Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8]1)(=[O:4])=[O:3].[I:19]I>C(Cl)(Cl)Cl.C(#N)C.FC(F)(F)C([O-])=O.[Ag+]>[CH3:1][S:2]([O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)[CH2:8]1)(=[O:3])=[O:4]
Reactant: II
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccccc2)C(=O)O1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Yield: 53 %

Procedure:
[(5R)-3-phenyl-2-oxo-1,3-oxazolidin-5-yl]methyl methanesulfonate (41 g, 152 mmol) was dissolved in chloroform/acetonitrile (250/250 ml). Silver trifluoroacetate (50 g, 228 mmol) was added followed by portionwise addition of iodine (58 g, 228 mmol). After stirring the reaction overnight, the silver iodide was filtered off, and the filtrate was washed with solutions of 5% sodium thiosulfate (2×500 ml), saturated sodium bicarbonate (500 ml), brine, and dried over magnesium sulfate. The dried solution was evaorated to give the desired product as a yellow solid (32 g) that was used without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C@@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:33](Cl)([CH3:36])(=[O:35])=[O:34].N1C=CC=CC=1>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 67.5 %

Procedure:
A solution of Example 40H (2.89 g, 6.07 mmol), mesyl chloride (1.88 mL, 24.3 mmol), and pyridine (3.93 mL, 48.6 mmol) in acetone (80 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (2.12 g, 68%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.43 m, 1 H) 0.74 m, 7 H) 1.34 (m, 1 H) 1.57 m, 3 H) 2.15 m, 2 H) 3.08 m, 3 H) 7.56 m, 3 H) 7.75 m, 3 H) 8.16 m, 1 H) 10.26 m, 1 H) 13.76 m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:13])[C@H:9](O)[CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[NH2:45][C:46]([CH3:50])([CH3:49])[CH2:47][OH:48]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@:8]2([OH:13])[O:48][CH2:47][C:46]([CH3:50])([CH3:49])[NH:45][C@H:9]2[CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](O)C(=O)c1cccc(Cl)c1
Reactant: CC(C)(N)CO
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H]1NC(C)(C)CO[C@@]1(O)c1cccc(Cl)c1

Procedure:
Compound 4s was synthesized by a procedure similar to that described for (2S,3S)-4a using (R)-1-(3-chlorophenyl)-2-hydroxybutan-1-one (10j, 1.13 g, 0.0568 mol), Proton sponge (1.43 g, 0.0667 mol), triflic anhydride (1.0 g, 0.063 mol), and 2-amino-2-methyl-1-propanol (1.09 g, 0.0122 mol) in CH2Cl2 (13 mL). After purification, the free base 4r was converted to 0.230 g of its D-tartrate salt: mp 160-161° C.; [α]20D +5.6° (c 0.8, CH3OH); 1H NMR (methanol-d4) δ 7.49-7.46 (m, 1H), 7.41-7.35 (m, 3H), 4.37-4.34 (m, 1H), 4.30-4.24 (m, 1H), 3.81-3.62 (m, 2H), 1.57 (s, 3H), 1.47-1.36 (m, 2H), 1.33 (s, 3H), 0.81-0.71 (m, 3H); 13C NMR (methanol-d4) δ 178.5, 145.2, 135.6, 131.2, 130.3, 128.2, 126.5, 97.1, 75.0, 67.8, 61.1, 55.0; LCMS (ESI) m/z 270.4 [(M-tartrate)+, M=C16H23ClNO5); Anal. (C16H23ClNO5.0.25H2O) calcd: C, 55.01; H, 6.78; N, 4.01. found: C, 54.99; H, 6.85; N, 4.08.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21])[C:14]([CH2:23][O:24][CH2:25][CH3:26])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[CH:27]([S:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH2:28].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C1(C)C=CC=CC=1>[BrH:1].[CH2:25]([O:24][CH2:23][C:14]1[N:15]([CH2:16][CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21])[C:6]2[C:5]3[CH:4]=[CH:3][C:2](/[CH:28]=[CH:27]/[S:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=1)[CH3:26]
Reactant: C=CSc1ccccc1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCOC(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Br
Product: CCOCc1nc2c(N)nc3cc(/C=C/Sc4ccccc4)ccc3c2n1CCCOC(C)C
Temperature: 110 °C
Yield: 25.5 %

Procedure:
7-Bromo-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinolin-4-ylamine (1.00 g, 2.46 mmol), tris(2-tolyl)phosphine (16 mg, 0.05 mmol) and a stir bar were added to a pressure vessel. Palladium(II) acetate (6 mg, 0.025 mmol), phenyl vinyl sulfide (0.330 mL, 2.53 mmol) and triethylamine (0.685 mL, 4.92 mmol) were subsequently added, followed by toluene (5 mL). The vessel was sealed with a TEFLON cap and the reaction was heated at 110° C. for 40 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, eluting with a linear gradient of 1-7% methanol in dichloromethane), followed by recrystallization from acetonitrile to provide 0.35 g of 2-ethoxymethyl-1-(3-isopropoxypropyl)-7-[(E)-2-(phenylthio)ethenyl]-1H-imidazo[4,5-c]quinolin-4-amine hydrobromide as yellow-orange crystals, mp 220-221° C.
Reaction SMILES: [C:1]1([CH2:7][S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:14]([C:16]1[CH:17]=[N:18][N:19]([C:26]2[C:31]([Cl:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:28][N:27]=2)[C:20]=1[CH:21]=[CH:22][C:23](Cl)=[O:24])#[N:15].O>O1CCCC1>[C:1]1([CH2:7][S:8]([NH:11][C:23](=[O:24])[CH:22]=[CH:21][C:20]2[N:19]([C:26]3[C:31]([Cl:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:28][N:27]=3)[N:18]=[CH:17][C:16]=2[C:14]#[N:15])(=[O:9])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)Cc1ccccc1
Reactant: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=CC(=O)NS(=O)(=O)Cc1ccccc1
Reaction time: 1.25 h
Yield: 26.2 %

Procedure:
To a stirred solution of 0.31 gram (0.002 mole) of phenylmethanesulfonamide in 15 mL of tetrahydrofuran was added 0.05 gram (0.002 mole) of sodium hydride which was washed into the reaction vessel with 10 mL of tetrahydrofuran. The reaction mixture was warmed to reflux temperature, and a solution of 0.32 gram (0.001 mole) of 3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylic acid chloride in 5 mL of tetrahydrofuran was added dropwise during a 20 minute period. Upon completion of the addition, heating of the reaction mixture at reflux was continued for 75 minutes. After this time, the reaction mixture was cooled, and 1 mL of water was added. The mixture was concentrated under reduced pressure to a residue. The residue was dissolved in 35 mL of water, and the solution was acidified with aqueous 4N hydrochloric acid. The resultant solid was collected by filtration, and the filter cake was washed with water. The filter cake was then stirred with hot water. The hot water was decanted away from a semi-solid material. The semi-solid was stirred with fresh cold water which caused the semi-solid to totally solidify. The solid was collected by filtration and was then dissolved in 1:1 toluene/ethyl acetate. The solution was passed through a column of silica gel. The eluate was concentrated under reduced pressure, yielding 0.13 gram of N-phenylmethanesulfonyl-3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylamide. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [ClH:1].C([NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:16]=2)[CH2:11]1)C1C=CC=CC=1>C(O)C.O.[Pd]>[ClH:1].[NH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:16]=2)[CH2:11]1
Reactant: CCOC(=O)COc1ccc2c(c1)CC(NCc1ccccc1)CC2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)COc1ccc2c(c1)CC(N)CC2
Reaction time: 3 h
Yield: 92.6 %

Procedure:
A solution of 27 g of 2-benzylamino-7-carbethoxymethoxytetraline hydrochloride, EXAMPLE 1, in 300 ml of 95% ethanol and 25 ml of water, is hydrogenated under ordinary pressure and at temperature of 50° C. by using 3 g of 10% palladium on charcoal as a catalyst. After 3 hours, the mixture is filtered, the residue is taken up twice with 100 ml of absolte ethanol and dried every time. The product so obtained is triturated in 150 ml of acetone, filtered and crystallized from 100 ml of isopropanol to give 19 g of 2-amino-7-carbethoxymethoxytetraline hydrochloride; m.p. 143°-145° C. The product thus obtained may be used for the preparation of the compound of formula (XV) above, in which X is hydrogen and O-R' is a carbethoxymethoxy group (COMPOUND 1), as follows:
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=O)[CH2:11][CH2:10]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:18][O:19][NH2:20]>N1C=CC=CC=1>[CH3:18][O:19][N:20]=[C:12]1[C:13]2[C:9](=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:15][CH:14]=2)[CH2:10][CH2:11]1
Reactant: O=C1CCc2cc(N3CCCCC3)ccc21
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CCc2cc(N3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 40 h

Procedure:
5-Piperidin-1-ylindan-1-one (4.31 g, 20 mmol) in pyridine (20 ml) was treated with methoxyamine hydrochloride (1.84 g, 22 mmol). After stirring at ambient temperature for 40 hours, the solvent was removed under vacuum and the residue taken in water and extracted with diethyl ether. The combined organic layers were washed with water, dried with magnesium sulfate, filtered, and the filtrate was removed under vacuum to provide the title compound which was used without further purification. 1H NMR (CDCl3) δ 1.56-1.73 (m, 6H), 2.78-2.89 (m, 1H), 2.91-3.02 (m, 1H), 3.20-3.30 (m, 2H), 3.95 (s, 3H), 6.78 (m, 1H), 6.84 (m, 1H), 7.54 (d, 1H); MS (DCI): 245 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[C:10](=[O:16])[NH:9][C:8]=2[C:7]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Se](=O)=O.C.[OH2:29].[O:30]1CCO[CH2:32][CH2:31]1>>[CH2:18]([O:17][C:7]1[C:8]2[NH:9][C:10](=[O:16])[C:11]([CH3:15])([CH3:14])[O:12][C:13]=2[C:4]([C:1](=[O:3])[CH:2]([O:30][CH2:31][CH3:32])[OH:29])=[CH:5][CH:6]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2c1OC(C)(C)C(=O)N2
Reactant: C1COCCO1
Agent: O=[Se]=O
Product: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c2c1OC(C)(C)C(=O)N2

Procedure:
9.6 g (30 mmol) 8-acetyl-5-benzyloxy-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one, 3.3 g (30 mmol) selenium dioxide and activated charcoal are stirred for 7 hours in 90 mL dioxane and 2 mL water at reflux temperature. The solid is suction filtered, the filtrate is evaporated down and the residue is refluxed for 30 minutes in 100 ml of ethanol. The solvent is distilled off and the residue is dissolved in 125 mL ethyl acetate. It is extracted successively with potassium carbonate solution and water, dried with sodium sulphate and evaporated down. The oil remaining (10.1 g) is further reacted directly.
Reaction SMILES: C1([Li])C=CC=CC=1.[CH3:8][C:9]1[N:14]=[C:13]([CH3:15])[C:12]([CH3:16])=[N:11][C:10]=1[CH3:17].[C:18]1([CH3:26])[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][CH:19]=1>CCOCC>[OH:25][CH:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:26])=[CH:19][CH:20]=1)[CH2:17][C:10]1[C:9]([CH3:8])=[N:14][C:13]([CH3:15])=[C:12]([CH3:16])[N:11]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Cc1nc(C)c(C)nc1C
Agent: [Li]c1ccccc1
Solvent: CCOCC
Product: Cc1ccc(C(O)Cc2nc(C)c(C)nc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.7 %

Procedure:
To a solution of phenyllithium in 150 milliliters 7:3 benzene-ether (0.1 mole) at 0° C. was slowly added a solution of 13.6 grams of tetramethylpyrazine (0.1 mole). The mixture was stirred at room temperature for 2 hours and heated under reflux for 1.5 hours. The mixture was cooled to 0° C., and a solution of 12.0 grams of p-tolualdehyde (0.1 mole) in 50 milliliters of ether was added dropwise. The reaction mixture was stirred at room temperature for 1 hour and then treated in the manner of Example I. The crude product was crystallized from ether to yield 10.7 grams of product (42%) as fine white needles, m.p. 99°-101° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[N:23]=[CH:22][C:21](N)=[CH:20][CH:19]=4)=[C:11]3[C:10]([CH3:25])=[N:9]2)=[CH:5][CH:4]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([C:38]2([C:41](F)=[O:42])[CH2:40][CH2:39]2)=[O:37])=[CH:31][CH:30]=1.C[N:45](C=O)C.CCN(C(C)C)C(C)C>O>[F:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]([C:21]2[CH:22]=[N:23][C:18]([O:17][C:16]3[CH:15]=[CH:14][N:13]=[C:12]4[N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:27][CH:26]=5)[N:9]=[C:10]([CH3:25])[C:11]=34)=[CH:19][CH:20]=2)[C:36]([C:38]2([C:41]([NH2:45])=[O:42])[CH2:40][CH2:39]2)=[O:37])=[CH:31][CH:30]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N)cn4)ccnc32)cc1
Reactant: O=C(F)C1(C(=O)Nc2ccc(F)cc2)CC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cn4)ccnc32)cc1
Temperature: 50 °C
Yield: 59 %

Procedure:
A 100 mL round-bottomed flask was charged with 6-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pyridin-3-amine (0.500 g, 1.38 mmol), 1-((4-fluorophenyl)carbamoyl)cyclopropanecarbonyl fluoride (0.545 g, 2.42 mmol; prepared as in Example 6, Step A), and DMF (10 mL). DIEA (0.723 mL, 4.15 mmol) was added under nitrogen and the reaction mixture was heated at 50° C. for 18 hours. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to provide the crude product (1.55 g, 59%). LRMS (esi+) 567 (M+H).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]1([CH:17]([N:19]2[CH2:30][CH:22]3[C:23]4[CH:24]=[CH:25][S:26][C:27]=4[C:28](=O)[CH:21]3[CH2:20]2)[CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.ClCCl>[CH2:1]=[C:28]1[C:27]2[S:26][CH:25]=[CH:24][C:23]=2[CH:22]2[CH2:30][N:19]([CH:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:18])[CH2:20][CH:21]12
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(c1ccccc1)N1CC2C(=O)c3sccc3C2C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C1c2sccc2C2CN(C(C)c3ccccc3)CC12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
Potassium bis(trimethylsilyl)amide (308 mg, 1.55 mmol) was added to a solution of methyl triphenylphosphonium bromide (575 mg, 1.61 mmol) in 7 mL of THF at 0° C. After 30 minutes of stirring at 0° C., the product from step e) (303 mg, 1.07 mmol) dissolved in 2 mL of THF was added to the reaction mixture and was allowed to come to room temperature over 1 hour. The reaction mixture was diluted with dichloromethane (30 mL) and was washed with brine, dried (MgSO4) and concentrated to an oil. The crude was purified by column chromatography (SiO2) using 5-55% ethylacetate-hexane gradient to afford the subtitle compound (226 mg, yield: 74.8%). MS calculated for C18H19NS +H: 282, observed: 282.
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([CH2:10][C:11]2([F:36])[CH:16]=[CH:15][C:14]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:35])([CH2:25][C:26]4[CH:31]=[CH:30][N:29]=[C:28](S(C)=O)[N:27]=4)[CH2:21][CH:20]=3)=[O:18])=[CH:13][CH2:12]2)[CH:7]=[CH:6][N:5]=1)=O.[CH3:37][O-:38].[Na+].O.C1[CH2:45][O:44]CC1>CO>[CH3:37][O:38][C:4]1[N:9]=[C:8]([CH2:10][C:11]2([F:36])[CH:16]=[CH:15][C:14]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:35])([CH2:25][C:26]4[CH:31]=[CH:30][N:29]=[C:28]([O:44][CH3:45])[N:27]=4)[CH2:21][CH:20]=3)=[O:18])=[CH:13][CH2:12]2)[CH:7]=[CH:6][N:5]=1
Reactant: C[O-]
Reactant: C1CCOC1
Reactant: CS(=O)c1nccc(CC2(F)C=CC(C(=O)C3=CCC(F)(Cc4ccnc(S(C)=O)n4)C=C3)=CC2)n1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nccc(CC2(F)C=CC(C(=O)C3=CCC(F)(Cc4ccnc(OC)n4)C=C3)=CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of 4-(2-methylsulfinylpyrimidinyl)methyl-4-fluorophenylketone (5.7 mmol) in 75 mL THF was added 22 mL of 25% NaOMe in MeOH at 0° C. The solution was warmed to room temperature and stirred for 1 h. The solution was then heated at 50° C. for 30 min. Next, the solution was cooled, 200 mL of H2O were added and it was extracted thrice with 100 mL of ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give a solid. The solid was then purified by silica gel chromatography with 15-30% ethyl acetate/hexane to give the title compound as a light yellow solid (0.8 g, 57%). ES(+)MS m/e=247 (MH+)
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][CH2:7][C@@H:6]([CH3:9])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1.[CH3:17][NH:18][CH3:19].C(O)C>>[CH3:17][N:18]([CH2:2][C@@H:3]1[O:8][CH2:7][C@@H:6]([CH3:9])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1)[CH3:19]
Reactant: C[C@@H]1CO[C@H](CCl)CN1Cc1ccccc1
Reactant: CNC
Solvent: CCO
Product: C[C@@H]1CO[C@@H](CN(C)C)CN1Cc1ccccc1
Temperature: 150 °C

Procedure:
A mixture of (2S,5R)-2-(chloromethyl)-5-methyl-4-benzylmorpholine (1 equivalent) and dimethylamine in ethanol (33%, approx. 5.6 M, 5 equivalents) was heated at 150° C. over 2 days in a glass pressure vessel. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 1 N HCl, and the solution was washed with CH2Cl2. The water phase was made basic with 30% NaOH solution (to pH=12) and extracted with CH2Cl2. The organic extracts were collected and dried (Na2SO4). Evaporation of the solvent under reduced pressure afforded (2S,5R)-2-[dimethylamino(methyl)]-5-methyl-4-benzylmorpholine as a brown oil which was used in the next step without purification. GC/MS: 247 (2%, M−H), 204 (55%, M−NMe2), Rt 15.5 minutes; LC/MS m/z 249.2 (MH+), Rt 0.72 minutes.
Reaction SMILES: [B:1]([O:10][CH:11]([CH3:13])[CH3:12])([O:6][CH:7]([CH3:9])[CH3:8])OC(C)C.[Br:14][CH2:15]Br.C([Li])CCC.CS(O)(=O)=O.OC(C(O)(C)C)(C)C>O1CCCC1>[Br:14][CH2:15][B:1]1[O:6][C:7]([CH3:8])([CH3:9])[C:11]([CH3:12])([CH3:13])[O:10]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: BrCBr
Agent: CC(C)(O)C(C)(C)O
Agent: CS(=O)(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(CBr)OC1(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 65.8 %

Procedure:
To a mixture of triisopropyl borate (20 g, 110 mmol), dibromomethane (8.6 mL, 120 mmol), and tetrahydrofuran (150 mL) was added dropwise n-butyl lithium (2.6 M n-hexane solution, 39 mL, 100 mmol) over a period of 1.5 hours at −78° C., and then the reaction mixture was stirred for 1.5 hours at the same temperature. This mixture was then stirred for 2 hours at room temperature, after which it was cooled to 0° C., methanesulfonic acid (6.5 mL, 100 mmol) was added to the reaction mixture, and then the reaction mixture was stirred for 1 hour at room temperature. The mixture was cooled to 0° C., pinacol (12 g, 100 mmol) was added to the reaction mixture, and the reaction mixture was then stirred for 1 hour at room temperature. The reaction mixture was concentrated under a reduced pressure, after which the residue thus obtained was distilled under a reduced pressure (74-76° C., 8 mmHg) to obtain the title compound (16 g, 68%).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[Cl:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:17][C:15]2[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([NH:7][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[N:13]3[N:14]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: Nc1nc2cccc(NC3CCCCC3)n2n1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Product: O=C(Nc1nc2cccc(NC3CCCCC3)n2n1)c1ccc(CCl)cc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from N5-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine ((A9), 800 mg; 3.46 mmol; 1.0 eq.) and 4-(chloromethyl)benzoyl chloride (981 mg; 5.2 mmol; 1.5 eq.) as a brownish foam (1.32 g, 99%). LC/MS, M+(ESI): 384.0, M−(ESI): 382.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[N:6]=[C:5]2O.[NH4+].[OH-].O=P(Cl)(Cl)[Cl:24]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[N:6]=[C:5]2[Cl:24]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(Br)cc2c(O)nc(-c3cccnc3)nc12
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc(Br)cc2c(Cl)nc(-c3cccnc3)nc12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
6-Bromo-8-methyl-2-(pyridin-3-yl)quinazolin-4-ol (870 mg, 2.76 mmol) was added POCl3 (10 mL). The resulting mixture was stirred at 120° C. overnight. After the reaction was completed, the mixture was carefully poured into ice-water. The pH was adjusted to 7 by slow addition of NH4OH at 0° C. The resultant solid was collected to give 1.00 g of v-h as a beige solid (quantitative yield). LCMS m/z=333.9, 335.9 (M+1) (Method B) (retention time=2.23 min).
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].C(NC(C)C)(C)C.[Cl-].[Li+].ICCCC.[OH:20][CH:21]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:22]([N:24]([CH3:35])[C:25](=[O:34])[CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH3:23]>>[OH:20][CH:21]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH:22]([N:24]([CH3:35])[C:25](=[O:34])[CH:26]([CH2:2][CH2:3][CH2:4][CH3:5])[CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH3:23]
Reactant: [Li]CCCC
Reactant: CC(C(O)c1ccccc1)N(C)C(=O)CCC1CCCCC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: CCCCI
Product: CCCCC(CC1CCCCC1)C(=O)N(C)C(C)C(O)c1ccccc1
Yield: 53 %

Procedure:
A solution of 2.5M nBuLi in hexanes (5.8 mL, 14.5 mmol), diisopropylamine (2.0 mL, 14.5 mmol), lithium chloride (1.6 g, 39 mmol), iodobutane (130 μL, 6.4 mmol) and the product from Example 1315A (2.0 g, 6.4 mmol) were allowed to react in a manner similar to that described by A. G. Myers et al., Journal of the American Chemical Society 1994, 116: 9361-9362. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1:4) to afford the title compound as a yellow oil (1.2 g, 53%). MS (CI/NH3) m/z: 360 (M+H)+.