Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C.N1C=CC=CC=1.[NH2:32][C:33]1[CH:34]=[C:35]([CH2:40][C:41]([CH3:50])([CH3:49])[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:36]=[CH:37][C:38]=1[Cl:39]>ClCCl>[Cl:39][C:38]1[CH:37]=[CH:36][C:35]([CH2:40][C:41]([CH3:50])([CH3:49])[C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])=[CH:34][C:33]=1[NH:32][C:9](=[O:11])[C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14]
Reactant: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(Cl)c(N)c1
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H]([C@H](C(=O)Nc1cc(CC(C)(C)C(=O)OC(C)(C)C)ccc1Cl)c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
400 mg (1.50 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in 24 ml of dichloromethane, 320 mg (2.40 mmol) of 1-chloro-N,N,2-trimethylprop-1-ene-1-amine were added and the mixture was stirred at room temperature for 30 min. 364 μl (4.5 mmol) of pyridine and 510 mg (1.80 mmol) of tert-butyl 3-(3-amino-4-chlorophenyl)-2,2-dimethylpropanoate were then added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated under reduced pressure, and the crude product obtained was purified by chromatography on silica gel (mobile phase cyclohexane/ethylacetate 20:1). This gave 462 mg of the target compound (58% of theory).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[N:19]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:18](=[O:39])[NH:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:41][C:42]([O:44][CH3:45])=[O:43].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[N:19]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:18](=[O:39])[N:17]([CH2:41][C:42]([O:44][CH3:45])=[O:43])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3[nH]c(=O)n(COC(=O)C(C)(C)C)c(=O)c3n2-c2ccccc2Cl)CC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)n(COC(=O)C(C)(C)C)c(=O)c2c1nc(N1CCN(C(=O)OC(C)(C)C)CC1)n2-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[7-(2-Chlorophenyl)-1-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (107 mg) was dissolved in N,N-dimethylformamide (2 ml), and methyl bromoacetate (0.025 ml) and potassium carbonate (50 mg) were added to the solution. Then, the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water. The organic layer was concentrated to give 139 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[N:29]=[C:28]2[NH:36][CH:37]2[CH2:42][CH2:41][N:40]([CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)[CH2:39][CH2:38]2)=[CH:22][CH:21]=1.[I-].[K+].C(=O)([O-])[O-:52].[K+].[K+]>O.ClC(Cl)Cl>[OH2:52].[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][N:27]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[N:29]=[C:28]2[NH:36][CH:37]2[CH2:42][CH2:41][N:40]([CH:43]3[CH2:48][CH2:47][N:46]([C:2]4[N:6]([CH2:7][C:8]5[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=5)[C:5]5[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=5[N:3]=4)[CH2:45][CH2:44]3)[CH2:39][CH2:38]2)=[CH:24][CH:25]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(Cn2c(Cl)nc3ccccc32)cc1
Reactant: Fc1ccc(Cn2c(NC3CCN(C4CCNCC4)CC3)nc3ccccc32)cc1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Fc1ccc(Cn2c(NC3CCN(C4CCN(c5nc6ccccc6n5Cc5ccc(F)cc5)CC4)CC3)nc3ccccc32)cc1
Temperature: 130 °C

Procedure:
A mixture of 4 parts of 2-chloro-1-[(4-fluorophenyl)methyl]-1H-benzimidazole, 6.1 parts of N-[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]-[1,4'-bipiperidine]-4-amine and 1 part of potassium iodide was stirred and heated for 3 hours at 130° C. The reaction mixture was cooled and taken up in water and trichloromethane. The whole was alkalized with potassium carbonate. The organic phase was separated, dried, filtered and evaporated. The residue was purified by HPLC using a mixture of trichloromethane and methanol (98:2 by volume), saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 1.6 parts of 1-[(4-fluorophenyl)methyl]-N-[1'-[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]-[1,4'-bipiperidin]-4-yl]-1H-benzimidazol-2-amine monohydrate; mp. 130.2° C. (compound 65).
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>>[CH2:19]([O:18][C:16]([NH:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reaction time: 0.33 h

Procedure:
A 15.0 g sample of D-phenylalanine was dissolved in 45 ml of aqueous solution containing 7.26 g of 50% sodium hydroxide. This solution was stirred at 0°-10° C. as 16.3 g of benzyl chloroformate was added rapidly in portions. The resulting reaction was mildly exothermic, and shortly after addition, solids precipitated. An additional 45 ml of water and 3.63 g of 50% sodium hydroxide were added, causing most of the solids to redissolve. The reaction mixture was stirred for 20 minutes and then acidified with 6 N hydrochloric acid. The resulting solids were filtered, washed with water and then with hexane, and dried by suction and then under vacuum to give 47 g of white solids. These solids dissolved in ether were washed twice with 1 N hydrochloric acid and then with water, dried over MgSO4 and stripped to 35° C. at 2.5 mm Hg to give 27.7 g of the desired product as a colorless oil.
Reaction SMILES: [NH3:1].[CH2:2]([O:6][CH2:7][CH2:8][CH2:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:3]1[O:5][CH2:4]1>>[Si:10]([CH2:9][CH2:8][CH2:7][O:6][CH2:2][CH:3]([OH:5])[CH2:4][NH2:1])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: N
Reactant: CC(C)(C)[Si](C)(C)CCCOCC1CO1
Product: CC(C)(C)[Si](C)(C)CCCOCC(O)CN
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methanolic ammonia (7 mol of ammonia in methanol, 100 mL, 0.7 mol,) was charged to a 500 mL, one-neck, round-bottom flask placed in an ice bath. To the above solution 3-t-butyldimethylsilylpropyl glycidyl ether (23.04 g, 0.1 mol) was added dropwise at 0° C. The mixture was allowed to warm up to room temperature and stirred for three days. The reaction solution was then warmed up to 40–50° C. to remove excess ammonia. Methanol was stripped off under reduced pressure. Crude 3-(t-butyldimethylsilylpropyloxy)-2-hydroxypropylamine was obtained as a clear and colorless oil (24 g, 98% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C.[C:29]([O:33][C:34](=[O:46])[NH:35][CH2:36][CH2:37][C:38](=[O:45])[NH:39][NH:40][C:41](=O)[CH2:42][CH3:43])([CH3:32])([CH3:31])[CH3:30]>ClCCl>[C:29]([O:33][C:34](=[O:46])[NH:35][CH2:36][CH2:37][C:38]1[O:45][C:41]([CH2:42][CH3:43])=[N:40][N:39]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CCC(=O)NNC(=O)CCNC(=O)OC(C)(C)C
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nnc(CCNC(=O)OC(C)(C)C)o1
Temperature: 25 °C
Reaction time: 0.1 h

Procedure:
11.49 g (24.70 mmol) PS-triphenylphosphine are placed in 240 ml dichloromethane, 6.27 g (24.70 mmol) iodine are added. The mixture is stirred for 0.1 hours at ambient temperature, then 7.00 ml (50.50 mmol) triethylamine are added dropwise. 3.20 g (12.34 mmol) tert-butyl[3-oxo-3-(N′-propionyl-hydrazino)-propyl]-carbamate dissolved in 150 ml dichloromethane are added. The reaction mixture is stirred for 24 hours at ambient temperature, then the precipitate is filtered off. The filtrate is evaporated down and purified by chromatography.
Reaction SMILES: [NH2:1][C@H](C(O)=O)CCC(=O)N.[NH2:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14](=O)[OH:15].N[C@H](C(O)=O)CCCCN.N[C@H](C(O)=O)CCCNC(=N)N>>[NH2:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14](=[O:15])[NH2:1]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Agent: NCCCC[C@H](N)C(=O)O
Product: NC(=O)C[C@H](N)C(=O)O

Procedure:
Gln -0.69; Asp -0.72; Lys -1.10; Arg -1.76.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[Cl:13][C:14]1[C:19]2[N:20]=[C:21]([S:23](Cl)(=[O:25])=[O:24])[S:22][C:18]=2[CH:17]=[CH:16][C:15]=1[O:27][CH3:28]>>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:23]([C:21]1[S:22][C:18]2[CH:17]=[CH:16][C:15]([O:27][CH3:28])=[C:14]([Cl:13])[C:19]=2[N:20]=1)(=[O:25])=[O:24])[CH3:4]
Reactant: CCOC(=O)CNCCN
Reactant: COc1ccc2sc(S(=O)(=O)Cl)nc2c1Cl
Agent: Cl
Product: CCOC(=O)CNCCNS(=O)(=O)c1nc2c(Cl)c(OC)ccc2s1
Yield: 89 %

Procedure:
The title compound (726 mg, 89%) was synthesized by the reaction of N-(2-aminoethyl)-glycine ethyl ester 2HCl (398 mg, 2.0 mmol) with 4-chloro-5-methoxy-benzothiazole-2-sulfonyl chloride (596 mg, 2.0 mmol) as per the procedure of Example 1. 1H NMR (500 MHz; DMSO-d6) δ 8.18 (d, 1H), 7.57 (d, 1H), 4.00 (q, 2H), 3.97 (s, 3H), 3.22 (s, 2H), 3.14 (t, 2H), 2.62 (t, 2H), 1.13 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:22]=[CH:21][C:18]([CH2:19]O)=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:22]=[CH:21][C:18]([CH2:19][Br:28])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CO)c(C(F)(F)F)c2)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CBr)c(C(F)(F)F)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-(N-tert-butyloxy-carbonyl-4-piperidinyloxy)-2-trifluoromethylbenzyl alcohol (0.63 g, 1.7 mmol) from Step 3 above in ether (10 mL) at 0° C. was added CBr4 (0.85 g, 2.6 mmol) and triphenylphosphine (0.68 g, 2.6 mmol). The mixture was stirred at 0° C. for 30 min and then at ambient temperature for 14 h. The ether solution was decanted away from the gummy precipitate of triphenylphosphine oxide that had formed and the solvent was removed unde reduced pressure. The residue was purified by pressurized silica gel column chromatography using 5% EtOAc:hexanes as eluant to give 4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-trifluoromethylbenzyl bromide as a colorless gum (HPLC retention time=12.6 min (method A)).
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH2:6]Cl)[CH:3]=[O:4].[CH3:8][O-:9].[K+].[CH3:11][OH:12]>>[CH3:1][CH:2]([CH2:5][CH:6]([O:12][CH3:11])[O:9][CH3:8])[CH:3]=[O:4]
Reactant: C[O-]
Reactant: CO
Reactant: CC(C=O)=CCCl
Agent: [K+]
Product: COC(CC(C)C=O)OC
Yield: 72 %

Procedure:
11.8 g (0.1 mole) 2-methyl-4-chloro-2-butenal is dripped at ambient temperature into a solution of 10.4 g (0.13 mole) of potassium methylate in 60 ml of methanol and the whole is stirred for an hour. The product is worked up as described in Example 1. 10.5 g of 2-methyl-4,4-dimethoxybutanal is obtained by distillation at subatmospheric pressure. According to gas chromatographic and nmr analysis it has a purity of more than 98%. The yield is 72% of theory.
Reaction SMILES: [CH3:1][C:2]1[N:37]=[C:5]2[N:6]([CH2:33][C:34](=O)[CH3:35])[C:7](=[O:32])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][C:29](=[O:31])[O:28][N:27]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.Cl.[NH2:39][O:40][CH3:41].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH3:41][O:40]/[N:39]=[C:34](\[CH3:35])/[CH2:33][N:6]1[C:7](=[O:32])[C:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][C:29](=[O:31])[O:28][N:27]=3)=[CH:16][CH:15]=2)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=[C:2]([CH3:1])[N:37]=[C:5]12
Reactant: CON
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(C)=O)c2nc(C)nn12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C/C(C)=N/OC)c2nc(C)nn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 33.5 %

Procedure:
A mixture of 2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(2-oxopropyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.2 g), (aminooxy)methane hydrochloride (0.67 g) and pyridine (10 mL) was stirred at 110° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.071 g, 34%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH:5]=[CH:6][S:7]([NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)(=[O:9])=[O:8].P(Cl)(Cl)(Cl)(Cl)[Cl:28]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH:5]=[CH:6][S:7]([N:10]=[C:11]([Cl:28])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)(=[O:9])=[O:8]
Reactant: COc1ccc(C(=O)NS(=O)(=O)C=Cc2ccc(Cl)c(Cl)c2)cc1OC
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc(C(Cl)=NS(=O)(=O)C=Cc2ccc(Cl)c(Cl)c2)cc1OC

Procedure:
A suspension of N-(3,4-dichlorostyrylsulfonyl)-3,4-dimethoxybenzamide (8.3 g., 0.02 mole) in 100 ml. of dry benzene is stirred and refluxed with phosphorus pentachloride (4.6 g., 0.022 mole) for a period of 1.5 hr. providing a clear solution which is concentrated under reduced pressure. Benzene is added to the residue and evaporated. The benzene treatment is repeated several times and the residue thus obtained triturated with isopropyl ether provides a quantitative yield of N-(3,4-dichlorostyrylsulfonyl)-3,4-dimethoxybenzimidoyl chloride, m.p. 120°-125° C.
Reaction SMILES: [CH2:1]([CH:3]([C:7](Cl)=[O:8])[C:4](Cl)=[O:5])[CH3:2].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([N:20](CC)CC)C>C(Cl)Cl>[CH2:1]([CH:3]([C:7]([NH2:20])=[O:8])[C:4]([NH:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C(N)=O)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a stirred, cooled (0° C.) solution of 14 g (0.093 mol) of ethyl malonyl chloride in 50 mL of methylene chloride under nitrogen was added dropwise a solution of 10 g (0.093 mol) of benzylamine in 50 mL of methylene chloride over a half-hour period. After the addition the reaction mixture was allowed to warm to room temperature and stir for 2 h. The reaction mixture was cooled to 0° C. and a solution of 13 mL (0.093 mol) of triethylamine in 50 mL of methylene chloride was added dropwise over 2 h. Additional methylene chloride was added to keep the slurry of salts stirring efficiently. After the addition the reaction mixture was kept cold by placing it in the freezer. After 12 h the reaction was allowed to warm to room temperature and was immediately washed with water three times to remove the salts. The organic layer was dried over magnesium sulfate and filtered. Removal of solvent gave a crude product which was purified by flash-chromatography (silica gel, 50% ethyl acetate/hexane eluent) to give 12.5 g (61% yield) of ethyl N-benzylmalonamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[I-].[Na+].[C:11](=O)([O-])[O-].[K+].[K+].Cl[CH2:18][CH2:19][O:20][CH3:21]>C(#N)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:18][CH2:19][O:20][CH3:21])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Reactant: COCCCl
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COCCCOc1ccc(Br)cc1
Temperature: 60 °C
Yield: 67.8 %

Procedure:
A mixture of 4-bromophenol (16-2, 1.01 g, 5.72 mmol), sodium iodide (1.02 g, 6.83 mmol), and potassium carbonate (1.88 g, 13.6 mmol) in acetonitrile (10.0 mL) was added with 1-chloro-2-methoxyethane (21-1, 0.89 g, 8.0 mmol). The mixture was heated to 60° C. for 48 h. The reaction mixture was cooled to room temperature and added with water (200 mL). The solution was extracted with EtOAc, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc:hexanes=1:20 as eluant) to give 1-bromo-4-isopropoxybenzene (21-2, 0.95 g) as a colorless oil in 68% yield: 1H NMR (CDCl3) δ 7.36 (dt, J=5.0, 2.0 Hz, 2 H), 6.78 (m, 2 H), 4.02 (t, J=6.3 Hz, 2 H), 3.54 (t, J=6.1 Hz, 2 H), 3.35 (s, 3 H), 2.03 (t, J=6.2 Hz, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([CH3:23])[N:9]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:22])[N:13]=[C:10]32)=[CH:5][CH:4]=1.C(Cl)(Cl)Cl>C1C2C(CCCC2)CCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([CH3:23])[N:9]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:22])[N:13]=[C:10]32)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)-c1nc(-c3ccccc3C)cn1C(C)C2
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: C1CCC2CCCCC2C1
Product: COc1ccc2cc(C)n3cc(-c4ccccc4C)nc3c2c1
Yield: 61.6 %

Procedure:
To a solution of 4.9 g of 9-methoxy-5-methyl-2-(2-methylphenyl)-5,6-dihydroimidazo[2,1-a]isoquinoline in 30 ml of decalin was added 0.97 g of palladium on activated carbon (Pd 10%) and the mixture was refluxed for 6 hours. After being cooled and an addition of 200 ml of chloroform, the mixture was filtered and the filtrate was evaporated in vacuo. The resultant residue was crystallized from a mixture of hexane and ethyl acetate(6:1) to give 3.0 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH:13]1[O:18][CH2:17][CH2:16][CH2:15][O:14]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C(#N)C>[O:14]1[CH2:15][CH2:16][CH2:17][O:18][CH:13]1[CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: BrCCC1OCCCO1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1ccc(OCCC2OCCCO2)cc1
Yield: 100.2 %

Procedure:
In a 500 ml flask, 120 ml of acetonitrile, 13.8 g of 4-hydroxybenzaldehyde, 21.1 g of 2-(2-bromoethyl)-1,3-dioxane, 1.8 g of potassium iodide, and 35.8 g of potassium carbonate were placed and then, reacted at 80° C. for 5 hrs. Thereafter, 200 ml of ethyl acetate was added to the reaction mixture and washed once with a saturated aqueous potassium carbonate solution, distilled water, and saturated saline. The washed organic phase was dried over anhydrous magnesium sulfate and removed solvent, to give 25.6 g of 4-(2-[1,3]-dioxane-2-yl-ethoxy)benzaldehyde.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.[CH3:6][O:7][S:8]([O:11]C)(=[O:10])=[O:9].[CH3:13][NH:14][CH3:15]>C1COCC1.C1(C)C=CC=CC=1>[CH3:6][O:7][S:8]([O-:11])(=[O:10])=[O:9].[CH3:1][N:2]([CH3:5])[CH:3]=[N+:14]([CH3:15])[CH3:13]
Reactant: CN(C)C=O
Reactant: COS(=O)(=O)OC
Reactant: CNC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN(C)C=[N+](C)C
Product: COS(=O)(=O)[O-]
Temperature: 60 °C

Procedure:
A mixture of N,N-dimethylformamide (7.31 g) and dimethylsulfate (12.60 g) are heated to 60° C. for 4 h. Then dimethylamine in THF (100 ml, 2 M solution) and toluene (15 ml) are added and the resulting mixture is stirred at reflux for 1 h. The reaction mixture is cooled to room temperature and the phases are separated. The lower layer is washed three times with anhydrous tert-butyl methyl ether to give N,N,N′,N′-tetramethylformamidinium methylsulfate (18, R6=Me, R7=Me). 1H NMR (C6D6), 7.95 (1H), 3.70 (3H), 3.32 (6H), 3.29 (6H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:30])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH2:16][CH2:15]2)[C:5]2[N:10]=[C:9](S(C)=O)[S:8][C:6]=2[N:7]=1.[F:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1>O1CCOCC1>[NH2:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:15][CH2:16][N:17]([C:20](=[O:30])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH2:18][CH2:19]2)[C:5]2[N:10]=[C:9]([NH:36][C:35]3[CH:37]=[CH:38][C:32]([F:31])=[CH:33][CH:34]=3)[S:8][C:6]=2[N:7]=1
Reactant: CS(=O)c1nc2c(N3CCN(C(=O)COc4ccc(Cl)cc4)CC3)nc(N)nc2s1
Reactant: Nc1ccc(F)cc1
Solvent: C1COCCO1
Product: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(Nc3ccc(F)cc3)sc2n1
Yield: 87.6 %

Procedure:
A mixture of 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-methylsulfinyl-thiazolo[5,4-d]pyrimidine (47 mg, 0.1 mmol) and 4-fluoroaniline (95 μl, 1 mmol) in dioxane (5 ml) was heated under reflux for 12 hours. The reaction mixture was evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/80), yielding the pure title compound (45 mg, 88%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([F:21])=[C:8]2[O:12][C:11]([N:13]([CH3:15])[CH3:14])=[N:10][C:9]2=[C:16]([C:19]#[N:20])[C:17]=1[CH3:18])=[CH2:5])C.O.[Br:23]N1C(=O)CCC1=O>O1CCCC1>[Br:23][CH2:3][C:4]([C:6]1[C:7]([F:21])=[C:8]2[O:12][C:11]([N:13]([CH3:15])[CH3:14])=[N:10][C:9]2=[C:16]([C:19]#[N:20])[C:17]=1[CH3:18])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)c1c(C)c(C#N)c2nc(N(C)C)oc2c1F
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)CBr)c(F)c2oc(N(C)C)nc2c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
6-(1-Ethoxyvinyl)-2-(dimethylamino)-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-169) (0.51 g, 1.76 mmol) was dissolved in tetrahydrofuran (10 ml), then water (1.0 ml), N-bromosuccinimide (0.30 g, 1.69 g) were added. After stirring at room temperature for 30 minutes, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane to dichloromethane:methanol=100:1) to obtain a pale brown solid (0.60 g, 100%).