Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]([NH:12][OH:13])=[NH:11])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[C:14]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=O)=[CH:24][CH:23]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]3[N:11]=[C:26]([C:25]4[CH:29]=[CH:30][C:22]([C:14]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)=[O:21])=[CH:23][CH:24]=4)[O:13][N:12]=3)[CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: N=C(NO)C1CCN(C2CC2)CC1
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Product: O=C(c1ccccc1)c1ccc(-c2nc(C3CCN(C4CC4)CC3)no2)cc1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 35a, starting from 1-cyclopropyl-N-hydroxypiperidine-4-carboxamidine and 4-benzoylbenzoyl chloride.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:10]=3[N:9]=2)=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[S:33](Cl)(=[O:35])=[O:34]>CC(C)=O.C(OCC)C>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[S:33]([O:17][C:15]1[CH:14]=[CH:13][C:11]2[NH:12][C:8]([NH:7][C:5](=[O:6])[NH:4][CH:1]3[CH2:3][CH2:2]3)=[N:9][C:10]=2[CH:16]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: O=C(Nc1nc2cc(O)ccc2[nH]1)NC1CC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(Nc1nc2cc(OS(=O)(=O)c3c(Cl)cccc3Cl)ccc2[nH]1)NC1CC1
Reaction time: 24 h
Yield: 22.8 %

Procedure:
To a suspension of 300 mg of 1-cyclopropyl-3-(5-hydroxy-1H-benzimidazol-2-yl)urea in 100 cm3 of acetone are added 186 mg of triethylamine and 349 mg of 2,6-dichlorobenzenesulfonyl chloride. After stirring overnight at a temperature in the region of 20° C., 90 mg of 2,6-dichlorobenzenesulfonyl chloride are added and the mixture is stirred for a further 24 hours. The reaction medium is evaporated to dryness under reduced pressure (2 kPa). The residue is taken up in 50 cm3 of water and then extracted with three times 40 cm3 of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (0.5 kPa). After flash chromatography on a column of silica [eluent: dichloromethane/methanol (96.5/3.5 by volume)], the product obtained is solidified in 10 cm3 of diethyl ether and then filtered off, washed with three times 5 cm3 of diethyl ether and dried under reduced pressure over phosphorus pentoxide. 130 mg of 2-[(cyclopropylcarbamoyl)amino]-1H-benzimidazol-5-yl 2,6-dichlorobenzenesulfonate are obtained in the form of a cream-coloured powder, the characteristics of which are as follows:
Reaction SMILES: [CH:1]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]=[C:3]([Cl:9])[CH:2]=1.O1CCOCC1.[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(OCC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:9][C:3]1[CH:2]=[CH:1][C:6]([CH2:7][O:8][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][O:16]2)=[CH:5][N:4]=1
Reactant: OCc1ccc(Cl)nc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Clc1ccc(COC2CCCCO2)cn1
Temperature: 65 °C
Reaction time: 2.75 h
Yield: 113.6 %

Procedure:
A mixture of 85 g of 6-chloro-3-pyridinecarbinol, 800 ml of dioxan and 129.8 g of 3,4-dihydro-2H-pyran was treated with 5.7 g of p-toluenesulphonic acid monohydrate, stirred at room temperature for 0.75 hours and subsequently at 65° C. for 2.75 hours. The reaction mixture was treated with 15 ml of triethylamine and, after cooling, taken up in diethyl ether. Repeated washing with saturated sodium chloride solution, drying over sodium sulphate and evaporation yielded 153.2 g of crude 2-chloro-5-[(tetrahydro-2-pyranyloxy)methyl]pyridine as a brown-red oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[Se:21][C:20]=1[C:28]([NH2:30])=[O:29].CN(C=O)C.[OH-].[Na+]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[NH:18][C:19]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:25])[CH3:26])[Se:21][C:20]=1[C:28]([NH2:30])=[O:29]
Reactant: COc1cc2c(Cl)ncnc2c(OC)c1OC
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3cc(C(C)(C)C)[se]c3C(N)=O)ncnc2c(OC)c1OC

Procedure:
The reaction of 4-chloro-6,7,8-trimethoxyquinazoline with 3-amino-5-tert-butylselenophene-2-carboxamide in presence of DMF/NaOH as described in Example 1 gave the title compound as an off-white color solid, mp 218-220° C. 1H NMR (400 MHz, CDCl3): δ 12.08 (1H, br s, exchangeable with D2O), 8.87 (1H, s), 8.78 (1H, s), 7.20 (1H, s), 5.49 (2H, br s, exchangeable with D2O), 4.15 (3H, s), 4.07 (3H, s), 4.06 (3H, s), 1.47 (9H, s); 13C NMR (100 MHz, CDCl3): δ 169.0, 168.6, 154.7, 153.1, 152.6, 147.9, 147.6, 146.6, 142.0, 121.7, 112.0, 109.4, 95.9, 62.1, 61.3, 56.1, 37.2, 32.6; LC-MS (positive ion mode): m/z 463, 465 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:15][O:14][C:7]1[C:8]([O:12][CH3:13])=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[C:4]([NH:16][C:17]1[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=1)[N:3]=[C:2]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1OC
Reactant: OB(O)c1ccccc1
Product: COc1ccc2c(-c3ccccc3)nc(Nc3cc(C)[nH]n3)cc2c1OC

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-5,6-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and phenylboronic acid to give (5,6-dimethoxy-1-phenyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 361(MH+).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][NH:10][C:11]2[N:20]=[C:19]([N:21]([CH3:23])[CH3:22])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[CH3:33][CH:34]([S:36](Cl)(=[O:38])=[O:37])[CH3:35]>C(Cl)Cl>[CH3:22][N:21]([CH3:23])[C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([NH:10][CH2:9][C@H:6]2[CH2:7][CH2:8][C@H:3]([CH2:2][NH:1][S:36]([CH:34]([CH3:35])[CH3:33])(=[O:38])=[O:37])[CH2:4][CH2:5]2)[N:20]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CN(C)c1nc(NC[C@H]2CC[C@H](CN)CC2)nc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC[C@H]1CC[C@H](CNc2nc(N(C)C)c3ccccc3n2)CC1
Temperature: 4 °C
Reaction time: 12 h

Procedure:
To a suspension of trans-N2-(4-aminomethyl-cyclohexylmethyl)-N4,N4-dimethyl-quinazoline-2,4-diamine obtained in step A of example 15 (227 mg, 0.72 mmol) in CH2Cl2 (4 mL) was added diisopropylethylamine (263 μL, 1.51 mmol). The mixture was cooled at 4° C. and a solution of 2-propanesulfonyl chloride (108 mg, 0.76 mmol) in CH2Cl2 (1 mL) was added below 5° C. The reaction mixture was stirred at ambient temperature for 12 hr. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 66% EtOAc in hexane) to give trans-propane-2-sulfonic acid {4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-amide (135 mg, 45%) as a pale yellow solid.
Reaction SMILES: [Cl-:1].[C:2]([O:6][C:7]([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][N+:12]([CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]([O:44]C)=[O:43])=[CH:36][CH:35]=2)([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]([O:29]C)=[O:28])=[CH:21][CH:20]=2)[CH2:11]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+]>CO>[Cl-:1].[C:2]([O:6][C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][N+:12]([CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:23][CH:24]=2)([CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]([OH:44])=[O:43])=[CH:36][CH:35]=2)[CH2:11]1)=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: COC(=O)COc1ccc(CCC[N+]2(CCCc3ccc(OCC(=O)OC)cc3)CCCC(NC(=O)OC(C)(C)C)C2)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCC[N+](CCCc2ccc(OCC(=O)O)cc2)(CCCc2ccc(OCC(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-tert-Butoxycarbonylamino-1,1-bis-[3-(4-methoxycarbonylmethoxy-phenyl)-propyl]-piperidinium chloride (450 mg, 0.69 mmol) is dissolved in methanol (8 ml), 1 M sodium hydroxide solution (6 ml, 6 mmol) are added and stirred at room temperature overnight. The methanol is evaporated and the aqueous solution is acidified with 1 M HCl. The water phase is decanted from the oily product which is washed again with a small amount of water. The compound is dissolved in methanol and concentrated in vacuo. LC (method L): tR=1.12 min; Mass spectrum (ESI+): m/z=585 [M]+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([S:14][C:15]([S:18][C:19]2[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[C:22]([OH:28])=[C:21]([CH:29]([CH3:31])[CH3:30])[CH:20]=2)([CH3:17])[CH3:16])[CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:9]=1[OH:10])([CH3:3])[CH3:2]>ClCCl.CCCCCC.[O-2].[O-2].[Mn+4]>[CH3:17][C:15]1([CH3:16])[S:14][C:6]2([CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9](=[O:10])[C:8]([CH:11]([CH3:12])[CH3:13])=[CH:7]2)[C:19]2([CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[C:22](=[O:28])[C:21]([CH:29]([CH3:31])[CH3:30])=[CH:20]2)[S:18]1
Reactant: CC(C)c1cc(SC(C)(C)Sc2cc(C(C)C)c(O)c(C(C)C)c2)cc(C(C)C)c1O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)C1=CC2(C=C(C(C)C)C1=O)SC(C)(C)SC21C=C(C(C)C)C(=O)C(C(C)C)=C1
Reaction time: 4 h

Procedure:
To a mixed solution of 2,2-bis(3,5-diisopropyl-4-hydroxyphenylthio)propane (500 mg, 1.09 mmol) in dichloromethane (5 mL) and hexane (5 mL) was added manganese dioxide (500 mg). The mixture was stirred for 4 hours and then filtered by using a celite, and the resulting filtrate was concentrated. Hexane was added to the residue, and the mixture was stored in a refrigerator. The generated solid was separated by a filtration, washed with hexane, and then dried to synthesize an, objective compound.
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][OH:12])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCc1ccc(C2CCCCC2)cc1
Temperature: 60 °C

Procedure:
To a solution of 4-cyclohexylbenzoic acid (Aldrich; 1 molar eq.) in toluene was added diiso-butylaluminum hydride (Aldrich; 1 M in toluene; 4 molar eq.) over a 2 hour period. After addition was complete, the reaction was heated to 60° C. for 1 hour. The reaction was cooled to 5° C. and quenched with saturated aqueous ammonium chloride. The layers we're separated and the aqueous layer extracted with ethyl acetate. The combined organics were filtered to remove salts and concentrated.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([C:5]2([CH2:3][OH:2])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[CH:12][CH:13]=1
Reactant: COC(=O)C1(c2ccc(Br)cc2)CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1(c2ccc(Br)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of intermediate D9 (1.07 g, 3.58 mmol) in THF (20 ml) stirred at −10° C. under N2 atmosphere, was added a 1.0 M solution of lithium aluminum hydride in THF dropwise (3.58 ml, 3.58 mmol). The resulting solution was gradually warmed to room temperature and further stirred for 2 hours. After cooling to 0° C. an aqueous 10% NaOH solution was carefully added and the resulting mixture was allowed to reach room temperature. Then it was extracted with DCM, dried (Na2SO4) and the solvent evaporated in vacuo to yield intermediate D10 (0.96 g, 99%) as a white solid that was used without further purification.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[N:19]=[CH:18][C:17]([CH:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH3:21])=[CH:16][CH:15]=1.[B:28]([O:37][CH:38]([CH3:40])[CH3:39])([O:33][CH:34]([CH3:36])[CH3:35])OC(C)C.OC(C(O)(C)C)(C)C.C(O)(=O)C>C1COCC1>[F:13][C:14]1[N:19]=[CH:18][C:17]([CH:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH3:21])=[CH:16][C:15]=1[B:28]1[O:33][C:34]([CH3:35])([CH3:36])[C:38]([CH3:39])([CH3:40])[O:37]1
Reactant: CC(c1ccc(F)nc1)N1CCOCC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)(O)C(C)(C)O
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(c1cnc(F)c(B2OC(C)(C)C(C)(C)O2)c1)N1CCOCC1
Temperature: 0 °C
Yield: 75 %

Procedure:
To a stirred solution of diisopropylamine (Aldrich, redistilled, 99.95%, 0.813 mL, 5.80 mmol) in THF (10 mL) in 150 mL round-bottomed flask, nBuLi (Aldrich, 2.5 M in hexanes, 2.32 mL, 5.80 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for min. The mixture was cooled to −78° C. and 4-(1-(6-fluoropyridin-3-yl)ethyl)morpholine (1.02 g, 4.84 mmol) in a total of 3 mL of THF was added dropwise. The mixture was stirred at −78° C. for 45 min. Triisopropyl borate (Aldrich, 1.39 mL, 6.04 mmol) in a total of 3 mL THF was added dropwise at that temperature, then the cold bath was removed. The mixture was stirred at room temperature for 1 h 20 min. Pinacol (0.773 g, 6.54 mmol) in a total of 5 mL THF was added at once and the mixture was stirred at room temperature for 10 min. Acetic acid (0.291 mL, 5.08 mmol) in a total of 3 mL THF was added at once and the mixture was stirred at room temperature for 2 h. The mixture was filtered through a pad of Celite® (diatomaceous earth), and extracted with 1 N NaOH (2×50 mL). The aqueous phase was treated with 4N HCl until a pH of about 6 to 7 while an ice-water bath was applied, then extracted with EtOAc (3×50 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude 4-(1-(6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)ethyl)morpholine (1.22 g, 75% yield) as a light brown viscous oil. This material was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:25])[C:8]2[O:14][C:13]3[C:15]([Cl:22])=[CH:16][C:17]([N+:19]([O-])=O)=[CH:18][C:12]=3[CH2:11][S:10](=[O:23])[C:9]=2[CH:24]=1)=[O:4]>CN(C=O)C.[Ni]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:25])[C:8]2[O:14][C:13]3[C:15]([Cl:22])=[CH:16][C:17]([NH2:19])=[CH:18][C:12]=3[CH2:11][S:10](=[O:23])[C:9]=2[CH:24]=1)=[O:4]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)Cc1cc([N+](=O)[O-])cc(Cl)c1O2
Agent: [Ni]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)Cc1cc(N)cc(Cl)c1O2

Procedure:
A solution of Example 154c (0.59 g, 1.54 mmol) in DMF (60 ml) was subjected to hydrogenation using activated Raney-Ni (0.3 g) at 50 psi for 3 h. It was filtered through a bed of celite, concentrated and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound. Yield: 0.39 g, (71%); 1HNMR (DMSO-d6): δ 2.6 (s, 3H, CH3), 3.88 (s, 3H, CH3), 4.65 (q, 2H, CH2), 5.6 (s, 2H, NH2), 6.65 (s, 2H, Ar), 8.0 (s, 1H, Ar), 8.16 (s, 1H, Ar); MS: m/e EI+) 351 (M+).
Reaction SMILES: [C:1]([C:4]1[C:9]([CH3:10])=[CH:8][C:7]([NH:11]C(=O)C)=[CH:6][C:5]=1[Cl:15])(=[O:3])[CH3:2].Cl.[OH-].[Na+]>C(O)C>[NH2:11][C:7]1[CH:8]=[C:9]([CH3:10])[C:4]([C:1](=[O:3])[CH3:2])=[C:5]([Cl:15])[CH:6]=1
Reactant: CC(=O)Nc1cc(C)c(C(C)=O)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)c1c(C)cc(N)cc1Cl
Yield: 87.6 %

Procedure:
An ethanol solution (4.0 mL) containing N-(4-acetyl-3-chloro-5-methylphenyl)acetamide (0.53 g, 2.3 mmol) and concentrated hydrochloric acid (1.6 mL) was heated at reflux for 15 h. The solution was added with 10% aqueous NaOH and the resultant solids were collected to give 1-(4-amino-2-chloro-6-methylphenyl)ethanone (0.37 g) as light yellow solids in 88% yield: 1H NMR (500 MHz, CDCl3) δ 6.46 (d, J=1.77 Hz, 1 H), 6.34 (s, 1 H), 3.85 (bs, 2 H), 2.49 (s, 3 H), 2.14 (s, 3 H): ESI-MS: m/z 183.4 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[O:12][C:11]([S:13]([NH:16][C:17]2[N:22]=[C:21]([S:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=3[F:32])[N:20]=[C:19]([O:33][C@H:34]([CH3:40])[C:35](OCC)=[O:36])[CH:18]=2)(=[O:15])=[O:14])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].Cl>C1COCC1>[C:1]([NH:5][C:6]([C:8]1[O:12][C:11]([S:13]([NH:16][C:17]2[CH:18]=[C:19]([O:33][C@H:34]([CH3:40])[CH2:35][OH:36])[N:20]=[C:21]([S:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=3[F:32])[N:22]=2)(=[O:14])=[O:15])=[CH:10][CH:9]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)c2ccc(C(=O)NC(C)(C)C)o2)nc(SCc2cccc(F)c2F)n1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CO)Oc1cc(NS(=O)(=O)c2ccc(C(=O)NC(C)(C)C)o2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl (2R)-2-({6-[({5-[(tert-butylamino)carbonyl]-2-furyl}sulfonyl)amino]-2-[(2,3-difluorobenzyl)thio]pyrimidin-4-yl}oxy)propanoate (the product of step iii) (0.25 g) in THF (10 mL) was added a solution of lithium borohydride (0.6 mL, 2.0M in hexanes) dropwise at 0° C. The mixture was warmed to room temperature and stirred for 18 h. After cooling to 0° C., 1N HCl (20 mL) was added slowly, and the mixture extracted with EtOAc (3×20 mL). The combined organic layers were dried (MgSO4), filtered and evaporated to dryness in vacuo. The resulting crude oil was purified by reverse phase HPLC (75% to 5% gradient of 0.2% aqueous trifluoroacetic acid in acetonitrile as eluent) to give the title compound as a white solid. Yield: 90 mg.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:24]=[S:25]1(=[O:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O1CCOCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][S:14]([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)(=[O:15])=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:28]2[CH2:29][CH2:30][S:25](=[O:31])(=[O:24])[CH2:26][CH2:27]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S1(=O)CCNCC1
Agent: Cc1ccc(S(=O)(=O)O[C@H]2CCN(Cc3ccccc3)C2)cc1
Solvent: C1COCCO1
Product: O=S1(=O)CCN([C@@H]2CCN(Cc3ccccc3)C2)CC1
Temperature: 140 °C
Yield: 49.5 %

Procedure:
(S)-Toluene-4-sulfonic acid 1-benzyl-pyrrolidin-3-yl ester was prepared as described in J. Med. Chem. 1992, 35, 4205. (S)-Toluene-4-sulfonic acid 1-benzyl-pyrrolidin-3-yl ester (400 mg, 1.208 mmol, 1 eq) and 1,1-dioxo-thiomorpholine (817 mg, 6.042 mmol, 5 eq) were taken up in dioxane and heated at 140° C. for 20 hours. The reaction mixture was cooled and the dioxane was removed using rotary evaporation. The resulting residue was purified on a Biotage 40M amine column using a gradient of 0-50% ethyl acetate/hexanes to obtain the title compound (88 mg, 25%) as a yellow oil. 1H NMR (400 MHz) CDCl3 δ 7.30-7.20 (m, 5H), 3.55-3.54 (s, 2H), 3.19-3.17 (m, 1H), 3.01-2.91 (m, 6H), 2.62-2.58 (m, 2H), 2.51-2.43 (m, 2H), 2.00-1.97 (m, 2H), 1.71-1.67 (m, 2H). ESMS m/z: 295.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:13])[CH:3]=1.[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:13])[C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1cccc2c(O)cc(=O)[nH]c12
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1cccc2c(O)c([N+](=O)[O-])c(=O)[nH]c12
Temperature: 100 °C

Procedure:
A suspension of 4-hydroxy-8-methylcarbostyril (1.63g; 0.0093 mole), in glacial acetic acid (10 ml) was stirred during the addition of concentrated nitric acid (2.5 ml, d, 1.42) and the mixture warmed for 8 minutes at 100° C, after which time the solution had cleared and began to precipitate the yellow nitro derivative. After cooling, ethanol was added and the solid filtered and washed well with ethanol. On drying in vacuo over P2O5NaOH it had m.p. 266°-267° C (Found: C, 54.41; H, 3.80; N, 12.51; C10H8N2O4 requires; C, 54.55; H, 3.66; N, 12.75%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10](O)=[O:11])=O)=[CH:4][CH:3]=1.[CH3:15][NH:16][NH2:17]>C(O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]2[CH2:8][CH2:9][C:10](=[O:11])[N:16]([CH3:15])[N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Reactant: CNN
Solvent: CCO
Product: CN1N=C(c2ccc(Cl)cc2)CCC1=O

Procedure:
To a 250 ml flask equipped with magnetic stirrer and reflux condenser was charged 10 g of 3-(4-chlorobenzoyl)-propionic acid, 250 ml of absolute ethanol, and 2.5 ml of methyl hydrazine. The reaction was refluxed for 3 hours and cooled to yield a solid which was collected by vacuum filtration, washed with 50 ml of hexane, and air dried. Isolated 9.5 g of product as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](OC)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O.Cl>C1COCC1>[OH:18][CH2:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:8](=[C:21]2[CH2:22][C:23]([CH3:30])([CH3:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH2:26]2)[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)CCc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(CCCO)cc2)CC(C)(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a solution of methyl 3-{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}propanoate (169) (0.176 g, 0.43 mmol) in THF (10 mL) at 0° C. was added LAH (1 M in THF, 1.10 mL, 1.10 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1 h, EtOAc (5 mL) was added, and stirring continued for 10 min. The mixture was then acidified to pH=2 with an aqueous solution of 1 N HCl, extracted with EtOAc (2×50 mL). The combined organic extract was washed with water, brine and dried (Na2SO4), filtered, and the filtrate was concentrated to give the crude product as white solid. The crude product was purified by flash chromatography on silica gel eluted with a gradient from hexanes to 40% EtOAc:hexanes to give a white residue, which upon trituration with hot hexanes containing 1% of MeOH yielded 0.15 g (92%) of compound 233 as a white solid. mp 160-161° C. 1H NMR (400 MHz, DMSO-d6): δ 0.85 (s, 6H), 0.86 (s, 6H), 1.23 (s, 2H), 1.60-1.70 (m, 2H), 1.86 (s, 2H), 1.88 (s, 2H), 2.53 (t, J=7.8 Hz, 2H), 3.35-3.40 (m, 2H), 4.42 (t, J=5.1 Hz, 1H), 6.64 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.5 Hz, 2H), 6.99 (d, J=8.1 Hz, 2H), 7.07 (d, J=8.1 Hz, 2H), 9.23 (s, 1H). LCMS (ES): m/z 401 (M+Na)+, 377 (M−H)−.