Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][C:7]=1[C:22]1[NH:23][C:24](=[O:35])[C:25]2[N:30]([CH3:31])[N:29]=[C:28]([CH2:32][CH2:33][CH3:34])[C:26]=2[N:27]=1.C(=O)([O-])[O-].[K+].[K+].CO>CC(=O)CC.CC(C)=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)(=[O:13])=[O:14])=[CH:8][C:7]=1[C:22]1[NH:23][C:24](=[O:35])[C:25]2[N:30]([CH3:31])[N:29]=[C:28]([CH2:32][CH2:33][CH3:34])[C:26]=2[N:27]=1)[CH:2]=[CH2:3]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3O)nc12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCC(C)=O
Solvent: CO
Product: C=CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 9.8 %

Procedure:
Allyl bromide (0.02 ml, 0.00023 mol) was added to a stirred suspension of 5-[2-hydroxy-5-(4-methylpiperazinylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (0.103 g, 0.00023 mol) and potassium carbonate (0.032 g, 0.00023 mol) in 2-butanone (10 ml) and the mixture heated under reflux for 8 hours. After cooling, the reaction mixture was evaporated under vacuum and the residue suspended in water (20 ml). The aqueous suspension was extracted with ethyl acetate (3×20 ml), the combined extracts dried (Na2SO4) and, after filtration, evaporated under vacuum to give an oil. Column chromatography on silica gel (2 g) using a methanol in. dichloromethane elution gradient (0-3%), followed by evaporation under vacuum of appropriate fractions, gave a semi-solid which was dissolved in acetone; evaporation under vacuum of the solution gave the title compound (0.011 g, 10%), m.p. 151°-153° C., Rf 0.5 (silica; dichloromethane, methanol; 95:5), m/e 487 (M+ +1).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].[CH2:12]([N:14]([CH2:18][CH3:19])[C:15](Cl)=[O:16])[CH3:13]>CC(N(C)C)=O>[CH2:12]([N:14]([CH2:18][CH3:19])[C:15]([N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])=[O:16])[CH3:13]
Reactant: CCN(CC)C(=O)Cl
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCN(CC)C(=O)n1cc(F)c(=O)[nH]c1=O
Temperature: 30 °C
Reaction time: 5 h
Yield: 75.5 %

Procedure:
1.3 g. (0.01 mole) of 5-fluorouracil was dissolved in 20 ml. of dimethyl acetamide and then 0.48 g. (0.01 mole) of 50% sodium hydride was added thereto. Subsequently, 1.36 g. (0.01 mole) of N,N-diethylcarbamoyl chloride in 5 ml. of dimethyl acetamide was added dropwise at 30° C. After stirring at 30° C. for 5 hours, the reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was filtered and the resultant filtrate was evaporated under reduced pressure. The residue obtained was extracted with 30 ml. of chloroform and the extract was concentrated to dryness to give 2.14 g. of crude product. The product was washed with diethyl ether and 1.73 g. (75.5% yield) of 1-(N,N-diethylcarbamoyl)-5-fluorouracil melting at 157°-160° C. was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[O:7][C:6]1=[O:17].[O-:18][CH2:19][CH3:20].[K+].CCOCC.O>CN1CCCC1=O>[CH2:19]([O:18][C:6]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[O:7][CH2:2][CH2:3][CH2:4]1)=[O:17])[CH3:20]
Reactant: CC[O-]
Reactant: O=c1oc2cc([N+](=O)[O-])ccc2n1CCCCl
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)N1CCCOc2cc([N+](=O)[O-])ccc21
Reaction time: 24 h
Yield: 50.4 %

Procedure:
3-(3-Chloro-propyl)-6-nitro-3H-benzoxazol-2-one (5.08 g, 19.8 mmol) and Potassium Ethoxide (1.80 g, 21.4 mmol) in N-Methylpyrrolidinone (60 mL) was stirred at room temperature under an atmosphere of Nitrogen. At 24 h, an additional aliquot of Potassium Ethoxide (0.91 g, 11 mmol) was added. After stirring overnight, the solution was poured into ether (100 mL) and water (50 mL), separated and extracted 2×100 mL ether. The organic extracts were washed with water (2×50 mL) and brine (50 mL), dried and conc. in vacuo. The residue was powdered onto silica gel and chromatographed (ISCO, 0-30% EtOAc:Hex) to afford 3-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester as a yellow solid (2.657 g, 50%). 1H-NMR (CDCl3): 7.84 (m, 2H), 7.45 (s, 1H), 4.29 (m, 4H), 3.85 (m, 2H), 2.14 (m, 2H), 1.26 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]2[N:30]=[CH:29][NH:28][N:27]=2)=[C:4]([NH:7][C:8](=[O:25])[CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:24])[S:5][CH:6]=1.[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39]O)[CH2:33][CH2:32]1>>[Cl:1][C:2]1[C:3]([C:26]2[N:30]=[CH:29][N:28]([CH2:39][CH2:38][CH2:37][N:34]3[CH2:35][CH2:36][O:31][CH2:32][CH2:33]3)[N:27]=2)=[C:4]([NH:7][C:8](=[O:25])[CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:24])[S:5][CH:6]=1
Reactant: OCCCN1CCOCC1
Reactant: O=C(Cn1c(=O)ccc2cc(C(F)(F)F)ccc21)Nc1scc(Cl)c1-c1nc[nH]n1
Product: O=C(Cn1c(=O)ccc2cc(C(F)(F)F)ccc21)Nc1scc(Cl)c1-c1ncn(CCCN2CCOCC2)n1

Procedure:
The title compound was prepared from N-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide (110 mg, 242 umol) and 3-morpholinopropan-1-ol (350 mg, 2.41 mmol) using the procedure described in Example 1.76. HPLC purification gave N-(4-chloro-3-(1-(3-morpholinopropyl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide. Method [7] Retention time 4.58 min by HPLC (M+=581 and 583) and (M+Na=603 and 605). 1H NMR (300 MHz, DMSO-d6) δ 12.10 (s, 1H), 8.47 (s, 1H), 8.26 (s, 1H), 8.20 (d, J=9.3 Hz, 1H), 7.91 (d, J=7.2 Hz, 1H), 7.70 (d, J=9.3 Hz, 1H), 7.16 (s, 1H), 6.86 (d, J=9.3 Hz, 1H), 5.30 (s, 2H), 4.30 (t, J=7.2 Hz, 2H), 3.20 (broad m, 10H), 1.20 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Cl)[CH:6]=[CH:7][CH:8]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=1.P>C1(C)C=CC=CC=1.C(Cl)C=CC1C=CC=CC=1.[Pd]>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH2:18][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:13][CH:12]=1
Reactant: COc1cccc(Cl)c1
Reactant: CC(=O)c1ccc(F)cc1
Agent: [Pd]
Agent: ClCC=Cc1ccccc1
Agent: P
Solvent: Cc1ccccc1
Product: COc1cccc(CC(=O)c2ccc(F)cc2)c1
Yield: 75.9 %

Procedure:
This reaction is carried out in the same manner as the reaction in example 3. The difference is that, the reactants are m-methoxyphenyl chloride (143.7 mg, 1.0 mmol), 1-(4′-fluorophenyl)ethanone (347.2 mg, 2.5 mmol), palladium cinnamyl chloride (7.8 mg, 0.015 mmol), 2-Methoxy-6-(N-methyl-N-phenyl-amino)phenyldicyclohexyl)phosphine (18.4 mg, 0.045 mmol), K3PO43H2O (664.2 mg, 2.5 mmol) in 3 mL dry toluene at 110° C. for 22.8 h. 1-(4′-Fluorophenyl)-2-(3′-methoxyphenyl)-1-ethanone (185.5 mg) was obtained with a yield of 75% as liquid. 1H NMR (300 MHz, CDCl3) δ 8.05-7.98 (m, 2H, ArH), 7.27-7.18 (m, 1H, ArH), 7.12-7.04 (m, 2H, ArH), 6.86-6.75 (m, 3H, ArH), 4.20 (s, 2H, CH2), 3.75 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3) δ 195.8, 167.2, 163.9, 159.7, 135.7, 132.8, 132.7, 131.2, 131.1, 129.6, 121.6, 115.7, 115.4, 115.0, 112.2, 55.0, 45.4; 19F NMR (282 MHz, CDCl3) 6-104.9; IR (neat) v (cm−1) 3072, 3002, 2940, 2836, 1682, 1597, 1506, 1491, 1455, 1437, 1331, 1264, 1232, 1157, 1099, 1050, 1002; MS (70 eV, EI) m/z (%): 245 (M++1, 3.27), 244 (M+, 17.36), 123 (100).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:4]1[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]1
Reactant: COC(=O)c1c[nH]nc1C
Reactant: OB(O)c1ccccc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: COC(=O)c1cn(-c2ccccc2Cl)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
Methyl 3-methyl-1H-pyrazole-4-carboxylate (4.5 g) synthesized in Example 1(3) was dissolved in N,N-dimethylacetamide (100 mL), 2-chlorophenylboronic acid (10.0 g), copper acetate (11.7 g) and pyridine (10.4 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (100 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (2.0 g, 25%) as a pale-yellow oil.
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[C:8]3=[C:11]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[C:26][Si](C)(C)C)=[CH:21][C:20]=4[F:31])[N:12]([CH3:17])[C:13](=[O:16])[C:14]([CH3:15])=[C:7]3[N:6]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:41])[CH3:40])[CH:35]=[CH:36][CH:37]=3)[C:5]2=[O:42])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CO.CN(C)C=O.Cl>O>[CH:1]1([N:4]2[C:9](=[O:10])[C:8]3=[C:11]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[CH:26])=[CH:21][C:20]=4[F:31])[N:12]([CH3:17])[C:13](=[O:16])[C:14]([CH3:15])=[C:7]3[N:6]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:41])[CH3:40])[CH:35]=[CH:36][CH:37]=3)[C:5]2=[O:42])[CH2:2][CH2:3]1
Reactant: CC(=O)Nc1cccc(-n2c(=O)n(C3CC3)c(=O)c3c(Nc4ccc(C#C[Si](C)(C)C)cc4F)n(C)c(=O)c(C)c32)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: C#Cc1ccc(Nc2c3c(=O)n(C4CC4)c(=O)n(-c4cccc(NC(C)=O)c4)c3c(C)c(=O)n2C)c(F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
To N-{3-[3-cyclopropyl-5-(2-fluoro-4-trimethylsilanylethynylphenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide 61 (1.00 g) obtained in Step 2 and potassium carbonate (236 mg) was added methanol/N,N-dimethylformamide [1:1 (volume ratio), 10.0 ml], and the mixture was stirred at room temperature for 20 hrs. The mixture was neutralized with 2N hydrochloric acid, water (10.0 ml) was added, and the mixture was stirred at room temperature for 1 hr. The crystals were collected by filtration and dried to give N-{3-[3-cyclopropyl-5-(4-ethynyl-2-fluorophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide 62 (815 mg, yield 93%) as pale-yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=1)[CH2:16][CH2:17][CH3:18]
Reactant: COC(=O)C=Cc1ccc(O)cc1
Reactant: CCCCBr
Product: CCCCOc1ccc(C=CC(=O)OC)cc1

Procedure:
Methyl 4-butoxycinnamate was prepared according to the method of Example 1, part a, except using methyl 4-hydroxycinnamate instead of 4-hydroxyacetophenone and using 1-bromobutane instead of benzylbromide.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:6]=1[NH:15][C:16](=[O:30])[CH2:17][CH:18]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)[CH3:19])=[O:4].[OH-].[Na+]>CO>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:6]=1[NH:15][C:16](=[O:30])[CH2:17][CH:18]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)[CH3:19])([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(NC(C)=O)cc1NC(=O)CC(C)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)Nc1ccc(C(=O)O)c(NC(=O)CC(C)c2ccc3ccccc3c2)c1

Procedure:
Prepared analogously to Example 2 from 3-(naphth-2-yl)-butanoic acid-N-(2-methoxycarbonyl-5-acetylamino-phenyl)-amide and sodium hydroxide solution in methanol.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([NH2:22])=[N:18][C:19]=1[O:20][CH3:21].[H-].[Na+]>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([NH:22][C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[C:19]([O:20][CH3:21])[N:18]=2)[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: COc1ccc(N)nc1OC
Reactant: Clc1cc(Br)c2nccn2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Nc2cc(Cl)nn3ccnc23)nc1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.3 %

Procedure:
A mixture of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (2 g, 8.6 mmol) and 5,6-dimethoxypyridin-2-amine (1.39 g, 9.03 mmol) in DMF (72 ml) was cooled to 0° C. To the mixture was added sodium hydride (1.1 g, 27.5 mmol, 60% dispersion in mineral oil). The reaction was stirred for 10 min then warmed to room temperature. After 15 h the reaction was quenched with saturated sodium bicarbonate solution, and then diluted with water and EtOAc. An insoluble solid was filtered off. The filtrate was separated and the aqueous phase was washed with EtOAc. The combined organic extracts were concentrated in vacuo and the residue obtained was crystallized from methanol to give 6-chloro-N-(5,6-dimethoxypyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (2.4 g, 7.85 mmol, 91.2%) as light brown needles. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.26 (br. s., 1H) 7.95 (s, 1H) 7.81 (s, 1H) 7.55 (s, 1H) 7.15 (d, J=7.93 Hz, 1H) 6.58 (d, J=8.31 Hz, 1H) 4.12 (s, 3H) 3.89 (s, 3H); LC/MS: 305.9 [MH]+.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:18][C:19]([C@@H:21]([NH:28][C:29]([C@H:31]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:32][C:33]([O:35]CC)=O)=[O:30])[CH2:22][C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)=[O:20])[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=[CH2:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:45]>CO>[C:33]([CH2:32][C@@H:31]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:29]([NH:28][C@@H:21]([CH2:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1)[C:19]([NH:18][C@@H:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=[CH2:13])=[O:20])=[O:30])(=[O:35])[NH2:45]
Reactant: N
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)OCC)Cc1ccccc1)C(C)C
Solvent: CO
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(N)=O)Cc1ccccc1)C(C)C
Reaction time: 12 h
Yield: 66 %

Procedure:
A solution of 100 mg of ethyl (R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyrate in 30 ml of methanol was saturated with ammonia for 1-2 minutes and subsequently left to stand at room temperature for 12 hours. Thereafter, the solvent was removed under reduced pressure and the residue was chromatographed on silica gel with 10% methanol in methylene chloride as the eluting agent, to obtain 63 mg (66%) of (S)-α-[(R)-α-(carbamoylmethyl)hydrocinnam-amido]-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide as a resin. MS: 580 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].[NH4+].[OH-]>O>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)C(N)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a 1 L beaker, 3.3 g of DL-tert-butylglycine (0.025 mol) was dissolved into 300 ml of water and the pH adjusted to 7.5-8.0 using concentrated NH4OH. The solution was transferred to a jacketed vessel and maintained at 25° C. Polypropylene glycol (1 ml) was added, and the mixture was agitated at 600 rpm. Oxygen gas was sparged via a metal frit at a flow rate of 1 L/min. The dissolved oxygen in the mixture was monitored using a calibrated oxygen electrode described in previous examples. Two milliliters of Catazyme (Novozymes) were preheated to 50° C. for 5 min and added to the mixture. Twenty grams of D-amino acid oxidase (500 units) were added to the mixture. An additional 1 ml of Catazyme (similarly preheated) was added to the reaction hourly following D-amino acid oxidase addition. When the DO2 returned to the initial reading, a sample was taken to determine the e.e. of L-tert-butylglycine by HPLC analysis. When the e.e. of L-tert-butylglycine was demonstrated to be >99%, the solution was decanted into a 2 L beaker. The final concentrations of trimethylpyruvate and residual L-tert-butylglycine were determined by HPLC analysis. The enzymes in the solution were removed by heating the solution to 90° C. and adding Celite® before filtering through a sintered glass funnel. The filtrate of the reaction was used directly in a subsequent reduction step, and L-tert-butylglycine was isolated by concentration and crystallization using standard methods.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:3]=1.[CH3:17][C:18]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30]B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=1)([CH3:23])[C:19]([O:21][CH3:22])=[O:20].C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>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].O>[Cl:16][C:12]1[CH:11]=[C:10]([C:4]2[N:3]=[C:2]([CH2:30][C:27]3[CH:26]=[CH:25][C:24]([C:18]([CH3:17])([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:29][CH:28]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C(C)(C)c1ccc(CB2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc(Cc2ccc(C(C)(C)C(=O)OC)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
A 20-mL sealed tube, with stirrer bar, was charged with 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.303 g, 1.20 mol), methyl 2-methyl-2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)propanoate (0.420 g, 1.32 mmol), Pd(dppf)Cl2 (0.098 g, 0.12 mmol), and powdered Na2CO3 (0.380 g, 3.60 mmol). Dioxane (6 mL) and water (3 mL) were added. The resulting mixture was stirred under Ar at 90° C. for 2 h. After this time, the mixture was cooled to room temperature and filtered through celite washing with ethyl acetate until the filtrate was colorless. The filtrate was washed with saturated sodium chloride (3×25 mL) then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue (0.87 g) was purified by chromatography on silica using hexane/dichloromethane (10:0 to 8:2) as eluent to afford the title compound (0.47 g, 96%) as a colorless oil. MW=408.92. 1H NMR (CDCl3, 300 MHz) δ 8.50-8.47 (m, 1H), 8.40-8.35 (m, 1H), 7.46-7.37 (m, 2H), 7.31-7.24 (m, 4H), 6.87 (s, 1H), 4.10 (s, 2H), 3.65 (s, 3H), 2.77 (q, J=7.8 Hz, 2H), 1.57 (s, 6H), 1.32 (t, J=7.5 Hz, 3H); ESI MS m/z 409 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:11].[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[C:5]2[CH3:11]
Reactant: c1c[nH]cn1
Reactant: Cc1c[nH]c2ccc(Cl)cc12
Product: Cc1c(-n2ccnc2)[nH]c2ccc(Cl)cc12

Procedure:
Condensation of 5-chloro-3-methylindole with imidazole according to the procedure described in the previous examples gives 5-chloro-2-(1-imidazolyl)-3-methylindole, m.p. 212°-215°.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C:11](=O)[CH2:12][CH2:13][C:14]#[C:15][Si:16]([CH3:19])([CH3:18])[CH3:17]>>[Br:1][C:2]1[C:3]2[N:4]([CH:10]=[C:11]([CH2:12][CH2:13][C:14]#[C:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncccc1Br
Reactant: C[Si](C)(C)C#CCCC(=O)CBr
Product: C[Si](C)(C)C#CCCc1cn2cccc(Br)c2n1
Yield: 61.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 223(D), from 3-bromopyridin-2-amine (280 mg, 1.60 mmol) and 1-bromo-6-(trimethylsilyl)hex-5-yn-2-one (compound 223(C), 870 mg, 3.5 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 315 mg of 8-bromo-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 61%) as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:35])[N:14]([CH3:34])[C:15]([CH:28]([OH:33])[C:29]([O:31][CH3:32])=[O:30])=[C:16]([C:17]3[C:18]([CH3:27])=[C:19]4[C:24](=[CH:25][CH:26]=3)[O:23][CH2:22][CH2:21][CH2:20]4)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]2[C:13](=[O:35])[N:14]([CH3:34])[C:15]([CH:28]([O:33][C:2]([CH3:7])([CH3:3])[CH3:1])[C:29]([O:31][CH3:32])=[O:30])=[C:16]([C:17]3[C:18]([CH3:27])=[C:19]4[C:24](=[CH:25][CH:26]=3)[O:23][CH2:22][CH2:21][CH2:20]4)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(O)c1c(-c2ccc3c(c2C)CCCO3)c2ccn(Cc3ccccc3)c2c(=O)n1C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2ccn(Cc3ccccc3)c2c(=O)n1C
Temperature: 0 °C
Reaction time: 48 h
Yield: 103.7 %

Procedure:
A solution of 2-(1-benzyl-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-((tetrahydro-2H-pyran-2-yl)oxy)acetonitrile (1.8 g, 3.09 mmol) in Ethanol (50 mL) was treated with NaOH (25 mL, 144 mmol) and the mixture was heated at 140° C. in a sealed tube overnight. HCl (conc.) was added until pH<2 and then the mixture was extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was dissolved in Methanol (30 mL), cooled to 0° C. and then treated with TMS-diazomethane (6.19 mL, 12.38 mmol). The mixture was stirred for 2 hours and then concentrated. The resulting residue was dissolved in t-Butyl acetate (10 mL), treated with perchloric acid (0.186 mL, 3.09 mmol) and then stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate, washed with 1M NaOH, then brine. The organic phase was then dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (0-70% ethyl acetate/hexanes) to afford the title compound (280 mg) as well as methyl 2-(1-benzyl-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-hydroxyacetate (500 mg). An ice cold solution of methyl 2-(1-benzyl-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-hydroxyacetate (500 mg) in t-Butyl acetate (5 mL) was treated with perchloric acid (1 eq.) then kept at 0° C. for 2 days without stirring. The mixture was diluted with ethyl acetate, washed with 1M NaOH, then brine. The organic phase was then dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (0-70% ethyl acetate/hexanes) to afford the title compound (290 mg). The material from each purification was combined to give the title compound (570 mg, 34% yield). 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.37-7.29 (m, 5H), 7.15 (m, 1H), 7.02-6.91 (m, 1H), 6.74 (m, 1H), 5.99-5.67 (m, 3H), 5.28 (s, 0.7H), 5.10 (s, 0.3H), 4.27-4.15 (m, 2H), 3.77 (s, 2H), 3.73 (s, 1H), 3.67 (s, 3H), 2.77-2.58 (m, 2H), 2.17-2.03 (m, 2H), 1.92 (s, 3H), 1.12 (s, 3H), 0.97 (s, 6H); LC/MS (m/z) ES+=529 (M+1).