Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Br[C:6]1[N:10]([C@@H:11]2[CH2:16][CH2:15][C@@H:14]([OH:17])[C@@H:13]([OH:18])[CH2:12]2)[C:9]2[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:8]=2[N:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH:1]([NH:4][C:6]1[N:10]([C@@H:11]2[CH2:16][CH2:15][C@@H:14]([OH:17])[C@@H:13]([OH:18])[CH2:12]2)[C:9]2[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:8]=2[N:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: O[C@@H]1CC[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)C[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)Nc1nc2cc(Cl)c(Cl)cc2n1[C@@H]1CC[C@@H](O)[C@@H](O)C1
Temperature: 100 °C
Yield: 8 %

Procedure:
Isopropylamine (99.5 mg, 1.68 mmol) was added to (±)-(1R*,2S*,4R*)-4-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)cyclohexane-1,2-diol (Example 49, part g, 64.0 mg, 168.4 mmol) in ethanol (3.4 ml) and the reaction was heated at 100° C. in a sealed tube for 67 hr. The reaction was cooled, saturated sodium carbonate added, extracted with ethyl acetate, dried with magnesium sulfate, and concentrated. The residue was purified by column chromatography eluting with methanol:ethyl acetate (1:19) to give the title compound (47.9 mg, 79%). Rf=0.24 (1:19 methanol:ethyl acetate); 1H-NMR (CD3OD, 300 MHz) δ7.46 (s, 1H), 7.31 (s, 1H), 4.44 (tt, 1H, J=13, 4), 4.11 (s, 1H), 4.05 (h, 1H, J=7), 3.82 (dt, 1H, J=10,4), 2.41 (dt, 1H, J=13,2), 2.26 (dq, 1H, J=13,4), 2.04-1.75 (m, 4H), 1.29 (d, 6H, J=6); MS (ES) M+H=358.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][SH:4].[H-].[Na+].CS(O[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=O)=O>CN(C=O)C.CCOC(C)=O>[F:1][C:2]([F:6])([F:5])[CH2:3][S:4][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]1
Reactant: FC(F)(F)CS
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CSCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
2,2,2-Trifluoroethane-1-thiol (0.151 mL, 1.636 mmol) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 0.065 g, 1.636 mmol) in anhydrous DMF (3 mL) at 0 C. A solution of tert-butyl 4-[(methanesulfonyloxy)methyl]piperidine-1-carboxylate (Intermediate 181, 0.320 g, 1.091 mmol) in DMF (4 mL) was then added dropwise and the reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with EtOAc (30 mL) and washed with a saturated aqueous solution of sodium bicarbonate (10 mL) followed by brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by FCC (EtOAc: heptane, 20:80) to provide the title compound as a colourless oil (0.288 g, 82%). Method B HPLC-MS: MH+ requires m/z=313 Found: m/z=257 (M minus tert-butyl), Rt=2.28 min (97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[C:14](=[O:15])[CH:13]=[CH:12][NH:11][CH:10]=2)=[CH:5][CH:4]=1.F[C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][N:20]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[I:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([N:11]2[CH:12]=[CH:13][C:14](=[O:15])[C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=3)=[CH:10]2)[CH:24]=1
Reactant: COc1ccc(COc2c[nH]ccc2=O)cc1
Reactant: Fc1cc(I)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(COc2cn(-c3cc(I)ccn3)ccc2=O)cc1
Temperature: 80 °C

Procedure:
A mixture of 3-[(4-methoxybenzyl)oxy]pyridin-4(1H)-one (7.30 g, 31.6 mmol), 2-fluoro-4-iodopyridine (10.56 g, 47.35 mmol), and K2CO3 (10.9 g, 79 mmol) in DMSO (80 mL) was heated at 80° C. overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), filtered and concentrated. The residue was washed with EtOAc and filtered, and the collected solid dried to give 4′-iodo-3-[(4-methoxybenzyl)oxy]-4H-1,2′-bipyridin-4-one. 1H-NMR (DMSO, 400 MHz) δ 8.41 (dd, J=8.0, 2.4 Hz, 1H), 8.30 (s, 1H), 8.20 (m, 2H), 7.81 (dd, J=4.0, 0.8 Hz, 1H), 7.35 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 6.28 (d, J=7.6 Hz, 1H), 4.96 (s, 2H), 3.72 (s, 3H). MS (M+H)+ 435.1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=[C:9]([NH2:16])[CH:8]=2)[CH2:3][CH2:2]1.[CH3:17][O:18][C:19]([C:21]1([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[CH2:23][CH2:22]1)=[O:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=[C:9]([NH:16][C:28]([C:27]3[CH:26]=[CH:25][C:24]([C:21]4([C:19]([O:18][CH3:17])=[O:20])[CH2:22][CH2:23]4)=[CH:32][CH:31]=3)=[O:29])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)C1(c2ccc(C(=O)O)cc2)CC1
Reactant: Nc1cc(N2CCOCC2)n2nccc2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Product: COC(=O)C1(c2ccc(C(=O)Nc3cc(N4CCOCC4)n4nccc4n3)cc2)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 34.2 %

Procedure:
7-Morpholinopyrazolo[1,5-a]pyrimidin-5-amine (9A, 110 mg, 0.50 mmol) and 4-(1-(methoxycarbonyl)cyclopropyl)benzoic acid (110 mg, 0.50 mmol) were mixed in pyridine (3 ml). TBTU (160 mg, 0.50 mmol) was then added and the mixture was heated to 80° C. for 15 hours. After cooling to room temperature, additional TBTU (53 mg, 0.17 mmol) was added before the heating continued for another 6 hours. After cooling to room temperature, the reaction mixture was quenched with water and was then concentrated to dryness in vacuo. The crude product was purified by preparatory HPLC (35-55% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white powder (72 mg, 35% yield). 1H NMR (400 MHz, DMSO-d6) δ=11.00 (s, 1H), 8.10 (d, J=2.3 Hz, 1H), 7.99 (d, J=8.3 Hz, 2H), 7.49 (d, J=8.3 Hz, 2H), 7.41 (s, 1H), 6.38 (d, J=2.3 Hz, 1H), 3.88-3.82 (m, 4H), 3.78-3.70 (m, 4H), 3.57 (s, 3H), 1.56-1.50 (m, 2H), 1.30-1.24 (m, 2H); ESI-MS: m/z 422.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:28])[CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:4][CH:3]=1.[C:29]([O:33]C)(=[O:32])[CH:30]=[CH2:31]>CO.C(COC)OC>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:14]=[CH:13][CH2:12][C:11]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:10](=[O:28])[CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:31][CH2:30][C:29]([OH:33])=[O:32]
Reactant: C=CC(=O)OC
Reactant: Cc1ccccc1C=CCC(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Solvent: COCCOC
Solvent: CO
Product: Cc1ccccc1C=CCC(CCC(=O)O)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Reaction time: 24 h

Procedure:
Triton B (1 ml., 40% in MeOH) is added to a stirred soluton of 1-(p-chlorophenyl)-4-phenyl-7-(o-methylphenyl)-1,6-heptadien-3-one (15.47 g., 0.04 mole) in glyme (150 ml.), followed by addition of methyl acrylate (4.13 g., 0.048 mole) in glyme (25 ml.). After stirring for 24 hours, the solvent is removed in vacuo, and water (600 ml.) and dilute hydrochloric acid (25 ml.) are added to the residue. The organic material is extracted into ether and these extracts are washed with water, saturated brine and dried (Na2SO4). After removal of the solvent, the residue is heated on a steam bath with a solution of 20% sodium hydroxide (25 ml.) in methanol (300 ml.) for 20 hours. The methanol is removed in vacuo and the residue is dissolved in water (1200 ml.). Extraction with ether removes unreacted ketone. Ether is expelled from the aqueous phase by warming. The solution is cooled in an ice bath, acidified with dilute hydrochloric acid (30 ml.), and the yellowish solid that precipitates is filtered and air-dried; yield 12.85 g., m.p. 60°-80°C. (glass). Several recrystallizations from n-butyl chloride, followed by a final recrystallization and ethanol gives material with m.p. 163.5°-165°C. Anal. Calcd. for C29H27ClO3 : C, 75.89; H, 5.93; Found: C, 75.67; H, 5.76.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[F:18])[CH:3]=[CH:2]1.[C:19]1([CH2:25][C:26]([N:28]=[C:29]=[S:30])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:29]([NH:28][C:26](=[O:27])[CH2:25][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[S:30])=[CH:13][C:12]=2[F:18])[CH:3]=[CH:2]1
Reactant: Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
A mixture of 268 (20 mg, 0.08 mmol) and 2-phenylacetyl isothiocyanate (16 □L, 0.08 mmol) in THF (1 mL) was stirred at room temperature for 2 hours and concentrated. The residue was purified by flash column chromatography (eluent EtOAc) followed by preparative HPLC (column Aqusil C18, gradient elution with 60-95% MeOH in water, 45 min) to afford the title compound 269a (13 mg, 40% yield) as an off-white solid. 1H NMR (CD3OD) δ (ppm): 8.41 (s, 1H), 8.16 (d, 1H, J=5.6 Hz), 8.02 (dd, 1H, J1=2.3Hz, J2=12.2 Hz), 7.62 (d, 1H, J=3.3 Hz), 7.44 (m, 1H), 7.37-7.33 (m, 4H) 7.31-7.26 (m, 1H), 6.65(d, 1H, J=3.1 Hz), 6.52(d, 1H, J=5.7 Hz), 3.76 (s, 2H), MS (m/z): 421.1 (M+H) (found).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([C:15]([O:17]C)=O)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][N:8]=1.[NH3:19]>CO>[CH3:1][NH:2][C:3]1[C:4]([C:15]([NH2:19])=[O:17])=[N:5][C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][N:8]=1
Reactant: CNc1ncc(-c2ccccc2)nc1C(=O)OC
Reactant: N
Solvent: CO
Product: CNc1ncc(-c2ccccc2)nc1C(N)=O
Temperature: 82.5 °C
Yield: 25 %

Procedure:
A solution of of methyl 3-(methylamino)-6-phenylpyrazine-2-carboxylate (31 mg, 0.13 mmol) in methanol (5 ml) was saturated with ammonia at 0° C. The pressure tube was sealed and heated at 80-85° C. overnight. The reaction was cooled to room temperature and the solvent removed at reduced pressure to afford crude solid product. Reverse-phase BPLC purification gave 3-(methylamino)-6-phenylpyrazine-2-carboxamide (7 mg, 25% yield) as a yellow solid: 1H NM (400 MHz, CDCl3): δ 8.42 (s, 1H), 8.50 (br s, 1H), 7.90 (d, 3H), 7.45 (m, 2H), 7.40 (m, 1H), 3.10 (br s, 3H); MS (EI) for C12H12N40: 229 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25]>C1C=CC=CC=1>[C:22]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)(=[O:26])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC(=O)Cl
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1
Reaction time: 0.03 h

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 4.0 ml. of absolute pyridine and cooled to -10° with stirring. 0.255 G. of butyric acid chloride are added dropwise thereto over a period of 2 minutes. The temperature rises to 0° and pyridine hydrochloride precipitates out. Subsequently, the mixture is stirred overnight at room temperature and the suspension poured on to a mixture of 12 g. of ice and 12 ml. of 20% hydrochloric acid. Thereafter, this mixture is extracted three times with ethyl acetate, washed with water, dried over sodium sulfate and evaporated in vacuum. The 0.552 g. of yellowish crystals obtained as the residue are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.521 g. of yellowish crystals which are recrystallized from acetone-hexene up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl butyrate obtained melts at 77.9°-78.2° and is liquid crystalline (monotrope) upon cooling to 74.7°. UV (EtOH): ε 272 = 26100.
Reaction SMILES: C([O:4]N([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(O)=O)C(C)=C1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C.[CH2:35]([O:38][N:39]([C@H:52]1[CH2:57][N:56]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:55]([CH2:65][OH:66])[C:54]([CH:67]([CH3:69])[CH3:68])=[CH:53]1)[S:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[N+:49]([O-:51])=[O:50])(=[O:42])=[O:41])[CH:36]=[CH2:37]>>[CH2:35]([O:38][N:39]([C@H:52]1[CH2:57][N:56]([C:58]([O:60][C:61]([CH3:62])([CH3:63])[CH3:64])=[O:59])[C@H:55]([C:65]([OH:4])=[O:66])[C:54]([CH:67]([CH3:69])[CH3:68])=[CH:53]1)[S:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[N+:49]([O-:51])=[O:50])(=[O:42])=[O:41])[CH:36]=[CH2:37]
Reactant: C=CCON([C@@H]1C=C(C)[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCON([C@@H]1C=C(C(C)C)[C@@H](CO)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@@H]1C=C(C(C)C)[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 87.76 %

Procedure:
((2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)-3-isopropyl-1,2,5,6-tetrahydropyridine-2-carboxylic acid (0.595 g, 87.76%) was prepared a similar manner as described in Intermediate 82 as a yellow oil, using (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-(hydroxymethyl)-3-isopropyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 92, 660 mg, 1.29 mmol) as a starting material.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:8]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)=[N:7][NH:6][C:5](=[O:21])[CH2:4]1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:22]([O:1][CH2:2][CH:3]1[C:8]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)=[N:7][NH:6][C:5](=[O:21])[CH2:4]1)(=[O:24])[CH3:23]
Reactant: CN1C(=O)CCc2cc(C3=NNC(=O)CC3CO)ccc21
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)OCC1CC(=O)NN=C1c1ccc2c(c1)CCC(=O)N2C
Yield: 46.8 %

Procedure:
A solution of 13.6 g of 6-(5-hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one, 5.8 g of acetic anhydride and 10 ml of triethylamine in 300 ml of chloroform was heated under reflux on a water bath for 3 hours. The reaction mixture was washed with water, dried over potassium carbonate and concentrated under reduced pressure. The residue was dissolved into a small amount of ethyl acetate. After the solution was allowed to stand, the precipitated crystals were filtered off and recrystallized from isopropanol to give 7.3 g of 6-(5-acetoxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one as needles, melting at 149°-153° C.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[F:23]>>[Cl:16][C:17]1[CH:18]=[C:19]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[C:10]([F:11])[C:5]3=[N:4][CH:3]=2)[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Yield: 85 %

Procedure:
2-(3-Bromo-8-fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol and 3-chloro-4-fluorobenzeneboronic acid were coupled together as described in Example 1 to give 2-[3-(3-chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as a white solid (7.10 g, 85%): δH (400 MHz, CDCl3) 1.74 (6H, s), 2.08 (1H, s), 7.21 (1H, t, J 7), 7.31 (1H, t, J 9), 7.40-7.44 (1H, m), 7.60 (1H, dd, J 7 and 2), 7.67 (1H, s), 8.01 (1H, d, J 7); m/z (ES+) 323 [MH+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].C[O:18][C:19]([C:21]1[N:22]=[C:23]([C:39]#[N:40])[C:24]2[C:29]([C:30]=1[OH:31])=[CH:28][CH:27]=[C:26]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:25]=2)=O.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[C:1]([O:5][C:6](=[O:16])[CH:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:8][NH:9][C:19]([C:21]1[N:22]=[C:23]([C:39]#[N:40])[C:24]2[C:29]([C:30]=1[OH:31])=[CH:28][CH:27]=[C:26]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:25]=2)=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)(C)OC(=O)C(CN)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)C(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)c1ccccc1
Temperature: 150 °C
Yield: 72.5 %

Procedure:
A mixture of 3-amino-2-phenyl-propionic acid tert-butyl ester (108 mg), 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (52 mg) and DBU (0.036 mL) in DMA (0.5 mL) was heated in an oil bath (150° C.) for 1.5 h. After cooling, the reaction mixture was partitioned between EtOAc and diluted HCl solution; EtOAc phase was separated and washed with water, diluted NaCl solution respectively and dried over anhydrous sodium sulfate solution, filtered, concentrated and silica gel column purified to give desired product as brown solid (60 mg). LC-MS ESI+: 510 (M+1)+.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[NH:7][CH:8]=[CH:9][N:10]=1)[CH3:3].C(N(CC)CC)C.[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:18]([N:7]1[CH:8]=[CH:9][N:10]=[C:6]1[N:5]=[CH:4][N:2]([CH3:3])[CH3:1])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(C)C=Nc1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C=Nc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the crude 2-[dimethylamino)methylene]aminoimidazole (2) was added methylene chloride (750 mL), triethylamine (98 mL, 700 mmol) and trityl chloride (62.98 g, 226 mmol) (Aldrich). The reaction mixture was stirred at room temperature for 3 hrs. Solvent was removed in vacuo and the crude 3 was crystallized from methanol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][N:16]([C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[C:34]([C:39]([OH:41])=O)=[CH:35][CH:36]=[CH:37][CH:38]=5)=[CH:29][CH:28]=4)=[O:26])[C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.[CH3:42][NH:43][CH3:44].O1CCCC1>CN1CCCC1=O>[CH3:42][N:43]([CH3:44])[C:39]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:30]1[CH:29]=[CH:28][C:27]([C:25]([N:16]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][N:20]3[C:11]([C:9]([NH:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:10])=[CH:12][CH:13]=[C:14]3[CH2:15]2)=[O:26])=[CH:32][CH:31]=1)=[O:41]
Reactant: CNC
Reactant: O=C(O)c1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 4′-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}-1,1′-biphenyl-2-carboxylic acid of Example 65 (92 mg, 0.17 mmol) in 1-methyl-2-pyrrolidinone (4.5 mL) was added a 2.0 M solution of dimethylamine in tetrahydrofuran (0.42 mL, 0.848 mmol) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,tetramethyluronium hexafluorophosphate (71 mg, 0.187 mmol) and the reaction mixture stirred at room temperature under nitrogen for 2 hours. The reaction mixture was then partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The organic phase was separated, washed with 2 M sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a white foam. Purification by flash chromatography using a solvent gradient of 1 to 7% methanol in dichloromethane gave a colorless glass that was crystallized from ethyl acetate/hexane to afford the title compound 0.082 g, 85%) as a white solid, m.p. 206-207° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:8]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[O:8]1[CH:12]=[CH:11][C:10]([CH2:13][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9]1
Reactant: O=Cc1ccoc1
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: c1ccc(NCc2ccoc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
A mixture of aniline (1.89 g, 19.6 mmol) and 3-furaldehyde (2.50 g, 26.8 mmol) in 1,2-dichloroethane (100 mL) under argon at 5° was treated with sodium triacetoxyborohydride (5.65 g, 26.8 mmol) and acetic acid (1.5 mL). The reaction mixture was stirred at room temperature overnight, concentrated in vacuo and the residue was diluted with ethyl acetate. The combined extracts were washed with satuirated sodium bicarbonate, dried over MgSO4 and concentrated. The product was purified by flash chromatography on silical gel (Hexane/EtOAc (20:1) to yield the title compound (3.31 g, 98%). Analysis calculated for C11H11NO: C, 76.28; H, 6.40; N, 8.09. Found: C, 76.58; H, 6.46; N, 8.33.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[C:5]([CH:12]=[O:13])=[CH:4]1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[C:14]1([S:20]([N:3]2[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:6]3[C:5]([CH:12]=[O:13])=[CH:4]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cn(S(=O)(=O)c2ccccc2)c2ncccc12
Temperature: 0 °C

Procedure:
Into a 100 ni 3-necked round bottom flask was placed tetrahydrofuran (50 mL). To the above was added NaH (2.19 g, 54.75 mmol) in several batches, while cooling to a temperature of 0° C. This was followed by the addition of a solution of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (2 g, 13.70 mmol) in tetrahydrofuran (400 mL), which was added dropwise with stirring, while cooling to a temperature of 0° C. The resulting solution was allowed to react, with stirring, for 30 minutes while the temperature was maintained at room temperature. This was followed by the addition of a solution of benzenesulfonyl chloride (3.63 g, 20.55 mmol) in tetrahydrofuran (50 mL), which was added dropwise with stirring, while cooling to a temperature of 0° C. The resulting solution was allowed to react, with stirring, for 3 hours while the temperature was maintained at room temperature. The reaction mixture was then quenched by the adding of H2O. The mixture was concentrated by evaporation under vacuum using a rotary evaporator. The residue was dissolved in 300 mL of ethyl acetate. The resulting mixture was washed two times with 200 mL of brine and the organic layers combined. The mixture was dried over Na2SO4 and concentrated by evaporation under vacuum using a rotary evaporator. The resulting mixture was washed with ethyl acetate/petroleum ether=1:40. This resulted in 3.4 g (82%) of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde as a light yellow solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].S(Cl)([Cl:19])(=O)=O>CCCCCCC>[Cl:19][C:2]([CH3:15])([CH3:1])[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)C(=O)c1cccc2ccccc12
Reactant: O=S(=O)(Cl)Cl
Solvent: CCCCCCC
Product: CC(C)(Cl)C(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-Methyl-1-(1-naphthalenyl)-1-propanone (30.0 g, 0.15 mole) was dissolved in heptane (10 ml), and sulfuryl chloride (30 g, 0.22 mole) was added at once. After about 5 min gas evolution occurred. After 3 h of stirring at room temperature the reaction mixture was concentrated. The concentrate was dissolved in heptane (200 ml) and washed with 150 ml of a 2 wt % aqueous sodium bicarbonate solution. After drying over magnesium sulfate the solvent was removed under reduced pressure. The yield of 2-chloro-2-methyl-1-(1-naphthalenyl)-1-propanone was 34.5 g or 98%.