:3]=[N:2][N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[CH:17][CH:18]=3)[CH:37]=2)=[CH:30][CH:29]=1
Reactant: C#CCOc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OCCOCCOCCN=[N+]=[N-])cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(OCCOCCOCCn2cc(COc3ccc(I)cc3)nn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To a solution of tert-butyl 4-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)phenylcarbamate (1.78 g, 4.86 mmol) and 1-iodo-4-(prop-2-ynyloxy)benzene (1.25 g, 4.86 mmol) in THF (30 mL) was added H2O (8.0 mL), Cu powder (0.31 g, 4.86 mmol) and CuSO4 (0.12 g, 0.486 mmol). The reaction mixture was stirred at room temperature for at least 12 hours (overnight). The reaction mixture was filtered through celite and washed with EtOAc. The organic layer was separated, washed with EDTA solution, dried and concentrated in vacuo to give a crude product which was purified by flash chromatography with hexane/EtOAc (1:1) as eluent to give tert-butyl 4-(2-(2-(2-(4-((4-iodophenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)ethoxy)phenylcarbamate (2.069 g, 68%). 1H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.46 (d, J=9.2 Hz, 2H), 7.15 (d, J=8.8 Hz, 2H), 6.74 (d, J=9.2 Hz, 2H), 6.66 (d, J=8.8 Hz, 2H), 6.25 (brs, 1H), 5.04 (s, 2H), 4.47 (t, J=5.0 Hz, 2H), 3.99 (t, J=4.8 Hz, 2H), 3.79 (t, J=5.0 Hz, 2H), 3.80 (t, J=5.0 Hz, 2H), 3.71 (t, J=5.0 Hz, 2H), 3.60-3.53 (m, 4H), 1.44 (s, 9H); MS (ESI), 625 (M+H)+.
Reaction SMILES: [CH3:1][C:2](OC(C)=O)=[O:3].[CH2:8]1[O:17][C:16]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=2[O:9]1.CO>O1CCOCC1>[O:17]1[C:16]2[CH:15]=[CH:14][C:12]([NH:13][C:2](=[O:3])[CH3:1])=[CH:11][C:10]=2[O:9][CH2:8]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)OCO2
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)Nc1ccc2c(c1)OCO2
Temperature: 16 °C
Reaction time: 16 h
Yield: 86.1 %

Procedure:
Ac2O (21.4 mL, 226 mmol) was added dropwise to a stirred solution of 3,4-methylendioxyaniline (217) (25.87 g, 189 mmol) in dioxane (200 mL) at 0° C. and the mixture was stirred at 16° C. for 16 h. MeOH (10 mL) was added to decompose excess Ac2O and the solvent evaporated. The residue was dissolved in EtOAc (200 mL), dried and the solvent evaporated. The residue was filtered through a short column of silica, eluting with a gradient (50-100%) of EtOAc/pet. ether, to give acetamide 218 (29.17 g, 86%) as a white solid: mp 133-135° C. [lit (Krasso, A. & Ramuz, H., U.S. Pat. No. 4,599,347, 1986) mp (toluene) 138-139° C.]; 1H NMR δ 7.09 (d, J=1.8 Hz, 1H, H-4), 7.06 (br s, 1H, NH), 6.77 (dd, J=8.3, 1.8 Hz, 1H, H-6), 6.72 (d, J=8.3 Hz, 1H, H-7), 5.94 (s, 2H, H-2), 2.14 (s, 3H, CH3).
Reaction SMILES: COCN[C:5]([C:7]1[C:12]([N:13]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=2)(=[O:19])=[O:18])COC)=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6].I[C:32]1[C:33]2[CH:40]=[CH:39][N:38](COCC[Si](C)(C)C)[C:34]=2[N:35]=[CH:36][N:37]=1.CO.Cl>C1COCC1.C([Mg]Cl)(C)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([NH:13][C:12]2[C:7]([C:5]([C:32]3[C:33]4[CH:40]=[CH:39][NH:38][C:34]=4[N:35]=[CH:36][N:37]=3)=[O:6])=[N:8][CH:9]=[CH:10][CH:11]=2)(=[O:18])=[O:19])=[CH:21][C:22]=1[C:27]([F:29])([F:28])[F:30]
Reactant: C[Si](C)(C)CCOCn1ccc2c(I)ncnc21
Reactant: COCNC(=O)c1ncccc1N(COC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(c1ncccc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ncnc2[nH]ccc12

Procedure:
Prepared from 248 mg (0.53 mmol) of 3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid methoxymethyl-amide, 239 mg (0.58 mmol) of 90% 4-iodo-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine dissolved in 2 mL THF with 0.32 mL of 2 M isopropylmagnesium chloride solution in THF added. All of the resulting intermediate ketone was used in the second step with 4 mL methanol and 4 mL 6N hydrochloric acid mixture to give after purification 29 mg of the final product as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[O:21][CH2:20][CH2:19]3)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>O1CCOCC1>[ClH:27].[N:11]1([CH2:14][CH2:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[O:21][CH2:20][CH2:19]3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2ccc3c(c2)CCOC3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1OCCc2cc(CCN3CCNCC3)ccc21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
tert-Butyl-4-[2-(1-oxo-3,4-dihydro-1H-isochromen-6-yl)ethyl]piperazine-1-carboxylate (2.24 g, 6.21 mmol) was treated with 4 M HCl in dioxane (Aldrich, 90 mL) and the resulting mixture was stirred at room temperature for 40 minutes. The reaction mixture was then concentrated to afford the title compound. LCMS: m/z 261 (M+1)+.
Reaction SMILES: CN(C)S([N:6]1[C:10]2=[C:11]3[C:16](=[CH:17][CH:18]=[C:9]2[CH:8]=[N:7]1)[C:15](=[O:19])[C:14](I)=[C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[O:12]3)(=O)=O.FC1C=[C:31]2C(=CC=1)O[C:34]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[C:33](I)[C:32]2=O.C[N:48](C)S(N1C2C(=CC=C(C(=O)C#CC3C=CC=CC=3)C=2OC)C=N1)(=O)=O>>[NH2:48][C:34]1([C:39]2[CH:40]=[CH:41][C:42]([C:14]3[C:15](=[O:19])[C:16]4[C:11]([O:12][C:13]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:10]3[NH:6][N:7]=[CH:8][C:9]3=[CH:18][CH:17]=4)=[CH:43][CH:44]=2)[CH2:31][CH2:32][CH2:33]1
Reactant: CN(C)S(=O)(=O)n1ncc2ccc3c(=O)c(I)c(-c4ccccc4)oc3c21
Reactant: O=c1c(I)c(-c2ccccc2)oc2ccc(F)cc12
Reactant: COc1c(C(=O)C#Cc2ccccc2)ccc2cnn(S(=O)(=O)N(C)C)c12
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5cn[nH]c54)c3=O)cc2)CCC1
Yield: 82 %

Procedure:
7-Iodo-6-oxo-8-phenyl-6H-9-oxa-1,2-diaza-cyclopenta[a]naphthalene-1-sulfonic acid dimethylamide Following the procedure used to prepare 6-fluoro-3-iodo-2-phenyl-chromen-4-one, 7-methoxy-6-(3-phenyl-propynoyl)-indazole-1-sulfonic acid dimethylamide was reacted to give the title compound as a tan solid (173 mg, 82%). LCMS (Method B): RT=4.42 min, [M+H]+=496.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:13][C:14]([OH:16])=[O:15].[CH3:17][C:18]([OH:20])=[O:19].[CH3:21][C:22]([OH:24])=[O:23].[CH3:25][C:26]([OH:28])=[O:27]>>[CH2:3]1[N:4]([CH2:13][C:14]([OH:16])=[O:15])[CH2:5][CH2:6][N:7]([CH2:17][C:18]([OH:20])=[O:19])[CH2:8][CH2:9][N:10]([CH2:21][C:22]([OH:24])=[O:23])[CH2:11][CH2:12][N:1]([CH2:25][C:26]([OH:28])=[O:27])[CH2:2]1
Reactant: C1CNCCNCCNCCN1
Reactant: CC(=O)O
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1

Procedure:
1,4,7,10 tetraazacyclododecane 1,4,7,10 N, N′, N″, N′″ tetraacetic acid
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:13][C:12]=1[CH:23]1[C:32]([CH3:34])([CH3:33])[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:35](O)=[O:36])[CH:29]=2)[NH:24]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:13][C:12]=1[CH:23]1[C:32]([CH3:33])([CH3:34])[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:35]([NH:7][S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])=[O:36])[CH:29]=2)[NH:24]1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(N2CCOCC2)ccc1F
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(=O)(=O)C3CC3)ccc2NC1c1cc(N2CCOCC2)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a suspension of cyclopropanesulfonic acid amide (78.7 mg, 0.65 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (26 mg, 0.65 mmol). The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-(2-fluoro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (50 mg, 0.13 mmol) and 1,1′-carbonyldiimidazole (42 mg, 0.26 mmol) in N,N-dimethylformamide (2 mL) was stirred at 70° C. for 1 h. Then the above suspension of cyclopropanesulfonic acid amide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [2-(2-fluoro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (19 mg, 30%) as a white solid: LC/MS m/e calcd for C25H30FN3O4S (M+H)+: 488.6, observed: 488.4.
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)[Cl:8].[CH2:11]([O:13][C:14]([N:16]1[CH:21]2[CH2:22][CH2:23][CH:17]1[CH2:18][C:19](=O)[CH2:20]2)=[O:15])[CH3:12]>C(Cl)Cl>[CH2:11]([O:13][C:14]([N:16]1[CH:21]2[CH2:22][CH2:23][CH:17]1[C:18]([CH:4]=[O:5])=[C:19]([Cl:8])[CH2:20]2)=[O:15])[CH3:12]
Reactant: CCOC(=O)N1C2CCC1CC(=O)C2
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)N1C2CCC1C(C=O)=C(Cl)C2
Temperature: 25 °C
Yield: 99.1 %

Procedure:
To a solution of dry DMF (45 g, 0.6 mol) in dry CH2Cl2 (150 ml) was added POCl3 (75 g, 0.5 mol) at 0°-10° C. 8-Ethoxycarbonyl-8-azabicyclo[3.2.1]octane-3-one (57 g, 0.29 mol) dissolved in dry CH2Cl2 (60 ml) was added. The reaction mixture was stirred over night at room temperature, then added to ice water (1.000 ml). The phases were separated and the water phase extracted with CH2Cl2 (2×200 ml). The combined CH2Cl2 extracts were washed with a saturated NaHCO3 solution and water, dried and evaporated to give 70 g of the title compound, which was used in the next step without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([CH3:3])[CH3:2].O[CH2:12][CH:13]([CH2:15]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O>>[CH:1]([C:4]1[CH:5]=[C:6]2[C:8]([CH:12]=[CH:13][CH:15]=[N:7]2)=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(N)c1
Reactant: OCC(O)CO
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Product: CC(C)c1ccc2cccnc2c1
Yield: 102.6 %

Procedure:
In a similar fashion using route 10 general procedure 20, 3-isopropylaniline (1 g, 7.4 mmol), glycerol (2.11 g, 22.9 mmol) and 3-nitro benzenesulfonic acid sodium salt (2.2 g, 9.61 mmol) gave the title compound (1.3 g, 100%) which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2([CH3:12])[CH3:11].N1C=CC=CC=1.[Cl:19][C:20]1[N:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>C(OCC)(=O)C>[Cl:19][C:20]1[C:21]([C:22]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH2:5][C:6]3([CH3:12])[CH3:11])=[O:23])=[CH:25][CH:26]=[CH:27][N:28]=1
Reactant: CC1(C)CCc2c(N)cccc21
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC1(C)CCc2c(NC(=O)c3cccnc3Cl)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a solution of 200 mg (1.2 mmol) of 4-amino-1,1-dimethylindane and 0.15 g (1.9 mmol) of pyridine in 15 ml of ethyl acetate was added 0.24 g (1.4 mmol) of 2-chloronicotinic acid chloride under ice cooling, and the mixture was stirred at room temperature for one hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried over Glauber's salt and then concentrated under reduced pressure. The white residue was recrystallized with hexane to obtain 300 mg of white crystals (Compound No. 1 shown in Table 2). The yield was 80.4%.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[F:10][C:11]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=1[CH:13]=O>>[F:10][C:11]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=1[CH2:13][NH:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2]
Reactant: O=Cc1ccc(F)cc1F
Reactant: CCOC(CN)OCC
Product: CCOC(CNCc1ccc(F)cc1F)OCC
Yield: 37.1 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-2, 2,2-diethoxyethanamine (75.6 ml, 520 mmol) was reacted with 2,4-difluorobenzaldehyde (75 g, 520 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=5:1 and 3:1) to obtain the title compound (50.0 g, 36%).
Reaction SMILES: [N:1]1([C:5]2[C:6]3[CH2:28][CH2:27][CH:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:7]=3[N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH:22]=[C:21]([Cl:23])[N:20]=[CH:19]4)=[C:14]([O:24][CH3:25])[CH:13]=3)[N:10]=2)[CH2:4][CH2:3][CH2:2]1.CO.CO.C(Cl)(Cl)Cl>C(=O)=O>[N:1]1([C:5]2[C:6]3[CH2:28][CH2:27][C@H:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:7]=3[N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH:22]=[C:21]([Cl:23])[N:20]=[CH:19]4)=[C:14]([O:24][CH3:25])[CH:13]=3)[N:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(Nc2nc3c(c(N4CCC4)n2)CCC3c2ccccc2)ccc1-n1cnc(Cl)c1
Agent: O=C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc(Nc2nc3c(c(N4CCC4)n2)CC[C@@H]3c2ccccc2)ccc1-n1cnc(Cl)c1

Procedure:
A racemic mixture of 4-(azetidin-1-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (Example 6) was purified using chiral SFC to afford peak A (Example 6A) and peak B (Example 6B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 35% methanol (0.1% diethylamine) in CO2, 35° C., flow rate 2.0 mL/min for 30 min, absorbance 268 nm, injection 5 μL of 2 mg/mL solution in 50:50 methanol/chloroform (multiple stacked injections), tR (peak A)=5.9 min, tR (peak B) 24.6 min. The absolute stereochemistry of individual enantiomers (Examples 6A and 6B) was not determined LC-MS and 1H NMR analytical data for the separated enantiomers was identical to the racemate (Example 6).
Reaction SMILES: CN(C=[O:5])C.[C:6]([CH:13]([NH2:16])[CH2:14]Br)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[CH:17]1[CH:18]=[CH:19][C:20]([NH:27][C:28]2[C:29]([Cl:35])=[CH:30][CH:31]=[CH:32][C:33]=2[Cl:34])=[C:21]([CH2:23][C:24]([O-:26])=[O:25])[CH:22]=1.[Na+]>C(OCC)(=O)C>[C:6]([C:13]([NH2:16])([OH:5])[CH3:14])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[CH:17]1[CH:18]=[CH:19][C:20]([NH:27][C:28]2[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:35])=[C:21]([CH2:23][C:24]([OH:26])=[O:25])[CH:22]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)C(N)CBr
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C)(N)O
Product: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
After ice-cooling 5 ml of DMF solution containing 2.287 g (10.2 mmol) of the Boc-aminoethyl bromide obtained in Reference Example 5, 6 ml of DMF solution containing 3.255 g (10.2 mmol) of diclofenac sodium was added thereto, followed by stirring at room temperature overnight. The mixture was stirred at 60° C. for 11 hours and then stirred at room temperature overnight. Ethyl acetate was added thereto, and separation by washing with 5% aqueous sodium hydrogen carbonate solution, water and saturated brine consecutively was carried. After dehydration with sodium sulfate, ethyl acetate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (toluene:ethyl acetate=20:1, 0.5% triethylamine) to give 2.675 g (60%) of the titled compound. The structure was identified by 1H-NMR.