Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+:22]>[Pd]>[Na+:22].[F:12][C:9]1[CH:10]=[CH:11][C:6]([C@H:2]([NH:1][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([O-:5])=[O:4])=[CH:7][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@H](C(=O)O)c1ccc(F)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])[C@@H](NCc1ccccc1)c1ccc(F)cc1
Temperature: 15 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
A solution of (S)-α-amino-4-fluorobenzeneacetic acid (1.00 kg, 5.91 moles) in aqueous sodium hydroxide (1 M, 5.91 L) was filtered and added to 10% palladium-on-carbon (25 g). A solution of benzaldehyde (941 g, 8.87 moles) was added and the batch was stirred under hydrogen (50 psi) for 4 hours. The batch was filtered and the filtrate was evaporated to residue under vacuum, then flushed with ethanol (2×3 L). The residue was slurried in boiling ethanol (1.5 L), then cooled to 15° C. The slurry was filtered and the filter cake was washed with cold ethanol (2×500 mL), then dried under vacuum at 55° C. to give 1.83 kg (92% yield) of (S)-4-fluoro-α-[(phenylmethyl)amino]-benzeneacetate sodium salt.
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8]O)[O:4][C@H:3]1[N:10]1[CH:17]=[C:16]([CH2:18][CH3:19])[C:14](=[O:15])[NH:13][C:11]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:39]=[N+:40]=[N-:41].[Na+].CNC=O.C(Br)(Br)(Br)Br>CO>[N:39]([CH2:8][C@H:5]1[O:4][C@@H:3]([N:10]2[CH:17]=[C:16]([CH2:18][CH3:19])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[C@@H:2]([F:1])[C@@H:6]1[OH:7])=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CNC=O
Solvent: CO
Product: CCc1cn([C@@H]2O[C@H](CN=[N+]=[N-])[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.6 %

Procedure:
A mixture of 0.4 g of 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil, 0.44 g of triphenylphosphine, 0.48 g of sodium azide and 6 ml of dry methylformamide was stirred at room temperature under nitrogen while 0.48 g of carbon tetrabromide was added portionwise. The mixture was stirred at room temperature under nitrogen for 20 hours. 3 ml of methanol were added, the mixture was stirred for 0.5 hour and then evaporated. The residue was stirred for 0.5 hour with 8 ml of 0.5M sodium hydroxide solution. The resulting suspension was filtered and the insoluble triphenylphosphine oxide was washed with water. The filtrate was acidified to pH 5 by the addition of hydrochloric acid and then extracted three times with 20 ml of ethyl acetate. The extracts were dried over magnesium sulfate, filtered and evaporated. The residual solid was washed on to a filter. with 10 ml of diethyl ether/petroleum ether (1:1) and then dried in vacuo to give 0.4 g of 1 -(5-azido-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil as a white solid of melting point 185°-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([I:20])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N+:8]([O-])=[CH:9]2)=[CH:4][N:3]=1.P(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([I:20])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:8]=[CH:9]2)=[CH:4][N:3]=1
Reactant: [O-][n+]1cc2cc(Cl)ncc2c(I)c1-c1ccccc1Cl
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: Clc1cc2cnc(-c3ccccc3Cl)c(I)c2cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
To a solution of 7-chloro-3-(2-chlorophenyl)-4-iodo-2,6-naphthyridine 2-oxide (870 mg, 2.1 mmol) in dichloromethane (13 mL) was added phosphorus trichloride (0.2 mL, 2.3 mmol). The reaction mixture was stirred at room temperature for 1 hour, and then diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford an orange residue that was purified by flash chromatography (silica, 40 g, ISCO, 0-30% ethyl acetate in heptane) to afford the title compound as an orange solid (400 mg, 50%). 1H NMR (400 MHz, CDCl3) δ 9.40 (s, 1H), 9.21 (s, 1H), 7.83 (s, 1H), 7.57-7.53 (m, 1H), 7.49-7.40 (m, 2H), 7.40-7.35 (m, 1H).
Reaction SMILES: Cl.Cl[C:3]1[N:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]2=[O:17])=[C:13]([F:18])[CH:12]=[CH:11][CH:10]=3)[C:6]2[CH:19]=[CH:20][N:21](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]=2[N:4]=1.[OH-].[NH4+:33].[CH3:34][O:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][C:44]=1[NH2:45])[N:41]([C:46](=[O:53])[CH2:47][N:48]([CH3:52])[CH2:49][CH2:50][CH3:51])[CH2:40][CH2:39]2>>[F:18][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:8][C:7]2[N:16]=[C:3]([NH:45][C:44]3[CH:43]=[C:42]4[C:38]([CH2:39][CH2:40][N:41]4[C:46](=[O:53])[CH2:47][N:48]([CH3:52])[CH2:49][CH2:50][CH3:51])=[CH:37][C:36]=3[O:35][CH3:34])[NH:4][C:5]3=[N:21][CH:20]=[CH:19][C:6]=23)[C:14]=1[C:15]([NH2:33])=[O:17]
Reactant: CCCN(C)CC(=O)N1CCc2cc(OC)c(N)cc21
Reactant: [NH4+]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2nc(Cl)n2c(=O)c4c(F)cccc4nc32)cc1
Agent: Cl
Agent: [OH-]
Product: CCCN(C)CC(=O)N1CCc2cc(OC)c(Nc3nc(Nc4cccc(F)c4C(N)=O)c4ccnc-4[nH]3)cc21

Procedure:
In a manner analogous to that described for Example 165, 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride (0.40 g, 0.90 mmol), 27% aqueous ammonium hydroxide, and 5-(methyloxy)-1-{[methyl(propyl)amino]acetyl}-2,3-dihydro-1H-indol-6-amine (0.30 g, 1.1 mmol) and isolated as a yellow solid (0.13 g); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.81 (t, J=7.33 Hz, 3 H), 1.41 (q, J=7.14 Hz, 2H),2.20 (s, 3 H), 2.34 (t, J=7.05 Hz, 2H),3.09 (t, J=8.06 Hz, 2 H), 3.21 (s, 2H), 3.74 (s, 3 H), 4.18 (t, J=8.24 Hz, 2 H), 6.20 (s,1 H), 6.86 (t, J=9.61 Hz, 1H), 6.93 (s, 2H),7.30 (m, 1 H), 7.58 (s, 1H), 8.00 (s,1H), 8.09 (s,1H),8.51 (d, J=8.42 Hz, 1H), 8.59 (s, 1 H), 10.53 (s, 1 H), 11.28 (s, 1 H); ESIMS (M+H)+=547.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.CN(C(ON1N=[N:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:37][N:38]([CH:40]=[O:41])C>>[CH3:22][C:27]1[C:26]([O:41][C:40]2[N:38]=[CH:37][C:2]([NH:1][C:10]([C:2]3[NH:1][C:9]4[C:4]([CH:3]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)=[O:12])=[CH:3][CH:4]=2)=[CH:25][CH:24]=[CH:23][N:28]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1ncccc1Oc1ccc(NC(=O)c2cc3ccccc3[nH]2)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
The bispyridine ester amine compound (120 mg, 0.62 mmol) in Example 1 and 1H-indole-2-carboxylic acid (100 ml, 0.62 mmol) were dissolved in DMF (5 ml), HBTU (240 mg, 0.62 mmol) was added to the solution, and the mixture was stirred at 80° C. for 8 hours. After the reaction was completed, the product was washed and filtered to yield a target compound as a brown solid (30 mg, 14%) by chromatography (methanol:dichloromethane=1:30).
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([F:14])=[CH:6][C:5]=1[CH2:15]Br.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[F:14][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([C:10]([F:11])([F:12])[F:13])[CH:8]=1)[C:3](=[O:17])[N:24]([CH2:23][C:22]1[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=1)[CH2:15]2
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=O)c1c(CBr)cc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2c(cc(F)cc2C(F)(F)F)CN1Cc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
A mixture of 4-fluoro-2-bromomethyl-6-trifluoromethyl-benzoic acid methyl ester (0.100 g, 0.32 mmol), 4-chloro-benzylamine (0.051 mL, 0.42 mmol), and K2CO3 (0.088 g, 0.64 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-fluoro-2-(4-chloro-benzyl)-7-trifluoromethyl-2,3-dihydro-isoindol-1-one (0.048 g, 44%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.28 (s, 2H), 4.75 (s, 2H) 7.24-7.51 (m, 6H). GC-MS: m/z 343 (M)+, 322 (M−21)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[F:26][C:27]([F:32])([F:31])[C:28]([O-:30])=[O:29]>>[OH:30][C:28]([C:27]([F:32])([F:31])[F:26])=[O:29].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ncc(-c3ccc(F)cc3)o2)C1
Reactant: O=C([O-])C(F)(F)F
Product: Fc1ccc(-c2cnc(C3CCCNC3)o2)cc1
Product: O=C(O)C(F)(F)F

Procedure:
This compound was synthesized from tert-butyl 3-(5-(4-fluorophenyl)oxazol-2-yl)piperidine-1-carboxylate as described for example 46 step 4 (150 mg, crude) as a trifluoroacetate salt and it was carried through without further purification. MS (ESI) m/z: Calculated for C14H16FN2O: 246.12. found: 247.0 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:5]2[N:6]=[C:7]([NH:16][NH2:17])[CH:8]=[C:9]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:4]2[N:3]=1.C(O)(=O)C.[CH:23]1[CH:28]=[C:27]2[C:29]([CH:32]=O)=[CH:30][NH:31][C:26]2=[CH:25][CH:24]=1>C(O)C>[NH:31]1[C:26]2[C:27](=[CH:28][CH:23]=[CH:24][CH:25]=2)[C:29]([CH:32]=[N:17][NH:16][C:7]2[CH:8]=[C:9]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[N:4]3[N:3]=[C:2]([CH3:1])[CH:18]=[C:5]3[N:6]=2)=[CH:30]1
Reactant: Cc1cc2nc(NN)cc(N3CCOCC3)n2n1
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc2nc(NN=Cc3c[nH]c4ccccc34)cc(N3CCOCC3)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
There was dissolved, in ethanol (2 mL), (2-methyl-7-morpholin-4-yl-pyrazolo-[1,5-a]pyrimidin-5-yl)-hydrazine (24.5 mg, 0.0988 mM) and then acetic acid (5.0 μL, 0.087 mM) and indole-3-carboxyaldehyde (15.8 mg, 0.109 mM) were added to the solution and the mixture was stirred at room temperature for 2 hours. This reaction liquid was filtered and then the resulting solid was washed with methanol to thus give the title compound (26.4 mg, yield: 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[C:4]=1[CH:15]([OH:21])[C:16](=[NH:20])[O:17]CC.[O:22]1CCC[CH2:23]1>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[C:4]=1[CH:15]1[O:21][C:23](=[O:22])[NH:17][C:16]1=[O:20]
Reactant: CCOC(=N)C(O)c1c(OC)ccc2cc(OC)ccc12
Reactant: C1CCOC1
Product: COc1ccc2c(C3OC(=O)NC3=O)c(OC)ccc2c1

Procedure:
By the procedure of Example 12, Method A, ethyl 1-(2,6-dimethoxy-1-naphthyl)-1-hydroxymethanecarboximidate (3.0 g.) in 125 ml. of tetrahydrofuran converted to the desired product. To isolate, the reaction mixture was quenched by pouring slowly into 200 ml. of crushed ice and extracted with two 100 ml. portions of ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered, evaporated to semi-solids (2.6 g.) and crystallized by trituration with ether, affording 5-(2,6-dimethoxy-1-naphthyl)oxazolidine-2,4-dione (0.43 g.; m.p. 175°-180° C.; m/e 287).
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([NH:20]C(=O)OC(C)(C)C)([CH3:19])[CH3:18])[CH:13]=[CH:14][CH:15]=1.C1(C)C=CC=CC=1>C(Cl)Cl>[NH2:20][C:17]([CH3:19])([CH3:18])[CH2:16][C:12]1[CH:11]=[C:10]([CH2:9][OH:8])[CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(Cc1cccc(CO)c1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)Cc1cccc(CO)c1
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl 1-(3-(hydroxymethyl)phenyl)-2-methylpropan-2-ylcarbamate (Example 275, step b) (0.7 g) in DCM (20 mL) and the resultant solution allowed to stand at 20° C. for 30 minutes. Toluene (40 mL) was added and the solvents evaporated under reduced pressure. The residue was partitioned between DCM and 1M aqueous sodium hydroxide, and the aqueous layer was extracted with DCM (×2). The combined organics were dried over sodium sulphate, filtered and the solvent removed under reduced pressure to afford the subtitled compound. Yield 0.440 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][NH:5]2.C(N(C(C)C)CC)(C)C.[CH2:22]1COCC1.Cl[C:28]([O:30][CH3:31])=[O:29]>O>[CH3:22][N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2)[N:5]([C:28]([O:30][CH3:31])=[O:29])[CH2:6][C:7]1=[O:12]
Reactant: C1CCOC1
Reactant: O=C1CNc2cc(F)ccc2N1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)N1CC(=O)N(C)c2ccc(F)cc21
Reaction time: 0.58 h

Procedure:
To a mixture of 1.97 g of 6-fluoro-1,2,3,4-tetrahydroquinoxalin-2-one (EXAMPLE 6), 3.1 ml of diisopropylethylamine, and 11 ml of THF is added 1.4 ml of methyl chloroformate. The reaction is cooled with cool tap water as an exotherm ensued. After 35 min, the mixture is partitioned between ethyl acetate, aq. sodium bicarbonate, and saline. The organic layers are dried over magnesium sulfate, concentrated, and the crude product is crystallized from dichloromethane/methanol/ethyl acetate to give 2.06 g of methyl 6-fluoro-1,2,3,4-tetrahydro-4-(methoxycarbonyl)quinoxaline-2-one; mp 206.5°-207.5°; NMR (CDCl3) 3.86, 4.43, 6.84, 7.48, 8.67 δ.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O-:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([O-:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1.[CH3:21][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: O=S(=O)([O-])c1ccc(Cl)cc1
Product: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 157.7 %

Procedure:
A mixture of 11.0 g (41.9 mmol) of triphenylphosphine and 9.16 g (44.4 mmol) of 4-chlorobenzenesulfonate was allowed to react for 2 hr at 140° C. A total of 16.4 g (35.0 mmol, 83.5%) of the title product was obtained. It was further purified by recrystallization from 95:5 toluene-acetonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:12])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:17]([O:19][CH3:20])=[O:18].[CH2:25](OC(OCC)OCC)C.C(O)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:12]=[CH:25][N:13]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:17]([O:19][CH3:20])=[O:18])[C:7]2=[O:8]
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: COC(=O)c1ccc(C)c(N)c1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C)c(-n2cnc3ccc(Br)cc3c2=O)c1
Temperature: 25 °C

Procedure:
To a stirred solution of methyl 5-bromo-2-aminobenzoate (10.0 g) and methyl 3-amino-4-methylbenzoate (7.90 g) in toluene (100 ml) at 50° C. were added triethylorthoformate (8.12 ml) and glacial acetic acid (2.50 ml). The mixture was heated to reflux for 16 hours. The alcohol by-products were distilled using Dean-stark conditions and the reaction cooled room temperature. The resultant solid was collected by filtration, washed with toluene (2×20 ml) and dried in vacuo at 40° C. to give the methyl 3-(6-bromo-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoate as a white solid (13.1 g); NMR Spectrum: (DMSOd6) 2.16 (s, 3H), 3.85 (s, 3H), 7.60 (d, 1H), 7.71 (d, 1H), 8.01 (m, 3H), 8.26 (s, 1H), 8.34 (s, 1H); Mass Spectrum: M+H+ 373.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[C:16]([S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:17]=1.CN(C)C=O>C(OCC)(=O)C>[C:22]([NH:21][S:18]([C:16]1[CH:17]=[C:12]([NH:11][CH:1]=[O:2])[CH:13]=[CH:14][C:15]=1[C:26]([N:28]([CH3:30])[CH3:29])=[O:27])(=[O:19])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=CO
Reactant: CN(C)C(=O)c1ccc(N)cc1S(=O)(=O)NC(C)(C)C
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(NC=O)cc1S(=O)(=O)NC(C)(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 0.34 ml of formic acid and 0.70 ml of acetic anhydride is heated at 50° C. for 2 hours, and a solution of 0.85 g of 5-amino-N-tert.-butyl-2-dimethylaminocarbonyl-benzenesulfonamide (Example e) and 3.5 ml of dimethylformamide (DMF) is added. After 4 hours, the mixture is taken up in ethyl acetate and washed successively with dilute hydrochloric acid and saturated NaHCO3 solution. After the mixture has been dried over MgSO4 and the organic phase has been concentrated, 0.88 g of a highly viscous substance, which is used in subsequent reactions without further purification (Example j), is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[NH:16])OCC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][NH2:20]>>[NH2:17][CH2:18][CH2:19][NH:20][C:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[NH:16]
Reactant: NCCN
Reactant: CCOC(=N)NC(=O)OCc1ccccc1
Product: N=C(NCCN)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-benzyloxycarbonyl-O-methyl-isourea (II-OMe) (0.42 g, 2.0 mmol) and 1,2-diaminoethane (Ic) (0.72 g, 12 mmol) was stirred at 40° C. for 3 h and at 25° C. for 1 h. The crystals were collected by filtration. The white crystalline product was washed with toluene (4×1 mL) and dried (vacuum, 30°-35° C., 2 h). The yield of N-(2-aminoethyl)-N'-benzyloxycarbonyl guanidine IlIc was 0.28 g (60% in theory).
Reaction SMILES: C(O[B:5]1[O:9][C:8]([CH3:11])([CH3:10])[C:7]([CH3:13])([CH3:12])[O:6]1)(C)C.C([Li])CCC.[F:19][C:20]1[CH:21]=[C:22]([C:27]2([OH:31])[CH2:30][CH2:29][CH2:28]2)[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([C:27]2([OH:31])[CH2:30][CH2:29][CH2:28]2)[CH:23]=[C:24]([F:26])[C:25]=1[B:5]1[O:6][C:7]([CH3:12])([CH3:13])[C:8]([CH3:10])([CH3:11])[O:9]1
Reactant: OC1(c2cc(F)cc(F)c2)CCC1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Product: CC1(C)OB(c2c(F)cc(C3(O)CCC3)cc2F)OC1(C)C
Yield: 100 %

Procedure:
Method 3 was followed using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.5 equiv.), butyllithium (2.4 equiv.) and 1-(3,5-difluorophenyl)cyclobutanol (1.0 equiv.) to give 1-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutanol in 100% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.23-1.25 (m, 12H), 1.69-1.82 (m, 1H), 2.05-2.12 (m, 1H), 2.37 (br. s., 2H), 2.47 (br. s., 2H), 7.00 (d, J=8.80 Hz, 2H).
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH3:10])[CH2:6][CH:5]1[N:11]1[CH2:15][CH:14]([C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])[CH2:13][C:12]1=[O:23])([CH3:3])[CH3:2].[CH:24](C1CCC(C)CC1N1C(=O)CC(C(O)=O)C1)(C)[CH3:25]>>[N:18]1([C:16]([CH:14]2[CH2:15][N:11]([CH:5]3[CH2:6][CH:7]([CH3:10])[CH2:8][CH2:9][CH:4]3[CH:1]([CH3:2])[CH3:3])[C:12](=[O:23])[CH2:13]2)=[O:17])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:25][CH2:24]1
Reactant: CC1CCC(C(C)C)C(N2CC(C(=O)O)CC2=O)C1
Reactant: CC1CCC(C(C)C)C(N2CC(C(=O)N3CCCC3)CC2=O)C1
Product: CC1CCC(C(C)C)C(N2CC(C(=O)N3CCCCCC3)CC2=O)C1

Procedure:
1-(2-Isopropyl-5-methyl-cyclohexyl)-4-(pyrrolidine-1-carbonyl)-pyrrolidin-2-one was similarly prepared as described in Examples I, II, and III. 1-(2-Isopropyl-5-methyl-cyclohexyl)-5-oxo-pyrrolidine-3-carboxylic acid (obtained as in EXAMPLE II, 5 g, 18.7 mmol) was used to provide 4-(azepane-1-carbonyl)-1-(2-isopropyl-5-methyl-cyclohexyl)-pyrrolidin-2-one (5.2 g, 15 mmol).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[I-].[Na+].[CH3:13][NH2:14]>CO>[CH3:13][NH:14][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: ClCCN1CCCCC1
Reactant: CN
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CNCCN1CCCCC1
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution of 8.0 g of N-(2-chloroethyl)piperidine hydrochloride and 0.5 g of sodium iodide in 60 ml of methanol which contained 40% of methylamine was reacted at 70° C. in a sealed tube for 20 hours. After allowing the reaction mixture to cool down, the reaction mixture was concentrated under reduced pressure. The residue was added with ether, followed by a further addition of 10 g of ground sodium hydroxide. The resulting mixture was stirred for 2 hours. The insoluble material was filtered off and the filtrate was concentrated under the atmospheric pressure. The residue was distilled under reduced pressure to give 4.5 g of a fraction at 80° C./18 Torr (yield: 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH3:10][O:11][CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH3:18])=[O:16].C(O)(=O)C.S([O-])([O-])(=O)=O.[Ca+2]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:13]([CH2:12][O:11][CH3:10])=[CH:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COc1ccccc1N
Reactant: COCC(=O)CC(=O)OC
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Solvent: CC(=O)O
Product: COCC(=CC(=O)OC)Nc1ccccc1OC
Yield: 73.5 %

Procedure:
A mixture of 100 g of o-anisidine, 190 g of methyl γ-methoxyacetoacetate, 2.3 ml of acetic acid, 203 g of calcium sulfate and 800 ml of absolute ethanol was refluxed for 16 hours. The residue after filtration and concentration of the filtrate under reduced pressure was taken up in ethyl acetate, the solution was extracted several times with 2 N NaOH and 5% strength citric acid solution and dried over Na2SO4, and the solvent was removed in a rotary evaporator. 150 g of crude product were obtained and were employed without further purification in the following stage.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][CH2:14][C:15]([NH2:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CN1CCCC1=O>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][CH2:14][C:15]([CH3:17])([NH2:18])[CH3:16])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: CC(C)(N)CN
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)(N)CNc1ccnc2cc(Cl)ccc12
Yield: 50.7 %

Procedure:
198 g of 4,7-dichloroquinoline, 97 g of 1,2-diamino-2-methyl-propane and 101 g of triethylamine were stirred in 1 l of N-methyl-2-pyrrolidone at 150° C. under argon for 5 hours. The solvent was evaporated in a vacuum and the residue was taken up in 1 l of water. The pH was adjusted to 1 using 220 ml of 25% hydrochloric acid and the mixture was diluted with 6 l of water and extracted four times with 0.5 l of ethyl acetate each time. The clear aqueous solution was treated with about 900 g of KOH, whereby the pH rose to 14 and the product separated in crystalline form. This was filtered off under suction, rinsed with about 3 l of water and, for further purification, recrystallized from 4 l of acetonitrile. There were obtained 126.7 g (73%) of N1 -(7-chloro-quinolin-4-yl)-2-methyl-propane-1,2-diamine, m.p. 182-184° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([CH3:32])([CH3:31])[C:14]([NH:16][C:17]2[CH:18]=[N:19][C:20]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:21][C:22]=2[I:23])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:35][Si]([N-][Si](C)(C)C)(C)C.[K+].IC>CN(C)C=O.O1CCCC1>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]([CH3:32])([CH3:31])[C:14]([N:16]([C:17]2[CH:18]=[N:19][C:20]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:21][C:22]=2[I:23])[CH3:35])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:8]=1
Reactant: CN1CCN(c2cc(I)c(NC(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCN(c2cc(I)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)CC1
Reaction time: 48 h
Yield: 31 %

Procedure:
To a solution of 3.09 g (5.15 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-iodo-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-isobutyramide in 30 ml N,N-dimethylformamide were added at 0° C. 6.8 ml (6.2 mmol) of a 0.91 M solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran. After stirring at 0° C. for 40 min 0.352 ml (5.66 mmol) iodomethane were added. The mixture was stirred for 2 days in a closed flask. The reaction mixture was concentrated in vacuo and purified by flash chromatography to give 980 mg (31%) of the title compound as a brown oil.