Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])[CH:5]=[CH:4][N:3]=1.[F:27][C:28]1[C:29]([CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:30][C:31]([O:35][CH3:36])=[C:32]([CH:34]=1)[NH2:33].C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(O)C>C(Cl)Cl>[F:27][C:28]1[C:29]([CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:30][C:31]([O:35][CH3:36])=[C:32]([NH:33][C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]4=[N:10][C:9]=3[C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([O:22][CH3:23])=[O:21])[CH:5]=[CH:4][N:3]=2)[CH:34]=1
Reactant: COc1cc(CCN2CCCCC2)c(F)cc1N
Reactant: COC(=O)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2nc3ccccn3c2-c2ccnc(Nc3cc(F)c(CCN4CCCCC4)cc3OC)n2)c1
Temperature: 180 °C
Yield: 51.4 %

Procedure:
Methyl 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzoate (Intermediate Example 3) (300 mg, 0.82 mmol), 5-fluoro-2-(methyloxy)-4-[2-(1-piperidinyl)ethyl]aniline (Example 127, step D) (187 mg, 0.74 mmol), and p-toluenesulfonic acid (375 mg, 1.97 mmol) were weighed into a 10 mL microwave vial. 7 mL of iPrOH was added and the mixture was heated in the microwave to 180° C. for 17 min. The mixture was transferred to a 50 mL round bottom and diluted with 10 mL of DCM. 2 g of silica gel was added. The solvent was rotovaped down and the residue purified by flash chromatography to give the title compound of step A (220 mg, 0.38 mmol, 46%). 1H NMR (400 MHz, CDCl3) δ ppm 9.51 (d, J=6.97 Hz, 1H), 8.37-8.39 (m, 1H), 8.23-8.30 (m, 2H), 8.08-8.11 (m, 1H), 7.84-7.87 (m, 1H), 7.79 (s, 1H), 7.74 (d, J=8.80 Hz, 1H), 7.50 (t, J=7.70 Hz, 1H), 7.35-7.41 (m, 1H), 6.95 (t, J=6.97 Hz, 1H), 6.76 (d, J=6.97 Hz, 1H), 6.60 (d, J=5.50 Hz, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 2.79-2.86 (m, 2H), 2.54-2.60 (m, 2H), 2.46-2.54 (m, 4H), 1.60-1.66 (m, J=5.68, 5.68, 5.68, 5.68 Hz, 4H), 1.43-1.50 (m, J=5.13 Hz, 2H).
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16]C(C)([O-])C.[K+].CI>C1COCC1>[C:1]1([C:7](=[O:8])[CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C(=O)c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To deoxybenzoin (0.500 g, 2.55 mmol) in THF (12 mL) at −78° C. were added a THF solution of potassium tert-butoxide 1M (2.5 mL, 2.55 mmol) and MeI (0.396 mL). After a period of 0.5 h, at room temperature, NH4OAc aqueous was added to the reaction mixture. The organic phase was separated, dried over NaSO4, filtered and evaporated. The residue was purified by flash chromatography to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][O:9][C:10](=[O:12])[CH:11]=2)[CH:2]=1.[N:13]([O-])=[O:14].[Na+]>O.C(O)(=O)C>[N:13](=[C:11]1[C:10](=[O:12])[O:9][N:8]=[C:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[OH:14]
Reactant: O=c1cc(-c2cccnc2)[nH]o1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1ON=C(c2cccnc2)C1=NO
Reaction time: 4 h

Procedure:
A suspension of 57 g of 3-(pyrid-3-yl)isoxazol-5-one in 50 ml of water and 350 ml of glacial acetic acid is treated dropwise at 15° C. with a solution of 27 g of sodium nitrite in 60 ml of water. After 4 hours, the precipitate is filtered off with suction, washed with water and dried.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:50]([CH3:52])[CH3:51])[C:10]([O:12][C@H:13]([C:15]1[N:19]2[N:20]([CH2:38][C:39]3[C:40]([CH3:49])=[N:41][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:43][CH:44]=3)[C:21](=[O:37])[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:18]2=[N:17][N:16]=1)[CH3:14])=[O:11])=O)(C)(C)C.[ClH:53]>>[NH2:8][C@@H:9]([CH:50]([CH3:52])[CH3:51])[C:10]([O:12][C@H:13]([C:15]1[N:19]2[N:20]([CH2:38][C:39]3[C:40]([CH3:49])=[N:41][C:42]([C:45]([F:46])([F:48])[F:47])=[CH:43][CH:44]=3)[C:21](=[O:37])[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:23]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C:18]2=[N:17][N:16]=1)[CH3:14])=[O:11].[ClH:53]
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccccc2)c(-c2ccc(Cl)cc2)c2nnc([C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)n21
Agent: Cl
Product: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccccc2)c(-c2ccc(Cl)cc2)c2nnc([C@H](C)OC(=O)[C@@H](N)C(C)C)n21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask was added (S)—((S)-1-(8-(4-chlorophenyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-7-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl) 2-( tert-butoxycarbonylamino)-3-methylbutanoate (39 mg, 0.529 mmol) and 4N HCl (2 ml). The reaction was stirred at rt for 30 min. After this time, the solution was concentrated under reduced pressure. To the residue was added CH2Cl2(2 ml) and hexanes (2 ml). The solvent was decanted. The remaining solid was dried under vacuum to give product (S)—((S)-1-(8-(4-chlorophenyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-7-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl) 2-amino-3-methylbutanoate as an HCl salt (30mg, 85% yield).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[Cl:19])=[CH:16][CH:15]=[CH:14][CH:13]=2>ClCCl>[Cl:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH:8][C:5](=[O:6])[CH2:4][O:3][CH2:1][CH3:2]
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: CCOCC(=O)Cl
Solvent: ClCCl
Product: CCOCC(=O)Nc1cnc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A solution of ethoxyacetyl chloride (4.2 g, 34 mmol) in dichloromethane was added dropwise to a stirred solution of 3-amino-4-chloroquinoline (5.1 g, 29 mmol) in dichloromethane (75 mL), and the reaction was stirred for one hour at room temperature. Additional ethoxyacetyl chloride (0.5 g, 4 mmol) was added, and the reaction was stirred for 30 minutes and diluted with dichloromethane (75 mL). The resulting mixture was washed with saturated aqueous sodium bicarbonate (50 mL), dried over potassium carbonate, and filtered. Methanol was added to facilitate the filtration. The filtrate was concentrated under reduced pressure to provide 7.3 g of N-(4-chloroquinolin-3-yl)-2-ethoxyacetamide as a dark solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([CH2:14][O:15][C:16]([C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=2)=[CH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:38].[Na+].OO>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([CH2:14][O:15][CH:16]([C:18]2[CH:19]=[C:20]([C:28]([F:31])([F:29])[F:30])[CH:21]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:23]=2)[CH2:17][OH:38])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [OH-]
Reactant: C=C(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COC(CO)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Reaction time: 3 h

Procedure:
The compound of step (c) above was treated with BH3.tetrahydrofuran (5 ml of a 1M solution in tetrahydrofuran) under an atmosphere of nitrogen for 2 hours. A mixture of 4N NaOH (10 ml) and H2O2 (5 ml of a 29% solution in water) was added and the reaction stirred for 3 hours, then extracted with diethyl ether. The ethereal extracts were washed with sodium bisulphite solution then dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate-petroleum ether (3:7) to give the title compound as a colourless oil.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[N:13]=[C:12]([C:14](OCC)=[O:15])[S:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[N:13]=[C:12]([CH2:14][OH:15])[S:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1nc(/C=C/c2ccccc2)ns1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1nc(/C=C/c2ccccc2)ns1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.3 %

Procedure:
Ethyl 3-[(E)-2-phenylethenyl]-1,2,4-thiadiazole-5-carboxylate (1.0 g, 3.8 mmol) was suspended in methanol (50 mL), and NaBH4 (220 mg, 5.8 mmol) was added in portions. The mixture was stirred for 16 h at ambient temperature. The reaction was concentrated in vacuo, acidified with aqueous HCl (4 M) to pH 2, and partitioned between Ethyl acetate and water. The organics were dried over Na2SO4, concentrated in vacuo, and the resultant material was rerystallized from ethyl acetate to afford {3-[(E)-2-phenylethenyl]-1,2,4-thiadiazol-5-yl}methanol (0.6 g, 71% yield) as a pale yellow solid. M.p. 119–120° C. 1H NMR (CDCl3, 300 MHz) δ 7.79 (d, J=16 Hz, 1H), 7.57 (m, 2H), 7.38 (m, 3H), 7.23 (d, J=16 Hz, 1H), 5.14 (d, J=5 Hz, 2H), 3.29 (t, J=5 Hz, 1H). MS (EI ionization) 217 (M+−H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]2[C:10](=[O:14])[CH:11]=[CH:12][O:13][C:8]=2[CH:7]=1.Cl.Cl.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.[I-].[Na+]>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:16]=[CH:15][C:9]3[C:10](=[O:14])[CH:11]=[CH:12][O:13][C:8]=3[CH:7]=2)[CH2:28][CH2:27]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: O=c1ccoc2cc(OCCCCl)ccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CN(C)C=O
Product: O=c1ccoc2cc(OCCCN3CCN(c4ccccc4Cl)CC3)ccc12

Procedure:
A mixture of 7-(3-chloropropoxy)-4H-benzopyran-4-one as prepared above in Preparation I (2.38 g; 10 mmol), 1-(2-chlorophenyl)piperazine dihydrochloride (2.96 g; 11 mmol), sodium bicarbonate (3 g; 35 mmol), sodium iodide (0.1 g; 0.6 mmole) in 50 ml dimethylformamide was mechanically stirred and heated at 85°-90° C. for seven hours. The solvent was then evaporated in vacuo and the residue partitioned between water and dichloromethane. The organic phase was treated with an excess of 10% HCl solution in methanol, evaporated in vacuo and the residue recrystallized from ethanol/ethyl acetate to yield 3.2 g of 7-[3-(4-(2-chlorophenyl)-1-piperazinyl)propoxy]-4H-1-benzopyran-4-one as its hydrochloride salt, mp 201°-203° C. (dec).
Reaction SMILES: [CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18]([CH:21]=[CH2:22])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[CH:27]2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.N#N>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(N(C)C)=O>[CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18](/[CH:21]=[CH:22]/[C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[NH:29][CH:28]=[CH:27]5)(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: C=CS(=O)(=O)N1CCC2(CC1)N=C(C1CCCCC1)NC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C1NC(C2CCCCC2)=NC12CCN(S(=O)(=O)/C=C/c1ccc3[nH]ccc3c1)CC2

Procedure:
2-Cyclohexyl-8-ethenesulfonyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (60.0 mg, 0.184 mmol), 5-bromo-indole (72.0 mg, 0.367 mmol), palladium(II) acetate (4.1 mg, 0.0183 mmol), tris(o-tolyl)phosphine (11.2 mg, 0.0368 mmol), triethylamine (0.077 ml, 0.552 mmol) and DMA (0.6 ml) were mixed in a sealed test tube in an N2 atmosphere. This mixture was irradiated with microwaves (190° C., 20 min). The reaction mixture was cooled, and then quenched with saturated brine and extracted with ethyl acetate three times. The organic layers were combined, sequentially washed with water and saturated brine and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (CH2Cl2-MeOH) to give 2-cyclohexyl-8-[(E)-2-(1H-indol-5-yl)-ethenesulfonyl]-1,3,8-triaza-spiro[4.5]dec-1-en-4-one as a yellow form (40.6 mg, 50%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[CH2:11][C:12]1[C:20]([OH:21])=[CH:19][C:15]2[CH2:16][CH2:17][O:18][C:14]=2[CH:13]=1.C(O)C>C(O)(=O)C.O=[Pt]=O.C(OCC)C>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][C:12]1[C:20]([OH:21])=[CH:19][C:15]2[CH2:16][CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: OCc1ccccc1/C=C/Cc1cc2c(cc1O)CCO2
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CCO
Product: OCc1ccccc1CCCc1cc2c(cc1O)CCO2
Reaction time: 0.05 h
Yield: 49.2 %

Procedure:
6-(3-(2-hydroxymethylphenyl)-trans-prop-2-enyl)-5-hydroxy-2,3-dihydrobenzofuran (2.82 g; 0.01 moles) was dissolved in acetic acid (35 ml) and ethyl alcohol (10 ml) and hydrogenated at 40 psi at room temperature using PtO2 (0.30 g) as a catalyst. The reduction was complete in approximately 3 minutes with a slight exotherm. The catalyst was removed via suction filtration through a bed of celite. The bed was washed with ethyl alcohol (2×10 ml) and the filtrate was relieved of solvent in vacuo to afford a crude gum. The gum was dissolved in ethyl ether (50 ml) and was washed sequentially with brine (2×50 ml) and saturated NaHCO3 solution (2×50 m). The organic layer was dried over MgSO4, filtered, and the filtrate evaported in vacuo to yield a crude solid. Recrystallization from ethyl acetate/n-hexane produced 6-(3-(2-hydroxymethyl-phenyl)propyl)-5-hydroxy-2,3-dihydrobenzofuran as white needles (1.4 g, 49%, m.p. 110°-111.5° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][N:9]=2)[C:5]2[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:4]=2[O:3]1.C(OCC)(=[O:29])C>>[C:24]([C:21]1[CH:22]=[CH:23][C:4]2[O:3][C:2]([CH3:26])([CH3:1])[CH2:7][CH:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:10][N+:9]=3[O-:29])[C:5]=2[CH:20]=1)#[N:25]
Reactant: CC1(C)CC(c2ccc(-c3ccccc3)cn2)c2cc(C#N)ccc2O1
Reactant: CCOC(C)=O
Product: CC1(C)CC(c2ccc(-c3ccccc3)c[n+]2[O-])c2cc(C#N)ccc2O1

Procedure:
In an analogous manner to that described in the first paragraph of Example 7, from 3,4-dihydro-2,2-dimethyl-4-(5-phenyl-2-pyridyl)-2H-1-benzopyran-6-carbonitrile there was obtained 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2-H-1-benzopyran-4-yl)-5-phenylpyridine N-oxide of melting point 174°-176° C. (from ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[C:25]1[N:26]=[C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[S:28][CH:29]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[C:25]1[N:26]=[C:27]([N:30]2[CH2:35][CH2:34][N:33]([C:9]([NH:8][C:5]3[O:4][N:3]=[C:2]([CH3:1])[C:6]=3[CH3:7])=[O:16])[CH2:32][CH2:31]2)[S:28][CH:29]=1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Reactant: Clc1cccc(-c2csc(N3CCNCC3)n2)c1Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4cccc(Cl)c4Cl)cs3)CC2)c1C
Temperature: 70 °C
Reaction time: 72 h
Yield: 15.6 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (121 mg, 0.420 mmol), 1-[4-(2,3-dichlorophenyl)-1,3-thiazol-2-yl]piperazine (120 mg, 0.382 mmol) and diisopropylethylamine (0.133 ml, 0.764 mmol) in dimethyl sulfoxide (1.2 ml) was stirred at 70° C. for 3 days. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1), and recrystallized from a mixed solvent of hexane and ethyl acetate to give 27.0 mg (15.6%) of the desired product as a solid. mp 175-176° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Cl[C:11]1[CH:16]=CC(C#C)=CN=1>>[C:11]([C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1)#[CH:16]
Reactant: C#Cc1ccc(Cl)nc1
Reactant: COc1ccc(Br)cn1
Product: C#Cc1ccc(OC)nc1

Procedure:
5-Ethynyl-2-methoxy pyridine was prepared from 5-bromo-2-methoxy-pyridine (Aldrich) in the same manner as 2-chloro-5-ethynyl-pyridine (Example 1).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].CS[C:17]1[NH:22][C:21](=[O:23])[C:20]([O:24][C:25]2[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=2)=[CH:19][N:18]=1>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]2[NH:22][C:21](=[O:23])[C:20]([O:24][C:25]3[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)=[CH:19][N:18]=2)[N:9]=1)[CH3:1]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: CSc1ncc(Oc2ccc(C)nc2)c(=O)[nH]1
Solvent: c1ccncc1
Product: Cc1ccc(Oc2cnc(NCCSCc3csc(CN(C)C)n3)[nH]c2=O)cn1

Procedure:
Following the procedure of Example 12, a mixture of 1.29 g. of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine and 1.38 g. of 2-methylthio-5-(6-methyl-3-pyridyl)oxy-4-pyrimidone in pyridine solution were heated to refluxing temperature for about 88 hours. After this time, the solvent was removed by evaporation in vacuo and the residue dissolved in ethanol. The ethanolic solution was evaporated to dryness. The residue was subjected to high pressure liquid chromatography over silica using a gradient elution technique with an ethyl acetate/ethanol/ammonium hydroxide solvent system as the eluant. Fractions shown by tlc to contain 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(6-methyl-3-pyridyl)oxy-4-pyrimidone were combined and the solvent removed by evaporation. The resulting residue was rechromatographed on a silica preparative plate using 3% ammoniated ethanol as the solvent. 2-[2-(2-Dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(6-methyl-3-pyridyl)oxy-4-pyrimidone free base thus obtained was converted to the corresponding trihydrochloride salt by standard procedures. 2-[2-(2-Dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(6-methyl-3-pyridyl)oxy-4-pyrimidone trihydrochloride melted at about 216°-220° C. after recrystallization from a mixture of ethanol, ethyl acetate and ether. Yield=0.36 g.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[F:24][C@@H:25]1[CH2:27][C@H:26]1[C:28]1[O:32][N:31]=[C:30]([C:33]2[CH:34]=[CH:35][C:36]([CH3:40])=[C:37]([CH:39]=2)[NH2:38])[N:29]=1>ClCCl.N1C=CC=CC=1>[F:24][C@H:25]1[CH2:27][C@@H:26]1[C:28]1[O:32][N:31]=[C:30]([C:33]2[CH:34]=[CH:35][C:36]([CH3:40])=[C:37]([NH:38][C:10]([C:3]3[N:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]4=[N:1][CH:2]=3)=[O:12])[CH:39]=2)[N:29]=1
Reactant: O=C(O)c1cnc2ccccn12
Reactant: Cc1ccc(-c2noc([C@@H]3C[C@H]3F)n2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1ccc(-c2noc([C@H]3C[C@@H]3F)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirring suspension of imidazo[1,2-a]pyridine-3-carboxylic acid (1) (52 mg, 0.32 mmol) in anhydrous dichloromethane (2 mL) at 0° C. under Argon was added dropwise oxalyl chloride (56 μL, 0.64 mmol). Then, a drop of anhydrous DMF was added and the reaction mixture was stirred at room temperature for 1.5 hours. The solvent was concentrated and the crude solid was added portion-wise to a stirring solution of 5-(5-((1S,2R)-2-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)-2-methylaniline (132) (62 mg, 0.27 mmol) in anhydrous pyridine (1 mL) at 0° C. The reaction was stirred at room temperature under Argon for 30 minutes and quenched with water. The crude product was purified by preparative HPLC to yield N-(5-(5-((1R,2S)-2-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F113). MS m/z 378.1 (M+1)+.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:7]1=2)=[O:5].C(N(CC)CC)C>C(O)C>[C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:7]1=2)(=[O:5])[CH:3]=[CH2:2]
Reactant: O=C1Nc2ccccc2N(C(=O)CCCl)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=CC(=O)N1c2ccccc2NC(=O)c2ccccc21

Procedure:
5.0 gm (0.017 mol) of 5-(3-chloro-propionyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 2.0 gm (0.02 mol) of triethylamine were refluxed in 250 ml of ethanol for 30 minutes. Subsequently, the reaction mixture was evaporated in vacuo, and the residue was stirred with water. After suction-filtering and drying, 5-acryloyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one was obtained with a quantitative yield. Recrystallization from ethanol.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]1([C:5]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCC1
Reactant: OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)C1CCC1
Yield: 56.2 %

Procedure:
Cyclobutanecarbonyl chloride (2.37 g, 20 mmols) was added to a chloroform (30 ml) solution of benzyl alcohol (2.16 g, 20 mmols) and triethylamine (2.2 g, 22 mmols) with cooling with ice, and then heated under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with ether. The organic layer was washed with 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate and the solvent was evaporated. The resulting oil was purified through silica gel column chromatography (developer: hexane/acetone=10/1) and distilled (110° C./1.2 mmHg) to obtain 2.14 g (yield: 56%) of benzyl cyclobutanecarboxylate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:11]([CH3:22])[C:12]4[CH:18]=[C:17]([C:19](O)=[O:20])[CH:16]=[CH:15][C:13]=4[N:14]=3)[S:8][C:4]=2[CH:3]=1.[NH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][NH:25][C:19]([C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)[N:11]([CH3:22])[C:12]=2[CH:18]=1)=[O:20]
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2ccc(C(=O)O)cc21
Reactant: NCCOCCO
Agent: CN(C)C(On1nnc2ccccc21)=[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: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2ccc(C(=O)NCCOCCO)cc21
Yield: 46 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide (40 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid (70 mg), 2-(2-amino-ethoxy)-ethanol (23 mg), HBTU (80 mg), and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z 445.6.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([CH2:43][C:44]([O:46][CH3:47])=[O:45])[C:35]2=[O:48])=[C:30]([OH:49])[CH:29]=1>>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2([CH2:5][OH:16])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([CH2:43][C:44]([O:46][CH3:47])=[O:45])[C:35]2=[O:48])=[C:30]([OH:49])[CH:29]=1
Reactant: COC(=O)CN1C(=O)C(c2ccc(Cl)cc2O)c2ccccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: COC(=O)CN1C(=O)C(CO)(c2ccc(Cl)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with methyl [3-(4-chloro-2-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained: MS (ES+) m/z 362.5 (M+1) 364.5 (M+1).