Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=Cc1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccc(C=O)s2)cc1
Temperature: 60 °C

Procedure:
To a stirred solution of 5-bromothiophene-2-carbaldehyde (1 g, 5.2 mmol) in toluene (40 mL) and ethanol (20 mL) was added (4-methoxyphenyl)boronic acid (1.59 g, 10.4 mmol), 2M Na2CO3 (14.7 mL), and Pd(PPh3)4 (60 mg, 0.05 mmol). The reaction was purged with argon and heated at 60° C. for about 5 h. The reaction mixture was concentrated, diluted with water (100 mL), and extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with brine solution (20 mL), the organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 60-120μ) using 10% ethyl acetate in hexane eluent to afford 5-(4-methoxyphenyl)thiophene-2-carbaldehyde as off white solid (1 g, 87.7% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.85 (s, 1H), 7.97 (d, 1H), 7.73 (d, 2H), 7.61 (d, 1H), 7.02 (d, 2H), 3.98 (s, 3H); LC-MS m/z calcd for [M+H]+ 219.04. found 219.3.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[Br:15]([O-])(=O)=O.[Na+].S(=O)(O)[O-].[Na+]>C(OC(C)C)(=O)C>[Br:15][CH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: Cc1ccc(C(=O)O)cc1C(F)(F)F
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Product: O=C(O)c1ccc(CBr)c(C(F)(F)F)c1

Procedure:
1.0 g of 4-methyl-3-(trifluoromethyl)benzoic acid was dissolved in isopropyl acetate (q.s.). To the mixture, sodium bromate aqueous solution (10 ml, containing 2.2 g of sodium bromate) and sodium bisulfite aqueous solution (10 ml, containing 1.52 g of sodium bisulfite) were added alternatively with stirring. After addition, the solution became brownish red. The mixture was heated to reflux until the solution became colorless. Then the organic layer was separated. Again, to the mixture, sodium bromate aqueous solution (10 ml, containing 2.2 g sodium bromate) and sodium bisulfite aqueous solution (10 ml, containing 1.52 g sodium bisulfite) were added alternatively and the mixture was heated to reflux until the solution became colorless. Then the organic layer was separated. Continually, to the mixture, a sodium bromate aqueous solution (10 ml, containing 2.2 g sodium bromate) and a sodium bisulfite aqueous solution (10 ml, containing 1.52 g sodium bisulfite) were added alternatively, and the mixture was heated to reflux until the solution became colorless. Then the organic layer was separated. The organic layer was washed with 5% sodium sulfate solution twice and 15% sodium chloride solution twice, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to dry. The is residue was stirred in petroleum ether, and filtered to give a white solid. m.p. 140-145° C.
Reaction SMILES: [C:1]([O:4][CH2:5]/[C:6](/[CH2:16][CH2:17]/[CH:18]=[C:19](\[CH3:26])/[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:15])=[CH:11]/[C:12]([OH:14])=O)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34]>>[CH2:33]([N:35]([CH2:36][CH3:37])[C:12](=[O:14])/[CH:11]=[C:10](\[CH3:15])/[CH2:9][CH2:8]/[CH:7]=[C:6](/[CH2:5][O:4][C:1](=[O:3])[CH3:2])\[CH2:16][CH2:17]/[CH:18]=[C:19](\[CH3:26])/[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH3:34]
Reactant: CC(=O)OC/C(=C/CC/C(C)=C/C(=O)O)CC/C=C(\C)CCC=C(C)C
Reactant: CCNCC
Agent: O=C(Cl)C(=O)Cl
Product: CCN(CC)C(=O)/C=C(\C)CC/C=C(\CC/C=C(\C)CCC=C(C)C)COC(C)=O

Procedure:
Following the same manner as in Example 12, 1.0 g of (E,Z,E) and (E,E,E)-7-acetoxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraenoic acid was converted to the corresponding acid chloride with 1.5 ml of oxalyl chloride and the reaction with 1.0 ml of diethylamine afforded 820 mg of the end product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:24])[CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26][S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:24])[CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([N:33]3[CH2:34][CH2:35][N:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:31][CH2:32]3)[N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)Cc2nc(Cl)ncc2Cl)CC1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(O)Cc2nc(N3CCN(S(C)(=O)=O)CC3)ncc2Cl)CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 4-[2-(2,5-dichloro-pyrimidin-4-yl)-1-hydroxy-ethyl]-piperidine-1-carboxylic acid tert-butyl ester (100 mg), 1-methanesulfonyl-piperazine hydrochloride (70 mg), potassium carbonate (100 mg), and N,N-dimethylformamide (1 mL) is stirred for 4 h at 60° C. After cooling to room temperature ethyl acetate is added. The organic phase is separated, washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 50:50→0:100) to give the title compound. LC (method 7): tR=1.46 min; Mass spectrum (ESI+): m/z=504 [M+H]+.
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:9]=[C:10]([CH2:17][C:18]#[N:19])[C:11]2[O:15][CH:14]=[CH:13][C:12]=2[CH:16]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][C:8]1[CH:9]=[C:10]([CH2:17][C:18]#[N:19])[C:11]2[O:15][CH:14]=[CH:13][C:12]=2[CH:16]=1
Reactant: N#CCc1cc(OC2CCCCO2)cc2ccoc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: N#CCc1cc(O)cc2ccoc12
Yield: 96.2 %

Procedure:
Dissolve [5-(tetrahydropyran-2-yloxy)benzofur-7-yl]acetonitrile (3.89 g, 0.015 mol) in methanol (100 mL) and add para-toluene sulfonic acid monohydrate (0.288 g, 0.1 equivalent). After 20 minutes extract with ethyl acetate against water, then wash with brine. Concentration in vacuo affords 2.5 g (95.5%) of the title compound as an off-white solid. HRMS(m/z): Calcd 173.0465 Found 173.0477.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:13])[CH:11]=2)[CH:6]([CH3:14])[C:5]1=[O:15])(=[O:3])[CH3:2].[H-].[Na+].CI.[CH2:20]1COCC1>O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:13])[CH:11]=2)[C:6]([CH3:20])([CH3:14])[C:5]1=[O:15])(=[O:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(=O)N1C(=O)C(C)c2ccc(Br)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC(=O)N1C(=O)C(C)(C)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1-acetyl-6-bromo-3-methyl-1,3-dihydro-2H-indol-2-one (9.5 g) were added NaH (1.57 g), methyl iodide (2.45 ml) and THF (70 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. This ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give the title compound (5.2 g) as a colorless crystal.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.[C:11]([O:14][CH2:15][CH3:16])(=[O:13])[CH3:12]>O1CCCC1>[OH:3][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:2])[CH2:12][C:11]([O:14][C@@H:15]1[CH2:5][C@H:4]([CH3:9])[CH2:1][CH2:2][C@H:16]1[CH:7]([CH3:8])[CH3:6])=[O:13]
Reactant: CCOC(C)=O
Reactant: CC(=O)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)CC(C)(O)c1ccccc1
Reaction time: 4 h
Yield: 92 %

Procedure:
20.4 mL (20 mmol, 2 equivalents) of the solution of (−)-menthyl bromozincacetate in tetrahydrofuran obtained in Example 63 was added dropwise to a solution of 0.58 mL (5 mmol) of acetophenone in 3 mL of THF at 5˜7° C. The mixture was stirred at 3˜7° C. for 4 hours. 10 mL of 1H hydrochloric acid was added at 20° C. or lower, followed by dilution with 20 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL of 1N hydrochloric acid, 5 mL of water, 10 mL and 5 mL of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, purification with silica gel column (developing solvent; ethyl acetate/n-hexane=1/5, 1/3) afforded 1.69 g of the desired product (NMR yield 92%; internal standard dioxane). Recrystallization with n-hexane afforded 0.74 g of the desired product (yield 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=[CH:7][N:6]=1.[NH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH2:21][CH2:20]2)=[O:13])=[CH:9][N:8]=[CH:7][N:6]=1
Reactant: O=C(O)c1cncnc1Oc1cc(Cl)ccc1Cl
Reactant: c1ccc2c(c1)NCCN2
Product: O=C(c1cncnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Yield: 20 %

Procedure:
The title compound was prepared in analogy to Example 77, from 4-(2,5-dichloro-phenoxy)-pyrimidine-5-carboxylic acid (Example 76, intermediate a) and 1,2,3,4-tetrahydroquinoxaline (commercially available, CAS RN 3476-89-9). The compound was purified by preparative HPLC (Phenomenex Gemini column) using a gradient of acetonitrile:water (10:90 to 98:2) to give 16 mg (20%) of the desired compound. MS (ESI): m/z=401.0 [M+H]+.
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[OH:11].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][Cl:21]>CC(C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:19][CH2:20][Cl:21]
Reactant: ClCCBr
Reactant: Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCOc1ccc2ccccc2c1

Procedure:
A mixture of β-naphthol (1 gm, 0.006 mole), anhydrous K2CO3 (10 gm, in excess) and 1-bromo-2-chloroethane (0.6 ml, 0.006 mole) was refluxed in dry acetone (50 ml) for 6 hours. Reaction mixture was filtered and filtrate was concentrated to get oily compound, which was crystallized with benzene-hexane to give the colorless crystals of pure desired compound. m.p. 94° C., (yield 1.36 gm, 96%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[O:5][N:4]=1.[Li+].[Br-:16].CC(=O)OCC>C1COCC1>[Br:16][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[O:5][N:4]=1
Reactant: ClCc1noc(-c2cccc(Cl)c2)n1
Reactant: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Clc1cccc(-c2nc(CBr)no2)c1
Temperature: 25 °C
Yield: 85.3 %

Procedure:
3-(chloromethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (1.38 g, 6.0 mmol) and LiBr (0.90 g, 10.3 mmol) in THF (50 ml) was heated to reflux under a nitrogen atmosphere o.n. After cooling to r.t. EA was added and the organic phase was washed with H2O and brine, dried and evaporated to give the title compound (1.40 g, 85%). MS (M++1) 275
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:8][CH:9]=[C:10]([Cl:13])[C:11]=2[Cl:12])=[N:5][C:4]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[N:3]1.C([O-])(=O)C.[Na+].[Br:27]Br.C(Cl)Cl>C(O)(=O)C>[CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]([Br:27])=[C:10]([Cl:13])[C:11]=2[Cl:12])=[N:5][C:4]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[N:3]1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1scc(Cl)c1Cl
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1sc(Br)c(Cl)c1Cl
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 96.6 %

Procedure:
To a mixture of 1-methyl-3-(2-chloro-6-fluorophenyl)-5-(3,4-dichlorothien-2-yl) [1,2,4]triazole (33.4 g, 92.1 mmol) and sodium acetate (7.6 g, 92.1 mmol) in acetic acid (250 mL) was added bromine (58.9 g, 368.4 mmol) dropwise at a rate which maintained the reaction temperature below 35° C. The resulting mixture was slowly heated to 70° C. and stirred for 2.5 hours, cooled to 50° C. and stirred overnight, and cooled to room temperature. TLC analysis (methylene chloride) indicates full consumption of the starting material. The reaction was slowly poured into a mixture of 10% aqueous sodium bisulfite and ice (300 mL), and the resulting pale yellow suspension was stirred for 20 minutes. The solids were collected by vacuum filtration, washed with water, and dissolved in methylene chloride. The organics were dried (sodium sulfate), filtered, and the solvent evaporated at reduced pressure to give 39.3 g (96%) of desired product as a tan solid: mp 178-180° C. 1H NMR (CDCl3) δ4.04 (s, 3H), 7.08-7.14 (Ar-m, 1H), 7.29-7.40 (Ar-m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[C:5](=O)[NH:4][N:3]=1.[OH-].[Na+].P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:5]1[C:6]2[CH:7]=[C:8]3[N:13]([C:14]=2[C:2]([CH3:1])=[N:3][N:4]=1)[CH:12]=[CH:11][CH:10]=[CH:9]3
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c2cc3ccccn3c12
Agent: [Na+]
Agent: [OH-]
Product: Cc1nnc(Cl)c2cc3ccccn3c12
Temperature: 0 °C
Yield: 52 %

Procedure:
The stirred suspension of the 4-methyl-2H-pyridazino[4,5-b]indolizine-1-one (10.0 g, 0.050 mole) in phosphoryl chloride (75 ml) was refluxed under nitrogen for 3 hours. After cooling, the reaction mixture was poured into ice-water (1 L) with vigorous stirring. Then, the solution was made alkaline (pH 8-9) by addition of a 50% W/W sodium hydroxide solution (cooling). The suspension was filtered and the solid was washed with water and dried to yield 1-chloro-4-methylpyridazino[4,5-b]indolizine (10.33 g). For analysis, a sample was recrystallized from dichloromethane and ether.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([CH2:22][N:23]3[CH2:28][CH2:27][N:26]([C:29]([CH3:34])([CH2:32][OH:33])[CH2:30][OH:31])[CH2:25][CH2:24]3)[N:18]2[CH3:21])=[C:14]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:13]=1>>[CH3:34][C:29]([N:26]1[CH2:25][CH2:24][N:23]([CH2:22][C:17]2[N:18]([CH3:21])[C:19]3[C:15]([N:16]=2)=[C:14]([N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)[N:13]=[C:12]([N:3]2[C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=[C:2]2[CH3:1])[N:20]=3)[CH2:28][CH2:27]1)([CH2:32][OH:33])[CH2:30][OH:31]
Reactant: Cn1c(CN2CCN(C(C)(CO)CO)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Cc1nc2ccccc2[nH]1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(CO)CO)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-methylbenzimidazole and 2-(4-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-1-yl)-2-methylpropane-1,3-diol were reacted to give 356. LCMS m/z: 536.3 (MH+)
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[NH2:7][C:8]1[CH2:13][CH2:12][CH:11](I)[C:10](=[O:15])[C:9]=1[CH3:16].S(OC)(OC)(=O)=O>C1COCC1>[CH3:1][O:15][C:10]1[C:9]([CH3:16])=[C:8]([CH:13]=[CH:12][CH:11]=1)[NH2:7]
Reactant: CC(C)(C)[O-]
Reactant: CC1=C(N)CCC(I)C1=O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: COc1cccc(N)c1C
Temperature: -15 °C
Yield: 89 %

Procedure:
2.24 g (20 mmol, 2 eq) of potassium tert-butoxide is dissolved in 60 ml of anhydrous THF and the resulting solution is cooled to −15° C. with stirring. A solution of 2.51 g (10 mmol, 1 eq) of 3-amino-6-iodo-2-methyl-2-cyclohexen-1-one in 25 ml anhydrous THF is added to the potassium tert-butoxide solution and the temperature is kept below −5° C. during addition. The cooling bath is removed after addition and the reaction is allowed to warm up to 5° C. within 1 hour. HPLC shows complete elimination. 1.20 g (9.5 mmol, 0.95 eq) of dimethyl sulfate is added to the reaction mixture with vigorous Stirring. The reaction is shown to be complete by HPLC (˜2 h). Then an HPLC weight assay indicates an 89% yield of the product. The isolation of the product was not optimized.
Reaction SMILES: [NH2:1][CH:2]([CH3:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1>CN(C)C=O>[CH3:5][CH:2]([NH2:1])[CH2:3][O:4][C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CC(N)CO
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(N)COc1ncccn1
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
2.0 g of 2-amino-1-propanol was added dropwise to a stirred mixture of 1.3 g of 60% sodium hydride and 30 ml of N,N-dimethylformamide at room temperature. After the reaction mixture was stirred for 30 minutes, a solution containing 3.7 g of 2-chloropyrimidine dissolved in N,N-dimethylformamide was added dropwise to the reaction mixture. The mixture was stirred for 2 hours at 100° C. After completion of the reaction, the reaction mixture was cooled. The solids in the reaction mixture were filtered off. The solvent in the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel to obtain 2.1 g of the desired product (yield: 50%).
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:10]=[N:11][C:12]([Cl:22])=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:22][C:12]1[N:11]=[CH:10][C:9]([NH:7][CH3:6])=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH:13]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cnc(Cl)cc1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cnc(Cl)cc1-c1ccccc1Cl
Yield: 99 %

Procedure:
A solution of 1.26 g (3.55 mmol) [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-carbamic acid tert-butyl ester and 3.34 ml (42.8 mmol) trifluoroacetic acid in 11 ml dichloromethane was stirred at room temperature for 2 h. Addition of 2 M aqueous sodium carbonate solution was followed by extraction with two portions of dichloromethane. The combined organic layers were dried with sodium sulfate and concentrated to give 0.89 g (99%) of the title compound as an off-white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:14](C)[C:15](=O)OC(C)(C)C)[CH2:11][CH:12]=[CH2:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@@H:10]([NH:14][CH3:15])[CH2:11][CH:12]=[CH2:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)pent-4-en-2-yl(methyl)carbamate (10.5 g, 31.9 mmol) in DCM (100 mL) was added 2,6-lutidine (4.8 mL, 41.4 mmol) followed by TMSOTf (7.5 mL, 41.4 mmol). The resulting solution was stirred at RT for 30 min. The solvent was removed and the remaining residue was dried under vacuum to give (S)-1-(tert-butyldimethylsilyloxy)-N-methylpent-4-en-2-amine, which was used without further purification. LRMS (M+H+) m/z 230.2.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][CH2:17][CH3:18])[N:4]=[C:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[C:6]2O.[OH-].[NH4+].P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:6]1[C:5]2=[N:4][N:3]([CH2:16][CH2:17][CH3:18])[C:2]([CH3:1])=[C:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCn1nc2c(O)nc3ccccc3c2c1C
Agent: [NH4+]
Agent: [OH-]
Product: CCCn1nc2c(Cl)nc3ccccc3c2c1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 1-methyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ol (5.11 g, 21.2 mmol) in phosphorus oxychloride (50 mL) was heated at reflux for 30 minutes, allowed to cool to room temperature, and stirred for two days. The reaction mixture was poured into ice water (500 mL) with stirring, and concentrated ammonium hydroxide (169 mL) and ice were added. A solid was present and was isolated by filtration, washed with water, and purified by automated flash chromatography (eluting with 5% to 25% CMA in chloroform). The resulting orange solid (5.5 g) was recrystallized from acetonitrile (25 mL). The crystals were washed with acetonitrile and dried for five hours to provide 3.85 g of 4-chloro-1-methyl-2-propyl-2H-pyrazolo[3,4-c]quinoline as a white solid, mp 145-147° C. Anal. Calcd for C14H14N3Cl: C, 64.74; H, 5.43; N, 16.18. Found: C, 64.50; H, 5.64; N, 16.20.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1([CH2:15][C:16](Cl)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.N1C=CC=CC=1>ClCCl>[CH:9]1([CH2:15][C:16]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)CC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CC1CCCCC1)Nc1ccc(O)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-aminophenol (3.83 g, 35.1 mmol) in dichloromethane (50 ml) were added cyclohexylacetyl chloride (11.26 g, 70.1 mmol) and pyridine (5.67 ml, 70.1 mmol), while cooling the reaction mixture in an ice bath. After the addition was completed, the cooling bath was removed and stirring was continued overnight at room temperature. The solvent was removed by evaporation and the residue was dissolved in THF (300 ml). 6N NaOH (aq, 41 ml) was added and the mixture was stirred at room temperature for 4 h. The solution was acidified with 1 N hydrochloric acid and the organic phase was removed by evaporation. The solid material was collected by filtration, dried and dissolved in methanol (100 ml). A solution of KOH (5.5 g) in methanol (50 ml) was added. After stirring for 1 h at room temperature water (200 ml) was added and the organic solvent was removed by evaporation. The aqueous phase was acidified with 1 N HCl. The title product was isolated by filtration and dried in vacuo (6.31 g, 77%, pink crystals).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]C)=[O:9])=[C:6]([CH3:12])[C:5]([F:13])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:12])[C:5]([F:13])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(Cl)ccc(F)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(F)ccc(Cl)c1C(=O)O

Procedure:
Methyl 6-chloro-3-fluoro-2-methylbenzoate 65 (14 g, 69 mmol, 1 eq) and NaOH (13.8 g, 345 mmol, 5 eq) were dissolved in a mixture of 1,4-dioxane (10 mL) and H2O (130 mL), and the resulting mixture was stirred at reflux overnight. The reaction mixture was cooled to RT and neutralized with conc. HCl to adjust the pH value to 1. The mixture was extracted with DCM (3×60 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the product 6-chloro-3-fluoro-2-methylbenzoic acid 66. The product was used directly in the next step.