Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=[C:19]3[C:18]2=[O:28])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[NH2:30][OH:31]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=[C:19]3[C:18]2=[O:28])[CH2:13][C:14]([NH:30][OH:31])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccc(C)cc3C2=O)ccc1OC
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3ccc(C)cc3C2=O)ccc1OC
Yield: 87.8 %

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-N-hydroxy-3-(4-methylphthalimido)propionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(4-methyl-phthalimido)propanoic acid (2.40 g, 6.26 mmol), N,N′-carbonyldiimidazole (1.12 g, 6.91 mmol) and hydroxylamine hydrochloride (530 mg, 7.62 mmol) in tetrahydrofuran (8 mL) to afford 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(4-methylphthalimido)propionamide as a white solid (2.19 g, 88% yield): mp, 180.0-181.5° C.; 1H NMR (DMSO-d6) δ1.31 (t, J=6.9 Hz, 3H, CH3), 2.49 (s, 3H, CH3), 3.09 (d, J=7.9 Hz, 2H, CH2), 3.71 (s, 3H, CH3), 3.97 (q, J=7.0 Hz, 2H, CH2), 5.65 (t, J=7.9 Hz, 1H, NCH), 6.89 (br s, 2H, Ar), 7.01 (br s, 1H, Ar), 7.61-7.74 (m, 3H, Ar), 8.78 (br s, 1H, OH), 10.57 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.67, 21.33, 34.31, 50.14, 55,45, 63.72, 111.75, 112.33, 119.61, 123.03, 123.52, 128.63, 131.32, 131.61, 134.88, 145.54, 147.67, 148.52, 166.02, 167.62, 167.73; Anal Calcd for C21H22N2O6: C, 63.31; H, 5.57; N, 7.03. Found: C, 63.29; H, 5.69; N, 6.86.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:39]>C(OCC)(=O)C.C(O)C>[ClH:39].[F:1][C:2]1[C:3]([CH2:23][NH:24][CH3:25])=[CH:4][N:5]([S:14]([C:17]2[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2nccn2C)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cn(S(=O)(=O)c2nccn2C)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
tert-Butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(1-methyl-1H-imidazol-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (229 mg) was dissolved in ethyl acetate (1 mL) and ethanol (1 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol=1:10 to give the title compound as colorless crystals (yield 174 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[C:7](Br)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ncccc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cccnc2Cl)CC1
Temperature: 100 °C
Yield: 50.5 %

Procedure:
Stir 2-chloro-3-bromopyridine (5.00 g, 26.0 mmol) and piperazine-1-carboxylic acid t-butyl ester (3.73 g, 20.0 mmol) in dry toluene (200 mL) at room temperature under nitrogen. Add sodium t-butoxide (2.88 g, 30.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.366 g, 0.40 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.694 g, 1.20 mmol), degas reaction and heat to 100° C. (oil bath temperature) for 3 hr. Cool to room temperature, add 100 mL water, extract with 2×200 mL ethyl acetate. Concentrate organic layer in vacuo, purify (silica gel chromatography, eluting with 30:70 ethyl acetate:isohexane) and dry in a vacuum oven over night to give 4-(2-chloro-pyridin-3-yl)-piperazine-1-carboxylic acid t-butyl ester as a beige powder (3.01 g, 51%). MS (m/z): 298 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:10]([O:12]C)=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1>ClCCl.[B]>[CH3:1][C:2]1([CH3:14])[C:11]2[C:10]([OH:12])=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: COc1cccc2c1C(C)(C)CCC2
Agent: [B]
Solvent: ClCCl
Product: CC1(C)CCCc2cccc(O)c21
Temperature: 0 °C
Yield: 73.9 %

Procedure:
To a solution of 8,8-dimethyl-1-methoxy-5,6,7,8-tetrahydronaphthalene (16.4 g, 86 mmole) in dry dichloromethane (300 ml), boron tribomide (23.75 g, 91 mmole) was added at -58°. The mixture was stirred and warmed to 0° over 3 hours, poured into ice-water (1 lit) and extracted with diethylether. The ethereal extract was washed with water and aqueous saturated sodium chloride, dried and evaporated. The residue was chromatographed in silica gel using dichloromethane as eluant to give 8,8-dimethyl-5,6,7,8-tetrahydro-1-naphthol as an oil (11.2 g, 73.2%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]([CH3:15])=[CH:13][C:8]2[C:9](=[O:12])[O:10][CH2:11][C:7]=2[C:6]=1[CH3:16])=[O:4].[Cl-].[OH:18][C@H:19]([C:27]1[CH:36]=[CH:35][C:30]2[C:31](=[O:34])[O:32][CH2:33][C:29]=2[C:28]=1[CH3:37])[CH2:20][NH+:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C1COCC1>[OH:18][C@H:19]([C:27]1[CH:36]=[CH:35][C:30]2[C:31](=[O:34])[O:32][CH2:33][C:29]=2[C:28]=1[CH3:37])[CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:2][C:3]([C:5]2[C:14]([CH3:15])=[CH:13][C:8]3[C:9](=[O:12])[O:10][CH2:11][C:7]=3[C:6]=2[CH3:16])=[O:4])[CH2:23][CH2:22]1
Reactant: Cc1cc2c(c(C)c1C(=O)CBr)COC2=O
Reactant: Cc1c([C@@H](O)C[NH+]2CCNCC2)ccc2c1COC2=O
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1cc2c(c(C)c1C(=O)CN1CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)CC1)COC2=O
Temperature: 50 °C

Procedure:
To a 5 ml microwave tube were added 5-(bromoacetyl)-4,6-dimethyl-2-benzofuran-1(3H)-one (0.220 g, 0.777 mmol), 1-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-ium chloride (0.215 g, 0.777 mmol), and a stir bar; the mixture was dissolved in THF (2 mL). The tube was capped, degassed and purged with N2. The tube was then placed in an oil bath and heated at 50° C. for 12 h; LC indicated formation of the desired product. The solution was concentrated to dryness, dissolved in MeOH (3.6 mL), filtered and was then subjected to purification by mass-directed HPLC to give 5-({4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}acetyl)-4,6-dimethyl-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 479 [M+1]+.
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].[H-].[Na+].F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>CN(C=O)C>[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][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc3ccccc3c2)cc1
Reaction time: 48 h
Yield: 41 %

Procedure:
To a solution of 2-naphthol (14.4 g) in DMF (100 ml) is added sodium hydride (4.2 g of 60% dispersion). When gas evolution ceases, 4-fluorobenzaldehyde (11.5 ml) is added, and the reaction mixture is stirred at 130° for 48 hr. The mixture is cooled, poured onto crushed ice, and the product extracted with ether. Chromatography of the concentrated extract with 3:2 dichloromethane-hexane provides 4-(2-naphthyloxy)benzaldehyde as a pale yellow solid (10.25 g, 41%).
Reaction SMILES: O=[C:2]1[C:19]2[C:20]3[C:5](=[C:6]4[C:21]5[C:14]([C:15]=3[CH:16]=[CH:17][CH:18]=2)=[CH:13][CH:12]=[CH:11][C:10]=5[C:9](=O)[CH:8]=[CH:7]4)[C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][C:3]1=2>[Zn].N1C=CC=CC=1.C(O)(=O)C>[CH:11]1[C:10]2[C:21]3[C:14]([C:15]4[CH:16]=[CH:17][CH:18]=[C:19]5[C:20]=4[C:5]([C:6]=3[CH:7]=[CH:8][CH:9]=2)=[C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][C:3]2=[CH:2]5)=[CH:13][CH:12]=1
Reactant: O=c1ccc2c3c1cccc3c1cccc3c(=O)c4ccccc4c2c31
Agent: [Zn]
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: c1ccc2c(c1)cc1cccc3c4cccc5cccc(c54)c2c13

Procedure:
In accordance with a conventional manner, 7,14-dioxo-7,14-dihydrobenzo[a]perylene was treated in zinc powder contained in pyridine, and then, treated in 80% acetic acid. The resultant was refined in a conventional manner to thereby obtain a target material, benzo[a]perylene
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[OH:10])[CH:5]=[CH:6][C:7]=1[Cl:8].CC(C)=O.S(=O)(=O)(O)O>O>[CH2:11]([C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:10])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC(Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: O=C(Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a 500 ml round bottomed flask was placed 75 g of crude 3,4-dichlorophenyl benzyl carbinol and 300 ml of acetone. The reaction mixture was cooled to 0° C. and a solution of 20 g of chromic anhydride and 17.25 ml of concentrated sulfuric acid in 60 ml of water was added at a rate to keep the internal temperature below 5° C. After stirring an additional 15 minutes, the reaction was quenched with 10 ml of isopropanol and partitioned between ethyl ether and water. The organic layer was washed with brine, dried, and concentrated. The resulting crude ketone was crystallized from hexane yielding 51 g of 3,4-dichlorophenyl benzyl ketone. NMR data was consistent with the structure.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]([F:20])[C:11]=2[F:21])=[O:9])=[CH:6][N:5]=[C:4](S(C)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)(=[O:35])=[O:34]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]([F:20])[C:11]=2[F:21])=[O:9])=[CH:6][N:5]=[C:4]([NH:42][CH:39]2[CH2:40][CH2:41][N:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:37][CH2:38]2)[N:3]=1
Reactant: COc1cc(F)c(F)c(C(=O)c2cnc(S(C)=O)nc2N)c1OC
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)c(F)c(C(=O)c2cnc(NC3CCN(S(C)(=O)=O)CC3)nc2N)c1OC

Procedure:
The compound was prepared from (4-amino-2-methylsulfinyl-pyrimidin-5-yl)-(2,3-difluoro-5,6-dimethoxy-phenyl)-methanone (Example 260) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) in an analogous manner as described in Example 172. HR-MS (ES, m/z) calculated for C19H24N5O5SF [(M+H)+]472.1465, observed 472.1461.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])=[O:8])[CH2:3]1.[N+:23]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)([O-:25])=[O:24]>>[CH:20]([O:19][C:10]1[CH:11]=[CH:12][C:13]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:14][C:9]=1[C:7]([N:4]1[CH2:5][CH2:6][CH:2]([O:1][C:29]2[CH:30]=[CH:31][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=2)[CH2:3]1)=[O:8])([CH3:22])[CH3:21]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)C1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)C1
Yield: 25 %

Procedure:
Prepared in analogy to Example 4 from rac-(3-hydroxy-pyrrolidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone (Example 9(a)) and 4-nitrophenol. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 25%). MS (m/e): 449.3 (M+H+, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:13](O)[C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[Cl:19][CH:13]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH3:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[C:14]#[N:15]
Reactant: O=S(Cl)Cl
Reactant: CCOc1ccc(C(O)C#N)cc1OCC
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(C(Cl)C#N)cc1OCC

Procedure:
In 60 ml of chloroform is dissolved 4.4 g of α-(3,4-diethoxyphenyl)-α-hydroxyacetonitrile and after addition of 1.5 ml of thionyl chloride, the mixture is heated under reflux for 15 minutes. After cooling, the reaction mixture is washed with a saturated aqueous solution of sodium hydrogen carbonate and water in the order mentioned, followed by drying over MgSO4. The solvent is then distilled off to give 4.8 g of a crude oil of α-chloro-α-(3,4-diethoxyphenyl)acetonitrile (quantitative yield). [If desired, this crude oil as it is can be used in the next reaction step.] The above crude oil is then purified by column chromatography (eluent: ether-n-hexane=1:5) and the resulting crystals are recrystallized from n-hexane. Colorless needles, m.p. 61°-62° C.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[OH:28][CH2:29][C@@H:30]1[CH2:34][NH:33][CH2:32][C@H:31]1[OH:35].Cl.CCN(C(C)C)C(C)C>CC(O)C.O>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[CH:23]=[N:24][CH:25]=[N:26][CH:27]=3)[C:2]([N:33]3[CH2:34][C@@H:30]([CH2:29][OH:28])[C@H:31]([OH:35])[CH2:32]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: OC[C@@H]1CNC[C@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2cncnc2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2C[C@@H](CO)[C@H](O)C2)c(-c2cncnc2)c1

Procedure:
A suspension of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(pyrimidin-5-yl)nicotinamide (Stage 247.1, 80 mg, 0.195 mmol), trans-4-(hydroxymethyl)pyrrolidin-3-ol (+/−), hydrochloride (80 mg, 0.521 mmol) in a mixture of DIPEA (136 μL, 0.778 mmol) and iPrOH (389 μL) was subjected to MW irradiation at 140° C. for 1.5 h. The RM was treated with water (10 mL) and extracted with EtOAc. The combined extracts were washed with sat. NaHCO3 and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product that was purified by preparative SFC (Column DEAP, from 22% to 27% in 10 min) to yield the title product as a white solid. UPLC-MS (Condition 3) tR=0.86 min, m/z=492.1 [M+H]+, m/z=536.2 [M+ formic acid-H]; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.04-2.14 (m, 1H) 2.89 (dd, J=11.13, 3.91 Hz, 1H) 3.10 (dd, J=11.13, 5.26 Hz, 1H) 3.20-3.29 (m, 2H) 3.34-3.48 (m, 2H) 3.92-4.01 (m, 1H) 4.63 (t, J=5.26 Hz, 1H) 4.98 (d, J=4.40 Hz, 1H) 7.35 (d, J=9.05 Hz, 2H) 7.81-7.90 (m, 2H) 8.10 (d, J=2.45 Hz, 1H) 8.80 (d, J=2.32 Hz, 1H) 8.90 (s, 2H) 9.20 (s, 1H) 10.19 (s, 1H).
Reaction SMILES: [F:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4][CH2:3]1.[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>>[F:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]([C:18]([C:17]2[CH:21]=[C:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:23]=[CH:24][C:16]=2[O:15][CH:12]([CH3:14])[CH3:13])=[O:19])[CH2:3]1
Reactant: FC1CNCc2ccccc21
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccccc2C(F)C1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-1,2,3,4-tetrahydro-isoquinoline (CA [537033-79-7]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 392.0 (M+H+).
Reaction SMILES: [O:1]([CH:8]([CH3:11])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:10][CH2:9][CH:8]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:11])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC(CO)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(COS(C)(=O)=O)Oc1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 15.2 g of 2-phenoxy-1-propanol, 20.8 ml of triethylamine and 300 ml of dichloromethane chilled to -10° C. in an ice-salt bath, is added dropwise 7.78 ml of methanesulfonyl chloride over 10 minutes. The solution is stirred at -10° C. for 30 minutes, washed with 100 ml of ice water, 100 ml of cold 10% hydrochloric acid, 100 ml of cold saturated sodium bicarbonate solution, 100 ml of cold saturated sodium chloride solution and dried (magnesium sulfate). The solvent is removed under vacuum to give the product as an oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[CH:10][CH:9]=1)=[O:7].CN(C)[CH:19]=[O:20]>>[CH:19]([C:12]1[C:11]2[C:15](=[CH:16][C:8]([CH:6]=[O:7])=[CH:9][CH:10]=2)[NH:14][CH:13]=1)=[O:20]
Reactant: O=Cc1ccc2cc[nH]c2c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2c(C=O)c[nH]c2c1
Reaction time: 1 h
Yield: 87 %

Procedure:
Phosphorous oxychloride (48.2 ml) was added dropwise to stirred N,N-dimethylformamide (72.8 ml) at 0° (internal temperature). Stirring was continued for about 1 hour, and a solution of 6-formylindole (32.7 g) (see Example 12, part b) in N,N-dimethylformamide (444 ml) was added dropwise, while maintaining the internal temperature at 0°. The cooling bath was removed and the mixture stirred for 18 hours before water (1 liter) was added and the mixture heated under reflux for 15 min. The mixture was cooled in an ice bath; and the precipitated product isolated by filtration, washed with water and dried under vacuum to give 3,6-diformylindole (33.97 g, 87%); mp 200°-203°; NMR (250 MHz, DMSO-d6): 7.75(dd, J=8.25, 1.25 Hz, 1H, H5 -indole), 8.10(s, 1H, H2 -indole), 8.24(d, J=8.25 Hz, 1H, H4 -indole), 8.57(s, 1H, H7 -indole), 10.00(s, 1H, CHO), 10.06(s, 1H, CHO); 12.61(br s, 1H, NH).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[CH:23]1([N:29]=[C:30]=[S:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:30]([NH:29][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[S:31])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: S=C=NC1CCCCC1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=S)NC1CCCCC1
Yield: 60 %

Procedure:
Using the general method of Example 149, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.53 g, 5.11 mmol) was reacted with cyclohexyl isothiocyanate (794 mg, 5.62 mmol) to provide 1.35 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-N′-cyclohexylthiourea as a tan powder, m.p. 199-200° C. Analysis: Calculated for C23H32N6OS: % C, 62.70; % H, 7.32; % N, 19.07. Found: % C, 62.37; % H, 7.20; % N, 18.70.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO.O>[Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1ccc(Cl)cc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1ccc(Cl)cc1Br
Reaction time: 1 h
Yield: 80.4 %

Procedure:
A solution of 2-bromo-4-chlorobenzaldehyde (21.95 g; 100.0 mmol) in 200 mL methanol was stirred and cooled in an ice bath for 15 minutes, and solid sodium borohydride (1.9 g; 50.0 mmol) was added. A yellow color formed and there was copious gas evolution. Stirring was continued in the bath for 1 hour. The solution was diluted with 200 mL water, and then the methanol was evaporated on a rotary evaporator. The residual mixture was extracted with 200 mL EtOAc. The organic layer was washed with 50 mL brine, then dried over sodium sulfate and evaporated. The residual solid was washed out of the flask with hexane and collected by filtration, ground with a mortar and pestle to break up the chunks, then washed with hexane and air-dried on the filter to give 17.8 g of (2-bromo-4-chlorophenyl)methanol as a white solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[CH:15]1([C:18]#[CH:19])[CH2:17][CH2:16]1>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:15]1([C:18]#[C:19][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16]1
Reactant: C#CC1CC1
Reactant: Ic1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C(#CC1CC1)c1ccccc1
Temperature: 75 °C
Yield: 99.2 %

Procedure:
To a degassed solution of iodobenzene (0.549 mL, 4.90 mmol), dichlorobis(triphenylphosphine)-palladium(II) (0.206 g, 0.294 mmol), copper(I) iodide (0.047 g, 0.245 mmol) and diisopropylamine (3.49 mL, 24.5 mmol) in N,N-dimethylformamide (20 mL) was added cyclopropylacetylene (0.622 mL, 7.35 mmol). The reaction mixture was heated to 75° C. for 45 minutes. The reaction mixture was then diluted with ethyl acetate (150 mL), washed with a 10% aqueous solution of lithium chloride (2×100 mL), washed with a 2M aqueous solution of ammonium hydroxide (100 mL), washed with brine (100 mL), and dried over anhydrous sodium sulfate. Concentration afforded a crude product which was purified by silica gel chromatography with hexanes/dichloromethane (10/1) to give (cyclopropylethynyl)benzene (691 mg). The compound had an HPLC ret. time=3.40 min.−Column. YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][CH:11]=1.O1CCCC1CO.O.[NH2:28][NH2:29]>O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:28][NH2:29])=[O:15])=[CH:12][CH:11]=1
Reactant: NN
Reactant: COCCCCCCOc1ccc(C(=O)OC)cc1
Solvent: OCC1CCCO1
Solvent: O
Product: COCCCCCCOc1ccc(C(=O)NN)cc1
Temperature: 25 °C

Procedure:
A solution of methyl 4-(6-methoxy-n-hexyloxy)benzoate (17.05 g) in 1:1 tetrahydrofuran-methanol (300 ml) was treated with hydrazine monohydrate (66 ml) and refluxed for 15 hours then cooled to room temperature. The reaction mixture was poured into water and the resulting precipitate collected by filtration, washed thoroughly with water then dried under hi-vacuum at 50° C. to give 4-(6-methoxy-n-hexyloxy)benzohydrazide (15.63 g) as a white solid.
Reaction SMILES: [Cl-].[NH4+].C(O)C.O.[N+:7]([C:10]1[CH:31]=[CH:30][C:13]([O:14][C:15]2[C:16]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)=[CH:12][CH:11]=1)([O-])=O>[Fe].O1CCCC1>[C:24]1([C:22]2[NH:21][C:17]3[N:18]=[CH:19][N:20]=[C:15]([O:14][C:13]4[CH:30]=[CH:31][C:10]([NH2:7])=[CH:11][CH:12]=4)[C:16]=3[CH:23]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ncnc3[nH]c(-c4ccccc4)cc23)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ncnc3[nH]c(-c4ccccc4)cc23)cc1
Temperature: 82.5 °C
Reaction time: 2.5 h
Yield: 89.9 %

Procedure:
After adding 110 mg of iron powder, 220 mg of ammonium chloride, 10 ml of ethanol and 2 ml of water to 110 mg of 4-(4-nitrophenoxy)-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine, the mixture was stirred at 80-85° C. for 2.5 hours. After returning the mixture to room temperature, 20 ml of tetrahydrofuran was added, and the mixture was stirred for 5 minutes and filtered with celite, after which 100 ml of ethyl acetate and 50 ml of water were added to the filtrate for liquid separation and extraction. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered with plug cotton and concentrated to dryness to obtain 90 mg of the title compound.