Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl.[F:22][C:23]([F:38])([F:37])[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[NH2:36])[CH:25]=1.[N:39]1[N:40]([C:44]2[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=2[C:46](O)=[O:47])[N:41]=[CH:42][CH:43]=1>C(Cl)Cl>[N:39]1[N:40]([C:44]2[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=2[C:46]([NH:36][CH:32]2[CH2:33][CH2:34][CH2:35][CH:31]2[CH2:30][C:26]2[CH:25]=[C:24]([C:23]([F:22])([F:37])[F:38])[CH:29]=[CH:28][N:27]=2)=[O:47])[N:41]=[CH:42][CH:43]=1
Reactant: O=C(O)c1ccccc1-n1nccn1
Reactant: NC1CCCC1Cc1cc(C(F)(F)F)ccn1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCCC1Cc1cc(C(F)(F)F)ccn1)c1ccccc1-n1nccn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Triethylamine (0.099 ml, 0.71 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.039 g, 0.29 mmol) and EDC (0.055 g, 0.29 mmol) were added to a solution 2-{[4-(trifluoromethyl)pyridin-2-yl]methyl}cyclopentan-1-amine (Intermediate 12; 0.058 g, 0.24 mmol) and 2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1001401-62-2; 0.054 g, 0.29 mmol) in DCM (3 ml). The reaction was stirred at room temperature for 24 hours and then diluted with DCM (40 ml) and washed with a saturated solution of sodium bicarbonate (10 ml). The organics were dried over magnesium sulfate, filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-80% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][NH:6][C:7](=[O:29])[CH2:8][CH2:9][CH2:10][C:11]1[O:15][C:14]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH3:21])=[N:13][C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1>CN(C)C=O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:12]2[N:13]=[C:14]([N:16]3[CH:20]=[CH:19][N:18]=[C:17]3[CH3:21])[O:15][C:11]=2[CH2:10][CH2:9][CH2:8][C:7]2[O:29][CH2:4][CH2:5][N:6]=2)=[CH:23][CH:24]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCC(=O)NCCCl)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCC2=NCCO2)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
Sodium hydride (60%, oil, 130 mg) was gradually added to a N,N-dimethylformamide solution (30 ml) of N-(2-chloroethyl)-4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutyramide (870 mg) at room temperature. After stirring for 4 hours at room temperature, the reaction mixture was poured into ice water. And this was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-oxazolin-2-yl)propyl]oxazole (615 mg, 78%) was obtained by evaporating the solvent. This was recrystallized from acetone-isopropyl ether to give colorless prisms. mp 88-89° C.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[N:12]O)[CH2:4][CH2:3]1.C(=O)([O-])[O-:15].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][CH:2]1[C:11]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:5](=[O:15])[CH2:4][CH2:3]1
Reactant: CC1CCC(=NO)c2ccccc21
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1CCC(=O)Nc2ccccc21
Temperature: 120 °C
Yield: 84 %

Procedure:
A mixture of 800 mg (4.57 mmol) of 4-methyl-1-tetralone oxime and 4.0 g of polyphosphoric acid was heated at 120° C. in an oil bath for 20 minutes. The dark brown mixture was cooled to 80° C. and poured into ice water. The solution was neutralized by the addition of 10% aqueous sodium carbonate then extracted chloroform (3×50 mL). The combined extracts were washed with water, dried over magnesium sulfate and filtered. Evaporation of the solvent followed by column chromatography on silica gave the product as an off-white solid (670 mg, 84%). 1H NMR (200 MHz, CDCl3): 1.30 (d, 8 Hz, 3H), 1.68 (m, 1H), 2.30 (m, 3H), 3.11 (m, 1H), 6.98 (m, 1H), 7.15-7.30 (m, 3H), 8.55 (br s, 1H). 13C NMR: 18.22, 32.89, 32.98, 37.28, 121.95, 125.67, 125.93, 126.98, 137.69, 137.80, 176.04.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH2:3]1.[H][H].CC(=CCCC(CCO)C)C.CC(=CCCC(CC=O)C)C>>[CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: [H][H]
Agent: CC(C)=CCCC(C)CC=O
Agent: CC(C)=CCCC(C)CCO
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Temperature: 80 °C

Procedure:
Example 1 was repeated using L-isopulegol with a purity of 97.1% and 84% ee, which was introduced at a rate of 24.5 g/h (total amount 466 g) into the reactor at a hydrogen pressure of 40 bar. The main reactor (MR) was heated to 80° C., the postreactor to 70° C. The L-isopulegol used had the following composition: L-isopulegol: 97.1 GC % by weight, citronellol: 0.05 GC % by weight, citronellal: 0.40 GC % by weight, isopulegol isomer: 0.45 GC % by weight, secondary components: 0.34 GC % by weight. L-menthol (84% ee) was obtained in an amount of 468 g, corresponding to a rate of 24.6 g/h. The chemical purity of the L-menthol output is shown in Table 3.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(O[CH:17](OCC)[CH2:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH3:27])[CH:21]=1)C>FC(F)(F)C(O)=O>[CH2:26]([C:22]1[CH:21]=[C:20]2[C:25]([CH:17]=[CH:18][NH:19]2)=[CH:24][CH:23]=1)[CH3:27]
Reactant: CCOC(CNc1cccc(CC)c1)OCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc2cc[nH]c2c1
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
To a solution of trifluoroacetic anhydride (45 mL) in trifluoroacetic acid (45 mL) at 4° C. under N2 was added (2,2-diethoxyethyl)-(3-ethylphenyl)amine (11.47 g, 48.36 mmol). After stirring for 30 min, the cold mixture was diluted with trifluoroacetic acid (60 mL). The mixture was stirred at reflux for 2.5 d, concentrated and extracted with methylene chloride (3×100 mL). The combined organic layers were washed with saturated NaHCO3 (3×60 mL), saturated NaCl (60 mL), dried (MgSO4) and concentrated. Flash chromatography (SiO2, 25% EtOAc/hexanes) gave the title compound (1.6 g, 23%) as a brown crystalline solid. 1H NMR (CDCl3) δ 8.03 (bs, 1H), 7.57 (m, 1H), 7.18 (s, 1H), 7.12 (m, 1H), 6.68 (m, 1H), 6.46 (m, 1H), 2.73 (m, 2H), 1.26 (m, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Clc1cc(Cl)cc(OCc2ccccc2)c1
Temperature: 45 °C

Procedure:
To a stirred mixture of 3,5-dichlorophenol (3.00 g, 18.4 mmol) and Cs2CO3 (12.0 g, 36.8 mmol) in dry, degassed DMF (150 mL) was added benzyl bromide (3.46 g, 20.2 mmol) dropwise. The reaction mixture was heated to 45° C. for 18 hours, then the solvent was removed under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 (75 mL) and CH2Cl2 (100 mL). The aqueous layer was extracted further with CH2Cl2 (25 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with hexane—2% EtOAc to yield the desired product as a colorless oil.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[C:19]1([NH:25][C:26]2[C:27]([NH2:32])=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O.C(O)(=O)C>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]3[N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[N:32]=3)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3ccccc3n2-c2ccccc2)[nH]1
Yield: 51.7 %

Procedure:
The product is prepared according to the procedure described in Example 3, using 300 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 423 mg of N-phenylbenzene-1,2-diamine and 330 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 2.5 ml of pyridine and 2.5 ml of dimethylformamide and then in 5 ml of acetic acid. After purification by silica column chromatography, eluent: CH2Cl2/MeOH: 95/05, 230 mg of 6-(morpholin-4-yl)-2-[(1-phenyl-1H-benzimidazol-2-yl)methyl]pyrimidin-4(3H)-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>ClCCl>[CH3:8][C:3]([CH3:9])([CH:2]=[O:1])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C)(C)CO
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Product: COC(=O)C(C)(C)C=O
Temperature: 2.5 °C
Yield: 510.9 %

Procedure:
Methyl 3-hydroxy-2,2-dimethyl-propanoate (25.4 kg, 192.2 mol) and dichloromethane (241 L) are combined under a nitrogen atmosphere at RT with stirring. (2,2,6,6-Tetramethyl-piperidin-1-yl)oxyl (0.61 kg, 3.9 mol) is added and the reaction mixture is cooled to 0-5° C. Trichloroisocyanuric acid (31.2 kg, 134.5 mol) is added portionwise at 0-5° C. and the reaction mixture is stirred for 16-18 h at this temperature. The reaction is filtered and the filtercake is washed with dichloromethane (25.4 L) and the filtrate concentrated under reduced pressure below 50° C. 1,4-Dioxane (25.4 L) is added and the organic phase is concentrated under reduced pressure below 65° C. to obtain the title compound as a yellow liquid (127.8 kg, 77%) that is used without further purification.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[O:12][CH:13]=2)O1.Br[C:22]1[N:27]=[C:26]([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:11]2[O:12][CH:13]=[C:9]([C:22]3[N:27]=[C:26]([C:28]4[N:29]=[CH:30][CH:31]=[CH:32][N:33]=4)[CH:25]=[CH:24][CH:23]=3)[CH:10]=2)[CH:15]=1
Reactant: CC1(C)OB(c2coc(-c3cccnc3)c2)OC1(C)C
Reactant: Brc1cccc(-c2ncccn2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: c1cnc(-c2cccc(-c3coc(-c4cccnc4)c3)n2)nc1
Yield: 49.7 %

Procedure:
400 mg (1.38 mmol) of 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-furyl]pyridine and 347 mg (1.38 mmol) of 2-(6-bromopyridin-2-yl)pyrimidine were initially charged in 20 ml of dioxane, and 3.46 ml of a 2 molar aqueous sodium carbonate solution were added. The reaction mixture was degassed in an ultrasonic bath under argon and then heated to reflux temperature, and, at 80° C., 48.0 mg (42.0 μmol) of tetrakis(triphenylphosphine)palladium(0) were added. The reaction mixture was stirred under reflux for 8 hours and then at room temperature overnight. The mixture was then poured into 100 ml of water and extracted with dichloromethane. The light-yellow organic phases were combined, washed with 100 ml of water and then dried over MgSO4. The mixture was then filtered and concentrated under reduced pressure on a rotary evaporator. Chromatographic purification gave 206 mg (50% of theory) of 2-{6-[5-(pyridin-3-yl)-3-furyl]pyridin-2-yl}pyrimidine.
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[N:13]1([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C@H:29]3[CH2:34][CH2:33][C@H:32]([CH2:35][OH:36])[CH2:31][CH2:30]3)[N:23]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1.O.CCOC(C)=O>CS(C)=O>[N:13]1([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH:29]3[CH2:30][CH2:31][CH:32]([CH:35]=[O:36])[CH2:33][CH2:34]3)[N:23]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1
Reactant: OC[C@H]1CC[C@H](Nc2nccc(-n3nnc4ccccc43)n2)CC1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=CC1CCC(Nc2nccc(-n3nnc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 71.2 %

Procedure:
Iodoxybenzoic acid (830 mg, 2.96 mmol) was added to a solution of trans-[4-(4-benzo-triazol-1-yl-pyrimidin-2-ylamino)-cyclohexyl]-methanol (640 mg, 1.97 mmol) in DMSO (10 mL) and the resulting mixture was stirred at RT for 23 hours. An additional aliquot of o-iodoxy-benzoic acid (830 mg, 2.96 mmol) was then added. After a few hours, the reaction was stopped. Water was added and the resulting mixture was stirred for 20 minutes, the solid formed was filtered and the filtrate was extracted 3 times with EtOAc. The combined organic extracts were washed once with water, dried over Na2SO4 and filtered; the solvent was evaporated under reduced pressure. The white solid formed was washed several times with EtOAc and it was combined with the previous obtained solid to give 789 mg of crude residue. This crude material was purified via flash chromatography (heptane/EtOAc, with a gradient from 20% to 50% of EtOAc) to give 452 mg (70% yield) of 4-(4-benzotriazol-1-yl-pyrimidin-2-ylamino)-cyclo-hexanecarbaldehyde.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[C:10]1([C:16]2[CH:17]=[CH:18][C:19]3[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]4([CH3:29])[CH2:28][O:27]4)[C:20]=3[CH:30]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[N:3]([CH2:28][C:26]2([CH3:29])[O:27][C:22](=[O:24])[N:21]([C:20]3[CH:30]=[C:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:17]=[CH:18][C:19]=3[OH:23])[CH2:25]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: CC1(Cn2c(=O)oc3ccc(-c4ccccc4)cc32)CO1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1(Cn2cc([N+](=O)[O-])nc2Cl)CN(c2cc(-c3ccccc3)ccc2O)C(=O)O1
Yield: 48.3 %

Procedure:
A mixture of 2-chloro-4-nitro-1H-imidazole (1.3 g, 8.78 mmol), 5-phenyl-3-(2-methyloxiran-2-yl-methyl)-3H-benzoxazol-2-one (2.47 g, 8.78 mmol), sodium acetate (792 mg, 9.66 mmol) and ethanol (30 ml) was stirred under reflux for 10 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. To the residue, water was added, and the resulting solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=10/1) to afford 5-(2-chloro-4-nitroimidazol-1-ylmethyl)-3-(4-hydroxybiphenyl-3-yl)-5-methyloxazolidin-2-one (1.82 g, yield 61%) as a white powder.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:35]([O:37][CH3:38])=[O:36])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[C:25]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:19]=2[O:18][CH2:17][C@H:16]([NH:33][CH3:34])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:40][CH2:41][NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46]>>[C:45]([O:44][C:43]([NH:42][CH2:41][CH2:40][N:33]([CH3:34])[C@@H:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:35]([O:37][CH3:38])=[O:36])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:21]2[C:20]2[CH:22]=[CH:23][CH:24]=[C:25]([CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:19]=2[O:18][CH2:17]1)=[O:49])([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: CN[C@H]1COc2c(CN3CCCCC3)cccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCNC(=O)OC(C)(C)C)COc1c(CN2CCCCC2)cccc1-3

Procedure:
The compound was prepared in analogy to Example 1, Step 6 from methyl (7R)-14-cyclohexyl-7-(methylamino)-4-(piperidin-1-ylmethyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate and tert-butyl (2-oxoethyl)carbamate. The compound was used without further purification. (ES+) m/z 659 (M+H)+.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][N:8]([C:11]2([O:37][CH2:36][C@H:23]([O:24][CH2:25][P:26]([O:32][CH:33]([CH3:35])[CH3:34])([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[C@H:13]2[O:14]C(=O)C2C=CC=CC=2)[OH:12])[C:7](=[O:38])[N:6]=1)(=O)C.N>CO>[N:8]1([C:11]2([O:37][CH2:36][C@H:23]([O:24][CH2:25][P:26]([O:28][CH:29]([CH3:31])[CH3:30])([O:32][CH:33]([CH3:34])[CH3:35])=[O:27])[C@H:13]2[OH:14])[OH:12])[CH:9]=[CH:10][C:5]([NH2:4])=[N:6][C:7]1=[O:38]
Reactant: CC(=O)Nc1ccn(C2(O)OC[C@H](OCP(=O)(OC(C)C)OC(C)C)[C@H]2OC(=O)c2ccccc2)c(=O)n1
Agent: N
Solvent: CO
Product: CC(C)OP(=O)(CO[C@H]1COC(O)(n2ccc(N)nc2=O)[C@@H]1O)OC(C)C
Yield: 85.7 %

Procedure:
A solution of 14 (450 mg, 0.84 mmol) in MeOH saturated with ammonia (100 mL) was stirred at room temperature overnight. The mixture was concentrated, and the residue was purified by column chromatography (CH2Cl2:MeOH=20:1) to give compound 18 (281 mg, 0.72 mmol) as a white powder in 86% yield which was characterized as follows:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.[OH-].[Na+].CN(C)[CH:20]=[O:21]>O>[Cl:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([CH:20]=[O:21])=[CH:10][NH:11]2
Reactant: CN(C)C=O
Reactant: Clc1cccc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1c[nH]c2cccc(Cl)c12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
During a period of five minutes 2.3 grams (0.015 mole) of phosphorus oxychloride was added dropwise to 10 mL of N,N-dimethylformamide. The solution was stirred for 30 minutes and then cooled in an ice bath. To this was added dropwise a solution of 2.0 grams (0.013 mole) of 4-chloroindole in 3 mL of N,N-dimethylformamide. Upon completion of the addition the ice bath was removed, and the reaction mixture was warmed to ambient tempeature, where it stirred for 1.5 hours. After this time the reaction mixture was warmed to 40° C., where it was stirred for 30 minutes, and then poured onto 50 grams of ice. A solution of 5.9 grams (0.146 mole) of sodium hydroxide in 20 mL of water was added during a 2-3 minute period, after which the mixture was heated to reflux and then cooled to ambient temperature. The cooled mixture was poured into 500 mL of water, stirred at ambient temperature for about 18 hours, and then filtered to collect a solid that had precipitated. The solid was washed with three portions of water and then dissolved in ethyl acetate. The ethyl acetate solution was subjected to column chromatography on silica gel with 1:1 ethyl acetate:hexane as eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 1.4 grams of 4-chloro-3-formylindole. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)O1>>[CH3:15][C:13]1([CH3:16])[CH2:14][CH:9]([NH:8][C:4]2[N:3]=[C:2]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:7]=[CH:6][N:5]=2)[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12]1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Product: CC1(C)CC(Nc2nccc(-c3ccc(S(N)(=O)=O)cc3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide according to Method C (Example 178). Yield: 443 mg (86%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][CH2:5]O>[Pd]>[CH3:1][N:2]([CH3:1])[C@@H:3]1[CH2:4][CH2:5][CH2:5][CH2:4][C@H:3]1[NH2:2]
Reactant: CNC
Reactant: CCO
Agent: [Pd]
Product: CN(C)[C@@H]1CCCC[C@H]1N
Reaction time: 19 h

Procedure:
A solution of the benzylamino compound was hydrogenated in two batches each containing 30.5 g. (0.131 mole), 175 ml. EtOH, 3.4 g Pd-C and 56.5 g. (0.394 mole) of 70% HClO4, at initial pressure of 51.5 p.s.i. for 19 hours. The two batches were combined, filtered through Celite and evaporated in vacuo at 45°. The residue was cooled in ice, basified with 40% KOH to pH 11. The resulting thick suspension was extracted with ether (5×200ml), the ether extract was dried (MgSO4) and evaporated through a 9" Vigreux. The residue was distilled at 13 mm to give 32.5 g. (87% yield), b.p. 77-78.5°. Vpc 100% at 3.8 mm. ir and nmr was identical to those of the sample prepared by the reaction of 7-aza-bicyclo[3.1.0]heptane with dimethylamine.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[CH:14]1([CH2:17][NH2:18])[CH2:16][CH2:15]1>C(O)C>[CH:14]1([CH2:17][NH:18][CH2:2][C:3]2[NH:4][C:5](=[O:13])[C:6]3[CH2:12][O:11][CH2:10][CH2:9][C:7]=3[N:8]=2)[CH2:16][CH2:15]1
Reactant: NCC1CC1
Reactant: O=c1[nH]c(CCl)nc2c1COCC2
Solvent: CCO
Product: O=c1[nH]c(CNCC2CC2)nc2c1COCC2
Temperature: 45 °C
Yield: 46.2 %

Procedure:
To a solution of 2-chloromethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (1.0 g, 4.98 mmol) in ethanol (30 mL) was added cyclopropylmethylamine (2.13 g, 29.9 mmol). The mixture was then heated at 45° C. for 60 hours. The reaction was then stopped and the mixture was concentrated under high vacuum for 24 h. The remaining semi-solid was subjected to column chromatography (Silica gel, 0-10% methanol in dichloromethane) to give 2-[(cyclopropylmethyl-amino)-methyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one as a light brown solid (540 mg, 2.30 mmol, 46% yield) that was directly used in the next step. m/z=236.4 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[CH:12]=[O:13].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][C:16]=1O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]1[O:13][C:16]2[CH:17]=[C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:20][C:15]=2[N:14]=1
Reactant: Cn1cc(C=O)c2cc(F)ccc21
Reactant: COC(=O)Cc1ccc(N)c(O)c1
Solvent: CCO
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc2nc(-c3cn(C)c4ccc(F)cc34)oc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.4 %

Procedure:
In ethanol (25 ml), 5-fluoro-1-methylindole-3-carbaldehyde (989 mg, 5.58 mmol) and methyl 4-amino-3-hydroxyphenylacetate (1.27 g, 6.99 mmol) were stirred at room temperature for 9 hours. Iodobenzene diacetate (2.16 g, 6.69 mmol) was added and the mixture was stirred further at room temperature for 18 hours. The reaction mixture was distilled under reduced pressure to remove the solvent. The residue thus obtained was purified by chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (1:2, v/v) eluate fractions, a mixture (933 mg) of methyl (2-(5-fluoro-1-methyl-3-indolyl)-6-benzoxazolyl)acetate and 5-fluoro-1-methylindole-3-carboxaldehyde was obtained as a red solid.