Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[C:13]([Cl:20])[C:9]=1[C:10](Cl)=[O:11].S(=O)(=O)(O)O>C(OCC)C>[Cl:7][C:8]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[C:13]([Cl:20])[C:9]=1[CH2:10][OH:11]
Reactant: O=C(Cl)c1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: O=[N+]([O-])c1cc(Cl)c(CO)c(Cl)c1
Yield: 26.7 %

Procedure:
Lithium aluminium hydride (400 mg, 10.4 mmol) was added in portions to a stirred solution of 2,6-dichloro-4-nitrobenzoyl chloride (3.0 g, 11.8 mmol) in diethyl ether (50 cm3) at room temperature. After 1.5 h the mixture was poured onto ice (80 g), acidified with 10% sulphuric acid (80 cm3) and extracted with ethyl acetate (3×60 cm3). The dried organic extracts were evaporated to an oil which was purified by chromatography over silica gel with a methanol-dichloromethane solvent gradient. The fractions containing 2,6-dichloro-4-nitrobenzylalcohol, were combined and evaporated under reduced pressure to a give a cream solid mp 111°-4° C. (0.7 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[CH2:13][CH2:14][OH:15].[H-].[Na+]>>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([Cl:9])[CH:11]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OCCc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: Clc1cccc(CCOc2cncc(Cl)n2)c1

Procedure:
The title compound was prepared according to the procedure of example 4, step 1 starting from 2,6-dichloropyrazine (444 mg, 3.00 mmol) and m-chlorophenethyl alcohol (515 mg, 3.30 mmol) and NaH (55% in mineral oil, 144 mg, 3.30 mmol). The crude product (0.92 g) was used directly in the next step. MS m/z 269 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:13]3[CH2:14][O:15][CH2:16][CH:9]2[CH2:10][O:11][CH2:12]3)[N:5]=[C:4]([N:17]2[CH:22]3[CH2:23][O:24][CH2:25][CH:18]2[CH2:19][O:20][CH2:21]3)[N:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.CCO>[CH:22]12[N:17]([C:4]3[N:5]=[C:6]([N:8]4[CH:13]5[CH2:14][O:15][CH2:16][CH:9]4[CH2:10][O:11][CH2:12]5)[N:7]=[C:2]([C:30]4[CH:31]=[CH:32][C:27]([NH2:26])=[CH:28][CH:29]=4)[N:3]=3)[CH:18]([CH2:25][O:24][CH2:23]1)[CH2:19][O:20][CH2:21]2
Reactant: Clc1nc(N2C3COCC2COC3)nc(N2C3COCC2COC3)n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
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: Cc1ccccc1
Solvent: CCO
Product: Nc1ccc(-c2nc(N3C4COCC3COC4)nc(N3C4COCC3COC4)n2)cc1
Temperature: 120 °C
Yield: 69.3 %

Procedure:
To a 10 mL vial were added 9,9′-(6-chloro-1,3,5-triazine-2,4-diyl)bis(3,7-dioxa-9-azabicyclo[3.3.1]nonane) (150 mg, 0.406 mmol), 4-aminophenylboronic acid pinacol ester (133 mg, 0.61 mmol), Pd(PPh3)4 (10 mg), toluene (1 mL), EtOH (1 mL) and 2M Na2CO3 aqueous solution (0.305 mL). The resulting mixture was heated at 120° C. for 20 minutes in microwave oven. The reaction mixture was cooled to room temperature. The aqueous phase was extracted with EtOAc, and the combined organic phases were dried over (MgSO4). The solvent was removed under reduced pressure and the residue was subjected to HPLC separation to give 4-(4,6-di(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl)aniline as a white solid (120 mg).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=2)[N:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=2)[N:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2ccnc3ccccc23)c2ccc(C)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1)c(C(=O)O)cn2-c1ccnc2ccccc12
Reaction time: 22 h
Yield: 98.3 %

Procedure:
0.422 g (10.05 mmol) of lithium hydroxide monohydrate and 50 cm3 of water are added at 25° C. to 1.06 g (3.35 mmol) of 3-methoxycarbonyl-5-methyl-1-(quinol-4-yl)-1H-indole dissolved in 50 cm3 of tetrahydrofuran. After stirring at the reflux point of the solvent for 22 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 25 cm3 of water and then triturated with 10 cm3 of N hydrochloric acid. After filtering off and drying the solid residue under reduced pressure (2.7 kPa) at 40° C., 0.996 g of 3-carboxy-5-methyl-1-(quinol-4-yl)-1H-indole is obtained in the form of a white solid. Mass spectrum (EI): m/e 302 (M+·).
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.B(O)(O)[C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1>>[CH3:7][N:6]1[C:2]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[C:3]([C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)[N:4]=[CH:5]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cc1ccc(-c2c(-c3cc(C#N)ccn3)ncn2C)cc1
Yield: 54 %

Procedure:
The title compound was prepared in 54% yield from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and p-tolylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C17H14N4, 275. Found, 275.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.Cl.[NH:39]1[CH2:43][CH2:42][CH:41]([C:44]([OH:47])([CH3:46])[CH3:45])[CH2:40]1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30][N:39]4[CH2:43][CH2:42][CH:41]([C:44]([OH:47])([CH3:46])[CH3:45])[CH2:40]4)=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:15][CH2:16][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:19]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Reactant: CC(C)(O)C1CCNC1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O=S(Cl)Cl
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCC(C(C)(C)O)C4)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a 0° C. cooled solution of (E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (100 mg, 0.221 mmol) in DCM (5 mL) was added thionyl chloride (0.081 mL, 1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30 minutes. The solvent was removed at reduced pressure, and the residue was suspended in ACN (2 mL) and re-concentrated to remove residual thionyl chloride. The residue was resuspended in ACN (2 mL), cooled to 0° C., and 2-(pyrrolidin-3-yl)propan-2-ol hydrochloride (110 mg, 0.663 mmol) and TEA (0.154 mL, 1.105 mmol) were added. The reaction was stirred for 16 hours at RT, followed by 4 hours at 50° C. and 6 hours at 80° C. The reaction was cooled to RT, DBU (0.17 mL, 1.105 mmol) was added, and the reaction was stirred overnight at 40° C. The reaction was concentrated, adsorbed onto a plug of silica gel, and purified by column chromatography, eluting with 0-100% (90:9:1 DCM/MeOH/NH4OH)/DCM, to provide (E)-4-fluoro-N-(6-((3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide as a light-yellow powder (65 mg, 52.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (s, 6H), 1.11 (d, J=6.7 Hz, 6H), 1.54-1.79 (m, 7H), 2.09-2.19 (m, 3H), 2.36 (br. s., 2H), 2.52 (br. s., 1H), 2.59 (br. s., 1H), 2.69-2.84 (m, 2H), 3.55 (br. s., 1H), 3.68 (br. s., 1H), 3.99-4.10 (m, 2H), 4.83 (br. s., 1H), 7.14-7.19 (m, 1H), 7.24 (dd, J=8.9 Hz, 8.9 Hz, 2H), 7.48 (d, J=8.0 Hz, 1H), 7.55-7.66 (m, 2H), 8.32 (dd, J=8.7, 6.0 Hz, 2H), 12.74 (br. s., 1H). MS, m/z (C32H42FN5O3): calcd, 563.3. found, 564.0 [M+H].
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:28])[C@@H:15]([O:24][CH:25]([CH3:27])[CH3:26])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)C1C=CC=CC=1.[OH-].[Li+].Cl.S([O-])([O-])=[O:33].[Na+].[Na+]>O1CCCC1.OO>[OH:23][C:19]1[CH:18]=[C:17]([CH2:16][C@H:15]([O:24][CH:25]([CH3:26])[CH3:27])[C:14]([OH:28])=[O:33])[CH:22]=[CH:21][CH:20]=1
Reactant: O=S([O-])[O-]
Reactant: CC(C)O[C@@H](Cc1cccc(O)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: Cl
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)O[C@@H](Cc1cccc(O)c1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
129.9 g of (4S)-4-benzyl-3-[(2S)-3-(3-hydroxyphenyl)-2-isopropoxypropionyl]-1,3-oxazolidin-2-one was dissolved in 2 L of tetrahydrofuran, to which 140 mL of 30% hydrogen peroxide solution was added. Under cooling with ice, 700 mL of 1N lithium hydroxide solution was added dropwise, followed by stirring at 0° C. for 1 hour. To the reaction mixture was added 1N hydrochloric acid (500 mL), to which a sodium sulfite aqueous solution (10%, 500 mL) was then added slowly. The mixture was poured into a separating funnel to separate a tetrahydrofuran layer, followed by making the aqueous layer at pH 2 with 1N hydrochloric acid before extraction 3 times with ethyl acetate (1 L). The organic layers were combined and washed with a saturated sodium chloride solution (1.5 L) before drying the organic layer with anhydrous magnesium sulfate, followed by distilling off the solvent under a reduced pressure to obtain 130 g of (2S)-3-(3-hydroxyphenyl)-2-isopropoxypropionic acid. This compound was dissolved in 1 L of N,N-dimethylformamide, to which 67.8 g of potassium bicarbonate and 100 mL of ethyl iodide were sequentially added under cooling with ice, followed by stirring the reaction mixture at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, and washed sequentially with 1N hydrochloric acid and a saturated sodium chloride solution. The organic layer was dried with anhydrous magnesium sulfate, followed by distilling off the solvent under a reduced pressure. The residue was purified using silica gel column chromatography to obtain 61.8 g of the title compound in the form of colorless oily matter from a hexane-ethyl acetate (3:1)-eluted fraction.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:16])[C:12]=2[C:13]([OH:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21](S(C)(=O)=O)[N:20]=1.[H-].[Na+]>O1CCCC1>[C:1]1([C:7]2[C:12]([C:13]([OH:15])=[O:14])=[C:11]([O:16][C:21]3[N:22]=[C:23]([O:25][CH3:26])[CH:24]=[C:19]([O:18][CH3:17])[N:20]=3)[CH:10]=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: O=C(O)c1c(O)cccc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OC)nc(Oc2cccc(-c3ccccc3)c2C(=O)O)n1
Yield: 160.8 %

Procedure:
This compound was prepared in a manner analogous to that of Example 5, Step D, using 0.5 gram (0.003 mole) of 6-phenylsalicylic acid, 0.6 gram (0.003 mole) of 4,6-dimethoxy-2-methylsulfonylpyrimidine, and 0.3 gram (0.005 mole) of 50% sodium hydride in mineral oil in 60 mL of tetrahydrofuran. This reaction mixture was combined with a second reaction mixture of 1.7 grams (0.008 mole) of 6-phenylsalicylic acid, 1.7 grams (.008 mole) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.8 gram (0.016 mole) of 50% sodium hydride in mineral oil in 120 mL of tetrahydrofuran. The combination was treated as described in Example 5, Step D, to yield 1.7 grams of 6-phenyl-2-(4,6-dimethoxypyrimidin-2-yloxy)benzoic acid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=1B(O)O>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=1[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][N:7]=1
Reactant: Brc1ccc(CNCCC2CCCCC2)cn1
Reactant: N#Cc1ccc(Cl)c(B(O)O)c1
Product: N#Cc1ccc(Cl)c(-c2ccc(CNCCC3CCCCC3)cn2)c1

Procedure:
Using the procedure outlined in Preparation 13, (6-bromopyridin-3-ylmethyl)-(2-cyclohexylethyl)amine and 2-chloro-5-cyanophenyl boronic acid were converted to the title compound: RT=2.79 min; m/z (ES+)=354.1 [M+H]+.
Reaction SMILES: [C:1]([OH:32])(=O)[CH2:2][CH2:3][C@H:4]([NH:8]C(C1C=CC(NCC2N=C3C(N=C(NC3=O)N)=NC=2)=CC=1)=O)[C:5]([OH:7])=[O:6].CSCC[C@H]([NH:41]C([C@@H](NC(CNC(CNC([C@@H](N)CC1C=CC(O)=CC=1)=O)=O)=O)CC1C=CC=CC=1)=O)C(O)=O>>[NH2:8][C@H:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2][C:1](=[O:32])[NH2:41]
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O
Reactant: Nc1nc2ncc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)nc2c(=O)[nH]1
Product: NC(=O)CC[C@H](N)C(=O)O

Procedure:
from about 0.05 mg to about 0.15 mg of folic acid for coenzymatically converting said neurotransmitter substrate into met-enkephalin.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:11]([O-])=O)=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8].CCOC(C)=O>CCO>[NH2:11][C:3]1[C:2]([OH:1])=[CH:9][C:6]([C:7]#[N:8])=[C:5]([CH3:10])[CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])c(O)cc1C#N
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(N)c(O)cc1C#N
Yield: 98.6 %

Procedure:
5-hydroxy-2-methyl-4-nitrobenzonitrile (D37, 185 mg, 1.04 mmol) was dissolved in EtOH:EtOAc (24 mL, 1:1) and was reduced using an H-Cube (full H2 mode, 25° C., 1 mL/min). The reaction was concentrated by rotary evaporation to give 4-amino-5-hydroxy-2-methylbenzonitrile (D38, 152 mg, 95%) as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([O:24][C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[NH:30][C:29]([CH3:34])=[CH:28]5)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:35][CH3:36])[CH2:7][CH2:6]1)=[O:4].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.[I-].[K+]>CN(C=O)C>[CH3:36][O:35][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:14]=1[O:13][CH2:12][CH2:11][N:8]1[CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH2:2][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:10][CH2:9]1)[N:21]=[CH:20][N:19]=[C:18]2[O:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([CH3:34])=[CH:28]2
Reactant: C1CCNC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCN1CCN(C(=O)CCl)CC1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCN1CCN(C(=O)CN2CCCC2)CC1
Temperature: 80 °C

Procedure:
A mixture of 7-{2-[4-(chloroacetyl)piperazin-1-yl]ethoxy}-6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]quinazoline (0.130 g), pyrrolidine (0.04 ml), potassium iodide (0.01 g) and DMF (3.5 ml) was stirred and heated to 80° C. for 1 hour. The mixture was cooled to ambient temperature, the solvent evaporated under vacuum and the residue was purified by column chromatography on silica using increasingly polar solvent mixtures, starting with dichloromethane and ending with dichloromethane/methanol saturated with ammonia (3.5M) (95/5). Evaporation of the solvents gave a foam, which was triturated under ether to give 6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-{2-[4-(pyrrolidin-1-ylacetyl)piperazin-1-yl]ethoxy}quinazoline (0.09 g) as a pale yellow solid which was collected by filtration and dried under vacuum.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:27]=[CH:26][C:11]([CH2:12][CH:13]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][CH2:30][C:31]1([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:33][CH2:32]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:1]([O:5][C:6]([C:8]1[CH:27]=[CH:26][C:11]([CH2:12][C:13]([CH2:29][CH2:30][C:31]2([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:33][CH2:32]2)([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])=[CH:10][CH:9]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)CC1(CCBr)CC1
Reactant: C=CCOC(=O)C(Cc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)OCC=C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C=CCOC(=O)C(CCC1(CC(=O)OCC)CC1)(Cc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)OCC=C

Procedure:
A solution of 19.85 g (43.4 mmol, purity 81.85%) of diallyl [4-(tert-butoxycarbonyl)benzyl]-malonate, 13.94 g (47.7 mmol, purity 80.5%) of ethyl [1-(2-bromoethyl)cyclopropyl]acetate and 28.56 g (87 mmol) of cesium carbonate in 310 ml of acetonitrile is stirred under reflux for 24 hours. The reaction mixture is then filtered, and the filtrate is concentrated to dryness. The crude product is purified by flash chromatography (3000 g of silica gel 60, mobile phase: cyclohexane/ethyl acetate 20:1). This gives 8 g (35% of theory) of the title compound in the form of a colorless oil.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[N:5][C:6]2[CH2:7][CH2:8][N:9]([C:13]([C@:15]34[CH2:22][C@H:21]([NH:23]C(=O)OC(C)(C)C)[CH2:20][C@H:16]3[O:17][CH2:18][CH2:19]4)=[O:14])[CH2:10][C:11]=2[CH:12]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:23][C@@H:21]1[CH2:20][C@H:16]2[O:17][CH2:18][CH2:19][C@@:15]2([C:13]([N:9]2[CH2:8][CH2:7][C:6]3[N:5]=[CH:4][C:3]([C:2]([F:32])([F:31])[F:1])=[CH:12][C:11]=3[CH2:10]2)=[O:14])[CH2:22]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reaction time: 1 h

Procedure:
To a solution of the product of Step F (12.54 g, 24.8 mmol, 1 eq) in DCM (100 mL) at rt was added TFA (20 mL, 261 mmol, 10.6 eq). After 1 hr, the solution was concentrated. 3 M NaOH was added and the solution extracted with DCM, the organics combined, dried over MgSO4, and concentrated to afford the title compound of Step G. 1H NMR (CHLOROFORM-d) δ: 8.72 (s, 1H), 7.69 (br. s., 1H), 5.07 (d, J=4.9 Hz, 1H), 4.71-4.90 (m, 2H), 3.84-4.03 (m, 3H), 3.58-3.71 (m, 2H), 3.09-3.20 (m, 2H), 2.14-2.41 (m, 3H), 1.99-2.13 (m, 1H), 1.65-1.75 (m, 1H), 1.43-1.58 (m, 1H). Calculated for C17H20F3N3O2: 356.2 (M+1). found: 356.3.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[C:4](=[O:32])[CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7])[CH3:2].N1CC[O:38]CC1>>[O:38]1[CH2:2][CH2:1][N:3]([C:4](=[O:32])[CH:5]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)[C:6]([NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)(=[O:10])=[O:11])=[O:7])[CH2:33][CH2:34]1
Reactant: CCN(CC)C(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Reactant: C1COCCN1
Product: O=C(NS(=O)(=O)c1ccc2ccccc2c1)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)N1CCOCC1

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (500 mg) obtained in Example 6 (4) and morpholine (204 μL). This was purified by silica gel column chromatography to give the title compound (304 mg) as a white powder.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[OH:30]>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[O:30][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: Oc1c(F)cccc1F
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Oc5c(F)cccc5F)nc34)cc21
Temperature: 120 °C
Yield: 54 %

Procedure:
Prepared in a manner similar to that described in Example 79 using 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 61 mg, 0.205 mmol) and 2,6-difluorophenol (133 mg, 1.024 mmol, Aldrich) and heating at 120° C. for 5 min in a microwave (Biotage Initiator). Purification by silica gel (100% DCM to 20% MeOH/DCM) provided 2-(2-(2,6-difluorophenoxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (54% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.51-2.57 (m, 2H) 3.34-3.39 (m, 2H) 6.86 (d, J=2.35 Hz, 1H) 6.91 (br. s., 1H) 7.40-7.47 (m, 2H) 7.48-7.54 (m, 1H) 7.55 (d, J=1.96 Hz, 1H) 7.57 (s, 1H) 7.87 (dd, J=8.02, 0.98 Hz, 1H) 8.11 (dd, J=7.43, 1.17 Hz, 1H) 8.58 (d, J=9.00 Hz, 1H) 10.96 (br. s., 1H). 19F NMR (376 MHz, DMSO-d6) δ ppm −126.54 (2F, s). MS (ESI, pos. ion) m/z: 392.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:4]([OH:6])=[O:5].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].C(=O)(O)[O-].[Na+].O>CN(C=O)C>[C:11]([O:10][C:8]([NH:7][C@@H:3]([CH2:2][NH:1][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])[C:4]([OH:6])=[O:5])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 80 °C
Yield: 62.8 %

Procedure:
To a solution of (S)-3-amino-2-tert-butoxycarbonylamino-propionic acid (Aldrich) (5 g, 24.48 mmol) in DMF (75 mL) was added 1-fluoro-2-nitro-benzene (2.92 mL, 26.93 mmol) and sodium bicarbonate (6.17 g, 73.44 mmol) at RT and the resulting mixture was heated at 80° C. for 18 h under nitrogen atmosphere. Water was added and the aqueous layer was washed with ethyl acetate. The pH of the aqueous solution was adjusted to 3 with the addition of 10% aqueous sodium bisulfate solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give crude mass which was triturated with hexanes to afford (S)-2-tert-butoxycarbonylamino-3-(2-nitro-phenylamino)-propionic acid (5 g, 63%) as an orange yellow solid. LC-MS: 326.2 (M+H).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH:17]=[CH:16][C:15]3[O:14][CH2:13][C:12]([C:18](O)=[O:19])=[CH:11][C:10]=3[C:9]=2[CH:21]=1>>[CH3:1][NH:2][C:18]([C:12]1[CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:8]3[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:21][C:9]=3[C:10]=2[CH:11]=1)=[O:19]
Reactant: CN
Reactant: COc1ccc2ccc3c(c2c1)C=C(C(=O)O)CO3
Product: CNC(=O)C1=Cc2c(ccc3ccc(OC)cc23)OC1

Procedure:
Methylamine, condensed with the compound obtained in Step A of Example 5, yields the title compound.
Reaction SMILES: [CH3:1][N:2]([N:4]=[N:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[Se:8][C:7]=1[C:17]([O:19]CC)=[O:18])[CH3:3].[OH-].[Na+].Cl>CO.O>[CH3:3][N:2]([N:4]=[N:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[Se:8][C:7]=1[C:17]([OH:19])=[O:18])[CH3:1]
Reactant: CCOC(=O)c1[se]c(-c2ccccc2)cc1N=NN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)N=Nc1cc(-c2ccccc2)[se]c1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.4 %

Procedure:
To a solution of ethyl 3-[(dimethylamino)diazenyl]-5-phenylselenophene-2-carboxylate (200 mg, 0.56 mmol) prepared as described in Example 3 step c) in methanol (5 mL) was added a solution of sodium hydroxide (113 mg, 2.84 mmol) in water (3 mL) and stirred at rt for 16 h. The mixture was diluted with ice cold water and acidified with dil. HCl. The mixture was stirred for 30 min and the precipitated solid was filtered, washed with water and dried. The product was recrystallized from hexane-chloroform to give the product as a brown color solid (100 mg, 54%), mp 212-214° C. IR (neat) νmax 3566, 2924, 1700, 1253, 1180, 1113, 1070, 1011, 838, 766 cm−; 1H NMR (400 MHz, CDCl3): δ 12.27 (1H, s, —COOH), 7.79 (1H, s, H-4), 7.55-7.57 (2H, m, Ar—H), 7.34-7.39 (3H, m, Ar—H), 3.65 (3H, s, —N—CH3), 3.25 (3H, s, —N—CH3); 13C NMR (100 MHz, CDCl3): δ 163.9, 155.2, 154.6, 135.5, 129.2, 129.1, 126.3, 124.9, 116.6, 44.4, 37.1; LC-MS (positive ion mode): m/z 346, 344 (M+Na)+.