Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH:10]2[C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[C:6]([CH3:18])[C:5]=1[CH3:19].Br.[OH-].[NH4+]>O>[NH:16]1[CH:17]=[C:13]([CH:10]2[C:11]3[C:7](=[C:6]([CH3:18])[C:5]([CH3:19])=[C:4]([OH:3])[CH:12]=3)[CH2:8][CH2:9]2)[N:14]=[CH:15]1
Reactant: COc1cc2c(c(C)c1C)CCC2c1c[nH]cn1
Agent: Br
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: Cc1c(O)cc2c(c1C)CCC2c1c[nH]cn1

Procedure:
A stirred mixture of 4-(6-methoxy-4,5-dimethylindan-1-yl)-1H-imidazole hydrochloride (0.29 g) and hydrobromic acid (15 ml) is heated under reflux for 40 minutes. The cooled reaction mixture is poured into water and is made basic with ammonium hydroxide solution. The product is extracted into ethyl acetate which is washed with water, dried with sodium sulfate and evaporated to dryness. The crude product is purified by flash chromatography and crystallized from ethyl acetate. M.p. 198-202° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:7][CH2:6][N:5]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[C:4]2=[N:3]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:27][CH:28]([CH3:30])[CH3:29].CCOC(C)=O>CS(C)=O.C1COCC1>[CH3:27][CH:28]([CH3:30])[CH2:29][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:4]3=[N:3][S:2](=[O:1])(=[O:19])[CH2:7][CH2:6][N:5]3[CH:8]=[CH:9][CH:10]=2)=[CH:13][CH:14]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)COc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a mixture of 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (200 mg), potassium carbonate (260 mg) in DMSO (4 mL) was added 1-iodo-2-methylpropane (173 mg). The mixture was stirred at 130° C. for 1 hr. Another 1-iodo-2-methylpropane (0.10 mL) was added and the mixture was stirred at room temperature overnight. 0.5N NaOHaq, EtOAc and THF were added and the extracted organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was crystallized from THF-MeOH/IPE to give the title compound (104 mg) as colorless crystals.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:26][CH:25]=1>>[CH3:23][C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:18]([C:12]3[S:13][C:14]4[CH2:15][CH2:16][O:17][C:8]5[CH:7]=[C:6]([C:4]6[CH:3]=[N:2][NH:1][CH:5]=6)[CH:22]=[CH:21][C:9]=5[C:10]=4[N:11]=3)=[O:20])[CH2:32][CH2:31]2)[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cccc(N2CCNCC2)n1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: Cc1cccc(N2CCN(C(=O)c3nc4c(s3)CCOc3cc(-c5cn[nH]c5)ccc3-4)CC2)n1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 1-(6-methylpyridin-2-yl)piperazine (1.2 equiv) to give 198 (M+1 473.0)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:15][CH3:16])[CH2:5][CH2:6][O:7][C:8]1[C:9]([F:14])=[N:10][CH:11]=[CH:12][CH:13]=1.[I:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([C:28](OCC)=[O:29])[CH:22]=[CH:21]2.C(N(CCNC(C1C=NC2C(=CC=C(I)C=2)N=1)=O)CCOC1C(F)=NC=CC=1)C>>[CH2:15]([N:4]([CH2:3][CH2:2][NH:1][C:28]([C:23]1[CH:22]=[CH:21][C:20]2[C:25](=[CH:26][CH:27]=[C:18]([I:17])[CH:19]=2)[N:24]=1)=[O:29])[CH2:5][CH2:6][O:7][C:8]1[C:9]([F:14])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:16]
Reactant: CCN(CCN)CCOc1cccnc1F
Reactant: CCOC(=O)c1ccc2cc(I)ccc2n1
Agent: CCN(CCNC(=O)c1cnc2cc(I)ccc2n1)CCOc1cccnc1F
Product: CCN(CCNC(=O)c1ccc2cc(I)ccc2n1)CCOc1cccnc1F
Yield: 95.2 %

Procedure:
This compound was prepared, starting from compound 5 (200 mg, 0.88 mmol) and ethyl 6-iodoquinoline-2-carboxylate (66) (203 mg, 0.62 mmol), according to the procedure developed for compound 10. Reaction time under reflux: 12 h; the purification was performed using column chromatography (Al2O3, CH2Cl2/EtOH, 98/2, v/v) to give compound 67 (302 mg, 0.59 mmol) as a brown oil. Yield 96%; Rf (Al2O3, CH2Cl2/EtOH, 98/2, v/v) 0.68; IR (CCl4) ν 1190, 1466, 1522, 1683, 2960 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.13 (t, 3H, J=7.1 Hz), 2.76 (q, 2H, J=7.1 Hz), 2.87 (t, 2H, J=6.0 Hz), 3.02 (t, 2H, J=5.8 Hz), 3.62 (q, 2H, J=6.0 Hz), 4.14 (t, 2H, J=5.8 Hz), 6.95 (ddd, 1H, 5JH-F=0.7 Hz, J=4.8, 7.8 Hz), 7.21 (ddd, 1H, 4JH-F=10.0 Hz, J=1.5, 7.8 Hz), 7.65 (m, 1H), 7.66 (d, 1H, J=8.9 Hz), 7.94 (dd, 1H, J=1.9, 8.9 Hz), 8.16 (d, 1H, J=8.6 Hz), 8.26 (s, 1H), 8.29 (d, 1H, J=8.6 Hz), 8.57 (m, 1H): ESI-MS m/z 508.9 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(O)(=O)C>[C:11]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)(=[O:13])[CH3:12]
Reactant: Nc1ccc2c(c1)CCC2
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2c(c1)CCC2
Temperature: 50 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
33.3 g (0.25 mol) of 5-aminoindane (a product of Tokyo Chemical Industry Co. Ltd.) was dissolved in 250 ml of glacial acetic acid, the resulting solution was heated to 50° C., and 51.0 g (0.5 mol) of acetic anhydride was added dropwise thereto. After completion of the dropwise addition, the resulting solution was stirred for 4 hours. After completion of the reaction, the reaction liquid was poured in 1,500 ml of ice water while stirring. Crystals precipitated were filtered off, and washed with 1,000 ml of water. The crystals obtained were dried to obtain 37.06 g of 5-(N-acetylamino)indane (yield: 84.6%, melting point: 100.5 to 103.5° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]#[CH:16])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[C:22](I)[C:21]([OH:25])=[CH:20][N:19]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[O:25][C:21]3=[CH:20][N:19]=[C:18]([Cl:17])[CH:23]=[C:22]3[CH:16]=2)([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1cnc(Cl)cc1I
Reactant: C#CC1(C)CCN(C(=O)OC(C)(C)C)CC1
Product: CC(C)(C)OC(=O)N1CCC(C)(c2cc3cc(Cl)ncc3o2)CC1

Procedure:
The title compound is prepared from 4-ethynyl-4-methyl-piperidine-1-carboxylic acid tert-butyl ester and 2-chloro-5-hydroxy-4-iodo-pyridine following a procedure analogous to that described for Intermediate 5. LC (method 4): tR=1.76 min; Mass spectrum (ESI+): m/z=351/353 (Cl) [M+H]+.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].P(Cl)(Cl)(Cl)=O.[CH3:20][NH2:21]>CN(C)C=O.O>[CH3:20][NH:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Reactant: CN
Solvent: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
To a solution of 5.7 g (0.30 mole) of 4-hydroxy-3-nitroquinoline in 50 ml of N,N-dimethylformamide was added 9.3 g (0.60 mole) of phosphorus oxychloride. The solution was heated on a steam bath for 5 minutes, then poured with stirring into 200 ml of 40% aqueous methylamine. The mixture was heated on a steam bath for fifteen minutes, then diluted with 200 ml of water. The solid was separated by filtration, then dissolved in dilute hydrochloric acid. The solution was filtered and the filtrate was basified with ammonium hydroxide. The solid precipitate was separated by filtration, washed with water and dried to provide Yellow solid 4-methylamino-3-nitroquinoline, m.p. 167°-171° C.
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:18]=[CH:17][C:10]([CH2:11][NH:12][C:13](=[O:16])[CH2:14][CH3:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Br[C:22]1([CH2:31][CH2:32][O:33][CH2:34][CH3:35])[C:27](=[O:28])[NH:26][C:25](=[O:29])[NH:24][C:23]1=[O:30].CCCCC=CCCCC.C1(F)(C2(F)OC(C(F)(F)F)(C(F)(F)F)OC2(F)F)OC(C(F)(F)F)(C(F)(F)F)OC1(F)F.C(N)(=O)CC>C(#N)C>[CH2:34]([O:33][CH2:32][CH2:31][C:22]1([O:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][C:7]3[CH:18]=[CH:17][C:10]([CH2:11][NH:12][C:13](=[O:16])[CH2:14][CH3:15])=[CH:9][CH:8]=3)=[CH:19][CH:20]=2)[C:23](=[O:30])[NH:24][C:25](=[O:29])[NH:26][C:27]1=[O:28])[CH3:35]
Reactant: CCOCCC1(Br)C(=O)NC(=O)NC1=O
Reactant: CCC(=O)NCc1ccc(Oc2ccc(O)cc2)cc1
Agent: CCC(N)=O
Agent: CCCCC=CCCCC
Agent: FC(F)(F)C1(C(F)(F)F)OC(F)(F)C(F)(C2(F)OC(C(F)(F)F)(C(F)(F)F)OC2(F)F)O1
Solvent: CC#N
Product: CCOCCC1(Oc2ccc(Oc3ccc(CNC(=O)CC)cc3)cc2)C(=O)NC(=O)NC1=O

Procedure:
Following the procedure outlined for the preparation of Example 1, N-[4-(4-hydroxy-phenoxy)-benzyl]-propionamide (0.13 g, 0.47 mmol) was reacted with 5-bromo-5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-trione (0.13 g, 0.48 mmol), 1,5,7-trazabicyclo[4.4.0]dec-5-ene bound to polystyrene crosslinked with 2% DVB (PTBD, Fluka, 0.31 g) and 1.55 mL of acetonitrile, benzyl)-propionamide (0.060 g) as a colorless solid.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.P(=O)([O-])[O-].[Si:21]([O:28][CH2:29][C@@H:30]1[C@H:34]([CH2:35][CH3:36])[CH2:33][C:32](=O)[CH2:31]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Si:21]([O:28][CH2:29][C@@H:30]1[C@H:34]([CH2:35][CH3:36])[CH2:33][C:32](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:31]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23]
Reactant: CC[C@@H]1CC(=O)C[C@@H]1CO[Si](C)(C)C(C)(C)C
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: O=[PH]([O-])[O-]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C=C1C[C@@H](CC)[C@@H](CO[Si](C)(C)C(C)(C)C)C1
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a slurry of NaH (60% dispersion in mineral oil, 0.608 g, 15.2 mmol) in THF (50 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (3.25 mL, 16.2 mmol). After about 30 min, the phosphonate solution was added to a flask charged with (3S,4R)-3-((tert-butyldimethylsilyloxy)methyl)-4-ethylcyclopentanone (2.6 g, 10.14 mmol). After about 20 h, EtOAc (20 mL) and saturated aqueous NH4Cl (20 mL) were added. The organic layer was removed concd in vacuo and purified by chromatography on silica gel eluting with EtOAc/heptane (20-60%) to provide ethyl 2-((3S,4R)-3-((tert-butyldimethylsilyloxy)methyl)-4-ethylcyclopentylidene)acetate (3.3 g, 100%) as an oil. LC/MS (Table 1, Method a) Rt=3.91, 3.96 min; MS m/z: 327 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH3:23][O:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([NH:38][C:39](=O)[O:40]C2C=CC=CC=2)[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:39]([NH:38][C:30]2[CH:31]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:33]=[C:28]([O:27][CH2:26][CH2:25][O:24][CH3:23])[CH:29]=2)=[O:40])[CH:20]=[CH:21][CH:22]=1
Reactant: COCCOc1cc(NC(=O)Oc2ccccc2)cc(C(F)(F)F)c1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: ClCCl
Solvent: CO
Product: COCCOc1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OC)c(OC)cc34)c2)cc(C(F)(F)F)c1
Yield: 90 %

Procedure:
The title compound was prepared from 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 g, 0.3 mmol) and phenyl 3-(2-methoxyethoxy)-5-(trifluoromethyl)phenylcarbamate from Example 117A (160 mg, 0.45 mmol) in the manner described in Example 115C. The final product was purified by column chromatography (25-100% EtOAc/hexanes then 5-10% MeOH/DCM) to give 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)urea (150 mg, 0.27 mmol, 90%). 1H NMR (300 MHz, DMSO-d6) δ 9.09 (s, 1H), 9.03 (s, 1H), 8.57 (s, 1H), 7.61-7.57 (m, 2H), 7.49 (s, 1H), 7.43-7.38 (m, 2H), 7.31-7.24 (m, 2H), 6.95 (d, 1H), 6.86 (s, 1H), 4.19-4.11 (m, 2H), 4.00 (s, 3H), 3.99 (s, 3H), 3.70-3.63 (m, 2H), 3.31 (s, 3H); LC-MS (ESI) m/z 559 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([S:22]C3C=CC([N+]([O-])=O)=CC=3[N+]([O-])=O)=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.O1CCCC1.[OH-].[K+].[F:42][C:43]([F:47])=[C:44]([F:46])[F:45]>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([S:22][C:44]([F:46])([F:45])[CH:43]([F:47])[F:42])=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(Sc3ccc([N+](=O)[O-])cc3[N+](=O)[O-])sc2-c2ccc(OC)cc2)cc1
Reactant: FC(F)=C(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2cc(SC(F)(F)C(F)F)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
2,3-bis(4-Methoxyphenyl)-5-(2,4-dinitrophenylthio)thiophene (4.9 g, 10 mmoles), tetrahydrofuran (60 ml), methanol/water (7.5 ml, 2.5 ml) and potassium hydroxide (1.3 g, 20 mmoles) were charged into a stainless steel bomb. The bomb was briefly evacuated, charged with tetrafluoroethylene (5 g, 50 mmoles) and agitated for 12 hours at room temperature. The reaction mixture was filtered and the filtrate concentrated to near dryness. The residue was taken up in ethyl acetate and filtered. The filtrate was washed three times with 1 N NaOH, three times with 1 N HCl, once with brine, dried and concentrated in vacuo. Crystallization from ethanol/water gave the title compound (2.4 g), m.p. 84°-7° (D). Infrared and H-NMR spectra were consistent with the assigned structure. MS 428 (M+)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: CC(C)(C)OC(=O)NCCCCCN(Cc1ccccn1)Cc1ccccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCCCN(Cc1ccccn1)Cc1ccccn1

Procedure:
A solution of tert-butyl 5-(bis(pyridin-2-ylmethyl)amino)pentylcarbamate (0.63 g, 1.64 mmol) in DCM (10 mL) and TFA (1.0 mL) was stirred at room temperature for 3 h. Upon completion the solvent was evaporated and the reaction mixture was diluted with DCM, washed with saturated aqueous potassium carbonate and concentrated under vacuum to afford N,N-bis(pyridin-2-ylmethyl)pentane-1,5-diamine. A solution of the above product N,N-bis(pyridin-2-ylmethyl)pentane-1,5-diamine, 4-isothiocyanatobenzenesulfonamide (0.35 g, 1.64 mmol) in acetonitrile (10 mL) and DIPEA (0.40 mL) was stirred at 50° C. under nitrogen for 3 h. The solvent was evaporated under reduced pressure to give a crude product, which was purified by flash chromatography eluting utilizing 5% MeOH in DCM followed by 15% MeOH in DCM to give 4-(3-(5-(bis(pyridin-2-ylmethyl)amino)pentyl)thioureido) benzenesulfonamide (0.145 g, 19%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.48 (d, 2H), 7.98 (s, 1H), 7.78-7.69 (m, 4H), 7.63 (d, 2H), 7.53 (d, 2H), 7.29-7.21 (m, 4H), 3.55 (s, 4H), 3.46-3.44 (m, 2H), 2.49-2.47 (m, 2H), 1.56-1.42 (m, 2H), 1.32-1.28 (m, 2H); ESMS m/z: 499.5 (M+H)+.
Reaction SMILES: CI.[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]([C:13]3[N:18]=[C:17]([NH:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH:22]([OH:26])[CH2:21]4)[C:16]([F:27])=[CH:15][N:14]=3)=[CH:11][N:10]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:7]2=[N:8][CH:9]=1.Cl[C:39]1C=C2C(C3N=C(NC4(O)CCCCC4)C(F)=CN=3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.S([O-])([O-])(=O)=O.[Ca+2]>[Ag]=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]([C:13]3[N:18]=[C:17]([NH:19][C@H:20]4[CH2:25][CH2:24][CH2:23][CH:22]([O:26][CH3:39])[CH2:21]4)[C:16]([F:27])=[CH:15][N:14]=3)=[CH:11][N:10]([S:28]([C:31]3[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=3)(=[O:30])=[O:29])[C:7]2=[N:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4(O)CCCCC4)n3)c3cc(Cl)cnc32)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCCC(O)C4)n3)c3cc(Cl)cnc32)cc1
Agent: O=[Ag]
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CI
Product: COC1CCC[C@H](Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of methyl iodide (0.20 g, 0.41 mmol) and 3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-cyclohexanol, 27a, (0.47 g, 2.04 mmol) was added silver oxide (0.578 g, 4.07 mmol and calcium sulfate (0.28 g, 2.04 (mmol). The reaction mixture was stirred at room temperature for 18 h. The mixture was filtered through celite and the resulting filtrate was concentrated in vacuo. The resulting crude mixture was purified by silica gel chromatography to afford 120 mg of the desired product, 27b.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].CS(O[CH2:19][C:20]([F:23])([F:22])[F:21])(=O)=O>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][N:8]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)OCC(F)(F)F
Product: CCOC(=O)c1nn(CC(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The product was obtained as a single regioisomer according to the method described in example 4, step 2 starting from 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester and 2,2,2-trifluoroethyl methanesulfonate after purification by silica gel chromatography using a heptane/ethyl acetate gradient as yellow oil (568 mg, 84%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([C:11]2[C:19]3[C:18]([C:20]([O:22]C)=O)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][CH:12]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:25][NH2:26]>CO.Cl>[CH2:8]([C:9]1[C:11]2=[CH:12][NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]=32)[C:20](=[O:22])[NH:26][N:25]=1)[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: COC(=O)c1cccc2[nH]cc(C(=O)CCc3ccccc3)c12
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C1NN=C(CCc2ccccc2)c2c[nH]c3cccc1c23

Procedure:
A solution of methyl indole-4-carboxylate (250 mg, 1.43 mmol) in dichloroethane (3 mL) was treated with 3-phenylpropionyl chloride (361 mg, 2.14 mmol) at room temperature. The orange solution was cooled to 0° C. and treated with aluminum chloride (572 mg, 4.29 mmol). The reaction mixture was stirred at room temperature for 2 h, then poured into ice-cold 1M aqueous HCl. The aqueous solution was adjusted to pH=8 with 1M NaOH, and extracted with CH2Cl2 (10 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated to give methyl 3-(3-phenylpropionyl)-indole-4-carboxylate as a pale-yellow solid, 395 mg (90%). A solution of the 3-(3-phenylpropionyl)-4-carboxy indole (95.5 mg, 0.31 mmol) in MeOH (3 mL) and HCl (0.1 mL) was treated with hydrazine hydrate (47 mg, 0.93 mmol) and the solution was heated at reflux for 8 h. The solution was cooled in an ice/water bath and the precipitated solid was collected by filtration to give 1,5-dihydro-3-phenethyl-[1,2]diazepino[4,5,6-cd]-indol-6-one, 60.2 mg (71%). The crude product was purified by radial chromatography (2 mm SiO2, 5:1 hexanes:EtOAc) to give a yellow solid. mp 182-183.5° C.; 1H NMR (300 MHz, d6-DMSO) δ 2.80 (m, 2H), 2.84 (m, 2H), 7.22 (m, 2H), 7.31 (m, 4H), 7.54 (m, 2H), 7.81 (s, 1H), 10.19 (s, 1H), 11.92 (br s, 1H); Anal. (C10H7N3O.0.1 H2O) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]([C:24]#[N:25])=[CH:22][C:21]([CH3:26])=[N:20]2)=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:25][CH2:24][C:23]1[N:19]([C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)[N:20]=[C:21]([CH3:26])[CH:22]=1)=[S:11]
Reactant: S=C=Nc1cccc(Cl)c1Cl
Reactant: Cc1cc(C#N)n(-c2ccc(Cl)cc2)n1
Product: Cc1cc(CNC(=S)Nc2cccc(Cl)c2Cl)n(-c2ccc(Cl)cc2)n1
Yield: 56 %

Procedure:
Prepared in 56% yield from 2,3-dichlorophenylisothiocyanate and the product of Example 205A according to the procedure described for Example 153B.
Reaction SMILES: [K].[OH:2][C:3]1[C:4]([N:15]2[S:19](=[O:21])(=[O:20])[NH:18][C:17](=[O:22])[CH2:16]2)=[CH:5][C:6]2[CH2:7][C:8]([CH3:14])([CH3:13])[CH2:9][CH2:10][C:11]=2[CH:12]=1.OC1C(N2S(=O)(=O)NC(=O)C2)=CC2CC(C)(C)CCC=2C=1.CC(C)([O-])C.[K+].[C:50](Cl)(=[O:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C=O)C>[CH3:13][C:8]1([CH3:14])[CH2:9][CH2:10][C:11]2[CH:12]=[C:3]([O:2][C:50](=[O:57])[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:4]([N:15]3[CH2:16][C:17](=[O:22])[NH:18][S:19]3(=[O:21])=[O:20])=[CH:5][C:6]=2[CH2:7]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)CCc2cc(O)c(N3CC(=O)NS3(=O)=O)cc2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: CC1(C)CCc2cc(OC(=O)c3ccccc3)c(N3CC(=O)NS3(=O)=O)cc2C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-(3-hydroxy-7,7-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one potassium salt (47 mg, 0.14 mmol; prepared from the title compound of Example 49 analogously to procedure as described in Example 1, step I) in DMF (3 mL) at 0° C. is added potassium t-butoxide (1M in THF, 0.13 mL,). After 5 min, benzoyl chloride (0.016 mL, 0.14 mmol) is added. The mixture is stirred at 0° C. for 5 min. The mixture is partitioned between Et2O and aq. K2CO3. The ether layer is removed. The aqueous layer is acidified by adding 3M HCl solution, and Et2O is added to extract the product. The organic residue is purified by HPLC to give the title compound as a solid: 1H NMR (CD3OD) δ 1.02 (s, 6H), 1.62 (t, J=7 Hz, 2H), 2.59 (s, 2H), 2.88 (t, J=7 Hz, 2H), 4.43 (s, 2H), 7.11 (s, 1H), 7.23 (s, 1H), 7.52-7.55 (m, 2H), 7.65-7.69 (m, 1H), 8.16-8.19 (m, 2H); (M+H)+=413.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:40])=[C:5]([C:24]([O:26][CH2:27][CH2:28][N:29]2C(=O)C3=CC=CC=C3C2=O)=[O:25])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])[C:7]=1[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9].O.NN>>[CH3:1][C:2]1[NH:3][C:4]([CH3:40])=[C:5]([C:24]([O:26][CH2:27][CH2:28][NH2:29])=[O:25])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])[C:7]=1[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9]
Reactant: CC1=C(C(=O)OCCN2C(=O)c3ccccc3C2=O)C(c2ccccc2[N+](=O)[O-])C(C(=O)OCC(C)C)=C(C)N1
Agent: NN
Solvent: O
Product: CC1=C(C(=O)OCCN)C(c2ccccc2[N+](=O)[O-])C(C(=O)OCC(C)C)=C(C)N1
Yield: 96.5 %

Procedure:
Prepared by a method analogous to that of Example 1(b) from 10.94 g (20 mmol) of 1,4-dihydro-2,6-dimethyl-3-isobutoxycarbonyl-4-(2-nitrophenyl)-5-(2-phthalimidoethoxycarbonyl)-pyridine and 3.0 ml (60 mmol) of hydrazine hydrate. 8.06 g (96%) of a viscous yellow oil are obtained. This product is used for reactions without further purification.