Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=O)[C:6](=[O:20])[N:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:4]=2[N:3]=1.[CH3:26][CH2:27][O-].[Na+]>CCO>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[O:18][N:10]=[C:2]([C:26]4[CH:27]=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:3]=3)[C:6](=[O:20])[N:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:4]=2[N:3]=1
Reactant: CCCCCn1c(=O)n(CCCCC(=O)OC)c(=O)c2[nH]c(Cl)nc21
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCn1c(=O)n(CCCCc2nc(-c3ccccc3)no2)c(=O)c2[nH]c(Cl)nc21
Yield: 41 %

Procedure:
A mixture of methyl 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (50 mg, 0.13 mmol), benzamidine oxime (20 mg, 0.15 mmol) and a 21% solution of NaOEt in EtOH (76 μl, 0.20 mmol) in EtOH (1.5 ml) was heated in the microwave at 140° C. for 10 min. After cooling the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, dried (MgSO4) and concentrated. Purification by the MDAP gave the title compound as a white solid (25 mg, 41%).
Reaction SMILES: [F:1][C:2]([F:32])([C:28]([F:31])([F:30])[F:29])[C:3]([F:27])([F:26])[C:4]([F:25])([F:24])[O:5][C:6]([F:23])([F:22])[C:7]([F:21])([F:20])[O:8][C:9]([F:19])([F:18])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.[CH2:33]([C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)=[N:47][CH:48]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C(=O)([O-])[O-].[K+].[K+].C(#N)C>CN(C)C=O>[CH2:33]([C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:50]=[CH:51][C:52]([O:55][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][CH2:10][C:9]([O:8][C:7]([F:21])([F:20])[C:6]([F:23])([F:22])[O:5][C:4]([F:25])([F:24])[C:3]([F:27])([F:26])[C:2]([F:32])([F:1])[C:28]([F:31])([F:30])[F:29])([F:19])[F:18])=[CH:53][CH:54]=2)=[N:47][CH:48]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(COCCCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCCCCCCCCc1cnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
Using essentially the procedure of Comparative Example A, the title compound was prepared by combining 5-(2-(2 -(nonafluorobutoxy)tetrafluoroethoxy)-2,2 -difluoroethoxy)-l-bromopentane (4.4 g, 7.6 mmol), 5 -decyl-2-(4-hydroxyphenyl)pyrimidine (2.0 g, 6.4 mmol), potassium carbonate (0.5 g, 10 mmol), acetonitrile (20 mL), and dimethyl formamide (20 mL). The resulting crude product was isolated and purified essentially as in Comparative Example A to yield 4.98 g.
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:10])[C:4]#[C:5][Si](C)(C)C.ON=CC#[C:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](C)[CH:17]=1>>[OH:1][N:2]=[C:3]([Cl:10])[C:4]#[C:5][C:18]1[CH:17]=[C:16]([CH3:15])[CH:21]=[CH:20][CH:19]=1
Reactant: C[Si](C)(C)C#CC(Cl)=NO
Reactant: Cc1cccc(C#CC=NO)c1
Product: Cc1cccc(C#CC(Cl)=NO)c1
Yield: 96.4 %

Procedure:
The title compound was prepared following the method herein described for Compound 3b, using Compound 91c instead of 3-trimethylsilylprop-2-ynal oxime. The residue was used in the next step without further purification. Yield: 96.4%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[C:14](=[O:15])[C:13](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:12][S:11][CH2:10]2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[S:26][CH2:27][CH2:28][N:29]=1>CC(C)=O>[S:26]1[CH2:27][CH2:28][N:29]=[C:25]1[NH:24][C:14]1([OH:15])[C:9](=[CH:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH2:10][S:11][CH2:12][C:13]1=[CH:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1
Reactant: Cc1ccc(C=C2CSCC(=Cc3ccc(C)cc3)C2=O)cc1
Reactant: NC1=NCCS1
Solvent: CC(C)=O
Product: Cc1ccc(C=C2CSCC(=Cc3ccc(C)cc3)C2(O)NC2=NCCS2)cc1

Procedure:
To a stirred suspension of tetrahydro-3,5-bis-(4-methylphenylmethylene)-4H-thiopyran-4-one (5 gm; 15.6 mmole) in acetone (150 ml) is added a freshly filtered solution of 2-amino-2-thiazoline (1.9 gm, 18.6 mmole) in acetone (100 ml).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[N:14][CH:13]=[C:12](Cl)[N:11]=1>>[CH2:1]([NH:8][C:12]1[CH:13]=[N:14][CH:15]=[C:10]([Cl:9])[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: NCc1ccccc1
Product: Clc1cncc(NCc2ccccc2)n1
Yield: 97.9 %

Procedure:
In a procedure analogous to example 1, reaction of benzylamine (3.21 g, 30.0 mmol) and 2,6-dichloropyrazine (1.49 g, 10.0 mmol) furnished the product ( 2.15 g, 98%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[C:12]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39]>ClCCl.NCCCCNC(=O)OC(C)(C)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[C:12]2[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2ccc(OCc3ccccc3)cc2c1Cl
Reactant: CC(C)(C)OC(=O)NCCCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2ccc(OCc3ccccc3)cc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.6 %

Procedure:
A solution of 6-benzyloxy-4-chloro-3-nitroquinoline (14.47 g, 46.29 mmol), prepared in Parts A-D of Example 57, and triethylamine (8.4 mL, 60.2 mmol) in dichloromethane (200 mL) was cooled to 0° C. tert-Butyl N-(4-aminobutyl)carbamate (8.71 g, 46.3 mmol) was added; the reaction was stirred for 15 minutes at 0° C. and then allowed to warm to ambient temperature and stirred for five hours. An analysis by TLC indicated the presence of starting material; therefore, additional tert-butyl N-(4-aminobutyl)carbamate (0.5 mL, 2.6 mmol) was added. The reaction was stirred overnight and then washed with water (2×200 mL). The combined washings were extracted with chloroform after the addition of sodium chloride. The combined organic solutions were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was recrystallized from ethyl acetate (100 mL). The crystals were isolated by filtration and washed with cold hexanes to provide 17.62 g of tert-butyl [4-(6-benzyloxy-3-nitroquinolin-4-ylamino)butyl]carbamate as an orange powder.
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[NH:5][C:4]1=[O:13])[CH3:2].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Br:20]>>[Br:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[NH:5][C:4]1=[O:13]
Reactant: BrCCCCCBr
Reactant: CCC1C(=O)Nc2ccc(F)cc21
Product: CCC1(CCCCCBr)C(=O)Nc2ccc(F)cc21

Procedure:
The title compound is prepared according to process E starting from 3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1,5-dibromopentane.
Reaction SMILES: [CH:1]1(CN2C(=O)C3NC(C4C=CC(COCCOCCOCCOCCOCCOCCOCCOCCOCCOC)=CC=4)=NC=3N(CC3CCCCC3)C2=O)CCCCC1.[CH:62]1([CH2:68][N:69]2[C:77](=[O:78])[C:76]3[N:75]=[C:74]([C:79]4[CH:89]=[CH:88][C:82](/[CH:83]=[CH:84]/[C:85]([OH:87])=[O:86])=[CH:81][CH:80]=4)[NH:73][C:72]=3[N:71]([CH2:90][CH:91]3[CH2:96][CH2:95][CH2:94][CH2:93][CH2:92]3)[C:70]2=[O:97])[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]1.C(=O)([O-])[O-].[K+].[K+].CO>C(#N)C>[CH3:1][O:86][C:85](=[O:87])/[CH:84]=[CH:83]/[C:82]1[CH:81]=[CH:80][C:79]([C:74]2[NH:73][C:72]3[N:71]([CH2:90][CH:91]4[CH2:92][CH2:93][CH2:94][CH2:95][CH2:96]4)[C:70](=[O:97])[N:69]([CH2:68][CH:62]4[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]4)[C:77](=[O:78])[C:76]=3[N:75]=2)=[CH:89][CH:88]=1
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCc1ccc(-c2nc3c([nH]2)c(=O)n(CC2CCCCC2)c(=O)n3CC2CCCCC2)cc1
Reactant: O=C(O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: COC(=O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
In the manner of Example 36, part (b), (E)-4-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6dioxo-9H-purin-8-yl]cinnamic acid was converted to (E)-1,3-bis(cyclohexylmethyl)-8-(3-(2-(1H-imidazol-1yxlcarbonyl)vinyl)phenyl)-9H-purin-2,6(1H,3H)-dione as a yellow powder. Such a sample (2.50 g, 4.62 mmol) was stirred at reflux in acetonitrile (75 ml) with potassium carbonate (1.28 g, 9.25 mmol) and methanol, (10 ml) for 24 hours. The mixture was cooled to room temperature and filtered and the filtrate-wash was adjusted to pH˜3 by addition of 6N hydrochloric acid. The resulting precipitate was filtered and washed with methanol and dried to give (E)-4-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]cinnamic acid methyl ester (1.70 g, 74%) as a white solid. 1H-NMR (300 MHz, DMSO-d6) δ: 8.16 (d, J=8.2 Hz, 2H, phenylCH), 7.83 (d, J=8.4 Hz, 2H, 2 phenylCH), 7.63 (d, J=15.9 Hz,1H, CH═), 6.70 (d, J=15.9 Hz, 1H, CH—), 3.95 (d, J=7.0 Hz, 2H, CH2N), 3.75 (d, J=6.8 Hz, 2H, CH2N), 3.70 (s, 3H, CH3), 2.0-1.50 and 1.20-0.80 (m, 22H, 2C6H11).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([O:22]C)=[O:21])[CH:17]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[N:15]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[OH-].[Na+].C1COCC1>O>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[N:15]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1COCCN1c1cc(C(=O)O)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
Methyl 2-[4-(cyclopropylcarbamoylamino)phenyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine-4-carboxylate (350 mg) was dissolved in water (15 mL) containing sodium hydroxide (67 mg) and the reaction was allowed to stir at RT for 1 h. A further 2 equivalents of sodium hydroxide were added along with THF (3 mL). The reaction was stirred for another 1 h then the THF removed under reduced pressure and the aqueous solution partitioned with ethyl acetate (15 mL). The aqueous layer was acidified with concentrated hydrochloric acid and the precipitate was filtered and dried in a vac-oven at 50° C. for 18 h to give the desired material (350 mg) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>CO.O1CCOCC1>[C:14]1([O:13][CH2:12][CH2:11][O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:24])=[O:2])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccccc1OCCOc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)c1ccccc1OCCOc1cccc2ccccc12
Yield: 77 %

Procedure:
A solution of 1.6 g (3.15 mmol) of 3,5-bis[2-[2-(naphthalenyloxy) ethoxy]benzoic acid methyl ester and 15 mL (15 mmol) of 1N NaOH in 45 mL of methanol and 20 mL of dioxane was stirred at reflux for 2 hours. The usual workup followed by recrystallization from THF-ethyl acetate gave 1.2 g (77% yield, mp 205°-207°) of 3,5-bis[2-[2-(naphthalenyloxy)ethoxy]benzoic acid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH3:29]>C(Cl)Cl.CO>[NH:1]1[C:5]2[CH:4]=[CH:9][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[C:25]([C:26]([NH2:29])=[O:28])=[CH:24][CH:23]=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:7][C:6]=2[N:3]=[CH:2]1
Reactant: N
Reactant: O=C(O)c1cccc2c1[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1cccc2c1[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Yield: 58 %

Procedure:
The title compound is prepared from cis-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-10-carboxylic acid and ammonia (7 mol/L in methanol) following a procedure analogous to that described in Example 1. Yield: 58% of theory; TLC: rf=0.24 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=375 [M+H]+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:28]=[N:27][CH:26]=[C:25]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])[C:21]=1[C:22](O)=[O:23].O.[NH2:39][NH2:40]>CS(C)=O>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:28]=[N:27][CH:26]=[C:25]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])[C:21]=1[C:22]([NH:39][NH2:40])=[O:23]
Reactant: O=C(O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1F
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CS(C)=O
Solvent: O
Product: NNC(=O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
1,1′-carbonyldiimidazole (21 mg, 0.13 mmol) was added to a solution of 3-(2-fluoro-phenyl)-5-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid (40 mg, 0.09 mmol) in DMSO (1 mL), and stirred overnight at 60° C. Hydrazine hydrate (13 mg, 0.27 mmol) was added, and the reaction solution was stirred for an additional 4 h at 60° C. The reaction solution was quenched with H2O, diluted with EtOAc, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 70% EtOAc in hexanes to afford the desired product (22 mg, 53%). LC-MS (M+H=467, obsd.=467).
Reaction SMILES: O[CH:2]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:3][CH3:4].P(Br)(Br)[Br:20]>C(Cl)(Cl)Cl>[Br:20][CH:2]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:3][CH3:4]
Reactant: BrP(Br)Br
Reactant: CCC(O)c1ccc(-c2ccc(C#N)cc2)cn1
Solvent: ClC(Cl)Cl
Product: CCC(Br)c1ccc(-c2ccc(C#N)cc2)cn1
Temperature: 25 °C
Yield: 145.5 %

Procedure:
To a solution of 4-(6-(1-hydroxypropyl)pyridin-3-yl)benzonitrile (0.10 g, 0.21 mmol) in chloroform (4 mL) was added PBr3 (0.34 g, 0.63 mmol) at 0-5° C. This temperature was maintained for 15 min, was slowly allowed to rt and was then maintained at rt for another 90 min. The contents were diluted with chloroform (100 mL) and washed with bicarbonate solution (2×30 mL). The organic layer was separated, dried over sodium sulphate and evaporated to provide 4-(6-(1-bromopropyl)pyridin-3-yl)benzonitrile (92 mg, 73% yield).
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]([C:17]2[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][CH2:19][C:18]=2[CH3:25])[CH2:8][C:7]1=[O:26])(=O)[CH2:2][CH2:3][CH3:4].[CH2:27]([O:29][NH2:30])[CH3:28]>C(O)C>[CH2:27]([O:29][NH:30][C:1](=[C:6]1[C:11](=[O:12])[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]([C:17]2[C:22]([CH3:23])([CH3:24])[CH2:21][CH2:20][CH2:19][C:18]=2[CH3:25])[CH2:8][C:7]1=[O:26])[CH2:2][CH2:3][CH3:4])[CH3:28]
Reactant: CCCC(=O)C1C(=O)CC(C2=C(C)CCCC2(C)C)C(C(=O)OC)C1=O
Reactant: CCON
Solvent: CCO
Product: CCCC(NOCC)=C1C(=O)CC(C2=C(C)CCCC2(C)C)C(C(=O)OC)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
9.0 parts by weight of 2-butyryl-4-carbomethoxy-5-(1,3,3-trimethylcyclohex-1-en-2-yl)-cyclohexane-1,3-dione are dissolved in 100 parts by volume of ethanol, and 1.5 parts by weight of ethoxyamine are added. The mixture is stirred at room temperature for 8 hours and concentrated under reduced pressure. The residue is taken up in 50 parts by volume of methylene chloride and the solution is washed with 5% strength hydrochloric acid and water and concentrated under reduced pressure. 2-(1-Ethoxyaminobutylidene)-4-carbomethoxy-5-(1,3,3-trimethylcyclohex-1-en-2-yl)-cyclohexane-1,3-dione is obtained in quantitative yield, as crystals of melting point 70° C. (active ingredient No.3).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13](Cl)=[O:14].[OH:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([CH3:27])[CH:18]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([CH3:27])[CH:18]=1)=[O:14]
Reactant: Cc1cc(O)c2ccccc2n1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1cc(OC(=O)c2c(-c3ccccc3)noc2C)c2ccccc2n1
Temperature: 70 °C
Yield: 64.4 %

Procedure:
5-Methyl-3-phenylisoxazole-4-carbonyl chloride (100 mg) and 4-hydroxy-2-methylquinoline (250 mg) were dissolved in dichlorormethane (10 mL) and pyridine (0.2 mL). The reaction solution was heated at 70° C. overnight and then diluted with ethyl acetate (60 mL). The organic solution was washed with water (60 mL), dried, evaporated and purified by flash column chromatography (EtOAc/hexanes=1/2) to give 5-methyl-3-phenyl-4-isoxazolecarboxylic acid, 2-methyl-4-quinolinyl ester (100 mg). 1H NMR (CDCl3): δ 2.74 (s, 3H), 2.91 (s, 3H), 7.29 (s, 1H), 7.33-7.46 (m, 5H), 7.64-7.71 (m, 3H), 8.01 (td, J=0.9 and 8.4 Hz, 1H); LCMS: ret. time: 23.10 min.; purity: 100%; MS (m/e): 345.02 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1.Cl[C:13]1[N:22]=[C:21]([NH:23][CH2:24][CH2:25][O:26][CH3:27])[C:20]2[C:19](=[O:28])[N:18]([CH3:29])[CH:17]=[N:16][C:15]=2[CH:14]=1>>[CH3:27][O:26][CH2:25][CH2:24][NH:23][C:21]1[C:20]2[C:19](=[O:28])[N:18]([CH3:29])[CH:17]=[N:16][C:15]=2[CH:14]=[C:13]([C:2]2[CH:11]=[CH:10][C:5]3[N:6]=[C:7]([CH3:9])[O:8][C:4]=3[CH:3]=2)[N:22]=1
Reactant: COCCNc1nc(Cl)cc2ncn(C)c(=O)c12
Reactant: Cc1nc2ccc(Br)cc2o1
Product: COCCNc1nc(-c2ccc3nc(C)oc3c2)cc2ncn(C)c(=O)c12

Procedure:
5-(2-Methoxyethylamino)-3-methyl-7-(2-methylbenzo[d]oxazol-6-yl)pyrido[4,3-d]pyrimidin-4(3H)-one was synthesized, as described in Example 9, from 6-bromo-2-methylbenzo[d]oxazole and 7-chloro-5-(2-methoxyethylamino)-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one. After purification by preparatory LC/MS, it was partially decomposed to N-(2-hydroxy-4-(5-(2-methoxyethylamino)-3-methyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)phenyl)acetamide. The two compounds are separated again by preparatory TLC.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8](/[CH:11]=[N:12]/[S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl-].[CH2:20]1COC[CH2:21]1>>[O:1]1[C:5]2([CH2:6][CH2:7][CH:8]([CH:11]([NH:12][S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH:20]=[CH2:21])[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: C1CCOC1
Reactant: CC(C)(C)S(=O)/N=C/C1CCC2(CC1)OCCO2
Agent: [Cl-]
Product: C=CC(NS(=O)C(C)(C)C)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution (E)-N-(1,4-dioxaspiro[4.5]decan-8-ylmethylene)-2-methylpropane-2-sulfinamide (1.89 g, 5.53 mmol), prepared in Example 11, step A, in dry THF (48 mL) was treated with a solution of vinylmagnesiumm chloride (10.4 mL, 16.6 mmol, 1.6 N in THF) dropwise at ambient temperature under argon. After the complete addition, the reaction mixture was allowed to stir at room temperature and for 3 hours and then quenched at 0° C. by the cautious addition of saturated ammonium chloride solution. After extraction with ethyl acetate, the organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0-5% MeOH/Ethyl Acetate) to afford the product as a mixture of disatereomers.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][C@H:20]([C@H:24]([OH:33])[CH2:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:21]([CH3:23])[CH3:22])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.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>[OH:33][C@H:24]([CH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[C@H:20]([CH:21]([CH3:23])[CH3:22])[O:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)=[CH:14][CH:15]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC(C)[C@H](Oc1ccc(Br)cc1)[C@H](O)CCc1cccnc1
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: CCO
Product: CC(C)[C@H](Oc1ccc(-c2cccc(C#N)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 56.6 %

Procedure:
Prepared according to the method described in Example 12b) from 3-cyanobenzeneboronic acid (0.40 g), (3S,4R)-3-(4-bromophenyloxy)-2-methyl-6-(3-pyridyl)hexan-4-ol (0.90 g, Example 61d)), 2M aqueous sodium carbonate (2.72 ml) and tetrakis(triphenylphosphine)palladium(0) (0.160 g) in ethanol (4 ml). The reaction mixture was heated at 90° C. for 4 hours. After cooling, the solution was poured onto water, and extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as a gum (0.54 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5]Cl.[C-:11]#[N:12].[K+]>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C:11]#[N:12])[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: ClCc1cc(Cl)cc(Cl)c1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: N#CCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a vigorously stirred solution of 3,5-dichlorobenzylchloride (28 g) in dichloromethane (150 ml) was added a mixture of KCN (27.5 g) and tetrabutylammonium hydrogen sulphate (2.38 g) in water (110 ml). After stirring at room temperature for 22 hours, the mixture was diluted with dichloromethane, the organic phase washed with water and concentrated in vacuo to leave an oil. Filtration through silica with toluene followed by concentration then trituration with hexane gave the desired product as a colourless solid. 15.8 g, mp. 31°-32° C.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([CH3:10])=[CH:4][N:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].COCCOC>O>[C:11]1([C:2]2[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([CH3:10])=[CH:4][N:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cnc(Br)c(C)c1C
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1cnc(-c2ccccc2)c(C)c1C

Procedure:
10.2 g (0.051 mol) of 2-bromo-3,4,5-trimethylpyridine was mixed with 7.86 g (0.061 mol) of phenylboronic acid, 1.8 g (0.0016 mol) of Pd(Ph3)4, 19.1 g (0.13 mol) of K2CO3 50 mL of DME and 50 mL of water. The reaction mixture was refluxed for 20 hours and separated on silica gel column. MS confirmed the desired product.