Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:17])[C:14]([OH:16])=O)=[CH:11][C:5]=2[O:4][CH2:3]1.[CH3:18][C:19]1[CH:31]=[CH:30][C:22]([CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:21][CH:20]=1>C(OCC)C>[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:14](=[O:16])[C:13]([NH:12][C:10]3[CH:9]=[CH:8][C:6]4[NH:7][C:2](=[O:1])[CH2:3][O:4][C:5]=4[CH:11]=3)=[O:17])[CH2:26][CH2:25]2)=[CH:30][CH:31]=1
Reactant: Cc1ccc(CC2CCNCC2)cc1
Reactant: O=C1COc2cc(NC(=O)C(=O)O)ccc2N1
Solvent: CCOCC
Product: Cc1ccc(CC2CCN(C(=O)C(=O)Nc3ccc4c(c3)OCC(=O)N4)CC2)cc1

Procedure:
The title compound is prepared from N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-oxalamic acid (Example 53b) and 4-(4-methylbenzyl)-piperidine [J Org. Chem., 64,3763. (1999)] according to the method described in Example 1c. Melting Point: 228-231° C. (diethylether)
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[N:5]=[C:6]([C:15]([O:17]C)=O)[S:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1>C(O)C>[CH3:1][NH:2][C:15]([C:6]1[S:7][C:8]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[C:4]([CH3:3])[N:5]=1)=[O:17]
Reactant: COC(=O)c1nc(C)c(-c2ccncc2)s1
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1nc(C)c(-c2ccncc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Methyl amine (0.5 ml) was added to a stirred solution of methyl 4-methyl-5-(4-pyridinyl)-thiazole-2-carboxylate (250 mg) in absolute ethanol (10 ml) at room temperature, and the mixture was stirred at room temperature for overnight. The mixture was evaporated to dryness and the residue was recrystallized from iso-propanol to give N,4-dimethyl-5-(4-pyridinyl)-thiazole-2-carboxamide (200 mg, yield 80.0%) as pale yellow needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[CH2:31]=O>CO.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:31][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[C:20]([OH:24])[CH:19]=3)[CH:16]=2)[NH:11][CH:10]=1
Reactant: C=O
Reactant: C1COCCN1
Reactant: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(O)c3)cc12
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(CN4CCOCC4)c(O)c3)cc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
A mixture of 3-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenol (14.2 mg, 0.045 mmol), morpholine (5.87 μl, 0.067 mmol) and paraformaldehyde (2.7 mg, 0.09 mmol) in 400 μl of methanol/toluene (3:7) was stirred at 60° C. for 1 hour, then 90° C. for 3 hours. The resulting light brown residue was purified by flash silica gel chromatography using a gradient of ethyl acetate in hexanes to afford 5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-morpholin-4-ylmethyl-phenol (11.7 mg, 63% yield) as white solid. 1H NMR (500 MHz, CD3OD) δ 8.44 (d, 1.5 Hz, 1H), 8.22 (d, 1.5 Hz, 1H), 7.65 (s, 1H), 7.56 (dd, 1.5 Hz, 7 Hz, 1H), 7.37 (d, 8 Hz, 1H), 7.32 (dt, 2 Hz, 7.8 Hz, 1H), 7.19 (dd, 2 Hz, 8 Hz, 1H), 7.17 (d, 1.5 Hz, 1H), 7.14 (d, 8 Hz, 1H), 7.06 (dt, 1 Hz, 7 Hz, 1H), 4.18 (s, 2H), 3.87 (s, 3H), 3.85 (br s, 4H), 3.09 (br s, 4H). MS: m/z 416.1 [MH+].
Reaction SMILES: [CH:1]([Si:4]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[SH:5])([CH3:3])[CH3:2].[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19](I)[CH:18]=[CH:17][C:16]=1[NH:22][C:23](=[O:31])[C@:24]([OH:30])([CH3:29])[C:25]([F:28])([F:27])[F:26].C(OCC)(=O)C>C1COCC1.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:15]1[CH:20]=[C:19]([S:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:6]([CH3:8])[CH3:7])[CH:9]([CH3:11])[CH3:10])[CH:18]=[CH:17][C:16]=1[NH:22][C:23](=[O:31])[C@:24]([OH:30])([CH3:29])[C:25]([F:26])([F:28])[F:27]
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Reactant: C[C@@](O)(C(=O)Nc1ccc(I)cc1Cl)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)[Si](Sc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1)(C(C)C)C(C)C
Temperature: 1 °C

Procedure:
Triisopropylsilanethiol (2.8 ml) was added to a stirred suspension of sodium hydride (60% mineral oil dispersion, 0.53 g) in anhydrous THF (40 ml) cooled to 1° C. under argon. After 15 minutes at this temperature tetrakis(triphenylphosphine)palladium (0) (1.21 g) was added and this solution was added to (R)-N-(2-chloro-4-iodophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 197) (5.2 g) in anhydrous toluene (40 ml) and the mixture was heated to 85° C. for 2 hours. The mixture was allowed to cool to ambient temperature, ethyl acetate (200 ml) was added and the mixture was washed with brine (100 ml) and dried. Volatile material was removed by evaporation and the residue was purified on a silica gel flash column eluting with 1-20% ethyl acetate/hexane to give the title compound (6.51 g) as a gum. NMR (CDCl3) 1.07-1.1 (d, 18H), 1.20-1.28 (m, 3H), 1.74 (s, 3H), 3.64 (s, 1H), 7.39-7.42 (m, 1H), 7.53 (s, 1H), 8.23 (d, 1H), 8.81 (s, 1H); MS (ESP−): 454.
Reaction SMILES: [CH2:1]([C:3]1([CH2:21][CH3:22])[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.[C:30](Cl)(=[O:34])[CH2:31][CH2:32][CH3:33].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:21]([C:3]1([CH2:1][CH3:2])[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:16][CH2:17][N:18]([C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[CH2:19][CH2:20]2)[CH2:5][CH2:4]1)[CH3:22]
Reactant: CCCC(=O)Cl
Reactant: CCC1(CC)CCC(c2ccccc2N2CCNCC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)N1CCN(c2ccccc2C2CCC(CC)(CC)CC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
To a solution of 1-[2-(4,4-diethylcyclohexyl)phenyl]piperazine (30 mg, 0.10 mmol) produced in Example (83a) in tetrahydrofuran (1 mL) was added triethylamine (15 mg, 0.15 mmol), followed by stirring at an external temperature of 0° C. Butyryl chloride (0.015 mL, 0.14 mmol) was added to the reaction mixture while stirring, and the stirring was continued for 9 hours and 30 minutes at an external temperature of 0° C. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and filtered through Celite, and the filtrate was concentrated. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 27 mg of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[C:20]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:10]1=[O:29])[CH2:5][C:6](O)=[O:7])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:42]1([S:48]([NH2:51])(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.N12CCCN=C1CCCCC2.Cl>C1COCC1.O>[CH2:1]([O:3][CH:4]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[C:20]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:10]1=[O:29])[CH2:5][C:6]([NH:51][S:48]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:50])=[O:49])=[O:7])[CH3:2]
Reactant: CCOC(CC(=O)O)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(CC(=O)NS(=O)(=O)c1ccccc1)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
3-Ethoxy-3-[3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid (45 mg, 0.11 mmol) is dissolved in dry THF (1.0 mL) and 1,1′-carbonyl diimidazole (40 mg, 0.25 mmol) is added into it at room temperature. The mixture is stirred for 30 min and then it is heated at 55° C. for 1 hr. After the mixture is cooled down to room temperature, benzenesulfonamide (34 mg, 0.22 mmol) is added and after 10 min, 1,8-diazabicyclo[5,4,0]undec-7-ene (0.033 mL, 0.22 mmol) is added. The mixture is stirred for 4 hr at room temperature and 1.0 M HCl solution (3 mL) is added followed by water (30 mL). The mixture is extracted with EtOAc (3×50 mL) and the organic layers are combined, dried and concentrated to give crude product. Purification by preparative TLC using 6% MeOH in CH2Cl2 with 1.0% concentrated aqueous NH4OH solution (28%) affords 22 mg (36%) of N-{3-Ethoxy-3-[3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionyl}-benzenesulfonamide. LCMS (ESMS): m/z 550.15 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[O:17][C:16]2=[O:25])[CH2:11][CH2:10]1)=[O:7].[BH4-].[Na+]>CO>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:6]([OH:7])[CH2:8][N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[CH2:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[O:17][C:16]3=[O:25])[CH2:13][CH2:14]2)[CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30]
Reactant: COc1cc(C(=O)CN2CCC(N3Cc4ccccc4OC3=O)CC2)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(O)CN2CCC(N3Cc4ccccc4OC3=O)CC2)cc(OC)c1OC
Reaction time: 2 h
Yield: 62.6 %

Procedure:
In this example, 2.8 g of 1-(3,4,5-trimethoxybenzoylmethyl)-4-(2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl)-piperidine obtained in the same manner as in Example 7 is mixed with 150 ml of methanol. While this mixture is stirred at 0° to 10° C., 1.5 g of sodium borohydride is added thereto over a period of 2 hours. Then, the mixture is stirred overnight at room temperature. The mixture is further mixed with 1 g of sodium borohydride and stirred overnight. The white crystals deposited are separated by filtration, washed with methanol and water and dried to obtain 1.96 g of a crude product. The crude product is recrystallized from ethanol to obtain 1.76 g of the desired product.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:30])[NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24]OS(C)(=O)=O)[N:22]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>>[CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24][S:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[N:22]=2)=[O:30])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccc(NC(=O)Nc2nc(CCOS(C)(=O)=O)cs2)c(C(=O)C2CCCC2)c1
Reactant: Sc1ccccn1
Product: Cc1ccc(NC(=O)Nc2nc(CCSc3ccccn3)cs2)c(C(=O)C2CCCC2)c1
Yield: 46.8 %

Procedure:
1-(2-cyclopentanecarbonyl-4-methyl-phenyl)-3-{4-[2-(pyridin-2-ylsulfanyl)-ethyl]-thiazol-2-yl}-urea (24 mg, 467%) was prepared from methanesulfonic acid 2-{2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-ethyl ester (0.05 g, 0.11 mmol) and 2-mercapto pyridine (0.012 g, 0.11 mmol) following the general procedure Z.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[F:21])O)=[CH:9][C:8]=1[O:22][CH3:23])(C)(C)C>CO.OS(O)(=O)=O.[Pd]>[F:21][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([OH:6])=[C:8]([O:22][CH3:23])[CH:9]=1
Reactant: COc1cc(C(O)c2ccncc2F)ccc1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Product: COc1cc(Cc2ccncc2F)ccc1O
Temperature: 35 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
Pd/C (0.02 mmol; 40 mg) was added to a solution of [4-(tert-Butyl-dimethyl-silanyloxy)-3-methoxy-phenyl]-(3-fluoro-pyridin-4-yl)-methanol (0.19 mmol; 70 mg) in methanol (2 mL) and H2SO4 (0.5 mL). The mixture was flushed twice with hydrogen, and the reaction was stirred overnight at 35° C. The mixture was filtered on celite, washed with methanol. After concentration, water was added (3 mL) and K2CO3 until pH 8. The aqueous phase was extracted with ethyl acetate (2*3 mL). Combined organic phases were dried over MgSO4, concentrated to yield the title compound as a white solid (32 mg; 0.14 mmol; 71%) used as such.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]=2[CH3:19])[CH:5]=[CH:6][CH:7]=1.[C:20]([O:28][CH2:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[CH2:38][O:39][C:40](=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:33]Br)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:21]1([C:20]([O:28][CH2:29][C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=2[CH2:38][O:39][C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:47])[CH2:33][O:1][C:2]2[CH:3]=[C:4]([C:8]3[C:9]([CH3:19])=[CH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:13]=3[CH3:14])[CH:5]=[CH:6][CH:7]=2)=[O:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cc(C)c(-c2cccc(O)c2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc(C)c(-c2cccc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)c2)c(C)c1

Procedure:
In a manner similar to that of Example 1(i), by reaction of 4.49 g (17.5 mmol) of methyl 3′-hydroxy-2,6-dimethylbiphenyl-4-carboxylate with 8.46 g (19 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide and 2.54 g (18 mmol) of potassium carbonate, the desired product is obtained in the form of a yellow oil (m=7.4 g; Y=69%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:16][CH:17]([F:19])[F:18])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]>C1COCC1>[C:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([O:16][CH:17]([F:18])[F:19])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cc(N)ccc1OC(F)F
Solvent: C1CCOC1
Product: COC(=O)c1cc(NC(C)=O)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Acetylchloride (1.8 mL, 25.3 mmol) in 25 mL THF was added to a mixture of methyl 5-amino-2-difluoromethoxy-benzoate (5.40 g, 24.9 mmol) with TEA (4.5 mL, 32.4 mmol) in 50 mL THF and the resulting mixture stirred for 15 min at ambient temperature. The mixture was filtered and the filtrate concentrated i. vac. The residue was mixed with acetonitrile and water, concentrated i. vac. and the solid filtered off. It was washed with water and dried at 40° C.
Reaction SMILES: FC(F)(F)C(O)=O.C[O:9][C:10](=[O:45])[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]([NH2:44])=[N:19][CH:20]=[N:21][C:22]=2[N:23]2[CH2:28][CH2:27][N:26]([CH:29]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=3)[CH2:30][N:31]([CH3:33])[CH3:32])[CH2:25][CH2:24]2)=[CH:13][CH:12]=1.O.O.[OH-].[Li+]>C1COCC1.O>[NH2:44][C:18]1[C:17]([C:14]2[CH:13]=[CH:12][C:11]([C:10]([OH:45])=[O:9])=[CH:16][CH:15]=2)=[C:22]([N:23]2[CH2:24][CH2:25][N:26]([CH:29]([C:34]3[CH:35]=[CH:36][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:39]=3)[CH2:30][N:31]([CH3:33])[CH3:32])[CH2:27][CH2:28]2)[N:21]=[CH:20][N:19]=1
Reactant: COC(=O)c1ccc(-c2c(N)ncnc2N2CCN(C(CN(C)C)c3ccc(C(F)(F)F)cc3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CC(c1ccc(C(F)(F)F)cc1)N1CCN(c2ncnc(N)c2-c2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a round bottle flask containing 4-(4-Amino-6-{4-[2-dimethylamino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-pyrimidin-5-yl)-benzoic acid methyl ester trifluoroacetic acid (36.00 mg; 0.06 mmol; 1.00 eq.) in THF (2.00 ml) and water (2.00 ml) was added 1 N lithium hydroxide monohydrate water solution. The mixture was stirred at rt for 4 h before it was concentrated and purified with waters prep-HPLC. LC-MS: (M+1=515, obsd.=515)
Reaction SMILES: [NH2:1][C:2](=[N:5][C:6](=[O:9])OC)[S:3][CH3:4].C(Cl)Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1.C[O-].[Na+]>CCOCC.CO>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:21](=[O:22])[N:1]=[C:2]([S:3][CH3:4])[NH:5][C:6]2=[O:9])=[CH:16][CH:15]=1
Reactant: COC(=O)N=C(N)SC
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: CSc1nc(=O)n(-c2ccc(Cl)cc2)c(=O)[nH]1
Reaction time: 72 h

Procedure:
To a solution of 148 parts of methyl N-(1-amino-1-methylthiomethylene)-carbamate, prepared as in Example 2, in 2,000 parts methylene chloride is added 154 parts of p-chlorophenyl isocyanate. The reaction is stirred for 3 days. Then to it is added 54 parts of sodium methoxide in 540 parts of methanol. The reaction mixture is then refluxed for 1 hour. The reaction mass is cooled, and 2,000 parts of ether are added. The solid collected by filtration is dissolved in water and the solution neutralized with hydrochloric acid. The new solid thus formed is collected, dried, and recrystallized from ethanol/H2O to give 140 parts of 3-(p-chlorophenyl)-6-methylthio-s-triazine-2,4(1H,3H)-dione melting at 292°-295°C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[N:34]=[C:33]([C:35](=[O:37])[CH3:36])[CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[CH:31][CH:32]=[C:33]([C:35](=[O:37])[CH3:36])[N:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: CC(=O)c1cccc(Br)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(C(C)=O)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 290, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 1-(6-bromo-pyridin-2-yl)-ethanone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13]([S:19][CH3:20])=[N:14][CH:15]=2)[NH:10][C:9]1=O.O=P(Cl)(Cl)[Cl:24].C(N(C(C)C)CC)(C)C>>[Cl:24][C:9]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:17](=[O:18])[C:16]2[C:11]([N:10]=1)=[N:12][C:13]([S:19][CH3:20])=[N:14][CH:15]=2
Reactant: CSc1ncc2c(=O)n(-c3ccccc3Cl)c(=O)[nH]c2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc2c(=O)n(-c3ccccc3Cl)c(Cl)nc2n1

Procedure:
A mixture of Example 1A (15.9 g, 49.6 mmol) in POCl3 (55 ml, 590 mmol) and diisopropylethylamine (55 ml, 315 mmol) was heated at 90° C. for 1.5 hours. The reaction mixture was concentrated. The residue was treated with ice and saturated NaHCO3 carefully and then extracted with ethyl acetate. The insoluble material suspended in the two layers was filtered, washed with ether and water, and oven dried to provide the title compound. The two layers in the filtrate were separated. The aqueous layer was washed with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, concentrated, and triturated (twice) with ethyl acetate/ether to provide additional title compound.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[N:3]=1.OC(C(F)(F)F)=O.[C:29]1([C:35]2[CH2:39][C:38]3([CH2:44][CH2:43][CH2:42][NH:41][CH2:40]3)[O:37][N:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:4]2[N:3]=[C:2]([N:41]3[CH2:42][CH2:43][CH2:44][C:38]4([O:37][N:36]=[C:35]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:39]4)[CH2:40]3)[CH:10]=[CH:9][C:5]=2[C:6]([NH2:8])=[O:7])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)c1ccc(Nc2nc(Cl)ccc2C(N)=O)cc1
Reactant: c1ccc(C2=NOC3(CCCNC3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(Nc2nc(N3CCCC4(CC(c5ccccc5)=NO4)C3)ccc2C(N)=O)cc1
Temperature: 120 °C
Reaction time: 20 h
Yield: 25.8 %

Procedure:
A mixture of 6-chloro-2-(4-(methylsulfonyl)phenylamino)nicotinamide (30 mg, 0.092 mmol), 3-phenyl-1-oxa-2,7-diazaspiro[4.5]dec-2-ene TFA salt (30.4 mg, 0.092 mmol) and N,N-diisopropylethylamine (0.064 mL, 0.368 mmol) in DMF (1 mL) was stirred at 120° C. for 20 h. The mixture was cooled to room temperature and purified by reverse phase HPLC, using Sunfire S10 30×250 mm column and eluting with 40% to 100% solvent B (10% MeOH-90% H2O-0.1% TFA) in solvent A (90% MeOH-10% H2O-0.1% TFA), to give a brown solid (12 mg, 21%). LCMS: (M+H)+=506.10. 1H NMR (400 MHz, acetonitrile-d3) δ ppm 7.69-7.80 (3H, m), 7.62-7.69 (2H, m), 7.55 (2H, d, J=9.03 Hz), 7.36-7.44 (3H, m), 6.28 (1H, d, J=9.04 Hz), 3.50-3.95 (4H, m), 3.08-3.38 (2H, m), 2.85 (3H, s), 2.01-2.13 (2H, m), 1.65-1.83 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[CH2:14][S:15](Cl)(=[O:17])=[O:16])=[O:4].[OH-].[NH4+:20].O>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[CH2:14][S:15]([NH2:20])(=[O:17])=[O:16])=[O:4]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CS(=O)(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc([N+](=O)[O-])c1CS(N)(=O)=O
Temperature: 25 °C

Procedure:
The crude product from Example 3 (15.1 g) was dissolved in 150 ml tetrahydrofuran and this solution was contacted at 0° C. with concentrated aqueous ammonium hydroxide. The resulting suspension was allowed to warm to room temperature over a 15-minute period and the solvent was removed in vacuo to yield an oily solid. Addition of water to this crude material resulted in gradual crystallization. The aqueous layer was extracted with ethyl acetate and the combined extracts were dried and concentrated in vacuo to give a yellow oil which solidified upon scratching. This material was washed with warm n-butyl chloride, filtered and dried to give the title compound as a pale yellow solid, m.p. 119°-123°; IR(nujol): 3490, 3330, 1710 cm-1 ; NMR (CDCl3): δ 4.0 (3H, s, CO2CH3), 5.4 (2H, s, --CH2 --), 6.8 (2H, s, NH2), 7.5.8.25 (3H, m).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH:11]([OH:16])[CH2:12][N:13]=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH:11]([OH:16])[CH2:12][NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=NCC(O)COCCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC(O)COCCc1ccccc1
Yield: 95.6 %

Procedure:
A procedure similar to that described in Preparation 13 was repeated, except that 5.30 g of 3-(2-phenylethoxy)-2-hydroxypropylazide (prepared as described in Preparation 56), 1.85 g of lithium aluminum hydride and 120 ml of anhydrous tetrahydrofuran were used, to give 4.47 g of the title compound as a colorless oil having an Rf value of 0.09 (on silica gel thin layer chromatography, using a 10:1 by volume mixture of ethyl acetate and methanol as the developing solvent).