Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([O:19][CH3:20])[C:14]=1[C:21]1[CH:29]=[CH:28][C:24]2[O:25][CH2:26][O:27][C:23]=2[CH:22]=1.CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[O:25]1[C:24]2[CH:28]=[CH:29][C:21]([C:14]3[C:15]([O:19][CH3:20])=[N:16][N:17]([CH3:18])[C:13]=3[NH:12][S:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])=[CH:22][C:23]=2[O:27][CH2:26]1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COc1nn(C)c(N)c1-c1ccc2c(c1)OCO2
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: COc1nn(C)c(NS(=O)(=O)c2ccc(Br)cc2)c1-c1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 2.1 %

Procedure:
4-Bromobenzenesulfonyl chloride (210 mg) was added at room temperature under an atmosphere of nitrogen to a solution of 5-amino-4-(1,3-benzodioxol-5-yl)-3-methoxy-1-methyl-1H-pyrazole (Preparation 43) (100 mg) and dimethylaminopyridine (50 mg) in anhydrous pyridine (4 ml). The reaction was stirred overnight. The mixture was concentrated under reduced pressure, then a saturated solution of ammonium chloride (6 ml), ethyl acetate (6 ml), and brine (6 ml) were sequentially added. The aqueous phase was extracted with ethyl acetate (2*8 ml) and the combined organic fractions were washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified to yield the title compound (4 mg).
Reaction SMILES: [C:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([OH:12])=[O:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>>[C:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([OH:12])=[O:11])[C:6]=1[N+:18]([O-:20])=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C(=O)O)n[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(C)(C)c1[nH]nc(C(=O)O)c1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
5-tert-Butyl-1H-pyrazol-3-carboxylic acid (5 g, 29.7 mmol) was added portionwise to concentrated sulfuric acid (25 ml) at room temperature with stirring. The reaction mixture was then heated to 60° C. and concentrated nitric acid (70%, 5.15 ml) was added dropwise, keeping the temperature at 60° C. The reaction was then stirred at 60° C. for 2.5 hours, cooled to room temperature and poured onto 50 ml of ice with stirring. After 15 minutes the white precipitate was isolated by filtration, washed with water and dried under reduced pressure to give 5-tert-butyl-4-nitro-1H-pyrazol-3-carboxylic acid (6.0 g) as a white solid. 1H NMR (400 MHz, DMSO-D6): δ=13.50-13.88 (2H, brs), 1.13 (9H, s) ppm. LRMS (electrospray): m/z [M+Na]+ 236, [M−H]+ 212.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]2[N:8]=[C:9]([CH2:11][N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[O:10][C:6]=2[CH:5]=1)([O-])=O.[O-2].[Al+3].[O-2].[O-2].[Al+3].ClCCl.C(O)C>CO>[N:12]1([CH2:11][C:9]2[O:10][C:6]3[CH:5]=[C:4]([NH2:1])[CH:18]=[CH:17][C:7]=3[N:8]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc2nc(CN3CCCC3)oc2c1
Agent: [Al+3]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: Nc1ccc2nc(CN3CCCC3)oc2c1

Procedure:
Prepared analogously to Example VI.1.d from 1.80 g (7.28 mmol) of 6-nitro-2-(pyrrolidin-1-ylmethyl)benzoxazole (VIII.1.b) in methanol as solvent. Yield: 1.10 g (70% of theory); Rf value: 0.60 (aluminum oxide, dichloromethane/ethanol=20:1); C12H15N3O; EII mass spectrum: m/z=218 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:12][CH2:13][NH:14]C(=O)C)[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)CO.[OH-].[K+].[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>O.C(O)C>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[NH2:14][CH2:13][CH2:12][N:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)NCCn1cccc1-c1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CCO
Solvent: O
Product: NCCn1cccc1-c1ccccc1
Reaction time: 24 h
Yield: 64 %

Procedure:
N-[2-(2-Phenylpyrrol-1-yl)ethyl]acetamide (0.9 g) and 5 ml of ethylene glycol was added in succession to a solution of 1.0 g of potassium hydroxide in 10 ml of water. The reaction mixture was stirred at the boiling point for 24 hours. The cold mixture was extracted twice with 50 ml of methylene chloride each time, the organic phases were combined and extracted twice with 50 ml of 2N hydrochloric acid each time. The aqueous phases were combined, brought to a pH value of 12 by the addition of 28% sodium hydroxide solution and again extracted twice with 50 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. 0.3 g of a total of 0.6 g of crude product were dissolved in a 20-fold amount of ethanol and treated with 2 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 0.3 g (64%) of 1-(2-aminoethyl)-2-phenylpyrrole fumarate (1:1); m.pt.: 169°-171° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[N:25]=[C:24]([NH2:26])[C:23]([N+:27]([O-])=O)=[CH:22][C:21]=4[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[C:5]2[CH:36]=[CH:37][CH:38]=[CH:39][C:4]=2[N:3]=1.[H][H]>[Pd].CCO>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[N:25]=[C:24]([NH2:26])[C:23]([NH2:27])=[CH:22][C:21]=4[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)[C:5]2[CH:36]=[CH:37][CH:38]=[CH:39][C:4]=2[N:3]=1
Reactant: [H][H]
Reactant: Cc1nc2ccccc2n1C1CCN(Cc2ccc(-c3nc(N)c([N+](=O)[O-])cc3-c3ccccc3)cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: Cc1nc2ccccc2n1C1CCN(Cc2ccc(-c3nc(N)c(N)cc3-c3ccccc3)cc2)CC1

Procedure:
6-(4-{[4-(2-Methyl-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-3-nitro-5-phenylpyridin-2-amine (4-3; 0.244 g, 0.470 mmol) and 300 mg 10% palladium on carbon was stirred in 10 ml EtOH. Hydrogenate under 1 atm of hydrogen for 1 h. The reaction was filtered through celite, washed with EtOH and concentrated to afford a yellow oil (4-4). 1H NMR (CDCl3) δ 7.70 (d, 1H, J=7.6 Hz), 7.62 (m, 1H), 7.36-7.20 (m, 9H), 7.10 (m, 2H), 7.03 (s, 1H), 4.22 (m, 1H), 3.67 (s, 2H), 2.61 (s overlapping with m, 5H), 2.27 (m, 2H), 1.87 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C@@H:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:21]([NH:23][CH3:24])=[O:22]>>[CH3:26][C:25]([CH3:28])([CH3:27])[C@H:20]([NH:19][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])[C:21](=[O:22])[NH:23][CH3:24]
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Product: CNC(=O)[C@@H](NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and (S)-2-amino-N,3,3-trimethylbutanamide (CAN 89226-12-0) as starting materials and isolated (115 mg, 52%) as a white solid; MS (ESI, m/z): 388.5 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24]O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:7][O:6][C:4](=[O:5])[C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[CH:9][C:8]=1[O:12][CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCCO
Reactant: COC(=O)c1c(O)cccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 2,6-dihydroxybenzoate (1.0 g, 5.95 mmol) and 4-(Boc-amino)-1-butanol (1.1 mL, 5.95 mmol) in 60 mL of THF is added PPh3 (1.7 g, 6.5 mmol) and DEAD (2.97 mL, 6.5 mmol). The solution is stirred at RT for 18 h then the solvent is removed under reduced pressure. The residue is purified by flash chromatography using a gradient of hexane/EtOAc (5:1 to 2:1) to give the product as a colorless liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]#[N:10])=[C:4]([Cl:11])[CH:3]=1.[CH3:12][N:13]1[C:17]([C:18]#[N:19])=[CH:16][CH:15]=[C:14]1B(O)O.C(=O)([O-])[O-].[K+].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[Br-]>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1COCC1>[Cl:11][C:4]1[CH:3]=[C:2]([C:14]2[N:13]([CH3:12])[C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9]#[N:10]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: N#CNc1ccc(Br)cc1Cl
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1CCOC1
Product: Cn1c(C#N)ccc1-c1ccc(NC#N)c(Cl)c1

Procedure:
4-bromo-2-chlorophenylcyanamide (0.114 g, 0.5 mmol), tris (dibenzylideneacetone) dipalladium (11.6 mg, 0.0126 mmol), N-methyl-5-cyanopyrroleboronic acid (0.150 g, 1 mmol), and potassium carbonate (0.276 g, 2 mmol) were placed in a 40 mL vial fitted with a septa. The vial was then filled with a continuous flow of nitrogen and THF (2 mL) was added with stirring. Tri-tert-butylphosphine (10 wt % in hexane) (0.0486 mL, 0.0252 mmol) was added to the mixture and allowed to stir until the starting bromide was consumed. The mixture was then diluted with 1/1 hexane/ethylacetate, filtered through a plug of silica gel, the solvent evaporated and the residue was flash chromatographed using 4/1 Hexane/THF to give [2-chloro-4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]cyanamide) (0.015 g, 12%).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH:3]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)[C:4]([OH:6])=O.C(Cl)CCl.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[C:20]([CH3:27])[CH:19]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:12][N:2]([CH3:1])[CH:3]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)[C:4]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[C:20]([CH3:27])[CH:19]=1)=[O:6]
Reactant: CN(C)C(C(=O)O)c1ccsc1
Reactant: Cc1cc(N)ccc1C(N)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Cc1cc(NC(=O)C(c2ccsc2)N(C)C)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To 2-(dimethylamino)-2-(thiophen-3-yl)acetic acid in pyridine was added EDC, DMAP and 4-amino-2-methylbenzamide (E112) and the solution was stirred for 10 hours at room temperature. The mixture was poured into NaHCO3 (sat) and extracted with EtOAc. The extracts were dried (MgSO4), filtered and evaporated. Column chromatography (SiO2, 0-100% EtOAc/Hex) gave pure 4-(2-(dimethylamino)-2-(thiophen-3-yl)acetamido)-2-methylbenzamide (E113).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([N:16]1[C:22](=[O:23])[CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=2)[CH2:18][CH2:17]1)[CH2:5][CH2:6][N:7]1[CH2:14][CH2:13][C:10]2([CH2:12][CH2:11]2)[C@H:9]([OH:15])[CH2:8]1.[Li+].[BH4-]>>[OH:15][C@@H:9]1[CH2:8][N:7]([CH2:6][CH2:5][C@H:4]([N:16]2[C:22](=[O:23])[CH2:21][CH2:20][N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:32])([F:33])[F:34])[CH:25]=3)[CH2:18][CH2:17]2)[CH2:3][OH:2])[CH2:14][CH2:13][C:10]21[CH2:12][CH2:11]2
Reactant: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(c2cccc(OC(F)(F)F)c2)CCC1=O
Agent: [BH4-]
Agent: [Li+]
Product: O=C1CCN(c2cccc(OC(F)(F)F)c2)CCN1[C@H](CO)CCN1CCC2(CC2)[C@H](O)C1
Yield: 73 %

Procedure:
In analogy to the procedure described in example 2, (S)-4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-2-[7-oxo-4-(3-trifluoromethoxy-phenyl)-[1,4]diazepan-1-yl]-butyric acid methyl ester and LiBH4 gave the title compound in 73% yield as a white foam. MS: 472.3 (MH+).
Reaction SMILES: [C:1]([CH2:9][N:10]1[CH2:15][CH2:14][N:13]([N:16]([CH2:19][C:20]#[N:21])[N:17]=[O:18])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:22]>CO>[ClH:22].[ClH:22].[C:1]([CH2:9][N:10]1[CH2:11][CH2:12][N:13]([N+:16]2[N-:17][O:18][C:20](=[NH:21])[CH:19]=2)[CH2:14][CH2:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCN(N=O)N1CCN(CC(=O)c2ccccc2)CC1
Agent: Cl
Solvent: CO
Product: N=c1c[n+](N2CCN(CC(=O)c3ccccc3)CC2)[n-]o1
Yield: 81.8 %

Procedure:
The resulting 4-(benzoylmethyl)-1-(N-nitrosocyanomethylamino)piperazine was dissolved in 10 ml of methanol. In the solution was added 12 ml of 10% methanolic hydrochloric acid, and the mixture was reacted at 5° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol-ether to give 1.8 g (yield 81.8%) of 3-[4- (benzoylmethyl)piperazin-1-yl]sydnonimine dihydrochloride having a melting point of 182° to 184° C. (decomp.).
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[NH:18][C:19]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)=[C:20]([C:24]#[N:25])[C:21](=O)[CH:22]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:41])=O>CN(C)C=O>[CH2:1]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[C:21]([Cl:41])[C:20]([C:24]#[N:25])=[C:19]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)[N:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)[nH]c(C2CCCN(C(=O)NCc3ccccc3)C2)cc1=O
Solvent: CN(C)C=O
Product: N#Cc1c(Cl)cc(C2CCCN(C(=O)NCc3ccccc3)C2)nc1-c1ccc(Oc2ccccc2)cc1
Yield: 82.9 %

Procedure:
A solution of N-benzyl-3-(5-cyano-4-oxo-6-(4-phenoxyphenyl)-1,4-dihydropyridin-2-yl)piperidine-1-carboxamide (167.9 mg, 0.333 mmol) and phosphorus oxychloride (0.093 mL, 0.998 mmol) in N,N-dimethylformamide (1 mL) was heated to 90° C. in a sealed tube for 50 min. The mixture was concentrated. The residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate and concentrated. Silica gel chromatography, eluting with 0-50% ethyl acetate in hexanes, gave N-benzyl-3-(4-chloro-5-cyano-6-(4-phenoxyphenyl)pyridin-2-yl)piperidine-1-carboxamide as white solid (144.4 mg, 83% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.92 (2H, δ, J=8.53 Hz), 7.28-7.46 (8H, m), 7.19 (1H, t, J=7.40 Hz), 7.06-7.14 (4H, m), 5.15 (2H, s), 4.36 (1H, hr. s), 4.12-4.25 (1H, m), 3.16 (1H, br. s), 2.92 (2H, br. s), 2.07 (1H, br. s), 1.84 (2H, hr. s), 1.58-1.70 (1H, m); MS (ES+) m/z: 524 (M+H); LC retention time: 4.330 min (analytical HPLC Method A).
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[S:13]([NH:16][CH:17]1[CH2:20][N:19]([C:21]2[N:26]=[CH:25][C:24]([C:27]([O:29]CC)=[O:28])=[CH:23][N:22]=2)[CH2:18]1)(=[O:15])=[O:14].Cl.C([O-])(O)=O.[Na+]>C1COCC1.CO>[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[S:13]([NH:16][CH:17]1[CH2:20][N:19]([C:21]2[N:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][N:22]=2)[CH2:18]1)(=[O:15])=[O:14]
Reactant: CCOC(=O)c1cnc(N2CC(NS(=O)(=O)c3ccc4ccccc4c3)C2)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc(N2CC(NS(=O)(=O)c3ccc4ccccc4c3)C2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
1M NaOH (10 ml) was added to a solution of ethyl 2-{3-[(2-naphthylsulfonyl)amino]azetidin-1-yl}pyrimidine-5-carboxylate (347 mg, 0.84 mmol) in THF (10 ml) and MeOH (2 ml) and the reaction stirred at r.t. overnight. The reaction mixture was acidified to pH˜2 (2M HCl) before adjusting to pH˜7 with sat. NaHCO3 giving a white precipitate. The reaction was cooled to 0° C. and the precipitate isolated by filtration affording the title compound as a white solid (303 mg, 94%). LCMS purity 97%, m/z 385 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:33])[NH:24][C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([I:32])[CH:26]=4)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C.C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=NC=2)=O)C=CC=1)(C)(C)C>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:23]([C:20]2[CH:21]=[CH:22][C:17]([N:14]3[CH2:13][CH2:12][N:11]([C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:34])=[O:3])=[CH:6][CH:7]=4)[CH2:16][CH2:15]3)=[N:18][CH:19]=2)=[O:33])=[CH:26][C:27]=1[I:32]
Reactant: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(Cl)c(I)c4)cn3)CC2)cc1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc2)c1
Product: O=C(O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(Cl)c(I)c4)cn3)CC2)cc1

Procedure:
4-{4-[5-(4-Chloro-3-iodo-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was prepared by the hydrolysis of 4-{4-[5-(4-chloro-3-iodo-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester with LiOH monohydrate in manner similar to the one described in the synthesis of 4-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid, above. The product was obtained after suspension in small volume of EtOAc and filtration. HRMS m/z calcd for C23H20N4O3ClI [M+H]+: 563.0342. Found: 563.0343.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[OH:15].[Cl:16][CH:17]([F:24])[C:18]([F:23])([F:22])[C:19](Cl)=[O:20]>Cl>[Cl:16][CH:17]([F:24])[C:18]([F:23])([F:22])[C:19]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[OH:15])=[O:20]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C(Cl)C(F)(F)C(F)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)C(F)(F)C(F)Cl
Temperature: 20 °C
Reaction time: 3 h

Procedure:
146.8 g (1.1 mole) of anhydrous aluminium chloride were added with stirring to a suspension of 154 g (1 mole) of 2-amino-5-nitrophenol. The brownish black solution was cooled down to 20° C. In 20 min 181 g (1 mole) of 3-chloro-2,2,3-trifluoro-propionyl chloride were added thereto, the temperature being kept at 30° C. by cooling. After 3 hours of stirring at room temperature the solution was poured out in 2 l of icewater and 200 ml of concentrated hydrochloric acid. Stirring was continued for 1 hour. The precipitate was collected and rinsed with water until free from acid.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:12]([CH2:22][CH2:23][N:24]2[C:29]3[CH:30]=[C:31]([C:34]#[N:35])[CH:32]=[CH:33][C:28]=3[O:27][CH2:26][C:25]2=[O:36])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[C:34]([C:31]1[CH:32]=[CH:33][C:28]2[O:27][CH2:26][C:25](=[O:36])[N:24]([CH2:23][CH2:22][C@H:12]3[CH2:11][CH2:10][C@@H:9]([OH:8])[CH2:14][N:13]3[C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[C:29]=2[CH:30]=1)#[N:35]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1CCN1C(=O)COc2ccc(C#N)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)CC[C@@H]1CCN1C(=O)COc2ccc(C#N)cc21
Reaction time: 5 h

Procedure:
To a solution of tert-butyl (2R,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidine-1-carboxylate (Intermediate 186, 1.01 g) in THF (10 mL) was added tetrabutylammonium fluoride (TBAF) (4 mL). After 5 hours, the reaction was diluted with ethyl acetate, washed with NaHCO3 and brine, dried over sodium sulfate and concentrated. The crude reaction mixture was used without further purification in the next step.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12](C(OC(C)(C)C)=O)[CH:13]=2)O1.Br[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:9]2[CH:13]=[N:12][NH:11][CH:10]=2)=[N:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Fc1ccc(Br)nc1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccc(-c2cn[nH]c2)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (15.4 g, 52.5 mmol) and 2-bromo-5-fluoropyridine (8.4 g, 47.7 mmol) in 1,4-dioxane (100 mL), Pd(PPh3)4 (5.5 g, 4.77 mmol) and a 2M aqueous solution of Na2CO3 (71.6 mL, 0.14 mol) were added, then the resulting mixture was stirred at 100° C. for 3 hours and then at room temperature for 72 hours. Water was added to the reaction mixture, followed by extraction with EtOAc. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over MgSO4, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure. A small amount of EtOAc was added to the obtained residue and the resulting mixture was filtered out and dried to obtain the title compound (4.9 g) (colorless solid).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2[CH2:18]O)=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=1[SH:40].C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=1[S:40][CH2:18][C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=1
Reactant: CCOC(=O)c1cnc(CO)n1-c1ccc(F)cc1
Reactant: Sc1c(Cl)cccc1Cl
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(CSc2c(Cl)cccc2Cl)n1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 1-(4-fluorophenyl)-2-(hydroxymethyl)-1H-imidazole-5-carboxylate (15) (1.25 g, 4.7 mmol) and triethylamine (0.95 g, 9.4 mmol) in CH2Cl2 (30 mL) was added methanesulfonyl chloride (0.65 g, 5.64 mmol) at 0° C. and the reaction was stirred at 0° C. After 3 hours, 2,6-dichlorobenzenethiol (0.84 g mg, 4.7 mmol) and cesium carbonate (2.28 g, 7 mmol) were added and the reaction was stirred at room temperature for 1 hour. The mixture was filtered by vacuum filtration, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford ethyl 2-(((2,6-dichlorophenyl)thio)methyl)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (72).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[N:9]=[CH:8][CH:7]=[C:6]2[O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[O:30])=[CH:24][CH:23]=1)#[N:2].[OH-].[Na+]>CO>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[N:9]=[CH:8][CH:7]=[C:6]2[O:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[O:30])=[CH:26][CH:27]=1)#[N:2]
Reactant: COC(=O)CCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(OC)cc4)cc3)c2cc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCCCC(=O)O)c(C#N)cc34)cc2)cc1
Temperature: 80 °C
Reaction time: 0.58 h

Procedure:
N-(4-(6-Cyano-7-(3-methoxycarbonylpropoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea (100 mg) was added to a methanol (16 ml) and 2N aqueous sodium hydroxide (3 ml) mixed solvent, and the mixture was heated and stirred at 80° C. for 35 minutes. The reaction solution was filtered, and then 1.2 ml of aqueous 5N hydrochloric acid was added. The precipitated solid was filtered out and washed with methanol and then ether to obtain 50 mg of the target substance as a light yellow solid.