Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH:5]1[CH2:4][CH2:3][NH:2]2.[OH-].[Na+].Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1(C)C=CC=CC=1.O>[CH:1]12[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH:5]1[CH2:4][CH2:3][N:2]2[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CC(C)(C)OC(=O)N1CC2CCNC2C1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC2CN(C(=O)OC(C)(C)C)CC21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
13 g (61.2 mmol) of tert.-butyl 2,7-diazabicyclo[3.3.0]octane-7-carboxylate are dissolved in 100 ml of toluene, a solution of 3 g of sodium hydroxide in 20 ml of water is added, and 7 g (64.5 mmol) of ethyl chloroformate are added dropwise at room temperature. The mixture is stirred for 3 hours at room temperature, and the aqueous phase is separated off and extracted twice using 100 ml portions of methylene chloride. The organic solutions are dried over magnesium sulphate, concentrated and distilled.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[CH:6]=[CH:7]/[C:8]1[NH:16][C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10]=2[N:9]=1.[C:30](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:30])[C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10]=2[N:9]=1
Reactant: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(OC)c3)nc2n(CCC)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCn1c(=O)c2c(nc(/C=C/c3ccc(OC)c(OC)c3)n2C)n(CCC)c1=O
Yield: 97.9 %

Procedure:
Compound B (1.20 g, 3.02 mmol) was dissolved in 20 ml of dimethylformamide. To the solution were added 1.04 g (7.55 mmol) of potassium carbonate and subsequently 0.38 ml (6.04 mmol) of methyl iodide, and the resultant mixture was stirred at 50° C. for 30 minutes. After cooling, insoluble matters were filtered off, and 400 ml of water was added to the filtrate. The mixture was extracted three times with 100 ml of chloroform. The extract was washed twice with water and once with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 1% methanol/chloroform), followed by recrystallization from propanol/water to give 1.22 g (yield 98%) of Compound 1 as white needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([OH:14])=O)[CH2:7][CH2:6]2.[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[CH:19]=[N:18]1)[CH3:16]>>[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][N:23]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)[C:12]([CH:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH2:6][CH2:7]2)=[O:14])[CH:19]=[N:18]1)[CH3:16]
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Reactant: COc1ccc2c(c1)CCC2C(=O)O
Product: CCn1cc(CN(C(=O)C2CCc3cc(OC)ccc32)c2ccc(C(C)C)cc2)cn1
Yield: 74.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 4 using 5-methoxyindan-1-carboxylic acid (0.29 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-5-methoxyindan-1-carboxamide (0.47 g) was obtained. melting point: 115-116° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:10][CH:11]=[CH:12][CH:13]=2)=[C:5]([CH3:14])[N:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:3]1=[O:25].[C:26]([C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1)#[N:27].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.[Cu]I>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[N:10]([C:31]3[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[CH:29][CH:30]=3)[CH:11]=[CH:12][CH:13]=2)=[C:5]([CH3:14])[N:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=2)[C:3]1=[O:25]
Reactant: Cc1c(-c2ccc[nH]2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(I)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(-c2cccn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Yield: 31.8 %

Procedure:
A solution of 3,6-dimethyl-5(1H-pyrrol-2-yl)-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 201) (20.0 mg), 4-cyanoiodobenzene (39.4 mg), copper(I) iodide (1.0 mg), cyclohexyldiamine (0.6 mg) and potassium phosphate (36.4 mg) in 1,4-dioxane (2.0 ml) was stirred with heating under reflux for fifteen hours. Thereto were added 4-cyanoiodobenzene (39.4 mg), copper(I) iodide (1.0 mg), cyclohexyldiamine (0.6 mg) and potassium phosphate (36.4 mg) and the resulting mixture was stirred with heating under reflux for four hours. To the reaction mixture was added water (10 ml) and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) and further purified by silica gel column chromatography (eluent: hexane/acetone/methanol) to afford 4-[2-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrrol-1-yl]benzonitrile (8.2 mg).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:9][CH2:10][CH2:11][OH:12].C(=O)(O)[O-].[Na+]>>[Cl:8][C:7]1[C:2]([NH:9][CH2:10][CH2:11][OH:12])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCO
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: OCCNc1ncccc1Cl

Procedure:
After 11.46 g of 2,3-dichloropyridine and 9.8 mL 2-aminoethanol were heated at 100° C. for 24 hours, an aqueous saturated sodium bicarbonate solution was added thereto, and the reaction mixture was extracted with ethyl acetate. The extract was washed with brine, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate/hexane) to give 2.1 g of the title compound (yellow oil).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+]([O-])=O)[CH:12]=2)[C:7]1=[O:19])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]([OH:29])[CH:25]=[C:26]([F:28])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:29][C:24]3[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=3)[CH:12]=2)[C:7]1=[O:19])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Reactant: Oc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CN1C(=O)c2ccc(Oc3cc(F)cc(F)c3)cc2C1=O

Procedure:
To an 80 mL microwave reaction vessel was added (5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetic acid ethyl ester (2 g), 3,5-difluorophenol (1.12 g), potassium carbonate (1.39 g), and dimethyl acetamide (27 mL). The resulting mixture was reacted in the microwave at 100° C. for 10 min. Water (280 mL) was added and the resulting precipitate was filtered, washed with water and dried. Further purification by silica gel chromatography generated 0.94 g of the title compound. 1H NMR (200 MHz, CDCl3) δ 7.86 (d, J=8.2 Hz, 1H), 7.41-7.31 (m, 2H), 6.67-6.57 (m, 3H), 4.41 (s, 2H), 4.22 (q, J=7.1 Hz, 2H), 1.29 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[F:5][C:6]([F:12])([F:11])[S:7]([NH2:10])(=[O:9])=[O:8].[OH-].[Na+]>CC(C)=O.O>[CH3:1][NH:2][C:3]([NH:10][S:7]([C:6]([F:12])([F:11])[F:5])(=[O:9])=[O:8])=[S:4]
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: CN=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CNC(=S)NS(=O)(=O)C(F)(F)F
Reaction time: 18 h
Yield: 42.3 %

Procedure:
A solution of methylisothiocyanate (0.21 g.) in acetone (10 ml.) was added to a solution of trifluoromethanesulphonamide (0.45 g.) and sodium hydroxide (0.12 g.) in water (5 ml.), the mixture stirred at 60° for 18 hours and then evaporated to dryness. The residue was dissolved in water and the solution washed with ethyl acetate and then adjusted to pH 1 with concentrated hydrochloric acid. The mixture was treated with charcoal and filtered and the filtrate extracted with ethyl acetate. The combined ethyl acetate extracts were dried and evaporated to dryness and the residue recrystallized from petroleum ether (b.p. 60°-80°) to give 1-methyl-3-trifluoromethanesulphonylthiourea (0.27 g.), m.p. 88°-90°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl.CN(C=O)C>[Cl:23][C:17]([CH:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1)=[O:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 3 h
Yield: 80.5 %

Procedure:
To a solution of 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid (4.50 g, 17.1 mmol, Preparation #5, Step A) in DCM (40 mL) at ambient temperature was added oxalyl chloride (3.00 mL, 34.2 mmol) followed by DMF (0.10 mL, 1.3 mmol). After about 3 h, the reaction was concentrated under reduced pressure to constant weight to afford benzyl 4-(chlorocarbonyl)piperidine-1-carboxylate as a yellow oil (3.88 g, 81%): 1H NMR (CDCl3) δ 7.44-7.35 (m, 5H), 5.16 (s, 2H), 4.20-4.10 (m, 2H), 3.03-2.89 (m, 3H), 2.15-2.05 (m, 2H), 1.81-1.76 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]([NH:15][C:16]1[N:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH2:20])=[O:19])=O.CCN(C(C)C)C(C)C>CN(C=O)C>[O:19]=[C:18]1[NH:20][C:13]([CH2:12][N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])=[N:15][C:16]2[N:24]=[CH:23][CH:22]=[CH:21][C:17]1=2
Reactant: NC(=O)c1cccnc1NC(=O)CN1C(=O)c2ccccc2C1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1Cc1nc2ncccc2c(=O)[nH]1
Yield: 88.3 %

Procedure:
A solution of 2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetylamino]-nicotinamide (7.24 g, 22.3 mmol) and DIPEA (14.4 ml, 111.6 mmol) in DMF (250 ml) was stirred overnight at 100° C. The reaction mixture was evaporated, redissolved in toluene and brought to dryness under reduced pressure. The residue was triturated with 100 ml EtOAc/MeOH (19/1) and filtrated to yield 2-(4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-isoindole-1,3-dione (6.03 g, 19.7 mmol; 88%) as light brown solid. MS (m/e): 307.2 [M+H+].
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>ClCCl>[C:2]1([C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:14][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzophenone imine (100 g, 0.54 mol), and 78.4 g, 0.56 mol) ethyl glycinate hydrochloride are combined in 2 L of dichloromethane and stirred overnight at room temperature. A precipitate (ammonium chloride) is filtered and the solution washed with water, dried over magnesium sulfate, and concentrated. The residual oil is dissolved in 200 mL of boiling diethyl ether, cooled to room temperature, and diluted with 600 mL of hexane. Some seed crystals from a previous experiment are added and the mixture cooled at +2° C. overnight. A white crystalline precipitate is collected and the mother liquor is concentrated to one-half of the volume, cooled overnight as above. This affords a second crop of product. The total yield is 133.0 g of the title compound; mp 52°-54° C.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[CH:11]=[N:12][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=3)[C:14]=2[OH:15])=[C:5]([CH3:25])[CH:4]=1)#[N:2].[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][C@H:29]1[CH3:34])[CH3:27]>>[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([C:20]([C:19]2[CH:23]=[CH:24][C:16]([N:13]3[C:14]([OH:15])=[C:10]([C:6]4[C:5]([CH3:25])=[CH:4][C:3]([C:1]#[N:2])=[C:8]([F:9])[CH:7]=4)[CH:11]=[N:12]3)=[N:17][CH:18]=2)=[O:22])[CH2:30][C@H:29]1[CH3:34])[CH3:27]
Reactant: CCN1CCNC[C@H]1C
Reactant: Cc1cc(C#N)c(F)cc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4cc(F)c(C#N)cc4C)c3O)nc2)C[C@H]1C

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-5-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-1-ethyl-2-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (t, J=7.20 Hz, 6 H) 2.33 (s, 3 H) 2.65-2.79 (m, 2 H) 2.88-3.02 (m, 2 H) 3.06 (d, J=10.86 Hz, 1 H) 3.10-3.21 (m, 1 H) 3.39 (br. s., 1 H) 3.57-4.21 (m, 2 H) 7.52 (d, J=7.07 Hz, 1 H) 7.84-7.92 (m, 1 H) 7.95 (s, 1 H) 8.23 (d, J=13.14 Hz, 1 H) 8.37-8.50 (m, 2H); ESI-MS m/z [M+H]+ 449.3.
Reaction SMILES: [CH3:1][S:2]([NH:5][NH2:6])(=[O:4])=[O:3].CCN(C(C)C)C(C)C.C[O:17][C:18](=O)[C:19]1[CH:24]=[C:23]([C:25]2[N:26]([CH3:30])[N:27]=[CH:28][CH:29]=2)[C:22]([CH:31]([CH3:33])[CH3:32])=[CH:21][C:20]=1[NH:34][C:35](OC1C=CC(Cl)=CC=1)=[O:36]>O1CCOCC1>[CH:31]([C:22]1[CH:21]=[C:20]2[C:19]([C:18](=[O:17])[N:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:35](=[O:36])[NH:34]2)=[CH:24][C:23]=1[C:25]1[N:26]([CH3:30])[N:27]=[CH:28][CH:29]=1)([CH3:33])[CH3:32]
Reactant: CS(=O)(=O)NN
Reactant: COC(=O)c1cc(-c2ccnn2C)c(C(C)C)cc1NC(=O)Oc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)c1cc2[nH]c(=O)n(NS(C)(=O)=O)c(=O)c2cc1-c1ccnn1C
Temperature: 80 °C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
CH3SO2NHNH2 (79.5 mg, 1.1 equiv) and i-Pr2NEt (225 μL, 2 equiv) were added to a solution of 2-(4-chloro-phenoxycarbonylamino)-4-isopropyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (281 mg, 0.65 mmol) in dioxane (8 mL). The mixture was stirred for 16 h (TLC control) at 80° C. The mixture was evaporated to dryness. The crude product was purified by flash chromatography (MeOH/DCM (1:9)) to provide N-[7-isopropyl-6-(2-methyl-2H-pyrazol-3-yl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide as a white solid (120 mg, 48%) (ESI-MS: m/z 378 [M+H]+, rt 4.20 min).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1.C(OCC)(OCC)OCC.[CH:20]1[CH:25]=CC(C2C=CC=CC=2)=C[CH:21]=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[N:4]1[C:5]2[C:6](=[N:9][CH:21]=[CH:20][CH:25]=2)[CH:7]=[CH:8][CH:3]=1
Reactant: COc1ccc(N)cn1
Reactant: c1ccc(-c2ccccc2)cc1
Solvent: CCOC(OCC)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: c1cnc2cccnc2c1

Procedure:
An alternative synthetic sequence to obtain the key intermediate E is described in Scheme 2. Commercially available 2-methoxy-5-aminopyridine F is converted by heating in the presence of ester B and triethyl orthoformate to the condensation product G as a mixture of olefin isomers (Scheme 2). Intermediate G is added to hot Dowtherm™ A to facilitate the ring closure and to yield the 1,5-naphthyridine H. Demethylation at the 6-position of H is conducted by treatment with trimethylsilyl chloride and sodium iodide in refluxing acetonitrile to give intermediate I, which may be used, without purification, for the reaction with phosphorus oxychloride to provide the key intermediate E (Scheme 2).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][C:8]1([C:14]#[N:15])[CH:13]=[CH:12][CH2:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2]>O.CO.[Pd]>[C:1]([O:5][C:6](=[O:16])[CH2:7][C:8]1([C:14]#[N:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC1(C#N)C=CCC=C1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CC1(C#N)CCCCC1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 56.5 %

Procedure:
Added 5% Pd/C, 50% H2O catalyst (94.0 mg, 22.1 μmol) to a solution of (1-cyanocyclohexa-2,5-dienyl)acetic acid t-butyl ester (0.50 g, 2.3 mmol) in MeOH (10 mL). After shaking the reaction mixture under 20 psi H2 at room temperature for 18.5 hours, the pressure was slowly released. The reaction was filtered and concentrated under reduced pressure. Flash chromatography (SiO2, 1:3 hexane:CH2Cl2-100% CH2Cl2) afforded 0.29 g (56%) of product as an oil.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH3:9][S:10](Cl)(=[O:12])=[O:11]>N1C=CC=CC=1>[CH3:9][S:10]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:8][S:10]([CH3:9])(=[O:12])=[O:11])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCCCO
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCCCCCOS(C)(=O)=O
Temperature: 5.5 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
A solution of 1,6-hexanediol (13.15 g, 111.3 mmol) in 70 mL of anhydrous pyridine was cooled to 0° C. using ice bath. To this methanesulfonyl chloride (27 g, 235.7 mmol) was slowly added under mixing such that the temperature was maintained at 5-6° C. The combined mixture was stirred overnight at the temperature below 10° C. and the precipitate formed was filtered off, washed with 20% HCl (3×), water (3×), 5% solution of sodium bicarbonate (3×), and then again with water (3×). Product was dried under vacuum to obtain Compound 1 as a white solid (yield 32.8%). The structure of Compound 1 is given below:
Reaction SMILES: [O:1]1[C:7]2[C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:15]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[Cl:15][C:10]1[CH:9]=[C:8]([C:12]([OH:14])=[O:13])[C:7]2[O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]=2[CH:11]=1
Reactant: O=C(O)c1cccc2c1OCCCC2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Cl)cc2c1OCCCC2
Reaction time: 8 h

Procedure:
To a solution of 1.7 g (8.9 mmol) of 2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid in 5 ml of DMF is added 1.41 g(10.6 mmol) of N-chlorosuccinimide (NCS) in one portion at room temperature. The solution is stirred overnight and then diluted with ethyl acetate and washed with water. The organic layer is then dried (MgSO4), filtered and concentrated to obtain 7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]2[NH:10][C:9](=[O:11])[CH2:8][O:7][C:6]=2[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[CH:23][N:22]=1.O>CN(C=O)C>[Cl:20][C:21]1[N:22]=[CH:23][N:24]=[C:25]([O:1][C:2]2[CH:3]=[C:4]([CH3:13])[C:5]3[NH:10][C:9](=[O:11])[CH2:8][O:7][C:6]=3[CH:12]=2)[CH:26]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1cc(O)cc2c1NC(=O)CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2cc(Cl)ncn2)cc2c1NC(=O)CO2
Temperature: 25 °C

Procedure:
0.10 g (0.56 mmol) 7-hydroxy-5-methyl-2H-benzo[b][1.4]oxazin-3(4H)-one and 0.10 g (0.73 mmol) potassium carbonate were placed in 2.0 mL DMF. After 15 min 86 mg (0.56 mmol) 4,6-dichloropyrimidine were added andtmw stirred at RT over the weekend. The reaction mixture was mixed with water, the substance was extracted with ethyl acetate and evaporated down i.vac.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20](OC)[O:21]C)[N:16]([C:25]([NH:27][C:28]1[N:33]=[C:32]([O:34][C@H:35]3[CH2:39][CH2:38][O:37][CH2:36]3)[C:31]([C:40]#[N:41])=[CH:30][N:29]=1)=[O:26])[CH2:15][CH2:14][CH2:13]2)(C(C)(C)C)(C)C.Cl>C1COCC1.O>[C:40]([C:31]1[C:32]([O:34][C@H:35]2[CH2:39][CH2:38][O:37][CH2:36]2)=[N:33][C:28]([NH:27][C:25]([N:16]2[C:17]3[C:12](=[CH:11][C:10]([CH2:9][OH:8])=[C:19]([CH:20]=[O:21])[N:18]=3)[CH2:13][CH2:14][CH2:15]2)=[O:26])=[N:29][CH:30]=1)#[N:41]
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Nc1ncc(C#N)c(O[C@H]2CCOC2)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cnc(NC(=O)N2CCCc3cc(CO)c(C=O)nc32)nc1O[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 37Q, 76 mg, 0.13 mmol) was dissolved in THF (2 ml) and water (1 ml), treated with conc. HCl (0.5 ml) and stirred for 16 h at room temperature. The reaction mixture was quenched with sat. aq. NaHCO3 and extracted with DCM (3×). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by preparative supercritical fluid chromatography (SFC 1, 4EP column) to give the title compound as a white solid.
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5])#[N:2].C(N(CC)CC)C.[C:22]([O:26][C:27](OC([O-])=O)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(#N)C.CN(C)C1C=CN=CC=1>[C:1]([C:3](=[CH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])=[CH:12][CH:13]=1)[C:4]([OH:6])=[O:5])#[N:2]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: N#CC(=Cc1ccc(O)cc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Oc1ccc(C=C(C#N)C(=O)O)cc1

Procedure:
5.6 g (30 mmol) of 2-cyano-3-(4-hydroxyphenyl) acrylic acid dissolved in 40 ml acetonitrile were stirred with 4.6 ml (33 mmol) of triethylamine until a clear solution was obtained. 0.2 g (4 mmol) 4-dimethylaminopyridine and 7.3 g (33 mmol) tert-butylpyrocarbonate were then added to the clear solution. After 2 hours reaction (the solution is at that point colourless), the solution was reduced to its half volume and washed with 200 ml of a cold 5% citric acid solution.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(O)(=O)C.S(=O)(=O)(O)O>O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([I:1])[CH:11]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(F)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
N-Iodosuccinimide (10 g, 45.0 mmol) and 4-fluoro-phenol (5.00 g, 40.0 mmol) were suspended in acetic acid (39 ml, 649.0 mmol) and stirred for 5 minutes before addition of concentrated sulphuric acid (0.79 ml, 13.4 mmol). The reaction mixture was stirred for 18 hours at room temperature before diluting with water (100 ml). The aqueous layer was extracted with dichloromethane (2×30 ml). The combined organic extracts were washed with sodium thiosulphate solution (20% aqueous, wt:v), water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (silica gel) eluting with toluene to afford the title compound as an off white solid, 4.5 g, 40% yield.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=[C:4]([CH3:19])[N:3]=1.[NH2:20][C@@H:21]([CH2:24][CH3:25])[CH2:22][OH:23]>CS(C)=O>[CH3:19][C:4]1[N:3]=[C:2]([NH:20][C@@H:21]([CH2:24][CH3:25])[CH2:22][OH:23])[C:7]([CH3:8])=[C:6]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=1
Reactant: Cc1cc(C)c(Oc2nc(C)nc(Cl)c2C)c(C)c1
Reactant: CC[C@H](N)CO
Solvent: CS(C)=O
Product: CC[C@@H](CO)Nc1nc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Temperature: 130 °C

Procedure:
A mixture of 4-chloro-2,5-dimethyl-6-(2,4,6-trimethylphenyoxy)-pyrimidine (30 mg) and 2-(S)-amino-1-butanol (0.5 ml) in 0.5 ml of DMSO was heated at 130° C. for 4 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a crude material. The crude residue was purified through silica gel column chromatography to give 24 mg of the title compound as white crystals. High MS for (C19H27N3O2) calc. 329.2103, found 329.21249; IR(KBr) 3400, 2940, 1580 cm-1; 1H NMR (CDCl3) δ 6.841 (s, 2H), 5.72 (brs, 1H), 4.45 (d, 1H), 3.82–3.96 (m, 1H), 3.72–3.9 (m, 1H), 3.5–3.6 (m, 1H), 2.27 (s, 3H), 2.21 (s, 3H), 2.08 (s, 3H), 2.02 (s, 6H), 1.4–1.7 (m, 2H), 1.03 (t, 3H) ppm.