Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NCCC1C2C(=CC=C(C#N)C=2)NC=1.[C:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2)#[N:16].[Cl:26][CH2:27][C:28](Cl)=[O:29]>>[Cl:26][CH2:27][C:28]([C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[C:17]([C:15]#[N:16])[CH:18]=2)[NH:22][CH:21]=1)=[O:29]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: O=C(Cl)CCl
Agent: N#Cc1ccc2[nH]cc(CCN)c2c1
Product: N#Cc1ccc2[nH]cc(C(=O)CCl)c2c1

Procedure:
A mixture of 2.6 g of 3-(2-aminoethyl)-5-cyanoindole [obtainable by reaction of 5-cyanoindole with 2-chloroacetyl chloride to give 3-(2-chloroacetyl)-5-cyanoindole, subsequent reduction with diborane, reaction with phthalimide and hydrolysis]and one equivalent of 5-[N,N-bis(2-chloroethyl)amino]benzofuran [obtainable by reaction of 2-chloroacetyl chloride with 5-aminobenzofuran and subsequent reduction with diborane] in 40 ml of acetone and 40 ml of water is boiled for 20 hours and then worked up in the customary manner. 1-[2-(5-Cyanoindol-3-yl)ethyl]-4-(benzofuran-5-yl)piperazine is obtained.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:3]1[C:13]([O:15][CH3:16])=[O:14].[CH2:17]([O:19][C:20](Cl)=[O:21])[CH3:18].O>C(Cl)Cl>[CH2:17]([O:19][C:20]([NH:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:3]1[C:13]([O:15][CH3:16])=[O:14])=[O:21])[CH3:18]
Reactant: COC(=O)c1c(-c2ccccc2)ccn1N
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Nn1ccc(-c2ccccc2)c1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
Methyl 1-amino-3-phenyl-1H-pyrrole-2-carboxylate (0.200 g, 0.925 mmol) was dissolved in CH2Cl2 (20 mL) and then was added TEA (0.387 mL, 2.77 mmol), followed by ethylchloroformate (0.0890 mL, 0.925 mmol). The reaction mixture was stirred at room temperature for overnight. Water (50 mL) was added to reaction mixture and the aqueous mixture was extracted with CH2Cl2 (25×2 mL). The organic layer separated and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using CombiFlash (REDISEP®, silica gel, 24 g, 15% EtOAc/hexanes) to afford methyl 1-((ethoxycarbonyl)amino)-3-phenyl-1H-pyrrole-2-carboxylate (0.100 g, 37.5%). LCMS Condition B-39: retention time 2.14 min, [M+1]=289.0.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:16])[C:10](=[O:15])[N:11]2[OH:14])=[CH:6][CH:5]=1)(O)=[O:2].C([O:24][N:25]1C2C(=CC=C(C(O)=O)C=2)NC(=O)C1=O)C1C=CC=CC=1.C(Br)C1C=CC=CC=1>P([O-])(O)(O)=O.[K+].C(O)C>[OH:14][N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([C:1](=[O:2])[NH:25][OH:24])[CH:13]=2)[NH:8][C:9](=[O:16])[C:10]1=[O:15]
Reactant: O=C(O)c1ccc2[nH]c(=O)c(=O)n(O)c2c1
Reactant: O=C(O)c1ccc2[nH]c(=O)c(=O)n(OCc3ccccc3)c2c1
Agent: BrCc1ccccc1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CCO
Product: O=C(NO)c1ccc2[nH]c(=O)c(=O)n(O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
1-Benzyloxy-7-carboxyquinoxaline-2,3(1H,4H)-dione 7-Carboxy-1-hydroxyquinoxaline-2,3(1H,4H)-dione (2.22 g, 10 mmol) was dissolved in a mixture of 50 ml of 1M potassium dihydrogen phosphate buffer (pH 7.4) and 25 ml of ethanol by gently heating. To the cooled mixture was added 1.19 ml (10 mmol) of benzylbromide and the mixture was stirred overnight at room temperature. The precipitate was isolated by filtration and washed with ethanol. The crude product was triturated with 4M hydrochloric acid and washed with water and dried in vacuo to give 1.56 g (50%) of the title compound. 1H-NMR (DMSO-d6): 5.22 (s, 2H, CH2), 7.2-7.9 (m, 8H, ArH), 12.35 (s, 1H, exchangeable), 13.05 (br.s, 1H, exchangeable).
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:8][Br:9])([CH2:6][OH:7])[CH2:4][OH:5].Cl.[CH2:11]=O>>[Br:1][CH2:2][C:3]1([CH2:8][Br:9])[CH2:6][O:7][CH2:11][O:5][CH2:4]1
Reactant: C=O
Reactant: OCC(CO)(CBr)CBr
Agent: Cl
Product: BrCC1(CBr)COCOC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A suspension of 26.2 g of 2,2-bis(bromomethyl)-1,3-propanediol, 50 ml of concentrated hydrochloric acid and 50 ml of 38% formaldehyde was stirred in a 50° C. oil bath overnight, then cooled to room temperature and filtered. The filtrate was extracted with three 100 ml portions of ether. The ether extracts were combined, washed with water, dried and evaporated to an oil. A small amount of solid which formed was removed by filtration and washing with ether. The combined filtrate and wash was evaporated under reduced pressure, giving 26.9 g of 5,5-bis(bromomethyl)-1,3-dioxane as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[S:13].C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:17]2[NH:11][C:12](=[S:13])[NH:14][C:15]2=[O:16])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: O=C1CNC(=S)N1
Reactant: O=Cc1ccc(O)c(Br)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)NC1=Cc1ccc(O)c(Br)c1
Yield: 75.8 %

Procedure:
Prepared according to the procedure described in Example 1 using 3-bromo-4-hydroxybenzaldehyde (3.1 g, 15 mmoles), 2-thiohydantoin (1.7 g, 15 mmoles), sodium acetate (4.5 g, 55 mmoles), and acetic acid (35 ml), to afford the pure product (3.4 g), mp 262° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.Cl.CN.[CH2:21]([N:23](CC)CC)C.[BH4-].[Na+].N>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].C(O)C>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH:14]([NH:23][CH3:21])[CH2:13][CH2:12]1
Reactant: CCN(CC)CC
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CN
Solvent: CCO
Product: CNC1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 398.6 %

Procedure:
A mixture of 1-(2-fluoro-4-nitrophenyl)piperidin-4-one (compound of Reference Example 26; 5.00 g, 2.10 mmol), methylamine hydrochloride (2.83 g, 4.20 mmol), titanium tetraisopropoxide (11.9 g, 4.20 mmol), triethylamine (4.25 g, 4.20 mmol) and ethanol (25 ml) was stirred at room temperature for 16 hours under argon atmosphere. Sodium borohydride (1.58 g, 4.20 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 7 hours. 2.8N aqueous ammonia (25 ml) was added to the reaction mixture at 0° C., and the mixture was stirred for 30 minutes. The reaction mixture was filtered, and the filtrate was extracted with dichloromethane. 2N aqueous hydrochloric acid was added to the organic layer, and the mixture was stirred. The water layer was adjusted to pH=12 by addition of 2N aqueous sodium hydroxide and extracted with dichloromethane. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (2.12 g, 40%) as a yellow-brown liquid.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[NH2:17][C:18]1[C:27]2[N:26]=[CH:25][C:24]([CH2:28][CH2:29][C:30]3[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][C:31]=3[CH3:38])=[CH:23][C:22]=2[C:21]2[CH:39]=[CH:40][C:41]([CH3:43])=[CH:42][C:20]=2[N:19]=1>C1COCC1>[NH2:17][C:18]1[C:27]2[N:26]=[CH:25][C:24]([CH2:28][CH2:29][C:30]3[CH:37]=[CH:36][C:33](/[CH:34]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:32][C:31]=3[CH3:38])=[CH:23][C:22]=2[C:21]2[CH:39]=[CH:40][C:41]([CH3:43])=[CH:42][C:20]=2[N:19]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C=O)cc3C)cc12
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Temperature: 0 °C

Procedure:
To a suspension of NaH (3 eq) in THF (0.2 M) stirred at 0° C. was added ethyl 2-(diethoxyphosphoryl)acetate (commercially available) (3 eq). After stirring for 30 minutes, a solution of 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzaldehyde (from the previous step) in THF (0.2 M) was added dropwise. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with sat. NH4Cl solution, and was extracted with EtOAc. Combined organic extracts were dried and concentrated to give a crude residue which was purified by chromatography (silica gel, 50-100% EtOAc in hexanes) to afford (E)-ethyl 3-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl)acrylate as a white solid. 1H NMR: (CDCl3): δ 8.54 (d, 1H), 8.29 (d, 1H), 7.99 (d, 1H), 7.57 (d, 1H), 7.44 (s, 1H), 7.23 (dd, 1H), 7.11 (dd, 1H), 7.05 (d, 1H), 6.33 (d, 1H), 5.93 (s, 2H), 4.19 (q, 2H), 3.10-2.95 (m, 4H), 2.44 (s, 3H), 2.23 (s, 3H), 1.26 (t, 3H). LRMS [M+H]=426.2
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][CH3:59])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:31][N:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:8]2[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]3[CH:4]=[CH:3][C:2]([C:46]4[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][CH3:59])=[CH:48][CH:47]=4)=[CH:32][C:6]=3[CH:7]=2)=[O:15])=[CH:18][CH:19]=1)[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CCCOCCCOc1ccc(OB([O-])[O-])cc1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: Cc1ccccc1
Solvent: CCO
Product: CCCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) were added toluene/ethanol/water (10/1/1, 19.2 ml) and then were added 4-(3-propoxypropoxy)phenyl borate (165 mg) and potassium carbonate (175 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed for 14 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate/THF, washed with, saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[4-(3-propoxypropoxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 103) (245 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH2:18][CH3:19])[NH:5][C:6](=[O:9])[C:7]=1[NH2:8].Cl.[C:21](N)(=N)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])(=O)C.[Na+]>C(O)C>[CH2:17]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:4]1[N:3]=[C:2]2[C:7](=[N:8][C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:1]2)[C:6](=[O:9])[N:5]=1)[CH2:18][CH3:19]
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Reactant: N=C(N)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCOc1ccccc1C1=NC(=O)C2=NC(c3ccccc3)=NC2=N1
Temperature: 165 °C

Procedure:
A mixture of 4,5-diamino-2-(2-propoxyphenyl)-pyrimidine-6-one (1.3 g), benzamidine hydrochloride (2 g) and anhydrous sodium acetate (0.9 g) was heated in an oil bath (temperature 160-170° C.) for 2 hours. The reaction mixture was digested with hot ethanol to give a solid, 0.76 g, m.p. 267-271° C. This was combined with a further sample, 0.2 g, (similarly prepared) and recrystallised from aqueous acetic acid to give the title compound, 0.74 g, m.p. 259-260° C.
Reaction SMILES: C(O[C:6]([N:8]([CH2:10][C:11]1[O:32][C:14]2[CH2:15][N:16]([C:19](=[O:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:17][CH2:18][C:13]=2[CH:12]=1)C)=O)(C)(C)C.[ClH:33]>CO>[ClH:33].[CH3:6][NH:8][CH2:10][C:11]1[O:32][C:14]2[CH2:15][N:16]([C:19](=[O:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:17][CH2:18][C:13]=2[CH:12]=1
Reactant: CN(Cc1cc2c(o1)CN(C(=O)CCCCCc1ccccc1)CC2)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CNCc1cc2c(o1)CN(C(=O)CCCCCc1ccccc1)CC2
Reaction time: 0.5 h

Procedure:
1-[2-(N-tert-Butoxycarbonyl-N-methylaminomethyl)-5,7-dihydro-4H-furo[2,3-c]pyridin-6-yl]-6-phenylhexan-1-one 0.191 g was dissolved in 2 ml of methanol; 0.5 ml of concentrated hydrochloric acid was added, followed by stirring for 30 minutes. This mixture was concentrated to yield the desired product.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[C:7](=[O:27])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:9][CH:10]=1.[NH2:29][O:30][K].C(O)(=O)C>CO.CO.C(Cl)(Cl)Cl>[OH:30][NH:29][C:3]([CH2:4][CH2:5][C:6]1[C:7](=[O:27])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:13]=2)[CH2:9][CH:10]=1)=[O:2]
Reactant: COC(=O)CCC1=CCN(Cc2ccc(NC(=O)c3ccccc3)cc2)C1=O
Reactant: NO[K]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(CCC1=CCN(Cc2ccc(NC(=O)c3ccccc3)cc2)C1=O)NO
Temperature: 0 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
7 mg of compound (i) prepared by the above Step 2 was dissolved in methanol solution (0.02 mM) and then 1.7 M methanolic suspension solution containing NH2OK (0.4 ml, 0.68 mM) was added thereto at 0° C. and the resulting mixture was stirred for 8 hrs at room temperature. The resulting mixture was neutralized with 0.01 ml of acetic acid, diluted with 10% methanol/chloroform solution, filtered and concentrated in vacuo. The resulting compound was purified by Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:9) as an eluant to give 3.2 mg of N-{4-[3-(2-hydroxycarbamoyl-ethyl)-2-oxo-2,5-dihydro-pyrrole-1-yl-methyl]-phenyl}-benzamide (j) (yield: 46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)([OH:24])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
(4-Methoxyphenyl)magnesium bromide (0.5 M in THF, 90 mL, 45.0 mmol) was added slowly (˜25 minutes) via cannula to a cold (0° C.) solution of 1-benzylpiperidin-4-one (5.4 mL, 30.2 mmol) in THF (60 mL). The reaction was stirred at 0° C. under nitrogen for 2 hours. The reaction was quenched with saturated aqueous NH4Cl then diluted with ether. The organic fraction was washed with saturated aqueous NH4Cl (2×) brine (1×) and concentrated. Purification using flash chromatography (5-100% EtOAc/hexane) provided 4.02 g (44%) of the titled compound. MS (DCI) m/z 298 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([F:20])[CH:3]=1.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(=O)([O-])O.[Na+]>O1CCOCC1.O.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:29]=[CH:30][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:26][CH:27]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([F:20])[CH:3]=1
Reactant: Cn1cc(C(=O)/C=C/c2ccc(Cl)cc2F)ccc1=O
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: O=C([O-])O
Solvent: O
Solvent: C1=CCCC=CCC1
Solvent: C1COCCO1
Product: Cn1cc(C(=O)CC(c2ccc(S(C)(=O)=O)cc2)c2ccc(Cl)cc2F)ccc1=O

Procedure:
In analogy to example 203, step 1, (E)-5-(3-(4-chloro-2-fluorophenyl)acryloyl)-1-methylpyridin-2(1H)-one (example 314, step 2) was reacted with 4-(methylsulfonyl)phenyl-boronic acid in the presence of chloro(1,5-cyclooctadiene)rhodium(I) dimer and sodium hydrogencarbonate in 1,4-dioxane and water at 60° C. to give the title compound as a colourless solid, MS (ESI+): m/z=448.0 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4]1.N1C(C)=CC=CC=1C.O1CCCC1.FC(F)(F)S(O[Si:62]([C:65]([CH3:68])([CH3:67])[CH3:66])([CH3:64])[CH3:63])(=O)=O>C(OCC)(=O)C>[Si:62]([O:1][CH2:2][C:3]1([CH2:7][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:24]=[CH:25][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:27][CH:28]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)[CH2:4][CH2:5][CH2:6]1)([C:65]([CH3:68])([CH3:67])[CH3:66])([CH3:64])[CH3:63]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(CO)CCC3)CC2)c2ncnn12
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(CO[Si](C)(C)C(C)(C)C)CCC3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 4′-{[4-(trans-4-{[1-(hydroxymethyl)cyclobutyl]methoxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.3 g), 2,6-lutidine (0.14 mL) and tetrahydrofuran (10 mL) was added tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.18 mL), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.31 g, 86%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:14])[C:3]=1[CH2:15][CH2:16]Cl.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.O>CN(C)C=O>[C:18]([N:22]1[C:2]2[N:7]3[N:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:6]3[N:5]=[C:4]([CH3:14])[C:3]=2[CH2:15][CH2:16]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1nc2c([N+](=O)[O-])cnn2c(Cl)c1CCCl
Reactant: CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2c([N+](=O)[O-])cnn2c2c1CCN2C(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 44.5 %

Procedure:
In 18 ml of anhydrous dimethylformamide were dissolved 1.75 g (6.36 mmol) of 7-chloro-6-(2-chloroethyl)-5-methyl-3-nitropyrazolo[1,5-a]pyrimidine, and 0.93 g (12.72 mmol) of tert-butylamine and 1.61 g (15.94 mmol) of triethylamine were successively added to the solution, and the mixture was stirred at room temperature for 6 hours. Thereafter, the reaction mixture was poured into water and extracted with ethyl acetate (150 ml×2). The ethyl acetate layers were put together, washed with a saturated saline solution and dried over anhydrous magnesium sulfate, and the solvent was then distilled off. The residue was subjected to column chromatography on silica gel (hexane:ethyl acetate=2:1) and recrystallized from ethanol to obtain 0.78 g (yield: 44.6%) of the intended product.
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:37][S:38]([CH:41]=[CH2:42])(=[O:40])=[O:39]>CC(N(C)C)=O>[CH:25]([O:24][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][C@H:2]4[NH:1][CH2:42][CH2:41][S:38]([CH3:37])(=[O:40])=[O:39])[N:15]=2)=[CH:23][C:20]=1[C:21]#[N:22])([CH3:27])[CH3:26]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N)no2)cc1C#N
Reactant: C=CS(C)(=O)=O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NCCS(C)(=O)=O)no2)cc1C#N
Temperature: 80 °C

Procedure:
To a solution of (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 (18 mg, 0.05 mmol) in DMA (0.5 mL) was added DIEA (87 μL, 0.5 mmol) and methylvinylsulfone (53 mg, 0.5 mmol). The reaction was heated to 80° C. for 24 h. The crude reaction mixture was purified by preparative HPLC to give (R)-2-isopropoxy-5-(3-(1-((2-(methylsulfonyl)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile 125. LCMS-ESI (m/z) calculated for C24H26N4O4S: 466.2. found 467.1 [M+H]+, tR=2.58 min. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=2.1 Hz, 1H), 8.32 (dd, J=8.9, 2.2 Hz, 1H), 8.07 (d, J=7.6 Hz, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.10 (d, J=9.0 Hz, 1H), 4.77 (hept, J=6.1 Hz, 1H), 4.33 (t, J=6.7 Hz, 1H), 3.44 (ddd, J=17.5, 8.7, 4.8 Hz, 1H), 3.36-3.10 (m, 5H), 3.03 (s, 3H), 2.57-2.43 (m, 1H), 1.98-1.83 (m, 1H), 1.46 (d, J=6.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 173.04, 168.94, 162.76, 146.05, 143.49, 134.11, 133.92, 128.24, 127.03, 126.83, 123.28, 116.84, 115.33, 113.58, 103.88, 72.76, 63.05, 55.41, 42.42, 40.86, 32.98, 31.86, 21.75. Compound 126 was made in an analogous fashion.
Reaction SMILES: [H-].[Na+].C1COCC1.[C:8]([CH:12]([C:29]([O:31][CH3:32])=[O:30])[C:13]1[CH:14]=[CH:15][N:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]2=[O:28])([O:10][CH3:11])=[O:9].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>O>[C:8]([C:12]([C:13]1[CH:14]=[CH:15][N:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]2=[O:28])([C:29]([O:31][CH3:32])=[O:30])[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)c1ccc2cc(C(C(=O)OC)C(=O)OC)ccn2c1=O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(C(=O)OC)(C(=O)OC)c1ccn2c(=O)c(C(=O)OCC)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
An oven-dried 50 ml three-necked round-bottom flask equipped with a reflux condenser was charged with NaH (160 mg, 60% suspension in oil, 4 mmol, washed with hexane) and 10 ml THF. Ethyl 8-(dicarbomethoxymethyl)-4-oxo-4H-quinolizine-3-carboxylate (19) (700 mg, 2 mmol) was added in three portions and stirring was continued for 1 h, followed by addition of ethyl bromoacetate (0.5 ml, 5.3 mmol). The reaction mixture was refluxed overnight, cooled to room temperature and poured into 100 ml water. The aqueous layer was extracted three times with 100 ml dichloromethane. The organic solvent was evaporated and the crude product was purified by flash chromatography (ethyl acetate) to give a yellow viscous oil (630 mg, 74%). 1H NMR (δ, CDCl3): 1.24 (t, J=7 Hz, 3H), 1.42 (t, J=7 Hz, 3H), 3.39 (s, 2H), 3.84 (s, 6H), 4.14 (q, J=7 Hz, 2H), 4.41 (q, J=7 Hz, 2H), 6.63 (d, J=8 Hz, 1H), 7.14 (dd, J=2 Hz, J=7 Hz, 1H), 7.61 (d, J=2 Hz, 1H), 8.40 (d, J=8 Hz, 1H), 9.29 (d, J=8 Hz, 1H). MS: m/z 433.1363; required for C21H21NO9: 433.1372.