Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[C:12]3=[N:13][C:14]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[CH:15][CH:16]=[C:11]3[C:10]([CH2:27]O)=[N:9]2)=[CH:5][CH:4]=1.S(Cl)([Cl:33])=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Cl:33][CH2:27][C:10]1[C:11]2[C:12](=[N:13][C:14]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)[N:8]([CH2:7][C:6]2[CH:29]=[CH:30][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:9]=1
Reactant: COc1ccc(CNc2ccc3c(CO)nn(Cc4ccc(OC)cc4)c3n2)cc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2ccc3c(CCl)nn(Cc4ccc(OC)cc4)c3n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a slurry of {1-(4-methoxybenzyl)-6-[(4-methoxybenzyl)amino]-1H-pyrazolo[3,4-b]pyridin-3-yl}methanol (1.49 g, 3.68 mmol) in chloroform (15 mL) cooled in an ice bath was added thionyl chloride (538 μL, 7.37 mmol). The resulting mixture was then allowed to warm to room temperature and left at room temperature for 30 minutes. The reaction was determined by LCMS monitoring not to be complete not complete, so the reaction mixture was re-cooled in an ice bath, treated with additional thionyl chloride (100 μL), and then stirred at room temperature for 30 minutes. The reaction mixture was then poured into aqueous NaHCO3, extracted into CHCl3 and the solvent removed in vacuo. This residue was purified on a silica gel (120 g) column (0-60% EtOAc/CHCl3 to give the title compound. LRMS (M+1)=422.9
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][CH:3]=1.[CH2:13]([NH2:16])[CH2:14][NH2:15]>>[ClH:1].[NH2:15][CH2:14][CH2:13][NH:16][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=1
Reactant: NCCN
Reactant: CCOC(=O)c1ccc(Cl)cc1
Product: Cl
Product: NCCNC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 116.3 %

Procedure:
18.5 g of ethyl 4-chlorobenzoate and 24 g of ethylenediamine are stirred at 130° for 17 hours. The mixture is cooled to room temperature, evaporated, and the residue is treated with 200 ml of ethyl acetate. The insoluble N,N'-ethylenebis(4-chlorobenzamide) (2.3 g), m.p. 266°-268°, is filtered off under suction, and the filtrate is washed three times with 50 ml of water each time and evaporated. The residue is treated with 100 ml of 1N hydrochloric acid, the insoluble N,N'-ethylenebis(4-chlorobenzamide) (1.0 g) is filtered off under suction, and the filtrate is evaporated to dryness. The residue is then evaporated twice with 100 ml of ethanol/benzene each time and recrystallized from ethanol/ether. There are obtained 13.7 g of N-(2-amino-ethyl)-4-chlorobenzamide hydrochloride, m.p. 216°-217°.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[N:30]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[C:15]=2[O:14]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cccc(-c2cccc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c1
Agent: [Na+]
Product: COc1cccc(-c2cccc3c2OC(CN=[N+]=[N-])C3)c1

Procedure:
Treatment of (±)-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (3.0 g, 7.82 mmol) with sodium azide (0.309 g, 4.48 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.030 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.25 g (80%) of (±)-1-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 152-154° C.; Anal. calcd. for C16H17NO2HCl: C, 65.86; H, 6.22; N, 4.8. Found: C, 65.21; H, 6.17; N, 4.46.
Reaction SMILES: C(NC(C1C=C(S([O:16][CH2:17][C@:18]([OH:68])([CH3:67])[C:19](=[O:66])[C@H:20]([CH2:62][CH:63]([CH3:65])[CH3:64])[NH:21][C:22](=[O:61])[C@H:23]([CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[NH:24][C:25](=[O:53])[C@H:26]([CH2:49][CH:50]([CH3:52])[CH3:51])[NH:27][C:28](=[O:48])[C@H:29]([CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:30][C:31](=[O:39])[CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)(=O)=O)C=CC=1)=O)C#C.[CH2:69]([O:72][C:73]1[CH:78]=[C:77]([CH3:79])[C:76]([S:80](Cl)(=[O:82])=[O:81])=[C:75]([CH3:84])[CH:74]=1)[C:70]#[CH:71].OC[C@](O)(C)C(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CN1CCOCC1)CCC1C=CC=CC=1)CC(C)C)CC1C=CC=CC=1)CC(C)C>>[CH3:79][C:77]1[CH:78]=[C:73]([O:72][CH2:69][C:70]#[CH:71])[CH:74]=[C:75]([CH3:84])[C:76]=1[S:80]([O:16][CH2:17][C:18]([OH:68])([CH3:67])[C:19](=[O:66])[C@H:20]([CH2:62][CH:63]([CH3:64])[CH3:65])[NH:21][C:22](=[O:61])[C@H:23]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[NH:24][C:25](=[O:53])[C@H:26]([CH2:49][CH:50]([CH3:52])[CH3:51])[NH:27][C:28](=[O:48])[C@H:29]([CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:30][C:31](=[O:39])[CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)(=[O:82])=[O:81]
Reactant: C#CCOc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: C#CCNC(=O)c1cccc(S(=O)(=O)OC[C@@](C)(O)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc2ccccc2)NC(=O)CN2CCOCC2)c1
Agent: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)[C@](C)(O)CO
Product: C#CCOc1cc(C)c(S(=O)(=O)OCC(C)(O)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc2ccccc2)NC(=O)CN2CCOCC2)c(C)c1

Procedure:
Prepared in a similar manner to compound 13, except from 4-(propargyloxy)-2,6-dimethylbenzene-1-sulfonyl chloride and (S)—N—((S)-1-(((2R,4S)-1,2-dihydroxy-2,6-dimethyl-3-oxoheptan-4-yl)amino)-1-oxo-3-phenylpropan-2-yl)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]([O:21][CH3:22])[CH:8]=1)=[O:5].[N:34](OCCCC)=O.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C(F)(F)F)=O>[CH3:22][O:21][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[CH:23]=[C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:25]=[CH:26][C:2]=3[N:1]=[N:34]2)[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COc1cc(NC(=O)c2cc(Oc3ccccc3)ccc2N)ccc1OCCN1CCCC1
Reactant: CCCCON=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(-n2nnc3ccc(Oc4ccccc4)cc3c2=O)ccc1OCCN1CCCC1
Reaction time: 0.02 h

Procedure:
A solution of the free base of this amine (58 mg, 0.13 mmol) in dichloromethane (2 ml) was acidified with 5 drops of TFA then treated with butyl nitrite (100 ul). A deep orange colour formed immediately. After 1 minute, DBU was introduced dropwise until basic. The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel (eluting with methanol-dichloromethane-aqueous ammonia) to give the title compound which crystallised as a pale yellow HCl salt on treatment with 1M HCl in ether;
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[Cl:59]C1C=CC=CC=1C(Cl)=O>>[Cl:59][C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)=[O:8]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4Cl)cc3)cc2C1=O
Yield: 89 %

Procedure:
The compound of example 131 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 2-chloro benzoyl chloride.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH3:18][CH:19]([NH2:21])[CH3:20].CCO>C(CC(C)(C)C)(C)C>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:21][CH:19]([CH3:20])[CH3:18])[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: CC(C)N
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Solvent: CC(C)CC(C)(C)C
Solvent: CCO
Product: CC(C)NCC1OCc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (8.5 mg, 0.026 mmol), propan-2-amine (0.5 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 303 (M+, 0.3), 95 (10), 86 (14), 75 (8), 72 (bp), 58 (9).
Reaction SMILES: C([Cl:4])(=O)C.[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C:15]1[N:20]([CH2:21][C:22]([NH:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[O:23])[C:19](=[S:35])[NH:18][C:17](=[O:36])[CH:16]=1>C(O)C>[ClH:4].[NH2:27][CH2:26][CH2:25][NH:24][C:22](=[O:23])[CH2:21][N:20]1[C:15]([C:8]2[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:7]=2[O:6][CH3:5])=[CH:16][C:17](=[O:36])[NH:18][C:19]1=[S:35]
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2cc(=O)[nH]c(=S)n2CC(=O)NCCNC(=O)OC(C)(C)C)c(OC)c1
Solvent: CCO
Product: COc1ccc(-c2cc(=O)[nH]c(=S)n2CC(=O)NCCN)c(OC)c1
Product: Cl
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
To cold (0° C.) ethanol (21.5 mL) under nitrogen was added acetyl chloride (1.55 mL) dropwise over 5 minutes, and the reaction mixture was then heated at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature and tert-butyl (2-(2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamido)ethyl)carbamate was added (1.0 g, 2.15 mmol), followed by heating to 50° C. for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was suspended in ethanol (10 mL), heated to 75° C. for 20 minutes, and EtOAc (20 mL) was added and heating was continued for another 20 minutes. The mixture was allowed to slowly cool to down to room temperature with stirring during 18 hours. The resultant precipitate was filtered and dried in a vacuum oven at 70° C. for 20 hours to give the title compound (751 mg, 87%) as a white solid.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH2:2]1.[Br:13]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.O.C(OCC)(=O)C>[Br:13][C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([CH2:1][CH2:2][N:3]3[CH2:4][CH2:5][CH2:6]2)[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1cc2c3c(c1)CCN3CCC2
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cc2c3c(c1)CCN3CCC2
Reaction time: 0.25 h
Yield: 86.7 %

Procedure:
A solution of 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline (4.0 g, 25.2 mmol) in N,N-dimethylformamide (160 ml) cooled to −30° C. was treated with a solution of N-bromosuccinimide (4.5 g, 25.3 mmol) in N,N-dimethylformamide (30 ml) dropwise over 5 minutes. The mixture was stirred for a further 15 minutes then treated with 10% aqueous sodium sulfite (100 ml) then diluted with water (500 ml) and ethyl acetate (300 ml). The aqueous layer was removed and the organic layer was washed with saturated aqueous sodium bicarbonate (100 ml), then water (3×150 ml). The organic layer was dried with anhydrous sodium sulfate and evaporated to dryness to give 8-bromo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline as a pale brown oil (5.2 g) which was used without further purification. 400 MHz 1H NMR (CDCl3) δ: 7.02 (m, 1H), 6.94 (m, 1H), 3.25 (t, 2H), 2.95 (m, 2H), 2.89 (t, 2H), 2.65 (t, 2H), 2.06 (m, 2H); LCMS: 238 and 240 [M+H].
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4]1.[S:13](=O)(=[O:16])([OH:15])[OH:14]>O>[OH:16][S:13]([O:1][CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4]1)(=[O:15])=[O:14]
Reactant: OC[C@@H]1Cc2ccccc2CN1
Reactant: O=S(=O)(O)O
Solvent: O
Product: O=S(=O)(O)OC[C@@H]1Cc2ccccc2CN1
Temperature: 110 °C

Procedure:
A solution of (S)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (41 g) in a mixture of sulphuric acid (d = 1.83; 13 cc) and water (70 cc) is heated at 110° C. Water (50 cc) is distilled off and the mixture is then concentrated under reduced pressure (20 mm Hg) at 100° C. The brown oily residue is taken up in a mixture of sulphuric acid (d = 1.83; 13 cc) and water (70 cc). Water (50 cc) is again distilled off and the mixture is then concentrated as previously described, after which the concentration is finished at 100° C under reduced pressure (1 mm Hg). The residue which crystallises on cooling, is redissolved in a hot mixture of ethanol (140 cc) and water (60 cc). After cooling for 15 hours at about 5° C the resulting crystals are filtered off and washed with a mixture (20 cc) of ethanol and water (3:1 by volume) and then with ethanol (2 × 25 cc). After drying at 60° C under reduced pressure (1 mm Hg), (S)-3-hydroxysulphonyloxymethyl-1,2,3,4-tetrahydroisoquinoline (48 g) is obtained in the form of white crystals.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[H-].[Na+].Br[CH2:24][CH2:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1.O>CN(C)C=O>[Br:1][C:2]1[N:3]([CH2:24][CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCOC3CCCCO3)c2c1

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (5.00 g, 14.8 mmol) in N,N-dimethylformamide (50 ml) was added sodium hydride (60% in oil, 713 mg, 17.8 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr. 2-(2-Bromoethoxy)tetrahydropyran (2.90 ml, 19.2 mmol) was added to the reaction mixture under ice-cooling, and the mixture m was stirred at room temperature for 4 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give methyl 2-bromo-3-cyclohexyl-1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-indole-6-carboxylate as a crude product. The obtained crude product was used for Step 2 without purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][Mg]Br.CCOCC>C1COCC1>[OH:9][CH:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)[CH3:10]
Reactant: C[Mg]Br
Reactant: Cc1cccc(C=O)n1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cccc(C(C)O)n1
Reaction time: 1 h

Procedure:
To 6-methylpyridine-2-carboxaldehyde (2.0 g, 16.5 mmol) in dry THF (55 mL) at 0° C. under nitrogen, add a solution of 3M methyl magnesium bromide in ether (6.0 mL, 18.0 mmol,) dropwise with stirring. After 1 h at 0° C., quench with saturated aqueous NH4Cl, extract three times with EtOAc, dry over anhydrous Na2SO4 and concentrate in vacuo to give the desired intermediate (crude, 2.3 g).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si](O[CH2:27][C:28]1[C:29]([N+:40]([O-:42])=[O:41])=[C:30]([CH:37]=[CH:38][CH:39]=1)[C:31]([NH:33][CH2:34][C:35]#[CH:36])=[O:32])(C(C)(C)C)(C)C.C(N(CC)CC)C.[Br:50][C:51]([CH3:56])([CH3:55])[C:52](Br)=[O:53]>C1COCC1>[Br:50][C:51]([CH3:56])([CH3:55])[C:52]([CH2:27][C:28]1[C:29]([N+:40]([O-:42])=[O:41])=[C:30]([CH:37]=[CH:38][CH:39]=1)[C:31]([NH:33][CH2:34][C:35]#[CH:36])=[O:32])=[O:53]
Reactant: C#CCNC(=O)c1cccc(CO[Si](C)(C)C(C)(C)C)c1[N+](=O)[O-]
Reactant: CC(C)(Br)C(=O)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCNC(=O)c1cccc(CC(=O)C(C)(C)Br)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
TBAF (4.19 mL of a 1.0 M solution in THF) was added dropwise to a stirring solution of Compound 11 (487 mg, 1.40 mmol) in THF (14 mL). TLC analysis showed complete reaction after 5 minutes, after which time the THF was removed on a rotary evaporator and the resulting oil was dissolved in EtOAc (50 mL), washed with saturated NH4Cl (2×20 mL), water (2×50 mL), dried over MgSO4, concentrated in vacuo. The resulting white solid (Compound 12) was dissolved in anhydrous THF (14 mL), triethylamine (184 mg, 1.81 mmol) was added, and the resulting solution was added dropwise to a stirring solution of □-bromoisobutyrylbromide (225 mg, 1.82 mmol) in THF (5 mL) at 0° C. A white precipitate formed immediately. The mixture was allowed to warm to room temperature and stirred overnight under argon atmosphere after which time the solid salts were filtered, and the solvent was removed on a rotary evaporator. The resulting yellow oil was dissolved in ethyl acetate (50 mL) and washed with water (3×20 mL), dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (50% EtOAc:hexanes) to yield Compound 13 (321 mg, 60%) as a white solid.
Reaction SMILES: [CH:1](Br)=[CH2:2].[CH2:4]=[CH:5]/[CH:6]=[CH:7]/[CH3:8].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[O:12]1[CH2:13][CH2:14][N:9]([CH:1]([CH3:2])[CH:4]=[CH:5][CH2:6][CH:7]=[CH2:8])[CH2:10][CH2:11]1
Reactant: C=CBr
Reactant: C=C/C=C/C
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Product: C=CCC=CC(C)N1CCOCC1
Yield: 52 %

Procedure:
Vinyl bromide, E-1,3-pentadiene, and morpholine reacted with one mole percent palladium acetate - two mole percent tri-o-tolylphosphine as catalyst in 17 hrs. at 100° C. to form 6-morpholino-1,4-heptadiene in 52% yield. (All yields hereinafter reported, except where otherwise noted, are of purified, isolated products.) In this instance a 3:1 ratio of diene to vinylic halide was used, it being found that better yields were obtained thereby than with the lower 1.25:1 ratio. The remainder of the product was polymer and higher boiling materials which were not identified.
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25](=[O:59])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[C:39]2[CH:44]=[C:43]([C:45](=[O:58])[NH:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([C:54]([F:57])([F:56])[F:55])[CH:49]=3)[CH:42]=[CH:41][N:40]=2)[N:20]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.ClCCl.C(O)(C(F)(F)F)=O.CN(CC1N=C(C(NC2C=CC(N3CCCCC3)=CC=2C2C=C(C(=O)NCC3C=CC=C(C(F)(F)F)C=3)C=CN=2)=O)C=CC=1)CCN1CCNCC1.C(N(CC)CC)C.[CH3:129][S:130](Cl)(=[O:132])=[O:131]>ClCCl>[CH3:1][N:2]([CH2:18][C:19]1[N:20]=[C:21]([C:25]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[C:39]2[CH:44]=[C:43]([C:45](=[O:58])[NH:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([C:54]([F:57])([F:56])[F:55])[CH:49]=3)[CH:42]=[CH:41][N:40]=2)=[O:59])[CH:22]=[CH:23][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([S:130]([CH3:129])(=[O:132])=[O:131])[CH2:7][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCN1CCN(C(=O)OC(C)(C)C)CC1)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)n1
Agent: CN(CCN1CCNCC1)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)n1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCN1CCN(S(C)(=O)=O)CC1)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)n1
Temperature: 0 °C
Yield: 28 %

Procedure:
The tert-butoxycarbonyl group of tert-butyl 4-(2-(methyl((6-((4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)pyridin-2-yl)methyl)amino)ethyl)piperazine-1-carboxylate 52 was cleaved by stirring for 1 hour in 1:1 dichloromethane/TFA and the resultant amine converted to the free base by partitioning between ethyl acetate and aqueous sodium bicarbonate solution. Into a 50-mL round-bottom flask, was placed a solution of 6-((methyl(2-(piperazin-1-yl)ethyl)amino)methyl)-N-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenyl)-picolinamide (110 mg, 0.15 mmol, 1.00 equiv) in dichloromethane (5 mL). To this was added triethylamine (23.3 mg, 0.23 mmol, 1.50 equiv). This was followed by dropwise addition of a solution of methanesulfonyl chloride (21.2 mg, 0.18 mmol, 1.20 equiv) in dichloromethane (2 mL) with stirring at 0° C. The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 58.1 mg (28%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.62 (s, 1H), 9.56 (t, J=6.0 Hz, 1H), 9.05 (d, J=5.4 Hz, 1H), 8.42 (d, J=9.0 Hz, 1H), 8.27 (s, 1H), 8.16 (dd, J=4.8 Hz, 2H), 7.88-7.81 (m, 2H), 7.71 (s, 1H), 7.67-7.54 (m, 4H), 7.30 (d, J=7.8 Hz, 1H), 4.63 (d, J=5.7 Hz, 2H), 4.35 (s, 2H), 3.32 (s, 4H), 3.18 (s, 6H), 2.99 (s, 2H), 2.88-2.84 (m, 7H), 2.68 (s, 3H), 1.73-1.59 (m, 6H). MS (ES, m/z): 793 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18]([Sn](CCCC)(CCCC)CCCC)[N:17]=[CH:16]3)[N:9]=2)=[CH:4][CH:3]=1.[C:33]([NH:37][S:38]([C:41]1[S:45][C:44](Cl)=[N:43][CH:42]=1)(=[O:40])=[O:39])([CH3:36])([CH3:35])[CH3:34].[F-].[K+].O>C1(C)C=CC=CC=1>[C:33]([NH:37][S:38]([C:41]1[S:45][C:44]([C:18]2[N:17]=[CH:16][N:15]([C:10]3[N:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH:13]=[C:12]([CH3:14])[N:11]=3)[CH:19]=2)=[N:43][CH:42]=1)(=[O:39])=[O:40])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(C)cc(-c3ccc(Cl)cc3)n2)cn1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3ncc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Yield: 25.6 %

Procedure:
A stirred mixture of 4-(4-chloro-phenyl)-6-methyl-2-(4-tributylstannanyl-imidazol-1-yl)-pyrimidine (Example G.3) (0.45 g, 0.80 mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (Example H.1) (0.225 g, 0.88 mmol), tetrakis(triphenyl-phosphine)palladium (0.056 g, 0.048 mmol) in toluene (10 mL) was heated under reflux conditions for 15 h. The mixture was poured into saturated potassium fluoride solution (10 mL), water (40 mL) was added and the water layer was extracted with ethyl acetate (2×60 mL). The combined organic layers were washed with brine (60 mL), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield N-tert-butyl-2-{1-[4-(4-chloro-phenyl)-6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonamide (0.1 g) as a light brown solid.