Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([C@H:20]([CH2:43][O:44][Si](C)(C)C)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:42]=[CH:41][CH:40]=[CH:39][C:33]=2[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:30])=[CH:24][CH:23]=1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)(C)(C)C.[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52]>ClCCCl>[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52].[OH:44][CH2:43][C@@H:20]([NH:8][CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:42]=[CH:41][CH:40]=[CH:39][C:33]=2[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:30])=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1ccccc1NC(=O)Nc1ccc(C[C@@H](CO[Si](C)(C)C)N(C[C@H](O)COc2ccccc2)C(=O)OC(C)(C)C)cc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccccc1NC(=O)Nc1ccc(C[C@@H](CO)NC[C@H](O)COc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-[[[[4-[(2S)-2-[N-(tert-butoxycarbonyl)-N-((2S)-2-hydroxy-3-phenoxypropyl)amino]-3-[(trimethylsilyl)oxy]propyl]phenyl]amino]carbonyl]amino]-benzoate (10.0 mg) in 1,2-dichloroethane (100 μl) was added trifluoroacetic acid (100 μl) and the solution was stirred at room temperature for 30 minutes. The solvent was removed by evaporation to give ethyl 2-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]amino]-carbonyl]amino]benzoate trifluoroacetate (10.3 mg) as a white foam.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:17].C(O)(=[O:20])C.S(=O)(=O)(O)O>O>[O:17]([C:6]12[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=[CH:16][C:5]1=[CH:4][CH:3]=[CH:2][O:1]2)[OH:20]
Reactant: O=C1CCCCCCCCCCC1CCCO
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: OOC12C=CC=CC=CC=CC=CC1=CC=CO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.5 %

Procedure:
A 4-neck flask equipped with mechanical stirring, an inlet funnel, a thermometer, a condenser and kept under nitrogen, was charged with 30 g (125 mmol) of 2-(3-hydroxypropyl)-1-cyclododecanone and 137.5 g (2.29 mol) of glacial acetic acid. The mixture was stirred at room temperature until it became homogeneous. A cooled mixture of water (12.5 g) and a 50% aqueous solution of sulphuric acid (12.5 g) was then added. The reaction mixture was cooled to 0° C. and then 10 ml of 70% oxygenated water were added thereto dropwise over 15 min; the temperature rose to 7° C. Once the introduction was completed, stirring was continued for 15 min at 0° C. The formed precipitate was filtered, washed with water and then with diluted aqueous NaHCO3. 62.0 G of wet product were thus obtained which, after drying, provided 25.6 g (yield 80%) of 14a-hydroperoxy-cyclododeca[b]-pyran which was used in the following step. M. p.: 104°-106° C.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[N:24]=[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[CH:21][N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[N:24]=[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[CH:21][N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cc(OCc2ncc(-c3cc(OC)ccc3F)c(OCC(C)C)n2)ncn1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2cnc(COc3cc(C(CC(=O)O)C4CC4)ncn3)nc2OCC(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(6-((5-(2-fluoro-5-methoxyphenyl)-4-isobutoxypyrimidin-2-yl)methoxy)pyrimidin-4-yl)propanoate (111 mg) in THF (2.0 mL) and methanol (1.0 ml) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added 1N hydrochloric acid (2.0 mL) at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (105 mg) as a white amorphous solid.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][N:35]4C(=O)C5=CC=CC=C5C4=O)[CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>ClCCl.CO>[NH2:35][CH2:34][CH2:33][C:29]1[CH:28]=[C:27]([N:14]2[C:12]3=[N:13][C:8]([NH:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:9][CH:10]=[C:11]3[CH2:17][N:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:15]2=[O:26])[CH:32]=[CH:31][CH:30]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1cccc(N2C(=O)N(c3ccc(Cl)cc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Agent: NN
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: NCCc1cccc(N2C(=O)N(c3ccc(Cl)cc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Yield: 33 %

Procedure:
A solution of 370 mg (0.6 mmol) of 7-anilino-3-(2,4-dichlorophenyl)-3,4-dihydro-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one and 0.3 ml (6 mmol) of hydrazine hydrate in 5 ml of dichloromethane/methanol was stirred at room temperature under an atmosphere of nitrogen overnight. The reaction mixture was evaporated and the residue purified by flash chromatography on silica gel, eluting with dichloromethane/methanol/acetic acid/water (120:14:3:2). Product containing fractions were combined and evaporated and the residue re-evaporated with toluene. The residue was then dissolved in 20 ml of dichloromethane, washed with saturated aqueous sodium bicarbonate (20 ml), dried over magnesium sulfate, filtered and evaporated to give 100 mg (33%) of 1-[3-(2-aminoethyl)phenyl]-7-anilino-3-(2,4-dichlorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 131-135° C. [Mass spectrum (ESI) MH+ =505].
Reaction SMILES: Br[CH:2]([CH3:9])[C:3](=O)[C:4]([O:6][CH3:7])=[O:5].[CH:10]1([N:13]([CH:35]2[CH2:37][CH2:36]2)[C:14]([C:16]2[N:32]([CH2:33][CH3:34])[C:19]3=[N:20][C:21]([NH:28][C:29]([NH2:31])=[S:30])=[C:22]4[N:26]=[CH:25][N:24]([CH3:27])[C:23]4=[C:18]3[CH:17]=2)=[O:15])[CH2:12][CH2:11]1>CCO>[CH:35]1([N:13]([CH:10]2[CH2:11][CH2:12]2)[C:14]([C:16]2[N:32]([CH2:33][CH3:34])[C:19]3=[N:20][C:21]([NH:28][C:29]4[S:30][C:2]([CH3:9])=[C:3]([C:4]([O:6][CH3:7])=[O:5])[N:31]=4)=[C:22]4[N:26]=[CH:25][N:24]([CH3:27])[C:23]4=[C:18]3[CH:17]=2)=[O:15])[CH2:36][CH2:37]1
Reactant: COC(=O)C(=O)C(C)Br
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(N)=S)nc21
Solvent: CCO
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C(=O)OC)c(C)s3)nc21
Temperature: 65 °C
Yield: 70.4 %

Procedure:
Methyl 3-bromo-2-oxobutanoate (320 mg, 1.642 mmol) was added to a suspension of N,N-dicyclopropyl-6-ethyl-1-methyl-4-thioureido-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 2B, 435 mg, 1.094 mmol) in EtOH (10 ml) and the reaction mixture was heated at 65° C. for 2 h. The solvent was removed in vacuo and the residue purified by silica gel chromatography (2-10% MeOH/dichloromethane) to give methyl 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-5-methylthiazole-4-carboxylate (380 mg, 70% yield) as yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([O-:13])=[O:12])#[N:8].[K+].[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([CH:24]=[N:25]O)=[CH:22][CH:21]=1.N1C=CC=CC=1>ClCCl>[C:7]([C:9]1[C:10]([C:11]([O:13][N:25]=[CH:24][C:23]2[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=2)=[O:12])=[CH:14][CH:15]=[CH:16][N:17]=1)#[N:8]
Reactant: ON=Cc1ccc(Cl)cc1
Reactant: N#Cc1ncccc1C(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ncccc1C(=O)ON=Cc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
Oxalyl chloride (2.8 g, 0.022 mole) is added dropwise to a suspension of potassium 2-cyanonicotinate (4.1 g, 0.022 mole) in dichloromethane (40 ml). The mixture is then heated under reflux for one hour. A solution of 4-chlorobenzaldehyde oxime (3.1 g, 0.02 mole) and pyridine (1.6 g, 0.02 mole) in dichloromethane (20 ml) is then added to the mixture, at 20° C. The mixture is then stirred for 2 hours at 20° C. The solvent is evaporated off and the residue treated with water (50 ml). The solid formed is filtered off and is washed with water and then with ethyl ether. A white solid 4.4 g, 77%) corresponding to the structure 2 is thus obtained (M.p.: 160° C.).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:24]=[CH:23][C:9]2[CH2:10][CH2:11][CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[N:13]3[CH2:14][C:8]=2[CH:7]=1)=[O:5].[CH:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26]>>[CH:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][C:4]([C:6]2[CH:24]=[CH:23][C:9]3[CH2:10][CH2:11][CH:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[O:22])[N:13]4[CH2:14][C:8]=3[CH:7]=2)=[O:5])[CH2:29][CH2:28]1)=[O:26]
Reactant: O=CN1CCNCC1
Reactant: O=C(CCCl)c1ccc2c(c1)CN1C(=O)c3ccccc3C1CC2
Product: O=CN1CCN(CCC(=O)c2ccc3c(c2)CN2C(=O)c4ccccc4C2CC3)CC1
Yield: 84.9 %

Procedure:
Using 3.45 g of 3-(3-chloro-1-oxopropyl)7,11b,12,13-tetrahydro-5H-isoindolo[2,1-b][2]benzazepin-7-one, corresponding to Reference Example 5 Compound No. 1, and 1.4 g of 1-formylpiperazine, the procedure of Example 1 was otherwise repeated to provide about 3.6 g of 3-[3-(4-formyl-1-piperazinyl)-1-oxopropyl]-7,11b,12,13-tetrahydro-5H-isoindolo[2,1-b][2]benzazepin-7-one as a crude oil. This oil was not further purified but directly dissolved in 50 ml of methanol and the solution was refluxed with 50 ml of concentrated hydrochloric acid for 4 hours. After the methanol was distilled off, the residual aqueous solution was adjusted to pH about 10 with 10% aqueous sodium hydroxide solution and the product was extracted into dichloromethane. The extract was washed with water and the solvent was distilled off under reduced pressure to provide 3.1 g of the title compound as a powder melting at 207°-210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]2([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:13][CH2:12][N:11](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:10][CH2:9]2)[CH:7]=1.C1(O)C=CC=CC=1.Br>C(O)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]2([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:7]=1
Reactant: CCOC(=O)C1(c2cc(Cl)ccc2OC)CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Agent: Br
Solvent: Oc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C1(c2cc(Cl)ccc2OC)CCNCC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A mixture of 17 parts of ethyl 4-(5-chloro-2-methoxyphenyl)-1-(4-methylphenylsulfonyl)-4-piperidinecarboxylate, 7.5 parts of phenol and 135 parts of a hydrobromic acid solution in acetic acid is stirred overnight at room temperature. The reaction mixture is poured onto water and the whole is washed with 2,2'-oxybispropane. The aqueous phase is alkalized with sodium hydroxide while cooling. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 2-propanol and 2,2'-oxybispropane, yielding 7 parts (55%) of ethyl 4-(5-chloro-2-methoxyphenyl)-4-piperidinecarboxylate hydrochloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:24][CH:25]([F:27])[F:26])[C:5]([F:28])=[CH:4][N:3]=1.C(OC([N:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[C:44]([O:49][CH3:50])[CH:43]=2)[CH2:38][CH2:37]1)=O)(C)(C)C>C(OC(O)C)C.Cl>[F:26][CH:25]([F:27])[O:24][C:10]1[CH:11]=[C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]2)[CH:13]=[CH:14][C:9]=1[NH:8][C:6]1[C:5]([F:28])=[CH:4][N:3]=[C:2]([NH:48][C:45]2[CH:46]=[CH:47][C:42]([N:39]3[CH2:38][CH2:37][NH:36][CH2:41][CH2:40]3)=[CH:43][C:44]=2[O:49][CH3:50])[N:7]=1
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reactant: CC(=O)N1CCN(c2ccc(Nc3nc(Cl)ncc3F)c(OC(F)F)c2)CC1
Agent: CCOC(C)O
Agent: Cl
Product: COc1cc(N2CCNCC2)ccc1Nc1ncc(F)c(Nc2ccc(N3CCN(C(C)=O)CC3)cc2OC(F)F)n1
Temperature: 115 °C
Reaction time: 8 h
Yield: 22.2 %

Procedure:
1-(4-(4-(2-chloro-5-fluoropyrimidine-4-ylamino)-3-(difluoromethoxy)phenyl)piperazin-1-yl)ethanone (320 mg) and tert-butyl-4-(4-amino-3-methoxyphenyl)piperazin-1-carboxylate (236 mg) were dissolved in 0.08M HCl ethoxyethanol solution (7.7 ml), and stirred at 115° C. overnight. Upon completion of the reaction, the mixture was distilled under reduced pressure to remove the solvent, and the thus obtained oil was diluted with ethyl acetate. The diluted mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, subjected to layer separation, and the extracted organic layer obtained as a result of layer separation was dried with sodium sulfate. The dried organic layer was distilled under reduced pressure to remove the solvent and purified by column chromatography to obtain a target compound (100 mg, 22%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:25])[CH:3]=1.[O:26]=[C:27]1[NH:31][C@H:30]([CH2:32][O:33]C(=O)C2C=CC=CC=2)[CH2:29][O:28]1>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:31]4[C@H:30]([CH2:32][OH:33])[CH2:29][O:28][C:27]4=[O:26])=[CH:3][C:4]=3[CH3:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)cc3C)CC2)c(C)c1
Yield: 73.4 %

Procedure:
By reaction and treatment in the same manner as in Example 19 and using (4-bromo-2-methylphenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (350 mg) described in Preparation Example 129 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (289 mg), the title compound (280 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:29])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][OH:28])[O:24][CH2:23]2)[CH:17]([CH:30]([OH:32])[CH3:31])[C:16]3=[O:33])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:29])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][O:28][S:41]([CH3:40])(=[O:43])=[O:42])[O:24][CH2:23]2)[CH:17]([CH:30]([OH:32])[CH3:31])[C:16]3=[O:33])=[O:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CO)C3)C(C)C12
Solvent: c1ccncc1
Solvent: O
Product: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(COS(C)(=O)=O)C3)C(C)C12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution, under argon, of 0.821 g of product from Example 56 and 3.4 ml of pyridine is added 148 microliter of methanesulfonyl chloride. The reaction is stirred at 0° C. for 2 hours, diluted with water and extracted with chloroform. The organic layer washed with water and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by chromatography (Silica Gel; 80% ethyl acetate/hexane) to give 0.632 g of the desired product.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH3:18])[CH2:11]2)[CH:7]=[CH:6][C:5]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+].Cl>CO>[CH2:20]([O:19][C:5]1[CH:6]=[CH:7][C:8]([CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH3:18])[CH2:11]2)=[CH:9][C:4]=1[C:3]([OH:27])=[O:2])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCCN1CCOC(c2ccc(OCc3ccccc3)c(C(=O)OC)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCN1CCOC(c2ccc(OCc3ccccc3)c(C(=O)O)c2)C1
Yield: 100 %

Procedure:
To the methyl ester from example 32 (105 mg, 0.28 mmol) in methanol (5 ml) was added 10% sodium hydroxide (aq) (15 ml) and the milky white suspension was refluxed for 2 hours. The now colourless reaction mixture was cooled then neutralised by addition of 2M HCl (aq) (few drops). The reaction mixture was then concentrated in vacuo to give the title compound as an off-white solid (99 mg, 0.28 mmol, 100%). LRMS: m/z 355 (M−H+). This material was taken on crude to example 34.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([N:9]([CH3:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=[C:5]([C:17]2[N:21]=[C:20]([CH:22]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]3)[O:19][N:18]=2)[N:4]=1>O1CCOCC1>[ClH:1].[CH3:16][N:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]1[N:8]=[C:3]([NH2:2])[N:4]=[C:5]([C:17]2[N:21]=[C:20]([CH:22]3[CH2:26][CH2:25][NH:24][CH2:23]3)[O:19][N:18]=2)[N:6]=1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CCN(C(=O)OC(C)(C)C)C3)n2)n1
Agent: Cl
Solvent: C1COCCO1
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CCNC3)n2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A 4N solution of HCl in dioxane (7 mL, 28.2 mmol) was added slowly to a solution of tert-butyl 3-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate (Intermediate 114, 1.24 g, 2.82 mmol) in dioxane (15 mL) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under vacuum to afford the title compound as a yellow solid (1.05 g, 100%). Method B HPLC-MS: MH+ (free-based) requires m/z=339 Found: m/z=339, Rt=1.20 min (96%).
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)C.[C:19]([C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28][NH2:29])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>C(O)C>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([CH2:27][CH2:28][NH:29][C:5]2[C:6](=[O:18])[C:7](=[O:17])[C:8]=2[C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[CH:30][CH:31]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(CCN)cc1
Reactant: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Solvent: CCO
Product: COc1ccc(-c2c(NCCc3ccc(C(C)(C)C)cc3)c(=O)c2=O)cc1
Yield: 81.3 %

Procedure:
In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) and 4-tert-butyl-phenethylamine (0.216 g, 1.22 mmol) in ethanol (2 mL) were converted to the title compound (0.180 g, 81%) m.p.: 258.1-260.2° C.; 1H NMR (DMSO-d6) δ 9.07(br t,1H), 7.97(ABq,2H), 7.29(ABq,2H), 7.14(d,2H), 7.09(d,2H), 3.87(m,2H), 3.83(s,3H), 2.84(t,2H), 1.23(s,9H); IR (KBr) 3160, 2950, 1775, 1720, 1580, 1425, 1350, 1300, 1250, 1180, 1020, 840 cm−1; MS (m/z) 364 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][N:12]=[C:13]=[O:14]>C(Cl)(Cl)Cl>[CH3:11][NH:12][C:13]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:14]
Reactant: CN=C=O
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CNC(=O)Nc1ccc(C(=O)O)cc1
Reaction time: 72 h
Yield: 5.3 %

Procedure:
A mixture of 3.0 g (0.22 mol) of 4-aminobenzoic acid (Aldrich) in 100 mL of chloroform was treated with 10 g (0.175 mol) of methylisocyanate (Aldrich), and the mixture was stirred at ambient temperatures for three days. The mixture was concentrated and the residue was triturated with diethyl ether/petroleum ether. The solid was collected by filtration, air-dried, and then slurried with 100 mL of water. The solid was collected by vacuum filtration and the cake was sucked dry. The cake was then recrystallized from acetonitrile/water to yield 1.8 g (43%) of the title compound as a fluffy white solid, mp>400° C. (lit1 mp>300° C.).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9]([CH3:15])([CH3:14])[CH2:8][CH2:7][C:6]2([CH3:17])[CH3:16].[C:18]1([P:24]([C:31]2C=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl[CH2:38]Cl>C(OCC)C>[Br-:1].[CH3:13][C:12]1[C:3]([C:2]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[P+:24]([CH3:38])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][C:5]2[C:6]([CH3:17])([CH3:16])[CH2:7][CH2:8][C:9]([CH3:15])([CH3:14])[C:10]=2[CH:11]=1
Reactant: ClCCl
Reactant: Cc1cc2c(cc1CBr)C(C)(C)CCC2(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Cc1cc2c(cc1-c1ccccc1[P+](C)(c1ccccc1)c1ccccc1)C(C)(C)CCC2(C)C
Product: [Br-]
Yield: 60 %

Procedure:
The raw 6-bromomethyl-1,1,4,4,7-pentamethyl-1,2,3,4-tetrahydronaphthalene (8.80 g, about 32 mmol) prepared previously is mixed with triphenylphosphine (10.1 g, 38.4 mmol) in solution in 50 ml of dichloromethane for 24 hours, then diluted with ethyl ether (200 ml). The [(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-methyl]triphenylphosphonium bromide precipitates, is filtered and washed abundantly with the ether. 10.72 g of white crystals (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-methyl-triphenylphosphonium bromide is obtained after drying (yield=60%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].C1C(O)=CC=CC=1C.Cl.[N:19]#[C:20][NH2:21].[OH-].[Na+]>CCOCC>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH:4][C:20]([NH2:21])=[NH:19]
Reactant: N#CN
Reactant: Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1cccc(O)c1
Solvent: CCOCC
Product: N=C(N)Nc1c(Cl)cccc1Cl

Procedure:
To 51 g. (0.315 mole) of 2,6-dichloroaniline is added 0.4 moles of etherial HCl and 200 ml of m-cresol. The mixture is then stirred and heated on a steam bath to drive off the ether and excess hydrogen chloride. To the resultant mixture is then added 13.3 g. (0.315 mole) of cyanamide then heated for 2 hours on a steam bath. The reaction mixture is then cooled, added to 150 ml of conc. sodium hydroxide solution, cooled and extracted with 2 liters of ether. The ether layer is washed with 2 × 1 liter of water, dried over sodium sulfate, charcoaled and evaporated. The residue is triturated with hexane and the precipitate is filtered off and washed with ether and dried to obtain 2,6-dichlorophenylguanidine.
Reaction SMILES: [OH-].[Na+].O.[C:4]([CH2:6][C:7]([NH2:9])=[O:8])#[N:5].[CH2:10]([N:17]=[N+:18]=[N-:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CS(C)=O>[NH2:5][C:4]1[N:17]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:18]=[N:19][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: N#CCC(N)=O
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1nnn(Cc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a separate reactor, DMSO (17.6 g, 16.0 ml) was charged followed by, 32% aqueous NaOH (7.86 g, 5.82 ml, 62.9 mmol, Eq: 1.0) and water (5.00 g, 5.00 ml). A solution of 2-cyanoacetamide (7.93 g, 94.3 mmol, Eq: 1.50) in DMSO (17.6 g, 16.0 ml) was added dropwise over 15 min at 25° C. The previously prepared benzyl azide solution was added dropwise over 4 h at 25° C. The reaction was stirred overnight at 25° C. and water (120 g, 120 ml) was added dropwise over 30 min at 25° C. (exothermic). The resulting suspension was cooled over 30 min to 0° C., stirred at 0° C. for 30 min and filtered. The filter cake was washed with water (40.0 g, 40.0 ml) and was dried at 50° C./5 mbar to give 12.6 g of the title compound.