Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:34][CH3:35])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH:21][C:22]2[N:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:24][N:23]=2)[CH:9]=1)([CH3:3])[CH3:2].[F:36][C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40]Br.[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[F:36][C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=1)[CH2:40][N:21]([CH2:20][C:11]1[CH:12]=[C:13]([C:16]([F:17])([F:19])[F:18])[CH:14]=[CH:15][C:10]=1[C:8]1[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[O:34][CH3:35])[C:22]1[N:27]=[CH:26][C:25]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[CH:24][N:23]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNc1ncc(N2CCOCC2)cn1
Reactant: Fc1cc(CBr)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
(5′-Isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (500 mg) is dissolved in N,N-dimethylformamide (3 ml), and thereto is added 3-fluoro-5-(trifluoromethyl)benzylbromide (528 mg) and thereto is added sodium hydride (60%) (82 mg) under ice-cooling, and the mixture is stirred at room temperature for 2 hours and a half. To the reaction solution are added a saturated brine, and the mixture is extracted with ethyl acetate. 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=49:1→22:3) to give (3-fluoro-5-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (440 mg). MS (m/z): 663 [M+H]+
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][C@@H:22]([N:24]1[C:28]([CH3:29])=[CH:27][CH:26]=[C:25]1[CH3:30])[CH3:23].C(Br)(Br)(Br)[Br:32]>C(#N)C>[Br:32][CH2:21][C@@H:22]([N:24]1[C:28]([CH3:29])=[CH:27][CH:26]=[C:25]1[CH3:30])[CH3:23]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccc(C)n1[C@@H](C)CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Cc1ccc(C)n1[C@@H](C)CBr
Temperature: 0 °C
Reaction time: 18 h
Yield: 86.3 %

Procedure:
Triphenylphosphine (2.24 g, 8.50 mmol) was added in four portions over 10 minutes to an ice cooled mixture of (S)-1-(2-hydroxy-1-methylethyl)-2,5-dimethylpyrrole (1.0 g, 6.54 mmol) and carbon tetrabromide (3.03 g, 9.15 mmol) in 50 mL of acetonitrile. The mixture was stirred at 0° C. for 1.5 h, room temperature for 18 h, and 50° C. for 6 h. The solvent was removed in vacuo. The residue was purified by flash column chromatography on 70 g of silica gel, eluting with 1 L of 15% dichloromethane in hexane to give 1.22 g (85% yield) of (S)-1-(2-bromo-1-methylethyl)-2,5-dimethylpyrrole as a yellow liquid.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10]1(CO)[CH2:15]CCC[CH2:11]1>[Sn]=O.C(O)(C)C>[CH:10]([C:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:15])[CH3:11]
Reactant: O=C(O)C1CCCCC1
Reactant: OCC1CCCCC1
Agent: O=[Sn]
Solvent: CC(C)O
Product: CC(C)C1(C(=O)O)CCCCC1

Procedure:
The reaction between cyclohexane carboxylic acid and isopropanol was conducted under the same conditions as in Example 1, except that 1 g of hydrous tin oxide catalyst prepared in Example C was used in place of 2 g of the hydrous zirconium oxide catalyst used in Example 1. It was discovered by gas chromatography that cyclohexyl methanol was formed at a conversion rate of 95% and selectivity of 39%. Isopropyl cyclohexane carboxylic acid was also obtained as a by-product in an amount of 41%.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[CH3:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.[OH-].[Na+]>>[CH3:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][S:10]([C:3]4[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=4[F:1])(=[O:12])=[O:11])[CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1F
Reactant: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Product: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)c4ccc(F)c(F)c4F)cc23)CC1
Yield: 105.8 %

Procedure:
By a method similar to Example 31, using 2,3,4-trifluorobenzenesulfonyl chloride (280 mg, 1.2 mmol) and 3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (231 mg, 1.0 mmol) and 0.2 N sodium hydroxide (5.5 mL, 1.1 mmol) gave 449 mg of a purple foam. The crude product was purified by radial chromatography (silica gel, 2000 micron rotor, 100/10 methylene chloride/methanol then 100/10/0.5 methylene chloride/methanol/ammonium hydroxide) to give 418 mg (98%) of homogeneous product. The product was crystallized from ethyl acetate/hexanes to give 280 mg of the title compound as a white powder: mp=160-162° C.; MS(m/e): 424 (M+); Calculated for C20H19F3N2O3S: C, 56.60; H, 4.51; N, 6.60. Found: C, 56.53; H, 4.78; N, 6.51.
Reaction SMILES: [OH:1][CH:2]1[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:3]1[NH:12][C:13]([CH3:15])=[O:14].[C:16]([O-:21])(=[O:20])[C:17]([CH3:19])=[O:18]>>[OH:1][CH:2]1[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:3]1[NH:12][C:13]([CH3:15])=[O:14].[OH:20][C:16]([C:17]1([O:5][C@@H:4]([C@@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:7])[C@H:3]([NH:12][C:13]([CH3:15])=[O:14])[C@@H:2]([OH:1])[CH2:19]1)[OH:18])=[O:21]
Reactant: CC(=O)C(=O)[O-]
Agent: CC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Product: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)O)C[C@@H]1O

Procedure:
The second reaction was run with the recovered enzyme under the same conditions with exceptions in the amounts of substrates (40 mmol of ManNAc and 400 mmol of pyruvate) and the volume of solution (260 mL). The 10-day operation gave 91% conversion of ManNAc to Neu5Ac. The recovered enzyme retained 50% of its initial activity, and the products in solution were stored at -10° C. until further purified. The excess pyruvate was removed three step procedure. Fifty-two mL portions of the solution were passed through a 2.5×40 cm column of Dowex 50W-X8 (hydrogen form) with water elution. The portion of the eluent which contained the product was lyophilized to a paste. The paste was slurried in ethyl acetate and the Neu5Ac product recovered by filtration. The collected white powder was dried under a stream of dry air to yield 2.7 g of Neu5Ac as a mono-hydrate. The 1H-NMR spectrum of the product so obtained was identical to the reported spectrum. Brown, E. B., Brey, W. S.,Jr., Weltner, W.,Jr. Biochem. Biophys. Acta 399 (1975) 124-30.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][O:64][CH2:65][C@H:66]1[CH2:70][CH2:69][CH2:68][NH:67]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:67]1[CH2:68][CH2:69][CH2:70][C@@H:66]1[CH2:65][O:64][CH3:63])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: COC[C@H]1CCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC[C@H]1CCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (2R)-2-methoxymethyl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C([NH:32][CH:33]2[C:46](=[O:47])[N:35]3[CH:36]([C:41]4[NH:45][N:44]=[N:43][N:42]=4)[C:37]([CH3:40])([CH3:39])[S:38][C@H:34]23)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].[C:50]1([CH2:56][C:57](Cl)=[O:58])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>O.CC(C)=O>[C:50]1([CH2:56][C:57]([NH:32][CH:33]2[C:46](=[O:47])[N:35]3[CH:36]([C:41]4[NH:42][N:43]=[N:44][N:45]=4)[C:37]([CH3:39])([CH3:40])[S:38][C@H:34]23)=[O:58])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1c1nnn[nH]1
Temperature: 25 °C

Procedure:
A mixture of p-toluenesulfonic acid monohydrate (788 mg., 4.14 mmoles), acetone (35 ml.) and 6-triphenylmethylamino-2,2-dimethyl-3-(5-tetrazoly)penam (2.0g., 4.14 mmole) is stirred for twenty minutes at room temperature and is then diluted with water (100 ml.) and ispropylether (100 ml.). The biphasic mixture is stirred vigorously and adjusted to pH 7 with 2N sodium hydroxide. Phenylacetyl chloride (700 mg., 4.55 mmole freshly distilled) is added and the reaction mixture maintained at pH 5.5-6.5 by addition of 2N sodium hydroxide as necessary. Reaction is continued until the pH levels off at 6.5. The two phases are separated and the aqueous phase is washed with ether (2 × 50 ml.). Chloroform (100 ml.) is added and the pH is adjusted to 2 by addition of 6N HCl. The mixture is stirred, the phases separated and the aqueous phase extracted with chloroform (2 × 50 ml.). The chloroform phases are combined, dried (Na2SO 4), and then concentrated under reduced pressure to about 50 ml. volume. A 1:1 solution of ether-hexane is added dropwise with vigorous stirring until precipitation of the product is complete. The white precipitate is filtered and air-dried. The yield is 850 mg. (57.4%), m.p. 168°-170°. NMR (DMSO-d6): 7.30 (s, 5H), 5.80-5.42 (m, 2H), 5.28 (s, 1H), 3.60 (s, 2H), 1.68 (s, 3H) and 1.10 ppm (s, 3H).
Reaction SMILES: N12CCCN=C1CCCCC2.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([OH:43])([C:39]([F:42])([F:41])[F:40])[C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[O:20])=[CH:15][C:14]=1[Cl:44].[C:45]([Si:49]([CH3:52])([CH3:51])Cl)([CH3:48])([CH3:47])[CH3:46]>ClCCl>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([O:43][Si:49]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:52])[CH3:51])([C:35]([F:36])([F:37])[F:38])[C:39]([F:41])([F:42])[F:40])=[CH:30][CH:29]=3)[CH2:25][CH2:26]2)=[O:20])=[CH:15][C:14]=1[Cl:44]
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](C)(C)OC(c1ccc(CN2CCN(C(=O)c3ccc(N)c(Cl)c3)CC2)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.5 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (4.22 mmol, 0.631 mL, 0.643 g) was added to a cooled (ice/slurry) solution of (4-amino-3-chlorophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (3.25 mmol, 1.61 g) and tert-butyldimethylchlorosilane (4.22 mmol, 0.636 g) in dichloromethane (20 mL) under nitrogen. The resulting solution was stirred for 15 minutes prior to the removal of the external cooling bath. The reaction was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was diluted with dichloromethane (100 ml) and washed with 0.5M hydrochloric acid (100 ml), 0.5M sodium hydroxide (100 ml) and brine (100 ml). The organic phase was dried on magnesium sulfate, filtered and concentrated under vacuum to give a crude oil. This oil was purified by SCX chromatography to afford the title compound (1.616 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18](=[O:29])[C@H:19]([N:26]([CH3:28])[CH3:27])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[C:30]([O:34][C:35]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([S:44][C:45]2[CH:53]=[CH:52][C:48]([C:49](O)=[O:50])=[CH:47][C:46]=2[NH:54][C:55]2[C:56]3[CH:64]=[CH:63][C:62]([CH:65]([CH3:67])[CH3:66])=[N:61][C:57]=3[N:58]=[CH:59][N:60]=2)=[CH:40][CH:39]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[CH3:28][N:26]([CH3:27])[C@H:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:18]([N:14]1[CH2:15][CH2:16][CH2:17][C@H:13]1[C:10]1[NH:11][CH:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:49]([C:48]3[CH:52]=[CH:53][C:45]([S:44][C:41]4[CH:40]=[CH:39][C:38]([NH:37][C:35](=[O:36])[O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:43][CH:42]=4)=[C:46]([NH:54][C:55]4[C:56]5[CH:64]=[CH:63][C:62]([CH:65]([CH3:67])[CH3:66])=[N:61][C:57]=5[N:58]=[CH:59][N:60]=4)[CH:47]=3)=[O:50])=[CH:3][CH:4]=2)[N:9]=1)=[O:29]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: CN(C)[C@@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(N)cc2)c[nH]1)c1ccccc1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(-c5c[nH]c([C@@H]6CCCN6C(=O)[C@@H](c6ccccc6)N(C)C)n5)cc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 55.4 %

Procedure:
A solution of the Product of Example 2C (0.081 g, 0.21 mmol) and the product from Example 1E (0.10 g, 0.188 mmol) was processed in the same manner as in Example 1K to give a solid (0.094 g, 55%).
Reaction SMILES: F[B-](F)(F)F.N1([O+]=C(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[C:24]1[C:32]1[C:33]([NH2:49])=[N:34][CH:35]=[C:36]([C:38]2[CH:39]=[N:40][N:41]([CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)[CH:42]=2)[CH:37]=1.[CH3:50][N:51]([CH3:56])[CH2:52][C:53](O)=[O:54].CN1CCOCC1>CN1C(=O)CCC1>[NH2:49][C:33]1[N:34]=[CH:35][C:36]([C:38]2[CH:39]=[N:40][N:41]([CH:43]3[CH2:44][CH2:45][N:46]([C:53](=[O:54])[CH2:52][N:51]([CH3:56])[CH3:50])[CH2:47][CH2:48]3)[CH:42]=2)=[CH:37][C:32]=1[C:24]1[O:23][C:31]2[C:26]([N:25]=1)=[N:27][CH:28]=[CH:29][CH:30]=2
Reactant: CN(C)CC(=O)O
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ncccc2o1
Agent: CN(C)C(=[O+]n1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CN(C)CC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ncccc5o4)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
Benzotriazol-1-yl-[bis(dimethylamino)methylene]oxonium tetrafluoroborate (96 mg) was added to a stirred suspension of 3-oxazolo[4,5-b]pyridin-2-yl-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (90 mg), 2-dimethylaminoacetic acid (27.0 mg) and 4-methylmorpholine (0.055 ml) in NMP (1 ml) at 25° C. The resulting solution was stirred at 25° C. for 2 hours. The reaction mixture was purified by preparative HPLC using a Waters OBD reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness, the solid was taken up in dichloromethane, dried over Magnesium sulphate, filtered and concentrated. A precipitate appeared which was diluted with diethyl ether, the solid was collected by filtration, washed with petroleum ether then triturated several hours with acetonitrile, filtered and dried under vacuum at 50° C. overnight to afford 1-[4-[4-(6-amino-5-oxazolo[4,5-b]pyridin-2-yl-3-pyridyl)pyrazol-1-yl]-1-piperidyl]-2-dimethylamino-ethanone (50.0 mg) as a solid. NMR Spectrum: (DMSOd6) 1.74-1.85 (m, 1H), 1.86-1.97 (m, 1H), 2.05-2.15 (m, 2H), 2.21 (s, 6H), 2.72-2.83 (m, 1H), 3.01-3.10 (m, 1H), 3.12-3.23 (m, 2H), 4.14-4.25 (m, 1H), 4.39-4.52 (m, 2H), 7.48 (dd, 1H), 7.68 (bs, 2H), 7.95 (s, 1H), 8.23 (dd, 1H), 8.36 (s, 1H), 8.47 (d, 1H), 8.56 (dd, 1H), 8.59 (d, 1H); Mass spectrum: M+H+ 447;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].C(N(CC)CC)C>C1COCC1>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[O:11])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: COc1ccc(N=C=O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.3 %

Procedure:
4-Methoxyphenyl isocyanate (0.4 g, 2.6 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol) and triethylamine (0.3 g, 2.8 mmol) in THF (30 mL) at 5-10° C. After 10 minutes, the mixture was stirred at room temperature overnight. The reaction was quenched with methanol (1 mL), and the mixture was concentrated. The residue was stirred with 1N HCl (30 mL) for one hour and then filtered. The solid was slurried with hot ethanol (20 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-(4-methoxy-phenyl)-urea (0.5 g, 59%) as a white solid: mp 205-207° C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H), 2.49-2.65 (m, 2H), 2.84-2.97 (m, 1H), 3.68 (s, 3H, OCH3), 4.70 (d, J=5.7 Hz, 2H, CH2), 5.13-5.20 (dd, J=5.2 and 12.4 Hz, 1H, CH), 6.66 (t, J=5.7 Hz, 1H, NH), 6.79 (d, J=9.0 Hz, 2H, Ar), 7.27 (d, J=9.0 Hz, 2H, Ar), 7.75-7.88 (m, 3H, Ar), 8.59 (a, 1H, NH), 11.65 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.94, 48.86, 55.10, 113.86, 119.50, 121.82, 127.15, 131.59, 133.38, 133.62, 134.70, 140.46, 154.03, 155.45, 167.02, 167.60, 169.84, 172.22; Anal. calcd. for C22H20N4O6: C, 60.55; H, 4.62; N, 12.84. Found: C, 60.43; H, 4.42; N, 12.58.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]([F:26])([F:25])[C:8]1[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=1[CH2:10][CH:11]1[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][NH:12]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:26][C:7]([F:25])([F:6])[C:8]1[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=1[CH2:10][CH:11]1[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][N:12]1[C:2]([O:4][CH3:5])=[O:3]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(Cc2ccccc2C(F)(F)F)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 108.5 %

Procedure:
Methyl chloroformate (1.399 mL, 18.07 mmol) in DCM (40 mL) was added to a solution of methyl 2-(2-(trifluoromethyl)benzyl)piperidine-4-carboxylate (4.19 g, 13.9 mmol) and DIPEA (7.28 mL, 41.69 mmol) in DCM (60 mL). The reaction mixture was stirred for 1.5 h at room temperature, then washed with satd NaHCO3. The phases were separated and the organic phase dried using a phase separator to give crude dimethyl 2-(2-(trifluoromethyl)-benzyl)piperidine-1,4-dicarboxylate (5.42 g, 109%). MS m/z 360 (M+H)+
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][N:36]4C(OC(C)(C)C)=O)=[O:34])[CH2:29][CH2:28]3)[CH:25]=2)[CH:20]=[N:19]1)[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][NH:36]4)=[O:34])[CH2:31][CH2:32]3)[CH:25]=2)[CH:20]=[N:19]1)[CH3:17]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(N3CCN(C(=O)[C@H]4CCCN4C(=O)OC(C)(C)C)CC3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(N3CCN(C(=O)[C@H]4CCCN4)CC3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of (R)-t-butyl 2-(4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-indazol-6-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.052 g, 0.088 mmol) in dichloromethane (2 mL) and the resulting solution was stirred at room temperature for 30 min. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (10 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 30% methanol in dichloromethane) to give the title compound as a white solid (0.025 g, 0.052 mmol, 57%). 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1 H), 7.58 (d, J=9.2 Hz, 1 H), 7.38 (d, J=2.0 Hz, 1 H), 7.16-7.09 (m, 2 H), 6.86 (dd, J=2.0, 8.0 Hz, 1 H), 6.64 (s, 1 H), 6.10 (q, J=6.8 Hz, 1 H), 4.35 (dd, J=6.4, 8.4 Hz, 1 H), 3.91-3.85 (m, 1 H), 3.80-3.60 (m, 3 H), 3.31-3.11 (m, 6 H), 2.36-2.28 (m, 1 H), 1.99 (d, J=6.8 Hz, 3 H), 1.87-1.80 (m, 3 H); MS: (ES) m/z calculated for C24H28Cl2N5O [M+H]+472.2, found 472.4.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:4]=1[Cl:11].[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([SH:20])[N:14]=1.C(N(CC)CC)C>C(O)C>[CH3:19][C:17]1[N:16]=[C:15]([S:20][CH2:2][C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([Cl:10])[C:8]=2[Cl:9])[N:14]=[C:13]([NH2:12])[CH:18]=1
Reactant: Clc1ccc(Cl)c(CBr)c1Cl
Reactant: Cc1cc(N)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(N)nc(SCc2c(Cl)ccc(Cl)c2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
In a 100 mL round bottom flask, 2-(bromomethyl)-1,3,4-trichlorobenzene (550 mg, 2.0 mmol), 4-amino-6-methylpyrimidine-2-thiol (282 mg, 2.0 mmol), and triethylamine (0.28 mL, 2.0 mmol) were mixed in ethanol (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated. To the crude solid, water (50 mL) was added. The suspension was filtered and washed with water and ethyl acetate to provide a white solid (530 mg, 95% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.18 (s, 3H), 4.65 (s, 2H), 6.03 (s, 1H), 6.90 (br, 1H), 7.55 (d, 1H), 7.64 (d, 1H); M+ 334, 336.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[OH:5][N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.ClCCl>[CH2:1]([O:5][N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)[C:2]#[CH:3]
Reactant: C#CCBr
Reactant: On1cccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: C#CCOn1cccn1
Reaction time: 12 h
Yield: 68.8 %

Procedure:
21.3 g of propargyl bromide are added to 15 g of 1-hydroxypyrazole and 15 g of sodium carbonate in 200 g of acetonitrile at 25° C., while stirring. Stirring is continued for 12 hours, after which the mixture is filtered under suction, the residue is washed with 100 g of acetonitrile, and the combined liquids are evaporated down in a rotary evaporator at 40° C. and under 20 mbar. The residue obtained in this procedure is dissolved in 200 g of dichloromethane, the solution is extracted 3 times with a total of 200 g of saturated aqueous sodium bicarbonate solution, and the organic phase is dried with magnesium sulfate and evaporated down. 15 g (70% of theory) of 1-pyrazolyl propargyl ether are obtained as an oil (H1 -NMR, δ in ppm: 2.6, t, 1H; 4.9, d, 2H; 6.2, m, 1H; 7.4, m, 2H). This substance is Example 10 in the Table below.