Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([O:16][CH3:17])[CH2:11][NH:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)=[CH:3][CH:2]=1.[C:24]([O:28][C:29]([NH:31][C@@H:32]([CH2:36][N:37]([CH2:50][CH2:51][CH2:52][CH:53]=[CH2:54])[S:38]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[N+:47]([O-:49])=[O:48])(=[O:40])=[O:39])[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:2]=[CH:3][C:4]([C@@:7]2([O:16][CH3:17])[CH2:11][N:10]([C:33](=[O:34])[C@@H:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:36][N:37]([CH2:50][CH2:51][CH2:52][CH:53]=[CH2:54])[S:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[N+:47]([O-:49])=[O:48])(=[O:40])=[O:39])[C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)=[CH:5][CH:6]=1
Reactant: C=CCCCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: COC(=O)[C@@H]1C[C@@](OC)(c2ccc(-c3ccccc3)cc2)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3)cc2)C[C@H]1C(=O)OC)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.2 %

Procedure:
A mixture of (2S,4R)-methyl 4-(biphenyl-4-yl)-4-methoxypyrrolidine-2-carboxylate (100 mg, 0.287 mmol), (S)-2-(tert-butoxycarbonylamino)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)propanoic acid (145 mg, 0.316 mmol), Hunig's Base (0.176 mL, 1.01 mmol) and HATU (131 mg, 0.345 mmol) in DCM (3 mL) was stirred at rt for 18 h. It was then concentrated in vacuo. The residue was dissolved in EtOAc and washed with dilute HCl, followed by sat.aq. NaHCO3 and water. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to yield 250 mg of the crude product as a brown oil. Purification by Biotage eluting with 60% EtOAc/Hexane gave 188 mg (87%) of (2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)propanoyl)-4-methoxypyrrolidine-2-carboxylate as an off-white foam.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].C(=O)([O-])[O-:16].[Na+].[Na+]>O.CC(C)=O>[OH:16][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(CO)c([N+](=O)[O-])c1
Yield: 95.7 %

Procedure:
4-Bromomethyl-3-nitrobenzoic acid (3.00 g, 11.5 mmol) and sodium carbonate (6.12 g, 57.7 mmol) were dissolved in water (40 mL) and acetone (40 mL). The reaction mixture was refluxed for 4 hours and then concentrated under reduced pressure to remove acetone. The residue was washed with diethyl ether three times. The aqueous layer was acidified with 6M hydrochloric acid, and then extracted with ethyl acetate three times. The combined organic layer was washed with water and brine, dried with sodium sulfate, filtered, concentrated under the reduced pressure. The residue was dried by means of a vacuum pump to give the desired product as brown solid (2.17 g, yield 95%).
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(OCC)(=O)C.ClCCl>[O:6]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:1][O:7][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: OCc1ccco1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)COCc1ccco1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine furfuryl alcohol (1 mL, 11.6 mmol) and tetrahydrofuran (20 mL). Add portionwise sodium hydride (0.57 g, 60% in oil, 14 mmol). After gas evolution ceases, add ethyl bromoacetate (1.3 mL, 11.7 mmol). Heat to reflux. After 2.5 hours cool to ambient temperature. After 18 hours, partition the reaction mixture between ethyl acetate and water. Separate the aqueous layer and extract twice with ethyl acetate. Combine the organic layers and extract with saturated aqueous sodium chloride solution, dry over Na2SO4, filter, and concentrate invacuo to give a residue. Chromatograph the residue on silica gel eluting with 1% ethyl acetate/dichloromethane to give ethyl fur-2-ylmethoxyacetate: Rf=0.62 (silica gel, 5% ethyl acetate/dichloromethane).
Reaction SMILES: [C:1]([C:5]1[O:9][C:8](=[NH:10])[N:7]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[Cl:46][C:47]1[CH:48]=[CH:49][C:50]([O:56][CH3:57])=[C:51]([CH:55]=1)[C:52](O)=[O:53]>O1CCCC1.C(OCC)(=O)C>[C:1]([C:5]1[O:9]/[C:8](=[N:10]\[C:52](=[O:53])[C:51]2[CH:55]=[C:47]([Cl:46])[CH:48]=[CH:49][C:50]=2[O:56][CH3:57])/[N:7]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)c(=N)o1
Reactant: COc1ccc(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\oc(C(C)(C)C)cn1C[C@H]1CCCO1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of Example 13B (1.24 g, 5.53 mmol) in tetrahydrofuran (10 mL) was added N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (1.06 g, 5.53 mmol), 1-hydroxybenzotriazole (0.85 g, 5.55 mmol), triethylamine (0.45 mL, 3.2 mmol) and 5-chloro-2-methoxybenzoic acid (Aldrich) (1.03 g, 5.55 mmol). The mixture was stirred at 80° C. overnight, cooled to room temperature, diluted with ethyl acetate, washed with 1 M aqueous NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in hexanes) to provide the title product. MS (ESI+) m/z 393 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 1.20 (s, 9H), 1.59-1.71 (m, 1H), 1.83-1.97 (m, 2H), 2.02-2.14 (m, 1H), 3.66 (dd, J=14.2, 7.5 Hz, 1H), 3.75-3.82 (m, 1H), 3.82 (s, 3H), 3.82-3.92 (m, 1H), 4.07 (dd, J=14.2, 2.7 Hz, 1H), 4.13-4.24 (m, 1H), 6.52 (s, 1H), 6.83 (d, J=8.8 Hz, 1H), 7.27 (dd, J=9.0, 2.7 Hz, 1H), 7.74 (d, J=2.7 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([I:12])=[CH:10][C:9](C(F)(F)F)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].NC1C=CC([O:28][C:29]([F:32])([F:31])[F:30])=CC=1C(OC)=O>>[NH2:1][C:2]1[C:11]([I:12])=[CH:10][C:9]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(OC(F)(F)F)ccc1N
Reactant: COC(=O)c1cc(C(F)(F)F)cc(I)c1N
Product: COC(=O)c1cc(OC(F)(F)F)cc(I)c1N

Procedure:
The title compound was prepared as in the method of compound 2 from methyl 2-amino-5-(trifluoromethoxy)benzoate to give a white solid (0.67 g, 82%).
Reaction SMILES: [C:1]1([CH2:7][O:8][CH:9]([C:27]([F:30])([F:29])[F:28])[CH2:10][CH:11]2[CH2:16][CH2:15][C:14]3[CH:17]=[C:18]([NH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:19]=[CH:20][C:13]=3[O:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][CH2:39][C@H]1COC(=O)O1>CN(C)C=O.O>[C:1]1([CH2:7][O:8][CH:9]([C:27]([F:30])([F:28])[F:29])[CH2:10][CH:11]2[CH2:16][CH2:15][C:14]3[CH:17]=[C:18]([N:21]4[CH2:26][C@H:25]([CH2:37][O:38][CH3:39])[O:24][C:22]4=[O:23])[CH:19]=[CH:20][C:13]=3[O:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC[C@H]1COC(=O)O1
Reactant: CCOC(=O)Nc1ccc2c(c1)CCC(CC(OCc1ccccc1)C(F)(F)F)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@H]1CN(c2ccc3c(c2)CCC(CC(OCc2ccccc2)C(F)(F)F)O3)C(=O)O1

Procedure:
A solution of 4.2 g (9.9 mmol) of 2-(2-phenylmethoxy-3,3,3-trifluoropropyl)-6-ethoxycarbonylamino-3,4-dihydro-2H-1-benzopyran in 40 ml of dimethylformamide is stirred for 24 hours, at 130° C., in the presence of 140 mg (1.0 mmol) of potassium carbonate and of 3.4 g (26 mmol) of 4(S)-methoxymethyl-1,3-dioxolan-2-one added in 3 hours. The mixture is cooled, diluted with water and the product is extracted with diethyl ether. The organic phase is then dried over sodium sulfate, concentrated under reduced pressure and chromatographed on a silica column using a 30/70 mixture of ethyl acetate and cyclohexane. The product obtained is used as such in the following step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:34]([C:31]4[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:38])[F:39])=[CH:33][CH:32]=4)(=[O:36])=[O:35])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)cc3)cc2C1=O

Procedure:
The compound of example 91 was prepared analogous to compound of example 77 by reaction of compound of example 6 with 4-trifluoromethylbenzene sulfonyl chloride. The compound of example 91 was used directly without isolation for the preparation of compound of example 92.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19](Cl)=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=3)[CH2:14][CH2:13][CH:12]2[C:26]2[CH:31]=[CH:30][C:29](Cl)=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][O:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][NH2:43])=[CH:40][CH:39]=1>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([NH:43][CH2:42][C:41]4[CH:44]=[CH:45][C:38]([O:37][CH3:36])=[CH:39][CH:40]=4)=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=3)[CH2:14][CH2:13][CH:12]2[C:26]2[CH:31]=[CH:30][C:29]([NH:43][CH2:42][C:41]3[CH:44]=[CH:45][C:38]([O:37][CH3:36])=[CH:39][CH:40]=3)=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN)cc1
Reactant: CC(C)(C)c1ccc(N2C(c3ccc(Cl)c([N+](=O)[O-])c3)CCC2c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Solvent: ClCCl
Product: COc1ccc(CNc2ccc(C3CCC(c4ccc(NCc5ccc(OC)cc5)c([N+](=O)[O-])c4)N3c3ccc(C(C)(C)C)cc3)cc2[N+](=O)[O-])cc1
Yield: 67.3 %

Procedure:
The product from Example 28D (4.41 g, 8.57 mmol) was combined, neat, with p-methoxy benzylamine (8.93 mL, 68.6 mmol) and heated at 145° C. for 1 h. The mixture was diluted with dichloromethane and filtered. The filtrate was washed with 0.5 M HCl, then NaHCO3 soln, then brine, concentrated and purified by chromatography on silica gel with an 80 g column, eluting with 0-50% ethyl acetate/hexanes to give 4.13 g (67%) of an orange foamy solid.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[O:19]([C:26]1[CH:27]=[C:28]([CH2:32][C:33](O)=[O:34])[CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:33](=[O:34])[CH2:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:27]=3)[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cccc(Oc2ccccc2)c1
Product: O=C(Cc1cccc(Oc2ccccc2)c1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(3-phenoxyphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.30 (dd, J=7.9, 1.3 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.89-7.93 (m, 1H), 7.36-7.43 (m, 3H), 7.14-7.18 (m, 2H), 7.00-7.08 (m, 3H), 6.91 (dd, J=8.2, 2.5 Hz, 1H), 3.80-3.85 (m, 4H), 3.67 (s, 2H) 3.06-3.12 (m, 4H); MS (ESI+) M/Z 457 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[N:15][C:16]([NH:19][C:20]3[N:21]=[CH:22][C:23]4[C:29]([CH3:30])=[C:28](Br)[C:27](=[O:32])[N:26]([CH:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[C:24]=4[N:25]=3)=[CH:17][CH:18]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:51]([O:53][CH2:54][CH3:55])=[CH2:52])CCC>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6](=[O:38])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[N:15][C:16]([NH:19][C:20]3[N:21]=[CH:22][C:23]4[C:29]([CH3:30])=[C:28]([C:51]([O:53][CH2:54][CH3:55])=[CH2:52])[C:27](=[O:32])[N:26]([CH:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[C:24]=4[N:25]=3)=[CH:17][CH:18]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCC(NC(=O)OC(C)(C)C)C4)cn3)ncc12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCC(NC(=O)OC(C)(C)C)C4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 110 °C
Reaction time: 12 h
Yield: 104.6 %

Procedure:
A 6-dram vial was charged with {1-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-y]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (379 mg, 0.65 mmol) and tetrakis(triphenylphosphine) palladium(0) (75 mg, 0.065 mmol) and the atmosphere replaced with argon. Toluene (5 ml) was added followed by tributyl-(1-ethoxy-vinyl)-stannane (352 mg, 0.97 mmol). The vial was heated to 110° C. and stirred for 12 h. The reaction mixture was diluted with chloroform (25 ml) and adsorbed onto silica gel. Chromatographic purification on silica gel (chloroform/2-propanol+1% TEA gradient) gave (1-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester as a yellow solid (394 mg, 0.68 mmol). MS: (APCI+) 576 (M+1, 100), 548.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]3[N:23]4[CH:24]=[CH:25][C:26]([C:28](=O)[CH3:29])=[CH:27][C:22]4=[N:21][CH:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1.Cl.[NH2:32][OH:33].N1C=CC=CC=1>CCO>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]3[N:23]4[CH:24]=[CH:25][C:26]([C:28](=[N:32][OH:33])[CH3:29])=[CH:27][C:22]4=[N:21][CH:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CC(=O)c1ccn2c(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)cnc2c1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NO)c1ccn2c(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)cnc2c1
Temperature: 90 °C
Yield: 55.6 %

Procedure:
To a stirred solution of 1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)ethanone (40 mg, 0.095 mmol) from Example 200 in EtOH (2 mL) at rt were added hydroxylamine hydrochloride (120 mg, excess) and pyridine (200 μL, excess). The mixture was heated at 90° C. for 1 h, and then cooled to rt. Purification by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH), CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase afforded 1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)ethanone oxime (23 mg, 61%) as yellow powder. 1H NMR (500 MHz, DMSO-d6) δ 11.46 (br s, 1H), 8.13 (d, J=7.4 Hz, 1H), 7.90 (d, J=7.4 Hz, 1H), 7.72 (s, 1H), 7.51 (s, 1H), 7.45 (s, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.44-6.58 (m, 1H), 5.89 (s, 1H), 4.78 (d, J=2.5 Hz, 1H), 4.29 (s, 2H), 3.50 (br s, 1H), 2.18 (s, 3H), 2.04 (d, J=12.3 Hz, 1H), 1.87 (d, J=10.8 Hz, 1H), 1.56-1.67 (m, 2H), 1.15-1.32 (m, 4H). LCMS (ESI) m/z 436 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].[Br:7][C:8]1[CH:17]=[C:16]2[C:11]([N:12]=[CH:13][C:14](Cl)=[N:15]2)=[CH:10][CH:9]=1>CN(C=O)C.C(Cl)(Cl)Cl.C(O)(C)C>[Br:7][C:8]1[CH:17]=[C:16]2[C:11]([N:12]=[CH:13][C:14]([O:5][CH2:4][CH2:3][OH:6])=[N:15]2)=[CH:10][CH:9]=1
Reactant: OCCO
Reactant: Clc1cnc2ccc(Br)cc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: OCCOc1cnc2ccc(Br)cc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
Suspend sodium hydride (310 mg, 13 mmol) in a solution of ethylene glycol (800 mg, 13 mmol) in DMF (50 mL) previously cooled to 0° C. Allow the mixture to warm to room temperature and stir for 30 min. Add 7-bromo-2-chloroquinoxaline (610 mg, 2.5 mmol) and stir the resulting mixture for 2 h at room temperature. Dilute the mixture with 3:1 chloroform/isopropyl alcohol and wash the resulting solution with saturated sodium chloride solution. Dry and concentrate the organic phase in vacuo and purify the residue via silica gel chromatography to provide 564 mg (85%) of the titled compound. MS ES+ m/e 268 (M+1). 1H NMR (400 MHz, CDCl3) δ 8. (s, 1H), 8.0 (d, J=2.0 Hz, 1H), 7.90 (dd, J=8.8, 2.0 Hz, 1H), 7.7 (d, J=8.8 Hz, 1H), 4.6 (t, J=4.8 Hz, 2H), 4.39 (t, J=4.8 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[N:6][CH:7]=1.[OH-].[NH4+:11]>CO.[Cu]Br>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([NH2:11])[CH:7]=[N:6][CH:5]=1
Reactant: [NH4+]
Reactant: COc1cncc(Br)c1
Agent: [Cu]Br
Agent: [OH-]
Solvent: CO
Product: COc1cncc(N)c1
Temperature: 171 °C

Procedure:
Crude 5-bromo-3-methoxypyridine (3.50 g, 18.62 mmol) was dissolved in methanol (50 mL) and added to concentrated ammonium hydroxide (29.7%, 14.8 M, 50 mL) and copper(I) bromide (2.67 g, 18.62 mmol) in a heavy-walled glass pressure-tube apparatus. The tube was flushed with nitrogen and sealed. The mixture Was stirred and heated at 170-172° C. (oil bath temperature) for 24 h. After cooling, the solution was concentrated by rotary evaporation to a gummy residue. The residue was diluted with sodium carbonate solution (17.6%, 200 mL) and extracted with CH2Cl2 (4×50 mL). The combined CH2Cl2 extracts were dried (MgSO4), filtered, and concentrated by rotary evaporation to give 1.26 g of a cream-brown solid. The aqueous phase was re-extracted with CH2Cl2 (4×50 mL). The combined CH2Cl2 extracts were similarly dried and concentrated to give an additional 0.34 g of a cream-brown solid, bringing the total yield to 1.60 g (69.2%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=[CH2:8])[CH:2]1[O:4][CH2:3]1.[CH3:9][C:10]([NH2:21])([CH3:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>>[OH:4][CH:2]([CH2:1][O:5][CH2:6][CH:7]=[CH2:8])[CH2:3][NH:21][C:10]([CH3:20])([CH3:9])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: C=CCOCC1CO1
Reactant: COc1ccc(CC(C)(C)N)cc1
Product: C=CCOCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Yield: 26.9 %

Procedure:
Using the method of Example 15, supra, allyl glycidyl ether (119 μL, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 79 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 294 (M+1, 0.1), 278 (0.9), 222 (1.5), 172 (100), 163 (11), 121 (20); 1H-NMR (CDCl3) δ 7.04 (2H, d, J=8.6), 6.79 (2H, d, J=8.6), 5.85 (1H, ddd, J=22.2, 10.5 and 5.7), 5.23 (1H, dd, J=17.3 and 1.5), 5.14 (1H, dd, J=10.3 and 1.5), 3.96 (2H, d, J=5.7), 3.74 (4H, m), 3.43 (2H, d, J=5.7), 2.83 (1H, broad s), 2.77 (1H, dd, J=11.7 and 4.1), 2.62 (5H, m), 1.02 (3H, s), 1.01 (3H, S); 13C-NMR (CDCl3) δ 158.0, 134.5, 131.3, 129.9, 117.0, 113.3, 72.8, 72.2; 69.0, 55.0, 53.3, 46.3, 44.5, 26.6, 26.4.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[O:10][C:9]([CH:11]=O)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[N:13]1([CH2:11][C:9]2[O:10][C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])=[CH:7][CH:8]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: CC(=O)OCc1ccc(C=O)o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(=O)OCc1ccc(CN2CCOCC2)o1
Reaction time: 3 h

Procedure:
Under nitrogen atmosphere, to a solution of 2.0 g of 5-acetoxymethyl-2-furanaldehyde and 1.1 mL of morpholine in 35 mL of 1,2-dichloroethane was added 4.0 g of sodium triacetoxy borohydride at room temperature, and stirred at this temperature for 3 hours. The reaction solution was diluted with dichloromethane, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified and separated by silica gel column chromatography, to afford 2.3 g of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:10]2[CH2:21][CH2:20][C:19]3[C:18]4[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15][C:14]=4[S:13][C:12]=3[C:11]2=[O:24])[C:7]=1[CH:8]=[O:9].[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([CH:54]4[CH2:57][O:56][CH2:55]4)[CH2:50][CH2:49]3)=[CH:44][N:43]=2)[C:27]1=[O:58].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:25][N:26]1[C:27](=[O:58])[C:28]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([CH:54]4[CH2:55][O:56][CH2:57]4)[CH2:50][CH2:49]3)=[CH:44][N:43]=2)=[CH:29][C:30]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([N:10]3[CH2:21][CH2:20][C:19]4[C:18]5[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15][C:14]=5[S:13][C:12]=4[C:11]3=[O:24])[C:7]=2[CH:8]=[O:9])=[CH:31]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reactant: CC1(C)Cc2sc3c(c2C1)CCN(c1cncc(Br)c1C=O)C3=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: Cn1cc(-c2cncc(N3CCc4c(sc5c4CC(C)(C)C5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 100 °C
Yield: 39.1 %

Procedure:
A sealed tube was charged with 106i (200 mg, 0.50 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl) piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 101l (240 mg, 0.51 mmol), PdCl2(dppf) (42 mg, 0.05 mmol), K3PO4 (230 mg, 1 mmol), and NaOAc (80 mg, 1 mmol) in CH3CN (5 mL) and H2O (1.5 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 10:1 DCM/MeOH to afford 106j (130 mg, 40%) as a pale yellow solid. MS: [M+H]+ 666.