Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[C:19]3[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].I[CH:27]([CH3:29])[CH3:28]>CN(C=O)C>[CH:27]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:21])[F:22])[C:11]([C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:10])=[N:12]1)([CH3:29])[CH3:28]
Reactant: CC(C)I
Reactant: COc1cccc(C(=O)c2n[nH]c3c(C(F)(F)F)cccc23)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)c2nn(C(C)C)c3c(C(F)(F)F)cccc23)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 59.4 %

Procedure:
To a solution of [3-(methoxy)phenyl](7-trifluoromethyl-1H-indazol-3-yl)methanone (0.27 g, 0.85 mmol) in 5 mL DMF was added in one portion sodium hydride (0.034 g, 0.85 mmol, 60% in oil). After the gas evolution ceased, 2-iodopropane (0.10 mL, 1.0 mmol) was added and the reaction was stirred at ambient to 50° C. for 24 hours. The cool reaction mixture was partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried (Na2SO4). Removal of the solvent in vacuo afforded the crude product which was purified by flash chromatography (silica gel, hexane/EtOAc, 9:1) to give the title compound (0.183 g) as an oil.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][CH2:12][C:13]#[N:14])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl>[Pd].C(O)C>[N:1]1([CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: N#CCCCn1cnc2ccccc21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCCCCn1cnc2ccccc21
Reaction time: 48 h

Procedure:
A solution was prepared from 8.9 grams of the nitrile and 150 ml of absolute ethanol, 0.8 grams of palladium on charcoal and 8 ml of concentrated hydrochloric acid were added, and the resulting mixture was hydrogenated at room temperature and pressure for 48 hours. The reaction mixture was then filtered, the solvent was evaporated from the filtrate, and the residue was treated with aqueous 2 N sodium hydroxide solution and extracted with chloroform. The chloroform solution was dried and then distilled to give 1H-benzimidazole-1-butanamine boiling at about 180°-186° C. at 1.2 mm pressure.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[C:4]1([CH3:19])[CH2:13][C:12](=[O:14])[C:11]2[C:6](=[C:7]([CH3:18])[C:8]([CH3:17])=[C:9]([OH:16])[C:10]=2[CH3:15])[O:5]1.[BH4-].[Na+].[OH-].[Na+].Cl>CO>[CH3:21][O:20][CH:3]([O:2][CH3:1])[C:4]1([CH3:19])[CH2:13][CH:12]([OH:14])[C:11]2[C:6](=[C:7]([CH3:18])[C:8]([CH3:17])=[C:9]([OH:16])[C:10]=2[CH3:15])[O:5]1
Reactant: COC(OC)C1(C)CC(=O)c2c(C)c(O)c(C)c(C)c2O1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(OC)C1(C)CC(O)c2c(C)c(O)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
9.4 g (32 mmoles) of the product from Example 2 were reacted with 2.43 g (64 mmoles) NaBH4 in 100 ml of methanol at 20°-60° C. After 6 hours, a further 2.43 g of NaBH4 were added, after which the reaction mixture was stirred at room temperature for 16 hours. 100 ml of 3N NaOH were then added, and the mixture was neutralized with dilute hydrochloric acid and then extracted with ether, a brown oil being obtained as the crude product in 95% yield. IR: 3,600 (broad) cm-1.
Reaction SMILES: N1[CH:6]=[C:5]([O:7][C:8]2[CH2:12][CH2:11][O:10][N:9]=2)[CH:4]=[N:3][CH:2]=1.Cl[C:14]1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[N:3]1[CH:2]=[CH:14][CH:6]=[C:5]([O:7][C:8]2[CH2:12][CH2:11][O:10][N:9]=2)[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ncc(OC2=NOCC2)cn1
Solvent: ClCCl
Product: c1cncc(OC2=NOCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Racemic 3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-132 was dissolved in methylene chloride (0.5 M with respect to isoxazole) after which point m-chloroperbenzoic acid (2.0 equiv) was added in 1 portion and the reaction was allowed to stir at room temperature for 1 h. After the reaction was determined to be complete by LC/MS, the solvent was evaporated. The crude mixture was then redissolved in tert-butylmethyl ether (0.5 M) after which hexane was slowly added until a solid precipitated. The solid was then collected via vacuum filtration and washed with 1:1 hexanes/tert-butylmethyl ether to provide the desired 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-133a and I-133b as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=404.1 m/z. Activity: A
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[C:13](F)=[C:12]([C:15]([OH:17])=[O:16])[S:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.[Na]>>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[S:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1snc(-c2cccc(C(F)(F)F)c2)c1F
Agent: [Na]
Product: O=C(O)c1cc(-c2cccc(C(F)(F)F)c2)ns1

Procedure:
3-(3-trifluoromethylphenyl)-4-fluoro-5-isothiazolecarboxylic acid, sodium salt
Reaction SMILES: C(OC(=O)[O:5][C:6]1[C:15]2[N:14]=[CH:13][CH:12]=[N:11][C:10]=2[C:9]([O:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]2[C:30](=[O:42])[N:31]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:32](=[O:33])[C:7]=12)C.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C1C=CN=CC=1)C.O>[CH:17]([O:16][C:9]1[C:10]2[N:11]=[CH:12][CH:13]=[N:14][C:15]=2[C:6]([OH:5])=[C:7]2[C:32](=[O:33])[N:31]([CH2:34][C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[C:30](=[O:42])[C:8]=12)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)Oc1c2c(c(OC(c3ccccc3)c3ccccc3)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2c(c(OC(c3ccccc3)c3ccccc3)c3nccnc3c2O)C(=O)N1Cc1ccc(F)cc1
Reaction time: 18 h
Yield: 94.3 %

Procedure:
Carbonic acid 9-benzhydryloxy-7-(4-fluoro-benzyl)-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoxalin-5-yl ester ethyl ester 244 (500 mg, 0.87 mmol) was dissolved in THF (9 mL, 0.1 M) along with DMAP (211 mg, 1.73 mmol, 2 equiv.). A solution of K2CO3 (1.20 g, 8.66 mmol, and 10 equiv.) was dissolved separately in H2O (6 mL) before being transferred to the reaction mixture. The reaction was allowed to stir for 18 hours and quenched with HCl (20 mL, 1 N) and extracted with ethyl acetate (2×30 mL). The organic layer was washed with saturated NH4Cl solution (25 mL), brine solution (25 mL) and dried over Na2SO4 and concentrated in vacuo to yield 5-benzhydryloxy-7-(4-fluoro-benzyl)-9-hydroxy-pyrrolo[3,4-g]quinoxaline-6,8-dione 245 (94%, 413 mg, 0.82 mmol). 1H NMR (300 MHz) CDCl3 δ 9.08 (d, J=1.5 Hz, 1 H), 8.92 (d, J=1.5 Hz, 1H), 7.67 (s, 1 H), 7.67-7.42 (dd, J1=1.5 Hz, J2=8.4 Hz, 4 H), 7.43-7.48 (m, 2 H), 7.19-7.27 (m, 7 H), 7.03-7.20 (m, 1 H), 4.86 (s, 2 H). MS: 528.0 (M+23). TLC Rf: 0.2 Hexanes/Ethyl acetate (8/2)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:16]([C:17]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:15][CH2:14][CH2:13][CH:12]2[C:24]2[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=2)=[C:6]([N+:31]([O-])=O)[CH:5]=1>CO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:12]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:13][CH2:14][CH2:15][CH:16]2[C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)=[C:6]([NH2:31])[CH:5]=1
Reactant: COC(=O)c1ccc(CN2C(c3ncccc3C)CCCC2c2ncccc2C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN2C(c3ncccc3C)CCCC2c2ncccc2C)c(N)c1
Yield: 69 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.829 g, 3.10 mmol), 4-bromomethyl-3-nitrobenzoic acid methyl ester (1.26 g, 4.61 mmol), KI (115 mg, 0.69 mmol), and DIPEA (1.20 mL, 6.89 mmol) in DMF (16 mL) was heated at 60° C. for 18 hours. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) provided 1.40 g (98%) of 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-3-nitro-benzoic acid methyl ester as a tan solid. To a solution of 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-3-nitro-benzoic acid methyl ester (1.40 g, 3.03 mmol) in MeOH (15 mL) and EtOAc (15 mL) was added palladium (50% wet with water), 10 wt. % on activated carbon (0.30 g). The resultant mixture was hydrogenated at 30 psi on a Parr shaker for 3 hours. The mixture was vacuum filtered through celite and the cake was washed with MeOH and EtOAc. The solvent was removed from the filtrate under reduced pressure and the thus obtained oil was purified by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) and provided 0.90 g (69%) of 3-amino-4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:3]1[CH2:17][C:18]([O:20]C)=[O:19].[Li+].[OH-].O.Cl>C1COCC1.O>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C:13]([F:15])([F:14])[F:16])[CH:8]=2)[N:3]1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: COC(=O)Cn1c(=O)ccc2cc(OC(F)(F)F)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cn1c(=O)ccc2cc(OC(F)(F)F)ccc21
Reaction time: 8 h

Procedure:
To a stirring solution of methyl 2-(2-oxo-6-(trifluoromethoxy)quinolin-1(2H)-yl)acetate (1.2 mmol) in THF/water (2:1) was added LiOH. H2O (8.1 mmol). The resulting mixture was stirred overnight. The crude product mixture was slowly acidified with 1N HCl solution and then extracted with EtOAc. The organic phase was separated, dried (MgSO4), filtered and concentrated under vacuum to give 2-(2-oxo-6-(trifluoromethoxy)quinolin-1(2H)-yl)acetic acid. Retention time (min)=1.783, method [1], MS(ESI) 288.1 (M+H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.[Br:40][C:41]1[CH:42]=[C:43]([CH:47]=[C:48]([N+:50]([O-:52])=[O:51])[CH:49]=1)[C:44](O)=[O:45]>CN(C=O)C.C(OCC)(=O)C>[Br:40][C:41]1[CH:42]=[C:43]([C:44]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:45])[CH:47]=[C:48]([N+:50]([O-:52])=[O:51])[CH:49]=1
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Br)cc([N+](=O)[O-])c1)N1CCOCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
HATU (927 mg, 2.44 mmol), morpholine (0.212 mL, 2.44 mmol), and diisopropylethylamine (0.532 mL, 3.05 mmol) were added sequentially to a solution of 3-bromo-5-nitrobenzoic acid (500 mg, 2.03 mmol) in DMF (10 mL) at 0° C. The reaction mixture was stirred for 2 hours at 0° C., then the mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous NaHCO3 (50 mL) followed by 1:1 water: brine (2×30 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) provided (3-bromo-5-nitrophenyl)(morpholin-4-yl)methanone as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.43 (t, J=1.9 Hz, 1H), 8.28-8.12 (m, 1H), 7.89 (t, J=1.5 Hz, 1H), 3.74 (br m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Cl)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Clc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 5-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (79, 1.40 g, 4.53 mmol) in tetrahydrofuran (15 mL) was added tetra-n-butylammonium fluoride (1.42 g, 5.43 mmol). The reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated and isolated by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give the compound (80, 0.40 g. 58% over 2 steps). MS (ESI) [M−H+]−=153.1.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH:16](O)[CH2:15][CH2:14][C:13]=3[CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:22][CH2:23][CH3:24])=[O:21]>C1(C)C=CC=CC=1>[CH2:23]([O:22][C:20](=[O:21])[CH2:25][CH:16]1[CH2:15][CH2:14][C:13]2[CH:19]=[C:9]([O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:10]=[CH:11][C:12]=2[O:17]1)[CH3:24]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC1CCc2cc(OCc3ccccc3)ccc2O1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CCc2cc(OCc3ccccc3)ccc2O1
Yield: 74.2 %

Procedure:
A solution of 1.8 g of racemic-3,4-dihydro-6-(phenylmethoxy)-2H-1-benzopyran-2-ol and 2.6 g of (carbethoxymethylene)triphenylphosphorane in 20 ml of toluene was stirred and refluxed for 22 hours. The solution was cooled and placed on a column of 50 g of silica gel packed in toluene. Elution with toluene and 19:1 toluene-ethyl acetate gave 1.7 g (74.2%) of racemic-3,4-dihydro-6-(phenylmethoxy)-2H-1-benzopyran-2-acetic acid ethyl ester as a pale-yellow oil. This material was dissolved in 25 ml of absolute ethanol and the solution was stirred in the presence of 0.2 g of 10% palladium on carbon, at room temperature, in an atmosphere of hydrogen. After 1.5 hours, hydrogen uptake ceasesd and the catalyst was removed by filtration. The filtrate was concentrated in vacuo to give 1.2 g (97.6%) of racemic-3,4-dihydro-6-hydroxy-2H-1-benzopyran-2-acetic acid ethyl ester as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[OH:12])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CCC(C)=O>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][O:12][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=1[C:2](=[O:3])[CH3:1])[CH3:25]
Reactant: COc1ccc(O)c(C(C)=O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(OC)cc1C(C)=O

Procedure:
A mixture of 16.6 g (100.0 mmol) of 2-hydroxi-5-methoxyacetophenone, 20 g (208 mmol) of potassium carbonate, 16.7 g (100.0 mmol) of ethyl bromoacetate and 200 ml of MEK is stirred at reflux temperature for 10 hr. The solids are filtered and the filtrate concentrated. The residue is suspended in water and the solid is filtered and dried. Yield: 10.2 g (40%).
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:42])[CH2:17][CH2:18][N:19]([CH2:23][CH2:24][C:25]([N:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[C:32]([O:34]CC1C=CC=CC=1)=[O:33])=[O:26])[CH2:20][CH2:21][CH3:22])=[O:10])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:32]([C@H:28]1[CH2:29][CH2:30][CH2:31][N:27]1[C:25](=[O:26])[CH2:24][CH2:23][N:19]([CH2:20][CH2:21][CH3:22])[CH2:18][CH2:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:42])([OH:34])=[O:33]
Reactant: CCCN(CCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1)CCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCN(CCC(=O)N1CCC[C@@H]1C(=O)O)CCC(=O)N1CCC[C@@H]1C(=O)O
Yield: 97.3 %

Procedure:
A solution of 84 mg (0.15 mmol) (R)-1-[3-[[3-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-propyl-amino]-propionyl]-pyrrolidine-2-carboxylic acid benzyl ester in 3 ml ethanol was stirred with 10 mg 10% palladium on carbon under 1 atm of hydrogen for 16 h at room temperature. After filtration to remove the catalyst, concentration in vacuo afforded 58 mg (100%) of the title compound (R)-1-[3-[[3-[(R)-2-carboxy-pyrrolidin-1-yl]-3-oxo-propyl]-propyl- amino]-propionyl]-pyrrolidine-2-carboxylic acid as a white solid. MS m/e (%): 398 (M+H+, 100).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[C:10]([O:17][CH3:18])=[N:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=2)[C:6]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:5]=2[N:4]([CH3:24])[C:3]1=[O:25].[C:26](Cl)(Cl)=[S:27]>>[Cl:23][C:20]1[CH:21]=[CH:22][C:5]2[N:4]([CH3:24])[C:3](=[O:25])[CH:2]([N:1]=[C:26]=[S:27])[N:8]=[C:7]([C:9]3[C:10]([O:17][CH3:18])=[N:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: S=C(Cl)Cl
Reactant: COc1ncc(C2=NC(N)C(=O)N(C)c3ccc(Cl)cc32)c(OC)n1
Product: COc1ncc(C2=NC(N=C=S)C(=O)N(C)c3ccc(Cl)cc32)c(OC)n1
Yield: 43.6 %

Procedure:
As illustrated in the scheme above and following General Procedure 2, 3-amino-7-chloro-5-(2,4-dimethoxy-5-pyrimidinyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (1.15 g, 3.18 mmol) and thiophosgene (0.49 mL, 6.4 mmol) were combined. Purification of the crude product by silica gel column chromatography (9:1 CH2Cl2:EtOAc) provided the title compound as a viscous dark yellow oil (0.560 g, 44%). 1H-NMR (CDCl3): δ 8.60 (s, 1H), 7.55 (dd, J=2.5 Hz, J=8.8 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 7.17 (d, J=2.5 Hz, 1H), 5.16 (s, 1H), 4.07 (s, 3H), 3.78 (s, 3H), 3.49 (s, 3H). MS (ESI) (M+H)+=404.
Reaction SMILES: [C:1]1([NH:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9](=O)/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[C:12]1(/[CH:11]=[CH:10]/[CH:9]=[N+:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O-:8])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ONc1ccccc1
Reactant: O=C/C=C/c1ccccc1
Solvent: CCO
Product: [O-][N+](=C/C=C/c1ccccc1)c1ccccc1
Temperature: 23 °C
Reaction time: 9 h
Yield: 77.2 %

Procedure:
According to the literature procedure (Utzinger et al. Helv. Chim. Acta 1954, 37, 1892; incorporated herein by reference) N-phenyl-hydroxylamine (188.7 mg, 1.7 mmol, 1.0 equiv) was added to a solution of (E)-cinnamaldehyde (218 μL, 1.73 mmol, 1 equiv) in ethanol (1.5 mL, absolute). The bright yellow solution was stirred for 9 h at 23° C. in the dark, and then was cooled in an ice bath. The cooled, heterogeneous solution was filtered and the filter cake was washed once with hexanes (10 mL). The filter cake was dried in vacuo overnight, furnishing α-(trans-2-phenyl-ethenyl)-N-phenylnitrone (293 mg, 76%, yellow solid) mp=150-152° C. (lit. 150-151° C.). 1H NMR data were in accord with that previously reported.
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:11]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-])=O)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].O.O.Cl[Sn]Cl>CO>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][N:11]([S:22]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)(=[O:24])=[O:23])[CH:3]([CH2:2][OH:1])[C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5]
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2[N+](=O)[O-])C(CO)C(=O)OC(C)(C)C)cc1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2N)C(CO)C(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Yield: 53.7 %

Procedure:
A mixture of 0.60 g (1.28 mmol) of 3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(2-nitrobenzyl)amino]propionic acid, tert-butyl ester and 1.45 g (6.45 mmol) of SnCl2.2H2O in 20 ml of methanol was heated in an oil bath at 90° C. for 2 hours. The solvent was removed under vacuum and ethyl acetate added to the residue. The mixture was neutralized with saturated sodium bicarbonate solution and filtered through diatomaceous earth. The ethyl acetate layer was separated and washed with H2O, brine and dried with Na2SO4. The solvent was removed under vacuum to give 0.30 g (53%) of a gum. Anal. for C21H28N2O6S: Calc'd: C, 57.8; H, 6.5; N, 6.4; Found: C, 57.8; H, 7.0; N, 6.2.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][O:5][C:4]([NH:7][C@@H:8]2[CH2:10][C@H:9]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][N:29]=2)[C:24]([CH:31]=O)=[CH:23]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:22]1[C:30]2=[N:29][CH:28]=[CH:27][CH:26]=[C:25]2[C:24]([CH:31]=[C:6]2[O:5][C:4]([NH:7][C@@H:8]3[CH2:10][C@H:9]3[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:3]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:2]2=[O:1])=[CH:23]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(N[C@@H]2C[C@H]2c2ccccc2)OCC1=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(N[C@@H]2C[C@H]2c2ccccc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 14.4 %

Procedure:
To a solution of ethyl 4-oxo-2-{[(1R,2S)-2-phenylcyclopropyl]amino}-4,5-dihydrofuran-3-carboxylate (0.090 g, 0.31 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.045 g, 0.30 mmol) in ethanol (5.0 mL), L-proline (0.0035 g, 0.031 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the solvent was removed under reduced pressure then the residue was purified by preparative HPLC to afford the titled compound as solid (0.018 g, y. 14%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[N:10]1[CH2:11][CH2:12][N:8]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:9]1=[O:13]
Reactant: Brc1nc2ccccc2s1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2nc3ccccc3s2)C1=O
Yield: 36.4 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.84 mmol) was reacted with 2-bromo-benzothiazole (179 mg, 0.847 mmol), 1,4-dioxane (10 mL), copper iodide (16 mg, 0.084 mmol), trans-1,2-diamino cyclohexane (28.8 mg, 0.25 mmol) and potassium carbonate (231 mg, 1.68 mmol) to afford the crude product. Purification by column chromatography on silica gel (1.5% MeOH in CHCl3) afforded 95 mg of the product (36.5% yield).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:9]1(B(O)O)[CH2:11][CH2:10]1.Cl[C:16]1[C:17]([CH:44]([F:46])[F:45])=[CH:18][C:19]([O:42][CH3:43])=[C:20]([C:22]2[C:31]3[C:26](=[CH:27][C:28]([S:32]([NH:35][C:36]4[CH:41]=[CH:40][N:39]=[CH:38][N:37]=4)(=[O:34])=[O:33])=[CH:29][CH:30]=3)[CH:25]=[CH:24][N:23]=2)[CH:21]=1.Cl>O1CCOCC1>[CH:9]1([C:16]2[C:17]([CH:44]([F:45])[F:46])=[CH:18][C:19]([O:42][CH3:43])=[C:20]([C:22]3[C:31]4[C:26](=[CH:27][C:28]([S:32]([NH:35][C:36]5[CH:41]=[CH:40][N:39]=[CH:38][N:37]=5)(=[O:33])=[O:34])=[CH:29][CH:30]=4)[CH:25]=[CH:24][N:23]=3)[CH:21]=2)[CH2:11][CH2:10]1
Reactant: COc1cc(C(F)F)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reactant: OB(O)C1CC1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(C(F)F)c(C2CC2)cc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reaction time: 0.17 h
Yield: 37.1 %

Procedure:
A solution of 2-dicyclohexylphosphino-2′,6′-dimethoxy-1′1′-biphenyl (4.59 mg, 0.011 mmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) methyl-t-butylether (8.48 mg, 0.011 mmol), potassium phosphate (0.190 g, 0.895 mmol), cyclopropylboronic acid (0.038 g, 0.448 mmol), and 1-(5-chloro-4-(difluoromethyl)-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (From Example 457; 0.108 g, 0.224 mmol) in 1.5 mL dioxane/0.5 mL water was heated to 180° C. in the microwave for 45 minutes. LC/MS showed product, so the aqueous layer was removed. The reaction mixture was treated with HCl (4N in dioxane) (0.224 ml, 0.895 mmol) and was allowed to stir for 10 minutes. The reaction mixture was then concentrated. Purification of the crude residue by reverse phase column chromatography [Puriflash C18, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 1-(5-cyclopropyl-4-(difluoromethyl)-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.040 g, 0.083 mmol, 37.0% yield). 1H NMR (MeCN-d3) δ: 8.65 (d, J=5.7 Hz, 1H), 8.58 (s, 1H), 8.44 (s, 1H), 8.14 (d, J=6.3 Hz, 1H), 7.86-7.95 (m, 2H), 7.63-7.69 (m, 1H), 7.15-7.45 (m, 2H), 7.12 (s, 1H), 6.96 (s, J=6.3, 1H), 3.67 (s, 3H), 2.03-2.14 (m, 1H), 0.88-1.00 (m, 2H), 0.59-0.70 (m, 2H); (M+H)+=483.0.