Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[C:18]5[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24][C:19]=5[N:20]([CH3:23])[C:21]=4[CH:22]=3)[C:10](=[O:35])[CH2:9]2)=[CH:4][CH:3]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:50].Cl>>[ClH:50].[ClH:50].[F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[C:18]5[CH2:27][NH:26][CH2:25][CH2:24][C:19]=5[N:20]([CH3:23])[C:21]=4[CH:22]=3)[C:10](=[O:35])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cn1c2c(c3ccc(N4CCN(CCc5ccc(F)cc5)CC4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccc(F)cc5)CC4=O)cc31)CNCC2
Yield: 63 %

Procedure:
tert-Butyl 7-(4-(4-fluorophenethyl)-2-oxopiperazin-1-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (730 mg, 1.44 mmol) was deprotected and converted to the dihydrochloride according to Example 2 (step g) to provide the title compound (433 mg, 63%) as a white solid: 298° C. dec; 1H NMR (500 MHz, DMSO-d6) δ 12.32 (s, 1H), 9.53 (s, 2H), 7.53 (d, J=8.3 Hz, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.39-7.34 (m, 2H), 7.20 (t, J=8.8 Hz, 2H), 7.02-7.00 (dd, J=8.3, 1.6 Hz, 1H), 4.38 (s, 2H), 4.27-4.19 (m, 1H), 4.19-3.99 (m, 2H), 3.94-3.81 (m, 2H), 3.66 (s, 3H), 3.64-3.54 (m, 1H), 3.54-3.33 (m, 4H), 3.19-3.11 (m, 2H), 3.10-3.05 (m, 2H); ESI MS m/z 407 [M+H]+; HPLC (Method B)>99% (AUC), tR=11.9 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.[N+:17]([O-])([OH:19])=[O:18].O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:17]([O-:19])=[O:18])=[C:9]([OH:13])[CH:8]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1cccc(OCc2cccc(F)c2)c1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.9 %

Procedure:
1.0 g (5 mmol) of 3-(3-fluoro-benzyloxy)-phenol is dissolved in 10 ml acetic acid and cooled to 10°. 0.44 g (5 mmol) of 65% nitric acid is dissolved in 10 ml acetic acid and slowly added to the previous solution. The colored mixture is stirred for 15 min. at 10° and for 2 h at room temperature. 50 ml of water is added and the product extracted 3 times with ethyl acetate. Chromatography (silica gel, dichloromethane/methanol 98:2) yields 0.38 g (32%) of the desired product as a yellow solid. MS: m/e=262.1 (M+−H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[CH2:36][OH:37].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]2[CH2:36][OH:37])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: OCC1CCCCN1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3CO)ccc21
Yield: 57.2 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (50.9 mg, 0.124 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 2-piperidine methanol (63.8 mg, 0.554 mmol), acetic acid (0.284 mL, 4.96 mmol) and sodium triacetoxyborohydride (158 mg, 0.745 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and ethyl acetate, followed by extracting with 1 mol/L hydrochloric acid. The aqueous layer was added with sodium hydrogen carbonate to adjust the pH to 9. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[2-(hydroxymethyl)piperidinomethyl]indol-2-yl}isoindolinone (36.2 mg, yield 57%).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([OH:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:36][C:37]1[O:38][C:39](=[O:43])[O:40][C:41]=1[CH3:42].CCOC(C)=O>CN(C=O)C>[CH3:42][C:41]1[O:40][C:39](=[O:43])[O:38][C:37]=1[CH2:36][O:12][C:11](=[O:13])[C@H:10]([OH:14])[CH2:9][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:6][CH:5]=1
Reactant: Cc1oc(=O)oc1CCl
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1oc(=O)oc1COC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(2R,4R)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxypentanoic acid (500 mg, 1.0 mmol, 1.0 eq.) was dissolved in dry DMF (10.0 mL). The solution was cooled to 0° C. and dicesium carbonate (465 mg, 1.4 mmol, 1.1 eq.) was added. The mixture was stirred for 30 minutes and 4-chloromethyl-5-methyl-1,3-dioxol-2-one (212 mg, 1.4 mmol, 1.1 eq.) was added. The resulting mixture was stirred for an additional 1 hour at 0° C., then warmed to room temperature while stirring. The mixture was further stirred overnight. EtOAc (20 mL) was added, followed by washing with saturated aqueous NaCl (100 mL). The product was dried under vacuum and purified using reverse phase chromatography (10-70% MeCN/H2O; 0.05% TFA over 70 minutes) to yield (2R,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxypentanoic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester. This material was dissolved in 4N HCL in dioxane and stirred for 2 hours at room temperature. The material was dried under vacuum then azeotroped with toluene to yield (2R,4R)-4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester, which was used in the next step without further purification.
Reaction SMILES: [O:1]1[C:5]([C:6]2[S:10][C:9]([S:11](Cl)(=[O:13])=[O:12])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]2[NH:26][N:25]=[N:24][N:23]=2)[CH:19]=[CH:20][CH:21]=1>>[O:1]1[C:5]([C:6]2[S:10][C:9]([S:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[NH:26][N:25]=[N:24][N:23]=4)[CH:17]=3)(=[O:13])=[O:12])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)s1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2cnco2)s1
Yield: 51.8 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting with 5-(1,3-oxazol-5-yl)thiophene-2-sulfonyl chloride (13.7 mg, 0.055 mmol) and 5-(3-amino-phenyl)tetrazole (8 mg, 0.05 mmol) yielding 9.7 mg (52%) of the title compound. MS (ESI+) calcd for C14H10N6O3S2 374.02558, found 374.02547.
Reaction SMILES: [CH3:1][C:2]1[CH:7]([N+:8]([O-:10])=[O:9])[C:6](=O)[CH:5]=[C:4]([CH3:12])[N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:6]1[CH:5]=[C:4]([CH3:12])[N:3]=[C:2]([CH3:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC1=CC(=O)C([N+](=O)[O-])C(C)=N1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)c([N+](=O)[O-])c(C)n1

Procedure:
By the method of Yakugaku Zasshi, 87, 387 (1967), 2,6-dimethyl-3-nitro-4-pyridone (11.23 g, 66.8 mmol) and phosphorus oxychloride (57 ml) were heated together at reflux for 11/2 hours. The excess reagent was removed under reduced pressure, and the residue dissolved in dichloromethane (150 ml). This solution was treated with dilute aqueous sodium bicarbonate until the aqueous layer was at pH7, and then the organic phase was separated, dried (MgSO4) and concentrated under reduced pressure to give a pale yellow solid, (9.8 g, 79%). Caution: this compound is believed to be a powerful skin irritant.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[H-].[Na+].CN(C)[C:15](=O)[CH3:16]>>[CH3:15][C:16]1[NH:6][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[N:10][C:2]=2[CH:1]=1
Reactant: Cc1ncccc1C(N)=O
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Product: Cc1cc2ncccc2c(=O)[nH]1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 272.3 mg (2 mmol) of 2-methylnicotinamide (2) and 0.34 mL (2.2 mmol) of 95% N,N-dimethylacetamide, dimethylacetal is heated at 50° C. for 1.5 hours, then a vacuum is applied for 1 hour with heating as described above. The oil is diluted with 2 mL of dry N,N-dimethylacetamide, treated with 96 mg of 60% sodium hydride, and heated at 80° C. for 2.5 hours. The solution is treated with 70 mg more of 60% sodium hydride, heated for an addition 4.5 hours, then quenched with excess acetic acid. The mixture is concentrated at 2 mm/70° C. to leave a residual solid that is triturated in hot chloroform, then filtered through a pad of silica gel (230-400 mesh). The pad is eluted with chloroform, then acetone to collect the product. The filtrate is concentrated to a solid that is dissolved in a minimum volume of hot water. The solution is stored at 5° C. for 2 weeks, and the precipitated solids are collected by filtration, washed well with propanol, and dried to give 73 mg of pure product, mp 244°-245° C.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[N+:20]([O-])([O-:22])=[O:21].[K+]>>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[C:9]([N+:20]([O-:22])=[O:21])[CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)N1CCc2ccc(Cl)cc2C1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)N1CCc2cc([N+](=O)[O-])c(Cl)cc2C1
Reaction time: 1 h

Procedure:
A solution of 20.9 g. (0.1 mole) of 2-acetyl-7-chloro-1,2,3,4-tetrahydroisoquinoline in 100 ml. of concentrated sulfuric acid is treated with 10 g. (0.1 mole) of potassium nitrate dissolved in 150 ml. of concentrated sulfuric acid. The mixture is stirred for one hour, quenched on ice, made alkaline with ammonium hydroxide and filtered to yield 2-acetyl-7-chloro-6-nitro-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: CN(C)C.[F:5][C:6]1[C:11]([F:12])=[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:9]=[CH:8][C:7]=1[C:22]1[N:27]=[CH:26][C:25]([OH:28])=[CH:24][N:23]=1.[Cl:29][C@@H:30]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C:31](Cl)=[O:32]>ClCCl>[F:5][C:6]1[C:11]([F:12])=[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:9]=[CH:8][C:7]=1[C:22]1[N:23]=[CH:24][C:25]([O:28][C:31](=[O:32])[C@@H:30]([Cl:29])[C@@H:34]([CH3:37])[CH2:35][CH3:36])=[CH:26][N:27]=1
Reactant: CCCCCCCCOc1ccc(-c2ncc(O)cn2)c(F)c1F
Reactant: CC[C@H](C)[C@H](Cl)C(=O)Cl
Agent: CN(C)C
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ncc(OC(=O)[C@@H](Cl)[C@@H](C)CC)cn2)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
--Trimethylamine (234 mg, 2.31 mmol) was added to a solution of the difluorophenylhydroxy-pyrimidine 35 (740 mg, 2.31 mmol) and (2S, 3S)-2-chloro-3-methylpentanoyl chloride 36 (388 mg, 2.31 mmol) in dry dichloromethane (8 ml) with stirring under nitrogen at room temperature for 2 h. Dichloromethane was added and the mixture was washed with dilute hydrochloric acid (twice), saturated sodium bicarbonate solution and brine, dried and evaporated. The residue was purified by flash chromatography (10% ethyl acetate-light petroleum) to give the ester 37 (670 mg, 58%) (from MeOH), m.p 66.2° C., [α]D26 +1.5° (c 2.4 in CHCl3); νmax /cm-1 (KBr) 2920, 1765 (CO), 1615, 1510, 1470, 1420, 1300, 1230, 1120 and 1080; δ 0.89 (3H, t,J6.5, Me), 1.00 (3H, t,J6.5, CH3CH2CH(CH3), 1.15 (3H, d,J7, CH(CH3)), 1.25-1.55 (10H, m), 1.76 (2H, m, CH3CH2CH(CH3), 1.85 (2H, quint, OCH2CH2), 2.25 (1H, m, CHMe), 4.11 (2H, d, J6.5, OCH2), 4.44 (1H, d, J7, CHCl), 6.84 (1H, ddd, J8, 7 and 2, 5'-H), 7.85 (1H, ddd, J8, 7 and 2, 6'-H) and 8.71 (2H, s 4- and 6-H); m/z 470 (M+), 468 (M+), 358 (M+ -C8H16), 356 (M+ -C8H16), 336, 237 and 224.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[NH:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.Cl[P:27]([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29]>>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[N:20][P:27]([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)P(Cl)C(C)C
Reactant: Cc1ccc(C(=N)Nc2ccccc2C(C)(C)C)cc1
Agent: [Li]CCCC
Product: Cc1ccc(C(=NP(C(C)C)C(C)C)Nc2ccccc2C(C)(C)C)cc1

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.33 g of N1-(2-tert-butylphenyl)-4-methylbenzamidine (Amidine VI, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.80 mL chlorodiisopropylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, a yellow semi-solid was isolated (1.9 g, 100%).
Reaction SMILES: N1C(C2C=C3C(=CC=2)N=CNC3=O)=NN=N1.F[C:18](F)(F)[C:19]1[O:23][C:22]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[CH:29][NH:28][C:27]3=[O:34])=[N:21][N:20]=1>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH3:18][C:19]1[O:23][C:22]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[CH:29][NH:28][C:27]3=[O:34])=[N:21][N:20]=1
Reactant: O=c1[nH]cnc2ccc(-c3nnc(C(F)(F)F)o3)cc12
Agent: O=c1[nH]cnc2ccc(-c3nnn[nH]3)cc12
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1nnc(-c2ccc3nc[nH]c(=O)c3c2)o1
Yield: 171.8 %

Procedure:
6-(5-Trifluoromethyl-1,3,4-oxadiazol-2-yl)quinazolin-4-one 6-(1,2,3,4-Tetrazol-5-yl)-quinazolin-4-one (1.0 g) was treated with trifluoroacetic anhydride (50 ml) at 50° C. under N2 for 5 hours. The anhydride was removed in vacuo, the residue absorbed onto silica and purified by chromatography to give the title compound as a white solid (0.79 g); δH [2H6]DMSO 12.63(1H,bs), 8.71(1H,d), 8.45(1H,dd), 8.27(1H,s), 7.90(1H,d); m/z (M−1+) 281.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]2[N:12]=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=2)=[C:5]([Br:7])[N:6]=1.[Cl-].[Li+].O1CCOCC1.[CH2:29]([Sn](CCCC)(CCCC)C#CC)[CH2:30][CH2:31]C>C(Cl)Cl.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O.CCCCCC>[Br:7][C:5]1[N:6]=[C:2]([C:29]#[C:30][CH3:31])[S:3][C:4]=1[C:8]1[N:12]=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=1
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Reactant: C[Si](C)(C)CCOCn1cnc(-c2sc(Br)nc2Br)n1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC#Cc1nc(Br)c(-c2ncn(COCC[Si](C)(C)C)n2)s1
Temperature: 100 °C
Yield: 76.2 %

Procedure:
A mixture of 3-(2,4-dibromo-1,3-thiazol-5-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazole (6.00 g, 13.6 mmol), Lithium chloride (1.73 g, 40.9 mmol), Copper(I) iodide (0.779 g, 4.09 mmol) and Tetrakis(triphenylphosphine)platinum (0) (0.848 g, 0.681 mmol) in anhydrous 1,4-Dioxane (120 mL, 1500 mmol) was sonicated under Argon atmosphere for 2 minutes in a 250 mL RBF. Tributyl(1-propynyl)tin (4.80 mL, 15.0 mmol) was added. The mixture was heated to 100° C. for 1 hour under Argon atmosphere. The mixture was cooled to r.t., diluted with DCM (˜150 mL), filtered through Celite, and washed with DCM. The filtrate was rotavaped to give a crude residue. Chromatograph in a 330 g ISCO column using EtOAc/hexane (0/100 to 50/50) gave a pure solid product (4.14 g, 76% yield). LCMS: (FA) ES+ 399, 401. 1H NMR (400 MHz, d1-chloroform) 8.29 (s, 1H), 5.54 (s, 2H), 3.69-3.74 (m, 2H), 2.15 (s, 3H), 0.93-0.97 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[C:4]([Cl:11])[CH:3]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][NH2:18].CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1.CCOC(C)=O>[Cl:11][C:4]1[CH:3]=[C:2]([NH:18][CH2:17][C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=1
Reactant: NC(=O)c1cnc(Cl)cc1Cl
Reactant: NCc1cccs1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc(Cl)cc1NCc1cccs1
Yield: 99 %

Procedure:
A solution of 4,6-dichloronicotinamide (123 mg, 0.643 mmol), thiophen-2-ylmethanamine (0.065 mL, 0.634 mmol) and DIPEA (0.230 mL, 1.32 mmol) in NMP (4 mL) was stirred at 90 C for 18 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, and concentrated in vacuo to give 6-chloro-4-(thiophen-2-ylmethylamino)nicotinamide as a solid (168 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-])=[O:25])=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].[CH3:28][N:29]1[CH:33]=[C:32]([CH2:34][NH2:35])[N:31]=[CH:30]1>>[CH3:28][N:29]1[CH:33]=[C:32]([CH2:34][NH:35][C:24]([C:21]2[O:22][C:23]3[C:15]([N:12]4[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH2:14][CH2:13]4)=[CH:16][CH:17]=[CH:18][C:19]=3[CH:20]=2)=[O:25])[N:31]=[CH:30]1
Reactant: Cn1cnc(CN)c1
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Agent: [Li+]
Product: Cn1cnc(CNC(=O)c2cc3cccc(N4CCN(CCc5ccccn5)CC4)c3o2)c1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (70 mg, 0.18 mmol) and (1-methyl-1H-imidazol-4-yl)methylamine (24 mg, 0.22 mmol). Yield: 42 mg (48%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C@@H:13]1[CH2:15][O:14]1.[F:16][C:17]([F:23])([F:22])[C:18]([OH:21])([CH3:20])[CH3:19].B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[CH:13]([O:21][C:18]([CH3:20])([CH3:19])[C:17]([F:23])([F:22])[F:16])[CH2:15][OH:14]
Reactant: CC(C)(O)C(F)(F)F
Reactant: Cc1cc2ccccc2c(Cl)c1[C@@H]1CO1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc2ccccc2c(Cl)c1C(CO)OC(C)(C)C(F)(F)F
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (R)-2-(1-chloro-3-methylnaphthalen-2-yl)oxirane (340 mg, 1.56 mmol) and 2-trifluoromethyl-2-propanol (4.3 mL, 38.97 mmol) in CH2Cl2 (4.3 mL), boron trifluoride diethyl etherate (1.9 mL, 15.60 mmol) was added at 0° C. The reaction mixture was stirred for 16 h at 0° C. and allowed to warm to room temperature overnight. The mixture was quenched with saturated aqueous NaHCO3, and then diluted with CH2Cl2. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give 2-(1-chloro-3-methylnaphthalen-2-yl)-2-(1,1,1-trifluoro-2-methylpropan-2-yloxy)ethanol. 1H-NMR: 400 MHz, (CDCl3) δ 8.27 (d, J=8.4 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.57-7.49 (m, 3H), 5.90 (dd, J=9.6, 4.4 Hz, 1H), 3.98 (t, J=11.2 Hz, 1H), 3.66 (dd, J=12.0, 4.0 Hz, 1H), 2.69 (s, 3H), 2.18 (br s, 1H), 1.45 (s, 3H), 1.19 (s, 3H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:54])[C@@H:14]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([O:37][CH2:38][C:39]([N:41]3[CH2:45][CH2:44][CH2:43][C@H:42]3[C:46](=[O:52])[NH:47][CH:48]3[CH2:51][CH2:50][CH2:49]3)=[O:40])[C:34]3[C:29](=[CH:30][C:31]([CH3:53])=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:15][CH2:16][C:17]([O:19][C:20](C)(C)[CH3:21])=[O:18])[CH2:9][CH2:8]1)=[O:6])[CH3:3].C1(C)C=CC=CC=1>C(O)C>[CH2:2]([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13](=[O:54])[C@@H:14]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([O:37][CH2:38][C:39]([N:41]3[CH2:45][CH2:44][CH2:43][C@H:42]3[C:46](=[O:52])[NH:47][CH:48]3[CH2:49][CH2:50][CH2:51]3)=[O:40])[C:34]3[C:29](=[CH:30][C:31]([CH3:53])=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][CH2:12]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)c3ccc(C)cc3n2)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)c2ccc(C)cc2n1)C(=O)N1CCN(C(=O)OCC)CC1
Reaction time: 2 h

Procedure:
To 100 ml of a saturated solution of hydrochloric acid in ethanol 5 g of 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester was added and the mixture was stirred for 2 h. Then, 30 ml of toluene was added and the solvents were removed under reduced pressure. The residue was filtered through a plug of silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. The residue was purified by re-crystallisation from n-heptane/ethyl acetate and dried under reduced pressure. Yield: 3.8 g MS (ES+): m/e=709.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[CH2:8]>C(O)C.[Pd]>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH:7]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[CH3:8]
Reactant: C=C(c1nc[nH]c1C)c1cccc2ccccc12
Agent: [Pd]
Solvent: CCO
Product: Cc1[nH]cnc1C(C)c1cccc2ccccc12
Yield: 73 %

Procedure:
Crude (13) in ethanol was hydrogenated (50 psi H2) over Pd/C (10%, 0.19 g) over night. The reaction was filtered through a bed of Celite. The filtrate was added silica gel, and the solvent was removed under vacuum. Crude product on silica was purified by chromatography on silica gel with 2% saturated ammonia methanol in dichloromethane to give (14) as a light tan foam (423 mg, 1.79 mmol, 73% over 2 steps).
Reaction SMILES: [CH3:1][CH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:5]=2[O:4][C:3]1=[O:19].[OH-:20].[K+]>>[OH:4][C:5]1[C:10]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:2]([CH3:1])[C:3]([OH:19])=[O:20]
Reactant: CC1C(=O)Oc2c(Sc3ccccc3Cl)cccc21
Reactant: [OH-]
Agent: [K+]
Product: CC(C(=O)O)c1cccc(Sc2ccccc2Cl)c1O

Procedure:
3-Methyl-7-(2-chlorophenylthio)-2,3-dihydrobenzofuran-2-one was treated with potassium hydroxide in the same manner as Example 21-(10) to give crystalline 2-[2-hydroxy-3-(2-chlorophenylthio)phenyl]propionic acid, mp. 143°-145° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1.O.O.[Sn](Cl)Cl>C(O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2F)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(Oc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
Add together 4-(2-fluoro-phenoxy)-nitrobenzene (3.18 g, 13.6 mmol) and Tin(II) chloride dihydrate (12.89 g, 5 Eq.) in absolute ethanol (20 mL) and heat to reflux while stirring under a nitrogen atmosphere for 3 hours. Cool to room temperature and dilute with ethyl acetate (50 mL). Wash this organic layer once with water, dry over potassium carbonate, filter, and concentrate under reduced vacuum to give 2.90 g as a dark oil. Purify the material by silica gel chromatography (Prep. 2000) eluting with methylene chloride to provide 1.74 g of the title compound as a tan solid. Mass spectrum (m/e): 204.2 (M*+1): (Bruker 300) 1H NMR (CDCl3) δ 7.08-7.15 (2H, m), 6.95-7.02 (3H, m), 6.81-6.92 (4H, m), 6.63-6.67 (2H, d).