Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4](O)=O)[CH3:3].[NH2:14][C:15]1[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=1[NH2:21].C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1.CCOC(C)=O.CC(O)=O>[F:22][C:17]1[CH:18]=[CH:19][C:20]2[N:21]=[C:4]([C@@H:2]([NH:1][C:7](=[O:8])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:3])[NH:14][C:15]=2[CH:16]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Boc-L-Ala-OH (3.00 g, 15.86 mmol) and 3,4-diamino-1-fluorobenzene (2.00 g, 15.86 mmol) were mixed in pyridine (52.9 mL). EDCBCl (9.12 g, 47.6 mmol) was added and the mixture was stirred at ambient temperature for 20 min. The reaction mixture was diluted with EtOAc, washed with water, 1.0 N HCl and brine. The organic layer was dried with Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography on a 120 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane as eluent. The desired fractions were combined and concentrated under reduced pressure to give the crude amide intermediate. The amide was dissolved in AcOH (26.9 mL) and heated in an oil bath at 70° C. for about 30 min. The reaction mixture was diluted with EtOAc and carefully neutralized with aq. K2CO3. The organic layer was washed with NaCl, dried with Na2SO4, and filtered. The filtrate was concentrated to dryness to yield (S)-tert-butyl 1-(6-fluoro-1H-benzo[d]imidazol-2-yl)ethylcarbamate: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.23 (1H, br. s.), 7.15-7.61 (3H, m), 6.98 (1H, t, J=8.5 Hz), 4.78-4.89 (1H, m), 1.46 (3H, d, J=7.0 Hz), 1.40 (9H, s); LC-MS (ESI) m/z 280.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5](=[CH2:9])[C:6]([O-])=[O:7].C(N=C=N)C.[CH2:16]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:17]=[CH2:18]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]([C:6](=[O:7])[N:19]([CH2:16][CH:17]=[CH2:18])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[CH2:9]
Reactant: C=C(CC(=O)OC)C(=O)[O-]
Reactant: C=CCNCc1ccccc1
Agent: CCN=C=N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCN(Cc1ccccc1)C(=O)C(=C)CC(=O)OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 48.8 %

Procedure:
587 mg of 2-methylene-succinate 4-methyl ester (4.07 mM), 781 mg of 143-(dimethylamino)propyl]-3-ethylcarbodiimide (4.07 mM) and 75 mg of 4-(dimethylamino)pyridine (0.61 mM) were added to the reaction solution containing 300 mg of allylbenzylamine (2.04 mM) dissolved in methylene chloride solution (0.5M) with stirring for 10 hrs at room temperature. After the resulting mixture was washed with 5% HCl solution (10 ml), the mixture was diluted with ethyl acetate, washed with 10 ml of solution mixture mixed with saturated NaHCO3 solution and saturated NaCl solution to separate into an organic layer and water layer. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with a solvent mixture mixed with EtOAc and hexanes (1:1) as an eluant to give 272 mg of 3-(allyl-benzyl-carbamoyl)-but-3-enoic acid methyl ester (o) (yield: 49%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[C:6]([F:16])[C:5]([CH:17](O)[CH2:18][CH3:19])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:41]>C(Cl)Cl>[Br:41][CH:17]([C:5]1[C:6]([F:16])=[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:18][CH3:19]
Reactant: CCC(O)c1ccc(Cl)c(C(=O)c2ccccc2)c1F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC(Br)c1ccc(Cl)c(C(=O)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
Step 2 [6-Chloro-2-fluoro-3-(1-hydroxy-propyl)-phenyl]-phenyl-methanone (760 mg; 2.6 mmol) was dissolved in DCM (20 ml), treated with triphenylphosphine (1.095 g; 1.6 equiv.) and carbon tetrabromide (1.275 g; 1.5 equiv.) and stirred at room temperature overnight. The reaction mixture was evaporated then purified by flash column chromatography eluting with 0 to 20% EtOAc/petroleum ether. Product containing fractions were combined and evaporated to give 650 mg of [3-(1-Bromo-propyl)-6-chloro-2-fluoro-phenyl]-phenyl-methanone as a colourless gum. 1H NMR (400 MHz, DMSO-d6): 7.89-7.69 (4H, m), 7.69-7.54 (3H, m), 5.34 (1H, dd), 2.38-2.12 (2H, m), 0.99 (3H, t).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([C@H:8]1[CH2:12][CH2:11][C@@:10]([CH3:14])([OH:13])[C@H:9]1[CH3:15])([CH3:7])=[CH2:6].C(OC(=O)C)(=O)C.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:13][C@:10]1([CH3:14])[CH2:11][CH2:12][C@H:8]([C:5]([CH3:7])=[CH2:6])[C@@H:9]1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: C=C(C)[C@H]1CC[C@@](C)(O)[C@H]1C
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: C=C(C)[C@H]1CC[C@@](C)(OC(C)=O)[C@H]1C
Temperature: 45 °C
Yield: 93.9 %

Procedure:
Acetyl chloride (27 g; 0.34 mol) was added dropwise to a stirred solution of (1R,2S,3S)-3-isopropenyl-1,2-dimethyl-1-cyclopentanol (50 g; 0.32 mol), acetic anhydride (20 g; 0.2 mol), pyridine (57 g; 0.72 mol) and toluene (600 ml) at room temperature and heated to 45° C. during 3 days. The cooled reaction mixture was poured onto ice and washed with H2SO4 (10%), water, NaHCO3 solution (5%) and brine, then distilled at 53-56°/0.7 hPa to give 59 g of (1R,2S,3S)-3-isopropenyl-1,2-dimethyl-1-cyclopentyl acetate of 90% purity. Fractional distillation finished 93% pure (1R,2S,3S)-3-isopropenyl-1,2-dimethyl-1-cyclopentyl acetate (48.7 g; 76.6%). This product showed an odor of the lactonic type, with connotations of jasmine and terpenyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:12][C:13]1[C:21]2[N:20]=[C:19]([S:22][C:23]3[O:27][C:26]([CH:28]=O)=[CH:25][CH:24]=3)[NH:18][C:17]=2[CH:16]=[C:15]([F:30])[CH:14]=1.[C:31]1(=O)[CH2:36][CH2:35][CH2:34][C:33](=[O:37])[CH2:32]1>C(O)CCC>[CH2:10]([O:9][C:7]([C:3]1[NH:4][CH:5]=[C:6]2[CH:28]([C:26]3[O:27][C:23]([S:22][C:19]4[NH:18][C:17]5[CH:16]=[C:15]([F:30])[CH:14]=[C:13]([F:12])[C:21]=5[N:20]=4)=[CH:24][CH:25]=3)[C:32]3[C:33](=[O:37])[CH2:34][CH2:35][CH2:36][C:31]=3[NH:1][C:2]=12)=[O:8])[CH3:11]
Reactant: O=Cc1ccc(Sc2nc3c(F)cc(F)cc3[nH]2)o1
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: O=C1CCCC(=O)C1
Solvent: CCCCO
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CCC1)C2c1ccc(Sc2nc3c(F)cc(F)cc3[nH]2)o1
Temperature: 25 °C
Yield: 36 %

Procedure:
A mixture of 3-amino-2-ethoxycarbonyl-pyrrole (3.19 g, 20.7 mmol), 5-(4,6-difluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde (5.80 g, 20.7 mmol) and 1,3-cyclohexanedione (2.32 g, 20.7 mmol) in 80 ml of 1-butanol is heated at reflux temperature for 3 hours. The reaction mixture is then concentrated under reduced pressure and the residue is purified on a silica gel column (150 g) eluted successively with cyclohexane/ethyl acetate (9/1, v/v) and cyclohexane/ethyl acetate (7/3, v/v). The fractions containing the expected product are concentrated under reduced pressure. The residue is resuspended in 100 ml of acetonitrile and heated at reflux temperature for 30 minutes. The mixture is allowed to cool to room temperature and the insoluble material is collected by filtration. The solid is washed with acetonitrile (400 ml), diisopropyl ether (100 ml) and pentane (100 ml) and dried under vacuum to yield 3.8 g of 9-[5-(4,6-difluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester as a white powder. Yield=36%. Analytical LC/MS method B: m/z=509 (negative ion mode [M−H]−), m/z=511 (positive ion mode [M+H]+).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].Cl[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1>CN(C=O)C>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
0.4 g (11 mmole) of 60% NaH is introduced into a flask containing 25 ml of anhydrous DMF under an argon atmosphere. A solution of 1.38 g (10 mmole) of 4-nitrophenol in 5 ml of anhydrous DMF is added dropwise, under agitation at 23° C. After 30 minutes a solution of 1.77 g (10 mmole) of 2-(chloromethyl)-quinoline in 5 ml of anhydrous DMF is added dropwise and agitation is continued for 15 hours while heating the mixture at 90° C. At the end of the reaction, the mixture is poured onto ice and an abundant precipitate forms. The suspension is filtered, rinsed twice with 25 ml of water followed by 20 ml of ethyl ether. A white solid is thus obtained with a yield of 75%. Melting point: 154-155° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:11][CH:12]=[C:13]([CH:19]=1)[C:14]([O:16]CC)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].CCOC(C)=O>CCO.O>[CH2:1]([O:8][C:9]1[C:10]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:11][CH:12]=[C:13]([CH:19]=1)[C:14]([OH:16])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc(NC(=O)OC(C)(C)C)c(OCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ncc(C(=O)O)cc1OCc1ccccc1
Temperature: 0 °C

Procedure:
To a cooled (0° C.) stirred mixture of ethyl 5-(benzyloxy)-6-((tert-butoxycarbonyl)amino)nicotinate (1.2 g, 0.0032 mol) in EtOH:water (1:1, 12 mL), was added LiOH (154 mg, 0.0064 mol, Aldrich). The reaction mixture was stirred for 2 h at room temperature. After completion of the reaction (monitored by TLC, 100% EtOAc), the reaction mixture was quenched with 1N HCl at 0° C. temperature and extracted with EtOAc (2 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 13.24 (s, 1H), 9.18 (s, 1H), 8.45 (d, J=1.2 Hz, 1H), 7.80 (d, J=1.5, Hz, 1H), 7.53 (d, J=5.4 Hz, 2H), 7.41-7.34 (m, 2H), 5.24 (s, 2H), 1.38 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[C:5]([F:10])=[CH:4][CH:3]=1.[CH2:11](P(=O)(OCC)OCC)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(C)([O-])C.[K+]>O1CCCC1>[Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([F:10])=[CH:4][CH:3]=1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: O=Cc1nc(Br)ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1ccc(Br)nc1/C=C/c1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 6-bromo-3-fluoropicolinaldehyde (2.147 g, 10.5 mmol) and diethyl benzylphosphonate (2.413 mL, 11.6 mmol) in tetrahydrofuran (80 mL) at 0° C., was added potassium tert-butoxide(1M in tetrahydrofuran, 11.6 mL, 11.6 mmol) dropwise over a couple of minutes. When addition was complete, the reaction was allowed to stir at 0° C. for 45 min and quenched by addition of saturated ammonium chloride. The reaction was diluted with ether, washed with water (4×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (8%→15% EtOAc/Hex) gave 121 mg (4.1%). 1H NMR (CDCl3) δ: 7.86 (d, J=16.2 Hz, 1H), 7.64 (d, J=7.3 Hz, 2H), 7.39-7.47 (m, 2H), 7.22-7.39 (m, 4H). 19F NMR (CDCl3) δ: −130.05 (br. s., 1F). Mass spec.: 278.0 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([O:14]C)=[O:13])=[N:4][C:5]([O:10][CH3:11])=[N:6][C:7]=1OC.[OH-:16].[Na+].[CH3:18]O>O>[Cl:1][C:2]1([O:16][CH3:18])[CH:7]=[N:6][C:5]([O:10][CH3:11])=[N:4][CH:3]1[C:12]([OH:14])=[O:13]
Reactant: CO
Reactant: [OH-]
Reactant: COC(=O)c1nc(OC)nc(OC)c1Cl
Agent: [Na+]
Solvent: O
Product: COC1=NC(C(=O)O)C(Cl)(OC)C=N1

Procedure:
29.5 g of methyl 5-chloro-2,6-dimethoxypyrimidine-4-carboxylate solid are added to a stirred solution of 5.4 g of sodium hydroxide in 100 ml of methanol and 5 ml of water. Stirring is continued at room temperature until completion of the hydrolysis (3H), methanol is distilled off and the residue is taken up in water. The aqueous phase is first extracted once using ethyl acetate, then acidified to pH 2-3 with conc. hydrochloric acid and extracted five times using dichloromethane. The combined dichloromethane extracts are dried over sodium sulfate, the solvent is distilled off and the residue is dried in vacuo at 50° c. 23.0 g of 5-chloro-2,5-dimethoxypyrimidine-4-carboxylic acid of melting point 117°-119° C. (dec.) are obtained in this way.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[N:5][C:6]2[C:7]=1[NH:8][C:9]([CH:12]1[CH2:17][CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:15][CH2:14][CH2:13]1)=[N:10][CH:11]=2.[Li+].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[CH3:25][CH:17]1[CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:15][CH2:14][CH2:13][CH:12]1[C:9]1[NH:8][C:7]2=[C:3]([CH3:2])[CH:4]=[N:5][C:6]2=[CH:11][N:10]=1
Reactant: Cc1cnc2cnc(C3CCNC(c4ccccc4)C3)[nH]c1-2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cnc2cnc(C3CCNC(c4ccccc4)C3C)[nH]c1-2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
To a 0° C. solution of 7-methyl-6-phenyl-4-piperidylpyrrolo[3,2-d]pyrimidine (Example 89) (177.3 mg, 0.61 mmol) in THF (10 mL) under a nitrogen atmosphere was added LiHMDS (1.0 M soln from Aldrich Chemical Company) (1.3 mL, 1.27 mmol). This mixture was stirred at 0° C. for 0.5 h then CH3I (Aldrich Chemical Comapny) (41 mL, 0.67 mmol) was added. The 0° C. bath was removed and the solution stirred at room temperature for 2.5 h. The reaction mixture was poured into a separatory funnel containing EtOAc (35 mL) and H2O (50 mL). The organic solution was collected washed with H2O (3×40 mL), saturated NaCl (70 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified via flash chromatography on silica gel 95:5 CHCl3/MeOH as eluant to give 164 mg (86%) of the title compound as a beige colored solid. Mp: 123.0-125.0° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.68 (m, 2), 1.78 (m, 4), 2.30 (s, 3), 3.42 (br s, 4), 3.66 (s, 3), 7.44-7.54 (m, 5), 8.61 (s, 1) MS m/z: 307 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([CH:21]3[CH2:23][CH2:22]3)([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]=[C:15]=3)O)[C:6]3[CH2:24][CH2:25][N:26]([CH3:28])[CH2:27][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)[OH:30]>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11]/[C:12](/[C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:21]/[CH2:22][CH2:23][OH:30])[C:6]3[CH2:24][CH2:25][N:26]([CH3:28])[CH2:27][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(O)(C2=C=C=C(F)C=C2)C2CC2)C1
Solvent: O
Product: CN1CCc2c(c3cc(Cl)ccc3n2C/C(=C/CCO)c2ccc(F)cc2)C1
Temperature: 110 °C

Procedure:
2-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-cyclopropyl-1-(4-fluorocyclohexa-1,2,3,5-tetraenyl)ethanol (1 g, 25 mmol) was dissolved in 10 mL 25% sulfuric acid and heated at 110° C. for 4 h. The reaction mixture was cooled to RT, diluted with water and the resultant solid was filtered, washed with water, and diethylether. The solid was purified by reverse phase HPLC, and separated from the regioisomeric Compound No. 348. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.48 (d, 1H), 7.40 (m, 1H), 7.15 (m, 1H), 7.0 (m, 4H), 5.60 (m, 1H), 5.0 (m, 2H), 4.80 (m, 2H), 4.60 (m, 1H), 4.30 (m, 1H), 3.80 (m, 1H), 3.42 (m, 2H), 3.05 (s, 3H), 3.0 (m, 1H), 2.10 (m, 2H).
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:12]=[C:11]([O:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]2[OH:20])[N:10]=[CH:9][N:8]=1.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23].[Cl-].[NH4+]>C(N(CC)CC)C>[Cl:6][C:7]1[CH:12]=[C:11]([O:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]2[O:20][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:10]=[CH:9][N:8]=1
Reactant: O[C@H]1CCCC[C@H]1Oc1cc(Cl)ncn1
Reactant: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)O[C@H]1CCCC[C@H]1Oc1cc(Cl)ncn1
Temperature: 0 °C

Procedure:
To 3.2 ml of tetrahydrofuran were added 0.37 g of 4-chloro-6-(cis-2-hydroxycyclohexyloxy)pyrimidine and 0.45 ml of triethylamine, to which 0.25 ml of chlorotrimethylsilane was slowly added dropwise with stirring at 0° C. After stirring at room temperature for 3 hours, the reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.5 g of 4-chloro-6-(cis-2-trimethylsilanyloxycyclohexyloxy)pyrimidine.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][NH:4][S:5]([NH:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([O:15][CH2:16][CH2:17][OH:18])[C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=1)(=[O:7])=[O:6].[Br:26][C:27]1[CH:28]=[N:29][C:30](Cl)=[N:31][CH:32]=1.C(O[K])(C)(C)C.Cl>C1(C)C=CC=CC=1.CN(C=O)C.O>[Br:25][C:22]1[CH:21]=[CH:20][C:19]([C:10]2[C:9]([NH:8][S:5]([NH:4][CH2:3][CH2:2][CH3:1])(=[O:6])=[O:7])=[N:14][CH:13]=[N:12][C:11]=2[O:15][CH2:16][CH2:17][O:18][C:30]2[N:31]=[CH:32][C:27]([Br:26])=[CH:28][N:29]=2)=[CH:24][CH:23]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCCNS(=O)(=O)Nc1ncnc(OCCO)c1-c1ccc(Br)cc1
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCNS(=O)(=O)Nc1ncnc(OCCOc2ncc(Br)cn2)c1-c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
N-(5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl)propane-1-sulfamide (200 g; 0.46 mol; see Example 2 or 3) and 5-bromo-2-chloropyrimidine (117 g; 0.60 mol; 1.3 eq) were dissolved in toluene (3 L) and DMF (400 mL). The reaction mixture was warmed up to 50° C. and toluene (approx. 400 mL) was distilled our under reduced pressure. The mixture was cooled to 0° C. and tBuOK (156 g, 3 eq, 1.38 mol) was added portionwise. It was stirred at 20° C. for 1 h. Water (1 L) was added and the pH of the solution was adjusted to 3-5 using 33% aq. HCl. The mixture was heated to 50° C. and the layers were separated. The org. phase was treated with charcoal at 50° C. and filtered over Celite. The filter cake was rinsed with toluene. At 50° C., water (1 L) was added to the org. layer. The layers were separated. The org. layer was concentrated under reduced pressure to a total volume of 1 L and cooled to 0° C. The solid obtained was filtered off. It was rinsed with toluene and MeOH. The crude material was suspended in EA (1 L) and heated to 50° C. 300 mL of EA were distilled out and MeOH (400 mL) was added. The suspension was cooled down to 0° C. The solid was filtered off, rinsed with MeOH and dried under reduced pressure to afford the title compound as a white solid (225 g; 83% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][C:11]([C:17]([OH:20])([CH3:19])[CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[OH:20][C:17]([C:11]1([C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:25]3[CH:24]=[C:23]([C:22]([F:36])([F:21])[F:35])[CH:28]=[CH:27][N:26]=3)[CH2:30][CH2:31]2)=[O:16])[CH2:12][CH2:13][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)([CH3:19])[CH3:18]
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC(C(=O)O)(C(C)(C)O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)(C(C)(C)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
To a suspension of (3S)-3-[(tert-butoxycarbonyl)amino]-1-(1-hydroxy-1-methylethyl)cyclopentanecarboxylic acid (150 mg, 0.52 mmol) and 1-[4-(trifluoromethyl)pyridin-2-yl]piperazine (130 mg, 0.57 mmol) in methylene chloride (3 mL) under N2 was added triethylamine (0.16 g, 1.6 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.25 g, 0.57 mmol). After being stirred at room temperature overnight, the reaction was quenched by saturated NaHCO3 solution and extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, concentrated and purified by flash column chromatography to yield the desired product (76 mg, 29%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=2)[C:15]([O:17][CH3:18])=[O:16])=[CH:6][CH:5]=1.[H][H]>C(O)(=O)C.[Pd].[Pt](=O)=O>[OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][NH:12][CH2:13][CH:14]([C:15]([O:17][CH3:18])=[O:16])[CH2:19]2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: COC(=O)c1cncc(-c2ccc(CCO)cc2)c1
Agent: O=[Pt]=O
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)C1CNCC(c2ccc(CCO)cc2)C1
Reaction time: 6 h

Procedure:
A solution of 5.40 g (19.6 mmol) of the compound from Example 55A in concentrated acetic acid (124 ml) was admixed with 1.00 g of palladium/carbon (10% palladium) and 1.00 g of platinum(IV) oxide. This was followed by hydrogenation under a hydrogen atmosphere at standard pressure for 6 h, then addition of another 1.00 g of palladium/carbon (10% palladium) and 1.00 g of platinum(IV) oxide, and hydrogenation under a hydrogen atmosphere at standard pressure overnight. This was followed by hydrogenation in a Parr apparatus under a 3 bar hydrogen atmosphere for a further 2 h. The reaction solution was filtered through Celite, the filter residue was washed with methanol/water and the combined filtrates were concentrated under reduced pressure. The residue was codistilled repeatedly with toluene and then dried under high vacuum. Yield: 6.63 g (56% of theory, purity 44%)
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:8]=2)[N:3]=1.[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH2:29])=[N:25]1.N1C(C)=CC=CC=1C>O1CCOCC1>[CH:13]1([NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)[CH:8]=3)[N:3]=[C:2]([NH:29][C:26]3[CH:27]=[CH:28][N:24]([CH3:23])[N:25]=3)[N:11]=2)[CH2:15][CH2:14]1
Reactant: Cn1ccc(N)n1
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(NC4CC4)c3c2)cc1
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Product: Cn1ccc(Nc2nc(NC3CC3)c3cc(-c4ccc(F)cc4)ccc3n2)n1
Temperature: 100 °C
Yield: 59.8 %

Procedure:
To a solution of [2-Chloro-6-(4-fluoro-phenyl)-quinazolin-4-yl]-cyclopropylamine (150 mg, 0.48 mmol) and 1-Methyl-1H-pyrazol-3-ylamine (70 mg, 0.72 mmol) in 1,4-dioxane (5 ml) was added 2,6-lutidine (2 equiv.; 102 mg, 0.96 mmol). The solution was heated to 100° C. for 3 hours, then cooled and purified by RP HPLC with a gradient of H2O, 0.1% TFA-acetonitrile, to provide the desired product (140 mg, 0.287 mmol, 60% yield). The product was characterized as follows: MS (m/z): 375 ([M+H]+, 100); HPLC Rt=1.60 minutes (Method B).