Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[F:9][C:10]1[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:12][C:13]([C:16]#[N:17])=[N:14][CH:15]=1>C(O)C>[F:9][C:10]1[C:11]([C:18]([F:21])([F:19])[F:20])=[CH:12][C:13]([C:16]([NH2:17])=[O:2])=[N:14][CH:15]=1
Reactant: O=C([O-])O
Reactant: N#Cc1cc(C(F)(F)F)c(F)cn1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cc(C(F)(F)F)c(F)cn1
Reaction time: 2 h
Yield: 60.9 %

Procedure:
To 12 ml of ethanol were added 1.01 g of sodium bicarbonate and 0.83 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.6 g of 5-fluoro-4-trifluoromethylpyridine-2-carbonitrile was added at 0° C., and the mixture was stirred for 2 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.4 g of 5-fluoro-4-trifluoromethylpyridine-2-carboxamide=oxime.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(Cl)(Cl)Cl.O>[OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:4]1
Reactant: CCOC(=O)Cl
Reactant: OCC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)N1CCCC(CO)C1
Temperature: 10 °C
Yield: 97.9 %

Procedure:
A mixture of 3-hydroxymethyl-piperidine (0.6 mol) and Na2CO3 (130 g) in CHCl3 (600 ml) and water (600 ml) was stirred at 10° C. Ethyl chloroformate (115 g) was added dropwise (temperature was kept at 10° C.). The mixture was stirred until the temperature reached room temperature and the reaction mixture was stirred overnight. Water (500 ml) was added. The organic layer was separated, washed with water, dried, filtered and the solvent was evaporated, yielding 110 g (98%) of (±)-ethyl 3-(hydroxymethyl)-1-piperidinecarboxylate (interm. 17).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C(C2C=CC([C:49]3[CH:54]=[CH:53][C:52]([C:55]#[N:56])=[CH:51][CH:50]=3)=CC=2)CC(OC)O1>>[CH2:1]([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:49]3[CH:54]=[CH:53][C:52]([C:55]#[N:56])=[CH:51][CH:50]=3)=[CH:33][CH:34]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1CC(c2ccc(-c3ccc(C#N)cc3)cc2)C(OC)O1
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccccc2)c1)C(C)(C)C
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)C(C)(C)C
Yield: 48 %

Procedure:
According to the procedure as described in Example 1(c) for N-(1,7-diaza-4-oxa-8-oxo-tricyclo-[9.6.1.0 12,17]-octadeca-11 (18),12,14,16-tetraen-9S-yl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)-sucinnamic acid benzyl ester, crude 3(R)-amino-N-(2,2-dimethyl-1(S)-methylcarbamoylpropyl)succinamic acid benzyl ester trifluoroacetate salt (prepared as described in Example 1(b)) and 4′-(2,5-dimethoxy-tetrahydrofuran-3-yl)-biphenyl-4-carbonitrile (prepared as described in Example 4(a)) were condensed to give 84 mg(48%) of 3(R)-[3-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid benzyl ester as a yellow solid, mp 120° C. 1H NMR (CDCl3): δ 7.72 (s, 4H), 7.59 (s, 4H), 7.32-7.28 (m, 2H), 7.26 (s, 3H), 7.12 (t, 1H, J=2.1 Hz), 6.82 (t, 1H, J=2.7 Hz), 6.61(dd, 1H, J=1.8, 3.0 Hz), 6.27 (d, 1H, J=9.0 Hz), 5.58 (m, 1H), 5.13 (s, 2H), 5.12 (m, 1H), 4.01 (d, 2H, 8.7 Hz), 3.41(dd, 1H, J=5.8, 16.7 Hz), 3.11(dd, 1H, 8.7, 16.8 Hz), 2.78 (d, 3H, J=5.0 Hz), 0.87 (s, 9H). IR (KBr): 2960, 2221, 1736, 1685, 1654, 1562, 1542 cm−1. HRFABMS: Calculated for C35H37N4O4 (M+H+): 577.2815. Found: 577.2832. Anal. Calculated for C35H36N4O4.0.2DMF 0.5 H2O: C, 71.23; H, 6.45; N, 9.80. Found: C, 71.14, H, 6.23; N, 10.19.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][O:11][C:12](=[O:33])[C@@H:13]([C@H:23](O)[C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25])[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH3:10][O:11][C:12](=[O:33])[C@@H:13]([C@@H:23]([F:7])[C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25])[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)[C@H](CCCc1ccccc1)[C@H](O)C(=O)N1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@H](CCCc1ccccc1)[C@@H](F)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
(Diethylamino) sulfur trifluoride (2.0 ml, 15.2 mmol) was added to a ice cold solution of (R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid methyl ester (4a) (0.85 g, 2.5 mmol) in dry methylene chloride (15 ml) and the reaction mixture was stirred overnight while warming to room temperature. The reaction was quenched with aqueous NaHCO3 solution and extracted with methylene chloride. The organic extracts were dried over Na2SO4 and concentrated under reduced pressure. Column chromatography on silica eluting with a mixture of ethyl acetate and methylene chloride gave the title compound as an off-white solid (230 mg). 1H NMR (CDCl3) δ 1.90–1.58 (m, 4H), 2.78–2.57 (m, 2H), 3.28–3.10 (m, 1H), 3.75 (s, 3H), 3.74–3.45 (m, 8H), 5.40–5.12 (m, 1H), 7.35–7.18 (m, 5H); MS: 338(MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][NH2:10])=[N:7][CH:8]=1)[CH3:2].[C:11]([CH2:14][C:15](=O)[CH3:16])(=O)[CH3:12].Cl.[OH-].[Na+]>O>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[C:15]([CH3:16])=[CH:14][C:11]([CH3:12])=[N:10]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(NN)nc1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cnc(-n2nc(C)cc2C)nc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 34.7 %

Procedure:
5-Ethyl-2-hydrazinopyrimidine (400 mg, 2.89 mmol) was suspended in 3 mL of water, and acetylacetone (314 μL, 3.04 mmol) and 2 mol/L hydrochloric acid (330 μL) were added thereto and stirred at room temperature for 23 hours. 2 mL of sodium hydroxide aqueous solution was added to the reaction mixture to adjust the pH to 12. The mixture was extracted with ethyl acetate three times, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10→10:90) and silica gel column chromatography (methylene chloride:methanol=100:0→95:5) to give 203 mg of the title compound (yield 35%).
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:13][C:14]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:15]=1[C:16](Cl)=[O:17].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C(O)C.C(Cl)(Cl)(Cl)Cl>[Cl:13][C:14]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:15]=1[C:16]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:17]
Reactant: O=C(Cl)c1cc(F)c(F)cc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Cl
Yield: 99.9 %

Procedure:
To 6.34 g of magnesium turnings, 13 cc of absolute ethanol and 1.2 ml of carbon tetrachloride were added, and the mixture was stirred. After the initiation of the reaction, a solution comprising 39.9 g of diethyl malonate, 22 cc of absolute ethanol and 75 cc of toluene was dropwise added thereto at a temperature of from 50° to 70° C. After the dropwise addition, the mixture was stirred for two hours. Then, the reaction solution was cooled to -10° to -5° C., and a solution comprising 50 g of 2-chloro-4,5-difluorobenzoyl chloride and 15 ml of toluene was dropwise added thereto. Then, the mixture was stirred for two hours. A dilute sulfuric acid aqueous solution cooled with ice was added thereto, and the content was dissolved, subjected to phase separation and extracted three times with 60 cc of toluene. The organic phase was washed with water, then dried over anhydrous magnesium sulfate and concentrated to obtain 79.2 g of the desired product as a slightly yellow oily substance.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][C@H:23]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]1>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][C@H:23]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](ON)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Yield: 99.9 %

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 553 mg, 2.00 mmol) of Example 9 or 16 and (S)-tert-butyl 3-(aminooxy)pyrrolidine-1-carboxylate (606 mg) described in Reference Example 24, 920.4 mg of the title compound was afforded (quantitative).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([O:16]CC)=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=[O:2].[OH-].[Na+:20]>C1COCC1.C(O)C>[CH:1]([C:3]1[CH:4]=[C:5]([C:14]([O-:16])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=[O:2].[Na+:20]
Reactant: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=Cc1cc(C(=O)[O-])c(=O)n2ccccc12
Reaction time: 4 h

Procedure:
To a solution of ethyl 1-formyl-4-oxo-4H-quinolizine-3-carboxylate (see Example 1, 10.1 g, 41.0 mmol) in a mixture of 137 mL of THF and 68 mL of ethanol was added aqueous sodium hydroxide (1N, 43.1 mL, 43.1 mmol). After 4 h, the reaction was concentrated in vacuo to provide sodium 1-formyl-4-oxo-4H-quinolizine-3-carboxylate that gave a mass ion (ES+) of 218.1 for [M+H]+.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].CCO[C:8]([CH2:10][C:11]#[N:12])=[O:9]>>[C:11]([CH2:10][C:8]([NH:4][CH2:1][C:2]#[CH:3])=[O:9])#[N:12]
Reactant: C#CCN
Reactant: CCOC(=O)CC#N
Product: C#CCNC(=O)CC#N
Yield: 94.2 %

Procedure:
A mixture of 15.4 ml (240 mmol) of propargyl amine and 17.1 ml (160 mmol) of ethyl cyano acetate was heated for 7 hours to 40° C. in a reaction flask. The crystalline material formed was heated for another 17 hours to 70° C. Then, the cooled reddish product was dried at high vacuum to yield 18.4 g (94%) of a red powder, m.p. 100-103° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:18][S:19]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:26][C:25]3[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:28][CH:27]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(S(C)(=O)=O)cc2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[(cyclopropylmethyl)(propyl)amino]pyrimidine-4-carboxylic acid (Intermediate 21) and 4-(methylsulfonyl)aniline (Enamine), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH:15]=[C:14]2[C:29]1[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH:34]=1.C(O)CC.C([O-])([O-])=O.[Na+].[Na+]>O.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>[CH3:35][N:32]1[CH2:33][CH:34]=[C:29]([C:14]2[C:13]3[C:17](=[CH:18][CH:19]=[C:11]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH:12]=3)[N:16]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:15]=2)[CH2:30][CH2:31]1
Reactant: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccc(Br)cc23)CC1
Reactant: OB(O)c1cccnc1
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: O
Solvent: CCCO
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccc(-c4ccncc4)cc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
Into a 100 mL 3-necked round bottom flask was placed pyridin-3-ylboronic acid (200 mg, 1.63 mmol), 5-bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-indole (470 mg, 1.08 mmol), and n-propanol (140 mL). The mixture was stirred at room temperature for 30 min during which time the solids dissolved. A solution of Na2CO3 (430 mg, 4.06 mmol) in water (5 mL) was then added, followed by the addition of Pd(PPh3)4 (130 mg, 0.108 mmol). The resulting solution was stirred at reflux temperature overnight, and then concentrated. The residue was dissolved in water (10 mL), and the resulting solution was extracted diethylether (2×50 mL). The organic layers were combined and the residue was purified by column chromatography using a 1:5 dichloromethane/methanol solvent system to afford 200 mg (42.5%) of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-5-(pyridin-4-yl)-1H-indole as a deep yellow solid. 1H NMR (CDCl3) δ 8.69 (d, 2H), 8.12 (d, 1H), 7.93 (t, 3H), 7.60 (d, 3H), 7.48 (d×d, 4H), 6.18 (s, 1H), 2.85 (2H), 1.52 (2H), 1.25 (3H), 0.87 (2H). LC/MS (EI) tR 2.18, m/z 430.0 (M++1)
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:8][CH2:7][CH2:6][N:5]2[CH:9]=[CH:10][N:11]=[C:4]12.Br[C:13]1[CH:14]=[CH:15][C:16]([F:28])=[C:17]([C:19]2[C:20]([C:26]#[N:27])=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH:18]=1.C([O-])(=O)C.[K+]>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:25][C:22]1[CH:21]=[C:20]([C:26]#[N:27])[C:19]([C:17]2[CH:18]=[C:13]([C:9]3[N:5]4[CH:6]=[CH:7][NH:8][C:3](=[O:2])[C:4]4=[N:11][CH:10]=3)[CH:14]=[CH:15][C:16]=2[F:28])=[CH:24][CH:23]=1
Reactant: N#Cc1cc(F)ccc1-c1cc(Br)ccc1F
Reactant: O=C1NCCn2ccnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(=O)N(C)C
Product: N#Cc1cc(F)ccc1-c1cc(-c2cnc3c(=O)[nH]ccn23)ccc1F
Temperature: 130 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
8-Oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine hydrochloride (87 mg, 0.53 mmol), prepared as described in Example 25, was reacted with 5′-bromo-4,2′-difluorobiphenyl-2-carbonitrile (prepared as described in WO 02/074773, 204 mg, 1.3 mol eq) in DMA (2 ml) in the presence of potassium acetate (280 mg, 1.5 mol eq), palladium acetate (6 mg, 5 mol %) and triphenylphosphine (7 mg, 5 mol %). After bubbling nitrogen through the reaction mixture for 10 min, the temperature was raised to 130° C. and heating continued for 3 h. After cooling, the crude reaction mixture was poured onto a column of silica and purified using 0-5% methanol in dichloromethane as eluent. Recrystallization from ethyl acetate/dichloromethane gave 4,2′-difluoro-5′-(8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-3-yl)biphenyl-2-carbonitrile (126 mg): δH (400 MHz, DMSO) 3.54-3.58 (2H, m), 4.28-4.32 (2H, m), 7.39 (1H, s), 7.54-7.59 (1H, m), 7.71-7.78 (4H, m), 8.05-8.08 (1H, m), 8.18 (1H, br s); m/z (ES+) 351 [M+H]+.
Reaction SMILES: [O-]S([O-])(=O)=O.[Na+].[Na+].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.[C:14]([OH:19])(=[O:18])[C:15]([OH:17])=[O:16].[OH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>CC(C)=O>[C:14]([OH:19])(=[O:18])[C:15]([OH:17])=[O:16].[O:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[O:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1
Reactant: C1=COCCC1
Reactant: OCCc1ccc(O)cc1
Agent: O=C(O)C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Oc1ccc(CCOC2CCCCO2)cc1

Procedure:
Alternatively, suitable 4-(hydroxyalkyl)phenols or 4-(hydroxyalkyl)thiophenols may be protected in one step by combining a solution of the selected 4-(hydroxyalkyl)phenol or 4-(hydroxyalkyl)thiophenol in acetone with Na2SO4, dihydropyran, and a catalytic amount of oxalic acid. For example, 4-(2-hydroxyethyl)phenol in acetone is reacted with Na2SO4, distilled dihydropyran, and a catalytic amount of oxalic acid for three hours to yield 4-(2-tetrahydropyran-2-yloxyethyl)phenol (9).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.FC(F)(F)S(O[C:16]1[C:17]2[CH2:37][N:36]([C:38](=[O:40])[CH3:39])[CH2:35][CH2:34][C:18]=2[N:19]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[O:33][CH:32]=[N:31][CH:30]=3)=[CH:25][CH:24]=2)[N:21]=1)(=O)=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O>>[N:1]1([C:16]2[C:17]3[CH2:37][N:36]([C:38](=[O:40])[CH3:39])[CH2:35][CH2:34][C:18]=3[N:19]=[C:20]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[O:33][CH:32]=[N:31][CH:30]=4)=[CH:27][CH:28]=3)[N:21]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCN2
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N3CCc4ccccc43)c2C1
Yield: 19.1 %

Procedure:
1-(4-(Indolin-1-yl)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (14.3 mg, 19.1%) was prepared from indoline and 6-acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (example 88a) according to the general procedure for amine substitution of tosylate on pyrimidines. MS (ES+) m/z 453.3 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH:15][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Sc1cnccn1
Product: CC(C)(C)OC(=O)N1CCC(Sc2cnccn2)CC1

Procedure:
By a similar manner to Reference Example 35, 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol) was reacted with mercaptopyrazine (0.67 g, 6.0 mmol) to give the titled compound as pale yellow oily substance (1.26 g, 85%).
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:5]2=[CH:6][CH:7]=[C:8]3[C:12]([NH:11][CH2:10][CH2:9]3)=[C:4]2[CH2:3]1.[C:22](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH3:22][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]3[CH:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[F:21])[CH2:14][N:2]([CH3:1])[CH2:3][C:4]3=2)[CH2:9][CH2:10]1
Reactant: CC(=O)O
Reactant: CN1Cc2c(ccc3c2NCC3)C(c2ccccc2F)C1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1Cc2c(ccc3c2N(C)CC3)C(c2ccccc2F)C1

Procedure:
2.3 g (0.00814 mol) of 8-methyl-6-(fluorophenyl)-2,3,6,7,8,9-hexahydro-1H-pyrido[4,3-g]indole are dissolved in 20 ml of MeOH, and 0.977 g (0.0163 mol) of acetic acid and 0.791 ml (0.00976 mol) of formalin are added at room temperature, with stirring. The reaction mixture is subsequently stirred for 1 hour and 1.53 g (0.0244 mol) of sodium cyanoborohydride are then added in several portions. In order to bring the reaction to completion, the mixture is subsequently stirred at room temperature for 1.5 hours. The solvent is then stripped off on a rotary evaporator, H2O is added to the residue and the mixture is rendered alkaline with 1N NaOH. The aqueous phase is extracted with CH2Cl2 and dried over NaSO4 and the solvent is evaporated off on a rotary evaporator. The oily residue is chromatographed on silica gel (silica gel 60 from E. Merck, Darmstadt) using an eluent mixture of: CH2Cl2 /MeOH (2.5:0.15). The product is dried in the absence of light in a desiccator over P2O5 at 10-2 bar.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:8](=[O:24])[CH:7]=1.[Cl:30]N1C(=O)CCC1=O.ClC(Cl)C(O)=O>ClC(Cl)C>[Cl:30][C:7]1[C:8](=[O:24])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=1[F:1]
Reactant: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(O)C(Cl)Cl
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Temperature: 50 °C

Procedure:
The title compound was prepared by taking up methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate (1.46 g, 3.66 mmol) in dichloroethane (25 ml) and adding N-chlorosuccinimide (0.49 g, 3.66 mmol), dichloroacetic acid (catalytic), and heating to 50° C. for 6 hours. At this time, the solvent was removed in vacuo and the residue taken up in diethyl ether. The precipitate was collected on a filter pad. 1H NMR (300 MHz, CDCl3) δ 8.07 (dd, J=7.85, 1.61 Hz, 1H), 7.80 (d, J=1.81 Hz, 2H), 7.62 (app q, J=8.46 Hz, 1H), 7.48 (d, J=7.85, 1H), 7.05-6.95 (m, 1H), 6.93-6.89 (m, 1H), 6.19 (s, 1H), 5.30 (s, 2H), 3.93 (s, 3H), 2.17 (s, 3H), 1.97 (s, 3H). ES-HRMS m/z 434.0932 (M+H calcd for C22H19ClF2NO4 requires 434.0965).
Reaction SMILES: C([C:8]([NH2:12])([OH:11])[CH2:9][CH3:10])(OC(C)(C)C)=O.[CH3:13][CH:14]([C:28]([OH:30])=[O:29])[C:15]1[CH:16]=[CH:17][C:18]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:19]([F:21])[CH:20]=1.[ClH:31].C(OCC)(=O)C.C(OCC)C>ClCCl>[NH2:12][CH:8]([OH:11])[CH2:9][CH3:10].[CH3:13][CH:14]([C:28]([OH:30])=[O:29])[C:15]1[CH:16]=[CH:17][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:19]([F:21])[CH:20]=1.[ClH:31]
Reactant: CCC(N)(O)C(=O)OC(C)(C)C
Agent: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(N)O
Temperature: 25 °C

Procedure:
In 1 ml of dichloromethane, 720 mg (1.79 mmol) of the Boc-aminopropanol-flurbiprofen obtained above was dissolved, and 4 ml of 4 M hydrochloric acid/ethyl acetate was added thereto under ice-cooling, followed by stirring under ice-cooling for 3 minutes and at room temperature for 3 hours and 10 minutes. After confirming disappearance of Boc-aminopropanol-flurbiprofen by TLC, diethyl ether was added thereto, followed by decantation twice. Thereafter, the residue was dried under reduced pressure to give the titled substance at a yield of 352 mg (94%). The structure was identified by 1H-NMR (CDCl3).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]([NH:11][C:12]3[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=[C:16]([Br:18])[CH:17]=3)=[N:9][CH:10]=2)[CH2:2]1.[CH3:21][CH:22]=O.[OH-].[Na+]>CO.C(O)(=O)C>[Br:18][C:16]1[CH:17]=[C:12]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([CH:3]3[CH2:4][N:1]([CH2:21][CH3:22])[CH2:2]3)=[CH:10][N:9]=2)[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(C3CNC3)cn2)c1=O
Reactant: CC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCN1CC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Yield: 43 %

Procedure:
To a solution of 3-(5-(azetidin-3-yl)pyridin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one 155n (crude, 4.6 mmol) in methanol (50 mL) and acetic acid (5 mL) at 0° C., was added CH3CHO (40% wt in H2O) (10 g, 92 mmol) followed by the addition of NaBH(CH3O)3 (20 g, 92 mmol) in small portions over a period of 1 h. After the reaction was finished, the mixture was adjusted to pH>7 with 2N NaOH. Then the mixture was extracted with DCM (80 mL×3), dried over Na2SO4 and concentrated to get a yellow solid, which was purified on flash column eluting with 50:1 DCM/MeOH containing 0.5% Et3N to afford 250a as a yellow solid (43%, two steps). LCMS: (M+H)+ 364. 1H NMR (500 MHz, DMSO) δ 8.72 (s, 1H), 8.66 (d, J=3, 1H), 8.21 (d, J=3, 1H), 7.68 (dd, J=9, 1H), 7.52 (d, J=2.5, 1H), 7.32 (d, J=9, 1H), 3.54 (m, 6H), 2.99 (m, 2H), 2.42 (m, 2H), 0.89 (t, J=7, 3H).