Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].C([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])C>C(Cl)Cl>[NH:22]1[C:23]2[C:24](=[CH:18][CH:5]=[CH:6][CH:7]=2)[C:26]([CH2:2][C:3]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3]2=[O:19])=[O:19])=[CH:25]1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1c[nH]c2ccccc12)NC1N=C(c2ccccc2)c2ccccc2NC1=O
Reaction time: 0.25 h

Procedure:
3-(RS)-Amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (75 mg, 0.298 mmol) and indole-3-acetyl chloride (57.8 mg, 0.298 mmol) were combined in CH2Cl2 (2 ml) and the pH adjusted to 9.0 with triethylamine (TEA) 41 μl, 0.298 mmol). After stirring 15 min., a second portion of indole-3-acetyl chloride (44 mg, 0.175 mmol) and TEA (30 μl, 0.215 mmol) were added and the reaction stirred an additional 15 min. The completed reaction was diluted with CH2Cl2, washed with H2O (1X) and brine (1X), dried over MgSO4, filtered and stripped to dryness in vacuo. The residue was chromatographed on silica gel (5% MeOH in CH2Cl2) to give the title compound as a pinkish solid from Et2O: (m.p. 264°-265°).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:18]([CH3:22])[C:19](F)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH3:29].O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:18]([CH3:22])[C:19]([NH2:29])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C(=O)F)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: N
Solvent: C1CCOC1
Solvent: O
Product: CC(C(N)=O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanoyl fluoride (0.32 mmol) in anhydrous THF (5 mL) at −78° C. was bubbled NH3 (g) for 10 minutes. The reaction mixture was sealed and stirred at −78° C. for 15 min and at rt for 1 hr. Water (100 mL) was added, the reaction mixture was extracted with ethyl acetate (100 mL), dried (Na2SO4), and concentrated to give 115 mg (100% yield) of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanamide, the NMR spectrum of which was consistent with the desired structure.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)SC)[C:4]([NH2:6])=[O:5])#[N:2].[NH2:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].O.[NH2:25][NH2:26]>CCO>[NH2:2][C:1]1[NH:26][N:25]=[C:7]([NH:12][C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:3]=1[C:4](=[O:5])[NH2:6]
Reactant: NN
Reactant: CSC(SC)=C(C#N)C(N)=O
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cccc(Nc2n[nH]c(N)c2C(N)=O)c1
Temperature: 75 °C

Procedure:
Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added Ethyl 3-aminobenzoate (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain ethyl 3-((5-amino-4-carbamoyl-1H-pyrazol-3-yl)amino)benzoate as a yellow powder. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [C:1]([C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH2:8][CH:9]=[CH2:10])[CH2:4][C:5]([OH:7])=O)#[N:2].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C=O)C>[C:1]([C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH2:8][CH:9]=[CH2:10])[CH2:4][C:5]([NH:23][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=1)=[O:7])#[N:2]
Reactant: NCc1ccc(F)cc1
Reactant: C=CCC(C#N)(CC(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCC(C#N)(CC(=O)NCc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution f 3-cyano-3-phenylhex-5-enoic acid (5.66 g, 26.3 mmol) and 4-fluorobenzylamine (3.95 g, 31.6 mmol) in DMF was added 1-hydroxybenzotriazole hydrate (6.04 g, 39.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.56 g, 39.4 mmol), and triethylamine (3.19 g, 31.5 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under vacuum. The residue was partitioned between EtOAc and water. The organic extract was dried with Na2SO4, filtered, and concentrated under vacuum to provide the title compound as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.47 (d, J=7.9 Hz, 2H), 7.36 (t, J=7 Hz, 2H) 7.35 (t, J=7 Hz, 1H), 7.04 (t, J=8.9 Hz, 2H), 6.97 (t, J=8.6 Hz, 2H), 5.53 (m, 1H), 5.12 (m, 2H), 4.21 (m, 1H), 4.08 (m, 1H), 2.88 (m, 3H), 2.77 (m, 1H) ppm. ES MS M+1=323.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([OH:9])[N:3]=1.[OH-].[Na+].[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][NH2:16]>O>[NH2:1][C:2]1[NH:3][C:4](=[O:9])[N:5]=[C:6]([NH:16][CH2:15][CH:14]([O:17][CH3:18])[O:13][CH3:12])[N:7]=1
Reactant: Nc1nc(O)nc(Cl)n1
Reactant: COC(CN)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(CNc1nc(N)[nH]c(=O)n1)OC
Temperature: 25 °C

Procedure:
A suspension of 2-amino-4-chloro-6-hydroxy-s-triazine (II) 15.0 g, 0.102 mol) in 250 mL of water was treated with sodium hydroxide (4.095 g, 0.102 mol), and the mixture was stirred to obtain a clear solution which was treated with aminoacetaldehyde dimethyl acetal (12.9 g, 0.12 mol). The mixture was heated under gentle reflux for 2.5 h. with stirring and then cooled to room temperature. The crystalline solid that separated was collected and washed with cold water (2×25 mL). Recrystallization from a large excess of water gave the compound as needles: 15.0 g (68.0%); mp 285° C. dec. Anal. (C7H13N5O3, 215.21) C, H, N.
Reaction SMILES: C([O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.Cl[C:24]1[CH:40]=[CH:39][C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[O:29])=[CH:26][N:25]=1.C1(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=NC=2)=O)C=CC=CC=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([NH:30][C:28]([C:27]2[CH:39]=[CH:40][C:24]([N:19]3[CH2:18][CH2:17][N:16]([C:13]4[CH:12]=[CH:11][C:10]([C:9]([OH:8])=[O:22])=[CH:15][CH:14]=4)[CH2:21][CH2:20]3)=[N:25][CH:26]=2)=[O:29])=[CH:36][CH:35]=1
Reactant: O=C(OCc1ccccc1)c1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Agent: O=C(O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccccc4)cn3)CC2)cc1
Product: COc1ccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc2)cc1

Procedure:
4-{4-[5-(4-Methoxy-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was prepared from 4-piperazin-1-yl-benzoic acid benzyl ester and 6-chloro-N-(4-methoxy-phenyl)-nicotinamide with a method similar to the one described in the synthesis of 4-[4-(5-phenylcarbamoyl-pyridin-2-yl)-piperazin-1-yl]-benzoic acid above. HRMS m/z calcd for C24H24N4O4 [M+H]+: 433.1871. Found: 433.1870.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:20]=O)[C:8]([OH:19])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>>[ClH:17].[C:1]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:19])=[C:7]([CH2:20][NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(Cl)c(Cl)c2)c1
Product: CC(C)(C)NCc1cc(C(C)(C)C)cc(-c2ccc(Cl)c(Cl)c2)c1O
Product: Cl

Procedure:
5-(tert-Butyl)-3-((tert-butylamino)methyl)-3′,4′-dichloro-[1,1′-biphenyl]-2-ol hydrochloride was prepared as a white solid using the procedure described in Example 9 from 5-(tert-butyl)-3′,4′-dichloro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde and tert-butylamine.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C:10](=[O:12])[N:9](C)[C:8]2=[NH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O-].[Na+]>>[C:1]1([N:7]2[CH2:11][C:10](=[O:12])[N:9]=[C:8]2[NH:14][CH3:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[O-]
Reactant: CN1C(=N)N(c2ccccc2)CC1=O
Agent: [Na+]
Product: CNC1=NC(=O)CN1c1ccccc1

Procedure:
2.2 g. of 1-phenyl-2-imino-3-methyl-4-oxoimidazolidine, 0.26 g. of sodium methoxide and 65 ml. of absolute alcohol were heated to reflux for 20 hours. The insoluble solid was filtered and ethanol was evaporated leaving a yellow solid.
Reaction SMILES: C(O)C.[CH2:4]1[CH2:9][CH:8]([C:10]([OH:12])=[O:11])[NH:7][CH2:6][CH2:5]1.C(O)(=O)[C@H]([C@@H](C(O)=O)O)O>O>[CH2:4]1[CH2:9][C@@H:8]([C:10]([OH:12])=[O:11])[NH:7][CH2:6][CH2:5]1
Reactant: O=C(O)C1CCCCN1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: O
Solvent: CCO
Product: O=C(O)[C@@H]1CCCCN1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a mixture of about 600 mL of 95% ethanol and 200 mL water at 80° C. was added about 40 g of DL-pipecolic acid followed by the addition of 49 g of D-tartaric acid. The reaction mixture was stirred at 80° C. for about an hour to get a clear solution. The solution was allowed to stand at about 25° C. for about 48 hrs and the solid precipitated was filtered. The filtrate was reduced to 260 mL by evaporation and allowed to stand at about 25° C. for 24 h. At the end of that period, more solid had precipitated out and was removed by filtration The filtrate was evaporated to dryness and the residue was dissolved in 1 L water. The water solution recovered was then treated with Amberlite Ion-Exchange resin IR-120 H+ form (Hydrous form) to remove the tartaric acid followed by 10% NH4OH solution treatment of the resin to give L-pipecolic acid of optical purity of about 85-90%. After drying 22 g of a solid was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][NH:9]2)[CH:3]=1.[CH3:20][O:21][CH2:22][CH2:23][NH2:24].C(N(CC)C(C)C)(C)C>C(O)CCC>[ClH:1].[CH3:20][O:21][CH2:22][CH2:23][NH:24][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][NH:9]2)[CH:3]=1
Reactant: COCCN
Reactant: O=c1c(-c2cccnc2)c[nH]n1-c1cc(Cl)ncn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COCCNc1cc(-n2[nH]cc(-c3cccnc3)c2=O)ncn1
Product: Cl

Procedure:
100 mg (0.4 mmol) of the compound from Example 23, 64 μl (55 mg, 0.7 mmol) of 2-methoxyethylamine and 127 μl of N,N-diisopropylethylamine (94 mg, 0.7 mmol) are stirred in 3 ml of n-butanol under reflux for 1.5 h. The solvent is then removed completely on a rotary evaporator. The residue is stirred with diethyl ether/methanol, the precipitate is filtered off and the filter residue is washed with diethyl ether. The solid is stirred in 1.5 ml of 1 N hydrochloric acid and concentrated again, and the product is dried under reduced pressure.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1([O:17][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:28][N:29]1[C@H:36]([C:37]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]3[C:57]4[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=4)[N:51]=[C:50]([CH3:58])[CH:49]=3)=[CH:42][CH:41]=2)=[O:38])[C@@H:35]([C:59](O)=[O:60])[CH2:34][C:31]2([CH2:33][CH2:32]2)[CH2:30]1.Cl.NO.CN1CCOCC1>CN(C=O)C>[OH:17][NH:8][C:59]([C@H:35]1[CH2:34][C:31]2([CH2:32][CH2:33]2)[CH2:30][N:29]([CH3:28])[C@@H:36]1[C:37]([NH:39][C:40]1[CH:41]=[CH:42][C:43]([O:46][CH2:47][C:48]2[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[N:51]=[C:50]([CH3:58])[CH:49]=2)=[CH:44][CH:45]=1)=[O:38])=[O:60]
Reactant: Cc1cc(COc2ccc(NC(=O)[C@@H]3[C@@H](C(=O)O)CC4(CC4)CN3C)cc2)c2ccccc2n1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(COc2ccc(NC(=O)[C@@H]3[C@@H](C(=O)NO)CC4(CC4)CN3C)cc2)c2ccccc2n1
Reaction time: 2 h

Procedure:
To BOP (120.0 mg, 0.24 mmol) was added to a solution of (6S,7S)-5-methyl-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylic acid (140 mg, 0.20 mmol) in DMF (1.0 mL) at 0° C. followed by hydroxylamine hydrochloride (28.0 mg, 0.40 mmol). 4-methylmorpholine (0.07 mL, 0.70 mmol) was then added to the above mixture at 0° C. and stirred at this temperature for 2 h. The product (70 mg) was purified by preparative HPLC. ESI (M+H)+ 475.4.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[NH:7]C(=O)O[C:10](=[O:11])[CH:5]2[C:4](OC)([CH3:14])[C:3]=1[I:17].[C:18]([O-:21])(=O)C.[NH4+:22]>CN(C)C=O>[NH2:7][C:6]1[C:13]([O:21][CH3:18])=[C:2]([Br:1])[C:3]([I:17])=[C:4]([CH3:14])[C:5]=1[C:10]([NH2:22])=[O:11]
Reactant: [NH4+]
Reactant: COC1(C)C(I)=C(Br)C=C2NC(=O)OC(=O)C21
Reactant: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COc1c(N)c(C(N)=O)c(C)c(I)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
Under nitrogen atmosphere, 7-bromo-6-iodo-5-methoxy-5-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (I-32) (3.68 g, 8.93 mmol) and ammonium acetate (3.44 g, 44.7 mmol) were added to dewatered N,N-dimethylformamide (80 ml), followed by stirring at room temperature for 2 hours. The reaction liquid was concentrated under reduced pressure, ethyl acetate and water were added to the residue, the precipitated insoluble matter was separated by filtration. The organic layer was collected by liquid-liquid separation, washed with aqueous saturated sodium chloride solution and dried on anhydrous magnesium sulfate, the solvent was evaporated away under reduced pressure to obtain the entitled compound (1.73 g, 50%) as a brown solid. Not further purified, this was used in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16].C(=O)([O-])[O-].[K+].[K+].C(O)CO>[Cu]I.O.C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[F:9])=[CH:4][N:3]=1
Reactant: Fc1ccccc1S
Reactant: Clc1ccc(I)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Solvent: OCCO
Product: Fc1ccccc1Sc1ccc(Cl)nc1
Yield: 66.8 %

Procedure:
2-chloro-5-iodopyridine (3.0 g, 12.5 mmol), 2-fluorobenzenethiol (1.6 g, 12.5 mmol), potassium carbonate (3.45 g, 25.0 mmol), ethylene glycol (1.55 g, 25.0 mmol) and copper(I) iodide (0.12 g, 0.63 mmol) were stirred in refluxing isopropyl alcohol (50 mL) for 40 hours. Room temperature was attained, water was added and the products extracted into ethyl acetate (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo while loading onto silica. Dry flash column chromatography using isohexane-2% ethyl acetate/isohexane gave 2-chloro-5-[(2-fluorophenyl)thio]pyridine as a pale yellow oil (2.0 g, 67%). δH (500 MHz, d6 DMSO): 7.25–7.29 (1H, m), 7.34–7.39 (1H, m), 7.44–7.51 (2H, m), 7.53 (1H, d, J=8.4 Hz), 7.75 (1H, dd, J=2.6, 8.4 Hz), 8.36 (1H, d, J=2.6 Hz); m/z (ES+) 240, 242 [MH+].
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]3[CH:11]=[CH:12][C:13]([OH:15])=[N:14][C:9]=3[N:8]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1.[H-].[Na+].IC.[C:25]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]3[CH:11]=[CH:12][C:13](=[O:15])[N:14]([CH3:25])[C:9]=3[N:8]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ncc2c3ccc(O)nc3n(C3CCCC3)c2n1
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)ccc2c3cnc(N)nc3n(C3CCCC3)c21
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
Compound 272 (100 mg, 0.37 mmol) was dissolved in dry DMF (1 mL). Sodium hydride, 60% dispersion in oil (16.0 mg, 0.4 mmol) was added and the reaction stirred at 60° C. for 20 minutes. Iodomethane (26.5 μl, 423 μmol) was the added and the reaction stirred at 60° C. for 2 hr. The solution was allowed to cool and added to water (10 mL1) and aqueous K2CO3 (saturated, 2 mL), and extracted with ethyl acetate (2×30 mL), and dichloromethane+10% methanol (2×30 mL1). The combined organics were dried (MgSO4) and evaporated to give an orange solid. Silica gel chromatography (gradient elution hexanes+2.5% TEA/0-70% ethyl acetate+2.5% TEA) afforded compound 273 as a white solid, 64 mg (61%).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6]N=C1)=[O:2].[F:13][C:14]([F:24])([F:23])[O:15][C:16]1[CH:17]=C(C=[CH:21][CH:22]=1)N.NC1C=[CH:42][C:29]([O:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][CH2:38][CH2:39][CH2:40][OH:41])[N:32]=2)=[CH:28][CH:27]=1>ClCCl>[OH:41][CH2:40][CH2:39][CH2:38][NH:37][C:33]1[N:32]=[C:31]([O:30][C:29]2[CH:42]=[CH:11][C:12]([NH:8][C:1]([NH:3][C:7]3[CH:6]=[CH:21][CH:22]=[C:16]([O:15][C:14]([F:13])([F:23])[F:24])[CH:17]=3)=[O:2])=[CH:27][CH:28]=2)[CH:36]=[CH:35][N:34]=1
Reactant: Nc1ccc(Oc2ccnc(NCCCO)n2)cc1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccnc(NCCCO)n2)cc1)Nc1cccc(OC(F)(F)F)c1
Reaction time: 12 h

Procedure:
149 mg (0.92 mmol) 1,1′-Carbonyl-diimidazol (CDI) were given to a solution of 148 mg (0.838 mmol) 3-trifluoromethoxyaniline in 4.0 ml dichloromethane and stirred for 12 h. A solution of 218 mg (0.838 mmol) 3-[4-(4-Amino-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol in 6 ml dichloromethane was added and the mixture stirred for 12 h at r.t. The reaction mixture was evaporated and the residue was purified by chromatography on silica gel (dichloromethane/methanol 95:5). The obtained material was washed with dichloromethane, the precipitate was isolated by filtration and dried. Yield: 140 mg (36%) of the title compound.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21]([OH:23])=O)=[CH:16][CH:15]=[CH:14]3)=[N:3][CH:2]=1.C(Cl)(C([Cl:28])=O)=O>C(Cl)Cl.CN(C=O)C>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21]([Cl:28])=[O:23])=[CH:16][CH:15]=[CH:14]3)=[N:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc2cc(Oc3ncnc4[nH]ccc34)ccc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc2cc(Oc3ncnc4[nH]ccc34)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-1-naphthoic acid (357 mg, 1.17 mmol) in DCM (11.7 mL) under an N2 atmosphere, was added DMF (2 drops) followed by (COCl)2 (143 μL, 1.64 mmol) dropwise. After stirring at RT for 4 hours, the reaction mixture became a yellow slurry. An aliquot was removed and placed in a vial containing 500 μl of 1 M MeNH2. After 5 min, the resulting solution was analyzed by LCMS to indicate complete conversion to the methylamine and that no acid was present in the reaction mixture. The slurry was concentrated to a yellow stable solid, which was taken directly to the next step of the reaction sequence.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH2:15]([C@@H:22]1[CH2:27][C@@H:26]([N:28]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]=[CH:38][CH:37]=2)[C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[CH2:25][CH2:24][NH:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>>[CH2:15]([C@@H:22]1[CH2:27][C@@H:26]([N:28]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]=[CH:38][CH:37]=2)[C:29](=[O:34])[C:30]([F:32])([F:33])[F:31])[CH2:25][CH2:24][N:23]1[C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(O)c1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(c1cccc(Br)c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Yield: 94.9 %

Procedure:
141 mg (0.70 mmol) of m-bromobenzoic acid are reacted in analogy to Example 2a first with 2 ml (27 mmol) of thionyl chloride and subsequently with 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine and 118 μl (0.842 mmol) of triethylamine to give the title compound (271 mg, 95%). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.7I, FD-MS: M+ =609, 611.
Reaction SMILES: O1CCCC1.[I:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[OH-].[Na+]>C(OCC)(=O)C>[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:25][CH2:26][N:27]([C:11]([C:10]2[CH:14]=[CH:15][C:7]([I:6])=[CH:8][CH:9]=2)=[O:12])[CH2:28][CH2:29]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.4 %

Procedure:
To tetrahydrofuran (60 mL) were added 4-iodobenzoyl chloride (5 g), 1-(2,4-dimethylphenyl)piperazine (3.6 g) and 1N aqueous sodium hydroxide solution (20 mL), and the mixture was stirred at room temperature overnight. Ethyl acetate was added and the mixture was partitioned. The organic layer was washed with saturated brine, and the solvent was evaporated to give the title compound (8 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][O:14][C:15](=[O:42])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30][C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:40])[CH3:39])=[CH:33][CH:32]=3)=[C:26]([NH2:41])[CH:25]=2)=[CH:18][CH:17]=1.[CH2:43](O)[CH3:44]>>[CH3:13][O:14][C:15](=[O:42])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30][C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:40])[CH3:39])=[CH:33][CH:32]=3)=[C:26]([NH:41][C:2]3[C:3]4[C:8](=[N:7][C:6]([CH2:12][CH2:43][CH3:44])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:25]=2)=[CH:18][CH:17]=1
Reactant: CCO
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: COC(=O)c1ccc(COc2ccc(Sc3ccc(NC(C)=O)cc3)c(N)c2)cc1
Product: CCCc1ccc2c(Nc3cc(OCc4ccc(C(=O)OC)cc4)ccc3Sc3ccc(NC(C)=O)cc3)ccnc2n1

Procedure:
The product from Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 mL) with the product from Example 236a (35 mg, 0.085 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (22 mg, 37%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.75-1.93 (m, 2H), 2.02 (s, 3H), 2.99 (t, J=7.54 Hz, 2H), 3.86 (s, 3H) 5.26 (s, 2H) 6.30 (d, J=6.99 Hz, 1H) 7.14 (d, J=8.82 Hz, 2H), 7.17-7.27 (m, 2H), 7.37 (d, J=8.46 Hz, 1H), 7.42 (d, J=8.82 Hz, 2H), 7.59 (d, J=8.46 Hz, 2H), 7.80 (d, J=8.46 Hz, 1H) 7.99 (d, J=8.09 Hz, 2H), 8.36 (d, J=7.35 Hz, 1H), 8.97 (d, J=8.46 Hz, 1H) 9.98 (s, 1H), 11.01 (s, 1H), 14.38 (s, 1H); MS (ESI+) m/z 593 (M+H)+.