Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.P(Cl)(Cl)([Cl:21])=O>CN(C)C1C=CC=CC=1>[Cl:21][C:6]1[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=[C:2]([CH3:1])[N:7]=1
Reactant: CCOC(=O)Cc1c(C(F)(F)F)nc(C)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)Cc1c(Cl)nc(C)nc1C(F)(F)F
Yield: 98 %

Procedure:
A solution of ethyl (2-methyl-6-trifluoromethyl-3H-pyrimidin-4-on-5-yl)acetate (2.50 g, 9.46 mmol), N,N-dimethylaniline (3 drops), and phosphorus oxychloride (35 mL) was heated under reflux for 4.5 h. The mixture was concentrated, cooled, and ice water was added. Solid KOH was added to neutralize the mixture and it was extracted with ether. The combined extracts were washed with brine, dried (MgSO4), and concentrated to give 2.61 g (98%) of product as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Br[CH2:10][CH2:11][CH2:12][O:13][CH3:14].[C:15]12([C:25](O)=[O:26])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2>>[CH3:14][O:13][CH2:12][CH2:11][CH2:10][N:3]1[C:2]([CH3:1])=[C:6]([CH3:7])[S:5]/[C:4]/1=[N:8]\[C:25]([C:15]12[CH2:24][CH:19]3[CH2:18][CH:17]([CH2:23][CH:21]([CH2:20]3)[CH2:22]1)[CH2:16]2)=[O:26]
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1nc(N)sc1C
Reactant: COCCCBr
Product: COCCCn1c(C)c(C)s/c1=N\C(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 85 °C
Yield: 46 %

Procedure:
A mixture of 4,5-dimethyl-thiazol-2-ylamine (0.20 g, 1.6 mmol) and 1-bromo-3-methoxypropane (0.28 g, 1.7 mmol) was heated at 85° C. for 14 hours. After cooling to ambient temperature, the unpurified residue (0.31 g, 1.1 mmol) and adamantane-1-carboxylic acid (0.22 g, 1.2 mmol) were processed as described in Example 3B. Purification by column chromatography (SiO2, 20-40% ethyl acetate/hexanes gradient) afforded 0.20 g (50%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 1.69-1.79 (m, 6H), 1.90-2.00 (m, 6H), 2.00-2.10 (m, 5H), 2.18 (s, 3H), 2.19 (s, 3H), 3.33 (s, 3H), 3.40 (t, J=5.9 Hz, 2H), 4.22 (s, 2H); MS (DCI/NH3) m/z 363 (M+H)+. Anal. Calculated for C20H30N2O2S: C, 66.26; H, 8.34; N, 7.73. Found: C, 66.00; H, 8.60; N, 7.37.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[C:16]1([C:22]2[N:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O.O1CCCC1.CCCCCC>[OH:37][CH:30]([C:26]1[CH:27]=[C:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:23]=[N:24][C:25]=1[O:28][CH3:29])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1ccc(-c2ccccc2)nn1
Reactant: O=Cc1ccccc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1nnc(-c2ccccc2)cc1C(O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
7,7 ml of a hexane solution containing 1.52 mol of normal butyllithium was slowly added dropwise into a solution of 50 ml of tetrahydrofuran containing 2.0 ml of 2,2,6,6-tetramethylpiperidine under ice-cooling. After stirring for one hour under ice-cooling, it was cooled to −78° C. and 10 ml of a tetrahydrofuran solution containing 1.68 g of 3-phenyl-6-methoxypyridazine was slowly added dropwise thereinto. After stirirng at −78° C. for 2 hours, benzaldehyde was slowly added dropwise thereinto. After stirring at −78° C. for further 30 minutes, it was stirred at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate and the organic phase was washed with brine. After removing the solvent, the residue was subjected to NH-silica gel (Fuji Silicia) chromatography and eluted with hexane/ethyl acetate (3:1) and then with hexane/ethyl acetate (1:1), to give 1.39 g of the target compound.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[C:25]([Cl:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:33]4[S:34][CH:35]=[C:36]([CH:38]([CH3:40])[CH3:39])[N:37]=4)[CH:21]=3)[CH2:16][N:15]2[C:41](=[O:52])[C:42]([CH3:51])([CH3:50])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[CH2:49])=[O:13])[CH2:8][CH:7]1C=C)=[O:5])C.C(C1N=C(C2C=C(OC3CC4N(C(=O)CCCCCCC=CC5C(C(O)=O)(NC4=O)C5)C3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[Cl:32][C:25]1[C:26]([O:30][CH3:31])=[CH:27][CH:28]=[C:29]2[C:24]=1[N:23]=[C:22]([C:33]1[S:34][CH:35]=[C:36]([CH:38]([CH3:39])[CH3:40])[N:37]=1)[CH:21]=[C:20]2[O:19][CH:17]1[CH2:18][CH:14]2[N:15]([C:41](=[O:52])[C:42]([CH3:51])([CH3:50])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[CH:49][CH:8]3[C:6]([C:4]([OH:3])=[O:5])([NH:11][C:12]2=[O:13])[CH2:7]3)[CH2:16]1
Reactant: C=CCCCCCC(C)(C)C(=O)N1CC(Oc2cc(-c3nc(C(C)C)cs3)nc3c(Cl)c(OC)ccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCC(C)(C)C(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl

Procedure:
The title compound was prepared from 1-[[4-[8-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-1-(2,2-dimethylnon-8-enoyl)pyrrolidine-2-carbonyl]amino]-2-vinylcyclopropanecarboxylic acid ethyl ester (53) following the procedure (Steps G and H) reported for 18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid 10: m/z=695 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([N:29]2[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30]2)[N:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:27]2[CH:28]=[CH:23][N:24]=[C:25]([N:29]3[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30]3)[N:26]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: OC1CCN(c2nccc(Cl)n2)C1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccnc(N4CCC(O)C4)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide and 1-(4-chloropyrimidin-2-yl)pyrrolidin-3-ol as the starting materials.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8](O)=[S:9])=[N:5][N:4]=[N:3]1.S(Cl)([Cl:13])=O>C1C=CC=CC=1.CN(C)C=O>[CH3:1][N:2]1[C:6]([CH2:7][C:8]([Cl:13])=[S:9])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1CC(O)=S
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: Cn1nnnc1CC(=S)Cl

Procedure:
To a suspension of (1-methyl-1H-tetrazol-5-yl)-thioacetic acid (10 g) in dried benzene (100 ml) were added a solution of thionyl chloride (10.2 g) in dried benzene (30 ml) and dimethylformamide (1 drop) in turn at room temperature, and the mixture was refluxed for 1 hour. After the reaction, the solvent was distilled off to give crystals of (1-methyl-1H-tetrazol-5-yl)thioacetyl chloride. To a solution of 3,4-dibenzyloxyphenethylamine (9.3 g) in a mixture of dried benzene (90 ml) and dried chloroform (10 ml) was firstly added triethylamine (3.66 g) and then was dropwise added over 20 minutes under stirring and ice cooling a solution of the above obtained (1-methyl-1H-tetrazol-5-yl)-thioacetyl chloride in a mixture of dried benzene (50 ml) and dried chloroform (5 ml). The mixture was stirred for 30 minutes at the same temperature and for 30 minutes at room temperature. The solvent was distilled off and the residue was dissolved in chloroform. The solution was in turn washed with 5% hydrochloric acid, water, dilute sodium bicarbonate aqueous solution and water and dried. The solvent was distilled off and the residue was crystallized from ether to give N-(3,4-dibenzyloxyphenethyl)-(1-methyl-1H-tetrazol-5-yl)-thioacetamide (10.7 g), mp 110° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:9]=2)[C:4]([C:15]2[N:20]=[C:19]3[C:21]([C:24](O)=[O:25])=[CH:22][NH:23][C:18]3=[N:17][CH:16]=2)=[N:3]1.[CH3:27][C:28]([NH2:31])([CH3:30])[CH3:29].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>ClCCl.O>[C:28]([NH:31][C:24]([C:21]1[C:19]2=[N:20][C:15]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:11]([F:13])([F:12])[F:14])[CH:6]=4)[N:2]([CH3:1])[N:3]=3)=[CH:16][N:17]=[C:18]2[NH:23][CH:22]=1)=[O:25])([CH3:30])([CH3:29])[CH3:27]
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2cc(C(F)(F)F)ccc21
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 15.4 %

Procedure:
A mixture of 2-(1-methyl-5-(trifluoromethyl)-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (100 mg, 0.28 mmol), 2-methylpropan-2-amine (20 mg, 0.28 mmol), HOBt (149 mg, 1.12 mmol), EDCI (211 mg, 1.12 mmol) and triethylamine (133 mg, 1.12 mmol) in dichloromethane (15 mL) was stirred at room temperature for 15 hours, then water (30 mL) was added, product extracted with dichloromethane (3×30 mL), the combined organic layers were concentrated and the residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with petroleum ether/ethyl acetate=10:1) to give N-tert-butyl-2-(1-methyl-5-(trifluoromethyl)-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (18 mg, 15.6%) as an orange solid. LCMS: (M+H)+=417; 1H NMR (300 MHz, DMSO): δ 12.89 (s, 1H), 9.06 (s, 1H), 8.71 (s, 1H), 8.44 (s, 1H), 8.05 (d, 1H, J=9.0 Hz), 7.93 (s, 1H), 7.84 (d, 1H, J=9.0 Hz), 4.28 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH3:30])[CH:20]=[CH:19][C:18](C2C=CC=CC=2B(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([C:18]2[CH:19]=[CH:20][C:15]([CH3:30])=[CH:16][CH:17]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reactant: Cc1ccc(-c2ccccc2B(O)O)cc1
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: Cc1ccccc1
Product: Cc1ccc(-c2ccc(C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
To a solution of tert-butyl-4-bromobenzoate (48 g, 0.186 mol), 4-tolyl-benzeneboronic acid (25.3 g, 0.186 mol), Na2CO3 (200 g in 500 mL of water) in toluene (750 mL) under N2 was added Pd (PPh3)4 (10.7 g, 0.009 mol) and reaction mixture was refluxed for 10 h. After cooling to rt, organic layer was separated and aqueous layer was extracted with EtOAc (2×200 mL). The combined layer was washed with brine and concentrated. The crude was purified by column chromatography over silica gel (pet. ether/ethylacetate, 4:1) to give tert-butyl-4-(4-tolyl)benzoate (40 g, 800%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:9]=[C:8]([OH:10])[N:7]([C:11]2C=CC=CC=2Cl)[N:6]=1.C(O)(=O)C.[CH2:23]([C:27](OCC)(OCC)[O:28][CH2:29][CH3:30])[CH2:24][CH2:25][CH3:26]>C(#N)C>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1=[N:6][N:7]([CH3:11])[C:8](=[O:10])/[C:9]/1=[C:27](\[O:28][CH2:29][CH3:30])/[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: COC(=O)Cc1cc(O)n(-c2ccccc2Cl)n1
Reactant: CCCCC(OCC)(OCC)OCC
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCC/C(OCC)=C1/C(=O)N(C)N=C1CC(=O)OC
Temperature: 70 °C

Procedure:
The mixture of the above obtained methyl (5-hydroxy-1-methyl-1H-pyrazol-3-yl)acetate (Compound of Formula (IV), 0.80 g) in acetonitrile (5 mL), glacial acetic acid (21 μl 0.1 equiv.) and BuC(OEt)3 (3 eq.) was heated at 70° C. for 1 h 15. The resulting red solution was concentrated in vacuo to afford a red syrup that was washed with cyclohexane and then dried in vacuo. Due to its relative instability, no further purification of methyl[(4Z)-4-(1-ethoxypentylidene)-1-methyl-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate was conducted (1.0 g, quantitative yield). MS (ESI+): 283.4; MS (ESI−): 281.3.
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:41][CH3:42])([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[C:27]([CH3:40])[CH:26]=2)[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:43])[C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH2:44]([O:46][C:47](=[O:56])[CH2:48][C:49]1[CH:50]=[N:51][C:52](Br)=[N:53][CH:54]=1)[CH3:45].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O>[CH2:44]([O:46][C:47](=[O:56])[CH2:48][C:49]1[CH:50]=[N:51][C:52]([C:28]2[CH:29]=[CH:30][C:25]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])[C:10]([CH3:11])([CH3:13])[CH3:12])=[C:17]([CH3:43])[CH:18]=3)([CH2:23][CH3:24])[CH2:41][CH3:42])=[CH:26][C:27]=2[CH3:40])=[N:53][CH:54]=1)[CH3:45]
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: CCOC(=O)Cc1cnc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)Cc1cnc(-c2ccc(C(CC)(CC)c3ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c3)cc2C)nc1
Temperature: 95.5 °C
Reaction time: 9 h
Yield: 86.1 %

Procedure:
Degassed N,N-dimethylformamide (0.30 mL) was added to t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 23-(1); 30.0 mg, 0.0494 mmol), 2-bromopyrimidine-5-acetic acid ethyl ester (Example 43-(3); 22.9 mg, 0.027 mmol), tetrakis(triphenylphosphine)palladium (0) (24.7 mg, 0.021 mmol) and potassium phosphate (29.3 mg, 0.138 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 91 to 100° C. for nine hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=10/1) to give the title compound (15 mg, 45%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.C([Li])CCC.[B:18](OC)([O:21]C)[O:19]C.[Cl-].[NH4+]>C1COCC1.CCCCCC>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([B:18]([OH:21])[OH:19])=[CH:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: COB(OC)OC
Reactant: Brc1ccc(-n2cccn2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(-n2cccn2)cc1
Reaction time: 1 h
Yield: 37.5 %

Procedure:
Under a nitrogen stream, to a solution of 1-(4-bromophenyl)-1H-pyrazole (995 mg, 4.46 mmol) in anhydrous THF (12 ml), a hexane solution of n-butyllithium (1.6 M, 2.79 ml, 4.46 mmol) was added dropwise at −78° C. After stirring at the same temperature for 1 hour, this solution was added dropwise at −78° C. to a solution of trimethyl borate (1.07 ml, 9.37 mmol) in anhydrous THF (8 ml). After stirring at the same temperature for 1 hour, the reaction mixture was stirred at room temperature for one day and a night. After addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. After filtration, the solvent was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (developing solution=methylene chloride:methanol (50:1)) to give the titled compound (314 mg, 37%).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[N:8]=1.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[C:19]([CH:22]=1)[CH:20]=[O:21].[Cl-].[NH4+]>C1COCC1>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[C:19]([CH:20]([C:12]2[C:7]([F:6])=[N:8][C:9]([F:13])=[CH:10][CH:11]=2)[OH:21])[CH:22]=1
Reactant: COc1ccc(Br)cc1C=O
Reactant: Fc1cccc(F)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1C(O)c1ccc(F)nc1F

Procedure:
DIPA (8.0 mL, 56.6 mmol) was dissolved in dry THF (40 mL) under nitrogen and cooled in a dry ice bath to −78°. n-Butyllithium solution, 2.5 m in hexanes (23.0 mL, 57.5 mmol) was added and the solution stirred for a few minutes prior to dropwise addition of 2,6-difluoropyridine (5.0 mL, 55.1 mmol) in dry THF (10 mL) via an addition funnel over 10 minutes. The pale yellow solution was stirred for 30 minutes then additional dry THF (70 mL) was added dropwise via an addition funnel. Solid 5-bromo-2-methoxybenzaldehyde (11.85 g, 55.1 mmol) was added in one portion and the reaction stirred for 5 minutes. Additional dry THF (100 mL) was added dropwise to keep the mixture stirring freely. After 15 minutes saturated ammonium chloride (20 mL) was added to quench followed by ethyl acetate (200 mL) and water (200 mL). The phases were mixed and separated and the organic dried with magnesium sulfate before evaporating to dryness under reduced pressure. Purification using silica chromatography (hexane to DCM gradient) gave (5-bromo-2-methoxyphenyl)(2,6-difluoropyridin-3-yl)methanol.
Reaction SMILES: ClC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50]CC)=O)=[C:33]2[S:53](Cl)(=[O:55])=[O:54].Cl.CN.[O:60]1[CH2:65][CH2:64][CH2:63][CH2:62][CH:61]1[CH2:66][NH:67][CH3:68]>>[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:48]([NH2:7])=[O:50])=[C:33]2[S:53]([N:67]([CH3:68])[CH2:66][CH:61]1[CH2:62][CH2:63][CH2:64][CH2:65][O:60]1)(=[O:54])=[O:55]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CNCC1CCCCO1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: CN
Agent: Cl
Product: CN(CC1CCCCO1)S(=O)(=O)c1c(C(N)=O)[nH]c2ccc(Br)cc12

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride with (±)-N-(1-tetrahydro-2H-pyran-2-ylmethyl) -N-methylamine, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+ MS: 429.96 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13]([OH:21])([CH2:17][C:18]([CH3:20])=[CH2:19])[CH:14]([CH3:16])[CH3:15])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:11][CH2:12][C:13]([CH:14]([CH3:15])[CH3:16])([CH2:17][C:18]([CH3:20])=[CH2:19])[O:21][C:30]2=[O:32])[CH3:9])=[CH:6][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=C(C)CC(O)(CCN[C@@H](C)c1ccc(Br)cc1)C(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)CC1(C(C)C)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a solution of 3-{(S)-2-[1-(4-bromophenyl)-ethylamino]-ethyl}-2,5-dimethyl-hex-5-en-3-ol (6.4 g, 16.8 mmol) and triethylamine (5.34 g, 52 mmol) in CH2Cl2 (260 mL) was added triphosgene (2.52 g, 8.5 mmol) at 0° C. under N2, and the mixture was stirred at room temperature overnight. The reaction was quenched with water, and the mixture was extracted with CH2Cl2 (3×50 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by column chromatography to give two isomers of 3-[(S)-1-(4-bromophenyl)ethyl]-6-isopropyl-6-(2-methylallyl)-1,3-oxazinan-2-one.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25]C(=O)CC4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][CH:18]2[O:36][S:37]([C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)(=[O:39])=[O:38])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl>ClCCl.CO>[C:8]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH2:25])[C@H:21]3[S:20][CH2:19][CH:18]2[O:36][S:37]([C:40]2[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=2)(=[O:39])=[O:38])=[O:16])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)OC(c2ccccc2)c2ccccc2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2CS[C@@H]3[C@H](N)C(=O)N3C2C(=O)OC(c2ccccc2)c2ccccc2)cc1
Temperature: -30 °C
Reaction time: 4 h

Procedure:
To a solution of 3-p-toluenesulfonyloxy-7beta-phenylacetylaminocepham-4-carboxylic acid diphenylmethyl ester (3d) in dichloromethane (7 parts) cooling at -25° to -20° C. under nitrogen are added pyridine (2 equivalents) and phosphorus pentachloride (1.7 equivalents). After stirring at -15° to -10° C. for 4 hours, the mixture is diluted with methanol (12 parts) cooled at -30° C., stirred at -30° to -25° C. for 30 minutes and at 0° to 5° C. for 2 hours. The reaction mixture is diluted with dichloromethane and ice-water and stirred at 0° to 5° C. for 20 minutes. The formed organic layer is taken, washed with water, dried, and concentrated. The residue is crystallized from dichloromethane-ether mixture to give 3-p-toluenesulfonyloxy-7beta-aminocepham-4-carboxylic acid diphenylmethyl ester (4d) p-toluenesulfonate salt. mp. 190°-194° C. (decomposition).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([NH:14]C(C1C=CC=CC=1)CO)([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]>C(O)C.[OH-].[Pd+2].[OH-]>[NH2:14][C:3]([CH3:13])([C:2]([F:1])([F:24])[F:25])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCC(C)(NC(CO)c1ccccc1)C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC(C)(N)C(F)(F)F
Reaction time: 16 h

Procedure:
39 g (107.6 mmol) of tert-butyl-{3,3,3-trifluoro-2-[(2-hydroxy-1-phenylethyl)amino]-2-methylpropyl}carbamate from Example 50A were initially charged under argon in ethanol (700 ml), and 5.44 g (53.8 mmol) of palladium(II) hydroxide (20% on activated carbon, water-moist, about 60%) were added. The reaction mixture was hydrogenated at standard pressure for 16 h. Then the reaction mixture was filtered through silica gel and concentrated. The residue was purified by means of silica gel chromatography (cyclohexane/ethyl acetate gradient: 9/1 to 6/4). This gave 15.8 g (61% of theory) of the target compound.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:19]=[C:18]([F:20])[C:14]([C:15](O)=[O:16])=[C:13]([F:21])[CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([N:24](CC)CC)C.ClC(OCC)=O.N>C1COCC1>[C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:19]=[C:18]([F:20])[C:14]([C:15]([NH2:24])=[O:16])=[C:13]([F:21])[CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCc1cc(F)c(C(=O)O)c(F)c1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1cc(F)c(C(N)=O)c(F)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To a stirred solution of the above benzoic cid intermediate (1.23 g, 4.08 mmol) and triethylamine (0.63 mL, 4.5 mmol) in THF (20 mL) at −25° C. was added ethyl chloroformate (0.43 mL, 4.5 mmol). The reaction was warmed to 0° C. in 1 h and an ammonia solution (0.5 N in dioxane, 20 mL, 10 mmol) was then added. The reaction was stirred at room temperature overnight, concentrated, diluted with dichloromethane, washed with 1N HCl and brine, dried with sodium sulfate, concentrated, and dried in vacuo to give 4-(N-boc-2-aminoethyl)-2,6-difluorobenzamide (0.8 g, 65%).