Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.P(Cl)(Cl)([Cl:22])=O>C(#N)C.O1CCOCC1>[Cl:22][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N#Cc1ccc(-c2cc3c(O)ncnc3[nH]2)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: N#Cc1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1

Procedure:
4-(4-Hydroxy-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzonitrile (2.36 g, 0.01 mol) are suspended in 40 ml acetonitril and 4.99 ml (0.02 mol) 4 N hydrochloric acid solution in dioxane. After addition of 3.66 ml (0.04 mol) phosphorus oxichloride the mixture is heated under reflux for 3 days. The solid is filtered off and the mother liquor evaporated. The residue and the solid are dissolved in 30 ml DMF at 60° C. and 25 ml of a conc. sodium bicarbonate solution and 25 ml water are added and the resulting suspension cooled, filtered and the solid washed with water. The title compound is dried at 100° C. for 6 h under reduced pressure; m.p. 296-297° C.; HPLC tR=11.59 min.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>C(#N)C>[CH3:24][O:23][C:21]([CH2:20][O:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:22]
Reactant: O=C1CCCc2c(O)cccc21
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1cccc2c1CCCC2=O
Reaction time: 3.5 h

Procedure:
A mixture of 1-hydroxy-5-oxo-5,6,7,8-tetrahydronaphthalene (10 g), potassium carbonate (9.4 g), methyl bromoacetate (6.2 ml) in acetonitrile (250 ml) was refluxed with stirring for 3.5 hours. The mixture was filtered off and the filtrate was evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The separated organic layer was wasted with 1N-hydrochloric acid, 1N-sodium hydroxide, brine, dried over magnesium sulfate and evaporated in vacuo. The residue was suspended in n-hexane and then the solid was collected by filtration to give 1-methoxycarbonylmethoxy-5-oxo-5,6,7,8-tetrahydronaphthalene (13.90 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[C:9]1[C:14]([I:15])=[CH:13][N:12]=[CH:11][N:10]=1>C1COCC1>[N:1]1([C:9]2[C:14]([I:15])=[CH:13][N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Clc1ncncc1I
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Ic1cncnc1-n1ccnc1
Reaction time: 0.25 h
Yield: 52 %

Procedure:
To a solution of 1H-imidazole (0.085 g, 1.248 mmol) in THF (Volume: 10 mL) was added sodium hydride (0.062 g, 1.560 mmol). After 15 minutes at room temperature, 4-chloro-5-iodopyrimidine (0.25 g, 1.040 mmol) was added as a solution in THF (5 mL). After 2 h at room temperature, the reaction was quenched with water. The reaction mixture was extracted with EtOAc (3×). The combined organics were dried over MgSO4, filtered and concentrated to give the title compound (0.155 g, 0.541 mmol, 52.1% yield) as a pale yellow solid. ESI MS (M+H)+=273.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@:8]23[O:16][CH2:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:9]3)[CH:7]=1.[Br:26][C:27]1[CH:28]=[CH:29][C:30]([C:33](O)=[O:34])=[N:31][CH:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@:8]34[O:16][CH2:15][CH2:14][C@H:13]3[CH2:12][S:11][C:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[N:9]4)[CH:7]=2)=[O:34])=[N:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)OCC[C@H]2CS1
Reactant: O=C(O)c1ccc(Br)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ccc(Br)cn4)ccc3F)OCC[C@H]2CS1
Yield: 68.8 %

Procedure:
A solution of (±)-tert-butyl (4aR,7aR)-7a-(5-amino-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-ylcarbamate (31 mg), 5-bromopicolinic acid (26 mg), HATU (48 mg), and DIEA (44 μL) in DMF (0.41 mL) was stirred at rt for 2 h, and the crude reaction mixture was subjected to preparative HPLC eluting with 0-100% A/B (A: 95% H2O/5% MeCN, 10 mM NH4OAc; B: 5% H2O/95% MeCN, 10 mM NH4OAC over 12 min period to give the title compound as a yellow foam (32 mg, 68%). 1H NMR (500 MHz, CDCl3) δ 9.89 (1H, s), 8.71 (1H, s),8.21 (1H, dd, J=0.4, 8.0 Hz), 8.07 (1H, dd, J=2.0, 8.0 Hz), 8.03 (1H, m), 7.72 (1H, m), 7.14 (1H, t, J=10.5 Hz), 4.15 (2H, m), 3.32 (1H, m), 3.03 (1H, m), 2.90 (1H, m), 2.40 (1H, m), 2.22 (1H, m), and 1.51 (9H, s). MS (M+H)+: 553.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH:32]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH:32]([N:45]1[CH2:50][CH2:49][N:48]([C:22]([C:21]2[CH:25]=[CH:26][C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:29])([F:31])[F:30])[C:9]=4[CH:17]=3)=[CH:19][CH:20]=2)=[O:24])[CH2:47][CH2:46]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-benzhydrylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z=680.99 (M+H+); retention time=1.00 minutes.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([N:20]4[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26]C(=O)OC(C)(C)C)[CH2:21]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([N:20]4[CH2:25][CH2:24][CH2:23][C@@H:22]([NH2:26])[CH2:21]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cccc3ccc(-c4nnc5ccccn45)nc23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCCN(c2cccc3ccc(-c4nnc5ccccn45)nc23)C1
Reaction time: 2 h
Yield: 43 %

Procedure:
(R)-tert-butyl 1-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yl)piperidin-3-ylcarbamate (0.030 g, 0.067 mmol) was added to a 1:1 TFA-DCM and stirred for about 2 hours, at which time the reaction appeared complete by LC/TLC. The crude mixture was evaporated and purified by flash column chromatography (Horizon, using a gradient elution of 5% NH4 in MeOH/DCM). The desired product was isolated as a light yellow solid (10 mg; 43% yield). MS ESI (+) m/z 345.2 (M+1) detected.
Reaction SMILES: C([O:3][C:4](=[O:12])[CH2:5][N:6]1[C:10](Cl)=[N:9][N:8]=[N:7]1)C.NC(N)=[S:15].O.Cl>C(O)C>[SH:15][C:10]1[N:6]([CH2:5][C:4]([OH:3])=[O:12])[N:7]=[N:8][N:9]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)Cn1nnnc1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)Cn1nnnc1S

Procedure:
In a 500 ml round flash equipped with agitator, relux condenser, thermometer and a dropping funnel a mixture of 100 g (0.52 mol) 5-Chloro-1H-tetrazole-1-acetic acid ethyl ester, 44 g (0,57 Mol) thiourea, 210 g water and 25 g of 38 wt.% aqueous hydrochloric acid was heated to reflux for 6 hours, while the ethanol formed during the reaction was distilled off. For working up purpose, the residue was extracted with methyl isobutyl ketone. After evaporation of the ketone 57.9 g=69% of the theory of a white crystalline solid (melting point 173° C.) of 5-Mercapto-1H-tetrazole-1-acetic acid was obtained (purity 99%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][NH2:12]>>[CH3:11][NH:12][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CN
Product: CNc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
1-Chloro-4-nitro-benzene (5.0 g, 31.7 mmol) was added to excess aqueous methylamine solution-(40%, 30 mL) and heated in a pressure bomb for 16 h. The reaction mass was cooled to room temperature and a solid filtered off. The filtrate was evaporated to dryness and the combined solids were purified by trituration with pentane to afford methyl-(4-nitro-phenyl)-amine (4.5 g, 93%) as a solid.
Reaction SMILES: [CH:1]1[C:18]2[C:19]3[C:24]4[C:3](=[CH:4][CH:5]=[C:6]5[C:23]=4[C:22]4[C:9](=[CH:10][CH:11]=[C:12]6[C:21]=4[C:20]=3[C:15](=[CH:16][CH:17]=2)[CH:14]=[CH:13]6)[CH:8]=[CH:7]5)[CH:2]=1.[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[O:31]=[C:25]([C:2]1[C:3]2[C:24]3[C:19]4[C:18](=[CH:17][CH:16]=[C:15]5[C:20]=4[C:21]4[C:12](=[CH:11][CH:10]=[C:9]6[C:22]=4[C:23]=3[C:6](=[CH:5][CH:4]=2)[CH:7]=[CH:8]6)[CH:13]=[CH:14]5)[CH:1]=1)[CH2:26][CH2:27][C:28]([OH:30])=[O:29]
Reactant: c1cc2ccc3ccc4ccc5ccc6ccc1c1c2c3c4c5c61
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)CCC(=O)c1cc2ccc3ccc4ccc5ccc6ccc1c1c6c5c4c3c21
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.4 %

Procedure:
The coronene 81 (0.699 g, 2.33 mmol) and 0.514 g (5.14 mmol) of succinic anhydride were put into a 100-ml two-inlet flask, and a nitrogen substitution was performed. The substance obtained here was immersed in an ice bath. After 2.80 g (21.0 mmol) of aluminum chloride dispersed in 20 ml of nitrobenzene was slowly dripped onto the substance, the reaction container was removed from the ice bath, and the substance was stirred at room temperature for 5 hours. After the reaction was completed, 10 ml of cooled 2M hydrochloric acid was added, followed by 10-minute stirring. The substance was cooled slowly down to room temperature, to precipitate a solid substance. The solid substance was collected by filtration. This solid substance was dispersed in 20 ml of xylene, and was heated to 140° C. In this manner, the solid substance was dissolved. The substance was then cooled slowly back to room temperature, to precipitate a solid substance. The solid substance obtained here was collected by filtration, and was dried under reduced pressure, to obtain 0.825 g of the yellow-green solid substance 82.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[CH2:17]([O:24][CH2:25][C:26](Cl)=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:26](=[O:27])[CH2:25][O:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)COCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(=O)COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a mixture of 4-amino-benzoic acid methyl ester 11 (10 grams, 66.15 mmol) and sodium bicarbonate (11 grams, 131.67 mmol) in ethyl acetate (150 mL) at 0° C. is added benzyloxy acetyl chloride (16.6 grams, 89.93 mmol) drop wise. The reaction mixture is stirred at room temperature for 10 hours. The solids are filtered off. The ethyl acetate layer is washed with 5% sodium bicarbonate solution (2×25 mL), water (2×25 mL), dried over sodium sulfate, and distilled to get crude 12, which can be purified in a suitable solvent.
Reaction SMILES: [Li+].[OH-].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:11]([N:17]2[CH:21]=[N:20][N:19]=[N:18]2)[C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1>C(O)C.O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)=[C:11]([N:17]2[CH:21]=[N:20][N:19]=[N:18]2)[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Reaction time: 2 h

Procedure:
The saponification was performed by the addition of 1.14 mL of 2.0 M LiOH solution to a solution of 0.27 g (0.76 mmole) of ethyl α-[bis(4-fluorophenyl)methylene]-1 H-tetrazole-1-acetate in 5 mL of 95% ethanol at room temperature. After two hours, the crude reaction mixture was diluted with water and washed with diethyl ether (20 mL×2). The free acid in the aqueous layer was regenerated by the addition of aqueous HCl then extracted with diethyl ether, dried and evaporated. The crude acid was dried under high vacuum for 48 hours before it was used in the next step.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:16][CH2:15][CH:14]([OH:17])[C:13]([CH3:19])([CH3:18])[CH2:12]1)C1C=CC=CC=1.C(Cl)Cl>[Pd].CO>[NH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([OH:17])[C:13]([CH3:19])([CH3:18])[CH2:12]1
Reactant: CC1(C)CC(NC(=O)OCc2ccccc2)CCC1O
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC1(C)CC(N)CCC1O
Yield: 95 %

Procedure:
Benzyl-4-hydroxy-3,3-dimethylcyclohexylcarbamate (peak 1) (1.0 equiv.) and palladium on carbon (10%) in MeOH (0.37 M) was stirred at room temperature under hydrogen balloon overnight. TLC (DCM:MeOH=10:1) showed that the reaction was completed. The mixture was filtered through a celite pad and evaporation of the solvents under reduced pressure provided 4-amino-2,2-dimethylcyclohexanol (95% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 3.70 (s, 2H), 3.16 (s, 1H), 2.65-2.71 (m, 1H), 1.18-1.65 (m, 6H), 0.83 (m, 6H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.[Pt]=O>[CH:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCCc1ccccc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: O=C(O)CCCC1CCCCC1
Yield: 77 %

Procedure:
4-Phenylbutanoic acid prepared as described in Example 21, Part A was dissolved in glacial acetic acid (25 ml). Platinum oxide (0.1 g) was added and the solution was hydrogenated in the Paar shaker at up to 55 p.s.i. until hydrogen uptake ceased (6.5 hours). The catalyst was removed by filtration and the acetic acid was removed in vacuo. The product crystallized and was recrystallized from Et2O (20 ml) to give title compound (1.18 g, 77%), m.p. 85°-88° C.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)[N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([O:19][C:20]4[CH:29]=[C:28]([N:30]5[CH2:35][CH2:34][N:33]([CH2:36][C:37]6[CH2:42][CH2:41][C:40]([CH3:44])([CH3:43])[CH2:39][C:38]=6[C:45]6[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=6)[CH2:32][CH2:31]5)[CH:27]=[CH:26][C:21]=4C(OC)=O)C=3N=C2)=CC=1.[CH3:60][N:61]([CH3:64])[CH:62]=[O:63].C(Cl)(=O)C(Cl)=O>ClCCl>[Cl:51][C:48]1[CH:47]=[CH:46][C:45]([C:38]2[CH2:39][C:40]([CH3:44])([CH3:43])[CH2:41][CH2:42][C:37]=2[CH2:36][N:33]2[CH2:32][CH2:31][N:30]([C:28]3[CH:27]=[CH:26][C:21]4[C:62](=[O:63])[N:61]5[CH:64]=[N:10][C:14]6[CH:15]=[CH:16][CH:17]=[C:18]([C:60]=65)[O:19][C:20]=4[CH:29]=3)[CH2:35][CH2:34]2)=[CH:50][CH:49]=1
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CC(C)(C)CC3)CC2)cc1Oc1cccc2c1ncn2C(c1ccc(OC)cc1)c1ccc(OC)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC1(C)CCC(CN2CCN(c3ccc4c(c3)Oc3cccc5ncn(c35)C4=O)CC2)=C(c2ccc(Cl)cc2)C1
Reaction time: 1 h

Procedure:
A solution of EXAMPLE 44G (4.5 g) in anhydrous dichloromethane (100 ml) was cooled in an ice bath and catalytic N,N-dimethylformamide was added. This was followed by the dropwise addition of a solution of oxalyl dichloride (1.231 ml) in anhydrous methylene chloride (5 ml). The ice bath was removed and the reaction stirred for 1 hour. The reaction was quenched by the addition of ice (ca. 150 ml) and saturated sodium bicarbonate solution (100 ml). The mixture further diluted with saturated aqueous sodium bicarbonate solution (200 ml) and methylene chloride (200 ml). The crude product was isolated by concentration of the organic layer and the residue was purified on silica gel, eluting with a 0, 10, 25, 100% ethyl acetate in methylene chloride step gradient.
Reaction SMILES: O1CCOCC1.[Cl:7][C:8]1[C:13](B(O)O)=[CH:12][C:11]([O:17][CH3:18])=[CH:10][N:9]=1.Cl[C:20]1[N:25]=[C:24]([CH3:26])[N:23]=[C:22]([NH2:27])[N:21]=1.C([O-])([O-])=O.[Na+].[Na+]>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.O>[Cl:7][C:8]1[C:13]([C:20]2[N:25]=[C:24]([CH3:26])[N:23]=[C:22]([NH2:27])[N:21]=2)=[CH:12][C:11]([O:17][CH3:18])=[CH:10][N:9]=1
Reactant: Cc1nc(N)nc(Cl)n1
Reactant: COc1cnc(Cl)c(B(O)O)c1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cnc(Cl)c(-c2nc(C)nc(N)n2)c1
Temperature: 90 °C
Yield: 51.4 %

Procedure:
1,4-dioxane (10.00 mL) and water (2.5 mL) were added to a stirred mixture of 2-chloro-5-methoxypyridin-3-ylboronic acid (1.03 g, 5.48 mmol), 4-chloro-6-methyl-1,3,5-triazin-2-amine (0.72 g, 4.98 mmol), Na2CO3 (1.32 g, 12.5 mmol), and Pd(PPh3)4 (0.576 g, 0.1 eq) and the mixture was sealed and heated at 90° C. overnight. After cooling, the mixture was concentrated. Flash column chromatographic purification (short column, SiO2, pure DCM to 5% MeOH in DCM) provided 4-(2-chloro-5-methoxypyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.644 g, 51%) as a white solid. LCMS (API-ES) m/z 252 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 8.24 (d, J=1.17 Hz, 1H) 7.68 (br. s., 2H) 7.65 (d, J=1.17 Hz, 1H) 3.87 (s, 3H) 2.36 (s, 3H).
Reaction SMILES: [S:1]1[C:5]2[C:6]([CH:10]=O)=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1C=CC=CC=1.Cl>[OH-].[Na+]>[S:1]1[C:5]2[C:6]([CH:10]=[CH:13][C:14]([OH:16])=[O:15])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=Cc1cccc2nnsc12
Reactant: O=C(O)CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cccc2nnsc12
Temperature: 0 °C
Yield: 447.6 %

Procedure:
A mixture of 1.96 g of benzo-1,2,3-thiadiazole-7-carbaldehyde, 1.24 g of malonic acid and 6 ml of pyridine are heated for 26 hours at 120° C., with 2 further additions of 0.6 g portions of malonic acid after 4 and 7 hours. The mixture is then cooled, poured into ice-water and acidified with concentrated hydrochloric acid. The precipitate which has formed is faltered off and dissolved in dilute sodium hydroxide solution, the mixture is washed three times with methylene chloride, and the aqueous phase is subsequently acidified once more, using hydrochloric acid. The precipitate obtained is filtered off, washed with water and dried in vacuo, resulting in 11 g of the title compound of m.p. 199°-202° C.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([CH3:39])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])C.[OH-].[Na+]>C(O)C.C1COCC1>[CH3:39][C:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:12][CH:13]=1)([CH3:6])[C:4]([OH:40])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cccc5ccccc45)cc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3cccc4ccccc34)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 55 °C

Procedure:
Under nitrogen, 2-methyl-2-(4- {2-[5-methyl-2-(4-naphthalen-1-ylphenyl)oxazol-4-yl]ethoxy}-phenoxy) propionic acid ethyl ester (0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 hand concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to yield of a white solid. Rf=0.25 in 6:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ7.96 (d, 2H), 7.78-7.70 (m, 3H), 7.41-7.29 (m, 6H), 6.78-6.60 (m, 4H), 4.04 (t, 2H), 2.84 (t, 2H), 2.22 (s, 3H), 1.37 (s, 6H); MS (EI) 508.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:27][NH:28][O:29][CH3:30]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([N:28]([O:29][CH3:30])[CH3:27])=[O:13])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)c1n[nH]c2ncc(Br)cc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1n[nH]c2ncc(Br)cc12
Temperature: 65 °C
Yield: 91 %

Procedure:
To a solution of 5-bromo-1H-pyrazole[3,4-b]pyridine-3-carboxylic acid (VIII) (0.242 g, 1 mmol) in dry DMF (5 mL) was added CDI (0.178 g, 1.1 mmol) and heated for 3 h at 65° C. under nitrogen. The solution was cooled to room temperature and N,O-dimethyl hydroxylamine hydrochloride (0.107 g, 1.1 mmol) was added to the solution. The solution was again heated for 3 h at 65° C. under nitrogen. The solution was cooled and the solvent was evaporated under reduced pressure. The residue was dissolved in DCM, washed successively with a 10% HCl solution, a saturated NaHCO3 solution and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to produce 5-bromo-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (IX) as a white solid (260 mg, 0.91 mmol, 92% yield). 1H NMR (CDCl3) δ ppm 3.55 (s, 3H), 3.78 (s, 3H), 8.59 (d, J=3.01 Hz, 1H), 8.67 (d, J=3.01 Hz, 1H); ESIMS found for C9H9BrN4O2 m/z 285.4 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])([CH2:31][OH:32])[CH2:18][O:19][C:20](=[O:30])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:43](OC)([CH3:45])[CH3:44].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:37]([O:36][C:34]([N:33]1[C:17]([CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=2)([CH2:18][O:19][C:20](=[O:30])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])[CH2:31][O:32][C:43]1([CH3:45])[CH3:44])=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)OC(=O)NC(CO)(CCc1ccc(OCc2ccccc2)cc1)COC(=O)c1ccccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(CCc2ccc(OCc3ccccc3)cc2)(COC(=O)c2ccccc2[N+](=O)[O-])COC1(C)C
Temperature: 95 °C
Reaction time: 6 h

Procedure:
To a solution of 2-nitro-benzoic acid 4-(4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-2-hydroxymethyl-butyl ester (105 mg, 0.19 mmol) in toluene (2 ml) is added 2.2 dimethoxypropane (0.06 ml, 0.57 mmol, 3 eq) and a catalytic amount of p-toluene sulfonic acid. The reaction mixture is stirred at 95° C. for 6 hours, then concentrated to dryness under negative pressure. 4-[2-(4-Benzyloxy-phenyl)-ethyl]-2,2-dimethyl-4-(2-nitro-benzoyloxy-methyl)-oxazolidine-3-carboxylic acid tert-butyl ester is isolated as an oil (88 mg, 78%) after purification by flash chromatography (Ethyl acetate/Hexane (1/3)).