Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([CH3:14])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[C@@H:15]1[CH2:17][C@@H:16]1[F:18].[CH:23]1([NH:26][CH2:27][C@@H:28]2[C@H:32]([F:33])[CH2:31][NH:30][CH2:29]2)[CH2:25][CH2:24]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:30]2[CH2:31][C@@H:32]([F:33])[C@@H:28]([CH2:27][NH:26][CH:23]3[CH2:24][CH2:25]3)[CH2:29]2)[C:9]([CH3:14])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[C@@H:15]1[CH2:17][C@@H:16]1[F:18]
Reactant: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Product: Cc1c(N2C[C@H](CNC3CC3)[C@H](F)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Yield: 33.3 %

Procedure:
Using 5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylic acid (20.0 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (15.2 mg), the same procedure was followed as in Example 36 to give 5-amino-7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylic acid as a yellow solid (9.6 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:23])[C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[NH:10][C:11]3([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]3)[C:12]=2[OH:13])[CH:7]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].N1C=CC=CC=1.Cl>C(#N)C>[CH2:28]([O:27][C:25](=[O:26])[O:13][C:12]1[C:11]2([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]2)[NH:10][C:9](=[O:21])[C:8]=1[C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([F:23])[C:5]=1[CH3:22])[CH3:29]
Reactant: CON1CCC2(CC1)NC(=O)C(c1cc(Br)cc(F)c1C)=C2O
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CCOC(=O)OC1=C(c2cc(Br)cc(F)c2C)C(=O)NC12CCN(OC)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(5-bromo-3-fluoro-2-methyl-phenyl)-4-hydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (350 mg) and ethyl chloroformate (77 μl) in acetonitrile (2 ml) was added pyridine (80 μA) and the reaction mixture stirred at room temperature for one hour. The mixture was poured on diluted HCl and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/cyclohexane 3:1). Yield: 310 mg of carbonic acid 3-(5-bromo-3-fluoro-2-methyl-phenyl)-8-methoxy-2-oxo-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester ethyl ester (title compound E4) as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH2:7][NH:8][CH:9]1[CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:21]([S:24][CH2:25][CH:26]([CH3:30])[C:27](Cl)=[O:28])(=[O:23])[CH3:22]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[CH2:7][N:8]([C:27](=[O:28])[CH:26]([CH3:30])[CH2:25][S:24][C:21](=[O:23])[CH3:22])[CH:9]1[CH2:10][CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)CNC1CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C1CCC1
Reaction time: 8 h
Yield: 72 %

Procedure:
To a chilled (0.5° C.) methylene chloride solution of N-cyclobutyl-glycine t-butyl ester (63.2 g, 0.34 mol) and triethylamine (26 g, 0.4 mol) was added dropwise 3-acetylthio-2-methylpropanoyl chloride (61.4 g, 0.34 mol). After stirring overnight the reaction mixture was filtered and the filtrate was concentrated. The residue was redissolved in ethyl acetate, washed with 5% HCl (3×500 ml), brine (500 ml) and saturated aqueous sodium bicarbonate (6×600 ml), dried over MgSO4, filtered, and concentrated yielding 80.6 g (72%) of the product as a brown oil.
Reaction SMILES: [NH2:1]/[C:2](/[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[CH:3]\[C:4]#[N:5].[C:19]1([CH:25]([C:31](OCC)=[O:32])[C:26](OCC)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[OH:32][C:31]1[C:3]([C:4]#[N:5])=[C:2]([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:7]=2)[NH:1][C:26](=[O:27])[C:25]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N#C/C=C(\N)c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)[nH]c(=O)c(-c2ccccc2)c1O
Temperature: 25 °C
Yield: 61.9 %

Procedure:
A mixture of (Z)-3-amino-3-(4-phenoxyphenyl)acrylonitrile (717 mg, 3.03 mmol) in diethyl 2-phenylmalonate (8 mL, 37.1 mmol) was microwaved at 250° C. for 15 min. After cooling to room temperature, the resulting suspension was filtered. The solid was washed with 20% isopropyl alcohol in heptanes and dried under vacuum to give 4-hydroxy-6-oxo-2-(4-phenoxyphenyl)-5-phenyl-1,6-dihydropyridine-3-carbonitrile (714 mg, 62% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.23 (1H, br. s), 10.76 (1H, br. s), 7.72 (2H, δ, J=8.80 Hz), 7.46-7.51 (2H, m), 7.39-7.44 (2H, m), 7.30-7.36 (3H, m), 7.26 (1H, t, J=7.42 Hz), 7.15 (2H, δ, J=7.70 Hz), 7.10 (2H, δ, J=8.80 Hz); MS (ES+) m/z: 381 (M+H); LC retention time: 3.820 min (analytical HPLC Method A).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][CH:8]([C:16](N1C(C)C(C2C=CC=CC=2)OC1=O)=[O:17])[CH2:9][C:10]([CH3:15])([CH3:14])[CH2:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-:33].OO>>[C:1]([O:5][C:6](=[O:31])[CH2:7][C@H:8]([CH2:9][C:10]([CH3:14])([CH3:15])[CH2:11][CH2:12][CH3:13])[C:16]([OH:17])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: [OH-]
Reactant: CCCC(C)(C)CC(CC(=O)OC(C)(C)C)C(=O)N1C(=O)OC(c2ccccc2)C1C
Agent: OO
Agent: [Li+]
Product: CCCC(C)(C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Yield: 112.5 %

Procedure:
According to example 1, 3.4 g (7.9 mmol) of 5,5-dimethyl-3-(4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-octanoic acid tert-butyl ester, 16 mL (12.8 mmol) of 0.8N LiOH and 4.5 mL of 30% H2O2 gave 2.42 g (>100%) of the title compound as an oil. 1HNMR (400 MHz; CDCl3): 0.77–0.82 (m, 9H), 1.14–1.29 (m, 5H), 1.42 (s, 9H), 1.77 (dd, 1H, J=8 Hz, 16 Hz), 2.36 (dd, 1H, J=6 Hz, 16 Hz), 2.59 (dd, 1H, J=8 Hz, 16 Hz), 2.75–2.85 (m, 1H).
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([OH:18])=O)[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2].Cl.[C:21]([O:24][CH2:25][CH2:26][NH2:27])(=[O:23])[CH3:22].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(CCCN=C=NCC)C>C(Cl)Cl>[C:21]([O:24][CH2:25][CH2:26][NH:27][C:16]([C@@H:9]1[NH:8][C:7](=[O:19])[C@@H:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:18])(=[O:23])[CH3:22]
Reactant: CC(=O)OCCN
Reactant: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)O)NC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(=O)OCCNC(=O)[C@H]1CCCCCC[C@H](CSC(C)=O)C(=O)N1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid (0.15 g, 0.52 mmol), 1-acetoxy-2-aminoethane hydrochloride (0.073 g, 0.52 mmol), 1-hydroxybenzotriazole (0.12 g, 0.52 mmol), and 4-methylmorpholine (0.17 mL, 1.56 mmol) are dissolved in methylene chloride (3.0 mL), and the reaction is cooled to 0° C. To this solution is added N-(dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.20 g, 1.04 mmol), and the reaction is allowed to warm up to room temperature and then stirred overnight. The reaction is diluted with more methylene chloride, and the organic layer is washed with 1N hydrochloric acid, saturated sodium bicarbonate, dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (75% ethyl acetate/hexane) to give 2-acetoxy-N-[[trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecan-10-yl]-carbonyl]-ethylamine, MS: M+1=373.
Reaction SMILES: [F:1][C:2]([F:26])([C:14](=O)[C:15]1[C:16]([C:21]([F:24])([F:23])[F:22])=[N:17][CH:18]=[CH:19][CH:20]=1)[C:3](=[CH2:13])[CH2:4][NH:5]C(=O)OC(C)(C)C.Cl>C(O)(=O)C>[F:1][C:2]1([F:26])[C:14]([C:15]2[C:16]([C:21]([F:24])([F:23])[F:22])=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:5][CH2:4][C:3]1=[CH2:13]
Reactant: C=C(CNC(=O)OC(C)(C)C)C(F)(F)C(=O)c1cccnc1C(F)(F)F
Agent: Cl
Solvent: CC(=O)O
Product: C=C1CN=C(c2cccnc2C(F)(F)F)C1(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a solution of tert-butyl {3,3-difluoro-2-methylene-4-oxo-4-[2-(trifluoromethyl)pyridin-3-yl]butyl}carbamate (3.25 g) in acetic acid (10 mL) was added dropwise concentrated hydrochloric acid (3 mL). The obtained mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=3:1) to give the title compound as a yellow oil (yield 1.85 g, 83%).
Reaction SMILES: [N:1]([CH:4]([C@H:7]1[CH2:11][CH2:10][CH2:9][O:8]1)[CH2:5][CH3:6])=[N+]=[N-].[H][H]>CCO.CC(O)=O.[Pd]>[O:8]1[CH2:9][CH2:10][CH2:11][CH:7]1[C@H:4]([NH2:1])[CH2:5][CH3:6]
Reactant: CCC(N=[N+]=[N-])[C@H]1CCCO1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC[C@@H](N)C1CCCO1

Procedure:
A solution of (2R)-2-(1-azidopropyl)tetrahydrofuran (1.9 g, 12.24 mmol, 1 equiv) in EtOH/AcOH (105 ml of a 100:5 mixture) and 10% Pd/C CATCart (12.24 mmol, 1 equiv) was placed under a positive pressure of hydrogen for 8 hours. The product mixture was concentrated in vacuo and diluted with DCM. The mixture was passed down a 10 g SCX-2 cartridge (resin loading 0.67 mmol/g), eluting with methanol followed by 2M ammonia in EtOH. The appropriate fractions were concentrated in vacuo to afford the title compound. 1.0 (3H, t, CH3), 1.3 (1H, m), 1.6 (2H, m), 1.9 (3H, m), 2.6 (0.5H, m, CHNH2 of one diastereomer), 2.8 (0.5H, m, CHNH2 of one diastereomer), 3.6 (1H, m, CHO), 3.75 (1H, m, CHO), 3.85 (1H, m, CHO).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[Cl:17][CH2:18][CH:19]([OH:22])[CH2:20]O.O.CC1C=CC(S(O)(=O)=O)=CC=1.CC1C=CC=CC=1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[O:22][CH:19]([CH2:18][Cl:17])[CH2:20][O:9]2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: OCC(O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(C2(c3ccc(F)cc3)OCC(CCl)O2)cc1
Yield: 100 %

Procedure:
A mixture of 10 parts of bis(4-fluorophenyl)methanone, 22.1 parts of 3-chloro-1,2-propanediol, 0.2 parts of 4-methylbenzenesulfonic acid hydrate and 90 parts of methylbenzene was stirred and refluxed for 23 hours using a water-separator. The reaction mixture was poured onto alkaline water. Upon stirring, the layers were separated. The organic phase was washed with alkaline water, dried, filtered and evaporated, yielding 14 parts (100%) of 2,2-bis(4-fluorophenyl)-4-(chloromethyl)-1,3-dioxolane as a residue (intermediate 99).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:6](=O)[C:5](=[O:8])[C:4]=1[O:9]C.[N:11]1([CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][NH2:28])[CH:19]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[N:11]1([CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][NH:28][C:6]3[C:5](=[O:8])[C:4](=[O:9])[C:3]=3[NH:2][CH3:1])[CH:19]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CNc1c(OC)c(=O)c1=O
Reactant: NCCCOc1cc(CN2CCCCC2)ccn1
Product: CNc1c(NCCCOc2cc(CN3CCCCC3)ccn2)c(=O)c1=O

Procedure:
By the methods of Example 1, 1-(methylamino)-2-methoxycyclobut-1-ene-3,4-dione and 3-[4-(piperidinomethyl)pyrid-2-yloxy]prop-1-ylamine are reacted to form the title product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[NH:12][C:11](=[O:19])[NH:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[F:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH2:37])[CH:35]=3)[NH:30][N:29]=2)[CH:24]=[CH:25][CH:26]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH:37][C:15]([C:14]4[CH:9]([C:4]5[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=5)[NH:10][C:11](=[O:19])[NH:12][C:13]=4[CH3:18])=[O:17])[CH:35]=3)[NH:30][N:29]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc2[nH]nc(Nc3cccc(F)c3)c2c1
Reactant: CC1=C(C(=O)O)C(c2cc(F)cc(F)c2)NC(=O)N1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4cccc(F)c4)c3c2)C(c2cc(F)cc(F)c2)NC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution 4-(3,5-Difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid (17 mg, 0.057 mmol), N3-(3-Fluoro-phenyl)-1H-indazole-3,5-diamine (14 mg, 0.057 mmol) and PyBroP (27 mg, 0.057 mmol) in methylene chloride (1 ml) was added diisopropylethylamine 20 μL. The mixture was allowed to stir overnight at room temperature and the titled compound (7.5 mg, 25%) was purified with HPLC. MS (ESI) m/z=493 [M+H]+. 1H NMR (400 MHz, d6-DMSO) δ8.02 (s, 1H), 7.38-7.30(m, 3H), 7.23-7.15 (m, 2H), 7.01-6.99 (m, 2H), 6.91-6.86 (m, 2H), 6.58-6.53 (m, 1H)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([CH2:6][OH:7])[CH2:2]1.Cl[C:9]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][N:17]=2)[CH:12]=[C:11]([Cl:19])[N:10]=1>>[Cl:19][C:11]1[N:10]=[C:9]([N:1]2[CH2:5][CH2:4][C@@H:3]([CH2:6][OH:7])[CH2:2]2)[C:18]2[C:13](=[N:14][CH:15]=[CH:16][N:17]=2)[CH:12]=1
Reactant: OC[C@@H]1CCNC1
Reactant: Clc1cc2nccnc2c(Cl)n1
Product: OC[C@@H]1CCN(c2nc(Cl)cc3nccnc23)C1

Procedure:
The title compound was prepared according to the procedure of Compound 1 (A) using (R)-pyrrolidin-3-ylmethanol and 5,7-dichloropyrido[4,3-b]pyrazine. MS (m/z): 265 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
[1,4]Diazepane-1-carboxylic acid tert-butyl ester was reacted with 1-Fluoro-4-nitro-benzene at 60° C. by method D. The product with the molecular weight of 321.38 (C16H23N3O4) was obtained in this way; MS (ESI): 322 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:20])[C@H:4]([CH:17]([CH3:19])[CH3:18])[NH:5][C:6]([N:8]([CH3:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:7].[OH-].[Li+]>O1CCOCC1>[CH3:16][N:8]([C:6]([NH:5][C@H:4]([C:3]([OH:20])=[O:2])[CH:17]([CH3:19])[CH3:18])=[O:7])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: COC(=O)[C@@H](NC(=O)N(C)Cc1ccccn1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)N(C)Cc1ccccn1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of 4.47 g (16 mmol) of N-((N-methyl-N-((2-pyridinyl)methyl)-amino)carbonyl)valine methyl ester in 65 ml of dioxane was treated with 65 ml of 0.5 M aqueous lithium hydroxide. After being stirred at ambient temperature for 1 h, the resulting solution was concentrated in vacuo to a small volume (ca. 5 ml), neutralized to pH 5 with 1 M aqueous HCl, and extracted with three 100 ml portions of ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide 3.61 g (85%) of the desired compound as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20]O)[CH:7]=1)[CH3:2].P(Br)(Br)[Br:24]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20][Br:24])[CH:7]=1)[CH3:2]
Reactant: BrP(Br)Br
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2CO)c1
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2CBr)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To [3-(4-bromo-2-hydroxymethyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.7 g, 1.86 mmol) in 1,4-dioxane (10 mL) was added phosphorus tribromide (0.19 mL, 2.04 mmol), and the reaction was stirred for 1 hour at room temperature. After work-up, 0.6 g of the desired product was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]#[C:13][Si](C)(C)C)=[C:6]([CH2:8][C:9]([NH2:11])=[O:10])[CH:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C(Cl)Cl>[C:12]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[CH2:8][C:9]([NH2:11])=[O:10])#[CH:13]
Reactant: C[Si](C)(C)C#Cc1ccc(F)cc1CC(N)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: O
Product: C#Cc1ccc(F)cc1CC(N)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(5-fluoro-2-((trimethylsilyl)ethynyl)phenyl)acetamide (A34) (0.239 g, 0.958 mmol) in DCM (10 mL) at 0° C. was added TBAF (1.0 M in THF; 1.44 mL, 1.44 mmol). The resulting mixture was stirred at 0° C. for 10 minutes, then poured into water (50 mL). The organic phase was separated and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were washed with brine, dried (MgSO4) and the volatiles removed in vacuo. The residue was adsorbed onto silica gel then purified by column chromatography (Biotage Isolera, SiO2, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A35 as a white solid (0.114 g, 67%); 1H NMR (400 MHz, d6-DMSO) δ 7.50 (dd, J=8.6, 5.9 Hz, 1H), 7.44 (s, 1H), 7.17 (dd, J=10.0, 2.7 Hz, 1H), 7.10 (td, J=8.6, 2.8 Hz, 1H), 6.99 (s, 1H), 4.32 (s, 1H), 3.61 (s, 2H). LCMS-A: rt 4.843 min; m/z 178 [M+H]+.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH:17]([C:19]1[N:20]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:22][N:23]=1)=O.O>O1CCCC1>[C:24]([N:20]1[CH:21]=[CH:22][N:23]=[C:19]1/[CH:17]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
To a suspension of sodium hydride (60% in oil, 0.811 g, 20.3 mmol) in tetrahydrofuran (60 ml) was added dropwise ethyl (diethoxyphosphoryl)acetate (4.33 ml, 21.8 mmol) and the mixture was stirred for 30 min. A solution of 2-formyl-1-tritylimidazole (5.28 g, 15.6 mmol) in tetrahydrofuran (30 ml) was added dropwise and the mixture was stirred for 8 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried (over anhydrous MgSO4). After concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (9:1-1:1, v/v). The title compound (3.28 g, 52%) was obtained as a colorless powder from the object fraction.
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:10][CH3:11])([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3]1.[H-].[Na+].I[CH3:20]>CN(C)C=O>[CH3:20][O:1][CH:2]1[C:7]([O:8][CH3:9])([O:10][CH3:11])[CH2:6][CH2:5][N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3]1
Reactant: CCOC(=O)N1CCC(OC)(OC)C(O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(OC)(OC)C(OC)C1
Temperature: 30 °C
Reaction time: 1.5 h
Yield: 95.7 %

Procedure:
To a stirred mixture of 35 parts of ethyl 3-hydroxy-4,4-dimethoxy-1-piperidinecarboxylate and 144 parts of N,N-dimethylformamide were added portionwise 8.2 parts of sodium hydride dispersion 50%; exothermic reaction (temp. roses to 30° C.; cooling in a water-bath was necessary to keep the temperature below 30° C.). The whole was stirred for 1.50 hours at about 30° C. and then it is cooled to room temperature. 24.1 Parts of iodomethane were added dropwise (strong exothermic reaction) while the temperature was kept below 30° C. Upon completion, stirring was continued over week-end at room temperature. The reaction mixture was poured onto water and the product was extracted with 4-methyl-2-pentanone. The extract was washed with water, dried, filtered and evaporated, yielding 35.9 parts (95.7%) of ethyl 3,4,4-trimethoxy-1-piperidinecarboxylate as an oily residue (intermediate 64).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[C:36](=[O:41])[CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:31][CH:32]([N:34]5[CH2:39][CH2:38][N:37]([CH3:40])[C:36](=[O:41])[CH2:35]5)[CH2:33]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CN1CCN(C2CNC2)CC1=O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCN(C)C(=O)C4)C3)n(C)c2n1
Reaction time: 16 h
Yield: 81.5 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (162 mg, 0.41 mmol), 4-azetidin-3-yl-1-methylpiperazin-2-one (77 mg, 0.46 mmol) and 4 Å powdered molecular sieves (250 mg) in DCE (10 mL) was stirred at room temperature for 2 h before the addition of sodium triacetoxyborohydride (175 mg, 0.83 mmol). The reaction mixture was stirred for 16 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-30%) affording 556 as a yellow foam (182 mg, 82%). LCMS (Method I): RT 2.34 min [M+H]+ 545.3. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.97 (m, 1 H); 7.77-7.72 (m, 1 H); 7.29-7.22 (m, 2 H); 4.35 (m, 4 H); 3.89-3.84 (m, 6 H); 3.83 (s, 3 H); 3.59 (t, J=5.3 Hz, 2 H); 3.39-3.31 (m, 4 H); 3.18-3.10 (m, 3 H); 3.05 (m, 2 H); 2.96 (s, 3 H); 2.59 (t, J=5.3 Hz, 2 H) and 1.43 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[CH:15][C:14]([CH:17]([OH:21])[CH2:18][CH2:19][CH3:20])=[C:13]([O:22][CH:23]([CH3:25])[CH3:24])[CH:12]=1)[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[CH:15][C:14]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[C:13]([O:22][CH:23]([CH3:25])[CH3:24])[CH:12]=1)[CH3:2]
Reactant: CCCC(O)c1cnc(-c2c(CC)cccc2CC)cc1OC(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCC(=O)c1cnc(-c2c(CC)cccc2CC)cc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[6-(2,6-diethyl-phenyl)-4-isopropoxy-pyridin-3-yl]-butan-1-ol (482 mg, 1.41 mmol, prepared analogously to Example 16) and pyridinium dichromate (1.0 g, 2.82 mmol) in CH2Cl2 (50 mL) is stirred at room temperature overnight. The mixture is washed with brine, dried and concentrated. The residue is chromatographed on silica gel to give 360 mg of 1-[6-(2,6-diethyl-phenyl)-4-isopropoxy-pyridin-3-yl]-butan-1-one.