Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([C:25]([NH:27][C@H:28]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:38])[CH3:37])[CH:31]=4)[CH3:29])=[O:26])=[CH:22][CH:23]=3)[C:18]([CH3:39])=[C:17]2[CH3:40])=[CH:11][CH:10]=1)#[N:2].[N:41]([Si](C)(C)C)=[N+:42]=[N-:43].C([Sn](CCCC)=O)CCC>C1(C)C=CC=CC=1>[N:2]1[NH:41][N:42]=[N:43][C:1]=1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([C:25]([NH:27][C@H:28]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:37])[CH3:38])[CH:31]=4)[CH3:29])=[O:26])=[CH:22][CH:23]=3)[C:18]([CH3:39])=[C:17]2[CH3:40])=[CH:13][CH:14]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C#N)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3-c3nn[nH]n3)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12
Temperature: 110 °C

Procedure:
The mixture of (S)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide (0.1 g, 0.19 mmol), azidotrimethylsilane 90.05 mL, 0.38 mmol) and dibutylstannanone (0.005 g, 0.019 mmol) in toluene (3 mL) was heated at 110° C. oil bath for 16 hr. The solvent was removed and the residue was purified by preparative-HPLC to obtain the title compound. ESI-MS (m/z): 569 [M+H]+.
Reaction SMILES: [CH:1](=[N:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[C:8]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19](=[O:28])(=[O:27])[N:18]=2)[C:7]1=[O:29])[CH2:2][CH2:3][CH3:4].CO.[BH4-].[Li+].Cl>O1CCCC1.O>[CH2:1]([NH:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[C:8]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19](=[O:28])(=[O:27])[N:18]=2)[C:7]1=[O:29])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCNn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 249A (0.040 g, 0.097 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.008 mL, 0.194 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.074 mL, 0.148 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (5.0 mL), and the resulting precipitate was collected by filtration and washed with water (2×5.0 ml) and dried. The crude product was triturated with diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.17 Hz, 3 H) 1.48 (m, 4 H) 2.77 (m, 2 H) 5.90 (t, J=6.99 Hz, 1 H) 7.07 (m, 1 H) 7.27 (m, 2 H) 7.58 (m, 3 H) 7.66 (d, J=8.09 Hz, 1 H) 8.08 (dd, J=8.09, 1.47 Hz, 1 H) 16.28 (s, 1 H). MS (ESI−) m/z 411 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:24])[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:15](=[O:17])[CH2:14][C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=3)[S:10][CH:11]=2)[CH2:28][CH2:27]1)[CH3:21]
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Reactant: CCOC(=O)CN1CCNCC1
Product: CCOC(=O)CN1CCN(C(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)CC1

Procedure:
22.1 Using general procedure A, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) was coupled with 1-(ethoxycarbonylmethyl)-piperazine to give (4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetic acid ethyl ester. Off-white solid. MS 473.1 ([M+Na]+)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:13][C:12]=1[CH3:25].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][C:12]=1[CH3:25]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Br
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a stirred solution of tert-butyl 4-[N′-(2-bromophenyl)ureido]-3-methylphenylacetate (1.27 g, 3.03 mmol) in CH2Cl2 (10 ml) was added TFA (5 ml) at room temperature. After 1 h stirring, the mixture was concentrated in vacuo. The residue was triturated by the addition of water, to give 4-[N′-(2bromophenyl)ureido]-3-methylphenylacetic acid (1.05 g, 95%) as a pale yellow powder. mp 245-248° C. (dec.); 1H-NMR (CDCl3) δ2.24 (s, 3H), 3.48 (s, 2H), 6.96 (dt, J=7.3, 1.5 Hz, 1H), 7.02 (d, J=8.3 Hz, 1H), 7.07 (s, 1H), 7.32 (t, J=8.1 Hz, 1H), 7.59-7.66 (m, 2H), 8.44 (s, 1H), 8.62 (s, 1H); MS (ESI), m/z 363 (M++1), 365 (M++3); Anal. Calcd. for C16H15BrN2O3.0.7H2O: C, 51.13; H, 4.40; Br, 21.26; N, 7.45. Found: C, 50.84; H, 4.62; Br, 21.72; N, 7.18.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[S:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: COc1nc2ccccc2nc1NC(=S)Oc1ccccc1
Product: COc1cc(OC)cc(N2CCN(C(=S)Nc3nc4ccccc4nc3OC)CC2)c1
Yield: 64.5 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)thiocarbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 63 to obtain the titled compound.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.C([O-])(=[O:16])C.[Na+].CN(C)C=O>O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][OH:16]
Reactant: CC(=O)[O-]
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCc1ccc2ccccc2n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A mixture of 2-chloromethylquinoline hydrochloride (21.4 g), sodium acetate (32.8 g) and N,N-dimethylformamide (200 ml) was stirred at 60° C. overnight. After cooling, the reaction solution was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. A mixture of the residue, 4N aqueous sodium hydroxide solution (50 ml), tetrahydrofuran (100 ml) and methanol (100 ml) was stirred at room temperature for 1 hour, and poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain 2-quinolylmethanol (14.0 g, yield 88%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 68–69° C.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(Cl)(O[C:19](=[O:25])OC(Cl)(Cl)Cl)Cl.[CH:27]([NH:29][NH2:30])=[O:28]>ClCCl.C(N(CC)CC)C>[CH:27]([NH:29][NH:30][C:19]([NH:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1)=[O:25])=[O:28]
Reactant: NNC=O
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CNNC(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 173.2 %

Procedure:
1-(Phenylmethyl)4-piperidinamine (3 g) in dichloromethane (10 mL) and triethylamine (4.5 mL) were added dropwise to a stirred solution of triphosgene (1.55 g) in dichloromethane (20 mL) at 0° C. under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The mixture was cooled to 0° C. and formyl hydrazine (1.4 g) and triethylamine (4.5 mL) were added. The reaction was stirred at room temperature for 1 hour and then evaporated to dryness. Purification (SiO2, methanol:dichloromethane:ammonium hydroxide solution 5:95:1 as eluant) gave the sub-title compound (2.5 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.[CH3:34][Si:35]([C:38]#[CH:39])([CH3:37])[CH3:36].CCN(CC)CC>CN(C=O)C.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.[Cu]I>[Cl:22][C:18]1[CH:17]=[C:16]2[NH:15][C:14](=[O:23])[C:13]3([CH:12]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[CH2:11][C:10](=[O:31])[NH:9][CH:8]3[C:6]3[CH:7]=[C:2]([C:39]#[C:38][Si:35]([CH3:37])([CH3:36])[CH3:34])[CH:3]=[CH:4][C:5]=3[O:32][CH3:33])[C:21]2=[CH:20][CH:19]=1
Reactant: COc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C#C[Si](C)(C)C)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in example 214e, racemic (2′R,3′R,4′S)-2′-[5-bromo-2-methoxy-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′-dione reacted with PdCl2(PPh3)2, CuI, trimethylsilyl acetylene and Et3N (Aldrich, 0.62 mL) in DMF to give the title compound. MS (H+),
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11]([OH:13])=O)[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7]1)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1>C(#N)C>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11](=[O:13])[NH:35][C:34]2[CH:36]=[CH:37][C:31]([Cl:30])=[CH:32][CH:33]=2)[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7]1)=[O:5])[CH3:2]
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)Nc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Compound 7a (4.91 g; 17.1 mmol) is suspended in acetonitrile (25 ml) and N,N-diisopropyl ethyl amin (3.58 ml; 20.5 mmol) is added at 0° C. Bis(2-oxo-3-oxazolidinyl) phosphinic chloride BOP-Cl (5.22 g; 20.5 mmol) is added as a solid and after stirring for 30 min at 0° C. 4-chloroaniline (2.18 g; 17.1 mmol) is added to the reaction mixture. The mixture is stirred for 2 h at 0° C., evaporated to dryness and dissolved in ethyl acetate (ml). The organic phase is washed with 0.1 N HCl (2×ml), with saturated aquous Na2CO3 solution, water and brine and dried over Na2SO4. The organic phase is filtered and the filtrate is evaporated to dryness. The crude product is purified by silica gel chromatography. Yield: 4.7 g (69.3%), ESI-MS: m/z=395 [M−H]−, Cl-pattern
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[I-].C[S+](C)(C)=O.O=C1C[CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]C1.O>COCCOC>[O:4]1[C:2]2([CH2:5][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:3]2)[CH2:1]1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reaction time: 1 h
Yield: 80.8 %

Procedure:
Potassium t-butoxide (31 g) was added to a stirred suspension of trimethylsulfoxonium iodide (60.8 g) in 1,2-dimethoxyethane (250 ml) at 20° C. After 1 hour, the mixture was added portionwise over 30 minutes to a stirred solution of 4-oxo-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (50 g) in 1,2-dimethoxyethane (50 ml) at 0° C. After a further 2 hours, water (500 ml) was added and the mixture extracted with tert.-butyl methyl ether (2×500 ml). The organic extracts were washed separately with saturated sodium bicarbonate solution (250 ml), combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residual oil was co-evaoprated with toluene (100 ml) to give the sub-title compound (43.25 g, 81%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[C:12](/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)\[C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:21][C:18]1[CH:17]=[CH:16][C:15](/[C:12](/[C:13]#[N:14])=[CH:11]/[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:20][CH:19]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(/C=C(\C#N)c2ccc(O)cc2)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(/C=C(\C#N)c2ccc(OC(C)=O)cc2)cc1OC
Yield: 94 %

Procedure:
Compound 48 (1.41 g) was acetylated with acetic anhydride and pyridine in accordance with a customary method, to thereby produce the target product (1.52 g, yield: 94%).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:15]=[C:16]([CH2:21][C:22]([NH:24][C:25]3[CH:33]=[CH:32][CH:31]=[C:30]4[C:26]=3[CH:27]=[CH:28][N:29]4C(OC(C)(C)C)=O)=[O:23])[NH:17][C:18](=[O:20])[CH:19]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>ClCCl>[NH:29]1[C:30]2[C:26](=[C:25]([NH:24][C:22](=[O:23])[CH2:21][C:16]3[NH:17][C:18](=[O:20])[CH:19]=[C:14]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[N:15]=3)[CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:28]1
Reactant: CC(C)(C)OC(=O)n1ccc2c(NC(=O)Cc3nc(N4CCOCC4)cc(=O)[nH]3)cccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.8 %

Procedure:
0.940 ml of trifluoroacetic acid is added dropwise to a solution of 200 mg of 2-methylpropan-2-yl 4-({[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}amino)-1H-indole-1-carboxylate in 8 ml of dichloromethane. After stirring at ambient temperature for 3 hours, the reaction medium is concentrated under reduced pressure, taken up with toluene and concentrated under reduced pressure. After purification by silica column chromatography, eluent: 90/10 CH2Cl2/MeOH, 48 mg of N-(1H-indol-4-yl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained, the characteristics of which are the following:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[CH:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][C:4]([NH:13][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(Cl)CCCl
Reactant: NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(CCCl)NC1CCCCC1

Procedure:
β-Chloropropionyl chloride (31.7 g.) is added dropwise to a stirred solution of cyclohexylamine (24.8 g.) and triethylamine (28.2 g.) in toluene (250 ml.). The mixture is cooled and filtered and the filtrate is evaporated to dryness under reduced pressure. There is thus obtained as residue β-chloro-N-cyclohexylpropionamide, m.p. 77°-80° C. β-Chloro-N- 2-furfurylpropionamide may similarly be obtained from furfurylamine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([C:17]([OH:19])=O)[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([C:27]([F:29])([F:28])[F:30])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([C:17]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[O:19])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7]
Reactant: CN1CCNCC1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C(=O)O)(c2ccc(Cl)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C(=O)N2CCN(C)CC2)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial was added 50 mg of 1-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carboxylic acid (0.11 mmol, 1.0 equiv), 14 μL of 1-methylpiperazine (0.13 mmol, 1.2 equiv), 60 μL TEA (0.43 mmol, 4.00 equiv), 71 mg BOP (0.16 mmol, 1.5 equiv), and 500 μL NMP. The mixture was stirred overnight at room temperature and the crude product was purified by reversed phase HPLC (acetonitrile—H2O with 0.1% TFA as the eluent) to yield 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-4-(4-methyl-piperazine-1-carbonyl)-piperidin-1-yl]-ethanone: MS (ES) M+H expected=546.4, found=546.1.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])[CH3:3].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O[NH:33][C:34](=[NH:51])[C:35]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:36]=1[CH:37]=[CH:38][N:39]2[CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>CN(C)C=O>[CH3:3][CH:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]2[O:11][N:51]=[C:34]([C:35]3[CH:43]=[CH:42][CH:41]=[C:40]4[C:36]=3[CH:37]=[CH:38][N:39]4[CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[N:33]=2)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])[CH3:1]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: CCOC(=O)CCn1ccc2c(C(=N)NO)cccc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)CCn1ccc2c(-c3noc(-c4ccc(OC(C)C)c(C(F)(F)F)c4)n3)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.7 %

Procedure:
4-[(1-Methylethyl)oxy]-3-(trifluoromethyl)benzoic acid (D71) (136 mg, 0.55 mmol), EDC (116 mg, 0.61 mmol) and HOBt (82 mg, 0.61 mmol) were stirred in N,N-dimethylformamide (5 mL) for 20 min. Ethyl 3-{-4-[(hydroxyamino)(imino)methyl]-1H-indol-1-yl}propanoate (D57) (150 mg, 0.55 mmol) was added and the reaction stirred at room temperature for 3 h and then 80° C. for 18 h. The reaction mixture was partitioned between ethyl acetate (25 mL) and water (25 mL). The organic layer was washed with aqueous sodium bicarbonate (25 mL) and water (25 mL) before it was dried (phase separator), filtered and concentrated in vacuo. The residue was triturated with ethanol to give the title compound (85 mg). δH (d6-DMSO, 400 MHz): 8.44 (1H, dd), 8.35 (1H, d), 7.95 (1H, d), 7.81 (1H, d), 7.62-7.58 (2H, m), 7.36 (1H,app. t), 7.07 (1H, d), 4.99 (1H, septet), 4.54 (2H, t), 4.02 (2H, q), 2.89 (2H, t), 1.36 (6H, d), 1.11 (3H, t). MS (ES+): C26H24F3N3O4 requires 487; found 488 (MH+).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:16]=2[O:17][CH3:18])[C:13]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[N:12][CH:11]=[C:10]3[CH:28]=[O:29])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Se](=O)=[O:31].C(OCC)(=O)C.CCCCCC>C(O)(=O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:16]=2[O:17][CH3:18])[C:13]([C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[N:12][CH:11]=[C:10]3[CH:28]=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cccc(Cc2ncc(C=O)c3cc(OC4CCCC4)c(OC)cc23)c1
Reactant: O=[Se]=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cccc(C(=O)c2ncc(C=O)c3cc(OC4CCCC4)c(OC)cc23)c1
Temperature: 120 °C
Yield: 64.1 %

Procedure:
To a stirred solution of 6-cyclopentyloxy-7-methoxy-1-(3-methoxy-benzyl)-isoquinoline-4-carbaldehyde (300 mg, 0.77 mmol) in acetic acid (7 μL) was added selenium dioxide (255 mg, 2.30 mmol). The reaction mixture was heated at 120° C. for 1 h. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 6-cyclopentyloxy-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carbaldehyde as a yellow solid (200 mg, 64% yield).
Reaction SMILES: S(Cl)(Cl)=O.O1CCN(CC2C=CC(C(Cl)=O)=CC=2)CC1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][CH:27]=[C:26]2[O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1.[O:43]1[CH2:48][CH2:47][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([C:56]([N:58]=[C:59]=[S:60])=[O:57])=[CH:52][CH:51]=2)[CH2:45][CH2:44]1>C1(C)C=CC=CC=1.C(O)C>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][CH:27]=[C:26]2[O:35][C:36]1[CH:42]=[CH:41][C:39]([NH:40][C:59]([NH:58][C:56](=[O:57])[C:53]2[CH:52]=[CH:51][C:50]([CH2:49][N:46]3[CH2:45][CH2:44][O:43][CH2:48][CH2:47]3)=[CH:55][CH:54]=2)=[S:60])=[CH:38][CH:37]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(N=C=S)c1ccc(CN2CCOCC2)cc1
Agent: O=C(Cl)c1ccc(CN2CCOCC2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(CN5CCOCC5)cc4)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
Commercially available 4-bromomethylbenzoic acid (300 mg) was dissolved in acetonitrile (10 ml). Potassium carbonate (30 mg) and morpholine (130 μl) were added to the solution, and the mixture was stirred at room temperature for one hr. The reaction layer was subjected to separation with chloroform and a saturated aqueous sodium hydrogencarbonate solution. The organic layer was then concentrated to give methyl 4-(morpholinomethyl)benzoate. Methanol (1 ml), water (150 μl), and potassium hydroxide (15 mg) were added to the residue, and the mixture was heated at 60° C. for one hr. After the completion of the reaction, the solvent was removed by distillation to give 4-(morpholinomethyl)benzoic acid. Toluene (20 ml) and thionyl chloride (1 ml) were added to the residule, and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 4-(morpholinomethyl)-1-benzenecarbonyl isothiocyanate was prepared using the resultant 4-(morpholinomethyl)-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-(morpholinomethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (74 mg, yield 78%).
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[CH3:24][C:25]([N:29]1[CH2:34][CH2:33][C:32]2[N:35]=[CH:36][S:37][C:31]=2[CH2:30]1)([CH3:28])[CH2:26][OH:27].O>CN(C)C=O.C(OCC)C>[Si:5]([O:27][CH2:26][C:25]([N:29]1[CH2:34][CH2:33][C:32]2[N:35]=[CH:36][S:37][C:31]=2[CH2:30]1)([CH3:24])[CH3:28])([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(CO)N1CCc2ncsc2C1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1CCc2ncsc2C1
Reaction time: 8 h
Yield: 93.5 %

Procedure:
tert-Butylchlorodiphenylsilane (1.93 g) and imidazole (994 mg) were added to a solution of 5-(1,1-dimethyl-2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine (1.24 g) in N,N-dimethylformamide (5 ml) at room temperature, and the mixture was stirred overnight. Water and diethyl ether were added to the reaction mixture to separate an organic layer. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to obtain the title compound (2.46 g) as a colorless oil.