Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:11]([O-])=[CH:12][C:13](=O)[C:14]([O:16]CC)=[O:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:44][C:45]1[CH:50]=[C:49]([NH:51][NH2:52])[CH:48]=[CH:47][N:46]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:11]2[N:51]([C:49]3[CH:48]=[CH:47][N:46]=[C:45]([Cl:44])[CH:50]=3)[N:52]=[C:13]([C:14]([OH:16])=[O:15])[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC)c1
Reactant: NNc1ccnc(Cl)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: COc1cc(Br)cc(-c2cc(C(=O)O)nn2-c2ccnc(Cl)c2)c1

Procedure:
500 mg (1.19 mmol) of the compound of Example 6A is reacted analogously to the synthesis of the compound of Example 20A with 322 mg (1.79 mmol) of 2-chloropyridin-4-yl-hydrazine hydrochloride. After hydrolysis, 259 mg (53% of theory) of the title compound is obtained.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[N:26])[CH2:20][CH2:19][N:18]([CH2:21][C:22](O)=[O:23])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N=C=NCCCN(C)C)C.ON1[C:43]2C=CC=[CH:47][C:42]=2[N:41]=N1.[CH3:48][O:49]C(ON)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH3:43][C:42]([NH:41][C:22](=[O:23])[CH2:21][N:18]1[CH2:17][CH2:16][C:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)([C:25]#[N:26])[CH2:20][CH2:19]1)([O:49][CH3:48])[CH3:47]
Reactant: COC(C)(C)ON
Reactant: On1nnc2ccccc21
Reactant: COc1ccc(C2(C#N)CCN(CC(=O)O)CC2)cc1OC1CCCC1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C2(C#N)CCN(CC(=O)NC(C)(C)OC)CC2)cc1OC1CCCC1

Procedure:
The compound (239 mg) prepared in Example 2, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC; 192 mg), 1-hydroxybenzotriazole (HOBt; 135 mg), dimethylformamide (4 ml) and (1-methoxy-1-methylethyl)oxyamine (0.35 ml) was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water (twice), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→ethyl acetate alone) to thereby obtain the title compound (289 mg) having the following physical properties.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12].[NH2:18][C:19]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:18][C:19]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Reactant: O=C(Cl)c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1ccccc1F
Reaction time: 2 h

Procedure:
0.059 mL of triethylamine and 0.037 mL of 2-fluorobenzoyl chloride were added to 3.0 mL of methylene chloride solution containing 60 mg of tert-butyl 2-amino-4-phenoxybenzoate at room temperature sequentially and stirred at the same temperature for 2 hours. 0.48 g of aminomethylated polystyrene was added to the reaction mixture and stirred at room temperature overnight. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(2-fluorobenzamido)-4-phenoxybenzoate.
Reaction SMILES: [CH2:1]([N:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1B1OC(C)(C)C(C)(C)O1)[S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2].Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=2)=[C:26]([F:37])[CH:25]=1>>[NH2:36][C:33]1[N:34]=[CH:35][C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[N:3]([CH2:1][CH3:2])[S:4]([CH3:7])(=[O:5])=[O:6])=[CH:25][C:26]=2[F:37])=[N:31][CH:32]=1
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Reactant: CCN(c1ccccc1B1OC(C)(C)C(C)(C)O1)S(C)(=O)=O
Product: CCN(c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1)S(C)(=O)=O

Procedure:
The title compound was prepared using methods analogous to those described in Step B of Example 369 by using N-ethyl-N-(2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide and 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine. MS (ESI): mass calcd. C19H19FN4O2S.C2HF3O2, 386.12; m/z found, 387.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J=1.2, 1H), 8.33 (d, J=1.2, 1H), 8.14-8.04 (m, 1H), 7.51-7.33 (m, 6H), 3.46 (s, 2H), 2.95 (s, 3H), 1.05 (t, J=7.2, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:6]
Reactant: NCC(CC1CC1)c1cncc(Cl)c1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(CC1CC1)c1cncc(Cl)c1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-(5-chloro-pyridin-3-yl)-propylamine. LCMS (MH+): m/z=383.0, tR (minutes, Method D)=0.74
Reaction SMILES: [O-:1][S:2]([O-:4])=[O:3].[Na+:5].[Na+].Cl[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[O:10]([CH2:9][CH2:8][S:2]([O-:4])(=[O:1])=[O:3])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+:5]
Reactant: O=S([O-])[O-]
Reactant: ClCCOc1ccccc1
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])CCOc1ccccc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
To a solution of Na2SO3 (12.9 g, 102.3 mmol) in 100 mL of water is added β-chlorophenetole (15.3 g, 97.4 mmol), and the mixture is stirred at 120° C. for 24 h. Cooling the mixture affords white precipitates, which are collected by filtration and dried in vacuo. The product is obtained as a white solid in 87% yield. The structure is confirmed by 1H-NMR spectrum (DMSO-d6). δ [ppm]: 2.88 (t, 2H), 4.18 (t, 2H), 6.88–6.93 (m, 3H), 7.24–7.29 (m, 2H).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:31]=[CH:30][C:11]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:20])[CH2:15][CH2:14]2)=[CH:10][CH:9]=1.[O:32]1[CH2:34][C@H:33]1[CH2:35][O:36][C:37]1[C:45]2[NH:44][C:43](=[O:46])[NH:42][C:41]=2[CH:40]=[CH:39][CH:38]=1>C(Cl)(Cl)Cl.CO>[CH2:22]([NH:21][C:19]([N:16]1[CH2:15][CH2:14][CH:13]([NH:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][NH:4][CH2:34][C@H:33]([OH:32])[CH2:35][O:36][C:37]3[C:45]4[NH:44][C:43](=[O:46])[NH:42][C:41]=4[CH:40]=[CH:39][CH:38]=3)=[CH:31][CH:30]=2)[CH2:18][CH2:17]1)=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: O=c1[nH]c2cccc(OC[C@@H]3CO3)c2[nH]1
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(OCCN)cc2)CC1
Solvent: CO
Solvent: O=CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(OCCNC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)cc2)CC1
Yield: 19.4 %

Procedure:
4-[4-(2-Aminoethoxy)anilino]-N-octyl-1-piperidinecarboxamide formate (0.32 g, 0.733 mmol) was reacted with 4-[(2S)oxiranylmethoxy]-1,3-dihydro-2H-benzimidazol-2-one (0.151 g, 0.732 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.085 g, 0.142 mmol).
Reaction SMILES: [NH2:1][C@H:2]([CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1)[CH2:3][N:4]([C@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([NH:12][CH3:13])=[O:11])[C:5](=[O:8])[CH2:6]Cl.C(=O)([O-])O.[Na+].O>CO>[CH3:13][NH:12][C:10](=[O:11])[C@H:9]([N:4]1[CH2:3][C@@H:2]([CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)[NH:1][CH2:6][C:5]1=[O:8])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C[C@H](N)Cc1ccc2ccccc2c1)C(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNC(=O)[C@@H](Cc1ccccc1)N1C[C@@H](Cc2ccc3ccccc3c2)NCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
##STR101## (2R)-2-(N-((2R)-2-Amino-3-(2-naphthyl)propyl)-N-chloroacetyl-amino)-N-methyl-3-phenylpropionamide (0.69 g, 1.58 mmol) was dissolved in methanol (14 ml) and sodium hydrogen carbonate (0.40 g, 4.73 mmol) and water (7 ml) were added. The mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was dissolved in a mixture of ethyl acetate (30 ml) and saturated aqueous sodium hydrogen carbonate (20 ml). The mixture was extracted with ethyl acetate (4×20 ml). The combined organic phases were dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was chromatographed on silica (2×20 cm) using methylene chloride/methanol/25% aqueous ammonia (100:10:1) to afford 0.19 g of (2R)-N-methyl-2-((5R)-5-((2-naphthyl)methyl)-2-oxopiperazin-1-yl)-3-phenylpropionamide
Reaction SMILES: [NH:1]([C:13]([O:15]CC1C=CC=CC=1)=O)[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:23]1[CH:27]=[N:26][N:25]=[N:24]1.[NH:28]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:29](C(O)=O)[CH2:30][NH2:31].CCOC(OC(OCC)=O)=O.CCN(C(C)C)C(C)C>C(O)C.[Pd]>[NH:28]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:29]([C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:15])[CH2:30][NH2:31].[NH:23]1[CH:27]=[N:26][N:25]=[N:24]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: [Pd]
Agent: CCOC(=O)OC(=O)OCC
Agent: c1nnn[nH]1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 2 h
Yield: 26.7 %

Procedure:
Cbz-Phe-Tetrazole (2.25 g, 6.25 mmole) was then dissolved in ethanol (100 ml) and treated with Pd/C 10% (500 mg, 0.3125 mmole) and stirred under hydrogen for 2 hr. The reaction mixture was filtered through a celite pad and concentrated to dryness. This material was reconstituted in dichloromethane (80 ml) and treated with Boc-Dap (1.88 g, 6.54 mmole), DEPC (1.42 ml, 9.38 mmole) and DIEA (3.8 ml, 21.88 mmole). After 16 hr volatiles were removed to afford crude Boc-Dap-Phe-Tetrazole which was purified by preparative HPLC to give 704 mg (20%) of 1001 as a white powder. Reverse-phase HPLC analysis: 99% at 6.3 min; LCMS (ESI): m/z 458.905 (MH)+, 480.874 (M+Na)+, eluted at 12.95 min.
Reaction SMILES: [CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6]2.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH2:34].ClCCl>N1C=CC=CC=1>[C:21]([OH:31])(=[O:34])[CH3:22].[CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH:23][S:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:32])=[O:31])[CH:20]=[CH:21][CH:22]=2)[CH:3]2[CH:7]1[CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4]2
Reactant: O
Reactant: CC1(c2cccc(N)c2)C2CN(CCCc3ccccc3)CC21
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O
Product: CC1(c2cccc(NS(=O)(=O)c3ccccc3)c2)C2CN(CCCc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 16 h
Yield: 2 %

Procedure:
To a solution of 3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine (Preparation 8, 200 mg, 0.65 mmol) in pyridine (2 ml) under nitrogen at 0° C. was added benzenesulfonylchloride (172 mg, 0.98 mmol), then the mixture was stirred at room temperature for 16 hours. Water (5 ml) and dichloromethane (5 ml) were added, and the mixture was stirred for 30 minutes. The organic phase was washed further with water (5 ml) for 30 minutes, separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica (10 g) column chromatography eluting with 20:80:1 ethyl acetate:hexane:ammonia solution (0.880), then 50:50:1 ethyl acetate:hexane:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo. The residue was further purified by preparative HPLC (condition 4). Combination and evaporation of appropriate fractions gave the title compound as a pale brown solid (5 mg, 2%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH:9][CH2:10][CH:11]2[CH2:13][C:12]2([Cl:15])[Cl:14])[N:3]=1.[C:16](O)(=[O:18])C.C(OC=O)=O>C(#N)C>[CH:16]([NH:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH:9][CH2:10][CH:11]2[CH2:13][C:12]2([Cl:14])[Cl:15])[N:3]=1)=[O:18]
Reactant: CC(=O)O
Reactant: Nc1nc(Cl)cc(NCC2CC2(Cl)Cl)n1
Agent: O=COC=O
Solvent: CC#N
Product: O=CNc1nc(Cl)cc(NCC2CC2(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A solution of 2.7 g (0.01 mol) of 2-amino-4-chloro-6-{[(2,2-dichloro-cyclopropyl)methyl]amino}pyrimidine in 300 ml of acetonitrile was added dropwise, while stirring, at room temperature over a period of 15 minutes to a solution of 0.9 gm (0.012 mol) of acetic acid-formic acid anhydride in 5 ml of acetonitrile. After stirring the mixture for about 30 hours at room temperature the solvent was distilled off in vacuo, and the residue was treated twice by dissolving it in about 30 ml of toluene and then distilling the toluene off again. The raw product was purified by column chromatography (150 gm silica gel; eluant: Diisopropyl ether/ethyl acetate 9:1), yielding the title compound as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:27]=[CH:26][C:19]([NH:20]C(OCC)=O)=[CH:18][CH:17]=1)[CH:6]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[CH2:5]2.[OH-:36].[Li+].Cl.[CH2:39]1[CH2:43][O:42]CC1>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:27]=[CH:26][C:19]([NH:20][CH2:39][C:43]([OH:36])=[O:42])=[CH:18][CH:17]=1)[CH:6]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1)[CH2:5]2
Reactant: C1CCOC1
Reactant: [OH-]
Reactant: CCOC(=O)Nc1ccc(CNCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Product: O=C(O)CNc1ccc(CNCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
4-[[2-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethylamino]methyl]-N-ethoxycarbonylaniline (10 mg, 0.02 mmol) obtained in Example 142 and lithium hydroxide.monohydrate (41 mg, 1.0 mmol) were dissolved in 1 mL of THF and 0.5 mL of water, followed by stirring at room temperature overnight. After completion of the reaction, 2N hydrochloric acid was added to the reaction liquid, followed by extraction with chloroform. The organic layer was then washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 3 mg (yield 44.2%) of a title compound as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][CH2:21][OH:22])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[N:10]=[N:11][C:12]([Cl:18])=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=1.CC(C)=[O:25].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:25])=[O:22])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[N:10]=[N:11][C:12]([Cl:18])=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(CCO)cc2Cl)nnc1Cl
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC(C)c1cc(Oc2c(Cl)cc(CC(=O)O)cc2Cl)nnc1Cl
Temperature: -1.5 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of 2-[3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-ethanol (17) (8.4 g, 23.2 mmol) in acetone (270 mL) was treated with Jones Reagent (34.8 mL of a 2.7 M solution, prepared via standard method) slowly dropwise at −4° C. The resulting red reaction mixture was stirred for 1 h at −3 to 0° C. The red reaction mixture was quenched with isopropanol. The resulting green suspension was filtered through celite and the celite was washed well with ethyl acetate (600 mL). The filtrate was washed with water (600 mL) and a saturated aqueous sodium chloride solution (300 mL). The organic layer was separated, dried with magnesium sulfate, filtered, and concentrated. The resulting solid was dried under vacuum overnight to afford [3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-acetic acid (18) (8.3 g, 95%) as a white solid; LRMS for C15H15Cl3N2O3 (M+) m/z=377. Molecular Weight=377.6574; Exact Mass=376.0148
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([O:19][C@@H:20]4[CH2:25][CH2:24][NH:23][C@H:22]([C:26]([O:28][CH3:29])=[O:27])[CH2:21]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(Cl)Cl.O>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([O:19][C@@H:20]4[CH2:25][CH2:24][N:23]([CH3:35])[C@H:22]([C:26]([O:28][CH3:29])=[O:27])[CH2:21]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C
Reaction time: 0.08 h
Yield: 69.8 %

Procedure:
Methyl (2S,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxylate (13) (0.35 g, 0.76 mmol) was dissolved in a solution of 15% Acetic acid/methylene chloride (6.1 ml). To this was then added powdered 4A° molecular sieves (0.63 g) and the resulting suspension stirred for 5 minutes. 37% formaldehyde in water (0.56 ml) was added drop-wise and the mixture stirred a further 2 minutes. Sodium triacetoxyborohydride (0.29 g) was added in one portion. The reaction mixture was stirred a further 2 hours at room temperature, filtered and evaporated. The residues were partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The combined organics were washed with brine, dried over MgSO4, filtered and evaporated. The crudes were purified by column chromatography on SiO2 eluting with increasingly polar mixtures of DCM/methanol (100/0-95/5). The fractions containing the desired product were combined and evaporated to give methyl (2S,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-1-methylpiperidine-2-carboxylate (14) as a foam (252 mg, 70%): 1H NMR Spectrum: (DMSO-d6) δ1.72-1.78 (2H, m), 2.05-2.35 (6H, m), 2.95-3.04 (2H, m), 3.63 (3H, s), 3.94 (3H, s), 4.51-4.59 (1H, m), 7.23 (1H, s), 7.29-7.31 (1H, m), 7.49-7.56 (2H, m), 7.84 (1H, s), 8.39 (1H, s), 9.55 (1H, s); Mass Spectrum: (M+H)+ 475.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)=[CH:4][CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].IC.N#N>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(-c2nn[nH]n2)cc1
Agent: N#N
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: Cn1nnc(-c2ccc(F)cc2)n1
Temperature: 82 °C
Yield: 70.9 %

Procedure:
A mixture of 5-(4-fluorophenyl)-2H-tetrazole (6.61 g, 40.3 mmol), K2CO3 (6.68 g, 48.3 mmol), and iodomethane (3.02 mL, 48.3 mmol) in acetonitrile (115 mL) was heated to reflux (ca. 82° C.) for one hour. After cooling, the mixture was concentrated to dryness and the residue was partitioned between water (75 mL) and EtOAc (100 mL). The layers were separated, the aqueous layer was back-extracted with EtOAc (50 mL) and the combined organic layers were washed with water (50 mL) and brine (50 mL). The organic layer was dried over anh. MgSO4, filtered and concentrated to give 9.5 g as a colorless oil that solidified upon standing. The residue was purified by flash chromatography to give 2 main products: Intermediate 35B as the N2 isomer: 5-(4-fluorophenyl)-2-methyl-2H-tetrazole (5.09 g, 70.9% yield) as a white solid: No NOE observed between the methyl group at 4.42 ppm and the aromatic protons; 1H NMR (400 MHz, DMSO-d6) δ ppm 4.42 (s, 3H) 7.33-7.45 (m, 2H) 8.03-8.14 (m, 2H); MS m/z 179.2 (M+H)+; HPLC >99.5%, RT=1.75 minutes.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([O-])=O>C(O)C.[Pd]>[N:10]1([C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH2:1])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=[N+]([O-])c1cnccc1N1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1cnccc1N1CCCCC1
Reaction time: 15 h
Yield: 93 %

Procedure:
To a solution of 3-nitro-4-(piperidin-1-yl)pyridine (1.0 equiv.) in ethanol, at a concentration of 0.1M, was added 10% palladium on carbon (0.1 eq.). The resultant heterogeneous solution was put under an atmosphere of hydrogen and was stirred for 15 hours. At this time the mixture was filtered through a pad of celite eluting with methanol. The volatiles were removed in vacuo yielding 4-(piperidin-1-yl)pyridin-3-amine (93%) as an oil. LCMS (m/z): 178.0 (MH+); LC Rt=1.68 min. 1H NMR (CDCl3): δ 8.01 (s, 1H), 7.96 (d, J=5.4, 1H), 6.78 (d, J=5.1, 1H), 3.64-3.74 (m, 2H), 2.86-2.94 (m, 4H), 1.66-1.78 (m, 4H), 1.58-1.64 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:20])[C@@H:18]([NH2:19])[C@H:15]3[S:14][C@:13]2([CH2:22][O:23][C:24](=[O:29])[NH:25][C:26](=[O:28])[CH3:27])[CH3:21])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl.C1([NH:48][CH2:49][C:50](Cl)=[O:51])C=CC=CC=1.O>C(Cl)Cl>[N+:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:20])[C@@H:18]([NH:19][C:50](=[O:51])[C@H:49]([NH2:48])[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C@H:15]3[S:14][C@:13]2([CH2:22][O:23][C:24](=[O:29])[NH:25][C:26](=[O:28])[CH3:27])[CH3:21])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)CNc1ccccc1
Reactant: CN(C)c1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
A solution of (2R,3S,5R,6R) 2-(N-acetyl)carbamoyloxymethyl-6-amino-2-methylpenam-3-carboxylic acid p-nitrobenzyl ester (0.80 gm, 1.77 mmol) in methylene chloride (10 ml) was cooled to 2° and dimethylaniline (0.214 gm, 1.77 mmol) was added. To the stirred mixture was added (-)-phenylglycyl chloride hydrochloride (0.392 gm, 1.83 mmol) in two equal portions. The first portion was added at 2° and the reaction mixture was gradually warmed to 20° over a 90 minute period. The reaction did not appear to begin at the lower temperatures. The second portion of the acid chloride was added at 20° and the reaction mixture was stirred at room temperature for 41/2 hours. Water (10 ml) was added and, with thorough mixing, the pH was adjusted to 1.7. The layers were separated, the water layer was washed with methylene chloride, and the methylene chloride layer was washed with pH 2.0 buffer. The aqueous layers were combined, adjusted to pH 7.0 with 10% KOH solution, and extracted with methylene chloride (2×10 ml). The methylene chloride extracts were combined, dried over molecular sieves and concentrated in vacuo to about 15 ml. This solution was added dropwise to 300 ml of stirring heptane and produced a fine white amorphous solid. This was removed by filtration and dried to give 0.61 gms of the title product. The purity was estimated from its nmr spectrum to be about 60%.