Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12]([CH3:22])([CH3:21])[CH2:13][N:14]([CH2:19][CH3:20])[C:15]3=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:31][N:32]1[CH:36]=[C:35]([S:37](Cl)(=[O:39])=[O:38])[N:34]=[CH:33]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([CH3:21])([CH3:22])[CH2:13][N:14]([CH2:19][CH3:20])[C:15]3=[O:18])=[CH:10][CH:9]=2)[S:37]([C:35]2[N:34]=[CH:33][N:32]([CH3:31])[CH:36]=2)(=[O:39])=[O:38])=[CH:23][CH:24]=1
Reactant: CCN1CC(C)(C)c2ccc(NCc3ccc(Cl)cc3)cc2C1=O
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: CC#N
Solvent: c1ccncc1
Product: CCN1CC(C)(C)c2ccc(N(Cc3ccc(Cl)cc3)S(=O)(=O)c3cn(C)cn3)cc2C1=O
Temperature: 150 °C
Yield: 20.5 %

Procedure:
To a stirred solution of 7-(4-chloro-benzylamino)-2-ethyl-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one (17 mg, 0.05 mmol) and pyridine (9 μl, 0.11 mmol) in anhydrous acetonitrile (1 ml) was added 1-methyl-1H-imidazole-4-sulfonyl chloride (20 mg, 0.11 mmol) and the reaction heated to 150° C. in a microwave for 0.5 hrs. The solvent was evaporated in vacuo and the crude residue purified by preparative tlc (5% methanol in dichloromethane) to afford the title compound as a colourless solid (5 mg, 21%). HPLC retention time 4.42 min. Mass spectrum (ES+) m/z 487 (M+H).
Reaction SMILES: O1CCCC1.C([O:8][C:9]([C:11]1[S:15][C:14]2[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:13]=2[CH:12]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)(=O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:13]2[CH:12]=[C:11]([CH2:9][OH:8])[S:15][C:14]=2[CH:16]=1
Reactant: CCOC(=O)c1cc2ccc(OC)cc2s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2cc(CO)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a tetrahydrofuran (100 mL) solution of (6-methoxy-benzo[b]-thiophene-2-carboxylic acid ethyl ester (5.0 g, 21.1 mmol) described in Production Example 77-1-1 was added lithium aluminum hydride (2.0 g, 52.8 mmol). The suspension was stirred at room temperature for 30 minutes. The reaction mixture was distributed between water and ethyl acetate. The organic layer was separated followed by drying over anhydrous magnesium sulfate and filtering. The residue was concentrated under a reduced pressure to obtain the title compound (4.1 g, quantitative).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[N:10][N:11]([CH:13]([CH3:15])[CH3:14])[CH:12]=1.[OH:16][C:17]([CH3:50])([CH3:49])[CH2:18][C@@:19]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:24][C:23](=[O:25])[N:22]([C@H:26]([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)[CH3:27])[CH2:21][CH2:20]1>CN(C)C=O>[CH:13]1([N:11]2[CH:12]=[C:8]([C:31]3[CH:30]=[CH:29][C:28]([C@@H:26]([N:22]4[CH2:21][CH2:20][C@:19]([CH2:18][C:17]([OH:16])([CH3:49])[CH3:50])([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)[O:24][C:23]4=[O:25])[CH3:27])=[CH:33][CH:32]=3)[CH:9]=[N:10]2)[CH2:15][CH2:14]1
Reactant: CC(C)n1cc(Br)cn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(-c2cnn(C3CC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
2 M aqueous Na2CO3 solution (0.37 mL) was added to a solution of 4-bromo-1-isopropyl-1H-pyrazole (0.15 g) and (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.35 g) in dimethylformamide (3 mL). The resulting mixture was sparged with argon for 10 min, before [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) dichloromethane complex (20 mg) was added. The mixture was heated to 90° C. and stirred at this temperature for 2 h. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (tert-butyl methyl ether/dichloromethane/NH4OH 96:4:0.1->94:6:0.1) to afford the title compound as a solid. Yield: 0.18 g (55% of theory); Mass spectrum (ESI+): m/z=460 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:33])[C@H:5]([CH3:32])[CH2:6][C@H:7]([NH:21][C:22]([C:24]1O[CH:26]=[C:27]([OH:31])[C:28](=[O:30])[CH:29]=1)=[O:23])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C.[CH3:34][NH2:35]>O>[C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:14][C:9]([CH2:8][C@@H:7]([NH:21][C:22]([C:24]2[N:35]([CH3:34])[CH:26]=[C:27]([OH:31])[C:28](=[O:30])[CH:29]=2)=[O:23])[CH2:6][C@@H:5]([CH3:32])[C:4]([OH:3])=[O:33])=[CH:10][CH:11]=1
Reactant: CN
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(=O)c(O)co1
Solvent: O
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(=O)c(O)cn1C)C(=O)O

Procedure:
To a suspension of (2R,4S)-5-biphenyl-4-yl-4-[(5-hydroxy-4-oxo-4H-pyran-2-carbonyl)-amino]-2-methyl-pentanoic acid ethyl ester (Example 23-1) (50 mg) in water (1 mL) is added methylamine (1 mL of a 40% solution in water) and the resulting mixture is heated to reflux for 6 hours. The mixture is under reduced pressure and is purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (0.1% TFA) to elute the title compound; HPLC Retention time 1.21 minutes (condition C): MS 435.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (d, J=7.07 Hz, 3H) 1.45-1.65 (m, 1H) 1.82-1.98 (m, 1H) 2.25-2.38 (m, 1H) 2.63-2.78 (m, 1H) 2.79-2.97 (m, 1H) 4.14-4.32 (m, 1H) 6.45 (br. s., 1H) 7.26-7.39 (m, 2H) 7.45 (t, J=7.58 Hz, 2H) 7.55-7.68 (m, 4H) 8.79 (d, J=9.09 Hz, 1H).
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1>>[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:12]([C:11]4[CH:10]=[CH:9][C:8]([CH2:7][N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:17])=[CH:16][CH:15]=4)=[O:14])[CH2:31][CH2:32]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1
Reactant: O=C(O)c1ccc(CN2CCCS2(=O)=O)cc1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(CN3CCCS3(=O)=O)cc2)CC1
Yield: 54.7 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)benzoic acid (153 mg) described in Preparation Example 18 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (196 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 87, the title compound (149 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:23]([N+:24]([O-])=O)=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=2)=[O:7])=[C:4]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[CH:3]=1>[Pd].C1COCC1.C(O)C>[NH2:1][C:2]1[C:23]([NH2:24])=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=2)=[O:7])=[C:4]([O:27][CH2:28][C:29]([F:32])([F:30])[F:31])[CH:3]=1
Reactant: CN(C)c1cc(C(F)(F)F)cc(NC(=O)c2cc([N+](=O)[O-])c(N)cc2OCC(F)(F)F)n1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)c1cc(C(F)(F)F)cc(NC(=O)c2cc(N)c(N)cc2OCC(F)(F)F)n1

Procedure:
Prepared analogously to example 655d by hydrogenation of the product obtained in 656c with palladium on charcoal in THF and ethanol.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=1[C:21]([F:24])([F:23])[F:22]>N1C=CC=CC=1>[Br:1][C:2]1[C:7]([NH:8][S:17]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[C:12]([C:21]([F:24])([F:22])[F:23])[CH:13]=2)(=[O:19])=[O:18])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1cnc(Br)c(N)c1
Solvent: c1ccncc1
Product: Cc1cnc(Br)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 61.4 %

Procedure:
A solution of 2-bromo-5-methyl-pyridin-3-ylamine (1 g, 5.38 mmol) and 4-chloro-3-trifluoromethylbenzenesulfonylchloride (1.8 g, 6.46 mmol) in pyridine (5 mL) was stirred at 60° C. for 12 h. The mixture was concentrated under reduced pressure and to it, was added 1:1 EtOAc-10% aqueous HCl (50 mL). Aqueous layer was separated and extracted with EtOAc (2×50 mL). Combined EtOAc layers were washed with 10% aqueous HCl (50 mL), dried (anhydrous Na2SO4), concentrated and column purified (SiO2, 50% EtOAc-hexanes) to obtain N-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-3-trifluoromethyl-benzenesulfonamide (1.42 g) in 84% yield as a half white solid. ESMS m/z (relative intensity): 429 (M+H)+ (100).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])=[CH:5][CH:4]=1.[OH:18][C:19]1[C:24]([CH2:25][CH2:26][CH3:27])=[C:23](O)[CH:22]=[CH:21][C:20]=1[C:29](=[O:31])[CH3:30]>>[C:29]([C:20]1[CH:21]=[CH:22][C:23]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([S:9][C:10]3[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=3)[C:15]#[N:16])=[CH:7][CH:8]=2)=[C:24]([CH2:25][CH2:26][CH3:27])[C:19]=1[OH:18])(=[O:31])[CH3:30]
Reactant: N#Cc1cncc(Sc2ccc(CO)cc2)c1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Product: CCCc1c(OCc2ccc(Sc3cncc(C#N)c3)cc2)ccc(C(C)=O)c1O

Procedure:
Using the method of Preparation 160 using 5-(4-(hydroxymethyl)phenylthio) nicotinonitrile (1.20 g, 4.95 nmol) and 1-(2,4-dihydroxy-3-propylphenyl)ethanone (1.01 g, 5.20 mmol) affords the title compound. MS (APCI-neg) m/z (rel intensity): 417 (M−H, 100%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Cl[CH2:10][C:11]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[C:18]2[C:13](=[CH:14][C:15]([O:38][CH3:39])=[C:16]([O:36][CH3:37])[CH:17]=2)[N:12]=1.O>CN(C)C=O>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([C:19]2[C:18]3[C:13](=[CH:14][C:15]([O:38][CH3:39])=[C:16]([O:36][CH3:37])[CH:17]=3)[N:12]=[C:11]([CH2:10][N:3]3[CH2:8][CH2:7][O:6][CH2:5][CH2:4]3)[C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:31]=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: C1COCCN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CN2CCOCC2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
Oily sodium hydride (60%, 0.27 g) was added to a solution of morpholine (0.537 g) in N,N-dimethylformamide (20 ml), and the mixture was stirred at room temperature for 15 minutes. Then ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (2.5 g) was added. The resulting mixture was stirred at 100° C. for 2 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The crystals were collected by filtration and then recrystallized from ethanol to give ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-morpholinomethylquinoline-3-carboxylate (1.9 g, 68%). Colorless prisms. mp. 146°-147° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[O:9][C:8]2[CH:16]=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:7]=2[CH2:6]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:35])[CH2:30][CH2:31][N:32]([CH2:2][CH2:3][CH:4]=[C:5]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[O:9][C:8]4[CH:16]=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:7]=4[CH2:6]3)[CH2:33][CH2:34]2)=[CH:25][CH:24]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: COc1cccc2c1CC(=CCCBr)c1cccnc1O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution the product of step 2 (1.1 g) in DMF (15 ml) were added 4-(4-chlorophenyl)-4-hydroxypiperidine (0.81 g) and potassium carbonate (0.53 g) and the mixture was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with methylene chloride-methanol (10:1) to give the titled compound as major regioisomer (0.86 g) and minor one (0.05 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]([O:54][C:55]([N:57]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:59]=[C:58]1[C:66]1[CH:71]=[CH:70][CH:69]=[C:68]([NH2:72])[CH:67]=1)=[O:56])([CH3:53])([CH3:52])[CH3:51]>CN(C=O)C>[C:50]([O:54][C:55]([N:57]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:59]=[C:58]1[C:66]1[CH:71]=[CH:70][CH:69]=[C:68]([NH:72][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])[CH:67]=1)=[O:56])([CH3:53])([CH3:51])[CH3:52]
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: CC(C)(C)OC(=O)n1c(-c2cccc(N)c2)cc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cc5ccccc5n4C(=O)OC(C)(C)C)c3)c(=O)oc12
Temperature: 25 °C
Yield: 72.3 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2-(3-Amino-phenyl)-indole-1-carboxylic acid tert-butyl ester (0.02 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.024 g of product in 76% yield: LCMS (ESI) m/z 511 (MH+).
Reaction SMILES: Cl.Cl.[C@H]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.[N:47]1([CH2:54]CN2CCC(N)CC2)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>>[N:47]1([CH2:54][CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (97, see example 42) and amine 5 analogously to the method described in example 1.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([S:19][CH3:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH:21]([C:23]2[O:27][C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:24]=2)O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.C(O)(=O)C.[C].[Pd]>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([S:19][CH3:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH2:21][C:23]2[O:27][C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:24]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(C(O)c2cc3cc(SC)ccc3n2S(=O)(=O)c2ccccc2)o1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(Cc2cc3cc(SC)ccc3n2S(=O)(=O)c2ccccc2)o1
Temperature: 50 °C
Reaction time: 15 h
Yield: 52.8 %

Procedure:
To a solution of the compound obtained in Example 30 (2) (0.3586 g) in ethanol (8 ml), acetic acid (1 ml) and 10% palladium carbon (0.3586 g) were added and the mixture was stirred at 50° C. for 15 hours under hydrogen atmosphere. The reaction solution was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 0.183 g of the desired product.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:14][N:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[Sn](CCCC)(CCCC)CCCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][O:10][C:5]1[CH:4]=[C:3]([O:12][CH3:13])[C:2]([C:16]2[N:15]([CH3:14])[CH:19]=[CH:18][CH:17]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Reactant: COc1cc(OC)c(C=O)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(OC)c(-c2cccn2C)cc1C=O
Yield: 46 %

Procedure:
Ex-44A: A solution of 5-bromo-2,4-dimethoxybenzaldehyde (1.90 g, 7.77 mmol) and trans-dichlorobis(triphenylphosphine)palladium(II) in dioxane (150 mL) was treated with 1-methyl-2-(tributylstannyl)-1H-pyrrole and then refluxed for 68 h. The reaction mixture was quenched with 10% potassium fluoride/ether (300 mL/100 mL) and filtered through Celite. The organic phase was extracted with saturated ammonium chloride solution (4×25 mL), dried over magnesium sulfate, and concentrated to a brown solid. The solid was purified by column chromatography (30% ethyl acetate/hexane) to yield 0.87 g (46%) of 2,4-dimethoxy-5-(1-methyl-1H-pyrrol-2-yl)benzaldehyde as a white solid. 1H-NMR (300 MHz, CDCl3) δ 10.34 (s, 1 H), 7.78 (s, 1H), 6.72 (m, 1H), 6.51 (s, 1H), 6.20 (m, 1H), 6.13 (m, 1H), 4.01 (s, 3H), 3.92 (s, 3H), 3.46 (s, 3H).
Reaction SMILES: FC(F)(F)S(OO[Si](C)(C)C)(=O)=O.[CH3:14][O:15][C:16]1[CH:21]=[C:20]2[O:22][C:23](=O)[CH2:24][C:25]3([CH2:30][CH2:29][CH2:28][N:27]4[CH:31]=[N:32][CH:33]=[C:26]34)[C:19]2=[CH:18][CH:17]=1.C([SiH](CC)CC)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:14][O:15][C:16]1[CH:21]=[C:20]2[O:22][CH2:23][CH2:24][C:25]3([CH2:30][CH2:29][CH2:28][N:27]4[CH:31]=[N:32][CH:33]=[C:26]34)[C:19]2=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)OC(=O)CC21CCCn2cncc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OOS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)OCCC21CCCn2cncc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2.61 mmol of trimethylsilyloxy trifluoromethanesulphonate in 1 ml of dichloro-methane at 0° C. is admixed with a solution of 1.27 mmol of titanium tetrachloride in 1.5 ml of dichloromethane. The mixture is stirred at room temperature for 4 hours and then cooled to 0° C. A solution of 0.83 mmol of 7-methoxy-6′,7′-dihydro-5′H-spiro[chromene-4,8′-imidazo[1,5-a]pyridin]-2(3H)-one and 4.17 mmol of triethylsilane in 2 ml of dichloromethane is added and the reaction mixture is stirred at room temperature for 20 hours. The reaction mixture is poured into ice-water and extracted with ethyl acetate (2×). The combined organic phases are washed with water and brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:15](O)=O>C=O>[CH3:15][N:10]([CH2:11][C:12]([OH:14])=[O:13])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=CO
Reactant: O=C(O)CNc1ccc([N+](=O)[O-])cc1
Agent: C=O
Product: CN(CC(=O)O)c1ccc([N+](=O)[O-])cc1
Yield: 86 %

Procedure:
A solution of (4-nitro-phenylamino)-acetic acid (1.3 g, 6.6 mmol) in formic acid (5 mL) and formaldehyde (5 mL) was heated at reflux overnight. The mixture was concentrated in vacuo and 1N hydrochloric acid added to the residue giving a pH ˜3. The mixture was extracted with ethyl acetate then the organic phase was washed with water and brine. Concentration in vacuo afforded [methyl-(4-nitro-phenyl)-amino]-acetic acid (1.2 g, 86%) as a yellow solid.
Reaction SMILES: C([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:24]=2)[CH3:22])[N:15]=1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:24]=2)[CH3:22])[N:15]=1)[CH3:7]
Reactant: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1)c1cccc(Oc2ccccc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)O)n1)c1cccc(Oc2ccccc2)c1
Reaction time: 0.5 h
Yield: 66 %

Procedure:
A solution of (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(3-phenoxyphenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one (70.1 mg, 0.147 mmol) in DCM (1.1 ml) was treated with TFA (368 ul) at room temperature. The resulting solution was let sit for 30 min, then concentrated. The crude material was purified by reverse phase HPLC. Product fractions were combined and lyophilized to afford (R)-4-((R)-1-hydroxyethyl)-3-(2-((S)-1-(3-phenoxyphenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one (41.3 mg, 0.097 mmol, 66% yield) as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ 0.64 (br. s., 3H) 1.42 (d, J=6.90 Hz, 3H) 3.70 (br. s., 1H) 4.32-4.48 (m, 3H) 4.67-4.75 (m, 1H) 5.08 (br. s., 1H) 6.78 (d, J=7.87 Hz, 1H) 6.91 (d, J=7.87 Hz, 2H) 7.00-7.18 (m, 3H) 7.22-7.37 (m, 4H) 8.14 (br. s., 1H). LCMS m/z 421.3 (M+H)+, Rt 0.72 min. HRMS(A) m/z 421.1873 (M+H)+, Rt 1.84 min.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(OP(CC1C=CC([N+]([O-])=O)=CC=1)(=O)OCC)C.IC.[CH2:29]([O:31][P:32]([C:37]([C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)(C)[CH3:38])(=[O:36])[O:33][CH2:34][CH3:35])[CH3:30]>C1COCC1.CCOC(C)=O.O>[CH2:29]([O:31][P:32]([CH:37]([C:40]1[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=1)[CH3:38])(=[O:36])[O:33][CH2:34][CH3:35])[CH3:30]
Reactant: CCOP(=O)(OCC)C(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)[N-]C(C)C
Agent: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: CCOP(=O)(OCC)C(C)c1ccc([N+](=O)[O-])cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
2M LDA in THF (1.83 mL, 3.66 mmol) was added dropwise under N2, to a stirred solution of diethyl(4-nitrobenzyl)phosphonate (1.00 g, 3.66 mmol) in THF (10 mL) at −78° C. After 1 hour, iodomethane (0.456 mL, 7.32 mmol) was added dropwise and the mixture stirred at −78° C. for 30 min then allowed to warm to room temperature during 3-4 h. Water (10 mL) was then added slowly followed by EtOAc (20 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×20 mL). The organic phases were combined, dried (MgSO4), concentrated in vacuo, and the residue purified by chromatography over silica gel eluting with 10% EtOAc in hexanes to afford 180 mg of pure diethyl[1-(4-nitrophenyl)ethyl]phosphonate (yield: 17%) and 680 mg of a mixture of diethyl(4-nitrobenzyl)phosphonate and diethyl[2-(4-nitrophenyl)propan-2-yl]phosphonate.