Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:43]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.[N:44]([C:47]1[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=1)=[C:45]=[O:46]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:43]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[N:37]1[CH2:42][CH2:41][N:40]([C:45]([NH:44][C:47]2[CH:48]=[CH:49][C:50]([C:53]([F:54])([F:55])[F:56])=[CH:51][CH:52]=2)=[O:46])[CH2:39][CH2:38]1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: Clc1cnc2nc1Nc1ccc(N3CCNCC3)c(c1)CCc1cccc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCN(c2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 41 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-piperazin-1-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate) and 1-isocyanato-4-(trifluoromethyl)benzene as the starting materials in 41% yield. LCMS for C30H28ClF3N7O (M+H)+: m/z=594.0. 1H NMR (400 MHz, DMSO-d6): δ 9.49 (s, 1H), 9.32 (br s, 1H), 9.00 (s, 1H), 8.13 (s, 1H), 7.96 (s, 1H), 7.79 (d, J=2.3 Hz, 1H), 7.72-7.70 (m, 2H), 7.60-7.57 (m, 2H), 7.12-7.03 (m, 3H), 6.88-6.82 (m, 2H), 3.64 (br s, 4H), 2.99 (s, 4H), 2.84 (br s, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[CH:17]=2)[C:12](O)=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:32])=O>>[N+:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[CH:17]=2)[C:12]([Cl:32])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Oc2ccc([N+](=O)[O-])cc2)cc(Oc2ccc([N+](=O)[O-])cc2)c1
Product: O=C(Cl)c1cc(Oc2ccc([N+](=O)[O-])cc2)cc(Oc2ccc([N+](=O)[O-])cc2)c1

Procedure:
A mixture of 3,5-bis (4-nitrophenoxy) benzoic acid (51.9 g, 0.131 mol) and thionyl chloride (478 ml, 6.55 mol) are heated at reflux for 5 hours, with the excess thionyl chloride being removed by distillation. The residue is dried at 85° C. under vacuum overnight in the same reactor.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][O:49][C:50]2[CH:59]=[CH:58][C:57]([C:60]3[CH:61]=[N:62][N:63]([CH2:65][CH2:66][O:67][CH3:68])[CH:64]=3)=[CH:56][C:51]=2[C:52](OC)=[O:53])=[CH:44][CH:43]=1>CN(C)C=O>[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][O:49][C:50]2[CH:59]=[CH:58][C:57]([C:60]3[CH:61]=[N:62][N:63]([CH2:65][CH2:66][O:67][CH3:68])[CH:64]=3)=[CH:56][C:51]=2[C:52]([NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:53])=[CH:44][CH:43]=1
Reactant: COCCn1cc(-c2ccc(OCc3ccc(F)cc3)c(C(=O)OC)c2)cn1
Reactant: Nc1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCn1cc(-c2ccc(OCc3ccc(F)cc3)c(C(=O)Nc3cccnc3)c2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Pyridinamine (49.0 mg, 0.52 mmol), HATU (148 mg, 0.39 mmol) and diisopropylethylamine (0.11 ml, 0.65 mmol) were added to a solution of methyl 2-{[(4-fluorophenyl)methyl]oxy}-5-{1-[2-(methyloxy)ethyl]-1H-pyrazol-4-yl}benzoate (may be prepared as described in Description 116; 100 mg, 0.26 mmol) in N,N-dimethylformamide (5 ml) and the mixture was stirred at room temperature overnight. The DMF was evaporated under reduced pressure on a buchi. Water (5 ml) and ethyl acetate (10 ml) were added to the residue. The organics were separated and the aqueous layer was further extracted with ethyl acetate (3×10 ml). The organics were combined and evaporated. The residue was purified using MDAP to yield the title compound. 36 mg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:12].C1N2CN3CN(C2)CN1C3.Cl.FC(F)(F)[C:26](O)=[O:27]>>[Br:1][C:2]1[C:3]([OH:12])=[C:4]([CH:5]=[C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])[CH:7]=1)[CH:26]=[O:27]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)c1ccc(O)c(Br)c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
A mixture of 2-bromo-4-(tert-butyl)phenol [Intermediate 1, Step 1] (6.87 g, 30 mmol) and hexamethylenetetramine (20 g, 143 mmol) in trifluoroacetic acid (60 mL) was heated at 90° C. under nitrogen for 22 hours. The hot reaction mixture was poured into 1M aqueous hydrochloric acid (200 mL) and the mixture stirred vigorously for 6 hours. The resulting suspension was filtered to give 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (6.79 g, 88% yield) as a yellow solid.
Reaction SMILES: O[CH:2]([CH3:13])[CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1.[CH3:14]I.C(=O)(O)[O-].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N-:32]=[N+:33]=[N-:34].[Na+]>CC(N(C)C)=O.N1C=CC=CC=1.CS(C)=O>[N:32]([CH:2]([CH3:13])[CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([O:12][CH3:14])=[O:11])=[CH:7][CH:6]=1)=[N+:33]=[N-:34]
Reactant: CI
Reactant: CC(O)CCc1ccc(C(=O)O)s1
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(CCC(C)N=[N+]=[N-])s1

Procedure:
For the preparation of the amine starting material of Example 7,4-(5-acetyl-2-thienyl)-2-butanone was reacted with ethylene glycol, triethyl o-formate and p-toluenesulfonic acid in methylene chloride selectively to give methyl 5-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-2-thienyl ketone. Oxidation with sodium hypobromite and subsequent hydrolysis gave 5-(3-oxobutyl)-2-thiophenecarboxylic acid. With sodiumborohydride there was obtained therefrom 5-(3-hydroxy-butyl)-2-thiophenecarboxylic acid which was converted in dimethylacetamide with methyl iodide and sodium bicarbonate into the methyl ester. Treatment with p-toluene-sulfonyl chloride in pyridine and reaction with sodium azide in dimethylsulfoxide gave methyl 5-(3-azidobutyl)-2-thiophenecarboxylate from which the corresponding acid was obtained by saponification. With thionyl chloride there was prepared its acid chloride from which, with concentrated ammonia in diethyl ether, there was obtained 5-(3-azidobutyl)-2-thiophenecarboxamide. Reduction of the azido group with triphenylphosphine and subsequent hydrolysis gave (R,S)-5-(3-aminobutyl)-2-thiophenecarboxamide, m.p. 65°-75°, ε256 =7780, ε275 =9900.
Reaction SMILES: [C:1](=O)(OC(Cl)(Cl)Cl)[O:2]C(Cl)(Cl)Cl.[CH:13]1([N:16]2[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]2)[CH2:15][CH2:14]1.[CH3:23][O:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:33]=1[CH:32]([NH:34][C:35]1[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40]([NH2:45])[CH:41]=3)[N:36]=1)[CH2:31][CH2:30]2>>[CH:13]1([N:16]2[CH2:21][CH2:20][CH:19]([NH:22][C:1]([NH:45][C:40]3[CH:41]=[C:42]4[C:37](=[CH:38][CH:39]=3)[N:36]=[C:35]([NH:34][CH:32]3[C:33]5[C:29](=[CH:28][CH:27]=[CH:26][C:25]=5[O:24][CH3:23])[CH2:30][CH2:31]3)[CH:44]=[CH:43]4)=[O:2])[CH2:18][CH2:17]2)[CH2:15][CH2:14]1
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC1CCN(C2CC2)CC1
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)NC4CCN(C5CC5)CC4)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-cyclopropyl-piperidin-4-ylamine and rac-N2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example 172); MS: m/e=472.8 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25]>>[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([N:17]1[CH2:16][CH:15]2[CH:19]([CH2:20][N:13]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][N:10]=3)[CH2:14]2)[CH2:18]1)=[O:25]
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Reactant: O=C(O)c1ccccc1Br
Product: O=C(c1ccccc1Br)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 2-bromobenzoic acid. MS (ESI) mass calcd. for C23H21BrN4O, 449.34; m/z found, 449.1, 451.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1N=CN([C:17](N2C=NC=C2)=[O:18])C=1>C1COCC1>[O:18]=[C:17]1[NH:1][C:2]2=[C:3]([C:4]([OH:6])=[O:5])[CH:7]=[CH:8][CH:9]=[C:10]2[O:11]1
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(O)c1cccc2oc(=O)[nH]c12
Temperature: 80 °C
Yield: 37.2 %

Procedure:
2-amino-3-hydroxybenzoic acid (1.2 g, 7.8 mmol) was suspended in 20 ml of THF and at 0° C. CDI (1.9 g, 1.5 equiv.) was added. The mixture was warmed at 80° C. for 5 hours. The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from EtOAc/ether gave 520 mg of an orange solid. Yield=37% 1HNMR (DMSO, 200 MHz) δ 7.45 (3H, m), 10.40 (1H, bs), 12.00 (1H, bs)
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][O:15][CH2:16][CH: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:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1>C(#N)CC.CO>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([N:42]2[CH2:47][CH2:46][N:45]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][O:15][CH2:16][CH:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:44][CH2:43]2)=[CH:40][CH:41]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCOCC12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2cc(CN3CCN(c4ccc(Cl)cc4)CC3)cnc2N2CCOCC12
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a suspension of 3-(hydroxymethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[4,3-a]pyrido[3,2-e]pyrazin-6(5H)-one (73.2 mg, 0.311 mmol) in propiononitrile (778 μl) was added (cyanomethyl)trimethylphosphonium iodide (91 mg, 0.373 mmol) and DIPEA (163 μl, 0.934 mmol) and finally 1-(4-chlorophenyl)piperazine (61.2 mg, 0.311 mmol). The mixture was heated to 90° C. for 4 hours. The crude product was cooled to RT and left to sit 16 hours, then treated with MeOH (5 mL). The precipitate was collected and refluxed in EtOH (15 mL) 2 hours. The suspension was cooled to room temperature and filtered to retrieve the title compound (75.6 mg, 58.7%) as a white solid. 1H NMR (CHLOROFORM-d) δ (ppm): 7.82 (d, J=1.8 Hz, 1H), 7.72 (br. s., 1H), 7.16-7.24 (m, 2H), 6.99 (br. s., 1H), 6.77-6.89 (m, 2H), 4.41 (dd, J=11.5, 3.7 Hz, 1H), 4.26 (dd, J=13.3, 1.6 Hz, 1H), 3.95-4.12 (m, 2H), 3.59-3.75 (m, 2H), 3.46 (br. s., 2H), 3.16 (br. s., 4H), 2.94-3.06 (m, 1H), 2.60 (br. s., 4H). [M+H] calc'd for C21H24ClN5O2, 414. found, 414.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH2:8])=[O:7].C(Cl)(=O)[C:10](Cl)=[O:11]>ClCCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]=[C:10]=[O:11])=[O:7]
Reactant: NC(=O)c1ccco1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccco1

Procedure:
A suspension of 2-furoamide in 1,2-dichloroethane was treated with oxalyl chloride; 2-furoylisocyanate was isolated by distillation. This product was reacted with the hydroxypropylimidazole, as for the starting material of Example 12, to give 2-fluoro-4-[3-(fur-2-yl)carbamoyloxypropyl]-1-triphenylmethylimidazole, having the following n.m.r. spectrum in d6DMSO: 1.82 (m, 2H); 2.47 (t, 2H); 4.07 (t, 2H); 6.3 (s, 1H); 6.64 (m, 1H); 7.0-7.45 (m, 15H); 7.5 (m, 1H); 7.91 (m, 1H); 10.1 (br, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[C:10]([O:14][C:15]([NH:17][C:18](=[N:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])SC)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CN(C=O)C.O.C([O-])(=O)C.[Ag+]>[C:25]([O:24][C:22]([NH:21][C:18]([NH:17][C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])=[N:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: NCc1cccc(O)c1
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(=NCc1cccc(O)c1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
3-hydroxybenzylamine, prepared as above (1.23 g) and N,N'-bis(tert-butoxycarbonyl)-S-methylisothiourea (2.90 g) were combined in 100 mL DMF, and silver acetate (2.9 g) was added in three portions over 30 min with mechanical stirring. The mixture became thick and a yellow color developed. After 1 hr, the mixture was diluted with 300 mL water, and the solids collected by filtration, re-suspended in dichloromethane, filtered to remove silver salts, and chromatographed on silica gel with 10% ethyl acetate in dichloromethane. Recrystallization provided the title compound as a white solid, mp 169°-172° C. (dec) (2.2 g, 61%).
Reaction SMILES: ClC1N=C(/C=C(/C2C=C(N[S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])C=CC=2)\O)C=CN=1.[NH2:29][C:30]1[C:31]([Cl:40])=[C:32]([CH:37]=[CH:38][CH:39]=1)[C:33]([O:35][CH3:36])=[O:34].N1C=CC=CC=1.FC1C=CC=C(F)C=1S(Cl)(=O)=O>C(Cl)Cl>[Cl:40][C:31]1[C:30]([NH:29][S:18]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])(=[O:20])=[O:19])=[CH:39][CH:38]=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)c1cccc(N)c1Cl
Reactant: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1Cl
Yield: 81.6 %

Procedure:
Following a procedure analogous to Intermediate 5, Step A using methyl 3-amino-2-chlorobenzoate (39 g, 211 mmol) in DCM (200 mL) was added pyridine (51 g, 633 mmol) and 2,6-difluorobenzene-1-sulfonyl chloride (49.1 g, 232 mmol) the title compound was obtained (62 g, 81.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.87 (dd, J=1.8 Hz, 8.38 Hz, 1H), 7.72-7.79 (br, 1H), 7.56 (dd, J=1.8 Hz, 7.94 Hz, 1H), 7.45-7.53 (m, 1H), 7.28 (dd, J=7.9 Hz, 8.4 Hz, 1H), 6.95-7.01 (m, 2H), 3.89 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:25]=[CH:24][C:5]2[NH:6][C:7]([C:9]3[C:21]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14](=[N:22]O)[C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[C:26](O)(=O)[CH3:27].[CH2:30](O)C>O.[Zn]>[CH:26]([O:1][CH:2]([CH3:3])[CH3:25])([CH3:27])[CH3:30].[OH:1][C:2]1[CH:25]=[CH:24][C:5]2[NH:6][C:7]([C:9]3[C:21]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[CH:14]([NH2:22])[C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CCO
Reactant: CC(=O)O
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2cc(O)ccc2[nH]1
Agent: [Zn]
Solvent: O
Product: CC(C)OC(C)C
Product: NC1c2ccccc2-c2c(-c3nc4cc(O)ccc4[nH]3)cccc21

Procedure:
The procedure used in Example 216 is followed. In a 50 ml round-bottomed flask under an argon atmosphere, dissolve 355 mg of an equimolecular mixture of 4-(5-hydroxy-1H-benzimidazol-2-yl)-9H -fluoren-9-one oxime (Z,E), obtained in the previous stage, in a mixture of 2.5 ml of ethanol and 2.5 ml of water and 2.5 ml of acetic acid, at room temperature, add 283 mg of zinc in three stages, and, between each addition, stir for approximately one hour to two hours. Add Celite and filter. The filtrate is concentrated under pressure. The crude product is purified by flash chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and ammonia as a 7N solution in methanol (9/1 by volume). After formation of a paste with diisopropyl ether, in this way we obtain 232 mg of 4-(5-hydroxy-1H-benzimidazol-2-yl)-9H-fluorene-9(R,S) -amine, in the form of an off-white powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [NH2:1][CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[OH:4].[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[OH:4][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[CH:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=1
Reactant: COc1ccc(C(O)C(N)Cc2ccc(C(F)(F)F)cc2)cc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C(O)C(Cc2ccc(C(F)(F)F)cc2)NC(=O)CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-methoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.38 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (308 ml, 2.07 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title-compound (574 mg, 91%).
Reaction SMILES: Br[C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])[C@@H:7]([CH3:17])[CH2:6][CH2:5]2.[CH2:25]([Sn](CCCC)(CCCC)C#C)[CH2:26]CC.C(OCC)(=O)C>CN(C)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>[CH:14]1([C:12]([N:8]2[C:9]3[C:4](=[C:3]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:2]([C:25]#[CH:26])=[CH:11][CH:10]=3)[CH2:5][CH2:6][C@@H:7]2[CH3:17])=[O:13])[CH2:16][CH2:15]1
Reactant: C[C@H]1CCc2c(ccc(Br)c2Oc2ccccc2)N1C(=O)C1CC1
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#Cc1ccc2c(c1Oc1ccccc1)CC[C@H](C)N2C(=O)C1CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.030 g, 0.08 mmol), tributyl(ethynyl)stannane (0.030 g, 0.09 mmol), and tetrakis(triphenylphosphine)palladium (O) (0.037 g, 0.03 mmol) in N,N-dimethylformamide (1.5 mL) stirred overnight at 120° C. The reaction mixture was cooled to room temperature, poured into ethyl acetate (15 mL), washed with water (2×5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via preparative thin layer chromatography (eluting with 1:5, ethyl acetate/petroleum ether). The product was further purified by preparative-HPLC with the following conditions (Waters III): Column, Xbridge RP C18, 19×150 mm, 5 um; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (50% to 100% acetonitrile in 10 min, flow rate: 20 mL/min); Detector, UV 220&254 nm. This afforded (S)-cyclopropyl(6-ethynyl-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)methanone (0.004 g, 16%) as a brown semi-solid. 1H NMR (300 MHz, CD3OD) δ ppm 0.65-0.85 (m, 1H), 0.87-1.04 (m, 2H), 1.05-1.25 (m, 4H), 1.38-1.52 (m, 1H), 1.85-2.02 (m, 1H), 2.11-2.47 (m, 2H), 2.62-2.85 (m, 1H), 3.47 (m, 1H), 4.75-4.82 (m, 1H), 6.79 (d, J=8.10 Hz, 2H), 6.95-7.05 (m, 1H), 7.19-7.39 (m, 3H), 7.45 (d, J=8.40 Hz, 1H). MS (ESI, pos. ion) m/z 332 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.S(Cl)([Cl:15])=O.[Cl-]>>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([Cl:15])=[O:12])=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1ccc(CCl)cc1
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Product: O=C(Cl)Cc1ccc(CCl)cc1

Procedure:
A mixture of 1 g of p-chloromethylphenylacetic acid and 6 ml of thionylchloride is stirred at room temperature for 25 hours after which the excessthionyl chloride is removed under vacuum to yield p-chloromethylphenylacetyl chloride.
Reaction SMILES: [NH2+]1[C:9]2[C:4](=[CH:5]C=CC=2)[CH:3]=[CH:2]1.S1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH+:12]=[CH:11]1.CO/[CH:21]=[CH:22]/[CH:23]=[C:24]1/[S:25](=[O:35])(=[O:34])[C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[C:28]/1=[O:29].C([O-])(=O)C.[Na+]>CO.C(Cl)(Cl)Cl>[CH3:11][N:12]1[C:13]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:4]([CH3:9])([CH3:5])/[C:3]/1=[CH:2]/[CH:21]=[CH:22]/[CH:23]=[C:24]1\[S:25](=[O:35])(=[O:34])[C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[C:28]\1=[O:29]
Reactant: C1=Cc2ccccc2[NH2+]1
Reactant: CO/C=C/C=C1\C(=O)c2ccccc2S1(=O)=O
Reactant: c1ccc2sc[nH+]c2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN1/C(=C\C=C\C=C2\C(=O)c3ccccc3S2(=O)=O)C(C)(C)c2ccccc21

Procedure:
General Procedure B (Dyes 1b, 1c, 2a, 2b, 3b, 4b). Indolium or benzothiazolium salt (5, 6, or 7, 1.00 mmol) was added at once to a boiling solution of enol ether 8 or 9 (500 mg, 2.0 mmol) in 5.0 mL of a methanol-chloroform mixture (1:1) followed by addition of 100 mg of sodium acetate. The reaction mixture was stirred at reflux for 30 min. After cooling, the dye separated as a crystalline solid. The dye was additionally purified by recrystallization from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.C[N:12]([CH3:15])C=O.C(Cl)(=O)[C:17](Cl)=[O:18]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]([O:18][CH3:17])[CH3:15])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
Under ice cooling, 6-chloronicotinic acid (5.00 g) was suspended in dichloromethane (150 ml), followed by the addition of a catalytic amount of N,N-dimethylformamide and oxalyl chloride (5.30 ml). The resulting mixture was stirred at room temperature for 23 hours. The residue obtained by concentrating the reaction mixture was dissolved in dichloromethane (100 ml), followed by the addition of N,O-dimethylhydroxylamine hydrochloride (6.18 g) and triethylamine (13.3 ml) under ice cooling. After stirring at room temperature for 6 hours, the reaction mixture was diluted with dichloromethane (150 ml), washed with a saturated aqueous solution of sodium bicarbonate, water and saturated aqueous NaCl solution and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (hexane:ethyl acetate=2:1), whereby the title compound (6.08 g, 96%) was obtained.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:14]=[CH:13][C:12]3[NH:11][CH2:10][C@@H:9]4[CH2:15][C@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=2[C:8]=34)=[CH:4][CH:3]=[N:2]1>C(Cl)Cl.O=[Mn]=O>[O:1]1[C:5]([C:6]2[CH:14]=[CH:13][C:12]3[NH:11][CH:10]=[C:9]4[CH2:15][C@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=2[C:8]=34)=[CH:4][CH:3]=[N:2]1
Reactant: CCCN(CCC)[C@@H]1Cc2c(-c3ccno3)ccc3c2[C@H](CN3)C1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCCN(CCC)[C@H]1Cc2c[nH]c3ccc(-c4ccno4)c(c23)C1
Reaction time: 4 h
Yield: 50.2 %

Procedure:
A mixture of (-)(2aR,4S)-6-(5-isoxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (253 mg, 0.8 mmol) and 1 g of MnO2 in 100 ml of CH2Cl2 was sonicated at 50-55 KHz for four hours. The reaction mixture was warmed to reflux during the time period. After four hours, the reaction mixture was filtered through a celite pad and the filtrate was concentrated to dryness in vacuo. The resulting residue was chromatographed (flash column, silica gel, EtOAc) to provide 130 mg of title product. Recrystallization from hexane gave 60 mg of purified title product. mp 126°-127° C. MS m/e 323 (FD)