Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[SH-].[Na+].[CH3:4][S:5]([C:8]1[CH2:12][C:11]([CH2:14][Cl:15])([CH3:13])[O:10][N:9]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(S([O-])=O)O.[Na+].BrC[C:30]1[C:31]([O:40][CH2:41][CH3:42])=[N:32][CH:33]=[N:34][C:35]=1[C:36]([F:39])([F:38])[F:37]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:41]([O:40][C:31]1[C:30]([CH2:4][S:5][C:8]2[CH2:12][C:11]([CH2:14][Cl:15])([CH3:13])[O:10][N:9]=2)=[C:35]([C:36]([F:38])([F:39])[F:37])[N:34]=[CH:33][N:32]=1)[CH3:42]
Reactant: CCOc1ncnc(C(F)(F)F)c1CBr
Reactant: CC1(CCl)CC(S(C)(=O)=O)=NO1
Agent: O=C([O-])[O-]
Agent: O=S([O-])CO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1ncnc(C(F)(F)F)c1CSC1=NOC(C)(CCl)C1
Reaction time: 2 h
Yield: 30.3 %

Procedure:
3.4 g (42.3 mmoles) of sodium hydrosulfide hydrate (purity: 70%) was added into a solution of 4.6 g (21.6 mmoles) of 3-methylsulfonyl-5-chloromethyl-5-methyl-2-isoxazoline dissolved in 70 ml of DMF. The mixture was stirred for 2 hours. Then, there were added 3.0 g (21.6 mmoles) of potassium carbonate, 3.3 g (21.6 mmoles) of Rongalit and 5-bromomethyl-4-ethoxy-6-trifluoromethylpyrimidine. The mixture was stirred at room temperature for 21 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with an aqueous sodium chloride solution, followed by drying over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (solvent system: hexane-ethyl acetate) to obtain 1.9 g (yield: 30.3%) of 3-(4-ethoxy-6-trifluoromethylpyrimidin-5-ylmethylthio)-5-chloromethyl-5-methyl-2-isoxazoline.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].C([NH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=1[N+:24]([O-:26])=[O:25])(=O)C.O>C(O)C>[NH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH:2][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])=[CH:18][C:17]=1[N+:24]([O-:26])=[O:25]
Reactant: CC(=O)c1ccccc1
Reactant: CC(=O)Nc1ccc(C=O)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(C=CC(=O)c2ccccc2)cc1[N+](=O)[O-]
Yield: 94.8 %

Procedure:
To a solution of acetophenone (7.2 g) and 4N-sodium hydroxide solution (14 ml) in ethanol (50 ml) was added 4-acetylamino-3-nitrobenzaldehyde (10.4 g) at ambient temperature under stirring and the resultant mixture was stirred at same condition for 2 hours. To the reaction mixture was added water and precipitate was collected by filtration. The precipitate was suspended in water (300 ml) and the resultant mixture was adjusted to pH 4.0 with 10% hydrochloric acid. The precipitate was collected by filtration and washed with brine and dried to give 3-(4-amino-3-nitrophenyl)-1-phenyl-2-propen-1-one (12.7 g).
Reaction SMILES: CO[C:3](=O)[NH:4][C:5]1[C:6]([Cl:16])=[N:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][C:10]=1I.[CH:18]([Li])(CC)C.COC(=O)NC1C(Cl)=NC(C(F)(F)F)=CC=1.CN(C)CCN(C)C.II>C1COCC1>[Cl:16][C:6]1[N:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:10]2[CH:18]=[CH:3][NH:4][C:5]=12
Reactant: COC(=O)Nc1c(I)cc(C(F)(F)F)nc1Cl
Reactant: [Li]C(C)CC
Agent: CN(C)CCN(C)C
Agent: COC(=O)Nc1ccc(C(F)(F)F)nc1Cl
Agent: II
Solvent: C1CCOC1
Product: FC(F)(F)c1cc2cc[nH]c2c(Cl)n1
Temperature: -10 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
(2-Chloro-4-iodo-6-trifluoromethyl-pyridin-3-yl)-carbamic acid methyl ester: sec-Butyllithium solution (1.3 M in cyclohexane, 7.55 mL, 5.81 mmol) was added at −78° C. to a solution of (2-chloro-6-trifluoromethyl-pyridin-3-yl)-carbamic acid methyl ester (1.00 g, 3.93 mmol) and N,N,N′,N′-tetramethylethylenediamine (1.14 g, 9.82 mmol) in THF (50 mL). The solution was stirred for 1 h at −10° C., then cooled again to −78° C. and treated with a solution of iodine (1.66 g, 6.52 mmol) in THF (20 mL). After stirring for 1 h at −10° C., the reaction mixture was partitioned between ethyl acetate and 30% aq. sodium sulfite solution. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography of the residue (SiO2, dichloromethane) afforded the title compound (810 mg, 54%). White solid, MS (EI) 345.0 (100), 379.9 (2, M+).
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[CH3:3].[NH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[OH:14]>>[OH:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]1[NH:7][C:1](=[O:6])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)O
Reactant: NC1CCCCC1O
Product: CC(C)C(=O)NC1CCCCC1O

Procedure:
Prepared as in Example 24a from isobutyric acid and 2-aminocyclohexanol as a colorless oil (53%). MS 186 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12](C)=[CH:11][CH:10]=1)=[O:8].Br[C:20]1C=CC(OC)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:20])[CH:14]=1)=[O:8]
Reactant: COc1ccc(Br)cc1
Reactant: COc1ccc(Br)cc1C(=O)c1ccc(C)cc1
Product: COc1ccc(Br)cc1C(=O)c1cccc(C)c1

Procedure:
Employing the same general procedure as for the preparation 5-bromo-2-methoxy-4′-methylbenzophenone (Compound H), 1.0 mL (1.5 g, 8.0 mmol) of 4-bromoanisole was converted into the title compound using 0.5 g (4.0 mmol) of aluminum chloride, 1.3 mL (1.5 g, 9.6 mmol) of m-toluoyl chloride and 20 mL of dichloromethane. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound as a white solid.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:18]([C:20]([CH2:22][CH2:23][C@@:9]34[OH:24])=[O:21])[O:19][C:4]([C:5]=25)=[C:3]([OH:25])[CH:2]=1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:17]1[CH:15]([CH2:14][N:13]2[C@@H:8]3[CH2:7][C:6]4[CH:1]=[CH:2][C:3]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[C:4]5[O:19][C@H:18]6[C:20]([CH2:22][CH2:23][C@:9]3([OH:24])[C@:10]6([C:5]=45)[CH2:11][CH2:12]2)=[O:21])[CH2:16]1
Reactant: BrCc1ccccc1
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(OCc5ccccc5)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Temperature: 60 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
To a solution of naltrexone (2.5 g, 7.3 mmol) and benzylbromide (1.5 g, 8.8 mmol) in DMF (25 mL) was added potassium carbonate (2.8 g, 20 mmol). The mixture was stirred for 12 hrs at 60° C., then cooled and diluted with water. The resulting oily product was extracted with EtOAc. The extract was washed with water dried over MgSO4 and concentrated. The residue was chromatographed on silica gel (hexane-EtOAc, 3;2) to afford 3-benzylnaltrexone (4) (2.3 g, 74%). 1H NMR (CDCl3) δ 0.15(2H, m, H-20β, H-21β), 0.56(2H, m, H-20α, H-21α), 0.87(1H, m, H-19), 1.58(1H, dd, J=12.3 Hz, 2.4 Hz, H-15), 1.64(1H, dt, J=13.5 Hz, 2.4 Hz, H-8), 1.89(1H, d, J= 13.5 Hz, H-8), 2.13(1H, dt, J=12.3 Hz, 2.4 Hz, H-15), 2.30(1H, dt, J=12.3 Hz, 2.4 Hz, H-16), 2.40(3H, m, H-7, H-18), 2.55(1H, dd, J=18.3 Hz, 6.0 Hz, H-10), 2.69(1H, dd, J=12.3 Hz, 2.4Hz, H-16), 3.03(2H, m, H-7, H-10), 3.18(1H, d, J=6.0 Hz, H-9), 4.70(1H, s, H-5), 5.20(1H, d, J=12.0 Hz, Bz CH), 5.29(1H, d, J=12.0 Hz, Bz CH), 6.56(1H, d, J=7.2 Hz, H-1), 6.71(1H, d, J=7.2 Hz, H-2), 7.25-7.60(5H, m, Bz aromatic H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[C:8]([O:21][CH3:22])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].[Br:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26](I)[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[Br:23][C:24]1[CH:29]=[C:28]([C:9]2[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:7][C:8]=2[O:21][CH3:22])[C:27]([OH:30])=[CH:26][CH:25]=1
Reactant: Oc1ccc(Br)cc1I
Reactant: CCS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)c1ccc(-c2cc(Br)ccc2O)c(OC)c1
Yield: 44 %

Procedure:
To a stirred solution of 2-(4-(ethylsulfonyl)-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 21, 600 mg, 1.84 mmol) in dioxane (30 mL) and water (10 mL) were added 4-bromo-2-iodophenol (604 mg, 2.02 mmol), sodium carbonate (488 mg, 4.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (106 mg, 0.092 mmol). The reaction was stirred at reflux for 18 hours. The reaction was allowed to cool temperature and then filtered through celite. The filtrate was reduced to dryness and then purified by silica gel column chromatography eluting with cyclohexane:EtOAc 1:1 followed by a second silica gel column chromatography eluting with CH2Cl2:MeOH 98:2 to give the title compound as pale yellow solid in 44% yield, 301 mg.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH2:31][CH2:30][N:12]2[C:13]3[CH:14]=[CH:15][C:16]([O:20][CH:21]4[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]4)=[CH:17][C:18]=3[CH:19]=[C:11]2[C:10]1=[O:32])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:6][CH2:7][CH2:8][N:9]1[CH2:31][CH2:30][N:12]2[C:13]3[CH:14]=[CH:15][C:16]([O:20][CH:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:25][CH2:26]4)=[CH:17][C:18]=3[CH:19]=[C:11]2[C:10]1=[O:32]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(CCO[Si](C)(C)C(C)(C)C)C2=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(CCO)C2=O)CC1
Yield: 88 %

Procedure:
To a cooled solution of 0.145 g (0.30 mmol) 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one in 3 mL dichloromethane, 1 mL (1.49 g, 13 mmol) trifluoroacetic acid was added and the cooling bath was removed. The solution was evaporated and the residue was taken up in ethyl acetate and was washed with 1M aqueous sodium hydroxide solution and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography on silica gel with dichloromethane: methanol:ammonia (9:1:0.1 v/v) to give the desired compound as a white foam (88%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[S:12][CH:13]=2)=[CH:5][CH:4]=1.ClCCl.B(Br)(Br)Br.O>CCCCCCC>[S:12]1[CH:13]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]1=2
Reactant: COc1ccc(-c2csc3ccccc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: O
Product: Oc1ccc(-c2csc3ccccc23)cc1
Yield: 92.4 %

Procedure:
Cool a solution of 3-(4-methoxy-phenyl)-benzo[b]thiophene (5.00 g, 20.8 mmol) and dichloromethane (anhydrous, 120 mL). Add 1.0 M solution of boron tribromide in dichloromethane (60.0 mL, 60.0 mmol) over a time period of 15 minutes. Stir reaction mixture at 0° C. for 2 hours and let warm and stir at room temperature overnight. TLC (40% dichloromethane in heptane) shows that the starting material is consumed. Transfer reaction mixture to a mixture of ice:water (200 g:200 mL) via a cannula and let stir for 0.5 hours. Separate the layers and extract the aqueous layer with dichloromethane (250 mL). Combine organic layers, wash with water (2×200 mL), dry (MgSO4), and concentrate (in vacuo) to obtain a brown, viscid residue. Purify residue by column (silica) chromatography (dichloromethane) to obtain a clear oil, which solidifies. Dry (room temperature, 0.8 mm Hg) for 3 hours to give the title compound (4.35 g, 92% Yield).
Reaction SMILES: [CH3:1][C@@:2]1([OH:21])[C@H:6]([O:7][CH3:8])[C@@H:5]([CH2:9][OH:10])[O:4][C@H:3]1[N:11]1[C:20]2[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=2[N:13]=[CH:12]1.[CH3:22]I>CC(C)C(N)=O>[CH3:22][NH:16][C:15]1[C:14]2[N:13]=[CH:12][N:11]([C:20]=2[N:19]=[CH:18][N:17]=1)[C@@H:3]1[O:4][C@H:5]([CH2:9][OH:10])[C@@H:6]([O:7][CH3:8])[C@@:2]1([CH3:1])[OH:21]
Reactant: CO[C@@H]1[C@@H](CO)O[C@@H](n2cnc3c(N)ncnc32)[C@]1(C)O
Reactant: CI
Agent: CC(C)C(N)=O
Product: CNc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](OC)[C@@]1(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 g of the compound obtained in Example 2 and 2 ml of methyl iodide were dissolved in dimethylacetoamide, and stirred overnight at room temperature. The reaction mixture was concentrated to dryness under reduced pressure and 10 ml of 2N sodium hydroxide solution was added thereto. The solution was refluxed for one hour with heating. After cooling to room temperature, the solution was neutralized with 2N HCl and applied on Amberlite XAD-7 column. The column was washed with water and eluted with 50% (V/V) aqueous solution of methanol. The eluate was concentrated to dryness under reduced pressure and recrystallized from ethyl acetate to give 1.8 g of N6,2',3'-O-trimethyladenosine (Compound 60).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.Cl[C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1>>[F:32][C:31]([F:34])([F:33])[C:29]1[CH:28]=[CH:27][N:26]=[C:25]([NH:2][C:3]2[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=2)[CH2:6][NH:7][C:8]2[C:17]3[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)[CH:30]=1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Agent: Cl
Product: NC(=O)c1cccc2c(NCc3cccc(Nc4cc(C(F)(F)F)ccn4)c3)ncnc12

Procedure:
The title compound was prepared according to Example 684 starting 4-(3-Amino-benzylamino)-quinazoline-8-carboxylic acid amide hydrochloride and 2-Chloro-4-trifluoromethyl-pyridine at 120° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[N:13]=[C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:15]=[C:16](Cl)[C:11]=2[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.C(N(C(C)C)C(C)C)C.[NH:34]1[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35]1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:12]2[N:13]=[C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:15]=[C:16]([N:34]3[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35]3)[C:11]=2[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@H]1CCNC1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3)c2n1
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc(N2CC[C@H](O)C2)c2nnn(Cc3ccccc3)c2n1
Reaction time: 2 h
Yield: 96.8 %

Procedure:
3-benzyl-5-tert-butyl-7-chloro-3H-[1,2,3]triazolo[4,5-d]pyrimidine (192.2 g, 548 mmol, Eq: 1.00) was charged in the reactor followed by Acetonitrile (780 g, 1.0 l) and N-Ethyldiisopropylamine (108 g, 143 ml, 822 mmol, Eq: 1.5). (S)-Pyrrolidin-3-ol (54.1 g, 51.6 ml, 603 mmol, Eq: 1.1) was added dropwise over 30 min at Tr=20 to <30° C. After 2 h at 25° C., the reaction mixture was transferred with Toluene (865 g, 1.0 l) into a 3 l round bottom flask and it was concentrated on a rotary evaporator, to switch solvent to toluene. The toluene solution was washed with a 10% aqueous citric acid solution (1.0 l). The aqueous phase was separated and extracted with toluene (434 g, 500 ml). The org. phases were washed sequentially with half saturated aqueous NaHCO3 (500 ml) and half saturated aqueous NaCl (500 ml). The org. phases were combined, dried over MgSO4 and concentrated at 45° C. to ca 500 mL. Heptane (684 g, 1.0 l) was added under stirring. After 5-10 min the product started to crystallize. The white suspension was stirred for 2 h at RT and was filtered. The white filter cake was washed with heptane (274 g, 400 ml) and dried at 45° C./5 mbar to give 186.9 g of the title compound as a white powder. MS(m/e): 353.1 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:6][C:5]1=[O:15].CN(C=O)C.[H-].[Na+].Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1>>[N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24]([O:1][CH2:2][CH2:3][N:4]2[CH:9]=[C:8]([C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)[CH:7]=[CH:6][C:5]2=[O:15])=[CH:25][CH:26]=1
Reactant: O=c1ccc(-c2cccs2)cn1CCO
Reactant: Clc1ccnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccc(-c2cccs2)cn1CCOc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 1-(2-hydroxyethyl)-5-(thiophen-2-yl)pyridin-2(1H)-one (0.050 g, 0.3 mmol) in DMF (1 mL, 13 mmol) was added sodium hydride (0.080 g, 3 mmol). The resulting mixture was allowed to stir 1.5 hours at ambient temperature. Then 4-chloroquinoline (0.080 g, 0.5 mmol) was added into the mixture and allowed to stir under inert atmosphere overnight. The progress of the reaction was monitored by LC/MS, which showed mostly desired product. The mixture was diluted with CH2Cl2 and water, then extracted the organic layer with CH2Cl2 (3×20 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in-vacuo. The crude material was purified by Reverse-Phase HPLC. This gave the desired product as an off-white solid (0.050 g, 45% yield). MS (ESI pos. ion) m/z (MH+): 349. Calc'd exact mass for C20H16N2O2S: 348. 1H NMR (300 MHz, CDCl3): 8.67 (d, J=4.82, 1H), 8.05 (d, J=8.33 Hz, 1H), 7.95 (d, J=8.33 Hz, 1H), 7.73 (s, 1H), 7.56 (d, J=9.79 Hz, 2H), 7.35 (s, 1H), 7.19 (s, 1H), 6.99 (d, J=2.34, 2H), 6.67 (d, J=4.97 Hz, 1H), 6.58 (d, J=9.35 Hz, 1H), 4.48 (s, 4H), 1.74 (s, 1H).
Reaction SMILES: Cl.Cl.[OH:3][CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[C:13]([O:14][CH2:15][C@H:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)=[CH:12][CH:11]=[CH:10][N:9]=1.[F:22][C:23]([F:34])([F:33])[C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30](O)=[O:31])[CH2:26][CH2:25]1.COC1C=C(OC[C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)C(C(O)=O)=NC=1>>[OH:3][CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[C:13]([O:14][CH2:15][C@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:30]([C@H:27]2[CH2:26][CH2:25][C@H:24]([C:23]([F:22])([F:33])[F:34])[CH2:29][CH2:28]2)=[O:31])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: O=C(NCCO)c1ncccc1OC[C@H]1CCCN1
Agent: COc1cnc(C(=O)O)c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Agent: Cl
Product: O=C(NCCO)c1ncccc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 5 of EXAMPLE 31 using (R)—N-(2-hydroxyethyl)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride (EXAMPLE 33 Step 4) and trans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of ammonium chloride and 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)m ethoxy)picolinic acid.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([O:17]C)[C:11]=2[CH:10]=[C:9]1[CH3:19]>CC(O)=O.Br>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][NH:13][C:12](=[O:17])[C:11]=2[CH:10]=[C:9]1[CH3:19]
Reactant: COc1nccc2c1cc(C)n2Cc1ccccc1-c1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: Cc1cc2c(=O)[nH]ccc2n1Cc1ccccc1-c1ccccc1
Temperature: 105 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-biphenyl-2-ylmethyl-4-methoxy-2-methyl-1H-pyrrolo[3,2-c]pyridine 4 (370 mg, 1.13 mmol) in AcOH (15 mL), 48% of HBr (5 mL) was added. The reaction mixture was heated to 105° C., and then stirred for 16 h, cooled to room temperature and evaporated. The obtained residue was dissolved in CH2Cl2 (100 mL), washed with saturated NaHCO3 (30 mL), brine (30 mL), dried over Na2SO4 and evaporated to afford crude product 5, which was used without further purification for next step. Yield: 355 mg (100%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([NH:40][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc12
Reactant: NCc1ccccc1
Product: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc12
Yield: 31.5 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(7-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.250 g, 0.546 mmol) obtained in step 2 and benzylamine (0.150 mL, 1.37 mmol), the title compound (0.091 g, 31%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[N+:9]([O-:11])=[O:10].[NH3:12].CO>O>[F:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH2:12]
Reactant: N
Reactant: O=[N+]([O-])c1c(F)cccc1F
Solvent: O
Solvent: CO
Product: Nc1cccc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 120 h
Yield: 51 %

Procedure:
To a pressure tube was added 1,3-difluoro-2-nitrobenzene (2.8 mL, 26.4 mmol) and 7 N NH3 in CH3OH (10 mL, 70 mmol). The tube was sealed and the mixture was stirred at room temperature for 5 days. The solution was diluted with H2O, extracted with CH2Cl2, and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to give an oil. The oil was triturated with hexane and the resulting orange solid was collected by filtration to give the title compound (2.1 g, 51%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[N:18]([C:19](=[O:37])[N:20]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]C=C)[CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH2:17][CH:16]([O:38][C:39](=[O:49])[C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)[CH2:15]2)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[CH2:1]([O:3][C:4]([C:6]12[CH2:8][CH:7]1[CH:9]=[CH:10][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][N:20]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:19](=[O:37])[N:18]1[CH:14]([CH2:15][CH:16]([O:38][C:39](=[O:49])[C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)[CH2:17]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCCN(Cc1ccc(OC)cc1)C(=O)N1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCCl
Product: CCOC(=O)C12CC1C=CCCCCCN(Cc1ccc(OC)cc1)C(=O)N1CC(OC(=O)c3ccc([N+](=O)[O-])cc3)CC1C(=O)N2

Procedure:
Compound 25 (406 mg, 0.6 mmol) was dissolved in DCE (250 ml) and degassed. Hoveyda-Grubbs Catalyst 2nd generation (26 mg, 0.042 mmol) was added and the solution was heated to reflux. After 3 h the solution was evaporated and used direct in the next step.