Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C@H:19]([CH3:23])[C:20]([OH:22])=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[C:40]1([C:46]2([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C@H:54]3[C@H:50]([CH2:51][NH:52][CH2:53]3)[C:49](=[O:55])[CH2:48][CH2:47]2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:56]1([C:46]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@H:54]3[C@H:50]([CH2:51][N:52]([C:20](=[O:22])[C@H:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[O:12][CH3:11])[CH3:23])[CH2:53]3)[C:49](=[O:55])[CH2:48][CH2:47]2)[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: COc1ccccc1[C@H](C)C(=O)O
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 1 h
Yield: 63.6 %

Procedure:
1-Hydroxybenzotriazole (0.59 g) is added to a solution of (S)-2-[2-methoxyphenyl]propionic acid (0.75 g) of 84% optical purity prepared by the method of T. Matsumoto et al: Bull. Chem. Soc. Jpn., 58, 340 (1985), in dry dimethylformamide (15 cc) and the solution is then cooled to 0° C. N,N'-Dicyclohexylcarbodiimide (0.91 g) is added, the mixture is stirred for 1 hour at this temperature and a solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.44 g) and N,N-diisopropylethylamine (0.76 cc) in dimethylformamide (10 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, diluted with ethyl acetate (100 cc) and concentrated to dryness under reduced pressure (2.7 kPa) after filtering off the precipitate. The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 3 cm, height 40 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (50/50 by volume) and collecting 125 cc fractions. Fractions 4 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by dissolving in boiling isopropyl ether (60 cc) to which hexane (30 cc) had been added. The cooled solution is filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give (3aR,7aR)-7,7-diphenyl-2-[(S)-2-(2-methoxyphenyl)propionyl]-4-perhydroisoindolone (1.2 g) in the form of a white meringue containing 10% of (3aR,7aR)-7,7-diphenyl-2-[(R)-2-(2-methoxyphenyl)propionyl]-4-perhydroisoindolone; [α]D20 =-181° (c=0.81, chloroform).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH3:15])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:16]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C=O)C>[CH:16]1([NH:21][C:2]2[C:3]3[N:4]([C:12]([CH3:15])=[N:13][N:14]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC1CCCC1
Reactant: Cc1nnc2c(Cl)nc3ccccc3n12
Solvent: CN(C)C=O
Product: Cc1nnc2c(NC3CCCC3)nc3ccccc3n12
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.2 %

Procedure:
A reaction mixture of 4-chloro-1-methyl[1,2,4]triazolo[4,3-a]quinoxaline (1.0 g; 0.004 mole) and cyclopentanamine (1.17 g; 0.013 mole) in 15 ml of DMF was stirred at room temperature for 20 hours. The reaction mixture was poured over ice-water and the precipitated solid was filtered, washed with water and dried affording 0.9 g (74%) of N-cyclopentyl-1methyl-[1,2,4]triazolo[4,3-a]quinoxalin-4-amine having a mp of 196°-198° C.
Reaction SMILES: [CH2:1]([NH2:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:7](Cl)(=[O:9])[CH3:8].C(N(CC)CC)C.C(Cl)Cl>O>[CH2:1]([NH:6][C:7](=[O:9])[CH3:8])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)CN
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCC(C)(C)C
Yield: 97.6 %

Procedure:
A solution of neopentylamine (2.0 g, 23.0 mmol), acetyl chloride (1.96 mL, 27.6 mmol), triethylamine (3.84 mL, 27.5 mmol), and DCM (100 mL) were stirred at room temp for 2 h. The mixture was poured into water and extracted with DCM (3×40 mL). The organic phase was dried over Na2SO4, and the solvent was removed to afford N-neopentylacetamide as white solid (2.90 g, 98%). NMR confirmed the structure of N-neopentylacetamide.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)[CH2:2]1.[NH2:15][C:16]1[C:17]([C:24]([NH:26][CH2:27][CH2:28][NH2:29])=[O:25])=[N:18][C:19]([Cl:23])=[C:20]([NH2:22])[N:21]=1.C(O)(C)C.[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36]>CO>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[NH2:15][C:16]1[C:17]([C:24]([NH:26][CH2:27][CH2:28][NH:29][CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)=[O:25])=[N:18][C:19]([Cl:23])=[C:20]([NH2:22])[N:21]=1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Reactant: NCCNC(=O)c1nc(Cl)c(N)nc1N
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CC(C)O
Product: Nc1nc(N)c(C(=O)NCCNCC(O)COc2cccc3[nH]ccc23)nc1Cl

Procedure:
A mixture of 1,2-epoxy-3-(indol-4-yloxy)propane (0.67 g.), 3,5-diamino-6-chloro-N-(2-aminoethyl)pyrazine-2-carboxamide (1.63 g.) and isopropanol (50 ml.) were refluxed together under nitrogen until thin layer chromatography indicated all of the epoxy compound had reacted (about 3 hours). The solvent was removed by rotary evaporator and the resulting yellow solid was chromatographed on silica gel with a 5:1 mixture of chloroform:methanol to give 1.03 g. of product. This material was dissolved in methanol (110 ml.) with warming and the solution was added to oxalic acid (1 equivalent) in methanol (20 ml.). Upon concentration and cooling of the solution, there was obtained 3,5-diamino-6-chloro-N-2-(2-hydroxy-3-indol-4-yloxy-propylamino)ethyl-pyrazine-2-carboxamide oxalate, m.p. 214°-216° C. with decomposition.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH:11](=[O:18])C1C=CC=CC=1.N1CCCC1>CO>[O:18]1[C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3](=[O:4])[CH2:2][CH2:11]1
Reactant: O=C(CO)c1ccccc1
Reactant: O=Cc1ccccc1
Solvent: CO
Solvent: C1CCNC1
Product: O=C1CCOc2ccccc21
Temperature: 50 °C

Procedure:
2-Hydroxyacetophenone compounds of structure XXXXI are treated with benzaldehyde compounds of structure XXXXII under suitable conditions to provide chroman-4-one compounds of structure XXXXIII. In some embodiments, 2-hydroxyacetophenone compounds of structure XXXXI are treated with benzaldehyde compounds of structure XXXXII, pyrrolidine, and methanol, with heating to about 50° C. for about 2 days to provide chroman-4-one compounds of structure XXXXIII. Chroman-4-one compounds of structure XXXXIII are then reacted tris(dibenzylideneacetone)dipalladium(0), tri-tert-butylphosphonium tetrafluoroborate, potassium bicarbonate, a suitable arylbromide, and 1,4-dioxane/water (4:1,) at about 110° C. to provide chroman-4-one compounds of structure XXXXIV. Chroman-4-one compounds of structure XXXXIV are then treated with methyl magnesium chloride in tetrahydrofuran at about 0° C., followed by 80% AcOH/H2O with warming to about 90° C. to provide compounds of structure XXXXV.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:22][CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CSc1ccc(O)cc1
Reactant: CCC(CC)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CSc1ccc(OCC(CC)CC)cc1
Temperature: 25 °C

Procedure:
To stirred solution of (4-Hydroxy-phenylsulfanyl)-acetic acid ethyl ester (2.12 g, 10 mmol), K2CO3 (anhydrous, 10 g) and 1-bromo-2-ethyl butane (3 g, excess) was added in boiling acetone. The reaction mixture was refluxed for 24 hrs and cooled to room temperature. The reaction mixture was filtered and concentrated. The residue obtained was extracted with chloroform; washed well with water and concentrated. The crude product obtained was taken to next step without purification. Yield 2.8 g (94%); (M+H)+ 297.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[CH2:28]C[CH2:26]3)=[O:24])=[CH:19][CH:18]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].BrC1C=CC(C(N(C)C)=O)=C([F:41])C=1.COC(C1C=C(O)C2CC(C)(C)OC=2C=1)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:24])[N:25]([CH3:28])[CH3:26])=[C:19]([F:41])[CH:18]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1ccc(Br)cc1F
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2)c2c(c1)OC(C)(C)C2
Agent: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Product: COC(=O)c1cc(Oc2ccc(C(=O)N(C)C)c(F)c2)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 35b, from 4-bromo-2-fluoro-N,N-dimethyl-benzamide (589 mg, 2.65 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (652 mg, 2.65 mmol) to give a white solid (861 mg, 84% yield). 1H NMR (400 MHz, CDCl3) δ 7.33-7.43 (m, 1 H) 7.25 (s, 1 H) 7.22 (s, 1 H) 6.75-6.84 (m, 1 H) 6.66-6.73 (m, 1 H) 3.88 (s, 3 H) 3.13 (s, 3 H) 2.98 (s, 3 H) 2.90 (s, 2 H) 1.49 (s, 6 H); LCMS for C21H22FNO5 m/z 388.00 (M+H)+.
Reaction SMILES: C(O)C(N)(CO)CO.Cl.N[C@H:11]([C:19]([OH:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:19]([OH:21])(=[O:20])[CH:11]=[CH:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: NC(CO)(CO)CO
Product: O=C(O)C=Cc1ccccc1
Reaction time: 0.33 h

Procedure:
First, cells were recovered from the culture by centrifugation. The collected cells were washed by suspending them in a 0.85% sodium chloride solution and recovered by centrifugation. The washed cells were then suspended in a 25 mM Tris-HCl buffer solution (pH 8.8) to give a cell concentration of about 1% by wet weight. The suspension was added to an enzymatic reaction medium comprising a 25 mM Tris-HCl buffer solution (pH 8.8) supplemented with 25 mM L-phenylalanine and 0.005% cetyl pyridium hydrochloride. The resultant reaction medium was incubated at 30° C. for 20 minutes. After the reaction was terminated by addition of 1N HCl, cinnamic acid formed in the reaction mixture was analyzed by liquid chromatography to estimate the PAL activity. One unit (U) as defined herein corresponds to the amount of enzyme to produce one micromole of cinnamic acid per minute.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=1)([O-:30])=[O:29].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:24][C:22]([F:25])([F:23])[C:19]1[CH:20]=[CH:21][C:16]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:26])[F:27])=[CH:8][CH:7]=2)=[C:10]2[CH2:15][CH2:14][N:13]([CH2:37][C:34]3[CH:35]=[CH:36][C:31]([N+:28]([O-:30])=[O:29])=[CH:32][CH:33]=3)[CH2:12][CH2:11]2)=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: FC(F)(F)c1ccc(C(=C2CCNCC2)c2ccc(C(F)(F)F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(CN2CCC(=C(c3ccc(C(F)(F)F)cc3)c3ccc(C(F)(F)F)cc3)CC2)cc1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
A stirred mixture of 3.8 grams (0.010 mole) of 4-{bis[4-(trifluoromethyl)phenyl]methylene}piperidine, 2.2 grams (0.010 mole) of 4-nitrophenylmethyl bromide, and 1.7 grams (0.012 mole) of potassium carbonate in about 20 mL of ethanol was warmed to 75° C., where it stirred for about 18 hours. After this time, an additional 0.2 gram (0.001 mole) of 4-nitrophenylmethyl bromide and an additional 0.2 gram (0.001 mole) of potassium carbonate was added to the reaction mixture. The reaction mixture was again heated to 75° C., where it stirred for about eight hours. After this time, the reaction mixture was cooled and filtered to remove excess potassium carbonate. The reaction mixture was then taken up in acetic acid, and 0.2 gram (catalyst) of 5% platinum on carbon was added to the mixture in preparation for the following hydrogenation step. A quantitative yield of the subject compound was assumed.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>ClCCl>[CH3:21][S:22]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)(=[O:24])=[O:23]
Reactant: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4)c2n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4S(C)(=O)=O)c2n1

Procedure:
A solution of 3-(2,3-dihydro-1H-indol-5-yl)-5-vinyl-3H-imidazo[4,5-b]pyridine (2.53 g, 9.64 mmol) (Intermediate 10.1), methanesulfonyl chloride (1.12 ml, 14.47 mmol), and triethylamine (2.94 ml, 21.22 mmol) in dichloromethane (50 ml) is stirred for 30 min at ambient temperature. The mixture is successively extracted with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. The organic layer is dried over sodium sulfate and concentrated in vacuo to render 3.24 g (99%) of the respective sulfonamide. HPLC (over 10 min 10-85% MeCN/100 mM aq. NaOAc): 92% purity, tR 7.16 min (tR(SM) 6.64 min). MS (ESI) m/z (C17H16N4O2S) 341.1 (M+1, 100) Finnegan LCQ.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F:10][CH2:11][C@@H:12]1[C@@H:16]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:25])=O)=[CH:19][CH:18]=2)[O:15][C:14]([CH3:27])([CH3:26])[N:13]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(=O)(O)[O-].[Na+]>ClCCl.[Sb](Cl)(Cl)Cl>[F:10][CH2:11][C@@H:12]1[C@@H:16]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH2:25][F:7])=[CH:19][CH:18]=2)[O:15][C:14]([CH3:27])([CH3:26])[N:13]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: CCN(CC)S(F)(F)F
Reactant: CS(=O)c1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]2CF)cc1
Agent: Cl[Sb](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(SCF)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
A solution of diethylamino sulfurtrifluoride (DAST), (9.34 g, 1.75 eq) in 10 ml of dichloromethane was added drop wise to the solution of 14 (12.3 g) and antimony (III) chloride (0.23 g, 0.03 eq) in 150 ml of dichloromethane (anhydrous) at −5° C., and the reaction mixture was warmed up to room temperature overnight. A cold saturated solution of sodium bicarbonate (80 ml) was added and stirred for 30 min and extracted with dichloromethane (100 ml×2). The organic layer was washed with a 10% solution of sodium bicarbonate and with brine (50 ml) and dried over sodium sulfate. After purification, via a column, 10.7 g of the desired product (as a heavy oil) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].CCN(CC)CC>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:11]([C:14]2[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(Br)ccc1O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(Br)ccc1OS(=O)(=O)c1ccc(C)cc1
Yield: 99.7 %

Procedure:
Dissolve 4-bromo-2-methoxy-phenol (1.032 g, 5.08 mmol) in CH2Cl2 (10 mL), and treat with TsCl (0.969 g, 5.08 mmol) followed by Et3N (1.06 mL, 7.62 mmol). Stir the reaction at RT for 2 h. Dilute with EtOAc (100 mL) and wash with water (2×30 mL). Dry with Na2SO4, filter, and concentrate to give 1.81 g (100%) of the title compound. MS/ES m/z (81Br) 380.9 [M+Na]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:18]O>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([O:7][CH3:18])=[O:6]
Reactant: CO
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(N)cc([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of 3-amino-5-nitrobenzoic acid 10.3 g (56.6 mmol) in methanol (100 mL) was added thionyl chloride 6.5 mL (89 mmol) dropwise under ice-cooing, and the mixture was stirred at 70° C. for 4 hours. The solvent was evaporated and thereto was added water and the mixture was extracted three times with ethyl acetate (100 mL). The organic layer was washed with an aqueous saturated sodium bicarbonate solution and dried on magnesium sulfate, filtered and concentrated to give 11.0 g (56.1 mmol) of methyl 3-amino-5-nitrobenzoate as a brown solid (yield: 99%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]2[CH:13]=[CH:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:7]=2[N:8]=[CH:9][N:10]=1)=O.[NH2:24][C:25]([NH2:27])=[S:26]>CC(C)=O>[C:20]1([CH3:23])[CH:21]=[CH:22][C:17]([S:14]([N:11]2[C:7]3[N:8]=[CH:9][N:10]=[C:5]([C:3]4[N:24]=[C:25]([NH2:27])[S:26][CH:2]=4)[C:6]=3[CH:13]=[CH:12]2)(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(=O)CBr)ncnc32)cc1
Reactant: NC(N)=S
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4csc(N)n4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
Into 75 mL of acetone was successively added [4.2 g, 10.65 mmol] of 2-Bromo-1-[7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-ethanone followed by [0.81 g, 10.65 mmol] of thiourea. The reaction was then stirred for 4.0 hours at ambient temperature. The pale yellow precipitate was collected via suction filtration and washed with more acetone. The crude cake was suspended into 20 mL of triethylamine and stirred for one hour. The material was then diluted with water and suction filtered to isolate the solid. The damp cake was triturated with acetonitrile, the solid isolated again via suction filtration and airdried. The beige solid, 2.6 g, represents a 72% yield of the free base.
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][C:23]1[N:24]=[CH:25][C:26]([C:29]([OH:31])=O)=[N:27][CH:28]=1)=[O:21].[CH2:32]1[C:40]2[C:35](=[CH:36]C=CC=2)[CH2:34][N:33]1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH3:34][CH:35]([CH3:36])[CH2:40][CH2:32][NH:33][C:29]([C:26]1[N:27]=[CH:28][C:23]([NH:22][C:20]([N:12]2[CH2:11][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:21])=[N:24][CH:25]=1)=[O:31]
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: O=C(O)c1cnc(NC(=O)N2Cc3ccccc3C2)cn1
Agent: NCCCc1ccccc1
Product: CC(C)CCNC(=O)c1cnc(NC(=O)N2Cc3ccccc3C2)cn1

Procedure:
The title compound was prepared as described in Example 1C, substituting 3-methylbutan-1-amine for 3-phenylpropan-1-amine and 5-(isoindoline-2-carboxamido)pyrazine-2-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6, Temp=90° C.) δ ppm 9.34 (bs, 1H), 9.17 (d, J=1.4 Hz, 1H), 8.82 (d, J=1.4 Hz, 1H), 8.30-8.23 (m, 1H), 7.36-7.26 (m, 4H), 4.86 (bs, 4H), 3.37-3.30 (m, 2H), 1.69-1.58 (m, 1H), 1.50-1.44 (m, 2H), 0.92 (d, J=6.5 Hz, 6H); MS (ESI(+)) m/e 354 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[S:15][C:16]([C:20]([OH:22])=O)=[C:17]([CH3:19])[N:18]=3)[C:10](=[O:23])[CH:9]=2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:20]([C:16]2[S:15][C:14]([N:11]3[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:25][CH:24]=4)=[CH:9][C:10]3=[O:23])=[N:18][C:17]=2[CH3:19])=[O:22])=[CH:29][CH:28]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1nc(-n2ccc(OCc3ccc(F)cc3)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(OCc3ccc(F)cc3)cc2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 34 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-(4-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with (4-fluorophenyl)methanamine, the title compound was obtained as a colorless solid in 34% yield: mp 249-251° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 8.78 (t, J=5.9 Hz, 1H), 8.60 (d, J=8.1 Hz, 1H), 7.51-7.47 (m, 2H), 7.34-7.29 (m, 2H), 7.25-7.08 (m, 4H), 6.37 (dd, J=8.1, 2.7 Hz, 1H), 6.23 (d, J=2.7 Hz, 1H), 5.14 (s, 2H), 4.35 (d, J=5.9 Hz, 2H), 2.53 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.4, 164.1, 163.2, 161.9, 160.9, 153.9, 150.4, 136.1, 132.1, 131.0, 130.9, 129.8, 123.6, 116.0, 115.7, 104.3, 97.5, 70.1, 42.4, 17.5; MS (ES+) m/z 468.3 (M+1).
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=1.IC>C1COCC1>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([CH3:2])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:15]=1
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
To a solution of LDA (8.66 mL, 2M in heptane/THF/ethylbenzene, 17.3 mmol) in 30 mL THF at −78° C., was added a solution of ethyl 4-bromophenylacetate (4.00 g, 16.5 mmol) in 20 mL THF. The mixture was stirred at −78° C. for 30 min, then a solution of iodomethane (10.7 mL, 2M in methyl tert-butyl ether, 21.5 mmol) was added. The mixture was stirred for 10 min at −78° C., then was removed from the cooling bath and stirred for 30 min. The reaction was quenched with sat. NH4Cl, then diluted with EtOAc. The organic phase washed with water, sat. Na2SO3 and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 10% EtOAc/hexanes gradient) to afford 3.07 g of 73A as a colorless oil. MS (ESI) m/z 257.1, 259.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]2([CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]2)[O:3]1.[H-].[Na+].[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)CCCC>[CH3:10][C:7]1[CH2:8][CH2:9][C:4]([C:2]([CH3:11])([S:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:1])([OH:3])[CH2:5][CH:6]=1
Reactant: CC1=CCC2(CC1)OC2(C)C
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCO
Product: CC1=CCC(O)(C(C)(C)Sc2ccccc2)CC1
Yield: 52.7 %

Procedure:
To a stirred solution of 76 g of 2,2,6-trimethyl-1-oxaspiro(2.5)oct-5-ene in 300 ml of n-pentanol were added 2.0 g of 60% sodium hydride and 60 g of thiophenol. After 18 hours reflux, the mixture was vacuum concentrated at 90°-95° C. The residue was dissolved in methylene chloride and washed twice with 2N sodium hydroxide. The dried solution was Claisen-distilled to give 106 g of crude product, b.p. 120°-125° C. Recrystallization from 250 ml of hexane gave 69.1 g of the desired product, m.p. 73°-74° C.
Reaction SMILES: O[C:2]1([CH:14]=O)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][CH2:3]1.C(O[C:21](=[O:32])[NH:22][CH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH:30]=[O:31])[CH2:25][CH2:24]1)(C)(C)C.[O:33]=[C:34]1[NH:39][C:38]2[CH:40]=[C:41](C(O)=O)[CH:42]=[CH:43][C:37]=2[O:36][CH2:35]1>>[CH3:13][O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]1[O:31][CH2:30][CH:29]([CH:26]3[CH2:25][CH2:24][CH:23]([NH:22][C:21]([C:41]4[CH:42]=[CH:43][C:37]5[O:36][CH2:35][C:34](=[O:33])[NH:39][C:38]=5[CH:40]=4)=[O:32])[CH2:28][CH2:27]3)[CH2:14][C:2]2=1
Reactant: CC(C)(C)OC(=O)NC1CCC(CC=O)CC1
Reactant: O=C1COc2ccc(C(=O)O)cc2N1
Reactant: COc1ccc2c(n1)C(O)(C=O)CC=N2
Product: COc1ccc2ncc3c(c2n1)CC(C1CCC(NC(=O)c2ccc4c(c2)NC(=O)CO4)CC1)CO3

Procedure:
The titled compound is prepared as a white lyophilizated powder following Scheme 6 and in analogy to Example 15 using 4-hydroxy-6-methoxy-[1,5]naphthyridine-4-carbaldehyde, [4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid as starting materials.