Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]([O:11][CH:12]([N:15]1[CH:23]=[N:22][C:21]2[C:20](=[O:24])[NH:19][CH:18]=[N:17][C:16]1=2)[CH:13]=[O:14])[CH2:4][P:5]([O:9][Na:10])([O:7][Na:8])=[O:6])=[O:2].[NH2:25][C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>O>[OH:14][CH:13]1[C@H:12]([N:15]2[CH:23]=[N:22][C:21]3[C:20](=[O:24])[NH:19][CH:18]=[N:17][C:16]2=3)[O:11][C@@H:3]([CH2:4][P:5]([O:9][Na:10])([O:7][Na:8])=[O:6])[CH:1]([OH:2])[N:25]1[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: Nc1ncccn1
Reactant: O=CC(CP(=O)(O[Na])O[Na])OC(C=O)n1cnc2c(=O)[nH]cnc21
Solvent: O
Product: O=c1[nH]cnc2c1ncn2[C@@H]1O[C@@H](CP(=O)(O[Na])O[Na])C(O)N(c2ncccn2)C1O
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 88.7 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-disodiophosphonoethoxy)-1,6-dihydro-6-oxo-9H-purine-9-acetaldehyde, (1.95 g) was dissolved in water (50 ml). To the solution was added 2-aminopyrimidine (0.48 g). The solution was stirred at ambient temperature for 1.3 hours and evaporated in vacuo. The residue was triturated with acetone and dried over phosphorus pentoxide in vacuo to give 9-[(2R, 6R)-3,5-dihydroxy-6-disodiophosphonomethyl-4-(pyrimidin-2-yl)morpholin-2-yl]hypoxanthine (2.1 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([CH2:26][OH:27])[N:25]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[C:14]([CH3:16])[CH:15]=1)[CH3:9])=[O:6].[C:28]([NH2:32])(=[O:31])[CH2:29][CH3:30].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[OH:27][CH2:26][C:24]1[CH:23]=[C:4]([CH:3]=[C:2]([NH:32][C:28](=[O:31])[CH2:29][CH3:30])[N:25]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[C:14]([CH3:16])[CH:15]=1)[CH3:9])=[O:6]
Reactant: CCC(N)=O
Reactant: Cc1cc(C(C)NC(=O)c2cc(Cl)nc(CO)c2)cnc1OCC(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCC(=O)Nc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)cc(CO)n1
Temperature: 150 °C
Yield: 25 %

Procedure:
A mixture of 2-chloro-6-(hydroxymethyl)-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)isonicotinamide (17 mg, 0.04 mmol, Step-3, single enantiomer), propionamide (6 mg, 0.08 mmol), tris(dibenzylideneacetone)dipalladium(0) (1 mg, 0.8 microM), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.5 mg, 2.5 microM), tripotassium phosphate (11 mg, 0.05 mmol) and 1,4-dioxane (1 mL) is heated by microwave irradiation at 150° C. for 1 hour. After cooling to room temperature, the mixture is filtered through a pad of celite. The filtrate is concentrated under reduced pressure and the residue is diluted with methanol (4 mL) and applied onto a strong cation exchange cartridge (BondElute(registered trademark) SCX, 1 g/6 mL, Varian Inc.), and the solid phase matrix is rinsed with methanol (5 mL). The crude mixture is eluted with 1M ammonia in methanol (5 mL) and concentrated under reduced pressure and then by preparative LC-MS to give 4.4 mg (24% yield) of the title compound.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Li+].[CH2:7]([O:10][CH2:11][C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:13])[CH:8]=[CH2:9].[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C@H:29]([NH:33][C:34](=[O:43])[O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:30]2[CH2:32][O:31]2)[CH:24]=[C:25]([F:27])[CH:26]=1.C([O-])(O)=O.[Na+]>CC#N.[Cl-].[Na+].O>[CH2:7]([O:10][CH2:11][C@H:12]([NH:13][CH2:32][C@@H:30]([OH:31])[C@@H:29]([NH:33][C:34](=[O:43])[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:28][C:23]1[CH:22]=[C:21]([F:20])[CH:26]=[C:25]([F:27])[CH:24]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:8]=[CH2:9]
Reactant: C=CCOC[C@H](N)c1ccccc1
Reactant: O=C(N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: O
Product: C=CCOC[C@H](NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OCc1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 72.1 %

Procedure:
Step Q (4): Lithium perchlorate (1.59 g, 15 mmol) was added to a solution of (R)-2-(allyloxy)-1-phenylethanamine (530 mg, 2.99 mmol) from Step Q (3) and benzyl (S)-2-(3,5-difluorophenyl)-1-((S)-oxiran-2-yl)ethylcarbamate (996 mg, 2.99 mmol) in CH3CN (10 mL). The resulting mixture was stirred at 50° C. for 16 h, then poured into a solution of brine and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 1.1 g (72% yield) of benzyl (2S,3R)-4-((R)-2-(allyloxy)-1-phenylethylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-ylcarbamate. LC-MS (M+H)+=511.5; 1H NMR (300 MHz, CDCl3) δ ppm 2.36-2.53 (m, J=10.98 Hz, 1H) 2.55-3.00 (m, 3H) 3.25-3.74 (m, 3H) 3.77-4.19 (m, 3H) 4.71-4.84 (m, 1H) 5.00 (s, 2H) 5.09-5.37 (m, 2H) 5.74-6.00 (m, 1H) 6.50-6.78 (m, 3H) 7.16-7.42 (m, 10H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].CCO[C:14]([CH3:16])=[O:15]>CO>[OH:15][C:14]1[CH:16]=[CH:5][C:4]([C:7]2[NH:10][C:9]3[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=3[N:1]=2)=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: CCOC(C)=O
Solvent: CO
Product: N#Cc1ccc2[nH]c(-c3ccc(O)cc3)nc2c1
Reaction time: 4 h
Yield: 85 %

Procedure:
A mixture of 3,4-diaminobenzonitrile (3.0 g, 0.023 mol) and the imidate in 500 mL of methanol was heated at 70° C. under nitrogen. The reaction was followed by TLC with 1:1 Hex/EtOAc. After 4 h the reaction solution was place under vac cuo to remove all solvents. The residue was recrystallized from ethyl acetate to afford 4.5 g (85%) of 2-(4-hydroxyphenyl)-1H-benzimidazole-5-nitrile.
Reaction SMILES: O=[C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[C:4]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:3]1.P(Cl)(Cl)([Cl:25])=O.N1C=CC=CC=1>O>[Cl:25][C:2]1[O:3][C:4]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:6]=1
Reactant: COC(=O)CCc1oc(=O)[nH]c1-c1ccc(C(F)(F)F)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)CCc1oc(Cl)nc1-c1ccc(C(F)(F)F)cc1
Temperature: 102.5 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 3-[2-oxo-4-(4-trifluoromethylphenyl)-4-oxazolin-5-yl]propionate (3.90 g), phosphorus oxychloride (11.5 g) and pyridine (0.98 g) was heated to 100-105° C. and stirred for 1 hour. The reaction mixture was added dropwise to heated water (100 ml) of 30 ° C. and extracted with ethyl acetate (150 ml×2). The organic layer was washed with a saturated aqueous solution of sodium chloride (100 ml), and dried over anhydrous magnesium sulfate. The organic layer was concentrated, the residue was subjected to silica gel column chromatography, and methyl 2-chloro-4-(4-trifluoromethylphenyl)-5-oxazolepropionate was obtained as a yellow oil (2.66 g, 64%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:21][C:22]1[CH:35]=[CH:34][C:25]([C:26]([N:28]2[CH2:32][CH2:31][C@@H:30]([NH2:33])[CH2:29]2)=[O:27])=[CH:24][CH:23]=1>CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:21][C:22]1[CH:35]=[CH:34][C:25]([C:26]([N:28]2[CH2:32][CH2:31][C@@H:30]([NH:33][C:2]3[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=3)[CH2:29]2)=[O:27])=[CH:24][CH:23]=1
Reactant: N[C@@H]1CCN(C(=O)c2ccc(Cl)cc2)C1
Reactant: CCOC(=O)/C=C/c1ccc(Cl)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)nc1
Temperature: 90 °C
Yield: 32.7 %

Procedure:
To a solution of ethyl (2E)-3-(6-chloro-3-pyridyl)acrylate (3.5 g) in dioxene (70 mL) was added palladium(II) acetate (371 mg) and 2′-(dicyclohexylphosphino)-N,N-dimethyl-2-diphenylamine (110 mg) and cesium carbonate (583 mg), and (3R)-1-(4-chlorobenzoyl)-3-pyrrolidinamine (4.09 g). The mixture was heated at 90° C. for 3 hours. The resulting mixture was diluted with AcOEt, and the precipitate was removed by filtration. The filtrate was concentrated and residual brown oil was purified by purified by silica gel column chromatography eluted with AcOEt and hexane (1:4)—AcOEt to give ethyl (2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (2.16 g) as dark yellow form.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9](Cl)=[O:10])[C:5](=[O:12])[C:4]1=[O:13])[CH3:2].[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:26]2[C@@H:35]3[C@@H:30]([CH2:31][CH:32]=[CH:33][CH2:34]3)[C:29](=[O:36])[N:28]([CH:37]3[CH2:42][CH2:41][N:40](S(C4C=CC(C)=CC=4)(=O)=O)[CH2:39][CH2:38]3)[N:27]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24]C)C>>[CH3:14][O:16][C:17]1[CH:18]=[C:19]([C:26]2[C@@H:35]3[C@@H:30]([CH2:31][CH:32]=[CH:33][CH2:34]3)[C:29](=[O:36])[N:28]([CH:37]3[CH2:42][CH2:41][N:40]([C:9]([N:6]4[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[C:4](=[O:13])[C:5]4=[O:12])=[O:10])[CH2:39][CH2:38]3)[N:27]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: CCOc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(C)cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Reactant: CCN1CCN(C(=O)Cl)C(=O)C1=O
Product: CCN1CCN(C(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)[C@H]4CC=CC[C@H]4C3=O)CC2)C(=O)C1=O

Procedure:
Prepared from 4-ethyl-2,3-dioxo-piperazine-1-carbonyl chloride and starting compound A1 as described for compound 1. Crystallisation from ethyl acetate/diethyl ether. M. p. 226-228° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.CO>[Fe].O>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([S:11][CH2:12][C:13]([F:16])([F:14])[F:15])=[CH:10][C:4]=1[NH2:1]
Reactant: Nc1ccc(SCC(F)(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CO
Solvent: O
Product: Nc1ccc(SCC(F)(F)F)cc1N
Reaction time: 2 h

Procedure:
4.1 G. of 2-nitro-4-(2,2,2-trifluoroethylthio) aniline in 60 ml. of methanol and 12 ml. of water is treated with 1.25 g. of ferrous sulfate and 3.3. g. of iron powder at reflux. After 2 hours, 1.25 g. of ferrous sulfate and 3.3 g. of iron powder are added and heating is continued for 4 hours. The mixture is poured into 600 ml. of hot tetrahydrofuran and filtered. 1,2-Diamino-4-(2,2,2-trifluoroethylthio) benzene is obtained from the filtrate by evaporation.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:9][C:8]=1[O:23][CH3:24].C(N(C(C)C)CC)(C)C.[CH3:37][O:38][C:39](=[O:42])[CH2:40]Br>C(#N)C>[CH3:37][O:38][C:39](=[O:42])[CH2:40][N:15]([CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:25]=[CH:26][CH:27]=[C:2]([F:1])[CH:3]=2)=[C:8]([O:23][CH3:24])[CH:9]=1)[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)CBr
Reactant: COc1cc(CCNCc2ccccc2)ccc1OCc1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)CN(CCc1ccc(OCc2cccc(F)c2)c(OC)c1)Cc1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
1.7 g (4.65 mmol) of [2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-benzylamine, 1.74 ml (10 mmol) of di-isopropylethylamine and 0.5 ml (5.11 mmol) of 2-bromo-acetic acid methyl ester were dissolved in 20 ml of acetonitrile and the reaction was stirred at 70° C. overnight. The solvent was removed under reduced pressure, water was added to the residue and the product was extracted with ethyl acetate. The crude product was purified by flash chromatography (hexane/ethyl acetate 100:0→80:20 gradient v:v) and 1.94 g (95% yield) of the title compound were isolated as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[N:11]([CH2:27][CH2:28][CH2:29][NH:30]C(=O)OC(C)(C)C)[C:12](=[N:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[S:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>>[NH2:30][CH2:29][CH2:28][CH2:27][N:11]1[C:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][S:13][C:12]1=[N:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)NCCCn1c(COCc2ccccc2)csc1=Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: NCCCn1c(COCc2ccccc2)csc1=Nc1ccc(OC(F)(F)F)cc1

Procedure:
The compound (137 mg) obtained in the above (3) was treated in a similar manner to in Example 9 (2) to give the title compound (133 mg) as hydrochloride.
Reaction SMILES: [BH4-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][C:9]=1[OH:17]>C(O)C.O1CCCC1>[Cl:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:15])[OH:16])=[CH:10][C:9]=1[OH:17]
Reactant: CC(=O)c1ccc(OCCCCl)c(O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(O)c1ccc(OCCCCl)c(O)c1
Temperature: 10 °C
Reaction time: 3 h
Yield: 54.6 %

Procedure:
To a flask charged with sodium borohydride (1.5 g, 39.4 mmol) under nitrogen and chilled to 10° C. was added, slowly, a solution of 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone (6.0 g, 26.2 mmol) dissolved in ethanol-tetrahydrofuran (120 ml, 2:1). After total addition, the ice bath was removed and the reaction was stirred at ambient temperature for 3 hours. An additional amount of sodium borohydride (0.2 g, 5.3 mmol) was carefully added. After stirring at ambient temperature for one hour, the solvent was removed in vacuo. The resultant solid residue was diluted with water (100 ml) and left overnight. The product was isolated by vacuum filtration yielding 3.8 g. Two consecutive recrystallizations from toluene provided 3.3 g (55%) of 4-(3-chloropropoxy)-3-hydroxy-α-methylbenzene methanol as a light brown solid, m.p.=107-109° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[CH2:29][CH2:28][N:17]2[C:18]3[N:27]=[CH:26][CH:25]=[CH:24][C:19]=3[NH:20][C:21](=O)[CH2:22][CH:16]2[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([N:14]1[CH2:29][CH2:28][N:17]2[C:18]3[N:27]=[CH:26][CH:25]=[CH:24][C:19]=3[NH:20][CH2:21][CH2:22][CH:16]2[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CC2CN(Cc3ccccc3)CCN2c2ncccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CN2CCN3c4ncccc4NCCC3C2)cc1

Procedure:
Solid LiAlH4 (255 mg, 6.72 mmol) was added gradually to a stirred suspension of the product of Example 51B (337 mg, 1.093 mmol) in tetrahydrofuran (25 mL). The resulting mixture was heated at reflux under nitrogen for 1 hour, then cooled in ice and quenched by successive addition of ethyl acetate (3 mL), water (0.25 mL), 15% NaOH (0.25 mL) and water (0.75 mL). The gray slurry was filtered through diatomaceous earth with an ethyl acetate (30 mL total) rinse. The filtrate was concentrated under vacuum and the residue was purified by HPLC (30×100 mm, C18, XBridge™ column eluting with aqueous 0.1 M (NH4)2CO3— methanol, 80:20-0:100 over 15 minutes) to provide the title compound: 1H NMR (300 MHz, CD3OD) δ ppm 1.75-1.89 (m, 1H), 1.90-2.04 (m, 1H), 2.30 (dd, J=11.0, 9.0 Hz, 1H), 2.44 (ddd, J=10.9, 9.6, 3.2 Hz, 1H), 2.59 (ddd, J=10.9, 2.8, 1.2 Hz, 1H), 2.72-2.83 (m, 1H), 3.17 (ddd, J=12.5, 5.4, 3.7 Hz, 1H), 3.26-3.34 (m, 1H), 3.33-3.53 (m, 3H), 3.52-3.63 (m, 2H), 6.73 (dd, J=7.8, 4.7 Hz, 1H), 6.91 (dd, J=7.6, 1.5 Hz, 1H), 7.20-7.40 (m, 5H), 7.61 (dd, J=4.9, 1.5 Hz, 1H); MS (ESI) m/z 295 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:16]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=2)[NH:17][CH:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[C:5]1=[O:34])(=[O:3])[CH3:2].CO.C(OCC)(=O)C.CN(C)C=O>O1CCCC1.[Ni]>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:16]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[NH:17][CH:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[C:5]1=[O:34])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)C(=C(NC1CCN(C)CC1)c1ccc([N+](=O)[O-])cc1)C(=O)N2C(C)=O
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)C(=C(NC1CCN(C)CC1)c1ccc(N)cc1)C(=O)N2C(C)=O
Reaction time: 2 h

Procedure:
2.4 g (5 mmol) 1,5-diacetyl-3-[4-nitrophenyl-(1-methyl-piperidin-4-ylamino)-methylidene]-2-indolinone are dissolved in 40 ml of tetrahydrofuran (THF), 30 ml of methanol and 30 ml of ethyl acetate, combined with 250 mg Raney nickel and hydrogenated for 6 h at ambient temperature at a pressure of 50 psi. Then 20 ml of dimethylformamide are added in order to dissolve the precipitate formed and hydrogenation is continued for 2 h. Then the catalyst is filtered off and the solution is evaporated down.
Reaction SMILES: C([Li])CCC.[N:6]1([C:11]2[CH:32]=[CH:31][C:14]([CH2:15][C:16]3[C:17]([O:29][CH3:30])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][C:20]=4[CH3:28])=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:33][N:34]1[C:38]([C:39]([C:41]2[N:45]([CH3:46])[CH:44]=[N:43][CH:42]=2)=[O:40])=[CH:37][N:36]=[CH:35]1.[NH4+].[Cl-]>C1COCC1.O.CCOC(C)=O>[N:6]1([C:11]2[CH:32]=[CH:31][C:14]([CH2:15][C:16]3[C:17]([O:29][CH3:30])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:39]([C:38]3[N:34]([CH3:33])[CH:35]=[N:36][CH:37]=3)([C:41]3[N:45]([CH3:46])[CH:44]=[N:43][CH:42]=3)[OH:40])=[CH:21][C:20]=4[CH3:28])=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: Cn1cncc1C(=O)c1cncn1C
Reactant: COc1nc2c(C)cc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1nc2c(C)cc(C(O)(c3cncn3C)c3cncn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
n-Butyllithium (1.6 M in hexane; 0.5 mL, 0.718 mmol) was added dropwise to a suspension of the 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxy-8-methylquinoline (0.29 g, 0.653 mmol, Intermediate 19: step b) in dry THF (4 mL) over a 2 minute period at −78° C. A heterogeneous mixture of bis(1-methyl-1H-imidazol-5-yl)methanone (0.14 g, 0.653 mmol, Intermediate 39: step b) in THF (3 mL) was added as a slurry and stirring was continued at −78° C. for 5 minutes. The resulting homogeneous mixture was warmed up to 0° C. and stirred for 10 minutes. The mixture was warmed to room temperature and saturated aqueous NH4Cl was added followed by EtOAc. H2O was added and layers were separated. The aqueous layer was again extracted with EtOAc and the combined organic extracts washed with brine, dried over Na2SO4, filtered, evaporated to dryness. The crude product was purified by chromatography (10% MeOH in CH2Cl2; gradient) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.95-8.04 (m, 1H), 7.79-7.89 (m, 1H), 7.65-7.71 (m, 1H), 7.50-7.60 (m, 2H), 7.34-7.45 (m, 5H), 7.32 (s, 1H), 6.36-6.52 (m, 2H), 4.31 (s, 2H), 4.10 (s, 3H), 3.53 (s, 6H), 2.62 (s, 3H). mass calcd. C30H28ClN7O2, 554.05; m/z found, 554.2
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3]([OH:5])=[O:4].Cl.[CH3:10]O>>[CH3:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3]([O:5][CH3:10])=[O:4]
Reactant: CO
Reactant: CC(C)(CO)C(=O)O
Agent: Cl
Product: COC(=O)C(C)(C)CO
Reaction time: 8 h

Procedure:
A mixture of 2,2-dimethyl-3-hydroxypropionic acid (CXXXII, 11.54 g, 97.7 mmol), methanol (150 ml) and methanol (25 ml) saturated with hydrochloric acid gas is stirred overnight at 20°-25°. The mixture is then concentrated under reduced pressure, ether is added, and again the mixture is concentrated. The residue is dissolved in ether and poured cautiously into a small amount of saturated sodium bicarbonate. The phases are separated and the aqueous phase is washed several times with ether. The combined organic phases are backwashed with saline, dried over magnesium sulfate, and concentrated under reduced pressure to give methyl 2,2-dimethyl-3-hydroxypropionate (CXXXII), NMR (CDCl3) 1.20, 2.48, 3.56 and 3.71 δ.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH2:12])[CH:4]=1.[CH:13]([C:16]1[N:17]=[C:18]([C:21](O)=[O:22])[S:19][CH:20]=1)([CH3:15])[CH3:14].CCN=C=NCCCN(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:7]([C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[NH:12][C:21]([C:18]1[S:19][CH:20]=[C:16]([CH:13]([CH3:15])[CH3:14])[N:17]=1)=[O:22])(=[O:8])[NH2:9]
Reactant: CC(C)c1csc(C(=O)O)n1
Reactant: COc1ccc(C(N)=O)c(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(C(N)=O)c(NC(=O)c2nc(C(C)C)cs2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled solution of 4-methoxy-2-aminobenzamide (5.6 g, 33.7 mmol), 4-isopropyl-thiazole-2-carboxlic acid (7.1 g, 42 mmol) and Hobt-hydrate (6.4 g, 42 mmol) in DMF (150 ml) was added EDAC (8.6 g, 45 mmol) and TEA (6.4 ml, 45 mmol) and the mixture was stirred overnight at room temperature. A 2.5% aqueous solution of citric acid (600 ml) was added and the mixture was extracted three times with ethyl acetate. The organic phase was washed with brine and saturated sodium hydrogencarbonate. The solution was dried over sodium sulfate and evaporated under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:15]([Cu])#[N:16].O>CN1CCCC1=O>[CH:4]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[C:2]([C:15]#[N:16])[CH:3]=1
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1ccc2[nH]c3ccccc3c2c1
Yield: 88.1 %

Procedure:
A solution of 3-bromo-9H-carbazole (123.4 mg, 0.50 mmol) and CuCN (49.9 mg, 0.56 mmol) in N-methyl-pyrrolidone (2 mL) was heated at 200° C. for 5 h. The cooled reaction mixture was poured into water and the precipitate was filtered and washed with ethyl acetate. The filtrate was extracted with ethyl acetate and the combined ethyl acetate extracts were washed with water, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to afford the product as a white solid (84.7 mg, 88%).