Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[C:24]1([C:34](O)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)=[O:35])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1nccc2ccccc12
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2nccc3ccccc23)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with Isoquinoline-1-carboxylic acid. LC-MS (basic): tR=0.96 min; [M+H]+=503.3.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[CH2:10][C:11]1([N:24]=[C:25]=[O:26])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C([Li])(C)(C)C>CC1CCCO1>[CH:7]([N:6]1[C:2]2[C:25](=[O:26])[NH:24][C:11]3([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13][CH2:12]3)[CH2:10][C:3]=2[CH:4]=[N:5]1)([CH3:8])[CH3:9]
Reactant: CC(C)n1ncc(CC2(N=C=O)CCN(C(=O)OC(C)(C)C)CC2)c1Br
Agent: [Li]C(C)(C)C
Solvent: CC1CCCO1
Product: CC(C)n1ncc2c1C(=O)NC1(CCN(C(=O)OC(C)(C)C)CC1)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a mixture of tert-butyl 4-((5-bromo-1-isopropyl-1H-pyrazol-4-yl)methyl)-4-isocyanatopiperidine-1-carboxylate (1.4 g, 3.3 mmol) in 2-methyl tetrahydrofuran (10 mL) was added t-butyl lithium (1.7 M in hexane, 4.3 mL, 7.2 mmol) at −78° C., under argon. After the addition was complete the mixture was allowed to warm to room temperature and was stirred for 18 hours. The mixture was quenched with water (10 mL) and then diluted with ethyl acetate (20 mL). The layers were separated and the organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude product was purified by flash column chromatography to give tert-butyl 1′-isopropyl-7′-oxo-1′,4′,6′,7′-tetrahydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridine]-1-carboxylate (0.77 g, 67%). +ESI (M+H) 374.1; 1H NMR (300 MHz, CDCl3, δ): 7.34 (s, 1H), 6.35 (s, 1H), 5.45 (m, 1H), 3.57 (m, 2H), 3.42 (m, 2H), 2.79 (s, 2H), 1.70 (m, 4H), 1.45 (m, 15H).
Reaction SMILES: I[C:2]1[CH:7]=[N:6][C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:4]2[O:23][CH:24]=[CH:25][C:3]=12.[Si:26]([O:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([N:40]2[CH:44]=[C:43](B(O)O)[CH:42]=[N:41]2)[CH2:36][CH2:35]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Si:26]([O:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([N:40]2[CH:44]=[C:43]([C:2]3[CH:7]=[N:6][C:5]([N:8]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[C:4]4[O:23][CH:24]=[CH:25][C:3]=34)[CH:42]=[N:41]2)[CH2:36][CH2:35]1)([C:29]([CH3:32])([CH3:30])[CH3:31])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(B(O)O)cn2)CC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(I)c2ccoc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2)c2ccoc12
Temperature: 70 °C

Procedure:
A mixture of di-tert-butyl (4-iodofuro[2,3-c]pyridin-7-yl)imidodicarbonate (1.2 g, 2.6 mmol), [1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]boronic acid (1.06 g, 3.26 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane complex (213 mg, 0.261 mmol) and potassium carbonate (0.901 g, 6.52 mmol) in 1,4-dioxane (10 mL) and water (5 mL) was degassed with nitrogen for 10 min. The mixture was then heated to 70° C. for 20 min. Ethyl acetate was added, and the layers separated. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated. Purification of the residue by ISCO chromatography (0% to 35% EtOAc:heptane) afforded 1.15 g (72%) of the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.38 (s, 1 H), 7.89 (s, 1 H), 7.82-7.77 (m, 2 H), 7.02 (d, J=2.0 Hz, 1 H), 4.21 (tdd, J=3.9, 7.7, 11.5 Hz, 1 H), 3.82-3.66 (m, 1 H), 2.33-2.17 (m, 2 H), 2.09-2.01 (m, 2 H), 2.00-1.87 (m, 2 H), 1.59-1.49 (m, 2 H), 1.40 (s, 18 H), 0.91 (s, 9 H), 0.09 (s, 6 H); MS (ESI): 613.46 [M+H]+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31]N)=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:27][CH:26]=1)(=[O:23])=[O:24]
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Product: CS(=O)(=O)c1ccc(-n2nccc2-c2nn(-c3ccccc3)ccc2=O)cc1
Yield: 12 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 4-(methylsulfonyl)phenylhydrazine according to the method described for Example 1 in 12% yield. MS: M=392.9 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[N:15]=[C:16]([CH3:19])[N:17]([CH3:18])[C:13]=2[CH:12]=[C:11]([NH:20][C:21](=[O:23])[CH3:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]I.[H-].[Na+].O>O1CCCC1>[CH2:1]([O:8][C:9]1[C:14]2[N:15]=[C:16]([CH3:19])[N:17]([CH3:18])[C:13]=2[CH:12]=[C:11]([N:20]([CH3:24])[C:21](=[O:23])[CH3:22])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cc(OCc2ccccc2)c2nc(C)n(C)c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N(C)c1cc(OCc2ccccc2)c2nc(C)n(C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a suspension of 5.8 g (18.8 mmol) N-(7-benzyloxy-2,3-dimethy-3H-benzimidazol-5-yl)-acetamide in tetrahydrofuran (200 ml) were added 1.3 ml (20.5 mmol) methyl iodide and 0.74 g (20.5 mmol) sodium hydride (60%) in portions. The reaction was stirred at room temperature for 1 h and then poured into water (100 ml) and extracted with ethyl acetate (4×50 ml). The organic layers were dried over magnesium sulphate and concentrated in vacuo. The residue afforded 6.0 g (99%) of the title compound as ochre solid. m.p. 144°-149° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)[CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][NH2:28]>ClC(Cl)C.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=3)[O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:28][CH2:27][C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCc1cccs1
Reactant: Fc1ccc2c(-c3cccc(OC[C@H]4CO4)c3)noc2c1
Solvent: CCO
Solvent: CC(Cl)Cl
Product: O[C@H](CNCc1cccs1)COc1cccc(-c2noc3cc(F)ccc23)c1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dichloroethane, 2-thiophenemethylamine and ethanol, essentially as described above in Example 57. Purity by LC/MS=100%, [M+H]+=399.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:9]#[N:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:11][O-:12].[Na+]>CO>[CH3:11][O:12][CH2:2][C:3]1[C:4]([C:9]#[N:10])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[O-]
Reactant: N#Cc1ncccc1CBr
Agent: [Na+]
Solvent: CO
Product: COCc1cccnc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A stirred solution of 3-bromomethylpyridine-2-carbonitrile (591 mg, 3.0 mmol) in MeOH (10 mL) at 0° C. was treated with NaOMe (324 mg, 6.0 mmol), warmed to room temperature, stirred for 2 h, concentrated in vacuo and partitioned between EtOAc (50 mL) and water (30 mL). The organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; hexane:EtOAc (9:1-4:1)] to give the title compound (297 mg, 67%) as a clear oil; NMR δH (400 MHz, CDCl3) 3.51 (3H, s), 4.68 (2H, s), 7.50-7.55 (1H, m), 7.92-7.96 (1H, m) and 8.63 (1H, dd, J 5.0, 1.5 Hz); Rf [isohexane:EtOAc (4:1)]=0.65.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F.[C:9](O)(=[O:11])[CH3:10]>>[CH3:10][C:9]([C:4]1[CH:3]=[CH:2][C:1]([OH:7])=[CH:6][CH:5]=1)=[O:11]
Reactant: CC(=O)O
Reactant: Oc1ccccc1
Agent: F
Product: CC(=O)c1ccc(O)cc1
Yield: 61.6 %

Procedure:
Dann and Mylius in a dissertation included as part of a series of Reports from the Institute for Applied Chemistry of the University of Erlangen, received for publication on Jan. 7, 1954 and published in Annalen der Chemie 587 Band, pages 1 to 15, disclose the reaction of phenol and glacial acetic acid in the presence of hydrogen fluoride to produce 4-hydroxyacetophenone (4-HAP) in a yield of 61.6%. This reaction may be conventionally characterized as a Friedel-Crafts acetylation of phenol with acetic acid as the acetylating agent.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[CH:32]=[C:31]([CH2:33][N:34]([C@@H:36]([CH3:39])CO)[CH3:35])[S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].N[C@H:44]([CH3:47])[CH2:45][OH:46]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[CH:32]=[C:31]([CH2:33][N:34]([CH3:35])[CH2:36][C@H:39]5[CH2:47][CH2:44][CH2:45][O:46]5)[S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:11])=[O:12])[CH3:9]
Reactant: C[C@@H](N)CO
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)[C@@H](C)CO)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)C[C@H]5CCCO5)c4)cc23)CC1
Yield: 35.1 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide trifluoroacetate (salt), substituting [(2R)-tetrahydro-2-furanylmethyl]amine (1.20 mmol) for (2R)-2-amino-1-propanol to afford 15.5 mg of the title compound (35.1%)
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:30])[NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][N:23]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)([CH3:6])([CH3:5])[CH3:4].CN(C=O)C.Br[CH2:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41]>O>[C:3]([O:7][C:8](=[O:30])[N:9]([CH2:10][CH:11]1[C:20]2[C:15](=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][N:23]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)[CH2:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)CCCBr
Reactant: CC(C)(C)OC(=O)NCC1CCCc2c(Oc3ccc(C#N)cn3)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCCN(CC1CCCc2c(Oc3ccc(C#N)cn3)cccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.9 %

Procedure:
Add NaH (60% oil suspension, 30 mg, 0.750 mmol) to a solution of [5-(5-cyanopyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamic acid tert-butyl ester (Intermediate 22, 189 mg, 0.500 mmol) and DMF (5 ml) stirring at ambient temperature under nitrogen. After 20 minutes, add 1-bromo-4-methylpentane (247 mg, 1.50 mmol) and beat the mixture at 60° C. overnight. After cooling, pour the mixture into water and extract with EtOAc (2×). Wash the extract with water and brine before drying ((MgSO4) and concentrating. Purify on silica gel (20% EtOAc/Hexane) to obtain 111 mg of [5-(5-cyano-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-(4-methyl-pentyl)carbamic acid tert-butyl ester as a colorless glass.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:8]([CH:18]=1)[C:9]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:10].ClC1C=CC(S(O[CH2:38][C@H:39]2[CH2:43][CH2:42][CH2:41][N:40]2[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])(=O)=O)=CC=1.O>CS(C)=O>[C:21]1([CH2:20][O:19][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:38][C@H:39]3[CH2:43][CH2:42][CH2:41][N:40]3[C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])=[CH:18][C:8]=2[C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:10])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(Nc1cccnc1)c1cc(O)ccc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COS(=O)(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (44.9 mg, 1.87 mmol) was added to a solution of 5-hydroxy-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 29; 500 mg, 1.56 mmol) in dimethylsulfoxide (8 ml) at 0° C., and the mixture was stirred at room temperature for 1 h. 1,1-Dimethylethyl (2R)-2-({[(4-chlorophenyl)sulfonyl]oxy}methyl)-1-pyrrolidinecarboxylate (555 mg, 1.56 mmol) in dimethylsulfoxide (7 ml) was added dropwise, and the mixture was stirred at 75° C. for 18 h. The mixture was poured into water (100 ml) and extracted with ethyl acetate. The organic layer was dried, and concentrated to obtain a crude product, which was purified by chromatography on silica gel (dichloromethane/methanol=50:1) to yield the title compound as a yellow oil. 0.55 g.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[S:8][C:7]([C:9]2[CH:10]=[N:11][C:12]3[CH:13]=[C:14]4[CH:21]=[N:20][NH:19][C:15]4=[CH:16][C:17]=3[N:18]=2)=[CH:6][CH:5]=1.I[CH3:23].O>C1COCC1>[CH3:23][N:19]1[C:15]2=[CH:16][C:17]3[N:18]=[C:9]([C:7]4[S:8][C:4]([Cl:3])=[CH:5][CH:6]=4)[CH:10]=[N:11][C:12]=3[CH:13]=[C:14]2[CH:21]=[N:20]1
Reactant: CI
Reactant: Clc1ccc(-c2cnc3cc4cn[nH]c4cc3n2)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc2cc3ncc(-c4ccc(Cl)s4)nc3cc21
Reaction time: 0.08 h

Procedure:
To an ice-colded suspension of NaH (0.062 g) in 20 ml of anhydrous THF under N2 is added 7-(5-chlorothien-2-yl)-1H-pyrazolo[3,4-g]quinoxaline (0.63 g). The orange-red mixture is stirred at the same temperature for 5 minutes, then iodomethane (0.374 g) is added dropwise to the orange-red mixture. The resulting mixture is stirred at room temperature overnight, then poured into water, extracted with methylene chloride, separated, dried (MeSO4), concentrated in vacuo to give a yellow solid. Purification is by chromatography eluting first with 5% ethylacetate in hexane, then gradually up to 30% ethylacetate in hexane to isolate 1-methyl-7-(5-chlorothien-2-yl)-1H-pyrazolo[3,4-g]quinoxaline (m.p. 225°-227° C.), then up to 10% hexane in ethylacetate to isolate 2-methyl-7-(5-chlorothien-2-yl)-2H-pyrazolo[3,4-g]quinoxaline (m.p. 222°-224° C.).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C(=O)N([Br:27])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.O>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:19][C:17]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH:18]=1
Reactant: COC(=O)c1ccc(C)cc1O[Si](C)(C)C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1O[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of methyl 2-{[tert-butyl(dimethyl)silyl]oxy}-4-methylbenzoate (3.4 g) in carbon tetrachloride (68 mL) were added, and NBS (2.16 g) and AIBN (398 mg) were added thereto at room temperature, followed by stirring at 80° C. for 1 hour. Completion of the reaction was confirmed by means of TLC, and to the reaction liquid was added water to stop the reaction, followed by extraction with EtOAc. The organic layer was washed with brine, dried using MgSO4, and then concentrated under reduced pressure, followed by purification by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 95:5) to obtain methyl 4-(bromomethyl)-2-{[tert-butyl(dimethyl)silyl]oxy}benzoate (3.79 g) as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.CCN(CC)CC.[F:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1>C(Cl)Cl>[F:35][C:36]1[CH:44]=[CH:43][C:39]([C:40]([N:24]2[CH2:23][CH2:22][N:21]([C:18]3[CH:19]=[CH:20][C:15]([C:7]4[NH:6][C:5](=[O:27])[C:4]5[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=5[O:2][CH3:1])[N:8]=4)=[CH:16][CH:17]=3)[CH2:26][CH2:25]2)=[O:41])=[CH:38][CH:37]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)c5ccc(F)cc5)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.5 %

Procedure:
To a solution of 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.150 g, 0.40 mmol) in CH2Cl2 (10 mL) was added Et3N (0.08 mL, 0.60 mmol) and 4-fluorobenzoyl chloride (0.04 mL, 0.36 mmol). The resulting solution was stirred at room temperature for 3 hours. The solution was concentrated in vacuo and the residue was purified by flash chromatography on silica gel, eluting with 0% to 10% of MeOH/EtOAc, to afford the title compound (0.080 g, 45%). 1H NMR (300 MHz, DMSO-d6): δ 11.79 (s, 1H), 8.11 (d, J=8.8 Hz, 2H), 7.44-7.62 (m, 2H), 7.21-7.39 (m, 2H), 7.04 (d, J=9.0 Hz, 2H), 6.68 (s, 1H), 6.47 (s, 1H), 3.64-3.94 (m, 8H), 3.22-3.60 (m, 6H); APCI MS m/z 489 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[C:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[CH3:1][C:2]1[C:7]([N:8]=[C:15]=[S:16])=[C:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(N2CCCCC2)c1N
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(N2CCCCC2)c1N=C=S

Procedure:
Reaction of 6-methyl-2-piperidinoaniline (6.4 g) in dioxan (20 ml) and water (65 ml) with thiophosgene (5.7 g) at 0° C. for 30 minutes and at room temperature for 2 hours gave 6-methyl-2-piperidinophenyl isothiocyanate as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:25]([O:27]CC)=[O:26])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Li+]>O1CCOCC1.O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:25]([OH:27])=[O:26])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)C1CC(c2ccc(CC)cc2)CN(C(=O)N2CCC(C#N)CC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(C#N)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
650 mg (1.60 mmol) of ethyl 5-(4-ethylphenyl)-1-[(4-cyanopiperidin-1-yl)carbonyl]piperidine-3-carboxylate were dissolved in a mixture of 20 ml of dioxane and 10 ml of water, 153 mg (6.40 mmol) of lithium hydroxide were added and the mixture was stirred at RT for 15 min. For work-up, the reaction solution was concentrated under reduced pressure, water was then added and the mixture was acidified with 1N hydrochloric acid. The precipitate formed was filtered off and dried under reduced pressure. The residue was purified by preparative HPLC. Yield: 347 mg (59% of theory)
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:22]=[C:23]4[N:27]([CH:28]=3)[C:26]3[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH2:35][N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[CH:32][C:25]=3[S:24]4)=[CH:17][CH:16]=2)=[O:13])[CH:7]=1)([CH3:5])[CH3:4].[CH3:42][O:43][C:44](=[O:65])[C@H:45]1[O:51][C@:49](Br)(O)[C@H:48]([O:53][C:54](=[O:56])[CH3:55])[C@@H:47]([O:57][C:58](=[O:60])[CH3:59])[C@@H:46]1[O:61][C:62](=[O:64])[CH3:63]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH3:42][O:43][C:44]([CH:45]1[CH:46]([O:61][C:62](=[O:64])[CH3:63])[CH:47]([O:57][C:58](=[O:60])[CH3:59])[CH:48]([O:53][C:54](=[O:56])[CH3:55])[CH:49]([O:1][CH2:2][C:3]([CH3:4])([C:6]2[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[N:22]=[C:23]5[N:27]([CH:28]=4)[C:26]4[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH2:35][N:36]6[CH2:41][CH2:40][O:39][CH2:38][CH2:37]6)=[CH:32][C:25]=4[S:24]5)=[CH:17][CH:16]=3)=[O:13])[CH:7]=2)[CH3:5])[O:51]1)=[O:65]
Reactant: CC(C)(CO)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Reactant: COC(=O)[C@H]1O[C@@](O)(Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)C1OC(OCC(C)(C)c2cc(NC(=O)Nc3ccc(-c4cn5c(n4)sc4cc(OCCN6CCOCC6)ccc45)cc3)no2)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Temperature: 25 °C

Procedure:
To a stirred mixture of 1-[5-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (I-1) (1 equivalent) and silver carbonate (0.5-1 equivalent) in toluene at rt is added 1-bromo-2,3,4-tri-O-acetyl-α-D-glucuronic acid methyl ester (0.8-1.5 equivalents) and the mixture is stirred at rt until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is filtered and the filtrate is partitioned between water and either dichloromethane or a mixture of dichloromethane and isopropanol. The separated aqueous layer is further extracted with dichloromethane or a mixture of dichloromethane and isopropanol. The combined organic layers are washed with 2N aq sodium hydroxide dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by preparative reverse-phase HPLC or silica gel flash chromatography to afford 3,4,5-triacetoxy-6-{2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propoxy}-tetrahydro-pyran-2-carboxylic acid methyl ester.
Reaction SMILES: Br[C:2]1(Br)[C:6]2[N:7]=[C:8]([Cl:17])[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]=2[N:4]([CH3:18])[C:3]1=[O:19].[Cl-].[NH4+]>C1COCC1.C(Cl)Cl.[Zn]>[Cl:17][C:8]1[N:9]=[C:10]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:5]2[N:4]([CH3:18])[C:3](=[O:19])[CH2:2][C:6]=2[N:7]=1
Reactant: CN1C(=O)C(Br)(Br)c2nc(Cl)nc(N3CCOCC3)c21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1C(=O)Cc2nc(Cl)nc(N3CCOCC3)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
To 7,7-dibromo-2-chloro-5-methyl-4-morpholino-5H-pyrrolo[3,2-d]pyrimidin-6(7H)-one (1.70 g, 3.99 mmol) in 2M aqueous ammonium chloride solution (9.96 mL, 19.9 mmol) and THF (40 mL) at 0° C. was added zinc dust (573.4 mg, 8.775 mmol). The reaction mixture was stirred at RT for 30 min and then diluted with DCM (40 mL). The reaction mixture was filtered through a pad of Celite. The layers were separated, and the organic layer was washed with saturated aqueous NaHCO3 solution, water, and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 679 mg (63.4%) of 2-chloro-5-methyl-4-morpholino-5H-pyrrolo[3,2-d]pyrimidin-6(7H)-one a solid. MS(ESI) m/z: 269.2 [M+1]+.