Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]([N+:13]([O-])=O)([CH2:11][OH:12])[CH2:9][OH:10])[CH:7]=1>CC(O)=O.[Zn]>[NH2:13][C:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:16])([CH2:9][OH:10])[CH2:11][OH:12]
Reactant: O=[N+]([O-])C(CO)(CO)c1cc(Br)ccc1F
Agent: [Zn]
Solvent: CC(=O)O
Product: NC(CO)(CO)c1cc(Br)ccc1F
Reaction time: 1 h

Procedure:
A solution of 2-(5-bromo-2-fluoro-phenyl)-2-nitro-propane-1,3-diol (7 g, 23.8 mmol) in 35 ml AcOH was added dropwise to a mixture of zinc (9.34 g, 143 mmol) in 35 ml AcOH while the temperature did not rise above 40° C. The mixture was stirred for 1 h, filtered over celite and washed with MeOH. The filtrate was evaporated, diluted with water and washed with TBME. The aqueous layer was basified with 2 N NaOH and NH3 (25%, aqueous), saturated with NaCl and extracted with EtOAc. The organic layer was washed with brine, dried with Na2SO4 and evaporated to provide the title compound as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.Cl.Cl.[C:20]1([CH3:32])[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:29]2[CH2:30][CH2:31][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:32])[CH2:27][CH2:28]2)[N:3]=1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Reactant: Cc1ccccc1N1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccccc1N1CCN(c2nc(NCCO)nc(NCCO)c2C#N)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-(o-tolyl)-piperazine dihydrochloride in dioxane in the presence of N-ethyl-diisopropylamine at 80° C. to yield 2,4-bis-(2-hydroxy-ethylamino)-6-(4-o-tolyl-piperazin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, light brown solid; MS: [M+H]+=398.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:74][N:75]1[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]1>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([N:78]4[CH2:79][CH2:80][N:75]([CH3:74])[CH2:76][CH2:77]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CN1CCNCC1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(C(=O)COc2cccc(-c3nc(Nc4ccc5[nH]ncc5c4)c4ccccc4n3)c2)CC1
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (100 mg, 0.24 mmol), PyBOP® (125 mg, 0.24 mmol), DIEA (125 μL, 0.24 mmol) in CH2Cl2 (5 mL) stirred at RT for 10-15 minutes. To this solution of activated acid was added 1-methylpiperazine (27 μL, 0.24 mmol) and the reaction mixture was stirred at RT for 1.5 h. Concentrated in vacuo and the crude product was purified using prep HPLC (method 10-35—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone. (32 mg, 0.065 mmol, 27%)
Reaction SMILES: [NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[O:7])=[C:4]([OH:17])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH:27]([CH3:31])[C:28](=[O:30])[CH3:29]>CN(C=O)C>[NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[O:7])=[C:4]([O:17][CH:27]([CH3:31])[C:28](=[O:30])[CH3:29])[CH:3]=1
Reactant: CN(C)CCNC(=O)c1cc(Cl)c(N)cc1O
Reactant: CC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)C(C)Oc1cc(N)c(Cl)cc1C(=O)NCCN(C)C
Yield: 76.6 %

Procedure:
A solution of 4-amino-5-chloro-N-[2-(dimethylamino)ethyl]-2-hydroxybenzamide (1.90 g, 7.37 mmoles) (prepared in Example 17), potassium carbonate (3.06 g, 2.21 mmoles), sodium iodide (1.11 g, 7.37 mmoles) and 91% 3-bromo-2-butanone (1.81 g, 12 mmoles) in DMF (30 ml) was stirred for 1.5 hours. The solvent was removed in vacuo and the residue partitioned between water and methylene chloride. The aqueous phase was extracted two more times with methylene chloride. The combined extracts were dried and concentrated in vacuo. The residue was chromatographed on a silica gel column using the solvent system of methylene chloride (99.5)-methanol (0.5)-ammonia (0.2). The appropriate fractions were combined and concentrated in vacuo to give a solid. This was recrystallized from acetonitrile to give 1.85 g of the title compound as a colorless solid, mp. 124°-125°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:11]([CH2:18][C:19](OC(C)(C)C)=[O:20])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O.[NH2:33][C:34]1[N:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][N:43]([C:46](=[O:48])[CH3:47])[CH2:42][CH2:41]2)=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl>[C:46]([N:43]1[CH2:42][CH2:41][N:40]([C:37]2[CH:36]=[CH:35][C:34]([NH:33][C:19](=[O:20])[CH2:18][C:11]3[CH:12]=[C:13]([C:14]([F:16])([F:17])[F:15])[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[N:9][CH:10]=3)=[N:39][CH:38]=2)[CH2:45][CH2:44]1)(=[O:48])[CH3:47]
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: Cc1cc(-c2ncc(CC(=O)OC(C)(C)C)cc2C(F)(F)F)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(-c4ccnc(C)c4)c(C(F)(F)F)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of tert-butyl 2-(2′-methyl-3-(trifluoromethyl)-2,4′-bipyridin-5-yl)acetate 189-4 (230 mg, 0.65 mmol) and TFA (1 mL) in DCM (5 mL) was stirred at room temperature for 5 hours. The solvents were evaporated to dryness under high vacuum. The crude product, 2-(2′-methyl-3-(trifluoromethyl)-2,4′-bipyridin-5-yl)acetic acid 189-5, was dissolved in DMF (4 mL). 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone (173 mg, 0.78 mmol) and DIEA (910 uL, 5.22 mmol) were added to the solution before O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (372 mg, 0.98 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(2′-methyl-3-(trifluoromethyl)-2,4′-bipyridin-5-yl)acetamide 189. MS m/z 499.2 (M+1); 1H NMR 400 MHz (MeOD) δ 8.78 (s, 1H), 8.48 (d, 1H), 8.26 (s, 1H), 7.99 (s, 1H), 7.88 (d, 1H), 7.42-7.36 (m, 2H), 7.31 (d, 1H), 3.92 (s, 2H), 3.69 (t, 2H), 3.65 (t, 2H), 3.16 (t, 2H), 3.11 (t, 2H), 2.57 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH:14]=[C:13]([NH2:17])[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2].[CH2:21]=[C:22]1O[C:24](=[O:25])[CH2:23]1.C1(C=CC(O)=CC=1)O>ClC(Cl)C>[C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:24](=[O:25])[CH:23]=[C:22]([CH3:21])[NH:17][C:13]=2[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)cc(N)n(C)c1=O
Reactant: C=C1CC(=O)O1
Agent: Oc1ccc(O)cc1
Solvent: CC(Cl)Cl
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(=O)cc(C)[nH]c2n(C)c1=O
Temperature: 25 °C
Yield: 39.2 %

Procedure:
A solution of (R)-3-(5-acetoxyhexyl)-6-amino-1-methyluracil (3.0 g, 10.6 mmol), diketene (1.2 ml, 15.9 mmol), hydroquinone (50 mg, 0.45 mmol) and dichloroethane (100 ml) was heated at reflux for 36 hours. After cooling to room temperature, the solution was washed with water, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with 20% ethyl acetate-toluene followed by 50% ethyl acetate-toluene) to provide (R)-3-(5-acetoxyhexyl)-1,7-dimethylpyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (1.45 g, 39% yield) followed by (R)-3-(5-acetoxyhexyl)-1,5-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione (1.26 g, 34% yield). 1H NMR (300 MHz, CDCl3) δ 1.17 (d, 3H), 1.28-1.67 (m, 6H), 1.99 (s, 3H), 2.67 (s, 3H), 3.59 (s, 3H), 3.95 (t, 2H), 4.85 (sextet, 1H), 6.23 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 19.65, 21.16, 22.58, 22.74, 27.31, 29.87, 35.25, 41.34, 70.88,100.16, 109.56, 150.05, 150.49, 156.07,160.41, 164.03,171.07.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=O)C.[CH3:28][N:29]([CH3:38])[CH2:30][CH2:31][N:32]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33]1>C(Cl)Cl.CO>[CH3:28][N:29]([CH3:38])[CH2:30][CH2:31][N:32]1[CH:36]=[CH:35][C:34]([NH:37][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=3[F:22])=[CH:14][CH:15]=2)=[O:3])=[CH:33]1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: CN(C)CCn1ccc(N)c1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccn(CCN(C)C)c3)c3nccnc23)c1F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), 1-(2-dimethylamino-ethyl)-1H-pyrrol-3-ylamine (Step 121.1) and stirring the reaction mixture for 14 h at rt. Title compound: ESI-MS: 482.1 [M+H]+; tR=3.66 min (System 1); TLC: Rf=0.21 (DCM/MeOH, 9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[C:9]([CH3:31])=[N:8]2)=[C:4]([C:34]([F:37])([F:36])[F:35])[CH:3]=1.[CH:38](=O)[CH3:39]>>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][N:26]([CH2:38][CH3:39])[CH2:25][C@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[C:9]([CH3:31])=[N:8]2)=[C:4]([C:34]([F:37])([F:36])[F:35])[CH:3]=1
Reactant: Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(/C=C3\SC(=O)N([C@@H]4CCNC[C@H]4F)C3=O)cc12
Reactant: CC=O
Product: CCN1CC[C@@H](N2C(=O)S/C(=C\c3ccc4c(c3)c(C)nn4Cc3ccc(Cl)cc3C(F)(F)F)C2=O)[C@H](F)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-yl}methylidene)-3-[(trans)-1-ethyl-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-yl}methylidene)-3-[(trans)-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione (Example 333) and acetaldehyde following General Procedure R2.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([NH2:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([NH:13][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cc1cc(N)c2ncccc2c1Cl
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccccc2)c2ncccc2c1Cl
Yield: 39.8 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5-chloro-6-methylquinolin-8-amine (Intermediate 51) (160 mg, 0.83 mmol), benzenesulfonyl chloride (175 mg, 0.99 mmol) and DMAP (cat.) gave the title compound (110 mg, 40%) after purification by column chromatography with n-hexane/EtOAc (1:1), followed by DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[C:19]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[O:10])[S:6][CH:7]=1.O=C1C2C(=CC=CC=2)C(=O)[N:28]1[CH2:37][CH2:38][S:39](Cl)(=[O:41])=[O:40].NN>>[CH:21]1([C:19]([C:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=2[NH:11][C:9](=[O:10])[NH:8][C:5]2[S:6][CH:7]=[C:3]([CH2:2][NH:1][S:39]([CH2:38][CH2:37][NH2:28])(=[O:41])=[O:40])[N:4]=2)=[O:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Reactant: Cc1ccc(NC(=O)Nc2nc(CN)cs2)c(C(=O)C2CCCC2)c1
Agent: NN
Product: Cc1ccc(NC(=O)Nc2nc(CNS(=O)(=O)CCN)cs2)c(C(=O)C2CCCC2)c1
Yield: 89.3 %

Procedure:
2-Amino-ethanesulfonic acid {2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl}-amide (104 mg, 83%) was prepared from 1-(4-aminomethyl-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (90 mg, 0.25 mmol) and 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (70 mg, 0.25 mmol) following the general procedure T. This intermediate was deprotected by heating with excess of hydrazine (0.2 mL, 1.0 M. in THF).
Reaction SMILES: [CH:1]1[C:2]2[N:3]([CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:5][N:6]=1.[Li+].[CH3:11][CH:12]([N-]C(C)C)C.ICC.O>O1CCCC1>[CH2:11]([C:4]1[N:3]2[CH:7]=[CH:8][CH:9]=[C:2]2[CH:1]=[N:6][CH:5]=1)[CH3:12]
Reactant: c1cc2cnccn2c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Solvent: O
Product: CCc1cncc2cccn12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1.0 g of pyrrolo[1,2-a]pyrazine prepared in Preparation Example 1 was dissolved in 10 ml of tetrahydrofuran and then cooled to -78° C. under nitrogen atmosphere. To this solution was added 1.2 equivalents of LDA solution; the resulting mixture was stirred for 30 minutes; and 1 ml of iodoethane was added to the mixture while maintaining the temperature of -78° C. The reaction mixture was stirred for 30 minutes, warmed to room temperature and then poured into water. The organic layer was isolated and then concentrated to dryness to obtain 0.3 g of title compound.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].B(O)(O)O.C1(C)C(C)=CC=CC=1.C([O:25][C:26](=[O:35])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])C>C(OCC)(=O)C.O>[CH:1]([N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:32](=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:26]([OH:35])=[O:25])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCCCCC(=O)O
Reactant: CC(C)Nc1ccccc1
Agent: OB(O)O
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CC(C)N(C(=O)CCCCCC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A dried, 200 mL, 3-necked, round-bottomed flask was equipped with a Teflon-coated magnetic bar and a vacuum jacketed Dean-Stark trap which was topped with a reflux condenser fitted with a Nitrogen inlet. The reaction vessel was charged with N-isopropyl-N-phenylamine (8.11 g, 60 mmol), boric acid (0.93 g, 15 mmol,), and xylene (88 mL). To the stirred reaction mixture was added 7-ethoxy-7-oxoheptanoic acid (11.29 g, 60 mmol) in one portion. The reaction was heated to reflux using a heating mantle. The azeotroped water began to separate and was collected in the Dean-Stark trap. After 16 hours of reflux, water was collected, and the reaction was allowed to cool to ambient temperature reaction. The reaction mixture was diluted with ethyl acetate (100 mL), and was washed with an aqueous 2N solution of HCl (50 mL), and followed with a saturated solution of sodium bicarbonate (60 mL). The majority of the organic solvent was removed in vacuum. To residue was added a 2 N aqueous solution of sodium hydroxide (60 mL). The mixture was heated at 60° C. for 4 hours. Upon cooling to room temperature, the mixture was washed 60 mL of ethyl acetate. After being carefully separated from the organic layer, the aqueous phase was subjected to evaporation to remove any residual ethyl acetate. Ice was added to the aqueous solution, followed by an aqueous solution of HCl (2N, 60 mL) leading to the precipitation of a white solid. Stirring was continued for an additional 30 minutes before the precipitate was collected with a sintered funnel. The collected white solid was successfully washed with water and hexane before it was in vacuo at room temperature for 12 h to afford 7.49 g (45%) of 7-[isopropyl(phenyl)amino]-7-oxoheptanoic acid as a white solid. HPLC: single peak at 4.83 min.; Mp: 62-63° C. 1H NMR (DMSO-d6,) δ: 0.95-0.97 (d, 6H), 1.08-1.10 (m, 2H), 1.34-1.40 (m, 4H), 1.76-1.79 (m, 2H), 2.09-2.13 (m, 2H), 4.81-4.85 (m, 1H), 7.18-7.20 (m, 2H), 7.44-7.46 (m, 3H). Mass (M+1): 278. Anal. Calc'd for C16H23NO3: C, 69.29; H, 8.36; N5.05. Found: C, 69.06; H, 8.45; N, 4.99.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]([O:17][CH3:18])=[O:16].[BH4-].[Na+]>CO>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH:3]1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a cold (0° C.) solution of 1-tert-butyl 3-methyl 4-oxo-1,3-piperidinedicarboxylate (134.0 g, 520.8 mmol) in methanol (800 mL) was added NaBH4 (9.85 g, 260.4 mmol) portionwise. The resulting mixture was stirred overnight to be allowed to warm to room temperature. The solvent was removed under reduced pressure, the residue was dissolved into ethyl acetate, washed with brine, dried over MgSO4, filterd, and concentrated under reduced pressure to give 1-tert-butyl 3-methyl 4-hydroxy-1,3-piperidinedicarboxylate, which was used for the next reaction without further purification. (120.8 g, yield 90%)
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([C:2]2[C:11]([CH2:12][OH:13])=[CH:10][C:9]3[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1cccc2cc(CO)c(Cl)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2nc3c(C)cccc3cc2CO)c1
Temperature: 150 °C
Yield: 75.5 %

Procedure:
To a solution of (2-chloro-8-methylquinolin-3-yl)methanol (300 mg, 1.45 mmol) in 1,4-dioxane/water (4 mL/1 mL) was added 3-methoxyphenylboronic acid (261 mg, 1.74 mmol), K2CO3 (400 mg, 2.9 mmol) and Pd(PPh3)4 (167 mg, 0.145 mmol). The mixture was degassed and heated in a microwave at 150° C. for 1 h. The solvent was removed in vacuo and the residue dissolved in DCM (50 mL) and washed with water (2×10 mL). The organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo. Purification by column chromatography (SiO2, 10-20% EtOAc in Petrol 40-60) yielded the title compound (306 mg, 76%) as a colourless gum. δH (CDCl3) 8.25 (s, 1H), 7.66 (d, J 8.2 Hz, 1H), 7.54 (d, J 7.1 Hz, 1H), 7.32-7.45 (m, 2H), 7.21-7.26 (m, 2H), 6.96-7.00 (m, 1H), 4.79 (s, 2H), 3.85 (s, 3H), 2.81 (s, 3H), 2.06 (s, 1H). LCMS (ES+) 280 (M+H)+, RT 3.03 minutes (Method 5).
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][C@@H:15]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:17]([CH2:18][CH2:19][C@@H:20]3[C@@H:29]2[C:28](=[O:34])[CH2:27][C@@:25]2([CH3:26])[C@H:21]3[CH2:22][CH2:23][C@@H:24]2[C:35]([O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[O:36])[CH2:16]1>CC(C)=O.C(Cl)(Cl)Cl>[O:44]1[CH2:43][CH2:42][N:41]([CH2:40][CH2:39][CH2:38][O:37][C:35]([C@H:24]2[CH2:23][CH2:22][C@H:21]3[C@H:20]4[C@H:29]([C:28](=[O:34])[CH2:27][C@:25]23[CH3:26])[C@:30]2([CH3:33])[C@H:17]([CH2:16][C:15](=[O:14])[CH2:32][CH2:31]2)[CH2:18][CH2:19]4)=[O:36])[CH2:46][CH2:45]1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)OCCCN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)OCCCN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12
Reaction time: 0.33 h

Procedure:
Jones reagent (0.4 ml.) was added to a solution of 3α-hydroxy-17β(3'-morpholinopropoxycarbonyl)-5α-androstan-11-one (325 mg.) in acetone (5 ml.). After stirring (20 min.) the reaction mixture was diluted with chloroform and washed with aqueous 10% sodium bicarbonate and water. The chloroform solution was dried, filtered and evaporated to give a gum (238 mg.) which, after purification by preparative thick layer chromatography, afforded the pure title compound; νmax.CHBr3 1703 (-C=O) and 1720 cm-1 (-COOR), (-OH absent).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:27][C:28]1([C:33]2([CH:36]=O)[CH2:35][CH2:34]2)[O:32][CH2:31][CH2:30][O:29]1>>[CH:36]([C:33]1([C:28]2([CH3:27])[O:29][CH2:30][CH2:31][O:32]2)[CH2:34][CH2:35]1)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C2(C=O)CC2)OCCO1
Agent: [Br-]
Product: CCCCCC=CC1(C2(C)OCCO2)CC1

Procedure:
1.93 g of hexyltriphenylphosphonium bromide and 900 mg of aldehyde 7 are reacted analogously to 193., and 879 mg of title substance 203 is obtained as a colorless oil (1:3 E,Z mixture that cannot be separated).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]3[NH:13][C:14](=[O:19])[O:15][C:16]([CH3:18])([CH3:17])[C:11]=3[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[S:22]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23]1>O>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]3[NH:13][C:14](=[O:19])[O:15][C:16]([CH3:18])([CH3:17])[C:11]=3[CH:10]=2)[CH:3]=[C:2]([C:24]2[CH:25]=[CH:26][S:22][CH:23]=2)[CH:7]=1
Reactant: OB(O)c1ccsc1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(Br)c3)cc21
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(-c4ccsc4)c3)cc21

Procedure:
Prepared from 6-(3-bromo-5-fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 3-thiophene boronic acid according to procedure B. A brownish-orange solid: mp 200-203° C.; 1H-NMR (CDCl3) δ8.62 (s, 1H), 7.53 (q, 1H, J=1.4 Hz), 7.50 (d, 1H, J=1.5 Hz), 7.49 (d, 1H, J=2.0 Hz), 7.45-7.40 (m, 1H), 7.35 (d, 1H, J=1.8 Hz), 7.27-7.24 (m, 2H), 7.15 (dt, 1H, J=5.8, 2.0 Hz), 6.94 (d, 1H, J=8.2 Hz), 1.80 (s, 6H); MS ((−)APCI) [M−H]− @ m/z 352. Anal. Calc. For C20H16FNO2S.0.50 H2O: C, 66.28, H, 4.73, N, 3.87. Found: C, 66.54, H, 5.03, N 3.52.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#[N:7].CO.[H][H]>[Pd]>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=1)[CH2:6][NH2:7]
Reactant: [H][H]
Reactant: N#Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 87 %

Procedure:
At first, a 1-liter autoclave equipped with a mechanical stirrer was charged with 50 g (0.21 mol) of 3,5-bis(trifluoromethyl)benzonitrile, 200 ml of 2M-ammoniacal methanol solution (containing 400 mmol of ammonia), and 3 g of a catalyst (i.e., a carbon powder (50% wet) carrying thereon 5% palladium), followed by introduction of hydrogen to have a pressure of 1 MPa. Then, the reaction mixture was stirred, while the reaction temperature was maintained at 20° C. and while hydrogen was gradually introduced into the autoclave in a manner to maintain the total pressure at 1 MPa. After conducting the reaction for 5.3 hr, the reaction was stopped, followed by removing the catalyst by filtration. As a result of analyzing the obtained reaction liquid by gas chromatography, 3,5-bis(trifluoromethyl)benzylamine was formed at a yield of 87.0%.