Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:14]=[N:15][C:16]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:17]([CH3:20])[C:18]=2[CH3:19])[CH2:9][CH2:8]1)=O)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:48]>C(#N)C>[CH2:21]([C:16]1[N:15]=[N:14][C:13]([N:10]2[CH2:11][CH2:12][CH:7]([C:5]3[NH:2][C:1]([Cl:48])=[CH:3][N:4]=3)[CH2:8][CH2:9]2)=[C:18]([CH3:19])[C:17]=1[CH3:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCC(C(=O)NCC#N)CC2)c1C
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Cc1c(Cc2ccccc2)nnc(N2CCC(c3ncc(Cl)[nH]3)CC2)c1C
Temperature: 50 °C
Reaction time: 3 h
Yield: 56.2 %

Procedure:
To a solution of 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperidine-4-carboxylic acid cyanomethyl-amide (20 mg, 0.055 mmol) and triphenyl phosphine in acetonitrile (1 mL) at 25° C. is added carbon tetrachloride (42 mg, 0.28 mmol). After being stirred at 50° C. for 3 h, the mixture is concentrated, and diluted with CH2Cl2 (10 mL) and washed with sodium hydroxide (2 mL, 1N), and H2O (2 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified by HPLC (CH3CN/H2O: 22%˜45% with 0.1% TFA) to give 3-benzyl-6-[4-(5-chloro-1H-imidazol-2-yl)-piperidin-1-yl]-4,5-dimethyl-pyridazine (11.8 mg, 56%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([S:11]([NH2:14])(=[O:13])=[O:12])=[C:4]([Cl:15])[CH:3]=1.Cl.C(O)C.O=[C:21]([C:27](OCC)=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CO.[C].[Pd]>[NH2:14][S:11]([C:5]1[CH:6]=[C:7]2[C:2](=[CH:3][C:4]=1[Cl:15])[N:1]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:27](=[O:28])[NH:8]2)(=[O:13])=[O:12]
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CCOC(=O)c1nc2cc(Cl)c(S(N)(=O)=O)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.9 %

Procedure:
To a solution of 4-amino-2-chloro-5-nitrobenzenesulfonamide (2.00 g, 7.95 mmol) in methanol (40 ml) were added 10% palladium-carbon (400 mg) and successively 10% hydrochloric acid (6 ml) at room temperature, and catalytic hydrogenation was conducted for 2 hours at ambient temperature under ambient pressure. Catalyst was filtered off using celite and the filtrate was distilled off under reduced pressure. After dissolved this into ethanol (16 ml), diethyl ketomalonate (1.21 ml, 7.95 mmol) was added, which was stirred for 5 hours at room temperature. The precipitate was collected by filtration, washed with ethanol and then purified by means of silica gel column chromatography [hexane-ethyl acetate=1:2] to obtain 288 mg of the title compound. Yield 11%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9](I)[S:8][C:6]=2[N:7]=1.[CH3:18][S:19]([NH:22][CH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:21])=[O:20].O>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9]([C:28]3[CH:29]=[C:24]([CH:25]=[CH:26][CH:27]=3)[CH2:23][NH:22][S:19]([CH3:18])(=[O:21])=[O:20])[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(I)sc2n1
Reactant: CS(=O)(=O)NCc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CS(=O)(=O)NCc1cccc(-c2nc3c(N4CCOCC4)nc(Cl)nc3s2)c1
Temperature: 100 °C
Yield: 90.9 %

Procedure:
A mixture of 4-(5-chloro-2-iodothiazolo[5,4-d]pyrimidin-7-yl)morpholine 18 (400 mg, 1 mmol), 3-methanesulphonylaminomethyl benzeneboronic acid (260 mg, 1.1 mmol), bis(triphenylphosphine)palladium(II) dichloride (37 mg, 0.052 mmol) in 4 ml of acetonitrile and 4 mL of 1.0 M of sodium carbonate aqueous solution was heated to 100° C. in a microwave for 10 min. Water (5 mL) was added and the resulting solid was filtered and washed with water and ethyl acetate to yield crude N-[3-(5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-yl)-benzyl]-methanesulfonamide (400 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](Cl)[N:3]=1.[NH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([NH:17][CH3:18])=[O:16].C(N(CC)C(C)C)(C)C>C(OCC)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([NH:17][CH3:18])=[O:16])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CNC(=O)c1ccccc1N
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1[N+](=O)[O-]
Yield: 49 %

Procedure:
In a similar fashion as outlined in Example 191a, 2,6-dichloro-5-nitropyrimidine was reacted with 2-amino-N-methylbenzamide and N,N-diisopropylethylamine in ethyl ether (no microwave—20° C., 3 hours) to afford 2-(2-chloro-5-nitro-pyrimidin-4-ylamino)-N-methyl-benzamide as a yellow solid in 49% yield. Mp: 201-3° C. (dec); MS: 308.09 (M+H); 1H NMR (d6-dmso): δ 12.43 (s, 1H), δ 9.20 (s, 1H), δ 8.75 (br s, 1H), δ 8.19 (d, J=9 Hz, 1H), δ 7.71 (d, J=8 Hz, 1H), δ 7.58 (t, J=8 Hz, 1H), δ 7.33 (t, J=8 Hz, 1H), δ 2.78 (d, J=5 Hz, 3H).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH:11]1[CH2:17][C:18]([O:20]CC)=[O:19])=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH:11]1[CH2:17][C:18]([OH:20])=[O:19])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CC1C(=O)NCCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCNC(=O)C1CC(=O)O
Reaction time: 2.5 h
Yield: 82.9 %

Procedure:
1N Sodium hydroxide (11.4 mL, 11.4 mmol) was added to 2-ethoxycarbonylmethyl-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (2.5 g, 8.73 mmol) in methanol (20 mL) at room temperature and then stirred for 2.5 hours. The reaction mixture was concentrated, acidified with 2N HCl to pH˜2 and extracted with dichloromethane (3 times). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the titled compound (1.87 g, 83%, white foam solid). 1H NMR (CDCl3) δ (ppm): 7.68 (bs, 1H), 4.78 (m, 1H), 4.19 (m, 1H), 3.45 (m, 1H), 3.34 (m, 2H), 2.97 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][N:19]=[C:18]([N:27]([CH3:29])[CH3:28])[N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([O:15][C:16]2[C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=[C:18]([N:27]([CH3:29])[CH3:28])[N:17]=2)[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc(N(C)C)nc1O[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)c1ncc(C(=O)O)c(O[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 15 mL of ethanol was dissolved 2.675 g of N-tert-butoxycarbonyl-trans-4-[5-ethoxycarbonyl-2-(dimethylamino)pyrimidin-4-yloxy]cyclohexylamine (the compound of Reference Example 9-50 prior to deprotection treatment), 3.27 mL of an aqueous 3N-sodium hydroxide solution was added thereto at room temperature, and the mixture was stirred overnight. The reaction mixture was diluted with water, and then, citric acid was added thereto until the solution became neutral. The precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to obtain 2.015 g of N-tert-butoxycarbonyl-trans-4-[5-carboxy-2-(dimethylamino)pyrimidin-4-yloxy]cyclohexylamine. (2) The compound obtained in the above (1) was used as a starting material and reacted with a starting amine compound in the same manner as in Reference Example 11-1. The resulting compound (hydrochloride) was made into an aqueous solution, and the solution was treated with potassium carbonate and extracted with chloroform to obtain a free form.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:35]=[CH:34][C:29]([O:30][CH2:31][CH2:32]Br)=[CH:28][CH:27]=1>>[C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:32][CH2:31][O:30][C:29]2[CH:34]=[CH:35][C:26]([F:25])=[CH:27][CH:28]=2)[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reactant: Fc1ccc(OCCBr)cc1
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(CCOc2ccc(F)cc2)c2ccccc2-c2ccccc21

Procedure:
Using ((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-carbamic acid tert-butyl ester and 4-fluorophenoxy-ethylbromide, the title product was prepared in the same manner as described for example 1a (84%). White solid. MS: m/e=463(M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH3:12][Si:13]([C:16]#[C:17][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)([CH3:15])[CH3:14]
Reactant: Brc1cnc2ccccc2c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOCC
Product: C[Si](C)(C)C#Cc1cnc2ccccc2c1
Temperature: 70 °C

Procedure:
A mixture of 3-bromoquinoline (10.40 g, 0.05 mol), trimethylsilylacetylene (8.48 mL, 0.06 mol), cuprous iodide (0.5 g) and trans-dichlorobis(triphenylphosphine)palladium (1 g) and TEA (15 mL) was heated at 70° C. in a sealed tube for 1 h. H2O (150 mL) was added, followed by Et2O (300 mL). The organic layer was separated and the aqueous layer extracted with Et2O (200 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (eluent: 100% DCM) to give 3-(trimethylsilylethynyl) quinoline as a brown oil. 3-(Trimethylsilylethynyl) quinoline was dissolved in anhydrous MeOH (100 mL) and K2CO3 (0.69 g, 5 mmol) was added. The mixture was stirred at rt for 1 h and DCM (250 mL) was added. The mixture was filtered over celite. The filtrate was evaporated and the residue was purified by flash column chromatography to give Compound 13b as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH2:10]([N:12](CC)[CH2:13][CH3:14])[CH3:11].C(NCC)C>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:12]([CH2:13][CH3:14])[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCN(CC)CC
Solvent: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.8 %

Procedure:
A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine (0.84 mL, 6.0 mmol) and diethylamine (0.84 mL, 8.0 mmol) in THF (20 mL) was stirred at ambient temperature for 16 h. The solvent was evaporated and the resultant residue diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound (0.85 g, 88%). 1H NMR (CDCl3, 300 MHz): 7.45-7.38 (m, 2H), 7.27-7.18 (m, 2H), 3.50 (s, 2H), 2.50 (q, J=7.1 Hz, 4H), 1.03 (t, J=7.1 Hz, 6H). LCMS (Method G): RT=1.98 min, M−H+=242.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]2)[CH:6]=[CH:7][C:8]=1[F:9].CCN(C(C)C)C(C)C.Cl[C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl>[F:2][C:3]1[CH:4]=[C:5]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]2[C:30]([O:32][CH3:33])=[O:31])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: COC(=O)C1CCNC(c2ccc(F)c(F)c2)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.4 %

Procedure:
Methyl 2-(3,4-difluorophenyl)piperidine-4-carboxylate hydrochloride (6.1 g, 20.91 mmol) and DIPEA (9.13 mL, 52.28 mmol) were dissolved in DCM (30 mL). Methyl chloroformate (1.944 mL, 25.09 mmol) was added and the reaction stirred at room temperature for 1.5 h. DCM (170 mL) was added. The organic phase was washed with 0.1 M HCl (2×200 mL), satd NaHCO3 (200 mL), dried with a phase separator and evaporated in vacuo yielding dimethyl 2-(3,4-difluorophenyl)piperidine-1,4-dicarboxylate (6.58 g, 100%) as a dark oil. MS m/z 314 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[CH:18]=[O:19])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>CC(O)C>[C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[CH2:18][OH:19])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cccc(OCCc2coc(-c3ccccc3)n2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: OCc1cccc(OCCc2coc(-c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
14.0 g (47.9 mM) of 3-[2-(2-phenyl-4-oxazolyl)ethoxy]benzaldehyde, prepared as described in Preparation 2 herein, was diluted with 200 mL i-PrOH and treated with 2.89 g (76.6 mM) of sodium borohydride. The mixture was stirred at ambient temperature for 24 hr. 250 mL of H2O was added slowly over a period of 1 hr to quench the reaction and the resulting mixture was stirred for 1 hr. It was then concentrated under reduced pressure and the residue was diluted with 300 mL EtOAc and washed with H2O (300 mL) and brine (300 mL). All the organics were combined, dried over MgSO4, and concentrated to yield 13.6 g of a yellow waxy solid.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[Cl:25][CH2:26][C:27](Cl)=[O:28].C(N(CC)CC)C>C1COCC1>[Cl:25][CH2:26][C:27]([NH:24][C:8]1[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])=[N:10][C:11]([CH3:13])=[CH:12][C:7]=1[NH:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:28]
Reactant: O=C(Cl)CCl
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1NC(=O)CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine (250 mg, 0.763 mmol) in dry THF was added chloroacetyl chloride (86 mg, 0.763 mmol) and triethylamine (77 mg, 0.763 mmol) at 0° C. The resulting mixture was warmed to room temperature and stirred for 1 hr. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound as a solid. The solid was purified through silica gel column chromatography to give 280 mg(91%) of tan crystals, mp. 152–154° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:30][C:31]1[S:35][C:34]([S:36](Cl)(=[O:38])=[O:37])=[CH:33][CH:32]=1.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:36]([C:34]2[S:35][C:31]([Cl:30])=[CH:32][CH:33]=2)(=[O:38])=[O:37])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccc(Cl)s2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 13w from {3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, prepared in Step A of Example 13i, and 5-chlorothiophene-2-sulfonyl chloride with the following exception. The sulfonyl chloride was dissolved in CH2Cl2 (1 mL) and 0.28 mL was added to the reaction mixture. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, 1H), 7.79 (d, 2H), 7.43 (d, 1H), 7.34 (d, 1H), 7.24 (m, 3H), 7.13 (m, 1H), 6.94 (d, 1H), 6.76 (m, 1H), 6.68 (m, 2H), 4.41 (s, 2H), 4.35 (s, 2H), 4.30 (s, 2H), 1.48 (s, 9H); MS 591 (M+).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[CH:42][CH:41]=3)=[CH:36][N:35]=2)=[CH:30][CH:29]=1)[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:14])=O)C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[NH2:11][C@@H:12]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[CH:42][CH:41]=3)=[CH:36][N:35]=2)=[CH:30][CH:29]=1)[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:14]
Reactant: [H][H]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)OCc4ccccc4)C(=O)N4CCC[C@H]4C(=O)OC(C)(C)C)cc3)nc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](N)C(=O)N4CCC[C@H]4C(=O)OC(C)(C)C)cc3)nc2)cc1
Yield: 87.2 %

Procedure:
Prepared using General Procedure 18: A solution of (S)-tert-butyl 1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate (436 mg, 0.6 mmol) in THF (25 mL) was hydrogenated in the H-Cube using a 10% Pd/C CatCart at 60° C. (Full hydrogen, 1 mL/min). The reaction mixture was passed over the catalyst a second time at 65° C. The solvent was removed to give 307 mg (83%) of (S)-tert-butyl 1-((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate INT-26 as a white powder. LCMS-ESI (m/z) calculated for C35H46N4O4: 586.4. found 587.4 [M+H]+, tR=6.99 min (Method 10).
Reaction SMILES: CC([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][CH2:14][C:15](=[O:17])[CH3:16])[C:5]1=[O:18])=C.Cl>CC(O)C>[O:17]=[C:15]([CH3:16])[CH2:14][CH2:13][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:4][C:5]1=[O:18]
Reactant: C=C(C)n1c(=O)n(CCC(C)=O)c2ccccc21
Agent: Cl
Solvent: CC(C)O
Product: CC(=O)CCn1c(=O)[nH]c2ccccc21
Yield: 73.4 %

Procedure:
A mixture of 48.8 parts of 1,3-dihydro-1-(1-methylethenyl)-3-(3-oxobutyl)-2H-benzimidazol-2-one, 12 parts of 2-propanol, saturated with gaseous hydrogen chloride and 240 parts of 2-propanol is stirred for 3 hours at room temperature. The precipitated product is filtered off, washed with 2,2'-oxybispropane and dried, yielding 30 parts (73.4%) of 1,3-dihydro-1-(3-oxobutyl)-2H-benzimidazol-2-one.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:13]=1[C:14](N(OC)C)=[O:15].CO>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:13]=1[CH:14]=[O:15]
Reactant: CON(C)C(=O)c1ccc([N+](=O)[O-])cc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=Cc1ccc([N+](=O)[O-])cc1Cl
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 52.7 %

Procedure:
Di-isobutylaluminium hydride (1.5M in toluene, 16.34 ml) was added to a stirred solution of 2-chloro-N-methoxy-N-methyl-4-nitrobenzamide (5 g) in toluene (100 ml) which had been cooled to -78° C. The mixture was stirred for 40 minutes. Methanol (10 ml) was added and the solvent was evaporated. The residue was partitioned between ethyl acetate and 2M aqueous hydrochloric acid. The organic solution was washed with water, dried (MgSO4) and evaporated to give 2-chloro-4-nitrobenzaldehyde (2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]([CH:11]1[O:13][CH2:12]1)Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:11]2[CH2:12][O:13]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: ClCC1CO1
Product: Clc1ccc(OCC2CO2)cc1

Procedure:
The title compound was prepared from 4-chlorophenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH3:15])[C:10](=[O:16])[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:8]2)=[O:4].[NH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+]>>[OH:23][C:6]1[C:5]([C:3]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])=[N:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:10](=[O:16])[N:11]2[CH3:15]
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2C)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)NCCC(=O)O)ncc21
Temperature: 25 °C
Yield: 74.2 %

Procedure:
A mixture of 5-hydroxy-1-methyl-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.11 mmol), β-alanine (805 mg, 9.0 mmol) and NaOMe solution (13.5 mL, 6.8 mmol, 0.5 M in MeOH) was refluxed for 48 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 1. The organic layer was dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH 2 with 6 M HCl, and the resulting suspension was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated to give 30 mg of the title compound as a light yellow solid. MS: (−) m/z 366.28 (M−1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH:17]=O)=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:25]([CH2:27]P(=O)(OCC)OCC)#[N:26]>>[CH3:1][C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH:17]=[CH:27]/[C:25]#[N:26])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cc1oc(COc2ccc(/C=C/C=O)cc2)nc1-c1ccccc1
Product: Cc1oc(COc2ccc(/C=C/C=C/C#N)cc2)nc1-c1ccccc1

Procedure:
According to the method described for Reference Example 35, (E)-3-[4-(5-methyl-4-phenyl-2-oxazolylmethoxy)phenyl]-2-propen-1-al was allowed to react with diethyl cyanomethylphosphonate to give (E,E)-5-[4-(5-methyl-4-phenyl-2-oxazolylmethoxy)phenyl]-2,4-pentadienenitrile. Then, according to the method described for Reference Example 16, (E,E)-5-[4-(5-methyl-4-phenyl-2-oxazolylmethoxy)phenyl]-2,4-pentadienenitrile was subjected to catalytic reduction to give 5-[4-(5-methyl-4-phenyl-2-oxazolylmethoxy)phenyl]valeronitrile. Recrystallization from ethyl acetate--ether--hexane gave colorless prisms, m.p.65°-66° C.