Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14](=O)[CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.B.C1COCC1>C1COCC1>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2cccnc2)CC1
Agent: B
Solvent: C1CCOC1
Product: c1cncc(CCN2CCNCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.3 %

Procedure:
1-Boc-4-[(3-pyridinyl)acetyl]piperazine (8.0 g, 26.2 mmol) was added to a solution of borane-THF (2.0 M in THF, 39.5 mL, 78.6 mmol) in THF (200 mL) at 0° C. The mixture was heated to reflux for 8 h and cooled to room temperature. The excess borane was quenched with methanol and 3 N HCl. The mixture stirred for 3 h at room temperature, and the solvents were removed under vacuum. The crude product was purified by chromatography (SiO2, 4:1 CH2Cl2:CMA) to provide 1-[2-(3-pyridinyl)ethyl]piperazine (2.82 g, 36%) as a light yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([NH2:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1.Cl>CCOC(C)=O>[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([NH:14][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:17]([NH2:16])=[CH:18][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(Br)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1ccc(N)cc1
Yield: 21.6 %

Procedure:
(S)-2-(4-Amino-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester (415 mg) was prepared from (S)-2-amino-3-(4-bromo-phenyl)-propionic acid methyl ester-hydrochloride (1.5 g, 5.1 mmol) and 4-amino-benzoic acid (698 mg, 5.1 mmol) as described in Procedure A, except for an adapted work-up. After reaction completion, the reaction mixture was poured onto 100 mL of 1N HCl and 100 mL of EtOAc. The organic layer was washed with 1N HCl (2×), 10% sodium carbonate, dried over sodium sulfate and evaporated. The crude material was purified over silica gel (DCM-EtOAc, 9-1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[C:38]([NH:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][N:10]3[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[CH:12][C:11]=23)=[CH:22][CH:23]=1)(=[O:29])=[O:28])(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: NS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3cc(C(F)(F)F)ccc23)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)NS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3cc(C(F)(F)F)ccc23)cc1
Yield: 29.9 %

Procedure:
A solution of 4-[2-(4-fluoro-phenyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridin-3-yl]benzenesulphonamide (0.185 g 0.42 mmol), triethylamine (0.4 ml), 4-dimethylaminopyridine (0.024 g 0.18 mmol) and acetic anhydride (0.12 ml 1.2 mmol) in chloroform (10 ml) was stirred at room temperature for 4 hr. The reaction mixture was washed with 2M hydrochloric acid (10 ml), M Na2CO3 (5 ml) and water (10 ml). Drying (MgSO4) and removal of solvent gave the title compound as a white solid (0.06 g 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Li+].[CH3:13][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:13])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C#N)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a −78° C. solution of (3,4-dichloro-phenyl)-acetonitrile (5.0 g, 26.9 mmol) in THF (60 mL) was added LHMDS (1 M in THF, 28.2 mL, 28.2 mmol). The reddish orange solution was stirred at −78° C. for 1 h and MeI (1.76 mL, 28.2 mmol) was added. The mixture was allowed to warm to rt overnight. The mixture was diluted with 1 M HCl (20 mL) and extracted with Et2O (3×). The combined organic layers were dried (MgSO4) and concentrated to provide a dark brown oil. The crude product was purified by flash chromatography (hexanes/EtOAc) to provide a colorless oil (5.0 g, 93%). 1H NMR (400 MHz, CDCl3): 7.52-7.42 (m, 2H), 7.25-7.18 (m, 1H), 3.88 (q, J=7.3, 1H), 1.64 (d, J=7.3, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].CC1C(N)C2C=C[S:30]C=2CC1>>[CH2:1]([C:3]1[C:4]([NH:11][CH:12]2[C:20]3[CH:19]=[CH:18][S:30][C:15]=3[CH2:16][CH2:17][CH:13]2[CH3:14])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CC1CCc2sccc2C1N
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1cnc(CC)c(NC2c3ccsc3CCC2C)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 5-methyl-4,5,6,7-tetrahydro-1-benzothien-4-ylamine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.66, 7.07, 6.91, 6.83, 5.62, 5.15, 4.46, 4.35, 3.09, 2.65–2.55, 2.28, 2.06–1.97, 1.80, 1.29, 1.11, 1.01; (MS/CI) calcd for C17H23N3S+H 301.6, found 301.9.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]2[NH:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.[C:21]([OH:27])([C:23]([F:26])([F:25])[F:24])=[O:22]>C(Cl)Cl>[F:19][C:16]([F:17])([F:18])[C:14]1[N:15]=[C:11]([C:8]2([NH2:7])[CH2:10][CH2:9]2)[NH:12][CH:13]=1.[C:21]([OH:27])([C:23]([F:26])([F:25])[F:24])=[O:22]
Reactant: CC(C)(C)OC(=O)NC1(c2nc(C(F)(F)F)c[nH]2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2nc(C(F)(F)F)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [1-(4-Trifluoromethyl-1H-imidazol-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester (32 mg, 0.11 mmol) in DCM (1 mL) was added TFA (500 uL). The clear solution was stirred at room temperature for overnight. Solvents were removed and the resulting materials were re-suspended in Toluene (15 mL) and concentrated down to dryness to provide the title compound 1-(4-Trifluoromethyl-1H-imidazol-2-yl)-cyclopropylamine as a TFA salt, m/z 192.41 [M+1]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32]O)=[CH:28][CH:27]=1>>[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:11]([C@@H:12]([C:13](=[O:14])[NH2:15])[C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: NC(=O)[C@H](NS(=O)(=O)c1ccc(Cl)cc1)c1ccc(F)cc1
Product: COC(=O)c1ccc(CN([C@@H](C(N)=O)c2ccc(F)cc2)S(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared employing the procedure in Example 2 using (R)-2-(4-chloro-benzenesulfonylamino)-2-(4-fluoro-phenyl)-acetamide and methyl-4-hydroxymethylbenzoate to afford the desired product. Diagnostic 13CNMR (100 MHz, CDCl3) 49.9, 52.3, 63.4, 116.0, 116.2, 127.9, 129.1, 129.5, 129.6, 132.0, 132.1, 139.8, 142.3. MS 491.2 m/z (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.C([NH2:13])=O.C(O)=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: NC=O
Reactant: CC(=O)c1ccc(Cl)cc1
Solvent: O=CO
Solvent: O
Product: CC(N)c1ccc(Cl)cc1
Temperature: 180 °C

Procedure:
A mixture of 4'-chloroacetophenone (103.3 g), formamide (98%; 123 g) and formic acid (97%; 8.3 ml) was stirred and heated at 180° C. The water produced in the reaction was removed by distillation together with some of the starting acetophenone which was separated and returned to the reaction vessel. Formic acid (70 ml total) was added in small aliquots over 8 hours. The reaction mixture was cooled and exhaustively extracted with toluene. The combined toluene extracts were washed with water, dried, filtered and the filtrate evaporated. Concentrated hydrochloric acid (70 ml) was added to the residue and the mixture boiled under reflux for 1 hour. The mixture was cooled, extracted with toluene and the aqueous layer basified with aqueous sodium hydroxide (5M). The solution was steam distilled until 1.4 1 of distillate had been collected and the distillate was extracted with ethyl acetate. The combined ethyl acetate extracts were dried, filtered and the filtrate evaporated to give an oil which was distilled to give (±)-1-(4-chlorophenyl)ethylamine, b.p. 120°-122° C. (19 mmHg). A small portion of the distillate was dissolved in dry ether and an equal volume of saturated ethereal hydrogen chloride was added. The solid formed was collected by filtration and dried to give (±)-1-(4-chlorophenyl)ethylamine hydrochloride, m.p. 186°-189° C.
Reaction SMILES: [OH-:1].[K+].[CH2:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1C=CC=CC=1>[CH2:3]([O:1][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: ClCc1ccccc1
Agent: [K+]
Solvent: c1ccccc1
Product: c1ccc(COCc2ccccc2)cc1
Yield: 190.5 %

Procedure:
A mechanically stirred mixture of 104 g (0.78 mole) of (R,S)-2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane, 500 ml of benzene, 86 g (1.53 mole) of powdered potassium hydroxide and 175 ml (1.52 mole) of benzyl chloride was refluxed for 17 hours while separating the condensed waterlayer (14 ml of water separated). After cooling the mixture was washed with water, 1M sodium hydrogen carbonate and brine respectively, dried with magnesium sulphate, filtered and evaporated to give 287 g of crude benzyl ether. This was stirred with a mixture of 300 ml of methanol, 100 ml of water and 20 ml of 36% hydrochloric acid for 1,5 hours. Next the mixture was neutralized with about 10 g of sodium hydroxide in water and concentrated in vacuum. The residue was extracted with diethyl ether and the extract was dried with magnesium sulphate, filtered and evaporated to give 163 g of residue. This was purified over silica to give 118 g of (R,S)-3 -benzyloxy-propane-1,2-diol.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][C:49]1[S:50][CH:51]=[CH:52][N:53]=1>C(Cl)Cl>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([O:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:14]([NH:48][C:49]3[S:50][CH:51]=[CH:52][N:53]=3)=[O:15])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reaction time: 0.25 h

Procedure:
2-(4-Cyclopropylsulfonylphenyl)-2-tetrahydropyran-4-yloxy-acetic acid (preparation 4; (1 equi.) and HATU (1.5 equi) was dissolved in DCM. To this solution was added D1PEA (2 equi.) and stirred for 15 minutes followed by addition of 2-aminothiazole (1 equi.) and continued to stir over night at room temperature. Reaction mixture was diluted with dichloromethane, washed with water, brine, dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to get the crude compound which was purified by flash chromatography to get the title product.
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[CH2:35]([O:42][CH2:43][C:44](Cl)=[O:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:42][CH2:43][C:44]([N:19]([CH2:18][C:17]1[CH:33]=[CH:34][C:14]([C:13]#[C:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:2][CH2:3][CH2:4][CH3:5])=[CH:11][CH:10]=2)=[CH:15][CH:16]=1)[C:20]1[CH:32]=[CH:31][C:23]2[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=2[CH:21]=1)=[O:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Reactant: O=C(Cl)COCc1ccccc1
Agent: Cl
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)COCc3ccccc3)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1

Procedure:
The titled compound was prepared following the procedure K using 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one hydrochloride and (benzyloxy)acetyl chloride as a yellow oil (88%). M+ (ESI): 588.5. HPLC, Rt: 5.76 min (Purity: 100%).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH:12][C:13]([N:15]2[CH2:19][C@@H:18]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@@:17]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[C@H:16]2[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=2[F:42])=[O:14])[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.O>[Cl:41][C:37]1[C:36]([F:42])=[C:35]([C@@H:16]2[C@:17]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[C@H:18]([CH2:20][C:21]([CH3:23])([CH3:24])[CH3:22])[CH2:19][N:15]2[C:13]([NH:12][CH2:11][CH:8]2[CH2:7][CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)=[O:14])[CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)C1CCC(CNC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1CN(C(=O)NCC2CCC(C(=O)O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
To a mixture of rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-cyclohexanecarboxylic acid methyl ester (65.0 mg, 0.105 mmol, example 21) in THF (4 mL) was added a solution of LiOH (Aldrich, 31.5 mg, 0.75 mmol) in water (2 mL) and the reaction mixture was stirred at rt for 6.5 hrs then more THF (2 mL) and water (1 mL) was added and stirred for 6 more hrs. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 5-6), extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]amino}-methyl)-cyclohexanecarboxylic acid (95.8 mg, 100%). HRMS (ES+) m/z Calcd for C31H35Cl2F2N3O3+H [(M+H)+]: 606.2097; Found: 606.2097.
Reaction SMILES: [CH2:1]([C:3]1[CH:13]=[C:6]2[C:7]([OH:12])=[CH:8][C:9]([F:11])=[CH:10][N:5]2[N:4]=1)[CH3:2].C(N(CC)CC)C.[F:21][C:22]([F:28])([F:27])[S:23](O)(=[O:25])=[O:24]>ClCCl>[CH2:1]([C:3]1[CH:13]=[C:6]2[C:7]([O:12][S:23]([C:22]([F:28])([F:27])[F:21])(=[O:25])=[O:24])=[CH:8][C:9]([F:11])=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CCc1cc2c(O)cc(F)cn2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc2c(OS(=O)(=O)C(F)(F)F)cc(F)cn2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound of Example 46 (2.88 g) was dissolved in dichloromethane (100 mL). To this solution, triethylamine (4.51 mL) was added, followed by addition of anhydrous trifluoromethanesulfonic acid (2.97 mL) at 0° C. The mixture was stirred at room temperature for 1 hour. Subsequently, the reaction was terminated by adding water and the mixture was extracted three times with ethylacetate. The organic layer was washed with saturated brine and dried over sodium sulfate. Evaporation of the solvent under reduced pressure and purification by silica gel column chromatography (hexane:ethyl acetate=20:1) afforded the title compound as a yellow oil (4.25).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:14](I)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[C-:25]#[N:26].[Na+]>O1CCCC1.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.[Cu]I>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:14]([C:25]#[N:26])=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Ic1cc2c(cc1OCc1ccccc1)CCN(C1CCC1)CC2
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cc2c(cc1OCc1ccccc1)CCN(C1CCC1)CC2

Procedure:
A mixture of 3-cyclobutyl-7-iodo-8-[(phenylmethyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E226) (250 mg, 0.58 mmol), tetrakis(triphenylphosphine)palladium (0) (33 mg, 0.029 mmol), copper (I) iodide (11 mg, 0.058 mmol) and sodium cyanide (56 mg, 1.15 mmol) in tetrahydrofuran (5 ml) was heated at reflux for 16 hours. The mixture was cooled and diluted with ethyl acetate, filtered through celite, washed with water then brine and dried over sodium sulfate and concentrated in vacuo. The crude mixture was purified by reverse phase HPLC to afford the title compound; MS (ES+) m/e 333 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[OH:22].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]1[CH:44]=[CH:43][CH:42]=[CH:41][C:32]=1[O:33][CH:34]([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[O:22][CH2:30][C:31]1[CH:44]=[CH:43][CH:42]=[CH:41][C:32]=1[O:33][CH:34]([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)C(C)Oc1ccccc1CBr
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccccc1COc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Yield: 72.5 %

Procedure:
Into 10 ml of N,N-dimethylformamide was dissolved 0.3 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidine-1-yl]phenol; 0.159 g of anhydrous potassium carbonate was added; 0.305 g of ethyl 2-[2-(bromomethyl)phenoxy]propionate was added at room temperature under stirring and the mixture was stirred overnight at room temperature. The reaction solution was poured into a mixture of ice and a saturated aqueous ammonium chloride solution and the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed once with a saturated aqueous ammonium chloride solution and once with saturated aqueous sodium chloride solution in turn, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give 0.35 g of ethyl 2-[2-({2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidine-1-yl]phenoxy}methyl)phenoxy]propionate [Compound 3-2].
Reaction SMILES: Cl.[C:2]([S:5][CH2:6][C:7]1[CH2:8][CH2:9][CH2:10][C:11]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:12]=2[CH:13]=1)(=[NH:4])[NH2:3].OS(C(F)(F)F)(=O)=O>C(O)(C(F)(F)F)=O>[Br:18][C:15]1[CH:16]=[CH:17][C:11]2[CH2:10][CH2:9][CH2:8][C@@H:7]3[CH2:6][S:5][C:2]([NH2:3])=[N:4][C@@H:13]3[C:12]=2[CH:14]=1
Reactant: N=C(N)SCC1=Cc2cc(Br)ccc2CCC1
Agent: Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@H]2c3cc(Br)ccc3CCC[C@@H]2CS1
Temperature: 25 °C
Reaction time: 18 h
Yield: 111.6 %

Procedure:
To a solution of 2-bromo-8-(chloromethyl)-6,7-dihydro-5H-benzo[7]annulene from step A6 (60 mg, 0.221 mmol) in ethanol (1 mL) was added thiourea (16.82 mg, 0.221 mmol). The mixture was heated at reflux for 4 h. The solvent was removed, and the solid residue was triturated with hexanes and dried in vacuo to give (2-bromo-6,7-dihydro-5H-benzo[7]annulen-8-yl)methyl carbamimidothioate hydrochloride (70 mg, 0.201 mmol, 91% yield). To a solution of (2-bromo-6,7-dihydro-5H-benzo[7]annulen-8-yl)methyl carbamimidothioate, hydrochloride (60 mg, 0.173 mmol) in TFA (1 mL) was added triflic acid (0.2 mL) at 0° C. The mixture was stirred at rt for 18 h and then heated to 80° C. for 4 h. Another 2 mL of TFA and 0.2 mL of trifilic acid were added, and the mixture was stirred at 60° C. for 20 h. The solvent was removed. The residue was dissolved in 50 mL of EtOAc and the organic layer was washed with saturated sodium bicarbonate/water, dried over sodium sulfate, filtered, and concentrated in vacuo to afford crude product (60 mg, 0.193 mmol, 112% yield), which was used for the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:4]=2[S:5][CH:6]=1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[F:20].O>CN1CCCC1=O>[F:11][C:8]1[CH:9]=[CH:10][C:3]2[C:2]([NH:1][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[CH:6][S:5][C:4]=2[CH:7]=1
Reactant: Nc1csc2cc(F)ccc12
Reactant: Fc1cnccc1Cl
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: Fc1ccc2c(Nc3ccncc3F)csc2c1
Yield: 82.6 %

Procedure:
A solution of 3-amino-6-fluorobenzo[b]thiophene (10 g, 60 mmol) and 4-chloro-3-fluoropyridine hydrochloride (12 g, 71 mmol) in 150 mL of 1-methyl-2-pyrrolidinone was stirred at 90-95° for 2.5 h, and thereafter cooled, stirred with water and extracted with ether. The aqueous layer was basified with 30% aqueous ammonium hydroxide and extracted with ether. The organic extract was washed with water and saturated sodium chloride solution, and dried (anhydrous magnesium sulfate), filtered and concentrated to give 13 g of a solid. Elution through silica with 10% ethyl acetate in dichloromethane via flash column chromatography yielded 7 g (44.6%) of a white solid, mp 155-157° C. Recrystallization of 2 g from acetonitrile afforded 1.3 g (29%) of white needles, mp 158-159° C.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]1N=N[N:19]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=1)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[CH3:40][N:41]1[C:45](=[O:46])[CH:44]=[CH:43][C:42]1=[O:47]>C1(C)C(C)=CC=CC=1>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]1[C@@H:44]3[C:45](=[O:46])[N:41]([CH3:40])[C:42](=[O:47])[C@@H:43]3[N:19]([C:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:20]=1)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)ccc2[nH]1
Reactant: CN1C(=O)C=CC1=O
Solvent: Cc1ccccc1C
Product: CCCCc1nc(=O)c2cc(C3=NN(C(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]4C(=O)N(C)C(=O)[C@@H]34)ccc2[nH]1
Temperature: 25 °C
Yield: 86.1 %

Procedure:
A mixture of 1.0 g of 2-Butyl-6-[2-(triphenylmethyl)-2H-tetrazol-5-yl]-4(1H)-quinazolinone and 1.0 g of N-methylmaleimide is heated at reflux in xylene for 6 hours. The reaction mixture is cooled to room temperature and evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 50% ethyl acetate-hexanes to give 1.0 g of the desired product as a yellow solid, m.p. 182° C.