Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:8][CH:7]=1.[OH-].[Na+]>CO.[Cl-].[NH4+]>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][CH2:14][CH2:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][C:3]([OH:22])=[O:2])=[CH:11][CH:10]=1
Reactant: COC(=O)CCc1ccc(OCCOC2CCCCO2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CCc1ccc(OCCOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-{4-[2-(Tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-propionic acid methyl ester (0.12 g, 0.39 mmol) is dissolved in MeOH (3 ml) and 2M NaOH solution (3 ml) is added and the resulting solution is stirred at room temperature for 18 hours. The reaction mixture is diluted with saturated ammonium chloride solution (20 ml) and extracted with EtOAc (100 ml×2). The organic phased are combined, dried over MgSO4, the solvent removed in vacuo to yield the title compound as a colourless oil; [M+H]+=295
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:44])[O:12][C@H:13]([C:15](=[O:43])[NH:16][C@@H:17]2[C:23](=[O:24])[N:22]([CH2:25][CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:21]3[CH:35]=[CH:36][CH:37]=[CH:38][C:20]=3[C:19]3[CH:39]=[CH:40][CH:41]=[CH:42][C:18]2=3)[CH3:14])=CC=1)([O-])=O.[F:45][C:46]([F:50])([F:49])[CH2:47][NH2:48]>>[CH2:28]([O:27][CH2:26][CH2:25][N:22]1[C:23](=[O:24])[C@@H:17]([NH:16][C:15]([C@@H:13]([O:12][C:11](=[O:44])[NH:48][CH2:47][C:46]([F:50])([F:49])[F:45])[CH3:14])=[O:43])[C:18]2[CH:42]=[CH:41][CH:40]=[CH:39][C:19]=2[C:20]2[CH:38]=[CH:37][CH:36]=[CH:35][C:21]1=2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCC(F)(F)F
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: C[C@H](OC(=O)NCC(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using carbonic acid (S)-1-[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl]-ethyl ester 4-nitro-phenyl ester and 2,2,2-trifluoroethylamine, the title compound was prepared in the same manner as described for example 5c. Colorless, waxy solid (94%). MS: m/e=556(M+H+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:11]2[C:6](=[N:7][CH:8]=[N:9][C:10]=2[NH2:12])[NH:5][N:4]=1.Br[CH:16]([C:18]1[O:19][C:20](=[O:34])[C:21]2[C:26]([C:27]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:17]>>[NH2:12][C:10]1[N:9]=[CH:8][N:7]=[C:6]2[N:5]([CH:16]([C:18]3[O:19][C:20](=[O:34])[C:21]4[C:26]([C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH3:17])[N:4]=[C:3]([C:2]([F:13])([F:1])[F:14])[C:11]=12
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1ccccc1
Reactant: Nc1ncnc2[nH]nc(C(F)(F)F)c12
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(C(F)(F)F)c2c(N)ncnc21
Yield: 14.9 %

Procedure:
The title compound was made in a similar way as that of the compound of example 1 using 3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate G16, 45 mg, 0.222 mmol) 3-(1-bromoethyl)-4-phenyl-1H-isochromen-1-one (intermediate C7, 72.9 mg, 0.222 mmol). to give the title compound (15 mg, 0.033 mmol, 15.0% yield) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32](Cl)[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:16]=[C:17]([F:24])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:24][C:17]1[CH:16]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:14]=[C:13]([F:12])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2cc(Cl)cc(Cl)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 20.4 %

Procedure:
3,5-Dichlorobenzeneboronic acid (30.7 mg, 0.16 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (13 mg, 20%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [CH2:1]([CH:5]([C:11]([O:13]CC)=O)[C:6]([O:8]CC)=O)[CH2:2][CH2:3][CH3:4].[Na].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1>C(O)C>[CH2:1]([CH:5]1[C:6](=[O:8])[N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=2)[N:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:11]1=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(NNc2ccccc2)cc1
Agent: [Na]
Solvent: CCO
Product: CCCCC1C(=O)N(c2ccccc2)N(c2ccc(OC)cc2)C1=O
Temperature: 142.5 °C
Yield: 56.7 %

Procedure:
Diethyl butylmalonate (4.33 g; 20.0 mmol) was added to a stirred solution of sodium (0.46 g; 20.0 mmol) in absolute ethanol (20 ml), followed by crude 1-(4-methoxyphenyl)-2-phenylhydrazine (4.3 g; 20 mmol max.) in absolute ethanol (5 ml). About ⅔ of the ethanol was distilled off and xylene (20 ml) was added to the residue. The reaction mixture was heated to 140-145° C. (bath temperature) for 15 h to distill off the rest of the ethanol. The reaction mixture was cooled to 0° C. (bath temperature) and poured into ice water (ca. 100 ml). The aqueous layer was extracted with CH2Cl2 (2×15 ml); the extracts were discarded. The cold aqueous layer was acidified with 6 H HCl (5 ml) and extracted with CH2Cl2 (3×10 ml). The combined extracts were washed with water (2×10 ml) and dried (MgSO4). Filtration and evaporation gave 3.84 g amber oil. Purified by flash chromatography on a 130×65 mm silica gel 60 column eluted with ethyl acetate-heptane (1:3) to give 1.45 g (21%) colourless oil.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].[H-].[Na+].CC1C=CC(S(O[CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=O)=O)=CC=1>O1CCCC1>[F:3][C:2]([F:5])([F:4])[CH2:1][O:6][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: OCC(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCCOCCOCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)COCCOCCOCCOCCOCCOCCOCc1ccccc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 62.6 %

Procedure:
To a stirred solution of trifluoroethanol (0.1 g) and sodium hydride (60% dispersion in mineral oil; (0.05 g) in tetrahydrofuran (10 ml) was added the product of step (b) (0.5 g) and the reaction stirred for 24 hours at 20° C. The reaction was quenched by the addition of methanol (5 ml) and the solvent removed in vacuo. The residue was partitioned between ethyl acetate (50 ml) and water (50 ml). The organic layer was washed with brine (50 ml), dried and the solvent removed in vacuo. Purification by column chromatography on silica gel (Biotage), eluting with 50% ethyl acetate in cyclohexane gave the title compound (0.27 g).
Reaction SMILES: [F:1][CH:2]([F:19])[CH:3]1[CH2:8][CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[CH2:5][CH2:4]1.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C.[H][H]>[Pd].CCO>[F:1][CH:2]([F:19])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1CCC(C(F)F)CC1
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: CCO
Product: FC(F)C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
A 250 flask charged with benzyl 4-(difluoromethyl)piperidine-1-carboxylate (1.16 g, 4.31 mmol), palladium, 10 wt. % (dry basis) on activated carbon, wet, degussa type e101 ne/w (0.563 g, 0.265 mmol) and EtOH (25 mL) was evacuated/backfilled with hydrogen (1 atm, 3×). After stirring overnight at room temperature, more palladium, 10 wt. % (dry basis) on activated carbon, wet, degussa type e101 ne/w (1.09 g) was added and the reaction was evacuated/backfilled with hydrogen (1 atm, 3×). After stirring overnight the reaction was filtered through a pad of Celite and the pad was washed with EtOH. Concentration of the filtrate in vacuo gave 4-(difluoromethyl)piperidine as a light-yellow oil (90 mg, 15% yield).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]4[N:23]=[CH:22][S:21][C:19]4=3)[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:13]2=[O:33])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[C:34]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:14]2[C:15]3[C:20](=[C:19]4[S:21][CH:22]=[N:23][C:18]4=[CH:17][CH:16]=3)[C:12]3([C:3]4[C:2](=[CH:11][C:6]5[O:7][CH2:8][CH2:9][O:10][C:5]=5[CH:4]=4)[O:1][CH2:34]3)[C:13]2=[O:33])=[CH:26][CH:27]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: COc1ccc(CN2C(=O)C(c3cc4c(cc3O)OCCO4)c3c2ccc2ncsc32)cc1
Product: COc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3c2ccc2ncsc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4-methoxybenzyl)-6,8-dihydro-7H-[1,3]thiazolo[5,4-e]indol-7-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 6′-(4-methoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one was obtained (80%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.76 (s, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.30 (d, J=8.6 Hz, 2H), 7.05 (d, J=8.5 Hz, 1H), 6.88 (d, J=8.6 Hz, 2H), 6.58 (s, 1H), 6.21 (s, 1H), 4.99 (ABq, 2H), 4.86 (ABq, 2H), 4.25-4.04 (m, 4H), 3.79 (s, 3H); MS (ES+) m/z 473.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7](Br)=[CH:6][CH:5]=[CH:4][N:3]=1.NC1C([N+:16]([O-:18])=[O:17])=CC=CN=1>Br>[Br:1][C:2]1[C:7]([N+:16]([O-:18])=[O:17])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1[N+](=O)[O-]
Reactant: Brc1cccnc1Br
Agent: Br
Product: O=[N+]([O-])c1cccnc1Br

Procedure:
Bouillon et al in Tetrahedron, 2002, 58, 17, 3323-3328 reported a three-step process for the preparation of 2,3-dibromopyridine from 2-amino-3-nitropyridine. The process involves diazotization of 2-amino-3-nitropyridine followed by addition of CuBr in 47% HBr to obtain 2-bromo-3-nitropyridine. The 2-bromo-3-nitropyridine so obtained is reduced with Fe and acetic acid to 3-amino-2-bromopyridine and subsequent diazotization to give 2,3-dibromopyridine.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@H:12]2[C@@H:16]([O:17][CH2:18][CH3:19])[CH2:15][N:14](C(OCC3C=CC=CC=3)=O)[CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].C(N(CC)CC)C.C([SiH](CC)CC)C>C(Cl)Cl.[Pd](Cl)Cl>[CH2:18]([O:17][C@H:16]1[CH2:15][NH:14][CH2:13][C@H:12]1[NH:11][C:4]1[C:3]([CH2:1][CH3:2])=[N:8][CH:7]=[C:6]([CH2:9][CH3:10])[N:5]=1)[CH3:19]
Reactant: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)cnc1CC
Agent: Cl[Pd]Cl
Agent: CC[SiH](CC)CC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCO[C@H]1CNC[C@H]1Nc1nc(CC)cnc1CC
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a solution of benzyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-ethoxypyrrolidine-1-carboxylate (14.55 g, 36.5 mmole) in CH2Cl2 (0.1 M, 365 ml) under N2 was added palladium chloride (1.29 g, 7.24 mmole) and triethyl amine (7.61 mL, 1.5 eq.). Triethylsilane (8.74 mL, 1.5 eq.) was added dropwise over 15 min. After one hour, an additional 8.74 mL of triethylsilane were added dropwise. After 2 additional hours, the reaction mixture was filtered through celite. Trifluoroacetic acid (8 mL) was added and the reaction mixture was stirred for 30 minutes, basified to pH 10 with 2 N aqueous NaOH and extracted with CH2Cl2 (3×300 ml), dried with MgSO4, filtered and concentrated. Vacuum chromatography was run on a 1 L frit funnel with 5-15% MeOH/CH2Cl2 with 0.5% NH4OH gave 8.75 g (91%) of N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine as an oil. IR (liq.) 3438, 2971, 2935, 2874, 2452, 1580, 1546, 1498, 1465, 1448, 1395, 1343, 1164, 1124, 1078 cm−1 HRMS (ESI) calcd for C14H24N4O+H1 265.2028. found 265.2026. [α]25D=−45° (c 1.02, chloroform).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][O:18][NH:19][CH3:20].C(N(C(C)C)CC)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:17][O:18][N:19]([CH3:20])[C:13]([C@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Yield: 91.8 %

Procedure:
(R)-1-(tert-Butoxycarbonyl)pyrrolidine-2-carboxylic acid (5.00 g, 23.2 mmol), O,N-dimethylhydroxylamine hydrochloride (2.49 g, 25.6 mmol), diisopropyl ethyl amine (8.09 mL, 46.5 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (“HATU”) (9.72 g, 25.6 mmol) in DCM (50 mL) were stirred at room temperature for 2 hours. The reaction mixture was quenched with water, and the layers were separated. The aqueous layer was extracted with DCM (1×), and the combined organics were dried, filtered and concentrated. The crude product was purified via column chromatography, eluting with hexanes/ethyl acetate (1:1) to give (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate as an oil (5.5 g, 92%). m/z (APCI-pos) (M+1)-Boc=159.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][C@H:10]([C:14]([N:16]2[CH2:23][CH2:22][CH2:21][C@H:17]2[C:18](O)=[O:19])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])=[CH:5][CH:4]=1.[NH2:26][CH:27]([CH:34]([CH3:36])[CH3:35])[CH:28]([OH:33])[C:29]([F:32])([F:31])[F:30]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C@@H:10]([CH:11]([CH3:12])[CH3:13])[C:14]([N:16]2[CH2:23][CH2:22][CH2:21][C@H:17]2[C:18]([NH:26][CH:27]([CH:28]([OH:33])[C:29]([F:30])([F:31])[F:32])[CH:34]([CH3:35])[CH3:36])=[O:19])=[O:15])=[O:8])=[CH:24][CH:25]=1
Reactant: CC(C)C(N)C(O)C(F)(F)F
Reactant: COc1ccc(C(=O)N[C@H](C(=O)N2CCC[C@H]2C(=O)O)C(C)C)cc1
Product: COc1ccc(C(=O)N[C@H](C(=O)N2CCC[C@H]2C(=O)NC(C(C)C)C(O)C(F)(F)F)C(C)C)cc1

Procedure:
reaction of N-(4-methoxybenzoyl)-L-valyl-L-proline with 3-amino-4-methyl-1,1,1-trifluoro-2-pentanol to give (S)-1-[(S)-2-(4-methoxybenzamido)-3-methylbutyryl]-N-[2-methyl-1-(2,2,2-trifluoro-1-hydroxyethyl)propyl]pyrrolidine-2-carboxamide; followed by
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([N:10]3[CH2:14][CH2:13][C@H:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11]3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[ClH:23]>CO>[ClH:23].[ClH:23].[ClH:23].[CH:1]1([N:4]2[CH2:5][CH2:6][CH:7]([N:10]3[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11]3)[CH2:8][CH2:9]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C2CCN(C3CC3)CC2)C1
Agent: Cl
Solvent: CO
Product: N[C@H]1CCN(C2CCN(C3CC3)CC2)C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
(S)-tert-Butyl 1-(1-cyclopropylpiperidin-4-yl)pyrrolidin-3-ylcarbamate (0.87 g, 2.282 mmol) was dissolved in methanol (4.6 ml), and HCl in methanol (1.25 M, 9.1 ml) was added. The reaction mixture was heated for 3 h at 50° C. and then stirred overnight at RT. The resulting precipitate was filtered off. The filtrate was concentrated to half, and diethyl ether was added. The resulting precipitate was filtered off again. Yield: >99% (0.72 g).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19]/[C:20](=[C:27]3\[C:28](=[O:39])[NH:29][C:30]4[C:35]\3=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=4)/[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19]/[C:20](=[C:27]3\[C:28](=[O:39])[NH:29][C:30]4[C:35]\3=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=4)/[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:18]=2)[CH2:8][CH2:7]1)([OH:5])=[O:3]
Reactant: CCOC(=O)C1CCN(Cc2ccc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(CN2CCC(C(=O)O)CC2)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 8 by saponification of (Z)-3-{1-[4-(4-ethoxycarbonylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone with sodium hydroxide solution in ethanol.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH3:5][Li].[Cl-].[Li+].[O:9]=[C:10]1[CH2:15][CH2:14][C:13]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)=[CH:12][CH2:11]1>C1COCC1.C(OCC)C.C(OCC)(=O)C>[OH:9][C:10]1([CH3:5])[CH2:15][CH2:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=2)=[CH:12][CH2:11]1
Reactant: [Li]C
Reactant: COC(=O)c1ccc(C2=CCC(=O)CC2)cc1
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(C2=CCC(C)(O)CC2)cc1
Temperature: 25 °C

Procedure:
A suspension of anhydrous cerium(III) chloride (2.71 g, 11 mmol) in THF (10 mL) at −78° C. was slowly treated with 1.5M methyllithium complexed with lithium chloride in diethyl ether (6.7 mL), warmed to room temperature over 2 hours, and added to a solution of Example 420C (1.15 g, 5.0mmol) in THF (10 mL) at −78° C. The reaction was gradually warmed to room temperature over 4 hours, diluted with ethyl acetate (100 mL), washed with water (45 mL) and brine (10 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10-30% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[C:6]3[C:12]([O:13][CH3:14])=[N:11][N:10]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([C:4]2[C:5]([N:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)=[C:6]3[C:12]([O:13][CH3:14])=[N:11][N:10]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[C:7]3=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(Cn2nc(OC)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C4CC4)cnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2nc(OC)c3c(N4CCNCC4)c(C4CC4)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
tert-Butyl 4-(5-cyclopropyl-3-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.300 g, 0.608 mmol) was placed in DCM (5 mL). TFA (1.5 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness to give the crude product 5-cyclopropyl-3-methoxy-1-(4-methoxybenzyl)-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine (0.239 g, quant.), which was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[F:12][C:13]1[C:18]2[N:19]=[C:20]([SH:22])[S:21][C:17]=2[C:16]([F:23])=[CH:15][C:14]=1[F:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl>O.CS(C)=O>[F:12][C:13]1[C:18]2[N:19]=[C:20]([S:22][CH2:2][C:3]([NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:4])[S:21][C:17]=2[C:16]([F:23])=[CH:15][C:14]=1[F:24]
Reactant: O=C(CCl)Nc1ccccc1
Reactant: Fc1cc(F)c2sc(S)nc2c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(CSc1nc2c(F)c(F)cc(F)c2s1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
To DMSO (15 ml) was added α-chloroacetoanilide (850 mg, 5 mmol), 4,5,7-trifluoro-2-mercaptobenzothiazole (1.1 g, 5 mmol), potassium carbonate (690 mg, 5 mmol) and potassium iodide (50 mg) and the mixture was stirred at room temperature for 4 hours. The resultant reaction mixture was diluted with water, acidified with 7% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried and then evaporated to yield a crude product, which was purified on a silica gel column to give 2-(4,5,7-trifluorobenzothiazol-2-ylthio)-N-phenylacetamide (0.97 g, 52%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:23]=[C:14]3[CH2:15][N:16]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][C:32](F)=[CH:31][C:30]=1[N:45]1[CH2:56][CH2:55][C:54]2[C:53]3[CH2:52][C:51]([CH3:58])([CH3:57])[CH2:50][C:49]=3[S:48][C:47]=2[C:46]1=[O:59])(=[O:26])[CH3:25].CC([O-])=O.[Na+]>CC#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:24]([O:27][CH2:28][C:29]1[C:34]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:23]=[C:14]4[CH2:15][N:16]([CH:19]5[CH2:22][O:21][CH2:20]5)[CH2:17][CH2:18][N:13]4[N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)=[CH:33][CH:32]=[CH:31][C:30]=1[N:45]1[CH2:56][CH2:55][C:54]2[C:53]3[CH2:52][C:51]([CH3:58])([CH3:57])[CH2:50][C:49]=3[S:48][C:47]=2[C:46]1=[O:59])(=[O:26])[CH3:25]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Reactant: Cn1cc(Br)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C3COC3)C4)c(=O)n(C)c2)cccc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Temperature: 110 °C
Yield: 64.1 %

Procedure:
A sealed tube was charged with the mixture of 5-bromo-1-methyl-3-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one 252a (275 mg, 0.7 mmol), (2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.02,6]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 131a (356 mg, 0.7 mmol), Pd(dppf)Cl2 (59 mg, 0.07 mmol), K3PO4.3H2O(317 mg, 1.4 mmol), and NaOAc (118 mg, 1.4 mmol) in CH3CN (20 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 110° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 30:1 methylene chloride/methanol to afford 317a as a yellow solid (300 mg, 61%). MS: [M+H]+ 669.
Reaction SMILES: C([O:5][C:6](=[O:75])[C@H:7]([CH2:66][CH2:67][C:68]([O:70]C(C)(C)C)=[O:69])[NH:8][C:9](=[O:65])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:64])[CH2:18][CH2:19][S:20][CH2:21][CH:22]([O:44][C:45](=[O:63])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:23][O:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:12][CH:11]=1)(C)(C)C>FC(F)(F)C(O)=O>[C:57]1([CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][C:45]([O:44][CH:22]([CH2:23][O:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:21][S:20][CH2:19][CH2:18][C:17]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]([NH:8][C@H:7]([C:6]([OH:75])=[O:5])[CH2:66][CH2:67][C:68]([OH:70])=[O:69])=[O:65])=[CH:11][CH:12]=2)=[O:64])=[O:63])[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(NC(=O)CCSCC(COC(=O)CCCCCCCCCCCc2ccccc2)OC(=O)CCCCCCCCCCCc2ccccc2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC[C@H](NC(=O)c1ccc(NC(=O)CCSCC(COC(=O)CCCCCCCCCCCc2ccccc2)OC(=O)CCCCCCCCCCCc2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A solution of 4-[6,7-bis(12-phenyldodecanoyloxy)-4-thiaheptanoylamino]benzoyl-glutamic acid di-t-butyl ester as obtained in Example 60 (275 mg) in trifiuoroacetic acid (2 ml) was stirred at room temperature for 2 hours, after which the solvent was distilled off under reduced pressure, to yield the title compound (207 mg, yield 84%) as a syrup.