Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:48])([CH3:47])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:46])([C@@:13]3([CH3:45])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.CC1(C)C(C)(C)OB([C:59]2[CH2:69][CH2:68][C:62]3([C:66](=[O:67])[O:65][CH2:64][CH2:63]3)[CH2:61][CH:60]=2)O1>>[CH3:45][C@:13]12[C@@:12]3([CH3:46])[C@@H:21]([C@:22]4([CH3:25])[C@@H:9]([CH2:10][CH2:11]3)[C:8]([CH3:48])([CH3:47])[C:7]([C:59]3[CH2:69][CH2:68][C:62]5([C:66](=[O:67])[O:65][CH2:64][CH2:63]5)[CH2:61][CH:60]=3)=[CH:24][CH2:23]4)[CH2:20][CH2:19][C@@H:18]1[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH:38]([S:41]([CH3:44])(=[O:42])=[O:43])[CH2:37][CH2:36]1)[CH2:15][CH2:14]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)OB(C2=CCC3(CCOC3=O)CC2)OC1(C)C
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC7(CCOC7=O)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 59 %

Procedure:
The title compound was prepared following the procedure described in general procedure Step 5, using (1R,3 aS,5aR,5bR,7aR,11aR,11bR,13 aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate and 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-oxaspiro[4.5]dec-7-en-1-one as reactants. The product was isolated as diastereomers (solid, 59% yield). MS: m/e 749.7 (M+H)+, 4.10 min (method 7). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.35 (d, J=2.8 Hz, 1H), 5.24-5.19 (m, 1H), 4.72 (d, J=2.0 Hz, 1H), 4.59 (dd, J=2.3, 1.5 Hz, 1H), 4.37-4.25 (m, 2H), 3.12 (dd, J=14.6, 12.0 Hz, 2H), 2.87-2.78 (m, 1H), 2.84 (s, 3H), 2.67-2.53 (m, 3H), 2.50-2.40 (m, 3H), 2.33-0.90 (m, 35H), 1.70 (s, 3H), 1.09 (s, 3H), 0.98-0.92 (m, 6H), 0.96 (s, 3H), 0.86 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=2[C:10]([NH:12][NH:13][C:14]([NH2:16])=[O:15])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=2[CH:10]2[NH:12][NH:13][C:14](=[O:15])[NH:16]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)NNC(N)=O)cc1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2ccccc2C2NNC(=O)N2)cc1
Yield: 78.6 %

Procedure:
1-[2-(4-Methylphenyl)benzoyl]semicarbazide (4.6 g) and phosphorus oxychloride (10.3 g) were suspended in benzene (100 ml), and the suspension was heated for 3 hours under reflux. The reaction mixture was concentrated to dryness under reduced pressure. To the residue was added water, and resulting crystalline precipitate was collected by filtration. Recrystallization from methanol afforded the title compound as colorless needles (3.4 g, 79%), m.p.245-246 ° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:23]([O:26][CH2:27][CH2:28]Br)(=[O:25])[CH3:24].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>C(#N)C.C(O)C>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[C:23]([O:26][CH2:27][CH2:28][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1)(=[O:25])[CH3:24]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)OCCBr
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: CC(=O)OCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), K2CO3 (3.5 g, 25 mmol), 2-bromoethyl acetate (4 g, 26.5 mmol) in acetonitrile (50 ml) was heated at reflux for 4 hours. After cooling to room temperature, the inorganic salts were filtered and washed with DCM (dichloromethane 50 ml). The organic solvent was removed on a rotary evaporator to give an oil. The oily product was purified on a flash chromatography column (60 g of SiO2 ; eluted with MeOH 2%-4% in DCM). The pure product thus obtained weighed 4.43 g. This oil was dissolved in ethanol and treated with a solution of fumaric acid (1.2 g) in ethanol. The salt crystallized out at room temperature to yield 3.44 g (57%), m.p.=154°-155° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([OH:27])(CC=C)[CH:20]([C:28]([O:30][CH3:31])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]>CO.O1CCCC1.[Os](=O)(=O)(=O)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:5][CH:4]([OH:3])[CH2:9][OH:10])[C:21]([OH:27])=[C:20]([C:28]([O:30][CH3:31])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: C=CCC1(O)C=CC(c2csc(-c3ccc(OCC)c(OCC)c3)n2)=CC1C(=O)OC
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(-c2nc(-c3cc(CC(O)CO)c(O)c(C(=O)OC)c3)cs2)cc1OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 160.4 %

Procedure:
To a solution of 1 g of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-4-allylphenyl)thiazole in 20 ml of methanol and 20 ml of tetrahydrofuran were added 0.5 ml of osmium tetroxide (a 4% aqueous solution) and 1.22 g of4-methylmorpholine N-oxide. The mixture was stirred at room temperature for 4 hours. The solvent was removed by distillation. The residue was mixed with 50 ml of dichloromethane and 25 ml of water for phase separation. The organic layer was washed with 25 ml of a saturated aqueous sodium chloride solution and dried. The solvent was removed by distillation. The residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=199/1) to obtain 860 mg of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-(2,3-dihydroxypropyl)phenyl]thiazole.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][F:20])[N:13]=[N:12]1.[CH2:21](Br)[C:22]#[CH:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:1][C:2]1[C:7]([O:8][CH2:23][C:22]#[CH:21])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][F:20])[N:13]=[N:12]1
Reactant: Nc1c(O)c(Cl)cc(F)c1-n1nnn(CCCF)c1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1c(Cl)cc(F)c(-n2nnn(CCCF)c2=O)c1N
Yield: 104.8 %

Procedure:
The mixture of 1-(2-amino-4-chloro-6-fluoro-3-hydroxyphenyl)(3-fluoropropyl)-tetrazolinone (0.28 g), propargyl bromide (0.13 g), and potassium carbonate (0.14 g) in acetonitrile (5 ml) was heated under reflux for 0.5 hour. The solvent and excess reagent were removed under reduced pressure. The residue was purified by a silica gel column, eluted with ethyl acetate to give the desired product (0.33 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[S:12]1[C:16]2[CH:17]=[C:18]([NH2:21])[CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1>N1C=CC=CC=1>[S:12]1[C:16]2[CH:17]=[C:18]([NH:21][S:8]([C:7]3[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=3)(=[O:10])=[O:9])[CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: Nc1ccc2ncsc2c1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc2ncsc2c1)c1cccnc1Cl
Yield: 50.8 %

Procedure:
The title compound (1.1 g, 3.38 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (1.56 g, 7.36 mmol), 1,3-benzothiazol-6-amine (1.0 g, 6.66 mmol) and pyridine (10 mL) at rt using the methods of (IntC1).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].O[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1.O>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][C:23]2[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=2)=[O:18])=[CH:20][CH:21]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
0.6 g of N,N'-dicyclodicyclohexylcarbodiimide is added at room temperature while stirring to a solution of 1.0 g of 4-[6-acryloyloxyhexyloxy]benzoic acid, 0.3 g of 4-hydroxybenzaldehyde and 0.04 g of 4-dimethylaminopyridine in 20 ml of dichloromethane. The reaction mixture is stirred at room temperature overnight, poured into 100 ml of water and then extracted three times with 50 ml of dichloromethane each time. The combined organic phases are washed twice with 100 ml of water each time, dried over magnesium sulphate, filtered and the filtrate is subsequently concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 1:1) and two-fold recrystallization from ethanol of the fractions which are pure according to thin-layer chromatography gives 0.9 g of 4-(4-[6-acryloyloxyhexyloxy]phenylcarbonyloxy)benzaldehyde.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5].[CH3:24][N:25]([CH3:34])[C:26]1[CH:31]=[CH:30][C:29]([Mg]Br)=[CH:28][CH:27]=1>>[CH3:24][N:25]([CH3:34])[C:26]1[CH:31]=[CH:30][C:29]([C:4]([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH2:14][CH2:15][N:16]4[CH2:20][CH2:19][CH2:18][C@H:17]4[CH3:21])=[CH:11][C:10]=3[CH:22]=2)=[O:5])=[CH:28][CH:27]=1
Reactant: CN(C)c1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Product: C[C@@H]1CCCN1CCc1cc2cc(C(=O)c3ccc(N(C)C)cc3)ccc2o1

Procedure:
The product from Example 71E and 4-(dimethylamino)phenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.44 (d, 3H), 1.73 (m, 1H), 1.80 (m, 2H), 2.15 (m, 2H), 2.35 (m, 1H), 3.18 (s, 6H), 3.50 (m, 2H), 3.55 (m, 1H), 3.80 (m, 2H), 6.80 (dd, 2H), 6.85 (s, 1H), 7.56 (dd, 1H), 7.65 (dd, 1H), 7.75 (dd, 2H), 7.95 (d, 1H); MS (ESI) m/z 377 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21]CC)=[O:20]>CC(C)=O>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([O:10][CH2:18][C:19]([OH:21])=[O:20])=[CH:9][C:2]=1[F:1])#[N:5]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCC(=O)O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
The mixture of 2-fluoro-4-hydroxybenzonitrile (274 mg, 2.1 mmol), potassium carbonate (910 mg, 6.6 mmol), ethyl bromoacetate (500 mg, 3.0 mmol) and acetone (25 ml) was refluxed for 6 h. After cooling, the mixture was filtered to remove potassium carbonate. The filtrate was concentrated under reduced pressure. To this residue, 10 ml dioxane and 14 ml 5% sodium hydroxide solution were added. After the mixture was stirred at room temperature overnight, it was acidified with concentrated hydrochloric acid to pH 1, and then extracted three times with ethyl acetate (20 ml each). Organic phases were combined, washed with water and brine, dried over magnesium sulfate, filtered, and then evaporated in vacuo. The residue was recrystallized from ethanol and petroleum ether to give 268 mg 4-cyano-3-fluorophenoxyacetic acid as white crystals, mp 150-152° C.
Reaction SMILES: [N:1]([CH:4]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:5]1[CH:6]=[C:7]([CH:22]=[C:23]([Br:25])[CH:24]=1)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]1[O:21][CH2:20][CH2:19][O:18]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[O:18]1[CH2:19][CH2:20][O:21][CH:17]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[C:5]([CH:4]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH2:1])[CH:24]=[C:23]([Br:25])[CH:22]=1
Reactant: [N-]=[N+]=NC(c1ccccc1)c1cc(Br)cc(OCCCCCCCCC2OCCO2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC(c1ccccc1)c1cc(Br)cc(OCCCCCCCCC2OCCO2)c1
Temperature: 60 °C
Yield: 68 %

Procedure:
To a stirred reaction of 2-(8-(3-(azido(phenyl)methyl)-5-bromophenoxy)octyl)-1,3-dioxolane (1.19 g, 2.45 mmol) in tetrahydrofuran (15 mL) and water (0.3 mL), was added triphenylphosphine (0.71 g, 2.69 mmol). The reaction mixture was heated to 60° C. for 16 hours. The reaction mixture was cooled, concentrated and purified by silica gel chromatography eluting with 0-100% ethyl acetate in iso-hexane to afford impure title compound as a colourless oil (0.77 g, 68%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: OCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2cccs2)c1C#N
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2ccccn2)nc(N)nc1-c1cccs1

Procedure:
From 2-amino-4-methanesulfinyl-6-thiophen-2-yl-pyrimidine-5-carbonitrile, 2-(hydroxymethyl)pyridine and DBU in dioxane. EI-MS m/e (%): 309 (M+, 53), 308 ([M—H]+, 48), 292 ([M—NH3]+, 32), 108 (100), 92 (50), 65 (49).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19]CC)=O)=[C:13]([CH2:22]Br)[N:12]=2)[CH:6]=[N:7][C:8]=1[O:9][CH3:10].[NH2:24][C:25]1[CH:26]=[N:27][N:28]([CH2:30][C:31]#[N:32])[CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:12]=[C:13]3[CH2:22][N:24]([C:25]4[CH:26]=[N:27][N:28]([CH2:30][C:31]#[N:32])[CH:29]=4)[C:17](=[O:19])[C:14]3=[CH:15][CH:16]=2)[CH:6]=[N:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1ccc(-c2cnc(OC)c(OC)c2)nc1CBr
Reactant: N#CCn1cc(N)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-c2ccc3c(n2)CN(c2cnn(CC#N)c2)C3=O)cnc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
As shown in step 8-iv of Scheme 8, a solution of the above mixture (Compound 2029, 2.2 g, about 60% pure) in DMF (40 mL) at 0° C. was added dropwise over 2 hours to a suspension of 2-(4-amino-1H-pyrazol-1-yl)acetonitrile (844 mg, 6.9 mmol) and sodium carbonate (732 mg, 6.9 mmol) in DMF (20 mL). After addition was complete, the reaction mixture was stirred at 0° C. for 2 hours and heated at 80° C. for 15 hours. Additional sodium carbonate (732 mg) was added and the reaction mixture was heated at 90° C. for an additional 7 hours. After cooling, the mixture was poured into water and a precipitate formed. The solid was collected by filtration, washed with methyl t-butyl ether, and dried under high vacuum to provide 2-(4-(2-(5,6-dimethoxypyridin-3-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-1H-pyrazol-1-yl)acetonitrile (Compound 25, 450 mg).
Reaction SMILES: C(O[C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])CCC.[C:18]([C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[CH2:23][NH2:24])#[N:19]>O1CCCC1>[CH3:15][C:11]([NH:10][C:9]1[C:8](=[O:16])[C:7](=[O:17])[C:6]=1[NH:24][CH2:23][C:22]1[CH:21]=[C:20]([CH:27]=[C:26]([CH3:28])[CH:25]=1)[C:18]#[N:19])([CH3:14])[CH2:12][CH3:13]
Reactant: CCCCOc1c(NC(C)(C)CC)c(=O)c1=O
Reactant: Cc1cc(C#N)cc(CN)c1
Solvent: C1CCOC1
Product: CCC(C)(C)Nc1c(NCc2cc(C)cc(C#N)c2)c(=O)c1=O
Reaction time: 48 h
Yield: 67 %

Procedure:
A solution of 3-butoxy-4-(1,1-dimethyl-propylamino)cyclobut-3-ene-1,2-dione (1.44 g, 6.0 mmol, Example 3) and 3-cyano-5-methylbenzylamine from Example 7, Step 3 (6.0 mmol) and tetrahydrofuran (15 mL) were stirred at room temperature for approximately 20 hours. An additional 7 mL of tetrahydrofuran were added and stirring continued for an additional 48 hours. The solvent was removed and the residue was recrystallized twice from methanol to provide 1.251 g (67%) of the title compound as a white solid: mp 231°-133° C. (softens 229° C.); 1H NMR (DMSO-d6) δ7.78 (m, 1H), 7.62 (m, 2H), 7.51 (s, 1H), 7.41 (s, br, 1H), 4.74 (d, 2H), 2.35 (s, 3H), 1.67 (m, 2H), 1.30 (s, 6H), 0.82 (m, 3H) ppm. IR (KBr): 3290, 2240, 1780, 1670 cm-1 ; MS (m/z) 311 (M+). HPLC indicates a major component (99.7%).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl[CH2:15][CH:16]([OH:27])[CH2:17][N:18]([CH2:24][CH2:25][OH:26])[CH2:19][CH:20]([OH:23])[CH2:21]Cl>C1(C)C(C)=CC=CC=1>[OH:27][CH:16]([CH2:17][N:18]([CH2:24][CH2:25][OH:26])[CH2:19][CH:20]([OH:23])[CH2:21][NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:15][NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: OCCN(CC(O)CCl)CC(O)CCl
Reactant: CCCCCCCCCCCCN
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCNCC(O)CN(CCO)CC(O)CNCCCCCCCCCCCC
Temperature: 70 °C
Yield: 77.2 %

Procedure:
A reactor was charged with 280 g (1.51 moles) of dodecylamine and 100 g of xylene, and the contents were heated to 70° C. To the contents, a solution with 38.5 g (0.18 mole) of N,N-bis(3-chloro-2-hydroxypropyl)hydroxyethylamine dissolved in 20 g of xylene was added dropwise over 30 minutes. The resultant mixture was aged further for 4 hours. Thereafter, xylene was distilled off under reduced pressure, and unreacted dodecylamine was then distilled off at 100° C. and 0.5 mmHg. The residue was subjected to extraction and washing with a mixture of 500 ml of hexane and 500 ml of 5% aqueous sodium hydroxide. Thereafter, a hexane layer was taken out and concentrated, thereby obtaining 75.6 g (yield: 77%) of 15,19-dihydroxy-17-hydroxyethyl-13,17,21-triazatritriacontane represented by the following formula. ##STR12##
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)C1C=CC=CC=1.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[C:15]([NH:19][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)NC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere a solution of 8.6 mL (78 mmol) TiCl4 in 100 mL toluene was added dropwise to a solution, cooled to 0° C., of 24.1 mL (130 mmol) 1-benzyl-piperidin-4-one and 55 mL (519 mmol) of tert-butylamine in 200 mL toluene in such a way that the internal temperature did not exceed 15° C. The reaction mixture was stirred overnight at RT, the precipitate formed was suction filtered and the solution remaining after the addition of 65 mg of platinum oxide was hydrogenated until the theoretical uptake of H2 had been achieved. After hydrogenation had ended, 160 mL of 2 N NaOH solution were added to the suspension, it was filtered, the organic phase was separated off, the aqueous solution was extracted three times with toluene and the combined organic phases were dried over Na2SO4. After the desiccant and solvent had been eliminated the product was further reacted without being purified.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][C:42]([F:44])([F:43])[F:45])=[CH:37][CH:36]=3)=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: FC(F)(F)Oc1ccc(Sc2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3ccc(OC(F)(F)F)cc3)cc2)c1C
Yield: 55.9 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-bromo-4-(4-(trifluoromethoxy)phenylsulfanyl)benzene (0.214 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-fluoro-3-methyl-4-[4-(4-trifluoromethoxyphenylsulfanyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.154 g, 55%) as a solid.
Reaction SMILES: [Br:1][CH2:2][C:3](=[N:9][OH:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:2][C:3](=[N:9][O:10][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([Cl:11])=[CH:13][CH:14]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(CBr)=NO
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(CBr)=NOC(=O)c1ccc(Cl)cc1
Yield: 100.3 %

Procedure:
To the mixture of ethyl 3-bromo-2-(hydorxyimino)propanoate (3 g, 14.3 mmole) and 4-chlorobenzoyl chloride (2.75 g, 15.71 mmole) in dry methylene chloride (100 ml) at 0° to 5° C. with stirring, was slowly added dry pyridine (1.2 g, 15.18 mmole). After addition, the reaction mixture was stirred at room temperature for one hour. The reaction mixture was diluted with 50 ml of methylene chloride and washed with water and brine. The organic layer was dried with magnesium sulfate and the solvent evaporated to afford 5.0 g (99% yield) of ethyl 3-bromo-2-(4-chlorobenzoyloximino)propanoate as a white solid, m.p. 82°-84.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH:13]([CH3:15])[CH3:14])[C:11]([CH3:16])=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[Cl:17]N1C(=O)CCC1=O>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH:13]([CH3:14])[CH3:15])[C:11]([CH3:16])=[N:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1
Reactant: Cc1ncc(-c2ccnc(N)n2)n1C(C)C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: Cc1ncc(-c2nc(N)ncc2Cl)n1C(C)C
Temperature: 25 °C

Procedure:
A solution of 2-amino-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidine (Method 39 of WO 03/076436; 0.5 g, 2.3 mmol) and N-chlorosuccinimide (0.4 g, 3 mmol) in acetic acid (5 ml) was stirred at 65° C. under nitrogen for 2 hours. Then the reaction mixture was allowed to cool down to room temperature and the solvent was removed under vacuum. The crude was taken up in EtOAc and water then portions of solid potassium carbonate were added to this stirred biphasic solution until pH 8-9 was reached. The two layers were separated, the aqueous layer was extracted once with EtOAc then the organics were combined, washed with brine and dried. Removal of the solvent left a residue, which was purified on silica (MeOH/DCM/EtOAc, from 0/50/50 to 6/47/47). Triturating the foam in ether gave a white solid, which was filtered off. (0.49 g, 85%). NMR (CDCl3): 1.51 (d, 6H), 2.55 (s, 3H), 4.85 (septuplet, 1H), 5.01 (b s, 2H), 7.48 (s, 1H), 8.31 (s, 1H); m/z 252 (35Cl), 254 (37Cl); m/z 250 (35Cl), 252 (37Cl).