Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([C:12]([OH:14])=[O:13])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[CH:15]1[C:24]2[C:19](=[C:20]([N:25]3[C:29]([C:30]4[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:31]=4[O:38][CH3:39])=[CH:28][C:27]([C:40](Cl)=[O:41])=[N:26]3)[CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1>N1C=CC=CC=1.ClCCl>[CH:15]1[C:24]2[C:19](=[C:20]([N:25]3[C:29]([C:30]4[C:31]([O:38][CH3:39])=[CH:32][CH:33]=[CH:34][C:35]=4[O:36][CH3:37])=[CH:28][C:27]([C:40]([NH:1][C:2]4([C:12]([OH:14])=[O:13])[CH:9]5[CH2:8][CH:7]6[CH2:6][CH:5]([CH2:4][CH:3]4[CH2:11]6)[CH2:10]5)=[O:41])=[N:26]3)[CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1
Reactant: COc1cccc(OC)c1-c1cc(C(=O)Cl)nn1-c1cccc2cnccc12
Reactant: NC1(C(=O)O)C2CC3CC(C2)CC1C3
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(OC)c1-c1cc(C(=O)NC2(C(=O)O)C3CC4CC(C3)CC2C4)nn1-c1cccc2cnccc12
Reaction time: 8 h

Procedure:
0.75 g of 2-amino-2-adamantanecarboxylic acid is dissolved in 20 ml of pyridine. 1.4 g of 1-(5-isoquinolyl)-5-(2,6-dimethoxyphenyl)-3-pyrazolecarbonyl chloride, dissolved in 20 ml of dichloromethane, are added and the reaction mixture is left overnight at room temperature. It is concentrated under vacuum, the residue is taken up with pH 2 buffer, the mixture is stirred and the precipitate is filtered off and rinsed with diisopropyl ether.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:13]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CCOCC.O.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>[C:13]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:2]2[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=[N:4][CH:3]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: OB(O)c1ccccc1-c1ccccc1OCc1ccccc1
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: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1cncc(-c2ccccc2-c2ccccc2OCc2ccccc2)c1
Temperature: 90 °C
Yield: 80.6 %

Procedure:
A mixture of ethyl 5-bromonicotinate (46 mg, 0.2 mmol), {2′-[(phenylmethyl)oxy]-2-biphenylyl}boronic acid (61 mg, 0.2 mmol), potassium carbonate (221 mg, 1.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol) was stirred and heated at 90° C. under nitrogen for 2 hours. After cooling the mixture was diluted with ether/water and the organic phase dried (magnesium sulphate), evaporated and chromatographed on silica eluting with ethyl acetate/iso-hexane (1:5) to give 66 mg of colourless gum.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([CH3:17])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][CH3:16])[CH:9]=1)[CH3:6])[CH3:2].[CH3:19][C:20]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=O.COC(=O)C1C=CC(C2C=CC(C(F)(F)F)=CC=2)=NC=1C>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([CH3:17])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH3:16])[C:22]([C:21]2[C:20]([CH3:19])=[N:28][C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[CH:26][CH:25]=2)=[O:24])[CH:9]=1)[CH3:6])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(=O)O
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CNC)c1
Agent: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Product: CCOC(=O)C(C)(C)Oc1cccc(CN(C)C(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-methyl-2-(3-methylaminomethyl-phenoxy)-propionic acid ethyl ester (example 52C]) was reacted with 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 1L]) in analogy to the procedure described in example 53B]) to give 2-methyl-2-[3-({methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless amorphous solid.
Reaction SMILES: [CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][C:23]1[N:27]=[C:26]([CH2:28][NH2:29])[O:25][N:24]=1>>[CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([NH:29][CH2:28][C:26]2[O:25][N:24]=[C:23]([CH3:22])[N:27]=2)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Reactant: Cc1noc(CN)n1
Product: Cc1noc(CNC(=O)c2cnc(OCC(F)(F)F)c(C3CCCCC3)c2)n1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 4b) (100 mg, 0.33 mmol) and 3-methyl-1,2,4-oxadiazole-5-methanamine (CAN 90928-92-0) (37 mg, 0.33 mmol) as starting materials; off white solid (30 mg, 22.9%). MS (ESI): 399 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27](Cl)(=[O:29])[CH3:28].C(N(CC)C(C)C)(C)C>ClCCl>[C:1]1([CH:7]2[CH2:8][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])=[CH:16][CH:15]=3)[CH2:10][CH2:11][N:12]2[C:27](=[O:29])[CH3:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ccccc1-c1ccc(CN2CCNC(c3ccccc3)C2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(Cc2ccc(-c3ccccc3Cl)cc2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound could be made the following manner: 100 mg of 3-phenyl-1-(2′-chloro-biphenyl-4-ylmethyl)-piperazine would be dissolved in dichloromethane, 1.1 equiv. of acetylchloride and 2 equiv. of N,N-diisoproylethylamine would be added. The reaction would be stirred at room temperature under nitrogen overnight. The reaction would be diluted with DCM, washed with 1M aqueous sodium hydroxide solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue would be purified by column chromatography to afford the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[N+:6]([O-:14])[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11].CCN(C(C)C)C(C)C.Cl[C:25]1[N:30]=[C:29]([Cl:31])[C:28]([C:32]([F:35])([F:34])[F:33])=[CH:27][N:26]=1>CN(C=O)C.[Cl-].[Na+].O.C(OCC)(=O)C.O>[Cl:31][C:29]1[C:28]([C:32]([F:34])([F:33])[F:35])=[CH:27][N:26]=[C:25]([NH:2][CH2:3][C:4]2[CH:5]=[N+:6]([O-:14])[CH:7]=[CH:8][C:9]=2[C:10]([F:11])([F:12])[F:13])[N:30]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: NCc1c[n+]([O-])ccc1C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: [O-][n+]1ccc(C(F)(F)F)c(CNc2ncc(C(F)(F)F)c(Cl)n2)c1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
3-(Aminomethyl)-4-(trifluoromethyl)pyridine 1-oxide hydrochloride (1.0 equiv.) was dissolved in DIEA (2.5 equiv.) and DMF (0.4 M). The homogeneous solution was cooled to −20° C. using an ice and brine bath. To the solution was added 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.0 equiv.). The solution was stirred for 10 min at −20° C. and then warmed to ambient temperature for 30 min. After 30 min, the solution was diluted with ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (3×). The organic layers were combined and dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure to afford a white solid. The solid was purified via biotage chromatography (0-60% ethyl acetate in hexanes, then 60% ethyl acetate) to afford the title compound as a white solid (47% yield). MS(ESI) m/z 372.8[M]+.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24](NC(=O)/C(/C4N=C(NC(OC(C)(C)C)=O)SC=4)=N\OC(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20](=[O:64])[CH2:19][C:18]=2[S:65][CH:66](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:67][C:68]2[N:72]=[CH:71][NH:70][N:69]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.C(OCC)(=O)C>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[CH2:24][C@H:21]3[S:20](=[O:64])[CH2:19][C:18]=2[S:65][CH2:66][S:67][C:68]2[N:72]=[CH:71][NH:70][N:69]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SC(Sc4nc[nH]n4)C(c4ccccc4)(c4ccccc4)c4ccccc4)CS(=O)[C@H]23)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(SCSc2nc[nH]n2)CS(=O)[C@@H]2CC(=O)N12
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.8 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol -4-yl)- 2-trityloxyiminoacetylamino]-3-(trityl-1,2,4-triazol -3-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide (11.3 g) in acetone (60 ml) under ice cooling is added toluene-p-sulfonic acid monohydrate (1.68 g : 8.83 mMol.), and the mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with ethyl acetate, washed with aqueous 5% sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene : ethyl acetate=1:1-1:2) to give 7β-(Z)-2-(2-t butoxycarbonylaminothiazol-4-yl) -2-trityloxyiminoacetylamino]-3-(1,2,4-triazol-3-ylthiomethylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide (2.84 g) as brown foam. Yield: 31%.
Reaction SMILES: [OH:1][C:2]([C:7]1[CH:8]=[C:9]2[C:32](=[CH:33][CH:34]=1)[C:13]1=[N:14][O:15][C:16]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)=[C:12]1[CH2:11][CH2:10]2)([CH3:6])[C:3]([OH:5])=O.[NH2:35][CH2:36][CH2:37][OH:38].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CO>[OH:1][C:2]([C:7]1[CH:8]=[C:9]2[C:32](=[CH:33][CH:34]=1)[C:13]1=[N:14][O:15][C:16]([C:17]3[C:21]([C:22]([F:23])([F:25])[F:24])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)=[C:12]1[CH2:11][CH2:10]2)([CH3:6])[C:3]([NH:35][CH2:36][CH2:37][OH:38])=[O:5]
Reactant: CC(O)(C(=O)O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: NCCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(O)(C(=O)NCCO)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reaction time: 1 h
Yield: 29.8 %

Procedure:
To 2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)propanoic acid (Preparation 134D, isomer 2, 15 mg, 0.032 mmol) in DMF (1 mL) was added 2-aminoethanol (2.9 mg, 0.048 mmol), 4-methylmorpholine (12.9 mg, 0.13 mmol) and BOP (18.3 mg, 0.041 mmol). The reaction mixture was stirred for 1 h. Methanol was added and it was purified by prep HPLC (Phenomenex Luna 5 u 21.2×100 mm, Solvent A: 90% water with 10% acetonitrile and 0.1% TFA, Solvent B: 90% acetonitrile with 10% water and 0.1% TFA, Gradient: 0% B to 100% B over 10 min, 20 mL/min, 220 nM) to yield 2-hydroxy-N-(2-hydroxyethyl)-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)propanamide (5 mg, 9.52 μmol, 29.9% yield) as a white solid: product HPLC ret. time=9.15 min. (condition G); LC/MS M+1=514.06; 1H NMR (400 MHz, CD3OD) δ ppm 8.09-8.20 (1H, m), 7.91 (1H, d, J=7.92 Hz), 7.77 (2H, d, J=7.48 Hz), 7.51-7.72 (5H, m), 3.60 (2H, td, J=5.72, 3.08 Hz), 3.36-3.40 (2H, m), 3.07 (4H, s), 1.78 (3H, s).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH2:11][C@@H:12]([CH3:33])[C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[C:20](=[CH:21][C:22](=[O:32])[CH2:23][CH2:24]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1.OO.[OH-:36].[Na+]>CO.ClCCl.O>[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:36]1[C:20]23[C@:25]([CH3:26])([CH2:24][CH2:23][C:22](=[O:32])[CH:21]12)[C@@H:27]1[C@H:17]([C@H:16]2[C@:30]([CH3:31])([CH2:29][CH2:28]1)[C@@H:13]([C@H:12]([CH3:33])[CH2:11][OH:10])[CH2:14][CH2:15]2)[CH2:18][CH2:19]3
Reactant: [OH-]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C(O)c1ccccc1
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC45OC4C(=O)CC[C@]5(C)[C@H]3CC[C@]12C
Reaction time: 4 h
Yield: 16.7 %

Procedure:
A solution of (20S)-21-hydroxy-20-methylpregn-4-en-3-one benzoate (8.9 g, 20.5 mmole) in methanol (80 mL) and dichloromethane (80mL) was cooled to 15° C. and treated sequentially with 30% hydrogen peroxide (5.0 mL) and sodium hydroxide (1.09 g) in water (6.7 mL). After 4 hours at room temperature, the product was isolated from the reaction mixture by the same procedure as described in Example 7 to give (20S)-4,5-epoxy-21-hydroxy-20-methylpregnan-3-one benzoate (1.6 g, 17.3%). IR 1720, 1280 cm-1 ; MS (CI) 451 (95%, M+1), 329 (100%, M+1 -PhCOOH); 1H NMR (CDCl3) δ0.76 (3H, s, C18 -Me), 1.13 (d, C22 -Me), 1.16 (s, C19 -Me), 2.98+3.04 (1H, s +s, C4 -H), 4.04 (1H, dd, 1/2C21 -CH2), 4.32 (1H, dd, 1/2C21 -CH2), 7.46 (2H, t), 7.57 (1H, t), 8.04 (1H, dd).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([F:12])[CH:6]=1)=[O:4].[BH4-].[Na+].C[O-].[Na+].COC(C)(C)C>C(O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]2[CH2:2][O:4]2)=[CH:6][C:7]=1[F:12]
Reactant: O=C(CBr)c1ccc(Br)c(F)c1
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: COC(C)(C)C
Product: Fc1cc(C2CO2)ccc1Br
Temperature: 5 °C
Reaction time: 1 h
Yield: 106.1 %

Procedure:
2-Bromo-1-(4-bromo-3-fluorophenyl)-ethanone [CAS 1003879-02-4] (32.3 g, 109 mmol) was dissolved in ethanol (250 ml). The reaction mixture was cooled to 5° C. to give a yellow suspension. Sodiumborohydride (4.13 g, 109 mmol) was added over 5 min. The reaction mixture was stirred at room temperature for 1 hour. Sodium methoxide (2.95 g, 54.6 mmol) was added. The reaction mixture was stirred at 50° C. for 6 h. The reaction mixture was poured into tert.butyl methyl ether and extracted with brine. The organic layer was dried over MgSO4 and concentrated in vacuo to yield a yellow oil (25.1 g, 94%). GC-EI-MS: 216 ([M.+]).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([O:16][CH3:17])([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([NH2:35])[CH:33]=3)[N:28]([C:36]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:27]=2)[CH:23]=[CH:22][N:21]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([O:16][CH3:17])([C:13](=[O:15])[NH:35][C:32]2[CH:33]=[C:34]3[C:29](=[CH:30][CH:31]=2)[N:28]([C:36]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:27]=[C:26]3[C:24]2[CH:23]=[CH:22][N:21]=[C:20]([O:19][CH3:18])[CH:25]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC1(C(=O)O)CCN(C(=O)OC(C)(C)C)C1
Reactant: COc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(N)cc23)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(NC(=O)C4(OC)CCN(C(=O)OC(C)(C)C)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the stirred suspension of 3-methoxy-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 6BV (4.16 mmole, crude) in DMF/DCM (25 mL/25 mL), 3-(2-methoxypyridin-4-yl)-1-trityl-1H-indazol-5-ylamine 5BV (2.008 g, 4.16 mmole) and Et3N (2.9 mL, 21 mmole) were added at r.t. under dry N2 gas followed by HATU (3.16 g, 8.32 mmole). The mixture was stirred at r.t. under dry N2 gas overnight. The mixture was partitioned between 1:1 EtOAc and sat. NaHCO3 solution. The organic phase was separated, washed with brine, dried over MgSO4 and evaporated to dryness. The crude solid was purified on RediSep 120 g cartridge eluting with 10-25% EtOAc/Hexanes to yield a brown solid 7BV (2.95 g, 100%).
Reaction SMILES: Br[C:2]1[C:6]2[O:7][C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:9][C:10](=[O:11])[C:5]=2[S:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH:27]([O:29]CCCC)=[CH2:28].Cl>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].CN(C)C=O>[C:27]([C:2]1[C:6]2[O:7][C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:9][C:10](=[O:11])[C:5]=2[S:4][CH:3]=1)(=[O:29])[CH3:28]
Reactant: O=c1cc(N2CCOCC2)oc2c(Br)csc12
Reactant: C=COCCCC
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1csc2c(=O)cc(N3CCOCC3)oc12
Temperature: 180 °C

Procedure:
A 2 mL conical microwave vial was charged with a magnetic stirring bar, 3-bromo-5-morpholino-7H-thieno[3,2-b]pyran-7-one (103) (100 mg, 316 gmol), dimethylformamide (0.5 mL), N,N-diisopropylethylamine (165 μL, 949 μmol), butyl vinyl ether (124 μL, 949 gmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (10 mg, 12.6 μmol). The reaction mixture was sealed, and the reaction mixture was magnetically stirred and heated via microwave irradiation to 180° C. for 15 minutes. After cooling to room temperature, the reaction was charged with aqueous hydrochloric acid (1.0 M, 2 mL) and stirred at room temperature for 2 hours to give 3-acetyl-5-morpholino-7H-thieno[3,2-b]pyran-7-one (74).
Reaction SMILES: C1(C)C=CC(S(N[C@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.[C:27]([C@H:30]1[CH2:34][N:33]([C@H:35]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[CH3:36])[C:32](=[O:45])[CH2:31]1)(=[O:29])[CH3:28].C(O)=O.Cl>C(#N)C.C[C]1[C](C)[C](C)[C](C)[C]1C.C[C]1[C](C)[C](C)[C](C)[C]1C.Cl[Rh]Cl.Cl[Rh]Cl.C(N(CC)CC)C>[OH:29][C@H:27]([C@H:30]1[CH2:34][N:33]([C@H:35]([C:37]2[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[CH3:36])[C:32](=[O:45])[CH2:31]1)[CH3:28]
Reactant: COc1ccc([C@H](C)N2C[C@H](C(C)=O)CC2=O)cc1
Agent: Cl[Rh]Cl
Agent: C[C]1[C](C)[C](C)[C](C)[C]1C
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Solvent: O=CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc([C@H](C)N2C[C@H]([C@H](C)O)CC2=O)cc1
Temperature: -15 °C
Reaction time: 22 h
Yield: 113.3 %

Procedure:
2.4 g of Dichloro-(pentamethylcyclopentadienyl)-rhodium-(III)-dimer and 2.8 g (R,R)—N-(p-toluenesulfonyl)-1,2-diphenylethylendiamine [(R,R)-TsDPEN] is added to a solution of 50 g (R)-4-acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]pyrrolidine-2-one in acetonitril at 25° C. The solution is cooled to −15° C. At this temperature a mixture of 22 mL formic acid and 135 mL triethylamine is added. The reaction mixture is stirred for 22 hours at −15° C. and then warmed up to 20° C. 230 mL of a 4 molar hydrochloric acid is added under cooling. The aqueous phase is extracted 3 times with ethyl acetate. The organic phase is washed with diluted and concentrated brine and treated with activated carbon. The organic phase is dried over sodium sulfate. The solvent is evaporated under reduced pressure to obtain 57.1 g of a beige solid with a diastereomeric purity of >97:3.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]2[C:16](=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1F)[NH:15][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]2=1.O>CN(C=O)C>[Cl:5][C:6]1[CH:7]=[C:8]2[C:16](=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1[O:2][CH3:1])[NH:15][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]2=1
Reactant: O=[N+]([O-])c1c(F)c(Cl)cc2c1[nH]c1cnccc12
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.7 %

Procedure:
Methanol (0.462 ml, 11.4 mmol) was added to a stirring suspension of NaH (684 mg, 17.1 mmol) in DMF (10 ml) under an argon atmosphere. The resulting solution was allowed to stir at RT for 20 min. 6-chloro-7-fluoro-8-nitro-9H-β-carboline (500 mg, 1.9 mmol) was added to the stirring solution and the resulting mixture was allowed to stir at RT. Upon addition of H2O, a brown solid precipitated out which was filtered to give the desired 6-chloro-7-methoxy-8-nitro-9H-β-carboline (510 mg, 97% yield). 1H-NMR (300 MHz, DMSO-d6): δ 4.02 (s, 3H), 8.52 (d, 1H), 8.60 (d, 1H), 9.05 (s, 1H), 9.12 (s, 1H), 12.78 (b, 1H). Retention Time (LC, method: ammonium acetate standard): 2.28 min. MS (M+H+): 278.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([C:12](OCC)=O)[C:8]2=[O:11])=[CH:4][C:3]=1[O:17][CH3:18].C([O-])([O-])=O.[K+].[K+].BrC[CH2:27][F:28].[OH-].[Na+]>CC(N(C)C)=O.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH2:12][CH2:27][F:28])[C:8]2=[O:11])=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: CCOC(=O)C1Cc2cc(OC)c(Cl)cc2C1=O
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc2c(cc1Cl)C(=O)C(CCF)C2
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 6-chloro-5-methoxy-1-oxoindane-2-carboxylate (crude product from the preceding step, ˜141 mmol) in anhydrous dimethylacetamide (540 mL) was added K2CO3 (39 g, 282 mmol), KI (46.8 g, 282 mmol) and 1-bromo-2-fluoroethane (13.5 mL, 183 mmol) and the mixture was stirred and heated at 65° C. for 6 hours. The reaction mixture was diluted with TUF (540 mL) and water (540 mL) and then cooled to 0° C. and treated with 5N aqueous NaOH (84 mL, 423 mmol). After 2 hours at 0° C., the reaction was quenched with 1N aqueous HCl (˜450 mL). Most of the THF was removed by rotary evaporation under reduced pressure and the aqueous residue was extracted with EtOAc. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered through a pad of silica gel and concentrated to give 6-chloro-2-(2-fluoroethyl)-5-methoxyindan-1-one.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=1.N1C=CC=CC=1>ClCCl.CN(C)C=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:7]([C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N+:11]([O-:13])=[O:12])=[O:9])=[N:22][CH:23]=1
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: Nc1ccc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1ccc([N+](=O)[O-])c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a solution of 5-methyl-2-nitrobenzoic acid (1 g, 5.52 mmol) in dichloromethane (5 ml) was added oxalyl chloride (0.964 ml, 11.04 mmol) and a few drops of dimethylformamide. The mixture was stirred at r.t. for 2 hrs. After the evaporation of the solvent, the residue was dissolved in dichloromethane (5 ml). 2-amino-5-chloropyridine (852 mg, 6.62 mmol) and pyridine (1.34 ml, 16.56 mmol) were added to the solution. The mixture was stirred at r.t. overnight. After the evaporation of the solvent, the crude residue was purified by silica gel column chromatography using solvent system 25% ethyl acetate in hexane as eluent to give N-(5-chloro(2-pyridyl))(5-methyl-2-nitrophenyl)carboxamide as a solid (1.48 g, 92%). MS found for C13H10ClN3O3 M+=291, (M+2)+=293.