Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].B(F)(F)F.[CH3:31]COCC>CO>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:31])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCOCC
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: FB(F)F
Solvent: CO
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)cc1
Temperature: 0 °C

Procedure:
A solution of 50.5 g of 4-(n-hexadecylamino)benzoic acid and 34.4 ml of boron trifluoride etherate in 200 ml of methanol is stirred under reflux for 44 hours, allowed to cool, and is poured into 1.20 liters of ice cold 5% aqueous sodium carbonate solution. The white solid is collected by filtration and recrystallized from benzene-ethanol to yield methyl 4-(n-hexadecylamino)benzoate, mp 92°-93° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[NH2:18][OH:19]>CCO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[C:13](=[N:18]/[OH:19])/[NH2:14])=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: NO
Reactant: CCCCCCCOc1ccc(C#N)cc1
Agent: Cl
Solvent: CCO
Product: CCCCCCCOc1ccc(/C(N)=N/O)cc1
Temperature: 85 °C
Yield: 91.2 %

Procedure:
Prepared using General Procedure 2: To a stirring solution of 4-(heptyloxy)benzonitrile (1.0 g, 4.6 mmol) in EtOH (15 mL) were added hydroxylamine hydrochloride (0.96 g, 13.8 mmol) and TEA (2.22 g, 23.0 mmol). The reaction was heated to 85° C. for 2 h. The solvent was removed under reduced pressure and the residue was diluted with water (20 mL) and extracted with DCM (3×10 mL). The combined organic layers were concentrated under reduced pressure. The crude material was crystallized from isopropanol (20 mL) to afford 1.05 g (91%) of (Z)-4-(heptyloxy)-N′-hydroxybenzimidamide as a white solid. LCMS-ESI (m/z) calculated for C14H22N2O2: 250.2. found 251.3 [M+H]+, tR=1.70 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 7.59 (d, J=8.6 Hz, 2H), 6.93 (t, J=14.7 Hz, 2H), 5.82-5.48 (m, 2H), 3.97 (t, J=6.5 Hz, 2H), 1.83-1.55 (m, 2H), 1.56-1.05 (m, 8H), 0.87 (t, J=6.7 Hz, 3H). 13C NMR (101 MHz CDCl3) δ 159.19, 150.53, 126.64, 125.55, 113.87, 67.40, 31.21, 28.62, 28.40, 25.44, 22.02, 13.92.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[O:21][CH3:22])[N:17]=[C:16]([CH3:23])[N:15]=[C:14]3Cl)[CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[Se:28][C:27]=1[C:35]([NH2:37])=[O:36].CN(C=O)C.[OH-].[Na+]>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[O:21][CH3:22])[N:17]=[C:16]([CH3:23])[N:15]=[C:14]3[NH:25][C:26]2[CH:30]=[C:29]([C:31]([CH3:34])([CH3:32])[CH3:33])[Se:28][C:27]=2[C:35]([NH2:37])=[O:36])[CH2:3][CH2:2]1
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Reactant: COc1cc2nc(C)nc(Cl)c2cc1OCCCN1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc2nc(C)nc(Nc3cc(C(C)(C)C)[se]c3C(N)=O)c2cc1OCCCN1CCOCC1

Procedure:
The reaction of 6-(3-morpholinopropoxy)-4-chloro-7-methoxy-2-methylquinazoline with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as a brown color solid, mp 204-206° C. 1H NMR (400 MHz, CDCl3): δ 11.92 (1H, br s), 8.95 (1H, s), 7.34 (1H, s), 7.18 (1H, s), 5.37 (2H, br s), 4.29 (2H, t, J=6.0 Hz), 3.98 (3H, s), 3.73 (4H, t, J=4.4 Hz), 2.70 (3H, s), 2.61 (2H, t, J=7.2 Hz), 2.50 (4H, br s), 2.11-2.14 (2H, m), 1.47 (9H, s); LC-MS (positive ion mode): m/z 560, 562 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[F:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>O1CCOCC1.O.[Cl-].[Na+].O.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>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:29]4[CH:30]=[N:31][C:26]([F:25])=[CH:27][CH:28]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: OB(O)c1ccc(F)nc1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(F)nc4)cc23)CC1
Reaction time: 0.33 h
Yield: 43 %

Procedure:
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (110 mg, 0.27 mmol) in dioxane (2.0 mL) and H2O (0.7 mL) was added (6-fluoro-3-pyridinyl)boronic acid (151 mg, 1.08 mmol), potassium carbonate (298 mg, 2.16 mmol), and tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.026 mmol). The reaction was run in the microwave for 20 min at 150° C. The reaction was then treated with EtOAc and brine and purified by flash chromatography to give 50 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(6-fluoro-3-pyridinyl)-1H-indole-7-carboxamide (43%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])=[C:4]([F:17])[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][CH:26]2[CH2:28][CH2:27]2)[C:22]([C:29]([F:32])([F:31])[F:30])=[CH:21][N:20]=1.Cl>CCCCO>[CH:26]1([NH:25][C:23]2[C:22]([C:29]([F:31])([F:32])[F:30])=[CH:21][N:20]=[C:19]([NH:1][C:2]3[C:7]([OH:8])=[CH:6][C:5]([C:9]([N:11]4[CH2:12][CH2:13][O:14][CH2:15][CH2:16]4)=[O:10])=[C:4]([F:17])[CH:3]=3)[N:24]=2)[CH2:27][CH2:28]1
Reactant: Nc1cc(F)c(C(=O)N2CCOCC2)cc1O
Reactant: FC(F)(F)c1cnc(Cl)nc1NC1CC1
Agent: Cl
Solvent: CCCCO
Product: O=C(c1cc(O)c(Nc2ncc(C(F)(F)F)c(NC3CC3)n2)cc1F)N1CCOCC1
Temperature: 100 °C
Reaction time: 10 h
Yield: 34.1 %

Procedure:
A mixture of (4-amino-2-fluoro-5-hydroxyphenyl)(morpholino)methanone (200 mg, 0.83 mmol), 2-chloro-N-cyclopropyl-5-(trifluoromethyl)pyrimidin-4-amine (198 mg, 0.83 mmol), concentrated HCl (0.1 mL), and n-BuOH (10 mL) was stirred at 100° C. for 10 h. The mixture was concentrated under reduced pressure and the residue was purified by rp-HPLC to afford the title compound as white solid (125 mg, 34%); 1H NMR (500 MHz, DMSO) δ 8.55-8.49 (m, 1H), 8.26 (s, 1H), 8.18-8.08 (m, 1H), 7.45 (br s, 1H), 6.77 (d, J=7.0 Hz, 1H), 3.62-3.53 (m, 4H), 3.48-3.46 (m, 2H), 3.30-3.11 (m, 2H), 2.84-2.82 (m, 1H), 0.84-0.78 (m, 2H), 0.75-0.68 (m, 2H); LCMS: m/z=442.3 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[CH2:14][NH:13][C:12]2=[O:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:17]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:30][CH:29]=1)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].[H-].[Na+]>CN(C)C=O>[CH2:21]([O:20][C:18]([CH:17]([N:13]1[CH2:14][CH:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:12]1=[O:15])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:30][CH:29]=1)=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(Cc1ccccc1)NC1CNC1=O
Reactant: O=C(OCc1ccccc1)C(Br)c1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)NC1CN(C(C(=O)OCc2ccccc2)c2ccc(OCc3ccccc3)cc2)C1=O

Procedure:
3-(2-Phenylacetamido)-2-azetidinone (750 mg.) and benzyl 2-bromo-2-(4-benzyloxyphenyl)acetate (1.51 g.) was added to anhydrous N,N-dimethylformamide (10 ml.), and disdolved in it by warming for a while. The solution was cooled in an ice-water bath, and to the solution was added all at once sodium hydride (50% oily) (178 mg.) under stirring. After removing the cooling bath, the reaction mixture was stirred for 30 minutes to which ethyl acetate was added. The reaction mixture was filtered and the filtrate was washed with water, 2% hydrochloric acid and water respectively, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to give an oily material (1.98 g.), which was subjected to column chromatography using silica.gel (40 g.). The fractions, eluted with a mixture of benzene and chloroform were subjected to thin layer chromatography using silica.gel, and the thin layer was developed with a mixture of chloroform and acetone to give two isomers of 1-(α-benzyloxycarbonyl-4-benzyloxybenzyl)-3-(2-phenylacetamido)-2-azetidinone. The isomer A was recrystallized from a mixture of chloroform and ether. Yield: 90 mg. Mp: 129° to 130° C. (dec.). The isomer B is oily material. Yield: 120 mg. The isomer A (90 mg.) obtained above was dissolved in methanol (7 ml.), and to the solution was added 10% palladium carbon (30 mg.). The mixture was reacted in hydrogen atmosphere at ordinary temperature and ordinary atm. until the absorption of hydrogen gas was completed. The catalyst was filtered off from the fraction mixture, and the filtrate was concentrated under reduced pressure. The residue obtained was crystallized from a mixture of ethyl acetate and ether to give crystals of 3-(2-phenylacetamido)lactacillanic acid. The product was identified by comparing an I.R. absorption spectrum and a N.M.R. absorption spectrum and a melting point with an authentic sample synthesized by another method from 3-aminolactacillanic acid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([C:14]#[N:15])[CH:8]=2)[CH:6]=1.[H][H]>N.CO.[Ni+2]>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([CH2:14][NH2:15])[CH:8]=2)[CH:6]=1
Reactant: Cc1cn(-c2ccc(N)c(C#N)c2)cn1
Reactant: [H][H]
Agent: [Ni+2]
Agent: N
Solvent: CO
Product: Cc1cn(-c2ccc(N)c(CN)c2)cn1
Yield: 81.6 %

Procedure:
To 4-(4-methyl-1H-imidazol-1-yl)-2-cyanoaniline (15.5 g; 78.2 mmol) dissolved in 10% NH3/methanol was added Raney-Nichel (5 g), the resulting mixture was hydrogenated at 60° C., at an hydrogen pressure of 60 bar, for 24 hours. The nitrogen purged reaction mixture was filtered on celite, the cake was washed with methanol and the combined filtrate and washings evaporated. The residue was purified by column chromatography over silica gel (DCM/MeOH/2M NH3, 85:10:5) evaporation of the combined appropriate fractions afforded the pure titled product as yellow-orange solid (12.9 g, 82%). C11H14N4, MW: 202.26; 1H-NMR (300 MHz, d6-DMSO) ppm: 2.13 (s, 3H), 5.24 (s, 2H), 6.67 (d, 1H), 7.08 (dd, 1H), 7.17 (t, 1H), 7.23 (d, 1H), 7.81 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([NH:12][S:13]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)(=[O:15])=[O:14])[CH2:8][NH:9]2)=[CH:4][CH:3]=1.Cl[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O>>[CH2:28]([N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)[CH2:6][CH:7]([NH:12][S:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)(=[O:15])=[O:14])[CH2:8]1)[C:27]1[CH:30]=[CH:31][CH:32]=[CH:25][CH:26]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: O=S(=O)(NC1CNc2cc(Cl)ccc2C1)c1cc(F)cc(F)c1
Product: O=S(=O)(NC1Cc2ccc(Cl)cc2N(Cc2ccccc2)C1)c1cc(F)cc(F)c1

Procedure:
The title compound was prepared from 152C and 3-chlorobenzaldehyde by procedures analogous to those described in Example 22A. HPLC: 99% at 4.20 min (retention time) (Conditions: Phenom Prime S5, C18 (4.6×50 mm); Eluted with 0% to 100% B, 4 min gradient (A=90% H2O−10% MeOH−0.1% TFA and B=10% H2O−90% MeOH−0.1% TFA); Flow rate at 4.0 mL/min, UV detection at 220 nm). MS (ES): m/z 484 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][CH2:10][N:9](CC2C=CC=CC=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl>CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(Cc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOC(=O)C1(Cc2ccccc2)CCNCC1

Procedure:
1,4-Dibenzyl-piperidine-4-carboxylic acid ethyl ester (11.8 g, 35 mmol) is dissolved in MeOH (200 mL) and 1M aqueous HCl (40 mL) and Pd—C (10%, 1 g) are added. The mixture is hydrogenated (7 bar, 70° C.) for 15 h. The catalyst is filtered off and the solvent evaporated to provide the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C([N:17]=[C:18]=[S:19])(=O)C1C=CC=CC=1>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][C:18]([NH2:17])=[S:19]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NCc1ccccn1
Solvent: ClCCl
Product: NC(=S)NCc1ccccn1
Temperature: 0 °C
Reaction time: 4 h
Yield: 43.6 %

Procedure:
2-(Aminomethyl)pyridine (2.0 g, 18.5 mmol) was added dropwise to a stirred solution of benzoyl isothiocyanate (3.3 g, 20.2 mmol) in CH2Cl2 (30 mL) at 0° C. The mixture was stirred at 0° C. for 4 h. The solvent was evaporated in vacuo and 1M sulfuric acid (40 mL) was added. The reaction mixture was stirred at rt for 19 h. The mixture was neutralized with saturated sodium carbonate (aq.). The oil that formed in the solution during neutralization was removed with a spatula. The solid was collected, washed and dried. The solid was then dissolved in sodium hydroxide (10% aq., 15 mL) and MeOH (5 mL) and the solution was stirred at r.t. for 20 h. The reaction mixture was neutralized with 2M sulfuric acid and the aqueous solution was extracted with ethyl acetate (2×50 mL). The organic phase was treated with activated charcoal, filtered, dried (Na2SO4) and evaporated. The residue was suspended in diethyl ether, filtered, washed with diethyl ether and dried, giving the title compound (1.35 g, 44%) as a solid. The crude product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:17]=[N:18][C:19]([NH:22][NH2:23])=[CH:20][CH:21]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.FC1C=CC(C2N=C3N(C=2)C=CO3)=CC=1.C1C(=O)N(I)C(=O)C1.FC1N=CC(B(O)O)=CC=1.NN.[Cl:59][C:60]1[CH:68]=[CH:67][CH:66]=[CH:65][C:61]=1[C:62](Cl)=[O:63]>C1COCC1.C(Cl)Cl>[Cl:59][C:60]1[CH:68]=[CH:67][CH:66]=[CH:65][C:61]=1[C:62]([NH:23][NH:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]2[N:14]3[C:10]([O:11][CH:12]=[CH:13]3)=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:17][N:18]=1)=[O:63]
Reactant: NNc1ccc(-c2c(-c3ccc(F)cc3)nc3occn23)cn1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Fc1ccc(-c2cn3ccoc3n2)cc1
Agent: NN
Agent: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(NNc1ccc(-c2c(-c3ccc(F)cc3)nc3occn23)cn1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A 100 mL round-bottom flask charged with 6-(4-fluorophenyl)-5-(6-hydrazinylpyridin-3-yl)imidazo[2,1-b]oxazole (0.35 g, 1.1 mmol; prepared from A using 6-(4-fluorophenyl)-imidazo[2,1-b]oxazole [WO2004110990A2, Example 1, Steps 1-3], and NIS, C using 6-fluoropyridin-3-ylboronic acid [Asymchem], and D using 1M hydrazine in THF) in THF (10 mL) and DCM (10 mL) was treated with TEA (0.17 mL, 1.2 mmol) and 2-chlorobenzoyl chloride (0.14 mL, 1.1 mmol). The reaction mixture was stirred at ambient temperature for about 30 min. The reaction mixture was then washed with water, dried over MgSO4, filtered, and evaporated under reduced pressure to give 2-chloro-N′-(5-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)pyridin-2-yl)benzohydrazide (0.50 g, 1.1 mmol, 89%). The crude material was dissolved in 1,4-dioxane (10 mL) and treated with thionyl chloride (0.2 mL, 2.8 mmol). After about 30 min at about 100° C., the reaction mixture was cooled to about 0° C. and the precipitate was collected by filtration and washed with DCM (5 mL). The solid was dissolved in EtOAc/MeOH and washed twice with water. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The mixture was purified by column chromatography using EtOAc then EtOAc/MeOH (98:2) as eluent and dried in a vacuum oven at about 50° C. to give the title compound as a tan solid (0.13 g, 27%): LC/MS (Table 1, Method a) Rt, =2.38 min; MS m/z: 430.1 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:16]#[N:17])[C:13]=1[O:14][CH3:15])[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.S(Cl)([Cl:27])=O>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:16]#[N:17])[C:13]=1[O:14][CH3:15])[C:8]([Cl:27])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C#N)cc(C(=O)O)cc1C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(C#N)cc(C(=O)Cl)cc1C(C)(C)C
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-t-butyl-5-cyano-4-methoxybenzoic acid (586 mg), toluene (10 mL), N,N-dimethylformamide (2 droplets) and thionyl chloride (0.27 mL) was added, and the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (630 mg) as a brown oily substance.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[C:10]([NH2:25])=[N:11][CH:12]=[C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH3:24])[CH:19]=[CH:18]4)[N:14]=2)[N:6]=[N:5]1)([CH3:3])[CH3:2].C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[C:10]([NH2:25])=[N:11][CH:12]=[C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH3:24])[CH2:19][CH2:18]4)[N:14]=2)[N:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cc(-c2nc(-c3ccc4c(ccn4C)c3)cnc2N)nn1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1cc(-c2nc(-c3ccc4c(c3)CCN4C)cnc2N)nn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-5-(1-methyl-1H-indol-5-yl)-pyrazin-2-ylamine (200 mg, 0.60 mmol) in TFA (10.0 mL) was added triethylsilane (0.19 mL, 1.20 mmol) at 0° C. The reaction temperature was stirred for 2 h at 0° C. The reaction mixture was poured into ice-cold water (20 mL), basified with saturated NaHCO3, extracted with EtOAc (30 mL), dried over anhydrous Na2SO4 and evaporated the solvent under reduced pressure to get crude compound. Crude compound was washed with diethyl ether to afford the title compound as a brown solid.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([OH:24])=O)=O)(C)(C)C.[NH2:25][C:26]1[C:27]([N:35]2[CH2:40][C@H:39]([C:41]([F:44])([F:43])[F:42])[CH2:38][C@H:37]([NH:45]C(=O)OC(C)(C)C)[CH2:36]2)=[C:28]2[CH2:34][CH2:33][O:32][C:29]2=[N:30][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:25][C:26]1[C:27]([N:35]2[CH2:40][C@H:39]([C:41]([F:44])([F:43])[F:42])[CH2:38][C@H:37]([NH2:45])[CH2:36]2)=[C:28]2[CH2:34][CH2:33][O:32][C:29]2=[N:30][CH:31]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c(N)cnc3c2CCO3)C1
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: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1C[C@@H](N)C[C@@H](C(F)(F)F)C1)CCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.1 %

Procedure:
To a mixture of 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (58.2 mg, 0.163 mmol), tert-butyl [(3S,5R)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (55.3 mg, 0.137 mmol) and HATU (180.9 mg, 0.4758 mmol) was added DMF (2.0 mL) followed by DIPEA (162.2 mg, 1.255 mmol). The reaction mixture was stirred at room temperature for 3 h, and then concentrated under reduced pressure. To the resulting residue was added DCM (2.0 mL), followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (9.7 mg, 13%). LCMS calc. for C23H22F5N6O2S (M+H)+: m/z=541.1. found 541.1.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11]C)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br>>[Cl:1][C:2]1[C:9]([OH:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(Cl)c1O
Agent: Br
Product: O=Cc1ccc(O)c(O)c1Cl

Procedure:
2-Chloro-3-hydroxy-4-methoxybenzaldehyde is treated with hydrogen bromide to give 2-chloro-3,4-dihydroxybenzaldehyde which is converted to the methylenedioxy derivative with dibromomethane as described above. The product is condensed with nitromethane and the resulting nitroethylene reduced to give the phenethylamine. This compound is condensed with p-methoxystyrene oxide to give the α-hydroxyphenethylamine intermediate which is treated with an excess of trifluoroacetic acid at room temperature for 18 hours to give 6-chloro-7,8-methylenedioxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine. This compound is split using boron trichloride as described above to give 6-chloro-7,8-dihydroxy-1-p-methoxyphenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]([N:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:12]([NH:14][C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])=[O:13])[CH3:10])=[CH:4][N:3]=1.CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[N:14]([C@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])[C:12](=[O:13])[N:11]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[CH:9]([CH3:10])[C:5]2=[CH:4][N:3]=1
Reactant: COc1ccc(N(C(=O)N[C@@H](C)c2ccccc2)C(C)c2cnc(Cl)nc2Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(N2C(=O)N([C@@H](C)c3ccccc3)c3nc(Cl)ncc3C2C)cc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
A solution of 1-[1-(2,4-dichloro-pyrimidin-5-yl)-ethyl]-1-(4-methoxy-phenyl)-3-[1-(S)-phenyl-ethyl]-urea (less polar diastereomer, 250 mg, 0.56 mmol) (from Example 16 supra) in tetrahydrofuran (5 mL). cooled to 5° C. was treated with potassium tert-butoxide (1.0 M solution in tetrahydrofuran, 0.62 mL, 0.62 mmol). After stirring at 5° C. for 15 minutes and then at room temperature for another 15 minutes, reaction mixture was diluted with ethyl acetate (20 mL) and was washed with water (2×10 mL) and dried over MgSO4. Solvent was evaporated under reduced pressure to give crude 7-chloro-3-(4-methoxy-phenyl)-4-methyl-1-[1-(S)-phenyl-ethyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one which was used directly in the following step. (308 mg, contains some solvent).