Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17]CC=C)=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])[CH:4]=1)#[N:2].N1CCOCC1>C1COCC1.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>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([CH:36]([CH3:38])[CH3:37])(=[O:34])=[O:35])[CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(=O)(=O)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC1=C(C(=O)O)C(c2ccc(C#N)cc2S(=O)(=O)C(C)C)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The reaction was carried out under argon. Allyl 4-{4-cyano-2-[(1-methylethyl)sulfonyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1200 mg, 2.19 mmol) and morpholine (1.5 eq., 286 mg, 3.30 mmol) were initially charged in dry THF (60 ml) at RT. The reaction mixture was degassed repeatedly (evacuation followed by venting with argon). Under protective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 127 mg, 0.110 mmol) was added, and the reaction mixture was stirred at RT for 0.5 h (HPLC control). The mixture was then concentrated, and the residue was taken up in ethyl acetate (100 ml). The organic phase was washed with 0.1 N hydrochloric acid (40 ml) and with saturated sodium chloride solution (3×30 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. Methanol (10 ml) was added to the residue. The precipitated product was filtered off with suction and washed with a little methanol (2×5 ml). The title compound was isolated as a solid (1060 mg, 95% of theory).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][S:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1/[CH:17]=[CH:18]/[CH:19]([OH:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C.P([O-])([O-])([O-])=O>[OH:27][CH:19]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)/[CH:18]=[CH:17]/[C@H:11]1[CH2:12][CH2:13][CH2:14][C:15](=[O:16])[N:10]1[CH2:9][CH2:8][S:7][CH2:6][CH2:5][CH2:4][C:3]([OH:28])=[O:2]
Reactant: COC(=O)CCCSCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: O=C(O)CCCSCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Reaction time: 24 h
Yield: 92.3 %

Procedure:
Rabbit liver esterase (134 units/mg, 1 mg) was added to a solution of 4-{2-[(R)-2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-ethylsulfanyl}-butyric acid methyl ester (5.2 mg, 0.013 mmol) in acetonitrile (0.2 mL) and pH 7.2 phosphate buffer (3.0 mL). After 24 h, acetonitrile (10 mL) was added and the reaction mixture was concentrated to dryness in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→5% MeOH/CH2Cl2, gradient) afforded 4.7 mg (94%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:8]=[C:7]([CH3:21])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:22]C1C=C(C2C=CC=C(C(F)(F)F)C=2)NC(=O)C=1C(O)=O.OS(O)(=O)=O>CO>[CH3:22][N:10]1[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)=[CH:8][C:7]([CH3:21])=[C:3]([C:4]([OH:6])=[O:5])[C:2]1=[O:1]
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)[nH]c(=O)c1C(=O)O
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)nc(O)c1C(=O)O
Agent: O=S(=O)(O)O
Solvent: CO
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)n(C)c(=O)c1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.1 %

Procedure:
A solution of 0.30 g (1.0 mmol) of 2-hydroxy-4-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid/4-methyl-2-oxo-6-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid in 15 ml of MeOH was treated with 0.06 ml=0.01 g (0.1 mmol) of H2SO4 (98%) and the reaction mixture was heated up to reflux. After 4 hours, it was cooled down to RT, poured into crashed ice and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 0.24 g (77%) of the title compound as off-white solid. MS: 312.0 (MH+).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Br:12])=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:13]([OH:15])=[O:14])[C:3]=1[OH:16].C(O)(=O)C.[Sn].Cl>O>[Br:12][C:8]1[CH:7]=[C:6]2[C:11]([CH:2]=[C:3]([OH:16])[C:4]([C:13]([OH:15])=[O:14])=[CH:5]2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1cc2cc(Br)ccc2c(Br)c1O
Agent: Cl
Agent: [Sn]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc2cc(Br)ccc2cc1O
Temperature: 125 °C
Yield: 96.5 %

Procedure:
In a 1 L three-necked bottle, 40 g of 4,7-dibromo-3-hydroxy-2-naphthoic acid (0.116 mol) and 500 ml of glacial acetic acid were added, and stirred to make homogenous. 18 g of tin powder (0.153 mol) and 130 ml of concentrated hydrochloric acid were then added to the mixture in order, heated to 125° C., and refluxed under heating for 12 h. 300 ml of water was added to the mixture, stirred to room temperature, filtered, and the filter cake was washed with water (200 ml*2), and dried in an oven to obtain 29.9 g of a solid with a yield of 96.5%.
Reaction SMILES: [C:1]1([C:15](O)=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=1)[N+:2]([O-:4])=[O:3].C1(C([O-])=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1)[N+:18]([O-])=O.[NH4+].S1(CCCC1)(=O)=O.CN1CCCC1=O>O>[CH:5]1[C:1]([N+:2]([O-:4])=[O:3])=[C:15]([NH2:18])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Agent: [NH4+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
Replacement of urea with an ammonium salt (or “NH3 reagent”) obtained from ammonia and weak acids (e.g., acetic, carbonic acid, phosphoric acid) produces picramide free of cyanuric acid. Thus, reaction of picric acid or ammonium picrate with an ammonium salt in dipolar aprotic solvents such as sulfolane or N-methylpyrrolidinone (NMP) for several hours at 175–185° C., followed by a water wash, produces picramide that is free of cyanuric acid and ammonium salts. Ammonium hydroxide (28% NH3 in H2O) is unsatisfactory for use as an NH3 reagent as picric acid/ammonium picrate are decomposed to black solids when exposed to the ammonium hydroxide. Example 2 and Table 1 list conversions of 0.18–0.92 g of ammonium picrate in sulfolane to picramide in 8 ml glass pressure tubes.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([NH:8][NH2:9])=O)([O-:3])=[O:2].[CH3:14][C:15]1[O:16][C:17](=[O:25])[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.CN1CCCC1=O>O>[CH3:14][C:15]1[N:20]([C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[C:17]([OH:25])=[O:16])[C:6]([C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])=[N:8][N:9]=1
Reactant: NNC(=O)c1ccccc1[N+](=O)[O-]
Reactant: Cc1nc2ccccc2c(=O)o1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nnc(-c2ccccc2[N+](=O)[O-])n1-c1ccccc1C(=O)O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The mixture consisting of 1.8 g of 2-nitrobenzoic hydrazide, 1.6 g of 2-methylbenzo[d][1,3]oxazin-4-one and 5 ml of N-methylpyrrolidone was heated to 80° C. with stirring for 2 hours. After cooling, the mixture was admixed with water to slight cloudiness and stirred for a further 1 hour, during which time a solid precipitated out which was filtered off with suction, recrystallized from ethanol and dried under reduced pressure.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][N:5]([CH2:18][C:19]#[CH:20])[C:6](=[O:17])OC1C=CC([N+]([O-])=O)=CC=1>C1COCC1.ClCCl>[CH3:1][N:2]([CH3:3])[C:6]([N:5]([CH3:4])[CH2:18][C:19]#[CH:20])=[O:17]
Reactant: CNC
Reactant: C#CCN(C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#CCN(C)C(=O)N(C)C
Yield: 46 %

Procedure:
N-Methylpropargylamine (600 mg, 8.70 mmol) and triethylamine (878 mg, 8.68 mmol) in dichloromethane (10 ml) were added dropwise, with ice cooling, to a stirred solution of 4-nitrophenyl chloroformate (1.75 g, 8.68 mmol) in dichloromethane (10 ml). The reaction was stirred at ice temperature for 3 hr. then the resulting solution purified by column chromatography on silica using 25% ethyl acetate in iso-hexane as eluent. Thus was obtained 4-nitrophenyl methyl(prop-2-yn-1-yl)carbamate (1.80 g, 89%) as a colourless oil. Dimethylamine (3.0 ml of a 2.0M solution in THF, 6.0 mmol) and 4-nitrophenyl methyl(prop-2-yn-1-yl)carbamate (600 mg, 2.56 mmol), in dichloromethane (7 ml) were stirred at room temperature for 6 days then the reaction solution purified by chromatography on silica using ethyl acetate as eluent to give N,N,N′-trimethyl-N′-prop-2-yn-1-ylurea (164 mg, 46%) as a colourless oil.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=2[CH3:26])[C:20]([OH:22])=O)[CH:11]=3)=[O:5])[CH2:3][CH2:2]1.[CH3:27][C:28]1([NH2:32])[CH2:31][CH2:30][CH2:29]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=2[CH3:26])[C:20]([NH:32][C:28]2([CH3:27])[CH2:31][CH2:30][CH2:29]2)=[O:22])[CH:11]=3)=[O:5])[CH2:2][CH2:3]1
Reactant: CC1(N)CCC1
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2(C)CCC2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 47.8 %

Procedure:
A mixture of 3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylbenzoic acid (41.0 mg, 0.118 mmol), 1-methylcyclobutylamine (22.5 mg, 0.264 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (81.1 mg, 0.156 mmol), N,N-diisopropylethylamine (64 uL, 0.37 mmol), 4-dimethylaminopyridine (2.89 mg, 0.0237 mmol), and N,N-dimethylformamide (2.0 mL, 26 mmol) was stirred at 50° C. for 15 hours. The reaction mixture was poured into ethyl acetate and washed with water and brine, filtered through a plug of silica gel, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 23.3 mg (78%) of 3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methyl-N-(1-methylcyclobutyl)benzamide. LCMS (ESI): RT (Min)=5.083, M+H=414.2, method=E; 1H NMR (400 MHz, DMSO) δ 10.90 (s, 1H), 9.19 (s, 1H), 8.51 (s, 1H), 8.35 (s, 1H), 8.04 (s, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.82 (s, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.73 (dd, J=8.5, 1.5 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 2.40-2.29 (m, 5H), 2.13-2.04 (m, 1H), 2.03-1.92 (m, 2H), 1.86-1.75 (m, 2H), 1.47 (s, 3H), 0.91-0.80 (m, 4H).
Reaction SMILES: Cl.[CH3:2][C@H:3]1[C@@H:12]([OH:13])[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4]1>CC(C)=O>[OH:13][C@H:12]1[CH2:11][CH2:10][C:5](=[O:6])[CH2:4][C@H:3]1[CH3:2]
Reactant: C[C@@H]1CC2(CC[C@@H]1O)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: C[C@@H]1CC(=O)CC[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.2 %

Procedure:
A 1 N hydrochloric acid (250 mL)/acetone (250 mL) mixed solution of cis-7-methyl-1,4-dioxa-spiro[4.5]-decan-8-ol (19.9 g) obtained in Example (14a) was stirred at room temperature for 16 hours. The organic solvent was removed under reduced pressure. The remaining aqueous mixture was subjected to 6 extractions with ethyl acetate. The organic layer was washed with saturated brine, then dried over sodium sulfate, and then concentrated. The residue was dried under reduced pressure to obtain the title compound (14.4 g, 97%) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.C[O:24][B:25]([O:28]C)[O:26]C.Cl.P(=O)(O)(O)O>C1COCC1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.O>[C:2]1([O:24][B:25]([OH:28])[OH:26])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2ccccc12
Reactant: COB(OC)OC
Agent: Cl
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: OB(O)Oc1cccc2ccccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
To a solution of 1-bromonaphthalene (10 g, 48 mmol) in THF (100 ml), a 1.65 M solution of n-butyl lithium in n-hexane (58 ml, 96 mmol of n-butyl lithium) and stirred at -78° C. for one hour. Then, trimethoxyborane (10 g, 96 mmol) was added, and the mixture was stirred at -78° C. for 30 minutes, and then at room temperature for one hour. To the mixture, phenothiazine (132 mg) and then a mixture of conc. hydrochloric acid (20 ml), phosphoric acid (30 ml) and water (220 ml) were gradually added. After heating the mixture to room temperature and stirring it for 20 hours, the organic layer was separated. The aqueous solution was washed with diethyl ether. The combined organic layer was washed with a 10% aqueous solution of sodium chloride. To the ice-cooled organic layer, a 5% aqueous solution of sodium hydroxide was added and stirred. Then, the mixture was phase separated, and the aqueous layer was saturated with sodium chloride, acidified with phosphoric acid, and extracted with diethyl ether. The diethyl ether layer was dried over anhydrous magnesium sulfate. The solvent was evaporated off, and the obtained solid residue was recrystallized from ethyl acetate/n-hexane to obtain naphthylboric acid (4.20 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:8]([C:15]([O:17]C)=[O:16])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1.[OH-].[K+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:8]([C:15]([OH:17])=[O:16])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1
Reactant: COC(=O)c1c(-c2ccccc2)c2ccc(OC)cc2c(=O)n1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(-c3ccccc3)c(C(=O)O)n(C)c(=O)c2c1
Reaction time: 2 h

Procedure:
The ester 5 (180 mg, 0.56 mmol) was suspended in ethanol (5 ml). 1M KOH (1 ml) was added and the resulting mixture heated at 80 C. A homogenous solution was obtained within minutes. After 2 h, the reaction mixture was cooled and acidified with 1M HCl. The ethanol was removed under reduced pressure and water was added to the residue. The mixture was filtered and the residue washed well with water and dried to give the acid 6.
Reaction SMILES: [NH2:1][C:2]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH2:3]1.Br[CH2:16][CH2:17][O:18][CH2:19][CH2:20]Br.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[CH3:9][C:4]1([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]([N:1]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3]1
Reactant: CCOC(=O)C1(N)CCCC(C)(C)C1
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(N2CCOCC2)CCCC(C)(C)C1
Temperature: 95 °C

Procedure:
To a solution of EXAMPLE 145C (3.5 g) in N,N-dimethylformamide (30 mL) was added 1-bromo-2-(2-bromoethoxy)ethane (5.8 g) and K2CO3 (6.5 g). The reaction mixture was heated to 95° C. for 18 hours. The mixture was cooled to room temperature, diluted with water, and extracted with methylene chloride (3×50 mL). The combined organic layers were washed with saturated NaCl solution (1×25 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with 4:1 petroleum ether/ethyl acetate solution, to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:18])/[CH:10]=[CH:11]/C2C=CC=CC=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[Cl-].[Cl-].[Al+3].FC1C(F)=C2C(C=CC(=O)N2)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:11]=[CH:10][C:9](=[O:18])[NH:8]2)=[CH:6][CH:7]=1
Reactant: O=C(/C=C/c1ccccc1)Nc1cccc(F)c1
Agent: O=c1ccc2ccc(F)c(F)c2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Product: O=c1ccc2ccc(F)cc2[nH]1

Procedure:
The compound was prepared from (2E)-N-(3-fluorophenyl)-3-phenylacrylamide (Intermediate 30) (13.8 g, 57.2 mmol) and aluminium trichloride (30.5 g, 229 mmol) in a similar way as described for Intermediate 21 to give a mixture of the title compound together with the corresponding 5-fluoro regioisomer in a ratio of 3:1. This mixture was vigorously stirred in dichloromethane (100 mL) for 3 hours at room temperature and then filtered. The solid obtained was resuspended in diethyl ether (200 mL) and stirred like above and filtered to give 3.63 g (34%) of the crude product containing 12% of the 5-fluoro regioisomer. This was used without further purification for the next step.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cn1ccc(=O)c(OCc2ccccc2)c1C(O)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cn1ccc(=O)c(O)c1C(O)c1ccccc1

Procedure:
Under normal pressure and at room temperature, 0.643 g of 3-benzyloxy-1-methyl-2-(hydroxy-phenyl-methyl)-1H-pyridin-4-one is hydrogenated in 25 ml of methanol over 0.1 g of palladium on carbon (5%) until 1 mol of H2 per mol of starting material has been taken up. Removal of the catalyst and recrystallisation from methanol yield 3-hydroxy-1-methyl-2-(hydroxy-phenyl-methyl)-1H-pyridin-4-one. M.p.: 210°-213° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:3]=1.[N+:16]([C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21])([O-:18])=[O:17].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N+:16]([C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:5]=[CH:6][N:7]=1)([O-:18])=[O:17]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: Clc1cc(NCc2ccncc2)ncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccccc1Nc1cc(NCc2ccncc2)ncn1
Temperature: 100 °C
Yield: 45.1 %

Procedure:
A degassed mixture of (6-chloro-pyrimidin-4-yl)-pyridin-4-ylmethyl-amine (500 g, 2.27 mmol), 2-nitroaniline (317 g, 2.3 mmol), Pd2(dba)3 (200 g, 0.22 mmol), Xantphos (253 g, 0.44 mmol) and Cs2CO3 (1.48 g, 9.35 mmol) in toluene (10 mL) was heated at 100° C. for 3 hours. The reaction was concentrated, and the residue was purified by reverse phase chromatography followed by flash chromatography on silica to obtain the title compound (330 mg, yield: 45%). MS (ESI): 323 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:21])=[C:12]([C:15](=[O:20])[C:16]([O:18][CH3:19])=[O:17])[C:13]([I:14])=[C:8]2[CH:7]=[CH:6]1.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.CCO.C(=O)=O.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.O.CCOC(C)=O.C1COCC1>[F:1][C:2]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:21])=[C:12]([C@H:15]([OH:20])[C:16]([O:18][CH3:19])=[O:17])[C:13]([I:14])=[C:8]2[CH:7]=[CH:6]1
Reactant: COC(=O)C(=O)c1c(C)nc2c(ccn2Cc2cccc(F)c2F)c1I
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)[C@@H](O)c1c(C)nc2c(ccn2Cc2cccc(F)c2F)c1I
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
To a solution of methyl 2-(1-(2,3-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-oxoacetate (5.8 g, 12.33 mmol) in toluene (120 mL) was added (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole [(R)-CBS, 0.855 g, 3.08 mmol) (1M/toluene) under nitrogen atmosphere and the mixture was cooled to −35° C. (EtOH/dry ice); then cathecolborane (38.2 mL, 38.2 mmol) (1M/THF) was slowly added in ˜30 min. The mixture was kept at −35° C. 30 min and then allowed to warm to 0° C. in ˜2 h. 2M Na2CO3/water was added followed by EtOAc and the mixture was stirred for 5 min at ambient temperature. Water was added and the organic phase was washed with 1M NaOH/water (2×), dried (Na2SO4), concentrated, dried in vacuo to provide (S)-methyl 2-(1-(2,3-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-hydroxyacetate (6.84 g, 12.31 mmol, 100% yield) as a yellowish solid. Chiral HPLC showed ˜97:3 selectivity. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.62 (s, 3 H), 3.78 (s, 3 H), 5.49 (d, J=15.24 Hz, 1 H), 5.52 (d, J=15.24, 1 H), 5.92 (s, 1 H), 6.34 (d, J=3.52 Hz, 1 H), 6.81-6.90 (m, 1 H), 6.91-7.01 (m, 1 H), 7.02-7.12 (m, 1 H), 7.20 (d, J=3.52 Hz, 1 H); LCMS (m/z) ES+=473 (M+1).
Reaction SMILES: FC1C=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4]C=1.[N:38]1C=C(B(O)O)C=[N:40][CH:39]=1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:16][CH2:15][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:5]4[CH:4]=[N:38][CH:39]=[N:40][CH:6]=4)[CH2:19][CH2:18]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:33])([F:35])[F:34]
Reactant: OB(O)c1cncnc1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2cncnc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using pyrimidin-5-ylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=499, obsd.=499).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[N:13][N:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])[C:11]=3[CH:24]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].Cl>C(O)C>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[N:13][N:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:11]=3[CH:24]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)CCCOn1nnc2ccc(Cn3ccnc3)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCOn1nnc2ccc(Cn3ccnc3)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
A mixture of 3.2 parts of ethyl 4-[[6-(1H-imidazol-1-ylmethyl)-1H-benzotriazol-1-yl]oxy]butanoate, 25 parts of a sodium hydroxide solution 1N and 20 parts of ethanol was stirred for 1.5 hours at room temperature. 25 Parts of a hydrochloric acid solution 1N were added and the whole was concentrated to a volume of about 20 parts. The precipitated product, which was formed during concentration, was filtered off, washed with water, 2-propanol and 1,1'-oxybisethane and dried, yielding 2.1 parts (71%) of 4-[[6-(1H-imidazol-1-ylmethyl)-1H-benzotriazol-1-yl]oxy]butanoic acid; mp. 170.5° C. (compound 236).