Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH2:5][C@H:6]1[C:11]([O:12][CH3:13])=N[C@H](C(C)C)C(OC)=[N:7]1.[ClH:23].[OH-:24].[Na+]>C(#N)C>[ClH:23].[NH2:7][C@@H:6]([CH2:5][C:4]1[CH:19]=[C:20]([F:22])[CH:21]=[C:2]([Br:1])[CH:3]=1)[C:11]([O:12][CH3:13])=[O:24]
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1cc(F)cc(Br)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)[C@@H](N)Cc1cc(F)cc(Br)c1
Reaction time: 2 h
Yield: 70 %

Procedure:
A stirred solution of (2S,5R)-2-(3-bromo-5-fluorobenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1.21 g, 3.27 mmol) in acetonitrile (15 mL) was treated with 0.3 N aqueous HCl (15 mL). The reaction was stirred for 2 h and then neutralized with the addition of 1N aq. NaOH. The acetonitrile was removed in vacuo and the solution was extracted with EtOAc. The organics were combined, dried over sodium sulfate, and removed in vacuo to provide (S)-methyl 2-amino-3-(3-bromo-5-fluorophenyl)propanoate hydrochloride (720 mg, 70%). MS (m/z) 276 [M+H]+.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[CH:10]12[CH2:11][CH2:12][CH:13]([CH:8]=[CH:9]1)[CH:2]1[C:1]([O:6][C:4](=[O:5])[CH:3]21)=[O:7]
Reactant: O=C1C=CC(=O)O1
Reactant: C1=CCCC=C1
Solvent: Cc1ccccc1
Product: O=C1OC(=O)C2C3C=CC(CC3)C12
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of maleic anhydride (10.30 g, 105.0 mmol) in toluene (100 mL) was added 1,3-cyclohexadiene (8.41 g, 105.0 mmol). The mixture was heated to reflux temperature and allowed to react for 3 hrs. After cooling to room temperature, the solvent was evaporated and the remaining solid was recrystallized from EtOAc/hexane to yield pure bicyclo[2.2.2]oct-5-en-2,3-dicarboxylic anhydride as colorless crystals: 14.11 g (75% yield), mp=117° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:6]([NH2:8])=[NH:7].C(ON=[CH:17][C:18]1[CH:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][N:19]=1)C>CO>[C:6]([C:5]1[CH:9]=[CH:10][C:11]2[NH:12][C:17]([C:18]3[CH:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][N:19]=3)=[N:2][C:3]=2[CH:4]=1)(=[NH:8])[NH2:7]
Reactant: N=C(N)c1ccc(N)c(N)c1
Reactant: CCON=Cc1cc(C(=O)OC)ccn1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccnc(-c2nc3cc(C(=N)N)ccc3[nH]2)c1
Yield: 82.3 %

Procedure:
A mixture comprising 3,4-diaminobenzamidine hydrochloride (1.16 g, 6.2 mmol), methyl 2-(C-ethoxyiminomethyl)pyridine-4-carboxylate (1.8 g, 7.4 mmol) and anhydrous methanol (6 mL) was stirred for 20 hours. The mixture was concentrated and the residue was trituated with hot methanol (5 mL). The solid was isolated and dried to provide methyl 2-(5-amidino-1H-benzimidazol-2-yl)pyridine-4-carboxylate (1.8 g, 5.1 mmol); Calculated for C15H13N5O2 : 295.3, Found (MH+): 295.7.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH3:13]O>>[CH3:13][O:11][C:10](=[O:12])[CH2:9][NH:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: CO
Reactant: O=C(O)CNc1ccc(O)cc1
Product: COC(=O)CNc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99 %

Procedure:
The p-hydroxy phenyl glycine (74.0 g, 442 mmol) was suspended in methanol (500 mL), cooled in an ice bath and HCl (gas) was bubbled through the reaction mixture for 20 minutes, to give a clear solution. The reaction was stirred at rt for 48 h, concentrated in vacuo to give an oil which was triturated with ethyl ether to give the p-hydroxy phenyl glycine methyl ester (95.8 g, 99%) as a white powder. MS found: (M+H)+=182.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:28][CH2:27][C@@H:15]3[N:16]4[C:25]5[C:24]([C@@H:14]3[CH2:13]2)=[CH:23][CH:22]=[CH:21][C:20]=5[N:19]([CH3:26])[CH2:18][CH2:17]4)=[CH:4][CH:3]=1.[CH3:30][Mg]Br.CCOCC>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:29])([CH2:9][CH2:10][CH2:11][N:12]2[CH2:28][CH2:27][C@@H:15]3[N:16]4[C:25]5[C:24]([C@@H:14]3[CH2:13]2)=[CH:23][CH:22]=[CH:21][C:20]=5[N:19]([CH3:26])[CH2:18][CH2:17]4)[CH3:30])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CN1CCN2c3c(cccc31)[C@@H]1CN(CCCC(=O)c3ccc(F)cc3)CC[C@@H]12
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1CCN2c3c(cccc31)[C@@H]1CN(CCCC(C)(O)c3ccc(F)cc3)CC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (99 mg, 0.25 mmol) in THF is added 3.0 M methyl magnesium bromide in ether (0.25 mL, 0.75 mmol) dropwise at 0° C. Upon the completion of the addition of CH3MgBr, the cooling bath is removed and the reaction mixture is stirred at room temperature for 2 hours. Another batch of 3.0 M methyl magnesium bromide in ether (0.25 mL, 0.75 mmol) is added dropwise, and the reaction mixture was stirred at room temperature overnight. The mixture is carefully quenched with water, basified with saturated sodium bicarbonate, and then extracted with methylene chloride four times. The combined organic phase is evaporated to dryness, and the residue is purified on a basic alumina column to give 28 mg of pure product as a white solid. 1H NMR (500 MHz, Chloroform-d) δ 8.22 (br, 1H), 7.58-7.37 (m, 2H), 7.07 (t, J=8.5 Hz, 1H), 7.01 (t, J=8.7 Hz, 1H), 6.65 (dt, J=10.6, 7.7 Hz, 1H), 6.57-6.29 (m, 2H), 3.59 (td, J=11.1, 3.0 Hz, 1H), 3.37-3.12 (m, 4H), 3.00-2.65 (m, 5H), 2.55-2.13 (m, 5H), 2.12-1.78 (m, 4H), 1.69-1.30 (m, 5H). MS (ESI) m/z 410.2 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][CH:11]3[CH2:16][CH2:15][CH:14]([N:18]4[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=5)=[O:24])[CH2:19]4)[CH2:13][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(Oc2ccc3c(c2)OCO3)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(Oc3ccc4c(c3)OCO4)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(benzo[1,3]dioxol-5-yloxy)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Cl:43][C:44]1C(CCl)=[N:46][C:47]([Cl:50])=[CH:48][CH:49]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:44]([Cl:43])=[CH:49][CH:48]=[C:47]([Cl:50])[N:46]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: ClCc1nc(Cl)ccc1Cl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3nc(Cl)ccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3,6-dichloro-2-(chloromethyl)pyridine and isolated as light-yellow gum. MS (m/e): 442.3 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].Cl.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:31]([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[O:38])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: O=C(Cl)c1ccncc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccncc3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 100, Step 1, using the following starting materials: {3-[4-amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and isonicotinoyl chloride hydrochloride.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1.O.[C:11]1(C)C(S(O)(=O)=O)=CC=CC=1.C(OC)(OC)OC>CO>[O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:11])=[O:8])[CH2:3]1
Reactant: O=C1CCC(C(=O)O)C1
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: CO
Solvent: O
Solvent: COC(OC)OC
Product: COC(=O)C1CCC(=O)C1

Procedure:
A solution of 193.8 g (1.51 moles) of 3-oxocyclopentane carboxylic acid in 580 ml of methanol, analytical grade, is treated with 1.8 g (9.5 mmoles) of toluene sulphonic acid hydrate with stirring, then 192.4 g (1.81 moles) of trimethyl orthoformate are added in the course of 10 minutes and the mixture is heated to boiling under reflux. This temperature is maintained for 1 hour. The solution is evaporated in vacuo (i.v.), the residue is treated with 200 ml of H2O, 220 ml of toluene and 1.9 ml of concentrated H2SO4 and stirred at room temperature for 1 hour. The phases are separated, the aqueous phase is extracted 3× using 50 ml of toluene each time, the combined organic phases are washed 1× using 90 ml of 2.5% strength LiOH solution and 2× using 50 ml of H2O each time. The organic phase is dried using magnesium sulphate and evaporated in vacuo. The oily residue is fractionally distilled using a water-jet vacuum.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4](=[O:13])[CH2:3]1.Br[CH2:15][CH:16]1[CH2:18][CH2:17]1>>[O:13]=[C:4]1[N:5]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:2](=[O:1])[CH2:3]1
Reactant: O=C1CC(=O)Nc2ccccc2N1
Reactant: BrCC1CC1
Product: O=C1CC(=O)N(CC2CC2)c2ccccc2N1CC1CC1

Procedure:
2,4-Dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was prepared following General Procedure 4-M using the product from Example 4-P, Step A, and (bromomethyl)cyclopropane (Lancaster). Purification was by flash chromatography eluting with EtOAc/hexanes (3:7 gradient to straight EtOAc), then recrystalization from EtOAc/hexanes.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])[N:11]=[C:12]3[C:17]([N:18]4[CH2:23][CH:22]5[CH2:24][CH:19]4[CH2:20][NH:21]5)=[N:16][CH:15]=[N:14][C:13]=23)=[CH:5][CH:4]=1.[Cl-].C([NH+](CC)CC)C.C(N(CC)CC)C.[C:47]1(=O)[CH2:51][CH2:50][CH2:49][CH2:48]1.[BH4-]>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])[N:11]=[C:12]3[C:17]([N:18]4[CH2:23][CH:22]5[CH2:24][CH:19]4[CH2:20][N:21]5[CH:47]4[CH2:51][CH2:50][CH2:49][CH2:48]4)=[N:16][CH:15]=[N:14][C:13]=23)=[CH:5][CH:4]=1
Reactant: O=C1CCCC1
Reactant: Clc1ccc(-c2c3ncnc(N4CC5CC4CN5)c3nn2-c2ccccc2Cl)cc1
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Clc1ccc(-c2c3ncnc(N4CC5CC4CN5C4CCCC4)c3nn2-c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
To the mixture of Rac-(S,S)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine HCl salt 4A-1 (50.5 mg, 0.1 mmol), triethylammonium chloride (27 mg, 0.2 mmol), and triethylamine (0.028 ml, 0.2 mmol) in absolute ethanol (1 ml) was added cyclopentanone (8.8 ml, 0.1 mmol), followed by borohydride resin (40 mg, 2.5 mmol/g). The mixture was stirred overnight at room temperature. After removal of solvent and resin, the residue was further purified by HPLC to give Rac-(S,S)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(5-cyclopentyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine 5A-1 (23 mg, 46%): MS: 504.8 (M+1)+; 1H NMR (400 MHz, CD3OD) δ 8.3 (s, 1H), 8.2 (s, 1H), 7.6 (m, 4H), 7.4 (m, 3H), 6.1 (s, 0.5H), 5.4 (s, 0.5H), 4.6 (m, 1.5H), 4.3 (m, 0.5H), 4.1 (m, 1H), 3.7 (m, 3H), 2.4 (m, 2H), 2.3 (m, 1H), 2.2 (m, 1H), 1.8 (m, 2H), 1.6 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:4][CH:3]=1.C1C(=O)N(Br)C(=O)C1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[N:20]1([CH2:1][C:2]2[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:4][CH:3]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: C1COCCN1
Reactant: COC(=O)c1cncc(C)n1
Agent: O=C1CCC(=O)N1Br
Product: COC(=O)c1cncc(CN2CCOCC2)n1

Procedure:
By using 3.42 g of methyl 6-methylpyrazine-2-carboxylate and 4.40 g of NBS, a bromination reaction was performed by the method similar to Preparation Example 62. Thereafter, by using 10 mL of morpholine as amine, the reaction similar to Preparation Example 9 was performed, thereby obtaining 987 mg of methyl 6-(morpholin-4-ylmethyl)pyrazine-2-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].CN(C)P(N(C)C)N(C)C>>[CH2:3]=[C:2]([CH2:3][CH2:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: C=CC(=O)OC(C)(C)C
Agent: CN(C)P(N(C)C)N(C)C
Product: C=C(CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
Tert-butyl acrylate (465 g, 3.628 mol) was warmed to 100° C. under nitrogen, then hexamethylphosphorous triamide (10 g, 61.2 mmol) was added dropwise and the addition rate was adjusted to maintain the reaction temperature at 100° C. The reaction mixture was allowed to cool, then poured over a plug of silica (˜1000 ml) and washed completely off the silica with 4:1 hexane/ethyl acetate. The solvent was removed under reduced pressure and the resulting oil was distilled. Some material was collected from room temperature to 50° C. under high vacuum, and discarded. The temperature was then raised to ˜80° C. and the product (300 g, 65%, b.p. 67-70° C. at 300μ) was collected as a clear oil. 1H NMR (CDCl3): δ1.4 (m, 18H), 2.4 (t, 2H), 2.6 (t, 2H), 5.5 (s, 1H), 6.0 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].[C:25]1([CH3:34])[C:26]([N:31]=[C:32]=[O:33])=[CH:27][CH:28]=[CH:29][CH:30]=1.CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:32]([NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH3:34])=[O:33])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: Cc1ccccc1N=C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4C)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethyl-aniline (120 mg) was dissolved in chloroform (10 ml), and o-toluyl isocyanate (55 μl) was added to the solution. The mixture was stirred at room temperature overnight. Methanol was added to the reaction solution, and the solvent was removed by distillation under the reduced pressure. The residue was dissolved in a minor amount of chloroform, and a large amount of ether was added to the solution to precipitate a crystal which was then collected by filtration to give 130 mg (yield 70%) of the title compound.
Reaction SMILES: C(O)=O.[CH3:4][C:5](=[CH2:8])[CH:6]=O.[NH2:9][C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)(C)C>[CH3:8][C:5]1[CH:4]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:9][CH:6]=1
Reactant: CCOC(=O)C=C(N)C(=O)OCC
Reactant: C=C(C)C=O
Solvent: CC(C)O
Solvent: O=CO
Product: CCOC(=O)c1cc(C)cnc1C(=O)OCC
Temperature: 70 °C
Yield: 50 %

Procedure:
Isopropyl alcohol 675 ml and 90% formic acid 61.5 g (1.20 mol) were placed in 1 liter four-neck flask equipped with a reflux condenser. After heating the content to 70° C., 2-methyl-2-propenal 84.3 g (1.20 mol) and ethyl β-amino-β-ethoxycarbonylacrylate 150 g (0.801 mol) were simultaneously added dropwise thereto over a period of 1 hour with air-bubbling and refluxed for 10 hours. After removing isopropyl alcohol, 400 ml of water was added thereto and neutralized with sodium bicarbonate. After standing at 65°-67° C., separated oil layer was concentrated under reduced pressure to obtain 200 g of oily substance, which was distilled under reduced pressure to give 95 g of 5-methyl-2,3-diethoxycarbonylpyridine.
Reaction SMILES: I[CH2:2][CH2:3][C@H:4]([O:11][C:12]1[C:20]2[S:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:23][NH2:24].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>O1CCCC1.CO>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[S:19]1[C:20]2[C:12]([O:11][C@H:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:3][CH2:2][NH:24][CH3:23])=[CH:13][CH:14]=[CH:15][C:16]=2[CH:17]=[C:18]1[C:21]#[N:22]
Reactant: CN
Reactant: N#Cc1cc2cccc(O[C@@H](CCI)c3ccccc3)c2s1
Agent: O=C(O)/C=C/C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CNCC[C@H](Oc1cccc2cc(C#N)sc12)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a solution of 7-{[(1S)-3-iodo-1-phenylpropyl]oxy}-1-benzothiophene-2-carbonitrile (222 mg, 0.5 mmol) in tetrahydrofuran (2 mL) was added 40% aqueous methylamine (0.83 mL) and the solution was stirred at room temperature for 16 hours. The solvent removed in vacuo and the residue purified by flash chromatography with a gradient of 0–15% methanol in dichloromethane. To a solution of free base (155 mg, 0.48 mmol) in methanol (1 mL) and added a warm solution of fumaric acid (40 mg, 0.48 mmol) in methanol (1 mL). The solvent removed in vacuo, and the solid residue triturated with diethyl ether (5 mL), then dried in a vacuum oven at 40° C. for 1 h to give the title compound (0.20 g, 85%); δH (300 MHz, DMSO) 8.40 (1H, s, 3-ArH), 7.61–7.52 (1H, m, ArH), 7.49–7.23 (6H, m, ArH), 7.05–6.98 (1H, m, ArH), 6.43 (2H, s, CHCO2H), 5.85–5.75 (1H, m, CHO), 3.05–2.90 (2H, m, 1-CH2), 2.52 (3H, s, NHCH3) and 2.46–2.07 (2H, m, 2-CH2).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C=O.[BH4-].[Na+].[C:24](O)(C(F)(F)F)=O.[OH-].[Na+]>C1COCC1>[CH3:24][N:11]([CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([CH3:1])=[N:3][N:4]=2)[N:7]=1
Reactant: Cc1nnc2ccc(NC(C)c3ccccc3)nn12
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nnc2ccc(N(C)C(C)c3ccccc3)nn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Methyl-N-(1-phenylethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine (100 mg, 0.395 mmol), paraformaldehyde (119 mg, 3.95 mmol), NaBH4 (74.7 mg, 1.974 mmol) and anhydrous THF (5 mL) were charged into a disposable reaction tube equipped with a stirbar and a septum. TFA (2.5 mL) was slowly added at room temperature over 1 h and the reaction was stirred for an additional 18 h at room temperature. A 1M aqueous solution of NaOH was added until pH˜12 and the product was extracted with CH2Cl2/MeOH (19:1) (4×25 mL). The organic layers were combined, dried over Na2SO4 and concentrated to dryness. The crude product was then diluted with MeOH/H2O (19:1), filtered, purified by preparative HPLC (reverse phase) and lyophilized to give the N,3-dimethyl-N-(1-phenylethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine (Compound 2) as a white solid (6 mg; 6% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.98 (d, J=10.1 Hz, 1H), 7.22-7.39 (m, 6H), 5.68 (q, J=6.9 Hz, 1H), 2.81 (s, 3H), 2.52 (s, 3H), 1.56 (d, J=7.1 Hz, 3H). LRMS [M+H]+: 268 m/z.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:33]=[C:34](\[C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([Br:48])[CH:39]=2)/[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[S:51][CH:52]=[CH:53][N:54]=1>C(Cl)Cl>[Br:48][C:40]1[CH:39]=[C:38](/[C:34](=[CH:33]\[CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)/[C:35]([NH:49][C:50]2[S:51][CH:52]=[CH:53][N:54]=2)=[O:37])[CH:43]=[CH:42][C:41]=1[S:44]([CH3:47])(=[O:46])=[O:45]
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1Br
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
A solution of triphenylphosphine (467 mg, 1.78 mmol) in methylene chloride (8 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (317 mg, 1.78 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution (E)-3-cyclopentyl-2-[3-bromo-4-(methanesulfonyl)-phenyl]-acrylic acid (334 mg, 0.89 mmol) in methylene chloride (4 mL). The reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (713 mg, 7.12 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (40 mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×25 mL). The combined organic extracts were successively washed with a 1N aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotaoe chromatography (FLASH 40S, Silica, 3/1 hexanes/ethyl acetate) afforded the pure (E)-2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-acrylamide (71 mg, 17.5%) as an amorphous white solid: EI-HRMS m/e calcd for C18H19BrN2O3S2 (M+) 454.0020, found 454.0025.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH:3]=O.[CH2:13]([NH:20][OH:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Ca+2].[Cl-]>CCOCC>[CH3:1][CH:2]([CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH:3]=[N+:20]([O-:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C=O)COC1CCCCO1
Reactant: ONCc1ccccc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCOCC
Product: CC(C=[N+]([O-])Cc1ccccc1)COC1CCCCO1
Yield: 62.9 %

Procedure:
An etheral solution (1 ml) of 2-methyl-3-tetrahydropyranyloxypropanal (37.9 mg; 0.20 mmol) was added dropwise to a suspension of benzylhydroxylamine (28.7 mg; 0.23 mmol) and powdery calcium chloride (22.2 mg; 0.20 mmol) in ether (0.5 ml) at 0° C., and the resultant mixture was stirred for 1.5 hours. The reaction mixture was purified by TLC using ethyl acetate to give N-(2-methyl-3-tetrahydropyranyloxypropylidene)-benzylamine-N-oxide (34.9 mg; yield, 57%).