Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[N:3]=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.[NH2:23][C:24]1[C:32]([I:33])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].O.N>CN(C=O)C.O>[NH2:23][C:24]1[C:32]([I:33])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH2:3])=[O:27]
Reactant: Nc1c(I)cccc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(I)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
EDCI hydrochloride (18.4 g) and 1-hydroxybenzotriazole (9.5 g) were added to a solution of 2-amino-3-iodobenzoic acid (16.4 g) synthesized using the method described in Journal of Medicinal Chemistry, 2004, 47 (6), 1448-1464 in DMF (120 mL), and subsequently ammonia water (21.2 ml) was added thereto. The reaction solution was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the deposit was filtrated and dried under reduced pressure to obtain 2-amino-3-iodobenzamide (12.8 g). 60% sodium hydride (2.29 g) was added to a solution of the obtained 2-amino-3-iodobenzamide (5.0 g) in ethanol (95 ml), then ethyl trifluoroacetate (10.8 g) was added thereto, and the mixture was heated to reflux for 15 hours. After cooling, water was added thereto, and the reaction solution was rendered acidic by the addition of 6 N hydrochloric acid. Then, the deposit was filtrated and dried under reduced pressure to obtain compound (4a) (6.4 g, yield based on 2 steps: 77%).
Reaction SMILES: N1C=CC=CC=1.F.C(#N)C.[C:11]([O:16][C:17]1[CH2:30][C@@H:29]([O:31][Si](C(C)(C)C)(C)C)[C@H:28](/[CH:39]=[CH:40]/[C@@H:41]([O:47][Si](C(C)(C)C)(C)C)[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:18]=1[S:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=O)(=[O:15])[CH2:12][CH2:13][CH3:14].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.N1C=CC=CC=1>[C:11]([O:16][C:17]1[CH2:30][C@@H:29]([OH:31])[C@H:28](/[CH:39]=[CH:40]/[C@@H:41]([OH:47])[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:18]=1[S:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:15])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCC[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)O)=C(OC(=O)CCC)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCCCSC1=C(OC(=O)CCC)C[C@@H](O)[C@@H]1/C=C/[C@@H](O)CCCCC
Temperature: 25 °C
Reaction time: 20 h
Yield: 35 %

Procedure:
A hydrogen fluoride-pyridine solution (0.1 ml) was added to a solution of ice-cooled acetonitrile (1 ml) and pyridine (0.1 ml), then a pyridine (0.1 ml) solution of (11R,12S,13E,15S)-9-butyryloxy-11,15-bis(tert-butyldimethylsiloxy)-7-thiaprosta-8,13-dienoic acid (79 mg) was added. The ice bath was detached, then the solution was stirred for 20 hours while raising it to room temperature. The reaction solution was poured into a mixture of ethyl acetate and saturated sodium hydrogencarbonate. The target substance was extracted from the mixture by ethyl acetate. The extract was washed with saturated sodium chloride solution, then was dried over anhydrous sodium sulfate. This solution was concentrated under reduced pressure, then was purified by a preparative TLC (Merck TLC plate silica gel 60 F254, 20×20 cm, layer thickness 0.25 mm, 2 pieces, ethyl acetate:hexane 4:1) to obtain (11R,12S,13E,15S)-9-butyryloxy-11,15-dihydroxy-7-thiaprosta-8,13-diene acid (17 mg, 33%).
Reaction SMILES: O.[NH2:2][NH2:3].C[O:5][C:6](=O)[C:7]([NH:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][C@@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:12][CH:11]=1)=[O:8]>CCO>[NH:2]([C:6](=[O:5])[C:7]([NH:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][C@@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:12][CH:11]=1)=[O:8])[NH2:3]
Reactant: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc(NC(=O)C(=O)OC)cc2)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc(NC(=O)C(=O)NN)cc2)CC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrazine monohydrate (2.29 mL, 47.1 mmol) was added in one portion to a stirred solution of ethyl cis-4-(4-{[methoxy(oxo)acetyl]amino}phenoxy)cyclohexanecarboxylate (8.23 g, 23.6 mmol) in EtOH (200 mL) and the reaction mixture was stirred at 70° C. for 1 h. After cooling to ambient temperature the mixture was filtered and washed with ether (200 mL) to leave the title compound (Intermediate 1) as a white solid (7.80 g, 95%) that was used with no further purification.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[NH2:10][C:11]([NH2:13])=[S:12]>C(O)C>[ClH:2].[ClH:1].[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][S:12][C:11](=[NH:10])[NH2:13]
Reactant: ClCc1ccccn1
Reactant: NC(N)=S
Agent: Cl
Solvent: CCO
Product: N=C(N)SCc1ccccn1
Yield: 94.9 %

Procedure:
A solution of 2-chloromethylpyridine hydrochloride (30 g) in ethanol (100 cc) at 60° C. is added dropwise, in the course of 15 minutes, to a suspension of thiourea (17.6 g) in boiling ethanol (100 cc). Boiling is maintained for 90 minutes and then, after cooling, the crystals which have appeared are filtered off, washed twice with ethanol (100 cc in total) and dried under reduced pressure (20 mm Hg) at a temperature of about 20° C., in the presence of potassium hydroxide pellets. 2-(Pyrid-2-ylmethyl)isothiourea dihydrochloride (41.7 g), melting at 220° C., is thus obtained.
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:22])[CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:21])=[O:20])=[CH:15][CH:14]=2)[CH2:10][C:11]=1[OH:12])(=O)[CH2:2][CH2:3][CH3:4].[CH2:23]([O:25][NH2:26])[CH3:24]>C(O)C>[CH2:23]([O:25][N:26]=[C:1]([C:6]1[C:7](=[O:22])[CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:21])=[O:20])=[CH:15][CH:14]=2)[CH2:10][C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4])[CH3:24]
Reactant: CCON
Reactant: CCCC(=O)C1=C(O)CC(c2ccc(S(C)=O)cc2)CC1=O
Solvent: CCO
Product: CCCC(=NOCC)C1=C(O)CC(c2ccc(S(C)=O)cc2)CC1=O
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Into 20 ml of ethanol was dissolved 1.6 g of 2-butyryl-3-hydroxy-5-(4-methylsulfinylphenyl)-2-cyclohexen-1-one and to the solution was added 0.5 g of ethoxyamine. The mixture was kept for 15 hours at room temperature and it was poured into ice water. The crystal sedimented was collected with a filtering step and recrystallized with methanol. Thus, 1.3 g of colorless objective crystals having a melting point of 72°-74° C. was obtained.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:25][CH2:26][CH3:27])[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[O:16][C:15]3([CH3:24])[CH3:23])=[CH:7][CH:6]=1)C.[OH-].[Na+]>C(O)C>[CH2:25]([N:11]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17]([CH3:22])([CH3:21])[O:16][C:15]2([CH3:23])[CH3:24])[C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:28])=[O:3])=[CH:10][CH:9]=1)[CH2:26][CH3:27]
Reactant: CCCN(c1ccc(C(=O)OCC)cc1)c1ccc2c(c1)C(C)(C)OC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCN(c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)OC2(C)C
Temperature: 55 °C
Yield: 58.5 %

Procedure:
A solution of 4-[n-propyl-(1,1,3,3-tetramethyl-1,3-dihydro-isobenzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 81, 0.22 g, 0.58 mmol) in 20 mL of ethanol was treated with 2 mL of 5M sodium hydroxide solution and the resulting solution was heated at 55° C. for 2 hours. The volatiles were removed by distillation in vacuo and the residue was acidified using hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate and evaporated to a residue which was recrystallized from hot ethyl acetate to afford the title compound (0.12 g, 55%) as a white solid. 1H NMR (300 MHz, acetone-d6): δ 7.80 (d, 2H, J=9.0 Hz), 7.28 (d, 1H, J=8.0 Hz), 7.04 (dd, 1H, J=8.0,1.8 Hz), 7.10 (d, 1H, J=1.8 Hz), 6.72 (d, 2H, J=8.9 Hz), 3.73 (t, 2H, J=7.8 Hz), 1.76-1.64 (m, 2H), 1.48 (s, 6H), 1.46 (s, 6H), 0.94 (t, 3H, J=7.4 Hz).
Reaction SMILES: [C:1]([O:4][C:5]1[C:21]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[C:20]([OH:27])[CH:19]=[C:18]([OH:28])[C:6]=1[C:7](=[O:17])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:4][C:5]1[C:21]([CH2:22][CH2:23][CH:24]([CH3:25])[CH3:26])=[C:20]([OH:27])[CH:19]=[C:18]([OH:28])[C:6]=1[C:7](=[O:17])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(CC=C(C)C)c(O)cc(O)c1C(=O)C=Cc1ccc(O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Oc1c(CCC(C)C)c(O)cc(O)c1C(=O)CCc1ccc(O)cc1
Reaction time: 1 h
Yield: 77.9 %

Procedure:
A solution of 1.55 g of the 2'-acetoxy-4,4',6'-trihydroxy-3'-(3-methyl-2-butenyl)chalcone obtained in Specific Example 18 in ethanol (30 ml) was added to a suspension of 1.5 g of 5% palladium/carbon in 30 ml of ethanol, in which hydrogen had been sufficiently absorbed in advance, and the mixture was stirred under atmospheric pressure in a hydrogen gas atmosphere for 1 hour. After the reaction, the reaction mixture was filtered and the solvent was removed from the filtrate by distillation. The obtained residue was subjected to the silica gel column chromatography (25 g of 230-400 mesh silica gel, n-hexane/ethyl acetate=3/1, 0.3 kg/cm2). Fractions of 50 ml were collected and the 5th to 9th fractions were combined. The solvent was removed by distillation and the obtained residue was recrystallized from a mixed solvent of n-hexane and ethyl acetate to obtain 1.22 g (yield=77.7%) of 1-(2-acetoxy-4,6-dihydroxy-3-isopentylphenyl)-3-(4-hydroxyphenyl)-1-propanone in the form of a colorless prism.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([I:11])=[CH:7][N:6]2[C:12]=1[CH3:13].[CH3:14][O-:15].[Na+]>CO>[I:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:12]([CH3:13])=[C:3]([CH2:2][O:15][CH3:14])[N:4]=2)[CH:7]=1
Reactant: C[O-]
Reactant: Cc1c(CCl)nc2ccc(I)cn12
Agent: [Na+]
Solvent: CO
Product: COCc1nc2ccc(I)cn2c1C
Temperature: 25 °C
Yield: 67.6 %

Procedure:
To a stirred solution of 2-(chloromethyl)-6-iodo-3-methylimidazo[1,2-a]pyridine (150 mg) in MeOH (2.5 ml) was added sodium methoxide (65 mg), and the resulting mixture was heated at reflux for 3 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The mixture was diluted with water, and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (100 mg) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C@H:12]2[CH3:24])=[N:9][CH:10]=1)=[O:4].Cl>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]2[CH3:24])=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)C[C@H]2C)cn1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cnc(N2CCNC[C@H]2C)cn1
Temperature: 70 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a solution of (R)-2-methyl-4-boc-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester (2 g, 5.94 mmol) in MeOH (17 mL) is added HCl (4M in dioxane, 4.5 mL, 18 mmol). The reaction mixture is stirred at 70° C. for 1 h. The reaction solution is concentrated, dissolved in DCM and organic layer is washed with Na2CO3 to adjust the pH value to 8.0. The solvents are removed under reduced pressure to afford a brown oil (1.2 g, 77%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1N

Procedure:
The title compound was prepared from (4-chloro-2-nitro-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A19) (3.37 g, 0.99 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as an orange solid (2.55 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([F:13])[C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:38]([O:45][C:46]1[C:51]([CH2:52][NH:53][CH2:54][CH2:55][OH:56])=[C:50]([CH3:57])[CH:49]=[C:48]([CH3:58])[N:47]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C>[CH2:38]([O:45][C:46]1[C:51]([CH2:52][N:53]([CH2:54][CH2:55][OH:56])[C:4](=[O:6])[C:3]2[C:7]([F:13])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:2]=2[Cl:1])=[C:50]([CH3:57])[CH:49]=[C:48]([CH3:58])[N:47]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Cc1cc(C)c(CNCCO)c(OCc2ccccc2)n1
Reactant: COc1ccc(F)c(C(=O)O)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(F)c(C(=O)N(CCO)Cc2c(C)cc(C)nc2OCc2ccccc2)c1Cl
Reaction time: 0.08 h
Yield: 99.9 %

Procedure:
To a solution of 2-chloro-6-fluoro-3-methoxy-benzoic acid (1.00 g, 4.89 mmol) in anhydrous DMF (30 mL) were added HATU (2.30 g, 5.85 mmol) and TEA (1.36 mL, 9.76 mmol). The reaction mixture was stirred for 5 minutes, then 2-[(2-benzyloxy-4,6-dimethyl-pyridin-3-ylmethyl)-amino]-ethanol (Cpd KK, 1.47 g, 5.12 mmol) was added as a solid in one portion. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate (200 mL) and water (200 mL). The organic phase was separated, washed with brine (2×200 mL), dried over sodium sulfate, and concentrated under vacuum to give N-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-2-chloro-6-fluoro-N-(2-hydroxyethyl)-3-methoxybenzamide (124a, 2.31 g, 100%) as a gum.
Reaction SMILES: Cl.[S:2]1[N:6]=[CH:5][C:4]([O:7][CH2:8][C@@H:9]2[O:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH2:26][CH2:25][N:24]([C:27]([C@@H:29]5[CH2:33][O:32]C(C)(C)[O:30]5)=[O:28])[CH2:23][CH:22]=4)=[C:17]([F:36])[CH:16]=3)[CH2:10]2)=[N:3]1>C1COCC1>[S:2]1[N:6]=[CH:5][C:4]([O:7][CH2:8][C@@H:9]2[O:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH2:26][CH2:25][N:24]([C:27](=[O:28])[C@@H:29]([OH:30])[CH2:33][OH:32])[CH2:23][CH:22]=4)=[C:17]([F:36])[CH:16]=3)[CH2:10]2)=[N:3]1
Reactant: CC1(C)OC[C@@H](C(=O)N2CC=C(c3ccc(N4C[C@H](COc5cnsn5)OC4=O)cc3F)CC2)O1
Agent: Cl
Solvent: C1CCOC1
Product: O=C([C@@H](O)CO)N1CC=C(c2ccc(N3C[C@H](COc4cnsn4)OC3=O)cc2F)CC1
Reaction time: 48 h
Yield: 24.9 %

Procedure:
1N aqueous HCl (1 ml) was added to a solution of 5(R)-(1,2,5-thiadiazol-3-yloxymethyl)-3-(3-fluoro4-(1-(2,2-dimethyl-1,3-dioxolan-4(S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-one (0.154 g, 0.32 mmol) in THF (3 ml) and the solution kept for two days. The solution was evaporated and the residue azeotroped twice with ethanol. The residue was purified by chromatography on a BondElut silica column, eluting first with dichloromethane and then 2% MeOH/dichloromethane to give the title product (37 mg, 26%) as a solid. MS: 465 (MH+); NMR(400 MHz): 2.5 (2H+DMSO); 3.3 (1H, s)3.4 (1H, m); 3.5 (1H, m); 3.76 (1H, m); 4.0 (1H, t); 4.15 (1H, s); 4.26 (1H, t); 4.4 (1H, m); 4.8 (3H, m); 4.97 (1H, m); 5.18 (1H, m); 6.03 (1H, s); 7.32-7.46 (2H, m); 7.53 (1H, d); 8.47 (1H, s).
Reaction SMILES: [C:1]1([C:14]2[C:22]3[C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[S:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[B:32](OC)([O:35]C)[O:33]C.Cl>CCCCCC.O1CCCC1>[C:1]1([C:14]2[C:22]3[C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[S:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[C:13]([B:32]([OH:35])[OH:33])[C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)sc1cccc(-c3cccc4sc5ccccc5c34)c12
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc2c1sc1cccc(-c3cccc4sc5ccccc5c34)c12
Temperature: -80 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
Into a 500-mL three-neck flask was put 5.0 g (13 mmol) of 4,4′-bidibenzothiophene, and the air in the flask was replaced with nitrogen. Into this flask was put 100 mL of tetrahydrofuran (THF), and this solution was cooled down to −80° C. To this solution, 8.7 mL (14 mmol) of n-butyllithium (a 1.6 mol/L hexane solution) was dripped with a syringe. After the dripping, this solution was stirred for 2 hours while its temperature was returned to room temperature. After the stirring, this solution was cooled down to −80° C. To this solution, 1.9 mL (17 mmol) of trimethyl borate was added, and the mixture was stirred for 18 hours while its temperature was returned to room temperature. After the stirring, approximately 50 mL of dilute hydrochloric acid (1.0 mol/L) was added to this solution, followed by stirring for 1 hour. After the stirring, the aqueous layer of this mixture was extracted with ethyl acetate, and the extracted solution and the organic layer were combined and washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated brine. The organic layer was dried with magnesium sulfate, and then this mixture was gravity-filtered. The resulting filtrate was concentrated to give a white solid. This solid was washed with 100 mL of hot toluene to give 2.6 g of white powder, which was an objective substance, in 50% yield. Synthesis Scheme (a-2) of Step 2 is shown below.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[CH:9]1[C:17]2[C:16]3[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=3[O:14][C:13]=2[CH:12]=[CH:11][C:10]=1[NH2:22]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:7][CH3:8])[C:4]([NH:22][C:10]1[CH:11]=[CH:12][C:13]2[O:14][C:15]3[CH2:21][CH2:20][CH2:19][CH2:18][C:16]=3[C:17]=2[CH:9]=1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)Cl
Reactant: Nc1ccc2oc3c(c2c1)CCCC3
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCN(CC)C(=O)Nc1ccc2oc3c(c2c1)CCCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
Diethylcarbamoyl chloride (0.72 mL, 5.5 mmol) was added to a solution of 6,7,8,9-tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol) in pyridine (15 mL). The reaction mixture was stirred overnight at room temperature. The crude material was diluted in chloroform and washed with 1 N HCl, water, and brine, dried (Na2SO4) and concentrated. The crude material was recrystallized from acetonitrile to provide 1,1-diethyl-3-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-urea (0.78 g). Mp 179-180° C.; Anal. Calcd. for C17H22N2O2: C, 71.30; H, 7.74; N, 9.78; Found: C, 71.29; H, 7.66; N, 9.72.
Reaction SMILES: [C:1]([CH2:3][CH:4]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[C:5](OCC)=[O:6])#[N:2].N>CO.[Ni].O>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([CH:4]2[CH2:3][CH2:1][NH:2][C:5]2=[O:6])=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(CC#N)c1ccc(C(F)(F)F)cc1
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CO
Product: O=C1NCCC1c1ccc(C(F)(F)F)cc1

Procedure:
A solution of the product from Example 266B (4.1 g, 15.12 mmol) in methanol (10 mL) was added to 7 M ammonia in methanol (5.00 mL) and Raney® nickel, water wet, A-7000 (12.30 g, 210 mmol) in a 250 mL stainless steel pressure bottle and stirred for 16 hours under hydrogen (30 psi) at room temperature. The mixture was filtered through a nylon membrane and then concentrated to obtain solid. The solid was slurried in 5% ethyl acetate/hexanes, filtered and dried to give the title compound. MS (DCI+) m/z 247 (M+NH4)+.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.Cl.C(N)C=C>C(O)(=O)C>[CH2:1]([N:7]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[N:9]=[CH:8]1)[CH:2]=[CH2:3]
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Agent: Cl
Solvent: C=CCN
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: C=CCn1cnc2c(-c3ccccc3)csc2c1=O
Yield: 57.5 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), allylamine hydrochloride (92.6 mg, 0.99 mmol), and acetic acid (0.1 ml) were used to give 66.4 mg (0.25 mmol, 57.5% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:27].[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:26])[CH3:25])=[CH:21][CH:22]=4)[C:6]([S:12]([CH3:15])(=[O:13])=[O:14])=[CH:7][N:8]=3)[N:3]=2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]
Reactant: CN(C)Cc1ccc(Nc2c(S(C)(=O)=O)cnc3ccc(Cl)nc23)cc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(C)Cc1ccc(Nc2c(S(C)(=O)=O)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)nc23)cc1
Yield: 84.6 %

Procedure:
Following general procedure II, 6-chloro-N-{4-[(dimethylamino)methyl]phenyl}-3-(methylsulfonyl)-1,5-naphthyridin-4-amine (50 mg, 0.14 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (58 mg, 0.21 mmol) followed by formation of the dihydrochloride salt to afford the desired product (51 mg, 63%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.12 (s, 1H), 8.46 (d, J=9.0 Hz, 1H), 8.37 (d, J=9.1 Hz, 1H), 7.68-7.61 (m, 2H), 7.60-7.53 (m, 2H), 7.22 (t, J=1.8 Hz, 1H), 7.06 (dd, J=11.9, 2.2 Hz, 1H), 4.43 (s, 2H), 3.48 (s, 3H), 2.88 (s, 6H); ESI MS m/z 501 [M+H]+; HPLC>99% (AUC), tR=10.68 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C@:13]([F:15])([CH3:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C@@:13]([F:15])([CH3:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(N)ccc1F
Product: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(NC(=O)c2ccc(Cl)cn2)ccc1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.3) and 5-chloro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=395.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[N:11]=[C:10]([C:23]([O:25]CC)=[O:24])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[N:11]=[C:10]([C:23]([OH:25])=[O:24])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)n(-c2cccc(C(F)(F)F)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(-c2cccc(Cl)c2)n(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.00 g (5.07 mmol) of the compound of Example 32A are provided in 37 ml of 1,4-dioxane, a solution of 1.07 g (20.0 mmol) of lithium hydroxide in 37 ml of water is added, and the mixture is stirred at room temperature overnight. The mixture is concentrated, a 1N aqueous hydrogen chloride solution is subsequently added to the residue until the pH is acidic, the mixture is extracted with ethyl acetate, and the combined organic phases are dried over sodium sulfate, filtered and concentrated. 0.74 g (40% of theory) of the title compound are obtained.