Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].C=O.[CH3:10][CH:11]1[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([CH3:18])=[C:12]1[CH3:19].N[CH2:21]C(OC)=O>C(O)(=O)C.O>[CH3:18][C:13]1([CH2:21][NH:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:12]([CH3:19])=[C:11]([CH3:10])[C:15]([CH3:16])=[C:14]1[CH3:17]
Reactant: COC(=O)CN
Reactant: CC1=C(C)C(C)C(C)=C1C
Agent: C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)CNCC1(C)C(C)=C(C)C(C)=C1C
Temperature: 35 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
To a stirred mixture of methyl glycinate hydrochloride (6.28 g, 0.05 mole) in 30 mL of glacial acetic acid and 37% aqueous formaldehyde (4.1 g, 1.5 g real, 0.05 mole) is added pentamethylcyclopentadiene (6.81 g, 0.05 mole) after all of the solid methyl glycinate has dissolved. A light brown solution is initially obtained. The temperature is kept at 35° C. for five minutes with ice-bath cooling to control the exotherm. The color of the solution changes to light purple and the temperature is then kept at 33° C. for about 6 hours. This reaction mixture is combined with 100 mL of water and the aqueous phase is extracted with two×20 mL portions of methylene chloride The clear aqueous phase is then treated with 50% sodium hydroxide, with cooling to maintain a temperature of 35° C., to pH 12. The basic aqueous phase is extracted with two×30 mL portions of methylene chloride. The organic layer is concentrated in vacuo to give approximately 5.0 g of the title compound. Yield is 40%, about 80% purity, of the product which is identified by proton nuclear magnetic resonance, carbon-13 nuclear magnetic resonance and electron impact mass spectral analyses.
Reaction SMILES: [C:1]12([CH2:13][CH:12]([NH2:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[O:5]1)[CH2:4][CH2:3][CH2:2]2.[C:15]1([CH2:25][C:26]([OH:28])=O)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.[ClH:40].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[Cl:40][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[O:5][C:1]1([CH2:4][CH2:3][CH2:2]1)[CH2:13][C@H:12]2[NH:14][C:26](=[O:28])[CH2:25][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: Cl
Reactant: NC1CC2(CCC2)Oc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1cccc2ccccc12)N[C@@H]1CC2(CCC2)Oc2c(Cl)cccc21

Procedure:
The title compound was prepared from Intermediate 3 (100 mg, 0.448 mmol) and 1-naphthylacetic acid (99 mg, 0.531 mmol) in presence of EDCI.HCl (128 mg, 0.672 mmol), HOBt (102 mg, 0.672 mmol) and triethylamine (185 μl, 2.022 mmol) in dichloromethane (10 ml) as described in Example 1 to give 100 mg of the product as a white solid; IR (KBr) 3271, 2938, 1636, 1449, 1244, 778 cm−1; 1H NMR (300 MHz, CDCl3) δ 1.62-1.78 (m, 5H), 2.11-2.30 (m, 3H), 4.09 (q, J=16.8 Hz, 2H), 5.23 (q, J=9.3 Hz, 1H), 5.46 (d, J=7.8 Hz, 1H), 6.52 (t, J=7.2 Hz, 1H), 6.60 (d, J=7.2 Hz, 1H), 7.07 (d, J=7.8 Hz, 1H), 7.37-7.42 (m, 2H), 7.48-7.59 (m, 2H), 7.77 (t, J=6.3 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H); ESI-MS (m/z) 392.59 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[N:13]([CH2:17]/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C@@H:27]([CH3:36])[C:28](N4CCOCC4)=[O:29])[CH:21]=3)[CH:14]=[CH:15][CH:16]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[OH-:37].[Li+]>O1CCCC1.CO.O>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[N:13]([CH2:17]/[CH:18]=[CH:19]/[C:20]3[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=3)[O:26][C@@H:27]([CH3:36])[C:28]([OH:37])=[O:29])[CH:14]=[CH:15][CH:16]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1cccc(NC(=O)c2cccn2C/C=C/c2cccc(O[C@@H](C)C(=O)N3CCOCC3)c2)c1
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cccc(NC(=O)c2cccn2C/C=C/c2cccc(O[C@@H](C)C(=O)O)c2)c1
Yield: 88 %

Procedure:
A mixture of N-(3-ethylphenyl)-1-[(2E)-3-(3-{[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]oxy}phenyl)prop-2-enyl]-1H-pyrrole-2-carboxamide (348 mg, 0.714 mmol) in tetrahydrofuran (4 ml), methanol (4 ml) and an aqueous 1N lithium hydroxide (6 ml) was stirred for 6 hours at 50° C. The reaction mixture was diluted with water, washed with diethyl ether. The aqueous layer was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed to give the subject compound (264 mg, 88%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=2)=[N:3]1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].O>C(Cl)Cl>[CH3:1][C:2]1([CH3:21])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][O:20][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:17][CH:18]=2)=[N:3]1
Reactant: CC1(C)COC(c2ccccc2-c2ccc(CO)cc2)=N1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC1(C)COC(c2ccccc2-c2ccc(COS(C)(=O)=O)cc2)=N1
Reaction time: 3 h
Yield: 99.1 %

Procedure:
2.0 g (7.1 mmol) of 4,4-dimethyl-2-(4'-hydroxymethylbiphenyl-2-yl)oxazoline and 1.43 g (14.1 mmol) of triethylamine were dissolved in methylene chloride (20 ml). A solution of 0.98 g (8.6 mmol) of methanesulfonyl chloride in methylene chloride (10 ml) was dropwise added thereto under cooling with salt-ice. After stirring for 3 hours as such, the reaction liquid was poured into water, followed by the extraction with methylene chloride. After washing with water and drying, vacuum concentration was conducted. 2.53 g of the title compound was obtained as an oil (yield 99%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:7][CH:8]=1.O.Cl.C[N:16](C=O)C>O1CCOCC1.CCOCC>[ClH:3].[NH2:16][N:7]1[CH:8]=[C:4]([Cl:3])[CH:5]=[C:6]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(Cl)c[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)cn1N
Reaction time: 0.33 h
Yield: 85 %

Procedure:
A mixture of sodium hydride (60%, 1.51 g, 38 mmol) and methyl 4-chloro-1H-pyrrole-2-carboxylate (Tetrahedron Letters, 1979, 27, 2505–2508; 4.80 g, 30 mmol) in DMF (40 mL) at 0° C. was stirred for 20 min, then was added 2, 4-dinitrophenolamine (Tetrahedron Lett. 1968, 16, 1909–1910 and J. Heterocyclic Chem. 1967, 413, 7.24 g, 36 mmol), and the reaction mixture was stirred at rt overnight. Water (100 mL) was added to the mixture, and the product was extracted with EtOAc (3×120 mL), the EtOAc solution was washed with 10% LiCl solution (2×120 mL), brine (120 mL), dried over MgSO4 and concentrated in vacuo to give the crude product as a brown oil. This crude product was treated with 4 N HCl in dioxane (8 mL) in Et2O (60 mL), the precipitated solid was collected, washed with Et2O and dried to give the title compound (5.40 g, 85%): 1H NMR (DMSO-d6) δ 7.17 (d, 1H, J=2.2 Hz), 6.68 (d, 1H, J=2.2 Hz), 3.74 (s, 3H).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[CH2:4]1[O:9][C:7](=[O:8])[O:6][CH2:5]1.[OH-].[Tl+]>>[CH2:4]1[O:9][C:7](=[O:8])[O:6][CH2:5]1.[C:7](=[O:8])([O:6][CH2:5][CH3:4])[O:3][CH2:1][CH3:2]
Reactant: CCO
Agent: [OH-]
Agent: [Tl+]
Solvent: O=C1OCCO1
Product: CCOC(=O)OCC
Reaction time: 2 h

Procedure:
A mixture of 640 g (21.5 mols) of ethanol, 264 g (3.0 mols) of glycol carbonate and 0.1 g of thallium hydroxide is kept at 150° for 2 hours and worked up as in Example 1. A conversion of glycol carbonate to diethyl carbonate of 58% is obtained. The distillation residue is 0.11 g, which corresponds to the amount of catalyst employed; diglycol and triglycol cannot be detected in the distillate.
Reaction SMILES: [CH3:1][C:2]1([C:5]2[O:9][N:8]=[C:7]([NH2:10])[CH:6]=2)[CH2:4][CH2:3]1.C(C1C=C(N[C:20](=[O:28])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)ON=1)(C)C>>[CH3:1][C:2]1([C:5]2[O:9][N:8]=[C:7]([NH:10][C:20](=[O:28])[O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:6]=2)[CH2:4][CH2:3]1
Reactant: CC1(c2cc(N)no2)CC1
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)on1
Product: CC1(c2cc(NC(=O)Oc3ccccc3)no2)CC1
Yield: 70 %

Procedure:
Prepared from 5-(1-methylcyclopropyl)isoxazol-3-amine (80 mg, 0.58 mmol) according to the method described for phenyl 3-isopropylisoxazol-5-ylcarbamate in Example 122A Step 3, to afford phenyl 5-(1-methylcyclopropyl)isoxazol-3-ylcarbamate as a colorless solid (105 mg, 70%). 1H NMR (300 MHz, CDCl3) δ 7.87 (brs, 1H), 7.39-7.44 (m, 2H), 7.18-7.29 (m, 3H), 6.52 (s, 1H), 1.58 (s, 3H), 1.20-1.24 (m, 2H), 0.84-0.87 (m, 2H); LC-MS (ESI) m/z 259 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([S:17][CH3:18])(=[S:16])[CH2:14][CH3:15].C(O[C@H:23]1[NH:26][C:25](=[O:27])[C@@H:24]1[C@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH3:29])(=O)C>O1CCCC1.CCCCCC.CC(C)[O-].CC(C)[O-].CC(C)[O-].Cl[Ti+3]>[Si:31]([O:30][C@@H:28]([C@@H:24]1[C@@H:23]([C@H:14]([C:13]([S:17][CH3:18])=[S:16])[CH3:15])[NH:26][C:25]1=[O:27])[CH3:29])([C:34]([CH3:35])([CH3:36])[CH3:37])([CH3:32])[CH3:33]
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: CCC(=S)SC
Agent: Cl[Ti+3]
Agent: CC(C)[O-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CSC(=S)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a solution of diisopropylamine (152 mg) in anhydrous tetrahydrofuran (2 ml) cooled to 0° C. was added a 1.56M solution of n-butyllithium in n-hexane (0.95 ml). After stirring for 30 minutes at 0° C., the solution was cooled to -78° C. and methyl dithiopropionate (120 mg) and a 1M solution of chlorotitanium triisopropoxide in hexane (4.0 ml) were added successively thereto. The mixture was warmed to -40° C. and (3R,4R)-4-acetoxy-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-2-oxoazetidine (287 mg) was added thereto. The solution was allowed to warm to 0° C., quenched by 1N hydrochrolic acid, and extracted with diethyl ether. The organic layer was washed with brine, dried, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (10% diethyl ether-hexane) to afford a mixture (202 mg) of (3S,4S)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4 -[(1R)-1-[(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine and (3S,4S)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1S)-1-{(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine. Recrystallization of the product obtained above from n-hexane gave (3S,4S)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-{(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine as a yellow needle.
Reaction SMILES: [CH2:1]1[O:18][C:17]2[CH:16]=[CH:15][C:5]([O:6][C:7]3[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=3)=[CH:4][C:3]=2[O:2]1.Cl.[NH2:20][NH:21][C:22]([NH2:24])=[O:23].C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:1]1[O:18][C:17]2[CH:16]=[CH:15][C:5]([O:6][C:7]3[CH:14]=[CH:13][C:10]([CH:11]=[N:20][NH:21][C:22]([NH2:24])=[O:23])=[CH:9][CH:8]=3)=[CH:4][C:3]=2[O:2]1
Reactant: O=Cc1ccc(Oc2ccc3c(c2)OCO3)cc1
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)NN=Cc1ccc(Oc2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
To a solution of 4-(3,4-methylenedioxyphenoxy)benzaldehyde (1.7 g, 7.0 mmol) in ethanol (40 mL) was added a solution of semicarbazide hydrochloride (0.82 g, 7.1 mmol) and sodium acetate (0.55 g, 6.7 mmol) in water (10 mL). The mixture was stirred at room temperature for 30 min. The resulting white solid was collected by filtration, washed with water and dried in vacuo to yield the title compound (1.2 g, 4.0 mmol, 57%), mp: 225-226° C. 1H NMR (DMSO-d6): δ 10.17 (s, 1H), 7.80 (s, 1H), 7.70 (d, J=8.7, 2H), 6.93 (d, J=8.3, 1H), 6.92 (d, J=8.7, 2H), 6.77 (d, J=2.4, 1H), 6.53 (dd, J=2.4, 8.3, 1H), 6.44 (s, 2H), 6.06 (s, 2H).
Reaction SMILES: C1(N2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[CH3:49][C:50]1[CH:56]=[CH:55][C:54]([CH3:57])=[CH:53][C:51]=1[NH2:52]>C(O)(=O)C>[CH3:49][C:50]1[CH:56]=[CH:55][C:54]([CH3:57])=[CH:53][C:51]=1[N:52]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[N:9]=[CH:8]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: Cc1ccc(C)c(N)c1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: Cc1ccc(C)c(-n2cnc3c(-c4ccccc4)csc3c2=O)c1
Yield: 44 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (45.6 mg, 0.20 mmol), triethyl orthoformate (0.40 ml), 2,5-dimethylaniline (44.8 mg, 0.37 mmol), and acetic acid (0.05 ml) were used to give 28.8 mg (0.087 mmol, 44% yield) of the title compound.
Reaction SMILES: I[CH2:2][C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[CH2:21]([O:25][C:26]1[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][CH:27]=1)[C:22]#[C:23][CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:21]([O:25][C:26]1[CH:27]=[CH:28][C:29]([S:32][CH2:2][C:3]2([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)=[CH:30][CH:31]=1)[C:22]#[C:23][CH3:24]
Reactant: CC#CCOc1ccc(S)cc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(SCC2(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
A mixture of 0.294 g (0.74 mmol) of 1-(tert-Butyl) 4-ethyl 4-(iodomethyl)piperidine-1,4-dicarboxylate, 0.145 (0.814 mmol) of 4-but-2-ynyloxy-benzenethiol and 0.204 g (1.48 mmol) of K2CO3 in 2.0 mL of DMF was stirred at room temperature for 18 h. The resulting mixture was diluted with EtOAc, washed with H2O, brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc:Hexanes (1:19) to provide 0.328 g (99%) of the desired product as a colorless oil. Electrospray Mass Spec: 448.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH2:20]1>CN(C=O)C>[CH2:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:6]2[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:20][CH2:21]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(CNc2nc(Cl)ncc2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2,4-dichloro-5-fluoro-pyrimidine (0.67 g, 4.03 mmol) and triethylamine (0.84 mL, 6.04 mmol) in DMF (5 mL) was added benzyl 4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1) (1.00 g, 4.03 mmol). The resulting reaction solution was stirred at rt for 1 h, and concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2/IPA/hexanes) to give 4-[(2-chloro-5-fluoro-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester. M.S. (M+1): 379.25
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([OH:7])=O.Cl.[CH:9]12[O:16][CH:13]([CH2:14][CH2:15]1)[CH2:12][NH:11][CH2:10]2.CCN(C(C)C)C(C)C.Cl.[Cl:27][C:28]1[CH:29]=[C:30]([OH:48])[CH:31]=[C:32]([NH:34][C:35]2[C:36]3[C:43]4[CH2:44][CH2:45][NH:46][CH2:47][C:42]=4[S:41][C:37]=3[N:38]=[CH:39][N:40]=2)[CH:33]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.O>[Cl:27][C:28]1[CH:29]=[C:30]([OH:48])[CH:31]=[C:32]([NH:34][C:35]2[C:36]3[C:43]4[CH2:44][CH2:45][N:46]([C:5](=[O:7])/[CH:4]=[CH:3]/[CH2:2][N:11]5[CH2:10][CH:9]6[O:16][CH:13]([CH2:14][CH2:15]6)[CH2:12]5)[CH2:47][C:42]=4[S:41][C:37]=3[N:38]=[CH:39][N:40]=2)[CH:33]=1
Reactant: Oc1cc(Cl)cc(Nc2ncnc3sc4c(c23)CCNC4)c1
Reactant: C1CC2CNCC1O2
Reactant: O=C(O)/C=C/CBr
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(/C=C/CN1CC2CCC(C1)O2)N1CCc2c(sc3ncnc(Nc4cc(O)cc(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.3 %

Procedure:
(2E)-4-Bromobut-2-enoic acid (168 mg, 0.81 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (130 mg, 0.87 mmol) were dissolved in DCM (2.0 mL). DIPEA (210 mg, 1.62 mmol) was added, and the mixture was stirred at rt for 2 h. Subsequently, 3-chloro-5-(5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)phenol hydrochloride from Example 65A (200 mg, 0.54 mmol), EDCI (104 mg, 0.54 mmol) and DIPEA (140 mg, 1.08 mmol) were added, and the mixture was stirred at rt overnight. Then, the reaction mixture was diluted with water, and after separation the organic layer was washed with water. The solvent was removed in vacuo, and the crude product was purified by preparative HPLC to yield 106 mg (38%) of the title compound.
Reaction SMILES: [Br-].[Li+].C[O:4][C:5](=[O:19])[CH:6]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>CC(C)=O>[C:11]([O:10][C:8](=[O:9])[CH2:7][CH:6]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:5]([OH:19])=[O:4])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)CC(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Yield: 97.2 %

Procedure:
Anhydrous lithium bromide (25 g, 287.3 mmol) was added to a stirring mixture of 2 (15.84 g, 57.4 mmol) in acetone (150 mL) under argon, and the mixture was refluxed for 2 hours. After cooling, the acetone was evaporated under reduced pressure, and the residue was taken up in ether (100 mL), washed with water (100 mL), brine, dried (MgSO4), and the solvent was evaporated under reduced pressure to give the dibromide 3 (13.5 g, 55.8 mmol, 97%) as an orange liquid; δH (400 MHz; CDCl3): 3.5 (4H, m), 2.45 (2H, m), 2.05 (2H, m), 1.6 (2H, m).
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH:15]1([NH:18][C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:15]1([NH:18][C:19]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([C:2]3[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]4[CH2:12][CH2:11]4)=[O:7])=[CH:4][N:3]=3)[CH:21]=2)=[O:36])[CH2:16][CH2:17]1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC2CC2)cn1

Procedure:
6-Chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) (25.5 mg, 0.10 mmol) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8) (30 mg, 0.10 mmol), aqueous sodium carbonate (2N, 0.5 ml) and tetrakis(triphenylphosphine)palladium (4 mg) were heated at 90° C. in DMF (1 ml) for 3 hours. The reaction was absorbed onto silica, applied to a bond-elut (5 g, silica) and eluted with an ethylacetate/cyclohexane (0 to 100%) and then acetone. The solvent was evaporated from the product fractions under vacuum and the residue triturated with ether to 6-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-N-cyclopropylmethyl-nicotinamide as a cream solid. LCMS: retention time 2.70 min, MH+ 350. NMR: δH [2H6]-DMSO 9.11,(1H, s), 8.84,(1H, t), 8.48,(1H, d) 8.31,(1H, dd), 7.88,(1H, s), 7.81,(1H, d), 7.70,(1H, d), 7.41,(1H, d), 3.20,(1H, t), 2.86,(1H, m), 2.37,(3H, s), 1.06,(1H, m), 0.69,(2H, m), 0.57,(2H, m), 0.46,(2H, m), 0.26,(2H, m).
Reaction SMILES: [C:1]([N:8]1[CH2:18][CH2:17][CH2:16][C@@H:10]([C:11]([O:13]CC)=[O:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[OH-].Cl>CO.O>[C:1]([N:8]1[CH2:18][CH2:17][CH2:16][C@@H:10]([C:11]([OH:13])=[O:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Temperature: 4 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a solution of ethyl N-Boc-(R)-nipecotate (7.61 g, 29.6 mmol) in 25 mL of methanol was added LiOH (2.48 g, 2 eq.) in 25 mL of H2O dropwise at 4° C. The reaction mixture was stirred overnight at 4° C. The pH of the mixture was adjusted to ca. 1 by adding aqueous HCl (10% w/w). The aqueous layer was extracted with ethyl acetate (3×100 mL). The extracts were combined and washed with aqueous NH4Cl (sat., 2×50 mL), brine (50 mL), and dried over anhydrous NaSO4, filtered and evaporated to give N-Boc-(R)-nipecotic acid 25 as a white solid 6.25 g (92%).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:18]=[C:17]([F:19])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:3])[CH3:2].[C:28](Cl)(=[O:38])[C:29]1[CH:37]=[CH:36][CH:35]=[C:31]([C:32](Cl)=[O:33])[CH:30]=1.C(N(CC)CC)C.[OH:47][C:48]1[CH:53]=[CH:52][NH:51][C:50](=[O:54])[CH:49]=1>O1CCOCC1>[C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:18]=[C:17]([F:19])[C:15](=[O:16])[N:14]([C:28](=[O:38])[C:29]3[CH:37]=[CH:36][CH:35]=[C:31]([C:32]([O:47][C:48]4[CH:53]=[CH:52][N:51]=[C:50]([OH:54])[CH:49]=4)=[O:33])[CH:30]=3)[C:12]2=[O:13])[CH2:8][C@@H:7]1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccccc1
Reactant: O=c1cc(O)cc[nH]1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3cccc(C(=O)Oc4ccnc(O)c4)c3)c2=O)C[C@@H]1OCc1ccccc1
Yield: 30.1 %

Procedure:
To a solution of 3.00 g of 5'-O-acetyl-3'-O-benzyl-2'-deoxy-5-fluorouridine in 100 ml of dry dioxane were added 2.40 g of isophthaloyl chloride and 8.5 ml of triethylamine, and the mixture was refluxed for 2 hours. Then, to the reaction mixture were added a suspension of 1.77 g of 4-hydroxy-2(1H)-pyridone and 9.60 ml of triethylamine in 100 ml of dry dioxane, and the mixture was refluxed for 2 hours. The insolubles were removed by filtration and the filtrate was concentrated. The residue was dissolved in 100 ml of ethyl acetate, and the solution was washed twice with 30 ml of saturated aqueous solution of sodium chloride. The ethyl acetate layer was dried on anhydrous sodium sulfate and concentrated. The residue was placed on a silica gel column to conduct a gradient elution using chloroform and mixtures of methanol (up to 2%) and chloroform. The fractions corresponding to the title compound were collected and concentrated to dryness, giving 1.48 g of the title compound as a powder in a yield of 30%.