Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[N:11][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13][C:14]=1[CH3:15])=O)(C)(C)C.C(O)(C)C.Cl.C(OCC)(=O)C>C(O)C.O>[NH2:8][C:9]1[C:10]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[N:11][C:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:13][C:14]=1[CH3:15]
Reactant: Cc1nc(-c2ccccc2)nc(-c2ccncc2)c1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccc2)nc(-c2ccncc2)c1N
Temperature: 25 °C

Procedure:
A mixture of 5-tert-butyloxycarbonylamino-6-methyl-2-phenyl-4-(4-pyridyl)pyrimidine (1.5 g) and an isopropanol solution of hydrogen chloride (4 ml, HCl 5 mMol/ml) in ethanol (15 ml) was stirred for 1 hour at 40° C. After cooling to room temperature, the reaction mixture was poured into a suspension of ethyl acetate (100 ml) and water (50 ml) under stirring, and the mixture was adjusted to pH 9.0. The separated organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residual crystal was recrystallized from ether to give 5-amino-6-methyl-2-phenyl-4-(4-pyridyl)pyrimidine, mp 208°-209° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:6]1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)C>[CH3:1][NH:2][CH2:3][CH:4]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=1)[OH:21]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CNCC=C1CC2(CCCC2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CNCC(O)C1=CC2(CCCC2)c2ccccc21
Temperature: 20 °C

Procedure:
N-Methyl-2-[spiro(cyclopentane-1,1'-indene)-3'-yliden]ethylamine (8.1 g; Swedish Pat. No. 7203905-0) in diethyl ether (100 ml) is treated with trifluoroacetic anhydride (8 ml) while being stirred with powdered anhydrous sodium carbonate (6 g). The solid is filtered off and the solvent is evaporated from the filtrate. The crude N-trifluoroacetyl-N-methylspiro(cyclopentane-1,1'-indan)-3'-ylideneethylamine is dissolved in dichloromethane (100 ml), added to sodium bicarbonate solution (40 ml; 0.5 M) and treated in portions with m-chloroperbenzoic acid (50%; 3.4 g) with stirring at about 20° C. After stirring for 2 hours, the solution is washed with saturated sodium carbonate solution and water, and dried with sodium sulphate. After filtration, the solvent is evaporated. The crude epoxy compound is dissolved in tetrahydrofuran (100 ml), and treated with perchloric acid (10 drops) at room temperature for 2 hours. After evaporation of the solvent the remaining crude 2-(N-methyltrifluoroacetamido)-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]-ethanol is dissolved in a mixture of methanol (20 ml), water (50 ml) and potassium carbonate (10 g) and stirred overnight. The methanol is evaporated under reduced pressure and the free amine is extracted into dichloromethane. After drying with sodium sulphate the solvent is evaporated. The title compound is crystallized from diisopropyl ether; m.p. 134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@@H:26]5[CH2:28][O:27]5)=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:29][O:30][CH2:31][CH3:32])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:35]([NH2:37])[CH3:36]>CO>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@@H:26]([OH:27])[CH2:28][NH:37][CH2:35][CH3:36])=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:29][O:30][CH2:31][CH3:32])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCN
Reactant: CCOCc1nc(-c2ccc(OC[C@@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: CO
Product: CCNC[C@H](O)COc1ccc(-c2cn(-c3ccc(Oc4ccc(Cl)cc4)cc3)c(COCC)n2)cc1

Procedure:
A solution of 1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-4-[4-((S)-1-oxiranylmethoxy)-phenyl]-1H-imidazole (50 mg, 0.11 mmol, from intermediate B3) in 4 mL of ethylamine in MeOH (2M) was stirred at 60° C. overnight in a teflon-capped vial. Upon completion (determined by LC/MS), the reaction was dried in vacuo and purified by silica gel flash column chromatography using a gradient of EtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford (S)-1-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-ethylamino-propan-2-ol.
Reaction SMILES: Br[C:2]1[C:29]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:28][C:5]([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:17][C@H:16]3[CH3:27])=[CH:13][CH:14]=2)=[O:7])=[CH:4][C:3]=1[Cl:35].[CH3:36][C@@H:37]1[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@H:39]([C:49]2[NH:50][CH:51]=[C:52]([C:54]3[CH:59]=[CH:58][C:57](B4OC(C)(C)C(C)(C)O4)=[CH:56][CH:55]=3)[N:53]=2)[CH2:38]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:35][C:3]1[CH:4]=[C:5]([C:6](=[O:7])[NH:8][C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:17][C@H:16]3[CH3:27])=[CH:13][CH:14]=2)[CH:28]=[C:29]([O:30][C:31]([F:34])([F:33])[F:32])[C:2]=1[C:57]1[CH:56]=[CH:55][C:54]([C:52]2[N:53]=[C:49]([C@@H:39]3[CH2:38][C@H:37]([CH3:36])[CH2:41][N:40]3[C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[NH:50][CH:51]=2)=[CH:59][CH:58]=1
Reactant: C[C@H]1C[C@@H](c2nc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: C[C@@H]1CN(C(=O)C(C)(C)C)CCN1c1ccc(NC(=O)c2cc(Cl)c(Br)c(OC(F)(F)F)c2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H]1C[C@@H](c2nc(-c3ccc(-c4c(Cl)cc(C(=O)Nc5ccc(N6CCN(C(=O)C(C)(C)C)C[C@H]6C)nc5)cc4OC(F)(F)F)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Yield: 50.3 %

Procedure:
To a mixture of (R)-4-bromo-3-chloro-N-(6-(2-methyl-4-pivaloylpiperazin-1-yl)pyridin-3-yl)-5-(trifluoromethoxy)benzamide (80.3 mg, 0.14 mmol; Preparation 51) and (2S,4S)-tert-butyl 4-methyl-2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (63.0 mg, 0.14 mmol) in a mixture of toluene (0.9 mL) and water (0.3 mL) was added potassium carbonate (86 mg, 0.63 mmol). The reaction mixture was flushed with nitrogen, PdCl2(dppf) (6.1 mg, 8.34 μmol) was added. The reaction mixture was capped, heated at 100° C. overnight, cooled to RT and partitioned between EtOAc (5 mL) and water (2 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give a brown oil, which was purified by silica gel chromatography (12 g silica gel, 0-100% EtOAc/hexanes). Desired fractions were combined and concentrated to give the title intermediate (58.1 mg, 51% yield) as a yellowish oil. (m/z): [M+H]+ calcd for C42H49ClF3N2O5 824.34. found 824.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].Cl[C:14]1[N:19]=[C:18]([NH2:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][CH:15]=1.C(=O)(O)[O-].[K+].O>CN(C=O)C>[NH2:20][C:18]1[N:19]=[C:14]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH:15]=[CH:16][C:17]=1[N+:21]([O-:23])=[O:22]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCNc1ccc([N+](=O)[O-])c(N)n1
Temperature: 90 °C

Procedure:
150.6 mg (0.864 mmol) of tert-butyl (3-aminopropyl)carbamate, 300 mg (1.73 mmol) of 6-chloro-3-nitropyridine-2-amine and 173 mg (1.73 mmol) of potassium bicarbonate are suspended in 10 ml of DMF and heated at 90° C. for 16 h. Water is added to the mixture, which is then extracted three times with ethyl acetate. Purification of the crude product by preparative HPLC and drying under high vacuum result in 195 mg (65% of theory) of product.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:22][CH:21](OS(C)(=O)=O)[CH2:20]2)[S:17][CH:18]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:28]([O-:31])(=[S:30])[CH3:29].[K+]>CN(C)C=O>[C:28]([S:30][CH:21]1[CH2:20][N:19]([C:16]2[S:17][CH:18]=[C:14]([C:12](=[O:13])[NH:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[N:15]=2)[CH2:22]1)(=[O:31])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)OCCNC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)NCCO[Si](C)(C)C(C)(C)C)cs2)C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 64.3 %

Procedure:
To a solution of 1-{4-[2-(t-butyldimethylsilyloxy)ethylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (647.1 mg, 1.49 mmol) (obtained as described in Reference Example 33(5)) in dimethylformamide (32.0 ml) was added potassium thioacetate (1.28 mg, 8.9 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) for 4 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (3:2) as the eluant to afford 3-acetylthio-1-{4-[2-(t-butyldimethylsilyloxy)ethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (398.2 mg, yield 65%) as a pale brown solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:11][CH:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(N)cn2)C1
Yield: 47.2 %

Procedure:
Following General procedure H, 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) was reacted with tert-butyl 3-aminopyrrolidine-1-carboxylate (632 mg, 3.5 mmol) followed by reduction to afford the desired product (407 mg, 47%) as a purple solid: ESI MS m/z 279 [C14H22N4O2+H]+.
Reaction SMILES: [OH:1][CH:2]([CH:7]([S:27][CH2:28][CH2:29][C:30]([O:32]C)=[O:31])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[O:23][CH:24]=[CH:25][CH:26]=1)[C:3]([O:5]C)=[O:4].[OH-].[Na+]>CO>[OH:1][CH:2]([CH:7]([S:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[O:23][CH:24]=[CH:25][CH:26]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)CCSC(c1ccccc1CCCCCCCCc1ccco1)C(O)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCSC(c1ccccc1CCCCCCCCc1ccco1)C(O)C(=O)O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Methyl 2-hydroxy-3-(2-carbomethoxyethylthio)-3-[2-(8-(2-furyl)octyl)phenyl]propanoate (0.068 g, 0.14 mmoles) was dissolved in methanol (2.0 ml), under argon, cooled to 0° C. and a 1N sodium hydroxide solution (0.54 ml) was added dropwise. The ice bath was removed and the reaction mixture permitted to warm to room temperature. After 5 hours, the methanol was evaporated and the residue diluted with water. The pH of the aqueous layer was adjusted to 2 with dilute hydrochloric acid. The acidic layer was then extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated. The residue was flash chromatographed on silica gel to provide the desired product as a mixture of diastereomers, -log KB value 7.7.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][C:16]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:15]3=[O:32])[O:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][CH:41]([CH3:43])[CH3:42]>CN(C)C=O>[CH2:40]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][C:16]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:15]3=[O:32])[O:10][N:9]=2)=[CH:6][CH:7]=1)[CH:41]([CH3:43])[CH3:42]
Reactant: CC(C)CBr
Reactant: O=C1N(Cc2nc(-c3ccc(O)cc3)no2)CCCC1(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(-c2noc(CN3CCCC(c4ccccc4)(c4ccccc4)C3=O)n2)cc1
Temperature: 75 °C

Procedure:
To 1-{[3-(4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl]methyl}-3,3-diphenylpiperidin-2-one (Example 206, 0.040 g, 0.094 mmol) and potassium carbonate (0.019 g, 0.141 mmol) in N,N-dimethylformamide (0.5 mL) was added 1-bromo-2-methylpropane (0.012 mL, 0.113 mmol) and the reaction heated to 75° C. for 3 hours. The reaction was cooled, loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 40% ethyl acetate/hexanes (Flow=35 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.11-7.94 (m, 2H), 7.39-7.13 (m, 10H), 7.06-6.93 (m, 2H), 4.90 (s, 2H), 3.80 (d, J=6.5, 2H), 3.61 (t, J=6.5, 2H), 2.77-2.62 (m, 2H), 2.13 (dp, J=6.8, 13.4, 1H), 2.01-1.80 (m, 2H), 1.04 (t, J=10.1, 6H); MS (ESI+) m/z 482.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([CH3:18])[CH:10]=2)=[O:8])=[CH:5][N:4]=[CH:3]1.[N:19]1([C:24]2[CH:43]=[CH:42][C:27]([CH2:28][C:29]3[C:30]([Cl:41])=NC4C([C:38]=3[Cl:39])=CC(Br)=CC=4)=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[N:20]1.O=P(Cl)(Cl)Cl.[NH4+].[OH-]>>[N:19]1([C:24]2[CH:25]=[CH:26][C:27]([CH2:28][C:29]3[C:30]([Cl:41])=[N:15][C:12]4[C:13]([C:38]=3[Cl:39])=[CH:14][C:9]([C:7]([C:6]3[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)=[O:8])=[CH:10][C:11]=4[CH3:18])=[CH:42][CH:43]=2)[CH:23]=[CH:22][CH:21]=[N:20]1
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Cc1cc(C(=O)c2cncn2C)ccc1[N+](=O)[O-]
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C(=O)c2cncn2C)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Temperature: 105 °C

Procedure:
A heterogeneous mixture of (4-amino-3-methylphenyl)(1-methyl-1H-imidazol-5-yl)methanone (1.0 g, 4.6 mmol, Intermediate 14: step c), 2-(4-(1H-pyrazol-1-yl)benzyl)malonic acid (1.3 g, 4.6 mmol, Intermediate 3: step b) and POCl3 (4.3 mL) was heated at 105° C. for 18 hours then cooled to room temperature. The mixture was poured into ice water and treated with aqueous NH4OH solution (kept adding ice during addition) to a basic pH 8-9. The aqueous layer was extracted with DCM, washed with a saturated aqueous solution of NaCl, dried (MgSO4) and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-100% EtOAc/DCM) to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([CH3:10])[CH3:9])[C:3]=1[Cl:11].[C:12]1([CH:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:11][C:3]1[C:4]([CH:8]([CH3:9])[CH3:10])=[N:5][CH:6]=[CH:7][C:2]=1[NH:1][C@H:21]1[CH2:20][CH2:19][C@@H:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:23][CH2:22]1
Reactant: CC(C)c1nccc(N)c1Cl
Reactant: O=C1CCC(c2ccccc2)CC1
Product: CC(C)c1nccc(N[C@H]2CC[C@@H](c3ccccc3)CC2)c1Cl
Yield: 26.6 %

Procedure:
Was prepared analogously to Example 75 starting from 4-amino-3-chloro-2-isopropylpyridine and 4-phenylcyclohexanone. Yield: 26.6%
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6]CC.[C:9]([OH:13])(=[O:12])[CH2:10][CH3:11]>O>[C:9]([OH:13])(=[O:12])[CH2:10][CH2:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCC(=O)O
Reactant: C=CCCCCCC
Solvent: O
Product: CCCCCCCCC(=O)O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
An autoclave was charged with 0.1 g of Rh(acac)(CO)2, 20 g of pyridineand 10 g of 1-octene in a mixture of 60 g of propionic acid and 10 g of water as solvent. A pressure of 30 bar was set using CO and the mixture was heated to 100° C. A reaction pressure of 100 bar was then set by injecting CO and was maintained by injection of further amounts (every 15 minutes). After 1 hour, the autoclave was depressurized and the reaction mixture produced was analyzed titrimetrically and by gas chromatography. Nonanoic acid (n/iso 2.6:1) was formed in an STY of 46 g/l/h (Sel.>95%). Nonanal (n/iso) could be detected in traces by gas chromatography. Hydrogenation products such as octane or nonanol were not found.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=O)C.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1B(O)O>>[O:7]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][C:29]=2[O:28][CH3:27])[CH:13]=1)[C@@H:6]1[S:15][CH2:16][C@@H:17]([OH:23])[C@H:18]([OH:19])[C@H:5]1[OH:4]
Reactant: COc1ccncc1B(O)O
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: COc1ccncc1-c1cncc(O[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)c1

Procedure:
By carrying out the operation analogously to example 239, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 4-methoxy-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=23%).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:15][C:16]1[N:17]([CH2:25][CH2:26][O:27][CH2:28][CH3:29])[C:18]2[C:23]([N:24]=1)=[CH:22][N:21]=[CH:20][N:19]=2.C(=O)([O-])O.[Na+]>C(O)C>[CH2:28]([O:27][CH2:26][CH2:25][N:17]1[C:16]([CH2:15][N:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:13][CH2:12]2)=[N:24][C:23]2[C:18]1=[N:19][CH:20]=[N:21][CH:22]=2)[CH3:29]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCOCCn1c(CCl)nc2cncnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOCCn1c(CN2CCN(Cc3ccccc3)CC2)nc2cncnc21
Yield: 62 %

Procedure:
A mixture of 4.4 parts of 1-(phenylmethyl)piperazine, 4.7 parts of 8-(chloromethyl)-9-(2-ethoxyethyl)-9H-purine, 2.1 parts of sodium hydrogen carbonate and 40 parts of ethanol was stirred and refluxed for 5 hours. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 4.6 parts (62.0%) of 9-(2-ethoxyethyl)-8-[[4-(phenylmethyl)-1-piperazinyl]methyl]-9H-purine as a residue (compound 23).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[F:24][C:25]([F:34])([F:33])[C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1.CN1CCOCC1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([C:25]([F:33])([F:24])[F:34])=[CH:31][N:30]=3)=[O:16])[C:9]2=[O:17])=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)C1=O)Nc1ccc(C(F)(F)F)cn1
Reaction time: 0.5 h

Procedure:
To a suspension of 2-(3-(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.088 g, 0.370 mmol; Example 216A) in dichloromethane (1 mL) was added oxalyl dichloride (0.308 mL, 0.617 mmol). After 30 minutes, the reaction was concentrated and dried. This residue was dissolved in dichloromethane (1 mL) and 5-(trifluoromethyl)pyridin-2-amine (0.050 g, 0.308 mmol) was added followed by 4-methylmorpholine (0.068 mL, 0.617 mmol). After stirring for 30 minutes, the reaction was loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate/hexanes (Flow=20 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.67 (s, 1H), 8.57-8.52 (m, 1H), 8.28 (d, J=8.7, 1H), 7.92 (dd, J=2.3, 8.8, 1H), 7.35-7.21 (m, 2H), 7.09-6.99 (m, 2H), 4.25 (d, J=16.0, 1H), 4.18 (d, J=16.0, 1H), 3.78 (t, J=9.0, 1H), 3.69-3.59 (m, 2H), 2.63 (m, 1H), 2.23 (m, 1H); MS (ESI+) m/z 382.0 (M+H)+.
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].CC(C)([O-])C.[K+].Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15]>O1CCOCC1>[C:1]([NH:6][C:14](=[O:15])[O:16][CH2:17][CH3:18])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(N)=O
Reactant: CCOC(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=C(C)C(=O)NC(=O)OCC
Temperature: 60 °C
Reaction time: 1 h
Yield: 12.7 %

Procedure:
In 200 g of dioxane, 4.26 g of methacrylamide and 6.37 g of potassium t-butoxide were dissolved and the solution was stirred for 60 minutes at 60° C. Then, 5.43 g of ethyl chloroformate was dissolved in 50 g of dioxane and the solution was added dropwise to the reaction mixture in 2 hours. After removing tetrahydrofurane in vacuo, 1000 g of water was added to the residue and the solution was extracted with 500 ml of ethyl acetate. The extract was evaporated in vacuo. The crude product was subjected to column chromatography, thereby obtaining 1.0 g of ethyl N-methacryloylcarbamate. Melting point of the product was 73°-74° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:38])C=1>C(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:38])=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1NCCCNC(=O)OC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c[n+]([O-])c3ccccc3c2n1NCCCNC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
A solution of tert-butyl {3-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)amino]propyl}carbamate (1.34 g, 3.35 mmol) in 30 mL of CHCl3 was treated with MCPBA (1.45 g, 5.03 mmol, 77% max). After 3 h, the reaction mixture was diluted with 10% Na2CO3 solution and CHCl3 and the phases were separated. The organic portion was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield tert-butyl {3-[(2-ethoxymethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)amino]propyl}carbamate (1.39 g) as an orange foam.
Reaction SMILES: [CH2:1]=[O:2].[N:3]1[C:10]([NH2:11])=[N:9][C:7]([NH2:8])=[N:6][C:4]=1[NH2:5].[OH-].[Na+]>O>[CH2:1]([NH:5][C:4]1[N:6]=[C:7]([NH2:8])[N:9]=[C:10]([NH2:11])[N:3]=1)[OH:2]
Reactant: Nc1nc(N)nc(N)n1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(N)nc(NCO)n1
Temperature: 70 °C

Procedure:
Formaldehyde (50%, 12.0 g, 0.2 mol) was added to a mixture of melamine (12.6 g, 0.1 mol) and water (40 ml) with stirring. The pH of the mixture was adjusted to 9.0-9.2 by addition of NaOH (0.5N). The mixture was heated to 70° C. and a dyestuff (Direct red 252 mg, 2000 ppm based on melamine) was added to give a colored methylolmelaminersolution. In this procedure, other dyestuffs can be used such as direct dyes, fluorescent dyes, dispersion dyes, and mixtures thereof. See Table 1.