Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].C([O-])([O-])=O.[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C=O)C>[CH2:25]([N:11]1[CH2:10][CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:15]([F:18])([F:16])[F:17])[CH:4]=2)([OH:14])[CH2:13][CH2:12]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Reaction time: 48 h

Procedure:
A mixture of 15 g of 4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol, 8.3 g of K2CO3 and 7.18 ml of benzyl bromide in 80 ml of DMF is left with stirring at AT for 2 days. The reaction mixture is poured into water and extracted with AcOEt, an insoluble product is filtered off, the organic phase is washed with water and with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/MeOH (95/5; v/v) mixture. This gives 14.6 g of the expected product.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]=O)=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[NH2:12][C:13]([CH3:18])([CH2:16][OH:17])[CH2:14][OH:15]>>[Cl:11][C:6]1[C:7]2[CH:8]=[CH:9][N:12]([C:13]([CH3:18])([CH2:16][OH:17])[CH2:14][OH:15])[C:2]=2[N:3]=[CH:4][N:5]=1
Reactant: CC(N)(CO)CO
Reactant: O=CCc1c(Cl)ncnc1Cl
Product: CC(CO)(CO)n1ccc2c(Cl)ncnc21

Procedure:
The title compound was prepared according to the method described for Preparation 1 using (4,6-dichloropyrimidin-5-yl)acetaldehyde (Preparation 208) and 2-amino-2-methylpropane-1,3-diol to afford the title compound as a yellow liquid in 79% yield, 3.88 g.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[Cl:18]N1C(=O)CCC1=O.N(OC(C)(C)C)=O>ClCCl>[Cl:18][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cnn(-c2ccccn2)c1N
Reactant: O=C1CCC(=O)N1Cl
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2ccccn2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl 5-amino-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylate (200 mg, 0.861 mmol) and 1-chloropyrrolidine-2,5-dione (172 mg, 1.292 mmol) in dichloromethane (8 mL) was added tert-butyl nitrite (0.154 mL, 1.292 mmol). The reaction mixture was stirred at rt for 30 minutes, after which time it was concentrated to yield a crude product which was purified on a silica gel column eluting with hexanes/EtOAc to yield ethyl 5-chloro-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylate. The material from Method 1 and Method 2 were combined (106 mg, 0.42 mmol). HPLC ret. time=2.50 min. HPLC: Column: YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 mL/min; Solvent A=10% MeOH—90% Water—0.2% H3PO4; Solvent B=90% MeOH—10% water—0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=252.1. 1H NMR (400 MHz, MeOD) δ ppm 8.61 (1 H, dd, J=4.89, 1.13 Hz), 8.16 (1 H, s), 8.09 (1 H, td, J=7.78, 1.76 Hz), 7.74 (1 H, d, J=8.03 Hz), 7.57 (1 H, ddd, J=7.53, 4.77, 1.00 Hz), 4.36 (2 H, q, J=7.28 Hz), 1.38 (3 H, t, J=7.15 Hz).
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=O>>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:15]=2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Product: COC(=S)c1cc(-c2nc(-c3ccc([N+](=O)[O-])cc3)cs2)c(C)s1
Yield: 112.9 %

Procedure:
A solution of 1 g (4 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was reacted with 987 mg (4 mmol) of 2-bromo-4′-nitroacetophenone in a manner similar to Example 8, step (a) to give methyl 4-(4-(4-nitrophenyl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (1.7 g, quantitive yield) as a brown solid. 1H-NMR (DMSO-d6; 300 MHz) δ8.57 (s, 1H), 8.34 (s, 4H), 8.25 (s, 1H), 3.94 (s, 3H), 3.81 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C16H12N2O4S3 393.0 (M+H), found 392.8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH2:23])=[CH:21][N:22]=2)[N:19]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:21][N:22]=2)[N:19]=1
Reactant: Nc1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a DCM (0.1 mL) solution of (R)-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-amine (Preparation B; 6 mg, 0.019 mmol) cooled in an ice bath was added acetic anhydride (2.1 mg, 0.021 mmol), followed by pyridine (2 mg, 0.025 mmol). The reaction was warmed to ambient temperature and stirred for 1 hour before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 5 to 60% acetonitrile/water to yield (R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)acetamide as an off-white solid (6 mg, 81% yield). MS (apci) m/z=358.2 (M+H).
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([I:11])=[C:9]([CH3:12])[S:8][C:7]=1[NH:13][C:14](=[O:18])[CH2:15][C:16]#[N:17])=[O:5])C.[H-].[Na+].CO>C1COCC1>[OH:5][C:4]1[C:6]2[C:10]([I:11])=[C:9]([CH3:12])[S:8][C:7]=2[NH:13][C:14](=[O:18])[C:15]=1[C:16]#[N:17]
Reactant: CCOC(=O)c1c(NC(=O)CC#N)sc(C)c1I
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1sc2[nH]c(=O)c(C#N)c(O)c2c1I
Yield: 22.9 %

Procedure:
2-(2-Cyano-acetylamino)-4-iodo-5-methyl-thiophene-3-carboxylic acid ethyl ester (189 mg, 0.5 mmol) was cyclized by NaH in THF at room temperature for 12 h as described in Example 29D. After reaction was finished, methanol (2 mL) was added and the mixture was evaporated. The residue was purified on HPLC to give 4-hydroxy-3-iodo-2methyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-cabonitrile (38 mg, 22.9%). This compound (33 mg, 0.1 mmol) was taken up in a Smith Process Vial (2–5 mL), CuI (7.6 mg, 0.04 mmol), Pd(PPh3)2Cl2 (14 mg, 0.02 mmol), DMF (2 ml), diisopro pylamine (1 mL) and phenylacetylene (20.4 mg, 0.2 mmol) were then added sequentially. After degassed, the vial was sealed and stirred at 70° C. for 2 h. The resulting mixture was filtered and the solid was washed with methanol (5 mL×2). The combined organic layers were concentrated under vacuum and purification on HPLC to give title compound (20 mg, 65%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.0 (s, 1H), 7.52–7.38 (m, 5H), 2.44 (s, 3H, MS (ESI) m/e 307 (M+H)+, 305 (M−H)−.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[NH2:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15](Cl)[N:14]=1.C(N(CC)CC)C>CS(C)=O>[NH2:12][C:13]1[N:14]=[C:15]([N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]2)[CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1CCCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Temperature: 100 °C
Yield: 34.9 %

Procedure:
To a solution of (R)-ethyl piperidine-3-carboxylate (1 g, 6.33 mmol) in dimethylsulfoxide (15 mL) were added 2-amino-3-nitro-6-chloropyridine (1.098 g, 6.33 mmol) and triethylamine (1.921 g, 18.99 mmol) at room temperature. The mixture was heated to 100° C. for 18 h, then was poured into ice water and extracted with ethyl acetate. The organic layer was dried, filtered and concentrated under reduced pressure. The crude material was purified via flash chromatography (100-200 mesh silica, 30% ethyl acetate in petroleum ether) to afford (R)-ethyl 1-(6-amino-5-nitropyridin-2-yl)piperidine-3-carboxylate (650 mg, 93.5%). MS (ES+APCI) (M+H) 295.1; LCMS retention time 2.832 min (Method G).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:17](=[O:18])[NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:2]2
Reactant: O=C=Nc1ccccc1
Reactant: OC1CN2CCC1CC2
Product: O=C(Nc1ccccc1)OC1CN2CCC1CC2
Yield: 86 %

Procedure:
1-Azabicyclo[2.2.2]octan-3-ol and phenyl isocyanate were used. The residual solid resulting from the above described procedure was purified via column chromatography eluting with a 1:10 ratio of methanol:chloroform to afford the title compound (86%) as a white solid: NMR (CDCl3) δ7.60-7.0 (m, 5H, Ph), 4.81 (m, 1H, CH--OCO), 3.27 (m, 1H, one of NCH2C--O), 2.9 (m, 5H, N(CH2)2 and one of NCH2C--O), 2.1 (m, 1H, methine at C4), 2.05-1.30 (m, 4H, CH2 at C5 and C8); FAB LRMS m /z (relative intensity, %) 247 ([MH+ ], 100).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[N:16]([CH3:18])[CH:15]=[CH:14]2)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:18][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[OH:8])[CH:14]=[CH:15]1
Reactant: [H][H]
Reactant: Cn1ccc2cccc(OCc3ccccc3)c21
Agent: [Pd]
Solvent: CCO
Product: Cn1ccc2cccc(O)c21
Yield: 87 %

Procedure:
To a solution of 7-benzyloxy-1methyl-1H-indole in 20 mL of ethanol was added 10% palladium on charcoal (0.2 g). This solution was stirred under balloon pressure hydrogen atmosphere for 4 h, then filtered through celite and concentrated in vacuo. This material was purified by flash chromatography, eluting silica gel with hexane:ethyl acetate (100:0 to 50:50) to give the product (0.58 g, 87%); Mass spectrum (TOF): m/z=147.1 (M).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:21](=[O:32])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].O>O1CCCC1>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:21]([OH:32])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCCCCC=O
Reactant: Brc1cccc(OCc2ccccc2)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCC(O)c1cccc(OCc2ccccc2)c1
Temperature: -70 °C
Yield: 89 %

Procedure:
Under a nitrogen atmosphere, a solution of 17.0 grams (0.065 mole) of 3-(phenylmethoxy)phenyl bromide in 125 mL of tetrahydrofuran was stirred and cooled to -70° C. To this was added dropwise 28.0 mL (0.071 mole) of 2.5M n-butyllithium (in hexanes) during a 15 minute period. The reaction mixture temperature was maintained below -60° C. during the addition. Upon completion of addition, a solution of 11.5 grams (0.068 mole) of undecanaldehyde in 15 mL of tetrahydrofuran was added dropwise during a 5 minute period. Upon completion of addition, the reaction mixture was allowed to warm to 0° C. during a one hour period. The reaction mixture was again cooled to -60° C., and 100 mL of water was added. The reaction mixture was allowed to warm to ambient temperature, and then it was extracted with 200 mL of diethyl ether. The ether extract was washed with 50 mL of water, and then it was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 9:1 petroleum ether and diethyl ether, and 7:3 petroleum ether and diethyl ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 20.5 grams of 1-[3-(phenylmethoxy)phenyl]undecanol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:11](Cl)=[C:10]([C:20]#[N:21])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>ClCCl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:11]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[C:10]([C:20]#[N:21])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1)c(Cl)c(C#N)c(=O)n2Cc1ccccc1
Reactant: C1CNCCN1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c(N1CCNCC1)c(C#N)c(=O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
A solution of Compound 21 (1.2 g, 3.9 mmol) in dichloromethane was added slowly to a stirred solution of piperazine (1.67 g, 19.4 mmol) in dichloromethane at room temperature. The solution was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was taken in water, sonicated briefly, and filtered. The solids were dissolved in ethyl acetate and washed by water. The organic layer was dried over Na2SO4 and concentrated to yield 1.34 g (96%) of yellow solids. M.P. 152° C. 1H NMR (DMSO-d6): δ 2.34 (s, 3H), 2.94 (m, 4H), 3.54 (m, 4H), 5.44 (s, 2H), 7.16-7.20 (m, 2H), 7.22 (d, J=7.6 Hz, 1H), 7.28-7.31 (m, 3H), 7.40 (d, J=8.8 Hz, 1H), 7.64 (s, 1H). EIMS m/z 359 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH2:8]([O:10][C:11](=[O:18])[CH:12]=[C:13]([NH2:17])[O:14][CH2:15][CH3:16])[CH3:9]>C(O)(C)C>[CH2:8]([O:10][C:11]([C:12]1[CH:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:12]([C:11]([O:10][CH2:8][CH3:9])=[O:18])[C:13]([O:14][CH2:15][CH3:16])=[N:17][C:13]=1[NH2:17])=[O:18])[CH3:9]
Reactant: O=Cc1ccco1
Reactant: CCOC(=O)C=C(N)OCC
Solvent: CC(C)O
Product: CCOC(=O)C1=C(N)N=C(OCC)C(C(=O)OCC)C1c1ccco1
Yield: 62 %

Procedure:
Upon heating a solution of 4.8 g of furan-2-aldehyde and 15.9 g of 3-amino-3-ethoxy-acrylic acid ethyl ester in 50 ml of alcohol for 8 hours, 2-amino-4-(2-furyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 110° C (isopropanol) is obtained. Yield: 62% of theory.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Br:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:33]=[CH:32][C:24]2[N:25]([CH3:31])[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][C:23]=2[CH:22]=1.Cl>C(O)CCC.O1CCOCC1>[Br:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[CH:33]=[CH:32][C:24]3[N:25]([CH3:31])[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Agent: Cl
Solvent: CCCCO
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3C)ncc1Br
Yield: 48.4 %

Procedure:
2-(2-chloro-5-bromo-pyrimidin-4-ylamino)-N-methyl-benzamide (52 mg, 0.15 mmol) and 7-amino-1-methyl-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (29 mg, 0.15 mmol) were combined in 5 mL n-butanol. A drop of a solution of 4N hydrochloric acid in dioxane was added and the mixture was refluxed for five hours. The mixture was concentrated and triturated with ether. The remaining solid was partitioned between dichloromethane and saturated sodium bicarbonate solution (100 mL each). The organic layer was separated, was dried (sodium sulfate), and was concentrated to afford an oil which was purified on silica (methanol:dichloromethane gradient elution) to afford 36 mg (48%) of 2-[5-bromo-2-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as an off-white solid. Mp: 238-40° C.; MS: 496.61 (M+H); 1H NMR (chloroform-d): δ 10.95 (s, 1H), δ 8.58 (d, J=8 Hz, 1H), δ 8.22 (s, 1H), δ 7.52 (d, J=8 Hz, 1H), δ 7.44 (m, 3H), δ 7.11 (t, J=8 Hz, 1H), δ 7.01 (s, 1H), δ 6.25 (br s, 1H), δ 3.35 (s, 3H), δ 3.06 (s, 3H), δ 2.67 (m, 2H), δ 2.33 (t, J=7 Hz, 2H), δ 2.16 (m, 2H).
Reaction SMILES: [Na].Cl[C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1.[CH2:14]([OH:17])[CH2:15][CH3:16]>>[CH2:14]([O:17][C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1)[CH2:15][CH3:16]
Reactant: CCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [Na]
Product: CCCOc1nsnc1-c1cccnc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of sodium (440 mg, 17 mmol) in 1-propanol (10 ml) was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (650 mg, 3.3 mmol). The mixture was stirred at 50° C. for 2 h and evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic phases were dried and evaporated to yield 700 mg (96%) of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:11]2([C:28]([F:31])([F:30])[F:29])[CH2:15][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21]3([CH2:27][NH:26][CH2:25]3)[O:20][CH2:19]4)=[N:13][CH2:12]2)[CH:6]=[C:7]([Cl:10])[C:8]=1[F:9].CCN(C(C)C)C(C)C.[C:41](O)(=[O:45])[CH:42]([CH3:44])[CH3:43].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[Cl:10][C:7]1[CH:6]=[C:5]([C:11]2([C:28]([F:30])([F:29])[F:31])[CH2:15][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21]3([CH2:25][N:26]([C:41](=[O:45])[CH:42]([CH3:44])[CH3:43])[CH2:27]3)[O:20][CH2:19]4)=[N:13][CH2:12]2)[CH:4]=[C:3]([Cl:2])[C:8]=1[F:9]
Reactant: Fc1c(Cl)cc(C2(C(F)(F)F)CN=C(c3ccc4c(c3)COC43CNC3)C2)cc1Cl
Reactant: CC(C)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)C(=O)N1CC2(C1)OCc1cc(C3=NCC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.1 %

Procedure:
To a stirred solution of 5′-(3-(3,5-dichloro-4-fluorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]hydrochloride (Preparation 9, 1 g, 2.02mmol) in THF (20 mL) was added DIPEA (3.53 mL, 20.24 mmol), isobutyric acid (0.368 g, 4.05 mmol) and T3P (2.94 mL, 10.12 mmol, 5 eq) at room temperature. Resulting reaction mixture was stirred at room temperature for 16 hours. After complete conversion of starting material, reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3×30 mL). Combined organic layer was washed with sodium bicarbonate solution (35 mL), brine (35 mL), dried over sodium sulfate and concentrated to get brown semi solid (1.1 g, crude). Crude compound was purified by column chromatography using 100-200 mesh silica gel. Desired compound was eluted in 0.5% methanol in dichloromethane to get pale green solid (0.45 g). 1H NMR (400 MHz, DMSO-d6) δ: 1.01-1.05 (m, 6H), 2.54-2.57 (m, 1H), 3.74 (d, J=18.12 Hz, 1H), 3.86 (d, J=18.08 Hz, 1H), 4.12 (s, 2H), 4.41-4.45 (m, 3H), 4.81 (d, J=17.36 Hz, 1H), 5.12 (s, 2H), 7.66 (d, J=7.96 Hz, 1H), 7.76 (d, J=6.24 Hz, 2H), 7.85 (s, 1H), 7.93 (d, J=7.88 Hz, 1H), LC-MS (m/z): 529.1 (M+H),
Reaction SMILES: [H-].[Na+].[C:3]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:4][CH2:5][C:6]([O:8]CC)=[O:7].CC(C)=O.[C:19]1(C)[CH:24]=[CH:23]C=[CH:21][CH:20]=1>>[C:6]1(=[O:7])[O:8][C:13]([CH3:14])([CH:19]([CH2:24][CH3:23])[CH2:20][CH3:21])[O:12][C:3](=[O:11])[CH2:4][CH2:5]1
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCC(CC)C1(C)OC(=O)CCC(=O)O1
Temperature: 40 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
Sodium hydride in an amount of 2 moles was suspended in 1.0 liter of toluene and heated at 40° C. To this, a mixed solution of 1 mole of diethyl succinate and 1.2 moles of acetone was added dropwise in 3 hours with stirring. The reaction was carried out for further 3 hours. Then, the reaction solution was poured into 1 kg of ice. The water layer was separated, made acidic by pouring 700 ml of 5M HCl thereinto, and extracted with 1.0 liter of 1,2-dichloroethane. The resulting organic layer was dried over anhydrous sodium sulfate, and concentrated. To the resulting residue, 1.0 liter of ethanol and 30 ml of concentrated sulfuric acid were added. The reaction was carried out under reflux for 4 hours. After the reaction, the solvent was removed from the reaction solution by distillation. The objected substance was extracted with dichloromethane and purified by distillation under reduced pressure to give diethylisopropylidene succinate in yield of 51%.
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:29]([CH2:30]C(O)=O)[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[N:22]=1>C1C=CC=CC=1>[CH3:14][C:11]([O:10][C:6](=[O:5])[CH2:30][N:29]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[N:22]=[C:21]1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=1)([CH3:12])[CH3:13]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: O=C(O)Cn1c(-c2ccccn2)nc2cccnc21
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)Cn1c(-c2ccccn2)nc2cccnc21
Temperature: 25 °C
Yield: 45.1 %

Procedure:
Under a nitrogen atmosphere, N,N-dimethylformamide-di-tert-butyl acetal (8.12 g, 0.040 mole) was added dropwise over a 20-minute period to a stirred, refluxing suspension of 2-(2-pyridyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (2.54 g, 0.010 mole) in anhydrous benzene (50 ml). The resulting solution was refluxed for 1 hour and allowed to cool to room temperature. The reaction mixture was washed with 10% potassium carbonate solution (2×25 ml), water (25 ml), dried over sodium sulfate and concentrated in vacuo. The residue (3.5 g) was dissolved in tetrahydrofuran and treated with excess ethereal hydrogen chloride. The crystalline solid was recrystallized from tetrahydrofuran, giving 1.5 g (43%). Drying in vacuo at 65° C. for 8 hours and then at 78° C. overnight gave 1.4 g of the compound as the free base, mp 124°-125.5° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1.[Cl:12][C:13]1[N:14]=[CH:15][C:16]2[C:21]([C:22]=1[CH2:23]Cl)=[CH:20][CH:19]=[CH:18][CH:17]=2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:12][C:13]1[N:14]=[CH:15][C:16]2[C:21]([C:22]=1[CH2:23][O:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: COc1cc(C=O)c(O)cn1
Reactant: ClCc1c(Cl)ncc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(OCc2c(Cl)ncc3ccccc23)cn1
Temperature: 60 °C
Yield: 14 %

Procedure:
A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (73 mg, 0.48 mmol, 1 eq.), 3-chloro-4-(chloromethyl)isoquinoline (crude above, 0.48 mmol), and K2CO3 (265 mg, 1.92 mmol, 4 eq.) in DMF (2.0 mL) was heated at 60° C. for 1 h. The mixture was cooled, filtered, concentrated to dryness. The crude was purified on silica gel using a mixture of EtOAc and hexanes to give 5-((3-chloroisoquinolin-4-yl)methoxy)-2-methoxyisonicotinaldehyde (22 mg, 14%) as an yellow solid. 1H NMR (400 MHz; CDCl3) δ=10.19 (s, 1H), 9.05 (s, 1H), 8.23 (s, 1H) 8.06 (d, 1H), 7.98 (d, 1H), 7.76 (t, 1H), 7.63 (t, 1H), 7.01 (s, 1H), 5.72 (s, 2H), 3.87 (s, 3H). LRMS (M+H+) m/z 329.1.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:12]2[CH:22]=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.ClCCl>[CH2:1]([S:8][C:9]1[N:13]([CH2:14][C:15]([OH:17])=[O:16])[C:12]2[CH:22]=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Cn1c(SCc2ccccc2)nc2cc([N+](=O)[O-])ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1c(SCc2ccccc2)nc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
tert-Butyl (2-benzylsulfanyl-5-nitro-benzoimidazol-1-yl)-acetate (Precursor 5-NO2-C-02b, 20 mg, 0.05 mmol) is dissolved in TFA/dichloromethane (1:1, 0.5 ml) and stirred for 2 h at rt. The solvents are evaporated under a stream of air and Et2O (1 ml) is added to the crude mixture. The solid obtained is filtered, rinsed twice with Et2O and dried under high vacuum yielding the title compound (10.4 mg) in 60% as a slightly yellow solid: tR=6.30 min (LC-1), ESI-MS (pos.): m/z 344.23 [M+H]+, ESI-MS (neg.): m/z 342.34 [M−H]+; 1H-NMR (DMSO-d6): δ (ppm) 4.66 (s, 2H, SCH2), 5.07 (s, 2H, CH2CO2), 7.23-7.33 (m, 3Harom), 7.46 (dd, 2Harom), 7.74 (d, 1Harom), 8.13 (dd, 1 Harom), 8.44 (d, 1Harom).