Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([BH3-])#N.[NH2:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8]([CH3:15])=[CH:7][C:6]=1[OH:16].[CH2:17]([O:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([N:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[CH2:23][CH2:22]1)[CH2:18][CH3:19].C(O)(=O)C>C1COCC1>[CH3:15][C:8]1[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:10][C:5]([NH:4][CH:30]2[CH2:29][CH2:28][N:27]([C@H:24]3[CH2:25][CH2:26][C@H:21]([O:20][CH2:17][CH2:18][CH3:19])[CH2:22][CH2:23]3)[CH2:32][CH2:31]2)=[C:6]([OH:16])[CH:7]=1
Reactant: Cc1cc(O)c(N)cc1S(C)(=O)=O
Reactant: CCCO[C@H]1CC[C@H](N2CCC(=O)CC2)CC1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCO[C@H]1CC[C@H](N2CCC(Nc3cc(S(C)(=O)=O)c(C)cc3O)CC2)CC1
Temperature: 100 °C

Procedure:
Polymer supported cyanoborohydride (110 mg, 0.47 mmol, 4.3 mmol/g) was added to a solution of 2-amino-5-methyl-4-(methylsulfonyl)phenol (D87, 48 mg, 0.24 mmol), 1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinone (D17, 65 mg, 0.26 mmol, this specific batch contained-25% 1-[trans-4-(propyloxy)cyclohexyl]-4-piperidinone) and acetic acid (0.07 mL, 1.19 mmol) in THF (2.5 mL). The mixture was heated by microwave at 100° C. for 30 min and then for a further 3×30 min. The reaction was then filtered and concentrated by rotary evaporation to give a yellow oil, which was purified by high pH MDAP to give 5-methyl-2-({1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)-4-(methylsulfonyl)phenol (D88, 49 mg, 46%) as a cream solid and 5-methyl-4-(methylsulfonyl)-2-({1-[trans-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)phenol (D89, 14 mg, 13%) as a yellow oil.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:32])/[CH:5]=[CH:6]/[C:7]1[S:11][CH:10]=[C:9]([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:8]=1.[CH:33]([C:35]1[N:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]2)=[CH:37][CH:36]=1)=O>>[CH3:2][O:3][C:4](=[O:32])/[CH:5]=[CH:6]/[C:7]1[S:11][CH:10]=[C:9]([CH:12]=[CH:33][C:35]2[N:40]=[CH:39][C:38]([N:41]3[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]3)=[CH:37][CH:36]=2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)nc2)CC1
Reactant: COC(=O)/C=C/c1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Agent: [Cl-]
Product: COC(=O)/C=C/c1cc(C=Cc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2)cs1
Yield: 94.8 %

Procedure:
By a method similar to Production Example 108, step 4, ({5-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]thiophen-3-yl}methyl)(triphenyl)phosphonium chloride (1.724 g, 3.600 mmol) and tert-butyl 4-(6-formylpyridin-3-yl)piperazine-1-carboxylate (874.1 mg, 3.000 mmol) were condensed to give tert-butyl 4-[6-(2-{5-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]thiophen-3-yl}vinyl)pyridin-3-yl]piperazine-1-carboxylate (1.295 g, yield 94.7%) as a yellow oil.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1.[NH2:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26]>ClCCl>[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Reactant: CC(C)(O)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
Triethylamine (17.35 mL, 124 mmol) was added to a solution of 7-bromo-4-chloro-3-nitroquinoline (29.84 g, 104 mmol) in dichloromethane (253 mL), and the reaction was cooled to 0° C. 1-Amino-2-methylpropan-2-ol (10.17 g, 114 mmol) was added dropwise, and then the reaction was allowed to warm to ambient temperature and stirred overnight. A precipitate formed and was isolated by filtration and washed with water. The crude solid was recrystallized from a mixture of isopropanol and acetonitrile to provide 27.78 g of 1-(7-bromo-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:4]=1[CH:5]=[O:6].[CH:12]([Mg]Br)=[CH:13][CH2:14][CH3:15].[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:4]=1[CH:5]([OH:6])[CH2:15][CH2:14][CH:13]=[CH2:12]
Reactant: CCC=C[Mg]Br
Reactant: COc1ccc(F)cc1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCCC(O)c1cc(F)ccc1OC
Yield: 79.8 %

Procedure:
To a solution of 2-methoxy-5-fluorobenzaldehyde (3.0 g, 19.5 mmol) in THF (20 mL) at 0° C. was added a solution 1-butenylmagnesium bromide (0.5 M in THF, 45 mL, 22.5 mmol) dropwise for 15 min. Then the reaction mixture was poured to a solution of saturated ammonium chloride (80 mL) in a separatory funnel. The organic fraction was extracted with ethyl acetate (3×60 mL) and the combined organic layers were washed with brine (50 mL) and dried over sodium sulfate. The solvent then was removed in vacuo and crude product thus obtained was purified by flash column chromatography (10% EtOAc in hexane, Rf=0.11) to give the product as an oil (3.27 g, 93%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=1[C:12]#[N:13])([O-])=O.C(=O)([O-])[O-].[K+].[K+].N1[CH2:24][CH2:23][CH2:22][CH2:21]1>O>[N:1]1([C:4]2[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=2[C:12]#[N:13])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1cccc(N2CCCC2)c1C#N
Yield: 56 %

Procedure:
A mixture of 3-nitrophthalonitrile (985 mg, 5.69 mmol), freshly dried potassium carbonate (3.0 g, 21 mmol) and pyrrolidine (15 mL) were heated at reflux for 4 h. The reaction mixture was poured into water (250 mL) to precipitate the product, and this was filtered off, washed with water, and dried to give 1 as an olive-brown powder (633 mg, 56%).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:20]([C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=1)#[N:21]
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1ccnc(C#N)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: N#Cc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 52.2 %

Procedure:
A mixture of methyl thiosalicylate (0.65 g, 3.9 mmol), 2,4-dicyanopyridine (0.50 g, 3.9 mmol), triethylamine (0.81 ml, 5.8 mmol) and toluene (2.0 ml) was refluxed for 2.5 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from acetone-chloroform to give the titled compound (0.54 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]#[CH:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: C#Cc1ccc(Cl)cc1C(=O)OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1ccc(Cl)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
To a solution of methyl 5-chloro-2-ethynylbenzoate (5.34 g, 27.44 mmol) in Ethyl acetate (135 ml) was added Pd/C (10%) (50% water, 2.92 g, 1.37 mmol). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. LCMS indicated the reaction had gone to completion and the mixture was filtered through Celite. The filter cake washed with EtOAc (50 ml) and the filtrate was concentrated under reduced pressure to give 5.12 g (93.9%) of methyl 5-chloro-2-ethylbenzoate as a brown oil which was suitable for use without any further purification. LC-MS 56%, 2.21 min (3 minute LC-MS method), m/z=198.9/200.9, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.84 (d, J=2.3 Hz, 1H), 7.39 (dd, J=8.3, 2.3 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 3.90 (s, 3H), 2.94 (q, J=7.5 Hz, 2H), 1.21 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]1[NH:16][C:15](=[O:17])[NH:14][C:13]1=[O:18].[Na].Cl.[CH2:21]([N:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26]Cl)[CH3:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]1[NH:16][C:15](=[O:17])[N:14]([CH2:26][CH2:25][CH2:24][N:23]([CH2:28][CH3:29])[CH2:21][CH3:22])[C:13]1=[O:18]
Reactant: O=C1NC(=O)C(Cc2c[nH]c3ccc(Cl)cc23)N1
Reactant: CCN(CC)CCCCl
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCN(CC)CCCN1C(=O)NC(Cc2c[nH]c3ccc(Cl)cc23)C1=O
Reaction time: 18 h

Procedure:
5-(5-Chloroindol-3-ylmethyl)hydantoin (5 g, 0.019 mole) was added to a solution of sodium (0.88 g) in 200 ml of anhydrous C2H5OH. After heating to reflux for 30 minutes, 3-diethylaminopropyl chloride hydrochloride (3.54 g, 0.019 mole) was added and the mixture was heated to reflux with stirring for 18 hours. The mixture was filtered and diluted with H2O to form a solid. The solid was recrystallized from aqueous 2-propanol, twice from acetone-petroleum ether and again from 2-propanol, yield 1.8 g, mp 186°.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[C:5]([C:7](=[CH:13][NH:14][CH:15]1[CH2:17][CH2:16]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>>[Cl:1][C:2]1[C:20]([F:21])=[CH:19][CH:18]=[C:4]2[C:3]=1[N:14]([CH:15]1[CH2:17][CH2:16]1)[CH:13]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2=[O:6]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1ccc(F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(F)ccc2c1=O

Procedure:
Reaction of 3-chloro-2,4-difluoro-benzoyl chloride with diethyl malonate gives diethyl (3-chloro-2,4-difluoro-benzoyl)-malonate, and partial hydrolysis and decarboxylation lead to ethyl (3-chloro-2,4-difluoro-benzoyl)-acetate, which is reacted with ethyl orthoformate/acetic anhydride to give ethyl 2-(3-chloro-2,4-di-fluorobenzoyl)-3-ethoxy-acrylate; further reaction with cyclopropylamine leads to ethyl 2-(3-chloro-2,4-difluoro-benzoyl)-3-cyclopropylaminoacrylate, which is cyclized with potassium carbonate/dimethylformamide to give ethyl 8-chloro-1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate; hydrolysis then finally leads to the corresponding carboxylic acid. The reaction sequence described can be represented by the following equation: ##STR4##
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[C:18]([O:22][C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:23](=[O:24])[O:22][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:28][CH:29]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Yield: 85.9 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (150 mg, 0.48 mmol) was reacted with 4-[(tert-butoxycarbonylamino)methyl]phenylboronic acid (180 mg, 0.73 mmol) to afford the desired product (180 mg, 83%) as a brown solid: ESI MS m/z 437 [C24H24N2O4S+H]+.
Reaction SMILES: [O:1]=[C:2]([N:15]1[CH2:27][CH2:26][C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH:16]1[C:28]1[CH:33]=[CH:32][C:31]2[O:34][CH2:35][O:36][C:30]=2[CH:29]=1)/[CH:3]=[CH:4]/[C:5]1[CH:14]=[CH:13][C:8]([C:9](OC)=[O:10])=[CH:7][CH:6]=1.[NH3:37]>CO>[O:1]=[C:2]([N:15]1[CH2:27][CH2:26][C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH:16]1[C:28]1[CH:33]=[CH:32][C:31]2[O:34][CH2:35][O:36][C:30]=2[CH:29]=1)/[CH:3]=[CH:4]/[C:5]1[CH:14]=[CH:13][C:8]([C:9]([NH2:37])=[O:10])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Reactant: N
Solvent: CO
Product: NC(=O)c1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Temperature: 35 °C
Reaction time: 48 h
Yield: 13 %

Procedure:
Into a solution of Example 28 (0.2 g, 0.4 mmol) in 50 mL of MeOH was bubbled ammonia and the resulting mixture was stirred at 35° C. for two days. The mixture was concentrated in vacuo to give a residue which was washed with 2×30 mL of water. Extraction, drying over MgSO4 and concentration in vacuo gave a residue that was purified via radial chromatography using DCM:MeOH (90:10) as eluting solvent and via preparative chromatography (20×20- cm plate, 0.5 mm, SiO2) using the same eluant. The title compound (0.025 g, 13%) was isolated as white crystals after recrystallization from MeOH:H2O. MP: 183° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:30]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]2[C:31]=1[CH:32]=[CH:33][C:34](=[O:41])[NH:35]2)[CH2:10][NH:11][CH2:12][CH2:13]CC#CC1C=CC(NC(=O)C(F)(F)F)=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].BrCC[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50]([NH:52][CH2:53][C:54]1[C:55]([NH:67][CH:68]2[CH2:73][CH2:72][O:71][CH2:70][CH2:69]2)=[C:56]2[CH:64]=[N:63][N:62]([CH2:65][CH3:66])[C:57]2=[N:58][C:59]=1[CH2:60][CH3:61])=[O:51]>>[Si:1]([O:8][C@H:9]([C:30]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]2[C:31]=1[CH:32]=[CH:33][C:34](=[O:41])[NH:35]2)[CH2:10][NH:11][CH2:12][CH2:13][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50]([NH:52][CH2:53][C:54]1[C:55]([NH:67][CH:68]2[CH2:69][CH2:70][O:71][CH2:72][CH2:73]2)=[C:56]2[CH:64]=[N:63][N:62]([CH2:65][CH3:66])[C:57]2=[N:58][C:59]=1[CH2:60][CH3:61])=[O:51])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCCCCCBr
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCC#Cc1ccc(NC(=O)C(F)(F)F)cc1)c1ccc(O)c2[nH]c(=O)ccc12
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12

Procedure:
The title compound was prepared in a manner analogous to that described for Intermediate 37, using Intermediate 33 in place of Intermediate 26. ES/MS calcd. for C41H64N7O5Si 762.5. found m/z=762.5 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:30]=[CH:29][C:10]([CH2:11][NH:12][CH2:13][C:14]3[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=3)[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Cl:33][C:34]1[C:35]([OH:45])=[C:36]([S:41](Cl)(=[O:43])=[O:42])[CH:37]=[C:38]([Cl:40])[CH:39]=1.CCN(CC)CC>C(Cl)Cl>[Cl:33][C:34]1[C:35]([OH:45])=[C:36]([S:41]([N:12]([CH2:13][C:14]2[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=2)[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:11][C:10]2[CH:29]=[CH:30][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:32][CH:31]=3)=[CH:8][CH:9]=2)(=[O:43])=[O:42])[CH:37]=[C:38]([Cl:40])[CH:39]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: CC(C)(C)OC(=O)NCc1cccc(CNCc2ccc(Oc3ccc(F)cc3)cc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cccc(CN(Cc2ccc(Oc3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 91.2 %

Procedure:
To a solution of tert-butyl 3-((4-(4-fluorophenoxy)benzylamino)methyl)benzylcarbamate (0.72 g, 1.64 mmol) in CH2Cl2 (15 mL) added 3,5-dichloro-2-hydroxybenzene-1-sulfonyl chloride (0.45 g, 1.72 mmol) and Et3N (0.68 ml, 4.91 mmol). The reaction mixture was stirred at 0° C. under nitrogen for 1.5 h. The reaction mixture was concentrated and the residue was extracted with ethyl acetate and saturated NaHCO3 solution. The organic layer was washed successively with brine, 1 N HCl, brine, and concentrated after drying over MgSO4 to give viscous solid (0.99 g, 82%). 1H NMR (CDCl3): δ 9.10 (bs, 1H), 7.52 (d, J=2.8 Hz, 1H), 7.40 (d, J=2.8 Hz, 1H), 7.28-7.17 (m, 1H), 7.14-6.90 (m, 9H), 6.85 (d, J=8.3 Hz, 2H), 4.36 (m, 4H), 4.23 (m, 2H), 1.46 (s, 9H); MS (ESI): (M+H)+=605.2.
Reaction SMILES: COCCOCC[C:8]1(CCOCCOC)[C:20]2[CH:19]=[C:18](C=C)[CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][C:11](C=C)=[CH:12][CH:13]=2.CC(N=NC(C#N)(C)C)(C#N)C>O.C1COCC1>[CH:10]1[C:9]2[CH2:8][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: C=Cc1ccc2c(c1)C(CCOCCOC)(CCOCCOC)c1cc(C=C)ccc1-2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(c1)Cc1ccccc1-2
Temperature: 85 °C
Reaction time: 48 h

Procedure:
A mixture of the polymeric macroinitiator, 7 (2.0 g, 0.22 mmol, Mw) 7700, PDI) 1.11), 3 (0.668 g, 1.55 mmol), and AIBN (0.43 mg, 0.03 mmol) was dissolved in 2% H2O in THF (6.0 mL), degassed by four freeze/pump/thaw cycles, and sealed under argon. The polymerization mixture was then stirred at 85° C. for 48 h and allowed to cool, and the star polymer, 23, was obtained after precipitation using ethyl acetate followed by dialysis against methanol (1.9 g, 71%, Mw) δ 500, PDI) 1.32). 1H NMR (CDCl3): δ (ppm) 7.10-7.28 (br m, ArH), 5.03 (br s, CH), 4.35 (br s, CH2), 2.68 (br s, CH2), 2.42 (br s, CH2), 1.95 (br s, CH2), 1.50-1.85 (br m, CH2).
Reaction SMILES: N[C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([Br:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[ClH:15].N([O-])=O.[Na+]>O>[Br:14][C:9]1[CH:10]=[C:11]([O:12][CH3:13])[C:2]([Cl:15])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)cc(OC)c1N
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(Br)cc(OC)c1Cl
Reaction time: 1 h

Procedure:
To a solution of compound 54 (27.0 g, 103 mmol) in H2O (70 mL) and conc.HCl (70 mL) was added dropwise a solution of NaNO2 (21.5 g, 311 mmol) in H2O (50 mL) at 0° C. After being stirred for 1 hour, a solution of Cu(I)Cl in conc.HCl (80 mL) was added to the reaction mixture dropwise at 0° C. The mixture was stirred at room temperature for 18 hours. To the mixture was added water (300 mL) and extracted with EtOAc (500 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product 55 was dried under high vacuum and used without further purification (29.0 g, 100%) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[N:8]1[C:15](Cl)=[N:14][C:12](Cl)=[N:11][C:9]=1Cl>>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][C:9]1[N:11]=[C:12]([NH:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])[N:14]=[C:15]([NH:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])[N:8]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COC(CN)OC
Product: COC(CNc1nc(NCC(OC)OC)nc(NCC(OC)OC)n1)OC

Procedure:
The procedure of Example 1 was repeated with the exception that aminoacetaldehyde dimethyl acetal (6.3 g, 0.060 mole) and cyanuric chloride (3.68 g, 0.02 mole) were used to give 2,4,6-tris-(2,2-dimethoxyethylamino)-1,3,5-triazine as an oily product in 80.8% isolated yield (6.3g). The structure was analyzed by infrared (IR) spectroscopy, and confirmed by NMR spectroscopy 1H NMR (δ): 4.2 (t, 1H), 3.6-3.2 (m, 2H), 3.4 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([NH:10][CH3:11])[CH:3]=1>ClCCl.C1COCC1.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][CH3:11])[C:5]([CH:8]=[O:9])=[CH:6][N:7]=1
Reactant: CNc1cc(Cl)ncc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNc1cc(Cl)ncc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A mixture of (6-chloro-4-(methylamino)pyridin-3-yl)methanol (4.2 g, 24.7 mmol) and manganese(IV) oxide (active, 25.8 g, 296.6 mmol) in dichloromethane (50 mL) and THF (50 mL) was stirred at RT overnight. LCMS showed the reaction was completed. The solid was filtered off, and the filtrate was concentrated to afford the title compound (3.7 g, crude) as a light yellow solid, which was directly used in the next step without further purification. MS (ES+) C7H7ClN2O requires: 170, 172. Found: 171, 173 [M+H]+.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[C:23]([C:30]4[CH:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=4)[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:29][CH:27]([F:28])[C:25]1[CH:24]=[C:23]([C:30]2[CH:31]=[N:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=2)[N:22]=[C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:10]=3)[CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 81.3 %

Procedure:
To a cooled and stirred solution of 3′-[4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.56 g) in dichloromethane (7 ml) was added TFA (7 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.41 g, 81%). MS (ISP) 507.2 [(M+H)+]; mp 222° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1>ClCCl>[CH3:16][O:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:13]([C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:14]
Reactant: COC[C@@H]1CCCN1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Solvent: ClCCl
Product: COC[C@@H]1CCCN1C(=O)c1cnoc1-c1ccc(C)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added (2S)-2-(methoxymethyl)pyrrolidine (5.7 mg, 0.050 mmol, 1.1 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C17H20N2O3: 300.1474, found 300.1481.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:12][C:11](=[S:22])[N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:26][CH2:27][OH:28].Cl>CN(C)P(=O)(N(C)C)N(C)C.CCCCCC>[OH:28][CH2:27][CH2:26][S:22][C:11]1[S:12][C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: OCCI
Reactant: COc1ccc(C2=NC(=S)SC2c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1ccc(-c2nc(SCCO)sc2-c2ccc(OC)cc2)cc1
Temperature: 0 °C

Procedure:
10 g of 4,5-bis-(p-methoxyphenyl)-thiazoline-2-thione are dissolved in 50 ml of hexamethylphosphoric acid triamide, the solution is cooled to 5° and, while stirring, sodium hydride (1.45 g of a 50% strength suspension in mineral oil, de-oiled with hexane) is added. The mixture is then stirred for 30 minutes at room temperature, 5.22 g of 2-iodoethanol are added dropwise thereto, and the mixture is then stirred for 15 minutes at room temperature and poured into a mixture of 30 ml of 2 N hydrochloric acid and 400 ml of ice-water. After being left to stand for some time the oil which separates crystallises and is taken up in 200 ml of methylene chloride. The solution is dried over magnesium sulphate and concentrated to dryness by evaporation. To crystallise, the residue is triturated with diethyl ether. 2-(2-hydroxyethylthio)-4,5-bis-(p-methoxyphenyl)-thiazole having a melting point of 83°-84° is obtained.