Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:18])[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=O>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCC>[CH:7](=[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH:9]([CH3:18])[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C(=O)c1cccnc1)c1ccc(Cl)cc1Cl
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCCC=C(c1cccnc1)C(C)c1ccc(Cl)cc1Cl

Procedure:
starting from 2-(2,4-dichlorophenyl)-1-(3-pyridyl)-1-propanone and butyltriphenylphosphonium bromide there is obtained 3-(α-butylidene-2,4-dichloro-β-methyl-phenethyl)-pyridine.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:30][CH2:29][CH2:28][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:27])[CH2:21][S:22]([CH:24]([CH3:26])[CH3:25])=[O:23])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C1CCC(N=C=NC2CCCCC2)CC1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:30][CH2:29][CH2:28][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](=[O:27])[CH2:21][S:22]([CH:24]([CH3:25])[CH3:26])=[O:23])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)S(=O)CC(O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Product: CC(C)S(=O)CC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Yield: 37.6 %

Procedure:
(2S)-1-(N-Benzyloxycarbonyl-L-prolyl)-2-[1-hydroxy-2(isopropylsulfinyl)ethyl]pyrrolidine (1.34 g) was subjected to DMSO-DCC oxidation as in Example 1-D) to give 502 mg of the title compound (See Table 3).
Reaction SMILES: [NH2:1][CH:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:32])([F:31])[CH:28]([F:30])[F:29])[CH:21]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11]CC2C=CC=CC=2)=[CH:7][CH:6]=1)[OH:4]>C(O)C.[Pd]>[NH2:1][CH:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:31])([F:32])[CH:28]([F:29])[F:30])[CH:21]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[OH:4]
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-[4-(benzyloxy)phenyl]-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-propan-1-ol (2.60 g, 5.79 mmol) in ethanol (20 ml) was added 10% palladium/carbon (containing water by 50%, 260 mg), and the mixture was stirred overnight under a hydrogen stream. The catalyst was removed from the reaction solution using celite, and the filtrate was concentrated. The residue was purified neutral alumina column chromatography (ethanol) to give the objective substance (0.80 g, 39%) as an amorphous compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[SH:11].[C:12]1(=O)[O:17][C:15](=[O:16])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>CN1C(=O)CCC1>[F:8][C:7]1[C:2]2[N:1]=[C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[S:11][C:3]=2[C:4]([F:10])=[CH:5][C:6]=1[F:9]
Reactant: O=C1CCC(=O)O1
Reactant: Nc1c(F)c(F)cc(F)c1S
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(O)CCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 100 °C
Yield: 82.7 %

Procedure:
To a solution of 2-amino-3,4,6-trifluorothiophenol (1.79 g, 10 mmol) in NMP (5 ml) was added dropwise a solution of succinic anhydride (1.0 g, 10 mmol) in NMP (5 ml) at ambient temperature under a nitrogen stream and the mixture was heated to 100° C. for 1 hour. The resultant mixture was basified by dilution with aqueous sodium carbonate and washed with ether. The aqueous layer was acidified with 7% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, then dried and evaporated to yield crude crystals, which were washed with hexane-isopropyl ether to give 3-(4,5,7-trifluorobenzothiazol-2-yl)propionic acid 2.16 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH:15]=O)[O:10][N:9]=2)=[CH:4][CH:3]=1.[C:17]1([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:30]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[CH2:25][CH2:26][N:27]([CH2:15][CH2:14][CH2:13][C:11]3[O:10][N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:12]=3)[CH2:28][CH2:29]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=CCCc1cc(-c2ccc(Cl)cc2)no1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1ccc(-c2cc(CCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)on2)cc1
Yield: 95.3 %

Procedure:
About 2 min after dissolving 3-[3-(4-chlorophenyl)isoxazol-5-yl]propanal (10 mg, 0.05 mmol) and 1-(diphenylmethyl)piperazine (11 mg, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (27 mg, 0.13 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 2.75 hr and followed the same processes as in Example 1 to obtain 18 mg (90.8%) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([C:13]([O:15]C)=[O:14])[CH2:10]2)=[CH:5][CH:4]=1.P([O-])([O-])([O-])=O.Cl.CC(=O)OCC(COC(=O)C)OC(=O)C.[OH-].[Na+]>C(O)(C)(C)C.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C@@H:9]([C:13]([OH:15])=[O:14])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)C1CCc2ccc(OC)cc2C1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)(C)O
Solvent: CC(=O)OCC(COC(C)=O)OC(C)=O
Product: COc1ccc2c(c1)C[C@H](C(=O)O)CC2
Reaction time: 6 h

Procedure:
5 g (0.022 mol) of methyl 7-methoxy-1,2,3,4-tetrahydro-2-naphthoate are dissolved in 175 ml of tert-butanol, and 500 ml of phosphate buffer at pH 7 are added to the solution prepared in this way. The pH of the solution, which rises to a value of 7.3-7.5, is lowered to 7.1 by the addition of 1 N HCl. 3.5 g of Sigma PPL enzyme (known as porcine pancreatic lipase type II, crude, Sigma L-3126 - 39 U/mg using triacetin) are added to the mixture. The pH tends to drop as the reaction progresses, but is kept constant by the addition of a 0.25 N solution of NaOH. After 6 hours, when about 31.75 ml of 0.25 N NaOH have been consumed, sodium bicarbonate is added to the solution until the pH is about 8 in order to stop the reaction by inactivation of the enzyme. Extraction is carried out with ethyl ether and the two phases are separated. The organic phase contains the unreacted ester principally of (S) configuration, which can be recovered as indicated in Example 5. The aqueous phase is acidified with concentrated sulfuric acid and the precipitate formed is filtered off to give 1.25 g of the title acid. [α]D20 =+43.67° (c=1.4%, CHCl3); ee 93.27% (HPLC performed under conditions (a)). This product is equivalent to that described in preparation (G) (i) of EP-A-436435, obtained after 10 crystallizations.
Reaction SMILES: C[O:2][C:3](=[O:9])[CH2:4][C@@H:5]([OH:8])[CH2:6]Cl.[CH3:10][N:11]([CH3:13])[CH3:12]>>[OH:8][C@H:5]([CH2:4][C:3](=[O:9])[O-:2])[CH2:6][N+:11]([CH3:13])([CH3:12])[CH3:10]
Reactant: CN(C)C
Reactant: COC(=O)C[C@@H](O)CCl
Product: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Yield: 32 %

Procedure:
An amount of 100 g of (3R)-4-chloro-3-hydroxybutyrylamide of L-tyrosine methylester is submitted to methanolysis under the same operating conditions as reported in Example 2. An amount is obtained of 20 g (70%) of (3R)-4-chloro-3-hydroxybutyric acid methylester with [α]D20 =-23° (c=1.5 in CHCL3). (3R)-4-Chloro-3-hydroxybutyric acid methylester is treated with trimethylamine and L-carnitine is obtained (yield 32%).
Reaction SMILES: CCOP(OCC)([CH:6]1[NH:12][C:10](=[O:11])[NH:9][C:7]1=[O:8])=O.C(N(CC)CC)C.[CH:23]1([O:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[CH:32]=O)[CH2:27][CH2:26][CH2:25][CH2:24]1>C(#N)C>[CH:23]1([O:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[CH:32]=[C:6]2[NH:12][C:10](=[O:11])[NH:9][C:7]2=[O:8])[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C=C2NC(=O)NC2=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
To a stirred solution of diethyl 5-hydantoylphosphonate (10 g, 42.3 mmol) and triethylamine (5.70 g, 56 mmol), in dry acetonitrile (100 ml) at room temperature was added a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (8 g, 36.3 mmol) in dry acetonitrile (75 ml), dropwise over 30 minutes. The resulting mixture was stirred at room temperature overnight, after which volatiles were removed in vacuo. The residue was diluted with 0.05N HCl (120 ml) and the precipitate collected by filtration. Recrystallization of this material with methylene chloride/methanol/diethyl ether afforded the title compound as a pale yellow solid (8.54 g). m.p. 220-222° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13](O)=[O:14])=[CH:12][C:7]=2[N:6]=[C:5]1[NH:16][C:17]1[S:18][C:19]2[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:20]=2[N:21]=1)([CH3:3])[CH3:2].[CH2:31]([NH2:33])[CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:31]([NH:33][C:13]([C:11]1[CH:10]=[CH:9][C:8]2[N:4]([CH:1]([CH3:2])[CH3:3])[C:5]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][C:27]([F:28])([F:30])[F:29])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:6][C:7]=2[CH:12]=1)=[O:14])[CH3:32]
Reactant: CCN
Reactant: CC(C)n1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C(C)C

Procedure:
1-Isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ethylamide (50.0 mg) was prepared by following General Procedure F starting from 1-isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (100.0 mg), ethylamine (2.0 M solution in THF, 0.5 mL), HBTU (130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 465; and 1H NMR (DMSO-d6, 400 MHz): δ 8.43 (1H, m), 8.11 (1H, m), 7.92 (1H, m), 7.71-7.67 (2H, m), 7.36-7.35 (1H, m), 5.15-5.12 (1H, m), 3.32 (2H, m), 1.58-1.57 (6H, d), 1.16-1.13 (3H, t), 2 —NH proton signals were not observed.
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([O:9][C:10]([CH3:23])([CH2:21][CH3:22])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:20])=[CH:16][CH2:17][CH2:18][OH:19])[CH3:8].[H][H]>[Pd].CO>[CH2:7]([O:9][C:10]([CH3:23])([CH2:21][CH3:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH2:18][OH:19])[CH3:8]
Reactant: [H][H]
Reactant: CCOC(C)(CC)CCCCC(C)=CCCO
Agent: [Pd]
Solvent: c1ccccc1
Solvent: CO
Product: CCOC(C)(CC)CCCCC(C)CCCO

Procedure:
A suspension of 0.5 g. of 5% palladium-on-carbon catalyst in 50 ml. of benzene is hydrogenated for 30 minutes. A mixture of 1.5 g. of 9-ethoxy-4,9-dimethylundec-3-en-1-ol in 75 ml. of methanol is added and hydrogenated with agitation until the theoretical amount of hydrogen is absorbed. The catalyst is removed by filtration and the solution evaporated to yield 9-ethoxy-4,9-dimethylundecan-1-ol which is purified by chromatography. The product is treated with phosphorus tribromide to yield 1-bromo-9-ethoxy-4,9-dimethylundecane which can be used as the alkylating agent for preparation of compounds of the present invention of formula I.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12](O)=[O:13])[NH:9]2)=[CH:5][C:4]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:47]1([S:53]([N:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)(=[O:55])=[O:54])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([N:59]3[CH2:58][CH2:57][N:56]([S:53]([N:47]4[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]4)(=[O:55])=[O:54])[CH2:61][CH2:60]3)=[O:13])[NH:9]2)=[CH:5][C:4]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:17]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)O)[nH]c3cc2Br)CC1
Reactant: O=S(=O)(N1CCCCC1)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(S(=O)(=O)N5CCCCC5)CC4)[nH]c3cc2Br)CC1
Yield: 55.9 %

Procedure:
To a solution of 0.5 g (1.20 mmol) 6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid hydrochloride in 8 mL N,N-dimethylformamide, 0.48 g (1.50 mmol) O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, 0.31 g (1.33 mmol) 1-(piperidin-1-yl-sulfonyl)-piperazine and 1.0 mL (0.77 g, 6.0 mmol) N,N-diisopropylethylamine were added. After 2 h the solution was poured on 10% aqueous sodium bicarbonate solution, the phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed three times with water followed by brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography twice on silica gel using a gradient of dichloromethane: methanol (100:0 to 50:50 v/v) as eluant, to afford 0.4 g (56%) of the title compound as a light-yellow foam.
Reaction SMILES: [C:1]([S:20][CH:21]1[NH:24][C:23](=[O:25])[CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28][O:29][CH2:30]Br>C1COCC1.CO.CCOCC>[CH3:28][O:29][CH2:30][N:24]1[CH:21]([S:20][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:22][C:23]1=[O:25]
Reactant: COCBr
Reactant: O=C1CC(SC(c2ccccc2)(c2ccccc2)c2ccccc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: COCN1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 110.4 %

Procedure:
A solution of 4-tritylthio-2-azetidinone (1.38 g, 4.0 mmoles) in THF (10 ml) was added to a well stirred suspension of sodium hydride (200 mg of commercial 50%, 4.1 mmoles, washed with pentane) in THF (10 ml) maintained at -15°. Methanol (12 drops) was added and the mixture was stirred at -15° for 0.5 h. Methoxymethyl bromide (0.58 g, 4.6 mmoles) was added and the mixture was stirred for 2 h, diluted with ether, washed with water and brine, dried and concentrated to leave an oil (1.72 g). Crystallization from pentane gave a white solid (1.41 g) m.p. 72-76 δ(ppm, CDCl3): 7.3 (15H, m, aromatics), 4.4 (3H, m, NCH2O and H-4), 3.22 (3H, s CH3), 2.76 (2H, m, H-3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH:15]([NH:17][CH2:18][C@@H:19]([C:21]2[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([NH:27][CH:28]=[O:29])[CH:26]=2)[OH:20])[CH3:16])=[CH:8][CH:7]=1.CCN(C(C)C)C(C)C.I.[NH2:41][C:42]1[C:43]([C:50]([NH:52][C:53](=[NH:56])SC)=[O:51])=[N:44][C:45]([Cl:49])=[C:46]([NH2:48])[N:47]=1>C(O)C>[NH2:41][C:42]1[C:43]([C:50]([N:52]=[C:53]([NH2:56])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][CH:15]([NH:17][CH2:18][C@@H:19]([C:21]3[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([NH:27][CH:28]=[O:29])[CH:26]=3)[OH:20])[CH3:16])=[CH:10][CH:11]=2)=[O:51])=[N:44][C:45]([Cl:49])=[C:46]([NH2:48])[N:47]=1
Reactant: CC(CCCc1ccc(CCCCN)cc1)NC[C@H](O)c1ccc(O)c(NC=O)c1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(CCCc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1)NC[C@H](O)c1ccc(O)c(NC=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
A solution composed of compound 28 (0.10 g, 0.25 mmol), Hunig's base (0.21 mL, 1.23 mmol) and ethanol (5 mL) was heated at 70° C. for 30 min before 1-(3,5-diamino-6-chloropyrazine-2-carbony)-2-methylisothiourea hydriodide (0.11 g, 0.27 mmol) was added. The resulting solution was continuously stirred at that temperature for an additional 3 h before it was cooled to room temperature. The solvent was removed by evaporation. The resulting residue was subjected to column chromatography eluting with a mixture of methanol (0-28%), concentrated ammonium hydroxide (0-2.8%) and dichloromethane (100-69.2%) to afford 30 (87 mg, 56%) as a yellow solid: m.p. 120-121° C. (decomposed); [α]D25 −6.65° (c 0.20, methanol); 1H NMR (500 MHz, DMSO-d6) δ 1.08 (d, 3H), 1.32 (m, 2H), 1.48-1.72 (m, 6H), 2.55 (m, 4H), 2.64-2.92 (m, 3H), 3.16 (m, 2H), 4.56 (m, 1H), 6.76 (m, 1H), 6.82 (m, 1H), 6.92 (m, 1H), 7.10 (m, 4H), 8.07 (s, 1H), 8.28 (s, 1H), 8.51 (s, 1H), 9.30 (s, 1H), 9.59 (s 1H); m/z (ESI) 626 [C30H40ClN9O4+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:8]([O:10]C)=[O:9])([CH3:4])([CH3:3])[CH3:2].CO.O.Cl>[OH-].[Na+]>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:8]([OH:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(OC)c(C(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)O)cc1C(C)(C)C
Yield: 93.6 %

Procedure:
Preparation C11, Step 2: Methyl 3-tert-butyl-4-methoxybenzoate (1.12 g, 5.03 mmol, 1 eq) was dissolved in 1N NaOH in methanol (50.38 mL, 50.3 mmol, 10 eq) at room temperature then refluxed for 4 hours. Worked up stripping off the methanol. Added H2O (10 mL) then adjusted the pH to 3 with 6N HCl. Solids precipitated. Extracted the suspension 3 times with methylene chloride (20 mL). The organic layers were combined, dried (sodium sulfate) and stripped to give 3-tert-butyl-4-methoxybenzoic acid (0.98 g) as a white solid. Yield=93%. LCMS detects (M+H)+=208.25.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:32]([O:38][CH2:39][CH3:40])(=[O:37])[CH2:33]C([O-])=O.Cl>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:19])[CH2:33][C:32]([O:38][CH2:39][CH3:40])=[O:37])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
A solution of 2.65 g (10 mmoles) of 6-benzyloxycarbonylaminohexanoic acid and 1.62 g (10 mmoles) of commercial 1,1'-carbonyldiimidazole in 25 ml of anhydrous tetrahydrofuran was stirred for 15 minutes at room temperature. To the reaction mixture was added a suspension of 6.18 g (40 mmoles) of a white powder of magnesium enolate of monoethyl malonate (prepared from 5.28 g of monoethyl malonate and 972 mg of magnesium) in 50 ml of anhydrous tetrahydrofuran. The mixture was stirred for 2 hours at room temperature. After addition of 50 ml of 1N hydrochloric acid and stirring for 10 minutes, the reaction mixture was extracted 3 times with 50 ml of chloroform. The chloroform layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline, then dried over anhydrous sodium sulfate and freed from the solvent by distillation. The residue was passed through a column of 100 g of "Silica Gel 60" (Merck & Co.) and eluted with chloroform (20 g fraction size). Fractions No. 43 to No. 105 were combined and evaporated to dryness to yield 2.35 g (70% yield) of ethyl 8-benzyloxycarbonylamino-3-ketooctanoate.
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([C:10]2[NH:14][N:13]=[CH:12][C:11]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:6][N:5]=1)=O.CS(C1N=C(C2NN=CC=2C2C=CC=CC=2)C=CN=1)(=O)=O.[CH3:42][C:43]1[CH:44]=[C:45]([CH:47]=[C:48]([CH3:50])[CH:49]=1)[NH2:46]>>[CH3:42][C:43]1[CH:44]=[C:45]([NH:46][C:4]2[N:9]=[C:8]([C:10]3[NH:14][N:13]=[CH:12][C:11]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:7]=[CH:6][N:5]=2)[CH:47]=[C:48]([CH3:50])[CH:49]=1
Reactant: CS(=O)c1nccc(-c2[nH]ncc2-c2ccccc2)n1
Reactant: Cc1cc(C)cc(N)c1
Agent: CS(=O)(=O)c1nccc(-c2[nH]ncc2-c2ccccc2)n1
Product: Cc1cc(C)cc(Nc2nccc(-c3[nH]ncc3-c3ccccc3)n2)c1
Temperature: 90 °C

Procedure:
A mixture of 2-(methylsulfinyl)-4-(4-phenyl-1H-pyrazol-5-yl)pyrimidine and 2-(methylsulfonyl)-4-(4-phenyl-1H-pyrazol-5-yl)pyrimidine (3-4, 3-5, 186 mg, 0.62 mg,) and 3,5-dimethylaniline (2 mL, excess) was heated at 90° C. for 24 hours. The reaction mixture was purified by flash chromatography. Elution with CH2Cl2 to 30% EtOAc/CH2Cl2 gave N-(3,5-dimethylphenyl)-4-(4-phenyl-1H-pyrazol-5-yl)pyrimidin-2-amine (3-6) as a pale yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.26 (d, 1H, J=5 Hz), 7.66 (s, 1H), 7.38–7.44 (m, 5 H), 7.21 (br s, 2H), 7.04 (br s, 1H), 6.75 (br s, 1H), 6.71 (d, 1H, J=5 Hz), 2.34 (s, 6H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:10]2[CH:11]=[C:12]([C:15]3[C:16]([C:39]4[S:43][C:42]([C:44]([O:46]C)=[O:45])=[CH:41][CH:40]=4)=[N:17][N:18]([C:20]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:19]=3)[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1.[OH-].[Li+].C(O)C.Cl>O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:10]2[CH:11]=[C:12]([C:15]3[C:16]([C:39]4[S:43][C:42]([C:44]([OH:46])=[O:45])=[CH:41][CH:40]=4)=[N:17][N:18]([C:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:19]=3)[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1
Reactant: COC(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4nccs4)n3c2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4nccs4)n3c2)s1
Yield: 92 %

Procedure:
1.20 g methyl 5-{4-[3-(1,3-thiazol-2-yl)imidazo-[1,2-a)pyridin-6-yl]-1-trityl-1H-3-pyrazolyl}-2-thiophene carboxylate obtained in Example 442, 0.16 g lithium hydroxide, 30 mL ethanol and 15 mL water were heated at 85° C. for 5 hours. Under ice-cooling, the reaction solution was neutralized by adding water and 1 N aqueous hydrochloric acid and then extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The drying agent was removed, and the solvent was concentrated, whereby 1.08 g of the title compound was obtained as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].C(N(CC)C(C)C)(C)C.[C:21]([O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)#[C:22][CH2:23][CH3:24]>C(Cl)Cl.C(#N)C>[CH2:21]([O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:11][C:6]2([C:4]([O:3][CH3:2])=[O:5])[CH2:10][CH2:9][CH2:8][CH2:7]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1)[C:22]#[C:23][CH3:24]
Reactant: COC(=O)C1(N)CCCC1
Reactant: CCC#COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)OC)CCCC2)cc1
Reaction time: 16 h

Procedure:
To a stirred suspension of methyl-1-amino-1-cyclopentane carboxylate hydrochloride (15 g, 84.0 mmol) and N,N-diisopropylethylamine in methylene chloride (200 mL) and acetonitrile (50 mL), 4-butynyloxyphenylsulfonylchloride (24.7 g, 100 mmol) was slowly added at room temperature. Reaction mixture was stirred for 16 hrs and evaporated to dryness. It was extracted with chloroform, washed well with water and dried over anhydrous MgSO4. Chloroform layer was filtered and concentrated. The product was crystallized from a mixture acetone:hexane (1:1) to give methyl 1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)cyclopentane carboxylate as white crystals, 26.8 g (91%), mp 81-3° C. Electrospray Mass Spec 352 (M+H)+.