Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:23])[N:14]([CH2:19][C:20]([OH:22])=O)[C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:25][N:26]1[CH:34]=[C:33]2[C:28]([CH2:29][CH2:30][CH:31]([CH2:35][NH2:36])[CH2:32]2)=[N:27]1>>[CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:23])[N:14]([CH2:19][C:20]([NH:36][CH2:35][CH:31]2[CH2:30][CH2:29][C:28]3[C:33](=[CH:34][N:26]([CH3:25])[N:27]=3)[CH2:32]2)=[O:22])[C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cc2c(n1)CCC(CN)C2
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)O
Agent: Cl
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)NCC1CCc2nn(C)cc2C1

Procedure:
The title compound was prepared from 2-[3-[(benzylsulfonyl)amino]-6 -methyl-2-oxo-1(2H)-pyridinyl]acetic acid and 2-methyl-4,5,6,7-tetrahydro-2H-indazol-5-ylmethanamine hydrochloride using the procedure of EXAMPLE 1 (STEP 6), and was obtained as a faint yellow solid compound.
Reaction SMILES: O.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]=1[C:7]#[N:8])([O-])=O.Cl[Sn]Cl>COCCOCCOC.Cl>[NH2:2][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]=1[C:7]#[N:8]
Reactant: N#Cc1c(Sc2ccccc2)cccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: COCCOCCOC
Product: N#Cc1c(N)cccc1Sc1ccccc1

Procedure:
To a water bath-cooled solution of 3.9 g (0.015 mol) of 2-nitro-6-(phenylthio)benzonitrile (Example 1) in 85 mL of diglyme was added dropwise, with stirring, 11.53 g (0.045 mol) of SnCl2.2H2 O in 35 mL of conc. HCl. The water bath was removed, and the reaction was stirred at room temperature for 0.5 h. This reaction mixture was poured into a vigorously stirring mixture of 100 mL of 50% NaOH and 300 g of crushed ice. Precipitate was collected by filtration and washed with 1N NaOH and water. Purification by flash column chromatography on silica gel with methylene chloride resulted in 2.3 g (68%) of 2-amino-6-(phenylthio)benzonitrile as a white solid: mp 73°-77° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:15][CH3:16])=[C:12]([CH:14]=2)N)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[BrH:21]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:15][CH3:16])=[C:12]([Br:21])[CH:14]=2)=[CH:4][CH:3]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1N
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1Br
Temperature: -5 °C

Procedure:
Hydrobromic acid (48% wt. in water, 85 ml) is added dropwise to a suspension of 5-(4-chlorophenyl)-2-ethylaniline (14.3 g, 0.062 mol) in water (57 ml), and the mixture stirred. The mixture is cooled to −5° C. and a solution of sodium nitrite (5.07 g, 0.072 mol) in water (25 ml) is added dropwise, maintaining the temperature at 0-5° C. The reaction mixture is stirred for 1 hour, then added to a pre-cooled solution of cuprous bromide (9 g, 0.062 mol) in hydrobromic acid (48% wt. in water, 64 ml) at 0° C. The reaction mixture is stirred and allowed to warm to room temperature overnight. The mixture is diluted with water, extracted with diethyl ether, and the organic extracts are combined, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue is further purified by column chromatography on silica gel, eluting with 2% ethyl acetate in hexane to give 5-(4-chlorophenyl)-2-ethyl-1-bromobenzene (10 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([NH:15]C(=O)C(C)(C)C)[NH:9][C:8](=[O:22])[C:7]=3[C:6]=2[CH:23]=1.[OH-].[Na+]>>[NH2:15][C:10]1[NH:9][C:8](=[O:22])[C:7]2[C:6]3[CH:23]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=3[CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CC(C)(C)C(=O)Nc1nc2ccc3ccc(N)cc3c2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc2ccc3nc(N)[nH]c(=O)c3c2c1

Procedure:
N-(9-Amino-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.065 g, 0.2 mmole) was reacted with aqueous sodium hydroxide in the same manner as in example 2. The product was precipitated from the basic reaction mixture with acetic acid, filtered and washed with water to give 3,9-diaminobenzo[f]quinazolin-1(2H)-one as a tan solid. (0.04 g, 84%) 1H NMR (DMSO-d6, 300 MHz) δ; 5.54(br s, 2H, NH2); 6.35(br s, 2H, NH2); 6.80(dd, J=8.5, 2.3 Hz, 1H, Ar); 6.87(d, J=8.6 Hz, 1H, Ar); 7.52(d, J=8.6 Hz, 1H, Ar); 7.76(d, J=8.6 Hz, 1H, Ar); 8.73(s, 1H, Ar); 10.91(br s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]([NH:8]C(=O)C(C)(C)C)=[N:6][CH:7]=1.S(=O)(=O)(O)O.[N+:21]([O-])([OH:23])=[O:22]>O>[Cl:1][C:2]1[C:3]([CH3:15])=[C:4]([N+:21]([O-:23])=[O:22])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(NC(=O)C(C)(C)C)ncc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(Cl)cnc(N)c1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
N-(5-chloro-4-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (3.0 g, 13.2 mmol) from Preparation 39 Step 2 was treated with concentrated sulfuric acid (19 ml) and allowed to stir for 30 min before cooling in an ice-water bath to between 0-10° C. and adding fuming red nitric acid (0.67 ml) over a 10 min period. The reaction mixture was heated (35° C.) overnight, then diluted with water (40 ml) and extracted with DCM (6×50 ml). The DCM was removed under vacuum and the residue was re-dissolved in conc. HCl (20 ml) and heated to 40° C. for 18 h, then 100° C. for 4 h, and finally 50° C. for 18 h. The mixture was cooled to RT, diluted with water (50 ml), and extracted with DCM (5×40 ml). The aqueous layer was treated with 30% (w/v) NaOH aq. until the pH=12, then extracted with DCM (6×60 ml). These latter extracts were combined, dried over Na2SO4, filtered, and concentrated to yield 5-chloro-4-methyl-3-nitro-pyridin-2-ylamine (1.0 g). 1H NMR (CDCl3) δ 8.15 (s, 1H), 5.93 (br s, 2H), 2.49 (s, 3H).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[C@@H:9]1([NH2:16])[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH2:15].I[C:18]1[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH3:24])[CH:23]=1>[Cu]I.COCCOCCOC>[CH3:24][C:22]1[CH:23]=[C:18]([N:15]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=2)[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]2[NH2:16])[CH:19]=[C:20]([CH3:25])[CH:21]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Product: Cc1cc(C)cc(N(c2cc(C)cc(C)c2)[C@@H]2CCCC[C@H]2N)c1
Temperature: 140 °C
Reaction time: 24 h
Yield: 72.1 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (40 mg, 0.210 mmol), K3PO4 (1.30 g, 6.12 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (240 μL, 2.00 mmol), 5-iodo-m-xylene (900 μL, 6.24 mmol) and 2-methoxyethyl ether (1.0 mL) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 140° C. for 24 h. The resulting dark brown suspension was cooled to room temperature and filtered through a 2×1 cm pad of Celite eluting with 50 mL of dichloromethane. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×20 cm; chloroform—chloroform saturated with aq NH3-methanol 40:40:1; 15 mL fractions). Fractions 7-14 provided 465 mg (72% yield) of the product as a tan solid. 1H NMR (400 MHz, CDCl3): δ 6.67 (s, 1H), 6.57 (s, 2H), 3.65-3.55 (m, 1H), 2.68-2.58 (m, 1H), 2.28 (s, 12H), 2.08-1.92 (m, 2H), 1.83-1.64 (m, 2H), 1.58-1.10 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)=O)[CH:5]=[CH:6][CH:7]=1.O.[NH2:21][NH2:22].CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:22][N:21]=[C:8]2[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=1
Reactant: COc1ccc(C(=O)c2cccc(Cl)c2F)cc1Cl
Reactant: NN
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1Cl

Procedure:
Prepared according to Method D, Step A from (3-chloro-2-fluorophenyl)(3-chloro-4-methoxyphenyl)methanone (2.04 g, 6.82 mmol), hydrazine hydrate (2.5 mL), dimethylaminopyridine (0.97 g) and pyridine (12.5 mL). The title compound was obtained as a white solid and recrystallized from ethyl acetate/hexane (1.74 g, 5.94 mmol, 87%).
Reaction SMILES: [NH2:1][C:2]1[C:12]([CH3:13])=[CH:11][C:10](Br)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cu](C#N)[C:16]#[N:17]>CN(C)C(=O)C>[NH2:1][C:2]1[C:12]([CH3:13])=[CH:11][C:10]([C:16]#[N:17])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(Br)cc(C)c1N
Reactant: N#C[Cu]C#N
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(C#N)cc(C)c1N
Yield: 83.2 %

Procedure:
The above-described method (Example 2) was repeated to react ethyl 2-amino-5-bromo-3-methylbenzoate (2.00 g, 7.65 mmol) with copper cyanide (0.70 g, 7.80 mmol) in N,N-dimethylacetamide at 160° C. for 8 hours. Following working up similar to Example 2, ethyl 2-amino-5-cyano-3-methylbenzoate (1.30 g, 80.2% of theory, 96.3 area % LC) was obtained as a brown solid.
Reaction SMILES: [CH3:1][C:2](=[C:4]([CH3:6])[CH3:5])[CH3:3].[N+](=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N-]>>[CH3:1][C:2]1([CH3:3])[C:4]([CH3:6])([CH3:5])[CH:9]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CC(C)=C(C)C
Reactant: CCOC(=O)C=[N+]=[N-]
Product: CCOC(=O)C1C(C)(C)C1(C)C

Procedure:
The method of Mesheheryakov, Chem. Abstr., 54, 24436d (1960) was employed. To a mixture of 19 g. (0.226 mole) of 2,3-dimethyl-2-butene and 2 g. of cupric sulfate is added at reflux a mixture of 51 g. (0.447 mole) ethyl diazoacetate and 19 g. of 2,3-dimethyl-2-butene. The resulting mixture is heated at reflux for 3 hours, cooled, filtered and distilled to afford 19.8 g. (26%) of the desired cyclic ester, B.P. 76°-77° (15 mm.)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24](O)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:24]([C:23]2[CH:22]=[N:21][N:18]3[CH:19]=[CH:20][C:15]([N:11]4[CH2:12][CH2:13][CH2:14][C@@H:10]4[C:4]4[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:16][C:17]=23)=[O:25])[CH2:29][CH2:28]1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: NC1CC1
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NC3CC3)c2n1
Yield: 57 %

Procedure:
Prepared by the method described in Example 1 using (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation K) and cyclopropanamine. The combined organic extracts were concentrated and the residue was purified by reverse phase HPLC (0-70% acetonitrile/water) to provide the title compound (19 mg, 57% yield). MS (apci) m/z=397.0 (M+H).
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[NH2:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8](Cl)[N:7]=1>O1CCOCC1.C(OCC)(=O)C>[NH2:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([O:2][CH3:1])[N:7]=1
Reactant: Nc1cncc(Cl)n1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cncc(N)n1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
To a stirred solution of methanol (89 μL; 2.2 mmol) in dioxane (1 mL) was added sodium hydride (53 mg; 2.2 mmol). After stirring for 30 minutes, 2-amino-6-chloropyrazine (258 mg; 2.0 mmol) was added and the reaction was heated to 90° C. After stirring for 12 hours, the reaction was cooled to room temperature, diluted with 30 mL of ethyl acetate and washed with aqueous 10% sodium carbonate (1×30 mL), and brine (30 mL), then dried (MgSO4), and filtered. The crude product was purified using the Biotage 12i cartridge eluting with hexane and ethyl acetate (3:1) to yield a white solid (11% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[C:29]#[CH:30]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:30][C:29]#[CH:28])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1ccc(OCC2CCCN2C(=O)OC(C)(C)C)cc1
Reaction time: 0.25 h
Yield: 88.5 %

Procedure:
To a solution of the product from step 2 (2.0 g, 6.82 mmol) in anhydrous DMF (50 mL) was added dry K2CO3 (4.6 g, 33 mmol) and allowed to stir for 15 min. Propargyl bromide (1.214 g, 10.20 mmol) in anhydrous DMF (10 mL) was added and the reaction mixture stirred at 50° C. for 6 h, then at rt for 48 h. The reaction mixture was concentrated, taken up in EtOAc, washed with water, dried over anhydrous MgSO4 and the solvent removed in vacuo. The product was purified by silica gel flash chromatography using EtOAc/hexane to obtain the title compound (2.0 g, 88%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:9])([F:8])[C:5]([OH:7])=[O:6].[CH3:10][N:11]1[CH2:25][C:16]2=[C:17]3[C:21](=[C:22]([CH3:24])[CH:23]=[C:15]2[O:14][CH2:13][CH2:12]1)[NH:20][CH:19]=[CH:18]3.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[F:3][C:4]([F:9])([F:8])[C:5]([OH:7])=[O:6].[CH3:10][N:11]1[CH2:25][C:16]2=[C:17]3[C:21](=[C:22]([CH3:24])[CH:23]=[C:15]2[O:14][CH2:13][CH2:12]1)[N:20]([S:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:34])=[O:33])[CH:19]=[CH:18]3
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc2c(c3cc[nH]c13)CN(C)CCO2
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccn(S(=O)(=O)c4ccccc4)c13)CN(C)CCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.5 %

Procedure:
Sodium hydride (60% in mineral oil, 14 mg, 0.54 mmol, 95%) was added to a solution of 2,7-dimethyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole trifluoroacetate (Intermediate 13, 0.060 g, 0.18 mmol) in DMF (2 mL) and stirred at room temperature for 5 minutes before benzenesulfonyl chloride (0.035 mL, 0.27 mmol) was added. The mixture was stirred at room temperature for 10 minutes and quenched with ice/water and extracted with DCM. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound as a brown oil (14 mg) in the form of the trifluoroacetate salt. MS m/z 357 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:12][C:13]1[C:18]([CH3:19])=[C:17]([CH3:20])[N:16]=[C:15]([Cl:21])[C:14]=1[NH2:22])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:30][CH2:31][C:32](Cl)=O>ClCCCl>[Si:1]([O:8][CH2:9][C@@H:10]([N:12]1[C:13]2[C:18]([CH3:19])=[C:17]([CH3:20])[N:16]=[C:15]([Cl:21])[C:14]=2[N:22]=[C:32]1[CH2:31][Cl:30])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1nc(Cl)c(N)c(N[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1C
Reactant: O=C(Cl)CCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c2nc(CCl)n([C@@H](C)CO[Si](C)(C)C(C)(C)C)c2c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13.2 %

Procedure:
N4-((1S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methylethyl)-2-chloro-5,6-dimethylpyridine-3,4-diamine (2.85 g, 8.29 mmol) was dissolved in 100 mL of dry 1,2-dichloroethane and the solution was cooled to 0° C. as it stirred under an atmosphere of N2. Triethylamine (2.3 mL, 16.58 mmol) and chloroacetyl chloride (0.92 mL, 11.60 mmol) were added sequentially. After 30 minutes, the reaction mixture was allowed to warm to ambient temperature and stirred for 3 days followed by heating to 70° C. for 2 days. The reaction mixture was allowed to cool to ambient temperature and was washed with saturated NaHCO3 solution (2×100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product as a brown solid. Chromatography (SiO2, 20-50% ethyl acetate/hexanes) gave 1-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-4-chloro-2-(chloromethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridine (0.44 g) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=[O:19])[CH2:11][CH2:12][CH:13]1[S:18][CH2:17][CH2:16][CH2:15][S:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20](O)[CH2:21][OH:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([O:8][CH2:9][C:10]1([O:22][CH2:21][CH2:20][O:19]1)[CH2:11][CH2:12][CH:13]1[S:18][CH2:17][CH2:16][CH2:15][S:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCC1SCCCS1)COCc1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: c1ccc(COCC2(CCC3SCCCS3)OCCO2)cc1
Reaction time: 1 h

Procedure:
Treatment of 1-benzyloxy-4-(1,3-dithian-2-yl)-butan-2-one (89.8 g) in benzene (3.5 l) with distilled ethylene glycol (220 ml) and p-toluenesulfonic acid (11.7 g) at reflux temperature in a Dean-Stark apparatus for 18 hours gives a mixture which is concentrated to 500 ml in vacuo and allowed to stir for one hour. After the addition of sodium carbonate (10 g), the mixture is then partitioned between ether (300 ml) and brine (300 ml). The aqueous phase is extracted with ether (600 ml) and the combined extracts are washed with 0.05% sodium carbonate (1.2 l), filtered through phase-separating paper and dried (sodium sulfate). The solvent is removed in vacuo to give a residue (102.15 g; 99%). A 200 mg portion of the residue is purified on Quantagram PQ1F plates (chloroform) to give 1-benzyloxy-2,2-ethylenedioxy-4-(1,3-dithian-2-yl)-butane (180 mg);
Reaction SMILES: [CH:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](Cl)=[O:19])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:29][NH:30][O:31][CH3:32]>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:19])[N:30]([O:31][CH3:32])[CH3:29])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(CCOc2ccc(NC(=O)Cl)cc2)cc1
Reactant: CNOC
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CON(C)C(=O)Nc1ccc(OCCc2ccc(C(C)C)cc2)cc1
Temperature: 0 °C
Yield: 42 %

Procedure:
Into a solution of 10.6 g of 4-(4-isopropylphenethyloxy)phenylcarbamyl chloride in 200 ml of toluene are added 4 ml of pyridine and a solution of 2.5 g of N,O-dimethylhydroxylamine in 50 ml of toluene at a temperature below 20° C. The mixture is heated under reflux for 4 hours. The reaction mixture is then poured into ice water, and the separated organic layer is washed with dilute hydrochloric acid, thoroughly washed with water and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure, and the crude crystals are recrystallized from ethanol to obtain 4.8 g of N'-[4-(4-isopropylphenethyloxy)phenyl]-N-methoxy-N-methylurea as white needles, M.P. 81°-82° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[I:12]N1C(=O)CCC1=O>CC(C)=O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br:1][C:2]1[C:3]([Cl:11])=[C:4]2[C:10]([I:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1c(Br)cnc2[nH]ccc12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Clc1c(Br)cnc2[nH]cc(I)c12
Temperature: 23 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
5-Bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (5.19 g, 22.4 mmol) and N-iodosuccinimide (5.55 g, 24.6 mmol) were suspended in 100 mL acetone. The mixture was stirred at 23° C. for 2 h and diluted with 150 mL water and 20 mL of saturated sodium thiosulfate solution. The precipitate was filtered and residual water was removed by dissolving the solids in dry benzene and followed by evaporation (2×100 mL) to yield 5-Bromo-4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (7.68 g, 21.5 mmol, 96%). 1H NMR (500 MHz, DMSO-d6) δ 12.65 (bs, 1H), 8.45 (s, 1H), 7.87 (d, J=3 Hz, 1H). MS: m/z 356.8/358.8 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.[CH3:25][C:26]([CH3:28])=O.[BH3-]C#N.[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][N:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH:26]([CH3:28])[CH3:25]
Reactant: CC(C)=O
Reactant: Fc1cccc(CNCc2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)N(Cc1cccc(F)c1)Cc1nccn1Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 26 %

Procedure:
A mixture of [1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylmethyl]-(3-fluoro-benzyl)-amine, (200 mg, 0.55 mmol), acetone (81 uL, 1.10 mmol) and 3A molecular sieves (300 mg) in MeOH (3 mL) was stirred at ambient temperature under N2. After 5 h, NaBH3CN was added and the mixture stirred for an additional 2 h. Water (2 mL) was added and the reaction mixture concentrated in vacuo. The residue was taken up in 1N NaOH (20 mL) and extracted with CH2Cl2 (3×30 mL). The combined extracts were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by chromatography (silica gel, 100% EtOAc) and the isolated product converted to the di-hydrochloride salt by treatment with excess anhydrous HCl in methanol solution. The volatiles were removed in vacuo to afford the desired product 6a (58 mg, 26%) as an off-white solid: ESI MS m/z 406 [C21H22Cl2FN3+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CC(C)([O-])C.[K+]>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([O:23][C:2]2[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1c(Cl)ncnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4,6-dichloro-5-methyl-pyrimidine (8.15 g, 50 mmol) in 200 mL of THF, was added 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (10 g, 1 eq) and potassium tert-butoxide (6.1 g, 1.2 eq) at 0° C. The resulting mixture was stirred at room temperature for 16 h then quenched with a saturated solution of NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate and concentrated to give crude 9a.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:17])[C:14]([OH:16])=O)=[C:9]([OH:18])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]3[CH:13]([CH3:17])[C:14](=[O:16])[O:18][C:9]=3[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C(=O)O)c1ccc(C2CCCCC2)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1C(=O)Oc2cc(C3CCCCC3)ccc21

Procedure:
5g of 2-(4-cyclohexyl-2-hydroxyphenyl)- propionic acid are heated at reflux in a water separator for 2 hours in the presence of 50 mg of p-toluenesulphonic acid in 200 cc of toluene. The solution is concentrated by evaporation and the residue is chromatographed on 500 g of silica gel. Elution with methylene chloride yields pure 6-cyclohexyl-2,3-dihydro-3-methylbenzofuran-2-one having an M.P. of 87-89° after crystallization from petroleum ether.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([NH:11]N)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[C:13]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)(=O)C>[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[C:13]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]=1[NH:11]2)([O-:4])=[O:3]
Reactant: O=C1CCCCCCC1
Reactant: NNc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc2[nH]c3c(c12)CCCCCC3
Yield: 32.7 %

Procedure:
3-Nitrophenylhydrazine hydrochloride (50 g, 0.26 mol) and cyclooctanone (32.2 g, 0.25 mol) were refluxed in 400 mL of glacial acetic acid for 6 hours. The solution was allowed to cool and the separated solid was filtered, washed with water and recrystallized from absolute ethanol to afford 20 g (31% yield) of 6,7,8,9,10,11-hexahydro-1-nitro-5H-cyclooct[b]indole; m.p. 189°-191° C.