Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=O)[CH2:10][CH2:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14].[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.B(F)(F)F.CCOCC>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1/[C:9](=[N:24]/[NH:23][C:20](=[NH:21])[NH2:22])/[CH2:10][CH2:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14]
Reactant: O=C(CCC(F)(F)C(F)(F)F)c1cc(Cl)ccc1Br
Reactant: N=C(N)NN
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: CO
Product: N=C(N)N/N=C(\CCC(F)(F)C(F)(F)F)c1cc(Cl)ccc1Br
Temperature: 100 °C

Procedure:
To a screw cap pressure vessel was added the intermediate from Step B (0.450 g, 1.2 mmol), aminoguanidine hydrochloride (0.456 g, 6.2 mmol), methanol (20 mL) and boron trifluoride diethyl etherate (0.94 mL, 7.4 mmol). The reaction solution was heated at 100° C. for 3 hours. The solution was concentrated and the residue partitioned between EtOAc and aqueous 1N NaOH. The organic phase was washed twice with aqueous 1N NaOH and brine (1×). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to give the indicated compound as a mixture of E,Z hyrazone isomers. 1H NMR (500 MHz, CH3OH-d4): δ 7.60 (d, J=8.6 Hz, 1H); 7.26-7.23 (m, 1H); 7.18 (d, J=2.5 Hz, 1H); 2.74 (s, 2H); 2.56 (s, 2H). m/z=421.2 (M+H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C@H:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:5][O:4][C:2]([NH:6][C@H:7]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:3]
Reactant: CC(C)(C)OC(=O)[C@H](N)c1ccccc1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Reaction time: 5.5 h
Yield: 71.6 %

Procedure:
ClCO2Me (3.2 mL, 41.4 mmol) was added dropwise to a cooled (ice/water) THF (410 mL) semi-solution of (R)-tert-butyl 2-amino-2-phenylacetate/HCl (9.877 g, 40.52 mmol) and diisopropylethylamine (14.2 mL, 81.52 mmol) over 6 min, and stirred at similar temperature for 5.5 hours. The volatile component was removed in vacuo, and the residue was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was washed with 1N HCl (25 mL) and saturated NaHCO3 solution (30 mL), dried (MgSO4), filtered, and concentrated in vacuo. The resultant colorless oil was triturated from hexanes, filtered and washed with hexanes (100 mL) to provide (R)-tert-butyl 2-(methoxycarbonylamino)-2-phenylacetate as a white solid (7.7 g). 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): 7.98 (d, J=8.0, 1H), 7.37-7.29 (m, 5H), 5.09 (d, J=8, 1H), 3.56 (s, 3H), 1.33 (s, 9H). LC (Cond. 1): RT=1.53 min; ˜90% homogeneity index; LC/MS: Anal. Calcd. for [M+Na]+ C14H19NNaO4: 288.12; found 288.15.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:16]([N:29]1[CH2:32][CH:31]([CH2:33]O)[CH2:30]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[C:17]1([CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:29]2[CH2:32][CH:31]([CH2:33][O:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)=[CH:4][CH:3]=3)[CH2:30]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N#CC1(c2ccc(O)cc2)CCOCC1
Reactant: OCC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: N#CC1(c2ccc(OCC3CN(C(c4ccccc4)c4ccccc4)C3)cc2)CCOCC1
Yield: 41 %

Procedure:
4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (6.18 g, 30.4 mmol), (1-benzhydryl-azetidin-3-yl)-methanol (7 g, 28 mmol), PPh3 (8 g, 30.4 mmol), and DIAD (69 mL, 30.4 mmol), were reacted together similarly to general procedure C. The crude material was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate:diethylamine (50:45:5 to 0:95:5) to provide the title compound (5.03 g, 41%) as a yellow solid. LRMS APCI+ m/z 439 [MH]+.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][NH:18][C:19]([N:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[O:20])[CH:14]=3)[C:9]2=[O:34])[CH2:6][CH2:5][C:4](=[O:35])[NH:3]1.Cl>C(Cl)Cl.C(OCC)C>[O:1]=[C:2]1[CH:7]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][NH:18][C:19]([N:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]4)=[O:20])[CH:14]=3)[C:9]2=[O:34])[CH2:6][CH2:5][C:4](=[O:35])[NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1CCC(N2Cc3cc(CNC(=O)N4CCNCC4)ccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methylcarbamoyl)piperazine-1-carboxylate (0.49 g, 1.0 mmol) in methylene chloride (100 mL) is treated with HCl (5 mL of a 2N solution in diethyl ether), and stirred at ambient temperature for 48 hours. The mixture is evaporated under vacuum, and triturated in ethyl acetate (10 mL), filtered, and dried under vacuum.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]2[C:12]([I:13])=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.[CH2:14](Br)[CH:15]=[CH2:16].O>CN(C)C=O>[Cl:3][C:4]1[C:5]2[C:12]([I:13])=[CH:11][N:10]([CH2:16][CH:15]=[CH2:14])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: C=CCBr
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1cc(I)c2c(Cl)ncnc21
Temperature: 25 °C

Procedure:
Sodium hydride (0.28 g of 60% dispersion in mineral oil) was added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.96 g) in dry N,N-dimethylformamide (40 ml) with stirring under nitrogen at ambient temperature. The mixture was then stirred for 30 minutes and allyl bromide (0.62 ml) was added dropwise. After stirring for 1 hour at ambient temperature more allyl bromide (0.20 ml) was added and the mixture was left stirring at ambient temperature for 18 hours. The mixture was added to water with stirring and the solid which precipitated was collected by filtration and dried to give 4-chloro-5-iodo-7-(prop-1-en-3-yl)-7H-pyrrolo[2,3-d]-pyrimidine which was used directly in b).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]2[C:4](=[CH:5][C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.C(N(CC)CC)C.O1CCCC1.[P:32](=[O:47])(Cl)([S:43][CH2:44][CH3:45])[O:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[P:32](=[O:47])([S:43][CH2:44][CH3:45])([O:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[C:13]2[C:4](=[CH:5][C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1)[O:33][C:34]1[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=1
Reactant: Oc1cc(C(F)(F)F)c2nc3ccccc3cc2c1
Reactant: CCSP(=O)(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCSP(=O)(Oc1ccc([N+](=O)[O-])cc1)Oc1cc(C(F)(F)F)c2nc3ccccc3cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Hydroxy-4-trifluoromethylacridine (0.01 mole), triethylamine (0.01 mole), tetrahydrofuran (25 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0° C. and O-(4-nitrophenyl) S-ethyl phosphorochloridothioate (0.01 mole) dissolved in toluene (25 ml) is added with stirring over a period of about 30 minutes. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 16 hours. After this time the reaction mixture is filtered to remove triethylamine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvents leaving a residue. This residue is subjected to flash chromatography using ethyl acetate as the eluant to yield the desired product O-(4-nitrophenyl) O-(4-trifluoromethylacridin-2-yl) S-ethyl phosphorothioate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]=[N+:19]=[N-:20])[CH2:8][C:9]#[CH:10])([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:7]1[CH2:8][C:9]2[N:18]([N:19]=[N:20][CH:10]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11]1)=[O:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CCN(Cc1ccccc1N=[N+]=[N-])C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1Cc2ccccc2-n2nncc2C1
Temperature: 100 °C
Yield: 94.5 %

Procedure:
Toluene (3 mL) was added to (2-azido-benzyl)-prop-2-ynyl-carbamic acid tert-butyl ester (100 mg, 0.34 mmol) and the resulting mixture was heated at 100° C. overnight. When the reaction was complete as confirmed by TLC, solvent was removed in vacuo to afford 4H,6H-1,2,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester (92 mg, 92%) which was used as such without any further purification for the next step. ESIMS (m/z): 309.4 (M+Na), 287.1 (M+1).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[NH:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1.Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[O:23]=[C:20]1[CH2:21][CH2:22][N:17]([C:2]2[N:11]=[C:10]([NH2:12])[C:9]3[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=3)[N:3]=2)[CH2:18][CH2:19]1
Reactant: O=C1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: COc1cc2nc(N3CCC(=O)CC3)nc(N)c2cc1OC

Procedure:
A mixture of 1.0 g of 2-Chloro-4-amino-6,7-dimethoxyquinazoline, 1.28 g of 4-piperidone.HCl and 1.15 g of potassium carbonate in 50 ml of n-butanol was refluxed for 8 hours. and the solvent was removed under reduced pressure. To the residue was added 50 ml. of water and extracted with Ethyl acetate. Ethyl acetate extract was concentrated and the residue was washed with n-hexane. 0.98 g. of desired compound was obtained. mp. 228°~230° C. I.R. (KBr) 3350, 3200, 2900, 1700, 1645, 1595, 1570, 1500, 1465, 1260 cm-1 .
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:32])([F:33])[F:19])=[CH:26][CH:25]=3)=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)s2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)n2)s1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 02: tR=1.04 min; [M+H]+=420.19.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([NH:20][CH3:21])=[O:19])[N:9]=1.[H-].[Na+].[F:24][CH2:25][CH2:26]Br>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([N:20]([CH3:21])[CH2:26][CH2:25][F:24])=[O:19])[N:9]=1
Reactant: CNC(=O)c1cc2ccccc2c(-c2ccccc2I)n1
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCF)C(=O)c1cc2ccccc2c(-c2ccccc2I)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 40.9 %

Procedure:
To a solution of 1-(2-iodophenyl)-N-methyl-3-isoquinolinecarboxamide (0.1042 g, 0.27 mmol) in DMF (6 mL) was added 60% NaH (43 mg, 1.08 mmol) in one portion. The mixture was stirred under Ar at room temperature for 30 min before 2-fluoroethylbromide (161 μl, 2.16 mmol) was added in one portion. The mixture was stirred at room temperature under Ar for 20 h, then quenched by adding H2O (5 mL). The mixture was extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried (MgSO4), and filtered. The filtrate was concentrated in vacuo. The residue was purified on flash column chromatography (SiO2 , 30% ethyl acetate/hexane, 0.035% Et3N). A white solid (48 mg, 41%) was obtained. mp 141.9-143.2° C. 1H NMR (CDCl3) d 3.22, 3.27 (two s, 3 H, N-methyl), 3.67-4.15 (m, 2 H, N--CH2), 4.42-4.92 (m, 2 H, CH2F), 7.15-7.25 (m, 1 H, aromatic), 7.27-7.37 (m, 1 H, aromatic), 7.45-7.64 (m, 3 H, aromatic), 7.67-7.77 (m, 1 H, aromatic), 7.97 (t, J=7.5 Hz, 2 H, aromatic), 8.11, 8.21 (two s, total 1 H, aromatic). Anal. Calcd for Cl19H16FIN2O: C, 52.55; H, 3.71; N, 6.45. Found: C, 52.64; H, 3.78; N, 6.38.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17]([N:32]2[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]2)(=[O:19])=[O:18])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: OC1CCNCC1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCC(O)CC3)sc2Br)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (3000 mg; 7.22 mmol; 1 eq), is dissolved in anhydrous DCM (400 ml). The reaction is put under nitrogen. Triethylamine (5.0 ml; 36.1 mmol; 5 eq) and 4-hydroxypiperidine (3649.4 mg; 36.1 mmol; 5 eq) are added successively and the reaction mixture is stirred for 6 hours at room temperature. It is washed with water, NaHCO3 sat., brine, and dried over MgSO4, affording the title compound (3500 mg; 88%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([C:23]2[O:24][C:25]([CH2:28][N:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=2)[NH2:22])=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32](Cl)(=[O:36])[CH:33]([CH3:35])[CH3:34].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([NH:22][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[C:23]2[O:24][C:25]([CH2:28][N:29]([CH3:30])[CH3:31])=[CH:26][CH:27]=2)=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Cl
Reactant: CN(C)Cc1ccc(C(N)Cc2cc(Cl)c3cccnc3c2OCc2ccccc2)o1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NC(Cc1cc(Cl)c2cccnc2c1OCc1ccccc1)c1ccc(CN(C)C)o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 48.5 %

Procedure:
To a round bottom flask containing 2-[8-(benzyloxy)-5-chloroquinolin-7-yl]-1-{5-[(dimethylamino)methyl]-2-furyl}ethanamine (0.710 mmol) at 0° C. was added a solution of isobutyryl chloride (0.852 mmol, 1.2 eq.) and triethylamine (0.852 mmol, 1.2 eq.) in tetrahydrofuran (5 mL) that was pre-mixed and stirred 5 min prior to addition. After warming to room temperature, the resulting solution was stirred 2 h and quenched with saturated aqueous sodium bicarbonate solution (1 mL) and stirred 5 min. The reaction was diluted with 0.1N NaOH (15 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to a yellow syrup that was purified by column chromatography to afford the final product as a white solid (0.344 mmol, 47% for 2 steps). HRMS: calcd for C29H32ClN3O3+H+, 506.22049; found (ESI, [M+H]+ Obs'd), 506.2208.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[C:5]([OH:7])=O.CN(C)C=O.C(Cl)(=O)C(Cl)=O.Cl.[NH2:20][C:21]1[N:22]=[C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:46])=[C:34]([NH:36][C:37]([C:39]4[N:43]([CH3:44])[N:42]=[C:41]([CH3:45])[CH:40]=4)=[O:38])[CH:35]=3)=[N:25][N:24]2[CH:47]=1>CN(C)C(=O)C.O1CCCC1>[F:46][C:33]1[CH:32]=[CH:31][C:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]3[N:24]([CH:47]=[C:21]([NH:20][C:5]([CH:3]4[CH2:4][CH:2]4[CH3:1])=[O:7])[N:22]=3)[N:25]=2)=[CH:35][C:34]=1[NH:36][C:37]([C:39]1[N:43]([CH3:44])[N:42]=[C:41]([CH3:45])[CH:40]=1)=[O:38]
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2F)n(C)n1
Reactant: CC1CC1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5C)cn4n3)ccc2F)n(C)n1
Yield: 24.7 %

Procedure:
Using 2-methylcyclopropanecarboxylic acid (72 mg, 0.72 mmol), tetrahydrofuran (2.0 mL), N,N-dimethylformamide (20 μL, 0.26 mmol), oxalyl chloride (63 μL, 0.72 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide.hydrochloride (200 mg, 0.48 mmol) and N,N-dimethylacetamide (4.0 mL), and in the same manner as in Example 239, the title compound (55 mg, 25%) was obtained as a white powder.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:37])C.[OH-].[Na+].Cl>C(O)C>[CH:31]1([CH2:30][O:29][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:38])=[O:3])=[C:8]([CH3:37])[CH:9]=3)[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:17]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCC3CCCCC3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#CCN3CCOCC3)cc(OCC3CCCCC3)c2)ccc1OCC(=O)O
Reaction time: 1 h

Procedure:
{4-[3-Cyclohexylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (200 mg; 0.37 mmol) was dissolved in ethanol (20 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 180 mg. HPLC-MS: m/z: 510.1 (M+); Rt: 1.98 min.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[N:17][CH:18]=1>C(Cl)Cl>[CH3:12][C:13]1[CH:18]=[N+:17]([O-:9])[C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(C(=O)O)nc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)O)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
m-CPBA (CAN 937-14-4, 5.0 g, 29.2 mmol) was added to a solution of 5-methyl-pyridine-2-carboxylic acid (CAN 4434-13-3, 2.0 g, 14.6 mmol) in methylene chloride (50 mL) and the mixture was stirred overnight at room temperature. The solid was filtered off, quenched with a saturated solution of sodium thiosulfate (50 mL), and the mixture was extracted with methylene chloride (3×60 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give yellow solid which was washed with ether (5×20 mL) to give the product (0.9 g, 40.3%); MS (EI): m/e=154.1 [M+H]+.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9]=2[C:8]([OH:14])=[CH:7][CH:6]=1.Br[CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18].O>CO.C1C=CC=CC=1.[I-].[K+]>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:16]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)=[CH:23][CH:22]=2)[C:17]([O:19][CH3:20])=[O:18])=[C:9]2[C:13]=1[CH2:12][CH2:11][CH2:10]2
Reactant: Oc1ccc(Cl)c2c1CCC2
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C(Oc1ccc(Cl)c2c1CCC2)c1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 80.6 %

Procedure:
To a solution of 1.19 g of sodium methoxide, 4.22 g of 7-chloro-4-indanol, and 100 mg of potassium iodide in 40 ml of methanol was added 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of benzene. The mixture was heated at reflux overnight, cooled, and then poured into 100 ml of water. The mixture was extracted with 2×75 ml of ether. The combined extracts were washed with 2×50 ml of 5% NaOH, 2×50 ml water, 50 ml saturated brine, and dried (MgSO4). Evaporation of the solvent yielded a yellow oil which solidified on trituration with petroleum ether to yield 7.14 g of product as a cream colored solid, mp 94°-96° C. The solid was taken up in 75 ml of hot hexane, decanted away from a small amount of oil, and the supernatant liquid cooled to yield 5 g of a cream colored crystal, mp 97°-98.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([S:13][C:14]#[N:15])=[CH:11][CH:10]=[C:9]2[C:16]([OH:18])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:19][C:20]1[C:28]([Br:29])=[CH:27][C:26]([Br:30])=[CH:25][C:21]=1[C:22](O)=[O:23].BrC1C=C(C(O)=O)N(C2C(Cl)=CC=CN=2)C=1.NC1C(C)=CC(Cl)=CC=1C(O)=O>>[Br:30][C:26]1[CH:27]=[C:28]([Br:29])[C:20]2[N:19]=[C:16]([C:9]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[C:12]([S:13][C:14]#[N:15])=[CH:11][CH:10]=3)[O:18][C:22](=[O:23])[C:21]=2[CH:25]=1
Reactant: Nc1c(Br)cc(Br)cc1C(=O)O
Reactant: N#CSc1ccc(C(=O)O)n1-c1ncccc1Cl
Agent: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: O=C(O)c1cc(Br)cn1-c1ncccc1Cl
Product: N#CSc1ccc(-c2nc3c(Br)cc(Br)cc3c(=O)o2)n1-c1ncccc1Cl

Procedure:
According to the same manner as that of Reference Preparation Example 71-(5), 1-(3-chloro-2-pyridinyl)-5-thiocyanato-1H-pyrrole-2-carboxylic acid and 2-amino-3,5-dibromobenzoic acid were used in place of 4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-5-chloro-3-methylbenzoic acid respectively to obtain 6,8-dibromo-2-[1-(3-chloro-2-pyridinyl)-5-thiocyanato-1H-pyrrol-2-yl]-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@@H:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=[C:11]2[NH:10][C:9]1=[O:20].O1CCOCC1.C(=O)([O-])O.[Na+].[CH3:32][N:33]([CH3:38])[S:34](Cl)(=[O:36])=[O:35]>C(Cl)(Cl)Cl>[CH3:32][N:33]([CH3:38])[S:34]([N:5]1[CH2:6][CH2:7][C@@H:2]([CH3:1])[C@@H:3]([N:8]2[C:12]3=[C:13]4[CH:19]=[CH:18][NH:17][C:14]4=[N:15][CH:16]=[C:11]3[NH:10][C:9]2=[O:20])[CH2:4]1)(=[O:36])=[O:35]
Reactant: C[C@@H]1CCNC[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Reactant: CN(C)S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: C[C@@H]1CCN(S(=O)(=O)N(C)C)C[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Reaction time: 2 h
Yield: 36.7 %

Procedure:
To a solution of rel-1-[(3R,4R)-4-methylpiperidin-3-yl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (80 mg), dioxane (1.6 mL) and 4M saturated aqueous sodium hydrogencarbonate (2.4 mL) was added dimethylsulfamoyl chloride (51 mg) at ambient temperature. The mixture was stirred for 2 hours then chloroform (8 mL) was added. The organic layer was separated and dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography to give rel-(3R,4R)—N,N,4-trimethyl-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)piperidine-1-sulfonamide (41 mg) as a colorless solid.