Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([C:19](=[O:21])[NH2:20])=[CH:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[C:19]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:8]([CH2:7][C:6]([OH:22])=[O:5])[CH:9]=1)(=[O:21])[NH2:20]
Reactant: COc1ccc2c(c1)c(C(N)=O)cn2CC(=O)OC(C)(C)C
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)c(C(N)=O)cn2CC(=O)O
Reaction time: 3 h

Procedure:
To a solution of (3-carbamoyl-5-methoxy-indol-1-yl)-acetic acid tert-butyl ester (45.0 mg, 0.118 mmol) in CH2Cl2 (2.0 mL) was added TFA (1.0 mL) at RT, and stirring was continued for 3 h. Methanol was then added to the reaction mixture and volatiles were removed in vacuo. The residue was taken up in methanol and concentrated again under reduced pressure to afford the title compound as a beige solid: MS (LC/MS): 249 [M+H]+, 277 [M+Na]+; tR (HPLC conditions c): 2.93 min. The material thus obtained was used in the next reaction step without further purification.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[C:13]1([CH3:21])[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][CH:14]=1.FC(F)(F)C1C=C(Cl)C=CC=1C(O)C1C=CC=CC=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:19]([OH:20])[C:16]1[CH:17]=[CH:18][C:13]([CH3:21])=[CH:14][CH:15]=1
Reactant: FC(F)(F)c1ccccc1[Mg]Br
Reactant: Cc1ccc(C=O)cc1
Agent: OC(c1ccccc1)c1ccc(Cl)cc1C(F)(F)F
Product: Cc1ccc(C(O)c2ccccc2C(F)(F)F)cc1

Procedure:
This material was prepared from 2-(trifluoromethyl)phenylmagnesium bromide (16 mmol) and p-tolualdehyde (1.82 mL, 15 mmol) using the procedure described for compound (96) (4.28 g, 100%).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11](=[O:12])[C:10]([O:13][CH3:14])=[CH:9][N:8]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[N:7]=1)=[O:5].[CH3:22][Mg+].[Br-]>C1COCC1>[C:4]([C:6]1[C:11](=[O:12])[C:10]([O:13][CH3:14])=[CH:9][N:8]([C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[N:7]=1)(=[O:5])[CH3:22]
Reactant: C[Mg+]
Reactant: COc1cn(-c2ccncc2)nc(C(=O)N(C)OC)c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2ccncc2)nc(C(C)=O)c1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a solution of N,5-dimethoxy-N-methyl-4-oxo-1-pyridin-4-yl-1,4-dihydropyridazine-3-carboxamide (9.6 g, 33 mmol) in THF (100 mL) was added dropwise 1 M MeMgBr in THF (66 mL, 66 mmol) at −78° C. for 15 min. After stirring at −78° C. for 1 h, the mixture was quenched with 1 M HCl aqueous solution (70 mL). The mixture was warmed to room temperature, basified with 1 M NaOH aqueous solution, washed with AcOEt. The aqueous layer was extracted with CH2Cl2 (50 mL×4). The combined extract was dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (2.1 g, 26% yield) as yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 2.70 (3H, s), 3.98 (3H, s), 7.64 (2H, dd, J=4.7, 1.6 Hz), 8.04 (1H, s), 8.79 (2H, dd, J=4.7, 1.6 Hz).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[NH2:30][C:31]1[CH:51]=[CH:50][C:34]([O:35][C:36]2[C:41]([C:42]3[CH:47]=[CH:46][N:45]=[C:44]([NH:48][CH3:49])[CH:43]=3)=[CH:40][CH:39]=[CH:38][N:37]=2)=[CH:33][CH:32]=1.Cl[C:53]1[C:58]2[CH2:59][CH2:60][CH2:61][C:57]=2[C:56]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[N:55][N:54]=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:49][NH:48][C:44]1[CH:43]=[C:42]([C:41]2[C:36]([O:35][C:34]3[CH:50]=[CH:51][C:31]([NH:30][C:53]4[N:54]=[N:55][C:56]([C:62]5[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=5)=[C:57]5[CH2:61][CH2:60][CH2:59][C:58]=45)=[CH:32][CH:33]=3)=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:47]=[CH:46][N:45]=1
Reactant: CNc1cc(-c2cccnc2Oc2ccc(N)cc2)ccn1
Reactant: Clc1nnc(-c2ccccc2)c2c1CCC2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: CNc1cc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)c4c3CCC4)cc2)ccn1
Temperature: 100 °C

Procedure:
A resealable reaction tube was charged with tris(dibenzylideneacetone)dipalladium (0) (0.012 g, 0.013 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.021 g, 0.051 mmol), 4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyridin-2-amine (0.075 g, 0.257 mmol), 1-chloro-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyridazine (0.059 g, 0.257 mmol), and sodium tert-butoxide (0.035 g, 0.359 mmol). This mixture was purged with nitrogen for several minutes, followed by addition of 0.780 mL of toluene. The vial was capped and heated at 100° C. for 1.5 h. Upon cooling, ethyl acetate was added and a precipitate formed. After filtration and washing with EtOAc, the crude material was purified by ISCO silica gel chromatography (90/10/1 DCM/MeOH/NH4OH, 12 g column), to provide N-(4-(3-(2-(methylamino)pyridin-4-yl)pyridin-2-yloxy)phenyl)-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine as a tan solid. MS m/z=487 [M+H]+. Calc'd for C30H26N6O: 486.57.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:14][N:15]3[C:20](Cl)=[CH:19][CH:18]=[CH:17][C:16]=23)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:29]([NH2:32])[CH:30]=[CH2:31]>>[CH2:29]([NH:32][C:20]1[N:15]2[N:14]=[C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:12]([C:10]3[CH:9]=[CH:8][N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:11]=3)=[C:16]2[CH:17]=[CH:18][CH:19]=1)[CH:30]=[CH2:31]
Reactant: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)n1
Reactant: C=CCN
Product: C=CCNc1cccc2c(-c3ccnc(NCCCC)n3)c(-c3ccc(F)cc3)nn12
Yield: 88.5 %

Procedure:
A solution of N-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamine (0.15 g, 0.38 mmol) in allylamine (5 mL, 67 mmol) was heated at 85° C. in a sealed tube for 88 hours. After cooling and concentrating the reaction mixture, flash chromatography (4:1 hexanes-ethyl acetate) afforded N-allyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-7-amine (0.14 g, 88%) as a pale yellow foam. 1H NMR (CDCl3): δ 7.89 (broad, 1H), 7.78 (d, 1H), 7.62 (m, 2H), 7.36 (t, 1H), 7.16 (t, 2H), 6.31–6.26 (m, 2H), 6.09–5.92 (m, 2H), 5.39–5.24 (m, 2H), 4.06 (t, 2H), 3.50 (q, 2H), 1.72–1.41 (m, 4H), 0.98 (t, 3H); 19F NMR (CDCl3) δ −113.16; MS m/z 417 (M+1); Anal. Calcd for C24H25FN6: C, 69.21; H, 6.05; N, 20.18. Found: C, 69.27; H, 6.07; N, 20.03.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]3)[C:8]2=O)=[CH:4][CH:3]=1.[CH3:22][Si:23]([CH3:31])([CH3:30])[CH2:24][CH2:25][S:26]([NH2:29])(=[O:28])=[O:27]>ClCCCl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]3)[C:8]2=[N:29][S:26]([CH2:25][CH2:24][Si:23]([CH3:31])([CH3:30])[CH3:22])(=[O:28])=[O:27])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CC2(Cc3ccc(Br)cc3C2=O)C1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC2(Cc3ccc(Br)cc3C2=NS(=O)(=O)CC[Si](C)(C)C)C1
Temperature: 110 °C
Yield: 97.7 %

Procedure:
A mixture of tert-butyl 6′-bromo-1′-oxo-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1-carboxylate (0.2863 g, 0.8 mmol), 2-(trimethylsilyl)ethanesulfonamide (0.2000 g, 1.1 mmol), and Ti(OEt)4 (0.6900 g, 3.0 mmol) in 1,2-dichloroethane (3 mL) was heated at 110° C. for 20 h. The reaction mixture was then quenched with ice, extracted with CH2Cl2, and dried over Na2SO4. After the solvent was evaporated under reduced pressure, the residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford 0.4031 g (96%) of tert-butyl 6′-bromo-1′-(((2-(trimethylsilyl)ethyl)sulfonyl)imino)-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1-carboxylate. LC-MS tR=2.31 min in 3 min chromatography, m/z 515, 517 (MH+), 459, 461 (MH+-56).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]([C:29]([F:32])([F:31])[F:30])=[CH:10][C@@H:11]1[C@H:13]([C:14]([O:16][CH2:17][C:18]2[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]([NH2:25])[C:19]=2[CH3:26])=[O:15])[C:12]1([CH3:28])[CH3:27].[C:33](Cl)(Cl)=[S:34]>C(Cl)(Cl)Cl>[Cl:8][C:9]([C:29]([F:30])([F:31])[F:32])=[CH:10][C@@H:11]1[C@H:13]([C:14]([O:16][CH2:17][C:18]2[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]([N:25]=[C:33]=[S:34])[C:19]=2[CH3:26])=[O:15])[C:12]1([CH3:28])[CH3:27]
Reactant: Cc1ccc(N)c(C)c1COC(=O)[C@H]1[C@@H](C=C(Cl)C(F)(F)F)C1(C)C
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(N=C=S)c(C)c1COC(=O)[C@H]1[C@@H](C=C(Cl)C(F)(F)F)C1(C)C
Yield: 81.8 %

Procedure:
Triethylamine (0.5 gram, 0.005 mole) was added to a solution of (3-amino-2,6-dimethylphenyl)methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate (2.03 grams, 0.005 mole) in chloroform (20 ml) and cooled to 0°. Thiophosgene (0.58 gram, 0.005 mole) was added, and the reaction mixture was allowed to come to room temperature. The solvent was evaporated, and the residue was dissolved in diethyl ether. The solution was washed with water, dried over magnesium sulfate and filtered. The solvent was evaporated to give (3-isothiocyanato-2,6-dimethylphenyl)methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate (1.71 grams, mp 60°).
Reaction SMILES: C([O:8][C:9]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[CH:12][N:13]2[CH3:19])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[Si:23]([O:22][CH2:21][CH2:20][C:11]1[C:10]2[C:9]([OH:8])=[C:17]([F:18])[CH:16]=[CH:15][C:14]=2[N:13]([CH3:19])[CH:12]=1)([C:26]([CH3:28])([CH3:29])[CH3:27])([CH3:25])[CH3:24]
Reactant: Cn1cc(CCO[Si](C)(C)C(C)(C)C)c2c(OCc3ccccc3)c(F)ccc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(CCO[Si](C)(C)C(C)(C)C)c2c(O)c(F)ccc21
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A mixture of 17-4 (454 mg, 1.098 mmol) and Pd(OH)2/C in MeOH (0.5 mL NH3) was hydrogenated at ambient pressure for 30 min at 25° C., then the mixture was filtered through a plug of Celite and washed with EtOAc. The crude product was purified by column chromatography on silica gel eluting with Hexane/EtOAc (20%) to afford a white solid 17-5 in 94% yield (334 mg). 1H NMR (300 MHz, CDCl3) δ (ppm) 8.27 (br, 1H), 6.96 (dd, J=10.9, 8.8 Hz, 1H), 6.73 (s, 1H), 6.68 (dd, J=8.8, 3.3 Hz, 1H), 3.90 (t, J=5.2 Hz, 2H), 3.67 (s, 3H), 3.07 (t, J=5.5 Hz, 2H), 0.84 (s, 9H), 0.01 (s, 6H). LRMS: calc 323.2 and found: 324.2 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1.N[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:3]=1
Reactant: NN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)cc1NN1CCOCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.8 %

Procedure:
A mixture of 45 g of 4-chloro-1,2-dinitrobenzene, 25 g of 4-aminomorpholine and 30 g of triethylamine in 250 ml of 96° EtOH is stirred for 48 hours at RT. The precipitate formed is filtered off and washed with iso ether to give 30.2 g of the expected product. M.p.=155° C.
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[O:14][C:13](=O)[NH:12][C:11](=[O:17])[C:10]=3[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH3:19]>>[C:1]1([CH:7]2[C:15]3[NH:19][C:13](=[O:14])[NH:12][C:11](=[O:17])[C:10]=3[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: O=c1[nH]c(=O)c2c(o1)C(c1ccccc1)CC2
Solvent: O
Product: O=c1[nH]c2c(c(=O)[nH]1)CCC2c1ccccc1
Yield: 100 %

Procedure:
A solution of 7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (3.751 g, 16.36 mmol) in concentrated ammonia in water (80 mL, 16.36 mmol) was heated in a 350 mL high-pressure flask for 5 h. The solvent was removed in vacuum to give 7-phenyl-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione (3.73 g, 16.34 mmol, 100% yield) as brown solid. LC-MS (M+H)+=229.1. 1H NMR (500 MHz, dimethylsulfoxide-d6) δ ppm 7.34 (2H, t, J=7.5 Hz), 7.26 (1H, t, J=7.3 Hz), 7.18 (2H, d, J=7.3 Hz), 5.39 (1H, br s), 4.14 (1H, d, J=7.3 Hz), 2.43-2.68 (2H, m), 1.80-1.88 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:11]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: COc1ccccc1C=O
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(=Cc1ccccc1OC)C(=O)OCC

Procedure:
By Knoevenagel condensation of o-methoxybenzaldehyde with diethyl malonate, there was obtained diethyl o-methoxybenzylidenemalonate, boiling point 140° C./0.05 Torr.
Reaction SMILES: [CH2:1]([CH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[C:10]=2[O:9][C:8]1=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-:25].[K+]>CO>[OH:9][C:10]1[C:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:14][CH:13]=[CH:12][C:11]=1[CH:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]([OH:24])=[O:25]
Reactant: CCCCCCC1C(=O)Oc2c(Oc3ccccc3C)cccc21
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Product: CCCCCCC(C(=O)O)c1cccc(Oc2ccccc2C)c1O

Procedure:
3-n-Hexyl-7-(o-tolyloxy)-2,3-dihydrobenzofuran-2-one was treated with potassium hydroxide in methanol in a similar manner to that of Example 21-(10) to give 2-[2-hydroxy-3-(o-tolyloxy)phenyl]n-octanoic acid, mp. 65°-66° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH:10]2[CH2:15][CH2:14][N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(O)C=CC=CC=1.[BrH:33]>O>[BrH:33].[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1ccc(S(=O)(=O)N2CCC(Sc3ccc(Cl)c(Cl)c3)CC2)cc1
Agent: Br
Solvent: Oc1ccccc1
Solvent: O
Product: Clc1ccc(SC2CCNCC2)cc1Cl
Temperature: 25 °C

Procedure:
A solution of 20.84 g (0.0502 mole) of 4-[(3,4-dichlorophenyl)thio]-1-[(4-methylphenyl)sulfonyl]piperidine, 36.58 g (0.338 mole) of phenol and 200 ml of 48% hydrobromic acid was heated at reflux for 25 hr. The reaction mixture was cooled to room temperature and diluted with water. The aqueous phase was extracted with benzene. The resulting aqueous acidic phase was made alkaline with 10% aqueous sodium hydroxide and extracted with chloroform. The chloroform layer was dried over sodium sulfate, filtered and evaporated to give a residue, the free base of the title compound. The free base was converted to the hydrobromide salt. The salt was recrystallized from methylene chloride-methanol diethyl ether to give 3.6 g (4.4%) of white solid, m.p. 125°-128° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].C([O-])([O-])=O.[Na+].[Na+].Br[C:44]1[CH:45]=[C:46]([C@:50]2([CH3:66])[CH2:55][C:54](=[O:56])[N:53]([CH3:57])[C:52](=[N:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[NH:51]2)[CH:47]=[CH:48][CH:49]=1>CN(C=O)C.CCOC(C)=O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].O>[F:9][S:8]([F:13])([F:12])([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([C@:50]3([CH3:66])[CH2:55][C:54](=[O:56])[N:53]([CH3:57])[C:52](=[N:58][C:59](=[O:65])[O:60][C:61]([CH3:63])([CH3:62])[CH3:64])[NH:51]3)[CH:45]=2)=[CH:3][CH:4]=1
Reactant: CN1C(=O)C[C@@](C)(c2cccc(Br)c2)NC1=NC(=O)OC(C)(C)C
Reactant: FS(F)(F)(F)(F)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)C[C@@](C)(c2cccc(-c3ccc(S(F)(F)(F)(F)F)cc3)c2)NC1=NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Stir 1-bromo-4-pentafluorosulfanylbenzene (100 mg) together with bis(pinacolato)diboron (90 mg), potassium acetate (104 mg) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (43 mg) in DMF (2 ml) at 80° C. for 2 h. Allow the reaction mixture to cool, then add Na2CO3 (225 mg), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (43 mg), water (0.7 ml) and (S)-tert-butyl 4-(3-bromophenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (240 mg). Stir the mixture at 80° C. for 3 h. Allow the reaction mixture to cool, dilute with EtOAc (20 ml) and wash with water (2×5 ml). Dry the organic layer (MgSO4), filter and evaporate the filtrate. Chromatograph the residue on a silica gel column and elute with EtOAc/hexanes to afford the product, (S)-tert-butyl 4-(4′-pentafluorosulfanylbiphenyl-3-yl)-1,4-dimethyl-6-oxotetrahydropyrimidin-2(1H)-ylidenecarbamate.
Reaction SMILES: C([O:5][C:6]([N:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[CH:14]1[N:20]([CH3:23])[CH2:21][CH2:22][C:13]21[CH3:24])[CH3:9])=O)(C)(C)C.[CH3:25][N:26]=C=O>ClCCl>[CH3:25][NH:26][C:6]([N:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[CH:14]1[N:20]([CH3:23])[CH2:21][CH2:22][C:13]21[CH3:24])[CH3:9])=[O:5]
Reactant: CN=C=O
Reactant: CN(C(=O)OC(C)(C)C)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Solvent: ClCCl
Product: CNC(=O)N(C)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
5-(t-Butoxycarbonyl-N-methylamino)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indole (100 mg) was heated under nitrogen without solvent to 200°-210° C. in an oil bath. After 1 hour, TLC (thin layer chromatography) indicated a conversion to a new compound. The flask was allowed to cool to ambient temperature and dichloromethane (5 ml) was added followed by the slow addition of a solution of methyl isocyanate (18 mg) in dichloromethane (3 ml) over a period of 45 minutes. The mixture was washed with water (2 ml), dried (Na2SO4), concentrated and purified by flash chromatography (eluting with 15% MeOH/EtOAc). The pure fractions were concentrated to give 5-(methylaminocarbonyl-N-methylamino)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indole (0.05 g).
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([NH2:11])([CH3:10])([CH3:9])[CH3:8]>C(OCC)C.CCCCC.[Ti](Cl)(Cl)(Cl)Cl>[C:7]([N:11]=[C:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)N
Reactant: O=C1CCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCC
Solvent: CCOCC
Product: CC(C)(C)N=C1CCCC1
Temperature: -55 °C
Reaction time: 6 h
Yield: 76.1 %

Procedure:
Cyclopentanone (13.3 mL, 150 mmol) and tert-butylamine (47.4 mL, 450 mmol) were combined in 110 mL diethyl ether under a nitrogen atmosphere and were then cooled to −55° C. in a dry ice/acetonitrile bath. Titanium tetrachloride (8.2 mL, 75 mmol) was taken up in 70 mL pentane and added dropwise to the above solution, being careful to maintain the temperature at −40° C. the reaction was then stirred at −40° C. for 6 h and was then allowed to warm to room temperature overnight. The reaction mixture was filtered through a short plug of celite and washed with diethyl ether. The filtrate was evaporated in vacuo to yield 15.9 g (76%) of the title product as a clear oil.
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]=[C:8]([N:15]([CH2:17][C:18]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:16])[N:7]=[C:6]2[NH2:30].[CH3:31][N:32]([CH3:37])[S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>O1CCCC1.O>[CH3:31][N:32]([CH3:37])[S:33]([N:21]1[CH2:20][CH2:19][C:18]([CH2:17][N:15]([C:8]2[N:7]=[C:6]([NH2:30])[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=2)[CH3:16])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22]1)(=[O:35])=[O:34]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1cc2nc(N(C)CC3(c4ccccc4)CCNCC3)nc(N)c2cc1OC
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2nc(N(C)CC3(c4ccccc4)CCN(S(=O)(=O)N(C)C)CC3)nc(N)c2cc1OC

Procedure:
A solution of 6,7-dimethoxy-N2-(4-phenyl-piperidin-4-ylmethyl)-N2-methyl-quinazoline-2,4-diamine 11 (350 mg), dimethylsulfamoyl chloride (140 μl), and triethylamine (240 μl) in tetrahydrofuran (10 ml) was stirred at room temperature for 24 hours. The mixture was diluted with water and extracted with ethyl acetate. The product was chromatographed on silica gel to yield 4-{[(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]-methyl}-4-phenyl-piperidine-1-sulfonic acid dimethylamide 19, MS: 515 ([M+H]+).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]([C:18]3[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=3)[C:21](OCC)=[O:22])[CH2:14][CH:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:29]=1)[CH3:2].[NH2:30][NH2:31]>C(O)C>[CH2:1]([NH:3][C:4]1[N:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]([C:18]3[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=3)[C:21]([NH:30][NH2:31])=[O:22])[CH2:14][C@H:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:29]=1)[CH3:2]
Reactant: CCNc1ncc2c(n1)N1CCCC1CN(c1cccc(C(=O)OCC)c1)C2=O
Reactant: NN
Solvent: CCO
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)NN)c1)C2=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Compound 18 (1.15 g, 2.19 mmol) obtained in Example 18 was dissolved in ethanol (11 mL), and the mixture was stirred overnight at 80° C. after adding hydrazine.monohydrate (1.06 mL, 21.9 mmol). The mixture was concentrated, diluted with chloroform, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (S)-3-(9-ethylamino-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic hydrazide (1.10 g, quantitative).
Reaction SMILES: [C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[N:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:28].[OH-].[K+]>CO>[C:16]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH2:15])=[O:28])=[N:12][CH:13]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O
Reactant: N#Cc1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
Dissolve 5g. of 5-(triphenylmethyl)-2-cyanopyridine in a mixture consisting of 50 ml. of water and 1.0 liter of methanol. Add 4 g. of potassium hydroxide and heat the mixture at reflux for 15 hours. Remove the methanol under reduced pressure, triturate the residue with water and dry the solids obtained thereby. Crystallize the product from acetonitrile to obtain the product of this example. m.p. 239°-240° C.
Reaction SMILES: C(N1[CH2:13][CH2:12][C:11](=O)[CH2:10]C1)C1C=CC=CC=1.[F:15][C:16]([F:48])([F:47])[C:17]1[CH:18]=[C:19]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:20]([N:22]1[CH2:39][CH2:38][C:25]2([N:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]([CH3:36])[NH:27][C:26]2=[O:37])[CH2:24][CH2:23]1)=[O:21].C1(CBr)CC1>>[F:48][C:16]([F:15])([F:47])[C:17]1[CH:18]=[C:19]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:20]([N:22]1[CH2:23][CH2:24][C:25]2([N:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:28]([CH3:36])[N:27]([CH2:10][CH:11]3[CH2:13][CH2:12]3)[C:26]2=[O:37])[CH2:38][CH2:39]1)=[O:21]
Reactant: CC1NC(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N1c1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: BrCC1CC1
Product: CC1N(CC2CC2)C(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N1c1ccccc1

Procedure:
The title compound, MS: m/e=540.3 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one 1-benzyl-piperidin-4-one and cyclopropyl methyl bromide.