Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.Cl[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14]>[OH-].[Na+]>[CH2:16]([O:15][C:13]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)=[O:14])[CH:17]=[CH2:18]
Reactant: C=CCOC(=O)Cl
Reactant: NCc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: C=CCOC(=O)NCc1ccc(C(=O)O)cc1
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
To a solution of 7.55 g of 4-(aminomethyl)-benzoic acid in 50 ml of 1N sodium hydroxide solution were added at 6°-8° C. over 1.5 h 6.55 g of allyl chloroformate. Stirring was continued at 0° C. for 0.5 h and the mixture was then extracted with 60 ml of diethyl ether. The organic phase was extracted with 20 ml of saturated sodium carbonate solution and the combined aqueous layers were then acidified to pH 1.8 by the addition of12N sulfuric acid and subsequently extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over sodium sulfate, and the solvent was evaporated in vacuo. The solid residue was crystallized from ethyl acetate/hexane to yield 7.61 g of 4-(allyloxycarbonylaminomethyl)-benzoic acid as a white solid, m.p. 175°-177° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([F:37])[CH:30]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][N:25]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:26][CH2:27]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([F:37])[CH:30]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCNCC4)cc3C2=O)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-2-(3-fluoro-4-methoxyphenyl)-6-(3-(piperazin-1-yl)propoxy)-1H-inden-1-one (70 mg, 1.2 eq, 0.1 mmol) obtained in Step 2 in CH2Cl2 at 0° C. was added triethylamine (1.5 eq) and methylsulfonyl chloride (1.0 eq). The mixture was stirred for 1 h at room temperature and diluted with CH2Cl2. The mixture was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound (47%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:11]=[CH:12][C:13]([N+:18]([O-:20])=[O:19])=[C:14]([CH:17]=1)[C:15]#[N:16].O.[OH-].[Na+]>CN(C)C=O>[N+:18]([C:13]1[CH:12]=[CH:11][C:10]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:17][C:14]=1[C:15]#[N:16])([O-:20])=[O:19]
Reactant: Oc1ccc(Cl)cc1
Reactant: N#Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(Oc2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Reaction time: 18 h
Yield: 52.6 %

Procedure:
Sodium hydride (60% in mineral oil), 1.5 grams (0.038 mole) was washed in petroleum ether. The petroleum ether was decanted , and the sodium hydride was suspended in about 20 mL of N,N-dimethylformamide. The suspension was stirred, and solutions of 4.5 grams (0.035 mole) of 4-chlorophenol in 20 mL of N,N-dimethylformamide and 5.0 grams (0.027 mole) of 5-chloro-2-nitrobenzonitrile in 20 mL of N,N-dimethylformamide were added, respectively. Upon completion of addition, the reaction mixture was warmed to reflux where it stirred for about 18 hours. The reaction mixture was then cooled and poured into a mixture of 500 mL of water and 50 mL of aqueous 2N sodium hydroxide. The mixture was stirred for about 15 minutes, then it was allowed to stand for about 18 hours. The resultant solid was collected by filtration and recrystallized from ethanol, yielding 3.9 grams of 2-nitro-5-(4-chlorophenoxy)benzonitrile, mp 120°-122° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12](=O)[C:13](Cl)=[O:14])=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.C([O:21][C:22](=[NH:37])[CH2:23][C:24]1[C:32]2[C:27](=[C:28]([N+:33]([O-:35])=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:26]([CH3:36])[CH:25]=1)(C)C>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[C:13](=[O:14])[NH:37][C:22](=[O:21])[C:23]=3[C:24]3[C:32]4[C:27](=[C:28]([N+:33]([O-:35])=[O:34])[CH:29]=[CH:30][CH:31]=4)[N:26]([CH3:36])[CH:25]=3)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)C(=O)Cl)c2ccc(F)cc21
Reactant: CC(C)OC(=N)Cc1cn(C)c2c([N+](=O)[O-])cccc12
Agent: Cl
Product: Cn1cc(C2=C(c3cn(C)c4c([N+](=O)[O-])cccc34)C(=O)NC2=O)c2ccc(F)cc21

Procedure:
3-(6-Fluoro-1-methyl-1H-indol-3-yl)-4-(1-methyl-7-nitro-1H-indol-3-yl)-pyrrole-2,5-dione was prepared from (6-Fluoro-1-methyl-1H-indol-3-yl)-oxo-acetyl chloride and 2-(1-methyl-7-nitro-1H-indol-3-yl)-acetimidic acid isopropyl ester hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[NH:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:11]=1.[OH:26]O.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:26])[CH:5]=[C:6]([Cl:25])[C:7]=1[NH:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:11]=1
Reactant: OO
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2c(Cl)c[n+]([O-])cc2Cl)cc1OC1CCCC1
Reaction time: 3 h

Procedure:
A stirred suspension of N-(3,5-dichloropyrid-4yl)-3-cyclopentyloxy-4-methoxybenzamide (2.0 g; that is prepared as described in Example 6) in glacial acetic acid (8 mL) is treated with an aqueous solution of hydrogen peroxide (6 mL; 27.5%). The mixture is stirred for 3 hours at 70°-80° C. and then it is treated with a further portion of hydrogen peroxide solution (4 mL), and the solution is stirred for a further 12 hours. The solution is then cooled, basified by treatment with concentrated aqueous sodium hydroxide solution, and extracted with dichloromethane (2×30 mL). The organic extract is washed with brine (30 mL), dried over magnesium sulfate and evaporated. The resulting residue is recrystallized from ethyl acetate, to give 3,5-dichloro-4-(3-cyclopentyloxy-4-methoxybenzamido)pyridine-N-oxide (0.73 g), m.p. 118°-120° C. [Elemental analysis: C,53.0; H,4.4; N,6.8%; calculated for C18H18O4N2Cl2 :0.5H2O: C,53.2;H 4.7;N 6.9%].
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][C:15]1[O:19][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:17][C:16]=1[CH2:26][CH2:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1>O1CCCC1>[CH3:14][C:15]1[O:19][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:17][C:16]=1[CH2:26][CH2:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[CH:5][C:3]#[N:4])=[CH:31][CH:30]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=CC#N)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.4 %

Procedure:
Sodium hydride (60% in oil, 2.0 g) was added, in small portions at 0° C. a solution of diethyl cyanomethylphosphonate (8.2 g) in tetrahydrofuran (150 ml). The mixture was stirred for about 15 minutes, to which was added 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde (13.0 g), and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into ice-water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off to leave 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]cinnamonitrile (11.8 g, 85%). The product was recrystallized from ethyl acetate--hexane to give colorless needles, m.p.112°-113° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21]O)=[CH:15][C:14]=3[F:23])=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS(Cl)(=O)=O.ClC1C=CC(CNC(C2C=NC3C(C=2O)=CC(CCl)=CC=3F)=O)=CC=1.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:65]2[CH2:70][CH2:69][O:68][CH2:67][CH2:66]2)=[CH:15][C:14]=3[F:23])=[O:9])=[CH:24][CH:25]=1
Reactant: C1COCCN1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(CO)cc2c1O
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(CCl)cc2c1O
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(CN3CCOCC3)cc2c1O
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxamide from Example No. 141 (500 mg), collidine (0.21 mL), and DMAP (28.3 mg) in 25 mL DMF is cooled to 0° C. Methanesulfonyl chloride (0.12 mL) is added dropwise. The reaction is stirred at room temperature and monitored by mass spectroscopy for complete conversion to N-(4-chlorobenzyl)-6-(chloromethyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide (approx. 2-3 hrs and reaction mixture turns yellow). Morpholine (0.24 mL) is added. The reaction is monitored by mass spectroscopy for complete conversion. The product is precipitated by addition of 25 mL H2O. The white solid is filtered and collected to afford 459.3 mg (78%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH:6]([Ge:8]([Cl:11])([Cl:10])[Cl:9])[CH3:7])[C:3](O)=[O:4].S(Cl)([Cl:14])=O>>[CH3:1][CH:2]([CH:6]([Ge:8]([Cl:11])([Cl:10])[Cl:9])[CH3:7])[C:3]([Cl:14])=[O:4]
Reactant: CC(C(=O)O)C(C)[Ge](Cl)(Cl)Cl
Reactant: O=S(Cl)Cl
Product: CC(C(=O)Cl)C(C)[Ge](Cl)(Cl)Cl
Yield: 90.4 %

Procedure:
28.0 g (0.1 mol) of 2-methyl-3-(trichlorogermyl)butanoic acid was treated with 100 ml of thionyl chloride. The reaction mixture was distilled under a reduced pressure to obtain 27.0 g of 2-methyl-3-(trichlorogermyl)butanoyl chloride as a pale yellow portion having a boiling point of 99° to 100° C./6 mmHg (yield: 90.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[CH:5]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[NH:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O>[CH2:24]([O:17][C:4]1[C:3]2[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])[N:7]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of methyl 5,7-dichloro-4-oxo-1,4-dihydroquinoline-2-carboxylate (3 g) in dry dimethyl-formamide (20 ml) was added potassium carbonate (6.1 g) followed by benzyl bromide (1.44 ml) and the mixture stirred at room temperature for 16 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (3×100 ml), the organic layers were combined and washed with water (2×100 ml), 1M hydrochloric acid (1×100 ml), brine (2×100 ml) and dried over magnesium sulphate. The solvent was removed under reduced pressure and the crude product purified by column chromatography to give methyl 4-benzyloxy-5,7-dichloroquinoline-2-carboxylate (2.8 g). δ (360 MHz, DMSO-d6) 3.95 (3H, s, OCH3), 5.48 (2H, s, CH2), 7.35 (1H, d, p-ArH), 7.38 (2H, t, m-ArH), 7.46 (2H, d, o-ArH), 7.59 (1H, s, 3-H), 7.83 (1H, d, 6-H) and 8.11 (1H, d, 8-H).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[N:5][OH:6])[NH2:4].C(=O)(O)[O-].[Na+].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=O)=[CH:15][CH:14]=1>CC(C)=O>[Cl:1][CH2:2][C:3]1[N:4]=[C:17]([C:16]2[CH:20]=[CH:21][C:13]([Cl:12])=[CH:14][CH:15]=2)[O:6][N:5]=1
Reactant: NC(CCl)=NO
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: ClCc1noc(-c2ccc(Cl)cc2)n1

Procedure:
A solution of 2-chloroacetamidoxime (0.5 g) and sodium bicarbonate (0.78 g) in 10 mL of anhydrous acetone was treated with 4-chlorobenzoyl chloride (0.58 mL) at room temperature for 2 hours, concentrated in vacuo, dissolved in water and extracted with ethyl acetate. The organic layers were combined, dried with MgSO4 and concentrated to a semi-solid. This material was redissolved in toluene (50 mL). refluxed under nitrogen for 15 hours, cooled and absorbed on to silica gel. Chromatography using ethyl acetate:hexane (1:9) gave the pure title product as a light yellow solid, mp 79-80° C. Mass spectrum m/e: 228 (M+), 1H NMR (250 MHz, CDCl3) δ 8.1 (d, 2H), 7.5 (d, 2H), 4.7 (s, 2H).
Reaction SMILES: [CH3:1][N:2]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-])=O)[CH:29]=1)[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N:6][N:7]2COCC[Si](C)(C)C.C1(N)C=CC=C(N)C=1>C(OCC)(=O)C.CCCCCC>[CH3:1][N:2]([C:3]1[CH:4]=[C:8]2[C:9]([C:5]([CH:20]=[CH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:6][NH:7]2)=[CH:10][CH:11]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH2:34])[CH:29]=1
Reactant: CN(c1cccc([N+](=O)[O-])c1)c1cccc2c1c(C=Cc1ccccc1)nn2COCC[Si](C)(C)C
Agent: Nc1cccc(N)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN(c1cccc(N)c1)c1ccc2c(C=Cc3ccccc3)n[nH]c2c1

Procedure:
Methyl-(3-nitro-phenyl)-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl)-1H-indazol-yl}-amine was converted to N-methyl-N{3-styryl-1-[2-trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-benzene-1,3-diamine as described in Example 11, step (iv). Rf sm 0.55, Rf p 0.31 (ethyl acetate:hexane 3:7); FTIR (thin film) 3455, 3360, 2951, 2893, 1621, 1601, 1494, 1449, 1249, 1074 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.81 (d, 1H, J=8.8 Hz) 7.58 (d, 2H, J=7.21 Hz), 7.26-7.50 (m, 5H), 7.12 (t, 1H, J=7.93 Hz), 7.01 (d, 1H, J=1.73 Hz), 6.95 (dd, 1H, J=1.99, 8.85 Hz), 5.67 (s, 2H), 3.63 (t, 2H, J=8.12 Hz), 3.38 (s, 3H), 0.93 (t, 2H, J=8.13 Hz), −0.04 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 150.3, 149.0, 147.7, 143.4, 143.0, 137.6, 131.3, 130.4, 128.9, 128.0, 126.7, 121.2, 120.6, 117.3, 117.0, 113.1, 110.1, 109.3, 97.5, 77.8, 66.6, 41.0, 18.0, −1.2; LCMS (ESI) [M+H]/z Calc'd 471, Found 471.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:2]=1.N1C2C(=NC=CC=2)N(CC2C=CC3N=C(S(C)(=O)=O)SC=3C=2)C=1.[NH2:46][C@@H:47]1[CH2:52][CH2:51][CH2:50][CH2:49][C@H:48]1[CH2:53][OH:54].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:46][C@@H:47]4[CH2:52][CH2:51][CH2:50][CH2:49][C@H:48]4[CH2:53][OH:54])[S:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: N[C@@H]1CCCC[C@H]1CO
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2s1
Agent: CS(=O)(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2s1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: OC[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Temperature: 120 °C
Reaction time: 4.5 h

Procedure:
A 4:1 mixture of 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole and 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfonyl)benzo[d]thiazole (120 mg) from Step 2 of Example 63 was dissolved in anhydrous DMA (2 mL), and then ((1R,2R)-2-aminocyclohexyl)methanol (180 mg, 1.40 mmol) from Step 1 of this Example and DIEA (188 mg, 1.46 mmol) were added. The reaction vessel was sealed and the mixture was heated with stirring at 120° C. for 4.5 h. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford ((1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH2:36]([S:44][C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1)[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([C:47]3[CH:48]=[CH:49][CH:50]=[C:45]([S:44][CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:46]=3)=[CH:35][CH:34]=2)[N:8]([C:20]2[CH:21]=[C:22]([N:26]3[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]3)[CH:23]=[CH:24][CH:25]=2)[CH:9]=1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Reactant: OB(O)c1cccc(SCCc2ccccc2)c1
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4cccc(SCCc5ccccc5)c4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (119 mg, 0.2 mmol) was treated as described in general procedure G using 3-(phenethylsulfanyl)phenylboronic acid (104 mg, 0.4 mmol, prepared according to general procedure I) to give 5-{3-[4-(2,4-dichloro-phenyl)-2-(3′-phenethylsulfanyl-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=1)=[O:12].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([C:21]([F:24])([F:22])[F:23])[CH:15]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=C(CCl)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C(COc1ccc(Br)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a round bottom flask was added 4-bromophenol (1.7 g, 9.8 mmol, 1.0 eq.), acetamide 21 (2.79 g, 10.3 mmol, 1.05 eq.), potassium iodide (1.7 g, 10.3 mmol, 1.05 eq.), potassium carbonate (2.7 g, 19.6 mmol, 2.0 eq.), and acetonitrile (35.0 mL). The reaction mixture was then reluxed with vigorous stirring for 2 h. The hot reaction was then filtered to remove the insoluble potassium carbonate. The filtrate was concentrated to give 3.8 g of crude bromo-phenoxy-acetamide 22 as a light brown solid. The solid was then triturated with 10 mL of cold acetonitrile, filtered, and rinsed with 5 mL of cold acetonitrile to give pure bromo-phenoxy-acetamide 22 (1.85 g, 45% yield). Note: there was still an abundant amount of crude product in the mother liquor. LC/MSD (HP Series 1100 MSD) MS (ES+) m/z 409.9 (M+H)+1 1H-NMR, Varian 400 MHz (DMSO-d6) δ 8.20 (d, 1H), 7.90 (dd, 1H), 7.68 (d, 1H), 7.48 (d, 2H), 6.99 (d, 2H), 4.75 (s, 2H) ppm.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C:8]1[CH:9]=[N:10][N:11]([CH:13]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14]2)[CH:12]=1>C1COCC1.CCOC(C)=O>[CH3:18][N:15]1[CH2:16][CH2:17][CH:13]([N:11]2[CH:12]=[C:8]([NH2:7])[CH:9]=[N:10]2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(N)cn2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC(n2cc(N)cn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
A reaction flask containing a suspension of LAH (499 mg, 13.2 mmol) in THF (22 mL) was evacuated and back-filled with nitrogen three times. A solution of tert-butyl 3-(4-amino-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (830 mg, 3.3 mmol) in THF (11 mL) was added dropwise, via an addition funnel and the reaction mixture was stirred at rt under nitrogen overnight. The reaction was quenched sequentially with water (1 mL), 1N NaOH (1 mL), and water (3 mL) to afford a suspension. The precipitate was filtered off and washed with ethyl acetate. The combined filtrates were diluted with a small amount of water and transferred to a separatory funnel. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The organics were combined and concentrated to give crude material (137 mg). To recover product in the aqueous layer, the aqueous extraces were lyophilized to give a solid residue. This was suspended in EtOAc and filtered. The filtrate was evaporated to give additional crude material (287 mg). The combined crude was purified via Biotage flash chromatography (25S column, eluting with 7 N NH3/MeOH in DCM (1%-4%)) to give the title compound (279 mg, 51% yield). m/z (APCI+) for C8H14N4 167.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.89-2.00 (m, 1H) 2.20-2.31 (m, 1H) 2.26 (s, 3H) 2.42 (td, J=8.40, 6.19 Hz, 1H) 2.60 (dd, J=9.60, 4.80 Hz, 1H) 2.64-2.77 (m, 2H) 3.79 (br. s., 2H) 4.67 (m, J=9.44, 7.23, 4.67, 4.67 Hz, 1H) 6.87 (s, 1H) 7.07 (s, 1H).
Reaction SMILES: C1(N=C=N)CCCCC1.[CH3:10][CH:11]([CH3:30])[CH2:12][S:13]([CH2:16][CH:17]([CH2:21][C:22]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:23])[C:18]([OH:20])=O)(=[O:15])=[O:14].[NH2:31][CH:32]([CH2:46][CH3:47])[C@@H:33]([C:35]1[N:39]=[C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:37][N:36]=1)[OH:34]>C(Cl)Cl>[OH:34][CH:33]([C:35]1[N:39]=[C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:37][N:36]=1)[C@@H:32]([NH:31][C:18](=[O:20])[CH:17]([CH2:16][S:13]([CH2:12][CH:11]([CH3:10])[CH3:30])(=[O:14])=[O:15])[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:23])[CH2:46][CH3:47]
Reactant: CCC(N)[C@H](O)c1noc(-c2ccccc2)n1
Reactant: CC(C)CS(=O)(=O)CC(CC(=O)N1CCOCC1)C(=O)O
Agent: N=C=NC1CCCCC1
Solvent: ClCCl
Product: CC[C@H](NC(=O)C(CC(=O)N1CCOCC1)CS(=O)(=O)CC(C)C)C(O)c1noc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A suspension of PS-bound N-cyclohexylcarbodiimide (HL 200–400 mesh cross linked with 2% DVB) from Novabiochem (436 mg, 0.841 mmol, 1.93 mmol/g loading) in methylene chloride (6 mL) was treated with 2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyric acid (154 mg, 0.480 mmol) in methylene chloride (3 mL) and stirred at room temperature for 10 minutes. A solution of (S)-2-Amino-1-(5-phenyl-1,2,4-oxadiazol-3-yl)-butan-1-ol (96 mg, 0.412 mmol) in methylene chloride (3 mL) was added and the reaction mixture was stirred at room temperature for 3 h. The mixture was filtered and the filtrate was evaporated under reduced pressure. Crude purified by flash chromatography eluting with a mixture of ethyl acetate and heptane to give N-{(S)-1-[Hydroxy-(5-phenyl-1,2,4-oxadiazol-3-yl)-methyl]-propyl}-2-(2-methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide as an off white solid (41 mg) (mixture of diastereoisomers).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:7]1[CH:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:23][CH:24]=[CH:25][C:26]=2[NH:27][S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])=[CH:18][CH:17]=1)#[N:6].[CH3:34][NH2:35]>ClCCl>[CH3:34][NH:35][C:13]([C:11]1[CH:10]=[CH:9][C:8]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[S:23][CH:24]=[CH:25][C:26]=3[NH:27][S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])=[CH:20][CH:21]=2)=[C:7]([C:5]#[N:6])[CH:12]=1)=[O:15]
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccc(C(=O)O)cc2C#N)cc1
Reactant: CN
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CNC(=O)c1ccc(-c2ccc(-c3sccc3NS(=O)(=O)C(C)C)cc2)c(C#N)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Add thionyl chloride (0.2 mmol) to a suspension of 2-Cyano-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-4-carboxylic acid (0.1 mmol) in dichloromethane at RT. Stir mixture for 1 h at 50° C. and concentrate to dryness under reduced pressure. Add to the resultant residue 0.5 mmol MeNH2 (2M in THF). Concentrate the reaction to dryness and purify with flash chromatography (Silica gel-5%MeOH/CH2Cl2). Concentrate the desired fractions to provide the title compound. MS (ES−):438 (M−1).