Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][N:4]=1.[CH2:9]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(O)C>[CH2:9]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:3]3[CH:8]=[CH:7][N:6]=[CH:5][N:4]=3)[CH2:26][CH2:25]2)=[O:23])[CH2:18][CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(C1CCNCC1)N1CCN(Cc2ccccc2)CC1
Reactant: Clc1ccncn1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(C1CCN(c2ccncn2)CC1)N1CCN(Cc2ccccc2)CC1
Yield: 45.3 %

Procedure:
4-Chloropyrimidine hydrochloride (3.5 g) was added to a stirred suspension of 1-benzyl-4-[4-piperidylcarbonyl]piperazine (6.6 g), triethylamine (12.8 ml) and ethanol (120 ml). The mixture was heated under reflux for four hours and evaporated in vacuo to yield a treacle like substance. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (Na2SO4) and evaporated. The residue was absorbed onto alumina and purified using dry flash chromatography eluting with increasingly polar mixtures of dichloromethane and methanol (1:0 to 98:2). The material obtained was triturated with diethylether to give 1-(benzyl)-4-[1 -(4-pyrimidinyl)-4-piperidylcarbonyl]piperazine (3.8 g, 45% yield), mp 107-108.5° C.;
Reaction SMILES: [N+:1]1([O-])[C:2]([CH3:8])=[CH:3][CH:4]=[CH:5][C:6]=1[CH3:7].S(OC)(OC)(=O)=O.COS([O-])(=O)=O.CO[N+:25]1C(C)=CC=C[C:26]=1C.[C-]#N.[K+]>O>[CH3:7][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([CH3:8])[N:1]=1)[C:26]#[N:25]
Reactant: CO[n+]1c(C)cccc1C
Reactant: Cc1cccc(C)[n+]1[O-]
Agent: COS(=O)(=O)[O-]
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: Cc1cc(C#N)cc(C)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
To a stirred quantity of 2,6-lutidine-1-oxide (12.3 g, 100 mmol) was slowly added dimethyl sulphate (12.6 g, 100 mmol) at such a rate that the temperature of the reaction mixture was maintained at 80° C. throughout the addition. When the addition was complete (about one hour) the solution was stirred at that temperature for an additional 2 h. The salt crystallised upon cooling and was recrystallised from anhydrous acetone giving white prisms; m.p 96-97° C. Yield 18 g (73%). To a solution of this 1-methoxy-2,6-dimethylpyridinium methyl sulphate (11.65 g, 50 mmol) dissolved in water (50 ml), under nitrogen, was added a solution of potassium cyanide (10 g, 150 mmol) dissolved in 50 ml of water. The solution was allowed to stand at room temperature for 2 days at which time the nitrile, which had separated from the solution as long white needles, was removed by filtration, yielding 2.8 g of pure product (42%) δH (CDCl3, 500 MHz) 2.44 (6 H, s, 2×CH3), 4.2 (2 H, d, J 5, NHCH2), 6.78 (2 H, s, ArH); δC (CDCl3, 500 MHz) 157.83 (2×C), 122.71 (C), 118.2 (2×CH), 24.28 (2×CH3)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[CH:3]=1.[Li]CCCC.[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]#N)=[N:23][CH:24]=1.CC[O:29]CC>>[F:12][C:4]1[CH:3]=[C:2]([C:25]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][N:23]=2)=[O:29])[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1
Reactant: CCOCC
Reactant: N#Cc1ccc(F)cn1
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Agent: [Li]CCCC
Product: O=C(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
An ether solution (2 mL) of 1-bromo-3-fluoro-5-(trifluoromethyl)benzene (0.200 g, 0.826 mmol) was stirred in an oven-dried round bottom flask at −78° C. under Ar. To this solution, n-BuLi (2.0 M in cyclohexane, 0.41 mL, 0.82 mmol, 1.0 eq) was added dropwise. The resulting solution was stirred at −78° C. for 30 min. 5-Fluoropicolinonitrile (0.101 g, 0.828 mmol, 1.0 eq), prepared as described in Procedure 1, was added as a solid via addition funnel The resulting red solution was stirred at −78° C. for 1 h. The reaction mixture was quenched with HCl (10 mL, 1.0 M) and extracted with EtOAc (3×10 mL). The combined organic portions were dried over Na2SO4, decanted and the volume was reduced to 5 mL under reduced pressure. The resulting oil was loaded directly onto a silica gel ISCO cartridge (40 g). Gradient elution from 0-70% EtOAc in hexane over 20 min yielded (3-fluoro-5-(trifluoromethyl)phenyl)(5-fluoropyridin-2-yl)methanone as a pale brown oil at a retention time of 7 min (0.117 g, 49% yield). LCMS: RT=1.91 min [M+H] 288.2 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.69 min (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm, purity 97%); NMR: 400 MHz 1H(CDCl3) ppm 8.50 (d, J=2.4 Hz, 1 H), 8.19 (dd, J=4.0 and J=8.0 Hz, 1 H), 8.15 (s, 1 H), 8.00 (d, J=8.0 Hz, 1 H), 7.57 (ddd, J=3.08, J=2.4 and J=8.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:11][C@H]2C#N)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:14]([OH:16])[CH3:15].[OH2:17].Cl>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:11][C@H:15]2[C:14]([OH:17])=[O:16])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#C[C@@H]1C[C@H]1c1ccc(F)c(F)c1
Reactant: O
Reactant: CCO
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(F)c(F)c1
Temperature: 82.5 °C
Yield: 94.3 %

Procedure:
(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarbonitrile (5 g), ethanol (25 mL) were charged to a round bottom flask followed by addition of caustic lye (10 mL). The reaction mixture was heated to 80-85° C. and maintained at the same temperature for 2-3 hours till the completion of reaction as monitored by TLC. The reaction mixture was cooled to 25-30° C. and then water (15 mL) was added to the mixture. The pH of the mixture was adjusted to 1-2 with conc. hydrochloric acid (15 mL) followed by addition of ethyl acetate (25 mL). The layers were separated and aqueous layer was extracted with ethyl acetate (25 mL). The organic layers were combined and charged with water (15 mL) and caustic lye (10 mL). After stirring, the organic layer was separated and pH of the aqueous layer was adjusted to 1-2 with conc. hydrochloric acid (10 mL). To this ethyl acetate (25 mL) and water (15 mL) were added and stirred for 10-15 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate (25 mL). The organic layers were combined and washed with water (2×15 mL) followed by complete distillation of solvent from organic layer under vacuum at 50-55° C. to afford the title compound in about 94.3% yield having HPLC purity of about 99%.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1C(OC(C)(C)C)=O)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:21])[F:22])(=[O:11])=[O:12])[CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1

Procedure:
In analogy to the procedure described in example 253a, (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester was treated with trifluoroacetic acid in dichloromethane to give the title compound as yellow oil. MS (ESI): m/z=356.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[C:17]#[N:18])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[C:4]([OH:28])[CH:3]=1.Br[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[C:17]#[N:18])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[C:4]([O:28][CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:3]=1
Reactant: BrCC1CCCC1
Reactant: N#Cc1cccc(Cn2c(-c3ccc(Cl)cc3O)nc3cc(F)c(F)cc32)c1
Product: N#Cc1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1

Procedure:
The title compound was prepared in analogy to Example 19, from 3-[2-(4-chloro-2-hydroxy-phenyl)-5,6-difluoro-benzoimidazol-1-ylmethyl]-benzonitrile and bromomethyl-cyclopentane (CAS Reg. No. 3814-30-0). Brown solid (33%). MS (Turbo Spray): m/z=378.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.O.O.O.[F:23][C:24]([F:32])([F:31])[C:25]([C:27]([F:30])([F:29])[F:28])=[O:26]>C1(C)C=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[CH:11]=[C:10]([C:25]([C:27]([F:30])([F:29])[F:28])([C:24]([F:32])([F:31])[F:23])[OH:26])[NH:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: Clc1ccc(-c2cc[nH]c2-c2ccc(Cl)cc2)cc1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Product: OC(c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)[nH]1)(C(F)(F)F)C(F)(F)F
Yield: 83.7 %

Procedure:
A mixture of 2.9 g (0.01 mole) of 2,3-bis(4-chlorophenyl)-1H-pyrrole and 2.5 g (0.011 mole) of hexafluoroacetone trihydrate in 50 ml toluene was heated at reflux overnight. The mixture was concentrated on a rotary evaporation and the solid residue was chromatographed on 200 g silica gel (eluting with toluene), then recrystallized from hexane to give 3.8 g of product, m.p. 144°-145° C.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][N:5]=[C:4]([CH2:12][OH:13])[CH:3]=1.C(N(CC)CC)C.O>CS(C)=O>[F:1][C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][N:5]=[C:4]([CH:12]=[O:13])[CH:3]=1
Reactant: COCOc1cnc(CO)cc1F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COCOc1cnc(C=O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a solution of (4-fluoro-5-(methoxymethoxy)pyridin-2-yl)methanol (3.59 g) and triethylamine (8.02 mL) in DMSO (30 mL) was added sulfur trioxide pyridine complex (9.16 g), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (2.43 g).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10](=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([C:23]#[N:24])(C)C.C(OCC)C.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CO.[I-].[Zn+2].[I-]>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)([C:23]#[N:24])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1COCCN1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: CO
Solvent: CCOCC
Product: N#CC1(N2CCOCC2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a flask in an ice-bath was added 1-(diphenylmethyl)azetidin-3-one (3.0 g, 12.6 mmol), trimethylsilylcyanide (1.69 ml, 12.6 mmol) and diethyl ether (1 ml) followed by addition of zinc iodide (0.003 g). This gave a yellow suspension which turned to an orange solution after 20 mins stirring at room temperature. To the solution was added a solution of morpholine (1.1 g, 12.6 mmol) in methanol (6 ml). The solution was then refluxed overnight and no starting material remained by tlc. The reaction mixture was evaporated to dryness and the product crystallised from ethyl acetate/iso-hexane to give 1-(diphenylmethyl)-3-morpholin-4-ylazetidine-3-carbonitrile as a pale yellow crystalline solid. Analytical LCMS: single peak (214 nm), 5.74 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14](O)=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=1[F:38]>CCCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:14]([NH:29][C:30]3[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=3[F:38])=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(N)c(F)c1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: N#Cc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
The title compound was prepared in analogy to example 22, int. d) from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid and 4-amino-3-fluorobenzonitrile and using a gradient of heptane:ethyl acetate (1:1 to 4:1) as eluant. The title product was crystallized from tert-butyl methyl ether to give 0.79 g (61%) of a white solid (29%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][C:14]=1[CH3:24])[CH:6]=[O:7].C(O)C.[BH4-].[Na+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[S:17][C:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:15][C:14]=1[CH3:24]
Reactant: COc1cc(C=O)ccc1OCc1sc(-c2ccccc2)nc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1OCc1sc(-c2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of 3-methoxy-4-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)methoxy]benzaldehyde (2.80 g) in tetrahydrofuran (50 mL)-ethanol (10 mL) was gradually added sodium borohydride (0.31 g) at room temperature. After stirring the reaction mixture at room temperature for 2 hrs, water was added, and the precipitated crystals were collected by filtration to give {3-methoxy-4-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)methoxy]phenyl}methanol as colorless crystals (2.57 g, yield 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 152-153° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CS(O[CH2:24][C@H:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH3:26])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:31]([O:30][C:28]([NH:27][C@H:25]([CH3:26])[CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: C[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc(OC[C@@H](C)NC(=O)OC(C)(C)C)cc2)cc1
Temperature: 50 °C
Reaction time: 21 h
Yield: 109 %

Procedure:
A suspension of ethyl 4′-hydroxybiphenyl-4-carboxylate (1.63 g), (R)-(+)-2-(tert-butoxycarbonylamino)propyl methanesulfonate (1.93 g), and cesium carbonate (2.70 g) in N,N-dimethylformamide (18 mL) was stirred at 50° C. for 21 hrs. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by aminopropyl silica gel flash column chromatography (eluent: n-hexane/ethyl acetate=1/1) to afford ethyl 4′-[(R)-2-(tert-butoxycarbonylamino)propyloxy]biphenyl-4-carboxylate (2.93 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:7][CH:6]([N:8]([CH:28]=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[CH:16]=[O:17])[CH2:5][C:4]([CH3:31])([CH3:30])[NH:3]1.[O-:33]S([O-])(=O)=O.[Mg+2].OO.[OH-:41].[K+]>CO>[OH:41][N:21]1[C:22]([CH3:24])([CH3:25])[CH2:23][CH:18]([N:15]([CH:16]=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH:6]2[CH2:5][C:4]([CH3:31])([CH3:30])[N:3]([OH:33])[C:2]([CH3:32])([CH3:1])[CH2:7]2)[CH:28]=[O:29])[CH2:19][C:20]1([CH3:27])[CH3:26]
Reactant: [OH-]
Reactant: O=S(=O)([O-])[O-]
Reactant: CC1(C)CC(N(C=O)CCCCCCN(C=O)C2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Agent: OO
Agent: [K+]
Agent: [Mg+2]
Solvent: CO
Product: CC1(C)CC(N(C=O)CCCCCCN(C=O)C2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Temperature: 81 °C
Reaction time: 6 h

Procedure:
A solution of 337.5 g (0.75 mol) of N,N′-bis-[2,2,6,6-tetra-methylpiperidin-4-yl]-N,N′-bisformyl-1,6-diaminohexane in 600 ml of methanol was treated with 0.15 g of MgSO4. 600 ml of a 30% strength H2O2 solution (5.87 mol) were added dropwise at 67° C. in the course of 6 h. The temperature was then increased to 81° C. and the mixture was kept at this temperature for a further 6 h, the pH of 7.8 being kept constant by metered addition of a 50% strength KOH solution. The pH was then adjusted to 9.0 by addition of KOH solution. After the mixture had been left at this pH for a further 2 h, the methanol was distilled off, the product being precipitated. It was washed with water and dried.
Reaction SMILES: [ClH:1].C1C2=C3C(C4C2=CC=CC=4)=CC=CC3=C(CNC(C)(CO)CO)C=1.[CH:26]1[C:40]2=[C:41]3[C:33]([C:34]4[C:35]([CH:42]=O)=[CH:36][CH:37]=[CH:38][C:39]=42)=[CH:32][CH:31]=[CH:30][C:29]3=[CH:28][CH:27]=1.[NH2:44][C:45]([CH3:50])([CH2:48][OH:49])[CH2:46][OH:47]>>[ClH:1].[CH:26]1[C:40]2=[C:41]3[C:33]([C:34]4[C:39]2=[CH:38][CH:37]=[CH:36][C:35]=4[CH2:42][NH:44][C:45]([CH3:50])([CH2:48][OH:49])[CH2:46][OH:47])=[CH:32][CH:31]=[CH:30][C:29]3=[CH:28][CH:27]=1
Reactant: O=Cc1cccc2c1-c1cccc3cccc-2c13
Reactant: CC(N)(CO)CO
Agent: CC(CO)(CO)NCc1ccc2c3c(cccc13)-c1ccccc1-2
Agent: Cl
Product: CC(CO)(CO)NCc1cccc2c1-c1cccc3cccc-2c13

Procedure:
Using the reductive amination procedure outlined in 1D, 7-fluoranthenecarbaldehyde (1B) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 2-((7-fluoranthenylmethyl)amino)-2-methyl-1,3-propanediol hydrochloride mp 204°-206° (dec), (CH3OH/Et2O), (C, H, Cl, N).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C@H:16]3[CH2:21][CH2:20][C@H:19]([CH2:22][C:23](O)=[O:24])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[C:7]([CH3:26])=[N:6][C:5]=1[CH3:27])(=[O:3])[NH2:2].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[OH:24][CH2:23][CH2:22][C@H:19]1[CH2:18][CH2:17][C@H:16]([C:13]2[CH:14]=[CH:15][C:10]([C:8]3[N:9]=[C:4]([C:1]([NH2:2])=[O:3])[C:5]([CH3:27])=[N:6][C:7]=3[CH3:26])=[CH:11][CH:12]=2)[CH2:21][CH2:20]1
Reactant: Cc1nc(C)c(-c2ccc([C@H]3CC[C@H](CC(=O)O)CC3)cc2)nc1C(N)=O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(C)c(-c2ccc([C@H]3CC[C@H](CCO)CC3)cc2)nc1C(N)=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of Example 1 (50 mg, 0.14 mmol) and NMM (71 μL, 0.64 mmol) in THF (1 mL) at 0° C. was added a solution of ethyl chloroformate (61 μL, 0.64 mmol) in THF (0.5 mL). The reaction was stirred at 0° C. for ˜3 h, but additional equivalents of NMM and ethyl chloroformate were needed during this time to drive the reaction. The reaction mixture was added dropwise to a solution of NaBH4 in water at 0-5° C. and the combined mixture was stirred for 30 min. The mixture was partitioned between EtOAc and 1M HCl and the organic layer was washed with water, dried through a phase separator and concentrated. The crude was dissolved in DMSO and purified by HPLC (neutral). Freeze-drying of pure fractions gave the title compound (8 mg, 17%) as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([Cl:15])=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]=[C:6]2[CH3:14].[N+:16]([O-])([OH:18])=[O:17].O>S(=O)(=O)(O)O>[N+:16]([C:11]1[CH:12]=[C:3]([O:2][CH3:1])[C:4]([Cl:15])=[C:5]2[C:10]=1[NH:9][C:8](=[O:13])[CH:7]=[C:6]2[CH3:14])([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2[nH]c(=O)cc(C)c2c1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc([N+](=O)[O-])c2[nH]c(=O)cc(C)c2c1Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a 200 ml, three-necked round bottom flask equipped with a mechanical stirrer, thermowatch, and addition funnel was placed 96% sulfuric acid (50 ml) and 6-methoxy-5-chloro-4-methyl-2-quinolone (10) (12.0 g, 53.66 mmoles). This was cooled to 0° C., then a solution of 70% nitric acid(6.04 g, 67.1 mmoles) in 96% sulfuric acid (10 ml) was added dropwise over 35 minutes. The mixture was stirred for 90 minutes at 0° C., then poured into 350 ml of water. The crude orange-brown solid was collected by suction filtration, washed with water (three×20 ml) and air dried. Crude yield is 10.82 g.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1>C1COCC1>[C:17]1([CH:14]2[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH2:8][NH:7][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])[CH2:16][CH2:15]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCCCN1CCC(c2ccccc2)CC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCCCN1CCC(c2ccccc2)CC1
Reaction time: 1 h
Yield: 104.8 %

Procedure:
Diketene (1.64 mL, 21.3 mmol, 1.50 equiv) was added at 0° C. to a stirred solution of 1-(3-aminopropyl)-4-phenylpiperidine (3.10 g, 14.2 mmol, 1.00 equiv) in anhydrous THF (30 mL) under argon, and stirring was continued at room temperature for 1 hour. The mixture was concentrated to give 4.50 g (100%) of viscous orange oil, which was characterized spectroscopically and used for the next reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Br:20])[CH:15]=O>>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)[CH:17]=[CH:18][C:19]=1[Br:20]
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: O=Cc1ccc(Br)c(Br)c1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc(Br)c(Br)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3,4-dibromobenzaldehyde in an analogous manner to that described in Example 1 gave 9-(3,4-dibromophenyl)-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from absolute ethanol gave a pale yellow crystalline solid of melting point >290° C. (decomposition).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[F:34][C:35]([F:46])([F:45])[O:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH:40]=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([CH2:40][C:39]5[CH:42]=[CH:43][CH:44]=[C:37]([O:36][C:35]([F:34])([F:45])[F:46])[CH:38]=5)[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(Cc3cccc(OC(F)(F)F)c3)CC2)cc1

Procedure:
4-(4-Methanesulfonyl-phenoxy)-1-[1-(3-trifluoromethoxy-benzyl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine was prepared according to General Procedure H by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with 3-(trifluoromethoxy)benzaldehyde (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.95-1.99 (m, 2H), 2.21-2.28 (m, 4H), 2.92-2.98 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.62 (s, 2H), 4.77-4.83 (m, 1H), 7.25-7.51 (m, 4H), 7.62-7.64 (m, 2H), 8.04-8.07 (m, 2H), 8.38 (s, 1H), 8.56 (s, 1H). Mass spectrum MH+=548.