Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(O)CCCCCC.[CH2:10]([C:22]1C=CC=C[C:23]=1S(Cl)(=O)=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]CC.[C:32]1(C)[CH:37]=[CH:36][C:35]([S:38]([O:41][CH:42]([CH3:49])[CH2:43]CCCCC)(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[CH2:19]([C:34]1[CH:33]=[CH:32][CH:37]=[CH:36][C:35]=1[S:38]([O:41][CH:42]([CH3:43])[CH3:49])(=[O:39])=[O:40])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCc1ccccc1S(=O)(=O)Cl
Reactant: CCCCCCC(C)OS(=O)(=O)c1ccc(C)cc1
Solvent: CCCCCCC(C)O
Product: CCCCCCCCCCCCc1ccccc1S(=O)(=O)OC(C)C
Yield: 83 %

Procedure:
In the Example of preparation of material 18, 2-octanol was used in place of 2-propanol in the Example of preparation of material 17. In the Example of preparation of material 19, dodecylbenzene sulfonyl chloride was used in place of p-toluene sulfonyl chloride in the Example of preparation of material 17. Other procedures were made in the same way as the Example of preparation of material 17. In the Example of preparation of material 18, 1-methylheptyl p-toluene sulfonate was obtained in the yield of 72% and, in the Example of preparation of material 19, 1-methylethyl dodecylbenzene sulfonate was obtained in the yield of 83%.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@H:5]1[C@H:14]2[CH2:15][CH2:16][N:17]([C:18]([C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]3[NH:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:19])[C@H:13]2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]1.CI.[C:37](=O)([O-])O.[Na+]>O1CCCC1>[CH3:37][O:3][CH2:4][C@H:5]1[C@H:14]2[CH2:15][CH2:16][N:17]([C:18]([C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]3[NH:26][C:27](=[O:34])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:19])[C@H:13]2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]1
Reactant: O=C(N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](CO)Nc3ccccc3[C@@H]21)c1ccccc1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccccc1
Reaction time: 1 h
Yield: 84 %

Procedure:
Sodium hydride (60% in oil, 14 mg, 0.1 mmol) was suspended in tetrahydrofuran (1 ml), the compound (35 mg, 0.08 mmol) synthesized in Example 50 was added under ice-cooling, and the suspension was stirred for 1 hr. Methyl iodide (14 mg, 0.1 mmol) was added thereto, and the mixture was stirred under ice-cooling for 30 min., and then at room temperature for 2 hrs. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried (over anhydrous Na2SO4), and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (10 g) and eluted with hexane-ethyl acetate (4:1, v/v) to give the title compound (30 mg, 84%) as an amorphous form.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[CH3:12][N:13]([CH3:16])C=O.[O:17]1CCC[CH2:18]1>>[CH3:12][N:13]([CH3:16])[C:2]1[S:3][C:4]([CH:18]=[O:17])=[CH:5][N:6]=1
Reactant: C1CCOC1
Reactant: CN(C)C=O
Reactant: Clc1nccs1
Agent: [Li]CCCC
Product: CN(C)c1ncc(C=O)s1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
To a solution of 2-chlorothiazole (300 mg, 2.51 mmol) in distilled tetrahydrofuran (4 mL) at −78° C. was added n-butyllithium (2.5M solution in hexane, 2.58 mmol, 1.03 mL) slowly dropwise. After stirring 10 min at −78° C., N,N-dimethylformamide (2.76 mmol, 0.213 mL) was added and the reaction was warmed slowly to room temperature over 2 h. The reaction mixture was quenched with water (80 μL) and stirred for 24 h at room temperature. After the volatiles were removed under reduced pressure, the residue was diluted with water (25 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (25 mL), dried (MgSO4), filtered, concentrated under reduced pressure. The residue was flash chromatographed (silica gel, 50% ethyl acetate in petroleum ether) to yield 2-(dimethylamino)thiazole-5-carboxaldehyde (170 mg, 43% yield) as an orange solid.
Reaction SMILES: [CH:1]1([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Na+].O>C(O)C.C1(C)C=CC=CC=1>[CH:1]1([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH2:12][NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nc1ccccc1
Reactant: O=Cc1ccccc1C1C=Cc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: C1=CC(c2ccccc2CNc2ccccc2)c2ccccc21
Temperature: 25 °C
Yield: 71.1 %

Procedure:
To a solution of 2-(1-indenyl)benzaldehyde (7.0 mmol) in ethanol (19.4 mL) was added dropwise aniline (7.3 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature. After disappearance of the aldehyde was confirmed by gas chromatography, The solvent was distilled off under reduced pressure. After addition of ethanol (19.4 mL), sodium borohydride (4.5 mmol) was added to the solution and the mixture was reacted at room temperature for 3 hrs. Water and toluene were then added to the reaction mixture. The organic layer was dried and concentrated. The obtained oily substance was purified by silica gel column chromatography to give N-[2-(1-indenyl)phenylmethyl]-N-phenylamine (1.48 g, yield 24.0%) as a yellow oily substance.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:15][CH:14]2[C:13](=O)[NH:12][C:11]3=O)=[CH:6][CH:5]=1)[CH3:3].Cl.[OH-].[Na+]>O1CCCC1>[NH3:12].[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]23[CH2:15][CH:14]2[CH2:13][NH:12][CH2:11]3)=[CH:8][CH:9]=1)[CH3:1]
Reactant: CC(C)c1ccc(C23CC2C(=O)NC3=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1ccc(C23CNCC2C3)cc1
Product: N
Temperature: 65 °C
Reaction time: 6 h
Yield: 75.9 %

Procedure:
To a solution of 1-[4-(1-methylethyl)phenyl]-3-azabicyclo[3.1.0]hexane-2,4-dione (P20, 1.5 g) in anhydrous tetrahydrofuran (45 mL), BH3 in tetrahydrofuran (1 M, 26 mL) was added at 0° C. The reaction mixture was stirred at 65° C. for 6 hours, then cooled to 0° C., 6N aqueous HCl was added and the mixture was refluxed for 3 hours. The mixture was then basified with 5N aqueous NaOH and extracted with diethyl ether, the organic layer was washed with saturated aqueous NaCl and dried over Na2SO4. The solution was filtered and the filtrate was concentrated in vacuo. The crude compound was purified by a SCX cartridge (strong cationic exchanger, 10 g) eluting with MeOH (150 mL) and then NH3 0.3M in MeOH (100 mL) to give the title compound as colourless oil (0.5 g).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:12](OC(=O)C)(=[O:14])[CH3:13].O>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:12](=[O:14])[CH3:13])=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(C(C)(C)C)cc1
Yield: 99.4 %

Procedure:
10.6 g (0.071 mol) of p-tertiarybutylaniline was dissolved in 19 ml of glacial acetic acid. 8.0 g (0.078 mol) of acetic anhydride was then added dropwise to the solution at a temperature of 30° C. After the completion of dropwise addition, the reaction mixture was then allowed to undergo reaction at a temperature of 40° C. for 3 hours. The reaction solution was then poured into 200 ml of water. The resulting crystal was filtered off, washed with water, and then dried to obtain 13.5 g (yield: 99.9%) of p-tertiarybutylacetanilide. The melting point of the crystal was from 172.5° C. to 173.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](Cl)=[N:13][CH:12]=1.[CH2:19]([NH2:22])[CH2:20][NH2:21]>>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([NH:21][CH2:20][CH2:19][NH2:22])=[N:13][CH:12]=1
Reactant: Nc1cc(Cl)ccc1NC(=O)c1ccc(Cl)nc1
Reactant: NCCN
Product: NCCNc1ccc(C(=O)Nc2ccc(Cl)cc2N)cn1
Yield: 59 %

Procedure:
N-(2-Amino-4-chlorophenyl)-6-chloronicotinamide (282 mg, 1 mmol) and 5 ml of ethylenediamine were heated to 80° C. for 3 hours. The excess ethylenediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (180 mg, 59% yield) as a brown solid. LC-MS (m/z) 306 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:17])[CH:3]=1.C(Cl)CCl.C1C=C[C:25]2N(O)N=[N:28][C:26]=2[CH:27]=1.CCN(C(C)C)C(C)C.C1(N)CC1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH:28][CH:26]3[CH2:27][CH2:25]3)=[O:16])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:17])[CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cnccc1-c1ccc(Cl)cc1F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1cnccc1-c1ccc(Cl)cc1F
Reaction time: 0.08 h
Yield: 83 %

Procedure:
To a solution of 4-(4-chloro-2-fluorophenyl)nicotinic acid (500 mg, 1.987 mmol) (prepared as in Ex. 2, Part A) in DMF (6 mL) cooled to 0° C. was added EDC (571 mg, 2.98 mmol) and HOBT (609 mg, 3.97 mmol) and the mixture was stirred for 5 min. To the resultant solution DIPEA (1.04 mL, 5.96 mmol) followed by cyclopropanamine (567 mg, 9.93 mmol) was added and the mixture was stirred at room temperature for 12 h. The reaction mixture was treated with ice and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (1×10 mL), dried (Na2SO4) and concentrated under reduced pressure to afford 4-(4-chloro-2-fluorophenyl)-N-cyclopropylnicotinamide (480 mg, 1.65 mmol, 83% yield). LC/MS (ESI) m/e 291.0 [(M+H)+, calcd for C15H13ClFN2O 291.1]; LC/MS retention time (method C): tR=1.79 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[CH3:51][O:52][C:53]1[CH:63]=[CH:62][C:56]([O:57][CH2:58][CH2:59]CO)=[CH:55][CH:54]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:59][CH2:58][O:57][C:56]2[CH:62]=[CH:63][C:53]([O:52][CH3:51])=[CH:54][CH:55]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1ccc(OCCCO)cc1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(OCCCOC(=O)Nc2cc(C)c(Oc3ccnc4cc(OC)c(OC)cc34)cc2C)cc1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (98 mg) was added to toluene/triethylamine=10/1 (10 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (136 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(4-methoxyphenoxy)-1-propanol (83 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (130 mg, yield 76%).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:16]4[CH:21]=[CH:20][N:19]([CH2:22][CH2:23][CH2:24]N5CCCCC5)[C:18](=[O:31])[CH:17]=4)=[CH:15][C:10]3=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.FC(F)(F)C(O)=[O:39]>O>[O:31]=[C:18]1[CH:17]=[C:16]([C:14]2[CH:13]=[CH:12][N:11]3[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][N:9]=[C:10]3[CH:15]=2)[CH:21]=[CH:20][N:19]1[CH2:22][CH2:23][CH:24]=[O:39]
Reactant: O=C(O)C(F)(F)F
Reactant: O=c1cc(-c2ccn3c(-c4ccccc4)cnc3c2)ccn1CCCN1CCCCC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=CCCn1ccc(-c2ccn3c(-c4ccccc4)cnc3c2)cc1=O

Procedure:
To a solution of 4-(3-phenylimidazo[1,2-a]pyridin-7-yl)-1-(3-piperidin-1-ylpropyl)pyridin-2(1H)-one (0.210 g, 0.503 mmol) in 5.0 mL of a 2:1 solution of chloroform: (50% trifluoracetic acid:water) at 0° C. After 1 hour solvent was removed under reduced pressure to give 3-[2-oxo-4-(3-phenylimidazo[1,2-a]pyridin-7-yl)pyridin-1(2H)-yl]propanal. 1H NMR (CDCl3) δ 8.94 (s, 1H), 8.90 (d, 1H, J=6.84 Hz), 8.05 (s, 1H), 7.73–7.64 (m, 6H), 7.60 (m, 4H), 4.90 (t, 2H, J=5.13 Hz), 2.60 (m, 2H). LCMS m/z (M+1) Calc: 344.1, found 344.0
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].F[C:9](F)(F)[C:10](O)=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:10]([N:43]1[CH2:44][CH2:45][CH:40]([CH2:39][C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:46])[CH2:41][CH2:42]1)(=[O:11])[CH3:9]
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Product: CC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 58 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and acetyl chloride as starting materials in 58% yield. LCMS for C27H30ClN6O2 (M+H)+: m/z=505.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23](N)=[CH:22][C:21]=3[F:27])=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([C:38]2([C:41]([OH:43])=O)[CH2:40][CH2:39]2)=[O:37])=[CH:31][CH:30]=1.C[N:45](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N:35]([C:32]4[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=4)[C:36]([C:38]4([C:41]([NH2:45])=[O:43])[CH2:39][CH2:40]4)=[O:37])=[CH:22][C:21]=3[F:27])=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Oc2ccnc3cc(OCc4ccccc4)ccc23)c(F)c1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(OCc5ccccc5)ccc34)c(F)c2)CC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of 4-(7-(benzyloxy)quinolin-4-yloxy)-3-fluorobenzenamine) (3.6 g, 10 mmol) and 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (2.678 g, 12 mmol) in DCM (50 mL) was added TEA (1 g, 10 mmol) and HATU (6.84 g, 18 mmol) at rt. The reaction was then heated to 40° C. and stirred overnight. The mixture was washed with H2O (25 mL), and the organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (1:1 EtOAc/petroleum ether) to afford the title compound as a yellow solid (5.5 g, 97%).
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[NH2:8][C@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@@H:10]1[NH:18][C:19]([C:21]1[NH:25][C:24]2[C:26]([Cl:30])=[C:27]([Cl:29])[S:28][C:23]=2[CH:22]=1)=[O:20].C(O)=O.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:29][C:27]1[S:28][C:23]2[CH:22]=[C:21]([C:19]([NH:18][C@H:10]3[CH2:11][C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C@@H:9]3[NH:8][CH:3]=[O:4])=[O:20])[NH:25][C:24]=2[C:26]=1[Cl:30]
Reactant: O=C(O)C(F)(F)F
Reactant: N[C@H]1c2ccccc2C[C@@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O=CO
Solvent: ClCCl
Product: O=CN[C@H]1c2ccccc2C[C@@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Reaction time: 0.08 h
Yield: 91.4 %

Procedure:
N-[(1S,2S)-1-Amino-2,3-dihydro-1H-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide trifluoroacetic acid salt (Method 9, 240 mg, 05 mmol), formic acid (50 μL, 1.4 mmol), DIPEA (174 μL, 1.0 mmol) and HOBT (67 mg, 0.5 mmol) were dissolved in DCM (5 ml), stirred for 5 mins, EDCI (120 mg, 0.625 mmol) added and the reaction stirred for 1 hr. Formic acid (50 μL, 1.4 mmol) and EDCI (240 mg, 1.25 mmol) were added, the reaction stirred for 2 hours and the volatiles removed by evaporation under reduced pressure. The residue was dissolved in EtOAc (20 mL), washed with water (2×10 mL), brine (10 mL), dried (MgSO4) and the volatiles removed by evaporation under reduced pressure. The residue was purified by column chromatography (2:1 EtOAc:Hexane) to afford the title compound (180 mg, 97%) as a white foam.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([Sn](C)(C)C)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([S:36][CH3:37])[N:31]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:30]5[CH:35]=[CH:34][N:33]=[C:32]([S:36][CH3:37])[N:31]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1nccc(Cl)n1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc([Sn](C)(C)C)ccc32)n1)c1ccccc1
Product: CSc1nccc(-c2ccc3c(c2)ncn3-c2ccnc(N[C@@H](C)c3ccccc3)n2)n1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 424, starting from 2-[(S)-1-Phenylethylamino]-4-[5-trimethylstannylbenzimidazol-1-yl]pyrimidine and 4-chloro-2-methylthio-pyrimidine. Mass spectrum (ESI) 440.4 (M+1).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:17][CH2:18][NH:19][C:20]1[S:21][C:22]([CH:25]=[O:26])=[CH:23][N:24]=1)[C:10]([O:12]C(C)(C)C)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@@H:9]([CH2:17][CH2:18][NH:19][C:20]1[S:21][C:22]([CH:25]=[O:26])=[CH:23][N:24]=1)[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCNc1ncc(C=O)s1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CCNc1ncc(C=O)s1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 299.1 %

Procedure:
Following the procedure as described in Example 11, except using material from Example 49 (3.8 g, 9.86 mmol), CH2Cl2 (41 mL), trifluoroacetic acid (8.21 mL, 107 mmol) and stirring at room temp for 16 h, 6.76 g (quantitative yield) of the title compound is isolated as a thick syrup as a TFA salt that is used directly “as is” in the next reaction. LC/MS (Condition A): ret. T=0.62 min, (M+H)+ 230.15.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:30][C:31](=[O:34])[CH2:32][CH3:33]>C(Cl)Cl>[O:34]=[C:31]([CH2:32][CH3:33])[CH2:30][S:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CCC(=O)CBr
Reactant: Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)CSc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C

Procedure:
To an ice bath cooled solution containing 1.0 g (3.4 mmole) of 2-(4-mercaptophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole prepared as in Example 16 and 0.5 ml (3.6 mmole) of triethylamine in 10 ml of methylene chloride is added 0.36 ml (3.5 mmole) of 1-bromo-2-butanone. The reaction is allowed to warm to room temperature and stirred at room temperature for several hours. Workup and chromatography in a manner analogous to that outlined in Example 18 affords the desired titled compound.
Reaction SMILES: [CH3:1][CH:2]1[C:8](=[O:9])[N:7]2[CH:3]1[CH2:4][C:5]([Cl:20])=[C:6]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C([N-]C(C)C)(C)C.[Li+].[CH:29](=[O:31])[CH3:30]>C1COCC1>[OH:31][CH:29]([C:2]1([CH3:1])[C:8](=[O:9])[N:7]2[CH:3]1[CH2:4][C:5]([Cl:20])=[C:6]2[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[CH3:30]
Reactant: CC=O
Reactant: CC1C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)C1(C)C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC21

Procedure:
Benzyl 6-methyl-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate is converted to its enolate derivative with lithium diisopropylamide in anhydrous THF at -78° as described in the previous example. To this solution is added 10 equivalents of acetaldehyde. Workup as described in example 12 yields benzyl 6-(1-hydroxyethyl)-6-methyl-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13])=[O:7])(C)(C)[CH3:2].[H-].[Na+].BrCCO.C(OCC)(=O)C>CN(C)C=O>[O:7]=[C:6]1[N:8]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[O:13])[CH2:2][CH2:1][O:5]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C=O)c1
Agent: OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1cccc(N2CCOC2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.6 %

Procedure:
To a solution of 2.93 g of 3-[N-(t-butoxycarbonyl)amino]benzaldehyde in 20 ml of dimethylformamide was added 0.58 g of sodium hydride (60% oily) under ice-cooling. After stirring at room temperature for 1 hour, a solution of 0.93 ml of 2-bromoethanol in 5 ml of dimethylformamide was added dropwise under ice-cooling. After stirring at room temperature for 14 hours, the mixture was heated to stir at 115° C. for 6 hours. Ethyl acetate was added, and this was washed successively with water and an aqueous saturated sedum chloride solution, dried with anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.75 g of oily 3-(2-oxo-oxazolidin-3-yl)benzaldehyde.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH2:34]([CH2:36][NH2:37])[OH:35]>C1COCC1.CCOC(C)=O>[OH:35][CH2:34][CH2:36][NH:37][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[CH:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][N:11]=2)[CH:15]=1)(=[O:21])=[O:22]
Reactant: NCCO
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)Cl)c3)c2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)NCCO)c3)c2)n1
Temperature: 25 °C
Yield: 21 %

Procedure:
The title compound was prepared from the solution of 3-[6-methyl-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl-2′-yl]-benzenesulfonyl chloride (example 346 step 2) (ca. 0.2 g, 0.41 mmol) by treatment with excess ethanolamine in THF (5 mL) at 50° C. for 16 h. Cooled to rt, diluted with EtOAc, washed with 1 N HCl, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc followed by trituration with n-heptane/diethyl ether to give the title compound (0.045 g, 21%) as a white solid. MS (ISP) 514.0 [(M+H)+]; mp 103° C. (dec.).