Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[C:5]([CH2:12][CH3:13])([CH3:11])[S:4]1)[OH:2].[CH3:14][N:15]=[C:16]=[O:17]>>[CH3:14][NH:15][C:16]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[C:5]([CH2:12][CH3:13])([CH3:11])[S:4]1)=[O:17]
Reactant: CN=C=O
Reactant: CCCC1=NC(=NO)SC1(C)CC
Product: CCCC1=NC(=NOC(=O)NC)SC1(C)CC

Procedure:
2-oxo-4-propyl-5-ethyl-5-methyl-3-thiazoline-oxime was reacted with methyl isocyanate as described in Example 4 to yield 2-oxo-4-propyl-5-ethyl-5-methyl-3-thiazoline-O-(methylcarbamoyl)-oxime, m.p. 124°-126° C. The 2-oxo-4-propyl-5-ethyl-5-methyl-3-thiazoline-oxime starting material melts at 132°-135° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:9][CH:10]=2)[O:5][C:4](=[O:20])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:31][C:32]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:33]=1[CH:34]=[O:35]>C1COCC1>[Cl:31][C:32]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:33]=1[CH:34]([OH:35])[CH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][S:13]([C:16]([F:18])([F:19])[F:17])(=[O:15])=[O:14])=[CH:9][CH:10]=2)[O:5][C:4](=[O:20])[CH:3]=1
Reactant: Cc1cc(=O)oc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1cc(CC(O)c2ccc(Cl)cc2Cl)c2ccc(OS(=O)(=O)C(F)(F)F)cc2o1
Reaction time: 1 h

Procedure:
To a solution of Trifluoro-methanesulfonic acid 4-methyl-2-oxo-2H-chromen-7-yl ester (340 mg, 1.1 mmol) in dry THF (8 mL0 at −20° C. was added drop wise 1.0 M LiHMDS solution in THF (1.2 mL). After 30 minutes 2,4-dichloro-benzaldehyde (130 μL) was added slowly into the reaction mixture and the reaction-mixture was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (50 mL). The organic layer was separated and dried over sodium sulfate, concentrated and purified on silica gel eluted with 30% ethyl acetate in hexanes to yield trifluoro-methanesulfonic acid 4-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-oxo-2H-chromen-7-yl ester as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[Br:12][C:13]1[C:14]([F:21])=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.C[O-].[Na+]>CO>[Br:12][C:13]1[C:14]([F:21])=[C:15](/[CH:16]=[C:8](/[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:11])\[C:9]#[N:10])[CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1cccc(Br)c1F
Reactant: N#CCc1ccc(Cl)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cccc(Br)c1F)c1ccc(Cl)cc1F
Yield: 79.1 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenylacetonitrile (1.39 g, 8.2 mmol) was reacted with 3-bromo-2-fluorobenzaldehyde (Apollo) (2 g, 9.9 mmol), methanolic solution (25 wt %) of sodium methoxide (2 g, 9 mmol) in methanol (40 mL) at 50° C. for 3 h to give (Z)-3-(3-bromo-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a white powder (2.3 g, 79%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([C:19]3[S:20][C:21]4[C:22](Cl)=[N:23][CH:24]=[CH:25][C:26]=4[N:27]=3)=[C:14]([Cl:29])[CH:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][C:31]1[N:36]=[CH:35][N:34]=[C:33]([NH2:37])[CH:32]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]([Cl:29])[C:15]([C:19]3[S:20][C:21]4[C:22]([NH:37][C:33]5[CH:32]=[C:31]([CH3:30])[N:36]=[CH:35][N:34]=5)=[N:23][CH:24]=[CH:25][C:26]=4[N:27]=3)=[C:16]([Cl:18])[CH:17]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(N)ncn1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(Cl)c(-c3nc4ccnc(Cl)c4s3)c(Cl)c2)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc3nc(-c4c(Cl)cc(C5CN(C(=O)OC(C)(C)C)C5)cc4Cl)sc23)ncn1
Temperature: 85 °C
Yield: 52.3 %

Procedure:
A mixture of 3-[3,5-dichloro-4-(4-chlorothiazolo[5,4-c]pyridin-2-yl)-phenyl]-azetidine-1-carboxylic acid tert-butyl ester (0.106 g, 0.225 mmol), 6-methylpyrimidin-4-ylamine (0.024 g, 0.248 mmol), XantPhos (0.013 g, 0.023 mmol), Pd2(dba)3 (0.010 g, 0.0113 mmol) and Cs2CO3 (0.147 g, 0.45 mmol) in dioxane (2 mL) was degassed with a stream of argon. The reaction mixture was heated at 85° C. for 18 hours. Additional Pd2(dba)3 (0.005 g), XantPhos (0.007 g) and 6-methylpyrimidin-4-ylamine (0.006 g) were added and the mixture was heated at 85° C. for 18 hours. After cooling to room temperature, the crude reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-90% EtOAc in petroleum ether to afford the title compound as a pale yellow glass (64 mg, 52% yield). 1H NMR (400 MHz, CDCl3): δ 8.71 (s, 1H), 8.45 (d, J=5.7 Hz, 1H), 8.15 (s, 1H), 7.76 (d, J=5.6 Hz, 1H), 7.51-7.41 (m, 3H), 4.39 (t, J=8.7 Hz, 2H), 4.02-3.92 (m, 2H), 3.80-3.70 (m, 1H), 2.56 (s, 3H), 1.48 (s, 9H).
Reaction SMILES: Cl.CO[C:4](=O)[C@@H:5]([CH2:11][OH:12])[NH:6][CH2:7][CH:8]([CH3:10])[CH3:9].O=S(Cl)Cl.[CH3:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[N:28]=[C:29]=[S:30]>>[CH2:7]([N:6]1[C:5](=[CH2:4])[C:11](=[O:12])[S:30][C:29]1=[N:28][C:20]1[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=1[CH3:18])[CH:8]([CH3:10])[CH3:9]
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: COC(=O)[C@@H](CO)NCC(C)C
Agent: Cl
Solvent: O=S(Cl)Cl
Product: C=C1C(=O)SC(=Nc2ccc([N+](=O)[O-])cc2C)N1CC(C)C
Yield: 10 %

Procedure:
(R)-N-Isobutylserine methyl ester HCl salt (Method B3a; 2.28 g, 10.8 mmol) was treated with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a. The resulting material was purified by column chromatography (SiO2, gradient from hexane to 10% EtOAc/hex) to give 3-isobutyl-4-methylene-2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidin-5-one (0.028 g, 10%) followed by (S)-3-isobutyl-4-carbomethoxy-2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine HCl salt (0.192 g, 56%). 3-Isobutyl-4-methylene-2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidin-5-one: TLC (25% EtOAc/hex) Rf 0.40. (S)-3-isobutyl-4-carbomethoxy-2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine HCl salt: TLC (free base, 25% EtOAc/hex) Rf0.50.
Reaction SMILES: [CH2:1]([O:4]C(N1CC=C(C2C(C3C=CN=C(F)C=3)=C(C3C=CC(F)=CC=3)NC=2)CC1)=O)[CH:2]=C.C(O[C:40]([N:42]1[CH2:49][C:48]([F:51])([F:50])[CH2:47][C@H:43]1[C:44](O)=O)=O)C1C=CC=CC=1.C(OC(N1C[C@H](OC)C[C@H]1C(O)=O)=O)C1C=CC=CC=1>>[F:51][C:48]1([F:50])[CH2:49][N:42]2[C@@H:43]([CH2:44][C:1](=[O:4])[CH2:2][CH2:40]2)[CH2:47]1
Reactant: O=C(O)[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1
Reactant: C=CCOC(=O)N1CC=C(c2c[nH]c(-c3ccc(F)cc3)c2-c2ccnc(F)c2)CC1
Agent: CO[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Product: O=C1CCN2CC(F)(F)C[C@@H]2C1

Procedure:
In a similar manner to the procedures described in Preparative Examples 1(i)′, (ii) and (iii) above, reactions were carried out successively, using (2S)-1-benzyloxycarbonyl-4,4-difluoroproline as a starting material instead of (2S,4R)-1-benzyloxycarbonyl-4-methoxyproline, to give the title compound as a pale yellow oil (total yield for the 3 steps: 14%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:19]([O:21]CC3C=CC=CC=3)=[O:20])[N:10]([CH3:18])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([C:7]2[N:8]=[C:9]([C:19]([OH:21])=[O:20])[N:10]([CH3:18])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cn1c(C(=O)OCc2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cn1c(C(=O)O)nc(-c2ccccc2)c1-c1ccccc1
Reaction time: 1 h

Procedure:
To a suspension of benzyl 4,5-diphenyl-1-methylimidazole-2-carboxylate (0.43 g, 1.2 mmol) from Example 1, Step C in methanol (10 mL) was added 20% palladium on carbon (50% w/w water, 110 mg) and the mixture was hydrogenated on a Parr shaker at 40 psi for 1 hr. The reaction was filtered and the filtrate was evaporated to dryness to afford the title compound as a white solid. (Note: The title compound readily decarboxylates as the acid.)
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[O:16][CH2:15][CH2:14][O:13]2)=[CH:8][C:7]=1[CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)[OH:25])=[O:4].CC(O)(C)C.[K].Cl>COCCOC>[Cl:32][C:28]1[CH:27]=[C:26]([CH:24]2[C:7]3[CH:8]=[C:9]([C:12]4([C:17]5[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=5)[O:16][CH2:15][CH2:14][O:13]4)[CH:10]=[CH:11][C:6]=3[NH:5][C:3](=[O:4])[CH2:2][O:25]2)[CH:31]=[CH:30][CH:29]=1
Reactant: O=C(CBr)Nc1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1C(O)c1cccc(Cl)c1
Agent: Cl
Agent: [K]
Solvent: CC(C)(C)O
Solvent: COCCOC
Product: O=C1COC(c2cccc(Cl)c2)c2cc(C3(c4ccc(Cl)cc4)OCCO3)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
A mixture of intermediate (10) (0.072 mol) in DME (300 ml) was cooled on an ice bath. 2-methyl-2-propanol, potassium salt (0.144 mol) was added portionwise. The mixture was stirred at a low temperature for 30 min, at room temperature for 30 min, hydrolyzed and acidified with HCl. The precipitate was filtered off, rinced and dried, yielding 17 g (51.8%) of 5-(3-chlorophenyl)-7-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-1,5-dihydro-4,1-benzoxazepin-2(3H)-one (intermediate 11), mp. 205° C.
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][C:3]([O-:5])=O.CN1CCOCC1.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[F:39][C:40]([F:49])([F:48])[C:41]1[CH:42]=[C:43]([NH2:47])[CH:44]=[CH:45][CH:46]=1>C1COCC1>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3]([NH:47][C:43]1[CH:44]=[CH:45][CH:46]=[C:41]([C:40]([F:39])([F:48])[F:49])[CH:42]=1)=[O:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C([O-])CC(=O)OCc1ccccc1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C(CC(=O)OCc1ccccc1)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
mono-Benzyl malonate (10 g) was dissolved in THF (100 ml), 4-methylmorpholine and cooled to −22° C. prior to the slow addition of diphenyl chlorophosphate (14 ml) and 3-trifluoromethyl-phenylamine (19 ml). After the reaction was warmed to rt overnight, it was heated to gently reflux for 0.5 h. After the reaction was cooled to rt, the solid was filtered off. The filtrate was concentrated. EtOAc was added along with 1N HCl solution. The organic layer was washed with NaHCO3 solution (aq) and brine, dried (MgSO4), filtered, and concentrated. Flash chromatography of the resulting residue gave N-(3-trifluoromethyl-phenyl)-malonamic acid benzyl ester (8.0 g): 1H NMR (CDCl3, δ ppm, 300 mHz) 3.56 (s, 2H),5.26 (s, 2H), 7.40 (m, 7H), 7.75 (d, 1H), 7.83 (s, 1H), 9.43 (s, br, 1H). (21b) A portion (6 g) of the above derivative (21a) was dissolved in MeOH (50 ml) prior to the addition of 10% Pd/C (4 g). A hydrogen balloon was added and the solution was stirred overnight. The palladium was filtered off and the solution was concentrated. Flash chromatography of the resulting residue gave N-(3-trifluoromethyl-phenyl)-malonamic acid (1.75 g). MS found: (2M−H)−=493.3. (21c) Derivative (21b)(65 mg) was incorporated into example (1e), to give the title compound (80 mg). MS found: (M+H)+=494.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][C:5]2[CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=[C:10]([CH:11]=[O:12])[C:4]=2[O:3]1.[BH4-].[Na+]>CO>[CH3:1][C:2]1([CH3:19])[CH2:6][C:5]2[CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=[C:10]([CH2:11][OH:12])[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cc(-c3ccccc3)cc(C=O)c2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)Cc2cc(-c3ccccc3)cc(CO)c2O1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To an ice cold solution of 2,2-dimethyl-5-phenyl-2,3-dihydrobenzofuran-7-carbaldehyde (545) (1 g, 3.96 mmol) in methanol (20 mL) was added portion wise sodium borohydride (179.9 mg, 4.76 mmol). The resulting mixture was stirred at 0° C. for 3 hours, quenched slowly with water. The product was extracted with dichloromethane. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (20% EtOAc in hexanes) to provide (2,2-dimethyl-5-phenyl-2,3-dihydrobenzofuran-7-yl)methanol (546).
Reaction SMILES: Cl[C:2]1N=C2C(N=CN2)=C(N2CCOCC2)[N:3]=1.BrCC(OC)=O.ClC1N=C2C(N=CN2CC(OC)=O)=C(N2CCOCC2)N=1.C(=O)([O-])OC1C=CC=C(B2OC(C)(C)C(C)(C)O2)C=1C(C)(C)C.[OH:67][C:68]1[CH:69]=[C:70]([C:74]2[N:82]=[C:81]3[C:77]([N:78]=[CH:79][N:80]3[CH2:83][C:84](O)=[O:85])=[C:76]([N:87]3[CH2:92][CH2:91][O:90][CH2:89][CH2:88]3)[N:75]=2)[CH:71]=[CH:72][CH:73]=1.CN>>[OH:67][C:68]1[CH:69]=[C:70]([C:74]2[N:82]=[C:81]3[C:77]([N:78]=[CH:79][N:80]3[CH2:83][C:84]([NH:3][CH3:2])=[O:85])=[C:76]([N:87]3[CH2:92][CH2:91][O:90][CH2:89][CH2:88]3)[N:75]=2)[CH:71]=[CH:72][CH:73]=1
Reactant: O=C(O)Cn1cnc2c(N3CCOCC3)nc(-c3cccc(O)c3)nc21
Reactant: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Agent: CC(C)(C)c1c(OC(=O)[O-])cccc1B1OC(C)(C)C(C)(C)O1
Agent: CN
Agent: COC(=O)CBr
Product: CNC(=O)Cn1cnc2c(N3CCOCC3)nc(-c3cccc(O)c3)nc21
Yield: 10.8 %

Procedure:
4-(2-Chloro-9H-purin-6-yl)morpholine (75 mg) was reacted with methyl 2-bromoacetate via General Procedure C. Methyl 2-(2-chloro-6-morpholino-9H-purin-9-yl)acetate was reacted with 150 mg tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl carbonate via General Procedure A. Crude 2-(2-(3-hydroxyphenyl)-6-morpholino-9H-purin-9-yl)acetic acid (50 mg) was reacted with methylamine via General Procedure F and purified via reverse phase HPLC to give 5.6 mg of 140 as a white solid. MS (Q1) 369.2 (M)+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:6]=2[CH:33]=1.[C:34](OC)(=[O:40])[CH2:35][C:36](OC)=[O:37]>>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([S:20]([N:7]2[C:6]3[CH:33]=[C:2]([CH:35]([CH2:34][OH:40])[CH2:36][OH:37])[CH:3]=[CH:4][C:5]=3[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[CH2:8]2)(=[O:22])=[O:21])=[CH:28][CH:27]=1)([CH3:30])([CH3:31])[CH3:32]
Reactant: COC(=O)CC(=O)OC
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(Br)cc32)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(CO)CO)cc32)cc1

Procedure:
Intermediate 53 was reacted with dimethyl malonate following the procedure as described in Hartwig, John F. (JOC 2002, 67, 541-555) to afford the desired product.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:19]=[C:18]([NH:20][CH2:21][CH3:22])[C:17]([N+:23]([O-])=O)=[CH:16][N:15]=2)=[CH:9][CH:8]=1)[CH3:2]>[Pd]>[NH2:23][C:17]1[C:18]([NH:20][CH2:21][CH3:22])=[N:19][C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:26][CH3:27])[CH2:1][CH3:2])=[CH:12][CH:11]=2)=[N:15][CH:16]=1
Reactant: CCNc1nc(Nc2ccc(OCCN(CC)CC)cc2)ncc1[N+](=O)[O-]
Agent: [Pd]
Product: CCNc1nc(Nc2ccc(OCCN(CC)CC)cc2)ncc1N

Procedure:
Hydrogenation of 2-[[4-[2-(diethylamino)ethoxy]phenyl]amino]-4-(ethylamino)-5-nitropyrimidine (from Example 2(7) above) over Pd/C gave the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH:4]=O.[C:7]([NH:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:9])[CH3:8]>>[C:7]([N:10]1[CH2:4][CH2:3][C:2]([CH3:6])([CH3:1])[C:11]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:9])[CH3:8]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CC(C)=CC=O
Product: CCOC(=O)C1(C(=O)OCC)N(C(C)=O)CCC1(C)C
Yield: 41.5 %

Procedure:
N-Acetyl-2-ethoxycarbonyl-3,3-dimethylproline, ethyl ester (6.4 g, 38%) was prepared from 3-methyl-2-butenal (Aldrich, 5.0 g, 59 mmol) and diethyl acetamidomalonate (Aldrich, 12 g, 54 mmol) by the procedure described by Chung et al (J. Org. Chem. 1990, 55, 270).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][C:15](=[O:34])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([C:24]23[CH2:33][CH:28]4[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]4)[CH2:25]2)[CH2:31]3)[CH:17]=1)[C:5]([O:7]CC=C)=[O:6].N1CCOCC1>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][C:15](=[O:34])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([C:24]23[CH2:31][CH:30]4[CH2:29][CH:28]([CH2:27][CH:26]([CH2:32]4)[CH2:25]2)[CH2:33]3)[CH:17]=1)[C:5]([OH:7])=[O:6]
Reactant: C=CCOC(=O)c1ccc(OC(=O)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)c(C)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Oc2ccc(C(=O)O)cc2C)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
2.35 g (5 mmoles) of the ester prepared in step 15 (b) above are dissolved in 50 ml of THF. Under a stream of nitrogen, 78.3 mg of tetrakis(triphenylphosphine) palladium (O) are added and then 4.4 ml (50 mmoles) of morpholine are slowly introduced. The reaction mixture is then stirred at ambient temperature for 2 hours and evaporated to dryness. The residue is ground in ethyl ether and the solid is filtered. The solid is then introduced into 10 ml of water, acidified to pH 1, extracted with a 3/1 mixture of ethyl ether and THF. The organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated. The residue is ground in 50 ml of ethyl ether, filtered and dried. 1.6 g (70% yield) 277° C. are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=S)[C@@H:10]2[F:23])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(O)C.[Ni]>[CH2:1]([O:3][C:4]([C:6]1([C@@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH3:15])[CH2:11][C@H:10]2[F:23])[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=S)[C@@H]2F)CC1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C1([C@@H]2CN([C@@H](C)c3ccccc3)C[C@H]2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
4-(S)-(1-Ethoxycarbonylcyclopropyl)-3-(R)-fluoro-1-[1-(S)-phenylethyl]-2-pyrrolidinethione (4.401 g, 13.12 mmol) was dissolved in anhydrous ethanol (150 ml), and the solution was mixed with Raney nickel (13 ml) and stirred at room temperature for 1 hour. After removing the catalyst by celite filtration (ethanol washing), the resulting filtrate was concentrated under reduced pressure. The thus obtained residue was dissolved in diethyl ether (250 ml), washed with 10% ammonia water (100 ml×5) and saturated brine (100 ml) in that order and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was subjected to flash silica gel chromatography and eluted with an eluant of n-hexane:ethyl acetate=4:1, to thereby obtain 3.794 g (94.7%) of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][C:22]1[N:23]=[C:24]([NH2:37])[S:25][C:26]=1[S:27]([N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1)(=[O:29])=[O:28]>>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([NH:37][C:24]2[S:25][C:26]([S:27]([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)(=[O:29])=[O:28])=[C:22]([CH3:21])[N:23]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Cc1nc(N)sc1S(=O)(=O)N1CCN(C)CC1
Product: Cc1nc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)sc1S(=O)(=O)N1CCN(C)CC1

Procedure:
3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[4-methyl-5-(4-methylpiperazine-1-sulfonyl)-thiazol-2-yl]-propionamide was prepared from 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid and 4-methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-ylamine as described in Example 1. 1H-NMR (CDCl3): δ 13.03 (broad s, 1H), 7.91 (d, 2H), 7.64 (d, 2H), 4.05 (t, 1H), 3.20 (s, 3H), 2.99 (m, 4H), 2.47 (s, 3H), 2.39 (m, 4H), 2.16 (m, 4H), 1.84-1.77 (m, 1H), 1.75-1.39 (m, 7H), 1.19-1.07 (m, 2H); HPLC-MS: m/z=555 (M+1); Rt=3.08 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:18])[CH2:16]Cl)=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CC(O)=O.O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:16][O:18]2)=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(C(O)CCl)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc([C@@H]2CO2)ccc1OCc1ccccc1
Reaction time: 1 h

Procedure:
151.8 g (0.49 mol) of 1-(4-benzyloxy-3-nitrophenyl)-2-chloroethanol was dissolved in THF (0.75 L) and treated dropwise with NaOH (4 mol/L, 182 mL, 0.73 mol). After 1 hour, AcOH (30 mL) was added followed by water (2.5 L). The mixture was cooled and the precipitated product was recovered by filtration and dried under vacuum at 65° C. Yield: 133.0 g (99.3%); mass spectroscopy: [M+H]+=272; m.p.=66° C.; e.e. 99.5%.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([CH3:14])[CH:7]=[CH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>C(OCC)C>[CH3:14][C:6]([CH:7]=[CH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:5][CH2:4][OH:3]
Reactant: CCOC(=O)C=C(C)C=CCC(C)(C)C
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: CC(C=CCC(C)(C)C)=CCO

Procedure:
A solution of 4.2 g. of 3,7,7-trimethyl-2,4-octadienoic acid ethyl ester in 90 ml. of absolute diethyl ether is mixed slowly at -20° C. with stirring and under a nitrogen atmosphere with a suspension of 0.75 g. of lithium aluminum hydride in 45 ml. of absolute diethyl ether. The mixture is allowed to attain room temperature in the course of 2 hours and subsequently decomposed in the cold by the dropwise addition of 60 ml. of 10% by weight aqueous ammonium chloride solution. The resulting mass is vacuum filtered over diatomaceous earth and ethereal phase in the filtrate separated. The aqueous phase is extracted with diethyl ether and the combined ether solutions are washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. There is obtained 3,7,7-trimethyl-2,4-octadien-1-ol which is purified by distillation. Boiling point (bulb-tube distillation) 60° C./0.03 mmHg; nD20 = 1.4790.
Reaction SMILES: [N:1]([C:4]1[C:13]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:5]=1[F:30])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][C:4]1[C:13]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:5]=1[F:30]
Reactant: COC(=O)c1cc(SCc2ccccc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(SCc2ccccc2)c(N)c(F)c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of methyl 4-azido-5-(benzylthio)-3-fluoro-2-((2-chlorophenyl)amino)benzoate (9.84 g, 22.23 mmol) in MeOH (200 mL) was added and 10% palladium on carbon (1.55 g) under nitrogen atmosphere. Then the nitrogen atmosphere was completely changed to hydrogen atmosphere. The mixture was stirred for 2 h at ambient temperature. After the insoluble matter was filtered off, the solvent was evaporated in vacuo to give the desired product (9.26 g, 100%). 1H NMR (400 MHz, DMSO-d6): δ 8.94 (s, 1H), 7.54 (s, 1H), 7.45 (m, 1H), 7.24 (m, 6H), 6.95 (m, 1H), 6.77 (m, 1H), 6.27 (s, 2H), 3.95 (s, 2H), 3.73 (s, 3H).