Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[S:16][C:15]([CH3:17])=[N:14][C:13]=3[CH:18]=2)[CH:5]=[N:4][CH:3]=1.[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:17][C:15]1[S:16][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[CH:5]=[N:4][CH:3]=[C:2]([C:22]4[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=4)[N:7]=3)=[CH:18][C:13]=2[N:14]=1
Reactant: Cc1nc2cc(Nc3cncc(Cl)n3)ccc2s1
Reactant: OB(O)c1ccncc1
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: O
Solvent: COCCOC
Product: Cc1nc2cc(Nc3cncc(-c4ccncc4)n3)ccc2s1
Yield: 86.7 %

Procedure:
A mixture of 2,6-dichloropyrazine (0.150 g, 1.006 mmol), 5-amino-2-methylbenzothiazole (0.250 g, 1.51 mmol), BINAP (0.0137 g, 0.02215 mmol), sodium tertiary butoxide (0.136 g, 1.409 mmol) and palladium acetate (0.005 g, 0.02215 mmol) in toluene (8 mL) was heated at 85° C. for 16 h under nitrogen. CH2Cl2 was added, the reaction mixture was filtered through Celite, and the solvent was evaporated. The residue was purified by column chromatography (5% methanol in CH2Cl2 as eluent) to give 0.180 g (65%) of intermediate (6-chloro-pyrazin-2-yl)-(2-methyl-benzothiazol-5-yl)-amine. 1H NMR (CDCl3) δ 7.59-7.54 (d, J=15.6 Hz, 2H), 7.38 (s, 1H), 7.19-7.16 (d, J=8.65 Hz, 1H), 6.98-6.95 (d, J=8.41 Hz, 1H), 6.71 (brs, 1H, NH), 2.31 (s, 3H, CH3); MS (API-ES/Positive); m/z: 277 (M+H)+. A mixture of (6-chloro-pyrazin-2-yl)-(2-methyl-benzothiazol-5-yl)-amine (0.075 g, 0.271 mmol), pyridine-4-boronic acid (0.040 g, 0.326 mmol), sodium carbonate (0.143 g, 1.35 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0156 g, 0.0135 mmol) in DME:water (3:2, 5 mL) was heated at reflux for 20 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was extracted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (5% methanol in CH2Cl2 as eluent) to yield 2-methyl-N-(6-pyridin-4-ylpyrazin-2-yl)-1,3-benzothiazol-5-amine (0.075 g, 86.5%) as a yellow solid. 1H NMR (CD3OD) δ 8.82 (m, 3H), 8.72 (s, 1H), 8.45-8.44 (m, 2H), 8.35 (s, 1H), 7.92-7.90 (d, J=8.67 Hz, 1H), 7.61-7.59 (dd, J=10.63, 1.94 Hz, 1H), 2.89 (s, 3H, CH3); MS (API-ES/Positive); m/z: 320 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:12][CH2:13][CH3:14].[Na+].O>C(O)C>[CH2:13]([O:12][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1)[CH3:14]
Reactant: Nc1nnc2ccc(Cl)nn12
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ccc2nnc(N)n2n1
Temperature: 55 °C
Reaction time: 2 h
Yield: 108.9 %

Procedure:
6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.001a, 616 mg) was dissolved in absolute ethanol (40 ml) and admixed with portions of solid sodium ethoxide (990 mg). After stirring at 55° C. for 2 h, water was added and the aqueous phase was extracted three times with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated. 709 mg of crude product of the desired compound were obtained in sufficient purity.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.[CH2:53]([N:60]1[CH2:64][CH:63]([C:65]2[CH:70]=[CH:69][C:68]([Cl:71])=[C:67]([Cl:72])[CH:66]=2)[CH:62]([CH:73](O)[CH3:74])[CH2:61]1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>C1COCC1>[CH2:53]([N:60]1[CH2:61][CH:62]([CH:73]([O:28][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:29])([F:30])[F:20])=[CH:27][CH:26]=2)[CH3:74])[CH:63]([C:65]2[CH:70]=[CH:69][C:68]([Cl:71])=[C:67]([Cl:72])[CH:66]=2)[CH2:64]1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: CC(O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1ccc(C(F)(F)F)cc1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
To a suspension of PPh3 (PPh3 polymer bound, 3 mmol PPh3/g resin) (1.80 g, 5.59 mmol) in THF (40 mL) at 0° C. were added 4-trifluoromethyl-phenol(0.618 g, 3.81 mmol) and then DBAD (0.936 g, 4.07 mmol). After 5 minutes was added (SR)-1-[(3SR,4RS)-1-benzyl-4-(3,4dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (X-B-1) (0.89 g, 2.54 mmol). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH 1M, followed by column chromatography (SiO2, EtOAc/H, 1:6) yielded 0.990 g (79%) of the title compound as a colorless oil. ES-MS m/e: 493.0 (M+H+).
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24].Cl.O.[N:27]1([CH2:33][CH:34]=O)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C([BH3-])#N.[Na+].O>CO>[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH2:34][CH2:33][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH2:15]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24]
Reactant: CCOC(=O)c1cn(CC2CCNC2)c2ccc(I)cc2c1=O
Reactant: O=CCN1CCOCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)c1cn(CC2CCN(CCN3CCOCC3)C2)c2ccc(I)cc2c1=O
Temperature: 23 °C
Reaction time: 16 h
Yield: 38.6 %

Procedure:
Ethyl 6-iodo-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate hydrochloride (Intermediate 127, 500 mg, 1.08 mmol) was suspended in methanol (15 mL) then morpholine-4-ylacetaldehyde monohydrate hydrochloride (1 g, 5.4 mmol) and sodium cyanoborohydride (612 mg, 9.7 mmol) were added. The reaction was stirred at 23° C. for 16 h. The volume of the reaction was reduced by half and water (25 mL) was added. The suspension was extracted with 2:1 ethyl acetate: tetrahydrofuran (3×10 mL). The organic phases were combined, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was passed through a plug of silica gel (2 g) eluting with 10% methanol in dichloromethane to remove any remaining borohydride. The solid was then dried in a vacuum oven at 50° C. for 18 h to give 225 mg (38% yield) of ethyl 6-iodo-1-((1-(2-morpholinoethyl)pyrrolidin-3-yl)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as an off white solid.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2OS(C(F)(F)F)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])[CH2:3][CH2:2]1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.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>[O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH:14]=[CH:15][C:16]=2[C:27]2[CH:28]=[C:29]([O:32][CH3:33])[CH:30]=[CH:31][C:26]=2[F:25])[CH2:3][CH2:2]1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C2=CCOCC2)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: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2=CCOCC2)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
To a stirred solution of 66.46E (555 mg, 1.52 mmol) in DMF (10 mL) at 23° C. was added 2-fluoro-5-methoxyphenylboronic acid (512.3 mg, 3.0 mmol) (commercially available from Aldrich) and potassium carbonate (630.1 mg, 4.56 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (176.8 mg, 0.15 mmol). The mixture was heated to 90° C. After 18 hours, LCMS showed the reaction was complete. The mixture was cooled to room temperature and diluted with water. After extracting three times with EtOAc, the mixture was concentrated in vacuo, and the residue was purified on silica gel (0-50% EtOAc in hexanes) to afford 66.46F (452.7 mg, 87% yield). MS ESI (pos.) m/e: 343.0 (M+H)+.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C@@H:10]1[CH3:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:22][C@H:10]1[CH2:11][NH:12][CH2:13][CH2:14][N:9]1[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CNCCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(S)-tert-butyl 4-benzoyl-3-methylpiperazine-1-carboxylate (8.16 g, 26.8 mmol) was dissolved in dichloromethane (200 mL). Trifluoroacetic acid (20.7 ml) was added and the reaction was stirred at rt for 1.5 hours. The reaction was quenched into saturated K2CO3 (30 mL) and neutralized by the portion-wise addition of solid NaHCO3. The layers were separated and extracted twice with dichloromethane. The combined organics were dried (MgSO4) and evaporated to give a yellow oil. MS (M+H)+=205.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:18])S(C2C=CC=CC=2)(=O)=O)=[C:4]([CH3:19])[CH:3]=1.[Li]C(C)(C)C.[F:25][C:26]([F:36])([F:35])[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28].C(O)(C(F)(F)F)=O>C1COCC1>[F:25][C:26]([F:35])([F:36])[C:27]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH3:18])=[C:4]([CH3:19])[CH:3]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[OH:28]
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: Cc1cc(Br)ccc1N(C)S(=O)(=O)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(C(O)(c2ccccc2)C(F)(F)F)cc1C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.03 g (3.23 mmol) of N-(4-bromo-2-methylphenyl)-N-methyl-benzenesulfonamide in 30 ml THF at −78° C. was added dropwise 3.9 ml (6.63 mmol) of a 1.7M solution of tert-BuLi in hexanes and the resultant mixture was stirred at −78° C. for 0.5 h. To this mixture was then added 0.66 ml (4.7 mmol) of 2,2,2-trifluoroacetophenone and the mixture stirred at −78° C. for an additional 0.5 h. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride, allowed to warm to room temperature, and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. 253 mg (0.61 mmol) of this material and 3 ml of TFA was heated to 50° C. for 4 hours. After this time, excess TFA was removed in vacuo, water was added and the mixture was neutralized by the addition of a saturated aqueous solution of NaHCO3. The mixture was extracted with EtOAc and combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:EtOAc, 3:1) to give the title compound. 1H-NMR (CDCl3) δ 2.12 (s, 3H), 2.92 (s, 3H), 6.57 (d, J=8.5 Hz, 1H), 7.16 (s, 1H), 7.16 (brs, 1H), 7.37-7.41 (m, 3H), 7.54-7.56 (m, 2H). Mass Spectrum (CI+) m/e=296.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.[NH2:12][OH:13].O>CC(O)C>[Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[N:12][OH:13]
Reactant: NO
Reactant: O=Cc1c(F)cc(Cl)cc1Br
Solvent: O
Solvent: CC(C)O
Product: ON=Cc1c(F)cc(Cl)cc1Br
Temperature: 40 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a solution of 2-bromo-4-chloro-6-fluoro-benzaldehyde (15 g, 63.16 mmol) in 2-propanol (130 ml) was added hydroxylamine (50% solution in water, 4.55 g, 68.90 mmol) at 25° C. and the mixture was warmed to 40° C. for 2 h. Water (55 ml) was then added slowly to this mixture and the slurry was aged for 1 h at 20° C. The reaction mixture was filtered and the remaining solid was washed with a mixture of 2-propanol and water (1.5:1) and dried under vacuum to yield the title compound (12.5 g, 77%) as white solid.
Reaction SMILES: [C:1]([C:4]1[S:32][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][C:13]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:14]=3[O:15][CH:16]([CH3:26])[CH2:17][NH:18]C(=O)OC(C)(C)C)[C:6]=2[C:5]=1[CH3:33])(=[O:3])[NH2:2].[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[NH2:18][CH2:17][CH:16]([O:15][C:14]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:13]=1[NH:12][C:11]1[C:6]2[C:5]([CH3:33])=[C:4]([C:1]([NH2:2])=[O:3])[S:32][C:7]=2[N:8]=[CH:9][N:10]=1)[CH3:26]
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC(C)CNC(=O)OC(C)(C)C)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC(C)CN)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-(2-(6-carbamoyl-5-methylthieno[2,3-d]pyrimidin-4-ylamino)-5-fluorophenoxy)propylcarbamate (740 mg) was dissolved in dichloromethane (20 ml) and trifluoroacetic acid (4 ml) was added and the reaction was stirred at room temperature overnight. The reaction was concentrated in vacuo to give the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[CH3:32].C(O)C>Cl.O>[CH:16]1([N:7]2[CH2:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[CH3:32])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Yield: 41.6 %

Procedure:
A mixture of 0.0398 g (0.00013 mole) of 2-chloro-9-cyclopentyl-5,7,7-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-38), 0.022 g (0.000143 mole) of 4-amino-3-methylbenzoic acid, 0.7 mL of ethanol, 2.8 mL of water and 3 drops of hydrochloric acid was heated at reflux for 17 hours. The mixture was cooled, and the white precipitate that formed was collected by filtration to give 0.0229 g of 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoic acid (I-56a) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([NH-])(C)C.[Li+].[I:23]I.CCOC(C)=O>C1COCC1>[I:23][C:10]1[O:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]=1
Reactant: II
Reactant: CCOC(=O)c1ncoc1-c1ccccc1
Agent: C[Si](C)(C)[NH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(I)oc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
To a solution of ethyl 5-phenyl-1,3-oxazole-4-carboxylate (Example 20, 0.921 mmol, 1 eq.) in THF (7 mL) at −78° C. was added a solution of lithium (trimethylsilyl) amide in THF (1 M in THF, 1.11 mmol, 1.2 eq.) dropwise by syringe. The resulting solution was stirred at −78° C. for 1 hour at which time a solution of iodine (1.38 mmol, 1.5 eq. in 2 mL THF) was added dropwise by a syringe. The reaction mixture was allowed to warm to rt and stirred at this temperature for 1.5 hours. The resulting solution was poured onto 10% aqueous NaS2O3 (15 mL) and extracted with EtOAc. The organic extracts were washed with brine, dried over anhyd. sodium sulfate, concentrated in vacuo, and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexanes:EtOAc=9:1). The product was obtained as a pale yellow solid in 82% yield. MH+=344.0, Rf=0.31 (hexanes:EtOAc=6:1), retention time (LC-MS)=3.01 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=O.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:15]3[C:10]([CH:11]=[N:12][C:13]([NH:16][C:17]4[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=4)=[N:14]3)=[C:8]([CH3:9])[N:7]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Agent: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Br)c4)n3n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.9 %

Procedure:
To a solution of 3-bromo-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 18) (490 mg, 1.0 mmol) and 1,2,4-triazole (210 mg, 3.0 mmol) in pyridine (10 mL) was added phosphorus oxychloride (0.14 mL, 1.5 mmol). The mixture was stirred at room temperature for 24 hours. The excess phosphorus oxychloride was quenched with methanol and ammonium hydroxide. The product was extracted into ethyl acetate (100 mL) and washed with 0.1N hydrochloric acid (3×50 mL). The solution was dried with magnesium sulfate and filtered. Silica gel (2.5 g) was added, followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexanes (25:75) to ethyl acetate:hexanes (75:25) using a RediSep silica gel cartridge (12 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)-imidazo[5,1-f][1,2,4]triazin-2-amine (0.23 g) as a yellow solid. 1H NMR (CD3OD): δ9.01 (s, 1H) 8.51 (dd, J=1.9, 1.6 Hz, 1H), 8.33 (ddd, J=7.9, 1.4, 1.1 Hz, 1H), 7.57 (ddd, J=7.9, 1.9, 1.1 Hz, 1H), 7.38 (dd, J=8.1, 7.9 Hz, 1H), 6.99 (s, 2H), 3.76 (s, 6H), 3.75 (s, 3H), 2.56 (s, 3H). MS m/z 470, 472 (M+1, M+3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37]([OH:39])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH:62]1[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:36][C:33]1[CH:34]=[CH:35][C:23]2[N:22]=[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:12]3[CH2:11][C@@H:10]([C:37]([N:62]4[CH2:67][CH2:66][O:65][CH2:64][CH2:63]4)=[O:39])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13]3)=[O:20])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]=2[CH:32]=1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2ccc(F)cc21
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccc(F)cc21
Temperature: 60 °C
Reaction time: 4 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (1.05 g), HOBt (361 mg) and WSC.HCl (549 mg) were dissolved in DMF (50 ml), morpholine (332 μl) and diisopropylethylamine (780 μl) were added, and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (1.14 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1.N(CC)CC.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][Si:19]([CH3:21])([CH3:20])[C:22]#[C:23][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C1CCSc2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1ccc2c(c1)C(=O)CCS2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 1.00 g (4.11 mmol) 2,3-dihydro-6-bromo-(4H)-1-benzothiopyran-4-one and 78.3 mg (0.41 mmol) Cul in 15.0 ml THF and 6.0 ml Et2NH was sparged with argon for 5 minutes. To this solution was added 2.0 ml (1.39 g, 14.2 mmol) of (trimethylsilyl)acetylene followed by 288.5 mg (0.41 mmol) of bis(triphenylphosphine)palladium(II) chloride. The resulting dark solution was stirred at room temperature for 3 days and then filtered through a pad of Celite, which was washed with EtOAc. The filtrate was washed with H2O and saturated aqueous NaCl before being dried over MgSO4. The title compound was isolated as an orange oil by column chromatography (4% EtOAc-hexanes). 1H NMR (CDCl3): δ 8.13 (1H, d, J=1.9 Hz), 7.36 (1H, dd, J=2.1, 8.2 Hz), 7.14 (1H, d, J=8.2 Hz), 3.19 (2H, d, J=6.3 Hz), 2.91 (2H, d, J=6.3 Hz), 0.21 (9H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([CH:13]([OH:17])[C:14]([OH:16])=[O:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([C@@H:26]([NH2:28])[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO.C(OCC)(=O)C>[C:20]1([C@@H:26]([NH2:28])[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([C@H:13]([OH:17])[C:14]([OH:16])=[O:15])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(O)c1ccc(OCc2ccccc2)cc1
Agent: C[C@H](N)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)[C@@H](O)c1ccc(OCc2ccccc2)cc1

Procedure:
4-Benzyloxymandelic acid (40.8 g) was dissolved in methanol (405 ml) and ethyl acetate (405 ml), and a solution of (S)-1-phenylethylamine (20.4 ml) in methanol (200 ml) and ethyl acetate (200 ml) was added to the solution. After the mixture was allowed to stand at room temperature, the resulting precipitates (37.9 g) were obtained. Recrystallization of the precipitates from methanol (926 ml) gave a salt of (S)-1-phenylethylamine and (S)-4-benzyloxymandelic acid (24.8 g) having a melting point of 174-180° C.
Reaction SMILES: [C:1]1([S:7]([CH3:9])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COCCN(S(F)(F)[F:20])CCOC>C(Cl)Cl>[C:1]1([S:7][CH2:9][F:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)c1ccccc1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: FCSc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A solution of methyl phenyl sulfoxide (140 mg, 1 mmol) in CH2Cl2 (5.0 mL) was added to bis(methoxyethyl)aminosulfur trifluoride (332 mg, 1.5 mmol ) under N2 and stirred for 16 h at room temperature. After work-up as above fluoromethyl phenyl sulfide (70% yield as determined by NMR) was obtained. 1H NMR (CDCl3) d 7.5-7.0 (m, 5H), 3.3 (d, 2H). 19F
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1.Cl>[C:11]([O:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([Br:1])=[C:3]([CH3:10])[CH:4]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(O)cc(C)c1Br
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(C)c(Br)c(C)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 128.9 %

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (10.1 g, 50.0 mmol) in pyridine (13 mL) was added acetic anhydride (7.66 g, 38.6 mmol), and the mixture was stirred at 50° C. for 30 min. The reaction mixture was ice-cooled, diluted with 0.5 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (12.1 g, yield 99%) as a yellow oil.