Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)C1C=CC=CC=1.[F:24][C:25]([F:37])([F:36])[C:26]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([OH:29])[CH:27]=[CH2:28]>>[OH:8][C:9]1[CH:14]=[C:13]([CH2:28][CH2:27][C:26]([OH:29])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:25]([F:24])([F:36])[F:37])[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:21])(=[O:22])[NH:19][C:18](=[O:23])[CH2:17]1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: C=CC(O)(c1ccccc1)C(F)(F)F
Product: O=C1CN(c2ccc(CCC(O)(c3ccccc3)C(F)(F)F)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one and 1,1,1-trifluoro-2-phenyl-but-3-en-2-ol analogous to Example 44: (M−1)−=429; HPLC retention time=1.29 min (method A).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][CH2:4][NH:5][C:6](=[O:21])[C@H:7]([CH3:20])[CH2:8][C@H:9]([OH:19])[C@@H:10]([NH2:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.[O:33]=[C:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39]1[CH:40]=[C:41]([CH:45]=[C:46]([N:48]2[CH2:52][CH2:51][CH2:50][C:49]2=[O:53])[CH:47]=1)[C:42](O)=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:11]([C@H:10]([NH:18][C:42](=[O:43])[C:41]1[CH:40]=[C:39]([N:35]2[CH2:36][CH2:37][CH2:38][C:34]2=[O:33])[CH:47]=[C:46]([N:48]2[CH2:52][CH2:51][CH2:50][C:49]2=[O:53])[CH:45]=1)[C@@H:9]([OH:19])[CH2:8][C@H:7]([C:6](=[O:21])[NH:5][CH2:4][CH2:3][C:2]([CH3:22])([CH3:1])[CH3:23])[CH3:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NCCC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.2 %

Procedure:
To a solution of (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (3,3-dimethylbutyl)amide (D2) (46 mg, 0.145 mmol) in DMF (2 ml) was added iPr2NEt (61 μl, 0.348 mmol) followed by 3,5-bis-2-oxopyrrolidin-1-yl)benzoic acid (D8) (50 mg, 0.174 mmol) and HATU (77 mg, 0.203 mmol). The reaction mixture was stirred at room temperature for 6 hours. The solvent was evaporated to dryness and the residue was partitioned between 0.5 M HCl and DCM. The organic phase was separated and washed with NaHCO3, brine and dried over MgSO4, filtered and evaporated to afford the crude product (61 mg) as yellow oil. The product was triturated in petroleum/diethylether which yielded E5 (55 mg) as a yellow solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[C:7]1([C:13]2[CH:14]=[C:15]3[C:21]([NH2:22])=[N:20][NH:19][C:16]3=[N:17][CH:18]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>N1C=CC=CC=1>[C:7]1([C:13]2[CH:14]=[C:15]3[C:21]([NH:22][C:4](=[O:5])[CH2:3][CH2:2][CH3:1])=[N:20][NH:19][C:16]3=[N:17][CH:18]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Nc1n[nH]c2ncc(-c3ccccc3)cc12
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1n[nH]c2ncc(-c3ccccc3)cc12

Procedure:
n-Butyryl chloride (40 μl, 0.36 mmol) was added to a solution of 5-phenyl-1H-pyrazolo[3,4-b]pyridin-3-ylamine (Description 2; 100 mg, 0.47 mmol) in pyridine (0.5 ml). The reaction mixture was stirred at reflux for 16 hours, then allowed to cool. The solution was acidified to pH 1 with 5N HCl, and the resulting solids were filtered and dried. Crystallization from DMF/MeOH afforded the title compound as a solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=O)[CH2:2][CH:3]=[CH2:4].C([O-])(=O)C.[Na+].Cl.[NH2:15][OH:16]>C(O)C.O>[CH2:1]([O:5][CH2:6][CH:7]=[N:15][OH:16])[CH2:2][CH:3]=[CH2:4]
Reactant: NO
Reactant: C=CCCOCC=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCCOCC=NO
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
(But-3-en-1-yloxy)acetaldehyde (C6) (40 g from the preceding step, ≦312 mmol) was dissolved in a 2:1 mixture of ethanol and water (700 mL). Sodium acetate (128 g, 1560 mmol) was added, and the mixture was stirred for 20 minutes. Hydroxylamine hydrochloride (98%, 66.4 g, 936 mmol) was then added, and the reaction mixture was heated to 60° C. for 18 hours, at which point it was cooled to room temperature and concentrated under reduced pressure to remove ethanol. The aqueous residue was poured into water (500 mL) and extracted four times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 40% ethyl acetate in heptane) afforded the product as an oil, presumed from the 1H NMR spectrum to be a mixture of E and Z oximes. Yield: 24 g, 0.19 mmol, 60% over three steps. 1H NMR (400 MHz, CDCl3) δ 2.33-2.41 (m, 2H), 3.51-3.57 (m, 2H), [4.11 (d, J=5.7 Hz) and 4.36 (d, J=3.7 Hz), total 2H], 5.04-5.16 (m, 2H), 5.76-5.89 (m, 1H), [6.92 (t, J=3.7 Hz) and 7.51 (t, J=5.6 Hz), total 1H].
Reaction SMILES: CS(O[CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])(=O)=O.[NH:25]1[CH2:29][CH:28]=[CH:27][CH2:26]1>C1(C)C=CC=CC=1>[N:25]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:29][CH:28]=[CH:27][CH2:26]1
Reactant: CC(COS(C)(=O)=O)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: C1=CCNC1
Solvent: Cc1ccccc1
Product: CC(CN1CC=CC1)N1c2ccccc2Sc2ccc(C#N)cc21
Reaction time: 18 h

Procedure:
A solution of 2-(2-cyano-10-phenothiazinyl)-1-propyl methanesulphonate, L series (44 g) and 2,5-dihydropyrrol (42.2 g) in anhydrous toluene (250 cc) is heated to 90° C. with stirring for 18 hours. After cooling, the reaction mixture is extracted with distilled water (2×100 cc) and then with N aqueous hydrochloric acid solution (250 cc). The combined acidic aqueous phases are alkalinized with aqueous N sodium hydroxide solution and extracted with ethyl acetate (3×100 cc). The organic phases are combined, washed successively with distilled water (100 cc) and then with saturated aqueous sodium chloride solution (100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The yellowish oily residue (30.4 g) is purified by chromatography on a column (height: 38 cm; diameter 3.8 cm) of silica gel (0.04-0.063 mm) under a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (75:25 by volume) (15 liters) of cyclohexane and ethyl acetate and collecting 1-liter fractions. Fractions 6 to 11 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 10-[1-(2,5-dihydro-1-pyrrolyl)-2-propyl]-2-phenothiazinecarbonitrile, L series (11.15 g) in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[S:3]([O:6][C:7]1[C:16]([CH3:17])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1Cl)(=[O:5])=[O:4].[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1C1C2C(=CC=CC=2)C=C(C)C=1O>>[F:1][C:2]([F:20])([F:19])[S:3]([O:6][C:7]1[C:16]([CH3:17])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:25]1[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][C:26]=1[Cl:28])(=[O:5])=[O:4]
Reactant: Cc1cc2ccccc2c(Cl)c1OS(=O)(=O)C(F)(F)F
Reactant: Cc1cc2ccccc2c(-c2ccc(Cl)cc2Cl)c1O
Product: Cc1cc2ccccc2c(-c2ccc(Cl)cc2Cl)c1OS(=O)(=O)C(F)(F)F

Procedure:
1-(2,4-dichlorophenyl)-3-methylnaphthalen-2-yl trifluoromethanesulfonate was prepared in a similar manner as compound 4C in Example 2, except starting from 1-(2,4-dichlorophenyl)-3-methylnaphthalen-2-ol instead of 4B. 1H-NMR: 400 MHz, (CDCl3) δ: 7.85-7.90 (m, 2H), 7.62 (d, 1H), 7.55 (app dt, 1H), 7.41-7.48 (m, 2H), 7.32-7.49 (m, 2H), 2.64 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CC(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][NH:25][CH3:26])=[CH:12]2)(=[O:9])=[O:10])[CH:5]=[N:6][CH:7]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cncc(Cl)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cncc(Cl)c2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 174.7 %

Procedure:
To a solution of tert-butyl ({1-[(5-chloropyridin-3-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}methyl)methylcarbamate (391 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 298 mg, 95%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[C:14]([C:15]([OH:17])=O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)C>[C:19]1([NH:18][C:15]([C:14]2[C:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[NH:3][C:2](=[O:1])[C:11]=3[NH:12][CH:13]=2)=[O:17])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Reactant: Nc1ccccc1
Solvent: CCOCC
Product: O=C(Nc1ccccc1)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Yield: 45 %

Procedure:
This compound is prepared according to synthesis 79 from 75 mg (0.33 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 75) and 33 μL (0.36 mmol) of aniline. After trituration in diethyl ether, 45 mg (45%) of N-(phenyl)-4-oxo-4,5-dihydro-3H -pyrrolo[2,3-c]quinoline-1-carboxamide is obtained in the form of a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=O.[NH2:11][C:12]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:35][CH2:34][CH2:33][N:32]([CH:36]([CH3:38])[CH3:37])[CH2:31][CH2:30]2)=[CH:25][C:13]=1[C:14]([NH:16][CH2:17][C:18](=[O:24])[NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:15].C(N(CC)CC)C.C[Si](Cl)(C)C>C(Cl)Cl>[C:20]([NH:19][C:18](=[O:24])[CH2:17][N:16]1[C:14](=[O:15])[C:13]2[C:12](=[CH:28][CH:27]=[C:26]([N:29]3[CH2:35][CH2:34][CH2:33][N:32]([CH:36]([CH3:38])[CH3:37])[CH2:31][CH2:30]3)[CH:25]=2)[N:11]=[C:5]1[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CC(C)N1CCCN(c2ccc(N)c(C(=O)NCC(=O)NC(C)(C)C)c2)CC1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N1CCCN(c2ccc3nc(-c4cccc(F)c4)n(CC(=O)NC(C)(C)C)c(=O)c3c2)CC1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 6.5 %

Procedure:
3-Fluorobenzoyl chloride (24 mg, 0.154 mmol, 0.019 mL) was added to an ice-water cooled solution of 2-amino-N-(tert-butylcarbamoylmethyl)-5-(4-isopropylperhydro-1,4-diazepin-1-yl)benzamide (INTERMEDIATE V.49) (60 mg, 0.154 mmol) and triethylamine (716 mg, 0.96 mL, 7.09 mmol) in DCM (2 mL). Stirring was continued for 15 min. Trimethylsilyl chloride (251 mg, 0.295 mL, 2.31 mmol) was added and the reaction mixture heated in the microwave at 150° C. for 7 min. The reaction mixture was diluted with DCM (10 mL) and washed with water. The organic phase was dried (MgSO4) and concentrated in vacuo. Crude product was purified by chromatography on silica gel with a gradient of DCM to DCM:MeOH:NH3 (95:4:1, v/v) as eluent. Further purification by preparative HPLC afforded N-tert-butyl-2-[2-(3-fluorophenyl)-6-(4-isopropylperhydro-1,4-diazepin-1-yl)-4-oxo-4H-quinazolin-3-yl]acetamide (EXAMPLE 7d) (5 mg, 10 μmol, 7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:22]([C:29]1[N:30]=[C:31]([CH2:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[O:32][C:33]=1[CH2:34]Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(C)=O>[CH2:22]([C:29]1[N:30]=[C:31]([CH2:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[O:32][C:33]=1[CH2:34][N:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:9][CH2:10]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: ClCc1oc(CC2CCCCC2)nc1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccccc1N1CCN(Cc2oc(CC3CCCCC3)nc2Cc2ccccc2)CC1
Yield: 65 %

Procedure:
A suspension containing 2-fluorophenylpiperazine (2.0 mmole), potassium carbonate (4.0 mmole), potassium iodide (1.0 mmole) and 4-benzyl-5-chloromethyl-2-cyclohexylmethyl oxazole (2.0 mmole) from example 8, was stirred in acetone (20 ml) at ambient temperature for 18 hr. The solvent was removed in vacuo, water (50 ml) added and the product extracted into ethyl acetate (3×50 ml). The combined organics were washed with water (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by “flash” chromatography over silica gel to afford the titled compound as an off-white crystalline powder (1.3 mmole, 65% yield). An ethyl acetate solution (10 ml) of the product was treated with 2 equivalents of ethereal 1N-HC1 to afford the HCl salt of the titled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:17])[CH3:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:18](=[O:33])([O:30][CH2:31][CH3:32])[O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1>CC(C)CC(=O)C>[C:18](=[O:33])([O:30][CH2:31][CH3:32])[O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]([N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:17])[CH3:16])[CH2:11][CH2:10]2)=[O:28])=[CH:24][CH:25]=1
Reactant: CC(C)N1CCC(Nc2ccc(Cl)cc2)CC1
Reactant: CCOC(=O)Oc1ccc(CC(=O)Cl)cc1
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)Oc1ccc(CC(=O)N(c2ccc(Cl)cc2)C2CCN(C(C)C)CC2)cc1
Reaction time: 1 h

Procedure:
To a stirred mixture of 7.5 parts of N-(4-chlorophenyl)-1-(1-methylethyl)-4-piperidinamine and 80 parts of 4-methyl-2-pentanone are added dropwise 9 parts of [4-(2-chloro-2-oxoethyl)-phenyl] ethyl carbonate. Upon completion, the whole is heated to reflux and stirring is continued for one hour at reflux temperature. After cooling, the precipitated product is filtered off and stirred for 30 minutes in a mixture of alkaline water and trichloromethane. The layers are separated. The organic phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated yielding 5.5 parts of {4-[2-{(4-chlorophenyl)-[1-(1-methylethyl)-4-piperidinyl]amino}-2-oxoethyl]phenyl} ethyl carbonate as an oily residue.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[C:20]([Cl:26])=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>C(O)C>[Cl:26][C:20]1[C:21]([OH:25])=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Oc1cccc(CBr)c1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2cccc(O)c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (152 mg, 1.1 mmol) was dissolved in absolute ethanol (8 mL), then triethylamine (140 μL, 1.0 mmol) and 3-(bromomethyl)-2-chlorophenol (200 mg, 0.9 mmol) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration, and the filtrate was evaporated. The residue was dissolved in DCM and purified on silica gel using 10% DCM/MeOH to afford 2-{[(2-chloro-3-hydroxyphenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (87 mg, 37% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.22 (s, 3H), 4.11 (bs, 1H), 4.44 (s, 2H), 5.99 (bs, 1H), 6.88-6.91 (m, 1H), 7.01-7.10 (m, 2H), 10.24 (bs, 1H); LRMS (ES+) m/z 283 (100%, M+1), 285 (50%, M+3).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([N:7]1[C:13](=[O:14])[CH:12]([CH3:15])[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[C:9]2[C:20]([NH2:24])=[CH:21][CH:22]=[CH:23][C:8]1=2)=[O:6])[CH3:4].N1C=CC=CC=1.[F:31][C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1>C1COCC1>[F:31][C:32]1[CH:33]=[C:34]([S:38]([NH:2][C@H:3]([C:5]([N:7]2[C:13](=[O:14])[CH:12]([CH3:15])[C:11]3[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=3[C:9]3[C:20]([NH2:24])=[CH:21][CH:22]=[CH:23][C:8]2=3)=[O:6])[CH3:4])(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1C(=O)N(C(=O)[C@H](C)NS(=O)(=O)c2cccc(F)c2)c2cccc(N)c2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7B) (0.1500 g, 0.434 mmol) in THF (4 ml) was added pyridine (0.088ml, 1.09 mmol) and 3-fluorobenzenesulfonyl chloride (Fluorochem Limited) (0.0928 ml, 0.477 mmol), stirred at RT overnight. The reaction mixture was evaporated to dryness. Water was added, filtered. The solid was purified with flash chromatography (silica, 6% MeOH/CH2Cl2, crystallized with CH2Cl2/hexane and washed with Et2O/hexane (1:1, v/v) to give the title compound (0.0580 g, 29%) as a white solid.
Reaction SMILES: C([N:4]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[C:9]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:8]=2[CH2:7][CH2:6][C:5]1=[O:20])(=O)C.C[O-].[Na+]>CO>[Cl:19][C:17]1[CH:16]=[CH:15][C:9]2[C:10](=[O:14])[CH2:11][CH2:12][CH2:13][NH:4][C:5](=[O:20])[CH2:6][CH2:7][C:8]=2[CH:18]=1
Reactant: CC(=O)N1CCCC(=O)c2ccc(Cl)cc2CCC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCc2cc(Cl)ccc2C(=O)CCCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.05 g (7 mmol) of 4-acetyl-11-chloro-1,2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione in 30 ml of methanol was treated with 0.85 g (15.4 mmol) of sodium methanolate, stirred at room temperature for 2 hours, the reaction mixture was concentrated in vacuo, treated with water and extracted at pH 14 with chloroform. After drying the chloroform phase with sodium sulphate and distillation of the solvent in vacuo there was obtained 11-chloro- 1,2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione of melting point 142°-144°.
Reaction SMILES: [N:1]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4](=[O:10])[NH:3][CH:2]=1.[Br:11]Br>C(O)(=O)C>[Br:11][C:8]1[S:7][C:6]2[N:1]=[CH:2][NH:3][C:4](=[O:10])[C:5]=2[CH:9]=1
Reactant: BrBr
Reactant: O=c1[nH]cnc2sccc12
Solvent: CC(=O)O
Product: O=c1[nH]cnc2sc(Br)cc12
Temperature: 80 °C

Procedure:
The product from Example 14 (0.75 g) was added to glacial acetic acid (10 ml) and heated with stirring until it dissolved. Bromine (0.75 ml) was then added and the mixture immediately set solid. More acetic acid was added and the mixture broken up. It was then heated at 80° C. for 6½ hours, cooled and poured into ice-water. The solid was filtered and washed with water followed by dichloromethane and dried to give the title product, m.p. 304° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][N:11]=[C:12](Cl)[C:13]([CH3:16])([CH3:15])[CH3:14].[O-:18][C:19]#[N:20].[K+]>C(O)C.O>[OH:18][C:19]1[N:10]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=2[Cl:9])[N:11]=[C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:20]=1
Reactant: N#C[O-]
Reactant: CC(C)(C)C(Cl)=NNc1c(Cl)cc(Cl)cc1Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1nc(O)n(-c2c(Cl)cc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
6.3 g (0.02 mol) of 2,2-dimethylpropionyl chloride 2,4,6-trichlorophenylhydrazone was dissolved in 50 ml of ethanol. Then, a solution of 3.2 g (0.04 mol) of potassium cyanate in 30 ml of water, was dropwise added thereto under stirring at room temperature. After completion of the dropwise addition, stirring was continued at the same temperature for further 0.5 hour. The precipitated crystals were collected by filtration and washed with n-hexane to obtain 6.1 g (yield: 95.3%) of 5-hydroxy-3-(tert-butyl)-1-(2,4,6-trichlorophenyl)-1H-1,2,4-triazole as white powder having a melting point of from 272° to 274° C.
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]4[CH:26]=[CH:27][C:28]([C:30]5[CH:35]=[CH:34][N:33]=[C:32]([CH2:36][CH2:37][CH:38]=O)[CH:31]=5)=[CH:29][C:24]4=[N:23][CH:22]=3)=[CH:17][C:16]=2[F:40])=[O:13])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH2:41]([NH:43][CH2:44][CH3:45])[CH3:42].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]4[CH:26]=[CH:27][C:28]([C:30]5[CH:35]=[CH:34][N:33]=[C:32]([CH2:36][CH2:37][CH2:38][N:43]([CH2:44][CH3:45])[CH2:41][CH3:42])[CH:31]=5)=[CH:29][C:24]4=[N:23][CH:22]=3)=[CH:17][C:16]=2[F:40])=[O:13])[CH:7]=1)([CH3:4])([CH3:3])[CH3:5]
Reactant: CCNCC
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cnc4cc(-c5ccnc(CCC=O)c5)ccn34)cc2F)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCN(CC)CCCc1cc(-c2ccn3c(-c4ccc(NC(=O)Nc5cc(C(C)(C)C)on5)c(F)c4)cnc3c2)ccn1
Reaction time: 0.33 h

Procedure:
Dissolve 1-(5-tert-butyl-isoxazol-3-yl)-3-(2-fluoro-4-{7-[2-(3-oxo-propyl)-pyridin-4-yl]-imidazo[1,2-a]pyridin-3-yl}-phenyl)-urea hydrochloride (0.5 g, 0.89 mmol) in acetic acid (20 mL) under nitrogen. Add diethylamine (0.46 mL, 5 equiv.) and stir overnight at room temperature. In the morning, add sodium triacetoxyborohydride (0.38 g, 2 equiv.) and stir 20 minutes. At this point add excess diethylamine and stir overnight at room temperature. Concentrate to dryness and purify by silica gel (10% Methanol:DCM) to give impure product. Purify by reverse phase (25% MeCN:0.03% HCl in water→100% MeCN). Dilute product containing fractions with ethyl acetate then wash with 1 N NaOH followed by aqueous saturated sodium chloride. Dry the organics over MgSO4, filter and concentrate to give the freebase (0.083 g, 16%) as a yellow solid. LCMS (ES), m/z 584.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[CH2:27]([O:29][C:30](=[O:47])[CH2:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1)[CH3:28].C(=O)(O)[O-].[Na+]>COCCOC.O>[CH2:27]([O:29][C:30](=[O:47])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:25])[C:13]=3[NH:12][C:11]([O:10][C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:26])=[CH:19][CH:20]=2)=[CH:34][CH:33]=1)[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3Cl)cc2)cc1

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester (3.0 g, 6.9 mmol), [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (2.2 g, 7.6 mmol), dichloro-bis(triphenylphosphine)palladium(II) (0.25 g, 0.35 mmol), and sodium bicarbonate (1.7 g, 20.7 mmol) were combined in DME (30 mL) and H2O (10 mL), and the reaction was stirred at 80° C. for 2 hours. After aqueous work-up, the crude material was purified by silica gel chromatography (0-40% EtOAc in hexanes) to give the title compound.