Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][CH:6]([C:8](OC)=[O:9])[CH2:5][CH:4]1[C:12]([OH:14])=[O:13])[CH3:2].[Li+].[BH4-].O>C1COCC1>[CH2:1]([CH:3]1[CH2:7][CH:6]([CH2:8][OH:9])[CH2:5][CH:4]1[C:12]([OH:14])=[O:13])[CH3:2]
Reactant: CCC1CC(C(=O)OC)CC1C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC1CC(CO)CC1C(=O)O
Temperature: -20 °C
Reaction time: 1 h
Yield: 101.5 %

Procedure:
To a solution of 2-ethyl-4-(methoxycarbonyl)cyclopentanecarboxylic acid (8.34 g, 41.7 mmol, Preparation #11, Step A) in THF (208 mL) was added LiBH4 (0.907 g, 41.7 mmol) at about −20° C. The reaction mixture was stirred at about −20° C. for about 1 h. The reaction mixture was allowed to warm to about 25° C. then was stirred at about 25° C. for about 16 h. Additional LiBH4 (0.907 g, 41.7 mmol) was added. The reaction mixture was stirred at about 25° C. for about 4 h. Water (10 mL) was added slowly to quench the reaction. The solid was removed by vacuum filtration. The filtrate was concd under reduced pressure. The resulting residue was partitioned between water (50 mL) and DCM (3×50 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give 2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylic acid (7.29 g, 100%): LC/MS (Table 1, Method n) Rt=0.44 min; MS m/z: 173 (M−H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.[CH:10](O)=O.C=O>O>[CH3:10][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1
Reactant: OCCC1CCNCC1
Reactant: O=CO
Agent: C=O
Solvent: O
Product: CN1CCC(CCO)CC1
Temperature: 95 °C
Reaction time: 2 h
Yield: 129 %

Procedure:
2-Piperidin-4-yl-ethanol (2.37 g, 18.3 mmol) was dissolved in formic acid (2.1 mL, 55.7 mmol), 35% aqueous formaldehyde solution (4.5 mL, 55.4 mmol) and water (20 mL). The reaction mixture was heated at 95° C. for 2 hours, and then cooled to room temperature. The reaction mixture was quenched by slowly pouring it onto a saturated NaHCO3 solution (200 mL) and concentrated in vacuo. The residue was suspended in MeOH (100 mL) and stirred for 2 hours, filtered, and the filtrate was concentrated in vacuo to give 2-(1-methyl-piperidin-4-yl)-ethanol (3.38 g, 129%) as a colourless oil which was used without further purification.
Reaction SMILES: [N:1]1[C:11]2[NH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)=[O:22]>CN(C)C=O>[O:16]=[C:7]1[N:6]([CH2:20][C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:32][CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:11]=2[NH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]1=2
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)CBr)cc2)CCC1
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)CN3C(=O)c4ccccc4Nc4ncccc43)cc2)CCC1
Temperature: 0 °C
Yield: 49.2 %

Procedure:
5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (0.362 g, 1.05 eq.) was suspended in dimethylformamide (DMF) (5 mL). The reaction was cooled to 0° C. and sodium hydride (60% in mineral oil) (0.2 g, 3.0 eq.) was added. The reaction was warmed to room temperature and stirred until gas evolution ceased. The reaction was cooled to 0° C. and tert-butyl (1-(4-(2-bromoacetyl)phenyl)cyclobutyl)carbamate (0.6 g, 1.0 eq.) in DMF (1 mL) was added. The reaction was stirred at room temperature overnight. The reaction was quenched by the addition of aqueous saturated ammonium chloride solution (1 mL). Dichloromethane was added (15 mL) and the phases were separated. The organic phase was washed with water (3×10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by column chromatography (50% ethyl acetate in dichloromethane), giving tert-butyl (1-(4-(2-(6-oxo-6,11-dihydro-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-5-yl)acetyl)phenyl)cyclobutyl)carbamate (0.4 g, 50%) as a yellow semi-solid. LCMS: 499 [M+H].
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[N:3]1.C(N(CC)C(C)C)(C)C.[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:30]=1[C:31](Cl)=[O:32]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:30]=1[C:31]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[CH:5]=2)=[CH:12][CH:11]=1)=[O:32]
Reactant: Cn1nc(-c2cccs2)cc1-c1ccc(N)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cccs2)cc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
To a solution of 66 (20 mg, 0.08 mmol) in CH2Cl2 (10 ml) was added N,N-diisopropylethylamine (DIEA, 26 mg, 36 μL, 0.2 mmol), 4-dimethylaminopyridine (DMAP, 0.6 mg, 0.05 mmol). The 2,6-difluorobenzoyl chloride (15 mg, 0.08 mmol) was dropped into above solution. The mixture was stirred for 2 h at room temperature. The reaction was quenched with saturated NaHCO3 (20 ml) and extracted with EtOAc. The dicarboxamide was hydrolyzed with 1M NaOH in THF and MeOH (1:1). The product was purified by HPLC and afforded 67 (20.5 mg, 65%) as yellow solid. LC-MS: calcd. for C21H15F2N3OS: 396 (M+1). 1H NMR (DMSO-d6) δ 3.86 (s, 3H), 6.77 (s, 1H), 7.08-7.10 (m, 1H), 7.26-7.29 (m, 2H), 7.42 (dd, 1H, J=0.88, 3.5), 7.42 (dd, 1H, J=0.88, 4.9), 7.59 (d, 2H, J=8.6), 7.62-7.63 (m, 1H), 7.83 (d, 2H, J=8.6), 11.00 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[N+:21]([O-])=O)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[H][H]>CCO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[NH2:21])(=[O:10])=[O:9])[CH2:6][CH2:7]1
Reactant: CN1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2N)CC1

Procedure:
1-methyl-4-(2-nitro-4-(trifluoromethyl)phenylsulfonyl)piperazine was dissolved in EtOH (20 mL) and the solution was purged with argon. Pd/C (365 mg, 0.34 mmol, 10%) was added to the solution, which was stirred for 3 days in an atmosphere of hydrogen gas. The mixture was again purged with argon, filtered through Celite and concentrated under reduced pressure to afford 2-(4-methylpiperazin-1-ylsulfonyl)-5-(trifluoromethyl)benzenamine. MS m/z=324 [M+H]+. Calc'd for C12H16F3N3O2S: 323.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][Mg]Br>O1CCCC1>[CH3:1][C:2]1[N:7]=[C:6]([CH:8]([OH:9])[CH3:10])[CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: Cc1cccc(C=O)n1
Solvent: C1CCOC1
Product: Cc1cccc(C(C)O)n1
Temperature: -10 °C
Yield: 100 %

Procedure:
To a −60° C. solution of 6-methyl-pyridine-2-carbaldehyde (25 g, 206 mmol) in tetrahydrofuran (200 mL) was added methyl magnesium bromide (200 mL, 1.4 M in tetrahydrofuran/toluene, 1.36 equiv) over 40 minutes. The reaction mixture was slowly warmed to −10° C. over 90 minutes, and then slowly quenched with saturated aqueous ammonium chloride (75 mL). The liquid phase was decanted from the solids and concentrated in vacuo. The resulting residue was dissolved in methylene chloride, dried over magnesium sulfate, and concentrated in vacuo to yield 1-(6-Methyl-pyridin-2-yl)-ethanol (28 g, 100%).
Reaction SMILES: [H-].[Na+].[F:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[C:10]1[C:11]2[S:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][C:12]=2[NH:13][CH:14]=1.Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>CN(C=O)C>[F:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[C:10]1[C:11]2[S:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][C:12]=2[N:13]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:14]=1
Reactant: COC(=O)c1cc2[nH]cc(C3CCCCC3F)c2s1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(C2CCCCC2F)c2sc(C(=O)OC)cc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
60% NaH in mineral oil (2 eq.) was added at RT to a 0.25M solution of methyl 6-(2-fluorocyclohexyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate in dry DMF, after few min methyl bromoacetate (3 eq.) was added and the mixture was stirred at 60° C. for 1 h and left overnight at RT. After dilution with EtOAc, the organic layer was washed with 1N HCl, sat. NaHCO3 and brine, dried over Na2SO4 and concentrated. Chromatography (PE/EtOAc) afforded the title compound (53%). 1H-NMR (400 MHz, CDCl3, 300K, δ) 7.60 (s, 1H), 6.92 (s, 1H), 4.74 (s, 2H), 4.50 (dtd, 1H, J 48.9, 10.3, 4.5), 3.88 (s, 3H), 3.77 (s, 3H), 2.85-2.76 (m, 1H), 2.25-2.11 (m, 2H), 1.90-1.74 (m, 2H), 1.68-1.54 (m, 2H), 1.44-1.33 (m, 2H); MS (ES+) m/z 354 (M+H)+.
Reaction SMILES: [Na].[CH3:2][CH:3]([OH:17])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([CH3:16])[CH2:14][CH3:15])=[CH:8][CH:7]=1.Cl[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH3:2][CH:3]([O:17][C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([CH3:16])[CH2:14][CH3:15])=[CH:8][CH:7]=1
Reactant: CCC(C)Oc1ccc(OCC(C)O)cc1
Reactant: Clc1ncccn1
Agent: [Na]
Product: CCC(C)Oc1ccc(OCC(C)Oc2ncccn2)cc1

Procedure:
In the same manner, the sodium salt of 1-methyl-2-[4-(1-methylpropoxy)phenoxy]ethanol and 2-chloropyrimidine are reacted together to give 2-{1-methyl-2-[4-(1-methylpropoxy)phenoxy]ethoxy}pyrimidine, MS m/e 320 (M+ +NH4).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[C:6]=2[N:7]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[Cl:20])[CH2:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:3]=[C:4]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: Clc1nc(N2CCOCC2)c2ncnc(SCc3ccc(Cl)c(Cl)c3)c2n1
Reactant: C1CNCCN1
Product: Clc1ccc(CSc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)cc1Cl

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(3,4-dichlorobenzyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 153°-156° C.) and piperazine.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].O[C:19]1C=CC(C(C)CC(OCC)=O)=CC=1>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: CCOC(=O)CC(C)c1ccc(O)cc1
Reactant: C=CCOc1ccc(CCC(=O)OCC)cc1
Product: C=CCOc1ccc(C(C)CC(=O)OCC)cc1

Procedure:
Ethyl 3-(4-benzyloxyphenyl)but-2-enoate (3.4 g) in ethyl acetate (100 ml) was hydrogenated over a 10% palladium-on-carbon catalyst (250 mg) at atmospheric pressure/ambient temperature. The catalyst was removed by filtration and the filtrate evaporated to give an oil. The oil was purified by chromatography on silica gel using a 4/1 (v/v) mixture of hexane and ethyl acetate as eluent to give ethyl 3-(4-hydroxyphenyl)butanoate (1.51 g) as a pale yellow oil; NMR(CDCl3): 1.20(3H,t), 1.27(3H,d), 2.52(2H,q), 3.22(1H,m), 4.08(2H,q), 4.84(1H,s), 6.71(2H,m) and 7.08(2H,m); m/z 208(M). Ethyl 3-(4-allyloxyphenyl)butanoate was prepared using the procedue used to prepare ethyl 3-(4-allyloxyphenyl)propionate (see Example 1) but using ethyl 3-(4-hydroxyphenyl)butanoate in place of ethyl 3-(4-hydroxyphenyl)propionate; NMR(CDCl3) 1.17(3H,t), 1.25(3H,d), 2.51(2H,m), 3.22(1H,m), 4.05(2H,q), 4.50(2H,m), 5.33(2H,m), 6.06(1H,m), 6.82(2H,m) and 7.11(2H,m); m/z 249 (M+H).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=1.[C:13]([N:20]1[CH2:24][CH2:23][CH:22]=[CH:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:16]([O:15][C:13]([N:20]1[CH2:24][C@H:23]2[C@H:22]([C:3]([C:4]3[CH:5]=[N:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=3)=[N:2][O:1]2)[CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1C=CCC1
Reactant: COc1ccc(C(Cl)=NO)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(C2=NO[C@H]3CN(C(=O)OC(C)(C)C)C[C@@H]23)cn1

Procedure:
Chloro oxime 2c (1.12 g; 5.99 mmol), N-Boc-pyrroline (0.5 mL; 2.90 mmol) and sodium bicarbonate (0.61 g) in ethyl acetate (40 mL) were stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgSO4), filtered and evaporated to yield crude cycloadduct. 3c was isolated as a white solid after chromatography with 25% ethyl acetate/hexanes.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[C:11]4[C:16](=[CH:17][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4.C1C2C3=CC4C(C(C=O)=C3[O:23][C:22]=2C=CC=1)=CC=CC=4>C1(C)C=CC=CC=1.CCCCCC>[CH:1]1[C:9]2[C:8]3[C:10]([CH:22]=[O:23])=[C:11]4[C:16](=[CH:17][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4
Reactant: O=Cc1c2ccccc2cc2c1oc1ccccc12
Reactant: c1ccc2cc3c(cc2c1)oc1ccccc13
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=Cc1c2ccccc2cc2oc3ccccc3c12
Yield: 58 %

Procedure:
Benzo[b]naphtho[2,3-d]furan (H. G. Pars Pharmaceutical Laboratories, Inc.) was formylated using the procedure of A. Rieche et al., Chem. Ber. 93, 88 (1960). The crude aldehyde appeared to be mainly one isomer accompanied by a small amount of a second aldehyde by TLC. Purification by chromatography (SiO2, PhCH3) followed by recrystallization (CH2Cl2 /hexane) gave the main component in 58% yield identified using NMR techniques to be benzo[b]naphtho[2,3-d]furan-6-carbaldehyde, (2A) mp 169°-171.5°, (C,H). The minor component, obtained in 3.4% yield was shown by NMR to be benzo[b]naphtho2,3-d]-furan-11-carbaldehyde, mp 128°-132°, (C,H), (PhCH3 /hexane).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([OH:16])=[CH:6][C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][C:8]=2[CH:15]=1)[CH3:2].[CH3:17]O.S(=O)(=O)(O)O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[C:5]([OH:16])=[CH:6][C:7]2[S:11][C:10]([C:12]([O:14][CH3:17])=[O:13])=[CH:9][C:8]=2[CH:15]=1)[CH3:2]
Reactant: CCOc1cc2cc(C(=O)O)sc2cc1O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOc1cc2cc(C(=O)OC)sc2cc1O

Procedure:
A solution of 0.71 g. of 5 -ethoxy-6-hydroxybenzothiophene-2-carboxylic acid, 0.29 g. of methanol, and a catalytic amount of sulfuric acid in methylene chloride was heated to reflux for 48 hours. The solution was diluted with ethyl acetate and was washed first with a 10% aqueous sodium bicarbonate solution and then with water. The organic solution was dried over sodium sulfate and evaporated to dryness providing the desired ester intermediate which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]([CH3:31])[C:16]([NH:18][C:19]2[C:24]([Cl:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=2[Cl:30])=[O:17])[CH:10]=1.C(N(CC)CC)C.[C:39](O)(=[O:43])/[CH:40]=[CH:41]\[CH3:42].C(Cl)Cl.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>>[Cl:25][C:24]1[C:23]([O:26][CH3:27])=[CH:22][C:21]([O:28][CH3:29])=[C:20]([Cl:30])[C:19]=1[NH:18][C:16](=[O:17])[N:15]([C:11]1[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:39](=[O:43])/[CH:40]=[CH:41]\[CH3:42])[CH:10]=1)[CH3:31]
Reactant: C/C=C\C(=O)O
Reactant: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccccc3N)ncn2)c1Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C/C=C\C(=O)Nc1ccccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
The title compound was synthesized following the approach outlined in Procedure 2A (Example 100), modifying step (i) to the following procedure: To a solution of 1-(6-((2-aminophenyl)amino)pyrimidin-4-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylurea (20 mg, 0.043 mmol), triethylamine (21.8 g, 0.22 mmol), and (Z)-but-2-enoic acid (4.5 g, 0.052 mmol) in DCM (0.86 ml, 13.3 mmol) was added a solution of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (49.4 g, 0.78 mmol, 50% solution EtOAc) at 0° C., and the resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated and the residue was purified by silica gel column to obtain the title compound (8.5 mg, yield: 37%). 1H NMR (400 MHz, CDCl3) δ 2.20 (dd, J=7.28, 1.76 Hz, 3H) 3.30 (s, 3H) 3.92 (s, 6H) 5.85 (dd, J=11.42, 1.76 Hz, 1H) 5.99 (s, 1H) 6.29 (dd, J=11.36, 7.34 Hz, 1H) 6.52 (s, 1H) 7.23-7.34 (m, 2H) 7.46 (d, J=7.40 Hz, 1H) 7.55 (br. s., 1H) 7.78 (d, J=7.53 Hz, 1H) 8.40 (d, J=0.88 Hz, 1H) 12.50 (s, 1H); MS (ESI): 531.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([C:14]#[N:15])[C:11]([S:16][C:17]([F:20])([F:19])[F:18])=[C:10]2[NH2:21])=[CH:5][CH:4]=1.[Br:24]Br>ClCCl.CCCCCC>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([Br:24])=[C:12]([C:14]#[N:15])[C:11]([S:16][C:17]([F:19])([F:20])[F:18])=[C:10]2[NH2:21])=[CH:5][CH:4]=1
Reactant: N#Cc1cn(-c2ccc(C(F)(F)F)cc2)c(N)c1SC(F)(F)F
Reactant: BrBr
Solvent: CCCCCC
Solvent: ClCCl
Product: N#Cc1c(SC(F)(F)F)c(N)n(-c2ccc(C(F)(F)F)cc2)c1Br
Yield: 52 %

Procedure:
To a suspension of 1.17 g (3.30 mmoles) of 1-(4-trifluoromethylphenyl)-2-amino-3-trifluoromethylthio-4-cyanopyrrole and 0.46 ml (0.34 g, 3.3 mmoles) of triethylamine in 20 ml of chloroform cooled to -20° C. was added a solution of 0.19 ml (0.59 g, 3.7 mmoles) of bromine in 5 ml of chloroform. The reaction mixture was stirred at -20° C. for 1 hour and then allowed to warm to 0° C. Another 0.04 ml (0.13 g, 0.8 mmole) of bromine was then added and after 15 minutes of additional stirring, the reaction mixture was diluted with dichloromethane and partitioned with water and a saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give 1.11 g of a brown solid. This material was combined with that from a previous reaction of 1.00 g (2.8 mmoles) of 1-(4-trifluoromethylphenyl)- 2-amino-3-trifluoromethylthio-4-cyanopyrrole and 0.15 ml of bromine. Chromatography on silica gel eluting with 3:1 v/v dichloromethane-hexane furnished 1.40 g (52%) of 1-(4-trifluoromethylphenyl)-2-amino-3-trifluoromethylthio-4-cyano-5-bromopyrrole (EXAMPLE 14A) as a yellow solid. Recrystallization from hexane-ethyl acetate provided the product as light yellow platelets, melting point about 175° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][NH:16]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[H-].[Na+].I[CH3:24].Cl>C1COCC1.O>[F:20][C:2]([F:1])([F:19])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][N:16]3[CH3:24])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: CI
Reactant: FC(F)(F)Oc1ccc(-c2ccc3cc[nH]c3c2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccc2ccc(-c3ccc(OC(F)(F)F)cc3)cc21
Reaction time: 0.5 h

Procedure:
To a solution of 6-(4-trifluoromethoxyphenyl)-1H-indole (0.853, 3.08 mmoles) in dry THF (10 mL) was added sodium hydride (60% dispersion on mineral oil, 0.47 g, 12.3 mmol), portionwise. The reaction mixture was stirred under nitrogen for 30 minutes and, then cooled in ice bath. A solution of iodomethane (0.38 mL, 6.1 mmole) in dry THF (10 mL) was added and the reaction mixture was stirred for 1 hour at room temperature. The mixture was then poured into excess water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography (Biotage apparatus) using 0.5% t-butyl methyl ether in hexane as an eluant. The title compound was obtained as a cream-colored solid that was vacuum dried at 66° C. (0.623 g, 70%). 1HNMR (300 MHz, DMSO-d6): δ7.85 (d, 2H, J=8.3 Hz), 7.75 (s, 1H), 7.65 (d, 1H, J=8.3 Hz), 7.45 (d, 2H, J=8.3 Hz), 7.3-7.4 (m, 2H), 6.45 (s, 1H), and 3.85 ppm (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][C:12]([O:14][CH2:20][CH3:21])=[O:13]
Reactant: CCO
Reactant: O=C(O)Cc1cc([N+](=O)[O-])ccc1Br
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc([N+](=O)[O-])ccc1Br

Procedure:
A mixture composed of 5.21 g (20 mmol) of (2-bromo-5-nitrophenyl)acetic acid (Zhumal Organicheskoi Khimii (1974) 10, 92-5), 80 ml of absolute ethanol and 0.1 ml of concentrated sulfuric acid is refluxed for 6 hours. After cooling, the reaction medium is concentrated under vacuum and taken up in ether. This organic phase is washed with saturated NaHCO3 solution and then with water, after which it is dried over Na2SO4. After concentrating under vacuum, 5.54 g of a beige solid are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[F:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:35]4[C:30]([F:29])=[N:31][CH:32]=[CH:33][CH:34]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1cccnc1F
Reactant: CC(C)(C)OC(=O)NC1=NC2(CS1)c1cc(I)ccc1Oc1ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)NC1=NC2(CS1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12
Temperature: 80 °C

Procedure:
A vial was charged with tert-butyl 3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate (0.454 g, 0.791 mmol), 2-fluoropyridin-3-ylboronic acid (0.167 g, 1.186 mmol), potassium carbonate (0.546 g, 3.95 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.091 g, 0.079 mmol). The vial was flushed with Ar (g), then Dioxane (5.27 mL) and water (2.64 mL) were added in sequence. The vial was sealed and heated at 80° C. for one hour. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel chromatography (gradient elution 0-50% EtOAc:Hex) to afford tert-butyl 3-bromo-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate as a light yellow solid. MS m/z=545.1. Calc'd for C24H20BrFN4O3S: 543.41
Reaction SMILES: C([N:8]1[CH2:11][CH:10]([C:12]#[N:13])[CH2:9]1)(OC(C)(C)C)=O.Cl.CCN(C(C)C)C(C)C.[CH3:24][N:25]1[CH:29]=[C:28]([S:30](Cl)(=[O:32])=[O:31])[N:27]=[CH:26]1>O1CCOCC1>[CH3:24][N:25]1[CH:29]=[C:28]([S:30]([N:8]2[CH2:9][CH:10]([C:12]#[N:13])[CH2:11]2)(=[O:32])=[O:31])[N:27]=[CH:26]1
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cn1cnc(S(=O)(=O)N2CC(C#N)C2)c1
Reaction time: 2 h
Yield: 79.9 %

Procedure:
To a solution of 1-N-Boc-3-cyanoazetidine (5.0 g, 27.5 mmol) in 1,4-dioxane (50 mL) was added 4 N HCl (50 mL) and stirred for 2 h. The reaction was concentrated under vacuum. The residue was dissolved in CH2Cl2 (60 mL) and DIPEA (10.6 mL, 60.4 mmol) and added 1-methylimidazole-4-sulfonyl chloride (4.94 g, 27.5 mmol) and stirred at room temperature for 20 h. The reaction mixture was washed with 2 N NaOH (50 mL), dried over MgSO4 and concentrated under vacuum to afford 8 as a white crystalline solid (4.97 g, 80%); 1H-nmr (300 MHz, CDCl3) δ 7.06 (s, 1H), 7.56 (s, 1H), 4.27-4.19 (m, 4H), 3.82 (s, 3H), 3.43-3.31 (m, 1H); LC-MS (214) 99%, 0.93 min, m/z 227.1 (M+H).