Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[N:26]=[CH:25][C:24]([C:27](=O)[CH3:28])=[CH:23][CH:22]=3)[O:18][N:17]=2)[N:3]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.[BH4-].[Na+]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:15][N:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([CH:27]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH3:28])=[CH:25][N:26]=3)[O:18][N:17]=2)[N:5]=1
Reactant: CC(=O)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)nc1
Reactant: C1CCNC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Product: CC(c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)nc1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
To a solution of 1-[6-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyridin-3-yl]ethan-1-one (prepared in an analogous manner to Example 296, 100 mg, 257 μmol) and pyrrolidine (53 μL, 643 μmol) in anhydrous THF (5 mL) at 0 C under nitrogen was added titanium isopropoxide (183 mg, 643 μmol) drop-wise. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was then cooled to 0 C and sodium borohydride (29 mg, 771 μmol) was added. The reaction mixture was stirred at room temperature for 3 h and then was quenched with water (10 mL) and extracted into EtOAc (3×25 mL). Combined organics were dried over magnesium sulfate, evaporated and the crude product was purified by silica chromatography (2% MeOH in DCM) to afford the title compound as a beige solid (13 mg, 12%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:10]3[C:27]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:25]=[N:24][C:11]=3[N:12]3[C:17]=2[CH:16]([CH2:18][C:19]([O:21]CC)=[O:20])[CH2:15][CH2:14][CH2:13]3)=[CH:4][CH:3]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:10]3[C:27]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:25]=[N:24][C:11]=3[N:12]3[C:17]=2[CH:16]([CH2:18][C:19]([OH:21])=[O:20])[CH2:15][CH2:14][CH2:13]3)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1CCCn2c1c(Sc1ccc(Cl)cc1)c1c(S(C)(=O)=O)ccnc12
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)c1ccnc2c1c(Sc1ccc(Cl)cc1)c1n2CCCC1CC(=O)O
Reaction time: 18 h

Procedure:
To the compound of Step 10 dissolved in a 1/1 mixture of TBF-MeOH was added 1N NaOH. After a period of 18 h at room temperature, the reaction mixture was partitioned between saturated NH4Cl and EtOAc. The organic phase was separated, dried over Na2SO4 and evaporated to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:4]([N+:17]([O-])=O)[C:3]=1[CH:20]=[O:21].C(O)(=O)C.Cl>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]2=[CH:20][O:21][N:17]=[C:4]2[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:6]([CH2:8][OH:9])[CH:7]=1
Reactant: O=Cc1c(Cl)cc(CO)c(-c2cccc(F)c2)c1[N+](=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: OCc1cc(Cl)c2conc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.4 %

Procedure:
To a mixture of 4-chloro-3′-fluoro-6-(hydroxymethyl)-2-nitrobiphenyl-3-carbaldehyde (0.50 g, 1.6 mmol), acetic acid (4 mL), and conc. HCl (4 mL) was added stannous chloride, dihydrate (1.4 g, 6.4 mmol). After stirring at room temperature for 2 hours, the resulting mixture was diluted with ethyl acetate, washed with water, brine, and then dried with sodium sulfate and concentrated to dryness. The residue was purified on silica gel, eluting with 0 to 50% ethyl acetate in hexane, to give the desired product (0.104 g, 23%). LCMS calculated for C14H10ClFNO2 (M+H)+: m/z=278.0; Found: 278.0.
Reaction SMILES: Br[C:2]1[C:3]2[S:9][CH:8]=[C:7]([Br:10])[C:4]=2[S:5][CH:6]=1.[CH3:11][O:12][C:13](=[O:46])[NH:14][C@H:15]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]1[NH:27][C:28]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)=[CH:29][N:30]=1)=[O:20])[CH:16]([CH3:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>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>[CH3:11][O:12][C:13](=[O:46])[NH:14][C@H:15]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]1[NH:30][CH:29]=[C:28]([C:31]2[CH:32]=[CH:33][C:34]([C:2]3[C:3]4[S:9][CH:8]=[C:7]([Br:10])[C:4]=4[S:5][CH:6]=3)=[CH:35][CH:36]=2)[N:27]=1)=[O:20])[CH:16]([CH3:18])[CH3:17]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Reactant: Brc1csc2c(Br)csc12
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: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3csc4c(Br)csc34)cc2)c[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
To a degassed mixture of 3,6-dibromo-thieno[3,2-b]thiophene (0.335 mmol), compound 8 (0.335 mmol), and sodium carbonate (1.34 mmol) in a mixture of DMF and water (10 mL/1 mL) was added Pd(PPh3)4 (0.335 mmol). The reaction mixture was heated for 1 hr at 80° C. Ethyl acetate and water were then added and the mixture was vigorously stirred for 10 min. The layers were partitioned into a phase separator. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: DCM to DCM/MeOH 9/1) to give compound A155 as a green gum in 74% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 0.85 (d, J=6.61 Hz, 3H), 0.90 (d, J=6.61 Hz, 3H), 1.92-2.19 (m, 5H), 3.53 (s, 3H), 3.77-3.84 (m, 2H), 4.06 (t, J=8.34 Hz, 1H), 5.07-5.09 (m, 1H), 7.28 (d, J=8.32 Hz, 1H), 7.54 (d, J=1.97 Hz, 1H), 7.70-7.76 (m, 2H), 7.84-7.93 (m, 3H), 8.08-8.14 (m, 1H), 11.81 (s, 1H); MS (ESI, EI+) m/z=587-589 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([C:17]([O:19]CC)=[O:18])[C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]([C:17]([OH:19])=[O:18])[C:10]=2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1C(c2ccccc2)=C1c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1C(c2ccccc2)=C1c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 45.3 %

Procedure:
Ethyl 2-(4-chlorophenyl)-3-phenyl-cycloprop-2-ene-1-carboxylate (0.66 g, 2.20 mmol) and potassium hydroxide (0.7 g, 12.95 mmol) were dissolved in methanol (25 cm3) and heated to reflux for 2 hours. The mixture was cooled to room temperature and the solvent evaporated. The residue was partitioned between water (30 cm3) and ethyl acetate (30 cm3). The aqueous layer was separated and washed with ethyl acetate (2×30 cm3) before being acidified to pH=1 with dilute hydrochloric acid and extracted with dichloromethane (3×40 cm3). The combined dichloromethane extracts were dried (MgSO4), evaporated and washed with heptane to give the cyclopropene acid 0.27 g, 45%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:17]=[CH:16][C:15]2[N:14]([CH3:18])[C:13](=[O:19])[C@@H:12]([CH2:20][CH3:21])[N:11]([CH:22]([CH3:24])[CH3:23])[C:10]=2[N:9]=1.[CH3:25][C:26]([CH3:32])([CH3:31])[CH2:27][C:28](O)=[O:29].C(O)(C(F)(F)F)=O>>[CH2:20]([C@H:12]1[N:11]([CH:22]([CH3:23])[CH3:24])[C:10]2[N:9]=[C:8]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[NH:1][C:28](=[O:29])[CH2:27][C:26]([CH3:32])([CH3:31])[CH3:25])[N:17]=[CH:16][C:15]=2[N:14]([CH3:18])[C:13]1=[O:19])[CH3:21]
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3N)nc2N1C(C)C
Reactant: CC(C)(C)CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3NC(=O)CC(C)(C)C)nc2N1C(C)C

Procedure:
The title compound was prepared similarly to the methods described in Example 102, with (R)-2-(3-aminopyridin-4-yl)-7-ethyl-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 93) instead of (R)-2-(3-aminopyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 91) and with 3,3-dimethylbutanoic acid instead of benzoic acid. LCMS (0.05% TFA): 425.3 m/z (M+H)+; 1H-NMR (DMSO-d6, 500 MHz): δ: 12.93 (bs, 1H), 9.89 (bs, 1H), 8.50 (bs, 2H), 8.30 (s, 1H), 4.59 (m, 1H), 4.49 (m, 1H), 3.36 (s, 3H), 2.37 (s, 2H), 1.87 (m, 1H), 1.77 (m, 1H), 1.45 (m, 6H), 0.77 (t, 3H, J=7.5 Hz).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Br:9][CH2:10][C:11](Br)=[O:12].CCN(CC)CC>C(Cl)Cl>[Br:9][CH2:10][C:11]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([I:1])[CH:3]=1)=[O:12]
Reactant: Nc1cccc(I)c1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)Nc1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of 3-iodoaniline (2.19 g, 10.0 mmol) and 2-bromoacetyl bromide (0.87 mL, 3.40 g, 10.0 mmol) in DCM (100 mL) was added Et3N (1.39 mL) at 0° C. The reaction mixtures were stirred at room temperature for overnight. The reaction mixtures were diluted with DCM (100 mL), washed with water, and dried over Na2SO4. Solvent was evaporated under reduce pressure to afford a residue, which was purified by biotage eluting with 10% EtOC in hexanes to 100% EtOAc to afford 2-bromo-N-(3-iodophenyl)acetamide (2.824 g, 83%). MS (ESI), 340, 342 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16](OCC)=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12.[BH4-].[Li+].Cl>O1CCCC1>[OH:17][CH2:16][C:15]1[N:14]=[CH:13][N:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2](=[O:1])[N:3]3[CH2:23][CH2:22][CH2:21][C@H:4]3[C:5]=12
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1c2ccccc2-n2cnc(CO)c2[C@@H]2CCCN12
Temperature: 25 °C

Procedure:
A solution of 46.7 g (150 mmol) of ethyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate in 300 ml of dry tetrahydrofuran is treated dropwise at ca 35° C. with a solution of 8.3 g (377 mmol) of lithium borohydride in 110 ml of dry tetrahydrofuran. The mixture is heated to boiling under reflux for ca 40 hours, cooled to room temperature, treated with 110 ml of 12 percent hydrochloric acid and 20 ml of concentrated hydrochloric acid and again heated to boiling under reflux for 2 hours. After removal of the tetrahydrofuran in vacuo, the residue is made alkaline with concentrated ammonia. The separated material is filtered off under suction and washed with water. After recrystallisation from ethanol, there is obtained (S)-11,12,13,13a-tetrahydro-1-(hydroxymethyl)-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 212°-214° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.C([Mg]Cl)(C)C.[CH:16](N1CCCCC1)=[O:17].Cl>C1COCC1>[F:10][C:4]1[CH:3]=[C:2]([CH:16]=[O:17])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: O=CN1CCCCC1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(C=O)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-bromo-2-fluorobenzonitrile (5.00 g, 25 mmol) in dry THF (50 mL) at −10° C. under argon was treated with a solution of isopropylmagnesium chloride (2M in THF, 15.0 mL, 30.0 mmol) dropwise before stirring at this temperature for 3 h. A solution of N-formylpiperidine (3.89 g, 35.0 mmol) in dry THF (15 mL) was added dropwise and the mixture allowed to warm to room temperature before stirring for 1.5 h. The resultant solution was treated with 4M aq HCl (250 mL each) and the organics extracted with EtOAc. The combined organics were dried (MgSO4), filtered and evaporated before purification of the residue by column chromatography (SiO2; eluting with 30% to 50% EtOAc in cyclohexane) to afford 2-fluoro-4-formyl-benzonitrile VII-a as a pale yellow solid (2.73 g, 73%). 1H NMR (300 MHz, CDCl3) δ 10.07 (d, J=1.7 Hz, 1H), 7.90-7.79 (m, 2H), 7.74 (dd, J=8.5, 0.8 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[N:16]=[CH:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)=[O:33].CO>[Pd]>[CH:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[N:16]=[CH:15]2)[CH2:12][CH2:13]1)=[O:33]
Reactant: Fc1ccc(-c2ncn(C3CCN(Cc4ccccc4)CC3)c2-c2ccncc2)cc1
Reactant: O=CO
Agent: [Pd]
Solvent: CO
Product: O=CN1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccncc2)CC1
Temperature: 25 °C

Procedure:
1-(1-Benzylpiperidin-4-yl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole (100 mg; prepared in Example 40) was dissolved in 10% formic acid/methanol under argon and palladium black (100 mg) mixed in 10% formic acid/methanol was added. The reaction was stirred under argon at room temperature for sixteen hours. The reaction mixture was evaporated and the residue mixed in H2O/ethyl acetate and the pH taken to 10. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic layers were evaporated and the residue was flash chromatographed (silica gel/methylene chloride/methanol) to yield the title compound, an off-white solid. ES (+) MS m/e=351 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12](COCC[Si](C)(C)C)[N:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1ncnc1-c1cccc(Br)c1
Agent: Cl
Solvent: CCO
Product: Brc1cccc(-c2ncn[nH]2)c1
Yield: 89.3 %

Procedure:
This reaction was carried out as described in Example 40, step b, using 5-(3-bromophenyl)-1-(2-trimethylsilanylethoxymethyl)-1H-[1,2,4]triazole (2.88 g, 8.1 mmol), 2 N HCl (50 ml) and ethanol (50 ml) to yield the title compound (1.62 g, 89%): 1H NMR (360 MHz, DMSO-d6) δ 8.70 (1H, s), 8.16 (1H, s), 8.01 (1H, d, J 7.8 Hz), 7.63 (1H, d, J 7.8 Hz), 7.46 (1H, t, J 7.8 Hz).
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([O:17][CH3:18])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1.C(N(CC)C(C)C)(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([O:17][CH3:18])[CH2:15][N:14]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1
Reactant: CO[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: CS(=O)(=O)Cl
Agent: I
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H]1CN(S(C)(=O)=O)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
A solution of 6-bromo-4-(((3R,4S)-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide (from Step 2 of Example 202, 210 mg, 0.436 mmol) in dichloromethane (2 mL), was added N,N-diisopropylethylamine (0.23 mL, 1.31 mmol) and methanesulfonyl chloride (0.043 mL, 0.52 mmol) at rt. The mixture was stirred at rt for 2 h. The reaction was then quenched with water, diluted with dichloromethane, washed with aq. sodium bicarbonate and brine. The organic layer was dried and concentrated. The crude was tritrated in ether and filtered to give 6-bromo-4-(((3R,4S)-4-methoxy-1-(methylsulfonyl)pyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (136 mg, 72% yield) as a yellow solid. MS (ES+) m/z: 432.3, 463.1 (M+H); LC retention time: 2.31 min (analytical HPLC Method H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([Cl:19])=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:11][C:12]1[N:17]=[C:16]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:15]([Cl:19])=[CH:14][N:13]=1
Reactant: COc1cccc(CN)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(CNc2nc(Cl)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of 3-methoxybenzylamine (0.75 g, 5.4 mmol) and 2,4,5-trichloropyrimidine (1.1 g, 6.0 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (2.3 g, 16 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water. Ethyl acetate (“EtOAc”) was added and the layers were separated. The aqueous layer was extracted with EtOAc once. The combined organic layers were washed with water and brine successively, then dried (Na2SO4), filtered, and concentrated. The crude product was purified by silica gel column chromatography to give the desired product as a white powder (1.43 g, 92%). LCMS for C12H12ClN3O (M+H)+: m/z=284.0, 286.0.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=1.[O:22]([CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[CH2:9][O:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([N:34]2[CH2:35][CH2:36][CH:31]([CH2:30][CH2:29][O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:32][CH2:33]2)[CH:7]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: c1ccc(OCCC2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CCC(CCOc3ccccc3)CC2)c1
Temperature: 99 °C
Yield: 52.8 %

Procedure:
To a solution of 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (212 mg, 0.59 mmol) and 4-(2-phenoxyethyl)piperidine (134 mg, 0.65 mmol, 1.1 equiv.) in anhydrous toluene (5 mL) were added successively sodium tert-butoxide (85 mg, 0.89 mmol, 1.5 equiv.), tris(dibenzylideneacetone)dipalladium(0) (10.8 mg, 12 μmol, 0.02 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 20.6 mg, 37 μmol, 0.06 equiv.). The mixture was degassed and purged with Ar (3 cycles), then warmed to 98-100° C. for 4 h. After cooling to room temperature, the mixture was diluted with EtOAc, and the solution was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by CC on SiO2 with CH2Cl2/EtOAc 4:1, then 1:1. The product (150 mg, 53%) was obtained as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.93-7.79 (m, 2H), 7.28 (t, 2H, J=8.0 Hz), 6.96-6.69 (m, 4H), 4.12 (m, 2H), 4.03 (t, 2H, J=6.0 Hz), 3.93-3.83 (m, 1H), 3.70 (m, 2H), 3.40 (m, 2H), 2.77 (m, 2H), 2.04-1.87 (m, 3H), 1.87-1.80 (m, 3H), 1.78-1.75 (m, 3H), 1.47 (s, 9H), 1.43-1.30 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 158.5, 155.1, 154.3, 148.0, 131.7, 130.9, 129.1, 127.8, 126.6, 120.2, 114.0, 108.7, 108.2, 79.4, 79.0, 68.4, 67.9, 64.8, 55.6, 48.7, 46.5, 46.2, 35.3, 32.2, 31.4, 28.1, 27.7, 23.4, 22.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:17][C:16](=O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.S(Cl)([Cl:21])=O.CN(C)C=O>C(Cl)(Cl)Cl>[Cl:21][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:17]=1
Reactant: O=c1[nH]c(-c2ccccc2F)nc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1ccccc1-c1nc(Cl)c2ccccc2n1
Temperature: 0 °C
Yield: 73 %

Procedure:
2-(2-Fluoro-phenyl)-3H-quinazolin-4-one from Step B (0.86 g, 3.5 mmol) was suspended in chloroform in a 50 ml round bottomed flask equipped with magnetic stirrer. The flask was cooled to 0° C. and to it was added thionyl chloride (1.2 ml) drop wise followed by N,N-dimethylformamide (0.01 ml) and the mixture heated to 80° C. for 4 hrs. The solvent was removed by evaporation in a rotary evaporator to leave a title compound as a solid (0.68 g, 73%). MS (ES) 259.1 (M+H)+
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]([F:15])=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1.[CH2:16](Br)[CH:17]=[CH2:18].O>CN(C)C=O>[CH2:18]([N:9]1[C:8]2[CH:14]=[C:4]([NH2:3])[C:5]([F:15])=[CH:6][C:7]=2[O:12][CH2:11][C:10]1=[O:13])[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: Nc1cc2c(cc1F)OCC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN1C(=O)COc2cc(F)c(N)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
While kept under N2, 2.41 g (60.4 mmol) of sodium hydride (60% dispersion in oil) was washed with 10 ml hexanes and then suspended in 20 ml anhydrous dimethylformamide. A solution of 10.0 g (54.9 mmol) of 6-amino-7-fluoro-2H-1,4-benzoxazin-3(4H)-one in 100 ml of dimethyl formamide was added to the sodium hydride slurry slowly by syringe with ice cooling and the reaction mixture was stirred at room temperature for 0.5 hr. Then there was added 7.91 g (65.9 mmol) of allyl bromide by syringe with ice bath cooling. The reaction mixture was allowed to warm to room temperature, and then poured into 100 ml of water. The resulting mixture was extracted with EtOAc (2×50 ml) and the organic layers were combined and washed with water (3×50 ml), dried over Na2SO4 and filtered. The solvent was removed in vacuo to yield 11.0 g (90% yield) of 4-allyl-6-amino- 7-fluoro-2H-1,4-benzoxazin-3(4H)-one as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[SH-:13].[K+:14]>C(O)(C)(C)C.CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][NH:8][C:9](=[S:13])[S-:10])=[CH:11][CH:12]=1.[K+:14]
Reactant: [SH-]
Reactant: S=C=NCOc1ccc(Cl)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Product: S=C([S-])NCOc1ccc(Cl)cc1

Procedure:
Potassium p-chlorophenoxymethyldithiocarbamate was prepared by the reaction of p-chlorophenoxymethyl isothiocyanate with potassium hydrosulfide in a mixture of t-butyl alcohol and acetone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:11](OCC)(=[O:13])[CH3:12]>CN(C)C=O.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:12][CH:11]=[O:13]
Reactant: Oc1cccc(F)c1
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=CCOc1cccc(F)c1
Temperature: 60 °C
Yield: 78.1 %

Procedure:
2.00 g (17.8 mmol) of m-fluorophenol was dissolved in 50 ml of dimethylformamide, 785 mg (19.6 mmol, 60% by weight, mineral) of sodium hydride and 3.21 ml (21.3 mmol) of bromoacetaldehydediethylacetal were successively added thereto, and the mixture was heated to 60° C. After completion of the reaction, brine was added thereto and the mixture was extractedwith ethyl acetate. Theorganiclayerwaswashedwith brine, dried over magnesium sulfate and then evaporated, to give a crude product. The crude product was subjected to 105 g of Cromatorex NH silica gel (ethyl acetate:hexane=1:40), to give 3.17 g (13.9 mmol, 78.1%) of the title compound as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:14](Cl)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>C1C=CC=CC=1.[Ag]>[C:15]([C:14]([O:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:13])[C:2](=[O:1])[CH:11]=1)=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Reactant: CC(C)(C)C(=O)Cl
Agent: [Ag]
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)OC1=CC(=O)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.5 %

Procedure:
A mixture of the silver salt of 2-hydroxy-1,4-naphthoquinone (842 mg, 3 mmol), and pivaloyl chloride (434 mg, 3.6 mmol) in benzene (5 mL) was stirred for 8 h at room temperature. The reaction mixture was filtered through Celite, the precipitate washed with EtOAc, and the combined organic solutions were concentrated in vacuo and purified by flash chromatography (EtOAc/hexane 1:10, 1:5). The product was recrystallized from hexane to afford a yellow solid (190 mg, 25%); mp 125-126° C.; 1H NMR (CDCl3) 8.15(dd, J=7.7, 1.1 Hz, 1H), 7.71(dt, J=7.7, 1.5 Hz, 1H), 7.59 (dt, J=7.5, 1.2 Hz, 1H), 7.57 (dd, J=7.6, 1.1 Hz, 1H), 6.48 (s, 1H), 1.44 (s, 9H).