Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:6]2[C:7]3[N:8]([CH:19]=[N:20][N:21]=3)[C:9]3[CH:17]=[CH:16][C:15](=[O:18])[CH2:14][C:10]=3[N:11]3[CH:12]=[CH:13][C:4]([C:5]=23)=[CH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O>[C:31]1([CH2:30][CH2:29][CH:14]2[C:10]3[N:11]4[CH:12]=[CH:13][C:4]5[C:5]4=[C:6]([CH2:1][CH2:2][CH:3]=5)[C:7]4[N:8]([CH:19]=[N:20][N:21]=4)[C:9]=3[CH:17]=[CH:16][C:15]2=[O:18])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCCc1ccccc1
Reactant: O=C1C=CC2=C(C1)n1ccc3c1=C(CCC=3)c1nncn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C=CC2=C(C1CCc1ccccc1)n1ccc3c1=C(CCC=3)c1nncn12
Temperature: 95 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
1,2-Dihydrobenzo[b]pyrrolo[3,2,1-jk][1,2,4]triazolo[4,3-d][1,4]benzodiazepin-8(7H)-one (2 g) was dissolved in dimethylformamide (50 ml). Potassium carbonate (0.5 g) was added followed by (2-bromoethyl)benzene (2.7 g). The mixture was stirred at 95° C. overnight, filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by high performance liquid chromatography (2% methano/dichloromethane) to yield 2.3 g, (84%) of product. Recrystallization from methanol gave the analytical sample, mp 157°-158° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH2:12]Br)[CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1([CH2:34][OH:35])[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.CC(C)([O-])C.[K+].CO>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[CH2:12][O:35][CH2:34][C:21]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[F:14])[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2F)CC1
Reactant: FC(F)(F)c1cc(Br)cc(CBr)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(C(F)(F)F)c2)(c2ccccc2F)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A flask was charged with 1-bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (0.149 g, 0.47 mmol) and tert-butyl 4-(2-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.112 g, 0.36 mmol) in tetrahydrofuran (2 mL) at 0° C. The reaction was treated with potassium tert-butoxide (0.41 mg, 0.36 mmol), stirred at 0° C. for 20 min, and treated with another aliquot of potassium tert-butoxide (0.41 mg, 0.36 mmol). The reaction was allowed to warm to room temperature and was stirred for 16 h. The reaction mixture was evaporated in vacuo and the crude oil was purified by silica gel chromatography (5% ethyl acetate/95% hexanes→30% ethyl acetate/70% hexanes) to afford 0.138 g (70%) of the desired ether. Mass spec.: 546.03 (MH)+ LC tr=4.501 min. (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=4 min, Flow rate=4 mL/min).
Reaction SMILES: Cl.NO.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:22])[C:12](=[CH:18][N:19](C)C)[C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])=[C:7]([N:23]([CH3:27])[C:24](=[O:26])[CH3:25])[CH:6]=1>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:12]2[CH:18]=[N:19][O:14][C:13]=2[CH:15]2[CH2:17][CH2:16]2)=[O:22])=[C:7]([N:23]([CH3:27])[C:24](=[O:26])[CH3:25])[CH:6]=1
Reactant: CC(=O)N(C)c1cc(Cl)ccc1C(=O)C(=CN(C)C)C(=O)C1CC1
Agent: Cl
Agent: NO
Solvent: CCO
Product: CC(=O)N(C)c1cc(Cl)ccc1C(=O)c1cnoc1C1CC1
Reaction time: 0.75 h
Yield: 41 %

Procedure:
Hydroxylamine hydrochloride (0.1 g) was added to a stirred solution of 1-[4-chloro-2-(N-methylacetamido)phenyl]-3-cyclopropyl-2-dimethylaminomethylenepropane-1,3-dione (0.32 g) in ethanol. The mixture was stirred for 0.75 hours and evaporated to dryness. Water was added to the residue, which was extracted (dichloromethane). The extract was dried (magnesium sulphate) and evaporated to give an oil. This was purified by chromatography eluting with ethyl acetate/dichloromethane (1:8) to give 4-[4-chloro-2-(N-methylacetamido)benzoyl]-5-cyclopropylisoxazole, (compound number 1, 0.12 g), m.p. 106.5-107.5° C., as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(#N)C>[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=2)=[CH:17][CH:16]=1
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Solvent: CC#N
Product: CCOC(=S)c1cnc(C)nc1Nc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 76.6 %

Procedure:
To a solution of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (Aldrich, 24 g, 103 mmol) in 250 mL of acetonitrile at room temperature was added 4-fluoroaniline (22.75 g, 205 mmol). After stirring for two days, the mixture was heated at 60° C. for four hours. The resulting solid was filtered and washed with EtOAc. The filtrate was concentrated, diluted in EtOAc (300 L), washed with brine, dried (MgSO4), filtered and concentrated to provide a crude product. The crude product was stirred with hexanes (400 mL) and then filtered to give 23 g of the ethyl 4-(4-fluorophenyl)amino-2-methylthiopyrimidine-5-carboxylate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[F:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[CH:13]=2)(=[O:20])=[O:19])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: COc1nc(Cl)cnc1N
Product: COc1nc(Cl)cnc1NS(=O)(=O)c1cccc(F)c1

Procedure:
By the method outlined in Example 1 (reaction performed at room temperature) using 5-chloro-3-methoxy-2-pyrazinamine (0.798 g) and 3-fluorobenzenesulphonyl chloride (1.17 g). Yield 0.64 g.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]([CH3:25])=[O:24])=[C:10]1[C:26]([O:28][CH2:29][CH3:30])=[O:27].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][CH:23]([OH:24])[CH3:25])=[C:10]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C1=C(COCC(C)=O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(COCC(C)O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 43.3 %

Procedure:
A solution of 1-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}acetone (0.46 g) and sodium borohydride (0.10 g) in ethanol (40 ml) was stirred at room temperature for 5 hours. The solution was evaporated, the residue dissolved in ethyl acetate and washed three times with water. The organic layer was dried over magnesium sulphate and evaporated. The residue was crystallized from diethyl ether/hexane to give the title compound (0.20 g), m.p. 110°-113°.
Reaction SMILES: BrBr.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:22]([C:29]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:30]=1[C:31]1[C:32]([CH2:45][O:46][CH3:47])=[C:33]([C:42]([NH2:44])=O)[N:34]=[CH:35][C:36]=1[NH:37]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl.O>[O:22]([C:29]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:30]=1[C:31]1[C:32]([CH2:45][O:46][CH3:47])=[C:33]([C:42]#[N:44])[N:34]=[CH:35][C:36]=1[NH:37]2)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COCc1c(C(N)=O)ncc2[nH]c3cccc(Oc4ccccc4)c3c12
Agent: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCc1c(C#N)ncc2[nH]c3cccc(Oc4ccccc4)c3c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
1.1 g of Br2 in 10 ml of methylene chloride is put in drop by drop into a stirred solution of 1.8 g (15 mmol) of triphenylphosphine in 50 ml of methylene chloride at 0° C. Then, 2 g of 5-phenoxy-4-methoxymethyl-beta-carboline-3-carboxamide and 1.9 ml of triethylamine are added. The reaction mixture is stirred for 1 hour at 0° C. and then vigorously stirred with 25 ml of methylene chloride and 25 ml of water for 5 minutes. After removal of the aqueous phase from the organic phase by concentration, 0.8 g of the desired product is obtained.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[O:20][CH3:21])[N:4]2[N:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][C:34]2[CH:37]=[CH:38][C:39]([NH2:41])=[CH:40][C:33]=2[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][C:34]2[CH:37]=[CH:38][C:39]([NH:41][C:2]3[N:22]=[C:5]4[CH:6]=[CH:7][CH:8]=[C:9]([C:10]5[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=5[O:20][CH3:21])[N:4]4[N:3]=3)=[CH:40][C:33]=2[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccc2nc(Cl)nn12
Product: COc1ccc(C(F)(F)F)cc1-c1cccc2nc(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)nn12

Procedure:
2-Chloro-5-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro[1,2,4]triazolo[1,5-a]pyridine (0.5 g, 2.15 mmol) and 2-methoxy-5-trifluoromethylbenzeneboronic acid (0.71 g, 3.23 mmol) in a manner analogous to Example 2c. Product was isolated as a foam (0.7 g, 82%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.80 (d, J=8.8 Hz, 1H), 7.75-7.70 (m, 2H), 7.68-7.62 (m, 1H), 7.16 (d, J=8.8 Hz, 1H), 7.09 (d, J=6.8 Hz, 1H), 3.87 (s, 3H). MS=328 (MH)+. 234b) 7-[5-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-5-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.46 g, 1.4 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.557 g, 2.12 mmol) in a manner analogous to Example 2d. Product was isolated as a foam (0.33 g, 42%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.94 (brs, 1H), 7.80-7.77 (m, 1H), 7.55-7.49 (m, 2H), 7.20-7.15 (m, 1H), 7.05-7.00 (m, 1H), 7.00-6.96 (m, 1H), 6.90 (brs, 1H), 3.88 (s, 3H), 3.60-3.48 (m, 4H), 2.89-2.78 (m, 4H), 1.52 (s, 9H). MS=554 (MH)+. 234c) 7-[5-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.33 g, 6.00 mmol), was dissolved in dichloromethane (10 mL, 156 mmol) and trifluoroacetic acid was added (2 mL, 20.0 mmol). Reaction was stirred at room temperature for 2 hours. Solvent was removed and residue was partitioned between dichloromethane and 1N sodium carbonate. Washed with water and brine, dried over sodium sulfate and concentrated. [5-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amino]-1,2,4,5-tetrahydro-3-benzazepin-7-yl)-amine was isolated as a foam (0.27 g, 96%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.94 (brs, 1H), 7.81-7.76 (m, 1H), 7.54-7.50 (m, 2H), 7.25 (brs, 1H), 7.17 (d, J=7.9 Hz, 1H), 7.02 (d, J=7.9 Hz, 1H), 6.99-6.95 (m, 1H), 6.83 (brs, 1H), 3.86 (s, 3H), 3.01-2.92 (m, 4H), 2.90-2.83 (m, 4H). MS=454 (MH)+.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[C:22]2[CH:21]=[C:20]([NH:23][C:24]([C@@H:26]3[CH2:28][C@H:27]3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:25])[CH:19]=[C:18]3[C:35](=[O:39])[NH:36][N:37]=[CH:38][C:16]([C:17]=23)=[CH:15]1.NN.C([OH:44])C>>[C:35]([OH:39])(=[O:44])[CH3:18].[NH2:3][CH2:12][CH2:13][N:14]1[C:22]2[CH:21]=[C:20]([NH:23][C:24]([C@@H:26]3[CH2:28][C@H:27]3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:25])[CH:19]=[C:18]3[C:35](=[O:39])[NH:36][N:37]=[CH:38][C:16]([C:17]=23)=[CH:15]1
Reactant: CCO
Reactant: O=C1NN=Cc2cn(CCN3C(=O)c4ccccc4C3=O)c3cc(NC(=O)[C@@H]4C[C@H]4c4ccccc4)cc1c23
Agent: NN
Product: CC(=O)O
Product: NCCn1cc2c3c(cc(NC(=O)[C@@H]4C[C@H]4c4ccccc4)cc31)C(=O)NN=C2
Yield: 89 %

Procedure:
The title compound of Example 242 (92 mg, 0.18 mmol) and hydrazine (0.2 ml) were refluxed together in ethanol (14 mL) 3 hours. After evaporation of the volatile components, the residue was subjected to preparative HPLC which afforded the title compound (71.4 mg) as an acetic acid salt in 89% yield.
Reaction SMILES: [C:1]1([CH:7]2[CH2:14][N:13]3[C:9]([S:10][CH2:11][CH2:12]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15][CH2:16][C:17]([OH:19])=[O:18].[CH3:20][C:21]([CH3:23])=O>>[Br-:15].[C:1]1([CH:7]2[CH2:14][N+:13]3[CH2:12][CH2:11][S:10][C:9]=3[N:8]2[CH2:16][C:17]([O:19][CH2:20][CH2:21][CH2:23][CH2:14][CH2:7][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CBr
Reactant: CC(C)=O
Reactant: c1ccc(C2CN3CCSC3=N2)cc1
Product: CCCCCCCCCCOC(=O)CN1C2=[N+](CCS2)CC1c1ccccc1
Product: [Br-]
Reaction time: 8 h
Yield: 75 %

Procedure:
2 g (0.01 mol) of 2,3,5,6-tetrahydro-6-phenylimidazo-[2,1-b]-thiazole and 2.8 g (0.01 mol) of decyl ester of monobromacetic acid are dissolved in 25 ml of acetone and allowed to stand overnight at room temperature. The product is filtered-off and washed with acetone to give 4.6 g (96%). After crystallization from dioxane there are obtained 3.6 g (75%) of 2,3,5,6-tetrahydro-6-phenyl-7-decyloxycarbonylmethylimidazo-[2,1-b]-thiazolium bromide, m.p. 127°-128° C.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:37]([CH3:38])=[CH:36][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28]CC4C=CC=CC=4)[CH:23]=3)[S:21][C:17]=2[C:16]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H][H].N1C=CC=CC=1.[O:54](S(C(F)(F)F)(=O)=O)[S:55]([C:58]([F:61])([F:60])[F:59])(=O)=[O:56]>CCO.CCOC(C)=O.[Pd]>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:15]1[C:37]([CH3:38])=[CH:36][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][S:55]([C:58]([F:61])([F:60])[F:59])(=[O:56])=[O:54])[CH:23]=3)[S:21][C:17]=2[C:16]=1[C:39]1[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=1)(=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5]
Reactant: [H][H]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc2nc(-c3cccc(OCc4ccccc4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Pd]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc2nc(-c3cccc(OS(=O)(=O)C(F)(F)F)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of (S)-2-(2-(3-(benzyloxy)phenyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (410 mg, 0.638 mmol) in EtOH/EtOAc (1:1, 4 mL) was added Pd/C (10%, 600 mg). Then hydrogen balloon was attached to the flask, and the reaction was reacted at room temperature for 1 h. After the reaction was finished, the catalyst was removed over Celite pad and the solution was concentrated down to dryness. The residue was dissolved in DCM (5 mL), to the solution was added pyridine (2 mL), Tf2O (210 μL, 1.25 mmol) at 0° C. and the reaction was stirred at 0° C. for 1 h. Then the reaction was quenched by sat. NaHCO3, extracted by DCM, dried over MgSO4, filtered, concentrated down and purified by silica gel column (0-40% EtOAc in hexanes) to give the product (360 mg, 82%). LCMS-ESI+: calc'd for C32H33ClF3NO6S2: 684.1 (M+H+); Found: 684.1 (M+H+).
Reaction SMILES: N1C=CC=CC=1.[FH:7].[CH2:8]([CH:15]1[CH2:17][N@@:16]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[F:7][C@H:15]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:17][NH:16][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: F
Reactant: Cc1ccc(S(=O)(=O)[N@]2CC2Cc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)[N@@]2CC2Cc2ccccc2)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NC[C@H](F)Cc2ccccc2)cc1

Procedure:
To a stirred solution of hydrogen fluoride-pyridine (13 mL) at 0° C. under nitrogen was added (S)-(+)-2-benzyl-1-(p-tolylsulfonyl)aziridine (2 g) in one portion. The cooling bath was removed briefly until reaction became exothermic and then returned. After an additional 5 min the reaction mixture was poured onto 100 mL of cracked ice. The product was extracted into ether, washed carefully with saturated NaHCO3 and brine, dried over Na2SO4, and evaporated to a white solid. The solid was triturated with hexane, collected and washed with ether/hexane to give 1.7 g of the title compound. M.P. 130–133° C.; MS ES (M++H)=308.
Reaction SMILES: [CH3:1][C:2]1[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:40])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:39])=[CH:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](\[CH3:38])/[CH:22]=[CH:23]/[CH:24]=[C:25](\[CH3:37])/[CH:26]=[CH:27]/[C:28]1[C:33]([CH3:35])([CH3:34])[CH2:32][C:30](=[O:31])[C:29]=1[CH3:36].C1(C)C=CC=CC=1.[Se](=O)=[O:49].[OH2:51]>>[CH3:36][C:29]1[C:30](=[O:31])[C:32](=[O:51])[C:33]([CH3:35])([CH3:34])[C:28]=1/[CH:27]=[CH:26]/[C:25](/[CH3:37])=[CH:24]/[CH:23]=[CH:22]/[C:21](/[CH3:38])=[CH:20]/[CH:19]=[CH:18]/[CH:17]=[C:16](\[CH3:39])/[CH:15]=[CH:14]/[CH:13]=[C:12](\[CH3:40])/[CH:11]=[CH:10]/[C:3]1[C:4]([CH3:8])([CH3:9])[C:5](=[O:49])[C:6](=[O:7])[C:2]=1[CH3:1]
Reactant: O=[Se]=O
Reactant: O
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C(=O)CC2(C)C)C(C)(C)CC1=O
Solvent: Cc1ccccc1
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C(=O)C(=O)C2(C)C)C(C)(C)C(=O)C1=O
Reaction time: 16 h

Procedure:
0.3 g. of all-trans di-nor-canthaxanthin are dissolved in 50 ml. of toluene. After the addition of 10.2 g. of selenium dioxide and 0.7 ml. of water, the mixture is heated to boiling for 16 hours under reflux conditions. The mixture is then introduced into water and extracted with toluene. After evaporation of the toluene extract, there is obtained di-nor-astacin [2,2'-di-nor-β-carotene-3,3',4,4'-tetraone; violerythrin] which, after recrystallization by adsorption on silica gel, has a mass spectrum m/e of 564.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[N:11]=[CH:12][C:13]2[CH:18]=[CH:17][NH:16][C:14]=2[N:15]=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(#N)C>[Cl:9][C:10]1[N:11]=[CH:12][C:13]2[C:18]([I:1])=[CH:17][NH:16][C:14]=2[N:15]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1ncc2cc[nH]c2n1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1ncc2c(I)c[nH]c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
N-Iodosuccinimide (742 g, 3.30 mol) was added to 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (482.5 g, 3.14 mol) in acetonitrile (2500 mL) at 12° C. The mixture was stirred at room temperature for 1 hour then sodium metabisulphite (650 g in 4500 mL of water) was added. The mixture was stirred for 1 hour then filtered to afford the title compound as a orange solid in 82% yield, 716.2 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[H-].[Na+].[H][H].[CH3:13][O:14][C:15]1[C:23]2[O:22][C:21]([C:24](Cl)=[O:25])=[CH:20][C:19]=2[CH:18]=[CH:17][CH:16]=1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:24]([C:21]2[O:22][C:23]3[C:15]([O:14][CH3:13])=[CH:16][CH:17]=[CH:18][C:19]=3[CH:20]=2)=[O:25])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: [H][H]
Reactant: COc1cccc2cc(C(=O)Cl)oc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc2cc(C(=O)Nc3cccc(F)c3)oc12
Temperature: 0 °C

Procedure:
Under a nitrogen atmosphere, 3-fluoroaniline (6.2 ml) was dissolved in dry THF (150 ml), and the solution was stirred at 0° C. Sodium hydride (3.4 g) was slowly added to the mixture followed by stirring at 0° C. for 20 minutes. After the generation of hydrogen ceased, 7-methoxybenzofuran-2-carbonyl chloride (9.0 g) was added to the mixture, followed by stirring at room temperature for 3 hours. The reaction was stopped with 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with a 1N aqueous solution of hydrochloric acid and with a saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was triturated with diethyl ether to give Compound IIbf-a (7.82 g, 64.2%) as a white solid.
Reaction SMILES: [Cl:1]C(OCC(C)C)=O.CN1CCOCC1.[Br:16][C:17]1[CH:18]=[C:19]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([NH2:34])[CH:32]=3)[N:27]=[CH:26][N:25]=2)[CH:20]=[CH:21][CH:22]=1.[O:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>N1C=CC=CC=1>[Br:16][C:17]1[CH:18]=[C:19]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([NH:34][C:36](=[O:35])[C:37]#[C:38][CH2:39][Cl:1])[CH:32]=3)[N:27]=[CH:26][N:25]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CC(C)COC(=O)Cl
Reactant: C1CCOC1
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Product: O=C(C#CCCl)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Isobutyl chloroformate (0.625 g, 4.58 mmol) and N-methylmorpholine (0.506 g, 5.00 mmol) were added to an ice cold solution of 0.542 g (4.58 mmol) of 4-chloro-but-2-yanoic acid in 7mL of tetrahydrofuran under nitrogen. After stirring for 30min, a solution of 0.72 g (2.287 mmol) of N-(3-bromophenyl)-4,6-quinazolindiamine in 3.35 mL of pyridine was added and the mixture was stirred at 0° C. for 1 h. The reaction was quenched with ice water. The product was collected by filtration, washed with water and ether, and dried in vacuo to give 0.537 g of brown solid; ESMS m/z 417.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[C:5]([CH3:12])=[CH:4][C:3]=1[NH:13][C@H:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:15]1=[O:25].[Cl:26][C:27]1[CH:32]=[N:31][C:30](Cl)=[CH:29][N:28]=1.C(N(C(C)C)C(C)C)C.O>CS(C)=O>[Cl:26][C:27]1[N:28]=[CH:29][C:30]([N:22]2[CH2:21][CH2:20][CH:19]([N:16]3[CH2:17][CH2:18][C@H:14]([NH:13][C:3]4[CH:4]=[C:5]([CH3:12])[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=4[F:1])[C:15]3=[O:25])[CH2:24][CH2:23]2)=[N:31][CH:32]=1
Reactant: Cc1cc(N[C@H]2CCN(C3CCNCC3)C2=O)c(F)cc1S(C)(=O)=O
Reactant: Clc1cnc(Cl)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(N[C@H]2CCN(C3CCN(c4cnc(Cl)cn4)CC3)C2=O)c(F)cc1S(C)(=O)=O
Temperature: 110 °C
Yield: 60.1 %

Procedure:
(S)-3-(2-Fluoro-5-methyl-4-(methylsulfonyl)phenylamino)-1-(piperidin-4-yl)pyrrolidin-2-one (420 mg, 1.14 mmol) was dissolved in DMSO (10 mL) and 2,5-dichloropyrazine (203 mg, 1.36 mmol) and N-ethyl-N-isopropylpropan-2-amine (297 μL, 1.71 mmol) were added and the reaction heated to 110° C. overnight. The reaction was cooled to ambient temperature, water (60 mL) was added and the solids filtered. The solids were dissolved in CH2Cl2, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (70 to 100% EtOAc in hexanes) to afford (S)-1-(1-(5-chloropyrazin-2-yl)piperidin-4-yl)-3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (330 mg, 0.685 mmol, 60.2% yield) as a pale yellow solid. Mass spectrum (apci) m/z=482.2 (M+H).