Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.[CH2:16]([O:18]/[CH:19]=[CH:20]/[C:21](Cl)=[O:22])[CH3:17]>C1COCC1>[CH2:16]([O:18]/[CH:19]=[CH:20]/[C:21]([NH:2][NH:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:22])[CH3:17]
Reactant: NNc1ccccn1
Reactant: CCO/C=C/C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCO/C=C/C(=O)NNc1ccccn1
Temperature: 25 °C

Procedure:
To a cold (0° C.) solution of 2-hydrazinopyridine (10.74 g, 98.4 mmol) and triethylamine (9.94 g, 98.4 mmol) in THF (100 mL) was added crude (2E)-3-ethoxyprop-2-enoyl chloride (based on 100% yield of previous step) dropwise. The resulting reaction mixture was allowed to warm to ambient temperature over 2 h and then heated at reflux for a further 5 h. The reaction mixture was quenched with water (50 mL), extracted with EtOAc (3×50 mL) and washed with brine. The organic phase was dried over Na2SO4, concentrated in vacuo, purified using liquid chromatography on silica gel eluting with EtOAc to afford (2E)-3-ethoxy-N′-pyridin-2-ylprop-2-enohydrazide as a brown oil. 1H NMR (CD3Cl, 300 MHz) δ 9.19 (br, 1H), 8.08 (d, 1H), 7.59˜7.44 (m, 3H), 6.75˜6.69 (m, 2H), 5.34 (d, 1H), 3.81 (q, 2H), 1.27 (t, 3H). MS (ESI) 208 (M++H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:31])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Br:30])[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:30][C:26]1[CH:25]=[C:24]([C:22]2[CH2:21][C:20](=[O:31])[NH:19][C:9]3[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:12]([CH3:14])=[CH:13][C:8]=3[N:7]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(Br)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(Br)c1)=N2

Procedure:
) The title compound was prepared from the above described {2-[3-(3-bromo-phenyl)-3-oxo-propionylamino]-5-methyl-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (3.50 g, 6.79 mmol) and TFA (20 mL) in DCM (60 mL) according to general procedure I step 2. Obtained as a light yellow solid (1.79 g, 64%). MS (ISP) 397.1 [(M+H)+] and 399.1 [(M+2+H)+]; mp 198-202° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[C@@H:23]1[C@H:29]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[S:28][C:27]2[C:38]3[C:43]([CH:44]=[CH:45][C:26]=2[N:25]([CH2:46][CH2:47][N:48]([CH3:50])[CH3:49])[C:24]1=[O:51])=[CH:42][CH:41]=[CH:40][CH:39]=3.[ClH:52]>O1CCCC1.CC(C)=O>[ClH:52].[ClH:52].[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([C@@H:29]2[S:28][C:27]3[C:38]4[C:43]([CH:44]=[CH:45][C:26]=3[N:25]([CH2:46][CH2:47][N:48]([CH3:50])[CH3:49])[C:24](=[O:51])[C@@H:23]2[O:8][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:9])=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:31][CH:32]=1
Reactant: O=C(O)c1cccnc1
Reactant: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A mixture of 0.5 g (0.004 mol) of nicotinic acid and 0.7 g (0.004 mol) of 1,1'-carbonyldiimidazole in 20 ml of dry tetrahydrofuran was stirred at room temperature for 1 hour. To the solution was added 1.3 g (0.003 mol) of (±)-cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-5-(2-(dimethylamino)ethyl]naphtho[1,2-b][1,4]thiazepin-4(5H)-one and the reaction mixture was stirred at room temperature for 17 hours. After concentrating to dryness the residue was partitioned between ethyl acetate and dilute ammonium hydroxide. The ethyl acetate solutions were washed with brine and dried (MgSO4). Removal of the solvent at reduced pressure gave 2.2 g of crude base which was dissolved in acetone and acidified with hydrogen chloride (anhydrous). The resulting crystals were separated to afford 1.9 g (99%) of (±)-cis-2,3-dihydro-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]-3-[(3-pyridinylcarbonyl)oxy]naphtho[1,2-b][1,4]thiazepin-4 (4H)-one dihydrochloride (4:5) hydrate, mp 178°-179°.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.[Br:8][C:9]1[C:10]([Cl:18])=[N:11][CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1.O>CN(C=O)C>[Br:8][C:9]1[C:10]([O:7][CH2:6][CH:3]2[CH2:5][CH2:4]2)=[N:11][CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1.[Br:8][C:9]1[C:10]([Cl:18])=[N:11][CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1
Reactant: OCC1CC1
Agent: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cnc(OCC2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a solution of sodium hydride (2.21 g, 55.34 mmol) in anhydrous DMF (20 ml) was added cyclopropylmethanol (CAS Registry No. 2516-33-8) (12.45 ml, 153.2 mmol) under nitrogen at 0° C. and the reaction mixture was stirred at 25° C. for 30 minutes. Then 3-bromo-2-chloro-5-nitropyridine (CAS Registry No. 5470-17-7) (7.3 g, 30.74 mmol) was added drop wise at 0° C. and stirred for two hours at 25° C. Water (60m1) was added to the reaction mixture and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated under reduced pressure to get the crude residue (12 g). The crude was purified by column chromatography (2% ethyl acetate/hexane) to get the desired product (2.06 g, 32%) as light yellow solid and 1.7 g of unreacted 3-bromo-2-chloro-5-nitropyridine was recovered. MS (LC/MS): not responding, NMR is in agreement with the structure: 1H-NMR (400 MHz, CDCl3): δ 0.41 (m, 2H), 0.65 (m, 2H), 1.32 (m, 1H), 4.34 (d, 2H), 8.60 (d, 1H), 8.96 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:17])=[C:13]([CH:16]=1)[CH:14]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[OH:19][NH3+:20].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:17])=[C:13](/[CH:14]=[N:20]/[OH:19])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH3+]O
Reactant: Cc1ccc(OCc2ccccc2)cc1C=O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(OCc2ccccc2)cc1/C=N/O
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.5 %

Procedure:
A mixture of 5-(benzyloxy)-2-methylbenzaldehyde (15.9 g), hydroxyl ammonium chloride (5.37 g), sodium bicarbonate (6.49 g), and ethanol (150 mL) was stirred at room temperature for 6 hours. The precipitate was filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (16.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:10][CH2:9][CH2:8][C:7](=[O:22])[C:6]=2[CH:23]=1.S(=O)(=O)(O)O.O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][CH2:8][C:7](=[O:22])[C:6]=2[CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(=O)c3cc(Cl)ccc32)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCCNc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
7-Chloro-1-p-toluenesulfonyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (5 g) is added to 90% (w/w) sulfuric acid (50 ml), and the mixture is stirred at 0° C. to 10° C. for 2.5 hours. The reaction mixture is added to a cool water (50 mL) and then is neutralized by gradually adding thereto a solution of sodium hydroxide (75 g) in an appropriate amount of water with attention to exothermal reaction. The reaction mixture is cooled to 25° C., and the resulting yellowish green suspension is extracted with toluene (50 mL), and the organic layer is separated, washed with water (25 ml×2) and dried over sodium sulfate. After filtering off sodium sulfate, the filtrate is concentrated under reduced pressure to give a pale yellow crystals. The crystals are subjected to azeotropic dehydration with toluene in order to remove a slight amount of water to give 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one having a moisture content of less than 100 ppm (2.5 g, yield 89%, M.p. 103-104° C.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:14][C:13](=O)[N:12]([CH3:16])[C:11]2=O)=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH3:16][N:12]1[CH2:13][CH2:14][CH:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:11]1
Reactant: CN1C(=O)CC(c2c[nH]c3ccccc23)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccccc23)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 3-(1-H-indol-3-yl)-1-methyl-pyrrolidine-2,5-dione (1.4 g) in tetrahydrofuran is treated with LiAlH4 (12 mL, 1.0 M solution, 2 equiv), stirred at 50° C. for 8 hr, cooled to room temperature, quenched with water and 15% aqueous NaOH and filtered. The filtrate is dried over MgSO4 and concentrated in vacuo to afford the title product as an oil, 1.1 g, identified by HPLC and mass spectral analyses.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:11]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[C:28]1[S:29][CH:30]=[CH:31][N:32]=1.CS(C)=O>CCOC(C)=O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([O:16][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)[CH:13]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:11]=1)#[N:2]
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cc2C#N)c1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Oc2nccs2)cc(-c2ccc(C)cc2C#N)c1
Temperature: 135 °C

Procedure:
A stirred mixture of methyl 2′-cyano-5-hydroxy-4′-methylbiphenyl-3-carboxylate (350 mg, 1.2 mmol), potassium carbonate (363 mg, 2.63 mmol), 2-bromothiazole (431 mg, 2.63 mmol), and dimethyl sulfoxide (10 mL) was heated at 135° C. overnight. After cooling, the reaction mixture was diluted with EtOAc. The organic phase was washed with aq. NaHCO3 (sat.), dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=1)([O-:3])=[O:2].Cl.[CH3:20][O:21][C:22](=[O:29])[C@H:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH2:24].N[C@H](C(O)=O)CCSC>>[CH3:20][O:21][C:22](=[O:29])[C@H:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:24][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1-c1ccccc1
Agent: CSCC[C@H](N)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1

Procedure:
This compound was prepared through the coupling of 4-nitro-2-phenylbenzoic acid with (L)-leucine methyl ester hydrochloride as for the preparation of the methionine derivative (see Example 26, section A). 1H NMR (CDCl3) δ 8.24-8.26 (m, 2H), 7.86 (d, 8.7 Hz, 1H), 7.41-7.46 (m, 5H), 5.71 (d, 7.4 Hz, 1H), 4.57 (ddd, 1H), 3.67 (s, 3H), 1.37-1.46 (m, 1H), 1.08-1.25 (m, 2H), 0.78 (dd, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([C:36]([F:39])([F:38])[F:37])[C:34]=1[OH:35])[CH2:5][C@@H:6]([CH2:11][C:12](=[O:31])[N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[NH:21][C:20]2=[O:30])[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8].[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([C:36]([F:39])([F:37])[F:38])[C:34]=1[OH:35])[CH2:5][C@@H:6]([CH2:11][C:12](=[O:31])[N:13]1[CH2:14][CH2:15][CH:16]([N:19]2[CH2:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[NH:21][C:20]2=[O:30])[CH2:17][CH2:18]1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)[C@H](CC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)Cc1cc(Cl)c(O)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](CC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)Cc1cc(Cl)c(O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.8 g methyl (S)-2-(3-chloro-4-hydroxy-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidin-1-yl]-butanoate dissolved in 50 ml THF was combined with a solution of 115.2 mg (4.8 mmol) lithium hydroxide in 50 ml of water and stirred overnight at RT. The reaction mixture was evaporated down under reduced pressure, combined with 150 ml of water and washed with 150 ml EtOAc. The aqueous phase was acidified with conc. hydrochloric acid and extracted with 150 ml EtOAc. The organic phase was separated off, dried and evaporated down under reduced pressure.
Reaction SMILES: S(=O)(=O)(O)O.[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]([CH:15]([OH:17])[CH3:16])=[N:7]1>O.C(OCC)C>[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]([C:15](=[O:17])[CH3:16])=[N:7]1
Reactant: CC(O)c1noc2ccccc12
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: CC(=O)c1noc2ccccc12
Reaction time: 1 h

Procedure:
A mixture of 1.1 g of sodium bichromate dihydrate and 0.8 ml of sulfuric acid in 5 ml of water is slowly added dropwise to 1.6 g of 1-(1,2-benzisoxazol-3-yl)ethanol in 5 ml of diethyl ether. This mixture is stirred for 1 hour at room temperatur and then, with ice cooling, 50 ml of water are added and extraction wth diethyl ether is carried out three times. The combined ethereal extracts are washed once with a saturated solution of sodium bicarbonate, once with water and finally once with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated under vacuum. The crude product is purified by chromatography over silica gel with ethyl acetate/hexane (1:3), giving 1-(1,2-benzisoxazol-3-yl)ethanone having a melting point of 30°-32° C.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[N:8][C:7]([C:15](OCC)=[O:16])=[N:6]1.[C-]#[N:25].[Na+].N.CO>>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[N:8][C:7]([C:15]([NH2:25])=[O:16])=[N:6]1
Reactant: [C-]#N
Reactant: CCOC(=O)c1nc(-c2nccs2)n(Cc2ccccc2F)n1
Agent: N
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1nc(-c2nccs2)n(Cc2ccccc2F)n1
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of ethyl 1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboxylate (Intermediate-3, 0.78 mmol) and sodium cyanide (0.1 equiv) in ammonia/MeOH (7N, 30 equiv, 3.4 mL) in a seal tube was heated at 90° C. for 24 h. The reaction mixture was cooled to room temperature, conc. and dried in vacuo to afford 1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboxamide as a tan solid (>99% yield).
Reaction SMILES: COC1C2CCNCCC=2C=CC=1.C([N:17]1[CH2:23][CH2:22][C:21]2[C:24]([Br:34])=[CH:25][C:26]([S:30]([CH3:33])(=[O:32])=[O:31])=[C:27]([O:28]C)[C:20]=2[CH2:19][CH2:18]1)(=O)C.Cl.COC1C2CCNCCC=2C=CC=1S(C)(=O)=O.Br>>[BrH:34].[OH:28][C:27]1[C:20]2[CH2:19][CH2:18][NH:17][CH2:23][CH2:22][C:21]=2[CH:24]=[CH:25][C:26]=1[S:30]([CH3:33])(=[O:32])=[O:31]
Reactant: COc1c(S(C)(=O)=O)cc(Br)c2c1CCN(C(C)=O)CC2
Agent: Br
Agent: COc1c(S(C)(=O)=O)ccc2c1CCNCC2
Agent: COc1cccc2c1CCNCC2
Product: CS(=O)(=O)c1ccc2c(c1O)CCNCC2

Procedure:
Following the procedure of Examples 1 and 8, 6-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine is converted via 3-acetyl-6-methoxy-7-methylsulfonyl-9-bromo-2,3,4,5-tetrahydro-1H-3-benzazepine to 6-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride which is treated with hydrobromic acid to give 6-hydroxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH:10](OCC)(OCC)OCC>>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:10]=[N:9][N:8]=2)[CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: NNc1ccc(I)cn1
Product: Ic1ccc2nncn2c1
Temperature: 25 °C

Procedure:
A mixture of the product (2.0 g, 8.51 mmol) from Step A above in triethyl orthoformate (100 mL) was warmed at reflux for 18 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 250 mL of dichloromethane and was filtered through a pad of silica gel. The pad was washed with 20% methanol/dichloromethane to elute the compound from the silica gel, and this filtrate was concentrated to dryness and then redissolved in dichloromethane. Addition of hexanes afforded a precipitate, which was collected. The filtrate was concentrated to half volume, and was then diluted with additional hexanes to yield a second crop of product. The combined solids were dried in vacuo to afford the title compound as a pale yellow solid. LC/MS 246.0 (M+1)
Reaction SMILES: [CH2:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:3]1[C:12]([OH:14])=[O:13].[C:15]([O-])([O-])=O.[K+].[K+].CI.Cl>CN(C=O)C>[CH2:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:3]1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: C=C1CCCC2(CCCC2)C1C(=O)O
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=C1CCCC2(CCCC2)C1C(=O)OC
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
At 5° C., a solution of the previously obtained 7-methylenespiro[4.5]decane-6-carboxylic acid (1.1 g, 5.66 mmol, prepared as described in Example 28) in DMF (20 ml) was treated with K2CO3 (0.86 g, 6.8 mmol). The resulting mixture was stirred for 30 min., treated with methyl iodide (0.53 ml, 8.5 mmol), stirred at 20° C. for 2 h, poured into cold 2N aqueous HCl (30 ml), and extracted twice with hexane (50 ml). The combined organic phases were washed with water (50 ml), with a saturated aqueous solution of NaCl (50 ml), dried (MgSO4), and concentrated. FC (30 g SiO2, hexane/MTBE 50:1) of the crude product (1 g) gave methyl 7-methylenespiro[4.5]decane-6-carboxylate (0.84 g, 71%). Boiling point: 90° C. (1.1 mbar).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5](=[O:31])[CH2:6][C:7](O)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][Si](C(C)(C)C)(C)C)=[CH:12][CH:11]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].C1COCC1>C1COCC1>[OH:31][C:5]1[CH2:6][C:7]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:32][C:3](=[O:2])[CH:4]=1
Reactant: COC(=O)CC(=O)CC(O)(CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(CCc2ccc(O)cc2)(c2ccccc2)O1

Procedure:
The title compound was prepared as described in General Method 7 and General Method 8 using 9.05 g (20 mmol) of 7-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-5-hydroxy-3-oxo-5-phenyl-heptanoic acid methyl ester from the previous paragraph, 40 mL (40 mmol) of 1 M tetrabutylammonium fluoride and 20 mL of THF. The resultant crude material was combined with 800 mL of 0.1N NaOH:THF (9:1). After workup the product was purified by silica gel chromatography, eluting with MeOH:CH2Cl2 (5:95 to 10:90) gave the title compound. 1H NMR (CDCl3) δ 2.24 (m, 2 H), 2.42 (m, 1H), 2.63 (m, 1 H), 2.96 (dd, 2 H), 3.33 (dd, 2 H), 5.17 (bs, 1 H), 6.73 (d, 2 H), 6.94 (d, 2 H), 7.33-7.45 (m, 5 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]1[CH:11]([CH3:20])[CH:12](OS(C)(=O)=O)[CH2:13][CH2:14][C:8]1=[C:7]2[CH2:21][C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23].[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C.CCOC(C)=O>[N:28]([CH:12]1[CH:11]([CH3:20])[N:9]2[C:10]3[C:6]([C:7]([CH2:21][C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23])=[C:8]2[CH2:14][CH2:13]1)=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCOC(=O)Cc1c2n(c3c(F)cccc13)C(C)C(OS(C)(=O)=O)CC2
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOC(=O)Cc1c2n(c3c(F)cccc13)C(C)C(N=[N+]=[N-])CC2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Propyl {4-fluoro-6-methyl-7-[(methylsulfonyl)oxy]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl}acetate was dissolved in DMF (1 M) and treated with NaN3 (2.0 eq.), warmed to 80° C. and stirred overnight. The reaction mixture was diluted with EtOAc and extracted with sat'd NH4Cl, water, dried (Na2SO4) and concentrated. Chromatography on SiO2 (0-100% EtOAc/hexanes) gave propyl (7-azido-4-fluoro-6-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate: 1H NMR (600 MHz, CDCl3) δ 7.30 (d, J=7.9 Hz, 1H), 6.96-6.99 (m, 1H), 6.80 (dd, J=12.6, 7.6 Hz, 1H), 4.87 (dd, J=13.2, 6.5 Hz, 1H), 4.10 (d, J=7.0 Hz, 1H), 4.02 (t, J=6.2 Hz, 2H), 3.61 (m, 2H), 3.01 (m, 2H), 2.10-2.20 (m, 2H), 1.57-1.63 (m, 2H), 1.43 (d, J=6.8 Hz, 3H), 0.87 (t, J=7.3 Hz, 3H); MS (EI) calc'd for C18H22FN4O2 [M+1]+345.2. found 345.1.
Reaction SMILES: [Br:1][C:2]1([Br:14])[CH2:4][C:3]1([Br:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].[OH2:15]>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[Br:1][C:2]1([Br:14])[CH2:4][C:3]1([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:15])=[O:12])[Br:13]
Reactant: O
Reactant: OCCCCCCCC1(Br)CC1(Br)Br
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: O=C(O)CCCCCCC1(Br)CC1(Br)Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1,1,2-Tribromo-2-(7-hydroxyheptyl)cyclopropane (0.90 g, 2.3 mmol) was dissolved in 60 ml of glacial acetic acid. A solution of 1.0 g (10 mmol) of chromium trioxide dissolved in 14 ml of 90% aqueous acetic acid was added and the reaction mixture was stirred at room temperature for 24 hours. Water (300 ml) was added. The solution was extracted with ether. The ether phase was extracted three times with 1N NaOH solution. A little sodium bisulfite was added. The aqueous extracts were acidified with 6N HCl, and extracted with ether twice. The ether extracts were washed with brine, dried over magnesium sulfate and stripped to give 0.56 g 7-(1,1,2-tribromo-cyclopropyl)-heptanoic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1)[C:7](=[O:21])[CH:6]=2.[C:22]1([CH2:28][C:29]#[CH:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C)C=O.[Cu]I.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>[F:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[F:19])[CH2:12][N:8]1[C:7](=[O:21])[CH:6]=[C:5]2[C:10]([N:11]=[C:2]([C:30]#[C:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:3]=[N:4]2)=[CH:9]1
Reactant: O=c1cc2ncc(Br)nc2cn1Cc1ccc(F)c(F)c1
Reactant: C#CCc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1cc2ncc(C#CCc3ccccc3)nc2cn1Cc1ccc(F)c(F)c1

Procedure:
The coupling of 7-bromo-2-(3,4-difluorobenzyl)-2H-5,8-diazaisoquinolin-3-one (0.80 g, 2.28 mmol) with 3-phenyl-1-propyne (0.71 mL, 5.74 mmol) using triethylamine (0.64 mL, 4.59 mmol), CuI (0.031 g, 0.16 mmol), and Pd(Ph3P)4 (0.106 g, 0.092 mmol) in dimethylformamide (6 mL) is carried out as described in Example 1, Step (2). The resulting red oil is evaporated onto silica gel and purified on a 3.5×20 cm silica gel column eluted with hexanes/ethyl acetate 3:1. The resulting red solid is triturated with ethyl ether and dried. This will afford the desired product.