Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@H:4]1[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)OC(=O)[NH:5]1)([CH3:3])[CH3:2].[H][H]>CO.CC(O)=O.[Pd]>[NH2:5][C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: CC(C)[C@@H]1NC(=O)OC1(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)[C@H](N)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
A solution of (S)-4-isopropyl-5,5-diphenyl-2-oxazolidinone (3) (2.9 g, 10.31 mmol) in MeOH/AcOH and a 10% Pd (435 mg, 4.09 mmol) on activated carbon was shaken for 68 h under 4–5 atm pressure of hydrogen at room temperature. The catalyst was filtered off over Hyflo Super Cell and organic solvents were evaporated under reduced pressure. The resulting residue was treated with HCl (2.0 M, 50 ml), stirred for 2 h at room temperature, made basic with NaOH pellets, and saturated with K2CO3 and NaCl. Organic compounds were then extracted into AcOEt (3×100 ml), dried over MgSO4/K2CO3 and concentrated under reduced pressure to obtain a crude product. Re-crystallisation from petroleum ether gave the title compound (4) (1.79 g, 72%) as a light-brown solid. m.p. 71–72° C. [α]D25=−4.19° (c, 0.1097 in CHCl3). δH 0.78 (3H, d, 3J=6.60 Hz, CH3), 0.91 (3H, d, 3J=7.20 Hz, CH3), 1.26 (2H, broad s, NH2), 1.62 (1H, ds, CHMe2), 3.45 (1H, dd, 3J=10.5 and 2.40 Hz, CH—NH2), 3.70 (1H, d, 3J=10.5 Hz, CH—Ph2), 7.00–7.40 (10H, m, Ar—H). δC 14.2 and 21.5 (CH3), 28.9 (CH—Me2), 58.1 and 58.9 (CH—NH2 and CH—Ph2), 126.5, 126.7, 128.2, 128.5, 128.8 and 129.0 (o-, m- and p-Ar), 143.5 (2×α-Ar). Anal. Calcld for C17H21N: C 85.30; H 8.84; N 5.85. Found: C 85.12; H 8.91; N 5.96. ir 3361 (NH2). m/e (CI—CH4) 240 (MH+, 8%), 72 (100%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=O)=[CH:7][C:6]=1[F:20].[C:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=O)[CH2:22][CH3:23]>>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][CH3:23])=[CH:7][C:6]=1[F:20]
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCBr)c(F)c1
Reactant: CCC(=O)c1ccccc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCBr)c(F)c1)c1ccccc1
Yield: 99.6 %

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, (4-(2-bromoethoxy)-3-fluorophenyl)(4-hydroxyphenyl)methanone (311 mg, 0.917 mmol) was reacted with propiophenone (246 mg, 1.83 mmol) to give 403 mg desired product (99.6% yield, Z/E=1/1) as a beige solid.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].N([O-])=[O:13].[Na+].C>S(=O)(=O)(O)O.O>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([OH:13])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(O)ccc1Cl
Temperature: 5 °C
Reaction time: 0.75 h
Yield: 78.1 %

Procedure:
5-Amino-2-chlorobenzoic acid (85%, 10 g, 49.7 mmol) was suspended in diluted sulphuric acid (1.25%, 800 mL) and cooled to 5° C. on an ice bath. Sodium nitrite (59,72 mmol) dissolved in water (150 mL) was added slowly while keeping the temperature of the reaction below 5° C. After addition of the sodium nitrite the reaction was stirred for another 45 min at 5-10° C. until a clear solution was obtained. The reaction mixture was poured into hot (70-85° C.) water (1.5 L), charcoal added and the reaction mixture heated at reflux for 25 min. Filtration and extraction with ethyl acetate afforded 6.7 g of the desired product as light brown crystals
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)O)=[N:7][CH:8]=[CH:9][CH:10]=1>C(O)C.[Pd]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:11][C:6]2[C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:18][CH:17]=1
Reactant: COCOc1cccnc1C(O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: COCOc1cccnc1Cc1ccc(N)cc1
Reaction time: 24 h
Yield: 29.5 %

Procedure:
A mixture of (3-methoxymethoxypyridin-2-yl)-(4-nitrophenyl)methanol (11.78 g) and 10% Pd—C (1.2 g) in ethanol (100 ml) was vigorously stirred under hydrogen atmosphere for 24 hours. The catalyst was filtered of, and the filtrate was concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:1→2:1) to give 2-(4-aminobenzyl)-3-methoxymethoxypyridine (2.92 g) as orange oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][NH2:8])[CH:2]=1.[CH2:9]([CH2:11][CH2:12][CH2:13][C:14](CC([O-])=O)=[O:15])[CH3:10]>>[CH2:11]([C:12]1[CH2:13][C:14](=[O:15])[N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=1)[CH2:9][CH3:10]
Reactant: CCCCCC(=O)CC(=O)[O-]
Reactant: NNc1cccnc1
Product: CCCC1=NN(c2cccnc2)C(=O)C1

Procedure:
From the reaction of 3-pyridylhydrazine and ethylbutyrylacetate, 2,4-dihydro-5-propyl-2-(3-pyridyl)-3H-pyrazol-3-one is obtained. Subsequent reaction with 2-ethylaniline yields 4-(2-ethylanilinomethylene)-2,4-dihydro-5-propyl-2-(3-pyridyl)-3H-pyrazo 1-3-one, Mp 143.9° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:3]=1.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[OH:30]>>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[O:30][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:3]=1
Reactant: Oc1ccc(F)cc1F
Reactant: COc1ccc(-c2nnc(Cl)cc2-c2ccncc2)cc1
Product: COc1ccc(-c2nnc(Oc3ccc(F)cc3F)cc2-c2ccncc2)cc1

Procedure:
In a similar manner as in Example 2, 6-chloro-3-(4-methoxyphenyl)-4-(4-pyridyl)pyridazine (150 mg, 0.504 mmol) and 2,4-difluorophenol were reacted as starting materials at 150° C. for 25 hours and post-treatment was then conducted, whereby the title compound was obtained as a pale yellow amorphous solid (157.0 mg, 79.6%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:32])=[CH:27][CH:26]=3)[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:14]([CH3:41])[C:13]=2[CH:42]=1)C1C=CC=CC=1>C(O)C.[Pt]=O>[CH:18]1([CH:17]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:32])=[CH:29][CH:30]=2)[C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:42][C:13]=3[C:14]=2[CH3:41])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(OCc4ccccc4)cc3c2C)C2CCCCC2)cc1
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(O)cc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
Ethyl 3-[{[4-({[5-(benzyloxy)-3-methyl-1-benzofuran-2-yl](cyclohexyl)methyl}amino)phenyl]carbonyl}amino]propanoate (5.6 g) synthesized in Example A158(1) was dissolved in ethanol (100 mL), and platinum oxide (0.50 g) was added to the solution. The reaction mixture was stirred under hydrogen atmosphere (1 atm) at room temperature overnight. The reaction mixture was filtered, and the residue was washed with ethanol. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give the title object compound (3.2 g, 68%) as a yellow oil.
Reaction SMILES: OS(O)(=O)=O.[C:6]1(=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH:8]=[CH:7]1.[N-:18]=[N+]=[N-].[Na+]>>[NH:18]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9](=[O:16])[CH2:8][CH2:7][C:6]1=[O:17]
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C1CCC(=O)c2ccccc2N1
Temperature: 0 °C
Reaction time: 48 h
Yield: 84.9 %

Procedure:
To 10 mL of H2SO4 (97% ) cooled in an ice-bath was added portionwise 1.08 g (6.86 mmol) of 1,4-naphthoquinone and it was stirred to become a solution. To the red solution was added portionwise 0.454 g (6.98 mmol) of NaN3. The mixture was stirred in ice bath for 2 h, then at room temperature for 2 days. It was added dropwise into 100 mL of ice-water and stirred for 1 h and allowed to stand overnight. The mixture was filtered and washed thoroughly by water, dried to leave brown solid 1.02 g. 1H NMR (CDCl3 +DMSO-d6) shows it is more than 80% pure. Portion of the solid was crystallized (DMSO/H2O) to give 32 as a brown solid, mp 225°-226° C. 1H NMR (CDCl3 +DMSO-d6) 6.544 (d, 1, J=12.9), 6.657 (d, 1, J=12.9), 6.978 (t, 1, J=7.5), 7.152 (d, 1, J=8.4), 7.323 (t, 1, J=7.5), 7.812 (d, 1, J=8.1), 10.55 (bs, 1).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][CH:12]=O)=O.[NH2:14][C@H:15]([C:21]([OH:23])=[O:22])[CH2:16][CH2:17][C:18](=[O:20])[NH2:19].[BH4-].[Na+]>CO.[OH-].[Na+]>[C:18]([CH2:17][CH2:16][CH:15]([N:14]1[CH2:1][C:3]2[C:4](=[CH:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=2)[N:11]=[CH:12]1)[C:21]([OH:23])=[O:22])(=[O:20])[NH2:19]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: COc1ccc(NC=O)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)CN(C(CCC(N)=O)C(=O)O)C=N2
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 0.79 g of the product from stage 3 in 30 ml of methanol was added to a solution of 0.58 g of L-glutamine in 10 ml of methanol and 2 ml of 2N sodium hydroxide solution. After stirring for 1 hour at 20° C., the mixture was cooled to 0° C. and 0.103 g of sodium borohydride was added in portions within 30 minutes. The mixture was stirred for 12 hours at 0° C., then adjusted to pH 2 to 3, and stirred for a further 4 hours at 20° C. After neutralizing the solution with sodium hydroxide, the methanol was distilled off. The aqueous residue was washed twice with 15 ml of diethyl ether each time, and then concentrated by evaporation in vacuo. The residue was taken up in 25 ml of methanol and freed from insoluble constituents by filtration. The residue obtained by evaporating the filtrate in vacuo was directly reacted further as described in stage 5, without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=2)=[CH:4][CH:3]=1.CN(C(O[N:33]1N=N[C:35]2C=CC=[CH:39][C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.NC1CCOCC1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:33][CH:34]([CH3:39])[CH3:35])=[O:22])=[CH:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Agent: F[B-](F)(F)F
Agent: NC1CCOCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)nnn2C)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a solution of 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (94 mg, 0.29 mmol) and TBTU (101 mg, 0.32 mmol) in DMF (1.5 mL) was added DIPEA (245 μL, 1.43 mmol). Then 4-aminotetrahydropyran (56 mg, 0.55 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (82 mg, 70%) as a white solid after recrystallisation from methanol/water. MS: m/e=412.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][CH2:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1)[CH3:2].I[CH:18]([CH3:20])[CH3:19].[H-].[Na+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:15]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][N:12]2[CH:18]([CH3:20])[CH3:19])=[CH:8][CH:7]=1)[CH3:16]
Reactant: CCN(CC)CCc1ccc2cc[nH]c2c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCN(CC)CCc1ccc2ccn(C(C)C)c2c1

Procedure:
Prepared from 6-(2-(Diethylamino)ethyl)-indole (14 mg, 0.0647 mmol), 2-iodopropane (44 μl, 0.259 mmol), NaH (3.1 mg, 0.129 mmol), K2CO3 (35 mg, 0.259 mmol) in 0.1 ml of DMF and 0.5 ml of toluene, according to example. Yield 8.5 mg (51%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[Cl:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:16]=1[CH2:17][S:18][CH2:19][CH2:20][NH2:21]>>[Cl:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:16]=1[CH2:17][S:18][CH2:19][CH2:20][NH:21][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13]
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: NCCSCc1c(F)cccc1Cl
Product: O=C(NCCSCc1c(F)cccc1Cl)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-(2-chloro-6-fluorobenzylsulfanyl)ethylamine. The product was purified by mass directed purification to give the title compound as a yellow solid. δH (CD3OD): 2.82 (2H, t), 3.64 (2H, t), 3.95 (2H, s), 7.04-7.09 (2H, m), 7.20-7.25 (2H, m), 7.67 (1H, s), 8.58 (1H, s); m/z (ES+)=398 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30](Br)=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:40]([N:42]([CH2:59][CH3:60])[CH2:43][CH2:44][N:45]1[CH:49]=[C:48](B2OC(C)(C)C(C)(C)O2)[CH:47]=[N:46]1)[CH3:41]>>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30]([C:48]4[CH:47]=[N:46][N:45]([CH2:44][CH2:43][N:42]([CH2:59][CH3:60])[CH2:40][CH3:41])[CH:49]=4)=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCN(CC)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCN(CC)CC)c4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure of Example 97 using diethyl[4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate and N,N-diethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethanamine (Compound 175A). MS (ES+): m/z 715.47 (100) [MH+]; HPLC: tR=0.75 min (UPLC, purity).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=3)[C:10]([C:18]([OH:20])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[C:27]([OH:31])([C:29]#[CH:30])[CH3:28]>C(N(CC)CC)C.C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:30]#[C:29][C:27]([OH:31])([C:22]4[N:23]=[CH:24][CH:25]=[CH:26][N:21]=4)[CH3:28])[CH:15]=3)[C:10]([C:18]([OH:20])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: C#CC(C)(O)c1ncccn1
Reactant: Nc1nccc(-n2nc(C(=O)O)c3ccc(I)cc32)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(O)(C#Cc1ccc2c(C(=O)O)nn(-c3ccnc(N)n3)c2c1)c1ncccn1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a pressure tube containing 1-(2-aminopyrimidin-4-yl)-6-iodoindazole-3-carboxylic acid (550 mg, 1.44 mmol), copper(I) iodide (27.48 mg, 0.14 mmol), bis(triphenylphosphine)palladium(II) chloride (101.29 mg, 0.14 mmol) in triethylamine (4 mL) and THF (4 mL), was added 2-(pyrimidin-2-yl)but-3-yn-2-ol (427.62 mg, 2.89 mmol). The reaction was sealed and stirred at 55° C. for 1 hr. The reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography (Biotage, 5-10% methanol in DCM followed by 10-20% [7M NH3 in methanol] in DCM) to give the title intermediate as an orange/brown oil: 1H NMR (250 MHz, DMSO) delta 1.92 (3H, s), 6.27 (1H, s), 6.98 (3H, s), 7.09 (1H, d, J=5.5 Hz), 7.26 (1H, d, J=9.5 Hz), 7.50 (1H, t, J=4.9 Hz), 8.20-8.41 (3H, m), 8.73-9.02 (2H, m); LC-MS: m/z=+402.00 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[S:7].[H][H]>C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH:6]=[S:7]
Reactant: [H][H]
Reactant: FC(F)(F)c1cccc(C(=S)Cl)c1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc(C=S)c1
Reaction time: 24 h
Yield: 73.9 %

Procedure:
A solution of 56.9 g (237 mmols) of 3-trifluoromethyl-thiobenzoic acid chloride in 285 ml of anhydrous toluene and 5.7 g of 5 percent strength palladium on barium sulphate is introduced into a one liter three-necked flask equipped with a condenser, a mechanical stirrer and a gas bubbler tube. This mixture is heated, with stirring, for 12 hours at the reflex temperature, while a gentle stream of hydrogen is bubbled through it. The catalyst is filtered off and washed with diethyl ether. 125 ml of a solution of sodium bisulphite (d=1.33) are added to the filtrate. This mixture is stirred vigorously for 24 hours and the bisulphite compound is filtered off, washed with diethyl ether and introduced into a three-necked flask. A solution of 80 g of potassium carbonate in 500 ml of water is added and the mixture is boiled, so as to steam distil the aldehyde as it is formed. The distillate is extracted twice in succession with diethyl ether. The combined ether phases are dried over sodium sulphate and filtered. The solvent is evaporated in vacuo on a water bath and the residue is rectified. 33.3 g (67% yield) of 3-trifluoromethylthio-benzaldehyde, as an oil, b.p. 108°-111° C./30-38 mm.Hg, are thus obtained.
Reaction SMILES: [F:1][C:2]([F:58])([F:57])[C:3]1[CH:4]=[C:5]([CH:50]=[C:51]([C:53]([F:56])([F:55])[F:54])[CH:52]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:43][CH2:44][O:45][C:46](C)(C)[CH3:47])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.C(=O)(O)[O-:60].[Na+]>Cl.C(OCC)(=O)C>[C:46]([O:45][CH2:44][CH2:43][N:31]([C:22]1[CH:23]=[CH:24][C:25]([C:27]([F:29])([F:30])[F:28])=[CH:26][C:21]=1[CH2:20][N:7]([CH2:6][C:5]1[CH:50]=[C:51]([C:53]([F:55])([F:54])[F:56])[CH:52]=[C:3]([C:2]([F:58])([F:1])[F:57])[CH:4]=1)[C:8]1[N:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:12][N:13]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])(=[O:60])[CH3:47]
Reactant: O=C([O-])O
Reactant: CCOC(=O)CCCCCCN(CCOC(C)(C)C)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCCN(CCOC(C)=O)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-(2-tert-butoxy-ethyl)-amino]-heptanoate (which is prepared by treating the corresponding starting compound in a same manner as in Example 12(1)-(4)) (260 mg) is dissolved in a 4N-hydrochloric acid in ethyl acetate (4 ml) and the mixture is stirred at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→3:2) to give ethyl 7-[(2-acetoxy-ethyl)-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-amino]-heptanoate (162 mg). MS (m/z): 822 [M+H]+
Reaction SMILES: [ClH:1].[C:2]1([CH2:12][CH2:13][C:14]2[N:15]=[C:16]([CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[S:17][CH:18]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1>C(OCC)C>[ClH:1].[C:2]1([CH2:12][CH2:13][C:14]2[N:15]=[C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[S:17][CH:18]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(CCc3cccc4ccccc34)cs2)CC1
Agent: Cl
Solvent: CCOCC
Product: c1ccc2c(CCc3csc(C4CCNCC4)n3)cccc2c1
Temperature: 0 °C

Procedure:
Under argon and at 0° C., a solution of hydrogen chloride in diethyl ether (2 M, 25 ml) is added to tert-butyl 4-{4-[2-(naphthalen-1-yl)ethyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (IV-2, 1.40 g). The mixture is stirred at 0° C. and then slowly warmed to room temperature. The mixture is stirred overnight, and the excess acid and solvent are then removed under reduced pressure. This gives 4-{4-[2-(naphthalen-1-yl)ethyl]-1,3-thiazol-2-yl}piperidine hydrochloride (1.28 g).
Reaction SMILES: [N:1]1([CH2:10][CH2:11][OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[N:1]1([CH2:10][CH2:11][O:12][C:14]2[CH:46]=[CH:45][C:17]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]3=[O:44])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1
Reactant: OCCn1ccc2cccnc21
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: O=C1SC(Cc2ccc(OCCn3ccc4cccnc43)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 79.5 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 1.77 g of 2-(7-azaindol-1-yl)ethanol (prepared as described in Preparation 18), 4.40 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 2.35 ml of tributylphosphine, 2.39 g of 1,1'-(azodicarbonyl)dipiperidine and 45 ml of anhydrous benzene were used, to give 4.58 g of the title compound, melting at 167.5-168.9° C.