Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18]3[N:19]=[C:20]4[N:24]([CH:25]=3)[N:23]=[C:22]([O:26][CH3:27])[S:21]4)[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1.CC1C(C)=C(C)C(C)=C(C)C=1.B(Cl)(Cl)Cl>ClCCl>[CH3:27][O:26][C:22]1[S:21][C:20]2=[N:19][C:18]([C:16]3[O:17][C:13]4[C:14](=[C:9]([OH:8])[CH:10]=[CH:11][CH:12]=4)[CH:15]=3)=[CH:25][N:24]2[N:23]=1
Reactant: COc1nn2cc(-c3cc4c(OCc5ccccc5)cccc4o3)nc2s1
Agent: Cc1cc(C)c(C)c(C)c1C
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COc1nn2cc(-c3cc4c(O)cccc4o3)nc2s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
A mixture of 6-(4-(benzyloxy)benzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole (Example 38F, 2.640 g, 6.99 mmol) and pentamethylbenzene (7.25 g, 48.9 mmol) in dichloromethane (400 mL) was cooled to −78° C. under a nitrogen atmosphere and then treated immediately with 18.2 mL (8.2 mmol) of a 1 M solution of boron trichloride in dichloromethane added dropwise over 3 min. The resulting mixture was stirred at −78° C. for 1 h. The reaction mixture was then quenched by the addition of a solution of sodium bicarbonate (10.6 g) in water (50 mL) added in one portion. The cooling bath was removed and the resulting mixture was stirred at room temperature for 1 h. The solid formed was filtered, washed successively with water (50 mL) and dichloromethane (25 mL). The filter cake was allowed to soak with anhydrous ethanol (10 ml) and then sucked dry. The white solid obtained was then dried under vacuum for a few days over phosphorous pentoxide until constant weight to give 1.459 g (72% yield) of title material. The combined filtrate and washings (organic and aqueous phases from the deprotection step) were diluted with dichloromethane (500 mL) and stirred in a warm water bath till the organic phase was clear with no apparent solid in suspension. The organic phase was collected, dried over anhydrous magnesium sulfate and rapidly filtered while still warm. The filtrate was evaporated and the residue (product and pentamethylbenzene) was triturated with toluene (20 mL). The solid was collected by filtration and washed with toluene (20 mL) to give, after drying in vacuo, 0.239 g (12% yield, 84% combined yield) of title material as a tan solid. LC (Method A): 1.908 min. HRMS (ESI) calcd for C13H10N3O3S [M+H]+ m/z 288.0437, found 288.0446. 1H NMR (DMSO-d6, 600 MHz) δ ppm: 4.46 (s, 3H), 6.58 (d, J=7.8 Hz, 1H), 6.97 (d, J=8.15 Hz, 1H), 7.0-7.07 (m, 3H), 8.40 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C([O:18][C:19](=[O:50])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38]CC)=[O:37])[CH:31]=2)=[O:29])[CH:25]=[CH:24][C:23]=1[O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]Br)C>CCCCCC.C(OCC)(=O)C>[C:36]([C:32]1[CH:31]=[C:30]([C:28]([C:26]2[CH:25]=[CH:24][C:23]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][O:1][C:2]3[CH:12]=[CH:11][C:5]4[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=4[C:3]=3[CH2:13][CH2:14][CH3:15])=[C:22]([CH2:21][CH2:20][C:19]([OH:50])=[O:18])[CH:27]=2)=[O:29])[CH:35]=[CH:34][CH:33]=1)([OH:38])=[O:37]
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OCCCCCCCBr
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1c(OCCCCCCCOc2ccc(C(=O)c3cccc(C(=O)O)c3)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 62.7 %

Procedure:
Starting with 0.153 g (0.74 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, and 0.41 g (0.74 mmol) of 2-[(7-bromoheptyl)oxy]-5-[[3-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester, the title compound (0.286 g; 77.8% overall yield) was obtained as a white solid, mp 152°-153° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 22.
Reaction SMILES: IC.[CH3:3][O:4][C:5](=[O:38])[CH2:6][C@H:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C@H:17]3[C:25]4[C:20](=[C:21]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=5)[C:22]([C:26]([F:29])([F:28])[F:27])=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)=[CH:15][C:10]=2[O:9][CH2:8]1.[C:39]([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:3][O:4][C:5](=[O:38])[CH2:6][C@H:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C@H:17]3[C:25]4[C:20](=[C:21]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([O:37][CH3:39])=[CH:33][CH:32]=5)[C:22]([C:26]([F:27])([F:28])[F:29])=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3ccc(O)cc3)ccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3ccc(OC)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iodomethane (8 μL) is added to a mixture of {(S)-6-[(R)-4-(4-hydroxy-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (30 mg), K2CO3 (15 mg), and N,N-dimethylformamide (1 mL) at room temperature. The mixture is stirred at room temperature overnight. The mixture is filtered and then chromatographed (HPLC; acetonitrile/water) to give the title compound. LC (method 6): tR=1.26 min; Mass spectrum (ESI+): m/z=535 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[C:5]#[N:6].Cl[CH2:13][CH2:14][CH2:15][C:16]#[CH:17].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[O:10][CH2:17][CH2:16][CH2:15][C:14]#[CH:13])[C:5]#[N:6]
Reactant: Cc1cc(C#N)cc(C)c1O
Reactant: C#CCCCCl
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C#CCCCOc1c(C)cc(C#N)cc1C
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 40 g 3,5-dimethyl-4-hydroxybenzonitrile, 32 ml 5-chloro-1-pentyne (d=0.968) and 74.63 g milled potassium carbonate in 25 ml N-methylpyrrolidine was heated under nitrogen at 100° C. with stirring for four hours. The mixture, after cooling to room temperature and addition of 300 ml water, was extracted with ethyl acetate. The ethyl acetate extracts were washed with aqueous 2N sodium hydroxide solution and saturated sodium chloride solution, dried (MgSO4) and then concentrated in vacuo. The residue was subjected to flash filtration (activated magnesium silicate; ether/hexane) and the filtrate was concentrated in vacuo to give, after recrystallization (methyl alcohol/0° C.) 34.64 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH:4]([OH:6])[CH3:5].C(N(CC)CC)C.Cl.CN(C)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>CC#N>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:6][C@H:4]([CH3:5])[C:3]([O:2][CH3:1])=[O:7])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: COC(=O)C(C)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@@H](C)OS(=O)(=O)c1ccc(C)cc1
Temperature: 5 °C

Procedure:
2-Hydroxy-propanoic acid methyl ester (6.66 g) was dissolved in MeCN (34 mL) and the solution cooled to 5° C. Triethylamine (9.8 mL) was added followed by trimethylamine hydrochloride (0.62 g). A solution of p-toluenesulfonyl chloride (11.6 g) in MeCN (34 mL) (sonicated to complete dissolution) was added over 20 min maintaining the temperature of the reaction below 5° C. The reaction was filtered through Celite and washed through with further MeCN. The filtrate was concentrated almost to dryness (bath 30° C.) and partitioned between diethyl ether and water. The organic layer was separated, dried (MgSO4) and the solvents removed to give the sub titled product as a yellow oil that solidified in the freezer (13.71g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:24])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[C:6]([CH:11]=1)[C:7](OC)=[O:8].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(=O)=O.CC(C)=O>C1COCC1>[Br:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][C:13](=[O:24])[C:14]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)=[C:7]2[OH:8]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)COc1ccc(C#N)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: N#Cc1ccc(Oc2c(O)c3cc(Br)ccc3[nH]c2=O)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of methyl 5-bromo-2-(2-(4-cyanophenoxy)acetamido)benzoate (0.240 g, 0.617 mmol, Intermediate 2: step b) in THF (6.65 mL) at −78° C. was added potassium bis(trimethylsilyl)amide (0.5 M in toluene, 3.66 mL, 1.83 mmol) over 1.5 minutes, and the mixture was stirred for 5 minutes. The dry-ice/acetone bath was replaced with wet-ice bath and the reaction was stirred for 1.5 hours. The reaction was then quenched with water and ethyl acetate was added. The organic layer was removed and the aqueous layer was acidified with 2 N HCl (kept pH above 2). An off-white precipitate was formed which was filtered and the solid was dried overnight in the air and 1 hour in an oven at 40° C. to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:13][C:12]=1[CH3:25].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][C:12]=1[CH3:25]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Cl
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To a stirred solution of tert-butyl 4-[N′-(2-chlorophenyl)ureido]-3-methylphenylacetate (1.57 g, 4.19 mmol) in CH2Cl2 (10 ml) was added TFA (6 ml) at room temperature. After 4 h stirring, the mixture was concentrated in vacuo. The residue was triturated by the addition of water to give 4-[N′-(2-chlorophenyl)ureido]-3-methylphenylacetic acid (1.33 g, 100%) as a yellow powder. mp 243-245° C. (dec.); 1H-NMR (CDCl3) δ2.24 (s, 3H), 3.47 (s, 2H), 6.99-7.08 (m, 3H), 7.28 (t, J=7.6 Hz, 1H), 7.44 (dt, J=8.0, 2.4 Hz, 1H), 7.66 (dd, J=8.3, 1.9 Hz, 1H), 8.13 (dd, J=6.1, 1.7 Hz, 1H), 8.61 (d, J=6.3 Hz, 2H); MS (ESI), m/z 319 (M++1), 321 (M++3); Anal. Calcd. for C16H15ClN2O3.0.7TFA: C, 59.33; H, 4.65; Cl, 10.85; N, 8.57. Found: C, 59.23; H, 4.64; Cl, 10.90; N, 8.40.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([F:20])[CH:19]=1)[C:14](Cl)=[O:15]>C(#N)C>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([C:14](=[O:15])[C:13]2[CH:12]=[C:11]([F:10])[CH:19]=[C:18]([F:20])[CH:17]=2)[C:4](=[O:9])[N:3]=1
Reactant: Nc1nc(O)ncc1F
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Solvent: CC#N
Product: Nc1nc(=O)n(C(=O)c2cc(F)cc(F)c2)cc1F
Temperature: 70 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
To an 8 mL screw-cap vial containing 4-amino-5-fluoro-pyrimidin-2-ol* (100 mg, 0.775 mmol) and acetonitrile (CH3CN; 3 mL) was added bis-N,O-trimethylsilylacetamide (BSA; 378 microliters (μL), 1.55 mmol). The mixture was heated to 70° C. for 1 h resulting in a clear solution. After cooling to room temperature, 3,5-difluorobenzoyl chloride (182 μL, 1.55 mmol) was added, and the mixture was stirred at room temperature for 12 h. A white precipitate formed and was collected by vacuum filtration. The solid was washed with Et2O (1×10 mL) and air-dried overnight to yield the final product as a white solid (126 mg, 60%): mp 227-231° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.54 (br s, 1H), 8.27 (br s, 1H), 8.14 (d, J=6.8 Hz, 1H), 7.80-7.35 (m, 3H); ESIMS m/z 270 (M+H), 268 (M−H). *4-Amino-5-fluoro-pyrimidin-2-ol can be purchased commercially.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:20])[C:11]([CH3:19])([S:17][CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[O-:22].[Na+]>O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:20])[C:11]([CH3:19])([S:17]([CH3:18])=[O:22])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)C(C)(SC)C(=O)Nc1cc(Cl)cc(Cl)c1
Reactant: [O-]Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C)(C(=O)Nc1cc(Cl)cc(Cl)c1)S(C)=O

Procedure:
Ethyl 3-[(3,5-dichlorophenyl)amino]-2-methyl-2-methylthio-3-oxopropanoate, prepared in Example XC (Compound 261), was reacted with aqueous sodium hypochlorite in a water-methylene chloride mixture in a manner similar to that described in Example XCIII to give ethyl 3-[(3,5-dichlorophenyl)amino]-2-methyl-2-methylsulfinyl-3-oxopropanoate having a melting point of 124° C.-127° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:29]C1C=CC=CC=1C1CCC2C(=CC=C(OC3N=CC(N)=CC=3)C=2)O1>>[F:29][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]3[N:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=3)[CH:13]=2)[O:8]1
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2F)O3)nc1
Product: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2F)O3)nc1

Procedure:
N-{6-[2-(2-Fluorophenyl)chroman-6-yloxy]pyridin-3-yl}methanesulfonamide was prepared as described for N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]methane sulfonamide in Example 46 starting from 400 mg of 6-[2-(2-fluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine (Example 51). The product was crystallised from a mixture of methanol and diethyl ether. 1H NMR (400 MHz, d6-DMSO) δ: 9.67 (s, 1H), 7.99 (d, 1H, J 2.8 Hz), 7.67 (dd, 1H, J 8.8, 2.8 Hz), 7.55 (m, 1H), 7.42 (m, 1H), 7.29-7.23 (m, 2H), 6.98 (dd, 1H, J 8.8 Hz), 6.92-6.84 (m, 3H), 5.35 (dd, 1H, J 10.4, 2.3 Hz), 3.01 (m, 1H), 2.99 (s, 3H), 2.76 (m, 1H), 2.16 (m, 1H), 2.04 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][N:13]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[N:14]1.C([O-])([O-])=O.[Na+].[Na+].O>CC(N(C)C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH3:12][N:13]1[CH:17]=[C:16]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)[CH:15]=[N:14]1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1cc(-c2ccc(N)c([N+](=O)[O-])c2)cn1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
4-Bromo-2-nitroaniline (1.0 g, 4.6 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.1 g, 5.1 mmol) were dissolved in 13 ml of DMA, placed under nitrogen, and heated to 80° C. A 2N aqueous solution of Na2CO3 was added, followed by PdCl2(dppf) dichloromethane adduct (0.076 g, 0.90 mmol). Reaction was stirred at 80° C. for 1 h and then cooled to rt, poured into 150 ml of water and extracted with EtOAc (3×), Combined organics were dried over anhydrous MgSO4, filtered, concentrated onto silica gel, and purified by flash chromatography using 0-50% EtOAc/hexanes. 4-(1-Methyl-1H-pyrazol-4-yl)-2-nitroaniline was isolated as a bright orange solid (1.0 g, 99%). MS (ESI): 219 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=2[C:16]([F:19])([F:18])[F:17])[C:5]2[CH2:20][CH2:21][CH2:22][C:4]=2[N:3]=1.C(N(C(C)C)CC)(C)C.[Cl:32][C:33]1[CH:44]=[CH:43][C:36]2[NH:37][C:38]([C@@H:40]([NH2:42])[CH3:41])=[N:39][C:35]=2[CH:34]=1.ClCl>CN(C)C=O>[Cl:32][C:33]1[CH:44]=[CH:43][C:36]2[NH:37][C:38]([C@@H:40]([NH:42][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][C:7]([N:6]4[C:5]5[CH2:20][CH2:21][CH2:22][C:4]=5[N:3]=[C:2]4[CH3:1])=[C:8]([C:16]([F:19])([F:17])[F:18])[CH:9]=3)[CH3:41])=[N:39][C:35]=2[CH:34]=1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1nc2c(n1-c1ccc(C(=O)O)cc1C(F)(F)F)CCC2
Agent: ClCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(n1-c1ccc(C(=O)N[C@@H](C)c3nc4cc(Cl)ccc4[nH]3)cc1C(F)(F)F)CCC2
Yield: 64 %

Procedure:
Prepared analogously to Example 1d from 4-(2-methyl-5,6-dihydro-4H-cyclopentaimidazol-1-yl)-3-trifluoromethylbenzoic acid, PFTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in dimethylformamide. Yield: 64%; C24H21ClF3N5O (487.911); mass spectrum: (M−H)−=486/488 (chlorine isotope).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.Cl[C:9]1[N:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[N:10]=1.CCN(C(C)C)C(C)C.O>CS(C)=O>[CH3:18][O:17][C:11]1[CH:12]=[C:13]([O:15][CH3:16])[N:14]=[C:9]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]2[CH3:1])[N:10]=1
Reactant: C[C@H]1COCCN1
Reactant: COc1cc(OC)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(OC)nc(N2CCOC[C@@H]2C)n1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
A solution of (S)-3-methylmorpholine (4.86 g, 48.0 mmol), 2-chloro-4,6-dimethoxypyrimidine (6.98 g, 40 mmol) and DIPEA (8.36 mL, 48.0 mmol) in DMSO (40 mL) was heated at 100° C. in a sealed flask for 22 h, and then allowed to cool to room temperature. The reaction mixture was placed in an ice bath, and water (120 mL) was added drop-wise. The mixture was decanted and the gummy precipitate was dissolved in ethyl acetate. The ethyl acetate solution was washed with brine, dried with MgSO4, filtered and concentrated by rotary evaporation to give the title compound (8.58 g, 90%). 1H NMR (400 MHz, CDCl3) δ 5.40 (s, 1 H), 4.69 (qd, J=6.8, 3.1 Hz, 1 H), 4.33 (dd, J=13.7, 2.9 Hz, 1 H), 4.01-3.93 (m, 1 H), 3.86 (s, 6 H), 3.78-3.73 (m, 1 H), 3.73-3.66 (m, 1 H), 3.54 (ddd, J=12.2, 11.4, 3.1 Hz, 1 H), 3.25 (ddd, J=13.5, 12.4, 3.8 Hz, 1 H), 1.29 (d, J=6.8 Hz, 3 H). m/z (APCI+) for C11H17N3O3 240.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH2:7]([OH:10])[C:8]#[CH:9]>C[O-].[Na+]>[CH2:7]([O:10][CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[C:8]#[CH:9]
Reactant: C#CCO
Reactant: C=CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: C#CCOCCC(=O)OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
25.8 g of methyl acrylate were added dropwise to a mixture of 16.8 g of propargyl alcohol and 0.1 g of sodium methoxide maintained at 55°-60° C. The mixture was then heated at 80° C. for 4 hours, after which it was left to stand overnight. The mixture was then poured into ice-water and extracted with ethyl acetate. The extract was dried and then purified by distillation to give 25.8 g of methyl β-propargyloxypropionate, boiling at 80°-83° C./10 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]3[NH:29][C:28](=[O:30])[NH:27][N:26]=3)[N:8]=[C:9]2[NH:12][C@H:13]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)=[CH:4][CH:3]=1>Cl.CCOC(C)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]3[NH:29][C:28](=[O:30])[NH:27][N:26]=3)[N:8]=[C:9]2[NH:12][C@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3ccc(F)cc23)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(-c2cc3ccc(F)cc3c(N[C@H]3CCNC3)n2)[nH]1

Procedure:
A solution of (S)-tert-butyl 3-((7-fluoro-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (120 mg, 0.29 mmol) in 4M HCl/EtOAc (10 mL) was stirred at RT for 30 minutes. The reaction mixture was concentrated in vacuo to give the title compound, which was used without further purification (100 mg, 100%). ESI-MS m/z [M+H]+ 315.2.
Reaction SMILES: [O:1]([CH:9](O)[CH2:10][CH3:11])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])(C)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.[N-:23]=[N+:24]=[N-:25].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.C1C=CC=CC=1.C(N(CC)CC)C>[N:23]([CH2:11][CH2:10][CH2:9][O:1][SiH2:2][C:5]([CH3:8])([CH3:7])[CH3:6])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC(O)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)(C)[SiH2]OCCCN=[N+]=[N-]

Procedure:
Following the procedure given in example 29, t-butyldimethylsiloxypropanol (prepared according to the method of McDougal et al, J. Org. Chem. 1986, 51, 3388) is first reacted with methanesulfonyl chloride in methylene chloride in the presence of triethylamine, and then the crude mesylate is reacted with tetra-n-butylammonium azide in benzene to afford 1-azido-3-t-butylsiloxypropane.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][NH:13][C:14]3[C:19]([N+:20]([O-])=O)=[CH:18][C:17]([C:23]([F:26])([F:25])[F:24])=[CH:16][N:15]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.CC(O)=O.CO>C(Cl)Cl.[Zn]>[CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][NH:13][C:14]3[C:19]([NH2:20])=[CH:18][C:17]([C:23]([F:26])([F:24])[F:25])=[CH:16][N:15]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CSc1nc2ccc(CNc3ncc(C(F)(F)F)cc3[N+](=O)[O-])cc2s1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CSc1nc2ccc(CNc3ncc(C(F)(F)F)cc3N)cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a mixture of N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitro-5-(trifluoromethyl)pyridin-2-amine (0.97 g, 2.42 mmol), HOAc (4 mL), and MeOH (4 mL) in DCM (30 mL) cooled in ice-water bath was slowly added zinc dust (1.6 g, 24.2 mmol). The reaction mixture was stirred at 0° C. for 2 h. The mixture was filtered and the filtrate was diluted with DCM and then washed with water and aq NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford N2-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-5-(trifluoromethyl)pyridine-2,3-diamine (0.89 g, 100%). 1H NMR (300 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.77 (s, 1H), 7.44-7.41 (m, 1H), 7.03 (d, J=1.8 Hz, 1H), 4.84 (br s, 1H), 4.78 (d, J=5.1 Hz, 2H), 3.29 (br s, 2H), 2.79 (s, 3H). LCMS (ESI) m/z 371 (M+H)+.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[CH:7]1[CH:12]=[C:11]2[C:13]([NH:15][C:16]([C:18]3=[CH:19][CH:20]=[CH:21][C:9](=[C:10]23)[CH:8]=1)=[O:17])=[O:14].C(Br)C#C.C(O)(=O)C>CN(C)C=O>[CH2:3]([N:15]1[C:16](=[O:17])[C:18]2[CH:19]=[CH:20][CH:21]=[C:9]3[C:10]=2[C:11](=[CH:12][CH:7]=[CH:8]3)[C:13]1=[O:14])[C:2]#[CH:1]
Reactant: O=C1NC(=O)c2cccc3cccc1c23
Reactant: CC(C)(C)[O-]
Agent: C#CCBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C#CCN1C(=O)c2cccc3cccc(c23)C1=O
Temperature: -20 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Potassium t-butoxide, 6.2 g (0.055 mol) was added to a solution of 9.9 g (0.05 mol) of naphthalimide in 50 ml of dimethylformamide cooled to -20° C. After stirring in the cold for 1 hour, 5 ml (0.055 mol) of propargyl bromide in 20 ml of dimethylformamide was added and the mixture was allowed to warm to room temperature. It was then heated to 45° C. for 45 minutes. After cooling, 15 ml of glacial acetic acid was added and the product was precipitated by addition of water. The solids were collected and recrystallized from ethyl acetate to leave 10 g (84%) of colorless crystals of 2-(2-propynyl)-1H-benz[de]isoquinoline-1,3-(2H)-dione with m.p. 235°-237° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](C)[CH:5]=[CH:4][N:3]=1.[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: Nc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a stirred solution of 2-amino-3-nitro-4-methylpyridine (25.6 g, 167 mmol) in conc. H2SO4 (100 mL) at 0° C. was added HNO3 (7.77 mL, d=1.49) dropwise over 30 min. The mixture was warmed to r.t. for 20 min then heated to 45° C. for 90 min. The reaction mixture was cooled and poured into 500 g of ice. The resulting percipitate was filtered and air dried to give 2-amino-3,5-dinitropyridine as a yellow solid.