Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][C:14]=1[O:22][CH3:23].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[NH:4][N:3]=2)=[CH:15][C:14]=1[O:22][CH3:23]
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: COc1cc(B(O)O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2n[nH]c3ncnc(N)c23)ccc1Cl
Temperature: 80 °C
Reaction time: 12 h
Yield: 13.2 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.430 g, 1.65 mmoles) in DMF (3.6 ml), ethanol (1.8 ml) and water (1.8 ml), 4-chloro-3-methoxyphenyl boronic acid (0.400 g, 2.145 mmoles) and sodium carbonate (0.873 g, 19.15 mmoles) were added and the system is degassed for 30 min Tetrakis triphenylphosphine Palladium (0.374 g, 0.313 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as green solid (0.060 g, 10% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 13.62(s, 1H), 8.20(s, 1H), 7.56(d, J=8.1Hz, 1H), 7.34(s, 1H),7.23(d, J=8.1Hz 1H),3.91(s,3H).
Reaction SMILES: [Cl:1][C@H:2]1[C@H:6]([CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[C@@H:5]([CH:17]=O)[C@H:4]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH2:3]1.C([C@H]1COC(=O)N1CCSC1SC=C(C(OCC)=O)N=1)=O.[CH3:47][C@@H:48]([CH2:59][CH2:60][CH2:61][CH3:62])[CH2:49][C:50](=[O:58])[CH2:51]P(=O)(OC)OC>>[Cl:1][C@H:2]1[C@H:6]([CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[C@@H:5](/[CH:17]=[CH:51]/[C:50](=[O:58])[CH2:49][C@@H:48]([CH3:47])[CH2:59][CH2:60][CH2:61][CH3:62])[C@H:4]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH2:3]1
Reactant: CCCC[C@H](C)CC(=O)CP(=O)(OC)OC
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@H]1Cl
Agent: CCOC(=O)c1csc(SCCN2C(=O)OC[C@@H]2C=O)n1
Product: CCCC[C@H](C)CC(=O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@H](Cl)C[C@H]1OC1CCCCO1

Procedure:
By the same procedure as the reaction of Example 6 using methyl (5Z)-7-[(1R,2R,3R,5R)-5-chloro-2-formyl-3-(tetrahydro-2 H-pyran-2-yloxy)cyclopentyl]-5-heptenoate (Reg. No. 261772-21-8) instead of the compound 5 and using dimethyl [(4S)-4-methyl-2-oxooctyl]phosphonate instead of dimethyl (3,3-dimethyl-2-oxoheptyl)phosphonate, the title compound (360 mg) having the following physical data was obtained.
Reaction SMILES: [O:1]=[C:2]1[N:13]2[C:14]3[C:10]([CH:11]=[CH:12]2)=[CH:9][C:8]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[CH:18]=O)=[CH:7][C:6]=3[CH2:5][NH:4][CH2:3]1.[CH3:23][NH2:24]>O>[CH3:23][NH:24][CH2:18][C:17]1[CH:16]=[C:15]([C:8]2[CH:9]=[C:10]3[C:14]4=[C:6]([CH2:5][NH:4][CH2:3][C:2](=[O:1])[N:13]4[CH:12]=[CH:11]3)[CH:7]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CN
Reactant: O=Cc1cccc(-c2cc3c4c(ccn4C(=O)CNC3)c2)c1
Solvent: O
Product: CNCc1cccc(-c2cc3c4c(ccn4C(=O)CNC3)c2)c1
Yield: 94 %

Procedure:
Using the reductive amination procedure described in Example 82, the title compound was synthesized from 3-(1-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-6-yl)-benzaldehyde and methylamine in 94% yield as a pale-yellow solid: mp 128-130° C.; 1H NMR (DMSO-d6) δ 2.29 (s, 3H), 3.48 (br s, 2H), 3.71 (s, 2H), 4.30-4.33 (m, 2H), 6.69 (s, 1H), 7.17 (t, 1H, J=9.0 Hz), 7.38-7.39 (m, 1H), 7.44-7.46 (m, 2H), 7.54 (s, 1H), 7.80 (t, 2H, J=9.0 Hz), 8.39 (t, 1H, J=6.0 Hz). HRMS calcd. for C19H19N3O 305.3828 (M+), found 305.1520. Anal. (C19H19N3O.0.6 H2O) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH2:28][CH2:29][OH:30])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5](O)=[O:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:64]1([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH2:28][CH2:29][OH:30])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5]([N:67]1[CH2:68][CH2:69][N:64]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:65][CH2:66]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc(N(CCO)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N(CCO)C(=O)c3cc4c(s3)-c3ccccc3OCC4)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
To a solution of 3-chloro-4-(N-(2-hydroxyethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid (0.100 g, 0.225 mmol) in 1 mL of THF was added as a whole HATU (0.094 g, 0.248 mmol) and DIEA (0.078 mL, 0.450 mmol). This reaction mixture was allowed to stir at room temperature for 30 minutes. Next, tert-butyl piperazine-1-carboxylate (0.12 g, 0.22 mmol) was added to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was taken into a large volume of ethyl acetate, washed with water, then saline and dried (Na2SO4). The organic was then conc. in vacuo to a solid residue and purified by RP-HPLC to give tert-butyl 4-(3-chloro-4-(N-(2-hydroxyethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoyl)piperazine-1-carboxylate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH2:18])(=[O:17])=[O:16])[CH:5]=[CH:4][N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH2:31])[CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28]>>[CH3:30][O:29][C:25]1[CH:24]=[C:23]([NH:31][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([NH2:18])(=[O:17])=[O:16])[CH:5]=[CH:4][N:3]=2)[CH:22]=[C:21]([O:20][CH3:19])[C:26]=1[O:27][CH3:28]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: NS(=O)(=O)c1ccccc1Nc1ccnc(Cl)n1
Product: COc1cc(Nc2nccc(Nc3ccccc3S(N)(=O)=O)n2)cc(OC)c1OC

Procedure:
The title compound is prepared from 2-(2-chloro-pyrimidin-4-ylamino)-benzenesulfonamide as described in Example 1 using 3,4,5-Trimethoxy-phenylamine instead of 6-aminoindazole in step (b).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH3:23])[CH2:11][CH2:12][CH2:13][C:14]([CH3:22])=[CH:15][CH2:16][CH2:17][C:18](=[O:21])[CH2:19][Br:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]([CH3:23])[CH2:11][CH2:12][CH2:13][C:14]1([CH3:22])[O:32][CH:15]1[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][Br:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=CCCC(=O)CBr)CCCC(C)COCc1ccccc1
Solvent: ClCCl
Product: CC(CCCC1(C)OC1CCC(=O)CBr)COCc1ccccc1
Yield: 107.7 %

Procedure:
11-Benzyloxy-1-bromo-6,10-dimethyl-2-oxo-undec-5-ene (15.6 g, 41 mM) in methylene chloride (250 ml) is treated with 85% m-chloroperbenzoic acid (8.35 g, 41 mM) in methylene chloride (200 ml) at 0° C. for 3 hours. The reaction mixture is washed with brine, saturated sodium sulfite, brine and then dried (Na2SO4). The solvent is removed in vacuo to give crude 11-benzyloxy-1-bromo-6,10-dimethyl-5,6-epoxy-undecan-2-one (17.5 g).
Reaction SMILES: [CH:1]1([C:6](O)([CH2:23][C:24]2[O:25]C(C)(C)[O:27][C:28](=[O:30])[CH:29]=2)[C:7]#[C:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]([CH3:21])([CH3:20])[C:18]#[N:19])=[C:11]([F:22])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(O)(CC2OC(C)(C)OC(=O)C=2)C#CC2C=CC(C(C)(C)C#N)=C(F)C=2)CCCC1>>[CH:1]1([C:6]2([CH2:7][CH2:8][C:9]3[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]([CH3:20])([CH3:21])[C:18]#[N:19])=[C:11]([F:22])[CH:10]=3)[CH2:23][C:24]([OH:25])=[CH:29][C:28](=[O:27])[O:30]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(C)(C)C#N)c(F)cc1C#CC(O)(CC1=CC(=O)OC(C)(C)O1)C1CCCC1
Agent: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C(C)(C)C#N)c(F)c2)C2CCCC2)O1
Product: COc1cc(C(C)(C)C#N)c(F)cc1CCC1(C2CCCC2)CC(O)=CC(=O)O1

Procedure:
The desired product was prepared analogously to Example A (97), step 4, substituting 2-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-5-methoxy-phenyl}-2-methyl-propionitrile (2.0 g, 4.39 mmol) from Step 6 below in place of 2-{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl}-2-methylpropanenitrile. Yield: 0.87 g, 49%. 1H NMR (CDCl3) δ: 1.39-1.48 (m, 2H), 1.59-1.68 (m, 5H), 1.79 (s, 6H), 1.83-1.95 (m, 3H), 2.30-2.37 (m, 1H), 2.54-2.69 (m, 4H), 3.83 (s, 3H), 5.30 (s, 1H), 6.86 (d, J=11.9 Hz, 1H), 6.95 (d, J=6.6 Hz, 1H). MS (ESI): 400 (M−1).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32]N)=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:28][CH:27]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)ccc1=O
Reactant: NNc1ccc(F)cc1
Product: CS(=O)(=O)c1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccc(F)cc3)n2)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-16) and 4-fluoro-phenylhydrazine according to the method described for example 43. MS: M=411.1 (M+H)+
Reaction SMILES: I[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27][C:28](=[O:58])[C:29](=[N:55][O:56][CH3:57])[C:30]3[N:31]=[C:32]([NH:35]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:33][CH:34]=3)[C:25](=[O:59])[N:7]2[C:8]=1[C:9]([O:11]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:10].[SH:60][C:61]1[S:62][C:63]([C:66]2[CH:71]=[CH:70][C:69]([O:72]COCCOC)=[C:68]([O:79]COCCOC)[CH:67]=2)=[N:64][N:65]=1.C(=O)([O-])O.[Na+:90].OC[C@@]1(OC[C@H](O)[C@@H](O)[C@@H]1O)O>O>[NH2:35][C:32]1[S:33][CH:34]=[C:30]([C:29](=[N:55][O:56][CH3:57])[C:28]([NH:27][C@@H:26]2[C:25](=[O:59])[N:7]3[C:8]([C:9]([O-:11])=[O:10])=[C:3]([CH2:2][S:60][C:61]4[S:62][C:63]([C:66]5[CH:71]=[CH:70][C:69]([OH:72])=[C:68]([OH:79])[CH:67]=5)=[N:64][N:65]=4)[CH2:4][S:5][C@H:6]23)=[O:58])[N:31]=1.[Na+:90]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: COCCOCOc1ccc(-c2nnc(S)s2)cc1OCOCCOC
Agent: O=C([O-])O
Agent: OC[C@]1(O)OC[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Na+]
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CSc3nnc(-c4ccc(O)c(O)c4)s3)CS[C@H]12)c1csc(N)n1

Procedure:
A trifluoroacetate obtained by the same operation as in EXAMPLE 1 by using 1.0 g (1.07 mmol) of benzhydryl 3-iodomethyl-7β-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl) acetamido]-3-cephem-4-carboxylate (syn-isomer) and 0.43 g (1.07 mmol) of 2-mercapto-5-[3,4-di(2-methoxyethoxymethoxy)phenyl]-1,3,4-thiadiazole, was suspended in water and adjusted to pH6.5 with a saturated sodium hydrogencarbonate aqueous solution. Then, the suspension was subjected to ODS column chromatography (LC Sorb RP-18, manufactured by Kemco Co.) and eluted with a 20% methanol aqueous solution. The fraction containing the desired compound was concentrated and freeze-dried to obtain 168 mg (yield: 24.3%) of the above identified compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2.[OH:28]O>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2)=[O:28]
Reactant: O=C1CCc2cc(OCCCCSc3ccc4ccccc4c3)ccc2N1
Reactant: OO
Product: O=C1CCc2cc(OCCCCS(=O)c3ccc4ccccc4c3)ccc2N1

Procedure:
Prepared analogous to Example 2 from 6-[4-(2-naphthyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:40]=[C:39]2[C:34]([CH:35]=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1.[OH-].[Na+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:30][C:31]1[CH:40]=[C:39]2[C:34]([CH:35]=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1
Reactant: Oc1ccc2cccnc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cccnc4c3)ncnc2cc1OCCCN1CCOCC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 38.8 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (225 mg, 0.67 mmol), (prepared as described for the starting material in Example 1), potassium carbonate (106 mg, 0.77 mmol) and 7-hydroxyquinoline (112 mg, 0.77 mmol) in DMF (7.5 ml) was stirred at 100° C. for 5 hours and allowed to cool to ambient temperature. The reaction mixture was treated with 1M aqueous sodium hydroxide solution (40 ml) and stirred at ambient temperature for a few minutes. The crude solid was collected by filtration washing with water. The resultant solid was dissolved in dichloromethane (2 ml) and filtered through phase separating paper. The filtrate was evaporated under vacuum to give a solid residue which was triturated with ether, filtered and dried to give 6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-7-yloxy)quinazoline (116 mg, 39%).
Reaction SMILES: BrC1C=[C:4]2[C:8](=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)[C:6](C(OCC)=O)=[C:5]2[S:25](Cl)(=O)=O.[Cl:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[C:33]2[S:53](Cl)(=[O:55])=[O:54].N1CCOCC1.N1CCSCC1>>[Cl:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[C:33]2[S:53]([N:7]1[CH2:6][CH2:5][S:25][CH2:4][CH2:8]1)(=[O:54])=[O:55]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: C1CSCCN1
Solvent: C1COCCN1
Product: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)N1CCSCC1

Procedure:
The titled compound was prepared using the procedures described in Steps B and C of Example 2, replacing in Step B ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and morpholine with thiomorpholine. Proton NMR for the product was consistent with the titled compound. ESI+MS: 389.1 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([N:20]1[CH2:23][CH:22]([OH:24])[CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCN(CC)CC.O>C(Cl)Cl.CS(C)=O>[CH:7]([N:20]1[CH2:23][C:22](=[O:24])[CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A three-neck flask was charged with oxalyl dichloride (10.6 mL, 119 mmol) and DCM (100.00 ml, 306 mmol), and the solution was cooled to −78° C. To the stirred solution was added, via dropping funnel, dimethylsulfoxide (16.9 mL, 238 mmol) in DCM (50 mL) over 30 min. The reaction was stirred at −78° C. for an additional 5 min, and then 1-benzhydrylazetidin-3-ol (25.90 g, 108 mmol) in DCM (50 mL) and DMSO (10 mL) was added dropwise over 5 min (T was maintained <−60° C.). The solution was stirred at −78° C. for an additional 20 min, and Et3N (75.3 mL, 541 mmol) was added slowly. The reaction was allowed to reach room temperature over 30 min and water (200 mL) was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4 and evaporated. Purification by flash chromatography using 2% Et3N/hexanes gave 1-benzhydrylazetidin-3-one. 1H NMR (300 MHz, CDCl3) δ ppm 7.41-7.52 (m, 4H), 7.26-7.35 (m, 4H), 7.16-7.26 (m, 2H), 4.59 (s, 1H), 3.90-4.07 (m, 4H).
Reaction SMILES: C1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)C=CC=CC=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1B(O)O>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:7]1[NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=1[C:14]=23
Reactant: OB(O)c1ccc(F)cc1F
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=C1NCCc2c(-c3ccc(F)cc3F)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (200 mg, 0.75 mmol) and 2,4-difluorophenylboronic acid (131 mg, 0.83 mmol) were coupled to yield 2-(2,4-difluoro-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 156 mg (69%), as a pale-yellow solid. mp 196-197° C.; 1H NMR (300 MHz, d6-DMSO) δ2.84 (m, 2H), 3.37 (m, 2H), 7.25 (app t, 1H, J=7.7 Hz), 7.27 (m, 1H), 7.47 (m, 1H), 7.57 (dd, 1H, J=8.1, 0.9 Hz), 7.64 (m, 1H), 7.70 (dd, 1H, J=7.5, 0.9 Hz) 8.08 (br t, 1H), 11.58 (br s, 1H); MS (FAB, MH+) 299; Anal. (C17H12N2OF2.0.3 H2O.0.37 CHCl3) C, H, N.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]3[CH:11]([CH:21]4[CH2:27][CH:26]5[NH:28][CH:23]([CH2:24][CH2:25]5)[CH2:22]4)[C:12]4[C:17]([O:18][C:19]=3[CH:20]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:2]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.[O:47]1[CH:51]=[CH:50][C:49]([CH:52]=O)=[CH:48]1>C(Cl)CCl.C(Cl)Cl>[O:47]1[CH:51]=[CH:50][C:49]([CH2:52][N:28]2[CH:23]3[CH2:24][CH2:25][CH:26]2[CH2:27][CH:21]([CH:11]2[C:10]4[CH:9]=[CH:8][C:7]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)=[CH:20][C:19]=4[O:18][C:17]4[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH2:22]3)=[CH:48]1
Reactant: O=Cc1ccoc1
Reactant: c1cncc(-c2ccc3c(c2)Oc2ccccc2C3C2CC3CCC(C2)N3)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: c1cncc(-c2ccc3c(c2)Oc2ccccc2C3C2CC3CCC(C2)N3Cc2ccoc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
To a solution of 3-(3-pyridin-3-yl-9H-xanthen-9-yl)-8-aza-bicyclo[3.2.1]octane, 3b (0.08 g, 0.134 mmol) in ClCH2CH2Cl (2 mL) was added tetramethyl-ammonium triacetoxyborohydride (0.053 g, 2.01 mmol) and 3-furaldehyde (0.17 mL, 2.0 mmol). The reaction was stirred at rt for 24 h. The reaction was diluted with CH2Cl2 (10 mL) and washed with 1 N NaOH. The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude product was purified via reverse phase chromatography (eluent: CH3CN in H2O containing 0.1% TFA) to yield 0.045 g (75%) of title compound 8-furan-3-ylmethyl-3-(3-pyridin-3-yl-9H-xanthen-9-yl)-8-aza-bicyclo[3.2.1]-octane, 4b as a TFA salt. MS m/z=449.1 (MH+).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]1[O:12][CH2:11]1.[CH3:13][CH:14]([CH3:40])[CH:15]([NH:27][C:28]([CH:30]1[CH2:34][CH:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][NH:31]1)=[O:29])[CH:16]1[CH:21]([OH:22])[CH:20]([OH:23])[CH:19]([OH:24])[CH:18]([S:25][CH3:26])[O:17]1>CO>[CH3:13][CH:14]([CH3:40])[CH:15]([NH:27][C:28]([CH:30]1[CH2:34][CH:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][N:31]1[CH2:10][CH2:11][OH:12])=[O:29])[CH:16]1[CH:21]([OH:22])[CH:20]([OH:23])[CH:19]([OH:24])[CH:18]([S:25][CH3:26])[O:17]1
Reactant: CCCCCC1CNC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)C1
Reactant: C1CO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCCCCC1CC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)N(CCO)C1
Temperature: -4 °C
Reaction time: 18 h
Yield: 30.2 %

Procedure:
DIEA (0.1 mL, 0.57 mmol) and liquid ethylene oxide (3 mL) were added to a stirred solution of crude 4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide, prepared as in Example 10 (237.4 mg), in anhydrous methanol (10 mL), at 0° C. and under nitrogen. The resulting solution was stirred at −4° C. for 18 h and evaporated to dryness. The residue obtained was purified by chromatography over silica gel with an eluent of 5% methanolic ammonia in dichloromethane. The desired fractions were evaporated and the residue lyophilized (deuterium oxide/anhydrous acetonitrile, 1:1, v/v, 10 mL) to furnish the title compound as a fluffy white powder (50.1 mg, 30.2%); TLC, Rf=0.68 (14% methanolic ammonia in dichloromethane); 1H NMR (300 MHz) δ 5.40 (d, J=5.8, 1), 4.55 (m, 1), 4.24 (s, 1), 4.17–4.11 (m, 1), 3.99–3.89 (m, 4), 3.69–3.65 (m, 1), 3.47 (d, J=4.4, 2), 3.01 (m, 1), 2.33 (br s, 4), 2.18 (s, 4), 1.57–1.32 (m, 9), 0.94–0.87 (m, 9).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH2:38][CH:39]([CH3:41])[CH3:40])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH2:38]([NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35])[CH:39]([CH3:41])[CH3:40]
Reactant: CC(C)CNS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)CNS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-isobutyl-benzenesulfonamide [CAS 608523-95-1] according to general procedure II. Yellow solid. MS (ISP) 584.1 [(M−H)−]; mp 205° C.
Reaction SMILES: Cl[C:2]([C:4]1[C:5]([Cl:15])=[C:6]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:7]([O:9][CH3:10])=[O:8])=[O:3].Cl.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][O:23][NH2:24])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][O:23][NH:24][C:2]([C:4]2[C:5]([Cl:15])=[C:6]([CH:11]=[CH:12][C:13]=2[Cl:14])[C:7]([O:9][CH3:10])=[O:8])=[O:3])=[CH:20][CH:19]=1
Reactant: NOCc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(Cl)c(C(=O)Cl)c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)c(C(=O)NOCc2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 122.2 %

Procedure:
At about 30° C., 10.70 g (0.04 mol) of methyl 3-chlorocarbonyl-2,4-dichlorobenzoate in 50 ml of methylene chloride were slowly added dropwise to a solution of 7.76 g (0.04 mol) of O-(4-chlorobenzyl)hydroxylamine hydrochloride and 4.05 g (0.04 mol) of triethylamine in 200 ml of methylene chloride. After stirring for 12 hours at room temperature, the reaction mixture was washed with dilute phosphoric acid, dried and concentrated. Trituration of the residue with diethyl ether gave 19.00 g of methyl 3-(4-chlorobenzyloxyaminocarbonyl)-2,4-dichlorobenzoate.