Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:14]2[S:15][CH:16]([CH3:18])[CH2:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.Cl[Si:25]([CH3:28])([CH3:27])[CH3:26].Cl>O1CCCC1.CCCCCC>[C:1]([NH:5][S:6]([C:9]1[C:14]2[S:15][CH:16]([CH3:18])[CH2:17][C:13]=2[CH:12]=[CH:11][C:10]=1[Si:25]([CH3:28])([CH3:27])[CH3:26])(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)Cl
Reactant: CC1Cc2cccc(S(=O)(=O)NC(C)(C)C)c2S1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1Cc2ccc([Si](C)(C)C)c(S(=O)(=O)NC(C)(C)C)c2S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4.0 g of N-t-butyl-2,3-dihydro-2-methylbenzo[b]thiophene-7-sulfonamide in 175 ml of dry tetrahydrofuran was added 20 ml of a 1.6M hexane solution of n-butyl lithium at -40° C. to -30° C. under an inert atmosphere. The mixture was allowed to warm and was stirred at room temperature for 30 minutes. It was recooled to -30° C. and was contacted with 3.0 ml of chlorotrimethylsilane. The mixture was stirred at room temperature for 2 hours and was acidified with 10 ml of 6N hydrochloric acid. The organic layer was separated, was dried over magnesium sulfate, and was concentrated to a crude solid which was suspended in chlorobutane/hexane and filtered to give 2.0 g of the title compound as a beige solid, m.p. 119°-124° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH3:23][O:24][CH2:25][C:26]([C:29]1[O:33][N:32]=[C:31]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[CH:30]=1)([CH3:28])[CH3:27].COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(NC(NC2ON=C(C(C)C)C=2)=O)C=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:35]([NH:34][C:31]2[CH:30]=[C:29]([C:26]([CH3:28])([CH3:27])[CH2:25][O:24][CH3:23])[O:33][N:32]=2)=[O:36])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: COCC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Agent: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Product: COCC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OC)c(OC)cc34)c2)no1
Yield: 48.1 %

Procedure:
Prepared from 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (50 mg, 0.16 mmol) and phenyl 5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-ylcarbamate from Example 130A (50 mg, 0.17 mmol) according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B. Purification via preparative silica gel TLC eluting with 10% methanol in dichloromethane afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-yl)urea as a colorless solid (38 mg, 44%). 1H NMR (300 MHz, DMSO-d6) δ 9.57 (brs, 1H), 9.01 (brs, 1H), 8.56 (s, 1H), 7.57-7.58 (m, 2H), 7.38-7.42 (m, 2H), 7.25 (m, 1H), 6.97 (m, 1H), 6.50 (s, 1H), 3.99 (s, 6H), 3.38 (s, 2H), 3.23 (s, 3H), 1.24 (s, 6H); LC-MS (ESI) m/z 494 (M+H)+.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH2:5]([O:7][C:8](=[O:29])[CH:9]=[C:10]1[CH2:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:13]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:12]=2[NH:11]1)[CH3:6].C(O)(=O)C>O>[CH2:5]([O:7][C:8](=[O:29])[C:9](=[N:1][OH:3])[C:10]1[CH2:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:13]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:12]=2[N:11]=1)[CH3:6]
Reactant: CCOC(=O)C=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium nitrite, 1.5 g. (0.022 mol), was added to a solution of 6.2 g. crude 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylideneacetic acid ethyl ester in 75 ml. of glacial acetic acid. After stirring at room temperature for 20 minutes the reaction mixture was diluted with 200 ml. of water. The precipitated product was collected, washed with water and sucked dry to give crude product. The analytical sample was recrystallized from methylene chloride/ethanol to give light yellow crystals with mp 219°-221°.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[CH3:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17](=[O:20])[C:16]2=O.[OH2:22].[OH-].[K+]>CCO>[CH3:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[N:18]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH:2]=[C:16]2[C:17]([OH:20])=[O:22]
Reactant: O
Reactant: Cc1cccc2c1NC(=O)C2=O
Reactant: CC(=O)c1ccccn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc2c(C(=O)O)cc(-c3ccccn3)nc12

Procedure:
A mixture of 2-acetylpyridine (IV; R1 =2-aza: 6.05 g, 0.05 mol) and 7-methylisatin (V; R2 =H: 8.52 g, 0.053 mol) in 65 mL of 50% EtOH--H2O containing KOH (13 g) was refluxed for 2 h, then diluted with 50% EtOH--H2O to obtain a homogeneous solution, filtered and acidified (HOAc). The resulting acid was collected, washed with 30% EtOH--H2O and recrystallized from DMF--EtOH to provide the product (9.4 g, 67%, mp. 319°-320° C. Anal. (C16H12N2O2) C,H,N.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH2:10][CH:11]=[CH2:12].[H][H]>C(O)C.[Rh]>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12]
Reactant: C=CCc1cc(CO)ccc1O
Reactant: [H][H]
Agent: [Rh]
Solvent: CCO
Product: CCCc1cc(CO)ccc1O
Reaction time: 0.5 h

Procedure:
To a solution of 0.370 g (2.25 mmol) of the product of Step H dissolved in 25 mL of absolute ethanol was added 53 mg of a 5% rhodium on carbon catalyst and the mixture was shaken under a 40 psig pressure of hydrogen on a Parr apparatus. After 30 minutes, the reaction mixture was removed, filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 35% ethyl acetate/hexane to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:8][C:7]=1[Cl:20])[CH3:2].[CH3:22]CCCCC.CCOC(C)=O>>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:18]3[N:19]=[CH:22]2)=[CH:8][C:7]=1[Cl:20])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(Nc2ncccc2N)cc1Cl
Reactant: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(-n2cnc3cccnc32)cc1Cl

Procedure:
The title compound is prepared as described in Step 1.2 but using [4-(3-amino-pyridin-2-ylamino)-2-chloro-phenyl]-acetic acid ethyl ester. Title compound: ES-MS: 316.1 [M+H]+; single peak at tR=4.24 min (System 1); Rf=0.16 (Hexane/EtOAc, 1:1).
Reaction SMILES: Cl.Cl.[CH3:3][Si:4]([CH3:31])([CH3:30])[CH2:5][CH2:6][O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:23]4([CH2:27][C:28]#[N:29])[CH2:26][NH:25][CH2:24]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1.[OH:32][C:33]([C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[N:39]=[C:38]([O:46][CH:47]2[CH2:52][CH2:51][C:50](=O)[CH2:49][CH2:48]2)[CH:37]=1)([CH3:35])[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[OH:32][C:33]([C:36]1[CH:41]=[C:40]([C:42]([F:43])([F:44])[F:45])[N:39]=[C:38]([O:46][C@@H:47]2[CH2:52][CH2:51][C@H:50]([N:25]3[CH2:24][C:23]([CH2:27][C:28]#[N:29])([N:21]4[CH:22]=[C:18]([C:17]5[C:12]6[CH:11]=[CH:10][N:9]([CH2:8][O:7][CH2:6][CH2:5][Si:4]([CH3:30])([CH3:3])[CH3:31])[C:13]=6[N:14]=[CH:15][N:16]=5)[CH:19]=[N:20]4)[CH2:26]3)[CH2:49][CH2:48]2)[CH:37]=1)([CH3:34])[CH3:35]
Reactant: CC(C)(O)c1cc(OC2CCC(=O)CC2)nc(C(F)(F)F)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(O)c1cc(O[C@H]2CC[C@@H](N3CC(CC#N)(n4cc(-c5ncnc6c5ccn6COCC[Si](C)(C)C)cn4)C3)CC2)nc(C(F)(F)F)c1
Reaction time: 0.08 h

Procedure:
{3-[4-(7-{[2-(Trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (55.3 mg, 0.115 mmol) and 4-{[4-(1-hydroxy-1-methylethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexanone were dissolved in dry 1,2-dichloroethane (1.38 mL) and were stirred for 5 min and sodium triacetoxyborohydride (86.1 mg, 0.406 mmol) was added. The reaction mixture was stirred at 25° C. for 16 h, at which time LCMS analysis showed mainly the two diastereomeric products. The reaction was quenched with water, neutralized with NaHCO3 and extracted with ethyl acetate and the solvent was evaporated. The residue was purified by LCMS (pH 10) and the fractions containing the second peak were combined and evaporated to give {1-(cis-4-{[4-(1-hydroxy-1-methylethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile. The first peak was also isolated to give {1-(trans-4-{[4-(1-hydroxy-1-methyl ethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile. MS (ES): 712(M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2C(=[CH:10][CH:11]=1)NC=[CH:6]2.[Br:12]Br.[H-].[Na+].IC.[CH3:18][N:19]([CH3:22])[CH:20]=O>>[Br:12][C:6]1[C:5]2[C:18](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:19]([CH3:22])[CH:20]=1
Reactant: CN(C)C=O
Reactant: BrBr
Reactant: COc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COc1ccc2c(c1)c(Br)cn2C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ambient solution of 5-methoxy-1H-indole (5 g, 34.0 mmol) in N,N-dimethylformamide (100 mL) was added a solution of bromine (1.75 mL, 34.0 mmol) in N,N-dimethylformamide (25 mL). The mixture was stirred for about 15 minutes. The mixture was cooled to about 0° C., and NaH (3.26 g, 82 mmol) was added in portions over 15 minutes. The mixture was stirred for 15 minutes, and then iodomethane (2.55 mL, 40.8 mmol) was added. The bath was removed and the slurry was warmed to room temperature. After about 45 minutes, the solvents were removed under reduced pressure, and the mixture was partitioned between dichloromethane (50 mL) and water (100 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with dichloromethane, to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]=[O:13].[Cl:14][CH2:15][CH2:16][OH:17].CCOCC>CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:13])[O:17][CH2:16][CH2:15][Cl:14]
Reactant: OCCCl
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1Cl
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(Nc1ccc([N+](=O)[O-])cc1Cl)OCCCl
Temperature: 15 °C
Reaction time: 0.03 h

Procedure:
50.0 g of 2-chloro-4-nitrophenyl isocyanate was added, with stirring, to 100 g of 2-chloroethanol. After 2 minutes, the temperature of the mixture rose to 65° C. The mixture then was heated at 80°-90° C. for 10 minutes, and cooled. 200 ml of ether and 200 ml of hexane were added, the mixture was cooled to 15° C. and filtered. Drying of the filter cake gave 2-chloroethyl (2-chloro-4-nitrophenyl)carbamate (1A), as a white solid, mp: 128°-130° C.
Reaction SMILES: [Br:1][C:2]1[C:22]([Br:23])=[CH:21][C:20]([Br:24])=[CH:19][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH2:12][C:13]([O:15]CC)=[O:14])=[CH:8][C:7]=1[CH3:18])=[O:5].C(I)CC>>[CH2:12]([C:9]1[N:10]([CH3:11])[C:6]([C:4](=[O:5])[C:3]2[CH:19]=[C:20]([Br:24])[CH:21]=[C:22]([Br:23])[C:2]=2[Br:1])=[C:7]([CH3:18])[CH:8]=1)[CH3:13].[CH2:9]([CH2:12][C:13]([O-:15])=[O:14])[CH2:8][CH3:7]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2cc(Br)cc(Br)c2Br)n1C
Solvent: CCCI
Product: CCCCC(=O)[O-]
Product: CCc1cc(C)c(C(=O)c2cc(Br)cc(Br)c2Br)n1C

Procedure:
The alkylation procedure of Example 77A is performed upon ethyl 5-(2',3',5'-tribromobenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 91), using an equivalent quantity of n-propyl iodide instead of methyl iodide used in Example 77A to yield ethyl 5-(2',3',5'-tribromobenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetate.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[CH2:11][CH2:10][CH2:9]2.O.[C:18]([OH:22])(=O)[CH:19]=O.O.[NH2:24][NH2:25]>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:12]3[C:11](=[CH:19][C:18](=[O:22])[NH:24][N:25]=3)[CH2:10][CH2:9][C:8]=2[CH:7]=1
Reactant: O=C1CCCc2cc(OCCCCl)ccc21
Reactant: O=CC(=O)O
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc2c(n[nH]1)-c1ccc(OCCCCl)cc1CC2

Procedure:
In a 100 mL round bottom flask, 6-(3-chloro-propoxy)-3,4-dihydro-2H-naphthalen-1-one (1 g, 4.2 mmol), and glyoxylic acid monohydrate (387 mg, 4.2 mmol), in acetic acid (10 mL) was heated to reflux 6 h. The reaction was cooled and hydrazine monohydrate (0.41 mL, 8.4 mmol) was added and the reaction was heated to reflux 14 h. The reaction was cooled and the solvent concentrated under vacuum. The slurry was partitioned between methylene chloride and water, separated, dried over MgSO4. Purification with silica gel chromatography eluting with methylene chloride/methanol (95:5) produced 620 mg (51%). MS m/z 291 (M+H).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1.C([Li])CCC>CCCCCC.O1CCCC1>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:22]3[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Reactant: OC1CCNCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1nc(-c2ccccc2)nc2ccccc12)N1CCC(O)CC1

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (2 g), piperidin-4-ol (1.4 g), a 1.6M solution of butyllithium in hexane (18 ml) and tetrahydrofuran (30 ml) as the starting materials. After recrystallisation from a mixture of methanol and methylene chloride, 1-[(2-phenylquinazolin-4-yl)-carbonyl]-piperidin-4-ol (2.1 g), melting at 209° C., is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C)C=O>CC(C)=O.C(=O)([O-])[O-].[Ag+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([O:14][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)c(=O)[nH]c2-c2ccc(F)cc2)cc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cc(C#N)c(OCc3ccccc3)nc2-c2ccc(F)cc2)cc1

Procedure:
6-(4-Fluorophenyl)-1,2-dihydro-5-[4-(methylsulfonyl)phenyl]-2-oxo-pyridine-3-carbonitrile (Example 1, Step 6) (200 mg, 0.54 mMol), silver carbonate (150 mg, 0.54 mMol) and benzyl chloride (1 ml) were stirred in acetone (100 ml) and dimethylformamide (25 ml) at room temperature for 48 hours. The mixture was filtered and the filtrate was concentrated to a white solid which was recrystallized from chloroform-methanol: m.p. (DSC): 204.81° C. Anal. Calc'd. for C26H19N2O3SF (458.52): C, 68.11; H, 4.18; N, 6.11. Found: C, 67.81; H, 4.16; N, 6.04.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:24]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:25])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:51]N1C(=O)CCC1=O>O1CCCC1>[ClH:51].[Cl:51][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:24]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:25])=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(Nc1nccs1)c1nc(-c2cccc3ccccc23)[nH]c1-c1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cl
Product: O=C(Nc1nccs1)c1nc(-c2cccc3ccccc23)[nH]c1-c1ccc(CCl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51.4 %

Procedure:
5-(4-Hydroxymethylphenyl)-2-(1-naphthyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (1.0 g) obtained in Example 61 was dissolved in tetrahydrofuran (200 ml), and triphenylphosphine (1.24 g) and N-chlorosuccinimide (633 mg) were added. The mixture was stirred for 15 min and triphenylphosphine (1.24 g) and N-chlorosuccinimide (633 mg) were added. The mixture was stirred for 30 min. The reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and, after drying, concentrated. The obtained residue was suspended in acetone (30 ml) and 1 M hydrochloric acid—ether solution (3 ml) was added. The solvent was evaporated and ethyl acetate was added to the obtained residue. The resulting crystals were collected by filtration to give 5-(4-chloromethylphenyl)-2-(1-naphthyl)-N-(2-thiazolyl)imidazole-4-carboxamide hydrochloride (580 mg), melting point 280° C. or above.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:28][C:29]1[C:34]([F:35])=[C:33]([F:36])[CH:32]=[CH:31][C:30]=1[C:37](=[O:41])[C:38]#[C:39][CH3:40].CCN(C(C)C)C(C)C>CO>[CH3:40]/[C:39](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:38]/[C:37](=[O:41])[C:30]1[CH:31]=[CH:32][C:33]([F:36])=[C:34]([F:35])[C:29]=1[F:28]
Reactant: CC#CC(=O)c1ccc(F)c(F)c1F
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C/C(=C/C(=O)c1ccc(F)c(F)c1F)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Yield: 58.6 %

Procedure:
A mixture of 680 mg (1.85 mmol) of Intermediate 45, 367 mg (1.85 mmol) of Intermediate 36, and 0.67 mL (3.7 mmol) of DIEA in 15 mL of MeOH was refluxed overnight (14 h). The solvent was evaporated under reduced pressure and the residue purified directly by silica gel chromatography. Elution with 5%-20% MeOH in CH2Cl2 gave 612 mg (58% yield) of the title compound as a solid: TLC (DCM/MeOH, 4/1): Rf=0.50; 1H NMR (DMSO-d6, 300 MHz) δ11.35 (d, 1H, J=9.0), 7.87 (m, 2H), 7.48 (m, 4H), 7.3 (q, 1H, J=5.4), 7.10 (d, 2H, J=8.7), 6.78 (d, 2H, J=8.7), 5.25 (s, 1H), 4.18 (m, 3H), 3.19 (m, 2H), 2.86 (t, 2H, J=6.3), 2.74 (dd, 1H, J=13.8, 9.0), 2.32 (s, 3H), 1.64 (s, 3H); low resolution MS (ES+)m/e 564.9 (MH+);
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].C(=O)([O-])[O-].[Ca+2].ClCCl.[CH2:13]([C:15]1[CH:21]=[C:20]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[C:18]([CH2:29][CH3:30])[C:16]=1[NH2:17])[CH3:14]>ClC(Cl)C.O>[CH2:13]([C:15]1[CH:21]=[C:20]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[C:18]([CH2:29][CH3:30])[C:16]=1[N:17]=[C:1]=[S:2])[CH3:14]
Reactant: CCc1cc(Cc2ccccc2)cc(CC)c1N
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCc1cc(Cc2ccccc2)cc(CC)c1N=C=S
Reaction time: 2 h

Procedure:
34.0 g of thiophosgene, 54.8 g of calcium carbonate and 460 ml of dichloromethane are stirred with 230 ml of water. A solution of 59.3 g of 2,6-diethyl-4-benzylaniline in 200 ml of dichloroethane is stirred dropwise into this mixture at room temperature. The reaction mixture is stirred for 2 hours under reflux and, after cooling, is filtered over diatomaceous earth. The organic phase is separated from the filtrate, dried over sodium sulfate and freed of the solvent to give the title compound of formula ##STR14## in the form of a yellow oil which is used without further purification for the next reaction.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[S:10](=[O:14])(=[O:13])[CH:11]=[CH:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[C:9]2[S:10](=[O:14])(=[O:13])[CH2:11][CH2:12][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc2c1S(=O)(=O)C=C2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc2c1S(=O)(=O)CC2
Yield: 80.1 %

Procedure:
7-Nitrobenzo[b]thiophene-1,1-dioxide (19 g, Example 17) was hydrogenated in 200 ml of ethyl acetate over 1.0 g of 10% palladium-on-charcoal catalyst at 500 pounds-per-square-inch of pressure and 100° C. until no more hydrogen gas was absorbed. The mixture was filtered through celite, and the filtrate was concentrated in vacuo. The solid residue was recrystallized from 1-chlorobutane to yield 13.2 g of the title compound; m.p. 117°-119° C.
Reaction SMILES: [Li]CCCC.[O:6]1[CH:10]=[C:9]([CH:11]=O)[N:8]=[CH:7]1.[OH2:13].[CH3:14][CH2:15][O:16][CH2:17][CH3:18]>>[CH2:15]([O:16][C:17](=[O:13])[CH:18]=[CH:11][C:9]1[N:8]=[CH:7][O:6][CH:10]=1)[CH3:14]
Reactant: O=Cc1cocn1
Reactant: O
Reactant: CCOCC
Agent: [Li]CCCC
Product: CCOC(=O)C=Cc1cocn1
Temperature: -78 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
Triethylphosphonoacetate (29.4 mL, 147 mmol) was dissolved in dry Et2O (200 mL) under nitrogen. The sol. was cooled to −78° C., and BuLi (1.6 M in hexane, 85 mL, 136 mmol) was added slowly. The mixture was stirred for 2 h at −78° C., and a sol. of the oxazole-4-carbaldehyde (11.9 g, 122 mmol) in dry Et2O was added slowly. The reaction mixture was stirred for 4 h. The reaction mixture was combined with Et2O and water, and the org. phase was washed with aq. sat. NaHCO3. The org. extracts were dried over MgSO4, filtered and the solvents were carefully removed under reduced pressure (volatile product). Purification of the residue by FC (heptane/EtOAc; 1.5:1→1:1→1:2) yielded the title compound (15.1 g, 74%). LC-MS: tR=0.77, ES+: 209.10.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([O:26][CH3:27])[O:24][CH3:25])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:3]=1.[F-:28].[K+]>CS(C)=O.CCOC(C)=O>[C:8]([C:7]1[C:2]([F:28])=[CH:3][C:4]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([O:26][CH3:27])[O:24][CH3:25])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:5][CH:6]=1)#[N:9]
Reactant: [F-]
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(Cl)c(C#N)cn1)CCC2
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(F)c(C#N)cn1)CCC2
Temperature: 110 °C
Reaction time: 16 h

Procedure:
N-(4-chloro-5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2J, 106 mg, 0.273 mmol) and KF (159 mg, 2.73 mmol) were dissolved in DMSO (3 ml). The mixture was stirred at 110° C. for 16 h. The mixture was cooled to room temperature, diluted in EtOAc and washed with sat. aq. NaHCO3 (2×) and brine. The org. layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 60:40) to give the title compound as a white solid. (UPLC-MS 3) tR 1.20 min; ESI-MS 372.1 [M+H]+.