Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl[CH2:10][C:11]1[CH:15]=[CH:14][O:13][CH:12]=1>C(Cl)Cl>[CH2:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])([CH3:3])[CH2:10][C:11]1[CH:15]=[CH:14][O:13][CH:12]=1)[CH3:8]
Reactant: ClCc1ccoc1
Reactant: CCOC(=O)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Cc1ccoc1
Yield: 82 %

Procedure:
Ethyl isobutyrate (10.7 mL, 80.1 mmol) is alkylated with 3-(chloromethyl)furan according to general procedure F to give the product as a yellow liquid (12.91 g, 82%) after FC (CH2Cl2) . 1H NMR (CDCl3) 7.32 (s, 1), 7.20 (s, 1), 6.20 (s, 1), 4.12 (t, 2, J=7.4), 2.66 (s, 2), 1.25 (t, 3, J=7.4), 1.18 (s, 6); 13C NMR (CDCl3) 177.56, 142.36, 140.54, 120.78, 112.76, 60.39, 42.85, 35.43, 24.96, 14.13; MS (MW=196.3, CI/CH4, eE=70 eV) m/z 197 (M+H)+, 195, 161, 151, 123 (base peak), 109, 81.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Cl)[N:3]=1.[CH2:14]([NH2:23])[C:15]1[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[CH:17][CH:16]=1>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]2[CH2:12][N:23]([CH2:14][C:15]3[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[CH:17][CH:16]=3)[C:6](=[O:8])[C:5]2=[CH:10][CH:11]=1
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)c1ccc(Cl)nc1CCl
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3nc(Cl)ccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
To a stirred solution of crude methyl 6-chloro-2-(chloromethyl)nicotinate (10 g, 45.4 mmol) in THF (150 mL) was added PMBNH2 (15.5 g, 113.5 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 16 hours before it was concentrated under reduced pressure to give a crude product. After washing with MTBE (100 mL×3), the title compound was obtained (8.8 g, yield 67%) as a white solid. MS: 288.8 (M+H+, 10).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[Cl:10][S:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18])(=[O:13])=[O:12]>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:17]([C:16]1[CH:15]=[C:14]([S:11]([Cl:10])(=[O:13])=[O:12])[CH:22]=[CH:21][CH:20]=1)=[O:18]
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: COc1ccccc1N
Product: COc1ccccc1NC(=O)c1cccc(S(=O)(=O)Cl)c1

Procedure:
The entitled compound was produced according to the method of Reference Example 1 but using 2-methoxyaniline and 3-(chlorosulfonyl)benzoyl chloride as the starting materials.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][CH:24]([OH:44])[CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([OH:43])=[C:31]([NH:33][S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH:32]=1>>[O:18]=[C:16]1[NH:15][C:14](=[O:19])[CH:13]([CH2:12][C:11]2[CH:20]=[CH:21][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([NH:22][CH2:23][C@H:24]([OH:44])[CH2:25][O:26][C:27]4[CH:28]=[CH:29][C:30]([OH:43])=[C:31]([NH:33][S:34]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)(=[O:35])=[O:36])[CH:32]=4)[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)[S:17]1
Reactant: NCC(O)COc1ccc(O)c(NS(=O)(=O)c2ccccc2)c1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)COc4ccc(O)c(NS(=O)(=O)c5ccccc5)c4)CC3)cc2)S1

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) and N-[5-(3-amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-benzenesulfonamide (which was obtained in Example 21) according to the procedure of Example 73 as an off-white solid; mp>120° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.30–1.55 (m, 2 H), 1.80–2.00(m, 2 H), 2.50–4.00(m, 12 H), 4.55(dd, J=9.6, 4.0 Hz, 1 H), 6.49(dd, J=8.7, 2.9 Hz, 1 H), 6.61(d, J=8.7 Hz, 1 H), 6.77(d, J=2.9 Hz, 1 H), 6.86(d, J=8.7 Hz, 2 H), 7.05(d, J=8.7 Hz, 2 H), 7.40–7.60(m, 3 H), 7.70–7.80(m, 2 H); MS (ES) m/z: 627.0 (MH+, 100%); HRMS Calcd. for C30H35N4O7S2 (MH+): 627.1941. Found: 627.1954.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C@H:19]([CH:25]2[CH2:30]CCC[CH2:26]2)[CH2:20][CH2:21][C:22](O)=[O:23])[CH2:4][C:5]2[CH:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]=[CH:8][C:6]=2[N:7]=1.C(Cl)(=O)C(Cl)=O.[CH2:37]([OH:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[CH2:37]([O:44][C:22](=[O:23])[CH2:21][CH2:20][CH:19]([N:3]1[CH2:4][C:5]2[CH:11]=[C:10]([O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:9]=[CH:8][C:6]=2[N:7]=[C:2]1[NH2:1])[CH:25]([CH3:30])[CH3:26])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NC1=Nc2cnc(Oc3ccccc3)cc2CN1[C@@H](CCC(=O)O)C1CCCCC1
Reactant: OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)C(CCC(=O)OCc1ccccc1)N1Cc2cc(Oc3ccccc3)ncc2N=C1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4-(2-amino-6-phenoxy-4H-pyrido[3,4-d]pyrimidin-3-yl)-4-(S)-cyclohexyl-butyric acid (0.1 g, 0.25 mmol) in DCM (10 mL) was added oxalyl chloride (2.0M in DCM, 0.8 mL, 2 mmol). The resulting mixture was stirred at room temperature one hour. An aliquot from the reaction mixture was quenched in MeOH and analyzed by MS-HPLC which indicated that all of the acid was converted to the corresponding acid chloride. The solvent and excess oxalyl chloride was removed by vacuum. DCM (10 mL) was added followed by benzyl alcohol (0.089 mL, 0.8 mmol). The resulting solution was stirred at room temperature for one hour. The solvent was removed under vacuum to yield an oil which was purified by Gilson HPLC to yield the title compound as a solid, as its corresponding TFA salt.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].N#N>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]([NH:13][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[N:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N=C(NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(N=C(NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 1 h
Yield: 19 %

Procedure:
The product was prepared as described in J.O.C., 1998, 63 (23), 8432-8439, starting from a solution of N,N′-bis(benzyloxycarbonyl)guanidine (prepared as described in J.O.C., 1998, 63 (23), 8432-8439), (3 g, 9.17 mmol) in anhydrous THF which was brought to T=−45° C., after which NaH (60% in mineral oil, 728 mg, 18.1 mmol) was added piecemeal in small portions. The suspension was kept at T=−45° C. for 1 hour after which benzylchloroformiate (1.55 g, 9.17 mmol) was added and the suspension was brought back to room temperature in an N2 atmosphere and left under stirring for 18 hours. The mixture was concentrated at reduced pressure, and then diluted with CH2Cl2 and H2O; the two phases were separated, the organic phase was washed with HCl 1N, NaCl s.s. and dried on anhydrous Na2SO4. The crude reaction product was purified by silica gel chromatography using CH2Cl2/Et2O as eluent to give 810 mg of product (yield: 19%). Analytical data as reported in the literature.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][CH2:10][CH2:9][C:8]12[O:16][CH2:15][CH2:14][O:13]1.[CH2:17]([Li])CCC.CI>O1CCCC1>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]([CH3:17])[CH2:10][CH2:9][C:8]12[O:16][CH2:15][CH2:14][O:13]1
Reactant: [Li]CCCC
Reactant: OCc1cccc2c1NCCC21OCCO1
Solvent: CI
Solvent: C1CCOC1
Product: CN1CCC2(OCCO2)c2cccc(CO)c21
Reaction time: 0.5 h

Procedure:
To a solution of 8-hydroxymethyl-4,4-ethylenedioxy1,2,3,4-tetrahydroquinoline (2.5 g) in tetrahydrofuran (30 ml) was added n-butyllithium (14.5 to 17% solution in n-hexane) (10 ml) at --40° C. and stirred for 30 minutes. Then methyl iodide (1.9 g) was added to the reaction mixture and the mixture was stirred for 3 hours at -30° C. to -10° C. and for 30 minutes at -5° C. After distilling off the solvent, n-hexane-ethyl acetate was added to the resulting residue and the insoluble matter was filtered off. The filtrate was concentrated to give 8-hydroxymethyl-4,4-ethylenedioxy-1-methyl-1,2,3,4-tetrahydroquinoline (1.9 g).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[S:3]1.[OH:22][C@@H:23]([CH2:36][NH2:37])[CH2:24][O:25][C:26]1[C:34]2[NH:33][C:32](=[O:35])[NH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1>>[OH:22][C@@H:23]([CH2:36][NH:37][CH:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:8][CH:4]3[S:3][C:2](=[NH:1])[NH:6][C:5]3=[O:7])=[CH:10][CH:11]=2)[CH2:16][CH2:17]1)[CH2:24][O:25][C:26]1[C:34]2[NH:33][C:32](=[O:35])[NH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1
Reactant: N=C1NC(=O)C(Cc2ccc(N3CCC(=O)CC3)cc2)S1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: N=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)S1

Procedure:
The title compound: was prepared from 1-[4-(2-imino-4-oxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-one (which was obtained in Example 45) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 73 as a pale yellowish solid; mp>155° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20–1.40 (m, 2 H), 1.80–1.95 (m, 2 H), 2.50–2.90 (m, 6 H), 3.24 (dd, J=14.1, 4.0 Hz; 1 H), 3.50–3.75 (m, 2 H), 3.80–4.05 (m, 3 H), 4.50 (dd, J=9.8, 4.0 Hz, 1 H), 4.88 (brs, 1 H), 6.57 (d, J=7.8 Hz, 1 H), 6.62 (d, J=8.1 Hz, 1 H), 6.80–6.90 (m, 3 H), 7.04 (d, J=8.7 Hz, 2 H), 8.73 (brs, 1 H); MS (ES) m/z: 256.3 ((M+2H)2+, 100%), 511.2 (MH+, 10%); HRMS Calcd. for C25H31N6O4S (MH+): 511.2128. Found: 511.2122.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH2:19]([NH:22][CH2:23][CH:24]=[CH2:25])[CH:20]=[CH2:21]>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([N:22]([CH2:23][CH:24]=[CH2:25])[CH2:19][CH:20]=[CH2:21])[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNCC=C
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Solvent: O
Product: C=CCNc1nc(N(CC=C)CC=C)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
A mixture of 300 mg (1.13 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 1.18 g (12.15 mmol) of diallylamine for 2 hours was stirred at room temperature, and then at 60° C. for one hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 325 mg (yield: 88.5%) of the title compound.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].N.[N+:11]([C:14]1[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=1)([O-:13])=[O:12]>>[CH:4]1[CH:5]=[CH:6][C:1]([O:7][C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)=[CH:2][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Oc1ccccc1
Agent: N
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1
Reaction time: 10 h

Procedure:
A steel autoclave was filled with 94 g (1 mole) of phenol and 40 g of sodium hydroxide pellets (1 mole), furthermore after sealing the autoclave 150 g of ammonia were injected. At 70° C., 157.5 g (1 mole) of p-nitrochlorobenzene were pumped into the autoclave as a liquid over a period of one hour; the mixture was stirred for a further 10 hours. After the pressure vessel was let town and the product obtained was washed with water, the 4-nitrodiphenyl ether was isolated at a more than 99% purity (by gas chromatography).
Reaction SMILES: [C:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:22]>CCOCC>[C:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([Cl:22])=[O:17])=[CH:14][CH:13]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(OCc1ccccc1)Oc1ccc(C(=O)O)cc1
Solvent: CCOCC
Product: O=C(OCc1ccccc1)Oc1ccc(C(=O)Cl)cc1
Yield: 57.7 %

Procedure:
A solution of 27 m moles (7.3 g) of the above 4-carbobenzoxyoxybenzoic acid and 27 m moles (5.6 g) of phosphorus pentachloride in 50 ml of ether was stirred for 24 hours at room temperature. After the reaction, deetherizing was carried out, and the obtained crystal was recrystallized from hexane, to obtain 4.5 g of 4-carbobenzoxyoxybenzoyl chloride [m.p. 65.5°-67.4° C⟧ (yield: 57%)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[C:9]([OH:13])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1.[H-].[Na+].CC(=O)OCC>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[C:9]([O:13][CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(O)cc(C(C)=O)cc1C(C)(C)C
Reactant: BrCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(OCCCOC2CCCCO2)cc(C(C)=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 112.3 %

Procedure:
1-(3-tert-Butyl-5-hydroxy-4-methoxyphenyl)ethanone (O3.070; 6.9 g) and 2-(3-bromo-propoxy)tetrahydropyran (8.31 g) were dissolved in DMF (80 ml), and sodium hydride (894 mg) was added. After stirring at RT for 5 hours, the solvent was drawn off and the residue was taken up with EA. The EA phase was washed with water, dried and concentrated. 12.7 g of the title compound were obtained as a crude product in sufficient purity.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[N:7]=[C:6]([C:27](O)=[O:28])[CH:5]=1)[CH2:2][CH3:3].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.[NH2:68][C@H:69]([CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=1[C:81]([F:84])([F:83])[F:82])[CH2:70][C:71]([OH:73])=[O:72].Cl>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[N:7]=[C:6]([C:27]([NH:68][C@H:69]([CH2:74][C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=2[C:81]([F:82])([F:83])[F:84])[CH2:70][C:71]([OH:73])=[O:72])=[O:28])[CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Reactant: N[C@@H](CC(=O)O)Cc1ccccc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(C(=O)N[C@@H](CC(=O)O)Cc2ccccc2C(F)(F)F)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of 5-propyl-1-{6-[2-(1H-tetrazol-5-yl)-phenyl]pyridin-3-ylmethyl}-1H-pyrazole-3-carboxylic acid (20 mg, 0.05 mmol), HATU (19.5 mg, 0.0514 mmol) and DIPEA (44.7 uL, 0.257 mmol) in DMF (1.59 mL, 20.5 mmol) was stirred to pre-activate the acid. After 30 minutes, (R)-3-amino-4-(2-trifluoromethylphenyl)butanoic acid.HCl (14.6 mg, 51.4 μmol)) was added. The resulting solution was stirred overnight. The mixture was concentrated, re-dissolved in water/MeCN/TFA and purified using reverse phase liquid chromatography to yield the title compound (21.1 mg; 100% purity) as a TFA salt. MS m/z: [M+H]+ calcd for C31H29F3N8O3, 619.23; found 619.6.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[N:16]1([CH:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=[N+]([O-])c1ccc(N2CCC(N3CCCCC3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCC(N3CCCCC3)CC2)cc1
Yield: 73.8 %

Procedure:
A solution of 1-fluoro-4-nitrobenzene (1.3 mL, 12.3 mmol), triethylamine (6.0 mL; 43.0 mmol) and 4-(piperidin-1-yl)piperidine (2.36 g; 14.0 mmol) in dioxane (10 mL) was heated at reflux for 18 hr. After cooling to room temperature the mixture was concentrated under reduced pressure and the residue dissolved in DCM (150 mL). The DCM solution was washed with saturated aqueous sodium bicarbonate and brine, then dried over magnesium sulfate and concentrated under reduced pressure to produce a yellow solid. Hexanes were added and the suspension briefly sonicated. The solid was collected by filtration and washed with hexanes to give 1-(4-nitrophenyl)-4-(piperidin-1-yl)piperidine (3.05 g) as a yellow solid. A solution of 1-(4-nitrophenyl)-4-(piperidin-1-yl)piperidine (3.05 g; 10.5 mmol) in ethanol (20 mL) was hydrogenated at atmospheric pressure with 10% palladium on carbon (0.251 g) at room temperature for 17 hr. The mixture was filtered through diatomaceous earth and concentrated under reduced pressure to give 4-[4-(piperidin-1-yl)piperidin-1-yl]benzenamine (2.01 g) as a purple/pink solid.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>CCCCCC.C(OCC)C>[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH:22]1[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Brc1ccc(Br)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: OC1CCN(Cc2ccccc2)C(c2ccc(Br)cc2)C1
Temperature: -70 °C
Reaction time: 2.5 h
Yield: 73.2 %

Procedure:
400 ml of a 1.2M solution of n-BuLi in hexane were added dropwise within 45 minutes to a solution, cooled to -70° C., of 112.5 g (0.48 mol) of 1,4-dibromobenzene in 1200 ml of diethyl ether in such a manner that the temperature did not rise above -60° C. After completion of the addition the mixture was stirred at -70° C. for 2.5 hours. Thereafter, a solution of 90.84 g (0.48 mol) of 1-benzyl-4-piperidone in 300 ml of ether was added dropwise at -70 to -65° C. during one hour. After the dropwise addition the mixture was stirred at -70° C. for 2 hours. For the working-up, the cold reaction mixture was poured into 1200 ml of a 15% ammonium chloride solution, the mixture was transferred to a separating funnel and the organic phase was separated. The aqueous phase was extracted twice with ether and subsequently the combined organic phases were extracted twice with water and saturated sodium chloride solution. Then, the organic phase was dried over magnesium sulphate evaporated under reduced pressure, with the crude product separating as a yellowish solid. For purification, this was dissolved in hot methylene chloride, the solution was treated with hexane until turbidity began and cooled to room temperature while stirring. The resulting precipitate was filtered off under suction and dried. There were obtained 121.65 g (73% of theory) of 1-benzyl-(4-bromo-phenyl)-piperidin-4-ol as a yellowish solid; m.p.: 106° C., MS: 346, 348 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.Cl[CH2:30][CH2:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:16][C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[CH2:5][CH2:4][C@@H:3]4[NH:2][S:32]([CH:31]=[CH2:30])(=[O:34])=[O:33])=[N:13][N:14]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4N)s2)cc1C#N
Reactant: O=S(=O)(Cl)CCCl
Agent: Cl
Solvent: ClCCl
Product: C=CS(=O)(=O)N[C@H]1CCc2c(-c3nnc(-c4ccc(OC(C)C)c(C#N)c4)s3)cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.4 %

Procedure:
To a stirred solution of (5)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 4 (40 mg, 0.5 mmol) and TEA (49 mg, 0.48 mmol) in DCM (2 mL) was added 2-chloroethanesulfonyl chloride (79 mg, 0.48 mmol) at 0° C. The reaction was warmed to room temperature and stirred for 2 h. The reaction was quenched by the addition of NaHCO3. The product was purified by chromatography (EA/hexane) to provide 30 mg (66%) of (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)ethenesulfonamide as yellow solid. LCMS-ESI (m/z) calculated for C23H22N4O3S2: 466.1; found 467.1 [M+H]+, tR=3.63 min.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([C:7]1[S:11][C:10]([C:12]([O:14]C)=O)=[CH:9][CH:8]=1)=[O:6])[CH3:3].O.[NH2:17][NH2:18]>C(O)C>[CH3:1][CH:2]([NH:4][C:5]([C:7]1[S:11][C:10]([C:12]([NH:17][NH2:18])=[O:14])=[CH:9][CH:8]=1)=[O:6])[CH3:3]
Reactant: COC(=O)c1ccc(C(=O)NC(C)C)s1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)NC(=O)c1ccc(C(=O)NN)s1
Yield: 45 %

Procedure:
Methyl 5-(2-propylcarbamoyl)thiophene-2-carboxylate (1.22 g, 5.37 mmol) in ethanol (40 mL) was heated with hydrazine monohydrate (2.7 g) at 85° C. for 16 hours with reflux. After cooling, the solvent was evaporated, the resulting solid was recrystallized from chloroform to give 549.2 mg of the desired product (yield 45%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[N+:6]([O-])[CH:7]=1.C[Si]([C:14]#[N:15])(C)C.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:7]([C:14]#[N:15])=[N:6][C:5]([Cl:9])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1cc(Br)ccc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1nc(Cl)ccc1Br
Temperature: 100 °C

Procedure:
To a solution of 5-bromo-2-chloropyridine 1-oxide (from step 1) (1.0 eq.) in acetonitrile (0.2 M) was added trimethylsilyl cyanide (TMSCN) (4.0 eq.) and triethylamine (3.0 eq.). The reaction was heated at 100° C. overnight. After cooling to room temperature, the solvent was concentrated en vacuo, and the residue was purified by a COMBIFLASH® system (ISCO) using 0-40% ethyl acetate in hexane to give 3-bromo-6-chloropicolinonitrile.
Reaction SMILES: [C:1]1([C:7]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][C:14]3[NH:13][N:12]=[C:11]([C:16]([O:18]CC)=[O:17])[C:10]=3[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(O)C.[OH-].[Na+]>[C:21]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:15][C:14]3[NH:13][N:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=3[CH:9]=[CH:8]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Yield: 80.6 %

Procedure:
A solution of 2 g of ethyl 6,6-diphenyl-6,7-dihydro-1H-indazole-3-carboxylate in 20 cm3 of ethanol and 8.7 cm3 of 1N sodium hydroxide solution are heated for 3 hours at a temperature in the region of 70° C. The ethanol is then removed under reduced pressure to give a solution, which is acidified to a pH in the region of 3 by addition of 1N hydrochloric acid. The resulting mixture is filtered to give 1.48 g of 6,6-diphenyl-6,7-dihydro-1H-indazole-3-carboxylic acid in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][C:4]=2[N:3]=[C:2]1[SH:14])[CH:11]=[CH:10][CH:9]=[CH:8]3.Cl.Cl[CH2:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1>CN(C)C=O>[NH:19]1[CH:20]=[CH:21][N:22]=[C:18]1[CH2:17][S:14][C:2]1[NH:3][C:4]2[CH:13]=[C:12]3[C:7](=[CH:6][C:5]=2[N:1]=1)[CH:8]=[CH:9][CH:10]=[CH:11]3
Reactant: Sc1nc2cc3ccccc3cc2[nH]1
Reactant: ClCc1ncc[nH]1
Agent: Cl
Solvent: CN(C)C=O
Product: c1ccc2cc3[nH]c(SCc4ncc[nH]4)nc3cc2c1
Yield: 10.7 %

Procedure:
1.0 g of 1H-Naphth[2,3-d]imidazole-2-thiol and 0.8 g of 2-chloromethylimidazole-hydrochloride were heated for 11/2 hours at 90° in 20 ml of dimethylformamide. The precipitate formed was filtered off, washed with a small amount of acetonitrile, and dissolved in 2 N sodium bicarbonate solution. The aqueous phase was extracted three times with 30 ml of ethyl acetate. The organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate, and then concentrated by evaporation. The residue was recrystallised from 150 ml of acetonitrile. 150 mg of 2-[(Imidazole-2-ylmethyl)thio]-1H-naphth[2,3-d]imidazole having a melting point of 172° was obtained.