Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[N:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:9]2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH2:19]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[N:13]=[C:14]([C:16](=[O:18])[NH:32][CH:29]3[CH2:30][CH2:31][N:26]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:27][CH2:28]3)[CH:15]=[C:9]2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2cc(C(=O)O)nn2c1=O
Reactant: NC1CCN(Cc2ccccc2)CC1
Product: CCOC(=O)c1c[nH]c2cc(C(=O)NC3CCN(Cc4ccccc4)CC3)nn2c1=O

Procedure:
The expected compound was obtained according to general procedure F using Key Intermediate V and 1-benzyl-piperidin-4-ylamine. The expected compound was isolated as white powder.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.Br[C:41]1[C:42]([CH2:59][O:60][CH3:61])=[N:43][N:44]([CH:46]2[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]2)[CH:45]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[C:14]([C:41]2[C:42]([CH2:59][O:60][CH3:61])=[N:43][N:44]([CH:46]3[CH2:47][CH2:48][N:49]([C:52]([O:54][C:55]([CH3:57])([CH3:58])[CH3:56])=[O:53])[CH2:50][CH2:51]3)[CH:45]=2)[CH:13]=[N:12][C:11]=1[N:25]([C:26]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:32])[C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34]
Reactant: COCc1nn(C2CCN(C(=O)OC(C)(C)C)CC2)cc1Br
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(B2OC(C)(C)C(C)(C)O2)cc1-c1nc2ccccc2o1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COCc1nn(C2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c2nc3ccccc3o2)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
A mixture of tert-butyl N-[3-(1,3-benzoxazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (808 mg), tert-butyl 4-(4-bromo-3-(methoxymethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (439 mg), trisdibenzylideneacetone dipalladium (53.7 mg), dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane (48.2 mgl) and potassium phosphate (0.233 g) in a mixture of dioxane (14 ml) and water (350 μl) was degassed. The resulting suspension was stirred at 120° C. for 3 hours under argon. After the mixture was cooled to room temperature the solvent was concentrated, ethyl acetate (80 ml) and water (20 ml) were added. The organic layer was washed with brine, dried over magnesium sulphate, filtered and evaporated under reduce pressure. The crude product was purified by flash chromatography on silica gel eluting with 30 to 80% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-[4-[5-(1,3-benzoxazol-2-yl)-6-(bis(tert-butoxycarbonyl)amino)-3-pyridyl]-3-(methoxymethyl)pyrazol-1-yl]piperidine-1-carboxylate (616 mg). The N-tert-butoxycarbonyl groups on the resultant product were removed by conventional treatment with hydrogen chloride in isopropanol to afford 3-(1,3-benzoxazol-2-yl)-5-[3-(methoxymethyl)-1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (300 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:21][C:22]2[CH:26]=[CH:25][O:24][N:23]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[NH2:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]1>CN1C(=O)CCC1>[F:20][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[NH:13][C:11]([C:8]1[N:6]2[N:7]=[C:2]([NH:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]3)[CH:3]=[C:4]([NH:21][C:22]3[CH:26]=[CH:25][O:24][N:23]=3)[C:5]2=[N:10][CH:9]=1)=[O:12]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Nc3ccon3)cc(Cl)nn12
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccncc1F)c1cnc2c(Nc3ccon3)cc(N[C@H]3CC[C@H](O)CC3)nn12
Temperature: 110 °C

Procedure:
A mixture of 6-chloro-N-(3-fluoropyridin-4-yl)-8-(isoxazol-3-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (20 mg, 0.054 mmol) and (trans)-4-aminocyclohexanol (61.6 mg, 0.535 mmol) in NMP (0.4 mL) was heated at 110° C. overnight. The reaction mixture was cooled to room temperature, and purified by reversed-phase preparative HPLC. The desired fractions were concentrated and dried to give 15 mg the title compound as a beige solid. HPLC Rt=2.615 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm), [M+1]=453.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.Br[C:17]1[N:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]([CH2:33][CH2:34][O:35][CH3:36])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:19][CH:18]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:17]3[N:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]([CH2:33][CH2:34][O:35][CH3:36])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[CH:19][CH:18]=3)[S:10][C:3]=12
Reactant: Clc1ccnc2ccsc12
Reactant: COCCN(CCc1ccc(Br)nc1)C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCN(CCc1ccc(-c2cc3nccc(Cl)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
To a stirred solution of 7-chlorothieno[3,2-b]pyridine (4.26 g, 25.09 mmol) in THF (64 mL) at −15° C. was added n-BuLi (10.77 mL, 25.09 mmol). After 30 min, ZincCl2 (3.42 g, 25.09 mmol) was added at −15° C. and the reaction mixture was allowed to warm to RT over 45 min. A solution of palladium tetrakistriphenylphosphine (0.387 g, 0.335 mmol) and bromide 285 (6.01 g, 16.73 mmol) in THF (20 mL) was added and the mixture was heated to reflux for 1 h and concentrated. The reaction was quenched by addition of water and ammonium hydroxide and the mixture was extracted with DCM. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 340 g cartridge; AcOEt/Hex:50/50 to 100/0 over 20 CV), to afford title compound 286 (3.74 g, 8.35 mmol, 50% yield) as yellow oil. MS (m/z): 448.48 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:27])[CH:26]=1)[CH2:5][C@H:6]1[CH2:11][C@@H:10]([C:12](=[O:19])[CH2:13][C:14](OCC)=[O:15])[CH2:9][CH2:8][N:7]1[C:20]([O:22][CH3:23])=[O:21].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:27])[CH:26]=1)[CH2:5][C@H:6]1[CH2:11][C@@H:10]([C:12]2[O:19][NH:30][C:14](=[O:15])[CH:13]=2)[CH2:9][CH2:8][N:7]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2cc(F)cc(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)cc(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 65.6 %

Procedure:
Cis-methyl 2-(3,5-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.662 g, 6.94 mmol) was dissolved in MeOH (24 mL) and cooled to −40° C. under nitrogen atmosphere. Sodium hydroxide (0.278 g, 6.94 mmol) dissolved in water (2.400 mL) was added over 13 min. After 20 min with stirring, hydroxylamine (50% by weight in water, 0.425 mL, 6.94 mmol) was added over 9 minutes and the solution was stirred for 3.5 hours at −40° C. The reaction mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (35.8 mL, 214.55 mmol) and the mixture continued to stir at 80° C. for 25 min. The solvent was evaporated and the crude mixture was redissolved in DCM/water. The organic phase was dried and concentrated. The compound was purified by preparative HPLC in 2 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(3,5-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.604 g, 65.6%) was isolated as a white solid. 1H NMR (400 MHz, cd3od) δ 1.91-2.07 (m, 4H), 2.62-2.80 (m, 2H), 2.97-3.04 (m, 1H), 3.23-3.34 (m, 1H), 3.54 (s, 3H), 3.89-3.99 (m, 1H), 4.26-4.36 (m, 1H), 5.73 (s, 1H), 6.69-6.79 (m, 3H). MS m/z 353 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:27]([CH3:30])=[N:28][N:29]=[C:11]3[C@H:10]([CH2:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[N:9]=2)=[CH:4][CH:3]=1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[CH:20]=[CH:21][C:22]([CH2:25][N:41]5[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]5)=[CH:23][CH:24]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:27]([CH3:30])=[N:28][N:29]=[C:11]3[C@H:10]([CH2:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccc(C=O)cc3)ccc2-n2c(C)nnc21
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccc(CN4CCN(C)CC4)cc3)ccc2-n2c(C)nnc21
Reaction time: 0.08 h

Procedure:
(S)-2-(6-(4-Chlorophenyl)-8-(4-formylphenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (for a preparation see Intermediate 6) (90 mg) was dissolved in DCM (5 ml). 1-Methylpiperazine (30 μl) and acetic acid (10.35 μl) were added and the reaction mixture was stirred for 5 min. Sodium triacetoxyborohydride (192 mg) was added and the reaction mixture was stirred at room temperature, under nitrogen, over the weekend. Saturated sodium hydrogen carbonate solution (5 ml) was added and the reaction mixture was stirred for 10 min. The organic phase was separated and the saturated sodium hydrogen carbonate solution was extracted with DCM (10 ml). The DCM extracts were combined, dried and the solvent was evaporated. The residue was chromatographed (0-15% methanol:DCM), triturated with diethyl ether and dried in a vacuum dessicator at 40° C. overnight to give (S)-2-(6-(4-chlorophenyl)-1-methyl-8-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (66.5 mg) as a white solid. LCMS (formate): MH+ 582, RT 0.65 min
Reaction SMILES: [H-].[Na+].[Cl:3][CH2:4][C:5]1([CH3:11])[O:9][C:8](=[O:10])[NH:7][CH2:6]1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>CN(C)C=O>[Cl:3][CH2:4][C:5]1([CH3:11])[O:9][C:8](=[O:10])[N:7]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH2:6]1
Reactant: COc1ccc(CCl)cc1
Reactant: CC1(CCl)CNC(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CC(C)(CCl)OC2=O)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 78.2 %

Procedure:
To a mixture was sodium hydride (401 mg, 60% dispersion) in 50 ml of dimethylformamide was added 5-(chloromethyl)-5-methyl-1,3-oxazolidin-2-one (1.00 g, INTERMEDIATE 16) followed by 4-methoxybenzylchloride (1.05 g). The mixture was stirred at 90° C. for 4 h. Excess sodium hydride was quenched by addition of 3 ml of methanol. The sample was then transferred to a Biotage 65i column and purified via column chromatography on a Biotage Horizon eluting with 0% ethyl acetate in hexanes (1 column volume), followed by a gradient to 50% ethyl acetate in hexanes (over 6 column volumes), and held at 50% ethyl acetate (2 column volumes) to provide the title compound (1.41 g, 78%). Mass spectrum (ESI) 271.9 (M+2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17]C(=O)C(F)(F)F)=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[N:6][CH:7]=1.N>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ncccc1NC(=O)C(F)(F)F
Agent: N
Solvent: CO
Product: Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Temperature: 50 °C
Yield: 99.8 %

Procedure:
To N-(5-chloropyridin-2-yl)-3-(trifluoroacetyl)amino-pyridine-2-carboxamide (1 g, 2.9 mmol) was added 5 mL of 2 M NH3 in MeOH. The reaction vessel was capped and heated to 50° C. for 12 h. The reaction mixture was cooled to 0° C. for 30 min and filtered to provide N-(5-chloropyridin-2-yl)-3-aminopyridine-2-carboxamide (0.72 g, 100%).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][C:21]([C:25]#[N:26])([CH3:24])[CH2:20][CH2:19]2)=[C:4]([C@H:10]([OH:17])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:18]2[CH2:19][CH2:20][C:21]([C:25]#[N:26])([CH3:24])[CH2:22][CH2:23]2)=[C:4]([C@H:10]([O:17][C:4]([CH3:10])([CH3:5])[CH3:3])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C)c([C@H](O)C(=O)OC(C)C)c(N2CCC(C)(C#N)CC2)c1Br
Solvent: ClCCl
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C)(C#N)CC2)c1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 171.5 %

Procedure:
The isobutylene gas was bubbled into a nitrogen purged, cooled (0° C.) solution of (S)-isopropyl 2-(5-bromo-4-(4-cyano-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (670 mg, 1.58 mmol) and 0.15 mL of 70% HClO4 in DCM (15 mL) for 20 min. The reaction mixture was allowed to warm to rt and stirred for 48 h in a pressure sealed vessel. The reaction was then diluted with DCM, washed with 1M Na2CO3 solution, and dried over MgSO4. The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient elution (0-50% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-4-(4-cyano-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate 651 mg (86%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 6.06 (br. s, 1H), 4.93-4.89 (m, 1H), 4.03 (br. s, 1H), 3.43-3.41 (m, 2H), 3.00 (br. s, 1H), 2.53 (s, 3H), 2.43 (s, 3H), 2.05 (br. s, 1H), 1.93 (br. s, 1H), 1.80-1.71 (m, 1H), 1.58 (br. s, 1H), 1.42 (s, 3H), 1.15-1.13 (m, 12H), 1.05 (d, J=6.2 Hz, 3H). UPLC (M+H)=482.4.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][SH:5].Cl[CH2:8][C@H:9]1[O:13][C@@H:12]([N:14]2[C:23]3[N:22]=[CH:21][N:20]=[C:18]([NH2:19])[C:17]=3[N:16]=[CH:15]2)[C@H:11]([OH:24])[C@@H:10]1[OH:25]>CN(C=O)C>[OH:6][CH2:3][CH2:4][S:5][CH2:8][C@H:9]1[O:13][C@@H:12]([N:14]2[C:23]3[N:22]=[CH:21][N:20]=[C:18]([NH2:19])[C:17]=3[N:16]=[CH:15]2)[C@H:11]([OH:24])[C@@H:10]1[OH:25]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Reactant: OCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CSCCO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
To a mixture of sodium hydride (1.5 g, 50% dispersion in oil, 31 mmol) in DMF (40 mL) was added 2-thioethanol (1.65 mL, 1.84 g, 24 mmol) dropwise, and the mixture was stirred under argon for 15 min at ambient temperature. 5'Chloro-5'-deoxyadenosine (1a) (4.3 g, 15 mmol) was added portion wise and stirring was continued overnight. The mixture was concentrated under reduced pressure and subjected to flash chromatography (MeOH/CHCl3, 3:7) to give the triol (1b) as a white solid (3.23 g, 66%) that was crystallized from EtOH to give colourless crystals of 1b with mp 198°-201° C.; UV (MeOH) max 259 nm (ε 15 900 ); 1H NMR (Me2SO-d6) δ 8.36 (s, 1, H8), 8.16 (s, 1, H2), 7.29 (br s, 2, NH2), 5.89 (d, J1'-2' =5.9 Hz, 1, H1'), 5.49 (d, JOH-2' =6.0 Hz, 1, OH2'), 5.31 (d, JOH-3' =5.0 Hz, 1, OH3'), 4.76 (t, J=5.5 Hz, 1, CH2OH), 4.75 ("q", J2'-3' =5.5 Hz, 1, H2'), 4.18 ("q", J3'-4' =4.8 Hz, 1, H3'), 4.02 (m, J4'-5'n =6.0 Hz, J4'-5'b =6.8 Hz, 1, H4'), 3.52 ("q", J=6.5 Hz, 2, CH2OH), 2.96 (m, J5'a-5'b =14.0 Hz, 1, H5'a), 2.85 (m, 1, H5'b), 2.60 (t, 2, SCH2); 13C NMR (Me2SO-d6) δ 155.97 (C6), 152.57 (C2), 149.36 (C4), 139.76 (C8), 119.06 (C5), 87.28 (C1'), 83.69 (C4'), 72.60, 72.44 (C3',3'), 60.76 (CH2OH), 34.55 (C5'), 34.19 (SCH2): MS m/z 327.0994 (M+ =327.1001). Anal. Calcd for C12H17N5O4S (327.4): C, 44.03; H, 5.23; N, 21.39; S, 9.79. Found: C, 43.91; H, 5.16; N, 21.52; S, 9.77.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=1[OH:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Ni]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[C:13]([OH:21])[CH:14]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1O)OCc1ccccc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(NC(=O)OCc2ccccc2)c(O)c1
Reaction time: 1 h

Procedure:
0.53 mole (153 g) of 2-(benzyloxycarbonylamino) -5-nitrophenol in 1 liter of ethanol is subjected to a hydrogen pressure of 8×105 pascals (8 bars) in an autoclave in the presence of 60 g of Raney nickel (water content 50%). After 1 hour at 65° C., the reaction medium is filtered while hot in order to remove the catalyst. On cooling the filtrate, the expected product crystallizes. After draining and drying, the product obtained is recrystallized in 96° strength ethanol. It melts at 148° C.
Reaction SMILES: C(OC(=O)[N:10]([C@@H:16]([CH2:36][CH2:37][CH:38]([F:62])[CH2:39][NH:40][C:41](=[O:61])[C@H:42]([CH:48]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[NH:43][C:44]([O:46][CH3:47])=[O:45])[CH2:17][O:18][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])C1C=CC=CC=1>CO.[Pd]>[Si:19]([O:18][CH2:17][C@@H:16]([NH:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:36][CH2:37][CH:38]([F:62])[CH2:39][NH:40][C:41](=[O:61])[C@H:42]([CH:48]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[NH:43][C:44]([O:46][CH3:47])=[O:45])([C:32]([CH3:33])([CH3:34])[CH3:35])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)N[C@H](C(=O)NCC(F)CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N(CCC(C)C)C(=O)OCc1ccccc1)C(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)N[C@H](C(=O)NCC(F)CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NCCC(C)C)C(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 92.2 %

Procedure:
A solution of the material from Step 11 (110 mg, 0.126 mmol) in methanol (1 mL) was degassed with nitrogen, then 10% Pd/C (14 mg, 0.013 mmol) was added. The reaction mixture was stirred under hydrogen (1 atm) for 3 hours. The mixture was filtered through celite and washed with dichloromethane. The filtrate was concentrated in vacuo to afford 86 mg of the title compound which was used directly at Step 13. LCMS (M+1)=740
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH3:9])[C:3]=1[F:10].[CH3:11][O:12][C:13]([C:15]1[C:20]([Cl:21])=[C:19]([NH:22][C:23](=[O:25])[CH3:24])[CH:18]=[C:17]([Sn](C)(C)C)[N:16]=1)=[O:14].C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F-].[Cs+]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:11][O:12][C:13]([C:15]1[C:20]([Cl:21])=[C:19]([NH:22][C:23](=[O:25])[CH3:24])[CH:18]=[C:17]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH3:9])[C:3]=2[F:10])[N:16]=1)=[O:14]
Reactant: Cc1c(F)ccc(Br)c1F
Reactant: COC(=O)c1nc([Sn](C)(C)C)cc(NC(C)=O)c1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(F)c(C)c2F)cc(NC(C)=O)c1Cl
Yield: 20 %

Procedure:
A solution of 1-bromo-2,4-difluoro-3-methylbenzene (2.10 g, 0.09 mol), 4-acetylamino-3-chloro-6-trimethylstannylpyridine-2-carboxylic acid methyl ester (4.00 g, 0.01 mol), 1,4-bis(diphenylphosphino)butane (0.140 g, 0.0003 mol) and cesium fluoride (4.5 g, 0.03 mol) in acetonitrile (100 mL) was degassed with nitrogen. Palladium acetate (0.70 g, 0.0003 mol) was added the solution heated to reflux for 2 hours. The reaction mixture was filtered through celite and the filtrate diluted with water (200 mL) and then extracted with ethyl acetate (2×150 mL). The combined organic phases were dried and concentrated and the residual solid was purified by chromatography (50% ethyl acetate in hexanes) to give 4-acetylamino-3-chloro-6-(2,4-difluoro-3-methylphenyl)-pyridine-2-carboxylic acid methyl ester (0.800 g, 0.002 mol): mp 152-153° C.
Reaction SMILES: [CH3:1]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.[CH3:13][C:14]([CH3:24])([CH2:17][O:18][CH:19]1[CH2:23][CH2:22][O:21][CH2:20]1)[CH:15]=O.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:13][C:14]([CH3:24])([C:15]#[CH:1])[CH2:17][O:18][CH:19]1[CH2:23][CH2:22][O:21][CH2:20]1
Reactant: CC(C)(C=O)COC1CCOC1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC(C)(C)COC1CCOC1
Yield: 69.3 %

Procedure:
(1-Diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (418 mg, 2.17 mmol) was added to a stirred suspension of 2,2-dimethyl-3-(tetrahydro-furan-3-yloxy)-propionaldehyde (250 mg, 1.45 mmol) and K2CO3 (601 mg, 4.35 mmol) in methanol (17.0 mL) at room temperature. After overnight stirring the bulk of the methanol was removed by rotary evaporation and the reaction mixture partitioned between ethyl ether and NaHCO3. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated to provide a crude liquid. Purification by flash column chromatography on silica gel using 30% ethyl acetate in hexanes followed by bulb to bulb distillation under reduced pressure provided 3-(2,2-dimethyl-but-3-ynyloxy)-tetrahydro-furan (169 mg, 69%) as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].C1(C)C=CC(S(O[CH2:23][CH2:24][CH2:25][Cl:26])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:26][CH2:25][CH2:24][CH2:23][O:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: Cc1ccc(S(=O)(=O)OCCCCl)cc1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1OCCCCl
Temperature: 80 °C
Yield: 19.1 %

Procedure:
A mixture of 2-methoxy-5-nitrophenol (16.90 g, 100 mmol), 3-chloropropyl p-toluenesulfonate (29.2 g, 120 mmol) and potassium carbonate (27.0 g, 195 mmol) in 160 mL of N,N-dimethylformamide was heated at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, dried over magnesium sulfate and filtered. The solution was concentrated in vacuo and recrystallized from hexane and ethyl acetate to give 4.68 g of 2-(3-chloropropoxy)-1-methoxy-4-nitrobenzene as a first crop of off-white crystals. A second crop of 11.10 g was obtained from the mother liquor. The remaining solution was concentrated in vacuo and purified by flash column chromatography, eluting with 4:1 hexane:ethyl acetate, to provide 1.31 g of 2-(3-chloropropoxy)-1-methoxy-4-nitrobenzene as off-white crystals, mp 85-87° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.23 (m, 2H), 3.79 (t, J=6 Hz, 2H), 3.92 (s, 3H), 4.21 (t, J=6 Hz, 2H), 7.19 (d, J=9 Hz, 1H), 7.77 (d, J=2 Hz, 1H), 7.92 (dd, J=9, 2 Hz, 1H); MS (ES) m/z246.1, 248.1 (M+H)+
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].[O-:14][Mn](=O)(=O)=O.[K+].Cl>CC#N.O>[I:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[C:4]([OH:14])=[O:5]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1cc(I)c(C=O)cc1OC
Agent: Cl
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(I)c(C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a stirred solution of 2-iodo-4,5-dimethoxybenzaldehyde (1.0 g, 3.42 mmol) in CH3CN (25 mL) was added a solution of KMnO4 (0.76 g, 4.79 mmol) in water (15 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. After the reaction was complete, the pH was adjusted to <7 with 1N HCl. The mixture was extracted with DCM and the organic layers combined, washed with brine, dried over sodium sulfate, and evaporated to give 2-Iodo-4,5-dimethoxybenzoic acid (0.89 g, 85%).