Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[NH:13][C:12]=2[CH:20]=O)[CH2:4][CH2:3]1.[CH2:22]([S:24]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])[CH2:30]2)(=[O:26])=[O:25])[CH3:23]>>[CH2:22]([S:24]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])/[C:30]/2=[CH:20]\[C:12]1[NH:13][C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[C:11]=1[CH2:10][CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]1)(=[O:25])=[O:26])[CH3:23]
Reactant: O=Cc1[nH]c2c(c1CCCN1CCC(O)CC1)CCCC2
Reactant: CCS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CCS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CCC(O)CC1)CCCC3)C(=O)N2
Yield: 31.1 %

Procedure:
3-[3-(4-Hydroxy-piperidin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (58 mg, 0.2 mmol), prepared as described in Example 20, was condensed with 5-ethylsulfonyloxindole (69 mg, 0.2 mmol, 65%pure) following the procedure used in Example 1 to provide 31 mg of the desired compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][NH:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH3:2].Br[CH2:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+].C(O)C(N)(CO)CO>C(#N)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][NH:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([O:30][CH3:31])=[O:29])=[CH:20][CH:21]=1)[CH3:2]
Reactant: CCOc1ccccc1CCNC(=O)CCc1ccc(O)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccccc1CCNC(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 5 %

Procedure:
N-[2-(2-ethoxyphenyl)ethyl]-3-(4-hydroxyphenyl)propanamide (0.35 g, 1.12 mmol) and methyl 2-(bromomethyl)benzoate (0.28 g, 1.23 mmol) was dissolved in acetonitrile (5 ml) and potassium carbonate (324 mg, 2.34 mmol) was added. The mixture was stirred at 60° C. for three hours. Polymer supported trisamine (0.3 eqv) was added and stirred overnight. The polymer was filtered off, solvent was removed by evaporation, addition of EtOAc (10 ml) and the organic phase was washed with three portions of water. After drying the crude (MgSO4) and the solvent was removed by evaporation, the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min)). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 26 mg of methyl 2-{[4-(3-{[2-(2-ethoxyphenyl)ethyl]amino}-3-oxopropyl)phenoxy]methyl}benzoate (yield 50.4%).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7](=O)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24]>CO>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]2[S:24][C:19]3[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:17][C:7]=2[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=O)C(=O)C(C(C)(C)C)=C1
Reactant: Nc1ccccc1S
Solvent: CO
Product: CC(C)(C)c1cc(C(C)(C)C)c2c(c1O)Nc1ccccc1S2
Reaction time: 2 h

Procedure:
To a solution of 3,5-di-t-butyl-1,2-benzoquinone (2.2 g) in methanol (15 ml) cooled in an ice bath was added 2-aminothiophenol (1.38 g) and the mixture was stirred for 2 hours. A solid precipitate was filtered off and crystallized from heptane to yield the title compound m.p. 202°-212° (dec.). From the methanol filtrate there was obtained, after chromatography and crystallization, an additional crop of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[NH:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17].[CH3:25][O:26][C:27]([N:29]1[C:37]2[C:32](=[CH:33][C:34]([S:38](Cl)(=[O:40])=[O:39])=[CH:35][CH:36]=2)[CH2:31][CH2:30]1)=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:38]([C:34]1[CH:33]=[C:32]3[C:37](=[CH:36][CH:35]=1)[N:29]([C:27]([O:26][CH3:25])=[O:28])[CH2:30][CH2:31]3)(=[O:39])=[O:40])[C:6](=[O:11])[C:5]2([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[NH:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17]
Reactant: COCCCNC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: COC(=O)N1CCc2cc(S(=O)(=O)Cl)ccc21
Product: COCCCNC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc3c(c2)CCN3C(=O)OC)c2ccc(Cl)cc21
Yield: 69.8 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 222 from 1.3 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-[(3-methoxypropyl)amino]indol-2-one and 0.980 g of 1-(methoxycarbonyl)indoline-5-sulfonyl chloride. 1.5 g of the expected product are obtained after crystallization from a DCM/iso ether/hexane mixture. M.p.=98° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CS(O[C@@H:16]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[C:17]1=[O:34])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C@H:16]3[CH2:20][CH2:19][N:18]([CH:21]4[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:25][CH2:26]4)[C:17]3=[O:34])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](OS(C)(=O)=O)C2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](Oc3ccc4[nH]ncc4c3)C2=O)CC1
Temperature: 130 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
A flask was charged with 1H-indazol-5-ol (0.89 g, 0.66 mmol), (R)-tert-butyl 4-(3-(methylsulfonyloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (Preparation D; 0.2 g, 0.55 mmol), K2CO3 (0.092 g, 0.66 mmol), and DMSO (4 mL). The reaction was stirred at 130° C. overnight. Added water and extracted with ethyl acetate. The organic layers were combined, dried, filtered and concentrated. The residue was purified using silica gel column chromatography with 50-100% ethyl acetate in hexanes to provide (S)-tert-butyl 4-(3-(1H-indazol-5-yloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (0.198 g, 90% yield).
Reaction SMILES: [Br-].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH2:15][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[C:13]([CH:35]([CH3:37])[CH3:36])[N:12]=[C:11]([N:38]([CH3:43])[S:39]([CH3:42])(=[O:41])=[O:40])[N:10]=2)=[CH:5][CH:4]=1.C[Si](C)(C)N[Si](C)(C)C.[Li].[Si:54]([O:61][C@H:62]1[CH2:67][C:66](=[O:68])[O:65][C@H:64]([CH:69]=O)[CH2:63]1)([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55].[Cl-].[NH4+]>O1CCCC1>[Si:54]([O:61][C@H:62]1[CH2:67][C:66](=[O:68])[O:65][C@H:64](/[CH:69]=[CH:15]/[C:14]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=3)=[N:10][C:11]([N:38]([CH3:43])[S:39]([CH3:42])(=[O:40])=[O:41])=[N:12][C:13]=2[CH:35]([CH3:37])[CH3:36])[CH2:63]1)([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](C=O)C1
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Temperature: -30 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a cold (−30° C.), stirred suspension of ((4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)methyl)triphenylphosphonium bromide (376 mg, 0.55 mmol) in dry tetrahydrofuran (10 mL) is added lithium hexamethyldisilazane in THF (0.42 mL of 1.33 M, 0.55 mmol). The reaction mixture is stirred for 30 min, cooled to −78° C., and treated with a solution of (2S,4R)-4-(tert-butyldimethylsilyloxy)-6-oxo-tetrahydro-2H-pyran-2-carbaldehyde (9) (130 mg, 0.50 mmol) in 5 mL of tetrahydrofuran. After 60 min, the solution is warmed to ambient temperature, stirred for 10 min, and treated with saturated ammonium chloride solution. The aqueous phase is extracted with t-BuMeO (2×10 mL), and the combined organic layers dried and concentrated. The residue is purified by silica gel chromatography (elution with t-BuMeO/hexane mixture) to give 190 mg (65%) of N-(5-((E)-2-((2S,4R)-4-(tert-butyldimethylsilyloxy)-6-oxo-tetrahydro-2H-pyran-2-yl)vinyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (10) as white amorphous solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:14])=[O:13])[C:6]=1[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1.[H-].[Na+].CN(C=O)C.Cl[C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][N:39]=1>C1COCC1>[C:26]1([CH3:29])[CH:27]=[CH:28][C:23]([C:6]2[C:7]([NH:11][S:12]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:13])=[O:14])=[N:8][CH:9]=[N:10][C:5]=2[O:4][CH2:3][CH2:2][O:1][C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][N:39]=2)=[CH:24][CH:25]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)C=Cc3ccccc3)ncnc2OCCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(NS(=O)(=O)C=Cc3ccccc3)ncnc2OCCOc2ccc(C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.1 %

Procedure:
2-Phenyl-ethenesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (150 mg) was dissolved in THF (10 ml) and sodium hydride (45 mg; 55-65% in mineral oil) was added. The mixture was stirred for 15 min at rt., followed by the addition of DMF (2 ml) and 2-chloro-5-trifluoromethyl-pyridine (146 mg) and heating to 75° C. for 5 h. Then the reaction mixture was evaporated to dryness and water (15 ml) and citric acid was added. The precipitated product was filtered off, washed with water and dried. 2-Phenyl-ethenesulfonic acid {5-p-tolyl-6-[2-(5-trifluoromethyl-pyridin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-amide (130 mg) could be obtained as a white powder. tR=5.92 (LC); [M+H]+=557.38 (ES+).
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33]>>[C:1]1([CH:7]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-:34])=[O:33])[CH2:11][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(OC2CCNCC2)c2cccnc2)cc1
Reactant: O=[N+]([O-])c1ccccc1OCCCCl
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2ccccc2)c2cccnc2)CC1

Procedure:
The procedure of Example 24 (a) was repeated except for using 4-(phenyl-3-pyridylmethoxy)piperidine and 1-chloro-3-(2-nitrophenoxy)propane instead of 4-[(2-chlorophenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane to give oily 4-(phenyl-3-pyridylmethoxy)-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [C:1]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[N:12]1([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH:2]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNCC1
Reactant: O=C1CCCc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C1=C(N2CCCCC2)c2ccccc2CC1

Procedure:
A solution of 146 g. (1.00 mole) of 1-tetralone and 150 ml. of piperidine in 1 l. of toluene is treated with 1 g. of p-toluenesulfonic acid and heated for 11 days under reflux with a water take-off trap attached. 13.1 ml. of water is collected. Fractional distillation affords 105.3 g. of 1-piperidino-3,4-dihydronaphthalene collected at 118°-120° (0.2 mm.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([NH:17][C:18](OC3C=CC=CC=3)=[O:19])=[CH:15][C:14]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:13]2)=[CH:8][CH:7]=1)[CH3:2].[N:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]2[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=2)=[CH:34][CH:33]=1>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:16]([NH:17][C:18]([NH:43][C:42]3[CH:41]=[CH:40][C:39]([O:38][C:35]4[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=4)=[CH:45][CH:44]=3)=[O:19])=[CH:15][C:14]([C:27]([CH3:28])([CH3:29])[CH3:30])=[N:13]2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Reactant: Nc1ccc(Oc2ccncc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Temperature: 60 °C
Yield: 70 %

Procedure:
A mixture of ethyl(4-{3-tert-butyl-5-[(phenoxycarbonyl)amino]-1H-pyrazol-1-yl}phenyl)acetate (3.0 g, 7.12 mmol) and 4-(pyridin-4-yloxy)aniline (1.26 g, 6.78 mmol) in THF (50 mL) was heated at 60° C. overnight. The reaction mixture was cooled to room temperature and then evaporated at reduced pressure to afford a brown syrup, which was purified by MPLC (25:75 to 70:30 EtOAc/hexane). The desired product was obtained as a white solid (2.42 g) in 70% yield. 1H-NMR (CD2Cl2-d2) δ 8.35 (m, 2H), 8.06 (s, 1H), 7.42 (m, 4H), 7.33 (s, 1H), 7.28 (d, J=8.3 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 6.88 (d, J=5.8 Hz, 2H), 6.35 (s, 1H), 4.12 (q, J=7.1 Hz, 2H), 3.63 (s, 2H), 1.31 (s, 9H), 1.27 (t, J=7.1 Hz, 3H); MS LC-MS [M+H]+=514.2, RT=2.66 min.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].CS(C)=O.[CH3:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:53][N:52]=[C:51]([CH2:54][NH2:55])[N:50]=2)=[CH:45][CH:44]=1>C(#N)C>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:55][CH2:54][C:51]4[N:50]=[C:49]([C:46]5[CH:45]=[CH:44][C:43]([O:42][CH3:41])=[CH:48][CH:47]=5)[O:53][N:52]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: COc1ccc(-c2nc(CN)no2)cc1
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1ccc(-c2nc(CNC(=O)c3ccc4n3Cc3ccccc3N(C(=O)c3ccc(-c5ccccc5C)c(C)c3)C4)no2)cc1
Temperature: 85 °C

Procedure:
A mixture of 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 9 (0.26 mmol), dimethylsulfoxide (100 uL) and [5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methylamine of Step A (0.546 mmol) in acetonitrile (2.5 mL) was heated to 85° C. for 16 hours. After cooling the solvent was evaporated and the residue was taken up in dichloromethane (10 mL). This was washed with water (2×), dried over anhydrous sodium sulfate, and evaporated. The residue was purified by HPLC (Normal phase, Luna CN bonded packing) and crystallized from ethyl acetate/hexane, m.p. 133-135° C.
Reaction SMILES: [C:1]([C:4]1[C:9]([OH:10])=[C:8]([CH3:11])[C:7]([CH3:12])=[C:6]([OH:13])[C:5]=1[CH3:14])(=[O:3])[CH3:2].[CH3:15][O:16][CH2:17][C:18](=O)[CH3:19].N1CCCC1>C1(C)C=CC=CC=1>[OH:13][C:6]1[C:5]([CH3:14])=[C:4]2[C:9](=[C:8]([CH3:11])[C:7]=1[CH3:12])[O:10][C:18]([CH2:17][O:16][CH3:15])([CH3:19])[CH2:2][C:1]2=[O:3]
Reactant: CC(=O)c1c(C)c(O)c(C)c(C)c1O
Reactant: COCC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: COCC1(C)CC(=O)c2c(C)c(O)c(C)c(C)c2O1
Yield: 37 %

Procedure:
3.00 g (15.6 mmoles) of acetyl-trimethylhydroquinone, 1.58 g (18 mmoles) of methoxyacetone and 250 g (30 mmoles) of pyrrolidine were reacted in toluene solution by a method similar to that of Example 1 to give the above product, which was obtained as an oil. Boiling point: 250°-270° C. (bulb tube); yield: 37%.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:20])=[C:10]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]=2[F:13])[C:6](=[O:21])[C:5]([C:22]([OH:24])=[O:23])=[CH:4]1)[CH3:2].C(=O)(O)[O-].[Na+].[I-].[K+].Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:35]>CN(C=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:20])=[C:10]([N:14]3[CH2:15][CH2:16][N:17]([CH2:33][C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:35])[CH2:18][CH2:19]3)[C:11]=2[F:13])[C:6](=[O:21])[C:5]([C:22]([OH:24])=[O:23])=[CH:4]1)[CH3:2]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(F)c21
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=O)c4ccccc4)CC3)c(F)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
A mixture of 1-ethyl-6,8-difluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydroquinoline-3-carboxylic acid ( 0.5 1.48 mmole) [J. B. Cornett et. al., Annu. Rep. Med. Chem., 21, 138 (1986).], sodium bicarbonate (0.12 g, 1.48 mmole), potassium iodide (0.08 g, 0.5 mmole), and 2-bromoacetophenone (0.37 g, 1.86 mmole) in DMF (40 ml) was stirred at room temperature for 3 hr, then poured into ice-water (50 ml), and extracted with CH2Cl2 (50 ml×3). The extract was washed with water, dried over Na2SO4, and evaporated. The residual solid was crystallized from ethanol-chloroform(5:1) to give 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-phenacyl-1-piperazinyl)-quinoline-3-carboxylic acid (0.49 g, 73%). Mp: 167° C. (dec). 1H NMR (DMSO-d6) δ1.44 (t, 3H, J=7.0), 2.70 and 3.32 (two m, 8H), 3.97 (s, 2H), 4.59 (q, 2H, J=7.0), 7.54 and 8.02 (m, 5H), 7.85 (d, 1H, J=13.6), 8.92 (s, 1H), 14.95 (br s, 1H). Anal. Calcd. for C24H23F2N3O4•0.5 H2O: C, 62.06; H, 5.21; N, 9.05. Found: C, 62.18; H, 5.09; N, 9.06.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:13])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12].CCN(CC)CC.[CH3:21][O:22][C:23](=[O:26])[C:24]#[CH:25]>C(Cl)Cl>[CH3:21][O:22][C:23](=[O:26])[CH:24]=[CH:25][O:1][NH:2][C:3](=[NH:13])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12]
Reactant: C#CC(=O)OC
Reactant: COCCOCCOCC(=N)NO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOCCOCC(=N)NOC=CC(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a vigorously stirred mixture of crude N-hydroxy-2-[2-(2-methoxy-ethoxy)-ethoxy]-acetamidine (3.02 g) and NEt3 (2.30 mL) in DCM (40 mL) was added propynoic acid methyl ester (1.43 mL) dropwise. The mixture was stirred for 30 min at RT, washed with water, dried over anhydrous MgSO4 and concentrated in vacuo. The residue, crude 3-({2-[2-(2-Methoxy-ethoxy)-ethoxy]-acetimidoyl}-aminooxy)-acrylic acid methyl ester (4.50 g) was directly used in the next step.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([N:9]=[N:10][C:11](Cl)([CH3:21])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])([CH3:8])([CH3:7])[CH3:6]>CO>[C:5]([N:9]=[N:10][C:11]([N:1]=[N+:2]=[N-:3])([CH3:21])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])([CH3:8])([CH3:7])[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCOC(=O)CCC(C)(Cl)N=NC(C)(C)C
Agent: [Na+]
Solvent: CO
Product: CCCCOC(=O)CCC(C)(N=NC(C)(C)C)N=[N+]=[N-]
Temperature: 15 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To a solution of 20.2 grams (0.31 moles) of sodium azide in 200 ml. of 70% aqueous methanol cooled in an ice bath, was added dropwise 80.0 grams (.29 moles) of n-butyl 4-t-butylazo-4-chlorovalerate (prepared as in Example XX) over a 20 minute period. After the addition was complete the reaction mixture was stirred for 1 hour at 15° C. It was then poured into 500 ml. of water and extracted with pentane. The pentane solution was washed with water, saturated NaHCO3 solution, water, dried over anhydrous sodium sulfate, filtered and the pentane evaporated to leave 77 grams (93.7% yield) of the desired product.
Reaction SMILES: [H-].[Na+].O([C:10]([NH:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])C1C=CC=CC=1.[CH3:20][NH:21][CH2:22][C:23]1[N:24]=[C:25]([CH:28]([CH3:30])[CH3:29])[S:26][CH:27]=1>C1COCC1>[CH3:20][N:21]([C:10]([NH:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:15])[CH3:16])=[O:11])[CH2:22][C:23]1[N:24]=[C:25]([CH:28]([CH3:30])[CH3:29])[S:26][CH:27]=1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Reactant: CNCc1csc(C(C)C)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Reaction time: 0.25 h
Yield: 23.6 %

Procedure:
To a stirred slurry of 60% oil dispersion NaH (200 mg, 5 mmol) at <5° C. in 10 mL of THF was added N-phenoxycarbonyl-L-Valine (1.0 g, 4.2 mmol) followed by a 10 mL THF rinse and keeping the temperature <5° C. using an ice-water bath. In another flask, N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amine (851 mg, 5 mmol) was added to a <5° C. slurry of 60% oil dispersion NaH (220 mg, 5.5 mmol) in 10 mL of THF maintaining the temperature <5° C. Both solutions were stirred for 15 minutes, and then the acid salt solution was added to the amine salt solution in one portion. The reaction was allowed to proceed at <10° C. for 1 hour and then at ambient temperature for 30 minutes. The reaction was quenched by the addition of 10 mL of MeOH, and the reaction mixture was then concentrated in vacuo. The resulting residue was dissolved in a minimum of EtOAc and flash chromatographed on silica gel eluting with 1:1 ethyl acetate in isopropanol. The residue obtained was further purified by preparative thin layer chromatography eluting with 33.6% CHCl3, 7.7% H2O, 3.5% HOAc, 25.2% MeOH and 30% EtOAc to afford the title compound (310 mg, 24%) as a yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Cc1csc2nc(Cl)nc(NCCc3ccc4c(c3)OCO4)c12
Product: Cc1csc2nc(-n3ccnc3)nc(NCCc3ccc4c(c3)OCO4)c12

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.