Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:54]1[CH:55]=[C:56]([C:62]2[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=2)[CH:57]=[CH:58][C:59]=1[CH2:60][CH3:61]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:68][C:65]1[CH:66]=[CH:67][C:62]([C:56]2[CH:55]=[CH:54][C:59]([CH2:60][CH3:61])=[C:58]([CH:3]3[C:4](=[O:9])[CH:5]4[CH2:8][CH:1]([CH2:7][CH2:6]4)[C:2]3=[O:10])[CH:57]=2)=[CH:63][CH:64]=1
Reactant: O=C1CC(=O)C2CCC1C2
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C2CCC(C2)C1=O
Temperature: 160 °C

Procedure:
To a microwave vial containing bicyclo[3.2.1]octane-2,4-dione (0.112 g, 0.812 mmol), palladium (II) acetate (7.6 mg, 0.034 mmol), 2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (24.2 mg, 0.051 mmol), and finely ground potassium phosphate (0.316 g, 1.49 mmol) is added degassed dimethoxyethane (2 ml), then 3-bromo-4′-chloro-4-ethylbiphenyl (0.200 g, 0.667 mmol). This reaction mixture is then heated at 160° C. under microwave irradiation for 60 minutes, then cooled to room temperature and washed with 2M hydrochloric acid (2 ml) and extracted with ethyl acetate (3×3 ml). The organic phase is dried over magnesium sulfate, filtered, and the filtrate concentrated in vacuo. The crude mixture is purified by flash column chromatography on silica gel (30% to 100% ethyl acetate/hexane eluant ratio) to afford 3-(4′-chloro-4-ethylbiphen-3-yl)bicyclo[3.2.1]octane-2,4-dione.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[O:15][CH:16]([F:18])[F:17])[C:9](Cl)=[O:10])[CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:39])[C:25]=1[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)=[O:28]>>[Cl:39][C:24]1[CH:23]=[N:22][CH:21]=[C:20]([Cl:19])[C:25]=1/[CH:26]=[C:27](\[O:28][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:14]([O:15][CH:16]([F:18])[F:17])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH:7]=1)/[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1
Reactant: O=C(Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC
Product: COc1ccc(/C(=C/c2c(Cl)cncc2Cl)OC(=O)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC

Procedure:
The compound was obtained starting from 3-cyclopropylmethoxy-4-difluoromethoxy -benzoyl chloride and 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy -phenyl)-ethanone, following the procedure of Example 7.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[C:7]([NH:9][CH:10]1[CH2:12][CH2:11]1)=[O:8].N1C=CC=CC=1.[Cl:21][C:22]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:33]([C:35]2[S:36][C:37]([Cl:40])=[CH:38][CH:39]=2)=[O:34])=[CH:27][C:23]=1[C:24](Cl)=[O:25]>C(#N)C.O>[Cl:14][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:24](=[O:25])[C:23]2[CH:27]=[C:28]([CH2:31][NH:32][C:33]([C:35]3[S:36][C:37]([Cl:40])=[CH:38][CH:39]=3)=[O:34])[CH:29]=[CH:30][C:22]=2[Cl:21])=[CH:13][C:6]=1[C:7]([NH:9][CH:10]1[CH2:11][CH2:12]1)=[O:8]
Reactant: Nc1ccc(Cl)c(C(=O)NC2CC2)c1
Reactant: O=C(NCc1ccc(Cl)c(C(=O)Cl)c1)c1ccc(Cl)s1
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: O=C(NCc1ccc(Cl)c(C(=O)Nc2ccc(Cl)c(C(=O)NC3CC3)c2)c1)c1ccc(Cl)s1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To 2.0 mL of a 0.05 M solution of 5-amino-2-chloro-N-cyclopropyl-benzamide (0.10 mmol) in acetonitrile was added pyridine (20 μL, 0.25 mmol) and then 1.0 mL of a 0.05 M solution of 2-chloro-5-(5-chloro-thien-2-yl)carbonylaminomethyl-benzoyl chloride (0.10 mmol, prepared from 5-(aminomethyl)-2-chloro-benzoic acid in analogy to step 1c and 1d) in acetonitrile. The reaction mixture was stirred overnight at 60° C., diluted with 200 μL of distilled water and filtered over Alox B. The Alox B pad was washed three times with 2.0 mL 9:1 DMF/MeOH-solution and the combined filtrate was concentrated in vacuo. The residue was dissolved in 2.0 mL of DMF and purified via prep. HPLC.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[CH:8](OC(=O)C)[O:7][C@@H:6]1[C:18]1[CH:22]=[C:21]([CH2:23][CH3:24])[O:20][N:19]=1)(=[O:3])[CH3:2].[Cl:25][C:26]1[N:34]=[C:33]2[C:29]([NH:30][CH:31]=[N:32]2)=[C:28]([Cl:35])[N:27]=1.N12CCCN=C1CCCCC2.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(#N)C>[C:11]([O:10][C@@H:9]1[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@@H:6]([C:18]2[CH:22]=[C:21]([CH2:23][CH3:24])[O:20][N:19]=2)[O:7][C@H:8]1[N:32]1[CH:31]=[N:30][C:29]2[C:33]1=[N:34][C:26]([Cl:25])=[N:27][C:28]=2[Cl:35])(=[O:13])[CH3:12]
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CCc1cc([C@H]2OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)no1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1cc([C@H]2O[C@@H](n3cnc4c(Cl)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)no1
Temperature: 60 °C
Reaction time: 21 h

Procedure:
(2R,3 R,4R)-4,5-bis(acetyloxy)-2-(5-ethyl isoxazol-3-yl)tetrahydrofuran-3-yl acetate isomer 1 (193 mg) was dissolved in acetonitrile (5 ml) and treated sequentially with 2,6-dichloropurine (213 mg), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.186 ml) and trimethylsilyl trifluoromethanesulphonate (TMSOTf) (0.225 ml) via a syringe over 5 min. The clear yellow solution was stirred at 22° C. for 40 h, at 60° C. for 21 h, and at 80° C. for 6 h. The mixture was cooled to room temperature and more DBU (0.186 ml) and TMSOTf (0.225 ml) were added. After stirring at 22° C. for 36 h the yellow mixture was heated at 60° C. overnight and at 80° C. for 6 h. The solvents were removed in vacuo and the resultant brown oily solid taken up in ethyl acetate and washed with water (20 ml, 3:1). The aqueous layer was extracted with ethyl acetate and the combined organic layers dried (MgSO4) and evaporated in vacuo to afford a brown oily solid. The residue was triturated with dichloromethane and a white solid removed by filtration. Evaporation of the filtrate afforded a tan solid. Purification by flash chromatography on silica gel eluting with ether:cyclohexane (1:1) afforded the title compound as a white solid (161 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH:10]=1)[CH:8]=O.Cl.[CH3:14][NH:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.C(N(CC)CC)C.[BH4-].[Na+]>CO>[CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH2:8][N:15]([CH3:14])[CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)[CH:10]=1
Reactant: CNCCc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)c1ccc(O)c(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(CCc1ccc([N+](=O)[O-])cc1)Cc1cc(N(C)C)ccc1O
Temperature: 0 °C
Yield: 34 %

Procedure:
0.5 g (3 mmol) of 5-(dimethylamino)-2-hydroxybenzaldehyde (Bull. Chem. Soc. Jpn. (1978), 51 (8), 2433–2434) and 0.72 g (3.33 mmol) of N-methyl2-(4-nitrophenyl)ethylamine hydrochloride are placed in solution in 30 ml of anhydrous methanol under an inert atmosphere in the presence of 0.65 ml of triethylamine (4.5 mmol). The reaction mixture is stirred vigorously for 18 hours before the addition, by portions, of 126 mg (3.33 mmol) of NaBH4. Stirring is maintained for a further 4 hours before adding 10 ml of ice-cold water. The reaction mixture is extracted twice with 50 ml of CH2Cl2. The organic phase is washed with 10 ml of water, dried over sodium sulphate, filtered and concentrated under vacuum. The residue is purified on a silica column (eluent: CH2Cl2/MeOH: 97/3). The expected product is obtained in the form of a brown oil with a yield of 34% (0.34 g).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[O:18][CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:20](=O)(=[O:23])([OH:22])[OH:21].O.C(=O)(O)[O-].[Na+]>CCCCCC.C(OCC)(=O)C.C(OCC)(=O)C>[CH3:19][O:18][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:17][C:8]=1[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: COc1c(Cc2ccccc2)ccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(Cc2ccccc2)cc(S(=O)(=O)O)c2ccccc12
Reaction time: 2 h
Yield: 52 %

Procedure:
The product of Example 94 Part A (3.0 g, 0.012 mole) was added in portions to concentrated sulfuric acid (10 ml) at -10°. The mixture was stirred at -10° for 2 hours and poured into water. Sodium bicarbonate (1.0 g) was added, and the crude product was isolated by extraction with ethyl acetate. The title compound (2.0 g, 52%) was obtained as a brown oil after chromatography (1:1 hexane/ethyl acetate; then 99:1 ethyl acetate/acetic acid; then methanol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH3:25][NH:26][C:27]([N:29]1[C:37]2[C:32](=[CH:33][C:34]([O:38][C:39]3[CH:44]=[CH:43][N:42]=[C:41]([NH:45][C:46]([N:48]4[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]4)=[O:47])[CH:40]=3)=[CH:35][CH:36]=2)[CH:31]=[CH:30]1)=[O:28]>ClCCl>[CH3:25][NH:26][C:27]([N:29]1[C:37]2[C:32](=[CH:33][C:34]([O:38][C:39]3[CH:44]=[CH:43][N:42]=[C:41]([NH:45][C:46]([N:48]4[CH2:53][CH2:52][CH:51]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[CH2:50][CH2:49]4)=[O:47])[CH:40]=3)=[CH:35][CH:36]=2)[CH:31]=[CH:30]1)=[O:28]
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(=O)CC4)c3)ccc21
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(N5CCOCC5)CC4)c3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
Morpholine (228 mg, 1.64 mmol), sodium triacetoxyborohydride (372 mg, 1.76 mmol), and acetic acid (0.134 ml, 2.34 mmol) were added to a dichloromethane (3.5 ml) solution of N1-methyl-5-(2-(4-oxopiperidin-1-ylcarbonyl)amino-4-pyridyl)oxy-1H-1-indolecarboxamide (476 mg) synthesized in Example 40, and stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure; and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate-methanol system). The resultant was washed with a solvent mixture of ether-hexane=1:1; and the solid was filtered off to yield the title compound (110 mg) as crystals.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:18][CH:19]([SH:21])[CH3:20].CC(C)([O-])C.[Na+]>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH:19]([S:21][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1)([CH3:20])[CH3:18]
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Reactant: CC(C)S
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)Sc1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
A mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (725 mg, 2.5 mmol), propane-2-thiol (281 mg, 3.75 mmol), palladium(II) acetate (11.2 mg, 0.05 mmol), 1,1′-bis(diphenylphosphino)ferrocene (33.4 mg, 0.06 mmol) and sodium tert-butoxide (480 mg, 5.0 mmol) in dioxane (5 mL) was stirred at 100° C. overnight under nitrogen. The reaction mixture was diluted with ethyl acetate (10 mL) and filtered. The solid was extracted with ethyl acetate (20 mL×3). The organic layer was combined, dried with sodium sulfate, filtered and concentrated in vacuo. It was purified by prep-HPLC to give the product (130 mg, 19%). LCMS (ESI): RT (Min)=1.285, M+H =286.9, method=A; 1H NMR (MeOD-d4, 400 MHz): δ 8.96 (s, 1H), 8.36 (s, 1H), 7.96 (t, J=0.8 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.65 (dd, J=2.0, 8.8 Hz, 1H), 3.59-3.55 (m, 1H), 1.93-1.91 (m, 1H), 1.33 (d, J=6.4 Hz, 6H), 1.01-0.99 (m, 2H), 0.91-0.89 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br-:13].[K+].B1([O-])OO1.O.O.O.O.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.N.N.N.N.N.N.O.O.O.O.O[Mo](O)(=O)=O.O[Mo](O)(=O)=O.O[Mo](O)(=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O>[Br:13][C:5]1[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:2]([CH3:1])[C:3]=1[NH2:4]
Reactant: Cc1cc(C(F)(F)F)ccc1N
Reactant: [Br-]
Agent: O=[Mo](=O)(O)O
Agent: O=[Mo](=O)=O
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C(F)(F)F)cc(Br)c1N
Reaction time: 0.17 h

Procedure:
To a suspension of 2-methyl-4-(trifluoromethyl)aniline (7.78 g, 44.4 mmol), potassium bromide (1.59 g, 13.3 mmol), and ammonium heptamolybdate tetrahydrate (140 mg, 0.111 mmol) in acetic acid (40 mL) at room temperature (in a room temperature waterbath) was added sodium perborate tetrahydrate (1.88 g, 12.2 mmol). After 10 min, the reaction was treated with an additional portion of potassium bromide (1.59 g, 13.3 mmol), ammonium heptamolybdate tetrahydrate (140 mg, 0.111 mmol), and sodium perborate tetrahydrate (1.88 g, 12.2 mmol). After 10 min, the reaction was treated with an additional portion of potassium bromide (1.59 g, 13.3 mmol), ammonium heptamolybdate tetrahydrate (140 mg, 0.111 mmol), and sodium perborate tetrahydrate (1.88 g, 12.2 mmol). After 10 min, the reaction was treated with an additional portion of potassium bromide (1.59 g, 13.33 mmol), ammonium heptamolybdate tetrahydrate (140 mg, 0.111 mmol), and sodium perborate tetrahydrate (1.88 g, 12.2 mmol). After 1 h, the reaction was treated with a final portion of everything in half the amounts of the previous additions. After 1 h, the mixture was poured into water, neutralized with solid sodium bicarbonate, extracted into diethyl ether, washed with water, then brine, dried over magnesium sulfate, and concentrated to give 11.3 g (100%) as an oil. 1H-NMR (CDCl3, 500 MHz) δ 7.56 (s, 1H), 7.23 (s, 1H), 4.36 (bs, 2H), 2.23 (s, 3H); 13C-NMR (CDCl3, 126 MHz) δ 145.3, 127.7 (q, J=3.8 Hz), 126.4 (q, J=3.8 Hz), 124.0 (q, J=272 Hz), 120.6 (q, J=34 Hz), 108.2, 18.3. Mass spec.: 253.95 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][CH:6]=1)=[O:4].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][CH2:11][C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(CNCc2ccc(Cl)cc2)cc1
Reaction time: 0.25 h
Yield: 78.2 %

Procedure:
To a solution of 4-formyl benzoic acid methyl (10.0 g) in chloroform (300 ml), 4-chlorobenzylamine (11.2 g) was added, and the mixed solution was stirred for 15 min. Then, to the resulting solution, sodium triacetoxyborohydride (16.8 g) was added, and the mixed solution was stirred at room temperature for two hours. To the resulting solution, acetic acid (10.5 ml) was added, and the solution was stirred for four hours. Saturated sodium bicarbonate water was added, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure to remove the solvent, and the resulting crude product was purified by column chromatography (neutral OH type silica gel, ethyl acetate/n-hexane=15 to 50%) to give methyl 4-{[(4-chlorobenzyl)amino]methyl}benzoate (13.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][Cl:20].[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:18][CH2:19][Cl:20])[N:11]=[C:10]([C:13]([F:14])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Br)cc2)[nH]n1
Reactant: ClCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(-c2ccc(Br)cc2)n(CCCl)n1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazole (2.05 g, 7 mmol) and 1-bromo-2-chloroethane (0.71 mL, 1.2 equiv) in DMF (30 mL) was added NaH (0.42 g, 60%, 1.5 equiv) and the mixture was stirred overnight at 20° C. The reaction was quenched by water. Solid was collected and washed by water and dried under high vacuum to give a crude, which was purified by column chromatography eluting with MeOH-DCM (6:96) to give 5-(4-bromophenyl)-1-(2-chloroethyl)-3-(trifluoromethyl)-1H-pyrazole (400 mg) as a minor product. 1H-NMR (CDCl3): δ 7.64 (d, 1H), 7.31 (d, 1H), 6.54 (s, 1H), 4.41 (t, 2H), 3.93 (t, 2H).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]=[CH:7]1.N1C=CC=CC=1.CS([Cl:21])(=O)=O>CN(C)C=O>[Cl:21][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]=[CH:7]1
Reactant: OCCCCC1C=CCC1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: ClCCCCC1C=CCC1

Procedure:
3-(4-Hydroxybut-1-yl)cyclopentene {2-cyclopentene-1-butanol} (51 g, 0.37 moles) is diluted in dimethylformamide (100 ml) and added to pyridine (38 g, 0.40 moles). The solution is stirred and methanesulfonyl chloride (46 g, 0.40 moles) is added dropwise over 10 minutes. The reaction is partitioned between hexane (500 ml) and the organic phase separated. The aqueous layer is extracted with hexane (2×500 ml) and the organic extracts combined. The solvent volume is reduced under vacuum and the residue dried over anhydrous magnesium sulfate. The solid is filtered off and the remaining solvent removed leaving a clear yellow oil. The crude product is fractionally distilled under reduced pressure leaving a clear, colorless oil (43 g, 0.27 moles), BP 40°0/0.2 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[C:27]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1)#[N:28].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:34][CH2:33][C:32]1[CH:35]=[CH:36][C:29]([C:27]#[N:28])=[CH:30][CH:31]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: N#Cc1ccc(CN)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 22.1 %

Procedure:
Use a method similar to the General Procedure 5-1 to react 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (504 mg, 1.2 mmol), 4-cyanobenzylamine (476 mg, 3.6 mmol), palladium(II) acetate (29 mg, 0.1 mmol), BINAP (148 mg, 0.2 mmol) and cesium carbonate (540 mg, 1.7 mmol) in toluene (5 mL). Purify by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 1:1) to give 7-chloro-6-(4-cyanobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a white gum (108 mg, 22%). MS (ES+) m/z: 408 (M+H)+.
Reaction SMILES: [C:1]([C:3](=[C:8](C(OC(F)(F)F)=O)[C:9]([F:12])([F:11])[F:10])[C:4]([O:6][CH3:7])=[O:5])#[N:2].C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl.N1C=CC=CC=1.O>[Cl:23][C:8]([C:9]([F:12])([F:11])[F:10])=[C:3]([C:1]#[N:2])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)C(C#N)=C(C(=O)OC(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(C#N)=C(Cl)C(F)(F)F

Procedure:
To a mixture of the compound 2a and 2b obtained in the above step (1) (27.6 g) in methylene chloride (200 mL) were gradually added dropwise oxalyl chloride (31.6 mL) and a few drops of pyridine, and the mixture was refluxed under heating for 4 hours. The reaction mixture was gradually poured in water, and the mixture was extracted with methylene chloride. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give methyl 3-chloro-2-cyano-4,4,4-trifluoro-2-butenoate as a crude product.
Reaction SMILES: [NH2:1][C:2]([CH3:38])([CH3:37])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[C:9]([C:29]2[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:36])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:14][C:13]=2[Cl:28])[CH:11]=1)=O.O=P(Cl)(Cl)Cl.O1CCOCC1.[OH-].[Na+]>CCOC(C)=O.O>[Cl:28][C:13]1[CH:14]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)[CH:16]=[CH:17][C:12]=1[N:10]1[CH:11]=[C:7]([C:5]2[NH:1][C:2]([CH3:38])([CH3:37])[CH2:3][N:4]=2)[N:8]=[C:9]1[C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:36]
Reactant: CC(C)(N)CNC(=O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2Cl)c(-c2c(Cl)cccc2Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)CN=C(c2cn(-c3ccc(-c4cccc(S(C)(=O)=O)c4)cc3Cl)c(-c3c(Cl)cccc3Cl)n2)N1
Yield: 50.2 %

Procedure:
To a N2 purged 100 mL round bottom flask attached with condenser was added 1-(3-Chloro-3′-methanesulfonyl-biphenyl-4-yl)-2-(2,6-dichloro-phenyl)-1H-imidazole-4-carboxylic acid (2-amino-2-methyl-propyl)-amide (590 mg, 1.00 mmol), POCl3 (0.91 mL, 10 mmol) and anhydrous 1,4-dioxane (35 mL). The reaction solution was heated at reflux for 2 hrs. The cooled reaction mixture was added H2O (50 mL) and the mixture as poured to a separatory funnel. To the mixture was added EtOAc (150 mL) and 1N aq. NaOH to raise the pH to 8. The aqueous phase was extracted with EtOAc (70 mL×2), and the combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo, and chromatographed through a 25 g SiO2 column using a gradient of 100% Hexane to 90% EtOAc to afford 288 mg (51% yield) of the title compound. MS (ESI) 573.3, 575.3, 577.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.07 (s, 1H), 8.23 (t, J=2 Hz, 1H), 8.21 (d, J=2 Hz, 1H), 8.11 (d, J=8 Hz, 1H), 7.96 (d, J=8 Hz, 1H), 7.86 (dd, J1=2 Hz, J2=8 Hz, 1H), 7.75 (t, J=8 Hz, 1H), 7.54-7.65 (m, 3H), 7.48 (d, J=8 Hz, 1H), 3.76 (s, 2H), 3.29 (s, 3H), 1.47 (s, 6H).
Reaction SMILES: Cl[C:2]1[S:10][C:9]2[C:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])=[N:7][C:6]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:5][C:4]=2[CH:3]=1.[C:26](P(C(C)(C)C)C(C)(C)C)(C)(C)[CH3:27].C(C([Sn])=C(CCCC)CCCC)CCC.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>O1CCCC1>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][NH:18][C:6]2[N:7]=[C:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])[C:9]3[S:10][C:2]([CH:26]=[CH2:27])=[CH:3][C:4]=3[N:5]=2)[CH:21]=1
Reactant: O=C(c1cccs1)c1nc(NCc2cccnc2)nc2cc(Cl)sc12
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CCCCC([Sn])=C(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: C=Cc1cc2nc(NCc3cccnc3)nc(C(=O)c3cccs3)c2s1
Temperature: 140 °C
Yield: 51 %

Procedure:
A stirred solution of Example 5 (0.05 g, 0.13 mmol) in tetrahydrofuran (3 ml) at room temperature was treated with tris[di(benzylidene)acetone]palladium (0) (0.006 g, 0.0065 mmol), tri-tert-butylphosphine (0.01 ml, 0.04 mmol), tributylvinyltin (0.06 ml, 0.0.195 mmol), and caesium carbonate (0.046 g, 0.14 mmol). The mixture was heated to 140° C. for 20 min in a microwave reactor. The cooled reaction mixture was poured onto aqueous HCl (2.5M, 25 ml), washed with ethylacetate, and basified (pH9) using aqueous sodium hydroxide solution (5M). The aqueous phase was extracted with ethyl acetate (2×30 ml). Combined extracts were dried over sodium sulfate and reduced in vacuo. Silica gel (10 g) column chromatography (ethyl acetate) afforded the title compound as a yellow solid in 51% yield, >95% purity. LC-MS m/z=379.0 [M+H]+; RT=3.15; LC-MS method 1. 1H NMR: δH (400 MHz, D6-DMSO) 4.73 (2H, b), 5.57 (1H, d, J 10.5 Hz), 6.00 (1H, d, J 17.5 Hz), 7.06-7.14 (1H, m), 7.29-7.35 (3H, m), 7.79 (1H, d, J 8.0 Hz), 8.11-8.19 (2H, m), 8.43 (1H, d, J 4.5 Hz), 8.64 (1H, bd), 8.43-8.64 (1H, b)