Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([F:26])[CH:25]=1)[CH2:21][OH:22]>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:22][CH2:21][C:20]3[CH:19]=[C:18]([F:17])[CH:25]=[C:24]([F:26])[CH:23]=3)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: OCc1cc(F)cc(F)c1
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3cc(F)cc(F)c3)c21
Yield: 41.6 %

Procedure:
The title compound (cis/trans=29/71) was prepared as a white powder in 41.6% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=24/76) and 3,5-difluorobenzyl alcohol.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[OH:9].N1C=CC=CC=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:17][S:18]([O:9][CH:3]1[C:4]([CH3:8])([CH3:7])[CH2:5][CH2:6][C:2]1([CH3:10])[CH3:1])(=[O:20])=[O:19]
Reactant: CC1(C)CCC(C)(C)C1O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CCC(C)(C)C1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 28.6 %

Procedure:
2.84 g of 2,2,5,5-tetramethylcyclopentanol and 3.2 ml of pyridine were dissolved in 20 ml of methylene chloride, and 4.5 g of methanesulfonyl chloride was added thereto. The mixture was stirred at room temperature for 12 hours, and then 50 ml of aqueous saturated sodium hydrogen carbonate solution was added thereto. The mixture was extracted with 50 ml of ethyl acetate, and the organic layer was washed with aqueous 10% copper sulfate solution, and concentrated under reduced pressure. The resulting residue was recrystallized from n-hexane, whereby 1.26 g of 1-methanesulfonyloxy-2,2,5,5-tetramethylcyclopentane was obtained (m.p 46° C.).
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Br:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br.Cl>CC(N(C)C)=O>[Br:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][N:9]1[C:10](=[O:23])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:12]([OH:13])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]1=[O:24]
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Reactant: BrCc1ccccc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2ccccc2Br)c1=O
Reaction time: 8 h
Yield: 31.2 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and 2-bromobenzyl bromide (480 mg, 1.92 mmoles) in dimethylacetamide (6 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from ethanol-water gave the title compound (150 mg, 38%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.11 (br. s., 1 H), 10.12 (br. s., 1 H), 7.65 (dd, J=7.96, 1.14 Hz, 1 H), 7.32 (ddd, J=7.52, 1.14 Hz, 1 H), 7.22 (ddd, J=7.64, 1.64 Hz, 1 H), 7.03 (dd, J=7.58, 1.26 Hz, 1 H), 5.00 (s, 2 H), 4.65 (t, J=12.13 Hz, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 2.25 (q, 2 H), 1.79 (d, J=12.88 Hz, 2 H), 1.54-1.72 (m, 3 H), 1.28 (q, J=13.14 Hz, 2 H), 1.10 (q, J=12.38 Hz, 1 H)
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:12][C:13](=[O:24])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][C:16]=1[F:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCOCC>[CH2:5]([O:12][C:13](=[O:24])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][Br:2])=[CH:17][C:16]=1[F:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrP(Br)Br
Reactant: O=C(Nc1ccc(CO)cc1F)OCc1ccccc1
Solvent: CCOCC
Product: O=C(Nc1ccc(CBr)cc1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Phosphorous tribromide (20.9 mL, 218 mmol) was added to diethylether (700 mL) at 0° C. To the PBr3 solution was added dropwise (2-fluoro-4-hydroxymethyl-phenyl)-carbamic acid benzyl ester (36.5 g, 133 mmol) in Et2O (400 mL) at 0° C. over 1 h. The reaction mixture was stirred at room temperature for 45 min and was carefully quenched at 0° C. with MeOH (100 mL). The reaction mixture was diluted with aq. NaHCO3 solution and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated to provide the title compound as a yellow foam: TLC (cyclohexane-EtOAc 1:1) Rf=0.88; HPLC RtI=1.16 min; 1H NMR (360 MHz, CDCl3): δ 8.13 (t, 1H), 7.48-0.37 (m, 5H), 7.21-7.14 (m, 2H), 6.78 (s broad, 1H), 5.25 (s, 2H), 4.47 (s, 2H).
Reaction SMILES: [C:1]([OH:22])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]CC>C(Cl)(Cl)Cl>[C:1]([OH:22])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCCC(=O)O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)O

Procedure:
Subsequently, a solution (0.5 ml) of arachidic acid (1×10-3 mol/l) in chloroform was spread on the aforesaid aqueous phase. After removal of chloroform from the surface of the aqueous phase by evaporation, the surface pressure of the aqueous phase was adjusted to 30 dyne/cm, and a film of stearic acid was formed thereon.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH2:17][O:18][C:19]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=5)[N:22]=[CH:21][CH:20]=4)=[N:15][N:16]=3)[N:13]=2)=[CH:4][CH:3]=1.[NH2:31][CH:32]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]1.CS(C)=O>O>[CH3:30][O:29][C:25]1[CH:24]=[C:23]2[C:28]([C:19]([O:18][CH2:17][C:14]3[N:12]4[N:13]=[C:8]([C:5]5[CH:4]=[CH:3][C:2]([NH:31][CH:32]6[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]6)=[N:7][CH:6]=5)[CH:9]=[CH:10][C:11]4=[N:16][N:15]=3)=[CH:20][CH:21]=[N:22]2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(F)nc5)nn34)ccnc2c1
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(NC6CCN(C(=O)OC(C)(C)C)C6)nc5)nn34)ccnc2c1
Reaction time: 1 h

Procedure:
A 0.5-2 mL microwave vial was charged with 4-((6-(6-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (0.100 g, 0.249 mmol), tert-butyl 3-aminopyrrolidine-1-carboxylate (0.116 g, 0.622 mmol), and DMSO (4.00 ml, 56.4 mmol), sealed and placed in a Personal Chemistry microwave for 1 hour at 100° C. and then 30 minutes at 120° C. Water was added slowly to the reaction mixture until a precipitate formed. The solid was collected and purified by MPLC using a 40 g RediSep column, eluting with a gradient of 3-6% MeOH/DCM over 40 minutes. The solid was triturated with MeCN and filtered; the mother liquor was concentrated to give tert-butyl 3-(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2-ylamino)pyrrolidine-1-carboxylate. MS (ESI pos. ion) m/z: 569 (MH+). Calc'd exact mass for C30H32N8O4: 568.
Reaction SMILES: Br[CH:2]1[CH:6]([Br:7])[C:5]2[CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=[CH:11][C:4]=2[O:3]1.[OH-].[K+]>C(O)C.O>[Br:7][C:6]1[C:5]2[CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=[CH:11][C:4]=2[O:3][CH:2]=1
Reactant: O=Cc1ccc2c(c1)C(Br)C(Br)O2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=Cc1ccc2occ(Br)c2c1
Temperature: 70 °C
Yield: 44.9 %

Procedure:
To a solution of 2,3-dibromo-2,3-dihydro-1-benzofuran-5-carbaldehyde (10 g) in dry ethanol (25 mL) was added a solution of KOH in dry ethanol (14 mL) and refluxed at 70° C. for 2 h. The reaction mixture was cooled, diluted with water and extracted with EtOAc (3×50 mL). The organic layer was washed with water, brine and dried. The solvent was removed under vacuum and the residue was purified by flash chromatography (PetEther/EtOAc 99.5/0.5) to give the title compound as a pale yellow solid (3.3 g, 45%). 1H NMR (DMSO-d6, 300 MHz) δ 10.12 (s, 1H), 8.47 (s, 1H), 8.14 (d, 1H, J=1.5 Hz), 7.97 (dd, 1H, J=8.6, 1.5 Hz), 7.87 (d, 1H, J=8.6 Hz).
Reaction SMILES: C([NH:8][C@H:9]([C:17]([C:19]1([NH2:33])[CH:26]2[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:28][C:20]1([C:29]([O:31][CH3:32])=[O:30])[CH2:21]3)[CH2:25]2)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@H:9]([C:17]([C:19]1([NH2:33])[CH:26]2[CH2:25][CH:24]3[CH2:23][CH:22]([CH2:21][C:20]1([C:29]([O:31][CH3:32])=[O:30])[CH2:28]3)[CH2:27]2)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C12CC3CC(CC(C3)C1(N)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C12CC3CC(CC(C3)C1(N)C(=O)[C@@H](N)Cc1ccccc1)C2

Procedure:
To a solution of 1.862 g of methyl Boc-L-phenylalanyl-2-amino-1-adamantanecarboxylate (Isomer A) in 10 ml of methylene chloride is added 5 ml of trifluoracetic acid. After 15 minutes at room temperature the reaction mixture is concentrated to a small volume and 5 ml of cold potassium carbonate is added. The mixture is extracted twice with 20 ml of chloroform. The combined chloroform extracts are dried over sodium sulfate to give methyl L-phenylalanyl-2-amino-1-adamantanecarboxylate (Isomer A) as a crystalline solid melting at 160°-167° C. Under a nitrogen atmosphere at -50° C. a dry (1 g of 4 A sieves) solution of 1.878 g of Boc-L-tyrosyl-D-methionyl-glycine and 0.444 ml of N-methylmorpholine in 25 ml of tetrahydrofuran is stirred while 0.52 ml of isobutylchloroformate is added. The reaction mixture is allowed to warm to -10° C. for 10 minutes then cooled to -40° C. and 1.24 g of methyl L-phenylalanyl- 2-amino-1-adamantanecarboxylate is added. The reaction mixture is stirred overnight at room temperature. Upon the addition of water a solid separates and is collected by filtration, washed and dried. The residue is dissolved in methanol, filtered through Filter Cel, concentrated and diluted with equal volumes of ethyl acetate and ether. The solid which precipitates is collected by filtration, washed with ether and dried to give methyl Boc-L-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-2-amino-1-adamantanecarboxylate (Isomer A). 2.34 Grams of this compound is dissolved in 10 ml of acetic acid and 20 ml of a 5 N solution of hydrogen chloride in dioxane is added. The reaction mixture is concentrated under a stream of nitrogen for 11/2 hours and diluted with 150 ml of ether. The solid which forms is collected, dissolved in methanol, concentrated to about 10 ml and diluted with 40 ml of water then allowed to stand overnight at room temperature. The solution is filtered and lyophilized to give methyl L-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-2-amino-1-adamantanecarboxylate hydrochloride (Isomer A) which is represented by the following formula ##STR47##
Reaction SMILES: [C:1]([N:8]([CH3:42])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1>>[Cl:29][C:19]1[C:20]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:21]=2[S:22][C:18]=1[C:16]([N:15]([CH2:30][C:31]1[CH:32]=[C:33]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH:12]1[CH2:11][CH2:10][CH:9]([N:8]([CH3:42])[C:1](=[O:2])[O:3][C:4]([CH3:6])([CH3:5])[CH3:7])[CH2:14][CH2:13]1)=[O:17]
Reactant: Brc1ccccn1
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccccn2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 9 (500 mg, 0.80 mmol) is coupled to 2-bromopyridine (77 μL, 0.80 mmol) using Method B to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[Cl:14].[O-:15]O>>[Cl:1][C:2]1[C:3]([Cl:14])=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[C:7]=1[OH:15]
Reactant: [O-]O
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(Cl)c1O

Procedure:
contacting 1,2-dichloro-3,5-dinitrobenzene with a hydroperoxide in the presence of anhydrous base to form 2,3-dichloro-4,6-dinitrophenol;
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][C:12]1[CH:29]=[CH:28][C:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20][C:14]=2[CH:13]=1>C(O)C.[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([O:11][C:12]2[CH:29]=[CH:28][C:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:19][CH2:20][C:14]=3[CH:13]=2)=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Oc3ccc([N+](=O)[O-])cc3F)cc2CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Oc3ccc(N)cc3F)cc2CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1,1-dimethylethyl 7-[(2-fluoro-4-nitrophenyl)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (E274, Step 1) (1.37 g, 3.40 mmol) in ethanol (25 ml) was added palladium on charcoal (10 wt % palladium) (300 mg) and the reaction was stirred at room temperature under hydrogen (1 atmosphere) for 3 hours. The reaction mixture was filtered through celite and concentrated in vacuo to afford the title compound. MS (ES+) m/e 273 [M-M-COOtBu]+.
Reaction SMILES: [I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:22]([Li])[CH2:23][CH2:24][CH3:25].[CH:27]([C:29]1[CH:30]=[C:31](C=CC=1)[C:32]([O:34][CH3:35])=[O:33])=O>O1CCCC1.CCCCCC>[CH:24]([C:23]1[CH:22]=[C:31]([CH:30]=[CH:29][CH:27]=1)[C:32]([O:34][CH3:35])=[O:33])=[CH2:25]
Reactant: [Li]CCCC
Reactant: COC(=O)c1cccc(C=O)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=Cc1cccc(C(=O)OC)c1
Temperature: -50 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 590 mg of methyl triphenylphosphonium iodide in 50 ml of dry tetrahydrofuran cooled to -50° C. was added dropwise 5.3 ml of 2.5M n-butyl lithium in hexane. The resulting mixture was allowed to warm to 0° C. over a period of one hour. The mixture was then cooled to -70° C. and 2.0 g of methyl 3-formylbenzoate in 20 ml of dry tetrahydrofuran was added dropwise over a period of 20 minutes. The reaction mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was concentrated in vacuo and the residue treated with water (200 ml) and extracted with diethyl ether (2×200 ml). The extracts were combined, washed with water and a brine solution and dried over magnesium sulfate. Removal of the solvent gave 2 g of an oil which was flash chromatographed on silica gel (30% ethyl acetate--hexane; v:v) , 2.0 g. Distillation in vacuo gave 1.36 g.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:2]1.[CH2:15]1[CH2:20][O:19][CH:18]=[CH:17][CH2:16]1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(#N)C>[O:19]1[CH2:20][CH2:15][CH2:16][CH2:17][CH:18]1[N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:2]1
Reactant: C1=COCCC1
Reactant: COC(=O)Cc1n[nH]c2ncccc12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC#N
Product: COC(=O)Cc1nn(C2CCCCO2)c2ncccc12
Temperature: 75 °C

Procedure:
To a solution of methyl 1H-pyrazolo[3,4-b]pyridin-3-ylacetate (84 mg, 0.439 mmol) in acetonitrile (3 mL) was added DHP (37 mg, 0.439 mmol) and DDQ (10 mg, 0.044 mmol). This mixture was heated to 75° C. for 20 minutes. After this time, additional DHP (37 μL, 0.44 mmol) was added and the reaction mixture heated to 85° C. for 1.5 hours. The reaction mixture was partitioned between water (10 mL) and ethyl acetate (2×20 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated in vacuo. This residue was purified by chromatography using RediSep column (12 g) and eluting with gradient of 0-20% EtOAc/CH2Cl2. The desired fractions were combined and the solvent evaporated in vacuo to give the title compound. LRMS (M+1): 276.1.
Reaction SMILES: [OH-].[Na+:2].[C:3]1([C:9]2[CH:10]=[C:11]([C:15]([NH:17][C:18]3[CH:26]=[C:25]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[CH:24]=[CH:23][C:19]=3[C:20]([OH:22])=[O:21])=[O:16])[CH:12]=[N:13][CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C>[C:3]1([C:9]2[CH:10]=[C:11]([C:15]([NH:17][C:18]3[CH:26]=[C:25]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[CH:24]=[CH:23][C:19]=3[C:20]([O-:22])=[O:21])=[O:16])[CH:12]=[N:13][CH:14]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.[Na+:2]
Reactant: O=C(Nc1cc(-c2cccs2)ccc1C(=O)O)c1cncc(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Nc1cc(-c2cccs2)ccc1C(=O)[O-])c1cncc(-c2ccccc2)c1
Reaction time: 0.5 h

Procedure:
A 1 mol/L aqueous solution of sodium hydroxide (0.13 mL) was added to an ethanol (4.0 mL) suspension of the obtained 2-(5-phenylpyridine-3-carboxamido)-4-(thiophen-2-yl)benzoic acid (54 mg) at room temperature, followed by stirring at the same temperature for 2 hours and 30 minutes. The solvent was evaporated under reduced pressure, and water was added to the obtained residue. The solid substance was collected by filtration to obtain 35 mg of sodium 2-(5-phenylpyridine-3-carboxamido)-4-(thiophen-2-yl)benzoate as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1)([O-:3])=[O:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl:27]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:27][C:8]1[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: C[Si](C)(C)CCOCn1cc([N+](=O)[O-])cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc([N+](=O)[O-])c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
In an oven-dried flask, 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (412.4 mg, 1.695 mmol) was dissolved in 5 mL THF and cooled at −78° C. To this solution was slowly added 1.0M Lithium hexamethyldisilazide in tetrahydrofuran (2.0 mL, 2.0 mmol). After stirring for 30 minutes at −78° C., a solution of hexachloroethane (455.2 mg, 1.923 mmol) in 3 mL THF was slowly added. The reaction mixture was kept at −78° C. for an additional hour, and then quenched with saturated aqueous ammonium chloride and warmed to room temperature. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer dried over magnesium sulfate and evaporated in vacuo to yield 0.4592 g (98%) of 5-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole, which was carried forward without further purification. LCMS (ESI) m+H=220.2; 1H NMR (400 MHz, DMSO-d6) δ: 8.52 (s, 1H), 5.56 (s, 2H), 3.67-3.57 (m, 2H), 0.91-0.83 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][NH:8]C(OC(C)(C)C)=O)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.F[C:24]1[C:29]([C:30](=O)[CH2:31][CH3:32])=[CH:28][CH:27]=[C:26]([F:34])[N:25]=1>ClCCl>[CH2:31]([C:30]1[C:29]2[C:24](=[N:25][C:26]([F:34])=[CH:27][CH:28]=2)[N:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[N:8]=1)[CH3:32]
Reactant: CCC(=O)c1ccc(F)nc1F
Reactant: CC(C)(C)OC(=O)NNC1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nn(C2CCOCC2)c2nc(F)ccc12
Temperature: 75 °C
Reaction time: 72 h
Yield: 83.7 %

Procedure:
A mixture of tert-butyl 2-(tetrahydro-2H-pyran-4-yl)hydrazinecarboxylate (3.8 g, 0.018 mol) and trifluoroacetic acid (20 mL, 0.3 mol) were stirred in dichloromethane (20 mL) for 90 minutes. The mixture was concentrated, and the residue was taken up in acetonitrile (30 mL). 1-(2,6-difluoropyridin-3-yl)propan-1-one (2.34 g, 0.0137 mol) was then added, and the resulting mixture was stirred at 75° C. for 72 hours. After cooling to room temperature, the mixture was concentrated, and the residue was purified by flash chromatography on silica gel using a 10-50% hexane:ethyl acetate gradient (flow rate 20 mL/min). The organics were combined and the crude product was then extracted with ethyl acetate. The combined extracts were washed with saturated sodium bicarbonate and then concentrated to afford 2.86 g (83.9%) of 3-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine as a white solid. LC/MS (EI) tR 3.5 (Method E), m/z 250 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH3:28].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C=O)C>[OH:16][C@H:15]([CH2:17][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[C:22]4[CH3:28])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: C1CCNC1
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H]1CO1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H](O)CN1CCCC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 88.2 %

Procedure:
A mixture of (2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (300 mg, 0.65 mmol), (prepared as described in Example 278), and pyrrolidine (0.17 ml, 2.04 mmol) in DMF (5 ml) was stirred at 60° C. for 24 hours and allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified by silica column chromatography using gradient elution (dichloromethane, 5% methanol/95% dichloromethane, methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1)) to give (2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (257 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[C:18]([C:17]2[CH:21]=[C:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:23]=[CH:24][C:16]=2[O:15][CH:12]([CH3:14])[CH3:13])=[O:19])=[CH:4][CH:3]=1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Clc1ccc2c(c1)NCCC2
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCCc2ccc(Cl)cc21

Procedure:
Prepared in analogy to example 1.1 from 7-chloro-1,2,3,4-tetrahydro-quinoline (CA [90562-35-9]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([P:33]([CH3:36])([CH3:35])=[O:34])=[CH:29][C:28]=2[S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])=[N:4][C:5]([NH:8][C:9]2SC(N3CCN(C4C=CC=CN=4)CC3)=NN=2)=[N:6][CH:7]=1.C(N)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH2:9]([NH:8][C:5]1[N:4]=[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([P:33]([CH3:35])([CH3:36])=[O:34])=[CH:29][C:28]=2[S:37]([CH:40]([CH3:42])[CH3:41])(=[O:38])=[O:39])[C:2]([Cl:1])=[CH:7][N:6]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1nc(Nc2nnc(N3CCN(c4ccccn4)CC3)s2)ncc1Cl
Reactant: NCc1ccccc1
Product: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1nc(NCc2ccccc2)ncc1Cl

Procedure:
This compound can be prepared as in Example 32 by reacting 2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (as described in Example 53) with benzylamine.