Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C@H:12]2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:34]I.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:34])[C@@H:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C@H:12]2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccc(Br)cc2)[C@H](c2ccc(Cl)c(Cl)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(Br)cc1)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 0.17 h
Yield: 92 %

Procedure:
To a solution of the compound (1.16 g) obtained in step 1 in DMF (22 mL) was added sodium hydride (60% in oil, 175 mg) at 0° C., and the mixture was stirred for 10 min. Then, methyl iodide (681 μL) was added, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10→90% ethyl acetate/hexane) to give tert-butyl (3R,4R)-4-{[(4-bromophenyl)carbonyl](methyl)amino}-3-(3,4-dichlorophenyl)piperidine-1-carboxylate (1.09 g, 92%) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:15]=3[CH2:14][CH:13]([CH3:24])[N:12]([C:25](=[O:27])[CH3:26])[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.O.NN>CO.[Ni]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:15]=3[CH2:14][CH:13]([CH3:24])[N:12]([C:25](=[O:27])[CH3:26])[N:11]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2CC1C)OCO3
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CC(=O)N1N=C(c2ccc(N)cc2)c2cc3c(cc2CC1C)OCO3
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a suspension of 1.91 g (5.37 mmol) of 1-(4-nitrophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine (product of Example 27) in 40 ml of methanol about 0.2 g of Raney nickel catalyst and 1.4 ml (28 mmol) of 100% hydrazine hydrate were added, then the reaction mixture was stirred at 20°-25° C. for one hour. The starting nitro derivative was dissolved within 10-20 minutes. After filtering the filtrate was evaporated under reduced pressure, the white crystalline residue was washed with 30 ml of distilled water onto a filter, it was washed with 3×10 ml of distilled water and dried at 100 ° C. to give 1.50 g of a raw product, m.p. 218°-220° C. This raw product was purified by treating with 12 ml of hot isopropanol. After cooling it was filtered at 5° C., washed with 3×1 ml of isopropanol and dried at 100° C. to yield 1.40 g (77.35%) of a white crystalline powder, m.p. 221°-223° C. On the basis of analyses and spectra it was identical to the product of Example 15 obtained by a different process.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[OH:6].[Cl-].O.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](O)(=[O:22])=[O:21])=[CH:16][CH:15]=1>CO>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:6][C@H:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3][NH:2][CH3:1])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CNCC[C@H](O)c1cccs1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CNCC[C@H](OS(=O)(=O)c1ccc(C)cc1)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
A mixture of (S)-3-methylamino-1-thiophen-2-yl-propan-1-ol (5.0 g, 29.2 mmol), methylene to chloride (50 mL), p-toluenesulfonic acid hydrate (5.55 g, 29.2 mmol) and methanol (20 mL) is stirred 1 h at 25° C., then concentrated to dryness. The residue (10.8 g) which solidifies after a few hours is finally recrystallised from butanol (30 mL) affording a white powder (6.0 g, 60%);
Reaction SMILES: [N:1]([CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](O)=[O:6])=[N+:2]=[N-:3].S(Cl)([Cl:16])=O>>[N:1]([CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([Cl:16])=[O:6])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC(C(=O)O)c1ccccc1
Reactant: O=S(Cl)Cl
Product: [N-]=[N+]=NC(C(=O)Cl)c1ccccc1

Procedure:
A solution of 1.61 grams (9.1 mmole) of 2-azido-2-phenylacetic acid [Forster and Mueller, J. Chem. Soc., 97, 138 (1910)] and 5 ml. of thionyl chloride is heated under reflux for hour. The reaction solution is evaporated under reduced pressure to furnish a residue of 2-azido-2-phenylacetyl chloride which is dissolved in 10 ml. of dichloromethane and is added over 5 minutes to a stirred ice-bath cooled solution of 2.4 grams (10 mmole) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, 2.02 grams (20 mmole) of triethylamine and 50 ml. of dichloromethane. After 30 minutes the reaction solution is allowed to warm to room temperature. After a further 3 hours, the more volatile components of the solution are evaporated under reduceed pressure and the residue is taken up in 50 ml. of water. The aqueous solution is washed twice with 25 ml. portions of ethyl acetate, and it is then adjusted to pH 2.5 by the careful addition of 6N hydrochloric acid. The resulting cloudy mixture is extracted twice with 30 ml. portions of ethyl acetate. After being dried using anhydrous sodium sulfate, the combined extracts are filtered and solvent is evaporated in vacuo. The residue is dissolved in 10 ml. of dichloromethane; 1.0 ml. of triethylamine is added, and the resulting solution is poured into 350 ml. of rapidly stirred diethyl ether. The solid which precipitates is filtered off giving 1.62 g. (38% yield) of the title compound as its triethylamine salt. IR (KBr disc): 1792 cm-1 (β-lactam) and 1693 cm-1 (amide I). NMR (in D2O/NaHCO3): 7.40 ppm (s,5H, aromatic hyddrogens), 5.60 and 5.80 ppm (m and m, 2H, C-5 and C-6 hydrogens), 5.30 ppm (m,2H, C-3 hydrogen and side-chain methine hydrogen), 3.20 (q,6H, NCH2CH3 (1.60 ppm (s,3H, C-2 methyl hydrogens), 1.30 ppm (t,9H, NCH2CH3), 1.10 ppm (s,3H, C-2 -methyl hydrogens).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.Cl[C:20]1[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:25]([C:22]1[S:21][C:20]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]3[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)=[N:24][CH:23]=1)#[N:26]
Reactant: N#Cc1cnc(Cl)s1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ncc(C#N)s3)cc(C)c21
Temperature: 70 °C
Yield: 80 %

Procedure:
To a mixture of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (3.75 g, 15 mmol, 1 eq.) and 2-chlorothiazole-5-carbonitrile (3.25 g, 22.5 mmol, 1.5 eq.) in 100 ml DMF was added cesium carbonate (14 g, 45 mmol, 3 eq.). The reaction was heated at 70° C. for two hours. It was then quenched by water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude was purified by column chromatography (4.3 g, yield 80%). MS (ESI) m/z=717 [2M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][Si:27]([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(O)cc1)c1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of 4-bromo-N-(4-hydroxyphenyl)benzamide in DMF (1.3 M), 2.5 eq of imidazole and 1.2 eq of TBDMSCl were added and the solution stirred at RT for 30 minutes. The reaction mixture was diluted with EtOAc. The organic phase was washed with aqueous HCl (1N), saturated aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (95%); MS (ES+) m/z 406 (M+H)+, m/z 408 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:13][C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(=CC#N)c2ccccc2)ccc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOc1cc(C(CC#N)c2ccccc2)ccc1OC
Yield: 16.7 %

Procedure:
To a solution of 3-(3-ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile (0.9 g, 3.2 mmol) in a mixture of ethanol and ethyl acetate (20 mL/30 mL) was added 0.5 g of 10% palladium on carbon catalyst in portions. The mixture was hydrogenated in a Parr-Shaker apparatus at 55-60 psi of hydrogen for 12 days. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford the crude product. The crude product was purified by flash column chromatography (silica gel, 4% hexane/methylene chloride) to afford 0.15 g (15%) of the product as an oil: 1H NMR (CDCl3) δ7.40-7.16 (m, 5 H); 6.88-6.78 (m, 3 H), 4.32 (t, J=7.5 Hz, 1 H), 4.03 (q, J=7 Hz, 2 H), 3.85 (s, 3 H), 3.00 (d, J=7.5 Hz, 2 H), 1.42 (t, J=7 Hz, 3 H); 13C NMR (CDCl3) δ148.7, 148.5, 141.5, 133.7, 128.8, 127.4, 127.3, 119.5, 118.5, 112.7, 111.6, 64.4, 55.9, 46.7, 24.5, 14.7; Anal. Calcd for C18H17NO2. Theoretical: C, 76.84; H, 6.81; N, 4.98. Found: C, 76.53; H, 6.92; N, 4.95.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][CH:8]=2)[CH:4]=[N:3]1.S(Cl)([Cl:18])=O>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]([C:13]([Cl:18])=[O:15])=[CH:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2ccc(C(=O)O)cn2)cn1
Reactant: O=S(Cl)Cl
Product: Cn1cc(-c2ccc(C(=O)Cl)cn2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxylic Acid (0.48 g) in thionyl chloride (5.0 ml) was stirred at room temperature for 2 hours. The volatile material was removed under reduced pressure to afford 6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carbonyl chloride as a solid, which was utilized without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:12][CH:13]1[C:17](=[O:18])[N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH:14]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C@H:13]2[C:17](=[O:18])[N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][C@H:14]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C1CN(c2ccccc2)C(=O)C1N
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NC(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
To a solution of 3,4-dichlorophenylisocyanate in CH2Cl2 (3 ml) was added a solution of aminopyrrolidinone of Example S (350 mg, 1.41 mmol) in CH2Cl2 (3 ml) and the resulting solution was stirred for 18 h at room temperature. Concentration in vacuo gave a solid which was triturated with CH2Cl2 and filtered to give the title compound (420 mg, 68%) as a solid. MS M+1 calcd for C20H19N3O4Cl2 437, found 437. DSC=249.1°-251.7° C. at 112.7 J/g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:21]([F:24])([F:23])[F:22])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:29][C:30]#[N:31]>CN(C=O)C>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:29][C:30]#[N:31])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:21]([F:22])([F:23])[F:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)Nc1cnccc1-c1ccccc1OC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC#N)c1cnccc1-c1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a solution of [4-(2-trifluoromethoxy-phenyl)-pyridin-3-yl]-carbamic acid tert-butyl ester (190 mg, 0.54 mmol) in DMF (5 mL) was added sodium hydride (24 mg, 0.59 mmol, 60% dispersion in mineral oil) at 0° C. The reaction mixture was stirred at 25° C. for 30 minutes. Then bromoacetonitrile (71 mg, 0.59 mmol) was added to the reaction mixture and it was stirred at 25° C. for 24 hours. The reaction mixture was quenched with 10 mL saturated NH4Cl solution and extracted with EtOAc (2×40 mL). The combined EtOAc part was dried over Na2SO4 and evaporated. The residue crude was purified by silica gel column chromatography eluting with a gradient of n-hexane:EtOAc (85:15 to 70:30) to get the desired compound as a light yellow sticky liquid (185 mg, 88%). LC-MS (ESI): m/z=394.4 [M+H]+.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:26]#[C:27][C:28]4[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][CH:19]3[CH2:23][O:22]C(C)(C)[O:20]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O>C(O)=O>[C:1]12([C:11]3[CH:12]=[C:13]([C:26]#[C:27][C:28]4[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][CH:19]([OH:20])[CH2:23][OH:22])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COC(=O)c1ccc(C#Cc2ccc(OCC3COC(C)(C)O3)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Solvent: O=CO
Solvent: O
Product: COC(=O)c1ccc(C#Cc2ccc(OCC(O)CO)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Temperature: 100 °C

Procedure:
450 mg (0.9 mmol) of methyl 4-[3-(1-adamantyl)-4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]phenyl-ethynyl]benzoate were placed in suspension in 10 ml of a formic acid solution (40%) and heated at 100° C. for three days. The reaction mixture was poured into water and extracted with ethyl acetate and the organic phase was separated by settling, dried over magnesium sulphate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with dichloromethane. 220 mg (53%) of the expected methyl ester were collected, which ester had the melting point 202°-3° C.
Reaction SMILES: O[C:2]([O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[CH2:24][CH2:23][CH2:22]2)([CH:9]1[O:14][CH2:13][CH2:12][N:11]([CH:15]([CH3:17])[CH3:16])[CH2:10]1)C1C=CC=CC=1.[C:28]1(C)[CH:33]=[CH:32][C:31](S(O)(=O)=O)=[CH:30][CH:29]=1>C1(C)C(C)=CC=CC=1>[CH:15]([N:11]1[CH2:12][CH2:13][O:14][CH:9]([CH2:2][O:18][C:19]2[CH:20]=[C:21]3[C:25]([C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][CH2:22]3)=[CH:26][CH:27]=2)[CH2:10]1)([CH3:17])[CH3:16]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)N1CCOC(C(O)(Oc2ccc3c(c2)CCC3)c2ccccc2)C1
Solvent: Cc1ccccc1C
Product: CC(C)N1CCOC(COc2ccc3c(c2)CC=C3c2ccccc2)C1
Yield: 70.2 %

Procedure:
In 50 ml. of xylene was dissolved 1.5 g. of 2-(1-hydroxy-1-phenyl-5-indanyloxymethyl)-4-isopropylmorpholine and after adding to the solution 5 mg. of p-toluenesulfonic acid, the mixture was refluxed for 8 hours. Thereafter, xylene was distilled off under reduced pressure and the residue was adsorbed on a silica gel column prepared from 100 ml. of silica gel in chloroform and eluted using ethyl acetate as the eluent. After removing the first 10 ml. of the ethyl acetate eluate emerging from the column, 200 ml. of the subsequent ethyl acetate eluate was collected and dried to provide 1.0 g. (yield 70.2%) of 4isopropyl-2-(3-phenyl-6-indenyloxymethyl)morpholine. The citrate of the product had a melting point of 107°-109° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[CH2:12]([NH:14][C:15]([C:17]1[S:25][C:24]2[C:19](=[N:20][CH:21]=[CH:22][C:23]=2Cl)[CH:18]=1)=[O:16])[CH3:13]>>[CH2:12]([NH:14][C:15]([C:17]1[S:25][C:24]2[C:19](=[N:20][CH:21]=[CH:22][C:23]=2[NH:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2]([CH3:1])=[CH:10]3)[CH:18]=1)=[O:16])[CH3:13]
Reactant: CCNC(=O)c1cc2nccc(Cl)c2s1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: CCNC(=O)c1cc2nccc(Nc3ccc4[nH]c(C)cc4c3)c2s1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-Chloro-thieno[3,2-b]pyridine-2-carboxylic acid ethylamide by a procedure analogous to Example 1C. MS: 351 (MH+); HPLC Rf: 4.33 min; HPLC purity: 98%.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6](Cl)(=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+]>O.CCOCC>[C:6]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCC(=O)Cl
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCCCCCC(=O)NCC(=O)O
Yield: 72.4 %

Procedure:
Glycine (1.5 g, 20 mmol) and heptanoyl chloride (22 mmol) were reacted in the presence of NaOH (40 mmol) in a mixture of water and ether using the method described in Example 5. The crude product was recrystallized from EtOAc (30 ml) to give title compound (2.71 g, 72%), m.p. 98°-100° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:30](O)(=[O:36])[CH2:31][NH:32][C:33]([NH2:35])=[O:34]>>[C:33]([NH:32][CH2:31][C:30]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[O:36])(=[O:34])[NH2:35]
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: NC(=O)NCC(=O)O
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)CNC(N)=O)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy) 1-(3-methoxyphenyl)propan-2-amine (6a, 200 mg, 0.51 mmol) and hydantoic acid (60 mg, 0.51 mmol).
Reaction SMILES: C(O[C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[CH:17]([CH3:23])[NH:18][C:19](=[O:22])[NH:20][N:21]=3)[CH:14]=[CH:15][C:10]=2[S:9][C:8]1=[O:24])=[O:5])C.[OH:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[OH:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([C:4]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]([CH3:23])[NH:18][C:19](=[O:22])[NH:20][N:21]=4)[CH:14]=[CH:15][C:10]=3[S:9][C:8]2=[O:24])=[O:5])[CH2:30][CH2:29]1
Reactant: CCOC(=O)Cn1c(=O)sc2ccc(C3=NNC(=O)NC3C)cc21
Reactant: OCCN1CCNCC1
Product: CC1NC(=O)NN=C1c1ccc2sc(=O)n(CC(=O)N3CCN(CCO)CC3)c2c1
Temperature: 120 °C
Reaction time: 4 h
Yield: 72.5 %

Procedure:
A mixture of the object compound of Example 21 (1.0 g) and 1-(2-hydroxyethyl)piperazine (1.2 g) was stirred for 4 hours at 120° C. After cooling, the reaction mixture was chromatographed on silica gel (45 g) by eluting with a mixture of chloroform and methanol (9:1) to give 0.9 g of 3-[4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-5-(5-methyl-3-oxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)benzothiazolin-2-one.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].C1(C)C(S(O[CH2:31][CH2:32][CH:33]2[CH2:37][CH:36]=[CH:35][CH2:34]2)(=O)=O)=CC=CC=1>>[CH:33]1([CH2:32][CH2:31][N:8]2[C:9]([S:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])[CH2:37][CH:36]=[CH:35][CH2:34]1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: Cc1ccccc1S(=O)(=O)OCCC1CC=CC1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2CCC2CC=CC2)c1
Yield: 34.8 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and 2-(cyclopent 3-en-1-yl)ethyl toluenesulfonate were reacted by the same method with example 35 to obtain the titled compound (134 mg).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=[C:9]2I.[C:24](=O)([O-])[O-:25].[Cs+].[Cs+].CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C>CO.[Cu]I>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=[C:9]2[O:25][CH3:24]
Reactant: O=C([O-])[O-]
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(C3OCCO3)ccc21
Agent: [Cu]I
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Agent: [Cs+]
Solvent: CO
Product: COc1nn(COCC[Si](C)(C)C)c2ccc(C3OCCO3)cc12
Temperature: 140 °C

Procedure:
To a microwave-flask containing 300 mg (0.672 mmol) 5-(1,3-dioxolan-2-yl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole (Example 6A), 438 mg (1.344 mmol) cesium carbonate and 32 mg (0.134 mmol) 3,4,7,8-tetramethyl-1,10-phenanthroline in methanol (4 ml) were added 13 mg (0.067 mmol) copper(I) iodide. The flask was placed in an ultrasonic bath, and argon was bubbled through for a period of five minutes. The flask was then sealed and heated to 140° C. for 2 h using microwave irradiation. The reaction mixture was filtered over celite which was washed with acetonitrile. The filtrates of a total of seven reactions at this scale were combined and purified by preparative RP-HPLC (acetonitrile/water gradient) to afford 940 mg (57% of th.) of the title compound.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:13]=1)C.[CH3:36][N:37]([CH3:42])[CH2:38][CH2:39][CH2:40][NH2:41]>>[Cl:18][C:17]1[C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:41][CH2:40][CH2:39][CH2:38][N:37]([CH3:42])[CH3:36])=[O:3])=[N:13][C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)=[N:15][CH:16]=1
Reactant: CN(C)CCCN
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NCCCN(C)C)n3)cc2CC1

Procedure:
The title compound was prepared from 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester and N(1), N(1)-dimethyl-propane-1,3-diamine in an analogous manner to Example 1396. Product isolated as a yellow foam (27 mg, 45%). LCMS (m/e) 552 (M+H): 1H-NMR (CDCl3, 400 MHz) δ 11.62 (s, 1H), 8.91 (s, 1H), 8.72 (d, 1H, J=8.5 Hz), 8.10 (s, 1H), 7.47 (d, 1H, J=7.9 Hz), 7.46-7.40 (m, 1H), 7.36 (s, 1H), 7.30-7.23 (m, 1H), 7.10-7.00 (m, 2H), 6.96 (s, 1H), 3.64-3.53 (m, 4H), 3.39 (s, 3H), 2.97-2.88 (m, 4H), 2.82-2.70 (m, 6H), 2.55 (t, 2H, J=5.4 Hz), 2.33 (s, 6H), 1.84-1.75 (m, 2H).