Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1I)([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.[C:25](=[O:27])=[O:26].[OH-].[Na+]>C(OCC)C.O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[C:25]([OH:27])=[O:26])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1I
Reactant: O=C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: CC(C)c1cccc(C(C)C)c1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a solution of 5.09 g (17.7 mmol) of 2, 6-diisopropylphenyl iodide in 70 ml of dry ethyl ether was dropwise added 1.6M solution of n-butyllithium in hexane (11.1 ml, 17.8 mmol) at -20° C. The reaction mixture was allowed to warm at 0° C., stirred for 1 hour and poured onto about 100 g of pulverized dry ice. The mixture was allowed to warm gradually to room temperature, mixed with 50 ml of water and the aqueous layer was made alkaline with aqueous sodium hydroxide. The organic layer was separated, and the aqueous layer was washed with ethyl ether, acidified With conc. hydrochloric acid and extracted with ethyl ether. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent evaporated to give 2.53 g of 2, 6-diisopropylbenzoic acid as white solid.
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][CH2:18]1)[CH:10]=[CH:9]2)([CH3:5])[CH2:3][OH:4].C(=O)=O>CO>[NH2:1][C@@:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([O:16][C@H:17]1[CH2:18][CH2:19][C@H:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:21][CH2:22]1)[CH:10]=[CH:9]2)([CH3:5])[CH2:3][OH:4]
Reactant: CC(N)(CO)c1ccc2nc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Agent: O=C=O
Solvent: CO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3n2)CC1

Procedure:
SFC separation of the above 2-amino-2-[2-(4-trans-tert-butyl-cyclohexyloxy)-quinolin-6-yl]-propan-1-ol (Example 78) (100 mg, 0.3 mmol) with Whelk-01 (R,R) (3×15cm) 08-10149 in 15% MeOH(0.1% DEA)/CO2, 100 bar, 85 mL/min, 220 nm gave 62 mg of peak 1 (>99% ee) and 12 mg of peak 2 (>99% ee). Peak 1 was subjected to chromatography purification with CH2Cl2/MeOH(20-50%) give (R)-2-amino-2-(2-(trans-4-tert-butylcyclohexyloxy)quinolin-6-yl)propan-1-ol as a foamy solid (39.4 mg). LCMS 1.42 min 357.30 ([M+1], 100%). 1H NMR (400 MHz, MeOD) δ=8.10 (d, J=8.8 Hz, 1H), 7.86 (s, 1H), 7.78 (s, 2H), 6.87 (d, J=8.8 Hz, 1H), 5.20-5.09 (m, 1H), 3.75 (d, J=11.0 Hz, 1H), 3.70 (d, J=11.0 Hz, 1H), 2.29 (d, J=8.0 Hz, 2H), 1.93 (d, J=14.5 Hz, 2H), 1.55 (s, 3H), 1.52-1.38 (m, 2H), 1.38-1.23 (m, 2H), 1.20-1.07 (m, 1H), 0.94 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].Br[CH:13]([CH3:19])[C:14]([O:16]CC)=[O:15].[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:13]([CH3:19])[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Cl)cc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1 g of 2,4-Dichlorophenol was dissolved in 15 ml of N,N-dimethylformamide, and 0.27 g of 60% sodium hydride was added thereto under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 1.1 ml of Ethyl α-bromopropionate was added to the mixture, and stirring was continued at room temperature for another 1 hour. To the reaction solution was added aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was subjected to silica gel column chromatography, and the fraction eluted with 50:1 n-hexane:ethyl acetate was evaporated and the residue was dissolved in ethanol. To this solution was added 6.5 ml of 5N sodium hydroxide. It was then refluxed for 1 hour. The reaction solution was cooled, and water was added thereto. Then, the mixture was acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated, to give 1.5 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C@@H:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[C:18]4=[N:19][CH:20]=[N:21][C:22]([NH2:23])=[C:17]4[C:16]([C:24]4[CH:25]=[N:26][C:27]([O:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[N:28][CH:29]=4)=[N:15]3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]\[C:40]([OH:42])=[O:41]>C(O)C>[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]\[C:40]([OH:42])=[O:41].[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]\[C:40]([OH:42])=[O:41].[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:18]4=[N:19][CH:20]=[N:21][C:22]([NH2:23])=[C:17]4[C:16]([C:24]4[CH:25]=[N:26][C:27]([O:30][C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[N:28][CH:29]=4)=[N:15]3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4cnc(Oc5ccccc5)nc4)c4c(N)ncnc43)CC2)CC1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Product: CN1CCN(C2CCC(n3nc(-c4cnc(Oc5ccccc5)nc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A solution of cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-(2-phenoxy-5-pyrimidinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (int AW) (0.193 g, 0.00040 mol) in absolute ethanol (15 mL) was heated to reflux. A solution of maleic acid (0.184 g, 0.00159 mol) in absolute ethanol (10 mL) heated to 78° C. was added and the mixture was heated at reflux for 10 minutes. The mixture was allowed to cool to room temperature, and the white precipitate which formed was collected by filtration and washed with absolute ethanol (2×10 mL). The residual solvent was removed in vacuo to give 1-[4-(4-methylpiperazino)cyclohexyl]-3-(2-phenoxy-5-pyrimidinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine bis maleate as a white solid (0.254 g, 0.00035 mol):
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:37]=[CH:36][C:25]([O:26]C2C=C(B(O)O)C=CC=2)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:37]=[CH:36][C:25]([O:26][C:5]2[CH:6]=[C:1]([C:7]3[NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=3[C:14]=45)[CH:2]=[CH:3][CH:4]=2)=[CH:24][CH:23]=1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: OB(O)c1cccc(Oc2ccc(F)cc2)c1
Product: O=C1NCCc2c(-c3cccc(Oc4ccc(F)cc4)c3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (200 mg, 0.75 mmol) and 3-(4-fluoro-phenoxy)-phenylboronic acid (213 mg, 0.83 mmol) were coupled to yield 2-[3-(4-fluoro-phenoxy)-phenyl]-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 170 mg (60%) as a yellow crystalline solid: m.p. 240-241° C.; 1H NMR (300 MHz, d6-DMSO) δ 3.01 (m, 2H), 3.38 (m, 2H), 6.99 (m, 2H), 7.21 (m, 6H), 7.42 (m, 1H), 7.54 (m, 2H), 7.68 (m, 1H), 8.09 (br t, 1H), 11.60 (br s, 1H). MS (FAB, MH+) 373. Anal. (C23H17N2O2F.0.5 H2O) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](OS(C(F)(F)F)(=O)=O)=[N:6][CH:7]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Oc1ccc(Br)cn1)C(F)(F)F
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: Brc1ccc(N2CCCCC2)nc1
Temperature: 40 °C

Procedure:
A mixture of trifluoromethanesulfonic acid 5-bromopyrid-2-yl ester (see step (a) above; 1.5 g, 4.9 mmol), piperidine (1.07 mL, 10.8 mmol) and DMF (5 mL) was heated at 40° C. for 3 h. DMF was then removed in vacuo, water (20 mL) was added to the residue and the product extracted with EtOAc (3×15 mL) and CH2Cl2 (15 mL). The combined organic extracts were washed with brine and dried (Na2SO4). After removal of the solvent, the residue was dissolved in Et2O and HCl (4M in dioxane; 4 mL) was added.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:30]=[CH:29][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:28])[C:15]([CH3:27])([CH2:24][CH2:25][CH3:26])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:31](Cl)([CH3:34])(=[O:33])=[O:32].N1C=CC=CC=1>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:27])([CH2:24][CH2:25][CH3:26])[C:14](=[O:28])[C:13]=1[C:8]1[NH:7][C:6]2[CH:29]=[CH:30][C:3]([NH:2][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 89.4 %

Procedure:
A solution of Example 32B (0.050 g, 0.112 mmol), mesyl chloride (0.035 mL, 0.447 mmol), and pyridine (0.073 mL, 0.893 mmol) in acetone (1.5 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.049 g, 89%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[CH:33]=[CH:32][C:19]([CH2:20][N:21]2[C:25]3=[N:26][C:27]([Br:30])=[CH:28][CH:29]=[C:24]3[N:23]=[C:22]2[CH3:31])=[C:18]([Cl:34])[CH:17]=1)C(OC(C)(C)C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][C:16]1[CH:33]=[CH:32][C:19]([CH2:20][N:21]2[C:25]3=[N:26][C:27]([Br:30])=[CH:28][CH:29]=[C:24]3[N:23]=[C:22]2[CH3:31])=[C:18]([Cl:34])[CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc2ccc(Br)nc2n1Cc1ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc2ccc(Br)nc2n1Cc1ccc(NC(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A crude product (1.90 g) of 3-(4-(N,N-bis-(tert-butoxycarbonyl)amino)-2-chlorobenzyl)-5-bromo-2-methyl-3H-imidazo[4,5-b]pyridine was dissolved in 1,4-dioxane (19 ml) and 1N aqueous sodium hydroxide solution (7.0 ml) was added, which was followed by refluxing under heating for 8 hr. The mixture was allowed to cool, neutralized and stirred at room temperature for 30 min. The precipitate was collected by filtration, and washed with water to give 3-(4-(N-(tert-butoxycarbonyl)amino)-2-chlorobenzyl)-5-bromo-2-methyl-3H-imidazo[4,5-b]pyridine (1.45 g) as a pale-gray powder.
Reaction SMILES: C(OC(N(C)[C@@H](C)C(N[C@@H](C(C)(C)C)C(N1[C@H](C(=O)N[C@H]2C3C(=CC=CC=3)CCC2)CC2C(=CC(C(O)=O)=CC=2)C1)=O)=O)=O)(C)(C)C.[C:48]([O:52][C:53]([N:55]([CH3:113])[C@@H:56]([CH3:112])[C:57]([NH:59][C@@H:60]([C:108]([CH3:111])([CH3:110])[CH3:109])[C:61]([N:63]1[C@H:72]([C:73](=[O:85])[NH:74][C@H:75]2[C:84]3[C:79](=[CH:80][CH:81]=[CH:82][CH:83]=3)[CH2:78][CH2:77][CH2:76]2)[CH2:71][C:70]2[C:65](=[CH:66][C:67]([C:86]([NH:88][C@@H:89]3[CH2:93][N:92]([C:94]([O:96][CH2:97][C:98]4[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=4)=[O:95])[C@H:91]([C:104]([O:106]C)=[O:105])[CH2:90]3)=[O:87])=[CH:68][CH:69]=2)[CH2:64]1)=[O:62])=[O:58])=[O:54])([CH3:51])([CH3:50])[CH3:49]>>[CH2:97]([O:96][C:94]([N:92]1[CH2:93][C@@H:89]([NH:88][C:86]([C:67]2[CH:66]=[C:65]3[C:70]([CH2:71][C@@H:72]([C:73](=[O:85])[NH:74][C@H:75]4[C:84]5[C:79](=[CH:80][CH:81]=[CH:82][CH:83]=5)[CH2:78][CH2:77][CH2:76]4)[N:63]([C:61](=[O:62])[C@@H:60]([NH:59][C:57](=[O:58])[C@@H:56]([N:55]([C:53]([O:52][C:48]([CH3:49])([CH3:51])[CH3:50])=[O:54])[CH3:113])[CH3:112])[C:108]([CH3:109])([CH3:110])[CH3:111])[CH2:64]3)=[CH:69][CH:68]=2)=[O:87])[CH2:90][C@H:91]1[C:104]([OH:106])=[O:105])=[O:95])[C:98]1[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=1
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C)[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)CN1C(=O)OCc1ccccc1
Agent: C[C@@H](C(=O)N[C@H](C(=O)N1Cc2cc(C(=O)O)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Product: C[C@@H](C(=O)N[C@H](C(=O)N1Cc2cc(C(=O)N[C@H]3C[C@@H](C(=O)O)N(C(=O)OCc4ccccc4)C3)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Yield: 99.5 %

Procedure:
Following a procedure analogous to that for the synthesis of Compound K, (2S,4S)-1-benzyl 2-methyl 4-((S)-2-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamido)pyrrolidine-1,2-dicarboxylate (192 mg, 0.21 mmol) was converted to the title compound (187 mg, 99%). MS (ESI+) m/z 895.5 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:28][CH2:27][CH2:26][C@H:25]([OH:29])[CH2:24]1>>[OH:29][C@@H:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:19])[CH2:24]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: O[C@H]1CCCNC1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCC[C@@H](O)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (S)-piperidin-3-ol (1.2 equiv) to give 172 (14.1 mg, M+1 397.1)
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([Cl:14])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)CCC>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C1(C)C=CC=CC=1>[Cl:14][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][CH:8]=2)[N:3]=[C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(Cl)nc2cc(F)ccc2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: N#Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Prepared according to procedure E using 2,4-dichloro-7-fluoroquinoline-3-carbonitrile (230 mg, 0.95 mmol) (described herein), 2-(tributylstannyl)pyridine (0.42 mL, 1.15 mmol), tetrakis(triphenylphosphine)palladium(o) (110 mg, 0.095 mmol), and toluene (4.1 mL). The reaction mixture was stirred at 100° C. for 18 h, and subsequent purification afforded 4-chloro-7-fluoro-2-(pyridin-2-yl)quinoline-3-carbonitrile as an off-white solid. Mass Spectrum (ESI) m/e=284 (M+1).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@@H:16]([CH3:19])[CH2:17][OH:18].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl.C(O)(=O)C>[CH2:20]([NH:15][C@@H:16]([CH3:19])[CH2:17][OH:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@H](N)CO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@@H](CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium triacetoxyborohydride (36.7 g) was added portion wisely to a mixture of (2S)-2-amino-1-propanol (10.0 g) and benzaldehyde (13.53 ml) in a mixture of dichloromethane (140 ml) and acetic acid (8.38 ml) at 0° C. and the whole was stirred at room temperature overnight. The mixture was washed successively with 2N sodium hydroxide and brine, and dried over sodium sulfate. The solution was evaporated under reduced pressure and the resulting residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (30:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give (2S)-2-benzylamino-1-propanol (15.96 g).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:22]([S:23][CH2:24][CH3:25])=[C:21]([C:26]([NH2:28])=[O:27])[CH:20]=[N:19][N:18]3[CH:29]=2)=[CH:11][CH:10]=1)#[N:8]>O.CC(C)=O>[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:22]([S:23]([CH2:24][CH3:25])=[O:1])=[C:21]([C:26]([NH2:28])=[O:27])[CH:20]=[N:19][N:18]3[CH:29]=2)=[CH:11][CH:10]=1)#[N:8]
Reactant: CCSc1c(C(N)=O)cnn2cc(-c3ccc(C#N)cc3)cc12
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCS(=O)c1c(C(N)=O)cnn2cc(-c3ccc(C#N)cc3)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of oxone (3.30 g, 5.37 mmol) in water (Volume: 40 mL) was added dropwise to a yellow suspension of impure 6-(4-cyanophenyl)-4-(ethylthio)pyrrolo[1,2-b]pyridazine-3-carboxamide (0.787 g, 2.441 mmol) in acetone (Ratio: 1.000, Volume: 40 mL) at rt. The resulting suspension was stirred at rt for 3 h. LCMS and HPLC showed that the starting material was consumed and the desired product was formed. The suspension was filtered, washed with water (2×10 mL), and dried under high vacuum to give a green-yellow solid. 1H NMR and HPLC indicated that the desired product was the major component, but the material was impure. The amount of the material is more than theoretical weight and the material is not totally soluble when making NMR solution, indicating the possible presence of inorganic salt. The material was treated with water (10 mL), stirred for 15 min, filtered, washed with H2O (2×5 mL), and dried under high vacuum to give a green-yellow solid (591.3 mg; 44% yield over 2 steps). 1H NMR, LCMS and HPLC indicated that the material was not pure, but the major component is consistent with the desired product. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.83 (1 H, d, J=1.54 Hz), 8.54 (1 H, s), 8.28 (1 H, br. s.), 8.07 (1 H, d, J=1.54 Hz), 8.03 (2 H, d, J=8.36 Hz), 7.89 (2 H, d, J=8.36 Hz), 7.80 (1 H, br. s.), 3.31-3.46 (2 H, m), 1.35 (3 H, t, J=7.48 Hz).
Reaction SMILES: [F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:24]([O:30]C)=[N:25][CH:26]=[C:27]([CH3:29])[CH:28]=5)[C:20]([CH3:32])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[Si](I)(C)(C)C>CC#N.C(Cl)Cl.CCOC(C)=O>[F:33][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:24]([OH:30])=[N:25][CH:26]=[C:27]([CH3:29])[CH:28]=5)[C:20]([CH3:32])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1ncc(C)cc1-c1nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)ccc1C
Agent: C[Si](C)(C)I
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cnc(O)c(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 673.6 %

Procedure:
To a mixture of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (0.181 g, 0.05 mmol) in CH3CN (0.5 mL) was added TMSI (114, 0.80 mmol) drop wise at 0° C. The reaction was stirred at 50° C. for 3 hours. The reaction was partitioned between ethyl acetate and H2O and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (0-10% MeOH-EtOAc) to yield a yellow solid. The solid was re-dissolved in DCM-EtOAc, washed with NaHSO3 (2×), brine, dried over MgSO4 and evaporated to dryness to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-hydroxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide as a white solid (0.148 g, 84%). ESI-MS m/z calc. 439.41. found 440.2 (M+1)+. Retention time 1.51 minutes.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:13])[NH:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-])=O.CO.[OH-].[NH4+].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>O>[NH2:1][C:4]1[C:5](=[O:13])[NH:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1
Reactant: O=c1[nH]cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1cc([N+](=O)[O-])c[nH]c1=O

Procedure:
A solution of 5.5 g. of 3,5-dinitro-2-pyridone in 200 ml. of methanol was adjusted to pH 8 with ammonium hydroxide. At 60-65° C., there was added slowly a solution of 10.8 g. of sodium sulfide nonahydrate in 30 ml. of water. After 1 hour at 60-65° C. the solvent was evaporated and the residue was extracted with hot benzene and acetic acid to neutralize any sodium salt. The benzene was decanted and cooled to give a precipitate. Recrystallization from methanol gave 3-amino-5-nitro-2-pyridone, m.p. 200°-201° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH:8]([Mg]Br)=[CH2:9]>C(OCC)C>[CH:8]([C:4]1([OH:7])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[CH2:9]
Reactant: C=C[Mg]Br
Reactant: O=C1CCOCC1
Solvent: CCOCC
Product: C=CC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dihydro-2H-pyran-4(3H)-one (8.01 g) in anhydrous ethyl ether (50 mL) was treated with 1.0 M vinylmagnesium bromide (104 mL) over 20 minutes at 0° C. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl, and the organic layer was separated. The aqueous layer was extracted with additional ethyl ether three times. The combined organic layers were washed with brine, dried, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel using 20% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2B(O)O)(=[O:9])=[O:8])[CH2:3][CH2:2]1.Br[C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:4]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:20]2[CH:26]=[CH:25][CH:24]=[C:22]([NH2:23])[CH:21]=2)(=[O:9])=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: O=S(=O)(c1ccccc1B(O)O)N1CCOCC1
Reactant: Nc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cccc(-c2ccccc2S(=O)(=O)N2CCOCC2)c1
Temperature: 25 °C
Yield: 77 %

Procedure:
2-(morpholinosulfonyl)phenylboronic acid (0.188 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (5-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.113 g in 77% yield.