Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[H-].[Na+].[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19]>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(Cl)cc1Cl
Yield: 70 %

Procedure:
Using 0.20 g of 2,4-dichlorobenzyl chloride, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.23 g of 2-(2,4-dichlorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (83)).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][C@@H:17]([CH3:19])[NH:16][C@@H:15]([CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl:29][C:30]1[S:34][C:33]([CH:35]=[CH:36][S:37](Cl)(=[O:39])=[O:38])=[CH:32][CH:31]=1>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][C@@H:17]([CH3:19])[N:16]([S:37]([CH:36]=[CH:35][C:33]4[S:34][C:30]([Cl:29])=[CH:31][CH:32]=4)(=[O:39])=[O:38])[C@@H:15]([CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)s1
Reactant: C[C@@H]1CN(Cc2ccc3c(N)ncnc3c2)C(=O)[C@H](C)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccc3c(N)ncnc3c2)C(=O)[C@H](C)N1S(=O)(=O)C=Cc1ccc(Cl)s1
Reaction time: 8 h
Yield: 2.3 %

Procedure:
(3S,5R)-1-(4-Amino-quinazolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one (43 mg, 0.123 mmol), minor epimer from EXAMPLE 88, Part D, is taken up in methylene chloride to this is added triethylamine (0.034 ml, 0.25 mmol) followed by 2-(5-chloro-thiophen-2-yl)-ethenesulfonyl chloride (40 mg, 0.16 mmol), EXAMPLE 3. The reaction is stirred overnight, and the crude material is purified by preparative thin layer chromatography (15% methanol/CH2Cl2). The product (1.4 mg, 2.3%) is isolated as a yellow wax. C21H22ClN5O3S2 MS m/z: 492, 494. 1H NMR (CD3OD) δ8.36 (s, 1H); 8.03 (d, 1H, J=7.5 Hz); 7.61 (s, 1H); 7.49-7.44 (m, 2H); 7.19 (d, 1H, J=3.83 Hz); 6.98 (d, 1H, J=3.75 Hz); 6.76 (d, 1H, J=15.1 Hz); 4.86-4.71 (m, 2H); 4.45-4.39 (m, 1H); 4.13-4.09 (m, 1H); 3.64-3.7 (m, 2H); 1.63 (d, 3H, J=7.09 Hz); 1.33 (d, 3H, J=6.80 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8]C)=[C:6]([Cl:10])[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]1=[O:24].C(Cl)Cl>ClCCCl>[NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:10])[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]1=[O:24]
Reactant: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Solvent: ClCCCl
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2N)c1=O
Yield: 62.8 %

Procedure:
3-(2-Amino-4-chloro-6-fluoro-3-methoxyphenyl)-1-methyl-6trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (1.1 g, 2.7 mmol) was dissolved in 50 ml of anhydrous 1,2-dichloroethane and 3.4 g (10.8 mmol) of borontribromide imethylsulfide complex was added to the solution. The solution was refluxed for 16 hr and methylene chloride (100 ml) was added. Washing with water followed by drying (anhydrous sodium sulfate) and removal of the solvent afforded a residue which was triturated with ether to afford the title compound (0.6 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:20]=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:23]([F:30])([F:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].[Cl-].[NH4+]>[Zn].C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:20]([OH:21])[C:23]([F:30])([F:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(F)(F)Br
Reactant: O=CC(Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)C(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a mixture of the objective compound of step (10) (42.8 g, 0.151 mol), zinc dust (15.9 g, 0.243 mol) and THF (105 ml) was added ethyl bromodifluoroacetate (31.6 mL, 0.246 mol) with dropwise over 2 hours at 26˜49° C. The resulting mixture was stirred at room temperature for 2 hours. To this reaction mixture was added saturated ammonium chloride aqueous solution (110 mL), and the mixture was stirred for a few minutes. The obtained mixture was added to saturated ammonium chloride aqueous solution (650 mL) and extracted with ethyl acetate (500 mL, 2×300 mL). The extract was washed with saturated brine (400 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2:1 hexane-ethyl acetate) to give 56.15 g of ethyl 4-benzyloxycarbonylamino-2,2-difluoro-3-hydroxy-5-phenylpentanoate as a light-yellow oil (a mixture of diastereomers, 75%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][CH2:15][C:16]1([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)=[CH:10][CH:9]=[CH:8][CH:7]=2>O1CCOCC1.C(OCC)C>[F:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][CH2:15][C:16]1([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccccc23)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOC(=O)C1(CCCc2c(F)cnc3ccccc23)CCNCC1
Temperature: 20 °C
Reaction time: 18 h
Yield: 69.7 %

Procedure:
50 cm3 of a solution of hydrogen chloride in dioxane at a concentration of 4M were added cautiously to a solution of 8.7 g of ethyl 4-[3-(3-fluoroquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-4-carboxylate in 150 cm3 of anhydrous dioxane, and the temperature was maintained below 30° C. during the addition. After stirring for 18 hours in the region of 20° C., the suspension was diluted with 250 cm3 of diethyl ether, filtered and washed with 5 times 50 cm3 of diethyl ether, and the solid was dried in a desiccator under reduced pressure (2 kPa) and at a temperature in the region of 20° C. The solid was taken up in 50 cm3 of water and aqueous 5N sodium hydroxide solution was added so that the pH was at about 10, and the mixture was then extracted with 5 times 100 cm3 of diethyl ether. The organic phases were combined, dried over magnesium sulfate, taken up with plant charcoal (3S), filtered and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50° C. 4.7 g of ethyl 4-[3-(3-fluoroquinolin-4-yl)propyl]piperidine-4-carboxylate were obtained in the form of a viscous orange-colored oil.
Reaction SMILES: C[C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[C:3]=1[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5]>C(O)C>[CH2:4]([O:5][C:11]1[C:10]([NH2:14])=[C:3]([CH:2]=[CH:13][CH:12]=1)[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])[CH:3]=[CH2:2]
Reactant: C=CCOC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: CCO
Product: C=CCOC(=O)c1cccc(OCC=C)c1N

Procedure:
The above nitro compound was reduced by the method described in example 6, for the reduction of allyl 2-methyl-6-nitrobenzoate, except that the solvent used was ethanol, to give allyl 3-allyloxy-2-aminobenzoate.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:29]([CH3:31])[CH3:30]>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH:29]([CH3:31])[CH3:30])[CH2:20]1
Reactant: CC(C)I
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCNC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCCN(C(C)C)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[4-(3-piperidinyl)butyl]-9H-purin-6-amine and 2-iodopropane.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Br[C:13]1[CH:18]=[CH:17]C(CC(OC2CCCCO2)=O)=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:9]([OH:11])=[O:10])[CH2:17][CH2:18][CH2:13][CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: O=C(Cc1ccc(Br)cc1)OC1CCCCO1
Product: O=C(O)C1(c2ccc(Br)cc2)CCCCC1
Yield: 25 %

Procedure:
The title compound was obtained in a manner analogous to that for 1-Phenylcyclohexanecarboxylic acid (1/3) starting with (4-bromophenyl)acetic acid (4d), via tetrahydro-2H-pyran-2-yl 2-(4-bromophenyl)acetate (5d). The crude product 1/9 was chromatographed on silica gel with petroleum ether-dioxane-acetic acid (85:15:2) and petroleum ether-tert-butylmethyl ether-acetic acid (8:2:0.1) as eluents to give 1-(4-bromophenyl)cyclohexanecarboxylic acid (1/9) in 25% yield. 1H NMR (CDCl3, HMDSO) δ: 1.17-1.92 (8H, m); 2.28-2.59 (2H, m); 7.33 (2H, d, J=8.8 Hz); 7.47 (2H, d, J=8.8 Hz); 10.34 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[Br:12]Br>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:11])[CH:9]([Br:12])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)c1cccc(Cl)c1
Reactant: BrBr
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(Br)C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
To a solution of 3′-chloropropiophenone (50.0 g, 297 mmol) in acetonitrile (595 mL) was added bromine (16.67 mL, 327 mmol) at room temperature. The reddish-yellow solution was allowed to stir for 18 h at room temperature. The solution was concentrated in vacuo to provide a reddish solid. The crude material was dissolved in 400 mL of ethyl acetate and washed with 400 mL of water. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give 72.6 g (98%) of crude product. 1H NMR (CDCl3) δ1.90 (d, J=6 Hz, 3H), 5.21 (q, J=6 Hz, 1H), 7.37-7.88 (m, 3H), 7.98 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[CH:12]([C:16](=[O:18])[CH3:17])[CH:11]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH:10]1[CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9]1.[BH4-].[Na+]>C(O)C>[OH:18][CH:16]([CH:12]1[C:13]2[CH:14]=[CH:15][C:2]([OH:1])=[CH:3][C:4]=2[CH:5]2[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:11]1[C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH3:17]
Reactant: CC(=O)C1c2ccc(O)cc2C2CCCCC2C1c1ccc(O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)C1c2ccc(O)cc2C2CCCCC2C1c1ccc(O)cc1
Reaction time: 72 h
Yield: 11.1 %

Procedure:
Combine 1-[6-hydroxy-10-(4-hydroxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthren-9-yl]-ethanone (0.027 g, 0.08 mmol), NaBH4 (0.010 g, 0.24 mmol), and ethanol (4 mL), and reflux under nitrogen atmosphere. After 72 hours, cool the reaction to room temperature, concentrate, and add ethyl acetate. Wash with sat ammonium chloride solution (aq), then brine, and purify using reverse phase chromatography (5% to 95% 0.001% TFA buffer in acetonitrile/water) to yield the titled compound (0.003 g, 11%) as a white solid. 1H NMR (d-methanol): 7.62 (d, 1H, J=8.4 Hz), 7.15 (m, 2H), 6.84 (s, 1H), 6.78 (m, 2H), 6.64 (m, 1H), 3.94 (m, 1H), 3.49 (d, 1H, J=11.5 Hz), 3.33 (m, 1H), 3.13 (s, 1H), 2.91 (dd, 1H, J=11.5, 3.5 Hz), 2.47 (m, 1H), 1.86 (m, 1H), 1.68 (m, 1H), 1.52 (m, 1H), 1.30 (m, 3H), 1.05 (m, 4H), 0.83 (d, 2H, J=6.2 Hz); MS m/z 337 (M−1).
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:31])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:18][CH:19]=[CH:20][CH2:21][CH:22]([OH:30])[C:23]1([CH2:27][CH2:28][CH3:29])[CH2:26][CH2:25][CH2:24]1)[S:14]([CH3:17])(=[O:16])=[O:15])C.Cl>O.C1COCC1>[OH:30][CH:22]([C:23]1([CH2:27][CH2:28][CH3:29])[CH2:26][CH2:25][CH2:24]1)[CH2:21][CH:20]=[CH:19][CH2:18][N:13]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:31])=[O:5]
Reactant: CCCC1(C(O)CC=CCN(CCCCCCC(=O)OCC)S(C)(=O)=O)CCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC1(C(O)CC=CCN(CCCCCCC(=O)O)S(C)(=O)=O)CCC1
Reaction time: 16 h
Yield: 73.5 %

Procedure:
Lithium hydroxide (0.50 mL of a 0.5N solution in H2O, 0.122 mmol) was added to a solution of the ester 11 (45 mg, 0.122 mmol) in THF (1.0 mL) at 23° C. The reaction mixture was stirred for 16 h, acidified with 1 N HCl and extracted with EtOAc. The organic portion was washed with brine (2×), dried (MgSO4), filtered and concentrated in vacuo. FCC (silica gel, 100% EtOAc) gave 36.2 mg (72%) of the free acid 12 as a light yellow, viscous oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[CH:20][CH:19]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:3].C(O)(=O)C.C(O)C>[Pd].[H][H]>[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][CH:8]([C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:3]
Reactant: CN(C)CCCOC(CCCc1ccccc1)c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CN(C)CCCOC(CCCc1ccccc1)c1ccc(O)cc1

Procedure:
A mixture of 1.5 g of 1-[3-(N,N-dimethylamino)propoxy]-1-(p-benzyloxyphenyl)-4-phenylbutane obtained in Example 6, 0.5 g of 10% palladium on charcoal (50% wet reagent), 1 g of acetic acid and 50 ml of ethanol was vigorously stirred in hydrogen atmosphere at room temperature until the theoretical amount of hydrogen was consumed. The reaction mixture was poured into water, made alkaline with aqueous ammonium hydroxide and extracted. After the catalyst was filtered off, the organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-[3-(N,N-dimethylamino)propoxy]-1-(p-hydroxyphenyl)-4-phenylbutane. M.P., 91.5°-94.5° C. (oxalate).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[C:12]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH3:39])[CH:31]=2)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21](F)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1.Cl.Cl.[CH3:42][N:43]([CH3:48])[CH:44]1[CH2:47][NH:46][CH2:45]1>CC(N(C)C)=O.CO>[Cl:10][C:11]1[C:12]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH3:39])[CH:31]=2)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([N:46]3[CH2:47][CH:44]([N:43]([CH3:48])[CH3:42])[CH2:45]3)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1
Reactant: CN(C)C1CNC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Agent: Cl
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Temperature: 100 °C
Yield: 100 %

Procedure:
DIPEA (0.408 mL, 2.33 mmol) was added to a mixture of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine. 0.8 toluene-4-sulfonic acid salt (Intermediate 87, 330 mg, 0.58 mmol) in DMA (3 mL). N,N-Dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 121 mg, 0.70 mmol) was then added in one portion. The mixture was heated in a microwave at 100° C. for 0.5 h then the mixture was cooled and diluted with CH3OH and absorbed onto an SCX column. The column was washed with CH3OH and eluted with 1:1 methanolic ammonia in CH2Cl2. Appropriate fractions were concentrated in vacuo. Further purification by FCC, eluting with 1-10% CH3OH in CH2Cl2 gave the title compound (295 mg, 100%) as a brown gum; 1H NMR: (CDCl3) 2.18 (6H, s), 3.13-3.24 (1H, m), 3.67-3.75 (2H, m), 3.89 (3H, s), 3.96 (3H, s), 4.13 (2H, t), 6.04 (1H, s), 7.21-7.29 (1H, m, partially obscured by chloroform signal), 7.29-7.41 (3H, m), 8.22 (1H, s), 8.37 (1H, s), 8.46 (1H, d), 9.05 (1H, s); m/z: ES+ MH+ 508.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][NH:9][C:8](=[O:13])[C:7]=2[CH:14]=1.[H-].[Na+].[CH3:17]N(C=O)C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][N:9]([CH3:17])[C:8](=[O:13])[C:7]=2[CH:14]=1
Reactant: CN(C)C=O
Reactant: COc1ccc2c(c1)C(=O)NCCC2
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(c1)C(=O)N(C)CCC2
Reaction time: 0.17 h

Procedure:
A mixture of 8-Methoxy-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (283 mgs, 1.48 mmol) in DMF (5 mL) was treated with NaH (60% dispersion in mineral oil, 75 mgs, 1.85 mmol) and stirred for 10 min. The mixture was quenched with water and extracted with ether. The organic layers were washed with brine and the organic layer dried (MgSO4), filtered and concentrated to give 8-Methoxy-2-methyl-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (227 mgs). 1H-NMR (CDCl3) δ 7.14 (d, J=2.7 Hz, 1H), 6.96 (d, J=8.1 Hz, 1H), 6.83-6.81 (m, 1H), 3.74 (s, 3H), 3.14 (t, J=6.6 Hz, 2H), 3.10 (s, 3H), 2.64 (t, J=8.1 Hz, 2H), 1.97-1.91 (m, 2H); LC/MS (ESI+): 273 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7]([OH:36])(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[Sn]>>[C:7]([O:1][CH2:2][CH:3]([CH2:5][OH:6])[O:4][C:7](=[O:36])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])(=[O:36])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: OCC(O)CO
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Sn]
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCCCCCCCCCCCCCCCCCCCCC
Temperature: 210 °C

Procedure:
A three-necked flask equipped with a stirrer, thermometer and descending Liebig condenser was charged with 19 g glycerol (0.207 mole), 165 g montanic acid (0.413 mole; Hoechst-Wachs S) and 0.4 g tin powder. The mixture was heated with stirring to 210° C. with application of a gentle vacuum which was increased to 20 mbar over a period of 1.5 h. Thereafter, the acid value had fallen to approximately 1. The mixture was cooled to 100° C., bleached and filtered. A pale yellow hard wax having a dropping point of 79° C. was obtained.
Reaction SMILES: [H-].[Na+].[N:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[C:5]([NH:12][C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])[CH:4]=1.I[CH2:19][CH3:20].CCOC(C)=O>C1COCC1.[NH4+].[Cl-].O>[CH2:19]([N:12]([C:5]1[CH:4]=[N:3][N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=12)[C:13]([CH:15]1[CH2:16][CH2:17]1)=[O:14])[CH3:20]
Reactant: O=C(Nc1cnn2ccccc12)C1CC1
Reactant: CCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(C(=O)C1CC1)c1cnn2ccccc12
Reaction time: 0.25 h
Yield: 69.5 %

Procedure:
To a suspension of NaH (0.23 g, 60% in mineral oil, 5.74 mmol) in THF (15.0 mL) was added a solution of N-pyrazolo[1,5-a]pyridin-3-ylcyclopropanecarboxamide (0.77 g, 3.83 mmol) in THF (5.0 mL) at room temperature, After 15 min, iodoethane (0.52 mL, 6.5 mmol) was added. The resulting mixture was stirred for 16 h and diluted with NH4Cl solution. EtOAc and H2O were added and separated. The aqueous layer was extracted with EtOAc (2×). The combined EtOAc solution was concentrated in vacuo to dryness and the residue was subjected to column chromatography (E:H=1:4). The product was recrystalized from EtOAc/hexane to give 0.61 g (70%) of colorless solid as the title compound: mp 83–86° C.; 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J=7.0 Hz, 1H), 7.95 (s, 1H), 7.47 (d, J=8.9 Hz, 1H), 7.26–7.21 (m, 1H), 6.87 (t, J=5.9 Hz, 1H), 3.77 (q, J=7.2 Hz, 2H), 1.40–1.33 (m, 1H), 1.12 (t, J=7.1 Hz, 3H), 1.00–0.96 (m, 2H), 0.59–0.53 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 174.4, 139.6, 136.7, 129.0, 124.7, 115.9, 114.8, 112.7, 44.4, 31.6, 13.5, 11.9, 8.2; IR (diffuse reflectance) 2970, 1639, 1476, 1444, 1417, 1375, 1340, 1261, 1221, 1111, 1084, 941, 881, 773, 762 cm−1; MS (EI) m/z 229 (M+), 230, 229, 161, 160, 146, 133, 118, 105, 78, 69; Anal. Calcd for C13H15N3O: C, 68.10; H, 6.59; N, 18.33. Found: C, 68.02; H, 6.64; N, 18.28.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:28]=[C:29]([CH:34]=[CH:35][N:36]=2)[C:30]([O:32][CH3:33])=[O:31])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.ClC1C=C(C=CN=1)C(OC)=O>>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[CH:28]=[C:29]([CH:34]=[CH:35][N:36]=3)[C:30]([O:32][CH3:33])=[O:31])=[CH:25][N:26]=2)=[O:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccnc(-c2cnc(C(CCCCCCc3ccccc3)O[Si](C)(C)C(C)(C)C)o2)c1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: COC(=O)c1ccnc(Cl)c1
Product: COC(=O)c1ccnc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)c1
Yield: 71 %

Procedure:
Methyl 2-(2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)isonicotinate. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (130 mg, 0.196 mmol) and methyl 2-chloroisonicotinate following General Procedure A. Flash chromatography (10% EtOAc/hexanes) yielded the title compound as a thick oil (72 mg, 71%): 1H NMR (CDCl3, 400 MHz) δ 8.77 (d, 1H, J=5.0 Hz), 8.20 (s, 1H), 7.77 (dd, 1H, J=5.0, 1.5 Hz), 7.70 (s, 1H), 7.28-7.24 (m, 2H), 7.18-7.15 (m, 3H), 4.88 (dd, 1H, J=7.0, 5.9 Hz), 4.00 (s, 3H), 2.60 (t, 2H, J=7.8 Hz), 1.95 (m, 2H), 1.61 (m, 2H), 1.36 (m, 4H), 0.92 (s, 9H), 0.11 (s, 3H), 0.02 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 166.2, 165.2, 150.7, 150.1, 148.4, 142.7, 138.3, 128.3, 128.2, 126.0, 125.5, 121.8, 118.3, 68.7, 52.8, 36.4, 35.9, 31.4, 29.1, 25.7, 25.7, 25.1, 18.2, −5.0, −5.1.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:14][CH:15]2[O:19][CH2:18][CH2:17][O:16]2)[CH:12]=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10].C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.ClCCl>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:14][CH:15]2[O:16][CH2:17][CH2:18][O:19]2)[CH2:12][OH:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: O=CC(CC1OCCO1)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCO
Product: OCC(CC1OCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.3 %

Procedure:
Sodium borohydride (5 g) was added in two portions, over 40 minutes, to an ice-cooled solution of 2-(3,4-dichlorophenyl)-3-(1,3-dioxolan-2-yl)propan-1-al (53.5 g) (see Preparation 14) in ethanol (300 ml). The mixture was stirred for a further 30 minutes before removing the solvent under reduced pressure to give a residue. This was suspended in water (200 ml), cooled to 0° C. and the mixture acidified (pH<6) with glacial acetic acid. Dichloromethane was added and the aqueous phase basified (pH>8) by addition of solid sodium carbonate. A further amount of dichloromethane (200 ml) was added and the organic and aqueous phases separated. The aqueous phase was further extracted with dichloromethane (200 ml). The organic phases were combined, washed with brine, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give 2-(3,4-dichlorophenyl)-3-(1,3-dioxolan-2-yl)propan-1-ol (54.6 g) as a yellow oil.