Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH3:36][S:37](Cl)(=[O:39])=[O:38].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(N)cc2CN(CC)C(=O)OCc2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(NS(C)(=O)=O)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
{4′-Amino-2′-[(benzyloxycarbonyl-ethyl-amino)-methyl]-6-methoxy-biphenyl-3-yl}-acetic acid ethyl ester (0.080 g, 0.2 mmol), methanesulfonyl chloride (0.04 mL, 0.3 mmol), and triethylamine were reacted in CH2Cl2 to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Li]C(C)(C)C.[Br:14][C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=1)[C:18](N(C)C)=[O:19].O>C1COCC1.CCCCC>[Br:14][C:15]1[CH:16]=[C:17]([C:18]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[O:19])[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1ccc(Br)cc1
Reactant: CN(C)C(=O)c1cccc(Br)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: O
Product: Cc1ccc(C(=O)c2cccc(Br)c2)cc1
Temperature: -80 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
To a solution of 38.5 g (0.225 mol) of 4-bromotoluene in 450 mL of THF, 300 mL (0.450 mol) of 1.5 M tBuLi in pentane was added dropwise with vigorous stirring for 2 hr at −80° C. This mixture was slowly warmed to room temperature and additionally stirred at this temperature for 30 min. To this mixture 52.0 g (0.23 mol) of 3-bromo-N,N-dimethylbenzamide was added at 0° C., and then this mixture was stirred for 12 hr at room temperature. Later, 300 mL of water was added, organic solvent was evaporated using a rotary evaporator. The product was extracted with 2×200 mL of dichloromethane. The combined organic extracts were evaporated to dryness, and the residue was dried in vacuum. This procedure gave 51.3 g (83%) of 40 which was further used without additional purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:45])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH:35]=2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:45])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([N:40]3[CH2:41][CH2:42][CH2:43][CH2:44]3)[CH:35]=2)[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(N3CCCC3)c2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(N3CCCC3)c2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (214 mg, 0.75 mmol) and 3-oxo-3-[3-(2-pyrrolidin-1-yl-pyridin-4-yl)-phenyl]-propionic acid tert-butyl ester (Example K63) (275 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white amorphous substance (334 mg, 78%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH2:12])[CH3:2].[C:14](Cl)(=[O:16])[CH3:15]>N1C=CC=CC=1.O>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH:12][C:14](=[O:16])[CH3:15])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1ccc(F)cc1N
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(F)cc1NC(C)=O
Reaction time: 1 h

Procedure:
A total of 3.84 g of 2-amino-4-fluoro-benzoic acid ethyl ester obtained in Production Example II-7-a was dissolved in 50 ml of pyridine, 1.64 ml of acetyl chloride was added under ice-cooling, and the mixture was stirred for 1 hours. The reaction mixture was diluted with water and was extracted with diethyl ether. The resulting organic layer was washed with 1 N hydrochloric acid and brine, dried over magnesium sulfate, and then evaporated, to give 4.0 g of the title compound.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:13]([NH2:16])(=[O:15])=[O:14])[CH:5]=[N:4][CH:3]=[N:2]1.C1([O:23][C:24](=O)[NH:25][C:26]2[N:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[N:27]=2)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1.O>[CH3:33][O:32][C:30]1[CH:29]=[C:28]([O:34][CH3:35])[N:27]=[C:26]([NH:25][C:24]([NH:16][S:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:1]2[CH2:5][N:4]=[CH:3][NH:2]2)(=[O:15])=[O:14])=[O:23])[N:31]=1
Reactant: NS(=O)(=O)c1ccccc1Cn1cncn1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2CN2CN=CN2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
By the procedure of Example 4, 0.4 g of the product of Example 7 was reacted with 0.52 g of phenyl(4,6-dimethoxypyrimidin-2-yl)carbamate and 0.26 g of "DBU" in 10 ml of p-dioxane. After stirring at 25° C. for two hours, the resulting suspension was diluted with about 50 ml of water, and filtered; the resulting filtrate was acidified with concentrated hydrochloric acid to pH 4, then filtered. The residue was washed 2×10 ml water, suction-dried 16 hours, then triturated with about 10 ml of warm ethyl acetate to yield 0.5 g of the subject compound; m.p. 219°-220° C. IR(nujol): 1690 cm-1 (c=o); NMR(CDCl3): ppm 3.9(S, 6H, OCH3); 5.8(S, 1H, py H); 6.0(S, 2H, CH2); 7.9 and 8.2(2S, 2H, tri 2H); 7.1-7.6(m, 4H, Ar+NH); 8.15(m, 1H, Ar).
Reaction SMILES: [Li]CCCC.CCCCCC.CC1(C)CCCC(C)(C)N1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([OH:28])=[O:27].[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([N:42]([C:46]2[C:47]([CH:53]=O)=[N:48][CH:49]=[C:50]([Cl:52])[CH:51]=2)[CH2:43][O:44][CH3:45])(=[O:41])=[O:40])=[CH:35][C:34]=1[C:55]([F:58])([F:57])[F:56]>C1COCC1.CCOCC>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([N:42]([C:46]2[C:47]([CH:53]3[C:24]4[C:25](=[CH:29][CH:30]=[CH:31][C:23]=4[Cl:22])[C:26](=[O:28])[O:27]3)=[N:48][CH:49]=[C:50]([Cl:52])[CH:51]=2)[CH2:43][O:44][CH3:45])(=[O:41])=[O:40])=[CH:35][C:34]=1[C:55]([F:56])([F:58])[F:57]
Reactant: COCN(c1cc(Cl)cnc1C=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C(O)c1cccc(Cl)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C1OC(=O)c2cccc(Cl)c21)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: -50 °C
Reaction time: 4 h
Yield: 26.5 %

Procedure:
To a solution of n-BuLi in hexane (0.69 mL, 1.1 mmol, 1.6 M solution in hexane) under N2 atm at −20° C. was added a solution of 2,2,6,6-tetramethyl piperidine (TMP, 187 μL) in THF (1 mL). The mixture cooled to −50° C. and a solution of 3-chlorobenzoic acid (78.3 mg, 0.5 mmol) in THF (0.5 mL) was added. The resulting reaction mixture was stirred at −50° C. for 4 h and treated slowly with 4-chloro-N-(5-chloro-2-formyl-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (884 mg, 2.0 mmol) in THF (1 mL), warmed to room temperature and stirred for 2 h. The reaction mixture was slowly poured in ice cold water (10 mL), and ether was added. The bilayer was separated and the aqueous portion was washed with diethyl ether (2×25 mL) and separated. The aqueous layer was acidified with 4 N HCl solutions to pH 2 and extracted with diethyl ether (2×25 mL). The combined organic extracts were dried (Na2SO4), filtered and evaporated. The residual solid was dissolved in CH2Cl2 (5 mL), treated with p-toluenesulfonic acid monohydrate (100 mg), and stirred at room temperature for 2 h. The reaction mixture was concentrated and purified by flash chromatography (25% EtOAc in hexanes) to obtain 4-chloro-N-[5-chloro-2-(7-chloro-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (77 mg) in 26.6% yield. MS m/z: 581 (M+H).
Reaction SMILES: [Cl-].[Na+].[Cl-].[Cl-].[Cl-].[Al+3].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:18])[CH2:15][CH2:16]Cl)=[C:10]([F:19])[CH:9]=1>Cl>[Br:7][C:8]1[CH:13]=[C:12]2[C:11](=[C:10]([F:19])[CH:9]=1)[C:14](=[O:18])[CH2:15][CH2:16]2
Reactant: O=C(CCCl)c1ccc(Br)cc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCc2cc(Br)cc(F)c21
Temperature: 180 °C
Yield: 30.4 %

Procedure:
A mixture of sodium chloride (333 g, 5.69 mol) and aluminum trichloride (1270 g, 9.52 mol) was added to 144c (210 g, 0.79 mol) in several portions at 130° C. See FIG. 3. The neat reaction mixture was then stirred at 180° C. After 5 h the reaction mixture was poured into a stirred solution of ice water (1000 mL) and concentrated HCl (100 mL). The quenched reaction was stirred for 40 min and then extracted with DCM (4000 mL×3). The combined organic phase was washed with saturated NaHCO3 solution (1000 mL), brine (2000 mL×2), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EA=50/1, 10/1) to afford 55.0 g (30.4%) of 5-bromo-7-fluoro-2,3-dihydro-1H-inden-1-one 144d. 1H NMR (400 MHz, CDCl3) δ 7.37 (s, 1H), 7.10-7.12 (d, J=8.4 Hz, 1H), 3.04-3.10 (m, 2H), 2.50-2.66 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[N:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[N:14][CH:13]=1.NC1N=CC(C2SC(CN3CCCCC3)=CC=2)=CC=1C(NC1C=CN=CC=1)=O>>[NH2:1][C:2]1[C:7]([C:8]([NH:18][C:15]2[CH:16]=[CH:17][N:12]=[CH:13][N:14]=2)=[O:10])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: Nc1ccncn1
Agent: Nc1ncc(-c2ccc(CN3CCCCC3)s2)cc1C(=O)Nc1ccncc1
Product: Nc1ncc(Br)cc1C(=O)Nc1ccncn1

Procedure:
6.1 Reaction of 2-amino-5-bromo-pyridine-3-carboxylic acid with pyrimidin-4-amine according to the synthesis described for “A1” step 1, gives 2-amino-5-bromo-N-pyrimidin-4-yl-pyridine-3-carboxamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19]2)[N:3]=1.[NH2:25][C:26]1[CH:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:23][C:20]1([F:24])[CH2:21][CH2:22][N:18]([C:4]2[N:3]=[C:2]([NH:25][C:26]3[CH:31]=[C:30]([CH:29]=[CH:28][N:27]=3)[C:32]#[N:33])[CH:7]=[C:6]([CH:8]3[CH2:13][CH2:12][N:11]([CH:14]4[CH2:17][O:16][CH2:15]4)[CH2:10][CH2:9]3)[CH:5]=2)[CH2:19]1
Reactant: FC1(F)CCN(c2cc(C3CCN(C4COC4)CC3)cc(Cl)n2)C1
Reactant: N#Cc1ccnc(N)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1ccnc(Nc2cc(C3CCN(C4COC4)CC3)cc(N3CCC(F)(F)C3)n2)c1
Temperature: 25 °C
Yield: 77 %

Procedure:
To a 50-mL recovery flask charged with 2-chloro-6-(3,3-difluoropyrrolidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridine (216 mg, 0.603 mmol, 1 equiv), 2-amino-4-cyanopyridine (122 mg, 1.03 mmol, 1.70 equiv), cesium carbonate (399 mg, 1.22 mmol, 2.03 equiv) in 1,4-dioxane was added tris(dibenzylideneacetone)dipalladium(0) (28 mg, 0.031 mmol, 0.051 equiv). The reaction flask was fitted with a microreflux condenser, and the reaction mixture was heated at reflux under nitrogen for 13 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (10 mL). The organic was separated and the aqueous wash was further extracted with ethyl acetate (2×10 mL). The combined organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (3% methanol in dichloromethane+0.1% ammonium hydroxide) provided product as a yellow solid (205 mg (77% yield). 1H NMR (400 MHz, DMSO-d6), δ: 9.72 (s, 1H), 8.46 (s, 1H), 8.41 (d, J=5.0 Hz, 1H), 7.20 (dd, J=5.1, 1.2 Hz, 1H), 6.60 (s, 1H), 6.00 (s, 1H), 4.54 (t, J=6.4 Hz, 2H), 4.44 (t, J=6.0 Hz, 2H), 3.85 (t, J=13.2 Hz, 2H), 3.65 (t, J=7.2 Hz, 2H), 3.40 (m, 1H), 2.80 (m, 2H), 2.56 (m, 2H), 2.39 (m, 1H), 1.84 (m, 2H), 1.61-1.76 (m, 4H). m/z (ESI-pos) M+1=441
Reaction SMILES: CN(C)C=O.[H-].[Na+].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][N:14]=[C:13]2[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:38])[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1.[CH2:39](I)[CH3:40]>O>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][N:14]=[C:13]2[O:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]([CH2:39][CH3:40])[C:30](=[O:38])[O:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)=[CH:27][CH:28]=1
Reactant: CCI
Reactant: COc1cc2ncnc(Oc3ccc(NC(=O)OC4CCCCC4)cc3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(=O)OC1CCCCC1)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (7 mg), and cyclohexyl N-{4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (35 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of ethyl iodide (52 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (35 mg, yield 93%).
Reaction SMILES: [Cl:1][C:2]([O:4]C(Cl)(Cl)Cl)=O.[F:9][C:10]([F:46])([F:45])[C:11]1[CH:12]=[C:13]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:14][N:15]([C@@H:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[N:30]=2)[NH:25][C@H:24]([CH2:36][CH3:37])[CH2:23]1)[C:16]1[N:17]=[N:18][N:19]([CH3:21])[N:20]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:46][C:10]([F:9])([F:45])[C:11]1[CH:12]=[C:13]([CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:40]=1)[CH2:14][N:15]([C:16]1[N:17]=[N:18][N:19]([CH3:21])[N:20]=1)[C@@H:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:33])([F:34])[F:35])[N:30]=2)[N:25]([C:2]([Cl:1])=[O:4])[C@H:24]([CH2:36][CH3:37])[CH2:23]1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2nc(C(F)(F)F)ccc2N1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2nc(C(F)(F)F)ccc2N1C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
Add trichloromethyl chloroformate (0.36 mL, 3.02 mmol) to a solution of (2R,4S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-[1,5]naphthyridin-4-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (1.67 g, 3.02 mmol) and triethylamine (0.84 mL, 6.04 mmol) in toluene (19 mL). Stir the mixture at room temperature under nitrogen for 3 h, then add more triethylamine (0.50 mL, 3.6 mmol) and trichloromethyl chloroformate (0.21 mL, 1.8 mmol). Stir the mixture overnight. Evaporate the solvent and purify the residue by silica gel chromatography (elution with hexane/ethyl acetate) to afford the title compound (1.83 g, 98%). MS (ES+): 616 (M+H).
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([C:14]#[N:15])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:37]2[C@H:38]([CH3:61])[C@H:39]3[C@@H:56]([C@H:57]([OH:59])[CH3:58])[C:55](=[O:60])[N:40]3[C:41]=2[C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][C:49]([N+:52]([O-:54])=[O:53])=[CH:48][CH:47]=2)=[O:43])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[C:14]([C:12]1[N:13]=[C:9]([N:7]2[CH2:8][CH:5]([S:4][C:37]3[C@H:38]([CH3:61])[C@@H:39]4[C@@H:56]([C@H:57]([OH:59])[CH3:58])[C:55](=[O:60])[N:40]4[C:41]=3[C:42]([O:44][CH2:45][C:46]3[CH:47]=[CH:48][C:49]([N+:52]([O-:54])=[O:53])=[CH:50][CH:51]=3)=[O:43])[CH2:6]2)[S:10][CH:11]=1)#[N:15]
Reactant: CC(=O)SC1CN(c2nc(C#N)cs2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C#N)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a solution of 3-acetylthio-1-(4-cyano-1,3-thiazol-2-yl)azetidine (760 mg, 3.18 mmol) (obtained as described in Reference Example 4) in dimethylformamide (38 ml) was added hydrazine acetate (351 mg, 3.81 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-diphenylphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.89 g, 3.18 mmol) in acetonitrile (95 ml) was added dropwise to the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (2.21 ml, 12.7 mmol). The mixture was stirred for 4 hours while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M aqueous sodium chloride solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:4) and ethyl acetate as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-[1-(4-cyano-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate as a pale yellow solid (1.65 g, yield 96%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[C:4]#[CH:5].Cl[C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=[CH:10][N:9]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:15]([O:14][C:12]1[CH:13]=[C:8]([O:6][CH2:3][C:4]#[CH:5])[N:9]=[CH:10][N:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C#CCO
Reactant: Clc1cc(OCc2ccccc2)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CCOc1cc(OCc2ccccc2)ncn1
Temperature: 25 °C
Yield: 39 %

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.13 g of sodium hydride (60% in oil), to which 0.7 ml of a tetrahydrofuran solution containing 0.12 g of 2-propyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes and then cooled to 0° C., to which 0.7 ml of a tetrahydrofuran solution containing 0.4 g of 4-chloro-6-benzyloxypyrimidine was slowly added dropwise. The mixture was further stirred at 0° C. for 4.5 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.17 g of 4-benzyloxy-6-(2-propynyloxy)pyrimidine (the present compound (13)).
Reaction SMILES: N1C=CC=CC=1.Cl.[CH3:8][O:9][C:10](=[O:13])[CH2:11][NH2:12].[CH:14]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20])=[O:15]>O1CCCC1>[CH3:8][O:9][C:10]([CH2:11][NH:12][C:14]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[CH:19]=[O:20])=[O:15])=[O:13]
Reactant: O=Cc1cccc(C(=O)Cl)c1
Reactant: COC(=O)CN
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)CNC(=O)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 20.1 %

Procedure:
To a mixture of 200 ml of tetrahydrofuran, 26.00 g of pyridine and 20.70 g of glycine methyl ester hydrochloride was added a solution of 16.00 g of 3-formylbenzoic acid chloride in 20 ml of tetrahydrofuran at 10° C. After stirred at room temperature for 60 hours, insolubles were filtered and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 4.23 g of oily 3-[[(methyoxycarbonylmethyl)amino]carbonyl]benzaldehyde [Compound No. (b)].
Reaction SMILES: [F:1][CH:2]([F:20])[C:3]1[CH:8]=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[C:5]([O:18][CH3:19])[CH:4]=1.[Br:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26](Cl)=[N:27][C:28]([CH3:32])=[N:29]2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C(Cl)Cl.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].C(Cl)Cl>[Br:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26]([C:6]3[CH:7]=[CH:8][C:3]([CH:2]([F:1])[F:20])=[CH:4][C:5]=3[O:18][CH3:19])=[N:27][C:28]([CH3:32])=[N:29]2)=[CH:24][CH:23]=1
Reactant: Cc1nc(Cl)c2ccc(Br)cc2n1
Reactant: COc1cc(C(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(C(F)F)ccc1-c1nc(C)nc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of PdCl2(dppf)-CH2Cl2 adduct (0.095 g, 0.116 mmol), 2-(4-(difluoromethyl)-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate TTT) (0.863 g, 4.27 mmol), 7-bromo-4-chloro-2-methylquinazoline (ACES Pharma, 1.000 g, 3.88 mmol), and potassium carbonate (2.147 g, 15.53 mmol) in 12 mL dioxane was treated with 4 mL water and was allowed to stir at room temperature overnight. LC/MS showed mostly product, so the reaction mixture was diluted with DCM and filtered through a plug of Celite. The aqueous layer was removed and the organics concentrated. The crude residue was carried on to step 2 without purification. (M+H)+=381.0.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([F:10])[CH:3]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)=[C:4]([F:10])[CH:3]=1
Reactant: OCc1ccc(Br)cc1F
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: Fc1cc(Br)ccc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.4 %

Procedure:
Mix under nitrogen atmosphere 4-bromo-2-fluorobenzyl alcohol, (4.1 g, 20 mmol), dihydropyran (2 g, 24 mmol), p-toluenesulfonic acid monohydrate (100 mg, 0.52 mmol), and anhydrous DCM (70 mL). Stir for 16 h at ambient temperature. Dilute with DCM, wash sequentially with saturated aqueous NaHCO3 then brine. Separate the organic layer, dry over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain the desired intermediate as a clear oil (4.36 g, 75%). MS (ES+) m/z: 312 (M+Na)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:14]([NH:16][O:17][CH3:18])=[O:15])[C:3]=1[C:23]#[N:24].Cl.[CH3:26][NH:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30].CCN(C(C)C)C(C)C>C1COCC1>[C:23]([C:3]1[C:4]([NH:10][C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:14]([NH:16][O:17][CH3:18])=[O:15])=[N:5][C:6]([S:8][CH3:9])=[N:7][C:2]=1[N:27]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:26])#[N:24]
Reactant: CNCC(C)(C)C
Reactant: CONC(=O)c1ccc(C)c(Nc2nc(SC)nc(Cl)c2C#N)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)c1ccc(C)c(Nc2nc(SC)nc(N(C)CC(C)(C)C)c2C#N)c1
Yield: 44.4 %

Procedure:
3-(6-Chloro-5-cyano-2-methylsulfanyl-pyrimidin-4-ylamino)-N-methoxy-4-methyl-benzamide (3.33 g, 9.2 mmol), N-methyl-neopentylamine hydrochloride (2.05 g, 15 mmol) and DIEA (3.87 g, 30 mmol) in THF (10 mL) were heated to 60° C. for overnight. The solvent was removed in vacuo and the product (1.75 g) was obtained after purification by silica gel column chromatography.