Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][C:5]1[N:10]=[C:9]2[CH2:11][O:12][C:13](=[C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=4)[NH:16][C:15]3=[O:24])[C:8]2=[CH:7][CH:6]=1.S(=O)(=O)(O)O>C1COCC1>[F:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:24])[C:14]2=[C:13]1[C:8]2[C:9](=[N:10][C:5]([CH2:4][CH:3]=[O:2])=[CH:6][CH:7]=2)[CH2:11][O:12]1
Reactant: COC(Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21)OC
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=CCc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Temperature: 60 °C
Yield: 54.4 %

Procedure:
A solution of 3-[2-(2,2-dimethoxy-ethyl)-7H-furo[3,4-b]pyridin-5-ylidene]-5-fluoro-1,3-dihydro-indol-2-one (52 mg, 0.16 mmol) in THF (5 ml) is treated with 0.63 mL of an aqueous 2.5 M sulfuric acid solution (0.63 mL). The reaction mixture is heated to 60° C. for 1 h, cooled to room temperature and poured into 100 mL ice water with stirring. The brown solid which precipitated is collected by filtration, washed with water, and dried under vacuum to give the title compound as brown solid (27 mg, 54%).
Reaction SMILES: [ClH:1].[CH2:2]([CH:4]1[C:9]2=[N:10][CH:11]=[CH:12][N:13]=[C:8]2[CH2:7][CH2:6][N:5]1C(OC(C)(C)C)=O)[CH3:3]>CO>[ClH:1].[ClH:1].[CH2:2]([CH:4]1[C:9]2=[N:10][CH:11]=[CH:12][N:13]=[C:8]2[CH2:7][CH2:6][NH:5]1)[CH3:3]
Reactant: CCC1c2nccnc2CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CCC1NCCc2nccnc21
Reaction time: 3.5 h

Procedure:
A solution methanolic hydrogen chloride (approx. 1.6M, 1.5 mL) was added to tert-butyl 5-ethyl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxylate (29 mg, 0.11 mmol) dissolved in 0.25 mL of methanol. After 3.5 h, the solution was concentrated under a stream of nitrogen. Methanol (two portions) was added, with evaporation of the solvent after each addition, to give the title compound as a hygroscopic foam. 1H NMR (500 MHz, CD3OD) δ 8.57 (d, 1H, J=3 Hz), 8.54 (d, 1, J=3 Hz), 4.57 (dd, 1H, J=8, 5 Hz), 3.77 (ddd, 1H, J=13, 6, 5 Hz), 3.59 (ddd, 1H, J=10, 6 Hz), 3.37 (ddd, 1H, J=18, 10, 7 Hz), 3.35 (dt, 1H, J=18, 5 Hz), 2.51-2.41 (m, 1H), 2.06-1.96 (m, 1H), 1.18 (t, 3H, J=8 Hz). LC/MS 164 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=4[F:34])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])(C)([CH3:3])[CH3:2].FC(F)(F)C(O)=O.ClC(OC(C)C)=O>>[CH:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=4[F:34])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Nc4ccc(S(C)(=O)=O)cc4F)ncnc32)CC1
Agent: CC(C)OC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OC(=O)N1CCC(n2ncc3c(Nc4ccc(S(C)(=O)=O)cc4F)ncnc32)CC1

Procedure:
4-[4-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester was prepared according to General Procedure D by the reaction of 4-[4-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 1) with trifluoroacetic acid, followed by reaction of the resulting amine with isopropyl chloroformate (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.20 (d, 6H, J=6.2 Hz), 1.94-2.03 (m, 4H), 3.00-3.10 (m, 2H), 3.30 (methyl sulfonyl and water peak), 4.05-4.15 (m, 2H), 4.77-4.84 (m, 1H), 4.92-4.96 (m, 1H), 7.79-7.81 (m, 1H), 7.89-7.92 (m, 1H), 8.20-8.23 (m, 1H), 8.40-8.43 (m, 2H), 10.38 (s, 1H). Mass spectrum MH+=477.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](O)=[O:15])[CH2:12][C@:11]2([CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(N(C)C)=C(C)C.[F:33][C:34]1[C:40]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:39][CH:38]=[CH:37][C:35]=1[NH2:36].CCN(C(C)C)C(C)C>C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:15])[NH:36][C:35]2[CH:37]=[CH:38][CH:39]=[C:40]([O:41][C:42]([F:43])([F:44])[F:45])[C:34]=2[F:33])[CH2:12][C@:11]2([CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[C@H:9]1[CH2:10]2)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)O)C[C@@]2(COC3CCCCO3)C[C@@H]12
Reactant: Nc1cccc(OC(F)(F)F)c1F
Agent: CC(C)=C(Cl)N(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H](C(=O)Nc2cccc(OC(F)(F)F)c2F)C[C@@]2(COC3CCCCO3)C[C@@H]12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of (1R,3S,5S)-5-(tetrahydro-pyran-2-yloxymethyl)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (100 mg, 0.29 mmol) in dry CH2Cl2 (1 mL) under argon at 0° C. was added 1-chloro-N,N,2-trimethylpropenylamine (58 μL, 0.44 mmol) and the reaction mixture was stirred at 0° C. for 1.5 h. 2-Fluoro-3-(trifluoromethoxy)aniline (86 mg, 0.44 mmol) was added, followed by DIPEA (100 μL, 0.59 mmol) and the mixture was stirred at RT overnight. Then poured into water and extracted with CH2Cl2 (×2), the organics were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (eluent: c-hexane to c-hexane/EtOAc 85:15). TLC, Rf (c-hexane/EtOAc 2:1)=0.45; MS (UPLC/MS): 519.3 [M+H]+, 536.3 [M+NH4]+, 517.4 [M−H]−, 563.3 [M−HCOO]−; tR (HPLC conditions f): 2.51 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1.Br[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[O:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]1[N:5]1[C:4](=[O:14])[CH:3]=[C:2]([O:1][CH2:16][C:17]2[CH:22]=[N:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=2)[CH:7]=[N:6]1
Reactant: O=c1cc(O)cnn1C1CCCCO1
Reactant: FC(F)(F)c1ccc(CBr)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccc(C(F)(F)F)nc2)cnn1C1CCCCO1
Yield: 123.1 %

Procedure:
5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (2.3 g, 12 mmol), 5-(bromomethyl)-2-(trifluoromethyl)pyridine (7.2 g, 30 mmol) and K2CO3 (8.4 g, 60 mmol) were stirred in DMF (40 ml) and CH2Cl2 (40 ml) for 48 h. The mixture was diluted with CH2Cl2, washed with 5% LiCl solution (4×) and concentrated. The residue was purified by column chromatography (40 g ISCO column column eluting with methylene chloride and a 10:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 95% methylene chloride) to yield the title compound (5.25 g, >100%) as a waxy white solid containing some DMF: 1H NMR (300 MHz, CDCl3) δ 8.78 (d, J=1.8 Hz, 1H), 7.97-7.88 (m, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.72 (m, 1H), 6.20 (d, J=2.9 Hz, 1H), 6.03-5.98 (d, J=10.9, 2.0 Hz, 1H), 5.11 (s, 2H), 4.16-4.08 (m, 1H), 3.79-3.69 (m, 1H), 2.24-1.96 (m, 2H), 1.83-1.48 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:19]([OH:21])=O)[C:16]([CH3:18])=[CH:17][C:12]=2[S:11][CH:10]([CH3:22])[C:9]1=[O:23])=[O:4].C(N(C(C)C)C(C)C)C.[CH:33]([NH:36][C@@H:37]1[CH2:42][CH2:41][CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]1)([CH3:35])[CH3:34].[Cl-].[Na+]>CN(C)C=O>[CH:33]([N:36]([C:19]([C:15]1[C:16]([CH3:18])=[CH:17][C:12]2[S:11][CH:10]([CH3:22])[C:9](=[O:23])[N:8]([CH2:7][CH2:6][NH:5][C:3]([O:2][CH3:1])=[O:4])[C:13]=2[CH:14]=1)=[O:21])[C@@H:37]1[CH2:42][CH2:41][CH2:40][N:39]([C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])[CH2:38]1)([CH3:35])[CH3:34]
Reactant: COC(=O)NCCN1C(=O)C(C)Sc2cc(C)c(C(=O)O)cc21
Reactant: CC(C)N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)NCCN1C(=O)C(C)Sc2cc(C)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Reaction time: 8 h

Procedure:
To a solution of 4-{2-[(methoxycarbonyl)amino]ethyl}-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylic acid (460 mg) in N,N-dimethylformamide (4 ml) were added CIP reagent, N-ethyldiisopropylamine, tert-butyl (3R)-3-(isopropylamino)piperidine-1-carboxylate, and the mixture was stirred overnight. After the reaction was complete, to the mixture was added a saturated aqueous sodium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (284 mg).
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:27])[CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=CC=1)([O-])=O.[CH2:28]([NH2:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>O1CCCC1>[CH2:20]([O:19][C:17]([N:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[C:11]([NH:34][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:27])=[O:18])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCCCCCN
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)C1CCCN1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: CCCCCCNC(=O)C1CCCN1C(=O)OCc1ccccc1

Procedure:
To a solution of 25.9 g. (0.07 mol.) of N-carbobenzoxy-DL-proline p-nitrophenyl ester in 250 ml. of dry tetrahydrofuran is added 14.1 g. (0.140 mol.) of n-hexylamine in 50 ml. of tetrahydrofuran, and the resulting solution is left overnight at room temperature. The solvent is removed in vacuo, the residue is diluted with ether, and this solution is then washed thoroughly with 1 N aqueous sodium hydroxide, water and then dilute hydrochloric acid. On drying the ether solution and concentrating in vacuo, a pale yellow oil comprising 1-[(benzyloxy)carbonyl]-2-[(hexylamino)carbonyl]pyrrolidine is obtained.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.F[C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16]>>[F:14][C:12]1[CH:11]=[CH:10][C:9]([N+:15]([O-:17])=[O:16])=[C:8]([CH:13]=1)[O:1][C@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: O[C@H]1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1O[C@H]1CCOC1

Procedure:
Prepared analogously to example I.1 from (S)-(+)-3-Hydroxytetrahydrofuran and 2,4-difluornitrobenzol
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6](S(C2C=CC=CC=2)(=O)=O)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[O:4].O1CCCC1.[OH-].[K+].Cl>CO>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2cc(S(C)(=O)=O)ccc2n1S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc2cc(S(C)(=O)=O)ccc2[nH]1
Reaction time: 3 h
Yield: 97.6 %

Procedure:
To a mixture of the resulting 1-benzenesulfonyl-5-methanesulfonylindole-2-carboxylic acid methyl ester (3.5 g), tetrahydrofuran (45 ml) and methanol (12 ml), potassium hydroxide (0.79 g) was added at 0° C. and the mixture was stirred at the same temperature for 3 hours. 2N hydrochloric acid was added, and the mixture was extracted with dichloromethane. The organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.2 g of a white amorphous 5-methanesulfonylindole-2-carboxylic acid methyl ester as a crude product.
Reaction SMILES: C[O:2][C:3](=[O:33])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:30][C:13]3([CH2:18]C[CH2:16][N:15]([CH2:19][C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]([CH3:29])[CH:21]=4)[CH2:14]3)N[C:11](=[O:31])[C:10]=2[CH:32]=1.[OH-].[Na+]>>[CH3:29][N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([CH2:19][N:15]2[CH2:14][C:13]3([CH2:18][C:11](=[O:31])[C:10]4[C:9](=[CH:8][CH:7]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:2])=[O:33])[CH:32]=4)[O:30]3)[CH2:16]2)=[CH:21]1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(Cc3cn(C)c4ccccc34)C1)O2
Agent: [Na+]
Agent: [OH-]
Product: Cn1cc(CN2CC3(CC(=O)c4cc(/C=C/C(=O)O)ccc4O3)C2)c2ccccc21
Yield: 66.4 %

Procedure:
(±)-(E)-3-{1′-(1-Methyl-1H-indol-3-ylmethyl)-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid methyl ester (250 mg, 0.561 mmol) was hydrolyzed with 1 M NaOH (0.73 ml) following the procedure described in Example 30, Step A, giving (E)-3-[1′-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (150 mg) as a brown solid.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH3:20][NH:21][CH2:22][CH:23]1[CH2:28][O:27][CH2:26][CH2:25][NH:24]1>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH:23]3[CH2:22][NH:21][CH3:20])[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: CNCC1COCCN1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOCC3CNC)c(F)c21

Procedure:
By the use of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 3-(methylaminomethyl)morpholine, the reaction is similarly carried out as Example 1 to give 1-ethyl-6,8-difluoro-1,4-dihydro-7-[3-(methylaminomethyl)morpholino]-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:14]1[N:18]=[C:17]([NH:19][C:20]2[CH:25]=[C:24]([F:26])[C:23]([N:27]3[CH:31]=[C:30]([Cl:32])[N:29]=[CH:28]3)=[C:22]([F:33])[CH:21]=2)[NH:16][N:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[Cl:32][C:30]1[N:29]=[CH:28][N:27]([C:23]2[C:24]([F:26])=[CH:25][C:20]([NH:19][C:17]3[N:18]=[C:14]4[CH:6]([C:7]5[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=5)[CH2:5][CH2:4][CH2:3][CH2:2][N:15]4[N:16]=3)=[CH:21][C:22]=2[F:33])[CH:31]=1
Reactant: Fc1ccc(C(CCCCCl)c2n[nH]c(Nc3cc(F)c(-n4cnc(Cl)c4)c(F)c3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(C2CCCCn3nc(Nc4cc(F)c(-n5cnc(Cl)c5)c(F)c4)nc32)cc1
Temperature: 55 °C
Yield: 75.3 %

Procedure:
A mixture of 3-(5-chloro-1-(4-fluorophenyl)pentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3,5-difluorophenyl)-1H-1,2,4-triazol-5-amine (40 mg, 0.081 mmol), potassium carbonate (11.2 mg, 0.081 mmol), and potassium iodide (13.4 mg, 0.081 mmol) in DMF (2 mL) was heated at 55° C. for 5 hrs. The solvent was removed in vacuo. The crude product was purified using silica gel column chromatography (0-10% MeOH/CH2Cl2, linear gradient) to afford 28 mg (72% yield) of the titled compound as a solid. LC-MS (M+H)+ 459.2. 1H NMR (500 MHz, chloroform-d) δ ppm 7.49 (s, 1 H) 7.19 (d, J=10.38 Hz, 2 H) 7.14 (dd, J=8.55, 5.49 Hz, 2 H) 7.06 (t, J=8.55 Hz, 2 H) 7.00 (s, 1 H) 4.18-4.33 (m, 3 H) 2.15-2.28 (m, 1H) 1.78-2.15 (m, 5 H).
Reaction SMILES: [CH2:1](O)[CH2:2][CH:3]=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:25][C:26]1([CH3:33])[NH:30][C:29](=[O:31])[NH:28][C:27]1=[O:32].CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[CH2:3]([N:28]1[C:27](=[O:32])[C:26]([CH3:33])([CH3:25])[NH:30][C:29]1=[O:31])[CH:2]=[CH2:1]
Reactant: C=CCCO
Reactant: CC1(C)NC(=O)NC1=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C=CCN1C(=O)NC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
A solution of 3-buten-1-ol (1 g, 13.9 mmol), triphenylphosphine (4.73 g, 18 mmol) and 5,5-dimethylhydantoin (2.1 g, 16.7 mmol) in THF (50 mL) was treated dropwise with diethylazodicarboxylate (3.13 g, 18.0 mmol), stirred at ambient temperature for 1 hour, treated with water and partitioned between ethyl acetate and brine. The organic layer was dried (Na2SO4), filtered, and concentrated to provide crude product which was purified on silica gel with 50% ethyl acetate/hexanes to provide 2.5 g (100%) of the title compound.
Reaction SMILES: Cl.[F:2][C:3]([F:33])([F:32])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:25]=[CH:24][C:18]4[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:17]=4[CH:16]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.Br[CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48]>CN(C=O)C>[F:33][C:3]([F:2])([F:32])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:25]=[CH:24][C:18]4[CH2:19][CH2:20][N:21]([CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:22][CH2:23][C:17]=4[CH:16]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: FC(F)(F)c1cc(-c2nc(-c3ccc4c(c3)CCNCC4)no2)ccc1-c1ccccc1
Reactant: CCOC(=O)CCCBr
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN1CCc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(C(F)(F)F)c4)n3)cc2CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 107.1 %

Procedure:
7-{5-[2-(Trifluoromethyl)-4-biphenylyl]-1,2,4-oxadiazol-3-yl}-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (Example 20) (200 mg, 0.424 mmol), DIPEA (0.281 ml, 1.608 mmol) and ethyl 4-bromobutanoate (0.131 ml, 0.919 mmol) were stirred at RT in DMF (10 ml) for 5 hours. The reaction mixture was then heated to 60° C. for 5 hrs, and then allowed to stand overnight at room temperature. Further ethyl 4-bromobutanoate (0.066 ml, 0.459 mmol) was added and the reaction mixture heated at 60° C. for 6 hours. The reaction mixture was partitioned between EtOAc (˜30 ml) and water (˜30 ml) and the aqueous layer extracted once more with EtOAc (˜40 ml). The combined organics were concentrated in vacuo to yield the title compound (277 mg, 0.454 mmol) as an orange solid. MS (ES): C31H30F3N3O3 requires 549; found 550 [M+H]+.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]([C:11]1[S:12][CH:13]=[C:14](Br)[N:15]=1)=[O:10])[CH2:2]2.C(O)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]([C:11]1[S:12][CH:13]=[C:14]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)[N:15]=1)=[O:10])[CH2:2]2
Reactant: O=C(c1nc(Br)cs1)N1CC2CCC(C1)O2
Reactant: OB(O)c1ccc(Cl)cc1
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: CCO
Solvent: Cc1ccccc1
Product: O=C(c1nc(-c2ccc(Cl)cc2)cs1)N1CC2CCC(C1)O2
Temperature: 92.5 °C
Yield: 57.6 %

Procedure:
To a solution of 8-oxa-3-azabicyclo[3.2.1]octan-3-yl(4-bromothiazol-2-yl)methanone (Step-1 of compound 67, 1.1 g, 3.63 mmol) in a mixture of toluene:ethanol (5 ml:15 ml) were added (4-chlorophenyl) boronic acid (0.85 g, 5.44 mmol) and potassium carbonate (1.25 g, 9.07 mmol) at 25° C. in a tube, the nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (0.41 g, 0.36 mmol) under nitrogen and the tube was sealed. The reaction mixture was heated at 90-95° C. for 18 hr with stirring. The progress of reaction was monitored by TLC; the reaction mixture was cooled to 25° C. and filtered through celite. The residue was washed with mixture of 10% methanol in dichloromethane (2×50 ml). The filtrate was concentrated under reduced pressure to obtain a crude product; which was purified by column chromatography over silica gel (100-200 mesh) using 25% ethyl acetate in hexanes as an eluent to obtain the title compound (0.7 g, 57.8%). MS: m/z 335 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([CH:9]=1)[CH:7]=O.O.O.[Sn](Cl)Cl.[CH2:18]([O:20][C:21](=[O:30])[CH2:22][CH:23](OCC)OCC)[CH3:19]>C(O)C>[Br:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:10]=[CH:23][C:22]([C:21]([O:20][CH2:18][CH3:19])=[O:30])=[CH:7]2
Reactant: CCOC(=O)CC(OCC)OCC
Reactant: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(Br)cc2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
To a solution of 5-bromo-2-nitrobenzaldehyde (2 g, 9 mmol) in ethanol (46 mL) was added tin(II) chloride dihydrate (7.95 g, 35.2 mmol) and 3,3-diethoxypropionic acid ethyl ester (4.2 mL, 22 mmol). The reaction was heated to 90° C. for 16 hours. The reaction was then allowed to cool to room temperature and stir overnight. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The mixture was poured into saturated aqueous sodium bicarbonate. The resulting emulsion was filtered through Celite, rinsing with ethyl acetate. The layers were separated and the aqueous was extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-50% ethyl acetate/heptanes) gave the title compound (1.41 g, 60%) as a solid.
Reaction SMILES: [CH:1]([O-])=[O:2].[Na+].[C]=O.Br[C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[CH:10][CH:9]=1>CN(C=O)C>[CH:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[CH:10][CH:9]=1)=[O:2]
Reactant: O=C(OCc1ccccc1)N1CCCC1c1ccc(Br)cc1
Reactant: O=C[O-]
Agent: [C]=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(C2CCCN2C(=O)OCc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a 50 mL round-bottomed flask were placed Pd (PPh3)2Cl2 (70 mg, 0.1 mmol), and sodium formate (510 mg, 7.5 mmol) and purged with carbon monoxide. DMF (7 mL) and benzyl 2-(4-bromophenyl)pyrrolidine-1-carboxylate (1.8 g, 5 mmol) were added via syringes. The mixture was vigorously stirred at 100° C. under carbon monoxide atmosphere for 8 hrs. Then the reaction mixture was cooled to room temperature and partitioned between ether (100 mL) and water (15 mL). The organic phase was washed with water (3×15 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc:hexane=1:10) to give the title compound (0.31 g, yield 20%) as a colorless oil. LC-MS (ESI) m/z: 309 (M+1)+; 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.73-1.88 (m, 3H), 2.31-2.41 (m, 1H), 3.57-3.67 (m, 2H), 4.84-5.06 (m, 3H), 6.84-6.86 (m, 1H), 7.12-7.34 (m, 4H), 7.41-7.43 (d, J=8.0 Hz, 2H), 7.85-7.87 (d, J=8.0 Hz, 2H), 9.98-9.99 (d, J=6.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[O:6][C:7]3[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=3[CH:9]([CH2:15][N+:16]([O-])=O)[CH:10]([C:11]([O:13][CH3:14])=[O:12])[C:4]=2[CH:3]=1.[H][H]>O1CCCC1.[Ni]>[NH2:16][CH2:15][CH:9]1[C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]=2[O:6][C:5]2[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][C:4]=2[CH:10]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C1c2cc(Cl)ccc2Oc2ccccc2C1C[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)C1c2cc(Cl)ccc2Oc2ccccc2C1CN

Procedure:
An aqueous slurry of Ni-Raney (containing 30 g of Ni on a dry basis) was washed with tetrahydrofuran, and added over a solution of 270 g (0.78 mol) of methyl 2-chloro-10-nitromethyl-10,11-dihydrodibenzo[b,f]oxepine-11-carboxylate (compound XIa), as obtained in Example 18, in 2.7 L of tetrahydrofuran. The suspension was stirred under 50-60 psi (3447-4136 hPa) of hydrogen at room temperature for 2 days. The catalyst was removed by filtration, and the resulting solution was concentrated under reduced pressure to obtain methyl 10-aminomethyl-2-chloro-10,11-dihydrodibenzo[b,f]oxepine-11-carboxylate (compound XIIa), which was used in the next step (see Example 20) without further purification.