Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10](/[C:14](=[CH:47]\[CH:48]=[C:49]2\[N:50]([CH2:72][CH2:73]CS([O-])(=O)=O)[C:51]3[CH:52]=[CH:53][C:54]4[C:63]([S:64]([O-:67])(=[O:66])=[O:65])=[CH:62][C:61]([S:68]([O-:71])(=[O:70])=[O:69])=[CH:60][C:55]=4[C:56]=3[C:57]\2([CH3:59])[CH3:58])/[CH:15]=[CH:16]/[C:17]2[C:25]([CH3:27])([CH3:26])[C:24]3[C:23]4[CH:28]=[C:29]([S:36]([O-:39])(=[O:38])=[O:37])[CH:30]=[C:31]([S:32]([O-:35])(=[O:34])=[O:33])[C:22]=4[CH:21]=[CH:20][C:19]=3[N+:18]=2[CH2:40][CH2:41][CH2:42]S([O-])(=O)=O)[CH:11]=CC=1)([OH:3])=[O:2].[Na+:79].[Na+].[Na+].[Na+].[Na+].B(C1C=C(C[CH2:94][C:95](O)=O)C=CC=1)(O)O>>[C:1]([CH2:4][CH2:5][C:6]1[CH:11]=[C:10](/[C:14](=[CH:47]\[CH:48]=[C:49]2\[N:50]([CH2:72][CH2:73][CH2:95][CH2:94][S:36]([O-:39])(=[O:38])=[O:37])[C:51]3[CH:52]=[CH:53][C:54]4[C:63]([S:64]([O-:67])(=[O:66])=[O:65])=[CH:62][C:61]([S:68]([O-:71])(=[O:70])=[O:69])=[CH:60][C:55]=4[C:56]=3[C:57]\2([CH3:58])[CH3:59])/[CH:15]=[CH:16]/[C:17]2[C:25]([CH3:27])([CH3:26])[C:24]3[C:23]4[CH:28]=[C:29]([S:36]([O-:39])(=[O:38])=[O:37])[CH:30]=[C:31]([S:32]([O-:35])(=[O:33])=[O:34])[C:22]=4[CH:21]=[CH:20][C:19]=3[N+:18]=2[CH2:40][CH2:41][CH2:42][CH2:31][S:32]([O-:35])(=[O:34])=[O:33])[CH:9]=[CH:8][CH:7]=1)([OH:3])=[O:2].[Na+:79].[Na+:79].[Na+:79].[Na+:79].[Na+:79]
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCCCC(=O)O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21
Reactant: O=C(O)CCc1cccc(B(O)O)c1
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCC(=O)O)c2)=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21

Procedure:
Compound 10 was prepared analogously to compound 8 (Example 8), except that 3-(3-boronophenyl)propionic acid is used as a starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C@@H:4]([NH:17][C:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[CH2:5][C@H:6]([C:13]([O:15]C)=O)[NH:7]2.[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH2:31]>>[CH3:27][N:28]([CH2:29][CH2:30][NH:31][C:13]([C@H:6]1[CH2:5][C@H:4]([NH:17][C:18]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[C:3]2[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])[NH:7]1)=[O:15])[CH3:32]
Reactant: COC(=O)[C@H]1C[C@H](NC(=O)Cc2ccccc2)c2c(Cl)cc(Cl)cc2N1
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)[C@H]1C[C@H](NC(=O)Cc2ccccc2)c2c(Cl)cc(Cl)cc2N1
Reaction time: 6 h

Procedure:
Trans 5,7-dichloro-2-methoxycarbonyl-4-phenylmethylcarbonylamino-1,2,3,4-tetrahydroquinoline (Example 37a) (0.3 g) was dissolved in N,N-dimethylethylenediamine (30 ml) and allowed to stand at room temperature for 6 h. After this time the reaction mixture was filtered and the solvent was removed under vacuum. The residue was dissolved in ethyl acetate (100 ml) and washed with water (100 ml) then brine (100 ml). The organic solution was dried (MgSO4), filtered and concentrated in vacuo to give a solid which was triturated with diethyl ether and collected by filtration to give the title compound (0.19 g) as a colourless solid, m.p. 158°-159° C.; δ (360 MHz, DMSO) 1.54 (1H, ddd, J=13.0, 12.5 and 4.0 Hz, CHACHBHCCHD), 2.08 (1H, dm, J=13.0 Hz, CHACHBHCCHD), 2.16 (6H, s, N(CH3)2), 2.33 (2H, t, J=6.7 Hz, CH2CH2N(CH3)2, 3.21 (2H, m, CH2CH2N(CH3)2), 3.37 (1H, d, J=14.0 Hz, CHEHFPh), 3.47 (1H, d, J=14.0 Hz, CHEHFPh), 3.74 (1H, dm, J=12.5 Hz, CHACHBHCCHD), 4.99 (1H, m, CHACHBHCCHD), 6.66 (1H, d, J=1.9 Hz, 6-H or 8-H), 6.79 (2H, m, 6-H or 8-H and ArNH), 7.26 (5H, m, ArH), 8.01 (1H, br, s, CONHCH2CH2N(CH3)2), 8.44 (1H, d, J=7.2 Hz, CHDNHCO); m/e 488 (M+); Found C, 58.47; H, 5.84; N, 12.39 C22H26Cl2N4O2 requires C, 58.80; H, 5.83; N, 12.47%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22]OS([O-])=O.[K+].[OH2:28]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)(=[O:22])=[O:28])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2ccc(F)cc2)CC1
Reactant: O=S([O-])OO
Reactant: O
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(F)cc2)CC1
Reaction time: 6 h
Yield: 97 %

Procedure:
A solution of tert-butyl 4-((4-fluorophenyl)thio)piperidine-1-carboxylate (1.5 g) in water (16.06 mL) and MeOH (16.06 mL) was treated with Oxone® (5.92 g, 9.63 mmol) at room temperature and the resulting reaction mixture was stirred for 6 h. The solution was filtered by suction and the solvent removed gave tert-butyl 4-((4-fluorophenyl)sulfonyl)piperidine-1-carboxylate (1.6 g, 4.66 mmol, 97% yield) as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[N+:13]([C:16]1[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([NH:24][NH2:25])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:25][NH:24][C:22](=[O:23])[CH2:21][O:20][C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:27][CH:26]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)COc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: O=C(COc1ccc([N+](=O)[O-])cc1)NN=C1C(=O)Nc2ccc(I)cc21
Temperature: 100 °C
Yield: 85 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 2-(4-nitrophenoxy)acetohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 395 mg of the title compound (85%) as a yellow solid in 97.3% purity by HPLC (Rt: 5.76, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:12][C:13](=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:29][CH2:30][C@@H:31]([C:33]1[CH:34]=[CH:35][C:36]([OH:44])=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=1)[OH:32]>>[CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:12][C:13](=[O:27])[C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([NH:29][CH2:30][C@H:31]([OH:32])[C:33]3[CH:34]=[CH:35][C:36]([OH:44])=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=3)[CH2:22][CH2:21]2)=[CH:18][CH:19]=1)[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from (2S)-2-[4-(4-oxo-piperidin-1-yl)-benzoylamino]-3-phenyl-propionic acid methyl ester (which was obtained in Example 164) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as an off-white solid; mp>98° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20–1.40 (m, 2 H), 1.80–1.90 (m, 2 H), 2.05–2.90 (m, 5 H), 2.91 (s, 3 H), 3.00–3.20 (m, 2 H), 3.70–3.80 (m, 2 H), 4.47 (dd, J=8.0, 4.3 Hz, 1 H), 4.50–4.65 (m, 1 H), 6.81 (d, J=8.2 Hz, 1 H), 6.92 (d, J=8.9 Hz, 2 H), 7.00 (dd, J=8.2, 2.0 Hz, 1 H), 7.10–7.30 (m, 6 H), 7.67 (d, J=8.9 Hz, 2 H), 8.47 (d, J=7.8 Hz, 1 H); MS (ES) m/z: 611.2 (MH+); HRMS Calcd. for C31H39N4O7S (MH+): 611.2534. Found: 611.2525.
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH2:2][CH3:3].[NH2:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[NH:24][CH2:25][C:26]([CH3:29])([OH:28])[CH3:27])=[CH:21][CH:20]=[C:19]([Br:30])[CH:18]=2>C1(C)C=CC=CC=1.Cl.N1C=CC=CC=1>[Br:30][C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[N:24]([CH2:25][C:26]([CH3:27])([OH:28])[CH3:29])[C:1]([CH2:2][CH3:3])=[N:13][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1
Reactant: CC(C)(O)CNc1c(N)cnc2cc(Br)ccc12
Reactant: CCOC(CC)(OCC)OCC
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCc1nc2cnc3cc(Br)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
Triethyl orthopropionate (12.9 g, 73.2 mmol) and pyridine hydrochloride (220 mg) were added to a solution of 1-(3-amino-7-bromoquinolin-4-ylamino)-2-methylpropan-2-ol (22.1 g, 70.6 mmol) in anhydrous toluene (300 mL), and the reaction was heated at reflux for three hours. The reaction was allowed to cool to ambient temperature and stand overnight; a precipitate formed. The precipitate was isolated by filtration, washed with toluene, and air-dried to provide 18.42 g of 1-(7-bromo-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as beige crystals.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([CH3:7])([CH3:6])[CH3:5])[CH3:3].C(=O)([O-])[O-].[K+].[K+].O.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18](F)[CH:17]=1>C1COCC1>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[C:20]([NH:1][C@H:2]([CH3:3])[C:4]([CH3:7])([CH3:6])[CH3:5])[CH:21]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: C[C@@H](N)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](Nc1cc(Cl)ccc1[N+](=O)[O-])C(C)(C)C
Temperature: 75 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
Add 2-(R)-amino-3,3-dimethylbutane (20 mL, 0.148 mol), potassium carbonate (14.3 g, 0.104 mol) and water (50 mL) to a solution of 4-chloro-2-fluoronitrobenzene (13.3 g, 0.076 mol) in THF (450 mL) and stir at 75° C. for 3 h Cool to ambient temperature. Concentrate to ½ volume, dilute with ethyl acetate and wash with 1N HCl (4×100 mL), water, saturated sodium bicarbonate, saturated sodium chloride, dry with magnesium sulfate and concentrate to give the title compound as an orange solid (19.6 g, quant).
Reaction SMILES: FC1C=C(F)C=CC=1NC1C=CC(C(C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=O)=C(C)C=1.Br[C:35]1[CH:40]=[CH:39][C:38]([C:41]([C:43]2[CH:48]=[C:47]([N:49]3[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]3)[CH:46]=[CH:45][C:44]=2[CH3:57])=[O:42])=[C:37]([Cl:58])[CH:36]=1.[F:59][C:60]1[CH:65]=[CH:64][C:63]([F:66])=[CH:62][C:61]=1[NH2:67]>>[Cl:58][C:37]1[CH:36]=[C:35]([NH:67][C:61]2[CH:62]=[C:63]([F:66])[CH:64]=[CH:65][C:60]=2[F:59])[CH:40]=[CH:39][C:38]=1[C:41]([C:43]1[CH:48]=[C:47]([N:49]2[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]2)[CH:46]=[CH:45][C:44]=1[CH3:57])=[O:42]
Reactant: Nc1cc(F)ccc1F
Reactant: Cc1ccc(-n2cc(CCO)nn2)cc1C(=O)c1ccc(Br)cc1Cl
Agent: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Product: Cc1ccc(-n2cc(CCO)nn2)cc1C(=O)c1ccc(Nc2cc(F)ccc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 471 (0.13 mmol) and 2,5-difluoro-phenylamine (0.13 mmol). The crude product was purified by flash chromatography using MeOH/DCM 1:20 as the eluent to afford the title compound. 13C NMR (CDCl3) δ 194.9, 158.8 (d), 150.2 (d), 146.3 (d), 140.4, 138.4, 135.2, 134.8, 133.5, 132.7, 129.9, 122.5, 121.0, 119.9, 117.9, 116.6 (dd), 114.5, 109.5 (dd), 107.1 (d), 61.6, 28.7, 20.1
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].Cl[C:14](OC1C=CC([N+]([O-])=O)=CC=1)=[O:15].C(N(CC)CC)C.[Cl:33][C:34]1[CH:43]=[C:42]2[C:37]([C:38]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[CH:39][CH:40]=[N:41]2)=[CH:36][CH:35]=1>>[Cl:33][C:34]1[CH:43]=[C:42]2[C:37]([C:38]([N:44]3[CH2:49][CH2:48][N:47]([C:14]([NH:6][CH2:5][C:4]4[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=4[C:2]([F:11])([F:12])[F:1])=[O:15])[CH2:46][CH2:45]3)=[CH:39][CH:40]=[N:41]2)=[CH:36][CH:35]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: NCc1ccccc1C(F)(F)F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1C(F)(F)F)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
2-Trifluoromethylbenzylamine (70 μL, 0.5 mmol), 4-nitrophenyl chloroformate (101 mg, 0.5 mmol), triethylamine (238 μL, 1.7 mmol), and 7-chloro-4-(piperazin-1-yl)quinoline (124 mg, 0.5 mmol) are treated according to method D delivering the title product as a pale yellow solid after column chromatography with hexane-EtOAc.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[CH2:19][CH2:20][N:21]([CH3:23])[CH3:22].C([Sn](CCCC)(CCCC)[C:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=1)CCC>C1(C)C=CC=CC=1>[C:29]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[C:5]3[CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=1
Reactant: CN(C)CCc1cn(C(=O)c2ccccc2)c2ccc(Br)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCCC1
Solvent: Cc1ccccc1
Product: CN(C)CCc1cn(C(=O)c2ccccc2)c2ccc(C3=CCCCC3)cc12
Yield: 27.7 %

Procedure:
A solution of 5-bromo-3-[2-(N,N-dimethylamino)ethyl]-1-benzoylindole (Example 5a, 109.8 mg 0.30 mmol), 1-tributylstannylcyclohex-1-ene (111 mg, 0.30 mmol) and tetrakistriphenyphosphine palladium (80 mg, 0.07 mmol) in toluene (2 mL) was stirred at 100-110° C. overnight. After removal of the solvent in vacuo, flash chromatography on silica gel (2-10% 2M methanolic ammonia in dichloromethane) yielded 5-(cyclohex-1-en-1-yl)-3-[2-(N,N-dimethylamino)ethyl]-1-benzoylindole (31 mg, 28%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[CH3:13]>>[CH2:12]([C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:16][CH:15]=1)[CH3:13]
Reactant: COC(=O)c1cncc(Br)c1
Reactant: CCc1ccc(B(O)O)cc1
Product: CCc1ccc(-c2cncc(C(=O)OC)c2)cc1

Procedure:
32 g (148 mmol) of methyl 5-bromonicotinate and 27 g (178 mmol, 1.2 eq.) of 4-ethylphenylboronic acid were reacted according to General Method 1A. Yield: 24 g (64% of theory)
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH2:14][CH2:15]O)[CH2:13][CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:17][N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[SH:23]>>[Si:1]([O:8][CH2:9][C:10]1([CH2:14][CH2:15][S:23][C:19]2[N:18]([CH3:17])[CH:22]=[CH:21][N:20]=2)[CH2:13][CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cn1ccnc1S
Reactant: CC(C)(C)[Si](C)(C)OCC1(CCO)CCC1
Product: Cn1ccnc1SCCC1(CO[Si](C)(C)C(C)(C)C)CCC1

Procedure:
The title compound was prepared using the same experimental procedure as in example 19a using 2-[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]ethanol and 1-methyl-1H-imidazole-2-thiol. 1H NMR (300 MHz, CDCl3) δ 7.22 (s, 1H), 7.01 (s, 1H), 3.58 (s, 3H), 3.43 (s, 2H), 1.85-1.73 (m, 6H), 2.91 (t, J=6 Hz, 2H), 1.48 (s, 9H), 1.21 (t, J=4 Hz, 2H), 0.04 (s, 6H). GC-MS m/z 341 (M+H).
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].Cl[C:6](Cl)([O:8]C(=O)OC(Cl)(Cl)Cl)Cl.[O:17]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)[C@@H:18]1[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]([OH:22])[C@H:19]1[OH:20].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC1C=C(C)C=C(C)N=1>[CH:1]([O:4][C:6]([O:28][CH2:27][C@H:25]1[O:26][C@@H:18]([O:17][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)[C@H:19]([OH:20])[C@@H:21]([OH:22])[C@@H:23]1[OH:24])=[O:8])([CH3:3])[CH3:2]
Reactant: COc1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1cc(C)nc(C)c1
Product: COc1ccc(Cc2ccccc2O[C@@H]2O[C@H](COC(=O)OC(C)C)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of isopropanol (0.12 g) in 2,4,6-trimethylpyridine (2 mL) was added triphosgene (0.022 g) at 0° C., and the mixture was stirred for 1 hour. Thereafter, 2-(4-methoxybenzyl)phenyl β-D-glucopyranoside (0.075 g) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous citric acid solution and water, and dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 2-(4-methoxybenzyl)-phenyl 6-O-isopropyloxycarbonyl-β-D-glucopyranoside (0.024 g).
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=O)(=O)C.S(Cl)(Cl)=O.[CH3:18][C:19]1[CH:24]=[C:23]([NH2:25])[CH:22]=[C:21]([Cl:26])[C:20]=1[OH:27].CN(C)C1C=CC=CC=1.C(OC1C(=CC=CC=1)C(Cl)=O)(=O)C>CC(C)=O>[Cl:26][C:21]1[CH:22]=[C:23]([CH:24]=[C:19]([CH3:18])[C:20]=1[OH:27])[NH:25][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=1[OH:4]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: Cc1cc(N)cc(Cl)c1O
Agent: CC(=O)Oc1ccccc1C(=O)Cl
Solvent: CC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1cc(NC(=O)c2ccccc2O)cc(Cl)c1O
Reaction time: 1.5 h
Yield: 50.4 %

Procedure:
Acetylsalicyclic acid (1.39g.) was converted to its acid chloride by conventional method using thionyl chloride and put in solution in acetone (25 ml.). 2-Methyl-4-amino-6-chlorophenol (1.35 g.) and N,N-dimethylaniline (about 1 ml.) were dissolved in acetone to which, with stirring in the cold at 1° to 2° C., the above-prepared acetone solution of acetylsalicyloyl chloride was added dropwise over 20-30 minutes, and reaction was continued for 1-2 hours. Then under reduced pressure the acetone was evaporated off, and the residue was put in solution in 2 N sodium hydroxide by stirring several hours at room temperature. Addition of 2 N hydrochloric acid to make the pH of the solution lower than 1 resulted in the formation of a precipitate which was recrystallized from aqueous acetone to give white crystals (1.08 g.) of 3'-chloro-2,4'-dihydroxy-5'-methylbenzanilide. Yield: 45.4%. Melting point: 192°-194° C.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br>CN(C=O)C.C(OCC)(=O)C>[F:19][C:20]([F:29])([F:30])[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2C(F)(F)F)CCCC1=O
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
40% Methanolic Triton B (2.18 mL, 4.8 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (973 mg, 4.0 mM) in 10 mL of DMF at −10° C. After 30 minutes, 2-(trifluoromethyl)benzyl bromide (1.3 g, 5.2 mM) was added and the resultant mixture stirred at room temperature for 23 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, once with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and dried in vacuo to afford 1.34 g (83%) of the 9-[(2-trifluoromethylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a tan solid. 1H NMR (CDCl3) δ7.7 (d, 1H, J=8 Hz), 7.4-7.1 (m, 5H), 6.4 (d, 1H, J=8 Hz), 5.5 (s, 2H), 4.05 (s, 3H), 2.8 (t, 2H, J=6 Hz), 2.6 (t, 2H, J=6 Hz), and 2.2 (m, 2H). IR (KBr, cm−1) 1729 and 1656. MS (ES) m/e 402.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([C:12]([CH2:15][C:16]4[CH:17]=[C:18]5[C:23](=[CH:24][CH:25]=4)[N:22]=[CH:21][CH:20]=[CH:19]5)=[N:13][N:14]=3)[N:11]=2)[CH:3]=[N:2]1.CCN(C(C)C)C(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:35][S:36]([N:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([C:12]([CH2:15][C:16]4[CH:17]=[C:18]5[C:23](=[CH:24][CH:25]=4)[N:22]=[CH:21][CH:20]=[CH:19]5)=[N:13][N:14]=3)[N:11]=2)[CH:3]=[N:2]1)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: c1cnc2ccc(Cc3nnc4ccc(-c5cn[nH]c5)nn34)cc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)n1cc(-c2ccc3nnc(Cc4ccc5ncccc5c4)n3n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To a solution of 6-[6-(1H-Pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl]-quinoline as prepared in Example 3 (10 mg, 0.03 mmol) and DIEA (9 μL, 0.05 mmol) in DCM (2 mL) was added methane sulfonylchloride (4 μL, 0.05 mmol). The reaction was stirred at rt overnight. The reaction was concentrated in vacuo followed by purification by HPLC (5-65% CH3CN over 35 min) resulting in the title compound (3.1 mg, 31%) as a white solid. 1H-NMR (CD3OD): δ 9.06-9.00 (2H, q, J=5.3, 7.0 Hz), 8.89 (1H, s), 8.44 (1H, s), 8.29-8.10 (4H, m), 7.96-7.92 (1H, q, J=5.3, 3.0), 7.75-7.73 (1H, d, J=9.8 Hz), 4.87 (2H, s), 3.42 (3H, s). ESI-MS (m/z): Calcd. For C19H15N7O2S: 405.10; found: 406.1 (M+H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([Cu])#[N:10].C[CH2:13][O:14]C(C)=O.[NH4+].[Cl-].[NH4+].[OH-]>CN(C=O)C>[OH:8][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:9]#[N:10])=[CH:4][C:3]=1[O:14][CH3:13]
Reactant: CCOC(C)=O
Reactant: N#C[Cu]
Reactant: OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc(C#N)ccc1CO
Temperature: 150 °C
Reaction time: 20 h

Procedure:
To the benzyl alcohol prepared in step 1 (0.86 g, 4.0 mmol) in DMF (8 mL) was added CuCN (1.1 g, 12 mmol). The mixture was warmed to 150° C. and stirred for 20 h. The mixture was then cooled to room temperature and EtOAc was added, followed by a saturated NH4Cl/NH4OH solution. The mixture was stirred vigorously for 10 minutes and extracted with EtOAc, then the organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography provided 4-hydroxymethyl-3-methoxy-benzonitrile (0.38 g, 2.3 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH:17]3[CH2:20][O:19][CH2:18]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C(O)C.[Cl-].[NH4+]>[Fe].O>[O:19]1[CH2:20][CH:17]([CH2:16][N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)[CH2:18]1
Reactant: O=[N+]([O-])c1ccc(N2CCN(CC3COC3)CC2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(N2CCN(CC3COC3)CC2)cc1
Temperature: 80 °C

Procedure:
To a round-bottomed flask equipped with a stirring bar, were added 1-(4-nitrophenyl)-4-(oxetan-3-ylmethyl)piperazine XXIX (3.20 g, 11.54 mmol), ethanol (60 mL) and water (60 mL). Following the addition of iron (4.51 g, 80.77 mmol) and ammonium chloride (4.32 g, 80.77 mmol), the reaction mixture was heated at 80° C. for 1 h, then filtered through Celite and washed with DCM (5 mL×5). The resulting filtrate was extracted with DCM (20 mL×3). The combined organic extracts were washed with water (20 mL×2), brine (20 mL×1), dried over Na2SO4, and concentrated in vacuo. The desired 4-(4-(oxetan-3-ylmethyl)piperazin-1-yl)aniline XXX was obtained.