Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[OH-].[Na+].[CH3:12][C:13]([CH3:18])=[CH:14][C:15](Cl)=[O:16]>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:15](=[O:16])[CH:14]=[C:13]([CH3:18])[CH3:12])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: CC(C)=CC(=O)Cl
Reactant: Cc1ccc(N)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)=CC(=O)Nc1ccc(C)c(Br)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
To a biphasic mixture of 3-bromo-4-methylaniline (50 g, 0.269 mol), 10% NaOH (270 mL) and dichloromethane (160 mL) was added dropwise over a period of 2 hours 3,3-dimethylacryloyl chloride (36 mL, 0.322 mol) in dichloromethane (95 mL). The solution was stirred at room temperature for 48 hours then diluted with water (100 mL). The aqueous layer was further extracted with dichloromethane. The organic layers were combined and washed with water and brine, dried (Mg2SO4), filtered and evaporated. The white solid was triturated with hexane and collected to give 70 g (97%) of 3-Methyl-but-2-enoic acid (3-bromo-4-methyl-phenyl)-amide. 1H NMR (300 MHz; CDCl3): 1.89 (s, 3 H), 2.21 (s, 3 H), 2.33 (s, 3 H), 5.68 (s, 1 H), 7.14 (d, J=8.0 Hz, 1 H), 7.17 (br s, 1 H), 7.33 (d, J=8.0 Hz, 1 H), 7.79 (s, 1 H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])=[C:9]([C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=3)[C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[N+:30]([O-:32])=[O:31].Cl.Cl[CH2:35][CH2:36][CH:37]1[CH2:41][CH2:40][CH2:39][N:38]1[CH3:42]>CN(C)C=O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([N:23]([CH2:35][CH2:36][CH:37]3[CH2:41][CH2:40][CH2:39][N:38]3[CH3:42])[C:24](=[O:29])[C:25]([F:28])([F:26])[F:27])=[C:9]([C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=3)[C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[N+:30]([O-:32])=[O:31]
Reactant: Cc1cc(C)cc(-c2c(NC(=O)C(F)(F)F)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Reactant: CN1CCCC1CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(-c2c(N(CCC3CCCN3C)C(=O)C(F)(F)F)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
To a suspension of 10 mg sodium hydride in 1.0 mL N,N-dimethylformamide was added 90 mg N-[7-chloro-3-(3,5-dimethylphenyl)-6-nitro-2-oxo-1,2-dihydroquinolin-4-yl]-2,2,2-trifluoroacetamide and the mixture stirred at room temperature for 1 hour. At this time, 75 mg of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride and the mixture heated to 80° C. on an oil bath. After 6 hours, the mixture was cooled to room temperature, diluted with ethyl acetate and extracted with water. The organic portion was washed with brine and dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol, 95:5+1% ammonium hydroxide) gave the title compound (50 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]([CH3:27])([CH3:26])[C:22]([O:24]C)=[O:23])[CH:19]=2)[NH:14][C:13]=1[C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[CH:29]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO>[CH2:1]([O:8][CH2:9][C@H:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]([CH3:26])([CH3:27])[C:22]([OH:24])=[O:23])[CH:19]=2)[NH:14][C:13]=1[C:28]1[CH:29]=[C:30]([CH3:35])[CH:31]=[C:32]([CH3:34])[CH:33]=1)[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)c1cnc2[nH]c(-c3cc(C)cc(C)c3)c([C@H](C)COCc3ccccc3)c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C)cc(-c2[nH]c3ncc(C(C)(C)C(=O)O)cc3c2[C@H](C)COCc2ccccc2)c1
Temperature: 80 °C

Procedure:
A vigorously stirred suspension of methyl (S)-2-[3-(2-benzyloxy-1-methylethyl)-2-(3,5-dimethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropanoate (3.82 g, 8.12 mmol) and 2N KOH (40.6 mL, 0.081 mol) in MeOH (40 mL) was heated at 80° C. for approximately 4 h. After cooling to room temperature, the reaction mixture was acidified to pH 6 with 2N HCl and extracted with ethyl acetate (×3). The combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue was used without further purification in the subsequent reaction.
Reaction SMILES: [CH3:1][Li].[C:3]([C:6]1[N:11]=[CH:10][C:9]([O:12][C:13]2[C:14]([CH:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33](=[O:35])[CH3:34])=[CH:15][C:16]3[NH:20][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[N:18][C:17]=3[CH:27]=2)=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[Cl-].[NH4+]>O1CCCC1>[OH:5][C:3]([C:6]1[N:11]=[CH:10][C:9]([O:12][C:13]2[C:14]([CH:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33](=[O:35])[CH3:34])=[CH:15][C:16]3[NH:20][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[N:18][C:17]=3[CH:27]=2)=[CH:8][CH:7]=1)([CH3:1])[CH3:4]
Reactant: [Li]C
Reactant: CC(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2C(C)=O)cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(C(C)(C)O)nc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
0.1 ml of methyl lithium (1.0 M diethyl ether solution) was added to a tetrahydrofuran (1.5 ml) solution of 15.0 mg of 1-(2-(6-(6-acetyl-pyridin-3-yloxy)-2-pyridin-2-yl-3H-benzimidazol-5-yl)-pyrrolidin-1-yl)-ethanone obtained in Example 341, at −78° C., and the reaction liquid was stirred at −78° C. for 30 minutes. The reaction liquid was poured into aqueous saturated ammonium chloride solution, extracted with chloroform, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=7.5/1) to obtain the entitled compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:39]1[N:40]=[CH:41][S:42][CH:43]=1)[C:12]([NH:14][CH:15]1[C:37](=[O:38])[N:17]2[C:18]([C:24]([O:26]CC3C=CC([N+]([O-])=O)=CC=3)=[O:25])=[C:19]([O:22][CH3:23])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.O1CCCC1.C(O)(=O)C.[Pd]>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:39]1[N:40]=[CH:41][S:42][CH:43]=1)[C:12]([NH:14][CH:15]1[C:37](=[O:38])[N:17]2[C:18]([C:24]([OH:26])=[O:25])=[C:19]([O:22][CH3:23])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3cscn3)[C@H]2SC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: COC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3cscn3)[C@H]2SC1
Yield: 74.9 %

Procedure:
4-Nitrobenzyl 7-[2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-methoxy-3-cephem-4-carboxylate (syn isomer) (2.9 g) was dissolved in a mixed solution of methanol (50 ml), tetrahydrofuran (30 ml) and glacial acetic acid (0.5 ml). After adding 10% palladium on carbon (1.5 g) to the solution, the mixture was subjected to catalytic reduction at ambient temperature under atmospheric pressure. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. Water and ethyl acetate were added to the residue and the mixture was adjusted to pH 7.5 with a saturated aqueous solution of potassium carbonate. The separated aqueous layer was adjusted to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to give 7-[2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer) (1.71 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1B1OC(C)(C)C(C)(C)O1.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[C:31]2[CH3:35])[N:26]=[N:27][CH:28]=1>>[ClH:22].[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:23]1[CH:24]=[C:25]([CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[C:31]2[CH3:35])[N:26]=[N:27][CH:28]=1
Reactant: COc1ccc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: COc1ccc2ccccc2c1-c1cnnc(Cn2ccnc2C)c1
Product: Cl

Procedure:
The title compound, MS: m/e=331.3 (M+H+), was prepared from 2-(2-methoxy-naphthalen-1-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:13]=[O:14]>O1CCOCC1>[CH2:15]([NH:12][C:13]([N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[N:2]([CH3:1])[C:3]1=[O:11])=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Cn1c(=O)[nH]c2ncccc21
Reactant: CCCCCCN=C=O
Solvent: C1COCCO1
Product: CCCCCCNC(=O)n1c(=O)n(C)c2cccnc21

Procedure:
1-Methyl-1,3-dihydroimidazo[4,5-b]pyridin-2-one (75 mg, 0.5 mmol) and 1-isocyanatohexane (64 mg, 0.5 mmol) were stirred at 80° C. in 3.5 ml of dioxane for 4 h. The reaction mixture was concentrated and purified by means of preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 40 mg (29%), M+H+: 277.16.
Reaction SMILES: C([O:4][C:5]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:9])[CH2:6][CH2:7][NH2:8])(=O)C.[OH-].[K+].O.C(Cl)(Cl)Cl>CO>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:5]([OH:4])([CH3:9])[CH2:6][CH2:7][NH2:8])=[CH:11][CH:12]=2)=[CH:21][CH:20]=1
Reactant: CC(=O)OC(C)(CCN)c1ccc(-c2ccc(F)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(O)(CCN)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
30.1 g of 3-acetoxy-3-(4'-fluoro-4-biphenylyl)-1-butylamine [obtainable from 3-bromo-3-(4'-fluoro-4-biphenylyl)-1-butylamine and potassium acetate] are boiled for 2 hours with 20 g of KOH in 500 ml of methanol, and the mixture is worked up with water and chloroform to give 3-(4'-fluoro-4-biphenylyl)-3-hydroxybutylamine, m.p. 144° - 146°.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[C:12](/[C:15](=O)[CH3:16])\[C:13]#[N:14])[CH:9]=2)[NH:4][N:3]=1.[F:18][C:19]([F:27])([CH2:25][CH3:26])[C:20](=O)[CH2:21][C:22]#[N:23].C([O-])(=O)C.[NH4+:32]>CC(O)C.C(O)(=O)C>[F:18][C:19]([C:20]1[NH:32][C:15]([CH3:16])=[C:12]([C:13]#[N:14])[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[CH3:1])[C:21]=1[C:22]#[N:23])([F:27])[CH2:25][CH3:26]
Reactant: [NH4+]
Reactant: CC(=O)/C(C#N)=C/c1ccc2[nH]nc(C)c2c1
Reactant: CCC(F)(F)C(=O)CC#N
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CCC(F)(F)C1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C)N1
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
A solution of 113 mg (0.50 mmol) (2E)-2-[(3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 2A) and 432 mg (0.50 mmol based on 17% purity) 4,4-difluoro-3-oxohexanenitrile (Example 13A) in 2-propanol (334 μl) and acetic acid (170 μl) was treated with 116 mg (1.5 mmol) ammonium acetate and stirred for 20 min at 90° C. under microwave conditions. After cooling, the mixture was concentrated under reduced pressure, and the residue was suspended in p-xylene (1.5 ml). Small amounts of p-toluenesulfonic acid and powdered 4 Å molecular sieve were added, and the mixture was stirred at reflux temperature for 48 h. Upon cooling, the mixture was diluted with acetonitrile, filtered and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (acetonitrile/water gradient, final mixture 9:1 v/v) followed by preparative thin layer silica gel chromatography (toluene/ethanol 5:1 v/v) to yield 7.2 mg (4% of th.) of the racemic title compound as a pale yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[C:3]=1[F:12].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:13]([O:20][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[C:3]=1[F:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
1,2,3-Trifluoro-4-nitro-benzene (30 g, 0.17 mol), benzyl alcohol (18.4 g, 0.17 mol) and K2CO3 (35 g, 0.25 mol) were combined in DMF (300 mL) and were stirred at RT for 8 h. Water (300 mL) was added, and the mixture was extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine, dried (MgSO4), concentrated in vacuo and purified by column chromatography on silica gel to give 1-benzyloxy-2,3-difluoro-4-nitro-benzene (16 g, 36% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.06 (m, 1 H), 7.49-7.30 (m, 6 H), 5.37 (s, 2 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH:25](=O)[CH2:26][CH3:27].[H][H]>CO.[Pd]>[CH2:25]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1)[CH2:26][CH3:27]
Reactant: NC(=O)c1cccc2nc(-c3ccc(C4CCNCC4)cc3)oc12
Reactant: CCC=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCN1CCC(c2ccc(-c3nc4cccc(C(N)=O)c4o3)cc2)CC1
Yield: 23.5 %

Procedure:
A solution of 2-(4-(piperidin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide (200 mg, 0.62 mmol), 10% Pd/C (50 mg) and propanal (0.8 mL, 1.86 mmol) in methanol (20 mL) was purged with hydrogen at room temperature overnight. The solution was filtered and the filtrate was concentrated, the residue was purified by prep-HPLC to give 2-(4-(1-propylpiperidin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide (53 mg, yield 23%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 1.01 (s, 3H), 1.79 (s, 2H), 2.03-2.09 (m, 4H), 3.31-3.34 (m, 2H), 3.67 (s, 2H), 7.30-7.41 (m, 3H), 7.83 (s, 2H), 8.16 (s, 2H); LC-MS (ESI) m/z: 364 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.Cl>CCOCC>[ClH:1].[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][NH:11][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: NCc1ccccn1
Reactant: Clc1ccc2nccn2n1
Agent: Cl
Solvent: CCOCC
Product: c1ccc(CNc2ccc3nccn3n2)nc1
Yield: 40 %

Procedure:
Prepared from 6-chloroimidazo[1,2-b]pyridazine (4) and 2-(aminomethyl)pyridine according to general procedure 2. The free-base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (135 mg, 40%) as a white solid; 1H NMR (500 MHz, CD3OD) δ 8.68-8.67 (m, 1H), 8.27 (dt, J=1.5, 9.4 Hz, 1H), 8.03 (d, J=10 Hz, 1H), 7.99-7.98 (m, 1H), 7.90-7.87 (m, 2H), 7.72 (t, J=6.5 Hz, 1H), 7.40 (d, J=10 Hz, 1H), 4.80 (s, J=Hz, 2H); 13C NMR (75 MHz, CD3OD) δ 157.2, 156.8, 145.7, 144.4, 134.0, 125.9, 125.7, 122.3, 121.9, 121.4, 119.7, 45.5; HPLC tR=6.3 min (Luna), 98.9%; ES-MS: (M+H)=226 m/z.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.OO.C(=O)([O-])[O-].[Na+].[Na+].[C:17]([OH:20])(=[O:19])[CH3:18]>>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH2:1][O:20][C:17](=[O:19])[CH3:18])[CH:7]=1
Reactant: CC(=O)O
Reactant: Cc1ccnc(C)c1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CC(=O)OCc1cc(C)ccn1

Procedure:
24.3 ml of 2,4-dimethylpyridine were dissolved in 80 ml of glacial acetic acid, the solution was mixed with 30 ml of 30% hydrogen peroxide and refluxed for 25 hours. The solution was then adjusted to approximately pH 8 with saturated sodium carbonate solution, the solution was extracted with dichloromethane and the organic phase rotated in. The residue was mixed with 90 ml of acetic anhydride and refluxed for 1.5 hours. The pH-value of the solution was adjusted to approximately 8 with 40% NaOH and the solution was extracted with trichloromethane. 30 g of crude 4-methyl-2-acetoxymethylpyridine were obtained.
Reaction SMILES: [C:1](Cl)(=[O:5])C(Cl)=O.[F:7][C:8]([F:29])([F:28])[O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[N:19][C:18]([C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=3)=[N:17]2)=[CH:12][CH:11]=1.C(N(CC)CC)C.[C:37]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]([NH2:43])=[CH:39][CH:40]=[CH:41][CH:42]=1>O1CCCC1>[C:37]1([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43][C:1]([NH:25][C:24]1[CH:26]=[CH:27][C:21]([C:18]2[N:19]=[CH:20][N:16]([C:13]3[CH:12]=[CH:11][C:10]([O:9][C:8]([F:7])([F:28])[F:29])=[CH:15][CH:14]=3)[N:17]=2)=[CH:22][CH:23]=1)=[O:5]
Reactant: Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1ccccc1-c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)Nc1ccccc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a three-necked round bottomed flask equipped with condenser and nitrogen inlet was charged with oxalyl chloride (0.378 g, 2.98 mmol). Tetrahydrofuran (25 mL) was added and the reaction was cooled to 0° C. 4-(1-(4-(Trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (0.800 g, 2.50 mmol) and triethylamine (1.74 mL, 12.5 mmol) were added at 0° C. After 30 minutes, [1,1′-biphenyl]-2-amine (0.508 g, 3.00 mmol) dissolved in tetrahydrofuran (25 mL) was added to the reaction mixture. The resulting reaction mixture was slowly warmed to room temperature. Upon completion, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (150 mL×2). The organic phase was washed with brine (50 mL). The combined organic layers were dried over sodium sulfate and were then concentrated under reduced pressure. Purification by flash column chromatography using 0-30% ethyl acetate/hexanes provided the title compound as an off white solid (0.560 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[N+:18]([O-])=O)[NH:11][C:10]2([CH3:25])CC(O)=O)=[CH:4][CH:3]=1.ClC1C=CC(SC2C3C(=CC=[C:40]([C:43]([O:45][CH3:46])=[O:44])C=3)NC=2C)=CC=1.[CH2:48](O)C>[Pt]>[NH2:18][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[C:9]([S:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[C:10]([CH3:25])[N:11]2[CH2:40][C:43]([O:45][CH2:46][CH3:48])=[O:44]
Reactant: COC(=O)c1ccc2[nH]c(C)c(Sc3ccc(Cl)cc3)c2c1
Reactant: CC1(CC(=O)O)Nc2cccc([N+](=O)[O-])c2C1Sc1ccc(Cl)cc1
Reactant: CCO
Agent: [Pt]
Product: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c(N)cccc21
Reaction time: 8 h

Procedure:
A suspension of the product from example 55 part (ii) (2.25 g) in ethanol (170 ml) was stirred in the presence of 5% Pt/C (0.5 g) under 2 bar pressure of H2. After stirring overnight the catalyst was removed by filtration and the filtrates concentrated in vacuo. Purification by flash column chromatography (14% EtOAc/hexane as eluent) gave the sub-title compound (1.4 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:3]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1>[O:19]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1cc(-n2cccn2)ncn1
Reactant: Oc1ccccc1
Solvent: c1ccccc1
Product: c1ccc(Oc2cc(-n3cccn3)ncn2)cc1

Procedure:
In 10 ml of benzene, 180 mg of 6-chloro-4-(1-pyrazolyl)pyrimidine, 175 ml of phenol, and 152 mg of 1,8-diazabicyclo-(5,4,0)-7-undecene (DBU) were dissolved, and refluxed for 7 hours. This reaction solution was washed with water, and an organic fraction was dried over anhydrous sodium sulfate. The resulting extract was distilled to give a residue, and the residue was purified by alumina gel column chromatography using a mixture of n-hexane and ethyl acetate (2:1) to yield 175 mg 6-phenoxy-4-(1-pyrazolyl)pyrimidine, recrystallized from n-hexane, to give an acicular crystal having a melting point of 92.5°-93.5° C.,
Reaction SMILES: IC1C=C2C(=CC=1)N(C)C(=O)N(C[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1)C2=O.C(N(C(C)C)CC)(C)C.[C:34]([Si:38]([CH3:50])([CH3:49])[O:39]C1C=CC(CC#C)=CC=1)([CH3:37])([CH3:36])[CH3:35].O>CN(C=O)C.[Cu]I>[C:34]([Si:38]([CH3:50])([CH3:49])[O:39][C:15]1[CH:16]=[CH:17][C:18]([CH:19]=[O:21])=[CH:22][CH:23]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: C#CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Reactant: Cn1c(=O)n(Cc2ccc(C(=O)O)cc2)c(=O)c2cc(I)ccc21
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To 0.65 g (1.5 mmol) 4-(6-Iodo-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzoic acid and 0.77 g (6.0 mmol) di-isopropyl ethylamine in 15 ml DMF is added bis-triphenylphosphine palladium di-chloride (catalytic) followed by CuI (catalytic). 0.5 g (2.0 mmol) tert-Butyl-dimethyl-(4-prop-2-ynyl-phenoxy)-silane is added and the mixture is heated to 70° C. for 6 hours. The mixture is allowed to cool to room temperature and stir overnight. Water is added and the mixture stirred 30 minutes. Filter and dry under reduced pressure. Purify by flash chromatography (EtOAc/hexane eluent)
Reaction SMILES: [N:1]1([C:6]([O:8][CH2:9][C@@H:10]([N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:19])[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:7])[CH:5]=[CH:4][N:3]=[CH:2]1.F[P-](F)(F)(F)(F)F.C([O+](CC)CC)C.C1C2[C:45](=[CH:46][CH:47]=[CH:48]C=2)[CH:44]=[C:43](N)N=1>C(Cl)Cl>[C:23]([O:22][C:20]([N:18]([CH3:19])[C@H:10]([CH2:9][O:8][C:6](=[O:7])[NH:1][C:2]1[N:3]=[CH:4][C:5]2[C:47]([CH:48]=1)=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: COC(=O)CCC[C@@H](COC(=O)n1ccnc1)N(C)C(=O)OC(C)(C)C
Reactant: Nc1cc2ccccc2cn1
Agent: CC[O+](CC)CC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCC[C@@H](COC(=O)Nc1cc2ccccc2cn1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.2 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonyl(methyl)amino)-6-methoxy-6-oxohexyl 1H-imidazole-1-carboxylate (2 g, 5.4 mmol) in DCM (10 mL) was added a solution of triethyloxonium hexafluorophosphate (1.61 g, 6.5 mmol, 1.2 equiv.) in DCM (5 mL) dropwise at 0° C. The solution was warmed up to RT and stirred for 15 min. A solution of isoquinolin-3-amine (0.94 g, 6.5 mmol, 1.2 equiv.) in DCM (5 mL) was added. The solution was stirred for overnight. DCM was removed and the residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give (S)-methyl 5-(tert-butoxycarbonyl(methyl)amino)-6-(isoquinolin-3-ylcarbamoyloxy)hexanoate (1.4 g, 58%). LRMS (M+H+) m/z 446.2.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:7]=C[C:9]=1[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([Cl:19])=[C:13]2[C:12]([CH:20]([CH3:22])[CH3:21])=[N:11]1)[C:5]#[N:6].IC.[H-].[Na+].C(OCC)(=O)C.[CH3:33][N:34]([CH:36]=O)[CH3:35]>O>[CH3:33][N:34]([CH3:35])[C:36]1[CH:7]=[C:4]([CH:3]=[CH:2][C:9]=1[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([Cl:19])=[C:13]2[C:12]([CH:20]([CH3:22])[CH3:21])=[N:11]1)[C:5]#[N:6]
Reactant: CN(C)C=O
Reactant: CC(C)c1nn(-c2ccc(C#N)cc2N)c2nccc(Cl)c12
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)c1nn(-c2ccc(C#N)cc2N(C)C)c2nccc(Cl)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
Compound (107a) (0.08 g) and iodomethane (0.16 mL) were dissolved in DMF, and sodium hydride (0.028 g, a 55% dispersion in paraffin liquid) was added to the resulting solution at 0° C., followed by stirring at room temperature for 1 hr. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away to obtain 3-(dimethylamino)-4-(4-chloro-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)benzonitrile, which was used in the subsequent reaction without being purified. According to Example 107(2), compound (108) (0.014 g, the third stage yield: 12%) was prepared using 3-(dimethylamino)-4-(4-chloro-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)benzonitrile instead of compound (107a).