Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:55])([O:24][C:25]1[C:26]([CH3:54])=[C:27]2[C:32](=[C:33]([CH3:36])[C:34]=1[CH3:35])[O:31][C:30]([CH3:53])([CH2:37][CH2:38][CH2:39][CH:40]([CH3:52])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:51])[CH2:45][CH2:46][CH2:47][CH:48]([CH3:50])[CH3:49])[CH2:29][CH2:28]2)[O:2][CH:3]([CH2:15][O:16]CC1C=CC=CC=1)[CH:4]([OH:14])[CH2:5][O:6]CC1C=CC=CC=1.C(O)C.[H][H]>[C].[Pd].C(O)(=O)C>[C:1](=[O:55])([O:24][C:25]1[C:26]([CH3:54])=[C:27]2[C:32](=[C:33]([CH3:36])[C:34]=1[CH3:35])[O:31][C:30]([CH3:53])([CH2:37][CH2:38][CH2:39][CH:40]([CH3:52])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:51])[CH2:45][CH2:46][CH2:47][CH:48]([CH3:49])[CH3:50])[CH2:29][CH2:28]2)[O:2][CH:3]([CH2:15][OH:16])[CH:4]([OH:14])[CH2:5][OH:6]
Reactant: Cc1c(C)c2c(c(C)c1OC(=O)OC(COCc1ccccc1)C(O)COCc1ccccc1)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1OC(=O)OC(CO)C(O)CO)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Yield: 128.2 %

Procedure:
A mixture comprising 4.4 g of 3-benzyloxy-1-benzyloxymethyl-2-hydroxypropyl 2,5,7,8-tetramethyl-2-(4',8', 12'-trimethyltridecyl)-6-chromanyl carbonate, 0.5 g of 5% palladium carbon, 150 ml of ethanol and 5 ml of acetic acid was catalytically reduced in a hydrogen gas stream of 4 kg/cm2 until no hydrogen was absorbed any more (approximately 6 hours). After filtering off the catalyst, the filtrate was concentrated to thereby reduce the amount to approximately 1/3. Then it was poured into water and extracted with ether. The extract was successively washed with an aqueous solution of sodium hydrogencarbonate and water, and dried over magnesium sulfate. After distilling off the solvent, the obtained oily residue was purified by column chromatography (silica gel, hexane : ethyl acetate=2:1) to thereby give 4.3 g of the title compound as a colorless viscous liquid.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[CH2:20][CH:19]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]#[N:28])[CH2:23][CH2:22]4)[O:18][C:15]3=[CH:16][N:17]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl.[NH2:30][OH:31]>>[OH:31][NH:30][C:27]([N:24]1[CH2:25][CH2:26][CH:21]([CH:19]2[O:18][C:15]3=[CH:16][N:17]=[C:12]([C:9]4[CH:10]=[CH:11][C:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][CH:8]=4)[CH:13]=[C:14]3[CH2:20]2)[CH2:22][CH2:23]1)=[NH:28]
Reactant: NO
Reactant: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCN(C#N)CC2)C3)cc1
Agent: Cl
Product: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCN(C(=N)NO)CC2)C3)cc1

Procedure:
The title compound is prepared from 4-[5-(4-methanesulfonylmethyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile and hydroxylamine hydrochloride following a procedure analogous to that described for Intermediate 11. LC (method 5): tR=0.83 min; Mass spectrum (ESI+): m/z=431 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH2:19][CH2:18][CH2:17][CH:16]([C:21](=[O:23])[NH2:22])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[O:24][CH2:25][C:26]([O:28]C)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.CO>[CH2:1]([N:8]1[C:20]2[CH2:19][CH2:18][CH2:17][CH:16]([C:21](=[O:23])[NH2:22])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[O:24][CH2:25][C:26]([OH:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)COc1cccc2c1c1c(n2Cc2ccccc2)CCCC1C(N)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)C1CCCc2c1c1c(OCC(=O)O)cccc1n2Cc1ccccc1
Reaction time: 18 h
Yield: 86.9 %

Procedure:
A solution of 30 mg (0.076 mmol) of [9-benzyl-4-carbamoyl-1,2,3,4-tetrahydrocarbazole-5-yl]oxyacetic acid, methyl ester in 1.0 mL of THF and 1.0 mL of MeOH was treated with 0.2 mL of 1 N aqueous LiOH (0.2 mmol). The mixture was stirred for 18 hours. An additional 0.2 mL of 1 N aqueous LiOH (0.2 mmol) was added and stirring continued. After 1 hour, the mixture was concentrated in vacuo. The residue was dissolved in 2.0 mL of H2O and the solution acidified with 0.2 N aqueous HCl. The solid was filtered and dried to afford 25 mg of [9-benzyl-4-carbamoyl-1,2,3,4-tetrahydrocarbazole-5-yl]oxyacetic acid as a white solid. 1H NMR (DMSO-d6) δ 7.36-7.12 (m, 5H), 7.05-6.83 (m, 5H), 6.71 (br s, 1H), 6.35 (d, 1H, J=7.6 Hz), 5.27 (s, 2H), 4.64 (s, 2H), 3.93-3.84 (m, 2H), 2.75-2.64 (m, 1H), 2.16-1.95 (m, 2H), 1.81-1.64 (m, 2H) and 1 proton masked by H2O peak between 2.58-2.40. IR (KBr, cm−1) 3435, 2936, 1722, 1644, 1586, 1566, 1495, 1451, 1354, 1227, 1134, 730, 716, and 698. MS (ES) m/e 377 (M−1) and 379 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:35]([CH2:44][C:45]2[CH:54]=[CH:53][C:48]([C:49]([NH:51]O)=[NH:50])=[CH:47][CH:46]=2)[CH:36]2[CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:37]2=[O:43])(=[O:34])=[O:33])=[CH:28][CH:27]=1.O>CN(C)C=O>[CH2:1]([O:8][CH2:9][C:10]1[O:12][N:50]=[C:49]([C:48]2[CH:53]=[CH:54][C:45]([CH2:44][N:35]([CH:36]3[CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:37]3=[O:43])[S:32]([C:29]3[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][CH:30]=3)(=[O:34])=[O:33])=[CH:46][CH:47]=2)[N:51]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N=C(NO)c1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: O=C(O)COCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCCCCC1N(Cc1ccc(-c2noc(COCc3ccccc3)n2)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
To a solution of benzyloxyacetic acid (162 μl, 1.10 mmol) in 5 ml dimethylformamide were added 1,1′-carbonyl-diimidazole (0.18 g, 1.10 mmol). The mixture was stirred at room temperature for 10 minutes, heated to 40° C. for a few minutes and cooled to room temperature. 4-{[(4-Chloro-benzenesulfonyl)-(2-oxo-azepan-3-yl)-amino]-methyl}-N-hydroxy-benzamidine (0.45 g, 1.00 mmol) was added and the mixture was stirred at 100° C. for 5 hours and then poured into water. Filtration and chromatography on silicagel with ethylacetate/heptane (1/1 to 4/1) yielded 0.51 g (87%) N-[4-(5-benzyloxymethyl-[1,2,4]oxadiazol-3-yl)-benzyl]-4-chloro-N-(2-oxo-azepan-3-yl)-benzenesulfonamide as white solid, MS: m/e (%)=581.1 (MH+, 100).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]=1[C:14]1[CH:28]=[C:27]([Br:29])[CH:26]=[CH:25][C:15]=1[C:16]([N:18](C(C)C)C(C)C)=[O:17].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Br:29][C:27]1[CH:26]=[CH:25][C:15]2[C:16](=[O:17])[NH:18][C:2]3[C:3]([C:14]=2[CH:28]=1)=[C:4]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])[N:5]=[C:6]([CH3:8])[CH:7]=3
Reactant: CCCCOc1nc(C)cc(N)c1-c1cc(Br)ccc1C(=O)N(C(C)C)C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOc1nc(C)cc2[nH]c(=O)c3ccc(Br)cc3c12

Procedure:
To a solution of 2-(4-amino-2-butoxy-6-methylpyridin-3-yl)-4-bromo-N,N-diisopropylbenzamide (50 mg, 0.10 mmol) in THF (50 mL) was added dropwise a solution of NaHMDS in THF (0.40 mL, 0.20 mmol) at room temperature over 1 h. The resulting mixture was quenched with saturated aqueous NH4Cl solution (3 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (5 mL), dried over magnesium sulfate, filtered and concentrated to afford a crude solid. The crude material was triturated with diethyl ether (5 mL) and filtered to afford 9-bromo-1-butoxy-3-methylbenzo[c]-1,6-naphthyridin-6(5H)-one. 1H-NMR (300 MHz, DMSO) δ 9.13 (d, J=5.7 Hz, 1H), 8.17 (d, J=8.7 Hz, 1H), 7.47 (dd, J1=8.4 Hz, J2=1.8 Hz, 1H), 4.41 (t, J=6.3 Hz, 2H), 2.27 (s, 3H), 1.82 (m, 2H), 1.60 (m, 2H), 1.00 (t, J=7.5 Hz, 3H). LRMS calc'd for (C17H17BrN2O2) [M+H]+, 361; found 362.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:19]=[C:13]3[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][N:12]3[N:11]=2)=[CH:5][C:4]([C:20]2[CH:27]=[N:26][CH:25]=[C:24]([N:28]3[CH2:40][CH2:39][N:31]4[C:32]5[CH2:33][CH2:34][CH2:35][CH2:36][C:37]=5[CH:38]=[C:30]4[C:29]3=[O:41])[C:21]=2[CH:22]=[O:23])=[CH:3]1.[BH4-].[Na+]>CO>[OH:23][CH2:22][C:21]1[C:20]([C:4]2[CH:5]=[C:6]([NH:9][C:10]3[CH:19]=[C:13]4[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][N:12]4[N:11]=3)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[CH:27][N:26]=[CH:25][C:24]=1[N:28]1[CH2:40][CH2:39][N:31]2[C:32]3[CH2:33][CH2:34][CH2:35][CH2:36][C:37]=3[CH:38]=[C:30]2[C:29]1=[O:41]
Reactant: CN1CCn2nc(Nc3cc(-c4cncc(N5CCn6c(cc7c6CCCC7)C5=O)c4C=O)cn(C)c3=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCn2nc(Nc3cc(-c4cncc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
A mixture of 138a (200 mg, 0.36 mmol) and NaBH4 (50 mg, 1.2 mmol) in MeOH (60 mL) was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc (10 mL×3). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 138 (162 mg, 85%). LCMS: [M+H]+ : 555.3. 1H NMR (500 MHz, CDCl3) δ 8.64 (s, 1H), 8.49 (s, 1H), 7.97 (d, J=2.5, 1H), 7.42 (s, 1H), 7.33 (d, J=2, 1H), 6.88 (s, 1H), 5.68 (s, 1H), 4.65-4.63 (m, 1H), 4.57-4.55 (m, 1H), 4.37 (t, J=11, 1H), 4.20-4.16 (m, 3H), 4.07-3.98 (m, 3H), 3.70 (s, 3H), 3.59 (s, 2H), 2.87 (t, J=5.5, 2H), 2.61-2.56 (m, 4H), 2.48 (s, 3H), 1.92-1.90 (m, 2H), 1.80-1.79 (m, 2H)
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([Si](C)(C)C)[N:10]=[N:9]2)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCOC(C)=O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)c1cn(-c2ccc(I)cc2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: Ic1ccc(-n2ccnn2)cc1
Temperature: 50 °C

Procedure:
To 1-(4-iodophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole, prepared in the previous step, at room temperature was added tetrabutylammonium fluoride (1 M in THF, 50 mL, 50 mmol). The reaction mixture was heated to 50° C. for 1.5 h and diluted with EtOAc. The organic phase was washed with water (2×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 10% to 50% EtOAc in hexanes) gave 1-(4-iodophenyl)-1H-1,2,3-triazole.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]2[CH3:22])=[CH:5][C:4]=1[C:23]([F:26])([F:25])[F:24])#[N:2]>FC(F)(F)C(O)=O>[CH3:22][CH:10]1[CH2:11][NH:12][CH2:13][CH2:14][N:9]1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:23]([F:26])([F:24])[F:25])[CH:5]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C#N)c(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Product: CC1CNCCN1c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
A 2.85 g portion of t-butyl 4-(4-cyano-3-trifluoromethylphenyl)-3-methylpiperazine-1-carboxylate synthesized in Reference Example 3 was stirred in 50 ml of trifluoroacetic acid at 0° C. to room temperature for 2 hours. The solvent was evaporated under reduced pressure, the resulting residue was neutralized with saturated aqueous sodium bicarbonate and then extracted with ethyl acetate, the organic layer was washed and dried and then the solvent was evaporated under reduced pressure. The residue was purified by a silica gel column chromatography, and 5.6 g of the title compound was obtained from chloroform-methanol-28% aqueous ammonia (10:1:0.1, v/v/v) eluate as light yellowish white crystals.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[NH:3]1.C([Li])CCC.[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:26](=[O:27])[CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
(4R,5S)-4-Methyl-5-phenyl-oxazolidin-2-one (25.21 g, 142.269 mmol) is dissolved in anhydrous THF (100 mL) and cooled to −78° C. n-Butyl lithium (2.5 M in hexanes, 62.60 mL, 156.5 mmol) is added dropwise over 10 min. The reaction is stirred at −78° C. for 10 min. Phenylacetyl chloride (20.73 mL, 156.5 mmol) is dissolved in anhydrous THF (50 mL) and added dropwise over 10 min. The reaction is stirred at −78° C. for 2 h. The reaction is poured onto brine (300 mL) and extracted with ethyl acetate (2×250 mL). Extracts are combined, dried over anhydrous sodium sulfate, filtered, and concentrated to a yellow oil which solidified upon standing. Therude product is purified by column chromatography over silica eluting with 5→45% ethyl acetate in hexanes to afford (4R,5S)-4-methyl-5-phenyl-3-phenylacetyl-oxazolidin-2-one as a white solid: 1H NMR (400 MHz, DMSO-D6) δ 0.8 (d, J=6.6 Hz, 3 H) 4.2 (m, 2 H) 4.8 (m, 1 H) 5.9 (d, J=7.3 Hz, 1 H) 7.2 (m, 3 H) 7.3 (m, 5 H) 7.4 (m, 2 H); LC/MS 296.2 (M+1), 294.1 (M−1).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Br:14][C:15]1[CH:31]=[CH:30][C:18]([O:19][CH2:20][C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23]([OH:25])=O)=[CH:17][CH:16]=1.B(F)(F)F.CCOCC>ClCCl>[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[O:19][CH2:20][C:21]3[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=3[C:23](=[O:25])[C:30]=2[CH:31]=1
Reactant: O=C(O)c1ccccc1COc1ccc(Br)cc1
Agent: FB(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1c2ccccc2COc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
Trifluoroacetic anhydride (56.0 mL, 400 mmol) was added dropwise to a dichloromethane (500 mL) solution of 2-(4-bromophenoxymethyl)benzoic acid (112 g, 364 mmol) at room temperature. The mixture was stirred at room temperature for 2 hour, BF3.OEt2 (10 mL, 169.3 mmol) was then added thereto, and the mixture was stirred at room temperature for additional 2 hours. The reaction mixture was washed with a saturated aqueous sodium bicarbonate solution, and then with a saturated sodium chloride solution, the washed mixture was then dried over anhydrous sodium sulfate, and the solvents were distilled off under a reduce pressure. The residue was purified by column chromatography (hexane-ethyl acetate=3:2), to give 96.0 g (91%) of the captioned compound in the form of crystals.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCCOC(=O)c1ncc[nH]1
Reactant: ClCc1ccccc1
Product: CCCCOC(=O)c1nccn1Cc1ccccc1
Yield: 88 %

Procedure:
5.4 g (32.1 mmol) of butyl imidazole-2-carboxylate were reacted with 4.1 g (32.1 mmol) of benzyl chloride analogously to procedure 8a. 7.3 g (78%) of the product were obtained.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9]NC(=O)C2C=CC=CC=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Sm+2].[I-]>CO.O1CCCC1>[CH3:8][C@H:7]([NH2:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](NNC(=O)c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Sm+2]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](N)c1ccccc1
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To (S)-(-)-2-phenyl-2-(2-benzoylhydrazino)ethane (0.40 g, 1.66 mmol, 89% ee) in methanol (7 mL) was added rapidly dropwise a solution of samarium(II) iodide (70 mL of a 0.05M solution in tetrahydrofuran). After complete addition, the reaction was allowed to stir for 30 min. The reaction was then concentrated on a rotovap, and to the resulting residue was added 1M HCl (15 mL). The aqueous layer was extracted with diethyl ether (8×25 mL). The aqueous layer was made basic to litmus by the addition of 3M NaOH and then was extracted with diethyl ether (8×25 mL). The combined ether extractions were dried over a small amount of magnesium sulfate. Concentration of the ether solution on a rotovap provided the product (S)-(-)-α-methylbenzylamine as a colorless oil (0.144 g, 72%): [α]D20 =-37.1° (c 1.33, C6H6), 1H NMR (CDCl3): δ 1.40 (d, JHH =6.3 Hz, 3H, CH3), 1.70 (br, 2H, NH), 4.14 (q, JHH =6.3 Hz, 1H, CH), 7.25 (m, 1H, Ph), 7.45 (m, 4H, Ph). The enantiomeric purity of the amine product (S)-(-)-α-methylbenzylamine was determined to be 89% ee using chiral capillary GC methods (J & W Cyclodex B column, 80° C., isothermal, (R) t1 20.57 min; (S) t2 21.33 min).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:13][C:14]([C:16]2([NH:34]C(=O)OC(C)(C)C)[CH2:21][CH2:20][N:19]([C:22]3[C:23]4[C:30]([CH:31]5[CH2:33][CH2:32]5)=[CH:29][NH:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1>O1CCOCC1.CO>[NH2:34][C:16]1([C:14]([NH:13][C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)[CH2:10][CH2:11][OH:12])=[O:15])[CH2:17][CH2:18][N:19]([C:22]2[C:23]3[C:30]([CH:31]4[CH2:32][CH2:33]4)=[CH:29][NH:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]cc(C4CC4)c23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]cc(C4CC4)c23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.2 %

Procedure:
Hydrogen chloride 4M in dioxane (0.923 mL, 3.69 mmol) was added to (S)-tert-butyl 4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 65) (420 mg, 0.74 mmol) in dioxane (25 mL). The resulting solution was stirred at ambient temperature for 2 hours. The reaction mixture was dissolved in methanol and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5N ammonia/MeOH and pure fractions were evaporated to dryness. The product was then purified by preparative LCMS (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (25.0 mg, 7.2%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]P(OCC)(OCC)=O)[CH:5]=1.[H-].[Na+].[Cl:22][C:23]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[N:34]([C:41]3[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][C:42]=3[Cl:48])[N:35]=[N:36][C:37]=2[CH:38]([CH3:40])[CH3:39])[CH:28]=[CH:27][C:24]=1[CH:25]=O>C(OCC)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[CH:25][C:24]2[CH:27]=[CH:28][C:29]([O:31][CH2:32][C:33]3[N:34]([C:41]4[C:42]([Cl:48])=[CH:43][CH:44]=[CH:45][C:46]=4[Cl:47])[N:35]=[N:36][C:37]=3[CH:38]([CH3:40])[CH3:39])=[CH:30][C:23]=2[Cl:22])[CH:5]=1
Reactant: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1COc1ccc(C=O)c(Cl)c1
Reactant: CCOP(=O)(Cc1cccc(C(=O)OC)c1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COC(=O)c1cccc(C=Cc2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2Cl)c1
Reaction time: 1 h
Yield: 79.6 %

Procedure:
To a 0° C. solution of 3-(diethoxy-phosphorylmethyl)-benzoic acid methyl ester (1.2 g, 4 eq) in diethyl ether (15 mL) is added sodium hydride (0.17 g, 4 eq). After 1 h, 2-chloro-4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-benzaldehyde (0.44 g, 1 eq) in diethyl ether (5 mL) is added and the reaction is stirred overnight. Upon completion, the reaction is quenched with water. The aqueous solution is acidified with 1N HCl and extracted two times with ethyl acetate. The organic layers are combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified via filter chromatography eluting with 10% ethyl acetate:toluene to give 3-(2-{2-Chloro-4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-phenyl}-vinyl)-benzoic acid methyl ester (0.459 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)(=[O:15])=[O:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl[Sn]Cl>Cl.CCO>[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:13]([NH:12][C:9]1[CH:10]=[CH:11][C:2]([F:1])=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2)(=[O:15])=[O:14]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1ccc(F)c2cccnc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccccc1S(=O)(=O)Nc1ccc(F)c2cccnc12
Yield: 81.7 %

Procedure:
In a similar fashion using route 1 general procedure 4, N-(5-Fluoro-quinolin-8-yl)-2-nitro-benzenesulfonamide (Intermediate 245) (470 mg, 1.35 mmol), SnCl2 (770 mg, 4.06 mmol), 6N HCl (6 drops) and EtOH (10 ml) for 6 h at 85° C. gave the title compound (350 mg, 82%) which was used in the next step without further purification.
Reaction SMILES: [C:1]([N:8]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C@@H:9]([C:11]([OH:13])=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+](C1C=CC(N[C@H](C(O)=O)C)=CC=1)([O-])=O>>[C:1]([N:8]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cc1
Agent: C[C@H](Nc1ccc([N+](=O)[O-])cc1)C(=O)O
Product: C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cc1
Yield: 86 %

Procedure:
The reaction described above for Nα -Boc-4-Nitrophenyl-D-alanine was repeated for the L-isomer. About 123 grams of 4-nitrophenyl-L-alanine was reacted as described and resulted in about 155 grams of Nα -Boc-4-Nitrophenyl-L-alanine (about 86% yield). [α]D =+7.1° (c=1.0 in MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Cl[C:12]1[C:17]([CH2:18][OH:19])=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)(O)[O-].[Na+].O1CCOCC1>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[C:17]([CH2:18][OH:19])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: OCc1cccnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: OCc1cccnc1-c1cccc(Cl)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of (3-chlorophenyl)boronic acid (1.6 g, 10.23 mmol, 1.20 equiv), (2-chloropyridin-3-yl)methanol (1 g, 6.97 mmol, 1.00 equiv), Pd(dppf)Cl2 (570 mg, 0.78 mmol, 0.10 equiv), and sodium bicarbonate (1.7 g, 20.24 mmol, 3.00 equiv) in a solvent mixture of dioxane (10 mL) and water (10 mL). The resulting solution was stirred for 3 h at 70° C., and then it was diluted with 20 mL of H2O. The resulting solution was extracted with 2×20 mL of dichloromethane, and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100-1:5) as eluent to yield 1.2 g (78%) of [2-(3-chlorophenyl)pyridin-3-yl]methanol as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4](Br)=[CH:5][N:6]=1.[NH:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:8]1([CH:4]2[S:3][CH:2]([NH2:1])[N:6]=[CH:5]2)[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: Nc1ncc(Br)s1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC1N=CC(n2cccn2)S1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.1 %

Procedure:
A solution of 2-amino-5-bromothiazole (2.6 g, 14.68 mmol), pyrazole (1 g, 14.68 mmol) and cesium carbonate (11.92 g, 36.7 mmol) in DMF (29 mL) was heated at 55° C. for 1 hr under argon argon atmosphere. After 1 hr, 2-amino-5-bromothiazole (2.6 g, 14.68 mmol) was added and continued for next 1 hr. Reaction mixture was cooled to rt and poured over ice cold water (200 mL), extracted with ethylacetate (4×100 mL), washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Crude compound was purified by silica gel column chromatography using 60% ethyl acetate in hexane as eluent to afford pure 5-pyrazol-1-yl-5H-thiazol-2-amine (0.2 g).