Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[N:11]=[CH:12][O:13][C:14]=2[C:15]([F:18])([F:17])[F:16])=[CH:4][C:3]=1[O:19][CH3:20].CON(C)[C:24](=[O:40])[CH:25]([O:38][CH3:39])[C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1>>[Br:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]([C:10]2[N:11]=[C:12]([C:24](=[O:40])[CH:25]([O:38][CH3:39])[C:26]3[CH:27]=[CH:28][C:29]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)=[CH:30][CH:31]=3)[O:13][C:14]=2[C:15]([F:16])([F:17])[F:18])=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1cc(-c2ncoc2C(F)(F)F)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Product: COc1cc(-c2nc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)oc2C(F)(F)F)cc(OC)c1Br

Procedure:
1-(4-(4-Bromo-3,5-dimethoxyphenyl)-5-(trifluoromethyl)oxazol-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone was prepared from 4-(4-bromo-3,5-dimethoxyphenyl)-5-(trifluoromethyl)oxazole (prepared from 4-bromo-3,5-dimethoxybenzaldehyde according to Heterocycles, 1992, 34, 1047) and N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (20-40% EtOAc-hexanes) gave the product as a yellow solid (0.032 g, 14% yield). MS: m/z 585.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]2[C:20]([C:23]([OH:25])=O)=[CH:21][CH:22]=[C:11]2[CH2:10]1)=[O:8].[CH3:35][N:36]([CH3:42])[CH2:37][CH2:38][CH2:39][NH:40][CH3:41].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]2[C:20]([C:23]([N:40]([CH2:39][CH2:38][CH2:37][N:36]([CH3:42])[CH3:35])[CH3:41])=[O:25])=[CH:21][CH:22]=[C:11]2[CH2:10]1)=[O:8]
Reactant: COc1cc(C2=CCCCC2)c(Cl)cc1C(=O)N1Cc2ccc(C(=O)O)n2Cc2ccccc21
Reactant: CNCCCN(C)C
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(C2=CCCCC2)c(Cl)cc1C(=O)N1Cc2ccc(C(=O)N(C)CCCN(C)C)n2Cc2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.3 %

Procedure:
10-(5-Chloro-4-cyclohex-1-en-1-yl-2-methoxybenzoyl)-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step G (0.200 g, 0.419 mmol), (3-dimethylaminopropyl)methylamine (0.074 mL, 0.503 mmol), 1-hydroxy benzotriazole (0.062 g, 0.461 mmol) and 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.088 g, 0.461 mmol) were combined in amine-free N,N-dimethylformamide (1.7 mL), followed by addition of N,N-diisopropylethyl amine (0.110 mL, 0.629 mmol). The reaction was stirred at room temperature for 12 hours, then diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and brine. The combined aqueous washings were saturated with sodium chloride and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 10% methanol in chloroform to provide the title compound (0.220 g) as a white powder, m.p. 116-119° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][CH2:11][CH2:10][NH:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].[CH:15](=O)[CH3:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(#N)C.C(OCC)(=O)C>[CH2:15]([N:9]1[C:8]2[CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:13][CH2:12][CH2:11][CH2:10]1)[CH3:16]
Reactant: CC=O
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CC(=O)O
Product: CCN1CCCOc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
1.00 M of Potassium hydroxide in Water (25 mL) was added to 2-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester (2.84 g, 10.7 mmol) in 2-Methoxyethanol (50 mL) and the reaction was heated at 110° C. After overnight heating, the mixture was cooled, extracted with DCM (2×50 mL); the combined organics were washed with water (50 mL) and brine (50 mL), dried and conc. in vacuo. The residue was chromatographed (120 g SiO2, ISCO, 0-20% EtOAc:Hex) to afford 2-Nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene as an orange solid (1.64 g, 79%). 1697d) 2-Nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (278 mg, 1.43 mmol) was dissolved in Acetonitrile (15 mL) and Acetaldehyde (0.80 mL, 14 mmol) was added. Acetic acid (0.15 mL, 2.6 mmol) was added, followed by Sodium triacetoxyborohydride (0.85 g, 4.0 mmol), and the mixture was stirred under an atmosphere of Nitrogen at room temperature for 1 h. The solution was diluted with ethyl acetate (50 mL) and satd. sodium bicarbonate (50 mL). The layers were separated, the organic washed with brine (50 mL) and dried over sodium sulfate. Conc. in vacuo followed by chromatography (ISCO, g SiO2, 0-50% EtOAc:Hex) afforded 9-Ethyl-2-nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene as an orange oil (272 mg, 85%). 1H-NMR (CDCl3) 7.58 (m, 2H), 6.87 (d, 1H, J=8.1 Hz), 4.31 (t, 2H, J=5.2 Hz), 3.40 (t, 2H, J=5.2 Hz), 3.33 (q, 2H, J=6.8 Hz), 2.05 (tt, 2H, J=5.2, 5.2 Hz), 1.24 (t, 3H, J=6.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:5]([O:6][CH2:7][C:8]#[N:9])=[C:4]([CH3:13])[CH:3]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[C:10]([CH3:12])[C:5]=1[O:6][CH2:7][C:8]#[N:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)cc(C)c1OCC#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Cl)cc(CBr)c1OCC#N

Procedure:
(4-Chloro-2,6-dimethyl-phenoxy)-acetonitrile (700 mg, 3.6 mmol), N-bromosuccinimide (510 mg, 2.9 mmol) and benzoyl peroxide (72 mg, 0.29 mmol) are heated at reflux in carbon tetrachloride (10 mL) for 16 h. The reaction is cooled, filtered and the filtrate is concentrated and purified by column chromatograpy (silica, 5% ethyl acetate in hexanes) to provide the title compound. MS (ES) 273, 275 (M)+, Br pattern.
Reaction SMILES: [OH-:1].[Na+].Br[CH:4](Br)[C:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=[O:6].[OH2:13]>>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[CH:5]([OH:6])[C:4]([OH:13])=[O:1]
Reactant: [OH-]
Reactant: O
Reactant: O=C(c1cccs1)C(Br)Br
Agent: [Na+]
Product: O=C(O)C(O)c1cccs1
Yield: 77 %

Procedure:
The reaction was performed in the same manner as in Example 4 except that a solution of 8.0 g (200 mmol) of sodium hydroxide in 90 ml of water was used and 14.2 g (50 mmol) of 2-(dibromoacetyl)thiophene was used, gave 5.6 g of 2-thiopheneglycolic acid (yield: 77%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:23]2([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:23]2([CH2:28][NH:29][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[O:12])[CH2:24][CH2:25][CH2:26][CH2:27]2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C2(CNC(=O)c3n[nH]c4ccccc34)CCCC2)cc1OC
Reaction time: 16 h
Yield: 9.9 %

Procedure:
1H-Indazole-3-carboxylic acid (32.4 mg, 0.200 mmol) and C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (47.1 g, 0.200 mmol) were dissolved in acetonitrile (1 mL) containing triethylamine (83.6 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (76.0 mg, 0.200 mmol) was added and the solution was allowed to stir for 16 hours. The mixture was then purified by reverse phase preparative liquid chromatography to yield the pure product (7.47 mg, 0.0197 mmol, 9.84%) ESI-MS m/z calc. 379.2, found 380.4 (M+1)+. Retention time of 3.02 minutes.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[BrH:14].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O>[Br:14][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: OCc1ccc2c(Cl)ccnc2c1
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1ccnc2cc(CBr)ccc12
Temperature: 120 °C

Procedure:
7-Hydroxymethyl-4-chloroquinoline (0.2 g, 0.97 mmol) is treated with 48% HBr and heated to 120° C. for 1 hours. The resulting solution is cooled with ice, diluted with water and treated with ethyl acetate and sodium bicarbonate until basic to pH paper. The layers are separated and the organic layer is washed with water, dried (Na2SO4) and concentrated to give 7-bromomethyl-4-chloroquinoline (0.23 g, 0.9 mmol). MS m/z: M+=255; 1H NMR (CDCl3, 300 MHz) δ8.75 (d, 1H), 8.25 (d, 1H), 8.1 (s, 1H), 7.7 (d, 1H), 7.5 (d, 1H), 4.7 (s. 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[F:23])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: Fc1ccccc1CBr
Reactant: COC(=O)c1[nH]c(=O)c2ccc(Br)cc2c1-c1ccccc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 15.6 %

Procedure:
6-Bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (54 mg), 2-fluorobenzylbromide (34 mg) and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine resin (2.2 mmol/g, 110 mg) were suspended in dimethylformamide (2 ml), and the suspension was shaken at room temperature for 15 hr. using a shaking machine. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by preparative HPLC to give the title compound (11 mg, 15%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][SH:14].[Na]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:13]([S:14][CH:13](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: SCc1ccccc1Cl
Agent: [Na]
Product: Clc1ccc(/C=C\C(SC(/C=C\c2ccc(Cl)cc2)c2ccccc2Cl)c2ccccc2Cl)cc1

Procedure:
A solution of 4-chlorophenylacetylene (0.02 mol) and 2-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to Procedure 2 to form (Z)-4-chlorostyryl 2-chlorobenzylsulfide. The title compound was obtained in 73% yield following oxidation. 1HNMR (CDC13) δ4.56 (2H, s), 6.70 (1H, d, JH,H=12.05), 7.18-7.64 (8H aromatic+1H ethylenic).
Reaction SMILES: I[C:2]1[N:6]([CH3:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][CH:22]=NN=2)=[CH:16][CH:15]=1.C([O-])([O-])=[O:26].[Cs+].[Cs+].CI>C1COCC1>[CH3:7][N:6]1[CH:2]=[C:3]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:21][CH3:22])=[O:26])=[CH:16][CH:15]=2)[N:4]=[C:5]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(-c3nnco3)cc2)c1I
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1ccc(-c2cn(C)c(-c3ccccn3)n2)cc1
Reaction time: 0.08 h
Yield: 60.9 %

Procedure:
Methyl 4-(2-pyridin-2-yl-1H-imidazol-4-yl)benzoate (from Step 1, 19.55 g, 70 mmol) was dissolve in THF (160 mL), to which was added Cs2CO3 (29.6 g, 91 mmol) at 0° C. After stirring for 5 min, MeI (11 mL, 175 mmol) was added. After stirring overnight at rt, the reaction was quenched with aq NH4Cl. The product was extracted with EtOAc and the organic layer was washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue was subject to silica column chromatography (0-20% EtOAc in hexanes) to give 12.5 g of methyl 4-(1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl)benzoate. LCMS: m/z 294 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C@H:15]([NH:19]C(=O)OC(C)(C)C)[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:29])[CH3:28])=[CH:4][CH:3]=1>O1CCOCC1>[ClH:1].[NH2:19][C@H:15]([CH:16]([CH3:18])[CH3:17])[C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]([CH3:28])([CH3:29])[CH2:10]1)=[O:27]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ccc(Cl)cc2)C(C)(C)C1
Solvent: C1COCCO1
Product: CC(C)[C@@H](N)C(=O)N1CCN(c2ccc(Cl)cc2)C(C)(C)C1
Product: Cl
Temperature: 25 °C

Procedure:
To a solution of 1-(4-chlorophenyl)-2,2-dimethylpiperazine (0.76 g, 3.38 mmol) in DMF (10 mL), was added (R)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (0.735 g, 3.38 mmol), BOP (1.496 g, 3.38 mmol) and DIPEA (0.588 mL, 3.38 mmol). The mixture was stirred at rt for 2 h, quenched with aq. NaHCO3, extracted with EtOAc, and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by a flash column chromatography using 30% EtOAc in hexanes as an eluent. The product containing fractions were concentrated and dried to give (R)-tert-butyl 1-(4-(4-chlorophenyl)-3,3-dimethylpiperazin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (1.36 g, 3.21 mmol, 95% yield) as a yellow oil. To (R)-tert-butyl 1-(4-(4-chlorophenyl)-3,3-dimethylpiperazin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate was added 4N HCL in dioxane and the resulting mixture stirred at room temperature until the starting material had been consumed. The volatile solvents were removed and the product dried to give (R)-2-Amino-1-(4-(4-chlorophenyl)-3,3-dimethylpiperazin-1-yl)-3-methylbutan-1-one hydrochloride as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([F:26])([F:25])[F:24])=[N:19][NH:20][C:21]=3[CH3:22])=[C:13]([N+:27]([O-])=O)[CH:12]=2)=[O:9])=[CH:4][CH:3]=1.Cl[Sn]Cl.Cl>CCO>[NH2:27][C:13]1[CH:12]=[C:11]([NH:10][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:9])[CH:16]=[CH:15][C:14]=1[C:17]1[C:18]([C:23]([F:26])([F:24])[F:25])=[N:19][NH:20][C:21]=1[CH3:22]
Reactant: Cc1[nH]nc(C(F)(F)F)c1-c1ccc(NC(=O)c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Cc1[nH]nc(C(F)(F)F)c1-c1ccc(NC(=O)c2ccc(Cl)cc2)cc1N
Yield: 48 %

Procedure:
The mixture of 23 (340 mg, 1.24 mmol), SnCl2 2H2O (902 mg, 6.22 mmol), HCl (0.33 mL) in EtOH (50 mL) stirred at reflux under a N2 atmosphere for 1 h. The solvent was removed under vacuo, washed with NaOH to PH=14, extracted with CH2Cl2, dried over Na2SO4 and purified by purified by column chromatography to give 24 (235 mg, 75% yield). 1H NMR (CDCl3, 300 MHz): δ=2.37 (s, 3H), 3.89 (s, 2H), 6.59 (s, 1H), 6.76-6.79 (m, 1H), 7.13 (d, 1H), 7.46-7.49 (m, 2H), 7.53 (d, 1H), 7.73 (s, 1H), 7.79-7.81 (m, 2H). LC-MS: 394.9 (M+1)+.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:7][NH:6][CH2:5][C@H:4]1[NH:8][C:9]1[C:10]2[N:11]([CH:18]=[C:19]([C:21]3[CH:22]=[N:23][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH2:30][O:31][CH3:32])=[CH:25][CH:26]=3)[CH:20]=2)[N:12]=[CH:13][C:14]=1[C:15]([NH2:17])=[O:16])[CH3:2].[C:34]([C:36]1([C:39](O)=[O:40])[CH2:38][CH2:37]1)#[N:35].CN([P+](ON1N=NC2C1=CC=CC=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:34]([C:36]1([C:39]([N:6]2[CH2:7][C@H:3]([CH2:1][CH3:2])[C@H:4]([NH:8][C:9]3[C:10]4[N:11]([CH:18]=[C:19]([C:21]5[CH:22]=[N:23][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH2:30][O:31][CH3:32])=[CH:25][CH:26]=5)[CH:20]=4)[N:12]=[CH:13][C:14]=3[C:15]([NH2:17])=[O:16])[CH2:5]2)=[O:40])[CH2:38][CH2:37]1)#[N:35]
Reactant: N#CC1(C(=O)O)CC1
Reactant: CC[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H]1CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of 4-(((3S,4S)-4-ethylpyrrolidin-3-yl)amino)-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide, 2hydroiodide (26 mg, 0.037 mmol), 1-cyanocyclopropanecarboxylic acid (12.25 mg, 0.110 mmol), BOP-reagent (48.8 mg, 0.110 mmol) and Hunig's Base (0.045 mL, 0.257 mmol) in DMF (1 mL) was stirred at rt overnight. The reaction mixture was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-100% B over 15 minutes, then a 7-minute hold at 100% B; Flow: 25 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (6 mg, 0.011 mmol, 30% yield). 1H NMR (500 MHz, METHANOL-d4) δ 8.78 (dd, J=11.9, 2.0 Hz, 1H), 8.19-8.10 (m, 1H), 8.07-7.90 (m, 2H), 7.38 (dd, J=8.2, 3.7 Hz, 1H), 7.20-7.06 (m, 1H), 5.05 (t, J=4.2 Hz, 0.5H), 4.91 (t, J=4.5 Hz, 0.5H), 4.57 (s, 2H), 4.37-4.25 (m, 1.5H), 4.18 (d, J=11.4 Hz, 0.5H), 3.97 (s, 2H), 3.94-3.75 (m, 1.5H), 3.49-3.37 (m, 3.5H), 2.69-2.59 (m, 0.5H), 2.58-2.46 (m, 0.5H), 1.83-1.32 (m, 6H), 1.08-0.96 (m, 3H) fractional peaks are due to the presence of amide rotomers. MS (ES+) m/z: 545.1 (M+H); LC retention time: 1.15 min (analytical LCMS Method H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:25]([NH:31][NH2:32])(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:32][NH:31][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CC(C)(C)C(=O)NN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: -60 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
In a 50 mL, 3-neck round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.2 g, 1.0 eq.) was dissolved in EtOAc (20 mL) and cooled to −60° C. where pivalohydrazide (0.08 g, 1.2 eq.) was introduced dropwise. T3P (50% in EtOAc) (0.4 mL, 4 eq.) was added dropwise followed by DIPEA (0.4 mL, 4 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-pivaloylacrylohydrazide (0.11 g, yield: 43%);
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C>ClCCl.Cl>[Cl:17][C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(Cl)cc1N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cl)cc1NS(C)(=O)=O
Reaction time: 0.17 h

Procedure:
A solution of methanesulphonyl chloride (6.3 g) in dichloromethane was added to a stirred, cooled (0°-5° C.) solution of methyl 2-amino-4-chlorobenzoate (9.5 g) in dichloromethane. Triethylamine (7.1 g) was then added and the mixture was stirred at 0°-5° C. for 10 minutes and then at room temperature for 0.5 hours. The mixture was diluted with 2N hydrochloric acid. The organic phase was separated, washed with water, dried and evaporated. The crude product was purified by column chromatography to yield methyl 4-chloro-2-(N-methylsulphonylamino)benzoate as a white solid, (3.6 g) m.p. 125.5°-128.1° C.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9]3[CH2:24][CH2:23][N:22]([C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)[N:13]=2)[CH2:6][CH2:5][O:4][CH2:3]1.[O:31]1CCN(C2C3CN(C4N=CC=CN=4)CCC=3N=C(C3C=CC(N)=CC=3)N=2)C[CH2:32]1.[CH3:60][C:61]1[O:65][C:64]([NH2:66])=[N:63][N:62]=1.C1(CN)CC1>>[CH3:60][C:61]1[O:65][C:64]([NH:66][C:32]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([C:12]3[N:13]=[C:8]([N:7]4[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]4[CH3:1])[C:9]4[CH2:24][CH2:23][N:22]([C:25]5[N:26]=[CH:27][CH:28]=[CH:29][N:30]=5)[CH2:21][C:10]=4[N:11]=3)=[CH:15][CH:16]=2)=[O:31])=[N:63][N:62]=1
Reactant: Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(c2ncccn2)CC3)cc1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2)nc2c1CCN(c1ncccn1)C2
Reactant: Cc1nnc(N)o1
Agent: NCC1CC1
Product: Cc1nnc(NC(=O)Nc2ccc(-c3nc4c(c(N5CCOC[C@@H]5C)n3)CCN(c3ncccn3)C4)cc2)o1

Procedure:
The title compound “of” was prepared by the general procedure of Example 30 substituting (S)-4-(4-(3-methylmorpholino)-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)aniline for 4-(4-morpholino-6-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)aniline and 5-methyl-1,3,4-oxadiazol-2-amine for cyclopropylmethylamine. LC-MS: m/z=+529 (M+H)+.
Reaction SMILES: N#N.[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10](/[CH:13]=C/C2C=CC=CC=2)[O:11][CH:12]=1)=[O:7])[CH3:4].[OH2:21]>CC(C)=O>[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH:13]=[O:21])[O:11][CH:12]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1coc(/C=C/c2ccccc2)n1
Reactant: O
Agent: N#N
Solvent: CC(C)=O
Product: CCOC(=O)c1coc(C=O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of NaIO4 (3.21 g, 15.00 mmol) in water (26.0) mL was slowly added to a vigorously stirred suspension of silica gel (15.0 g) in acetone (60.0 mL). The mixture was then concentrated under reduced pressure and the lumpy solid slurried in CH2Cl2 and the solvent was evaporated under reduced pressure. CH2Cl2 (40.0 mL) was added and the reaction mixture was treated at rt with (E)-2-styryl-oxazole-4-carboxylic acid ethyl ester (1.22 g, 5.00 mmol) and RuCl3 hydrate (82 mg, 0.15 mmol). The reaction mixture was stirred at rt in the dark for 30 min, filtered and concentrated under reduced pressure. Purification of the residue by FC (1:9 to 1:2 EA-Hept) gave the title compound as a yellow solid. TLC:rf (3:2 EA-Hept)=0.21. LC-MS-conditions 02: tR=0.51 min; [M+H2O+H]+=188.50.