Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[F:23][C:24]1[CH:33]=[CH:32][C:27]([CH2:28][NH:29][CH2:30][CH3:31])=[CH:26][CH:25]=1>>[CH2:30]([N:29]([CH2:28][C:27]1[CH:26]=[CH:25][C:24]([F:23])=[CH:33][CH:32]=1)[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)[CH3:31]
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: CCNCc1ccc(F)cc1
Product: CCN(CCn1cnc(-c2cc(C(=O)O)ccn2)c1)Cc1ccc(F)cc1
Yield: 14 %

Procedure:
The title compound was prepared in 14% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 4-fluoro-N-ethylbenzylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 0.90 (3H, t, J=6.9 Hz), 2.74 (2H, t, J=6.4 Hz), 3.58 (2H, s), 4.08 (2H, t, J=5.9 Hz), 7.03 (2H, t, J=8.9 Hz), 7.23 (2H, dd, J=7.0 Hz and 2.6 Hz), 7.43 (1H, d, J=5.2 Hz), 7.66 (1H, d, J=4.4 Hz), 8.21 (1H, s), 8.35 (1H, d, J=4.5 Hz), 8.54 (1H, s). [M+H] Calc'd for C20H21FN4O2, 369. Found, 369.
Reaction SMILES: O[N:2]1[C:10]2[C:5](=[C:6]([I:11])[CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:12].C(N(S(F)(F)[F:19])CC)C>ClCCl.C(OCC)(=O)C.ClCCl>[F:19][C:7]1[C:6]([I:11])=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:2][C:3](=[O:12])[CH2:4]2
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1Cc2c(I)cccc2N1O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1Cc2c(ccc(F)c2I)N1
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 1,3-dihydro-1-hydroxy-4-iodo-2H-indol-2-one, (2.43 g, 9 mmol) (see below) in dry dichloromethane (500 mL) was cooled to −25° C. under an argon atmosphere with magnetic stirring. A solution of (diethylamino)sulfur trifluoride (DAST, 1.35 mL) (Aldrich) in dry dichloromethane (40 mL) was added dropwise at such a rate that the reaction temperature did not rise above −25° C. (about 15 min.). After stirring for an additional 30 min. at −25° C., the reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution (180 mL) and allowed to warm to room temperature. The mixture was then filtered through Celite® (Fisher Scientific) and the layers separated. The aqueous layer was extracted with dichloromethane (2×300 mL). The dichloromethane layers were washed with saturated aqueous sodium chloride solution (200 mL), combined, dried (magnesium sulfate) and concentrated. Residue was purified by flash chromatography on sitics get using ethyl acetate-dichloromethane (1:7, V/V) as solvent to give 1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one. (Yield 1.08 g, 43%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.[Cl:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18]2>>[Cl:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]([OH:24])=[O:23])=[C:18]2[N+:1]([O-:4])=[O:2]
Reactant: O=C(O)c1cc2cccc(Cl)c2[nH]1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1[nH]c2c(Cl)cccc2c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Seventy percent nitric acid (3.4 ml) was added to dropwise to acetic anhydride (35 ml) with stirring at room temperature. The mixture was then cooled in an ice bath and 7-chloroindole-2-carboxylic acid (EP 0 622 356 A1, 1.71 g, 8.74 mmol) was added carefully. After stirring for an additional 1.5 h, the suspension was filtered and the filter cake washed with hexane and air-dried. The yield of 7-chloro-3-nitroindole-2-carboxylic acid , yellow solids, was 283 mg (14%). 1H-NMR (DMSO-d6) δ: 13.66 (1H, br s), 8.04 (1H, dd, J=1.1, 8.1 Hz), 7.53 (1H, dd, J=1.1, 7.7 Hz), 7.42 (1H, dd, J=7.7, 8.1 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.B(O)(O)[C:33]1[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=1>COCCOC>[C:18]1([N:13]2[C:12]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccccc3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Solvent: COCCOC
Product: Cc1ccc(-c2c3c(nn2-c2ccccc2)CCNCC3)cc1
Yield: 14.1 %

Procedure:
The title compound (17.5 mg) was prepared from 188.9 mg of 2-phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 176, Step B) and 93.3 mg of p-tolylboronic acid as in Example 199, using DME as the solvent. MS (ESI): exact mass calculated for C20H21N3, 303.17. found, m/z 304.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.26-7.23 (m, 2H), 7.21-7.16 (m, 3H), 7.15-7.12 (m, 2H), 7.04-7.01 (m, 2H), 3.11-3.07 (m, 2H), 3.04-3.00 (m, 2H), 2.98-2.96 (m, 2H), 2.68-2.65 (m, 2H), 2.35 (s, 3H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](=O)[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)C.[NH2:21][NH2:22]>C(#N)C>[CH3:18][O:17][C:9]1[CH:8]=[C:7]([C:6]2[CH2:5][C:4](=[O:3])[NH:21][N:22]=2)[CH:12]=[C:11]([O:13][CH3:14])[C:10]=1[O:15][CH3:16]
Reactant: NN
Reactant: CCOC(=O)CC(=O)c1cc(OC)c(OC)c(OC)c1
Solvent: CC#N
Product: COc1cc(C2=NNC(=O)C2)cc(OC)c1OC
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a stirred solution of 3-oxo-3-(3,4,5-trimethoxyphenyl)-propionic acid ethyl ester (2.82 g, 10 mmol) in dry acetonitrile (15 mL) was added to anhydrous hydrazine (640 mL, 20 mmol) at room temperature. After 1 hour, the mixture was heated to reflux for 16 hours. The mixture was diluted with acetonitrile (20 mL) and the solid was filtered. The solid was washed with acetonitrile (10 mL) and dried under nitrogen to afford 2.2 g of title compound (k). Preparation of 4-Dimethylaminomethylene-5-(3,4,5-Trimethoxyphenyl)-2,4-Dihydro-Pyrazol-3-one (1):
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[CH3:11][C:12]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:13]=1[NH2:14]>C1COCC1>[CH:5]([NH:14][C:13]1[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:12]=1[CH3:11])=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Solvent: O=CO
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])ccc1NC=O
Temperature: 55 °C
Yield: 77.2 %

Procedure:
25 g (0.26 mol) of acetic anhydride were cooled to 0° C. under nitrogen. 15 g (0.32 mol) of formic acid were added dropwise at this temperature. The resultant mixture was then allowed to melt, and was then warmed to from 50 to 60° C. over the course of two hours. The mixture was then cooled to room temperature, and 20 ml of dry tetrahydrofuran were added, and the resultant mixture was again cooled to 0° C. A suspension of 15.2 g (0.1 mol) of 2-methyl-4-nitroaniline in 100 ml of THF was then added dropwise to this mixture, and the resultant mixture was left at 0° C. for one hour and then warmed to room temperature. The resultant yellow precipitate was filtered off with suction, washed with water and dried at 50° C. under reduced pressure, to give 13.9 g of N-formyl-2-methyl-4-nitroaniline (yield: 77%). The product had the same physical/chemical properties as that prepared in the above-described manner (compare section 1.1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH:8]=[O:9])=[C:4]([CH3:12])[CH:3]=1.[C:13]([NH2:17])(=[O:16])[CH2:14]O>O1CCCC1.CCOCC>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH:8]2[NH:17][C:13](=[O:16])[CH2:14][O:9]2)=[C:4]([CH3:12])[CH:3]=1
Reactant: NC(=O)CO
Reactant: Cc1cc(Cl)ccc1OCC=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1OCC1NC(=O)CO1
Reaction time: 24 h
Yield: 18.2 %

Procedure:
A solution containing 4.6 g (0.025 mole) of (4-chloro-2-methylphenoxy)acetaldehyde and 2.1 g (0.028 mole) of glycolamide in 25 ml of tetrahydrofuran and 25 ml of ether was allowed to stand at ambient temperature for 24 hours. The resulting product was washed with 5% sodium carbonate and water, dried and purified by silica chromatography to give 1.1 g of 2-(4-chloro-2-methylphenoxymethyl)-4-oxazolidinone as a white crystalline solid melting at 109°-112°.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>O1CCCC1>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][NH:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)[CH3:21]
Reactant: CCOC(=O)CCl
Reactant: NCc1ccco1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCc1ccco1
Temperature: 25 °C

Procedure:
Furfurylamine (48.6 g, 0.5 mol) and triethylamine (50.6 g, 0.5 mol) were dissolved in tetrahydrofuran (1000 mL) and cooled to 0°-5° C. with an ice water bath. Ethyl chloroacetate (61.3 g, 0.5 mol) was dropwise added at 0°-5° C. to the solution. After addition the mixture was allowed to warm up to room temperature and then stirred over night. The precipitated white triethylamine hydrochloride was filtered off and the filtrate concentrated to an oil which was dissolved in ether and cooled by means of an ice water bath. Ether which has been saturated with dry hydrogen chloride was added to the solution whereby the HCl salt of the product precipitated first as a sticky semisolid. Repeated treatment with anhydrous ether afforded the desired product. Filtration yielded 48.4 g product as an amber solid. Used as is for further synthesis.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([C:18]([F:21])([F:20])[F:19])=[O:17])=[CH:12][CH:11]=1)=[O:8].[NH:24]1[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]1>>[Br:1][C:2]1[C:3]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([C:18]([F:21])([F:20])[F:19])=[O:17])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(S(=O)C(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: O[C@@H]1CCNC1
Product: O=C(Nc1ccc(S(=O)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(4-((trifluoromethyl)sulfinyl)phenyl)nicotinamide (Stage 222.2) and (R)-pyrrolidin-3-ol to afford an amorphous off-white solid. HPLC (Condition 4) tR=4.83 min, UPLC-MS (Condition 3) tR=0.95 min, m/z=478.2 [M+H]+.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][C:22]([C:24](O)=[O:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:24]([C:22]1[O:23][C:19]([C:16]3[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=3)=[CH:20][CH:21]=1)=[O:25])[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(-c2ccc(Cl)cc2)o1

Procedure:
Prepared by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and 5-(4-chlorophenyl)furoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 331, 333 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].O>CN(C)C=O>[Si:18]([O:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CCOC(=O)c1cc(CO)on1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(CO[Si](C)(C)C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 10 h
Yield: 100.4 %

Procedure:
14.22 g of ethyl 5-(hydroxymethyl)-isoxazole-3-carboxylate was dissolved in 80 ml of N,N-dimethylformamide, and 6.13 g of imidazole and 13.57 g of t-butyldimethylsilyl chloride were then added. The mixture was stirred at room temperature for 10 hours. After water was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to obtain 23.82 g of ethyl 5-(t-butyldimethylsilanyloxymethyl)-isoxazole-3-carboxylate.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC(=O)CC>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:33][CH2:34]3)[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Solvent: O
Solvent: CCC(C)=O
Product: COc1ccccc1OCCCc1oc(N2CCN(c3ccccc3)CC2)nc1-c1ccc(Cl)cc1

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (378 mg), 1-phenylpiperazine (810 mg) and 2-butanone (15 ml) was stirred with heating under reflux for 12 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (150 ml×2). The organic layer was washed with a 10% aqueous solution of citric acid (100 ml), dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]-2-(4-phenyl-1-piperazinyl)oxazole was obtained as an oil (168 mg, 33%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[CH2:4][CH3:5].[F:15][C:16]1[CH:35]=[CH:34][C:19]([CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:23])=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][C:22](=[O:23])[C:24]2[CH:29]=[CH:28][C:27]([S:30]([N:8]3[C:9]4[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:6]([CH2:3][CH2:4][CH3:5])=[CH:7]3)(=[O:31])=[O:32])=[CH:26][CH:25]=2)=[CH:34][CH:35]=1
Reactant: CCCc1c[nH]c2ccccc12
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1cn(S(=O)(=O)c2ccc(C(=O)NCc3ccc(F)cc3)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Add NaH 60% in mineral oil (0.080 g, 2.0 mmol) to a stirred solution of 3-propyl-indole (0.266 g, 1.67 mmol) in dr THF (25 mL) under N2. Stir the reaction mixture at ambient temperature for 45 min. Add 4-(4-fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (0.547 g, 1.67 mmol) portion wise at ambient temperature. Stir the reaction mixture overnight at ambient temperature. Pour the reaction mixture into a two-phase mixture of EtOAc (150 mL) and saturated solution of NaHCO3 (50 mL). Separate the organic layer, wash with brine, separate and dry (MgSO4). Filter and evaporate the filtrate. Purify the residue on the chromatron using a 4 mm plate and eluting with a gradient hexane-EtOAC system to give 0.262 g (34%) of N-(4-fluoro-benzyl)-4-([3-propyl-indole-1-sulfonyl]-benzamide. Mass spectrum (m/e) M+1) 451.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:3]=12.[H-].[Na+].[CH3:25][O:26][C:27]([C:29]1[O:30][C:31]([N+]([O-])=O)=[CH:32][CH:33]=1)=[O:28]>CS(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:31]4[O:30][C:29]([C:27]([O:26][CH3:25])=[O:28])=[CH:33][CH:32]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: COC(=O)c1ccc([N+](=O)[O-])o1
Reactant: Nc1ncnc2c1c(-c1ccc(O)cc1)nn2C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(Oc2ccc(-c3nn(C4CCCC4)c4ncnc(N)c34)cc2)o1
Temperature: 90 °C
Yield: 47.2 %

Procedure:
A mixture of 4-(4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenol (0.107 g, 0.362 mmol, 1.0 equiv), DMSO (0.5 mL), sodium hydride (60%, 0.030 g, 0.72 mmol, 2.0 equiv), and methyl-5-nitro-2-furoate (0.062 g, 0.36 mmol, 1.0 equiv) was heated at 90° C. for 3 h. The reaction mixture was allowed to cool to room temperature, poured into ice water (10 mL), and extracted with three portions of CH2Cl2 (50 mL each). The combined organic extracts were washed with 5% aqueous KOH (50 mL) and the organic layer was dried over MgSO4, filtered, and concentrated to afford a red oil which was purified by column chromatography on silica gel (elution with 300 mL of 5% MeOH/CH2Cl2) to afford methyl 5-[4-(4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenoxy]-2-furoate as a red solid (0.070 g, 0.17 mmol):
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:12])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH2:46]Cl>CC(=O)CC.C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:46][CH2:45][S:12]/[C:11]/1=[N:13]/[N:14]=[CH:15]\[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=3)[N:23]=2)=[CH:20][CH:21]=1)([CH3:3])[CH3:2]
Reactant: ClCCBr
Reactant: CC(C)c1ccccc1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CC(C)c1ccccc1N1CCS/C1=N/N=C\c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 90 °C
Yield: 61.2 %

Procedure:
To (E)-N-(2-isopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (214 mg, 0.407 mmol) and potassium carbonate (225 mg, 1.63 mmol) in butanone (4 ml) was added 1-bromo-2-chloroethane (70.0 mg, 0.489 mmol). The reaction was heated to 90° C. overnight. The reaction was determined to be complete by LCMS. The reaction mixture was cooled, diluted with DCM and washed with water. The aqueous layer was extracted with DCM. The organic layers were filtered through a phase separator and concentrated. Separation by flash column chromatography and drying the recovered solid at 55° C. under vacuum provided the title compound as a white solid (137 mg, 0.249 mmol, 61%): mp 193-196° C.; 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.22 (s, 1H), 8.17 (d, J=8.4 Hz, 2H), 7.80 (ddd, J=9.5, 6.9, 4.9 Hz, 4H), 7.43-7.33 (m, 4H), 7.31-7.21 (m, 2H), 4.05 (td, J=9.4, 7.1 Hz, 1H), 3.97-3.87 (m, 1H), 3.42-3.33 (m, 1H), 3.33-3.24 (m, 1H), 3.12 (heptet, J=6.8 Hz, 1H), 1.27 (d, J=6.8 Hz, 3H), 1.22 (d, J=6.9 Hz, 3H); ESIMS m/z 552 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]([CH3:16])([CH3:15])[C:8]([O:10]C(C)(C)C)=[O:9])[N:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[I:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]([CH3:16])([CH3:15])[C:8]([OH:10])=[O:9])[N:3]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)n1ccc(I)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C(=O)O)n1ccc(I)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-butyl 2-(3-iodo-1H-pyrazol-1-yl)-2-methylpropanoate 7.03 (530 mg, 1.58 mmol) was dissolved in DCM (7 mL) and TFA (7 mL). The reaction was stirred at r.t. for 18 h and was concentrated in vacuo to afford crude 2-(3-iodo-1H-pyrazol-1-yl)-2-methylpropanoic acid 7.04 that was used without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C7H10IN2O2: 280.98; found: 280.91.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([NH2:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1>C1(C)C=CC=CC=1.C1C=CC=CC=1>[CH:5]1([N:15]=[C:1]=[O:2])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: NC1CCCc2ccccc21
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: O=C=NC1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a stirred solution of 242.4 grams (2.46 moles) of phosgene in 200 ml of toluene and 600 ml of benzene is slowly added a solution of 119.9 grams (0.814 mole) of 1,2,3,4-tetrahydro-1-naphthylamine, while maintaining the reaction temperature at 10°C. to 15°C. The mixture is stirred overnight at room temperature and then heated to reflux under a nitrogen atmosphere. After 4 hours reflux, most of the solvent is distilled from the reaction at atmospheric pressure. The residual solvent is evaporated at reduced pressure. The crude product is distilled to give 121.4 grams of product with boiling point 90°C. to 96°C. (0.3 mm).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([O:12][C:13]2[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([CH3:19])[CH:18]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(P(CCCC)CCCC)CCC.[CH2:34](O)[CH2:35][CH2:36][OH:37].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[C:1]([C:3]1[CH:4]=[C:5]([S:9]([O:12][C:13]2[CH:14]=[C:15]([CH:16]=[C:17]([CH3:19])[CH:18]=2)[O:20][CH2:34][CH2:35][CH2:36][OH:37])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(C#N)c2)c1
Reactant: OCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a solution of 3-(3-cyanophenylsulfonyloxy)-5-methylphenol (2.30 g, 8.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (2.4 g, 12.0 mmol) and 1,3-propanediol (3.0 g, 40 mmol) in anhydrous tetrahydrofuran (50 mL) was added 1,1'-(azodicarbonyl)dipiperidine (3.0 g, 12.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (100 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (10% ethyl acetate in dichloromethane) to give the title compound as a colorless oil (2.2 g, 79%). 1H-NMR (300 MHz, CDCl3) δ 8.13 (s, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.71 (t, J=7.9 Hz, 1H), 6.65 (s, 1H), 6.40 (s, 1H), 6.37 (s, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.82 (t, J=6.0 Hz, 2H), 2.26 (s, 3H), 2.00 (t, J=6.0 Hz, 2H), 1.67 (br s, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH2:18])[C:6]([NH:9][CH:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])=[CH:7][CH:8]=1.N[C:20](N)=[O:21].O>ClC(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]([CH:10]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH3:11])[C:20](=[O:21])[NH:18][C:5]=2[CH:4]=1
Reactant: CC(Nc1ccc(Cl)cc1N)c1cccnc1
Reactant: NC(N)=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(c1cccnc1)n1c(=O)[nH]c2cc(Cl)ccc21
Temperature: 190 °C
Yield: 63.5 %

Procedure:
A mixture of 41.5 parts of 4-chloro-N1 -[1-(3-pyridinyl)ethyl]-1,2-benzenediamine monohydrochloride and 27 parts of urea is stirred and heated for 1.50 hours in an oil-bath at about 190° C. The reaction mixture is cooled, water and trichloromethane are added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 26 parts (63.5%) of 5-chloro-1,3-dihydro-1-[1-(3-pyridinyl)ethyl]-2H-benzimidazol-2-one; mp. 190° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]#[N:7])[CH:3]=[N:2]1.CC(C)([O-])C.[K+].[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[CH:17]=[O:18]>CS(C)=O>[Br:14][C:15]1[C:16]([CH:17]=[O:18])=[C:19]([N:1]2[CH:5]=[C:4]([C:6]#[N:7])[CH:3]=[N:2]2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1c(F)cccc1Br
Reactant: N#Cc1cn[nH]c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cnn(-c2cccc(Br)c2C=O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.4 %

Procedure:
1H-pyrazole-4-carbonitrile (935 mg, 10.0 mmol, Eq: 1.00) was dissolved in 15 mL of dry DMSO and potassium tert-butoxide (1.19 g, 10.0 mmol, Eq: 1.00) was added. The mixture was stirred at room temperature for 20 minutes and 2-bromo-6-fluorobenzaldehyde (4.08 g, 20.1 mmol, Eq: 2) was added. The mixture was stirred at room temperature overnight and then extracted with ethyl acetate and water. The organic layer was dried and concentrated. The crude material was purified by flash chromatography (silica gel, 40 g, 20% to 40% EtOAc in hexanes) to give 1-(3-bromo-2-formylphenyl)-1H-pyrazole-4-carbonitrile (1.53 g, 55%).