Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][CH2:12][C:13]1[C:14]([NH:21][CH3:22])=[N:15][C:16]([S:19][CH3:20])=[N:17][CH:18]=1.[C:23](=[O:26])([O-])[O-].[K+].[K+].C1N=CN(C(N2C=NC=C2)=O)C=1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[CH2:12][C:13]2[C:14](=[N:15][C:16]([S:19][CH3:20])=[N:17][CH:18]=2)[N:21]([CH3:22])[C:23]1=[O:26]
Reactant: CNc1nc(SC)ncc1CNc1cc([N+](=O)[O-])ccc1Cl
Reactant: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Solvent: CC#N
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1cc([N+](=O)[O-])ccc1Cl)C2
Temperature: 50 °C
Yield: 96 %

Procedure:
20.796 g {5-[(2-Chloro-5-nitro-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl}-methyl-amine were dissolved in 500 ml acetonitrile, 25.375 g potassium carbonate and 19.847 g N,N-carbonyldiimidazole (CDI) were added, and the solution was heated at 50° C. for 24 hrs. The solvent was dried over sodium sulfate, evaporated, and the residue was extracted with diethyl ether to give the title product in 96% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=1)[C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20]2)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]([O:35][C:36](=[O:39])[CH2:37]Br)([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=1)[C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([O:27][CH2:37][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:39])[CH:21]=[CH:20]2)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(C(=O)c2ccc3cc(O)ccc3c2)c1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc2cc(C(=O)c3cccc(OCCNC(=O)OC(C)(C)C)c3)ccc2c1
Yield: 81.8 %

Procedure:
2-Hydroxynaphthalene 330e (0.60 g, 1.5 mmol) was alkylated with t-butylbromoacetate (0.24 mL, 1.5 mmol) in the presence of K2 CO3 (0.20 g, 1.5 mmol) in DMF (7 mL) in the usual way to yield a colorless solid (0.64 g) after silica gel chromatography. IR(KBr): cm-1 3340, 1746, 1684. 1H NMR(300 MHz, CDCl3): 8.21 (s, 1H), 7.94-7.10 (m, 9H), 5.0 (br, 1H), 4.68 (s, 2H), 4.09 (t, 2H, J=7 Hz), 3.56-3.52 m, 2H), 1.52 (s, 9H), 1.44 (2, 9H). MS(NH3): 539 (base, M+NH4), 522 (25%, M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][C:18](=[O:20])[CH3:19])[C:13]([CH2:21][CH2:22][CH3:23])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:24]1([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:14]([CH2:15][CH2:16][CH2:17][C:18](=[O:20])[CH3:19])[C:13]([CH2:21][CH2:22][CH3:23])=[N:12][C:7]=4[CH:8]=[N:9][C:10]=3[CH:11]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCCc1nc2cnc3cc(Br)ccc3c2n1CCCC(C)=O
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: CCCc1nc2cnc3cc(-c4ccccc4)ccc3c2n1CCCC(C)=O
Temperature: 100 °C
Yield: 40.3 %

Procedure:
5-(7-Bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one (2.5 g, 6.68 mmol) was dissolved in propanol (25 mL) and water (5 mL) and degassed with nitrogen for 5 minutes. Phenylboronic acid (1.97 g, 7.35 mmol), palladium (II) acetate (7 mg, 0.03 mmol), triphenylphosphine (0.17 g, 0.06 mmol), and sodium carbonate (0.85 g, 8.01 mmol) were added sequentially to the reaction mixture and heated at 100° C. overnight. The mixture was concentrated under reduced pressure and the residue was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated under reduced pressure. Purification was performed with flash column chromatography on silica gel (eluting with 3% methanol in dichloromethane) to obtain 1.0 g of 5-(7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)[NH2:17]>ClCCl>[Cl:1][C:2]1[C:7]([C:8]([NH:17][C:16]2[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=[C:14]([O:13][CH3:12])[CH:15]=2)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Reactant: COc1cc(N)cc(OC)c1
Solvent: ClCCl
Product: COc1cc(NC(=O)c2c(Cl)ncnc2Cl)cc(OC)c1
Reaction time: 1 h
Yield: 64 %

Procedure:
4,6-Dichloropyrimidine-5-carbonyl chloride (590 mg, 2.79 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was dissolved in dichloromethane (3 ml) and TEA (283 μl, 2.03 mmol) was added. To this solution, 3,5-dimethoxyaniline (312 mg, 2.04 mmol) dissolved in 3 ml dichloromethane was added dropwise and the mixture was stirred for 60 min. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated. The crude (684 mg, 62% purity, 64% yield) was used in the next synthetic step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([O:13][C:14]3[C:22]4[C:17](=[CH:18][C:19]([N+:23]([O-])=O)=[CH:20][CH:21]=4)[NH:16][N:15]=3)=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O>[Pd]>[NH2:23][C:19]1[CH:18]=[C:17]2[C:22]([C:14]([O:13][C:8]3[C:7]4[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=4)[NH:10][N:9]=3)=[N:15][NH:16]2)=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc2c(Oc3n[nH]c4cc([N+](=O)[O-])ccc34)n[nH]c2c1
Agent: [Pd]
Product: Nc1ccc2c(Oc3n[nH]c4cc(N)ccc34)n[nH]c2c1

Procedure:
Indazolyl ethers 38 can be prepared by the procedure described in Scheme 13. 6-Nitro-1H-2-hydroindazol-3-one 37 is protected such as with Boc2O and DMAP in CH2Cl2 at a temperature of about RT, to give the protected 6-nitro-2-hydroindazol-3-one. The protected 6-nitro-2-hydroindazol-3-one is reacted with an alcohol (where Rx is an appropriate substituent selected from the possible substituents on R1) and Ph3P in a solvent, such as THF, and DEAD, at a temperature of about RT, to give the protected 6-nitro(indazol-3-yl) ether. The nitro intermediate is hydrogenated, such as with an H2 atmosphere in the presence of a catalyst, such as Pd/C, to give the protected 6-amino(indazol-3-yl) ether 38. The amine 38 is coupled with 2-chloronicotinic acid in a solvent, such as an alcohol, preferably pentanol, at a temperature above RT, preferably at a temperature above about 75° C., and more preferably at a temperature at about 130° C. to give the coupled and deprotected compound 39.
Reaction SMILES: [O:1]([C:8]([P:10](=[O:22])([O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[O:11]CC)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:23].[Na+].[Na+].OC(P(=O)(O)O)=O>>[O:1]([C:8]([P:10](=[O:11])([O-:22])[O:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:23]
Reactant: CCOP(=O)(Oc1ccc(Cl)cc1)C(=O)Oc1ccccc1
Agent: O=C(O)P(=O)(O)O
Agent: [Na+]
Product: O=C(Oc1ccccc1)P(=O)([O-])Oc1ccc(Cl)cc1
Yield: 36 %

Procedure:
From ethyl p-chlorophenyl phenoxycarbonylphosphonate. Yield 36%. T.l.c. Rf 0.54 single spot. By t.l.c. the compound was estimated to contain <0.2% of trisodium osycarbonylphosphonate. IR(KBr) cm-1 : 1710 (CO), 1490, 1270, 1090, 910. Preparation of monoesters of hydroxycarbonylphosphonic acid (of the phosphonic acid group).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]2[CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[O:13][C:9]=2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=1Br)(=[O:3])[CH3:2].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[C:1]([NH:4][C:5]1[CH:6]=[C:12]([C:14]([CH3:16])([CH3:17])[CH3:15])[O:13][C:9]2[C:10]=1[C:11]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:7][C:8]=2[C:18]([O:20][CH3:21])=[O:19])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(Br)c(NC(C)=O)c2cc(C(C)(C)C)oc12
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2ccccc2)c2c(NC(C)=O)cc(C(C)(C)C)oc1-2
Temperature: 100 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
Under nitrogen atmosphere, methyl 4-acetylamino-5-bromo-2-tert-butyl-1-benzofuran-7-carboxylate (I-252) (147 mg, 0.4 mmol), phenylboronic acid (61 mg, 0.5 mmol), aqueous 2 M cesium carbonate solution (0.5 ml, 1.0 mmol) and tetrakistriphenylphosphine palladium(0) (23 mg, 0.02 mmol) were added, followed by stirring at 100° C. for 6 hours. After cooling to room temperature, ethyl acetate was added to the reaction liquid, followed by washing with saturated sodium bicarbonate water and saturated brine and drying over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with n-hexane/ethyl acetate (2:1) gave the entitled compound (117 mg, 80%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][O:13][C:12]([CH3:15])=[N:11]2)=[CH:4][CH:3]=1.[C:25]([O-:28])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:18]([O:17][CH2:16][C:10]1([CH2:9][CH2:8][C:5]2([CH:25]=[O:28])[CH:6]=[CH:7][C:2]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:3][CH2:4]2)[CH2:14][O:13][C:12]([CH3:15])=[N:11]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: O=C([O-])[O-]
Reactant: CC1=NC(CCc2ccc(Br)cc2)(CO[Si](C)(C)C(C)(C)C)CO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1=NC(CCC2(C=O)C=CC(c3ccccc3)=CC2)(CO[Si](C)(C)C(C)(C)C)CO1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
The mixture of 4-[2-(4-bromophenyl)ethyl]-4-(t-butyldimethylsilanyloxymethyl)-2-methyl-4,5-dihydrooxazole (2 mmol), 4-fomylphenylboronic acid (2.4 mmol), Pd(PPh3)4 (0.2 mmol) and Na2CO3 (9.6 mmol) in toluene (5 mL), EtOH (1.5 mL) and H2O (5 mL) is stirred at 90° C. for 5 h. It is diluted with H2O (15 mL) and EtOAc (15 mL) and the organic phase is washed with brine and dried over Na2SO4. After concentration, the crude product is purified by column chromatography using EtOAc/hexane (1/4) to give the desired product as a white solid. MS: (ES+): 438.2 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[Cl-].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH:23]=[N+:24]([CH3:26])[CH3:25].COC1C=C(C=CC=1OC)C=O.CNC>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:23]([N:24]([CH3:26])[CH3:25])[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COc1ccc(C=[N+](C)C)cc1OC
Reactant: Fc1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: CNC
Agent: COc1ccc(C=O)cc1OC
Agent: [Cl-]
Product: COc1ccc(C(c2c(-c3ccc(F)cc3)[nH]c3ccccc23)N(C)C)cc1OC

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-(4-fluoro-phenyl)-1H-indole and (3,4-dimethoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3,4-dimethoxy-benzaldehyde and dimethylamine.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1.[CH3:31][N:32]([CH:34]([CH3:37])[CH2:35]Cl)[CH3:33]>>[Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([O:14][CH2:35][CH:34]([N:32]([CH3:33])[CH3:31])[CH3:37])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1
Reactant: CC(CCl)N(C)C
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2Br)cc(OC)c1OC
Product: COc1cc(-c2nc3ccc(OCC(C)N(C)C)cc3n2Cc2ccccc2Br)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 114 with 2-(N,N-dimethylamino)propyl chloride essentially as previously described. mp 152° C., NMR, IR, MS 553, 555.
Reaction SMILES: [C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH2:25][CH2:26][CH3:27])(=[O:5])[CH:2]([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[Cl:37][C:38]1[CH:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40](Cl)=[O:41]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:37][C:38]1[CH:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH:10]=2)[C:6]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[C:7]1[CH2:25][CH2:26][CH3:27])=[O:41]
Reactant: CCCc1[nH]c2cc(C(=O)OCc3ccccc3)ccc2c1C(=O)C(C)C
Reactant: O=C(Cl)c1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1c(C(=O)C(C)C)c2ccc(C(=O)OCc3ccccc3)cc2n1C(=O)c1ccccc1Cl
Temperature: 20 °C
Yield: 115.4 %

Procedure:
To a stirred mixture of benzyl 3-isobutyryl-2-propylindole-6-carboxylate (207 mg) and diisopropylethylamine (295 mg) in dichloromethane (6 ml) were added 2-chlorobenzoyl chloride (299 mg) and 4-dimethylaminopyridine (12 mg) at 0° C. The reaction mixture was refluxed for 15 hours. The reaction mixture was cooled to 20° C. and washed with 1N hydrochloric acid, water, saturated sodium bicarbonate, water and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed or silica gel eluting with a mixture of ethyl acetate and hexane (1:10) to give benzyl 1-(2-chlorobenzoyl)-3-isobutyryl-2-propylindole-6-carboxylate (330 mg) as yellow crystals.
Reaction SMILES: [CH2:1]1OC1.[CH3:4][C:5]1([CH3:24])[CH2:10][CH:9]([NH:11][CH:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][C:14]([CH3:21])([CH3:20])[CH2:13]2)[CH2:8][C:7]([CH3:23])([CH3:22])[NH:6]1.CSC[C@H](NC(CC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)C(O)=O.C=O.C(O)=O.C(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][N:11]([CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][C:14]([CH3:21])([CH3:20])[CH2:13]1)[CH:9]1[CH2:10][C:5]([CH3:24])([CH3:4])[NH:6][C:7]([CH3:23])([CH3:22])[CH2:8]1
Reactant: CC1(C)CC(NC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: C1CO1
Agent: C=O
Agent: CSC[C@H](NC(=O)CC1c2ccccc2-c2ccccc21)C(=O)O
Agent: O=C([O-])[O-]
Solvent: O=CO
Product: CN(C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Yield: 49 %

Procedure:
) In accordance with the general procedure of Example 1b), the HALS diol (204) is prepared starting from 2-N-morpholino-4,6-bis[N-n-butyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,3,5-triazine (Example yl) with ethylene oxide; m.p. 114°-117° C. Analysis: calcd: C 65.84%; H 10.45%; N 16.60%. found: C 65.86%; H 10.33%; N 16.01%. ##STR61## δ) 1.) 40.48 g (0.14 mol) of bis(2,2,6,6-tetramethylpiperidin-4-yl)amine [EP-A-336 895, Ciba-Geigy] and 11.4 g (0.14 mol) of a 36% aqueous solution of formaldehyde are placed in a 200 ml sulfonation flask. Then 25.8 g (0.56 mol) of formic acid are added dropwise at room temperature. In the course of this addition the temperature in the reactor rises to 70° C., with evolution of CO2. The reaction mixture is then further stirred until it has cooled to room temperature. The aqueous phase is saturated with potassium carbonate and the reaction mixture is extracted 3 times with chloroform. The organic phases are combined, dried over potassium carbonate and concentrated on a vacuum rotary evaporator. Chromatography of the residue on silica gel with the solvent system hexane/dichloromethane 9:1+5% triethylamine yields 21 g (49%) of methyl-bis(2,2,6,6-tetramethylpiperidin-4-yl)amine, m.p. 51°-53° C., as a white powder. 1H-NMR (300 MHz, CDCl3):δ=2.25 ppm (s, 3H) methyl group at the nitrogen.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH2:9][S:8][CH2:7]1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].[Br-]>[Na+].[I-].CO.C(Cl)(Cl)Cl.CC#N>[F:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[CH2:9][S:8][CH2:7]3)[CH2:21][CH2:20]2)=[CH:17][CH:18]=1
Reactant: O=C1CSCN1CCCCBr
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [I-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=C1CSCN1CCCCN1CCN(c2ccc(F)cc2)CC1
Temperature: 100 °C
Yield: 69.2 %

Procedure:
A mixture of 3-(4-bromobutyl)-4-thiazolidinone (4.01 g), 1-(4-fluorophenyl)piperazine (3.35 g), K2CO3 (4.64 g), NaI (150 mg) and CH3CN (150 ml) was heated at 100° C. (bath temperature) under N2 for 18 h. TLC analysis (silica gel, 8% MeOH/CHCl3) showed one major product at Rf =0.36, and the absence of starting bromide. The reaction mixture was cooled to room temperature and concentrated in vacuo to an oil which was taken up in EtOAc. The mixture was filtered to remove the precipitate and the filtrate concentrated in vacuo to an amber oil which solidified under vacuum. The solid (5.86 g) was dissolved in CHCl3 and flash chromatographed (silica gel) and thereafter recrystallized from hexane/CH2Cl2 to yield in two crops 3.93 g of white crystals, mp 83°-85° C. TLC analysis showed a trace of slower moving impurity. Recrystallization from hexane/CH2Cl2 afforded 3.1 g of white needles which were still slightly impure by TLC. The material was again flash chromatographed (silica gel) and recrystallized from hexane/CH2Cl2 to give 2.67 g of pure product, mp 84°-85° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]#[C:10][C:11]2[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=2)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:6]([C:24]([F:27])([F:26])[F:25])=[CH:5][N:4]=1>C1COCC1.[Pd]>[CH3:1][S:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=2)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:6]([C:24]([F:25])([F:26])[F:27])=[CH:5][N:4]=1
Reactant: CSc1ncc(C(F)(F)F)c(C#Cc2cccc(C(=O)OC(C)(C)C)c2)n1
Agent: [Pd]
Solvent: C1CCOC1
Product: CSc1ncc(C(F)(F)F)c(CCc2cccc(C(=O)OC(C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
tert-Butyl 3-((2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)benzoate (I18) (0.624 g, 1.58 mmol) and 10% Pd/C (0.206 g) was taken up in THF (20 mL) and H2 bubbled through the mixture for 5 minutes before stirring at room temperature for 20 hours under a hydrogen atmosphere. The mixture was filtered through celite and concentrated under reduced pressure. This procedure was repeated twice with 10% Pd/C (0.212 g) and 20% Pearlman's catalyst (0.316 g) respectively to give the title compound (I19) as a yellow oil that was reacted without further purification. LCMS Method C: rt 7.14 min.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C#N.[NH2:45][C:46](=[N:58]O)[C:47]1[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[C:49]([F:57])[CH:48]=1.CCN(C(C)C)C(C)C>C1COCC1>[F:57][C:49]1[CH:48]=[C:47]([C:46]2[N:45]=[C:13]([C:12]3[CH:11]=[CH:10][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:19])[F:18])=[CH:17][CH:16]=3)[O:15][N:58]=2)[CH:56]=[CH:55][C:50]=1[C:51]([O:53][CH3:54])=[O:52]
Reactant: COC(=O)c1ccc(C(N)=NO)cc1F
Reactant: O=C(O)c1ccc(-c2ccccc2C(F)(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: N#CC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-c2noc(-c3ccc(-c4ccccc4C(F)(F)F)cc3)n2)cc1F
Temperature: 100 °C
Yield: 70 %

Procedure:
In a microwave vial were added 4-(2-trifluoromethylphenyl)benzoic acid (Fluorochem, 53.2 mg; 0.20 mmol; 1 eq.), triphenylphosphine polymer bound (375 mg; 0.60 mmol; 3 eq.) and trichloroacetonitrile (30 μl; 0.30 mmol; 1.50 eq.). Anhydrous THF (2 mL) was added and the reaction vessel was sealed and heated to 100° C. for 5 min in the microwave. After cooling, the reaction vessel was uncapped and without filtering, Intermediate 1 (46.7 mg; 0.22 mmol; 1.10 eq.) in anhydrous THF (2 mL) was added to the solution along with DIEA (69 μl; 0.40 mmol; 2 eq.). The reaction was capped and heated at 150° C. for 15 min. After cooling, the reaction vessel was uncapped again and the resin was filtered, the filtrate passed through an NH2 SPE column (2 g) and washed by additional THF (2×2 mL). Solvents were evaporated, affording the title compound as a brown solid (61.9 mg; 70%). It was used in the next step without further purification. LC/MS (Method A): 443.3 (M+H)+. HPLC (Method A), Rt 5.98 min (Purity: 87.9%).
Reaction SMILES: [I-].[CH2:2]([N+:6]1[N:10]=[C:9]([CH3:11])[S:8][C:7]=1[CH3:12])[CH2:3][CH2:4][CH3:5].C1CCN2C(=NCCC2)CC1.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29]([N:31]=[C:32]=[O:33])[CH:30]=1>O>[CH2:2]([N:6]1[N:10]=[C:9]([CH3:11])[S:8]/[C:7]/1=[CH:12]\[C:32]([NH:31][C:29]1[CH:30]=[C:25]([Cl:24])[CH:26]=[CH:27][C:28]=1[O:34][CH3:35])=[O:33])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: COc1ccc(Cl)cc1N=C=O
Agent: [I-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCCCN1N=C(C)S/C1=C\C(=O)Nc1cc(Cl)ccc1OC

Procedure:
A solution of the product from Example 47A (149 mg, 0.5 mmol), DBU (105 μL, 0.75 mmol) and 5-chloro-2-methoxy phenyl isocyanate (91 mg, 0.5 mmol) was stirred overnight. The solution was diluted with water (10 mL), extracted with dichloromethane (3×5 mL). The organic layers were combined, washed with brine, dried with sodium sulfate and concentrated in vacuo. The residue was purified by the HPLC procedure specified in Example 47B to obtain the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.5 Hz, 3 H), 1.27-1.39 (m, 2 H), 1.64-1.75 (m, 2 H), 2.36 (s, 3 H), 3.82-3.91 (m, 5 H), 5.81 (s, 1 H), 6.92-7.01 (m, 2 H), 8.36 (d, J=2.4 Hz, 1 H), 8.68 (s, 1 H); MS (ESI) m/z 354 (M+H)+. Anal. Calcd for C16H20ClN3O2S.0.5 C2HF3O2: C, 48.92; H, 4.92; N, 9.99. Found: C, 49.28; H, 5.09; N, 10.07.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.C1([SiH3])C=CC=CC=1>C1COCC1>[N:15]1([C:18]2[CH:19]=[CH:20][C:21]([NH:22][CH2:1][C:3]3[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=3)=[CH:23][CH:24]=2)[CH2:14][CH2:13][O:12][CH2:17][CH2:16]1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CNc2ccc(N3CCOCC3)cc2)cc1

Procedure:
A suspension of 4-formylbenzoic acid (2.53g; 16.8 mmol; 1 eq), 4-morpholinoaniline (3g; 16.8 mmol; 1 eq) and BU2SnCl2 (510 mg; 1.68 mmol; 0.1 eq) in dry THF (20 ml) was treated with PhSiH3 (3.31 ml; 16.8 mmol; 1 eq) at room temperature for 12 h. The reaction was filtered and the solid product was washed with MeOH. The yield of the reaction was 5.25g (99%). LRMS: calc 312.37; found: 313.2.