Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=3)[C:12]([C:22]([F:25])([F:24])[F:23])=[CH:11][N:10]=2)[C:5]([CH3:26])=[CH:4][C:3]=1[CH:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(O)(=O)C.C([BH3-])#N.[Na+]>>[CH3:26][C:5]1[CH:4]=[C:3]([C@H:27]2[CH2:32][CH2:31][C@H:30]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH2:29][CH2:28]2)[C:2]([CH3:1])=[CH:7][C:6]=1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=2)[C:12]([C:22]([F:23])([F:24])[F:25])=[CH:11][N:10]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCC(=O)CC4)cc3C)ncc2C(F)(F)F)n[nH]1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c([C@H]4CC[C@H](N5CCOCC5)CC4)cc3C)ncc2C(F)(F)F)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(2,5-dimethyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanone (40 mg, 0.087 mmol), morpholine (15 μL, 0.174 mmol) and acetic acid (75 μL, 0.13 mmol) was stirred at room temperature for 1 h. Sodium cyanoborohydride (8.2 mg, 0.13 mmol) was added to the reaction and the reaction mixture was stirred overnight. The mixture was concentrated and purified by silica chromatography (MeOH/DCM 8:92) to afford N2-(2,5-dimethyl-4-(trans-4-morpholinocyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine; Rf: 0.38 (Silica; MeOH/DCM 8:92); ESMS m/z 530.3 (M+H+).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[CH2:12]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[CH2:20]([N:19]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Product: O=C(Cc1ccccn1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.6 %

Procedure:
To a solution of 413 mg of 2-pyridylacetic acid hydrochloride, 470 mg of dibenzylamine and 321 mg of 1-hydroxybenzotriazole in 5 ml of dry pyridine was added 637 mg of 1,3-dicyclohexylcarbodiimide, and the mixture was stirred for 15 hours at room temperature. Precipitates were filtered off, the filtrate was concentrated under reduced pressure. The residue was dissolved in a 1N-hydrochloric acid and washed twice with 25 ml of diethyl ether, and then a 2N-aqueous hydroxide was added to the solution to a pH of 11. A separated oil was extracted with 50 ml of dichloromethane, and the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 486 mg of N,N-dibenzyl-2-pyridylacetamide as an oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH:13]2[O:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:6][C:5]=1[O:20][CH3:21].Cl[CH2:23][C:24]1[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:27][CH:28]=1.Cl>CN(C)C=O.O>[CH3:21][O:20][C:5]1[CH:6]=[C:7]([CH2:10][CH2:11][CH2:12][CH:13]2[O:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])[CH:8]=[CH:9][C:4]=1[O:3][CH2:23][C:24]1[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:27][CH:28]=1
Reactant: ClCc1coc(/C=C/c2ccccc2)n1
Reactant: COc1cc(CCCC2OC(=O)NC2=O)ccc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CCCC2OC(=O)NC2=O)ccc1OCc1coc(/C=C/c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
Sodium hydride (60% in oil, 0.32 g) was added, at 0° C., to a solution of 5-[3-(4-hydroxy-3-methoxyphenyl]propyl]-2,4-oxazolidinedione (1.0 g) in N,N-dimethylformamide (DMF) (20 ml). The mixture was stirred for one hour at room temperature. To the reaction mixture was then added 4-chloromethyl-2-[(E)-styryl]oxazole (0.87 g), which was stirred for 3.5 hours at 90° C. The reaction mixture was poured into water, which was acidified with 2N HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated under reduced pressure to yield 5-[3-[3-methoxy-4-[2-[(E)-styryl]-4-oxazolylmethoxy]phenyl]propyl]-2,4-oxazolidinedione (1.1 g, 66%). The product was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.178-179° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][N:18]([CH2:19][C:20]([N:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)=[O:21])[C:12]2=[N:11][C:10]=1[C:35](=[O:37])[SH:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]1[CH:44]=[CH:43][C:42](O)=[C:41](S(N2CCOCC2)(=O)=O)[CH:40]=1>>[C:31]([O:30][C:28]([N:25]1[CH2:26][CH2:27][N:22]([C:20](=[O:21])[CH2:19][N:18]2[C:12]3=[N:11][C:10]([C:35]([S:36][CH:2]([CH:1]=[O:8])[CH2:3][C:42]4[CH:41]=[CH:40][C:39]([F:38])=[CH:44][CH:43]=4)=[O:37])=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:14](=[O:15])[N:13]3[CH:16]=[CH:17]2)[CH2:23][CH2:24]1)=[O:29])([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cn2ccn3c(=O)c(OCc4ccccc4)c(C(=O)S)nc23)CC1
Reactant: O=S(=O)(c1cc(F)ccc1O)N1CCOCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cn2ccn3c(=O)c(OCc4ccccc4)c(C(=O)SC(C=O)Cc4ccc(F)cc4)nc23)CC1

Procedure:
Adapted from the procedure of example 39 using the product of example 109 and the product of example 84
Reaction SMILES: Cl.C(O[C:7](=[O:50])[NH:8][C@H:9]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][O:45]C(C)(C)C)=[CH:38][CH:37]=1)[C:10](=[O:35])[NH:11][C@H:12]([C:21]1[NH:22][C:23]([C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[C:24]([Cl:26])[N:25]=1)[C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])(C)(C)C.C(N(CC)CC)C.Cl[Si](C)(C)C.O=C(Cl)OC(Cl)(Cl)Cl>O1CCOCC1.C1(C)C=CC=CC=1.O1CCCC1.O>[Cl:26][C:24]1[N:25]=[C:21]([C@@H:12]([N:11]2[C:10](=[O:35])[C@@H:9]([C:36]3[CH:37]=[CH:38][C:39]([O:42][CH2:43][CH2:44][OH:45])=[CH:40][CH:41]=3)[NH:8][C:7]2=[O:50])[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[NH:22][C:23]=1[C:27]1[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=1[F:34]
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(OCCOC(C)(C)C)cc1)c1nc(Cl)c(-c2ccc(I)cc2F)[nH]1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: C[C@@H](c1ccccc1)[C@@H](c1nc(Cl)c(-c2ccc(I)cc2F)[nH]1)N1C(=O)N[C@H](c2ccc(OCCO)cc2)C1=O
Temperature: 10 °C
Reaction time: 3 h
Yield: 61.7 %

Procedure:
Hydrogen chloride gas was bubbled into a solution of ((R)-[4-(2-tert-butoxy-ethoxy)-phenyl]-{(1S,2S)-1-[4-chloro-5-(2-fluoro-4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propylcarbamoyl}-methyl)-carbamic acid tert-butyl ester (440 mg, 0.55 mmol) in dioxane for 15 minutes at room temperature and the resulting mixture was allowed to stir under an atmosphere of nitrogen for 3 hours. The reaction was concentrated in vacuo and the residue was dissolved in tetrahydrofuran (15 mL) containing triethylamine (609 μL, 4.37 mmol). Chlorotrimethylsilane (416 μL, 3.28 mmol) was added via syringe at room temperature and the resulting mixture was allowed to stir under an atmosphere of nitrogen for one hour. The reaction was poured into water (10 mL) and extracted with ethyl acetate (2×25 mL). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product, dissolved in tetrahydrofuran (5 mL) containing N,N-diisopropylethylamine was added via an addition funnel to diphosgene (46 μL, 0.38 mmol) in 1:1 v/v toluene/tetrahydrofuran (5 mL) at −78° C. under an atmosphere of nitrogen with stirring. The reaction was allowed to warm to 10° C. then quenched with ice/water (5 mL) and stirred for 2 minutes. The mixture was acidified with 1.0 N aqueous hydrochloric acid solution (10 mL), stirred for 5 minutes then extracted with ethyl acetate (2×25 mL). The organic extracts were combined, washed with water (2×10 mL), brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography over silica gel gradient eluted with 50 to 80% v/v ethyl acetate/hexanes to give (R)-3-{(1S,2S)-1-[4-chloro-5-(2-fluoro-4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-5-[4-(2-hydroxy-ethoxy)-phenyl]-imidazolidine-2,4-dione (229 mg, 62%). HR-MS: calcd for C29H25ClFlN4O4 [M+H+] 675.0666. Found 675.0660.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][N:2]=1.[N+]([O-])([O-])=O.[Ag+:15]>O>[Ag:15].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][N:2]=1
Reactant: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: c1ccc2cnncc2c1
Solvent: O
Product: [Ag]
Temperature: 25 °C

Procedure:
A silver-phthalazine dispersion (1:1 molar ratio) was prepared by first dissolving 1.96 g phthalazine and 0.78 g of 35% gelatin solution (cattle bone, alkali treated, deionized gelatin) in 37.2 g demineralized water. This solution was stirred vigorously at room temperature while adding 4.70 g of 5.72 M AgNO3 solution.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][CH3:13])=[C:4]([C:7]([CH2:10][CH3:11])=[CH:8][CH:9]=1)[CH:5]=O.[C:14](Br)(Br)([Br:16])[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[C:4]([CH:5]=[C:14]([Br:16])[Br:15])[C:3]=1[CH2:12][CH3:13]
Reactant: CCc1ccc(Cl)c(CC)c1C=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCc1ccc(Cl)c(CC)c1C=C(Br)Br

Procedure:
1-Chloro-3-(2,2-dibromo-vinyl)-2,4-diethyl-benzene was prepared from 3-chloro-2,6-diethyl-benzaldehyde, carbon tetrabromide and triphenylphosphine in analogy to Example 1d): colourless oil; 1H-NMR (CDCl3): 1.14 (3H, t, CH3), 1.17 (3H, t, CH3), 2.56 (2H, qd, CH2), 2.72 (2H, q, CH2), 7.03 (1H, d, ArH), 7.29 (1H, d, ArH), 7.44 (1H, s, CH═CBr2).
Reaction SMILES: [NH2:1][C:2]1([C:23]([NH2:25])=[O:24])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])=[O:13])[CH2:4][CH2:3]1.[C:26](N1C=CN=C1)(N1C=CN=C1)=[S:27].CN(C=O)C>O>[Cl:20][C:18]1[CH:17]=[CH:16][C:15]([O:21][CH3:22])=[C:14]([C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][C:2]3([NH:1][C:26](=[S:27])[NH:25][C:23]3=[O:24])[CH2:7][CH2:6]2)[CH:19]=1
Reactant: COc1ccc(Cl)cc1C(=O)CCCCN1CCC(N)(C(N)=O)CC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)CCCCN1CCC2(CC1)NC(=S)NC2=O
Yield: 29 %

Procedure:
A mixture of 4-amino-1-[5-(5-chloro-2-methoxyphenyl)-5-oxopentyl]-piperidine-4-carboxamide (0.36 g, 1 mmol), prepared as in Example 21, 1,1'-thiocarbonyldiimidazole (0.23 g, 1.3 mmol), and DMF (3 mL) was heated 5 hours at 50°-60° C. and then diluted with water. The mixture was extracted with ethyl acetate and the extract was dried (MgSO4) and concentrated. The residue was purified by column chromatography eluting with methylene chloride/methanol+ammonium hydroxide (95:5) to give 8-[5-(5-chloro-2-methoxyphenyl)-5-oxopentyl]-2-thioxo-1,3,8-triazaspiro[4.5]decane-4-one (0.12 g, 0.29 mmol), m.p. 152°-154° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.[OH:21][CH2:22][C:23]([NH:25][NH2:26])=O>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:23]([CH2:22][OH:21])=[N:25][N:26]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Reactant: NNC(=O)CO
Solvent: CCCCO
Product: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
A solution of 1,3-dihydro-7-chloro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione (9.63 g., 0.03 mole) and hydroxy-acetic acid hydrazide (6.66 g.) in n-butyl alcohol (300 ml.) is refluxed for about 15 hours with a slow stream of nitrogen bubbling through the reaction mixture for the first hour. The mixture is then cooled and concentrated in vacuo and the resulting residue is suspended in water, treated with a little ether and crystallized. The solid is collected by filtration and dried in vacuo. Recrystallization of this material from methylene chloride-methanol gives 8-chloro-1-(hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in three crops: 4.96 g. of melting point 239°-241° C., 1.58 g. of melting point 236°-239° C., and 0.365 g. of melting point 232°-236° C. The analytical sample has a melting point of 239.5°-241° C. Anal. calcd. for C17H12Cl2N4O: C, 56.84; H, 3.37; Cl, 19.74; N, 15.60. Found: C, 56.27; H, 3.28; Cl, 19.75; N, 15.55. Preparation 2 8-Chloro-1-(hydroxymethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:33]=[CH:32][C:22]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:21][CH:20]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:33]=[CH:32][C:22]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[CH:21][CH:20]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Product: CC(C)(C)OC(=O)NCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Yield: 78.1 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (290 mg, 0.934 mmol) was reacted with tert-butyl 4-aminobenzylcarbamate (312 mg, 1.40 mmol) to afford the desired product (362 mg, 78%) as a yellow solid: ESI MS m/z 496 [C25H26BrN3O3+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][O:21][CH2:22][CH3:23].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(Cl)(Cl)Cl>C(Cl)Cl.CO>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][O:21][CH2:22][CH3:23])[N:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][S:32]([CH3:31])(=[O:34])=[O:33])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCN
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCNS(C)(=O)=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 52.6 %

Procedure:
A solution of N1-(3-aminopropyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.250 g, 0.795 mmol) in 10 mL of CH2Cl2 was treated with triethylamine (0.221 mL, 1.67 mmol) under an atmosphere of nitrogen and cooled to 0° C. The reaction mixture was treated dropwise with methanesulfonyl chloride (0.065 mL, 0.835 mmol). After 16 h, the reaction mixture was quenched by 10% Na2CO3 solution, diluted with CHCl3 and the phases were separated. The organic portion was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield a light yellow solid. Chromatography (SiO2, 95:5 CHCl3:MeOH) gave an off-white foam. The foam was triturated with diethyl ether and filtered to give N-{3-[(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)amino]propyl}methanesulfonamide (0.164 g) as an off white solid. mp 148–150° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J=7.8 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.44 (t, J=7.1 Hz, 1H), 7.25 (t, J=7.4 Hz, 1H), 7.05–6.95 (m, 2H), 6.61 (s, 2H), 4.76 (s, 2H), 3.62 (q, J=7.0 Hz, 2H), 3.22 (q, J=6.8 Hz, 2H), 3.07 (q, J=6.2 Hz, 2H), 2.88 (s, 3H), 1.78 (p, J=6.3 Hz, 2H), 1.18 (t, J=7.0 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ 152.3, 149.5, 145.3, 132.5, 127.4, 126.1, 124.2, 121.3, 121.3, 114.7, 65.9, 63.1, 49.9, 39.6, 28.1, 15.4; MS (APCI) m/z 393 (M+H)+; Anal. Calcd for C17H24N6O3: C, 52.03; H, 6.16; N, 21.41; Found: C, 51.84; H, 6.28; N, 21.18.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[CH:14]=2)[CH:9]=[CH:8]1)[CH3:6])C.[Li+].[OH-]>>[F:31][C:29]([F:30])([F:32])[O:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]#[C:20][CH2:19][CH2:18][CH2:17][O:16][C:13]2[CH:14]=[C:15]3[C:10]([CH:9]=[CH:8][N:7]3[CH:5]([CH3:6])[C:4]([OH:33])=[O:3])=[CH:11][CH:12]=2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)C(C)n1ccc2ccc(OCCCC#Cc3ccc(OC(F)(F)F)cc3)cc21
Agent: [Li+]
Agent: [OH-]
Product: CC(C(=O)O)n1ccc2ccc(OCCCC#Cc3ccc(OC(F)(F)F)cc3)cc21

Procedure:
In analogy to the procedure described for example 1 e], [rac]-2-{6-[5-(4-trifluoromethoxy-phenyl)-pent-4-ynyloxy]-indol-1-yl}-propionic acid ethyl ester was treated with LiOH to obtain the title compound as yellow oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33](O)=[O:34])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[NH2:41][CH:42]1[CH2:47][CH2:46][O:45][C:43]1=[O:44]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]([NH:41][CH:42]3[CH2:47][CH2:46][O:45][C:43]3=[O:44])=[O:34])=[CH:36][CH:37]=2)=[CH:38][CH:39]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCOC1=O
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCC(=O)O)cc2)cc1
Agent: Br
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCC(=O)NC3CCOC3=O)cc2)cc1

Procedure:
The product from Example 95C and alpha-amino-gamma-butyrolactone hydrobromide were processed as described in Example 251A to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ8.94 (s, 1 H), 8.62 (d, 1 H), 7.23 (m, 7 H), 7.00 (m, 7 H), 6.84 (d, 2 H), 4.69 (dd, 1 H), 4.52 (d, 2 H), 4.36 (m, 1 H), 4.23 (dd, 1 H), 4.05 (s, 2 H), 4.00 (s, 2 H), 2.91 (s, 3 H), 2.39 (m, 4 H), 2.27 (m, 1 H); MS (ESI+) m/z 630 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:16](B(O)O)=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:25]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.C(O)C>C(OCC)C.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>[Cl:36][C:34]1[CH:33]=[C:32]([C:16]2[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:35]=1
Reactant: CCOC(=O)c1ccc(Cl)cc1Br
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: O
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1ccc(Cl)cc1-c1ccccc1-c1ccccc1OCc1ccccc1
Temperature: 90 °C

Procedure:
A mixture of 2′-benzyloxybiphenyl boronic acid (50 mg, 0.16 mmol), ethyl 2-bromo-4-chlorobenzoate (66 mg, 0.25 mmol), potassium carbonate (88 mg, 0.64 mmol) and tetrakis(triphenylphosphine)palladium(0) (10 mg, 5 mol %) in 1:1 toluene/ethanol (2 ml) was stirred and heated at 90° C. under nitrogen for 12 hours. After cooling the mixture was diluted with diethyl ether and water and the organic phase dried (MgSO4) and evaporated to dryness. The residue was chromatographed with ethyl acetate/iso-hexane (1:9) to yield the title compound as a pale yellow gum. (46 mg, 66%).
Reaction SMILES: [CH:1]([N:4]([CH2:9][CH:10]([O:14]CC)[O:11][CH2:12]C)[C:5](=[O:8])[CH2:6][Cl:7])([CH3:3])[CH3:2].[C:17]1([CH3:27])[C:18](S(O)(=O)=O)=[CH:19]C=C[CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH:1]([N:4]([CH2:9][CH:10]1[O:11][CH2:12][CH:18]([CH3:19])[CH:17]([CH3:27])[CH2:22][O:14]1)[C:5](=[O:8])[CH2:6][Cl:7])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: CCOC(CN(C(=O)CCl)C(C)C)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1COC(CN(C(=O)CCl)C(C)C)OCC1C

Procedure:
N-Isopropyl-N-(2,2-diethoxyethyl)-α-chloroacetamide (10 grams), 2,3-dimethylbutandiol-1,4 (4.5 grams) and trace amounts of toluenesulfonic acid are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated until no more ethanol is given off. After this time sodium carbonate (1 gram) is added to the mixture with stirring and the resulting mixture is distilled to yield the desired product N-isopropyl-N-(5,6-dimethyl-1,3-dioxepan-2-ylmethyl)-α-chloroacetamide as an oil.
Reaction SMILES: C[N:2]([CH3:21])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][NH:15][C:16](=[O:20])[O:17][CH2:18][CH3:19])[CH:10]=[CH:11][CH:12]=1)=O.N[C:23]1[C:27]([C:28]#[N:29])=C[NH:25][N:24]=1>>[C:28]([C:27]1[CH:23]=[N:24][N:25]2[C:5]([C:7]3[CH:8]=[C:9]([CH2:13][CH2:14][NH:15][C:16](=[O:20])[O:17][CH2:18][CH3:19])[CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:21]=12)#[N:29]
Reactant: N#Cc1c[nH]nc1N
Reactant: CCOC(=O)NCCc1cccc(C(=O)C=CN(C)C)c1
Product: CCOC(=O)NCCc1cccc(-c2ccnc3c(C#N)cnn23)c1

Procedure:
A 2.0 g portion of [3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]ethylcarbamic acid, ethyl ester was reacted with 1.08 g of 3-aminopyrazole-4-carbonitrile as described in Example 13, giving 2.52 g of the desired product, mp 133°-135° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]2[CH:37]=[C:36]([CH3:38])[C:31]3[NH:32][C:33](=[O:35])[O:34][C:30]=3[CH:29]=2)[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN1C(=O)CCC1.O.CN(C=O)C>[CH3:38][C:36]1[C:31]2[NH:32][C:33](=[O:35])[O:34][C:30]=2[CH:29]=[C:28]([NH:27][C:23]2[CH:22]=[C:21]([NH:1][C:2]3[CH:3]=[C:4]4[C:17](=[CH:18][CH:19]=3)[CH2:16][C:6]3([C:14]5[C:9](=[N:10][CH:11]=[CH:12][CH:13]=5)[NH:8][C:7]3=[O:15])[CH2:5]4)[N:26]=[CH:25][N:24]=2)[CH:37]=1
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: Cc1cc(Nc2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(Nc2cc(Nc3ccc4c(c3)CC3(C4)C(=O)Nc4ncccc43)ncn2)cc2oc(=O)[nH]c12
Temperature: 130 °C
Reaction time: 2 h

Procedure:
57 mg (0.23 mmol) 5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 80 mg (0.23 mmol) 6-(6-chloro-pyrimidin-4-ylamino)-4-methyl-3H-benzoxazol-2-one and 69 mg (0.50 mmol) potassium carbonate were combined in 1.5 mL NMP and stirred for 2 h at 130° C. Then the reaction mixture was cooled, acidified with 1M aqueous hydrochloric acid solution and stirred for 1 h at 50° C. The reaction mixture was diluted with water, the precipitate was taken up in DMF and purified by preparative HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(=O)([O-])[O-].[Na+].[Na+].[Cl:11][C:12]([Cl:19])([Cl:18])[CH2:13][O:14][C:15](Cl)=[O:16]>CC(C)=O.O>[Cl:11][C:12]([Cl:19])([Cl:18])[CH2:13][O:14][C:15]([NH:1][CH2:2][CH2:3][OH:4])=[O:16]
Reactant: NCCO
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NCCO)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2-Aminoethanol (20 g.) and sodium carbonate (27.8 g.) is dissolved in acetone-water (4:1) (500 ml.) and 2,2,2-trichloroethylchloroformate (104.2 g.) is added dropwise to the stirred solution at 0° C. over a period of 0.5 hours. The mixture is stirred at 0° C. for a further 3 hours. The solids are filtered off and washed with acetone and the filtrate is evaporated to dryness. The resulting gum is taken up in chloroform (500 ml.) and washed with water (3×100 ml.). The chloroform solution is evaporated to dryness to give 2-(2,2,2-trichloroethoxycarbonylamino)ethanol; ν max (film), 3300, 2910, 1700, 1520, 1240, 1140, 1055, cm-1 ; δ (CDCl3) 3.43 (2H, t, J 7.5 Hz, HOCH2CH2NH--), 3.77 (2H, t, J 7.5 Hz, HOCH2CH2NH--) and 4.77 ppm (2H, s, --COOCH2CCl3).