Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:37]([C:39]1[C:40]([N:49]2[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH2:51][CH2:50]2)=[CH:41][C:42]([O:46][CH2:47][CH3:48])=[C:43]([NH2:45])[CH:44]=1)[CH3:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.N>C(O)C(F)(F)F.CO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:45][C:43]3[CH:44]=[C:39]([CH2:37][CH3:38])[C:40]([N:49]4[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH2:51][CH2:50]4)=[CH:41][C:42]=3[O:46][CH2:47][CH3:48])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(CC)cc1N
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: CO
Solvent: OCC(F)(F)F
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(CC)cc1Nc1nccc(-c2c(-c3ccc(OCC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 85 °C
Yield: 31 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (0.43 g, 0.84 mmol) and (5-ethyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}phenyl)amine (0.30 g, 0.84 mmol) in trifluoroethanol (5 mL) was added p-toluene sulfonic acid (0.32 g, 1.7 mmol), and the vial was sealed and heated to 85° C. overnight. The reaction was then cooled to rt and excess NH3 in MeOH (10% in DCM) was added. The solution was transferred to a roundbottom flask and silica was added. The solvent was removed on a rotovap and the product purified on a 40 g ISCO column. Desired fractions were combined and rotovaped down. The resulting foam was dissolved in DCM and ether was added to provide the title compound (0.23 g, 0.26 mmol, 30% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.71 (s, 1H), 9.29 (d, J=6.2 Hz, 1H), 8.36 (s, 1H), 8.24 (d, J=5.3 Hz, 1H), 8.03 (s, 1H), 7.73-7.70 (m, 1H), 7.67 (d, J=9.0 Hz, 1H), 7.56 (s, 1H), 7.42-7.31 (m, 2H), 7.23 (d, J=8.4 Hz, 1H), 7.16 (t, J=8.2 Hz, 2H), 6.90 (t, J=6.6 Hz, 1H), 6.78 (s, 1H), 6.57 (d, J=5.3 Hz, 1H), 4.23 (q, J=7.3 Hz, 2H), 4.04 (q, J=7.1 Hz, 2H), 3.31-3.26 (m, 2H), 3.03 (s, 3H), 2.84-2.78 (m, 2H), 2.74 (t, J=6.5 Hz, 2H), 2.63-2.46 (m, 6H), 1.40 (t, J=6.8 Hz, 3H), 1.22 (t, J=6.9 Hz, 3H), 1.05 (t, J=7.5 Hz, 3H). MS (ESI) m/z=824 [M+H]+.
Reaction SMILES: [CH3:1][O:2][N:3]=C1C2C=CN=NC=2OC1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[O:21][CH2:22][C:23](=O)[C:16]=12>>[CH3:1][O:2][N:3]=[C:23]1[C:16]2[C:17](=[N:18][CH:19]=[CH:20][C:15]=2[C:14]([F:26])([F:25])[F:13])[O:21][CH2:22]1
Reactant: O=C1COc2nccc(C(F)(F)F)c21
Reactant: CON=C1COc2nnccc21
Product: CON=C1COc2nccc(C(F)(F)F)c21

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime (A.2.3.3), 4-(trifluoromethyl)furo[2,3-b]pyridin-3(2H)-one replacing furo[2,3-c]pyridazin-5(6H)-one. Purification by (KP-SIL™ from Biotage) using Hept/EtOAc (9/1) gives the desired product as colorless foam;
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]([O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2([CH2:28][O:29][CH3:30])[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[O:14])[CH:9]=[CH:10][CH:11]=1)=[O:4].Cl>CO>[CH3:31][N:2]([CH3:1])[C:3](=[O:4])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2([CH2:28][O:29][CH3:30])[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)=[O:14])[CH:7]=1
Reactant: COCC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: COCC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCNCC1
Temperature: 50 °C

Procedure:
To a solution of tert-butyl 4-(3-(dimethylcarbamoyloxy)-phenylcarbamoyl)-4-(methoxymethyl)piperidine-1-carboxylate from step C (1.03 g, 2.37 mmol) in methanol (10 mL) was added HCl (4 M solution in dioxane, 2 mL). The reaction was heated at 50° C. for 1 hour, and then concentrated under vacuum to provide the title compound as the hydrochloride salt. MS (ES+) [M+H]−=336.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13][CH2:14]Br>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:9][NH2:10])[CH2:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1cccc(Cl)c1
Reactant: BrCCCBr
Product: NCC1(c2cccc(Cl)c2)CCC1

Procedure:
(1-(3-Chlorophenyl)cyclobutyl)methylamine is prepared from (3-chlorophenyl)acetonitrile (3.79 g, 25 mmol) and 1,3-dibromopropane (7.57 g, 375 mmol) as described in Example 1 in 60% overall yield.
Reaction SMILES: [CH3:1][SH-:2][C:3](=[N:5][OH:6])[CH3:4].[CH3:7][N:8]([S:12][N:13]([CH3:15])[CH3:14])[C:9](F)=[O:10].C(N(CC)CC)C>O1CCCC1>[CH3:7][N:8]([S:12][N:13]([CH3:15])[CH3:14])[C:9]([O:6][N:5]=[C:3]([S:2][CH3:1])[CH3:4])=[O:10]
Reactant: C[SH-]C(C)=NO
Reactant: CN(C)SN(C)C(=O)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSC(C)=NOC(=O)N(C)SN(C)C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
A mixture of 5.25 g (0.05 mole) of S-methyl-N-hydroxythioacetimidate, 7.9 g of N-methyl-N-(dimethylaminosulfenyl)carbamoyl fluoride, and 5.1 g of triethylamine in 75 ml of tetrahydrofuran was stirred and heated at 40°-60° C. for 3 hrs. and then at 25° C. for 8 hrs. The solvent was removed in vacuo, and the residue was taken up in chloroform. This solution was extracted with water and 10% potassium carbonate, dried (MgSO4) and then was concentrated in vacuo. The crude syrupy residue obtained was purified by column chromatography on silica gel to give 1.6 g of S-methyl N-[N'-methyl-N'-(dimethylaminosulfenyl)-carbamoyloxy]thioacetimidate, a yellow syrup.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([CH3:20])[CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[O:23][C:24](=O)[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>C(O)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:24](=[O:23])[C:25]4[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:27]=[C:22]3[CH3:21])=[C:15]([CH3:20])[CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C#Cc2ccc(C(C)(C)C)cc2)ccc1N
Reactant: Cc1nc2ccccc2c(=O)o1
Solvent: CC(=O)O
Product: Cc1cc(C#Cc2ccc(C(C)(C)C)cc2)ccc1-n1c(C)nc2ccccc2c1=O

Procedure:
4-iodo-2-methylbenzenamine 24 (233 mg, 1 mmol) on reaction with 1-tert-butyl-4-ethynylbenzene (25b, 158 mg, 1 mmol) by employing Sonagashira coupling conditions using Pd(PPh3)4 (69.3 mg, 0.06 equiv) as catalyst, CuI (22.8 mg, 0.12 equiv) as cocatalyst, butyl amine (261 mg, 3 equiv) as base and ether as solvent and kept the reaction for 6 h. After completion of the reaction as indicated by TLC and the reaction mixture is extracted into ether (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain 4-((4-tert-butylphenyl)ethynyl)-2-methyl benzene amine (26b) as pure product. Anthranilic acid (27, 137 mg, 1 mmol) on reaction with acetic anhydride at 150° C. and reflux for 30 min, after completion of reaction aqueous sodium bicarbonate solution is added and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo afforded 2-methyl 4H-benzo[d][1,3]oxazin-4-one compound (28) as pure product. To a stirred solution of 4-((4-tert-butylphenyl)ethynyl)-2-methylbenzenamine (26b, 263 mg, 1 mmol) with 2-methyl-4H-benzo[d][1,3]oxazin-4-one (28, 161 mg, 1 mmol) in acetic acid and reflux for 8 h After completion of the reaction as indicated by TLC. then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4 afforded 3-(4-((4-tert-butylphenyl)ethynyl)-2-methylphenyl)-2-methylquinazolin-4(3H)-one (29b). Reaction of 3-(4-((4-tert-butylphenyl)ethynyl)-2-methylphenyl)-2-methyl quinazolin-4(3H)-one (29b, 406 mg, 1 mmol) with 2,4-dihydroxybenzaldehyde (30d, 138 mg, 1 mmol) was taken in acetic acid Then the resulting mixture was stirred under reflux conditions for 8 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (5d) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5](CC2C=NC(C)=NC=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.C([BH3-])#N.[Na+].[F:35][C:36]([F:46])([F:45])[C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH:39]=O>>[CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:39][C:38]2[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=2[C:36]([F:46])([F:45])[F:35])[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@@H]1CN(Cc2ccccc2C(F)(F)F)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting sodium cyanoborohydride and 2-(trifluoromethyl)benzaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 10.58 (brs, 1H), 8.01 (s, 1H), 7.79-7.76 (m, 1H), 7.64-7.58 (m, 2H), 7.37-7.34 (m, 1H), 4.83-4.76 (m, 1H), 4.14-4.08 (m, 2H), 3.88 (m, 2H), 3.62-3.54 (m, 2H), 3.39 (t, J=8.3 Hz, 1H), 3.02-2.97 (m, 1H), 2.85 (m, 1H), 2.66 (m, 1H), 2.44-2.27 (m, 3H), 2.06-2.03 (m, 1H), 1.91-1.83(m,2H), 1.21 (d,J=7.1 Hz, 3H). MS: (M+H m/z 462.1).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[OH-].[Na+].[N+:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)([O-:9])=[O:8].O>CC(C)=O>[CH:1]([NH:4][C:14](=[O:15])[C:13]1[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:18][CH:17]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 74 %

Procedure:
32.5 g of isopropylamine dissolved in 250 ml of acetone are added with 71 g of a 30% sodium hydroxide aqueous solution. This mixture, cooled to 0° C., is slowly added with 92.7 g of p-nitrobenzoyl chloride dissolved in 300 ml of acetone, coo ling with an ice bath to keep temperature from 0° to 5° C. Subsequently stirring is continued for 1 more hour allowing temperature to raise to 20°-30° C. Then the reaction mixture is poured into cold water. The formed precipitate is filtered, washed with water, dried and crystallized from isopropanol. 77 g of N-isopropyl-p-nitrobenzamide are obtained as a whitish solid substance with m.p. 152°-154° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([CH3:21])[NH2:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][N:34]=[C:35]=[S:36].O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:20][C:35]([NH:34][CH2:33][C:29]4[O:28][CH:32]=[CH:31][CH:30]=4)=[S:36])[CH3:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: S=C=NCc1ccco1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: C[C@H](NC(=S)NCc1ccco1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Yield: 76.8 %

Procedure:
(αS,βR)-β-{[1-(4-Fluorophenyl)-1H-indazole-5-yl]oxy}-α-methylbenzeneethanamine (50 mg, 0.14 mmol), as described in Example 1, is dissolved in 0.89 mL dichloromethane and furylmethylisothiocyanate (19.3 mg, 0.14 mmol) is dropwise added. After stirring for 90 min at r.t. water (5 mL) is added and the reaction mixture extracted once with ethyl acetate (50 mL). The organic phase is washed with water (10 mL) and dried over Na2SO4. After filtration the solvent is removed and the residue purified by chromatography (silicagel, eluents: hexane/ethylacetate). 53.8 mg (77.7%) of the title compound are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2[CH:11]=[CH:12][S:13][C:3]1=2.[F:14][C:15]([F:26])([F:25])[C:16](OC1C=CC=CN=1)=[O:17].[Al+3].[Cl-].[Cl-].[Cl-].O>ClCCCl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2[C:11]([C:16](=[O:17])[C:15]([F:26])([F:25])[F:14])=[CH:12][S:13][C:3]1=2
Reactant: Cn1c2ccccc2c2ccsc21
Reactant: O=C(Oc1ccccn1)C(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: Cn1c2ccccc2c2c(C(=O)C(F)(F)F)csc21
Temperature: -10 °C

Procedure:
A mixture of 1 g of (73) and 1.1 g of 2-trifluoromethylcarbonyloxypyridine, prepared according to the literature (Keumi, T. et. al. Chem. Lett. 5 (1990) 783-6), in 25 ml of 1,2-dichloroethane, was cooled to -10° C. with stirring. 1.5 g of AlCl3 was added over 15 minutes at this temperature, the reaction mixture was stirred at 0° C. for 4 hours, and at room temperature overnight. Water was added, the phases separated, and the organic phase dried and evaporated to dryness. Purification by column chromatography on silica gel in toluene gave the pure (74). Yield 590 mg. M.p. 138°-40° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:35][O:34][C:5]2([CH2:33][CH2:32][C:8]3([O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]4[CH:22]=[CH:21][C:20](B5OC(C)(C)C(C)(C)O5)=[CH:19][CH:18]=4)[CH3:16])[CH2:10][CH2:9]3)[CH2:7][CH2:6]2)[O:4][CH2:3]1.Br[C:38]1[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=1>>[CH3:36][C:2]1([CH3:1])[CH2:3][O:4][C:5]2([CH2:6][CH2:7][C:8]3([O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]4[CH:22]=[CH:21][C:20]([C:38]5[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=5)=[CH:19][CH:18]=4)[CH3:16])[CH2:10][CH2:9]3)[CH2:32][CH2:33]2)[O:34][CH2:35]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Reactant: Cn1ccc(Br)cc1=O
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Yield: 71 %

Procedure:
The title compound is prepared from 12,12-dimethyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one and 4-bromo-1-methyl-1H-pyridin-2-one following a procedure analogous to that described in Example 7. Yield: 71% of theory; LC (method 3): tR=3.40 min; Mass spectrum (ESI+): m/z=481 [M+H]+.
Reaction SMILES: [C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH3:10].[N+:14]([O-])([O-:16])=[O:15].[K+]>S(=O)(=O)(O)O>[C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[C:7]([N+:14]([O-:16])=[O:15])[C:6]([F:9])=[CH:5][C:4]=1[CH3:10]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)Oc1ccc(F)cc1C
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
4-Fluoro-2-methylphenyl methyl carbonate (D14) (2.5 mmol, 468 mg) was dissolved in concentrated sulphuric acid under argon and cooled to 0° C. KNO3 (2.5 mmol, 253 mg, 1 eq) was then added cautiously while keeping the temperature around 0° C. The mixture was then allowed to stir for 2 h while warming up to room temperature, then it was poured onto ice cautiously and extracted with ether twice. Organics were combined, dried on MgSO4 and concentrated under reduced pressure to give the title compound as a light brown solid (2.36 mmol, 540 mg, 94% yield). 1H NMR (CDCl3) 7.92 (1H, d), 7.18 (1H, d), 3.95 (3H, s), 2.33 (3H, s).
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CCN(C(C)C)C(C)C.[NH:23]1[CH2:28][CH2:27][S:26][CH2:25][CH2:24]1>C(#N)C>[C:8]1([CH:2]([N:23]2[CH2:28][CH2:27][S:26][CH2:25][CH2:24]2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1CSCCN1
Reactant: CCOC(=O)C(Br)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(c1ccccc1)N1CCSCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 110.9 %

Procedure:
Ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol) was dissolved in acetonitrile (4.0 ml). DIPEA (0.26 ml, 1.481 mmol) and thiomorpholine (0.15 ml, 1.41 mmol) were sequentially added and the solution was stirred at room temperature for 1.5 hours. Acetonitrile was evaporated and the residue was purified by flash chromatography (petroleum ether/EtOAc=95/5) to obtain ethyl 2-phenyl-2-thiomorpholinoacetate (362 mg, quantitative yield) as a colorless oil.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:9])[CH3:8])[CH:2]=1.[Br:11]Br.CCOCC>O1CCOCC1>[Br:11][CH2:8][C:7]([C:3]1[CH:2]=[C:1]([CH3:10])[CH:6]=[CH:5][CH:4]=1)=[O:9]
Reactant: CC(=O)c1cccc(C)c1
Reactant: BrBr
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-m-tolyl-ethanone (6.0 g, 44.72 mmol) in dioxane (5 ml), bromine (7.14 g, 44.72 mmol) in dioxane (10 ml) and ether (15 ml) was added and stirred at room temperature for 5 hr. The reaction mixture was poured into ice water and the compound was extracted using ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and then evaporated to give crude 2-bromo-1-m-tolyl-ethanone, 7.6 g (80%). The crude compound obtained was used in the next step without further purification.
Reaction SMILES: C(O[C:5]1[CH:20]=[C:19]([O:21][C:22](=[O:24])[CH3:23])[C:8]2[C:9]([CH3:18])=[C:10]3[N:15]([C:16](=[O:17])[C:7]=2[CH:6]=1)[CH2:14][CH2:13][CH2:12][CH2:11]3)(=O)C.[C:25]([O:28]C(=O)C)(=[O:27])[CH3:26].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:25]([O:28][C:20]1[CH:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]3[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)[C:9](=[CH2:18])[C:8]=2[C:19]=1[O:21][C:22](=[O:24])[CH3:23])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Oc1cc(OC(C)=O)c2c(C)c3n(c(=O)c2c1)CCCC3
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: C=C1c2c(ccc(OC(C)=O)c2OC(C)=O)C(=O)N2CCCCC12

Procedure:
Reflux crude 8,10-bis(acetyloxy)-1,2,3,4-tetrahydro-11-methyl-6H-benzo[b]quinolizin-6-one (11.8 g), acetic anhydride (20.2 ml), pyridine (20.2 ml), and chloroform (400 ml) for 20 hrs. Concentrate the cooled solution to dryness, and dilute the residue with ethyl acetate. Separate the resulting crystals by filtration, and concentrate the mother liquor. Chromatograph the residue over silica gel, and elute the column with 10% ethyl acetate in dichloromethane. Combine and concentrate fractions, and crystallize to obtain 9,10-bis(acetyloxy)-1,2,3,4,11,11a-hexahydro-11-methylene-6H-benzo[b]quinolizin-6-one, m.p. 129°-132° C. (from CHCl3 -EtOAc).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([N:16]1[C:20](=[O:21])[C:19](Cl)=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:17]1(=[O:30])=[O:29])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([N:16]1[C:20](=[O:21])[C:19]([NH:11][CH2:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:17]1(=[O:29])=[O:30])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCCCOc1ccccc1
Product: CC(C)(C)N1C(=O)C(NCCCOc2ccccc2)=C(c2ccccc2)S1(=O)=O
Yield: 73 %

Procedure:
The title compound was prepared as described for Example 24 from (3-phenoxypropyl)amine and 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide. The residue was purified by silica gel column chromatography (Horizons Biotage) using 17-20% EtOAc in hexane as eluent to give the title compound (0.152 g, 73%). 1H NMR (500 MHz CDCl3): δ 7.52-7.47 (m, 2H), 7.44-7.38 (m, 3H), 7.32-7.24 (m, 2H), 6.95 (t, 1H), 6.84 (d, 2H), 5.74 (t, 1H), 3.87 (t, 2H), 3.12-3.04 (m, 2H), 1.86-1.78 (m, 2H), 1.72 (s, 9H); 13C NMR (125 MHz CDCl3): δ 159.8, 158.8, 135.3, 131.8, 129.7, 128.7, 125.3, 121.3, 114.6, 107.2, 65.9, 61.7, 42.5, 29.0, 27.8; Mass Spectrum M+H+ 415.
Reaction SMILES: [C:1]1([N:11]2[C:15](=[S:16])[N:14]=[N:13][NH:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH:25]1[O:27][CH2:26]1.CCN(CC)CC>CO>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH:25]([OH:27])[CH2:26][S:16][C:15]1[N:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:12]=[N:13][N:14]=1
Reactant: S=c1nn[nH]n1-c1cccc2ccccc12
Reactant: Clc1ccccc1CC1CO1
Solvent: CCN(CC)CC
Solvent: CO
Product: OC(CSc1nnnn1-c1cccc2ccccc12)Cc1ccccc1Cl
Yield: 13.7 %

Procedure:
A solution of 1,2-dihydro-1-(1-naphthalenyl)-5H-tetrazole-5-thione (50.0 mg, 0.22 mmol), 2-chloro-1-(2,3-epoxypropyl)benzene (36.9 mg, 0.22 mmol) and Et3N (0.15 mL, 1.10 mmol) in MeOH (5 mL) was heated at reflux for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by HPLC using a gradient of MeCN/H2O containing TFA (0.1%) (CombiPrep ODS-AQ 50×20 mm, 5μ, 120 Å). The pure fractions were concentrated to give the title compound (12 mg, 14% yield) as a colorless solid.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH:10]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[O:9][CH2:8][CH2:7]3)[CH2:4][O:3]1.C(=O)(O)[O-].[Cl-].[OH:32][CH:33]([C:41]1[CH:50]=[CH:49][C:44]2[C:45](=[O:48])[O:46][CH2:47][C:43]=2[C:42]=1[CH3:51])[CH2:34][NH+:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(#N)C>[OH:32][CH:33]([C:41]1[CH:50]=[CH:49][C:44]2[C:45](=[O:48])[O:46][CH2:47][C:43]=2[C:42]=1[CH3:51])[CH2:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:15][CH:10]2[C:11]3[C:6](=[C:5]4[CH2:4][O:3][C:2](=[O:1])[C:14]4=[CH:13][CH:12]=3)[CH2:7][CH2:8][O:9]2)[CH2:37][CH2:36]1
Reactant: Cc1ccc(S(=O)(=O)OCC2OCCc3c2ccc2c3COC2=O)cc1
Reactant: Cc1c(C(O)C[NH+]2CCNCC2)ccc2c1COC2=O
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CC#N
Product: Cc1c(C(O)CN2CCN(CC3OCCc4c3ccc3c4COC3=O)CC2)ccc2c1COC2=O
Temperature: 120 °C

Procedure:
To a 5 mL microwave tube were added (3-oxo-3,6,8,9-tetrahydro-1H-furo[3,4-f]isochromen-6-yl)methyl-4-methylbenzenesulfonate (50 mg, 0.13 mmol), the free base generated by aqueous bicarbonate wash of 1-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-ium chloride (55 mg, 0.20 mmol), and a stir bar; the mixture was dissolved in acetonitrile (2.5 mL). The tube was capped, degassed and purged with N2. The tube was then placed in a microwave reactor and heated at 120° C. for 1 h; LC indicated formation of the desired product. The solution was concentrated to dryness, dissolved in MeOH (3.5 mL), filtered and was then subjected to mass-directed HPLC for purification to give 6-({4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)-8,9-dihydro-1H-furo[3,4-f]isochromen-3(6H)-one, as a mixture of isomers which could be partially separated under the purification conditions. LC-MS (IE, m/z): 478 [M+1]+.