Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:8]2[N:16](S(C3C=CC=CC=3)(=O)=O)[C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[OH:7])=[CH:2]1.[OH-].[Na+]>C(O)C>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:8]2[NH:16][C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[OH:7])=[CH:2]1
Reactant: O=S(=O)(c1ccccc1)n1c(C(O)c2ccoc2)cc2ccncc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OC(c1ccoc1)c1cc2ccncc2[nH]1
Yield: 122.7 %

Procedure:
3-Furyl[1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methanol (186 mg, 0.51 mmol) was dissolved in ethanol (10 mL). A 10% solution of sodium hydroxide (6 mL) was added and the reaction mixture was refluxed for 3 hours. The solvent was removed under vacuum. The residue was taken up in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated to give 3-furyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (134 mg, quant.) as a yellow foam: 1H NMR (500 MHz, DMSO-d6) δ 5.87 (1H, d, J=4.7 Hz), 6.06 (1H, d, J=4.9 Hz), 6.29 (1H, s), 6.49 (1H, s), 7.42 (1H, d, J=5.4 Hz), 7.60 (2H, s), 8.03 (1H, d, J=5.4 Hz), 8.65 (1H, s), 11.49 (1H, s).
Reaction SMILES: Br[C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]2([C:34]([O:36]CC)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:3]=1.[CH3:41][S:42]([NH:45][C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1)(=[O:44])=[O:43]>>[CH3:41][S:42]([NH:45][C:46]1[CH:47]=[CH:48][C:49]([C:2]2[CH:40]=[CH:39][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]5[CH:27]=[CH:26][C:25]6[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=6)[N:19]=5)=[CH:15][C:10]=4[N:9]=[C:8]3[CH2:28][C:29]3([C:34]([OH:36])=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:4][CH:3]=2)=[CH:50][CH:51]=1)(=[O:44])=[O:43]
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)CCCC1
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Product: CS(=O)(=O)Nc1ccc(-c2ccc(Cn3c(CC4(C(=O)O)CCCC4)nc4cc(OCc5ccc6ccccc6n5)ccc43)cc2)cc1

Procedure:
The title compound was prepared using similar methods to those in Example 110 using ethyl 1-((1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate and 4-(methanesulfonylamino)phenyl boronic acid in Step A. MS (ESI): mass calcd. for C38H36N4O5S, 660.24; m/z found, 661.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J=8.5, 1H), 8.10 (d, J=8.4, 1H), 7.84-7.81 (m, 1H), 7.76-7.72 (m, 1H), 7.69 (d, J=8.5, 1H), 7.57-7.53 (m, 1H), 7.51-7.47 (m, 4H), 7.36-7.34 (m, 1H), 7.29-7.27 (m, 2H), 7.23-7.20 (m, 1H), 7.10-7.07 (m, 3H), 5.43 (s, 2H), 5.34 (s, 2H), 3.08 (s, 2H), 3.04 (s, 3H), 2.41-2.34 (m, 2H), 1.73-1.66 (m, 2H), 1.48-1.44 (m, 3H), 1.28-1.23 (m, 1H).
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]#[N:11])=[CH:2]1.CCO>N.[Ni]>[S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][NH2:11])=[CH:2]1
Reactant: N#Cc1csc2ncccc12
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCc1csc2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of thieno[2,3-b]pyridine-3-carbonitrile (J-4) (320 mg, 2 mmol) in NH3.EtOH (25 mL) was added Ranye/Ni (about 300 mg). The reaction was degassed with hydrogen and stirred at room temperature for 2 h. Then the mixture was filtered, and the filtrate was concentrated to give the title compound, which was used for next step without purification. MS (m/z): 165 (M+1)+.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:17]1[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:18]=1.C(N(CC)CC)C>O1CCCC1>[CH2:3]([NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:17]2[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[N:18]=2)[CH2:12]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: c1ccc(CN[C@@H]2CCNC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CC[C@@H](NCc3ccccc3)C2)nc(-c2ccncc2)cc1=O
Yield: 73.8 %

Procedure:
A solution of (R)-benzylpyrrolidin-3-yl-amine dihydrochloride (3.0 g, 12 mmol), 2-chloro-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (2.6 g, 12 mmol), and triethylamine (6 g, 60 mmol) in tetrahydrofuran (40 ml) was stirred for 12 hours at 95° C. The solvent was evaporated off under reduced pressure and the residue was partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate) to afford 2-((R)-3-benzylaminopyrrolidin-1-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (3.2 g, 75%) as pale yellow oil.
Reaction SMILES: CN1C(C(OC(C)(C)C)=O)CNC1=O.BrC1N=CC=CN=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:70][N:71]1[CH:75]([C:76]([O:78]C(C)(C)C)=[O:77])[CH2:74][N:73]([C:83]2[N:88]=[CH:87][CH:86]=[CH:85][N:84]=2)[C:72]1=[O:89].[C:90]([OH:96])([C:92]([F:95])([F:94])[F:93])=[O:91].C(Cl)Cl>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:96][C:90]([C:92]([F:95])([F:94])[F:93])=[O:91].[CH3:70][N:71]1[C@H:75]([C:76]([OH:78])=[O:77])[CH2:74][N:73]([C:83]2[N:84]=[CH:85][CH:86]=[CH:87][N:88]=2)[C:72]1=[O:89]
Reactant: CN1C(=O)N(c2ncccn2)CC1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: Brc1ncccn1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)N(c2ncccn2)C[C@H]1C(=O)O
Temperature: 25 °C

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (801 mg, 4 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2-bromopyrimidine (636 mg, 4 mmol) in 1,4-dioxane (20 ml) was treated with cesium carbonate (1955 mg, 6 mmol), Xantphos™ (174 mg, 0.3 mmol) and tris(dibenzylideneacetone)dipalladium(0) (92 mg, 0.1 mmol) and the mixture was heated under reflux under argon for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-20% methanol in ethyl acetate to 1,1-dimethylethyl 3-methyl-2-oxo-1-(2-pyrimidinyl)-4-imidazolidinecarboxylate (360 mg, 32%). LC/MS [M+H]+=279. (ii) A solution of 1,1-dimethylethyl 3-methyl-2-oxo-1-(2-pyrimidinyl)-4-imidazolidinecarboxylate (0.557 g, 2 mmol) in TFA/DCM (1:2, 7.5 ml) was stirred at room temperature for 6 hours. The solution was evaporated and the residue was dried to give crude (4S)-3-methyl-2-oxo-1-(2-pyrimidinyl)-4-imidazolidinecarboxylic acid TFA salt (assume ˜2 mmol) which was used in the next step. LC/MS [M+H]+=223.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=[O:6].[NH3:15]>CO>[CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH2:15])=[O:6]
Reactant: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Reactant: N
Solvent: CO
Product: Cc1cccc(C(N)=O)c1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
Methyl 3-methyl-2-nitrobenzoate (10.02 g, 51.3 mmol) was added to a 7N solution of ammonia in methanol (50 mL) and the mixture was heated at 100° C. in a Fisher-Porter tube for 3 hours. The solution was then cooled, concentrated and triturated with dichloromethane to give the title compound of Step A as a white solid (1.4 g).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18](B4OC(C)(C)C(C)(C)O4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:29]1[C:30]([C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=2)=[N:31][N:32]([CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH:33]=1>>[CH3:37][N:36]([CH3:38])[CH2:35][CH2:34][N:32]1[CH:33]=[C:29]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[C:30]([C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=2)=[N:31]1
Reactant: CC1(C)OB(c2ccnc3c2ccn3S(=O)(=O)c2ccccc2)OC1(C)C
Reactant: CN(C)CCn1cc(Br)c(-c2ccc([N+](=O)[O-])cc2)n1
Product: CN(C)CCn1cc(-c2ccnc3c2ccn3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 100 using 1-(phenylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine and 2-[4-bromo-3-(4-nitrophenyl)-1H-pyrazol-1-yl]-N,N-dimethylethanamine provided the title compound. ESMS [M+H]+: 517.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][NH:10][S:9]1(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>>[CH2:1]([N:8]1[S:9](=[O:14])(=[O:13])[N:10]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:11][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=S1(=O)NCCN1Cc1ccccc1
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)S2(=O)=O)cc1
Yield: 79 %

Procedure:
The title compound was prepared in 79% yield from 2-benzyl-1,2,5-thiadiazolidine-1,1-dioxide and 1-fluoro-4-nitrobenzene using a similar method to that described for Example 20 (step 1). The crude product was crystallised from ethyl acetate to give a yellow solid; mp 164°-165° C.; δH (360 MHz, DMSO-d6) 8.30 (2H, d, J=9.2 Hz, Ar--H), 7.40 (5H, m, Ph), 7.33 (2H, d, J=9.2 Hz, Ar--H), 4.31 (2H, s, PhCH2 --), 3.98 (2H, t, J=6.4 Hz, --CH2 --), 3.49 (2H, t, J=6.4 Hz, --CH2 --); m/z (EI) 333 (M+).
Reaction SMILES: CN(C=O)C.P(Cl)(Cl)Cl.[ClH:10].Cl[C:12]([C:22]#[N:23])([CH2:18][CH2:19][CH:20]=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1(C)C=CC=CC=1>[Cl:10][C:22]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][CH:19]=[CH:20][N:23]=1
Reactant: CCOC(=O)C(Cl)(C#N)CCC=O
Reactant: Cl
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of DMF (3.22 g, 44 mmol) in 30 mL of toluene were added 6.05 g of PCl3 (44 mmol). Anhydrous HCl was introduced until saturated. Ethyl 2-chloro-2-cyano-5-oxopentanoate (4.5 g, 20 mmol) in 10 mL of toluene was added in 30 minutes. The resulting mixture was stirred for 1 h at 80° C., cooled to room temperature, quenched with water, and extracted with toluene. GLC analysis indicated that the title compound was formed in 87% yield.
Reaction SMILES: Cl.[CH3:2][O:3][C@H:4]1[C@@H:9]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7][NH:6][CH2:5]1.Br[C:22]1[CH:23]=[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=[N:26][CH:27]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:13]([O:12][C:11]([NH:10][C@H:9]1[CH2:8][CH2:7][N:6]([C:22]2[CH:23]=[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=[N:26][CH:27]=2)[CH2:5][C@H:4]1[O:3][CH3:2])=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: CO[C@@H]1CNCC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Product: CCOC(=O)c1cncc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)c1
Yield: 51.2 %

Procedure:
The same operation as in Example (160b) was performed using benzyl cis(±)-[3-methoxypiperidin-4-yl]carbamate hydrochloride obtained in Example (160a) (832 mg, 2.76 mmol), ethyl 5-bromopyridine-3-carboxylate (530 mg, 2.3 mmol), palladium acetate (51.72 mg, 0.23 mmol), BINAP (286.89 mg, 0.46 mmol), and cesium carbonate (2.25 g, 6.91 mmol), to obtain 487 mg of the title compound as a yellow oily substance.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.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.C(OCC)(=O)C>[Br:8][C:6]1[CH:7]=[C:2]([C:14]2[CH:13]=[CH:12][C:11]([F:10])=[CH:16][C:15]=2[F:17])[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Nc1ncc(Br)cc1Br
Reactant: OB(O)c1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1ncc(Br)cc1-c1ccc(F)cc1F

Procedure:
A solution of 3,5-dibromopyridin-2-amine (2.95 g, 11.71 mmol) and 2,4-difluorophenylboronic acid (1.85 g, 11.71 mmol) in toluene was degassed via nitrogen bubble for 20 mins. The mixture was then added Pd(PPh3)4 (0.677 g, 0.585 mmol), K3PO4 (2 M, 11.8 mL, 23.4 mmol) and Ethanol (1 mL) and heated at 80° C. overnight. The reaction was cooled, poured into ethyl acetate (150 mL), washed with brine, separated, dried over Na2SO4 and concentrated to give a crude 5-bromo-3-(2,4-difluorophenyl)pyridin-2-amine (3) which was used directly in next step without purification.
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][C@@H:14]3[CH2:16][C@H:11]2[C@@H:12]([NH:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[NH:24]C(=O)OC(C)(C)C)[CH2:13]3)=[CH:6][CH:5]=1)#[N:3].CO>O1CCOCC1>[ClH:1].[ClH:1].[NH2:24][C@@H:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C@H:18]1[NH:17][C@@H:12]1[C@H:11]2[CH2:16][C@H:14]([CH2:15][N:10]2[C:7]2[CH:8]=[CH:9][C:4]([C:2]#[N:3])=[CH:5][CH:6]=2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N[C@H]1C[C@H]2C[C@@H]1N(c1ccc(C#N)cc1)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N#Cc1ccc(N2C[C@@H]3C[C@H](N[C@@H]4CCCC[C@H]4N)[C@H]2C3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of HCl (4.0 N in 1,4-dioxane, 2 ml)) was added to a mixture of tert-butyl (1R,2R)-2-((1S,4S,6S)-2-(4-cyanophenyl)-2-azabicyclo[2.2.1]heptan-6-ylamino)cyclohexylcarbamate (445 mg, 1.084 mmol) in 1,4-dioxane (2 ml). The starting material formed a gum. MeOH (1 mL) was then added. Eventually all solids went into solution. The reaction was stirred at rt for 2 hrs. The reaction mixture was concentrated to give 4-((1R,4R,6S)-6-((1R,2R)-2-aminocyclohexylamino)-2-azabicyclo[2.2.1]heptan-2-yl)benzonitrile bishydrochloride (440 mg, 1.084 mmol, 100% yield) of an off white solid. Calcd. for C19H26N4 m/z 310.4, found: 311.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)CCC>CN(C=O)C.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>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(Br)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(-c3ccccn3)c2s1
Temperature: 100 °C
Yield: 69.6 %

Procedure:
To a stirred of 1-(5-benzyloxy-7-bromo-1,3-benzothiazol-2-yl)-3-ethyl-urea (110 g, 0.27 mol) in DMF (1.1 L) was added 2-tributylstannyl pyridine (298 g, 0.81 mol). The resulting solution was purged with N2 for 15-20 min followed by addition of tetrakis(triphenylphosphine)palladium (0) (25.41 g, 0.022 mol). The resulting mixture was then heated to 100° C. under N2 atmosphere for 15-16 h. The reaction mass was cooled to 40-45° C. then filtered through celite. The celite bed was washed with DMF (500 mL) and hot EtOAc (1.50 L) and the combined filtrate concentrated at 60-70° C. under reduced pressure. The residue was purified through silica gel (20% EtOAc-Hexanes to 100% EtOAc) to obtain the desired product (76 g, 70%). 1H-NMR (DMSO-d6): δ 1.08 (t, J=7.20 Hz, 3H), 3.19 (q, J=6.80 Hz, 2H), 5.26 (s, 2H), 6.84 (br s, 1H), 7.32-7.43 (m, 5H), 7.51 (d, J=7.20 Hz, 2H), 7.69 (d, J=2.0 Hz, 1H), 7.95 (m, 1H), 8.25 (m, 1H), 8.78 (m, 1H) and 10.46 (br s, 1H). LCMS: 405.30 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([OH:10])=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[OH:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([O:10][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][O:14]2)=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]
Reactant: C1=COCCC1
Reactant: CC(=O)c1cc(O)c(C)c(C)c1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1cc(OC2CCCCO2)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-(2,5-Dihydroxy-3,4-dimethyl-phenyl)-ethanone of Step 3 (275 mg) was dissolved in dichloromethane (20 mL) and 3,4-dihydro-2H-pyran (0.2 mL) was added followed by pyridinium p-toluenesulfonate (PPTS) (30 mg). The mixture was stirred at room temperature for 4 h. The mixture was dried over MgSO4 and purified on silica gel column eluting with 30% EtOAc in hexane to give 397 mg of 1-[2-hydroxy-3,4-dimethyl-5-(tetrahydro-pyran-2-yloxy)-phenyl]-ethanone as a yellow solid.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[NH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[NH2:22].[F:23][C:24]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=O.[OH-].[Na+]>CS(O)(=O)=O>[F:23][C:24]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]1[NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[N:22]=1
Reactant: O=C(O)c1cccc(F)c1F
Reactant: Nc1ccncc1N
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Product: Fc1cccc(-c2nc3ccncc3[nH]2)c1F
Temperature: 190 °C

Procedure:
Phosphorous pentoxide (24.56 g) was dissolved in methanesulfonic acid (165.8 mL) at 50° C. with stirring. To the solution, 3,4-diaminopyridine (12.3 g, 0—11 moles) and 2,3-difluorobenzoic acid (19.4 g, 0.12 moles) were added. The reaction mixture was heated to 190° C. for 3 hours. The reaction was done three times. The reaction mixtures was cooled to 50° C. and poured into ice with stirring. At this stage, all three batches were combined. The reaction mixture was neutralized by the addition of NaOH with stirring until the pH is 8. Solid material precipitated out of solution, was collected by filtration and air-dried. The final product was re-crystallized from ethanol/water twice to yield 36 g of 2-(2,3-difluorophenyl)-3H-imidazo[4,5-c]pyridine. 1H 300 Mhz (CD3OD) sigma 7.3-7.42 (m, 1p); 7.43-7.58 (m, 1p); 7.70 (d, 1p); 8.0 (m, 1p); 8.34 (d, 1p); and 8.95 (s, 1p). LC/MS data M/z=232.
Reaction SMILES: C(OC([N:6]1[CH2:10][CH2:9][CH:8]([C:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[O:13][N:12]=2)[CH2:7]1)=O)=C.[ClH:21]>C(O)(C)C>[ClH:21].[F:20][C:18]1[CH:17]=[CH:16][C:15]2[C:11]([CH:8]3[CH2:9][CH2:10][NH:6][CH2:7]3)=[N:12][O:13][C:14]=2[CH:19]=1
Reactant: C=COC(=O)N1CCC(c2noc3cc(F)ccc23)C1
Agent: Cl
Solvent: CC(C)O
Product: Fc1ccc2c(C3CCNC3)noc2c1
Temperature: 0 °C

Procedure:
A mixture of 3-(6-fluoro-1,2-benzisoxazol-3-yl)-1-pyrrolidinylcarboxylic acid ethenyl ester (5.1 g, 18.4 mmol, hydrochloric acid (5 ml), and isopropyl alcohol (50 ml) was heated at reflux for 3.5 hr. At the end of the reaction, the solvent was reduced to about 30 ml on a rotary evaporator and the mixture was cooled to 0° C. for 2 hr. The crystals were collected by filtration and rinsed with cold isopropyl alcohol. The 6-fluoro-3-(3-pyrrolidinyl)-1,2-benzisoxazole hydrochloride product weighed 3.09 g (69%), m.p.=225°-227° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]2[C:5]([CH2:6][N:7]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>ClCCl>[Cl:1][C:2]1[N:11]2[C:5]([CH2:6][N:7]([C:16]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=4[CH3:32])=[CH:21][CH:22]=3)=[O:24])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10]2)=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccc(Cl)n3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccc(Cl)n3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1 mmol of 3-chloro-10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 2 mmol of triethylamine, and 1.1 mmol of 2-methylbenzoylchloride in 8 ml of dichloromethane is stirred at room temperature overnight. The mixture is washed with water, and 1M NaHCO3 and dried (Na2SO4). The solvent is removed in vacuo to give a solid which is recrystallized from dichloromethane-hexane to give crystals, 185-187° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[C:6]=1[F:17].Br[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[C:6]=1[F:17]
Reactant: COC(=O)Cc1cc(O)c2cc(F)ccc2c1F
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc(Oc2ccc(S(C)(=O)=O)cn2)c2cc(F)ccc2c1F
Temperature: 70 °C
Yield: 86.8 %

Procedure:
A mixture of (1,6-difluoro-4-hydroxy-naphthalen-2-yl)acetic acid methyl ester (50 mg, 0.198 mmol), 2-bromo-5-methanesulfonyl-pyridin (52 mg, 0.22 mmol), potassium carbonate (60 mg, 0.434 mmol) and N,N-dimethylformamide (2.0 mL) was heated at 70° C. for 3 hours. The resulting mixture was cooled to room temperature, acidified with 1 N hydrochloric acid to pH 3, and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over sodium sulfate, and concentrated in vacuo to afford [1,6-difluoro-4-(5-methanesulfonyl-pyridin-2-yloxy)-naphthalen-2-yl]-acetic acid methyl ester (70 mg, 87%) as a white solid which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-])=O)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].N>C(OCC)(=O)C>[NH2:18][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: N
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Reaction time: 2 h
Yield: 80.8 %

Procedure:
To a stirred solution of 5-Chloro-N-(5-chloro-pyridin-2-yl)-2-nitro-benzamide (26 g, 0.0833 mol) in ethyl acetate (170 mL) was added Stannous chloride dihydrate (75 g, 0.333 mol) at 25-30° C. After stirring at same temperature for 2 hr, reaction mixture was diluted with 250 mL ethyl acetate and made alkaline with aqueous ammonia solution. Reaction mixture was then filtered through hyflow bed and organic layer was dried over sodium sulfate. Evaporation of solvent afforded 19 g of titled compound in 81% yield.