Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][O:11][CH3:12])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:20][CH:21]([F:31])[C:22]1[C:26]([C:27](Cl)=[O:28])=[CH:25][N:24]([CH3:30])[N:23]=1>ClCCl>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:10]([O:11][CH3:12])[C:27]([C:26]2[C:22]([CH:21]([F:31])[F:20])=[N:23][N:24]([CH3:30])[CH:25]=2)=[O:28])[CH3:9])=[CH:6][CH:7]=1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CONC(C)c1ccc(I)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
To a stirred solution of N-[1-(4-Iodo-phenyl)-ethyl]-O-methyl-hydroxylamine (2.1 g, 7.57 mmol), prepared as described in example P12, in dichloromethane (25 ml) was added triethyl amine (3.15 ml, 22.68 mmol) followed by a solution of 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (1.5 g, 7.94 mmol) in dichloromethane (5 ml) slowly in ice cold condition. The reaction mixture was stirred at ambient temperature for 16 h. Reaction mixture was poured into 40 ml ice-water. Aqueous layer was extracted with dichloromethane (2×40 ml). The combined organic layer was washed with 2(N) HCl(2×20 ml) followed by saturated sodium bicarbonate (2×20 ml) and dried over sodium sulfate. Organic layer was concentrated under vacuum to give light yellow liquid. Crude was purified by chromatography to afford 2.05 g (62% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [1-(4-iodo-phenyl)ethyl]-methoxy-amide as white solid. Mp. 72-74° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][CH2:11][C:12]3C=CC4[C:14](=[CH:15]C=CC=4)[CH:13]=3)=[CH:9][C:4]=2[N:3]=[N:2]1.C(O[CH2:25][CH3:26])C>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][CH2:11][C:12]3[C:25]4[C:26](=[CH:9][CH:4]=[CH:5][CH:6]=4)[CH:15]=[CH:14][CH:13]=3)=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2cc(CNc3ccc4[nH]nnc4c3)ccc2c1
Reactant: CCOCC
Product: c1ccc2c(CNc3ccc4[nH]nnc4c3)cccc2c1
Yield: 64 %

Procedure:
As per the general procedure for compound [11]. Trituration from diethyl ether afforded [12] as a white solid (700 mg, 64%). Rf (A) 0.30 δH(400 MHz; DMSO-d6 {D2O shake}) 4.75 (2H, s, CH2) 6.49 (1H, s, BT) 6.77 (1H, s, NH, disappeared) 6.91 (1H, d, J9.0, BT) 7.43 (1H, t, Nap) 7.51-7.59 (3H, m, Nap) 7.65 (1H, d, J9.0, BT) 7.82 (1H, d, J8.1, Nap) 7.94 (1H, d, J8.4, Nap) 8.14 (1H, d, J8.1, Nap) 14.74 (1H, s, NH, disappeared); m/z (EI−HR) 274.12148 [(M) calc. for C17H14N4 274.12185]. (1H-Benzotriazol-5-yl)-(3,5-dimethoxy-benzyl)-amine [13]
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][CH:4]=1.O.[NH2:14][NH2:15]>C(O)C>[OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:14][NH2:15])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(CO)cc1
Reaction time: 2 h

Procedure:
To a solution of 1.66 g (10.0 mmol) of methyl 4-hydroxymethylbenzoate (19) in 20 ml of ethanol was added 3.0 g (60 mmol) of hydrazine hydrate. The mixture was stirred for 2 h, an additional 3.0 g hydrazine hydrate was added and the mixture was allowed to stand overnight. The precipitate was filtered, washed twice with ethanol and dried in vacuo to yield 20 as a white powder. (Literature references for compound: Yaroshenko, V. V.; Grekov, A. P.; Tkach, V. P.; Yakovenko, A. G. Inst. Khim. Vysokomol. Soedin. Sint. Fiz.-Khim. Polim. 1975, 17 97; and Galiano, R.; Joaquin, A.; Soria, A. (Instituto de Investigacion y Desarrollo Quimico Biologico, S. A., Spain). Span. (1993), 24 pp. CODEN: SPXXAD ES 2039161 A1 19930816)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]([NH:28]C(=O)OC(C)(C)C)[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.Cl>C(Cl)Cl.O1CCOCC1>[NH2:28][C@H:26]([CH3:27])[CH2:25][N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]2[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:13][C:12]=2[F:24])=[N:9]1
Reactant: C[C@H](Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H](N)Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
To a solution of tert-butyl N-[(1R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-methyl-ethyl]carbamate (2.56 g, 5.35 mmol) in DCM (20 mL) was added 4N HCl in dioxane (15 ml). After stirring 18 h at room temperature, the reaction was diluted with DCM (100 mL) and extracted with water (200 mL). The aqueous layer was washed again with DCM (50 mL). The aqueous layer was placed in a 2 L beaker along with ethyl acetate (50 mL) and stirred while adding NaOH (beads) to adjust the pH to ˜11. More ethyl acetate (100 mL) was added and then the layers were separated and the aqueous layer was washed with ethyl acetate. The combined organic layers were washed with brine and then dried (MgSO4), filtered and concentrated to obtain 1.8 g (90%) of 1-[(2R)-2-aminopropyl]-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-amine as a solid.
Reaction SMILES: [C:1]([O:9]C)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C[O-].[Na+].[CH3:14][C:15]([CH3:17])=[O:16].C(O)(=O)C>C(OCC)C>[O:9]=[C:1]([C:2]1[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=1)[CH2:14][C:15](=[O:16])[CH3:17]
Reactant: COC(=O)c1ccncc1
Reactant: CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(=O)CC(=O)c1ccncc1
Reaction time: 2 h

Procedure:
To a suspension of methyl isonicotinate (96.0 g, 0.7 mol) and sodium methoxide (45.4 g, 0.84 mol) in ethyl ether (1 l), acetone (81.3 g, 1.4 mol) was added dropwise at 25°~30° C. and stirring was continued for 2 hrs. under reflux. After cooling, acetic acid (50.4 g, 0.84 mol) was added to the reaction mixture, the organic layer was separated, washed twice with H2O, dried over anhydrous MgSO4 and evaporated. The residue (87.5 g) was distilled under reduced pressure to give the title compound as a pale yellow oil which solidified in the refrigerator; yield: 40.2 g; bp 135°~138° C./10 mmHg; mp 62°~64.5° C. (Lit. bp 118°~120° C.; mp 66.5°~67° C.; R. Levine, J. K. Sneed, J. Am. Chem. Soc., 73, 5614 (1951).). ##STR30##
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)[CH3:2].[C:10]1([CH2:16][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:20]2[CH2:21][CH2:22][N:17]([CH2:16][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:18][CH2:19]2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC(=O)CC1
Reactant: c1ccc(CN2CCNCC2)cc1
Product: CCN1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Yield: 71 %

Procedure:
Prepared analogously to Example A19a) from 1-ethyl-4-piperidinone and 1-(phenylmethyl)piperazine in a yield of 71% of theory. Colourless, amorphous substance, Rf=0.46 (FM4).
Reaction SMILES: [CH:1]([CH:3]=O)=[O:2].C(N(CC)CC)C.[CH3:12][NH:13][C:14]([NH:16][CH3:17])=[O:15]>O>[CH3:12][N:13]1[CH2:3][C:1](=[O:2])[N:16]([CH3:17])[C:14]1=[O:15]
Reactant: O=CC=O
Reactant: CNC(=O)NC
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CC(=O)N(C)C1=O
Temperature: 30 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
In a 1000 ml glass vessel equipped with a stirrer, thermometer, a dropping funnel and a distillation unit was charged 290 g (2.0 mol) of 40 wt % aqueous glyoxal solution. And then, triethylamine is added thereto to prepare a basic mixed solution (At this time, the solution had a pH of 9). To the mixed solution was gradually added dropwise a solution comprising 176 g (2.0 mol) of 1,3-dimethylurea and 176 ml of water while maintaining a liquid temperature to 25 to 35° C. After stirring the solution at room temperature for 3 hours, the mixture was reacted by elevating the temperature to 200° C. over 2 hours while removing triethylamine and water under normal pressure by distillation. After completion of the reaction, the obtained reaction mixture was distilled under reduced pressure (105 to 107° C./0.67 to 1.33 kPa) to obtain 217 g (Isolation yield; 85%) of 1,3-dimethylimidazolidin-2,4-dione as a pale yellowish liquid.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[CH:12][C:13]([Cl:16])([Cl:15])[Cl:14]>C1C=CC=CC=1>[C:1]([NH:9][N:10]=[CH:12][C:13]([Cl:16])([Cl:15])[Cl:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: O=CC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: O=C(NN=CC(Cl)(Cl)Cl)c1ccccc1

Procedure:
10 g (0.073 mol) of benzoylhydrazine were suspended in benzene, 200 ml, and 18.3 g (0.124 mol) of chloral were added dropwise to the suspension which was then refluxed under agitation for 3 hours. Upon cooling, the sedimented crystals were collected by filtration and washed well with benzene. In this way, white brown crystals, 19 g, were obtained substantially quantatively. m.p. 188°-189° C. (decomposed). When recrystallized from acetone, the Compound No. 1, m.p. 194°-195° (decomposed), was obtained in white needles. Yield: 15.4 g (81% of the theoretical).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][C:8]2[N:12]3[C:13](=[O:25])[C:14]4[NH:15][CH:16]=[N:17][C:18]=4[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:11]3=[N:10][N:9]=2)=[CH:5][CH:4]=1.[Br:28]N1C(=O)CCC1=O>C1COCC1>[Br:28][C:16]1[NH:15][C:14]2[C:13](=[O:25])[N:12]3[C:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:27][CH:26]=4)=[N:9][N:10]=[C:11]3[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:18]=2[N:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(Cc3ccc(OC)cc3)nnc12
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(Cc3ccc(OC)cc3)nnc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To the solution of 3-(4-methoxybenzyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (0.40 g, 1.1 mmol) in THF was added N-Bromosuccinimide (0.29 g, 1.6 mmol). The mixture was stirred at 70° C. for 1 hour. The mixture was concentrated and purified by preparative LCMS to yield the desired product (290 mg, 60%). 1HNMR (300 MHz, d6-DMSO): δ 7.16 (d, J=8.3 Hz, 2H), 6.81 (d, J=8.3 Hz, 2H), 4.46 (s, 3H), 4.20 (t, J=7.2 Hz, 2H), 3.67 (s, 2H), 1.79 (m, 2H), 1.28 (m, 4H), 0.83 (m, 3H). LCMS calculated for C19H21BrN6O2(M+H): 445.1; found: 445,0, 447.0.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]=[CH:8][C:7]2=O.O=P(Cl)(Cl)[Cl:15]>CN(C=O)C>[Cl:15][C:7]1[C:6]2[C:11](=[C:2]([I:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: O=c1cc[nH]c2c(I)cccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1ccnc2c(I)cccc12
Yield: 97.8 %

Procedure:
8-Iodo-1H-quinolin-4-one (3.36 g, 8.72 mmol) was suspended in POCl3 (8 mL, 87.2 mmol) and catalytic anhydrous DMF (6.72 μL) was added. The mixture was refluxed for 1 h. The hot crude was poured over ice and the mixture stirred until ice was completely melted. Solid was filtered off, thoroughly washed with water and kept in the vacuum oven overnight to afford 4-chloro-8-iodo-quinoline as a grayish solid (2.47 g, 98%). 1H NMR (DMSO-d6, 400 MHz) δ 7.45 (t, 1H), 7.81 (d, 1H), 8.19 (dd, 1H), 8.45 (dd, 1H), 8.87 (d, 1H). Exact mass calculated for C9H5ClIN 288.92, found 289.9 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1.[CH:15]1([C:19]2[N:20]=[C:21](/[CH:24]=[CH:25]/[C:26]3[CH:27]=[C:28]([NH2:32])[CH:29]=[CH:30][CH:31]=3)[S:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26](/[CH:25]=[CH:24]/[C:21]3[S:22][CH:23]=[C:19]([CH:15]4[CH2:18][CH2:17][CH2:16]4)[N:20]=3)[CH:27]=2)=[O:13])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CC(=O)O)cc1
Reactant: Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CC(=O)Nc2cccc(/C=C/c3nc(C4CCC4)cs3)c2)cc1
Reaction time: 16 h
Yield: 95.7 %

Procedure:
A solution composed of 1.0 g of 4-carboxymethyl benzoic acid methyl ester, 1.3 g of (E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzeneamine, 1.0 g of N-ethyl-N-(dimethylaminopropyl) carbodiimide, 2.4 g of 4-dimethylaminopyridine and 75 ml of methylene chloride at 0° C. After 16 hr. the reaction mixture was washed with 75 ml of water, dried (MgSO4) and the solvents removed by rotary evaporation. The residual materials were recrystallized with ethyl acetate to yield 2.1 g of (E)-4-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid methyl ester; m.p. 163°-164° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:21]3[CH2:20][N:19]([C:22]4[N:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][N:23]=4)[CH2:18][CH2:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:61][O:62][CH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][O:64]1>C(Cl)Cl>[O:64]1[CH2:65][CH2:66][CH2:67][CH2:68][CH:63]1[O:62][NH:61][C:28]([C:25]1[CH:24]=[N:23][C:22]([N:19]2[CH2:18][CH2:17][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]([CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[C:21]=3[CH2:20]2)=[N:27][CH:26]=1)=[O:29]
Reactant: NOC1CCCCO1
Reactant: O=C(O)c1cnc(N2CCc3c(n(CCN4CCOCC4)c4ccccc34)C2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NOC1CCCCO1)c1cnc(N2CCc3c(n(CCN4CCOCC4)c4ccccc34)C2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.3 %

Procedure:
To a solution of 2-[9-(2-morpholin-4-ylethyl)-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl]pyrimidine-5-carboxylic acid (160 mg, 0.39 mmol) in DCM (20 mL) were added EDCI (170 mg, 0.88 mmol), HOBT (90 mg, 0.66 mmol), DIEA (152 mg, 1.17 mmol) and NH2OTHP (47 mg, 0.4 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography using EtOAc in hexanes (50%) to obtain N-(tetrahydro-2H-pyran-2-yloxy)-2-[9-(2-morpholin-4-ylethyl)-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl]pyrimidine-5-carboxamide (46 mg, 23% yield). 1H NMR (200 MHz, CDCl3) ppm: 8.75 (s, 2H), 7.50 (d, 1H, J=7.0 Hz), 7.30 (m, 1H), 7.16 (m, 2H), 5.13 (s, 2H), 5.04 (s, 1H), 4.24 (m, 4H), 4.00 (m, 1H), 3.69 (m, 4H), 2.91 (m, 2H), 2.70 (m, 2H), 2.49 (m, 4H), 1.85 (m, 2H), 1.47 (m, 5H); m/e=506 (M+1).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[N:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:6]=1[C:19]([O:21]CC)=[O:20])([CH3:3])[CH3:2].[OH-].[K+]>CO>[CH:1]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[N:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:6]=1[C:19]([OH:21])=[O:20])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1c(OC(C)C)cc(OC(C)C)nc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1cc(OC(C)C)c(C(=O)O)c(C(F)(F)F)n1
Yield: 73.6 %

Procedure:
A mixture of 9.5 g (0.0283 mol) of product of Example 6, 10 g of KOH and 150 ml of methanol was held at reflux for 16 hours. Methanol was removed under reduced pressure. The residue was treated with 300 ml of water and extracted with ether. The aqueous layer was poured into 50 ml of concentrated HCl and extracted with ether. The ether extract was concentrated. The residue solid (7.7 g) was recrystallized from hexane-ether to give 6.4 g (73.6%) of acid product: mp 147°-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:26])[N:12]([C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[NH:22][CH:21]=[CH:20]5)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:26])[N:12]([C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[N:22]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH:21]=[CH:20]5)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: BrCc1ccccn1
Reactant: O=C1c2sc(-c3ccc(Cl)cc3)nc2CCN1c1ccc2[nH]ccc2c1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2sc(-c3ccc(Cl)cc3)nc2CCN1c1ccc2c(ccn2Cc2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-5-(1H-indol-5-yl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (49 mg, 0.13 mmol) in DMF (1 mL) and add sodium hydride (17 mg, 0.42 mmol). Stir the mixture at room temperature for 30 min then add 2-bromomethyl-pyridine hydrobromide (35 mg, 0.14 mmol). Stir the mixture at room temperature for 5 h, then dilute with EtOAc (30 mL) and wash with saturated NaHCO3 (10 mL). Dry, filter and concentrate the organic solution. Purify the crude material by flash chromatography, using a linear gradient of 20% to 80% EtOAc/hexanes as eluent, to give the title compound (32 mg, 52%). MS (ES+) 471.0 (M+1)+. 1H NMR (400 MHz, CDCl3) δ: 8.55-8.53 (m, 1H), 8.05 (d, 2H, J=8.4 Hz), 7.73 (dt, 1H, J=7.7, 1.8 Hz), 7.62 (d, 2H, J=8.8 Hz), 7.57-7.55 (m, 2H), 7.45 (d, 1H, J=8.8 Hz), 7.30-7.26 (m, 1H), 7.10 (dd, 1H, J=8.6, 2.0 Hz), 7.03 (d, 1H, J=7.9 Hz), 6.52 (d, 1H, J=3.5 Hz), 5.53 (s, 2H), 4.10 (t, 2H, J=7.0 Hz), 3.27 (t, 2H, J=7.0 Hz).
Reaction SMILES: [C:1]1(=[O:24])[N:5]([CH:6]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]2=[O:18])[C:4](=[O:19])[C:3]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]12.CC(C)([O-])C.[K+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].O>CN(C)C=O>[CH2:36]([O:35][C:33]([CH2:32][N:8]1[C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[CH2:11][CH2:12][CH2:13][CH:6]([N:5]2[C:4](=[O:19])[C:3]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]3[C:1]2=[O:24])[C:7]1=[O:18])=[O:34])[CH3:37]
Reactant: O=C1Nc2ccccc2CCCC1N1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C(N2C(=O)c3ccccc3C2=O)CCCc2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 3-phthalimido-3,4,5,6-tetrahydro-1-benzazocin-2(1H)one (1.7 g) in dimethylformamide (10 ml) is stirred at 0° C. under a nitrogen atmosphere. A solution of potassium t-butoxide (0.75 g) in dimethylformamide (6 ml) is added and the reaction mixture is stirred at 0° C. for five minutes. A solution of ethyl bromoacetate (1.0 g) in dimethylformamide (5 ml) is added and the reaction mixture stirred at 0° C. for 11/2 hours. Water (3 ml) is added, and the reaction mixture is evaporated under high vacuum. The residue is distributed between ethyl acetate (100 ml) and water (50 ml) and the aqueous layer is washed with water (50 ml) and dried over sodium sulfate. The residue is recrystallized from methanol/ether to give 1-ethoxycarbonylmethyl-3-phthalimido-3,4,5,6-tetrahydro-1-benzazocin-2(1H)one, mp 79°-81° C. used in the next synthetic step.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=O)=[CH:6][C:5]=1[NH:14][C:15](=[O:23])[CH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)([O-:3])=[O:2].[F:24][C:25]([F:34])([F:33])[C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[B][B][B][B][B][B][B][B][B][B]>CO>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH:10]2[NH:30][C:29]2[CH:31]=[CH:32][C:26]([C:25]([F:24])([F:33])[F:34])=[CH:27][CH:28]=2)=[CH:6][C:5]=1[NH:14][C:15](=[O:23])[CH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)([O-:3])=[O:2]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(CCC1CCCC1)Nc1cc2c(cc1[N+](=O)[O-])C(=O)CC2
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: O=C(CCC1CCCC1)Nc1cc2c(cc1[N+](=O)[O-])C(Nc1ccc(C(F)(F)F)cc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
A mixture of N-(6-nitro-1-oxo-indan-5-yl)-3-cyclopentyl-propionamide (0.57 g, 1.8 mmol), 4-trifluoromethylaniline (0.35 g, 2.2 mmol), and decaborane (200 mg) in 20 ml of anhydrous methanol was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified by column (hexane/EtOAc, 5:1) to give a pure product (0.65 g, 90%).
Reaction SMILES: [CH3:1][NH:2][NH2:3].O=[C:5]([CH2:12][C:13](=O)[CH2:14][CH2:15]C)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].O>C(O)C>[CH3:1][N:2]1[C:12]([CH2:13][CH2:14][CH3:15])=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:3]1
Reactant: CCCC(=O)CC(=O)CC(=O)OCC
Reactant: CNN
Solvent: O
Solvent: CCO
Product: CCCc1cc(C(=O)OCC)nn1C
Yield: 7.9 %

Procedure:
10.4 g of methylhydrazine were initially charged in 50 ml of ethanol and, with stirring and external cooling, admixed with a solution of 42.9 g of ethyl 2,4-diketoheptanecarboxylate in 50 ml of ethanol, during which the internal temperature was kept at 5 to 10° C. (time for the dropwise addition: 10 minutes). The solution was stirred at 5 to 10° C. for another 30 minutes, the solvent and the water which had been formed were distilled off and the residue was fractionated under reduced pressure. The desired ethyl 1-methyl-3-n-propyl-pyrazole-5-carboxylate passed over at 125 to 128° C. (13 mm). The yield was 78.3% of theory. By further distillation (166 to 168° C./13 mm), the undesired isomer (=ethyl 1-methyl-5-n-propyl-pyrazole-3-carboxylate) was obtained in a yield of 7.9% of theory. Thus, the isomer ratio was approximately 10:1 in favor of the desired isomer.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:7][OH:8])[S:5][CH:6]=1.C1C(=O)N([Br:16])C(=O)C1>CN(C=O)C.O>[Br:16][C:6]1[S:5][C:4]([CH2:7][OH:8])=[N:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc(CO)n1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(CO)sc1Br
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a solution of (4-methyl-thiazol-2-yl)-methanol (7.0 g, 54.3 mmol) in DMF (80 mL) was added NBS (10.6 mg, 59.6 mmol), and the mixture was stirred at 50° C. overnight. TLC (petroleum ether:EtOAc 2:1) indicated the reaction was completed. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×3), dried over sodium sulfate, and concentrated in vacuum to give the residue which was purified by a silica gel column (petroleum ether:EtOAc 10:1) to give the title compound (11.2 g, 99%) as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[ClH:10].[CH2:11]([OH:13])[CH3:12]>>[ClH:10].[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[O:13][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: N#Cc1ccc(F)cc1
Agent: Cl
Product: CCOC(=N)c1ccc(F)cc1

Procedure:
Ethyl 4-fluorobenzimidate hydrochloride was synthesized in the same manner as in Reference Example 2. That is, 4-fluorobenzonitrile (50.8 g, 0.407 mol) was treated with hydrogen chloride in ethanol (500 mL) to give 82.1 g (99%) of the target compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:26]=[CH:27]/[C:28]([O:30][CH3:31])=[O:29])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[H][H]>C1COCC1.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: [H][H]
Reactant: COC(=O)/C=C/c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reaction time: 3 h

Procedure:
A slurry of (E)-methyl 3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)acrylate (0.116 g, 0.269 mmol) and Pd/C 10%, 50% water (0.115 g, 0.108 mmol) in 2 mL THF was treated with a hydrogen balloon with rapid stirring for 3 h. The reaction mixture was flushed with nitrogen, diluted with DCM, filtered through celite, rinsing with DCM. The filtrate was concentrated in vacuo to give methyl 3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)propanoate as a white solid. MS (ESI) m/z; calculated: 432.1; Observed: 433.1 (M++1).