Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)[N:9]=[CH:10][C:3]=12.[C:21]([O:25][C:26](=[O:35])[NH:27][CH:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:21]([O:25][C:26](=[O:35])[NH:27][CH:28]1[CH2:29][CH2:30][CH:31]([NH:34][C:2]2[N:7]=[CH:6][N:5]=[C:4]3[N:8]([C:11]4[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=4)[N:9]=[CH:10][C:3]=23)[CH2:32][CH2:33]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A mixture of 4-chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (308 mg, 1 mmol), (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (257 mg, 1.2 mmol) and potassium carbonate (166 mg, 1.2 mmol) in THF (10 mL) was stirred at rt overnight. The mixture was purified by column chromatography to provide Compound A35 as a solid (76%). 1H NMR (CDCl3, 400 MHz) δ 1.46 (s, 9H), 1.74–2.04 (m, 8H), 3.09 (s, 3H), 3.73 (s, 1H), 4.62 (s, 1H), 8.07–8.09 (m, 3H), 8.49 (s, 1H), 8.57–8.59 (m, 2H). Exact mass calculated for C23H30N6O4S 486.2, found 487.2 (MH+).
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:26]=[CH:25][C:22](C=O)=[C:21]([Cl:27])[CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C([C:35]([O:37]O)=[O:36])C=1>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:35]([O:37][C:22]1[CH:25]=[CH:26][C:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:20][C:21]=1[Cl:27])=[O:36]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)[Si](Oc1ccc(C=O)c(Cl)c1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1ccc(OC=O)c(Cl)c1)(c1ccccc1)c1ccccc1
Yield: 81.9 %

Procedure:
4-{[t-butyl(diphenyl)silyl]oxy}-2-chlorobenzaldehyde (11.00 g, 28 mmol) was dissolved in CHCl3 (150 ml). In one portion m-chloroperbenzoic acid (MCPBA) (7.21 g, 41.8 mmol) was added and the solution heated to reflux for 72 h. The solution was diluted with CH2Cl2, washed with sat. NaHSO3, sat. NaHCO3, brine and dried (MgSO4). The solvent was removed to provide 9.42 g of the title compound.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[C@H:28]([NH:29][C:30](=[O:37])[CH2:31][C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C:27](=[O:38])[N:9]2[C:10]=1[C:11]([O:13]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:12])#[N:2].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[C:1]([CH2:3][CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[C@H:28]([NH:29][C:30](=[O:37])[CH2:31][C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C:27](=[O:38])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])#[N:2]
Reactant: N#CCCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#CCCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1

Procedure:
A solution of diphenylmethyl 3-(2-cyanoethyl)-7β-(2-thienylacetamido)ceph-3-em-4-carboxylate (1g.) in anisole (1 ml.) was treated with trifluoroacetic acid (4 ml.). After 5 minutes at 23° the solvents were removed in vacuo and the residue was partitioned between ethyl acetate and dilute aqueous sodium bicarbonate solution. The alkaline phase was washed thoroughly with ethyl acetate, then taken to pH2 with 2N-hydrochloric acid. The acidic mixture was extracted with ethyl acetate and the organic extracts washed with brine, and dried and evaporated in vacuo. The residual gum was dissolved in ethyl acetate and the solution run into petroleum ether to give, after filtration and drying, the title acid (567 mg., 82%) as an amorphous solid, m.p. ca 105° (decomp.) [α]D22 + 102° (C 0.75, 1% NaHCO3), λinflex. (0.1 M-pH 6 phosphate buffer) 260 nm. (ε 7,290), νmax. (Nujol) 3300 (NH), 3675 to 2400 (bonded OH), 2210 and 2250 (CN), 1775 (β-lactam), 1715 (CO2H), and 1665 and 1530 cm.-1 (CONH), τ (D2O with NaHCO3) 4.43 (C(7) --H, d, J 4.5 Hz), 4.95 (C(6) --H, d, J 4.5 Hz.), 6.13 (CH2CONH), 6.42 and 6.82 (C(2), AB-q, J 18 Hz.), and 7.1 to 7.6 (CH2CH2CN, ABCD-complex) (Found: C, 50.7; H, 4.0; N, 10.7; S, 16.0; C16H15N3O4S2 requires C, 50.9; H, 4.0; N, 11.1; S, 17.0%), Rf 0.28 (System C) and Rf 0.6 (System B).
Reaction SMILES: Br[C:2]1[C:3]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:4][C:5]([NH2:16])=[N:6][C:7]=1[C:8]#[C:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[C:10]1([C:9]#[C:8][C:7]2[N:6]=[C:5]([NH2:16])[CH:4]=[C:3]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:2]=2[C:27]2[CH:28]=[N:23][CH:24]=[N:25][CH:26]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1cc(-c2ccncc2)c(Br)c(C#Cc2ccccc2)n1
Reactant: OB(O)c1cncnc1
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: CC#N
Product: Nc1cc(-c2ccncc2)c(-c2cncnc2)c(C#Cc2ccccc2)n1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (30 mg, 26 μmol) is added to a mixture of 5-bromo-6-(2-phenylethynyl)-4-(pyridin-4-yl)pyridin-2-amine G8 (90 mg, 0.26 mmol), pyrimidine-5-boronic acid (48 mg, 0.39 mmol), sodium carbonate (aqueous solution, 2 mol/l, 0.39 ml, 0.78 mmol) and ACN (2.4 ml) under nitrogen atmosphere at RT and is stirred at 150° C. for 1 h. The mixture is concentrated in vacuo and the product purified by NP chromatography. Yield: 72 mg (80%). HPLC-MS: M+H=350; tR=1.11 min (METHOD—5).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:19]([O:21]CC)=[O:20])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:25].[OH-].[Na+].O.Cl>C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:19]([OH:21])=[O:20])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:25]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(Cl)c(F)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(Cl)c(F)cc2c1=O
Yield: 94.8 %

Procedure:
A mixture of 320 mg of the above ester, 5 ml of 1N sodium hydroxide, 5 ml of water and 5 ml of ethanol was heated for 30 minutes, then cooled and adjusted to pH 7 with dilute hydrochloric acid. The solid was collected, giving 280 mg of 7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[N:15][C:16]=3[O:18][CH2:19][CH3:20])[NH:11][C:10]([CH3:21])=[C:9]2[C:22]([O:24][CH2:25][CH2:26][C:27]#[N:28])=[O:23])=[C:4]([O:29][C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][N:35](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:34]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[N:15][C:16]=3[O:18][CH2:19][CH3:20])[NH:11][C:10]([CH3:21])=[C:9]2[C:22]([O:24][CH2:25][CH2:26][C:27]#[N:28])=[O:23])=[C:4]([O:29][C:30]([F:32])([F:33])[F:31])[CH:3]=1)#[N:35]
Reactant: CN(C)C=O
Reactant: CCOc1nccc2c1C(c1ccc(Br)cc1OC(F)(F)F)C(C(=O)OCCC#N)=C(C)N2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1OC(F)(F)F)C(C(=O)OCCC#N)=C(C)N2
Temperature: 220 °C

Procedure:
4.59 g (8.72 mmol) of the compound from Example 35A, 758 mg (6.45 mmol) of zinc cyanide and 504 mg (0.436 mmol) of tetrakis(triphenylphosphine)palladium(0) are dissolved in 40 ml of DMF and then, divided into three mixtures, heated in a single mode microwave (Emrys Opzimizer) at 220° C. for 5 min. The individual mixtures are then recombined, and the solvent is removed in a rotary evaporator. The crude product is taken up in ethyl acetate and filtered through kieselguhr. The organic phase is washed with water (2×) and with saturated sodium chloride solution. After removal of the solvent by distillation, the crude product is purified by column chromatography (silica gel; mobile phase: cyclohexane/ethyl acetate 7:3→1:1). 1.40 g (31% of theory) of the title compound are obtained.
Reaction SMILES: [SiH3:1][SiH2:2][SiH2:3][SiH2:4][SiH2:5][SiH2:6][SiH2:7][SiH2:8][SiH2:9][SiH2:10][SiH2:11][SiH2:12][SiH2:13][SiH2:14][SiH2:15][SiH3:16].[F:17][C:18]([F:24])([F:23])[S:19]([OH:22])(=[O:21])=[O:20]>ClCCl>[F:17][C:18]([F:24])([F:23])[S:19]([O:22][SiH2:16][SiH2:15][SiH2:14][SiH2:13][SiH2:12][SiH2:11][SiH2:10][SiH2:9][SiH2:8][SiH2:7][SiH2:6][SiH2:5][SiH2:4][SiH2:3][SiH2:2][SiH3:1])(=[O:21])=[O:20]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: [SiH3][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH3]
Solvent: ClCCl
Product: O=S(=O)(O[SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH3])C(F)(F)F

Procedure:
In an argon atmosphere, to a tetrahydrofuran solution (1 ml) of 52 mg (0.15 mmol) of octaethylcyclotetrasilane was added 0.58 ml (0.15 mmol) of a tetrahydrofuran solution (0.27M) of phenyldimethylsilyllithium, and stirred at 0° C. for 15 minutes. Then, tetrahydrofuran was distilled out under vacuum, and hexane (1 ml) was added to give a hexane solution (Solution 1). A dichloromethane solution (1 ml) of 68 mg (0.05 mmol) of hexadecasilane (9) obtained in Example 9 was treated with 7.5 mg (0.05 mmol) of trifluoromethanesulfonic acid at room temperature for 30 minutes to give 1-(trifluoromethanesulfonyloxy)hexadecasilane. Then, dichloromethane was distilled out under vacuum, and hexane (1 ml) was added to give a hexane solution (solution 2). The Solution 1 was added to the Solution 2 at -78° C. and stirred for 15 minutes. Methanol (0.1 ml) and triethylamine (0.1 ml) were added, then saturated aqueous sodium bicarbonate solution (2 ml) was added, stirred, the hexane layer was separated, and dried with magnesium sulfate. The resulting crude product was purified by a silica gel column chromatography (hexane) to give 137 mg (39% yield) of eicosasilane (10) as a colorless crystal.
Reaction SMILES: COC1C=C2C(C(OCC(O)C)=CC=N2)=CC=1.[CH3:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([O:30][CH:31]([CH3:34])[CH2:32]O)=[CH:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1.P(Br)(Br)[Br:36]>C(Cl)Cl>[Br:36][CH2:32][CH:31]([O:30][C:24]1[C:23]2[C:28](=[CH:29][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[N:27]=[CH:26][CH:25]=1)[CH3:34]
Reactant: BrP(Br)Br
Reactant: COc1ccc2c(OC(C)CO)ccnc2c1
Agent: COc1ccc2c(OCC(C)O)ccnc2c1
Solvent: ClCCl
Product: COc1ccc2c(OC(C)CBr)ccnc2c1

Procedure:
To a stirred solution of 1-(7-methoxyquinolin-4-yloxy)propan-2-ol (235 mg, 1007 μmol) and 2-(7-methoxyquinolin-4-yloxy)propan-1-ol (235 mg, 1007 μmol) (mixture of isomers) in CH2Cl2 (3 mL) was added phosphorus tribromide (94.7 μl, 1007 μmol). The mixture was heated to reflux for 18 h. The mixture was quenched with 5% NaHCO3, and was extracted with CH2Cl2 (3×5 mL). The combined organics were dried over MgSO4 and concentrated to a white solid (150 mg) under reduced pressure. MS (ESI pos. ion) m/z (MH+): 296/298. Calc'd exact mass for C13H14BrNO2: 295.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[CH3:52][S:53]([C:56]1[N:61]=[CH:60][C:59]([C@@H:62]([NH2:65])[CH2:63][CH3:64])=[CH:58][CH:57]=1)(=[O:55])=[O:54].C(=O)(O)[O-].[Na+]>CN(C=O)C.O>[CH3:52][S:53]([C:56]1[N:61]=[CH:60][C:59]([C@@H:62]([NH:65][C:17]([C:16]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:12]=3[CH:13]=[N:14][CH:15]=2)=[O:19])[CH2:63][CH3:64])=[CH:58][CH:57]=1)(=[O:55])=[O:54]
Reactant: O=C(O)c1cncc2c1cnn2-c1ccc(F)cc1
Reactant: CC[C@H](N)c1ccc(S(C)(=O)=O)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccc(S(C)(=O)=O)nc1
Reaction time: 1 h

Procedure:
To a suspension of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (37.8 g, 146.9 mmol) in DMF (400 mL) was added DIPEA (50 mL, 287.0 mmol) followed by TBTU (49.5 g, 154.1 mmol). The mixture stirred for 1 hour, to afford a precipitate. To the mixture was added (S)-1-(6-methanesulfonyl-pyridin-3-yl)-propylamine hydrochloride (32.0 g, 127.6 mmol) followed by DIPEA (30 mL, 172.2 mmol). The mixture stirred overnight and was then poured into water (2.5 L) with sodium bicarbonate (50 g) added. The solid was collected by filtration washing with aqueous sodium carbonate (2 L) and then water (3 L). The solid was dried by pulling vacuum through the filter cake. The crude material was dissolved in dichloromethane and passed through a pad of silica gel (2000 mL funnel) using ethyl acetate-dichloromethane (1:9, then 2:8, then 100:0). The material from the pad was triturated with ether and the solid was collected by filtration. The solid was then dissolved in hot acetonitrile (1 L) and diluted with water (1 L). The product crystallized from the light yellow solution upon cooling overnight. The solid was collected by filtration washing with a 1:1 mixture of acetonitrile-water and then dried by pulling vacuum through the filter cake for 4 hours and then at 90° C. under house vacuum for approximately 11 hours (until a constant weight) to afford the title compound as a crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:20](OC)=[O:21])[C:17]2[C:12](=[C:13]([F:19])[CH:14]=[C:15]([F:18])[CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[C:17]2[C:12]=1[CH2:11][CH2:10][C:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:20][OH:21]
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCc2c(F)cc(F)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(CO)CCc2c(F)cc(F)cc21
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 1-[(tert-butoxycarbonyl)amino]-4,6-difluoroindane-1-carboxylate from Step D (2.80 g, 8.55 mmol) in THF (30 mL) at −78° C. was added LiAlH4 (18.0 mL of a 1 M solution in THF, 18.0 mmol), dropwise, over 30 min. The reaction mixture was stirred at −78° C. for 2 h, then quenched with H2O (1 mL), then 1 N aqueous NaOH (2 mL), then H2O (2 mL), then EtOAc (2 mL). The reaction mixture was warmed to ambient temperature, saturated aqueous NaHCO3 (150 mL) was added, and the mixture was extracted with EtOAc (200 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=244 (M−C4H7).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[CH3:9]O>>[ClH:1].[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: NCCCC(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)CCCN
Reaction time: 0.08 h

Procedure:
Anhydrous HCl was slowly bubbled into a heterogeneous mixture of 20.64 g (0.2 mole) of 4-aminobutyric acid in 200 ml of methanol at room temperature. After adding the HCl for about 5 minutes the reaction mixture warmed to a gentle reflux at which time it was submerged into a 0° C. ice bath. HCl addition was continued for an additional 5 minutes after the reaction mixture was cooled. The reaction mixture was then placed under nitrogen and refluxed for 17 hours. The solvent was evaporated in vacuo giving 30.70 g of a white solid, mp 110°14 115° C. The title compound was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[CH2:9])[CH:5]=[CH:4][C:3]=1F.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[O:14].O.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8](=[CH2:9])[CH2:10][CH:13]([OH:14])[C:12]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=O
Reactant: C=C(C)c1ccc(F)c(Br)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: CC#N
Product: C=C(CC(O)C(=O)OCC)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 2-bromo-1-fluoro-4-(prop-1-en-2-yl)benzene (12.3 g, 62.2 mmol, 1.0 equiv) in acetonitrile (124 mL, 0.5 M) are added ethyl glyoxalate (38.1 g, 37 mL, 187 mmoles, 3 equiv) and ytterbium trifluoromethanesulfonate, hydrate (7.72 g, 12.4 mmoles, 0.2 equiv). The mixture is stirred overnight at room temperature. The mixture is concentrated under reduced pressure and diluted with diethyl ether. The resulting solution is washed twice with water. The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified via flash column chromatography on silica gel (330 g) in two batches using a gradient of 0-100% ethyl acetate/hexanes to yield the title compound (87% yield): 1H NMR (CDCl3, 400 MHz): δ 7.53 (t, 1H, J=1.9 Hz), 7.41-7.37 (dt, 1H), 7.33-7.30 (dt, 1H), 7.18 (t, 1H, J=7.6 Hz), 5.37 (s, 1H), 5.22 (s, 1H), 4.26-4.21 (m, 1H), 4.17-3.99 (m, 2H), 2.99 (dd, J=14.8, 4.8 Hz), 2.83-2.72 (m, 2H), 1.23 (t, 3H, J=7.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.Cl>[Zn].Cl[Hg]Cl.O>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(c1cccnc1)c1cccc(F)c1
Agent: Cl
Agent: Cl[Hg]Cl
Agent: [Zn]
Solvent: O
Product: Fc1cccc(Cc2cccnc2)c1
Reaction time: 20 h
Yield: 29.2 %

Procedure:
Zinc amalgam prepared from zinc (41 g) and HgCl2 (4.1 g) was stirred in a mixture of 3-(3-fluorobenzoyl)pyridine (19.0 g, 0.095 mol), H2O (25 ml) and 12 N HCL (60 ml). The resulting mixture was stirred and heated at reflux for 30 hours. Occasionally during the course of the reaction HCl gas was passed through the mixture, and after 20 hours, additional zinc metal (41 g) was added. After 30 hours the reaction mixture was cooled, decanted, made strongly basic with 10% NaOH, and extracted three times with CH2Cl2. The extracts were dried (Na2SO4) and concentrated, and the residue was distilled to yield 5.2 g (29%) of 3-(3-fluorobenzyl)pyridine: bp 100°-110° C./79.99 Nm-2.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C@@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[C@@:12]3([CH2:38][F:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:40]>O1CCOCC1>[NH2:40][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C@@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[C@@:12]3([CH2:38][F:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N
Reactant: O[C@]1(CF)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Solvent: C1COCCO1
Product: Nc1ncnc2c1ccn2[C@@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@]1(O)CF
Temperature: -78 °C

Procedure:
The compound from Step A (18 mg, 0.03 mmol) was dissolved in the minimum amount of 1,4-dioxane and placed in a stainless steel bomb. The bomb was cooled to −78° C. and liquid ammonia was added. The bomb was sealed and heated at 90° C. for 24 h. The ammonia was allowed to evaporate and the residue concentrated to a white solid which was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8](=[O:9])[NH:7][C:6]2[CH2:10][CH2:11][CH2:12][C:5]=2[C:4]=1C.[O:14]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[O:9]=[C:8]1[NH:7][C:6]2[CH2:10][CH2:11][CH2:12][C:5]=2[CH:4]=[C:3]1[CH2:2][NH:1][C:25](=[O:26])[C:24]1[CH:23]=[CH:22][C:21]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:29][CH:28]=1
Reactant: Cc1c2c([nH]c(=O)c1CN)CCC2
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCc1cc2c([nH]c1=O)CCC2)c1ccc(Oc2ccccc2)cc1
Yield: 56.8 %

Procedure:
In a pyrex vial 3-(aminomethyl)-4-methyl-6,7-dihydro-1H-cyclopenta[b]pyridin-2(5H)-one (35 mg, 0.21 mmol), 4-phenoxybenzoic acid (50 mg, 0.23 mmol), HOBT (36 mg, 0.23 mmol) and DMF (1.5 mL) were cooled to 0° C. EDC (45 mg, 0.23 mmol) was then added in one portion and the cold bath was removed. The reaction was mixed at ambient temperature overnight then diluted with MeOH (2 mL) and water (1 mL), filtered through a PTFE screen and purified by reverse-phase HPLC 10-95% gradient of MeCN in water (0.1% TFA). The product fractions were lyophilized to produce N-((2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl)methyl)-4-phenoxybenzamide as a white solid (43 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ 8.70 (t, J=5.71 Hz, 1H), 7.87-7.96 (m, 2H), 7.38-7.47 (m, 2H), 7.15-7.23 (m, 2H), 7.05-7.11 (m, 2H), 6.99-7.05 (m, 2H), 4.19 (d, J=5.61 Hz, 2H), 2.69 (t, J=7.48 Hz, 2H), 2.58 (t, J=7.17 Hz, 2H), 1.98 (quin, J=7.43 Hz, 1H). LRMS (M+H+) m/z: calcd 361.15. found 361.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([CH:45]=O)=[CH:41][C:40]=2[N:47]2[CH:51]=[CH:50][C:49]([CH3:52])=[N:48]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:71]([CH3:73])[CH3:72]>ClC(Cl)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][N:71]([CH3:73])[CH3:72])=[CH:41][C:40]=2[N:47]2[CH:51]=[CH:50][C:49]([CH3:52])=[N:48]2)[C:35]([F:37])([F:36])[F:38])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(C=O)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(CN(C)C)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-formyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (166 mg, 0.23 mmol, see Ex. 25) in dichloroethane (4 mL) and HOAc (10 mg) was added NaBH(OAc)3 (242 mg, 1.15 mmol) and Me2NH (2M in THF, 0.58 mL, 1.15 mmol). The reaction mixture was stirred at RT for 20 h then concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and purified by reverse phase HPLC (MeOH/H2O/HOAc) to provide (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-((dimethylamino)methyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.