Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@H:6]2[C:38](=[O:39])[N:37]3[CH2:40][C@@H:34]([CH2:35][C@H:36]3[C:41](=[O:57])[NH:42][C@:43]3([C:48](=[O:56])[NH:49][S:50]([CH:53]4[CH2:55][CH2:54]4)(=[O:52])=[O:51])[CH2:45][C@H:44]3[CH:46]=[CH2:47])[O:33][C:18]3=[N:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:26]([O:27][CH2:28][C:29]([O:31]C)=[O:30])=[C:17]3[CH2:16][CH:15]=[CH:14][CH2:13][CH2:12][C@@H:11]3[CH2:58][CH2:59][CH2:60][C@H:10]3[O:9][C:8](=[O:61])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[Li+].[OH-]>C1COCC1.CO>[CH:1]1([C@H:6]2[C:38](=[O:39])[N:37]3[CH2:40][C@@H:34]([CH2:35][C@H:36]3[C:41](=[O:57])[NH:42][C@:43]3([C:48](=[O:56])[NH:49][S:50]([CH:53]4[CH2:54][CH2:55]4)(=[O:51])=[O:52])[CH2:45][C@H:44]3[CH:46]=[CH2:47])[O:33][C:18]3=[N:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:17]3[CH2:16][CH:15]=[CH:14][CH2:13][CH2:12][C@@H:11]3[CH2:58][CH2:59][CH2:60][C@H:10]3[O:9][C:8](=[O:61])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCc1c(nc3ccccc3c1OCC(=O)OC)O2)C(=O)NS(=O)(=O)C1CC1
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1OCC(=O)O)O2)C(=O)NS(=O)(=O)C1CC1
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1OCC(=O)OC)O2)C(=O)NS(=O)(=O)C1CC1
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCc1c(nc3ccccc3c1OCC(=O)O)O2)C(=O)NS(=O)(=O)C1CC1

Procedure:
The product of Step 1 (43 mg) was dissolved in THF (1 ml) and methanol (0.2 ml). Water (0.5 ml) and LiOH (11.95 mg) were added and the reaction was stirred until complete conversion. The reaction was quenched with 1N HCl (0.4 mL) and 5% KHSO4 was added until the pH was 3. The mixture was extracted with ether then ethyl acetate. The combined organics were washed with water (5×) then brine, dried over magnesium sulfate, filtered and concentrated to yield 42 mg of pure product. HRMS (ES+) m/z 848.3522 (M+H)+.
Reaction SMILES: [O:1](S(C(F)(F)F)(=O)=O)[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[CH2:16]([N:23]([CH3:35])[C@H:24]1[CH2:33][CH2:32][C:31]2[C:30](O)=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:25]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(CC)CC.[O-]S(C(F)(F)F)(=O)=O>C(Cl)Cl.CO.C(Cl)Cl>[F:6][C:5]([F:8])([F:7])[S:2]([O:1][C:30]1[C:31]2[CH2:32][CH2:33][C@H:24]([N:23]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:35])[CH2:25][C:26]=2[CH:27]=[CH:28][CH:29]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CN(Cc1ccccc1)[C@H]1CCc2c(O)cccc2C1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CN(Cc1ccccc1)[C@H]1CCc2c(cccc2OS(=O)(=O)C(F)(F)F)C1
Reaction time: 0.25 h
Yield: 24 %

Procedure:
Tf2O (3.6 mL, 21.309 mmol) was dropwise added to a −78° C. cooled solution of (6S)-6-[benzyl(methyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol (5.30 g, 19.822 mmol) and Et3N (6 mL, 43.04 mmol) in CH2Cl2 (100 mL). Addition time: ca. 5 min. The reaction was completed after 15 min at low temperature (TLC analysis). The reaction mixture was poured into CH2Cl2 (250 mL) and washed with H2O (200 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was flash chromatographed on silica gel (1-2-3% MeOH/CH2Cl2), to furnish two batches of product: 5.78 g of pure triflate, and 1.90 g of product slightly impure (TLC analysis) (Rf=0.8 (10% MeOH/CH2Cl2), off-white solid, 73% and 24% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:11][CH3:12])=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9].Cl>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[CH:10]=[C:7]([CH2:8][NH2:9])[CH:6]=[N:5][C:4]=1[O:11][CH3:12]
Reactant: COc1cc(C#N)cnc1OC
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COc1cc(CN)cnc1OC
Reaction time: 2 h

Procedure:
To a solution of 5,6-dimethoxynicotinonitrile (4-3, 0.600 g, 3.65 mmol, 1.0 equiv) in methanol (20 mL) under a nitrogen atmosphere was added Pearlman's catalyst (0.205 g, 0.292 mmol, 0.08 equiv, 20 weight percent) and concentrated HCl (2.44 mL), and the reaction was place under an atmosphere of hydrogen. After 2 h, the reaction was placed under an atmosphere of nitrogen and filtered through celite to remove the catalyst. The reaction mixture was dissolved in EtOAc, dried over MgSO4 and concentrated to an oily solid (4-4) of high purity. ESI+MS[M+H]+C8H12N2O2 calc'd 169.1. found 169.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[N:22](S(C2C=CC(C)=CC=2)(=O)=O)[C:15]2[N:16]=[CH:17][CH:18]=[C:19]([C:20]#[N:21])[C:14]=2[CH:13]=1.[OH-:33].[Na+].OO>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[NH:22][C:15]2[N:16]=[CH:17][CH:18]=[C:19]([C:20]([NH2:21])=[O:33])[C:14]=2[CH:13]=1
Reactant: [OH-]
Reactant: COc1ccc2[nH]cc(-c3cc4c(C#N)ccnc4n3S(=O)(=O)c3ccc(C)cc3)c2c1
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COc1ccc2[nH]cc(-c3cc4c(C(N)=O)ccnc4[nH]3)c2c1
Reaction time: 3 h

Procedure:
A suspension of 2-(5-methoxy-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-4 carbonitrile [0.25 g, Reference Example 67(e)] in methanol (25 mL) was treated with sodium hydroxide solution (1.5 g in 4 mL water). The mixture was cooled in an ice-bath and then treated dropwise with hydrogen peroxide (0.35 mL, 30%). After stirring at room temperature for 1 hour a further aliquot of hydrogen peroxide (0.3 mL) was added to the reaction mixture and stirring was continued for a further 3 hours then the reaction was quenched by addition of sodium metabisulfite to remove excess hydrogen peroxide. The reaction mixture was then diluted with water (75 mL) and extracted twice with ethyl acetate (50 mL). The combined extracts were washed twice with brine (30 mL), then dried over sodium sulfate and then evaporated. The residual yellow solid was subjected to chromatography on silica eluting with a mixture of ethyl acetate and dichloromethane (1:1, v/v) to give, after trituration with methanol and washing with diethyl ether, the title compound (50 mg) as a yellow solid, m.p.>320° C. MS: 307 (MH+).
Reaction SMILES: [CH3:1][C:2]1(Br)[CH2:4][CH2:3]1.[CH2:6]([NH:13][C:14](=[O:36])[N:15]([C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][C:24]=2[OH:35])[CH:20]=[CH:21][CH:22]=1)[CH3:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH:4]1([CH2:3][O:35][C:24]2[CH:25]=[C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][C:23]=2[C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([N:15]([CH3:16])[C:14]([NH:13][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:36])[CH:18]=2)[CH2:2][CH2:1]1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Reactant: CC1(Br)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCC2CC2)c1

Procedure:
In a manner similar to that of Example (25a), by reaction of 170 μL (1.75 mmol, 1.5 eq) of methylcyclopropyl bromide and 500 mg (1.17 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f) in 10 ml of methyl ethyl ketone in the presence of 500 mg (3.61 mmol, 3 eq) of potassium carbonate, methyl 3-[2-cyclopropylmethoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate is obtained in oil form and is used in the following reaction without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[C:14]1([Li])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2([CH:12]([NH2:13])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1
Reactant: [Li]c1ccccc1
Reactant: CN1CCN(C2(C#N)CCC2)CC1
Product: CN1CCN(C2(C(N)c3ccccc3)CCC2)CC1

Procedure:
The title compound, yellow liquid, MS: m/e=260.2 [(M+H)+], was prepared in accordance with the general method of intermediate B from 1-(4-methyl-piperazin-1-yl)-cyclobutanecarbonitrile (intermediate V) and phenyllithium.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:3]=1[N:4]([CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH3:16])[CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH3:10]>CO.[Pd]>[F:1][C:2]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:3]=1[N:4]([CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH3:16])[CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCOCCN(CCOCCC)c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CO
Product: CCCOCCN(CCOCCC)c1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
To a solution of 2-fluoro-4-nitro-N,N-bis(2-propoxyethyl)aniline (1.47 g, 4.48 mmol) in MeOH (50 mL) was added catalyst Pd/C (0.15 g). The reaction was stirred at rt under H2 overnight, then filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as blackish oil (0.50 g, 34%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccccc2n1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.9 %

Procedure:
A solution of ethyl-2-indolecarboxylate (500 mg, 2.64 mmol) in dry THF (5 mL) under an argon atmosphere was cooled to 0° C. and treated with sodium hydride (116 mg, 2.90 mmol). After stirring at room temperature for 5 minutes, the reaction was cooled to 0° C. and treated with methanesulfonyl chloride (0.23 mL, 2.90 mmol). The resulting mixture was gradually warmed to room temperature and stirred for 20 h. The reaction was quenched with saturated NaHCO3 and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The resulting golden yellow oil was chromatographed over silica gel eluting with 5%, 10%, and 15% ethyl acetate/hexane to provide the title compound (79%, 556.6 mg) as a cream solid. 1H NMR (400 MHz, CDCl3) δ8.05 (d, 1H), 7.65 (d, 1H), 744 (t, 1H), 7.31 (m, 2H), 4.42 (q, 2H), 3.71 (s, 3H), 1.42 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](Cl)=[N:8][CH:9]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].C(OC(=O)[CH2:23][C:24]#[N:25])(C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:23][C:24]#[N:25])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)CC#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CCc1ccc([N+](=O)[O-])cn1
Reaction time: 20 h
Yield: 55.6 %

Procedure:
To a solution of 5-nitro-2-chloropyridine (18 g, 113.5 mmol) in THF (100 ml) at room temperature K2CO3 (39.2 g, 283.8 mmol), cyanoacetic acid tert-butyl ester (24 g, 170.30 mmol) and 4 Å molecular sieves were added. The mixture was heated to reflux and stirred for 20 h. After concentrating the mixture under reduced pressure the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over MgSO4, filtered and the solvent evaporated under reduced pressure. The obtained oil was dissolved in toluene (300 ml), toluene-4-sulfonic acid (2 g, 11.6 mmol) was added, and the mixture was heated to reflux for 2 h. The mixture then was stirred at room temperature for 16 h. After which the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over MgSO4, filtered, and the solvent evaporated under reduced pressure. Column chromatography (cyclohexane/dichloromethane, 4/1) gave the product as a colorless oil (10.3 g, 66%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:37]=[CH:36][C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:24][CH2:25][C:26]4[CH:35]=[CH:34][C:29]5[C:30]([OH:33])=[N:31][O:32][C:28]=5[CH:27]=4)=[C:17]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:18]=3)=[O:12])=[C:9]([OH:38])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:46](Cl)([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.Cl>C(Cl)Cl.O>[CH:1]1([O:6][C:7]2[CH:37]=[CH:36][C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:24][CH2:25][C:26]4[CH:35]=[CH:34][C:29]5[C:30](=[O:33])[N:31]([C:46]([C:47]6[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=6)([C:59]6[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=6)[C:53]6[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=6)[O:32][C:28]=5[CH:27]=4)=[C:17]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:18]=3)=[O:12])=[C:9]([OH:38])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CCc1cc(C(=O)c2ccc(OC3CCCC3)cc2O)ccc1OCc1ccc2c(O)noc2c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)CCc1cc(C(=O)c2ccc(OC3CCCC3)cc2O)ccc1OCc1ccc2c(=O)n(C(c3ccccc3)(c3ccccc3)c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
5.80 g of 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl} propanoic acid was suspended in 58 mL of methylene chloride, to which 6.2 mL of triethylamine was added at room temperature followed by addition of 3.44 g of trityl chloride in an ice bath, and this mixture was stirred for 30 minutes at room temperature. The reaction mixture to which water was added was adjusted to pH 3 with 6M hydrochloric acid, and the organic phase was separated therefrom. After the resultant organic phase was washed with water, the solvent was distilled out under reduced pressure. The resultant residue was washed with hexane and then purified by silica gel column chromatography [eluent; chloroform:ethanol=50:1] to yield 6.83 g of 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-oxo-2-trityl-2,3-dihydro-1,2-benzisoxazol-6-yl)methoxy]phenyl} propanoic acid as yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[N:12]1[CH:29]=[C:15]2[C:16]([NH:21][C:22]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=3)=[N:17][CH:18]=[C:19]([F:20])[C:14]2=[N:13]1.Br[C:31]1C2=CN(C3C(Cl)=CC([N+]([O-])=O)=CC=3C#N)N=C2C(F)=C[N:32]=1>>[Cl:11][C:4]1[C:3]([N:12]2[CH:29]=[C:15]3[C:16]([NH:21][C:22]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=4)=[N:17][CH:18]=[C:19]([F:20])[C:14]3=[N:13]2)=[C:2]([CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=1)[C:31]#[N:32]
Reactant: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc([N+](=O)[O-])cc4Cl)cc23)ncn1
Reactant: N#Cc1cc([N+](=O)[O-])cc(Cl)c1-n1cc2c(Br)ncc(F)c2n1
Product: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc([N+](=O)[O-])cc4C#N)cc23)ncn1
Temperature: 80 °C
Yield: 20 %

Procedure:
Following the procedure described for [2-(2,6-dichloro-4-nitrophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine, 2-(4-bromo-7-fluoropyrazolo[4,3-c]pyridin-2-yl)-3-chloro-5-nitrobenzonitrile was heated at 80° C. overnight to afford the title compound as a pale yellow solid (43 mg, 20% yield). LCMS (Method C): RT=2.56 min, m/z: 425 [M+H+].
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[Br:7][C:8]1[CH:9]=C(C)[CH:11]=[CH:12][C:13]=1[Br:14].[C:16]([OH:19])(=[O:18])[CH3:17]>>[Br:7][C:8]1[CH:9]=[C:17]([CH:11]=[CH:12][C:13]=1[Br:14])[C:16]([OH:19])=[O:18]
Reactant: Cc1ccc(Br)c(Br)c1
Reactant: CC(=O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: O=C(O)c1ccc(Br)c(Br)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
A saturated aqueous solution of potassium permanganate (61.3 g, 388 mmol) was added in portions to a well stirred solution of 3,4-dibromotoluene (40.4 g, 162 mmol) in acetic acid (700 mL) while maintaining the temperature between 70 and 80° C. After addition, the suspension was stirred for an additional 4 hours at 80° C. The solution was concentrated on a rotary evaporator, the residue treated with 5 N NaOH (700 mL) and heated under reflux for 2 hours. The MnO2 cake was filtered from solution and washed thoroughly with hot water. The filtrate was extracted with hexane (2×100 mL) and acidified with concentrated HCl pH 2. Collected white precipitate by filtration. Washed precipitate with water and dried under high vacuum. Obtained 16.59 gram (37% yield) of 3,4-dibromobenzoic acid. 1H NMR (300 MHz, DMSO-d6): δ13.47 (singlet, 1H), 8.14 (singlet, 1H), 7.88 (doublet, J=8.1 Hz, 1H), 7.99 (doublet, J=8.1 Hz, 1H). 13C NMR (300 MHz, DMSO-d6): δ165.72, 134.42, 134.18, 132.07, 129.96, 129.32, 124.40.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[C:16]([O:17][CH3:18])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:19])[CH:13]=2)[N:8]=1.CN([CH:23]=[O:24])C.Cl>C1COCC1.CC(=O)OCC.CC(O)=O>[Cl:6][C:7]1[C:16]([O:17][CH3:18])=[N:15][C:14]2[C:13]([CH:23]=[O:24])=[C:12]([F:19])[CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: COc1nc2cc(F)ccc2nc1Cl
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1nc2c(C=O)c(F)ccc2nc1Cl
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To a solution of DIPA (22.3 mL) in THF (150 mL) was added at −20° C., n-BuLi (2.3M, 63.7 mL, 159 mmol). The mixture was stirred at −20° C. for 10 min. After cooling to −78° C., a solution of 2-chloro-6-fluoro-3-methoxy-quinoxaline (27.1 g, 127.4 mmol) in THF (100 mL+10 mL rinse) was added over 40 min. The reddish mixture was stirred at −78° C. for 40 min. DMF (15 mL) was added keeping the internal temperature below −70° C. The reaction proceeded 20 min. AcOH (15 mL) was added. Once the mixture had warmed up to rt, 3M HCl (180 mL) and EA (500 mL) were added. The mixture was further diluted with EA (400 mL) until two clear layers were obtained. The two layers were separated and the aq. layer was extracted with EA (3×300 mL). The org. layer was washed twice with sat. aq. NaHCO3 (200 mL) and brine (200 mL), dried over MgSO4, filtered and concentrated to dryness. The crude product was triturated with an ether-EA mixture (1-1, 250 mL), washed with ether (2×100 mL), and dried under high vacuum to afford the title aldehyde as a beige solid (23 g, 76% yield).
Reaction SMILES: [OH-].[Na+].[C:3]1([S:9](Cl)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[NH:38][C:37]3[CH:36]=[CH:35][N:34]=[C:33]([Cl:39])[C:32]=3[CH:31]=2)[C:25](=[O:40])[CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O.C(Cl)Cl>[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[N:38]([S:9]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)(=[O:11])=[O:10])[C:37]3[CH:36]=[CH:35][N:34]=[C:33]([Cl:39])[C:32]=3[CH:31]=2)[C:25](=[O:40])[CH2:24]1)=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1cc2c(Cl)nccc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1cc2c(Cl)nccc2n1S(=O)(=O)c1ccccc1
Reaction time: 3.5 h
Yield: 98.1 %

Procedure:
Powdered NaOH (0.96 g, 23.9 mmol) followed by nBu4NHSO4 (0.32 g, 0.96 mmol) and benzene sulfonyl chloride (1.8 mL, 14.1 mmol) is added to a solution of 4-(4-chloro-1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-3-oxo-piperazine-1-carboxylic acid benzyl ester (3.81 g, 9.56 mmol) in CH2Cl2(32 mL) at RT. The resulting slurry is stirred for 3.5 h then diluted with CH2Cl2 and washed with saturated NaHCO3 and brine. The organic layer is dried over MgSO4, filtered and concentrated to dryness. The crude product is chromatographed eluting with 1-5% MeOH/CH2Cl2 to yield the title product (5.06 g, 9.38 mmol). 1H NMR (CDCl3, 300 MHz) δ8.23 (d, 1H), 7.97 (d, 1H), 7.84 (d, 2H), 7.61 (d, 1H), 7.51 (m, 2H), 7.38 (s, 5H), 6.50 (s, 1H), 5.18 (s, 2H), 5.03 (s, 2H), 4.29 (s, 2H), 4.29 (s, 2H), 3.80 (m, 2H), 3.51 (m, 2H). Ion spray [M+H]+=539, 541, Cl pattern.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[CH2:11][O:12][CH3:13].[OH:14][CH:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)Cl>[CH3:13][O:12][CH2:11][O:14][CH:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: COCCl
Reactant: CCOC(=O)C(C)(C)C(O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)C(OCOC)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Diisopropylethylamine (15.9 ml) and chloro(methoxy)methane (5.48 ml) were added dropwise to a methylene chloride (270 ml) solution of ethyl 3-hydroxy-2,2-dimethyl-3-phenylpropanoate (13.5 g) under ice cooling, followed by stirring at room temperature for 3 days. After the reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate and water and the organic layer washed with an aqueous hydrochloric acid solution (1M), a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The organic layer was subjected to evaporation under reduced pressure and then the residue was purified by silica gel column chromatography to obtain ethyl 3-(methoxymethoxy)-2,2-dimethyl-3-phenylpropanoate (13.1 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:12]([OH:14])=O.Cl.Cl.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][CH2:33][CH2:34][NH2:35])=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:12]([NH:35][CH2:34][CH2:33][NH:32][C:29]1[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=1)=[O:14]
Reactant: O=C(O)[C@H](CC1CCCCC1)Nc1nc2ccccc2o1
Reactant: COc1ccc(NCCN)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NCCNC(=O)[C@H](CC2CCCCC2)Nc2nc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.7 %

Procedure:
To a stirring solution of 2-(S)-(benzooxazol-2-ylamino)-3-cyclohexyl propionic acid (288 mg, 1.0 mmol), N1-(4-methoxy-phenyl)-ethane-1,2-diamine-2HCl (239 mg, 1.0 mmol), and iPr2NEt (0.87 mL, 5.0 mmol) in dichloromethane (4 mL) was added HATU (418 mg, 1.1 mmol). The solution was stirred at room temperature for 4 hours and then evaporated to dryness. The crude material was chromatographed over silica gel (Hexanes/EtOAc) to afford the title compound as a white powder (243 mg, 56%). HPLC-MS calcd. for C25H32N4O3 (M+H+) 437.25, found 437.5.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]=12.Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13].[Li+].[BH4-]>C1COCC1>[N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[CH2:7][N:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[CH:10][C:2]=12
Reactant: c1cc2nccnc2cn1
Reactant: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)N1C=Cc2nccnc2C1
Temperature: -25 °C
Reaction time: 1 h

Procedure:
A solution of pyrido[3,4-b]pyrazine (20.0 g, 153 mmol) in anhydrous THF (250 mL) is cooled to −25° C. A solution of ethyl chloroformate (17.5 ml, 183 mmol) in THF (46 mL) is added dropwise. The mixture is stirred 1 hr at −25° C., and then LiBH4 (2.0 M, 23 mL, 46 mmol) is added dropwise and the mixture is stirred for 1 hr. The reaction is quenched with the addition of 1N NaOH (100 mL) and extracted with Et2O (3×100 mL). The organic extractions are combined, dried and evaporated. The crude product is purified by silica gel column chromatography eluting with hexane/EtOAc (3:2) to yield the title compound. MS (+VE) m/z 206.14 (M++1).