Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]([C:17]3([C:21]([O:23][CH2:24]C)=[O:22])[CH2:20][CH2:19][CH2:18]3)[NH:10][CH2:9][CH2:8][C:7]2=1.Cl.[Cl:27]C1C=C2C(=CC=1)NC1C(C3(C(OC)=O)CCC3)NCCC2=1>>[ClH:27].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]([C:17]3([C:21]([O:23][CH3:24])=[O:22])[CH2:20][CH2:19][CH2:18]3)[NH:10][CH2:9][CH2:8][C:7]2=1
Reactant: COC(=O)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Reactant: CCOC(=O)C1(C2NCCc3c2[nH]c2ccc(OC)cc32)CCC1
Agent: Cl
Product: COC(=O)C1(C2NCCc3c2[nH]c2ccc(OC)cc32)CCC1

Procedure:
The procedure is as in Example 23, starting from the compound of Example 7 and the reagent of Example 26.
Reaction SMILES: C([O:5][C:6](=[O:42])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23]([NH:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31](C(OC(C)(C)C)=O)[N:30]=[CH:29]4)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:31]1[C:32]2[C:28](=[CH:27][C:26]([NH:25][C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]([C:11]4[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=4)[O:8][CH2:7][C:6]([OH:42])=[O:5])[N:24]=3)=[CH:34][CH:33]=2)[CH:29]=[N:30]1
Reactant: CC(C)(C)OC(=O)COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1

Procedure:
A solution of tert-butyl 5-(2-(3-(2-tert-butoxy-2-oxoethoxy)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate was stirred in CH2Cl2 (2 mL) and TFA (2 mL) for 1 h. The volatiles were removed in vacuo and the residue was triturated with ethyl ether. The crude product was purified using prep HPLC (method 10-35—90 mins) to afford to give 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid. (0.43 mg, 0.10 mmol)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)=[O:7].C([Li])CCC.[N+:35]([C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)([O-:37])=[O:36].O>O1CCCC1>[N+:35]([C:38]1[CH:39]=[CH:40][C:41]([C:42]([N:20]2[C:21]3[C:16](=[CH:15][C:14]([N:11]4[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]5[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:3]([O:2][CH3:1])[CH:4]=5)[CH2:13][CH2:12]4)=[CH:23][CH:22]=3)[CH2:17][CH2:18][C:19]2=[O:24])=[O:43])=[CH:45][CH:46]=1)([O-:37])=[O:36]
Reactant: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4C(=O)c3ccc([N+](=O)[O-])cc3)CC2)cc1OC
Yield: 18.9 %

Procedure:
To a suspension of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (10 g) in anhydrous tetrahydrofuran (250 ml) was added slowly n-butyllithium (20 ml, 1.5N hexane solution) with stirring and under ice-cooling. After completion of addition, the mixture was stirred at room temperature for 2 hours. Then, to the mixture was added slowly a solution of p-nitrobenzoyl chloride (6.1 g) in anhydrous tetrahydrofuran (25 ml) with stirring and under ice-cooling. After completion of addition, the mixture was stirred at the same temperature for 30 minutes. After completion of reaction, the reaction mixture was poured into water and extracted with chloroform. The chloroform layer was washed successively with water and saturated saline solution and dried over magnesium sulfate. The choloroform extract was evaporated under reduced pressure and the resultant residue was purified by silica-gel column chromatography (eluent:dichloromethane:methanol=100:1) to give 1-(4-nitrobenzoyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]3,4-dihydrocarbostyril (2.6 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH:11]1(Br)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:11]1([O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[OH:1])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: BrC1CCCC1
Reactant: O=Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC2CCCC2)c(O)c1
Temperature: 77.5 °C
Yield: 54 %

Procedure:
In a 10 L 4 necked RB flask fitted with a mechanical stirrer, reflux condenser, was added DMF (3.5 L), 3,4-Dihydroxybenzaldehyde (1.15 Kg, 8.3M), cyclopentyl bromide (3.1 kg, 20.3 M) and powdered anhydrous potassium carbonate (1.15 kg, 20.3 M) at temperature in the range of 25-35° C. under stirring. The reaction mixture was heated to temperature of 75-80° C. under stirring and maintained under stirring for 1 hr. To the reaction mixture, powdered potassium carbonate (140 g, 1M) was added at temperature of 75-80° C. under stirring. After addition, the reaction mixture was maintained at 75-80° C. for 1 hr. The progress of the reaction was monitored by TLC and HPLC. After ascertaining the completion of the reaction, the reaction mixture was brought to 25-35° C. and filtered. The inorganic salt cake was washed with DMF (300 ml×2) and combine the washings with filtrate. The organic layer was concentrated at temperature below 75° C. under high vaccum. Add toluene (2 L) to the residue of distil of the residual DMF. Add toluene (2 L) to the resulting mass and distill off the traces of DMF. To the resulting mass, add toluene (5.7 L), celite (300 g), activated charcoal (100 g), 5% sodium hydroxide solution (1.2 L) and cool to 10-15° C. under stirring. Separate the organic and aqueous layer. The organic layer was repeatedly extracted with 5% sodium hydroxide solution (1.2 L×5) and combine the aqueous sodium hydroxide layers. The aqueous layer was washed with toluene (2 L×2) and separate the aqueous layer. The pH of the aqueous layer was adjusted to acidic 2-3 with conc. HCl (1.1 L) at 10-15° C. under stirring. The precipitated solid was filtered, washed with water(2 L×3) filtered and dried in the hot air oven below 60° C. temp. The product appear as cream color solid, weighing about 920-950 g, yield 54%-56% purity 98-99%, m.p 87-89° C. The IR (KBr) spectrum shows 3300 (OH str), 3150 (CH str), 1670 (CHO str), 1620 (C═C str). The 1H-NMR (DMSO-d6) shows δ 9.8 (s, 1H), 9.2 (s, 1H), 7.1 (d, 1H), 7.2-7.4 (m, 2H), 4.9 (m, 1H), 1.4-2.0 (m, 8H). The CI mass shows m/z 206 (M+). The elemental analysis shows calculated % C, 69.88; % H, 6.84; % O, 23.27; observed % C, 69.70; % H, 6.65; % O, 23.15.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH:13]=O.[Cl-].[CH2:16]([O:23][C:24]1[CH:49]=[CH:48][CH:47]=[CH:46][C:25]=1[CH2:26][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH:13]=[CH:26][C:25]1[CH:46]=[CH:47][CH:48]=[CH:49][C:24]=1[O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=CCCc1ccc2ccccc2c1
Reactant: c1ccc(COc2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C(=Cc1ccccc1OCc1ccccc1)CCc1ccc2ccccc2c1
Yield: 82.7 %

Procedure:
Following a procedure similar to that described in the first part of Preparation 3, 1.73 g of 3-(2-naphthyl)propanal prepared as described above, 4.65 g of 2-benzyloxybenzyltriphenylphosphonium chloride (prepared as described in Preparation 1) and 2.15 g of 1,8 -diazabicyclo[5,4,0]undec-7-ene were reacted in 200 ml of acetonitrile. The reaction mixture was worked up and purified as described in the first part of Preparation 3, to obtain 2.83 g (yield 82%) of 4-(2-naphthyl)-1-(2-benzyloxyphenyl)-1-butene as a colorless oil.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=2)=[C:13]([F:24])[C:12]=1[O:25][CH3:26]>>[F:24][C:13]1[C:12]([O:25][CH3:26])=[C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=[CH:15][C:14]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: COc1c(Br)ccc(-c2cnc(N)cn2)c1F
Reactant: OB(O)c1ccccc1
Product: COc1c(-c2ccccc2)ccc(-c2cnc(N)cn2)c1F

Procedure:
The title compound was prepared by a method analogous to Example 461 using phenylboronic acid and 5-(4-bromo-2-fluoro-3-methoxyphenyl)pyrazin-2-amine. MS (ESI): mass calcd. for C17H14FN3O, 295.11; m/z found, 296.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.58-8.55 (m, 1H), 8.12 (d, J=1.5, 1H), 7.65 (dd, J=8.1, 7.5, 1H), 7.61-7.54 (m, 2H), 7.48-7.42 (m, 2H), 7.41-7.34 (m, 1H), 7.23 (dd, J=8.2, 1.4, 1H), 4.69 (s, 2H), 3.74 (d, J=0.9, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH:7]=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](Br)[CH:23]=1>CS(C)=O>[Br:21][C:22]1[CH:23]=[C:24]([N:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([N:2]([CH3:14])[CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:25]=[CH:26][CH:27]=1
Reactant: Brc1cccc(Br)c1
Reactant: CN(C)c1ccc2c(=O)[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN(C)c1ccc2c(=O)n(-c3cccc(Br)c3)ccc2c1
Temperature: 150 °C
Yield: 61.9 %

Procedure:
6-Dimethylamino-2H-isoquinolin-1-one (39 mg, 0.21 mmol), cuprous iodide (8.0 mg, 0.041 mmol), and potassium carbonate (29 mg, 0.21 mmol) were deposited in sealed vessel. 3 mL DMSO and 1,3-dibromobenzene (98 mg, 0.42 mmol) were added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 150° C. for 5 hours. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (25% ethyl acetate/hexanes) to yield 2-(3-Bromo-phenyl)-6-dimethylamino-2H-isoquinolin-1-one (45 mg, 0.13 mmol). MS (ESI) 345.0 (M+H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][C:13]([C:16]1[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][C:17]=1[NH2:18])([CH3:15])[CH3:14]>>[CH3:15][C:13]([C:16]1[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][C:17]=1[NH:18][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:11])([CH3:12])[CH3:14]
Reactant: CC(C)(C)c1ccc(C(C)(C)C)c(N)c1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: CC(C)(C)c1ccc(C(C)(C)C)c(NC(=O)c2cc(Cl)ccc2O)c1
Yield: 75.7 %

Procedure:
Using 5-chlorosalicylic acid and 2,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[CH2:13]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:14]1[O:16][CH2:15]1>CO>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][CH2:15][C@H:14]([OH:16])[CH2:13][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CO
Product: COc1ccc(CNC[C@H](O)COCc2ccccc2)c(OC)c1
Yield: 75.4 %

Procedure:
To a stirred solution of 2,4-dimethoxybenzylamine (1.00 g, 5.99 mmol) in MeOH (30 mL) at room temperature was added benzyl(S)-(+)-glycidyl ether (0.88 g, 5.40 mmol). After 12 h the reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate (75 mL) and washed sequentially with 1 N HCl (25 mL) and brine (25 mL). The solution was dried over MgSO4, filtered and the solvent removed under reduced pressure to give 1.35 g of the crude oil that was used in the next step without further purification. MS (ES+) m/z 332.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[O:10][C:9]([C:11]3[CH:12]=[C:13]([NH:18][C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:20])[CH:14]=[CH:15][C:16]=3[Cl:17])=[N:8][C:5]2=[N:6][CH:7]=1.Cl[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28].N1C=CC=CC=1>COCCOC>[CH:30]([O:29][C:27](=[O:28])[NH:1][C:2]1[CH:3]=[C:4]2[O:10][C:9]([C:11]3[CH:12]=[C:13]([NH:18][C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:20])[CH:14]=[CH:15][C:16]=3[Cl:17])=[N:8][C:5]2=[N:6][CH:7]=1)([CH3:32])[CH3:31]
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1cnc2nc(-c3cc(NC(=O)N4CCCC4)ccc3Cl)oc2c1
Solvent: COCCOC
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1cnc2nc(-c3cc(NC(=O)N4CCCC4)ccc3Cl)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-[6-amino-[1,3]oxazolo[4,5-b]pyridin-2-yl]-4-chlorophenyl)pyrrolidine-1-carboxamide (100 mg, 0.28 mmol, 1.00 equiv), propan-2-yl chloroformate (68.3 mg, 0.56 mmol, 1.99 equiv), pyridine (111 mg, 1.40 mmol, 5.02 equiv) in ethylene glycol dimethyl ether (15 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). The collected fractions were combined and concentrated under vacuum. This resulted in 60.8 mg (49%) of propan-2-yl N-[2-(2-chloro-5-[[(pyrrolidin-1-yl)carbonyl]amino]phenyl)-[1,3]oxazolo[4,5-b]pyridin-6-yl]carbamate (75) as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][N:11]([CH3:25])[S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:6][CH2:5]1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[CH3:25][N:11]([CH2:10][C@H:7]1[CH2:8][CH2:9][C@H:4]([CH2:3][CH2:2][O:1][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:5][CH2:6]1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: CN(C[C@H]1CC[C@H](CCO)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cl
Product: CN(C[C@H]1CC[C@H](CCOS(C)(=O)=O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 3.4, trans-N-[4-(2-hydroxy-ethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was treated with methanesulfonyl chloride to yield trans-methanesulfonic acid 2-(4-{[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-methyl}-cyclohexyl)-ethyl ester as colorless solid, MS: 358 (MH+).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[CH3:23])[C:6]=2[CH:5]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:3]=1.[CH3:30]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.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][C:8]1[N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[C:14]=2[CH3:23])[C:6]2[CH:5]=[C:4]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH:3]=[C:2]([CH3:30])[C:10]=2[N:9]=1
Reactant: Cc1c(Cn2c(C)nc3c(Br)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Reactant: CB1OB(C)OB(C)O1
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: C1COCCO1
Product: Cc1c(Cn2c(C)nc3c(C)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Yield: 42.5 %

Procedure:
A mixture of 4-bromo-2-methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazole, prepared as described in Example 62 (200 mg, 0.427 mmol), trimethylboroxine (0.239 mL, 1.708 mmol), Pd(Ph3P)4 (49.4 mg, 0.043 mmol) and potassium carbonate (118 mg, 0.854 mmol) in 1,4-Dioxane (2.5 mL)/Water (0.25 mL) was irradiated at 120° C. in a microwave synthesizer for 40 min, then cooled and poured into water. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by RP-HPLC (25-45% AcCN in water plus 0.1% TFA) to give the desired compound (77 mg, 0.181 mmol, 42.5% yield) as a white solid (contains 3-5% of the 4-H compound). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.58 (d, J=8.08 Hz, 1 H), 7.12 (t, J=7.83 Hz, 1 H), 6.80 (d, J=1.01 Hz, 1 H), 6.51 (d, J=7.83 Hz, 1 H), 6.40 (d, J=1.77 Hz, 1 H), 5.26 (s, 2 H), 3.78-3.91 (m, 4 H), 3.01-3.15 (m, 4 H), 2.67 (s, 3 H), 2.56 (s, 3 H), 2.50 (s, 3 H). MS(ES+) m/e 404.1 [M+H]+. (NOTE: The reaction was repeated using PdCl2(dppf) as catalyst. Less (to negligible) reduction was observed).
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH3:19])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])[CH3:19])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCCCCCC[C@@H](O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 4 (380 mg, 1.50 mmol) and 1-bromononadecane (1.30 g, 3.75 mmol), alcohol 49 was obtained as a colorless oil (349 mg, 45% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([F:24])[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19](I)=[CH:18][C:17]=2[F:23])=[CH:13][C:8]2=[N:9][CH2:10][N:11]([CH3:12])[C:7]2=[CH:6]1)=[O:4].[CH:25]([Sn](CCCC)(CCCC)CCCC)=[CH2:26]>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1([F:24])[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:25]=[CH2:26])=[CH:18][C:17]=2[F:23])=[CH:13][C:8]2=[N:9][CH2:10][N:11]([CH3:12])[C:7]2=[CH:6]1)=[O:4]
Reactant: COC(=O)C1(F)C=C2C(=NCN2C)C=C1Nc1ccc(I)cc1F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: C1COCCO1
Product: C=Cc1ccc(NC2=CC3=NCN(C)C3=CC2(F)C(=O)OC)c(F)c1
Temperature: 25 °C
Yield: 42.8 %

Procedure:
A solution of 5-Fluoro-6-(2-fluoro-4-iodo-phenylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (6.36 g, 14.4 mmol) and vinyl tributylstannane (5.0 g, 15.8 mmol) in dioxane (100 mL) was de-gassed by freeze-pump-thaw cycle (twice). Tetrakis(triphenylphoshine)palladium was added and the reaction mixture was refluxed under an atmosphere of nitrogen until mass spectrometry indicated complete consumption of the aryl iodide. The reaction mixture was allowed to cool to ambient temperature and was filtered through a pad of Celite and washed with ethyl acetate (255 mL). Aqueous potassium fluoride (1M, 50 mL) was added to the filtrate and the biphasic mixture was shaken. The resultant precipitate was removed by filtration and the organics were further washed with aqueous potassium fluoride (1M, 50 mL), water (2×100 mL), and saturated brine (100 mL). The solution was dried over anhydrous sodium sulfate, concentrated in vacuo and chromatographed on silica gel. Elution with ethyl acetate afforded 5-Fluoro-6-(2-fluoro-4-vinyl-phenylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (2.13 g, 44% yield): 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1 H), 8.09 (br s, 1 H), 8.06 (s, 1 H), 5.36 (dd, J=13.2, 1.5 Hz, 1 H), 5.05 (dd, J=8.3, 1.5 Hz, 1 H), 6.60 (dd, J=15.5, 10.9 Hz, 1 H), 6.50 (td, J=8.8, 4.6 Hz, 1 H), 5.65 (d, J=15.4 Hz, 1 H), 5.11 (d, J=11.2 Hz, 1 H), 3.92 (s, 3 H), 3.82 (s, 3 H).
Reaction SMILES: BrBr.Cl.[CH3:4][C:5]1[CH:10]=[CH:9][CH2:8][C:7]([CH3:12])([CH3:11])[C:6]=1[CH2:13][CH2:14][C:15](=[O:17])[CH3:16]>C(Cl)(Cl)Cl>[CH3:11][C:7]1([CH3:12])[CH:6]([CH2:13][CH2:14][C:15](=[O:17])[CH3:16])[C:5](=[CH2:4])[CH:10]=[CH:9][CH2:8]1
Reactant: CC(=O)CCC1=C(C)C=CCC1(C)C
Agent: BrBr
Agent: Cl
Solvent: ClC(Cl)Cl
Product: C=C1C=CCC(C)(C)C1CCC(C)=O
Reaction time: 0.5 h
Yield: 8.8 %

Procedure:
The resulting mixture is cooled in an ice-sodium chloride bath and a mixture of 3.2 grams of bromine and 9 ml chloroform is added drop-wise with stirring over a half hour period. The reaction mass is then stirred at 5°C for a period of 5 hours and then concentrated under reduced pressure. The resulting residue is then heated on a steam bath for a period of 3 hours after 11 ml of N,N-Diethyl-aniline has been added to the residue. After 3 hours 2.5 ml pyridine is then added to the reaction mass and heating is continued for 1/2 hour longer. To the cooled reaction mixture are added 50 ml of 5 N Hydrochloric acid. The aqueous layer is then extracted with three 100 ml portions of n-pentane. The combined pentane extracts are washed with two 50 ml portions of 5 N hydrochloric acid, then two 50 ml 10% sodium bicarbonate solution portions and two 100 ml portions of distilled water. The pentane extracts are then evaporated after drying over anhydrous sodium sulfate yielding (confirmed by infrared and mass spectral analysis) a mixture containing 90% 4-(2,6,6-trimethyl-1,3-cyclohexadien-1-yl)-2-butanone and 10% 4-(6,6-dimethyl-2-methylene-3-cyclohexen-1-yl)-2-butanone (over-all yield: 8.8%). The 90:10 mixture of 4-(2,6,6-trimethyl-1,3-cyclohexadien-1-yl)-2-butanone and 4-(6,6-dimethyl-2-methylene-3-cyclohexen-1-yl)-2-butanone distills at 65°C and at 15 mm Hg. pressure.
Reaction SMILES: [NH2:1][C:2](=[N:5][C:6](=[O:9])[O:7][CH3:8])[O:3][CH3:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>C(Cl)Cl>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:19])[NH:1][C:2](=[N:5][C:6]([O:7][CH3:8])=[O:9])[O:3][CH3:4])=[CH:13][CH:12]=1
Reactant: COC(=O)N=C(N)OC
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: COC(=O)N=C(NC(=O)Nc1ccc(Cl)cc1)OC
Reaction time: 8 h

Procedure:
To 13 parts of this methyl N-(1-amino-1-methoxymethylene)carbamate, m.p. 36°-39.5° in 140 parts of methylene chloride is added 15 parts of 4-chlorophenyl isocyanate. The reaction mixture is stirred overnight and the solution filtered to give 10 parts of methyl 4-(4-chlorophenyl)-N-methoxycarbonylallophanimidate melting at 170° dec.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3Cl)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH2:38]([NH2:46])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(#N)C>[C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3[NH:46][CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: NCCc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCCc4ccccc4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
A solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanyl acetate (1.96 g, 4.48 mmol) (Preparation 10) and triethylamine (1.8 g, 17.8 mmol) in acetonitrile (20 ml) was treated with phenethylamine (0.60 g, 4.96 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (75 ml) and water (20 ml). The organic phase was separated and the solvent was removed under reduced pressure. The foam was purified by column chromatography on silica gel eluting with dichloromethane:ethyl acetate (4:1 by volume) to give a product which was then azeotroped with diethyl ether to afford the title compound as a foam (2.05 g).
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][NH:20]C(NC)=O>C(OCC)(=O)C>[CH3:19][NH:20]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1
Reactant: CNC(=O)NC
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Solvent: CCOC(C)=O
Product: CN/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Yield: 66 %

Procedure:
Prepared as in Example 31 from 2-benzoyl-benzo[b]thiophen-3-ol, but using N,N'-dimethylurea in place of ammonium acetate, with a yield of 66% of theory, m.p. 156°-157° C. (ethyl acetate). On the basis of its thin-layer chromatogram, mixed melting point, elemental analysis and IR spectrum, the product was identical to that of Example 2.