Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=3)[NH:21][CH:20]=2)=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29]>ClCCl>[ClH:29].[ClH:29].[F:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:17](=[O:18])[CH2:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCC(=O)c2c[nH]c3ccc(F)cc23)CC1
Agent: Cl
Solvent: ClCCl
Product: O=C(CCCN1CCNCC1)c1c[nH]c2ccc(F)cc12
Yield: 89.4 %

Procedure:
To a magnetically stirred solution of 4-[4-(5-fluoro-1H-indol-3-yl)-4-oxobutyl]-piperazine-1-carboxylic acid tert-butyl ester (3.85 g, 9.88 mmol) in dichloromethane was added hydrochloric acid (dissolved in dioxane: 4.94 ml, 4M solution, 19.8 mmol HCl) and the resulting mixture was reacted at room temperature for 4 hours. The reaction mixture was thoroughly concentrated in vacuo to give 1-(5-fluoro-1H-indol-3-yl)-4-(piperazin-1-yl)butan-1-one dihydrochloride (3.20 g). Some characteristic 1H-NMR signals from 1-(5-fluoro-1H-indol-3-yl)-4-(piperazin-1-yl)butan-1-one dihydrochloride are: (400 MHz, DMSO-d6) δ 2.07 (quintet, J=7, 2H), 3.03 (t, J=7, 2H), 7.08 (dt, J˜9 and 3, 1H), 7.50 (dd, J˜9 and 4, 1H), 7.85 (dd, j˜9 and 3, 1H), 8.43 (d, J˜3, 1H), 12.21 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[CH:16][C:15]3[N:14]=[CH:13][C:12]4[N:18]([CH3:29])[C:19](=[O:28])[N:20]([C:21]5[C:22]([CH3:27])=[N:23][N:24]([CH3:26])[CH:25]=5)[C:11]=4[C:10]=3[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[CH:30](=O)[CH3:31].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:26][N:24]1[CH:25]=[C:21]([N:20]2[C:11]3[C:10]4[CH:9]=[C:8]([C:4]5[CH:5]=[N:6][CH:7]=[C:2]([NH:1][CH2:30][CH3:31])[CH:3]=5)[CH:17]=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:18]([CH3:29])[C:19]2=[O:28])[C:22]([CH3:27])=[N:23]1
Reactant: CC=O
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(N)c4)cc3c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCNc1cncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 8-(5-amino-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 45, 38 mg, 0.099 mmol), acetaldehyde (Fluka, Buchs, Switzerland, 4.8 mg, 0.108 mmol) in DCM (2 ml) was stirred for 1.5 h at rt in presence of acetic acid (0.02 ml, 3.54 mmol). Was added sodium triacetoxyborohydride (52.2 mg, 0.246 mmol) and the RM was stirred 1.5 h at rt, before being quenched with aqueous saturated NaHCO3 and extracted with DCM (2×). The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by Prep.HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 60:40). The fractions containing products were collected together and basified with NaHCO3 (0.3 g), before being concentrated, saturated with NaCl and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and evaporated to give the title compound as an off-white solid. (HPLC: tR 2.13 min (Method A); M+H=414 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.13-8.08 (m, 2H), 7.97-7.95 (m, 1H), 7.92-7.88 (m, 2H), 7.60-7.58 (m, 1H), 6.88-6.85 (m, 1H), 6.01 (t, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 3.15-3.06 (m, 2H), 1.95 (s, 3H), 1.21 (t, 3H))
Reaction SMILES: [C:1]1([CH2:7][C:8]2[N:12]=[C:11](C(Cl)(Cl)Cl)[O:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:17].[Na+]>C(O)C>[C:1]1([CH2:7][C:8]2[NH:12][C:11](=[O:17])[O:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(Cl)(Cl)c1nc(Cc2ccccc2)no1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c(Cc2ccccc2)no1

Procedure:
60 g. (0.22 moles) of 3-(phenylmethyl)-5-trichloromethyl-1,2,4-oxadiazole is dissolved in 100 ml. of ethanol. The solution is stirred and 132 ml. (0.264 mole) of 2N sodium hydroxide solution are added dropwise. The temperature of the mixture rises to about 40°. After the addition has been completed, the mixture is stirred for an additional 30 minutes and then concentrated in a rotary evaporator. The residue is treated with water, filtered and the filtrate is acidified with 2N hydrochloric acid. The crystals are filtered under suction, and purified by dissolving in sodium bicarbonate solution, filtering and precipitating with dilute hydrochloric acid. 29.7 g. of 3-(phenylmethyl)-1,2,4-oxadiazol-5-(4H)-one are obtained, m.p. 114°-116°.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)=[CH:7]2.[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:19][C:15]1[CH:14]=[C:13]([CH2:12][C:8]2[CH:9]=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[N:23]2[CH2:22][CH2:21][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24]2)[CH:18]=[CH:17][CH:16]=1
Reactant: Clc1cccc(Cc2cnc3c(Cl)cccc3c2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3cc(Cc4cccc(Cl)c4)cnc23)CC1
Temperature: 80 °C
Yield: 52.9 %

Procedure:
A stirred suspension of 8-chloro-3-[(3-chlorophenyl)methyl]quinoline (D3)(0.25 g, 0.87 mmol), 1,1-dimethylethyl 1-piperazinecarboxylate (0.228 g, 1.2 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.025 g, 0.027 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.03 g, 0.076 mmol) and sodium tert-butoxide (0.118 g, 1.23 mmol) in degassed 1,4-dioxan (3.8 ml) under argon was heated at 80° C. under argon of 18 h. The cooled reaction mixture was diluted with dichloromethane (50 ml) and washed with water (50 ml), dried (MgSO4) and concentrated in vacuo to an oil. The oil was purified by chromatography over silica gel eluting with a gradient of acetone/toluene to give the title compound (D4) as an oil (0.202 g, 0.46 mmol, 53%).
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([N:10]=[C:11]=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:16]=1[NH2:17].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:25][O:24][C:18]1[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=[C:15]([O:14][CH3:13])[C:16]=1[NH:17][C:11]([NH:10][CH:7]1[CH2:8][CH2:9][CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]1)=[O:12]
Reactant: CC(C)C1CCC(N=C=O)CC1
Reactant: COc1cc(OC)c(N)c(OC)c1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(OC)c(NC(=O)NC2CCC(C(C)C)CC2)c(OC)c1
Temperature: 25 °C

Procedure:
To a solution of 1.6 g of 4-isopropylcyclohexylisocyanate in chloroform is added a solution of 1.8 g of 2,4,6-trimethoxyaniline in chloroform dropwise in the presence of pyridine. The mixture is stirred at room temperature until starting compounds disappear on TLC. The resultant mixture is concentrated and the residue is dissolved in ethyl acetate. The solution is washed with diluted hydrochloric acid, aqueous sodium hydrogencarbonate solution and brine. The organic layer is dried over magnesium sulfate and filtered off. The filtrate is distilled away and the resulting residue is crystallized to give N-(2,4,6-trimethoxyphenyl)-N'-(4-isopropylcyclohexyl)urea.
Reaction SMILES: [C:1]1([CH:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][N:9]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([CH:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][N:9]([CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCc2ccccc2C(c2ccccc2)C1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCN1CCc2ccccc2C(c2ccccc2)C1

Procedure:
Batch size: 38.0 g (<89.5 mmol) 2-[4-(1-phenyl-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-butyl]-isoindol-1,3-dione and 8.7 ml (179 mmol) hydrazine hydrate in 200 ml ethanol. The reaction mixture is filtered and the filtrate is concentrated under vacuum. The residue is taken up in 400 ml dichloromethane and washed twice each with 50 ml 10% NaCH solution. The organic phase is dried over sodium sulfate and, subsequently, the solvent is removed under vacuum. The purification occurs chromatographically over silica gel with CHCl3/CH3OH/TEA (95/5/0 to 90/9/1): Yield 15.6 g (59%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].[C:10]([O:14][C:15](=[O:37])[CH2:16][N:17]1[C:21]2[CH:22]=[CH:23][C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:25][C:20]=2[N:19]=[C:18]1[CH2:34][CH2:35][CH3:36])([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:10]([O:14][C:15](=[O:37])[CH2:16][N:17]1[C:21]2[CH:22]=[CH:23][C:24]([N:26]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[CH3:1])=[O:8])=[CH:25][C:20]=2[N:19]=[C:18]1[CH2:34][CH2:35][CH3:36])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: Cc1ccsc1C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3sccc3C)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methyl-thiophene-2-carbonyl chloride (41 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C29H33N3O3S+H: 504, observed: 504.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:39][O:40][C:41]1[N:46]=[CH:45][C:44]([CH2:47]O)=[CH:43][CH:42]=1>C1COCC1>[CH3:39][O:40][C:41]1[CH:42]=[CH:43][C:44]([CH2:47][O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:45][N:46]=1
Reactant: Oc1ccccc1
Reactant: COc1ccc(CO)cn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(COc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
According to Scheme 16 Method A: Phenol (1.5 eq, 2.80 mmol, 0.26 g), PPh3 (2 eq, 3.70 mmol, 1.20 g) and DEAD (2 eq, 3.70 mmol, 1.60 g) were added to a solution of (6-methoxypyridin-3-yl)methanol (1 eq, 1.87 mmol, 0.26 g) in THF (6 mL). The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent, the reaction mixture was diluted with water. The organic layer washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and evaporated. The resulting crude residue was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2) using cyclohexane/AcOEt 85/15 to afford 2-methoxy-5-(phenoxymethyl)pyridine (0.93 mmol, 0.20 g, 49%) as a pale oil.
Reaction SMILES: CC[O-].[Na+].S(O)(O)(=O)=O.[CH3:10][O:11][C:12]([NH2:14])=[NH:13].C[CH2:16][CH:17]([C:22](OCC)=[O:23])[C:18](OC)=[O:19]>C(O)C>[CH3:10][O:11][C:12]1[N:14]=[C:18]([OH:19])[C:17]([CH3:16])=[C:22]([OH:23])[N:13]=1
Reactant: CCOC(=O)C(CC)C(=O)OC
Reactant: COC(=N)N
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: COc1nc(O)c(C)c(O)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
13.8 g (200 mmoles) of sodium ethylate is added to a solution of 10 g (58 mmoles) of methoxyformamidine sulphate in 100 ml of ethanol cooled down to 0° C. and the mixture is stirred for 15 minutes; then a solution of 9 ml (52 mmoles) of diethyl methyl malonate in 50 ml of ethanol is added followed by stirring overnight at ambient temperature. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is taken up in 100 ml of a saturated solution of sodium chloride and extracted with 800 and 200 ml of n-butanol. The organic phases are dried over sodium sulphate, filtered and evaporated to dryness under reduced pressure (2 kPa), 5.9 g of expected product is obtained in the form of a white solid.
Reaction SMILES: [C@@H:1]1([N:10]2[CH2:18][CH:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@H:4]([OH:5])[C@@H:2]1[OH:3].[BH4-].[Na+]>>[CH3:17][CH:16]1[CH2:18][N:10]([C@@H:1]2[O:7][C@H:6]([CH2:8][OH:9])[C@H:4]([OH:5])[C@@H:2]2[OH:3])[C:11](=[O:12])[NH:13][CH:14]1[OH:15]
Reactant: CC1CN([C@@H]2O[C@H](CO)[C@H](O)[C@@H]2O)C(=O)NC1=O
Agent: [BH4-]
Agent: [Na+]
Product: CC1CN([C@@H]2O[C@H](CO)[C@H](O)[C@@H]2O)C(=O)NC1O

Procedure:
In the manner given in Example 2C 1-β-D-lyxofuranosyl-dihydrothymine was reduced with sodium borohydride to give 5-methyl-4-hydroxy-1-β-D-lyxofuranosyl-tetrahydro-2(1H)-pyrimidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:17]1([CH2:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:8][C:24](=[O:25])[CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[S:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC(=S)c1ccc(Cl)cc1
Solvent: O
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1)NC(=S)c1ccc(Cl)cc1
Temperature: 55 °C
Yield: 82.4 %

Procedure:
To a solution of 4-chlorothiobenzamide (0.519 g, 3.02 mmol) in acetone (5 mL) was added pyridine (0.367 mL, 4.53 mmol) and phenylacetyl chloride (0.480 mL, 3.63 mmol). The bright orange reaction mixture was heated to 55° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, and water (20 mL) was added. The precipitate was removed by filtration, washed with water, and dried to provide 0.721 g (82%) of the product as a red solid: 1H NMR (CDCl3) δ 9.34 (br s, 1H), 7.50-7.22 (m, 9H), 3.96 (s, 2H) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:18][N:17]([CH3:26])[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=CC(C(=O)CC2C=CN=CC=2)=C([F:50])C=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:19]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[CH:18][N:17]([CH3:26])[N:16]=2)=[C:13]([F:50])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccccc2)cc1F
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccccc3)cc2)n1
Product: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccccc3)cc2F)n1

Procedure:
Following the procedure for the preparation of 4-[3-(4-Benzyloxy-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyridine but substituting 1-(4-Benzyloxy-2-fluoro-phenyl)-2-pyridin-4-yl-ethanone provided the title compound. MS: (M+H m/z=360.1).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:20][O:21][CH2:22]Cl>C(Cl)Cl.O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:20][O:21][CH3:22])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: COCCl
Reactant: CC(C)c1cccc(O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COCOc1cccc(C(C)C)c1
Reaction time: 16 h
Yield: 55.5 %

Procedure:
Into methylene chloride (300 mL) was dissolved 3-isopropylphenol (27.24 g, 200 mmol). After cooling the solution in an ice bath, diisopropylethyl amine (69.7 mL, 400 mmol) was added in one portion, followed by the dropwise addition of chloromethyl methyl ether (18.9 mL, 236 mmol) in methylene chloride (50 mL). The reaction mixture was gradually allowed to come to room temperature. After 16 h, the reaction mixture was diluted with cold water (500 mL) and methylene chloride. The mixture was shaken in a separatory funnel and the layers were separated. The organic layer was extracted with cold water (2×500 mL), dried (MgSO4), and concentrated under vacuum. The product was dissolved in ether (200 mL) and stirred with 5 N NaOH (200 mL) at room temperature for 5 min. The ether layer was separated and extracted with cold 1N HCl (200 mL), dried (MgSO4), and concentrated under vacuum. The product was chromatographed over silica (0 to 30% EtOAc in hexane gradient), giving 20.0 g (56%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[N:6][C:7]=1[S:8][CH2:9][CH:10]([CH3:12])[CH3:11].S(=O)(=O)(O)O.[CH3:21]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([O:15][CH3:21])=[O:14])=[N:6][C:7]=1[S:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)CSc1nc(C(=O)O)ccc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)c(SCC(C)C)n1
Temperature: 80 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
5-Bromo-6-(isobutylthio)picolinic acid (500 mg, 1.72 mmol) was dissolved in methanol (5 mL) to give a yellow solution. Sulfuric acid (169 mg, 92.3 μL, 1.72 mmol) was added. The reaction mixture was heated to 80° C. and stirred for 1 d. The reaction mixture was cooled to 0° C. and poured onto ice-water/brine (25 mL). The aqueous layer was extracted with EtOAc (2×40 mL) and washed with ice-water/brine (20 mL). The organic layers were combined, dried over Na2SO4 and concentrated in vacuo to give crude title compound as a yellow oil. The oil was purified by flash chromatography (silica gel, 5 g, 0% to 15% EtOAc in heptane) to give the title product (205 mg, 39%) as a colorless oil. MS (EI): m/e=306.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([OH:8])=[O:7].[Si:14]([O:21][C@H:22]1[CH2:31][C@H:30](O)[C@H:29]2[C:24]([CH:25]=[CH:26][C@H:27]([CH3:50])[C@@H:28]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH2:36]2)=[CH:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[Si:14]([O:21][C@H:22]1[CH2:31][C@H:30]([O:7][C:6](=[O:8])[CH:5]([O:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]=2[CH3:1])[CH3:9])[C@H:29]2[C:24]([CH:25]=[CH:26][C@H:27]([CH3:50])[C@@H:28]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:44])[CH3:45])[CH2:36]2)=[CH:23]1)([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:16])[CH3:15]
Reactant: Cc1ccccc1OC(C)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: Cc1ccccc1OC(C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 80.3 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 0.65 g of (2RS)-2-(2-methylphenoxy)propionic acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.04 g of the title compound as a colorless foam.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][NH:5][C:4](=[O:8])[C:3]1=[O:9].[CH3:10][C:11]1[O:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>C(O)(=O)C>[CH3:15][C:14]1[O:17][C:11]([CH:10]=[N:1][N:2]2[CH2:7][CH2:6][NH:5][C:4](=[O:8])[C:3]2=[O:9])=[CH:12][CH:13]=1
Reactant: NN1CCNC(=O)C1=O
Reactant: Cc1ccc(C=O)o1
Solvent: CC(=O)O
Product: Cc1ccc(C=NN2CCNC(=O)C2=O)o1
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
1.3 pts. by wt. of 1-amino-2,3-dioxo-piperazine, 1.3 pts. by wt. of 5-methyl-furfural and 7 pts. by vol. of glacial acetic acid are warmed to 90° C. for 10 minutes and then left for 30 minutes at RT. The precipitate is filtered off, washed first with 3 pts. by vol. of glacial acetic acid and then three times with 10 pts. by vol. of ethyl acetate and dried in air. 1.7 pts. by wt. (76.6%) of 1-(5-methyl-furfurylideneamino)-2,3-dioxo-piperazine of decomp. pt. 245°-8° C. are obtained.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[C:19](=[O:22])([O-])[O-].[Cs+].[Cs+]>C(#N)CCC.[Cu]I>[NH2:6][C@@H:5]([CH3:4])[C@@H:19]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:22][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=1)[N:6]=[CH:5]2
Reactant: O=C([O-])[O-]
Reactant: OCc1ccc(-n2ncc3cc(I)ccc32)cc1
Agent: [Cu]I
Agent: [Cs+]
Solvent: CCCC#N
Product: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(CO)cc2)c1)c1ccccc1
Reaction time: 0.83 h
Yield: 92.1 %

Procedure:
(4-(5-iodo-1H-indazol-1-yl)phenyl)methanol (141b, 1.06 g, 3 mmol), (2R,3S-norephedrine (1.39 g, 9.2 mmol), CuI (206 mg, 1 mmol) and was stirred under argon atmosphere in butyronitrile (14 mL) at 125° C. Caesium carbonate (5.1 g, 15.7 mmol) was added and the mixture was vigorously stirred for 50 min, cooled, filtered and evaporated. Chromatography (SiO2, 040% MeOH in EtOAc) afforded (4-(5-((1R,2S)-2-amino-1-phenylpropoxy)-1H-indazol-1-yl)phenyl)methanol (516 mg, 45%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:4]2[C:13]3[CH:12]=[CH:11][C:10]([O:14][CH2:15][CH2:16][CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[CH:9][C:8]=3[N:7]=[C:6]([NH2:23])[C:5]=2[N:24]=1.[CH:29]1([N:35]=[C:36]=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>ClCCl>[NH2:23][C:6]1[C:5]2[N:24]=[C:2]([CH3:1])[N:3]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:4]=2[C:13]2[CH:12]=[CH:11][C:10]([O:14][CH2:15][CH2:16][CH:17]3[CH2:18][CH2:19][N:20]([C:36]([NH:35][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[O:37])[CH2:21][CH2:22]3)=[CH:9][C:8]=2[N:7]=1
Reactant: O=C=NC1CCCCC1
Reactant: Cc1nc2c(N)nc3cc(OCCC4CCNCC4)ccc3c2n1CC(C)C
Solvent: ClCCl
Product: Cc1nc2c(N)nc3cc(OCCC4CCN(C(=O)NC5CCCCC5)CC4)ccc3c2n1CC(C)C
Reaction time: 0.5 h

Procedure:
The preparation of 2-methyl-1-(2-methylpropyl)-7-(2-piperidin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-amine is described in Example 24. Cyclohexyl isocyanate (0.100 mL, 0.786 mmol) was added dropwise to a stirred solution of 2-methyl-1-(2-methylpropyl)-7-(2-piperidin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-amine (0.300 g, 0.786 mmol) in dichloromethane (10 mL) at 0° C. After 30 minutes, the solution was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (silica gel, sequential elution with 2% and 5% methanol in dichloromethane) followed by recrystallization from ethanol to afford 0.141 g of 4-{2-[(4-amino-1-isobutyl-2-methyl-1H-imidazo[4,5-c]quinolin-7-yl)oxy]ethyl}-N-cyclohexylpiperidine-1-carboxamide as a white powder, mp 213.7-215.7° C.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=1)[C:3]#[C:4][C:5]([O:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[O:6]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:24][O:23][C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([O:19][CH3:20])[C:16]=1[O:21][CH3:22])[C:2]([C:3]#[C:4][C:5]([O:7][CH2:8][CH:9]=[C:10]([CH3:11])[CH3:12])=[O:6])=[O:1]
Reactant: COc1cc(C(O)C#CC(=O)OCC=C(C)C)cc(OC)c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(C(=O)C#CC(=O)OCC=C(C)C)cc(OC)c1OC
Reaction time: 2 h

Procedure:
A solution of 10.7 g (32 mmol) of 3-methyl-2-butenyl 4-hydroxy-4-(3,4,5-trimethoxyphenyl)-2-butynoate in 200 ml of methylene chloride was added dropwise at 0° to a suspension of 84 g (0.97 mol) of manganese dioxide in 200 ml of methylene chloride. The reaction mixture was stirred at 0° for 2 hours, filtered over magnesium sulphate and concentrated. The residue was purified by flash chromatography on 500 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1) and crystallized from ether/hexane. There was obtained 3-methyl-2-butenyl 3-(3,4,5-trimethoxybenzoyl)propiolate of melting point 52°-53°.