Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[O:18])=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[C:7]([CH:11]=1)[C:8](O)=[O:9].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][CH2:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[C:4]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[O:18])=[CH:5][C:6]([C:12]([F:15])([F:13])[F:14])=[C:7]([CH:11]=1)[C:8]([NH:51][CH2:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1)=[O:9]
Reactant: COc1cc(C(=O)O)c(C(F)(F)F)cc1NC(=O)Nc1cnc(C)cn1
Reactant: NCCc1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCCc2ccccn2)c(C(F)(F)F)cc1NC(=O)Nc1cnc(C)cn1
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
To a stirred solution of 5-methoxy-4-[3-(5-methyl-pyrazin-2yl)-ureido]-2-trifluoromethyl-benzoic acid (37 mg, 0.1 mmol) in 1 mL NMP at room temperature in a capped reaction vial was added HBTU (42 mg, 0.11 mmol) and the suspension stirred for 15 minutes. 2-aminoethylpyridine (13 μL, 0.11 mmol) was added followed by DIEA (35 μL, 0.2 mmol) and the reaction was stirred overnight. NMP was then removed by bulb to bulb transfer under high vacuum at 70° C. and the residue triturated and filtered with EtOAc to give the desired amide as a tan solid (32 mg, 68%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH:47]([CH3:49])[CH3:48])=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH:47]([CH3:48])[CH3:49])=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: CC(C)c1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: CC(C)c1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(6-isopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K22) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light brown substance (368 mg, 77%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH:19]([CH3:21])[CH3:20])=[CH:10][C:11]=2/[C:13](/[CH3:18])=[C:14](/[F:17])\[CH2:15][OH:16])[C:6]([CH3:23])([CH3:22])[CH2:5][CH2:4]1)[CH3:2].[CH3:24][N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:17]/[C:14](=[C:13](/[C:11]1[CH:10]=[C:9]([CH:19]([CH3:20])[CH3:21])[CH:8]=[C:7]2[C:12]=1[N:3]([CH2:1][CH2:2][CH3:24])[CH2:4][CH2:5][C:6]2([CH3:22])[CH3:23])\[CH3:18])/[CH2:15][OH:16]
Reactant: CCN1CCC(C)(C)c2cc(C(C)C)cc(/C(C)=C(/F)CO)c21
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(/C(C)=C(/F)CO)c21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of (E)-3-(1-ethyl-6-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-8-yl)-2-fluoro-but-2-en-1-ol (Intermediate 18, 133 mg, 0.35 mmol) in 2 ml of CH2Cl2 at 0° C. was added 4-methylmorpholine N-oxide (83 mg, 0.71 mmol), tetrapropylammonium perruthenate (18.6 mg, 0.05 mmol), and 4 Å molecular sieve powder (10 mg). The mixture was stirred at 0° C. for 5 min, and the bath was removed. The temperature of reaction mixture was monitored carefully, and as soon as the temperature rose to 25° C., the reaction was re-cooled in an ice bath. The cooled reaction mixture was loaded onto a pre-packed silica gel column, and the product was eluted with 100% hexane followed by 2% ethyl acetate in hexane to yield the title compound as a bright yellow solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](CC(N3CCOCC3)=S)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:19]([OH:22])(=[O:21])[CH3:20].S(=O)(=O)(O)O>O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:20][C:19]([OH:22])=[O:21])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: S=C(Cc1ccc2c(c1)CCO2)N1CCOCC1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)CCO2

Procedure:
2,3-dihydrobenzofuran-5-ylthioacetic acid morpholide (5.0 g) was heated at reflux in a solution of acetic acid (20 ml), concentrated sulfuric acid (3.0 ml) and water (4.5 ml). After 3 hours the reaction mixture was cooled and added to water. The product was extracted with ethyl acetate and the combined extracts washed five times with water. The organic solution was then extracted with aqueous saturated sodium bicarbonate solution. The aqueous solution was then acidified and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated to give a residue which was recrystallized from acetone/hexane to give 2,3-dihydrobenzofuran-5-ylacetic acid, m.p. --96°-98° C.
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([N:18]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:17])[CH2:12][CH2:11]2)=[N:8][CH:9]=1)#[N:3].[C:25]1(=O)[CH2:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(Cl)Cl>[ClH:1].[CH:25]1([N:21]2[CH2:22][CH2:23][CH2:24][N:18]([C:16]([CH:13]3[CH2:12][CH2:11][N:10]([C:7]4[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:9][N:8]=4)[CH2:15][CH2:14]3)=[O:17])[CH2:19][CH2:20]2)[CH2:28][CH2:27][CH2:26]1
Reactant: N#Cc1ccc(N2CCC(C(=O)N3CCCNCC3)CC2)nc1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(N2CCC(C(=O)N3CCCN(C4CCC4)CC3)CC2)nc1
Reaction time: 0.08 h

Procedure:
1-[1-(5-Cyanopyridin-2-yl)-piperidine-4-carbonyl]-[1,4]-diazepane hydrochloride (D14) (0.30 g) was dissolved in DCM (10 ml) and TEA (0.4 ml) was added followed by cyclobutanone (0.14 ml). The reaction was stirred for 5 min under argon and then sodium triacetoxyborohydride (0.41 g) was added and the reaction stirred at rt for 4 h. The reaction mixture was washed with saturated aqueous potassium carbonate (2×30 ml), saturated sodium hydrogen carbonate (2×50 ml) and brine (50 ml). The organic layer was then dried (MgSO4) and evaporated to a crude which was purified by column chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM] to give the free base product which was converted to the HCl salt by redissolving in DCM and then treating with excess hydrogen chloride (1M solution in diethyl ether) and concentrating to yield the title compound (E37) as a pale yellow solid (0.047 g). MS electrospray (+ve) 368 (MH+). 1H NMR δ [DMSO-d6]: 10.80-10.50 (1H, m), 8.47 (1H, s), 7.83 (1H, d, J=8.8 Hz), 6.95 (2H, d, J=8.8 Hz), 4.44 (2H, m), 4.05 (1H, m), 3.85-3.28 (6H, m), 3.07-2.72 (5H, m), 2.41-2.01 (6H, m), 1.82-1.41 (6H, m).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)=[CH:11][CH:10]=2)=[O:7])=[N:2]1.Cl[C:29]1[N:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:36][C:35]([F:38])([F:37])[C:32]1[CH:31]=[N:30][C:29]([N:1]2[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([C@@H:15]4[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]4)=[CH:11][CH:10]=3)=[O:7])=[N:2]2)=[N:34][CH:33]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cc[nH]n3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3ccn(-c4ncc(C(F)(F)F)cn4)n3)cc2)C1
Reaction time: 20 h
Yield: 23.8 %

Procedure:
(S)-tert-Butyl 2-(4-(1H-pyrazole-3-carboxamido)phenyl)morpholine-4-carboxylate (33 mg, 0.089 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (16.2 mg, 0.089 mmol) were dissolved in DMSO (0.7 ml) and potassium carbonate (24.5 mg, 0.177 mmol) was added. The reaction mixture was placed on a Büchi shaker for 20 hours at 120° C. After cooling the mixture, water was added followed by extraction with ethyl acetate twice. The combined organic layers were dried over MgSO4 and evaporated. The crude material was purified by flash chromatography (silica gel, 5 g, 25% to 50% EtOAc in heptane) to yield an off-white solid (11 mg, 24%). MS (ISP): 463.1 (100%, [M−tBu+H]+), 519.3 (10%, [M+H]+).
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][CH2:11]I)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C1C=CC=CC=1.CN(C=O)C.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:5]([O:8][CH2:9][CH2:10][CH2:11][C:20]([C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][CH:23]=1)=[O:21])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[Si](C)(C)OCCCI
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
A mixture of Zn—Cu couple (2.68 g, 41.3 mmol) and tert-butyl(3-iodopropoxy)dimethylsilane (8.26 g, 27.5 mmol) in benzene (55 mL) and DMF (3.6 mL) was stirred vigorously at room temperature for 1 hour, heated to 60° C. for 4 hours, cooled to room temperature, and treated with a solution of 4-nitrobenzoyl chloride (3.4 g, 18.3 mmol) and (Ph3P)4Pd (0.847 g, 0.73 mmol) in benzene (36 mL) by cannula. The mixture was stirred for 1 hour, filtered through diatomaceous earth (Celite™), and partitioned between saturated NH4Cl and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5% ethyl acetate/hexanes to provide 2.81 g of the desired product. MS(ESI(−)) m/e 322 (M−H)−.
Reaction SMILES: I[CH2:2][CH3:3].[Br:4][C:5]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:9]([F:18])[C:8]([OH:19])=[C:7]([CH:20]=[O:21])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:4][C:5]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:9]([F:18])[C:8]([O:19][CH2:2][CH3:3])=[C:7]([CH:20]=[O:21])[CH:6]=1
Reactant: O=Cc1cc(Br)c(-c2ccc(F)cc2)c(F)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1c(C=O)cc(Br)c(-c2ccc(F)cc2)c1F
Temperature: 60 °C
Reaction time: 5 h
Yield: 95.8 %

Procedure:
Iodoethane (2.54 g) was added to a mixture of 6-Bromo-2,4′-difluoro-3-hydroxybiphenyl-4-carbaldehyde (3.40 g) and potassium carbonate (3.00 g) in DMF (35 mL) at room temperature. The mixture was stirred at 60° C. under nitrogen atmosphere for 5 hours. The mixture was quenched with water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.55 g).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9](=[CH:17][C:18]1[CH:23]=[C:22]([C:24]2[C:28]([Cl:29])=[C:27]([O:30][CH:31]([F:33])[F:32])[N:26]([CH3:34])[N:25]=2)[C:21]([Cl:35])=[CH:20][C:19]=1[Cl:36])[C:10]([O:12]C(C)(C)C)=[O:11]>ClCCl>[Cl:8][C:9](=[CH:17][C:18]1[CH:23]=[C:22]([C:24]2[C:28]([Cl:29])=[C:27]([O:30][CH:31]([F:32])[F:33])[N:26]([CH3:34])[N:25]=2)[C:21]([Cl:35])=[CH:20][C:19]=1[Cl:36])[C:10]([OH:12])=[O:11]
Reactant: Cn1nc(-c2cc(C=C(Cl)C(=O)OC(C)(C)C)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(-c2cc(C=C(Cl)C(=O)O)c(Cl)cc2Cl)c(Cl)c1OC(F)F

Procedure:
85 ml of trifluoroacetic acid were added dropwise to a solution of 34.4 g (70 mmol) of tert-butyl 2-chloro-3-(2,4-dichloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)phenyl)-propenoate in 85 ml of dichloromethane. After 3 hours the mixture was concentrated. The residue was triturated with n-hexane, then filtered off and dried. Yield: 19.9 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:33])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH2:31][CH3:32])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:36][S:37]([CH2:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:39])=[O:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:33])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:46]3[CH2:45][CH2:44][N:43]([CH2:42][CH2:41][CH2:40][S:37]([CH3:36])(=[O:38])=[O:39])[CH2:48][CH2:47]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH2:31][CH3:32])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1ccccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1ccccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% of 1:1 ethanol/acetonitrile in carbon dioxide). HR-MS (ES, m/z) calculated for C34H41N4O4SCl2 [(M+H)+] 671.2220, observed 671.2218.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:10]=[CH:11][C:12]([C:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH:27]=2)=[N:13][C:14]=1[C:15]1[O:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18][N:19]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:20]1([C:17]2[O:16][C:15]([C:14]3[C:9]([NH2:8])=[N:10][CH:11]=[C:12]([C:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH:27]=4)[N:13]=3)=[N:19][N:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3nnc(-c4ccccc4)o3)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(C2=CCNCC2)nc1-c1nnc(-c2ccccc2)o1
Reaction time: 8 h
Yield: 152.6 %

Procedure:
Tert-butyl 4-(5-(bis(tert-butoxycarbonyl)amino)-6-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.4 g, 3.867 mmol) was dissolved in DCM (40 mL) and treated with TFA (8 mL, 103.8 mmol). The reaction was allowed to stir overnight and then the solvent was removed in vacuo. The mixture was azeotroped with DCM (×3) and dried under vacuum to give the desired product as an orange solid (1.89 g, 100% Yield).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH:14][C:15]1[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].[CH3:25][C:26]([CH3:28])=O>FC(F)(F)C(O)=O>[OH:24][C:23]1[C:15]2[O:14][C:26]([CH3:28])([CH3:25])[O:18][C:17](=[O:19])[C:16]=2[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)c1cccc(O)c1O
Reactant: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1(C)OC(=O)c2cccc(O)c2O1
Temperature: 25 °C
Yield: 33.9 %

Procedure:
Trifluoroacetic acid anhydride (42.0 mL, 300 mmol) was added dropwise to a cooled (−5° C.) solution of 2,3-dihydroxybenzoic acid (8.30 g, 53.9 mmol) in trifluoroacetic acid (83 mL), with stirring. Acetone (14.0 mL, 190 mmol) was then added dropwise over 27 minutes, and the mixture stirred and allowed to warm gradually to room temperature over 16.5 hours. The volatiles were concentrated under vacuum, the residue was dissolved in ethyl acetate (100 mL), and the solution slowly added to a rapidly stirred saturated aqueous sodium bicarbonate solution (200 mL). After gas evolution ceased, the mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography (ethyl acetate/heptane) to give 8-hydroxy-2,2-dimethyl-4H-1,3-benzodioxin-4-one (123a, 3.55 g, 34% yield) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:12])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH:10]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)([CH3:12])[CH3:9]
Reactant: Cc1ccc(N)cc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1ccc(NC(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
To a stirred solution of 5.65 g (52.7 mmol) p-Toluidine and 3.21 g (55.4 mmol, 1.05 equiv) Acetone in 50 mL DCE is added 14.52 g (68.5 mmol, 1.3 equiv) Sodium triacetoxyborohydride and stirred 18 h at ambient temperature. The reaction mixture is diluted with DCM (200 mL), washed successively with H2O (75 mL), satd. NaHCO3 (75 mL), and brine (75 mL), dried (MgSO4), filtered and concentrated in vacuo to give 7.67 g (51.4 mmol) of Isopropyl-p-tolyl-amine as a pale amber oil: 1H NMR (CDCl3, 300 MHz) δ7.00 (d, 2H, J=8.3), 6.54 (d, 2H, J=8.4), 3.61 (m, 1H), 2.25 (s, 3H), 1.21 (d, 6H, J=6.3); TLC Rf =0.50 (EtOAc/Hexanes, 1:9).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH3:15])=[C:9]([N+:16]([O-])=O)[CH:8]=1)=[O:5].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:31]([N:38]1[C:42](=[O:43])[C:41](=[C:44]2[N:48]([CH3:49])[C:47]3[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=3[S:45]2)[S:40][CH2+:39]1SC)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:38]1[C:42](=[O:43])[C:41](=[C:44]2[N:48]([CH3:49])[C:47]3[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=3[S:45]2)[S:40][C:39]1=[N:16][C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][N:2]([CH3:19])[CH3:1])[CH:12]=[CH:11][C:10]=1[NH:13][CH2:14][CH3:15])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCNc1ccc(NC(=O)CN(C)C)cc1[N+](=O)[O-]
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 2-dimethylamino-4′-ethylamino-3′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 8.85 (1H, s), 7.43 (3H, t), 7.18–7.28 (5H, m), 7.10 (2H, t), 6.95 (1H, d), 6.48 (1H, d), 5.10 (2H, s), 3.71 (3H, s), 3.03 (2H, s), 2.93 (2H, q), 2.33 (6H, s), 0.97 (3H, t); MS(ESI): 584(MH+).
Reaction SMILES: [CH:1]1([NH2:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CO>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][NH:10][CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)[CH3:23]
Reactant: NC1CCc2ccccc21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCOC(=O)CNC1CCc2ccccc21
Temperature: 0 °C
Yield: 41.1 %

Procedure:
To a solution of 13.3 g of 1-indanamine in 100 ml of methanol are added 6.9 g of potassium carbonate and 16.9 g of ethyl bromoacetate, and the mixture is refluxed for 30 minutes. The reaction mixture is poured into 300 ml of ice-water, and subjected to extraction with 500 ml of ethyl acetate. The extract is washed with water, dried, and concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography and eluted with acetone-benzene (1:20) to give 9.0 g of N-(1-indanyl) glycine ethyl ester as a colorless oil. To this oil are added 5 ml of 20% alcoholic hydrochloric acid and 200 ml of ethyl ether, and the mixture is allowed to stand at room temperature to give 9.0 g of N-(1-indanyl)glycine ethyl ester hydrochloride as colorless needles. Melting point: 130°-132° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:3]=1.[CH2:21]([CH2:23][NH2:24])[OH:22].CCN(C(C)C)C(C)C>CCCCO>[O:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:24][CH2:23][CH2:21][OH:22])[CH:3]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: NCCO
Reactant: Clc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: OCCNc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Temperature: 200 °C
Yield: 77 %

Procedure:
78 mg of 6-chloro-N-(4-morpholinophenyl)pyrimidin-4-amine, 33 mg of ethanolamine and 70 mg of DIPEA were dissolved in 2 mL of n-BuOH and the mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. Progress of the reaction was monitored by TLC. Upon termination of the reaction n-BuOH. was evaporated off and the evaporation residue obtained was subjected to crystallization from n-BuOH-EtOH solvent mixture. 2-(6-(4-Morpholinophenylamino)pyrimidin-4-ylamino)ethan-1-ol was obtained in the form of a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][C@@H:9]([CH2:11][P:12]([O:16]C)([O:14]C)=[O:13])[CH2:8][CH2:7][N:6]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:4].C[Si](I)(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][C@@H:9]([CH2:11][P:12]([OH:16])([OH:14])=[O:13])[CH2:8][CH2:7][N:6]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:4]
Reactant: COC(=O)[C@H]1C[C@@H](CP(=O)(OC)OC)CCN1C(=O)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@@H](CP(=O)(O)O)CCN1C(=O)OCc1ccccc1

Procedure:
A mixture of 600 mg of cis-1-benzyloxycarbonyl-4-dimethylphosphonomethyl-2-piperidinecarboxylic acid methyl ester in 10 ml of methylene chloride is treated with 538 mg of trimethylsilyl iodide at room temperature to yield cis 1-benzyloxycarbonyl-4-phosphonomethyl-2-piperidine-carboxylic acid methyl ester as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[CH3:14][O:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[OH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]([O:15][CH3:14])=[O:17])=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(OCCCCCCCCCCCO)cc1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
With 100 ml of 2-butanone were mixed 20.0 g (79.6 mmol) of 11-bromoundecane-1-ol, 11.0 g (72.5 mmol) of methyl p-hydroxybenzoate, and 10.0 g (72.4 mmol) of potassium carbonate. The whole was refluxed for 48 hours. Upon cooling the reaction mixture to room temperature, a large amount of precipitate appeared. The precipitate was collected by filtration under washing with hexane and dried to obtain 20.2 g of methyl p-(11-hydroxyundecyloxy)benzoate (1) (yield: 86.7%).