Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[C:21]([O:23][CH3:24])=[O:22].C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C(O)(C)(C)C>[CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH:8]=[CH:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CC(C)(C)O
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Methyl androst-4-ene-3-one-17β-carboxylate (10 g, 30.3 mmol, prepared according to Rasmusson, et al., J. Med. Chem. 27 1960 (1984)) and chloranil (8.95 g, 36.4 mmol) in 700 ml t-butanol was heated at reflux for 3.5 hours then cooled and filtered. The filtrate was concentrated and the residue taken up in 700 ml chloroform and washed successively with 4×150 ml water, 3×150 ml saturated sodium bicarbonate, 3×150 ml 5% sodium hydroxide, 3×150 ml brine, dried over sodium sulfate, and concentrated to yield methyl androst-4,6-diene-3-one-17β-carboxylate as a dark foam (7.0 g, 70%).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])[C:8]([CH3:28])=[CH:7][C:5]=2[N:6]=1.[Cl:29][C:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][N:31]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>O1CCOCC1.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>[C:24]([O:23][C@@H:18]([C:9]1[C:8]([CH3:28])=[CH:7][C:5]2[N:6]=[C:2]([C:34]3[CH:33]=[CH:32][N:31]=[C:30]([Cl:29])[CH:35]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH3:22])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: OB(O)c1ccnc(Cl)c1
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: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 95 °C

Procedure:
The reaction mixture of (S)-methyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (370 mg, 0.769 mol), 2-chloropyridine-4-boronic acid (157 mg, 0.99 mmol), 2N K2CO3 (1.9 mL), Pd(PPh3)4 (80 mg, 0.077 mmol) in dioxane (10 mL) was heated at 95° C. for 2 hrs. The reaction mixture was diluted by EtOAc, washed by sat. NaHCO3, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C26H24Cl2N2O3S: 515.1 (M+H+); Found: 515.1 (M+H+).
Reaction SMILES: [CH2:1]([C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(Cl)([Cl:17])=O>>[CH2:1]([C:7]1[S:11][C:10]([C:12]([Cl:17])=[O:14])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCc1ccc(C(=O)O)s1
Product: CCCCCCc1ccc(C(=O)Cl)s1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
10 ml of thionyl chloride was added to 1.0 g (4.72×10-3 ml) of 5-hexylthiophene-2-carboxylic acid, followed by stirring for 4 hours under heating at 80° C. and removal of excessive thionyl chloride by reduced-pressure distillation to obtain 5-hexylthiophene-2-carboxylic chloride.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](=[O:18])OCC(Cl)(Cl)Cl.[C:19]1([C:25]2[N:29]=[C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[NH:10][C:11]([N:33]1[CH2:34][CH2:35][N:30]([C:28]2[S:27][N:26]=[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:29]=2)[CH2:31][CH2:32]1)=[O:18]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1nc2ccccc2[nH]1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1nc2ccccc2[nH]1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 11.9 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl 1H-benzimidazol-2-ylcarbamate (228 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3.5 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column-chromatography (hexane:ethyl acetate=2:8) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 35.6 mg (11.9%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[NH:16][C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26]C1C=C(C=CC=1)CN>>[Cl:26][C:6]1[CH:7]=[C:2]([CH:3]=[CH:4][CH:5]=1)[CH2:1][NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[NH:16][C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1)=[O:10]
Reactant: NCc1cccc(Cl)c1
Reactant: O=C(NCc1ccccc1)c1sccc1Nc1ncnc2[nH]ccc12
Product: O=C(NCc1cccc(Cl)c1)c1sccc1Nc1ncnc2[nH]ccc12
Yield: 15 %

Procedure:
The title compound was prepared in an analogous manner as 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid benzylamide using 3-chlorobenzylamine instead of benzylamine and obtained in 15% yield (HPLC: 94%, RT: 6.54 min). 1H NMR (DMSO-d6) 11.98 (br s, 1H), 11.33 (s, 1H), 8.61 (t, J=6.0 Hz, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.39 (s, 1H), 7.81 (d, J=5.5 Hz, 1H), 7.41-7.29 (m, 5H), 6.43 (dd, J=3.7, 1.8 Hz, 1H), 4.50 (d, J=5.9 Hz, 2H); MS (m/z) 384 [M+H]+ (35Cl).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=3)[NH:13][C:12]2=[O:21])=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:30][CH2:31][C:32](Cl)=[O:33].O>C1COCC1>[Cl:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:21])[C:11]2=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:32](=[O:33])[CH:31]=[CH2:30])[CH:10]=2)[CH2:6][O:7]1
Reactant: O=C(Cl)CCBr
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccc(Cl)cc31)OC2
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc2c(c1)C(=C1C(=O)Nc3ccc(Cl)cc31)OC2
Temperature: 45 °C
Yield: 89.3 %

Procedure:
To a stirred mixture of 3-(6-amino-3H-isobenzofuran-1-ylidene)-5-chloro-1,3-dihydro-indol-2-one (300 mg, 1.0 mmol) and triethylamine (0.41 ml, 3.0 mmol) in THF (10 ml), was added 3-bromopropionyl chloride (0.12 ml, 1.2 mmol). The mixture was heated at 45° C. for 2 hours, cooled to room temperature and poured into water (150 ml). The solid was filtered, washed with water and dried under vacuum to give crude product. The crude product was triturated with toluene to afforded N-[3-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-5-yl]-acrylamide as a bright yellow solid (315 mg, 89%).
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH:12]4[CH2:16][CH:15]([C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[NH:14][CH2:13]4.[CH3:17][C:18]1[N:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1>>[CH3:17][C:18]1[N:23]=[CH:22][C:21]([C:2]2[C:10]3[NH:9][C:8]4[CH2:11][CH:12]5[CH2:16][CH:15]([C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[NH:14][CH2:13]5)=[CH:20][CH:19]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cccc2c3c([nH]c12)CC1CNC3C1
Product: Cc1ccc(-c2cccc3c4c([nH]c23)CC2CNC4C2)cn1

Procedure:
The product of Example 30A (55 mg, 0.20 mmol) and 6-methylpyridine-3-boronic acid pinacol ester (44 mg, 0.20 mmol; Synthonix) were processed as described in Example 11 to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 1.99-2.05 (m, 1H), 2.09-2.17 (m, 1H), 2.60 (s, 3H), 2.88 (dd, J=17.1, 2.4 Hz, 1H), 3.12-3.20 (m, 2H), 3.23-3.28 (m, 1H), 3.57 (t, J=3.4 Hz, 1H), 4.05 (dt, J=5.5, 2.7 Hz, 1H), 7.01-7.05 (m, 1H), 7.11 (t, J=7.5 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H), 7.50 (dd, J=7.8, 1.1 Hz, 1H), 7.94 (dd, J=7.9, 2.1 Hz, 1H), 8.61 (d, J=2.1 Hz, 1H); MS (ESI+) m/z 290 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.S([O-])(O)(=O)=O.[K+]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[C:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)C(O)c1ccc(OC)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)C(C)=Cc1ccc(OC)cc1

Procedure:
A mixture of 71.8 g (0.30 mole) of ethyl β-(p-methoxyphenyl)-β-hydroxy-α-methylpropionate is refluxed with 41.0 g (0.30 mole) of potassium hydrogen sulfate in 718 ml of benzene for one hour. The insoluble white crystals formed are filtered off, washed with benzene and the solvent of the filtrate is removed on evaporation. This is dissolved in 700 ml of ether. The ether solution is washed with 4 × 100 ml of cold water until neutral followed by 80 ml of saturated sodium chloride solution, then it is dried over magnesium sulfate for 1.5 hours and filtered. The solvent is removed on an evaporator to give ethyl p-methoxy-α-methylcinnamate.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH:9](=O)[CH:10]([CH3:12])[CH3:11].O>C1C=CC=CC=1.S(=O)(=O)(O)O>[CH:10]([CH:12]1[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1)([CH3:11])[CH3:9]
Reactant: CC(C)C=O
Reactant: Oc1ccccc1O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: CC(C)C1Oc2ccccc2O1
Yield: 33.5 %

Procedure:
Catechol (22 g, 0.2 mole) and isobutyraldehyde (16 g, 0.24 mole) were dissolved in benzene (600 ml). A catalytic amount (5 drops) of sulfuric acid was added to the mixture. The mixture was heated under reflux and the water formed in the reaction was removed by use of a Dean-Stark trap. The reaction mixture was washed twice with aqueous sodium carbonate solution and dried. 2-Isopropyl-1,3-benzodioxole (11 g, 0.067 mole) was obtained by vacuum distillation. The 2-isopropyl-1,3-benzodioxole thus obtained boiled at 29-31° C. at 0.25 mm Hg. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:35][O:36][C:37](=[O:41])[CH2:38][CH2:39][NH2:40]>CN(C=O)C.C(N(CC)CC)C>[CH3:35][O:36][C:37](=[O:41])[CH2:38][CH2:39][NH:40][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=1
Reactant: COC(=O)CCN
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
4-Formylbenzoic acid (15 g, 100 mmol) was dissolved in DMF (250 mL) and 1-hydroxybenzotriazole (14.9 g, 110 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (21.1 g, 110 mmol) were added and the resulting mixture was stirred at room temperature for 30 minutes. Triethylamine (34.8 mL, 250 mmol) and β-alanine methyl ester hydrochloride (15.4 g, 110 mmol) were added and the resulting mixture was stirred at room temperature for 1 hour. More triethylamine (17.4 mL) and β-alanine methyl ester hydrochloride (7.7 g) were added and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (200 mL) and water (200 mL). The organic phase was dried (MgSO4) and concentrated to afford 16.2 g (70%) of 3-(4-formylbenzoylamino)propionic acid methyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[N:32]1([C:38]2[CH:43]=[N:42][CH:41]=[CH:40][N:39]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:35]4[CH2:36][CH2:37][N:32]([C:38]5[CH:43]=[N:42][CH:41]=[CH:40][N:39]=5)[CH2:33][CH2:34]4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: c1cnc(N2CCNCC2)cn1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(c2cnccn2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-(1-piperazinyl)pyrazine as in General Procedure 10 to give the title compound. LCMS: m/z=593.98 (M+H+); retention time=0.79 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[CH:9].C([Li])CCC.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[O:22])[CH:16]=1.O>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][CH:21]([C:17]1[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=1)[OH:22]
Reactant: C#Cc1ccccc1Cl
Reactant: O=Cc1cccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: OC(C#Cc1ccccc1Cl)c1cccnc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 655 mg (4.8 mmol) of 2-chlorophenylacetylene in 10 mL of tetrahydrofuran (THF) cooled to −78° C. under a nitrogen atmosphere was added 3.0 mL (4.8 mmol) of 1.6M n-butyllithium in hexane. The solution was stirred at −78° C. for 2 hrs, and then a solution of 514 mg (4.8 mmol) of 3-pyridinecarboxaldehyde in 2.5 mL of tetrahydrofuran (THF) was added. After 3.5 hrs, the reaction mixture was poured into water. The organic product was extracted with ether several times. Combined ether extracts were washed with saturated sodium bicarbonate and dried over magnesium sulfate. The drying agent was filtered off, and the ether was removed by rotoevaporation to give the oily 3-(2-chlorophenyl)-1-(3-pyridyl)-2-propyn-1-ol.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:11](=[N:24][NH2:25])([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.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2].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>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([CH3:10])=[CH:3][C:2]=1[NH:25][N:24]=[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C)cc1NN=C(c1ccccc1)c1ccccc1
Temperature: 85 °C
Reaction time: 12 h
Yield: 95.4 %

Procedure:
To a stirred, degassed suspension of 3-iodo-4-methoxytoluene (19.84 g, 80 mmol, 1 equiv), benzophenone hydrazone (17.99 g, 88 mmol, 1.1 equiv), Xantphos (93 mg, 0.16 mmol, 0.2 mol %), and Pd(OAc)2 (36 mg, 0.16 mmol, 0.2 mol %) in anhydrous toluene (96 mL) was added NaOtBu (11.09 g, 112 mmol, 1.4 equiv) in one portion at rt. The mixture was heated to 85° C. and stirred for 12 h. The reaction mixture was cooled, diluted with 200 mL EtOAc and 100 mL water, then the layers separated. The insoluble Pd residues were separated as the aqueous layer was removed. The organic phase was washed 2×100 mL water, then brine, and dried over Na2SO4. The solution was concentrated under reduced pressure, giving an orange-yellow solid. The solid was triturated in 50 mL MeOH, collected via filtration, and washed with 50 mL MeOH. Drying under suction gave the title compound as a yellow solid (24.16 g, 95% yield). 1H NMR (400 MHz, DMSO-d6) δ 2.25 (s, 3H), 3.56 (s, 3H), 6.53 (dd, 1H), 6.72 (d, 1H), 7.30 (m, 6H), 7.46 (d, 2H), 7.56 (m, 1H), 7.62 (m, 2H), 7.79 (s, 1H). ES-MS m/z 317.1 (MH+); HPLC RT (min) 4.26.
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])(=O)=O.[CH2:18]([O:22][C:23]1[N:28]=[C:27]([CH3:29])[C:26]([C:30](O)=[O:31])=[CH:25][N:24]=1)[CH2:19][CH2:20][CH3:21].C(=O)([O-])O.[Na+]>O>[CH2:18]([O:22][C:23]1[N:28]=[C:27]([CH3:29])[C:26]([C:30]([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])=[O:31])=[CH:25][N:24]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Reactant: CCCCOc1ncc(C(=O)O)c(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1ncc(C(=O)OCCC(C)=C(F)F)c(C)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
To 50 ml of N,N-dimethylformamide were dissolved 6.6 g (33 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate and 7.6 g (36 mmol) of 2-butoxy-4-methylpyrimidine-5-carboxylic acid, followed by the addition of 3.6 g (43 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 2 hours. The reaction liquid was then poured in water and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:9) to obtain 3.3 g (yield: 32%) of 4,4-difluoro-3-methyl-3-butenyl 2-butoxy-4-methylpyrimidine-5-carboxylate.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][O:11]C(=O)C)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].Cl.C(OC)(=O)C.CO>CO>[CH2:6]([O:5][P:4]([CH2:9][CH2:10][OH:11])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(CCOC(C)=O)OCC
Agent: Cl
Solvent: COC(C)=O
Solvent: CO
Product: CCOP(=O)(CCO)OCC
Yield: 83.7 %

Procedure:
100 g of 2-acetoxyethane phosphonic acid diethyl ester are blended with 200 ml of methanol containing 1 wt.% of HCl and heated to 65°-70°C for 4 hours. A mixture of methyl acetate/methanol is removed continuously from the reaction mixture by distillation. Upon submitting the mixture of methyl acetate/methanol to gas chromatography no ethyl acetate at all and only traces of ethanol are found. The crude 2-hydroxyethanephosphonic acid diethyl ester is distilled under reduced pressure. 68 g of 2-hydroxyethane-phosphonic acid diethyl ester (b.p. 106°-109°C/0.1 torr) are obtained, corresponding to a yield of 83.5% of the theoretical.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18](=[CH2:20])[CH3:19].C(=O)=O>C(Cl)Cl.S(=O)(=O)(O)O>[C:18]([O:15][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:20])([CH3:19])[CH3:17]
Reactant: C=C(C)C
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzyloxycarbonyl-L-alanine (15.0 g) (67.2 mmol) was dissolved in methylene chloride with about 1 mL of concentrated sulfuric acid. Isobutylene was added via a dry-ice, cold finger trap. The solution was allowed to warm to room temperature and left stirring overnight. The solution was charged with isobutylene again and left stirring overnight. The solution was extracted with 0.8N aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and evaporated under vacuum to give benzyloxycarbonyl-L-alanine t-butyl ester. 1H NMR (CDCl3) δ7.35 (s, 5H), 5.12 (s, 2H), 4.23 (m, 2H), 1.45-1.30 (s/d, 12H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([O:13]CC)=O)[N:7]=1.Cl.[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1.[OH-].[Na+].O.CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH2:32][NH:33][C:11]([C:8]1[N:7]=[C:6]([CH2:5][C:4]2[CH:16]=[C:17]([F:19])[CH:18]=[C:2]([F:1])[CH:3]=2)[O:10][N:9]=1)=[O:13]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CCOC(=O)c1noc(Cc2cc(F)cc(F)c2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2cc(F)cc(F)c2)n1
Yield: 29.6 %

Procedure:
This compound was prepared according to method F with ethyl 5-(3,5-difluorobenzyl)-1,2,4-oxadiazole-3-carboxylate (0.116 g; 0.433 mmol) in THF (1 mL) and sodium hydroxide in water (2M, 1 mL); and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), HATU (0.164 g; 0.432 mmol), N,N diisopropylethylamine (0.075 mL; 0.432 mmol), in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) and by preparative HPLC method 2 to yield 0.0535 g (30%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(3,5-difluorobenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][N:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.BrC1SN=CC=1.O1C2(CCC(=O)CC2)OCC1.[NH:31]1[CH2:34][CH:33]([NH:35][C:36](=[O:53])[CH2:37][NH:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[C:46]([C:49]([F:52])([F:51])[F:50])[CH:47]=3)[N:42]=[CH:41][N:40]=2)[CH2:32]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[OH:1][C:2]1([C:9]2[S:13][N:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:31]2[CH2:32][CH:33]([NH:35][C:36](=[O:53])[CH2:37][NH:38][C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[C:46]([C:49]([F:50])([F:52])[F:51])[CH:47]=4)[N:42]=[CH:41][N:40]=3)[CH2:34]2)[CH2:4][CH2:3]1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: O=C1CCC(O)(c2ccns2)CC1
Agent: Brc1ccns1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C1CCC2(CC1)OCCO2
Product: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(O)(c3ccns3)CC2)C1

Procedure:
Reaction of 4-hydroxy-4-(isothiazol-5-yl)cyclohexanone (prepared by the reaction of 5-bromoisothiazole with 1,4-dioxaspiro[4.5]decan-8-one using the sequence described in Example 24 Step A-B) with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product. 1H NMR (CHLOROFORM-d) δ: 8.61 (s, 1 H), 8.45-8.51 (m, 1 H), 8.35 (d, J=1.8 Hz, 1 H), 7.92-7.98 (m, 1 H), 7.87-7.92 (m, 1 H), 7.04 (d, J=1.8 Hz, 1 H), 4.62 (t, J=6.8 Hz, 1 H), 4.21-4.31 (m, 2 H), 3.97-4.09 (m, 2 H), 3.79-3.88 (m, 1 H), 3.13 (q, J=7.3 Hz, 6 H), 2.05-2.26 (m, 2 H), 1.78 (d, J=12.9 Hz, 6 H), 1.35 (t, J=7.3 Hz, 9 H); ESI-MS (m/z): Calcd. For C23H25F3N6O2S: 506.17. found: 507 (M+H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22](OCC)=[O:23])[N:21]=2)[CH:18]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]([NH:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)=[O:23])[N:21]=2)[CH:18]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: CC(C)c1ccc(CN)cc1
Product: CC(C)c1ccc(CNC(=O)c2cn3cc(Br)ccc3n2)cc1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (4-isopropylphenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.