Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[C:4]([CH3:10])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(Br)ccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: Cc1cc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
A 500 mL round-bottom flask was charged with 4-bromo-2-methylbenzaldehyde (8.00 g, 40.2 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (9.40 g, 50.5 mmol, 1.26 equiv), triethylamine (6.50 g, 64.2 mmol, 1.60 equiv) and dichloroethane (200 mL). The resulting solution was stirred for 30 min at room temperature. Solid sodium triacetoxyborohydride (27.0 g, 127 mmol, 3.17 equiv) was added. The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with dichloromethane (3×200 mL) and the organic layers were combined, washed with brine (2×200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (2/3) to yield 10.0 g (67% yield) of tert-butyl 4-[(4-bromo-2-methylphenyl)methyl]piperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 369 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]([CH3:31])[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([N:22]([CH3:31])[CH3:21])[CH:24]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CN(C)c1cccc(CN)c1
Product: CN(C)c1cccc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)c1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 3-dimethylamino-benzylamine (58.3 mg, 0.39 mmol). The title compound was obtained as a solid (98.2 mg, 51% yield). 1H NMR (400 MHz; d6-DMSO) δ: 9.31 (1H, m), 8.98 (2H, s), 8.49 (1H, s), 7.11 (1H, m), 6.63 (2H, m), 6.55 (1H, m), 4.33 (2H, m), 2.86 (6H, s). MS m/z: 483.10, 485.11 [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:22])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][C:19](O)=[O:20])([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:26])=O>C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([CH3:22])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][C:19]([Cl:26])=[O:20])([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)O)O2
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)Cl)O2
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
In a dry flask, a solution of 15.32 g. (50 mmol.) of (±)-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid in 100 ml. of benzene was heated under N2 to 50° C. as 21.15 ml. (0.25 mol.) of oxalyl chloride was added over 20 minutes. The solution was stirred at 50° C. for another 20 minutes, cooled and stripped of solvent to produce (±)-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)acetyl chloride. To a solution of this acid chloride in 200 ml. of dry toluene was added 15 g. of sodium acetate and 1.5 g. of 10% by weight palladium on 90% by weight carbon and 0.30 ml. of quinoline. This mixture was hydrogenated in a Parr apparatus. After 12 hours, the uptake of H2 (about 55 mmole) had virtually ceased. The catalyst was removed by filtration and the filtrates were stripped of solvent. The residue was taken up in ether, washed with 2N aqueous HCl, saturated aqueous sodium bicarbonate solution and saturated brine, dried over sodium sulfate and stripped of solvent to give 15.4 g. of light yellow solid which was chromatographed on 1 kg. of 0.063-0.2 mm silica gel. Elution with 95:5 parts by volume benzene-ethyl acetate gave 11.0 g. of light yellow resin. The material from two such reactions was combined and crystallized from acetone-petroleum ether (b.p. 30°-60° C.) to give (±)-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)-acetaldehyde as a white powder, sint 66.5° C., m.p. 68°-70° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([NH2:20])[CH:17]=[N:16][CH:15]=2)=[CH:10][N:9]=1.[CH3:23][N:24]1[C:32](=[O:33])[C:31]2[N:30]([C@@H:34]([CH3:38])[C:35](O)=[O:36])[CH:29]=[N:28][C:27]=2[N:26]([CH3:39])[C:25]1=[O:40].C1CCC(N=C=NC2CCCCC2)CC1.N1C=CC=CC=1>C(Cl)Cl>[CH3:23][N:24]1[C:32](=[O:33])[C:31]2[N:30]([C@@H:34]([CH3:38])[C:35]([NH:20][C:18]3[CH:17]=[N:16][CH:15]=[C:14]([C:11]4[CH:10]=[N:9][C:8]([N:4]5[CH2:5][CH2:6][CH2:7][C@H:3]5[C:2]([F:21])([F:1])[F:22])=[N:13][CH:12]=4)[N:19]=3)=[O:36])[CH:29]=[N:28][C:27]=2[N:26]([CH3:39])[C:25]1=[O:40]
Reactant: C[C@@H](C(=O)O)n1cnc2c1c(=O)n(C)c(=O)n2C
Reactant: Nc1cncc(-c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H](C(=O)Nc1cncc(-c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)n1)n1cnc2c1c(=O)n(C)c(=O)n2C
Reaction time: 0.08 h

Procedure:
A round bottom flask was charged with (S)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrazin-2-amine (5.097 g, 16.43 mmol) and (S)-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanoic acid (Intermediate 8) (4.97 g, 19.71 mmol). The reagents were suspended in DCM (Volume: 36.5 ml, Ratio: 4), sonicated and allowed to stir for 5 minutes. To the yellow heterogenous mixture was added DCC (5.76 g, 27.9 mmol) and finally pyridine (Volume: 18.25 ml, Ratio: 2) was added and the mixture was allowed to stir for 3 hours. The reaction mixture was diluted with CH2Cl2 and filtered over Celite®. The filtrate was then concentrated and redissolved in a minimal amount of and added dropwise to stirring hexanes to precipitate out crude 2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6-(2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrazin-2-yl)propanamide, which was dried overnight. The mixture of diasteromers was resolved using SFC purification to give the (S,S)-isomer in 2.58 g (retention time: 2.5 min, de: 98%); and the (R,S)-isomer in 0.208 g (retention time: 2.2 min, de: 99%); 1H NMR, (S,S)-isomer (300 MHz, DMSO-d6) δ 11.40 (s, 1H), 9.16 (d, J=3.5 Hz, 3H), 8.97 (s, 1H), 8.36 (s, 1H), 5.86 (d, J=7.3 Hz, 1H), 5.20-5.03 (m, 1H), 3.73 (t, J=6.5 Hz, 2H), 3.46 (s, 3H), 3.19 (s, 3H), 2.29-2.04 (m, 4H), 1.89 (d, J=7.3 Hz, 3H); m/z found [M+H]+=545.19
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[C:32]([F:36])=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37](O)=[O:38])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[N:41]1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:37]([C@@H:10]1[CH2:11][C@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[C:32]([F:36])=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9]1)(=[O:38])[NH2:41]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2cccc(F)c21
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(N)=O)CN(C(=O)OC(C)(C)C)C2)nc2cccc(F)c21
Temperature: 50 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[7-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (360 mg), 1H-1,2,3-benzotriazol-1-ol ammonium salt (250 mg) and triethylamine (360 μl) were dissolved in DMF (10 ml), WSC.HCl (315 mg) was added, and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (3:7)-ethyl acetate-ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object product (263 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([CH3:13])[C:10](=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:22])C(=O)C1.C(=O)(O)[O-].[Na+]>C(#N)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([CH3:13])[C:10](=[O:14])[CH2:9]2)=[CH:4][C:3]=1[Br:22]
Reactant: CN1CC(c2ccc(N)nc2)CC1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN1CC(c2cnc(N)c(Br)c2)CC1=O
Reaction time: 0.25 h

Procedure:
To 4-(6-aminopyridin-3-yl)-1-methylpyrrolidin-2-one (90 mg, 0.377 mmol) in Acetonitrile 3 mL) in ice bath was added NBS (60.3 mg, 0.339 mmol). The reaction mixture was stirred in ice bath for 15 min and room temperature for 30 min. LC-MS shows mixture of SM and product. Added 0.1 equiv. more of NBS and stirred another 1h at room temperature. Reaction mixture was diluted with EtOAc and added 2 mL of Satd sodium bicarbonate. Stirred 10 min. The organic layer was separated, dried over sodium sulfate, filtered and evaporated. Proceed for next step (73%). LCMS (m/z): 270.2/272.2 (MH+), 0.302 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:37])=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@@H:13]2[C@@H:11]([CH2:12]2)[N:10]1[C:15](=[O:33])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH2:27][CH2:28][OH:29])[CH:24]=2)[N:19]([C:30]([NH2:32])=[O:31])[CH:18]=1)=[O:8].CCN(CC)CC.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl>[C:30]([N:19]1[C:20]2[C:25](=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][S:46]([CH3:45])(=[O:48])=[O:47])=[CH:22][CH:21]=2)[C:17]([CH2:16][C:15]([N:10]2[C@H:9]([C:7](=[O:8])[NH:6][CH2:5][C:4]3[CH:34]=[CH:35][CH:36]=[C:2]([Cl:1])[C:3]=3[F:37])[CH2:14][C@@H:13]3[C@H:11]2[CH2:12]3)=[O:33])=[CH:18]1)(=[O:31])[NH2:32]
Reactant: NC(=O)n1cc(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(OCCO)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccc2c(c1)c(CC(=O)N1[C@@H]3C[C@@H]3C[C@H]1C(=O)NCc1cccc(Cl)c1F)cn2C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 453: 3-{2-[(1R,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl}-5-(2-hydroxy-ethoxy)-indole-1-carboxylic acid amide (45 mg, 0.08 mmol) and Et3N (56 μL, 0.41 mmol) in CH2Cl2 (1 mL) at 0° C. was added methanesulfonyl chloride (31 μL, 0.41 mmol) and the white suspension was stirred at RT under nitrogen overnight. Et3N (56 μL, 0.41 mmol) and methanesulfonyl chloride (31 μL, 0.41 mmol) were added and the mixture was further stirred for 1.5 h to complete the reaction. The reaction mixture was quenched by addition of saturated aqueous NaHCO3, extracted with CH2Cl2, dried (Na2SO4) and evaporated in vacuo. The crude residue was purified by column chromatography on silica gel (eluent: EtOAc to EtOAc/acetone 1-1). TLC, Rf (EtOAc)=0.2; MS (UPLC/MS): 607.4/609.3 [M+H]+, 629.2/631.2 [M+Na]+, 562.2/564.1 [M−CONH2]−, 651.3/653.3 [M+HCOO]−; tR (HPLC conditions f): 1.88 min.
Reaction SMILES: Br[C:2]1[CH:15]=[N:14][C:5]2[NH:6][CH2:7][CH2:8][C:9](=[O:13])[N:10]([CH3:12])[CH2:11][C:4]=2[CH:3]=1.[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH:17]=[CH2:18].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:12][N:10]1[C:9](=[O:13])[CH2:8][CH2:7][NH:6][C:5]2[N:14]=[CH:15][C:2](/[CH:18]=[CH:17]/[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:3][C:4]=2[CH2:11]1
Reactant: CN1Cc2cc(Br)cnc2NCCC1=O
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1Cc2cc(/C=C/C(=O)OC(C)(C)C)cnc2NCCC1=O
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A suspension of 8-bromo-5-methyl-2,3,5,6-tetrahydropyrido[2,3-b][1,5]diazocin-4(1H)-one (670 mg, 2.48 mmol), tert-butyl acrylate (1.8 mL, 12.4 mmol) and (i-Pr)2EtN (1.3 mL, 7.44 mmol) in 30 mL of DMF:Propionitriole (4:1) was de-oxygenated with Ar for 30 min. The mixture was treated with Pd(OAc)2 (19.4 mg, 0.09 mmol) and P(o-tol)3 (51.7 mg, 0.18 mmol) then heated to 110° C. for 16 h. The hot mixture was filtered through a pad of celite. The filtrate was diluted with 100 mL H2O then extracted with 2×100 mL ethyl acetate. The resulting brown solid was triturated with a solution of hexanes:ethyl acetate (4:1) followed by filtration to yield the brown solid product. Yield 391 mg (50%); 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.51 (s, 1H), 7.49 (d, J=16.4 Hz, 1H), 6.26 (d, J=16.0 Hz, 1H), 5.22 (bm, 1H), 4.55 (s, 2H), 3.66 (q, J=7.2 Hz, 2H), 3.07 (t, J=7.2 Hz, 2H), 2.81 (s, 3H), 1.55 (s, 9H); ESI MS m/z 318 [C17H23N3O3+H]+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1(O)[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1.O=S(Cl)Cl>N1C=CC=CC=1>[O:14]1[C:10]2([CH2:15][CH2:16][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: OC1(c2ccccn2)CCC2(CC1)OCCO2
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: C1=C(c2ccccn2)CCC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
The ketal (2 g, 8.5 mmol) obtained from step A, Example 7 was dissolved in pyridine (40 mL) and the solution was cooled in an ice bath. To it was added SOCl2 (3.1 mL, 42.5 mmol). The solution was allowed to warm to room temperature and stirring was continued overnight. The reaction was quenched by addition of ice and then water. The resulting solution was extracted with EtOAc three times. The combined EtOAc layer was dried over MgSO4 and concentrated. Flash chromatography on silica gel eluting with 0 to 55% EtOAc/hexanes provided 1.54 g of the title compound. MS calculated (M+H)+ 218, found 218.
Reaction SMILES: [CH:1]([N:4]([CH:12]([CH3:14])[CH3:13])[CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])[CH3:2].Br[CH2:16]CC(OCC)=O.CC1CCCC(C)N1.[ClH:31]>O.C(O)C>[ClH:31].[CH3:14][CH:12]1[CH2:13][CH2:16][CH2:2][CH:1]([CH3:3])[N:4]1[CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CCBr
Reactant: CCOC(=O)CCN(C(C)C)C(C)C
Agent: CC1CCCC(C)N1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCN1C(C)CCCC1C

Procedure:
Ethyl 3-(2,6-dimethylpiperidino)propionate hydrochloride may be obtained by working according to the method described in Example 6 for the preparation of ethyl 3- diisopropylaminopropionate, but starting with ethyl 3bromopropionate (18.1 g), 2,6-dimethylpiperidine (27 cc) and ethanol (30 cc). The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue obtained is taken up with water (50 cc) and 4N aqueous hydrochloric acid solution (30 cc). The aqueous phase is washed with ethyl ether (2×80 cc) and neutralized with 4N aqueous sodium hydroxide solution (40 cc). The insoluble oil is extracted with ethyl ether (3×120 cc); the organic extracts are then washed with water (2×80 cc) and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue is dissolved in ethyl ether (100 cc). A 4.5N solution (13.4 cc) of gaseous hydrochloric acid in ethyl ether is added to the solution obtained. A product precipitates. It is separated by filtration, washed and dried in the air. Ethyl 3-(2,6-dimetylpiperidino)-propionate hydrochloride (14.4 g), m.p. 146° C., is thereby obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].I[CH2:22][CH2:23][CH3:24]>>[Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:8]([CH2:22][CH2:23][CH3:24])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Product: CCCn1nc2c(Cl)cccc2c1-c1ccc(OC)cc1
Yield: 8.6 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxyphenyl)-1H-indazole (0.129 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 1-iodopropane (0.098 mL, 1.0 mmol) to give the title compound (0.013 g).
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.C([NH:20][C:21]1[C:26]([NH2:27])=[C:25]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:24]=[C:23]([C:36]2[N:37]([CH3:41])[CH:38]=[CH:39][N:40]=2)[N:22]=1)C1C=CC=CC=1>CN(C=O)C>[NH2:20][C:21]1[C:26]2[NH:27][C:6](=[O:7])[N:28]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:25]=2[CH:24]=[C:23]([C:36]2[N:37]([CH3:41])[CH:38]=[CH:39][N:40]=2)[N:22]=1
Reactant: Cn1ccnc1-c1cc(NCc2ccccc2)c(N)c(NCc2ccccc2)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cn1ccnc1-c1cc2c([nH]c(=O)n2Cc2ccccc2)c(N)n1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
CDI (184 mg, 1.13 mmol) was added to a solution of the N*2*,N*4*-Dibenzyl-6-(1-methyl-1H-imidazol-2-yl)-pyridine-2,3,4-triamine (218 mg, 0.567 mmol) in DMF (3 ml) in a ReactiVial. The vial was flushed with nitrogen then sealed and heated in an aluminium block at 60° C. (block temperature). The dark brown solution was left to stir at this temperature for 16 hrs. The solution was concentrated under high-vacuum then dissolved in concentrated sulphuric acid (5 ml). The brown solution was left to stir at room temperature for 30 minutes then poured onto crushed ice (˜20 ml). A saturated aqueous solution of potassium carbonate was added drop-wise until pH˜8. The aqueous solution was decanted from the solid that had precipitated out during neutralisation, then extracted with EtOAc (2×50 ml). The combined organics were dried (MgSO4) and evaporated to a yellow solid (106 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=O)=[CH:4][CH:3]=1.[C@@H:17]1([NH2:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12][NH:27][C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cccc(Sc2ccc(Cl)cc2)c1
Product: Clc1ccc(Sc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
The product from Example 75A and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[C:17]([NH:25][CH3:26])[N:16]=1>ClCCl>[Cl:14][C:15]1[N:20]=[C:19]([NH:4][CH:1]([CH3:3])[CH3:2])[C:18]([N+:22]([O-:24])=[O:23])=[C:17]([NH:25][CH3:26])[N:16]=1
Reactant: CC(C)N
Reactant: CNc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNc1nc(Cl)nc(NC(C)C)c1[N+](=O)[O-]
Yield: 82.1 %

Procedure:
Isopropylamine (4.5 ml) and N,N-diisopropylethylamine (13.2 ml) were dissolved into 150 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitro-6-methylaminopyrimidine (11.5 g) in dichloromethane (30 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for half an hour. Purification was conducted by a column chromatography to obtain a yellow solid (10.4 g) in a yield of 82.1%. 1H NMR (400 MHz, CDCl3): δ8.17 (s, 1H), 4.48 (m, 1H), 2.78 (s, 3H), 1.31 (d, J=6.8 Hz, 6H) ppm.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[N:6][NH:5][C:4](=[S:9])[C:3]=1[C:10]#[N:11].C([O-])(=O)C.[Na+].Cl[CH2:18][C:19]#[N:20]>C(O)C.CC(O)C>[NH2:11][C:10]1[C:3]2[C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=[N:5][C:4]=2[S:9][C:18]=1[C:19]#[N:20]
Reactant: Cc1n[nH]c(=S)c(C#N)c1C
Reactant: N#CCCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)O
Product: Cc1nnc2sc(C#N)c(N)c2c1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The 5,6,-dimethyl-3-thioxo-2,3-dihydropyridazine-4-carbonitrile (99 mg, 0.60 mmol) was stirred in ethanol (6.0 mL). Sodium acetate (50 mg, 0.60 mmol) and chloroacetonitrile (0.040 mL, 0.60 mmol) were added and the mixture was stirred at ambient temperature for 90 minutes. The mixture was then diluted with IPA, stirred for 15 minutes, and filtered. The solute was concentrated in vacuo, and the resulting solid was dried overnight at 60° C. in a vacuum oven to give the product. LC/MS: RT=0.38 min., m/z=205 [M+H]+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:6]=1.[CH3:19][C:20]([CH3:23])([O-:22])[CH3:21].[Na+]>C(O)(C)C.C(O)(C)(C)C>[C:20]([O:22][C:12]([NH:11][CH2:10][CH2:9][S:8][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:6]=1)=[O:13])([CH3:23])([CH3:21])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCSCc1csc(Br)n1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCCSCc1csc(SCCNC(=O)OC(C)(C)C)n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-4-[(2-tert-butoxycarbonylaminoethyl)thiomethyl]-1,3-thiazole (421 mg, 1.2 mmol) and 2-(tert-butoxycarbonylamino)ethylthiol (234 mg, 1.3 mmol) in isopropyl alcohol (5 mL) was added 1.0 M sodium t-butoxide in t-butanol (1.2 mL) and stirred at 80° C. for 1 h. After cooling, the mixture was concentrated and partitioned between ethyl acetate and water. The ethyl acetate extract was concentrated. The residue was chromatographed on silica gel (1% methanol/dichloromethane), affording 364 mg of the title compound. 1H NMR (CDCl3) δ 1.63 (18H), 2.78 (t, 2H), 3.42 (m, 4H), 3.61 (t, 2H), 3.90 (s, 2H), 5.18 (br s, 1H), 7.13 (1H).
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:10]=3[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:16][C:17]1[CH:36]=[CH:35][C:20]([CH2:21][NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[O:24])=[CH:19][CH:18]=1>C1COCC1>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][NH:22][C:23](=[O:24])[C:25]2[CH:30]=[CH:29][C:28]([S:31]([N:9]3[C:10]4[CH:15]=[CH:14][N:13]=[CH:12][C:11]=4[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8]3)(=[O:32])=[O:33])=[CH:27][CH:26]=2)=[CH:35][CH:36]=1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc(-c2c[nH]c3ccncc23)cc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3cnccc32)cc1
Yield: 78.7 %

Procedure:
Add a 5 ml THF solution of 3-Phenyl-1H-pyrrolo[3,2-c]pyridine (500 mg, 2.57 mmol, 1 eq) to a 4 ml THF solution of KotBu (303 mg, 2.70 mmol, 1.05 eq) under N2 atmosphere. Stir reaction for 10 minutes and then add a 5 ml THF solution of 4-(4-Fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (844 mg, 2.57 mmol, 1 eq). Stir reaction for 16 hours, remove solvent on rotovap, and purify by silica gel chromatography to give N-(4-Fluoro-benzyl)-4-(3-phenyl-pyrrolo[3,2-c]pyridine-1-sulfonyl)-benzamide (982 mg, 79% yield). Mass Spectrum (m/e): 485.96 (MH+).