Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:3][C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:5].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].C(O)(=O)C>C(O)C>[CH3:17][N:18]([CH:20]=[C:3]([C:4](=[O:5])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:2]([O:12][CH2:13][CH3:14])=[O:11])[CH3:19]
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: COC(OC)N(C)C
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(=O)C(=CN(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
To a solution of diethyl oxalacetate sodium salt (100 g, 476 mmol) in ethanol (250.00 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (113 g, 952 mmol) and the reaction was stirred at room temperature for 30 min. Acetic acid (54.5 mL, 952 mmol) was added slowly over a period of 3 h and stirred at room temperature for 24 h. The volatile components were evaporated under reduced pressure and the oily residue was purified by silica gel chromatography (750 g REDISEP® column, eluting with 30% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 104A (43 g, 30.8%). MS(ES): m/z=244 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 7.84 (s, 1H), 4.31 (q, J=7.2 Hz, 2H), 4.18 (q, J=5.4 Hz, 2H), 3.35 (s, 3H), 3.04 (s, 3H), 1.36 (t, J=7.2 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:12][C:13]1[C:17]([CH2:18][N:19]2[CH:23]=[C:22]([NH2:24])[CH:21]=[N:20]2)=[C:16]([CH3:25])[O:15][N:14]=1>>[CH:1]1([CH2:7][C:8]([NH:24][C:22]2[CH:21]=[N:20][N:19]([CH2:18][C:17]3[C:13]([CH3:12])=[N:14][O:15][C:16]=3[CH3:25])[CH:23]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CC1CCCCC1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(NC(=O)CC2CCCCC2)cn1
Yield: 17 %

Procedure:
Prepared as in Example 4-8 from 2-cyclohexylacetic acid and 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a). Yield 17%. MS M+H calculated 317.6. Found 317.4.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([Cl:18])[CH:20]=2)=[CH:7][C:3]=1[C:4]([O:6][CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([Cl:18])[CH:20]=1)=[O:5]
Reactant: Clc1cccc(CBr)c1
Reactant: O=C(O)c1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1cccc(Cl)c1)c1cc(OCc2cccc(Cl)c2)ccc1Cl
Temperature: 60 °C
Yield: 94.9 %

Procedure:
To a mixture of 2-chloro-5-hydroxybenzoic acid (500 mg, 2.9 mmol) in DMF (20 ml) were added potassium carbonate (1.0 g, 7.3 mmol, 2.5 eq) and 3-chlorobenzyl bromide (0.8 ml, 6.1 mmol, 2.1 eq). The mixture was heated at 60° C. for 2.5 hours. On cooling the mixture was diluted with ethyl acetate (300 ml) and washed with water (2×100 ml) then brine (70 ml). Organic layer dried and evaporated in vacuo. The residue was purified by column chromatography (Biotage SP4, 100 g silica column) eluting with 0-30% ethyl acetate in hexanes to afford the title compound as a clear oil (1.16 g). MS (ES+) m/z 421 [M+H]+ (C21H1535Cl3O3). 1H-NMR (400 MHz, d6-DMSO) δ 5.19 (2H,s), 5.35 (2H,s), 7.26 (1H,dd, J 8.8, J 3.2), 7.40-7.56 (10H,m).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](O)=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:31][CH3:32])=[O:10].[CH3:33][NH:34][CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23]([N:34]([CH3:35])[CH3:33])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:31][CH3:32])=[O:10]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1C(=O)O
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1C(=O)N(C)C

Procedure:
A solution of Cis(±)-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid (0.062 g, 0.12 mmol, Example 188), dimethylamine (0.06 mL, 2M solution in THF, Aldrich), HATU (0.05 g, 0.13 mmol) and triethylamine (0.018 mL, 0.13 mmol) was stirred at room temperature until complete by LCMS (about 30 min). The crude reaction mixture was slowly poured into water and the resulting white precipitate was filtered, washed with water and dried under vacuum to yield pure product (0.028 g). MS (ES) MH+: 532 for C21H27Cl2N5O5S; NMR: 1.20 (t, 3 H) 1.76 (s, 2 H) 2.18 (s, 3 H) 2.78 (s, 3 H) 2.93 (s, 3 H) 3.29 (d, 1 H) 3.36 (s, 3 H) 3.39-3.43 (m, 1 H) 3.55 (s, 1 H) 3.91 (s, 1 H) 4.15 (q, 2 H) 4.29 (s, 2 H) 7.15 (d, 1 H) 12.14 (s, 1 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:9]=[CH:8][C:7]=2[N:6]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:5]=1.[CH3:30]C(C)([O-])C.[Na+].CI>O>[CH3:30][O:1][CH2:2][CH2:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:20])[CH3:21])[N:9]=[CH:8][C:7]=2[N:6]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[CH:5]=1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CCO)cn2COCC[Si](C)(C)C)c1=O
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COCCc1cn(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To 5 ml of mixed solvent (dehydrated tetrahydrofuran:N,N-dimethylformamide=3:1 (V/V)) solution containing 1.29 g (2.93 mmol) of 3-(2-hydroxyethyl)-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 57-(e) was added 0.56 g (5.83 mmol) of sodium tert-butoxide under room temperature, and the mixture was stirred at the same temperature for 2 hours. Then, 1.1 ml (17.7 mmol) of methyl iodide was added to the mixture, and the mixture was further stirred for 16-hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=1:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 1.18 g of the title compound as a slightly yellowish oil. (Yield: 89%)
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][C:6]2=[N:5][CH:4]=[C:3]1[C:11]([O:13]CC)=O.[OH-].[NH4+:17]>>[C:11]([C:3]1[C:2](=[O:1])[N:7]2[CH2:8][CH2:9][CH2:10][C:6]2=[N:5][CH:4]=1)(=[O:13])[NH2:17]
Reactant: [NH4+]
Reactant: CCOC(=O)c1cnc2n(c1=O)CCC2
Agent: [OH-]
Product: NC(=O)c1cnc2n(c1=O)CCC2
Yield: 96.6 %

Procedure:
10.4 g. of ethyl 4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-3-carboxylate are dissolved in 30 ml. of 30% by weight of ammonium hydroxide solution. The precipitated crystals are filtered after 2 hours. 8.7 g. of 3-carbamoyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine are obtained with a yield of 96.6%, which melts at 293° C. after recrystallization from dimethyl formamide.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O>CO.C(O)(=O)C.[Zn]>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([NH2:12])=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COCCNc1ccccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: COCCNc1ccccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
The residue 109A was dissolved in methanol (60 mL) and acetic acid (4 mL). Zinc metal (3.24 g, 49.6 mmol) was added and the mixture was stirred overnight at room temperature. The reaction was decanted off from unreacted zinc metal. The solvent was removed under vacuum and resuspended in ethyl acetate (30 mL). The precipitate was removed by filtration on a Buchner funnel with Celite. Solvent was removed from the filtrate and the residue was purified by column chromatography (2% MeOH/DCM) to give the product N1-(2-methoxyethyl)benzene-1,2-diamine (109B) as a red oil (422 mg, 72% yield over two steps). ESI-MS:m/z 167.4 (M+H)+.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].C([Li])CCC.[CH3:17][C:18]([CH3:27])([CH2:23][CH2:24][CH2:25][CH3:26])[C:19](OC)=[O:20]>CCCCCC.O1CCCC1>[O:20]=[C:19]([C:18]([CH3:27])([CH3:17])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCCCC(C)(C)C(=O)OC
Reactant: COP(C)(=O)OC
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC(C)(C)C(=O)CP(=O)(OC)OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 18.4 g. (0.116 moles) dimethyl methylphosphonate (Aldrich) in 200 ml. dry tetrahydrofuran is cooled to -78° in a dry nitrogen at atmosphere. To the stirred phosphonate solution is added 67.3 ml. (127.8 mmoles) of 1.90 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 40 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 10.2 g. (58.1 mmoles) methyl 2,2-dimethylhexanoate in 10 ml. of tetrahydrofuran is added dropwise at a rate that kept the reaction temperature less than - 70° (20 minutes). After 1.0 hour at -78° the reaction mixture is allowed to warm to ambient temperature, neutralized with 10 ml. acetic acid and rotary evaporated to a white gel. The gelatinous material is taken up in 75 ml. water, the aqueous phase extracted with 100 ml. portions of chloroform (3x), the combined organic extracts are backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled (b.p. 80°-85° at 0.05 mm) to give dimethyl 2-oxo-3,3-dimethylheptylphosphonate.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.OC[CH2:28][N:29]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[Na]>C1(C)C=CC=CC=1>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]([O:18][CH2:19][CH2:28][N:29]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:17])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccccc1Nc1ccnc2cc(C(F)(F)F)ccc12
Reactant: OCCN1CCCCCC1
Agent: [Na]
Solvent: Cc1ccccc1
Product: O=C(OCCN1CCCCCC1)c1ccccc1Nc1ccnc2cc(C(F)(F)F)ccc12
Yield: 59.9 %

Procedure:
By treating 17.31 g of methyl 2-(7-trifluoromethyl-4-quinolyl)aminobenzoate (II, R=CF3, R"=CH3), 10.5 g of 1-(2-hydroxyethyl)homopiperidine in 130 ml of toluene and in the presence of sodium as described in Example 1, 20.6 g of a crude material are isolated. The recrystallization in diisopropyl ether enables to isolate 13.7 g (yield: 60%) of a whitish solid with m.p. 72°-75° C. and elemental analysis C, H, N, F correct.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:20]([CH3:22])[CH:21]=2)=[CH:13][C:12]=1[C:29]([F:32])([F:31])[F:30].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[N:6][C:7]=1[N:26]1[CH2:27][CH2:28][CH:23]([C:19]2[N:20]([CH3:22])[CH:21]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([F:10])=[C:12]([C:29]([F:32])([F:30])[F:31])[CH:13]=3)[N:18]=2)[CH2:24][CH2:25]1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Reactant: Nc1ncnc(Cl)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2Br)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A mixture of 5-bromo-6-chloropyrimidin-4-amine (357.2 mg; 1.71 mmol; 1.02 eq.), 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine (550.00 mg; 1.68 mmol; 1.0 eq.), potassium carbonate (464.4 mg; 3.36 mmol; 2.0 eq.) in DMSO (6.0 ml) was stirred at 60° C. overnight. The reaction mixture was poured into water. The precipitate was filtered, washed with water and dried under vacuum to afford the title compound in 86% yield. LC-MS: (M+1=499, obsd.=499).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CC(C)([O-])C.[K+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](F)=[CH:17][C:16]=1[Cl:22]>C1COCC1.C(OCC)(=O)C>[Cl:14][C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][C:16]=1[Cl:22])[O:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: OC1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1ccc(OC2CCNCC2)cc1Cl
Temperature: 25 °C

Procedure:
4-Hydroxypiperidine (50 g) was added portionwise to a stirred suspension of potassium tert-butoxide (110.9 g) in THF (900 mL) at room temperature and under nitrogen. The mixture was heated at reflux and 1,2-dichloro-4-fluorobenzene (98 g) added dropwise over 30 min. The mixture was stirred at reflux for another 1 h then cooled down to room temperature, diluted with ethyl acetate (500 mL) and washed with water (500 mL). The organic phase was diluted further with ethyl acetate (500 mL) and extracted with 1M hydrochloric acid (200 mL). The aqueous extract was adjusted to over pH 10 by addition of a solution of sodium hydroxide and extracted twice with tert-butylmethyl ether (750 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under vacuum to yield the sub-title compound as a dark oil which was used as such in the next step.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[N:45]=[C:44]([O:46][CH3:47])[CH:43]=[CH:42][CH:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[C:44]([O:46][CH3:47])[N:45]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: COc1cccc(CCl)n1
Agent: Cl
Product: COc1cccc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)n1
Yield: 48.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 6-chloromethyl-2-methoxypyridine (0.47 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-methoxypyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.44 g) was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][NH:5][C:4]([CH:16]=[CH:17][C:18]([OH:20])=O)=[CH:3]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[C:46]([O:50][C:51]([NH:53][NH2:54])=[O:52])([CH3:49])([CH3:48])[CH3:47]>CN(C)C=O>[CH3:47][C:46]([CH3:49])([O:50][C:51]([NH:53][NH:54][C:18](=[O:20])[CH:17]=[CH:16][C:4]1[NH:5][CH:6]=[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:2](=[O:1])[CH:3]=1)=[O:52])[CH3:48]
Reactant: O=C(O)C=Cc1cc(=O)c(OCc2ccccc2)c[nH]1
Reactant: CC(C)(C)OC(=O)NN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)C=Cc1cc(=O)c(OCc2ccccc2)c[nH]1
Reaction time: 8 h

Procedure:
3-[1,4-Dihydro-4-oxo-5-(phenylmethoxy)-2pyridinyl]-2-propenoic acid (1.36 g), 0.75 g of N-hydroxybenzotriazole, 0.01 g of N,N-dimethylaminopyridine and 1.06 g of dicyclohexylcarbodiimide were stirred in 20 ml of dimethylformamide at 0° C. for 20 minutes. 0.66 g of N-(t-butoxycarbonyl)hydrazine was added. After stirring overnight, the formed dicyclohexylurea was filtered off and the filtrate was washed with 10 ml of dimethylformamide. The filtrate was evaporated to dryness and the residue was suspended in 30 ml of water, 1 g of sodium bicarbonate was added, and after stirring, the title compound was isolated by filtration. Recrystallization from dimethylformamide/water gave white crystals. Yield: 1.47 g, melting point 141° C.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O[N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][O:15][N:19]2[C:20](=[O:29])[C:21]3=[CH:28][CH:27]=[CH:26][CH:25]=[C:22]3[C:23]2=[O:24])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCCCCCCCOc1ccc(CO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(CON2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
To a suspension of 4-octyloxybenzyl alcohol (25 g), N-hydroxyphthalimide (17.15 g) and triphenylphosphine (27.74 g) in tetrahydrofuran (250 ml) was added dropwise diethyl azodicarboxylate (18.4 g) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours, and evaporated in vacuo. The residue was purified by chromatography on silica gel to give N-(4-octyloxybenzyloxy)phthalimide (33.45 g) as crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:12][NH2:13].[BH4-].[Na+].O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH:13][CH3:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNCc1ccc2[nH]ccc2c1
Reaction time: 3 h
Yield: 88.6 %

Procedure:
Indole-5-carbaldehyde (1.0 g, 6.9 mmol) was dissolved in anhydrous methanol (15 mL). Methylamine (9.9 mL of 2M solution in methanol, 19.8 mmol) was added and the reaction was stirred for 3 hr. The solution was concentrated to a yellow oil and then dissolved into anhydrous methanol (20 mL). Sodium borohydride (262 mg, 6.9 mmol) was added and the mixture was stirred overnight. Water (1 mL) was added and the solution was concentrated. Sodium hydroxide (5 mL, 1N) was added and the product was extracted with ethyl acetate (3×20 mL), dried over MgSO4 and concentrated to afford the title compound as a brown oil (980 mg, 91%). 1H NMR (200 MHz, CDCl3) δ 8.60 (s, 1H), 7.56 (s, 1H), 7.35-7.15 (m, 3H), 6.55 (m, 1H), 3.85 (s, 2H), 2.49 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][N:5]1[C:9](=[O:10])[N:8]([CH2:11][CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[C:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:6]1.[OH-].[Li+]>CO.O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:7]2[N:8]([CH2:11][CH:12]([OH:17])[C:13]([F:16])([F:14])[F:15])[C:9](=[O:10])[N:5]([CH2:4][C:3]([OH:25])=[O:2])[N:6]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The enantiomerically pure ester from Example 227A (265 mg, 0.70 mmol) is dissolved in 14 ml methanol and treated with 2.8 ml of a 1 M solution of lithium hydroxide in water. The mixture is stirred for 1 hr at RT and then freed of methanol on the rotary evaporator. The residue is diluted with 200 ml water and extracted once with dichloromethane. This organic phase is discarded. The aqueous phase is slowly acidified to pH 2 with 1 N hydrochloric acid. The product is extracted three times with dichloromethane, the combined organic phases are dried over sodium sulphate and the solvent removed on the rotary evaporator. The residue is dried under high vacuum. 142 mg (56% of theory) of the title compound are thus obtained. Since the aqueous phase still contains more product, it is evaporated to dryness on the rotary evaporator, and the residue is dissolved in a little DMSO and purified by preparative HPLC (Method 20). A further 71 mg (28% of theory) of the pure title compound are obtained.
Reaction SMILES: Cl.[C:2]1([CH3:11])[CH:7]=[CH:6][C:5]([C:8]([NH2:10])=[NH:9])=[CH:4][CH:3]=1.[C:12](OCC)(=[O:19])[CH2:13][C:14](OCC)=[O:15]>>[C:2]1([CH3:11])[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:12](=[O:19])[CH2:13][C:14](=[O:15])[N:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=N)N)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Product: Cc1ccc(C2=NC(=O)CC(=O)N2)cc1

Procedure:
Similarly, reacting p-toluamidine hydrochloride with diethyl malonate affords 2-(4-tolyl)-4,6-(1H,5H)-pyrimidinedione which is then reacted with phosphoryl chloride to produce 4,6-dichloro-2-(4-tolyl)-pyrimidine, m.p. 84°-85°C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:16]=1)[C:11]([OH:13])=[O:12].C1(N=C=NC2CCCCC2)CCCCC1.O[N:40]1[C:44](=[O:45])[CH2:43][CH2:42][C:41]1=[O:46].CCOCC>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:16]=1)[C:11]([O:13][N:40]1[C:44](=[O:45])[CH2:43][CH2:42][C:41]1=[O:46])=[O:12]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)c1cc(OC2CCCCO2)cc(OC2CCCCO2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(ON1C(=O)CCC1=O)c1cc(OC2CCCCO2)cc(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 89.8 %

Procedure:
A mixture of 3,5-bis[(tetrahydro-2H-pyran-2-yl)oxy]benzoic acid (5.00 g, 15.5 mmol), 1,3-dicyclohexylcarbodiimide (3.72 g, 18.1 mmol) and N-hydroxysuccinimide (2.08 g, 18.0 mmol) in tetrahydrofuran (100 Ml) was stirred at room temperature for 40 h. Ether (100 Ml) was added and the mixture was stirred for 20 min. The white solid was filtered off and discarded. The solvent was evaporated from the filtrate, and the residue was coated onto silica gel and chromatographed (50–75% ethyl acetate/hexanes) to give 1-[[3,5-bis[(tetrahydro-2H-pyran-2-yl)oxy]benzoyl]oxy]-2,5-pyrrolidinedione (5.84 g, 90%) as a white solid.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[O:12])[CH:6]=1)(=O)C.O1CCCC1.[OH-].[Na+]>CO>[OH:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=1)=[O:12]
Reactant: CC(=O)Oc1cccc(C(=O)Nc2ccc(C(F)(F)F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
To a solution of 3-({[4-(trifluoromethyl)phenyl]amino}carbonyl)phenyl acetate (27.7 g, 85.5 mmol) in methanol (100 mL)/tetrahydrofuran (100 mL) was added 8N aqueous sodium hydroxide solution (20 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hr and dried under reduced pressure to solidness. The residue was poured into dilute hydrochloric acid (pH=2) and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was triturated with diethyl ether to give the title compound (21.7 g, 90%) as a white solid.