Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[OH-:13].[Na+].[C:15]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])(=O)[CH3:16]>O>[C:20]([C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[C:15]1[CH:16]=[C:5]([C:6]([OH:11])=[O:13])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=2)[N:7]=1)([OH:22])=[O:21]
Reactant: CC(=O)c1ccccc1C(=O)O
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc2nc(-c3ccccc3C(=O)O)cc(C(=O)O)c2c1
Temperature: 90 °C
Yield: 34.3 %

Procedure:
To 9.93 ml of water were added 10.0 g (62.1 mmol) of 5-methylisatin obtained in Example 1 and 4.96 g (0.12 mol) of sodium hydroxide. 10.2 g (62.1 mmol) of 2-acetylbenzoic acid was added thereto and the mixture was heated to 90° C. under reflux. The mixture was heated further at 115° C. for one hour after the reaction became mild. Thereafter, the mixture was allowed to cool to room temperature and poured into 200 g of iced water. The aqueous layer was washed with ether and acidified with 2M hydrochloric acid. The formed precipitate was collected by filtration to obtain 6.55 g of 2-(2-carboxyphenyl)-6-methyl-4-quinolinecarboxylic acid. NMR (270 MHz, Acetone-d6):
Reaction SMILES: [C:1]([N:8]([CH3:29])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19]([B:26]([OH:28])[OH:27])[CH:20]=[CH:21][C:22]=2[O:23][CH2:24][CH3:25])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[Cl:37][C:38]1[C:39]2[CH:49]=[CH:48][CH:47]=[CH:46][C:40]=2[S:41][C:42]=1[C:43](Cl)=[O:44]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]([N:8]([CH3:29])[CH:9]1[CH2:10][CH2:11][CH:12]([N:15]([CH2:16][C:17]2[CH:18]=[C:19]([B:26]([OH:27])[OH:28])[CH:20]=[CH:21][C:22]=2[O:23][CH2:24][CH3:25])[C:43]([C:42]2[S:41][C:40]3[CH:46]=[CH:47][CH:48]=[CH:49][C:39]=3[C:38]=2[Cl:37])=[O:44])[CH2:13][CH2:14]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: CCOc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of boronic acid 11 (700 mg, 1.72 mmol) in DCM (15 mL) at 0° C. is treated with triethylamine (0.48 mL, 3.45 mmol), followed by 3-chlorobenzo-[b]thiophene-2-carbonyl chloride (439 mg, 1.90 mmol) in one portion. After warming to RT, the solution is stirred 16 h. Analysis by LC/MS at this juncture confirmed the reaction is complete. Thus the reaction is diluted with aqueous NaHCO3 (20 mL) and extracted into EtOAc (3×25 mL). The combined EtOAc phases are dried (Na2SO4) and reduced in vacuo to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:22])[C:5]2[CH2:11][CH:10]([CH2:12][CH2:13][C:14]3[CH:15]=[C:16]([C:19]([OH:21])=O)[NH:17][CH:18]=3)[CH2:9][NH:8][C:6]=2[N:7]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[NH2:42][C@H:43]([C:50]([O:52][CH3:53])=[O:51])[CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([OH:22])[C:5]2[CH2:11][CH:10]([CH2:12][CH2:13][C:14]3[CH:15]=[C:16]([C:19]([NH:42][C@H:43]([C:50]([O:52][CH3:53])=[O:51])[CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47])=[O:21])[NH:17][CH:18]=3)[CH2:9][NH:8][C:6]=2[N:7]=1
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Reactant: Nc1nc(O)c2c(n1)NCC(CCc1c[nH]c(C(=O)O)c1)C2
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)CC[C@H](NC(=O)c1cc(CCC2CNc3nc(N)nc(O)c3C2)c[nH]1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
A solution of 4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6yl)ethyl]pyrrole-2-carboxylic acid (152 mg, 0.5 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (98 mg, 0.55 mmol), and 4-methylmorpholine (0.066 mL, 0.6 mmol) in DMF (3 mL) was stirred at room temperature for 2 hours. Dimethyl L-glutamate hydrochloride (0.116 g, 0.55 mmol) and 4-methylmorpholine (0.066 mL, 0.6 mmol) were sequentially added and the mixture was stirred overnight at room temperature. The solvent was removed in vacuo, and the residue chromatographed using chloroform:methanol (9:1) to give dimethyl N-{4-[2-(amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]pyrrol-2-ylcarbonyl}-L-glutamate (152 mg, 66%) as a white solid, mp 151-153° C.: 1H N (CDCl3 /1 drop CD3OD) δ 10.20 (br s, 1H), 7.27 (s, 1H, J=7.9 Hz), 6.70 (s, 1H), 6.82 (s, 1H), 5.83 (br s, 2H), 5.38 (br s, 1H), 4.80 (m, 1H), 3.84 (s, 3H), 3.73 (s, 3H), 3.42 (br d, 1H, J=10.1 Hz), 3.05 (m, 1H), 2.76 (dd, 1H, J=15.0, 4.4 Hz), 2.65 (m, 2H), 2.56 (m, 2H), 2.36 (m, 1H), 2.14 (m, 2H), 1.91 (m, 1H), 1.68 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:11](=[O:12])[C@@H:10]([NH:13][C:14](=[O:19])[CH2:15][C:16]([OH:18])=O)[C:9]2[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=2[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]1=2.[F:28][C:29]([F:36])([C:32]([F:35])([F:34])[F:33])[CH2:30][NH2:31]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:11](=[O:12])[C@@H:10]([NH:13][C:14](=[O:19])[CH2:15][C:16]([NH:31][CH2:30][C:29]([F:36])([F:28])[C:32]([F:35])([F:34])[F:33])=[O:18])[C:9]2[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=2[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]1=2
Reactant: COCCN1C(=O)[C@@H](NC(=O)CC(=O)O)c2ccccc2-c2ccccc21
Reactant: NCC(F)(F)C(F)(F)F
Product: COCCN1C(=O)[C@@H](NC(=O)CC(=O)NCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Using N—[(S)-5-(2-methoxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-malonamic acid and 2,2,3,3,3-pentafluoropropylamine, the title compound was prepared in the same manner as described for example 1c. White solid (80%). MS: m/e=500(M+H+).
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=O)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([NH:34][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=2)(=[O:32])=[O:33])=[O:23])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)NS(=O)(=O)c2ccc(C)cc2)o1

Procedure:
The title compound was prepared as described in Example 1 starting from 0.228 g (0.7 mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid and 0.361 g (2.1 mmol) of 4-methylbenzenesulfonamide. MS (m/z, ES−): 476.63 (M+1, 100%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[C@H:39]([CH3:40])[CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:41])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:42]2[CH:43]=[C:44]([CH:51]=[CH:52][CH:53]=2)[CH2:45][O:46]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:54]1[CH2:58][CH2:57][CH2:56][CH2:55]1.C1C[O:62]CC1>>[CH:45]([OH:46])=[O:62].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[C@H:35]([CH3:41])[CH2:36][CH2:37][CH2:38][C@@H:39]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:42]2[CH:53]=[CH:52][CH:51]=[C:44]([CH2:45][N:54]3[CH2:58][CH2:57][CH2:56][CH2:55]3)[CH:43]=2)[N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: C1CCNC1
Reactant: C1CCOC1
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(COS(C)(=O)=O)c4)c4ccccc43)cn12
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CN5CCCC5)c4)c4ccccc43)cn12
Product: O=CO
Temperature: 50 °C
Reaction time: 24 h
Yield: 24 %

Procedure:
To a solution of Intermediate 130b (0.32 mmol) in THF (3.0 mL) was added pyrrolidine (530 μL 6.4 mmol) and the reaction stirred at 50° C. for 24 h. After cooling, the mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM, followed by MDAP (Method 7) purification, to give the title compound (60 mg, 24%). LCMS (Method 5): Rt 3.79 min, m/z 716 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.55 (3H, d, J=6.2 Hz), 0.58 (3H, d, J=6.2 Hz), 1.23 (9H, s), 1.35-1.54 (3H, m), 1.60-1.68 (6H, m), 1.72-1.85 (2H, m), 1.86-1.92 (1H, m), 2.01-2.06 (2H, m), 2.38-2.44 (4H, m), 3.08-3.20 (2H, m), 3.58 (2H, s), 4.77 (1H, td, J=8.6, 5.9 Hz), 5.48 (1H, t, J=4.2 Hz), 6.28 (1H, s), 7.00 (1H, d, J=8.6 Hz), 7.15 (1H, dd, J=9.8, 2.1 Hz), 7.18-7.25 (2H, m), 7.26-7.35 (4H, m), 7.37 (1H, s), 7.41 (1H, t, J=7.6 Hz), 7.61 (1H, d, J=9.7 Hz), 7.83 (1H, d, J=1.8 Hz), 8.05 (1H, s), 8.13 (1.2H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([CH3:21])[C:19]=3[CH3:20])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[C:22](=O)([O-])[O-].[K+].[K+].[S:28](=[N:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)(=[O:30])=[O:29].Cl>CN(C)C(=O)C.C(#N)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.O>[ClH:1].[CH3:21][N:18]1[C:19]([CH3:20])=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[C:2]([C:37]4[CH:38]=[CH:39][C:34]([CH2:33][CH2:32][NH:31][S:28]([CH3:22])(=[O:30])=[O:29])=[CH:35][CH:36]=4)=[N:7][CH:6]=[CH:5][N:4]=3)[CH2:9][CH2:10]2)[CH:16]=[N:17]1
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)=NCCc1ccc(B(O)O)cc1
Reactant: Cc1c(CN2CCN(c3nccnc3Cl)CC2)cnn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: Cc1c(CN2CCN(c3nccnc3-c3ccc(CCNS(C)(=O)=O)cc3)CC2)cnn1C
Temperature: 120 °C
Yield: 72.1 %

Procedure:
Dissolve 3′-chloro-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (307 mg, 1.0 mmol) in N,N-dimethylacetamide (4 mL). Add potassium carbonate (331 mg, 2.4 mmol), 4-sulfonylaminoethyl benzene boronic acid (292 mg, 1.2 mmol), tetrakis(triphenylphosphine)palladium(0) (0.0050 g, 0.0058 mmol), then water (2 mL) and degas with nitrogen for 10 min. Heat at 120° C. for 20 hr., then purify by SCX-2® chromatography washing with methanol. Elute with 2 M ammonia in methanol and concentrate. Recrystallize from DMSO:methanol (1:1), filter and wash with diethyl ether, to give a whitish powder. Dissolve the powder in acetonitrile and convert to the hydrochloride salt by adding 2 M aq HCl solution. Add water and lyophilize to give the title compound as a yellow powder (365 mg, 71%). MS (ES): m/z=470 [M+H]+.
Reaction SMILES: C(OC[C:6]1([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH2:7]1)(=O)C.[CH2:17]1COCC1>>[CH2:6]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:11]1[CH:17]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)OCC1(c2cccs2)C=CC=CC1
Reactant: C1CCOC1
Product: c1ccc(Cc2cccs2)cc1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A solution of 1-(2-thienyl)benzyl acetate in THF (5 ml) was added carefully to dry liquid ammonia (100 ml). Lithium metal was added in small portions until the blue color persisted. The resulting reaction mixture was stirred for 30 min, and the reaction was quenched by addition of solid ammonium chloride. The residue, after complete evaporation of liquid ammonia, was dissolved in water (50 ml) and was extracted with methylene chloride (2×50 ml). The combined organic layers was dried over MgSO4 and filtered. Removal of the solvent gave crude product, which was purified by column chromatography using hexane as eluent to give 2-benzylthiophene (1.2 g, 68% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[O:28][N:27]=[C:26]([C:29]([NH2:31])=[O:30])[C:25]=1I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[O:28][N:27]=[C:26]([C:29]([NH2:31])=[O:30])[C:25]=1[C:37]1[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1I
Reactant: OB(O)c1ccc(F)cc1
Product: NC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(F)cc1

Procedure:
5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-iodo-isoxazole-3-carboxylic acid amide (0.45 g, 0.80 mmol) was cross coupled to 4-fluorophenylboronic acid (0.17 g, 1.5 equiv.) using the standard conditions described above. The crude product, an orange solid (0.40 g), was taken on to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-])[CH:5]=[CH:6][C:7]=1[Cl:8].COS(OC)(=O)=O.[C-:25]#[N:26].[Na+]>CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]2[N:12]=[C:13]([C:25]#[N:26])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [C-]#N
Reactant: [O-][n+]1ccccc1C=Cc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CCCCCC
Product: N#Cc1cccc(C=Cc2ccc(Cl)c(Cl)c2)n1

Procedure:
Following the general method described in example 2b, 2-[2-(3,4-dichloro-phenyl)-vinyl]-pyridine 1-oxide was reacted first with dimethylsulfate and then with NaCN. After extraction and crystallization the title compound was obtained as a white crystalline material. Mp. 124–125° C. (hexane), MS: m/e=274 (M+).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O1CCCC1.C(OCC)C.O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:7]([C:8]#[N:9])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:26]
Reactant: N#CCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Combine phenylacetonitrile (175.5 g, 1.5 mol) and tetrahydrofuran (1.95 L). Cool to about 0° C. Add dropwise over about 15 minutes, a solution of sodium bis(trimethylsilyl)amide (3.2 L, 1M in tetrahydrofuran, 3.2 mol). When the addition is complete, warm the reaction mixture to ambient temperature and allow to stir for 1 hour. Transfer the above solution over about 45 minutes into a cooled (about -20° C.) solution of ethyl bromoacetate (510 g, 3.05 mol) in tetrahydrofuran (1.95 L). Warm to ambient temperature and allow to stir. After 18 hours, dilute with diethyl ether (3 L) and water (1.5 L). Extract twice with saturated aqueous solution of ammonium chloride (2.25 L) and then brine. Dry the organic layer over MgSO4, filter, and concentrate invacuo to obtain a residue. Distill the residue by bulb-to-bulb distillation to give the title compound: bp; 180°-190° C. at 30 mm of Hg. Elemental Analysis calculated for C16H19NO4 : C, 66.43; H, 6.62; N, 4.84. Found: C, 66.34; H, 6.57; N, 4.82.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([CH:14]=[CH:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[S:13][C:6]=12.[NH4+].[Cl-].O>CCO.[Fe]>[CH3:20][N:18]([CH3:19])[CH2:17][CH2:16]/[CH:15]=[CH:14]\[C:12]1[S:13][C:6]2[C:7](=[N:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]2[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:2]=2[F:1])[CH:11]=1
Reactant: CN(C)CCC=Cc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN(C)CC/C=C\c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reaction time: 0.67 h
Yield: 68.2 %

Procedure:
To a mixture of 4-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-N,N-dimethylbut-3-en-1-amine (234) (171 mg, 0.44 mmol) and NH4Cl (20 mg, 0.37 mmol) in EtOH (4.4 mL)/water (2.2 mL) at 100° C., Fe (209 mg, 3.75 mmol) was added in one portion and the mixture was heated to reflux with vigorous stirring for 40 min. The mixture was filtered through Celite®, the Celite® washed with EtOH and the combined organic solutions concentrated under reduced pressure. The residue was dissolved in MeOH and purified by preparative HPLC (gradient 40% to 95% MeOH in water, 45 min) giving title compound 235 as a yellow solid (122.8 mg, 0.3 mmol, 69% yield). MS (m/z): (M+1) 358.1 (100%).
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([NH:6][CH:7]2[CH2:11][CH2:10][CH:9]([OH:12])[CH:8]2[OH:13])=[C:4]([N+:17]([O-])=O)[CH:3]=1.[H][H].CO.[CH:24](Cl)(Cl)Cl>C(O)(C)C.[Ni].C(O)=O>[Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[N:6]([CH:7]3[CH2:11][CH2:10][CH:9]([OH:12])[CH:8]3[OH:13])[CH:24]=[N:17][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1NC1CCC(O)C1O
Reactant: ClC(Cl)Cl
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(C)O
Solvent: CO
Solvent: O=CO
Product: OC1CCC(n2cnc3cc(Cl)c(Cl)cc32)C1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(±)-(1S*, 2R*, 3R*)-3-(4,5-Dichloro-2-nitroanilino)-1,2-cyclopentanediol (3.77 g, 12.3 mmol) in isopropanol (250 mL) was shaken in a Parr shaker with Raney nickel (Aldrich, prewashed with water until neutral, ca. 1 tsp) under hydrogen (50 psi) for 2 hours, at which point uptake of hydrogen had ceased. TLC (silica gel, methanol:chloroform/1:10) shows one spot at lower Rf than starting material. The catalyst was filtered off (Celite) and volatiles evaporated to leave a glass which was refluxed in formic acid (65 mL) for 40 minutes. The formic acid was evaporated and the residual oil dissolved in ethanol (50 mL) and adjusted to pH 13 with 5N sodium hydroxide. After stirring at ambient temperature for 18 hours, the pH was adjusted to 7 with hydrochloric acid and the volatiles removed by evaporation in vacuo. The residue was triturated with methanol. The methanol solution was evaporated to dryness to give white solid which contained product and some salts (7.41 g). A portion of this solid (1.05 g) was chromatographed on silica gel and product was eluted with 6-8% methanol-chloroform as white powder, after solidification from ethanol (350 mg), m.p. 180°-182° C.; 1H-NMR(DMSO-d6)δ: 8.46, 8.08, and 7.93 (all s, 1 each, 3 aromatic CH), 4.96 (d, J=4.7 Hz, 1, OH), 4.92-4.85 (m, 1, NCH), 4.81 (d, J=5.9 Hz, 1, OH), 4.19-4.11 (m, 1, OCH), 4.08-3.93 (m, 1, OCH), 2.38-2.04 (m, 2, CH2), 2.03-1.72 (m, 2, CH2); mass spectrum(CI): 287 (M+1).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].[N+](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=1)[CH3:20]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: OCc1cccc(C(F)(F)F)c1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: CCCCCCC
Solvent: ClCCl
Product: CCOC(=O)COCc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
To a solution of 3-trifluoromethylbenzyl alcohol (1.62 g, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixture is stirred at RT for 30 min. The reaction mixture is diluted with heptane, filtered through Celite, and the filtrate is evaporated and the residue is vacuum distilled at 150° C. to give 2.31 g of the product 394. 1H NMR (CDCl3) δ 7.65 (bs, 1H), 7.57 (m, 2H), 7.48 (t, 1H), 4.69 (s, 2H), 4.24 (q, 2H), 4.14 (s, 2H), 1.30 (t, 3H); MS: m/z 263 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[C:5]#[N:6])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1cc(O)cc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1cc(O)cc(OCc2ccccc2)c1
Yield: 29.4 %

Procedure:
To a mixture of 3,5-dihydroxybenzonitrile (1.08 g, 8 mmol) and K2CO3 (1.104 g, 8 mmol) in CH3CN (50 mL), benzyl bromide (1.438 g, 8 mmol) was added. The mixture was heated to reflux for 2 hours. Solvent was evaporated under vacuum. The residue was treated with EtOAc (200 mL) and 1M HCl (200 mL). The organic layer was washed, dried, and evaporated in vacuo. The residue was chromatographed (gradient, Hexanes-CH2Cl2-MeOH) to give 3-benzyloxy-5-hydroxybenzonitrile (529 mg, 29%), 3,5-dibenzyloxybenzonitryl (784 mg, 31%) and 256 mg (23.7 mg, 24%) of the starting material. The product 3-benzyloxy-5-hydroxybenzonitrile had: MP 144-145° C.; 1H NMR δ 9.15 (s, 1H, OH), 7.47 (d, 2H, J=7.0 Hz, 2′ and 6′), 7.40 (ddd, 2H, J=7.0, 7.0, 2.0 Hz, 3′ and 5′), 7.34 (dd, 1H, J=7.7 and 2.1 Hz, 4′), 6.89 (dd, 1H, J=1.5 Hz, 4), 6.78 (d, 2H, J=1.8 Hz), 5.16 (s, 2H).
Reaction SMILES: [NH2:1][CH:2]([C:9]([CH3:13])([CH3:12])[CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:14][C:15]1[C:20]([C:21]#[N:22])=[CH:19][C:18]([F:23])=[C:17](Cl)[N:16]=1.CCN(CC)CC>C(#N)C>[Cl:14][C:15]1[N:16]=[C:17]([NH:1][CH:2]([C:9]([CH3:12])([CH3:13])[CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:18]([F:23])=[CH:19][C:20]=1[C:21]#[N:22]
Reactant: CCOC(=O)CC(N)C(C)(C)CC
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CC(Nc1nc(Cl)c(C#N)cc1F)C(C)(C)CC

Procedure:
A solution of ethyl 3-amino-4,4-dimethyl-hexanoate, 27a, (0.24 g, 1.28 mmol), 2,6-dichloro-5-fluoro-pyridine-3-carbonitrile (0.29 g, 1.53 mmol) and Et3N (0.43 mL, 3.07 mmol) in acetonitrile (4.8 mL) was stirred at 70° C. overnight. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (10-40% EtOAc/Hexanes gradient) to provide 205 mg of ethyl 3-[(6-chloro-5-cyano-3-fluoro-2-pyridyl)amino]-4,4-dimethyl-hexanoate; LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.75 minutes (M+H) 342.04.
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.[NH2:27][CH2:28][C:29]1[CH:44]=[CH:43][C:32]([C:33]([NH:35][CH:36]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:34])=[C:31]([CH3:45])[CH:30]=1>C1(C)C=CC=CC=1>[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:27][CH2:28][C:29]1[CH:44]=[CH:43][C:32]([C:33](=[O:34])[NH:35][CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)=[C:31]([CH3:45])[CH:30]=1
Reactant: Cc1cc(CN)ccc1C(=O)NC1CCCCCC1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1cc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)ccc1C(=O)NC1CCCCCC1
Yield: 80.5 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (660 mg, 1.6 mmol) with 4-aminomethyl-N-cycloheptyl-2-methyl-benzamide (810 mg, 3.1 mmol) in anhydrous toluene (18 mL). Purify the crude mixture by chromatography on silica gel eluting with hexane/THF (19:1 to 7:3 gradient) to obtain 7-chloro-6-(4-cycloheptylcarbamoyl-3-methyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (690 mg, 83%). MS (ES+) m/z: 536.3 (M+H)+.