Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[N:20]4[CH:21]=[CH:22][N:23]=[C:19]4[CH:18]=[C:17]([C:24]4[CH:29]=[CH:28][C:27](N5CCOCC5)=[CH:26][CH:25]=4)[N:16]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:36](O)[CH3:37]>>[CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[N:20]4[CH:21]=[CH:22][N:23]=[C:19]4[CH:18]=[C:17]([C:24]4[CH:25]=[CH:26][C:27]([CH:37]5[CH2:36][CH2:15][N:20]([CH3:21])[CH2:19][CH2:18]5)=[CH:28][CH:29]=4)[N:16]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCC(C1CCCC1)n1cc(-c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccn23)cn1
Reactant: CCO
Product: CN1CCC(c2ccc(-c3cc4nccn4c(-c4cnn(C(CC#N)C5CCCC5)c4)n3)cc2)CC1
Yield: 40 %

Procedure:
3-Cyclopentyl-3-(4-(7-(4-morpholinophenyl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (Example 113; 0.015 g, 0.032 mmol) was separated by chiral HPLC (Chiral Tech. OD-H, 2.2 cm×250 mm; 220 nm, 21 mL/min; 50% Ethanol: 50% Hexanes). Peak 1 was isolated to afford the single enantiomer 1 of 3-cyclopentyl-3-(4-(7-(4-(1-methylpiperidin-4-yl)phenyl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (6.0 mg, 40% yield). MS (apci) m/z=468.2 (M+H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[NH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33]>>[OH:33][CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:23]([C:22]1[CH:26]=[CH:27][C:19]([C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:12][CH2:13]2)=[O:18])=[CH:20][CH:21]=1)=[O:25]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Reactant: NCCCCO
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCCCO)cc2)CC1
Yield: 84 %

Procedure:
By the same procedure as described in the example 1, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid and using 4-amino-1-butanol. Then, the product was recrystallized using ethyl acetate and isopropyl ether to give the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[N:24][N:25]=2)=[N:10]1.C1C(=O)N([Br:33])C(=O)C1>>[Br:33][CH2:20][C:13]1[NH:12][C:11]([C:21]2[S:22][CH:23]=[N:24][N:25]=2)=[N:10][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(C)NC(c2nncs2)=NC1c1ccc(Cl)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C1=C(CBr)NC(c2nncs2)=NC1c1ccc(Cl)cc1Cl
Yield: 59.6 %

Procedure:
Ethyl 4-(2,4-dichlorophenyl)-6-methyl-2-(1,3,4-thiadiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2.5 mmol) was reacted with NBS (0.5 g, 2.8 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.71 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2>>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[CH:7][C:6]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: COc1ccc(C=O)cc1C(C)C
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: COc1ccc(C=C2C(=O)Nc3ccc(Cl)cc32)cc1C(C)C

Procedure:
3-Isopropyl-4-methoxybenzaldehyde was condensed with 5-chloro-2-oxindole to give 0.3 g of 5-chloro-3-(3-isopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:17])=[C:10]([Cl:16])[C:11]=2[N+:13]([O-:15])=[O:14])[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4]1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.O1CCOCC1.Cl>O>[ClH:16].[CH3:1][N:2]([CH3:22])[N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:17])=[C:10]([N:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)[C:11]=2[N+:13]([O-:15])=[O:14])[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4]1
Reactant: CN1CCNCC1
Reactant: CN(C)n1cc(C(=O)O)c(=O)c2cc(F)c(Cl)c([N+](=O)[O-])c21
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(N(C)C)c3c2[N+](=O)[O-])CC1
Yield: 83.7 %

Procedure:
A mixture of 3.3 g of 1-dimethylamino-7-chloro-6-fluoro-8-nitro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 3.1 g of 1-methylpiperazine and 25 ml of dioxane is refluxed for 3 hours. The solvent is stripped off in vacuo, the residue is suspended in 25 ml of H2O and the pH is brought to 1 with 10% strength hydrochloric acid. The precipitate is filtered off with suction in the cold and washed with a little cold 10% strength hydrochloric acid and ethanol. 3.6 g of 1-dimethylamino-6-fluoro-8-nitro-7-(4-methyl-1-piperazinyl)1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride of decomposition point 292°-294° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[N:18]([CH:21]([CH:27]([CH3:29])[CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:19]=[O:20]>>[CH2:25]([O:24][C:22]([CH:21]([NH:18][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:20])[CH:27]([CH3:28])[CH3:29])=[O:23])[CH3:26]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CCOC(=O)C(N=C=O)C(C)C
Product: CCOC(=O)C(NC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1)C(C)C
Yield: 95.3 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 14.56 mg (0.0852 mMol) ethyl 2-isocyanato-3-methylbutyrate, 25.0 mg (95%) of the title compound were recovered.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C(#N)C>[CH2:7]([NH:14][CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCc1ccccc1
Reactant: C[Si](C)(C)CCl
Solvent: CC#N
Solvent: O
Product: C[Si](C)(C)CNCc1ccccc1
Temperature: 25 °C
Yield: 63.4 %

Procedure:
To a stirred solution of chloromethyl-trimethyl-silane (25 g, 203.79 mmol, 1 eq.) in acetonitrile (250 mL) was added distilled benzyl amine (44.56 mL, 407.59 mmol, 2 eq) at room temperature. Resulting reaction mixture was refluxed for 16 hours. After consumption of starting material, reaction mixture was cooled to room temperature; benzyl amine hydrochloride salt was precipitate out. Solid was removed by filtration and filtrate was concentrated under reduced pressure to get yellow semi solid. Water was added to residue and extracted with ethyl acetate (3×100 mL). Combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford product as yellow liquid (25 g, crude). Crude used as such for next reaction. 1H-NMR (400 MHz, CDCl3) δ: 0.03 (s, 9H), 2.04 (s, 2H), 3.79 (s, 2H), 3.86 (s, 1H), 7.29-7.33 (m, 5H). (m/z): 193.8 (M+H)
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([CH3:11])([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[S-:12][C:13]#[N:14].[K+]>CN(C)C=O.O>[CH3:10][C:4]([CH3:11])([CH2:3][CH2:2][S:12][C:13]#[N:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: N#C[S-]
Reactant: CCOC(=O)C(C)(C)CCCl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)CCSC#N
Temperature: 100 °C
Reaction time: 7 h
Yield: 65.9 %

Procedure:
In 100 ml of dimethylformamide were dissolved 22.1 g of ethyl 4-chloro-2,2-dimethylbutyrate and 14.5 g of potassium thiocyanate and the solution was stirred at 100° C. for 7 hours. The reaction mixture was poured in 500 ml of water and extracted with ethyl ether. The extract was washed with water and dried (MgSO4) and the solvent was distilled off. The residue was subjected to vacuum distillation to provide 16.4 g of the title compound as colorless oil. b.p. 109°-111° C./0.3 mmHg
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([OH:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:12][CH:13]1[O:18][CH:17]([CH3:19])[CH2:16][N:15]([C:20](Cl)=[O:21])[CH2:14]1>>[CH3:12][CH:13]1[O:18][CH:17]([CH3:19])[CH2:16][N:15]([C:20]([O:11][C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[N:8]([C:20]([N:15]3[CH2:16][CH:17]([CH3:19])[O:18][CH:13]([CH3:12])[CH2:14]3)=[O:21])[N:7]=2)=[O:21])[CH2:14]1
Reactant: Oc1n[nH]c2cc(F)ccc12
Reactant: CC1CN(C(=O)Cl)CC(C)O1
Product: CC1CN(C(=O)Oc2nn(C(=O)N3CC(C)OC(C)C3)c3cc(F)ccc23)CC(C)O1

Procedure:
In analogy to example 1, 200 mg (1.315 mmol) of 6-fluoro-1H-indazol-3-ol were reacted with 280.3 mg (1.578 mmol) of 2,6-dimethylmorpholine-4-carbonyl chloride. Yield: 16 mg (3%), M+H+: 435.29.
Reaction SMILES: [C:1]([O:5][C:6]([C:9]([C:12]([O:15][CH:16]([C:18]([C:21]([O:23]C)=[O:22])([F:20])[F:19])[F:17])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7])([F:4])([F:3])[F:2].C(O)C.[OH-].[K+:29]>O>[C:1]([O:5][C:6]([C:9]([C:12]([O:15][CH:16]([C:18]([C:21]([O:23][K:29])=[O:22])([F:20])[F:19])[F:17])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7])([F:4])([F:3])[F:2]
Reactant: COC(=O)C(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Reactant: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O[K])C(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Temperature: 40 °C
Reaction time: 6 h

Procedure:
CF3O(CF2)3OCHFCF2COOCH3 (19.6 grams, 50.0 mmol), 15 grams of ethanol, 2.8 grams (50 mmol) of potassium hydroxide, and 2 grams of water were added to a 100-mL, 3-necked flask, equipped with a stirrer, a condenser, and a thermometer. The reaction mixture was heated on a heating mantle and stirred for 6 hours at 40° C. A clear, colorless solution of CF3O(CF2)3OCHFCF2COOK was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13](Cl)(=[O:15])=[O:14].[NH2:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([Br:26])=[CH:21][N:20]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([Br:26])=[CH:21][N:20]=1)(=[O:15])=[O:14]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: Cc1cc(Br)cnc1N
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1cc(Br)cnc1NS(=O)(=O)c1cccc2c(N(C)C)cccc12

Procedure:
A solution of 5-dimethylamino-1-naphthalenesulphonyl chloride (269.5 mg), 2-amino-5-bromo-3-methylpyridine (187 mg) and 4-dimethylaminopyridine (100 mg) in pyridine (5 ml) was heated at 85° C. for 18 hours. Volatile material was removed by evaporation and dichloromethane (50 ml) was added. Insoluble material was removed by filtration and the filtrate was concentrated by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:1 v/v), to give 5-(dimethylamino)-N-(5-bromo-3-methyl-2-pyridyl)-1-naphthalenesulphonamide as a foam (135) mg); NMR (CDCl3): 2.2(s, 3H), 2.9(s, 6H), 7.15 (d, 1H), (7.4-7.8(m, 4H), 8.4(d, 1H), 8.5(d, 2H); mass spectrum (+ve CI): 420 (M+H)+.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([N:17]3[CH2:20][CH:19]([NH:21][C:22](=[NH:37])[CH2:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=4)=[O:25])[CH2:18]3)=[O:16])[CH2:10]2)=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>C1(OC)C=CC=CC=1>[SH:8][CH:9]1[CH2:13][N:12]([CH3:14])[CH:11]([C:15]([N:17]2[CH2:20][CH:19]([NH:21][C:22](=[NH:37])[CH2:23][C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=3)=[O:25])[CH2:18]2)=[O:16])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(NC(=N)CC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN1CC(S)CC1C(=O)N1CC(NC(=N)CC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h
Yield: 93.7 %

Procedure:
610 mg of (2S,4S)-4-(4-methoxybenzylthio)-1-methyl-2-[3-(N-4-nitrobenzyloxycarbonylacetimidoylamino)azetidin-1-ylcarbonyl]pyrrolidine [prepared as described in step (a) above] were dissolved in 1.19 ml of anisole, and 4.23 ml of trifluoroacetic acid and 193 μl of trifluoromethanesulfonic acid were added to the resulting solution, whilst ice-cooling. The mixture was then stirred for 1 hour under the same conditions and then at room temperature for a further 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was washed with hexane and with diethyl ether and dried by evaporation under reduced pressure, to convert it to the trifluoromethanesulfonate in the form of a powder. Ethyl acetate was added to the whole of this compound, followed by sufficient of a saturated aqueous solution of sodium hydrogencarbonate to make it alkaline. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under reduced pressure, to give 448 mg of the title compound as a powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]4[CH:33]=[CH:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]=4)=[CH:18][CH:17]=3)=[CH:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)=[O:4].CN1C2C(=CC=C(C(O)=O)C=2)[C:37](CC2C=CC(OCC3C=CC4C(=CC=CC=4)N=3)=CC=2)=[CH:36]1>>[CH2:14]([N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:13]=2)[C:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)=[CH:10]1)[CH2:36][CH3:37]
Reactant: COC(=O)c1ccc2c(Cc3ccc(OCc4ccc5ccccc5n4)cc3)cn(C)c2c1
Reactant: Cn1cc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c2ccc(C(=O)O)cc21
Product: CCCn1cc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c2ccc(C(=O)O)cc21

Procedure:
This compound was prepared from the methyl ester (Example 11, part ii) by the method described in Example 10, part iii, m.p. 80°-82° C.
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][CH2:24][O:25]C)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[N:33]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[N:34]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>CO.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>[OH:25][CH2:24][CH2:23][O:22][C:3]1[C:2]([C:37]2[N:33]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][O:27]3)[N:34]=[CH:35][CH:36]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:14][CH:15]=2)=[O:8])=[CH:5][N:4]=1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: COCCOc1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(OCCO)c(-c2ccnn2C2CCCCO2)c1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
A mixture of 5-bromo-6-(2-methoxyethoxy)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 52.1, 100 mg, 0.237 mmol), 1-(tetrahydro-2h-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (66 mg, 0.237 mmol), Pd(Ph3P)4 (27 mg, 0.024 mmol), K3PO4 (151 mg, 0.712 mmol) and toluene (1.5 mL) was stirred at 110° C. for 5 h under an argon atmosphere. The RM was diluted with MeOH, filtered through a cartridge of PL-Thiol MP-Resin, and the filtrate was evaporated to dryness under reduced pressure to afford 6-(2-hydroxyethoxy)-5-(1-(tetrahydro-2h-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide, which was dissolved in DCM (0.4 mL), treated with TFA (0.25 mL, 3.24 mmol) and stirred overnight at RT. The mixture was treated with a solution of Na2CO3 (2 M) and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product was purified by preparative SFC (Column DEAP; gradient 25% to 30% in 6 min.) and lyophilized to afford the title compound as a white powder. UPLC-MS (Condition 2) tR=0.92 min, m/z=409.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 3.82 (t, J=4.90 Hz, 2H) 4.48 (t, J=4.89 Hz, 2H) 6.98 (d, J=1.69 Hz, 1H) 7.37 (d, J=8.66 Hz, 2H) 7.75-7.83 (m, 1H) 7.88 (s, 2H) 8.70 (d, J=2.26 Hz, 2H) 8.79 (br. s, 1H) 10.54 (s, 1H) 12.86-13.40 (m, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([NH:15][NH2:16])=[O:14])=[CH:5][CH:4]=1.[C:20]([O:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=[O:26])(=[O:22])[CH3:21]>CN(C)C(=O)C.C(OCC)(=O)C>[C:20]([O:23][C:24]([CH3:29])([CH3:28])[C:25]([NH:16][NH:15][C:13](=[O:14])[C:12]1[CH:17]=[CH:18][N:19]=[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[CH:11]=1)=[O:26])(=[O:22])[CH3:21]
Reactant: CSc1ccc(Nc2cc(C(=O)NN)ccn2)cc1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CSc1ccc(Nc2cc(C(=O)NNC(=O)C(C)(C)OC(C)=O)ccn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
To a solution of 2-[[4-(methylthio)phenyl]amino]isonicotinohydrazide (513 mg, 1.87 mmol) in N,N-dimethylacetamide (5 mL) was added dropwise 2-chloro-1,1-dimethyl-2-oxoethyl acetate (0.294 mL, 2.06 mmol) under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (624 mg, yield 83%) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[O:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[CH2:17]OS(C)(=O)=O.O>CN(C=O)C>[O:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[CH2:17][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(O)ccc21
Reactant: CS(=O)(=O)OC[C@H]1CCCO1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(OC[C@H]3CCCO3)ccc21

Procedure:
A solution of 5-hydroxyindanone (80 mg) and methanesulfonic acid (R)-1-(tetrahydrofuran-2-yl)methyl ester (107 mg) in DMF (1 mL) was stirred at 70° C. for 16 h. After adding water it was extracted with ether, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel. In this way the product was obtained with molecular weight 232.28 (C14H16O3); MS (ESI): 233 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8](=[O:10])[CH3:9])=[CH:3][CH:2]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CCCCC1>C1C=CC=CC=1>[C:12]1([CH:11]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[C:8](=[O:10])[CH3:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)Cc1ccncc1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CC(=O)C(=Cc1ccccc1)c1ccncc1
Yield: 78.7 %

Procedure:
Using the procedure of Example A-1, step 1, 4-pyridylacetone (step 1) (1 g, 7.4 mmol) was condensed with benzaldehyde (790 mg, 7.4 mmol) in benzene (15 mL) containing piperidine (50 mg) at reflux. The desired 4-phenyl-3-(4-pyridyl)-3-butene-2-one (1.3 g, 78%) was obtained as a crystalline solid: m. p. 101–103° C. Anal. Calc'd for C15H13NO (223.28): C, 80.69; H, 5.87; N, 6.27. Found: C, 80.59; H, 5.79; N, 6.18.
Reaction SMILES: [N+](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-])=O.BrBr.N12CCCN=C1CCCCC2.[OH:25][C:26]1[C:27](=[O:37])[C:28]2[C:33]([C:34](=[O:36])[CH:35]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2>ClCCl>[C:6]1([C:5]2[C:35]3[C:34](=[O:36])[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27](=[O:37])[C:26]=3[O:25][CH:4]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: BrBr
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1c2ccccc2C(=O)c2c(-c3ccccc3)coc21
Yield: 69.7 %

Procedure:
To the solution of 5 grams (33.5 mmoles) of [(E)-2-nitroethenyl]benzene in 100 mL of dichloromethane, 5.6 grams (35.2 mmoles) of bromine was added. The mixture was refluxed for 12 hours, and then evaporated to dryness. To the residue solution in 150 mL of tetrahydrofuran cooled in ice bath, 5.3 grams (35.2 mmoles) of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) was dropped slowly over 20 minutes while stirring vigorously. The reaction mixture was further stirred for 30 minutes in ice bath, then 5.8 grams (33.5 mmoles) of 2-hydroxy-1,4-naphthoquinone and 5.3 grams (35.2 mmoles) of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) were added. The mixture was reflux for 3 hours, and then evaporated to sticky residue. The residue was dissolved in 300 mL of dichloromethane, and washed with 300 mL of water, 300 mL of 2% aqueous citric acid solution, successively, and dried with 30 grams of anhydrous sodium sulfate. The 3-phenyl-naphtho[2,3-b]furan-4,9-dione product was purified with silica gel column using dichloromethane/hexane (3:1) as elution solvent. 6.4 grams of product (overall yield 70%) was obtained and characterized by 1H NMR and mass spectrum. 1H NMR (in DMSO) δ 7.44-7.52 (m, 3H), 7.77-7.79 (m, 2H), 7.89-7.93 (m, 2H), 8.10-8.15 (m, 2H), 8.58 (s, 1H). Mass (M+H) is 275.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:38]1[C:39]2[N:46]=[N:45][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[CH3:53])[C:40]=2[N:41]=[CH:42][N:43]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:36][C:38]1[C:39]2[N:46]=[N:45][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[CH3:53])[C:40]=2[N:41]=[CH:42][N:43]=1)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:17])([CH3:18])[CH3:19])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccccc1-n1nnc2c(Cl)ncnc21
Reactant: CC(C)(C)[Si](OCCOC[C@H](O)C(=O)Nc1ccc(Cl)cn1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1-n1nnc2c(O[C@@H](COCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C(=O)Nc3ccc(Cl)cn3)ncnc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
Sodium hydride (57.7 mg, 1.44 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-chloropyridin-2-yl)-2-hydroxypropanamide (Intermediate AU3) (300 mg, 0.60 mmol) in anhydrous THF (7 ml) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 7-chloro-3-o-tolyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (148 mg, 0.60 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (15 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 50% EtOAc in isohexane to give (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-chloropyridin-2-yl)-2-(3-o-tolyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy)propanamide (410 mg, 100%). 1H NMR (400 MHz, CDCl3) δ0.97 (s, 9H), 2.19 (s, 3H), 3.67-3.85 (m, 4H), 4.26 (d, 2H), 6.14 (t, 1H), 7.31-7.54 (m, 10H), 7.60-7.68 (m, 5H), 8.18-8.23 (m, 2H), 8.66 (s, 1H), 8.91 (s, 1H); m/z (ES+), (M+H)+=708.61; HPLC tR=4.02 min