Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:15]3=[CH:16][C:17]4[O:21][CH2:20][O:19][C:18]=4[CH:22]=[C:14]3[O:13][CH2:12]1)[C:5](=[O:11])[NH:6]2.BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2CCCCC.[N:50]1[CH:55]=[C:54](B(O)O)[CH:53]=[N:52][CH:51]=1.CN(C)C1N=CC(B(O)O)=CC=1>>[N:50]1[CH:55]=[C:54]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([C:15]4=[CH:16][C:17]5[O:21][CH2:20][O:19][C:18]=5[CH:22]=[C:14]4[O:13][CH2:12]2)[C:5](=[O:11])[NH:6]3)[CH:53]=[N:52][CH:51]=1
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Reactant: OB(O)c1cncnc1
Agent: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: CN(C)c1ccc(B(O)O)cn1
Product: O=C1Nc2cccc(-c3cncnc3)c2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and pyrimidin-5-ylboronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (32%) as a colorless solid: mp 185-187° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.02 (s, 1H), 8.19 (s, 2H), 7.33 (t, 1H), 7.00 (d, 1H), 6.83 (d, 1H), 6.37 (s, 1H), 6.19 (s, 1H), 5.89 (d, 2H); 13C NMR (75 MHz, DMSO-d6) δ 178.7, 157.5, 156.0, 155.6, 148.8, 142.3, 133.1, 132.6, 131.8, 129.5, 124.5, 120.3, 110.9, 103.2, 101.9, 93.3, 79.5, 66.8, 58.5; MS (ES+) m/z 360.4 (M+1).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH:15]=[C:14]([I:16])[CH:13]=[N:12]3)[CH2:7][CH2:6]2)[O:4]CC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O.O.CCOC(C)=O>[I:16][C:14]1[CH:13]=[N:12][N:11]([CH:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)[CH:15]=1
Reactant: Ic1cnn(C2CCC3(CC2)OCCO3)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C1CCC(n2cc(I)cn2)CC1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A solution of 1-(1,4-Dioxa-spiro[4.5]dec-8-yl)-4-iodo-1H-pyrazole (2.81 g; 8.41 mmol; 1.00 eq.) and pyridinium para-toluenesulfonate (4.23 g; 16.8 mmol; 2.0 eq.) in acetone (40 mL) and water (40 mL) was heated at reflux O/N. It was then allowed to cool to RT and diluted with EtOAc. Aqueous phase was extracted with EtOAc (twice) and combined organic phases were washed with water and brine, dried over sodium sulftate, filtered and concentrated to give the title compound as a white powder (2.34 g, 96%). HPLC (Condition A): Rt 2.83 min (purity 99.2%). MS (ESI+): 291.1.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][C@:17]3([CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[C:16]2=[O:25])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:26][C:27]1[CH:32]=[CH:31][C:30](I)=[C:29]([Cl:34])[CH:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>C(O)CCC.[Cu]I>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([N:21]2[CH2:22][CH2:23][CH2:24][C@@:17]3([C:16](=[O:25])[N:15]([C@H:12]4[CH2:13][CH2:14][C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH2:10][CH2:11]4)[CH2:19][CH2:18]3)[CH2:20]2)=[C:29]([Cl:34])[CH:28]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CC[C@]3(CCCNC3)C2=O)CC1
Reactant: Clc1cc(Br)ccc1I
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: OCCO
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CC[C@]3(CCCN(c4ccc(Br)cc4Cl)C3)C2=O)CC1
Temperature: 100 °C

Procedure:
A mixture of (5S)-2-(cis-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (0.282 g, 0.000769 mol), 4-bromo-2-chloro-1-iodobenzene (0.293 g, 0.000922 mol) (Lancaster, cat #: 19245), copper(I) iodide (0.015 g, 0.000077 mol), potassium phosphate (0.490 g, 0.00231 mol) and 1,2-ethanediol (0.0857 mL, 0.00154 mol) in 1-butanol (0.75 mL) was heated at 100° C. under nitrogen for 2 d. The reaction mixture was filtered, concentrated under reduced pressure, and the residue was purified by flash chromatography on a silica gel column (eluting with 0 to 50% ethyl acetate in hexanes) to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]([CH3:22])[CH:11]=2)=[S:9])=[CH:4][CH:3]=1.[CH2:25]([OH:28])[C:26]#[CH:27]>C(NCC)C.[Cu](I)I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:27]#[C:26][CH2:25][OH:28])[CH:17]=3)[N:12]([CH3:22])[CH:11]=2)=[S:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Cn1cc(C(=S)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: Cn1cc(C(=S)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21

Procedure:
A suspension of N-(4-chlorobenzyl)-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbothioamide (0.20 g) from Preparation No. 44, propargyl alcohol (0.030 mL), copper iodide (0.028 g), and bis(triphenylphosphine)palladium(II)chloride (0.0095 g) in diethylamine (10 mL) is stirred at room temperature for 18 h. The solid in the reaction mixture is filtered, then dissolved in CH2Cl2/MeOH, and adsorbed onto silica. Purification by chromatography (eluent 1% MeOH:CH2Cl2 (1 L), 2% MeOH:CH2Cl2 (1 L)) affords the title compound as a yellow solid (0.12 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([F:17])=[CH:9][CH:8]=1.[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>C1COCC1.O.CCOC(C)=O>[F:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Fc1ccc(Br)c2ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)c1ccc(F)c2ccccc12
Temperature: -20 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
A solution of n-butyllithium (2.5 M in THF, 20 mL, 50 mmol) was cooled to −78° C., and a solution of 1-bromo-4-fluoronaphthalene (11.25 g, 50 mmol) in THF (40 mL) was added slowly and the mixture was stirred for 1 hour. The reaction mixture was warmed to −20° C., then added to a solution of diethyl oxalate (29.2 g, 200 mmol) in THF (40 mL) at −78° C. After slowly warming-up to room temperature, EtOAc (100 mL), 10% HCl (50 mL) and water (50 mL) were added and the phases were separated. The aqueous layer was extracted with EtOAc (2×100 mL), and the organic layers were combined, washed with brine (50 mL), and dried over Na2SO4. After evaporating the solvent and the excess diethyl oxalate under high vacuum, the residue was purified by flash column chromatography (1:1 DCM:hexane) to give the title compound (9.4 g, 76% yield) as a white solid. 1H—NMR (400 MHz, CDCl3) δ (9.13 (d, J=8.6 Hz, 1H), 8.20 (d, J=8.4 Hz, 1H), 8.01 (dd, J=8.2, 5.4 Hz, 1H), 7.76 (t, J=7.2 Hz, 1H), 7.67 (t, J=8.1 Hz, 1H), 7.21 (t, J=8.5 Hz, 1H), 4.49 (q, J=7.1 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([N:16]3[CH2:20][CH2:19][CH:18]([N:21]4[C:25]5=[N:26][CH:27]=[CH:28][CH:29]=[C:24]5[C:23]([C:30]#[N:31])=[N:22]4)[C:17]3=[O:32])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:33](N)[CH2:34][NH2:35]>CC(O)=O.CCO>[NH:31]1[CH2:33][CH2:34][N:35]=[C:30]1[C:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:21]([CH:18]2[CH2:19][CH2:20][N:16]([C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:12]=3[CH:13]([CH3:14])[CH3:15])[C:17]2=[O:32])[N:22]=1
Reactant: CC(C)c1c(N2CCC(n3nc(C#N)c4cccnc43)C2=O)cnn1-c1ccc(F)cc1
Reactant: NCCN
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)c1c(N2CCC(n3nc(C4=NCCN4)c4cccnc43)C2=O)cnn1-c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A mixture of 1-[1-[1-(4-fluorophenyl)-5-isopropyl-pyrazol-4-yl]-2-oxo-pyrrolidin-3-yl]pyrazolo[3,4-b]pyridine-3-carbonitrile (0.082 g, 0.19 mmol) in ethane-1,2-diamine (1 mL), HOAc (0.1 mL) and EtOH (2.5 mL) was stirred at 100° C. for 1 hr. The mixture was then cooled to room temperature, quenched with saturated aqueous NaHCO3 (50 mL) and extracted with EtOAc (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-[3-(4,5-dihydro-1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2-one (0.085 g, 94%).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:28])([F:27])[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:26])[CH2:17][C@@H:18](OS(C)(=O)=O)[CH2:19][CH3:20])=[CH:11][CH:10]=1.O>O1CCCC1>[CH2:19]([C@H:18]1[N:15]([C:12]2[CH:13]=[CH:14][C:9]([C:8]([F:28])([F:27])[F:7])=[CH:10][CH:11]=2)[C:16](=[O:26])[CH2:17]1)[CH3:20]
Reactant: CC[C@@H](CC(=O)Nc1ccc(C(F)(F)F)cc1)OS(C)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@@H]1CC(=O)N1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.2 %

Procedure:
99.2 mg (0.884 mmol) of potassium tert-butoxide was suspended in tetrahydrofuran (1.5 mL) and a tetrahydrofuran solution (1.5 mL) containing 300 mg (0.884 mmol) of (S)-N-[4-(trifluoromethyl)phenyl]-3-methanesulfonyloxypentanoic acid amide produced in Example 3 was added dropwise thereto at room temperature for 5 minutes. After stirring at room temperature for further 5.5 hours, water (5 mL) was added and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine and the product was dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain (R)-4-ethyl-1-[4-(trifluoromethyl)phenyl]-2-azetidinone as a brown solid (194.0 mg). The reaction yield of the product was determined by the method described in Example 7 to be 81%.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH:26]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([CH3:45])([CH3:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:33][C:32]=2[O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>CCOCC>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]([CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([OH:30])[CH:26]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([CH3:44])([CH3:45])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:33][C:32]=2[O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCCCC(C)(C)c1ccc(C2CN(Cc3ccccc3)CCC2=O)c(OCc2ccccc2)c1
Reactant: Br[Mg]CCCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1ccc(C2CN(Cc3ccccc3)CCC2(O)CCCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
To a 0° C. solution of 7.0 mmols. of 3-phenylpropylmagnesium bromide in 7 ml. of tetrahydrofuran is slowly added a solution of 2.48 g. (5.0 mmols) of 1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidone in 10 ml. of tetrahydrofuran. The resultant mixture is stirred for one hour and is then added to 250 ml. of saturated ammonium chloride-250 ml. ether. The ether phase is dried over magnesium sulfate and evaporated. The residue is purified via column chromatography on 200 g. of silica gel eluted with 50% ether-cyclohexane to yield the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH:11][CH:12]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[C:24]([C@:32]([C:47]([OH:49])=[O:48])([OH:46])[C@:33]([C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([OH:37])[C:34]([OH:36])=[O:35])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(O)C>[C:38]([C@:33]([C:34]([OH:36])=[O:35])([OH:37])[C@:32]([C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([OH:46])[C:47]([OH:49])=[O:48])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C@@H:12]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc3cnccc23)C1
Agent: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2cccc3cnccc23)C1
Temperature: 42 °C

Procedure:
Salt Formation: To a 5 L flask equipped with an internal temperature probe, a heating mantle and a mechanical stirrer were added tert-butyl 3-(isoquinolin-5-ylamino)pyrrolidine-1-carboxylate (250 g, 0.798 mol, from Example 1) and 3 L of 2-propanol. The mixture was stirred and warmed to 42° C. to form a homogeneous solution. To the stirred solution was added dibenzoyl-D-tartaric acid (D-DBTA) (242.9 g, 0.678 mol) in one portion and another 0.9 L of 2-propanol. The mixture was stirred at 40° C. for 15 minutes to form a solution. The mixture was stirred at 40° C. to form a yellow slurry. The slurry was cooled to 30° C. The suspension was filtered, washed with 2×250 mL of 2-propanol and dried in a vacuum oven at ˜35° C. Approximately 204.3 g of (R)-tert-butyl 3-(isoquinolin-5-ylamino)pyrrolidine-1-carboxylate dibenzoyl-D-tartaric acid salt crude product was obtained as a yellow solid (84% ee, 38% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])[C:11]([CH3:18])=[CH:10][C:9]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH2:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C
Agent: [Pd]
Product: CCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C

Procedure:
The title compound was prepared from [5-(ethyl-methyl-amino)-4-methyl-2-nitro-phenyl]-carbamic acid tert-butyl ester (Example C22) (3.28 g, 10.6 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a purple solid (2.94 g, 99%).
Reaction SMILES: [Cl:1][C:2]([C:24]([F:27])([F:26])[F:25])=[CH:3][C@@H:4]1[C@H:6]([C:7]([O:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-])=O)[C:12]=2[CH3:21])=[O:8])[C:5]1([CH3:23])[CH3:22]>[Ni]>[Cl:1][C:2]([C:24]([F:25])([F:26])[F:27])=[CH:3][C@@H:4]1[C@H:6]([C:7]([O:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]([NH2:18])[C:12]=2[CH3:21])=[O:8])[C:5]1([CH3:23])[CH3:22]
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1COC(=O)[C@H]1[C@@H](C=C(Cl)C(F)(F)F)C1(C)C
Agent: [Ni]
Product: Cc1ccc(N)c(C)c1COC(=O)[C@H]1[C@@H](C=C(Cl)C(F)(F)F)C1(C)C
Yield: 32.8 %

Procedure:
(2,6-Dimethyl-3-nitrophenyl)methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate (11.27 grams, 0.028 mole) was hydrogenated over Raney nickel. The product was chromatographed on an alumina column eluted with toluene to give (3-amino-2,6-dimethylphenyl)methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)2,2-dimethylcyclopropanecarboxylate (3.45 grams) as a liquid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:33][CH2:34]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(C)=O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f22) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16]([C:18]3[CH:23]=[C:22]([N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH:21]=[CH:20][C:19]=3[NH:30][C:31]([C:33]3[CH:34]=[C:35]([CH:47]=[CH:48][CH:49]=3)[CH2:36][S:37][CH2:38][CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])=[O:32])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16]([C:18]3[CH:23]=[C:22]([N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)[CH:21]=[CH:20][C:19]=3[NH:30][C:31]([C:33]3[CH:34]=[C:35]([CH:47]=[CH:48][CH:49]=3)[CH2:36][S:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:32])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)OC(C)(C)C)c3)nc2)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)O)c3)nc2)cc1C
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 8.1 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-(2-(5-(3,4-dimethylphenyl)pyrimidin-2-ylcarbamoyl)-4-(piperidin-1-yl)phenylcarbamoyl)benzylthio)propanoate (340 mg, 0.5 mmol, 1.00 equiv) in dichloromethane (18 mL), and trifluoroacetic acid (8.9 mL). The resulting solution was stirred for ca. 5.5 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by HPLC reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 25.3 mg (8%) of a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.35 (s, 1H), 11.26 (s, 1H), 8.72 (s, 2H), 8.25 (d, J=9 Hz, 1H), 7.86 (s, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.56˜7.741 (m, 3H), 7.37 (s, 1H), 7.28˜7.13 (m, 3H), 4.34 (s, 1H), 3.84 (s, 2H), 3.31 (m, 4H), 2.60˜2.55 (m, 2H), 2.32 (s, 3H), 2.16 (s, 3H), 1.71˜1.58 (m, 6H). MS (ES, m/z): 624 [M+H]+.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6])[CH2:3][OH:4].[CH3:33][C:34]([NH:45][CH2:46][CH:47]([OH:63])[CH2:48][O:49][C:50]1[C:55]2[C:56]3[C:61]([NH:62][C:54]=2[CH:53]=[CH:52][CH:51]=1)=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:36]1[CH:41]=[CH:40][C:39]([N:42]=[N+:43]=[N-:44])=[CH:38][CH:37]=1)[CH3:35].[CH3:64][C:65]1[C@@H:82]([O:83][C:84]([C@H:86]([OH:103])[C@@H:87]([NH:94][C:95]([C:97]2[CH:98]=[CH:99][CH:100]=[CH:101][CH:102]=2)=[O:96])[C:88]2[CH:89]=[CH:90][CH:91]=[CH:92][CH:93]=2)=[O:85])[CH2:81][C@:77]2([OH:104])[C:78]([CH3:80])([CH3:79])[C:66]=1[C@@H:67]([O:122][C:123]([CH3:125])=[O:124])[C:68]([C@@:70]1([CH3:121])[C@H:75]([C@@H:76]2[O:105][C:106]([C:108]2[CH:109]=[CH:110][CH:111]=[CH:112][CH:113]=2)=[O:107])[C@:74]2([O:116][C:117]([CH3:119])=[O:118])[CH2:114][O:115][C@@H:73]2[CH2:72][C@@H:71]1[OH:120])=[O:69].C1CCN2C(=NCCC2)CC1>C1COCC1>[NH2:1][C@H:2]([C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][CH:10]([CH3:11])[CH3:12])=[O:6])[CH2:3][OH:4].[CH3:35][C:34]([NH:45][CH2:46][CH:47]([OH:63])[CH2:48][O:49][C:50]1[C:55]2[C:56]3[C:61]([NH:62][C:54]=2[CH:53]=[CH:52][CH:51]=1)=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:36]1[CH:41]=[CH:40][C:39]([N:42]=[N+:43]=[N-:44])=[CH:38][CH:37]=1)[CH3:33].[CH3:64][C:65]1[C@@H:82]([O:83][C:84]([C@H:86]([OH:103])[C@@H:87]([NH:94][C:95]([C:97]2[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=2)=[O:96])[C:88]2[CH:89]=[CH:90][CH:91]=[CH:92][CH:93]=2)=[O:85])[CH2:81][C@:77]2([OH:104])[C:78]([CH3:79])([CH3:80])[C:66]=1[C@@H:67]([O:122][C:123]([CH3:125])=[O:124])[C:68]([C@@:70]1([CH3:121])[C@H:75]([C@@H:76]2[O:105][C:106]([C:108]2[CH:113]=[CH:112][CH:111]=[CH:110][CH:109]=2)=[O:107])[C@:74]2([O:116][C:117]([CH3:119])=[O:118])[CH2:114][O:115][C@@H:73]2[CH2:72][C@@H:71]1[OH:120])=[O:69]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Agent: CC(C)(NCC(O)COc1cccc2[nH]c3ccccc3c12)c1ccc(N=[N+]=[N-])cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)C[C@H](NC(=O)[C@@H](N)CO)C(=O)O

Procedure:
11 (0.1 g, 0.070 mmol) was treated with 1% DBU in THF (3 mL) for 45 seconds at room temperature and the product was precipitated by 1 M HCl in diethyl ether (200 mL) then it was purified on a silica gel column using chloroform/methanol (7:1) to afford 12 (75 mg, 89%) as a white powder. ESI-MS (5 kV, MeOH): m/z (%)=1225.1 (100) [M+Na]+; HPLC (230 nm): >95%.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:14]([C:22]1([C:28](O)=[O:29])[S:27][CH2:26][CH2:25][CH2:24][S:23]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].S1CCCSC1C(O)=O.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].C(Br)CCCCCCC>>[CH3:13][O:12][C:11]1[C:2]([NH:1][C:28]([C:22]2([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[S:23][CH2:24][CH2:25][CH2:26][S:27]2)=[O:29])=[C:3]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][CH:5]=[CH:4]2
Reactant: COc1ccc2ncccc2c1N
Reactant: CCCCCCCCC1(C(=O)O)SCCCS1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)C1SCCCS1
Agent: [Na+]
Solvent: CCCCCCCCBr
Product: CCCCCCCCC1(C(=O)Nc2c(OC)ccc3ncccc23)SCCCS1

Procedure:
5-Amino-6-methoxyquinoline, prepared as described in Example 60, was coupled with 2-octanyl-1,3-dithiane-2-carboxylic acid, prepared by treatment of 1,3-dithiane-2-carboxylic acid with sodium hexamethyldisilazide and octanyl bromide, according to the procedure described in Example 48 to give the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=1)(=[O:7])=[O:6].C(N(CC)C(C)C)(C)C>CN(C=O)C.O.Cl.[Cl-].[Na+].O>[O:6]=[S:5]1(=[O:7])[CH2:4][CH2:3][CH2:2][N:8]1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=1
Reactant: COC(=O)C(OC)c1ccc(NS(=O)(=O)CCCCl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(OC)c1ccc(N2CCCS2(=O)=O)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a solution of methyl 2-(4-(3-chloropropylsulfonamido)phenyl)-2-methoxyacetate (1.03 g, 3.07 mmol) in anhydr DMF (10 mL) was added N,N-diisopropylethylamine (2.0 mL, 11.5 mmol). The mixture was heated at 50° C. under argon for 17 hrs. After cooling to room temperature, the reaction was diluted with H2O, 1 M HCl and brine then extracted with EtOAc. The combined organics were washed with 1 M HCl, H2O and brine the dried over Na2SO4 and concentrated in vacuo. The residue was triturated with Et2O-EtOAc. After sitting overnight, the solution was decanted from solids then concentrated in vacuo. Purification by chromatography (50-70% EtOAc-hexanes) provided methyl 2-(4-(1,1-dioxidoisothiazolidin-2-yl)phenyl)-2-methoxyacetate as an impure oil (0.69 g, 75% yield). The product was used in the next synthetic step without further purification.
Reaction SMILES: [C:1]([C:3]1([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:2][CH2:1][C:3]1([S:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(Sc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CN)(Sc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Example 252A (1.0 g, 3.1 mmol) in THF (5 mL) at 0° C. was treated dropwise with 1M LiAlH4 in THF (3 mL), warmed to room temperature, stirred for 2 hours, quenched with methanol (1 mL), treated with 1N NaOH (50 mL), and extracted with ethyl acetate(3×100 mL). The combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product. MS (APCI) m/e 323 (M+H)+.