Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:9][N:8]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1.[NH:29]1[CH:33]=[CH:32][C:31](B(O)O)=[N:30]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:33]3[CH:32]=[CH:31][NH:30][N:29]=3)[CH:3]=2)[N:8]([S:19]([C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)(=[O:21])=[O:20])[CH:9]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(Br)cc12
Reactant: OB(O)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc[nH]n3)cc12
Temperature: 165 °C
Yield: 80.1 %

Procedure:
5-Bromo-3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (200 mg, 0.438 mmol), commercial 1H-pyrazole-3-boronic acid (73.6 mg, 0.637 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (17.8 mg, 0.022 mmol) were combined in dimethylformamide (1.4 mL) and 2 M saturated sodium carbonate (657 μL) under nitrogen. The mixture was heated to 165° C. in the microwave for 900 s. The mixture was diluted with ethyl acetate and the aqueous layer was removed. After drying over sodium sulfate, the crude material was purified by silica gel chromatography to afford 3-(2-methoxy-phenyl)-5-(1H-pyrazol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (156 mg, 80.2%). %). MS: m/z 445 (M+H+).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:20]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:22]=2[N:21]=1)[CH2:13][CH2:14][C:15]1[NH:19][N:18]=[N:17][N:16]=1)=O)C1C=CC=CC=1.I[Si](C)(C)C.CO>ClCCl>[Cl:29][C:27]1[CH:26]=[CH:25][C:23]2[NH:24][C:20]([C@@H:12]([NH2:11])[CH2:13][CH2:14][C:15]3[NH:19][N:18]=[N:17][N:16]=3)=[N:21][C:22]=2[CH:28]=1
Reactant: O=C(N[C@@H](CCc1nnn[nH]1)c1nc2cc(Cl)ccc2[nH]1)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CO
Product: N[C@@H](CCc1nnn[nH]1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.10 g (4.45 mmol) (1S)-N-(benzyloxycarbonyl)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(1H-tetrazol-5-yl)-propylamine in 30 ml dichloromethane are combined with 1.9 ml (13.4 mmol) iodo-trimethylsilane and stirred for 16 hours at ambient temperature. Then 20 ml of methanol are added, the mixture is stirred for a further 30 minutes at ambient temperature and the reaction mixture is evaporated down completely i. vac. The residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/(ethanol/conc. ammonia 95:5)=70/30->60:40).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]2[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([C:32]3([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O>[CH3:10][C:6]1[N:5]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([C:26]3[CH:27]=[CH:28][C:29]([C:32]4([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:33][CH2:34][CH2:35]4)=[CH:30][CH:31]=3)[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=1
Reactant: Cc1cccc2nc(Br)c(-c3ccccc3)n12
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1cccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n12
Temperature: 120 °C
Yield: 83.1 %

Procedure:
A mixture of 2-bromo-5-methyl-3-phenylimidazo[1,2-a]pyridine (38 mg, 0.13 mmol), tert-butyl {1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl}carbamate (see step 4, 64 mg, 0.17 mmol) and potassium phosphate (84.3 mg, 0.40 mmol) in 1.2 ml toluene/ethanol/water (1/2/1) was heated to 120° C. in a single mode microwave reactor (Biotage). This experiment was repeated employing the same protocol. Both reaction mixtures were combined and partitioned between dichloromethane and water. The mixture was filtered through a phase separator and concentrated in vacuo. The crude material was purified by column chromatography (Snap cartridge, hexane/ethyl acetate 95/5->hexane/ethyl acetate 1/1) to give 49 mg of the title compound (34% overall yield).
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[C:35]([OH:36])=[CH:34][CH:33]=[CH:32][C:31]=5[Cl:37])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:45](Br)[CH:46]=[CH2:47].O>CC(C)=O>[CH2:47]([O:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:37])[C:30]=1[CH:28]1[O:27][N:26]=[C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:12](=[O:13])[CH2:11][N:5]4[C:6]([CH:8]([F:10])[F:9])=[CH:7][C:3]([CH:2]([F:1])[F:38])=[N:4]4)[CH2:15][CH2:16]3)[S:21][CH:22]=2)[CH2:29]1)[CH:46]=[CH2:45]
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4c(O)cccc4Cl)C3)cs2)CC1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1cccc(Cl)c1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Yield: 62.3 %

Procedure:
To a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-chloro-6-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (39 mg) and potassium carbonate (47 mg) in acetone (5 ml) is added, at room temperature, allyl bromide (33 mg). The reaction mixture is stirred at reflux for 5 h. Then the mixture is admixed with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated. Purification by column chromatography gives 1-[4-(4-{5-[2-(allyloxy)-6-chlorophenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]-2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]ethanone (26 mg).
Reaction SMILES: Cl[CH:2]([CH3:4])[CH3:3].[Mg:5].[CH3:6][CH:7]1[CH:12]=[C:11]([CH3:13])[CH2:10][CH2:9][CH:8]1[CH:14]=[O:15].[ClH:16]>CCOCC>[CH:2]([Mg:5][Cl:16])([CH3:4])[CH3:3].[CH3:6][CH:7]1[CH:12]=[C:11]([CH3:13])[CH2:10][CH2:9][CH:8]1[CH:14]=[O:15]
Reactant: Cl
Reactant: [Mg]
Reactant: CC(C)Cl
Agent: CC1=CC(C)C(C=O)CC1
Solvent: CCOCC
Product: CC(C)[Mg]Cl
Temperature: 0 °C

Procedure:
A solution of isopropyl magnesium chloride in ether is prepared by dropwise adding a solution of 164 grams (2.1 moles) of 2-chloropropane in 200 ml of ether to a stirred slurry of 50 grams (2.1 moles) of magnesium in 500 ml of ether at reflux under nitrogen. The resulting solution is stirred at reflux for 30 minutes. A solution of 164 grams (2 moles) of 2,4-dimethyl-3-cyclohexenecarboxaldehyde in 200 ml of ether is added over a 45-minute period to the reaction mixture at reflux under nitrogen. The resulting slurry is heated at reflux for 30 minutes and then cooled to 0° C. 400 ml of 18% aqueous hydrochloric acid is slowly added with cooling and stirring. Two clear layers are formed. The aqueous layer is discarded and the organic layer is washed twice with H2O, neutralizing the second wash with aqueous caustic soda. The ether is removed by distillation at atmospheric pressure. Fractional distillation of the remaining oil (375 grams) through a 11/2"×12" Goodloe packed column affords 121 grams of recovered 2,4-dimethyl-3-cyclohexenecarboxaldehyde; 54 grams of 1,5-dimethyl-3-isopropyl-2-oxabicyclo[2.2.2]octane; and 173 grams of 2,4-dimethyl-alpha-isopropyl-3-cyclohexene-1-methanol (b.p. 91° C., 2.1 mm Hg pressure).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCOCC2)C2N=NNC=2N=1)(C)(C)C.BrCC1C=CC([F:55])=CC=1Cl>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:55])=[CH:17][C:16]=3[Cl:21])[N:13]=2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nn(Cc3ccccc3Cl)nc2n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCOCC2)c2nn(Cc3ccc(F)cc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-2-(2-chloro-benzyl)-7-morpholin-4-yl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step d), the title compound was prepared from 5-tert-butyl-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-chloro-4-fluorobenzene and isolated as white solid (5.1 mg, 30%). MS (m/e): 405.4 (MH+).
Reaction SMILES: [Na+].[CH2:2]([C:6]1([CH3:35])[CH2:11][CH2:10][N:9]([C:12]2[N:17]3[CH:18]=[C:19]([C:21]([O-])=[O:22])[N:20]=[C:16]3[CH:15]=[C:14]([CH3:24])[C:13]=2[C@H:25]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:26]([O:28][CH3:29])=[O:27])[CH2:8][CH2:7]1)[CH2:3][CH:4]=[CH2:5].[CH2:36]([O:39][C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42][NH2:43])[CH:37]=[CH2:38].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH2:36]([O:39][C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42][NH:43][C:21]([C:19]1[N:20]=[C:16]2[CH:15]=[C:14]([CH3:24])[C:13]([C@H:25]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])[C:26]([O:28][CH3:29])=[O:27])=[C:12]([N:9]3[CH2:10][CH2:11][C:6]([CH2:2][CH2:3][CH:4]=[CH2:5])([CH3:35])[CH2:7][CH2:8]3)[N:17]2[CH:18]=1)=[O:22])[CH:37]=[CH2:38]
Reactant: C=CCOc1ccccc1CN
Reactant: C=CCCC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(C(=O)[O-])cn23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=CCCC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(C(=O)NCc4ccccc4OCC=C)cn23)CC1
Yield: 60 %

Procedure:
A yellow solution of (S)-5-(4-(but-3-en-1-yl)-4-methylpiperidin-1-yl)-6-(1-(tert-butoxy)-2-methoxy-2-oxoethyl)-7-methylimidazo[1,2-a]pyridine-2-carboxylic acid sodium salt (40 mg, 0.081 mmol, 1 equiv), 2-allyloxybenzylamine (18 mg, 0.113 mmol, 1.4 equiv), DIPEA (0.042 mL, 0.243 mmol, 3 equiv), and HATU (43 mg, 0.113 mmol, 1.4 equiv) in DMF (0.81 mL) was stirred 2 h. The reaction was then diluted with EtOAc, washed with saturated aqueous NaHCO3, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc/hex) to provide the product (30 mg, 60%) as a colorless oil. 1H NMR (400 MHz, CDCl3) [note: appears to be at least two rotamers, only major rotamer transcribed] δ 8.21 (s, 1H), 7.81 (t, J=6.1 Hz, 1H), 7.26-7.16 (m, 2H), 6.97-6.85 (m, 2H), 6.19-6.06 (m, 2H), 5.93-5.82 (m, 1H), 5.47 (dq, J=17.3, 1.5 Hz, 1H), 5.31 (dq, J=10.5, 1.4 Hz, 1H), 5.14-4.95 (m, 2H), 4.72 (d, J=6.0 Hz, 2H), 4.63 (dt, J=5.0, 1.5 Hz, 2H), 3.70 (s, 3H), 3.61-3.48 (m, 2H), 3.07 (d, J=13.8 Hz, 1H), 2.85 (d, J=12.0 Hz, 1H), 2.45 (d, J=1.0 Hz, 3H), 2.17-2.07 (m, 2H), 1.71-1.40 (m, 6H), 1.24 (s, 9H), 1.13 (s, 3H); LCMS (ESI, M+1): 617.4.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]>C(O)C.C1CCCCC=1.[OH-].[Pd+2].[OH-]>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(N(C(=O)NC2CCN(Cc3ccccc3)CC2)C2CCCCCC2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: N#Cc1cccc(N(C(=O)NC2CCNCC2)C2CCCCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-(3-Cyanophenyl)-N'-(1-benzylpiperidin-4-yl)cycloheptylurea (0.1 g 0.26 mmol) was dissolved in ethanol (10 ml) and cyclohexene (2 ml). Palladium hydroxide catalyst (0.05 g) was added and the reaction was heated at reflux under a nitrogen atmosphere. After 30 min the reaction was allowed to cool to ambient temperature, filtered and concentrated to give a viscous oil. The crude product was purified by flash chromatography on silica gel by eluting with methylene chloride:methanol 85:15 with 3% triethylamine. The product, N-(3-cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea, was concentrated to give an oil which crystallized from ethyl ether (0.05 g, 48%, mp 157-8° C.); LRMS (M+H)+ m/z 299; 1H NMR (CDCl3): 7.5-7.3(m, 4H), 4.05(m, 1H), 3.60(m, 2H), 3.32(m, 2H), 3.17(m, 2H), 2.72(m, 2H), 2.0-1.6(m, 8H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27](=[NH:31])OCC>C(O)C.C(Cl)(Cl)Cl>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:7]2[C:2]([NH:1][C:27](=[NH:31])[CH2:26][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:19])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: CCOC(=N)Cc1ccccc1C
Reactant: COc1ccc(COc2cccnc2N)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1ccc(COc2cccnc2NC(=N)Cc2ccccc2C)cc1
Yield: 5.3 %

Procedure:
A mixture of 2-amino-3-(4-methoxybenzyloxy)pyridine (4.6 g, 20 mmol) and ethyl 2methylphenylacetimidate hydrochloride (4.69 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was taken up in chloroform, convened to the free base by washing with aqueous sodium bicarbonate, and purified by flash chromatography (chloroform/methanol) to obtain the product as a gum (0.38 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][N:3]=1.[NH2:10][CH2:11][CH2:12][SH:13]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[NH:10][CH2:11][CH2:12][S:13]2)=[CH:4][N:3]=1
Reactant: NCCS
Reactant: O=Cc1ccc(Cl)nc1
Solvent: c1ccccc1
Product: Clc1ccc(C2NCCS2)cn1
Reaction time: 5 h
Yield: 89.9 %

Procedure:
A solution composed of 6-chloronicotinaldehyde (14.2 g), 2-aminoethanethiol (7.7 g) and benzene (80 ml) was heated with stirring for 5 hours while removing water as an azeotrope. After the reaction, benzene was distilled off under reduced pressure, and further volatile materials were removed at 1 mmHg and 70° C. to give 2-(2-chloro-5-pyridyl)thiazolidine (18 g) as a residue. Ten grams of 2-(2-chloro-5-pyridyl)thiazolidine was dissolved in 100 ml of ethanol, and sodium borohydride was added. With stirring, the mixture was gradually heated and thereafter re-fluxed for 1 hour. Ethanol was distilled off under reduced pressure, and chloroform was added to the residue. Insoluble materials were separated by filtration and the chloroform layer was washed with water and dehydrated. Chloroform was distilled off under reduced pressure to give the desired N-(2-chloro-5-pyridylmethyl)2-aminoethanethiol (8.3 g).
Reaction SMILES: [O:1]=[S:2]([Cl:4])Cl.[N+:5]([C:8]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:9]=1N)([O-:7])=[O:6].N([O-])=[O:17].[Na+].Cl>O.Cl[Cu]>[F:15][C:13]1[CH:12]=[CH:11][C:9]([S:2]([Cl:4])(=[O:1])=[O:17])=[C:8]([N+:5]([O-:7])=[O:6])[CH:14]=1
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Reactant: O=N[O-]
Agent: Cl[Cu]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(F)ccc1S(=O)(=O)Cl
Yield: 81.5 %

Procedure:
In a similar fashion using route 3a general procedure 10, SOCl2 (51.4 g, 704 mmol) in water (260 ml), CuCl (0.65 g, 6.4 mmol), 2-nitro 4-fluro-aniline (20 g, 128 mmol), NaNO2 (12.7 g, 184 mmol) and conc. HCl (200 ml) gave the title compound (25 g, 81%) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([CH3:25])[CH2:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[C:12]3[CH2:20][N:21]([CH3:24])[CH2:22][CH2:23][C:11]2=3)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH-].[K+].[F:34][C:35]1[CH:40]=[CH:39][C:38](/[C:41](/[CH3:58])=[CH:42]\[N:43]2[C:51]3[CH:50]=[CH:49][C:48]([CH3:52])=[CH:47][C:46]=3[C:45]3[CH2:53][N:54]([CH3:57])[CH2:55][CH2:56][C:44]2=3)=[CH:37][CH:36]=1>CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH3:25])=[CH:9]/[N:10]2[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[C:12]3[CH2:20][N:21]([CH3:24])[CH2:22][CH2:23][C:11]2=3)=[CH:6][CH:7]=1.[F:34][C:35]1[CH:36]=[CH:37][C:38]([C:41](=[CH2:58])[CH2:42][N:43]2[C:51]3[CH:50]=[CH:49][C:48]([CH3:52])=[CH:47][C:46]=3[C:45]3[CH2:53][N:54]([CH3:57])[CH2:55][CH2:56][C:44]2=3)=[CH:39][CH:40]=1
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(F)cc2)CCN(C)C1
Reactant: C/C(=C/n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1
Product: C=C(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 2.5 °C

Procedure:
2-(4-Fluorophenyl)-1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propan-2-ol (4.6 g, 13.05 mmol, 1 equiv.) was heated to reflux with 14 mL of 25% aq. sulfuric acid for 2 h. The reaction mixture was cooled to 0-5° C. and made alkaline with 15% aq. KOH solution and extracted with THF:EtOAc (1:1 mixture, 2×30 mL). The combined organic layer was washed with water (15 mL) and then brine, dried over sodium sulfate and evaporated under vacuum. 4.1 g of crude product was obtained which contained 5-((Z)-2-(4-fluorophenyl)prop-1-enyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole as the minor isomer. This isomer was isolated by repeated flash chromatography using 230-400 mesh silica gel using EtOAc as eluent. Yield: 500 mg of 5-((E)-2-(4-fluorophenyl)prop-1-enyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole and 1 g of 5-(2-(4-fluorophenyl)allyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole were isolated as pure products.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[F:8][C:9]1[CH:30]=[CH:29][CH:28]=[CH:27][C:10]=1[CH:11]=[C:12]1[C:17](=[O:18])[C:16](=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH2:15][NH:14][CH2:13]1>C(O)=O>[CH:1]([N:14]1[CH2:13][C:12](=[CH:11][C:10]2[CH:27]=[CH:28][CH:29]=[CH:30][C:9]=2[F:8])[C:17](=[O:18])[C:16](=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH2:15]1)=[O:3]
Reactant: O=C1C(=Cc2ccccc2F)CNCC1=Cc1ccccc1F
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CN1CC(=Cc2ccccc2F)C(=O)C(=Cc2ccccc2F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
Compound 18 was synthesized by two methods. In the first method, acetic anhydride (3 ml) was added drop-wise to an ice-cold solution of compound 1 (300 mg, 0.96 mmol) in formic acid (6 ml), and the reaction mixture was stirred at room temperature for 16 h. The solvent was distilled-off under vacuum. The solid obtained was recrystallized from chloroform and hexanes to obtain 18 as a yellow solid (148 mg, 45% yield). In the second method, ammonium formate (121 mg, 1.92 mmol) was added to a solution of compound 1 (300 mg, 0.96 mmol) in dry acetonitrile. The mixture was refluxed for 24 h, before evaporating to dryness. The solid was recrystallized from methylene chloride and hexanes to obtain pure 18 as a yellow solid (190 mg, 57% yield). Rf (60:40 ethyl acetate:hexanes)=0.60. 1H NMR (400 MHz, CDCl3): δ 8.16 (s, 1H, CHO), 8.09, 8.06 (2s, 2H, C═CH), 7.60-7.22 (m, 8H, Ar—H), 4.87, 4.66 (2s, 4H). 13C NMR (100 MHz, CDCl3): δ 185.34, 162.14 (d, J=45.6), 160.95, 159.87 (d, J=45.9), 132.85, 132.19 (d, J=25.7), 131.12 (d, J=25.4), 130.78, 124.46 (d, J=3.1), 116.49 (d, J=22.1), 116.18 (d, J=22.3), 46.38 (d, J=5.4), 41.11 (d, J=5.2). ESI Mass calculated for C20H15F2NNaO2 (M+Na)+362.10. found 362.07.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2.[CH2:23]([O:25][CH:26](OCC)[O:27][CH2:28][CH3:29])[CH3:24]>>[CH2:23]([O:25][CH:26]([O:27][CH2:28][CH3:29])[N:5]1[C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]=2[C:2]([CH3:22])([CH3:1])[O:7][C:6]1=[O:8])[CH3:24]
Reactant: CCOC(OCC)OCC
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Product: CCOC(OCC)N1C(=O)OC(C)(C)c2cc(-c3cc(F)cc(C#N)c3)ccc21
Temperature: 160 °C
Yield: 33 %

Procedure:
A mixture of 3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6yl)-5-fluoro-benzonitrile (0.25 g, 0.84 mmol) and triethylorthoformate (50 mL) was heated at 160° C. for 12 hours. The excess triethylorthoformate was removed in vacuo and purification via chromatography (silica gel, 20% ethyl acetate/hexane) gave 3-(1-diethoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluoro-benzonitrile (0.116 g, 33%) as a white solid: mp 123-124° C.; 1H-NMR (DMSO-d6) δ7.97 (d, 1H, J=8.68 Hz), 7.66 (bs, 1H), 7.53-7.44 (m, 2H), 7.35-7.32 (m, 2H), 6.65 (s, 1H), 3.88-3.78 (m, 2H), 3.73-3.61 (m, 2H), 1.77 (s, 6H), 1.27 (t, 6H, J=7.05 Hz); MS (ESI) m/z 295 ([M−H]−, 100%, lower MW ion consistent with loss of diethyl acetal); Anal. Calc. For C22H23FN2O4: C, 66.32, H, 5.82, N, 7.03. Found: C, 65.89, H, 5.92, N, 6.66.
Reaction SMILES: [C:1]([O-])(=[S:3])[CH3:2].[K+].I[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C@H:20]2[CH2:37][C@@:35]3([CH3:36])[C@@H:31]([CH2:32][CH2:33][C@@H:34]3[OH:38])[C@H:30]3[C@H:21]2[C:22]2[CH:23]=[CH:24][C:25]([OH:39])=[CH:26][C:27]=2[CH2:28][CH2:29]3)=[CH:16][CH:15]=1>C(O)C>[C:1]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C@H:20]2[CH2:37][C@@:35]3([CH3:36])[C@@H:31]([CH2:32][CH2:33][C@@H:34]3[OH:38])[C@H:30]3[C@H:21]2[C:22]2[CH:23]=[CH:24][C:25]([OH:39])=[CH:26][C:27]=2[CH2:28][CH2:29]3)=[CH:16][CH:15]=1)(=[S:3])[CH3:2]
Reactant: CC([O-])=S
Reactant: C[C@]12C[C@H](c3ccc(OCCCCCCI)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: [K+]
Solvent: CCO
Product: CC(=S)CCCCCCOc1ccc([C@H]2C[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]3CCc4cc(O)ccc4[C@H]32)cc1
Reaction time: 0.83 h
Yield: 96.5 %

Procedure:
150 mg of potassium thioacetate is added to a solution of 470 mg of the product obtained in Stage D in 6 cm3 of ethanol and agitation is carried out for 1 hour 50 minutes at 50° C. The ethanol is distilled off, the residue is taken up in ethyl acetate, washed with water, dried and evaporated to dryness under reduced pressure. 400 mg of residue is obtained which is chromatographed on silica (eluant ethyl acetate-essence G 6/4 then 8/2). 265 mg of desired product is collected (M.p. #90° C.).
Reaction SMILES: [CH:1]12NC(CC1)CC(C1C3C=CC(C4C=CC=CC=4NC(=O)C)=CC=3OC3C1=CC=CC=3)C2.N1C=CC=C(C2C=CC3C(C4CC5NC(CC5)C4)C4C(OC=3C=2)=CC=CC=4)C=1.[O:61]1[CH:65]=[CH:64]C=[C:62]1[CH2:66][N:67]1[CH:72]2[CH2:73][CH2:74][CH:68]1[CH2:69][CH:70]([CH:75]1[C:88]3[CH:87]=[CH:86][C:85]([C:89]4[CH:94]=[CH:93][CH:92]=[CH:91][C:90]=4[NH:95][C:96](=[O:98])[CH3:97])=[CH:84][C:83]=3[O:82][C:81]3[C:76]1=[CH:77][CH:78]=[CH:79][CH:80]=3)[CH2:71]2>>[O:61]1[CH:65]=[CH:64][C:66]([N:67]2[CH:68]3[CH2:74][CH2:73][C:72]2([CH3:1])[CH2:71][CH:70]([CH:75]2[C:88]4[CH:87]=[CH:86][C:85]([C:89]5[CH:94]=[CH:93][CH:92]=[CH:91][C:90]=5[NH:95][C:96](=[O:98])[CH3:97])=[CH:84][C:83]=4[O:82][C:81]4[C:76]2=[CH:77][CH:78]=[CH:79][CH:80]=4)[CH2:69]3)=[CH:62]1
Reactant: CC(=O)Nc1ccccc1-c1ccc2c(c1)Oc1ccccc1C2C1CC2CCC(C1)N2Cc1ccco1
Reactant: CC(=O)Nc1ccccc1-c1ccc2c(c1)Oc1ccccc1C2C1CC2CCC(C1)N2
Agent: c1cncc(-c2ccc3c(c2)Oc2ccccc2C3C2CC3CCC(C2)N3)c1
Product: CC(=O)Nc1ccccc1-c1ccc2c(c1)Oc1ccccc1C2C1CC2CCC(C)(C1)N2c1ccoc1

Procedure:
Using an adaptation of the method described in Procedure 12, substituting N-{2-[9-(8-aza-bicyclo[3.2.1]oct-3-yl)-9H-xanthen-3-yl]-phenyl}-acetamide, 7b for 3-(3-pyridin-3-yl-9H-xanthen-9-yl)-8-aza-bicyclo[3.2.1]octane, 3b, title compound N-{2-[9-(8-furan-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-9H-xanthen-3-yl]-phenyl}-acetamide, 13b was obtained as a TFA salt. MS m/z (MH+) 505.2.