Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:1][C@@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:8][CH:9]=1
Reactant: N[C@H](Cc1ccc(O)cc1)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reaction time: 0.5 h

Procedure:
7,5 g of a chloromethylated styrene-divinylbenzene copolymer (Merrifield resin, 1% cross-linked) are esterified with 1.113 g of Boc-D-Tyr(Bzl)-OH (3 mmoles) by refluxing for 45 hours in 60 ml of ethyl acetate in the presence of 0.42 ml of triethylamine. The resin is separated by filtration, washed successively with ethyl acetate, ethanol and water, and dried under vacuum at 25° C. 8.09 g of Boc-D-Tyr(Bzl)-resin are obtained having an esterification degree of 0.201 mmoles of D-Tyr/g calculated on the basis of the difference between the total amount of D-Tyr derivative employed and the one remained in mother liquors and in washings (determination by UV at 276 nm). The resin is Boc-deprotected by treatment with 70 ml of TFA/CH2Cl2 1/1 for 30 minutes at room temperature; thereafter it is filtered and suspended for 30 minutes under stirring in 70 ml of 10% triethylamine in chloroform. After filtrating, washing with chloroform and drying under vacuum, the product H-D-Tyr(Bzl)-resin is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C@@H:5]([O:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)[CH3:2].[NH:28]1[C:36]2[C:31](=[CH:32][C:33](B(O)O)=[CH:34][CH:35]=2)[CH:30]=[CH:29]1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.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>[CH2:1]([O:3][C:4](=[O:27])[C@@H:5]([O:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:33]3[CH:32]=[C:31]4[C:36](=[CH:35][CH:34]=3)[NH:28][CH:29]=[CH:30]4)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(I)cc2)cc1)OC
Reactant: OB(O)c1ccc2[nH]ccc2c1
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: [Cs+]
Solvent: COCCOC
Product: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(-c3ccc4[nH]ccc4c3)cc2)cc1)OC
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a stirred mixture of (2S)-3-{4-[3-(4-iodo-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (0.10 mmol, 50 mg) (Step A), 5-indolyl-boronic acid (0.114 mmol, 18 mg) and powered cesium carbonate (0.23 mmol, 35 mg) in DME (0.5 mL) was added Pd(PPh3)4 (0.003 mmol, 4 mg). The mixture was flushed with nitrogen and maintained under nitrogen while being heated at reflux in a 100° C. oil bath. The mixture was stirred for 6 hours, and then cooled to room temperature and diluted with ethyl acetate and water. The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by chromatography on silica gel (CH2Cl2/EtOAc 96:4) to afford the title compound 1H-NMR (CDCl3, 200.15 MHz): δ 8.20 (broad s, 1H), 7.80 (d, 1H, J=0.8), 7.56 (d, 3H, J=8.9), 7.41 (d, 2H, J=1.6), 7.23 (dd, 1H, J=3.2, 2.4), 7.15 (d, 3H, J=8.6), 6.99 (d, 2H, J=8.9), 6.85 (d, 3H, J=8.6), 6.60–6.58 (m, 1H), 4.24–4.11 (m, 8H), 3.92 (dd, 1H, J=7.3, 5.9), 3.35 (s, 4H), 2.98–2.94 (m, 3H), 2.28 (qn, 2H, J=5.9), 1.24 (t, 4H, J=7.3).
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[C:3]=1[C:4]([N:6]([CH3:28])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[O:14])[N:8]=1)=[O:5]>FC(F)(F)C(O)=O.C(Cl)Cl>[F:34][C:29]1[CH:30]=[C:31]([F:33])[CH:32]=[C:2]([F:1])[C:3]=1[C:4]([N:6]([CH3:28])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:14])[N:8]=1)=[O:5]
Reactant: CN(C(=O)c1c(F)cc(F)cc1F)c1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)c1c(F)cc(F)cc1F)c1cccc(C(=O)C2CCNCC2)n1
Reaction time: 0.75 h
Yield: 85 %

Procedure:
Dissolve the 2,4,6-trifluoro-N-methyl-N-[6-(1-t-butoxycarbonyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide in 50% trifluoroacetic acid/CH2Cl2 (24 mL) and stir for 45 min. Remove volatiles under reduced pressure and extract with ethyl acetate and aqueous NaOH (2M). Combine the organic layers and dry with sodium sulfate. Concentrate and purify the residue by chromatography (silica gel/6% of (2M NH3 in methanol)/CH2Cl2) to afford 2,4,6-trifluoro-N-methyl-N-[6-(piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide (77 mg, 85% yield).
Reaction SMILES: O[C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22]CC)=[O:21].C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)[CH:3]1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccccc1OC
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccccc1C1c2ccccc2C(c2ccc3c(c2)OCO3)C1C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 101.9 %

Procedure:
Ethyl (RS)-1-(2-Methoxyphenyl)-3-(3,4-methylene-dioxyphenyl)indene-2-carboxylate. To a solution of ethyl (1RS)-1-hydroxy-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (100 mg, 0.23 mmol) in CH2Cl2 (5 ml) was added triethylsilane (32 mg, 0.28 mmol), followed by boron trifluoride etherate (0.13 ml, 1.05 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 10 min, at which time was added slowly 3 M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to provide the title compound (91 mg, 96%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][C:43]([OH:45])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:46][NH2:47]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][C:43](=[O:45])[NH:47][CH3:46])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: CN
Product: CNC(=O)C[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1C(=O)OCc1ccccc1

Procedure:
Similar to example 6a, 50.0 mg of (2S,4R,5R)-2-carboxymethyl-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (from example 9b) reacted with methylamine to afford the title compound as a yellow oil. Rf=0.35 (dichlormethane-methanol 9:1); Rt=4.57.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1.[CH3:20][NH:21][CH2:22][CH2:23][OH:24]>>[OH:24][CH2:23][CH2:22][N:21]([CH3:20])[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([N:21]([CH2:22][CH2:23][OH:24])[CH3:20])[CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[C:18]([N:21]([CH3:20])[CH2:22][CH2:23][OH:24])[CH:17]=[CH:16][N:15]=2)[CH:3]=1
Reactant: CNCCO
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Product: CN(CCO)c1ccnc(-c2cc(N(C)CCO)cc(-c3cc(N(C)CCO)ccn3)n2)c1

Procedure:
This compound is prepared in a manner analogous to that described in Example 7 with 4′-chloro-[2,2′;6′,2″]terpyridine, but instead the trichloro-substituted terpyridine L22 from Example 28, and 2-methylaminoethanol as amine component are used. 2-({4′,4″-Bis[(2-hydroxy-ethyl)-methyl-amino]-[2,2′;6′,2′]terpyridin-4-yl}methyl-amino)-ethanol, white solid. 13 C-NMR (90 MHz, DMSO-d6): 156.4 (quart.); 155.7 (quart.); 155.3 (quart.); 154.4 (quart.); 149.2 (tert.); 106.7 (tert.); 103.4 (tert.); 103.1 (tert.); 58.4 (2 signals, sec.); 58.2 (sec.); 53.6 (sec.); 53.5 (2 signals, sec.); 38.6 (prim.); 38.3 (2 signals, prim.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11]([Si:14](OS(C(F)(F)F)(=O)=O)([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:12].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:14]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:11]([CH3:13])[CH3:12])[CH:6]=[CH:5]2
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: Brc1ccc2[nH]ccc2c1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Place a 35% oil dispersion of KH (6 g) in a flask under nitrogen, rinse with 50 mL hexanes and dry under vacuum. Cool the solid suspension in 100 mL anhydrous DMF to 0° C. Add dropwise over 10 minutes a solution of 5-bromoindole (10.3 g, 52.5 mmol) in 25 mL DMF. Stir the mixture 1 hour at 0° C. then treat with triisopropylsilyltrifluoromethane sulfonate (32.2 g, 105.1 mmol). Remove the cooling bath and stir the reaction 72 hours before pouring into 500 mL water and extracting with EtOAc. Dilute the combined extracts with hexanes, wash with brine then dry over MgSO4. Concentration under vacuum and chromatograph on silica gel eluting with 1% EtOAc in hexanes to give 5-Bromo-1-triisopropylsilanyl-1H-indole as a colorless oil: 1H NMR (CDCl3) 7.73–7.72 (d, 1H), 7.36–7.34 (d, 1H), 7.24–7.23 (d, 1H), 7.21–7.19 (m, 1H), 6.55–6.54 (m, 1H), 1.72–1.61 (m, 3H, 1.13–1.10 (m, 18H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:30]C(=O)[O-])[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:20]4[CH:27]([CH3:28])[S:26](=[O:29])[CH2:25][C:21]=4[N:22]=[CH:23][N:24]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1>C(Cl)Cl.CO>[NH2:30][C@H:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=1)[C:11]([N:13]1[CH2:14][CH2:15][N:16]([C:19]2[C:20]3[CH:27]([CH3:28])[S:26](=[O:29])[CH2:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH2:17][CH2:18]1)=[O:12]
Reactant: CC1c2c(ncnc2N2CCN(C(=O)C(Cc3ccc(Cl)cc3)NC(=O)[O-])CC2)CS1=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC1c2c(ncnc2N2CCN(C(=O)[C@H](N)Cc3ccc(Cl)cc3)CC2)CS1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
HCl (4M, 1 mL) was added to a solution of 3-(4-chlorophenyl)-1-(4-(5-methyl-6-oxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (0.050 g, 0.091 mmol) in DCM (4 mL) and MeOH (1 mL). The mixture was stirred at room temperature for 6 hours. The solvent was removed to afford (2R)-2-amino-3-(4-chlorophenyl)-1-(4-(5-methyl-6-oxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one as the di-hydrochloride salt (0.40 g). LCMS: 450.1 [M+H+] (APCI+).
Reaction SMILES: [C:1](=[O:16])([S:14][CH3:15])[O:2][O:3][CH:4]([O:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH:5]([CH3:7])[CH3:6].[C:17](O)(=O)C(C)(C)C>>[C:1](=[O:16])([S:14][CH3:15])[O:2][O:3][CH:4]([O:8][C:9](=[O:13])[C:10]([CH3:17])([CH3:11])[CH3:12])[CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)(C)C(=O)O
Reactant: CSC(=O)OOC(OC(=O)C(C)C)C(C)C
Product: CSC(=O)OOC(OC(=O)C(C)(C)C)C(C)C

Procedure:
Following the procedures for synthesizing O-(1-isobutanoyloxyisobutoxy) S-methyl thiocarbonate (11) and replacing isobutyric acid with pivalic acid affords O-(1-pivaloyloxyisobutoxy) S-methyl thiocarbonate (15) as an oil.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28][OH:29])[O:25][C:24]4=[O:30])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28][O:29][S:39]([CH3:38])(=[O:41])=[O:40])[O:25][C:24]4=[O:30])=[CH:19][CH:18]=3)[CH2:15][CH2:16]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N1CC=C(c2ccc(N3C[C@H](CO)OC3=O)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(C3=CCN(C(=O)OCc4ccccc4)CC3)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (R)-(-)-3,6-dihydro-4-[4-[5-hydroxymethyl-2-oxo-3-oxazolidinyl]phenyl]-1(2H)-pyridinecarboxylic acid phenylmethyl ester (EXAMPLE 17, Step 3, 970 mg) and triethylamine (0.50 mL) in dry methylene chloride (9.5 mL) at 0° C. under N2 is treated with methanesulfonyl chloride (0.20 mL) dropwise. The resulting mixture is stirred at 0° C. for one hour, diluted with methylene chloride (40 mL), washed with water (10 mL), saturated aqueous sodium bicarbonate (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, mp 166-168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][N:19]=1)[C:14]([OH:16])=[O:15].Cl.O1CCOC[CH2:22]1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][N:19]=1)[C:14]([O:16][CH3:22])=[O:15]
Reactant: C1COCCO1
Reactant: O=C(O)c1ccnc(-c2cc([N+](=O)[O-])ccc2Cl)c1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccnc(-c2cc([N+](=O)[O-])ccc2Cl)c1

Procedure:
75 mL of (4-methylpyridin-2-yl)zinc(II) bromide was reacted with 4 g of 1-chloro-2-iodo-4-nitrobenzene via Procedure B. To 300 mg of 2-(2-chloro-5-nitrophenyl)-4-methylpyridine in 1.5 mL of Sulfuric Acid was slowly added 362 mg of Chromium (III) Oxide and the reaction was stirred for several hours at room temperature until complete. Icewater was added to dilute the reaction and the aqueous layer was extracted 3 times with Ethyl Acetate. The organic layers were combined, dried over Magnesium Sulfate, filtered and concentrated to give 2-(2-chloro-5-nitrophenyl)isonicotinic acid. 300 mg of 2-(2-chloro-5-nitrophenyl)isonicotinic acid was esterified with 750 μL of 4N HCl in Dioxane in 10 mL of MeOH at 55° C. for 16 hours. The reaction was concentrated and subjected to basic workup, dried over Magnesium Sulfate, filtered and concentrated to give methyl 2-(2-chloro-5-nitrophenyl)isonicotinate. 259 mg of methyl 2-(2-chloro-5-nitrophenyl)isonicotinate was treated with 200 mg of Tin (II) Chloride and 500 μL of HCl in 10 mL of EtOH. Upon completion, EtOH was concentrated and the reaction was extracted with Ethyl Acetate and water with TEA to decrease emulsions. The organic layer was dried over Magnesium Sulfate, filtered and concentrated to give crude methyl 2-(5-amino-2-chlorophenyl)isonicotinate. 240 mg of methyl 2-(5-amino-2-chlorophenyl)isonicotinate was treated with 204 μL of 2-methyl-6-(trifluoromethyl)nicotinoyl chloride via Procedure D. To 100 mg of methyl 2-(2-chloro-5-(2-methyl-6-(trifluoromethyl)nicotinamido)phenyl)isonicotinate at 0° C. in 5 mL of EtOH was slowly added 135 mg of Sodium Borohydride. The reaction was subsequently refluxed for 1 hour until complete, quenched with water and extracted with Ethyl Acetate. The organic layer was dried over Magnesium Sulfate, filtered, concentrated and purified by reverse phase HPLC to give pure N-(4-chloro-3-(4-(hydroxymethyl)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide. MS (Q1) 422.1 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:16][C:17]1[C:18](Cl)=[N:19][CH:20]=[CH:21][CH:22]=1>>[C:6]1([C:4]2[C:3]3[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=3[NH:1][C:18]3[N:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1cccnc1Cl
Reactant: Nc1ccccc1C(=O)c1ccccc1
Product: c1ccc(C2=Nc3cccnc3Nc3ccccc32)cc1
Temperature: 190 °C
Yield: 26.9 %

Procedure:
A mixture of 19.7 g (0.1 mole) of 2-aminobenzophenone and 15.0 g (0.12 mole) of 3-amino-2-chloropyridine was heated under nitrogen atmosphere at 190° C. for 1.75 hr. The mixture was cooled to room temperature and partitioned between 3 N aqueous sodium hydroxide and methylene chloride. The combined methylene chloride extracts were washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue, 32.7 g, was dissolved in benzene and chromatographed on a column of florisil packed in benzene, eluting with benzene and 1-2% acetone-benzene mixtures. After evaporation, the solid was crystallized from benzene to give 7.3 g product; m.p. 106°-108° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH2:14]([CH2:16][NH2:17])[OH:15]>>[OH:15][CH2:14][CH2:16][NH:17][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: NCCO
Product: O=C(O)c1cccc(S(=O)(=O)NCCO)c1

Procedure:
Procedure H was performed to couple 3-(chlorosulfonyl)benzoic acid with ethanolamine to produce 3-(2-hydroxyethylsulfamoyl)benzoic acid which was purified by reverse phase HPLC.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>C(O)C>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]2[CH2:16][CH2:15][C:14](=[N:19][OH:20])[CH2:13][CH2:12]2)[CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCN(c2cccc3c2OCCC3)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1CCN(c2cccc3c2OCCC3)CC1
Yield: 84.6 %

Procedure:
A mixture composed of 1 g (4.32 mmol) of the product obtained in Step 1, 1.26 g of hydroxylamine hydrochloride, 1.26 g of sodium acetate and 20 ml of ethanol are heated at reflux for 1 hour. After removal of the solvent by evaporation, the residue is taken up in 100 ml of methylene chloride, washed with water, dried and evaporated to yield 0.9 g of the expected product.
Reaction SMILES: [CH:1]1([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[Li+].CC([N-]C(C)C)C>C1COCC1>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][C:1]1([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCOC(=O)C1CCCC1
Reactant: BrCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCOC(=O)C1(CCCCBr)CCCC1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 49 %

Procedure:
Under a N2 atmosphere at −60° C., a solution of butyl cyclopentanecarboxylate (prepared according to Payne, G. B.; Smith, C. W., J. Org. Chem., 1957, 22, 1680-1682, 80.0 g, 0.42 mol) and 1,4-dibromobutane (183.3 g, 0.84 mol) in dry THF (700 mL) was added drop wise to a mixture of LDA (2M in THF/heptane/ethylbenzene, 250 mL, 0.50 mol) and dry THF (250 mL) in 1.5 h. After that, the reaction mixture was allowed to slowly reach rt during 3.5 h. Then, the reaction mixture was poured into ice-cold saturated aqueous NH4Cl (1 L). The organic layer was decanted and concentrated in vacuo to a smaller volume. The aqueous layer was extracted with Et2O (3×250 mL). The combined organic layers were washed with saturated aqueous NH4Cl (250 mL) and brine (2×250 mL), dried (Na2SO4) and evaporated in vacuo. The remaining residue was purified by fractional distillation to give butyl 1-(4-bromo-butyl)-cyclopentanecarboxylate (62.8 g, 49%) as a light yellow liquid. bp: T=116-117° C. (p=0.040-0.051 Torr). 1H NMR (CDCl3): δ=4.07 (t, J=6.6 Hz, 2H), 3.38 (t, J=6.8 Hz, 2H), 2.16-2.10 (m, 2H), 1.83 (quintet, J=7.1 Hz, 2H), 1.65-1.59 (m, 8H), 1.50-1.31 (m, 6H), 0.94 (t, J=7.2 Hz, 3H). 13C NMR (CDCl3): δ=177.6, 64.1, 53.9, 38.2, 36.0 (2×), 33.3, 33.0, 30.6, 24.8 (2×), 24.6, 19.1, 13.6. HRMS calcd for C14H25BrO2 (M+): 304.1038, found: 304.1042.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CS(C)=O>[CH3:11][S:8]([C:7]1[CH:6]=[CH:5][C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])=[CH:3][C:2]=1[N:26]1[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]1)(=[O:10])=[O:9]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(N3CCN(C)CC3)c2)s1
Temperature: 115 °C

Procedure:
A stirred mixture of N-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) (0.05 g, 0.15 mmol) and 1-methylpiperazine (0.1 ml, 0.9 mmol) in dry DMSO (1 ml) is heated under argon at 115° C. for 1 hour. The solvent is removed and water (30 ml) is added. The product is extracted with ethyl acetate (2×30 ml) and the combined organic extracts are washed with brine (20 ml) and dried (MgSO4). Removal of the solvent and trituration with diethyl ether affords the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[C:11](=S)[NH:10][C@@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[CH2:8][C:6]=2[N:7]=1.[Si:22]([O:29][NH2:30])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[Si:22]([O:29]/[N:30]=[C:11]1\[NH:10][C@@H:9]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[Br:20])[CH2:8][C:6]2[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([CH3:21])[C:5]\1=2)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: Cc1nc(N)nc2c1C(=S)N[C@@H](c1ccc(F)cc1Br)C2
Reactant: CC(C)(C)[Si](C)(C)ON
Solvent: Cc1ccccc1
Product: Cc1nc(N)nc2c1/C(=N/O[Si](C)(C)C(C)(C)C)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 100 °C
Yield: 79.9 %

Procedure:
A mixture of (R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione (31I, 366 mg, 1.0 mmol), O-(tert-butyldimethylsilyl)hydroxylamine (588 mg, 4.0 mmol), Hg(OAC)2 (640 mg, 2.0 mmol) and toluene (5 mL) was heated at 100° C. for 2 h. The mixture was cooled to r.t. and filtered through celite. Filtrate concentrated and the resulting oily residue was triturated with dry methanol to afford a pale yellow solid. Filtered and dried to afford ((R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-tert-butyldimethylsilyloxime (105a, 384 mg, 80%) as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.22 (s, 3H), 0.23 (s, 3H) 0.97 (s, 9H) 2.70 (s, 3H) 2.91 (dd, J=16.42, 8.08 Hz, 1H) 3.19 (ddd, J=16.36, 4.86, 1.26 Hz, 1H) 4.99 (ddd, J=7.77, 5.12, 2.02 Hz, 1H) 7.05 (td, J=8.27, 2.65 Hz, 1H) 7.33 (dd, J=8.08, 2.78 Hz, 1H) 7.39 (dd, J=8.72, 5.94 Hz, 1H). MS (ES) [M+H] calculated for C20H28BrFN5OSi, 480.12. found 480.30.