Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].CN(C=O)C.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25].N1C=CN=C1>CCOC(C)=O>[Si:27]([O:1][CH2:2][C@@H:3]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5])([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CON(C)C(=O)[C@@H](CO)NC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
(R)-tert-butyl 3-hydroxy-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (21) (4.4 g, 17.5 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by DMF (35 mL) and cooled to 0° C. via an ice bath. Next, TBDMSCl (2.9 g, 19.3 mmol, 1.1 equiv.) and imidazole (2.4 g, 35.1 mmol, 2.0 equiv.) were added to the reaction flask. The solution was stirred at 0° C. for 1 h and then allowed to warm to rt, stirring an additional 2 h. The reaction solution was transferred to a 500 mL separatory funnel with EtOAc (150 mL). The mixture was washed with 1% HCl (3×40 mL), sat. NaHCO3 (1×40 mL), and sat. NaCl (2×40 mL). The organic layer was separated and dried over Na2SO4. The solution was concentrated on a rotary evaporator and dried under vacuum to give 5.9 g (93%) of 22 as a colorless oil. Rf=0.54 (50% EtOAc/hexanes); [α]D23.5=+3.55 (c 1.22, MeOH); IR (film) 3437, 3324, 2953, 2929, 2884, 2856, 1715, 1666, 1496, 1471, 1365, 1253, 1171, 1114 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.34 (br d, J=8.5 Hz, 1H, carbamate-NH), 4.73 (br s, 1H, Boc-NH—CH), 3.83 (m, 1H, CH—CH2), 3.77 (m, 1H, CH—CH2), 3.73 (s, 3H, N—OCH3), 3.19 (s, 3H, NCH3), 1.41 (s, 9H, Boc-t-butyl-CH3), 0.84 (s, 9H, Si-t-butyl-CH3), 0.00 (s, 6H, Si—(CH3)2); 13C NMR (125 MHz, CDCl3) δ 170.9, 155.5, 79.7, 63.6, 61.6, 52.6, 32.3, 28.5, 25.9, 18.4, −5.4; LRMS (ESI-MS m/z): Mass calcd for C16H34N2O5Si [M]+, 362.54. Found 363. Anal. calcd for C16H34N2O5Si: C, 53.01; H, 9.45; N, 7.73. Found: C, 53.26; H, 9.63; N, 7.68.
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:10])[N:4]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH3:23])[C:15]([CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])=[N:16][CH:17]=1.[NH3:24]>CO>[Br:11][C:12]1[CH:13]=[C:14]([CH3:23])[C:15]([CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:3]2[C:7]([NH2:24])=[N:6][S:5](=[O:10])[N:4]=2)=[N:16][CH:17]=1
Reactant: Cc1cc(Br)cnc1CCCCN
Reactant: N
Reactant: COC1=NS(=O)N=C1OC
Solvent: CO
Product: Cc1cc(Br)cnc1CCCCNC1=NS(=O)N=C1N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (1.62 g) in methanol was reacted with a solution of 4-(5-bromo-3-methylpyrid-2-yl)-butylamine (2.43 g) in methanol. After 2 hours at room temperature, the reaction was cooled to 0° C. and saturated by passing ammonia gas for 10 mins. After 1.5 hours the product (which precipitated) was filtered off and recrystallised from ethanol to yield 3-[4-(5-bromo-3-methylpyrid-2-yl)-butylamino]-4-amino-1,2,5-thiadiazole-1-oxide (1.12 g) m.p. 188°-190° C.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1(S(C2ON2C2C=CC=CC=2)(=O)=[O:36])C=CC=CC=1>C1COCC1>[OH:36][CH:5]1[CH2:4][CH2:3][CH2:2][CH:1]1[CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:8]
Reactant: O=S(=O)(c1ccccc1)C1ON1c1ccccc1
Reactant: COc1ccc(COC(=O)CC2CCCC2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)CC2CCCC2O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.7 %

Procedure:
A solution of 450 mg (1.81 mmol) of cyclopentylacetic acid, 4-(methoxy)benzyl ester (from EXAMPLE 15, Step A) in 6 mL of THF was added to 2.15 mL of 1.0 M sodium bis(trimethylsilyl)amide solution in THF at −78° C. and the resulting mixture was stirred cold for 15 min. A solution of 700 mg (2.67 mmol) of (benzenesulfonyl)phenyloxaziridine in 3 mL of THF was the added and the resulting mixture was stirred at −78° C. for 1 h. The reaction was quenched with sat'd NH4Cl and warmed to rt. The mixture was concentrated and the residue was dissolved in 100 mL of ether and washed with 100 mL of sat'd NaCl. The phases were separated and the aqueous layer was extracted with 100 mL of ether. The combined organic layers were dried over MgSO4 and concentrated. Flash chromatography on silica gel using 9:1 v/v hexanes/EtOAc as the eluant afforded 233 mg (48%) of the title compound: RF: 0.37 (4:1 v/v hexanes/EtOAc); 1H NMR (300 MHz) δ 1.36-1.69 (m, 8H), 2.22 (m, 11H), 3.81 (s, 3H), 4.14 (d, J=4.9, 11H), 5.14 (ABq, J=11.8, 2H), 6.89 (d, J=8.8, 2H), 7.29 (d, J=8.8, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([C:14]([OH:17])([CH3:16])[CH3:15])[C:11](O)=[O:12])=[C:5]([CH3:18])[C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=[O:30])=[CH:27][CH:26]=1)#[N:24].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1.C(OCC)(=O)C>[C:23]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:31][NH:32][C:11](=[O:12])[C@H:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:19]([F:22])([F:21])[F:20])[C:5]=2[CH3:18])[C:14]([OH:17])([CH3:16])[CH3:15])=[O:30])=[CH:33][CH:34]=1)#[N:24]
Reactant: Cc1c(N[C@@H](C(=O)O)C(C)(C)O)ccc(C#N)c1C(F)(F)F
Reactant: N#Cc1ccc(C(=O)NN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)C(C)(C)O)ccc(C#N)c1C(F)(F)F
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 108.8 %

Procedure:
(R)-2-(4-cyano-2-methyl-3-(trifluoromethyl)phenylamino)-3-hydroxy-3-methylbutanoic acid (500 mg, 1.58 mmol) and 4-cyanobenzohydrazide (301 mg, 1.87 mmol) were mixed together in THF (20 mL) and cooled to −15° C. under N2 atmosphere. To the pre-cooled reaction mixture were added hydroxybenzotriazole (HOBT) (230 mg, 1.70 mmol), TEA (0.36 mL, 2.55 mmol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (489 mg, 2.55 mmol). The reaction mixture was allowed to stir at −20° C. for 20 min and then at room temperature overnight. After the reaction was complete, ethyl acetate (50 mL) was added and the solution was washed with 5% citric acid (2×40 mL), 5% NaHCO3 (2×40 mL) followed by water (40 mL) and then dried (Na2SO4) to provide the crude product as a yellow solid (790 mg, 99%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.92 (br s, 1H), 9.49 (br s, 1H), 7.99 (d, J=9 Hz, 2H), 7.81 (d, J=9 Hz, 2H), 7.42 (d, J=9 Hz, 1H), 6.61 (d, J=9 Hz, 1H), 6.53 (dd, J=12 and 18 Hz, 1H), 5.99 (d, J=9 Hz, 1H), 5.73 (dd, J=2 and 12 Hz, 2H), 5.64 (dd, J=2 and 18 Hz), 4.29-4.22 (m, 1H), 4.01-3.99 (m, 1H) and 1.20 (d, J=7 Hz, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[N-:12]=[N+:13]=[N-:14].[Na+].O>CO>[N:12]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N+:13]=[N-:14]
Reactant: CCOC(=O)CCCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CCCCCN=[N+]=[N-]
Yield: 103.5 %

Procedure:
A solution of ethyl 6-bromohexanoate (10.0 g, 44.8 mmol), NaN3 (5.83 g, 89.6 mmol) and 25 ml of water in 75 ml of MeOH was refluxed for 3.5 hrs. The MeOH was removed in vacuo and the residue was partitioned between CHCl3 (200 ml) and water (50 ml). The organic layer was separated and washed with water. After drying (Na2SO4) and evaporation of solvent, ethyl 6-azidohexanoate (8.59 g, 100%) was obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][OH:15].[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][O:15][C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1
Reactant: CSc1nsc(Cl)n1
Reactant: OCc1ccco1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2ccco2)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 54.8 %

Procedure:
To 4 ml of N,N-dimethylformamide, 0.334 g of 5-chloro-3-methylthio-1,2,4-thiadiazole and 0.196 g of 2-furanmethanol were dissolved, and added 0.084 g of sodium hydride (60% in oil) at about 0° C., followed by stirring at about 0° C. for 0.5 hours and at room temperature for 4 hours. Then, the reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with tert-butylmethylether. The organic layer was concentrated, and the residue obtaind was subjected to silica gel column chromatography to obtain 0.25 g of 5-(2-furyl)methoxy-3-methylthio-1,2,4-thiadiazole.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].Cl[C:8]([O:10][CH2:11][CH:12]1[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9].O>C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>[C:8]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])([O:10][CH2:11][CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[C:24]1=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:9]
Reactant: C[C@H](N)C(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Yield: 90.1 %

Procedure:
To a solution of L-alanine (1.78g, 20 mmol) in 10% Na2CO3 (53 ml) was added dropwise (within 50 min) with stirring and ice bath cooling a solution of 9-fluorenylmethyl chloroformate (5.17g, 20 mmol) in dioxane (40 ml). The mixture was stirred for 1 hr at 0° and 15 hr at 5°, poured into H2O (1.5 liters) and extracted with ether (2 x). The aqueous layer was cooled in an ice bath, acidified with concentrated HCl to pH 2-3 (white precipitate) and extracted with EtOAc (3 × 500 ml). The organic phase was washed with H2O, dried (MgSO4), filtered, and evaporated. Ether-petroleum ether was added to the residue which crystallized while being kept at 5°. The crude product (5.94g, 95.5%) was recrystallized from methanol-petroleum ether to yield colorless crystals of Fmoc-L-alanine (5.61g, 90.2%), mp 144.5°-145.5° ; [α]D25 = - 11.7° (c 1, CH3OH); tlc, Rf 0.8 (A), 0.3 (B); uv max (CH2Cl2) 267 nm (ε18,950), 290 (5,280), 301 (6,200).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[N:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([NH2:29])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C(N(CC)CC)C.[Cl:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][C:39]=1[N:45]1[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]1>ClCCl>[Cl:37][C:38]1[CH:44]=[CH:43][C:41]([NH:42][C:2]([NH:29][C:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19]([C:16]3[CH:15]=[CH:14][N:13]=[CH:18][CH:17]=3)=[CH:20][CH:21]=2)=[O:4])=[CH:40][C:39]=1[N:45]1[CH2:46][CH2:47][N:48]([CH3:51])[CH2:49][CH2:50]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(-c2ccncc2)c2ccccc12
Reactant: CN1CCN(c2cc(N)ccc2Cl)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cc(NC(=O)Nc3ccc(-c4ccncc4)c4ccccc34)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of triphosgene (39 mg, 0.13 mmole) in dichloromethane (10 ml) was added a solution of 4-(pyridin-4-yl)naphth-1-ylamine (D1, 82 mg, 0.37 mmole) and triethylamine (0.05 ml, 0.37 mmole) dropwise over 30 minutes. When the addition was complete the mixture was stirred at room temperature for 15 minutes, then a solution of 4-chloro-3-(4-methylpiperazin-1-yl)aniline (100 mg, 0.44 mmole, EP0533268A1) in dichloromethane (10 ml) was added over 5 minutes. After 18 h, the mixture was washed with 10% aqueous sodium carbonate solution and water, dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 10% methanol/dichloromethane and the title compound was obtained as a white solid on trituration with ether (47 mg, 27%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[C:6](=[O:8])[N:7]=1.[OH:23][C@@H:24]([CH2:37][NH2:38])[CH2:25][O:26][C:27]1[C:35]2[NH:34][C:33](=[O:36])[NH:32][C:31]=2[CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(O)(=O)C>[OH:23][C@@H:24]([CH2:37][NH:38][CH:19]1[CH2:20][CH2:21][N:16]([C:13]2[CH:14]=[CH:15][C:10]([CH:9]=[C:5]3[S:4][C:3]([NH:2][CH3:1])=[N:7][C:6]3=[O:8])=[CH:11][CH:12]=2)[CH2:17][CH2:18]1)[CH2:25][O:26][C:27]1[C:35]2[NH:34][C:33](=[O:36])[NH:32][C:31]=2[CH:30]=[CH:29][CH:28]=1
Reactant: CNC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CNC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)S1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.1 %

Procedure:
1-[4-(2-Methylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 18)(0.15 g, 0.47 mmol) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (Jesudason, C. D., et al., EP 0 764 640) (0.119, 0.47 mmol) were mixed in dimethylformamide (15 mL) and then treated with sodium triacetoxyborohydride (0.16 g, 0.75 mmol) and acetic acid (0.15 mL). After stirring at room temperature under a nitrogen atmosphere for one day the mixture was poured into a saturated aqueous sodium bicarbonate solution. The precipitate was collected and purified by column chromatography (eluent: methanol/methylene chloride) to give the title compound as a pale yellowish solid(0.16 g, 65%); mp>160° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ1.20-1.45 (m, 2 H), 1.75-2.00 (m, 2 H), 2.60-3.00 (m, 5 H), 3.05 (s, 3 H), 3.75-4.15 (m, 5 H), 6.57 (d, J=7.8 Hz, 1 H), 6.62 (d, J=8.1 Hz, 1 H), 6.87 (t, J=8.1 Hz, 1 H), 7.02 (d, J=8.7 Hz, 2 H), 7.38 (d, J=8.7 Hz, 2 H), 7.47 (s, 1 H), 10.56 (s, 1 H), 10.70 (brs, 1 H); MS (ES) m/z: 262.1 ((M+2H)2+, 100%); 522.9 (MH+, 75%); HRMS Calcd. for C26H31N6O4S (MH+): 523.2128. Found: 523.2142.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClCCl.[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([S:35]([CH2:33][CH3:34])(=[O:37])=[O:36])[CH2:26][CH2:25]3)=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCNCC3)cn2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCN(c2ccc(N3CCN(C(=O)OC(C)(C)C)c4ccccc43)nc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.8 g of 4-(5-(piperazin-1-yl)pyridin-2-yl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester is placed in a 25 ml round-bottomed flask. ml of dichloromethane are added, followed by 0.37 ml of triethylamine and finally 0.23 ml of ethylsulphonyl chloride. The reaction mixture is stirred at ambient temperature for 3 h, then washed twice with water and once with a saturated sodium chloride solution and then evaporated under reduced pressure. 0.98 g of 4-[5-(4-(ethanesulphonyl)piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester is obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:23])=[C:9]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[C:15]([O:21][CH3:22])[CH:14]=2)[N:10]=1.C(O)C.[BH4-].[Na+].O>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:23])=[C:9]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[C:15]([O:21][CH3:22])[CH:14]=2)[N:10]=1
Reactant: COc1cc(OCc2nc(-c3ccco3)oc2C)ccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(OCc2nc(-c3ccco3)oc2C)ccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a solution of 4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-2-methoxybenzaldehyde (3.00 g) in tetrahydrofuran (30 mL)-ethanol (10 mL) was gradually added sodium borohydride (0.36 g) at 0° C. After stirring at room temperature for 1 hr., water was added to the reaction mixture and the precipitated crystals were collected by filtration to give (4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-2-methoxyphenyl)methanol as colorless crystals (2.91 g, yield 96%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 117-118° C.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][N:31]([CH3:38])[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.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>[CH3:27][N:26]([CH3:28])[C:25]([C:7]1[N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:35]4[CH2:36][CH2:37][CH:32]([N:31]([CH3:38])[CH3:30])[CH2:33][CH2:34]4)=[O:21])=[CH:18][N:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=1)=[O:29]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: CN(C)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CCC(N(C)C)CC4)cn3)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.6 %

Procedure:
To a solution of 6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (100 mg, 0.25 mmol) (Example D) in 3 mL of DMF is added dimethyl-piperidin-4-yl-amine (33 mg, 0.25 mmol), HBTU (140 mg, 0.38 mmol), and DIPEA (0.088 mL, 0.51 mmol). After 48 h stirring at room temperature, the resulting mixture is concentrated and diluted with saturated NaHCO3 and extracted with ethyl acetate (3×100 mL). The combine organics are dried over Na2CO3 and concentrated to give a reddish residue. Preparative HPLC to give 7-cyclopentyl-2-[5-(4-dimethylamino-piperidine-1-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (60 mg, 46%). MS (ESI) m/z 505.5 (M+H)+
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.Cl[CH2:24][C:25](=O)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].CN(C)C(=O)C>O>[CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:14][CH:24]=[C:25]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:13]=1)=[CH:8]2
Reactant: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)Cc1csc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
A mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.40 g), ethyl 4-chloro-3-oxobutyrate (0.55 g) and N,N-dimethylacetamide (6 mL) was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.38 g, yield 75%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). melting point 117-118° C.
Reaction SMILES: [CH3:1][N:2]([CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][C:68]([O:70]C(C)(C)C)=[O:69])[C:3]([C@@H:5]1[CH2:10][O:9][CH2:8][CH2:7][N:6]1[CH2:11][CH2:12][N:13]([CH3:56])[C:14](=[O:55])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:54])[NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:25][C:24]=2[C:35]2[CH:40]=[C:39]([C:41](=[O:53])[NH:42][C@@H:43]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH2:46][CH2:45][CH2:44]3)[CH:38]=[CH:37][N:36]=2)[CH:16]=1)=[O:4]>ClCCl.FC(F)(F)C(O)=O>[CH3:1][N:2]([CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][C:68]([OH:70])=[O:69])[C:3]([C@@H:5]1[CH2:10][O:9][CH2:8][CH2:7][N:6]1[CH2:11][CH2:12][N:13]([CH3:56])[C:14](=[O:55])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:54])[NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:25][C:24]=2[C:35]2[CH:40]=[C:39]([C:41](=[O:53])[NH:42][C@@H:43]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH2:46][CH2:45][CH2:44]3)[CH:38]=[CH:37][N:36]=2)[CH:16]=1)=[O:4]
Reactant: CN(CCN1CCOC[C@H]1C(=O)N(C)CCOCCOCCOCCC(=O)OC(C)(C)C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCN1CCOC[C@H]1C(=O)N(C)CCOCCOCCOCCC(=O)O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 2-methyl-1-((S)-4-(2-(N-methyl-3-(4-(piperidin-1-yl)-2-(4-((S)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)benzamido)ethyl)morpholin-3-yl)-1-oxo-5,8,11-trioxa-2-azatetradecan-14-oate Example 242 (100 mg, 0.10 mmol, 1.00 equiv) in dichloromethane (4 mL), trifluoroacetic acid (2 mL). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (5% CH3CN up to 28% in 1 min, up to 38% in 6 min); Detector, Waters2545 UvDector 254&270 nm. 8.4 mg product was obtained. This resulted in 8.4 mg (7%) of 2-methyl-1-((S)-4-(2-(N-methyl-3-(4-(piperidin-1-yl)-2-(4-((S)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)benzamido)ethyl)morpholin-3-yl)-1-oxo-5,8,11-trioxa-2-azatetradecan-14-oic acid as a yellow solid. LC-MS (ES, m/z): 962 [M+H]+ H-NMR (300 MHz, CD3OD, ppm): 8.93 (d, J=5.1 Hz, 1H), 8.65 (d, J=9.3 Hz, 1H), 8.39 (s, 1H), 8.24 (s, 1H), 8.14-8.11 (m, 1H), 8.03-8.02 (m, 1H), 7.86-7.84 (m, 2H), 7.76-7.72 (m, 1H), 7.64-7.61 (m, 1H), 7.28-7.25 (m, 1H), 7.18-7.14 (m, 3H), 5.39 (m, 1H), 4.50-4.45 (m, 2H), 4.30-4.20 (m, 1H), 4.09-4.05 (m, 1H), 3.86-3.43 (m, 25H), 3.21 (s, 1H), 3.10-3.08 (m, 3H), 3.00 (s, 1H), 2.91-2.84 (m, 2H), 2.57-2.51 (m, 2H), 2.04-1.79 (m, 10H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=1[N+:22]([O-:24])=[O:23].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[N+:22]([C:15]1[CH:16]=[C:17]([CH:18]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[OH:19])[CH:20]=[CH:21][C:14]=1[Cl:13])([O-:24])=[O:23].[ClH:13]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Brc1ccccn1
Agent: O=S(=O)([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cl
Product: O=[N+]([O-])c1cc(C(O)c2ccccn2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 200 ml. (0.32 mol) of n-butyllithium in 400 ml. of tetrahydrofuran was added to a solution of 48 g. (0.286 mol) of 2-bromopyridine in 120 ml. of tetrahydrofuran under argon cooled to -78° C. over 20 min. After 30 min. the resulting dark orange mixture was transferred under argon into a solution of 50 g. (0.27 mol) of 4-chloro-3-nitrobenzaldehyde in 600 ml. of tetrahydrofuran over a 30 min. period and the resulting dark solution was allowed to warm to room temperature overnight. The mixture was hydrolyzed with 32 g. (0.1 mol) of sodium sulfate decahydrate, filtered and concentrated in vacuo to a dark oil which was then warmed to 80° C. in 300 ml. of 3N hydrochloric acid, then cooled to 10° C. and the product was filtered, washed successively with 2-propanol and ether to yield 3-nitro-4-chlorophenyl-2-pyridylmethanol as its hydrochloride, mp. 195° -205° C.