Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[C:3]1(C)[CH:8]=CC=C[CH:4]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[O:12].C(Br)C#C>C1COCC1.CCOCC.[Zn].C(Br)C#C>[CH2:15]([O:14][C:10](=[O:13])[CH:11]([OH:12])[CH2:8][C:3]#[CH:4])[CH3:16]
Reactant: Cc1ccccc1
Reactant: CCOC(=O)C=O
Agent: C#CCBr
Agent: N#N
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CCC(O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
Propargyl bromide (˜10 g) was added under a blanket of N2 to a 3-L round bottom flask containing 350 mL anhydrous THF and Zn (230 g, 3.5 mol). The mixture was stirred at room temperature for 30 min and then cooled in an ice bath. A toluene solution of ethyl glyoxylate (51 wt %, determined by NMR, 473 g, 2.36 mol) and a toluene solution of propargyl bromide (80 wt %, 352 g, 2.36 mol) were combined in 500 mL dry THF and 700 mL dry ether. This mixture was then added dropwise to the stirred slurry. After the addition was complete, the mixture was stirred at 0° C. overnight. The reaction mixture was then poured into a 4-L Erlenmeyer flask containing 1 L of ice-cold 3M HCl. After separation of the organic layer, the aqueous layer was extracted with ether (3×300 mL) and the combined organic layers were dried over MgSO4. Filtration and removal of the solvents by rotary evaporation gave a dark blue oil, which was purified by column chromatography using silica gel with EtOAc/hexanes (30/70) as the eluent. Vacuum distillation of the resulting material (50-55° C./100 mTorr) gave the ester 2 as a colorless oil (170 g, 51%). 1H NMR δ 4.25 (m, 3H), 3.11 (d, 1H, J=6.4 Hz), 2.65 (m, 2H), 2.03 (t, 1H, J=2.7 Hz), 1.28 (t, 3H, J=7.2 Hz). 13C NMR δ 172.99, 78.53, 71.25, 68.64, 62.11, 24.81, 14.13.
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:28][C:27]=2[O:38][CH3:39])[C:22]([Cl:40])=[CH:21][N:20]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(O)(C)C>[Cl:40][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:28][C:27]=2[O:38][CH3:39])=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: COc1cc2c(cc1N)C(C)(C)CCC(=O)N2
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCOCC4)cc3OC)n1)C(C)(C)CCC(=O)N2
Yield: 41.2 %

Procedure:
7-Amino-8-methoxy-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (59 mg, 0.25 mmol), (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (89 mg, 0.25 mmol), and 10-Camphorsulfonic acid (59 mg, 0.25 mmol) in Isopropyl alcohol (4 mL) were irradiated at 120° C. for 40 min in a CEM microwave. The sample was cooled, treated with MP-carbonate resin, filtered and conc. in vacuo. Silica gel chromatography afforded 7-[5-Chloro-4-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-2-ylamino]-8-methoxy-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a white solid (57 mg, 41%). MP: 246-248° C., LCMS: 553 (M+H); 1H-NMR, CDCl3: 8.39 (s, 1H), 8.26 (d, 1H, J=8.8 Hz), 8.08 (s, 1H), 7.60 (s, 1H), 7.25 (m, 1H), 7.06 (s, 1H), 6.55 (s, 1H), 6.47 (m, 1H), 6.45 (s, 1H), 3.94 (s, 3H), 3.89 (m, 7H), 3.14 (m, 4H), 2.40 (t, 2H, J=7.0 Hz), 2.10 (t, 2H, J=7.0 Hz), 1.32 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[NH:10]1[CH2:14][CH2:13][N:12]=[C:11]1S(O)(=O)=O.C(O)C(C)C>C(Cl)(Cl)Cl>[CH:7]1[CH:8]=[C:2]([Cl:1])[C:3]([NH:4][C:11]2[NH:12][CH2:13][CH2:14][N:10]=2)=[C:5]([Cl:9])[CH:6]=1
Reactant: O=S(=O)(O)C1=NCCN1
Reactant: Nc1c(Cl)cccc1Cl
Solvent: ClC(Cl)Cl
Solvent: CC(C)CO
Product: Clc1cccc(Cl)c1NC1=NCCN1
Temperature: 125 °C
Yield: 64 %

Procedure:
A mixture of 2,6-dichloroaniline (0.162 g, 1 mmol), imidazoline-2-sulfonic acid (0.30 g, 2 mmol) and isobutanol (3 ml) was heated to 125° C. and maintained at this temperature for 16 hours. The mixture was then cooled to room temperature, diluted with CHCl3 (10 ml) and washed twice with 2 ml of aqueous 1 N NaOH. The organic extracts were combined, dried over MgSO4 and concentrated in vacuo to yield a solid which was chromatographed (silica gel, 10:1 CHCl3 /CH3OH saturated with NH3 (g)) to yield 0.147 g (a yield of 64%) of the title compound as a white solid, which was characterized spectroscopically.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[C:4]([CH3:9])[CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:9][C:4]1[CH:3]=[C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:6][C:5]=1[CH:7]=[O:8]
Reactant: Cc1cc(Br)sc1C=O
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2ccccc2)sc1C=O
Yield: 62.8 %

Procedure:
A mixture of 5-bromo-3-methylthiophene-2-carbaldehyde (2.1 g), phenylboronic acid (1.5 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.3 g, 66%) as a yellow crystal.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(-c2ccccc2)ncc1[N+](=O)[O-]
Yield: 88.2 %

Procedure:
A mixture of 2 g (11.59 mmol) of 2-chloro-4-methyl-5-nitropyridine, 1.41 g (11.59 mmol) of phenylboronic acid, 1.33 g (1.16 mmol) of tetrakis(triphenylphosphine)palladium and 4 g (28.97 mmol) of potassium carbonate suspended in 50 ml of degassed dioxane is refluxed for 12 hours. The mixture is then cooled, diluted with 50 ml of ethyl acetate, successively washed twice with 20 ml of water and then with 20 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica (eluents: heptane/ethyl acetate) and then recrystallized from an isopropanol/isopropyl ether mixture. 2.19 g of a yellow solid are thus isolated, and are used without further purification in the following synthesis.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11]([NH2:14])(=[O:13])=[O:12])[C:4]=2[S:3]1.C[Al](C)C.[CH3:20][O:21][C:22]1[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:29][C:30](=O)[O:31]C)[N:23]=1.C(O)(=O)C>C(Cl)Cl.Cl>[CH3:20][O:21][C:22]1[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:29][C:30]([NH:14][S:11]([C:10]2[C:4]3[S:3][C:2]([CH3:15])([CH3:1])[S:6][C:5]=3[CH:7]=[CH:8][CH:9]=2)(=[O:13])=[O:12])=[O:31])[N:23]=1
Reactant: COC(=O)Nc1nc(C)nc(OC)n1
Reactant: CC1(C)Sc2cccc(S(N)(=O)=O)c2S1
Agent: C[Al](C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cccc3c2SC(C)(C)S3)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2.6 g 2,2-dimethyl-1,3-benzodithiole-4-sulfonamide prepared in Example 7, in 60 ml methylene chloride at room temperature under nitrogen is added 5.5 ml trimethylaluminum (2M in toluene). After stirring 15 minutes at room temperature, 2.0 g of methyl [4-methoxy-6-methyl-1,3,5-triazin-2-yl]carbamate, prepared according to the procedure of Example 5, was added and the reaction mixture was heated at reflux for 72 hours. The reaction mixture was cooled to room temperature and 75 ml ice, 3 ml glacial acetic acid, and 10 drops of hydrochloric acid were sequentially added. The organic phase was separated, dried and the solvent removed under reduced pressure to give an oil. Crystallization of the oil from an appropriate solvent gave a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1F)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:28]([NH2:30])[CH3:29]>>[C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[NH:30][CH2:28][CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1F)C(=O)OC(C)(C)C
Agent: Cl
Product: CCNc1ccc([N+](=O)[O-])cc1CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 52 %

Procedure:
Using the compound obtained in Example 263 as a starting material and also using ethylamine hydrochloride as a reagent, the same procedure of Example 264 gave the titled compound (yield, 52%).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].N1C=CC=CC=1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:15]>C(Cl)Cl>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][C:14]([O:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])=[O:15])=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: COC(=O)CO
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.6 %

Procedure:
A mixture of 640 mg of methyl glycolate, 0.60 mL of pyridine, and 10 mL of methylene chloride was added to 10 mL of a methylene chloride solution including 1.44 g of 4-nitrophenyl chloroformate at room temperature, followed by stirring for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and diethyl ether and water were added to the residue and an organic layer was separated. The organic layer was sequentially washed with water and saturated brine and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (using chloroform only), thereby obtaining 320 mg of methyl {[(4-nitrophenoxy)carbonyl]oxy}acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[C:18](Cl)(=[O:20])[CH3:19].N1C=CC=CC=1>CCOCC>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]([C:3]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:2]=1[NH:1][C:18](=[O:20])[CH3:19])=[O:5]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Preparation 1, 2-amino-2',5-dichlorobenzophenone, acetyl chloride and pyridine were reacted in ether to give 2'-(o-chlorobenzoyl)-4'-chloroacetanilide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])=O.CN1CCOCC1.ClC(OC)=O.ClC([O-])=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[O:10][C:9](=[O:11])[CH2:8][N:7]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=C(O)CNC(=O)c1ccc(F)c(F)c1
Agent: COC(=O)Cl
Agent: O=C([O-])Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C1CN=C(c2ccc(F)c(F)c2)O1
Temperature: -10 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of 2-(3,4-difluorobenzamido)acetic acid (5.18 g, 24.1 mmol) in THF (25 mL) in a 100 mL round-bottomed flask was added 4-methylmorpholine (2.44 g, 24.1 mmol) to give a colorless solution. The solution was cooled to −10° C. and methyl chloroformate (2.28 g, 24.1 mmol) was added slowly over the course of thirty minutes while maintaining the solution at −10° C. A white precipitate started to form almost immediately and the solution became increasingly orange in color. Once the addition of chloroformate was complete the solution was stirred at −10° C. for 1 hour and warmed to room temperature over the course of an hour. The solution was filtered through a glass frit and the remaining solid was washed thoroughly with THF until colorless. The combined filtrate was evaporated under reduced pressure to provide 2-(3,4-difluoro-phenyl)oxazol-5(4H)-one as a light orange solid (4.5 g, 95%). LCMS (+ESI) m/z 198.2 [M+H]+. 1H-NMR (CDCl3) δ 7.85 (m, 1H), 7.78 (m, 1H), 7.30 (m, 1H), 4.45 (s, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:22][OH:23])[C:8]([O:20][CH3:21])=[C:9]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26]1.C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]([CH2:22][OH:23])[C:8]([O:20][CH3:21])=[C:9]([NH:11][C:12]([NH:24][CH:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:19])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1c(CO)cc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Reactant: NC1Cc2ccccc2C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(CO)cc(C(C)(C)C)cc1NC(=O)NC1Cc2ccccc2C1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
To a solution of 2,2,2-trichloroethyl 5-tert-butyl-3-(hydroxymethyl)-2-methoxyphenylcarbamate (0.096 g, 0.250 mmol) and 2-aminoindane (0.033 g, 0.248 mmol) in acetonitrile (1.0 mL), N,N-diisopropylethylamine (0.065 mL, 0.38 mmol) was added, and the mixture was stirred at 70° C. for 12 hours. The reaction mixture was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=0/100-60/40) to obtain 0.092 g (quantitative) of the captioned compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:29]1[C:37]2[C:32](=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30]1>>[NH:29]1[C:37]2[C:32](=[C:33]([C:2]3[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]4[N:11]=[C:10]([CH2:12][N:13]5[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]5)[CH:9]=[CH:8][C:6]=4[N:7]=3)[CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30]1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: OB(O)c1cccc2[nH]ccc12
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-c4cccc5[nH]ccc45)nc(N4CCOCC4)c3n2)CC1

Procedure:
2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (88 mg) was reacted with 1H-indol-4-ylboronic acid via General Procedure A to produce 22.8 mg of 109 following reverse phase HPLC purification. MS (Q1) 487.3 (M)+
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([NH:24]C1C=C(B(O)O)C=CC=1)(=[O:23])[CH3:22]>>[O:20]=[C:19]1[C:13]2[C:14]3[C:15](=[C:7]([C:1]4[CH:2]=[C:3]([NH:24][C:21](=[O:23])[CH3:22])[CH:4]=[CH:5][CH:6]=4)[NH:8][C:9]=3[CH:10]=[CH:11][CH:12]=2)[CH2:16][CH2:17][NH:18]1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Product: CC(=O)Nc1cccc(-c2[nH]c3cccc4c3c2CCNC4=O)c1

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 3-acetamidophenylboronic acid (304 mg, 1.70 mmol) were coupled to yield N-[3-(6-Oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-phenyl]-acetamide, 10 mg (3%) as a clear solid: m.p. 300.5-302.0° C.; 1H NMR (300 MHz, d6-DMSO) δ 2.09 (s, 3H), 3.05 (m, 2H), 3.36 (m, 2H), 7.21 (app t, J=7.8 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.57 (m, 2H), 7.68 (d, J=7.5 Hz, 1H), 7.92 (br s, 1H), 8.08 (br t, 1H), 10.10 (br s, 1H), 11.56 (br s, 1H). MS (FAB, MH+) 320. Anal. (C19H17N3O2) C, H, N.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH:10]([CH3:28])[CH2:9]1)=O)(C)(C)C.[F:29][C:30]1[CH:31]=[C:32]([CH2:37][CH2:38][NH2:39])[CH:33]=[C:34]([F:36])[CH:35]=1>>[F:29][C:30]1[CH:31]=[C:32]([CH2:37][CH2:38][NH:39][C:23]2[N:22]=[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][N:11]4[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]4[CH3:28])[CH:16]=3)[CH:26]=[CH:25][N:24]=2)[CH:33]=[C:34]([F:36])[CH:35]=1
Reactant: NCCc1cc(F)cc(F)c1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(Cl)n2)c1
Product: C[C@@H]1CNCCN1Cc1cccc(-c2ccnc(NCCc3cc(F)cc(F)c3)n2)c1

Procedure:
Intermediate 111 was coupled with 2-(3,5-difluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 425. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.72 (s, 1H), 8.36 (t, 2H), 7.97 (d, 1H), 7.73 (d, 1H), 7.69 (d, 1H), 7.01 (d, 2H), 6.72 (s, 1H), 4.43 (d, 1H), 4.05 (m, 3H), 3.55 (m, 6H), 3.39 (m, 1H), 3.06 (t, 2H), 1.77 (d, 3H).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1.[Cl:17]([O-])(=O)=O.[Na+].S(=O)(O)[O-].[Na+]>Cl.C(O)(=O)C.O>[Cl:17][CH:2]1[CH2:3][CH:4]([CH2:7][C:8]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:9])[CH2:5][CH2:6][CH2:1]1
Reactant: [O-][Cl+2]([O-])[O-]
Reactant: O=C(CC1CCCCC1)Nc1ccccc1
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(CC1CCCC(Cl)C1)Nc1ccccc1
Temperature: 25 °C

Procedure:
4-Cyclohexylacetanilide (24 g, 110 mmol) is dissolved in a mixture of concentrated HCl (25 mL) and acetic acid (75 mL). The mixture is cooled in an ice bath and a solution of sodium chlorate (NaClO3, 7.5 g, 70 mmol) in water (30 mL) is added via a dropping funnel. The reaction is allowed to warm to room temperature and then poured into saturated sodium bisulfite solution (500 mL). The solid which forms is isolated by filtration and subsequently washed first with water (500 mL) and then a mixture of hexanes/Et2O (10:1, 500 mL). The resulting solid is air dried to yield 2-chloro-4-cyclohexylacetanilide (m.p. 110–112° C.).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)[CH2:7][OH:8])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:33][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: CC(=O)OCC(CO)c1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(COS(=O)(=O)c1ccc(C)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a solution of (−)-2-(4-bromophenyl)-3-hydroxypropyl acetate (5.88 g, 21.5 mmol) in dichloromethane (100 ml) was added triethylamine (5.45 g, 53.8 mmol), p-toluenesulfonyl chloride (4.93 g, 25.8 mmol) and 4-dimethylaminopyridine (0.263 g, 2.15 mmol) at 0° C. The mixture was stirred at room temperature for 2 hours and partitioned between saturated ammonium chloride solution and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=4/1) to afford (+)-3-acetoxy-2-(4-bromophenyl)propyl 4-methyl-benzenesulfonate as colorless oil (8.32 g, 90%). [α]D=+1.63 (C=0.5, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([CH2:15][CH3:16])([OH:14])[C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:19]([N:23]=[C:24]=[O:25])[CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:15][CH3:16])([OH:14])[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:24](=[O:25])[NH:23][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=2)=[CH:17][CH:18]=1
Reactant: CCC(O)(c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: CCCCN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCNC(=O)Oc1ccc(C(O)(CC)c2ccc(Cl)cc2)cc1
Reaction time: 20 h

Procedure:
7.9 g. of 4-chloro-4'-hydroxy-α-ethyl-benzhydrol, 3.3 g. of n-butyl-isocyanate and 0.3 ml. of triethyl amine are dissolved in 40 ml. of dry tetrahydrofurane under stirring at 25° C., and the solution is allowed to stand at this temperature for 20 hours. When the reaction is complete, tetrahydrofurane is distilled off under reduced pressure, the residue is taken up in ether, the ethereal solution is shaken with a 5% aqueous sodium hydroxide solution and washed to neutral with water. The organic phase is dried over anhydrous magnesium sulfate, filtered and ether is distilled off in vacuo. Crystallization of the residue from a mixture of n-hexane and ethyl acetate yields 9.3 g. of the named compound, which melts at 78° to 79° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[C:5]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(C)ccc1-n1nccn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-n2nccn2)c(C(=O)O)n1

Procedure:
A solution of methyl 6-methyl-3-(2H-1,2,3-triazol-2-yl)-2-pyridinecarboxylate D39 (36 mg) and LiOH (5.93 mg, 0.247 mmol) in THF/water (2:1, 3 ml) was stirred overnight. The mixture was evaporated under reduced pressure; the residue was taken up in water (2 ml) and neutralised with 1 M HCl water solution and then loaded onto a pre-conditioned C18 5 g column (the column was eluted with water and then MeOH). The methanol fractions were evaporated under reduced pressure to give the title compound D40 (34 mg) as a white solid. UPLC (Basic QC_POS—50-800): rt=0.30 minutes. peak observed: 205 (M+1). C9H8N4O2 requires 204. 1H NMR (400 MHz, MeOD) δ (ppm) 8.24 (d, 1 H), 7.99 (s, 2 H), 7.61 (d, 1 H), 2.67 (s, 3 H).
Reaction SMILES: Br[CH:2]([CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([F:17])([F:16])[C:8]([F:19])([F:18])[C:7]2[CH:20]=[CH:21][CH:22]=[CH:23][C:6]1=2)[CH2:3][CH3:4].[NH3:24]>>[F:19][C:8]1([F:18])[C:7]2[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=2[CH:5]([CH2:2][CH2:3][CH2:4][NH2:24])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]1([F:17])[F:16]
Reactant: N
Reactant: CCC(Br)C1c2ccccc2C(F)(F)C(F)(F)c2ccccc21
Product: NCCCC1c2ccccc2C(F)(F)C(F)(F)c2ccccc21

Procedure:
A mixture of 1 gram of 5-(1-bromopropyl)-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene and 20 ml. of liquid ammonia is heated in a sealed tube at 100°C. for 8 hours. After cooling, the ammonia is allowed to evaporate at room temperature and the residual product diluted with ether and the ethereal solution of the product washed with water, dried, and concentrated to leave as a residue 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-propylamine.