Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li])CCC.Cl.Cl[CH2:17][C:18]1[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=1.Cl>O1CCCC1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:17][C:18]2[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=2)=[CH:2]1
Reactant: C1=Cc2ccccc2C1
Reactant: Cn1ccnc1CCl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1ccnc1CC1=CCc2ccccc21
Temperature: 25 °C
Yield: 76.7 %

Procedure:
A solution of 17.4 ml of indene (0.1497 mol) in 150 ml of tetrahydrofuran (THF) was cooled to −60° C. and 61.8 ml of n-butyllithium (2M in hexane, 0.136 mol) were subsequently added while stirring. The mixture was allowed to warm to room temperature while stirring for 3 h and 5 g (0.0299 mol) of 2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride was then added while stirring. The mixture was then stirred for a further 12 hours and hydrolyzed with 400 ml of dilute hydrochloric acid, the organic phase was separated off and the aqueous phase was extracted once with ethyl acetate. The aqueous phase was then neutralized with aqueous ammonia solution and extracted 3 times with 80 ml each time of dichloromethane. The organic phases were combined and dried over magnesium sulfate. After the magnesium sulfate had been filtered off, the solvent was distilled off. The crude product was purified by column chromatography using a mixture of hexane:ethyl acetate=1:1 and then the percentage of ethyl acetate slowly increased. Thus 4.82 g of 2-(1H-inden-3-ylmethyl)-1-methyl-1H-imidazole were obtained (77%).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[CH:18]=[O:19].[CH2:20]=[N:21][CH:22](S(C1C=CC(C)=CC=1)(=O)=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[C:23]1([C:22]2[N:21]=[CH:20][O:19][C:18]=2[C:3]2[C:2](=[O:1])[CH:7]=[CH:6][N:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[N:4]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C=NC(c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ocnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.6 %

Procedure:
To a solution of 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carbaldehyde (52.8 mg, 0.197 mmol) in MeCN (0.4 mL) were added N-methylidene-1-[(4-methylphenyl)sulfonyl]-1-phenylmethanamine (53.8 mg, 0.197 mmol) and K2CO3 (35.4 mg, 0.256 mmol) at room temperature. The suspension was stirred at room temperature for 1 day. The suspension was diluted with water, extracted with AcOEt, washed with brine, dried over MgSO4, filtered, concentrated in vacuo, purified by column chromatography on silica gel (hexane/AcOEt=90/10 to 0/100) and crystallized with AcOEt/hexane to yield the title compound (18.6 mg, 25% yield) as a solid: NMR (DMSO-d6, 300 MHz): δ ppm 6.75 (1H, d, J=8.5 Hz), 7.33-7.43 (3H, m), 7.64-7.70 (2H, m), 7.72-7.83 (2H, m), 7.92-8.01 (2H, m), 8.65 (1H, s), 9.02 (1H, d, J=7.7 Hz). Anal. Calcd for C20H12F3N3O2.0.2H2O: C, 62.08; H, 3.23; N, 10.86. Found: C, 62.08; H, 3.38; N, 10.67.
Reaction SMILES: [Cl:1][C:2](=[N:16][OH:17])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>C(OCC)C>[Cl:1][C:2](=[N:16][O:17][S:19]([CH3:18])(=[O:21])=[O:20])[CH:3]1[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:7][CH2:8]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C(Cl)=NO)CC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(Cl)=NOS(C)(=O)=O)CC1
Temperature: 25 °C
Yield: 53.7 %

Procedure:
tert-Butyl 4-(chloro(hydroxyimino)methyl)piperidine-1-carboxylate (2.3 g, 8.75 mmol) and methanesulfonyl chloride (0.68 mL, 8.75 mmol) were suspended in diethyl ether (200 mL). Triethylamine (1.22 mL, 8.75 mmol) was added and the reaction stirred at ambient temperature until consumption of starting material. The mixture was filtered and the filtrate was concentrated. The residue was purified by flash chromatography (using dichloromethane) to afford the title compound (1.6 g, 53% yield) as a clear oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]1[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[C:42]=1[O:43][CH2:44][C:45](O)=[O:46].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]1[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[C:42]=1[O:43][CH2:44][C:45]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:46]
Reactant: Cc1cccc(C)c1OCC(=O)O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)COc1c(C)cccc1C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
A solution containing the product from Example 2C (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with 2,6-dimethylphenoxy acetic acid (U.S. Pat. No. 5,914,332, see Example 1H) (0.008 g, 0.044 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.030 mL, 0.172 mmol), stirred at 25° C. for 16 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-80% ethyl acetate/chloroform to give the title compound (0.021 g, 77% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.83 (s, 9 H), 1.52 (m, 2 H), 2.08 (s, 6 H), 2.72 (m, 2 H), 2.80 (m, 2 H), 3.51 (s, 3 H), 3.72 (m, 1 H), 3.85 (d, J=9.19 Hz, 1 H), 4.01 (s, 2 H), 4.22 (m, 2 H), 5.05 (d, J=5.88 Hz, 1 H), 6.71 (d, J=9.93 Hz, 1 H), 6.92(m, 3 H), 7.26 (m, 8 H), 7.45 (d, J=9.56 Hz, 1 H), 7.85 (m, 5 H), 8.62 (d, J=4.78 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](OC(=O)C(C)(C)C)[N:6]=[C:5]2[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28].C(N(CC)CC)C>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1)=[O:28]
Reactant: CC(C)(C)C(=O)On1nc(-c2ccc[nH]2)c2cc(N)ccc21
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2[nH]nc(-c3ccc[nH]3)c2c1)c1cccc(Cl)c1
Yield: 32 %

Procedure:
2,2-Dimethyl-propionic acid 5-amino-3-(1H-pyrrol-2-yl)-indazol-1-yl ester (0.38 mmol) (From Example 28) was coupled with 3-chloro-benzoyl chloride (0.4 mmol) and triethylamine in DCM at 0° C. to give 41 mg of the titled compound as a white solid.
Reaction SMILES: [F:1][C:2]([P:8]([C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])(=[O:16])[O:9][CH2:10][CH2:11][O:12][CH2:13][CH:14]=[CH2:15])([F:7])[C:3]([F:6])([F:5])[F:4].[CH3:24][N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>>[F:7][C:2]([P:8]([C:17]([F:22])([F:23])[C:18]([F:21])([F:20])[F:19])(=[O:9])[O-:16])([F:1])[C:3]([F:6])([F:5])[F:4].[CH2:13]([O:12][CH2:11][CH2:10][N:27]1[CH:28]=[CH:29][N+:25]([CH3:24])=[CH:26]1)[CH:14]=[CH2:15]
Reactant: C=CCOCCOP(=O)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: Cn1ccnc1
Product: C=CCOCCn1cc[n+](C)c1
Product: O=P([O-])(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
2-(Allyloxy)ethyl bis(pentafluoroethyl)phosphinate, (C2F5)2P(O)OCH2CH2—OCH2CH═CH2, (4.135 g; 10.7 mmol) is slowly added dropwise to dry and cooled (0° C.) N-methylimidazole (0.793 g; 9.7 mmol) (exothermic) in a 50 ml glass flask. A pale-yellow, more highly viscous solution forms spontaneously, which is stirred at 0° C. for 1.5 h, warmed and stirred at room temperature for 5 h. The readily volatile constituents are removed in vacuo (10−3 mbar) at room temperature. 3-[2-(Allyloxy)ethyl]-1-methylimidazolium bis(pentafluoroethyl)phosphinate, [CH2═CHCH2OCH2CH2MIM][(C2F5)2—P(O)O], (4.521 g; 9.7 mmol) is isolated as highly viscous, pale-yellow liquid in quantitative yield and a purity of 94%.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(N(CC)CC)C>CO>[CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1
Reactant: CNc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CNC1CCC(O)CC1
Reaction time: 16 h

Procedure:
17 Grams of p-methylaminophenol, 20 ml of triethylamine and 9 g of 5% rhodium alumina are added to 200 ml of methanol and the mixture is shaken at the temperature of 60° to 70° C. and under hydrogen pressure of 3 to 4 atm. for 16 hours to effect hydrogenation. After the reaction, the catalyst is filtered off and the mother liquor is concentrated and evaporated to dryness, and the residue is added with 500 ml of chloroform and 200 ml of 5% aqueous NaOH solution. After separating the liquid, the chloroform layer is washed with water and concentrated, and the residue is further distilled under reduced pressure. This treatment gives 11 g of 4-methylaminocyclohexanol with boiling point of 123°-129° C. (at 22 mmHg).
Reaction SMILES: [C:1]([C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])#[N:2].C1(N=[CH:17][C:18]2[O:19][CH:20]=[CH:21][C:22]=2[CH3:23])C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH2:6]([O:5][C:3]([C:1]1[CH:23]=[C:22]2[CH:21]=[CH:20][O:19][C:18]2=[CH:17][N:2]=1)=[O:4])[CH2:7][CH2:8][CH3:9]
Reactant: Cc1ccoc1C=Nc1ccccc1
Reactant: CCCCOC(=O)C#N
Solvent: Cc1ccccc1C
Product: CCCCOC(=O)c1cc2ccoc2cn1
Temperature: 130 °C
Yield: 45.8 %

Procedure:
n-Butyl cyanoformate(13.7 g, 0.108 mol) and 3-methylfuran-2-carbaldehyde-N-phenylimine(5.0 g, 27.0 mmol) were mixed at room temperature in xylene (25 mL) then heated to reflux at 120 to 140° C. with stirring. A xylene (15 mL) solution of 7.40 g (54.2 mol) of n-butyl chlorofornate was added dropwise for an hour to the resulting mixture. After all the solution had been added, the reaction mixture was heated to reflux for 2 hours, it was allowed to cool to room temperature, and the solvent was distilled off to give 7.10 g of crude product. This product was purified by column chromatography on silica gel, giving 2.71 g (45.8% yield) of 5-n-butoxycarbonylfuro[2,3-c]pyridine.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:11]=1[C:12]#[C:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[SH:30].C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30][CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:11]=1[C:12]#[C:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1
Reactant: Sc1ccccn1
Reactant: FC(F)(F)c1cccc(C#Cc2c(CCl)nc3ccccn23)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: FC(F)(F)c1cccc(C#Cc2c(CSc3ccccn3)nc3ccccn23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
150 mg (0.421 mmol) of 2-(chloromethyl)-3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2-a]pyridine were dissolved in 5 ml of acetonitrile followed by the addition of 96 mg (0.842 mmol) of pyridine-2-thiol and 274 mg (0.842 mmol) of cesium carbonate. The solvent was stirred at r.t. for 2 h 30 min. The mixture was then poured into 40 ml of water, and then extracted 3 times with 15 ml of ethyl acetate. The collected organic phases were washed with 30 ml of a saturated sodium hydrogencarbonate solution, with 30 ml of brine and then were dried on Na2SO4 which was then removed by filtration and the obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: heptane/ethyl acetate gradient, 80% to 70% of heptane, v/v). 129 mg (yield=74%) of 2-((pyridin-2-ylthio)methyl)-3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo-[1,2-a]pyridine were obtained as a beige solid. LC-MS: m/z=410 (MH+) UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.70 (d, J=6.7 Hz, 1H), 8.52-8.37 (m, 1H), 8.02 (s, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.71 (dd, J=41.7, 4.5 Hz, 4H), 7.43 (s, 2H), 7.13 (d, J=1.1 Hz, 2H), 4.73 (s, 2H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][N:18]=[C:17]2[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Br:31])[CH:26]=1.[C:32](O)(=[O:35])[C:33]#[CH:34]>CN(C=O)C>[Br:31][C:27]1[CH:26]=[C:25]([NH:24][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:32](=[O:35])[C:33]#[CH:34])[CH:15]=3)[N:20]=[CH:19][N:18]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: C#CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: C#CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (200 mg, 1.04 mmol) was added to a solution of 6-amino-4-[(3-bromophenyl)-amino]quinazoline (158 mg, 0.5 mmol) and propiolic acid (0.08 mL, 1.1 mmol) in DMF (1.5 mL) stirred under N2 at 0° C. The resulting solution was stirred at 0° C. for 30 minutes and quenched with water. The formed fine solid was collected by Buchner filtration then dissolved in methanol and purified by preparative tlc on silica, eluting with 10% MeOH/CHCl3. The title compound was isolated as a yellow solid (21 mg, 12%), mp >310° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:31].CCOCC>O1CCOCC1>[ClH:31].[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2nc3ccccc3s2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: c1ccc2sc(Cc3ccc(OC[C@H]4CCCN4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a 20 mL vial which contained a solution of the product from step 2 (170 mg, 0.4 mmol) in dioxane (1 mL) was added HCl (4 N in dioxane, 2 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 16 h. The solvent was reduced to 1 mL and ether (15 mL) was added to this vial. The resulting solid was filtered out and dried in vacuo to yield the title product, (120 mg, 80%); LCMS; 98% ESI+, Calcd: 324.5; Found m/z: 326.1 (M+2); 1H NMR (400 MHz, DMSO-d6); δ 1.66-1.79 (m, 1H), 1.84-2.05 (m, 2H), 2.05-2.16 (m, 1H), 3.15-3.27 (m, 2H), 3.82-3.97 (m, 1H), 4.13-4.16 (m, 1H), 4.24 (dd, J1=10.4 Hz, J2=3.2 Hz, 1H), 4.62 (s, 2H), 6.98 (d, J=8.4, 2H), 7.35 (d, J=8.4, 2H), 7.39 (d, J=7.6, 1H), 7.48 (t, J=7.2, 1H), 7.94 (d, J=8.4, 1H), 8.01 (d, J=8.0, 1H),
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([CH3:22])=[N:11][N:12]([CH:19]3[CH2:21][CH2:20]3)[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.C(N(CC)CC)C.O(S(C)(=O)=O)S(C)(=O)=O.[CH3:40][O:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH2:47])=[CH:44][CH:43]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:47][CH2:46][C:45]2[CH:48]=[CH:49][C:42]([O:41][CH3:40])=[CH:43][CH:44]=2)[C:9]2[C:10]([CH3:22])=[N:11][N:12]([CH:19]3[CH2:21][CH2:20]3)[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(C(O)c2ccc(Cl)cc2)c(C)nn1C1CC1
Reactant: COc1ccc(CN)cc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C(NCc2ccc(OC)cc2)c2ccc(Cl)cc2)c(C)nn1C1CC1
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a stirred solution of ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-cyclopropyl-3-methyl-1H-pyrazole-5-carboxylate (Step 23.5) (2.12 g, 6.33 mmol) and triethylamine (4.41 mL, 31.7 mmol) in CH2Cl2 (4 mL) under Ar was added Ms2O (2.206 g, 12.66 mmol) at −10° C. The reaction mixture was stirred for 30 min at this temperature. 4-Methoxybenzylamine (0.827 ml, 6.33 mmol) was added at 30° C. After 15 h at rt, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3 (100 mL), and extracted with CH2Cl2 (2×100 mL). The combined organic layers were washed with a saturated aqueous solution of NaHCO3 (100 mL), dried (Na2SO4) and evaporated. The crude material was purified by silica gel column chromatography (Hex/EtOAc 5-20%) to afford the title product (2.22 g, 4.89 mmol, 77% yield) as a colorless oil. tR: 1.12 min (LC-MS 2); ESI-MS: 454 [M+H]+ (LC-MS 2); Rf=0.85 (hexane/EtOAc 1:1).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=O)[CH2:11][CH2:10]1.Cl>C(O)C>[CH:12](=[C:11]1[C:1](=[O:8])[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:9][CH2:10]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCOc2ccccc21
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)COc2ccccc21

Procedure:
(66) To a solution of benzaldehyde (430 mg, 4.05 mmol) and 4-chromanone (500 mg, 3.37 mmol) in 8.4 ml of ethanol heated almost to boiling was added 1.7 ml of concentrated hydrochloric acid dropwise. After refluxing for 2 days, the solution was cooled overnight, and a precipitate formed. The precipitate was recrystallized from ethanol to afford 367 mg (46.1%) of white flakes: mp 111.8-113.4° C. (lit. mp 112° C., Powell, J. Am. Chem. Soc., 1923, 45, 2708-2711). 1H NMR (250 MHz) δ 8.06-8.02 (dd, 1H), 7.90 (s, 1H), 7.54-7.31 (m, 6H), 7.09 (t, 1H), 7.00-6.96 (d, 1H), 5.37 (s, 2H), 13C NMR (62.7 MHz) 182.4, 161.3, 137.7, 136.1, 134.6, 131.1, 130.2, 129.7, 128.9, 128.1, 122.1, 118.1, 67.8 ppm.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH3:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23][NH2:24].[BH4-].[Na+]>CO>[CH3:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23][NH:24][CH2:18][C:16]1[CH:15]=[CH:14][C:3]([O:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=2)=[C:2]([F:1])[CH:17]=1
Reactant: CC(C)(C)CCN
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)CCNCc1ccc(Oc2ccc(C(N)=O)nc2)c(F)c1
Reaction time: 8 h
Yield: 62.9 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.650 g, 2.50 mmol), 3,3-dimethylbutylamine (0.278 g, 2.75 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (12 mL), cap and stir overnight. Add NaBH4 (slight excess) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 10% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound (0.543 g, 63%): TOF MS ES+ 346.2 (M+H)+, HRMS calcd for C19H25N3O2F 346.1931 (M+H)+, found 346.1921, time 0.48 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=11.3 min, 100% purity.
Reaction SMILES: C[O:2][B:3]([C:6]1[C:11](=[O:12])[C:10]([O:13]CC2C=CC=CC=2)=[CH:9][N:8]([C:21]2[CH:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[CH:25][CH:26]=2)[CH:7]=1)[O:4]C>C1COCC1.CO.CO.[Pd]>[C:23]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:25][CH:26]=[C:21]([N:8]2[CH:9]=[C:10]([OH:13])[C:11](=[O:12])[C:6]([B:3]([OH:2])[OH:4])=[CH:7]2)[CH:22]=1
Reactant: COB(OC)c1cn(-c2cccc(-c3ccccc3)c2)cc(OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=c1c(O)cn(-c2cccc(-c3ccccc3)c2)cc1B(O)O

Procedure:
The solution of crude dimethyl[5-(benzyloxy)-1-(biphenyl-3-yl)-4-oxo-1,4-dihydropyridin-3-yl]boronate (2.4 mmol) in THF/MeOH from the preceeding step and 10% Pd/C (52 mg, 0.49 mmol) was stirred under H2 (1 atm) for 18 h. The reaction mixture was diluted with MeOH (20 mL), filtered through a pad of Celite (MeOH wash), and concentrated under reduced pressure, The residue was diluted with DMF (10 mL) and 0.5 M aq, HCl (0.4 mL) and purified by reversed phase HPLC (2 cm×5 cm C18, acetonitrile-water gradient, 0.05% TFA added, fractions were lyopholized) to provide [1-(biphenyl-3-yl)-5-hydroxy-4-oxo-1,4-dihydropyridin-3-yl]boronic acid. ′H NMR (599 MHz, DMSO, 75° C.): S 8.19 (d, J=2.3 Hz, 1H); 7.89 (d, J=2.3 Hz, 1H); 7.83 (s, 1H); 7.79-7.74 (m, 3H); 7.67-7.61 (m, 1H); 7.56 (d, J=8.1 Hz, 1H); 7.49 (t, J Hz, 2H); 7.46-7.38 (m, 1H). HRMS (ES) calc (M+H)+ −308.1089. found 308.1092.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([O:15][C:16](=[O:18])[CH3:17])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:19]([OH:22])(=O)=[O:20])[CH:11]=2)[CH:6]=1)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:24].O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[C:14]([O:15][C:16](=[O:18])[CH3:17])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:19]([Cl:24])(=[O:22])=[O:20])[CH:11]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2ccc(S(=O)(=O)O)cc2cc1OC(C)=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(=O)Oc1cc2ccc(S(=O)(=O)Cl)cc2cc1OC(C)=O
Temperature: 80 °C
Yield: 15.6 %

Procedure:
To a suspension of the crude 2,3-diacetoxy-6-naphthalenesulphonic acid (973 mg) in CCl4 (3 ml) was added phosphorus pentachloride (750 mg). The mixture was heated at 80° C. for 20 minutes, cooled, and water added cautiously. The CCl4 was separated from the aqueous layer and the latter was extracted with CH2Cl2. The organic extracts were combined, washed with water and dried over magnesium sulphate. Evaporation of the solvent yielded 2,3-diacetoxy-6-naphthalenesulphonyl chloride (160 mg, yield: 15%). NMR in CDCl3 : 2.37(s,6H); 7.82(s,1H); 7.87(s,1H); 7.99(s,1H); 8.01(s,1H); 8.54(br.s,1H).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl.N1C=CC=CC=1>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C[C@@H]1CN(c2ccc(OCc3ccccc3)c(N)c2)C[C@H](C)N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(OCc3ccccc3)c(NS(=O)(=O)c3ccc(Br)cc3)c2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-[(phenylmethyl)oxy]aniline (D39) (500 mg, 1.61 mmol) in dichloromethane (8 ml) and pyridine (8 ml) was added 4-bromobenzenesulfonyl chloride (820 mg, 3.21 mmol) and the resulting mixture stirred at room temperature, under an atmosphere of argon for 2 hours. The mixture was then reduced in vacuo, azeotroped with methanol and the residue partitioned between dichloromethane (75 ml) and saturated aqueous sodium hydrogen carbonate (75 ml). The layers were separated, the aqueous re-extracted with dichloromethane (50 ml) and the combined organic layers washed with brine (125 ml), dried over anhydrous magnesium sulphate, filtered and reduced in vacuo. The residue was purified by chromatography on silica gel (gradient: dichloromethane:methanol 25:1 to 10:1) to afford the title compound (D40). MS (ES+) m/e 530/532 [M+H]+.