Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[CH3:10][CH:11]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:12][OH:13].[OH-].[Na+]>CS(C)=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:13][CH2:12][CH:11]([CH3:10])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N+:3]=1[O-:9]
Reactant: [O-][n+]1c(Cl)cccc1Cl
Reactant: CC(CO)CC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(COc1cccc(Cl)[n+]1[O-])CC(C)(C)C

Procedure:
The 0.82 g (0.0050 moles) of 2,6-dichloropyridine N-oxide and 0.664 g (98%) (0.0050 moles) of 2,4,4-trimethyl-1-pentanol was reacted with 0.211 g (0.0050 moles) of ground sodium hydroxide in 8.2 ml of DMSO at 100° C. overnight to give 2-chloro-6-(2,4,4-trimethypentyloxy) pyridine N-oxide. It was reacted with 0.600 g (0.015 moles) of ground sodium hydroxide at 100° C. for 4.5 hours to give 1-hydroxy-6-(2,4,4-trimethylpentyloxy)pyridine-2(1H)-one. After cooling, it was added 74 ml of water and was adjusted with 6N HCl to pH 3. It was extracted with ethyl acetate (3×25 ml). The combined ethyl acetate extract was washed with a saturated sodium chloride solution (2×10 ml) and dried over sodium sulfate. The ethyl acetate extract was filtered and stripped in vacuo to give 1.08 g (90%). It was recrystallized from ethyl acetate and hexanes: mp 133.5°-134° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([C:16]([O:18]C)=O)[CH2:5]1.[NH2:20][NH2:21].O>CO>[NH:20]([C:16]([C@@H:6]1[CH2:5][C:4](=[N:3][O:2][CH3:1])[CH2:8][N:7]1[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[O:18])[NH2:21]
Reactant: CON=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Reactant: NN
Solvent: CO
Solvent: O
Product: CON=C1C[C@@H](C(=O)NN)N(C(=O)OC(C)(C)C)C1
Reaction time: 48 h

Procedure:
1-tert-butyl 2-methyl (2S,4EZ)-4-(methoxyimino)-1,2-pyrrolidinedicarboxylate (1.95 mmoles; 530 mg) was dissolved in 4 mL of MeOH and a solution of 4 mL of MeOH and 1.5 mL (d=1.03; 30.86 mmoles) of 80% hydrazine.hydrate was added (final c(NH2NH2)=13%). The reaction mixture was agitated for 2 days. Solvents were evaporated in vacuo and the residue re-dissolved in MeOH and evaporated (3×). The desired compound, tert-butyl (2S,4EZ)-2-(hydrazinocarbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate, was isolated as a yellow oil (500 mg; 94%).
Reaction SMILES: C(Br)(Br)(Br)Br.[C:6]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O.[O:34]=[C:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1.[Cl-].[NH4+]>ClCCl.O1CCCC1.CCCCCC>[C:44]([O:43][C:41]([N:38]1[CH2:37][CH2:36][C:35]([C:6]#[C:28][C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[F:25])([OH:34])[CH2:40][CH2:39]1)=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: O=Cc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: BrC(Br)(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(C#Cc2ccccc2F)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
After dissolving 12.6 g of carbon tetrabromide in 80 ml of dichloromethane, the solution was cooled to 0° C. A 20 g portion of triphenylphosphine was added thereto in small portions at a time, and the mixture was stirred for 1 hour. A solution of 2.4 g of 2-fluorobenzaldehyde in dichloromethane (70 ml) was added dropwise and stirring was continued at 0° C. for 4 hours. After stirring overnight at room temperature, hexane was added and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate). The obtained 3.7 g of 1,1-dibromo-2-(2-fluorophenyl)ethene was dissolved in 30 ml of tetrahydrofuran, and the solution was cooled to −78° C. Next, 18 ml of n-butyllithium (1.6 M, n-hexane solution) was added dropwise. The mixture was stirred at −78° C. for 1 hour and then at room temperature for 1 hour. The obtained reaction solution was added dropwise to a solution of 2.6 g of tert-butyl 4-oxo-1-piperidinecarboxylate in tetrahydrofuran (100 ml) which had been cooled to −78° C. After stirring the mixture for 4 hours while slowly raising the temperature to room temperature, saturated aqueous ammonium chloride solution was added and extraction was performed with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (1.4 g, 23% yield, 2 steps).
Reaction SMILES: C1(C(C2(O)CCCCC2)=[O:8])C=CC=CC=1.O[C:17]1[C:30]2[C:29](=[O:31])[C:28]3[C:23](=[C:24]([OH:32])[CH:25]=[CH:26][CH:27]=3)[C:22](=[O:33])[C:21]=2[CH:20]=[CH:19][CH:18]=1.C1(C(=O)CC(C2C=CC=CC=2)=O)C=CC=CC=1>>[OH:32][C:24]1[CH:25]=[CH:26][C:27]2[C:22](=[O:33])[C:21]3[C:30](=[CH:17][CH:18]=[C:19]([OH:8])[CH:20]=3)[C:29](=[O:31])[C:28]=2[CH:23]=1
Reactant: O=C(c1ccccc1)C1(O)CCCCC1
Reactant: O=C1c2cccc(O)c2C(=O)c2cccc(O)c21
Agent: O=C(CC(=O)c1ccccc1)c1ccccc1
Product: O=C1c2ccc(O)cc2C(=O)c2ccc(O)cc21

Procedure:
1-hydroxycyclohexyl phenyl ketone; 1,5-dihydroxyanthraquinone; 1,3-diphenyl-1,3-propanedione;
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[N:19]=1>CN(C=O)C>[NH2:24][C:20]1[N:21]=[C:22]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:10]=3)[C:6]([C:11]([OH:14])([CH3:12])[CH3:13])=[N:7]2)[CH:23]=[CH:18][N:19]=1
Reactant: CC(C)(O)c1n[nH]c2cc(I)ccc12
Reactant: Nc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(O)c1nn(-c2ccnc(N)n2)c2cc(I)ccc12
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 2-(6-iodo-1H-indazol-3-yl)propan-2-ol (1.00 g, 3.31 mmol) in dry DMF (30 mL) at 0° C. under an atmosphere of nitrogen was introduced sodium hydride (212 mg of a 60% dispersion in mineral oil, 5.3 mmol). After 20 minutes at this temperature, 4-chloropyrimidin-2-amine (858 mg, 6.62 mmol) was added and the solution warmed to RT for 10 minutes, then to 65° C. for 23 hr. The reaction mixture was cooled to RT, quenched carefully with water (20 mL) and extracted with EtOAc (2×20 mL extractions). The organic extracts were combined, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by silica gel flash column chromatography (4:1 to 1:1 heptane/EtOAc gradient) furnished the title compound as an off-white solid: 1H NMR (250 MHz, CDCl3) delta 1.73-1.83 (6H, m), 2.77 (1H, s), 5.16 (2H, s), 7.23-7.33 (1H, m), 7.55-7.64 (1H, m), 7.68-7.78 (1H, m), 8.30 (1H, d, J=5.79 Hz), 9.15-9.28 (1 H, m); LC-MS: m/z=+395.90 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]([CH2:14][CH3:15])=[C:12]([CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3[O:27][CH2:28][CH3:29])[C:11]([CH2:30][CH3:31])=[N:10]2)=[C:4]([CH3:32])[CH:3]=1.[C:33](=[O:35])=O.[CH3:36][C:37](C)=O.C([Li])CCC.C(=O)CC>O1CCCC1.CCCCCC>[CH2:28]([O:27][C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]=1[CH2:16][C:12]1[C:11]([CH2:30][CH3:31])=[N:10][N:9]([C:5]2[C:6]([CH3:8])=[CH:7][C:2]([CH:33]([OH:35])[CH2:36][CH3:37])=[CH:3][C:4]=2[CH3:32])[C:13]=1[CH2:14][CH3:15])[CH3:29]
Reactant: CCOc1ccc2ccccc2c1Cc1c(CC)nn(-c2c(C)cc(Br)cc2C)c1CC
Reactant: O=C=O
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCC=O
Product: CCOc1ccc2ccccc2c1Cc1c(CC)nn(-c2c(C)cc(C(O)CC)cc2C)c1CC
Reaction time: 0.17 h

Procedure:
A solution of 1-(4-bromo-2,6-dimethylphenyl)4-(2-ethoxy-naphthalen-1ylmethyl)-3,5-diethyl-1H pyrazole (0.200 g, 0.41 mmol) in 1.0 ml of anhydrous tetrahydrofuran was added dropwise to a dry ice-acetone both cooled 2.5 M solution of n-butyl lithium (0.179 ml, 0.45 mmol) in hexane. After stirring the reaction mixture 10 minutes, propionaldehyde (0.089 ml, 1.23 mmol) was added. The resulting mixture was stirred 10 minutes, and then removed from the cooling bath and stirred 2 hours. 0.5 ml aqueous saturated ammonium chloride solution was added to quench the reaction. After stirring 10 minutes, the reaction mixture was extracted with methylene chloride/brine (10 ml of each). The aqueous phase was then twice extracted with fresh 10 ml portions of methylene chloride. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to afford an oil (216 mg). Flash chromatography of the entire sample (silica gel, 40 micron mesh; elution with ethyl acetate/hexanes=3:7 in volume) yielded 133 mg of the title compound as an oil.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([C:35](Cl)=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][C:35]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)=[O:36])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1)c1cccc2ccccc12

Procedure:
150 mg (0.431 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reacted in analogy to Example 39a with 75 μl (0.495 mmol) of 1-naphthoyl chloride and 81 μl (0.578 mmol) of triethylamine. The title compound ##STR89## is obtained (208 mg, 97%) as oil. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.85, FD-MS: M+ =516, 518; IR: 3680, 3400, 1620 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]=[C:9]=[S:10])[CH:5]=[C:4]([Cl:11])[CH:3]=1.[C:12]([NH-:14])#[N:13].[Na+].[CH3:16]I>C(#N)C.CO>[C:12]([NH:14][C:9](=[N:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([Cl:11])[CH:5]=1)[S:10][CH3:16])#[N:13]
Reactant: N#C[NH-]
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CI
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CSC(=Nc1cc(Cl)cc(Cl)c1)NC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a solution of 1,3-dichloro-5-isothiocyanatobenzene (10 g, 49.0 mmol, Adrich) in acetonitrile (90 ml) and MeOH (100 ml) was added a suspension of sodium hydrogencyanamide (3.45 g, 53.9 mmol) in MeOH (30 ml). The reaction was stirred at room temperature for 1 hour and methyl iodide (13.9 g, 6.13 ml, 98.0 mmol) was added. Continued stirring for 4 hours, and the reaction mixture was filtered, and washed with acetonitrile to give a white solid as desired product (8.04 g, 63% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[O:19][CH3:20])[C:3]=1[NH2:21].[N:22]([O-])=O.[Na+]>>[Cl:1][C:2]1[C:3]2[N:21]=[N:22][N:9]([CH2:10][C:11]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=3[O:19][CH3:20])[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: O=N[O-]
Reactant: COc1ccc(OC)c(CNc2nc(N)nc(Cl)c2N)c1
Agent: [Na+]
Product: COc1ccc(OC)c(Cn2nnc3c(Cl)nc(N)nc32)c1

Procedure:
A solution of 6-chloro-N4-(2,5-dimethoxy-benzyl)-pyrimidine-2,4,5-triamine was treated with a cold aqueous solution of NaNO2, following the general procedure 2. HPLC RT was 6.130 min. 1HNMR (CDCl3): δ 6.84–6.83 (m, 2H), 6.64–6.63 (d, 1H), 5.67 (s, 2H), 5.54 (s, 2H), 3.83 (s, 3H), 3.73 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=O)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27]C)=[O:25])C.[C:30](=O)([O-])[O-].[K+].[K+].C/C(/[O-])=C(/P(OC)(OC)=O)\[N+]#N>CO>[CH3:1][O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[CH:30])[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCC=O)c1CCC(=O)OCC
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)/C([N+]#N)=C(/C)[O-]
Agent: [K+]
Solvent: CO
Product: C#CCCCCCc1cccc(OCCCC(=O)OC)c1CCC(=O)OC
Temperature: 0 °C
Reaction time: 5 h
Yield: 71.3 %

Procedure:
To a solution of 4-[2-(2-ethoxycarbonyl-ethyl)-3-(6-oxo-hexyl)-phenoxy]-butyric acid ethyl ester (7.0 g, 17.24 mmol) was added a solution of potassium carbonate (7.14 g, 51.72 mmol) in MeOH (200 mL) and the resulting mixture was cooled to 0° C. Then the Ohira's reagent (ref. cited in Synlett, 1996, 521) (6.3 g, 32.8 mmol) in MeOH (50 mL) was added slowly. The cooling bath was removed upon the end of addition and the reaction mixture was stirred at room temperature for 5 hr. The reaction was then extracted into ethyl acetate and washed with brine. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography using 50% ethyl acetate-hexanes as eluant to give the title compound (4.6 g, 71%) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23](O)=[O:24])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([F:29])[CH:3]=1.[NH2:30][CH2:31][CH2:32][OH:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23]([NH:30][CH2:31][CH2:32][OH:33])=[O:24])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([F:29])[CH:3]=1
Reactant: NCCO
Reactant: Cn1cc(C(=O)CC(c2cccc(C(=O)O)c2)c2ccc(Cl)cc2F)ccc1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(C(=O)CC(c2cccc(C(=O)NCCO)c2)c2ccc(Cl)cc2F)ccc1=O

Procedure:
In analogy to example 207, step 2, 3-(1-(4-chloro-2-fluorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)benzoic acid (example 320, step 4) was coupled with 2-aminoethanol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as a colourless foam, MS (ESI+): m/z=457.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>ClCCl>[C:25]([N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:13][CH2:14]1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(N2CCN(C(C)=O)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To a solution of 1-[3-(methyloxy)-4-nitrophenyl]piperazine (0.5 g, 2.11 mmol) and triethylamine (1.27 g, 12.63 mmol, Aldrich) in dichloromethane (25 mL) was added acetic anhydride (0.64 g, 6.35 mmol, Aldrich). After stirring 3 hrs at rt, the reaction was washed with water (25 mL), organic layer adsorbed to silica gel and purified by column chromatography (dichloromethane to 10% methanol/dichloromethane) to give 1-acetyl-4-[3-(methyloxy)-4-nitrophenyl]piperazine (0.4 g, 68%). ESIMS (M+H)+=280.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:19])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:31]=[C:30]2[C:26]([CH:27]=[CH:28][NH:29]2)=[CH:25][CH:24]=1>>[ClH:19].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][C:23]3[CH:31]=[C:30]4[C:26]([CH:27]=[CH:28][NH:29]4)=[CH:25][CH:24]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc2cc[nH]c2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Product: COc1cc2c(Nc3ccc4cc[nH]c4c3)ncnc2cc1OCc1ccccc1
Product: Cl
Yield: 88.5 %

Procedure:
Using an analogous procedure to that described for the preparation of the starting material in Example 201, 7-benzyloxy-4-chloro-6-methoxyquinazoline (2.5 g, 8.3 mmol), (prepared as described for the starting material in Example 1), was reacted with 6-aminoindole (1.5 g, 11.4 mmol) to give 7-benzyloxy-4-(indol-6-ylamino)-6-methoxyquinazoline hydrochloride (3.18 g, 89%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](OCC)=[O:24])=[CH:17][C:15]=2[N:16]=1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:17][C:15]=2[N:16]=1
Reactant: CCOC(=O)CCc1ccc2oc(Cc3ccc4ccccc4c3)nc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: OCCCc1ccc2oc(Cc3ccc4ccccc4c3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a solution of ethyl 3-[2-(2-naphthylmethyl)benzoxazol-5-yl]propionate (5.8 g) in ether (100 ml)-tetrahydrofuran (100 ml) was added lithium aluminum hydride (0.73 g), and the mixture was stirred at room temperature for one hour. To the reaction mixture was added water (4 ml). Insolubles were filtered off. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1:1, v/v), 3-[2-(2-naphthylmethyl)benzoxazol-5-yl]propanol (2.1 g, 41%) was obtained. Recrystallization from dichloromethane-isopropylether gave colorless prisms. Melting point: 102-103° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH:7]=[C:8]([C:10](O)=[O:11])[O:9][C:5]=2[CH:4]=1.C(Cl)(=O)C([Cl:18])=O>O1CCCC1.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH:7]=[C:8]([C:10]([Cl:18])=[O:11])[O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2cc(C(=O)O)oc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2cc(C(=O)Cl)oc2c1
Reaction time: 0.08 h

Procedure:
To a stirred solution of 6.0 g (0,031 mole) of 6-methoxy-2-benzofurancarboxylic acid (A. McGookin, A. Robertson, and W. B. Whalley, J. Chem. Soc. 787 (1940)) in 100 ml of tetrahydrofuran (under a nitrogen atmosphere) was added in one portion, 3.3 ml (4.8 g; 0,038 mole) of oxalyl chloride. The mixture was stirred for 5 minutes, then treated with 3 drops of N,N-dimethylformamide. After stirring at room temperature for 2 hours, the solvent was evaporated to leave a residue of crude 6-methoxy-2-benzofurancarbonyl chloride, mp 96°-99° (amp of 101° is given by A. McGookin, etc., cited above). The residue was re-dissolved in 100 ml of dichloromethane, and the solution was filtered. The filtrate was added dropwise over 20 minutes to an ice-cooled solution of 3.6 g (0,037 mole) of N,)-dimethylhydroxylamine hydrochloride and 9.4 ml (7.7 g; 0,077 mole) of 1-methylpiperidine in 100 ml of dichloromethane. After stirring for 2 hours, the mixture was added to 400 ml of ice-cold 5% aqueous hydrochloric acid. The layers were separated, and the aqueous layer was extracted with fresh dichloromethane (3X 100 ml). The combined organic layers were washed with water (1X 200 ml), 3% aqueous sodium bicarbonate (2X 200 ml), and water again. The extracts were dried (anhydrous magnesium sulfate) and evaporated. Trituration of the residue with ether yielded 5.4 g (74% yield) of the analytically pure amide product, mp 73°-77°.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH2:6][C:7]1[C:8]([F:17])=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)[C:12](O)=[O:13])=[O:4].C(Cl)(=O)C(Cl)=O.[NH3:26]>C1COCC1>[F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH2:6][C:7]1[C:8]([F:17])=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)[C:12]([NH2:26])=[O:13])=[O:4]
Reactant: N
Reactant: O=C(O)c1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)c1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-26 by using 5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoic acid (1.0 g), oxalyl chloride (1.0 mL), THF (50 mL) and ammonia gas to afford 0.800 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 4.53 (m, 2H), 7.43 (m, 1H) 7.44 (m, 2H), 7.48 (m, 1H), 10.0 (br s, 1H)); MS (m/z): 297.10 (M−H)−.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:22]([O:31][CH3:32])=[N:23][N:24]([CH3:30])[C:25]=2[C:26]([F:29])([F:28])[F:27])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH3:32][O:31][C:22]1[C:21]([CH:18]2[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]2)=[C:25]([C:26]([F:28])([F:27])[F:29])[N:24]([CH3:30])[N:23]=1
Reactant: COc1nn(C)c(C(F)(F)F)c1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1nn(C)c(C(F)(F)F)c1C1CCNCC1
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (3.0 mL) was added to a solution of 1-(tert-butoxycarbonyl-4-(3-methoxy-1-methyl-5-(trifluoromethyl)-(1H)-pyrazol-4-yl)piperidine (150 mg, 0.41 mmol, from Step D) in CH2Cl2 (3.0 mL). After 2 h, the reaction was concentrated and the residue was dissolved in EtOAc (15 mL) and washed with saturated aq. NaHCO3 (6 mL) followed by saturated aq. NaCl (5 mL). The organic layer was dried (Na2SO4), decanted, and evaporated to give the title compound as a white solid. For the title compound: 1H NMR (500 MHz, CD3OD) δ 3.89 (s, 3H), 3.80 (s, 3H), 3.32 (d, J=13, 2H), 2.95 (tt, J=13, 4, 1H), 2.93 (td, J=13, 3, 2H), 2.18 (qd, J=13, 4, 2H), 1.76 (d, J=13, 2H); ESI-MS 264.1 (M+H); HPLC A: 1.3 min.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[CH:8]=1)(=O)=O.[N-:16]=[N+:17]=[N-:18].[Na+]>O>[N:16]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[CH:8]=1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCc1ccc(C#N)c(F)c1
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(CN=[N+]=[N-])cc1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice cooled solution of 4-cyano-3-fluorobenzyl methanesulfonate (1.8 g, 7.9 mmol; see step (iii) above) was added sodium azide (0.80 g, 0.012 mol). The mixture was stirred overnight and then poured into 200 mL of water and extracted three times with diethyl ether. The combinied ethereal phase was washed five times with water, dried (Na2SO4) and evaporated. The crude colourless oil could be used without further purification. Yield: 1.2 g (87%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([F:10])[CH:3]=1.[C-]#[N:12].[Na+].[CH2:14]([OH:16])C>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:14]([NH2:12])=[O:16])=[C:4]([F:10])[CH:3]=1
Reactant: [C-]#N
Reactant: Fc1cc(Br)ccc1CBr
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: NC(=O)Cc1ccc(Br)cc1F
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of 4-bromo-1-(bromomethyl)-2-fluorobenzene (56.0 mmol) in ethanol (75.0 ml) and water (15.0 ml) was added sodium cyanide (67.2 mmol). The reaction was refluxed for 3 days then cooled and diluted with water. The solids were collected, slurried in water (100 mL) and 6N aq HCl (50 mL) for 1 h, and then filtered and dried via suction. The collected solids were slurried again in dichloromethane, and the solids were collected and dried to afford 2-(4-bromo-2-fluorophenyl)acetamide (6.9 g, 52% yield) as a white solid. The dichloromethane filtrate was evaporated to afford a crude mixture (72% purity by LCMS) of the title product and 2-(4-bromo-2-fluorophenyl)acetamide (1.4:1 ratio) as a light yellow solid (4.5 g). A portion of this mixture was used directly in the next step. Title product: MS(ES)+ m/e 214.0, 216.2 [M+H]+.