Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:17])[CH2:13][N:14]=[N+]=[N-])[CH3:10].[NH4+].[Cl-].C([O-])(=O)C=C>O.CCOCC.C(O)C>[CH2:9]([O:11][C:12]([C:13]1[NH:14][C:4]2[CH:3]=[C:2]([Cl:1])[S:6][C:5]=2[CH:7]=1)=[O:17])[CH3:10]
Reactant: O=Cc1ccc(Cl)s1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: C=CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1cc2sc(Cl)cc2[nH]1

Procedure:
5-Chloro-thiophene-2-carbaldehyde was annulated according to Procedure H (aldehyde and azido-acetic acid ethyl ester added as ethanol solution (1.2 M of ester) such that reaction temperature maintained at 0-5° C.; reaction mixture allowed to warm to room temperature, stirred for 2 h, poured into cold saturated aqueous NH4Cl; after ether extractions, combined acrylate organic phases washed with water until aqueous phase was neutral; 0.5 M solution of crude acrylate heated for 1.5 h).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH2:24])[CH:21]([CH3:23])[CH3:22]>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([NH:24][CH2:20][CH:21]([CH3:23])[CH3:22])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CN
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl

Procedure:
The title compound was prepared from (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B2) (3.0 g, 9.77 mmol) and isobutylamine (3.57 g, 48.8 mmol) in DMSO (20 mL) at 55° C. according to the general procedure C. Obtained as a brown solid (2.26 g, 67%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.C(Cl)CCl.Cl.[CH3:30][NH:31][O:32][CH3:33]>ClCCl.C(N(CC)CC)C>[CH3:33][O:32][N:31]([CH3:30])[C:12]([CH:10]1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:11]1)=[O:14]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution containing 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (60.4 g, 0.30 mol), hydroxybenzotriazole (49 g, 0.36 mol), EDC (69.4 g, 0.36 mol), and triethyamine (142 ml) in 620 ml of dichloromethane was added N,O-dimethylhydroxyl-amine hydrochloride (35.4 g, 0.36 mol). The mixture obtained was stirred overnight at room temperature. The solution was partitioned between 500 ml of water and 200 ml of dichloromethane, and the aqueous layer was washed with 200 ml of dichloromethane. The combined organic layers were washed with 250 ml of brine, dried over magnesium sulfate, filtered and concentrated to afford tert-butyl 3-{[methoxy(methyl)amino]carbonyl}azetidine-1-carboxylate, which was used without additional purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][NH2:25].C(OCC)(=O)C>CS(C)=O>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][NH:25][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)cnc2c1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(CNc2cnc3cc(OC)ccc3n2)c(OC)c1
Yield: 94.1 %

Procedure:
2-Chloro-6-methoxyquinoxaline (0.93 g, 4.77 mmol) and (2,4-dimethoxyphenyl)methanamine (2.2 ml, 14.64 mmol) were microwaved in dimethylsulfoxide (5 mL) for 30 min at 150° C. The reaction was diluted into ethyl acetate (250 mL) and extracted with brine (3×100 mL). The crude product was purified by column chromatography (20 to 80% ethyl acetate/hexanes) to afford N-(2,4-dimethoxybenzyl)-6-methoxyquinoxalin-2-amine (1.46 g, 87% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.13 (1H, s), 7.59-7.63 (1H, m), 7.30 (1H, d, J=8.31 Hz), 7.21-7.24 (2H, m), 6.47 (1H, d, J=2.27 Hz), 6.42 (1H, dd, J=8.31, 2.27 Hz), 5.10 (1H, t, J=5.92 Hz), 4.61 (2H, d, J=5.79 Hz), 3.88 (3H, s), 3.84 (3H, s), 3.78 (3H, s). MS (LC/MS) R.T.=1.95; [M+H]+=326.23.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[C:8]([C:10]1[NH:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])[N:14]=1)#[N:9].[H-].[Na+]>>[C:8]([C:10]1[N:11]([S:3](=[O:5])(=[O:4])[N:2]([CH3:7])[CH3:1])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])[N:14]=1)#[N:9]
Reactant: N#Cc1nc(-c2ccccc2[N+](=O)[O-])c[nH]1
Reactant: CN(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: CN(C)S(=O)(=O)n1cc(-c2ccccc2[N+](=O)[O-])nc1C#N
Temperature: 0 °C

Procedure:
Dimethylsulphamoyl chloride (0.54 ml) was added to a mixture of 2-cyano-4-(2-nitrophenyl)-1H-imidazole (0.865 g) and sodium hydride (150 mg of 80% in oil). The mixture was heated under reflux for one hour and then poured into ice/water and extracted with ethyl acetate. The extract was washed with brine, dried and evaporated. The residual oil slowly solidified and was washed with ether and filtered to give 2-cyano-1-(dimethylsulphamoyl)4-(2-nitrophenyl)imidazole, m.p. 111°-4°. (Compound 4)
Reaction SMILES: C([O:8][C:9](=[O:36])[C@H:10]([CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1)[N:11]([C:13](=[O:29])[C@H:14]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:12])C1C=CC=CC=1>[Pd]>[CH2:22]([C@H:14]([CH2:15][C:16](=[O:21])[C:17]([CH3:19])([CH3:18])[CH3:20])[C:13]([N:11]([CH3:12])[C@H:10]([C:9]([OH:36])=[O:8])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1)=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN(C(=O)[C@@H](CC(=O)C(C)(C)C)Cc1ccccc1)[C@@H](Cc1c[nH]cn1)C(=O)OCc1ccccc1
Agent: [Pd]
Product: CN(C(=O)[C@@H](CC(=O)C(C)(C)C)Cc1ccccc1)[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
195 mg of N-[(R)-2-benzyl-5,5-dimethyl-4-oxohexanoyl]-N-methyl-L-histidine benzyl ester were hydrogenated in the presence of 25 mg of palladium-on-carbon (5%) for 2 hours and the N-[(R)-2-benzyl-5,5-dimethyl-4-oxohexanoyl]-N-methyl-L-histidine obtained was reacted in the usual manner with (αS,βS)-β-amino-α-[(S)-2-isopropyl-3-butenyl]cyclohexanepropanol. Chromatographic purification of the crude product obtained on silica gel with a 140:10:0.1 mixture of methylene chloride, methanol and ammonia yielded N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-α-[(R)-2-benzyl-N,5,5-trimethyl-4-oxohexanamido]imidazole-4-propionamide as a thin-layer chromatographically uniform substance, MS: 635 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:29])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[CH3:28].CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1CCCC1=O.O.[Cu]Cl>[CH3:16][O:17][C:18](=[O:29])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)=[CH:23][C:22]=1[CH3:28]
Reactant: COC(=O)CCc1ccc(O)cc1C
Reactant: Brc1cccc(OCc2ccccc2)c1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)CCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1C
Temperature: 120 °C
Yield: 50.7 %

Procedure:
A mixture of 3-benzyloxy-1-bromobenzene (14.53 g, 55.2 mmol), 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (10.72 g, 55.2 mmol) cesium carbonate (21.59 g, 66.3 mmol), and 2,2,6,6-tetramethyl-3,5-heptanedione (2.54 g, 13.8 mmol) in 1-methyl-2-pyrrolidinone (100 mL) is purged with N2, and then copper (I) chloride (2.73 g, 27.6 mmol) is added. The reaction mixture is heated to 120° C. for 18 hours under N2. The mixture is diluted with water and extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using a gradient of 19/1 to 9/1 hexanes/ethyl acetate to afford about 10.54 g (51%) of the titled compound. Rf=0.53 (100% hexanes). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C24H24O4 376, found 377 (M+1, 100%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]([N:16]([CH2:18][C:19](O)=[O:20])[CH3:17])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C(Cl)Cl>[C:12]([O:11][C:9]([N:16]([CH2:18][C:19]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH2:8])=[O:20])[CH3:17])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: Nc1ccccc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(CC(=O)Nc1ccccc1N)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
A solution of phenylenediamine (100 g, 0.924 mole) and Boc-sarcosine (175 g, 0.924 mole) in DMF (1750 mL) was cooled to -10° C. under argon, and a solution of DCC (190.8 g, 0.924 mole) in CH2Cl2 (1750 mL) was added in a slow stream over 1 hr. The temperature rose to 0° C. during the addition. The reaction was stirred overnight while the temperature was allowed to rise to RT. The white precipitate was removed by filtration, and the filtrate was diluted with H2O (3.5 L) and saturated brine (1 L). The CH2Cl2 layer was separated and the aqueous phase was extracted with EtOAc (2×1 L). The combined organic layers were washed with H2O (1 L) and brine (0.5 L), then were concentrated to a yellow residue (341 g). This was triturated with EtOAc to afford the title compound (179.4 g, 70%): mp 134-136° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].Br[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:21][O:20][C:17]1[N:18]=[CH:19][C:14]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: COc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(-c2ccc(C(=O)O)cc2)cn1
Temperature: 25 °C
Yield: 90.8 %

Procedure:
4-Carboxybenzeneboronic acid (2.87 g, 17.3 mmol), 5-bromo-2-methoxypyridine (3.25 g, 17.3 mmol), 0.4M aqueous sodium carbonate (87 ml, 34.8 mmol) and acetonitrile (86 mL) were combined under nitrogen, and palladium tetrakistriphenylphosphine (1.00 g, 0.87 mmol) added. The reaction mixture was refluxed for 3 hours, cooled to room temperature, and filtered through celite (washed celite with 50:50 acetonitrile/water). Removed acetonitrile in vacuo, diluted residue with water (100 mL) and acidified to pH 2 with 2M HCl. The precipitate which formed was collected, washed with water, and dried under high vacuum to give the product as a white powder (3.6 g, 15.7 mmol). 1H NMR (DMSO) δ 12.90 (br s, 1H), 8.56 (s, 1H), 8.08 (dd, 1H), 7.98 (d, 2H), 7.75 (d, 2H), 6.94 (d, 1H), 3.90 (s, 3H). ESI MS (M+1)+: 230.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:9][O:10][C:11]2[C:19]3[C:18]4[CH:20]=[C:21]([C:24]#[N:25])[N:22]=[CH:23][C:17]=4[NH:16][C:15]=3[N:14]=[CH:13][CH:12]=2)([CH3:8])[CH2:4][CH2:3]1.C([O-])(=O)C.[Na+].[Br:31]Br.[OH-].[Na+]>C(O)(=O)C.O>[Br:31][C:12]1[CH:13]=[N:14][C:15]2[NH:16][C:17]3[CH:23]=[N:22][C:21]([C:24]#[N:25])=[CH:20][C:18]=3[C:19]=2[C:11]=1[O:10][CH2:9][C:5]1([CH3:8])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCC(C)(COc2ccnc3[nH]c4cnc(C#N)cc4c23)CC1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CN1CCC(C)(COc2c(Br)cnc3[nH]c4cnc(C#N)cc4c23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.7 %

Procedure:
A mixture of 4-((1,4-dimethylpiperidin-4-yl)methoxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (50 mg, 0.16 mmol), sodium acetate (26 mg, 0.3 mmol), and bromine (32 L, 0.6 mmol) in acetic acid (1 mL) was stirred at ambient temperature for 10 minutes. The reaction mixture was diluted with water (1 mL) and basified to pH ˜8 by dropwise addition of 6N sodium hydroxide solution, producing a yellow precipitate. The solid was collected by centrifugation, dissolved in dimethylsulfoxide (2 mL), and purified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as a white solid (25 mg, 38%). 1H NMR (500 MHz, d6-DMSO) δ 9.02 (d, J=8.7, 1H), 8.70 (d, J=9.9, 1H), 8.43 (s, 1H), 4.21 (s, 2H), 2.81 (m, 2H), 2.62 (m, 2H), 2.45 (s, 3H), 1.97 (m, 2H), 1.68 (m, 2H), 1.30 (s, 3H), NH signal not observed. LCMS (Method D): RT=8.660 min, M+H+=414.0/416.0.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].[CH2:8](Br)[CH:9]=[CH2:10].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:10]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7])[CH:9]=[CH2:8]
Reactant: C=CCBr
Reactant: O=Cc1ncc[nH]1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCn1ccnc1C=O
Yield: 60.3 %

Procedure:
A solution of 2-imidazole carboxaldehyde (15.0 g, 156 mmol), allyl bromide (22.6 g, 187 mmol) and diisopropylethylamine (40.7 mL, 234 mmol) was stirred in N,N-dimethylformamide (500 mL) for 23 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (370 mL). The solution was washed once with a saturated solution of sodium carbonate (185 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×280 mL). The combined organic portions were dried with sodium sulfate, filtered and concentrated under reduced pressure to afford a yellow oil. The crude material was then purified by flash chromatography (99:1 CH2Cl2/methanol) to provide the desired compound (12.8 g, 60%) as yellow oil. 1H NMR (300 MHz, CDCl3, δ ppm) 5.04 (d, 2H, J=5.5 Hz), 5.11 (d, 1H, J=17.5 Hz), 5.25 (d, 1H, J=10.0 Hz), 5.90-6.05 (m, 1H), 7.16 (s, 1H), 7.30 (s, 1H), 9.81 (s, 1H); 13C NMR (75 MHz, CDCl3, ppm) 49.77, 118.61, 126.00, 131.74, 132.39, 143.17, 182.05.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:25]I.NC(N)=O.S(=O)(=O)(O)O.[N+]([O-])(O)=O>C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[I:25][C:22]1[CH:23]=[CH:24][C:19]([C:14]2[C:13]([C:8]3[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:20][CH:21]=1
Reactant: II
Reactant: c1ccc(-c2ccccc2-c2ccccc2-c2ccccc2)cc1
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: Ic1ccc(-c2ccccc2-c2ccccc2-c2ccccc2)cc1
Temperature: 116 °C
Reaction time: 2.5 h
Yield: 35 %

Procedure:
To a first mixture containing 5.0 g of quaterphenyl, 8.28 g of iodine, 75 ml of glacial acetic acid, 10 ml of carbon tetrachloride and 2.51 g of urea, a second mixture containing 7.5 ml of concentrated sulfuric acid and 2.00 ml of nitric acid (d=1.4) was added over a period of 0.5 hours while the first mixture was stirred at 115-117° C. Heating continued for another 2.5 hours. The product then was cooled, filtered, washed with sodium bisulphite (NaHSO3), water and methylene chloride. The reaction yield was 35%.
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].Cl.C([O-])(=O)CCCCCCCCCCCCCCCCC.[Mg+2].C([O-])(=O)CCCCCCCCCCCCCCCCC>O>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3]
Reactant: CN(C)C(=N)N=C(N)N
Agent: CCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: Cl
Agent: [Mg+2]
Solvent: O
Product: CN(C)C(=N)NC(=N)N

Procedure:
Metformin hydrochloride is screened through 1 mm sieve. Screened metformin hydrochloride and hydroxypropylmethylcellulose are granulated in fluid bed granulator with demineralized water and dried in the same device. Dried granulate is screened through 1 mm sieve. Obtained granulate and microcrystalline cellulose are homogenously blended in a bin blender. Pre-sieved magnesium stearate is added to the obtained blend and blended in a bin blender so that the final blend is obtained.
Reaction SMILES: Cl.[O:2]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([CH:25]3[CH2:30][O:29]C(C4C=CC=CC=4)[O:27][CH2:26]3)[CH:16]=2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)CC>CO>[NH2:24][C:22]1[C:23]2[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)=[CH:10][CH:11]=3)=[CH:16][N:17]([CH:25]([CH2:26][OH:27])[CH2:30][OH:29])[C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1COC(c2ccccc2)OC1
Agent: Cl
Solvent: CCCO
Solvent: CO
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C(CO)CO

Procedure:
Dilute hydrochloric acid (45 ml of 2M solution) was added to 5-(4-phenoxyphenyl)-7-(2-phenyl-1,3-dioxan-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (170 mg) and the mixture heated to boiling under reflux. Propan-1-ol (30 ml) was added and the mixture boiled under reflux for 6 hours and then the propanol was distilled off. The mixture was evaporated under reduced pressure to give a residue which was triturated with ethyl acetate and then filtered to give a solid which was dissolved in methanol, and purified by chromatography to give 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]propan-1,3-diol. The structure was confirmed by 1H nmr and mass spectra.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:22][CH3:23])[CH:9]=[CH:10][C:11]=2[S:13][CH2:14][CH:15](OCC)OCC)[C:6]([S:24][CH2:25][CH:26](OCC)OCC)=[CH:5][CH:4]=1.ClCCl>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:12]2[C:11]3[S:13][CH:14]=[CH:15][C:10]=3[CH:9]=[C:8]([O:22][CH3:23])[C:7]=2[C:6]2[S:24][CH:25]=[CH:26][C:5]=2[CH:4]=1
Reactant: CCOC(CSc1ccc(OC)c2c(SCC(OCC)OCC)ccc(OC)c12)OCC
Solvent: ClCCl
Solvent: Clc1ccccc1
Product: COc1cc2ccsc2c2c(OC)cc3ccsc3c12
Temperature: 25 °C

Procedure:
Polyphosphoric acid (0.29 g) was solubilized in chlorobenzene (10.0 mL) and heated at reflux for 3 hours under nitrogen. A solution of compound 3 (0.225 g, 0.464 mmol) in chlorobenzene (3.0 mL) was added dropwise to the reaction mixture. The mixture was stirring was continued at reflux overnight. After the mixture was cooled down to room temperature, dichloromethane (100 mL) was added, and the mixture was washed with NaHCO3 (saturated, 2×50 mL) and brine (50 mL). The solution was dried over Na2SO4 and concentrated under vacuum. The residual was refluxed in isopropanol (30 mL) for 2 hours. After cooling down to room temperature, compound 4 was obtained by filtration as a pale yellow solid (120 mg, 86%). 1H NMR (500 MHz, CDCl3): δ 7.59 (d, J=5.5 Hz, 2H), 7.45 (d, J=5.5 Hz, 2H), 7.44 (s, 2H), 4.19 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17]([Si:19]([CH3:22])([CH3:21])[CH3:20])#[CH:18]>C1COCC1.[Cu]I>[CH3:20][Si:19]([C:17]#[C:18][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([CH3:22])[CH3:21]
Reactant: O=Cc1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(C=O)cc1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
4-Bromobenzaldehyde (1) (185 g, 1.0 mole) was dissolved in THF (1 L) followed by addition of copper (I) iodide (7.6 g, 0.04 mol), dicholobis(triphenylphospine) palladium (II) (14.02 g, 0.02 mol) and triethylamine (151.5 g, 1.5 mol). Ethynyltrimethylsilane (109.1 g, 1.11 mol) was added from addition funnel as a solution in THF (0.2 L). The reaction was stirred at 30° C. for 30 min and then at 25° C. for 20 hours. Analysis by HPLC indicated the completion of the reaction. THF was removed and the residue was treated with hexane (1.8 L). The solid was removed by filtration and the filter cake washed with hexane (0.3 L). The combined hexane solution was washed with water (2×0.5 L). Hexane was removed in a rotovap. The residue was dissolved in EtOH (0.5 L) at 50° C. The solution was then slowly cooled to 16° C. and was stirred for 30 minutes. Product started to crystallize. The mixture was further cooled to 5° C. 1:1 of EtOH/H2O (0.24 L) was added slowly. The mixture was stirred at 5° C. for 30 minutes. Solid was collected by filtration, washed with 4:1 of EtOH/H2O (0.2 L) and dried to provide 137.0 g of product. The mother liquor was concentrated to dryness. The residue was partitioned between hexane (0.5 L) and brine (0.25 L). Hexane layer was separated and concentrated to dryness. The residue was crystallized from hexane (40 ml) and further recrystallized from 4:1 of EtOH/H2O (0.1 L) to provide second crop of aldehyde 2 (27.0 g). The combined yield for aldehyde 2 was 81%. 1H NMR (300 MHz, CDCl3) δ 0.081 (s, 9H), 7.41 (d, 2H, J=8.1 Hz), 7.63 (d, 2H, J=8.4 Hz), 9.81 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][N:3]=1.[Br:13]Br.N#N.CC(C)=O.C(Cl)(Cl)(Cl)Cl>C(O)(=O)C>[Br:13][C:10]1[C:5]2[O:4][N:3]=[C:2]([Cl:1])[C:6]=2[CH:7]=[CH:8][C:9]=1[O:11][CH3:12]
Reactant: BrBr
Reactant: COc1ccc2c(Cl)noc2c1
Agent: N#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: COc1ccc2c(Cl)noc2c1Br
Reaction time: 8 h

Procedure:
To a stirred solution of 3-chloro-6-methoxy-1,2-benzisoxazole (25 g) in acetic acid (200 ml) was added to a solution of bromine (32.6 g) in acetic acid (100 ml) dropwise under N2 at ambient temperature. The mixture was allowed to stir overnight. TLC (silica gel, 5% acetone/CCl4) revealed the presence of starting material. Additional bromine (11 g) in acetic acid (50 ml) was added, and the reaction mixture was allowed to stir overnight. The reaction was filtered and washed with water. The precipitate was collected and recrystallized from methanol to yield the desired compound, m.p. 134-135° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].O>CO>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:10]([OH:9])[CH:11]=2)[CH:7]=1
Reactant: Nc1cccc(O)c1
Reactant: Clc1cc(Cl)ncn1
Solvent: CO
Solvent: O
Product: Oc1cccc(Nc2cc(Cl)ncn2)c1

Procedure:
The reaction of 4,6-dichloropyrimidine with excess 3-hydroxyaniline in MeOH at 80 0° C. for 24 h followed by dilution with water and acidification gave the crude product which was purified by silica gel column chromatography to obtain 6-chloro N4-(3-hydroxyphenyl)-4-pyrimidineamine. 1H NMR (CD3OD): δ 8.36 (d, 1H, J=1.2 Hz), 7.15 (t, 1H, J=8.4 Hz), 6.93 (dd, 1.2 and 8.1 Hz), 6.74 (d, 1H, J=1.2 Hz), 6.55 (dd, 1.8 and 8.1 Hz); LCMS (m/e): ret. time: 19.75 min.; purity: 99%; MS (m/e): 222 (MH+).
Reaction SMILES: O1CCCC1.[CH:6]1([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19](Cl)=[N:20][OH:21])=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1.[C:23]([C:25]1[C:26]([NH2:31])=[N:27][CH:28]=[CH:29][CH:30]=1)#[CH:24].C(N(CC)CC)C>O>[CH:6]1([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[CH:24]=[C:23]([C:25]4[C:26]([NH2:31])=[N:27][CH:28]=[CH:29][CH:30]=4)[O:21][N:20]=3)=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: ON=C(Cl)Cc1ccc(OC2CCCC2)cc1
Reactant: C#Cc1cccnc1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(OC3CCCC3)cc2)no1
Temperature: 50 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-cyclopentyloxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.592 mmol) described in Manufacturing Example 78-1-4 and 3-ethynyl-pyridin-2-ylamine described in Manufacturing Example 1-2-3 (45 mg, 0.378 mmol) was added triethylamine (206 μL, 1.48 mmol), which was stirred for 3 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (44 mg, 22%).