Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]([N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:26][CH2:25][CH2:24][C@@H:23]([C:27]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[O:28])[CH2:22]4)[CH2:17][CH2:16]3)=[O:14])[CH:10]=[C:9]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[N:50]1([C:56](Cl)=[O:57])[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>ClCCl>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]([N:15]3[CH2:16][CH2:17][CH:18]([N:21]4[CH2:26][CH2:25][CH2:24][C@@H:23]([C:27]([N:29]5[CH2:34][CH2:33][N:32]([C:56]([N:50]6[CH2:55][CH2:54][O:53][CH2:52][CH2:51]6)=[O:57])[CH2:31][CH2:30]5)=[O:28])[CH2:22]4)[CH2:19][CH2:20]3)=[O:14])[CH:10]=[C:9]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C(c1cc(-c2ccccc2)nc(-c2ccccc2)c1)N1CCC(N2CCC[C@@H](C(=O)N3CCNCC3)C2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(-c2ccccc2)nc(-c2ccccc2)c1)N1CCC(N2CCC[C@@H](C(=O)N3CCN(C(=O)N4CCOCC4)CC3)C2)CC1
Temperature: 25 °C
Reaction time: 66 h
Yield: 82 %

Procedure:
(3R)-(2,6-Diphenyl-pyridin-4-yl)-[3-(piperazine-1-carbonyl)-[1,4′]bipiperidinyl-1′-yl]-methanone (0.507 mmol, 272 mg) was dissolved in anhydrous dichloromethane and N,N-diisopropylethylamine (2 eq. 180 μl) followed by N-morpholine carbonyl chloride (1 eq. 60 μl ) were added. After 3 hr a further aliquot of N-morpholine carbonyl chloride (40 μl) was added and the mixture was stirred at room temperature for 66 hr. The solution was washed with 0.1M sodium hydroxide solution, dried over anhydrous sodium sulfate, diluted with toluene and evaporated to dryness. The product was purified by chromatography on silica gel eluting with a 2.5% to 10% methanol-dichloromethane gradient to give the title compound (270 mg, 82%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([OH:30])[N:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([O:30][CH2:39][C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[N:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 8.0 g 4-{(S)-3-tert-Butoxycarbonyl-2-[(5-hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]propionyl}-piperazine-1-carboxylic acid ethyl ester in 50 ml DMF were added 2.5 ml benzyl bromoacetate and 10.1 g cesium carbonate. After stirring at RT for 12 h the solution was reduced to a volume of 50 ml, diluted with 400 ml ethyl acetate and extracted with aqueous LiCl (4% w/w) and aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used in the subsequent reaction.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:21](=[O:23])(=[O:22])[NH:20][C:19](=[O:24])[CH:18]=2)=[CH:13][CH:12]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CN(C=O)C>C(Cl)Cl>[O:22]=[S:21]1(=[O:23])[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][NH:8][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:12][CH:13]=2)=[CH:18][C:19](=[O:24])[NH:20]1
Reactant: NCCc1ccc(C2=CC(=O)NS2(=O)=O)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1C=C(c2ccc(CCNC(=O)c3ccccc3)cc2)S(=O)(=O)N1
Temperature: 25 °C
Yield: 29.5 %

Procedure:
23-F (7.0 mg, 0.019 mmol) and triethylamine (8 μL, 0.0573 mmol) were dissolved in methylene chloride (0.25 mL). Benzoyl chloride (2.8 μL, 0.0239 mmol) was added and the reaction was allowed to stir at room temperature. DMF (0.25 mL) was added and allowed to stir overnight. The reaction was chromatographed on a 21 mm Luna C18 column using a 10–90% acetonitrile in water gradient with 0.05% trifluoroacetic acid at 12.5 mL per minute over a 30 minute period. The major fraction was lyophilized to give a white powder (2.0 mg, 29%). 1H NMR (500 MHz, CD3OD): δ 7.91 (d, J=8.7 hz, 2H), 7.81 (d, J=8.9 Hz, 2H), 7.52 (d, J=8.8 Hz, 2H), 7.43 (m, 3H), 6.97 (s, 1H), 6.69 (br s, 1H), 3.47 (t, J=7.0 Hz, 2H), 2.91 (t, J=7.0 Hz, 2H); LCMS found for C18H17N2O4S (M+H)+: m/z=357.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][N:10](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:9]2)=[CH:4][CH:3]=1.[C:25](Cl)(Cl)=[O:26]>ClCCl.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][N:10]([C:25]([NH:10][CH2:9][CH:8]=[CH2:5])=[O:26])[CH2:11]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: Fc1ccc(C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=CCNC(=O)N1CC(c2ccc(F)cc2)C1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3-(4-fluorophenyl)-N-(diphenylnethyl)azetidine (17) (0.67 g) in dichloromethane (5 mL) at 0° C. was added dropwise a solution of 20% phosgene in toluene (2.5 mL). The mixture was stirred for 90 minutes then concentrated in vacuo. To the concentrate was added dichloromethafe (5 mL) and to this solution at 0° C. was added, dropwise, with stirring, allylamine (0.5 mL). The mixture was stirred for 18 hrs at room temperature, diluted with dichloromethane (20 mL), washed (water. brine), dried (Na2SO4) and concentrated in vacuo. Recrystallisation from diisopropyl ether gave 3-(4-(fluorophenyl)-N-(2-propeny)azetidine-1-carboxamide (18) (0.30 g), m.p. 119-120° C. (diisopropyl ether). Found: C, 66.61; H, 6.37; N, 11.74. C13H15FN2O requires C, 66.65; H. 6.45; N, 11.95%.
Reaction SMILES: [CH3:1][C:2]([CH3:47])=[CH:3][CH2:4][CH2:5][C@:6]1([CH3:46])[O:11][C:10]2[C:12]([CH2:41][CH:42]=[C:43]([CH3:45])[CH3:44])=[C:13]3[O:25][C@@:24]45[C:26]6([CH2:33]/[CH:34]=[C:35](/[C:38]([OH:40])=[O:39])\[CH2:36]O)[O:29][C:30]([CH3:32])([CH3:31])[CH:23]4[CH2:22][C@H:21]([C:27]6=[O:28])[CH:20]=[C:19]5[C:17](=[O:18])[C:14]3=[C:15]([OH:16])[C:9]=2[CH:8]=[CH:7]1>C(Cl)(Cl)Cl>[CH3:1][C:2]([CH3:47])=[CH:3][CH2:4][CH2:5][C@@:6]1([CH3:46])[O:11][C:10]2[C:12]([CH2:41][CH:42]=[C:43]([CH3:45])[CH3:44])=[C:13]3[O:25][C@@:24]45[C:26]6([CH2:33]/[CH:34]=[C:35](/[C:38]([OH:40])=[O:39])\[CH3:36])[O:29][C:30]([CH3:31])([CH3:32])[CH:23]4[CH2:22][C@H:21]([C:27]6=[O:28])[CH:20]=[C:19]5[C:17](=[O:18])[C:14]3=[C:15]([OH:16])[C:9]=2[CH:8]=[CH:7]1
Reactant: CC(C)=CCC[C@@]1(C)C=Cc2c(O)c3c(c(CC=C(C)C)c2O1)O[C@]12C(=C[C@@H]4CC1C(C)(C)OC2(C/C=C(\CO)C(=O)O)C4=O)C3=O
Solvent: ClC(Cl)Cl
Product: CC(C)=CCC[C@]1(C)C=Cc2c(O)c3c(c(CC=C(C)C)c2O1)O[C@]12C(=C[C@@H]4CC1C(C)(C)OC2(C/C=C(\C)C(=O)O)C4=O)C3=O

Procedure:
Isogambogic acid (1) obtained was a bright yellow amorphous powder. [α]D20=−660° (c=0.321, CHCl3). ESIMS: m/z=629 ([M+H]+); (+)FABMS: m/z=629 ([M+H]+); HRESIMS: m/z=obsd. 629.3133 [M+H]+, calcd. 629.3114. Epiisogambogic acid (2) was also a bright yellow amorphous powder. [α]D20=−587° (c=0.261, CHCl3). ESIMS: m/z=629 ([M+H]+); (+)FABMS: m/z=629 ([M+H]+); HRESIMS: m/z=obsd. 629.3101 [M+H]+, calcd. 629.3114. More analytic data are shown in the following table 5:
Reaction SMILES: [CH3:1][C:2]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18]C2CCCCO2)=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:18][CH2:17][CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:2]([CH3:1])([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCOC2CCCCO2)cc1)Oc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)C(C)(Cc1ccc(OCCO)cc1)Oc1ccccc1
Yield: 85.5 %

Procedure:
In a similar manner to that described in Reference example 3(f), a reaction was carried out using ethyl 2-methyl-2-phenoxy-3-[4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl]propionate (1.60 g), which is the product of Reference example 8(c), and p-toluenesulfonic acid monohydrate (0.70 g) and the reaction mixture was treated to afford the desired compound (1.10 g) as a syrup.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:13])[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.[F-].[K+].O>C1(C)C=CC=CC=1.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][CH:10]([CH3:12])[CH2:9][CH:8]([C:5]1[CH:4]=[N:3][C:2]([C:19]2[CH:20]=[CH:21][C:16]([C:15]([F:26])([F:25])[F:14])=[CH:17][CH:18]=2)=[N:7][CH:6]=1)[OH:13]
Reactant: CC(C)CC(O)c1cnc(Cl)nc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)CC(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Yield: 14.9 %

Procedure:
To a solution of the 1-(2-chloropyrimidin-5-yl)-3-methylbutan-1-ol (600 mg, 2.99 mmol) in toluene (15.0 mL) was added Pd(PPh3)4 (346 mg, 0.299 mmol), 4-(trifluoromethyl)phenyl boronic acid (682 mg, 3.59 mmol), potassium fluoride (521 mg, 8.97 mmol) and water (3.7 mL). The reaction mixture was purged with nitrogen and heated to reflux for 5 h. The phases were separated and the aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic layers were concentrated under reduced pressure. The crude solid was purified by silicas gel chromatography to give 3-methyl-1-(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)butan-1-ol (138 mg) as a yellow solid. 1HNMR (400 MHz, CDCl3) δ 8.77 (s, 2H), 8.55 (d, J=8.4 Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 4.81-4.84 (m, 1H), 1.92-1.65 (m, 2H), 1.53-1.47 (m, 1H), 0.94 (d, J=6.4 Hz, 6H).
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]([CH:25]([CH3:27])[CH3:26])=[C:7]([C:22]([O-:24])=O)[CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:3])[CH3:2].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>O1CCCC1>[CH:1]([C:4]1[NH:5][C:6]([CH:25]([CH3:27])[CH3:26])=[C:7]([C:22]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:24])[CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)C1=C(C(C)C)NC(C(C)C)=C(C(=O)[O-])C1c1ccc(F)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C(C)C)NC(C(C)C)=C(C(=O)N2CCOCC2)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.05 g (6.5 mmol) of N,N'-carbonylimidazole are added under a nitrogen atmosphere to 1.875 g (5 mmol) of the compound from Example 95 dissolved in 20 ml of dry tetrahydrofuran and the mixture is stirred for 30 minutes at room temperature. It is subsequently heated to reflux for 30 minutes, a solution of 0.87 ml (10 mmol) of morpholine in 5 ml of dry tetrahydrofuran is added and it is heated to boiling for a further 2 hours. After cooling to room temperature, the mixture is concentrated in vacuo and the residue is taken up in dichloromethane and washed successively with 1N hydrochloric acid, 1N sodium hydroxide solution and water. The organic phase is dried over magnesium sulphate and concentrated in vacuo, and the crystalline residue is dried in a desiccator.
Reaction SMILES: O[N:2]=[CH:3][C@@H:4]([N:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[N:29]([C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:28]=[N:27][N:26]=2)=[CH:15][CH:14]=1)[C:7](=[O:11])[CH2:8][CH2:9][CH3:10])[CH3:5].C([BH3-])#N.[Na+].C([O-])(=O)C.[NH4+].[OH-].[NH4+]>[Ti].CO>[NH2:2][CH2:3][C@@H:4]([N:6]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[N:29]([C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:28]=[N:27][N:26]=2)=[CH:17][CH:18]=1)[C:7](=[O:11])[CH2:8][CH2:9][CH3:10])[CH3:5]
Reactant: CCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)[C@@H](C)C=NO
Agent: [Ti]
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Solvent: CO
Product: CCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)[C@@H](C)CN
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.5 %

Procedure:
A solution of intermediate (5d) (105 mg, 0.2 mmol), sodium cyanoborohydride (47 mg, 0.7 mmol), ammonium acetate (28 mg, 0.4 mmol), and MeOH (6.0 mL) was cooled to 0° C. After 15 minutes, titanium (H) chloride (83 mg, 0.5 mmol) was added. After 10 minutes, ammonium hydroxide (1 mL) was added and the mixture was stirred at room temperature for 5 minutes. The mixture was filtered through Celite®, rinsing with MeOH, and the filtrate was concentrated in vacuo to yield a white solid. The solid was extracted with DCM and water. The combined organic extracts were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated in vacuo to afford intermediate (5e) (95 mg), which was used directly in the next step.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C(=O)=O.C[O:14][C:15]([C:17]1[C:18]([CH2:33][CH2:34][O:35][CH3:36])=[N:19][C:20]([C:23]2[CH:24]=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=2)=[N:21][CH:22]=1)=O.C(OC(C1C(CCOC)=NC(C2C=NC(C(F)(F)F)=CC=2)=NC=1)=O)C.OS([O-])(=O)=O.[K+]>C1COCC1>[CH3:36][O:35][CH2:34][CH2:33][C:18]1[C:17]([CH2:15][OH:14])=[CH:22][N:21]=[C:20]([C:23]2[CH:24]=[N:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=2)[N:19]=1
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)nc2)ncc1C(=O)OC
Agent: CC(C)C[AlH]CC(C)C
Agent: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)nc2)nc1CCOC
Agent: O=C=O
Solvent: C1CCOC1
Product: COCCc1nc(-c2ccc(C(F)(F)F)nc2)ncc1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 107.3 %

Procedure:
Within 20 min was dropped 50 ml (60 mmol) of DIBALH (1.2 M solution in toluene) to a dry ice cooled (−30° C.) solution of 6.83 g (20 mmol) 4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine-5-carboxylic acid methyl ester and 4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine-5-carboxylic acid ethyl ester in 100 ml of THF. The reaction was warmed up (0° C. for 1 h) and stirred 1 h at RT. The reaction was cooled (0° C.) and neutralized with KHSO4 solution (10%). The mixture was extracted with ether (3×), the organic phase was washed with a NaCl solution (10%), dried (Na2SO4) and evaporated. The crude product was crystallized (dichloromethane/ether, 0° C.) to give 6.72 g of pure [4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-5-yl]-methanol.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)([OH:3])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[Cl:42][C:43]1[CH:64]=[C:63]([NH2:65])[CH:62]=[CH:61][C:44]=1[C:45]([N:47]1[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=2[CH2:51][N:50]2[CH:58]=[CH:59][CH:60]=[C:49]2[CH2:48]1)=[O:46].C(N(CC)CC)C>ClCCl.O1CCCC1.ClCCl>[Cl:42][C:43]1[CH:64]=[C:63]([NH:65][C:1](=[O:3])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[CH:62]=[CH:61][C:44]=1[C:45]([N:47]1[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=2[CH2:51][N:50]2[CH:58]=[CH:59][CH:60]=[C:49]2[CH2:48]1)=[O:46]
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Reactant: O=C(O)c1ccccc1-n1cccc1
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1)c1ccccc1-n1cccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
A solution of 1-(2-carboxyphenyl)pyrrole (188 mg, 1 mmol) and triphenylphosphine (264 mg, 1 mmol) in dichloromethane (6 ml) was cooled to 0° C. To this solution was added, portionwise, N-chlorosuccinimide (131 mg, 0.9 mmol). The solution was stirred for 30 minutes and allowed to warm to room temperature. To this solution was added a solution of 10,11-dihydro-10-(2-chloro-4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine (338 mg, 1 mmol) and triethylamine (0.15 ml, 1.06 mmol) in 15 ml of a mixture of a tetrahydrofuran-dichloromethane (1:2). The reaction was stirred for two hours at room temperature and then was concentrated to a solid in vacuo. The solid was disolved in ether (100 ml) and filtered. The filtrate was concentrated in vacuo and chromatographed over silica gel with ethyl acetate-hexane (1:1) as the mobile phase to afford 270 mg of the product as a yellow solid. Recrystallization from ethyl acetate-ether-hexane gave 180 mg of the product as a colorless solid. MS (EI),m/z 506/508 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH:9]([OH:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16](OC)=[O:17])[CH:11]=2)[N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C(O)(C)C.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH:9]([OH:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[CH:11]=2)[N:3]=1
Reactant: COC(=O)c1cccc(C(O)Cc2cccc(Br)n2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: OCc1cccc(C(O)Cc2cccc(Br)n2)c1
Reaction time: 3 h
Yield: 62.4 %

Procedure:
A solution of 180 mg of 2-bromo-6-[(2RS)-2-hydroxy-2-(3-methoxycarbonylphenyl)-ethyl]-pyridine in 4 ml of toluene is mixed under argon atmosphere at -70° C. with 0.88 ml of diisobutylaluminum hydride (20% in toluene) and-stirred for 3 hours at this temperature. The reaction mixture is mixed in succession at -70° C. with 0.3 ml of isopropanol and 0.3 ml of water and stirred overnight at room temperature. The precipitate is filtered off, the filtrate is dried on sodium sulfate and concentrated by evaporation. The crude product is dissolved in 3 ml of methanol, mixed with 82 mg of sodium borohydride and stirred overnight at room temperature. The reaction mixture is acidified to pH 1 with 2 n hydrochloric acid, shaken out with ethyl acetate, the organic phase is dried on sodium sulfate, concentrated by evaporation and the residue is chromatographed on silica gel with hexane/0-10% ethyl acetate. 103 mg of 2-bromo-6[(2RS)-2-hydroxy-2-(3-hydroxymethylphenyl)-ethyl]-pyridine is obtained as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH3:11])=[CH:4][C:3]=1[N+:13]([O-])=O.CC(O)C.Cl.[H][H]>[Pd].CO>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH2:13])[CH:4]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCC(=O)c1ccc(C)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: CCCCc1ccc(C)c(N)c1

Procedure:
A mixture of 34 parts of 1-(4-methyl-3-nitrophenyl)-1-butanone, 24 parts of 2-propanol saturated with hydrochloric acid and 400 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. Water is added to the residue and the whole is alkalized with ammonium hydroxide. The product is extracted with 2,2'-oxybispropane. The extract is dried, filtered and evaporated, yielding 25.5 parts of 5-butyl-2-methylbenzenamine as a residue.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([C:15](OC3C=CC([N+]([O-])=O)=CC=3)=[O:16])[C:13](=[O:27])[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)[C:11]3[CH2:38][CH2:39][C:40](=[O:41])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2].[NH2:42][CH2:43][C:44]([CH3:47])([OH:46])[CH3:45]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([C:15]([NH:42][CH2:43][C:44]([OH:46])([CH3:47])[CH3:45])=[O:16])[C:13](=[O:27])[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:35])[F:37])[CH:29]=3)[C:11]3[CH2:38][CH2:39][C:40](=[O:41])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(O)CN
Reactant: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CC#N
Product: CC(C)(O)CNC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-nitrophenyl 4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidine-3(2H)-carboxylate (intermediate 4, 250 mg, 0.44 mmol) in acetonitrile (5.0 mL) is treated with 1-amino-2-methylpropan-2-ol (80 mg, 0.90 mmol), and the mixture is stirred at room temperature for 1 h and purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 179 mg; ESI mass spectrum [M+H]+=513; Retention time HPLC: 0.86 min (Z011_803).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:9][CH2:10][NH:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19])=[O:13].C(Cl)Cl>CN(C=O)C>[O:19]=[C:15]1[CH2:16][CH2:17][CH2:18][N:14]1[C:12](=[O:13])[NH:11][CH2:10][CH2:9][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: O=C1CCCN1C(=O)NCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCCN1C(=O)NCCn1cncn1
Temperature: 90 °C
Yield: 55.6 %

Procedure:
To a solution of 1.9 g (27.5 mmol) of 1,2,4-triazole in 15 ml of DMF was added 1.1 g (27.5 mmol) of 60% NaH, and the mixture was heated at 90° C. for about 2 hr. Then, 13 ml of DMF containing 3.50 g (18.4 mmol) of 1-[(2-chloroethyl)carbamoyl]-2-oxopyrrolidine (III-1) was added to the mixture, which was heated at 90° C. for 4.5 hr. The reaction solution was poured into CH2Cl2, and the insoluble material was removed by filtration. After evaporating the solvent, the CH2Cl2 layer was refined by silica gel column chromatography, whereby 2.28 g (55.6%) of the objective compound (Ia-34) was obtained from the eluate with CH2Cl2 - methanol (20/1 v/v). The crystals melting at 106.0°-107.0° C. were obtained by recrystallizing from ethanol.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][N:4]=1.C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]([Cl:15])=[O:11])[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(C(=O)O)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSc1nccc(C(=O)Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a solution of 2-methylsulfanyl-pyrimidine-4-carboxylic acid (20 g, 117.7 mmol) in CH2Cl2 (100 mL) is added oxalyl chloride (17.2 g, 197 mmol) and DMF (20 drops). The reaction solution is stirred at room temperature for 18 hours after which the solvent is removed in vacuo to afford 21.2 g, (95% yield) of the desired product as a dark green solid.