Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=O)[C:5]=2[C:4]2([C:25]3[C:16](=[CH:17][C:18]4[O:23][CH2:22][CH2:21][O:20][C:19]=4[CH:24]=3)[O:15][CH2:14]2)[C:3]1=[O:26].C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.O[C:48]1[C:56]2N=N[NH:53][C:52]=2[CH:51]=[CH:50][CH:49]=1.C1(N)CCCCC1>CN(C)C=O>[CH:52]1([NH:53][C:11]([C:6]2[C:5]3[C:4]4([C:25]5[C:16](=[CH:17][C:18]6[O:23][CH2:22][CH2:21][O:20][C:19]=6[CH:24]=5)[O:15][CH2:14]4)[C:3](=[O:26])[N:2]([CH3:1])[C:10]=3[CH:9]=[CH:8][CH:7]=2)=[O:13])[CH2:56][CH2:48][CH2:49][CH2:50][CH2:51]1
Reactant: Oc1cccc2[nH]nnc12
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C(=O)O)cccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: NC1CCCCC1
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C(=O)NC3CCCCC3)cccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
To a stirred solution of 1′-methyl-2′-oxo-1,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxylic acid (0.200 g, 0.566 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (0.114 g, 0.736 mmol) in N,N-dimethylformamide (20 mL) was added N,N-diisoproylethylamine (0.30 mL, 1.72 mmol) and hydroxybenzotriazole (0.092 g, 0.68 mmol). The reaction mixture was stirred at ambient temperature for 10 min and cyclohexylamine (0.10 mL, 0.87 mmol) was added. The reaction mixture was stirred at ambient temperature for 40 h and concentrated in vacuo to remove most of the N,N-dimethylformamide. The mixture was diluted with ethyl acetate (150 mL), washed with water (3×150 mL) and brine (3×100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with ethyl acetate/hexanes (1/1) to afford N-cyclohexyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide (0.127 g, 51%) as a colorless solid: mp 139-140° C.; 1H NMR (300 MHz, CDCl3) δ7.42-7.36 (m, 1H), 7.24-7.20 (m, 1H), 6.98-6.94 (m, 1H), 6.51 (s, 1H), 6.17 (s, 1H), 5.30-5.27 (m, 1H), 4.95 (ABq, 2H), 4.24-4.04 (m, 4H), 3.71-3.61 (m, 1H), 3.26 (s, 3H), 1.78-1.57 (m, 5H), 1.36-1.22 (m, 2H), 1.12-0.99 (m, 1H), 0.89-0.82 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.6, 166.3, 155.9, 145.0, 144.3, 137.9. 134.7, 129.5, 127.4, 122.8, 120.4, 110.7, 109.9, 100.1. 78.0, 64.5, 64.0, 58.2, 48.7, 32.4, 32.1, 26.7, 25.5, 24.9, 24.7; MS (ES+) m/z 435.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH:9]2[CH2:11][O:10]2)=[CH:4][N:3]=1.[NH2:12][CH2:13][CH2:14][OH:15].CCOC(C)=O.C1COCC1>C1COCC1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH:9]([OH:10])[CH2:11][NH:12][CH2:13][CH2:14][OH:15])=[CH:6][C:7]=1[CH3:8]
Reactant: NCCO
Reactant: Cc1cc(C2CO2)cnc1Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(O)CNCCO)cnc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (RS)-2-bromo-3-methyl-5-(oxiran-2-yl)pyridine (1.4 g) in THF (6 ml) was added 2-aminoethanol (3.92 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into EtOAc/THF (1:1) and the mixture was washed with saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford (RS)-1-(6-bromo-5-methylpyridin-3-yl)-2-(2-hydroxyethylamino)ethanol (1.76 g) as an off-white solid which was used in the next step without further purification. MS (ISP): 277.0 ([{81Br}M+H]+), 275.0 ([{79Br}M+H]+), 258.9 ([{81Br}M+H—H2O]+), 257.0 ([{79Br}M+H—H2O]+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:13])[CH:11]=[CH2:12])=[CH:5][CH:4]=1.[OH:14][C:15]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)[C:16]([O:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][CH3:26])[CH2:21][CH2:20]1)=[O:17]>O1CCCC1>[OH:14][C:15]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)[C:16]([O:18][C@H:19]1[CH2:20][CH2:21][C@H:22]([N:25]([CH2:12][CH2:11][C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:8][CH:7]=2)=[O:13])[CH3:26])[CH2:23][CH2:24]1)=[O:17]
Reactant: C=CC(=O)Nc1ccc(CO)cc1
Reactant: CN[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Solvent: C1CCOC1
Product: CN(CCC(=O)Nc1ccc(CO)cc1)[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Temperature: 75 °C
Reaction time: 96 h

Procedure:
To a solution of N-[4-(hydroxymethyl)phenyl]acrylamide (intermediate 79; 0.3 g, 1.7 mmol) in tetrahydrofuran (6 mL) was added trans-4-(methylamino)cyclohexyl hydroxy(di-2-thienyl)acetate (intermediate 5; 0.5 g, 1.42 mmol). The mixture was placed in a sealed vessel and stirred for 4 days at 75° C. The solvent was removed under reduced pressure and the crude obtained was purified by preparative reversed-phase HPLC (System 2) to give the title compound (34%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([CH:11]=1)[CH2:9][C:8]1[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:7]=1[N:6]=[C:5]2[N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]([CH3:30])([CH3:29])[C:25]([O:27][CH3:28])=[O:26])[CH2:19][CH2:18]1.[CH3:31][C:32]1(C)[C:36](C)(C)OB(C(C)=C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH3:29][C:24]([CH3:30])([CH2:23][N:20]1[CH2:19][CH2:18][N:17]([C:5]2[C:4]3=[CH:3][C:2]([CH:32]([CH3:36])[CH3:31])=[CH:11][N:10]3[CH2:9][C:8]3[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:7]=3[N:6]=2)[CH2:22][CH2:21]1)[C:25]([O:27][CH3:28])=[O:26]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)C(C)(C)CN1CCN(C2=Nc3ccc(C)cc3Cn3cc(Br)cc32)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CO
Product: COC(=O)C(C)(C)CN1CCN(C2=Nc3ccc(C)cc3Cn3cc(C(C)C)cc32)CC1
Temperature: 140 °C

Procedure:
Mix methyl 3-[4-(2-bromo-7-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-2,2-dimethylpropanoate (1.00 equiv; 600.00 mg, 1.27 mmoles), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (3.00 equiv; 638.93 mg, 3.80 mmoles) in methanol (15 mL). Add a pre-blended mixture of 1.09 wt % tris(dibenzylideneacetonyl)bis-palladium (Pd2(dba)3), 1.16 wt % 1,1′-bis(di-tert-butylphosphino)ferrocene (dtbpf) and 97.75 wt % tripotassium phosphate (1.06 g) and heat at 140° C. for 25 mins in a microwave. Filter the reaction mixture through celite and dilute to 25 mL volume with methanol. Hydrogenate the methanolic solution by passing at 1 mL/min. through a H-Cube® flow hydrogenator using a 10% Pd/C catalytic cartridge at 50° C. Evaporate the solvent in vacuo to give methyl 2,2-dimethyl-3-{4-[7-methyl-2-(propan-2-yl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl]piperazin-1-yl}propanoate. MS (m/z): 437.28 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])=[CH:4][CH:3]=1.Cl[C:20](=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]>N1C=CC=CC=1>[CH3:28][O:27][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[O:7])=[CH:17][CH:18]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(N)cc1
Reactant: COC(=O)CCCCC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)CCCCC(=O)Nc1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 2-(4-aminobenzoyl)hydrazinecarboxylate (1.0 g, 3.98 mmol) in anhydrous pyridine (20 mL) was added dropwise methyl 6-chloro-6-oxohexanoate (Fluka) (750 μL) at rt. After 30 min, aminomethyl resin (Polymers Laboratories PL-AMS, 1.96 mmol/g, 970 mg) was added and the resulting mixture was stirred overnight at rt. After filtration and rinsing the resin, water (160 mL) was added into the filtrate and a white solid precipitated out. Filtration and washing with water gave a white solid, which was dried under vacuo at 50° C. for 5 hrs. The title compound (981 mg) was obtained as a white solid (63%) in 99.8% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH:9]([CH3:11])[CH2:8][C:7]2[NH:6][CH:5]=[C:4]([C:12]([O:14]CC)=[O:13])[C:3]1=2.[OH-].[Na+].Cl>C(O)C>[O:1]=[C:2]1[CH2:10][CH:9]([CH3:11])[CH2:8][C:7]2[NH:6][CH:5]=[C:4]([C:12]([OH:14])=[O:13])[C:3]1=2
Reactant: CCOC(=O)c1c[nH]c2c1C(=O)CC(C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1CC(=O)c2c(C(=O)O)c[nH]c2C1

Procedure:
A stirred mixture of ethyl 4-oxo-6-methyl-4,5,6,7-tetrahydrobenzofuran-3-carboxylate (15.7 g, 71 mmol) and ammonium acetate (9.54 g, 124 mmol) in N,N,-dimethylformamide (75 mL) was heated at 100° C. for 2 hour The reaction mixture was concentrated in vacuo, ice water was added, and the precipitate collected, rinsed with water then diethyl ether and dried to give ethyl 4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylate (5.94 g). To this ester was added aqueous 5N sodium hydroxide (50 mL) and ethyl alcohol (10 mL) and the mixture heated at reflux for 40 minutes. The reaction mixture was cooled in an ice water bath, acidified with aqueous hydrochloric acid, and the precipitate collected, rinsed with water then diethyl ether and dried to give 4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (5.2 g). m.p. 210-211° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1B(O)O.Br[C:16]1[N:17]=[CH:18][C:19]([NH:22][C:23](=[O:32])[C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[N:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>[Pd].O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:16]1[N:17]=[CH:18][C:19]([NH:22][C:23](=[O:32])[C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[N:20][CH:21]=1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: O=C(Nc1cnc(Br)cn1)c1c(F)cccc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(Nc1cnc(-c2cc(C(F)(F)F)ccc2Cl)cn1)c1c(F)cccc1F
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-5-trifluoromethyl-benzeneboronic acid (a, 5 mmol), N-(5-bromo-pyrazin-2-yl)-2,6-difluoro-benzamide (b, 5 mmol), palladium catalyst (0.30 mmol), potassium carbonate (1 g) in dry 1,4-dioxane (20 mL) was heated at 100° C. for 24 h. The mixture was taken up with ethyl acetate (EtOAc) (100 mL), washed with water (2×100 mL) and dried over Na2SO4. The oil obtained on concentration was purified by flash chromatography followed by recrystallization to give Compound 1 as a yellowish solid (0.19 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[NH2:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1.O>[OH-].[Na+].ClCCl.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[NH2:11][C:12]1[C:17]([O:18][CH2:4][C:3]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=2[Cl:1])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: Clc1ccc(CBr)c(Cl)c1
Reactant: Nc1ncccc1O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Nc1ncccc1OCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2,4-dichlorobenzyl bromide (15 g, 76.7 mmol) and 2-amino-3hydroxypyridine (7.7 g, 69.7 mmol) in 40% aqueous sodium hydroxide solution (52 ml) and dichloromethane (52 ml) was treated with Adogen 464 (5 ml) and stirred vigorously at room temperature for 16 hours. More water was added and the product extracted into dichloromethane, dried, and the solvent evaporated to obtain the product after trituration with ether (13.3 g, 70%), m.p. 120°-121° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:11]2[CH:12]=[N:13][N:14]([CH2:15][CH3:16])[C:10]=2[N:9]=[C:8]2[C:17](=NCCCC)[C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[CH2:20][CH2:21][C:7]=12)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)[OH:32]>C(OCC)(=O)C.CCOCC>[CH2:1]([NH:5][C:6]1[C:11]2[CH:12]=[N:13][N:14]([CH2:15][CH3:16])[C:10]=2[N:9]=[C:8]2[C:17](=[O:32])[C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[CH2:20][CH2:21][C:7]=12)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(O)O
Reactant: CCCCN=C1c2ccccc2CCc2c1nc1c(cnn1CC)c2NCCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCNc1c2c(nc3c1cnn3CC)C(=O)c1ccccc1CC2

Procedure:
7.2 g. of N-butyl-11-(butylimino)-1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]-pyridin-4-amine (0.018 mol.) and 100 ml. of aqueous sulfuric acid (30%) are reacted according to the procedure of Example 6, yield: 4.7 g. (75%); m.p. 181°-183° (ethyl acetate/ether).
Reaction SMILES: I[C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1.[CH3:25][C:26]1([CH3:33])[C:30]([CH3:32])([CH3:31])[O:29][BH:28][O:27]1.C(N(CC)CC)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:11]1([C:9]2[C:10]3[C:2]([B:28]4[O:29][C:30]([CH3:32])([CH3:31])[C:26]([CH3:33])([CH3:25])[O:27]4)=[CH:3][N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]=3[N:6]=[CH:7][N:8]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(N3CCOCC3)ncnc21
Reactant: CC1(C)OBOC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2cn(COCC[Si](C)(C)C)c3ncnc(N4CCOCC4)c23)OC1(C)C
Temperature: 95 °C

Procedure:
To a solution of 5-iodo-4-(morpholin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (P1) (500 mg, 1.09 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (543 mg, 4.24 mmol) in 1,4-dioxane (20 mL) was added tris(dibenzylideneacetone)dipalladium(0) (99.7 mg, 0.109 mmol), triethylamine (439 mg, 4.34 mmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos, 51.8 mg, 0.109 mmol), and the reaction mixture was heated at 95° C. for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 30% ethyl acetate in petroleum ether) afforded the product as a yellow oil. Yield: 415 mg, 0.901 mmol, 83%. LCMS m/z 461.3 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.73 (s, 1H), 5.59 (s, 2H), 3.87-3.93 (m, 4H), 3.68-3.74 (m, 4H), 3.49-3.56 (m, 2H), 1.35 (s, 12H), 0.87-0.93 (m, 2H), −0.06 (s, 9H).
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:15]([O:17]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CC(O)C.[O:32]([C:34]#[N:35])[K].Cl>C(O)C.CO.O.O(C#N)[K]>[C:21]1([CH2:20][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][C:15](=[O:17])[NH:35][C:34]2=[O:32])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)CCNCCCN(Cc1ccccc1)Cc1ccccc1
Reactant: N#CO[K]
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CC(C)O
Product: O=C1CCN(CCCN(Cc2ccccc2)Cc2ccccc2)C(=O)N1
Reaction time: 0.25 h

Procedure:
Intermediate (52) was stirred in ethanol (150 ml). The mixture was acidified with HCl/2-propanol (±60 ml)+water (2 ml). The mixture was stirred for 15 minutes. The solvent was evaporated at 60° C. Ethanol was added to the residue. The solvent was evaporated. A mixture of methanol in water (70:30; 200 ml) was added to the residue and the mixture was stirred, then warmed slightly until complete dissolution. The acidic solution was added dropwise (over 30 minutes, under argon) to a solution of KOCN (0.100 mol) in a mixture of methanol in water (70:30; 100 ml), stirred at room temperature pH went from ±8 to ±6). The reaction mixture was stirred for 19 hours at room temperature. More KOCN (0.32 g) was added and the reaction mixture was stirred for 90 minutes at room temperature. More KOCN (0.9 g) was added and the reaction mixture was stirred for 75 minutes at room temperature, then for 6 days at 95° C. The reaction mixture was cooled. Concentrated HCl (20 ml) was added dropwise. The reaction mixture was stirred for 2 hours at 95° C., then stood overnight at room temperature. The precipitate was filtered off, and the filtrate was stirred and cooled for 3 hours on an ice-bath. The resulting precipitate was filtered off and dried, yielding 19.6 g of 1-[3-[bis(phenylmethyl)amino]propyl]dihydro-2,4(1H,3H)-pyrimidinedione (intermediate 53).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[C:3]=1[CH3:16].[CH3:17][S:18]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O)(=[O:20])=[O:19]>CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+]>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[NH:21][S:18]([CH3:17])(=[O:20])=[O:19])=[C:3]([CH3:16])[C:4]=2[F:15])=[N:9][CH:10]=1
Reactant: CS(=O)(=O)Nc1ccccc1B(O)O
Reactant: Cc1c(Cl)ccc(-c2cnc(N)cn2)c1F
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Product: Cc1c(-c2ccccc2NS(C)(=O)=O)ccc(-c2cnc(N)cn2)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.9 %

Procedure:
To a mixture of 5-(4-chloro-2-fluoro-3-methylphenyl)pyrazin-2-amine (75 mg, 0.32 mmol), (2-(methylsulfonamido)phenyl)boronic acid (85 mg, 0.39 mmol) and chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (5.0 mg, 0.006 mmol) in a sealed tube flushed with N2 were added N2 sparged K3PO4 (1.26 ml, 0.5 N) followed by N2 sparged THF (0.63 ml). The reaction mixture was stirred at rt for 18 hours. The reaction mixture was then partitioned between EtOAc and brine. The organic layer was isolated, dried over MgSO4, filtered and concentrated to dryness. Purification by FCC afforded the title compound (100 mg, 85%). MS (ESI): mass calcd. for C18H17FN4O2S, 372.10; m/z found, 373.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.39-8.35 (m, 1H), 8.02 (d, J=1.5, 1H), 7.70 (m, 1H), 7.47 (dd, J=8.1, 1.0, 1H), 7.45-7.39 (m, 1H), 7.29 (m, 1H), 7.21 (dd, J=7.6, 1.5, 1H), 7.07 (d, J=8.0, 1H), 6.67 (s, 2H), 2.87 (s, 3H), 2.01 (d, J=2.5, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:48]/[O:49][CH2:50][CH:51]([C:53]([OH:55])=[O:54])[CH3:52])/[C:8]([NH:10][C@H:11]2[CH2:14][N:13]([C:15]([NH:17][S:18]([NH:21][C:22]3[C:27]([OH:28])=[C:26]([OH:29])[CH:25]=[CH:24][C:23]=3[CH2:30][C:31]([O:33]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:32])(=[O:20])=[O:19])=[O:16])[C:12]2=[O:47])=[O:9])[N:6]=1.C1(OC)C=CC=CC=1.[F:64][C:65]([F:70])([F:69])[C:66]([OH:68])=[O:67]>ClCCl>[F:64][C:65]([F:70])([F:69])[C:66]([OH:68])=[O:67].[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:48]/[O:49][CH2:50][CH:51]([C:53]([OH:55])=[O:54])[CH3:52])/[C:8]([NH:10][C@H:11]2[CH2:14][N:13]([C:15]([NH:17][S:18]([NH:21][C:22]3[C:27]([OH:28])=[C:26]([OH:29])[CH:25]=[CH:24][C:23]=3[CH2:30][C:31]([OH:33])=[O:32])(=[O:19])=[O:20])=[O:16])[C:12]2=[O:47])=[O:9])[N:6]=1
Reactant: CC(CO/N=C(\C(=O)N[C@H]1CN(C(=O)NS(=O)(=O)Nc2c(CC(=O)OC(c3ccccc3)c3ccccc3)ccc(O)c2O)C1=O)c1csc(N)n1)C(=O)O
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(CO/N=C(\C(=O)N[C@H]1CN(C(=O)NS(=O)(=O)Nc2c(CC(=O)O)ccc(O)c2O)C1=O)c1csc(N)n1)C(=O)O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 10.83 g (13.6 mmol) of the crude [[[[[(S)-3-[[(Z)-(2-amino-4-thiazolyl)[(2-carboxy-2-methylethoxy)imino]acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]amino]sulfonyl]amino]-3,4-dihydroxybenzeneacetic acid, diphenylmethyl ester in 45 ml of dry dichloromethane at -10° C., a cold solution of 11 ml of anisole in 110 ml of trifluoroacetic acid was added. After being stirred at 0° C. for 10 minutes, the clear solution was evaporated in vacuo at 0°-5° C. and the residue was treated with dry ether. The solid was collected by suction, washed with dry ether, dried in vacuo to give 7.28 g of impure [[[[[(S)-3-[[(Z)-(2-amino-4-thiazolyl)[(2-carboxy-2-methylethoxy)imino]acetyl]amino]-2-oxo-1-azetidinyl]carbonyl]amino]sulfonyl]amino]-3,4-dihydroxybenzeneacetic acid, trifluoroacetate salt.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[O:18][CH2:17][CH:16]([NH:22][C:23](=[O:27])[O:24][CH2:25][CH3:26])[C:15]2=[O:28]>C1COCC1>[CH2:1]([C:15]1([OH:28])[C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][CH3:10])[CH:13]=2)[O:18][CH2:17][CH:16]1[NH:22][C:23](=[O:27])[O:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCOC(=O)NC1COc2ccc(OC)cc2C1=O
Solvent: C1CCOC1
Product: CCOC(=O)NC1COc2ccc(OC)cc2C1(O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
26.4 ml (52.8 mmol) of benzylmagnesium chloride under nitrogen atmosphere were cooled to 0° C. with an ice bath and 3.5 g (13.2 mmol) ethyl 6-methoxy-4-oxochroman-3-ylcarbamate dissolved in 100 ml dry THF were slowly added. The mixture was stirred at 0° C. for 1 h. The cooling bath was removed and saturated ammonium chloride solution was added. Water was added until a clear solution was obtained. The phases were separated and the organic phase was washed with saturated ammonium chloride solution, dried over MgSO4, and concentrated in vacuo to give 6.87 g (9.1 mmol, quant.) of crude material.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2C)=[CH:7][CH:6]=1)[CH3:4].C1N2CN3CN(C2)CN1C3.F[C:30](F)(F)[C:31]([OH:33])=O>>[CH3:18][N:2]([CH3:1])[CH:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:30]([CH:31]=[O:33])=[C:13]([CH3:14])[CH:12]=2)=[CH:9][CH:10]=1)[CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccccc1-c1ccc(C(C)N(C)C)cc1
Agent: C1N2CN3CN1CN(C2)C3
Product: Cc1cc(-c2ccc(C(C)N(C)C)cc2)ccc1C=O
Reaction time: 0.25 h
Yield: 52 %

Procedure:
A mixture of 4.76 g of (±)-4'-[1-(dimethylamino)ethyl]-2-methylbiphenyl, 2.94 g of hexamethylenetetramine and 30 mL of trifluoroacetic acid was heated to boiling under reflux for 5 days. The reaction mixture was then concentrated and treated with 100 mL of ice-water, whereupon it was stirred for 15 minutes, made basic with sodium carbonate and extracted with ether. After evaporation of the ethereal extracts and chromatography of the residue on silica gel with methylene chloride/methanol 9:1 as the elution agent there were obtained 2.8 g (52%) of (±)-4-[4'-(1-(dimethylamino)ethyl)phenyl]-2-methylbenzaldehyde as a yellow oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:11]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:8]2([CH2:9][CH3:10])[C:7](=[O:25])[CH2:6]1)[C@@H:20]1[C:15](=[CH:16][C:17](=[O:24])[CH2:18][CH2:19]1)[CH2:14][CH2:13]3)(=[O:3])[CH3:2].[C:26]1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>COC(OC)(C)C>[C:1]([O:4][C@@H:5]1[C@H:11]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:8]2([CH2:9][CH3:10])[C:7](=[O:25])[CH2:6]1)[C@@H:20]1[C:15]([CH:16]=[C:17]([O:24][CH3:26])[CH2:18][CH2:19]1)=[CH:14][CH2:13]3)(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Agent: c1cc[nH+]cc1
Solvent: COC(C)(C)OC
Product: CC[C@]12CC[C@H]3[C@@H](CC=C4C=C(OC)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Temperature: -10 °C
Yield: 623.6 %

Procedure:
A suspension of 15α-acetoxy-18-methyl-estr-4-en-3,17-dione (48 g, 139 mmol) and pyridinium p-Toluenesulfonate (4.8 g, 19.1 mmol) in 2,2-dimethoxypropane (400 ml) was refluxed for 6 h. The mixture was then cooled to −10° C. for 2 h. The precipitate was filtered, washed with cooled methanol and dried under vacuum to afford 15α-acetoxy-3-methoxy-18-methyl-estra-3,5-dien-17-one (42.7 g, yield: 86%).