Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][O:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:29]([C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1)=O>CCCCCC.O1CCCC1>[CH3:7][O:8][CH:9]=[CH:29][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC=Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
In an atmosphere of argon, a solution containing butyllithium dissolved in hexane was added to a solution containing 120 g of methoxymethyltriphenylphosphonium bromide dissolved in tetrahydrofuran (THF), and the mixture was stirred for one hour at room temperature. A solution containing 50 g of methyl 4-formylbenzoate dissolved in THF was added thereto, and stirring was continued for two hours. The reaction solution was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 47 g of methyl 4-(2-methoxyethenyl)benzoate (45).
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:11])[C:5]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[C:16](Cl)(=O)C(Cl)=O.CN(C=O)C>C(Cl)Cl>[Br:1][C:2]1[C:7]([C:8]([O:10][CH3:16])=[O:9])=[C:6]([CH3:11])[C:5]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(OC(C)C)ccc(Br)c1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1c(Br)ccc(OC(C)C)c1C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 64.9 %

Procedure:
To a 0° C. solution of 6-bromo-2-methyl-3-(propan-2-yloxy)benzoic acid (Cpd OO, 1.30 g, 4.80 mmol) in DCM (5 mL) was added oxalyl chloride (810 mg, 6.19 mmol) followed by DMF (10 mL). The reaction mixture was stirred at 0° C. for 1.5 hours, then concentrated under vacuum. The residue was dissolved in MeOH (15 mL) and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under vacuum and the residue dissolved in EtOAc. The organic layer was washed with brine, dried with Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (0-50%, EtOAc/heptane) to give the title compound (Cpd PP, 894 mg, 65%) as an amber oil. 1H NMR (400 MHz, chloroform-d) δ 1.33 (d, J=6.11 Hz, 6H) 2.16 (s, 3H) 3.95 (s, 3H) 4.50 (dt, J=12.04, 6.08 Hz, 1H) 6.75 (d, J=8.80 Hz, 1H) 7.31 (d, J=8.80 Hz, 1H); MS 287 [M+H].
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]#[N:24])[CH:14]=2)=[O:10])[CH2:5][CH2:4]1.[NH:25]1[CH:29]=[C:28]([CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])[N:27]=[N:26]1.C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O>[NH:25]1[CH:29]=[C:28]([CH2:30][CH2:31][CH2:32][C:33]([NH:2][CH:3]2[CH2:4][CH2:5][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[C:15]([C:23]#[N:24])[CH:14]=3)=[O:10])[CH2:7][CH2:8]2)=[O:34])[N:27]=[N:26]1
Reactant: O=C(O)CCCc1c[nH]nn1
Reactant: N#Cc1cc(COC(=O)N2CCC(N)CC2)cc(C(F)(F)F)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1cc(COC(=O)N2CCC(NC(=O)CCCc3c[nH]nn3)CC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3-Cyano-5-(trifluoromethyl)benzyl 4-aminopiperidine-1-carboxylate hydrochloride (50 mg, 0.137 mmol) and 4-(1H-1,2,3-triazol-4-yl)butanoic acid (25.6 mg, 0.165 mmol) were suspended in EtOAc (5 mL) and triethylamine (0.067 mL, 0.481 mmol) was added. After 5 mins at RT, T3P, 50% in EtOAC (0.164 mL, 0.275 mmol) was added and the mixture allowed to stir at RT for 20 hours. EtOAc (30 ml) was added and the mixture washed with a 10% solution of citric acid and a saturated solution of brine. The organics were dried over MgSO4, filtered and concentrated in vacuo. Purification via silica chromatography eluting with 0-10% MeOH/DCM gave the title compound.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[CH3:15][N:16]([CH3:20])[C:17](Cl)=[S:18]>CO>[CH3:15][N:16]([C:17](=[S:18])[O:3][C:4]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH3:20]
Reactant: CN(C)C(=S)Cl
Reactant: COC(=O)c1cccc(C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cccc(C)c1OC(=S)N(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A mixture of 12 g of KOH pellets, 150 mL of methanol and 24.9 g of methyl 2-hydroxy-3-methylbenzoate (I) was stirred at room temperature for 0.5 hours. The mixture was then cooled to 5° C. and 19 g of dimethylthiocarbamoyl chloride was added in one portion. An exotherm of 5° C. was observed. The resulting mixture was stirred for 2 hours and then added to 300 mL of ice water. After filtering, the crystalline product was washed with water and oven dried to yield 30-35 g of methyl 2-[(dimethyl-amino)thioxomethoxy]-3-methylbenzoate II, (E is O, W is S) in 80-92% yield, mp 94-96° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]([O:15]CC)=[O:14])[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1(NC(=O)OC(C)(C)C)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A 64.28 g (264 mmol) portion of ethyl 1-tert-butoxycarbonylaminocyclobutanecarboxylate was dissolved in 400 ml of methanol, mixed with 400 ml of 1N sodium hydroxide aqueous solution and then stirred overnight at room temperature. After evaporation of the solvent, the resulting residue was mixed with 20% citric acid aqueous solution-chloroform. The resulting organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to yield 55.29 g (97%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].OO.C(OCC)(=O)C.CCCCCC.[ClH:24]>>[NH2:1][C:2]1[C:3]([Cl:24])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: Cl
Reactant: COc1ccncc1N
Agent: OO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccnc(Cl)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a magnetically stirred mixture of 3-Amino-4-methoxypyridine (4.45 g, 35.89 mmole) in 12N HCl (25 mL) cooled in an ice bath was added hydrogen peroxide (5.3 g, 46.65 mmol, 30% solution). The reaction was allowed to slowly warm to room temperature and stirred for 1 h. TLC (50% ethyl acetate/hexane) indicated complete consumption of starting material. The reaction mixture was slowly poured into saturated sodium bicarbonate solution (400 mL) to neutralize the reaction and extracted with ethyl acetate. The resulting organic layers were washed with saturated sodium chloride solution and dried over magnesium sulfate. Filtration and concentration gave 3-Amino-2-chloro-4 methoxypyridine (4.56 g, 28.77 mmol, 80% yield) as an orange solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[S:13][C:14]2[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([F:22])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:20]1[C:14]2[S:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[C:17]([F:22])=[CH:18][CH:19]=1
Reactant: C#CCCc1nc2c(F)ccc(Cl)c2s1
Reactant: Brc1ccccn1
Product: Fc1ccc(Cl)c2sc(CCC#Cc3ccccn3)nc12
Yield: 11.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (66 mg, 0.42 mmol) and 2-but-3-ynyl-7-chloro-4-fluoro-benzo[d]thiazole (100 mg, 0.42 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 15 mg (47 μmol, 11%) of 7-chloro-4-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a brown oil.
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=O.[CH:11](=O)C1C=CC=CC=1>[Pd]>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:8])[CH3:11]
Reactant: O=Cc1ccccc1
Reactant: OCc1ccccc1
Agent: [Pd]
Agent: O=O
Product: CC(=O)c1ccccc1

Procedure:
Expectedly, benzylic alcohols such as PhCH2OH, 4-CH3OPhCH2OH, 4-CF3PhCH2OH, and PhCHOHCH3 were also reactive (0.1 mmol substrate, 5 μmol Pd-POM-1, 1 ml TFT, 2 bar O2, and 110° C. for 20 minutes), all yielding the corresponding benzaldehyde derivatives or acetophenone with >95% yields with no observed by-products.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:7]([C:14](=[O:16])[CH3:15])[C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.[C:24](=[O:31])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[NH2:25]>>[C:14]([C:7]1[C:8]([CH3:13])([CH3:12])[O:9][C:10]2[C:5]([C:6]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[CH:4][CH:3]=[C:2]([NH:25][C:24](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:11]=2)(=[O:16])[CH3:15]
Reactant: CC(=O)C1=C(c2ccc(F)cc2)c2ccc(Cl)cc2OC1(C)C
Reactant: CC(C)(C)OC(N)=O
Product: CC(=O)C1=C(c2ccc(F)cc2)c2ccc(NC(=O)OC(C)(C)C)cc2OC1(C)C

Procedure:
The compound obtained in (2) described above (118 mg) and tert-butyl carbamate (130 mg) were treated in the same manner as Reference Example 5(4) to give the titled compound (147 mg) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].C([O:14][C:15]1[C:16](=[O:27])[C:17](=O)[C:18]=1[NH:19][C@H:20]([CH3:25])[C:21]([CH3:24])([CH3:23])[CH3:22])C>C(O)C.C(OCC)C>[Cl:1][C:2]1[CH:9]=[C:8]([CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:17]1[C:16](=[O:27])[C:15](=[O:14])[C:18]=1[NH:19][C@H:20]([CH3:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:10]#[N:11]
Reactant: N#Cc1ccc(CN)c(Cl)c1
Reactant: CCOc1c(N[C@H](C)C(C)(C)C)c(=O)c1=O
Solvent: CCOCC
Solvent: CCO
Product: C[C@@H](Nc1c(NCc2ccc(C#N)cc2Cl)c(=O)c1=O)C(C)(C)C
Yield: 78.7 %

Procedure:
2-Chloro-4-cyano-benzylamine (0.30 g, 1.80 mmol, Example 2, Step 3) and (R)-3-ethoxy-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione (0.406 g, 1.80 mmol) were stirred in ethanol (10 mL) at 70° C. for 18 hours. The reaction was cooled and diluted with diethyl ether. Filtration afforded 0.49 g (79%) of (R)-3-chloro-4-{[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-methyl]-benzonitrile which was collected as a white solid: mp 237°-241° C.; [α]25D =+27.30° (10.99 mg/mL, DMSO); 1H NMR (DMSO-d6) δ8.10 (d, 1H), 7.89 (dd, 1H), 7.68 (m, 1H), 7.69 (d, 1H), 7.36 (br d, 1H), 4.87 (m, 2H), 3.90 (m, 1H), 1.12 (d, 3H), 0.86 (s, 9H) ppm. IR (KBr): 3100, 2950, 2250, 1800 cm-1. MS (m/z) 345/347 (M+).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][N:7]=[C:6]([NH:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:5]=1)[CH3:2]>[Pd]>[NH2:10][C:9]1[C:4]([NH:3][CH2:1][CH3:2])=[N:5][C:6]([NH:13][C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[N:7][CH:8]=1
Reactant: CCNc1nc(Nc2ccncc2)ncc1[N+](=O)[O-]
Agent: [Pd]
Product: CCNc1nc(Nc2ccncc2)ncc1N

Procedure:
Hydrogenation of 4-(ethylamino)-2-[(pyridin4-yl)amino]-5-nitropyrimidine (from Example 2(8) above) over Pd/C gave the title compound as a solid.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[C:41]([O:45][C:46](=[O:71])[NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][N:55]1[C:63]2[CH:62]=[C:61]3[NH:64][C:65]([NH2:67])=[N:66][C:60]3=[CH:59][C:58]=2[C:57]([CH3:69])([CH3:68])[C:56]1=[O:70])([CH3:44])([CH3:43])[CH3:42]>CN(C)C=O>[C:41]([O:45][C:46](=[O:71])[NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][N:55]1[C:63]2[CH:62]=[C:61]3[NH:64][C:65]([NH:67][C:1]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)=[O:9])=[N:66][C:60]3=[CH:59][C:58]=2[C:57]([CH3:69])([CH3:68])[C:56]1=[O:70])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1CN1C(=O)C(C)(C)c2cc3nc(N)[nH]c3cc21
Reactant: O=C(O)c1cccnc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccccc1CN1C(=O)C(C)(C)c2cc3nc(NC(=O)c4cccnc4)[nH]c3cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of nicotinic acid (11.8 mg; 0.09 mmol), TBTU (28.1 mg; 0.09 mmol) and DIPEA (33 μl) in N,N-dimethylformamide (600 μl) is stirred at RT for 5 min. Afterwards D18 (26.5 mg) is added and the mixture is stirred at RT for 18 h. After evaporation of the solvent the crude material is used without further purification.
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:25]N)[CH:22]=[CH:23][CH:24]=1>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:20]=1[C:3]([S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)=[C:2]([CH3:15])[NH:25]2
Reactant: COc1cccc(NN)c1
Reactant: CC(=O)CSc1cccc(CC(=O)O)c1
Agent: Cl
Product: COc1cccc2[nH]c(C)c(Sc3cccc(CC(=O)O)c3)c12

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: [3-(2-oxo-propylsulfanyl)-phenyl]-acetic acid and 3-methoxyphenylhydrazine hydrochloride.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:24]([NH2:26])=[O:25])=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:17])=[CH:12][CH:11]=2)[N:8]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.CCN(C(C)C)C(C)C.[NH2:47][C@@H:48]1[CH2:53][CH2:52][CH2:51][N:50]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:49]1>CN1C(=O)CCC1.CCOC(C)=O>[C:24]([C:6]1[N:5]=[N:4][C:3]([NH:47][C@@H:48]2[CH2:53][CH2:52][CH2:51][N:50]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:49]2)=[N:8][C:7]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])=[CH:12][CH:11]=1)(=[O:25])[NH2:26]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: CSc1nnc(C(N)=O)c(Nc2ccc(C(=O)N3CCOCC3)cc2)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nnc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of 3-(methylthio)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide (170 mg, 0.46 mmol) in NMP (20 mL) was added mCPBA (77% strength, 310 mg, 1.38 mmol). The mixture was stirred at RT for 1 h to yield a mixture of corresponding sulfone and sulfoxide. To the mixture was then added DIEA (0.40 mL, 2.30 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (184 mg, 0.92 mmol). The mixture was heated at 90° C. for 90 m. The mixture was cooled, diluted with 300 mL EtOAc, washed with 1N NaOH and brine, dried, and concentrated in vacuo. The residue was subjected to flash column chromatography with 0 to 6% MeOH in DCM to yield the title compound (74) (210 mg, 87% yield). MS found C25H34N8O5 as (M+H)+ 527.2, (M−H)− 525.3. UV: λ=252, 267, 283 nm.
Reaction SMILES: Br[CH2:2][C:3](=[O:24])[CH:4]=[P:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32].[OH-].[K+].O>C(O)C>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:2][C:3](=[O:24])[CH:4]=[P:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)CBr
Reactant: Oc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)COc1ccccc1Cl
Yield: 50.2 %

Procedure:
3-Bromo-2-oxopropylidenetriphenylphosphorane (8.0 g) was added to a solution of o-chlorophenol (3.8 g) and potassium hydroxide (1.56 g) in anhydrous ethanol (60 ml), and the resulting mixture was heated at reflux for 2 hours and was then poured into water (200 ml). The mixture was extracted with methylene chloride and the extract was washed with dilute aqueous sodium hydroxide solution (2 N) and with water, dried over magnesium sulphate, and evaporated. The residual solid was recrystallised from a mixture of petroleum ether (b.p. 60°-80° C.) and ethyl acetate, to give 3-(2-chlorophenoxy)-2-oxopropylidenetriphenylphosphorane (4.5 g), m.p. 102°-104° C. A further recrystallisation from a similar solvent gave a purer sample, m.p. 107°-109° C. [elemental analysis: C, 73.1; H, 5.3; P, 7.0%. C27H22ClO2P requires C, 72.9; H, 5.0; P, 6.95%. νmax 715, 750, 1110, 1405, 1440, 1485 and 1550 cm-1 ].
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=2[OH:20])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12>C(Cl)Cl>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([C:16]([CH3:17])([CH3:19])[CH3:18])[CH:13]=[C:12]([C:12]3[C:11]([OH:20])=[C:10]([N:2]4[N:3]=[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]5=[N:1]4)[CH:15]=[C:14]([C:16]([CH3:17])([CH3:19])[CH3:18])[CH:13]=3)[C:11]=2[OH:20])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)c1ccc(O)c(-n2nc3ccccc3n2)c1
Solvent: ClCCl
Product: CC(C)(C)c1cc(-c2cc(C(C)(C)C)cc(-n3nc4ccccc4n3)c2O)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Anhydrous ferric chloride (6.44 g, 0.038 mol) was added over a period of 30 minutes to a methylene chloride (300 ml) solution of 2-(2H-benzotriazol-2-yl)-4-tert-butyl-phenol (5.3 g, 0.019 mol) known as TINUVIN® PS Light Stabilizer, a product of CIBA SPECIALTIES, Hawthorne, N.Y. The resulting mixture was stirred at room temperature for 6 hours. After filtering over diatomaceous earth, the filtrate was extracted with dilute hydrochloric acid, washed with water and dried. Evaporation of the solvent gave 3,3′bis-(2H-benzotriazol-2-yl)-5,5′-di-tert-butyl-1,1′-biphenyl-2,2′-diol (COMPOUND 2) as a white powder; m.p. 234° C.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)#[N:32].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:37]3[CH:38]=[C:33]([CH:34]=[CH:35][CH:36]=3)[C:31]#[N:32])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(C#N)c2)CC1
Yield: 77 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 3-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (77%).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH3:36])[C:10](=[O:35])[CH2:11][CH2:12][C@H:13]([N:17]2[CH2:22][C:21]3[CH:23]=[C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:25]=[CH:26][C:20]=3[N:19]=[C:18]2[NH2:34])[CH:14]([CH3:16])[CH3:15])[CH2:5][CH2:4]1)#[N:2].C[Si]([N:41]=[N+:42]=[N-:43])(C)C.C([Sn](=O)CCCC)CCC>COCCOC>[CH3:36][N:9]([CH:6]1[CH2:7][CH2:8][CH:3]([C:1]2[NH:43][N:42]=[N:41][N:2]=2)[CH2:4][CH2:5]1)[C:10](=[O:35])[CH2:11][CH2:12][C@H:13]([N:17]1[CH2:22][C:21]2[CH:23]=[C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]=[CH:26][C:20]=2[N:19]=[C:18]1[NH2:34])[CH:14]([CH3:16])[CH3:15]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)[C@H](CCC(=O)N(C)C1CCC(C#N)CC1)N1Cc2cc(Oc3ccccc3)ncc2N=C1N
Agent: CCCC[Sn](=O)CCCC
Solvent: COCCOC
Product: CC(C)[C@H](CCC(=O)N(C)C1CCC(c2nnn[nH]2)CC1)N1Cc2cc(Oc3ccccc3)ncc2N=C1N
Temperature: 150 °C

Procedure:
To a solution of 4-(S)-(2-amino-6-phenoxy-4H-pyrido[3,4-d]pyrimidin-3-yl)-5-methyl-hexanoic acid (4-cyano-cyclohexyl)-methyl-amide (0.26 g, 0.43 mmol) and trimethylsilylazide (0.17 mL, 1.29 mmol) in DME (1.5 mL) was added dibutyltin oxide (0.10 g, 0.40 mmol). The mixture was then heated in a microwave at 150° C. for 20 min. The solution was purified by HPLC to yield 4-(S)-(2-amino-6-phenoxy-4H-pyrido[3,4-d]pyrimidin-3-yl)-5-methyl-hexanoic acid methyl-[4-(1H-tetrazol-5-yl)-cyclohexyl]-amide as a white solid, as its corresponding trifluoroacetate salt.
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[S:11])[N:4]2[CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=2[C:24]([NH:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([C:22]2[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=2[C:24]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([N:7]3[C:8]4[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=4[C:10](=[S:11])[N:4]4[CH2:3][CH2:2][CH2:1][C@H:5]4[CH2:6]3)=[O:32])=[CH:34][CH:35]=2)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: S=C1c2ccccc2NC[C@@H]2CCCN12
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Product: O=C(Nc1ccc(C(=O)N2C[C@@H]3CCCN3C(=S)c3ccccc32)cc1)c1ccccc1-c1ccccc1
Yield: 81.9 %

Procedure:
The same procedures used in Example 25 were repeated using (11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-thione prepared in Reference Example 32 and 4-[(2-phenylbenzoyl)amino]benzoic acid to give the title compound. Yield 81.9%.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C.O>[CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])([C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Temperature: 15 °C

Procedure:
Sodium metal (23 gram, 1 mole) was dissolved in dry ethanol (500 ml) with stirring. To this 160 gram (1 mole) of diethyl malonate (compound [2]) was added in 30 minutes. The reaction mixture was cooled to 15° C. and ethyl chloroacetate (compound [1], 117 gm, 0.095 mole) was then added drop wise in 30 minutes. On completion of addition the reaction mass was refluxed for 6 hours and then poured in 2 liters of water. The organic materials were extracted with dichloromethane (three times with 500 ml). Next, the organic extracts were dried over sodium sulfate, filtered and evaporated to give an oily substance which was then vacuum distilled to give 220 gm (89% of the theoretical maximum yield) of triethyl ethane-1,1,2-tricarboxylate, compound [3].
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]1(=[O:25])[O:24][CH2:23][CH2:22][CH2:21]1>>[OH:25][CH2:20][CH2:21][CH2:22][C:23]([NH:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:24]
Reactant: O=C1CCCO1
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Product: CCCCCCCCC=CCCCCCCCCNC(=O)CCCO
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Oleylamine derived from fat was titrated and found to have an equivalent weight of 266.9 grams (theory=267.5 grams). In a glass reaction vessel, 266.9 grams of the oleylamine were admixed with 86.1 grams of butyrolactone and the mixture heated to 100° C. on a steam bath until reaction was completed in a period of 2 hours. Greater than 95% conversion of the butyrolactone was achieved. The product upon cooling to room temperature produced a slightly off-white, hard, waxy solid which was found to be readily soluble in alcohols. IR=6.14 mu.