Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[O:14][CH2:15][CH3:16])C.O1CCCC1.CO.[BH4-].[Li+]>O>[CH2:15]([O:14][C:6]1[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][OH:3])[CH3:16]
Reactant: CCOC(=O)c1cccc([N+](=O)[O-])c1OCC
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1c(CO)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of the compound (117 mg) obtained in Example 417a, tetrahydrofuran (5 ml) and methanol (2 ml), lithium borohydride (10.7 mg) was added. The reaction mixture was stirred at room temperature for 15 h, and, after addition of water, concentrated under reduced pressure. To the resulting residue, 2 N HCl was added and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=1:2) to give the titled compound quantitatively.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:28]4[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.CN(C=O)C.C[Si](C)(C)[C:42]#[C:43][C:44]1([CH3:48])[CH2:47][O:46][CH2:45]1>CCOC(C)=O.[Cu]I.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:34][C:29]1[C:28]([C:12]2[CH:13]=[C:14]3[C@@:15]4([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[N:16]4)[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:42]#[C:43][C:44]5([CH3:48])[CH2:47][O:46][CH2:45]5)[CH:3]=4)[O:8][C:9]3=[CH:10][CH:11]=2)=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: CC1(C#C[Si](C)(C)C)COC1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C#Cc2cnc3c(c2)[C@]2(CSC(NC(=O)OC(C)(C)C)=N2)c2cc(-c4cccnc4F)ccc2O3)COC1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A vial was charged with (5)-tert-butyl 3-bromo-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate (0.181 g, 0.333 mmol), copper(i) iodide (0.013 g, 0.067 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.024 g, 0.033 mmol). The vial was flushed with Ar (g), then DMF (1.665 mL), DIPA (0.712 mL, 5.00 mmol), and trimethyl((3-methyloxetan-3-yl)ethynyl)silane (0.201 mL, 0.999 mmol) were added in sequence. The reaction was heated to 90° C. and stirred for three hours. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel chromatography (gradient elution 0-50% EtOAc:Hex) to afford (S)-tert-butyl 7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate as a yellow solid. MS m/z=559.2. Calc'd for C30H27FN4O4S: 558.62.
Reaction SMILES: [CH2:1]1[CH2:26][O:25][C:3]2([CH2:20][CH2:19][C@@:18]3([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]4[C@:17]3([OH:22])[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][C@H:11]([CH3:24])[C:12]3=O)[CH2:4]2)[O:2]1.[Cl:27][C:28](Cl)(Cl)[C:29]([O:31][CH2:32][CH3:33])=[O:30].[Cl-].C([Al+]CC)C>[Zn].C1(C)C=CC=CC=1.CC(C)=O>[Cl:27]/[C:28](=[C:12]1\[C@@H:11]([CH3:24])[CH2:10][C@@H:9]2[C@:13]\1([CH3:14])[CH2:15][CH2:16][C@@:17]1([OH:22])[C@H:8]2[CH2:7][CH:6]=[C:5]2[C@:18]1([CH3:21])[CH2:19][CH2:20][C:3]1([O:25][CH2:26][CH2:1][O:2]1)[CH2:4]2)/[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: C[C@H]1C[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@@]3(O)CC[C@]2(C)C1=O)OCCO5
Reactant: CCOC(=O)C(Cl)(Cl)Cl
Agent: CC[Al+]CC
Agent: [Cl-]
Agent: [Zn]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(Cl)=C1/[C@@H](C)C[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@@]3(O)CC[C@]12C)OCCO5

Procedure:
Using the procedure of Example 18, 3,3-ethylenedioxy-9α-hydroxy-16β-methylandrost-5-en-17-one (3.60 g) was reacted with ethyl trichloroacetate (2.78 ml) in the presence of zinc dust (2.83 g) and diethylaluminium chloride (20 ml, 1M in hexane). Chromatography (silica gel, toluene/acetone 3/1) of the crude product (3.0 g) afforded the title compound as a single isomer.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][CH3:12])=[CH:9][C:4]=2[N:3]=[CH:2]1.CNCC1C=CC2C(=CC=CC=2)C=1CCC.Cl.[O:30]=[C:31]1[NH:40][C:39]2[N:38]=[CH:37][C:36](/[CH:41]=[CH:42]/[C:43]([OH:45])=O)=[CH:35][C:34]=2[CH2:33][CH2:32]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([CH3:12])[C:43](=[O:45])/[CH:42]=[CH:41]/[C:36]3[CH:37]=[N:38][C:39]4[NH:40][C:31](=[O:30])[CH2:32][CH2:33][C:34]=4[CH:35]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1ccc2[nH]cnc2c1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CN(Cc1ccc2[nH]cnc2c1)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 37 %

Procedure:
According to the procedure of Example 1 (a), except substituting ((1H-benzo[d]imidazol-5-yl)-N-methylmethanamine) for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride. Purification by preparative HPLC (water/acetonitrile/0.05% TFA mixture) gave the title compound ((E)-N-((1H-benzo[d]imidazol-5-yl)methyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide) (143 mg, 37%) as a white solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 10.60 (m, 1H), 8.36 (m, 1H), 8.21 (s, 1H), 8.07 (s, 1H), 7.59-7.21 (m, 4H), 7.12-7.08 (m, 1H), 4.91-4.72 (m, 2H), 3.10-2.86 (m, 5H), 2.55-2.49 (m, 2H); ESI MS m/z 362 [C20H19N5O2+H]+.
Reaction SMILES: S1C=CC=C1[C:6]1[S:10][C:9]([CH:11]=O)=[CH:8][CH:7]=1.[NH2:13][C:14]1[S:15][C:16]([NH2:29])=[C:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[C:30](O)([C:32](F)(F)F)=O>C(O)(C)C>[CH2:22]([O:21][C:19]([C:18]1[C:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:16]([N:29]=[CH:8][C:9]2[S:10][CH:6]=[CH:30][CH:32]=2)[S:15][C:14]=1[N:13]=[CH:11][C:9]1[S:10][CH:6]=[CH:7][CH:8]=1)=[O:20])[CH3:23]
Reactant: O=Cc1ccc(-c2cccs2)s1
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)c1c(N)sc(N)c1C(=O)OCC
Solvent: CC(C)O
Product: CCOC(=O)c1c(N=Cc2cccs2)sc(N=Cc2cccs2)c1C(=O)OCC
Yield: 74 %

Procedure:
This compound can be synthesized either step-wise or one-pot. Step-wise formation was achieved by adding 5-(thiophen-2-yl)thiophene-2-carbaldehyde (30 mg, 0.15 mmol) to diethyl 2,5-diaminothiophene-3,4-dicarboxylate (48 mg, 0.19 mmol) followed by refluxing in isopropanol for 12 hours with a catalytic amount of TFA. The intermediate product was isolated as a yellow powder 3 (50 mg, 1.1 mmol 74%) after purification by flash chromatography. To the resulting product was added 2-thiophene carboxaldehyde (13 mg, 1.2 mmol) in isopropanol with a catalytic amount of TFA. The reaction was refluxed for 12 hours. The title product was isolated as a red colored powder following flash chromatography (37.5 mg, 0.1 mmol, 46%). 1H-NMR (400 MHz, [D] acetone): δ=8.75 (s, 1H), 8.69 (d, 1H, 3J=3.6), 7.86 (d, 1H, 3J=4.96), 7.78 (d, 1H, 3J=2.84), 7.71 (d, 1H, 3J=3.88), 7.59 (dd, 1H, 3J=5.04, 4J=0.76), 7.51 (d, 1H, 3J=3.68), 7.26 (dd, 1H, 3J=3.76, 4J=1.2), 7.17 (dd, 1H, 3J=3.68, 4J=1.36), 4.35 (m, 4H), 1.40 (m, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:13]1([C:10]([C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)=[O:12])[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2cc[nH]c2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 41 %

Procedure:
The title compound is prepared from 1H-indole-6-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 41% of theory; LC (method 4): tR=2.00 min; Mass spectrum (ESI+): m/z=317 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([CH:13]=[CH2:14])[N:10]=[C:9]([N:15]([CH3:17])[CH3:16])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[N:10]=[C:9]([N:15]([CH3:16])[CH3:17])[CH:8]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C=Cc1cc(C(=O)OC(C)(C)C)cc(N(C)C)n1
Agent: [Pd]
Solvent: CO
Product: CCc1cc(C(=O)OC(C)(C)C)cc(N(C)C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-dimethylamino-6-vinyl-isonicotinic acid tert-butyl ester (877 mg, 3.53 mmol) in methanol (15 mL), Pd/C (150 mg, 10% Pd) is added and the mixture is stirred under 2 atm of H2 at rt for 3 h. The catalyst is filtered off and the filtrate is evaporated to give crude 2-dimethylamino-6-ethyl-isonicotinic acid tert-butyl ester; LC-MS: tR=0.76 min, [M+1]+=251.10. This material is dissolved in 6 N aq. HCl (60 mL) and the mixture is stirred at 80° C. for 72 h before the solvent is evaporated. The crude product is purified by MPLC on RP-C18-silica gel to give 2-dimethylamino-6-ethyl-isonicotinic acid (332 mg) as an orange oil, LC-MS: tR=0.51 min, [M+1]+=195.10.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O.[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[N:27][N:28]([C:31]2[C:36]([Cl:37])=[CH:35][C:34](Br)=[CH:33][N:32]=2)[C:29]=1[CH3:30])=[O:24])[CH3:21]>O>[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[N:27][N:28]([C:31]2[C:36]([Cl:37])=[CH:35][C:34]([CH:1]3[CH2:3][CH2:2]3)=[CH:33][N:32]=2)[C:29]=1[CH3:30])=[O:24])[CH3:21]
Reactant: OB(O)C1CC1
Reactant: CCOC(=O)c1cnn(-c2ncc(Br)cc2Cl)c1C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2ncc(C3CC3)cc2Cl)c1C
Temperature: 100 °C
Reaction time: 6 h
Yield: 26.3 %

Procedure:
Cyclopropylboronic acid (269 mg), tripotassium phosphate (1.61 g) and 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (124 mg) were added to a N,N-dimethylformamide solution (15 ml) of 1-(5-bromo-3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.03 g) described in Reference Example 44(2), and the mixture was stirred at 100° C. for six hours. The reaction solution was cooled to room temperature, diluted with water, filtered through Celite and the filtrate was extracted with ethyl acetate three times. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-(3-chloro-5-cyclopropylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (240 mg) as a pale yellow solid.
Reaction SMILES: CO[C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[S:12])[NH:11][C:7]=2[CH:6]=1)=[O:4].Br[CH2:16][CH2:17][CH2:18]Br.Cl.[OH-].[Na+]>C(O)C.CN(C=O)C>[S:12]1[C:10]2[N:11]([C:7]3[C:8]([N:9]=2)=[CH:13][CH:14]=[C:5]([CH2:3][OH:4])[CH:6]=3)[CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1ccc2[nH]c(=S)[nH]c2c1
Reactant: BrCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: OCc1ccc2nc3n(c2c1)CCCS3
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.8 %

Procedure:
To a round bottomed flask was added 4.06 grams of 2-Thioxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester, 4.04 grams of 1,3-dibromopropane and 50 ml DMF and 50 ml ethanol. The mixture was refluxed for 10 hours. Then it was concentrated to dry on a rotary evaporator. The solid was next dissolved in 100 ml THF and 20 ml of 1M LiAlH4 (in THF) was next injected within five minutes. The reaction media was stirred at room temperature for one hour. Ethanol was next added (˜10 ml), followed by 50 ml 2N HCl. The aqueous layer was adjusted to basic Ph=14 with 10N sodium hydroxide. The aqueous was extracted with 2×500 ml ethyl acetate. The combined organic layers was dried over magnesium sulfate. Filter off the drying agent and concentrate yielded 3 grams (68%) product. NMR (DMSO): δ 7.91 (m, 3H), 4.13 (m, 2H), 3.93 (s, 1H), 3.23 (m, 2H, CH2), 2.48 (m, 2H, CH2). MS: 221.0 (M+H).
Reaction SMILES: [O:1]1[C:5]2=[CH:6][CH2:7][CH2:8][CH2:9][CH:4]2[CH2:3][CH:2]1O.[N+](C1C=C([N+]([O-])=O)C=CC=1C([O-])=O)([O-])=[O:12]>CCCCCC.C(O)(C)C>[O:1]1[C@@H:5]2[CH2:6][CH2:7][CH2:8][C@H:9]([OH:12])[C@@H:4]2[CH2:3][CH2:2]1
Reactant: O=C([O-])c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: OC1CC2CCCC=C2O1
Solvent: CC(C)O
Solvent: CCCCCC
Product: O[C@H]1CCC[C@H]2OCC[C@@H]12

Procedure:
Racemic alcohol 12 (70 mg, 0.5 mmol) was dissolved in THF (5 mL), vinyl acetate (120 μL, 1.25 mmol) was added. Amano lipase PS-30 (30 mg) was added and the resulting suspension was stirred at 15-17° C. After 48 h, 30 mg additional enzyme was added and the mixture was left for additional 48 h until which ca. 54% conv. was reached (NMR and GC). The resulting suspension was diluted with Et2O and filtered on celite, the filter cake rinsed with Et2O. After evaporation of the remaining solvent, the residue was purified by column chromatography using hexanes/EtOAc (5:1, 3:1 then 2:1) as the eluent to yield acetyl furanol 13 (38 mg, 41%) and the desired enantioenriched (−)-hexahydrobenzofuranol (−)-12 (24 mg, 35%). The enantiomeric excess of the 2,4-dinitrobenzoate derivative of (−)-12 was determined to be 98.8% ee by chiral HPLC, Column ChiralPak IA, hexane/isopropanol (90/10 to 50/50, 40 min), 1 mL/min, 35° C., λ=254 nm, Rt Major=16.54 min, Rt minor=37.1 min.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[CH:28][C:27]([CH2:30][C:31]([OH:33])=O)=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[C:65]1([NH2:71])[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CN(C=O)C>[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[C:23]4[CH:26]=[C:27]([CH2:30][C:31]([NH:71][C:65]5[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=5)=[O:33])[CH:28]=[CH:29][C:22]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(CC(=O)O)ccc1OCC2
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(CC(=O)Nc3ccccc3)ccc1OCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
To a mixture of [2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-yl]acetic acid trifluoroacetic acid salt from Example 120 (100 mg, 0.21 mmol), HATU (96 mg, 0.25 mmol) and NEt3 (63 mg, 0.63 mmol) in DMF (2 mL) was added a solution of phenylamine (23 mg, 0.25 mmol) in DMF (0.2 mL) and the resulting mixture stirred at RT for 16 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-8% MeOH in DCM) affording 119 as a white solid (51 mg, 57%). LCMS: RT 4.09 min [M+H]+ 429.3. 1H NMR (CDCl3, 400 MHz): δ 8.43 (1H, d, J=2.27 Hz), 7.91 (1H, s), 7.72 (1H, s), 7.47 (2H, d, J=8.02 Hz), 7.43 (1H, s), 7.29-7.26 (2H, m), 7.09-7.06 (2H, m), 5.86-5.85 (1H, m), 4.46-4.45 (4H, m), 3.78 (2H, s), 1.55 (6H, d, J=6.61 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH:7]([CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH2:6]2.ClC1C=CC=C(C(OO)=[O:30])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH:7]([CH2:15][C:16]1[CH:21]=[CH:20][N+:19]([O-:30])=[CH:18][CH:17]=1)[CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)C(Cc1ccncc1)C2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(=O)C(Cc1cc[n+]([O-])cc1)C2
Reaction time: 4 h

Procedure:
4-[(5,6-Dimethoxy-1-indanon-2-yl)methyl]pyridine (1.2 g) was dissolved in methylene chloride (18 ml) and chilled. m-Chloroperbenzoic acid (0.9 g) was added to reaction mixture and then stirred for 4 hours. Reaction mass was stirred with 10% aqueous solution of sodium bicarbonate. The organic layer was separated and washed with 50 ml water. Organic layer was distilled off, title compound is obtained (1.2 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1>CO>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1
Reactant: Nc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CO
Product: Nc1cc([N+](=O)[O-])cnc1N
Temperature: 25 °C
Yield: 80.6 %

Procedure:
To a suspension of 61 (1.617 g, 8.79 mmol) in MeOH (75 mL) was added 20% aq. (NH4)2S (15 mL, 44 mmol) dropwise at room temperature with stirring. The resulting dark-red solution was stirred at room temperature for 0.5 h, then refluxed for 0.5 h, then cooled to room temperature. The resulting mixture was filtered. The filtrate was concentrated to about 30 mL and cooled in ice-water. The precipitate was filtered, washed with cooled EtOH (2×5 mL), and dried to give 1.092 g (80%) of 62 as a deep red powder, mp 260°-2° C.(dec) (Lit., 260° C., Chemical Abstracts 65:3826 (1966)). 1H NMR (DMSO-d6): 5.311 (s, 2H), 6.984 (s, 2H), 7.342 (d, 1H, J=2.2), 8.171 (d, 1H, J=2.2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:12]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.C(Cl)(C(Cl)=O)=O.[CH2:26]([NH2:29])[CH2:27][CH3:28]>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:12]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:10]=[C:6]([C:7]([NH:29][CH2:26][CH2:27][CH3:28])=[O:9])[CH:5]=1
Reactant: CCCN
Reactant: COC(=O)c1cc(C(=O)O)cc(N2CCCC2=O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCNC(=O)c1cc(C(=O)OC)cc(N2CCCC2=O)c1
Reaction time: 1 h
Yield: 17.4 %

Procedure:
A suspension of 5-(2-oxo-pyrrolidin-1-yl)-isophthalic acid monomethyl ester (A75) (200 mg, 76 mmol, 1 equiv) in CH2Cl2 (20 ml) at room temperature was treated with a few drops of DMF followed by (COCl)2 (100 mg, 0.8 mmol, 1.1 equiv). The resulting mixture was stirred for 1 h and then propylamine (140 mg, 2.4 mmol, 3.3 equiv) was added and the resulting solution was stirred for 30 min. The solution was then washed with 2N aqueous HCl solution (30 ml), saturated aqueous NaHCO3 solution (30 ml), dried over MgSO4 and concentrated in vacuo to give 5-(2-oxo-pyrrolidin-1-yl)-N-propyl-isophthalamic acid methyl ester (B77) (127 mg, 55%) as a cream waxy solid.
Reaction SMILES: [NH4+:1].[OH-].Cl[C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=[C:6]([S:15][CH3:16])[N:5]=1>CCO>[NH2:1][C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=[C:6]([S:15][CH3:16])[N:5]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
140 ml of a 20% NH4OH solution was added to a suspension of 50.7 g of ethyl 4-chloro-2-(methylthio)pyrimidin-5-carboxylate in 400 ml of EtOH over 20 minutes, keeping the temperature at about 20° C. After stirring for 20 hours at ambient temperature, the reaction medium was concentrated under vacuum almost to dryness, then the residue was taken up in 350 ml of water, stirred for 20 minutes, filtered, and washed with 3×60 ml of water then vacuum dried in the presence of P2O5. A white solid was obtained: MP=134-135° C., m=39.9 g.
Reaction SMILES: [O:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10](=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:5][C:4]=2[CH:3]=[CH:2]1.[CH3:25][NH:26][CH3:27].[CH2:28]=O>C(O)(=O)C>[CH3:25][N:26]([CH2:28][C:2]1[O:1][C:9]2[CH2:8][CH2:7][N:6]([C:10](=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:5][C:4]=2[CH:3]=1)[CH3:27]
Reactant: C=O
Reactant: CNC
Reactant: O=C(CCCCS(=O)(=O)c1ccccc1)N1CCc2occc2C1
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(C(=O)CCCCS(=O)(=O)c1ccccc1)C2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.230 g (0.662 mmol) of 1-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)-5-phenylsulfonylpentan-1-one in 20 ml of acetic acid, 0.090 ml (0.99 mmol) of 50% aqueous dimethylamine and 0.081 ml (0.99 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 60 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 1N aqueous sodium hydroxide and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform to chloroform/methanol=50/1 to 25/1) to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19]C(OC(C)(C)C)=O)[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][CH:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]2[CH:40]=[N:41][C:42]([C:45]#[N:46])=[CH:43][CH:44]=2)[C:29]([F:32])([F:31])[F:30])[N:3]=1>FC(F)(F)C(O)=O.ClCCl>[NH2:19][C@@H:15]([CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:5]=[C:4]([O:27][CH:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[CH:40]=[N:41][C:42]([C:45]#[N:46])=[CH:43][CH:44]=3)[C:29]([F:32])([F:30])[F:31])[N:3]=[C:2]([NH2:1])[N:7]=2)=[CH:13][CH:12]=1)[C:16]([OH:18])=[O:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(OC(c3ccccc3-c3ccc(C#N)nc3)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccccc2C(Oc2cc(-c3ccc(C[C@H](N)C(=O)O)cc3)nc(N)n2)C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.7 %

Procedure:
80 mg of (S)-3-[4-(2-amino-6-{1-[2-(6-cyanopyridin-3-yl)-phenyl]-2,2,2-trifluoro-ethoxy}-pyrimidin-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid was dissolved in the solution of 30% trifluoro acetic acid in dichloromethane (5 ml). The mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was purified by preparative HPLC to give 12.6 mg of (S)-2-amino-3[4-(2-amino-6-{1-[2-(6-cyano-pyridin-3-yl)-phenyl]-2,2,2-trifluoro-ethoxy}-pyrimidin-4-yl)-phenyl]-propionic acid. 1H NMR (400 MHz, CD3OD) δ (ppm) 8.86(s, 1H), 8.17(d, J=2 Hz, 1H), 8.15(d, J=2 Hz, 1H), 7.96(m,2H), 7.59(m,1H), 7.36(m, 3H), 6.7(s, 1H), 6.65(d, J=6.8 Hz, 1H), 4.25(m, 1H), 3.47(m, 1H), 3.23(m, 1H).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:7][C:8](=[O:10])[CH:9]=1)=[O:6])[CH2:2][CH3:3].C(C1CC(=O)OC1=O)=CC>>[CH2:1]([CH:4]1[CH2:9][C:8](=[O:10])[O:7][C:5]1=[O:6])[CH:2]=[CH2:3]
Reactant: CCCC1=CC(=O)OC1=O
Agent: CC=CC1CC(=O)OC1=O
Product: C=CCC1CC(=O)OC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
After 60 minutes, the reaction product was allowed to cool to room temperature, and gas chromatographic analysis of the product confirmed a product distribution of 34.7% propyl maleic anhydride and the balance propenyl succinic anhydride.