Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C-:10]#[N:11].[Na+]>CS(C)=O.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:10]#[N:11]
Reactant: BrCc1ccccc1Br
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#CCc1ccccc1Br
Temperature: 60 °C
Yield: 80.9 %

Procedure:
N-Boc-protected 3-[2-(aminoethyl)phenyl]-2-propenoic acid (Compound 23) was prepared as outlined in Scheme IV. A mixture of o-bromobenzyl bromide (10.45 g; 41.81 mmol) and sodium cyanide (2.55 g; 52.25 mmol) in 100 ml of DMSO was heated at 60° C. for 5 hours. After being cooled, the reaction mixture was diluted with 200 ml of water and 200 ml of ethyl acetate. The layers were separated and the aqueous layer was extracted with any additional 100 ml of ethyl acetate. The combined organic layers were dried and concentrated, and the residue was purified on a flash column, eluting with 10% ether/hexane to obtain 6.63 g (81%) of 2-bromobenzyl cyanide 19, 1H NMR (CDCl3): δ 3.83 (s, 2H); 7.18 (m, 1h); 7.29 (t, 1H); 7.52 (d, 1H);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)=[O:15]>>[CH3:1][O:2][C:3]1[C:4]2[CH:13]=[C:14]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[O:15][C:5]=2[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(C(=O)CBr)cc(OC)c1OC
Reactant: COc1cc(O)cc(OC)c1
Product: COc1cc(OC)c2cc(-c3cc(OC)c(OC)c(OC)c3)oc2c1
Yield: 75 %

Procedure:
This compound was prepared using Method A from 3,5-dimethoxyphenol and 2-bromo-1-(3,4,5-trimethoxyphenyl)ethanone: Yield 75% following procedure A.2; m.p. 131-132° C.; IR 2960, 1619, 1497, 1227, 1203, 1134, 1110 cm−1; 1H-NMR (500 MHz, δ ppm, CDCl3) 7.04 (s, 2H), 7.00 (s, 1H), 6.74 (s, 1H), 6.36 (d, J=1.8 Hz, 1H), 3.97 (s, 6H), 3.95 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H); 13C-NMR (126 MHz, δ ppm, CDCl3) 159.4, 156.7, 153.8, 153.7, 153.6, 138.4, 126.6, 113.5, 101.9, 98.7, 94.6, 88.5, 61.2, 56.4, 56.0, 55.8.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=[CH:2]1.N=C=N.C1C=CC2N(O)N=NC=2C=1.[NH2:22][C@H:23]([C:33]1[NH:34][C:35]([C:38]2[C:39]([O:48][CH3:49])=[N:40][C:41]3[C:46]([CH:47]=2)=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:36][N:37]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:31][CH3:32])=[O:30].C(O)C(N)(CO)CO>C(Cl)Cl.CN(C=O)C>[CH3:49][O:48][C:39]1[C:38]([C:35]2[NH:34][C:33]([C@@H:23]([NH:22][C:6]([C:5]3[S:1][CH:2]=[N:3][CH:4]=3)=[O:8])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:31][CH3:32])=[O:30])=[N:37][CH:36]=2)=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=1
Reactant: CNC(=O)CCCCC[C@H](N)c1ncc(-c2cc3ccccc3nc2OC)[nH]1
Reactant: O=C(O)c1cncs1
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)CCCCC[C@H](NC(=O)c1cncs1)c1ncc(-c2cc3ccccc3nc2OC)[nH]1
Reaction time: 0.17 h

Procedure:
A glass tube was charged with thiazole-5-carboxylic acid (1.5 eq.), PS-carbodiimide resin (2 eq.), HOBt (1.7 eq.) and diluted with DCM (0.04 M). The tube was capped and stirred on a rotor for 10 min. Then, a solution of A4 in DMF (0.06 M) was added and the reaction mixture was stirred in a rotor for 24 h. After addition of MP-Trisamine resin (10 eq.) the reaction was stirred for additional 24 h. The resulting reaction mixture was filtered through a fritted syringe and washed with DCM. The combined organic solutions were concentrated under reduced pressure to give the title compound. MS (ES+) C25H28N6O3S: 493 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH2:22][CH2:23][C@H:24]1[C@H:28]([CH3:29])[CH2:27][NH:26][CH2:25]1>CN(C)C=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:27][C@@H:28]([CH3:29])[C@H:24]([CH2:23][NH2:22])[CH2:25]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: C[C@@H]1CNC[C@H]1CN
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C[C@H]1CN
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In the same manner as described in Example 16 (1), a mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, trans-3-aminomethyl-4-methylpyrrolidine, and dimethylformamide was stirred at room temperature for 24 hours to give 5-amino-7-(trans-3-aminomethyl-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro4-oxoquinoline-3-carboxylic acid, which was recrystallized from ethanol, m.p. 223°-225° C.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][CH2:9][S:10][C:11]1[O:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2].[CH2:18]([NH2:20])[CH3:19]>>[N+:1]([CH:4]=[C:5]([NH:20][CH2:18][CH3:19])[NH:6][CH2:7][CH2:8][CH2:9][S:10][C:11]1[O:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2]
Reactant: CCN
Reactant: CSC(=C[N+](=O)[O-])NCCCSc1ncco1
Product: CCNC(=C[N+](=O)[O-])NCCCSc1ncco1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[3-(2-oxazolylthio)propylamino]ethylene (see Example 19 (iv)) with ethylamine by the procedure of Example 8(ii) gives the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[CH2:30]([NH2:33])[C:31]#[CH:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:33][CH2:30][C:31]#[CH:32])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: C#CCN
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C#CCNCc1ccc2c(c1)cc(-c1ccc(Cl)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with propargylamine (0.013 mL, 0.19 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(2-propynylaminomethyl)indol-2-yl]isoindolinone.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S@@:7]([NH2:9])=[O:8])=[CH:3][CH:2]=1.[CH3:11][C@@H:12]([C@@H:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=CC=1)[CH3:16])[CH:13]=O.[OH2:25]>ClCCl>[CH3:13][C@@H:12]([C@@H:15]([O:17][CH:18]1[CH2:19][CH2:24][CH2:23][CH2:22][O:25]1)[CH3:16])[CH:11]=[N:9][S@:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)=[O:8]
Reactant: Cc1ccc([S@@](N)=O)cc1
Reactant: C[C@H](C=O)[C@H](C)OCc1ccccc1
Reactant: O
Solvent: ClCCl
Product: Cc1ccc([S@](=O)N=C[C@@H](C)[C@H](C)OC2CCCCO2)cc1
Yield: 77 %

Procedure:
Ti(OEt)4 (1.71 g, 1.57 ml, 7.5 mmol, 5 eq.) was added dropwise, at room temperature, to a mixture of (S)-(+)-p-toluenesulfinamide (233 mg, 1.50 mmol) and (2S,3S)-2-methyl-3-benzyloxybutyraldehyde (6) (280 mg, 1.50 mmol) in dichloromethane (25 ml). The solution was refluxed under argon for 5.5 hours. The reaction was neutralized at 0° C. adding water (25 ml). The cloudy solution was filtered on Celite and the filter cake was washed with dichloromethane (2×25 ml). The phases were separated, the aqueous phase was extracted with dichloromethane and the combined organic portions were dried over Na2SO4 and they were concentrated. Flash chromatography on a silica gel column (heptane/EtOAc=6:1) produced (S)-N-[(2R,3S)-2-methyl-3-tetrahydropyranyloxybutylidene]-p-toluenesulfinamide (7) (375 mg, 77%): IR (CHCl3) 3010, 2976, 2946, 2878, 2854, 1620, 1598, 1494, 1455, 1443, 1380, 1354, 1214 cm−1; 1H NMR (250 MHz, CDCl3) δ 8.31 (d, J=5.8 Hz, 0.5H); 8.23 (d, J=5.3 Hz, 0.5H); 7.55 (m, 2H); 7.29 (m, 2H); 4.79 to 4.70 (m, 0.5H); 4.55 to 4.51 (m, 0.5H); 4.00 to 3.82 (m, 1.5H); 3.77 to 3.70 (m, 0.5H); 3.48 to 3.41 (m, 1H); 2.84 to 2.64 (m, 1H); 2.39 (s, 3H); 1.78 to 1.41 (m, 6H); 1.25 (d, J=6.4 Hz, 1.5H); 1.14 (d, J=5.7 Hz, 3H); 1.14 (d, J=7.1 Hz, 1.5H); 1.09 (d, J=7.0 Hz, 1.5H); 13C NMR (75 MHz, CDCl3) δ 169.2; 168.6; 141.9; 141.8; 141.2; 129.4; 124.4; 124.2; 99.6; 94.6; 76.4; 72.2; 62.3; 61.8; 45.6; 45.2; 30.6; 30.5; 25.2; 25.2; 21.1; 19.4; 19.1; 18.9; 16.3; 13.0; 12.5; MS (CI) m/z 324 [M+H]+. HRMS: calculated for C17H26NO3S (M+H), 324.16333; found, 324.16141.
Reaction SMILES: C[C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH:5]([C:12]([OH:14])=O)[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8].[C:19]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:38][C:39]1[CH:40]=C2C(=[CH:47][CH:48]=1)C=C(O)C=C2.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:38][C:39]1[CH:40]=[C:17]2[C:18](=[CH:47][CH:48]=1)[CH:2]=[C:3]([O:4][CH:5]1[CH2:6][CH:7]([C:9]([O:11][CH3:19])=[O:10])[NH:8][C:12]1=[O:14])[CH:15]=[CH:16]2
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccccc1OC(C[C@H](N)C(=O)O)C(=O)O
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: COC(=O)C1CC(Oc2ccc3cc(Br)ccc3c2)C(=O)N1
Temperature: 25 °C
Reaction time: 23 h
Yield: 108.6 %

Procedure:
A mixture of the compound prepared as described in Example 4 (0.498 g), triphenylphosphine (0.932 g), and 6-bromo-2-naphthol (0.793 g) in tetrahydrofuran (4.3 ml) was cooled to approximately 1°-2° C., and treated with a solution of diethylazodicarboxylate (0.619 g) in tetrahydrofuran (4.3 ml) over a one minute period. After the addition was complete, the reaction was allowed to warm to room temperature. After about 23 hours, the solution was concentrated in vacuo. The residue was diluted with chloroform (2 ml), the insoluble material removed by filtration, and the filtrate concentrated in vacuo. The oil was dissolved in methylene chloride and purified by preparative centrifugal thin-layer chromatography (4 mm plate, flow rate=8 ml/min), eluting with ethyl acetate/hexane (1:1) until first band elutes then solvent switched to hexane:ethyl acetate (1:3). The fractions containing the title compound were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to give methyl 3-(6-bromo-2-naphthyloxy)-2-pyrrolidone-5-carboxylate (778 mg).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH:10](OCC)[N:9]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([Si](C)(C)C)[CH:24]=[CH2:25].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(OC)(C)C>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH:10]([CH2:25][CH:24]=[CH2:23])[N:9]1[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CC[Si](C)(C)C
Reactant: CCOC1CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCC1CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
A solution of 12.6 g of the α-methoxycarbamate 45 (40.0 mmol) and 16.0 ml of allyltrimethylsilane (100 mmol, 2.5 eq.) in 100 ml of anhydrous CH2Cl2 was cooled to −78° C. and added dropwise with 10.1 ml of BF3.OEt2 (80.0 mmol, 2 eq.). After completed addition, stirring was continued for 30 min, and completion of the reaction was checked by means of TLC (EE/CH 1:9). Thereafter, 10 ml of a saturated NaHCO3 solution was added, and the batch was allowed to come to RT. After transferring into a separating funnel together with 200 ml of MTBE, the phases were separated and the aqueous phase was extracted with 2×100 ml of MTBE. The combined organic phases were washed with 100 ml of half-conc. NaCl solution, dried over MgSO4 and concentrated. The residue was purified using silica gel column chromatography (EE/CH 1:9), thereby obtaining 9.62 g of allyl substitution product 46 (30.9 mmol, 77%) as a colorless oil (mixture of epimers, cis/trans 75:25).
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[C:5]([NH2:12])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH2:28][N:29]=[C:30]=[O:31]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:30]([NH:29][CH2:28][C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[Cl:20])=[O:31])=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Reactant: Nc1ccc(Br)c2cnccc12
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1Cl)Nc1ccc(Br)c2cnccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
8-Bromo-5-isoquinolinamine (120 mg, 0.52 mmol) in THF:toluene (5 mL, 1:4) was treated with 2,4-dichloro-1-(isocyanatomethyl)benzene (108 mg, 0.52 mmol) in THF (0.5 mL). After stirring for 16 hours at room temperature, the mixture was filtered and the filter cake was dried under reduced pressure to provide the title compound. MS (ESI+) m/z 426 (M+H)+; MS (ESI−) m/z 424 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 4.42 (d, 5.8, 2H), 7.22 (t, J 5.8, 1H), 7.65 (m, 1H), 7.91 (d, J 8.5, 1H), 8.02 (d, J 6.1, 1H), 8.22 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 9.01 (s, 1H), 9.44 (s, 1H); Anal. Calcd for C17H12BrCl2N3O.HCl+0.25EtOH: C, 44.41; H, 3.14; N, 8.88. Found: C, 44.80; H, 2.76; N, 8.84.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][C:15]3=[O:23])[CH:11]=[C:10]([C:24](O)=[O:25])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:27][C:28]1[N:29]=[CH:30][C:31]([CH2:34][NH2:35])=[N:32][CH:33]=1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:27][C:28]1[N:29]=[CH:30][C:31]([CH2:34][NH:35][C:24]([C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[CH:13]=[C:12]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][C:15]3=[O:23])[CH:11]=2)=[O:25])=[N:32][CH:33]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(N3C(=O)Cc4ccccc43)c2)cc1
Reactant: Cc1cnc(CN)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)cn3)cc(N3C(=O)Cc4ccccc43)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5 %

Procedure:
The 4′-methyl-5-(2-oxo-2,3-dihydro-indol-1-yl)-biphenyl-3-carboxylic acid from step 3 was added to DMF (3 mL), together with C-(5-methyl-pyrazin-2-yl)-methylamine (0.1 mL), HOAt (15 mg, catalytic amount), NMM (0.4 mL) and EDCI (200 mg). The reaction mixture was stirred overnight at room temperature, then partitioned between water and ethyl acetate. The organic layer was separated and concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer chromatography (7% MeOH in dichloromethane) to give 20 mg (5% overall) of 4′-methyl-5-(2-oxo-2,3-dihydro-indol-1-yl)-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide, MS (M+H)=449.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.Cl.[N:12]([O-])=O.[Na+].[CH:16]1[C:21]([OH:22])=[CH:20][CH:19]=[C:18]([CH3:23])[CH:17]=1>[OH-].[Na+]>[N:1]1[N:12]([C:16]2[CH:17]=[C:18]([CH3:23])[CH:19]=[CH:20][C:21]=2[OH:22])[N:6]=[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=12
Reactant: O=N[O-]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: Cc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Reaction time: 1 h

Procedure:
o-Nitroaniline (0.5 mole) was diazotized in the usual manner with concentrated hydrochloric acid (200 ml.) and sodium nitrite (0.5 mole). The clear diazonium solution was added slowly to a cold solution (0°-5°) of p-cresol (0.5 mole) in 450 ml of 10% sodium hydroxide. The mixture was stirred for 1 hour and 2-nitro-2'-hydroxy-5'-methylazoaniline (A) was filtered out (60% yield). One-tenth mole of A was dissolved in 100 ml. of 2N NaOH. Zinc dust (30 g.) and sodium hydroxide (50 ml. of a 25% solution) were added slowly to the well-stirred solution to keep the temperature below 45°C. The mixture was then cooled to <30°C. and acidified with concentrated hydrochloric acid. After stirring for 2 hours, the precipitate was filtered and recrystallized from toluene (mp 122-24°) to give o-[2H-benzotriazol-2-yl)-4-methylphenol (B). A solution containing 9.0 g. (0.04 mole) of B and 4.0 6 gm. (0.02 mole) of isophthaloyl chloride in 200 ml. of pyridine was heated with stirring at 50°-60° for 15 hrs. The reaction mixture was poured into cold dilute hydrochloric acid and a solid precipitated. The solid was filtered, and air-dried to give 1 as a white solid (30%, mp. 115°-8°).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][CH2:13][CH3:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=[CH:19][CH:18]=[CH:17][CH:16]=1.C([S:24](Cl)(=[O:26])=[O:25])C=C>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:16]([S:24]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][CH2:13][CH3:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:26])=[O:25])[CH2:17][CH:18]=[CH2:19]
Reactant: c1ccncc1
Reactant: CCCc1cc(N)cc(C(=O)OC)c1
Reactant: C=CCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCCS(=O)(=O)Nc1cc(CCC)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 32.4 %

Procedure:
To a solution of methyl 3-amino-5-propylbenzoate (D133) (2.49 g, 12.9 mmol, 1 equiv) in CH2Cl2 (25 ml) were added pyridine (1.13 ml, 14 mmol, 1.1 equiv), 2-propene-1-sulfonyl chloride (2 g, 12.9 mmol, 1 equiv) and DMAP (350 mg, 2.9 mmol, 0.2 equiv) and the resulting mixture was stirred at room temperature for 4 days. The solution was diluted with AcOEt and the organic phase was washed with H2O, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 4:1) gave methyl 3-[(3-buten-1-ylsulfonyl)amino]-5-propylbenzoate (D134) (1.3 g, 32%) as a colourless oil. [M−H]−=310.0, RT=3.39 min.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([Cl:7])[C:3]=1[Cl:8].[F:9][C:10]([F:19])([F:18])[S:11]([O:14][CH2:15][CH2:16][CH3:17])(=[O:13])=[O:12]>C(Cl)(Cl)(Cl)Cl>[F:9][C:10]([F:19])([F:18])[S:11]([O-:14])(=[O:13])=[O:12].[CH2:15]([N+:5]1[S:6][C:2]([Cl:1])=[C:3]([Cl:8])[C:4]=1[Cl:7])[CH2:16][CH3:17]
Reactant: Clc1nsc(Cl)c1Cl
Reactant: CCCOS(=O)(=O)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: CCC[n+]1sc(Cl)c(Cl)c1Cl
Product: O=S(=O)([O-])C(F)(F)F
Yield: 27.6 %

Procedure:
Trichloroisothiazole (4.7 g, 0.025 mol) and a solution of 0.02 mol of n-propyl trifluoromethane sulfonate in CCl4 were heated at 110° and CCl4 was removed via distillation. After heating at 110° for 11/2 hrs, the reaction was cooled and ether added. The ether was cooled in an ice bath and the solid collected to yield 2.1 g (28%) of product, mp 95°-99°. Analysis calculated for C7H7Cl3F3NO3S: C, 22.09; H, 1.86; Cl, 27.95; N, 3.68; S, 16.84. Found: C, 2160; H, 1.94; Cl, 27.15; N, 3.57; S, 16.27.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(OC([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[N:35][C:36]([NH2:39])=[CH:37][CH:38]=2)[CH2:29][CH2:28]1)=O)(C)(C)C>>[CH3:1][NH:2][C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:39][C:36]3[CH:37]=[CH:38][C:33]([N:30]4[CH2:29][CH2:28][NH:27][CH2:32][CH2:31]4)=[CH:34][N:35]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CNC(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CNC(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Yield: 76.6 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methylamide (500 mg, 1.80 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (550 mg, 1.98 mmol) gave 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methylamide (580 mg, 77%). MS(ESI) m/z 421.2 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][S:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:47])[CH:28]([C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1)[CH:29]([CH3:31])[CH3:30])[CH3:25]>>[CH2:24]([O:26][C:27](=[O:47])[CH:28]([C:32]1[CH:33]=[CH:34][C:35]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH2:14][S:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:36][CH:37]=1)[CH:29]([CH3:31])[CH3:30])[CH3:25]
Reactant: CCOC(=O)C(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(C)C
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CSCCc1ccccc1
Product: CCOC(=O)C(c1ccc(-c2ccc(-c3onc(C)c3CSCCc3ccccc3)cc2)cc1)C(C)C

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 5-(4-bromo-phenyl)-3-methyl-4-phenethylsulfanylmethyl-isoxazole and 3-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-butyric acid ethyl ester.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C@H:7]2[CH2:9][C@H:8]2[CH2:10][CH2:11][OH:12])[CH2:3][CH2:2]1.Br[C:14]1[N:22]=[C:17]2[N:18]=[CH:19][CH:20]=[CH:21][N:16]2[N:15]=1.CCN(C(C)C)C(C)C>C(O)C>[N:15]1[N:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]2=[N:22][C:14]=1[N:1]1[CH2:6][CH2:5][CH:4]([C@H:7]2[CH2:9][C@H:8]2[CH2:10][CH2:11][OH:12])[CH2:3][CH2:2]1
Reactant: Brc1nc2ncccn2n1
Reactant: OCC[C@@H]1C[C@@H]1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: OCC[C@@H]1C[C@@H]1C1CCN(c2nc3ncccn3n2)CC1
Temperature: 120 °C

Procedure:
To a mixture of 2-((1S,2R)-2-(piperidin-4-yl)cyclopropyl)ethanol (Intermediate 11; 70 mg, 0.4 mmol) and 2-bromo[1,2,4]triazolo[1,5-a]pyrimidine (9 mg, 0.496 mmol) in ethanol (2 mL) was added DIEA (0.22 mL, 1.21 mmol) and the resulting mixture heated via microwave to 120° C. for 1 hr. HPLC of the reaction mixture proved the reaction was complete with the absence of Intermediate 11. The mixture was filtered (glass wool filter paper, Whatman 1821 110), and washed with ethanol. The filtrate was concentrated to dryness under reduced pressure and the resulting residue purified via preparative TLC plates (2×1000 μM silica gel) eluting with 50% ethyl acetate in hexane. The product was removed from the silica gel by extracting with ethyl acetate and the solvent was removed under reduced pressure to afford the title compound as an off-white solid. MS (Multimode) m/z 288 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[CH:18]1[CH2:23][CH2:22][C:21]([N:30]([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)(=[O:3])[CH3:2].[Si]([Cl:37])(C)(C)C>C(OCC)(=O)C>[ClH:37].[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[CH:18]1[CH2:19][CH2:20][C:21]([N:30]([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:23]1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)Cl
Agent: CC(=O)OCCCCc1c(C2CCC(c3ccccc3)(N(C)C)CC2)[nH]c2ccccc12
Solvent: CCOC(C)=O
Product: Cl
Reaction time: 1 h

Procedure:
4-(2-(4-(Dimethylamino)-4-phenylcyclohexyl)-1H-indol-3-yl)butyl acetate (polar diastereomer) (112 mg, 0.26 mmol) was dissolved in ethyl acetate (20 ml). Me3SiCl (65 μl, 0.52 mmol) was then added dropwise at RT and the mixture was stirred for 1 h. A white precipitate precipitated out. The precipitate was filtered off with suction, washed with ethyl acetate (2×5 ml) and then dried. Example 179 (97 mg, m.p. 165-169° C., 80%) was a white solid.