Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+].Cl.[CH2:20]([O:22][C:23](=[O:28])[CH:24]([CH3:27])[CH2:25][NH2:26])[CH3:21]>CO>[CH2:20]([O:22][C:23](=[O:28])[CH:24]([CH3:27])[CH2:25][NH:26][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:21]
Reactant: CCOC(=O)C(C)CN
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CCOC(=O)C(C)CNCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.1 %

Procedure:
4-Fluorobenzaldehyde (0.622 mL, 5.80 mmol), sodium acetate (0.951 g, 11.6 mmol), powdered/activated 4 Å molecular sieves (2.0 g) and sodium cyanoborohydride (0.729 g, 11.6 mmol) were added sequentially to a solution of racemic 3-amino-2-methyl-propionic acid ethyl ester hydrochloride (0.972 g, 5.80 mmol) in methanol (30 mL) at 25° C. The mixture was stirred at 25° C. for 20 h, and then was filtered through Celite. The Celite was washed with methanol (2×30 mL) and the combined filtrate and washings were concentrated in vacuo. The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0-80% ethyl acetate in hexanes) to afford rac-3-(4-fluoro-benzylamino)-2-methyl-propionic acid ethyl ester (0.821 g, 3.43 mmol, 59%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 1.18 (3H, d, J=7.2 Hz), 1.26 (3H, t, J=6.9 Hz), 2.63-2.72 (2H, m), 2.84-2.91 (1H, m), 3.75 (1H, d, J=13.3 Hz), 3.79 (1H, d, J=13.4 Hz), 4.14 (2H, q, J=6.9 Hz), 6.97-7.01 (2H, m), 7.25-7.29 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]=[O:14])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]([Mg]Br)=[CH2:18]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C@H:13]([OH:14])[CH:17]=[CH2:18])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](C=O)COC1(C)C
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=C[C@@H](O)[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a −78° C. solution of (S)-Garner aldehyde (3, 7.0 g, 30.5 mmol) in dry THF (50 mL) under N2 was slowly added vinylmagnesium bromide (92 mL, 92 mmol, a 1 M solution in THF) via cannula. After the cloudy yellow solution was stirred for 2 h at −78° C., it was warmed to 0° C., and the reaction was quenched with saturated aqueous NH4Cl solution (60 mL). The product was extracted with Et2O (2×60 mL). The combined organic layers were washed with brine (60 mL), dried (Na2SO4), and concentrated. The mixture of erythro and threo diastereomers was separated by column chromatography by gravity (hexane/EtOAc 5:1) to afford 4 (4.8 g, 62%) and its C3-epimer 4a (0.8 g, 10.2%). Compound 4: [α]25D −37.7° (c 1.8, CHCl3); Rf 0.26 (EtOAc/hexane 1:3); 1H NMR (CDCl3) δ 1.48 (s, 3H), 1.50 (s, 9H), 1.58 (s, 3H), 3.91 (m, 2H), 3.98 (m, 1H), 4.25 (m, 1H), 4.39 (m, 1H), 5.24 (m, 1H), 5.38 (m, 1H), 5.85 (m, 1H); 13C NMR (CDCl3) δ 24.2, 26.3, 28.3, 61.8, 64.4, 73.3, 81.4, 94.4, 116.1, 117.8, 137.6, 155.0; ESI-HRMS [M+Na]+ C13H23NO4Na calcd for m/z 280.1525, found 280.1519.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:21]O>>[CH3:14][C:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)([CH3:15])[C:11]([O:13][CH3:21])=[O:12]
Reactant: CC(C)(C(=O)O)c1ccc([N+](=O)[O-])cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1

Procedure:
To a solution of 5 g of 2-(4-nitrophenyl)-2-methylpropionic acid in 40 mL of methanol, under argon, are added 4 mL of sulphuric acid. The reaction medium is heated at reflux for 3 hours and concentrated under reduced pressure. The residue is taken up in a mixture of ice-water and dichloromethane, the phases are separated and the organic phase is dried over magnesium sulphate and filtered. The filtrate is concentrated under reduced pressure to give 5.18 g of methyl 2-methyl-2-(4-nitrophenyl)propanoate in the form of a pale yellow solid, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]([CH:4](O)[CH2:5][CH2:6][C:7](=[CH2:10])[CH:8]=[CH2:9])=[CH2:3].[C:12](OCC)([O:17]CC)([O:14][CH2:15][CH3:16])[CH3:13].C(O)(=O)CC>N1C=CC=CC=1>[CH3:1]/[C:2](=[CH:4]\[CH2:5][CH2:6][C:7](=[CH2:10])[CH:8]=[CH2:9])/[CH2:3][CH2:13][C:12]([O:14][CH2:15][CH3:16])=[O:17]
Reactant: C=CC(=C)CCC(O)C(=C)C
Reactant: CCOC(C)(OCC)OCC
Solvent: CCC(=O)O
Solvent: c1ccncc1
Product: C=CC(=C)CC/C=C(\C)CCC(=O)OCC
Temperature: 135 °C
Yield: 70.5 %

Procedure:
A mixture of 2-methyl-6-methylene-1,7-octadien-3-ol (34 g, 0.224 M), triethyl orthoacetate (80 g, 0.5 M) and propionic acid (1 ml) is heated at 135° C. (bath temperature) under nitrogen for four hours. The resulting mixture is cooled to room temperature and treated with pyridine (1 ml). Most of the excess reagent is removed in vacuo (high vacuum pump) and the residue is purified by column chromatography on silica gel (300 g) with 5% ether in petroleum ether, to give ethyl 4-methyl-8-methylene-(E)-4,9-decadienoate (35 g, 70%) as a colorless liquid.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:26]([NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:27])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)Nc2ccccc2)CC1
Temperature: 50 °C
Yield: 67.2 %

Procedure:
To a stirred solution of 1-(2-tert-butylphenyl)piperazine dihydrochloride (0.120 g, 0.41 mmol) in pyridine (4.0 mL) was added phenyl isocyanate (0.055 g, 0.46 mmol) and the reaction mixture was heated to 50° C. After 18 h the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 90:10 to 0:100 heptane/ethyl acetate, gradient elution) to provide 4-(2-tert-butylphenyl)-N-phenylpiperazine-1-carboxamide (0.093 g, 67%) as an off-white solid, mp 68-72° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([C:6]([Cl:9])=[CH:7][CH:8]=1)[NH2:5].[OH-].[Na+].S(OC)(O[CH3:17])(=O)=O.C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[C:3]([F:10])=[C:4]([NH:5][CH3:17])[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: Nc1c(Cl)ccc(Br)c1F
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1c(Cl)ccc(Br)c1F
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 65.3 %

Procedure:
3-Bromo-6-chloro-2-fluoroaniline (1.2 g, 5.2 mmol) was dissolved in THF (12 mL) in a 100 mL round bottomed flask and treated with tetra-N-butyl ammonium bromide (0.015 g, 0.05 mmol) and powdered sodium hydroxide (0.83 g, 20.9 mmol) with stirring. After 5 minutes, the dark mixture was treated with dimethyl sulfate (1.3 g, 10.4 mmol) and the mixture heated at 60° C. for 2 hours. Analysis by TLC (hexanes: ethyl acetate/20:1) indicated some starting material remained. Added additional dimethyl sulfate (0.66 g, 5.2 mmol) and continued heating for 1.5 hour then stirred at room temperature overnight. The reaction was partitioned between diethyl ether and water and the layers separated and the aqueous phase extracted with ether. The combined ether layers were washed with water and dried (MgSO4). Filtration, concentration and purification by flash silica gel chromatography (hexanes) gave N-(3-bromo-6-chloro-2-fluorophenyl)-N-methylamine (0.81 g) as a colorless oil: 1H NMR (300 MHz, CDCl3): δ 6.93 (dd, 1H, J=8.4), 6.83 (dd, 1H), 4.00 (bs, 1H), 3.09 (d, 3H).
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[O:13][CH2:14][CH2:15][CH3:16])[CH3:3].Cl[C:18]1[N:19]=[N:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CN1C(=O)CCC1>[Br:12][C:10]1[CH:9]=[CH:8][C:7]([O:13][CH2:14][CH2:15][CH3:16])=[C:6]([CH:11]=1)[CH2:5][N:4]([C:18]1[N:19]=[N:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(Br)cc1CNCC
Reactant: N#Cc1ccc(Cl)nn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCCOc1ccc(Br)cc1CN(CC)c1ccc(C#N)nn1
Temperature: 110 °C
Yield: 76.1 %

Procedure:
N-ethyl 2-propoxy-5-bromobenzylamine hydrochloride 2 (5.17 g, 16.8 mmol) and 3-chloro-6-cyanopyridazine (2.65 g, 16.8 mmol) were dissolved in NMP (25 ml) and sodium hydrogen carbonate added (3.54 g, 42.1 mmol). The mixture was heated at 110 ° C. under argon for 7.5 hours and then allowed to cool to ambient temperature. The mixture was poured into ethyl acetate (200 ml) washed with water (5×200 ml) and brine (200 ml), the organic phase dried over MgSO4 and concentrated in vacuo. The residue was purified by MPLC (20% ethyl acetate/hexane) and then crystallised from ether/hexane to give the title product (4.80 g, 76%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][C:3]=1[OH:12].FC(F)(F)S(O[CH2:19][C:20]([F:23])([F:22])[F:21])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=CC=1C([O-])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>C1COCC1.CCOC(C)=O.[Cl-].[Na+].O.C(Cl)Cl.Cl>[F:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[O:8])=[CH:4][C:3]=1[O:12][CH2:19][C:20]([F:23])([F:22])[F:21]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(F)c(O)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(F)c(OCC(F)(F)F)c1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Methyl 4-fluoro-3-hydroxybenzoate (10 g, 58.8 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (20.4 g, 88 mmol), and Cs2CO3 (51 g, 157 mmol) were dissolved in 200 ml of THF and stirred at 65° C. overnight. Cooled to room temperature and diluted with EtOAc and brine. Layers were separated and the aqueous layer was extracted twice with EtOAc. The organic extracts were combined, dried (Na2SO4), and concentrated to yield 14.82 g (58.8 mmol, 100%). A solution of hydroxybenzoate intermediate (14.82 g, 58.8 mmol) in 150 ml of THF was cooled to 0° C., treated with LiAlH4 (3.95 g, 104 mmol), and allowed to warm to room temperature over 1 hour. Reaction quenched sequentially with 4 ml of water, 4 ml of 1 N NaOH, and 12 ml of water and left to stir for thirty minutes. Reaction was filtered and the filtrate concentrated to a yellow oil (13.33 g, 59 mmol, 100%). A solution of DMSO (10.26 ml, 145 mmol) in 10 ml of dry CH2Cl2 was added dropwise to a solution of oxalyl chloride (33.3 ml, 66.6 mmol) in an additional 100 ml of dry CH2Cl2 and stirred at −78° C. for 20 minutes. A solution of alcohol intermediate (13.33 g, 59 mmol) in 50 ml dry CH2Cl2 was then added and the reaction was stirred at −78° C. for 30 minutes. The reaction was treated with triethylamine (30.8 ml, 221 mmol) and stirred at −78° C. for 30 minutes. The reaction was warmed to 0° C., stirred for 30 minutes, and then allowed to warm to room temperature. Diluted with 1 N HCl and CH2Cl2. The aqueous layer was separated and extracted once with CH2Cl2. The organic layers were combined and washed sequentially with sat'd NaHCO3, 10 vol % bleach in water, and brine. The organic layer was dried (Na2SO4) and concentrated to a yellow solid (12.37 g, 55.7 mmol, 94%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:23][O:24][CH3:25])[CH:10]([N:12]2C(=O)C3=CC=CC=C3C2=O)[CH3:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.O.NN>C(O)C>[CH3:25][O:24][N:23]=[C:9]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)[CH:10]([NH2:12])[CH3:11]
Reactant: CON=C(c1ncc(Cl)cc1Cl)C(C)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CON=C(c1ncc(Cl)cc1Cl)C(C)N
Yield: 80.9 %

Procedure:
To 810 mg of N-[2-(3,5-dichloropyridin-2-yl)-2-methoxyinnino-1-methylethyl]phthalimide in 30 ml of ethanol, 161 mg of hydrazine monohydrate was added and refluxed with heating for 1 hour with stirring. After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting residue was mixed with 20 ml of water and extracted with ethyl acetate (30 ml×1). The resulting organic layer was washed with water (20 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 430 mg of the desired crude product as a pale yellow oil. The oil was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C@H:4]1[C@:21]2(O)[C@:16](C)([CH2:17][CH2:18][C:19](=[O:23])[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:25])[CH2:9][CH2:8]3)[CH2:5]1)[C:2]#[CH:3].C([C@H]1[C@]2(O)[C@H](CCC(=O)C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)C#C>CC(C)=O.CCCCCC>[CH2:1]([C@H:4]1[C:21]2[C@H:16]([CH2:17][CH2:18][C:19](=[O:23])[CH:20]=2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:25])[CH2:9][CH2:8]3)[CH2:5]1)[C:2]#[CH:3]
Reactant: C#CC[C@@H]1C[C@H]2[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C[C@]12O
Agent: C#CC[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@H]2CCC(=O)C[C@]12O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: C#CC[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@H]2CCC(=O)C=C12

Procedure:
Using a procedure similar to that described at Example 1 except replacing the 6β-propargyl-5α-hydroxyandrostane-3,17-dione (10) used therein with 6β-propargyl-5α-hydroxyestrane-3,17-dione (11), the title compound was prepared; 60%; m.p. 194°-195° C. (from acetone/hexane); 1H-NMR (CDCl3) δ 0.94 (s, 3H, 18-CH3), 2.73 (m, 1H), 5.94 (s, 1H, 4-H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([OH:23])=[O:22])[C:15]=3[N:14]=[C:13]2[C:24](=[O:35])[NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]3[CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[O:10])=[N:6][CH:7]=1.[CH:36]1([CH2:39]O)[CH2:38][CH2:37]1>>[CH:36]1([CH2:39][O:22][C:21]([C:20]2[C:15]3[N:14]=[C:13]([C:24](=[O:35])[NH:25][CH:26]4[CH2:31][CH2:30][N:29]([CH:32]5[CH2:34][CH2:33]5)[CH2:28][CH2:27]4)[N:12]([CH2:11][C:9](=[O:10])[NH:8][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=4)[C:16]=3[CH:17]=[CH:18][CH:19]=2)=[O:23])[CH2:38][CH2:37]1
Reactant: OCC1CC1
Reactant: O=C(Cn1c(C(=O)NC2CCN(C3CC3)CC2)nc2c(C(=O)O)cccc21)Nc1ccc(Cl)cn1
Product: O=C(Cn1c(C(=O)NC2CCN(C3CC3)CC2)nc2c(C(=O)OCC3CC3)cccc21)Nc1ccc(Cl)cn1

Procedure:
1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid cyclopropylmethyl ester was prepared by a procedure according to example 69 starting from 589.0 mg (1.19 mmol) 1-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid and 1.92 mL (23.8 mmol) cyclopropyl-methanol.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][C:24](=[O:26])[CH3:25])[CH:20]=2)[NH:15][CH:14]=1)=[O:4]>CO>[OH:26][CH:24]([CH3:25])[CH2:23][CH2:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:12][C@H:8]1[CH2:9][CH2:10][CH2:11][N:7]1[CH2:6][CH2:5][C:3](=[O:4])[N:2]([CH3:27])[CH3:1]
Reactant: CC(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3CCC(=O)N(C)C)c2c1
Solvent: CO
Product: CC(O)CCc1ccc2[nH]cc(C[C@H]3CCCN3CCC(=O)N(C)C)c2c1

Procedure:
Obtained from the title compound of Example 70, by a procedure similar to that described in Example 38, as a foam. Rf 0.28 (SS 7). [α]D25 +51° (c=0.1, CH3OH). Found: C,69.12; H,9.34; N,10.93. C22H33N3O2 ; 0.67 requires C,68.90; H,9.02; N,10.96%. LRMS: m/z 372.2 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2=[N:12][N:13]([CH2:21][CH2:22][O:23][CH3:24])[C:14]([CH2:15][C:16]([CH3:20])([CH3:19])[C:17]#[N:18])=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C([OH:27])C.[OH-].[Na+].OO>O>[NH2:1][C:2]1[C:11]2=[N:12][N:13]([CH2:21][CH2:22][O:23][CH3:24])[C:14]([CH2:15][C:16]([CH3:20])([CH3:19])[C:17]([NH2:18])=[O:27])=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCO
Reactant: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)C#N
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)C(N)=O
Temperature: 50 °C

Procedure:
3-[4-Amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-2,2-dimethylpropanenitrile (436 mg, 1.35 mmol), ethanol (5 mL), sodium hydroxide (0.056 mL of 6 N), and 30% w/w hydrogen peroxide (0.54 mL, 4.7 mmol) were combined and heated at 50° C. for 18.5 hours. Water was added, and the ethanol was removed under reduced pressure. The mixture was extracted with chloroform, and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by IFC (silica cartridge) and recrystallized from 75% ethyl acetate in hexane. The crystals were washed with 50% ethyl acetate in hexane, dried on the vacuum filter funnel overnight, and further dried under vacuum at 9 Pa and 98° C. to provide 3-[4-amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-2,2-dimethylpropanamide as a white solid, mp 225-226° C.
Reaction SMILES: C1COCC1.Br.[CH3:7][C:8]1([CH3:31])[CH2:17][CH2:16][C:15]([CH3:19])([CH3:18])[C:14]2[CH:13]=[C:12]([C:20]3[N:21]=[C:22]([CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[S:23][CH:24]=3)[CH:11]=[CH:10][C:9]1=2.O=[CH:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:7][C:8]1([CH3:31])[CH2:17][CH2:16][C:15]([CH3:18])([CH3:19])[C:14]2[CH:13]=[C:12]([C:20]3[N:21]=[C:22]([CH:25]4[CH2:30][CH2:29][N:28]([CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:27][CH2:26]4)[S:23][CH:24]=3)[CH:11]=[CH:10][C:9]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCNCC4)n3)ccc21
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCN1CCC(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10 ml of THF and 200 μl of glacial acetic acid are added to 200 mg (0.46 mmol) of 4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine hydrobromide, and 154 mg (0.92 mmol) of tert-butyl (2-oxoethyl)carbamate are added. 195 mg (0.92 mmol) of sodium trisacetoxyborohydride are subsequently added, and the reaction mixture is stirred at room temperature for 24 h. The reaction mixture is filtered, the mother liquor is evaporated, and the residue is purified by preparative HPLC, giving “A37”;
Reaction SMILES: [F:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]#[N:6].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33](Cl)=[C:28]3[CH:27]=[N:26]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33]([O:11][C:3]4[C:4]([C:5]#[N:6])=[CH:7][CH:8]=[C:9]([F:10])[C:2]=4[F:1])=[C:28]3[CH:27]=[N:26]2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: N#Cc1ccc(F)c(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4c(C#N)ccc(F)c4F)ncnc32)CC1
Temperature: 160 °C
Yield: 17.2 %

Procedure:
A mixture of 3,4-difluoro-2-hydroxy-benzonitrile (Oakwood Products, Inc., West Columbia, S.C., USA; 14 mg, 0.089 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.089 mmol), and potassium carbonate (27 mg, 0.196 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to give 4-[4-(6-cyano-2,3-difluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (7 mg, 17%) as a white solid. Mass spectrum MH+=457.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C([O:32][C:33](=[O:54])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([CH3:44])[CH3:43])=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:63]([O:70][C:71]([N:73]1[CH2:82][CH2:81][C:80]2[C:75](=[C:76](Cl)[CH:77]=[CH:78][C:79]=2[C:83]#[N:84])[CH2:74]1)=[O:72])[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:63]([O:70][C:71]([N:73]1[CH2:82][CH2:81][C:80]2[C:75](=[C:76]([C:37]3[CH:36]=[C:35]([CH2:34][C:33]([OH:32])=[O:54])[CH:40]=[CH:39][C:38]=3[O:41][CH:42]([CH3:43])[CH3:44])[CH:77]=[CH:78][C:79]=2[C:83]#[N:84])[CH2:74]1)=[O:72])[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: N#Cc1ccc(Cl)c2c1CCN(C(=O)OCc1ccccc1)C2
Reactant: CCOC(=O)Cc1ccc(OC(C)C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(CC(=O)O)cc1-c1ccc(C#N)c2c1CN(C(=O)OCc1ccccc1)CC2
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A mixture under N2 of palladium(II) acetate (0.21 mg, 0.9 μmol, 0.01 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.78 mg, 1.9 mmol, 0.02 eq.), [4-isopropoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (34 mg, 94.3 μmol, 1.00 eq.) and potassium phosphate (40 mg, 0.19 mmol, 2.00 eq.) in toluene (0.3 mL) and water (0.04 mL) was stirred at r.t. for 2 min. A solution of 8-chloro-5-cyano-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (32.1 mg, 94.3 μmol, 1.00 eq.) in toluene (0.3 mL) was added and the mixture was stirred at 100° C. for 48 hours. The mixture was allowed to cool to r.t., filtered through celite, and concentrated in vacuo. The residue, redissolved in MeCN/H2O (1.6 mL) and formic acid (0.2 mL), was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated. The residue was redissolved in DMF (0.45 mL) and 2M aq. NaOH soln. (0.2 mL) was added. The resulting mixture was stirred at r.t. for 1 hour. Formic acid (0.2 mL) was added. The crude mixture was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the title compound as a milky oil.