Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:14][C:13]2[C:3](=[CH:4][C:5]3[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=3[CH:12]=2)[O:2]1.C1C=CC=CC=1.[OH-].[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>O>[Cl:23][CH2:24][C:25]([N:9]1[CH2:10][CH2:11][C:5]2[CH:4]=[C:3]3[O:2][CH2:1][O:14][C:13]3=[CH:12][C:6]=2[CH2:7][CH2:8]1)=[O:26]
Reactant: O=C(Cl)CCl
Reactant: c1c2c(cc3c1OCO3)CCNCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: O=C(CCl)N1CCc2cc3c(cc2CC1)OCO3
Reaction time: 0.17 h

Procedure:
One-tenth mole, 22.7 g, of 2,3,4,5-tetrahydro-7,8-methylenedioxy-1H-3-benzazepine was dissolved in 200 ml of water and 200 ml of benzene added. Forty ml of a 10% solution of sodium hydroxide was added to the vigorously stirred emulsion and 17 g (0.15 mole) of chloroacetyl chloride was added dropwise. As the pH approached 5, another 10-ml portion of 10% sodium hydroxide solution was added until a total of 100 ml has been added. After all the chloroacetyl chloride had been added, the mixture, which has an acid reaction, was stirred for another 10 minutes then allowed to stand overnight at room temperature.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[C:17]([OH:19])=O.S(Cl)([Cl:22])=O>ClCCl>[CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[C:17]([Cl:22])=[O:19]
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)c1ccc2c(c1)C(=O)c1ccccc1C2=O

Procedure:
Anthraquinone-2-carboxylic acid (2.52 g, 10 mmol) was suspended in dichloro methane (100 ml). Thionyl chloride (50 ml) was added and the mixture heated to reflux in a nitrogen atmosphere for several hours giving a clear yellow solution. Dichloro methane and excess thionyl chloride was removed in vacuo giving a yellow solid. The solid was filtered off, washed several times with petroleum ether and dried in vacuo. Yield 2.69 g (99% from anthraquinone-2-carboxylic acid); MP: 143-144.5° C.; TLC (analyzed as the methyl ester: a small sample of the acid chloride was dissolved in dry methanol and analyzed immediately using ethyl acetate as eluent); Rf =0.68. MS (FAB+): 307.1 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([NH2:23])[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[CH2:16][P:17]([O:21]C)([O:19]C)=[O:18])[N:12]=[CH:11][CH:10]=[N:9]2.COC(=O)CN=CC1C=CC=CC=1.Cl>>[NH2:23][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[CH2:16][P:17]([OH:19])([OH:21])=[O:18])[N:12]=[CH:11][CH:10]=[N:9]2)[C:3]([OH:24])=[O:2]
Reactant: COC(=O)C(N)Cc1cc2nccnc2cc1CP(=O)(OC)OC
Agent: COC(=O)CN=Cc1ccccc1
Agent: Cl
Product: NC(Cc1cc2nccnc2cc1CP(=O)(O)O)C(=O)O

Procedure:
The 6,7-bis(bromomethyl)quinoxaline was reacted with trimethyl phosphite to obtain the intermediate dimethyl phosphonate which was converted to α-amino-7-[(dimethoxyphosphinyl)methyl]-6-quinoxalinepropanoic acid methyl ester using N-benzylidene glycine methyl ester. Hydrolysis with 6N hydrochloric acid afforded α-amino-7-(phosphonomethyl)-6-quinoxalinepropanoic acid; m.p. 250° C.; MS (neg. FAB) 310; 1H NMR (DMSO-d6, 1 drop of DCl, 400 MHz): δ3.3-3.6 (overlapping multiplets, 4H, CH2), 4.39 (t, J=6 Hz, 1H, CH), 7.99 (d, J=3.5 Hz, 1H, ArH), 8.03 (s, 1H, ArH), 8.89 (broad s, 2H, H-2 and H-3).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH3:5])C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:46][CH2:47][C:48]1[C:49]([OH:56])=[N:50][C:51]([CH3:55])=[CH:52][C:53]=1[CH3:54]>ClCCl.O>[OH:56][C:49]1[C:48]([CH2:47][NH:46][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([CH:4]([O:3][CH3:1])[CH3:5])=[CH:14][CH:13]=2)=[C:53]([CH3:54])[CH:52]=[C:51]([CH3:55])[N:50]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CCOC(C)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(C)c1ccc(C(=O)NCc2c(C)cc(C)nc2O)cc1
Temperature: 25 °C
Yield: 23.3 %

Procedure:
To the solution of 4-(1-ethoxyethyl)benzoic acid (162 mg, 0.9 mmol) in dichloromethane (80 mL) was added o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (513 mg, 1.35 mmol) and triethylamine (273 mg, 2.7 mmol). then the 3-(aminomethyl)-4,6-dimethyl pyridine-2-ol (137 mg, 0.9 mmol) was added, the solution was stirred at room temperature, water (80 mL) was added and washed 3 times, the organic layer was evaporated and purified by column chromatography (silica gel, dichloromethane/meth anol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-methoxyethyl)benzamide (66 mg, 23%). LRMS (M+H+) m/z: calcd: 314.16. found 314; 1H-NMR (300 MHz, CD3OD)1H-NMR (300 MHz, CD3OD) δ 1.379 (d, 3H), 2.241 (s, 3H), 2.368 (s, 3H), 3.207 (s, 3H), 4.368-4.389 (m, 1H), 4.497 (s, 2H), 6.110 (s, 1H), 7.377 (d, J=8.4 Hz, 2H), 7.779 (d, J=8.4 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[C:20]([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[CH2:23][CH2:24][NH:25][CH:26]3[CH3:31])=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][CH:29]=[CH:30][C:21]=4[C:20]4[C:15]([F:14])=[N:16][CH:17]=[CH:18][CH:19]=4)[CH:26]3[CH3:31])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2c(-c3cccnc3F)cccc21
Product: CC1c2cccc(-c3cccnc3F)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(2-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [I:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7](Cl)=[O:8].CCN(C(C)C)C(C)C.[F:19][C:20]([F:24])([F:23])[CH2:21][NH2:22]>O1CCCC1>[I:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([NH:22][CH2:21][C:20]([F:24])([F:23])[F:19])=[O:8]
Reactant: O=C(Cl)c1ccoc1I
Reactant: NCC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCC(F)(F)F)c1ccoc1I
Reaction time: 1 h
Yield: 52.6 %

Procedure:
To a stirred solution of 2-iodofuran-3-carbonyl chloride (6.69 g, 26.1 mmol) in anhydrous tetrahydrofuran (120 ml) was added DIPEA (9.11 ml, 52.2 mmol) followed by 2,2,2-trifluoroethanamine (2.08 ml, 26.1 mmol) and the solution stirred for 1 h. The mixture was concentrated in vacuo. The residue was partitioned between 2M hydrochloric acid (aq) solution (100 ml) and dichloromethane (100 ml). The aqueous layer was separated and extracted with dichloromethane (2×100 ml). The combined organic layers were dried (phase separator) and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (gradient 0-50% ethyl acetate in cyclohexane) to afford the title compound (4.38 g, 53%). LCMS RT=0.98 min, M+H+=319.9.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[N+:11]([C:14]1[O:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([O-:13])=[O:12]>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=3[CH:18]([C:17]3[O:20][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=3)[C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc([N+](=O)[O-])o1

Procedure:
3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 5-nitro-furfuraldehyde in an analogous manner to that described in Example 1 to give 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9-(5-nitro-2-furyl)-1,8(2H,5H)-acridinedione. Crystallization from ethyl acetate/methanol gave a beige crystalline solid of melting point 248-250° C. (decomposition).
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.CCN(CC)CC>CC(O)C>[I:8][C:7]1[C:2]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:3][C:4]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1ccc(I)c(Cl)n1
Reactant: C1CCNCC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc(I)c(N2CCCCC2)n1
Yield: 58.4 %

Procedure:
A solution of 2-chloro-3-iodo-6-(trifluoromethyl)pyridine (Tet. Lett., 1998, 39(13), 1749-1752) (350 mg, 1.14 mmol), piperidine (135 μl, 1.37 mmol) and Et3N (640 μl, 4.56 mmol) in i-PrOH (2 mL) was heated for 1 h at 140° C. in a microwave reactor. The reaction mixture was concentrated to dryness and the crude was purified through flash chromatography (SiO2, heptane) to afford 237 mg (58%) of the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([OH:21])([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[H][H]>[Pd].C(O)C>[OH:21][C:11]1([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(C2(O)CCNCC2)cc1

Procedure:
30 g of N-benzyl-4-hydroxy-4-(4-methylphenyl)-piperidine in a mixture of equal parts of ethyl acetate and ethanol with palladium (5% on charcoal) is hydrogenated until one equivalent of hydrogen has been absorbed to give 4-hydroxy-4-(4-methylphenyl)-piperidine, m.p. 137°-138° (from ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].F[B-](F)(F)F.[CH2:17]([O+](CC)CC)[CH3:18]>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[NH:6])[O:5][CH2:17][CH3:18]
Reactant: CC[O+](CC)CC
Reactant: NC(=O)c1cccc(Cl)c1Cl
Agent: F[B-](F)(F)F
Product: CCOC(=N)c1cccc(Cl)c1Cl

Procedure:
starting from 2,3-dichlorobenzamide and triethyloxonium tetrafluoroborate there is obtained ethyl 2,3-dichlorobenzimidate as an oil; mass spectrum: 216 (16), 189 (20), 182 (9), 173 (100), 172 (56);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]4[C:31]([C:36]([O:38]C(C)(C)C)=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:26][CH:25]=2)[C:18]([CH3:43])=[C:17]3[CH3:44])=[O:13])[CH3:10])=[CH:5][CH:4]=1.N1C(C)=CC=CC=1C.[Si](OS(C(F)(F)F)(=O)=O)(CC)(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]4[C:31]([C:36]([OH:38])=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:26][CH:25]=2)[C:18]([CH3:43])=[C:17]3[CH3:44])=[O:13])[CH3:10])=[CH:5][CH:4]=1
Reactant: COc1ccc([C@H](C)NC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)cc1
Agent: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COc1ccc([C@H](C)NC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (S)-tert-butyl 4′-((5-(1-(4-methoxyphenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylate (58.9 mg, 0.1 mmol) and 2,6-lutidine (0.13 mL, 1.15 mmol) in DCM (1 mL) at 0° C. was added TESOTf (0.17 mL, 0.75 mmol). The reaction mixture was stirred at rt for 2 h. The completion of the reaction was monitored by anal. HPLC. The mixture was evaporated in vacuo to obtain the crude which was purified by prep. HPLC (MeOH/Acetonitrile/water) to obtain the title compound. ESI-MS (m/z): 533 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[OH:9].[CH3:10][CH:11]([CH3:15])[CH2:12][C:13]#[CH:14]>N1C=CC=CC=1>[Br:8][C:4]1[C:3]2[O:9][C:13]([CH2:12][CH:11]([CH3:15])[CH3:10])=[CH:14][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Oc1c(Br)cccc1Br
Reactant: C#CCC(C)C
Solvent: c1ccncc1
Product: CC(C)Cc1cc2cccc(Br)c2o1

Procedure:
A stirred mixture of 2,6-dibromophenol (946 mg, 3.76 mmol), Cu2O (322 mg, 2.25 mmol), 4-methylpentyne (0.5 mL, 3.9 mmol) and pyridine (5 mL) was heated at vigorous reflux for 0.5 h. The mixture was concentrated under reduced pressure to remove pyridine, diluted with ether (100 mL), washed with water (50 mL), 5% aq HCl (2×50 mL) and 1M aq NaOH (50 mL) and dried over MgSO4. Removal of the solvent left an oil (650 mg) containing 7-bromo-2-isobutylbenzofuran (˜70% pure).
Reaction SMILES: C(O)C.C(O[C:7](=[O:37])/[C:8](=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]2)=[C:25]([O:35][CH3:36])[CH:24]=1)/[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)C.[OH-].[Na+].Cl>C(OCC)(=O)C>[F:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][N:13]1[CH2:12][CH2:11][CH2:10][CH2:9]/[C:8](=[CH:22]\[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]3)=[C:25]([O:35][CH3:36])[CH:24]=2)/[C:7]1=[O:37]
Reactant: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCCCNCc1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(/C=C2\CCCCN(Cc3cccc(F)c3)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
To a to ethanol (2.0 mL) solution of (E)-6-(3-fluorobenzylamino)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)hexanoic acid ethyl ester (173 mg), 2N sodium hydroxide solution (2.0 mL) was added. After refluxing the reaction solution for 1 hour and confirming disappearance of the starting materials, 2N hydrochloric acid and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. IPEA (134 μL), EDC (98.2 mg), and HOBT (69.2 mg) were added to a DMF (5.0 mL) solution of the obtained carboxylic acid compound (112 mg) one by one, and the reaction solution was agitated at room temperature overnight. After confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate), and 70.3 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][N:11]([C@H:14]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([N:28](S(C5C=CC(OC)=CC=5)(=O)=O)[C:29]5[S:30][CH:31]=[CH:32][N:33]=5)(=[O:27])=[O:26])=[CH:21][CH:20]=4)[C:15]3=[O:45])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1CCOCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][N:11]([C@H:14]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[CH:21][C:22]([S:25]([NH:28][C:29]5[S:30][CH:31]=[CH:32][N:33]=5)(=[O:26])=[O:27])=[CH:23][CH:24]=4)[C:15]3=[O:45])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COc1ccc(S(=O)(=O)N(c2nccs2)S(=O)(=O)c2ccc(N3CC[C@H](N4CC[C@H](c5cc(Cl)cc(Cl)c5)C4)C3=O)cc2)cc1
Solvent: C1COCCN1
Solvent: ClCCl
Product: O=C1[C@@H](N2CC[C@H](c3cc(Cl)cc(Cl)c3)C2)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
Synthesized according to General Procedure 14. To a stirred solution of 4-[(3R,3′S)-3-(3,5-dichlorophenyl)-2′-oxo-1,3′-bipyrrolidin-1′-yl]-N-(4-methoxyphenylsulfonyl)-N-(thiazol-2-yl)benzenesulfonamide (40 g, 56.5 mmol) in anhydrous DCM (320 mL) under nitrogen at 0° C. was added morpholine (5.42 g, 5.42 mL, 62.2 mmol) dropwise over 5 minutes. The cooling bath was removed and the reaction mixture was allowed to warm up to RT. Stirring was continued at RT for 2 hours during which time the product precipitated. The solid was filtered, washed with ethyl acetate (100 mL) and dried under vacuum to constant weight to provide 4-[(3R,3′S)-3-(3,5-dichlorophenyl)-2′-oxo-1,3′-bipyrrolidin-1′-yl]-N-(thiazol-2-yl)benzenesulfonamide as a white solid (23.50 g, 43.7 mmol, 77% yield). 1H-NMR (400 MHz, DMSO-d6) δ 7.84-7.77 (m, 4H), 7.43-7.37 (m, 3H), 7.24 (d, J=4.6 Hz, 1H), 6.81 (d, J=4.6 Hz, 1H), 3.83-3.72 (m, 2H), 3.58 (t, J=8.8 Hz, 1H), 3.07-2.96 (m, 3H), 2.87 (td, J=8.6, 4.3 Hz, 1H), 2.34-2.20 (m, 2H), 2.11-2.02 (m, 1H) and 1.74 (dt, J=19.9, 6.9 Hz, 1H) ppm. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=537.3; tR=1.30 min. SFC (Chiralpak AS-H, (0.46×25 cm), 40% methanol (1% DEA)/CO2, 3 mL/min): tR=13.0 min.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[Cl:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:21]=[CH:20][N:19]([CH2:22][C@@H:23]([NH:25][C:26]([C:28]3[N:29]=[C:30]([CH2:33]O)[S:31][CH:32]=3)=[O:27])[CH3:24])[N:18]=2)[CH:12]=[CH:13][C:14]=1[C:15]#[N:16]>>[CH3:1][N:2]([CH3:7])[CH2:3][C:4]([O:6][CH2:33][C:30]1[S:31][CH:32]=[C:28]([C:26](=[O:27])[NH:25][C@@H:23]([CH3:24])[CH2:22][N:19]2[CH:20]=[CH:21][C:17]([C:11]3[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[C:9]([Cl:8])[CH:10]=3)=[N:18]2)[N:29]=1)=[O:5]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(CO)n1
Reactant: CN(C)CC(=O)O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(COC(=O)CN(C)C)n1
Yield: 39.5 %

Procedure:
(S)-(4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)thiazol-2-yl)methyl 2-(dimethylamino)acetate was prepared using the method of Example 34(d) starting from N,N-dimethylglycine (0.062 g, 0.597 mmol) and (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(hydroxymethyl)thiazole-4-carboxamide (0.2 g, 0.498 mmol). The product was triturated using diethyl ether and purified by Flash-chromatography, respectively. Yield 39.5%. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 2.39 (s, 6H), 3.30 (s, 2H), 4.31 (dd, 1H), 4.43 (dd, 1H), 4.60 (m, 1H), 5.43 (d, 2H), 6.63 (d, 1H), 7.49 (d, 1H), 7.70 (d, 1H), 7.84 (dd, 1H), 7.95 (d, 1H), 7.97 (d, 1H), 8.12 (s, 1H).
Reaction SMILES: [Cl-].[Li+].BrC(Br)C.Cl[Si](C)(C)C.[C:12]([N:19]1[CH2:22][CH:21](I)[CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[CH:24]1([C:27]2[CH:43]=[CH:42][C:30]([CH2:31][O:32][C:33]3[CH:38]=[CH:37][C:36](I)=[CH:35][C:34]=3[O:40][CH3:41])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1>O1CCCC1.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Zn]>[CH:24]1([C:27]2[CH:43]=[CH:42][C:30]([CH2:31][O:32][C:33]3[CH:38]=[CH:37][C:36]([CH:21]4[CH2:22][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:20]4)=[CH:35][C:34]=3[O:40][CH3:41])=[CH:29][CH:28]=2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: COc1cc(I)ccc1OCc1ccc(C2CC2)cc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(Br)Br
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: COc1cc(C2CN(C(=O)OC(C)(C)C)C2)ccc1OCc1ccc(C2CC2)cc1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
To a suspension of zinc (3.0 g) and lithium chloride (1.5 g) in THF (25 mL) were added dibromoethane (0.30 mL) and chlorotrimethylsilane (0.44 mL) at 70° C. under argon atmosphere. The mixture was stirred at 70° C. for 10 min. A solution of 1-Boc-3-iodoazetidine (9.8 g) in THF (10 mL) was added dropwise to the mixture at RT. The mixture was stirred at RT for 1 hr. To the mixture were added a solution of 1-(4-cyclopropylbenzyloxy)-4-iodo-2-methoxybenzene (5.3 g) prepared in (3) in THF (15 mL) and bis(triphenylphosphine)palladium (II) dichloride (0.49 g). The reaction mixture was stirred at RT for 3 hr. The reaction mixture was quenched with saturated aqueous NH4C1 and extracted with ethyl acetate. The organic layer was dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by silica-gel chromatography (Developing solvent: hexane/ethyl acetate=9/1 to 4/1) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]=[C:10]=[O:11])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[CH3:17][N:18]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:27])[C:21]=2[CH:20]=[N:19]1.N1C2C=CC=C(N)C=2C=N1>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:8][NH:9][C:10]([NH:27][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:21]=1[CH:20]=[N:19][N:18]2[CH3:17])=[O:11]
Reactant: Cn1ncc2c(N)cccc21
Reactant: O=C=NCc1ccc(N2CCCC2)c(F)c1
Agent: Nc1cccc2[nH]ncc12
Product: Cn1ncc2c(NC(=O)NCc3ccc(N4CCCC4)c(F)c3)cccc21

Procedure:
The title compound was prepared using the procedure described in Example 89B using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]pyrrolidine and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) δ 8.98 (s, 1H), 8.18 (s, 1H), 7.63 (d, 1H), 7.12 (t, 1H), 7.10 (m, 2H), 7.01 (m, 2H), 6.75 (t, 1H), 4.22 (s, 2H), 3.99 (s, 3H), 3.30 (m, 4H), 1.89 (m, 4H); MS (ESI) (M+H)+ 368.
Reaction SMILES: [CH3:1][NH2:2].[N:3]1([C:8]2[N:13]=[C:12]([CH:14]3[CH:18]([C:19]([O:21]CC)=O)[CH2:17][CH2:16][N:15]3[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:11]=[C:10]([CH3:31])[N:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.O>C1COCC1>[N:3]1([C:8]2[N:13]=[C:12]([CH:14]3[CH:18]([C:19](=[O:21])[NH:2][CH3:1])[CH2:17][CH2:16][N:15]3[C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH:11]=[C:10]([CH3:31])[N:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)C1c1cc(C)nc(-n2ccnc2)n1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)C1CCN(C(=O)OC(C)(C)C)C1c1cc(C)nc(-n2ccnc2)n1
Temperature: 60 °C

Procedure:
Methylamine (35 mL of a 25 wt % solution in THF) was added all at once to a solution of 1-tert-butyl 3-ethyl 2-(2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)pyrrolidine-1,3-dicarboxylate (650 mg, 1.6 mmol) in THF (30 mL). The reaction mixture was heated to 60° C. for a period 12 h then cooled to rt. Water (50 mL) was added and the resulting solution was extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to afford tert-butyl 2-(2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)-3-(methylcarbamoyl)pyrrolidine-1-carboxylate (620 mg) as yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17]C)=[CH:14][CH:15]=3)[N:10]([CH3:19])[C:9]=2[CH3:20])=[O:7])[CH2:3][CH2:2]1.C(Cl)Cl>>[CH:1]1([CH2:4][NH:5][C:6]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[N:10]([CH3:19])[C:9]=2[CH3:20])=[O:7])[CH2:3][CH2:2]1
Reactant: COc1ccc2c(C(=O)NCC3CC3)c(C)n(C)c2c1
Solvent: ClCCl
Product: Cc1c(C(=O)NCC2CC2)c2ccc(O)cc2n1C
Yield: 76.9 %

Procedure:
This material was prepared by reaction of N-(cyclopropylmethyl)-6-methoxy-1,2-dimethyl-1H-indole-3-carboxamide 55a (0.38 g, 1.4 mmole) with 1.0 M BBr3in CH2Cl2 (4.19 ml, 4.19 mmole) in a manner as previously described for example 1d to give a pale yellow solid (0.278 g, 77%). 1H NMR (400 MHz, CD3OD) δ7.55 (1H, d, J=8.5 Hz), 6.77 (1H, s), 6.71 (1H, d, J=8.5 Hz), 3.63 (3H, s), 3.28 (2H, m), 2.61 (3H, s), 1.18 (1H, m), 0.56 (2H, m); ESIMS (MH+): 259.10.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1.[CH:16]1([C:19](=[S:21])[NH2:20])[CH2:18][CH2:17]1>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:19]([CH:16]2[CH2:18][CH2:17]2)[S:21][C:5]=1[C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)=[O:15]
Reactant: NC(=S)C1CC1
Reactant: COC(=O)C(=O)C(Cl)c1cccc(C)c1
Product: COC(=O)c1nc(C2CC2)sc1-c1cccc(C)c1

Procedure:
prepared by reaction of 3-chloro-2-oxo-3-m-tolyl-propionic acid methyl ester with cyclopropanecarbothioic acid amide. LC-MS: tR=0.99 min; [M+H]+=274.3.