Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:24]=[CH:23]2.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:30]([C:25]2[CH:24]=[CH:23][C:22]3[C:27](=[CH:28][CH:29]=[C:20]([Cl:19])[CH:21]=3)[CH:26]=2)(=[O:31])=[O:32])[CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 63 h

Procedure:
In dichloromethane (18 ml), 1-tert-butoxycarbonyl-3-ethoxycarbonylpiperazine (517 mg) and 6-chloro-2-naphthylsulfonyl chloride (588 mg) were dissolved under ice cooling. To the resulting solution, diisopropylethylamine (0.59 ml) was added, followed by stirring at room temperature for 63 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (hexane:ethyl acetate=3:1), whereby the title compound (688 mg, 71%) was obtained.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:49][CH:50]=[CH2:51])[CH2:13][C:14]([NH:16][C@@H:17]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44]C(C)(C)C)=[CH:40][CH:39]=1)[C:18]([N:20]([CH2:29][CH:30](OCC)OCC)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[N:23]=1)=[O:19])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)=O>[CH2:1]([NH:8][C:9]([N:11]1[C@H:30]2[CH2:29][N:20]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[N:23]=3)[C:18](=[O:19])[C@H:17]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([OH:44])=[CH:42][CH:43]=3)[N:16]2[C:14](=[O:15])[CH2:13][N:12]1[CH2:49][CH:50]=[CH2:51])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCN(CC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc(F)n1)CC(OCC)OCC)NC(=O)NCc1ccccc1
Solvent: O=CO
Product: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3)C(=O)N(Cc3cccc(F)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
A mixed solution of (2S)-2-(2-(((benzylcarbamoyl)amino)(prop-2-en-1-yl)amino)acetamido)-3-(4-(tert-butoxy)phenyl)-N-(2,2-diethoxyethyl)-N-((6-fluoropyridin-2-yl)methyl)propanamide (1.22 g, 1.73 mmol) described in Production Example 2-3 and formic acid (26 mL) was stirred at 70° C. for 3 hours. The reaction mixture was concentrated under a reduced pressure, water was added to the residue, and the resultant solution was extracted with ethyl acetate. An organic layer was washed with water and then with saturated brine, then dried over anhydrous magnesium sulfate, and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1) to give the title compound (865 mg, yield: 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[C:18](F)=[CH:19][C:20]([F:33])=[C:21]([CH:32]=1)[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)=[O:23]>CS(C)=O.C(OCC)(=O)C>[Cl:16][C:17]1[C:18]([O:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[CH:19][C:20]([F:33])=[C:21]([CH:32]=1)[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)=[O:23]
Reactant: Cc1ccc(OC(=O)c2cc(Cl)c(F)cc2F)cc1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(OC(=O)c2cc(Cl)c(Oc3ccc(Cl)c(Cl)c3)cc2F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100.3 %

Procedure:
3,4-Dichlorophenol (110 mg, 0.67 mmol) and potassium carbonate (20 mg, 1.42 mmol) were stirred in dimethylsulfoxide (20 mL). After 5 minutes, 4-methylphenyl 5-chloro-2,4-difluorobenzoate (Preparation 10, 200 mg, 0.71 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with a 1M aqueous solution of sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo to give a white solid. The solid was purified by silica gel column chromatography (50% ethyl acetate in heptane elution) to afford the title compound as a white solid (286 mg, 95%).
Reaction SMILES: C([N:8]1[C:15]2[CH:14]3[CH2:16][CH:13]3[CH2:12][C:11]=2[C:10]([C:17]2[N:18]=[N:19][NH:20][N:21]=2)=[N:9]1)C1C=CC=CC=1.CC([O-])(C)C.[K+]>C1COCC1.CS(C)=O>[N:21]1[NH:20][N:19]=[N:18][C:17]=1[C:10]1[NH:9][N:8]=[C:15]2[C:11]=1[CH2:12][C@H:13]1[CH2:16][C@H:14]12
Reactant: c1ccc(Cn2nc(-c3nn[nH]n3)c3c2C2CC2C3)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: C1c2c(n[nH]c2-c2nn[nH]n2)[C@@H]2C[C@H]12

Procedure:
Air was bubbled through a stirring solution of 2-benzyl-4-(2H-tetrazol-5-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene (10.4 g, 37.4 mmol) and KOt-Bu (374 mL of a 1M solution in THF, 374 mmol) in DMSO (300 mL) for 20 h at rt. The remaining THF was removed in vacuo and the reaction was acidified to pH=2 by the addition of HCl (3M aq). The mixture was concentrated in vacuo to near dryness. The residue was dissolved in HCl (1N aq., 250 mL) and extracted with EtOAc (5×250 mL). The organics were dried over MgSO4, filtered, and concentrated. The product was purified and converted to the ammonium salt by loading material (as a solution in MeOH) on to a column containing Bondesil SCX SPE resin (˜250 g). The column was flushed with MeOH (200 mL) to remove unbound impurities. The product was eluted using 2N NH3/MeOH (approx. 200 mL). Concentration of the basic eluant yielded the ammonium salt of Compound 4 as a white solid. 1H NMR (400 MHz, MeOD): δ 3.02 (1H, dd, J=16.4, 6.0 Hz), 2.90 (1H, d, J=16.0 Hz), 2.19 (2H, m), 1.17 (1H, m), 0.33 (1H, m). HPLC/MS: Discovery® C18 column (5 μ, 50×2.1 mm), 5% v/v CH3CN (containing 1% v/v TFA) in H2O (containing 1% v/v TFA) gradient to 99% v/v CH3CN in H2O, 0.75 mL/min, tr=1.21 min, ESI+=189.0 (M+H). [α]25D+35.7 (c 0.39, MeOH).
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:6]=1[CH3:25])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([Li])[CH2:27]CC.IC>O1CCCC1>[C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N:16]([CH2:26][CH3:27])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:6]=1[CH3:25])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(Nc2cc3c(c(C(C)(C)C)c2C)OCC3(C)C)cc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCN(c1ccc(OC)cc1)c1cc2c(c(C(C)(C)C)c1C)OCC2(C)C
Yield: 92 %

Procedure:
Following general procedure L and using 7-t-butyl-5-[(4-methoxy-phenyl)-amino]-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 53), (0.12 g, 0.35 mmol), 1.6M solution of n-butyllithium in hexanes (0.442 mL, 0.7 mmol) and iodomethane (0.281 mL, 3.5 mmol) in 2 mL of anhydrous tetrahydrofuran, the title compound (0.11 9 g, 92%) was obtained as a brown oil. 1H NMR (300 MHz, CDCl3): δ 6.76 (d, 2H, J=9.0 Hz), 6.72 (s, 1H), 6.41 (d, 2H, J=9.0 Hz), 4.14 (s, 2H), 3.73 (s, 3H), 2.60 (s, 3H), 1.52 (s, 9H), 1.26 (s, 6H), 1.20 (t, 3H, J=7.1 Hz).
Reaction SMILES: NC[C:3](O)=[O:4].[NH2:6][CH:7]([CH:11]([OH:16])[CH2:12][CH2:13][CH2:14][OH:15])[C:8]([OH:10])=[O:9]>>[NH2:6][CH:7]([CH:11]([OH:16])[CH2:12][CH2:13][CH2:14][O:15][CH:3]=[O:4])[C:8]([OH:10])=[O:9]
Reactant: NC(C(=O)O)C(O)CCCO
Reactant: NCC(=O)O
Product: NC(C(=O)O)C(O)CCCOC=O
Reaction time: 0.5 h

Procedure:
From the first aliquot taken at 0.5 h, two new amino aids were noted upon amino acid analysis. A small peak appeared at 15.6 min, just after the glycine peak. The other was a large, sharp peak at 22.5 minutes. By three hours, the peak at 22.5 minutes, corresponding to the expected amino acid reached a maximum at about 10% of the glycine peak and then slowly decreased while the peak at 15.6 minutes increased slightly in intensity. The amino acid eluting at 15.6 min is the product from slow hydrolysis of the formate ester in the reaction medium. The structure corresponds to α-amino-β-hydroxy-6-hydroxyhexanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[CH:6]=[CH:7][CH2:8]Cl.[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:24]=2[N:25]=1>C(Cl)(Cl)Cl>[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][N:21]([CH2:8][CH:7]=[CH:6][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=3)[CH2:22][CH2:23][C:24]=2[N:25]=1
Reactant: COc1cc(C=CCCl)cc(OC)c1
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: ClC(Cl)Cl
Product: COc1cc(C=CCN2CCc3nc(N)sc3CC2)cc(OC)c1
Yield: 21 %

Procedure:
Prepared from 3,5-dimethoxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield 21% of theory, Melting point: 114°-19° C. (petroleum ether).
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][N:10]3[CH:19]=2)=[CH:3][CH:2]=1.O.[C:22]([OH:26])(=[O:25])[CH:23]=[O:24]>ClCCl>[OH:24][CH:23]([C:7]1([C:4]2[CH:3]=[CH:2][C:1]([CH3:20])=[CH:6][CH:5]=2)[N:8]2[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:14][C:9]2=[N:10][CH2:19]1)[C:22]([OH:26])=[O:25]
Reactant: COC(=O)c1ccc2nc(-c3ccc(C)cc3)cn2c1
Reactant: O=CC(=O)O
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1=CN2C(=NCC2(c2ccc(C)cc2)C(O)C(=O)O)C=C1
Temperature: 25 °C
Yield: 87 %

Procedure:
To a suspension of methyl 2-(4-tolyl)imidazo[1,2-a]pyridine-6-carboxylate 3 (13.31 g, 50 mmol) in dichloromethane (100 ml) was added solid glyoxylic acid monohydrate (6 g) and the mixture was heated at reflux for 4 h. The mixture was then cooled to room temperature and the white solid filtered, washed by dichloromethane, and dried under vacuum to give (14.9 g, 87%) of 2-hydroxy-2-[6-methoxycarbonyl-3-(4-tolyl)imidazo[1,2-a]pyridine-3-yl]acetic acid 4 as a white solid.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)(=O)=O.O[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:25][CH:24]=1>>[CH:20]1[C:21]2[N:8]([CH2:7][CH2:6][O:5][C:23]3[CH:24]=[CH:25][C:26]([CH2:29][CH:30]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][CH:28]=3)[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:15][C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)OCCN1c2ccccc2Oc2ccccc21
Reactant: CCCCCCOC(Cc1ccc(O)cc1)C(=O)OCC
Product: CCCCCCOC(Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)OCC
Yield: 52.4 %

Procedure:
The title compound (0.52 g, 53%) was prepared as a pale yellow oil from 2-(phenoxazin-10-yl)ethyl methanesulfonate (0.6 g and 1.97 mmol) and ethyl 3-(4-hydroxyphenyl)-2-hexyloxypropanoate (0.70 g, 2.4 mmol) obtained in preparation 8 by an analogous procedure to that described in example 6 (Method B).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[K+].[Br-]>>[CH2:24]([O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][S:15][C:12]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])=[C:7]3[C:11]=2[CH2:10][CH2:9][CH2:8]3)=[CH:22][CH:21]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccccc3)cc2)c2c1CCC2
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1ccc(SCc2ccc(OCc3ccccc3)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 69A. mp 145-147° C.; IR (KBr) cm−1:3066,2584, 1742, 1511, 1234; 400 MHz 1H NMR (DMSO-d6): δ 12.94 (br(s), 1H), 7.21-7.44 (m, 5H), 6.99-7.15 (m, 3H) 6.80-6.90 (m, 2H), 6.56 (d, 1H, J=8.3 Hz), 5.01 (s, 2H), 4.61 (s, 2H), 3.93 (s, 2H), 2.75 (t, 2H, J=7.3 Hz), 2.67 (t, 2H, J=7.3 Hz), 1.89 (pentet, 2H); MS m/z 419 (M−1). Anal. Calc'd for C25H24O4S: C, 71.40; H, 5.75. found: C, 71.46; H, 5.75.
Reaction SMILES: [CH2:1]([C:3]1([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)[CH:12]([CH2:13]CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(O)=O)[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2].[F:47][C:48]([F:69])([C:65]([F:68])([F:67])[F:66])[CH2:49][CH2:50][CH2:51][CH:52]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH:63]=[CH2:64])[C:53]([O:55]CC)=[O:54]>>[CH2:1]([C:3]1([C:40]2[CH:41]=[CH:42][C:43]([OH:46])=[CH:44][CH:45]=2)[CH:12]([CH2:13][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][CH:52]([CH2:51][CH2:50][CH2:49][C:48]([F:47])([F:69])[C:65]([F:66])([F:67])[F:68])[C:53]([OH:55])=[O:54])[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2]
Reactant: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Reactant: C=CCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Product: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 21 and the ethyl 2-(4,4,5,5,5-pentafluoropentyl)-8-nonenoate prepared in Example 10, the same procedure as shown in Example 21 was repeated to give 10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:15]3[CH:16]=[C:17]([N:20]4[C:25](=[O:26])[CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[N:22]([CH3:31])[C:21]4=[O:32])[CH:18]=[CH:19][C:14]=3[S:13][N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:33]Br>C(OCC)(=O)C.Br>[Br:33][CH:10]([S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:8])=[O:9])[C:11]1[C:15]2[CH:16]=[C:17]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([C:27]([F:29])([F:28])[F:30])[N:22]([CH3:31])[C:21]3=[O:32])[CH:18]=[CH:19][C:14]=2[S:13][N:12]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CS(=O)(=O)c4ccccc4)c3c2)c1=O
Reactant: BrBr
Agent: Br
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(Br)S(=O)(=O)c4ccccc4)c3c2)c1=O
Temperature: 25 °C
Yield: 90.1 %

Procedure:
To a solution of 3-[3-(phenylsulfonyl)methyl-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.400 g, 0.000831 mol) in ethyl acetate is added 48% hydrobromic acid (4 drops) followed by bromine in ethyl acetate (0.522 M, 1.67 ml, 0.000872 mol). The resultant mixture is stirred 1.5 hours at reflux. Additional bromine in ethyl acetate (1.67 ml) is added and the resultant mixture is stirred one hour at reflux. The mixture is cooled to room temperature, diluted with ethyl acetate, washed sequentially with 0.1 M sodium sulfite, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is chromatographed on silica gel with hexanes:ethyl acetate to give the title compound as a white crystalline solid (0.420 g, 90.1%, mp 182-183° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6]([CH2:8][N:9]1[C:13](/[CH:14]=[C:15]2\[CH2:16][N:17]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][CH2:19][C:20]\2=[O:21])=[CH:12][N:11]=[CH:10]1)=[O:7])[CH3:4].ClCCl>C(O)C>[CH2:3]([O:5][C:6]([CH2:8][N:9]1[C:13](/[CH:14]=[C:15]2\[CH2:16][N:17]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:18][CH2:19][CH:20]\2[OH:21])=[CH:12][N:11]=[CH:10]1)=[O:7])[CH3:4]
Reactant: CCOC(=O)Cn1cncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)Cn1cncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.2 %

Procedure:
Sodium borohydride (0.06 g) was added to a solution of (E)-3-{[1-(ethoxycarbonylmethyl)-1H-imidazol-5-yl]methylidene}-1-(triphenylmethyl)piperidin-4-one (1.5 g) in a mixed solvent of dichloromethane (10 ml) and ethanol (10 ml) at 0° C. After the mixture was stirred at 0° C. for 0.5 hour and then at room temperature for 1.5 hour, it was partitioned between water and ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure followed by purification of the residue by silica gel chromatography using dichloromethane and methanol (19:1) as an eluent to give the title compound (560 mg, yield: 37%) as a yellow amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:12](=[O:11])[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1Br
Reactant: COC(=O)c1ccc(CN2CCN(C)CC2)cc1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Br

Procedure:
Another process, depicted in Scheme 2, involves reacting 3-bromo-4-methyl-aniline with 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester to obtain N-(3-bromo-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide. The latter is reacted with 4-(3-pyridyl)-2-pyrimidine amine (which is obtained by reacting cyanamide with 3-dimethylamino-1-pyridin-3-yl-propenone) to obtain imatinib.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:17]3[CH2:22][CH2:21][CH2:20][O:19][CH2:18]3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>>[O:19]1[CH2:20][CH2:21][CH2:22][CH:17]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C3CCCOC3)cc2C1
Agent: Cl
Product: c1cc2c(cc1C1CCCOC1)CNC2

Procedure:
Prepared in analogy to Example A3(e) from rac-5-(tetrahydro-pyran-3-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Brown oil. MS (m/e): 204.3 ([M+H]+, 100%).
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:64]([O:68][C:69](=[O:81])[NH:70][CH:71]1[CH2:76][CH2:75][N:74]([C:77](=[O:80])[CH2:78][NH2:79])[CH2:73][CH2:72]1)[CH2:65][CH2:66][CH3:67]>CN(C=O)C>[CH2:64]([O:68][C:69](=[O:81])[NH:70][CH:71]1[CH2:72][CH2:73][N:74]([C:77](=[O:80])[CH2:78][NH:79][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:30])[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=2)=[O:28])[CH2:75][CH2:76]1)[CH2:65][CH2:66][CH3:67]
Reactant: CCCCOC(=O)NC1CCN(C(=O)CN)CC1
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOC(=O)NC1CCN(C(=O)CNC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To solution of 250 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 4 ml DMF were added 231 mg HATU, 0.10 ml DIPEA and 156 mg [1-(2-Amino-acetyl)-piperidin-4-yl]-carbamic acid butyl ester. After stirring for 12 h it was concentrated and the residue dissolved in dichloromethane. It was extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated to furnish the crude coupling product which was further purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][C:9]#[N:10])=[O:7].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N:19]=[C:20]=[O:21].CCN(CC)CC>C(COC)OC>[O:7]=[C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)[CH:8]([C:20](=[O:21])[NH:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[F:11])[C:9]#[N:10]
Reactant: N#CCC(=O)c1ccc[nH]1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: N#CC(C(=O)Nc1ccc(F)cc1F)C(=O)c1ccc[nH]1

Procedure:
Reaction of 2.4 g of 2-pyrroloylacetonitrile with 3.1 g of 2,4-difluorophenyl isocyanate in the presence of 2.0 g Et3N in 25 ml of glyme and isolation similarly to the preceding examples, followed by trituration with and recrystallization from ethanol gives β-oxo-α-(2,4-difluorophenylcarbamoyl)-β-(2-pyrrolyl)-propionitrile, m.p. 169°-171°.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([C:14]([OH:16])=[O:15])[CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(=O)C(Cl)=O>ClCCl>[CH3:17][O:15][C:14]([CH:10]1[CH2:9][CH2:8][C:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=2[C:12](=[O:13])[CH2:11]1)=[O:16]
Reactant: Cc1cccc2c1CCC(C(=O)O)CC2=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)C1CCc2c(C)cccc2C(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.8 %

Procedure:
To a solution of 1-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-carboxylic acid (5 g, 22.91 mmol) in dry dichloromethane (DCM) (15 mL), oxalyl chloride (6 mL, 68.75 mmol) was added dropwise at 0° C. The reaction mixture was stirred overnight at room temperature, concentrated in vacuo and to the residue dissolved in DCM (30 mL), methanol (15 mL) was added at 0° C. After stirring 1.5 h at room temperature, the mixture was diluted with water (60 mL) and extracted with DCM (100 mL), the organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give 6.0 g of a yellow oil. Purification by flash chromatography on silica gel (hexane/diethyl ether: 8/2) afforded the title compound as a pale yellow oil (5.6 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](=O)[CH:14](Br)[F:15])[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[CH3:20][C:21]1[N:26]=[C:25]([NH:27][C:28]([NH2:30])=[S:29])[CH:24]=[CH:23][CH:22]=1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:30]=[C:28]([NH:27][C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([CH3:20])[N:26]=4)[S:29][C:14]=3[F:15])[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: Cc1cccc(NC(N)=S)n1
Reactant: COc1ccc(Cn2cc(C(=O)C(F)Br)cn2)cc1
Solvent: CC(C)=O
Product: COc1ccc(Cn2cc(-c3nc(Nc4cccc(C)n4)sc3F)cn2)cc1
Yield: 92.3 %

Procedure:
According to Scheme 6 Step 3: A solution of 1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-bromo-2-fluoroethanone (0.26 mmol, 110 mg) and of 1-(6-methylpyridin-2-yl)thiourea (0.26 mmol, 44 mg) in acetone (3 mL) was stirred at 50° C. for 5 hours. A precipitate was formed, was filtered and was washed with Et2O to yield N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-fluorothiazol-2-yl)-6-methylpyridin-2-amine (0.24 mmol, 95 mg, 92%) as a beige solid.
Reaction SMILES: [NH:1]1[C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][CH2:3][C:2]1=[O:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O[K])(C)(C)C.O.CCOC(C)=O>C1COCC1>[CH2:9]([O:8][C:6](=[O:7])[C@@H:5]1[CH2:4][CH2:3][C:2](=[O:11])[N:1]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:10]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)[C@@H]1CCC(=O)N1
Agent: CC(C)(C)O[K]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CCC(=O)N1Cc1ccccc1
Temperature: 0 °C

Procedure:
Ethyl (S)-(+)-2-pyrrolidone-5-carboxylate (1 g, 6.36 mmol) and benzyl bromide (0.76 mL, 6.36 mmol) were placed in dry THF (30 mL). The reaction mixture was stirred and cooled to 0° C. A 1M solution of tert-BuOK was added dropwise (6.36 ML, 6.36 mmol) and the reaction was stirred for an additional 0.5 h at 0° C. and allowed to come to room temperate where it was stirred for 24 hours under N2. The reaction was then dissolved into a 1:1 mixture of H2O/EtOAc. The organic layer was washed with 1M HCl, H2O and brine, and then dried over MgSO4 to afford N-benzyl-L-pyroglutamic acid ethyl ester an oil.