Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:5][C:6]=1[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CCN(C(C)C)C(C)C.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[C:42]1([C:48]#[CH:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CCOC(C)=O.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.[Cu]I>[C:11]([O:10][C:8]([NH:7][C:6]1[S:5][C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:3][C:2]=1[C:49]#[C:48][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1cc(Br)c(NC(=O)OC(C)(C)C)s1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: N#Cc1ccccc1
Product: CCOC(=O)c1cc(C#Cc2ccccc2)c(NC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Pd(PhCN)2Cl2 (0.03 eq.) and CuI (0.02 eq.) were added to a dry septum-capped vial, which was then sparged with argon and charged with ethyl 4-bromo-5-[(tert-butoxycarbonyl)amino]thiophene-2-carboxylate (prepared as described in example 14, step 4) (1 M solution in dioxane), DIEA (1.2 eq.), P(t-Bu)3 (0.06 eq., 0.8 M solution in dioxane) and phenylacetylene (1.2 eq.). The reaction was stirred overnight at RT, then diluted with AcOEt and filtered trough a small pad of silica gel. The filtrate was concentrated giving a residue that was purified by flash chromatography on silica gel (1:5 AcOEt/petroleum ether) to afford the title compound (96%) as a solid.
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14])[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].C(=O)([O-])[O-].[K+].[K+].[Cl:24][C:25]1[N:30]=[C:29](Cl)[C:28]([Cl:32])=[CH:27][N:26]=1>CN(C)C=O>[NH2:14][C:13]1[CH:12]=[C:11]([CH2:1][CH2:2][CH2:3][C:4]2[CH:5]=[C:6]([NH:7][C:27]3[C:28]([Cl:32])=[CH:29][N:30]=[C:25]([Cl:24])[N:26]=3)[CH:8]=[CH:9][CH:10]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cccc(CCCc2cccc(N)c2)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cccc(CCCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Reaction time: 2.5 h
Yield: 33.1 %

Procedure:
To a solution of 3,3′-propane-1,3-diyldianiline (41.0 mg, 0.181 mmol) in N,N-dimethylformamide (1.0 mL), potassium carbonate (72 mg, 0.52 mmol) was added followed by 2,4,5-trichloropyrimidine (20 μL, 0.17 mmol). The mixture was stirred for 2.5 hours and purified by preparative LCMS (pH 10) to give the desired product (21 mg, 32%). LCMS for C19H19Cl2N4 (M+H)+: m/z=373.1.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=1.Cl[C:28]1[N:33]=[CH:32][C:31]([Br:34])=[CH:30][N:29]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Br:34][C:31]1[CH:30]=[N:29][C:28]([N:24]2[CH2:25][CH2:26][CH:21]([CH2:20][O:19][C:16]3[CH:15]=[CH:14][C:13]([C:4]4[CH:5]=[CH:6][C:7]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:8][C:3]=4[F:2])=[CH:18][CH:17]=3)[CH2:22][CH2:23]2)=[N:33][CH:32]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cc2)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(c4ncc(Br)cn4)CC3)cc2)c(F)c1
Temperature: 100 °C
Yield: 91 %

Procedure:
A mixture of 4-({[2′-fluoro-4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)piperidine hydrochloride (Example 66, Step 1, 0.12 g, 0.30 mmol), 2-chloro-5-bromopyrimidine (89 mg, 0.45 mmol) and K2CO3 (0.13 g, 0.90 mmol) in DMSO (5 mL) was degassed, purged with N2 and heated at 100° C. overnight. The mixture was allowed to cool to ambient temperature, and was poured into water (50 mL) and extracted with EtOAc. The combined organic extract was washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a yellow solid. The crude product was triturated with hot hexanes containing 1% of MeOH to give 0.142 g (91%) of the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.29 (s, 2H), 7.80-7.70 (m, 2H), 7.65-7.55 (m, 1H), 7.50 (d, 2H, J=7.6 Hz), 6.99 (d, 2H, J=8.7 Hz), 4.85-4.75 (m, 2H), 3.88 (d, 2H, J=6.3 Hz), 3.09 (s, 3H), 3.00-2.90 (m, 2H), 2.20-2.05 (m, 1H), 2.00-1.90 (m, 2H), 1.45-1.30 (m, 2H); LRMS (ESI), m/z 520/522 (M+H).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[CH:21]=2)[CH:16]([C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH:15]1[CH2:36][C:37]#N)([OH:3])=[O:2].[OH-:39].[Na+].[OH2:41]>CO>[C:1]([CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[CH:21]=2)[CH:16]([C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH:15]1[CH2:36][C:37]([OH:41])=[O:39])([OH:3])=[O:2]
Reactant: [OH-]
Reactant: O
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)O)C(CC#N)C2c1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: CO
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)O)C(CC(=O)O)C2c1ccc2c(c1)OCO2
Temperature: 70 °C
Reaction time: 20 h
Yield: 90 %

Procedure:
To a solution of 1RS,2RS,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-2-cyanomethyl-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (290 mg, 0.56 mmol) in methanol (ca. 1 ml) was added aqueous 2N NaOH solution (0.3 ml) followed by H2O (8 ml) then (with caution) Na2O2 (120 mg). The mixture was heated to 70° C. and stirred for 20 h at which time HPLC showed only 15% hydrolysis. The mixture was stirred at 85° C. for 3 days with 3 (100 mg) portions of Na202 added each day. the reaction mixture was partitioned between EtOAc and 3N HCl. The organic extract was washed with H2O then brine, dried (Na2SO4) and solvent removed in vacuo to afford the product as an oil (228 mg, 90% pure by HPLC) Final purification was obtained by crystallization as the his cyclohexylamine salt. mp 210°-212° C.
Reaction SMILES: C[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12](=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH:21]=[CH2:22]>C(#N)C>[CH2:19]([O:11][C:3]1[CH:2]=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([CH3:12])[CH:4]=1)[CH2:20][CH:21]=[CH2:22]
Reactant: C=CCCBr
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCCOc1ccc([N+](=O)[O-])c(C)c1

Procedure:
To an acetonitrile (50 mL) solution of 2-methyl-4-nitrophenol (3.05 g; 19.9 mmol) and potassium carbonate (4.27 g; 30.9 mmol), 4-bromo-1-butene (4.02 g; 29.8 mmol) was added, and the mixture was refluxed and then reacted for 12 hours. After completion of the reaction, the solution was filtrated by Celite, and then filtrate was concentrated under a reduced pressure. The residue was purified by flash column chromatography using methylene chloride, and then the effluent was concentrated to obtain 4-(3-butenyloxy)-2-methylnitrobenzene (1c) (2.61 g, 63% of yield, a light yellow oil) represented by the following formula.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[S:14]1[CH2:20][C:18](=[O:19])[N:17]([CH2:21][C:22]([OH:24])=[O:23])[C:15]1=[S:16].[Cl-].[NH4+].N>C(O)C>[OH2:9].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[C:20]2[S:14][C:15](=[S:16])[N:17]([CH2:21][C:22]([OH:24])=[O:23])[C:18]2=[O:19])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(N)n1
Product: O
Reaction time: 0.25 h

Procedure:
The desired compound was prepared by reacting at room temperature, for 15 minutes, 20 g of ethyl 2-aminothiazol-4-ylglyoxylate, 22.9 g of rhodanine-3-acetic acid, 11 g of ammonium chloride, 15 ml of 28% v/v aqueous ammonia and 200 ml of ethanol, following a procedure similar to that described in Example 1. The resulting orange product had the following physical properties.
Reaction SMILES: [CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[CH3:7][N+:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-])=O.[H][H]>O.[Pd]>[CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][N+:8]=1[CH3:7]
Reactant: [H][H]
Reactant: C[n+]1ccccc1CCOc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: COS(=O)(=O)[O-]
Solvent: O
Product: C[n+]1ccccc1CCOc1ccccc1N
Reaction time: 2 h

Procedure:
3.7 g (10 mmol) of the compound from Step 3.2 was hydrogenated in 25 mL of water in the presence of 0.3 g of Pd/C (10%) under 9 bar of hydrogen pressure. After 2 hours, the catalyst was filtered off, and the solution obtained was directly subjected to further reaction.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Br[CH2:18][CH2:19][C:20]([O:22]CC)=[O:21].C(=O)(O)[O-].[Na+]>C(O)C>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCBr
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
The reaction mixture of 1-(3-trifluoromethylphenyl)piperazine (510 mg, 2.2 mmol), ethyl 3-bromopropionate (500 mg, 2.7 mmol), sodium bicarbonate (300 mg, 3.5 mmol) and ethanol (15 ml) was refluxed for 3 h till the amine disappeared completely. After the mixture was filtered, the resulting solid was dissolved in 5 ml dioxane and 14 ml 5% sodium hydroxide solution. The mixture was stirred at room temperature overnight, then it was acidified with concentrated hydrogen chloride. Solid was filtered and washed with water, and then dried to give 500 mg 3-[4-(3-trifluoromethylphenyl)-1-piperazinyl]propionic acid as a white solid, mp 228-230° C.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[C:8]=1[CH:9]=O)(OCC)=[O:2].C([O-])(=O)C.[NH4+:22].[Cl-].[NH4+]>C(O)(=O)C.O>[CH2:16]1[O:15][C:12]2[C:11](=[C:8]3[C:7](=[CH:14][CH:13]=2)[NH:6][C:1](=[O:2])[N:22]=[CH:9]3)[O:17]1
Reactant: [NH4+]
Reactant: CCOC(=O)Nc1ccc2c(c1C=O)OCO2
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1ncc2c3c(ccc2[nH]1)OCO3
Temperature: 90 °C
Reaction time: 15 h
Yield: 6.2 %

Procedure:
2-Carboethoxyamino-5,6-methylenedioxybenzaldehyde (5.0 g, 21.1 mmoles) was added to a suspension of ammonium acetate (1.63 g, 21.1 mmoles) and ammonium chloride (1.13 g, 21.1 mmoles) in 50 ml of acetic acid. The temperature was slowly raised to 90° C. and held there for 15 hours. The mixture was diluted with one volume of water and then extracted with ethyl acetate, after adjusting the pH to 9 with concentrated ammonium hydroxide. The ethyl acetate layers were evaporated to dryness and the residue was recrystallized first from 10% NH4OH then from methanol to give 250 mg of 5,6-methylenedioxy-2(1H)-quinazolinone (6%), mp >300° C., M+ 190. PG,10
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[O:17][CH3:18].Cl[C:20]1[CH:21]=[C:22]([CH2:26][N:27]2[CH:31]=[CH:30][N:29]=[C:28]2[CH3:32])[N:23]=[N:24][CH:25]=1>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:20]2[CH:21]=[C:22]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[C:28]3[CH3:32])[N:23]=[N:24][CH:25]=2)=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1Cl
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: COc1cc(-c2cnnc(Cn3ccnc3C)c2)ccc1Cl
Product: Cl

Procedure:
The title compound, MS: m/e=315.3 (M+H+), was prepared from 2-(4-chloro-3-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:5][C@:4]1([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[C:6]#N.[OH-:18].[Na+].Cl>ClCCl>[C:8]1([C@:4]23[CH2:5][C@H:3]2[CH2:2][O:1][C:6]3=[O:18])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: N#C[C@@]1(c2cccc3ccccc23)CC1CO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C1OC[C@@H]2C[C@]12c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
(1S)-2-hydroxymethyl-1-(1-naphthyl)-cyclopropanecarbonitrile (300 mg, 1.3 mmol) ethanol (0.6 mL) and 25N sodium hydroxide solution (0.3 mL) were heated under reflux for 18 hours. The reaction is monitored by TLC (dichloromethane (100%)). The reaction mixture was cooled to room temperature and ice cold water (12 mL) was added to the reaction mixture followed by concentrated hydrochloric acid drop to adjust the pH of the reaction mass to 1-2 and stirred for overnight. The aqueous layer was extracted with dichloromethane (25 mL). The organic layer was washed with 3% sodium bicarbonate solution, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 128 mg (44%) of product. 1H NMR δ(300 MHz,CDCl3): 1.51-1.54 (1H,t, J=4.58,), 1.74-1.78 (1H,dd, J=7.7,4.8 Hz), 2.53-2.57 (1H,m), 4.43-4.46 (1H,d,J=9.5 Hz), 4.71-4.76 (1H,dd,J=9.3,4.5 Hz), 7.40-7.58 (4H,m), 7.83-7.89 (2H,m), 7.95-7.98 (1H d,J=8.2 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=O)C=1.C[Si]([C:31]#[N:32])(C)C.CN(C)C(Cl)=O>C(OCC)(=O)C.O>[C:31]([C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]=[CH:6][N:1]=1)#[N:32]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)OC(=O)CCc1ccncc1
Agent: CN(C)C(=O)Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CCc1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
tert-Butyl 3-(4-pyridyl)propionate (0.58 g, 2.8 mmol) was dissolved in ethyl acetate (4 ml), and 3-chloroperbenzoic acid (ca. 77%, 0.65 g, 2.9 mmol) was added thereto. The reaction mixture was stirred at room temperature for 18 hrs and subjected to a silica gel (35 g) column chromatography. The fractions eluted with ethyl acetate-ethanol (3:1, v/v) were collected and concentrated. The residue was dissolved in nitroethane (4 ml), and trimethylsilyl cyanide (0.50 g, 5.1 mmol) and N,N-dimethylcarbamoyl chloride (0.54 g, 5.1 mmol) were added thereto. The reaction mixture was stirred at room temperature for 16 hrs and combined with ethyl acetate and water. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (30 g) column chromatography. The fractions eluted with hexane-ethyl acetate (4:1, v/v) were collected and concentrated to give the titled compound (0.52 g, 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:37][CH2:38][CH:39]([OH:43])[CH2:40][C:41]#[CH:42].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:43][CH:39]([CH2:38][CH3:37])[CH2:40][C:41]#[CH:42])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C#CCC(O)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCC(CC)OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1C
Yield: 62.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 5-hexyn-3-ol (23 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (43 mg, yield 59%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.Cl[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37]>CN(C=O)C>[CH:39]([O:38][C:36]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:16]2[C:17]([N+:18]([O-:20])=[O:19])=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[N:13]=[CH:14][N:15]=2)[CH2:23][CH2:24]1)=[O:37])([CH3:41])[CH3:40]
Reactant: CC(C)OC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
General procedure for the syntheses of carbamates, pyridinamides, and sulfonamides. In a 16 mL reaction vessel was placed (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Comound A2) (42 mg, 0.1 mmol), triethylamine (90 μl) and DMF (1.5 mL) was added to completely dissolve the solid material. Isopropyl chloroformate (0.15 mL, 1.0M in toluene) was added to the solution and the mixture was stirred 30 min under N2 at room temperature. After all of the starting amine was completely converted as indicated by LCMS, the reaction was stopped by quenching with water. The reaction mixture was concentrated under vacuum and purified by preparative HPLC to give Compound A22, 1H NMR (CDCl3, 400 MHz) δ 1.26 (d,6H), 1.89 (m, 2H), 1.93 (m,2H), 3.07 (s, 3H), 3.63 (m, 2H), 3.67 (m, 2H), 4.94 (m, 1H), 5.61 (m, 1H), 7.87 (d, 2H), 7.97 (d, 2H), 8.40 (s, 1H), 10.18 (s, 1H). Exact mass calculated for C20H25N5O7S 479.15, found 480.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=1.[C:11]1([CH3:20])[C:12]([N:17]=[C:18]=[O:19])=[CH:13][CH:14]=[CH:15][CH:16]=1>CC(C)=O>[C:11]1([CH3:20])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18](=[O:19])[NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=1
Reactant: Cc1ccccc1N=C=O
Reactant: Nc1nc(CC(=O)O)cs1
Solvent: CC(C)=O
Product: Cc1ccccc1NC(=O)Nc1nc(CC(=O)O)cs1
Yield: 65.9 %

Procedure:
To a suspension of 2-amino-4-thiazoleacetic acid (4 g, 25 mmol) in 1:1 CH2Cl:acetone (100 mL) was added o-tolylisocyanate (3.5 g, 26 mmol). The mixture was heated to reflux for 8 hr at which time a yellow precipitate had formed. the precipitate was filtered and the solid washed generously with 1:1 CH2Cl2:acetone. The solid was recrystallized with hot methanol and dried under vacuum to yield 4.8 g (66% yield) of the desired 2-(o-tolylureido)-4-thiazoleacetic acid 225.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[NH:45]1[CH2:59][CH2:58][CH2:57][C@H:46]1[C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48].Cl.C(N(CC)C(C)C)(C)C>ClCCl>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([N:45]1[CH2:59][CH2:58][CH2:57][C@H:46]1[C:47]([O:49][CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:48])=[O:12])[CH2:3][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 98.5 %

Procedure:
To a stirred solution of 11.64 g of Boc-D-Cha-OH in 100 mL of dichloromethane at 0° C. was added 6.36 g of HOBt and 9.72 g of DCC. After 20 minutes a solution of 10.35 g of H-Pro-OBzl.HCl in 40 mL of dichloromethane adjusted with N,N-diisopropyl ethylamine to pH 8 was added. After 16 h the reaction mixture was filtered and the filtrate was washed successively with water, 0.1 N hydrochloric acid, water, aqueous 5% sodium hydrogencarbonate and brine. All aqueous washes were extracted twice with ethyl acetate, all organic extracts combined, dried over sodium sulfate and concentrated. To the residue was added a mixture of ethyl acetate/heptanes=1/1 (v/v), the resulting suspension filtered and the filtrate purified by chromatography on silica gel (eluent: ethyl acetate/heptanes=1/1 v/v) to yield 19.34 g of Boc-D-Cha-Pro-OBzl.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[CH:14]1[CH2:16][CH2:15]1.[OH-].[Na+]>C(O)C>[CH:14]1([C:5]2[CH:6]=[C:7]([C:10]([F:11])([F:12])[F:13])[CH:8]=[CH:9][C:4]=2[C:3]([OH:17])=[O:2])[CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(C(F)(F)F)cc1C1CC1
Temperature: 80 °C
Yield: 43.1 %

Procedure:
To a suspension of 485 mg (1.986 mmol) 2-cyclopropyl-4-trifluoromethyl-benzoic acid methyl ester in 8 ml ethanol at room temperature, was added 1.99 ml (3.972 mmol) 2N NaOH. The mixture was heated in an 80° C. oil bath for 30 minutes. The solution was cooled to room temperature and the ethanol was evaporated. The residue was diluted with water, acidified with 2N HCl to pH 2 and dichloromethane was added. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 0.197 g (27%) of the title compound as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@@H:7]([CH3:12])[C:8]([O:10]C)=[O:9])=[C:4]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][C:17]=2[Cl:27])[CH:3]=1.[OH-].[Li+]>O.C1COCC1>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@@H:7]([CH3:12])[C:8]([OH:10])=[O:9])=[C:4]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:23])=[O:24])=[CH:18][C:17]=2[Cl:27])[CH:3]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(Cl)ccc2O[C@@H](C)C(=O)OC)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(Oc2cc(Cl)ccc2O[C@@H](C)C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the product from step (iii) (2.3 g) and lithium hydroxide (0.303 g) in water (10 ml) and THF (10 ml) was stirred at RT for 1 h. The mixture was diluted with water, extracted with diethylether then the aqueous layer acidified by 2M hydrochloric acid and extracted with ethylacetate. The ethyl acetate layer was dried, evaporated under reduced pressure and the residue purified by RPHPLC.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([N:12]1[C:16]2=[N:17][CH:18]=[CH:19][C:20](Cl)=[C:15]2[CH:14]=[N:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O)(=O)C>CN(C)C=O>[N:1]([C:20]1[CH:19]=[CH:18][N:17]=[C:16]2[N:12]([CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:13]=[CH:14][C:15]=12)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1ccnc2c1cnn2Cc1ccccc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccnc2c1cnn2Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
Sodium azide (2.5 g) was added to a solution (50 ml) of 1-benzyl-4-chloro-1H-pyrazolo[3,4-b]pyridine (4.7 g) in dimethylformamide and the mixture was stirred at 100°-120° C. for 1 hour. After completion of the reaction, the reaction mixture was poured into ice water, made acidic with acetic acid and extracted with ethyl acetate. The extract was washed with water, dried and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 2.7 g of 4-azido-1-benzyl-1H-pyrazolo[3,4-b]pyridine.