Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][NH:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([NH2:13])[C:7]=1[OH:14].C(N(CC)CC)C.[C:25]([O:28][CH2:29][C:30](Cl)=[O:31])(=[O:27])[CH3:26]>C1COCC1>[F:17][C:2]([F:1])([F:16])[CH2:3][NH:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([NH:13][C:30](=[O:31])[CH2:29][O:28][C:25](=[O:27])[CH3:26])[C:7]=1[OH:14]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1cc(F)cc(C(=O)NCC(F)(F)F)c1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1cc(F)cc(C(=O)NCC(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
6.3 (25 mmol) of crude 3-amino-5-fluoro-2-hydroxybenzoic acid-(2,2,2,-trifluoro-ethyl)amide is dissolved in 30 ml of THF, 3.04 g (30 mmol) of triethylamine as well as 4.1 g (30 mmol) of acetoxyacetylchloride are added and stirred for 12 hours at room temperature. The reaction solution is then concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel 60 with ethyl acetate/hexane. 5.52 g=62.7% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:8]([F:11])([F:10])[F:9])([OH:7])[C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1)=[O:36]>O1CCCC1>[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:4](=[O:5])[C:3]([OH:7])([C:8]([F:11])([F:10])[F:9])[C:2]([F:13])([F:12])[F:1])=[CH:39][CH:38]=1)=[O:36]
Reactant: O=C(O)C(O)(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc(C(=O)c2ccccn2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: C1CCOC1
Product: O=C(c1ccc(NC(=O)C(O)(C(F)(F)F)C(F)(F)F)cc1)c1ccccn1
Temperature: 43 °C
Reaction time: 0.25 h
Yield: 18.5 %

Procedure:
Tetrahydrofuran (15 ml, dry) was added to a mixture of 2,2-bis-trifluoromethyl-2-hydroxyacetic acid (1.08 g, 5.1 mmol) and 1,1'-carbonyldiimidazole (0.83 g, 5.1 mmol) while under a nitrogen atmosphere. There was an immediate evolution of carbon dioxide. The reaction was placed in an ultrasound bath at 23° C. for 15 min. The reaction was treated with 4-(2-pyridylcarbonyl)benzeneamine (1.01 g, 5.1 mmol), and heated to 43° C. in an ultrasound bath for 48 hr. The incomplete reaction was treated with a solid mixture of 2,2-bis-tri-fluoromethyl-2-hydroxyacetic acid (0.22 g, 1.04 mmol) and 1,1'-carbonyldiimidazole (0.20 g, 1.2 mmol) and heated to 53° C. in an ultrasound bath for 72 hr. The reaction was evaporated to a gold oil, which was treated with water (100 ml) and extracted with ethyl acetate (2×100 ml) the combined organic portions were dried (MgSO4) and eluting with methylenechloride/ethyl acetate (first 100:0 and then 85:15) provided a tan solid (0.37 g, 19%); mp 197°-200° C. 1H-NMR (250 MHz, d6 -DMSO): 7.68 (m, 1H, ArH), 8.00 (m, 6H, ArH), 8.74 (d, J=4.33, 1H, ArH), 9.93 (br s, 1H, OH), 10.83 (br s, 1H, NH). MS(CI,CH4): 393 (M+1) Analysis for C14H10F6N2O3Calculated: C, 48.99; H, 2.57; N, 7.14 Found: C, 49.23; H, 2.69; N, 7.33
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Cl:9][CH2:10][C:11](Cl)=[O:12].[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[Cl:9][CH2:10][C:11]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[F:8])=[O:12]
Reactant: Fc1ccc(F)cc1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCl)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.3 %

Procedure:
100.0 g (876.5 mmol) of 1,4-difluorobenzene and 90.83 ml (1139 mmol) of chloroacetyl chloride were cooled to 10° C. Within 5 minutes at 10–17° C. 153.5 g (1139 mmol) of aluminium chloride (99%) were added and the mixture warmed to room temperature. The mixture was heated for 30 minutes to 60° C. and the heating continued at this temperature for another 70 minutes. The reaction mixture was cooled to room temperature and poured onto a mixture of 0.8 l of ice and 400 ml at concentrated aqueous hydrochloric acid, extracted twice with each 500 ml of ethyl acetate, and the organic phases were washed once with 200 ml of water, three times with 400 ml of half-saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, dissolved for 1 hour at 80° C. in 400 ml of n-hexane and, after the addition of 4 g of active carbon, filtered hot, stirred at room temperature and cooled to 0° C.; the crystals formed were dried at room temperature under reduced pressure to give 104 g (69%) of 2-chloro-1-(2,5-difluoro-phenyl)-ethanone.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][C:10]([F:13])([F:12])[C:9](=[O:14])[N:8]([CH3:15])[C:7]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:6]2=3)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[CH3:63][C:64]([O:67][C:68]([N:70]1[CH2:75][CH2:74][CH:73]([NH2:76])[CH2:72][CH2:71]1)=[O:69])([CH3:66])[CH3:65]>ClCCl.CN(C)C=O>[C:64]([O:67][C:68]([N:70]1[CH2:75][CH2:74][CH:73]([NH:76][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([NH:20][C:18]3[N:17]=[CH:16][C:7]4[N:8]([CH3:15])[C:9](=[O:14])[C:10]([F:12])([F:13])[CH2:11][N:5]([CH:1]5[CH2:4][CH2:3][CH2:2]5)[C:6]=4[N:19]=3)=[C:22]([O:30][CH3:31])[CH:23]=2)[CH2:72][CH2:71]1)=[O:69])([CH3:63])([CH3:65])[CH3:66]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.25 h
Yield: 57.6 %

Procedure:
A mixture of 0.095 g (0.22 mmole) of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-1), 0.089 g (0.88 mmole) of triethylamine, 0.125 g (0.33 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 5 mL of dimethylformamide was stirred for 15 minutes and then 0.066 g (0.33 mmole) of 4-amino-1-piperidinecarboxylic acid 1,1-dimethylethyl ester was added. The mixture was stirred for 3 hours, then taken up in 50 mL of dichloromethane and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (gradient 50:50-0:100) to give 0.078 g of 4-[4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester. A mixture of 0.078 g (0.013 mmole) of 4-[4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester 1 mL of trifluoroacetic acid and 5 mL of dichloromethane was stirred for 1 hour and then concentrated under reduced pressure. The residue was taken up in 30 mL of ethyl acetate, washed twice with 30 mL of saturated aqueous sodium bicarbonate and then brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with ether, to give 0.055 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-piperidin-4-yl-benzamide (I-5).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:20][CH:19]=3)[N:9]=2)[CH2:3]1.[CH:32]1([C:35]2[S:39][C:38]([NH:40][C:41](=O)[O:42]C3C=CC=CC=3)=[N:37][N:36]=2)[CH2:34][CH2:33]1.CCN(CC)CC>C(Cl)Cl>[CH:32]1([C:35]2[S:39][C:38]([NH:40][C:41](=[O:42])[NH:1][C@@H:2]3[CH2:7][CH2:6][CH2:5][N:4]([C:8]4[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]5[CH:19]=[CH:20][C:21]([C:24]([N:26]6[CH2:31][CH2:30][O:29][CH2:28][CH2:27]6)=[O:25])=[CH:22][CH:23]=5)[N:9]=4)[CH2:3]3)=[N:37][N:36]=2)[CH2:34][CH2:33]1
Reactant: NC(=O)c1ccc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: O=C(Nc1nnc(C2CC2)s1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1ccc(N2CCC[C@@H](NC(=O)Nc3nnc(C4CC4)s3)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
A suspension of (R)-6-(3-aminopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (40 mg, 0.094 mmol), phenyl 5-cyclopropyl-1,3,4-thiadiazol-2-ylcarbamate (29.5 mg, 0.113 mmol), and Et3N (0.016 mL, 0.113 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The reaction mixture was diluted with CH2Cl2, washed with water, and concentrated. The residue was purified by prep-HPLC. The product containing fractions were collected, neutralized with saturated NaHCO3, extracted with CH2Cl2, separated, and concentrated to give 28 mg of (R)-6-(3-(3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)ureido)piperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide as a light pink solid. LCMS: (M+H)+=592.18. 1H NMR (400 MHz, CDCl3-MIX) δ ppm 11.09 (1H, s), 7.59 (2H, d, J=8.79 Hz), 7.55 (1H, d, J=9.23 Hz), 7.24-7.28 (2H, m), 6.04 (1H, d, J=8.79 Hz), 3.93 (1H, dd, J=13.18, 3.08 Hz), 3.73-3.86 (2H, m), 3.53 (7H, d, J=6.15 Hz), 3.31-3.41 (1H, m), 3.22-3.31 (2H, m), 2.11-2.21 (1H, m), 1.90-2.00 (1H, m), 1.67-1.79 (1H, m), 1.51-1.65 (2H, m), 1.03-1.12 (2H, m), 0.89-0.96 (2H, m).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([OH:14])=O)[NH:9][C:6]2=[CH:7][N:8]=1)#[N:2].Cl.[NH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19].CN1CCOCC1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C1COCC1>[O:19]=[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17][NH:16][C:12]([C:10]1[NH:9][C:6]2=[CH:7][N:8]=[C:3]([C:1]#[N:2])[CH:4]=[C:5]2[CH:11]=1)=[O:14]
Reactant: NCC(=O)c1ccccc1
Reactant: N#Cc1cc2cc(C(=O)O)[nH]c2cn1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: N#Cc1cc2cc(C(=O)NCC(=O)c3ccccc3)[nH]c2cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-cyano-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 62, 0.035 g, 0.19 mmol) in THF (15 mL) under argon was added 2-aminoacetophenone hydrochloride (0.036 g, 0.21 mmol), N-methylmorpholine (25 μM, 0.23 mmol) and DMTMM (0.072 g, 0.27 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated to dryness in vacuo. The residue was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic phase was separated and the aqueous phase was further extracted with ethyl acetate (100 mL). The combined organic extract was washed with 1N NaOH (40 mL), saturated sodium chloride (40 mL), dried (MgSO4), filtered and concentrated in vacuo. Crude material was purified by chromatography in hexane/ethyl acetate (1:2) and recrystallised from methanol to give the title compound. m/z (ES+)=304 [M+H]+; RT=4.37.
Reaction SMILES: [Cl:1][C@H:2]1[C@H:6]([CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[C@@H:5](/[CH:19]=[CH:20]/[C@@H:21]([OH:28])[CH2:22][CH2:23][CH2:24][C@H:25]([OH:27])[CH3:26])[C@H:4]([O:29]C2CCCCO2)[CH2:3]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO.CCOC(C)=O>[Cl:1][C@H:2]1[C@H:6]([CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[C@@H:5](/[CH:19]=[CH:20]/[C@@H:21]([OH:28])[CH2:22][CH2:23][CH2:24][C@H:25]([OH:27])[CH3:26])[C@H:4]([OH:29])[CH2:3]1
Reactant: C=CCOC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCC[C@@H](C)O)[C@H](OC2CCCCO2)C[C@H]1Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: C=CCOC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCC[C@@H](C)O)[C@H](O)C[C@H]1Cl
Temperature: 22 °C
Reaction time: 7.5 h

Procedure:
A 20 mL vial equipped with a magnetic stirbar was charged with 175 mg (0.34 mmol) of TAP-ether 8 dissolved in 5 mL of methanol. To this was then added 300 mg (1.20 mmol) of pyridinium p-toluenesulfonate and the mixture was stirred at 22° C. over 7.5 h. The reaction was sampled by TLC (Rf of product was 0.6 in EtOAc) and worked up by concentration in vacuo to remove methanol. The residual products were taken up in ethyl acetate and filtered through a 22 g plug of silica gel, eluting the polar product away from the salts with ethyl acetate (350 mL). Concentration of the filtrate yielded 125 mg of product triol 9 as an oil; 1H NMR (CDCl3): 1.18 (d, J=6.3 hz, 3H), 1.34-1.62 (m, 5H), 1.69 (m, 2H), 1.84-2.38 (m, 11H), 2.47 (br s, 1H), 3.53 (br s, 1H), 3.70 (br s, 1H), 3.79 (br m, 1H), 3.99 (m, 1H), 4.08 (m, 2H), 4.57 (m, 2H), 5.18-5.60 (m, 6H), 5.91 (m, 1H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:38]3[CH:39]=[CH:40][C:35]([O:34][CH3:33])=[CH:36][CH:37]=3)[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc32)cc1
Yield: 73 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 4-methoxyphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (73%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:4]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)=[CH:5][C:6]=1[C:7](OC)=[O:8].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:18])[C:4]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)=[CH:5][C:6]=1[CH2:7][OH:8]
Reactant: COC(=O)c1cc(-c2ccsc2)n(S(=O)(=O)c2ccccc2)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: Cc1c(CO)cc(-c2ccsc2)n1S(=O)(=O)c1ccccc1
Yield: 60.7 %

Procedure:
Using methyl 2-methyl-1-(phenylsulfonyl)-5-(3-thienyl)-1H-pyrrole-3-carboxylate (0.75 g) and a 1.5 mol/L solution (4.0 mL) of diisobutylaluminum hydride in toluene, a procedure as in Reference Example 5 was performed to give the title compound as a brown oil (yield 0.42 g, 63%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[O:10][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=C(C(C)C)C=CC=2C2C(C(C)C)=CC=CC=2C(C)C)CCCCC1.[C:52]([Zn]C#N)#[N:53]>CC(N(C)C)=O.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].[Zn]>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:52]#[N:53])=[N:3][C:4]=1[C:9]1[O:10][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[N:12][N:13]=1
Reactant: CC(C)(C)c1nnc(-c2nc(Br)cnc2N)o1
Reactant: N#C[Zn]C#N
Agent: [Pd]
Agent: CC(C)c1ccc(-c2c(C(C)C)cccc2C(C)C)c(P(C2CCCCC2)C2CCCCC2)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1nnc(-c2nc(C#N)cnc2N)o1
Temperature: 100 °C
Reaction time: 1 h
Yield: 158.5 %

Procedure:
A stream of nitrogen gas was passed through a solution of 5-bromo-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (89.35 g, 239.75 mmol) in DMA (1.2 L) for 20 minutes. Dicyclohexyl(2′,4,6′-triisopropylbiphenyl-2-yl)phosphine (11.43 g, 23.98 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.49 g, 5.99 mmol), zinc (1.568 g, 23.98 mmol) and dicyanozinc (16.89 g, 143.85 mmol) were added sequentially to the stirred mixture. The mixture was heated to 100° C. and stirred for 1 hour. The mixture was cooled and partitioned between DCM (3 L) and water (1 L). The black mixture was filtered through celite and the organic layer was separated. The solution was washed with water then brine. The solution was dried with magnesium sulfate and concentrated under reduced pressure. The residue was triturated with MTBE and isolated by filtration, washing with MTBE. The filter cake was dried in vacuo to afford 5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazine-2-carbonitrile (55.7 g, 95%) as a pale orange solid: 1H NMR Spectrum: (DMSO-d6) 1.46 (9H, s), 6.02 (1H, s), 8.38 (2H, s): Mass Spectrum [M−H]−=242.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:41]=[CH:40][C:39]([N+:42]([O-])=O)=[CH:38][C:9]=2[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[C:21]4[CH:29]=[CH:30][C:31]([C:33]([O:35][CH3:36])=[O:34])=[CH:32][C:20]=4[N:19]=3)=[C:14]([F:37])[CH:13]=2)=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl>C(O)C>[NH2:42][C:39]1[CH:40]=[CH:41][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:9]([CH:38]=1)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:22]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:21]3[CH:29]=[CH:30][C:31]([C:33]([O:35][CH3:36])=[O:34])=[CH:32][C:20]=3[N:19]=2)=[C:14]([F:37])[CH:13]=1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc([N+](=O)[O-])ccc3-c3ccc(Cl)cc3)cc1F)n2C1CCCCC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(N)ccc3-c3ccc(Cl)cc3)cc1F)n2C1CCCCC1
Yield: 83 %

Procedure:
Methyl 2-[4-{2-(4-chlorophenyl)-5-nitrobenzyloxy}-2-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylate (1.9 g) obtained in Example 337 was suspended in ethanol (40 ml), and tin(II) chloride dihydrate (3.5 g) was added, which was followed by refluxing under heating for 30 min. The reaction mixture was concentrated under reduced pressure, 4N sodium hydroxide was added and the mixture was extracted with chloroform. The organic layer was washed with 2N sodium hydroxide and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the precipitated crystals were collected by filtration to give the title compound (1.5 g, yield 82%).
Reaction SMILES: C([C:3]1[C:13]2[CH2:12][CH:11]([CH2:14][C:15]([OH:17])=[O:16])[C:10]3[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=3[CH2:8][C:7]=2[CH:6]=[C:5]([O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][CH2:32][CH3:33])[N:26]=2)[CH:4]=1)C.[OH-].[Na+]>CO>[CH2:32]([NH:31][C:27]1[N:26]=[C:25]([CH2:24][CH2:23][O:22][C:5]2[CH:4]=[CH:3][C:13]3[CH2:12][CH:11]([CH2:14][C:15]([OH:17])=[O:16])[C:10]4[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=4[CH2:8][C:7]=3[CH:6]=2)[CH:30]=[CH:29][CH:28]=1)[CH3:33]
Reactant: CCNc1cccc(CCOc2cc(CC)c3c(c2)Cc2ccccc2C(CC(=O)O)C3)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCNc1cccc(CCOc2ccc3c(c2)Cc2ccccc2C(CC(=O)O)C3)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl (±)-10,11-dihydro-3-[2-[6-(ethylamino)-2-pyridyl]-1-ethoxy]-5H-dibenzo[a,d]cycloheptene-10-acetic acid (80 mg, 0.18 mmol) was dissolved in MeOH (3 mL), and 1.0 N NaOH (0.22 mL, 0.22 mmol) was added. The solution was stirred at RT overnight, then was concentrated in vacuum. The residue was dissolved in H2O (3 mL), and the solution was acidified with 20% TFA. Chromatography on C-18 Bond Elute (30% CH3CN/H2O containing 0. 1% TFA) gave the title compound as a white solid: MS(ES) 417 (M+H)+. Anal. Calcd for C26H28N2O3 . 1.3 OF3CO2H: C, 60.83; H, 5.23; N, 4.96. Found: C, 60.64; H, 5.26; N, 4.26.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1.[C:26]1([OH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1
Reactant: Oc1ccccc1
Reactant: COc1cc(-c2nc(N)nc(S(C)(=O)=O)c2C#N)cc(OC)c1OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: COc1cc(-c2nc(N)nc(Oc3ccccc3)c2C#N)cc(OC)c1OC

Procedure:
From 2-amino-4-methanesulfonyl-6-(3,4,5-trimethoxy-phenyl)-pyrimidine-5-carbonitrile, phenol and DBU in DME. ES-MS m/e (%): 379 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([C@@H:13]1[CH2:15][C@@H:14]1[F:16])[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[CH:21]1([NH:24][CH2:25][C@@H:26]2[C@H:30]([F:31])[CH2:29][NH:28][CH2:27]2)[CH2:23][CH2:22]1>>[CH:21]1([NH:24][CH2:25][C@@H:26]2[C@H:30]([F:31])[CH2:29][N:28]([C:11]3[CH:10]=[C:9]4[C:4]([C:5](=[O:20])[C:6]([C:17]([OH:19])=[O:18])=[CH:7][N:8]4[C@@H:13]4[CH2:15][C@@H:14]4[F:16])=[CH:3][C:2]=3[F:1])[CH2:27]2)[CH2:23][CH2:22]1
Reactant: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2cc(F)c(F)cc2c1=O
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Product: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2cc(N3C[C@H](CNC4CC4)[C@H](F)C3)c(F)cc2c1=O
Yield: 48.2 %

Procedure:
Using 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (283 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (190 mg), the same procedure was followed as in Example 23 to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as pale yellow crystals (203 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[C@H:14]3[CH2:15][C@H:11]([CH:12]=[CH:13]3)[C@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:22]([O:34][CH3:35])=[CH:23][C:24]2[N:30]([CH3:31])[C:29](=[O:32])[O:28][CH2:27][CH2:26][C:25]=2[CH:33]=1>>[Cl:19][C:5]1[C:6]([NH:8][C@H:9]2[C@H:14]3[CH2:15][C@H:11]([CH:12]=[CH:13]3)[C@H:10]2[C:16]([NH2:18])=[O:17])=[N:7][C:2]([NH:20][C:21]2[C:22]([O:34][CH3:35])=[CH:23][C:24]3[N:30]([CH3:31])[C:29](=[O:32])[O:28][CH2:27][CH2:26][C:25]=3[CH:33]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCOC(=O)N2C
Reactant: NC(=O)[C@H]1[C@@H](Nc2nc(Cl)ncc2Cl)[C@@H]2C=C[C@H]1C2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3[C@H](C(N)=O)[C@H]4C=C[C@@H]3C4)n1)CCOC(=O)N2C
Yield: 72 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from (1R,2R,3S,4S)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 2-Amino-3-methoxy-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one. Product isolated as a light grey solid (70 mg, 72%). mp: 168-170° C., MS (ESI+): 485 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.03 (s, 1H), 7.96 (s, 1H), 7.75 (br s, 1H), 7.72 (s, 2H), 7.25 (s, 1H), 7.01 (s, 1H), 6.34 (br s, 1H), 6.19 (br s, 1H), 4.34 (t, 2H), 4.12 (t, 1H), 3.87 (s, 3H), 3.30 (s, 4H), 2.86 (s, 3H), 2.73 (s, 1H), 2.10 (d, 1H), 1.4 (d, 1H).