Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[C:7](B(O)O)[CH:6]=1)[CH2:2][CH2:3][CH3:4].Br[C:22]1[CH:33]=[CH:32][C:25]([CH2:26][N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)=[CH:24][CH:23]=1.C1(C)C=CC=CC=1.[OH-].[Na+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[N:27]1([CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:7]3[CH:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[S:9][C:8]=3[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[CH:33][CH:32]=2)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: CCCCc1cc(B(O)O)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: Brc1ccc(Cn2ccnc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(=O)(=O)NC(C)(C)C)s1

Procedure:
5-Butyl-2-(N-tert-butylaminosulfonyl)thiophene-3-boronic acid (300 mg, 1.27 mmol, see step (b) above), 1-(4-bromobenzyl)-1H-imidazole (606 mg, 1.90 mmol, see Example 1(d) above), toluene (15 mL), ethanol (4 mL), NaOH (1.0 M, 4.0 mL, 5.1 mmol) and Pd(PPh3)4 (43.9 mg, 0.038 mmol) were mixed under N2. The mixture was warmed to reflux for 2 hours, diluted with EtOAc (50 mL), washed with water and brine, and dried over MgSO4. The solvent was removed and the residue was separated by column chromatography using chloroform:methanol (20:1) as eluent. The product was not completely pure but was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]([NH:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:36]([O:40][C:41]([NH:43][CH2:44][C:45]([NH:47][CH2:48][C:49](O)=[O:50])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].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>C(Cl)Cl>[C:36]([O:40][C:41]([NH:43][CH2:44][C:45]([NH:47][CH2:48][C:49]([NH:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[N:11]=[C:10]([NH:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1)=[O:50])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(N)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)Nc1ccc(CNc2nc(Nc3ccc(C(=O)OC(C)(C)C)cc3)nc(OCC(F)(F)F)n2)cc1
Yield: 100.2 %

Procedure:
tert-butyl 4-(4-(4-aminobenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (100 mg, 0.204 mmol), 2-(2-(tert-butoxycarbonylamino)acetamido)acetic acid (56.8 mg, 0.245 mmol), HATU (116 mg, 0.306 mmol), and Hunig's Base (0.178 mL, 1.019 mmol) were stirred in DCM (3 mL) for 16 h. The solvent was removed and the crude material was purified by silica gel chromatography using EtOAc to give tert-butyl 4-(4-(4-(2-(2-(tert-butoxycarbonylamino)acetamido)acetamido)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (144 mg).
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][C:7]=2[O:6][CH:5]=1)(O)=[O:2].P(Cl)(Cl)(Cl)=O.[NH3:32].Cl>CN(C)C=O>[C:1]([C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][C:7]=2[O:6][CH:5]=1)(=[O:2])[NH2:32]
Reactant: CS(=O)(=O)Nc1cc2occ(C(=O)O)c(=O)c2cc1Oc1ccccc1
Reactant: N
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc2occ(C(N)=O)c(=O)c2cc1Oc1ccccc1
Reaction time: 3 h
Yield: 75.1 %

Procedure:
3.75 g of 3-carboxy-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was suspended in 75 ml of N,N-dimethylformamide. Thereto was dropwise added 4.6 g of phosphorus oxychloride at -10° to -5° C. The mixture was stirred for 3 hours at the same temperature. The reaction mixture was dropwise added to 40 ml of a concentrated aqueous ammonia solution at 10°-20° C. The mixture was stirred for 30 minutes at the same temperature and then adjusted to pH 4 with 4N hydrochloric acid. The resulting crystal was collected by filtration, washed with water and recrystallized from acetic acid to obtain 2.81 g (yield: 75.1%) of 3-carbamoyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of >250° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][CH:14]=1.Cl[C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[C:30]([CH3:34])([CH3:33])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[N:13][C:12]([C:15]([F:17])([F:18])[F:16])=[N:11][CH:10]=1)[CH2:19][O:20][C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[C:30]([CH3:34])([CH3:33])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1
Reactant: OCc1ccc(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCc3ccc(Oc4cnc(C(F)(F)F)nc4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.CCN(C(C)C)C(C)C.Cl.[Cl:36][C:37]1[CH:38]=[C:39]([CH:45]=[CH:46][C:47]=1[N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[C:40]([NH:42][CH2:43][CH3:44])=[O:41]>C(#N)CC.CS(C)=O>[Cl:36][C:37]1[CH:38]=[C:39]([CH:45]=[CH:46][C:47]=1[N:48]1[CH2:49][CH2:50][N:51]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]4[C:7](=[O:17])[NH:6][C:5]=3[CH:4]=2)[CH2:52][CH2:53]1)[C:40]([NH:42][CH2:43][CH3:44])=[O:41]
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(Cl)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)c(Cl)c1
Temperature: 90 °C
Yield: 41.8 %

Procedure:
To a suspension of (S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (81 mg, 0.347 mmol) in propiononitrile (1.2 mL) was added (cyanomethyl)trimethylphosphonium iodide (101 mg, 0.417 mmol) and DIEA (182 μl, 1.042 mmol) and finally 3-chloro-N-ethyl-4-(piperazin-1-yl)benzamide hydrochloride (106 mg, 0.347 mmol). The vial was heated to 90° C. for 16 hours. The crude r×n was cooled to RT, DMSO (1 ml) was added, and purified via HPLC (55-90, basic). The fractions were collected, concentrated until a precipitate was visible and filtered. The solids were washed with water and collected to retrieve the product as a white solid (70 mg, 20% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.48 (s, 1H), 8.43 (t, J=5.4 Hz, 1H), 7.87 (d, J=2.3 Hz, 1H), 7.76 (dd, J=8.3, 2.0 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.17 (d, J=8.6 Hz, 1H), 6.97 (d, J=2.0 Hz, 1H), 4.50 (d, J=12.9 Hz, 1H), 3.84 (dd, J=11.4, 2.8 Hz, 1H), 3.38 (s, 2H), 3.18-3.31 (m, 2H), 3.03 (br. s., 4H), 2.60 (td, J=12.7, 2.7 Hz, 1H), 2.51 (br. s., 4H), 2.04 (d, J=12.9 Hz, 1H), 1.85 (d, J=12.1 Hz, 1H), 1.64 (d, J=12.6 Hz, 1H), 1.32-1.58 (m, 3H), 1.10 (t, J=7.1 Hz, 3H). [M+H] calc'd for C25H31ClN6O2, 483. found, 483.
Reaction SMILES: C=C([O:4][C:5](=O)[NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:14]([CH3:34])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][N:19]=[C:18]([N:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH3:24])[CH:17]=3)[CH:10]=[CH:9][C:8]=1[F:35])C.[CH3:37][C:38]([CH3:43])([CH3:42])[CH2:39][CH2:40][NH2:41].C1CCN2C(=NCCC2)CC1.CCOC(C)=O>O1CCOCC1>[CH3:37][C:38]([CH3:43])([CH3:42])[CH2:39][CH2:40][NH:41][C:5]([NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:14]([CH3:34])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][N:19]=[C:18]([N:23]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH3:24])[CH:17]=3)[CH:10]=[CH:9][C:8]=1[F:35])=[O:4]
Reactant: CC(C)(C)CCN
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(N(C)Cc4ccc(OC)cc4)cc3nc2C)ccc1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(C)c2cc3nc(C)c(-c4ccc(F)c(NC(=O)NCCC(C)(C)C)c4)cc3cn2)cc1
Temperature: 80 °C
Yield: 85.4 %

Procedure:
Treat a solution of prop-1-en-2-yl(2-fluoro-5-(7-((4-methoxybenzyl)(methyl)amino)-2-methyl-1,6-naphthyridin-3-yl)phenyl)carbamate (0.398 g, 0.818 mmol) and 3,3-dimethylbutylamine (0.166 g, 1.636 mmol) in dioxane (10 mL) with DBU (0.025 ml, 0.164 mmol) and heat at 80° C. overnight. Cool to RT, add EtOAc and wash with 10% LiCl, then brine. Dry the organic layer over MgSO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (370 mg, 85%). 1H NMR (400 MHz, DMSO-d6): δ 8.97 (s, 1H), 8.37 (s, 1H), 8.22 (d, J=7.9 Hz, 1H), 7.99 (s, 1H), 7.26 (dd, J=11.4, 8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 2H), 6.98 (m, 1H), 6.85 (d, J=8.5 Hz, 2H), 6.73 (s, 1H), 6.55 (t, J=5.5 Hz, 1H), 4.86 (s, 2H), 3.69 (s, 3H), 3.08 (m, 5H), 2.48 (s, 3H), 1.33 (m, 2H), 0.88 (s, 9H); MS (ESI) m/z: 530.0 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:19])=[C:11](Cl)[C:12]([F:17])=[CH:13]2)=[C:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=1)=[O:5])C.[N:23]1([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(#N)C>[N:23]1([CH:29]2[CH2:34][CH2:33][N:32]([C:11]3[C:12]([F:17])=[CH:13][N:14]4[C:9]([C:10]=3[CH3:19])=[C:8]([CH:20]3[CH2:22][CH2:21]3)[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[C:15]4=[O:16])[CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Solvent: CC#N
Product: Cc1c(N2CCC(N3CCCCC3)CC2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12

Procedure:
A 70 mg sample of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 2 mL of anhydrous acetonitrile, reacted with 4-(1-piperidyl)piperidine (70 mg, 0.4 mmol, Aldrich Chem. Co.), and carried forward as described in Example 253j-k to give the title product. MS 428 (M+H)+ ; 1H NMR (CDCl3) ∂: 0.69 (m, 2H), 1.02 (m, 2H), 1.18 (m, 4H), 2.27 (n, 1H), 2.78 (s, 3H), 2.72 (m, 1H), 3.35 (m, 3H), 3.55 (m, 1H), 3.75 (m, 1H), 8.36 (s, 1H), 9.20 (d, 1H). Anal. Calcd for C24H30N3O3F.1.5 H2O: C, 63.42; H, 7.32; N, 9.24; Found: C, 62.99; H, 7.04; N, 8.78.
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH:12]([OH:14])=[O:13].C(N(CC)CC)C.O>C(#N)C>[CH:12]([O:14][CH:2]([CH3:11])[C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:13]
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: O=CO
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC(OC=O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-bromo-1-phenylpropan-1-one (25 g) in acetonitrile (250 ml) was added formic acid (7.7 ml), and thereto was added dropwise triethylamine (25 ml) under ice-cooling. Then, the mixture was stirred at room temperature for 5 hours. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with water and aqueous sodium chloride solution, dried over magnesium sulfate, and filtered and concentrated to give the title compound (19 g). The obtained crude product was used in the next reaction without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([C@@H:27]2[CH2:31][CH2:30][CH2:29][NH:28]2)[NH:10][C:11]([N:13]2[CH2:22][CH2:21][C:20]3[CH:19]=[N:18][C:17]([NH:23][CH:24]([CH3:26])[CH3:25])=[N:16][C:15]=3[CH2:14]2)=[O:12])=[CH:5][C:4]=1[F:32].[CH3:33][C:34](OC(C)=O)=[O:35].C(Cl)Cl>O>[C:34]([N:28]1[CH2:29][CH2:30][CH2:31][C@H:27]1[C@H:9]([C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([F:32])[CH:5]=1)[NH:10][C:11]([N:13]1[CH2:22][CH2:21][C:20]2[CH:19]=[N:18][C:17]([NH:23][CH:24]([CH3:25])[CH3:26])=[N:16][C:15]=2[CH2:14]1)=[O:12])(=[O:35])[CH3:33]
Reactant: CC(C)Nc1ncc2c(n1)CN(C(=O)N[C@@H](c1ccc(Cl)c(F)c1)[C@@H]1CCCN1)CC2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCC[C@H]1[C@@H](NC(=O)N1CCc2cnc(NC(C)C)nc2C1)c1ccc(Cl)c(F)c1

Procedure:
A solution of 83 and Ac2O (6.45 μL, 0.0683 mmol), TEA (25.9 μL, 0.186 mmol) and DCM (5 mL) was stirred for 1 h then poured into water and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:10) to afford 0.020 g (65.9%) of I-87: MS m/z (APCI-pos) M+1=489.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH:5]([C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4]1.[OH:19][CH2:20][CH2:21][NH:22][CH3:23].Cl>C1(C)C(C)=CC=CC=1.CCOCC.C(O)(C)C>[OH:19][CH2:20][CH2:21][N:22]([CH2:2][C:3]1[C:4]2[CH:5]3[CH2:6][CH2:7][CH:8]([C:13]4[C:18]3=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:9]=2[CH:10]=[CH:11][CH:12]=1)[CH3:23]
Reactant: ClCC1CC2c3ccccc3C1c1ccccc12
Reactant: CNCCO
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: CN(CCO)Cc1cccc2c1C1CCC2c2ccccc21
Temperature: 25 °C

Procedure:
11-Chloromethyl-9,10-dihydro-9,10-ethanoanthracene (45 gm) was combined with 2-hydroxyethylmethylamine (45 gm) in xylene (300 ml) and the mixture heated to reflux for 17 days. The mixture was cooled to room temperature and extracted with 1 N hydrochloric acid (3×100 ml). The combined acid solutions were washed with ether (100 ml), made basic with the addition of 50% sodium hydroxide solution and the mixture extracted with ether (3×100 ml). The combined ether solutions were dried over magnesium sulfate and the ether removed on a rotary evaporator. The residue was distilled (220° C. at 7 mm Hg) to yield a colorless oil. The material was dissolved in ether (200 ml) and treated with 6 N hydrochloric acid in isopropyl alcohol (2 ml). The resulting precipitate was filtered and washed with ether to provide the product. Analytical data are reported in Table I.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28](Cl)=[O:29]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:28](=[O:29])[C:27]5[CH:31]=[CH:32][C:33]([F:34])=[C:25]([F:24])[CH:26]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4ccc(F)c(F)c4)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-3,4-difluoro-benzamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 3,4-difluorobenzoyl chloride (111 μl, 0.89 mmol). The title compound was obtained as yellow powder (242 mg, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[S:8][C:7]=2[CH:25]=1.[Cu][C:27]#[N:28].[CH3:29][N:30]1[CH2:34][CH2:33][CH2:32][C:31]1=O>[Cl-].[Na+].O>[C:27]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:25][C:3]=1[CH2:29][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:10][C:10]1[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:25][C:7]=2[S:8][C:9]=1[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:16]=1)#[N:28]
Reactant: N#C[Cu]
Reactant: CN1CCCC1=O
Reactant: COc1ccc2cc(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(Cc3ccc(CN4CCCC4)c(C#N)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Temperature: 200 °C
Reaction time: 5 h
Yield: 44 %

Procedure:
A suspension of 3-[3-bromo-4-[(1-pyrrolidinyl)]methyl]benzyl]-6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (158 mg, 0.26 mmol) and copper(I) cyanide (40 mg) in 1-methyl-2-pyrrolidinone (3 mL) was allowed to stir at 200° C. under nitrogen for 5 h. The cooled reaction mixture was diluted with brine (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography of the residue with Et3N:MeOH:EtOAc (5:5:90) afforded the product (64 mg, 44%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][N:6]1[C:14]2[CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][NH:25][CH3:26])=[C:17]([C:27]([F:30])([F:29])[F:28])[CH:16]=3)[N:11]=[C:10]([C:31]#[N:32])[C:9]=2[N:8]=[CH:7]1.C(N(C(C)C)CC)(C)C>C1COCC1>[C:1]([N:25]([CH2:24][CH2:23][CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:11]=[C:10]([C:31]#[N:32])[C:9]3[N:8]=[CH:7][N:6]([CH3:5])[C:14]=3[CH:13]=2)=[CH:16][C:17]=1[C:27]([F:30])([F:29])[F:28])[CH3:26])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CNCCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C)CCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (0.011 ml) was added dropwise to a solution of 1-methyl-6-(4-(3-(methylamino)propoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (20 mg) and diisopropylethylamine (0.045 ml) in THF (2 ml). The reaction mixture was stirred at room temperature for 1 hour. The product was then purified by acidic prep HPLC to give 6-{-4-[3-(N-acetyl-N-methylamino)propoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (9.2 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:10][C:9]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[S:8](=O)[CH2:7]1.[Cl:17][C:18]1[CH:32]=[CH:31][C:21]2[C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:23][S:24][C:20]=2[CH:19]=1.C([O-])([O-])=[O:34].[K+].[K+].[Na+].[I-]>C(#N)C>[ClH:17].[Cl:17][C:18]1[CH:32]=[CH:31][C:21]2[C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]4[C:10](=[O:34])[C:9]5([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]5)[S:8][CH2:7]4)[CH2:27][CH2:26]3)=[N:23][S:24][C:20]=2[CH:19]=1
Reactant: Clc1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=S1CN(CCCCBr)CC12CCCCC2
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: Cl
Product: O=C1N(CCCCN2CCN(c3nsc4cc(Cl)ccc34)CC2)CSC12CCCCC2
Temperature: 80 °C
Yield: 76632.9 %

Procedure:
A mixture of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.5]decanone (2.7 g), 6-chloro-1,2-benzisothiazol-3-yl piperazine (2.0 g), K2CO3 (2.2 g) and NaI (200 mg) in acetonitrile (100 ml) was heated at 80° C. for 8 hours and the product was processed in substantially the same manner as in Example 10 to afford 1,557 g of solid, m.p. 202-205° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:28][O:29][CH2:30][CH2:31][N:32]([CH3:37])[CH:33]([CH3:36])[C:34]#[CH:35]>>[CH3:28][O:29][CH2:30][CH2:31][N:32]([CH3:37])[CH:33]([CH3:36])[C:34]#[C:35][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:27])[F:26])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: C#CC(C)N(C)CCOC
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Product: COCCN(C)C(C)C#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and (2-Methoxy-ethyl)-methyl-(1-methyl-prop-2-ynyl)-amine were converted to yield (2-Methoxy-ethyl)-methyl-{1-methyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amine as brown oil, MS: 419 (MH+).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[CH3:42][S:43]([OH:46])(=[O:45])=[O:44].C(Cl)(Cl)Cl>>[CH3:42][S:43]([O-:46])(=[O:45])=[O:44].[O:1]([C:8]1[CH:13]=[CH:12][C:11]([S+:14]([C:39]2[CH:40]=[CH:41][C:36]([O:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:37][CH:38]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: O=S(c1ccc(Oc2ccccc2)cc1)c1ccc(Oc2ccccc2)cc1
Reactant: CS(=O)(=O)O
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)[O-]
Product: c1ccc(Oc2ccc([S+](c3ccc(Oc4ccccc4)cc3)c3ccc(Oc4ccccc4)cc3)cc2)cc1
Temperature: 100 °C
Yield: 131.3 %

Procedure:
A mixture of 42.51 g of bis-(4-phenoxyphenyl)sulfoxide,187.23 g of diphenyl ether and 105.71 g of methane sulfonic acid was heated at 100° C. for 24 hours with stirring. The mixture was poured into 700 g of ice water and the resultant aqueous and sulfonium layers extracted four times with 200-ml portions of ether and five times with 200-ml portions of chloroform. The combined chloroform extracts were dried with magnesium sulfate and the chloroform removed on a rotary evaporator to give 91.66 g of tris-(4-phenoxyphenyl)sulfonium methane sulfonate with 1.7 equivalents of chloroform of solvation. This represents a 100 percent yield.
Reaction SMILES: [C:1]1([C:7](=[O:17])[CH2:8][C:9](=[O:16])[C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.C(O)(=O)C>O>[C:12]([C:11]1[O:17][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][C:9](=[O:16])[C:10]=1[OH:15])(=[O:14])[CH3:13]
Reactant: CC(=O)CC(=O)C(=O)CC(=O)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: CC(=O)c1oc(-c2ccccc2)cc(=O)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 14 %

Procedure:
A mixture of 1-phenylheptane-1,3,4,6-tetrone (2.3 g), iodobenzene diacetate (6.7 g) and acetic acid (80 mL) was stirred at room temperature for 16 hr, the reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.32 g).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:4].[N+:18]([O-])([OH:20])=[O:19]>FC(F)(F)C(O)=O>[F:1][C:2]([F:16])([F:17])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([N+:18]([O-:20])=[O:19])[CH:9]=1)=[O:4]
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CCNC(=O)C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a solution of 30 g (0.121 mole) of the amide in 254 ml of trifluoroacetic acid at 0° under an argon atmosphere was added dropwise with stirring a solution of 7.5 ml (0.12 mole) of conc. nitric acid in 56 ml of trifluoroacetic acid. The reaction mixture was stirred at 0° for 1/2 hour and at room temperature for 2 hours. The solvents were evaporated. The residue was dissolved in ethyl acetate which was extracted with 5% hydrochloric acid, dilute sodium bicarbonate solution and brine, then dried over anhydrous magnesium sulfate and activated charcoal. After filtering, the solvents were removed to give 34.8 g (98%) of crude (2-trifluoroacetamidoethyl)-3-nitro-4-methoxybenzene which was an amber-colored solid. This material was recrystallized from 400 ml of 1:3 ethyl acetatehexane to give 25.3 g (71.5%) of the product, m.p. 92.5°-93.0°. The mother liquors were concentrated and recrystallized to give a second crop, 4.59 g (13 %), m.p. 90°-92° C.