Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12][NH:11]1)([O-])=O.[C:23](N1C=CN=C1)(N1C=CN=C1)=[S:24]>COCCOC.C(Cl)(Cl)Cl>[C:17]1([N:14]2[CH2:15][CH2:16][N:10]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[NH:1][C:23](=[S:24])[N:11]3[CH2:12][CH2:13]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: O=[N+]([O-])c1ccccc1N1CCN(c2ccccc2)CCN1
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: S=C1Nc2ccccc2N2CCN(c3ccccc3)CCN12

Procedure:
Hexahydro-1-(2-nitrophenyl)-5-phenyl-1H-1,2,5-triazepine (22.4 g) was hydrogenated in 1,2-dimethoxyethane (800 ml) as in Example 11 and the volume reduced to 250 ml. 1,1'-Thiocarbonyldiimidazole (27 g) was added and the mixture, protected from moisture, was heated under reflux on a steam bath overnight. The solution was evaporated to dryness. The residue was dissolved in toluene and applied to a column (63×8.0 cm) of dry column grade neutral alumina prepacked in toluene. Elution with toluene (several liters) removed a faster moving yellow component from the column. The eluting solvent was changed to toluene-chloroform (4:1, 2 l) and then to chloroform. Monitoring of fractions was by t.l.c. on Alox-25 uv254 plates (Brinkmann) with chloroform as developer and on silica gel GF (Analtech) plates with chloroform as developer. A slightly faster moving minor purple component was eluted in the earlier fractions containing the major component. In later fractions a slower moving yellow component contaminated the major component. The first fraction (having none of the slower yellow minor component) were evaporated to smaller volume. Coevaporation with toluene caused crystallization. Addition of heptane completed the process; wt. 12.46 g (crop 1), mp=206°-208°. The later yellow fractions similarly gave 5.33 g (crop 2), mp=203°-208° of crude titled product. Recrystallization of crop 2 (from chloroform-toluene-heptane) gave material which was combined with crop 1. This material was dissolved in chloroform and the solution was decolorized. Evaporation to smaller volume followed by coevaporation with toluene and addition of heptane gave 17.6 g (76%) of crude titled product, mp=205°-209°. Recrystallization from the same solvent system gave titled product, mp=205°-208°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.Cl.[NH2:11][OH:12].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)/[CH:5]=[N:11]\[OH:12]
Reactant: NO
Reactant: O=Cc1cccc(Cl)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O/N=C\c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a suspension of 3-chlorobenzaldehyde (50 g, 355 mmol) and hydroxylamine hydrochloride (38 g, 543 mmol) in ethanol (200 mL) containing sodium acetate (46 g, 558 mmol) was heated under reflux for 3 h. After 30 min stirring at room temperature a white solid precipitated and the resulting mixture was then diluted with water and acidified with HCl (4 N). The white precipitate was then filtered off, washed with water and dried under high vacuum to afford the title compound (54 g, 98%) which was obtained as a white solid. Mp: 64-66° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[C:4]#[N:5].CO>C1COCC1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[C:3]=1[CH2:4][NH2:5]
Reactant: N#Cc1c(F)cccc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: NCc1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Yield: 100 %

Procedure:
To 2-fluoro-6-(trifluoromethyl)benzonitrile (45 g, 0.238 mmol) in 60 mL of THF was added 1 M BH3:THF slowly at 60° C. and the resulting solution was refluxed overnight. The reaction mixture was cooled to ambient temperature. Methanol (420 mL) was added slowly and stirred well. The solvents were then evaporated and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4. Evaporation gave 1a as a yellow oil (46 g, 0.238 mmol). MS (CI) m/z 194.0 (MH+).
Reaction SMILES: [C:1]([CH:3]([C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([CH3:16])=[C:10]2[C:6]=1[CH:7]=[CH:8][N:9]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:4])#[N:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:34](Br)[CH:35]=[CH2:36]>C1COCC1>[C:1]([C:3]([C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([CH3:16])=[C:10]2[C:6]=1[CH:7]=[CH:8][N:9]2[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])([CH2:36][CH:35]=[CH2:34])[CH3:4])#[N:2]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)C#N
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(C)(C#N)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Reaction time: 0.12 h

Procedure:
To (±)-tert-butyl 4-(1-cyanoethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 156-A) (0.82 g, 2.61 mmol) in THF (13.04 ml) at −78° C. was added LiHMDS (1M in hexane, 3.13 ml, 3.13 mmol) and stirred for 7 minutes. At this point, allyl bromide (0.563 ml, 6.52 mmol) was added and the reaction stirred for 2 hours at −78° C. Reaction was then quenched with a saturated solution of aq. ammonium chloride and diluted with DCM. The layers were separated and the organic layer was dried over Na2SO4 and concentrated to an oil that was absorbed onto silica and purified via FCC (0-30% EtOAc:heptanes) to give the title compound. MS (ESI+) m/z 355.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[C:6]([CH2:8][N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(Cl)ccc2N2CCOCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(N2CCOCC2)c(CN2CCNCC2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 120.1 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 4-[[5-chloro-2-(morpholin-4-yl)phenyl]methyl]piperazine-1-carboxylate (2.90 g, 7.32 mmol, 1.00 equiv), dichloromethane (35 mL). The mixture was cooled to 0° C. and trifluoroacetic acid (7 mL) was added dropwise. The resulting solution was stirred overnight at room temperature. The resulting solution was concentrated under reduced pressure to yield 2.60 g (crude) of 4-[4-chloro-2-(piperazin-1-ylmethyl)phenyl]morpholine as light yellow oil. LCMS (ESI, m/z): 296 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[C:6]2[CH2:15][CH2:16]O)#[N:2].[Br:18]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ClCCl>C(OCC)C>[Br:18][CH2:16][CH2:15][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=2)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(=O)cc(CCO)c2cc(C#N)ccc21
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1c(=O)cc(CCBr)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
0.24 g (1.05 mmol) of 6- cyano-4-(2-hydroxyethyl)-1-methyl-2(1H)-quinolone is added in small amounts to 0.48 g (1.14 mmol) of dibromotriphenylphosphorane in 14 ml of dichdoromethane at room temperature. After 75 minutes of stirring at room temperature, the reaction medium is poured into 200 ml of dichloromethane and the mixture is washed with water. The organic phase is dried over sodium sulphate, filtered and condensed under vacuum. The white residue is ground in diethylether. The solid obtained is taken up in a minimum of dichloromethane, the mixture is filtered rapidly through a layer of silica, eluting with ether, and the filtrate is evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12]O>OS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(Cl)cc1
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution of 2-(4-chlorophenyl)acetic acid (20.0 g, 117 mmol) in dry methanol (235 mL) was treated with 5 drops of concentrated H2SO4 (cat.) at room temperature. The mixture was stirred overnight to completion and was concentrated in vacuo to about 40 mL. The concentrate was partitioned between an ether and half saturated NaHCO3 solution. The aqueous portion was back-extracted once with ether, and the organics were combined. The organic portion was washed with water, then brine, dried over MgSO4, and concentrated in vacuo. The material was placed under high vacuum for one hour to afford the pure methyl 2-(4-chlorophenyl)acetate as a pale yellow oil (19.8 g, 92%). 1H NMR (CDCl3, 400 MHz) δ 7.30 (d, J=8.4 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 3.70 (s, 3H), 3.60 (2, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][C:20](=O)[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:17])[O:18][CH2:19][C:20]=2[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(OCc2ccccc2)cc1)OCC(=O)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1OCC(c2ccncc2)=C1c1ccc(OCc2ccccc2)cc1
Yield: 10.2 %

Procedure:
To a stirred solution of 2-oxo-2-(pyridin-4-yl)ethyl 2-(4-(benzyloxy)phenyl)acetate (1.8 g, 0.004 mol) in acetonitrile (50 mL) was added triethylamine (10 mL, 0.07 mol) under an inert atmosphere. The reaction mixture was then refluxed for 2 h, concentrated in vacuo, and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to yield the crude product. The crude material was purified via silica gel column chromatography to afford 3-(4-(benzyloxy)phenyl)-4-(pyridin-4-yl)furan-2(5H)-one (140 mg, 8%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[OH:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[C:43](=[O:47])[NH:42][CH:41]=[CH:40]2.[N:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH2:54][CH2:55][N:56]([CH2:61][C:62]2[CH:67]=[CH:66][N:65]=[CH:64][CH:63]=2)[CH2:57][CH2:58][CH2:59]O)[CH:49]=1.C(OC(=O)C)C.[ClH:74]>C(OCC)(=O)C.O1CCCC1>[ClH:74].[ClH:74].[ClH:74].[N:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH2:54][CH2:55][N:56]([CH2:61][C:62]2[CH:63]=[CH:64][N:65]=[CH:66][CH:67]=2)[CH2:57][CH2:58][CH2:59][O:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[C:43](=[O:47])[NH:42][CH:41]=[CH:40]3)[CH:49]=1
Reactant: OCCCN(CCc1cccnc1)Cc1ccncc1
Reactant: O=c1[nH]ccc2cc(O)ccc12
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1[nH]ccc2cc(OCCCN(CCc3cccnc3)Cc3ccncc3)ccc12
Reaction time: 8 h

Procedure:
Triphenyl phosphine (51 mg) and di-tert-butyl azodicarboxylate (45 mg) were added to a tetrahydrofuran (THF) solution (1.5 ml) of 6-hydroxy-2H-isoquinolin-1-one (29 mg), and 3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propan-1-ol (40 mg). The mixture was stirred overnight. After the reaction mixture was condensed under reduced pressure, the residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=1:0→4:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (0.06 ml) was added to an ethyl acetate solution of the residue, which was stirred at room temperature for 30 minutes. The generated insoluble matter was separated by filtration, and was dried to produce the title compound (31.4 mg) as a white powder.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:31][CH2:32][CH2:33][OH:34]>CN(C=O)C.O>[CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:31][CH2:32][CH2:33][OH:34])[CH2:12][C:11]=2[C:10]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCCN1CCc2c(c(-c3ccc(Cl)cc3)cn2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-benzyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (Example 25; 0.51 g) in DMF (14 mL) was added 1.39 g of Cs2CO3 and 142 μL of 3-bromo-1-propanol. The mixture was stirred at RT for 12 h and then was diluted with water. The aqueous layer was extracted with Et2O and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on SiO2 (2% 2 M NH3 in MeOH/CH2Cl2) afforded 0.15 g of the title compound. The product was dissolved in Et2O and treated with excess 1.0 M HCl in Et2O to afford 0.16 g the corresponding HCl salt. MS (ESI): exact mass calculated for C23H25ClN2O, 380.17. found, m/z 381.2 [M+H]+, 383.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.37-7.27 (m, 7H), 7.19-7.17 (m, 3H), 5.15 (s, 2H), 4.47 (br s, 2H), 3.93-3.25 (m, 6H), 2.94-2.93 (m, 2H), 2.01-1.96 (m, 2H).
Reaction SMILES: [C:1]([C:6]1[CH:22]=[CH:21][C:9]([O:10][CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:12](O)=[O:13])=[C:8]([Cl:23])[CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].S(Cl)([Cl:26])=O>C1(C)C=CC=CC=1>[C:1]([C:6]1[CH:22]=[CH:21][C:9]([O:10][CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:12]([Cl:26])=[O:13])=[C:8]([Cl:23])[CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCC(Oc1ccc(C(C)(C)CC)cc1Cl)C(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCC(Oc1ccc(C(C)(C)CC)cc1Cl)C(=O)Cl
Temperature: 60 °C

Procedure:
A mixture of 46 g of 2-(4-t-amyl-2-chlorophenoxy)octanoic acid and 46 ml of toluene was heated to 60° C., and 20.3 ml of thionyl chloride was slowly added thereto dropwise while stirring. After allowing the mixture to react at that temperature for 2 hours, the excess thionyl chloride and toluene were removed by distillation under reduced pressure to obtain 48 g of 2-(4-t-amyl-2-chlorophenoxy)octanoic acid chloride.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[CH:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][C:35]=1[C:44](=O)[CH3:45]>>[C:38]1([CH2:37][CH:36]=[C:35]([C:44]2[CH:2]=[CH:3][C:4]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:45]=2)[CH3:34])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(=O)c1ccc2ccccc2c1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(=CCc1ccccc1)c1ccc2ccccc2c1
Yield: 53.5 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (2.30 g, 5.14 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 3.2 mL, 5.14 mmol, 1.0 equiv.) and 1-(naphthalen-2-yl)ethanone (1.22 g, 7.20 mmol, 1.4 equiv.), 0.71 g (54%) of the title compound as a yellow oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 995:5).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@@H:18](O)[CH2:19][CH:20]=[CH2:21])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:1]1([C:7]2[N:8]=[C:9]([C@H:18]([N:27]3[C:26](=[O:28])[C:25]4=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]4[C:23]3=[O:33])[CH2:19][CH:20]=[CH2:21])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CC[C@H](O)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC[C@H](c1nc(-c2ccccc2)c(-c2ccccc2)o1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a solution of (4S)-4-(4,5-diphenyloxazol-2-yl)-4-hydroxy-1-butene (9.2 g) in THF (100 ml) were added phthalimide (7.0 g) and triphenylphosphine (12.5 g) and diethyl azodiformate (7.5 ml) at room temperature. The mixture was stirred for 2 hours at room temperature and partitioned between ethyl acetate and water. The organic layer was washed with 1N-HCl, water, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (4R)-4-(4,5-diphenyloxazol-2-yl)-4-phthalimido-1-butene (9.7 g).
Reaction SMILES: [NH2:1][CH:2]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[N:15][C:16]=3[NH2:18])[N:11]([C@H:19]3[CH2:24][CH2:23][C@@H:22]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)[N:10]=2)=[CH:5][CH:4]=1.[C:38]1([CH2:44][CH:45]=O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:31][N:28]1[CH2:27][CH2:26][N:25]([CH:22]2[CH2:23][CH2:24][CH:19]([N:11]3[C:12]4=[N:13][CH:14]=[N:15][C:16]([NH2:18])=[C:17]4[C:9]([C:6]4[CH:5]=[CH:4][C:3]([CH:2]([NH:1][CH2:45][CH2:44][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)=[CH:8][CH:7]=4)=[N:10]3)[CH2:20][CH2:21]2)[CH2:30][CH2:29]1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(C(N)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCN(C2CCC(n3nc(-c4ccc(C(NCCc5ccccc5)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Reaction time: 18 h
Yield: 46.6 %

Procedure:
To a solution of cis-3-{4-[amino(phenyl)methyl]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.10 mmol), phenylacetaldehyde (13 mg) and glacial acetic acid (0.013 mL) in 1,2-dichloroethane (1 mL) under nitrogen was added sodium triacetoxyborohydride (2 equivs., 43 mg). The solution was stirred for 18 h then concentrated in vacuo, partitioned between dichloromethane (10 mL) and saturated aqueous NaHCO3 (10 mL) and the organic layer separated. The aqueous layer was further extracted with dichloromethane (4×10 mL) and the combined organic layers were dried over anhydrous magnesium sulfate and evaporated to dryness. Purification was effected using mass actuated preparative RP-HPLC (Micromass/Gilson, Hypersil BDS C18, 5 μm, 100×21.2 mm column; 0-100% acetonitrile and 0.05M ammonium acetate, buffered to pH 4.5, over 12.5 min at 25 mL/min) to afford 1-[4-(4-methylpiperazino)cyclohexyl]-3-{4-[(phenethylamino)(phenyl)methyl]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (28 mg); RP-HPLC (10 to 90% CH3CN in 0.1 N aqueous ammonium acetate, buffered to pH 4.5, over 12 min at 2 mL/min using a Waters Symmetry C18, 250×4.6 mm column) Rt=12.269 min, 95.2%; m/z (MH+) 601.3.
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[S:11]([NH:14][CH:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:16][C:17](O)=[O:18])(=[O:13])=[O:12].[CH3:26][O:27][C:28]([C:30]1[CH:31]=[CH:32][C:33]2[CH:38]([NH2:39])[CH2:37][S:36](=[O:41])(=[O:40])[N:35]([CH3:42])[C:34]=2[CH:43]=1)=[O:29]>>[CH3:26][O:27][C:28]([C:30]1[CH:31]=[CH:32][C:33]2[CH:38]([NH:39][C:17](=[O:18])[CH2:16][CH:15]([NH:14][S:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)(=[O:13])=[O:12])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:37][S:36](=[O:41])(=[O:40])[N:35]([CH3:42])[C:34]=2[CH:43]=1)=[O:29]
Reactant: O=C(O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Reactant: COC(=O)c1ccc2c(c1)N(C)S(=O)(=O)CC2N
Product: COC(=O)c1ccc2c(c1)N(C)S(=O)(=O)CC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1

Procedure:
The title compound was prepared from 3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionic acid Example 1, Step H and 4-amino-1-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2λ6-benzo[c][1,2]thiazine-7-carboxylic acid methyl ester (Step B) similar to that described in Example 1, Step F. MS (+APCI, m/z): 608 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12]O>S(=O)(=O)(O)O>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[CH3:11]
Reactant: Cc1c(Cl)cccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(Cl)c1C
Temperature: 25 °C

Procedure:
Approximately two drops of sulfuric acid were added to a solution of 3-chloro-2-methyl-benzoic acid (5.00 g, 29.30 mmol) in methanol and the resulting reaction mixture was refluxed for 14 hours. The reaction mixture was cooled to room temperature, and concentrated, then diluted with EtOAc. The organic layer was washed with saturated NaHCO3 (3×150 mL), H2O (2×250 mL), brine (1×250 mL) and dried over MgSO4. The crude product was purified by column chromatography using hex:EtOAc (4.5:0.5) as the eluant to give the title ester. Spectroscopic data: 1H NMR (300 MHz, CDCl3.) δ 2.60 (s, 3H), 3.90 (s, 3H), 7.16 (t, J=7.325 Hz, 1H), 7.49 (d, J=7.91 Hz, 1H), 7.69 (d, J=7.91 Hz, 1H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.[S:19](N)([NH2:22])(=[O:21])=[O:20]>O1CCOCC1>[NH2:22][S:19]([N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C:4]([N:3]([CH3:11])[CH3:2])=[O:10])(=[O:21])=[O:20]
Reactant: NS(N)(=O)=O
Reactant: CN(C)C(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(C)C(=O)[C@@H]1CCCN1S(N)(=O)=O

Procedure:
To a solution of the subtitle product of step ii) (3.70 g) in dioxane (50 ml) was added triethylamine (2.02 g) and sulfamide (9.96 g). The mixture was heated at reflux for 3 days before the reaction mixture was cooled, filtered and washed with methanol (50 ml). The solvent was evaporated and the residue purified by column chromatography (2% methanol/EtOAc) to afford the subtitle compound as an oil. Yield: 1.70 g.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[C:11]1[CH:18]3[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:20][CH:12]1[CH2:13]4)[CH2:17]3)[CH2:8]2.[Br:21]N1C(=O)CCC1=O>C(Cl)Cl>[Br:21][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[C:2]1=[C:11]1[CH:12]3[CH2:20][CH:16]4[CH2:15][CH:14]([CH2:19][CH:18]1[CH2:17]4)[CH2:13]3)[CH2:10]2
Reactant: C1C2CC3CC1CC(C2)C3=C1C2CC3CC(C2)CC1C3
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: BrC12CC3CC(CC(C3)C1=C1C3CC4CC(C3)CC1C4)C2
Reaction time: 12 h

Procedure:
To a solution of 3 mmols (804 mg) adamantylideneadamantane in 40 cm3CH2Cl2, 6.6 mmols (1.175 g) N-bromosuccinimide was added. The reaction mixture was refluxed and stirred for 12 hours. The reaction mixture was diluted with CH2Cl2 and washed twice with water and a saturated Na2S3O3 -solution. The organic layer was dried with MgSO4 and evaporated. The yield of 4-eq.-bromoadamantylideneadamantane having formula 20 was 1.05 g (97%). An analytically pure sample could be obtained by crystallization from acetone and sublimation (115° C./0.002 mm); melting point 130.5-131.5° C. 1H NMR (CDCl3); δ 4.4 (br s, 1H); 3.05 (br s, 1H); 2.8 (br s, 3H); 2.6-1.2 (br m, 22H); 13C NMR (CDCl3); δ 136.9 (s); 131.0 (s); 63.8 (d) and 12 signals between 39.9 and 27.6. Analysis, calculated: 69.16 C; 7.84 H; 23.01 Br; found: 69.21 C; 7.82 H; 22.99 Br. Mass m/e 346:348 (1:1).