Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[Na+].Br[C:14]1[CH:22]=[CH:21][C:20]2[N:19]([CH3:23])[C:18]3[CH2:24][CH:25]4[NH:29][CH:28]([C:17]=3[C:16]=2[C:15]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]4>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:14]2[CH:22]=[CH:21][C:20]3[N:19]([CH3:23])[C:18]4[CH2:24][CH:25]5[NH:29][CH:28]([C:17]=4[C:16]=3[C:15]=2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]5)(=[O:11])=[O:10])=[CH:7][CH:8]=1)#[N:2]
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Reactant: N#Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccc(C#N)cc4)ccc31)C1CCC(C2)N1
Yield: 50 %

Procedure:
Intermediate 11 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude product was purified by flash column chromatography (SiO2, 8:2 hexane/ethyl acetate) to give tert-butyl 2-(4-cyanophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (184 mg, 50%) as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.18 (s, 1H), 8.05 (dd, J=6.9, 1.5 Hz, 2H), 7.75 (dd, J=6.9, 1.5 Hz, 2H), 7.66 (dd, J=8.7, 1.5 Hz, 1H), 7.33 (d, J=8.7 Hz, 1H), 5.26 (br s, 1H), 4.69 (br s, 1H), 3.62 (s, 3H), 3.37 (br s, 1H), 2.51 (d, J=15.9 Hz, 1H), 2.13-2.41 (m, 2H), 1.87-1.99 (m, 1H), 1.67-1.70 (m, 1H), 1.39 (br s, 9H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[N:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C(Cl)Cl>[NH3:4].[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:16][N:17]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2ccc(C=O)cn2)CC1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2ccc(CN3CCCCC3)cn2)CC1
Product: N
Reaction time: 18 h
Yield: 18.9 %
Yield: 4 %

Procedure:
To a solution of 6-(4-isopropyl-piperazine-1-carbonyl)-pyridine-3-carbaldehyde (0.250 g, 0.96 mmol) and piperidine (0.11 mL, 1.10 mmol) in DCM (20 mL) was added NaB(OAc)3H (0.300 g, 1.44 mmol). After 18 h, 1 N NaOH (15 mL) was added and the mixture was extracted with DCM (3×25mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the resulting residue (SiO2: 4-8% 2 M NH3 in MeOH/DCM) gave the title compound as an oil (0.030 g, 9%). MS (ESI): exact mass calcd. for C19H30N4O, 330.2; m/z found, 331.5 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.49 (s, 1H), 7.77 (dd, J=7.8, 2.0, 1H), 7.58 (d, J=7.8, 1H), 3.82 (t, J=5.0, 2H), 3.61 (t, J=5.0, 2H), 3.49 (s, 2H), 2.75-2.72 (m, 1H), 2.62 (t, J=5.0, 2H), 2.51 (t, J=5.0, 2H), 2.37 (br s, 4H), 1.60-1.54 (m, 4H), 1.45-1.43 (m, 2H), 1.05 (d, J=6.6, 6H).
Reaction SMILES: B.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([N+:13]([O-:15])=[O:14])=[C:8]([CH2:10][C:11]#[N:12])[CH:9]=1.CO.Cl>C1COCC1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([N+:13]([O-:15])=[O:14])=[C:8]([CH2:10][CH2:11][NH2:12])[CH:9]=1
Reactant: COc1ccc([N+](=O)[O-])c(CC#N)c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(CCN)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere 200 mL (200 mmol) of a 1M borane in THF solution were slowly added dropwise at RT to 12.6 g (65.7 mmol) (5-methoxy-2-nitrophenyl)-acetonitrile in 380 mL THF. The reaction mixture was refluxed for 2 h. After cooling 30 mL methanol were added dropwise within 20 min. During this time the temperature was maintained at 10° C. to 20° C. with an ice bath. The reaction mixture was stirred for 30 min at RT and then 45 mL of a 2M aqueous hydrochloric acid solution was added dropwise thereto within 30 min. The reaction mixture was concentrated by rotary evaporation i. vac. with gentle heating. The residue was diluted with water to approx. 200 mL and extracted with 200 mL EtOAc. The aqueous phase was made alkaline with a 15% (w/v) aqueous potassium carbonate solution and continuously extracted overnight with a rotary perforator according to Ludwig (Messrs. Normag) with diethyl ether. The organic extract was evaporated to dryness by rotary evaporation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:21][N:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=3.[CH:30]([N:33]=[C:34]=[O:35])([CH3:32])[CH3:31].CCOCC>C(Cl)(Cl)Cl>[CH:30]([NH:33][C:34]([N:22]1[CH:23]=[CH:24][C:20]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:25])[C:12]2[N:26]([CH3:29])[C:27](=[O:28])[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])=[CH:10][C:11]3=2)=[N:21]1)=[O:35])([CH3:32])[CH3:31]
Reactant: CC(C)N=C=O
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CC(C)NC(=O)n1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
100 mg (0.24 mmol) of compound from Example 39, 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(2H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one, are dissolved in 4 ml of chloroform. 232 μl (2.36 mmol) of isopropyl isocyanate are added and the mixture is then refluxed for 16 hours. The reaction medium is left to cool and then Et2O is added, and the mixture is filtered and washed with a minimum amount of Et2O.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:12][CH2:13][CH2:14][Cl:15]
Reactant: ClCCCBr
Reactant: N#Cc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCCCl)c(Cl)c1
Temperature: 100 °C
Yield: 95 %

Procedure:
A mixture of 2-chloro-4-cyanophenol (2.15 g), 3-bromo-1-chloropropane (2.3 g), dimethylformamide (3 ml) and potassium carbonate (1.5 g) was heated at 100° C. for one hour. The inorganic salt was then filtered off and the solvent was distilled off. The residue was dissolved in chloroform, chromatographed on a column of silica gel (80 g), and eluted with a solution of petroleum ether-ethyl acetate (10:1) to give 3-(2-chloro-4-cyanophenoxy)propyl chloride as a colorless oil (3.06 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([CH:17]=[O:18])=[CH:11][NH:12]2.I[CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[Br:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([CH:17]=[O:18])=[CH:11][N:12]2[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)I
Reactant: O=Cc1c[nH]c2cccc(Br)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(C=O)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.6 %

Procedure:
Cesium carbonate (873 mg, 12.68 mmol) was added to a solution of 4-bromo-1H-indole-3-carboxaldehyde (200 mg, 0.893 mmol) in DMF (2.0 mL) and the mixture was stirred at room temperature for 10 minutes. Then 2-iodopropane (0.179 ml, 1.785 mmol) was added and the solution was stirred for 80° C. for 2 hours. The solution was cooled to room temperature and then partitioned between ethyl acetate and water and extracted twice with ethyl acetate. The organic layers were washed twice with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude title intermediate (175 mg).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]([C:29]4[CH:33]=[CH:32][O:31][N:30]=4)[C:21]([O:23][CH2:24][C:25]([Cl:28])([Cl:27])[Cl:26])=[O:22])[O:16][C:15]3=[O:34])=[CH:10][C:9]=2[F:35])[CH2:4]1.C(=O)(O)[O-].[Na+].ClCCl.[C:44](OC(=O)C)(=[O:46])[CH3:45]>O>[C:44]([NH:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]([C:29]4[CH:33]=[CH:32][O:31][N:30]=4)[C:21]([O:23][CH2:24][C:25]([Cl:28])([Cl:26])[Cl:27])=[O:22])[O:16][C:15]3=[O:34])=[CH:10][C:9]=2[F:35])[CH2:4]1)(=[O:46])[CH3:45]
Reactant: N[C@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1
Reaction time: 18 h
Yield: 83.7 %

Procedure:
3-(4-(3(S)-Aminopyrrolidin-1-yl)-3-fluorophenyl)-5(R)-(N-(2,2,2-trichloroethyloxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one hydrochloride salt (400 mg, 0.74 mM) was dissolved in water (5 ml) and treated with aqueous sodium bicarbonate solution (5 ml) and dichloromethane (10 ml) in an ice-bath. Acetic anhydride (216 mg, 2 mM) was added, the mixture stirred 18 hours, allowing the temperature to rise to ambient, followed by addition of a further portion of acetic anhydride (216 mg ), and a further period of 10 hours stirring. The organic phase was separated, washed with aqueous sodium dihydrogen phosphate (2%, 2×15 ml), brine (10 ml), and dried (magnesium sulfate). Evaporation gave the desired product (338 mg ). NMR (DMSO-d6) δ: 1.79 (s overlapping m, 4H); 2.11 (hextet, 1H); 3.11 (m, 1H); 3.26 (m overlapped by H2O, ˜1H); 3.40 (dd, 1H); 3.49 (m, 1H); 3.8.2 (dd, 1H); 4.13 (t overlapping dd, 2H); 4.27 (dd, 1H); 4.35 (dd, 1H); 4.97 (d, 1H); 5.01 (m, 1H); 5.07 (d, 1H); 6.73 (t, 1H); 6.88 (d, 1H); 7.08 (dd, 1H); 7.35 (dd, 1H); 8.08 (d, 1H); 8.89 (d, 1H). MS (ESP): 578 (MH+) for C22H23Cl3FN5O6
Reaction SMILES: [C:1]([C:3]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]2[N:16]([C:17](=[O:27])[C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][CH2:14][O:13][C:12]2([CH3:29])[CH3:28])=[O:8])#[CH:2].C(=O)(O)[O-].[K+].[Br:40][C:41](Br)=[N:42][OH:43]>C(OCC)(=O)C.O>[Br:40][C:41]1[CH:2]=[C:1]([C:3]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:4]=2[CH2:5][NH:6][C:7]([C:9]2[N:10]=[C:11]3[N:16]([C:17](=[O:27])[C:18]=2[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14][O:13][C:12]3([CH3:29])[CH3:28])=[O:8])[O:43][N:42]=1
Reactant: ON=C(Br)Br
Reactant: C#Cc1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1-c1cc(Br)no1)c(OCc1ccccc1)c2=O
Temperature: 22 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
A solution of intermediate 179, N-(2-ethynyl-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.350 g, 0.76 mmol) in a mixture of ethyl acetate (10 ml) and water (2 ml) was treated with potassium bicarbonate (0.230 g, 2.3 mmol) followed by dibromoformaldoxime (0.354 g, 1.75 mmol) (D. M. Vyas, Y. Chiang and T. W. Doyle, Tetrahedron Letters, 1984, 25, 487–490) and the resulting mixture stirred at 22° C. After 1 h, identical quantities of potassium bicarbonate and dibromoformaldoxime were added and the mixture stirred for another 1.5 h. The reaction mixture was then diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystallization of the residue from ether gave 0.300 g (68% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.63 (6H, s, 2×CH3), 4.04 (4H, m, 2×CH2), 4.67 (2H, d, J=6.6 Hz, NCH2), 5.32 (2H, s, OCH2), 6.60 (1H, s, CH), 7.17 (1H, m, aromatic), 7.30–7.36 (4H, m, aromatics), 7.51–7.53 (2H, m, aromatics), 7.60 (1H,dd, J=5.5 Hz and J=8.6 Hz, aromatic), 8.01 (1H, broad t, NH). HRMS (ESI+) calculated for C27H25BrFN4O5 [M+H+]: 583.0992. found: 583.0986.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.I[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1>CS(C)=O>[N:11]1[CH:12]=[CH:13][C:8]([O:7][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:9][CH:10]=1
Reactant: Oc1ccncc1
Reactant: N#Cc1ccc(I)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccncc2)cc1
Temperature: 160 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
Potassium tert-butoxide (1.0 M in THF, 10.5 mL) was slowly added to a solution of 4-hydroxypyridine (997 mg, 10.5 mmol) in anhydrous DMSO (10.0 mL). After the mixture was stirred for 3 hours, a solution of 4-iodobenzonitrile (1.2 g, 5.2 mmol) in DMSO (10.0 mL) was added and the reaction mixture was heated at 160° C. for 44 hours. The mixture was cooled to room temperature and partitioned between methylene chloride (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with methylene chloride (2×100 mL). The organic layers were combined and concentrated in vacuo. The crude solid was purified by silica gel column chromatography (Hex/EtOAc 1:1) then (CH2Cl2/MeOH 98:2 to 96:4) to give the product as a light yellow solid (480 mg, 47%). 1H NMR (500 MHz, CDCL3) δ(ppm): 6.52 (2H, d, J=8.0 Hz), 7.53 (2H, d, J=8.8 Hz), 7.64 (2H, d, J=8.0 Hz), 7.87 (2H, d, J=8.8 Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 112.4, 117.6, 119.8 (CH), 123.2 (CH), 134.5 (CH), 138.2 (CH), 146.2, 179.0. MS (FAB+): 197 (MH+). HRMS for O12H8N2O (MH+): calculated: 197.0715; found 197.0716.
Reaction SMILES: Cl.CN(C)[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)=O.[CH2:19]([O:21][C:22](=[O:29])[CH:23]=[C:24]([NH2:28])[CH:25]1[CH2:27][CH2:26]1)[CH3:20]>CC(O)=O>[CH2:19]([O:21][C:22](=[O:29])[C:23]1[CH:4]=[CH:5][C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=2)=[N:28][C:24]=1[CH:25]1[CH2:27][CH2:26]1)[CH3:20]
Reactant: CCOC(=O)C=C(N)C1CC1
Reactant: CN(C)CCC(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1

Procedure:
0.657 g (2.33 mmol) of the above prepared (example 1L]) 3-dimethylamino-1-(4-trifluoromethyl-phenyl)-propan-1-one hydrochloride and 0.362 g (1.0 eq., not corrected for impurities) of the above synthesised 3-amino-3-cyclopropyl-acrylic acid ethyl ester was dissolved in 7 ml of AcOH and heated to reflux for 3 h. After cooling, the bulk of the solvent was evaporated i. V. Ensuing flash chromatography (SiO2, hexane/AcOEt=93/7) yielded 0.101 g of the title compound as light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.COC(OC)[N:18]([CH3:20])C.O.[NH2:24]N>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:20][NH:18][N:24]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CC(=O)c1cccc(Br)c1
Reactant: COC(OC)N(C)C
Reactant: NN
Solvent: O
Product: CS(=O)(=O)c1c[nH]nc1-c1cccc(Br)c1
Temperature: 70 °C

Procedure:
1.1 g (0.004 mol) of (3'-bromo)(methylsulphonyl)acetophenone is dissolved in 20 ml (0.14 mol) of N,N-dimethylformamide dimethyl acetal and heated to 70° C. and then, after isolation of the intermediate enaminone, treated with 0.3 ml (0.006 mol) of hydrazine hydrate according to the procedure described in Example 1. After purification by trituration in diisopropyl ether, a beige powder is obtained:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:17][NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:25]3[CH:24]=[CH:23][C:22]([S:19]([NH:18][CH3:17])(=[O:20])=[O:21])=[CH:27][CH:26]=3)[N:3]=2)[NH:8][CH:9]=1)=[O:16]
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: CNS(=O)(=O)c1ccc(B(O)O)cc1
Product: CNS(=O)(=O)c1ccc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)cc1

Procedure:
4-[7-(2,2-Dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-N-methyl-benzenesulfonamide was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 4-methylsulfamoylphenylboronic acid following general procedures as described in these Examples. MP 278-280° C., M+H=373.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:10]([CH2:16][CH2:17][CH2:18][CH3:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12].O.CCOC(C)=O>C(O)C>[CH2:17]([C:16]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[NH:7][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:18][CH3:19]
Reactant: CCCCC(=O)C(=O)OCC
Reactant: NNc1ccccc1
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCc1c(C(=O)OCC)[nH]c2ccccc12
Reaction time: 18 h
Yield: 58.1 %

Procedure:
A solution of phenylhydrazine (1.0 g, 6.92 mmol) in absolute ethanol (50 mL) was placed in an oil bath at 60° C. and a reflux condenser attached. Ethyl 2-oxohexanoate (1.0 g, 6.33 mmol) (prepared according to Singh, J; Kissick, T. P.; Mueller, R. H. Organic Preparations and Procedures International (1989), 21(4), 501-4.) was added dropwise. The reaction mixture was heated to reflux and stirred for 18 h. Water (25 mL) and EtOAc (25 mL) were added and the layers separated. The aqueous layer was extracted with EtOAc (2×25 mL), the organic layers combined, dried over sodium sulfate, filtered and concentrated. Trituration of the crude material (9:1 hexanes/EtOAc) afforded ethyl 3-propyl-1H-indole-2-carboxylate (0.850 g, 58%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.46 (s, 1H) 7.65 (d, 1H) 7.40 (d, 1H) 7.25 (d, 1H) 7.04 (t, 1H) 4.33 (q, 2H) 3.02 (t, 2H) 1.56-1.67 (m, 2H) 1.35 (t, 3H) 0.91 (t, 3H). MS: m/z 232.0 (M+1).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH:10]([O:12][CH3:13])[CH3:11])=[CH:4][C:3]=1[O:14][CH3:15].C([Li])CCC.[B:21](OC)([O:24]C)[O:22]C.[Cl-].[NH4+]>O1CCCC1>[CH3:15][O:14][C:3]1[CH:4]=[C:5]([CH:10]([O:12][CH3:13])[CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[B:21]([OH:24])[OH:22]
Reactant: COc1cc(C(C)OC)cc(OC)c1Br
Reactant: COB(OC)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C(C)OC)cc(OC)c1B(O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a tetrahydrofuran (200 ml) solution of 2-bromo-1,3-dimethoxy-5-(1-methoxyethyl)benzene (7.39 g, 26.9 mmol), was added dropwise 1.57M n-butyl lithium (18.8 ml, 29.6 mmol) at −78° C., and the mixture was stirred for 30 minutes. To the mixture, was added dropwise trimethyl borate (6.00 ml, 53.8 mmol), and warmed to room temperature. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added while cooling on ice, which was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane/ethyl acetate=1/1) to obtain the title compound (4.97 g, 20.7 mmol)
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:13]([OH:15])=O)[CH:10]=[CH:11][CH:12]=3)[N:8]=2)[CH2:3][CH2:2]1.Cl.Cl.[NH2:18][C@H:19]1[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:21]12[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22]1)[C@H:19]([NH:18][C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:6]3[O:5][C:4]([CH:1]4[CH2:2][CH2:3]4)=[N:8][C:7]=13)=[O:15])[CH2:20]2
Reactant: O=C(O)c1cccc2oc(C3CC3)nc12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2oc(C3CC3)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.2 %

Procedure:
A mixture of 2-cyclopropylbenzoxazole-4-carboxylic acid (65 mg, 0.32 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (64 mg, 0.32 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (123 mg, 0.64 mmol) and 1-hydroxybenzotriazole (86 mg, 0.64 mmol) in DMF (2 mL) was stirred at room temperature for 5 min, then triethylamine (0.17 mL, 1.28 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyclopropylbenzoxazole-4-carboxamide (43 mg, 43%) as a colorless semisolid: 1H NMR (500 MHz, CDCl3) δ 9.43 (d, J=7.0 Hz, 1H), 8.10 (dd, J=7.5, 1.0 Hz, 1H), 7.56 (dd, J=8.0, 2.0 Hz, 1H), 7.36 (t, J=8.5 Hz, 1H), 4.28-4.22 (m, 1H), 3.49 (ddd, J=11.5, 9.5, 2.0 Hz, 1H), 3.10-2.85 (m, 4H), 2.75 (dd, J=14.0, 4.5 Hz, 1H), 2.28-2.20 (m, 1H), 2.12-2.06 (m, 1H), 2.00-1.90 (m, 1H), 1.75-1.69 (m, 2H), 1.60-1.50 (m, 1H), 1.35-1.22 (m, 4H); MS (ESI+) m/z 312 (M+H); HPLC >99% (AUC), tR=12.31 min.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]([C:8]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:20]([O:22][C:23](OCC)([O:26]CC)[C:24]#[CH:25])[CH3:21].O.CC1C=CC(S(O)(=O)=O)=CC=1>C(#N)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:3]([C:25]#[C:24][C:23]([O:22][CH2:20][CH3:21])=[O:26])=[C:4]([C:8]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(c2cccc(Cl)c2I)CCOCC1
Reactant: C#CC(OCC)(OCC)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C#Cc1c(Cl)cccc1C1(C(=O)OCC)CCOCC1
Temperature: 55 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A mixture of ethyl 4-(3-chloro-2-iodophenyl)-tetrahydro-2H-pyran-4-carboxylate (0.57 g, 1.4 mmol) and TEA (1.8 mL, 13 mmol) in 10 mL ACN was degassed by vacuum and back filled with nitrogen 3 times. The mixture was treated with 3,3,3-triethoxyprop-1-yne (0.37 g, 2.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.051 g, 0.072 mmol) and copper(I) iodide (0.028 g, 0.14 mmol) and stirred at 55° C. for 2 hours. The mixture was cooled to room temperature and concentrated. The residue was diluted with 50 mL EtOH and 10 mL water. The mixture was treated with 4-methylbenzenesulfonic acid hydrate (0.105 g, 0.551 mmol) and stirred at room temperature for 2 hours. The mixture was diluted with 100 mL EtOAc, washed with 20 mL saturated NaHCO3, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography (10-25% EtOAc/hexane) to give 0.5 g yellow oil. MS m/e: (M+H)+ 365.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]#[N:17])=[C:14]([S:18][CH3:19])[S:13][C:12]=2[C:20]([NH2:22])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC#N.[N-:26]=[N+:27]=[N-:28].[Na+].[Si](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]#[N:17])=[C:14]([S:18][CH3:19])[S:13][C:12]=2[C:20]2[NH:22][N:28]=[N:27][N:26]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1sc(C(N)=O)c(-c2ccc(C(C)(C)C)cc2)c1C#N
Reactant: [N-]=[N+]=[N-]
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CSc1sc(-c2nnn[nH]2)c(-c2ccc(C(C)(C)C)cc2)c1C#N

Procedure:
Combine 3-(4-tert-butyl-phenyl)-4-cyano-5-methylsulfanyl-thiophene-2-carboxylic acid amide (0.142 mmol) and 1.5 ml CH3CN with NaN3 (0.43 mmol) and SiCl4 (0.142 mmol) in CH2Cl2 and reflux the mixture for 16 hrs. MS shows desired product and starting material. Conc. to dryness and purification by radial chromatography (Si) on a 1000 micron plate eluting with 5% MeOH/0.5% AcOH/CH2Cl2. Concentrate desired fractions to provide the desired title compound: 1H NMR (400 MHz, CDCl3) δ 7.40 (q, 4H, J=22 Hz), 2.73 (s, 3H), and 1.35 (s, 9H), MS found (M+1) 356.2.