Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Cl)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[CH3:38][N:39]([CH3:49])[C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([N:39]([CH3:49])[CH3:38])[CH:45]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Cl)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CN(C)c1cccc(B(O)O)c1
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(-c4cccc(N(C)C)c4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene 57 obtained in Example 120 (1) and 3-dimethylaminophenylboronic acid were used and treated in a manner similar to Example 120-(2) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-dimethylaminophenyl)-2-thienylmethyl)-4-methylbenzene. APCI-Mass m/Z 638 (M+H).
Reaction SMILES: [CH2:1]1[CH2:39][O:38][C:3]2([CH2:20][CH2:19][C@H:18]3[C@@:5]([OH:37])([C@H:6]([CH3:36])[CH2:7][C@@H:8]4[C@@H:17]3[C@@H:16]([C:21]3[CH:26]=[CH:25][C:24](OS(C(F)(F)F)(=O)=O)=[CH:23][CH:22]=3)[CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C:12]3=[O:35])[CH2:4]2)[O:2]1.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+].C(B(CC)[C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1)C.[Cl-].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH2:1]1[CH2:39][O:38][C:3]2([CH2:20][CH2:19][C@H:18]3[C@@:5]([OH:37])([C@H:6]([CH3:36])[CH2:7][C@@H:8]4[C@@H:17]3[C@@H:16]([C:21]3[CH:22]=[CH:23][C:24]([C:51]5[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=5)=[CH:25][CH:26]=3)[CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C:12]3=[O:35])[CH2:4]2)[O:2]1
Reactant: C[C@@H]1C[C@@H]2[C@H]([C@@H](c3ccc(OS(=O)(=O)C(F)(F)F)cc3)C[C@]3(C)C(=O)CC[C@@H]23)[C@H]2CCC3(C[C@]12O)OCCO3
Reactant: CCB(CC)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[C@@H]1C[C@@H]2[C@H]([C@@H](c3ccc(-c4cccnc4)cc3)C[C@]3(C)C(=O)CC[C@@H]23)[C@H]2CCC3(C[C@]12O)OCCO3
Temperature: 110 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
10 g of the 3,3-(ethylenedioxy)-5α-hydroxy-6β-methyl-11β-(4-trifluoromethylsulphonyloxyphenyl)-oestran-17-one prepared in accordance with the directions given in Example 4 e) are dissolved in a mixture of 80 ml of toluene and 35 ml of ethanol and 1 g of palladium tetrakistriphenylphosphine, 1.47 g of lithium chloride, 22.5 ml of 2M sodium carbonate solution and 2.8 g of diethyl-(3-pyridyl)-borane are added in succession. The reaction mixture is then stirred at 110° C. for 3 hours and cooled to room temperature, and saturated sodium chloride solution is added. The organic phase is removed, washed in succession with 5% sodium hydroxide solution and water, dried over sodium sulphate and concentrated in vacuo. The residue is chromatographed on silica gel with a mixture of ethyl acetate/hexane. 7.53 g of 3,3-(ethylenedioxy)-5α-hydroxy-6β-methyl-11β-[4-(3-pyridyl)-phenyl]-oestran-17-one are obtained in the form of a white foam.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][C@@H:4]([CH2:8][OH:9])[CH2:3]1.[H-].[Na+].[N+](C1C=CC([O:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)=O)=CC=1)([O-])=O>C1COCC1>[F:36][C:33]1[CH:32]=[CH:31][C:30]([N:27]2[CH2:26][CH2:25][N:24]([C:22]([O:9][CH2:8][C@@H:4]3[O:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]3)=[O:21])[CH2:29][CH2:28]2)=[CH:35][CH:34]=1
Reactant: CN1CCO[C@@H](CO)C1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCO[C@@H](COC(=O)N2CCN(c3ccc(F)cc3)CC2)C1
Reaction time: 0.5 h
Yield: 39 %

Procedure:
(R)-(4-Methyl-morpholin-2-yl)-methanol (Intermediate 11; 100 mg, 0.76 mmol) was added to a suspension of NaH (60% dispersion in oil; 90.0 mg, 2.28 mmol) in anhydrous THF (7 mL) and stirred under nitrogen for 30 min. 4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 6; 314 mg, 0.91 mmol) was added and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was filtered through celite and the solid washed with THF (10 mL). The filtrates were combined and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase silica, 5 g Isolute-Si column, gradient 1-5% MeOH in DCM) and then reverse phase HPLC (YMC ODS-A 100×20 mm, 5 μm, 25 mL/min, gradient 20% to 100% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water). The pure product was taken up in DCM (5 mL), filtered, and dried in vacuo to give [(2R)-4-methylmorpholin-2-yl]methyl 4-(4-fluorophenyl)piperazine-1-carboxylate (100 mg, 28%) as a colourless gum.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[O:30][CH2:31][CH2:32][CH2:33]Cl>CS(C)=O.O>[CH2:7]([NH:19][CH2:33][CH2:32][CH2:31][O:30][C:21]1[CH:22]=[CH:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCN
Reactant: ClCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCCCNCCCOc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and n-dodecylamine (0.51 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(n-dodecyl)-(3-(naphthalen-2-yloxy)-propyl)amine, solid. m.p. 126° C., (yield 0.78 gm, 92.8%).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([N:15]([CH3:18])[CH:16]=[O:17])=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37]F)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[C:11](=[CH:10][C:9]([N:15]([CH3:18])[CH:16]=[O:17])=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH:14]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCF)cc1
Reactant: CN(C=O)c1ccc2c(c1)[nH]c1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOc2ccc3c(c2)[nH]c2cc(N(C)C=O)ccc23)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 48.7 %

Procedure:
To N-(7-hydroxy-9H-carbazol-2-yl)-N-methylformamide (45 mg, 0.187 mmol) and 2-(2-(2-fluoroethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (172 mg, 0.38 mmol) in 0.5 mL NMP was added Cs2CO3 (65 mg, 0.2 mmol). The mixture was stirred at rt for 15 h under Ar atmosphere and diluted with EtOAc (50 mL). It was washed with water (2×50 mL), 0.5 M HCl (50 mL) and brine (50 mL), and dried over MgSO4. Solvent was removed under reduced pressure and the crude product was purified with silica chromatography (hexane/EtOAc) to afford 2-(2-(2-(7-(N-methylformamido)-9H-carbazol-2-yloxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (AD-CB-004 Pa-WZ01179) as a light-brown oil (48 mg, 48%). 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.45 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.80-7.77 (m, 2H), 7.30 (d, J=8.0 Hz, 2H), 7.17 (d, J=2.4 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 7.01 (dd, J=8.0, 2.0 Hz, 1H), 6.89 (dd, J=8.8, 2.4 Hz, 1H), 4.23 (m, 1H), 4.17 (m, 2H), 3.88 (m, 2H), 3.72-3.68 (m, 4H), 3.66-3.61 (m, 2H), 3.39 (s, 3H), 2.41 (s, 3H); MS (ESI) m/z 527 (M+H+).
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][C:7](=[O:21])[C:8]([CH2:18][CH:19]=O)=[C:9]([N:11]([C:15](=[O:17])[CH3:16])[C:12](=[O:14])[CH3:13])[N:10]=1)(=[O:3])[CH3:2].[NH2:22][C:23]1[CH:42]=[CH:41][C:26]([C:27]([NH:29][C@H:30]([C:37]([O:39][CH3:40])=[O:38])[CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:28])=[CH:25][CH:24]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[C:1]([NH:4][C:5]1[NH:6][C:7](=[O:21])[C:8]([CH2:18][CH2:19][NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([NH:29][C@H:30]([C:37]([O:39][CH3:40])=[O:38])[CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:28])=[CH:41][CH:42]=2)=[C:9]([N:11]([C:15](=[O:17])[CH3:16])[C:12](=[O:14])[CH3:13])[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(N(C(C)=O)C(C)=O)c(CC=O)c(=O)[nH]1
Reactant: COC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)CC[C@H](NC(=O)c1ccc(NCCc2c(N(C(C)=O)C(C)=O)nc(NC(C)=O)[nH]c2=O)cc1)C(=O)OC
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
A solution of 2-(2-acetylamino-4-diacetylamino-1,6-dihydro-6-oxo-5-pyrimidinyl)acetaldehyde (1.74 g, 5.92 mmol) and dimethyl N-(4-aminobenzoyl)-L-glutamate (J. Am. Chem. Soc., 1958, 80, 5779) (1.74 g, 5.92 mmol) in acetic acid (90 ml) was stirred for 10 minutes. Sodium cyanoborohydride (0.84 g, 13.4 mmol) was added in small portions over 1 hour. After an additional 30 minutes, the reaction was spin evaporated in vacuo to a thick oil. The oil was dissolved in ethyl acetate (500 ml) and washed with 5% aqueous sodium bicarbonate until neutral, water (50 ml), brine (50 ml), dried with magnesium sulfate and spin evaporated in vacuo. Recrystallization from ethyl acetate, with filtration to remove insolubles, yielded 1.5 g (49% of theory) of dimethyl N-[4-[2-(2-acetylamino-4-diacetylamino-1,6-dihydro-6-oxo-5-pyrimidinyl)ethylamino]benzoyl]-L-glutamate, mp 168°-178° C. Recrystallization from ethyl acetate (Norite) gave 0.830 g (25% of theory) of the analytical sample, mp 176°-179° C.
Reaction SMILES: [Si]([C:5]#[N:6])(C)(C)C.CN(C)NC(Cl)=O.[CH2:14]([NH:16][C:17]1[CH:18]=[N+:19]([O-])[CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])[CH3:15]>CN(C=O)C.C(Cl)Cl.O>[CH2:14]([NH:16][C:17]1[C:18]([C:5]#[N:6])=[N:19][CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])[CH3:15]
Reactant: CCNc1c[n+]([O-])ccc1[N+](=O)[O-]
Reactant: C[Si](C)(C)C#N
Agent: CN(C)NC(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCNc1c([N+](=O)[O-])ccnc1C#N
Temperature: 80 °C
Reaction time: 8 h

Procedure:
TMSCN (1.1 ml, 8.33 mmol) and dimethyl amino carbamoyl chloride (0.76 mL, 8.33 mmol.) are added to a solution of 3-ethylamino-4-nitro-pyridine-1-oxide (1 g, 6.94 mmol) in anhydrous DMF (10 mL) were added. The reaction mixture is stirred overnight at 80° C., cooled to room temperature, and diluted with CH2Cl2 and water. The combined organic layer is washed with water, brine, dried over Na2SO4, and concentrated. The residue is chromatographed eluting with 40% EtOAc-hexanes to afford 3-ethylamino-4-nitro-pyridine-2-carbonitrile as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 7.82 (d, J=4.5 Hz, 1H), 7.50 (d, J=4.5 Hz, 1H), 3.70 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH2:18][C:19](=[N:25]O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)C(C)C)(C)C>ClCCl.N1C=CC=CC=1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][C:9]1[O:11][N:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: CCOC(=O)C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1noc(Cc2cccc(Cl)c2)n1
Yield: 28.1 %

Procedure:
This compound was prepared according to general method 2 with (step I) 2-(3-chlorophenyl)acetic acid (0.646 g; 3.78 mmol) and oxalyl chloride (0.352 mL; 4.16 mmol) in dichloromethane (12 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.5 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (6 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.283 g (28%) of ethyl 5-(3-chlorobenzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:9]1[S:20]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:19][C:16]1[CH:15]=[CH:14][C:13]([CH:10]2[N:9]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:22])=[O:21])[CH:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:2])[CH2:12][CH2:11]2)=[CH:18][CH:17]=1
Reactant: COC(=O)CCCCC1CCC(c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2C(CCCCCO)CCC2c2ccc(F)cc2)cc1

Procedure:
Reduction of (2RS,5RS)-5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentanoic acid methyl ester with lithium aluminum hydride (1.5 eq.) in THF at RT, aqueous work-up and purification by column chromatography yielded the title compound as a light orange oil, MS: m/e=406.2 (M+H+).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:48])=[N:17][C:18]([CH3:47])=[C:19]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)=[CH:33][CH:32]=2)[C:20]=1[N:21]1[CH2:26][CH2:25][CH:24]([C:27]([F:30])([F:29])[F:28])[CH2:23][CH2:22]1)[C:9]([O:11]C(C)C)=[O:10])([CH3:6])([CH3:5])[CH3:4].Cl>C(O)C>[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:48])=[N:17][C:18]([CH3:47])=[C:19]([C:31]2[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH2:39][C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)=[CH:35][CH:36]=2)[C:20]=1[N:21]1[CH2:22][CH2:23][CH:24]([C:27]([F:30])([F:29])[F:28])[CH2:25][CH2:26]1)[C:9]([OH:11])=[O:10])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C(F)(F)F)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C(F)(F)F)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 89.3 %

Procedure:
The 0.23 mL of 1M sodium hydroxide (9.3 mg, 0.23 mmol) was added to a solution (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)acetate (50 mg, 0.078 mmol) in ethanol (1 mL) and stirred for 24 h at 90° C. An additional 0.23 mL sodium hydroxide was added and the reaction was continued for 24 h. The reaction mixture was neutralized with 1N HCl solution, extracted with EtOAc, and the organic layer was washed with brine, and dried (MgSO4). The crude material was purified by prep to afford (S)-2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)acetic acid 42 mg (89%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.41-7.38 (m, 2H), 7.21-7.20 (m, 1H), 7.14 (t, J=8.8 Hz, 2H), 7.0 (d, J=8.4 Hz, 2H), 6.95 (d, J=7.7 Hz, 1H), 5.54 (br. s, 1H), 4.23 (t, J=6.7 Hz, 2H), 3.96-3.94 (m, 2H), 3.07 (t, J=6.6 Hz, 2H), 2.90/2.74 (s, 2H), 2.46 (s, 3H), 2.55 (br. s, 1H), 2.03 (s, 3H), 1.72-1.61 (m, 3H), 1.56-1.54 (m, 1H), 1.10 (s, 9H). UPLC (M+H)=603.5.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:12]([OH:14])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5])[CH3:3].[Na+].[CH3:16][CH:17]([CH3:24])[CH2:18][C:19](=O)[C:20]([O-:22])=[O:21].C([BH3-])#N.[Na+]>O>[C:20]([CH:19]([NH:1][C@H:2]([C:4]([NH:6][C@H:7]([C:12]([OH:14])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5])[CH3:3])[CH2:18][CH:17]([CH3:24])[CH3:16])([OH:22])=[O:21]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](C)N)C(=O)O
Reactant: CC(C)CC(=O)C(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(CC(C)C)C(=O)O)C(=O)O
Yield: 85.2 %

Procedure:
A solution of L-alanyl-L-isoleucine (150 mg) and 4-methyl-2-oxopentanoic acid sodium salt (564 mg) in water was adjusted to pH 7 and treated with 140 mg of sodium cyanoborohydride at room temperature for several days. The reaction was quenched with strong acid ion-exchange resin, added to a column of the same resin, and eluted with 2% pyridine in water. Freeze drying afforded 200 mg (84.9%) of white fluffy solid, N-(1-carboxy-3-methylbutyl)-L-alanyl-L-isoleucine. Mass spectrum showed peaks at 460 for the disilylated derivative, and 445 for disilyl molecular ion minus methyl (460-15). The nmr spectrum showed a broad doublet centered at 0.95 ppm, complex absorption in the 1.2-1.8 ppm range, and a broad weak singlet at 3.7 ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][Si](C(C)(C)C)(C)C)[CH:31]=4)=[N:18][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][C:6](=[O:44])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=4)=[N:18][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2cc3nc(-c4cccc(O[Si](C)(C)C(C)(C)C)c4)nc(N4CCOCC4)c3s2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(Cc2cc3nc(-c4cccc(O)c4)nc(N4CCOCC4)c3s2)CC1
Yield: 87.3 %

Procedure:
(1-{2-[3-(Tert-butyl-dimethyl-silanyloxy)-phenyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl}-piperidin-4-yl)-carbamic acid tert-butyl ester (250 mg, 0.39 mmol) was dissolved in THF (4 mL), to this was added TBAF (1.4 eq., 0.55 mL). After 30 min. the reaction mixture was quenched with silica, evaporated in vacuo and purified by chromatography to give {1-[2-(3-hydroxy-phenyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester as a white solid (179 mg, 88%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[NH:15][CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O[CH2:27][CH2:28][CH2:29][NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C.O>[CH2:1]([N:8]1[CH2:14][CH:13]2[N:15]([CH2:27][CH2:28][CH2:29][NH:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=3)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CC3CCC(C2)N3)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCCNc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(NCCCN2C3CCC2CN(Cc2ccccc2)C3)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
A mixture of 3-benzyl-3,8-diazabicyclo[3.2.1]octane (3.63 g, 17.9 mmol; from Preparation B, step (e) above), 3-(4-cyanoanilino)propyl 4-methylbenzenesulfonate (5.93 g, 17.9 mmol; from step (b) above) and potassium carbonate (2.47 g, 17.9 mmol) in dry DMF (85 mL) was stirred at 80° C. for 4 h. The reaction mixture was diluted with water (200 mL) and extracted with ether (4×200 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated ill vacuo to give the crude product. Flash chromatography on silica gel eluting with CH2Cl2:CMA (4:1) gave 6.26 g (97%) of the sub-title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:13]O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:12])[CH:6]=[CH:5]2>C(O)C.Cl.[Pt].[Pd]>[F:1][C:2]1[C:3]([CH3:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:12])[CH2:6][CH2:5]2
Reactant: CC1C=Cc2c(ccc(F)c2CO)N1
Agent: [Pd]
Agent: [Pt]
Agent: Cl
Solvent: CCO
Product: Cc1c(F)ccc2c1CCC(C)N2
Reaction time: 16 h

Procedure:
A solid which was chiefly 1,2-dihydro-6-fluoro-5-hydroxymethylquinaldine (13.2 g) prepared according to Example 2 was dissolved in 300 ml of ethanol and 10 ml of concentrated hydrochloric acid. To this solution was added 1 g of 5% platinum on charcoal and 3 g of 5% palladium on charcoal. The solution was hydrogenated at 50 psi at about 20° C. on a Paar apparatus. After absorption of about 12 psi of hydrogen (the theoretical amount needed), the solution was filtered and the solvent was removed by evaporation to provide a solid. Nuclear magnetic resonance spectral analysis showed slightly incomplete reduction. Therefore the solid was dissolved in 300 ml of aqueous (95%) ethanol to which 2 g of platinum on charcoal was added, and the solution was hydrogenated at 50 psi on the Paar apparatus for about 16 hours. The solution was then filtered and the solvent was evaporated. The solid recovered was dissolved in 50 ml of water. This solution was basified with aqueous sodium hydroxide and then extracted with diethyl ether. Evaporation of the ether provided 6-fluoro-5-methyl-1,2,3,4-tetrahydroquinaldine as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:22]([O-])=O)=[C:6]([CH:21]=1)[O:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1>CO.[Pd]>[NH2:22][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:21][C:6]=1[O:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2cc(F)ccc2N)C1

Procedure:
To a solution of (S)-tert-butyl 3-(5-fluoro-2-nitrophenoxy)piperidine-1-carboxylate (6.41 g) in MeOH (70.0 ml) was added palladium on charcoal (600.0 mg), the mixture hydrogenated at room temperature and 50 psi. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica chromatography to give the desired product.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH2:12][CH2:11]2)[C:3]=1[CH:4]=O.[CH3:20][S:21][C:22]1[N:27]=[C:26]([NH:28][NH2:29])[CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>CS(C)=O>[CH3:19][S:16]([CH:13]1[CH2:14][CH2:15][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:2]3[C:3]=2[CH:4]=[N:29][N:28]3[C:26]2[CH:25]=[CH:24][N:23]=[C:22]([S:21][CH3:20])[N:27]=2)[CH2:11][CH2:12]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)C1CCN(c2cccc(F)c2C=O)CC1
Reactant: CSc1nccc(NN)n1
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CSc1nccc(-n2ncc3c(N4CCC(S(C)(=O)=O)CC4)cccc32)n1
Temperature: 180 °C
Reaction time: 1.5 h
Yield: 38.7 %

Procedure:
In a 50 ml, round bottom flask, 2-fluoro-6-(4-methanesulfonylpiperidine-1-yl)benzaldehyde (1.37 g, 4.8 mmol), N-(2-methylsulfanyl-pyrimidin-4-yl)-hydrazine (0.75 g, 4.8 mmol) and DBU (2.19 g, 14.4 mmol) were combined with DMSO (17 mL). The mixture was stirred at 180° C. for 1.5 hr in a microwave. The brown solution was blown to dryness and the residue was purified through ISCO flash column chromatography (30% to 100% ethyl acetate in hexanes) to provide 4-(4-methanesulfonyl-piperidin-1-yl)-1-(2-methylsulfanyl-pyrimidin-4-yl)-1H-indazole as a pale orange solid (750 mg, 38.7% yield). LC-MS calcd for C18H21N5O2S2 (m/e) 403.11, obsd 404.0 (M+H).