Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH2:33][C:34]1[NH:38][N:37]=[C:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:35]=1.C(O)(C(F)(F)F)=O.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:30])([F:29])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:32][CH2:33][C:34]1[NH:38][N:37]=[C:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:35]=1)=[O:4]
Reactant: CCOC(=O)c1n[nH]c(CN)n1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1n[nH]c(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)n1
Reaction time: 1 h
Yield: 20.77 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 120 mg, 0.278 mmol), ethyl 5-(aminomethyl)-1H-1,2,4-triazole-3-carboxylate, TFA (Int-XIV, 95 mg, 0.334 mmol), 4-methylmorpholine (113 mg, 1.113 mmol), and HATU (138 mg, 0.362 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=30.1 min) to provide ethyl 5-((2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)methyl)-1H-1,2,4-triazole-3-carboxylate (40 mg, 0.058 mmol, 20.77% yield) as a single enantiomer. LCMS=584.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.08-8.22 (2 H, m), 7.50-7.78 (7 H, m), 5.22 (1 H, s), 4.48-4.72 (2 H, m), 4.42 (2 H, q, J=7.04 Hz), 1.39 (3 H, t, J=7.04 Hz); HPLC peak RT=10.0 min (Method A).
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[N:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH2:16])=[N:8][CH:9]=1.[N:19]1([C:25]2[C:26]([C:31](O)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[N:19]1([C:25]2[C:26]([C:31]([NH:16][C@H:12]3[CH2:13][CH2:14][CH2:15][C@@H:11]3[NH:10][C:7]3[CH:6]=[N:5][C:4]([C:3]([F:2])([F:17])[F:18])=[CH:9][N:8]=3)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(O)c1ncccc1N1CCCCC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ncccc1N1CCCCC1

Procedure:
A solution of (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 75 mg, 0.27 mmol), 3-(piperidin-1-yl)pyridine-2-carboxylic acid (CAS number 898289-01-5; 66 mg, 0.32 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (54 mg, 0.40 mmol), EDC (76 mg, 0.40 mmol) and triethylamine (0.111 ml, 0.80 mmol) in DCM (1 ml) was stirred at room temperature overnight. The reaction was partitioned between DCM and a saturated solution of sodium bicarbonate, filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 40-100% ethyl acetate/petrol) and then further purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:27]=[CH:26][C:13]([CH2:14][O:15][C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH2:24][NH2:25])[CH2:20][CH2:19]2)=[O:17])=[CH:12][CH:11]=1>>[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][O:15][C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH2:24][NH:25][C:2]3[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:26][CH:27]=1
Reactant: Cc1ccc(COC(=O)N2CCC(CN)CC2)cc1
Reactant: Clc1nccnc1Cl
Product: Cc1ccc(COC(=O)N2CCC(CNc3nccnc3Cl)CC2)cc1

Procedure:
The title compound was prepared as described in EXAMPLE 47, reacting 2,3-dichloropyrazine with INTERMEDIATE 2a to give the title compound. M.S.(M+1): 375.
Reaction SMILES: [C:1]([C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=[S:5])(=[O:3])[NH2:2]>[OH-].[K+].O.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH3:16][O:15][C:9]1[C:10]([O:13][CH3:14])=[CH:11][C:12]2[S:5][C:4]([C:1]([NH2:2])=[O:3])=[N:6][C:7]=2[CH:8]=1
Reactant: COc1ccc(NC(=S)C(N)=O)cc1OC
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cc2nc(C(N)=O)sc2cc1OC
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
A solution of N-(carbamoyl-thiocarbonyl-)-3,4-dimethoxy-aniline (14 g) in 12% aqueous potassium hydroxide solution (1.26 l) was added slowly to a stirred solution of potassium ferricyanide (251.5 g) in water (560 ml) cooled to 10° C. The thick, yellow precipitate formed was stirred for 30 min., collected by filtration, washed with water, and dried. Crystallisation from dichloromethane/ethanol gave 5,6-dimethoxy-benzothiazole-2-carboxamide (11.98 g); m.p. 211°-212° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[C:10]#[C:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][N:22]=1.C([O-])([O-])=O.[K+].[K+]>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>[CH2:8]([C:4]1[C:3]([C:10]#[C:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=2)=[C:2]([C:24]2[CH:23]=[N:22][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:26][CH:25]=2)[CH:7]=[CH:6][N:5]=1)[CH3:9]
Reactant: CCc1nccc(Cl)c1C#Cc1ccc(N)nc1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
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: COCCOC
Solvent: O
Product: CCc1nccc(-c2ccc(C(F)(F)F)nc2)c1C#Cc1ccc(N)nc1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
The title compound is synthesized according to general procedure GP3 starting from 150 mg (0.58 mmol) 5-(4-Chloro-2-ethyl-pyridin-3-ylethynyl)-pyridin-2-ylamine (A-30) using 167 mg (0.87 mmoL) 2-trifluoromethyl-pyrid-5-yl boronic acid, 4.5 mg (0.03 mmol) Pd(PPh3)4 and 154 mg (1.11 mmol) K2CO3 in a mixture of 6.0 mL DME and 1.5 mL water. The reaction mixture is stirred twice under microwave irradiation at 150° C. for 120 min. The reaction mixture is concentrated in vaccuo and the crude product is purified by chromatography on silica gel using a DCM/MeOH-gradient. Yield: 15 mg (7%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:36])=[O:35])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:19][CH:20]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3ccccc3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3ccccc3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared following the method described in Step B of Example 1 from 3-(3-{[(biphenyl-4-ylmethyl)-amino]-methyl}-phenyl)-propionic acid methyl ester of Step A and benzenesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.85 (d, 2H), 7.60-7.29 (m, 10H), 7.08 (m, 3H), 7.01 (d, 1H), 6.88 (d, 1H), 6.78 (s, 1H), 4.33 (s, 2H), 4.32 (s, 2H), 3.63 (s, 3H), 2.78 (t, 2H), 2.47 (t, 2H); MS 500 (M+1).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3I)[C@@H:15]([CH3:32])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2([CH2:46][OH:47])[CH2:45][CH2:44]2)=[CH:39][C:38]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3[C:38]3[CH:39]=[C:40]([C:43]4([CH2:46][OH:47])[CH2:44][CH2:45]4)[CH:41]=[CH:42][C:37]=3[O:36][CH3:35])[C@@H:15]([CH3:32])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Reactant: COc1ccc(C2(CO)CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C2(CO)CC2)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C

Procedure:
(4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazinan-2-one (Intermediate 23; 28 mg; 0.046 mmol) was treated with {1-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl}methanol (Intermediate 28; 18 mg; 0.060 mmol), 1-1′-bis(di tert-butylphosphino) ferrocene palladium dichloride (3.0 mg; 0.0046 mmol), 1 N K2CO3 (2 mL) and THF (2 mL) as described in Example 38 to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-[1-(hydroxymethyl)cyclopropyl]-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazinan-2-one as a white solid. LCMS=662.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers): δ 7.86-7.82 (m, 2H), 7.76 (s, 1H), 7.66-7.61 (m, 2H), 7.40-7.37 (m, 1H), 7.27-7.24 (m, 2H), 6.96-6.93 (m, 1H), 5.40 (d, J=15.6 Hz, 1H), 4.91 (d, J=10.5 Hz, 1H), 4.11 (d, J=15.6 Hz, 1H), 3.91 (s, 3H), 3.68-3.56 (m, 2H), 3.39-3.32 (m, 1H), 2.24-2.16 (m, 1H), 1.80-1.64 (m, 1H), 1.05 (d, J=6.2 Hz, 3H), 0.88-0.74 (m, 4H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH2:9][N:8]([S:12]([CH3:15])(=[O:14])=[O:13])[C:7]=2[CH:16]=1.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C>CC(O)C>[CH3:15][S:12]([N:8]1[C:7]2[CH:16]=[C:3]([CH2:2][N:20]3[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]3)[CH:4]=[CH:5][C:6]=2[O:11][CH2:10][CH2:9]1)(=[O:14])=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)N1CCOc2ccc(CBr)cc21
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc3c(c2)N(S(C)(=O)=O)CCO3)CC1
Yield: 71.5 %

Procedure:
6-Bromomethyl-4-methanesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazine (2.6 g, 8.5 mmol) and tert-butyl piperazine-1-carboxylate (1.58 g, 8.5 mmol) were treated with propan-2-ol (100 mL) followed by N,N-diisopropylethylamine (10.96 g, 85 mmol) and the resulting mixture heated at reflux for 72 h then evaporated to dryness under reduced pressure. The residue was partitioned between ethyl acetate and saturated NaHCO3 aq. and the phases separated. The organic phase was washed with water, saturated brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography on SiO2, eluting with ethyl acetate in 60°–80° petroleum ether, gave the title compound (2.5 g, 71%) as a brown foam.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([CH2:15][OH:16])=[CH:4][CH:3]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:28][C:27]=2[F:36])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[F:36][C:27]1[CH:28]=[C:29]([C:32]([OH:35])([CH3:33])[CH3:34])[CH:30]=[CH:31][C:26]=1[C:20]1[S:19][C:18]([NH:17][C:2]2[CH:3]=[CH:4][C:5]([CH2:15][OH:16])=[C:6]([CH2:8][N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[N:7]=2)=[C:22]([C:23]([NH2:25])=[O:24])[CH:21]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: OCc1ccc(Cl)nc1CN1CCOCC1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3ccc(CO)c(CN4CCOCC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using [6-chloro-2-(morpholin-4-ylmethyl)pyridin-3-yl]methanol (66.0 mg, 0.27 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (80 mg, 0.27 mmol) as the starting materials.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH:3]1[CH2:25][CH2:24][N:6]2[C:7]3[CH:19]=[C:18](C(F)(F)F)[CH:17]=[CH:16][C:8]=3S[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:5]2[CH2:4]1.[CH:27](Cl)(Cl)Cl.CO>>[CH3:1][N:2]([CH3:26])[CH:3]1[CH2:25][CH2:24][N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:27][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:5]2[CH2:4]1
Reactant: CN(C)C1CCN2c3cc(C(F)(F)F)ccc3Sc3ccccc3C2C1
Reactant: ClC(Cl)Cl
Solvent: CO
Product: CN(C)C1CCN2c3ccccc3Cc3ccccc3C2C1

Procedure:
2-dimethylamino-7-trifluoromethyl-1,3,4,14b-tetrahydro-2H-pyridino[ 1,2-d]-dibenzo[b,f](1,4)-thiazepine (2-equatorial), (oil); Rf = 0.45 in chloroform:methanol (8:2).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH2:8].Cl.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[N:22]=[CH:21][N:20]([CH2:34][O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[C:19]2=[O:42].C(N(CC)CC)C>CO.C(Cl)Cl>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH2:27][CH:28]1[CH2:29][CH2:30][N:31]([CH2:8][CH2:7][S:9]([CH3:12])(=[O:11])=[O:10])[CH2:32][CH2:33]1)[N:22]=[CH:21][N:20]([CH2:34][O:35][C:36](=[O:41])[C:37]([CH3:38])([CH3:39])[CH3:40])[C:19]2=[O:42]
Reactant: C=CS(C)(=O)=O
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCN(CCS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
Potassium carbonate (280 mg, 2 mmol) and methyl vinyl sulfone (0.4 ml, 2.1 mmol) were added to a solution of 6-methoxy-7-((piperidin-4-yl)methoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one hydrochloride (0.88 g, 2 mmol) and triethylamine (0.3 ml, 2.1 mmol) in methanol (10 ml) and methylene chloride (10 ml). After stirring for 2 hours at ambient temperature, the volatiles were removed under vacuum. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and evaporated to give 6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (0.55 g, 54%).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[C:8]1([CH3:16])[C:9]([CH:14]=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=1>CCCCCC.C1COCC1.CS(C)=O>[CH3:16][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1[O:15][CH2:4]1
Reactant: C[S+](C)C
Reactant: Cc1ccccc1C=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1ccccc1C1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
Sodium hydride (57%) (4.84 g., 0.115 mole) previously washed with hexane was stirred with dry dimethylsulfoxide (70 ml) at 65°-70° for 2 hours under argon. The mixture was diluted with dry THF (70 ml), cooled to -5° and trimethylsulfonium iodide (23.5 g, 0.115 mole) in 100 ml of dry DMSO was added over a period of 3 minutes. After stirring for one minute o-tolualdehyde (11.5 g, 0.0926 mole) was added at a moderate rate while keeping the reaction mixture at 0° to -5°. The mixture was stirred at 0° for 5 minutes and at room temperature for 1 hour, diluted with 500 ml of ice water and extracted three times with ether. The ether solution was washed with saturated sodium chloride, dried with sodium sulfate and evaporated to an oil which was distilled under reduced pressure (~0.25-0.50 mm) to give 10.25 g (83 %) of o-methylstyrene oxide as a clear liquid (b.p. 35°-38°).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:11][C:12]([F:25])([F:24])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][CH:22]=[N:21][CH:20]=2)=[CH:15][CH:14]=1.[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:26][C:22]1[O:23][C:19]([C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:11])([F:24])[F:25])=[CH:18][CH:17]=2)=[CH:20][N:21]=1
Reactant: FC(F)(F)c1ccc(-c2cnco2)cc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(-c2cnc(Cl)o2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
LiHMDS (1.06 M in THF, 28.59 mL, 30.3 mmol) was added to a solution of 5-(4-(trifluoromethyl)phenyl)oxazole 30 (5.38 g, 25.25 mmol) in THF (100 mL) at −78° C., and the mixture was stirred at −78° C. for 1 h. A solution of hexachloroethane (8.96 g, 37.87 mmol) in THF (10 mL) was added at −78° C., and the mixture was stirred at −78° C. for 2 h and allowed to warm to room temperature and stirred for 14 h. The reaction was quenched by adding EtOAC:H2O (50 mL:15 mL), and then extracted with Ethyl acetate. The extracts were washed with brine, dried (Na2SO4) and concentrated. The product was purified by column chromatography (Acetone/hexane as an eluent) to provide 2-chloro-5-(4-(trifluoromethyl)phenyl)oxazole 31 (6.05 g, 97% yield) as white solid. MS (ES) m/z 248 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6]>C1C=CC=CC=1.[O-2].[Mn+4].[O-2]>[CH3:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: Cc1cccc(CO)c1[N+](=O)[O-]
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: Cc1cccc(C=O)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 24 h
Yield: 98.1 %

Procedure:
To a solution of 3-methyl-2-nitrobenzyl alcohol (16.7 g, 100 mmol) in 300 mL of benzene was added activated manganese (IV) oxide (43.5 g, 500 mmol). The resulting mixture was stirred at 80° C. for 24 h. The reaction mixture was allowed to cool and then was filtered through a pad of Celite and concentrated in vacuo to afford 16.2 g of 3-methyl-2-nitrobenzaldehyde, which was pure enough to be used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12]O)[C:7]=2[CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:34]I.N1C=CN=C1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12][I:34])[C:7]=2[CH:14]=1
Reactant: II
Reactant: COc1ccc2occ(CCO)c2c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2occ(CCI)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-(5-methoxy-1-benzofuran-3-yl)ethanol (960 mg, 5 mmol) in anhydrous THF (50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hrs and quenched with water. It was extracted with chloroform, washed well with 5% Na2S2O3 solution and the organic layer was dried over anhydrous MgSO4. It was filtered and concentrated. The residue was purified by silica-gel column chromatography by eluting it with 30% ethyl acetate:hexane. The product, namely 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide, was obtained as brown liquid. Yield: 1.1 g (73%); 302 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:11]=[N:10][CH:9]([CH3:12])[N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH3:18]>O1CCOCC1>[Cl:1][C:2]1[N:7]([CH2:16][CH2:17][CH3:18])[C:6](=[O:8])[N:5]2[C:9]([CH3:12])=[N:10][CH:11]=[C:4]2[CH:3]=1
Reactant: CCCBr
Reactant: CC1N=Cc2cc(Cl)nc(=O)n21
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCn1c(Cl)cc2cnc(C)n2c1=O
Temperature: 0 °C

Procedure:
To a mixture of 2.0 g (10.9 mmole) of 7-chloro-3-methylimidazo[1,5-c]pyrimidin-5-one (from Example 4, Part B) in 50 ml of dioxane was added 0.52 g (13 mmole) of 60% sodium hydride in oil. After ten minutes of stirring, 1.6 g (13 mmole) of 3-bromopropane was added and the mixture was stirred for 16 hours at 50° C. The solution was poured into 100 ml of an ice water mixture. The resulting solution was extracted four times with 75 ml portions of chloroform. The extracts were washed twice with water, dried, and evaporated. The residue was dissolved in 80 ml of chloroform, washed with six 100 ml portions of water, dried and evaporated. The residue was recrystallized with treatment with decolorizing charcoal from cyclohexane to provide 7-chloro-3-methyl-6-n-propylimidazo[1,5-c]pyrimidin-5-one, m.p. 125°-126° C. Analysis: Calculated for C10H12ClNO: %C, 53.2 ; %H, 5.4; %N, 18.6; Found: %C, 53.5; %H, 5.3; %N, 18.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[C:17]([NH:19][C:20]2[C:25]([NH:26][C:27](=[O:44])/[CH:28]=[CH:29]/[CH:30]=[CH:31]/[C:32]3[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([O:42][CH3:43])[CH:33]=3)=[CH:24][CH:23]=[CH:22][C:21]=2[O:45]C(=O)/C=C/C=C/C2C=C(OC)C(OC)=C(OC)C=2)=[O:18])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+]>CO.O1CCCC1>[CH3:12][O:11][C:7]1[CH:6]=[C:5](/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[C:17]([NH:19][C:20]2[C:25]([NH:26][C:27](=[O:44])/[CH:28]=[CH:29]/[CH:30]=[CH:31]/[C:32]3[CH:33]=[C:34]([O:42][CH3:43])[C:35]([O:40][CH3:41])=[C:36]([O:38][CH3:39])[CH:37]=3)=[CH:24][CH:23]=[CH:22][C:21]=2[OH:45])=[O:18])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(/C=C/C=C/C(=O)Nc2cccc(OC(=O)/C=C/C=C/c3cc(OC)c(OC)c(OC)c3)c2NC(=O)/C=C/C=C/c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(/C=C/C=C/C(=O)Nc2cccc(O)c2NC(=O)/C=C/C=C/c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 196 mg (0.23 mmol) of N,N′,O-tri[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-2,3-diaminophenol synthesized by the process described above in anhydrous methanol-tetrahydrofuran (3 ml-3 ml) was cooled in an ice bath. To the solution was added 19 mg (0.14 mmol) of potassium carbonate. The ice bath was removed, and the mixture was stirred for 1 hour at room temperature. Added to the reaction mixture were 0.5 ml of 1N hydrochloric acid and 5 ml of a saturated saline solution to conduct extraction with chloroform. An organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil (515 mg) was purified by column chromatography on silica gel, thereby obtaining 126 mg (yield: 90%) of crude crystals of the title compound. The crude crystals thus obtained were recrystallized from ethanol-ether, thereby obtaining a pale yellow crystalline powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH3:12])[CH:5]=1)[CH3:2].[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1.[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCCl>[CH2:11]([O:10][C:6]1[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[CH:8][C:7]=1[C:13]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:19])[CH3:12]
Reactant: O=C1CCC(=O)O1
Reactant: CCOc1cccc(OCC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: CCOc1ccc(C(=O)CCC(=O)O)c(OCC)c1
Reaction time: 1 h

Procedure:
A mixture of m-diethoxybenzene (22 g.) and succinic anhydride (15 g.) was dissolved in 1,2-dichloroethane and the resultant solution was stirred and treated with powdered aluminium chloride (30 g.), added gradually during 1 hour with external cooling to keep the reaction temperature at 10° C. The reaction mixture was stirred for 1 hour further, poured into water and the solvent was boiled off. The remaining oily suspension crystallised on stirring and cooling and the solid was collected and dried (Yield 15.5 g.). It had m.p. 139°-141° C after crystallisation from toluene.