Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(CC(=O)O)cn1
Temperature: 65 °C
Yield: 99.2 %

Procedure:
To a stirred solution of methyl (6-methylpyridin-3-yl)acetate (60 mg, 0.36 mmol) in methanol (5 ml) was added NaOH (1.0 ml of a 2M aqueous solution, 2.0 mmol) and the resulting solution was heated at 65° C. for 2 hours. The solvent was then removed at reduced pressure and the resulting residue was dissolved in methanolic HCl (5 ml) and then reconcentrated to yield the title product (54 mg, quant. yield) that was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23].[C:29]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:32])[NH:30][NH2:31].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:31][NH:30][C:29]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:23]
Reactant: Cc1cccc(C)c1Nc1c(-c2ccccc2C(=O)O)nc2ccc(F)cn12
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1Nc1c(-c2ccccc2C(=O)NNC(=O)OC(C)(C)C)nc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 57 %

Procedure:
2.2 250 mg (0.666 mmol) of 2-[3-(2,6-dimethylphenylamino)-6-fluoroimidazo[1,2-a]pyridin-2-yl]benzoic acid, 88 mg (0.666 mmol) of tert-butyl carbazate, 153 mg (0.800 mmol) of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (DAPECI) are dissolved in 1 ml of DMF and stirred at RT for 5 hours. The mixture is subsequently added to water, the precipitated solid is filtered off with suction and dried, giving 187 mg (57%) of tert-butyl N′-{2-[3-(2,6-dimethylphenylamino)-6-fluoroimidazo[1,2-a]-pyridin-2-yl]benzoyl}hydrazinecarboxylate as solid; MS-FAB (M+H+)=490.8; Rf (HPLC, polar method): 1.47 min. This is employed in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.Cl.[NH2:36][C@@H:37]([C:41]([O:43]C(C)(C)C)=[O:42])[CH:38]([CH3:40])[CH3:39].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[O:16])[C@H:9]2[C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([NH:36][C@@H:37]([C:41]([OH:43])=[O:42])[CH:38]([CH3:40])[CH3:39])=[O:32])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Reaction time: 0.08 h

Procedure:
[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetic acid, (50.0 mg, 0.10 mmol) was dissolved in DCM (2 ml). tert-Butyl D-valinate hydrochloride (28.4 mg, 0.14 mmol) and N-methylmorpholine (3.0 μl, 0.31 mmol) were added. After 5 minutes, TBTU (43.7 mg, 0.14 mmol) was added and the mixture was stirred overnight. The intermediate tert-butylester of the title compound was confirmed. M/z: 637.1 (M−H). The solvent was removed under reduced pressure. The yellow residue was dissolved in formic acid (1.5 ml) and heated at 50° C. for 5 h. The solvent was evaporated and the residue was purified by preparative HPLC on a C8 column. A gradient from 20 to 50% MeCN in 0.1 M ammonium acetate buffer was used as eluent. After lyophilisation, the title compound was obtained as a white solid (30.5 mg, 51%). 1H-NMR (400 MHz, DMS-d6): 0.74 (t, 6H), 1.98-2.07 (m, 1H), 3.84 (brs, 1H), 4.32 (d, 1H), 4.35 (s, 1H), 4.36 (s, 1H), 4.50 (brs, 2H), 5.16 (d, 1H), 6.96 (d, 2H), 7.10-7.17 (m, 2H), 7.19-7.24 (m, 2H), 7.31-7.38 (m, 4H), 7.66 (brs, 1H), 7.99-8.04 (m, 2H). M/z: 583.0 (M+H) and 581.0 (M−H).
Reaction SMILES: BrN1C(=[O:7])CCC1=O.C[C:10]1[C:15]2[O:16]C3C(=NC=2[C:13]([C:63]([NH:65][C@@H]2C(=O)N[C@H](C(C)C)C(=O)N4[C@@H](CCC4)C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]2C)=O)=[CH:12][CH:11]=1)C(C(N[C@@H]1C(=O)N[C@H](C(C)C)C(=O)N2[C@@H](CCC2)C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]1C)=O)=C(N)C(=O)C=3C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC1C=CC=CC=1>[CH2:12]([CH2:13][CH2:63][NH2:65])[CH2:11][CH2:10][C:15]([OH:7])=[O:16]
Reactant: Cc1c2oc3c(C)ccc(C(=O)N[C@@H]4C(=O)N[C@H](C(C)C)C(=O)N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)c3nc-2c(C(=O)N[C@@H]2C(=O)N[C@H](C(C)C)C(=O)N3CCC[C@H]3C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]2C)c(N)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: NCCCCCC(=O)O
Temperature: 80 °C

Procedure:
Bromination with N-bromosuccinimide (NBS) is accomplished by adding 2.24 mmoles of actinomycin D in chlorobenzene to 2 mmoles of NBS and a trace of dibenzoyl peroxide. The mixture is heated to 80° C. and allowed to react for 6 hours. The yield of AMD--CH2Br is 70-80%. The brominated derivative is then reacted further with aminocaprioic acid to yield an AMD-aminocaproic acid complex (AMD--CH2NH (CH2)5COOH).
Reaction SMILES: C([NH:18][C@H:19]([C:31]([OH:33])=[O:32])[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[NH2:34][C@H:35]([C:39]([O:41][CH2:42][CH:43]=[CH2:44])=[O:40])[CH:36]([CH3:38])[CH3:37].N1CCCCC1>C(Cl)Cl>[C:21]1([CH2:20][C@@H:19]([C:31]([OH:33])=[O:32])[NH2:18])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.[NH2:34][C@H:35]([C:39]([O:41][CH2:42][CH:43]=[CH2:44])=[O:40])[CH:36]([CH3:38])[CH3:37]
Reactant: O=C(N[C@@H](Cc1cccc2ccccc12)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: C=CCOC(=O)[C@@H](N)C(C)C
Solvent: ClCCl
Solvent: C1CCNCC1
Product: N[C@@H](Cc1cccc2ccccc12)C(=O)O
Reaction time: 0.75 h
Yield: 91.7 %

Procedure:
Fmoc-3-(1-naphtyl)-L-alanine-Val-OAllyl (0.67 g, 1.16 mmol) was solvated in CH2Cl2 (5 mL) followed by addition of piperidine (0.920 mL). After 45 min, the mixture was evaporated to dryness and co-evaporated with CH2Cl2 (20 mL*2) followed with high vacuum (without heating) for 10 min to remove the excess of piperidine. The sample was purified on silica with a gradient of MeOH/CH2Cl2 (0 to 5%) to get 0.396 g of the desired compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([C:58]1[CH:63]=[CH:62][CH:61]=[C:60]([CH3:64])[CH:59]=1)=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:56]([NH:55][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([CH3:64])[CH:59]=2)=[O:57])[CH2:49][CH2:48]1
Reactant: Cc1cccc(N=C=O)c1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(NC(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)c1
Yield: 27 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1-isocyanato-3-methylbenzene as starting materials in 27% yield. LCMS for C32H34ClN8O2 (M+H)+: m/z=597.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:18]([CH2:19][C:20]([OH:22])=[O:21])[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:28](O)[CH3:29]>>[CH2:28]([O:21][C:20](=[O:22])[CH2:19][N:18]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=[C:10]1[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH3:29]
Reactant: CCO
Reactant: O=C(O)Cn1c(-c2ccc([N+](=O)[O-])cc2)nc2cccnc21
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cn1c(-c2ccc([N+](=O)[O-])cc2)nc2cccnc21
Temperature: 25 °C
Yield: 71 %

Procedure:
A suspension of crude 2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (1.5 g, 0.00503 mole) in absolute ethanol was acidified with 0.5 ml of concentrated sulfuric acid and refluxed under nitrogen for three days. The solution was evaporated to approximately one-third of its original volume (reduced pressure), and saturated sodium bicarbonate solution and ethyl acetate were added. The layers were separated, the aqueous layer was re-extracted with ethyl acetate and the combined organic layers were washed twice with water, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give a solid. The solid was dissolved in hot absolute ethanol and filtered hot. Upon cooling to room temperature, a solid formed which was collected by filtration, rinsed with water, and dried under high vacuum at 50° C. overnight to give 1.17 g (71%) of title compound, mp 191.5°-193.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1.[H-].[Na+].Cl.Cl[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][N:16]=1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(O)c1ccc(Br)cc1
Reactant: Clc1ccncn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1ccncn1)c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 1-(4-bromophenyl)ethanol (1 g, 5 mmol) in 20 mL of anhydrous N,N-dimethylformamide was added sodium hydride (0.36 g, 15 mmol) at room temperature and then stirred for 1 hour, 4-chloropyrimidine hydrochloride (1 g, 6 mmol) was added, and then heated at 100° C. for 12 hours. The reaction mixture was concentrated, the residue was purified by chromatography with petroleum/ethyl acetate=1:1 to afford 4-(1-(4-bromophenyl)ethoxy)pyrimidine (1.2 g, 86% yield). LRMS (M+H+) m/z: calcd for 278.01. found 278. 1H NMR (300 MHz, CD3OD) δ 8.65 (s, 1H), 8.42 (d, J=6.0 Hz, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 6.92 (dd, J=6.0 and 1.2 Hz, 1H), 6.26 (q, J=6.6 Hz, 1H), 1.64 (d, J=6.6 Hz, 3H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH:24]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:26]=1)[O:19][CH2:20][C:21](=O)[CH3:22].[CH2:31]([NH2:34])[CH2:32][CH3:33].C(O)(=O)C>ClCCCl>[F:15][C:16]1[CH:17]=[C:18]([CH:24]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:26]=1)[O:19][CH2:20][CH:21]([NH:34][CH2:31][CH2:32][CH3:33])[CH3:22]
Reactant: CCCN
Reactant: CC(=O)COc1cc(F)cc(S(C)(=O)=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCNC(C)COc1cc(F)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium triacetoxyborohydride (1.16 g, 5.51 mmol) was added to a stirred mixture of 1-(3-fluoro-5-methylsulfonyl-phenoxy)propan-2-one (0.905 g, 3.67 mmol), propylamine (0.24 g, 4.04 mmol), acetic acid (0.5 g, 8.33 mmol) and molecular sieves (2 g, 4 Å, 4-8 mesh) in dry 1,2-dichloroethane (20 ml) the mixture was stirred at ambient temperature for 24 h, the suspension was filtrated and sodium carbonate (100 ml, 10% aqueous solution) was added. The aqueous phase was extracted with dichloromethane (3×50 ml). The combined organic phase was dried with Na2SO4 and evaporated. Purification on flash chromatography (ethyl acetate:methanol 1:0 to 4:1). 0.3 g, 28%. MS m/z (relative intensity, 70 eV) 289 (M+, 1), 260 (9), 152 (4), 87 (6), 86 (bp).
Reaction SMILES: Br[C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[C:21](OCC)(=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[C:11]([O:10][C:9]([NH:8][C:7]1[C:2]([C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:3][CH:4]=[CH:5][CH:6]=1)=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(C)(C)OC(=O)Nc1cccnc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1ncccc1NC(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
A solution of tert-butyl 2-bromopyridin-3-ylcarbamate (3.85 g, 14 mmol) (prepared from the procedure used by Kowol etc, J. Med. Chem., 2009, 52, 5032-5043) in dry THF (20 mL) was cooled to −78° C. and was treated drop-wise with n-butyllithium (11.2 mL of 2.5M solution in hexane, 2.0 eq) such that the temperature never exceeded −65° C., and the resulting mixture was stirred at −78° C. for an additional hour. After drop-wise addition of diethyl oxalate (4 mL, 29 mmol, 2.1 eq), the reaction mixture was allowed to warm to 0° C., maintained there for 1 h, and then quenched by the addition of NH4Cl (40 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (3×20 mL) and brine (20 mL). After drying, filtration, and evaporation, the residue was purified by column chromatography on silica gel with dichloromethane as eluant to afford ethyl 2-(3-(tert-butoxycarbonylamino)pyridin-2-yl)-2-oxoacetate as a white solid. Mass Spectrum (ESI) m/e=295 (M+1).
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+].[C:20]([O:24][C:25](=[O:51])[NH:26][CH2:27][C:28]1[N:29]([CH2:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:30](=[O:45])[C:31]2[C:36]([C:37]=1[O:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:35][C:34]([CH:43]=O)=[CH:33][CH:32]=2)([CH3:23])([CH3:22])[CH3:21].CO>COCCOC.O>[C:20]([O:24][C:25](=[O:51])[NH:26][CH2:27][C:28]1[N:29]([CH2:46][C:47]([CH3:49])([CH3:50])[CH3:48])[C:30](=[O:45])[C:31]2[C:36]([C:37]=1[O:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:35][C:34]([CH2:43][C:10]#[N:11])=[CH:33][CH:32]=2)([CH3:21])([CH3:22])[CH3:23]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(C=O)cc12
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CO
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(CC#N)cc12
Temperature: -70 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
To a solution of p-toluenesulfonylmetyl isocyanide (0.94 g, 4.8 mmol) in 1,2-dimethoxyethane (20 ml) were added potassium t-butoxide (0.90 g, 8 mmol) and tert-butyl(4-butoxy-6-formyl-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (1.78 g, 4 mmol) at −70° C., and the mixture was stirred at −70° C. for 1 h. To the mixture was added methanol (30 ml), and the mixture was refluxed for 30 min. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[4-butoxy-6-(cyanomethyl)-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.66 g, 36.3%) as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]2[C:19]3[C:18]([NH:20][C@H:21]([C:23]4[N:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:27](=[O:35])[C:26]5=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]5[N:24]=4)[CH3:22])=[N:17][CH:16]=[N:15][C:14]=3[N:13](COCC[Si](C)(C)C)[CH:12]=2)[CH:10]=1)[C:6]#[N:7].FC(F)(F)C(O)=O.N>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]2[C:19]3[C:18]([NH:20][C@H:21]([C:23]4[N:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:27](=[O:35])[C:26]5=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]5[N:24]=4)[CH3:22])=[N:17][CH:16]=[N:15][C:14]=3[NH:13][CH:12]=2)[CH:10]=1)[C:6]#[N:7]
Reactant: COc1cc(C#N)cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C#N)cc(-c2c[nH]c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Yield: 53.2 %

Procedure:
(S)-3-Methoxy-5-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (24 mg, 0.04 mmol) was treated with trifluoroacetic acid (480 μl, 6.23 mmol) and a solution of ammonia (7N in methanol, 480 μl, 3.36 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 15% dichloromethane-2-propanol) to obtain 11 mg (56% yield) of the title compound.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)(=O)C>CC(OC)(C)C>[CH2:11]([C@@:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])([OH:4])[CH:2]=[O:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: OCc1ccccc1
Solvent: COC(C)(C)C
Solvent: CC(=O)Cl
Product: O=C[C@](O)(Cc1ccccc1)[C@H](O)[C@H](O)CO
Temperature: 35 °C
Reaction time: 8 h

Procedure:
D-Arabinose (50 kg, 330.04 moles) and benzyl alcohol (132.2 kg, 4.33 equivalents) were stirred and heated to 35° C. Acetyl chloride (10.9 kg, 0.42 equivalents) was added slowly, keeping the temperature <45° C., then stirred 50° C. overnight. The mixture was cooled to 20° C. and diluted with MTBE (600 kg). The mixture was stirred for 0.5-5 h. The solids were collected by filtration and washed with MTBE (2×40 kg). The material was dried in a filter drier. 2-Benzyl-D-arabinose (1) was obtained as an off-white solid, 70.9 kg (88.6%). 1H NMR (300 MHz, DMSO-d6): δ 7.32 (m, 5H), 4.76 (s, 1H), 4.66 (d, J=12 Hz, 1H), 4.59 (m, 3H), 4.45 (d, J=12 Hz, 1H), 3.70 (m, 4H), 3.47 (dd, J=12, 3 Hz, 1H).
Reaction SMILES: [C:1]([O:9][CH:10]([CH2:63][CH3:64])[CH:11]([CH3:62])[CH:12]1[O:61][CH:13]1[CH2:14][CH:15]([CH3:60])/[CH:16]=[CH:17]/[CH:18]=[C:19](\[CH3:59])/[CH:20]1[O:32][C:30](=[O:31])[CH2:29][CH:28]([O:33][Si](CC)(CC)CC)[CH2:27][CH2:26][C:25]([O:42]C(OCC)C)([CH3:41])[CH:24]([O:48][C:49]([N:51]2[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]2)=[O:50])[CH:23]=[CH:22][CH:21]1[CH3:58])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[C:1]([O:9][CH:10]([CH2:63][CH3:64])[CH:11]([CH3:62])[CH:12]1[O:61][CH:13]1[CH2:14][CH:15]([CH3:60])/[CH:16]=[CH:17]/[CH:18]=[C:19](\[CH3:59])/[CH:20]1[O:32][C:30](=[O:31])[CH2:29][CH:28]([OH:33])[CH2:27][CH2:26][C:25]([OH:42])([CH3:41])[CH:24]([O:48][C:49]([N:51]2[CH2:52][CH2:53][N:54]([CH3:57])[CH2:55][CH2:56]2)=[O:50])[CH:23]=[CH:22][CH:21]1[CH3:58])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)OC1(C)CCC(O[Si](CC)(CC)CC)CC(=O)OC(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(=O)c2ccccc2)C(C)C=CC1OC(=O)N1CCN(C)CC1
Agent: CCC(OC(=O)c1ccccc1)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(=O)N2CCN(C)CC2)/C=C/C1C
Agent: CCOC(C)OC1(C)CCC(O[Si](CC)(CC)CC)CC(=O)OC(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(=O)c2ccccc2)C(C)/C=C/C1OC(=O)N1CCN(C)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Product: CCC(OC(=O)c1ccccc1)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(=O)N2CCN(C)CC2)C=CC1C
Reaction time: 5.5 h

Procedure:
(8E,12E,14E)-21-benzoyloxy-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-3-triethylsiloxy-18,19-epoxytricosa-8,12,14-trien-11-olide (19.7 mg, 21.6 μmol) was dissolved in methanol (1 mL). Pyridinium p-toluenesulfonate (12.2 mg, 48.5 μmol) was added to the reaction solution at room temperature, and the reaction solution was stirred at the same temperature for 5.5 hours. The reaction solution was concentrated, and the concentrate was suspended in ethyl acetate (30 mL). This suspension was washed with a saturated aqueous solution of sodium hydrogencarbonate (6 mL) twice, purified water (6 mL) twice, and brine (6 mL). The resulting organic layer was dried over sodium sulfate, and then filtered. The filtrate was concentrated. The concentrate was purified by thin-layer chromatography (Fuji Silysia, NH Silica gel Plate; chloroform:methanol=40:1) to obtain the title compound (14.3 mg, 19.7 μmol, 91.2%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10]C)[CH:5]=[O:6].B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: COc1ccc(C=O)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1ccc(O)c(F)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged with 20 mL of dichloromethane. To the stirred solvent was added 3-fluoro-4-methoxybenzaldehyde (2 g, 12.97 mmol). The reaction mixture was cooled to −78° C. and boron tribromide (51 mL) was added drop wise, stirred for 2 h at the same temperature and stirred at RT about 16 h. The reaction mixture was quenched with NaHCO3 solution at 0° C. by slow addition. The reaction mixture was concentrated to distill off the solvent; ethyl acetate (20 mL) was added. The organic layer was washed with saturated NaHCO3 solution (20 mL), followed by brine solution (20 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as white solid (1.0 g, yield: 54.94%). 1H NMR (300 MHz, CDCl3): δ 9.77 (s, 1H), 7.54-7.59 (m, 1H), 7.08-7.12 (t, 1H), 6.40 (s, 1H).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH:13]=[CH:12][N:11]=1)=O)(C)(C)C.[C:26](O)(C(F)(F)F)=O.C=O>C(Cl)Cl.O>[CH3:26][N:8]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=2)[CH:13]=[CH:12][N:11]=1)[CH3:6]
Reactant: COC(=O)c1ccc(-c2ccnc(CNC(=O)OC(C)(C)C)c2)cc1
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(-c2ccnc(CN(C)C)c2)cc1
Reaction time: 1.5 h

Procedure:
To a solution of Methyl 4-(2-[t-butyloxycarbonylamino-methyl]-pyridin-4-yl)-benzoate (reference example 56) (520 mg, 1.5 mmol) in CH2Cl2 (5 mL) is added TFA (1.5 mL) and 2 drops of water (approx. 100 mL). The resulting solution is stirred for 90 minutes, then concentrated under reduced pressure. The residue is dissolved in THF (4 mL) then NaBH4 added (222 mg, 6 mmol) followed by paraformaldehyde (360 mg, 12 mmol). To this mixture is added TFA (4 mL) dropwise. The resulting mixture is stirred for 6 hours then concentrated. The residue is brought to pH 8 with aqueous NaOH (1M) and sat NaHCO3. The mixture is then extracted with ethyl acetate then ethyl acetate methanol (9/1). The combined organic extracts are washed with brine dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 10% methanol in CH2Cl2) to give 329 mg of the title compound. 1H NMR (CD3OD) δ 3.00 (s, 6H), 3.94 (s, 3H), 4.56 (s, 2H), 7.74 (d, J=5 Hz, 1H), 7.83 (s, 1H), 7.88 (d, J=8 Hz, 2H), 8.17 (d, J=8 Hz, 2H), 8.76 (d, J=5 Hz, 1H). MS (ion spray) m/z 271 (M+H).