Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:5]2=[N:6][CH:7]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=2)[N:17]=[C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[C:15]=1[CH3:31].Cl.O1CCOCC1>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[C:15]=3[CH3:31])[CH2:9][C:8]([CH3:12])([CH3:11])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: CC1(C)CNc2cc(Br)cnc21
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(Br)cc21
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (200 mg, 0.88 mmol), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (240 mg, 0.88 mmol) and 4.0M solution of HCl in 1,4-dioxane (0.22 mL, 0.88 mmol) in NMP (1.0 mL) and heating at 150° C. for 3 h in the microwave. After purification 4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline was obtained as a yellow film. Mass Spectrum (ESI) m/e=463 [(M+1) (79Br)] and 465 [(M+1) (81Br)].
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[C:6]=1[C:7]#[N:8])([CH3:3])[CH3:2].Cl>CO.[Fe]>[NH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])[C:6]=1[C:7]#[N:8]
Reactant: CC(C)Nc1cccc([N+](=O)[O-])c1C#N
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: CC(C)Nc1cccc(N)c1C#N
Temperature: 90 °C
Yield: 106.3 %

Procedure:
To a solution of 2-(isopropylamino)-6-nitrobenzonitrile (Example 157c) (0.21 g, 1.02 mmol) in MeOH (9 mL) was added concentrated HCl (2 mL). Then Fe (0.17 g, 3.07 mmol) was added portionwise, and the reaction mixture was refluxed at 90° C. for 15 minutes. After cooling to room temperature, dilution with H2O (50 mL) and extraction with DCM (3×50 mL), the combined organic phases were washed with brine, dried over MgSO4 and the solvents were evaporated to give 2-amino-6-(isopropylamino)benzonitrile (0.19 g, 100%) as a brown oil which was used in the next step without any further purification. MS 176 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=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]>[C:2]1([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccccc2)cc1
Reaction time: 25 h
Yield: 74.5 %

Procedure:
The above general procedure was followed using chlorobenzene (135 mg, 1.20 mmol) and aniline (93 mg, 1.00 mmol) with 5 mol % Pd(dba)2 and 4 mol % tri-t-butylphosphine in 2.0 mL of toluene. After 25 hours, the reaction mixture was adsorbed onto silica gel and chromatographed with 2.5% ethyl acetate/hexanes to give 126 mg (75%) of diphenylamine as an off-white solid.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[CH:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[NH:3]1.[H-].[Na+].Cl[C:33]([O:35][CH3:36])=[O:34].O>O1CCCC1>[C:26]([C:25]1[CH:24]=[CH:23][C:22]([CH:4]2[N:3]([C:33]([O:35][CH3:36])=[O:34])[C:2](=[O:1])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=3)[C:6]3[CH2:18][CH2:19][C:20](=[O:21])[C:5]2=3)=[CH:29][CH:28]=1)#[N:27]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 1, 30 mg, 0.076 mmol) in tetrahydrofuran (0.5 mL) is added to a suspension of sodium hydride (60% in mineral oil, 4 mg, 0.1 mmol) in dry tetrahydrofuran. After 20 min methyl chloroformate (6 μL, 0.078 mmol) is added, and the mixture is stirred at room temperature for 1 h. Water is added and the mixture is a) extracted with dichloromethane. The combined organic layers are concentrated, and the residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 2 mg; ESI mass spectrum [M+H]+=456; Retention time HPLC: 1.10 min (V011_S01).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:40]1([CH2:46][CH2:47][NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:43]3[CH2:44][CH2:45][N:40]([CH2:46][CH2:47][NH:48][S:49]([CH3:52])(=[O:50])=[O:51])[CH2:41][CH2:42]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)NCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 4) was reacted with N-(2-piperazin-1-yl-ethyl)-methanesulfonamide dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound. HR-MS (ES, m/z) calculated for C37H48N5O4SCl2 [(M+H)+] 782.2799, observed 782.2787.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[N:16]2[CH2:19][CH:18]([NH:20][CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=3)[CH2:17]2)=[CH:11][CH:10]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[N:16]2[CH2:17][CH:18]([N:20]([CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=3)[S:38]([CH3:37])(=[O:40])=[O:39])[CH2:19]2)=[CH:31][CH:32]=1
Reactant: Fc1cc(F)cc(CNC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 0 °C

Procedure:
347 mm3 of triethylamine are added, at room temperature under an argon atmosphere, to a solution of 433 mg of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorobenzyl)amine in 30 cm3 of dichloro-methane. The mixture is cooled to around 0° C. before adding thereto a solution of 46.4 mm3 of methylsulfonyl chloride in 5 mm3 of dichloromethane, and then it is stirred at room temperature for 1 hour. The reaction mixture is diluted with 20 cm3 of dichloromethane and is then washed with twice 20 cm3 of distilled water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is introduced into solution in methanol on a Bond Elut® SCX cartridge (10 g), eluting successively with methanol and with a 1 M solution of ammonia in methanol. The ammoniacal fractions are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 0.44 g of N-{1-[bis(4-chloro-phenyl)methyl]azetidin-3-yl}-N-(3,5-difluorobenzyl)-methylsulfonamide is thus obtained in the form of a cream-colored foam [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 2.81 (s:3H); 3.02 (broad t, J=7.5 Hz: 2H); 3.38 (broad t, J=7.5 Hz:2H); 4.23 (s:1H); 4.40 (mt:1H); 4.54 (s:2H); 6.75 (tt, J=9 and 2 Hz:1H); 6.95 (mt:2H); 7.25 (mt:8H)].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[C:20]([Cl:27])=[CH:21][C:22]([Cl:26])=[C:23]([OH:25])[CH:24]=1>>[Cl:27][C:20]1[CH:21]=[C:22]([Cl:26])[C:23]([OH:25])=[CH:24][C:19]=1[NH:18][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Nc1cc(O)c(Cl)cc1Cl
Product: Oc1cc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c(Cl)cc1Cl

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 5-amino-2,4-dichlorobenzenol (51 mg, 0.289 mmol) similar to Example 117 and isolated as a white solid (24 mg, 31%). 1H NMR (DMSO-d6): 10.80 (s, 1H), 9.90 (s, 1H), 9.39-9.38 (m, 1H), 8.75-8.72 (m, 1H), 8.57-8.53 (m, 1H), 7.63 (s, 1H), 7.61 (s, 1H), 7.59-7.55 (m, 1H), 7.31 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[C@H:9]([NH:20][CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[CH2:8][C@@H:7]1[CH2:36][CH3:37])=[O:5])[CH3:2].N1C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:17])([F:18])[F:19])=[CH:13][CH:14]=2)[C@H:9]([N:20]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[C:24]([C:32]([F:35])([F:33])[F:34])[CH:23]=2)[C:4]([O:3][CH3:1])=[O:5])[CH2:8][C@@H:7]1[CH2:36][CH3:37])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 162 %

Procedure:
A solution of cis-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 7E) (2.0 g, 3.7 mmol) and pyridine (0.58 g, 7.4 mmol) in 100 mL of dichloromethane was cooled in an ice/water bath as methyl chlorofomate (0.87 g, 9.2 mmol) was added slowly. After stirring overnight at room temperature, the reaction mixture was washed twice with a 2N hydrochloric acid solution, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude product, which was purified by silica gel chromatography using 5-10% ethyl acetate/hexanes as eluent to afford 1.8 g of the title product. MS m/z 601 (M++1); 1H NMR (coalescing mixture of conformers, CDCl3) δ 0.6-0.8 (bm, 3H), 1.2-1.3 (bm, 3H), 1.3-1.5 (bm, 2H), 1.6-1.75 (bm, 1H), 2.1-2.3 (bm, 1H), 3.7-3.9 (bs, 3H), 4.0-4.4 (bm, 4H), 5.0-5.6 (bm, 2H), 7.1 (s, 1H), 7.4-7.6 (bm, 2H), 7.6-7.8 (bm, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH:8]C(=O)C)[CH:7]=1.ClC1C=CC([N+]([O-])=O)=C(C=1)N.[CH3:26][O:27][CH:28]1[CH:32]([CH2:33]OC)[CH2:31][CH:30](OC)O1>CC(O)=O>[CH3:26][O:27][CH2:28][C:32]1[CH:31]=[CH:30][N:1]([C:2]2[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH2:8])[CH:7]=2)[CH:33]=1
Reactant: COCC1CC(OC)OC1OC
Reactant: CC(=O)Nc1cc(N)ccc1[N+](=O)[O-]
Agent: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: COCc1ccn(-c2ccc([N+](=O)[O-])c(N)c2)c1

Procedure:
The title compound was prepared from N-(5-amino-2-nitro-phenyl)-acetamide [prepared from commercially available 5-chloro-2-nitroaniline as described in Example F6] and 2,5-dimethoxy-3-methoxymethyl-tetrahydro-furan [prepared from (2,5-dimethoxy-tetrahydro-furan-3-yl)-methanol [CAS-no. 207119-66-2] by methylation with 2.1 eq. NaH (95%) and 5.5 eq. Mel in Et2O at 0° C. for 2 h] in HOAc at 60° C. for 18 h according to the general procedure F. Obtained as a light yellow solid (86 mg). Deacetylation of this material was perfomed by stirring with 2 eq. 2 N NaOH-sol. in 1,4-dioxane at 60° C. for 2 h. Obtained as a yellow solid (69 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=O)[O:27]C(C)(C)C)[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:17][C:7]2=1.I(O)(=O)(=O)=O.OS(O)(=O)=O.II.[CH3:45][C:46]([OH:48])=O>>[CH3:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([O:18][CH2:19][C@@H:20]([N:25]3[C:46](=[O:48])[C:45]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:26]3=[O:27])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:17][C:7]2=1
Reactant: CC(=O)O
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc21
Agent: II
Agent: O=S(=O)(O)O
Agent: [O-][I+3]([O-])([O-])O
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)N3C(=O)c4ccccc4C3=O)ccc21
Temperature: 80 °C
Reaction time: 3 h

Procedure:
(S)-tert-Butyl (1-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (300 mg, 0.683 mmol) was taken up in AcOH (15 mL) and treated with periodic acid (156 mg, 0.683 mmol), and H2SO4 (0.018 mL, 0.341 mmol). The reaction mixture was heated to 80° C. and maintained for 20 min after which iodine (104 mg, 0.410 mmol) was added and heating was continued at 80° C. for an additional 3 h. After cooling, the volatiles were evaporated and the residue was taken up in with ethyl acetate (25 mL). The organic layer was washed with saturated aqueous NaHCO3 (10 mL), then brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford (S)-2-(1-(4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yloxy)-4-methylpentan-2-yl)isoindoline-1,3-dione (300 mg, 0.61 mmol, 90% crude yield) as a brown solid. The material was taken to the next step without further purification. LC/MS (ESI) m/e 466.1 [(M+H)+, calcd for C20H25IN3O2 466.1] LC/MS retention time (method D): tR=0.58 min.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]([CH3:16])([CH3:15])[C:10](=[O:14])[CH2:11][C:12]#[N:13].[Cl:17][C:18]1[CH:26]=[C:25]([S:27][CH3:28])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].CC(C)(O)C#N>ClCCl>[Cl:17][C:18]1[CH:26]=[C:25]([S:27][CH3:28])[CH:24]=[CH:23][C:19]=1[C:20](=[O:21])[CH:11]([C:12]#[N:13])[C:10](=[O:14])[C:9]([CH3:16])([CH3:15])[CH3:8]
Reactant: CSc1ccc(C(=O)Cl)c(Cl)c1
Reactant: CC(C)(C)C(=O)CC#N
Agent: CC(C)(O)C#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ccc(C(=O)C(C#N)C(=O)C(C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.8 %

Procedure:
Triethylamine (1.78 g) was added to a stirred solution of 4,4-dimethyl-3-oxopentanenitrile (2.0 g) in dichloromethane and the mixture was stirred at room temperature for 2 hours. A solution of 2-chloro-4-methylsulphenylbenzoyl chloride (3.02 g) in dichloromethane was added and the mixture stirred at room temperature overnight. Acetone cyanohydrin (1.36 g) was added and the mixture stirred for 4 days, then filtered. The filtrate was washed with hydrochloric acid (2M), water, aqueous sodium bicarbonate solution, water, then dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue purified by column chromatography (hexane, ethyl acetate and acetic acid). The main fraction was washed with aqueous sodium hydroxide (2M), water, dried and evaporated to dryness to give 1-(2-chloro-4-methylsulphenylphenyl)-2-cyano-4,4-dimethylpentan-1,3-dione (COMPOUND 664, 0.16 g) as a white solid, m.p. 97°-99° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:22])[CH2:9][CH2:10][C:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[NH:13][C:12]=2[CH:20]=O)[CH2:4][CH2:3]1.[CH3:23][NH:24][S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[CH2:31]2)(=[O:27])=[O:26]>>[CH3:23][NH:24][S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])/[C:31]/2=[CH:20]\[C:12]1[NH:13][C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[C:11]=1[CH2:10][CH2:9][C:8]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:22])(=[O:27])=[O:26]
Reactant: CN1CCN(C(=O)CCc2c(C=O)[nH]c3c2CCCC3)CC1
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCC(=O)N1CCN(C)CC1)CCCC3)C(=O)N2
Yield: 56 %

Procedure:
3-[3-(4-Methylpiperazin-1-yl)-3-oxo-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (121 mg, 0.3 mmol) was condensed with 5-methylaminosulfonyl-oxindole (68 mg, 0.3 mmol) following the same procedure used in Example 1 to give the desired product (86 mg, 56% yield).
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[F:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.C1(C)C=CC=CC=1.[Sn](Cl)(Cl)(Cl)Cl>CCCCCC>[NH2:17][C:16](=[C:6]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C:7]([O:9][CH3:10])=[O:8])[C:15]1[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: COC(=O)CC(=O)C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)C(C(=O)C(C)C)=C(N)c1ccc(F)cc1
Temperature: 80 °C
Yield: 75.2 %

Procedure:
75.09 g of methyl isobutyrylacetate (0.50 mol, concentration 96%) and 61.80 g of 4-fluorobenzonitrile (0.50 mol, concentration 98%) were introduced into [500 ml of toluene and treated with 144.7 g of tin tetrachloride (0.55 mol, concentration 99%) at room temperature over the course of 16 min. After half an hour at room temperature, the thick suspension was heated to 80° C. After. 3 h, 175 ml of toluene were distilled off at normal pressure, and the mixture was cooled to room temperature and treated with 450 ml of saturated sodium carbonate and 300 ml of ethyl acetate. The organic phase was separated off and the aqueous phase (after dilution with 300 ml of water) was again extracted with 300 ml of ethyl acetate. After drying the combined organic phases over sodium sulphate, the solvent was removed in vacuo (40° C./25 mbar). 127.2 g of crude product were obtained in the form of a slightly yellowish solid, which was dissolved in 160 ml of n-hexane (slightly turbid solution). After hot filtration and subsequent cooling in an ice bath, 99.8 g of methyl 2-[1-amino-1-(4-fluorophenyl)-methylene]-4-methyl-3-oxopentanoate were obtained after filtration in the form of a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][CH2:16]1)[C:6]([O:8]C)=[O:7])#[N:2].C(C1C=C(C=C(OC(C)C)C=1)C(O)=O)#N>>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:16][CH2:17]1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(OCC2CC2)c(C#N)c1
Agent: CC(C)Oc1cc(C#N)cc(C(=O)O)c1
Product: N#Cc1cc(C(=O)O)ccc1OCC1CC1

Procedure:
Prepared from methyl 3-cyano-4-(cyclopropylmethoxy)benzoate according to the procedure for 3-cyano-5-isopropoxybenzoic acid. LCMS-ESI (m/z) calculated for C12H11NO3; 217.2; no ink observed, tR=2.92 min. 1H NMR (400 MHz, CDCl3) δ 8.24-8.08 (m, 2H), 7.32 (d, J=8.9 Hz, 1H), 4.09 (d, J=7.1 Hz, 2H), 1.28 (s, 1H), 0.71-0.52 (m, 2H), 0.49-0.31 (m, 2H).
Reaction SMILES: Cl.N[OH:3].[OH-].[Na+].C[N:7]([CH:9]=[N:10][C:11]([C:13]1[N:14]=[CH:15][C:16]2[NH:17][C:18]3[C:23]([C:24]=2[CH:25]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:12])C>O.C(O)(=O)C>[OH:3][NH:7][CH:9]=[N:10][C:11]([C:13]1[N:14]=[CH:15][C:16]2[NH:17][C:18]3[C:23]([C:24]=2[CH:25]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:12]
Reactant: CN(C)C=NC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(N=CNO)c1cc2c(cn1)[nH]c1ccccc12
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
A mixture of 0.35 g of hydroxylamine hydrochloride, 1.5 ml of water, 1.0 ml of 5 N sodium hydroxide, 3.5 ml of acetic acid and 1.1 g of N-[(dimethylamino)methylene]-beta-carboline-3-carboxamide is allowed to stand for 1/2 h at room temperature. After adding 3 ml of water, the white precipitate is filtered off and washed with water. 1.0 g of N-[(hydroxyamino)methylene]-beta-carboline-3-carboxamide with a m.p. of 235°-240° C. is obtained.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:9])[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH3:8].[C:10]1([C:16](Br)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][CH:3]([CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH3:8])[C:2]#[CH:1])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C#CC(O)C/C=C\CC
Product: C#CC(C/C=C\CC)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Treatment of 22 g. of cis-oct-5-en-1-yne-3-ol, prepared according to the procedure of J. Fried, C. W. Lin, J. C. Sih, P. Delvon, G. F. Cooper, J. Amer. Chem. Soc., 94, 4342 (1972), with 58 g. of triphenylmethyl bromide in 100 ml. of pyridine and purification on Florisil®, all as described in Example 728 gives the title compound.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][S+](C)C)=[O:6])[CH3:3].N12CCCN=C1CCCCC2.[C:22]1(=[O:27])[CH2:26][CH2:25][CH:24]=[CH:23]1.COC(C)(C)C>C(#N)C>[O:27]=[C:22]1[CH2:26][CH2:25][CH:24]2[CH:23]1[C@H:7]2[C:5]([O:4][CH2:2][CH3:3])=[O:6]
Reactant: O=C1C=CCC1
Reactant: CCOC(=O)C[S+](C)C
Agent: [Br-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COC(C)(C)C
Product: CCOC(=O)[C@H]1C2CCC(=O)C21
Reaction time: 1 h
Yield: 103.5 %

Procedure:
To a suspension of (ethoxycarbonylmethyl)dimethyl sulfonium bromide (134 g, 585 mmol) in 486 mL of acetonitrile at room temperature is added 87.4 mL (585 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene dropwise over 15 minutes. After stirring for 1 hour, the yellow mixture is treated with 40 g (487 mmol) of 2-cyclopenten-1-one over 10 minutes. The mixture is allowed to stir over night at which time 480 mL of tert-butyl methyl ether is added, followed by washing with 1N hydrochloric acid (1×240 mL). The aqueous layer was washed with tert-butyl methyl ether (1×240 mL). The combined organic extracts were washed with brine (1×400 mL), dried (MgSO4), filtered, and concentrated in vacuo to provide crude ethyl (6S)-2-oxobicyclo[3.1.0]hexane-6-carboxylate as an orange solid (84.8 g). The crude material may be purified through distillation (˜138° C., 10 mm Hg), followed by slurrying the solidified distillate in heptane, filtering, and drying.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[H-].[Na+].[CH3:11]Br>O1CCCC1>[CH3:11][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(O)cc1

Procedure:
Hydroquinone can be added to a solution of sodium hydride (NaH) dissolved in tetrahydrofuran (THF) and combined with methyl bromide yielding para-methoxyphenol. The para-methoxyphenol can be extracted and added to a solution of tosyl chloride (TsCl) dissolved in pyridine and tetrahydrofuran (THF) at room temperature, yielding para-methoxytosyloxybenzene. The para-methoxytosyloxybenzene can be extracted and added to a solution of diatomic iodine (I2) and potassium iodide trioxide (KIO3) dissolved in sulfuric acid (H2SO4) and acetic acid (CH3COOH) yielding 4-methoxy-3-iodo-1-tosyloxybenzene. The 4-methoxy-3-iodo-1-tosyloxybenzene can be extracted and added to a solution of aqueous sodium hydroxide (NaOH) and tert-butanol, removing the tosylate protecting group and yielding 4-methoxy-3-iodophenol. The 4-methoxy-3-iodophenol can be extracted and exposed to resin-bound triphenylphosphine (PPh3) in a solution of azopyridine and ethanol (CH3CH2OH) in a salt bath at 0° C., yielding 4-ethoxy-2-iodomethoxybenzene. The 4-ethoxy-2-iodomethoxybenzene can be extracted and added to a solution of titanium tetrachloride (TiCl4) and 1,1-dichlorodimethylether (CHCl2OCH3) dissolved in dichloromethane (CH2Cl2) in a salt bath at −10° C., yielding 2-ethoxy-4-iodo-5-methoxybenzaldehyde. The 2-ethoxy-4-iodo-5-methoxybenzaldehyde can be added to lithium aluminum hydride (LiAlH4) and methanesulfonyl chloride (CH3SO2Cl) dissolved in pyridine, and then sodium iodide (NaI) and triethyl phosphite (P(OCH2CH3)3) can be added to the reaction mixture, yielding diethyl 2-ethoxy-4-iodo-5-methoxybenzylphosphonate.