Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][CH:12]=[CH:11][C@H:10]1[OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Br.C(=O)([O-])[O-:28].[Na+].[Na+]>C1COCC1>[CH2:1]([O:8][C@H:9]([C@@H:14]([CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:13])[C@H:10]([OH:24])[CH2:11][CH:12]=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H]1C=CO[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: Br
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=CC[C@@H](O)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Temperature: 25 °C
Yield: 63 %

Procedure:
4,6-di-O-benzyl-D-glucal (4.9 mmol) was dissolved in THF (60 mL). 48% Water solution of hydrobromic acid (0.4 mL) was added and the reaction mixture was stirred at room temperature. After reaction was completed, water (250 mL) was added, and pH of obtained solution was adjusted to 8 using saturated sodium carbonate. Water solution was then extracted with ethyl acetate (3×100 mL). Combined water extracts were washed with water until neutral, and dried over anhydrous sodium sulfate. Solids and solvents were removed and crude product was purified by column chromatography (SilicaGel 60) using hexanes:ethyl acetate as eluents. Pure 4,6-di-O-benzyl-2-deoxy-D-glucose (3.1 mmol, yield 63%) was obtained.
Reaction SMILES: [C:1]1([C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:25][CH2:26][CH:27]=[C:28]1[C:34]2[CH:35]=[CH:36][CH:37]=[N:38][C:33]=2[CH2:32][O:31][C:30]2[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]1=2>C(O)(C)C>[OH:46][C:43]([C:41]1[CH:40]=[CH:39][C:30]2[O:31][CH2:32][C:33]3[N:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:28](=[CH:27][CH2:26][CH2:25][N:10]3[CH2:11][CH2:12][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([OH:13])[CH2:8][CH2:9]3)[C:29]=2[CH:42]=1)([CH3:45])[CH3:44]
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: OC1(c2ccccc2)CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(O)(c3ccccc3)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 14 h
Yield: 49.6 %

Procedure:
To a solution of the 4-phenyl-piperidin-4-ol (0.212 g, 1.2 mmol) in isopropanol was added 2,6-lutidine (0.240 mL, 2.1 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.224 g, 0.6 mmol), added in portions over 1 h. The solution was then stirred at 80° C. for an additional 14 h. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (15% methanol/85% methylene chloride) to yield the title compound (0.140 g, 50%). 1H-NMR (CDCl3): δ 1.12 (t, 3H), 1.57(s, 6H), 2.67–2.80 (m, 4H), 1.95–2.11 (m, 2H), 2.34–2.41 (m, 2H), 2.43–2.54 (m, 2H), 2.88 (d, 2H), 3.22 (q, 2H), 3.43 (m, 1H), 5.28 (bs, 2H), 6.12 (t, 1H), 6.60 (d, 2H), 6.80 (d, 1H), 7.13 (d, 2H), 7.21–7.30 (m, 2H), 7.45 (s, 1H), 7.56 (d, 1H), 8.48 (dd, 1H). ESI-MS m/z: 534 (M+1), retention time 2.47.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:11]([N:9]1[C:8](=[O:15])[N:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:27]=[N:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=3)=[C:3]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:4]2=[N:10]1)[CH:12]([CH3:14])[CH3:13]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccc(-c2c(Br)ccn3c(=O)n(CC(C)C)nc23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccn3c(=O)n(CC(C)C)nc3c2-c2ccc(C)cc2)cn1
Temperature: 150 °C
Yield: 32.2 %

Procedure:
To a stirring, degassed mixture of 7-bromo-2-isobutyl-8-p-tolyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (0.015 g, 0.04 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.04 g, 0.17 mmol), and tetrakis(triphenylphosphine)palladium (2.5 mg, 0.002 mmol) in dioxane (0.3 mL) at 20° C. was added K2CO3 (0.024 g, 0.17 mmol) in water (0.11 mL). The resulting reaction mixture was heated in a microwave reactor at 150° C. for 10 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate 5 mg of the title compound as a white solid. MS: [M+H]+=388.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]Cl)[CH2:21][CH2:20]3)[C:4]=2[CH:3]=1.[ClH:28].[CH3:29][N:30]([CH3:42])[CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1.[OH-].[Na+]>CS(C)=O.O>[ClH:1].[ClH:28].[ClH:1].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:41][C:38]4[CH:37]=[CH:36][C:35]([O:34][CH2:33][CH2:32][CH2:31][N:30]([CH3:29])[CH3:42])=[CH:40][CH:39]=4)[CH2:23][CH2:24]3)[C:4]=2[CH:3]=1
Reactant: CN(C)CCCOc1ccc(O)cc1
Reactant: ClCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)CCCOc1ccc(OCCN2CCN(CCCN3c4ccccc4Sc4ccc(Cl)cc43)CC2)cc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
A solution of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-(2-chloroethyl)piperazine (4.22 g) and 4-(3-dimethylaminopropoxy)phenol hydrochloride, (2.3 g) in dimethylsulfoxide (100 ml) was stirred under nitrogen and warmed to 55° C. Then a solution of sodium hydroxide (0.8 g) in water (3 ml) was added and the reaction was stirred at 55°-65° for 2 hours. The usual work-up furnished the crude salt, which was crystallized from methanol-ethyl acetate to give 1.5 g of 3-[[4-[2-[4-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-1-piperazinyl]ethoxy]phenyl]oxy] -N,N-dimethylpropanamine trihydrochloride, mp 228°-230°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH3:9].[Cl:10][S:11](O)(=[O:13])=[O:12]>>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([Cl:8])[CH:5]=[CH:6][C:7]=1[S:11]([Cl:10])(=[O:13])=[O:12]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1c(Cl)cccc1Cl
Product: Cc1c(Cl)ccc(S(=O)(=O)Cl)c1Cl
Temperature: 25 °C
Yield: 85 %

Procedure:
10 ml of chlorosulfonic acid were dropwise added with 4.8 ml of 2,6-dichlorotoluene in two hours, under magnetic stirring at room temperature. After completion of the addition, the mixture was heated at 40° C. for two hours, thereby obtaining a purple solution, which was cooled and carefully poured into ice-water (0.5 l), stirring vigorously. The separated white solid was filtered, triturated, washed with water, dried over KOH and purified by washing with n-hexane, adding 200 ml of solvent under strong stirring. The mixture was filtered, the solid was discarded and the solvent was evaporated to dryness to obtain 2,4-dichloro-3-methyl-benzenesulfonyl chloride as a crystalline white solid. Yield: 85%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13](Cl)=[O:14])[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][CH2:25][CH3:26])=[N:10][CH:9]2[CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([C:13]([N:37]3[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]3)=[O:14])[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][CH2:25][CH3:26])=[N:10][CH:9]2[CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 113.1 %

Procedure:
A solution of 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (50 mg, 0.105 mmol) in methylene chloride (2 mL) was added to a stirred mixture of 1-methylpiperazine (18 μL, 0.158 mmol) and triethylamine (29 μL, 0.210 mmol) in methylene chloride (3 mL) cooled to 0° C. The reaction mixture was stirred at room temperature for 30 min then concentrated in vacuo. Purification of the crude residue by preparative HPLC (Zorbax C18) gave [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (64 mg, 93%, white solids) as trifluoroacetic acid salt. HR-MS (ES, m/z) observed 539.2789, calculated for C30H40N4O3Cl [(M+H)+]539.2784.
Reaction SMILES: [CH3:1][C:2]([OH:9])([C:5]([CH3:8])([CH3:7])[CH3:6])[C:3]#[CH:4].Br[C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:14]=[CH:15][CH:16]=1.CN(C=O)C>C(N(CC)CC)C>[F:23][C:22]([F:24])([F:25])[C:21]([NH:20][CH2:19][CH2:18][CH2:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:4]#[C:3][C:2]([OH:9])([CH3:1])[C:5]([CH3:8])([CH3:7])[CH3:6])[CH:12]=1)=[O:26]
Reactant: C#CC(C)(O)C(C)(C)C
Reactant: O=C(NCCCc1cccc(Br)c1)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(C)(O)C#Cc1cccc(CCCNC(=O)C(F)(F)F)c1

Procedure:
Coupling of 3,4,4-trimethylpent-1-yn-3-ol with bromide 3 in a 1:1 mixture of DMF and triethylamine gave 2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3,4,4-trimethylpent-1-ynyl)phenyl)propyl)acetamide as an orange oil. Yield (0.84 g, 73%): 1H NMR (400 MHz, CD3OD) δ 7.15-7.25 (m, 4H), 3.29 (t, J=7.2 Hz, 2H), 2.61 (t, J=8.0 Hz, 2H), 1.86 (quint, J=7.6 Hz, 2H), 1.49 (s, 3H), 1.09 (br s, 9H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][N:10]=2)[N:6]=[CH:5]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].CO>C(Cl)Cl>[CH3:19][S:20]([O:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][N:10]=2)[N:6]=[CH:5]1)(=[O:22])=[O:21]
Reactant: COC(=O)c1ccnc(-c2cn(CCO)cn2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of methyl 2-[1-(2-hydroxyethyl)-1H-imidazol-4-yl]pyridine-4-carboxylate (500 mg, 2 mmol) in DCM (10 mL) was added TEA (255 mg, 2.5 mmol) followed by drop-wise addition of a solution of methanesulfonyl chloride (255 mg, 2.22 mmol) in DCM (2 mL). The solution was stirred at 0° C. for 1 hr and then allowed to warm to r.t. where stirring was continued for 1 hr. MeOH (1 mL) was then added and stirring was continued for 30 min. The solution was diluted with DCM (50 mL), washed with water (50 mL), dried (MgSO4), filtered, and concentrated to give the title compound as an oily residue (649 mg).
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@:30]([OH:34])([C:32]#[CH:33])[CH3:31]>>[F:23][C:3]1[C:2]([C:33]#[C:32][C@@:30]([OH:34])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[CH3:31])=[CH:22][C:6]2[C:7]3[N:8]([C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1ccccn1
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(C#C[C@@](C)(O)c3ccccn3)cc1-2
Yield: 10 %

Procedure:
10-bromo-9-fluoro-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide was reacted (2R)-2-(2-pyridyl)but-3-yn-2-ol via General Procedure E to afford 8.9 mg (10%) of 9-fluoro-10-[(3R)-3-hydroxy-3-(2-pyridyl)but-1-ynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide. M+1=450.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](F)[CH:13]=2)[NH:8][CH:7]=1.F[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[NH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][CH:26]([C:20]3[C:19]4[C:23](=[CH:24][CH:25]=[CH:17][CH:18]=4)[NH:22][CH:21]=3)[CH2:27][CH2:28]2)=[CH:7]1
Reactant: Fc1ccc2[nH]cc(CCCCCl)c2c1
Reactant: Fc1ccc2[nH]cc(C3CCNCC3)c2c1
Product: c1ccc2c(CCCCN3CCC(c4c[nH]c5ccccc45)CC3)c[nH]c2c1

Procedure:
of 3-(4-chlorobutyl)-5-fluoroindole with 4-(5-fluoroindol-3-yl)piperidine:
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[F:23][C:24]([F:47])([F:46])[C@H:25]([CH3:45])[O:26][C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:44])[CH3:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1.Br[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[S:56]([CH3:59])(=[O:58])=[O:57]>>[CH3:59][S:56]([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[CH2:49][N:34]1[N:33]=[C:31]2[N:32]=[C:27]([O:26][C@@H:25]([CH3:45])[C:24]([F:23])([F:46])[F:47])[N:28]=[C:29]([N:36]3[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:44])[CH3:43])[CH2:37]3)[C:30]2=[N:35]1)(=[O:57])=[O:58]
Reactant: CC(=O)N[C@H]1CCN(c2nc(O[C@@H](C)C(F)(F)F)nc3[nH]nnc23)C1
Reactant: CS(=O)(=O)c1ccccc1CBr
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: CC(=O)N[C@H]1CCN(c2nc(O[C@@H](C)C(F)(F)F)nc3nn(Cc4ccccc4S(C)(=O)=O)nc23)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from N—{(S)-1-[5-((S)-2,2,2-Trifluoro-1-methyl-ethoxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-yl}-acetamide and 1-(bromomethyl)-2-(methylsulfonyl)benzene. MS (m/e): 528.5 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:15])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[Cl:16][S:17](O)(=[O:19])=[O:18].C(Cl)(=O)C(Cl)=O.CN(C)C=O>ClCCl>[CH3:1][O:2][C:3]1[C:4]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:5][C:6]2[CH2:7][CH2:8][C:9](=[O:15])[C:10]([CH3:13])([CH3:14])[C:11]=2[CH:12]=1
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Reactant: O=S(=O)(O)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(cc1S(=O)(=O)Cl)CCC(=O)C2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the dichloromethane (2 ml) solution of 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 200 mg, 0.980 mmol), chlorosulfonic acid (110 μl, 1.70 eq.) was added and the mixture was stirred at room temperature for 2 hr. To the reaction solution, oxalyl chloride (297 μl, 3.0 eq.) and N,N-dimethyl formamide (45 μl, 0.6 eq.) were added in three divided portions, and the mixture was stirred at room temperature for 30 min. The reaction solution was concentrated under reduced pressure to obtain the title compound (295 mg). Since the title compound is unstable, its structure was identified in the next step.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[N:33][C:34]([S:37][CH2:38][C:39]5[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=5)=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:54])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[N:33][C:34]([S:37]([CH2:38][C:39]5[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=5)=[O:54])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnc4)nc2)CCN3CCC)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccnc4)nc2)CCN3CCC)cc1
Reaction time: 0.25 h
Yield: 27.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[6-[(3-pyridinylmethyl)sulfanyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.91 g) in methylene chloride (27.3 ml) was added dropwise a solution of m-chloroperbenzoic acid (303 mg) in methylene chloride (18.2 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[6-[(3-pyridinylmethyl)sulfinyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 274) (258 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[C:4]2[NH:9][CH:10]=[N:11][C:3]=12.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:6]1[N:5]=[C:4]2[NH:9][CH:10]=[N:11][C:3]2=[C:2]([Cl:1])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1ccc(Cl)c2nc[nH]c21
Product: Clc1cc(Cl)c2nc[nH]c2n1

Procedure:
7-Chloro-3H-imidazo[4,5-b]pyridine-4-oxide (15 g, 88.5 mMol) and 300 mL phosphorus oxychloride were heated at 110° C. under a nitrogen atmosphere. After 4 hours the excess phosphorus oxychloride was removed in vacuo. The residue was dissolved in water and the solution was neutralized by the addition of aqueous ammonium hydroxide. The suspension was cooled and the solid isolated. After drying, the product, 5,7-dichloro-3H-imidazo[4,5-b]pyridine, weighed 10.5 g (54.5 mMol, 61.6%); m.p. 263° C.; NMR (DMSO-d6): 8.58 δ (s, 1H, H2); 7.58 (s, 1H, H5).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].Cl.[F:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][NH2:27])=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[F:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][NH:27][C:2]2[N:9]=[C:8]([NH:10][C:11]3[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=3)[CH:7]=[C:6]([CH3:17])[C:3]=2[C:4]#[N:5])=[CH:22][CH:21]=1
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Reactant: NCCOc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(C)c(C#N)c(NCCOc3ccc(F)cc3)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h
Yield: 4.3 %

Procedure:
Compound A (200 mg, 813 mmol), 2-(4-fluorophenoxy)ethylamine hydrochloride (466 mg) and sodium hydrogencarbonate (683 mg) were added to DMSO (6 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate to give the object compound of 2-(2-(4-fluorophenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile (38 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[CH:35]([C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=1)([CH3:37])[CH3:36]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:44][C:41]2[CH:42]=[CH:43][C:38]([CH:35]([CH3:37])[CH3:36])=[CH:39][CH:40]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CC(C)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.5 %

Procedure:
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (2.293 g) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (1.84 g) in acetonitrile (50 ml) were treated under ice cooling and an argon atmosphere with N-methyl-morpholine (3.034 g) and the mixture was stirred for 2 h at 0° C. Then 4-isopropyl-phenylamine (1.42 g) in acetonitrile was added dropwise and the reaction mixture was stirred at RT for 48 h. The reaction mixture was partitioned between ethyl acetate and aqueous 1M HCl, the layers were separated and the aqueous layer washed with 2M aqueous KHCO3 then dried over Na2SO4. The solvent was evaporated off. The residue was then triturated with AcOEt/diethyl ether/heptane to give the desired 4-(4-isopropyl-phenylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (1.68 g) as white solid. MS (ESI): 347.28 (MH+)
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([O:11]N2C(=O)CCC2=O)=O)=[C:7]([Cl:21])[CH:6]=1)=[N+:2]=[N-:3].Cl.[C:23]([NH:31][CH2:32][C@@H:33]([C:35]([O:37][CH3:38])=[O:36])[NH2:34])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C)C=O>[N:1]([CH2:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([NH:34][C@H:33]([C:35]([O:37][CH3:38])=[O:36])[CH2:32][NH:31][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:11])=[C:7]([Cl:21])[CH:6]=1)=[N+:2]=[N-:3]
Reactant: COC(=O)[C@@H](N)CNC(=O)c1ccccc1
Reactant: [N-]=[N+]=NCc1ccc(C(=O)ON2C(=O)CCC2=O)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)c1ccccc1)NC(=O)c1ccc(CN=[N+]=[N-])cc1Cl
Yield: 69.6 %

Procedure:
A solution of 1-[[4-(azidomethyl)-2-chlorobenzoyl]oxy]-2,5-pyrrolidinedione (4.64 g, 15.0 mmol), 3-(benzoyl)amino-L-alanine, methyl ester hydrochloride (4.00 g, 15.5 mmol), and triethylamine (4.00 g, 39.5 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 3 h. The solvent was evaporated, and 1 M HCl (100 mL) was added. The mixture was extracted with ethyl acetate (2×100 mL), washed with brine (100 mL), dried (MgSO4), filtered, evaporated, and chromatographed (50-75% ethyl acetate/hexanes) to give N-[4-(azidomethyl)-2-chlorobenzoyl]-3-(benzoyl)amino-L-alanine, methyl ester (4.34 g, 69%) as a colorless oil that solidified on standing, mp 112-114° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][C:11](=[O:21])[NH:12][CH2:13][CH2:14][CH2:15][C:16](=[O:20])[NH:17][CH2:18][CH3:19])(C)(C)C.[C:23]([NH:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=O)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CO.Cl>[C:26]([O:25][C:23](=[O:24])[NH:30][CH2:31][CH2:32][CH2:33][C:34](=[O:36])[NH:7][CH2:8][CH2:9][CH2:10][C:11](=[O:21])[NH:12][CH2:13][CH2:14][CH2:15][C:16](=[O:20])[NH:17][CH2:18][CH3:19])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: CCNC(=O)CCCNC(=O)CCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CCNC(=O)CCCNC(=O)CCCNC(=O)CCCNC(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
Boc-Protected derivative 4 (22.3 g, 70.7 mmol) was stirred in a mixture of MeOH (200 ml) and HCl (12%, 81 ml) for 48 h, concentrated to dryness in vacuo, dissolved in H2O, and washed 3 times with CHCl3. Water was removed on a rotary evaporator at 45° C. The resulting hydrochloride was dissolved in a mixture of CH2Cl2 (600 ml) and aq. Na2CO3 (20%, 100 ml), cooled on an ice bath, and Bt-derivative 2 (22.47 g, 70.15 mmol) was added. The cooling bath was removed and the mixture was stirred for 18 h with a mechanical stirrer. The main part of the CH2Cl2 was removed on a rotary evaporator, the reaction mixture was suspended in water and filtered. The product was triturated in EtOAc, filtered, washed with petr. ether and dried in vacuo. Yield 25.46 g (90%). mp: 170-171° C. 1H NMR (CDCl3/CD3OD): 1.14 (t, J=7.30, 3H), 1.44 (s, 9H), 1.72-1.85 (m, 6H), 2.10-2.23 (m, 6H), 3.06-3.12 (m, 2H), 3.18-3.26 (m, 6H), 5.57 (bs, 1H), 7.32 (bs, 1H), 7.46 (bs, 1H), 7.60 (bs, 1H). 13C NMR (CDCl3/CD3OD): 14.22, 24.73, 25.32, 25.39, 25.96, 28.15, 33.33, 33.59, 34.12, 34.25, 38.60, 39.64, 79.29, 156.68, 173.39, 173.88. ESI-MS: 423.4 (MNa+), 401.4 (MH+).