Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[NH:28][S:27](=[O:30])(=[O:29])[CH2:26][C:25]=2[CH:31]=1>>[O:29]=[S:27]1(=[O:30])[CH2:26][C:25]2[CH:31]=[C:21]([NH:20][C:14](=[O:16])[C:13]([N:10]3[CH2:9][CH2:8][CH:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=4)[CH2:12][CH2:11]3)=[O:17])[CH:22]=[CH:23][C:24]=2[NH:28]1
Reactant: Nc1ccc2c(c1)CS(=O)(=O)N2
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Product: O=C(Nc1ccc2c(c1)CS(=O)(=O)N2)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-fluoro-benzyl) piperidin-1-yl]-oxo-acetic acid (Example 1a) and 5-amino-1,3-dihydro-2,1-benzisothiazole-2,2-dioxide according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 183-184° C. (isopropanol)
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:14])[C:4]([CH3:16])([CH3:15])[CH2:3]1.[N:17]([Na])=[N+:18]=[N-:19]>CN(C=O)C>[N:17]([CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:14])[C:4]([CH3:16])([CH3:15])[CH2:3]1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=N[Na]
Reactant: COc1ccc2c(c1)C(Br)CC(C)(C)C2=O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(N=[N+]=[N-])CC(C)(C)C2=O
Temperature: 60 °C
Yield: 88.8 %

Procedure:
4-Bromo-6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one (3.9 g, 14 mmol) was added to DMF (10 mL) followed by azidosodium (3.6 g, 55 mmol). The mixture was heated to 60° C. overnight. The reaction was cooled to RT and quenched with water (25 mL). The aqueous layer was extracted with Et2O (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and the residue was purified by column chromatography (0-50% EtOAc/Hexane to provide the title compound as a white solid (3.05 g, 90% yield). MS m/z: 268.2 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1F)[C:29]#[N:30].C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:8][C:6]1[CH:5]=[CH:4][C:3]([CH:9]([CH3:24])[C:10]([OH:15])([C:16]2[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=2)[C:11]([F:13])([F:14])[F:12])=[C:2]([Cl:1])[CH:7]=1)[C:29]#[N:30]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(c1ccc(Oc2ccc(C#N)cc2Cl)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F

Procedure:
In analogy to Example 197, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 196) was reacted with 3-chloro-4-fluorobenzonitrile and cesium carbonate to give the title compound as a colorless solid. MS (m/e)=497.3 [M+H+].
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[CH:3]1.C([Li])CCC.C=O.[OH:15][CH2:16]C1N2CCCCC2=CN=1>>[CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[C:3]1[CH2:16][OH:15]
Reactant: Cc1cn(C)cn1
Reactant: OCc1ncc2n1CCCC2
Agent: C=O
Agent: [Li]CCCC
Product: Cc1cn(C)c(CO)n1

Procedure:
The reaction of 1,4-dimethylimidazole (5.65 g.) with n-butyl lithium followed by treatment with formaldehyde according to the method described for the preparation of 3hydroxymethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (used for Example 224) gave 1,4-dimethyl-2-hydroxymethylimidazol (2.71 g.), m.p. 125°-126° (ethyl acetate-petroleum ether).
Reaction SMILES: [Si](O[C@@H]1[C@@H](CO[Si](C(C)(C)C)(C)C)O[C@@H](N2C3N=CN=C(OC)C=3N=C2)C1)([C:4](C)([CH3:6])[CH3:5])(C)C.N1([O:43][C:44]2[C:45]3[N:46]=[CH:47][N:48]([C:71]=3[N:72]=[CH:73][N:74]=2)[C@@H:49]2[O:70][C@H:60]([CH2:61][O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[C@@H:51]([O:52][Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54])[CH2:50]2)C2C=CC=CC=2N=N1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(O)C>[Si:63]([O:62][C@@H:61]1[C@@H:60]([CH2:51][O:52][Si:53]([C:56]([CH3:57])([CH3:59])[CH3:58])([CH3:54])[CH3:55])[O:70][C@@H:49]([N:48]2[C:71]3[N:72]=[CH:73][N:74]=[C:44]([O:43][CH:4]([CH3:6])[CH3:5])[C:45]=3[N:46]=[CH:47]2)[CH2:50]1)([C:66]([CH3:67])([CH3:69])[CH3:68])([CH3:64])[CH3:65]
Reactant: COc1ncnc2c1ncn2[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: CC(C)Oc1ncnc2c1ncn2[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Yield: 84 %

Procedure:
As described for the synthesis of 3′,5′-bis-O-(tert-butyldimethylsilyl)-O6-methyl-2′-deoxyinosine, the isopropyl derivative was prepared by a reaction between O6-(benzotriazol-1-yl)-3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (26) (59.8 mg, 0.100 mmol) and 2-propanol (1 mL) in the presence of Cs2CO3 (65.2 mg, 0.200 mmol) over 10 h. Chromatographic purification (SiO2, elution with 20% EtOAc in hexanes) afforded 44.1 mg (84% yield) of the title compound as a clear gum. Rf (20% EtOAc in hexanes)=0.31. 1H NMR (500 MHz, CDCl3): δ 8.50 (s, 1H, Ar—H), 8.23 (s, 1H, Ar—H), 6.49 (t, 1H, H-1′, J=6.3), 5.67 (septet, 1H, —CH—, J=6.3), 4.61 (m, 1H, H-3′), 4.02 (m, 1H, H-4′), 3.87 (dd, 1H, H-5′, J=11.2, 3.9), 3.78 (dd, 1H, H-5′, J=10.7, 2.9), 2.63 (app quint, 1H, H-2′, Japp˜6.3), 2.44 (ddd, 1H, H-2′, J=13.2, 5.9, 3.9), 1.47 (d, 6H, CH3, J=6.5), 0.91 (s, 18H, tert-Bu), 0.10, 0.09 (2 s, 12H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 160.5, 152.0, 151.5, 140.3, 122.0, 87.9, 84.4, 71.9, 71.2, 62.8, 41.4, 26.0, 25.7, 22.0, 18.4, 18.0, −4.7, −4.8, −5.4, −5.5. FAB HRMS calcd for C25H47N4O4Si2 (M++H) 523.3136. found 523.3130.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[N:7][CH:8]([Cl:11])[CH2:9][Cl:10])[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2Cl)[C:3]1=[O:20].[Cl:21][C:22]1C=[CH:26][CH:25]=[CH:24][C:23]=1N1C(=NC(Cl)CCl)CN(C)C1>>[Cl:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:1]=1[N:2]1[C:6](=[N:7][CH:8]([Cl:11])[CH2:9][Cl:10])[C:5](=[O:12])[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:3]1=[O:20]
Reactant: CN1C(=O)N(c2ccccc2Cl)C(=O)C1=NC(Cl)CCl
Reactant: CN1CC(=NC(Cl)CCl)N(c2ccccc2Cl)C1
Product: O=C1C(=NC(Cl)CCl)N(c2ccccc2Cl)C(=O)N1C1CCCCC1

Procedure:
Similarly the reverse 1-position-3-position isomers of each of the above prepared compounds are prepared by using the corresponding position isomer of formula A as the starting material. For example, by using 1-methyl-3-(2-chlorophenyl)-5-(1,2-dichloroethyl)imino-1,3-diazolidine-2,4-dione in place of 1-(2-chlorophenyl-3-methyl-5-(1,2-dichloroethyl)imino-1,3-diazolidine the following compounds (as well as the other 1-3 positions isomers of each of the above products are prepared:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH2:13])[C:10]2=[N:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:16][C:17](=[O:18])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:25]([O:29][C:30]([N:32]1[CH2:41][CH2:40][C:39]2[C:34](=[CH:35][C:36]([C:42](O)=[O:43])=[CH:37][CH:38]=2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].N1C=CC=CC=1C(O)=O>>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH:13][C:42]([C:36]2[CH:35]=[C:34]3[C:39]([CH2:40][CH2:41][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:33]3)=[CH:38][CH:37]=2)=[O:43])[C:10]2=[N:14][C:15]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[CH:16][C:17](=[O:18])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCn2c(nc(-c3ccncc3)cc2=O)C(N)C1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C(=O)O)cc2C1
Agent: O=C(O)c1ccccn1
Product: CCOC(=O)N1CCn2c(nc(-c3ccncc3)cc2=O)C(NC(=O)c2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)C1

Procedure:
By analogy with the method described in example 1 (step 1.5), using 9-amino-4-oxo-2-pyridin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester and 3,4-dihydro-1H-isoquinoline-2,7-dicarboxylic acid 2-tert-butyl ester in place of (+/−)-9-amino-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza benzocycloheptene-7-carboxylic acid ethyl ester hydrobromide (1:1) and 2-pyridine carboxylic acid, the compound, 0.286 g (80%), was obtained as a white powder.
Reaction SMILES: C([O:5][NH:6][C:7](=[O:28])[CH2:8][C:9]1([S:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1)(C)(C)C>FC(F)(F)C(O)=O>[OH:5][NH:6][C:7](=[O:28])[CH2:8][C:9]1([S:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:17][CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)ONC(=O)CC1(Sc2ccc(Oc3ccccc3)cc2)CCCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1(Sc2ccc(Oc3ccccc3)cc2)CCCC1)NO
Reaction time: 24 h

Procedure:
The N-tert-butoxy-2-[1-(4-phenoxyphenylthio)-cyclopent-1-yl]-acetamide was dissolved in trifluoroacetic acid (6 ml) and allowed to stand for 24 hours. The acid was evaporated off under reduced pressure and the product purified by preparative TLC, eluting with 6.5% methanol/methylene chloride gave N-hydroxy-2-[1-(4-phenoxyphenylthio)-cyclopent-1-yl]-acetamide (100 mg).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[O:17][CH:16]=[N:15][CH:14]=1>ClCCl>[O:17]1[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[OH:6])=[CH:14][N:15]=[CH:16]1
Reactant: COc1ccccc1-c1cnco1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccccc1-c1cnco1
Temperature: 25 °C
Yield: 114.7 %

Procedure:
Boron tribromide (1M in dichloromethane, 36 ml) is added slowly to a cold solution (0° C.) of the above oxazole (3.0 g, 17.1 mmol) in dichloromethane (215 ml). After stirring over night at room temperature, ice-water (50 ml) is added carefully. The aqueous layer is extracted with dichloromethane (50 ml), and the combined organic layers are dried over sodium sulfate and concentrated under reduced pressure. The precipitate which formed after addition of dichloromethane (70 ml) is collected by filtration, heated with dichloromethane (15 ml), and filtered again to give 3.16 g of 2-(5-oxazolyl)phenol. This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to give 400 mg of the title epoxide (9.5%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9](Cl)[N:8]=[CH:7][N:6]=1>CO>[Cl:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:2][CH3:1])[N:8]=[CH:7][N:6]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1ncnc(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
Sodium methoxide (2.70 g, 50.0 mmol) was added portionwise over 10 min to a 0° C. suspension of 4,6-dichloro-5-nitropyrimidine (4.85 g, 25.0 mmol) in methanol (90 ml). On complete addition the mixture was stirred at 0° C for 2 h. The precipitate was filtered and the filtrate evaporated. The residue was suspended in isohexane and filtered. The filtrate was evaporated and the residue purified by flash column chromatography on silica, eluting with 5% ethyl acetate in isohexane. Collecting appropriate fractions gave 4-chloro-6-methoxy-5-nitropyrimidine (3.50 g, 74%) as a white solid: δH (400 MHz, CDCl3) 4.15 (3H, s), 8.65 (1H, s).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[N:6]=[CH:5][C:4]([C:3]([N:26]4[CH2:31][CH2:30][S:29][CH2:28][CH2:27]4)=[O:2])=[CH:9][CH:8]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C)nc1
Reactant: C1CSCCN1
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)N2CCSCC2)cn1
Yield: 95 %

Procedure:
As described for example 117, 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (72 mg, 0.2 mmol) was converted, using thiomorpholine instead of 2,2,2-trifluoroethylamine, to the title compound (82 mg, 95%) which was obtained as a white solid. MS: m/e=430.5 [M+H]+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CC1C=CC(S(O[C@H:16]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:31]=[C:30]4[C:26]([C:27]([S:45]([CH3:47])=[O:46])=[CH:28][N:29]4[C:32]4[N:37]=[CH:36][C:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=5[F:44])=[CH:34][N:33]=4)=[CH:25][CH:24]=3)=[O:22])[CH2:17]2)(=O)=O)=CC=1>CN(C=O)C>[N:1]([C@@H:20]1[CH2:16][CH2:17][N:18]([C:21]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([S:45]([CH3:47])=[O:46])=[CH:28][N:29]3[C:32]3[N:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[F:44])=[CH:34][N:33]=3)=[CH:25][CH:24]=2)=[O:22])[CH2:19]1)=[N+:2]=[N-:3]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCN(C(=O)c3ccc4c(S(C)=O)cn(-c5ncc(-c6ccccc6F)cn5)c4c3)C2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CC[C@@H](N=[N+]=[N-])C3)ccc12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Sodium azide (0.31 g, 4.79 mmol) was added to a solution of 68a) (0.75 g, 1.37 mmol) in DMF (8.65 mL) and the resulting mixture was stirred at 60° C. for 2 h. After cooling to ambient temperature, the reaction mixture was poured onto water and extracted with dichloromethane (3×30 mL). The organic phase was dried over sodium sulfate and concentrated. The remnant was purified by flash column chromatography [silica; 2.5% methanol in dichloromethane]. White solid. Yield: 0.4 g (59% of theory). HPLC-MS (method 4): Rt=3.04 min; m/z [M+H]+=490.2
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1.[Cl-].[CH3:19][O:20][C:21]1([O:42][CH3:43])[CH2:25][NH2+:24][C@@H:23]([C:26](=[O:41])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]3=[O:40])=[CH:30][CH:29]=2)[CH2:22]1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:24]2[CH2:25][C:21]([O:42][CH3:43])([O:20][CH3:19])[CH2:22][C@@H:23]2[C:26]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]3=[O:40])=[CH:30][CH:29]=2)=[O:41])=[O:17])=[CH:11][CH:10]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC1(OC)C[NH2+][C@@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2)C1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1(OC)C[C@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2)N(C(=O)Nc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.4 0.12 ml of triethylamine and 127 mg (0.830 mmol) of 4-chlorophenyl isocyanate are added to a solution of 250 mg (0.658 mmol) of (R)-4,4-dimethoxy-2-[4-(2-oxo-2H-pyridin-1-yl)phenylcarbamoyl]pyrrolidinium chloride in 10 ml of dichloromethane. After stirring at room temperature for one hour, the reaction mixture is evaporated, and the residue is chromatographed on a silica-gel column with dichloromethane/methanol 95:5 as eluent, giving 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-2H-pyridin-1-yl)phenyl]}-(R)-4,4-dimethoxypyrrolidine-1,2-dicarboxamide (“A7”) as a colourless solid; ESI 497.
Reaction SMILES: [O-:1][N+:2]1[C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:6]=2[N:5]=[C:4]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[N:3]=1)[CH2:12][CH2:11][CH2:10]3.C[OH:21].C(Cl)Cl>>[O-:1][N+:2]1[C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:6]=2[N+:5]([O-:21])=[C:4]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[N:3]=1)[CH2:12][CH2:11][CH2:10]3
Reactant: [O-][n+]1nc(NCCCO)nc2cc3c(cc21)CCC3
Reactant: CO
Solvent: ClCCl
Product: [O-][n+]1nc(NCCCO)[n+]([O-])c2cc3c(cc21)CCC3

Procedure:
TFM (0.44 mL, 2.4 mmol) was added to a stirred solution of 1-oxide 50 (486 mg, 2.2 mmol) in DCM (20 mL) at 0° C. and the solution stirred at 20° C. for 16 h. H2O2 (70%, 1.1 mL, ca. 21.9 mmol) was added dropwise to a stirred solution of TFAA (3.1 mL, 21.9 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to the solution of 1-oxide 50 prepared above and the resulting solution was stirred at 20° C. for 16 h. Dilute aqueous NH3 solution (40 mL) was added and the mixture stirred vigorously for 4 h, then the mixture extracted with DCM (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 50 (254 mg, 52%); and (ii) 1,4-dioxide 51 (166 mg, 27%) as a red solid: mp (MeOH/DCM) 182-184° C.; 1H NMR δ 8.05 (s, 1H, H-9), 8.03 (s, 1H, H-5), 7.61 (br t, J=5.7 Hz, 1H, NH), 3.82 (br t, J=5.7 Hz, 2H, CH2O), 3.78 (br s, 1H, OH), 3.71-3.77 (m, 2H, CH2N), 3.10 (br t, J=7.5 Hz, 2H, H-6), 3.04 (br t, J=7.5 Hz, 2H, H-8), 2.20 (p, J=7.5 Hz, 2H, H-7), 1.97 (br p, J=6.0 Hz, 2H, CH2); 13C NMR δ 156.1, 149.5, 145.8, 137.8, 129.7, 115.7, 111.3, 60.2, 39.1, 33.4, 32.3, 31.5, 25.5. Anal. calcd for C13H16N4O3: C, 56.5; H, 5.8; N, 20.3. Found: C, 56.8; H, 5.9; N, 20.2%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[O:21]=[C:22]1[NH:28][C:27]2[CH:29]=[C:30]([C:33](O)=[O:34])[CH:31]=[CH:32][C:26]=2[C:25](=[O:36])[NH:24][CH2:23]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:33]([C:30]1[CH:31]=[CH:32][C:26]2[C:25](=[O:36])[NH:24][CH2:23][C:22](=[O:21])[NH:28][C:27]=2[CH:29]=1)=[O:34]
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Reactant: O=C1CNC(=O)c2ccc(C(=O)O)cc2N1
Product: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1NC(=O)c1ccc2c(c1)NC(=O)CNC2=O

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxylic acid. MS: 476.3 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[NH:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:3]1.[C:16]1([CH3:28])[CH:21]=[CH:20][C:19]([S:22]([N:25]=[C:26]=[O:27])(=[O:24])=[O:23])=[CH:18][CH:17]=1>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[N:6]([C:26](=[O:27])[NH:25][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:28])=[CH:17][CH:18]=2)(=[O:23])=[O:24])[CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:3]1
Reactant: CC1(C)NCC(COc2ccccc2)O1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)N2CC(COc3ccccc3)OC2(C)C)cc1

Procedure:
To 20.7 milliliters of 2,2-dimethyl-5-phenoxymethyl oxazolidine, 25 percent w/v in 50 milliliters of benzene was added 419 grams of p-toluene sulfonyl isocyanate. Upon completion of the reaction the solvent, benzene, was removed in vacuo. There was obtained 12.8 grams of the title compound, as a glass. Analytical data supports the structure.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([NH:16][CH2:17][C:18]([NH:24]CC2C=CC(OC)=CC=2)([CH3:23])[C:19]([F:22])([F:21])[F:20])=[O:15])=[N:4][C:5]([O:12][CH3:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[NH2:1][C:2]1[C:3]([C:14]([NH:16][CH2:17][C:18]([NH2:24])([CH3:23])[C:19]([F:22])([F:20])[F:21])=[O:15])=[N:4][C:5]([O:12][CH3:13])=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: COc1ccc(CNC(C)(CNC(=O)c2nc(OC)c(C(F)(F)F)cc2N)C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(C(=O)NCC(C)(N)C(F)(F)F)c(N)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture comprising 3-amino-6-methoxy-N-(3,3,3-trifluoro-2-(4-methoxybenzylamino)-2-methylpropyl)-5-(trifluoromethyl)picolinamide (Ex. 18) (0.9 g, 1.873 mmo) in TFA (50 ml) was heated to 50° C. for 2 h. After cooling to RT, the pH was adjusted to pH 12 using 2M NaOH. The product was extracted with DCM and the organic extract was washed with water, dried over MgSO4 and concentrated in vacuo. The crude product was loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions were concentrated in vacuo and dried under vacuum to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (1H, m), 7.67 (1H, s), 6.67 (2H, s), 3.93 (3H, s), 3.58 (1H, m), 3.40 (1H, m), 2.22 (2H, s), 1.14 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[Cl:27][C:28]1[CH:29]=[C:30]([CH2:35][CH2:36][NH2:37])[CH:31]=[C:32]([Cl:34])[CH:33]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:37][CH2:36][CH2:35][C:30]3[CH:29]=[C:28]([Cl:27])[CH:33]=[C:32]([Cl:34])[CH:31]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: NCCc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4cc(Cl)cc(Cl)c4)cc3)c(Cl)cc21
Reaction time: 24 h
Yield: 96.5 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (54.2 mg, 0.144 mmol), in 1:1 DCM:DMF (0.1 M) was sequentially treated with 2-(3,5-dichlorophenyl)ethanamine (30.1 mg, 0.158 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (33.1 mg, 0.173 mmol), 1-Hydroxy-7-azabenzotriazole (5.87 mg, 0.0432 mmol), and N,N-diisopropylethylamine (27.9 mg, 0.216 mmol) at ambient temperature. After 24 hours the reaction was applied directly to a silica gel column and eluted with a gradient (15% to 60%) of ethyl acetate-hexanes to provide the title compound (76.4 mg, 0.139 mmol, 96.8% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[CH2:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O)[CH3:34]>COCCOC>[C:25]([C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH2:33][CH3:34])[CH:24]=1)#[N:26]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(C#N)cc1Br
Reactant: CCc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCc1ccccc1-c1cc(C#N)ccc1OCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 83.5 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-cyano-phenoxy)-acetyl]-N′-isopropyl-hydrazide (200 mg, 0.480 mmol) in DME (3 ml)/2M Na2CO3 (0.840 ml, 1.68 mmol) was treated with 2-ethylphenylboronic acid (144 mg, 0.9608 mmol) and Pd[PPh3]4 (55 mg, 0.048 mmol) in a microwave oven at 150° C. for 10 min. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 30% ethyl acetate/hexanes to afford the product as a white solid (177 mg, 84%). MS m/e 442.25 (M+H+)
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].[CH3:10][NH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[CH:14][CH:13]=1.[OH-].[Na+]>O>[CH3:10][NH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:9]=2)=[CH:14][CH:13]=1
Reactant: CNc1ccccc1N
Reactant: CNc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNc1ccc(-c2nc3ccccc3n2C)cc1
Temperature: 80 °C

Procedure:
10.14 mL (86.5 mmol) N-Methyl-o-phenylenediamine and 13.08 g (86.5 mmol) 4-(methylamino)benzoic acid are stirred in 70.0 g polyphosphoric acid at 200° C. for 3 hours. The mixture is cooled to 80° C., poured into water and stirred over night at RT. The mixture is alkalinized with sodium hydroxide solution. The precipitate is filtered off and washed with water. The product is dried in vacuo at 50° C.