Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH3:11][CH:12]([CH3:35])[CH:13]([NH:18][C:19]([C:21]1[S:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=2)=[CH:24][N:25]=1)=[O:20])[C:14]([O:16][CH3:17])=[O:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:32][C:29]2[CH:30]=[CH:31][C:26]([C:23]3[S:22][C:21]([C:19]([NH:18][C@@H:13]([CH:12]([CH3:35])[CH3:11])[C:14]([O:16][CH3:17])=[O:15])=[O:20])=[N:25][CH:24]=3)=[CH:27][CH:28]=2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Product: COC(=O)[C@@H](NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccc(Cl)cc3)cc2)s1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 9, using 1-chloro-4-isocyanatobenzene and intermediate 2. 1HNMR (DMSO-d6, 300 MHz): δ 8.991 (s, 1H), 8.897 (s, 1H), 8.737-8.710 (d, 1H), 8.353 (s, 1H), 7.730-7.701 (d, J=8.7 Hz, 2H), 7.583-7.554 (d, J=8.7 Hz, 2H), 7.513-7.484 (d, J=8.7 Hz, 2H), 7.355-7.325 (d, J=9 Hz, 2H), 4.324-4.287 (t, J=7.2, 7.8 Hz, 1H), 3.681 (s, 3H), 2.342-2.242 (m, 1H), 0.965-0.923 (d, J=6.3 Hz, 6H); MS (ESI) m/z 487 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[C:9]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(N(C(C)C)CC)(C)C>C(O)CCC>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:9](=[O:10])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[CH:22][CH:21]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2cc(Cl)ncn2)cc1

Procedure:
4,6-Dichloropyrimidine (14.89 g, 0.1 mol), N-Boc-1,4-phenylenediamine (20.83 g, 0.1 mol) and diisopropylethylamine (17.11 mL, 0.1 mol) are heated in n-butanol (160 mL) for 20 h at 90° C. After evaporation, the residue is extracted and purified by crystallization.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24]([C:26]5[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=5)[CH:23]=[CH:22][N:21]4[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>CO.C(Cl)Cl>[C:33]1([C:32]2[N:21]3[CH:22]=[CH:23][C:24]([C:26]4[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=4)=[CH:25][C:20]3=[N:19][C:18]=2[C:15]2[CH:14]=[CH:13][C:12]([C:8]3([NH2:7])[CH2:11][CH2:10][CH2:9]3)=[CH:17][CH:16]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(-c5ccncc5)ccn4c3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3nc4cc(-c5ccncc5)ccn4c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
To a solution of {1-[4-(3-phenyl-7-pyridin-4-yl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (60 mg, 0.12 mmol) in MeOH (0.5 mL) and CH2Cl2 (0.7 mL) was added a 4 molar solution of HCl in dioxane (0.6 mL, 2.3 mmol, 20 equiv) and the resulting solution was stirred at room temperature for 12 h. The resulting solution was added to ice water, and the resulting mixture was extracted with CH2Cl2 (3×25 mL). The combined organic phases were dried (Na2SO4 anh), and concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera Flash NH2 Snap 10 reverse phase column; 100% CH2Cl2 for 4 min., gradient to 95% CH2Cl2: 5% MeOH over 1 min.; 95% CH2Cl2: 5% MeOH for 2.5 min., gradient to 90% CH2Cl2: 10% MeOH over 1 min., 90% CH2Cl2: 10% MeOH for 2.5 min., gradient to 80% CH2Cl2: 20% MeOH over 1.5 min., 80% CH2Cl2: 20% MeOH for 0.8 min., gradient to 74% CH2Cl2: 26% MeOH over 2.2 min., gradient to 70% CH2Cl2: 30% MeOH over 1.8 min., 70% CH2Cl2: 30% MeOH for 7.4 min.) to give 1-[4-(3-phenyl-7-pyridin-4-yl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine (40 mg, 83%): UPLC-MS (Method 2): RT=1.22 min; m/z (rel intensity) 417 (700, (M+H)+), 833 (40, (2M+H)+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]2=[N:9][C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:25]([F:28])([F:27])[F:26])=[C:16]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:17]=3)=[CH:11][N:5]2[N:4]=1)#[N:2].CC[OH:31].CS(C)=O.[OH-].[Na+].OO>O>[CH3:21][C:20]([CH3:23])([CH3:22])[C:19]([NH:18][C:16]1[CH:17]=[C:12]([C:10]2[N:9]=[C:6]3[N:5]([CH:11]=2)[N:4]=[C:3]([C:1]([NH2:2])=[O:31])[CH:8]=[CH:7]3)[CH:13]=[CH:14][C:15]=1[C:25]([F:28])([F:26])[F:27])=[O:24]
Reactant: CC(C)(C)C(=O)Nc1cc(-c2cn3nc(C#N)ccc3n2)ccc1C(F)(F)F
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)C(=O)Nc1cc(-c2cn3nc(C(N)=O)ccc3n2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
An 8 mL vial is charged with N-[5-(6-cyanoimidazo[2,1-f]pyridazin-2-yl)-2-(trifluoromethyl)phenyl]-2,2-dimethyl-propanamide (0.019 g, 0.05 mmol), EtOH-DMSO (1.2 mL, 5:1), NaOH (0.1 mL, 1M in water), and H2O2 (0.1 mL, 30% in water). The mixture is stirred for 2 hr at room temp, diluted with water (4 mL), extracted EtOAc (2×) and CH2Cl2 (1 x). Organics are dried, concentrated onto celite and purified on silica (0-100% EtOAc in CH2Cl2) to give the title compound (12 mg, 60% yield). LCMS m/z=406.5 [M+H]+, tR=2.12 min. (compound same as Example 180)
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([O:20][C:21]([NH:23][CH:24]1[C:31](=[O:32])[N:30]2[CH:25]1[S:26][CH2:27][C:28]([CH3:36])=[C:29]2[C:33]([OH:35])=[O:34])=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(#N)C>[CH:7]([O:35][C:33]([C:29]1[N:30]2[CH:25]([S:26][CH2:27][C:28]=1[CH3:36])[CH:24]([NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[C:31]2=[O:32])=[O:34])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Temperature: 22 °C
Reaction time: 16 h
Yield: 66.3 %

Procedure:
A solution of diphenyldiazomethane (116.5 g) in acetonitrile (800 cc) is added dropwise, in the course of 45 minutes, at a temperature of between 25° and 30° C., to a solution of 7-tert.-butoxycarbonylamino-2-carboxy-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (188.6 g) in acetonitrile (2,100 cc). The reaction mixture is stirred for 16 hours at 22° C. and is then concentrated to dryness under reduced pressure (20 mm Hg) at 40° C. The residue is redissolved in ethyl acetate (2 liters) and the solution is washed with 2 N hydrochloric acid (700 cc) and then with a saturated aqueous sodium bicarbonate solution (700 cc) and a saturated aqueous sodium chloride solution (700 cc). The solution is dried over sodium sulphate, treated with decolorising charcoal, filtered, and then concentrated to dryness under reduced pressure (20 mm Hg) at 40° C. The residue is dissolved in boiling ethyl acetate (600 cc). Cyclohexane (1 liter) is added, and the mixture is heated to the reflux temperature and then allowed to cool. The crystals which have appeared are filtered off, washed with diethyl ether (3×250 cc) and then dried. 2-Benzhydryloxycarbonyl-7-tert.-butoxycarbonylamino- 3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (191 g) is obtained in the form of white crystals (m.p.=179° C.). On concentrating the mother liquor to 500 cc. a second fraction of product (32.6 g, m.p.=178° C.) is obtained.
Reaction SMILES: [C:1](#[N:10])[C:2]1[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:4]#[N:5].[NH2:11][OH:12].CC[OH:15]>>[C:1]1(=[N:10][OH:15])[C:2]2[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:11][OH:12])[NH:5]1
Reactant: CCO
Reactant: N#Cc1ccccc1C#N
Reactant: NO
Product: ON=C1NC(=NO)c2ccccc21
Yield: 85.4 %

Procedure:
Phthalonitrile (1 g, 7.8 mmol) and hydroxylamine (1.9 cm3, 31.2 mmol, 4 eq) in EtOH (25 cm3) were stirred under reflux for 60 hours, after which the volatiles were removed under reduced pressure and the residue was washed with EtOH (2 cm3) and CH2Cl2 (2 cm3) to give the cyclised product isoindoline-1,3-dione dioxime (1.18 g, 85.4%) as a pale yellow solid, mp 272-275° C. (decomposed) (lit 271° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[F:43][C:44]1[CH:49]=[CH:48][C:47]([CH:50]([NH2:52])[CH3:51])=[CH:46][CH:45]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:35]([NH:52][CH:50]([C:47]1[CH:48]=[CH:49][C:44]([F:43])=[CH:45][CH:46]=1)[CH3:51])=[O:41]
Reactant: CC(N)c1ccc(F)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4ccc(F)cc4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.2 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (82 mg) was dissolved in chloroform (2 ml) and triethylamine (0.2 ml) to prepare a solution. A solution of triphosgene (70 mg) in chloroform (0.4 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(4-fluorophenyl)ethylamine (70 mg) in chloroform (0.4 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (40 mg, yield 32%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.Cl[C:23]1[C:32]([C:33]#[N:34])=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[N:28][CH:29]=2)[N:24]=1.C(N(C(C)C)CC)(C)C>CCO>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:23]2[C:32]([C:33]#[N:34])=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[N:28][CH:29]=3)[N:24]=2)=[CH:8][CH:7]=1
Reactant: N#Cc1cc2cnccc2nc1Cl
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COC(=O)[C@H](Cc1ccc(Nc2nc3ccncc3cc2C#N)cc1)NC(=O)OC(C)(C)C
Yield: 34.8 %

Procedure:
A solution of (S)-3-(4-Aminophenyl)-2-tert-butoxycarbonylaminopropionic acid methyl ester (0.25 g, 0.84 mmol), 2-chloro[1,6]naphthyridine-3-carbonitrile (0.15 g, 0.77 mmol) (prepared according to the method of E. M. Hawes et al., J. Med. Chem. 1973,16, 849) and diisopropylethylamine (0.11 g, 0.84 mmol) in EtOH (1 ml) were heated under reflux for 3 h. The solvent was removed under reduced pressure and the resulting crude was purified by flash chromatography (CH2Cl2;AcOEt, 1:1) to yield (S)-2-tert-Butoxycarbonylamino-3-[4-(3-cyano[1,6]naphthyridin-2-ylamino)phenyl]propionic acid methyl ester (0.12 g, 34%) as a yellow solid.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>C1COCC1>[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([N:12]1[C:13]2[C:18](=[CH:17][N:16]=[CH:15][CH:14]=2)[C:10]([C:7]2[CH2:8][CH:9]3[N:4]([CH2:3][CH2:2][CH2:1]3)[CH2:5][CH:6]=2)=[CH:11]1)=[O:33]
Reactant: C1=C(c2c[nH]c3ccncc23)CC2CCCN2C1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1Cl)n1cc(C2=CCN3CCCC3C2)c2cnccc21
Reaction time: 0.17 h
Yield: 56.3 %

Procedure:
To a THF (1 mL) solution of 3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1H-5-azaindole (10 mg, 0.0418 mmol) at RT, 1M NaN(TMS)2 (100 μl, 0.1 mmol) was added and the mixture stirred for 10 mins. 2-chlorobenzoyl chloride (13 μL, 0.103 mmol) was added and the reaction mixture stirred overnight. After dilution with dichloromethane, purification by column chromatography with 2% methanol (2M/NH3) in dichloromethane gave 1-(2-chlorobenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-5-azaindole (8.9 mg, 56.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:45])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:31]([O:33]CC)=[O:32])([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH2:14][C:13](=[O:36])[NH:12][CH:11]3[C:37]3[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=3[CH3:44])[C:5]2=[CH:4][CH:3]=1.O[Li].O.O>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:45])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:31]([OH:33])=[O:32])([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH2:14][C:13](=[O:36])[NH:12][CH:11]3[C:37]3[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=3[CH3:44])[C:5]2=[CH:4][CH:3]=1
Reactant: CCCC(CCC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)OCC
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CCCC(CCC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-propyl-butoxy)-phenyl]-2′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (280 mg, 0.41 mmol), LiOH.H2O (1 g, 24.6 mmol), H2O (12 mL) and methanol (38 mL) was refluxed for 2 h. After cooled to room temperature, the solution was concentrated and then the mixture was acidified to “pH” 1-2 by addition of concentrated HCl solution and then extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated to give the title compound as a light yellow solid (220 mg).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][CH2:9][C:10]#[N:11])=[CH:3][CH:2]=1.CN(P(N(C)C)(N(C)C)=O)C.[Li+].CC([N-]C(C)C)C.Cl[CH:38]([C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:43]=[CH:42][CH:41]=1)[CH3:39]>C1COCC1>[C:7](=[N:8][CH:9]([CH:38]([C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:43]=[CH:42][CH:41]=1)[CH3:39])[C:10]#[N:11])([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(Cl)c1ccnc2ccccc12
Reactant: N#CCN=C(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(c1ccnc2ccccc12)C(C#N)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To N-(Diphenylmethylene)aminoacetonitrile (2.26 g, 10.2 mmol) in 10 ml of anhydrous THF and HMPA (2.17 ml, 12.14 mmol), at −78° C. LDA (2.0 M, 6.0 ml, 12.14 mmol) was added dropwise over a period of 5 minutes. The color of solution turns from coloress to yellow to dark brown. It was then stirred at −78° C. for one hour. Then 4-(1-Chloroethyl)-quinoline (1.79 g, 9.34 mmol), was added dropwise and the reaction mixture was slowly brought to room temperature over a period of five minutes, quenched by addition of ice and partitioned between EtOAc (20 ml) and water (5 ml). The organic layer was dried over sodium sulfate, filtered, concentrated and column purified (hexanes:EtOAc; 3.5:1.5) to give 3.0 g (86%) of the product as a syrup which was used as such for the subsequent step.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].CN(C=O)C.[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CCOC(C)=O>[Cl:23][CH2:22][CH2:21][CH2:20][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11]
Reactant: O=c1ccc2ccccc2[nH]1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1ccc2ccccc2n1CCCCl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 40.8 %

Procedure:
A 7 mL vial was charged with 1H-quinolin-2-one (0.62 g, 4.2 mmol), 4 mL dry DMF and NaH (60% in oil, 0.200 g, 5.1 mmol). The mixture was stirred under a N2 atmosphere at rt for 45 min, and thereafter 1-bromo-3-chloropropane (0.42 mL, 4.2 mmol) was added and the reaction was stirred at rt overnight. The reaction was diluted with EtOAc (50 mL) and washed with water (15 mL). The water phase was extracted with EtOAc (25 mL) and the combined organic phase was dried (Na2SO4), filtered, concentrated under reduced pressure and the residue was purified by flash chromatography (SiO2; CH2Cl2) to yield the title compound (0.38 g, 41%), containing 15% of 1-(3-bromopropyl)-1H-quinolin-2-one. 1H NMR (CD3OD) δ 7.90 (d, J=9.4 Hz, 1H), 7.73-7.57 (m, 3H), 7.34-7.28 (m, 1H), 6.66 (d, J=9.4 Hz), 4.46 (t, J=7.4 Hz, 2H), 3.71 (t, J=6.4 Hz, 2H), 2.21-2.02 (m, 2H); 13C NMR (CD3OD) δ 163.2, 140.7, 138.8, 131.3, 129.3, 122.8, 121.4, 120.2, 114.4, 42.18, 40.2, 30.5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][C:31](=[O:36])[CH2:32][C:33](=[O:35])[CH3:34])([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.[N:37]([O-])=[O:38].[Na+]>C(O)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][C:31](=[O:36])[C:32](=[N:37][OH:38])[C:33](=[O:35])[CH3:34])([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1
Reactant: O=N[O-]
Reactant: CC(=O)CC(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)C(=NO)C(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.6 %

Procedure:
To a solution of (R)—N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-oxobutanamide (Example 251, 62 mg, 0.12 mmol), in acetic acid (0.5 mL) was added dropwise a solution of NaNO2 (25 mg, 0.36 mmol) in H2O (0.5 mL). The reaction mixture was stirred at rt for 10 min and diluted with H2O (10 mL). The aqueous portion was extracted with EtOAc (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to yield (R)—N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-(hydroxyimino)-3-oxobutanamide (Example 331) as a yellow solid (65 mg, 100% yield). LCMS: RT=1.99 min [M+H] 539.4 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 10.07 (1H, s), 7.15-7.21 (2H, m), 7.07-7.14 (7H, m), 7.00-7.05 (4H, m), 6.84-6.96 (6H, m), 6.55-6.60 (2H, m), 5.88 (1H, t, J=2.78 Hz), 3.91 (1H, d, J=13.14 Hz), 3.72-3.80 (1H, m), 2.52 (3H, s).
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]#[C:16][CH:17]2[CH2:19][CH2:18]2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:20][N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]2[CH:33]=[CH:32]C(N)=[CH:30][CH:29]=2)[CH2:23][CH2:22]1>>[CH:17]1([C:16]#[C:15][C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([C:14]4[CH:32]=[CH:33][C:28]([N:24]5[CH2:25][CH2:26][CH2:27][N:21]([CH3:20])[CH2:22][CH2:23]5)=[CH:29][CH:30]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)[CH2:18][CH2:19]1
Reactant: COC(=O)c1sc(C#CC2CC2)cc1N=CN(C)C
Reactant: CN1CCCN(c2ccc(N)cc2)CC1
Product: CN1CCCN(c2ccc(-n3cnc4cc(C#CC5CC5)sc4c3=O)cc2)CC1

Procedure:
5-Cyclopropylethynyl-3-(dimethylaminomethyleneamino)thiophene-2-carboxylic acid methyl ester was reacted with 4-(4-methyl[1,4]diazepan-1-yl)phenylamine by method A1. The product with the molecular weight of 404.53 (C23H24N4OS) was obtained in this way; MS (ESI): 405 (M+H+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:30][CH2:31][OH:32])[CH2:15][N:16]([CH3:29])[C:17]([C:19]2[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[CH:22]=[CH:21][CH:20]=2)=[O:18])=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH2:30][CH:31]=[O:32])[CH2:15][N:16]([CH3:29])[C:17]([C:19]2[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[CH:22]=[CH:21][CH:20]=2)=[O:18])=[CH:12][CH:13]=1
Reactant: CN(CC(CCO)c1ccc(Cl)cc1)C(=O)c1cccc2c1CCCC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(CC(CC=O)c1ccc(Cl)cc1)C(=O)c1cccc2c1CCCC2
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
To a stirred cooled (−78° C.) solution of oxalyl chloride (0.39 mL, 4.47 mmol) in DCM (10 mL) was added DMSO (0.64 mL, 9.00 mmol) in DCM (5 mL) dropwise. The solution was stirred at −78 ° C. for 5 min and a solution of N-[2-(4-chlorophenyl)-4-hydroxybutyl]-N-methyl-5,6,7,8-tetrahydro-1-naphthamide (1.11 g, 2.98 mmol) in DCM (6.0 mL) and DMSO (3.4 mL) was added dropwise. The solution was stirred at −78 ° C. for 15 min and triethylamine (2.50 mL, 17.9 mmol) was added. Stirring was continued at −78 ° C. for 30 min and then at room temperature for 2 h. 1N NCI (75 mL) and DCM (75 mL) were added, the layers separated, and the organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Purification by chromatography (silica gel; 50% Et2O/DCM) provided the title compound (1.10 g, 95%) as a tacky solid. MS rm/z 370 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=C([CH:7]=[C:8]([O:10][CH2:11][CH3:12])[CH:9]=1)C#N.[OH-:13].[Na+].[CH2:15]([OH:17])[CH3:16]>O>[Br:1][C:2]1[CH:3]=[C:16]([CH:7]=[C:8]([O:10][CH2:11][CH3:12])[CH:9]=1)[C:15]([OH:13])=[O:17]
Reactant: CCOc1cc(Br)cc(C#N)c1
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: CCOc1cc(Br)cc(C(=O)O)c1

Procedure:
A solution of 3-bromo-5-ethoxy-benzonitrile (529 mg, 2.3 mmol) in a mixture of ethanol (8 mL) and water (1 mL) was treated with a solution of sodium hydroxide (47%, 0.66 mL) and the mixture heated under reflux for 1 hour. For the working-up, the mixture was evaporated under reduced pressure and the oily residue dissolved in tert-butylmethyl ether (60 mL) and water (30 mL). The organic layer was separated and evaporated, then treated again with tert-butylmethyl ether (120 mL) and 1 N hydrochloric acid (60 mL). The organic layer was separated and re-extracted twice with tert-butylmethyl ether (2×60 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. The title compound was obtained in quantitative yield and engaged in the next step without further purification. Mass (calculated) C9H9BrO3 [244]; (found) [M−H]+=243, 245.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[O:5][C:6]1[C:7]([CH2:18][CH3:19])=[N:8][N:9]([CH2:13][C:14]([NH:16][NH2:17])=[O:15])[C:10]=1[CH2:11][CH3:12].[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[O:5][C:6]1[C:7]([CH2:18][CH3:19])=[N:8][N:9]([CH2:13][C:14]2[O:15][C:24](=[O:25])[NH:17][N:16]=2)[C:10]=1[CH2:11][CH3:12]
Reactant: CCc1nn(CC(=O)NN)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: CCc1nn(Cc2n[nH]c(=O)o2)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Yield: 38 %

Procedure:
A stirred solution of the hydrazide (275 mg, 0.77 mmol) of Example 11 and 1,1′-carbonyl diimidazole 187 mg, 1.16 mmol) in dioxane (50 ml) was heated under reflux for 18 hours. After cooling, the mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (50 ml) and washed with water (25 ml). The organic layer was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (95:5, by volume) to afford the title compound (112 mg) as a white solid m.p. 138-142° C.