Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:33][NH:34][CH3:35]>O1CCCC1>[CH3:33][N:34]([CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:35]
Reactant: CNC
Reactant: COC(=O)c1ccc(-c2cccc(C=O)c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2cccc(CN(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 3′-formylbiphenyl-4-carboxylate (0.338 g) was dissolved in 2 mol/L dimethylamine in tetrahydrofuran (20 mL) and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.895 g) was added. The reaction was stirred at room temperature for 5 days and then partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organics were dried over magnesium sulfate and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 0-5% methanol/dichloromethane (0.5% triethylamine) to furnish the title compound (0.112 g) having the following physical data.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11]C)=O.[NH2:17][CH2:18][CH:19]([OH:31])[CH2:20][N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1>CCO>[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:29][CH2:30][N:21]1[CH2:20][CH:19]([OH:31])[CH2:18][NH:17][C:9](=[O:11])[C:8]1[CH:13]=[CH:14][CH:15]=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:16])[CH:7]=1
Reactant: COC(=O)c1cccc(OCCN(C)C)c1
Reactant: NCC(O)CN1CCc2ccccc2C1
Solvent: CCO
Product: CN(C)CCOc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 120 °C
Yield: 6.4 %

Procedure:
A mixture of crude methyl 3-(2-(dimethylamino)ethoxy)benzoate (300 mg, 1.34 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (332 mg, 1.61 mmol) in EtOH (2 mL) was heated at 120° C. in a microwave reactor for 3 h. After evaporation of the solvent, the residue was purified by prep-HPLC to give the title compound (34 mg, Yield 6.4%). 1H NMR (CD3OD, 400 MHz): δ 7.43-7.42 (m, 1H), 7.34-7.29 (m, 2H), 7.12-7.10 (m, 4H), 7.09-7.03 (m, 1H), 4.20-4.10 (m, 3H), 3.75 (brs, 2H), 3.59-3.42 (m, 2H), 2.95-2.85 (m, 4H), 2.82-2.77 (m, 2H), 2.72-2.65 (m, 2H), 2.37 (s, 6H). LCMS (m/z): 398.1 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:40])[C:29]([NH:31][CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])=[O:30])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[CH:19][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:40])[C:29]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To an ice-cooled solution of tert-butyl 2-[(2-{1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}-2-oxoacetyl)amino]acetate (1.33 g, 2.41 mmol) in methylene chloride (25 mL) was added 12 mL (160 mmol) of trifluoroacetic acid. The reaction mixture was stirred for two hours at room temperature then concentrated. The residue was crystallized twice from isopropanol. It was dried for 15 hours at 95° C. to give the title compound as yellow solid (0.928 g, 77%), mp 211–2° C. (dec.). Mass spectrum (−ESI, [M−H]−) m/z 495; 1HNMR (500 MHz, DMSO-d6): δ12.5–13.0 (br, 1H), 9.05 (s, 1H), 8.95 (t, 1H, J=6.1 Hz), 8.5 (d, 1H, J=1.5 Hz), 7.75–7.8 (m, 2H), 7.7 (d, 1H, J=8.6 Hz), 7.6 (dd, 1H, J=8.6 Hz and 1.8 Hz), 7.45 (d, 2H, J=8.1 Hz), 7.25–7.35 (m, 5H), 5.65 (s, 2H), and 3.9 ppm (d, 2H, J=6.1 Hz).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=3[S:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl.[CH2:32]([O:34][C:35](=[O:38])[CH2:36][NH2:37])[CH3:33]>CCO>[CH2:32]([O:34][C:35](=[O:38])[CH2:36][NH:37][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[N:9][CH:8]=[CH:7][C:6]=2[NH:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[S:20][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:25][CH:26]=2)[N:11]=1)[CH3:33]
Reactant: CCOC(=O)CN
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(Cl)ccc23)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CNc1ccc2c(Nc3cc(C)ccc3Sc3ccc(NC(C)=O)cc3)ccnc2n1
Temperature: 25 °C

Procedure:
The product from Example 24a (47 mg, 0.10 mmol) was reacted with the glycine ethyl ester hydrochloride (84 mg, 0.10 mmol) in 2 mL of EtOH in a sealed tube at 150° C. for 1 h. Cooled to room temperature and concentrated. Adjusted to pH 7 with 1M HCl and extracted with EtOAc, dried over Na2SO4, filtered and concentrated under vacuum giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid solid (12 mg, 19%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.22 (t, J=6.99 Hz, 3H) 2.04 (s, 3H) 2.33 (s, 3H) 4.15 (q, J=7.23 Hz, 2H) 4.27 (d, J=6.25 Hz, 2H) 6.08 (d, J=6.99 Hz, 1H) 7.04 (d, J=5.52 Hz, 1H) 7.07 (d, J=6.62 Hz, 1H) 7.19-7.30 (m, 4H) 7.57 (d, J=8.46 Hz, 2H) 8.04 (t, J=6.62 Hz, 1H) 8.53 (d, J=9.19 Hz, 1H) 8.72 (t, J=5.88 Hz, 1H) 10.08 (s, 1H) 10.43 (s, 1H) 13.43 (d, J=5.88 Hz, 1H); MS (ESI+) m/z 502(M+H−TFA)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][OH:12])=[N:9][N:8]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:5]2=[N:6][CH:7]=1.[K+].[Br-].[O-]Cl.[Na+]>C(Cl)Cl.O.CC1(C)N([O])C(C)(C)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[N:9][N:8]([C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:5]2=[N:6][CH:7]=1
Reactant: OCc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)cc12
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a solution of (5-bromo-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)methanol (XXIII) (4.05 Kg, 8.6 mol) in DCM (97 L) was added a solution of KBr (205 g, 1.72 mol) in water (4 L). The solution was cooled to 0° C. before adding TEMPO (107.5 g, 688 mmol) and stirring for 30 min. To this solution was added a solution of KHCO3 (10.8 Kg, 107.4 mol) and aqueous 7% NaClO (13.4 L) in water (40 L). The reaction was stirred at 0° C. for 18 hours. A solution of Na2S2O3.5H2O (1.4 Kg, 5.7 mol) in water (9.1 L) was added dropwise to the reaction at 0° C. and stirred for 30 min. The aqueous layer was then separated and washed with DCM (48 L). The combined organic phases were washed with aqueous 25% NaCl (48 L), dried over Na2SO4, filtered and concentrated under vacuum. The residue was co-evaporated with 3×MeOH (20 L) and the solid was washed with 2×n-heptane (8 L). The solid was dried under vacuum at 45° C. to give 5-bromo-1-trityl-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (XXIV) (3.25 Kg, 6.94 mol, 92.3% purity, 80.6% assay yield). 1H NMR (CDCl3, 400 MHz) δ ppm 7.19 (d, J=6 Hz, 5H), 7.22-7.34 (m, 10H), 8.28 (d, J=2.4 Hz, 1H), 8.70 (d, J=2.4 Hz, 1H), 10.07 (s, 1H); ESIMS found C26H18BrN3O m/z 490.0 (M+Na).
Reaction SMILES: CC([PH+](C(C)(C)C)CCCS([O-])(=O)=O)(C)C.[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[N:22][CH:23]=1.Br[C:28]1[CH:37]=[C:36]2[C:31]([CH2:32][CH2:33][CH2:34][C:35]32[N:41]=[C:40]([NH2:42])[C:39]([CH3:43])=[N:38]3)=[CH:30][CH:29]=1.CC1CCCO1.C([O-])([O-])=O.[K+].[K+]>[Na+].[Na+].Cl[Pd+2](Cl)(Cl)Cl>[Cl:17][C:18]1[CH:19]=[C:20]([C:28]2[CH:37]=[C:36]3[C:31]([CH2:32][CH2:33][CH2:34][C:35]43[N:41]=[C:40]([NH2:42])[C:39]([CH3:43])=[N:38]4)=[CH:30][CH:29]=2)[CH:21]=[N:22][CH:23]=1
Reactant: CC1=NC2(CCCc3ccc(Br)cc32)N=C1N
Reactant: OB(O)c1cncc(Cl)c1
Agent: Cl[Pd]Cl
Agent: CC(C)(C)[PH+](CCCS(=O)(=O)[O-])C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CC1CCCO1
Product: CC1=NC2(CCCc3ccc(-c4cncc(Cl)c4)cc32)N=C1N
Temperature: 90 °C
Yield: 33.4 %

Procedure:
Sodium tetrachloropalladate(II) (3.52 mg, 0.01 mmol), 3-(di-tert-butylphosphonium)propane sulfonate (6.43 mg, 0.02 mmol), 5-chloropyridin-3-ylboronic acid (51.6 mg, 0.31 mmol) and 7′-bromo-5-methyl-3′,4′-dihydro-2′H-spiro[imidazole-2,1′-naphthalen]-4-amine (Example 51 Step 4, 70 mg, 0.24 mmol) were added to a vial. 2-Methyl-tetrahydrofuran (1 mL) and K2CO3 (2 M aq.) (0.359 mL, 0.72 mmol) were added and the mixture was degassed by bubbling N2 (g). The vial was sealed and heated in a microwave reactor at 90° C. for 30 min. EtOAc (5 mL) and water (5 mL) were added and the phases were separated. The aqueous phase was extracted with EtOAc twice and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (4 g SiO2, 0-10% McOH containing 0.1M NH3 in DCM). The fractions containing product were combined and concentrated, yielding the title compound (26 mg, 33% yield). 1H NMR (500 MHz, CD3OD) δ ppm 1.85-1.94 (m, 1H), 2.01 (ddd, 1H), 2.08-2.17 (m, 1H), 2.17-2.27 (m, 1H), 2.35 (s, 3H), 3.02 (t, 2H), 6.84 (d, 1H), 7.34 (d, 1H), 7.48 (dd, 1H), 7.97 (t, 1H), 8.48 (d, 1H), 8.57 (d, 1H); MS (ES+) m/z 325 [M+H]+.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.C(O)(C(F)(F)F)=O.[CH2:45]([CH2:47][NH2:48])[OH:46]>>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH:48][CH2:47][CH2:45][OH:46])[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2
Reactant: NCCO
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCC(NCCO)CC3)nc(N3CC4CCC(C3)O4)n2)cc1

Procedure:
Starting from 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea.TFA (50 mg) and ethanolamine (0.020 mL) and following the procedure as outlined in example 118, the title compound was isolated as its di-TFA salt after HPLC purification. MS (ES+) 546.7 (M+H)+
Reaction SMILES: Br[C:2]1[C:7]([N:8](COC)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:25])=[CH:4][N:3]=1.[F:26][C:27]1[CH:38]=[CH:37][CH:36]=[CH:35][C:28]=1[C:29](N(OC)C)=[O:30].Cl.O>CCOC(C)=O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:7]2[C:2]([C:29](=[O:30])[C:28]3[CH:35]=[CH:36][CH:37]=[CH:38][C:27]=3[F:26])=[N:3][CH:4]=[C:5]([Cl:25])[CH:6]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1)([CH3:19])([CH3:21])[CH3:20]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: CON(C)C(=O)c1ccccc1F
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 0.1 %

Procedure:
N-(2-Bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide (140 mg, 300 mmol) was placed in a dry 2-neck 10 mL round-bottom flask. The flask was evacuated and purged with nitrogen, followed by the addition of THF (1 mL). The homogeneous mixture was lowered to −5° C. and iPrMgCl (0.33 mL, 2.0 M) was added dropwise. Upon completion of the addition, the reaction was stirred 90 minutes, followed by the slow addition of 2-fluoro-N-methoxy-N-methyl-benzamide (140 mg, 750 mmol). The reaction was stirred overnight, during which the ice-bath warmed to room temperature. The following day, the reaction was quenched with a small quantity of MeOH and the solvents evaporated in vacuo. The residue was subsequently treated with 4.0 M HCl (in dioxane) (1 mL, 4.0 mmol) and H2O (0.33 mL), and then stirred at 80° C. for two hours. The resultant solution was diluted with EtOAc, washed with water, saturated sodium bicarbonate, and brine; dried with MgSO4, and evaporated employing reduced pressure. The crude sulfonamide was finally purified via preparatory TLC (20% EtOAc/hexanes) and recrystallization from MeCN/H2O to afford 98 mg of the title compound: 1H NMR (400 MHz, CDCl3) δ 10.6 (s, 1H), 8.3 (d, 1H), 8.2 (d, 1H), 7.74 (d, 2H), 7.6 (d, 1H), 7.5 (d, 1H), 7.43 (d, 2H), 7.42-7.37 (m, 2H), 1.26 (s, 9H); MS (ES) M+H expect 447.1. found 447.5.
Reaction SMILES: CC1C=CC(C2C=NN(C)C=2)=C(C=1)C(O)=O.[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:28]2[CH:32]=[CH:31][N:30]([CH3:33])[N:29]=2)=[C:22]([CH:27]=1)[C:23]([O:25]C)=[O:24]>>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:28]2[CH:32]=[CH:31][N:30]([CH3:33])[N:29]=2)=[C:22]([CH:27]=1)[C:23]([OH:25])=[O:24]
Reactant: COC(=O)c1cc(C)ccc1-c1ccn(C)n1
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Product: Cc1ccc(-c2ccn(C)n2)c(C(=O)O)c1

Procedure:
The title compound was synthesized following the same general protocol as described for 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid in Example A1, using methyl 5-methyl-2-(1-methyl-1H-pyrazol-3-yl)benzoate. ESI-MS (m/z): 217 [M+1]+.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[N:14][CH:15]=[CH:16][CH:17]=1)SC)#[N:2].[CH3:18][NH2:19]>>[C:1]([NH:3][C:4]([NH:19][CH3:18])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[N:14][CH:15]=[CH:16][CH:17]=1)#[N:2]
Reactant: CSC(=NCCSCc1cccnn1)NC#N
Reactant: CN
Product: CNC(=NCCSCc1cccnn1)NC#N

Procedure:
Reacting this isothiourea with methylamine by the procedure of Example 3(c)(ii) gives N-cyano-N'-methyl-N"-[2-(3-pyridazinylmethylthio)ethyl]guanidine.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17]>>[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17].[OH:1][CH2:2][CH:3]1[CH2:6][NH:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Solvent: O=C(O)C(F)(F)F
Product: OCC1CNC1
Reaction time: 0.5 h

Procedure:
To tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (125 mg) was added trifluoroacetic acid (0.413 ml) while cooling in an ice bath, followed by stirring at the same temperature for 30 min. Then, the reaction mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated to provide a crude product of the titled compound as a yellow oil (209.8 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH2:10].[OH-].[K+].[C:13](=S)=[S:14].C>O.C(O)C>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]2[N:10]=[C:13]([SH:14])[NH:1][C:2]=2[CH:7]=1
Reactant: S=C=S
Reactant: Nc1cc(Cl)c(Cl)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Sc1nc2cc(Cl)c(Cl)cc2[nH]1
Reaction time: 8 h
Yield: 86.4 %

Procedure:
The procedure of Van Allan, J. A. V. and Deacon, B. D., Organic Synthesis. IV: 569 was adapted. A mixture of 1,2-diamino-4,5-dichlorobenzene (510 mg, 2.88 mMol, Aldrich), potassium hydroxide (190 mg, 3.40 mMol), carbon disulfide (260 mg, 3.40 mMol), 95% ethanol (3 mL) and water (0.45 ml) was heated under reflux for 3 h. Activated charcoal (120 mg) was then added cautiously, and after the mixture has been heated at the refluxing temperature for 10 min the activated charcoal was removed by filtration. The filtrate was heated to 60°-70° C., warm water (3 mL) was added, and then acetic acid (0.25 mL) in water (0.5 mL) was added with good stirring overnight. The mixture was placed in a refrigerator for 3h to get two crystals (brown and white). The brown crystals were removed by washing with chloroform (5 mL). Recrystallization from hot EtOH/H2O gave pure 5,6-dichloro-2-mercaptobenzimidazole (545 mg, 86%) as white long needles. Mp was measured: the color of 5,6-dichloro-2-mercaptobenzimidazole changed to yellow at 303° C.; the decomposition of 5,6-dichloro-2-mercaptobenzimidazole is obvious at 305° C. and it melted to a black liquid at 308°-10° C. IR (KBr, cm-1): 3447; 3107; 3043; 1607; 1496; 1461. NMR (1H, DMSO-d6): δ 7.305 (s, 2H); 12.781 (s, 2H). HRMS: calcd for C7H4Cl2N2S (M+) m/z: 217.9425, Found: 217.9482.
Reaction SMILES: [OH:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][C:3]=1[CH:4]=[N:5]O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C>O1CCCC1>[OH:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][C:3]=1[C:4]#[N:5]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=NO)c1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(Br)c(O)c(C#N)c1
Yield: 93.6 %

Procedure:
A mixture of 12.0 g (44.0 mmol) of 2-hydroxy-3-bromo-5-(1,1-dimethylethyl)benzaldehyde oxime and 18.9 g (90.0 mmol) of trifluoroacetic anhydride in 100 ml of tetrahydrofuran was cooled in an ice-water bath. A solution of 15.2 g (150.0 mmol) of triethylamine in 40 ml of tetrahydrofuran was added. After refluxing overnight, the solvent was stripped. The residue was partitioned between water and methylene chloride. The organic phase was washed with 1N hydrochloric acid followed by saturated sodium bicarbonate, then dried and evaporated. The residue was crystallized from hexane to provide 10.4 g (41.2 mmol, 94%) of 2-hydroxy-3-bromo-5-(1,1 dimethylethyl)benzonitrile; mp 69°-71° C.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[N:14]=[C:13]([SH:15])[CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:3][CH:2]=1.[OH2:17].[OH2:18].[OH2:19].O.O.O.O.O.[OH-].[Ba+2].[OH-]>O>[C:1]1([CH3:16])[CH:2]=[CH:3][C:4]([C:7]([C:9]2[N:14]=[C:13]([S:15]([OH:19])(=[O:18])=[O:17])[CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: O
Reactant: Cc1ccc(C(=O)c2cccc(S)n2)cc1
Agent: [Ba+2]
Agent: [OH-]
Product: Cc1ccc(C(=O)c2cccc(S(=O)(=O)O)n2)cc1
Yield: 80.6 %

Procedure:
This thiol (9.16 g) was dissolved in a solution of barium hydroxide octahydrate (12.62 g) in water (250 ml) and the solution filtered. To the stirred and ice-cooled solution was then added dropwise 30% aqueous hydrogen peroxide (14.0 ml). After allowing to warm to room-temperature the mixture was heated on the steam bath for one hour with stirring. The resultant solution was filtered hot and then allowed to cool whereupon the barium salt of the sulphonic acid crystallised from solution. To the suspension of the barium salt was added with stirring 1.0N aqueous sulphuric acid (40 ml) and the resultant mixture heated on the steam bath for 15 minutes and then allowed to cool. The precipitate of barium sulphate was filtered off and the filtrate concentration to dryness in vacuo and the residue treated with ethanol and reconcentrated to dryness. Trituration with ethanol, filtration and washing with acetone gave 6-(4-toluoyl)pyridine-2-sulphonic acid (8.93 g) as a yellow solid. M.p.>300°.
Reaction SMILES: CS(O[CH2:6][CH2:7]/[CH:8]=[CH:9]/[CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:12])(=O)=O.[O:28]=[C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](=[O:38])[N-:30]1.[K+].O>CN(C=O)C>[C:24]([O:23][C:21](=[O:22])[NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:11](=[O:12])/[CH:10]=[CH:9]/[CH2:8][CH2:7][CH2:6][N:30]1[C:31](=[O:38])[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]1=[O:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)C/C=C/CCOS(C)(=O)=O
Reactant: O=C1[N-]C(=O)c2ccccc21
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/CCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.1 %

Procedure:
To a solution of (E)-6-(2-(tert-butoxycarbonylamino)phenylamino)-6-oxohex-4-enyl methanesulfonate (1) (200 mg, 0.5 mmol) in DMF was added potassium 1,3-dioxoisoindolin-2-ide (111 mg, 0.6 mmol), the mixture was stirred at RT for 12 hours. The mixture was poured into 100 mL water, then extracted with MTBE (25 mL×2), and the organic layers were washed with water (25 mL×3) and brine (3×20 mL), dried over Na2SO4 and concentrated to give the desired compound of (E)-tert-butyl 2-(6-(1,3-dioxoisoindolin-2-yl)hex-2-enamido)phenylcarbamate (3) (135 mg, yield 60%) as a yellow oil after purification by column chromatography on silica gel (eluent: PE:EA=1:1). LC-MC found 450 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH:5]([OH:22])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]=1)=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:1][CH2:4][CH:5]([OH:22])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]=1
Reactant: [N-]=[N+]=NCC(O)CCOc1cccc(CN2CCCCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC(O)CCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A solution of 1-azido-4[3-(1-piperidinylmethyl)phenoxy]-2-butanol (10 g) in dry tetrahydrofuran (100 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (4 g) in tetrahydrofuran (200 ml) under nitrogen. The resulting mixture was stirred at room temperature for 1 h and quenched with water (4 ml), followed by 15% sodium hydroxide (4 ml) and water (12 ml). The mixture was then filtered and the residue washed with tetrahydrofuran (50 ml). The combined filtrate was evaporated to give the title compound (7.5 g) as a pale pink oil.
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]2([C:12]3([CH3:17])OCC[O:13]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>CC(C)=O.C1(C)C=CC=CC=1>[C:12]([C:9]1([CH2:8][S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][CH2:10]1)(=[O:13])[CH3:17]
Reactant: CC1(C2(CSc3ccccc3)CC2)OCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)C1(CSc2ccccc2)CC1
Temperature: 4 °C
Reaction time: 120 h
Yield: 1520.1 %

Procedure:
A mixture of 5 (7.23 g, 2.94 mmol) and pyridinium p-toluenesulfonate (0.74 g, 2.94 mmol) in acetone (150 mL) was stirred in a cold room at 4° C. for 5 days. The mixture was neutralized with sodium bicarbonate solution, and diluted with toluene. After evaporation of acetone, the residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, and dried over sodium sulfate. Filtration and concentration gave 9.22 g of an oily material, which was purified by column chromatography (silica gel 60 g, 4-16% ethyl acetate in n-hexane) to give 6.16 g (quantitative) of 6, as a pale yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([F:11])[CH:3]=1.[CH3:12][NH2:13]>>[F:11][C:4]1[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9]([NH:13][CH3:12])=[O:10]
Reactant: CN
Reactant: O=C=Nc1ccc(I)cc1F
Product: CNC(=O)Nc1ccc(I)cc1F
Reaction time: 0.5 h

Procedure:
A solution of 4-Iodo-2-fluorophenyl isocyanate (6-1, 5.15 g, 19.6 mmol) in Hexanes (80 ml) was treated with a solution of Methylamine (2M in THF, 9.8 mL, 19.6 mmol, 1.0 eq). A white precipitate formed as the mixture stirred at 23 deg C. for 30 min. The precipitate was collected via filtration and air dried, affording the title compound, N-(2-fluoro-4-iodophenyl)-N′-methylurea (6-2), as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.89 (t, 2H, J=8.6 Hz), 7.47-7.38 (m, 2H), 6.31 (bs, 1H), 4.58 (bs, 1H), 2.88 (d, 3H, J-4.9 Hz). LRMS m/z: Calc'd for C8H8FIN2O (M+H) 295.1, found 294.9.