Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=S.N=C=N>CC(C)=O.[Hg]=O>[CH3:19][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]=[C:7]=[N:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: CN(C)CCCNC(=S)NCCCN1CCOCC1
Agent: N=C=N
Agent: O=[Hg]
Solvent: CC(C)=O
Product: CN(C)CCCN=C=NCCCN1CCOCC1
Reaction time: 2 h
Yield: 59 %

Procedure:
In 35 ml of acetone was dissolved 2.7 g (10 mmol) of N-[3-(dimethylamino)]propyl-N'-(3-morpholino)propyl -thiourea (Compound (1)). Further, 4.2 g (20 mmol) of mercury oxide was added, and the resulting mixture was stirred for 2 hours under reflux. Then, the reaction mixture was allowed to cool and filtered. The solvent was distilled off to obtain a crude product. This product was evaporated under reduced pressure to obtain 1.5 g (yield: 60%) of N-[3-(dimethyl-amino)]propyl-N'-(3-morpholino)propyl-carbodiimide (Compound (2) in the following reaction formula (1)). Its boiling point (b.p.) was from 125° to 128° C./0.2 mmHg. NMR spectrum data of Compound (2) are shown below.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Li+].[OH-]>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:16](=[O:17])[C:15]3[CH:19]=[CH:20][CH:21]=[N:22][C:14]=3[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ncccc1C(=O)O
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ncccc1C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.7 %

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 2-methylnicotinic acid (250 mg, 1.83 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (465 mg, 1.83 mmol), and triethylamine (0.606 mL, 4.35 mmol) were placed in DCM (5 mL) and stirred at room temperature for 90 minutes. 3M LiOH (5 mL) was added. The reaction was stirred for 20 minutes and then was poured onto water. The mixture was then filtered and washed with water and DCM. The filtered solid was dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylnicotinamide (254 mg, 84% yield).
Reaction SMILES: C[O:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[C:10]([O:18]C)[CH:11]=[CH:12][CH:13]=3)[O:8][C:7]=2[CH:6]=[C:5]([O:20]C)[CH:4]=1.C1(O)C=CC=CC=1.I.OS([O-])=O.[Na+]>>[OH:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[C:10]([OH:18])[CH:11]=[CH:12][CH:13]=3)[O:8][C:7]=2[CH:6]=[C:5]([OH:20])[CH:4]=1
Reactant: COc1cc(OC)c2c(=O)c3cccc(OC)c3oc2c1
Agent: I
Agent: O=S([O-])O
Agent: [Na+]
Solvent: Oc1ccccc1
Product: O=c1c2cccc(O)c2oc2cc(O)cc(O)c12
Temperature: 160 °C

Procedure:
A mixture of compound 19 (1.9 g, 6.64 mmol) phenol (42 ml) and HI (35 ml) was refluxed at 160° C. for 8 hour and the reaction mixture was poured into aqueous NaHSO3 solution. The resulting yellow precipitate, was collected, purified by silica gel column chromatography (CH2Cl2 --MeOH, 4:1), and crystallized from methanol to give pale yellow needles 20, 1.41 g (5.78 mmol, 87%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]1=[O:23].C(N(CC)CC)C.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[C:41](Cl)=[O:42]>O1CCOCC1>[Cl:9][C:6]1[CH:5]=[C:4]([F:10])[C:3]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[C:2]([NH:1][C:41]([C:32]2[CH:33]=[CH:34][C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:31]=2)=[O:42])[C:7]=1[CH3:8]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1NC(=O)c1ccc2ccccc2c1

Procedure:
3-(2-Amino-4-chloro-6-fluoro-3-methylphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.5 g, 1.4 mmol) was dissolved in 1,4-dioxane (20 ml) and triethyl amine (0.29 g, 2.9 mmol) and 2-naphthoyl chloride (0.41 g, 2.2 mmol) were added. Solution was heated under reflux for 4 hr and solvent removed under reduced pressure. Product was subjected to column chromatography on silica gel and the title compound was eluted with hexane-ethyl acetate (8:2; 0.3 g).
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[C:8]1([CH:15]=[CH:14][CH:13]=[C:11]([OH:12])[CH:10]=1)[OH:9].B(F)(F)F.CCOCC.C([O-])(=O)C.[Na+]>>[OH:9][C:8]1[CH:10]=[C:11]([OH:12])[CH:13]=[CH:14][C:15]=1[C:1](=[O:7])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: Oc1cccc(O)c1
Reactant: CC(C)CC(=O)O
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)CC(=O)c1ccc(O)cc1O
Temperature: 90 °C
Reaction time: 8 h
Yield: 111.2 %

Procedure:
Add isovaleric acid (5.10 g, 50 mmol, 5.5 mL) in one portion to a mixture of resorcinol (5.00 g, 45.4 mmol) in boron trifluoride etherate (38.67 g, 272.5 mmol, 34.5 mL) at room temperature under Argon gas. Heat the reaction mixture at 90° C. for 1.5 hr. Cool the reaction to room temperature and pour it into a 20% aqueous sodium acetate solution and stir overnight. Extract the aqueous mixture with ethyl acetate (3×). Combine the organic layers, wash with saturated aqueous sodium bicarbonate solution and brine sequentially. Dry the organic phase over sodium sulfate, filter and concentrate under reduced pressure to provide the product as a brownish oil (9.80 g; 50.5 mmol, 111% yield). MS (m/z): 195 (M+1).
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=O)[NH:11]3)[CH2:4][CH2:3][CH2:2]1.Cl.Cl.Cl.[N:22]1([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([CH2:29][CH2:30][N:31]2[CH2:32][CH2:33][CH:34]([NH:37][C:16]([C:10]3[NH:11][C:12]4[C:8]([CH:9]=3)=[C:7]([O:6][CH2:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)[CH:15]=[CH:14][CH:13]=4)=[O:18])[CH2:35][CH2:36]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(OCC3CCC3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-Cyclobutylmethoxy-1H-indole-2-carboxylic acid 82 (preparation see below) and amine 5.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:27])[C:13]1[CH:18]=[CH:17][C:16]([O:19]COC)=[C:15]([O:23]COC)[CH:14]=1.[C:28](Cl)(=[O:30])[CH3:29].O>N1C=CC=CC=1.ClCCl>[C:28]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:27])[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:23])[CH:14]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: COCOc1ccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)cc1OCOC
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1c(C(=O)c2ccc(O)c(O)c2)[nH]c2cc(Cl)ccc12
Reaction time: 1 h
Yield: 17.9 %

Procedure:
To a solution of 3-amino-6-chloro-2-[[3,4-bis(methoxymethyloxy)]benzoyl]indole (step 3, 0.50 g, 1.3 mmol) in pyridine (1.0 ml) and dichloromethane (20 ml) cooled to 0° C. was added acetyl chloride (0.10 ml, 1.40 mmol). After stiiring for 1 h at room temperature, the reaction mixture was poured into water (20 ml) and extracted with dichloromethane (30 ml×2). The organic extracts were dried (MgSO4) and solvent removed by evaporation. The residue was dissolved in dichloromethane (30 ml), trifluoroacetic acid (0.50 ml) added and the mixture heated at reflux for 5 h. The mixture was cooled, poured into water and extracted with ethyl acetate (80 ml×2). The organic extracts were dried (MgSO4) and solvent removed by evaporation. The residual oil was purified by flash column chromatography eluting with hexane/ethyl acetate (1/3) to give 80 mg (20%) of the title compound. Recrystallization from ethyl acetate/hexane afforded the title compound as a yellow solid. m.p.: 193-200° C. 1H-NMR (CDCl3) δ: 11.64 (1H, br s), 9.66 (1H, br s), 7.58 (1H, d, J=8.4 Hz), 7.41 (1H, J=1.5 Hz), 7.24 (1H, d, J=2.2 Hz), 7.15 (1H, dd, J=8.8, 1.8 Hz), 7.08 (1H, dd, J=8.8, 1.5 Hz), 6.80 (1H, d, J=8.4 Hz), 1.98 (3H, s)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([CH2:17][S:18]([CH2:21][C:22](O)=[O:23])(=[O:20])=[O:19])=[CH:15][CH:14]=1>C(O)(=O)C>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][S:18]([C:21]2[C:22](=[O:23])[O:10][C:5]3[C:6]([CH:7]=2)=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:19])=[O:20])=[CH:25][CH:26]=1
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)cc1
Reactant: O=Cc1cc(Cl)ccc1O
Solvent: CC(=O)O
Product: COc1ccc(CS(=O)(=O)c2cc3cc(Cl)ccc3oc2=O)cc1
Yield: 66 %

Procedure:
A solution of 5-chlorosalicylaldehyde (1 mmol) and 2-(4-methoxybenzylsulfonyl)acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 2, Method A to generate a 66% yield of the title compound; m.p. 224-226° C.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:27]=[CH:26][C:12]([C:13]([NH:15][C@@H:16]([CH2:21][N+:22]([CH3:25])([CH3:24])[CH3:23])[CH2:17][C:18]([O-:20])=[O:19])=[O:14])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].CO>[CH2:8]([C:9]1[CH:27]=[CH:26][C:12]([C:13]([NH:15][C@@H:16]([CH2:21][N+:22]([CH3:23])([CH3:25])[CH3:24])[CH2:17][C:18]([O-:20])=[O:19])=[O:14])=[CH:11][CH:10]=1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)c1ccc(C#Cc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)c1ccc(CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
(R)-3-(4-(phenylethynyl)benzamido)-4-(trimethylammonio)butanoate (10 mg, 0.027 mmol) was dissolved into MeOH (1 mL). The solution was treated with 10% Pd/C (0.5 mg). The mixture was stirred under hydrogen at room temperature overnight, and filtered through celite. MeOH was removed under vacuum. The residue was loaded onto a silica gel column and eluted with 4:1 MeOH/DCM to give the title compound as a white powder (2 mg, 22%). 1H NMR (400 MHz, D2O) δ 7.54 (d, 2H, J=8 Hz), 7.22-7.18 (m, 4H), 7.13-7.10 (m, 3H), 4.87-4.81 (m, 1H), 3.65-3.59 (m, 1H), 3.70 (d, 1H, J=13.2 Hz), 3.10 (s, 9H), 2.92-2.85 (m, 4H), 2.46 (d, 2H, J=6.8 Hz); MS ESI 369.2 [M+H]+, calcd for [C22H28N2O3+H]+ 369.22.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH3:14])[C@@H:10]([OH:13])[CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[C:23]([Si:20]([CH3:22])([CH3:21])[O:12][CH2:11][C@H:10]([OH:13])[C@@H:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:14])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](c1ccc(Cl)c(Cl)c1)[C@@H](O)CO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@H](c1ccc(Cl)c(Cl)c1)[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a stirred solution of (2R,3R)-3-(3,4-dichloro-phenyl)-butane-1,2-diol (3.20 g, 13.6 mmol) and imidazole (1.39 g, 20.4 mmol) in DCM (28 mL) at rt was added tert-butyldimethylsilyl chloride (TBSCl; 2.15 g, 14.3 mmol). The solution was stirred for 1 h then quenched by addition of satd. aq. NH4Cl (100 mL). The mixture was stirred for 5 min, the layers were separated, and the aqueous layer was extracted with DCM (3×). The combined organic layers were dried (Na2SO4) and concentrated to yield a viscous yellow liquid. The product was purified by flash chromatography (EtOAc/hexanes) to afford 4.52 g (95%) of the desired product as a colorless viscous liquid. 1H NMR (400 MHz, CDCl3): 7.37 (d, J=8.3, 1H), 7.36 (d, J=2.1, 1H), 7.10 (dd, J=8.2, 2.1, 1H), 3.75-3.68 (m, 1H), 3.65 (dd, J=9.9, 3.8, 1H), 3.45 (dd, J=9.9, 7.1, 1H), 2.81 (quint, J=7.0, 1H), 2.37 (d, J=4.0, 1H), 1.25 (d, J=7.2, 3H), 0.89 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[Br:30][C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>C(N(CC)CC)C>[Br:30][C:31]1[CH:32]=[C:33]([S:37]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCN(S(=O)(=O)c2cccc(Br)c2)CC1

Procedure:
In the manner given in Example 15, 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine is reacted with 3-bromophenylsulfonyl chloride, in the presence of triethylamine to give 1-[(3-bromophenyl)sulfonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]([O:14]CC)=[O:13])[CH2:3]1.[OH-]>C(O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]([OH:14])=[O:13])[CH2:3]1
Reactant: CCOC(=O)C1CC(=O)c2ccccc2O1
Agent: [OH-]
Solvent: CCO
Product: O=C1CC(C(=O)O)Oc2ccccc21

Procedure:
The carboxylic acid group of the compound of Example 2 (ethyl 4-oxochromane-2-carboxylate) was treated with a metallic hydroxide base in ethanol, and then the aqueous layer was treated with an acid to form the free acid, which was washed with water and then dried to yield 3 g of 4-oxo-chromane-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:19])[CH:11](Cl)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:22]([NH2:24])[CH3:23].[I-].[K+]>CCCCCC.C(OCC)(=O)C>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:19])[CH:11]([NH:24][CH2:22][CH3:23])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)C(Cl)c1ccccc1
Reactant: CCN
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCNC(C(=O)Nc1cccc(C(F)(F)F)c1)c1ccccc1
Yield: 89 %

Procedure:
An ethanolic (200 mL) solution of N-(3-trifluoromethylphenyl)-2-chloro-2-phenylacetamide (200.0 grams, 0.06 mol) and 70% aqueous ethylamine (75 mL, excess) and potassium iodide (1.0 gram, catalytic) was stirred at room temperature. The reaction was followed by thin layer chromatography (3:1 hexane-ethyl acetate). The mixture was worked up by removing the ethanol and the excess ethyl amine in a rotary evaporator. The residue was redissolved in fresh ethanol and concentrated hydrochloric acid (excess) was added to convert the product to its hydrochloride salt. Water and other excess reagents were removed by azeotropic distillation in a rotary evaporator. The salt was washed with ethyl ether and dissolved in saturated sodium bicarbonte to regenerate the amine. The product was extracted into ethyl acetate and isolated to give the desired N-(3-trifluoromethylphenyl)-2-ethylamino-2-phenylacetamide (17.1 grams, 89% yield) whose structure was confirmed by nuclear magnetic resonance, infra-red spectroscopy, and mass spectroscopy analysis.
Reaction SMILES: [ClH:1].Cl.[O:3]=[C:4]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH:18][C@H:19]3[CH2:28][CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:29]C)[CH:25]=4)[C@H:20]3[CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[O:17])[CH2:11][CH2:10]2)[C:7]2[CH:38]=[CH:39][CH:40]=[CH:41][C:6]=2[NH:5]1.B(Br)(Br)Br.CO>ClCCl>[ClH:1].[ClH:1].[O:3]=[C:4]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH:18][C@H:19]3[CH2:28][CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([OH:29])[CH:25]=4)[C@H:20]3[CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[O:17])[CH2:13][CH2:14]2)[C:7]2[CH:38]=[CH:39][CH:40]=[CH:41][C:6]=2[NH:5]1
Reactant: COc1ccc2c(c1)CC[C@H](NC(=O)CN1CCC(n3c(=O)[nH]c4ccccc43)CC1)[C@@H]2Cc1cccnc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(CN1CCC(n2c(=O)[nH]c3ccccc32)CC1)N[C@H]1CCc2cc(O)ccc2[C@H]1Cc1cccnc1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A solution of 4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-N-[cis-1,2,3,4-tetrahydro-6-methoxy-1-(3-pyridinylmethyl)-2-naphthalenyl]-1-piperidineacetamide 19 (0.28 g, 0.37 mmol) in dichloromethane (2 mL) was added dropwise to a solution of boron tribromide (1.8 mmol) in dichloromethane (22 mL) at 0° C. After stirring the resultant solution at 0° C. for 1.5 h, methanol (˜2 mL) was added and stirring was continued at 0° C. for an additional 0.5 h. The solvent was evaporated in vacuo, and the residue was purified by reverse phase C18 HPLC using a water/acetonitrile/TFA gradient, 90/10/0.1 to 10/90/0.1, as the eluant. The product was dissolved in methanol and treated with ethanolic hydrochloric acid. The solvent was evaporated and the process repeated twice to give 4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-N-[cis-1,2,3,4-tetrahydro-6-hydroxy-1-(3-pyridinylmethyl)-2-naphthalenyl]-1-piperidineacetamide bis-hydrochloride salt 23 (0.148, 68%) as a colorless solid: 1H NMR(DMSO-d6) δ 1.73–2.03 (m, 4 H), 2.70–2.94 (m, 4 H), 3.05–3.20 (br s, 2 H), 3.27–3.47 (m, 3 H), 3.55–3.76 (m, 2 H), 3.92–4.15 (m, 3 H), 4.54–4.67 (m, 1 H), 6.46 (d, 1 H), 6.58 (s, 2 H), 7.05 (m, s, 3 H), 7.60 (br s, 1 H), 7.94 (t, 1 H), 8.30 (d, 1 H), 8.72–8.83 (m, 2 H), 8.96 (d, 1 H), 9.30 (br s, 1 H), 10.64 (br s, 1 H), and 11.05 (s, 1 H); MS m/e 512 (MH+) (FIG. 9).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[C:15]1([S:21][C:22]2[CH2:28][CH:27]3[CH:24]([C:25](=[O:29])[CH2:26]3)[C:23]=2[C:30]([O:32][CH:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH:46](=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>O1CCCC1.C(O)(=O)C>[C:15]1([S:21][C:22]2[CH2:28][CH:27]3[CH:24]([C:25](=[O:29])[CH:26]3[CH:46]([OH:53])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:23]=2[C:30]([O:32][CH:33]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(Sc2ccccc2)CC2CC(=O)C12
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(Sc2ccccc2)CC2C1C(=O)C2C(O)c1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of 235 μL of hexamethyldisilazane in 30 mL of dry tetrahydrofuran under argon at 0° was added 735 μL of butyllithium (1.37M in hexane) over a 2 min period. After addition was complete, the solution was cooled to -78°. A solution of 425 mg of 3-phenylthio-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester, in 3 mL of dry tetrahydrofuran was added over a 3 min period. After addition was complete, the solution was stirred for 10 min at -78° and then 120 μL of freshly distilled benzaldehyde was added. After an additional 5 min, 150 μL of acetic acid was added and the reaction mixture was evaporated to a small volume on the rotary evaporator. The residue was partitioned between water and methylene chloride and water, and the organic layer was washed with brine, dried over sodium sulfate and evaporated to dryness. The crude reaction product was subjected to preparative thin layer chromatography on four 20×20×0.2 cm silica gel plates eluted with ether-petroleum ether (1:1) to afford two diastereomers of 3-phenylthio-6-(α-hydroxybenzyl)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester, as glasses. Isomer A (153 mg, 28.8%) was the less polar compound; Isomer B (278 mg, 52.4%) was more polar. Material prepared by essentially the same procedure had the following spectral characteristics:
Reaction SMILES: C1C=CC(C(Cl)([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][CH:15]=2)C2C=CC=CC=2)=CC=1.I[C:23]1[CH:39]=[CH:38][C:26]([O:27][CH2:28][C:29]2[CH:30]=[C:31]([C:35]([OH:37])=[O:36])[O:32][C:33]=2[CH3:34])=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:20][C:19]1[CH:14]=[CH:15][C:16]([C:23]2[CH:39]=[CH:38][C:26]([O:27][CH2:28][C:29]3[CH:30]=[C:31]([C:35]([OH:37])=[O:36])[O:32][C:33]=3[CH3:34])=[CH:25][CH:24]=2)=[CH:17][CH:18]=1
Reactant: Cc1oc(C(=O)O)cc1COc1ccc(I)cc1
Reactant: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(C(=O)O)cc1COc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 3.8 %

Procedure:
2-Chlorotrityl chloride resin (2.55 g of nominal loading 1.3 mmol/g) was swelled with dichloromethane (20 mL). After draining, a solution of 4-(4-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid (26) (1.18 g) and diisopropylethylamine (2.3 mL) in dichloromethane (30 mL) was added and the mixture was shaken at room temperature for 72 hours. The resin was drained, washed sequentially with dichloromethane/triethylamine/methanol (20:1:3 by volume) (3×30 mL), dichloromethane (6×30 mL), N,N-dimethylformamide (2×25 mL), dichloromethane (6×25 mL), and diethyl ether (2×25 mL) and dried at 40° C. in vacuo, (ii) A stirred mixture of the resin from (i) (0.38 g), 4-chlorophenylboronic acid (0.30 g), [1,1′-bis-(diphenylphosphino)-ferrocene]-dichloropalladium(II) complex with dichloromethane (1:1) (30 mg), potassium acetate (0.20 g) in N,N-dimethylformamide (15 mL) was heated at 40° C. for 48 hours. The resin was drained, then washed sequentially with tetrahydrofuran/water (1:1 by volume), tetrahydrofuran, N,N-dimethylformamide, dichloromethane, diethyl ether and then dried at 45° C. in vacuo. The resin was treated with dichloromethane/trifluoroacetic acid (19:1 by volume) (20 mL) for 20 mins and the solution drained from the resin. This procedure was repeated. The combined solutions were concentrated in vacuo and the residue purified by HPLC to afford compound 27 as a white solid (43 mg). LC/MS System D: Rt=8.83 mins, m/z (ES−)=341 (M− for C19H15ClO4).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].C(Cl)Cl>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[O:15])[CH:11]=[N:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cncc(Oc2ccccc2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cncc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a methylene chloride (20 mL) solution of (5-phenoxy-pyridin-3-yl)-methanol (756 mg, 3.76 mmol) described in Manufacturing Example 145-1-2 was added manganese(IV) dioxide (3.27 g, 37.6 mmol), which was stirred for 2 hours at room temperature. The insolubles were removed by filtrating through a Celite pad, after which the filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1 to 1:1) to obtain the title compound (607 mg, 81%).
Reaction SMILES: [CH3:1]I.[NH2:3][N:4]1[C:9](=[O:10])[C:8]([CH:11]([CH2:13][CH3:14])[CH3:12])=[N:7][NH:6][C:5]1=[S:15].[OH-].[Na+]>O>[NH2:3][N:4]1[C:9](=[O:10])[C:8]([CH:11]([CH2:13][CH3:14])[CH3:12])=[N:7][N:6]=[C:5]1[S:15][CH3:1]
Reactant: CI
Reactant: CCC(C)c1n[nH]c(=S)n(N)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(C)c1nnc(SC)n(N)c1=O
Yield: 96 %

Procedure:
66 ml of methyl iodide were added to a solution of 200 g of 4-amino-6-sec.-butyl-3-thioxo-1,2,4-triazin-5(2H,4H)-one in a solution of 40 g of sodium hydroxide in 1 liter of water, at 20° C, whilst stirring. When the slightly exothermic reaction had subsided, stirring was continued until the pH value reached 7 - 8 and the reaction product which had crystallized out was filtered off and washed with cold water. After drying, 205 g (96%) of 4-amino-6-sec.-butyl-3-methylthio-1,2,4-triazin-5(4H)-one were obtained, melting point 60° C (from carbon tetrachloride/petroleum ether).