Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[CH:18]1[C:23]([NH2:24])=[CH:22][C:21]2[O:25][C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[O:28][C:20]=2[CH:19]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[F:30][C:27]1([F:29])[O:28][C:20]2[CH:19]=[CH:18][C:23]([NH:24][C:13]3[N:12]=[C:11]([C:7]4[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][CH:8]=4)[CH:16]=[N:15][CH:14]=3)=[CH:22][C:21]=2[O:25][C:26]1([F:31])[F:32]
Reactant: Nc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Reactant: CC(=O)Nc1cccc(-c2cncc(Cl)n2)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(-c2cncc(Nc3ccc4c(c3)OC(F)(F)C(F)(F)O4)n2)c1
Yield: 10.4 %

Procedure:
Following Method L, 2-(3-acetamidophenyl)-6-chloropyrazine (4a) (60 mg, 0.24 mmol), 2,2,3,3-tetrafluoro-6-amino-1,4-benzodioxene (78.1 mg, 0.35 mmol), Pd(0)2 dba3 (9 mg, 0.01 mmol), BINAP (50 mg, 0.04 mmol), sodium tert-butoxide (33 mg, 0.34 mmol) and toluene (5 mL) were reacted at 85° C. for 16 hours. Evaporation under vacuo followed. The resulting solid was washed with 50 mL dichloromethane and filtered. The insoluble solid was dissolved in 3 mL of hot ethyl acetate. When this mixture was allowed to cool down in the freezer some crystals appeared. Filtration and washing with 2 mL of cold ethyl acetate gave 10.8 mg of the title compound. Yield: 10.4%. 1 H NMR (250 MHz, DMSO-d6) δ 2.08 (s, 3 H), 7.44 (d, 1 H, J=9.1 Hz), 7.47 (d, 1 H, J=7.8 Hz), 7.59 (bd, 1 H, J=7.6 Hz), 7.704-7.759 (m, 2 H), 7.96 (d, 1 H, 2.4 Hz), 8.21 (s, 1 H), 8.45 (bs, 1 H), 8.51 (s, 1 H), 9.95 (s, 1 H), 10.10 (s, 1 H); 13C NMR (62.9 MHZ, DMSO-d6) δ 24.00, 106.13, 115.92, 117.34, 118.01, 120.13, 121.08, 129.31, 130.04, 130.98, 133.62, 136.16, 136.79, 139.03, 139.99, 147.90, 150.84, 168.40; m/z 435.1 [(M+H)+, calcd for C20H14F4N4O3 434.1].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[C:30]([O:34][C:35](=[O:46])[NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][NH2:45])[CH:39]=1)([CH3:33])([CH3:32])[CH3:31]>C1COCC1.CCOC(C)=O>[C:30]([O:34][C:35](=[O:46])[NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][NH:45][C:15]([C:11]2[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:17])[CH:39]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN)c1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)NCc1cccc(CNC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 79.8 %

Procedure:
To a solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (0.195 g, 0.89 mmol) in THF (5 mL) is added carbonyl diimidazole (0.18 g, 1.1 mmol) and heated at 60° C. for 2 hours. The mixture is cooled to room temperature. (3-Aminomethyl-benzyl)-carbamic acid tert-butyl ester (0.25 mL, 1.1 mmol) is added and the mixture is stirred for 12 hours. The mixture is diluted with EtOAc (100 mL), washed with brine (2×50 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue is purified by flash chromatography eluting with 20%-80% EtOAc/heptane to afford [3-({[2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-methyl)-benzyl]-carbamic acid tert-butyl ester (0.32 g, 80%) as a solid. MS: 451 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 1.38 (s, 9H), 2.65 (s, 3H), 4.14 (d, J=6.1 Hz, 2H), 4.50 (d, J=5.6 Hz, 2H), 7.15 (m, 1H), 7.24 (m, 1H), 7.31 (m, 1H), 7.43 (m, 1H), 7.62 (m, 1H), 8.13 (m, 1H), 8.28 (m, 1H), 8.89 (s, 1H), 9.23 (m, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[CH:11][C:12]([N+:14]([O-])=O)=[CH:13][C:8]=2[CH2:7][N:6]([CH:17]([CH3:19])[CH3:18])[S:5]1(=[O:21])=[O:20].CC(N1CC2C=C([N+]([O-])=O)C=CC=2NS1(=O)=O)C.[N+](C1C=CC(N)=CC=1)([O-])=O.C(NS(Cl)(=O)=O)(C)C>C(O)C.[Pd]>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]2[N:4]([CH2:3][CH2:2][Cl:1])[S:5](=[O:21])(=[O:20])[N:6]([CH:17]([CH3:18])[CH3:19])[CH2:7][C:8]=2[CH:13]=1
Reactant: CC(C)N1Cc2cc([N+](=O)[O-])ccc2N(CCCl)S1(=O)=O
Agent: [Pd]
Agent: CC(C)N1Cc2cc([N+](=O)[O-])ccc2NS1(=O)=O
Agent: CC(C)NS(=O)(=O)Cl
Solvent: CCO
Product: CC(C)N1Cc2cc(N)ccc2N(CCCl)S1(=O)=O
Reaction time: 1 h

Procedure:
1-(2-Chloroethyl)-3,4-dihydro-3-(1-methylethyl)-6-nitro-1H-2,1,3-benzothiadiazine-2,2-dioxide(1.67 g, 0.005 mol) prepared from 3,4-dihydro-3-(1-methylethyl)-6-nitro-1H-2,1,3-benzothiadiazine-2,2-dioxide (prepared from 4-nitroaniline and isopropyl sulfamoyl chloride by methods described above was dissolved in absolute ethanol (50 ml) and hydrogenated at 60 psi in the presence of 5% palladium on charcoal (0.2 g). After 1 hour and no further hydrogen uptake, the catalyst was filtered, washed with ethanol and the solution evaporated to dryness giving 6-amino-1-(2-chloroethyl)-3,4-dihydro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[OH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C(=O)C.O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:27]1[CH2:28][CH2:29][CH:24]([OH:23])[CH2:25][CH2:26]1)=[O:6]
Reactant: OC1CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 97.1 %

Procedure:
A solution of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (1 g, 3.35 mmol) in N,N-dimethylacetamide (30 mL) was treated with 4-hydroxypiperidine (396 mg, 3.92 mmol) and triethylamine (1 mL, 7.17 mmol). O-Benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (1.77 g, 4.67 mmol) was added and the resulting solution was stirred at ambient temperature for 17 hours. The reaction mixture was then poured into water (300 mL) and extracted with dichloromethane (2×200 mL). Combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated to afford the crude product, which was purified by flash silica chromatography, elution gradient 0 to 20% MeOH in dichloromethane. Pure fractions were evaporated to dryness to afford the desired compound as a pale yellow gum (1.24 g, 97% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.42-1.54 (1H, m), 1.55-1.67 (2H, m), 1.76-1.84 (1H, m), 1.92-2.01 (1H, m), 3.05-3.15 (1H, m), 3.38-3.55 (2H, m), 3.94-3.99 (1H, m), 4.14-4.22 (1H, m), 4.27 (2H, s), 7.02 (1H, t), 7.26-7.32 (2H, m), 7.70-7.79 (3H, m), 8.44-8.48 (1H, m), 10.07 (1H, s); m/z (LC-MS, ESI+), RT=1.44 (M+H 382.1).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:29])[C:5]2[N:6]=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][O:15][C:16]([C:18]3([NH:21]C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[O:17])[C:9]=2[N:10]=1.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>C(Cl)Cl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[NH2:1][C:2]1[NH:3][C:4](=[O:29])[C:5]2[N:6]=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][O:15][C:16]([C:18]3([NH2:21])[CH2:20][CH2:19]3)=[O:17])[C:9]=2[N:10]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)OCCOCn2cnc3c(=O)[nH]c(N)nc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc2c(ncn2COCCOC(=O)C2(N)CC2)c(=O)[nH]1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
Suspend 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid 2-(2-amino-6-oxo-1,6-dihydro-purin-9-ylmethoxy)-ethyl ester (0.20 g, 0.49 mmol) of Preparation 1 in methylene chloride (2 mL) and stir at room temperature. Add trifluoroacetic acid (2 mL) dropwise and continue stirring. The suspension dissolves to give clear solution. Concentrate to dryness under vacuum. Triturate with ethyl acetate several times to isolate a white solid. Yield: 67.7% MS (ES+): 309.2 (M+1) MS (ES−): 307.2 (M−1)
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[NH:10][C:8]=2[N:9]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>CN(C)C=O>[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:20])[C:11](=[O:22])[N:10]([CH2:29][C:28]3[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[C:8]=2[N:9]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c(-c3c(Cl)cccc3Cl)cc3cnc(N)nc32)cc1
Temperature: 50 °C

Procedure:
To a suspension of NaH (60% in mineral oil, 38 mg) in 8 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (208 mg, 0.68 mmol). The mixture was heated at 50° C. for 1 hour, resulting in a clear solution. 4-Methoxybenzyl chloride (130 μL, 0.95 mmol) was added, and the reaction mixture was heated at 50° C. for 30 minutes, then poured onto ice water. The resulting precipitate was removed by filtration and washed with water. The solid was purified by flash chromatography, eluting with 1:1 hexane:ethyl acetate, then dried in vacuo to provide 208 (72%) mg of 2-amino-6-(2,6-dichlorophenyl)-8-(4-methoxybenzyl)-8H-pyrido[2,3-d]pyrimidin-7-one; mp 208°-209° C.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:56])[C@@H:24]([NH:25][C:26](=[O:55])[C@@H:27]([C:41]4[CH:46]=[CH:45][C:44](C(OC(C)(C)C)=O)=[CH:43][C:42]=4N)[NH:28][C:29]([N:31]4[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[C:33](=[O:39])[C:32]4=[O:40])=[O:30])[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:57][O:58][C:59](=[O:61])[NH2:60])=[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.O.[C:63]1([CH3:73])[CH:68]=[CH:67][C:66]([S:69]([OH:72])(=[O:71])=[O:70])=[CH:65][CH:64]=1.C(#[N:76])C>>[C:63]1([CH3:73])[CH:64]=[CH:65][C:66]([S:69]([OH:72])(=[O:70])=[O:71])=[CH:67][CH:68]=1.[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:56])[C@@H:24]([NH:25][C:26](=[O:55])[C@@H:27]([C:41]4[CH:42]=[CH:43][C:44]([NH2:76])=[CH:45][CH:46]=4)[NH:28][C:29]([N:31]4[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[C:33](=[O:39])[C:32]4=[O:40])=[O:30])[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:57][O:58][C:59](=[O:61])[NH2:60])=[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
Reactant: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(COC(N)=O)CS[C@H]23)c2ccc(C(=O)OC(C)(C)C)cc2N)C(=O)C1=O
Reactant: CC#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(COC(N)=O)CS[C@H]23)c2ccc(N)cc2)C(=O)C1=O

Procedure:
5.5 g of 7β-[(2R)-2-(4-BOC-aminophenyl)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 200 ml of acetonitrile with 2.44 g of p-toluenesulphonic acid monohydrate in the manner described in Example 22. 7β-[(2R)-2-(4-Aminophenyl)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester p-toluenesulphonate is obtained. [α]D20 =+11°±1° (1.098% in CH3OH);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[N:4]([CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[C:30]1[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[CH:33]=[CH:32][C:31]=1[O:39][CH3:40])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([N+:16]([O-])=O)[CH:7]=1>C1COCC1.O=[Pt]=O>[CH3:1][O:2][C:3](=[O:41])[N:4]([CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([NH2:16])[CH:7]=1)[CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[C:30]1[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[CH:33]=[CH:32][C:31]=1[O:39][CH3:40]
Reactant: COC(=O)N(Cc1cc([N+](=O)[O-])cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: COC(=O)N(Cc1cc(N)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}[3-nitro-5-(trifluoromethyl)benzyl]carbamate (174 mg, 0.03 mmol) (Example 22) and PtO2 (10 mg) in THF (10 mL) was placed under hydrogen. The reaction was stirred at room temperature under hydrogen for two hours. The reaction was then diluted with hexanes (25 mL), loaded on a silica gel column, and purified with 15% EtOAc/hexanes to afford methyl[3-amino-5-(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. Rf=0.31 (25% EtOAc/hexanes). LCMS=555.3 (M+1)+. 1H NMR (CDCl3, 600 MHz) δ 7.59-6.28 (m, 9H), 4.48-3.62 (m, 12H), 2.87 (m, 1H), 1.22 (broad singlet, 6H).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[S:13]1[CH:17]=[C:16]([CH2:18][NH:19][CH:20]2[CH2:22][CH2:21]2)[N:15]=[CH:14]1.C(N(CC)CC)C.CCCCC.C(OCC)(=O)C>O1CCCC1>[CH:20]1([N:19]([CH2:18][C:16]2[N:15]=[CH:14][S:13][CH:17]=2)[C:8]([C:7]2[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=2)=[O:9])[CH2:22][CH2:21]1
Reactant: c1nc(CNC2CC2)cs1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: CCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cc(C(=O)N(Cc2cscn2)C2CC2)c(C(F)F)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 0 %

Procedure:
20 ml (0.29 mol) of cyclopropylamine was added to a solution of 4.9 g (29.0 mmol) of 4-(chloromethyl)-thiazole hydrochloride in 45 ml ethanol and 45 ml of saturated aqueous sodium hydrogen carbonate. The reaction mixture was stirred for 20 hrs at ambient temperature and extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over magnesium sulphate and concentrated in vacuum. Column chromatography (gradient n-pentane/ethyl acetate) yielded 1.5 g (32% yield) of N-(1,3-thiazol-4-ylmethyl)cyclopropylamine. At ambient temperature a solution of 0.28 g (1.4 mmol) of 3-(difluoromethyl)-1-methyl-pyrazole-4-carbonyl chloride in 2 ml of tetrahydrofurane was added drop wise to a solution of 0.20 g (1.3 mmol) of N-(1,3-thiazol-4-ylmethyl)-cyclopropylamine and 0.6 ml triethylamine in 4 ml tetrahydrofurane. The reaction mixture was stirred for 16 hrs at ambient temperature and quenched with water. The watery layer was extracted three times with ethyl acetate (3×20 ml), the combined organic layers were dried over magnesium sulphate and concentrated in vacuum. Column chromatography (gradient n-pentane/ethyl acetate) yielded 0.13 mg (51% yield) of N-cyclopropyl-N-(1,3-thiazol-4-yl-methyl)-1-methyl-3-difluoromethyl-pyrazole-4-carboxamide (M+1=313).
Reaction SMILES: [CH3:1][C:2]([C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[O:17]C1CCCCO1)[C:10]([O:12][CH3:13])=[O:11])=[CH2:6])([CH3:4])[CH3:3].CO.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>>[CH3:4][C:2]([C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[OH:17])[C:10]([O:12][CH3:13])=[O:11])=[CH2:6])([CH3:1])[CH3:3]
Reactant: C=C(c1cc(C(=O)OC)ccc1OC1CCCCO1)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: C=C(c1cc(C(=O)OC)ccc1O)C(C)(C)C
Temperature: 60 °C
Reaction time: 19 h
Yield: 81.6 %

Procedure:
To a stirred solution of 66.18C (2.500 g, 7.85 mmol) in MeOH (10.00 mL, 7.85 mmol) at 23° C. was added PPTS (0.197 g, 0.785 mmol). The reaction was heated to 60° C. and stirred for 19 hours. The reaction was then concentrated in vacuo to give a clear oil. The product was then purified on silica gel (0-20% EtOAc in hexanes) to yield 66.18D as a colorless oil (1.50 g, 81.5% yield).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][C:9]([CH:11]1[CH2:16][S:15][CH2:14][CH2:13][N:12]1[C:17]([O-:19])=O)=[O:10])C(OC)=O.C(O)(C(F)(F)F)=O>ClCCl>[OH:1][CH2:2][CH:3]1[C:17](=[O:19])[N:12]2[CH:11]([CH2:16][S:15][CH2:14][CH2:13]2)[C:9](=[O:10])[NH:8]1
Reactant: COC(=O)[C@@H](CO)NC(=O)C1CSCCN1C(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NC(CO)C(=O)N2CCSCC12
Temperature: 25 °C
Reaction time: 4 h
Yield: 28 %

Procedure:
To a solution of the crude 1,1-dimethylethyl (3R or S)-({[(1R)-1-(hydroxymethyl)-2-(methyloxy)-2-oxoethyl]amino}carbonyl)-4-thiomorpholinecarboxylate (D26) in 20 mL of dichloromethane were added 10 mL of TFA. The reaction mixture was stirred at room temperature for 4 hrs. The solvent was removed under reduced pressure and the residue was taken up in MeOH and loaded on a SCX cartridge. The fractions eluted with methanolic ammonia were collected, the volume was reduced and the solution was stirred at 50° C. for 45 min. Then it was irradiated three times by microwave [set parameters: T=80° C., t=10 min (1×); T=120° C., t=5 min (2×)]. The solvent was removed and after 2 days the crude revealed the formation of a white solid. So it was precipitated with DME and it was collected by filtration, washing with Et2O, to give the 1st batch of the title compound (120 mg, y=28% over 2 steps). The filtered solution was evaporated to dryness and the resulting crude, dissolved in DME, was irradiated two times by microwave (set parameters: T=130° C., t=30 min). After filtration, the 2nd batch of the title compound was isolated as a brownish solid (94 mg, y=22% over 2 steps). The filtered solution was treated in the same way as before and after four microwave irradiation [set parameters: T=130° C., t=30 min (3×) and t=90 min (1×)] the 3rd batch of the title compound was isolated as a brownish solid (50 mg, y=12% over 2 steps).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C(OP([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])(OCC)=O)C.C1(C)C=CC=CC=1.[O-]CC.[Na+]>C(O)C.O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(-c2ccc(C=O)cc2)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1ccc(-c2ccc(CCC(=O)OCC)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
4′-Propyl-4-formyl-1,1′-biphenyl (s56) (30.0 g), ethyl diethylphosphonoacetate (36.0 g) and toluene (300 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to 0° C. Sodium ethoxide in ethanol solution (20%; 54.6 g) was added at the same temperature, and the stirring was continued for another 2 hours. After the reaction mixture had been returned to 25° C., the stirring was continued for another 2 hours. The reaction mixture was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with a mixed solvent of toluene and heptane (toluene:heptane=2:1 by volume) as an eluent and silica gel as a stationary phase powder. The purified product was dissolved in 2-propanol (300 ml), to which Pd/C (1.5 g) was added. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The residue was purified by column chromatography with a mixed solvent of toluene and heptane (toluene:heptane=2:1 by volume) as an eluent and silica gel as a stationary phase powder to give ethyl 3-(4′-propyl-1,1′-biphenyl-4-yl)propionate (s57) (29.8 g). The yield based on the compound (s56) was 75.2%.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.C(OCC)(=O)C>CN(C=O)C>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:6]2[C:2]([CH3:21])([CH3:1])[C:3](=[O:20])[N:4]([C:8]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][CH:11]=3)=[O:9])[C:5]2=[O:7])=[CH:27][CH:26]=1
Reactant: CC1(C)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Reactant: Clc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
5,5-Dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione (35 mg) was dissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) was added. Then, 4-chlorobenzyl bromide (26 mg) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 20 mg of white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].[C:25]1([CH3:37])[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:34]3[CH2:35][CH2:36][N:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH3:37])[CH2:32][CH2:33]3)[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2]
Reactant: Cc1ccccc1N1CCNCC1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(Br)c1)N2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N3CCN(c4ccccc4C)CC3)c1)N2
Temperature: 120 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.2 g, 3.1 mmol), 1-o-tolyl-piperazine (987 mg, 4.6 mmol), copper(I) iodide (180 mg, 0.93 mmol), N,N-dimethylglycine hydrochloride (260 mg, 1.86 mmol) and potassium carbonate (1.3 g, 9.3 mmol) in dimethyl sulfoxide (10 mL) was stirred at 120° C. for 16 hours. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×200 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 3,3-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.2 g, 80%) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C31H37N3O2 (M+H)+: 484.56, observed: 484.2.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH2:9]Cl)[CH2:3][CH2:2]1.[C-:18]#[N:19].[Na+]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH2:9][C:18]#[N:19])[CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH2:3][CH2:2]1
Reactant: [C-]#N
Reactant: FC(F)Oc1ccc(CCl)cc1OCC1CC1
Agent: [Na+]
Product: N#CCc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To 3-cyclopropylmethoxy-4-difluoromethoxybenzyl chloride (26 g) in dimethylflormamide (150 mL) under an argon atmosphere was added sodium cyanide (9.7 g, 198 mmol). The resulting mixture was stirred at room temperature and heated gently for 2 h, then cooled and concentrated. The mixture was partitioned between basic brine and ether and extracted twice. The organic extract was washed with brine and was dried (sodium sulfate). The solvent was removed in vacuo to provide an orange-brown oil (24 g), which was used without purification.