Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][C:27]1([CH3:39])[O:31][C@H:30]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]2)[CH2:29][O:28]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:13]=[N:12]2)[C:8]([NH:38][C:35]2[CH:36]=[CH:37][N:33]([CH2:32][C@@H:30]3[CH2:29][O:28][C:27]([CH3:39])([CH3:26])[O:31]3)[N:34]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ncccc2F)cc1=O
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(Oc4ncccc4F)cc3=O)n2)O1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[4-(3-fluoro-pyridin-2-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 73) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(3-fluoro-pyridin-2-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as a yellow solid as a mixture of diastereomers (1.29 g, 85%).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9](CO)[OH:10])[OH:8])[OH:6])=[O:4].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)CO

Procedure:
Reference XI or XI mutein is produced and purified as described in Example I. The purified protein is adjusted to an average activity of 1.8-2.0 U/ml as determined by HPLC assay, and after precooling in a salt and ice bath, is mixed with glucose solution also precooled (400 g/l glucose, 25 mM maleic acid, 10 mM MgSO4 --H2O, 1 mM Fe++ (FeSO4.7H2O, pH 6.5) in a 1:1 ratio at 1° C. and distributed into 100 μl thin-walled glass micropipettes (Fisher Scientific, Pittsburgh, Pa.) which are flamed sealed and incubated in heating baths at different isomerization temperatures for 40 minutes. Temperatures of the heating baths are set at 1° C. intervals over the range at which the enzyme shows the full range of inactivation (85° C. to 100° C. for the reference XI). One bath is set at the reference temperature approximately 10° C. below the temperature of half maximum enzyme activity. For the blank samples, the buffer solution is mixed with the glucose substrate in a 1:1 ratio and distributed into 100 μl thin-walled glass micropipettes which are sealed and incubated in water baths at the same temperatures and incubation time as used for the enzyme test samples. The reaction is terminated by immersing the micropipettes in a salt-ice bath, and 65 μl of isomerase is removed from each micropipette. 2 μl of 1N HCl is added to stop the isomerase reaction. The isomerase is assayed for fructose and glucose by HPLC using a Beckman Liquid Chromatograph as described in Example I.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH2:28][O:29][Si](C(C)(C)C)(C)C)=[CH:25][C:19]=2[CH:18]=1)=[O:16])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.[Cl-].[Na+].O>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH2:28][OH:29])=[CH:25][C:19]=2[CH:18]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(OCCO[Si](C)(C)C(C)(C)C)ccc2s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccccc1NC(=O)c1cc2cc(OCCO)ccc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of 55 mg (0.100 mmol) [2-({5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-benzo[b]thiophene-2-carbonyl}-amino)-phenyl]-carbamic acid tert-butyl ester (40) in 5 ml tetrahydrofurane was added 38 mg (0.120 mmol) tetra-n-butylammonium fluoride. The reaction mixture was stirred at room temperature for 1 h and poured into brine. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed brine and dried over sodium sulfate. The solvent was evaporated and the residue of (2-{[5-(2-Hydroxy-ethoxy)-benzo[b]thiophene-2-carbonyl]-amino}-phenyl)-carbamic acid tert-butyl ester was dissolved in 1.0 ml trifluoroacetic acid. The reaction mixture was stirred for 45 min at room temperature and then added to an aqueous solution of sodium bicarbonate. After extraction with ethyl acetate and removal of the solvent the residue was recrystallized from ethyl acetate/diethyl ether to yield 17 mg (0.052 mmol) of 5-(2-Hydroxy-ethoxy)-benzo[b]thiophene-2-carboxylic acid (2-amino-phenyl)-amide (39) as a white solid, mp. 215–216° C.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][N:5]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40]>>[F:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]3([C:39]4[C:30](=[CH:31][C:32]5[O:37][CH2:36][CH2:35][O:34][C:33]=5[CH:38]=4)[O:29][CH2:28]3)[C:20]2=[O:40])=[N:5][CH:6]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: Fc1ccc(CCl)nc1
Agent: BrCC1CCCCO1
Agent: Cl
Product: O=C1N(Cc2ccc(F)cn2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(chloromethyl)-5-fluoropyridine hydrochloride (Cai, Z. et al. US 2007/0072831) to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[(5-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (99%) as a colorless solid: mp 174-176° C.; 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J=2.7 Hz, 1H), 7.41-7.11 (m, 4H), 7.01 (t, J=7.4 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.48 (s, 1H), 6.25 (s, 1H), 5.16 (d, J=15.7 Hz, 1H), 4.98-4.88 (m, 2H), 4.65 (d, J=8.9 Hz, 1H), 4.20-4.07 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.5, 160.2, 157.2, 155.3, 151.5, 151.5, 144.7, 142.0, 138.3, 137.8, 137.5, 132.2, 128.8, 124.1, 123.9, 123.8, 123.6, 122.9, 122.8, 121.0, 111.6, 109.4, 99.4, 80.1, 64.5, 63.9, 58.1, 45.4; MS (ES+) m/z 404.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][C:50]([OH:52])=[O:51])=[CH:44][CH:43]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][C:50]([OH:52])=[O:51])=[CH:44][CH:43]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(CCC(=O)O)cc3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and 3-(4-bromo-phenyl)-propionic acid (47 mg), in the same manner as Step A in Example 1-D-19, 3-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-propionic acid was obtained as a crude product (65 mg).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[Cl:24][C:25]1[C:30]([C:31](O)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:27][CH:26]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[C:30]([C:31]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[N:10]=[CH:9][CH:8]=[C:7]3[O:6][C:5]2[CH:18]=[CH:19][C:2]([F:1])=[C:3]([C:20]([F:23])([F:21])[F:22])[CH:4]=2)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:27][CH:26]=1
Reactant: Nc1cccc2c(Oc3ccc(F)c(C(F)(F)F)c3)ccnc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4ccc(F)c(C(F)(F)F)c4)ccnc23)c1F
Yield: 32.8 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(4-fluoro-3-(trifluoromethyl)phenoxy)quinolin-8-amine (Intermediate-44, 60 mg, 0.18 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 80 mg, 0.27 mmol), oxalyl chloride (52 mg, 0.41 mmol), DMF (1 drop) and DIPEA (70 mg, 0.54 mmol) in CH2Cl2 (2 mL) to afford 35 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.75 (s, 1H), 8.79 (d, J=7.5 Hz, 1H), 8.71 (d, J=5.1 Hz, 1H), 8.16 (t, 1H), 8.09 (d, J=8.7 Hz, 1H), 7.88 (m, 1H), 7.75-7.70 (m, 3H), 7.38 (m, 2H), 6.83 (d, J=5.4 Hz, 1H), 4.32 (d, J=5.1 Hz, 2H), 1.14 (s, 9H); MS (m/z): 592.29 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:10][C:11]([C:15]([O:20][CH3:21])([O:18][CH3:19])[CH2:16][OH:17])=[C:12]([CH3:14])[N:13]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.[H-].[Na+]>CN(C)C=O>[CH3:21][O:20][C:15]([C:11]1[S:10][C:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[N:13][C:12]=1[CH3:14])([O:18][CH3:19])[CH2:16][O:17][CH2:28][C:27]1[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COC(CO)(OC)c1sc(-c2ccc(C)cc2C)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COCC(OC)(OC)c2sc(-c3ccc(C)cc3C)nc2C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.7 %

Procedure:
To N,N-dimethylformamide (2 ml), 2-[2-(2,4-dimethylphenyl)-4-methylthiazol-5-yl]-2,2-dimethoxyethanol (100 mg) prepared in the Step 31-1-2 and 4-methoxybenzyl chloride (61 mg) were added, and 60% sodium hydride suspension in oil (20 mg) was added thereto under an argon atmosphere. Then, the mixture was stirred at a room temperature for 4 hours. Ice water was added to the reaction solution, and then the mixture was subjected to extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then concentrated under a reduced pressure. The residue was purified by thin-layer chromatography (hexane:ethyl acetate=3:1) to give the title compound (90 mg, 64%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:10][OH:11])[CH:9]=1)[C:5]#[N:6].Cl[C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:10][O:11][C:13]2[CH:23]=[C:17]3[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]3[C:15](=[O:24])[N:14]=2)[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(F)cc(CO)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1cc(F)cc(C#N)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 3-fluoro-5-(hydroxymethyl)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25]Cl)=[CH:20][CH:19]=1>>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:25][CH2:24][C:21]3[CH:22]=[CH:23][C:18]([OH:17])=[CH:19][CH:20]=3)[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Oc1ccc(CCCl)cc1
Reactant: FC(F)(F)c1cccc(C2CCNCC2)c1
Product: Oc1ccc(CCN2CCC(c3cccc(C(F)(F)F)c3)CC2)cc1
Yield: 65 %

Procedure:
The procedure described in Example 1 was repeated except that 4-(3-trifluoromethylphenyl)piperidine (the product of Preparation L) and 2-(p-hydroxyphenyl)ethyl chloride were the respective starting materials employed, using the same molar porportions as before. In this particular case, the corresponding final product obtained 4-{2-[4-(3-trifluoromethylphenyl)-piperidinyl]ethyl}phenol (yield, 65%), which was also converted to the hydrochloride salt. The pure base product was characterized by means of nuclear magnetic resonance data: NMR (CDCl3) δ6.8-7.6 (m, 8H), 0.6-4.0 (m, 14H). The hydrochloride salt melted at 207°-210° C. and was further characterized by means of elemental analysis.
Reaction SMILES: [F:1][CH2:2][CH:3]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([NH2:19])[C:15]([O:17][CH3:18])=[CH:16][C:9]=2[CH2:8][CH2:7]1)[CH2:4][F:5].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[C:24]([Cl:40])=[CH:23][N:22]=1>>[Cl:40][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])=[N:26][C:21]([NH:19][C:14]2[C:15]([O:17][CH3:18])=[CH:16][C:9]3[CH2:8][CH2:7][N:6]([CH:3]([CH2:2][F:1])[CH2:4][F:5])[CH2:12][CH2:11][C:10]=3[CH:13]=2)=[N:22][CH:23]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(C(CF)CF)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(C(CF)CF)CC2

Procedure:
2-{5-Chloro-2-[3-(2-fluoro-1-fluoromethyl-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N,N-dimethyl-benzenesulfonamide was prepared from 3-(2-fluoro-1-fluoromethyl-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide in an analogous manner to Example 308c. Product isolated as a white foam (60 mg, 60%). LCMS (m/e) 581 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 9.35 (s, 1H), 8.54 (d, 1H, J=8.3 Hz), 8.16 (s, 1H), 8.01 (s, 1H), 7.90 (d, 1H, J=8.0 Hz), 7.62-7.53 (m, 1H), 7.51 (s, 1H), 7.28-7.21 (m, 1H), 6.67 (s, 1H), 4.75-4.67 (m, 2H), 4.64-4.57 (m, 2H), 3.89 (s, 3H), 2.91-2.81 (m, 6H), 2.76 (s, 6H), 2.75-2.70 (m, 2H).
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:31]1(B2OC(C)(C)C(C)(C)O2)[CH2:35][CH2:34][CH2:33][CH:32]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([C:31]4[CH2:35][CH2:34][CH2:33][CH:32]=4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(C4=CCCC4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 125 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide, cesium carbonate, 2-cyclopent-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and tetrakis(triphenylphosphine)Palladium (0). 1H NMR (400 MHz, DMSO-d6): δ 8.63 (t, J=5.91 Hz, 1H), 8.06 (d, J=8.92 Hz, 1H), 7.96 (dd, J=4.43, 8.92 Hz, 2H), 7.73 (d, J=9.01 Hz, 1H), 6.89 (s, 1H), 4.18 (s, 1H), 3.29 (s, 1H), 2.85-2.87 (m, 2H), 2.48-2.49 (m, 2H), 1.96-2.03 (m, 1H), 1.45-1.78 (m, 6H), 1.28-1.32 (m, 5H). m/z: 399.2 [M+H]+
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:11][NH:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH2:24]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:38][CH2:37][CH:36]2[C:39]([O-])=[O:40])[CH2:31][CH2:30]1)=[O:28])[CH3:25].[Li+]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:18]=[CH:19][C:20]([CH3:21])=[CH:22][CH:23]=3)(=[O:16])=[O:15])[CH2:11][N:10]2[C:39]([CH:36]2[CH2:37][CH2:38][N:35]2[CH:32]2[CH2:31][CH2:30][N:29]([C:27]([O:26][CH2:24][CH3:25])=[O:28])[CH2:34][CH2:33]2)=[O:40])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)[C@H]2CN[C@H](C(=O)NC3(C#N)CC3)C2)cc1
Reactant: CCOC(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Agent: [Li+]
Product: CCOC(=O)N1CCC(N2CCC2C(=O)N2C[C@H](S(=O)(=O)c3ccc(C)cc3)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-N-(1-cyanocyclopropyl)-4-tosylpyrrolidine-2-carboxamide 7G and lithium 1-(1-(ethoxycarbonyl)piperidin-4-yl)azetidine-2-carboxylate 20J carried out according to the general procedure L yielded ethyl 4-(2-((2S,4R)-2-(1-cyanocyclopropylcarbamoyl)-4-tosylpyrrolidine-1-carbonyl)azetidin-1-yl)piperidine-1-carboxylate 1:1 epimers as a white solid (70%). MS ISP (m/e): 572.2 (100) [(M+H)]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[S:20][CH:21]=[C:22]([CH2:24][OH:25])[N:23]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:33]1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.IC.C([O-])(O)=O.[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[S:20][CH:21]=[C:22]([CH2:24][O:25][CH3:33])[N:23]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(-c4nc(CO)cs4)ccc3n(C)c21
Reactant: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COCc1csc(-c2ccc3c(c2)c2cc(-c4ccc(F)cc4)c(=O)n(C)c2n3C)n1
Reaction time: 0.08 h

Procedure:
120 mg (0.286 mmol) of compound from Example 100 above, 3-(4-fluorophenyl)-6-(4-hydroxymethylthiazol-2-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one, are dissolved in 3 ml of DMF. 17 mg (0.429 mmol) of 60% NaH and a spatula of dibenzo-18-crown-6 are added. After stirring for 5 minutes, 27 μl (0.429 mmol) of iodomethane are added. The mixture is allowed to stir for 4 h at ambient temperature. A saturated NaHCO3 solution is added, the mixture is extracted with EtOAc and then with CH2Cl2 and the organic phase is concentrated to dryness without drying. The residue is taken up in MeOH, and the white precipitate is filtered off and washed with MeOH and then with a minimum amount of Et2O.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH:30]([CH3:32])[CH3:31])[N:19]=2)=[C:9]1[CH3:33])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH:30]([N:20]1[N:19]=[C:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:34])=[O:5])[C:9]=2[CH3:33])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21]1(=[O:29])=[O:28])([CH3:32])[CH3:31]
Reactant: Cc1c(C2=NN(C(C)C)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C2=NN(C(C)C)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)O

Procedure:
[3-(2-Isopropyl-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-acetic acid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 8.08 (d, 1H), 7.90 (t, 1H), 7.83 (t, 1H), 7.47 (m, 2H), 6.97 (m, 2H), 4.71 (m, 1H), 4.53 (s, 2H), 2.23 (s, 3H), 1.47 (m, 6H) ppm. MS calculated for C21H20FN3O4S—H: 428, observed: 428.
Reaction SMILES: [C:1]1(=[O:15])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](O)=[O:12])[C:4](=[O:14])[CH:3]=[CH:2]1.S(Cl)([Cl:18])=O>>[C:1]1(=[O:15])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([Cl:18])=[O:12])[C:4](=[O:14])[CH:3]=[CH:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCCN1C(=O)C=CC1=O
Product: O=C(Cl)CCCCCN1C(=O)C=CC1=O

Procedure:
6-Maleimidocaproic acid is treated with excess thionyl chloride at 50° C. for three hours. Remaining thionyl chloride is distilled off to leave the product, 6-maleimidocaproic chloride.
Reaction SMILES: Cl.Cl[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([CH3:24])([CH3:23])[CH2:7]1)=[O:5].[C:25]([O:29][C:30]([N:32]1[CH2:37][C@H:36]([CH2:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][C@H:40]2[CH3:45])[NH:35][CH2:34][C@H:33]1[CH3:46])=[O:31])([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.O>[C:25]([O:29][C:30]([N:32]1[CH2:37][C@H:36]([CH2:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][C@H:40]2[CH3:45])[N:35]([CH2:3][C:4]([N:6]2[C:14]3[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)[CH:13]=3)[C:8]([CH3:24])([CH3:23])[CH2:7]2)=[O:5])[CH2:34][C@H:33]1[CH3:46])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1
Reactant: CC1(C)CN(C(=O)CCl)c2cc(Cc3ccc(F)cc3)cnc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC#N
Product: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2ncc(Cc3ccc(F)cc3)cc21
Temperature: 20 °C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
A mixture of 2-chloro-1-[6-(4-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-ethanone hydrochloride (6.63 g, 17.96 mmol), (2R,5S)-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (5.62 g, 17.96 mmol), potassium carbonate (9.95 g, 72 mmol) and finely ground potassium iodide (5.98 g, 36 mmol) in acetonitrile (40 mL) was stirred at 20° C. for 1 h. Water (200 mL) was added and mixture stirred for 0.2 h, then the mixture was extracted with EtOAc (200 mL). The organic phase was dried (Na2SO4) and evaporated in vacuo to give the title compound (11.3 g) as an oil, used without further purification. 1H NMR (Me-d3-OD): 8.28-8.19 (1H, m), 8.13-8.04 (1H, m), 7.25 (2H, dd), 7.04 (2H, t), 4.23-4.13 (1H, m), 4.13-4.04 (2H, m), 4.04-3.95 (3H, m), 3.81-3.58 (4H, m), 3.54 (1H, d), 3.25 (2H, dd), 3.01-2.66 (4H, m), 2.62-2.42 (2H, m), 2.42-2.17 (2H, m), 1.47 (9H, s), 1.43-1.37 (6H, m), 1.29-1.21 (3H, m), 1.01 (3H, d). MS: [M+H]+=610. IR: vC═O 1685, 1653 cm−1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13][CH3:14])[C:11]=1N)[C:5]([O:7][CH3:8])=[O:6].N([O-])=O.[Na+].P(P(O)(O)=O)(O)(O)=O>C(O)C.S(=O)(=O)(O)O.C(O)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13][CH3:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)c(N)c(OC)c1
Agent: O=N[O-]
Agent: O=P(O)(O)P(=O)(O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(Br)cc(OC)c1
Yield: 100.2 %

Procedure:
A 500 ml round bottom flask fitted with overhead stirring was charged with 16.5 grams (55 mmole) of methyl 3-bromo-5-methoxy-4-aminobenzoate in 80 ml ethanol, 15 ml sulfuric acid and 20 ml acetic acid. The solution was chilled in an ice bath and 6.6 gms (95 mmole) of sodium nitrite in 30 ml water was added dropwise while maintaining the temperature below 10° C. After stirring an additional 25 minutes, 100 ml of 50% hypophosphoric acid was added and the mixture was stirred cold for 2 hours. The reaction mixture was diluted with 500 ml water, extracted with ether, and then evaporated under reduced pressure to give 13.5 grams of methyl 3-bromo-5-methoxybenzoate as a reddish oil.