Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C@H:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19]([C:21]3[C:22]([CH3:28])=[N:23][CH:24]=[N:25][C:26]=3[CH3:27])=[O:20])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Br[CH2:31][C:32]1[CH:36]=[CH:35][S:34][CH:33]=1>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:31][C:32]2[CH:36]=[CH:35][S:34][CH:33]=2)[CH:9]2[CH2:10][CH2:11][N:12]([C@H:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19]([C:21]3[C:26]([CH3:27])=[N:25][CH:24]=[N:23][C:22]=3[CH3:28])=[O:20])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccsc1
Reactant: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(Nc2ccc(Cl)cc2)CC1
Solvent: CC#N
Product: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2ccsc2)c2ccc(Cl)cc2)CC1
Yield: 22.9 %

Procedure:
A solution of the above aniline (119 mg, 0.29 mmol) and 3-(bromomethyl)thiophene (61 mg, 0.34 mmol) in CH3CN (5 mL) was stirred at room temperature overnight to afford COMPOUND 292 as a white solid (34 mg, 23%) following work-up and purification. 1H NMR (CDCl3) δ 0.89-1.19 (m, 2H), 1.01 (d, 3H, J=6.6 Hz), 1.54-1.58 (m, 1H), 1.73-1.80 (m, 3H), 2.16 (t, 1H, J=12.3 Hz), 2.52 (s, 6H), 2.56 (t, 1H, J=12.3 Hz), 2.73-2.89 (m, 3H), 3.28-3.36 (m, 1H), 3.49-3.57 (m, 1H), 3.82 (s, 2H), 3.84-3.92 (m, 1H), 6.54 (d, 2H, J=8.7 Hz), 6.98-7.01 (m, 2H), 7.06-7.09 (m, 2H), 7.28 (dd, 1H, J=4.8, 3.0 Hz), 8.71 (br s, 1H), 8.88 (s, 1H). ES-MS m/z 512 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:22]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)=[N:4][C:5]2[N:6]([N:9]=[CH:10][C:11]=2[C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=1[NH2:8].CCN(C(C)C)C(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>CN(C=O)C>[Br:1][C:2]1[C:3]([CH:22]2[CH2:27][CH2:26][CH2:25][N:24]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:23]2)=[N:4][C:5]2[N:6]([N:9]=[CH:10][C:11]=2[C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=1[NH2:8]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1c(Br)c(C2CCCNC2)nc2c(-c3cnc4ccccc4c3)cnn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 6-bromo-5-(piperidin-3-yl)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine (HCl salt, 46 mg, 0.10 mmol) in DMF (2.0 mL) was added DIEA (0.10 mL, 0.30 mmol) and methylsulfonyl chloride (14 mg, 0.12 mmol). The reaction mixture was stirred at rt for 3 h and concentrated in vacuo. The residue was purified by prep-LC to give the title compound. LC/MS RT=2.49 min. Mass calculated for, M+H 486.05, observed 389.17.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@@H:41]([CH3:44])[CH2:42][CH3:43])[C:7]([N:9]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]1[C:15]([O:17][CH2:18][C:19]([C:21]1[CH:22]=[CH:23][C:24]2[C:33]3[CH:32]=[C:31]4[CH2:34][CH2:35][CH:36](Br)[C:37](=[O:38])[C:30]4=[CH:29][C:28]=3[O:27][CH2:26][C:25]=2[CH:40]=1)=[O:20])=[O:16])=[O:8])=[O:4].[C:45]([O:49][C:50]([N:52]1[C@@H:56]([CH3:57])[CH2:55][CH2:54][C@H:53]1[C:58]([OH:60])=[O:59])=[O:51])([CH3:48])([CH3:47])[CH3:46].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CCOC(C)=O>[CH3:57][C@@H:56]1[N:52]([C:50]([O:49][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:51])[C@H:53]([C:58]([O:60][CH:36]2[CH2:35][CH2:34][C:31]3=[CH:32][C:33]4[C:24]5[CH:23]=[CH:22][C:21]([C:19](=[O:20])[CH2:18][O:17][C:15]([C@@H:10]6[CH2:11][CH2:12][C@H:13]([CH3:14])[N:9]6[C:7](=[O:8])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[C@@H:41]([CH3:44])[CH2:42][CH3:43])=[O:16])=[CH:40][C:25]=5[CH2:26][O:27][C:28]=4[CH:29]=[C:30]3[C:37]2=[O:38])=[O:59])[CH2:54][CH2:55]1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N1[C@@H](C)CC[C@H]1C(=O)OCC(=O)c1ccc2c(c1)COc1cc3c(cc1-2)CCC(Br)C3=O
Reactant: C[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N1[C@@H](C)CC[C@H]1C(=O)OCC(=O)c1ccc2c(c1)COc1cc3c(cc1-2)CCC(OC(=O)[C@@H]1CC[C@H](C)N1C(=O)OC(C)(C)C)C3=O
Temperature: 50 °C
Yield: 43 %

Procedure:
To a solution of (2S,5S)-2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl 1-((2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoyl)-5-methylpyrrolidine-2-carboxylate (5.95 g, 8.88 mmol) in THF (60 mL) was added (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (3.05 g, 13.3 mmol) and Cs2CO3 (2.31 g, 7.09 mmol). The resulting solution was heated to 50° C. for 18 h. The solution was cooled to room temperature and diluted with EtOAc and washed with aqueous HCl (0.5 M). The aqueous layer was backextracted with EtOAc (2×), and the combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified by column chromatography (SiO2, 25-100% EtOAc (5% MeOH)/Hexanes) to provide (2S,5S)-1-tert-butyl 2-(3-(2-((2S,5S)-1-((2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoyl)-5-methylpyrrolidine-2-carbonyloxy)acetyl)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-9-yl) 5-methylpyrrolidine-1,2-dicarboxylate (3.116, 43% over 2 steps) as a orange foam. LCMS-ESI+: calc'd for C44H55N3O12: 817.38 (M+). Found: 817.65 (M+).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]2[C:10]3([CH2:20][O:21][C:6]=2[CH:5]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19].Br[C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2C=1C1(C3=CC4OCOC=4C=C3OC1)[C:28](=O)[NH:29]2.Br.BrCC1C=NC=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:33]([CH2:25][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]3([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:5][C:6]=4[O:21][CH2:20]3)[C:11]2=[O:19])[CH:28]=1
Reactant: O=C1Nc2ccccc2C12COc1cc(OC(F)(F)F)ccc12
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Agent: Br
Agent: BrCc1cccnc1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2cccnc2)c2ccccc2C12COc1cc(OC(F)(F)F)ccc12

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using 6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 3-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-(pyridin-3-ylmethyl)-6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained, which was treated with 4.0 M HCl in dioxane to give the title compound (70%) as a white solid: mp 151-153° C.; 1H NMR (300 MHz, CD3OD) δ 9.07-8.61 (m, 3H), 8.19-8.04 (m, 1H), 7.42-6.71 (m, 7H), 5.28 (s, 2H), 5.05 (d, 1H), 4.86 (d, 1H); 13C NMR (75 MHz, CD3OD) δ 179.43, 163.5, 151.8, 147.0, 142.9, 142.4, 142.2, 133.0, 130.6, 129.3, 128.9, 125.5, 125.4, 125.3, 114.9, 110.5, 104.9, 82.0, 58.9, 42.0; MS (ES+) m/z 413 (M+1).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][CH:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]([OH:24])[CH2:22][N:23]=2)=[CH:14][CH:13]=1>ClCCCl>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[O:19][CH:20]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:21]([O:24][C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:22][N:23]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(C2=NCC(O)C(c3ccccc3)O2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCCl
Product: COc1ccc(C2=NCC(OC(=O)Nc3ccccc3)C(c3ccccc3)O2)cc1
Yield: 24.4 %

Procedure:
Phenyl isocyanate (1.25 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (5RS, 6SR)-2-(4-methoxyphenyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.5 g) in 1,2-dichloroethane (20 cc). The solution obtained is heated to reflux for 6 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on silica (0.063-0.2 mm; 50 g) contained in a column 2 cm in diameter [eluent: cyclohexane/ethyl acetate/triethylamine (60:35:5 by volume)], collecting 20-cc fractions. Fractions 4 to 10 are combined and concentrated to dryness under reduced pressure (2. 7 kPa) at 40° C. After recrystallization in diisopropyl ether, (5RS, 6SR)-2-(4-methoxyphenyl)-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (0.52 g), m.p. 223° C., is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([NH:29][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:13])[CH2:31][CH2:32]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)N[C@H]3CC[C@H](O)CC3)ccc21

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (trans-4-hydroxy-cyclohexyl)-amide (42 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), trans-4-amino-cyclohexanol (23 mg), HBTU (84 mg), and DIEA (48 uL). LC/MS: m/z 506.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.40 (s, 1H), 8.17 (s, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.82-7.64 (m, 2H), 7.47 (d, 1H), 7.36 (d, 1H), 4.57 (d, 1H), 3.81-3.68 (m, 1H), 3.64 (bs, 3H), 3.46-3.35 (m, 1H), 1.92-1.78 (m, 4H), 1.39 (q, 2H), 1.26 (q, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH3:17])[N:5]=[CH:4][N:3]=1.[C:18]([O:22][C:23](=[O:32])[NH:24][CH2:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:21])([CH3:20])[CH3:19].CCN(C(C)C)C(C)C>C(#N)C>[C:18]([O:22][C:23](=[O:32])[NH:24][CH2:25][CH:26]1[CH2:27][CH2:28][N:29]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[C:6]([CH3:17])[N:5]=[CH:4][N:3]=2)[CH2:30][CH2:31]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1ncnc(Cl)c1C#Cc1ccc(N)nc1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncnc(N2CCC(CNC(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
The title compound is synthesized according to general procedure GP7 (method 2) starting from 2.0 g (8.17 mmol) 4-chloro-6-methyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine and 2.33 g (9.81 mmol) piperidin-4-ylmethyl-carbamic acid tert-butyl ester using 1.82 mL (10.6 mmoL) DIPEA in 50 mL ACN. The reaction mixture is stirred for 1 h at 80° C. The solvent is removed under reduced pressure. The residue is taken up in DCM/MeOH and filtered over silica. After removal of the solvent and extractive work up 3.1 g (90%) of the desired product is obtained. The product is used without further purification for the next step.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[H][H].C1(C)C=CC=CC=1>CO.Cl>[OH:1][C@H:2]([CH2:8][CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCC(=O)CC(=O)OC
Reactant: [H][H]
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: CCC[C@@H](O)CC(=O)OC

Procedure:
Methyl 3-ketohexanoate (44.7 g, 310 mmol) was diluted with methanol (75 mL) and 0.2N HCl (2 mL). Et2NH2 +Ru2Cl5- (BINAP)2 (200 mg) was added and the mixture was heated at 60° under 100 psi of hydrogen for 2 hours. Toluene (100 mL) was added and the mixture was concentrated to an oil weighing 75 g.
Reaction SMILES: O=[O+][O-].[C:4]1([CH:10]([O:17][C:18](=[O:50])/[C:19](/[N:23]2[CH:26]([S:27][S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:25]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:24]2=[O:49])=[C:20](\O)/[CH3:21])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:51](Cl)Cl>>[C:4]1([CH:10]([O:17][C:18](=[O:50])[CH:19]([N:23]2[CH:26]([S:27][S:28]([C:31]3[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=3)(=[O:30])=[O:29])[CH:25]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:24]2=[O:49])[C:20](=[CH2:51])[CH3:21])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C/C(O)=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Reactant: ClCCl
Agent: O=[O+][O-]
Product: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1

Procedure:
Analogously to Example 1d), 10.8 g (16.2 mM) of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyric acid diphenylmethyl ester in 1 l of methylene chloride and 1.1 equivalents of ozone give 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonic acid diphenylmethyl ester; melting point 142°-143° C. (from ether/pentane).
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[H-].[Na+].[CH2:12](Br)[CH:13]=[CH2:14]>CN(C=O)C.CCOCC>[CH2:14]([O:9][C:3]1([C:1]#[CH:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: C#CC1(O)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CC1(OCC=C)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
A solution of 1-ethynylcyclohexanol (2.28 g, 18.36 mmol) in DMF (25 ml) was cooled (0° C. ice bath) and treated with 60% NaH (0.890 g, 22.25 mmol). The reaction was stirred for 30 min, then warmed to room temperature and stirred for 1 hr. To this was added allyl bromide (4.8 ml, 55.5 mmol) over 5 min and continued stirring for 16 h. The reaction was diluted with Et2O (75 mL), washed with water (4×50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated to give the product, 1-(allyloxy)-1-ethynylcyclohexane (2.873 g, 12.24 mmol, 66.7% yield) as a pale yellow mobile oil. 1H NMR consistent with expected product, consists of approx 3:1 product/SM. Used as-is without further purification 1H NMR (CDCl3) δ: 5.94-6.04 (m, 1H), 5.33 (dq, J=17.2, 1.7 Hz, 1H), 5.17 (dq, J=10.3, 1.5 Hz, 1H), 4.15 (dt, J=5.6, 1.5 Hz, 2H), 2.50 (s, 1H), 2.49 (s, 1H), 1.91-1.98 (m, 3H), 1.49-1.77 (m, 12H), 1.24-1.38 (m, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:8][OH:9])[CH:2]=1.[CH2:10]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])[CH:11]=[CH2:12]>C(Cl)(Cl)Cl.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:12][CH:11]([CH2:10][N:13]3[CH2:17][CH2:16][CH2:15][C:14]3=[O:18])[O:9][N:8]=2)[CH:2]=1
Reactant: ON=Cc1cccnc1
Reactant: C=CCN1CCCC1=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1CCCN1CC1CC(c2cccnc2)=NO1
Yield: 57.7 %

Procedure:
The desired compound was prepared by the method of Example 8 from 500 mg (4.09 mmol) of 3-pyridine aldoxime and 1.02 g (2 equivalents) of 1-allyl pyrrolidin-2-one prepared in Example 6, and purified by separation with silica gel column chromatography using ethyl acetate and then chloroform/methanol (30:1) as eluent to obtain 578.4 mg (58% yield) of 1-(3-pyridin-3-yl-4,5-dihydro-isoxazol-5-yl-methyl)-pyrrolidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([O:26][C:27]1(OCCCC)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:23][CH2:24][CH3:25]>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:27]3([O:26][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CCCCOC1(OCCCC)CCCCCC1
Product: CCCCOC1(OCCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCCCC1
Yield: 20.8 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the acetal with 1,1-di-n-butoxycycloheptane (2.42 g, 10 mmol) in the same manner as the example 20 to give the compound 29 (107 mg, 20.8%). PMR (CDCl3 -0.1% d5 -Py): δH 0.90 (3 H, t, J 7.4 Hz, CH3) 1.24 (6H, d, J 7Hz, (CH3)2C), 3.00 (2H, t, J 6Hz, CH2 -Im), 3.11 (3 H, m, OCH2CH3, (CH3)2CH), 3.52(3 H, s, NCH3), 3.71 (2 H, t, J 6 Hz, OCH2), 6.83 (2 H, d, J 1.6 Hz, arom-H), 7.12 (t-like, arom-H). Elementary analysis (for C26H38N2O2Cl2S) Calcd. : C, 60.80% H, 7.46% N, 5.46% Found: C, 60.99% H, 6.56% N, 5.41%
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][CH2:25][CH2:26]Br>CC(C)=O>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([O:17][CH2:24][CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CCCBr
Reactant: O=c1c2ccccc2sc2c(O)ccc(Cl)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccc(Cl)c2c(=O)c3ccccc3sc12
Yield: 75.5 %

Procedure:
1-Chloro-4-hydroxythioxanthone (7.8 g; 0.03 mol) prepared as above and potassium carbonate (5.0 g; 0.036 mol) was stirred and refluxed for 10 minutes in acetone (50 ml). n-Propyl bromide (5.5 g; 0.045 mol) was added and the resulting mixture heated under reflux for 16 hours. The mixture was then cooled and quenched on to water (250 ml). The solid was filtered and washed with water the resulting damp solid recrystallised from ethanol (50 ml) to afford the title compound (6.9 g; 75.5%) of mp 102°-3°. Analysis C16H13ClO2S=304.777 Requires C 63.05%; H 4.30%; Cl 11.63%; S 10.52% Found C 63.14%; H 4.37%; Cl 11.66%; S 10.63%
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:10](O)=[O:11])([O:5][CH3:6])=[O:4].C(OC(=O)CCN)(C)(C)C.[C:36]([CH2:38][CH2:39][N:40]1[C:44]([CH2:45][CH2:46][NH2:47])=[N:43][N:42]=[N:41]1)#[N:37]>>[CH3:6][O:5][P:3]([CH2:7][NH:8][CH:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1)[C:10]([N:41]1[NH:42][N:43]=[C:44]([CH2:45][CH2:46][NH2:47])[N:40]1[CH2:39][CH2:38][C:36]#[N:37])=[O:11])([O:2][CH3:1])=[O:4]
Reactant: N#CCCn1nnnc1CCN
Reactant: COP(=O)(CN[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)OC
Agent: CC(C)(C)OC(=O)CCN
Product: COP(=O)(CNC(Cc1ccc(-c2ccccc2)cc1)C(=O)N1NN=C(CCN)N1CCC#N)OC

Procedure:
(S)-2-(dimethylphosphonomethylamino)-3-(4-biphenylyl)-propionic acid is treated (under conditions described in example 2 for the condensation with β-alanine t-butyl ester) with 1-(2-cyanoethyl)-5-(2-aminoethyl)tetrazole to yield (S)-5-[N-[2-(dimethylphosphonomethylamino)-3-(4-biphenylyl)propionyl[-2-aminoethyl]-1-(2-cyanoethyl)-tetrazole.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH3:8])=[O:3].[S:15]1[CH:19]=[C:18]([C:20]2[NH:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[N:17]=[CH:16]1>N1C=CC=CC=1>[CH2:5]([O:4][C:2]([N:24]1[C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[N:21]=[C:20]1[C:18]1[N:17]=[CH:16][S:15][CH:19]=1)=[O:3])[CH2:6][CH:7]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH3:8]
Reactant: CC(C)=CCCC(C)CCOC(=O)Cl
Reactant: c1ccc2[nH]c(-c3cscn3)nc2c1
Solvent: c1ccncc1
Product: CC(C)=CCCC(C)CCOC(=O)n1c(-c2cscn2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
11.0 Grams (0.05 moles) of citronellyl chloroformate is added over a period of 1/2 hour to a stirred suspension of 10 grams (0.05 moles) of 2-(4-thiazolyl)benzimidazole and 75 ml. of pyridine at room temperature. The reaction mixture is stirred overnight at room temperature protected from moisture. The solid material is filtered, washed with pryidine and the filtrate and washings evaporated to dryness in vacuo. The residue is dissolved in methylene chloride and the solution washed successively with dilute cold hydrochloric acid, cold water, cold dilute sodium bicarbonate solution and water. The methylene chloride is dried, evaporated to dryness in vacuo affording 16.6 grams of a viscous oil. The oil is chromatographed on a column of silica gel eluting with hexane affording 14.6 grams (76%) of an oil which thin layer chromatography reveals to be pure material and which analyzes as 1-citronellyloxycarbonyl-2-(4-thiazolyl)benzimidazole.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[C:10]([NH:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([C:24]([NH2:26])=[O:25])=[C:19]([NH2:23])[NH:20]2)=[CH:16][CH:15]=1)(=[O:12])[CH3:11].N.CO>O1CCCC1>[C:10]([NH:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([C:24]([NH2:26])=[O:25])=[C:19]([NH:23][C:3]([NH2:5])=[O:4])[NH:20]2)=[CH:16][CH:15]=1)(=[O:12])[CH3:11]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(=O)Nc1ccc2c(C(N)=O)c(N)[nH]c2c1
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.9 %

Procedure:
Trichloroacetyl isocyanate (48 μL, 0.36 mmol) was added to a solution of 6-acetylamino-2-aminoindole-3-carboxamide (Reference compound 15-1, 26 mg, 0.11 mmol) in anhydrous tetrahydrofuran (1.5 mL), and the mixture was stirred at room temperature for 18 hours. 2.0 M Ammonia in methanol solution (2.0 mL, 4.0 mmol) was added thereto, and the mixture was stirred at room temperature for 6 hours. The precipitated solid was separated by filtration using methanol (0.5 mL), and dried under reduced pressure to give the title compound (13 mg) as a colorless solid (yield 43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].Br[CH:37]([CH2:39][CH3:40])[CH3:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH:37]([CH2:39][CH3:40])[CH3:38])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: COc1ccc(CC2c3c(OC)ccc(O)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Reactant: CCC(C)Br
Product: CCC(C)Oc1ccc(OC)c2c1CCN(CC(=O)NCc1ccccn1)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with 2-bromo-butane
Reaction SMILES: O=[C:2]1O[N:5]=[N+:4]2[CH2:7][CH2:8][CH2:9][CH:3]12.C(OCCOCC)C.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[C:19]#C.C(=O)=O>>[N:5]1[N:4]2[CH2:7][CH2:8][CH2:9][C:3]2=[CH:2][C:19]=1[C:18]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: C#CC(=O)OCC
Reactant: O=C1ON=[N+]2CCCC12
Agent: CCOCCOCC
Agent: O=C=O
Product: CCOC(=O)c1cc2n(n1)CCC2
Temperature: 122.5 °C
Reaction time: 5 h

Procedure:
The 3a,4,5,6-Tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium ylide (971 g, 7.70 mol, made as in example 2) and 1,2-diethoxyethane (DEE, 2913 mL) are charged to a multinecked 12 L round bottom flask, is equipped with a water cooled condenser, and purged with nitrogen. The stirred solution is heated to 120-125° C. under a nitrogen atmosphere and ethyl propiolate (971 g, 9.90 mol) is added dropwise over a period of 3 hours (carbon dioxide evolution). The reaction is held at 120-125° C. for about 5 hours until the conversion is >99% (<1% of residual 3a,4,5,6-tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium ylide, by GC-MS analysis). The mixture is then concentrated under oil pump vacuum using a rotary evaporator with a bath temperature up to 70° C. to a residue. About 1.5 kg of toluene is then added to the residue and the mixture is concentrated once more. A dark oil is obtained [1218 g, 46.9% strength, (HPLC) in 41% (real yield of ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate, from crude 3a,4,5,6-tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium ylide].