Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][C@H:21]([O:23][CH3:24])[CH2:20][N:19]3[CH2:25][C:26]3[CH:27]=[C:28]([CH:36]=[CH:37][CH:38]=3)[O:29][CH2:30][C:31]([O:33]CC)=[O:32])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CCO>[C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][C@H:21]([O:23][CH3:24])[CH2:20][N:19]3[CH2:25][C:26]3[CH:27]=[C:28]([CH:36]=[CH:37][CH:38]=3)[O:29][CH2:30][C:31]([OH:33])=[O:32])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)COc1cccc(CN2C[C@@H](OC)C[C@@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CO[C@H]1C[C@H](c2nc(-c3ccccc3)c(-c3ccccc3)o2)N(Cc2cccc(OCC(=O)O)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of Ethyl 3-{[(2R, 4S)-2-(4,5-diphenyloxazol-2-yl)-4-methoxypyrrolidin-1-yl]methyl}phenoxyacetate (3.00 g) in EtOH (30 mL) was added 1N NaOH solution (6.00 mL) at 5° C., and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1N HCl (6.00 mL) at 5° C. and evaporated. The residue was extracted with EtOAc, washed with water and brine, dried (Na2SO4), and evaporated in vacuo to give 3-{[(2R, 4S)-2-(4,5-diphenyloxazol-2-yl)-4-methoxypyrrolidin-1-yl]methyl}phenoxyacetic acid (2.75 g).
Reaction SMILES: Cl.[NH2:2][OH:3].[NH:4]1[C:8]([CH2:9][C:10]2[S:14][C:13]([C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=2)=[N:7][N:6]=[N:5]1>C(O)C>[NH:4]1[C:8]([CH2:9][C:10]2[S:14][C:13]([C:15](=[N:2][OH:3])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=2)=[N:7][N:6]=[N:5]1
Reactant: NO
Reactant: CCOC(=O)C(=O)c1ccc(Cc2nnn[nH]2)s1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(=NO)c1ccc(Cc2nnn[nH]2)s1
Reaction time: 72 h
Yield: 90.3 %

Procedure:
Hydroxylamine hydrochloride (205 mg) was added to a stirred mixture of ethyl 2-[5-(1-tetrazolylmethyl)thien-2-yl]-2-oxoacetate (Description 50) (394 mg) and ethanol (10 ml). The mixture was left at room temperature for 3 days, then the solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with water and brine and dried over magnesium sulphate. The solution was evaporated to give the product (376 mg) as a mixture of isomers. νmax (nujol) 3131, 1746, 1724 cm-1. δ (CD3COCD3), 1.31-1.39 (3H, m), 4.36 and 4.42 (2H, two q's, J 7.22 Hz), 6.02 and 6.08 (2H, two s's), 7.10 and 7.25 (1H, two d's, J 3.73 Hz), 7.31 and 7.78 (1H, two d's, J 3.98 Hz), 9.26 and 9.30 (1H, two s's), 11.14 and 12.25 (1H, two broad s's). m/z 280 (M-H)-. [Found: m/z 281.0584. Calc. for C10H11N5O3S; 281.0583].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([S:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)(=[O:22])=[O:21])[CH2:16][CH2:15]1)=[O:13].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][C:12]([N:14]1[CH2:15][CH2:16][N:17]([S:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)(=[O:21])=[O:22])[CH2:18][CH2:19]1)=[O:13]
Reactant: Oc1ccc(F)cc1F
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(COc1ccc(F)cc1F)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 73.8 %

Procedure:
2,4-difluoro phenol (110 mg, 0.85 mmol), 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 5, 0.3 g, 0.85 mmol) and anhydrous potassium carbonate (0.352 g, 2.55 mmol) were stirred for over night in dry acetonitrile (20 mL). The mixture was poured into a large volume of water and the solution extracted with ether. Un-reacted phenol was removed with cold 1N NaOH solution. The ether extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by re-crystallization to yield the title compound (280 mg, 73.87% yield) as an off-white solid.
Reaction SMILES: [CH2:1]([C:3]1([CH2:24][CH3:25])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][C:13]([O:16]CC1C=CC=CC=1)=[CH:12][CH:11]=3)[CH3:2]>[Pd].C(O)C>[CH2:24]([C:3]1([CH2:1][CH3:2])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[CH3:25]
Reactant: CCC1(CC)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Agent: [Pd]
Solvent: CCO
Product: CCC1(CC)OCCc2c1[nH]c1ccc(O)cc21
Reaction time: 18 h
Yield: 109.8 %

Procedure:
A mixture consisting of 10% Pd/c on charcoal (1.0 g), ethanol (125 mL), and 1,3,4,9-tetrahydro-1,1-diethyl-6-(phenylmethoxy)pyrano[3,4-b]indole (6.5 g, 0.0193 mol), of Step A, is hydrogenated at 30 psi for 18 hours. The reaction mixture is filtered and concentrated to give 5.2 g of product which is used in the next reaction without further purification.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].S(Cl)([Cl:13])(=O)=O>C1(C)C=CC=CC=1>[Cl:13][CH:3]([C:2](=[O:1])[CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCC(=O)CC(=O)OC
Solvent: Cc1ccccc1
Product: CCC(=O)C(Cl)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of 104 g (0.8 mol) of methyl 3-oxopentanoate (available from Wacker Chemical) in 500 ml of toluene was cooled to 0 to 5° C., and 108 g (0.8 mol) of sulfuryl chloride was added thereto dropwise, followed by stirring at room temperature overnight. Toluene was removed by evaporation to give 131.6 g (0.8 mol; yield: 100%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.[Li+].CCC[CH2-].Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31].[NH4+].[Cl-]>O1CCCC1.CCCCCC>[CH3:21][O:20][C:14]1[C:13]2([C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:12][C:11]3=[C:6]4[C:5]52[C:17](=[CH:16][CH:15]=1)[CH:18]([CH2:19][C:7]4=[CH:8][CH:9]=[C:10]3[O:22][CH3:23])[N:2]([CH3:1])[CH2:3][CH2:4]5
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Reactant: CCOC(=O)Cl
Agent: [CH2-]CCC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C12Oc3c(OC)ccc4c3C13CCN(C)C(C4)C3=CC=C2OC
Temperature: -78 °C
Yield: 64 %

Procedure:
A solution of 1 g of thebaine 1 in 20 mL of tetrahydrofuran (THF) was placed in a flame-dried round-bottom flask, and 1.92 mL (1.5 equiv) of a 2.5 M solution of N-butyllithium in hexane was added while stirring at −78° C. under nitrogen. The mixture immediately turned deep wine-red and was stirred for 45 min at −78° C. Ethyl chloroformate (0.36 mL, 1.2 equiv) was added and the mixture was stirred for 4 h at −78° C. The color changed to orange-yellow. Saturated NH4Cl (5 mL) was then added per drop and most part of the solvent was removed under reduced pressure. The residual brown product was dissolved in chloroform, washed with brine solution, dried (Na2SO4) and concentrated. The residue was subjected to column chromatography on silica gel using dichloromethane-methanol (95:5) as the eluent to isolate 0.786 g (64% yield) of 5-carbethoxythebaine 2 as a pale yellow foam. 1H NMR (CDCl3, 400 MHz): δ 6.67 d (1H, J=8.6 Hz), 6.61 d (1H, J=8.6 Hz), 5.2 d (1H, J=6.2 Hz), 5.19 d (1H, J=6.2 Hz), 4.44-4.33 m (1H), 4.28-4.16 m (1H), 3.85 s (3H), 3.66 d (1H, J=6.2 Hz), 3.57 s (3H), 3.29 d (1H, J=17.9 Hz), 2.87-2.74 m (1H), 2.7 d (1H, J=7.0 Hz), 2.68-2.57 m (1H), 2.45 s (3H), 2.16 td (1H, J=4.6, 12.5 Hz), 1.64 d (1H, J=13.3 Hz), 1.30 t (3H, J=7.0 Hz). 13C NMR (CDCl3, 100 MHz): δ 168.31, 152.64, 143.62, 142.66, 132.30, 130.56, 127.38, 119.86, 113.44, 112.09, 97.05, 95.42, 61.80, 61.26, 56.45, 55.27, 49.09, 45.49, 42.12, 31.01, 30.42, 14.21. MS (ESI): m/z 384.1 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]([C:20]3[C:28]4[CH:27]=[N:26][CH:25]=[N:24][C:23]=4[N:22]([CH2:29][C:30]([O:32]C)=[O:31])[CH:21]=3)=[O:19])[CH:15]=[N:16][CH:17]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[K+:35]>CO>[K+:35].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]([C:20]3[C:28]4[CH:27]=[N:26][CH:25]=[N:24][C:23]=4[N:22]([CH2:29][C:30]([O-:32])=[O:31])[CH:21]=3)=[O:19])[CH:15]=[N:16][CH:17]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)Cn1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])Cn1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a suspension of methyl {5-[(5-{[(4-chlorophenyl)acetyl]amino}pyridin-3-yl)carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}acetate (Example 306, 197 mg, 0.425 mmol) in MeOH (4 mL) was added an aqueous solution of KOH (0.425 mL of a 1M solution, 0.425 mmol) and then further MeOH (4 mL) was added. The reaction was stirred for 2 hours at room temperature. The reaction was concentrated in vacuo to give the title compound as a light brown solid in 99% yield, 205 mg.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].Cl>C(O)C.O=[Pt]=O>[NH2:1][C@@H:2]([CH2:6][CH:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)[C:3]([OH:5])=[O:4]
Reactant: N[C@@H](Cc1ccncc1)C(=O)O
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: N[C@@H](CC1CCNCC1)C(=O)O

Procedure:
To a solution of (2S)-2-amino-3-(pyridin-4-yl)propanoic acid LXXIII (660 mg, 4.0 mmol) in ethanol (120 mL) was added 1 N HCl (10 mL) and PtO2 (150 mg). The mixture was vigorously shaken 70 psi H2 in a Parr apparatus for 48 h. The mixture was filtered through Celite and the filtrate was concentrated to dryness giving crude (2S)-2-amino-3-(piperidin-4-yl)propanoic acid LXXIV as the hydrochloride salt (988 mg). ESIMS found for C8H16NO2 m/z 172.0 (M+).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH2:7][C:8]1[C:29]([OH:30])=[CH:28][C:11]2[CH2:12][C@@H:13]3[C:18]([CH3:20])([CH3:19])[C@:17]([CH3:21])([C:10]=2[CH:9]=1)[CH2:16][CH2:15][N:14]3[C:22](=[O:27])[C:23]([F:26])([F:25])[F:24].C(N(CC)CC)C.N>ClCCl.CO>[OH:30][C:29]1[C:8]([NH:7][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:9][C:10]2[C@@:17]3([CH3:21])[C:18]([CH3:20])([CH3:19])[C@H:13]([N:14]([C:22](=[O:27])[C:23]([F:26])([F:24])[F:25])[CH2:15][CH2:16]3)[CH2:12][C:11]=2[CH:28]=1
Reactant: O=C(Cl)C1CC1
Reactant: CC1(C)[C@H]2Cc3cc(O)c(N)cc3[C@]1(C)CCN2C(=O)C(F)(F)F
Agent: N
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC1(C)[C@H]2Cc3cc(O)c(NC(=O)C4CC4)cc3[C@]1(C)CCN2C(=O)C(F)(F)F
Reaction time: 2 h

Procedure:
Cyclopropylcarbonyl chloride (0.13 mL) is added to a solution of 1-[(2R,6S)-8-amino-9-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone (0.50 g) and triethylamine (0.25 mL) in dichloromethane (3 mL). After stirring the solution at room temperature overnight, concentrated aqueous ammonia solution (1 mL) and methanol (2 mL) are added and the resulting mixture is stirred for additional 2 h. Then, the solution is concentrated and water is added to the residue. The resulting mixture is extracted with ethyl acetate and the combined organic extracts are washed with brine and dried (MgSO4). The solvent is removed under reduced pressure to give the crude title compound that is used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28](=[O:34])[CH:29]=[CH:30][C:31](O)=[O:32])[CH3:26].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.O>[CH2:25]([O:27][C:28](=[O:34])[CH:29]=[CH:30][C:31]([N:22]1[CH2:23][CH2:24][N:19]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:7]=2)[CH2:20][CH2:21]1)=[O:32])[CH3:26]
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Reactant: CCOC(=O)C=CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C=CC(=O)N1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)CC1
Reaction time: 0.33 h
Yield: 91 %

Procedure:
To 2-(7-methyl-4-piperazin-1-yl-quinazolin-2-yl)-phenol (787 mg, 2.46 mmol) in 8 mL of CH2Cl2 at room temperature was added sequentially but-2-enedioic acid monoethyl ester (531 mg, 3.69 mmol), triethylamine (686 μL, 4.92 mmol), BOP (1.63 g, 3.69 mmol). The reaction mixture was stirred for 20 min and diluted with water and CH2Cl2. The organic layer was separated and dried over Na2SO4, and the solvent was removed under reduced pressure to give an oil. The residue was subjected to purification by normal phase LC using 10-100% EtOAc-hexanes to give 4-{4-[2-(2-Hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-oxo-but-2-enoic acid ethyl ester (1.00 g, 91% yield). LC/MS: m/z 447.3 (M+H)+ at 2.93 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.CN1CC[CH2:19][C:18]1=O>C1C=C2C(C=C(C([O-])=O)C=C2)=CC=1.C1C=C2C(C=C(C([O-])=O)C=C2)=CC=1.[Zn+2]>[CH:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)=[CH2:19]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: CN1CCCC1=O
Agent: O=C([O-])c1ccc2ccccc2c1
Agent: [Zn+2]
Product: C=COc1ccc(C(=O)c2ccccc2)cc1
Temperature: 190 °C

Procedure:
A mixture of 650 g of 4-hydroxybenzophenone (98% by weight, Avocado, Research Chemicals Ltd.), 750 ml of N-methylpyrrolidone (>99% by weight, BASF AG) and 60 g of zinc naphthenate (Nusa; zinc salts of naphthenic acids, zinc content 12% by weight) was charged with stirring to a 2.5 l autoclave and flushed with nitrogen. After it had been heated to 190° C., injection was carried out first with nitrogen to 2 bar and then with acetylene to 20 bar. During the reaction, further acetylene was supplied to replace that consumed by reaction, so as to maintain a constant pressure of 20 bar. After a reaction time of 12 hours the batch was cooled to 20–25° C. (room temperature) and let down to atmospheric pressure. The solvent was distilled off under reduced pressure at a bridge temperature of from 70 to 80° C. with a pressure of 1 mbar (absolute). 310 g of Pluriol® E 600 (polyethylene glycol, trademark of BASF AG) were then added and the product was purified by a Sambay distillation at 1.2 mbar (absolute) and a bridge temperature of 163° C. This gave a total of 522 g of 4-vinyloxybenzophenone having a purity of from 96 to 99% by weight and a melting point of 58° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:6]([CH2:8][N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(Cl)ccc2N2CCCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(N2CCCC2)c(CN2CCNCC2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 132.7 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 4-[[5-chloro-2-(pyrrolidin-1-yl)phenyl]methyl]piperazine-1-carboxylate (500 mg, 1.32 mmol, 1.00 equiv), dichloromethane (10 mL). The mixture was cooled to 0° C. Trifluoroacetic acid (1 mL) was added dropwise at 0° C. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure to yield 490 mg (crude) of 1-[[5-chloro-2-(pyrrolidin-1-yl)phenyl]methyl]piperazine as a brown solid. LCMS (ESI, m/z): 280 [M+H]+.
Reaction SMILES: [NH2:1]O.[F:3][C:4]([F:19])([C:15]([F:18])([F:17])[F:16])[CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=O.[OH-].[Na+]>CO.C(O)(C(F)(F)F)=O.[Zn]>[F:3][C:4]([F:19])([C:15]([F:18])([F:17])[F:16])[CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[NH2:1]
Reactant: NO
Reactant: O=C(CCC(F)(F)C(F)(F)F)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NC(CCC(F)(F)C(F)(F)F)c1ccccn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Hydroxylamine (0.216 mL, 3.53 mmol) was added to a solution of 4,4,5,5,5-pentafluoro-1-(pyridin-2-yl)pentan-1-one (0.894 g, 3.53 mmol) in MeOH (10.87 mL) and the resulting solution was stirred at 25° C. for 5 h. Another 1 eq. hydroxylamine was added and the reaction was stirred overnight. Another 2 eq hydroxylamine was added and the reaction was stirred overnight. The reaction mixture was concentrated in vacuo and the resulting residue was diluted with EtOAc and the resulting organic phase was washed with water and brine, then dried (Na2SO4) and concentrated in vacuo to give the crude oxime, as a colorless solid. This was redissolved in TFA (6.52 mL) and cooled to 0° C. Zinc (1.155 g, 17.66 mmol) was added in one portion. After 3 h at 0° C. the reaction mixture was poured into a mixture of ice and 5 N aq. NaOH. The pH was adjusted to pH 10. The mixture was extracted with DCM (3×). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give the desired amine product. m/z=255.1 (M+H).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].Br[CH2:10][CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:1]([CH:3]([CH2:10][CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(CBr)OCC
Reactant: CCOC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C(C#N)CC(OCC)OCC
Yield: 29.2 %

Procedure:
A mixture of ethyl 2-cyanoacetate (1000 g, 8.84 mol), 2-bromo-1,1-diethoxyethane (400 g, 2.03 mol), KI (33.4 g, 0.201 mol) and K2CO3 (280 g, 2.03 mol) was heated to reflux for 12 hrs. The reaction mixture was diluted with CH2Cl2 (1000 mL) and the resulting precipitate was filtered off and the filtrate was washed with brine and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue distilled to give the title compound (136 g, 29.2% yield) as a light yellow oil that was used as is in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:27]([O:29]CC)=[O:28])=[C:21]([C:23]([NH:25][CH3:26])=[O:24])[N:22]=2)[CH2:14][C@@H:13]1[O:32][CH3:33])=[O:10].[OH-].[Ba+2].[OH-].O.Cl>CO>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:27]([OH:29])=[O:28])=[C:21]([C:23]([NH:25][CH3:26])=[O:24])[N:22]=2)[CH2:14][C@@H:13]1[O:32][CH3:33])=[O:10]
Reactant: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OC)C2)nc1C(=O)NC
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNC(=O)c1nc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OC)C2)sc1C(=O)O

Procedure:
To a suspension/solution of ethyl 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-[(methylamino)carbonyl]-1,3-thiazole-5-carboxylate (0.078 g, 0.15 mmol, Example 218) in methanol (2 mL) was added barium hydroxide (0.052 g, 0.30 mmol) and water (0.5 mL). After stirring several hours the reaction was complete. The reaction was acidified with 1N HCl and then concentrated to remove methanol. The residue was extracted with EtOAc (×3), dried with MgSO4 and concentrated to a white solid (0.059 g). MS (ES) M+H+: 490 for C18H21Cl2N5O5S; NMR: 1.76 (s, 2 H) 2.18 (s, 3 H) 2.86 (s, 3 H) 3.38 (s, 3 H) 3.56 (s, 2 H) 4.02 (s, 1 H) 4.27 (s, 2 H) 4.40 (s, 1 H) 7.15 (s, 1 H) 9.38 (s, 1 H) 12.15 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:15][CH2:16][CH:17]([CH:19]1[CH2:21][CH2:20]1)[OH:18].C(N(CC)CC)C>O1CCOCC1.O>[CH:19]1([CH:17]([OH:18])[CH2:16][NH:15][C:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:10])[CH2:21][CH2:20]1
Reactant: NCC(O)C1CC1
Reactant: O=C(O)c1ccc(Cl)nn1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(NCC(O)C1CC1)c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.1 %

Procedure:
To the solution of 6-chloropyridazine-3-carboxylic acid (375 mg, 2.37 mmol) in 5 mL of dioxane was added thionyl chloride (420 mg, 3.56 mmol). The mixture was refluxed for 4 hours and the solvent was removed in vacuo. 2-Amino-1-cyclopropylethanol (479 mg, 4.73 mmol) in 5 mL of dioxane was added to the residue and followed by the addition of triethylamine (0.2 mL). The mixture was stirred at ambient temperature overnight. Water was added to the mixture and then extracted with ethyl acetate. The organic extract was separated, washed with water and brine; dried over Na2SO4. The residue after removal of solvent was purified by column chromatography eluted with ethyl acetate:hexane (70:30) to yield 58 mg of the white desired product.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:11]([CH3:19])[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=1)(C(C)(C)C)(C)C.O1CCCC1.C(O)(=O)C>O>[OH:8][CH2:9][C:10]1[N:11]([CH3:19])[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=1
Reactant: Cn1c(CO[Si](C)(C)C(C)(C)C)nc2cnccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cn1c(CO)nc2cnccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.6 %

Procedure:
A solution of 3.00 g of 2-t-butyldimethylsilyloxymethyl-1-methyl-1H-imidazo[4,5-c]pyridine (prepared as described in Preparation 72) in 60 ml of a 1:1:1 by volume mixture of tetrahydrofuran, acetic acid and water was stirred at room temperature for 1 hour and then at 60° C. for 5 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation. The resulting residue was mixed with an aqueous solution of sodium hydrogencarbonate and then concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 1.97 g of the title compound, melting at 285-290° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[N:14]=3)[CH:11]=2)=[N:2]1.CC(C)(OC(NC1N=C(C2C=CC3N(C=C(C(O)=O)N=3)C=2)C=CC=1)=O)C>>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=3)[CH:11]=2)=[N:2]1
Reactant: CCOC(=O)c1cn2cc(-c3cc[nH]n3)ccc2n1
Agent: CC(C)(C)OC(=O)Nc1cccc(-c2ccc3nc(C(=O)O)cn3c2)n1
Product: O=C(O)c1cn2cc(-c3cc[nH]n3)ccc2n1
Yield: 99.1 %

Procedure:
128 mg of ethyl 6-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylate are saponified under conditions similar to those described for the preparation of Intermediate 11 (step 11.3) to give 113 mg of 6-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-2-carboxylic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C@H:22]([OH:24])[CH3:23])=[CH:17][CH:16]=1>>[OH:24][C@H:22]([CH3:23])[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])=[CH:16][CH:17]=1
Reactant: C[C@@H](O)Cc1ccc(N)cc1
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Product: CC(=O)c1ccc(Nc2ccc(C[C@@H](C)O)cc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 162 from 1-(4-chloro-3-nitrophenyl)ethanone and (2R)-1-(4-aminophenyl)-2-propanol (step 2).