Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:44]=[CH:43][C:28]([C:29]([NH:31][CH2:32][C:33]5([CH2:36][NH:37][C:38](=[O:42])[C:39](O)=[O:40])[CH2:35][CH2:34]5)=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:67][C:68]1[CH:74]=[CH:73][C:71]([NH2:72])=[CH:70][CH:69]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[N:15]=[C:14]([NH:24][C:25]4[CH:44]=[CH:43][C:28]([C:29]([NH:31][CH2:32][C:33]5([CH2:36][NH:37][C:38](=[O:42])[C:39]([NH:72][C:71]6[CH:73]=[CH:74][C:68]([F:67])=[CH:69][CH:70]=6)=[O:40])[CH2:34][CH2:35]5)=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)C(=O)NCC1(CNC(=O)c2ccc(Nc3nc(NC4(c5ccc(Cl)cc5)CC4)nc(OCC(F)(F)F)n3)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCC1(CNC(=O)c2ccc(Nc3nc(NC4(c5ccc(Cl)cc5)CC4)nc(OCC(F)(F)F)n3)cc2)CC1)C(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(((1-((4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)methyl)cyclopropyl)methyl)amino)-2-oxoacetic acid (17 mg) and TBTU (10.33 mg) in DMF (2 mL) was added 4-fluoroaniline (3.58 mg). The mixture was stirred at room temperature for 16 hours, before being purified by preparative HPLC.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:17][CH2:18][C@H:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([C:28]([NH2:30])=[O:29])[CH2:20]1>CS(C)=O>[NH:13]1[C:10]2=[CH:11][N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:17][CH2:18][C@H:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]([C:28]([NH2:30])=[O:29])[CH2:20]4)[CH2:5][CH2:6]3)[CH:8]=[C:9]2[CH:15]=[CH:14]1
Reactant: c1cc2cc(N3CCNCC3)ncc2[nH]1
Reactant: NC(=O)N1C[C@@H](CCBr)c2ccccc21
Solvent: CS(C)=O
Product: NC(=O)N1C[C@@H](CCN2CCN(c3cc4cc[nH]c4cn3)CC2)c2ccccc21

Procedure:
from 5-piperazin-1-yl-1H-pyrrolo[2,3-c]pyridine and (S)-3-(2-bromoethyl)-2,3-dihydro-1H-indole-1-carboxylic acid amide. Assignment of the optical rotation was done in dimethyl sulfoxide.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2Cl)n1
Reactant: O=C(Cl)Oc1ccccc1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2Cl)n1

Procedure:
Following the procedure in Example 118A, 3-tert-butyl-1-(2-chlorophenyl)-1H-pyrazol-5-amine (1.30 g, 5.21 mmol) and phenyl chloroformate (2.0 mL, 15.63 mmol) were reacted to give phenyl 3-tert-butyl-1-(2-chlorophenyl)-1H-pyrazol-5-ylcarbamate. 1H NMR (300 MHz, DMSO-d6) δ 10.18 (br s, 1H), 7.67 (d, 1H), 7.55-7.48 (m, 3H), 7.41-7.36 (m, 2H), 7.24 (t, 1H), 7.02 (br s, 2H), 6.31 (s, 1H), 1.23 (s, 9H); LC-MS (ESI) m/z 370 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]3[N:20]([CH3:24])[N:21]=[CH:22][CH:23]=3)[CH:13]=2)=[O:10])=[CH:4][CH:3]=1.[Cl:25]N1C(=O)CCC1=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C.O>[Cl:25][C:23]1[CH:22]=[N:21][N:20]([CH3:24])[C:19]=1[C:14]1[CH:13]=[C:12]([NH:11][C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:10])[CH:17]=[CH:16][C:15]=1[OH:18]
Reactant: Cn1nccc1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1O
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1O
Yield: 58.9 %

Procedure:
To a stirred and cooled solution of Compound 119 (0.22 g, 0.63 mmol), in DMF (2.0 mL) was added N-chlorosuccinimide (0.168, 1.26 mmol). The reaction was stirred until the LCMS showed no starting material (2.5 hrs). The reaction mixture was poured into ice cooled water containing Na2S2O3 and NaHCO3 and the resulting solid was filtered, washed with ice-cooled water and dried in vacuo to afford a off-white solid 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(4-chloro-phenyl)-urea (0.14 g, 58%). LCMS m/z (%)=377 (M+H, 35Cl, 35Cl, 100), 379 (M+H, 35Cl, 37Cl, 59.4), 381 (M+H, 37Cl, 37Cl, 10.0). 1H NMR (400 MHz, DMSO-d6) δ: 9.76 (bs, 1H), 8.73 (bs, 1H), 8.56 (bs, 1H), 7.58 (s, 1H), 7.44-7.46 (dd, J=8.6, 2.03 Hz, 2H), 7.34-7.37 (dd, J=8.79, 2.7 Hz, 1H), 7.29 (dd, J=8.85, 2.07 Hz, 3H), 6.92-6.94 (d, J=6.78 Hz, 1H), 3.64 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[Cl:1][C:2]1[C:7]([NH:8][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1ccc(N)c(Cl)n1
Product: CCOC(=O)C(=CNc1ccc(C)nc1Cl)C(=O)OCC
Temperature: 140 °C
Yield: 95 %

Procedure:
A mixture of 2-chloro-6-methyl-3-pyridinylamine (8.5 g) and diethyl ethoxymethylenemalonate (22.0 mL) is heated at 140° C. for 18 hours. The mixture is cooled to room temperature and the resulting solids are recrystallized from a mixture of heptane (400 mL) and CH2Cl2 (2 mL) to obtain 17.9 g (95%) of the title compound as a pale red solid. Physical characteristics: MS (ESI+) m/z 313 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:26])[NH:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:34][CH2:35][F:36].O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:26])[N:24]([CH2:34][CH2:35][F:36])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c[nH]1
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1CCF
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide (100 mg, 0.271 mmol) suspended in acetonitrile (5 ml). Into the mixture, cesium carbonate (124 mg, 0.380 mmol) and 1-Iodo-2-fluoroethane (0.049 ml, 0.596 mmol) were added and the resulting mixture was stirred overnight at RT. Water (2 ml) was added and the mixture was evaporated. The product was purified with LC/MS-trigger. 1H-NMR (400 MHz; CDCl3): δ 1.23 (d, 3H), 2.42 (s, 3H), 4.12-4.23 (m, 2H), 4.30 (dd, 1H), 4.39 (dd, 1H), 4.51-4.61 (m, 1H), 4.58-4.73 (m, 2H), 6.61 (d, 1H), 7.49 (d, 1H), 7.51 (d, 1H), 7.62 (d, 1H), 7.77 (dd, 1H), 7.85 (dd, 1H), 8.00 (dd, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br)([O-:3])=[O:2].[C:12]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CCCCCC.O>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]([O:20][CH2:21][CH3:22])=[O:19])([O-:3])=[O:2]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)C(Cc1ccccc1[N+](=O)[O-])C(=O)OCC
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 2-nitrobenzyl bromide (1.00 g, 4.63 mmol) and diethyl malonate (0.741 g, 4.63 mmol) in 30 ml of hexane was added potassium carbonate (0.640 g, 4.63 mmol) and 18-Crown-6 (0.012 g, 0.05 mmol). After stirred at 80° C. for 18 hours, the mixture was diluted with water and was extracted with ethyl acetate. The organic layer was washed with water, then with brine, and concentrated under reduced pressure to obtain crude diethyl (2-nitrobenzyl)malonate.
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=2[CH3:21])[CH2:6]1)C.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH2:38])=[NH:37])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:21][C:13]1[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=1[N:7]1[CH2:8][CH2:9][C:10]2[N:37]=[C:36]([NH:35][C:32]3[CH:31]=[CH:30][C:29]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[CH:34][CH:33]=3)[N:38]=[CH:4][C:5]=2[CH2:6]1
Reactant: CN1CCN(c2ccc(NC(=N)N)cc2)CC1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CCC(=O)C(=CN(C)C)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])cc1N1CCc2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2C1
Temperature: 25 °C

Procedure:
To a solution of 3-Dimethylaminomethylene-1-(2-methyl-5-nitrophenyl)-piperidin-4-one (12.06 gm, 41.7 mmol)[as prepared in reference 1] in Ethanol (250 ml) were added N-[4-(4-Methyl-piperazin-1-yl)-phenyl]-guanidine (38.9 gm, 167 mmol) and sodium acetate (27.32 gm, 334 mmol) and solution was heated under reflux for 12 hours. After cooling to room temperature, the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was washed with brine, dried [sodium sulfate] and concentrated under vacuum. The crude product obtained was further purified by silica gel chromatography using 5-10% Methanol/Chloroform as eluent to give pure desired product [47] i.e., [6-(2-Methyl-5-nitro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine as yellow solid. (Yield: 3.65 gm, 19.0%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].[CH3:7][N:8]([CH3:13])[S:9](Cl)(=[O:11])=[O:10]>CCOCC>[CH3:4][C:3]([NH2:6])([CH3:5])[CH2:2][NH:1][S:9]([N:8]([CH3:13])[CH3:7])(=[O:11])=[O:10]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC(C)(N)CN
Solvent: CCOCC
Product: CN(C)S(=O)(=O)NCC(C)(C)N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
A mixture of 30.7 g (0.35 mol) of 1,2-diamino-2-methylpropane, 150 ml of ether and 50 ml of trienthylamine was cooled to 0° C. and 20 g (0.14 mol) of dimethylsulfamoyl chloride was added slowly. The reaction mixture was stirred for 30 minutes and evaporated to dryness. The residue was mixed with water, basified with K2CO3 and evaporated to dryness. Acetone was added and the mixture was filtered. Evaporation of the filtrate gave a solid which recrystallized from toluene to give 16.5 g (60.3%) of product, mp 77°-78° C. The NMR and IR were consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[CH3:15].CC(O)=O>CO.[Pd]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[CH3:15]
Reactant: COC(=O)COc1ccc([N+](=O)[O-])cc1C
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)COc1ccc(N)cc1C

Procedure:
A solution of 36.3 g (161 mmol) of the above prepared (2-methyl-4-nitro-phenoxy)-acetic acid methyl ester in 400 ml MeOH and 11.2 ml (177 mmol) AcOH was hydrogenated in the presence of 3.63 g 10% Pd/C for 7 h at atmospheric pressure. After removal of the catalyst the reaction was evaporated, dissolved in toluene and evaporated (5×) to give 32.5g of (4-amino-2-methyl-phenoxy)-acetic acid methyl ester as a brown crystalline residue.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:38](Cl)(=[O:43])[CH2:39][CH:40]([CH3:42])[CH3:41]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:38](=[O:43])[CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)CC(=O)Cl
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CC(C)CC(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 89.8 %

Procedure:
A procedure similar to that described in Example 4, above, was followed, but using 1.10 g (2.0 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 3, above] and 361 mg (3.0 mmol) of isovaleryl chloride, to provide 1.14 g of the title compound.
Reaction SMILES: [I-:1].C([N:9]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[CH:17]=[C:18]([CH2:36][CH3:37])[C:19]3[C:28]([CH:29]=2)=[S+:27][C:26]2[C:21](=[C:22]([CH3:35])[CH:23]=[C:24]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:25]=2)[N:20]=3)[CH2:11][CH2:10]1)(OC(C)(C)C)=O>ClCCl.FC(F)(F)C(O)=O>[I-:1].[N:12]1([C:16]2[CH:17]=[C:18]([CH2:36][CH3:37])[C:19]3[C:28]([CH:29]=2)=[S+:27][C:26]2[C:21](=[C:22]([CH3:35])[CH:23]=[C:24]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:25]=2)[N:20]=3)[CH2:13][CH2:14][CH2:15][NH:9][CH2:10][CH2:11]1
Reactant: CCc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)cc2[s+]c3cc(N4CCCC4)cc(C)c3nc12
Agent: [I-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(N2CCCNCC2)cc2[s+]c3cc(N4CCCC4)cc(C)c3nc12

Procedure:
A solution of 3-(4-Boc-1,4-diazepan-1-yl)-1-ethyl-9-methyl-7-(pyrrolidin-1-yl)-phenothiazin-5-ium iodide (65 mg, 0.01 mmol) in dichloromethane (10 mL) and trifluoroacetic acid (1.0 mL) was stirred for 3 h at 50° C. The resulting mixture was washed by toluene (2×5 mL), pentane (2×5 mL) and concentrated to dryness.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Cl[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)Cl
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 10 h
Yield: 53.7 %

Procedure:
A solution of 73.5 g of 4-(4-trifluoromethylphenoxy)phenol and 49.2 g of ethyl α-chloropropionate and 100 g of potassium carbonate were added to 100 ml of methyl ethyl ketone, and the mixture was heated. With stirring, the reaction was performed for 10 hours at the reflux temperature (80° to 85° C.). Inorganic salts were separated from the reaction product by filtration. The filtrate was evaporated and dried. The resulting ester was extracted with chloroform, and washed with water. The chloroform was distilled off to afford 55 g of the final product (yield: 54%). The final product had a boiling point of 176° to 185° C./3 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[O:25]1[C:29]2([CH2:34][CH2:33][CH:32](CS([O-])(=O)=O)[CH2:31][CH2:30]2)[O:28][CH2:27][CH2:26]1>>[O:25]1[C:29]2([CH2:34][CH2:33][CH:32]([N:23]3[CH:24]=[C:20]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([S:11]([C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)(=[O:12])=[O:13])[CH:7]=4)[CH:21]=[N:22]3)[CH2:31][CH2:30]2)[O:28][CH2:27][CH2:26]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Reactant: O=S(=O)([O-])CC1CCC2(CC1)OCCO2
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCC4(CC3)OCCO4)c2)c2ccc(F)cc21
Yield: 59 %

Procedure:
Following the general method as outlined in Intermediate 16, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 600 mg; 1.76 mmol) and 1,4-dioxaspiro[4.5]decan-8-ylmethanesulfonate (498 mg; 2.11 mmol), 500 mg (59%) of the title compound was obtained as a white solid after purification by reverse phase flash chromatography.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][C@H:9]([C@@H:13]([NH:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH3:14])[C:10]([OH:12])=[O:11].[C:23](OC=O)(=[O:25])C>N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][C@H:9]([C@@H:13]([N:15]([CH:23]=[O:25])[O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH3:14])[C:10]([OH:12])=[O:11]
Reactant: C[C@H](NOC1CCCCO1)[C@@H](CCCc1cccs1)C(=O)O
Reactant: CC(=O)OC=O
Solvent: c1ccncc1
Product: C[C@@H]([C@@H](CCCc1cccs1)C(=O)O)N(C=O)OC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of (2R,3S)-2-(3-(thiophene-2-yl)-1-propyl)-3-(2-tetrahydropyranyloxyamino)butanoic acid (91 mg, 0.278 mmol) in pyridine (1 mL) at 0° C. is added formic acetic anhydride (0.3 mL). The resulting solution is allowed to warm to 25° C., stirred for 3 h, and then concentrated to dryness under reduced pressure. The resulting gum is dissolved in ethyl acetate (30 mL) and washed sequentially with 1 M hydrochloric acid (20 mL) and saturated aqueous sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3S)-2-(3-(thiophene-2-yl)-1-propyl)-3-(formyl-2-tetrahydropyranyloxyamino)butanoic acid as an oil (90 mg, 91% yield).
Reaction SMILES: CS[C:3]([NH:8][CH2:9][C:10]#[CH:11])=[CH:4][N+:5]([O-:7])=[O:6].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][S:19][CH2:20][CH2:21][NH2:22]>>[N+:5]([CH:4]=[C:3]([NH:8][C:9]#[C:10][CH3:11])[NH:22][CH2:21][CH2:20][S:19][CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)([O-:7])=[O:6]
Reactant: C#CCNC(=C[N+](=O)[O-])SC
Reactant: NCCSCc1ccccn1
Product: CC#CNC(=C[N+](=O)[O-])NCCSCc1ccccn1

Procedure:
A solution of the product of Step A is treated with about an equimolar amount of 2-[(2-pyridyl)methylthio]-ethylamine to produce, after workup, the title product.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]3[C:19](=[CH:20][CH:21]=2)[O:18][C:12]2([CH2:17][CH2:16][CH2:15][O:14][CH2:13]2)[CH2:11][C:10]3=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N:27]=[C:28]=[N:29][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH:1]1([C:7]2[CH:8]=[C:9]3[C:19](=[CH:20][CH:21]=2)[O:18][C:12]2([CH2:17][CH2:16][CH2:15][O:14][CH2:13]2)[CH2:11]/[C:10]/3=[N:29]\[C:28]#[N:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1CC2(CCCOC2)Oc2ccc(C3CCCCC3)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\CC2(CCCOC2)Oc2ccc(C3CCCCC3)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 7.7 %

Procedure:
To a solution of 6-cyclohexyl-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (240 mg, 0.804 mmol) in anhydrous DCM (10 mL) was added TiCl4 (1 M solution in DCM, 608.6 mg, 3.2 mmol) dropwise within 15 min at room temperature. The mixture was stirred for 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (380.6 mg, 3.12 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (100 g) and extracted with DCM (3×50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give (E)-N-(6-cyclohexyl-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-ylidene)cyanamide (20 mg, 10%), which was used for next step without further purification.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3(O)[CH2:13][O:12][CH2:11]3)=[CH:7][CH:8]=2)[CH2:3][NH:2]1.C(N(S(F)(F)[F:21])CC)C>C(#N)C.[N+](C)([O-])=O>[F:21][C:10]1([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][NH:2][CH2:3]3)[CH2:13][O:12][CH2:11]1
Reactant: OC1(c2ccc3c(c2)CNC3)COC1
Reactant: CCN(CC)S(F)(F)F
Solvent: C[N+](=O)[O-]
Solvent: CC#N
Product: FC1(c2ccc3c(c2)CNC3)COC1
Temperature: 0 °C
Yield: 67 %

Procedure:
To 0.58 mmol 3-(2,3-dihydro-1H-isoindol-5-yl)-oxetan-3-ol in 2 ml acetonitrile and 2 ml nitromethane at −60° C. was added 1.15 mmol diethylaminosulfur trifluoride and the mixture was allowed to warm to 0° C. over 30 min. The reaction mixture was re-cooled to −60° C. and quenched by addition of 5 ml saturated aq. sodium carbonate solution. The mixture was warmed to RT and diluted with THF and ethyl acetate, then washed sequentially with water and with brine. The organic phase was separated, dried over sodium sulfate, and concentrated in vacuo to afford the title compound as a brown oil (67% yield). MS (m/e): 194.3 ([M+H]+, 100%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH2:27]([NH2:30])[CH:28]=[CH2:29]>C(O)C.O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:30][CH2:27][CH:28]=[CH2:29])[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: C=CCN
Solvent: O
Solvent: CCO
Product: C=CCNc1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1
Temperature: 140 °C

Procedure:
6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.25 g, 0.669 mmol) was suspended in ethanol (4 mL) followed by addition of allylamine (0.753 mL, 10.03 mmol). The sealed contents were heated (heat block) at 140° C. for ca. 60 h, and then allowed to cool to room temperature. The reaction mixture was diluted with water (100 mL) and then filtered. The collected solid was washed with additional water and then dried in vacuum oven at 45° C. for 18 h. The final product was isolated as an off-white solid, 0.225 g (83%). LCMS E-S (M+H)=394.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (d, J=6.82 Hz, 6H), 2.12 (s, 3H), 2.21 (s, 3H), 4.00 (t, J=5.43 Hz, 2H), 4.32 (d, J=5.05 Hz, 2H), 4.94 (quin, J=6.69 Hz, 1H), 5.09 (dd, J=10.36, 1.77 Hz, 1H), 5.18-5.29 (m, 1H), 5.85-6.01 (m, 2H), 6.68 (s, 1H), 7.37 (t, J=5.56 Hz, 1H), 7.84 (s, 1H), 8.45 (t, J=5.05 Hz, 1H), 11.55 (br. s., 1H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:11]([N:18]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)[S:19]([C:22]1[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCN(C)C1=O>[CH2:11]([N:18]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)[S:19]([C:22]1[CH:27]=[CH:26][C:25]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: COc1ccc(N(Cc2ccccc2)S(=O)(=O)c2ccc(F)cc2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCN(C)C1=O
Product: COc1ccc(N(Cc2ccccc2)S(=O)(=O)c2ccc(N3CCC4(CC3)OCCO4)cc2)cc1OC
Temperature: 70 °C
Reaction time: 48 h

Procedure:
1,4-Dioxa-8-azaspiro[4.5]decane (0.14 ml, 0.95 mM) was added to a solution of N-Benzyl-N-(3,4-dimethoxy-phenyl)-4-fluoro-benzenesulfonamide(0.19 g, 0.47 mM) and potassium carbonate (0.66 g, 4.82 mM)in anhyrous 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H)-pyrimidinone(5 ml). The reaction was stirred at 70° C. for two days. The reaction was quenched with water(50 ml). The precipitate was washed with water and dried under reduced pressure to afford 0.15 g of the desired product as a tan solid. H1 NMR(CDCl3) δ 1.81 (t, 4H, J=5.67 Hz), 3.50(t, 4H, J=5.97 Hz), 3.65(s, 3H), 3.81 (s, 3H), 4.01 (s, 4H), 4.66(s, 2H), 6.43(d, 1H, J=2.34 Hz), 6.53(m, 1H), 6.66(d, 1H, J=8.58 Hz), 6.90 (d, 1H, J=9.03 Hz), 7.19(m, 6H), 7.53(d, 2H, J=9.00 Hz). MS(ES) m/z 525.0; (MH+); HRMS for C28H32SN2O6: 525.2049.