Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:19][CH2:20][CH2:21][NH2:22])[CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(Cl)Cl>[C:23]([NH:22][CH2:21][CH2:20][O:19][C:4]1[CH:3]=[C:2]([NH2:1])[C:17]([Cl:18])=[CH:16][C:5]=1[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])(=[O:25])[CH3:24]
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCN
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCNC(C)=O
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of 4-amino-2-(2-aminoethoxy)-5-chloro-N-[2-(diethylamino)ethyl]benzamide (780 mg, 2.4 mmoles) (prepared in Example 47) in methylene chloride was added acetic anhydride (245 mg, 2.4 mmoles) and the mixture stirred for 30 minutes. This was concentrated in vacuo and the residue was partitioned between methylene chloride and sodium bicarbonate solution. The organic phase was concentrated and the residue flash-chromatographed on silica using methylene chloride:methanol:ammonia (100:4:0.5) solvent system. The appropriate fractions were combined and concentrated in vacuo. The residue was recrystallized from methylene chloride-ether to give 445 mg of the title compound as a white solid, mp. 143°-145° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:42])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[S:32][C:31]5[C:26](=[N:27][CH:28]=[CH:29][C:30]=5[Cl:33])[CH:25]=4)[N:22]=3)[N:17](COCC[Si](C)(C)C)[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:42])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[S:32][C:31]5[C:26](=[N:27][CH:28]=[CH:29][C:30]=5[Cl:33])[CH:25]=4)[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:6]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(-c3cc4nccc(Cl)c4s3)cnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1CN(C(=O)[C@H](NC(=O)c2c[nH]c3ncc(-c4cc5nccc(Cl)c5s4)nc23)C2CC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a solution of 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (30 mg, 0.048 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.37 mL, 4.82 mmol). The reaction mixture was stirred for 3 h at room temperature then concentrated and dried under high vacuum for 1 h. The residue was dissolved in 3 mL of CH2Cl2:MeOH:NH4OH (80:19:1) and stirred at room temperature for 18 h then evaporated to dryness under vacuum. The crude residue was washed with MeOH (3×3 mL) to give 17 mg (72%) of 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide. MS: (M+H)+=492.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:9]([CH2:10][N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:8][N:7]([CH2:26][C@@H:27]2[C@H:30]([NH:31][C:32](=[O:68])/[C:33](=[N:47]\[O:48][C:49]3([C:52]([O:54][CH:55]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)[C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[O:53])[CH2:51][CH2:50]3)/[C:34]3[N:35]=[C:36]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[S:37][CH:38]=3)[C:29](=[O:69])[N:28]2[S:70]([OH:73])(=[O:72])=[O:71])[N:6]=1)=[N+]=[N-]>CCOC(C)=O.CCO.[Pd]>[NH2:1][CH2:4][C:5]1[C:9]([CH2:10][N:11]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:8][N:7]([CH2:26][C@@H:27]2[C@H:30]([NH:31][C:32](=[O:68])/[C:33](=[N:47]\[O:48][C:49]3([C:52]([O:54][CH:55]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[C:62]4[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=4)=[O:53])[CH2:51][CH2:50]3)/[C:34]3[N:35]=[C:36]([NH:39][C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[S:37][CH:38]=3)[C:29](=[O:69])[N:28]2[S:70]([OH:73])(=[O:71])=[O:72])[N:6]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2nc(CN=[N+]=[N-])c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n2)cs1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2nc(CN)c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n2)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2R,3S)-2-((4-(azidomethyl)-5-((bis(tert-butoxycarbonyl)amino)methyl)-2H-1,2,3-triazol-2-yl)methyl)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidine-1-sulfonic acid (111 mg, 0.11 mmol) in EtOAc (1.1 mL) and EtOH (0.22 mL) under N2 was added Pd—C (22 mg, 0.021 mmol). The system was evacuated and backfilled with H2 (3×). After stirring at rt for 4 h, the reaction mixture was filtered through celite with EtOAc and EtOH wash. The filtrate was concentrated in vacuo to afford the title compound (assumed quantitative). The crude residue was used as such in the following step. LCMS: Rt=1.06 min, m/z=1025.7 (M+1), Method 2m_acidic.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](N2C(C)=CC=C2C)=[C:7]([N+:18]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCO[C:24]([CH3:26])=O>[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[C:7]([CH3:8])[NH:18][C:24]=2[CH3:26])=[C:7]([CH:6]=1)[NH2:18])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(C)=O
Reactant: Cc1ccc(C)n1-c1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Product: Cc1cc(-c2ccc(C(C)(C)C)cc2N)c(C)[nH]1
Yield: 99 %

Procedure:
A slurry of 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole (0.341 g, 1.25 mmol), 10% Pd/C (0.056 g) and EtOAc (50 mL) under an H2 atmosphere (balloon) was stirred for 72 h, then filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to give 5-tert--butyl-2-(2,5-dimethylpyrrolyl)aniline as yellowish solids (0.30 g, 99%): TLC (10% EtOAc/90% hexane) Rf 0.43; 1H NMR (CDCl3) δ1.28 (s, 9H), 1.87-1.91 (m, 8H), 5.85 (br s, 2H), 6.73-6.96 (m, 3H), 7.28 (br s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27](B(O)O)=[CH:28][C:23]=2[O:22][CH2:21]1>>[F:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([C:27]2[CH:26]=[CH:25][C:24]3[O:20][CH2:21][O:22][C:23]=3[CH:28]=2)=[C:3]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:4]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2-c2ccc3c(c2)OCO3)cc1
Yield: 98.6 %

Procedure:
Following the general procedure outlined in Synthetic Scheme I, 2.24 g (6.45 mmol) of 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene (Example 18, Step 2) was reacted with 1.39 g (8.38 mmol) of (1,3-benzodioxol-5-yl)boronic acid (Step 1). Purification by silica gel chromatography (MPLC) with ethyl acetate/hexane (1:4) gave 2.47 g (99%) of 5-[4,5-difluoro-2-[4-(methylsulfonyl)phenyl]phenyl]-1,3-benzodioxole as a colorless solid: mp 110.0-111.0° C.; NMR (CDCl3) δ 3.05 (s, 3H), 5.95 (s, 2H), 6.47-6.52 (m, 2H), 6.67 (d, J=8.5 Hz, 1H),-7.16-7.24 (m, 2H), 7.32 (d, J=8.5 Hz, 2H), 7.82 (d, J=8.5 Hz, 2H). MS (FAB): m/e 395 (M+Li). Anal. Calc'd for C20H14F2O4S: C, 61.85; H, 3.63. Found: C, 61.92; H, 3.66.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=2)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(C(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(bromomethyl)-4-(trifluoromethyl)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.79 min.; [M+H]+: 394.17 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][NH:39][CH2:40][CH2:41][OH:42]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:39]([CH2:40][CH2:41][OH:42])[CH3:38])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: CNCCO
Product: CN(CCO)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 2-methylaminoethanol according to conditions described in general procedure C. Mp: 100-102° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.77-3.52 (m, 4 H), 3.26 (s, 4 H), 3.76 (m, 4 H), 4.62 (m, 1 H), 6.19-6.22 (m, 1 H), 7.02-7.05 (m, 1 H), 7.26 (d, J=8.4 Hz, 1 H), 7.41 (d, J=8.0 Hz, 1 H), 7.50 (s, 1 H), 7.56-7.63 (m, 3 H), 7.85 (d, J=7.6 Hz, 1 H), 8.00 (d, J=7.6 Hz, 1 H), 8.25 (d, J=5.4 Hz, 1 H), 10.47 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([NH:31][C:32]([C:34]2[C:35](=[O:48])[N:36]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)[C:37]([CH3:40])=[CH:38][CH:39]=2)=[O:33])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:15]=[N:16][N:17](C(OC(C)(C)C)=O)[CH:18]=1)[N:10]([CH3:26])[N:9]=[CH:8]2.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:30]=[C:29]([NH:31][C:32]([C:34]2[C:35](=[O:48])[N:36]([C:41]3[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=3)[C:37]([CH3:40])=[CH:38][CH:39]=2)=[O:33])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:15]=[N:16][NH:17][CH:18]=1)[N:10]([CH3:26])[N:9]=[CH:8]2
Reactant: Cc1ccc(C(=O)Nc2ccc(Oc3cc4cnn(C)c4cc3-c3cnn(C(=O)OC(C)(C)C)c3)c(F)c2)c(=O)n1-c1ccc(F)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(Oc3cc4cnn(C)c4cc3-c3cn[nH]c3)c(F)c2)c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a round bottom flask is added tert-butyl 4-(5-(2-fluoro-4-(1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-carboxylate (1.92 g, 2.94 mmol) and DCM (50 mL) followed by triethylsilane (1.88 mL, 11.77 mmol) and TFA (17.8 mL, 235.35 mmol). The reaction mixture is allowed to stir at RT for 1.5 hours. The solvent is removed and diluted into DCM (150 mL) and washed with saturated aqueous NaHCO3 solution (2×100 mL). The organic solution is dried with Na2SO4, and concentrated under reduced pressure to give a solid material. The solid is purified on a silica gel column eluting with DCM (A) and a 10% MeOH in DCM solution (B), gradient from 100% (A) to 75%(A):25%(B) over 70 min, held at this 75:25 ratio for 15 min to give the title compound as an off-white solid. The solid is dissolved in hot EtOH (50 mL) followed by a portion-wise addition of distilled water (250 mL) causing a white solid to precipitate. The solid is filtered over a Buchner funnel and washed with distilled water (3×15 mL), air dried, and vacuum dried at 60° C. for 15 hours to give the title compound as an off-white solid (1.27 g, 78% yield). MS (m/z): 552.8 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][CH:11]([CH2:13][C:14]([O:16]CC)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:20][NH2:21]>CCO>[NH:20]([C:14](=[O:16])[CH2:13][CH:11]1[CH2:12][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10]1)[NH2:21]
Reactant: NN
Reactant: CCOC(=O)CC1CC(NC(=O)OC(C)(C)C)C1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1CC(CC(=O)NN)C1
Yield: 96.2 %

Procedure:
A solution of ethyl 2-(3-(tert-butoxycarbonylamino)cyclobutyl)acetate (1.2 g, 4.7 mmol) and hydrazine hydrate (1.4 g, 23.5 mmol) in EtOH (8 mL) was heated at 80° C. for 17 hrs. The reaction mixture was concentrated and the residue was dissolved in DCM (20 mL). The organic phase was washed with saturated sodium chloride (10 mL) and water (10 mL). The water layer was exacted with EtOAc (3×). The combined organic layer was dried over Na2SO4 and concentrated to afford tert-butyl 3-(2-hydrazinyl-2-oxoethyl)cyclobutylcarbamate (1.1 g, 97%). ESI-MS (EI+, m/z): 244 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@@H:23](OS(C)(=O)=O)[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([N:37]=[N+:38]=[N-:39])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](N=[N+]=[N-])CC1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-[(cis-4-methanesulfonyloxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (1.16 g, 2.00 mmol) in 10 ml of DMF is added sodium azide (0.65 g, 10 mmol). The reaction mixture is stirred for 48 h at 50° C. The mixture is diluted with ethyl acetate, washed 3 times with water and 1 time with brine. The organic layer is dried with sodium sulfate, filtered and concentrated under reduce pressure to give 3-[(trans-4-azido-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[C:23]1([CH2:29][CH2:30][CH2:31][C:32]([OH:34])=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH3:35][C:36]1([CH2:49][N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH2:40][C:39]2[C:41]([CH3:48])=[C:42]([NH2:47])[C:43]([CH3:46])=[C:44]([CH3:45])[C:38]=2[O:37]1>CN(C)C=O.O>[CH3:35][C:36]1([CH2:49][N:50]2[CH2:55][CH2:54][N:53]([C:32](=[O:34])[CH2:31][CH2:30][CH2:29][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:52][CH2:51]2)[CH2:40][C:39]2[C:41]([CH3:48])=[C:42]([NH2:47])[C:43]([CH3:46])=[C:44]([CH3:45])[C:38]=2[O:37]1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCNCC1)O2
Reactant: O=C(O)CCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCN(C(=O)CCCc3ccccc3)CC1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.22 g) and 1-hydroxybenzotriazole (0.13 g) in N,N-dimethylformamide (5 mL) was added 0.12 g of 4-phenylbutyric acid at 0° C. and the mixture was stirred at that temperature for 5 minutes and further at room temperature for 2 hours. This reaction mixture was added to a solution of 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl)methyl]-5-benzofuranamine (0.20 g) in N,N-dimethylformamide (2 mL) at 0° C. and the mixture was further stirred for 30 minutes. This reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1:2) to provide 0.22 g of the title compound. Yield 74%.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][CH2:8][CH:7]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6]1)[CH2:2][CH:3]=[CH2:4].[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30](I)[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([CH2:4][CH2:3][CH2:2][CH2:1][N:5]2[CH2:9][CH2:8][CH:7]([S:10]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)(=[O:12])=[O:11])[CH2:6]2)[CH:31]=[CH:32][CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C=CCCN1CCC(S(=O)(=O)c2ccc(O)cc2)C1
Reactant: Ic1cccc(OCc2ccccc2)c1
Product: O=S(=O)(c1ccc(O)cc1)C1CCN(CCCCc2cccc(OCc3ccccc3)c2)C1

Procedure:
The title compound, MS: m/e 464.3 (M−H+) was prepared from (RS)-4-(1-but-3-enyl-pyrrolidine-3-sulfonyl)-phenol and benzyl-(3-iodo-phenyl)-ether. Benzyl-(3-iodo-phenyl)-ether is a known compound and has been prepared as described in the following reference: W. Kipping; J. Chem. Soc.; 1957; 3246-3250.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)=O)[N:12]=3)=[CH:9][N:8]=[C:7]([NH2:20])[N:6]=2)[CH2:3][CH2:2]1.Cl.[O:22]1[CH2:27][CH2:26][CH2:25][CH:24]([NH2:28])[CH2:23]1.C(N(CC)CC)C>CS(C)=O>[CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:28][CH:24]4[CH2:25][CH2:26][CH2:27][O:22][CH2:23]4)[N:12]=3)=[CH:9][N:8]=[C:7]([NH2:20])[N:6]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)c1nccc(-c2cnc(N)nc2CC2CC2)n1
Reactant: NC1CCCOC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1ncc(-c2ccnc(NC3CCCOC3)n2)c(CC2CC2)n1
Yield: 13 %

Procedure:
To a solution of 4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-amine (5-2) (50 mg, 0.173 mmol) in DMSO (1 ml), was added Tetrahydro-pyran-3-ylamine HCl (119 mg, 0.864 mmol) and triethylamine (0.120 ml, 0.864 mmol) and the reaction was microwaved for 45 min at 160° C. The reaction was purified directly by reverse phase HPLC with a gradient of 10-90% acetonitrile in water over 15 minutes and then further purified by flash chromatography with a gradient of 25-100% ethyl acetate in heptane to give the desired product as a white solid (7.36 mg).
Reaction SMILES: CC([O-])(C)C.[K+].[CH2:7]([O:9][C:10](=[O:14])[CH2:11][N+:12]#[C-:13])[CH3:8].[N:15]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[C:16]=[S:17]>O1CCCC1>[CH2:7]([O:9][C:10]([C:11]1[N:12]=[CH:13][S:17][C:16]=1[NH:15][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:14])[CH3:8]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: S=C=Nc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncsc1Nc1cccnc1
Temperature: -40 °C
Yield: 44 %

Procedure:
A three-necked flask equipped with a mechanical stirrer, a dropping funnel and an argon inlet was charged with anhydrous tetrahydrofurane (THF) (25.00 ml). Solid potassium tert-butylate (5.46 g, 44.20 mmol) was added and the slurry was stirred until dissolution was complete. The mixture was cooled to −40° C. by means of a dry ice/acetone bath. A solution of isocyano-acetic acid ethyl ester (5.00 g, 44.20 mmol) and 3-isothiocyanato-pyridine (6.02 g, 44.20 mmol) in anhydrous THF (50.00 ml) was added dropwise via the dropping funnel at such a rate that the temperature did not exceed −35° C. and the mixture remained homogeneously stirred (a thick precipitate forms). After addition was complete, the mixture was stirred for further 1 hour letting the temperature free to rise. The reaction was quenched by addition of glacial acetic acid (2.50 ml). The mixture was diluted with THF and ethyl acetate and filtered through celite. The filtrate was evaporated to a dark yellow solid residue, which was purified by flash chromatography (heptane/ethyl acetate) to yield 5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester (4.85 g, 44%) as a light yellow solid, MS (ISP): m/e=250.2 (M+H+).
Reaction SMILES: O.[OH:2][C:3]([C:6]1[N:7]=[C:8]([CH2:59][CH2:60][CH3:61])[N:9]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[O:16][C:17](=[O:21])[O:18][C:19]=1[CH3:20])=[O:12])([CH3:5])[CH3:4]>C(O)(=O)C>[OH:2][C:3]([C:6]1[N:7]=[C:8]([CH2:59][CH2:60][CH3:61])[N:9]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[O:16][C:17](=[O:21])[O:18][C:19]=1[CH3:20])=[O:12])([CH3:5])[CH3:4]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
75 ml of water were added to a suspension of 29.3 g of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] in 225 ml of acetic acid, and the resulting mixture was stirred at 60° C. for 1.5 hours. At the end of this time, 75 ml of water were added to the mixture, which was then cooled. Precipitated trityl alcohol was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. Toluene was added to the residue, and the mixture was again concentrated by evaporation under reduced pressure, to remove the remaining water and acetic acid. The residue was crystallized in ethyl acetate, to give 16.6 g of the title compound as crystals, melting at 177°-180° C. (with decomposition).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH2:16][OH:17].C(N(CC)CC)C>CO>[C:1]([N:8]1[CH2:13][CH2:12][C:11](=[N:16][OH:17])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(=NO)CC1
Yield: 63.8 %

Procedure:
15.5 g (77.6 mmol) of N-Boc-4-piperidone was refluxed for one hour in methanol in the presence of 7.0 g (100.8 mmol) of hydroxylamine hydrochloride and 14.1 ml (100.8 mmol) of triethylamine. Then, methanol was distilled off, and the residue was thoroughly washed with water in chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 10.6 g of N-Boc-4-hydroxyiminopiperidine as white powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[CH:3]=[CH:2]1.[Al+3].[Cl-].[Cl-].[Cl-].[C:14](Cl)(=[O:16])[CH3:15]>C(Cl)Cl>[NH:1]1[C:9]2=[CH:8][N:7]=[CH:6][CH:5]=[C:4]2[C:3]([C:14](=[O:16])[CH3:15])=[CH:2]1
Reactant: CC(=O)Cl
Reactant: c1cc2cc[nH]c2cn1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1c[nH]c2cnccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
(Ref.: J. Org. Chem. 2002, 67, 6226-6227) 6-Azaindole (2.5 g, 21.25 mmol) is added to a stirred suspension of AlCl3 (11.3 g, 84.5 mmol) in CH2Cl2 (150 mL). After stirring at rt for 1 h, acetyl chloride (6.65 g, 84.5 mmol) is added drop wise and the resulting mixture is stirred for 18 h. The mixture is cooled to 0° C., quenched with MeOH (75 mL) and stirred for 1 h. Silica gel (40 mL), MeOH and DCM are added to the mixture, the solvents are removed under vacuum and the residue is purified by silica gel chromatography eluting with 10% MeOHl in DCM to afford 1-(1H-pyrrolo[2,3-c]pyridin-3-yl)-ethanone (1.52 g, 45%). MS: 161 (M+H); 1H NMR (300 MHz, CD3OD): δ 9.20 (s, 1H), 8.95 (s, H), 7.82(d, 1H), 8.72 (d, 1H), 8.43 (d, 1-H), 2.64(s, 3H).