Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[Br:18][CH2:19][C:20](Cl)=[O:21]>C(OCC)C>[Br:18][CH2:19][C:20]([NH:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5])=[O:21]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: O=C(Cl)CBr
Solvent: CCOCC
Product: O=C(CBr)Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
To an iced solution of 266 g (1 mol) of 2-amino-2',5-dichlorobenzophenone in 3 liters of ethyl ether there are added, drop by drop, 90 cc (1.1 mol) of bromacetyl chloride dissolved in 500 cc of ethyl ether. The batch is allowed to come to room temperature, whereupon it is evaporated to dryness and the crystalline residue extracted with petroleum ether and filtered. In this manner, 371 g of crystals are recovered.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][CH:5]([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:9][CH:8]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[S:25][CH:26]=[C:27]([C:29](=[O:32])[CH2:30]Br)[N:28]=1.C(=O)([O-])O.[K+].[BH4-].[Na+]>CC(C)=O.FC(F)(F)C(O)=O>[OH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([N:4]2[CH2:3][CH2:2][O:32][CH:29]([C:27]3[N:28]=[C:24]([C:23]([F:34])([F:33])[F:22])[S:25][CH:26]=3)[CH2:30]2)[CH3:21])=[CH:8][CH:9]=1
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Reactant: CC(Cc1ccc(OCCCCCCO)cc1)NCCO
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: CC(Cc1ccc(OCCCCCCO)cc1)N1CCOC(c2csc(C(F)(F)F)n2)C1

Procedure:
Prepared by analogy to Example 32 by reaction of N-(2-hydroxyethyl)-2-(4-(6-hydroxyhexoxy)phenyl)-1-methylethylamine with 2-trifluoromethyl-4-bromoacetyl-thiazole and potassium hydrogen carbonate in acetone at room temperature, followed by reduction with sodium borohydride in trifluoroacetic acid. The resulting crude product is purified on a silica gel column using toluene/ethyl acetate=6:4 as eluant.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCNCC
Reactant: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Product: CCOC(=O)c1c(N(CC)CC)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 37 step A from 2,6-dichloro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 11 step B, 100 mg, 0.29 mmol) and diethyl-amine (0.06 ml, 0.58 mmol). Sticky liquid (70 mg, 63%). LC-MS: 383 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:13])[CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.N#N.C([N-]C(C)C)(C)C.[Li+].[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[C:27]([I:33])[CH:26]=1>C1COCC1>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:6]2([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4][CH:3]([CH:2]([F:13])[F:1])[CH2:8][CH2:7]2)=[C:27]([I:33])[CH:26]=1
Reactant: COC(=O)C1CCC(C(F)F)CC1
Reactant: BrCc1ccc(Br)cc1I
Agent: CC(C)[N-]C(C)C
Agent: N#N
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccc(Br)cc2I)CCC(C(F)F)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
Methyl 4-(difluoromethyl)cyclohexanecarboxylate (Intermediate 89, 2.46 g, 12.8 mmol) was dissolved in THF (25 mL). The atmosphere was exchanged to N2 (g), and the solution was cooled to −78° C. Lithium diisopropylamide (1.8M in THF/heptane/ethylbenzene) (8.51 mL, 15.3 mmol) was added, while the temperature was kept at −78° C. The solution was stirred for 60 min at −78° C. A solution of 4-bromo-1-(bromomethyl)-2-iodobenzene (see Caruso, A.; Tovar, J., D. J. Org. Chem. 2011, 76, 2227-2239., 4.8 g, 12.8 mmol) in THF (5.0 mL) was added via syringe. The reaction was removed from the cooling bath, and allowed to reach r.t., while stirred for 2.5 h. Water (30 mL) was added, followed by DCM (30 mL). The organic layer was collected and dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by flash chromatography, (0-100% EtOAc in heptanes, 220 g SiO2) to give the title compound (3.29 g, 53% yield): 1H NMR (500 MHz, CDCl3) δ ppm 1.11-1.20 (m, 2 H), 1.39 (td, 2 H), 1.67-1.80 (m, 3 H), 2.30 (d, 2 H), 3.01 (s, 2 H), 3.70 (s, 3 H), 5.49 (d, 1 H), 6.89 (d, 1 H), 7.38 (dd, 1 H), 7.99 (d, 1 H), MS (CI) m/z 487 [M+H]1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([C:19]([OH:21])=O)[CH:13]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[C:14]([C:19](=[O:21])[NH:22][C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:27][CH:28]=3)[CH:15]=[CH:16][C:17]=2[Cl:18])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cc(C(=O)O)ccc2Cl)cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2cc(C(=O)Nc3ccc(N4CCOCC4)cc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
A mixture of 6-chloro-biphenyl-3,4′-dicarboxylic acid 4′-ethyl ester (800 mg), N-(4-aminophenyl)morpholine (469 mg), EDAC (504 mg), HOBT (355 mg) and N-methylmorpholine (578 μl) in DMF (10 ml) was stirred at room temperature. After 1 h, water (80 ml) was added and the resulting suspension filtered. The residue was then purified by chromatography. Elution with 1:1 ethyl acetate:petrol gave a yellow crystalline solid (437 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14](O)=[O:15])=[C:11]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:10]3=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:14]([NH:38][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:15])=[C:11]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:10]3=[N:9]2)=[CH:6][CH:7]=1
Reactant: NC1CCCCC1
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCCC2)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(NC1CCCCC1)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCCC2)C1CCCCC1

Procedure:
In analogy to the procedure described in example 9.6, [2-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazol-3-yl]-cyclohexyl-acetic acid (example 9.3) was converted into the corresponding acid chloride with thionyl chloride which subsequently reacted with cyclohexylamine (CAS Reg. No. 108-91-8) in the presence of DMAP to give the title compound as off-white solid. MS: m/e=468.3 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[CH:24]=[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH:22]=[CH:21][C:20]=2[CH3:35])=[O:18])=[C:13]([N+:36]([O-:38])=[O:37])[CH:12]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[CH:24]=[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH:22]=[CH:21][C:20]=2[CH3:35])=[O:18])=[C:13]([N+:36]([O-:38])=[O:37])[CH:12]=1
Reactant: COc1ccc(COc2ccc(C)c(C(=O)c3ccc(Br)cc3[N+](=O)[O-])c2)cc1
Reactant: Nc1ccc(F)cc1F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(COc2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3[N+](=O)[O-])c2)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
2,4-Difluoro-phenylamine (26 μL, 0.25 mmol) was dissolved in dry 1,4-dioxane (3 mL) in a vial under an argon atmosphere. Compound 504 (114 mg, 0.25 mmol) was added and dissolved in the solvent. Rac-BINAP (7.0 mg, 0.012 mmol), Pd2(dba)3 (7.0 mg, 0.008 mmol) and Cs2CO3 (114 mg, 0.35 mmol) were added, and the reaction mixture was stirred under an argon atmosphere at 100° C. for 16 h. The reaction mixture was filtered through Celite and then purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v:v=1:9 to 1:3) as the eluent to afford the title compound as curry yellow solid. 13C NMR (CDCl3) δ 194.5, 159.6 (dd), 159.5, 156.1, 155.9 (dd), 149.6, 147.1, 137.2, 132.8, 131.8, 131.7, 129.2, 128.5, 126.8, 124.8 (dd), 123.8 (dd), 117.9, 117.1, 114.1, 111.8 (dd), 109.5, 105.2 (dd), 70.1, 55.3, 19.9
Reaction SMILES: BrC1C=C(CC2CC3CCN2CC3)C=NC=1.BrC1C=C(C=O)C=NC=1.Cl.N12CCC(CC1)C(=O)C2.[OH-].[K+].[C].[C].[Br:40][C:41]1[CH:42]=[C:43]([CH:47]=[C:48]2[C:53](=[O:54])[CH:52]3[CH2:55][CH2:56][N:49]2[CH2:50][CH2:51]3)[CH:44]=[N:45][CH:46]=1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].C([BH-](C(CC)C)C(CC)C)(CC)C.[K+].[BH4-].[Na+]>CO.O1CCCC1.O.O.O.O.O.O.[Ni]Cl>[Br:40][C:41]1[CH:42]=[C:43]([CH2:47][CH:48]2[C:53](=[O:54])[CH:52]3[CH2:55][CH2:56][N:49]2[CH2:50][CH2:51]3)[CH:44]=[N:45][CH:46]=1
Reactant: O=C1C(=Cc2cncc(Br)c2)N2CCC1CC2
Agent: Cl[Ni]
Agent: Brc1cncc(CC2CC3CCN2CC3)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C1C2CCN(CC2)C1Cc1cncc(Br)c1
Yield: 75 %

Procedure:
The manner in which 2-((5-bromo-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane and other analogous compounds possessing substituents at the C-5 position of the pyridine ring are synthesized can vary. In another example, 2-((5-bromo-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane can be prepared starting with the aldol condensation of 5-bromo-3-pyridinecarboxaldehyde and 3-quinuclidinone hydrochloride (commercially available from Aldrich Chemical Company) which proceeds in 75% yield using potassium hydroxide in methanol. The carbon-carbon double bond of the resulting 2-((5-bromo-3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one can be selectively reduced with an appropriate reducing agent, such as lithium tri-sec-butylborohydride (L-Selectride®) or potassium tri-sec-butylborohydride (K-Selectride®) (available from Aldrich Chemical Company) in tetrahydrofuran at −78° C. using methodology described by J. M. Fortunato et al., J Org. Chem. 41 (12): 2194-2200 (1976) or with sodium borohydride modified with nickel(1) chloride hexahydrate in an ethanolic or aqueous solution to give 2-((5-bromo-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octan-3-one. The latter ketone can be reduced under Wolff-Kishner conditions with hydrazine and base (or under modified Wolff-Kishner conditions with tosylhydrazine and sodium cyanoborohydride) to yield 2-((5-bromo-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]2[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])=[N:18][O:19][C:15]=2[C:14]=1[Cl:29])C.O.[OH-].[Na+]>CCOCC>[Cl:29][C:14]1[C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:16]=2[CH:27]=[CH:28][C:13]=1[O:12][CH2:11][CH2:10][OH:9]
Reactant: CCOC(=O)COc1ccc2c(-c3ccccc3F)noc2c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCCOc1ccc2c(-c3ccccc3F)noc2c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.9 g lithium aluminum hydride (98%) in 100 ml anhydrous ether is added a solution of 10 g ethyl-2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}acetate of Example 1 d in 200 ml ether containing sufficient tetrahydrofuran to effect solution. The reaction mixture is stirred for two hours at room temperature and one hour at reflux. To the reaction mixture is added 0.9 ml H2O, 0.9 ml 15% NaOH and 2.7 ml H2O. The stirred suspension is filtered and the filtrate is concentrated to afford 2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}ethanol, mp 112° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12]CC)=[O:11])=[CH:7][C:6]=2[CH:15]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O.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.O1CCOCC1>[C:16]1([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][C:6]=3[CH:15]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc2cc(-c3ccccc3)ccc2o1
Temperature: 100 °C
Yield: 99.3 %

Procedure:
A mixture of ethyl 5-bromo-benzofuran-2-carboxylate 15 (2.5 g, 9.3 mmole), benzeneboronic acid (1.25 g, 10.2 mmole), tetrakis(triphenylphosphine)palladium (0) (118 mg), sodium carbonate (3.25 g, 30.6 mmole) in water (25 ml), and dioxane (25 ml) was stirred under an argon atmosphere and heated to 100° C. for 16 hrs. The white heterogeneous mass was acidified with 1M HCl, extracted, washed, dried, and evaporated, to give about 2.2 g of 5-phenyl-benzofuran-2-carboxylic acid 16, mp. 218-220° C.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[C:11]([OH:19])(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)CCl.Cl.[NH2:25][CH:26]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:27]([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=[O:28]>CN(C=O)C.CCN(C(C)C)C(C)C.CO>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([CH:32]2[CH2:31][CH2:30][N:29]([C:27](=[O:28])[CH:26]([NH:25][C:11](=[O:19])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:42]([CH3:43])([CH3:45])[CH3:44])[CH2:34][CH2:33]2)=[CH:36][CH:37]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)C(N)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)C(NC(=O)c1ccccc1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Reaction time: 0.25 h

Procedure:
A reaction tube was charged with HOBt (13 mg), benzoic acid (9 mg) and EDC (18 mg) in DMF (0.75 mL) and then agitated for 15 min. After this time, a solution of 2-amino-1-(4-(4-chlorophenyl)piperidin-1-yl)-3,3-dimethylbutan-1-one hydrochloride (21 mg) in DIEA (65 μL) and DMF (185 μL) was added to the tube and the reaction mixture was shaken overnight at rt. At the conclusion of this period, the resulting solution was diluted with MeOH and purified by preparative LC-MS to provide Example 194. MS found: (M+H)+=414.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][C@H:3]1[F:15].[O-]S([O-])(=O)=O.[Na+].[Na+].[N:23]1[C:31]2[C:26](=[N:27][CH:28]=[C:29]([CH:32]=O)[CH:30]=2)[S:25][N:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCO>[F:15][C@@H:3]1[C@H:2]([NH:1][CH2:32][C:29]2[CH:30]=[C:31]3[N:23]=[N:24][S:25][C:26]3=[N:27][CH:28]=2)[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: O=Cc1cnc2snnc2c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: F[C@H]1CNCC[C@H]1NCc1cnc2snnc2c1
Temperature: 25 °C

Procedure:
A solution of cis-4-amino-1-tert-butoxycarbonyl-3-fluoropiperidine (1a) (1.00 mmole) in CH2Cl2 (5 mL) and EtOH (0.5 mL) is treated with anhydrous Na2SO4 (280 mg) and [1,2,3]thiadiazolo[5,4-b]pyridine-6-carboxaldehyde (1b) (1.10 mmole). The resulting solution is stirred at room temperature, then sodium triacetoxy borohydride (320 mg, 1.50 mmole) is added. The mixture is quenched by the addition of water (2 mL) and the volatiles removed in vacuo. Purification gives the desired compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[C:10]([C:14]#[N:15])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])[CH3:2].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.N1C=CC=CC=1.CS(C)=O>O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[C:10]([C:14]#[N:15])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])[CH3:2]
Reactant: CCOC(=O)CNc1cc(F)c(C#N)cc1[N+](=O)[O-]
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)CNc1cc(-n2ccnc2)c(C#N)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 4 h
Yield: 95.6 %

Procedure:
A mixture of 2.50 g of N-(4-cyano-5-fluoro-2-nitrophenyl)glycine ethyl ester, 0.67 g of imidazole, 7.40 g of pyridine and 40 ml of DMSO was stirred at 80° C. for 4 hours. After the addition of water, the reaction product was extracted with chloroform. The extract was washed successively with water and brine, dried over anhydrous sodium sulfate and then, concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (eluent:chloroform:methanol=95:5) to give 2.82 g (92%) of N-[4-cyano-5-(1H-imidazol-1-yl)-2--nitrophenyl]glycine ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[N:8]=[C:7]2N.N(OCCC(C)C)=O.CC(=O)OCC.C(Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[N:8]=[CH:7]2
Reactant: Nc1nc(Cl)nc2c(Br)cccc12
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Clc1ncc2cccc(Br)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.4 %

Procedure:
To a stirred mixture of 8-bromo-2-chloroquinazolin-4-amine (12.93 g, 50 mmol) in THF (500 mL) was added isoamyl nitrite (23.43 g, 200 mmol) over 3 hours and 40 mins at 60° C. The mixture was stirred for another 5 hours. TLC (PE:EA, 1:1) showed reaction complete. After cooling to room temperature, the solvent was stripped and the residue was taken into DCM (300 mL). The organic layer was washed with brine (100 mL), water (100 mL), then dried over anhydrous Na2SO4 and purified by chromatography (DCM:PE, 1:1) to give the title compound as a yellow solid (8.21 g, 67%). 1HNMR (DMSO-d6, 400 MHz): δ 9.66 (s, 1H), 8.45 (dd, J=0.8, 7.6 Hz, 1H), 8.26 (dd, J=0.8, 8.0 Hz, 7.73 (dd, J=7.6, 8.0 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:5][C:6]([Cl:9])=[N:7][CH:8]=1.CCN(C(C)C)C(C)C.CN(C=O)C.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39](O)=[O:40])=[CH:34][CH:33]=1>C(OCC)(=O)C>[Cl:9][C:6]1[N:5]=[C:4]([NH:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]([CH2:2][NH:1][C:39](=[O:40])[CH2:38][C:35]2[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)=[CH:8][N:7]=1
Reactant: CC(C)(C)CNc1nc(Cl)ncc1CN
Reactant: COc1ccc(CC(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CC(=O)NCc2cnc(Cl)nc2NCC(C)(C)C)cc1
Reaction time: 16 h

Procedure:
To a solution of 0.089 g (0.38 mmol) of (5-aminomethyl-2-chloro-pyrimidin-4-yl](2,2-dimethyl-propyl)-amine and 0.27 ml (1.6 mmol) DIEA in 2.5 ml of DMF 0.063 g (0.38 mmol) of (4-methoxy-phenyl)-acetic acid is added and the reaction mixture is stirred at r.t for 16 h. The reaction mixture is then diluted with ethyl acetate and twice washed with H2O, the organic layer is separated and dried over Na2SO4 and then concentrated under reduced pressure. Flash chromatography (ethyl acetate/hexanes 1:1) of the residue provided N-[2-chloro-4-(2,2-dimethyl-propylamino)-pyrimidin-5-ylmethyl]-2-(4-methoxy-phenyl)acetamide as white crystalls.
Reaction SMILES: [N+](=[C:3]([C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH:17]1[C:22](O)=[CH:21][CH:20]=[C:19]([CH3:24])[CH:18]=1>C(Cl)(Cl)(Cl)Cl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[CH3:24][C:19]1[CH:20]=[CH:21][C:22]([CH:3]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(=[N+]=[N-])C(=O)c1ccccc1
Reactant: Cc1ccc(O)cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C(=O)c1ccccc1)c1ccc(C)cc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 26.1 %

Procedure:
A mixture of 7.66 g of ethyl α-diazobenzoylacetate, 3.8 g of p-cresol and 150 mg of rhodium(II) acetate in 40 cc of carbon tetrachloride was stirred at a temperature of 40-50° C. for 2 hours. After cooling, the insoluble materials were filtered off and the solvent was distilled off. The crude product thus obtained was purified by a silica gel column chromatography (eluent: chloroform/hexane=1/2) to obtain 2.59 g of compound E. Yield: 24.7%.
Reaction SMILES: C(=O)(O)[O-].[Na+].[C:6]([O:10][C:11]([C:13]1[N:14]2[CH:17]([S:18][CH2:19][C:20]=1[CH2:21][S:22][C:23]1[S:24][C:25]([CH3:28])=[N:26][N:27]=1)[CH:16]([NH2:29])[C:15]2=[O:30])=[O:12])([CH3:9])([CH3:8])[CH3:7].C1(N=C=NC2CCCCC2)CCCCC1.[N:46]1([CH2:51][C:52](O)=[O:53])[CH:50]=[CH:49][CH:48]=[CH:47]1.N=C=N>O1CCOCC1.O>[N:46]1([CH2:51][C:52]([NH:29][CH:16]2[C:15](=[O:30])[N:14]3[CH:17]2[S:18][CH2:19][C:20]([CH2:21][S:22][C:23]2[S:24][C:25]([CH3:28])=[N:26][N:27]=2)=[C:13]3[C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:12])=[O:53])[CH:50]=[CH:49][CH:48]=[CH:47]1
Reactant: O=C(O)Cn1cccc1
Reactant: Cc1nnc(SCC2=C(C(=O)OC(C)(C)C)N3C(=O)C(N)C3SC2)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N=C=N
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Product: Cc1nnc(SCC2=C(C(=O)OC(C)(C)C)N3C(=O)C(NC(=O)Cn4cccc4)C3SC2)s1
Reaction time: 8 h

Procedure:
(1-Pyrryl)acetic (0.03m) is added to water, the pH of which is adjusted to about 6.5 by the addition of sodium bicarbonate. This solution is cooled in an ice bath and to it is added 3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid tert-butyl ester (0.1 m) (7-ATDCA) followed by N, N'-dicyclohexylcarbodiimide (0.01m) in cold dioxane. The mole ratio of (1-pyrryl) acetic acid/7-ATDCA/carbodiimide is 3/1/1. After standing overnight at ice bath temperature, the reaction mixture is filtered to remove solids. The filtrate is evaporated to dryness, the solids taken up in ethyl acetate, dried over magnesium sulfate and filtered. The ethyl acetate solution is concentrated and then treated with hexane. The title compound precipitates from solution, and is recovered.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][CH2:13][C@@:9]1([CH3:16])[C:10]([OH:12])=O)=O)(C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[F:50][C:51]1[CH:66]=[CH:65][C:54]([CH2:55][C:56]2[C:57]([CH3:64])=[C:58]([CH3:63])[C:59](=[O:62])[NH:60][N:61]=2)=[CH:53][C:52]=1[C:67]([N:69]1[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]1)=[O:68]>CN(C=O)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:50][C:51]1[CH:66]=[CH:65][C:54]([CH2:55][C:56]2[C:57]([CH3:64])=[C:58]([CH3:63])[C:59](=[O:62])[NH:60][N:61]=2)=[CH:53][C:52]=1[C:67]([N:69]1[CH2:74][CH2:73][N:72]([C:10](=[O:12])[C@:9]2([CH3:16])[CH2:13][CH2:14][CH2:15][NH:8]2)[CH2:71][CH2:70]1)=[O:68]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Reactant: Cc1c(Cc2ccc(F)c(C(=O)N3CCNCC3)c2)n[nH]c(=O)c1C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(Cc2ccc(F)c(C(=O)N3CCN(C(=O)[C@]4(C)CCCN4)CC3)c2)n[nH]c(=O)c1C
Temperature: 60 °C

Procedure:
A mixture of 1-(tert-butoxycarbonyl)-2-methylproline (1 eq), TEA (2 eq), PyBOP (1 eq) and 6-[4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-one (II) in dry DMF (0.1 M) was heated at 60° C. with microwaves irradiation for 2 hours. The product was isolated by preparative-HPLC. After lyophilization of the pooled product fractions the residue was dissolved in 10% TFA/DCM and the solution was warmed to 45° C. for 1 h. The residue obtained after solvent evaporation was further purified by SCX cartridge. Lyophilization from water/MeCN afforded the title compound as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 12.67 (1H, s), 7.38-7.13 (3H, m), 3.96 (2H, s), 3.8-3.5 (5H, m), 3.3 (1H under water signal), 3.26-3.13 (2H, m), 2.92-2.78 (1H, m), 2.76-2.58 (1H, m), 2.34-2.15 (1H, m), 2.02 (3H, s), 2.00 (3H, s), 1.75-1.46 (3H, m), 1.26 (3H, s). MS (ES) C24H30FN5O3 requires: 455. found: 456 (M+H)+.