Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:21])[NH:5][N:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].O.[Na+].Br[CH2:31][CH2:32][S:33]([O-:36])(=[O:35])=[O:34]>CN(C=O)C>[OH2:21].[C:1]([C:3]1[C:4](=[O:21])[N:5]([CH2:31][CH2:32][S:33]([OH:36])(=[O:35])=[O:34])[N:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2]
Reactant: O=S(=O)([O-])CCBr
Reactant: N#Cc1c(-c2ccccc2)c(-c2ccccc2)n[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(-c2ccccc2)c(-c2ccccc2)nn(CCS(=O)(=O)O)c1=O
Temperature: 110 °C
Yield: 50.1 %

Procedure:
7.5 grams (0.027 mole) of the product of Example 1 was caused to react with 3.79 grams of K2CO3 in the least amount of water along with 200 mls of DMF. To this mixture was added 5 drops of 18 crown-6-ether. Into this solution was added 5.79 grams (0.027 mole) of 2-bromoethane sulfonic acid sodium salt and the mixture heated to 110° C. for 3 hours. The solution was filtered and the filtrate was distilled at reduced pressure. The residual solid was dissolved in excess water and poured into conc. hydrochloric acid. The solid that precipitated was filtered and washed with water and then air dried. The recovered solid was recrystallized from acetonitrile to give 2.7 grams of a yellow solid which melted at 138°-140° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([C:21]2[CH:25]=[CH:24][N:23]([Si](C(C)C)(C(C)C)C(C)C)[CH:22]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([C:21]2[CH:25]=[CH:24][NH:23][CH:22]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2
Reactant: COC(=O)c1ccc2nc(-c3ccn([Si](C(C)C)(C(C)C)C(C)C)c3)c(N3CCC[C@@H]3C)nc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2nc(-c3cc[nH]c3)c(N3CCC[C@@H]3C)nc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.1 %

Procedure:
To a solution of methyl 3-[(2S)-2-methylpyrrolidin-1-yl]-2-[1-[tris(propan-2-yl)silyl]-1H-pyrrol-3-yl]quinoxaline-6-carboxylate (150 mg, 0.30 mmol) in tetrahydrofuran (30 ml) was added Tetra-n-butylammonium fluoride (TBAF) (80 mg, 0.31 mmol) with stirring for 10 min at room temperature. The reaction was then quenched with water (10 ml). The resulting solution was extracted with dichloromethane (3×10 ml) and the organic layers combined and dried over anhydrous magnesium sulfate, concentrated under vacuum to afford methyl 3-[(2S)-2-methylpyrrolidin-1-yl]-2-(1H-pyrrol-3-yl)quinoxaline-6-carboxylate as a light yellow solid (100 mg, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH:12]([CH3:14])[CH3:13])=[CH:4][C:3]=1[CH3:15].Cl>C(O)C.[Fe]>[Br:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]([O:11][CH:12]([CH3:13])[CH3:14])=[C:6]([NH2:8])[CH:7]=1
Reactant: Cc1cc(OC(C)C)c([N+](=O)[O-])cc1Br
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Cc1cc(OC(C)C)c(N)cc1Br

Procedure:
To 1-Bromo-4-isopropoxy-2-methyl-5-nitro-benzene from the previous step (0.734 g, 2.68 mmol) and iron (powder, 325 mesh, 1.05 g) in 20 mL ethanol is added 1 mL of 1N aqueous HCl with cooling in an ice bath. Following this addition, the reaction is heated at reflux for 2 hrs. Then an additional 0.5 g of iron is added and the reaction is heated at reflux for an additional 2 hrs. The reaction mixture is cooled down and filtered though a pad of Celite. The filtrate is concentrated in vacuo, affording 5-Bromo-2-isopropoxy-4-methyl-phenylamine as an orange oil. The product is used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)(O)[CH3:13])[C:8]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>S(Cl)(Cl)=O.O>[F:1][C:2]1[C:10]2[N:9](/[CH:11]=[C:12](/[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)\[CH3:13])[C:8]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCc2c(c3cccc(F)c3n2CC(C)(O)c2ccncc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: C/C(=C\n1c2c(c3cccc(F)c31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(6-Fluoro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propan-2-ol (510 mg, 1.5 mmol) was dissolved in thionylchloride (5 mL) and stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in N-methyl-2-pyrrolidone (3 mL) and stirred for 5 min. at RT. Powdered KOH (616 mg, 10 mmol) was added, and the stirring was continued for additional 10 min. The reaction mixture was heated at 100° C. for 2 h. The progress of reaction was monitored by TLC and NMR. The reaction mixture was diluted with water and extracted with EtOAc, washed with water, concentrated to obtain the crude product which was purified by HPLC. 1H NMR (DMSO-d6, TFA salt) δ (ppm): 8.80 (d, 2H), 8.0 (d, 2H), 7.70 (s, 1H), 7.40 (d, 1H), 7.30 (m, 1H), 7.10 (m, 1H), 4.80 (m, 1H), 4.30 (m, 1H), 3.80 (m, 2H), 3.10 (m, 2H), 3.0 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][CH:8]([CH2:11][CH2:12][C@H:13]1[CH2:18][C@H:17]2[CH2:19][C@H:15]([C:16]2([CH3:21])[CH3:20])[C@@H:14]1[CH3:22])[CH:9]=[O:10].O.[OH-].[Na+]>C(OCC)C>[CH3:7][CH:8]([CH2:11][CH2:12][C@H:13]1[CH2:18][C@H:17]2[CH2:19][C@H:15]([C:16]2([CH3:20])[CH3:21])[C@@H:14]1[CH3:22])[CH2:9][OH:10]
Reactant: CC(C=O)CC[C@H]1C[C@H]2C[C@@H]([C@@H]1C)C2(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(CO)CC[C@H]1C[C@H]2C[C@@H]([C@@H]1C)C2(C)C
Temperature: 10 °C
Yield: 80.9 %

Procedure:
7.9 ml (7.9 mmol) of 1M LiAlH4 solution in ethyl ether and 6 ml of anhydrous ethyl ether are charged under nitrogen into a 25 ml three-necked flask equipped with a thermometer, a condenser and a magnetic stirrer and 3.5 g (15.7 mmol) of (R/S)-2-methyl-4-[(1S,2R,3S,5S)-3-pinanyl]butanal diluted in 6 ml of the same solvent are then added. The mixture is heated at reflux for 2 h. and is then cooled to 10° C. 0.3 ml of water, 0.3 ml of 15% aqueous NaOH solution and 0.8 ml of water are added successively and stirring is maintained for 10 minutes. After filteration through kieselguhr and evaporation of the ether phase the residue is purified by flash chromatography on silica (eluent: petroleum ether/ethyl ether 93:7) and distilled in a bulb-tube (Kugelrohr) to give 2.85 g of (R/S)-2-methyl-4-[(1S,2R,3S,5S)-3-pinanyl]-1-butanol (yield 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](C)(C)C)[S:10][C:3]=12.Br[C:16]1[N:21]=[C:20]([CH:22]=[O:23])[CH:19]=[CH:18][CH:17]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:16]3[N:21]=[C:20]([CH:22]=[O:23])[CH:19]=[CH:18][CH:17]=3)[S:10][C:3]=12
Reactant: O=Cc1cccc(Br)n1
Reactant: C[Sn](C)(C)c1cc2nccc(Cl)c2s1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=Cc1cccc(-c2cc3nccc(Cl)c3s2)n1
Yield: 27 %

Procedure:
This material was prepared by coupling 7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.707 g, 2.17 mmole) with 6-bromopyridine-2-carbaldehyde (0.396 g, 2.17 mmole) using tereakis (triphenylphosphine) palladium(0) (100 mg) as catalyst in a manner as previously described for example 39b to give a white solid (0.161 g, 27%). 1H NMR (300 MHz, CDCl3) δ10.15 (1H, s), 8.61 (1H, d, J=5.1 Hz), 7.93-8.09 (4H, m) 7.31 (1H, d, J=5.1 Hz); ESIMS (MH+): 275.00.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[N:10]=1)=[O:5])C.O.[Li+].[OH-]>C1COCC1>[Cl:17][C:13]1[CH:12]=[C:11]([N:9]2[N:8]=[N:7][C:6]([C:4]([OH:5])=[O:3])=[N:10]2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1nnn(-c2cccc(Cl)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nnn(-c2cccc(Cl)c2)n1

Procedure:
7.00 g (27.7 mmol) 2-(3-chloro-phenyl)-2H-tetrazole-5-carboxylic acid ethyl ester was dissolved in 50 mL THF and 50 mL water and treated with 2.33 g (55.4 mmol) LiOH at RT for 14 h. The reaction mixture was concentrated and acidified with 1 M aqueous hydrochlorid acid. The precipitate was filtered off, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:29](O)=[O:30])=[CH:19][N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.C([N:35]([CH2:39][CH3:40])[CH:36](C)C)(C)C.CN(C)CCCN=C=NCC.CC1CN1.Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:29]([N:35]5[CH2:36][CH:39]5[CH3:40])=[O:30])=[CH:19][N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Agent: CC1CN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1CN1C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64.6 %

Procedure:
2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (100 mg, 0.218 mmol) was suspended in dichloromethane (2.2 ml). 4-Dimethylaminopyridine (5.3 mg, 0.044 mmol), N,N-diisopropylethylamine (76 ul, 0.44 mmol) and then 1-(3-(dimethylamino)-propyl)-3-ethylcarbodiimide (84 mg, 0.44 mmol) were added. The solution was stirred for 5 min then cooled in an ice bath. 2-Methylaziridine (23 ul, 0.33 mmol) was added and the reaction was warmed to room temperature. Stirring was continued until judged to be complete by TLC then water, dilute HCl and ethyl acetate were added. The aqueous layer was extracted once more with ethyl acetate and the combined organic layers were washed with sodium bicarbonate solution and dried over sodium sulfate. After evaporation the residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give 70 mg (64%) of [2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-(2-methyl-aziridin-1-yl)-methanone. 1H NMR (300 MHz, CDCl3) δ ppm 9.23 (s, 1H) 8.76 (d, J=8.7 Hz, 1H) 8.33 (s, 1H) 7.44 (s, 1H) 7.24 (d, J=8.7 Hz, 1H) 5.73 (s, 2H) 4.14 (s, 3H) 3.56-3.65 (m, 6H) 2.80-2.91 (m, 1H) 2.59 (d, J=6.0 Hz, 1H) 2.33 (d, J=3.8 Hz, 1H) 1.41 (d, J=5.3 Hz, 3H) 0.89-0.99 (m, 2H)-0.05 (s, 9H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=4)[N:17]=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[CH3:32][N:33]([CH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH3:34].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(Cl)Cl>[CH3:34][N:33]([CH3:32])[CH2:35][CH2:36][CH2:37][N:38]1[CH2:39][CH2:40][N:41]([C:27]([C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:18]3[N:17]=[C:16]([C:13]4[CH:12]=[CH:11][C:10]([S:7]([CH:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)(=[O:8])=[O:9])=[CH:15][CH:14]=4)[CH:21]=[CH:20][N:19]=3)=[CH:31][CH:30]=2)=[O:29])[CH2:42][CH2:43]1
Reactant: CN(C)CCCN1CCNCC1
Reactant: O=C(O)c1ccc(Nc2nccc(-c3ccc(S(=O)(=O)C4CCOCC4)cc3)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)CCCN1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(S(=O)(=O)C5CCOCC5)cc4)n3)cc2)CC1
Reaction time: 12 h
Yield: 22.2 %

Procedure:
4-{4-[4-(Tetrahydropyran-4-sulfonyl)-phenyl]pyrimidin-2-ylamino}benzoic acid 4 (0.26 g, 0.6 mmol) was dissolved in THF (5 mL). To this solution was added 1-(N,N-dimethylaminopropyl)piperazine (0.130 g), EDCI (0.136 g), and HOBt (0.096 g). The mixture was stirred 12 h. The mixture was then diluted with CH2Cl2 (20 mL) and washed with 2% NaOH (aq, 30 mL), water (30 mL), and then brine (30 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The crude solid was subjected to preparative HPLC (20–70 acetonitrile/water gradient, 20 min). The desired fractions were concentrated to remove most of the acetonitrile, and then the aqueous mixture was extracted with CH2Cl2/2% NaOH (aq). The organic layer was dried (Na2SO4), filtered, and concentrated to afford [4-(3-dimethylamino-propyl)piperazin-1-yl]-(4-{4-[4-(tetrahydropyran-4-sulfonyl)phenyl]pyrimidin-2-ylamino}phenyl)methanone 5 (0.079 g, 22%): HPLC Retention Time; 7.93 min. (Method B) M+1=593.3
Reaction SMILES: [CH2:1]([C@@:4]1(C)[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH:34]([CH3:36])[CH3:35])[CH2:25][N:26]([CH3:33])[S:27]([CH:30]2[CH2:32][CH2:31]2)(=[O:29])=[O:28])[C:5]1=[O:37])C=C.I([O-])(=O)(=O)=O.[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[C:59]([O:62]CC)(=[O:61])[CH3:60]>C(#N)C.C(Cl)(Cl)(Cl)Cl.O.[Ru](Cl)(Cl)Cl>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:6]([C@@H:24]([CH:34]([CH3:35])[CH3:36])[CH2:25][N:26]([CH3:33])[S:27]([CH:30]3[CH2:31][CH2:32]3)(=[O:28])=[O:29])[C:5](=[O:37])[C@:4]([CH2:60][C:59]([OH:62])=[O:61])([CH3:1])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(C)=O
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CN(C)S(=O)(=O)C2CC2)C(C)C)C1=O
Agent: Cl[Ru](Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-3-methylbutyl)-N-methylcyclopropanesulfonamide (Example 295, Step A, 112.5 mg, 0.195 mmol), sodium periodate (170 mg, 0.795 mmol), and ruthenium(III) chloride hydrate (6 mg, 0.023 mmol) in acetonitrile (1.0 mL), carbon tetrachloride (1.0 mL), and water (1.5 mL) was vigorously stirred at ambient temperature overnight. The reaction mixture was acidified with aqueous citric acid (10% by weight), diluted in ethyl acetate, and filtered through a pad of Celite® (J.T. Baker, Phillipsberg, N.J., diatomaceous earth). The filtrate was partitioned between 2 M aqueous HCl and ethyl acetate. Combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to a residue that was purified by preparative HPLC (Sunfire™ Prep C18 OBD 10 μm column, 30×150 mm, Waters, Milford, Mass.) eluting with a gradient of 50 to 100% acetonitrile in water (0.1% trifluoroacetic acid in both solvents). Chromatography fractions containing the product were stripped of volatiles, redissolved in minimal volumes of acetonitrile and water, frozen, and lyophilized to give the product as a white solid.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:16]2([CH3:17])[N:12](/[C:13](=[N:18]/[C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[C:20]=3[CH3:28])/[O:14][CH2:15]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl-].[NH4+].CCOC(C)=O>C1COCC1>[OH:8][C@@H:9]1[C@@:16]2([CH3:17])[N:12](/[C:13](=[N:18]/[C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[C:20]=3[CH3:28])/[O:14][CH2:15]2)[CH2:11][CH2:10]1
Reactant: Cc1c(/N=C2\OC[C@@]3(C)[C@@H](O[Si](C)(C)C(C)(C)C)CCN23)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(/N=C2\OC[C@@]3(C)[C@@H](O)CCN23)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.9 %

Procedure:
To compound 3E (8.0 mg, 0.0190 mmol) in THF (1 mL) was added a 1 M solution of TBAF in THF (0.190 mL, 0.190 mmol). After stirring at rt for 1.5 h, saturated aqueous ammonium chloride and EtOAc were added and the layers were separated. The organic layer was washed with brine then dried (MgSO4), filtered and concentrated. The resulting residue was purified via preparative HPLC (YMC ODS C-1 8, 21.2×100 mm, eluting with 40-100% solvent B (A=90% H2O-10% MeOH and B=10% H2O-90% MeOH) over 10 min; Flow rate at 20 mL/min; UV detection at 220 nm) to provide the title compound (4.0 mg) as a white solid. MS: m/z 306 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=2.[OH-].[Na+]>CO.O>[OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC[C@H]3CO)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCC[C@H]3CO)nc2c1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of (S)-methyl 3-(2-(hydroxymethyl)pyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate (104 mg, 0.29 mmol, 1.00 equiv) and sodium hydroxide (57.3 mg, 1.43 mmol, 5.00 equiv) in methanol/H2O (20/5 mL). The reaction was stirred for 5 h at 70° C., concentrated to dryness, dissolved in 20 mL of H2O and washed with 10 mL EtOAc. The aqueous layer was adjusted pH to 7 with 1N HCl and extracted with DCM/MeOH (10/1, 20 mL×5). The organic layer was combined, dried over Na2SO4, and concentrated in vacuo. This resulted 45 mg (43%) of (S)-3-(2-(hydroxymethyl)pyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [C:1]1([C:7]([NH:10][C:11]2[N:12]=[C:13]([NH2:29])[C:14]3[N:15]=[CH:16][N:17]([C:27]=3[N:28]=2)[C@H:18]2[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]2[OH:20])([CH3:9])C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:30][C@H](N)CC1C=CC=CC=1>>[C:1]1([CH:7]([NH:10][C:11]2[N:12]=[C:13]([NH2:29])[C:14]3[N:15]=[CH:16][N:17]([C:27]=3[N:28]=2)[C@@H:18]2[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]2[OH:20])[CH2:9][CH3:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](N)Cc1ccccc1
Reactant: CC(C)(Nc1nc(N)c2ncn([C@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccccc1
Product: CCC(Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccccc1
Yield: 74.8 %

Procedure:
Combine the acetonide (2) (638 mg, 1.87 mmol) with D-(+)-amphetamine (4.5 g) and heat to 130° C. for 5 hours under nitrogen with stirring. After cooling, purify by flash chromatography (3% to 5% to 10% methanol/chloroform) followed by radial chromatography four times (2% to 4% to 6% to 8% to 10% methanol/chloroform, 4 mm plate) to provide the secondary amine (3) (0.56 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:31])[NH:6][C:7]([C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([NH:22][C:23]([CH2:25][O:26]C(=O)C)=[O:24])=[C:17]([CH3:30])[CH:16]=1)=[N:8]2.C(=O)([O-])[O-].[K+].[K+].Cl>CO.ClCCl.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:31])[NH:6][C:7]([C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([NH:22][C:23](=[O:24])[CH2:25][OH:26])=[C:17]([CH3:30])[CH:16]=1)=[N:8]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(NC(=O)COC(C)=O)c(C)c3)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(NC(=O)CO)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 48.9 %

Procedure:
A mixture of 2,6-dimethyl-phenylamine (0.62 mL, 5.0 mmol), DMSO (100 mL), conc. Aqueous HCl (36.5-38%, 5.0 mL), and dried CuCl2 was stirred at 90° C. under nitrogen for 5 h. The reaction was quenched with water. The pH of the mixture was adjusted to ˜8 using a 10% sodium hydroxide solution. The mixture was extracted with ether (3×100 mL). The solution was dried over Na2SO4 and concentrated to dryness. The resulting brown oil was dissolved in dichloromethane (anhydrous, 20 mL) and N-ethyldiisopropylamine (DIPEA, 1.0 mL, 5.8 mmol) was added. The mixture was cooled to 0° C., acetoxyacetyl chloride (0.8 mL, 7.4 mmol) was added slowly. The mixture was stirred at room temperature under nitrogen for 17 h. The mixture was concentrated to dryness and purified by column chromatography. Acetic acid (4-formyl-2,6-dimethyl-phenylcarbamoyl)-methyl ester was obtained as yellow/beige solid (96 mg). A mixture of acetic acid (4-formyl-2,6-dimethyl-phenylcarbamoyl)-methyl ester (96 mg, 0.38 mmol), 2-amino-4,6-dimethoxy-benzamide (74 mg, 0.38 mmol), p-toluenesulfonic acid monohydrate (21 mg, 0.11 mmol), sodium hydrogensulfite (96 mg, 0.53 mmol) and dimethylacetamide (3 mL) was stirred in a 150° C. oil bath under nitrogen for 17 h. After cooling to room temperature, water (50 mL) was added. The precipitate was filtered off and washed with water. The filtrate was extracted with dichloromethane, dried over Na2SO4, purified by column chromatography, using (1) 5% methanol/dichloromethane, and (2) 10% methanol/dichloromethane as eluents. Acetic acid [4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenylcarbamoyl]-methyl ester was obtained as a beige solid (70 mg, 43%). Acetic acid [4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenylcarbamoyl]-methyl ester (70 mg, 0.16 mmol) was dissolved in methanol/dichloromethane (10 mL) and a solution of potassium carbonate (442 mg, 20 mmol) in water was added. The solution was stirred at room temperature for 17 h. 2 N HCl was added to adjust the reaction mixture pH to ˜8. The mixture was then concentrated under reduced pressure. The resulting precipitate was filtered off, washed with water, air-dried, then washed with ether and dried, leaving N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-2-hydroxyacetamide (30 mg, 49%) as a light brown solid. Selected data: MS (ES) m/z: 384.1; MP 190-192° C.
Reaction SMILES: C([O:8][C:9](=[O:19])[CH2:10][C:11]1([C:17]#[N:18])[CH:16]=[CH:15][CH2:14][CH:13]=[CH:12]1)C1C=CC=CC=1.[NH4+].[OH-]>[Pd].CO>[NH2:18][CH2:17][C:11]1([CH2:10][C:9]([OH:19])=[O:8])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: N#CC1(CC(=O)OCc2ccccc2)C=CCC=C1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NCC1(CC(=O)O)CCCCC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 93.1 %

Procedure:
Added 5% Pd/C catalyst (0.84 g, 0.40 mmol) to a solution of (1-cyanocyclohexa-2,5-dienyl)acetic acid benzyl ester (1.00 g, 3.95 mmol) and 28% NH4OH (0.55 mL, 0.50 g, 4.0 mmol) in MeOH (20 mL). After shaking the reaction mixture under 50 psi H2 at 50° C. for 18 hours, the pressure was slowly released, and the reaction was cooled to room temperature. The reaction was filtered and concentrated under reduced pressure to afford 0.63 g (93%) of crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl.Cl[CH2:13][CH2:14][NH2:15]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:13][CH2:14][NH2:15]
Reactant: NCCCl
Reactant: Oc1cccc(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NCCOc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Add 5.0 g (38.9 mmol) of 3-chlorophenol to a 0° C. suspension of 3.42 g (85.6 mmol, 2.2 eq., 60% by wt. in mineral oil) of sodium hydride in 100 mL of dry tetrahydrofuran. Once the 3-chlorophenol is dissolved add 9.93 g (85.6 mmol, 2.2 eq.) of 2-chloroethylamine hydrochloride and stir at room temperature for 17 hr. Concentrate the reaction mixture and partition between 200 mL of methylene chloride and 50 mL water. Dry the organic layer over Na2SO4 and concentrate in vacuo to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]=O)=[CH:8]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:25]([CH3:28])([O-:27])=[O:26]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]=[CH:28][N+:25]([O-:27])=[O:26])=[CH:8]2)=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cn(Cc2ccc(Cl)cc2)c2ccccc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=[N+]([O-])C=Cc1cn(Cc2ccc(Cl)cc2)c2ccccc12

Procedure:
80.9 g of 1-(4-chlorobenzyl)-3-formylindole, prepared in Example 5, 18 g of ammonium acetate and 300 ml of nitromethane are refluxed for 30 min.