Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15](S(C)(=O)=O)[N:14]=[C:13]([C:21]([NH2:23])=[O:22])[CH:12]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].CN1CCOCC1>CS(C)=O>[CH2:24]([N:26]([CH2:27][CH3:28])[C:15]1[N:14]=[C:13]([C:21]([NH2:23])=[O:22])[CH:12]=[C:11]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=2[O:9][CH3:10])[N:16]=1)[CH3:25]
Reactant: COc1cccc(OC)c1-c1cc(C(N)=O)nc(S(C)(=O)=O)n1
Reactant: CCNCC
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Product: CCN(CC)c1nc(C(N)=O)cc(-c2c(OC)cccc2OC)n1
Temperature: 75 °C
Yield: 18 %

Procedure:
A 4 mL screw-cap vial was charged with a solution of 6-(2,6-dimethoxy-phenyl)-2-methanesulfonyl-pyrimidine-4-carboxylic acid amide (assumed 0.3 mmol) in DMSO (0.9 mL). A solution of diethylamine and N-methyl-morpholine (NMM) in DMSO (0.3 mL, 3 M in both, 0.9 mmol, 3 eq.) was added, and the sealed vial was heated at 75° C. for 22 hours. The mixture was then submitted for purification by preparative HPLC to afford 18 mg (18%) of the 2-diethylamino-6-(2,6-dimethoxy-phenyl)-pyrimidine-4-carboxylic acid amide. 1H NMR (300 MHz, CDCl3) □ 7.79 (br s, 1H), 7.30 (t, J=8.3 Hz, 1H), 7.26 (s, 1H), 6.61 (d, J=8.3 Hz, 2H), 6.16 (brs, 1H), 3.74 (s, 6H), 3.66 (q, J=6.9 Hz, 4H), 1.22 (t, J=6.9 Hz, 6H); HPLC ret. time 2.85 min., 10-100% CH3CN, 5 min gradient; ESI-MS m/z 330.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[N:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)[CH:8]=1)([O-])=O.[BH4-].[Na+].O>C(O)C.[Ni]>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([C:19]3[N:20]=[CH:21][CH:22]=[CH:23][N:24]=3)[CH2:17][CH2:18]2)[CH:8]=1
Reactant: O=[N+]([O-])c1cnn(CCCCN2CCN(c3ncccn3)CC2)c1
Agent: [Ni]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cnn(CCCCN2CCN(c3ncccn3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
10.2 g (43.2 mmol) of nickel II chloride hexahydrate are added to a solution of 7.2 g (21 mmol) of 4nitro-1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-pyrazole, Example no. 7, in 60 ml of ethanol, with vigorous stirring. The mixture is cooled in an ice bath and 10.2 g (81 mmol) of sodium borohydride are added slowly. The mixture is left stirring for 1 hour and, after 1 hour at room temperature, water is added, the mixture is evaporated under vacuum, the residue is acidified with concentrated hydrochloric acid and the mixture is filtered, alkalinised with ammonia solution and extracted with ethyl ether. 4.4 g of 4-amino-1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-pyrazole are thereby obtained in liquid form.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:10]=[C:11]([B:15]([OH:17])[OH:16])[CH:12]=[CH:13][CH:14]=1.O>N1C=CC=CC=1>[OH:16][B:15]([OH:17])[C:11]1[CH:10]=[C:9]([NH:8][C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)O1
Reactant: Nc1cccc(B(O)O)c1
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)Nc1cccc(B(O)O)c1
Reaction time: 8 h
Yield: 72.6 %

Procedure:
Succinic anhydride (5.00 grams, 0.05 mole) and (3-aminophenyl)boronic acid (7.75 grams, 0.05 mole) are dissolved in anhydrous pyridine (40 ml), and then allowed to stand overnight at room temperature. Water (20 ml) is added and the resulting solution allowed to stand for 1 hour. The product is then concentrated on a rotary evaporator at 85°-90° C. The resulting aqueous solution is frozen in a dry-ice-acetone-slurry and lyophilized overnight. The lyophilized product is dissolved in water (50 ml) and acidified with concentrated HCl to approximately pH 1.0. The acidified solution is cooled in an ice bath for 1 hour, and the precipitate collected by filtration. The precipitate is recrystallized from boiling water (200 ml) and dried overnight in vacuo over NaOH pellets, to afford 8.60 grams (70% yield) of N-(3-dihydroxyborylphenyl)succinamic acid. Homogeneous by TLC (CHCl3 /CH3OH/CH3COOH; 60:35:5), Rf =0.5. Melting point 186°-188° C. The structure was confirmed by 300 MHz, 1 H NMR, spectrometry in d6 -DMSO.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=2)[C:20](O)=[O:21])[N:10]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:57][C:58]([F:68])([F:67])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=1[CH2:65][NH2:66]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=2)[C:20]([NH:66][CH2:65][C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=2[C:58]([F:57])([F:67])[F:68])=[O:21])[N:10]=1
Reactant: COc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1C(=O)O
Reactant: NCc1ccccc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1C(=O)NCc1ccccc1C(F)(F)F
Yield: 24.9 %

Procedure:
The title compound was prepared according to the procedure described in Example-17 by using 5-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-methoxybenzoic acid (Intermediate-11, 0.100 g, 0.270 mmol), THF (5 mL), di-isopropyl ethyl amine (1.0 mL), TBTU (0.177 g, 0.540 mmol) and 1-[2-(trifluoromethyl)phenyl]methanamine (0.072 g, 0.410 mmol) to afford 0.035 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.95 (s, 3H), 4.62-4.71 (br s, 2H), 7.30 (d, J=8.7 Hz, 1H), 7.46-7.52 (m, 2H), 7.56-7.59 (m, 2H), 7.65-7.75 (m, 3H), 8.02 (dd, J=2.4 Hz, 1H), 8.28 (s, 1H), 8.90 (br s, 1H), 12.58 (s, 1H); MS (m/z): 519.30 (M−H)−.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[C:9]([OH:23])=[N:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][CH:14]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=2)=[O:7])C>CO.C1COCC1>[OH:23][C:9]1[C:8]([C:6]([OH:7])=[O:5])=[C:17]([CH3:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([F:21])([F:20])[F:22])=[CH:14][CH:15]=2)[N:10]=1
Reactant: CCOC(=O)c1c(O)nc2cc(C(F)(F)F)ccc2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)c(O)nc2cc(C(F)(F)F)ccc12
Temperature: 60 °C
Yield: 88.2 %

Procedure:
2M aq. LiOH sol. (125 ml) was added to a solution of 15.0 g (50.1 mmol) 2-hydroxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester in a MeOH/THF mixture (in each case 175 ml) and the solution was subsequently heated to 60° C. for 16 h. The solution was subsequently concentrated in a vacuum. The residue was taken up with water and adjusted to pH 2 with a 2M hydrochloric acid. Extraction was then performed with EtOAc. The organic phase was washed with brine, dried over MgSO4 and concentrated in a vacuum. 12.0 g (44.2 mmol, 88%) 2-hydroxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid was obtained as a residue. The raw product was further converted without additional purification.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([S:21](=[O:24])(=[O:23])[NH2:22])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][NH2:10])[CH2:2][CH2:3][CH3:4].[OH2:25]>N1C=CC=CC=1.C(O)(=O)C>[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([S:21](=[O:24])(=[O:23])[NH2:22])[C:13]=1[O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][NH:10][C:15]([O:14][CH2:13][CH3:6])=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cc(CN)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CCCCNc1cc(CNC(=O)OCC)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3-n-butylamino-4-phenoxy-5-sulfamylbenzylamine (1.05 g; prepared as described in Example 289) in pyridine (7 ml) ethyl chloroformate (0.3 ml) is dropwise added at 22°-25° C., and the mixture is stirred for a further 1.5 hours. The mixture is then diluted with water (30 ml) and acetic acid (10 ml) to precipitate crude N-(3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)urethan. After filtration and recrystallization from ethanol it is obtained with a melting point of 105°-107° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=[N:19][C:18]1[CH:20]=[CH:21][C:15]([F:14])=[CH:16][CH:17]=1
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: Nc1ccc(F)cc1
Solvent: CO
Product: COc1cc(C=Nc2ccc(F)cc2)cc(OC)c1O

Procedure:
3,5-Dimethoxy-4-hydroxybenzaldehyde (1 g, 5.46 mmol) was dissolved in methanol (30 ml) and to this solution was added 4-fluoroaniline (600 mg, 5.46 mmol, 0.51 ml). The resultant reaction solution was stirred for forty-eight (48) hours at room temperature under nitrogen. The reaction solution was then cooled in the freezer and the resultant precipitate was isolated by filtration and washed with cold methanol and ether. The isolated light yellow powder was the title product: 1H NMR (300 MHz, CDCl3); δ 8.31 (S, 1H), 7.20-7.04 (m, 4H) 5.85 (S, 1H), 3.98 (S, 6H).
Reaction SMILES: S(=O)(=O)(O)O.COC(C1C=CC2C(=CC=CC=2)C=1C1C2C(C(C3C4C(=CC=CC=4)C=CC=3C(OC)=O)=C3C=1C=CC=C3)=CC=CC=2)=O.C(Cl)(Cl)Cl.[CH:52]1[C:57]2=[C:58]3[C:75](=[CH:76][CH:77]=[C:56]2[CH:55]=[CH:54][CH:53]=1)[C:74](=[O:78])[C:73]1[C:60]2[C:61]4[C:70](=[CH:71][CH:72]=1)[C:69](=[O:79])[C:68]1[C:63](=[C:64]5[CH:83]=[CH:82][CH:81]=[CH:80][C:65]5=[CH:66][CH:67]=1)[C:62]=4[C:84]1[CH:85]=[CH:86][CH:87]=[CH:88][C:89]=1[C:59]3=2>O>[CH:76]1[C:75]2[C:74](=[O:78])[C:73]3[C:60]4[C:59]([C:58]=2[C:57]2[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:77]=1)=[C:89]1[C:84]2[C:85](=[CH:86][CH:87]=[CH:88]1)[C:69](=[O:79])[C:68]1[CH:67]=[CH:66][C:65]5[C:64]([C:63]=1[C:62]=2[C:61]=4[CH:70]=[CH:71][CH:72]=3)=[CH:83][CH:82]=[CH:81][CH:80]=5
Reactant: O=C1c2ccc3ccccc3c2-c2c3ccccc3c3c4c(ccc1c24)C(=O)c1ccc2ccccc2c1-3
Agent: COC(=O)c1ccc2ccccc2c1-c1c2ccccc2c(-c2c(C(=O)OC)ccc3ccccc23)c2ccccc12
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=c1c2ccc3ccccc3c2c2c3cccc4c(=O)c5ccc6ccccc6c5c(c5cccc1c52)c43
Yield: 28 %

Procedure:
Anthracene-9,10-diboronic acid (15.0 g, 56.4 mmol), palladium acetate (633 mg, 2.82 mmol), tri(t-butyl)phosphine (1.71 g, 8.46 mmol), methyl-1-bromonaphthalene-2-carboxylate (31.4 g, 118 mmol) and cesium carbonate (73.5 g, 226 mmol) were dissolved in 200 mL of xylene and the solution was reacted under reflux at the boiling point for 5 hours in a nitrogen atmosphere to obtain dimethyl-1,1′-(anthracene-9,10-diyl)bis(2-naphthoate) at a yield of 78%. Concentrated sulfuric acid (400 mL) was added to the dimethyl-1,1′-(anthracene-9,10-diyl)bis(2-naphthoate) (24.0 g, 44.0 mmol) to react at 180° C. for 4 hours. Thereafter, chloroform and water were added to the reaction mixture to separate the organic phase. The organic phase was washed with water and a saturated sodium chloride solution, and concentrated under reduced pressure. The resulting reaction mixture was purified by silica gel column chromatography (chloroform) to obtain dinaphtho[1,2-a:1′,2′-j]perylene-10,20-dione (yield: 28%) and dibenzo[a,o]naphtho[1,2,3,4-rst]pentaphene-7,10-dione (22%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]=[C:9]([Cl:30])[C:10]=1[NH:11][C:12]1[N:22]=[C:21]2[C:15]([N:16]([CH3:29])[C:17](=[O:28])[CH2:18][CH2:19][N:20]2[CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:14][N:13]=1)[C:5](O)=[O:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:56][CH:57]1[CH2:62][CH2:61][N:60]([CH3:63])[CH2:59][CH2:58]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]=[C:9]([Cl:30])[C:10]=1[NH:11][C:12]1[N:22]=[C:21]2[C:15]([N:16]([CH3:29])[C:17](=[O:28])[CH2:18][CH2:19][N:20]2[CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:14][N:13]=1)[C:5]([NH:56][CH:57]1[CH2:62][CH2:61][N:60]([CH3:63])[CH2:59][CH2:58]1)=[O:6]
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Nc3c(Cl)cc(C(=O)O)c(F)c3Cl)ncc21
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2cc(Cl)c(Nc3ncc4c(n3)N(C3CCCC3)CCC(=O)N4C)c(Cl)c2F)CC1
Reaction time: 2 h
Yield: 65.9 %

Procedure:
3,5-dichloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-2-fluoro-benzoic acid (Intermediate 221; 85 mg, 0.18 mmol), HATU (104 mg, 0.27 mmol) and 4-amino-1-methylpiperidine (32 mg, 0.27 mmol) were stirred in DMF (3 mL) and diisopropylethylamine (95 μl, 0.54 mmol) added. The mixture was stirred for 2 hours and absorbed on to an SCX column, which was subsequently washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated and the residue purified by column chromatography (4% ammonia in methanol/DCM) to yield the title compound as a white solid (67 mg, 66%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:19][CH:20]1[CH2:22][CH2:21]1)[CH:13]([OH:18])[C:14]([O:16]C)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:19][CH:20]1[CH2:21][CH2:22]1)[CH:13]([OH:18])[C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(O)[C@H](CC1CC1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@@H](CC1CC1)C(O)C(=O)O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of the methyl ester of Step 2 (400 mg; 1.3 mmol) in THF (8 mL) and water (6.63 mL) was added LiOH (1 N, 1.37 mL). The reaction mixture was stirred for 30 minutes and then acidified with 1.0 N HCl to pH=3˜4. The mixture was extracted with EtOAc (20 mL, twice). The combined organic layer was washed with water, brine, and then concentrated in vacuo to afford the title compound (370 mg). (M+1) 294.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)=[O:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>ClCCl>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:11]=1)[C:8]([NH:34][CH2:33][C:32]1[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:37])[F:38])=[CH:36][CH:35]=1)=[O:10])=[O:2]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(C=O)cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Reaction time: 8 h

Procedure:
Publicly known [e.g. E. J. Wayne et al, J. Chem. Soc., 1022(1922)] 5-formyl-2-methoxybenzoic acid (4.05 g, 22.5 mmol) was dissolved in 80 ml of dichloromethane, which was cooled with ice. Triethylamine (7.94 ml, 56.2 mmol) was added under stirring. Next, ethyl chlorocarbonate (2.44 ml, 24.8 mmol) was added and, after stirring for 10 minutes, 4-(trifluoromethyl)benzylamine (3.31 ml, 22.5 mmol) was added dropwise, which was allowed to stand overnight. After washed with water, the reaction mixture was dried over anhydrous sodium sulfate and concentrated. Water was added to the residue, which was made acidic with dilute hydrochloric acid. Then, the precipitates were filtered and dried to quantitatively obtain the title compound as milky white crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].C([O-])([O-])=O.[Cs+].[Cs+].C(#N)C>C(OCC)(=O)C>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:2][C:3]1[N:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][CH:4]=1
Reactant: N#Cc1cccc(CCl)n1
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1cccc(COc2ccccc2Br)n1
Temperature: 80 °C

Procedure:
To a sealable 4 mL vial, containing 6-(chloromethyl)picolinonitrile (100 mg, 0.66 mmol) and 2-bromophenol (113 mg, 0.66 mmol), were added Cs2CO3 (320 mg, 0.98 mmol) and acetonitrile (1.7 mL). The vial was then heated at 80° Celsius for 15 hours. The reaction was then diluted with ethyl acetate, filtered through a celite plug and concentrated to dryness. The material was used without further purification. 1H NMR (500 MHz, CDCl3) δ 8.02-7.93 (m, 1H), 7.93-7.85 (m, 1H), 7.65-7.59 (dd, J=7.7, 1.1, 1H), 7.58-7.53 (dd, J=7.9, 1.6, 1H), 7.29-7.22 (m, 1H), 6.93-6.90 (dd, J=8.3, 1.3, 1H), 6.90-6.86 (m, 1H), 5.23 (s, 2H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[OH:22][C:23]1([CH3:31])[CH2:27][NH:26][C@H:25]([C:28]([NH2:30])=[O:29])[CH2:24]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][C:23]([OH:22])([CH3:31])[CH2:24][C@H:25]3[C:28]([NH2:30])=[O:29])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC1(O)CN[C@H](C(N)=O)C1
Agent: Cl
Product: CC1(O)C[C@@H](C(N)=O)N(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C1
Yield: 76.1 %

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 20 mg, 70.4 μmol) was reacted with (2S)-4-hydroxy-4-methylpyrrolidine-2-carboxamide hydrochloride (Example 132 b, 15.3 mg, 84.4 μmol) to obtain the title compound (22 mg, 76%) as off-white solid; MS (EI): m/e=411.5 [MH+].
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[F:19][C:20]([F:44])([F:43])[CH2:21][NH:22][C:23]([C:25]1([CH2:38][CH2:39][CH2:40][CH2:41]Br)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24].C(#N)C>O>[F:19][C:20]([F:43])([F:44])[CH2:21][NH:22][C:23]([C:25]1([CH2:38][CH2:39][CH2:40][CH2:41][N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][C:1]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc(-c2ccc(N3CCNCC3)cc2)cc1
Solvent: CC#N
Solvent: O
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc(-c4ccccc4)cc3)CC2)c2ccccc2-c2ccccc21

Procedure:
A solution of 0.4 g (1.678 mmol) of 1-biphenyl-4-yl-piperazine, 0.682 g (1.6 mmol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide and 0.223 ml (1.6 mmol) of triethylaminein 20 ml acetonitrile is stirred for 14 hours at 60° C. and then diluted with water. It is extracted with ethyl acetate and the organic phase is dried over sodium sulphate. Purification is by column chromatography on silica gel (eluant: dichloromethane/ethanol=40:1).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[O:10][C:11]([NH:13][CH2:14][C:15]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:12])(=O)C.[OH-].[Na+].Cl>CO.O>[OH:4][C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[O:10][C:11]([NH:13][CH2:14][C:15]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:12]
Reactant: CC(=O)O[C@@H]1CCC[C@H]1OC(=O)NCC1(CC(=O)O)CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CC1(CNC(=O)O[C@@H]2CCC[C@H]2O)CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a stirred solution of compound (48) (2.0 g, 5.9 mmol) in methanol (25 mL) was added a solution of NaOH (0.8 g, 20 mmol) in 20 mL of water. The reaction mixture was stirred at room temperature for 2 h (monitored by TLC). The reaction mixture was acidified to about pH 5.0 using 0.1 N HCl and then extracted using ethyl acetate (2×50 mL). The combined extracts were washed with brine (40 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified using flash chromatography on silica gel using hexane/ethyl acetate (1:1) as eluant to provide 1.3 g (75%) of compound (49) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.36-1.78 (14H, m); 1.99-2.12 (2H, m); 2.34 (2H, s); 3.23 (2H, d, J=6.4 Hz); 4.09 (1H, m); 5.26 (1H, t, J=6.4 Hz); 5.89 (1H, m). MS (ESI): m/z=298.23 (M−H−).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[O:22]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23]1>>[O:22]1[CH:26]=[CH:25][C:24]([C:2]2[C:3]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=3)=[CH:23]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: OB(O)c1ccoc1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(-c3ccoc3)nc2c1
Yield: 25.1 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and furan-3-yl boronic acid (48.8 mg, 0.44 mmol, 1.50 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (10:1)) yielded 23 mg (24%) of 3-(furan-3-yl)-2-phenylquinoxaline-6-carboxylic acid as a white solid.
Reaction SMILES: [CH3:1][Mg]Cl.[C:4]([NH:12][C:13]1([CH2:17][CH:18]=[O:19])[CH2:16][CH2:15][CH2:14]1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH4+].[Cl-]>C1COCC1>[C:4]([NH:12][C:13]1([CH2:17][CH:18]([OH:19])[CH3:1])[CH2:16][CH2:15][CH2:14]1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[Mg]Cl
Reactant: O=CCC1(NC(=O)c2ccccc2)CCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)CC1(NC(=O)c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
Methyl magnesium chloride (14.0 mL, 3M solution in THF) was added to a stirred solution of [1-(benzoylamino)cyclobutyl]acetaldehyde (2.82 g, 13.0 mmol) in THF (30 mL) at −0° C., and the mixture was stirred at room temperature for 5 hours. Saturated aqueous NH4Cl (10 mL) was added to the mixture 0° C., and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (hexane:AcOEt=2:1) of the residue gave the title compound as a colorless oil (2.65 g, 87%). 1H-NMR (400 MHz, CDCl3) δ 1.25 (3H, d, J=6.1 Hz), 1.77-2.12 (5H, m), 2.28-2.40 (1H, m), 2.52 (1H, q, J=10.4 Hz), 2.75-2.85 (1H, m), 3.26 (1H, d, J=3.7 Hz), 3.97-4.07 (1H, m), 6.91 (1H, brs), 7.39-7.46 (2H, m), 7.46-7.53 (1H, m), 7.75-7.82 (2H, m).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[CH:6][N:5]([C:8]2[N:18]=[CH:17][CH:16]=[CH:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=1.[F:19][C:20]1([F:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:19][C:20]1([F:26])[CH2:25][CH2:24][N:23]([CH2:2][C:3]2[CH:7]=[CH:6][N:5]([C:8]3[N:18]=[CH:17][CH:16]=[CH:15][C:9]=3[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=2)[CH2:22][CH2:21]1
Reactant: CCOC(=O)c1cccnc1-n1ccc(CCl)n1
Reactant: FC1(F)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cccnc1-n1ccc(CN2CCC(F)(F)CC2)n1
Yield: 94 %

Procedure:
The mixture of ethyl 2-(3-(chloromethyl)-1H-pyrazol-1-yl)nicotinate (500 mg, 1.882 mmol), 4,4-difluoropiperidine (328 mg, 2.7 mmol), and K2CO3 were stirred at room temperature in acetonitrile (25 mL) until completion of the reaction. The mixture was concentrated, pardoned between water and dichlormethane (60 mL), the organic layer separated, washed twice with water, dried (MgSO4), filtered and dried to give a brown oil, which then was purified by chromatography over silica gel (CH2Cl2+methanol) to yield 620 mg of the title compound as clear oil. ESI-MS [M+H]+: 351.15.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].Br[C:10]1[C:11]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])=[N:12][CH:13]=[C:14]([CH3:16])[N:15]=1>>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:11]1[C:10]([O:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:15][C:14]([CH3:16])=[CH:13][N:12]=1)(=[O:19])=[O:20]
Reactant: OCc1ccccn1
Reactant: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(Br)n1
Product: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OCc2ccccn2)n1

Procedure:
Prepared by the method of Example 20 using pyridine-2-methanol (0.05 g) and N-(3-bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (0.1 g). Yield 0.07 g.