Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([OH:23])=[C:18]([CH2:24][CH3:25])[CH:17]=3)[N:12]=2)[CH:6]=[N:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH2:9]([C:8]1[C:3]([CH2:1][CH3:2])=[CH:4][C:5]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH2:26][CH:28]4[CH2:29][O:30]4)=[C:18]([CH2:24][CH3:25])[CH:17]=3)[N:12]=2)=[CH:6][N:7]=1)[CH3:10]
Reactant: ClCC1CO1
Reactant: CCc1cc(-c2nc(-c3cc(C)c(O)c(CC)c3)no2)cnc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCc1cc(-c2nc(-c3cc(C)c(OCC4CO4)c(CC)c3)no2)cnc1CC
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.5 %

Procedure:
To a solution of 4-[5-(5,6-diethyl-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (150 mg, 0.445 mmol) in isopropanol (10 mL) and 3 N aq. NaOH (3 mL), epichlorhydrine (164 mg, 1.78 mmol) is added. The mixture is stirred at rt for 20 h. The mixture is diluted with EA and washed with sat. aq. NaHCO3 solution. The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by chromatography on prep. TLC plates with EA-heptane to give (RS)-2,3-diethyl-5-[3-(3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-pyridine (92 mg) as an oil.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15]>N1C=CC=CC=1>[C:17]1([O:16][C:14](=[O:15])[NH:12][C:9]2[CH:10]=[N:11][C:6]([N:1]3[CH:5]=[N:4][N:3]=[N:2]3)=[CH:7][CH:8]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(-n2cnnn2)nc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-n2cnnn2)nc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(1H-Tetrazol-1-yl)pyridin-3-amine (50 mg, 0.308 mmol) was dissolved in pyridine (1.5 mL), followed by addition of phenyl chloroformate (53.1 mg, 0.339 mmol). The mixture was stirred at RT overnight, and was concentrated to give crude title compound. LC/MS: [(M+1]+=283.14, [(M+1-28)]+=255.13.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH3:22])=[O:7].CN1CCOCC1.[C:35]([O:39][C:40]([NH:42][CH2:43][CH2:44][C:45](O)=[O:46])=[O:41])([CH3:38])([CH3:37])[CH3:36].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[C:35]([O:39][C:40](=[O:41])[NH:42][CH2:43][CH2:44][C:45](=[O:46])[NH:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH3:22])=[O:7])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1N
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1NC(=O)CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 60 h
Yield: 119.1 %

Procedure:
To a solution of 2-(2-amino-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-ethanone (0.066 g, 0.17 mmol) in methylene chloride (2 mL) at ambient temperature was added N-methylmorpholine (0.025 mL, 0.23 mmol), 3-tert-butoxycarbonylamino-propionic acid (0.044 g, 0.23 mmol) and O-benzotriazole-1-yl-N,N,N′, N′-tetramethyluronium hexafluorophosphate (0.076 g, 0.20 mmol). The resulting solution was stirred at ambient temperature for 60 hours, then concentrated. Radial chromatography (2 mm plate) gave the title compound (0.114 g)
Reaction SMILES: [CH2:1]([N:3]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C:4]1([C:7]([OH:9])=O)[CH2:6][CH2:5]1)[CH3:2].CCOC(OC(OCC)=O)=O.[F:31][C:32]([F:49])([F:48])[O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[C:44]([CH2:46][NH2:47])[CH:43]=[CH:42][N:41]=2)=[CH:36][CH:35]=1>C1COCC1>[CH2:1]([N:3]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C:4]1([C:7]([NH:47][CH2:46][C:44]2[CH:43]=[CH:42][N:41]=[C:40]([C:37]3[CH:36]=[CH:35][C:34]([O:33][C:32]([F:49])([F:31])[F:48])=[CH:39][CH:38]=3)[CH:45]=2)=[O:9])[CH2:5][CH2:6]1)[CH3:2]
Reactant: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(F)cc1
Reactant: NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: CCN(C1(C(=O)NCc2ccnc(-c3ccc(OC(F)(F)F)cc3)c2)CC1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 19.7 %

Procedure:
A solution of acid 15A (0.5 g, 1.7 mmol) in THF (30 mL) was added with DEPC (0.34 mL, 1.3 mol eq) and the mixture was stirred at room temperature for about 5 minutes. Then [2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (0.51 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was suspended in EtOAc (40 mL) and washed with water (50 mL) and brine. The separated organic phase was dried over Na2SO4 and evaporated under reduced pressure and the residue was purified by flash chromatography (7:3 EtOAc:Petroleum ether) to afford a white solid (0.18 g) after crystallization from diethyl ether. Yield=30%, 1HNMR (DMSO, 200 MHz) δ 1.09 (bs, 2H), 1.22 (t, 3H, J=8), 1.26 (bs, 2H), 3.41 (bs, 2H), 4.43 (d, 2H, J=6); 7.27 (d, 1H, J=4), 7.46-7.42 (m, 4H), 7.90 (m, 3H), 8.23 (m, 3H), 8.61 (d, 1H, J=5.2). [M+1] 537.53 (C25H23F4N3O4S requires 537.13).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]([C:20]2[CH:21]=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=2)=[O:19])[C:12]=1[F:27])[CH2:9][CH3:10])(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:7][C@@H:8]([C:11]1[C:12]([F:27])=[C:13]([C:18]([C:20]2[CH:21]=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=2)=[O:19])[C:14]([Cl:17])=[CH:15][CH:16]=1)[CH2:9][CH3:10]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(N)nc2)c1F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2ccc(N)nc2)c1F
Reaction time: 18 h
Yield: 98.2 %

Procedure:
Step 3 To a solution of {(R)-1-[3-(6-amino-pyridine-3-carbonyl)-4-chloro-2-fluoro-phenyl]-propyl}-carbamic acid tert-butyl ester (2.18 g, 4.43 mmol) in DCM (50 mL) was added 4M HCl in dioxane (7.75 mL, 31 mmol, 7 eq) and the reaction stirred for 18 h. Complete conversion. Mixture was concentrated and then triturated with diethyl ether (50 mL) and the solid filtered off and dried in a vacuum oven to give [3-((R)-1-amino-propyl)-6-chloro-2-fluoro-phenyl]-(6-amino-pyridin-3-yl)-methanone (1.54 g, 4.35 mmol, 98%) as a beige solid and the HCl salt
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH3:16])[O:15][CH:10]2[C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1.B(F)(F)F.CCOCC.[CH3:26][OH:27]>>[CH3:26][O:27][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:16])[CH:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12]
Reactant: CO
Reactant: COC(=O)C1OC1(C)c1cccc(OC)c1
Agent: FB(F)F
Solvent: CCOCC
Product: COC(=O)C(O)C(C)(OC)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
19.5 g (88 mmol) of methyl 3-(3-methoxyphenyl)-2,3-epoxybutyrate are dissolved in 200 ml of absolute methanol, and 0.1 ml of boron trifluoride etherate is added. The mixture is stirred at room temperature for 12 hours and the solvent is removed by distillation. The residue is taken up in ethyl acetate, washed with sodium bicarbonate solution and water and dried over sodium sulfate. After removal of the solvent by distillation, 21.1 g of a pale yellow oil remain.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15](=O)[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].[CH3:21][O:22][CH2:23]CCOS(C1C=CC(C)=CC=1)(=O)=O>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][CH2:15][CH2:16][CH2:21][O:22][CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCCCSC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.25 h

Procedure:
Amine preparation: A mixture of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (2.82 g) and potassium thioacetate (2.31 g) was heated to 60° C. in DMF (10 mL). After 4 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo and then purified by flash chromatography to give 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (1.80 g). To a solution of 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (607 mg) in dry MeOH (5 mL) was added a solution of sodium methoxide in MeOH (25% wt, 0.59 mL). After stirring for 15 min, toluene-4-sulfonic acid 3-methoxy-propyl ester (described elsewhere, 571 mg) was added in MeOH. After 24 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo to yield 4-(3-methoxy-propylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester. Treatment with mCPBA (as described above) yielded 4-(3-methoxy-propane-1-sulfonyl)-piperidine-1-carboxylic acid tert-butyl ester. Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, isolated as the hydrochloride salt.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:28]=[CH:27][C:13]([O:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:62]1([C@H:68]([NH2:70])[CH3:69])[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>ClCCl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH2:21][CH2:22][CH2:23][C:24]([NH:70][C@@H:68]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[CH3:69])=[O:25])=[CH:27][CH:28]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)CCCN1CCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: C[C@@H](N)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)CCCN1CCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.6 %

Procedure:
To a suspension of 4-{(S)-2-[4-(4-chloro-phenyoxy)-phenoxymethyl]-pyrrolidin-1-yl}-butyric acid HCl salt (220 mg, 0.5 mmol, 1 eq.) in dichloromethane (5 ml) was added PyBrOP (280 mg, 0.6 mmol, 1.2 eq.), DIPEA (200 mg, 1.5 mmol, 3 eq.) and (R)-1-phenyl ethylamine (80 mg, 0.6 mmol 1.2 eq.). The mixture was stirred at room temperature for 24 h. The mixture was poured onto 30 mL ice-water solution and this solution was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (2×30 mL), brine (30 mL) and dried over anhy. Na2SO4. The solvent was removed in vacuo to provide the crude product which was purified by silica gel flash chromatography to afford the title product (68 mg, 25%); LCMS; 95%; APCI+, Calcd 493.05. Found m/z 493.2 (M). 1H NMR (400 MHz, CDCL3); δ 1.47 (d, J=5.6 Hz, 3H), 1.52-2.01 (m, 6H), 2.21-2.59 (m, 4H), 2.79-2.98 (m, 2H), 3.12-3.23 (m, 1H), 3.68-3.89 (m, 2H), 5.10-5.17 (m, 1H), 6.81 (d, J=9.2 Hz, 2H), 6.86 (d, J=9.2 Hz, 2H), 6.92 (d, J=9.2 Hz, 2H), 7.22-7.26 (m, 5H), 7.29 (d, J=4.4 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][CH2:38][N:39]3C(=O)C4C(=CC=CC=4)C3=O)[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CCO>[NH2:39][CH2:38][CH2:37][CH2:36][O:35][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=1)[O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]2[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:23][CH:24]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCN3C(=O)c4ccccc4C3=O)c2)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCN)c2)cc1
Yield: 61.2 %

Procedure:
The product from Example 70B (0.323 g, 0.479 mmoles) in EtOH (5 mL) was treated with hydrazine hydrate (0.15 mL, 4.79 mmoles). The reaction was heated overnight at 60 C. Reaction mixture concentrated under reduced pressure, and residue dissolved in ethyl acetate. The mixture was washed with H2O (2×), brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 10% to 20% MeOH:CHCl3) to provide the title compound (0.160 g, 61%). MS (ESI+) m/z 546 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.Br[CH2:28][C:29]([O:31][CH2:32][CH2:33][CH3:34])=[O:30]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:28][C:29]([O:31][CH2:32][CH2:33][CH3:34])=[O:30])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCCOC(=O)CBr
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Product: CCCOC(=O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Yield: 55 %

Procedure:
The procedure of Example 3 was repeated by using 10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (250 mg) and n-propyl bromoacetate (0.1 ml) to obtain the title compound (170 mg, 55%).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH:11]1[NH:14][C:13](=[O:15])[CH:12]1[CH2:16][CH3:17])C1C=CC=CC=1.CO[C:20]([CH3:22])=[CH2:21].B(F)(F)F.CCOCC.[CH3:32][C:33]([CH3:36])([O-])[CH3:34].[K+]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:32]([C:9](=[O:8])[CH2:10][CH:11]1[NH:14][C:13](=[O:15])[CH:12]1[CH2:16][CH3:17])[C:33]1[CH:36]=[CH:22][CH:20]=[CH:21][CH:34]=1
Reactant: C=C(C)OC
Reactant: CCC1C(=O)NC1CCOCc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: FB(F)F
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCC1C(=O)NC1CC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(2-benzyloxyethyl)-3-ethyl-2-azetidinone (11.65 g), 2-methoxypropene (7.1 ml), borontrifluoride etherate (0.5 ml) in anhydrous toluene (87 ml) is stirred at room temperature for 31/2 hours. Then potassium t-butoxide (3.13 g) is added at room temperature monitoring the epimerization by means of gas-chromatographic assays. After one hour, 40% acetic acid (30 ml) is added and the mixture is heated to 75° C. for two hours and allowed to stand at room temperature overnight. The aqueous acidic phase which separates is extracted with toluene (two 30-ml portions) and the toluene extracts are combined, dried over Na2SO4 and concentrated to dryness under vacuum yielding 10.5 g of crude 4-(2-benzyloxoethyl)-3-ethyl-2-azetidinone which contains 90% of the trans-isomer (estimated by N.M.R.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:13]#[N:14])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:19](Cl)([CH3:22])([CH3:21])[CH3:20]>ClCCl>[C:19]([C:11]1[CH:10]=[C:9]([C:13]#[N:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:12]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)Cl
Reactant: Cc1ccc(-n2cccc2C#N)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc(-n2cc(C(C)(C)C)cc2C#N)cc1
Reaction time: 0.33 h
Yield: 92.4 %

Procedure:
To a mixture of 1-(4-methylphenyl)pyrrole-2-carbonitrile (546 mg) and aluminum chloride (532 mg) in dichloromethane (10 ml) was added t-butyl chloride (368 mg) in dichloromethane (10 ml) in one portion at 5° C. The mixture was stirred at the same temperature for 20 minutes. The reaction mixture was quenched with 10% hydrochloric acid. The separated organic layer was washed with 10% hydrochloric acid and water, successively, dried, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted by a mixture of ethyl acetate and n-hexane (1:6) to yield 4-t-butyl-1-(4-methylphenyl)pyrrole-2-carbonitrile (660 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH2:18][CH3:19])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:20]=1.[F:21][C:22]1[CH:23]=[C:24]([C:31]#[N:32])[CH:25]=[C:26](B(O)O)[CH:27]=1>>[CH2:18]([C:7]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[O:8][CH2:9][C:10](=[O:12])[NH:11][C:5]2[CH:4]=[CH:3][C:2]([C:26]3[CH:25]=[C:24]([CH:23]=[C:22]([F:21])[CH:27]=3)[C:31]#[N:32])=[CH:20][C:6]1=2)[CH3:19]
Reactant: CCC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Product: CCC1(c2cccs2)OCC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5-ethyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 5-fluoro-3-cyanobenzeneboronic acid using the coupling procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.12 (s, 1H), 8.07 (s, 1H), 7.95 (dt, J=10.3, 2.0 Hz, 1H), 7.81 (m, 2H), 7.69 (d, J=2.0 Hz, 1H), 7.57 (dd, J=5.0, 0.9 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.01 (m, 1H), 6.95 (m, 1H), 4.10 (d, J=15.5 Hz, 1H), 4.01 (d, J=15.5 Hz, 1H), 2.65 (m, 2H), 0.78 (t, J=7.0 Hz, 3H); MS (ES) m/z 391 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6]2[C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:23])[C@@H:20]([CH3:22])[NH2:21])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:24][C:2]1([CH3:1])[C:6]2[C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[C:19](=[O:23])[C@@H:20]([CH3:22])[NH:21][C:33]4=[O:35])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: C[C@@H](N)C(=O)Nc1ccc(Oc2cccc3c2C(C)(C)CO3)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1NC(=O)N(c2ccc(Oc3cccc4c3C(C)(C)CO4)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 140.1 %

Procedure:
To a solution of N1-{4-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]phenyl}-D-alaninamide (Intermediate 57, 66 mg) in dichloromethane (20 ml, SCRC) was added triethylamine (0.085 ml, 0.607 mmol, SCRC). Triphosgene (24.00 mg, 0.081 mmol, SCRC) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 0.5 hours. The mixture was quenched with water (20 ml) and it was extracted with dichloromethane (3 times 50 ml, SCRC). The combined organic layers were dried, evaporated and purified by column chromatography on silica gel with EtAc/PE (1/30) as eluents to afford the title compound as a white solid (40 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:8](Cl)=[N:7]2.[Br:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[N:21]=[C:22](Cl)[C:23]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[N:24]2.[F-:35].[K+]>CS(C)=O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]([F:35])=[N:7]2.[Br:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[N:21]=[C:22]([F:35])[C:23]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[N:24]2
Reactant: CC(C)(C)Nc1nc2cccc(Br)c2nc1Cl
Reactant: [F-]
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2nc1Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)Nc1nc2c(Br)cccc2nc1F
Product: CC(C)(C)Nc1nc2cccc(Br)c2nc1F
Temperature: 90 °C
Yield: 64 %

Procedure:
A mixture of Intermediate 304a (as a ˜2.5:1 mixture of 8-bromo-N-(tert-butyl)-3-chloroquinoxalin-2-amine and 5-bromo-N-(tert-butyl)-3-chloroquinoxalin-2-amine (407 mg, 0.6 mmol) and KF (113 mg, 1.94 mmol) in DMSO (1.3 mL) was heated to 90° C. for 24 h. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (2×75 mL) before the organic layer was separated, dried over Na2SO4, and concentrated to give an inseparable mixture (˜2.5:1) of 8-bromo-N-(tert-butyl)-3-fluoroquinoxalin-2-amine/5-bromo-N-(tert-butyl)-3-fluoroquinoxalin-2-amine (343a) (124 mg, 0.41 mmol, 64% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.57 (s, 9H) 1.63 (s, 18H) 5.22 (br. s., 0H) 5.25 (br. s., 1H) 7.20 (t, J=7.92 Hz, 1H) 7.37 (t, J=8.02 Hz, 1H) 7.61-7.65 (m, 2H) 7.67 (d, J=8.41 Hz, 1H) 7.83 (d, J=7.63 Hz, 1H). 19F NMR (376 MHz, CDCl3) δ ppm −82.18 (s, 2F) −80.01 (s, 1F). MS (ESI, pos. ion) m/z: 298.0/300.0 (M+1).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[C:6]([O:10][CH3:11])(=[O:9])C=C.[CH3:12][CH2:13]OCC>>[CH:2]12[CH2:1][CH:5]([CH:12]=[CH:13]1)[CH2:4][CH:3]2[C:6]([O:10][CH3:11])=[O:9]
Reactant: C=CC(=O)OC
Reactant: C1=CCC=C1
Reactant: CCOCC
Product: COC(=O)C1CC2C=CC1C2
Reaction time: 8 h

Procedure:
In 100 ml of anhydrous ether at 0° C. is mixed 30 ml of cyclopentadiene and 32 ml of methyl acrylate. The ice bath is removed and the mixture allowed to stir overnight. The solvent, unreacted methyl acrylate, and cyclopentadiene are removed at ambient temperature at reduced pressure; as less material distilled out of the mixture the pressure is gradually reduced to 0.5 mm. The desired epimeric mixture of methyl carboxylates is distilled at 42°-43° and 0.5 mm; ir: 3118, 3060, 2965, 2941, 2862, 1734, 1428, 1329, 1264, 1190, 1024, 704, cm-1 ; 60 MHz NMR: endo/exo=80/20.
Reaction SMILES: CS[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[N:12]=[C:13]3[CH:19]=[CH:18][N:17]([S:20]([C:23]4[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[C:14]3=[N:15][CH:16]=2)[NH2:10])=[CH:5][CH:4]=1.[Br-].[Mg+2].[Br-].[CH2:33]1COCC1.OO[S:40]([O-:42])=[O:41].[K+]>O>[CH3:33][S:40]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:11]2[N:12]=[C:13]3[CH:19]=[CH:18][N:17]([S:20]([C:23]4[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=4)(=[O:21])=[O:22])[C:14]3=[N:15][CH:16]=2)[NH2:10])=[CH:7][CH:8]=1)(=[O:42])=[O:41]
Reactant: C1CCOC1
Reactant: O=S([O-])OO
Reactant: CSc1ccc(C(N)c2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n2)cc1
Agent: [Br-]
Agent: [K+]
Agent: [Mg+2]
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C(N)c4ccc(S(C)(=O)=O)cc4)cnc32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
In a round flask was added (4-(methylthio)phenyl)(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine (0.453 g, 1.067 mmol, prepared using AF from Preparation #AE.1 with 4-(methylthio)phenyl)magnesium bromide and AG) and THF (5 mL) and mixture was cooled to about 0° C. Oxone® (1.312 g, 2.134 mmol) in water (2 mL) was added and the mixture was stirred for about 1 h. The mixture was diluted with water (5 mL) and extracted with DCM (10 mL), dried over MgSO4 and concentrated to provide (4-(methylsulfonyl)phenyl)(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine (0.487 g, 100%): LC/MS (Table 2, Method c) Rt=1.25 min; MS m/z 457 (M+H)+.
Reaction SMILES: [C:1]([S:20][CH2:21][CH2:22][NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1[C:37](=[O:38])CCC1.[S:39](Cl)([CH3:42])(=[O:41])=[O:40]>C1COCC1>[C:1]([S:20][CH2:21][CH2:22][NH:23][C:24]([C:25]1[CH:30]=[CH:29][C:28]([CH2:37][O:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:27][CH:26]=1)=[O:31])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCCC1=O
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CS(=O)(=O)OCc1ccc(C(=O)NCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.1 %

Procedure:
To a solution of 4-hydroxymethyl)-N-[2-(tritylsulphanyl)ethyl]benzamide (226 mg, 0.500 mmol) in dry THF (8 ml) was added N-methyl pyrrolidinone (NMP) (61 μl, 0.55 mmol) and mesyl chloride (85 μl, 1.1 mmol). The reaction mixture was stirred at room temperature for 48 hours, filtered through silica and concentrated. The product was purified by column chromatography (silica, 1% methanol in chloroform) to give 213 mg of an oil that solidified slowly. NMR analysis was in accordance with the structure.