Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.C([N:24]1[CH2:30][CH2:29][C:28]2[CH:31]=[N:32][C:33]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=3)=[N:34][C:27]=2[CH2:26][CH2:25]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCl>[Cl:42][C:38]1[CH:37]=[C:36]([CH:41]=[CH:40][CH:39]=1)[CH2:35][C:33]1[N:32]=[CH:31][C:28]2[CH2:29][CH2:30][NH:24][CH2:25][CH2:26][C:27]=2[N:34]=1
Reactant: Clc1cccc(Cc2ncc3c(n2)CCN(Cc2ccccc2)CC3)c1
Agent: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCl
Product: Clc1cccc(Cc2ncc3c(n2)CCNCC3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18 %

Procedure:
1,8-Bis-(dimethylamino)naphthalene (80 mg, 0.37 mmol) was added to a solution of 7-benzyl-2-(3-chlorobenzyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine of Preparation 28, Step C, (135 mg, 0.37 mmol) in dichloromethane (5 ml). Then 1-chloroethyl chloroformate (80.9 μl, 0.74 mmol) was added and stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane (10 ml) then washed with 5% aqueous citric acid (15 ml). The organic phase was dried over magnesium sulphate and concentrated in vacuo. The residue was dissolved in methanol (5 ml) then heated to reflux, under nitrogen, for 1.5 h. The reaction mixture was concentrated in vacuo then the residue was partitioned between dichloromethane (10 ml) and 1N NaOH (10 ml). The organic phase was dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with DCM:MeOH:0.880NH3 (100:0:0 to 90:10:1), to afford the title compound as a yellow oil in 18% yield, 18 mg.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8](O)=[O:9])=[O:4].Cl.[CH:38]1([NH2:41])[CH2:40][CH2:39]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:38]1([NH:41][C:8](=[O:9])[CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH:2]([OH:1])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:21]=[C:20]([C:22]4[O:26][N:25]=[C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:23]=4[C:33]([F:36])([F:34])[F:35])[O:19][N:18]=3)=[CH:15][CH:16]=2)[CH2:40][CH2:39]1
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1)NC1CC1
Reaction time: 1 h
Yield: 36.4 %

Procedure:
(R/S)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Example 22, 22 mg, 0.044 mmol), cyclopropanamine-HCl (6.15 mg, 0.066 mmol), 4-methylmorpholine (17.72 mg, 0.175 mmol), and HATU (21.65 mg, 0.057 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention=13.3 min) to provide (R/S)-N-cyclopropyl-3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanamide (9 mg, 0.016 mmol, 35.5% yield): LCMS=542.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.36 Hz), 7.54-7.75 (7 H, m), 5.10 (1 H, s), 3.45-3.55 (2 H, m), 2.56-2.68 (1 H, m), 2.37 (2 H, t, J=6.49 Hz), 0.63-0.76 (2 H, m), 0.35-0.49 (2 H, m); HPLC peak RT=8.7 min (Method A).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13](OC)[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:21](=[O:24])([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][CH2:30][Cl:31]>S1(CCCC1)(=O)=O>[Cl:31][CH2:30][CH2:29][CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[C:11]([O:24][CH3:21])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2nc(-c3ccc(O)cc3)[nH]c(=O)c2c1
Reactant: ClCCCBr
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: COc1cccc2c(=O)[nH]c(-c3ccc(OCCCCl)cc3)nc12
Temperature: 0 °C

Procedure:
2.7 gm (10 mmols) of 2-(4-hydroxy-phenyl)-6-methoxy-3,4-dihydro-quinazolin-4-one were dissolved in 30 ml of sulfolane, and the solution was mixed with 1.5 gm (10 mmols+10%) of potassium carbonate. The resulting clear solution was admixed with 2.7 ml of 1-bromo-3-chloropropane, and the reaction mixture was stirred until the reaction was complete. After pouring it into ice water, the aqueous mixture was extracted with ethyl acetate, and the combined organic extracts were dried over sodium sulfate and evaporated. A colorless oil was obtained, which crystallized upon cooling.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:24]([F:35])[CH:23]=3)[CH:15]=2)=[C:9]([CH3:36])[CH:8]=1)[CH3:2].[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:24]([F:35])[CH:23]=3)[CH:15]=2)=[C:9]([CH3:36])[CH:8]=1)[CH3:2]
Reactant: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)OCC)c(F)c3)c2)c(C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)O)c(F)c3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
To a solution of ethyl 3-[4-({[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methyl}amino)-2-fluorophenyl]propanoate (2.88 g, 5.83 mmol) in a mixture of ethanol (90 mL) and tetrahydrofuran (90 mL) was added 2 M aqueous sodium hydroxide solution (30 mL), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was weakly acidified with 10% aqueous citric acid solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-80% ethyl acetate/hexane) to give the title compound (2.70 g, yield 99%) as a pale-yellow oil.
Reaction SMILES: [O:1]=[C:2]1[N:10]2[C:11]([CH2:14][NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:12][N:13]=[C:9]2[N:8]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2.[Br:29]N1C(=O)CCC1=O>C1COCC1>[Br:29][C:5]1[NH:4][C:3]2[C:2](=[O:1])[N:10]3[C:11]([CH2:14][NH:15][C:16](=[O:23])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[N:12][N:13]=[C:9]3[N:8]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7]=2[N:6]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(CNC(=O)c3ccccc3)nnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CNC(=O)c3ccccc3)nnc12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To the solution of N-[(5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)methyl]benzamide (0.11 g, 0.28 mmol) in THF (10 mL) was added N-Bromosuccinimide (0.076 g, 0.42 mmol). The mixture was stirred at 70° C. for 1 hour. The reaction mixture was concentrated and purified by preparative LCMS. LCMS calculated for C19H21BrN7O2 (M+H): 458.1. found: 458.0, 460.0.
Reaction SMILES: C12(COC3C=CC(C(N)=O)=CC=3C3C(OC)=NC=CC=3)CC3CC(CC(C3)C1)C2.[C:30]12([CH2:40][O:41][C:42]3[C:50]([CH:51]4[CH2:53][CH2:52]4)=[CH:49][C:45]([C:46]([NH2:48])=[O:47])=[C:44]([F:54])[CH:43]=3)[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2.CS(Cl)(=O)=O.[O:60]1[CH2:65][CH2:64][CH:63]([S:66](Cl)(=[O:68])=[O:67])[CH2:62][CH2:61]1>>[C:30]12([CH2:40][O:41][C:42]3[C:50]([CH:51]4[CH2:52][CH2:53]4)=[CH:49][C:45]([C:46]([NH:48][S:66]([CH:63]4[CH2:64][CH2:65][O:60][CH2:61][CH2:62]4)(=[O:68])=[O:67])=[O:47])=[C:44]([F:54])[CH:43]=3)[CH2:37][CH:36]3[CH2:38][CH:32]([CH2:33][CH:34]([CH2:35]3)[CH2:39]1)[CH2:31]2
Reactant: NC(=O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: O=S(=O)(Cl)C1CCOCC1
Agent: COc1ncccc1-c1cc(C(N)=O)ccc1OCC12CC3CC(CC(C3)C1)C2
Agent: CS(=O)(=O)Cl
Product: O=C(NS(=O)(=O)C1CCOCC1)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 38 step 4 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzamide with 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamide and to replace methanesulfonyl chloride with tetrahydro-2H-pyran-4-sulfonyl chloride, the title compound was obtained as a colorless solid (0.15 g, 30%): 1H NMR (300 MHz, CDCl3) δ8.55-8.44 (m, 1H), 7.60-7.52 (m, 1H), 6.62-6.52 (m, 1H), 4.17-3.90 (m, 3H), 3.56 (s, 2H), 3.47-3.36 (m, 2H), 2.12-1.95 (m, 8H), 1.84-1.65 (m, 12H), 1.00-0.90 (m, 2H), 0.71-0.58 (m, 2H); MS (ES+) m/z 492.21 (M+1).
Reaction SMILES: O=[C:2]1[C:11]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.Cl.[NH2:13][OH:14]>N1C=CC=CC=1>[OH:14][N:13]=[C:2]1[C:11]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: O=C1CCCc2ccncc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1CCCc2ccncc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 103.6 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-8-oxo-isoquinoline (850 mg) in pyridine (10 ml) was added hydroxylamine hydrochloride (803 mg), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen-carbonate solution and brine. Evaporation of the dried (Na2SO4) organic layer gave 8-hydroxyimino-5,6,7,8-tetrahydroisoquinoline (970 mg).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[NH:26]1[CH2:29][CH:28]([C:30]#[N:31])[CH2:27]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:26]3[CH2:29][CH:28]([C:30]#[N:31])[CH2:27]3)=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:8]=1
Reactant: N#CC1CNC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Temperature: -60 °C
Reaction time: 0.75 h
Yield: 59.2 %

Procedure:
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.2 g, 1.0 eq.) was dissolved in DCM (20 mL). The reaction mixture was cooled to −60° C. where azetidine-3-carbonitrile hydrochloride (0.08 g, 1.2 eq), T3P (50% in EtOAc) (0.4 mL, 1.2 eq) followed by DIPEA (0.2 mL, 2 eq) were added dropwise. The clear reaction mixture was stirred at −60° C. for 45 min. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product, which was purified by chromatography (3-5% Methanol in DCM). to obtain (Z)-1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)azetidine-3-carbonitrile (0.14 g, 60% yield). 1H NMR (400 MHz, DMSO) δ=9.36 (s, 1H), 8.54 (s, 2H), 8.30 (s, 1H), 7.45-7.43 (d, J=10 Hz, 1H), 5.95-5.92 (d, J=10 Hz, 1H), 4.39-4.37 (t, 1H), 4.29-4.11 (m, 3H), 3.84-3.82 (m, 1H); LCMS calcd. for C17H12F6N5O [M+H]+ 416.29. found 416.14, at 2.64 min retention time
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:18]1([N:24]=[C:25]=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>CCOCC>[F:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25]([NH:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C=Nc1ccccc1
Reactant: Nc1ncccc1OCc1c(F)cccc1F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1cccc(F)c1COc1cccnc1NC(=S)Nc1ccccc1

Procedure:
A mixture of 2-amino-3-(2,6-difluorobenzyloxy)pyridine (2.1 g, 0.09 mol), phenyl isothiocyanate (1.43 g, 0.011 mol) and toluene (10 ml) was heated under reflux for 3 hours, then cooled and diluted with ether to induce crystallisation of the product, which was recrystallised from ethanol/ether. Yield 2.0 g (82%), m.p. 132°-133 ° C.
Reaction SMILES: O.[BH4-].[Na+].Cl[CH2:5][C:6]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[CH3:20])=[CH:12][CH:13]=1)=[O:7]>O1CCOCC1.O1CCCC1>[CH3:20][C:15]1[N:14]([C:11]2[CH:12]=[CH:13][C:8]([CH:6]3[CH2:5][O:7]3)=[CH:9][N:10]=2)[C:18]([CH3:19])=[CH:17][CH:16]=1
Reactant: Cc1ccc(C)n1-c1ccc(C(=O)CCl)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C)n1-c1ccc(C2CO2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Water (1.08 Kg) was added dropwise to a suspension of sodium borohydride (0.17 Kg, 4.36 mol) in 1,4-dioxane (6.49 L) at 16° C. and the resulting solution stirred at room temperature. A solution of 2-chloro-1-[6-(2,5-dimethylpyrrol-1-yl)pyridin-3-yl]ethanone (1.08 Kg, 4.35 mol) in tetrahydrofuran (2.16 L) was added over 1 hour and the resulting solution stirred for 45 minutes at room temperature. When all the 2-chloro-1-[6-(2,5-dimethylpyrrol-1-yl)pyridin-3-yl]ethanone was consumed the reaction mixture was cooled to 19° C. and treated with concentrated HCl (36% w/w) (1.08 L) over 40 minutes. The mixture was cooled to 11° C. and NaOH (32% w/w) (1.64 L) was added over 45 minutes maintaining the temperature below 25° C. The mixture was then allowed to granulate at room temperature overnight. When all the chloroalcohol intermediate was consumed, DCM (5.0 L) and water (5.0 L) were added and the mixture was stirred before allowing the phases to separate. The aqueous phase was extracted with DCM (2.50 L) and the combined organic phases were washed with water (2×1.0 L) and concentrated in vacuo. Yield 98% (0.92 Kg) δH (CDCl3, 300 MHz) 2.10 (6H, s), 2.90 (1H, dd), 3.25 (1H, dd), 4.00 (1H, dd), 5.90 (2H, s), 7.20 (1H, d), 7.70 (1H, dd), 8.40 (1H, d) ppm. MS m/z 215 (MH+).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:11]([O:13][C:14](=[O:25])[CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH3:12].Br[CH2:27][C:28]1[C:29]([F:40])=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[C:35]([O:38][CH3:39])[CH:34]=[CH:33]2.O>C1COCC1.CC(=O)OCC>[CH2:11]([O:13][C:14](=[O:25])[CH:15]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:27][C:28]1[C:29]([F:40])=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[C:35]([O:38][CH3:39])[CH:34]=[CH:33]2)[CH3:12]
Reactant: COc1ccc2ccc(F)c(CBr)c2n1
Reactant: CCOC(=O)CCNC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(CNC(=O)OC(C)(C)C)Cc1c(F)ccc2ccc(OC)nc12
Reaction time: 1.5 h
Yield: 75 %

Procedure:
To a solution of LiHMDS (1M, 20 mL), cooled to −78° C., was added dropwise a solution of 3-tert-butoxycarbonylamino-propionic acid ethyl ester (2.01 g, 9.26 mmol; prepared as in Tetrahedron Lett. (2003), 44(14), 2807) in THF (20 mL). The solution was stirred at the same temperature for 90 min. A solution of 8-bromomethyl-7-fluoro-2-methoxy-quinoline (2.5 g; prepared as in WO 2007/081597) in THF (10 mL) was quickly added and the reaction proceeded for 2 h, keeping the internal temperature below −50° C. Water (100 mL) and EA (200 mL) were added. The two layers were separated and the aq. layer was extracted with EA. The combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA 2:1) to afford the title intermediate as a pale yellow oil, which solidified (2.83 g, 75% yield) after standing at rt for one day.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[OH-].[K+].O.Cl[CH2:13][CH:14]([OH:18])[CH2:15][CH2:16][Cl:17]>C(O)(C)C>[Cl:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: OC(CCl)CCCl
Reactant: Oc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: OC(CCCl)COc1ccccc1Cl
Temperature: 50 °C

Procedure:
To a mixture of 129 g. (1 mole) of 2-chlorophenol, 60 g. of potassium hydroxide, 100 ml. of water and 400 ml. of isopropanol was added 1.3 moles (185.9 g.) of 1,4-dichloro-2-butanol with stirring at 50° C. The resulting mixture was heated in a steam bath at 65° C. overnight and extracted with 300 ml. of isopropyl ether. The ether extract was washed successively with 1N sodium hydroxide, water and dried over sodium sulfate. The dried ether solution was concentrated and the oily residue was distilled under reduced pressure yielding 152 g. of an oily substance (b.p. 130°-131° C./0.01 mm.).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:8])[CH3:7].[N-:9]=[N+:10]=[N-:11].[Na+]>O.C(O)(C)(C)C>[N:9]([CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:8])[CH3:7])=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OCCCBr
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(=O)OCCCN=[N+]=[N-]
Yield: 59.7 %

Procedure:
Acetic acid 3-bromo-propyl ester (6.7 g, 37 mmol) was suspended in water (50 mL) and tert-butanol (20 mL). To the resulting mixture was then added sodium azide (2.76 g, 42.6 mmol) and the reaction mixture was heated to reflux for 18 hours, then concentrated to half of its volume. The reaction mixture was partitioned with water and ethyl acetate. The organic layer was washed with water, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield the acetic acid 3-azido-propyl ester (3.16 g) as an oil which used in the next step without further purification.
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].C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.O>C1(C)C=CC=CC=1>[S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=1)([O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:27])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Oc1ccc2ccccc2c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)Oc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
A 2 L four-necked round-bottomed flask equipped with a Teflon® coated magnetic stirring bar, dropping funnel, thermometer, and a gas inlet was evacuated and filled with nitrogen. 2-naphthol (51.8 g, 359.3 mmol, 1.0 equivalent), dehydrated toluene (800 mL), and triethylamine (52.6 mL, 377.3 mmol, 1.05 equivalents) were charged into the flask successively. Subsequently, to the solution was added p-toluenesulfonyl chloride (69.9 g, 366.5 mmol, 1.02 equivalents) in dehydrated toluene (140 mL) dropwise via the dropping funnel over 15 minutes at such a rate that the internal temperature was kept at 50° C. or lower, and the mixture was stirred for further 2 hours at room temperature. The thus-obtained white suspension was poured into water, and the aqueous layer was separated off. The organic layer was passed through a silica gel pad, and concentrated under reduced pressure to give solid residue, which was purified by recrystallization from toluene/methanol to afford 94.2 g of 2-naphthyl tosylate as a white powder. The mother liquor was concentrated under reduced pressure to give solid residue, which was recrystallized to recover further 9.2 g of 2-naphthyl tosylate.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:10][CH3:11])[CH2:8][CH2:7][O:6][CH2:5][C:4]1=[O:9].[B]>>[CH3:1][O:2][C:3]1([O:10][CH3:11])[CH2:8][CH2:7][O:6][CH2:5][C@@H:4]1[OH:9]
Reactant: COC1(OC)CCOCC1=O
Agent: [B]
Product: COC1(OC)CCOC[C@@H]1O

Procedure:
reacting 4,4-dimethoxydihydro-2H-pyran-3(4H)-one with a boron reducing agent and R-(+)-2-methyl-CBS-oxazaborolidine, over a period of at least six hours to provide the (S)-4,4-dimethoxytetrahydro-2H-pyran-3-ol in at least 60% enantiomeric excess, wherein the reaction is run at a temperature range from 20° C. to 60° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[N:3]=1.[CH:17]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[OH-].[Na+].O>CC(C)=O>[OH-:16].[NH4+:3].[Cl:8][C:6]1[N:7]=[C:2]([NH:24][CH:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=[C:4]([NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[N:5]=1
Reactant: OC1CCC(Nc2nc(Cl)nc(Cl)n2)CC1
Reactant: NC1CCCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: OC1CCC(Nc2nc(Cl)nc(NC3CCCCCC3)n2)CC1
Product: [NH4+]

Procedure:
To 155a (1.0003 g, 3.8 mmol) dissolved in acetone (20 mL) was added a solution of cycloheptylamine (0.5 mL, 3.8 mmol) in acetone (5 mL) followed by addition of 2.5 N NaOH (1.5 mL, 3.8 mmol) and water (4 mL). The reaction mixture was allowed to stir at reflux for 3 hours under nitrogen. The reaction mixture was extracted 3 times with dichloromethane; the combined organic layers were washed with brine and dried over sodium sulfate. The filtered sample was concentrated on the rotary evaporator and the resulting solid was dried overnight under vacuum. Flash column chromatography (SiO2, 90:9:1 dichloromethane:methanol:conc. ammonium hydroxide) yielded a white solid (155b, 856 mg, 66%), mp>210° C.; HPLC: Inertsil ODS-3V C18, 40:10:50 [KH2PO4 (0.01M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt 10.0 min, 96.0% purity; MS (TOF MS ES+): m/z 342 (51.5), 341 (35.1), 340 (M+H, 100).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:39]O>>[CH3:39][O:2][C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:3]
Reactant: O=C(O)CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Yield: 54 %

Procedure:
A mixture of 1-(7-carboxyheptyl)-2,4,5-triphenyl-imidazole (0.5 g), concentrated sulphuric acid (2 ml) and methanol (100 ml) was heated at reflux for 24 h. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (50 ml), washed with water (50 ml), saturated NaHCO3 solution (50 ml), water (50 ml), dried over anhydrous magnesinm sulphate and evaporated to dryness in vacuo. Column chromatography on silica gel eluted with a dichloromethane:methanol gradient gave 1-(7-methoxycarbonylheptyl)-2,4,5-triphenylimidazole (0.28 g, 54%) as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=2)[NH:8][N:7]=1.[C:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])[CH3:32]>>[C:31]([N:34]1[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[C:14]3[C:9](=[N:10][CH:11]=[N:12][C:13]=3[NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[C:18]([Cl:30])[CH:17]=3)[NH:8][N:7]=2)[CH2:36][CH2:35]1)(=[O:33])[CH3:32]
Reactant: CC(=O)N1CCNCC1
Reactant: ClCCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CC(=O)N1CCN(CCCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CC1
Yield: 14 %

Procedure:
The procedure described in Example 23 was repeated using 3-(3-chloropropoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and N-acetylpiperazine to give the title compound in 14% yield; NMR Spectrum: 1.97 (s, 3H), 1.97-2.01 (m, 2H), 2.31 (t, 2H), 2.38 (t, 2H), 2.45 (t, 2H), 3.33-3.40 (m, 4H), 4.35 (t, 2H), 5.29 (s, 2H), 7.23 (d, 1H), 7.37 (t, 1H), 7.54-7.58 (m, 2H), 7.86-7.90 (m, 2H), 8.27 (s, 1H), 8.45 (br s, 1H), 8.60 (d, 1H); Mass Spectrum: 537 (MH+).