Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.N([F:44])(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O>C1COCC1>[CH2:16]([CH:15]([NH:14][C:11]1[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([O:6][C:5]2[C:21]([CH3:23])=[CH:22][C:2]([F:44])=[CH:3][C:4]=2[CH3:24])[C:12]=1[CH3:13])[CH2:18][CH3:19])[CH3:17]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(F)cc2C)c1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added n-butylitium at −78° C. After stirring at −78° C. for 10 min, (PhSO2)2NF was added and the resulting mixture was stirred at −78° C. for 30 min, the dry-ice bath was removed. After stirring for 5 min, the mixture was quenched with brine and extracted with ethyl acetate. The organic layer was separated, dried, and concentrated to dryness. The residue was purified through silica gel chromatography to give the title compound. 1H NMR(CDCl3) d 6.77(s, 1H), 6.73(s, 1H), 6.08(s, 1H), 3.3(m, 1H), 2.12(s, 3H), 2.09(s, 6H), 2.08(s, 3H), 1.4-1.8(m, 4H), 0.97(t, 6H), ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.[NH2:11]OS(O)(=O)=O.C(=O)(O)[O-].[Na+]>C(O)C.ClCCl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][N:11]=[CH:7][C:6]=2[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: NOS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: Brc1ccc2oncc2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 5-bromo-2-hydroxy-benzaldehyde (2.0 g, 10 mmol) in ethanol (10 mL) at room temperature was treated with hydroxylamine-O-sulfonic acid (1.69 g, 15 mmol), stirred for 20 minutes, diluted with dichloromethane (50 mL), cooled to 0° C. and treated with a solution of sodium bicarbonate (3 g) in water (25 mL). The solution was stirred at 0° C. for 30 minutes. The organic layer was removed and the aqueous layer was extracted with dichloromethane. The aqueous layer was treated with additional dichloromethane (50 mL) and stirring was continued for one hour. The layers were separated and the aqueous layer was extracted with dicloromethane. The combined organic layers were washed with brine, dried (MgSO4) and concentrated. The concentrate was recrystallized from ethanol to give 970 mg (49%) yield of the desired product. MS (ESI(−)) m/e 195.9, 197.9 (M−H)−
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]([CH3:30])=[CH:16][C:17]([N:18]3[CH2:23][CH2:22][C:21](=[O:24])[CH:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19]3)=[C:12]2[C:11]([CH3:31])=[C:10]1[CH3:32].[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]([CH3:30])=[CH:16][C:17]([N:18]3[CH2:23][CH2:22][CH:21]([OH:24])[CH:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19]3)=[C:12]2[C:11]([CH3:31])=[C:10]1[CH3:32]
Reactant: CCOC(=O)C1CN(c2cc(C)nc3c2c(C)c(C)n3-c2ccc(Cl)cc2Cl)CCC1=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C1CN(c2cc(C)nc3c2c(C)c(C)n3-c2ccc(Cl)cc2Cl)CCC1O
Temperature: -15 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
In ethanol (3.0 mL) was dissolved 1-(2,4-dichlorophenyl)-4-(3-ethoxycarbonyl-4-oxopiperidin-1-yl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine (0.13 g), and the solution was cooled to −15° C. Then, sodium boro hydride (26 mg) was added thereto and the resulting mixture was stirred overnight while being slowly heated to 0° C. A saturated aqueous ammonium chloride solution was poured into the reaction mixture, which was then extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: chloroform-methanol=50:1) to obtain 1-(2,4-dichlorophenyl)-4-(3-ethoxycarbonyl-4-hydroxy-piperidin-1-yl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine (35 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH2:9]>CS(C)=O.C(OCC)C>[S:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[S:8][C:5]1[CH:6]=[CH:7][C:2]([OH:9])=[CH:3][CH:4]=1
Reactant: Oc1ccc(S)cc1
Reactant: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: Oc1ccc(SSc2ccc(O)cc2)cc1
Reaction time: 24 h
Yield: 96 %

Procedure:
25.0 g of para-hydroxy thiophenol (Wako Pure Chemical Industries, Ltd.) was dissolved in 100 ml of dimethyl sulfoxide (Kanto Chemical Co., Ltd.) at 0 degree C. The reaction solution was stirred for 24 hours at 65 degree C. and cooled to 0 degree C. after the completion of the reaction. Then the mixture was diluted with 100 ml of diethyl ether (Wako Pure Chemical Industries, Ltd.). Water was added to this solution and the aqueous phase was extracted with 50 ml of diethyl ether three times. Then the organic phase was dried by using sodium sulfate (Wako Pure Chemical Industries, Ltd.) and recrystallized in chloroform (Wako Pure Chemical Industries, Ltd.). 4,4′-disulfanediyldiphenol was obtained (23.8 g, yield 96%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].[CH3:24][N:25]([CH3:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([N:25]([CH3:35])[CH3:24])[CH:31]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)c1cccc(B(O)O)c1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccc(N(C)C)c3)c(C)sc2n1
Temperature: 150 °C
Yield: 36.1 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (100 mg, 0.232 mmol) (Example 61) was dissolved in toluene (2 mL) and [3-(dimethylamino)phenyl]boronic acid (57.3 mg, 0.347 mmol), PdCl2(dppf).DCM (18.91 mg, 0.023 mmol) and Cs2CO3 (226 mg, 0.695 mmol) were added and the mixture heated in a microwave at 150° C. for 30 min. Water (10 mL) was then added and the mixture extracted with ethyl acetate (3×10 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo. Purification by chromatography on silica gel, eluting with a gradient of 0-30% ethyl acetate in cyclohexane, was followed by trituration with MeOH, to afford the title compound (39.5 mg). LCMS (A) m/z: 472 [M+1]+, Rt 0.97 min (basic), Rt 1.51 min (acidic).
Reaction SMILES: C(O[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:12][CH:13]=2)[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[N:23]=2)[CH:7]=1)=[O:5])C.Cl.[CH3:30][NH:31][O:32][CH3:33].C[Al](C)C>C1(C)C=CC=CC=1>[CH3:33][O:32][N:31]([CH3:30])[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([C:17]([F:18])([F:20])[F:19])=[CH:12][CH:13]=2)[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[N:23]=2)[CH:7]=1)=[O:5]
Reactant: CCOC(=O)c1cn(Cc2cccc(Br)n2)c2nc(C(F)(F)F)ccc2c1=O
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2nc(C(F)(F)F)ccc2c1=O

Procedure:
A mixture of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (0.72 g, 1.6 mmol, 1 equiv) and methylmethoxyamine hydrochloride (0.16 g, 1 equiv) in 2 mL of toluene was treated with AlMe3 (0.5 M in toluene, 3.5 mL, 1.1 equiv) at rt for 1 h. The reaction was quenched by slow addition of saturated aqueous solution of sodium potassium tartrate. The organic layer was dried over sodium sulfate, filtered and evaporated to give crude 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-3carboxylic acid methoxy-methyl-amide.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH:23][C:24]4[C:29]([NH2:30])=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31]OC(OC)OC>C(O)=O>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:23]4[C:24]5=[N:25][CH:26]=[CH:27][CH:28]=[C:29]5[N:30]=[CH:31]4)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(OC)OC
Reactant: Nc1cccnc1NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: O=CO
Product: c1cnc2c(c1)ncn2CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 71 %

Procedure:
N*2*-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-pyridine-2,3-diamine (350 mg, 0.85 mmol), trimethylorthoformate (5 mL) and formic acid (0.5 mL) were stirred at 40° C. for 3 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between saturated NaHCO3 solution (40 mL) and DCM (2×40 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated in vacuo to give a brown oil. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (97:3:0.3 to 93:7:0.7 by volume) to provide the title compound as a brown oil (255 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 1.78-1.82 (m, 4H), 1.99-2.10 (m, 6H), 2.57 (m, 4H), 2.64 (t, 2H), 3.56 (m, 2H), 3.92 (m, 2H), 4.03 (t, 2H), 4.40 (s, 2H), 6.82 (s, 1H), 6.90 (d, 2H), 7.02 (d, 2H), 7.20 (m, 1H), 7.99 (d, 1H), 8.38 (d, 1H). HRMS ESI+ m/z 421.2586 [MH]+.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=[O:7])[CH3:6].[I:9][C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1>ClCCl>[C:5]([C:13]1[CH:14]=[CH:15][C:10]([I:9])=[CH:11][C:12]=1[CH3:16])(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: Cc1cccc(I)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(I)cc1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51.2 %

Procedure:
To a suspension of 20 gm of aluminum trichloride in 500 mL of dichloromethane was added 10.2 mL of acetyl chloride under Argon. After the reaction mixture was stirred for 15 min, 3-iodotoluene (20 gm) was added through a syringe. The mixture was stirred overnight under Argon and poured into 500 gm of ice-water. Organic layer was separated and washed once with the saturated ammonium chloride solution, and washed once with 10% sodium thiosulfate solution and dried over sodium sulfate. After removing the solvent, the residue was dissolved in hexane for the column purification. Silica gel (260 gm) was packed with hexane, after loading the sample solution, the column was eluted with 750 mL of hexane, 750 mL of 1% v/v ether/hexane, 750 mL of 2% v/v ether/hexane and 1500 mL of 3% v/v ether/hexane. The fractions containing the right isomer were identified by GC-MS and 1H NMR and pooled and concentrated to dryness to afford 12.2 gm (51.2%) of the title product (P 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:25]([CH2:26][C:27](O)=[O:28])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[ClH:30].Cl.[NH:32]1[CH2:36][CH2:35][N:34]=[C:33]1[C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][NH2:45])=[CH:39][CH:38]=1>>[ClH:30].[NH:34]1[CH2:35][CH2:36][N:32]=[C:33]1[C:37]1[CH:38]=[CH:39][C:40]([CH2:43][CH2:44][NH:45][C:27](=[O:28])[CH2:26][CH:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]2[S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:11])=[O:10])=[CH:41][CH:42]=1
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2CC(=O)O)cc1
Reactant: NCCc1ccc(C2=NCCN2)cc1
Agent: Cl
Product: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2CC(=O)NCCc2ccc(C3=NCCN3)cc2)cc1

Procedure:
The title compound was prepared from [5-(4-methoxy-benzenesulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetic acid and 2-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethylamine dihydrochloride (Reference Example 2) according to the method described in Example 1e. MS (EI) 581.6 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)[C:7]=1[CH3:32])C.Cl>CO.[OH-].[Na+].O>[CH2:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[C:6]([CH2:5][C:4]([OH:33])=[O:3])=[C:7]2[CH3:32])=[CH:19][CH:20]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)Cc1c(C)n(Cc2ccc(OCc3ccccc3)cc2)c2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)c(CC(=O)O)c(C)n2Cc1ccc(OCc2ccccc2)cc1
Reaction time: 16 h
Yield: 32 %

Procedure:
1-[(4-Benzyloxyphenyl)methyl]-5-methoxy-2-methyl-1H-indole-3-acetic acid. Using the method described in Example 6, Part A, 2.0 g (8.12 mmol) of 5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester, 0.325 g (8.12 mmol) of 60% NaH/mineral oil, and 1.88 g (8.12 mmol) of 4-benzyloxy-1-chloromethylbenzene were reacted to give on workup 800 mg of crude 1-[(4-benzyloxyphenyl)methyl]-5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester. The crude ester in 50 mL of MeOH and 15 mL of 1N NaOH was heated at reflux temperature for 3 hours and left standing for 16 hours. After diluting with water, the mixture was made acidic with 1N HCl and extracted with EtOAc. The EtOAc solution was dried (Na2SO4) and concentrated. The residue was crystallized from MeOH to give 280 mg (32% yield) of 1-[(4-benzyloxyphenyl)-methyl]-5-methoxy-2-methyl-1H-indole-3-acetic acid, mp, 175°-179° C.
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[ClH:10].N([O-])=O.[Na+]>CCOCC>[Cl:10][C@@H:2]([C@@H:3]([CH3:4])[CH2:5][CH3:6])[C:7]([OH:9])=[O:8]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC[C@H](C)[C@H](Cl)C(=O)O

Procedure:
L-isoleucine (105 g) was added to 6N-hydrochloric acid (1 l), followed by agitating the mixture, cooling it with ice, adding sodium nitrite (80 g), agitating the mixture at 0° C. for 3 hours, adding ether (300 ml), separating the resulting organic layer, extracting the aqueous layer with ether (150 ml), combining the organic layers, drying over MgSO4, distilling off ether and distilling the residue under reduced pressure, to obtain (2S,3S)-2-chloro-3-methylvaleric acid (34.2 g, b.p. 96-97/4 mmHg).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)=[O:9])[C@@H:3]1[CH2:23][NH:24]C1C=CC(C(F)(F)F)=CN=1.Cl[C:36]1[C:41]([C:42]([F:45])([F:44])[F:43])=[CH:40][CH:39]=[CH:38][N:37]=1>>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)=[O:9])[C@@H:3]1[CH2:23][NH:24][C:36]1[C:41]([C:42]([F:45])([F:44])[F:43])=[CH:40][CH:39]=[CH:38][N:37]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncccc2C(F)(F)F)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using 2-chloro-3-(trifluoromethyl)pyridine. ESI-MS (m/z): 472 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11]C)[C:5]([OH:7])=[O:6].Br>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6]
Reactant: COc1ccc(C(=O)O)cc1F
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1ccc(O)c(F)c1

Procedure:
Next, the 3-fluoro-4-methoxybenzoic acid (IV) was digested with HBr (20 ml) and glacial acetic acid (40 ml) overnight. Most of the acetic acid was distilled off and the remaining mixture was diluted with water. The precipitated benzoic acid was extracted in ether; the ether layer was dried, filtered and rotary evaporated to produce 11.0 g of the 3-fluoro-4-hydroxybenzoic acid (V).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([OH:7])=O.[NH2:12][C:13]1[C:18](O)=[CH:17][CH:16]=[CH:15][N:14]=1>>[Br:11][C:9]1[CH:8]=[C:4]([C:5]2[O:7][C:18]3[C:13]([N:12]=2)=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:3]=[C:2]([Br:1])[CH:10]=1
Reactant: Nc1ncccc1O
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Product: Brc1cc(Br)cc(-c2nc3ncccc3o2)c1

Procedure:
3,5-Dibromo-benzoic acid and 2-amino-pyridin-3-ol were condensed to give 2-(3,5-dibromo-phenyl)-oxazolo[4,5-b]pyridine using the conditions of Clark, R. L., et al., J. Med. Chem. 21: 1158-62 (1978). This compound was converted to N-(3-bromo-5-oxazolo[4,5-b]pyridin-2-yl-phenyl)-acetamide as described in Example 82. Conversion to N-[3-(1H-Indol-4-yl)-5-oxazolo[4,5-b]pyridin-2-yl-phenyl]-acetamide was carried out as described in Example 75. 1H NMR (400 MHz, CD3OD): δ 8.39-8.43 (m, 2H), 8.28 (d, J=1.4 Hz, 1H), 8.15 (t, J=1.7 Hz, 1H), 7.95 (dt, J=4.7, 2.7 Hz, 1H), 7.38-7.41 (m, 1H), 7.30-7.34 (m, 1H), 7.25 (d, J=3.1 Hz, 1H), 7.14-7.17 (m, 2H), 6.67 (d, J=3.1 Hz, 1H), 2.13 (s, 3H).
Reaction SMILES: C1(O[N:8]=[C:9]([C:11]2[N:12]=[CH:13][N:14]([C@@H:17]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]3[OH:19])[C:15]=2[NH2:16])[NH2:10])CCCCC1.[C:26](=S)=[S:27]>C(N(CC)CC)C.CN(C)C=O>[CH:13]1[N:14]([C@@H:17]2[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]2[OH:19])[C:15]2[C:11](=[C:9]([NH2:10])[NH:8][C:26]([N:16]=2)=[S:27])[N:12]=1
Reactant: S=C=S
Reactant: NC(=NOC1CCCCC1)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 65 %

Procedure:
0.45 g of 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide O-cyclohexyl-oxime was dissolved in a mixture of 0.2 ml of triethylamine and 5 ml of N,N-dimethylformamide, and 0.5 ml of carbon disulfide was further added to the solution. The resulting mixture was allowed to react in an autoclave at 125° C for 5 hours under autogenous pressure (about 10 Kg/cm2) followed by working up in the same manner as described in Example 15 to obtain 0.26 g (yield, 65%) of 2-thioadenosine having a melting point of 197° C (with decomposition).
Reaction SMILES: [N-]=[N+]=[N-].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:24]([CH2:27][C:28]1[N:29]=[C:30]([C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]3=[O:45])=[CH:35][C:34]=2[F:46])[NH:31][CH:32]=1)=[N+]=[N-]>>[NH2:24][CH2:27][C:28]1[N:29]=[C:30]([C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]3=[O:45])=[CH:35][C:34]=2[F:46])[NH:31][CH:32]=1
Reactant: [N-]=[N+]=NCc1c[nH]c(-c2ccc(-n3ccccc3=O)cc2F)n1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: NCc1c[nH]c(-c2ccc(-n3ccccc3=O)cc2F)n1

Procedure:
Alternatively as shown in Scheme 4,1-iodo-2-fluoro-4-(2-oxopyridin-1(2H)-yl)benzene 3-2 prepared as above, is treated with 4-hydroxymethylimidazole II-1 in the presence of 8-hydroxyquinoline, and K2CO3 in DMSO. The resulting mixture is degassed before being charged with CuI to give 4-hydroxymethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole 4-1. The compound 4-1 is treated with thionyl chloride to give 4-chloromethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole which is then treated with NaN3 to result in 4-azidomethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole 4-2. The azide 4-2 is reduced with Ph3P to give 4-aminomethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole 4-3. The compound 4-3 is then treated with 5-chlorothiophene-2-carboxylic acid 1-5 to give the title compound 21.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:28][CH:27]=1)[C:5](=[O:25])[N:6]2[C:11]1[CH:12]=[C:13]([NH:17]C(=O)OC(C)(C)C)[CH:14]=[CH:15][CH:16]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:28][CH:27]=1)[C:5](=[O:25])[N:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-n2c(=O)n(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(-n2c(=O)n(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenylcarbamate (6) (404 mg, 0.8 mmol) in 8 mL DCM was added 2 mL TFA dropwise. The reaction mixture was stirred at rt for 1 hr, then concentrated to dryness. The residue was purified by column chromatography (silica gel, 0 to 5% methanol in DCM (0.3% Et3N)) to give 6-amino-9-(3-aminophenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one (7) (325 mg, 100%) as a yellow solid. LC-MS (ESI): m/z (M+1) 411.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[C:6]([CH2:13][CH3:14])=[C:5]2[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O.[CH2:30]([O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>COCCOC>[CH2:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([C:2]2[CH:3]=[C:4]3[N:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=24)[C:6]([CH2:13][CH3:14])=[C:5]3[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:40][CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCc1c(-c2ccc(OC)cc2)c2cc(Br)c3cccc1n32
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCc1c(-c2ccc(OC)cc2)c2cc(-c3ccc(OCc4ccccc4)cc3)c3cccc1n32
Temperature: 87.5 °C
Reaction time: 0.17 h
Yield: 67.8 %

Procedure:
4-Bromo-1-ethyl-2-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine (0.354 g, 1.0 mmol), prepared in example 75, step 2, was dissolved in 15 ml of 1,2-dimethoxyethane under a nitrogen atmosphere. tetrakistriphenylphospine palladium(0) (0.06 g, 0.052 mmol) was added, and the mixture was stirred for 10 minutes. Sodium carbonate (0.65 g, 6.13 mmol) and water 2 ml was added and stirring was continued for 10 minutes. 4-Benzyloxyphenyl boronic acid (0.91 g, 3.99 mmol) dissolved in 10 ml of hot 1,2-dimethoxyethane was added and the mixture was heated to 85-90° C. for 18 hours. The suspension was poured into 100 ml of water and the organic material was extracted into dichloromethane (1×100 ml and 3×50 ml). The combined organic layers were washed with brine, dried overmagnesium sulfate, and evaporated. The crude product was purified by column chromatography over silica gel 60, using 3% of diethyl ether in hexane as the eluent to afford a yellow solid, which was recrystallised from dichloromethane and petroleum ether, to afford 0.31 g (68%) of 4-(4-benzyloxyphenyl)-1-ethyl-2-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine as yellow crystals. MS(SP): m/z 457 (M+). 1H--NMR (CDCl3, 400 MHz) δ: 1.48 (t, 3 H); 3.25 (q, 2 H); 3.91 (s, 3 H); 5.14 (s, 2 H); 7.07-7.13 (m,4 H); 7.31-7.51 (m, 5 H); 7.67 (dd, 1 H); 7.70 (s, 1 H); 7.73-7.82 (m, 4 H); 7.92 (d, 1 H); 8.13 (d, 1 H). Analysis: Calculated for C32H27N1O2 : C, 84.00; H, 5.95; N, 3.06%; Found: C, 84.07; H, 6.02; N, 2.90%.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH2:18]>>[Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([F:12])=[C:6]([S:8]([NH:18][CH2:17][CH2:16][N:15]([CH3:19])[CH3:14])(=[O:10])=[O:9])[CH:7]=1
Reactant: CN(C)CCN
Reactant: O=S(=O)(Cl)c1cc(Br)c(F)cc1F
Product: CN(C)CCNS(=O)(=O)c1cc(Br)c(F)cc1F
Yield: 101.1 %

Procedure:
Prepared by general procedure III from 5-bromo-2,4-difluorobenzene sulfonyl chloride (1.0 g, 3.4 mmol) and N,N-Dimethylethylenediamine (333 mg, 3.77 mmol) to give the title compound (1.18 g, 100%) as an off-white solid. MS (ISP) 344.9[(M+H)+].