Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:65])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[NH:56][C:55]([CH:60]([OH:62])[CH3:61])=[CH:54]4)[CH:46]([O:63][CH3:64])[CH2:45]2)[CH:7]([CH3:66])[CH:6]([OH:67])[CH2:5][C:4]1=[O:68])[CH3:2].[CH3:69][N:70]([CH3:75])[CH2:71][C:72](O)=[O:73].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:65])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[NH:56][C:55]([CH:60]([O:62][C:72](=[O:73])[CH2:71][N:70]([CH3:75])[CH3:69])[CH3:61])=[CH:54]4)[CH:46]([O:63][CH3:64])[CH2:45]2)[CH:7]([CH3:66])[CH:6]([OH:67])[CH2:5][C:4]1=[O:68])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5[nH]c(C(C)O)cc5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: CN(C)CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5[nH]c(C(C)OC(=O)CN(C)C)cc5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 4 h
Yield: 79.4 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-hydroxyethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (26.6 mg) in dry methylene chloride (0.3 mL) was added hydrochloride salt of N,N-dimethylglycine (5.8 mg), DMAP (3.4 mg) and EDC (8 mg), respectively at room temperature. The reaction mixture was stirred for 4 h, then diluted with ethyl acetate and washed with saturated sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuo. The crude material was purified by flash chromatography (1:2/acetone:hexane). to give 23 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:12][C:13]([CH2:16][OH:17])=[N:14][CH:15]=1.[CH:23]1([CH:26]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34](O)[CH:33]=2)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:25][CH2:24]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH:23]1([CH:26]([C:32]2[CH:33]=[CH:34][CH:35]=[C:36]([O:17][CH2:16][C:13]3[CH:12]=[C:11]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[CH:15][N:14]=3)[CH:37]=2)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:25]1
Reactant: COc1ccc(F)c(-c2cnc(CO)cc2OCC(C)C)c1
Reactant: COC(=O)CC(c1cccc(O)c1)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)CC(c1cccc(OCc2cc(OCC(C)C)c(-c3cc(OC)ccc3F)cn2)c1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
Under a nitrogen atmosphere, to a solution of (5-(2-fluoro-5-methoxyphenyl)-4-isobutoxypyridin-2-yl)methanol (214 mg) and methyl 3-cyclopropyl-3-(3-hydroxyphenyl)propanoate (155 mg) in toluene (10 mL) were added 1,1′-(azodicarbonyl)dipiperidine (283 mg) and tributylphosphine (280 μL), and the mixture was stirred at room temperature overnight. Hexane/ethyl acetate (1:1) was added to the reaction mixture, and the resulting precipitate was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (302 mg) as a colorless amorphous solid.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>C(O)(=O)C.[Pt]>[CH2:7]1[CH2:6][CH2:5][CH:4]([CH2:3][C@H:2]([NH2:1])[C:10]([OH:12])=[O:11])[CH2:9][CH2:8]1
Reactant: [H][H]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Pt]
Solvent: CC(=O)O
Product: N[C@@H](CC1CCCCC1)C(=O)O
Yield: 106.1 %

Procedure:
2 g of L-phenylalanine was dissolved in 30 ml of a 50% of acetic acid, and hydrogenated by using 200 mg of platinum as catalyst under elevated pressure (hydrogen pressure: 50 kg/cm2) for 2 hours at a temperature from 40° to 70° C. The catalyst was filtered off and the solvent was distilled off under reduced pressured to obtain 2.2 g of L-cyclohexylalanine as a colorless needle crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[CH:47][C:4]=1[CH2:5][N:6]([C:42]1[S:46][N:45]=[CH:44][N:43]=1)[S:7]([C:10]1[N:15]=[C:14]2[N:16](C(OC(C)(C)C)=O)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=3[C:29]3[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=3)[C:13]2=[CH:12][CH:11]=1)(=[O:9])=[O:8].C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[CH:47][C:4]=1[CH2:5][N:6]([C:42]1[S:46][N:45]=[CH:44][N:43]=1)[S:7]([C:10]1[N:15]=[C:14]2[NH:16][CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][C:20]=3[C:29]3[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=3)[C:13]2=[CH:12][CH:11]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccnn4C)cn(C(=O)OC(C)(C)C)c3n2)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccnn4C)c[nH]c3n2)c(OC)c1
Reaction time: 3 h
Yield: 89.4 %

Procedure:
A 50-mL round-bottom flask was charged with tert-butyl 6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (469 mg, 0.621 mmol) and THF (4 mL) to give a clear solution. Tetra-n-butylammonium fluoride (1M in THF) (3103 μl, 3.10 mmol) was added in one portion. The mixture was stirred for 3 h, then diluted with EtOAc. The organic solution was washed with a saturated aq. ammonium chloride solution, washed with water (2×), washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (10 to 60% EtOAc/Heptane) to give N-(2,4-dimethoxybenzyl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-6-sulfonamide (363.86 mg, 0.555 mmol, 89% yield) as an off-white foam. 1H NMR (400 MHz, DMSO-d6) δ=12.68 (s, 1 H), 8.36 (s, 1 H), 8.09 (s, 1 H), 7.98-7.87 (m, 2 H), 7.83-7.79 (m, 1 H), 7.73 (d, J=8.3 Hz, 1 H), 7.43-7.36 (m, 2 H), 6.98 (s, 1 H), 6.46-6.31 (m, 3 H), 5.18 (s, 2 H), 3.70 (s, 3 H), 3.69 (s, 3 H), 3.26 (s, 3 H). m/z (ESI) 656.2 (M+H)+.
Reaction SMILES: [OH2:1].C([O-])(=O)C.[Na+].Cl.[NH2:8]O.[C:10]1(=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1>C(O)C>[C:10]1(=[N:8][OH:1])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: NO
Reactant: O=C1CCCc2ccccc21
Reactant: O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1CCCc2ccccc21
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
To 4.6L of water at room temperature in a 4-neck 50 L flask sitting in a steam bath apparatus equipped with an overhead stirrer, a temperature probe and reflux condenser was added 3.72 Kg (27.36 mol) of sodium acetate with stirring, followed by 1.9 Kg of hydroxylamine hydrochloride (27.36 mol). To this slurry at room temperature, 12 L of ethanol was added followed by 1.994 Kg (13.68 mol) of 1-tetralone. Additional ethanol (1.7 L) was used to rinse off the funnel and added to the reaction mixture. The resulting light orange slurry was heated to 75° C. over 40 minutes and maintained at 75°-85° C. for another 75 minutes. The reaction mixture was cooled with the aid of ice packed around the flask. When the internal temperature reached 32° C., the reaction mixture was pumped over 15 minutes into 60 L of ice contained in a 200 L vessel. The reaction vessel was washed with an additional 2 L of water which was added to the 200 L vessel. When the ice melted, the mixture was filtered through a filter pad and the wet cake washed with 4 L of water. The wet cake was suction dried for 1 hour then transferred to two trays and dried under vacuum at a40° C. for 2 days to give 2.094 Kg (13.01 mol, 95%) of product. 1H NMR (250 MHz, CDCl3): 1.90 (m,2 H), 2.80 (t,6 Hz,2H), 2.88 (t,6 Hz,2H), 7.15-7.35 (m,3H), 7.90 (d,8 Hz,1H), 8.9 (br s,1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][C:12]1=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C2C=CC=CC=2NC1=O.BrCCCCCCCC.[CH3:40][O:41][C:42](=[O:51])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]Br>CN(C=O)C>[CH3:40][O:41][C:42](=[O:51])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:11]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:12]1=[O:20]
Reactant: COC(=O)CCCCCCCBr
Reactant: CCCCCCCCn1c(=O)[nH]c2ccccc21
Agent: O=c1[nH]c2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCCCBr
Solvent: CN(C)C=O
Product: CCCCCCCCn1c(=O)n(CCCCCCCC(=O)OC)c2ccccc21

Procedure:
The product is produced as described in example 1 from 0.9 g. of NaH (80% suspension in mineral oil), 7.5 g. of 1-octylbenzimidazolin-2-one (produced) by alkylation from benzimidazolin-2-one with bromooctane according to example 8), 100 cc. of DMF, 7.1 g. of 8-bromocaprylic acid methyl ester and 0.9 g. of NaJ. Eluant in chromatographic purification: hexane/ethylacetate.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=[CH:13][C:8]=2[O:7][CH:6]=1.C(N(CC)CC)C.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31]>C(Cl)Cl>[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30]([NH:2][CH2:3][CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=[CH:13][C:8]=2[O:7][CH:6]=1)=[O:31]
Reactant: COC(=O)c1ccc2occ(CCN)c2c1
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2occ(CCNC(=O)c3ccco3)c2c1
Reaction time: 0.33 h

Procedure:
1 mmol of the compound obtained in Step A is introduced into 30 ml of anhydrous CH2Cl2. The temperature is lowered with the aid of an ice bath, and 1.5 mmol of triethylamine and then 1.5 mmol of 2-furoic acid chloride are added dropwise in succession. The mixture is stirred for 20 minutes, and the organic phase is then washed with water, dried over MgSO4 and evaporated. The residue is purified by chromatography on a silica gel column and the title product is recrystallised.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH2:23]Br)[CH:7]=1)[CH3:2].[F:26][C:27]([F:31])([F:30])[CH2:28][SH:29]>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH2:23][S:29][CH2:28][C:27]([F:31])([F:30])[F:26])[CH:7]=1)[CH3:2]
Reactant: FC(F)(F)CS
Reactant: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc([N+](=O)[O-])cc2CBr)c1
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1

Procedure:
As described for Example 21, [3-(2-bromomethyl-4-nitro-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester and 2,2,2-trifluoroethanethiol were reacted to provide {4-chloro-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester, which was reduced to the amine and then treated with pivaloyl chloride to provide {4-chloro-3-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester provided the acid.
Reaction SMILES: ClC1C=C(C=C(Cl)C=1)[C:5](Cl)=[O:6].Cl[C:13]1[CH:14]=[C:15]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28]CC)=[O:27])=[CH:21][CH:20]=1)=[O:17].ClC1C=C(C=C(Cl)C=1)C(NC1C=CC(CC(O)=O)=CC=1)=O>>[Cl:34][C:32]1[CH:33]=[CH:13][C:14]([O:6][CH3:5])=[C:15]([CH:31]=1)[C:16]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:23][CH:24]=1)=[O:17]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2cc(Cl)cc(Cl)c2)cc1
Agent: O=C(O)Cc1ccc(NC(=O)c2cc(Cl)cc(Cl)c2)cc1
Product: COc1ccc(Cl)cc1C(=O)Nc1ccc(CC(=O)O)cc1

Procedure:
with 3,5-dichlorobenzoyl chloride, ethyl 4-(3,5-dichlorobenzamido)-phenylacetate; m.p. 152° C. (crude melting point); and from this, by saponification, 4-(3,5-dichlorobenzamido)-phenylacetic acid; m.p. 189° C., after recrystallization from ethanol-water.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].S(=O)(=O)(O)O.[CH3:20]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:20])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a solution of 4-chlor-3-(trifluoromethyl)benzoic acid (1037 g, 46.2 mmol) in methanol (100 mL) was added concentrated sulfuric acid (0.51 mL, 9.24 mmol). The mixture was heated under reflux overnight. The mixture was allowed to cool to room temperature and concentrated under reduced pressure to form a solid. The solid was filtered and washed with water. The solid was then stirred with saturated aqueous sodium bicarbonate solution to remove any residual sulfuric acid, filtered and dried under vacuum to give the title compound as a white solid (10.18 g). 1H NMR (400 MHz, CDCl3) δ ppm 3.96 (s, 31), 7.60 (d, J=8.34 Hz, 1H), 8.14 (dd, J=8.34, 2.02 Hz, 1H), 8.37 (d, J 2.02 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH2:15][OH:16])=[CH:13][N:12]=[C:11]([NH:17][CH2:18][CH2:19][NH:20]C(OC(C)(C)C)=O)[N:10]=1>FC(F)(F)C(O)=O>[NH2:20][CH2:19][CH2:18][NH:17][C:11]1[N:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:14]([CH2:15][OH:16])=[CH:13][N:12]=1
Reactant: CC(C)(C)OC(=O)NCCNc1ncc(CO)c(-c2ccc(Cl)cc2Cl)n1
Solvent: O=C(O)C(F)(F)F
Product: NCCNc1ncc(CO)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(2-{[4-(2,4-dichlorophenyl)-5-(hydroxymethyl)pyrimidin-2-yl]amino}ethyl)(tert-butoxy)carboxamide (372 mg, 0.90 mmol) was dissolved in 2 mL of anhdyrous trifluoroacetic acid and stirred at room temperature for 2 h. Evaporation of the solvent afforded {2-[(2-aminoethyl)amino]-4-(2,4-dichlorophenyl)pyrimidin-5-yl]methan-1-ol, as its trifluoracetate salt, in quantitative yield.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([CH2:9][O:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1.[H-].[Na+].[CH2:23]([C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)=[N:27][C:26]=1[CH2:40]I)[CH3:24].O>CC(OC)(C)C>[CH2:23]([C:25]1[O:29][C:28]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=2)=[N:27][C:26]=1[CH2:40][O:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([CH2:9][O:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1)[CH3:24]
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)nc1CI
Reactant: CC(C)(C)OC(=O)C(C)(C)OC[C@@H]1CCC[C@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)nc1COC[C@@H]1CCC[C@H](COC(C)(C)C(=O)OC(C)(C)C)C1

Procedure:
300 mg of tert-butyl 2-((1R,3S)-3-hydroxymethylcyclohexylmethoxy)-2-methylpropionate are dissolved in 10 ml of MTBE, and 50 mg of sodium hydride (60% in mineral oil) are added. After gas evolution ceases, 600 mg of 5-ethyl-4-iodomethyl-2-(4-trifluoromethylphenyl)oxazole are added, and the suspension is heated under reflux overnight. After addition of water and MTBE, the phases are separated, and the organic phase is washed with saturated sodium chloride solution, dried over MgSO4 and concentrated. The residue is purified by preparative HPLC, resulting in 190 mg of tert-butyl 2-{(1S,3R)-3-[5-ethyl-2-(4-trifluoromethylphenyl)oxazol-4-ylmethoxymethyl]-cyclohexylmethoxy}-2-methylpropionate as yellow oil.
Reaction SMILES: C([CH:3]([C:5]1[N:6]=[C:7]([CH2:11][N:12]([CH3:14])[CH3:13])[S:8][C:9]=1[CH3:10])O)C.Cl.[NH2:16][CH2:17][CH2:18][SH:19].Br>>[CH3:14][N:12]([CH2:11][C:7]1[S:8][C:9]([CH3:10])=[C:5]([CH2:3][S:19][CH2:18][CH2:17][NH2:16])[N:6]=1)[CH3:13]
Reactant: CCC(O)c1nc(CN(C)C)sc1C
Reactant: NCCS
Agent: Br
Agent: Cl
Product: Cc1sc(CN(C)C)nc1CSCCN

Procedure:
Following the procedure of Example 3, a reaction mixture consisting of 6.4 g. of ethyl 2-(dimethylaminomethyl)-5-methyl-4-thiazolemethanol, 4.2 g. of cysteamine hydrochloride and 30 ml. of 48% aqueous hydrobromic acid was maintained at a temperature of about 100° C. under a nitrogen atmosphere for about 4 hours. The reaction mixture was cooled and the volatile constituents removed in vacuo. The resulting dark residue was twice trituated with ethanol and the ethanol removed by evaporation to remove residual HBr. The residue was then treated with 50 ml. of 5 N aqueous sodium hydroxide. The alkaline layer was continuously extracted with ether over an 18 hour period. The ether extract was dried and the ether removed therefrom in vacuo to provide 2-([2-(dimethylaminomethyl)-5-methyl-4-thiazolyl]methylthio)ethylamine prepared in the above reaction. The compound was a brown oil having the following physical characteristics: yield=1.38 g.
Reaction SMILES: Cl.[C:2]([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:25]4[CH:26]=[CH:27][C:28]([C:30]5[CH:35]=[CH:34][C:33]([C:36]([N:38]6[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]6)=[O:37])=[CH:32][CH:31]=5)=[CH:29][C:24]4=[N:23][CH:22]=3)=[CH:17][C:16]=2[F:44])=[O:13])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:45][C:46]([CH3:48])=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:2]([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:25]4[CH:26]=[CH:27][C:28]([C:30]5[CH:35]=[CH:34][C:33]([C:36]([N:38]6[CH2:39][CH2:40][N:41]([CH:46]([CH3:48])[CH3:45])[CH2:42][CH2:43]6)=[O:37])=[CH:32][CH:31]=5)=[CH:29][C:24]4=[N:23][CH:22]=3)=[CH:17][C:16]=2[F:44])=[O:13])[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cnc4cc(-c5ccc(C(=O)N6CCNCC6)cc5)ccn34)cc2F)no1
Reactant: CC(C)=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)N1CCN(C(=O)c2ccc(-c3ccn4c(-c5ccc(NC(=O)Nc6cc(C(C)(C)C)on6)c(F)c5)cnc4c3)cc2)CC1
Reaction time: 0.08 h
Yield: 6.5 %

Procedure:
Dissolve 1-(5-tert-butyl-isoxazol-3-yl)-3-(2-fluoro-4-{7-[4-(piperazine-1-carbonyl)-phenyl]-imidazo[1,2-a]pyridin-3-yl}-phenyl)-urea hydrochloride (0.290 g, 0.469 mmol) in methanol (5 mL) and acetone (0.041 mL, 0.563 mmol). Add acetic acid (0.032 mL, 0.563 mmol); stir the mixture for five minutes. Add sodium cyanoboro-hydride (0.053 g, 0.845 mmol). Stir the mixture at room temperature for 14 hours. Concentrate to dryness and quench with 1 N HCl (5 mL). Partition between ethyl acetate and 1 N NaOH, wash with aqueous saturated sodium chloride, dry the organics over magnesium sulfate, filter, and concentrate. Purify by column chromatography (hexanes→5% methanol in dichloromethane→10% methanol in dichloromethane→10% 2 M NH3 in methanol in dichloromethane) to afford product (0.019 g, 7%). MS(ES), m/z 624 (M+1).
Reaction SMILES: ClC1C=NC=C(Cl)C=1[NH:8][C:9]([C:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([NH2:24])[CH:21]=3)[N:16]([CH3:25])[C:15]=2[C:14]([O:26][CH3:27])=[CH:13][CH:12]=1)=[O:10].N1C=CC=CC=1.[CH2:35]([S:37](Cl)(=[O:39])=[O:38])[CH3:36]>C1COCC1>[CH3:27][O:26][C:14]1[C:15]2[N:16]([CH3:25])[C:17]3[C:22](=[CH:21][C:20]([NH:24][S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])=[CH:19][CH:18]=3)[C:23]=2[C:11]([C:9]([NH2:8])=[O:10])=[CH:12][CH:13]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3cc(N)ccc3n(C)c12
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCS(=O)(=O)Nc1ccc2c(c1)c1c(C(N)=O)ccc(OC)c1n2C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30.7 %

Procedure:
N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-amino-9H-4-carbazolecarboxamide (75 mg, 0.00018 mol) was suspended in THF (5 ml) and added with pyridine (28 mg, 0.00036 mol) and stirred at room temperature for 10 minutes. The solution obtained, was added with a solution of ethane sulphonyl chloride (34 mg, 0.00027 mol) in dry THF (5 ml). The reaction mixture was stirred for 1 hr THF was evaporated and the solid was washed with water to get crude solid which was column chromatographed using 10% methanol in chloroform to give N-3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-ethane sulphonamido-9H-4-carbazolecarboxamide (20 mg), mp>250° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:18])[N:4]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[CH2:28]Br>CC(N(C)C)=O.O>[Cl:1][C:2]1[C:3](=[O:18])[N:4]([C:10]2[C:11]([F:17])=[CH:12][CH:13]=[CH:14][C:15]=2[F:16])[C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:28][C:27]1[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:26]=1[F:25]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: Cc1cc(O)c(Cl)c(=O)n1-c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-chloro-1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.27 g, 1.00 mmol) in DMA (5 mL) was added K2CO3 followed by the addition of 2,4-difluorobenzyl bromide (0.128 mL, 1 mmol). The reaction mixture stirred at room temperature for 2 hours and then was diluted in water. The reaction mixture was extracted with ethyl acetate, the organic extracts were dried over Na2SO4 and the filtrate was concentrated. The resulting residue was purified by flash column chromatography (ethyl acetate/hexane 3:4 v/v) to afford the desired product. 1H-NMR (CD3OD, 400 MHz) δ 7.60 (m, 2H), 7.25 (m, 2H), 7.04 (m, 2H), 6.71 (s, 1H), 5.36 (s, 2H), 2.11 (s, 3H); ES-HRMS m/z 398.0551 (M+H calculated for C19H13NO2F4Cl requires 398.0571).
Reaction SMILES: NC1C(NC2C=CC=C(O)C=2)=NC(NC2C=CC=C(O)C=2)=NC=1C(OCC)=O.[CH2:29]([O:31][C:32]([C:34]1[N:39]=[C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]3[O:47][CH2:48][CH2:49][O:50][C:43]=3[CH:42]=2)[N:37]=[C:36]([NH:51][C:52]2[CH:57]=[CH:56][C:55]3[O:58][CH2:59][CH2:60][O:61][C:54]=3[CH:53]=2)[C:35]=1[N+:62]([O-])=O)=[O:33])[CH3:30].[H][H]>[Pd]>[NH2:62][C:35]1[C:36]([NH:51][C:52]2[CH:57]=[CH:56][C:55]3[O:58][CH2:59][CH2:60][O:61][C:54]=3[CH:53]=2)=[N:37][C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]3[O:47][CH2:48][CH2:49][O:50][C:43]=3[CH:42]=2)=[N:39][C:34]=1[C:32]([O:31][CH2:29][CH3:30])=[O:33]
Reactant: CCOC(=O)c1nc(Nc2ccc3c(c2)OCCO3)nc(Nc2ccc3c(c2)OCCO3)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: CCOC(=O)c1nc(Nc2cccc(O)c2)nc(Nc2cccc(O)c2)c1N
Product: CCOC(=O)c1nc(Nc2ccc3c(c2)OCCO3)nc(Nc2ccc3c(c2)OCCO3)c1N

Procedure:
In a manner similar to the preparation of 5-amino-6-ethoxycarbonyl-N2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine, 6-ethoxycarbonyl-N2,N4-bis(3,4-ethylenedioxyphenyl)-5-nitro-2,4-pyrimidinediamine, hydrogen, and 10% Pd/C were reacted to yield 5-amino-6-ethoxycarbonyl-N2,N4-bis(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.16 (d, 1H, J=2.4 Hz), 7.07 (d, 1H, J=2.4 Hz), 7.04 (dd, 1H, J=2.4 and 9.0 Hz), 6.84-6.79 (m, 2H), 6.70 (d, 1H, J=9.0), 4.43 (q, 2H, J=7.8 Hz), 4.25 (s, 4H), 4.21 (bs, 4H), 1.43 (t, 3H, J=7.8 Hz); LCMS: ret. time: 23.70 min.; purity: 100%; MS (m/e): 466 (MH+).