Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C@@H:10]([OH:29])[CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[C:17]4[N:18]([CH2:26][CH2:27][N:28]=4)[C:19]([NH2:25])=[N:20][C:21]=3[C:22]=2[O:23][CH3:24])[CH2:3]1.[C:30](O)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[N:33][CH:32]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C@@H:10]([OH:29])[CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[C:17]4[N:18]([CH2:26][CH2:27][N:28]=4)[C:19]([NH:25][C:30]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)=[O:37])=[N:20][C:21]=3[C:22]=2[O:23][CH3:24])[CH2:3]1
Reactant: COc1c(OC[C@H](O)CN2C[C@@H](C)O[C@@H](C)C2)ccc2c1N=C(N)N1CCN=C21
Reactant: O=C(O)c1cccnc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(OC[C@H](O)CN2C[C@@H](C)O[C@@H](C)C2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.4 %

Procedure:
A mixture of N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxypropyl}oxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]amine (2.02 g, 5.01 mmol) and nicotinic acid (0.80 g, 6.51 mmol, 1.3 equiv) in DMF (139 mL) was treated with PyBOP (3.39 g, 6.51 mmol, 1.3 equiv.) followed by N,N-diisopropylethylamine (3.50 mL, 20.0 mmol, 4.0 equiv.) slowly leading to a clear solution. The mixture was stirred at room temperature for 24 h. The resulting solids were filtered and washed with DMF, H2O, and MeOH, then dried at 60° C. under reduced pressure to give N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxypropyl}oxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyridine-3-carboxamide (1.64 g, 64%): TLC (9:1 CH2Cl2/MeOH+1% NH4OH in MeOH)Rf 0.40; 1H NMR (DMSO-d6+1 drop TFA-d) δ 1.15 (d, J=9.5 Hz, 3H), 1.16 (d, J=9.5 Hz, 3H), 2.76 (t, J=11.2 Hz, 1H), 2.83 (t, J=11.4 Hz, 1H), 3.26-3.38 (m, 2H), 3.50-3.58 (m, 2H), 3.86-3.93 (m, 1H), 3.95-4.02 (m, 1H), 4.08 (s, 3H), 4.26-4.33 (m, 4H), 4.50 (br s, 1H), 4.61 (app t, J=10.7 Hz, 2H), 7.54 (d, J=9.1 Hz, 1H), 7.96 (dd, J=5.7, 7.6 Hz, 1H), 8.09 (d, J=9.1 Hz, 1H), 8.92 (d, J=7.9 Hz, 1H), 9.01 (d, J=4.1 Hz, 1H), 9.53 (s, 1H); mass spectrum m/z 507 ((M−1)−, 100%), 509 ((M+1)+, 24%).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:10][CH3:11])[CH2:8][CH2:7][O:6][CH2:5][C:4]1=[O:9].[B].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2>>[CH3:1][O:2][C:3]1([O:10][CH3:11])[CH2:8][CH2:7][O:6][CH2:5][C@H:4]1[OH:9]
Reactant: COC1(OC)CCOCC1=O
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: [B]
Product: COC1(OC)CCOC[C@H]1O

Procedure:
reacting 4,4-dimethoxydihydro-2H-pyran-3(4H)-one with a boron reducing agent and S-(−)-2-methyl-CBS-oxazaborolidine, over a period of at least six hours to provide the (R)-4,4-dimethoxytetrahydro-2H-pyran-3-ol in at least 60% enantiomeric excess, wherein the reaction is run at a temperature range from 20° C. to 60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=O)[C:5]([O:8][CH2:9][C:10]([N:12]2[CH2:17][CH:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:14][CH:13]2[CH3:27])=[O:11])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:36]([O-:39])(=[O:38])[CH3:37].[CH2:40]([PH+](CC)CC)[CH3:41]>C(O)C.O>[CH2:40]([O:38][C:36](=[O:39])[CH:37]=[CH:28][C:4]1[C:5]([O:8][CH2:9][C:10]([N:12]2[CH2:17][C@H:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:14][C@H:13]2[CH3:27])=[O:11])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:41]
Reactant: CC[PH+](CC)CC
Reactant: CC(=O)[O-]
Reactant: CC1CN(C(=O)COc2ncc(Cl)cc2C=O)C(C)CN1Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C=Cc1cc(Cl)cnc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 25 °C
Yield: 44.3 %

Procedure:
To a 0° C. solution of 5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridine-3-carbaldehyde (0.200 g, 0.47 mmol) in ethanol (5 mL) was added potassium carbonate (0.131 g, 0.95 mmol) in water (0.30 mL) and triethyl phosphonium acetate (0.21 g, 0.19 mL). The reaction mixture was warmed to room temperature over 48 hours, filtered through celite, the filter cake was washed with ethanol and concentrated in vacuo. Purification via chromatography on silica gel gave the title compound (0.102 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH:2]=1.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][N:10]=[C:9]([C:12]([Cl:18])=[O:14])[CH:8]=2)[CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(-c2cccnc2)on1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(-c2cccnc2)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.5 g (2.63 mmol) of 5-(pyridin-3-yl)-1,2-oxazole-3-carboxylic acid (known from the literature, no reference) in 25 ml of dichloromethane was admixed with 2 drops of N,N-dimethylformamide. Subsequently, 0.97 g (7.63 mmol) of oxalyl chloride was added dropwise under argon and the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the crude product was converted farther immediately.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][O:27][C:28]1[N:33]=[C:32]([CH3:34])[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[C:32]([CH3:34])=[N:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)c(C)n1
Temperature: 80 °C
Yield: 76.1 %

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (73 mg, 0.20 mmol) was dissolved in 2 mL of 1,2-dimethoxyethane in a reaction tube. 6-Methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (65 mg, 0.26 mmol), 0.2 mL of an aqueous 2 M sodium carbonate solution, and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.010 mmol) were added and the reaction mixture was heated at 80° C. overnight. The reaction was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexane to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-2′,3-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (69 mg, 76%). ESI-MS m/z calc. 453.4. found 454.3 (M+1)+. Retention time 1.98 minutes.
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].[CH:13]1(Br)[CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)C>[CH:13]1([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrC1CCCC1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C1CCCC1
Yield: 70.6 %

Procedure:
To a solution of 4.6 g (0.2 mol) sodium in 80 mL absolute ethanol was added 30.4 mL (0.2 mol) diethyl malonate. After briefly stirring, 21.4 mL (0.2 mol) cyclopentyl bromide was added, and the resulting solution refluxed for 12 hrs. Most of the ethanol was then removed by rotary evaporation, and the reaction was quenched with 250 mL of water and extracted 3 ×, each with 100 mL ether. The extracts were dried over MgSO4, filtered, and concentrated. Distillation through a 6" Vigreaux at 6 mm Hg provided 32.232 g of a clear colorless oil at bp 122-125 C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][C:13]#[N:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.CN([CH:18]=[O:19])C.C([O-])=O.[Na+]>O>[CH:18]([C:2]1[CH:3]=[C:4]([CH2:12][C:13]#[N:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)=[O:19]
Reactant: CN(C)C=O
Reactant: N#CCc1cc(Br)c2ncccc2c1
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Product: N#CCc1cc(C=O)c2ncccc2c1
Temperature: 80 °C

Procedure:
To a solution of (8-bromoquinolin-6-yl)acetonitrile (1 eq.) in anhydrous, deoxygenated DMF (0.08 M) was added freshly-dried sodium formate (1.5 eq.) and Pd(PPh3)Cl2 (2% loading). Through the resulting yellow suspension, was bubbled CO and then reaction was heated to 80° C. for 16 h. The now black reaction suspension was cooled to RT, diluted with water, and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:14][NH:15][O:16][CH3:17].C(N1CCOCC1)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:14][N:15]([O:16][CH3:17])[C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CNOC
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 96.1 %

Procedure:
A solution containing 18.8 g of N-tert.-butoxycarbonylglycine in 180 ml of anhydrous dichloromethane was stirred under nitrogen and cooled at 0-5° C. while 11.5 g of N,O-dimethylhydroxylamine hydrochloride, 27.1 g of N-ethylmorpholine and 22.5 g of N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride were added. The mixture was allowed to warm slowly to room temperature and stirred for 16 h. The mixture was washed twice with 150 ml of 1M hydrochloric acid, and 150 ml of saturated sodium hydrogen carbonate then dried over anhydrous sodium sulphate, filtered and evaporated to give 22.5 g of N-tert.-butoxycarbonylglycine N-methyl-N-methoxyamide as a white solid which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:38])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:38])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[C:3]=12
Reactant: COc1cccc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2cccc(O)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of Example 51 (0.150 g, 0.290 mmoles) in dichloromethane (25 ml), BBr3 (1M in dichloromethane, 1.5 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as grey colour solid (0.110 g, 75% yield). MP: 282-285° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 9.69(s,1H), 8.06(s, 1H), 8.05(dd, J=8.0, 1.6 Hz, 1H), 7.86(dt, J=7.2,1.6 Hz, 1H), 7.68(t, J=8.2 Hz, 1H), 7.53 (dt, J=8.0,0.9 Hz, 1H), 7.34(t, J=8.0 Hz, 1H), 7.29 (br s,1H), 7.06-6.84(m, 6H), 6.03(q, J=7.1 Hz, 1H), 1.89(d, J=7.1 Hz, 3H). Mass: 493.95(M+).
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:11][NH2:12]>C(O)C>[CH3:8][C:7]([CH3:10])([CH3:9])[C:6]#[C:5][CH:4]=[CH:3][CH2:2][NH:12][CH3:11]
Reactant: CN
Reactant: CC(C)(C)C#CC=CCBr
Solvent: CCO
Product: CNCC=CC#CC(C)(C)C
Reaction time: 3 h

Procedure:
24.3 g of 1-bromo-6,6-dimethylhept-2-en-4-yne in 750 ml of ethanol are added at -50° to 245 ml of a 33% ethanolic solution of methylamine and the mixture stirred in a closed vessel at 55° for 3 hours. The resulting mixture is concentrated in a rotary evaporator and the residue taken up with chloroform and washed with 1 N NaOH and saturated NaCl. After drying over MgSO4 the crude product is purified by chromatography on kieselgel (eluant toluene/ethylacetate; 4/1). A colourless oil is obtained (trans- and cis compound in ratio 3:1).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26][NH2:27].CCN(C(C)C)C(C)C>>[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26][NH:27][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: NCCc1cccs1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCCc2cccs2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-thiophen-2-yl-ethylamine and DIEA to give 2-(2-thiophen-2-yl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 366 (MH+).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:10]=1[CH:11]([OH:27])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:33].[OH-:34].[Na+]>C(OC(=O)C)C>[CH2:1]([N:8]1[C:9]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:10]=2[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:13]=2)[O:27][CH:10]([CH2:9][C:31]([OH:34])=[O:33])[C:11]1=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2NCc2ccccc2)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1cccc(C2OC(CC(=O)O)C(=O)N(Cc3ccccc3)c3ccc(Cl)cc32)c1
Reaction time: 1 h

Procedure:
To a solution of 2-benzylamino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.91 g) in acetic acid ethyl ester (10 ml) were added water (4 ml) and a 1N aqueous solution of sodium hydroxide (3 ml). To the mixture was added monoethyl fumarate ester chloride (330 mg), which was stirred for one hour under ice-cooling. To the mixture was added acetic acid ethyl ester (30 ml). The organic layer was washed with water and dried over anhydrous MgSO41 followed by distilling off the solvent. The residue was dissolved in ethanol (10 mL), to which was added potassium carbonate (400 mg). The mixture was stirred overnight at room temperature. Insolubles were filtered off, and the solvent was distilled off. The residue was purified by means of a silica gel column chromatography to give ethyl ester of 1-benzyl-5-(3-tert-butoxycarbonylaminomethylphenyl)-7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (1.06 g).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[S-:13][C:14]#[N:15].[K+].BrBr.O>CO.[Br-].[K+]>[CH:1]([C:4]1[C:12]([S:13][C:14]#[N:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc2ccccn2n1
Reactant: N#C[S-]
Agent: BrBr
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)c1nn2ccccc2c1SC#N
Temperature: 25 °C
Yield: 86.8 %

Procedure:
To a solution of 3 g of 2-isopropylpyrazolo[1,5-a]pyridine in 56 ml of methanol was added 5.74 g of potassium thiocyanate and stirred at room temperature. 3.3 g of bromine was dissolved in 13 ml of methanol saturated with potassium bromide and added dropwise to the previous solution. Then, the mixture was stirred at room temperature for an hour, poured into 130 ml of water and resulting precipitate was filtered and dried. This crude precipitate was recrystallized from methanol to give 3.53 g (yield 87%) of the aimed compound as pale yellow prismatic crystals. mp 91°-92.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([I:15])=[C:11](I)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[N:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=1.[OH-].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([I:15])=[C:11]([O:25][CH2:24][C:21]3[CH:22]=[N:23][C:18]([Cl:17])=[CH:19][CH:20]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: OCc1ccc(Cl)nc1
Reactant: O=c1c(I)c(I)cnn1-c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1c(I)c(OCc2ccc(Cl)nc2)cnn1-c1ccc(Cl)cc1
Yield: 61.5 %

Procedure:
The procedures in Synthesis Example 2 were repeated by using 3.3 g (7.2 m mol) of 2-(4-chlorophenyl)-4,5-diiodo-3(2H)-pyridazinone, 1.1 g (7.7 m mol) of 6-chloro-3-pyridine-methanol, 0.4 g of potassium hydroxide and 80 ml of N,N-dimethylformamide to give 2.1 g of the intended product. (recrystallized from benzene)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C@@H:16]([CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[C:17]([N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C@H:20]1[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:14])[C@@H:9]([CH3:13])[C:10]([NH:15][C@@H:16]([CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[C:17]([N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C@H:20]1[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:18])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CCOC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](N)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C1CCOCC1
Temperature: 25 °C
Yield: 86.3 %

Procedure:
In a 100 mL round-bottomed flask, (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (128 mg, 630 μmol, Eq: 1.5), (S)-ethyl 1-((S)-2-amino-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (140 mg, 420 μmol, Eq: 1.00) and HATU (240 mg, 630 μmol, Eq: 1.5) were combined with DMF (2 mL) to give a light yellow solution. Diisopropylethylamine (110 μL, 630 μmol, Eq: 1.5) was added and the reaction was stirred at rt over the weekend. The reaction mixture was partitioned between EtOAc and water and the separated organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 40% EtOAc in hexanes) to give (S)-ethyl 1-((S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (188 mg), m/z=519 (M+H).
Reaction SMILES: C(OC([C:8]12[CH2:14][CH2:13][CH:12]1[CH2:11][NH:10][CH2:9]2)=O)(C)(C)C.[F:15][C@H:16]1[CH2:18][C@H:17]1[N:19]1[C:28]2[C:23](=[CH:24][C:25]([F:32])=[C:26](F)[C:27]=2[O:29][CH3:30])[C:22](=[O:33])[C:21]([C:34]([OH:36])=[O:35])=[CH:20]1.C([N:39](CC)CC)C>CS(C)=O>[NH2:39][C:8]12[CH2:14][CH2:13][CH:12]1[CH2:11][N:10]([C:26]1[C:27]([O:29][CH3:30])=[C:28]3[C:23]([C:22](=[O:33])[C:21]([C:34]([OH:36])=[O:35])=[CH:20][N:19]3[C@@H:17]3[CH2:18][C@@H:16]3[F:15])=[CH:24][C:25]=1[F:32])[CH2:9]2
Reactant: CCN(CC)CC
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CC(C)(C)OC(=O)C12CCC1CNC2
Solvent: CS(C)=O
Product: COc1c(N2CC3CCC3(N)C2)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 25 °C
Reaction time: 110 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-3-azabicyclo[3.2.0]heptane (1.02 mmol) in dimethyl sulfoxide (1.5 ml) were added 180 mg (0.5 mmol) of difluoroboric acid ester of 1-[2-(S)-fluoro-1-(R)-cyclopropyl]-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 0.5 ml of triethylamine, followed by 110 hours of stirring at room temperature. After evaporation of triethylamine, the resulting residue was mixed with water, and the thus precipitated crystals were collected by filtration. To the thus collected crystals were added 15 ml of 90% methanol and 3 ml of triethylamine, subsequently carrying out 4 hours of reflux. This was cooled to room temperature and then concentrated. The resulting residue was mixed with 10% citric acid and extracted with chloroform. The organic layer was washed with water and saturated brine and dried on anhydrous sodium sulfate, subsequently evaporating the solvent. To the thus obtained residue dissolved in dichloromethane (5 ml) and cooled in an ice bath was added trifluoroacetic acid (5 ml), followed by 1 hour of stirring at room temperature. After concentration, the resulting residue was mixed with concentrated hydrochloric acid and washed with chloroform. The resulting solution was adjusted to pH 7.5 with concentrated sodium hydroxide aqueous solution and then extracted with chloroform. The extract was dried over anhydrous sodium sulfate, subsequently evaporating the solvent. By recrystallizing the resulting residue from ethanol, 75.9 mg of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15]I)[O:11][CH:12]=2)=[CH:4][CH:3]=1.[C:17]1([O:24][CH3:25])[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][O:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:24][CH3:25])[O:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COc1ccccc1O
Reactant: Clc1ccc(-c2coc(CCCI)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1OCCCc1nc(-c2ccc(Cl)cc2)co1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A mixture of 4-(4-chlorophenyl)-2-(3-iodopropyl)oxazole (0.5 g), guaiacol (0.19 ml), potassium carbonate (0.24 g) and N,N-dimethylformamide (5 ml) was stirred for 30 minutes at 60° to 65° C. and poured into water. The precipitated crystals were collected by filtration to obtain 4-(4-chlorophenyl)-2-[3-(2-methoxyphenoxy) propyl]oxazole (0.445 g, 90%). Recrystallization from ether-hexane gave colorless prisms of mp 94°-95° C.
Reaction SMILES: [CH3:1][CH:2]([C@@:4]12[C@@H:19](O)[C@:18]34[O:21][C@H:17]3[CH2:16][C@@H:15]3[C@:10]([CH3:26])([CH2:11][CH2:12][C:13]5[C:24](=[O:25])[O:23][CH2:22][C:14]=53)[C@:8]34[O:9][C@H:7]3[C@@H:5]1[O:6]2)[CH3:3].C(N(S(F)(F)[F:33])CC)C.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][CH:2]([C@@:4]12[C@H:19]([F:33])[C@:18]34[O:21][C@H:17]3[CH2:16][C@@H:15]3[C@:10]([CH3:26])([CH2:11][CH2:12][C:13]5[C:24](=[O:25])[O:23][CH2:22][C:14]=53)[C@:8]34[O:9][C@H:7]3[C@@H:5]1[O:6]2)[CH3:3]
Reactant: CC(C)[C@]12O[C@H]1[C@@H]1O[C@]13[C@]1(O[C@H]1C[C@H]1C4=C(CC[C@@]13C)C(=O)OC4)[C@@H]2O
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[C@]12O[C@H]1[C@@H]1O[C@]13[C@]1(O[C@H]1C[C@H]1C4=C(CC[C@@]13C)C(=O)OC4)[C@H]2F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of PG490 (triptolide, 17.3 mg, 0.048 mmol) in dichloromethane (1.0 ml) at 0° C. was added (diethylamino)sulfur trifluoride (DAST, 100 μl, 0.763 mmol) under N2. The reaction mixture was stirred at 0° C. for 2 hrs, and saturated NaHCO3 solution (0.8 ml) was then added. The reaction mixture was extracted with 3×2 ml of dichloromethane. The combined organic layer was dried over anhydrous NaSO4 and concentrated under vacuum. The desired product (PG763) was obtained in quantitative yield.