Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[CH2:13][C:14]([N:16]1[C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20](=[O:28])[NH:19][C:18]2[C:29]([CH3:34])=[CH:30][C:31]([CH3:33])=[N:32][C:17]1=2)=[O:15])[CH2:4][CH3:5])[CH3:2]>C(#N)C>[CH2:1]([N:3]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[CH2:13][C:14]([N:16]1[C:22]2[C:23]([CH3:24])=[CH:27][CH:25]=[CH:26][C:21]=2[C:20](=[O:28])[NH:19][C:18]2[C:29]([CH3:34])=[CH:30][C:31]([CH3:33])=[N:32][C:17]1=2)=[O:15])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CC1CCCCN1CC(=O)N1c2ccc(C)cc2C(=O)Nc2c(C)cc(C)nc21
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2nc(C)cc(C)c2NC(=O)c2cccc(C)c21

Procedure:
11-[[2-[(Diethylamino)methyl]-1-piperidinyl]acetyl]5,11-dihydro-2,4,8-trimethyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one of m.p. 213° to 215° C. (acetonitrile);
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[S:15][C:14]([NH:16][C:17](=[O:40])[CH:18]([C:26]3[CH:27]=[N:28][C:29]([S:32]([CH:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)(=[O:34])=[O:33])=[CH:30][CH:31]=3)[O:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:13][CH:12]=2)[CH:5]=1.[Li+].[OH-]>O.C1COCC1.CO>[CH:35]1([S:32]([C:29]2[N:28]=[CH:27][C:26]([CH:18]([O:19][CH:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[C:17]([NH:16][C:14]3[S:15][C:11]([O:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:41])=[O:2])=[CH:12][N:13]=3)=[O:40])=[CH:31][CH:30]=2)(=[O:33])=[O:34])[CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: COC(=O)c1cccc(Oc2cnc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CCCC4)nc3)s2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(Oc2cnc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CCCC4)nc3)s2)c1
Yield: 73.3 %

Procedure:
The compound of example B8 was obtained by similar method described in example B1 using 3-[2-[[2-(6-cyclopentylsulfonyl-3-pyridyl)-2-tetrahydropyran-4-yloxy-acetyl]amino]thiazol-5-yl]oxybenzoic acid methyl ester (Example A10; 0.140 g, 0.232 mmol), LiOH (0.049 g, 1.16 mmol) in Water:THF:MeOH (2:1:0.2 8 mL) to provide the title compound (0.100 g).
Reaction SMILES: [C:1]([CH2:4][CH:5]([CH3:19])[CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:18])[NH:13]2)([OH:3])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:35]([NH:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[CH3:36]>CN(C=O)C>[CH:38]1([N:37]([CH2:35][CH3:36])[C:1]([CH2:4][CH:5]([CH3:19])[CH2:6][O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH2:10][CH2:11][C:12](=[O:18])[NH:13]3)=[O:3])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CC(COc1cccc2c1CCC(=O)N2)CC(=O)O
Reactant: CCNC1CCCCC1
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(C(=O)CC(C)COc1cccc2c1CCC(=O)N2)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.3 Grams of 5-(3-carboxy-2-methylpropoxy)-3,4-dihydrocarbostyril and 0.8 ml of triethylamine are added to 50 ml of DMF, and the mixture is added dropwise with 0.65 ml of isobutyl chloroformate under external ice cooling and agitation at internal temperature of 0° to 10° C. After this dropwise addition, the mixture is agitated at room temperature for 30 minutes, added dropwise with 0.7 g of N-ethylcyclohexylamine and further agitated at room temperature for 2 hours. The solvent is distilled off and the residue is dissolved in 200 ml of chloroform, washed with diluted hydrochloric acid, aqueous K2CO3 solution and water in that order and then dried with anhydrous Na2SO4. After filtering off the inorganic matter, the mother liquor is concentrated and the residue is recrystallized from ligroin-benzene to obtain 0.8 g of 5-[3-(N-cyclohexyl-N-ethylaminocarbonyl)-2-methylpropoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals. m.p. 114°-115.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)([C:20]4[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=4)[OH:19])[CH:16]=3)[N:11]3[N:33]=[N:34][N:35]=[C:10]3[NH:9]2)[CH:5]=[CH:6][CH:7]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[CH:16]=[C:15]([C:18]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)([C:20]4[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=4)[OH:19])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]3=[N:35][N:34]=[N:33][N:9]23)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cncc1C(O)(c1ccc(F)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)Nc1nnnn1-2
Solvent: Cc1ccccc1
Product: Cn1cncc1C(O)(c1ccc(F)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)n1nnnc1N2
Yield: 51.2 %

Procedure:
A mixture of intermediate 9 (0.0014 mol) in toluene (10 ml) was stirred and refluxed for 48 hours, then brought to room temperature and the solvent was evaporated till dryness. The residue was taken up in DCM. The solvent was evaporated till dryness. The residue was purified by column chromatography over kromasil® (10 μm) (eluent: DCM/MeOH/Et3N 95/5/0.1). The pure fractions were collected and the solvent was evaporated. The residue (0.4 g, 57%) was washed with diethyl ether. The precipitate was filtered off and dried under a vacuo, yielding 0.35 g (50%) of 9-(3-chlorophenyl)-α-(4-fluorophenyl)-4,9-dihydro-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[5,1-b]quinazoline-7-methanol (compound 2), mp. 180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][N:14]([C:34](=[O:43])[C:35]4[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=4[Cl:42])[C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:44]I.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([N:26]([CH3:44])[S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][N:14]([C:34](=[O:43])[C:35]4[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=4[Cl:42])[C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Solvent: CN(C)C=O
Solvent: O
Product: CCCS(=O)(=O)N(C)c1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C

Procedure:
Propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1-(2,6-dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (0.5 g, 0.8 mmol) were dissolved in 1 ml dimethylformamide 0.1 g sodium carbonate was added under stirring at room temperature. Methyl iodide (70 μl, 0.16 g, 1.1 mmol) was added dropwise under vigorous stirring at room temperature by a syringe. The reaction mixture was stirred at room temperature overnight. Water was added to the stirred suspension, and the mixture was stirred for 1 hour. The reaction mixture was extracted with ethyl acetate twice (2×20 ml). The organic layer was dried over sodium sulfate. After drying of the organic layer, the solvent was evaporated under reduced pressure at 46° C. The brownish remaining crude product was used for the further synthesis without purification.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37](=O)[CH3:38])=[CH:31][CH:30]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:40][O:41][C:42](=[O:44])[CH3:43])[CH2:7][O:8]2)(=[O:3])[CH3:2].N1C=CC=CC=1.Cl.[CH3:52][O:53][NH2:54].O>C(O)C>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:30]=[CH:31][C:32]([O:35][CH2:36][C:37](=[N:54][O:53][CH3:52])[CH3:38])=[CH:33][CH:34]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:40][O:41][C:42](=[O:44])[CH3:43])[CH2:7][O:8]2)(=[O:3])[CH3:2]
Reactant: CON
Reactant: CC(=O)COc1ccc(Cc2cc([C@]34OC[C@](COC(C)=O)(O3)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc2Cl)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C(C)COc1ccc(Cc2cc([C@]34OC[C@](COC(C)=O)(O3)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc2Cl)cc1
Yield: 64.7 %

Procedure:
To a solution of (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(4-chloro-3-(4-(2-oxopropoxy)benzyl)phenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (180 mg, 0.28 mmol), in ethanol (8 mL) under nitrogen atmosphere, were added pyridine (0.114 mL, 1.42 mmol) and O-methylhydroxylamine hydrochloride (72 mg, 0.85 mmol). The reaction mixture was refluxed for 2 h. After completion of the reaction as confirmed by TLC, water (10 mL) was added to the reaction mixture and the crude compound was extracted with ethyl acetate (3×25 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1.5:8.5 Acetone:Pet. Ether) to afford the title compound (120 mg, 63.8%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5].[CH2:16](OC(OCC)OCC)C.COCC(O)C>C(O)C>[NH:8]1[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:1]=[CH:16]2)=[N:11][N:10]=[N:9]1
Reactant: Nc1ccccc1C(=O)Nc1nnn[nH]1
Reactant: CCOC(OCC)OCC
Solvent: CCO
Solvent: COCC(C)O
Product: O=c1c2ccccc2ncn1-c1nnn[nH]1
Temperature: 10 °C
Reaction time: 0.75 h

Procedure:
A mixture of 326 g of 2-amino-N-(1H-tetrazol-5-yl)benzamide, 680 ml of triethoxymethane and 2 liters of 1-methoxy-2-propanol was heated at reflux. The ethanol which formed was removed through a reflux head. After about 30-60 minutes with a pot temperature above 100° C., HPLC showed that all the starting material had reacted. The mixture was then cooled to 10° C. and the solid which formed was separated by filtration, washed with methanol and dried. The crude product was dissolved in hot dimethylformamide and the solution was diluted with methanol and cooled. The solid which precipitated was separated by filtration to give 3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone melting at about 259°-260° C. This compound has the following structural formula: ##STR4##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]([NH:17][NH2:18])=[O:16])=[CH:4][CH:3]=1.[C:19]1([CH2:25][C:26](Cl)=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:25]([C:26]1[O:16][C:15]([CH2:14][C:9]2[C:10]([CH3:13])=[N:11][O:12][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[N:17][N:18]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)NN
Product: Cc1noc(-c2ccc(Br)cc2)c1Cc1nnc(Cc2ccccc2)o1

Procedure:
Prepared according to the procedure described in Example 8, Step 6, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-acetic acid hydrazide and phenylacetyl chloride.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:18][CH3:19])/[CH:4]=[C:5](/S(C1C=CC=CC=1)=O)\[C:6]([O:8][CH3:9])=[O:7].[OH:20]/[N:21]=[C:22](\Cl)/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(CC)CC.CCCCCC>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:18][CH3:19])[C:4]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:21][O:20][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: O/N=C(\Cl)c1ccccc1
Reactant: COC(=O)/C(=C\C(OC)OC)S(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COC(=O)c1onc(-c2ccccc2)c1C(OC)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.1 %

Procedure:
To a solution of (E)-methyl 4,4-dimethoxy-2-(phenylsulfinyl)but-2-enoate (0.284 g, 1 mmol) and (Z)-N-hydroxybenzimidoyl chloride (0.370 g, 2.378 mmol) in DCM (5 mL) at rt was added Et3N (0.488 mL, 3.50 mmol) dropwise over 30 minutes as a solution in 5 mL of DCM. After stirring 18 hr at rt, the reaction mixture was cooled to 0° C. and additional (Z)-N-hydroxybenzimidoyl chloride (0.370 g, 2.378 mmol) was added. The cooling bath was removed and the reaction mixture stirred for 2 hr during which the temperature of the reaction reached rt, Et3N (0.488 mL, 3.50 mmol) was added over ˜2 minutes. The reaction mixture was stirred an additional 18 hr at rt. The reaction mixture was poured into ˜100 ml of hexane. The resulting suspension was allowed to stand at rt for 30 minutes. After filtration, the filtrate was concentrated and the residue was chromatographed on a 5×12 cm silica gel column, eluting with a 0-6% EtOAc/Hex gradient. (Note: to load the column, the residue was slurried in 5% CH2Cl2/Hex. Not all of the material dissolved). The essentially pure fractions containing the product were concentrated to afford methyl 4-(dimethoxymethyl)-3-phenylisoxazole-5-carboxylate (125 mg, 0.451 mmol, 45.1% yield) as a colorless oil. (Note: The desired product is the third product to elute and began eluting at 6% EtOAc/Hex.). HPLC retention time=1.63 minutes (PHENOMENEX® Luna 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1% TFA over a 2 minute gradient. MS: (M+H)=278.12. 1H NMR (400 MHz, chloroform-d) δ ppm 3.41 (s, 6H), 4.03 (s, 3H), 5.95 (s, 1H), 7.45 (m, 3H), 7.96 (dd, J=7.8, 2.0 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][C:23]([O:26]C(=O)C)=[CH:22][CH:21]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][F:17].C([O-])([O-])=O.[K+].[K+]>CCO.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4](/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][F:17]
Reactant: CC(=O)Oc1ccc(/C=C/c2cnc(OCCOCCOCCF)c(Br)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: Oc1ccc(/C=C/c2cnc(OCCOCCOCCF)c(Br)c2)cc1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
Acetate 11d (0.145 g, 0.31 mmol) and K2CO3 (0.064 g, 0.465 mmol) were placed in EtOH/THF (5 mL/5 mL) and the reaction mixture was stirred at r.t. 2 h. After standard workup with EtOAc, the crude product was purified by PTLC to give 11e as a white solid (0.128 g, 97%). 1H NMR δ8.07 (d, 1H, J=2.1 Hz), 7.99 (d, 1H, J=2.1 Hz), 7.35 (d, 2H, J=8.6 Hz), 6.96-6.74 (m, 4H), 5.22 (br s, 1H), 4.69 (t, 1H, J=4.2 Hz), 4.54 (t, 2H, J=4.8 Hz), 4.45 (t, 1H, J=4.2 Hz), 3.94-3.68 (m, 8H). 13C NMR δ 158.5, 156.4, 143.6, 138.2, 129.2, 129.0, 127.9, 120.7, 116.0, 107.6, 84.9, 81.6, 71.1, 71.0, 70.8, 70.4, 69.6, 66.8. HRMS calcd for C19H21BrFNO4 (M+), 425.0638. found, 425.0651.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Br:9]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[Br:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ncc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
To a solution of 5-chloropyridin-2-amine (5.0 g) in acetic acid (90 mL) was added dropwise a solution of bromine (12.4 g) in acetic acid (4 mL) at 10° C. The reaction solution was stirred at room temperature for 2 hr, and saturated aqueous sodium thiosulfate solution was added thereto at 0° C. The mixture was stirred for 30 min, the solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.75 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([O:27]N4C5C=CC=CC=5N=N4)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:45]1(O)[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1>C(#N)C>[CH3:1][C:2]1([CH3:38])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([O:27][C:53]4[C:54]5[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=5)[CH:50]=[CH:51][CH:52]=4)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:18])[CH3:19])=[N:9]2)[CH2:4][O:3]1
Reactant: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(On2nnc3ccccc32)cc1=O
Reactant: Oc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(Oc2cccc3ccccc23)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
A solution of 2-[4-(benzotriazol-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (0.30 g, 0.57 mmol) in acetonitrile (12 mL, 0.048M) was treated with cesium carbonate (0.37 g, 1.14 mmol) and naphthalen-1-ol (0.10 g, 0.69 mmol). The resulting reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was then concentrated in vacuo and partitioned between water (100 mL) and ethyl acetate (100 mL). The organics were washed with a saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered, rinsed, and concentrated in vacuo. Silica gel column chromatography (AnaLogix 40 g, 25-75% ethyl acetate/hexanes) afforded 4-methyl-2-[4-(naphthalen-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (208.7 mg, 68%) as a light orange solid as a mixture of diastereomers.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=2[O:40][CH3:41])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([S:12]([N:15](CC1C=CC(OC)=CC=1)[C:16]1[S:17][CH:18]=[CH:19][N:20]=1)(=[O:14])=[O:13])=[CH:7][CH:6]=2.[C:42]([Zn]C#N)#[N:43].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C>FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O.[Zn]>[C:42]([C:2]1[N:3]=[C:4]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:32][C:31]=2[O:40][CH3:41])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([S:12]([NH:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)(=[O:14])=[O:13])=[CH:7][CH:6]=2)#[N:43]
Reactant: N#C[Zn]C#N
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)nc(Cl)cc3c2)cc1
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Agent: O=C([O-])C(F)(F)F
Product: COc1cc(C(F)(F)F)ccc1-c1nc(C#N)cc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
A vial was charged with 3-chloro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate RRR) (59.39 mg, 0.096 mmol), dicyanozinc (22.49 mg, 0.192 mmol), racemic-2-di-t-butylphosphino-1,1′-binaphthyl (Strem Chemical, Newburyport, Mass.) (7.63 mg, 0.019 mmol), palladium(ii) trifluoroacetate (3.18 mg, 9.58 μmol), and zinc (3.13 mg, 0.048 mmol). The vial was flushed with Ar (g), then DMAC (479 μl) was added. The vial was sealed and heated in a 95° C. heating bath for 15 h. The mixture was diluted with water and extracted with EtOAc (4× via pipette). The combined organic extracts were combined and concentrated. The residue was taken up in DCM (1 mL) and TFA (0.5 mL). After 30 min, the mixture was diluted with MeOH, then concentrated. The residue was purified by chromatography on silica gel (12-g column, 0 to 6% MeOH/DCM). The resulting material was concentrated from DCM (3×), then taken up in DCM and filtered through a membrane filter. The collected solid was washed with DCM (2×), dried under a flow of N2 (g), then dried under vacuum to give 3-cyano-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.99 (br. s., 1H), 8.95 (s, 1H), 8.70 (d, J=1.8 Hz, 1H), 8.07 (dd, J=1.9, 8.9 Hz, 1H), 7.83 (d, J=8.9 Hz, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.57-7.50 (m, 2H), 7.31 (d, J=4.5 Hz, 1H), 6.91 (d, J=4.6 Hz, 1H), 3.76 (s, 3H); m/z (ESI) 491.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:11]2[CH2:16][CH2:15][C@@:14]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:17][CH2:18][OH:19])[O:13][C:12]2=[O:27])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1B(O)O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:11]2[CH2:16][CH2:15][C@@:14]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:17][CH2:18][OH:19])[O:13][C:12]2=[O:27])[CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CC[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Yield: 25.9 %

Procedure:
To a solution of (S)-3-((S)-1-(4-bromophenyl)propyl)-6-(4-fluorophenyl)-6-(2-hydroxy ethyl)-1,3-oxazinan-2-one (60 mg, 0.14 mmol), 2,4-difluorophenylboronic acid (26 mg, 0.17 mmol) and Pd(PPh3)4 (16 mg, 0.01 mmol) in dioxane (5 mL) was added a solution of CsCO3 (2 M, 1 mL) at 0° C. Then the reaction mixture was refluxed overnight under nitrogen. The reaction mixture was washed with water and then extract with CH2Cl2 twice. The combined organic phases were dried over Na2SO4, filtered and concentrated to give the residue, which was purified by preparative HPLC to afford (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl) propyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (17 mg, 26%). 1H NMR (CD3OD): 0.96 (m, 3H), 2.01 (m, 2H), 2.12 (m, 2H), 2.30 (m, 2H), 2.48 (m, 1H), 3.10 (m, 1H), 3.33 (m, 1H), 3.65 (m, 1H), 5.38 (m, 1H), 7.02 (m, 4H), 7.08 (m, 2H), 7.28 (m, 4H), 7.42 (m, 1H). 443-114-3.
Reaction SMILES: [CH2:1]([CH:3]([C:26]([OH:28])=[O:27])[N:4]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=1)[CH3:2].CO.[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([CH:3]([C:26]([OH:28])=[O:27])[N:4]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=1)[CH3:2]
Reactant: CCC(C(=O)O)N(CCCCc1ccc([N+](=O)[O-])cc1)c1cccc(C#N)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(C(=O)O)N(CCCCc1ccc(N)cc1)c1cccc(C#N)c1
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
Part D. A solution of ethyl N-[4-[4-nitrophenyl]butyl]-N-[3-cyanophenyl]glycine (0.31 gm, 0.81 mmol) and 20 mL methanol:ethyl acetate (v:v, 50:50) was degassed with nitrogen in a Parr shaker bottle, then 10% palladium on carbon was added. The reaction was charged to 50 PSI hydrogen and shaken for 1/2 hr. The catalyst was filtered off over celite, the filtrate concentrated and the product purifed by flash chropmatography on silica gel eluting ethyl acetate:methylene chloride (v:v, 10:90) to give ethyl N-[4-[4-aminophenyl]butyl]-N-[3-cyanophenyl]glycine as a semisolid 0.27 gm (94%). MS 352(M+H)+ 1 H NMR (CDCl3): 7.2(m, 1H), 7.0(m, 3H), 6.8(m, 2H), 6.6(d, 2H), 4.2(q, 2H), 4.0(s, 2H), 3.6(bs, 2H), 3.4(m, 2H), 2.6(m, 2H), 1.6(m, 4H), 1.2(t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])/[CH:5]=[CH:6]/[C:7]([OH:9])=O.[CH3:14][CH:15]1[NH:21][C:20](=[O:22])[CH2:19][CH2:18][NH:17][CH2:16]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:6]/[C:7]([N:17]2[CH2:18][CH2:19][C:20](=[O:22])[NH:21][CH:15]([CH3:14])[CH2:16]2)=[O:9])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: CC1CNCCC(=O)N1
Reactant: O=C(O)/C=C/c1ccc(Cl)c(Cl)c1
Product: CC1CN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC(=O)N1

Procedure:
In analogy to the procedure described in intermediate 1A, (E)-3,4-dichlorocinnamic acid and 3-methyl-[1,4]diazepan-5-one gave the title compound as a white solid. MS: 327.2 (MH+).