Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1C([O-])=O.ClCCl.[CH3:14][O:15][C:16]([C:18]1[C@H:19]2[CH2:27][C@@H:26]3[O:28][C@:25]3([CH3:29])[C@@H:20]2[CH:21]([OH:24])[O:22][CH:23]=1)=[O:17].CCCCCC.[C:36]([O:39]CC)(=[O:38])C>CN(C1C=CN=CC=1)C>[CH3:14][O:15][C:16]([C:18]1[C@H:19]2[CH2:27][C@@H:26]3[O:28][C@:25]3([CH3:29])[C@@H:20]2[C@H:21]([O:24][C:36]([O:39][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:38])[O:22][CH:23]=1)=[O:17]
Reactant: COC(=O)C1=COC(O)[C@@H]2[C@@H]1C[C@@H]1O[C@@]12C
Reactant: O=C([O-])c1ccccc1Cl
Reactant: CCOC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Product: COC(=O)C1=CO[C@@H](OC(=O)Oc2ccccc2)[C@@H]2[C@@H]1C[C@@H]1O[C@]21C
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
1.2 mg of DMAP and 0.9 ml of chlorophenylformate were added to a dichloromethane solution containing 1.12 g of a known (4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-1-hydroxy-7-methylcyclopenta[c]pyrane-4-carboxylic acid methylester followed by stirring for 1 hour at room temperature. The reaction mixture was then extracted with dichloromethane. After washing the organic phase with dilute hydrochloric acid and brine, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless powder from the hexane-ethyl acetate eluate in the form of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(phenoxycarbonyloxy)cyclopenta[c]pyrane-4-carboxylic acid methylester (1.16 g, yield: 70%). The physicochemical properties of this compound are as shown below.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:14])[CH:6]([NH:10][CH:11]1[CH2:13][CH2:12]1)[C:7](=[O:9])[CH3:8])[CH3:3].[N:15]1([C:21]2[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=2)[C:24](O)=[O:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[CH2:2]([O:4][C:5](=[O:14])[CH:6]([N:10]([CH:11]1[CH2:12][CH2:13]1)[C:24](=[O:25])[C:23]1[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:21]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:22]=1)[C:7](=[O:9])[CH3:8])[CH3:3]
Reactant: CCOC(=O)C(NC1CC1)C(C)=O
Reactant: O=C(O)c1cc(N2CCOCC2)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(C)=O)N(C(=O)c1cc(N2CCOCC2)cc(C(F)(F)F)c1)C1CC1
Reaction time: 3 h
Yield: 90.4 %

Procedure:
To 0.4 g (2 mmol) of 2-cyclopropylamino-3-oxo-butyric acid ethyl ester hydrochloride salt, 0.6 g (2 mmol) of 3-morpholin-4-yl-5-trifluoromethyl-benzoic acid, 0.4 g (2 mmol) of EDCI and 0.3 g (2 mmol) of HOBT was added 2 ml of DMF and 0.6 ml (4 mmol) of triethylamine. The mixture was stirred for 3 h after which time the solvent was removed by evaporation; the residue was then re-dissolved in EtOAc, washed with 10% citric acid solution, saturated sodium hydrogen carbonate solution, dried with sodium sulfate and re-concentrated to afford 0.8 g (93%) of crude 2-[cyclopropyl-(3-morpholin-4-yl-5-trifluoromethyl-benzoyl)-amino]-3-oxo-butyric acid ethyl ester. This material was re-dissolved in 5 ml of EtOH and 1 g (8 mmol) of ammonium trifluoroacetate was added. The solvent was evaporated and the residue heated to 130° C. for 16 h. The cooled residue was partitioned between saturated sodium hydrogen carbonate solution and CH2Cl2. The organic phase was dried with sodium sulfate and concentrated. Purification by flash column chromatography [n-heptane/EtOAc 6:4] afforded 0.4 g (55%) of the title compound as colorless solid. MS: 424.2 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:22]I.O>CN(C=O)C>[CH3:22][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=2)[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:10]1
Reactant: CI
Reactant: COC(=O)c1ccc2c(-c3ccccc3)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(-c3ccccc3)cn(C)c2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
NaH (60% dispersion in mineral oil, 4.52 mmol, 186 mg) was added portion-wise to a solution of methyl 3-phenyl-1H-indole-6-carboxylate (2.07 mmol, 757 mg) in DMF at 0° C. and the mixture was stirred for 20 min. Methyl iodide (2.28 mmol, 0.14 mL) was added and the reaction mixture was maintained at 0° C. for 1 h. Water was then added and the reaction was extracted with EtOAc. The organics were concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give 16c.
Reaction SMILES: O[N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].ClC1C=CC(B(O)O)=CC=1.N1C=CC=CC=1>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2].O>[C:6]1(=[O:7])[NH:2][C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]12
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OB(O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: O=C1NC(=O)c2ccccc21
Reaction time: 18 h
Yield: 136.9 %

Procedure:
A mixture of N-hydroxyphthalimide (664 mg, 4.07 mmol), 4-chlorophenylboronic acid (635 mg, 4.06 mmol) and powdered 4 Å molecular sieves (1.02 g) in dichloromethane (20 mL) was stirred open to the air. Pyridine (0.37 mL, 4.6 mmol) and Cu(OAc)2-H2O (812 mg, 4.07 mmol) were added, and stirring was continued for 18 h. Silica gel (10 g) was added, and the mixture was concentrated to dryness. The residue was added to the top of a silica gel chromatography column, and eluted with hexanes-EtOAc (4:1) to provide 24-chlorophenoxy)phthalimide as a white solid (820 mg). This was dissolved in chloroform (37 mL) and methanol (4 mL) and hydrazine hydrate (0.56 mL, 12 mmol) was added. The solution was stirred at room temperature for 24 h. Silica gel (10 g) was added, and the slurry was concentrated to dryness. The solid was added to the top of a silica gel chromatography column, and eluted with hexanes-EtOAc (4:1) to provide O-(4-chlorophenyl)hydroxylamine as a yellow oil (416 mg). This was dissolved in ethanol (5 mL) and treated with HCl/dioxane (4N, 1 mL), followed by gradual addition of EtOAc (50 mL) to precipitate the product. The mixture was filtered and dried under vacuum to provide the titled salt as an off-white crystalline solid (442 mg, 60%). 1H NMR (300 MHz, CD3OD) δ ppm 7.15-7.22 (m, 2H), 7.42-7.49 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[CH:3][CH:2]=1.[N+:13]([CH:16]=[C:17](SC)SC)([O-:15])=[O:14]>CO>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:9][CH2:10][CH2:11][NH:12][C:17]2=[CH:16][N+:13]([O-:15])=[O:14])=[CH:3][CH:2]=1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCCNCc1ccncc1
Solvent: CO
Product: O=[N+]([O-])C=C1NCCCN1Cc1ccncc1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A mixture of N-(4-pyridylmethyl)trimethylenediamine (16.5 g), 1-nitro-2,2-bis(methylthio)ethylene (16.5 g) and methanol (100 ml) was refluxed for 2 hours with stirring. The generated gas was collected by an alkali trap. The reaction mixture was cooled to room temperature, and the resulting crystals were filtered to give 1-(4-pyridylmethyl)-2-(nitromethylene)tetrahydropyrimidine (16 g) of the following formula as pale yellow crystals. Concentrating the filtrate further gave 3 g of this compound.mp. 226°-228° C. ##STR14##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](C(OC)=O)[C:9]([O:11][CH3:12])=[O:10])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.[Li+].[Cl-].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)Cc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
Prepared according to procedure H using dimethyl 2-(4-bromo-2-nitrophenyl)-malonate in DMSO (40 mL), LiCl (1.16 g, 27.4 mmol) and water (0.25 mL, 13.88 mmol) and heating at 100° C. for 15 h. After purification methyl 2-(4-bromo-2-nitrophenyl)acetate was obtained as an orange oil. Mass Spectrum (ESI) m/e=274 [(M+1) (79Br)] and 276 [(M+1) (81Br)].
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:32]=[C:31]3[C:27]([CH2:28][C:29](=[O:33])[NH:30]3)=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1)[CH3:16]>N1CCCCC1.C(O)C>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:32]=[C:31]3[C:27]([C:28](=[CH:12][C:9]4[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=4[CH3:11])[C:29](=[O:33])[NH:30]3)=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1)[CH3:16]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C)c(CCC(=O)O)c2C)c1
Yield: 105.5 %

Procedure:
3-(2-carboxyethyl)-2,4-dimethyl-5-formylpyrrole (97.6 mg), 127 mg 6-(3-ethoxyphenyl)-2-oxindole, and 2 drops piperidine in 2 mL ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 227 mg of the title compound (−100%) as a brown solid.
Reaction SMILES: C(OC(N1CCCC1C1NC(C2C=CC(C3C=CC(C4NC(C5CCN(C(OC(C)(C)C)=O)C5)=NC=4)=CC=3)=CC=2)=CN=1)=O)(C)(C)C.[CH3:47][O:48][C:49](=[O:84])[NH:50][CH:51]([C:55]([N:57]1[CH:62]([C:63]2[NH:64][C:65]([C:68]3[CH:73]=[CH:72][C:71](B4OC(C)(C)C(C)(C)O4)=[CH:70][CH:69]=3)=[CH:66][N:67]=2)[CH:61]2[CH2:83][CH:58]1[CH2:59][CH2:60]2)=[O:56])[CH:52]([CH3:54])[CH3:53].[CH3:85][O:86][C:87](=[O:112])[NH:88][CH:89]([C:93]([N:95]1[CH2:99][CH2:98][CH2:97][CH:96]1[C:100]1[NH:101][C:102]([C:105]2[CH:110]=[CH:109][C:108](Br)=[CH:107][CH:106]=2)=[CH:103][N:104]=1)=[O:94])[CH:90]([CH3:92])[CH3:91].C(OC(N1CCCC1C1NC(C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=CN=1)=O)(C)(C)C.C(OC(N1CCC(C2NC(C3C=CC(Br)=CC=3)=CN=2)C1)=O)(C)(C)C>>[CH3:85][O:86][C:87](=[O:112])[NH:88][CH:89]([C:93]([N:95]1[CH2:99][CH2:98][CH2:97][CH:96]1[C:100]1[NH:101][C:102]([C:105]2[CH:110]=[CH:109][C:108]([C:71]3[CH:70]=[CH:69][C:68]([C:65]4[NH:64][C:63]([CH:62]5[CH:61]6[CH2:83][CH:58]([CH2:59][CH2:60]6)[N:57]5[C:55](=[O:56])[CH:51]([NH:50][C:49]([O:48][CH3:47])=[O:84])[CH:52]([CH3:54])[CH3:53])=[N:67][CH:66]=4)=[CH:73][CH:72]=3)=[CH:107][CH:106]=2)=[CH:103][N:104]=1)=[O:94])[CH:90]([CH3:92])[CH3:91]
Reactant: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Agent: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3ccc(-c4ccc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)cc3)[nH]2)C1
Agent: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Agent: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5C6CCC(C6)N5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C

Procedure:
Following the procedure used to prepare compound 2-(5-{4′-[2-(1-Boc-pyrrolidin-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester, except that [2-methyl-1-(3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-propyl]-carbamic acid methyl ester and (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester were used instead of 2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester and 3-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester. 1H-NMR (300 MHz, CD3OD) δ 7.90-7.70 (m, 10H), 7.20-7.10 (m, 1H), 5.24 (t, 1H), 4.63 (s, 1H), 4.40-3.80 (m, 4H), 3.68 (s, 3H), 3.66 (s, 3H), 2.60-1.60 (m, 13H), 1.05-0.90 (m, 12H); m/z 765.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][C:8]3(OCC[O:15]3)[CH2:7][CH2:6][C:5]2=1>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][C:8](=[O:15])[CH2:7][CH2:6][C:5]2=1
Reactant: Clc1ccc2[nH]c3c(c2c1)CCC1(C3)OCCO1
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCc2c([nH]c3ccc(Cl)cc23)C1
Yield: 26 %

Procedure:
A suspension of 6-chloro-2,2-ethylenedioxy-1,2,3,4-tetrahydrocarbazole in 200 ml. of 1:1 acetic acid/water was heated at reflux under nitrogen for 1.5 hours. The mixture was filtered hot and the filtrate was cooled in an ice bath and again filtered. Crystallization of the solid from methylene chloride/30°-60° petroleum ether gave 5.74 g. (26% yield) of 6-chloro-1,2,3,4-tetrahydrocarbazole-2-one as a flocculent solid, mp 194°-196°.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C@H:12]1[O:16][C:15](=[O:17])[NH:14][C@@H:13]1[CH3:18].[H-].[Na+].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26]Br>CN(C=O)C.CCOC(C)=O.O>[F:21][C:22]([F:35])([F:36])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=1)[CH2:26][N:14]1[C@H:13]([CH3:18])[C@@H:12]([C:3]2[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=2[I:1])[O:16][C:15]1=[O:17]
Reactant: C[C@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)ccc1I
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1[C@@H](c2cc(C(F)(F)F)ccc2I)OC(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of 95 mg of (4R,5R)-5-[2-iodo-5-(trifluoromethyl)phenyl]4-methyl-1,3-oxazolidin-2-one in 1 mL of DMF was added 20 mg of sodium hydride. The mixture was stirred 10 min at 0° C.; then 94 mg of 3,5-bis(trifluoromethyl)benzyl bromide was added. The mixture was stirred 10 min at 0° C., then diluted with 10 mL of EtOAc and 10 mL of water. The phases were separated and the aqueous phase was extracted with 10 mL of EtOAc. The combined organic phases were washed with 10 mL of brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25M column, eluting with 1 CV of 2% EtOAc in hexanes, followed by a linear gradient of EtOAc in hexanes from 2 to 100% over 10 CV to provide the title compound. Mass spectrum (ESI) 598.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.00 (d, J=8.5 Hz, 1H), 7.77 (s, 1H), 7.58 (br s, 3H), 7.34 (dd, J=1.5 Hz, 8 Hz, 1H), 5.36 (d, J=4 Hz, 1H), 4.89 (d, J=16 Hz, 1H), 4.31 (d, J=16 Hz, 1H), 4.48 (dq, J=6 Hz, 4 Hz, 1H), 1.55 (d, J=6.5 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.C(Cl)Cl.[Pt]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc([N+](=O)[O-])c3)c12
Agent: [Pt]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3)c12
Reaction time: 8 h

Procedure:
To ethyl 4-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (7.60 g, 24.3 mmol) in methanol (40.6 mL) and CH2Cl2 (40.6 mL) was added 3% Pt on carbon doped with 0.6% V (4.75 g, 0.730 mmol) and the mixture was stirred under a H2 balloon overnight. The mixture was filtered with celite and washed with DCM and MeOH solution to give ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate after removal of solvent. LRMS (ESI) calc'd for C15H15N4O2 [M+H]+: 283, found 283. 1H NMR (600 MHz, DMSO-D6) δ 12.85 (s, 1H), 8.85 (s, 1H), 8.22 (s, 1H), 7.09 (t, J=7.8 Hz, 1H), 6.90 (s, 1H), 6.71 (d, J=7.2 Hz, 1H), 6.67 (d, J 6.0 Hz, 1H), 5.17 (s, 2H, NH2), 3.86 (q, J=7.2 Hz, 2H), 0.84 (t, J=7.2 Hz, 3H).
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.[CH3:12][N:13]([CH3:26])[C:14]([C:16]1[S:24][C:23]2[C:18](=[N:19][CH:20]=[CH:21][C:22]=2Cl)[CH:17]=1)=[O:15]>>[CH3:12][N:13]([CH3:26])[C:14]([C:16]1[S:24][C:23]2[C:18](=[N:19][CH:20]=[CH:21][C:22]=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:17]=1)=[O:15]
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: CN(C)C(=O)c1cc2nccc(Cl)c2s1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N(C)C)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid dimethylamide by a procedure analogous to Example 1C. MS: 351 (MH+); HPLC Rf: 3.87 min.; HPLC purity: 94%.
Reaction SMILES: [Cl:1][C:2]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14](Cl)[N:5]2[N:6]=[C:7]3[C:12]([CH:11]=[C:10]([F:13])[CH:9]=[CH:8]3)=[C:4]2[N:3]=1.[CH3:23][NH2:24]>O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([CH2:23][NH2:24])[N:5]2[N:6]=[C:7]3[C:12]([CH:11]=[C:10]([F:13])[CH:9]=[CH:8]3)=[C:4]2[N:3]=1
Reactant: CN
Reactant: Fc1ccc2nn3c(Cl)c(-c4ccccc4)c(Cl)nc3c2c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NCc1c(-c2ccccc2)c(Cl)nc2c3cc(F)ccc3nn12
Temperature: 100 °C
Yield: 46.4 %

Procedure:
2 g (7.5 mmol) 2,4-Dichloro-9-fluoro-3-phenylpyrimido[1,2-b]indazole (intermediate example Int-1-0, step 2) and 7.5 mL (15 mmol) of a 2M solution of methylamine in tetrahydrofuran were dissolved in 16.8 mL N,N-dimethylformamide and heated in the microwave for 20′ at 100° C. The solvent was evaporated and the residue was purified by chromatography on silicagel (eluents: dichloromethane/methanol) yielding 960 mg (46.4%) of the desired compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH2:21][C:22](O)=[O:23])[CH:18]=[CH:19][CH:20]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:66][O:67][C:68](=[O:71])[CH2:69][NH2:70]>CN(C=O)C.CCOCC>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH2:21][C:22]([NH:70][CH2:69][C:68]([O:67][CH3:66])=[O:71])=[O:23])[CH:18]=[CH:19][CH:20]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]
Reactant: COC(=O)CN
Reactant: COCc1cc(-c2nc(-c3cccc(CC(=O)O)c3)no2)ccc1-c1ccccc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCc1cc(-c2nc(-c3cccc(CC(=O)NCC(=O)OC)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of crude (3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)acetic acid (308 mg; 0.74 mmol) in DMF (6 mL) at 0° C. was added DIEA (267 4, 1.5 mmol) and HATU (282 mg; 0.74 mmol). After 10 min, a solution of glycine methyl ester hydrochloride (93 mg; 0.74 mmol) in DMF (2 mL) was added and the reaction mixture stirred at RT overnight. Et2O was added and the mixture was washed with water. The organic phase was then dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by preparative HPLC affording the title compound as a white solid. LC/MS (Method B): 484.4 (M−H)−, 486.3 (M+H)+. HPLC (Method A) Rt 5.40 min (Purity: 99.1%).
Reaction SMILES: [CH:1]1C2C(=O)NC3C=CC=CC=3NC=2C=CC=1.Cl.CC1C=C(C=CN=1)C(Cl)=O.[CH3:28][C:29]1[CH:34]=[C:33]([C:35]([N:37]2[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[C:41](=[O:48])[NH:40][C:39]3[CH:49]=[CH:50][CH:51]=[CH:52][C:38]2=3)=[O:36])[CH:32]=[CH:31][N:30]=1>>[CH3:1][N:30]1[CH:29]([CH3:28])[CH2:34][C:33]([C:35]([N:37]2[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[C:41](=[O:48])[NH:40][C:39]3[CH:49]=[CH:50][CH:51]=[CH:52][C:38]2=3)=[O:36])=[CH:32][CH2:31]1
Reactant: Cc1cc(C(=O)N2c3ccccc3NC(=O)c3ccccc32)ccn1
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Agent: Cc1cc(C(=O)Cl)ccn1
Agent: Cl
Product: CC1CC(C(=O)N2c3ccccc3NC(=O)c3ccccc32)=CCN1C

Procedure:
From 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 2-methylisonicotinic acid chloride hydrochloride via 5,10-dihydro-5-[(2-methyl-4-pyridinyl)carbonyl]-11H-dibenzo[b,e][1,4]diazepin-11-one and 5,10-dihydro-5-[(2-methyl-4-pyridinyl)carbonyl]-11H-dibenzo[b,e][1,4]-diazepin-11-one methoiodide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14].N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24].C(N(CC)CC)C>C1C=CC=CC=1>[C:23]([O:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:14])=[O:15])(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: NS(=O)(=O)c1ccccc1C#CCCCO
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(=O)OCCCC#Cc1ccccc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The starting material and analogous starting material may be prepared as follows: 3.0 g of 2-(5-hydroxypent-1-yn-1-yl)-benzenesulfonamide and 4.7 ml of pyridine are dissolved at 45° in 200 ml of benzene. The solution is cooled to room temperature and 1.23 ml of acetyl chloride and 3.2 ml of triethylamine are added. The batch is stirred for 1 hour at room temperature under argon until the thin layer chromatogram no longer shows any starting material. The solvent is evaporated off at 15 torr and 40°. A mixture of ethyl acetate, water and 1N hydrochloric acid (100 ml) is added to the residue. In a separating funnel, after shaking, the organic phase is removed and washed with 0.1N hydrochloric acid and with saturated sodium chloride solution, dried (over magnesium sulfate) and concentrated by evaporation at 15 torr and 40°. The crude product is purified on 200 g of silica gel (Merck, ST 60, 40-63 μm) with hexane/ethyl acetate=1/1 as eluant to yield 2-(5-acetoxy-pent-1-yn-1-yl)-benzenesulfonamide in the form of white crystals. The melting point is 66°-68°. 1H-NMR (300 MHz, DMSO-d6): 7.87 (d, d, 1H); 7.45-7.60 (m, 3H); 7.20 (s, 2H); 4.13 (t, 2H); 2.57 (t, 2H); 2.02 (S, 3H); 1.86 (m, 2H).
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([N:15]2[CH2:20][CH2:19][C@:18]([CH2:27][C:28](=O)[CH3:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][C:16]2=[O:31])[CH3:14])=[CH:9][CH:8]=1>C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br-].C1COCC1>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C@@H:13]([N:15]2[CH2:20][CH2:19][C@:18]([CH2:27][C:28]([CH3:2])=[CH2:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][C:16]2=[O:31])[CH3:14])=[CH:11][CH:12]=1
Reactant: CC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)C1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(C)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a solution of CH3PPh3Br (863.9 mg 2.42 mmol) in THF (8 mL) was added n-BuLi (0.678 ml, 1.69 mmol) at −78° C. under N2. The mixture was stirred at rt for 1 h, a solution of (R)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-oxopropyl)-4-phenylpiperidin-2-one (100 mg 0.24 mmol) in THF (5 mL) was added, and the mixture was stirred at reflux overnight. The reaction was quenched by satd aq NH4Cl and extracted with EtOAc. The combined organic phase was dried and concentrated to give the crude product, which was purified by preparative TLC to give (S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-methylallyl)-4-phenylpiperidin-2-one (60 mg, 60%).