Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:18][CH3:19])=[CH:5][C:6]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:9](=[O:16])[NH:8][C:7]=2[CH:17]=1.Cl.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C>C(O)C>[CH3:1][O:2][C:3]1[C:4]([O:18][CH3:19])=[CH:5][C:6]2[C:15]3[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:11][C:10]=3[C:9](=[O:16])[NH:8][C:7]=2[CH:17]=1
Reactant: ClCCN1CCCCC1
Reactant: COc1cc2[nH]c(=O)c3c(c2cc1OC)CCNC3
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2[nH]c(=O)c3c(c2cc1OC)CCN(CCN1CCCCC1)C3

Procedure:
A solution of 4.2 g (0.02 m) of 1,2,3,4-tetrahydro-8,9-dimethoxybenzo[c][2,7]naphthyridin-5(6H)-one, 4.05 g (0.022m) of N-(2-chloroethyl)piperidine HCl and 4.45 g (0.044 m) of triethylamine in 125 cc of ethyl alcohol was refluxed for 18 hr. After evaporation, the residue was dissolved in 100 ml of water, made strongly basic with conc NH4OH solution and extracted with three 50 ml portions of chloroform. The chloroform extract was dried (Na2SO4) and evaporated in vacuo. The residue was crystallized from acetonitrile affording 3.3 g (44% of crude material. Recrystallization from 2-propanol afforded analytical material, mp 185°-188° C.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1.[CH3:33][S:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Cl)=[CH:37][CH:36]=1>>[CH3:33][S:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][O:1][CH:2]2[CH:7]([C:8]3[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:12][CH:13]=3)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]2)=[CH:37][CH:36]=1
Reactant: CSc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCCc3ccccc3)cc2)C(O)C1
Product: CSc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCOCCc3ccccc3)cc2)cc1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(2-phenethyloxy-ethoxy)-phenyl]-piperidine-1-carboxylate with 4-methylthio-benzyl chloride [J.Org.Chem. (1988), 53(3), 561-569] there was obtained tert-butyl (3RS,4RS)-3-(4-methylsulphanyl-benzyloxy)-4-[4-(2-phenethyloxy-ethoxy)-phenyl]-piperidine-1-carboxylate as a colourless oil; MS: 578 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][C@@H:6]([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][C:11]([Cl:32])=[N:12][C:13]=3[NH:17][CH2:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:5]([OH:33])[C@@H:4]1[OH:34].C(N(C(C)C)CC)(C)C.[CH:44]1([C:47](Cl)=[O:48])[CH2:46][CH2:45]1>C1COCC1>[Cl:32][C:11]1[N:10]=[C:9]2[C:14]([N:15]=[CH:16][N:8]2[C@@H:6]2[CH2:7][C@H:3]([NH:2][C:47]([CH:44]3[CH2:46][CH2:45]3)=[O:48])[C@@H:4]([OH:34])[C@H:5]2[OH:33])=[C:13]([NH:17][CH2:18][CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]=1
Reactant: O=C(Cl)C1CC1
Reactant: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O)C1CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of (1S,2R,3S,5R)-3-Amino-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol hydrochloride (200 mg, 0.4 mmol) in dry THF (2.5 ml) is treated with diisopropylethylamine (0.35 ml, 2 mmol) and cyclopropanecarboxylic acid chloride (0.036 ml, 0.4 mmol) and the mixture is stirred at room temperature for 48 hours. The solvent is removed under reduced pressure and the residue is purified by reverse-phase chromatography eluting with a gradient system of acetonitrile (0.1% TFA):water (0.1% TFA) (0:100 by volume) gradually changing to acetonitrile (0.1% TFA):water (0.1% TFA) (100:0 by volume) to afford the title compound. LCMS (electrospray): m/z [MH+] 533.25 1H nmr (MeOD, 400 MHz); 8.00(s, 1H), 7.40-7.25(m, 8H), 7.25-7.20(m, 2H), 4.75(m, 1H), 4.60(m, 1H), 4.50(m, 1H), 4.20(m, 2H), 4.00(m, 1H), 2.85(m, 1H), 2.10(m, 1H), 1.85(m, 1H), 0.95-0.80(m, 4H)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[C:18]#[N:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C(N(CC)CC)C>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[C:18]([NH2:19])=[N:21][OH:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CO[C@@H]1C[C@@H](C#N)N(C(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CO[C@@H]1C[C@@H](C(N)=NO)N(C(=O)OCc2ccccc2)C1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To benzyl-(2S,4R)-2-cyano-4-methoxypyrrolidine-1-carboxylate, dissolved in ethanol (0.4 M), hydroxylamine hydrochloride (1.3 eq.) and triethylamine (1.5 eq.) were added. The mixture was stirred at 40° C. for 4 hours then at room temperature overnight. The mixture was concentrated in vacuo and the residue dissolved in ethyl acetate washed with brine, dried over Na2SO4, filtered and concentrated to give title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:23]=[CH:22][C:17]2[O:18][C:19](=[O:21])[O:20][C:16]=2[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][CH:25]([CH3:34])[C:26]([O:28][C@H:29]([CH3:33])[C@H:30](O)[CH3:31])=[O:27].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:23]=[CH:22][C:17]2[O:18][C:19](=[O:21])[O:20][C:16]=2[CH:15]=1)[C:10]([O:12][C@H:30]([CH3:31])[C@H:29]([O:28][C:26](=[O:27])[CH:25]([CH3:34])[CH3:24])[CH3:33])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)C(=O)O[C@H](C)[C@@H](C)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc2oc(=O)oc2c1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)C(=O)O[C@H](C)[C@@H](C)OC(=O)[C@H](Cc1ccc2oc(=O)oc2c1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a mixture of (2S)-2-[(tert-butoxy)carbonylamino]-3-(2-oxobenzo[3,4-d]1,3-dioxolen-5-yl)propanoic acid (16) (5.86 g, 18.1 mmol) and (1R,2R)-2-hydroxy-1-methylpropyl 2-methylpropanoate (15) (4.15 g, 21.84 mmol) in anhydrous dichloromethane (40 mL), a solution of dicyclohexylcarbodiimide (5.62 g, 27.3 mmol) in anhydrous dichloromethane (10 mL) was added dropwise at 0° C. To the solution, a catalytic amount of 4-(dimethylamino)pyridine was added. The resulting mixture was stirred at 0° C. for 30 min, then at room temperature for 2 hours. TLC indicated a completed reaction. The side product, dicyclohexylurea, was removed by filtration. The filtrate was diluted with dichloromethane (100 mL) and washed with 10% citric acid and water. The organic layer was collected, dried over MgSO4, and concentrated to provide the title compound (17) (6.4 g, 76% yield). MS (ESI) m/z 465.9 (M+H)+.
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([CH:10]2[CH2:15][CH:14]3[CH2:16][CH:11]2[CH2:12][CH2:13]3)[S:7][N:6]=1)(=O)=O.[CH2:17]([OH:22])[C:18]#[C:19][CH2:20]C.[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH:11]12[CH2:16][CH:14]([CH2:13][CH2:12]1)[CH2:15][CH:10]2[C:8]1[S:7][N:6]=[C:5]([O:22][CH2:17][C:18]#[C:19][CH3:20])[N:9]=1
Reactant: CS(=O)(=O)c1nsc(C2CC3CCC2C3)n1
Reactant: CCC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1nsc(C2CC3CCC2C3)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
300 mg of 3-methylsulfonyl-5-(2-norbornyl)-1,2,4-thiadiazole and 107 mg of 2-pentyn-1-ol were dissolved in 2.5 g of N,N-dimethylformamide, 60 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 30 minutes under ice-cooling and for 1 hour under room temperature. Then, the reaction mixture was added to saturated brine, and extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to give 5-(2-norbornyl)-3-(2-butynyloxy)-1,2,4-thiadiazole. 150 mg of the exo-isomer having low polarity (hereinafter referred to as the present invention compound (9-1)) and 50 mg of the endo-isomer having high polarity (hereinafter referred to as the present invention compound (9-2)) were obtained by using hexane-ethyl acetate system as a carrier solvent.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O:14][CH:15](OC)[C:16]1[C:43]([O:44]COC)=[C:42]([C:48]([F:51])([F:50])[F:49])[CH:41]=[CH:40][C:17]=1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34])=[CH:28][CH:27]=2)=[CH:22][C:21]=1[F:39]>CC(C)=O>[F:39][C:21]1[CH:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34])=[CH:28][CH:27]=2)[CH:24]=[CH:25][C:20]=1[O:19][CH2:18][C:17]1[CH:40]=[CH:41][C:42]([C:48]([F:51])([F:50])[F:49])=[C:43]([OH:44])[C:16]=1[CH:15]=[O:14]
Reactant: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCOC)c3C(OC)OC)c(F)c2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C=O)c(F)c2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
p-Toluenesulfonic acid monohydrate (223 mg, 1.18 mmol) was added to a solution of allyl (4′-{[2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzyl]oxy}-3′-fluoro-1,1′-biphenyl-4-yl)acetate (618 mg, 1.06 mmol) obtained in Example (12-3) in acetone (10 ml), and the mixture was stirred at 50° C. for 1 hour. The residue obtained by concentrating the reaction mixture was diluted with ethyl acetate. The obtained solution was successively washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=3/1) to give allyl (3′-fluoro-4′-{[2-formyl-3-hydroxy-4-(trifluoromethyl)benzyl]oxy}-1,1′-biphenyl-4-yl)acetate (476 mg, yield: 91%).
Reaction SMILES: [CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][NH:22][CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.[CH3:45][N:46]([CH3:51])[CH2:47][C:48](O)=[O:49].C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[CH3:45][N:46]([CH3:51])[CH2:47][C:48]([N:22]1[CH2:23][C@@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C@H:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:21]1)=[O:49]
Reactant: CN(C)CC(=O)O
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CNC[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(C(=O)CN(C)C)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.4 %

Procedure:
Compound 1 (100 mg, 0.167 mmol) obtained in Example 1 was dissolved in chloroform (2 mL), and stirred at room temperature for 1.5 hours after adding N,N-dimethylglycine hydrochloride (Tokyo Chemical Industry Co.; 46.5 mg, 0.333 mmol), diisopropylethylamine (0.146 mL, 0.833 mmol), and (benzotriazol-1-yloxy)tripyrrolizinophosphonium hexafluorophosphate (Watanabe Chemical Industries, Ltd.; 217 mg, 0.417 mmol). The aqueous layer was extracted with chloroform after adding a saturated sodium bicarbonate aqueous solution to the reaction mixture. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/5) to give compound 25 (98.9 mg, 86.8%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=[O:17].[CH:18]([Mg]Cl)=[CH2:19].CCOCC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([CH:18]=[CH2:19])[OH:17]
Reactant: O=c1c2cc(Br)ccc2oc2cnc(Cl)cc12
Reactant: C=C[Mg]Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC1(O)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
To a solution of 7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one (3.0 g, 9.66 mmol) at −78° C. in THF (48 mL) was added dropwise of vinylmagnesium chloride (17.51 mL, 28.0 mmol). After 30 min, the reaction was allowed to slowly warm to rt, then the reaction was quenched with 60 mL of saturated aqueious NH4Cl. The mixture was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to yield 3.2 g of crude product as orange foam. This material was added ˜4 mL of Et2O and precipitate was formed and filtered through Bucher funnel to yield 7-bromo-3-chloro-5-vinyl-5H-chromeno[2,3-c]pyridin-5-ol (2.70 g, 7.97 mmol) as a yellow solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH3:14][NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=1)(=[O:18])=[O:17]>CN(C=O)C.[Cu]I>[CH3:14][NH:15][S:16]([C:19]1[CH:20]=[C:21]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17]
Reactant: CNS(=O)(=O)c1cccc(Br)c1
Reactant: Oc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1cccc(Oc2ccccc2)c1
Yield: 11.4 %

Procedure:
To a slurry of phenol (1.9 g, 20 mmol), K2CO3 (6.0 g, 40 mmol), and CuI (4 g, 20 mmol) in DMF (25 mL) was added N-methyl-3-bromobenzenesulfonamide (2.5 g, 10 mmol), and the resulting mixture was stirred at the reflux temp. overnight, cooled to room temp., and separated between EtOAc (50 mL) and a 1 N HCl solution (50 mL). The aqueous layer was back-extracted with EtOAc (2×50 mL). The combined organic phases were sequentially washed with water (2×50 mL) and a saturated NaCl solution (50 mL), dried (MgSO4), and concentrated under reduced pressure. The residual oil was purified by column chromatography (30% EtOAc/70% hexane) to give 4-(3-(N-methylsulfamoyl)phenyloxy)benzene (0.30 g). Step 3. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH2:22](Br)[CH:23]=[CH2:24]>>[CH2:24]([N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20])[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: C=CCn1c(C(=O)c2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Yield: 64.3 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and allyl bromide were reacted by the same way with the example 45-1 to obtain the titled compound (211 mg, yield: 64.3%).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([C:18]1[CH:31]=[CH:30][C:21]2[O:22][C:23]([CH3:29])([CH3:28])[C@@:24]3([CH3:27])[O:26][C@H:25]3[C:20]=2[CH:19]=1)(=[O:17])=[O:16])(C(C)(C)C)(C)C.[CH3:32][N:33]1[C:38](=[O:39])[CH:37]=[CH:36][C:35]([OH:40])=[N:34]1.N1C=CC=CC=1>O1CCOCC1>[CH3:32][N:33]1[C:38](=[O:39])[CH:37]=[CH:36][C:35]([O:40][C@H:25]2[C@@:24]([OH:26])([CH3:27])[C:23]([CH3:29])([CH3:28])[O:22][C:21]3[CH:30]=[CH:31][C:18]([S:15]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[OH:8])(=[O:17])=[O:16])=[CH:19][C:20]2=3)=[N:34]1
Reactant: Cn1nc(O)ccc1=O
Reactant: CC1(C)Oc2ccc(S(=O)(=O)c3ccccc3O[Si](C)(C)C(C)(C)C)cc2[C@@H]2O[C@@]21C
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Cn1nc(O[C@@H]2c3cc(S(=O)(=O)c4ccccc4O)ccc3OC(C)(C)[C@@]2(C)O)ccc1=O

Procedure:
(3S,4S)-6-(2-tert-Butyldimethylsilyloxyphenyl)sulphonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo[b]pyran (0.5 g) (see Preparation 16) and 2,3-dihydro-2-methyl-3-oxo-6-hydroxypyridazin (0.41 g) (see J.Org.Chem., 1971, 36, 3372) were suspended in dry 1,4-dioxane (8 ml), pyridine (0.085 g) was added and the mixture was heated under reflux (a calcium chloride drying tube was attached to the flask) for 20 hours. The solvent was removed under reduced pressure, the residue was stirred with dichloromethane (30 ml) and filtered. The filtrate was evaporated and the residue was chromatographed on silica using 1:1 hexane:ethyl acetate as the eluent to yield a mixture of the required product and the epoxide starting material. This mixture was redissolved in dry 1,4-dioxane (7 ml), 2,3-dihydro-2-methyl-3-oxo-6-hydroxypyridazin (0.2 g) and pyridine (0.08 g) were added and the reaction was heated under reflux for a further 18 hours. The solvent was removed under reduced pressure and the residue was dissolved in 5% methanol/dichloromethane and filtered. The filtrate was evaporated and the residue was chromatographed on silica using 2.5:97.5 methanol:dichloromethane as the eluent to yield (3S,4R)-3,4-dihydro-4-(2,3-dihydro-2-methyl-3-oxopyridazin-6-yl)oxy-3-hydroxy-6-(2-hydroxyphenyl)-sulphonyl-2,2,3-trimethyl-2H-benzo[b]pyran (0.17 g) as a yellow foam. Found: C,54.19; H,4.85; N,5.21. C23H24N2O7S, 0.625 CH2Cl2 requires C,54.06; H,4.73; N,5.34%.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][C:10]=2[O:18][CH2:19][CH3:20])[C:5]2[C:21]([O:25][CH3:26])=[CH:22][CH:23]=[CH:24][C:4]=2[N:3]=1.[C:27](OC)(=[O:30])[C:28]#[CH:29]>CO>[CH3:26][O:25][C:21]1[C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][C:10]=3[O:18][CH2:19][CH3:20])=[N:7][CH2:8][C:2]3[N:3]([CH:29]=[CH:28][C:27](=[O:30])[N:1]=3)[C:4]=2[CH:24]=[CH:23][CH:22]=1
Reactant: C#CC(=O)OC
Reactant: CCOc1ccc(C2=NCC(N)=Nc3cccc(OC)c32)c(OCC)c1
Solvent: CO
Product: CCOc1ccc(C2=NCc3nc(=O)ccn3-c3cccc(OC)c32)c(OCC)c1

Procedure:
In the manner given in Example 1, 2-amino-6-methoxy-5-(2,4-diethoxyphenyl)-3H-1,4-benzodiazepine, methyl propiolate and methanol were refluxed. The mixture was chromatographed to give 8-methoxy-7-(2,4-diethoxyphenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8][C:9]2[C:10](=O)[C:11](=[O:15])[C:12]=2[O:13]C)=[CH:6][N:5]=[CH:4][N:3]=1.[CH3:17][C:18]1[O:22][C:21]([CH:23]([NH2:29])[C:24]2([CH3:28])[CH2:27][O:26][CH2:25]2)=[CH:20][CH:19]=1>CO>[OH:1][C:2]1[C:7]([NH:8][C:9]2[C:12](=[O:13])[C:11](=[O:15])[C:10]=2[NH:29][CH:23]([C:21]2[O:22][C:18]([CH3:17])=[CH:19][CH:20]=2)[C:24]2([CH3:28])[CH2:25][O:26][CH2:27]2)=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Reactant: COc1c(Nc2cncnc2O)c(=O)c1=O
Solvent: CO
Product: Cc1ccc(C(Nc2c(Nc3cncnc3O)c(=O)c2=O)C2(C)COC2)o1
Temperature: 50 °C
Yield: 71.5 %

Procedure:
A mixture of 300 mg (1.36 mmol, 1 eq) of 3-(4-hydroxypyrimidin-5-ylamino)-4-methoxycyclobut-3-ene-1,2-dione and 504 mg (2.78 mmol, 2 eq) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine in 25 ml of methanol was heated at 50° C. for 22 hours. The reaction medium was filtered and the insoluble material was washed with methanol and with diethyl ether. 0.36 g of product was obtained in the form of a white solid. Yield=72%, HPLC purity=97.81%, Mp=281° C. (degradation).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:46])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([CH2:37][O:38]C3CCCCO3)[CH:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([CH2:37][OH:38])[CH:32]=4)[CH:26]=3)[CH2:23][C:22](=[O:46])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(COC4CCCCO4)c3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-(isobutyl-methyl-amino)-2-(3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M281) (0.34 g, 0.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (152 mg, 64%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:19][CH2:18][C@@:10]3([NH:14]C(=O)N(C)[C:11]3=[O:17])[CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].[O:22]1CCOCC1.Cl>O.C(O)(=O)C>[NH2:14][C@:10]1([C:11]([OH:22])=[O:17])[CH2:18][CH2:19][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: CN1C(=O)N[C@@]2(CC[C@H](c3ccc(Br)cc3)C2)C1=O
Reactant: C1COCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: N[C@]1(C(=O)O)CC[C@H](c2ccc(Br)cc2)C1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a slurry of (5R,7S)-7-(4-bromo-phenyl)-3-methyl-1,3-diaza-spiro[4.4]nonane-2,4-dione (79 g, 0.24 mol) in water (1 L) was added 2 M aqueous NaOH (1 L, 2 mol) and dioxane (200 mL). The resulting mixture was heated to reflux for 24 hours. The reaction mixture was cooled to room temperature, diluted with water (2 L) and acidified with concentrated HCl until a precipitate began to form (about pH 7). Acetic acid (about 20 mL) was added, producing a thick precipitate. The white precipitate was collected and washed with water (2×1 L) and EtOAc (1 L). The filter cake was suspended in toluene (1 L) and concentrated in vacuo at 45° C. This process was repeated once more. The white precipitate was dried to a constant weight under vacuum to give (1R,3S)-1-amino-3-(4-bromo-phenyl)-cyclopentanecarboxylic acid (65 g, 95%).
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH:34]([OH:42])[CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH:34]([OH:42])[CH2:35][N:36]2[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]2)=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Reactant: NCCCC(O)CN1CCCCC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCC(O)CN3CCCCC3)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 5-amino-1-piperidin-1-yl-pentan-2-ol by the procedure analogous to Example 6. HPLC ret. time: 3.3 minutes. 1H NMR (400 MHz, CD3OD) δ7.18 (dd, 1H, J=6.0, 9.2 Hz), 7.05 (dd, 1H, J=6.0, 10 Hz), 5.47 (s, 2H), 3.80 (m, 1H), 3.23 (t, 2H, J=6.4 Hz), 2.7-2.4 (m, 7H), 2.25 (s, 3H), 1.8-1.4 (m, nH) ppm; Ms (APCI, m/z): 512 [M+H]+.