Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1
Reactant: CCOC(=O)C[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C[C@@H]1CCCNC1

Procedure:
280 mg (1.03 mmol) of ethyl (S)-(1-tert-butoxycarbonylpiperidin-3-yl)acetate (Example 16A) are stirred with 2 ml of dichloromethane and 2 ml of trifluoroacetic acid at RT for 1 h. The volatile components are removed on a rotary evaporator and the residue is dried under high vacuum. The resulting oil (290 mg, 99% of theory) is reacted further as it is.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[S:30]1[CH:34]=[CH:33][N:32]=[C:31]1[CH2:35]O>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:35][C:31]5[S:30][CH:34]=[CH:33][N:32]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: OCc1nccs1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1nccs1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(1,3-thiazol-2-ylmethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and thiazol-2-yl-methanol following General Procedure J.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:12]=[C:11](OC2C=CC=CC=2)[N:10]=1.[C:30]1([CH:37]=[CH:36][CH:35]=[C:33]([OH:34])[CH:32]=1)[OH:31].[Cl-].[Al+3].[Cl-].[Cl-].Cl>CCCCCCC.C1(C)C=CC=C(C)C=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:12]=[C:11]([C:35]2[CH:36]=[CH:37][C:30]([OH:31])=[CH:32][C:33]=2[OH:34])[N:10]=1
Reactant: Oc1cccc(O)c1
Reactant: Cc1ccc(-c2nc(Oc3ccccc3)nc(-c3ccc(C)cc3C)n2)c(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1cccc(C)c1
Solvent: CCCCCCC
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(O)cc3O)n2)c(C)c1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
To a 250 mL round-bottomed flask fitted with a magnetic stirrer, a condenser and a nitrogen atmosphere are charged 7.85 g (0.0206 mol) of the product of Example 2, 13.5 g (0.123 mol) of resorcinol, 4 mL of m-xylene and 0.954 g (7.16 mmol) of aluminum chloride. The mixture is heated to 150° C. for 13.5 hours and then allowed to cool to 90° C. Portions of 2N hydrochloric acid and heptane are added and the mixture is stirred at 90° C. for 30 minutes followed by stirring for 18 hours at room temperature. The mixture is then warmed to 35° C. The crude solid formed is collected by vacuum filtration and is washed with portions of water and heptane. The solid is then recrystallized twice from methanol to afford 4.76 g (62% yield) of the title compound as a yellow solid melting at 194-196° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:64]=[C:65]([Cl:67])[CH:66]=1)[CH2:23][N:24]1[C:32]2[C:27](=[N:28][C:29](Cl)=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:34]([O:36][CH2:37][C:38]1[CH:43]=[C:42]([Cl:44])[CH:41]=[C:40]([CH2:45][O:46][Si:47]([C:60]([CH3:63])([CH3:62])[CH3:61])([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:39]=1)=[O:35])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:68]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[NH:69][C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:64]=[C:65]([Cl:67])[CH:66]=1)[CH2:23][N:24]1[C:32]2[C:27](=[N:28][C:29]([N:68]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[NH:69][C:70]([O:72][C:73]([CH3:74])([CH3:75])[CH3:76])=[O:71])=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:34]([O:36][CH2:37][C:38]1[CH:43]=[C:42]([Cl:44])[CH:41]=[C:40]([CH2:45][O:46][Si:47]([C:60]([CH3:63])([CH3:61])[CH3:62])([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:39]=1)=[O:35])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](OCc1cc(Cl)cc(COC(=O)c2cc3nc(Cl)ccc3n2Cc2cc(Cl)cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)c1)(c1ccccc1)c1ccccc1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(C(=O)OCc3cc(Cl)cc(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)c3)n2Cc2cc(Cl)cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)n1
Temperature: 110 °C

Procedure:
A degassed mixture of 3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-chlorobenzyl 1-[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-chlorobenzyl]-5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (3.11 g, 3.16 mmol, from Step 4), di-tert-butyl hydrazine-1,2-dicarboxylate (0.81 g, 3.5 mmol, Aldrich), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.29 g, 0.37 mmol, Aldrich) and Cs2CO3 (1.1 g, 3.5 mmol) in toluene (36 mL) was sealed and heated at 110° C. for 4 hours. The reaction mixture was partitioned between water and ethyl acetate and the aqueous was extracted three times. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-25% EtOAc in hexanes. Yield: (1.19 g, 32%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[N:3]=1.Cl.[NH2:19][C:20]1[C:25]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])=[CH:24][CH:23]=[C:22]([NH:32][CH:33]2[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]2)[N:21]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:19][C:20]1[N:21]=[C:22]([NH:32][CH:33]2[CH2:38][CH2:37][CH2:36][N:35]([C:2]3[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=4[Cl:17])[N:3]=3)[CH2:34]2)[CH:23]=[CH:24][C:25]=1[C:26](=[O:31])[C:27]([F:30])([F:29])[F:28]
Reactant: N#Cc1ccc(-c2ccc(Cl)cc2Cl)nc1Cl
Reactant: Nc1nc(NC2CCCNC2)ccc1C(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2ccc(Cl)cc2Cl)nc1N1CCCC(Nc2ccc(C(=O)C(F)(F)F)c(N)n2)C1
Temperature: 120 °C

Procedure:
29.5 mg (0.1 mmol) of 2-chloro-6-(2,4-dichlorophenyl)pyridine-3-carbonitrile, 30 mg (0.1 mmol) of 1-[2-amino-6-(piperidin-3-ylamino)pyridin-3-yl]-2,2,2-trifluoroethanone hydrochloride (Example 13A) and 0.09 ml (0.52 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated at 120° C. in a microwave for 30 min. The crude product was purified by means of preparative HPLC (method 13). 35 mg (63% of theory) of the product were obtained in solid form.
Reaction SMILES: [H-].[Na+].C(S(CC)=O)C.[N:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:23][C:22]3[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:11][CH:10]=1.[N:30]1[CH:35]=[CH:34][C:33]([CH2:36]Cl)=[CH:32][CH:31]=1>CS(C)=O>[N:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]2([CH2:36][C:33]3[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[S:23][C:24]3[C:29]2=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:13][CH:14]=1
Reactant: c1ccc2c(c1)Sc1ccccc1C2Cc1ccncc1
Reactant: ClCc1ccncc1
Agent: CCS(=O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc2c(c1)Sc1ccccc1C2(Cc1ccncc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
A quantity of 0.38 g (8.0 mmole) of 50% sodium hydride oil dispersion was added slowly during 15 minutes to 20 ml of ethyl sulfoxide at room temperature. After completion of addition, the reaction mixture was heated at 45° for 30 minutes. It was cooled to 15° and a solution of 2.3 g (8.0 mmole) of 9-(4-pyridinylmethyl)thioxanthene in 10 ml of dimethylsulfoxide was added dropwise during 15 minutes at room temperature. After completion of addition, the reaction mixture was stirred 30 minutes at room temperature. Then a solution of 4-picolylchloride (8.75 mmole) in 5 ml of dimethylsulfoxide was added dropwise during 30 minutes at ambient temperature. The reaction was then heated at 40° for 30 minutes. The reaction was quenched by addition of water (50 ml). Trituration of the precipitated oil yielded a crystalline solid, which was filtered off, washed with water and dried. The tan solid was dissolved in benzene and decolorized by stirring with 1 g of Magnesol® for 30 minutes. Filtration and evaporation yielded a colorless product (2.0 g) which was recrystallized from ethylacetate, m.p., 201.4°-203.4°.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][OH:7])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:14](Cl)(=[O:16])[CH3:15].Cl.N1C=CC=CC=1>O.C(Cl)Cl>[C:14]([O:7][CH2:6][CH2:5][CH2:4][C:1](=[O:3])[CH3:2])(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: CC(=O)CCCO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)CCCOC(C)=O
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To a 1 liter 3-neck round bottom flask equipped with a stirrer, thermometer, condenser and addition funnel, was added 102 grams (1 mole) of 3-acetylpropanol, 125 mls of pyridine and 600 mls of methylene chloride. With ice cooling and good agitation, 78.5 grams (1 mole) of acetyl chloride was added slowly from the addition funnel while holding the temperature at 25° C. or below. Pyridine hydrochloride began coming out of solution about 1/3 of the way through the addition. After the addition was complete, the reaction mixture was stirred an additional 15 minutes at 20°-25° C. and then warmed to 40° C. and stirred an hour at 40° C. Then 150 mls of water were added to dissolve the pyridine hydrochloride and the aqueous layer was separated. The organic layer was washed twice with 200 mls of 10% HCl, once with water and saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered and the methylene chloride stripped off on a rotary evaporator under reduced pressure. The light yellow liquid weighed 104 grams (72% crude yield). The infrared spectrum of the product contained two strong carbonyl bands at 1720 cm-1 and 1745cm-1 and there was no OH band.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([NH:2][OH:1])=[O:5])=[N:21][CH:22]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(OCc2ccccc2)cn1
Reactant: NO
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(CCCCCCN(c1ccccn1)c1ccc(OCc2ccccc2)cn1)NO
Reaction time: 72 h
Yield: 74 %

Procedure:
HONH2 (50% aqueous, 0.5 mL) was added to III (26 mg, 0.06 mmol) in DMF (0.2 mL) and MeOH (0.5 mL) at rt. The reaction mixture was stirred for 72 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×10 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 to 100:8) to furnish IV as a colourless oil (18.66 mg, 74%).
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[CH:7][C:6](O)=[C:5]([N+:10]([O-:12])=[O:11])[C:4]1=[O:13])[CH3:2].O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:6]1[CH:7]=[CH:8][N:3]([CH2:1][CH3:2])[C:4](=[O:13])[C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: CCn1ccc(O)c([N+](=O)[O-])c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCn1ccc(Cl)c([N+](=O)[O-])c1=O
Temperature: 25 °C
Yield: 52.7 %

Procedure:
A suspension of 1-ethyl-4-hydroxy-3-nitro-1H-pyridine-2-one (1.0 g, 5.43 mmol) in POCl3 (8.33 g, 54.3 mmol) was heated at refluxed for 1 h. After cooling to room temperature, the solvent was evaporated under reduced pressure and water was carefully added to the chilled residue. The mixture was neutralized with 2 N NaOH, extracted with CHCl3, washed with brine, dried over MgSO4 and concentrated under reduced pressure. The resulting solid was washed with Et2O to give 4-chloro-1-ethyl-3-nitro-1H-pyridin-2-one (0.58 g, 53% yield). 1H-NMR (CDCl3): δ, 7.48 (d, 1H, J=7.6 Hz), 6.37 (d, 1H, J=7.6 Hz), 4.07 (q, 2H, J=7.2 Hz), 1.40 (t, 3H, J=7.2 Hz). MS: calculated for C7H7ClN2O3+H 203.0; found: 203.1.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:24]1([N:30]2[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:33][C:32]([CH:41]=O)=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][NH:21][CH2:41][C:32]3[CH:33]=[C:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:31]=3)[CH2:17][CH2:18]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:22][CH:23]=1
Reactant: O=Cc1cc(-c2ccccc2)n(-c2ccccc2)n1
Reactant: NCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Product: Clc1ccc(C(c2ccccc2)N2CCN(CCNCc3cc(-c4ccccc4)n(-c4ccccc4)n3)CC2)cc1
Yield: 61 %

Procedure:
Compound 98 was prepared using the same method as that of Example 1 except that 4-(4-chlorobenzhydryl)piperazin-1-ylethylamine and 1,5-diphenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C@@H:13]([OH:26])[CH2:14][O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[N:21]3)[CH2:8][CH2:7]1)=[O:5])C.O.CO.[OH-].[Li+:31]>O1CCCC1>[OH:26][C@@H:13]([CH2:14][O:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2)[CH2:12][N:9]1[CH2:10][CH2:11][CH:6]([C:4]([O-:5])=[O:3])[CH2:7][CH2:8]1.[Li+:31]
Reactant: CCOC(=O)C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C([O-])C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
(R)-1-[2-Hydroxy-3-(quinolin-5-yloxy)-propyl]-piperidine-4-carboxylic acid ethyl ester (31) (1.15 g; 3.21 mmol) is dissolved in 21 mL of a 40:40:20 mixture of tetrahydrofuran:water:methanol. Lithium hydroxide (81 mg; 3.37 mmol) is added and the mixture stirred at ambient temperature. After 4.5 hours, the mixture is concentrated in vacuo at 40° C. Further drying on the vacuum pump affords the desired product (32) as a white solid.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[C:12]([CH:14]([OH:17])[CH2:15][CH3:16])[O:11][N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1C=C(C(=O)CC)ON=1.C(O)(C)C>CC(C)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>[C:1]([C:9]1[CH:13]=[C:12]([C:14](=[O:17])[CH2:15][CH3:16])[O:11][N:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(O)c1cc(C(=O)c2ccccc2)no1
Agent: O=[Cr](=O)=O
Agent: CCC(=O)c1cc(Br)no1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CCC(=O)c1cc(C(=O)c2ccccc2)no1

Procedure:
Reacted under reflux for 2 hours were 5.0 g (27.3 mmol) of benzoylacetohydroxamoyl chloride prepared by a known process [J. Org. Chem., 409 (1942)] and 5.0 g (59.5 mmol) of 1-pentyne-3-ol. The reaction mixture was added into water, followed by extraction with ethyl ether. The extract was concentrated and then purified by silica gel chromatography (eluent: chloroform), whereby the title compound, namely, 3-benzoyl-5-(1-hydroxypropyl)isoxazole was obtained. It was dissolved in acetone, to which the Jones' reagent was added dropwise under ice cooling so that it was oxidized from the alcohol form to a ketone form. Isopropyl alcohol was added to the reaction mixture. After an insoluble material was filtered off, the solvent was distilled off so that 3-benzoyl-5-propionylisoxazole was obtained as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[H-].[Na+].[Cl:24][CH:25]=[CH:26][CH2:27]Cl>CN(C=O)C.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:14]([CH2:27][CH:26]=[CH:25][Cl:24])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19]
Reactant: ClC=CCCl
Reactant: CC(C)(C)OC(=O)Nc1ccc2cc(C#N)ccc2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC=CCl)c1ccc2cc(C#N)ccc2c1Br
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.7 %

Procedure:
A stirred solution of nitrile 141 (5.78 g, 16.6 mmol) in dry DMF (50 mL) was treated at 0° C. with NaH (0.80 g, 20.0 mmol, 60% in oil). The resulting suspension was warmed to room temperature for 30 min, then cooled to 0° C. again and treated with 1,3-dichloropropene (4.8 mL, 52 mmol, mixed isomers). After stirring at room temperature for a further 6 h, the mixture was diluted with water and extracted with EtOAc (×3). The combined organic extracts were washed with water (×3), dried, and concentrated to dryness under high vacuum at 80° C. The residue was chromatographed on silica gel, eluting with CH2Cl2, to give tert-butyl 1-bromo-6-cyano-2-naphthyl(3-chloro-2-propenyl)carbamate (142) (6.77 g, 96%) as a foam; 1H NMR [(CD3)2SO] (mixture of rotamers and E and Z forms) δ 8.69 (s, 1H), 8.35 (d, J=8.8 Hz, 1H), 8.13, 8.12 (2 d, J=8.6 Hz, 1H), 7.96 (d, J=8.9 Hz, 1H), 7.69, 7.63 (2d, J=8.7 Hz, 1H), 6.42-6.29 (m, 1H), 6.17-5.99 (m, 1H), 4.55-4.45, 4.40-4.19, 4.15-3.98 (3 m, 2H), 1.48, 1.24 (2 s, 9H). HRMS (FAB) calcd. for C19H1979Br35ClN2O2(m/z 421.0318, found 421.0306.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]2[C:7](=[O:29])/[C:8](=[CH:10]/[C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[CH:18]=4)[NH:13][N:12]=3)/[O:9][C:5]=2[C:4]=1[CH2:32][N:33]1[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]1.Cl>C(Cl)Cl.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]2[C:7](=[O:29])/[C:8](=[CH:10]/[C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)[CH:18]=4)[NH:13][N:12]=3)/[O:9][C:5]=2[C:4]=1[CH2:32][N:33]1[CH2:34][CH2:35][NH:36][CH2:37][CH2:38]1
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccc(OCCN4CCOCC4)cc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1CN1CCNCC1)O/C(=C\c1n[nH]c3ccc(OCCN4CCOCC4)cc13)C2=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.7 %

Procedure:
A solution of tert-butyl (Z)-4-[(6-methoxy-2-{[5-(2-morpholinoethoxy)-1H-indazol-3-yl]methylene}-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0273 g, 0.0441 mmol) in methylene chloride (2 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (1 mL), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted five times with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain (Z)-6-methoxy-2-{[5-(2-morpholinoethoxy)-1H-indazol-3-yl]methylene}-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0130 g, 56%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: Fc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-fluorobenzaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][C:17]4[CH:18]=[CH:19][C:20]5[N:21]([C:23]([C:26](=[O:28])[CH3:27])=[CH:24][N:25]=5)[CH:22]=4)=[CH:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1.O.[BH4-].[Na+].O1CCOCC1>CO>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][C:17]4[CH:18]=[CH:19][C:20]5[N:21]([C:23]([CH:26]([OH:28])[CH3:27])=[CH:24][N:25]=5)[CH:22]=4)=[CH:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1
Reactant: CC(=O)c1cnc2ccc(Cc3cnc4ccc(-c5cnn(C)c5)nn34)cn12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CC(O)c1cnc2ccc(Cc3cnc4ccc(-c5cnn(C)c5)nn34)cn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-{6-[6-(1-Methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-imidazo[1,2-a]pyridin-3-yl}-ethanone (Example 301, 50 mg, 0.135 mmol) was dissolved in MeOH (3 mL) and water (1 mL) then NaBH4 (3.1 mg, 0.081 mmol) was added. The RM was stirred at rt for 2 h. More equivalents of NaBH4 (3 times 5.1 mg, 0.135 mmol) were added to RM over 18 h. Then dioxane was added and it was stirred at 60° C. for 2 h. It was quenched with EtOAc and solvents were removed. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and lyophilized. The residue was dissolved in MeOH and it was passed through an SPE cartridge of HCO3− to remove the TFA salt. The filtrate was evaporated to give the free salt compound of the title compound as a white solid (tR 0.6 min (conditions 2), MH+=374).
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:27]=[C:28]([F:30])[CH:29]=1)[C:12]([C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)=[O:13].CO>C1COCC1.CCOC(C)=O>[Cl:8][C:9]1[CH:10]=[C:11]([C@H:12]([OH:13])[C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:15]2)[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cc(F)cc(Cl)c2)C1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2cc(F)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a solution of 1 M R-CBS-oxazaborolidine in toluene (11 mL, 11 mmol, 0.15 eq) and 10 M BH3 in THF (7.3 mL, 73 mmol, 1.0 eq) at −15° C. under nitrogen was added dropwise a solution of (R)-tert-butyl 3-(3-chloro-5-fluorobenzoyl)piperidine-1-carboxylate (25 g, 73 mmol) in anhydrous THF (50 mL). After addition, the reaction mixture was stirred for 1 hr at rt. Methanol (100 mL) was added dropwise carefully at 0° C. The solvent was removed under reduced pressure to provide the crude product. The crude product was dissolved in EtOAc until the alcohol was just dissolved (about 5 mL/1 g), the solvent was removed on the rotary evaporator until a few crystals appeared. To the above solution was added petroleum ether (about 300 mL) under stirring, which was allowed to stir at rt for 2 hr and then filtered, the crystals were washed with petroleum ether and re-crystallized a few more times to afford pure (R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (9.2 g, 37%). 1H NMR (DMSO, 400 MHz): δ 7.44 (d, 1H), 7.38 (s, 1H), 7.30 (d, 1H), 4.48 (t, 1H), 4.20 (brs, 1H), 3.98 (d, 1H), 2.73 (s, 2H), 1.70 (s, 2H), 1.48 (s, 10H), 1.36-1.39 (m, 2H).