Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]Br)[CH3:2].[CH:10]1([NH:16][CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][N:16]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:17])[CH3:2]
Reactant: CNC1CCCCC1
Reactant: CCOC(=O)CCCBr
Solvent: CCO
Product: CCOC(=O)CCCN(C)C1CCCCC1
Yield: 90.1 %

Procedure:
10 g of 4-bromobutyric acid ethyl ester and 15 g of N-cyclohexyl-N-methylamine were added to 40 mL of ethanol, and the mixture was heated to reflux for 2 hours. After air-cooling, the mixture was concentrated under reduced pressure and extracted with 200 mL of ethyl acetate. The extracted material was washed with purified water, dried with magnesium sulfate, and then concentrated. The obtained residue was distilled under reduced pressure to give 10.5 g of N-cyclohexyl-N-methyl-gamma-aminobutyric acid ethyl ester. The obtained N-cyclohexyl-N-methyl-gamma-aminobutyric acid ethyl ester was added to a sodium hydroxide solution (2.4 g of sodium hydroxide/100 mL of purified water), and THF was added thereto until the mixture became homogeneous. After stirring at room temperature for 3 hours, the mixture was neutralized with DOWEX50W [H+ form] and concentrated under reduced pressure. The obtained residue was recrystallized to give 5.2 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:27](O)=[O:28])[CH:25]=[CH:26][C:17]=4[C:16]=3[N:30]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(OC(=O)NCCNC(C1C=C[C:46]2[C:52]3[N:53]=C(NC4C=CC(OC)=C(OC)C=4)N=CC=3CC(=O)[NH:48][C:47]=2C=1)=O)(C)(C)C>>[NH2:48][CH2:47][CH2:46][CH2:52][NH:53][C:27]([C:24]1[CH:25]=[CH:26][C:17]2[C:16]3[N:30]=[C:12]([NH:11][C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:13]=[CH:14][C:15]=3[CH2:21][C:20](=[O:22])[NH:19][C:18]=2[CH:23]=1)=[O:28]
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(C(=O)O)cc2NC(=O)C3)cc1OC
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(C(=O)NCCNC(=O)OC(C)(C)C)cc2NC(=O)C3)cc1OC
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(C(=O)NCCCN)cc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described for Method N, 2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carboxylic acid (I-53) and tert-butyl 4-aminopropylcarbamate were converted to (2-{[2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carbonyl]-amino}-ethyl)-carbamic acid tert-butyl ester, which was subsequently deprotected (Method K) to give I-72 (30%): HRMS Calcd. for C24H26N6O4: 463.2093, Found 463.2078.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=[CH:15][CH:16]=3)[C:11]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.[C:38](Cl)(=[O:43])[O:39][CH:40]([CH3:42])[CH3:41]>C(Cl)Cl>[CH2:25]([NH:24][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:43])[O:39][CH:40]([CH3:42])[CH3:41])[CH:7]=[N:6][CH:5]=2)=[N:9][N:10]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)cccc23)c1
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)OC(=O)Nc1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)cccc23)c1
Reaction time: 5 h
Yield: 68.5 %

Procedure:
To a solution of 4-(5-aminopyridin-3-yl)-N-benzyl-8-phenylphthalazin-1-amine (60.0 mg, 0.149 mmol) in DCM (20 mL) was added pyridine (0.241 mL, 0.297 mmol) at room temperature followed by isopropyl carbonochloridate (18.2 mg, 0.149 mmol) and the reaction mixture stirred for 5 h. The volatile components were removed under reduced pressure and the resulting residue was purified by preparative HPLC (Condition 23 as described in general methods) to afford isopropyl (5-(4-(benzylamino)-5-phenylphthalazin-1-yl)pyridin-3-yl)carbamate (50.0 mg, 68.7%) as a white solid. LCMS (Condition 4): retention time 2.60 min, [M+1]=490.2. HPLC (Condition 28): retention time=7.65 min, purity 99.27%. 1H NMR (400 MHz, DMSO-d6) δ 1.29 (d, J=6.4 Hz, 6 H), 4.51 (d, J=4.8 Hz, 2 H), 4.93 (sept, J=6.4 Hz, 1 H), 5.06 (dd, J=4.8 Hz, J=5.2 Hz, 1 H), 7.01-7.03 (m, 2 H), 7.21-7.28 (m, 3 H), 7.42-7.52 (m, 5 H), 7.69 (dd, J=1.2 Hz, J=6.8 Hz, 1 H), 7.85-7.93 (m, 2 H), 8.16 (br s, 1 H), 8.47 (d, J=1.6 Hz, 1 H), 8.80 (d, J=2.4 Hz, 1 H), 10.00 (s, 1 H).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:21][CH:20]=1)[CH3:17]
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: CCOc1ccc(B(O)O)cc1
Product: CCOc1ccc(-c2c(-c3cc(C#N)ccn3)ncn2C)cc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-ethoxyphenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C18H16N4O, 305. Found, 305.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=2)[C:6]([O:20]C)=[CH:5][C:4]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=1.B(Br)(Br)Br>ClCCl>[CH2:28]([C:25]1[CH:24]=[CH:23][C:22]([C:4]2[C:3]([OH:2])=[CH:8][C:7]([C:9]3[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:13][CH:14]=3)=[C:6]([OH:20])[CH:5]=2)=[CH:27][CH:26]=1)[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCc1ccc(-c2cc(OC)c(-c3ccc(CCCCC)cc3)cc2OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCc1ccc(-c2cc(O)c(-c3ccc(CCCCC)cc3)cc2O)cc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A solution of 2′,5′-dimethoxy-4,4″-dipentyl[1,1′;4′,1″]terphenyl (2.15 g) in dichloromethane (40 ml) is cooled to −76° C. and treated with a dropwise addition of 1 M solution of boron tribromide in CH2Cl2 (12 ml). After complete addition the reaction mixture is allowed to reach room temperature and stirring is continued for 6 hours. The reaction mixture is then carefully poured into ice-water (100 g) and stirred for further 20 min. The obtained mixture is then saturated with NaCl and extracted with diethyl ether (3×150 ml). The combined organic extracts are washed with saturated NaCl solution (150 ml), dried over magnesium sulphate and evaporated under reduced pressure to afford 4,4″-dipentyl[1,1′;4′,1″]terphenyl-2′,5′-diol as white crystalline material.
Reaction SMILES: C(O[CH2:7][CH:8](O)[CH2:9][O:10][C:11](=O)C=NOC)(=O)C(C)=C.[C:18](OCCC(OC(=O)C=NOC)O)(=[O:22])[C:19](C)=[CH2:20]>C(Cl)(Cl)Cl>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:18]([OH:22])=[CH:19][CH:20]=1
Reactant: C=C(C)C(=O)OCCC(O)OC(=O)C=NOC
Reactant: C=C(C)C(=O)OCC(O)COC(=O)C=NOC
Solvent: ClC(Cl)Cl
Product: COc1ccc(O)cc1

Procedure:
In this way a milky suspension is obtained which is washed twice with 136 g of dichloromethane, then the chloromethylenic phases are reunited, dried over anhydrous magnesium sulphate and finally concentrated under vacuum. In this way 7.5 g of a yellow oil is isolated which is purified by preparative chromatography on a column (500×25) filled with silica of a size grading of 10 micrometers, eluting with a hexane-ethyl acetate mixture 8/2 by volume, which allows the isolation on the one hand of, 5 g (20.4 mmoles) of 1-methacryloyloxy-3-methoxyiminoacetoxy-2-propanol, and on the other hand of, 2 g (8.15 mmoles) of 3-methacryloyloxy-2-methoxyiminoacetoxy-1-propanol characterised by their NMR1H spectra registered in deuterized chloroform.
Reaction SMILES: C([O:8][C:9]1[CH:27]=[CH:26][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][C:15]=2[N+:23]([O-])=O)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.O1CCCC1.[C].[Pd]>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:12]2[CH:26]=[CH:27][C:9]([OH:8])=[CH:10][CH:11]=2)=[C:15]([CH:16]=1)[NH2:23])[CH3:22]
Reactant: CCOc1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1ccc(Oc2ccc(O)cc2)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution of 4-[4-(benzyloxy)phenoxy]-3-nitrophenetole (4.26 g, 11.7 mmol) in a mixture of ethanol (70 ml) and tetrahydrofuran (50 ml) was added 10% palladium-carbon (430 mg), followed by stirring under a hydrogen gas atmosphere at room temperature overnight. After removal of the insoluble matter by filtration, the solvent was evaporated under reduced pressure. The resulting crude crystals were recrystallized from a mixture of ethyl acetate and hexane (1:9) to give the title compound (2.63 g).
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13](=[O:51])/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][N:30]3[C:38](=[O:39])[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:31]3=[O:40])=[C:24]([C:41]34[CH2:50][CH:45]5[CH2:46][CH:47]([CH2:49][CH:43]([CH2:44]5)[CH2:42]3)[CH2:48]4)[CH:23]=2)=[CH:18][CH:17]=1)(C)(C)C>C(Cl)Cl>[C:41]12([C:24]3[CH:23]=[C:22]([C:19]4[CH:18]=[CH:17][C:16](/[CH:15]=[CH:14]/[C:13]([OH:51])=[O:12])=[CH:21][CH:20]=4)[CH:27]=[CH:26][C:25]=3[O:28][CH2:29][N:30]3[C:38](=[O:39])[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:31]3=[O:40])[CH2:50][CH:45]3[CH2:46][CH:47]([CH2:49][CH:43]([CH2:44]3)[CH2:42]1)[CH2:48]2
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(-c2ccc(OCN3C(=O)c4ccccc4C3=O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccc(-c2ccc(OCN3C(=O)c4ccccc4C3=O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
TFA (1.8 ml) was dropped into an ice-cooled solution of (E)-3-[3′-adamantan-1-yl-4′-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethoxy)-biphenyl-4-yl]acrylic acid tert-butyl ester (110 mg, 0.186 mmol) in DCM (1.8 ml), and the mixture was stirred at 0° C. for 10 min. The solvent was removed in vacuo and the residue was rinsed with hexane to obtain, after filtration, 97 mg (98%) of the title compound.
Reaction SMILES: [C:1]([N:6]1[CH2:10][CH2:9][O:8][C:7]1=[O:11])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CS(O)(=O)=O>C(OCC)(=O)C>[C:13]1([NH:12][CH:3]([CH3:4])[CH2:2][C:1]([N:6]2[CH2:10][CH2:9][O:8][C:7]2=[O:11])=[O:5])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C/C=C/C(=O)N1CCOC1=O
Reactant: Nc1ccccc1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Product: CC(CC(=O)N1CCOC1=O)Nc1ccccc1
Temperature: 0 °C
Yield: 14.9 %

Procedure:
To a solution of 3-crotonoyl-1,3-oxazolidin-2-one (155 mg, 1.0 mmol) in ethyl acetate (3 ml) in a stream of nitrogen was added Pd((R)-binap)(H2O)2(OTf)2 (26.6 mg, 0.025 mmol), and the resulting mixture was cooled to 0° C. Aniline (0.11 ml, 1.2 mmol) was added to the mixture, and to the solution was added slowly methanesulfonic acid (0.078 ml, 1.2 mmol). Then, the cooling ice-bath was removed and the reaction mixture was reacted at room temperature for 18 hours with stirring. After completion of the reaction, the solvent was evaporated off, and the crude product obtained was purified by a silica gel column chromatography (hexane:ethyl acetate=1:1) to give the objective compound 3-(3-phenylaminobutyryl)-oxazolidin-2-one (37 mg, 15% yield). Enantiomeric excess ratio of this product was determined by a liquid chromatography using a column for separation of optical isomers (column: AD-H) to be 82% e.e.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:9][N:10]=2)[CH:7]=1.C([Mg]Cl)(C)C.[CH3:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>C1COCC1>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[N:6]2[CH:7]=[C:2]([CH:28]([C:27]3[CH:30]=[CH:31][C:24]([CH3:23])=[CH:25][CH:26]=3)[OH:29])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: Clc1ccccc1-c1nnc2ccc(Br)cn12
Reactant: Cc1ccc(C=O)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2ccc3nnc(-c4ccccc4Cl)n3c2)cc1
Temperature: 50 °C
Yield: 29 %

Procedure:
In a flame-dried flash under nitrogen a solution of 6-bromo-3-(2-chloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridine (205 mg, 0.66 mmol) in THF (2.5 mL) was cooled to 0° C. A solution of isopropylmagnesium chloride (1.3 eq) was added dropwise, followed by 4-methylbenzaldehyde (1 equivalent), and the resulting mixture was warmed to 50° C. for 3 hours. The reaction was cooled and quenched with water/ethyl acetate. The organic layer was separated, concentrated in vacuo, and the residue purified by flash chromatography (eluting with 80% ethyl acetate/hexane) to give the title compound (67 mg, 29%). MS (M+1)=350.5.
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8](=[O:18])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15](O)=[O:16])[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][O:26][C:27](=[O:31])[C@H:28]([CH3:30])[NH2:29]>>[CH3:25][O:26][C:27](=[O:31])[CH:28]([NH:29][C:15]([C:13]1[N:14]=[C:10]([NH:9][C:8]([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)=[O:18])[S:11][CH:12]=1)=[O:16])[CH3:30]
Reactant: O=C(O)c1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1
Reactant: COC(=O)[C@H](C)N
Product: COC(=O)C(C)NC(=O)c1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1
Yield: 17 %

Procedure:
Prepared in 17% yield (44 mg) as described in general procedure (K) from 2-(3,3-dicyclohexylureido)-thiazole-4-carboxylic acid (210 mg, 0.60 mmol) and (S)-alanine methyl ester (HCl salt, 84 mg, 0.6 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2O)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCCC1[O:43][CH2:44][CH2:45][OH:46].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([CH:10]=[CH:9][CH:8]=2)[O:43][CH2:44][CH2:45][OH:46])[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1
Reactant: OCCOC1CCCCO1
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2O)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(N)n(-c2cccc(OCCO)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A solution of Intermediate 95a (1.2 g, 5.2 mmol) and triphenyl phosphine (2.72 g, 10.4 mmol) in THF (30 mL), under an atmosphere of argon was treated with 2-(tetrahydro-pyran-2-yloxy)-ethanol (1.05 mL, 7.78 mmol), followed by the dropwise addition of diisopropylazodicarboxylate (1.64 mL, 10.4 mmol). The reaction mixture was then stirred at RT for 1 h. The reaction mixture was eluted on a SCX-2 cartridge using MeOH and 2M NH3 in MeOH. The basic fractions were evaporated under reduced pressure and the product was purified by FCC, using EtOAc/DCM 0-60% to afford the title compound as a brown gum (1.0 g, 80%). LCMS (Method 3): Rt 2.27 min, m/z 276 [MH+].
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([CH2:21][CH3:22])[C:8]=1[C:9]([O:11]CC)=[O:10])([O:3][CH2:4][CH3:5])=[O:2]>O1CCCC1.[OH-].[Na+]>[C:1]([NH:6][C:7]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([CH2:21][CH3:22])[C:8]=1[C:9]([OH:11])=[O:10])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)Nc1cc([N+](=O)[O-])cc(CC)c1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cc([N+](=O)[O-])cc(CC)c1C(=O)O

Procedure:
A solution of ethyl 2-carboethoxyamino-4-nitro-6-ethyl-benzoate in tetrahydrofuran (10 ml) and sodium hydroxide (20 ml, 10%) was stirred at room temperature for 20 hours. The solution was extracted with ethyl acetate. The aqueous layer was acidified to pH=1 with 6M HCl, and then immediately extracted with ethylacetate. The ethyl acetate extract was washed with water and dried over magnesium sulphate. Solvent evaporation gave a solid which was further recrystallized from methylene chloride:petroleum ether to yield 2-carboethoxyamino-4-nitro-6-ethyl benzoic acid,
Reaction SMILES: [Cl-].[C:2]([O:6][C:7](=[O:10])[CH2:8][Zn+])([CH3:5])([CH3:4])[CH3:3].[Br:11][C:12]1[CH:13]=[C:14]2[C:25](=[CH:26][CH:27]=1)[O:24][C:17]1[C:18]([F:23])=[N:19][C:20]([Cl:22])=[CH:21][C:16]=1[C:15]2=[O:28]>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]2[C:25](=[CH:26][CH:27]=1)[O:24][C:17]1[C:18]([F:23])=[N:19][C:20]([Cl:22])=[CH:21][C:16]=1[C:15]2([CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:10])[OH:28]
Reactant: O=c1c2cc(Br)ccc2oc2c(F)nc(Cl)cc12
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1(O)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a solution of (2-tert-butoxy-2-oxoethyl)zinc(II) chloride (0.5M in Et2O; 670 ml, 335 mmol) at 0° C. was added drop wise a solution of 7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one (55 g, 167 mmol) in THF (30 mL). The resulting reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with aqueous, saturated NH4Cl solution and extracted with EtOAc. The organic extracts were dried over Na2SO4 and concentrated under reduced pressure to afford tert-butyl 2-(7-bromo-3-chloro-1-fluoro-5-hydroxy-5H-chromeno[2,3-c]pyridin-5-yl)acetate (66.0 g, 148 mmol, 89% yield) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([NH2:11])[CH:5]=1
Reactant: COC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(Br)c(N)c1
Yield: 51 %

Procedure:
Dissolve 4-bromo-3-nitro-benzoic acid methyl ester (4.25 g, 16.3 mmol) in ethanol (100 ml) and water (30 ml). Add sodium dithionite (15 g, 75 mmol) in a single portion and heat the mixture under reflux for 4 h. Evaporate ethanol and add water. Basify the aqueous layer with 10% sodium carbonate solution. Extract the product with EtOAc (×2). Dry the combined organic layers over anhydrous sodium sulfate, filter and concentrate to yield 3-amino-4-bromo-benzoic acid methyl ester (51%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4]=[CH:3]1.CC([O-])(C)C.[K+].[SiH:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19]>O1CCCC1>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4]=[C:3]1[Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19]
Reactant: CC[SiH](CC)CC
Reactant: Cn1ccc2cccnc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc2cccnc2n1C
Yield: 72.2 %

Procedure:
The reaction was conducted according to the General Procedure by heating N-methyl-1H-pyrrolo[2,3-b]pyridine (66 mg, 0.5 mmol, 1 equiv.), KOt-Bu (11 mg, 0.1 mmol, 0.2 equiv.) and Et3SiH (239 microliters, 1.5 mmol, 3 equiv.) in 1 mL of tetrahydrofuran for 45 hours at 35° C. After aqueous work up, the crude reaction mixture was purified by chromatography on silica using step gradient elution (starting with 100% hexanes and increasing the polarity of the eluent stepwise to 30% EtOAc in Hexanes) to obtain 89 mg (73%) of the title compound as a pale yellow oil. 1H NMR (500 MHz, THF-d8) δ 8.45-7.95 (m, 1H), 7.97-7.66 (m, 1H), 6.95 (dd, J=7.7, 4.6 Hz, 1H), 6.68 (s, 1H), 3.94 (s, 2H), 1.05-1.00 (m, 9H), 0.97 (td, J=7.1, 1.7 Hz, 6H). 13C NMR (126 MHz, THF-d8) δ 150.95, 142.87, 137.82, 127.38, 120.13, 114.79, 110.76, 30.27, 6.74, 3.31. HRMS: [C14H23N2Si] calculated 247.1642. measured 247.1631. The HSQC spectrum of this reaction product as provided in FIG. 10.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([O:26]CCCC)=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([OH:26])=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCCCOC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 10-mL sealed tube, was placed (S)-butyl 2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (150 mg, 0.37 mmol, 1.00 equiv), methanol (15 mL), sodium hydroxide (74 mg, 1.85 mmol, 5.02 equiv), water (2 mL). The resulting solution was stirred for 2 hrs at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum and diluted with 20 mL of H2O. The pH value of the aqueous solution was adjusted to 4-5 with aq. hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-1): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (60% CH3CN up to 75% in 8 min, up to 100% in 1.5 min); Detector, UV 220 254 nm. This resulted in 60 mg (46%) of (S)-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH2:17](OC(OCC)OCC)C>FC(F)(F)C(O)=O>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:11]=[C:12]([NH:16][CH3:17])[CH:13]=[CH:14][CH:15]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CCOC(OCC)OCC
Reactant: N=C(N)Nc1nc(-c2cccc(N)c2)cs1
Solvent: O=C(O)C(F)(F)F
Product: CNc1cccc(-c2csc(NC(=N)N)n2)c1
Temperature: 0 °C

Procedure:
A mixture of 9.3 g (0.04 mole) of 3-(2-guanidino-4-thiazolyl)benzeneamine, 20 ml of triethylorthoformate, and 2 drops of trifluoroacetic acid is stirred at reflux for 5 hours after which it is concentrated in vacuo. The residue is dissolved in 20 ml of ethanol, the solution cooled to 0° C. and then treated with excess sodium borohydride. The mixture is allowed to warm to room temperature, then stirred at reflux for 4 hours. Upon concentration in vacuo the residue is partitioned between water and dichloromethane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].Cl.[CH3:27]O>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:27])=[O:23])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: CO
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCC(=O)O)=C(C)C1=O
Agent: Cl
Product: COC(=O)CCCCCCCCCC1=C(C)C(=O)C(OC)=C(OC)C1=O

Procedure:
2,3-Dimethoxy-5-methyl-6-(9'-carboxynonyl)-1,4-benzoquinone (formula I-2 wherein R=H3CO, n=8, in the free form) (4 parts) was esterified with methanol (500 volume parts) saturated with hydrogen chloride gas in a manner similar to that described in Example 13. The procedure provided 2,3-dimethoxy-5-methyl-6-(9'-methoxycarbonylnonyl)-1,4-benzoquinone (formula I-2 wherein R=H3CO, n=8, in the form of methyl ester) (4.2 parts) as orange-colored needles melting at 37°-37.5° C.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][NH2:15].[BH4-].[Na+]>CO.ClCCl>[C:4]([O:3][C:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:15][CH3:14])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CNC1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 1-N-BOC-3-pyrrolidinone (3.0 g) in methanol (30 ml) was added a solution of freshly prepared methylamine (0.75 g) in methanol (3.1 ml). The reaction mixture was stirred for 1 hour and then sodium borohydride (0.61 g) was added. After stirring for 4 hours the reaction mixture was then diluted with dichloromethane, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo to give 3-methylamino-pyrrolidine-1-carboxylic acid tert-butyl ester (3.18 g).