Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([C:12](=O)[CH:13]([CH:21]([C:25]2[CH:42]=[CH:41][C:28]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])=[O:30])=[CH:27][CH:26]=2)[CH2:22][CH2:23][CH3:24])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:45]1([NH:51][NH2:52])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>N1C=CC=CC=1.CCOC(C)=O>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH:13]([C:12]2[N:51]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:52]=[C:3]3[C:4]=2[CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=[C:2]3[Cl:1])[CH:21]([C:25]2[CH:42]=[CH:41][C:28]([C:29]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:26]=2)[CH2:22][CH2:23][CH3:24])=[CH:19][CH:18]=1
Reactant: NNc1ccccc1
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(C(=O)c1cc(C(F)(F)F)cc(Cl)c1F)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCC(c1ccc(C(=O)NCCC(=O)O)cc1)C(c1ccc(Cl)cc1)c1c2cc(C(F)(F)F)cc(Cl)c2nn1-c1ccccc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of the major diastereomer of tert-butyl N-(4-{1-[2-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-1-(4-chlorophenyl)-2-oxoethyl]butyl}benzoyl)-β-alaninate (EXAMPLE 2, Step A, 100 mg, 0.153 mmol) in pyridine (1.5 mL) was added phenylhydrazine (0.083 mL, 0.076 mmol). The mixture was stirred at 80° C. for 18 hours in a sealed tube. The mixture was diluted with EtOAc then washed with 2 N HCl (aq) then saturated NaCl (aq). The organic layer was dried over sodium sulfate, filtered, then concentrated. The resulting residue was purified by silica gel chromatography eluting with 0-50% EtOAc/hexanes to afford the title compound. This diastereomer was resolved to provide enantiopure material by HPLC on a ChiralPak IA column (2 cm×25 cm) eluting with 9 mL/min of 5% EtOH/n-heptane. LC1 2.98 min. (M-tBu+H)+ 668.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19](=[S:21])[NH2:20])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:22][CH2:23][C:24]([CH2:26]Cl)=O>C(O)C>[Cl:22][CH2:23][C:24]1[N:20]=[C:19]([C:10]2[C:11]3[C:16](=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:9]=2)[S:21][CH:26]=1
Reactant: COc1cccc2c(C(N)=S)cn(CC3CCCCC3)c12
Reactant: O=C(CCl)CCl
Solvent: CCO
Product: COc1cccc2c(-c3nc(CCl)cs3)cn(CC3CCCCC3)c12
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
A mixture of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid amide (prepared from 7-methoxyindole as described in Example 1; 5.10 g, 17.8 mmol), Lawesson's reagent (7.92 g, 19.6 mmol), and toluene (150 ml) was stirred at room temperature for 4 days. The reaction mixture was concentrated in vacuo and the obtained reside was purified by column chromatography eluting with dichloromethane to afford 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbothioic acid amide (3.58 g). A mixture of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbothioic acid amide (200 mg, 0.66 mmol), 1,3-dichloroacetone (126 mg, 0.99 mmol), and ethanol (2.0 ml) was stirred at 60° C. for 1 h. The reaction mixture was concentrated in vacuo, and the obtained residue was mixed with 5% aqueous sodium carbonate (100 ml). The resulting mixture was extracted with dichloromethane (4×100 ml). The organic layers were combined, washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The obtained residue was purified by column chromatography eluting with 25% (v/v) ethyl acetate in n-heptane to give 3-[4-(chloromethyl)thiazol-2-yl]-1-(cyclohexyl)methyl-7-methoxy-1H-indole (200 mg).
Reaction SMILES: [H-].[Na+].C1C[O:6]CC1.[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:10]=1[CH:11]=O.[N+:18]([CH2:20][C:21]([O:23][CH3:24])=[O:22])#[C-:19]>CC(O)=O>[CH3:24][O:23][C:21](=[O:22])[C:20]([NH:18][CH:19]=[O:6])=[CH:11][C:10]1[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:9]=1[Cl:8]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: C1CCOC1
Reactant: O=Cc1c(F)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C(=Cc1c(F)cccc1Cl)NC=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
NaH (60% in oil, 2.4 g, 0.06 mol, approx. 1.2 eq) was placed in a dry 50 ml flask and heated to 35 degrees. To it was slowly added 50 ml of a THF solution containing 2-chloro-6-fluorobenzaldehyde (7.93 g, 0.05 mol) and methyl isocyanoacetate (5 g, 0.05 mol). The reaction was then cooled to RT, and stirred for 3 hr. At that time, 10 ml of 10% HOAc was added. After 10 min, the contents were concentrated in vacuo to a dark brown oil, then diluted with CHCl3, and transferred to a sep funnel. The aqueous phase was reextracted (3×) with CHCl3, and the combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to crude product. Purification over a pad of silica gel was accomplished by elution with 10:1 CHCl3/EtOAc to afford the title compound, clean Z/E olefins (1:1 mix, 8.24 g, 64%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.C(N(CC)CC)C.O.[NH2:32][NH2:33]>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:32][NH2:33])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Reactant: NN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: NNC(=O)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 7.5 h

Procedure:
To a mixture of 4-benzyloxyphenylacetyl chloride (1.1 g) and THF (10 mL) were added triethylamine (1.8 mL) and hydrazine hydrate (0.20 mL) at room temperature, which was stirred at the same temperature for 7.5 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate, and the organic layer was washed with saturated brine. The solvent was evaporated under a reduced pressure, after which the residue was purified by silica gel chromatography (methanol:ethyl acetate=1:30) to obtain the titled compound (0.23 g).
Reaction SMILES: S(O)(=O)(=O)C.[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([SH:14])[N:8]=1.[H-].[Na+].Cl[CH2:18]/[CH:19]=[CH:20]/[C:21]([N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])=[O:22]>CN(C=O)C>[CH2:27]([N:23]([CH2:24][CH2:25][CH3:26])[C:21](=[O:22])/[CH:20]=[CH:19]/[CH2:18][S:14][C:9]1[N:8]=[C:7]([NH2:6])[CH:12]=[C:11]([Cl:13])[N:10]=1)[CH2:28][CH3:29]
Reactant: Nc1cc(Cl)nc(S)n1
Reactant: CCCN(CCC)C(=O)/C=C/CCl
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)/C=C/CSc1nc(N)cc(Cl)n1
Reaction time: 8.5 h

Procedure:
4-Chlorocrotonyl chloride (1.02 g, 7.35 mmol) in ether (10 ml) is combined with dipropylamine (1.64 g, 16.17 mmol) in ether (5 ml) at -15° C. in a flame dried flask. The reaction is warmed to ambient temperature, stirred for 1 to 2 hours, quenched with water (30 ml), extracted with ethyl acetate (2×30 ml), washed with saline (30 ml), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with hexane/ethyl acetate (60/40). The appropriate fractions are combined (Rf =0.53, TLC, hexane/ethyl acetate, 25/75) and concentrated in vacuo to give 4-chloro-N,N-dipropylcrotonamide. 4-Amino-6-chloro-2-mercaptopyrimidine mesylate (0.30 g, 1.16 mmol) is dissolved in DMF (5 ml) and sodium hydride (0.06 g, 2.55 mmol) at ambient temperature followed by the addition of 4-chloro-N,N-dipropylcrotonamide (0.23 g, 1.13 mmol). The reaction is stirred for 2 to 15 hours, quenched with excess water, extracted with ethyl acetate (3×20 ml). The extracts are combined, washed with saline (20 ml), dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with hexane/ethyl acetate (60/40). The appropriate fractions are combined (Rf =0.40, TLC, hexane/ethyl acetate, 25/75) and concentrated in vacuo to give the title compound, mp 139-142° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=1.CN1CCOCC1.[CH2:25]([N:27]([CH2:43][CH3:44])[C:28]1[C:33]([CH:34]=[CH:35][C:36](O)=[O:37])=[CH:32][CH:31]=[C:30]([C:39]([F:42])([F:41])[F:40])[N:29]=1)[CH3:26].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1>[CH2:43]([N:27]([CH2:25][CH3:26])[C:28]1[C:33]([CH:34]=[CH:35][C:36]([NH:2][CH2:3][C:4]2[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=2)=[O:37])=[CH:32][CH:31]=[C:30]([C:39]([F:42])([F:40])[F:41])[N:29]=1)[CH3:44]
Reactant: CCN(CC)c1nc(C(F)(F)F)ccc1C=CC(=O)O
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2N(CC)CC)cc(F)c1NS(C)(=O)=O
Reaction time: 0.08 h
Yield: 83.3 %

Procedure:
To a suspension of N-(4-aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (476 mg, 1.66 mmol) in THF (5 mL) was added N-methylmorpholine (0.365 ml, 3.32 mmol). The mixture was stirred for 5 minutes, to which were added 3-(2-diethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (434 mg, 1.51 mmol) and 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMTMM, 459 mg, 1.66 mmol). The mixture was stirred overnight at room temperature and was concentrated under reduced pressure. The residue was diluted with EtOAc and water. The organic layer was washed with saturated sodium bicarbonate, 1N HCl and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by recrystallization from CH2Cl2 to give the title compound (645 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[OH:27])=[N:7][C:6]=2[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC(C)=O>[CH2:34]([O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:8]1[N:9]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10](=[O:12])[C:11]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][C:6]=2[N:7]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=c1c2c(Cl)nccc2nc(-c2ccccc2O)n1CCc1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1c2c(Cl)nccc2nc(-c2ccccc2OCc2ccccc2)n1CCc1ccccc1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
5-Chloro-2-(2-methoxy-phenyl)-3-phenethyl-3H-pyrido[4,3-d]pyrimidin-4-one was subjected to the same deprotection conditions found in the final step of Example 1 to provide the desired 5-chloro-2-(2-hydroxy-phenyl)-3-phenethyl-3H-pyrido[4,3-d]pyrimidin-4-one. A mixture of 5-chloro-2-(2-hydroxy-phenyl)-3-phenethyl-3H-pyrido[4,3-d]pyrimidin-4-one (88 mg, 0.233 mmol), potassium carbonate (64 mg, 0.466 mmol, 2 equiv.) and benzyl bromide (0.029 mL, 0.245 mmol, 1.05 equiv.) in 2 mL of acetone was heated to reflux overnight. The reaction mixture was cooled to RT, filtered through celite, concentrated and the residue purified on preparative TLC plate using 1:1 ethyl acetate:heptane to give 95 mg (87%) of the desired product.
Reaction SMILES: F[C:2](F)(F)S(OC[Si](C)(C)C)(=O)=O.CS[C:16]1[S:17][CH:18]=[CH:19][N:20]=1.[CH2:21]([O:23][C:24](=[O:27])[C:25]#[CH:26])[CH3:22].[F-].[Cs+]>C(#N)C>[CH2:21]([O:23][C:24]([C:25]1[CH:26]=[CH:2][N:20]2[CH:19]=[CH:18][S:17][C:16]=12)=[O:27])[CH3:22]
Reactant: C[Si](C)(C)COS(=O)(=O)C(F)(F)F
Reactant: C#CC(=O)OCC
Reactant: CSc1nccs1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: CCOC(=O)c1ccn2ccsc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere (trimethylsilyl)methyl trifluoromethanesulfonate (16.3 mmol) is added dropwise to a mixture of 2-methylthio-1,3-thiazole (15.5 mmol) in acetonitrile (75 mL). The mixture is treated with propynoic acid ethyl ester (23.2 mmol), kept with occasional shaking for 30 min at RT and added dropwise to a vigorously stirred solution of CsF (21.7 mmol) and propynoic acid ethyl ester (23.2 mmol) in acetonitrile (75 mL). After stirring for 1 h the mixture is concentrated in vacuo, diluted with DCM (100 mL), washed twice with water and twice with brine and dried over Na2SO4. The solvents are removed in vacuo and the residue is purified by flash chromatography (gradient: heptane to heptane/EtOAc 8/2) to give the desired product. LC-MS: tR=0.87 min; [M+H]+=196.0.
Reaction SMILES: [BrH:1].N1C=CC=CC=1.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[C:9]1[C:17]([CH3:19])=[O:18]>CO>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[C:9]1[C:17](=[O:18])[CH2:19][Br:1]
Reactant: CC(=O)c1cc2ccccc2o1
Reactant: Br
Solvent: c1ccncc1
Solvent: CO
Product: O=C(CBr)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 7 h
Yield: 120.5 %

Procedure:
A polymer of perbromide of pyridine hydrobromide (8.75 g; 17.5 mmol; 1.4 equivalent) is added to a solution of (benzofuran-2-yl)methylketone (2 g; 12.5 mmol) in methanol (40 ml). The resulting mixture is stirred at ambient temperature for 7 hours and the reaction is stopped by filtration. The methanol is eliminated under reduced pressure and an additional addition of diethyl ether allows crystallization of the expected product (3.6 g; yield=60%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35]([NH2:42])([CH2:38][C:39]([OH:41])=[O:40])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C[O-].[Na+].Cl>O.CC(N(C)C)=O>[C:25]([O:29][C:30]([N:32]1[CH2:33][CH2:34][C:35]([CH2:38][C:39]([OH:41])=[O:40])([NH:42][C:3]([C:5]2[N:6]=[C:7]([C:23]#[N:24])[C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=3)=[O:4])[CH2:36][CH2:37]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)(C)OC(=O)N1CCC(N)(CC(=O)O)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)O)(NC(=O)c2nc(C#N)c3cc(Oc4ccccc4)ccc3c2O)CC1
Temperature: 150 °C
Yield: 51.6 %

Procedure:
A 20-mL scintillation vial was charged with 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.31 mmol), 4-amino-4-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (322 mg, 1.25 mmol), NaOMe (59 mg, 1.09 mmol) and dimethylacetamide (3 mL). It was close-capped and heated in a 150° C. oil bath for 4 h. Reaction mixture was diluted with water (70 mL) and acidified by 1 N HCl to pH=4-5. Precipitate was collected, rinsed with water and dried. Crude product was purified by silica gel chromatography, eluting with 10-100% EtOAc/hexanes, to provide the title compound 92 mg (0.16 mmol) in 54% yield. LC-MS ESI−: 545.08 (M−1)−.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:15])([CH3:14])[C@H:8]1[NH:12][C:11](=[O:13])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH2:23]Cl)[CH:22]=1.[H-].[Na+]>>[Br:16][C:17]1[CH:22]=[C:21]([CH2:23][N:12]2[C@H:8]([C:7]([CH3:15])([CH3:14])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][CH2:10][C:11]2=[O:13])[CH:20]=[N:19][CH:18]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CCC(=O)N1
Reactant: ClCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CCC(=O)N1Cc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediates A-12 [B], (S)-5-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-2-one was reacted with 3-bromo-5-chloromethyl-pyridine (intermediate A-12 [A]) in presence of NaH to give the title compound as a colorless oil. MS: 399.2, 401.2 (M+H+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([N:24]3[CH2:30][CH2:29][CH2:28][N:27]([CH3:31])[CH2:26][CH2:25]3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F.N1C=CC=CC=1.FC1C=C(S([Cl:48])(=O)=O)C=CC=1>C(Cl)Cl>[ClH:48].[F:2][C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([N:24]3[CH2:30][CH2:29][CH2:28][N:27]([CH3:31])[CH2:26][CH2:25]3)=[CH:16][CH:15]=2)(=[O:11])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CN1CCCN(c2ccc(NS(=O)(=O)c3ccc(F)c(F)c3)c3ccccc23)CC1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN1CCCN(c2ccc(NS(=O)(=O)c3cccc(F)c3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.9 %

Procedure:
To a solution of (intermediate 3 after reduction according to Method A) 4-(4-methyl-1,4-diazepan-1-yl)-1-naphthylamine (0.173 g, 0.676 mmol) and pyridine (450 μL, 4.73 mmol) in CH2Cl2 (3.0 mL) was added 3-fluorobenzenesulfonyl chloride (0.145 g, 0.743 mmol) in CH2Cl2 (1.0 mL). The solution was stirred at room temperature for 16 hours and the volatiles were evaporated. The crude product was purified by column chromatography (SiO2, CHCl3/MeOH/NH3 9:1:0.4%) to give 240 mg of the product as solid that was triturated with MeOH/ether to give 0.180 g (64%) of the free base which was converted to its HCl-salt: 1 H NMR (DMSO-d6) δ 11.07 (br s, 1H), 10.28 (br s, 1H), 8.20–8.16 (m, 1H), 7.98–7.94 (m, 1H), 7.60–7.40 (m, 6H), 7.16–7.12 (m, 1H), 7.06–7.02 (m, 1H), 3.65–3.30 (m, partly obscured by solvent signal, HDO, 6H), 3.26–3.18 (m, 2H), 2.84 (s, 3H), 2.30–2.05 (m, 2H); MS (posES-FIA) m/z=414 (M+H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][N:59]1[CH2:64][CH2:63][N:62]([CH3:65])[CH2:61][CH2:60]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][N:59]5[CH2:64][CH2:63][N:62]([CH3:65])[CH2:61][CH2:60]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCN(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NN2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-amino 4-methylpiperazine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.85 (m, 10H) 2.18 (s, 3H) 2.93 (br. s., 3H) 3.22-3.47 (m, 7H) 3.93 (s, 3H) 4.06 (t, J=13.39 Hz, 2H) 4.46 (m, 1H) 7.44 (br. s., 1H) 7.42 (d, J=8.84 Hz, 1H) 7.90 (s, 1H) 8.21 (s, 1H) 8.27 (d, J=8.08 Hz, 1H) 9.40 (s, 1H). [M+H] calculated for C27H36F2N8O3, 559. found 559.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#N.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.[Cl-].[NH4+].[O:34]1CCCC1>CO>[F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:34]
Reactant: C1CCOC1
Reactant: N#Cc1ccc(N2CCOCC2)cc1F
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=Cc1ccc(N2CCOCC2)cc1F
Temperature: 25 °C
Reaction time: 23.5 h
Yield: 68 %

Procedure:
To a solution of 2-fluoro-4-(morpholino)-benzonitrile (2.82 g, 13.7 mmol) in tetrahydrofuran (27 ml) under a nitrogen atmosphere was added dropwise a 1.5 M solution of DIBAL-H in toluene (18.3 ml, 27.3 mmol) during 13 minutes and the resulting mixture stirred for 23.5 hr at room temperature. The mixture was cooled to −50° C. and the excess DIBAL-H deastoyed by careful addition of methanol (27 ml). The mixture was then stirred at room temperature for 10 mins, saturated ammonium chloride (27 ml) added and the resulting mixture stirred at room temperature for 40 mins., and then evaporated under reduced pressure to a yellow solid. This solid was partitioned between dichloromethane (120 ml) and water (120 ml) and solid potassium carbonate added until the aqueous phase was pH10. The phases were separate via a hyrophobic frit and the organic phase evaporated and the residue purified by a Biotage™ column (40 g, silica) eluting with cyclohexane:ethyl acetate: (7:3) to give 2-fluoro-4-(morpholino)-benzaldehyde (1.96 g, 68%) as a white solid.
Reaction SMILES: [CH2:1]([C:13]1[S:17][C:16]([CH:18]([OH:26])[CH:19]([NH:22][C:23](=[O:25])[CH3:24])[CH2:20][OH:21])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[O:50]1CC[CH2:52][CH2:51]1>>[CH2:1]([C:13]1[S:17][C:16]([CH:18]([O:26][C:51](=[O:50])[CH3:52])[CH:19]([NH:22][C:23](=[O:25])[CH3:24])[CH2:20][O:21][C:27](=[O:29])[CH3:28])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCc1ccc(C(O)C(CO)NC(C)=O)s1
Reactant: C1CCOC1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCc1ccc(C(OC(C)=O)C(COC(C)=O)NC(C)=O)s1
Yield: 93.5 %

Procedure:
A solution of erythro N-[1-[5-(1-dodecyl)-2-thienyl]-1,3-dihydroxy-2-propyl]acetamide (12.0 g), acetic anhydride (19.2 g), triethylamine (28.4 g),and dimethylaminopyridine (0.4 g) in dry tetrahydrofuran (150 ml) was stirred at ambient temperature for 3 hrs. The reaction mixture was evaporated and the residue was dissolved in chloroform. The solution was washed with water, dried, filtered, and the filtrate was evaporated. The residue was dried to give 13.6 g (93.5%) of product, mp 105-107° C.
Reaction SMILES: C([S:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH2:7][CH2:6]1)(=O)C.[ClH:24]>C(O)C>[ClH:24].[CH:21]1([C:19]([CH:11]([N:8]2[CH2:7][CH2:6][CH:5]([SH:4])[CH2:10][CH2:9]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[O:20])[CH2:23][CH2:22]1
Reactant: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)CC1
Agent: Cl
Solvent: CCO
Product: O=C(C1CC1)C(c1ccccc1F)N1CCC(S)CC1
Reaction time: 8 h

Procedure:
2.00 g (5.97 mmol) of the 4-acetylthio-1-(α-cyclopropylcarbonyl-2-fluorobenzyl)piperidine obtained in the above-described step (a) were dissolved in 50 ml of ethanol. An appropriate amount of a hydrogen chloride gas was blown through the resulting solution and the resulting mixture was allowed to stand overnight at room temperature. The solvent was then distilled off under reduced pressure. The residue was crystallized from diethyl ether, whereby 1.95 g of 1-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4-mercaptopiperidine hydrochloride were obtained as faintly brown crystals (yield: 99%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3].C([CH:20]([S:26][CH:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:28])[C:21](=O)[C:22]([O-:24])=[O:23])C.C([BH3-])#N.[Na+].[CH2:38](O)[CH3:39]>>[CH2:32]([O:31][C:29]([CH:27]([S:26][CH2:20][CH:21]([NH:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3])[C:22]([O:24][CH2:38][CH3:39])=[O:23])[CH3:28])=[O:30])[CH3:33]
Reactant: C[C@H](N)C(=O)N1C2CCCCC2C[C@H]1C(=O)O
Reactant: CCOC(=O)C(C)SC(CC)C(=O)C(=O)[O-]
Reactant: CCO
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCOC(=O)C(CSC(C)C(=O)OCC)N[C@@H](C)C(=O)N1C2CCCCC2C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1 g (4.17 m mols) of (2S)-1-[(S)-alanyl]-2-carboxyperhydroindole, prepared as described in Example 3, Step F, and 4.72 g (19 m mols) of ethyl[(1RS)-1-ethoxycarbonylethylthio]-pyruvate are dissolved in 50 ml of anhydrous ethanol in the presence of 15 g of molecular sieve 4 Å. After 45 minutes' stirring at room temperature, 0.25 g of sodium cyanoborohydride in solution in 2.25 ml of anhydrous ethanol are added within 6 hours.