Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(O[C:16](=[O:18])[CH3:17])(=O)C>C1(C)C=CC=CC=1>[C@@H:9]1([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]=2[NH:11][C:16](=[O:18])[CH3:17])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1c([C@H]2CCCc3ccccc32)ccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-1,2,3,4-tetrahydro-1-naphthylamine (26.9 g.) is dissolved in 200 ml. of toluene and 36 g. of acetic anhydride is added while the temperature from the reaction exotherm is moderated at 50° C. to 60° C. with an ice-bath. The solution is heated to reflux for 0.5 hr. and then stirred at room temperature overnight. The mixture is then evaporated to dryness and the residue is washed well with ether. On drying, 26.1 g. of the title compound, m.p. 153° C. to 155° C., is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[NH:18][CH2:17][CH2:16]2.C(=O)([O-])O.[Na+]>CS(C)=O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH2:17][CH2:16]2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1cc2c(cc1OC)NCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc2c(cc1OC)N(c1ccc([N+](=O)[O-])cc1)CC2
Yield: 65.6 %

Procedure:
6.3 g of 4-nitrofluorobenzene (0.045 mol) were stirred with 8.0 g of 5,6-dimethoxyindoline (0.045 mol) and 4.2 g of sodium hydrogen carbonate (0.050 mol) for 2.5 h at 80° C. in 50 ml of DMSO. After cooling, the mixture was poured onto ice, the precipitate was removed by filtration under suction and the product was dried in vacuo at 45° C. The intermediate product 5,6-dimethoxy-1-(4-nitrophenyl)-indoline was obtained in a yield of 65.6% (melting point: 176-179° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][CH2:12]2)[CH:9]=[O:10])=[CH:4][CH:3]=1.CC(=CC)C.[OH:27]P([O-])(O)=O.[K+].Cl([O-])=O.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC(O)(C)C.O>[C:17]([O:16][C:15]([NH:14][C:11]1([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]([OH:27])=[O:10])[CH2:12][CH2:13]1)=[O:21])([CH3:18])([CH3:20])[CH3:19]
Reactant: O=P([O-])(O)O
Reactant: CC(C)(C)OC(=O)NC1(C(C=O)c2ccc(Cl)cc2)CC1
Agent: CC=C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C(C(=O)O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
tert-Butyl 1-(1-(4-chlorophenyl)-2-oxoethyl)cyclopropylcarbamate (0.64 mmol), 2-methyl-2-butene (1.6 mL, 2.0 M THF solution, 3.2 mmol) and KH2PO4 (0.087 g, 0.64 mmol) were dissolved in t-BuOH (20 mL)-water (6 mL). Sodium chlorite (0.174 g, 1.93 mmol) was added portionwise at 0° C. The mixture was stirred at room temperature for 2 hours and then acidified with 10% citric acid. The reaction was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated to give 2-(1-(tert-butoxycarbonylamino)cyclopropyl)-2-(4-chlorophenyl)acetic acid (0.19 g, 91%) as a colorless syrup, which was used for amide coupling without further purification. LCMS: 325.8 [M+H+] (APCI+); Rf: 3.31 min.
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[OH:16][CH2:17][CH2:18][NH:19][NH2:20]>O>[NH2:11][C:10]1[N:19]([CH2:18][CH2:17][OH:16])[N:20]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1
Reactant: NNCCO
Reactant: N#CCC(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(-c2ccccc2)nn1CCO
Yield: 78.7 %

Procedure:
Benzoylacetonitrile (25 g, 0.17 mol) was suspended in a mixture of 125 mL reagent grade anhydrous alcohol and 20 mL glacial acetic acid. 2-Hydroxyethylhydrazine (14.4 g, 1.1 equiv) dissolved in 35 mL alcohol was added all at once. The mixture was heated at reflux for 4 h, cooled, water was added to make 500 mL total volume and the solution was chilled in a refrigerator overnight. Crystals were filtered cold on a Buchner funnel, washed with cold water and dried on high vacuum to give the desired product (27.2 g, 79%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14](F)[CH:13]=2)=[O:9])=[C:6]([CH3:20])[CH:5]=[C:4]([Cl:21])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:28]([SH:30])[CH3:29].O>CN(C=O)C>[Cl:21][C:4]1[N:3]=[C:2]([S:30][CH2:28][CH3:29])[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([F:18])[CH:17]=2)=[O:9])=[C:6]([CH3:20])[CH:5]=1
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)NCc1cc(F)cc(F)c1
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1nc(Cl)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
A solution of 4.0 g (12.8 mmol) 2,6-dichloro-N-(3,5-difluorobenzyl)-4-methyl-pyridine-3-carboxylic acid amide in DMF (30 ml) was treated with 2.6 g (19.2 mmol) K2CO3 and 1.2 ml (16.0 mmol) ethanethiol, followed by stirring in a closed vessel at RT for 16 h. Then water (35 ml) was added and the mixture was extracted with EtOAc (2×70 ml). The combined organic layers were washed with water, a 2M aq. NaOH sol. and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:1) provided 3.3 g (9.7 mmol, 76%) 6-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide.
Reaction SMILES: [Li].[F:2][C:3]([F:22])([F:21])[O:4][C:5]1[CH:6]=[C:7]([C:11]([O-])=[CH:12][C:13](=O)[C:14]([O:16]CC)=[O:15])[CH:8]=[N:9][CH:10]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:46][C:47]1[CH:48]=[C:49]([NH:53][NH2:54])[CH:50]=[CH:51][CH:52]=1>>[Cl:46][C:47]1[CH:48]=[C:49]([N:53]2[C:11]([C:7]3[CH:8]=[N:9][CH:10]=[C:5]([O:4][C:3]([F:2])([F:21])[F:22])[CH:6]=3)=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[N:54]2)[CH:50]=[CH:51][CH:52]=1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cncc(OC(F)(F)F)c1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cncc(OC(F)(F)F)c2)n(-c2cccc(Cl)c2)n1

Procedure:
1.13 g (3.25 mmol) of the compound of Example 18A is reacted analogously to the synthesis of the compound of Example 20A with 874 mg (4.88 mmol) of 3-chlorophenylhydrazine hydrochloride. After hydrolysis, 609 mg (49% of theory) of the title compound is obtained.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:28][CH2:29][N:30]([CH:33]3[CH2:35][CH2:34]3)[C:31](=[O:32])[C:10]=12)C1C=CC=CC=1>C(O)(=O)C.OS(O)(=O)=O>[CH:33]1([N:30]2[CH2:29][CH2:28][N:11]3[C:12]([CH2:16][C:17]4([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=5)[CH2:21][CH2:20][CH2:19][CH2:18]4)=[N:13][C:14](=[O:15])[C:9]([OH:8])=[C:10]3[C:31]2=[O:32])[CH2:34][CH2:35]1
Reactant: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccn4)CCCC3)n2CCN1C1CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C1c2c(O)c(=O)nc(CC3(c4ccccn4)CCCC3)n2CCN1C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.6 %

Procedure:
To a stirred solution of 9-benzyloxy-2-cyclopropyl-6-(1-pyridin-2-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (452) (250 mg, crude) in acetic acid (4 mL), concentrated H2SO4 (0.001 mL) was added and the reaction mixture was stirred for 2 h at room temperature (monitored by LC-MS). Volatiles were removed from the reaction mixture ant the residue was quenched with ice water (10 mL). The pH of the mixture was adjusted to 8 using NaHCO3 and extracted with 10% methanol in dichloromethane (2×40 mL). The crude product obtained after drying and concentrating the organic part was purified by preparative HPLC to get 2-cyclopropyl-9-hydroxy-6-(1-pyridin-2-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (453) (17.3 mg, 30% 2 steps) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH:13]=2)[O:3]1.[ClH:28]>O1CCOCC1>[ClH:28].[CH3:1][C:2]1([CH3:27])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:13]=2)[O:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)OB(c2cnn(C3CCNCC3)c2)OC1(C)C
Temperature: 35 °C
Reaction time: 3 h
Yield: 120.1 %

Procedure:
A solution of tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (5.02 g, 13.3 mmol) in 1,4-dioxane (40 mL) was treated with HCl (4.0 M in 1,4-dioxane, 50 mL, 200 mmol) and stirred at 35° C. for 3 h. The reaction mixture was concentrated in vacuo to a white solid, affording 5.01 g (100%) of the title compound. The material was used without additional purification. 1H NMR (400 MHz, CDCl3) δ 1.33 (s, 12H), 2.50 (br s, 4H), 3.09-3.41 (m, 2H), 3.57-3.79 (m, 2H), 4.73 (br s, 1H), 7.87 (s, 2H), 9.82 (br s, 2H); MS (ESI): 278.15 [M+H]+; HPLC tR=2.01 min.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].O.[C:11]1(C)[CH:16]=CC(S(O)(=O)=O)=C[CH:12]=1.COC(OC)(C)C>CN(C)C=O>[CH3:12][C:11]1([CH3:16])[O:5][CH2:4][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:2][O:1]1
Reactant: OCC(CO)(CO)CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCC(CO)(CO)CO1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
Pentaerythritol (50 g, 0.36 mol) and p-toluenesulfonic acid monohydrate (0.61 g) were dissolved in 500 ml N,N-dimethylformamide (DMF, dried by molecular sieve at room temperature) at about 80° C., and then the mixture was allowed to cool undisturbed. When the solution cooled to about 40° C., stirring was started and 55.4 ml 2,2-dimethoxypropane (0.36 mol) was added. After 24 hours of stirring at room temperature, the solution was stirred at room temperature with 9.0 g of base treated DOWEX 1XZ-100 ion-exchange resin for 1 hour, filtered and then the solvent was evaporated under reduced pressure at 85° C. The base treated DOWEX 1XZ-100 ion exchange was prepared by washing 30 g. twice with 200 ml of deionized water, then washed with 300 ml of 4% aq. NaOH and then washed three times with 200 ml of water, filtered and then air-dried in a hood. After the treatment with this resin as noted above, the dry product was ground and extracted (Soxhlet), first with light petroleum ether (b.p. 40-60° C.) for 6 hours, then with diethyl ether for 12 hours, collected and dried. Yield: White crystals (40.0 g, 61.9%). M.P. 124.5°-125.5° C.; 11H-NMR (300 MHz, DMSO-d6) 1.28 ppm (s, 6H), 3.34 ppm (d, J=5.7 Hz, 4H), 3.58 ppm (s, 4H), 4.47 ppm (t, J=5.4 Hz, 2H);
Reaction SMILES: [C:1]([C:6]1[N:10]2[CH:11]=[C:12]([CH3:27])[CH:13]=[C:14]([NH:15][CH2:16][C:17]3[C:22]([CH2:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:25][CH3:26])[C:9]2=[N:8][C:7]=1[CH3:28])(OCC)=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:23]([C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:25][CH3:26])[C:17]=1[CH2:16][NH:15][C:14]1[C:9]2[N:10]([C:6]([CH2:1][OH:2])=[C:7]([CH3:28])[N:8]=2)[CH:11]=[C:12]([CH3:27])[CH:13]=1)[CH3:24]
Reactant: CCOC(=O)c1c(C)nc2c(NCc3c(CC)cccc3CC)cc(C)cn12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1CNc1cc(C)cn2c(CO)c(C)nc12
Reaction time: 4 h

Procedure:
A solution of 3-carboethoxy-2,6-dimethyl-8-(2,6-diethylbenzylamino)imidazo[1,2-a]pyridine (1.75 g, 4.6 mmol) in 30 ml tetrahydrofuran was treated with lithium aluminiumhydride (0.7 g, 18.5 mmol) at room temperature during 3.5 h. The reaction was complete after 4 h and was quenched carefully by dropwise addition of water (0.7 ml), aqueous sodium hydroxide (0.7 ml, 15%) and again water (2 ml). The mixture was extracted with chloroform and the organic layer was concentrated. The residue was recrystallized in ethanol and the white crystalline product was filtrated, washed with diethyl ether and dried in vacuo, which gave 1.5 g (96%) yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:24]2[CH:28]=[C:27]([C:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=3)[S:26][C:25]=2[C:35]([O:37][CH3:38])=[O:36])[C:15]([C@H:17]2[CH2:22][CH2:21][C@H:20]([CH3:23])[CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:38][O:37][C:35]([C:25]1[S:26][C:27]([C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)=[CH:28][C:24]=1[N:14]([C:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH3:23])[CH2:19][CH2:18]1)=[O:16])[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:36]
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCNCC1

Procedure:
A solution of 4-[(5-cyclohex-1-enyl-2-methoxycarbonyl-thiophen-3-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (2.3 g, 4.22 mmol) in dichloromethane (15 mL) and trifluoroacetic acid (15 mL) was stirred at room temperature under N2 atmosphere for 4 h. Solvents were removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated NaHCO3. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using methanol, chloroform and triethyl amine (10:89:1) as eluent to obtain 5-cyclohex-1-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-thiophene-2-carboxylic acid methyl ester (1.5 g, 80%) as a solid.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])CCC.[NH2:26][C@H:27]([C:29]([OH:31])=[O:30])[CH3:28]>C[O-].[Na+].CO>[CH:20]1([O:19][C:13]2[CH:12]=[C:11]3[C:16]([C:17]([OH:18])=[C:8]([C:6]([NH:26][C@@H:27]([CH3:28])[C:29]([OH:31])=[O:30])=[O:7])[N:9]=[CH:10]3)=[CH:15][CH:14]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C[C@H](N)C(=O)O
Reactant: CCCCOC(=O)c1ncc2cc(OC3CCCCC3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](NC(=O)c1ncc2cc(OC3CCCCC3)ccc2c1O)C(=O)O
Yield: 62.3 %

Procedure:
A mixture of 7-cyclohexyloxyl-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (80 mg) and L-alanine (207 mg) in 0.5 M sodium methoxide in methanol (3.7 ml) was heated in a microwave reactor (sealed tube) at 120° C. for 40 min. Reaction mixture was concentrated, dissolved in water (30 ml), and acidified by 2 N HCl to pH=4. It was extracted with ethyl acetate. Organic layer was washed with water, brine, dried over magnesium sulfate, and filtered. Filtrate was concentrated and purified by silica gel chromatography to give the title compound (52 mg). MS-(+)-ion M+1=359.18.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][C:14]=2[CH3:15])[S:6][CH:7]=1.[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30]([O:32][CH3:33])=[O:31].CN(C)C=O.[H-].[Na+]>O>[CH3:15][C:14]1[O:13][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:11][C:10]=1[CH2:9][CH2:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([O:32][CH3:33])=[O:31])[N:4]=1
Reactant: COC(=O)Cc1ccccc1O
Reactant: Cc1oc(-c2ccccc2)nc1CCc1nc(CCl)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccccc1OCc1csc(CCc2nc(-c3ccccc3)oc2C)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.5 %

Procedure:
To a mixture of 4-[2-(4-chloromethyl-2-thiazolyl)ethyl]-5-methyl-2-phenyloxazole (0.64 g), methyl 2-(2-hydroxyphenyl)acetate (0.30 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.09 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water, 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give methyl 2-[2-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-thiazolyl]methoxy]phenyl]acetate as a colorless oil (0.49 g, 60%) from a fraction eluted with ethyl acetate-hexane (1:3, v/v).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][N:46]1[C:50]([NH:51][C:52]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[C:49]([NH2:71])[CH:48]=[N:47]1>C(Cl)Cl.O>[C:19]([O:18][C:16]([NH:15][CH2:14][CH:10]([C:11]([NH:71][C:49]1[CH:48]=[N:47][N:46]([CH3:45])[C:50]=1[NH:51][C:52]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1)[C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)=[O:13])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cn1ncc(N)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: ClCCl
Product: Cn1ncc(NC(=O)C(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 27.6 %

Procedure:
To a solution of 3-[(tert-butoxycarbonyl)amino]-2-{[(tert-butoxycarbonyl)amino]methyl}propanoic acid (476 mg) in methylene chloride (6 ml) were added hydroxybenzotriazole (222 mg) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (573 mg), and the mixture was stirred for 10 minutes. 1-Methyl-N5-trityl-1H-pyrazole-4,5-diamine (530 mg) was added to the above mixture, and the whole mixture was stirred at room temperature for 1 hour. Water was added to the mixture and the whole mixture was extracted with ethyl acetate. The extract was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give tert-butyl (2-{[(tert-butoxycarbonyl)amino]methyl}-3-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3-oxopropyl)carbamate (270 mg).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[C:10]([O:12]C)[C:9]([Cl:14])=[CH:8][C:7]=1[CH2:15][C:16]([OH:18])=[O:17].[CH3:19]O>ClCCl>[Cl:5][C:6]1[CH:11]=[C:10]([OH:12])[C:9]([Cl:14])=[CH:8][C:7]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: CO
Reactant: COc1cc(Cl)c(CC(=O)O)cc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)Cc1cc(Cl)c(O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
Boron tribromide (1.581 mL, 16.72 mmol) was added dropwise to 2-(2,5-dichloro-4-methoxyphenyl)acetic acid (Intermediate 4-4; 655 mg, 2.79 mmol) in dichloromethane (20 mL) at ambient temperature under nitrogen. The resulting solution was stirred at ambient temperature for 60 minutes. The reaction mixture was cautiously added to methanol (100 mL) (—care reaction is vigorous and exothermic—mixture became reasonably warm during the addition) and the mixture was stirred for a further 2 hours at ambient temperature. The reaction mixture was evaporated to dryness and redissolved in DCM (100 mL), and washed sequentially with 2M HCl (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(2,5-dichloro-4-hydroxyphenyl)acetate (258 mg, 39.4%) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH2:14][CH2:15][OH:16])=[O:12])[C:5]([F:21])=[CH:4][N:3]=1.[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]2[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=2)[NH2:33])[CH2:24][CH2:23]1.Cl>C(O)(C)C>[F:21][C:5]1[C:6]([NH:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH2:14][CH2:15][OH:16])=[O:12])=[N:7][C:2]([NH:33][C:32]2[CH:34]=[CH:35][CH:36]=[C:30]([CH2:29][CH2:28][N:25]3[CH2:24][CH2:23][O:22][CH2:27][CH2:26]3)[CH:31]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(CCN2CCOCC2)c1
Reactant: O=C(NCCO)c1ccccc1Nc1nc(Cl)ncc1F
Agent: Cl
Solvent: CC(C)O
Product: O=C(NCCO)c1ccccc1Nc1nc(Nc2cccc(CCN3CCOCC3)c2)ncc1F
Temperature: 90 °C
Reaction time: 18 h
Yield: 71.1 %

Procedure:
2-[(2-Chloro-5-fluoro-4-pyrimidinyl)amino]-N-(2-hydroxyethyl)benzamide (500 mg, 1.61 mmol) and 3-(morpholinoethyl)aniline (352 mg, 1.61 mmol) were combined in a tube with 30 mL isopropanol and 12N HCl (134 μL, 1.60 mmol). The vessel was sealed and heated with stirring at 90° C. for 18 h. The reaction was cooled to room temperature and the solid was filtered off and washed with isopropanol and ether to give 550 mg (71% yield) of a white solid as the HCl salt, LC/MS (M+H)+480, 481.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]1([C:18]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:23]=[CH:22][S:21](=[O:24])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[C:12]1([C:18]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=[CH:20][S:21](=[O:6])(=[O:24])[CH2:22][CH2:23]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S1C=CC(c2ccccc2)(c2ccccc2)CC1
Solvent: ClCCl
Product: O=S1(=O)C=CC(c2ccccc2)(c2ccccc2)CC1
Temperature: 20 °C
Reaction time: 20 h
Yield: 83.5 %

Procedure:
A solution of 1.12 g of 3-chloroperoxybenzoic acid (at 85%) in 25 cm3 of dry dichloromethane is added to a solution of 1.47 g of 3,4-dihydro-4,4-diphenyl-2H-thiapyran 1-oxide in 15 cm3 of dry dichloromethane. After stirring for 20 hours at 20° C. the reaction mixture is washed with 50 cm3 of a 10% aqueous solution of sodium thiosulphate and then with 50 cm3 of a saturated aqueous solution of sodium hydrogen carbonate. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The crystalline residue is washed with ethyl ether, drained and dried under reduced pressure (2.7 kPa). 1.3 g of 3,4-dihydro-4,4-diphenyl2H-thiapyran 1,1-dioxide are obtained in the form of white crystals; melting point 166° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:27]=[C:28]([C:32]([OH:34])=O)[CH:29]=[N:30][CH:31]=1.CCN(C(C)C)C(C)C.[CH3:44][C@@H:45]1[NH:50][CH2:49][CH2:48][N:47]([S:51]([C:54]2[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=2)(=[O:53])=[O:52])[CH2:46]1>CN(C=O)C>[Br:25][C:26]1[CH:27]=[C:28]([C:32]([N:50]2[CH2:49][CH2:48][N:47]([S:51]([C:54]3[CH:55]=[CH:56][C:57]([C:60]([F:63])([F:61])[F:62])=[CH:58][CH:59]=3)(=[O:52])=[O:53])[CH2:46][C@@H:45]2[CH3:44])=[O:34])[CH:29]=[N:30][CH:31]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
HATU (458 mg, 1.21 mmol) was added to a solution of 5-bromo-3-pyridinecarboxylic acid (supplied by Aldrich) (203 mg, 1.01 mmol) in DMF (4 ml) and the mixture was treated with DIPEA (0.438 ml, 2.51 mmol). This mixture was stirred for ca. 10 min at ambient temperature. (3S)-3-Methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 2) (372 mg, 1.21 mmol) was added and stirring was continued for 1.5 h. The reaction mixture was partitioned between DCM and sat aq. NaHCO3 solution (20 ml each). The layers were separated and the aqueous was washed with further DCM (2×20 ml). The combined organic layers were concentrated to leave an dark brown gum.