Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[C@@H:10]1[CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC(O)C.[Pd]>[CH3:25][C@@H:10]1[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][CH2:13][CH2:12][NH:11]1
Reactant: C[C@@H]1[C@H](NC(=O)OC(C)(C)C)CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(C)O
Product: C[C@H]1NCCC[C@H]1NC(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 104.1 %

Procedure:
(2R,3R)-Benzyl 3-(tert-butoxycarbonylamino)-2-methylpiperidine-1-carboxylate (308) (1.7 g, 4.9 mmol) was dissolved in IPA (20 mL). 10% Pd/C (1 g) was added and the mixture was hydrogenated on a Parr shaker at 50 psi pressure for 12 hours. The reaction mixture was filtered through celite, and the solvent was removed under reduced pressure to give tert-butyl (2R,3R)-2-methylpiperidin-3-ylcarbamate (310), (1.1 g, 5.1 mmol, 100% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:19])=[CH:4][C:5]([O:11][C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>CN(C=O)C>[Br:1][C:2]1[C:3]([F:19])=[CH:4][C:5]([O:11][C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:6]([CH:10]=1)[C:7]([N:22]([CH2:23][CH3:24])[CH2:20][CH3:21])=[O:9]
Reactant: O=C(O)c1cc(Br)c(F)cc1Oc1ccc(Cl)nc1
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1cc(Br)c(F)cc1Oc1ccc(Cl)nc1
Reaction time: 1.5 h

Procedure:
(N,N,N′,N′-Tetramethyl-o-(1h-benzotriazol-1-yl)uronium tetrafluoroborate (6.95 g, 21.64 mmol) was added to a solution of 5-bromo-2-(6-chloropyridin-3-yloxy)-4-fluorobenzoic acid (5.00 g, 14.43 mmol) and diethylamine (8.00 mL, 77 mmol) in DMF (70 mL) at 0° C. The reaction was stirred 1.5 hours before being quenched with saturated sodium bicarbonate (100 mL). The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with saturated aqueous ammonium chloride, water, 10% aqueous sodium carbonate, saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to provide a residue that was purified by silica gel chromatography (1:2 EtOAc in hexane) to provide 5-bromo-2-(6-chloropyridin-3-yloxy)-N,N-diethyl-4-fluorobenzamide. MS m/z=403.0 [M+H].
Reaction SMILES: [Tl].[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:4]=1[C:5]([OH:7])=[O:6].Cl[CH2:14][N:15]1[C:19](=[O:20])[CH:18]([CH2:21][CH2:22][CH3:23])[NH:17][S:16]1(=[O:25])=[O:24]>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:4]=1[C:5]([O:7][CH2:14][N:15]1[C:19](=[O:20])[CH:18]([CH2:21][CH2:22][CH3:23])[NH:17][S:16]1(=[O:24])=[O:25])=[O:6]
Reactant: CCCC1NS(=O)(=O)N(CCl)C1=O
Reactant: O=C(O)c1c(Cl)cccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Tl]
Solvent: CN(C)C=O
Product: CCCC1NS(=O)(=O)N(COC(=O)c2c(Cl)cccc2Cl)C1=O
Yield: 28.5 %

Procedure:
The thallium salt of 2,6-dichlorobenzoic acid (0.96 g; 2.43 mmol, prepared from 0.46 g of 2,6-dichlorobenzoic acid and 0.605 g of TlOC2H5 in ethanol ) was added to a solution of 2-chloromethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.5 g; 2.21 mmol) in DMF (10 ml) containing tetrabutylammonium bromide (70 mg; 0.22 mmol). The mixture was allowed to react at 50° C. for 15 hours and at 100° C. for an additional hour, and then cooled. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (25%-30% ethyl acetate in hexane) to afford 0.24 g (29%) of 2-(2,6-dichlorophenylcarbonyloxymethyl)-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: Ar=2,6-Cl2 -phenyl; R1 =H; R2 =propyl; R3 =H) as a solid, m.p.95°-97° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[Br:10][CH2:11][C:12]1[CH:19]=[C:18]([O:20][C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>C(O)C>[BrH:10].[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:6]1[CH2:11][C:12]2[C:13](=[CH:16][CH:17]=[C:18]([O:20][C:21]([F:24])([F:22])[F:23])[CH:19]=2)[C:14]1=[NH:15]
Reactant: NCc1cccc(Cl)c1
Reactant: N#Cc1ccc(OC(F)(F)F)cc1CBr
Solvent: CCO
Product: Br
Product: N=C1c2ccc(OC(F)(F)F)cc2CN1Cc1cccc(Cl)c1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of 3-chlorobenzylamine (62 mg, 0.442 mmol) in ethanol (500 μL) at 80° C. was added 2-bromomethyl-4-trifluoromethoxy-benzonitrile 16 (95 mg, 0.34 mmol) as a solution in ethanol (100 μL). After 30 min at 80° C., the ethanol was removed under reduced pressure, and the resulting residue was triturated with ether/ethanol to yield the title compound (colorless solid 90%). 1H NMR (400 MHz, CD3OD) δ8.48 (d, J=8.0 Hz, 1 H, Ar), 7.78 (s, 1 H, Ar), 7.71 (d, J=8.8 Hz, 1 H, Ar), 7.56 (s, 1 H, Ar), 7.45 (m, 2 H, Ar), 7.38 (m, 1 H, Ar), 5.12 (s, 2 H, CH2), 4.84 (s, 2 H, CH2); M/Z (ESI+) 341 ([M+H]+).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][CH:13]2[CH:10]([C:11](=[O:15])[CH2:12]2)[C:9]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:2].C(OC(=O)C)C.[C:25]1([CH:35]=[N+]=[N-])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>CO>[C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][CH:13]2[CH:10]([C:11](=[O:15])[CH2:12]2)[C:9]=1[C:16]([O:18][CH2:35][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[O:17])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=Cc1cccc2ccccc12
Reactant: CC(=O)NCCSC1=C(C(=O)O)C2C(=O)CC2C1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)NCCSC1=C(C(=O)OCc2cccc3ccccc23)C2C(=O)CC2C1
Reaction time: 1 h

Procedure:
A solution of 100 mg of 3-(2'-acetamidoethylthio)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid in 5 mL of a mixture of ethylacetate and methanol was treated with a slight excess of α-naphthyldiazomethane. After the solution was stirred for 1 hr and then concentrated on a rotary evaporator, the crude product was purified by preparative thin layer chromatography on a 20×20×0.2 cm silica gel plate eluted with 5% methanol in methylene chloride affording 130 mg (85.5%) of 3-(2'-acetamidoethylthio)7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, 1-naphthylmethyl ester, as a glass. IR (neat): 3200, 1780, 1690, 1660 cm-1 ; NMR (220 MHz; CDCl3): δ 1.86 (3H, s), 2.6-3.0 (5H, m), 3.0-3.5 (4H, m), 4.43 (1H, m), 5.61 (1H, d, J=18), 5.64 (1H, d, J=18 ), 6.30 (1H, m), and 7.3-8.2 (7H, m); MS (chemical ionization) confirmed molecular weight of 409.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([OH:12])=[C:7]([N+:13]([O-:15])=[O:14])[C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH4+:20].[OH-]>C1(C)C=CC=CC=1>[Cl:11][C:9]1[CH:10]=[C:2]([Cl:1])[C:3]([C:4]([NH2:20])=[O:5])=[C:7]([N+:13]([O-:15])=[O:14])[C:8]=1[OH:12]
Reactant: [NH4+]
Reactant: O=C(O)c1c(Cl)cc(Cl)c(O)c1[N+](=O)[O-]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1c(Cl)cc(Cl)c(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2,4-dichloro-5-hydroxy-6-nitrobenzoic acid (Step A) (4.40 g, 17.6 mmol) and thionyl chloride (2 mL, 27 mmol) in toluene (60 mL) was heated under reflux for 1 h and allowed to cool to room temperature. The solution was added to conc NH4OH (40 mL) at 0° C. The cooling bath was removed and the mixture stirred at room temperature for 2 h and then concentrated to give crude 4,6-dichloro-3-hydroxy-2-nitrobenzamide as a brown solid.—1H NMR (CD3OD): δ 7.33 (s, 1H); mass spectrum: m/z 249, 251, 253 (M+−1, 100%, 66%, 11%).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH:8]2[CH2:10][CH:6]([C:7]2([CH3:12])[CH3:11])[CH:5]1[CH3:13])(O)=[O:2].S(Cl)([Cl:16])=O>CO>[CH:6]12[CH2:10][CH:8]([C:7]1([CH3:12])[CH3:11])[CH2:9][CH:4]([C:1]([Cl:16])=[O:2])[CH:5]2[CH3:13]
Reactant: CC1C(C(=O)O)CC2CC1C2(C)C
Reactant: O=S(Cl)Cl
Solvent: CO
Product: CC1C(C(=O)Cl)CC2CC1C2(C)C

Procedure:
15 g of (+)-3-carboxypinane of optical rotation [α]D25 = +20.2° (c = 1, CH3OH) are boiled with excess thionyl chloride under reflux in the absence of moisture, until the evolution of gas has ceased. The excess thionylchloride is then distilled, followed by the acid chloride boiling at from 62° to 64° C/0.08 mm Hg and having an optical rotation of [α]D24 = +28.1° (pure).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[OH:27])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Cl[CH2:29][C:30]1[CH:31]=[CH:32][C:33]2[O:38][CH2:37][C:36](=[O:39])[N:35]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:34]=2[CH:45]=1>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:29][C:30]2[CH:31]=[CH:32][C:33]3[O:38][CH2:37][C:36](=[O:39])[N:35]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:34]=3[CH:45]=2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: C=CCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(c2)N(CCCOC)C(=O)CO3)cc1

Procedure:
Analogously to Method D, 20.0 g of benzyl 4-(4-allyloxyphenyl)-3-hydroxypiperidine-1-carboxylate and 15.6 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a yellowish oil. Rf=0.20 (1:1 EtOAc-heptane); Rt=5.43.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:16]1[CH:21]=[C:20]([Cl:22])[N:19]=[CH:18][N:17]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.P(Cl)(Cl)(Cl)=O>C(Cl)Cl>[Cl:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]([CH:8]([NH2:7])[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:21]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)c1cc(Cl)ncn1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: NC(Cc1ccccc1)c1cc(Cl)ncn1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
[1-(6-Chloro-pyrimidin-4-yl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester: A white suspension of 10A (1.39 g, 4.41 mmol) in phosphorus oxychloride (20.54 mL, 220 mmol) was warmed to 50° C. to give a clear, pale yellow solution. After 3 h, the orange-brown solution was cooled to rt and concentrated in vacuo to give an orange-brown residue. The residue was dissolved in CH2Cl2 and concentrated (2×). The residue was dissolved in CH2Cl2 and sat. NaHCO3 was added. The mixture was stirred vigorously for 10-15 min. The layers were separated and the aqueous layer was extracted with CH2Cl2 (1×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give 0.990 g of 1-(6-chloropyrimidin-4-yl)-2-phenylethanamine as a thick, viscous orange-brown residue. MS 234.0 (M+H)+; 236 (M+2+H)+.
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]4[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.[NH2:30][C:31]1[C:36]([C:37](=[O:40])[CH2:38][CH3:39])=[CH:35][CH:34]=[C:33]([NH:41][CH:42]2[CH2:47][CH2:46][CH2:45][NH:44][CH2:43]2)[N:32]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:30][C:31]1[C:36]([C:37](=[O:40])[CH2:38][CH3:39])=[CH:35][CH:34]=[C:33]([NH:41][CH:42]2[CH2:47][CH2:46][CH2:45][N:44]([C:3]3[N:8]4[N:9]=[C:10]([CH:12]5[CH2:17][CH2:16][N:15]([CH:18]6[CH2:19][CH2:20]6)[CH2:14][CH2:13]5)[N:11]=[C:7]4[CH:6]=[C:5]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[N:4]=3)[CH2:43]2)[N:32]=1
Reactant: CCC(=O)c1ccc(NC2CCCNC2)nc1N
Reactant: Clc1ccc(-c2cc3nc(C4CCN(C5CC5)CC4)nn3c(Cl)n2)c(Cl)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)c1ccc(NC2CCCN(c3nc(-c4ccc(Cl)cc4Cl)cc4nc(C5CCN(C6CC6)CC5)nn34)C2)nc1N
Temperature: 120 °C

Procedure:
25 mg (0.06 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-(1-cyclopropylpiperidin-4-yl)-[1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride, 20 mg (0.07 mmol) of 1-[2-amino-6-(piperidin-3-ylamino)pyridin-3-yl]propan-1-one hydrochloride (Example 27A) and 65 μl (0.4 mmol) of N,N-diisopropylethylamine were initially charged in 1.25 ml of DMSO. The mixture was heated in the microwave at 120° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 21 mg (56% of theory) of the product as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:25]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([F:25])=[O:16])[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)F
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a cooled (-15° C.) solution of t-butoxycarbonylisoleucine (0.482 g, 2 mmol) and pyridine (0.16 ml) in methylene chloride (5 ml) is dropped cyanuric fluoride (0.9 ml) and the mixture is stirred at -15° C. for 1 hour. The reaction mixture is diluted with methylene chloride and ice, and filtered on Celite. The filtrate is diluted with ice water and extracted with methylene chloride. The organic layer is dried over magnesium sulfate and concentrated in vacuo to give t-butoxycarbonylisoleucine fluoride.
Reaction SMILES: C(O)(=O)C.[N:5]([O-:7])=[O:6].[Na+].[Br:9][C:10]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:11]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14].[N+]([O-])(O)=O>O>[Br:9][C:10]1[CH:25]=[C:24]([N+:5]([O-:7])=[O:6])[C:23]([Br:26])=[CH:22][C:11]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: O=N[O-]
Reactant: O=S(=O)(Nc1cc(Br)ccc1Br)c1ccccc1
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Br)c(NS(=O)(=O)c2ccccc2)cc1Br
Temperature: 90 °C

Procedure:
To 250 ml of acetic acid, diluted with 130 ml of water, are added: 1.5 g of sodium nitrite, 0.13 mole of 2,5-dibromo-N-benzenesulphonylaniline prepared in the previous stage and 0.78 mole (32.5 ml) of nitric acid (d=1.52). The reaction mixture is heated for 1 hour at 90° C. The reaction mixture, cooled beforehand, is poured onto 1 kg of ice and the expected product precipitates. It is filtered off, washed to neutrality and then recrystallized from acetic acid; it melts at 148° C.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([OH:26])=O)[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:59][NH:60][CH2:61][C:62]1[CH:75]=[CH:74][C:65]([CH2:66][N:67]2[CH2:72][CH2:71][CH2:70][CH:69]([OH:73])[CH2:68]2)=[CH:64][CH:63]=1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:60]([CH2:61][C:62]3[CH:75]=[CH:74][C:65]([CH2:66][N:67]4[CH2:72][CH2:71][CH2:70][CH:69]([OH:73])[CH2:68]4)=[CH:64][CH:63]=3)[CH3:59])=[O:26])[CH:20]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Reactant: CNCc1ccc(CN2CCCC(O)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N(C)Cc3ccc(CN4CCCC(O)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (40 mg, 0.105 mmol), EDCI (28 mg, 0.158 mmol), HOBt (21 mg, 0.16 mmol), DIPEA (0.036 mL, 0.21 mmol), 1-{4-[(methylamino)methyl]benzyl}piperidin-3-ol dihydrochloride (34 mg, 0.13 mmol) and DCM (10 mL).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[C:10]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][S:40][CH2:41][CH2:42][CH2:43]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:43][CH2:42][CH2:41][S:40][CH3:39])=[CH:29][CH:28]=2)[C:10]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSCCCO
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(OCCCSC)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 94.9 %

Procedure:
To a stirred solution of ethyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-hydroxyphenyl)-1H-pyrrole-2-carboxylate (36) (350 mg, 0.68 mmol) in THF (2 mL) at 0° C. was added 3-(methylthio)propan-1-ol (84 μL, 0.82 mmol), triphenylphosphine (214 mg, 0.82 mmol), and DIAD (159 μL, 0.82 mmol). After 2 h further portions of 3-(methylthio)propan-1-ol (84 μL, 0.82 mmol), triphenylphosphine (214 mg, 0.82 mmol) and DIAD (159 μL, 0.82 mmol) were added, and the reaction mixture was allowed to stir at RT for 4 days. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2×20 mL), the combined organics were washed with brine (30 mL), dried (MgSO4) filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (12 g, 0-100% EtOAc in isohexane) to afford ethyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-(3-(methylthio)propoxy)phenyl)-1H-pyrrole-2-carboxylate (43) (389 mg, 85%) as a clear yellow oil: m/z 603 (M+H)+ (ES+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:16]#[N:17])[C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[CH:4][CH:3]=1.[H-].[Na+].[H][H].Br[CH2:23][CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36]>CN(C=O)C>[C:27]1(=[O:36])[N:26]([CH2:25][CH2:24][CH2:23][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]=[C:10]([C:16]#[N:17])[C:11](=[O:15])[NH:12][C:13]=3[CH3:14])=[CH:6][CH:7]=2)[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(O)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
A solution of 2.00 g (8.84 mmol) of 5-(4-hydroxyphenyl)-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile in 15 ml of DMF is added dropwise to a suspension of 707 mg (17.7 mmol) of 60% sodium hydride-mineral oil in DMF (5 ml). When hydrogen evolution ceases, the mixture is warmed to 60° C. and a solution of 2.37 g (8.84 mmol) of N-(3-bromopropyl)phthalimide in 5 ml of DMF is added dropwise. After 1 hr at 60° C., the temperature of the mixture is raised to 80° C. for an additional hr of heating. After cooling, the DMF is removed under vacuum. The residue is triturated with water and EtOAc to give a yellow solid that is collected by suction filtration. Thissolid is dried at 80° C. under vacuum to give 1.885 g of 5-(4-phthalimidopropyloxyphenyl)-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile as a yellow solid. 1H-NMR (d6 -DMSO): δ 2.07 (t,2H); 2.23 (s,3H); 3.78 (t,2H); 4.05 (t,2H); 6.83 (d, 2H); 7.20 (d,2H): 7.80 (m, 4H); 8.00 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[S:31][C:30]([C:32]3([NH2:36])[CH2:35][CH2:34][CH2:33]3)=[N:29][CH:28]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:8]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:5]2=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:44][N:45]([CH3:49])[C:46](Cl)=[O:47]>O1CCCC1.O>[Cl:1][C:2]1[C:3]([C:27]2[S:31][C:30]([C:32]3([NH:36][C:46](=[O:47])[N:45]([CH3:49])[CH3:44])[CH2:33][CH2:34][CH2:35]3)=[N:29][CH:28]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:8]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(-c4cnc(C5(N)CCC5)s4)c(Cl)cnc32)cc1
Reactant: CN(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(-c4cnc(C5(NC(=O)N(C)C)CCC5)s4)c(Cl)cnc32)cc1
Temperature: 70 °C

Procedure:
A mixture of 1-(5-(5-chloro-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanamine (40 mg, 0.074 mmol) (Example 121A) in anhydrous tetrahydrofuran (1 mL) was treated with triethylamine (0.014 ml, 0.104 mmol) and dimethylcarbamoyl chloride (8.18 μl, 0.089 mmol), and the reaction mixture was heated to 70° C. for 16 hours. Additional dimethylcarbamoyl chloride (4.09 μl, 0.044 mmol) and triethylamine (0.007 ml, 0.052 mmol) were added, and reaction solution heated for another 16 hours at 70° C. The reaction was cooled, diluted with water, and extracted with dichloromethane. The extracts were combined and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 2 to 5% methanol in dichloromethane, to provide the title compound. MS ESI(+) m/z 610.3 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH2:16]>CO>[CH2:15]([OH:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=[CH:7][CH:6]=[CH:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: O
Reactant: CCCCC=CC=CCCCCCCC
Solvent: CO
Product: CCCCC=CC=CCCCCCCCO
Yield: 66 %

Procedure:
The pentadecadiene (D) (5.9 g) in 200 ml methanol containing eight drops concentrated HCl was refluxed for 15 minutes. After the solution was cooled, 400 ml of water were added, and the mixture was extracted three times with hexane. The hexane extract was dried over sodium sulfate, and the hexane was removed with a rotary evaporator leaving 3.1 g of crude 8,10-pentadecadienol, which was purified by silica gel liquid chromatography. Unwanted side products were eluted with 10% ether/hexane, and the alcohol was eluted with 50% ether/hexane, giving 2.5 g (66% yield based on the decenenitrile (B)). 8,10-Pentadecadienol in 75 ml pyridine and 5 ml acetic anhydride was refluxed 1.5 hours. After the solution was cooled, 200 ml hexane was added, and the mixture was extracted successively with water, 6N hydrochloric acid (twice), and water. The pentane phase was dried over sodium sulfate, filtered, and the pentane was removed by rotary evaporation, leaving crude product, which was purified by silica gel liquid chromatography (elution in 10% ether/hexane); the yield was 2.8 g (94% based on the alcohol). The product was 39% EE and 61% EZ by GC analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([N:8]=[C:9]=[O:10])[CH:7]=1.Cl.[NH2:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([NH:8][C:9]([NH:14][CH2:15][C:16](=[O:17])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:10])[CH:7]=1
Reactant: COc1ccc(Cl)cc1N=C=O
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1NC(=O)NCC(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
5-Chloro-2-methoxyphenylisocyanate (5.3 g, 29 mmol) was dissolved in THF (250 ml) under N2 and heated to 60° C. To this solution was added 2-aminoacetophenone-HCl (5 g, 29 mmol) followed by triethylamine (3.8 g, 30 mmol). After being stirred 1.5 h, the reaction mixture was diluted with ethyl acetate (2 vol) and washed with 1N HCl solution, saturated NaCO3 solution, and brine before being dried, MgSO4. Concentration gave a solid which was washed with diethylether 6 g (65%). mp 171-173° C.; IR(KBr, υ=cm−1) 3336, 1706, 1644, 1600, 1560, 1482, 1262, 1220, 1182, 1126; 1H NMR (300 MHz, CDCl3) δ 3.79 (3H, s), 4.84 (2H, d, J=4.3 Hz), 5.97 (1H, br.s), 6.71 (1H, d, J=8.7 Hz), 6.88 (1H, dd, J=8.7 Hz, 2.5 Hz), 7.97-8.00 (2H, m), 8.18 (1H, d, J=2.5 Hz); MS(DCl)m/z: 319(MH+); Anal. calcd. for C16H15ClN2O3: C, 60.29; H, 4.74; N, 8.79. Found: C, 60.17; H, 4.64; N, 8.70.