Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8](CC1C=CC=CC=1)[C:7](C)=[C:6]2[CH2:20][C:21]([NH:23][NH2:24])=[O:22].[CH2:25]([O:27][C:28](=O)[CH2:29]C1C2C(=CC=C(OC)C=2)N(CC2C=CC=CC=2)C=1C)[CH3:26].NN>CO>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[CH:11][CH:10]=2)[C:6]([CH2:20][C:21]([NH:23][NH2:24])=[O:22])=[CH:7]1.[CH3:26][CH2:25][O:27][CH2:28][CH3:29]
Reactant: CCOC(=O)Cc1c(C)n(Cc2ccccc2)c2ccc(OC)cc12
Reactant: COc1ccc2c(c1)c(CC(=O)NN)c(C)n2Cc1ccccc1
Agent: NN
Solvent: CO
Product: CCOCC
Product: NNC(=O)Cc1c[nH]c2ccccc12
Yield: 96 %

Procedure:
5-Methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid hydrazide. A solution of 1.0 g (2.96 mmol) of 5-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid ethyl ester and 5 mL of hydrazine in 50 mL of MeOH was reacted as described in Example 3, Part C, to give by trituration with ether 920 mg (96% yield) of 5-methoxy-2-methyl-1-phenylmethyl)-1H-indole-3-acetic acid hydrazide, mp, 161-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.[Br:14]Br.O>C(O)(=O)C>[Br:14][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][C:6]=1[C:11]([OH:13])=[O:12]
Reactant: BrBr
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1[nH]c2ccc(Cl)cc2c1Br
Reaction time: 0.33 h
Yield: 92.9 %

Procedure:
To a solution of 5-chloro-1H-indole-2-carboxylic acid (2.0 g, 10.2 mmol) in acetic acid (24 mL) was added a solution of bromine (0.53 mL, 10.2 mmol) in acetic acid (16 mL). After 20 minutes, the mixture was poured into water and extracted with chloroform twice. The combined extracts were washed with water twice and brine, dried over magnesium sulfate and concentrated. The product was obtained as a solid (2.6 g, 89%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([NH2:9])=[O:8].[Br:10][CH2:11][C:12](=O)[CH3:13]>C(#N)C>[Br-:10].[CH3:1][N+:2]1[CH:6]=[CH:5][N:4]2[CH:11]=[C:12]([CH3:13])[NH:9][C:7](=[O:8])[C:3]=12
Reactant: Cn1ccnc1C(N)=O
Reactant: CC(=O)CBr
Solvent: CC#N
Product: Cc1cn2cc[n+](C)c2c(=O)[nH]1
Product: [Br-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 123.2 %

Procedure:
A mixture of 1-Methyl-1H-imidazole-2-carboxylic acid amide (3.0 g, 14.3 mmol), bromoacetone (2.36 g, 17.2 mmol) and acetonitrile (40 mL) is stirred overnight at 80° C. The solid formed is filtered and washed with acetonitrile to give 1,6-dimethyl-8-oxo-7,8-dihydro-imidazo[1,2-a]pyrazin-1-ium bromide salt (4.3 g, 86%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.[O:17]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH2:19][CH:18]1[C:27]([N:29]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28]>C(O)CCC>[ClH:16].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:32]2[CH2:33][CH2:34][CH2:35][N:29]([C:27]([CH:18]3[O:17][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][CH2:19]3)=[O:28])[CH2:30][CH2:31]2)[N:3]=1
Reactant: O=C(C1COc2ccccc2O1)N1CCCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CCCCO
Product: COc1cc2nc(N3CCCN(C(=O)C4COc5ccccc5O4)CC3)nc(N)c2cc1OC
Product: Cl
Yield: 17.2 %

Procedure:
4-Amino-2-chloro-6,7-dimethoxyquinazoline (1.58 g.) and N-(1,4-benzodioxan-2-carbonyl)homopiperazine (2.0 g.) were heated under reflux in n-butanol (114 ml.) for 60 hours. The mixture was then cooled, butanol removed in vacuo and the solid residue triturated with ether, taken up in hot methanol, filtered and cooled. The solid product was collected, then the residual solution was evaporated in vacuo and the residue taken up in hot isopropanol, cooled, filtered, then re-evaporated in vacuo. The residue was combined with the original solid product, treated with cold methanol, and recrystallized from ethanol to give 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl)homopiperazin-1-yl]-6,7-dimethoxyquinazoline hydrochloride (0.57 g.), m.p. 250°-251° C.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.I.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](SC)=[NH:24].N>CCO.CO>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:23]([C:19]3[S:18][CH:22]=[CH:21][CH:20]=3)=[NH:24])=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: CN(C)CCN1CCCc2cc(N)ccc21
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: N
Solvent: CO
Solvent: CCO
Product: CN(C)CCN1CCCc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(2-(dimethylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-amine (900 mg, 4.10 mmol) in 25 mL EtOH was treated with methyl thiophene-2-carbimidothioate hydroiodide (2.34 g, 1.43 mmol) and stirred overnight at room temperature. Argon was bubbled through the mixture for 20 minutes then it was partitioned between CH2Cl2 (100 mL) and saturated sodium bicarbonate (20 mL). The organic layer was separated and the aqueous layer was extracted with an additional 50 mL CH2Cl2. The combined organic layers were rinsed with water, dried over sodium sulfate, filtered and concentrated to give a dark oil which was subjected to flash chromatography on silica gel using 5% MeOH/CH2CH2then 5% 2M NH3 in MeOH/CH2C12 to give an orange solid. 1H-NMR (DMSO-d6) δ: 7.66 (d, J=3.6 Hz, 1H), 7.55 (d, J=4.8 Hz, 1H), 7.08-7.05 (m, 1H), 6.57-6.48 (m, 3H), 6.25 (brs, 2H), 3.29-3.21 (m, 4H), 2.65 (t, J=6.3 Hz, 2H), 2.39 (t, J=6.3 Hz, 2H), 2.19 (s, 6H), 1.85-1.82 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.ClCCCOC1C=C(C2C3SC=CC=3ON=2)C=CC=1.[NH2:39][CH2:40][CH:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[OH:42].C(=O)([O-])[O-].[K+].[K+]>>[C:43]1([CH:41]([OH:42])[CH2:40][NH:39][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[C:16]4[S:17][CH:18]=[CH:19][C:15]=4[O:14][N:13]=3)[CH:7]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCC(O)c1ccccc1
Agent: ClCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OC(CNCCCOc1cccc(-c2noc3ccsc23)c1)c1ccccc1
Yield: 100 %

Procedure:
The title compound is prepared from a mixture of 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-[3-(3-chloro-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 2-amino-1-phenylethanol and potassium carbonate essentially as described above in example 4 except that the column is eluted with a mixture of dichloromethane:methanol (95:5). Combine the appropriate fractions and concentrate to give the title compound (0.62 g, 100% Yield) as a solid. Purity by LC/MS (APCI)=100% area, [M+H]+=395 m/e.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:7]([F:14])=[C:8]([NH2:13])[CH:9]=[CH:10][C:11]=1[F:12].[CH3:15][N:16]([CH3:27])[S:17]([N:20]1[CH:24]=[C:23](C=O)[N:22]=[CH:21]1)(=[O:19])=[O:18].[BH4-].[Na+].[CH3:30]O>>[CH3:15][N:16]([CH3:27])[S:17]([N:20]1[C:24]([CH2:30][NH:13][C:8]2[CH:9]=[CH:10][C:11]([F:12])=[C:6]([CH:2]3[O:3][CH2:4][CH2:5][O:1]3)[C:7]=2[F:14])=[CH:23][N:22]=[CH:21]1)(=[O:19])=[O:18]
Reactant: Nc1ccc(F)c(C2OCCO2)c1F
Reactant: CO
Reactant: CN(C)S(=O)(=O)n1cnc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Product: CN(C)S(=O)(=O)n1cncc1CNc1ccc(F)c(C2OCCO2)c1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a stirred solution of 3-[1,3]dioxolan-2-yl-2,4-difluoro-phenylamine (0.41 g, 1.94 mmol) in methanol (10 ml) was added 4-formyl-imidazole-1-sulfonic acid dimethylamide (0.46 g, 2.24 mmol) and the mixture was heated at 60° C. for 18 h. After cooling to room temperature sodium borohydride (0.39 g, 10.3 mmol) was added and the mixture stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (column: Isolute® Flash-NH2 (Separtis); eluent: ethyl acetate/cyclohexane gradient) to yield a light brown gum (604 mg, 76%); MS (ISP): 389.1 ((M+H)+.).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:7]([CH3:15])=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O.[Al+3].[Cl-].[Cl-].[Cl-].[CH:20]1C=CC=C[CH:21]=1>ClC(Cl)C>[Cl:5][C:6]1[C:7]([CH3:15])=[C:8]2[C:12]([CH2:20][CH2:21][C:9]2=[O:11])=[CH:13][CH:14]=1
Reactant: Cc1c(Cl)cccc1C(=O)O
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: Cc1c(Cl)ccc2c1C(=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Thionyl chloride (10.0 mL, 1.5 eq) and 3-chloro-2-methyl-benzoic acid (commercially available from Aldrich) (15.6 g, 91.4 mmol) in benzene was refluxed until no more gas evolution was observed. After cooling to rt the mixture was concentrated. The concentrate was diluted with dichloroethane and added to a solution of AlCl3 (12.2 g, 1.0 eq) in dichloroethane at 10-20° C. Ethylene was bubbled through the mixture for 4 h. and the mixture was stirred overnight. The mixture was quenched with 4 N HCl. The resulting layers were separated and the aqueous layer was extracted with Et2O (3×250 mL). The combined organic extract was washed with H2O (3×150 mL), saturated NaHCO3 (3×150 mL), brine (1×150 mL), dried over MgSO4 and concentrated. Concentrated sulfuric acid was added and the mixture was stirred at 85° C. for 1 h. After cooling to rt, the reaction mixture was quenched with ice-water. The mixture was extracted with Et2O (3×250 mL) and the combined organic extracts were washed with H2O (3×200 mL), saturated NaHCO3 (3×200 mL), brine (1×100 μL), dried over MgSO4 and concentrated. Pure 6-chloro-7-methyl-1-indanone (11.9 g, 72%) was obtained after column chromatography using 20% EtOAc:hexane as eluant. Use of 6-chloro-7-methyl-1-indanone in Method NINETEEN produced 4-(5-chloro-4-methyl-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 152).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl:16][C:17]1[C:18]([CH3:41])=[C:19]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39]O)[CH:34]=2)[C:20]([CH3:32])=[C:21]([Cl:31])[C:22]=1[O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:39][C:35]3[CH:34]=[C:33]([C:19]4[C:20]([CH3:32])=[C:21]([Cl:31])[C:22]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])=[C:17]([Cl:16])[C:18]=4[CH3:41])[CH:38]=[CH:37][CH:36]=3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1c(Cl)c(OCCCS(C)(=O)=O)c(Cl)c(C)c1-c1cccc(CO)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)c(Cl)c(OCCCS(C)(=O)=O)c(Cl)c4C)c3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A solution of methyl[(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (0.237 g, 1.14 mmol), {3′,5′-dichloro-2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methanol (0.475 g, 1.14 mmol) and tributylphosphine (0.453 mL, 1.82 mmol) in toluene (18 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.459 g, 1.82 mmol) was added, and the mixture was stirred at room temperature for 1 hr under nitrogen atmosphere. Hexane (9 mL) was added to the reaction mixture, the precipitated insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30) to give the title compound (0.622 g, yield 89%) as a yellow oil.
Reaction SMILES: COC1C=CC2CC(C3C=CC=CC=3N)CCCC=2C=1.Cl.[N:22]1([CH2:29][CH2:30][O:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=O)=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.N1(CCOC2C=C[C:54]([CH2:55][NH:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=3[CH:63]3[CH2:69][CH2:68][CH2:67][C:66]4[CH:70]=[C:71]([O:74][CH3:75])[CH:72]=[CH:73][C:65]=4[CH2:64]3)=CC=2)CCCCCC1>>[N:22]1([CH2:29][CH2:30][O:31][C:32]2[CH:40]=[CH:39][C:35]([CH2:36][N:56]([CH2:55][CH3:54])[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=3[CH:63]3[CH2:69][CH2:68][CH2:67][C:66]4[CH:70]=[C:71]([O:74][CH3:75])[CH:72]=[CH:73][C:65]=4[CH2:64]3)=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1ccc2c(c1)CCCC(c1ccccc1NCc1ccc(OCCN3CCCCCC3)cc1)C2
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Agent: COc1ccc2c(c1)CCCC(c1ccccc1N)C2
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1ccccc1C1CCCc2cc(OC)ccc2C1

Procedure:
Synthesized from 2-(2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl][2-(2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)phenyl]amine (477 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl[2-(2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)phenyl]amine (431 mg). This compound (429 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (371 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[C:14](=O)([O-])[O-].[Na+].[Na+].CI.O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH3:14])[C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)oc(=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
6-Chloro-1Hbenzo[d][1,3]oxazine-2,4-dione (22.88 g, 116 mmol) was dissolved in dimethylformamide (150 mL), and sodium carbonate (14.73 g, 139 mmol) was added. Methyl iodide (10.86 mL, 174 mmol) was then added dropwise. The reaction was stirred at room temperature overnight. Water (150 mL) was then added, and the mixture was stirred for 1 hour. The solid was collected by filtration. The impure solid was sonicated in methyl-tert-butyl ether for several minutes, and then collected by filtration yielding the product as a white solid (19.38 g, 79%). 1H NMR (300 MHz, DMSO-d6) δ 3.45 (s, 3H), 7.47 (d, 1H), 7.89 (dd, 1H), 7.94 (d, 1H).
Reaction SMILES: NC(C)(C)C[O:4]C1C=CC(C#N)=CC=1F.[CH3:16][N:17]([CH3:32])[C:18]([CH3:31])([CH3:30])[CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#N)=[CH:23][C:22]=1[F:29]>>[CH3:16][N:17]([CH3:32])[C:18]([CH3:31])([CH3:30])[CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:4])=[CH:23][C:22]=1[F:29]
Reactant: CN(C)C(C)(C)COc1ccc(C#N)cc1F
Reactant: CC(C)(N)COc1ccc(C#N)cc1F
Product: CN(C)C(C)(C)COc1ccc(C=O)cc1F

Procedure:
Synthesized from 4-(2-amino-2-methylpropoxy)-3-fluorobenzonitrile according to an analogous synthetic method to Preparation Example 18, 4-(2-dimethylamino-2-methylpropoxy)-3-fluorobenzonitrile (1.4 g) was used according to an analogous synthetic method to Preparation Example 16 to provide the title compound (965 mg).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.O1CCCC1.[Li]CCCC.CCCCCC.[B:37](OC(C)C)([O:42]C(C)C)[O:38]C(C)C>O>[BH:37]([OH:42])[OH:38].[C:14]1([N:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[BH:37]([OH:42])[OH:38]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: OBO
Product: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
Also, triphenylamine boronic acid product was synthesized as follows. Under an argon (Ar) atmosphere, 246 g of 4-bromotriphenylamine (commercially available product), and 1500 ml of anhydrous tetrahydrofuran were placed in a 5 liter flask, and 570 ml of 1.6M n-BuLi/hexane solution was added dropwise over 3 hours at −60° C. After 30 minutes, 429 g of triisopropyl borate was added dropwise over 1 hour. Then, reaction overnight at ambient temperature was allowed. After the reaction, 2 liters of water was added dropwise, and after that, the mixture was extracted and the liquid was separated using 2 liters of toluene. The organic layer was concentrated, recrystallized, filtered, dried and 160 g of white boronic acid product, a target compound, was obtained.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[OH:10][N:11]=[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:13]#[N:14].C(N(CC)CC)C.O>C1C=CC=CC=1>[Cl:7][C:6]([Cl:9])([Cl:8])[CH2:5][O:4][C:2]([O:10][N:11]=[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:13]#[N:14])=[O:3]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: N#CC(=NO)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: N#CC(=NOC(=O)OCC(Cl)(Cl)Cl)c1ccccc1
Reaction time: 3 h
Yield: 81.8 %

Procedure:
A solution of 2,2,2-trichloroethyl chloroformate (2.2 g.) in benzene (10 ml.) was dropwise added to a solution of 2-hydroxyimino-2-phenylacetonitrile (1.5 g.) and triethylamine (1.40 ml.) in benzene (20 ml.) at room temperature, and the mixture was stirred for 3 hours at the same temperature. To the reaction mixture were added benzene and water, and the organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off and the residue was crystallized by adding a small amount of ether and n-hexane. The crystals were collected by filtration and recrystallized from methanol to give 2-(2,2,2-trichloroethoxycarbonyloxyimino)-2-phenylacetonitrile (2.7 g.), mp 82° to 84° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)(=O)=O.[C:25]([C:27]1([OH:35])[CH:32]2[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]2)[CH2:28]1)#[CH:26].C(N(CC)CC)C.N>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.CN(C)C=O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C:8]2[C:7]([C:26]#[C:25][C:27]3([OH:35])[CH:32]4[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]4)[CH2:28]3)=[CH:12][CH:11]=[C:10]([CH3:13])[N:9]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(Cc2nc(C)ccc2OS(=O)(=O)C(F)(F)F)cc1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Cc2nc(C)ccc2C#CC2(O)CN3CCC2CC3)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
A mixture of 230 mg of 2-(4-methoxybenzyl)-6-methyl-3-pyridyl trifluoromethane sulfonate, 116 mg of 3-ethynyl-3-quinuclidinol, 147 mg of tetrakis(triphenylphosphine)palladium(0), 24 mg of cuprous iodide, 266 μl of triethylamine and 5.0 ml of N,N-dimethylformamide was heated under stirring at 80° C. for 3 hours in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia, and the mixture was extracted with ethyl acetate. Then, the organic phase was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (20:1), to give 192 mg of the target compound.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:21]([O:23][CH:24](OCC)[CH:25]=[CH2:26])[CH3:22].[OH-].[Na+]>O.C(#N)C>[CH2:21]([O:23][CH:24]1[CH2:25][CH2:26][C:8]2[C:1](=[CH:3][C:4]([OH:5])=[CH:6][CH:7]=2)[O:2]1)[CH3:22]
Reactant: Oc1cccc(O)c1
Reactant: C=CC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCOC1CCc2ccc(O)cc2O1
Reaction time: 1 h
Yield: 62 %

Procedure:
A 500-milliliter (ml) flask fitted with a dropping funnel was charged with 10.0 g of resorcinol, 0.2 g of p-toluenesulfonic acid monohydrate, and 100 ml of acetonitrile for dissolution, and the mixture was cooled with ice. To this solution was slowly added dropwise 11.1 ml of acrolein diethyl acetal under room temperature. After the dropwise addition, the mixture was stirred for 1 hour while being cooled with ice. After 5 ml of a 5% sodium hydroxide aqueous solution and 30 ml of water were added thereto, the acetonitrile was removed by distillation in vacuo (under vacuum pressure), and the residue was extracted three times with 50 ml of chloroform. Subsequently, the chloroform layer obtained was washed with 30 ml of water, the chloroform was then removed by distillation in vacuo, and the resulting residue was purified by distillation to obtain 10.9 g of a colorless liquid (yield 62%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6]Br)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[C:22](=[C:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH2:15][CH2:14][C:13]=2[CH:29]=1>C1COCC1>[CH2:5]([O:4][C:1](=[O:3])[CH2:2][N:26]1[CH2:25][CH2:24][C:23](=[C:22]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH2:15][CH2:14][C:13]3[CH:29]=[C:9]([Cl:8])[CH:10]=[CH:11][C:12]2=3)[CH2:28][CH2:27]1)[CH3:6]
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Reactant: CC(=O)OCCBr
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
2-Bromoethyl acetate (267 mg, 1.6 mmol) was added dropwise to a stirred solution of 4-{8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene}piperidine (500 mg, 1.6 mmol) in THF (12 ml) and the reaction stirred at room temperature overnight. THF was removed under reduced pressure and the residue partitioned between ethylacetate and saturated sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulphate, filtered and solvent removed to leave a white solid. The product was purified by column chromatography on silica gel eluting with 5% methanol/DCM. Product containing fractions were combined and solvent removed to yield ethyl-(4-{8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)acetate as a white solid (214 mg, 34%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:24][C:25]1[CH:26]=[C:27]([CH2:31][CH2:32][NH2:33])[CH:28]=[CH:29][CH:30]=1.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:33][CH2:32][CH2:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[CH:26]=1)=[O:8]
Reactant: Cc1cccc(CCN)c1
Reactant: COc1cccc(C(=O)O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(=O)NCCc2cccc(C)c2)c1
Reaction time: 1 h

Procedure:
A solution of 3-methoxybenzoic acid (5.2 g, 0.034 mol) and carbonyldimidazole (5.5 g, 0.034 mol) in THF (200 ml) was stirred in a flask protected from moisture. To this solution was added 4.6 g (0.034 mol) of 2-(3-methylphenyl)ethylamine in a small volume of THF. Stirring was continued for 1 h and then the reaction mixture was poured into 500 ml of water and extracted twice with 100 ml portions of methylene chloride. The methylene chloride solution was washed with 5% HCl, 10% Na2CO3, and water. Evaportion of this solution afforded the amide G1 (8.7 g, 94%) as a viscous oil.