Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:4][CH2:3]1.C([Li])(C)(C)C.[C:10]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11]1.O>C(OCC)C.CCCCC>[CH:2]1([C:10]2([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:4][CH2:3]1
Reactant: BrC1CC1
Reactant: O=C1CCCC1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: O
Solvent: CCCCC
Product: OC1(C2CC2)CCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of bromocyclopropane (2.54 ml, 31.7 mmol) in diethyl ether (50 ml) at −78° C. under nitrogen was added, dropwise, tert-butyllithium (18.2 ml of a 1.7 M solution in pentane, 31 mmol). Diethyl ether (30 ml) was then added and the mixture stirred for 1 hour at −78° C. A solution of cyclopentanone (2.74 ml, 34 mmol) in diethyl ether (40 ml) was then added dropwise. The reaction was stirred for 4 hours at −78° C. and was then allowed to warm to room temperature over 16 hours. Water (40 ml) was added, cautiously, and the aqueous layer extracted with diethyl ether (2×40 ml). The combined ether layers were dried using sodium sulphate, filtered and evaporated under reduced pressure to give an oily residue. This was chromatographed using silica gel eluting with a solvent gradient of dichloromethane:methanol (100:0 changing to 9:1, by volume) to provide the title compound (3.5 g). TLC Rf=0.4 (silica, dichloromethane:methanol, 9:1, by volume).
Reaction SMILES: [H-].[Na+].[S:3]([N:13]1[C:17]2=[N:18][CH:19]=[C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:21]=[C:16]2[CH:15]=[CH:14]1)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].Br[CH2:31][C:32]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:33]>CN(C=O)C>[CH:34]1([C:32](=[O:33])[CH2:31][N:22]([C:20]2[N:21]=[C:16]3[CH:15]=[CH:14][N:13]([S:3]([C:6]4[CH:7]=[CH:8][C:9]([CH3:10])=[CH:11][CH:12]=4)(=[O:5])=[O:4])[C:17]3=[N:18][CH:19]=2)[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C(CBr)C1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NC(=O)OC(C)(C)C)cnc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(N(CC(=O)C4CCCCC4)C(=O)OC(C)(C)C)cnc32)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 31.9 %

Procedure:
NaH (60% in mineral oil, 0.020 g, 0.49 mmol) was added to dry DMF (3 mL). The suspension was cooled to about 0° C. and a solution of tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (0.19 g, 0.489 mmol, Example #8, Step A) in dry DMF (2 mL) was added drop-wise. The reaction mixture was allowed to warm to ambient temperature and 2-bromo-1-cyclohexylethanone (0.10 g, 0.49 mmol, 3B PharmaChem) was added. The reaction mixture was stirred for about 2 h and then concentrated under reduced pressure. Purification by silica gel flash chromatography eluting with 100% heptane for 10 min and a gradient of 10-20% EtOAc in heptane over 20 min yielded tert-butyl 2-cyclohexyl-2-oxoethyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate as a yellow amorphous solid (0.080 g, 32%): LC/MS (Table 2, Method a) Rt=3.13 min; MS m/z: 513 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[F:7][C:8]([F:31])([C:13]1[N:14]=[CH:15][C:16]([N:19]2[C:26]3[C@@H:25]4[CH2:27][C@@H:24]4[CH2:23][C:22]=3[C:21]([C:28](O)=[O:29])=[N:20]2)=[N:17][CH:18]=1)[C:9]([F:12])([F:11])[F:10]>>[OH:4][CH2:3][C:2]([NH:1][C:28]([C:21]1[C:22]2[CH2:23][C@H:24]3[CH2:27][C@H:25]3[C:26]=2[N:19]([C:16]2[CH:15]=[N:14][C:13]([C:8]([F:7])([F:31])[C:9]([F:12])([F:10])[F:11])=[CH:18][N:17]=2)[N:20]=1)=[O:29])([CH3:6])[CH3:5]
Reactant: O=C(O)c1nn(-c2cnc(C(F)(F)C(F)(F)F)cn2)c2c1C[C@H]1C[C@@H]21
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NC(=O)c1nn(-c2cnc(C(F)(F)C(F)(F)F)cn2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G, using 2-amino-2-methylpropan-1-ol and (1aR,5aR)-2-(5-(perfluoroethyl)pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid. LCMS m/z=432.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.47 (td, J=4.7, 3.3 Hz, 1H), 1.29 (td, J=8.0, 4.9 Hz, 1H), 1.42 (s, 6H), 2.30-2.37 (m, 1H), 2.75-2.79 (m, 1H), 2.93 (d, J=16.9 Hz, 1H), 3.02 (dd, J=16.7, 6.3 Hz, 1H), 3.71 (d, J=6.1 Hz, 2H), 4.40 (d, J=6.1 Hz, 1H), 6.93 (s, 1H), 8.78 (d, J=1.3 Hz, 1H), 9.35 (d, J=1.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][C:14](OCC)=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][O:10][CH3:11].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][OH:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][O:10][CH3:11]
Reactant: CCOC(=O)CCc1ccc(OCOC)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COCOc1ccc(CCCO)cc1Cl
Yield: 97 %

Procedure:
In substantially the same manner as in Reference Example 82, ethyl 3-(3-chloro-4-methoxymethoxyphenyl)propionate was subjected to reduction with lithium aluminum hydride to obtain 3-(3-chloro-4-methoxymethoxyphenyl)propanol as an oil. The yield was 97%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=O)=[CH:6][CH:5]=[C:4]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([C:30]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:31])[CH2:25]2)[N:3]=1.C[O-].[Na+]>CO.C(O)(CC)C.CO>[N:32]1([C:30]([CH:26]2[CH2:27][CH2:28][CH2:29][N:24]([C:4]3[N:3]=[C:2]4[NH:1][C:9]([C@@H:11]5[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]5)=[N:8][C:7]4=[CH:6][CH:5]=3)[CH2:25]2)=[O:31])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)Nc2ccc(N3CCC[C@@H](C(=O)N4CCCC4)C3)nc2N)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCC(C)O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](c2nc3ccc(N4CCCC(C(=O)N5CCCC5)C4)nc3[nH]2)C1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 3-((2-amino-6-((R)-3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)carbamoyl)piperidine-1-carboxylate in methanol/sec-butanol (1:2, 15 mL) was added a solution of 25% sodium methoxide in methanol (9.0 mL). The reaction mixture was stirred at 90° C. for 16 h. The solvent was removed under reduced pressure and a solution of methanol/dichloromethane (1:9, 50 mL) and a saturated aqueous solution of sodium bicarbonate (50 mL) were added to the residue, and the layers were separated. The aqueous layer was extracted again with methanol/dichloromethane (1:9, 25 mL). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via column chromatography to afford (R)-tert-butyl 3-(5-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)-3H-imidazo[4,5-b]pyridine-2-yl)piperidine-1-carboxylate.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][Si](C)(C)C)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>CO.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[CH:18])=[CH:13][CH:12]=2)[C:3]([OH:23])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(C#C[Si](C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101 %

Procedure:
A solution of 3-cyclopentyl-2-(4-trimethylsilanylethynyl-phenyl)-propionic acid methyl ester (600 mg, 1.83 mmol) in methanol (10 mL) and water (10 mL) was treated with lithium hydroxide (877 mg, 20.9 mmol). The reaction mixture was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was re-dissolved in water (40 mL) which was then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2×40 mL). The combined organic extracts were washed with a half-saturated aqueous sodium chloride solution (1×40 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-(4-ethynyl-phenyl)-propionic acid (448 mg, 100%) as a tan solid: mp 80-83° C.; EI-HRMS m/e calcd for C16H18O2 (M+) 242.1306, found 242.1309.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[C:24]([OH:26])=O)/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][NH2:36])[CH2:31][CH2:30]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C1COCC1.CN(C=O)C>[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][NH:36][C:24]([C:23]2[CH:22]=[C:21]([CH3:27])[NH:20][C:19]=2/[CH:18]=[C:10]2\[C:11](=[O:17])[NH:12][C:13]3[C:9]\2=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:16]=[CH:15][CH:14]=3)=[O:26])[CH2:31][CH2:30]1
Reactant: CN1CCC(CN)CC1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NCC2CCN(C)CC2)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Yield: 55 %

Procedure:
2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (90.5 mg) was coupled with C-(1-methyl-piperidin-4-yl)-methylamine (1.5 eq.), HOBt (1 eq.), EDC (1.5 eq.) and TEA (3 drops) in THF (2 mL), DMF (0.3 mL) at rt for overnight to give 65 mg (55%) of the titled compound as a yellow solid.
Reaction SMILES: ON[C:3]([C@H]1[C@@](O)(C)CCCN1S(C1C=CC(OCC2C=CC(F)=CC=2Cl)=CC=1)(=O)=O)=O.ONC(C1(NS(C2C=CC(OC3C=CC(F)=CC=3)=CC=2)(=O)=O)CCOCC1)=O.[F:60][C:61]1[CH:90]=[CH:89][C:64]([O:65][C:66]2[CH:71]=[CH:70][C:69]([S:72]([N:75]([C:81]3([C:85](=[O:88])[NH:86][OH:87])[CH2:84][CH2:83][CH2:82]3)[CH2:76][CH2:77][C:78]([OH:80])=[O:79])(=[O:74])=[O:73])=[CH:68][CH:67]=2)=[CH:63][CH:62]=1.ONC(C1(NS(C2C=CC(OC3C=CC(Cl)=CC=3)=CC=2)(=O)=O)CCOCC1)=O.ONC([C@@]1(NS(C2C=CC(OC3C=CC(Cl)=CC=3)=CC=2)(=O)=O)CCCOC1)=O.ONC([C@H]1[C@@](O)(C)CCCN1S(C1C=CC(OCC2C=CC(F)=CC=2C)=CC=1)(=O)=O)=O>>[F:60][C:61]1[CH:62]=[CH:63][C:64]([O:65][C:66]2[CH:71]=[CH:70][C:69]([S:72]([N:75]([C:81]3([C:85](=[O:88])[NH:86][OH:87])[CH2:84][CH2:83][CH2:82][CH2:3]3)[CH2:76][CH2:77][C:78]([OH:80])=[O:79])(=[O:74])=[O:73])=[CH:68][CH:67]=2)=[CH:89][CH:90]=1
Reactant: O=C(O)CCN(C1(C(=O)NO)CCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: C[C@@]1(O)CCCN(S(=O)(=O)c2ccc(OCc3ccc(F)cc3Cl)cc2)[C@H]1C(=O)NO
Agent: Cc1cc(F)ccc1COc1ccc(S(=O)(=O)N2CCC[C@@](C)(O)[C@@H]2C(=O)NO)cc1
Agent: O=C(NO)C1(NS(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCOCC1
Agent: O=C(NO)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCOCC1
Product: O=C(O)CCN(C1(C(=O)NO)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1

Procedure:
3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide; (2R,3R)1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide; 4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic acid hydroxyamide; 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)-amino]-propionic acid; 4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic acid hydroxyamide; (R)3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylic acid hydroxyamide; (2R,3R)1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;
Reaction SMILES: [F:1][CH:2]1[CH2:8][CH:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:6][CH2:5][N:4]([C:19](OC(C)(C)C)=O)[CH2:3]1.Cl.[F-].[K+].Cl[C:30]1[N:34](C)[N:33]=[CH:32][C:31]=1[N+:36]([O-:38])=[O:37]>CO.CS(C)=O.O>[F:1][CH:2]1[CH2:8][CH:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH2:6][CH2:5][N:4]([C:19]2[N:33]([CH3:32])[N:34]=[CH:30][C:31]=2[N+:36]([O-:38])=[O:37])[CH2:3]1
Reactant: COc1ccc(COC2CCN(C(=O)OC(C)(C)C)CC(F)C2)cc1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: COc1ccc(COC2CCN(c3c([N+](=O)[O-])cnn3C)CC(F)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 3-fluoro-5-(4-methoxybenzyloxy)azepane-1-carboxylate (740 mg, 0.21 mmol) in MeOH (5 mL) was added HCl (4 M in 1,4-dioxane, 5.3 mL, 21 mmol) and the solution was stirred at room temperature for 16 hr. The solvents were removed under reduced pressure and the residue was dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and eluted with 7 N ammonia in MeOH. The solvents were removed under reduced pressure to afford a yellow oil. To a solution of this oil in dry DMSO (15 mL) was added potassium fluoride (0.32 g, 8.4 mmol) and 5-chloro-1-methyl-4-nitro-1H-pyrazole (372 mg, 2.31 mmol) and the mixture was heated at 65° C. for 16 hr. After cooling to room temperature, the mixture was diluted with water (300 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (3×50 mL) and the solvent was removed under reduced pressure. Purification via silica gel column chromatography (20-100% EtOAc/isohexane) gave 3-fluoro-5-(4-methoxybenzyloxy)-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepane as a yellow oil (300 g, 55% over two steps). 1H NMR (400 MHz, CDCl3) δ 7.33-7.23 (m, 3H), 6.89-6.86 (m, 2H), 4.82-4.66 (m, 2H), 4.49-3.93 (m, 1H), 3.81 (s, 3H), 3.30-2.99 (m, 4H), 2.95-2.74 (m, 4H), 2.35-2.03 (m, 2H), 1.98-1.83 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7]2)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7]2
Reactant: O=C1NCc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)CNC2=O
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a solution of 5-nitroisoindolin-1-one (60 mg, 0.337 mmol) in methanol (20 mL) was added palladium on carbon (10%, 50 mg). The mixture was stirred under an atmosphere of hydrogen for 1 hour. Filtration through Celite, followed by concentration led to 5-aminoisoindolin-1-one as a tan solid (38 mg, yield 76.2%).
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH2:2][CH:3]=[CH2:4].B1C2CCCC1CCC2.C([O-])([O-])=O.[K+].[K+].Br[C:32]1[CH:33]=[CH:34][C:35]([CH2:38][CH2:39][CH2:40][N:41]2[C:49](=[O:50])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]2=[O:51])=[N:36][CH:37]=1>C1COCC1.CN(C=O)C.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].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.[Fe+2]>[O:15]=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13](=[O:14])[N:5]1[CH2:1][CH2:2][CH2:3][CH2:4][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][CH2:39][CH2:40][N:41]2[C:42](=[O:51])[C:43]3[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:49]2=[O:50])=[N:36][CH:37]=1
Reactant: C=CCCN1C(=O)c2ccccc2C1=O
Reactant: O=C1c2ccccc2C(=O)N1CCCc1ccc(Br)cn1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: B1C2CCCC1CCC2
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCCc1ccc(CCCN2C(=O)c3ccccc3C2=O)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.2 %

Procedure:
To a stirred solution of 3-3 (9.1 g, 45.4 mmol) in degassed THF (50 mL) at 0° C. was added dropwise a solution of 9-BBN (110 mL of 0.5M in THF, 55 mmol) and the mixture stirred for 18 hours at ambient temperature. K2CO3 (10.8 g, 77.4 mmol) and 3-2 (5.0 g, 17.4 mmol) were added, followed by a premixed and aged (70° C. for 30 min) suspension of Pd(OAc)2 (1.2 g, 5.2 mmol) and DPPF (3.2 g, 5.6 mmol) in degassed DMF (50 mL). The resulting mixture was stirred for 18 hours at 70° C., cooled, diluted with ethyl acetate, washed with water and brine, dried over MgSO4, and concentrated. The residue was chromatographed on silica gel (40-50% EtOAc/hexane) to give 6.2 g of 3-4 as a white solid.
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7](COC)[C:8]([C:10]2[C:11]3[CH:12]=[N:13][N:14]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:15]=3[CH:16]=[CH:17][CH:18]=2)=[O:9])=[C:4]([Cl:31])[CH:3]=1.[CH3:32][N:33](C=O)C>[Cl-].[NH4+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.[Fe+2].[C-]#N.[C-]#N.[Zn+2].[Zn]>[Cl:31][C:4]1[CH:3]=[C:2]([C:32]#[N:33])[CH:30]=[CH:29][C:5]=1[CH2:6][NH:7][C:8]([C:10]1[C:11]2[CH:12]=[N:13][N:14]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:15]=2[CH:16]=[CH:17][CH:18]=1)=[O:9]
Reactant: COCN(Cc1ccc(Br)cc1Cl)C(=O)c1cccc2c1cnn2-c1ccc(F)cc1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)c(Cl)c1
Temperature: 120 °C

Procedure:
In a sealed tube, 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (4-bromo-2-chloro-benzyl)-methoxymethyl-amide (0.30 g, 0.65 mmol), Pd2(dba)3 (40.0 mg, 0.440 mmol), dppf (44 mg, 0.079 mmol), Zn(CN)2 (77 mg, 0.66 mmol), and Zn (10.5 mg, 0.160 mmol) were dissolved in anhydrous DMF (3 mL). The mixture was warmed at 120° C. for 3 hours. The mixture cooled to room temperature, and diluted with saturated aqueous ammonium chloride (20 mL), extracted with ethyl acetate (20 mL), washed with brine (30 mL), and dried over sodium sulfate. The crude was purified by silica gel chromatography eluting with a gradient of 0-70% ethyl acetate in hexanes to afford the title compound as a white powder.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[CH3:11][NH2:12].[BH4-].[Na+]>CO>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([CH2:1][NH:12][CH3:11])[CH:7]=[CH:6][CH:5]=1
Reactant: CN
Reactant: COc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cccc(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a solution of m-anisaldehyde (205 g, 1.5 mol) in methanol (800 mL) at room temperature was added methylamine (130 mL of 40% in water, 1.5 mol). The resulting solution was cooled to 0° C. and sodium borohydride (83 g, 2.3 mol) was added in batches. The reaction solution was stirred at 0° C. for 2 h, then warmed to room temperature, concentrated in vacuo and diluted with water. The organic phase was separated, diluted with ethyl acetate, washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (158.5 g, 70%) as a clear oil. The combined aqueous extracts were extracted with dichloromethane (3×). The combined methylene chloride extracts were washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give additional benzylamine (66.7 g, 29%) as a clear oil: 1H NMR (300 MHz, CDCl3) 7.24 (t, J=8.4 Hz, 1H), 6.91-6.78 (m, 3H), 3.81 (s, 3H), 3.73 (s, 2H), 2.46 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[C:10]([CH3:19])=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:20])[CH:3]=1.[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[C:10]([CH3:19])=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:20])[CH:3]=1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: COC(=O)c1cccc(-n2c(C)cc(O)cc2=O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1C
Reaction time: 8 h

Procedure:
Methyl-3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-2-methylbenzoate (from Step 1) (42.0 g, 154 mmol) was stirred briskly at room temperature with 2,4-difluorobenzyl bromide (19.7 ml, 154 mmol) and K2CO3 (31.8 g, 231 mmol) in 250 ml of N,N-dimethylformamide. After stirring overnight, the reaction was poured into 1 L of cold water. The solution was extracted 3 times with ethyl acetate and the organic layers were dried over MgSO4, and evaporated. The product was carried on to the next step as a crude oil (60.4 g, 85%). 1H NMR (400 MHz, CDCl3) δ 7.96 (dd, J=7.85, 1.28 Hz, 1H), 7.45-7.34 (m, 2H), 7.27-7.23 (m, 1H), 6.94-6.84 (m, 2H), 5.98 (d, J=2.68 Hz, 1H), 5.92 (dd, J=2.69, 0.81 Hz, 1H), 5.01 (s, 2H), 3.88 (s, 3H), 2.28 (s, 3H), 1.81 (s, 3H); LC/MS, tr=2.96 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50° C.), ES-MS m/z 400 (M+H). ES-HRMS m/z 400.1341 (M+H calcd for C22H19F2NO4 requires 400.1355).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([NH:11][C:12]1[CH:40]=[CH:39][C:15]([CH2:16][C@@H:17]([C:36]([OH:38])=[O:37])[NH:18]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=[CH:14][CH:13]=1)=[O:10].N1CCCCC1>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([NH:11][C:12]1[CH:40]=[CH:39][C:15]([CH2:16][C@@H:17]([C:36]([OH:38])=[O:37])[NH2:18])=[CH:14][CH:13]=1)=[O:10]
Reactant: O=C(N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: CN1CCCC1=O
Product: N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To the 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-phenylalanine on Wang resin prepared above (12.1 mmol, 17.4 g) was added 20% of piperidine in NMP at room temperature. The mixture was shaken for 1.5 h at room temperature and the resin was filtered and washed with DMF (2×20 mL). Then, the resin was suspended in 20% piperidine in NMP (100 mL) and the solvent was decanted. The resin was washed with dichloromethane (2×20 mL) and dried under high vacuum to obtain 13.5 g of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine on Wang resin.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.C1([NH2+]C2CCCCC2)CCCCC1.[C:26]([NH:33][C@H:34]([C:38]([O-:40])=O)[CH2:35][CH2:36][CH3:37])([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].Cl.[CH3:42][NH:43][O:44][CH3:45].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH3:42][N:43]([O:44][CH3:45])[C:38](=[O:40])[C@H:34]([CH2:35][CH2:36][CH3:37])[NH:33][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)[O-]
Reactant: CNOC
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (443 mg) in one portion was added to a mixture of N-Boc-L-norvaline dicyclohexylammonium salt (838 mg), N,O-dimethylhydroxylamine hydrochloride (215 mg), 1-hydroxybenzotriazole monohydrate (340 mg), and N-methylmorpholine (0.28 ml) in dimethyl formamide (DMF, 20 ml) at 0° C. The mixture was stirred at 0° C. for 2 hours, then at room temperature for 40 hours. The reaction was quenched with water (80 mL) and the mixture was extracted with ethyl acetate (EtOAc, 3×100 mL). The combined organic layers were washed with aqueous 10% hydrogen chloride (HCl), saturated sodium bicarbonate (NaHCO3), and brine, then dried over anhydrous magnesium sulfate (MgSO4), filtered, and evaporated to afford the product (546 mg) as an oil.