Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:9]2[C:10](=[O:14])[CH:11]=[CH:12][O:13][C:8]=2[CH:7]=1)(=[O:4])=[O:3].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[C:24]([N:5]([C:6]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:9]2[C:10](=[O:14])[CH:11]=[CH:12][O:13][C:8]=2[CH:7]=1)[S:2]([CH3:1])(=[O:3])=[O:4])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CS(=O)(=O)Nc1cc2occc(=O)c2cc1Oc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CS(=O)(=O)N(C(=O)c1ccccc1)c1cc2occc(=O)c2cc1Oc1ccccc1

Procedure:
7-Methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was reacted with benzoyl chloride in the presence of aluminum chloride to obtain 7-(N-benzoyl-N-methylsulfonylamino)-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]([NH2:25])=[O:24])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[F:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]([NH2:25])=[O:24])[CH:21]=4)[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Cn1cc(-c2cc3c(-c4cccc(F)n4)n[nH]c3cn2)cn1
Reaction time: 18 h

Procedure:
A mixture of 60 mg (0.142 mmol) of 2-(4-(3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1H-pyrazol-1-yl)acetamide and 2 ml of trifluoroacetic acid was stirred for 18 hours. The mixture was concentrated in vacuum, the residue stirred with 5 ml of saturated aqueous sodium bicarbonate for 30 min. The precipitate was collected by filtration, washed with water and recrystallized from methanol affording 35 mg (26%) of 178 over 4 steps. ESI MS m/z 338.0 (M+1). 1H NMR (400 MHz, DMSO): 14.02 (s, 1H), 9.10 (s, 1H), 8.46 (s, 1H), 8.28 (s, 1H), 8.17-8.09 (m, 2H), 7.99 (s, 1H), 7.51 (s, 1H), 7.28 (s, 1H), 7.20 (dt, J=5.4, 2.7 Hz, 1H), 4.84 (s, 2H)
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[O:16][C:15](=[O:17])[C:14]4[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=4[N:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:15](=[O:17])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[NH:12][C:11]([N:8]2[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]2)=[O:16])=[N:24][CH:25]=1
Reactant: O=c1oc(N2CCC3(CC2)OCCO3)nc2ccccc12
Reactant: Nc1ccc(Cl)cn1
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1NC(=O)N1CCC2(CC1)OCCO2

Procedure:
Using a similar procedure to that described in example 51-D, 2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-4H-3,1-benzoxazin-4-one (1.30 g, 4.51 mmol) and 2-amino-5-chloropyridine (573 mg, 4.51 mmol) yielded, after recrystallization from EtOAc, 880 mg (47%) of the titled compound.
Reaction SMILES: Cl.Cl[C:3]1[N:4]=[CH:5][C:6]2[N:12]([CH3:13])[C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH2:9][N:8]([C@@H:17]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]3)[C:7]=2[N:24]=1.[NH2:25][C:26]1[CH:37]=[CH:36][C:29]([C:30]([NH:32][CH:33]2[CH2:35][CH2:34]2)=[O:31])=[CH:28][C:27]=1[O:38][CH3:39]>C(O)C.O>[CH:33]1([NH:32][C:30](=[O:31])[C:29]2[CH:36]=[CH:37][C:26]([NH:25][C:3]3[N:4]=[CH:5][C:6]4[N:12]([CH3:13])[C:11](=[O:14])[C:10]([CH3:15])([CH3:16])[CH2:9][N:8]([C@@H:17]5[CH2:21][CH2:20][C:19]([F:22])([F:23])[CH2:18]5)[C:7]=4[N:24]=3)=[C:27]([O:38][CH3:39])[CH:28]=2)[CH2:34][CH2:35]1
Reactant: COc1cc(C(=O)NC2CC2)ccc1N
Reactant: CN1C(=O)C(C)(C)CN([C@@H]2CCC(F)(F)C2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)NC2CC2)ccc1Nc1ncc2c(n1)N([C@@H]1CCC(F)(F)C1)CC(C)(C)C(=O)N2C
Temperature: 85 °C
Reaction time: 48 h
Yield: 55.6 %

Procedure:
Concentrated hydrochloric acid (52 μl) was added to a mixture of (R)-2-chloro-9-(3,3-difluorocyclopentyl)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (100 mg, 0.29 mmol) and 4-amino-N-cyclopropyl-3-methoxybenzamide (90 mg, 0.44 mmol) in ethanol (1.4 mL) and water (5.2 mL). The reaction mixture was heated to 85° C. and stirred for 48 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with an aqueous saturated solution of sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a white solid (83 mg, 56% yield).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.Br[C:16]1[C:24]2[C:19](=[CH:20][C:21]([S:25]([N:28](CC3C=CC(OC)=CC=3OC)[C:29]3[S:33][N:32]=[CH:31][N:30]=3)(=[O:27])=[O:26])=[CH:22][CH:23]=2)[N:18]([CH3:45])[CH:17]=1>>[CH3:45][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[C:21]([S:25]([NH:28][C:29]3[S:33][N:32]=[CH:31][N:30]=3)(=[O:26])=[O:27])[CH:20]=2)[C:16]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=2)=[CH:17]1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Product: Cn1cc(-c2ccc(OC(F)(F)F)cc2)c2ccc(S(=O)(=O)Nc3ncns3)cc21

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using (4-(trifluoromethoxy)phenyl)boronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 1-methyl-N-(1,2,4-thiadiazol-5-yl)-3-(4-(trifluoromethoxy)phenyl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.90 (s, 3 H) 7.41 (m, J=8.13 Hz, 2 H) 7.52-7.58 (m, 1 H) 7.74-7.79 (m, 2 H) 7.88-8.00 (m, 4 H). m/z (ESI) 454.0 (M+H)+.
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][CH:10]1[C:15](=[O:16])[N:14]2[CH:17]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:18](=[O:24])[N:19]([CH:21]([CH3:23])[CH3:22])[CH2:20][CH:13]2[N:12]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=2[Cl:43])(=[O:35])=[O:34])[CH2:11]1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH:17]2[N:14]3[C:15](=[O:16])[CH:10]([NH:9][C:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:7])[CH2:11][N:12]([S:33]([C:36]4[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=4[Cl:43])(=[O:35])=[O:34])[CH:13]3[CH2:20][N:19]([CH:21]([CH3:23])[CH3:22])[C:18]2=[O:24])=[CH:27][CH:28]=1
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Reactant: O=C(Cl)C1CCCC1
Product: CC(C)N1CC2N(C(=O)C(NC(=O)C3CCCC3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O

Procedure:
Synthesis took place in analogy to Example 22 using cyclopentanecarbonyl chloride and 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW=654.12 (calculated, monoisotopic); measured value (M+H)+: 655.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:5][NH:6][C:7]1[C:12]([CH:13]=[O:14])=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=1.[Li].[CH3:23][N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:5][NH:6][C:7]1[C:12]([CH:13]([OH:14])[C:25]2[N:24]([CH3:23])[CH:28]=[CH:27][N:26]=2)=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=1
Reactant: COc1ccc(CNc2nc(SC)ncc2C=O)cc1Cl
Reactant: Cn1ccnc1
Agent: [Li]
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(SC)ncc2C(O)c2nccn2C)cc1Cl

Procedure:
A solution of 4-(3-chloro-4-methoxybenzylamino)-5-formyl-2-methylthiopyrimidine 0.5 g in tetrahydrofuran 20 ml is reacted at −78° C. with lithium salt of 1-methylimidazole 0.394 ml in the same manner as Example 86 to give 4-(3-chloro-4-methoxybenzylamino)-5-[(hydroxy)(1-methyl-2-imidazolyl)methyl]-2-methylthiopyrimidine. Thus obtained compound is oxidized at room temperature with manganese dioxide in chloroform and then the oxidized compound is post-treated in the same manner as Example 86 to give 4-(3-chloro-4-methoxybenzylamino)-5-(1-methyl-2-imidazolylcarbonyl-2-methylthiopyrimidine 0.5913 g. mp 158–159° C.
Reaction SMILES: [OH:1][CH:2]([CH2:35][OH:36])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:8](O)=[O:9].[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[OH:1][CH:2]([CH2:35][OH:36])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH:23][S:24]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)(=[O:26])=[O:25])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:8]([NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:9]
Reactant: Nc1ccccc1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(C(=O)O)cc(OCC(O)CO)c2Oc2cccc(OC)c2)cc1
Product: COc1ccc(S(=O)(=O)Nc2cc(C(=O)Nc3ccccc3)cc(OCC(O)CO)c2Oc2cccc(OC)c2)cc1

Procedure:
In analogy to Example 121, by coupling 3-(2,3-dihydroxy-propoxy)-5-(4-methoxy-benzenesulphonylamino)-4-(3-methoxy-phenoxy)-benzoic acid with aniline there was obtained 3-(2,3-dihydroxy-propoxy)-5-(4-methoxy-benzenesulphonylamino)-4-(3-methoxy-phenoxy)-N-phenyl-benzamide as a foam.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32](=[O:37])[NH:33][CH2:34][CH2:35][NH2:36])([CH3:30])([CH3:29])[CH3:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:24]([NH:36][CH2:35][CH2:34][NH:33][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:37])=[O:26])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)NCCN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 300 mg (0.82 mmol) of N2-[(benzyloxy)carbonyl]-N5-(tert-butoxycarbonyl)-L-ornithine and 171 mg (1.06 mmol) of tert-butyl-(2-aminoethyl)carbamate are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 204 mg (1.06 mmol) of EDC and 33 mg (0.25 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried under high vacuum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][CH2:11][OH:12])[C:6]=2[C:13]=1[F:14].P([O-])([O-])([O-])=[O:16].[Na+].[Na+].[Na+].CC1(C)N([O])C(C)(C)CCC1.[O-]Cl=O.[Na+].[O-]Cl.[Na+].[O-]S([O-])=O.[Na+].[Na+].[OH-].[Na+]>O.CC#N>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:16])=[O:12])[C:6]=2[C:13]=1[F:14]
Reactant: O=P([O-])([O-])[O-]
Reactant: OCCn1cnc2ccc(F)c(F)c21
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)Cn1cnc2ccc(F)c(F)c21
Temperature: 42 °C
Reaction time: 48 h

Procedure:
2-(6,7-difluoro-1H-benzimidazol-1-yl)ethanol (2.96 g, 15 mmol) is taken into 75 ml of MeCN and sodium phosphate buffer (56 ml, 0.67 M, pH 6.8) and the mixture is heated to 42° C. TEMPO (165 mg, 1.05 mol) is added followed by the simultaneous dropwise addition of a solution of NaClO2 (3.38 g, 80% pure, 30 mmol in 15 ml water) and a solution of bleach (350 μL of 6% NaOCl in 7.5 mL water) over 1.5 hours. After 48 hrs, the same quantities of NaClO2 and bleach are added. After a further 24 hours, TEMPO (165 mg, 1.05 mol) is added and the reaction is stirred for 72 hrs. The darkened reaction is allowed to cool to room temperature followed by the dropwise addition of 30 ml of a saturated solution of Na2SO3 (exothermic). The reaction becomes almost colourless. Using 2 N NaOH, the pH is raised to 9.2 and the reaction is extracted 4 times with ethyl acetate. The pH is then lowered to 3.8 with 2 N HCl and the solution allowed to stand for 48 hours. 1.98 grams of white crystalline material is recovered. The mother liquor is reduced to half the volume and allowed to stand. A further 260 mg is collected. (Combined yield 2.23 g, 70%)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15](Br)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1.[NH2:18][C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1
Reactant: Nc1cnccn1
Reactant: Cc1ccc(Br)c(C(=O)Nc2ccn(C)n2)n1
Product: Cc1ccc(Nc2cnccn2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Bromo-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of Example 78, step 3 using Aminopyrazine instead of 3-Amino-1-methyl-pyrazole to yield the final compound as a yellow solid, MS (ISP): m/e=310.3 (M+H+).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:33]CCl>C(O)C>[ClH:33].[C:24]1([N:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCCN(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOCCN(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The ester prepared in Example 1 (3.5 g, 8.8 mmol) was dissolved in ethanol (10 ml) and a 12 N sodium hydroxide solution (1.5 ml) was added. The reaction mixture was stirred at room temperature for 5 h. A concentrated hydrochloric acid solution (2.2 ml) was added with cooling of the reaction vessel in an ice-bath and dichloromethane (300 ml) was added. The resulting emulsion was dried (Na2SO4) and the solvent evaporated in vacuo to give a residue which was crystallised from acetone. This afforded 1.5 g (43%) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][S:8][C:9]2[N:10]=[C:11]([Cl:19])[C:12]3[S:17][C:16](Br)=[N:15][C:13]=3[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C(N(CC)CC)C>C(#N)C>[C:30]([O:29][C:27]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:16]2[S:17][C:12]3[C:11]([Cl:19])=[N:10][C:9]([S:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[N:14][C:13]=3[N:15]=2)[CH2:22][CH2:23]1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc3nc(SCc4ccccc4)nc(Cl)c3s2)CC1
Temperature: 35 °C
Reaction time: 24 h
Yield: 57.5 %

Procedure:
5-Phenylmethylthio-2-bromo-7-chloro-thiazolo[4,5-d]pyrimidine (WO 00/09511) (525 mg, 1.4 mmol), 4-amino-1-N-Boc-piperidine (339 mg, 1.7 mmol) and triethylamine (196 μL, 1.4 mmol) were dissolved in anhydrous acetonitrile (15 mL) and the mixture was stirred under a nitrogen atmosphere at 35° C. for 24 hours. The mixture was filtered and the remaining solid was washed with acetonitrile. After drying in air for 48 hours, 396 mg (57% yield) of the title compound was obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[C:21]1[S:25][C:24]([NH2:26])=[N:23][CH:22]=1>C1COCC1>[NH2:26][C:24]1[S:25][C:21]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:10][N:9]=3)=[CH:6][CH:7]=2)=[CH:22][N:23]=1
Reactant: CCOC(=O)c1cc(-c2ccc(O)cc2)no1
Reactant: Nc1ncc(Br)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(Oc3cnc(N)s3)cc2)no1
Reaction time: 0.17 h
Yield: 20.7 %

Procedure:
To a stirred solution of ethyl 3-(4-hydroxyphenyl)isoxazole-5-carboxylate (0.97 g, 4.16 mmol) in dry THF, sodium hydride (60%, 0.25 g, 6.09 mmol) was added at room temperature and stirred for 10 min. 5-bromothiazol-2-amine (0.5 g, 2.77 mmol) dissolved in 10 mL dry THF was added and continued to stir for additional 1 hr. Reaction mixture was poured on ice cold water and extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with water, brine and dried over sodium sulfate, filtered and concentrated under reduced pressure to get crude material which was purified by silica gel column chromatography using 40-50% ethyl acetate in hexane to provide the title compound (0.19 g).
Reaction SMILES: [Si:1]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[Mg]Br.CCCCC>C1COCC1>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[Si:1]([O:5][CH2:6][CH3:7])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13]
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Reactant: CCO[Si](OCC)(OCC)OCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCO[Si](OCC)(OCC)c1c(C)cc(C)cc1C
Temperature: 23 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To tetraethyl orthosilicate (3.30 mL, 15.0 mmol, 3.00 equiv) in 10 mL of THF at −30° C. was added 2,4,6-trimethylphenylmagnesium bromide solution (1.0 M in THF, 5.0 mL, 5.0 mmol, 1.0 equiv) dropwise over 10 min. After stiffing at −30° C. for 1 h, the reaction mixture was warmed to 23° C. and was further stirred for 12 h. The reaction mixture was poured into 100 mL of pentane, and was washed three times with water (3×20 mL) and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure. Bulb-to-bulb distillation (125° C., 0.5 Torr) afforded 0.87 g of the title compound as a colorless oil (62% yield). Rf=0.14 (hexanes). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23° C., δ): 6.80 (s, 2H), 3.83 (q, J=7.0 Hz, 6H), 2.51 (s, 6H), 2.26 (s, 3H), 1.24 (t, J=7.0 Hz, 9H). 13C NMR (125 MHz, CDCl3, 23° C., δ): 145.92, 139.79, 128.81, 124.99, 58.10, 23.73, 21.08, 18.15.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].[CH2:6]([OH:11])[CH2:7][CH2:8][CH2:9]O>C1C=CC=CC=1>[C:1]([O:5][CH2:9][CH2:8][CH2:7][CH2:6][O:11][C:1](=[O:4])[C:2]#[CH:3])(=[O:4])[C:2]#[CH:3]
Reactant: C#CC(=O)O
Reactant: OCCCCO
Solvent: c1ccccc1
Product: C#CC(=O)OCCCCOC(=O)C#C

Procedure:
The 1,4-butanediol dipropiolate was prepared as follows. A solution of 27.5 g. (0.393 mole) of propiolic acid in 75 ml of benzene was reacted with 16.07 g. (0.179 mole) of 1,4-butanediol in the presence of 1.5 g. paratoluenesulfonic acid as a catalyst. The reaction mixture was stirred and heated to reflux under nitrogen until 6.44 g. of water was azeotroped over into a Dean-Stark trap. The reaction mixture was washed with 10% sodium carbonate aqueous solution until the pH value of the mixture was basic, then washed with deionized water several times and dried over sodium carbonate. The solvent was removed on a Rotavapor and 1,4-butanediol dipropiolate was obtained in 90% yield as white crystals with a melting point of 59° C. The structure of 1,4-butanediol dipropiolate is as follows:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.Br[C:24]1[C:25](=[O:33])[N:26]([CH2:30][CH2:31][CH3:32])[CH:27]=[CH:28][CH:29]=1>>[O:33]=[C:25]1[C:24]([N:17]2[CH2:16][CH2:15][C:12]3([C:11](=[O:20])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:19][CH2:18]2)=[CH:29][CH:28]=[CH:27][N:26]1[CH2:30][CH2:31][CH3:32]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: CCCn1cccc(Br)c1=O
Product: CCCn1cccc(N2CCC3(CC2)CCN(c2ccc(OC(F)(F)F)cc2)C3=O)c1=O

Procedure:
The title compound was prepared in analogy to example 1 step D from a mixture of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C) and 3-bromo-1-propyl-1H-pyridin-2-one. Off-white solid. MS (ESI): 450.2 (MH+)
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[N:36][OH:37])[CH2:10][O:11][CH:12]([CH:34]=[CH2:35])[CH2:13][O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C=CC(O)=CC=1)O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]12[CH2:10][O:11][CH:12]([CH2:13][O:14][C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:34]1[CH2:35][O:37][NH:36]2
Reactant: C=CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCC(=NO)c1cccc(F)c1F
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: Fc1cccc(C23COC(COC(c4ccccc4)(c4ccccc4)c4ccccc4)C2CON3)c1F
Temperature: 112.5 °C
Reaction time: 13 h
Yield: 66.1 %

Procedure:
To a solution of 1-(2,3-Difluorophenyl)-2-(1-(trityloxy)but-3-en-2-yloxy)ethanone oxime 16 (20.0 g, 0.0400 mol, 1.0 equiv.) in toluene (140 mL) was charged hydroquinone (0.0882 g, 0.008 mol, 0.2 equiv.). The reaction mixture was heated to reflux (110-115° C.) and held for 13 hours. The reaction mixture was cooled to 20-25° C. and then concentrated under vacuum (T<45° C.). The solvents were chased with 2-propanol (100 mL). To the crude residue was charged isopropanol (140 mL) and the mixture was heated to 65-70° C. until a clear solution is formed. The solution was cooled to 0° C. at 10° C./hr and then held for 1 hour. The resulting suspension was filtered and the solid was rinsed with cold 2-propanol (40.0). After drying the title compound 17 was obtained as a powder (13.2 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:18][C:19]1[CH:20]=[C:21]([NH:22][C:15](=[O:17])[CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)O)CC1
Reactant: Nc1cccc(Cl)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)Nc2cccc(Cl)c2)CC1
Reaction time: 20 h

Procedure:
To a round-bottomed flask containing 2-(1-tert-butoxycarbonyl-piperazin-4-yl)-acetic acid×2HCl (0.100 g, 0.36 mmol) was added 3-chloroaniline (0.050 g, 0.40 mmol) with the aid of anhydrous dichloromethane (4.5 ml). The reaction mixture was cooled into an ice-bath under argon, and then diisopropylethylamine (0.139 g, 1.08 mmol) was added followed by PyBOP (0.187 g, 0.36 mmol). The ice-bath was removed and the reaction mixture was allowed to stir for 20 h under argon. The solvent was removed in vacuo, the residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 25% ethyl acetate in dichloromethane. The title compound was obtained as a white solid (0.079 g, 62%). 1H-NMR (500 MHz, DMSO-d6) 1.40 (s, 9H, C(CH3)3), 2.46 (br s, 4H, piperazine N(CH2)2), 3.39 (br s, 4H, piperazine N(CH2)2), 3.16 (s, 2H, NCH2CO), 7.11 (d, J=8.59 Hz, 1H) and 7.55 (d, J=8.19 Hz, 1H) (4-ArH and 6-ArH), 7.34 (t, J=8.19 Hz, 1H, 5-ArH), 7.84 (t, J=1.9 Hz, 1H, 2-ArH), 9.89 (s, 1H, CONH);