Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][CH2:38][O:39][CH2:40][C@H:41]([O:53][C:54]1[N:59]=[CH:58][N:57]=[C:56]2[N:60]([C:63]3[CH:68]=[CH:67][CH:66]=[C:65]([F:69])[C:64]=3[CH3:70])[N:61]=[CH:62][C:55]=12)[C:42]([NH:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]#[N:52])=[CH:47][N:46]=1)=[O:43])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[C:51]([C:48]1[CH:49]=[CH:50][C:45]([NH:44][C:42](=[O:43])[C@@H:41]([O:53][C:54]2[C:55]3[CH:62]=[N:61][N:60]([C:63]4[CH:68]=[CH:67][CH:66]=[C:65]([F:69])[C:64]=4[CH3:70])[C:56]=3[N:57]=[CH:58][N:59]=2)[CH2:40][O:39][CH2:38][CH2:37][OH:36])=[N:46][CH:47]=1)#[N:52]
Reactant: Cc1c(F)cccc1-n1ncc2c(O[C@@H](COCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C(=O)Nc3ccc(C#N)cn3)ncnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(F)cccc1-n1ncc2c(O[C@@H](COCCO)C(=O)Nc3ccc(C#N)cn3)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.7 %

Procedure:
A solution of tetrabutylammonium fluoride (1M in THF, 1.504 mL, 1.50 mmol) was added dropwise to a stirred solution of (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-cyanopyridin-2-yl)-2-(1-(3-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (Intermediate AF1) (520 mg, 0.73 mmol) in THF (15 mL) over a period of 1 minute and the resulting solution stirred at ambient temperature for 3 hours. Saturated ammonium chloride (20 mL) was added to the reaction mixture which was then diluted with EtOAc (25 mL), and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 60 to 100% EtOAc in isohexane and then by chiral HPLC to afford the product (250 mg, 72%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH3:15])[CH:11]=[CH:10][C:9]=2[F:16])=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[C:12]([CH3:15])[CH:11]=[CH:10][C:9]=2[F:16])=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2c(C)ccc(F)c2[nH]1
Product: CCOC(=O)c1cc2c(C)ccc(F)c2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound was prepared in accordance with the general method of example 12b) from 7-fluoro-4-methyl-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)=[NH:4].[C:26](Cl)(=O)C(Cl)=O>CO>[CH3:26][O:14][C:13](=[O:15])[CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=1)[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([C:3](=[NH:4])[NH:2][OH:1])=[CH:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: N=C(NO)c1ccc(CC(C(=O)O)c2cccc(C(F)(F)F)c2)cc1
Solvent: CO
Product: COC(=O)C(Cc1ccc(C(=N)NO)cc1)c1cccc(C(F)(F)F)c1
Yield: 102.8 %

Procedure:
A solution of 3-[4-(N-hydroxycarbamimidoyl)-phenyl]-2-(3-trifluoromethyl-phenyl)-propionic acid (300 mg, 0.85 mmol, example 258/259 b1)) and oxalyl dichloride (119 mg, 0.95 mmol) in methanol (10 ml) was stirred for 1.5 days. The solvent was evaporated, and the residue solved in water and lyophilized to give 320 mg of the desired product (quantitative). MS m/z: 367.2 (M+H)+.
Reaction SMILES: C([NH:8][C:9]1([CH:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][NH2:15])[CH2:12][CH2:11][CH2:10]1)C1C=CC=CC=1>CCO.[Pd]>[NH2:8][C:9]1([CH:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][NH2:15])[CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)C(CN)C1(NCc2ccccc2)CCC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)C(CN)C1(N)CCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.4 %

Procedure:
To a solution of 2-[1-(benzylamino)cyclobutyl]-N-(tert-butoxycarbonyl)ethylamine (117 mg, 0.384 mmol) in EtOH (5 mL) was added 10% Pd—C (35 mg) and the mixture was stirred under H2 gas 5 kgf/cm2 at room temperature for 5 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The distillation of the residue gave the title compound as a colorless solid (76.0 mg, 92%). 1H-NMR (400 MHz, DMSO-d6) δ 1.37 (9H, s), 1.49-1.58 (2H, m), 1.62-1.77 (4H, m), 1.82-1.91 (2H, m), 2.92-3.01 (2H, m), 6.78 (1H, t, J=5.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([NH:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[N:22]=[CH:21][N:20]=1>CN(C=O)C>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]1[N:22]=[CH:21][N:20]=[C:19]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][S:9]([NH:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH:24]=1
Reactant: COc1ccccc1-c1cc(Cl)ncn1
Reactant: COCCCNS(=O)(=O)Cc1cccc(N)c1
Solvent: CN(C)C=O
Product: COCCCNS(=O)(=O)Cc1cccc(Nc2cc(-c3ccccc3OC)ncn2)c1
Temperature: 80 °C

Procedure:
A mixture of C-(3-amino-phenyl)-N-(3-methoxy-propyl)-methanesulfonamide (0.129 g, 0.50 mmol) and 4-chloro-6-(2-methoxyphenyl)-pyrimidine (0.110 g, 0.10 mmol) in DMFA (3 mL) was stirred at 80° C. till the reaction completion (TLC control), then evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel yielding C-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-(3-methoxy-propyl)-methanesulfonamide
Reaction SMILES: C1(C[O:8][NH:9][C:10]([C:12]2[CH:13]=[C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:17]=2)=[O:11])C=CC=CC=1>C(O)C.[Pd]>[OH:8][NH:9][C:10]([C:12]1[CH:13]=[C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:17]=1)=[O:11]
Reactant: CCOC(=O)c1cc(C(=O)NOCc2ccccc2)cc(C(=O)OCC)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc(C(=O)NO)cc(C(=O)OCC)c1
Reaction time: 20 h
Yield: 67.6 %

Procedure:
To a solution of diethyl 5-[[(phenylmethoxy)amino]carbonyl]-1,3-benzenedicarboxylate (0.742 g, 2.0 mmol) in ethanol (10 mL) was added a suspension of Pd/C in ethanol (5 mL), and the mixture was shaken under hydrogen (50 psi) for 20 hours. The catalyst was removed by filtration through a pad of celite and the filtrate was concentrated to give white powder. This material was washed with ethanol (10 mL×2) and dried under vacuum to give 0.380 g of white powder: 1H NMR (CD3OD) δ 1.44 (t, 6H), 4.45 (q, 4H), 8.60 (s, 2H), 8.72 (s, 1H). TLC: Rf 0.20 (EtOAc/Hexanes 1/1).
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]2)=[C:4]([C:7]([F:13])=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5]O.C(N(S(F)(F)[F:31])CC)C.C(N(CC)CC)C>ClCCl>[F:13][C:7]1[C:4]([CH2:5][F:31])=[C:3]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:19]2)[C:2]([F:1])=[CH:9][C:8]=1[N+:10]([O-:12])=[O:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2CO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2CF)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
3,6-Difluoro-2-(4-ethoxycarbonyl-1-piperazinyl)-5-nitrobenzyl alcohol (1.5 g) is dissolved in dichloromethane (18 ml), and thereto is added dropwise a solution of diethylaminosulfur trifluoride (DAST) (0.7 ml) and triethylamine (0.78 ml) in dichloromethane (3 ml) over a period of 5 minutes while stirring at 0° C. in ice bath. The mixture is stirred at 0° C. for 1.2 hour, and thereto is further added DAST (0.3 ml). After 5 minutes, the reaction mixture is poured into ice water, and the organic layer is separated. The solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography (solvent, ethyl acetate:n-hexane=1:10→1:5 v/v) to give 2,5-difluoro-3-fluoromethyl-4-(4-ethoxycarbonyl-1-piperazinyl)nitrobenzene (1.1 g).
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:19]1([NH:22][C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:25][C:23]([NH:22][CH:19]3[CH2:21][CH2:20]3)=[O:24])=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: Fc1cccc(Cl)c1-c1nc2ccnc(Br)c2s1
Reactant: NC(=O)NC1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1nccc2nc(-c3c(F)cccc3Cl)sc12)NC1CC1
Temperature: 25 °C
Yield: 21.3 %

Procedure:
To a microwave tube was added 4-bromo-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridine (0.050 g, 1.5 mmol), 1-cyclopropylurea (0.043 g, 0.22 mmol), Pd2(dba)3 (0.013 g, 0.017 mmol), XantPhos (0.017 g, 0.034 mmol) and Cs2CO3 (0.11 g, 0.34 mmol) in dioxane (2.0 mL). The mixture was degassed with N2 for 10 minutes and then irradiated in a microwave reactor at 160° C. for 2 hours. After cooling to room temperature, solid was removed via filtration and the filtrate was concentrated under reduced pressure. The residue was purified with reverse phase column chromatography eluting with a 0-60% gradient of CH3CN in 0.5% NH4HCO3 to give the desired product as a yellow solid (0.017 g, 26% yield). 1H NMR (500 MHz, DMSO-d6): δ 9.64 (s, 1H), 8.32 (d, J=7.5 Hz, 1H), 7.99 (br, 1H), 7.75-7.49 (m, 4H), 2.63 (m, 1H), 0.72-0.66 (m, 2H), 0.52-0.46 (m, 2H). LCMS (Method A): RT=5.63 min, m/z: 363.0 [M+H+].
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3].Br[CH2:13][C:14]([C:16]1C=CC=C[CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl>CC(=O)CC.C(OCC)(=O)C>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([O:11][CH2:13][C:14]([CH2:16][CH3:17])=[O:15])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: O=C(CBr)c1ccccc1
Reactant: C=CCOc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: C=CCOc1cccc(OCC(=O)CC)c1

Procedure:
A solution of 3-allyloxyphenol (1.19 g), 2-bromoacetophenone (1.0 g) and potassium carbonate (1.10 g) in 2-butanone (15 ml) was refluxed for four hours. The mixture was partioned between 0.2N HCl and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, concentrated in vacuo. Column Chromatography (silica gel 60, 50% methylene chloride in hexane) gave the title compound.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20][C@H:21]([NH:23]C(=O)OC(C)(C)C)[CH3:22])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>Cl>[C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20][C@H:21]([NH2:23])[CH3:22])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C[C@H](Cc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1)NC(=O)OC(C)(C)C
Agent: Cl
Product: C[C@@H](N)Cc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
Obtained from Intermediate 65 (5.8 g, 14 mmol) and hydrogen chloride (4M in dioxane, 20 mL) by the same procedure described in Intermediate 8. The crude obtained was purified by column chromatography with silica gel, eluting with methylen chloride/methanol/ammonium (40:4:0.2) and the title compound was obtained (2.5 g, 58%). MS (M+): 314.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]([CH2:12][NH:13][C:14]2[CH:31]=[CH:30][C:17]([C:18](=[O:29])[NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:16][CH:15]=2)[CH2:10][NH:9][C:8]2[N:7]=[C:6]([NH2:32])[NH:5][C:4](=[O:33])[C:3]1=2.[OH:34][CH:35]1[O:43][C@H:42]([CH2:44][OH:45])[C@H:40]([OH:41])[C@H:38]([OH:39])[C@H:36]1[NH2:37]>>[OH:34][CH:35]1[O:43][C@H:42]([CH2:44][OH:45])[C@H:40]([OH:41])[C@H:38]([OH:39])[C@H:36]1[NH2:37].[CH3:1][N:2]1[C@H:11]([CH2:12][NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18](=[O:29])[NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][C:23]([O-:25])=[O:24])=[CH:30][CH:31]=2)[CH2:10][NH:9][C:8]2[N:7]=[C:6]([NH2:32])[NH:5][C:4](=[O:33])[C:3]1=2
Reactant: CN1c2c(nc(N)[nH]c2=O)NC[C@H]1CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Agent: N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O
Product: CN1c2c(nc(N)[nH]c2=O)NC[C@H]1CNc1ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)O)cc1
Yield: 136.8 %

Procedure:
4.60 g (10 mmol) of 5-methyl-(6R,S)-tetrahydrofolic acid were added portion-wise and completely dissolved in 30 ml of an aqueous solution of D-galactosamine (3.58 g, 20 mmol) stirred under nitrogen. The resulting solution (pH 6.53) was freeze-dried, obtaining 8.72 g of the title product.
Reaction SMILES: [CH3:1][N:2]1[C@H:8]([CH2:9][OH:10])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[CH3:18][S:19]([O:10][CH2:9][C@@H:8]1[CH2:7][CH2:6][C:3]2([CH2:5][CH2:4]2)[N:2]1[CH3:1])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CN1[C@H](CO)CCC12CC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1[C@H](COS(C)(=O)=O)CCC12CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A mixture of (5S)-4-methyl-5-(hydroxymethyl)-4-azaspiro[2.4]heptane (0.2 g, 1.42 mmol) and triethylamine (0.287 g, 2.84 mmol, Shantou Xilong chemical factory) in 5 mL of dichloromethane was stirred at 0° C. for 30 min. To the mixture was added methanesulfonyl chloride (0.325 g, 2.84 mmol, Shanghai Haiqu chemical. Ltd.) via a syringe. The reaction mixture was stirred at 0° C. for 4 hrs and quenched with a mixture of 5 mL of saturated Na2CO3 aqueous solution and 5 mL of water. The resulted mixture was extracted with dichloromethane (20 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give ((5S)-4-methyl-4-azaspiro[2.4]heptane-5-yl)methyl methanesulfonate as yellow oil (150 mg, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[C:12]1[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=1.[Sn].Cl>C(O)C>[NH2:9][C:5]1[C:6]([OH:8])=[CH:7][C:2]([Cl:1])=[C:3]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=2)[CH:4]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc([N+](=O)[O-])c(O)cc2Cl)c1=O
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: Cn1c(C(F)(F)F)ccc(-c2cc(N)c(O)cc2Cl)c1=O
Temperature: 25 °C
Yield: 88.7 %

Procedure:
8.0 g (23 mmol) of 3-(2-chloro-4-hydroxy-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone and 8.2 g (69 mmol) of tin were added to 100 ml of ethanol, and 5 ml of concentrated hydrochloric acid was added thereto under stirring at room temperature, followed by stirring for 1 hour. After completion of the reaction, excess ethanol was distilled off, and the residue was neutralized with a saturated sodium hydrogencarbonate aqueous solution and then extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure to obtain 6.5 g (yield: 90%) of the desired product. 1H-NMR (300 MHz, CDCl3) δ value: 3.74(3H,s), 6.83(1H,d), 7.23(1H,d), 7.30(1H,d), 7.57(1H,d)ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.BrBr>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:15])=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: CC1CC(=O)NN=C1c1ccc(Br)cc1
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1cc(=O)[nH]nc1-c1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
A 2.67 g. portion of 6-(p-bromophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (prepared as described in Example 38 of U.S. Pat. No. 3,824,271) is suspended in 20 ml. of acetic acid. A 1.91 g. (0.62 ml.) portion of bromine in 5 ml. of acetic acid is added dropwise, while the reaction mixture is heated on a steam bath. Heating is continued for an additional 30 minutes. The reaction mixture is poured into crushed ice. The resulting solid is recovered by filtration, washed with water and dried, yielding 6-(p-bromophenyl)-5-methyl-3(2H)-pyridazinone.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:19]=[C:18]([CH3:20])[NH:17][N:16]=3)=[N:8][C:4]=2[CH:3]=1.CI.[C:29]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]([C:21]([CH3:23])([CH3:22])[CH3:24])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:19]=[C:18]([CH3:20])[N:17]([CH3:29])[N:16]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1nc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)n[nH]1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)nn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a vial is added 5-bromo-1-tert-butyl-2-[2-(5-methyl-1H-[1,2,4]triazol-3-yl)-phenyl]-1H-benzimidazole (73 mg, 0.178 mmol) in DMF (1.5 mL), followed by the addition of MeI (40 mg, 0.282 mmol) and K2CO3 (49 mg, 0.355 mmol). The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with EtOAc (20 mL), washed with water, brine, dried under anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel flash column chromatography with 0-3% 7M NH3 in MeOH/CH2Cl2 as the eluent to afford 5-bromo-1-tert-butyl-2-[2-(1,5-dimethyl-1H-[1,2,4]triazol-3-yl)-phenyl]-1H-benzimidazole (44 mg, 58%) as an off-white solid. LCMS (ESMS): m/z 424.58, 426.51 (M++1).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][CH3:14])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.Br>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:13][CH3:14])[C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1
Reactant: CCC(C(=O)O)c1ccc(OC)cc1
Agent: Br
Product: CCC(C(=O)O)c1ccc(O)cc1

Procedure:
The m- or p-hydroxyphenyl alkanol can also be prepared using conventional techniques. For example, a m- or p-methoxyphenylbutyric acid can be reacted at reflux temperature with hydrogen bromide to form a m or p-hydroxyphenylbutyric acid. This acid can then be reacted with borane in tetrahydrofuran to form m- or p-hydroxyphenylbutanol. This latter compound is reported in JACS, 84, 788 (1962).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.[OH:22][CH:23]1[CH2:26][N:25]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][N:28]=2)[CH2:24]1>>[OH:22][CH:23]1[CH2:26][N:25]([C:27]2[N:28]=[CH:29][C:30]([NH:33][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)=[O:21])=[CH:31][CH:32]=2)[CH2:24]1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: Nc1ccc(N2CC(O)C2)nc1
Product: O=C(Nc1ccc(N2CC(O)C2)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1

Procedure:
The process is carried out according to the method described in example 2, using 0.5 g (1.74 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (example 1.1) and 0.35 g (2.09 mmol) of 2-(3-hydroxyazetidin-1-yl)-5-aminopyridine, obtained in step 10.2 (Compound Ve).
Reaction SMILES: [OH:1][CH:2]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.C1(C)C=CC=CC=1.S(=O)(=O)(O)O>[Zn].O>[C:2]1(=[O:1])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1CCCCCCCCC=CCCCCCCCCC1O
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCCCCCCCC=CCCCCCCCCC1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 90.4 %

Procedure:
In a 50 ml four neck reactor equipped with a thermometer, a dripping funnel and a refrigerant, zinc powder (2.3 g), 2-hydroxy-11-cycloeicosenone (1.4 g) and toluene (10 ml) were mixed, stirred and heated at 90° C. under nitrogen flow. A 20N sulphuric acid aqueous-solution (2.8 ml) was added thereto dropwise over 2.5 hours and the resulting mixture was stirred under heating for 30 minutes. Toluene and water were added after the reaction and the resulting solution was allowed to stand to separate into two phases. The organic phase was washed twice with water and then washed with a saturated sodium chloride aqueous solution. The solvent was removed under reduced pressure to give 1.4 g of crude product. The crude product was purified on a silica gel column chromatograph (hexane/ethyl acetate=10/1, v/v) to give 1.2 g of 10-cycloeicosenone (yield 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[N+:12]([O-])=O>CC#N>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[CH:4][C:3]=1[NH2:12]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)cc1Cl
Solvent: CC#N
Product: Nc1cc(N)c(Cl)cc1Cl

Procedure:
4,6-Dichloro-benzene-1,3-diamine (D-2) was synthesized following the general scheme above starting from 1,5-dichloro-2,4-dinitro-benzene. Yield (95%). HPLC ret. time 1.88 min, 10-99% CH3CN, 5 min run; ESI-MS 177.1 m/z (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:19])[N:4]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:5]([CH:8]([CH3:10])[CH3:9])=[CH:6][CH:7]=1.CN1CCOCC1.[C:27]1([CH3:37])[CH:32]=[CH:31][CH:30]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:28]=1>C(Cl)Cl>[CH3:37][C:27]1[CH:28]=[C:29]([S:33]([NH:1][C:2]2[C:3](=[O:19])[N:4]([CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[C:5]([CH:8]([CH3:9])[CH3:10])=[CH:6][CH:7]=2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)c1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cccc(S(=O)(=O)Nc2ccc(C(C)C)n(CC(=O)OC(C)(C)C)c2=O)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
3-Amino-6-isopropyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (assumed to be 3.37 mmol), as prepared in the preceding step, and N-methylmorpholine (1.0 mL, 9.1 mmol) were dissolved in methylene chloride (20 mL) and cooled to 0° C. A solution of m-toluenesulfonyl chloride (0.67 g, 3.5 mmol) in methylene chloride (5 mL) was added and the reaction stirred at ambient temperature for 16 hours. After evaporation in vacuo, the crude product was dissolved in methylene chloride, washed with 10% aqueous citric acid, saturated NaHCO3, and brine, dried over MgSO4, and filtered. The evaporated filtrate gave the title compound (1.24 g, 88%) as a tan solid. 1H NMR (300 MHz, CDCl3) δ7.65 (m, 2H), 7.58 (br s, 1H), 7.46 (d, 1H, J=7.8 Hz), 7.3 (m, 2H), 6.08 (d, 1H, J=7.9 Hz), 4.69 (s, 2H), 2.67 (m, 1H), 2.38 (s, 3H), 1.41 (s, 9H), 1.22 (s, 3H), 1.19 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[N:7]([CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[N:4][C:3]=1[CH3:22].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=1>>[C:31]([C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][O:1][C:2]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[N:7]([CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[N:4][C:3]=1[CH3:22])#[N:32]
Reactant: N#Cc1cccc(CBr)c1
Reactant: Cc1ncc2c(c1O)COC(=O)N2Cc1ccc(C#N)cc1
Product: Cc1ncc2c(c1OCc1cccc(C#N)c1)COC(=O)N2Cc1ccc(C#N)cc1
Yield: 28 %

Procedure:
The coupling of 4-(5-hydroxy-6-methyl-2-oxo-4H-pyrido[3,4-d][1,3]oxazin-1-ylmethyl)-benzonitrile (82) (0.8 g, 2.8 mmol) and α-bromo-m-tolunitrile (5.9 g, 30 mmol), as described in Example 1, gave 4-[5-(3-cyano-benzyloxy)-6-methyl-2-oxo-4H-pyrido[3,4-d][1,3]oxazin-1ylmethyl]-benzonitrile (85) (322 mg, 28% yield) as.