Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[CH3:38][O:39][C:40]([CH:42]1[CH2:47][CH2:46][CH:45]([CH2:48][C:49]#[CH:50])[CH2:44][CH2:43]1)=[O:41].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C.CN(C=O)C>[CH3:38][O:39][C:40]([CH:42]1[CH2:47][CH2:46][CH:45]([CH2:48][C:49]#[C:50][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@@H:11]3[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]3[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:3]=2)[CH2:44][CH2:43]1)=[O:41]
Reactant: C#CCC1CCC(C(=O)OC)CC1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C#CCC4CCC(C(=O)OC)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 120 °C

Procedure:
The title compound is prepared by combining N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (intermediate J), 4-prop-2-ynyl-cyclohexanecarboxylic acid methyl ester (prepared as described by Rieger J. M., Brown M. L., Sullivan G. W., Linden J. and Macdonald T. L.′; J. Med. Chem.(2001), 44, 531-539), copper (I) iodide, triphenylphosphine and dichlorobis(triphenylphosphine)palladium(II) in a 2:1 mixture of triethylamine/DMF, and heating by microwave irradiation for 3600 seconds at 120° C. Purification by column chromatography affords the title compound.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:15]([O:17][C:18]([C:20]1([NH:25][C:26]([CH:28]2[CH2:32][CH:31]([OH:33])[CH2:30][CH:29]2[C:34](=[O:43])[N:35]([CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])[CH3:36])=[O:27])[CH2:22][CH:21]1[CH:23]=[CH2:24])=[O:19])[CH3:16].O[C:45]1[C:54]2[C:49](=[C:50]([CH3:57])[C:51]([O:55][CH3:56])=[CH:52][CH:53]=2)[N:48]=[C:47]([N:58]2[CH:62]=[CH:61][C:60]([CH:63]([CH3:65])[CH3:64])=[N:59]2)[N:46]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[CH2:15]([O:17][C:18]([C:20]1([NH:25][C:26]([CH:28]2[CH2:32][CH:31]([O:33][C:45]3[C:54]4[C:49](=[C:50]([CH3:57])[C:51]([O:55][CH3:56])=[CH:52][CH:53]=4)[N:48]=[C:47]([N:58]4[CH:62]=[CH:61][C:60]([CH:63]([CH3:65])[CH3:64])=[N:59]4)[N:46]=3)[CH2:30][CH:29]2[C:34](=[O:43])[N:35]([CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])[CH3:36])=[O:27])[CH2:22][CH:21]1[CH:23]=[CH2:24])=[O:19])[CH3:16]
Reactant: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Reactant: COc1ccc2c(O)nc(-n3ccc(C(C)C)n3)nc2c1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCCCCN(C)C(=O)C1CC(Oc2nc(-n3ccc(C(C)C)n3)nc3c(C)c(OC)ccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
DIAD (280 μL, 1.42 mmol) was added at −20° C. under nitrogen atmosphere to a solution of the alcohol (143) (367 mg, 0.90 mmol), 4-hydroxy-2-(3-isopropylpyrazol-1-yl)-7-methoxy-8-methylquinazoline (141) (270 mg, 0.90 mmol) and triphenyl-phosphine (288 mg, 1.42 mmol) in dry DMF (35 mL). After 2 h, the solution was warmed up to room temperature. After 12 h, the reaction mixture was partitioned between ice-cold water and ether, organic layer was dried (Na2SO4) and evaporated. The residue was purified by column chromatography (gradient AcOEt/CH2Cl2, 1:9 to 10:0) to give the title compound (230 mg, 34%), m/z=687 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[NH:7][C:8]1[C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1)([O-:3])=[O:2].[NH4+:20].[OH-].O.[Cl-].[NH4+]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[NH:7][C:8]1[C:13]([C:14](=[O:15])[NH2:20])=[CH:12][CH:11]=[CH:10][N:9]=1)([O-:3])=[O:2]
Reactant: [NH4+]
Reactant: O=C(Cl)c1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1cccnc1Nc1cccc([N+](=O)[O-])c1
Yield: 99 %

Procedure:
The 2-(3-nitroanilino)-3-chloroformylpyridine was dissolved in tetrahydrofuran (2000 ml) and 70 ml of 30% solution of NH4OH was added dropwise with stirring to the reaction mixture. The reaction mixture was stirred at room temperature for 18 hours. Water was added to the mixture to dissolve the solid ammonium chloride that was formed. The tetrahydrofuran was removed, and the resulting aqueous slurry was filtered and washed yielding a yellow solid. The solid was washed with water and air dried yielding 64.8 g (250 mmole, 99% yield) of 2-(3-nitroanilino)-3-carbamoylpyridine (mp 240°-241° C.).
Reaction SMILES: C([O:8][C:9](=[O:34])[C@H:10]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:11][C:12](=[O:26])[C@H:13]([CH3:25])[NH:14]C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1>C(O)C>[NH2:14][C@H:13]([C:12]([NH:11][C@H:10]([C:9]([OH:34])=[O:8])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26])[CH3:25]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: CCO
Product: C[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 20 °C
Reaction time: 6.5 h
Yield: 100 %

Procedure:
A mixture of N-benzyloxycarbonyl-L-alanyl-L-phenylalanine benzyl ester (0.50 g, 1.1 mmol) and 10% Pd palladium on carbon (0.1 g) in ethyl alcohol (150 mL) was shaken in a Parr hydrogenation apparatus for 6.5 h at 20° C. The reaction mixture was filtered and the filtrate rinsed with water (100 mL). The solution was concentrated to give 0.26 g (100%) of L-alanyl-L-phenylalanine. HPLC analysis showed >99% purity and no evidence of racemization.
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]2[O:27][CH2:26][CH2:25][CH:24](Br)[C:23](=[O:29])[C:22]=2[CH:30]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]2[O:27][CH2:26][CH2:25][CH:24]([O:7][CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:23](=[O:29])[C:22]=2[CH:30]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OCC1CCCC1
Reactant: O=C1c2cc(OCc3ccccc3)ccc2OCCC1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2cc(OCc3ccccc3)ccc2OCCC1OCC1CCCC1

Procedure:
To a solution of 1.5 g of (cyclopentyl)methanol in 50 ml of tetrahydrofuran is added 720 mg of 50% sodium hydride. After stirring until evolution of H2 is substantially complete (about 30 minutes), a solution of 4.5 g of crude 7-benzyloxy-4-bromo-3,4-dihydro-1-benzoxepin-5 (2H)-one is added. The reaction is allowed to stir at room temperature for 5 hours. The tetrahydrofuran is evaporated in vacuo, and the residue dissolved in ethyl acetate and washed with water. The ethyl acetate layer is dried over sodium sulfate and evaporated in vacuo to yield present title product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([CH2:22][N:23]([CH3:25])[CH3:24])[CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:26]#[N:27])[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C>[Fe].CO>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([CH2:22][N:23]([CH3:24])[CH3:25])[CH:15]=1)[N:12]=[CH:11][C:10]([C:26]#[N:27])=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CN(C)Cc1cc([N+](=O)[O-])cc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)Cc1cc(N)cc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Yield: 59.8 %

Procedure:
A stirred mixture of 4-[(3-bromophenyl)amino]-8-dimethylaminomethyl-6-nitro-quinoline-3-carbonitrile (5.98 g, 14.1 mmol), iron powder (2.76 g, 49 mg-atoms), acetic acid (5.67 ml, 99 mmol), and 70 ml of methanol was refluxed for 2 h and then evaporated to remove methanol. The residue was stirred with water for 10 m, and the orange solid was filtered off and washed with 2% acetic acid. The total filtrate was basified to pH 10 with 5 N sodium hydroxide. The resulting precipitate was extracted with methylene chloride. The extract was washed with water, dried, and concentrated. The residue was subjected to chromatography on silica gel with ethyl acetate-methanol-triethylamine to give 3.34 g of amber solid; mass spectrum (electrospray, m/e) M+H 396.2, 398.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[C:18]([NH2:20])=[O:19].CCN(C(C)C)C(C)C>C(#N)C>[C:18]([C@@H:14]1[CH2:15][CH2:16][CH2:17][N:13]1[C:4]1[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=1)(=[O:19])[NH2:20]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(N2CCC[C@H]2C(N)=O)nc(Cl)n1
Temperature: 50 °C
Yield: 23.6 %

Procedure:
To a mixture of methyl 2,6-dichloropyrimidine-4-carboxylate (2.074 g, 10.02 mmol) in acetonitrile (50 mL) was added (S)-pyrrolidine-2-carboxamide (1.150 g, 10.07 mmol) and iPr2NEt (1.92 mL, 11.02 mmol). The mixture was heated at 50° C. overnight and then filtered while still warm. The filter cake was washed with acetonitrile (1×10 mL) then dried under vacuum at 40° C. to give a first batch of (S)-methyl 6-(2-carbamoylpyrrolidin-1-yl)-2-chloropyrimidine-4-carboxylate as a tan solid (0.671 g, 2.36 mmol, 24% yield). The filtrate and washes were evaporated in vacuo and triturated with warm acetonitrile (10 mL). The solid was filtered, washed with acetonitrile (2×5 mL), and dried under vacuum at 40° C. to give a second batch of (S)-methyl 6-(2-carbamoylpyrrolidin-1-yl)-2-chloropyrimidine-4-carboxylate as a solid (0.849 g, 2.98 mmol, 30% yield). LC/MS: m/z=285.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N:11]2[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]2)=[C:9]([Cl:18])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:21])=O>CN(C)C=O.ClCCCl>[Cl:1][C:2]1[C:10]([N:11]2[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]2)=[C:9]([Cl:18])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:21])=[O:5]
Reactant: Cn1nnn(-c2c(Cl)ccc(C(=O)O)c2Cl)c1=O
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cn1nnn(-c2c(Cl)ccc(C(=O)Cl)c2Cl)c1=O
Yield: 100.3 %

Procedure:
2,4-Dichloro-3-(4,5-dihydro-4-methyl-5-oxo-1H-tetrazol-1-yl)benzoic acid (3.42 g) and thionylchloride (4.22 g) were added to 1,2-dichloroethane (50 ml). The mixture, after adding several drops of N,N-dimethylformamide, was refluxed upon heating for 4 hours. After cooling, the solvent was distilled off to obtain crude 2,4-dichloro-3-(4,5-dihydro4-methyl-5-oxo-1H-tetrazol-1-yl)benzoyl chloride (3.65 g).
Reaction SMILES: [NH:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=O)[CH2:12][CH2:11][CH2:10][CH2:9]3.B.O1CCCC1.[ClH:26].[H][H]>O1CCCC1>[ClH:26].[NH:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][CH2:2]1)[CH2:12][CH2:11][CH2:10][CH2:9]3
Reactant: [H][H]
Reactant: O=C1COc2cccc3nc4c(c(c23)N1)CCCC4
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: c1cc2c3c(c4c(nc3c1)CCCC4)NCCO2
Reaction time: 2 h
Yield: 57.5 %

Procedure:
1,3,9,10,11,12-Hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.00 g) was suspended in dry tetrahydrofuran (100 ml) and 1M borane/tetrahydrofuran (16.0 ml) was added. After 2 hrs, an additional 30 ml of 1M borane/tetrahydrofuran was added, and the reaction mixture was stirred overnight. The reaction mixture was poured into 5% hydrochloric acid and stirred unit hydrogen evolution ceased. The organic layer was separated and the aqueous phase was washed once with ethyl acetate. The aqueous phase was basified with 10% sodium hydroxide solution and precipitate was collected. The precipitate was treated with methanol/ether/hydrogen chloride. Recrystallized from methanol/ether gave 2.50 g (57.5%) of product, mp 300° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16](Cl)[N:17]=2)[C:12](=[O:21])[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]1.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([OH:39])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C1CCN2C(=NCCC2)CC1.[H-].[Na+]>CN(C=O)C>[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([O:39][C:16]2[N:17]=[C:18]3[C:13]([C:12](=[O:21])[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]=2[F:20])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(OC3CCN(C(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Temperature: 25 °C
Yield: 53 %

Procedure:
To a mixture of 325 mg of ethyl 1-(2,4-difluorophenyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, 325 mg of 1-t-butoxycarbonyl-3hydroxypyrrolidine, 194 mg of DBU and 3 ml of DMF was added 46 mg of 55% sodium hydride while the former was stirred at room temperature. After the resultant mixture was stirred for 1.5 hours at room temperature, the reaction mixture was treated in a similar manner to Example 1-(1), whereby 240 mg of ethyl 7-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])#[N:2].[CH3:18][N:19]([CH3:23])[C:20](Cl)=[S:21]>>[CH3:18][N:19]([CH3:23])[C:20](=[S:21])[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:9](=[O:10])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])=[CH:16][CH:15]=1
Reactant: N#Cc1ccccc1C(=O)c1ccc(O)cc1
Reactant: CN(C)C(=S)Cl
Product: CN(C)C(=S)Oc1ccc(C(=O)c2ccccc2C#N)cc1
Yield: 90.1 %

Procedure:
Following the procedure described in Preparation I and starting from 13.3 g (0.059 mol) of 2-cyanophenyl 4-hydroxyphenyl methanone and 8.5 g (0.068 mol) of dimethylthiocarbamoyl chloride, 16.5 g (yield: 89%) of O-4-(2-cyanobenzoyl)phenyl dimethylthiocarbamate melting at 138° C. are obtained.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:20](=O)[C:21]1[C:22]([O:27][CH3:28])=[CH:23][CH:24]=[CH:25][CH:26]=1>[OH-].[K+].CCO.O>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccccc1C=O
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccccc1C=C1CCc2cc(OCCn3ccnc3)ccc2C1=O
Yield: 85.3 %

Procedure:
6-(2-Imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.200 g, 0.78 mmol) was reacted with o-anisaldehyde (0.117 g, 0.87 mmol) in 2 mL of 4% KOH in EtOH at room temperature overnight. The reaction was diluted with water to induce the precipitation of a red gum. The aqueous layer was decanted, and the remaining residue was concentrated several times from EtOH and then chromatographed (SiO2, 30 g, 8% MeOH in DCM) to afford 0.249 g (84%) of the title compound as a yellow foam: APCI-MS m/e 375.3 M++1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[C:18]([NH2:21])([CH3:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](=[O:25])([O-])[O-:23].[K+].[K+]>>[C:2]([O:23][C:22](=[O:25])[NH:21][C:18]([C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:19])[CH3:20])([CH3:7])([CH3:3])[CH3:1]
Reactant: CC(C)(N)c1cc([N+](=O)[O-])ccc1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)NC(C)(C)c1cc([N+](=O)[O-])ccc1OCc1ccccc1
Yield: 94 %

Procedure:
Using the compound obtained in Example 564 as a starting material and also using potassium carbonate as a base, the same procedure of Example 63 gave 828 mg of the titled compound (yield, 94%).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[S:5][CH3:6])#[N:2].[CH3:9][N:10]([CH3:14])[CH2:11][CH2:12][NH2:13]>C(O)C>[C:1]([NH:3][C:4](=[N:13][CH2:12][CH2:11][N:10]([CH3:14])[CH3:9])[S:5][CH3:6])#[N:2]
Reactant: CN(C)CCN
Reactant: CSC(=NC#N)SC
Solvent: CCO
Product: CSC(=NCCN(C)C)NC#N
Reaction time: 3 h

Procedure:
A stirred solution of N-cyano-bis(methylthio)methanimine (30 g) in warm ethanol (150 ml) was treated dropwise with 2-dimethylaminoethylamine (24 ml) during 1 hour and stirring was continued for a further period of 3 hours. The resulting white precipitate was recrystallised from ethanol, to give N-cyano-N'-(2-dimethylaminoethyl)-S-methylisothiourea (13.4 g), m.p. 94°-95° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[N+:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20])([O-:15])=[O:14]>N1C=CC=CC=1>[C:4]([C:3]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=1[NH:1][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=1)#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: N#Cc1cc([N+](=O)[O-])ccc1NC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 8.16 gm. (0.05 mole) of 2-amino-5-nitrobenzonitrile and 9.28 gm. (0.05 mole) of m-nitro benzoyl chloride in 50 ml. of dry pyridine is refluxed for three hours. The pyridine is removed by distillation in vacuo and the solid residue triturated with water. There is obtained 15.3 gm. (95%) of a yellow solid that melts at 203°-205°. Recrystallization from aqueous ethanol (2:1) gives material melting at 205°-206°.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[N+:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:21])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:7](=[O:15])[NH:8]2)=[CH:3][C:2]=1[N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)([O-:14])=[O:13]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: C1CCNC1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N3CCCC3)cc2c1=O
Yield: 35 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with pyrrolidine according to the GPA affording 12.2 mg (35%) of an orange-light powder. Rt=4.37 min.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]1[C@H:7]2[CH2:8][O:9][CH2:10][C@H:6]2[O:5][N:4]=1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19]>>[F:11][CH:2]([F:1])[C@@:3]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C@H:7]2[CH2:8][O:9][CH2:10][C@H:6]2[O:5][NH:4]1
Reactant: Fc1ccccc1Br
Reactant: FC(F)C1=NO[C@@H]2COC[C@H]12
Product: Fc1ccccc1[C@@]1(C(F)F)NO[C@@H]2COC[C@@H]21

Procedure:
Intermediate VI-3: Starting from (3aS,6aS)-rel-3-difluoromethyl-3a,4,6,6a-tetrahydro-furo[3,4-d]isoxazole and 1-bromo-2-fluorobenzene, the product (3S,3aS,6aS)-rel-3-difluoromethyl-3-(2-fluorophenyl)-hexahydro-furo[3,4-d]isoxazole was obtained as an orange oil. MS: m/z=260.2 [M+H]+.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C@H:10]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:12]([C:22]([O:24][CH3:25])=[O:23])[CH2:11]1.N1C=CN=C1>CN(C=O)C>[C:4]([Si:1]([CH3:3])([CH3:2])[O:9][C@H:10]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[C@@H:12]([C:22]([O:24][CH3:25])=[O:23])[CH2:11]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 19 h
Yield: 51.1 %

Procedure:
Tert-Butyldimethylsilylchloride (9.36 g) was added to a mixture of O1-tert-butyl O2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (13.83 g) and imidazole (9.61 g) in DMF (100 ml). The reaction was stirred at 20° C. for 19 hours and then evaporated to dryness. The residues were slurried in diethyl ether and filtered. The filtrate was evaporated to dryness and the residues purified by flash chromatography on silica eluting with increasingly polar mixtures of methanol/dichloromethane (0/100-5/95). Fractions containing the desired product were combined and evaporated to dryness to give O1-tert-butyl O2-methyl (2R,4R) 4-(tert-butyl-dimethyl-silyl)oxypyrrolidine-1,2-dicarboxylate (10.35 g) as a colourless oil. NMR Spectrum: (DMSOd6) 0.00 (6H, s); 0.80 (9H, s); 1.32-1.38 (9H, m); 1.84-1.89 (1H, m); 2.30-2.35 (1H, m); 3.06-3.10 (1H, m); 3.49 (1H, q); 3.59 (3H, d); 4.22-4.26 (1H, m); 4.37 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=3[N:10]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=3)[N:9]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=3[N:10]([CH2:18][C:19]3[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
A solution of 3-(4-chloro-phenyl)-1-(3-methoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 105, 0.1 mmol) in CH2Cl2 (5 mL) was cooled to 0° C., and 1 M BBr3 in CH2Cl2 (0.5 mL) was added. The mixture was allowed to warm to 25° C. After 2 h, satd. aq. NaHCO3 (5 mL) was added. The layers were separated, and the aqueous layer was extracted with EtOAc (2×5 mL). The combined organic layers were dried over Na2SO4 and concentrated. Purification by flash chromatography (2 M NH3 in MeOH/CH2Cl2) provided the title compound (10 mg). MS (ESI): exact mass calculated for C20H20ClN3O, 353.13; found, m/z 354.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.40-7.38 (m, 2H), 7.35-7.32 (m, 2H), 7.03 (t, J=7.9 Hz, 1H), 6.57 (dd, J=8.1, 2.0 Hz, 1H), 6.49 (d, J=8.1 Hz, 1H), 6.39-6.37 (br m, 1H), 5.20 (s, 2H), 2.81-2.78 (br m, 4H), 2.74-2.72 (br m, 2H), 2.70-2.68 (br m, 2H).