Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=O)=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]C#N)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:21][N:19]=[C:16]3[CH:15]=[CH:14][C:13]([C:12]4[N:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[N:9]=[CH:10][CH:11]=4)=[CH:18][C:17]=23)=[CH:25][CH:24]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccccc2F)cc1
Product: Fc1ccccc1-n1nccc1-c1ccc2noc(-c3ccc(Cl)cc3)c2c1

Procedure:
The title compound, light yellow solid (96 mg, 70%), MS (ISP) m/z=390.2 [(M+H)+], mp 191° C., was prepared in accordance with the general method of example 1 from 1-(2-fluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate B) (100 mg, 353 μmol) and commercially available 2-(4-chloro-phenyl)-acetonitrile.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[N:22][C:21](Cl)=[CH:20][N:19]=3)=[O:17])[CH:12]=[CH:11][C:9]=2[N:10]=1.[Cl:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1B(O)O>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[N:22][C:21]([C:29]4[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:28]=4[Cl:27])=[CH:20][N:19]=3)=[O:17])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: CN(C)CCN(C)c1nc2ccc(NC(=O)c3cnc(Cl)cn3)cc2s1
Reactant: COc1ccc(B(O)O)c(Cl)c1
Product: COc1ccc(-c2cnc(C(=O)Nc3ccc4nc(N(C)CCN(C)C)sc4c3)cn2)c(Cl)c1

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using 5-chloro-pyrazine-2-carboxylic acid {2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-amide (0.10 g, 0.26 mmol) and 2-chloro-4-methoxy-phenyl boronic acid (0.057 g, 0.31 mmol) to afford 0.062 g (48%). LC/MS, Retention time=4.89 nm in; (m/z): calcd for C24H25ClN6O2S: 497.0; found: 499.0.
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[CH3:30][O:31][CH2:32][CH2:33][CH2:34][N:35]1[C:39]2[CH:40]=[C:41](B3OC(C)(C)C(C)(C)O3)[CH:42]=[CH:43][C:38]=2[O:37][C:36]1=[O:53].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:41]2[CH:42]=[CH:43][C:38]3[O:37][C:36](=[O:53])[N:35]([CH2:34][CH2:33][CH2:32][O:31][CH3:30])[C:39]=3[CH:40]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Reactant: COCCCn1c(=O)oc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COCCCn1c(=O)oc2ccc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cc21
Temperature: 85 °C
Yield: 36.1 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 363 mg) and 3-(3-methoxypropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (Example 11, step (ii), 234 mg) in acetonitrile (8 mL) were treated with aqueous sodium carbonate (2M, 0.70 mL) and nitrogen was bubbled through the mixture. 1,1 bis(Di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added and the mixture was heated at 85° C. for 18 h. The mixture was purified by chromatography on silica eluting with 50-100% ethyl acetate/isohexane to yield the sub-titled compound (151 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH:10]=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH2:23]([O:25][CH2:26][CH2:27]Br)[CH3:24].O>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH:8]=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:24][CH2:23][O:25][CH2:26][CH3:27])[CH:13]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOCCBr
Reactant: CCOC(=O)N1CC=C(c2c[nH]c3ncccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCn1cc(C2=CCN(C(=O)OCC)CC2)c2cccnc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.30 g (4.76 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid ethyl ester were dissolved in 11 ml of DMF and, at room temperature, 0.25 g (5.6 mmol) of 60% sodium hydride were carefully added. This mixture was stirred for half an hour at room temperature. 0.75 ml (6.0 mmol) of 2-bromoethyl ethyl ether were dropwise added and the stirring was continued for 24 hours at 60° C. The reaction mixture was cooled to room temperature and poured over cold water. This aqueous phase was extracted twice with dichloromethane and the organic phase was washed with water and brine, dried with magnesium sulphate, filtered and evaporated to dryness. The 1.46 g (74% of yield) of crude material were pure enough for the next synthetic step.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][CH:4]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=1)[NH:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([CH3:16])[CH:10]=2.Cl.[CH3:28][O:29][C:30](=[O:34])[CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CCOC(C)=O>[CH3:28][O:29][C:30](=[O:34])[CH2:31][CH2:32][NH:33][C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([CH:4]([NH:5][C:6]2[CH:7]=[N:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[C:11]([CH3:16])[CH:10]=3)[CH2:3][CH:2]([CH3:26])[CH3:1])=[CH:25][CH:24]=1
Reactant: COC(=O)CCN
Reactant: Cc1ccc2cc(NC(CC(C)C)c3ccc(C(=O)O)cc3)cnc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Nc2cnc3cc(C)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
To a solution of 4-[3-Methyl-1-(7-methyl-quinolin-3-ylamino)-butyl]-benzoic acid (44 mg, 0.13 mM) in DCM (1 mL) was added TEA (63.6 mg, 0.629 mM) and followed by 3-amino-propionic acid methyl ester hydrochloric acid (6) (26.4 mg, 0.189 mM) and then HBTU (57.3 mg, 0.151 mM). The reaction was stirred at RT for 16 h. The reaction mixture was diluted with EtOAc (5 mL) and washed with water (2×2 mL). The organic layer was separated, dried over Na2SO4 and concentrated. The crude material was separated by a 12 g silica gel column with 10-100% EtOAc in heptane to afford desired product (49 mg, 90%). 1H NMR (500 MHz, CDCl3) 6 ppm 0.98 (d, J=6.10 Hz, 3H) 1.04 (d, J=6.34 Hz, 3H) 1.61-1.70 (m, 1H) 1.71-1.86 (m, 2H) 2.66 (t, 2H) 2.82 (s, 3H) 3.68-3.76 (m, 5H) 4.36 (d, J=4.88 Hz, 1H) 4.44-4.54 (m, 1H) 6.73 (d, J=2.20 Hz, 1H) 6.80 (t, J=5.49 Hz, 1H) 7.20 (d, J=8.29 Hz, 1H) 7.35 (d, J=8.54 Hz, 1H) 7.45 (d, J=8.29 Hz, 2H) 7.67 (s, 1H) 7.75 (d, 2H) 8.45 (d, J=2.44 Hz, 1H). LC-MS: 434.2 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].Cl.[CH3:27][O:28][CH2:29][CH:30]1[CH2:35][NH:34][CH2:33][CH:32]([CH2:36][O:37][CH3:38])[N:31]1[CH3:39].C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:38][O:37][CH2:36][CH:32]1[N:31]([CH3:39])[CH:30]([CH2:29][O:28][CH3:27])[CH2:35][N:34]([CH2:2][C:3]([NH:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([NH:14][C@H:15]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH2:17][CH2:16]4)[O:12][CH2:13][C:8]=3[CH:7]=2)=[O:4])[CH2:33]1
Reactant: COCC1CNCC(COC)N1C
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCC1CN(CC(=O)Nc2ccc3c(c2)COC(N[C@@H]2CCc4ccccc42)=N3)CC(COC)N1C
Yield: 10.5 %

Procedure:
Prepared from 2-chloro-N-[2-((R)-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 3 step A) (100 mg, 0.281 mmol), the above described (2SR,6SR)-2,6-bis-methoxymethyl-1-methyl-piperazine hydrochloride (69.5 mg, 0.309 mmol) and diisopropylethyl amine (144 ul, 0.843 mmol) in acetonitrile (2 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a light yellow solid (15 mg, 11%), MS (ISP) m/e=508.4 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CC(C)N=C=NC(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:39][CH2:38][C:37]2[C:36]3[C:35]([Cl:40])=[C:34]([Cl:41])[CH:33]=[CH:32][C:31]=3[N:30]([CH2:42][C:43](O)=[O:44])[C:29]=2[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[Cl:41][C:34]1[CH:33]=[CH:32][C:31]2[N:30]([CH2:42][C:43]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:44])[C:29]3[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[CH2:39][CH2:38][C:37]=3[C:36]=2[C:35]=1[Cl:40]
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3ccc(Cl)c(Cl)c23)CC1
Reactant: COc1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)Cn2c3c(c4c(Cl)c(Cl)ccc42)CCN(C(=O)OC(C)(C)C)CC3)cc1
Reaction time: 4 h
Yield: 37 %

Procedure:
DMAP (89 mg, 0.73 mmol), p-anisidine (0.10 g, 0.81 mmol) and DIC (0.13 mL, 0.81 mmol) were added to the solution of crude [3-(tert-butoxycarbonyl)-9,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.30 g, 0.73 mmol) in dry THF (3.5 mL). After 4 h, additional p-anisidine (45 mg, 0.37 mmol) was added. The reaction was diluted with EtOAc after another 17 h and washed with 10% aqueous citric acid (20 mL), saturated aqueous NaHCO3 (20 mL), and brine (20 mL). The organic layer was then dried over Na2SO4, decanted, and concentrated impure product. It was then crystallized from EtOAc/heptane, triturated with pentane, and recrystallized from EtOAc/heptane to give 0.14 g (36%) of a white solid: mp 143.0-144.0° C.; 1H NMR (300 MHz, DMSO) δ 10.30 (s, 1H), 7.47 (m, 3H), 7.25 (d, J 8.7 Hz, 1H), 6.88 (d, J=9.0 Hz, 2H), 5.04 (br s, 2H), 3.71 (s, 3H), 3.63 (m, 4H), 3.39 (m, 2H), 2.99 (m, 2H), 1.40 (app d, 9H); IR (diffuse reflectance) 2975, 1666, 1545, 1514, 1474, 1451, 1414, 1365, 1253, 1239, 1222, 1173, 1158, 830, 784 cm1; MS (EI) m/z 517 (M+), 377, 375, 227, 224, 212, 134, 124, 121, 55, 53; MS (FAB) m/z 518 (M+H+), 520, 519, 518, 517, 464, 463, 462, 461, 418, 57; HRMS (EI) calcd for C26H29Cl2N3O4 517.1535, found 517.1537; Anal. Calcd for C26H29Cl2N3O4: C, 60.24; H, 5.64; N, 8.10; found: C, 59.86; H, 5.68; N, 7.94.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9](=[O:23])[NH:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.O[C@H:25]([C@H:27]1[CH2:31][N:30]([C@@H:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH3:33])[C:29](=[O:42])[CH2:28]1)[CH3:26].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(Cl)Cl>[CH:1]1([N:4]2[C:8]3[C:9]([O:23][C@@H:25]([C@H:27]4[CH2:31][N:30]([C@@H:32]([C:34]5[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=5)[CH3:33])[C:29](=[O:42])[CH2:28]4)[CH3:26])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COc1ccc(-c2cc3ncn(C4CC4)c3c(=O)[nH]2)cc1OC
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)O)CC2=O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(-c4ccc(OC)c(OC)c4)cc4ncn(C5CC5)c34)CC2=O)cc1
Temperature: 40 °C
Reaction time: 15 h

Procedure:
3-cyclopropyl-6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4 (5H)-one 2.37 (48.9 mg, 0.157 mmol), lactam alcohol 1.05 (63 mg, 0.24 mmol), and PPh3 (63 mg, 0.24 mmol) were taken up in THF (1.6 mL). To the resulting suspension was added DEAD (38 μL, 0.24 mmol) dropwise. The resulting mixture was heated to 40° C. and stirred 15 h. The solution was then diluted with DCM and concentrated directly onto silica gel. Purification by silica gel chromatography (35% to 55% to 65% to 100% acetone in hexanes) gave (R)-4-((R)-1-(3-cyclopropyl-6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.38.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([CH3:14])=[C:7](Cl)[C:6]=1[N+:16]([O-:18])=[O:17])[CH2:2][CH3:3].[NH3:22]>>[CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[C:5]1[C:6]([N+:16]([O-:18])=[O:17])=[C:7]([NH2:22])[C:8]([CH3:14])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH2:2][CH3:3]
Reactant: CCCN(CCC)c1c([N+](=O)[O-])cc(C)c(Cl)c1[N+](=O)[O-]
Reactant: N
Product: CCCN(CCC)c1c([N+](=O)[O-])cc(C)c(N)c1[N+](=O)[O-]

Procedure:
This compound was prepared in a similar manner by reaction of N,N-di-n-propyl-3-chloro-2,6-dinitro-4-methylaniline with ammonia. The crystalline product melts at 126°-127°C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(Cl)(Cl)(=O)=O.[CH2:29]([NH2:31])[CH3:30]>C1COCC1>[CH2:29]([NH:31][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3])[CH3:30]
Reactant: CCOC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN
Solvent: C1CCOC1
Solvent: O=S(=O)(Cl)Cl
Product: CCNS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)OCC)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Ethyl(4-nitrophenyl)acetate (25.0 g, 119.5 mmol) was alkylated with 4-iodomethyltetrahydropyran (32.4 g, 143.4 mmol), according to the protocol described in Preparation 41, to give ethyl 2-(4-nitrophenyl)-3-(tetrahydropyran-4-yl)propionate: δH (CDCl3): 1.21 (3H, t), 1.25-1.45 (3H, m), 1.55-1.65 (2H, m), 1.70-1.80 (1H, m), 2.05-2.15 (1H, m), 3.25-3.35 (2H, m), 3.79 (1H, t), 3.90-3.95 (2H, m), 4.10-4.20 (2H, m), 7.49 (2H, d), 8.19 (2H, d). The nitro group of this compound (6.55 g, 18.1 mmol) was reduced utilising the procedure described in EXAMPLE 145 to give ethyl 2-(4-aminophenyl)-3-(tetrahydropyran-4-yl)propionate: m/z (ES+)=278.2 [M+H]+. This compound (30.5 g, 110 mmol) was transformed into ethyl 2-(4-chlorosulfonylphenyl)-3-(tetrahydropyran-4-yl)propionate employing the protocol described in Preparation 59. A solution of this sulfonyl chloride (33.6 g, 93.2 mmol) in anhydrous THF (100 mL) was added over 30 min at 0° C. to EtNH2 (116.5 mL of a 2.0M solution in THF, 233.0 mmol). The mixture was warmed up to 20° C., before being stirred for 16 h. The suspension was filtered through a Celite pad, which was washed with THF (3×50 mL). The combined THF solutions were concentrated to furnish crude ethyl 2-(4-ethylsulfamoylphenyl)-3-(tetrahydropyran-4-yl)propionate: m/z (ES+)=370.2 [M+H]+. Hydrolysis of this ester (33.7 g, 91.2 mmol), utilising the procedure outlined in Preparation 41, followed by purification via RP-HPLC afforded the title compound: m/z (ES+)=342.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:22]=[N:21][C:7]2[N:8]([CH2:19][CH3:20])[C:9]3[N:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=3[NH:11][C:12](=[O:13])[C:6]=2[CH:5]=1.O.[CH3:24]N(C=O)C>>[Br:3][C:4]1[CH:22]=[N:21][C:7]2[N:8]([CH2:19][CH3:20])[C:9]3[N:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=3[N:11]([CH3:24])[C:12](=[O:13])[C:6]=2[CH:5]=1
Reactant: CN(C)C=O
Reactant: CCN1c2nc(Cl)ccc2NC(=O)c2cc(Br)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCN1c2ncc(Br)cc2C(=O)N(C)c2ccc(Cl)nc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Solid NaH (60% oil dispersion, 3.46 g, 86.1 mmol) was added over 30 min to a solution of 8-bromo-2-chloro-5,11-dihydro-11-ethyl-6H-dipyrido[3,2-b:2′,3′-e] [1,4]diazepin-6-one (23.4 g, 66.3 mmol) in DMF (220 mL) at 50° C. The mixture was stirred at 50° C. for 1 h then was allow to cool to room temperature. The mixture was poured into water (1 L) and the resulting suspension was filtered. The solid was successively washed with water and hexane then dried under reduced pressure to give the title compound (23.0 g, 94% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Cl[CH2:12][C:13]1[S:14][CH:15]=[CH:16][C:17]=1[CH3:18].O>CN(C)C=O>[NH2:1][C:2]1[C:7]([O:8][CH2:12][C:13]2[S:14][CH:15]=[CH:16][C:17]=2[CH3:18])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccsc1CCl
Reactant: Nc1ncccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccsc1COc1cccnc1N
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
To a solution of 2-amino-3-hydroxypyridine (15.18 g) in N,N-dimethylformamide (150 ml) was added portionwise a 60% dispersion of sodium hydride in mineral oil (6.06 g) with ice-cooling and stirring over a period of 10 minutes. After being stirred at 0°-5° C. for 30 minutes and then at ambient temperature for 1 hour, a solution of 2-chloromethyl-3-methylthiophene (23.9 g) in N,N-dimethylformamide (10 ml) was added dropwise to the reaction mixture. The mixture was stirred at ambient temperature for 20 hours and poured into water. The resulting precipitate was collected by filtration and dissolved in methylene chloride. The solution was treated with activated charcoal and evaporated in vacuo. The residue was crystallized from diethyl ether to give 2-amino-3-(3-methyl-2-thienylmethoxy)pyridine (23.6 g).
Reaction SMILES: [F:1][CH:2]([F:37])[O:3][C:4]1[CH:36]=[CH:35][CH:34]=[CH:33][C:5]=1[CH2:6][C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[CH:17]=[N:18][C:19]([N:22]4[CH2:26][CH2:25][CH:24]([C:27]([O:29]CC)=[O:28])[CH2:23]4)=[N:20][CH:21]=3)[CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[CH3:32].[OH-].[Na+]>C1COCC1.O>[F:37][CH:2]([F:1])[O:3][C:4]1[CH:36]=[CH:35][CH:34]=[CH:33][C:5]=1[CH2:6][C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[CH:21]=[N:20][C:19]([N:22]4[CH2:26][CH2:25][CH:24]([C:27]([OH:29])=[O:28])[CH2:23]4)=[N:18][CH:17]=3)[CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[CH3:32]
Reactant: CCOC(=O)C1CCN(c2ncc(-c3ccc4nc(C)c(Cc5ccccc5OC(F)F)n4c3)cn2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2ccc(-c3cnc(N4CCC(C(=O)O)C4)nc3)cn2c1Cc1ccccc1OC(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.1 %

Procedure:
To a solution of Example 280 (0.11 g, 0.22 mmol) in THF (12 mL) and water (4 mL) was added 1M aqueous NaOH solution (0.22 mL). The resulting mixture was stirred for 18 h at r.t. and concentrated in vacuo. The crude residue was purified by preparative HPLC to afford the title compound (18 mg, 17%) as a white solid. HPLC-MS (pH 10): m/z 480.8 [M+H]+, RT 1.37 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[OH:20].[CH3:26]I>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[CH:14][C:9]=2[N:8]([CH3:26])[C:7]1=[O:20]
Reactant: CCOC(=O)c1ccc2nc(O)n(NCc3ccc(Cl)cc3Cl)c2c1
Reactant: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)n(NCc1ccc(Cl)cc1Cl)c(=O)n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
Sodium hydrite (0.080 g, 60% suspension in oil) was added to a solution of 1-(2,4-dichlorobenzylamino)-2-hydroxy-6-(ethoxycarbonyl)benzimidazole (0.396 g) in N,N′-dimethylformamide (4 ml), and the mixture was stirred at room temperature for 1 hr. Methyl iodide (0.307 g) was added, and the mixture was stirred for 2 hr. The precipitated crystals were collected by filtration, washed with water and ethanol and dried to give the objective compound (0.348 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:9]=2[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18]([O:20]CC)=[O:19])[NH:6]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CO.O>[CH3:1][C:2]1[C:10]2[S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:9]=2[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18]([OH:20])=[O:19])[NH:6]2
Reactant: CCOC(=O)c1cc2c(C)c3sc4ccccc4c3cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: Cc1c2cc(C(=O)O)[nH]c2cc2c1sc1ccccc12
Temperature: 25 °C

Procedure:
Ethyl 4-methyl-1H-[1]-benzothieno[2,3-f]indole-2-carboxylate (1.0 g, 3.2 mmol) was suspended in a mixture of methanol (110 ml) and water (30 ml). Caesium carbonate (10 g) was added and the mixture was heated at reflux under nitrogen for 2 h. The solution was allowed to cool to room temperature, and the methanol was removed in vacuo. The solution was acidified with 0.1 Molar Hydrochloric acid and the resulting yellow precipitate was collected by filtration and washed with water. The wet precipitate was dissolved in acetone and the solvent removed in vacuo to give the product as a yellow solid with m.p. 271-272° C.; δH [2H6 ]-DMSO 11.88 (1H, s, 1-NH), 8.29 (1H, dd, J 6, 3, 9-H), 8.18 (1H, s, 10-H), 7.89-7.99 (1H, m, 6-H), 7.44-7.54 (2H, m, 7-H, 8-H), 7.35 (1H, d, J 2, 3-H), 2.72 (3H, s, 4-CH3), m/z (%) 281 (90, M+), 263 (100) 235 (69).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:35])([CH2:28][N:29]1[C:33](=[S:34])[NH:32][N:31]=[N:30]1)[C:10]([C:13]1[N:18]=[CH:17][C:16]([O:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)([F:12])[F:11].[H-].[Na+].N#N.[CH3:40]I>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:35])([CH2:28][N:29]1[C:33]([S:34][CH3:40])=[N:32][N:31]=[N:30]1)[C:10]([C:13]1[N:18]=[CH:17][C:16]([O:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=2)=[CH:15][CH:14]=1)([F:12])[F:11]
Reactant: CI
Reactant: N#Cc1ccc(Oc2ccc(C(F)(F)C(O)(Cn3nn[nH]c3=S)c3ccc(F)cc3F)nc2)cc1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nnnn1CC(O)(c1ccc(F)cc1F)C(F)(F)c1ccc(Oc2ccc(C#N)cc2)cn1
Reaction time: 1 h

Procedure:
To a magnetically stirred mixture of 4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(5-thioxo-4,5-dihydro-1H-tetrazol-1-yl)propyl)pyridin-3-yl)oxy)benzonitrile (100 mg, 0.199 mmol) in dry THF (1990 μL) was added sodium hydride (17.51 mg, 0.438 mmol) in a 10 mL vial under N2 atmosphere. The reaction mixture was stirred at 0° C. for 15 min at which point methyl iodide (12.44 μL, 0.199 mmol) was added via microsyringe. The reaction was allowed to continue stifling at 0° C. for 1 hour. At this point the reaction was quenched with water and allowed to stir, then removed from the ice bath and extracted with CH2Cl2 (3×). The combined organic layers were dried by passing through a phase separator and volatiles were removed under a gentle stream of N2. The resulting residue was loaded onto a pad of celite and purified (SiO2, 10-35% Ethyl Acetate/Hexanes over 8 min, 35% for 4 min) to give the title compound as an off white foamy solid (82 mg, 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[C:2]1([NH:1][C:21](=[O:22])[CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1)Nc1ccccc1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a stirred solution of 9.3 g (0.10 Mole) of aniline (IIIa) and 8.3 g (0.10 Mole) pyridine in 100 mL CH2Cl2 at 0° C. under an argon atmosphere was added a solution of 15.5 g (0.10 Mole) phenylacetyl chloride (IIa) in 25 mL CH2Cl2 over a 30 minute period. The solution was allowed to warm to 25° C. over 1 hour and was quenched into 200 mL H2O. The aqueous layer was washed with two 100 mL portions of CH2Cl2 and the combined organic layers were washed with two 100 mL portions of 10% HCl solution. The organic extract was dried over MgSO4, filtered, concentrated, and crystallized from CH2Cl2 /hexane to give 20.07 g (95%) of colorless needles. mp. 115°-116° C. δ1H-NMR (CDCl3) ppm 7.0-7.6 (m, 11 H); 3.67 (S, 2H).