Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:12]([O:14][CH3:15])=[O:13])#[N:2].[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.N1C=CC=CC=1>C(Cl)Cl>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([F:16])[CH:22]=2)[C:4]=1[C:12]([O:14][CH3:15])=[O:13])#[N:2]
Reactant: COC(=O)c1[nH]c2ccccc2c1C#N
Reactant: OB(O)c1cccc(F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(C#N)c2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
Activated molecular sieves (6.0 g, 27 mmol) 4 Å were placed in an oven dried flask and cooled to room temperature under nitrogen. To the flask was charged with methyl 3-cyano-1H-indole-2-carboxylate (0.45 g, 2.2 mmol), (3-fluorophenyl)boronic acid (0.94 g, 6.7 mmol), cupric acetate (0.61 g, 3.4 mmol), methylene chloride (43 mL) and pyridine (0.73 mL, 9.0 mmol). The reaction mixture was stirred at room temperature over the weekend. The mixture was filtered through a pad of Celite. The filtrate was concentrated and purified on silica gel (eluting with 0-60% EtOAc/hexane) to give the desired product (0.39 g, 59%). LCMS calculated for C17H12FN2O2(M+H)+: m/z=295.1. Found: 295.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:5]=[C:4]([Cl:20])[N:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(O)C>[Cl:20][C:4]1[N:3]=[C:2]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:5]=1
Reactant: C1COCCN1
Reactant: FC(F)(F)Oc1ccc(Nc2cc(Cl)nc(Cl)n2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: FC(F)(F)Oc1ccc(Nc2cc(Cl)nc(N3CCOCC3)n2)cc1
Temperature: 30 °C
Yield: 73.6 %

Procedure:
A mixture of compound (2,6-dichloro-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine (0.4 g, 1.23 mmol), morpholine (0.1 g, 1.16 mmol) and triethyl amine (0.5 ml, 3.66 mmol) in solvent ethanol (10 mL) was refluxed for 12 hours under nitrogen atmosphere. The reaction mixture was cooled to temperature in the range of 20-40° C. and concentrated under vacuum. The crude compound was passed through the silica gel by using 8-10% ethylacetate in pet-ether to afford the compound (6-chloro-2-morpholin-4-yl-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine (0.32 g, 69%) as white solid.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.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>[C:16]1([C:22]#[C:23][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C(#Cc1ccncc1)c1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
To a suspension of 4-bromopyridine hydrochloride (3.9 g, 20 mmol), tetrakis(triphenylphosphine)palladium (2.32 g, 2.0 mmol), triethylamine (16.8 mL, 120 mmol) in dry DMF (150 mL) is added phenylacetylene (4.2 mL, 40 mmol) at room temperature. After stirring for 3 hours at 80° C., the reaction mixture is concentrated. The residue is dissolved in CH2Cl2 (100 mL), washed with H2O, brine (50 mL), dried (MgSO4) and concentrated. The crude material is purified by chromatography (silica gel, EtOAc/hexane: 10/90) to afford the title compound as a solid (3.25 g, 91%). Mp 51-53° C. MS (+) ES: 180 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH2:8][CH3:9])=[CH:6][NH:5][C:4]=1[CH:10]=O)[CH3:2].[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C(NCC)C>C(O)C>[CH2:18]([O:17][C:15](=[O:16])[C:14]([C:12]#[N:13])=[CH:10][C:4]1[NH:5][CH:6]=[C:7]([CH2:8][CH3:9])[C:3]=1[CH2:1][CH3:2])[CH3:19]
Reactant: CCOC(=O)CC#N
Reactant: CCc1c[nH]c(C=O)c1CC
Solvent: CCO
Solvent: CCNCC
Product: CCOC(=O)C(C#N)=Cc1[nH]cc(CC)c1CC
Temperature: 25 °C

Procedure:
The 3,4-diethyl-2-formylpyrrole (14.1 g, 93.1 mmol) was dissolved in 200 mL of dry ethanol, and ethyl cyanoacetate (20 mL, 137.9 mmol) and diethylamine (20 mL, 193.3 mmol) were added to the solution. The reaction mixture was heated to reflux under an inert atmosphere and stirred under reflux for 2 hours, after which it was cooled to room temperature and then placed in an ice bath. The resulting dark suspension was filtered through a medium filter, and the light brown solids were washed with cold ethanol. The collected filtrates were concentrated under reduced pressure, precipitating more solids. The thick suspension was filtered, and the combined solids were separated and purified to give 2-cyano-3-(3,4-diethyl -1H-pyrrol-2-yl) acrylic acid ethyl ester, a compound of formula 201 in which R1 and R2 are both ethyl.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH:4]=[CH2:5].[Br:7][C:8]1[CH:13]=[CH:12][C:11](F)=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1>C1COCC1>[CH2:3]([O:6][C:11]1[CH:12]=[CH:13][C:8]([Br:7])=[CH:9][C:10]=1[N+:15]([O-:17])=[O:16])[CH:4]=[CH2:5]
Reactant: C=CCO
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOc1ccc(Br)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a mixture of anhydrous THF (200 mL) and 95% NaH (757 mg, 29.96 mmol) at 0° C. under N2 was added allyl alcohol (2.04 mL, 29.96 mmol) dropwise. After 0.5 hour, 4-bromo-1-fluoro-2-nitro-benzene (5.07 g, 23.04 mmol) was added dropwise. The reaction was warmed from 0° C. to room temperature under N2 overnight, and inorganic salt was filtered. The filtrate was concentrated with silica gel powder (20 g), and purified by flash chromatogrphy eluting with 10% ethyl acetate in hexanes (1 L) and 20% ethyl acetate in hexanes (1 L) to give the title compound (5.06 g, 85%). MS (DCI) m/z 257.35 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 4.65–4.70 (m, 2 H) 5.35 (m, 1 H) 5.48 (m, 1 H) 6.02 (m, 1 H) 6.97 (d, J=9.16 Hz, 1 H) 7.61 (dd, J=8.99, 2.54 Hz, 1 H) 7.97 (d, J=2.37 Hz, 1 H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[N+:13]([C:16]1[N:17]=[C:18]2[N:23]([CH:24]=1)[CH2:22][CH2:21][C@H:20]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]3)=[CH:29][CH:28]=1)[O:19]2)([O-:15])=[O:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.ClCCCl>[N+:13]([C:16]1[N:17]=[C:18]2[N:23]([CH:24]=1)[CH2:22][CH2:21][C@H:20]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][CH:36]([NH:8][C:7]4[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=4)[CH2:35][CH2:34]3)=[CH:29][CH:28]=1)[O:19]2)([O-:15])=[O:14]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCC(Nc4ccc(OC(F)(F)F)cc4)CC3)cc1)CC2
Temperature: 25 °C
Reaction time: 21 h

Procedure:
4-(Trifluoromethoxy)aniline (1.271 ml) was added to a 1,2-dichloroethane solution (50 ml) of 1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-one (2.5 g). Subsequently, sodium triacetoxyborohydride (1.992 g) and acetic acid (0.538 ml) were added thereto and the mixture was stirred at room temperature for 21 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1) and recrystallized from ethyl acetate to afford the title compound as a yellow powder (2.55 g).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][OH:29]>CN(C)C=O>[OH:29][CH2:28][CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: OCCBr
Reactant: COc1ccc(COC(=O)c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)c2ccc(OCCO)cc2)cc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution of 4methoxybenzyl 4-hydroxybenzoate (7.0 g, 27 mmole) in dry N,N-dimethylformamide (50 ml) was added potassium carbonate (4.15 g, 30 mmole) and 2-bromoethanol. The mixture was stirred 48 hours at 80° C., evaporated under reduced pressure and ethyl acetate and water were added. The organic phase was washed five times with water and dried with sodium sulfate. The solution was evaporated under reduced pressure and the product was isolated by silica gel column chromatography with hexane/ethyl acetate.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.N>C1(C)C=CC=CC=1.O>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][O:3][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][O:20]1)[CH3:7]
Reactant: CCOC(=O)CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)COC1CCCCO1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
100.00 kg (960.52 mol) ethyl glycolate (A) were dissolved in 180.0 L toluene and 365.22 g (1.92 mol) 4-toluenesulphonic acid monohydrate were added. At 20° C. a solution of 80.80 kg (960.52 mol) 3,4-dihydro-2H-pyran was added dropwise to the reaction mixture obtained and then the mixture was washed with 20.0 L toluene. The reaction mixture was stirred for 1 hour at 20° C. and after the reaction was complete it was combined with 100.0 L water and 6.53 kg (96.05 mol) ammonia solution (25%). After phase separation the organic phase was washed with 100.0 L water and then the solvent was distilled off completely in vacuo.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].F[C:25]1[C:30]([CH:31]2[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]2)=[CH:29][CH:28]=[CH:27][N:26]=1>CN1C(=O)CCC1.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:25]2[C:30]([CH:31]3[CH2:32][CH2:33][CH:34]([OH:37])[CH2:35][CH2:36]3)=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: OC1CCC(c2cccnc2F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: OC1CCC(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1
Temperature: 200 °C

Procedure:
To a vial containing 4-(benzo[d]thiazol-2-ylamino)phenol (819 mg, 3.38 mmol) was added cesium carbonate (918 mg, 2.82 mmol) followed by 4-(2-fluoropyridin-3-yl)cyclohexanol (220 mg, 1.127 mmol) as a solution in NMP (7.5 mL). The reaction mixture was heated to 200° C. for 2.5 h with microwave irradiation. The reaction mixture was diluted with water and extracted with 15% IPA:chloroform before drying over magnesium sulfate, filtering, and concentrating to a dark brown residue under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1.[CH:34](=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCC2CCCCC2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN(Cc2ccccc2)CC2CCCCC2)CC1
Yield: 52.2 %

Procedure:
4-Amino-5-chloro-N-((1-(5-(cyclohexylmethylamino)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide (0.79 g) as starting compound, benzaldehyde (0.19 g) and sodium cyanoborohydride (0.23 g) were reacted and treated in the same manner as in Example 136 to give 0.49 g of 4-amino-N-((1-(5-(N-benzyl-N-(cyclohexylmethyl)amino)pentyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:19][CH:18]3[CH:14]([N:15](C(OCC4C5C=CC=CC=5C5C4=CC=CC=5)=O)[CH2:16][CH2:17]3)[CH2:13]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.N1CCCCC1>C(Cl)Cl>[Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:19][CH:18]3[CH:14]([NH:15][CH2:16][CH2:17]3)[CH2:13]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC2CN(c3nc(Cl)cc4nccnc34)CC21
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Clc1cc2nccnc2c(N2CC3CCNC3C2)n1

Procedure:
A solution of (9H-fluoren-9-yl)methyl 5-(7-chloropyrido[4,3-b]pyrazin-5-yl)hexahydropyrrolo[3,4-b]pyrrole-1 (2H)-carboxylate (140 mg) and piperidine (2 mL) in CH2Cl2 (8 mL) was stirred at room temperature for 3 hours. The volatiles were removed under reduced pressure. The residue was treated with EtOAc/H2O, separated, and the aqueous solution was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography to afford the title compound. MS (m/z): 276 (M+H)+.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[CH:10]=[CH:9][N:8]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH:30]1([NH2:33])[CH2:32][CH2:31]1.C(N(CC)CC)C>O1CCCC1>[C:1]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:33][CH:30]3[CH2:32][CH2:31]3)=[O:29])=[CH:18][CH:19]=2)[CH:10]=[CH:9][N:8]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Nc1cc(Oc2ccc(NC(=O)Oc3ccccc3)cc2)ccn1
Reactant: NC1CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)Nc1cc(Oc2ccc(NC(=O)NC3CC3)cc2)ccn1

Procedure:
Phenyl N-(4-[2-(butyroylamino)pyridin-4-yl]oxyphenyl}carbamate (0.116 g), cyclopropylamine (0.034 g), triethylamine (0.041 ml) and tetrahydrofuran (10 ml) were heated together in a sealed tube at 100° C. for 1 hour. NH type silica gel was added to the reaction solution, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (ethyl acetate). The solvent was distilled off under reduced pressure, ethyl acetate and hexane were added to the residue, and the precipitated solid was filtered out to obtain 20 mg of the target substance as a white solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:26])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[C:17]([O:24]C)[CH:18]=[CH:19][CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.B(Br)(Br)Br>C(Cl)Cl>[CH:1]1([NH:4][C:5](=[O:26])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[C:17]([OH:24])[CH:18]=[CH:19][CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: COc1cccc2c(=O)n(-c3cc(C(=O)NC4CC4)ccc3C)cnc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(O)cccc2c1=O

Procedure:
Using an analogous procedure to that described in paragraph (A) in the portion of Example 24 which is concerned with the preparation of starting material, 2-amino-3-methoxybenzoic acid was reacted with 3-amino-N-cyclopropyl-4-methylbenzamide to give N-cyclopropyl-3-(8-methoxy-4-oxoquinazolin-3(4H)-yl)-4-methylbenzamide (AZ12304507); NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.68 (m, 2H), 2.12 (s, 3H), 2.84 (m, 1H), 3.94 (s, 3H), 7.49 (m, 3H), 7.74 (d, 1H), 7.83 (s, 1H), 7.89 (d, 1H), 8.24 (s, 1H), 8.44 (s, 1H); Mass Spectrum: M+H+ 350. B) Using an analogous procedure to that described in paragraph (B) in the portion of Example 24 which is concerned with the preparation of starting material, N-cyclopropyl-3-(8-methoxy-4-oxoquinazolin-3(4H)-yl)-4-methylbenzamide was reacted with a 1M solution of boron tribromide in methylene chloride to give N-cyclopropyl-3-(8-hydroxy-4-oxoquinazolin-3(4H)-yl)-4-methylbenzamide; Mass Spectrum: M+H+ 336.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])[CH:8]=1)#[N:2].Cl.[OH-:20].[Na+]>>[C:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])[CH:8]=1)(=[O:20])[NH2:2]
Reactant: Cc1cccc(C)c1-n1cc(C#N)c(=O)[nH]c1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Cc1cccc(C)c1-n1cc(C(N)=O)c(=O)[nH]c1=O

Procedure:
A mixture of 5-cyano-1-(2,6-dimethylphenyl)uracil (0.01 mol) and 50 ml of NaOH (2.5 N) is heated for 2 hours at about 90°. After cooling, a small amount of dilute HCl is added to precipitate product. The mixture is filtered to the collected precipitate washed with water to yield 5-carbamoyl-1-(2,6-dimethylphenyl)uracil.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:9]([Si](C)(C)C)=[N+:10]=[N-:11]>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:9]=[N:10][NH:11][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: c1ccc(-c2c[nH]nn2)cc1
Temperature: 100 °C

Procedure:
To a stirred solution of phenylacetylene (1.098 ml, 10 mmol) in abs. toluene (10 ml) was added azidotrimethylsilane (2.65 ml, 20.00 mmol) in one portion. The reaction was heated at 100° C. for 3 days, whereupon was cooled to room temperature and toluene was removed by vacuum. The residue was partitioned between DCM and water. The organic phase was dried over MgSO4 and filtered. After evaporation the crude product was chromatographed in petroleumether:EtOAc=2:1. (Yield: 355 mg, 24%).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[CH:12][C:11]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:18][C:10]2=3)=[CH:5][CH:4]=1.[H-].[Na+].S(Cl)([Cl:34])=O.C([O-])(O)=O.[Na+]>C1COCC1.CN(C=O)C>[Cl:34][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[CH:12][C:11]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:18][C:10]2=3)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc(CO)cc2)c1-c1ccccc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc(CCl)cc2)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of the compound of Example 88 (130 mg, 0.32 mmol) in THF (2 mL) was added NaH (14 mg of 60% dispersion in oil, 0.35 mmol). DMF (0.5 mL) was added to aid solubility and the reaction was stirred for 1 h. Thionyl chloride (25 μL, 0.35 mmol) was added to the reaction mixture cooled in an ice-bath. The mixture was stirred in the ice-bath for 30 mins before quenching the reaction with water (20 mL) and basifying with NaHCO3(aq). The product was extracted into DCM (2×15 mL) and the combined DCM layers dried over MgSO4, filtered and concentrated in vacuo to give ethyl 7-(4-chloromethylphenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate LCMS (ES+) RT 3.97 minutes, 424 (M+H)+. To a solution of this compound in DMF (1 mL) was added 2-methylimidazole (13 mg, 0.16 mmol) and caesium carbonate (52 mg, 0.16 mmol) and the mixture heated at 80° for 3 h. DMF was removed in vacuo and the residue purified by column chromatography (silica, 40–100% EtOAc in isohexane followed by 5% MeOH in DCM) and also mass directed hpic to give the title compound as a solid (3 mg). δH (MeOH-d4) 7.47–7.27 (10 H, m), 7.06 (1H, d, J 1.4 Hz), 6.82 (1H, d, J 1.4 Hz), 6.50 (1H, d, J 9.6 Hz), 5.26 (2H, s), 4.00 (2H, q, J 7.1 Hz), 2.28 (3H, s), 0.99 (3H, t, J 7.1 Hz). LCMS (ES+) RT 2.53 minutes, 470 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]([C:10]([OH:12])=[O:11])[C@@H:7]([CH3:9])[OH:8].[CH3:13]O>>[NH2:5][C@@H:6]([C@H:7]([OH:8])[CH3:9])[C:10]([O:12][CH3:13])=[O:11]
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)[C@@H](C)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
109 ml (1.5 mol) of thionyl chloride are added dropwise at 0° C. with strong cooling to 240 ml of methanol. 60 g (0.5 mol) of L-threonine are then added and the mixture is stirred at room temperature for 2 days, a clear solution resulting. After concentration, 85 g of a colorless oil are obtained.
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:10]=2)[C:5]1=O.Cl>O1CCCC1.CO>[CH3:3][C:4]1[CH2:12][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[C:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:10]=2
Reactant: CC(C)Cc1ccc2c(c1)CC(C)C2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1=Cc2ccc(CC(C)C)cc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
2.4 g (62 mmol) of sodium borohydride were added to a solution of 8.3 g (41 mmol) of 1 in 50 ml of tetrahydrofuran/methanol (2:1), and the mixture was stirred at room temperature for 16 hours. 50 ml of conc. aqueous HCl were subsequently added, and the mixture was extracted 3 times with 50 ml of diethyl ether in each case. The combined organic phases were dried (MgSO4) and freed from solvent on a rotary evaporator. The residue was taken up in 100 ml of toluene, 0.4 g of p-toluenesulfonic acid was added, and the mixture was refluxed for 2 hours. The reaction mixture was washed twice with 50 ml of saturated aqueous NaHCO3 solution in each case and freed from solvent on a rotary evaporator. The residue was purified by chromatography on 400 g of silica gel (hexane), giving 7.17 g (95%) of 2 as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([CH3:31])[O:11][C@H:10]1[CH2:32][CH2:33][CH2:34][OH:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl>[CH3:45][S:46]([O:35][CH2:34][CH2:33][CH2:32][C@@H:10]1[O:11][C@@H:12]([CH3:31])[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:9]1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:48])=[O:47]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1O[C@@H](CCCO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1O[C@@H](CCCOS(C)(=O)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 1 h
Yield: 102.3 %

Procedure:
To a solution of 3-(2,3,4-tri-O-benzyl-α-L-fucopyranosyl)propanol [ML-36 step D] (10.6 g, 22.2 mmol) and Hunig's Base (4.66 mL, 26.7 mmol) in anhydrous DCM (100 mL) cooled in an ice bath was added dropwise methanesulfonyl chloride (1.9 mL, 24.5 mmol). After complete addition the mixture was stirred at ice bath temperature for 1 hour. Mixture washed with water (100 mL), sat. NaCl (50 mL); dried over Na2SO4, filtered and evaporated to give the title compound (12.6 g, 100%). 1H NMR (CDCl3) δ 7.37 (15H, m), 4.80 (2H, m), 4.68 (2H, m), 4.63 (1H, d, J=11.8 Hz), 4.53 (1H, J=11.8 Hz), 4.22 (2H, m), 4.00 (1H, d, J=9.8 Hz), 3.94 (1H, m), 2.99 (3H, s), 1.88 (1H, m), 1.75 (2H, m), 1.62 (1H, m), 1.31 (3H, d, J=6.6 Hz).