Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:11][CH2:10][C@H:9](O)[CH2:8]2)[CH:2]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:11][CH2:10][C@@H:9]([N:17]3[C:16](=[O:18])[C:15]4=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]4[C:13]3=[O:23])[CH2:8]2)[CH:2]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O[C@H]1CC[C@@H](c2cccnc2)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1[C@@H]1CC[C@@H](c2cccnc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
A solution of (1S,3R)-3-(3-pyridyl)cyclopentanol (3.95 g, 24.2 mmol) in THF (80 mL) was cooled to 4° C. and treated with phthalimide (3.91 g, 26.6 mmol), Diisopropylazodicarboxylate (5.24 mL, 26.6 mmol) and triphenylphosphine (6.98 g, 26.6 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc, and washed with H2O and brine. The organic layers was dried over Na2SO4. After concentration under reduced pressure, the residue was purified by column chromatography (Hexane/EtOAc=4/1) to yield (1R,3R)-N-[3-(3-pyridyl)cyclopentyl]phthalimide (6.27 g, 89%) as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)(O)[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[OH-].[K+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)\[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(O)c2cccnc2)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1cccnc1
Temperature: 5 °C

Procedure:
1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(pyridin-3-yl)propan-2-ol (1 g, 2.81 mmol, 1 equiv.) was refluxed with 25% sulfuric acid (7 mL) for 2 h. The reaction mixture was cooled to 5° C. in an ice-water bath. KOH (15% aqueous solution) was added dropwise to the reaction mixture until pH 9-10 was achieved. The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with water (10 mL) followed by brine, dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of isomers, which were separated by HPLC. 1HNMR (DMSO, TFA salt) δ (ppm): 8.90 (s, 1H), 8.60 (d, 1H), 8.10 (d, 1H), 7.50 (m, 2H), 7.22 (d, 2H), 7.10 (d, 1H), 3.6 (m, 2H), 2.70 (m, 4H), 2.45 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[CH:6][N:5]=[C:4]2[N:15]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:16]=[CH:17][C:3]=12.[N:27]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.O>CN1C(=O)CCC1>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[C:2]([N:30]2[CH2:29][CH2:28][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31]2)=[C:3]2[CH:17]=[CH:16][N:15]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:19])=[O:20])[C:4]2=[N:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(F)c(-c3ccccc3F)cnc21
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3F)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 160 °C
Yield: 35.2 %

Procedure:
4-Fluoro-5-(2-fluorophenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.200 g, 0.540 mmol) and tert-butyl piperazine-1-carboxylate (0.121 g, 0.648 mmol) were placed in NMP (2 mL). The reaction was then placed in the microwave and heated to 160° C. for 1 hour. The reaction was then cooled, poured into water and extracted with ether. The combined organic fractions were dried, filtered, and concentrated to give a crude oil that was purified by column chromatography (3:1 hexane:EtOAc) to give tert-butyl 4-(5-(2-fluorophenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (0.102 g, 35.2% yield).
Reaction SMILES: [C:1]([OH:14])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:15][C:16]([CH2:21][CH3:22])([CH2:19]O)[CH2:17][OH:18]>>[OH:18][CH2:17][C:16]1([CH2:21][CH3:22])[CH2:19][O:14][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[N:15]1
Reactant: CCC(N)(CO)CO
Reactant: CCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCC1=NC(CC)(CO)CO1
Yield: 90.1 %

Procedure:
26 g (130 mmoles) of dodecanoic acid and 31 g (260 mmoles) of 2-amino-2-ethyl-1,3-propanediol were condensed together by heating at 185°-190° C. for 30 hours. Work up and distillation of the residue at 160°-162° C./1 mm Hg gave 33.19 g (90%) of the product.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:25][CH2:26][C:27](Cl)=[O:28]>O>[Cl:25][CH2:26][C:27]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[C:8]([CH3:12])=[CH:9][CH:10]=[CH:11][C:2]=1[CH3:1])=[O:28]
Reactant: Cc1cccc(C)c1NCC=O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1cccc(C)c1N(CC=O)C(=O)CCl
Temperature: 0 °C

Procedure:
The diethyl acetal of 2-(2,6-dimethylanilino)-acetaldehyde (13.0 grams), sodium carbonate (5.8 grams) dissolved in water (50 ml) and benzene (50 ml) were charged into a reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture was cooled to about 0°C and chloroacetyl chloride (6.2 grams) was incrementally added with stirring. After the addition was complete stirring was continued and the reaction mixture was permitted to warm to room temperature. After this time the mixture was filtered, washed with dilute hydrochloric acid and stripped of solvent under reduced pressure to yield the desired product the diethyl acetal of 2-(N-α-chloroacetyl-2,6-dimethylanilino)-acetaldehyde.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[Br:23][C:24]1[CH:25]=[C:26]([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36]OS(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH:27]=[CH:28][CH:29]=1>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:36][CH2:35][C:33]2[N:34]=[C:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([Br:23])[CH:25]=3)[O:31][C:32]=2[CH3:48])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(Br)c3)oc2C)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(-c3cccc(Br)c3)oc2C)cc1)Oc1ccccc1

Procedure:
This compound was prepared according to the procedure in Example 1, part D, using 3-(4-hydroxyphenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (551.5 mg, 1.84 mmol) and toluene-4-sulfonic acid 2-[2-(3-bromophenyl)-5-methyloxazol-4-yl]ethyl ester (1.04 g, 2.39 mmol): Rf=0.54 in 1:4 EtOAc:hexanes; 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H) 7.30 (t, J=7.6 Hz, 1H), 7.21 (t, J=7.6 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 6.98-6.95 (m, 1H), 6.82 (d, J=8.4 Hz, 2H) 6.83-6.81 (m, 2H), 4.23 (t, J=6.8 Hz, 2H), 4.20 (q, J=7.6 Hz, 2H), 3.26 (d, J=14.0 Hz, 1H), 3.09 (d, J=14.0 Hz, 1H), 2.97 (t, J=7.6 Hz, 2H), 2.38 (s, 3H), 1.38 (s, 3H), 1.21 (t, J=7.6 Hz, 3H); MS (EI)=564.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]=2[N+:28]([O-])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:15]=2[NH2:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(NCc3ccccc3)c2[N+](=O)[O-])CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(NCc3ccccc3)c2N)CC1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 92.8 %

Procedure:
A solution of 4-(3-benzylamino-2-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.200 g, 0.485 mmol) in 5 mL ethanol was added to a solution sodium dithionite (0.565 g, 3.245 mmol) in 10 mL water, and the reaction mixture was heated to 100° C. The mixture was stirred for 5 minutes, cooled to room temperature, and concentrated in vacuo to remove ethanol. A yellow solid precipitates and was filtered and dried under vacuum for 18 hours to give 0.173 g (0.45 mmol, 90%) of 4-(2-amino-3-benzylamino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. MS: 383 (M+H)+.
Reaction SMILES: [Li]CCCC.[CH3:6][O:7][CH2:8][O:9][CH2:10][Sn](CCCC)(CCCC)CCCC.[CH:24]([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)=[O:25]>C1COCC1.O>[OH:25][CH:24]([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)[CH2:10][O:9][CH2:8][O:7][CH3:6]
Reactant: O=Cc1nccs1
Reactant: CCCC[Sn](CCCC)(CCCC)COCOC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COCOCC(O)c1nccs1
Reaction time: 8 h
Yield: 34.8 %

Procedure:
n-BuLi (2.87 mmol, 1.8 mL, 1.6M) was added dropwise to a -78° C. solution of (methoxymethoxymethyl)tributyl tin (1.05 g, 2.87 mmol) in dry THF (10 mL). After stirring for 30 minutes a solution of 2-formylthiazole (2.73 mmol, 0.31 g) in THF (2 mL) was added and the solution stirred overnight. The reaction was diluted with water and extracted with ethyl acetate, dried (MgSO4), filtered and concentrated. The residue was subjected to flash chromatography (45% ethyl acetate/hexane) to afford 0.18 g (34%) of 2-(1-hydroxy-2-(methoxymethoxy)ethyl)thiazole.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[N:3]1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[CH:23][CH:24]=[O:25])=[CH:9][CH:8]=2)=[N:3]1
Reactant: Cn1ccc(-c2ccc(C=O)cc2)n1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: Cn1ccc(-c2ccc(C=CC=O)cc2)n1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(l-methyl-1H-pyrazol-3-yl)benzaldehyde (prepared as described in J. Med. Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 213 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[S:18][CH2:17][C:16]3[C:15](=[O:19])[CH:14]=[C:13]([C:20]([OH:22])=[O:21])[NH:12][C:11]=3[C:9]=2[CH:10]=1)[CH2:2][CH2:3][CH3:4].Cl.[CH3:24]O>>[CH3:24][O:21][C:20]([C:13]1[NH:12][C:11]2[C:9]3[CH:10]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=[CH:7][C:8]=3[S:18][CH2:17][C:16]=2[C:15](=[O:19])[CH:14]=1)=[O:22]
Reactant: CCCCc1ccc2c(c1)-c1[nH]c(C(=O)O)cc(=O)c1CS2
Reactant: CO
Agent: Cl
Product: CCCCc1ccc2c(c1)-c1[nH]c(C(=O)OC)cc(=O)c1CS2

Procedure:
A solution of 9-butyl-1,4-dihydro-4-oxo-5H-[1]benzothiopyrano-[4,3-b]pyridine-2-carboxylic acid (1.82 g, described in Example 84) in 350 ml of anhydrous methanol saturated with hydrogen chloride is heated at reflux for 17 hours. The solvent is removed by evaporation. Water is added to the residue and the aqueous mixture is extracted with chloroform. The organic extract is dried over magnesium sulfate and evaporated. The residue is subjected to chromatography on silica gel using benzene-ethyl acetate (4:1) as eluant. The eluate is evaporated and the residue is crystallized from ether to give the title compound, m.p. 144°-146° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([C:12]1[CH:21]=[CH:20][C:15]([C:16](=O)[CH2:17]Cl)=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C(=O)(O)[O-].[Na+]>C(O)(C)C>[C:8]([C:12]1[CH:13]=[CH:14][C:15]([C:16]2[N:1]=[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]3[CH:17]=2)=[CH:20][CH:21]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: Nc1ccccn1
Reactant: CC(C)(C)c1ccc(C(=O)CCl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)c1ccc(-c2cn3ccccc3n2)cc1
Temperature: 80 °C
Yield: 61.8 %

Procedure:
A solution of 2-aminopyridine (0.512 g, 5.44 mmol) and 4-tert-butylphenacyl chloride (1.26 g, 5.98 mmol) in isopropanol (16 mL) was treated with sodium bicarbonate (0.914 g, 10.9 mmol) and heated in a sealed tube at 80° C. overnight. The mixture was concentrated under reduced pressure, re-dissolved in ethyl acetate (200 mL) and washed with water (2×100 mL) and saturated sodium chloride (100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash silica gel chromatography, eluting with 20% acetone/hexanes to yield 0.841 g (62%) of the purified product. MS (ESI) m/z 251.1528; HPLC (Method B): r.t.=8.4 min., purity 100% at 210-370 nm, 100% at 306 nm. HRMS: calcd for C17H18N2+H+, 251.15427; found (ESI, [M+H]+), 251.1528.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12]S(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=2)[CH2:19][CH2:18]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH:17]3[CH2:18][CH2:19]3)=[CH:23][CH:24]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: Oc1ccc(OCC2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(OCC3CC3)cc2)C1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 2.6 g (10.4 mmol) 3-methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester, 1.7 g (10.4 mmol) 4-cyclopropylmethoxy-phenol and 6.7 g (20.7 mmol) Cs2CO3 in 60 mL DMF is stirred for 12 h at 80° C. Water is added and the mixture is extracted with ethyl acetate (2×). The combined organic layers are washed with NaHCO3 solution and are dried over MgSO4. The solvent is evaporated and the residue is purified by column chromatography (silica gel; PE/ethyl acetate; gradient 9:1→8:2) to yield the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]1[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[C:9]([CH3:15])[C:8]=1[OH:16])[CH3:2].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]1[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[C:9]([CH3:15])[C:8]=1[O:16][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=1)[CH3:2]
Reactant: CCOC(=O)CCc1c(CO)cnc(C)c1O
Reactant: N#Cc1ccc(CBr)cc1
Product: CCOC(=O)CCc1c(CO)cnc(C)c1OCc1ccc(C#N)cc1
Yield: 69.5 %

Procedure:
The coupling of 3-(3-hydroxy-5-hydroxymethyl-2-methyl-pyridin-4-yl)-propionic acid ethyl ester (35) (3.4 g, 14.2 mmol) and α-bromo-p-tolunitrile (4.2 g, 21.4 mmol), as described in Example 1, gave 3-[3-(4-cyano-benzyloxy)-5-hydroxymethyl-2-methyl-pyridin-4-yl]-propionic acid ethyl ester (36) (3.5 g, 70% yield).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17]O)[CH2:3][CH2:2]1.P(Br)(Br)[Br:20]>ClCCl>[Br:20][CH2:17][C:5]1[C:6]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])=[N:7][O:8][C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Temperature: 25 °C
Yield: 81.2 %

Procedure:
To a 0° C. solution of (5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-yl)-methanol (0.124 g, 0.44 mmol) in dichloromethane (4 mL) is added phosphorous tribromide (0.261 g, 0.963 mmol). The ice bath is removed after 20 minutes and the reaction is allowed to stir for an additional twenty minutes at room temperature. The reaction mixture is quenched with pH 7 buffer and extracted with dichloromethane several times. The organic layers are combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield the title compound (0.124 g, 82%). 1H-NMR (400 MHz CDCl3) δ 7.45-7.33 (m, 3H), 4.20 (s, 2H), 2.09 (m, 1H), 1.27 (m, 2H), 1.16 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[C:13](Cl)[CH:14]=[CH:15][C:16]=3[O:19][CH3:20])[N:11]([CH2:22][CH2:23][F:24])[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C>CO.[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[O:19][CH3:20])[N:11]([CH2:22][CH2:23][F:24])[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCc2c1c1c(OC)ccc(Cl)c1n2CCF
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCCc2c1c1c(OC)cccc1n2CCF
Reaction time: 18 h
Yield: 87.7 %

Procedure:
8-chloro-9-(2-Fluoroethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid ethyl ester (15) (5.3 g, 15.0 mmol) was dissolved in methanol (180 mL) and triethylamine (1.8 g, 18.0 mmol, 2.5 mL) and 10% Pd/C (2 g in methanol (20 mL)) were added. The mixture was placed on the Parr hydrogenator and shaken for 18 h under a hydrogen atmosphere. The reaction was filtered through a pad of celite, washed with methanol and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed with 10% aqueous potassium carbonate (200 mL), dried over magnesium sulfate and concentrated in vacuo to give 4.2 g (88%) of 9-(2-Fluoroethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid ethyl ester (16) as a light brown solid. The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC 14.3, 20.6, 21.8, 27.6, 40.3, 43.3 (d, JCF=23 Hz), 54.9, 60.1, 82.0 d, JCF=165 Hz), 99.8, 102.1, 107.3, 117.2, 121.8, 134.9, 137.6, 153.8, and 176.0.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:42][C@H:43]1[CH2:49][CH2:48][CH2:47][CH2:46][N:45]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[CH:52]=2)[C:44]1=[O:58]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:42][C@H:43]1[CH2:49][CH2:48][CH2:47][CH2:46][N:45]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[CH:52]=2)[C:44]1=[O:58])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@H]1CCCCN(Cc2cccc(Cl)c2)C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Agent: Cl
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(Cc4cccc(Cl)c4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S)-1-(3-chlorobenzyl)-2-oxoazepan-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (7.0 mg, 0.012 mmol) and Intermediate 47 (3.6 mg, 0.012 mmol) to give a white solid (7.0 mg, 69% yield). Anal. Calcd. for C44H53ClN4O6S m/z 800.4. found: 801.4 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.25-7.19 (m, 7H), 7.18-7.12 (m, 6H), 7.10 (d, J=4.40 Hz, 1H), 6.96 (d, J=6.60 Hz, 1H), 6.92 (d, J=6.60 Hz, 1H), 5.33 (t, J=4.67 Hz, 1H), 5.17-5.12 (m, 1H), 5.03-4.93 (m, 1H), 4.64 (d, J=14.85 Hz, 1H), 4.59 (dd, J=10.45, 6.60 Hz, 1H), 4.42 (d, J=14.85 Hz, 1H), 3.67 (s, 3H), 3.49 (dd, J=15.40, 11.55 Hz, 1H), 3.24-3.09 (m, 2H), 2.90-2.78 (m, 3H), 2.77-2.68 (m, 2H), 2.45-2.34 (m, 3H), 2.02 (d, J=5.50 Hz, 2H), 1.90-1.79 (m, 2H), 1.72 (br. s., 4H), 1.68-1.49 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[Cl:9]N1C(=O)CCC1=O>C(OCC)(=O)C>[NH2:8][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([Cl:9])=[CH:6][N:5]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)c(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-2-aminopyridine (Matrix Scientific, cat. #23809; 1.29 g, 0.01 mol) is dissolved by stirring in 500 ml of ethyl acetate. A thermometer is placed in the solution to monitor temperature. N-Chlorosuccinimide (13.3 g, 0.01 mol) is added in several portions to keep the solution at room temperature. The solution becomes dark in color and is stirred at room temperature overnight. The supernatant is decanted from the dark solids that formed and transferred to a separatory funnel. The organic solution is washed with 500 ml saturated aqueous sodium bisulfite and then 500 ml brine. The organic layer is dried with MgSO4 and concentrated on a rotovap. The dark brown crude product is chromatographed on 500 g of flash silica-gel eluting with CH2Cl2. Concentration of the appropriate fractions on a rotovap gives a light tan solid. The solid is dissolved in EtOAc and decolorized with activated carbon. EtoAc is removed using a rotovap and the resulting solid is suspended in ice-cold CH2Cl2 and filtered to give the product as a white solid. (MP 142-143° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)[CH2:7]1)=[O:5])[CH3:2].[Li+].[CH3:24]C([N-]C(C)C)C.CI>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([CH3:24])[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCN(CC2COc3ccccc3O2)C1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCCN(CC2COc3ccccc3O2)C1
Reaction time: 1 h

Procedure:
To a solution of 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidine-3-carboxylic acid ethyl ester (10.05 g, 32.90 mmol) in dry THF (100 ml) at −78° C. was slowly added LDA (20.1 ml, 1.8 M). The reaction mixture was stirred at this temperature for 1 h. Methyl iodide (2.25 ml, 36.21 mmol) was then added, the cooling bath removed and stirring was continued for 10 h. After addition of water, the reaction mixture was extracted with EtOAc (3×25 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give the title compound, which was purified by column chromatography (EtOAc/heptane, 70:30).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[CH3:6][C:7]1[C:12]([CH:13]=O)=[C:11]([CH3:15])[CH:10]=[CH:9][N:8]=1>O.C(O)C>[CH3:6][C:7]1[C:12]([CH:13]=[N:2][OH:3])=[C:11]([CH3:15])[CH:10]=[CH:9][N:8]=1
Reactant: NO
Reactant: Cc1ccnc(C)c1C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccnc(C)c1C=NO
Temperature: 65 °C
Yield: 88.4 %

Procedure:
A solution of hydroxylamine hydrochloride (0.21 g, 3.0 mmol) and sodium hydroxide (0.12 g, 3.0 mmol) in water (1.9 mL) was added to a solution of 2,4-dimethyl-3-pyridinecarbaldehyde (0.35 g, 2.6 mmol) in ethanol (3.8 mL). The solution was heated in a 65° C. oil bath for 2 hours. The mixture was concentrated and the residue diluted with water and filtered. The resulting white solid was dried in a 45° C. vacuum oven with P2O5 to yield 2,4-dimethyl-3-pyridinecarbaldehyde oxime (345 mg, 88%). 1H NMR (400 MHz, DMSO-d6): δ 11.44 (s, 1H), 8.33 (s, 1H), 8.23 (d, J=5 Hz, 1H), 7.08 (d, J=5 Hz, 1H), 2.48 (s, overlapping DMSO), 2.33 (s, 3H).