Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH2:13](Br)[C:14]#[CH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:15]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)[C:14]#[CH:13]
Reactant: C#CCBr
Reactant: O=c1ccc2ccc(O)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1ccc2ccc(=O)oc2c1
Yield: 60 %

Procedure:
In 100 ml DMF at 70° C. for 12 hours, 0.1 mole 7-hydroxy-coumarin is reacted with 0.1 mole propargyl bromide in the presence of 0.1 mole potassium carbonate. The compound of the title is obtained at a 60% yield. This compound melts at 118° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10]1([C:20](Cl)=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:9][C:20]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:21])=[CH:4][C:5]([O:8][C:20]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:21])=[N:6][CH:7]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: O=c1cc(O)c(Cl)c[nH]1
Solvent: c1ccncc1
Product: O=C(Oc1cc(OC(=O)c2cccc3ccccc23)c(Cl)cn1)c1cccc2ccccc12
Yield: 81.9 %

Procedure:
The general procedure of Example 45 was followed using 2.00 g of 5-chloro-4-hydroxy-2-pyridone, 3.93 g of α-naphthoyl chloride and 100 ml of pyridine, thereby producing 3.83 g of the title compound in a yield of 61%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:38][N:39]1[CH2:44][CH2:43][C:42]2[N:45]=[C:46]([C:48]([NH:50][C@@H:51]3[CH2:55][CH2:54][CH2:53][C@H:52]3[NH2:56])=[O:49])[S:47][C:41]=2[CH2:40]1>CN(C)C=O.C(N(CC)CC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:56][C@@H:52]1[CH2:53][CH2:54][CH2:55][C@H:51]1[NH:50][C:48]([C:46]1[S:47][C:41]3[CH2:40][N:39]([CH3:38])[CH2:44][CH2:43][C:42]=3[N:45]=1)=[O:49])=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CN1CCc2nc(C(=O)N[C@@H]3CCC[C@H]3N)sc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCc2nc(C(=O)N[C@@H]3CCC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 107.8 %

Procedure:
5-Chloroindole-2-carboxylic acid (80 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (98 mg), 1-hydroxybenzotriazole monohydrate (23 mg) and triethylamine (141 μl) were added to a solution with (±)-trans-N-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediamine hydrochloride (120 mg) dissolved in N,N-dimethylformamide (5 ml), and the mixture was stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure, and dichloromethane and a saturated aqueous solution of sodium hydrogencarbonate were added to the residue to conduct liquid separation. The resultant organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography on silica gel (dichloromethane:methanol=93:7). After dichloromethane (5 ml) and a 1N ethanol solution (282 μl) of hydrochloric acid were added to the thus-obtained pale yellow solid. Ethyl acetate was added, solvent was distilled off under reduced pressure and precipitate formed was collected by filtration to obtain the title compound (109 mg) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15].N1C=CN=C1.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]N.CCOCC>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[N:6]([CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])[C:5]2=[O:15]
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Reactant: CN(C)CCN
Agent: c1c[nH]cn1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CN(C)CCN1C(=O)c2cc(N)c([N+](=O)[O-])cc2C1=O
Temperature: 150 °C
Yield: 95.2 %

Procedure:
To a suspension of 5-Amino-6-nitroisoindoline-1,3-dione (5.0 g, 24.15 mmol) in Dowtherm (75 mL) were added imidazole (1.64 g, 24.15 mmol) and N1,N1-dimethylethane-1,2-diamine (3.16 mL, 24.15 mmol) and the resulting mixture was heated at 150° C. for overnight. The reaction mixture was cooled to RT, was added ether (100 mL). The yellow precipitate was collected by filtration and washed with ether (2×50 mL) and dried to afford 5-Amino-2-(2-(dimethylamino)ethyl)-6-nitroisoindoline-1,3-dione (6.4 g, 95%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1.[C:41](Cl)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.[Cl-].[NH4+]>C(Cl)Cl>[C:41]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: Nc1ccc2ccccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc2ccccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.1 %

Procedure:
1.00 gram (2.21 mmol) of (−)-2-amino-2′-diphenylphosphino-1,1′-binaphthyl (the formula (1-1a)) was dissolved in 44 ml of methylene chloride, followed by the addition of 0.21 ml (2.65 mmol) of pyridine and 0.28 ml (2.43 mmol) of benzoyl chloride under 0° C. The reaction mixture was stirred at room temperature for 5 hours. To the reaction solution, 30 ml of saturated aqueous solution of ammonium chloride was added and extracted with 100 ml of methylene chloride. The extract was washed with 70 ml of brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified using a silica gel column chromatography (eluent: 1:6 mixture of ethyl acetate and hexane) to obtain 1.16 gram of the titled compound.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:14]=[C:13]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:12]=2)=[CH:7][CH:6]=1.Cl>O1CCCC1.C(O)(C)C>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([N:15]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=3)=[CH:12][C:13]([S:24]([CH3:27])(=[O:26])=[O:25])=[N:14]2)=[CH:21][CH:20]=1
Reactant: COCOc1ccc(-c2cc(S(C)(=O)=O)nn2-c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(S(C)(=O)=O)cc2-c2ccc(O)cc2)cc1
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To the solution of 5-[4-(methoxymethoxy)phenyl]-1-(4-methoxyphenyl)-3-(methylsulfonyl)-1H-pyrazole (0.93 g) in a mixture of tetrahydrofuran (10 ml) and isopropyl alcohol (5 ml) was added hydrogen chloride aqueous solution (20%, 8 ml) at ambient temperature. The solution was stirred for 3 hours, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, and evaporated to give 0.82 g of 4-[1-(4-methoxyphenyl)-3-(methylsulfonyl)-1H-pyrazol-5-yl]phenol (P0025).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:56]=[CH:55][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:32](=[O:33])[N:31]([C:34]6[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=6)[N:30]=[CH:29][CH:28]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([CH:42]3[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44][CH2:43]3)=[N:9]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]2[C:32](=[O:33])[N:31]([C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)[N:30]=[CH:29][CH:28]=2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:56][CH:55]=3)[N:9]=[C:10]([CH:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)[C:11]=12
Reactant: COc1ccc(Cn2nc(C3CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cn2nc(C3CCNCC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
A round-bottomed flask was charged with tert-butyl 4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidine-1-carboxylate (74.3 mg, 0.0973 mmol), 2,2,2-trifluoroacetic acid (111 mg, 0.973 mmol) and CH2Cl2 (10 mL). The reaction mixture was stirred at ambient temperature 1 hour. The solvent was removed and the residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (58.8 mg, 91.1%). LRMS (APCI pos): >99% purity, 254 nm, m/e 664 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([F:14])=[C:12]([Cl:15])[C:11]([N+:16]([O-:18])=[O:17])=[C:10](F)[C:9]=2[CH3:20])[CH2:4][CH2:3]1.[F-].[K+].[CH:23]1([NH2:26])[CH2:25][CH2:24]1>CN(C)C=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([CH3:20])=[C:10]([C:11]([N+:16]([O-:18])=[O:17])=[C:12]([Cl:15])[C:13]=2[F:14])[NH:26][CH:23]2[CH2:25][CH2:24]2)[CH2:4][CH2:3]1
Reactant: NC1CC1
Reactant: Cc1c(F)c([N+](=O)[O-])c(Cl)c(F)c1N1CCN(C)CC1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(NC2CC2)c([N+](=O)[O-])c(Cl)c(F)c1N1CCN(C)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To the thus obtained 2-(4-methyl-1-piperazinyl)-3,6-difluoro-4-chloro-5-nitrotoluene (0.13 g) are added anhydrous dimethylformamide (2 ml), potassium fluoride (37 mg) and cyclopropylamine (0.15 ml) and the mixture is stirred at 100° C. for 3 hours. After cooling, the reaction mixture is poured into ice-water, extracted with dichloromethane and the extract is dried. The solvent is distilled off under reduced pressure and purified by silica-gel column-chromatography (eluent; dichloromethane : methanol=10 : 1) to give 3-(4-methyl-1-piperazinyl)-4-fluoro-5-chloro-2-methyl-6 -nitro-N-cyclopropylaniline (0.14 g).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[NH2:7][C:4]1[CH:3]=[C:2]([CH3:1])[N:6]([CH2:15][C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:22][CH2:23]2)=[O:17])[N:5]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: Cc1cc(N)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1cc(N)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 5-methyl-1H-pyrazol-3-ylamine, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4) afforded the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): 7.12-7.18 (m, 3H), 7.0-7.08 (t, 2H), 4.8 (s, 2H), 5.1 (s, 2H), 3.78-3.88 (m, 4H), 3.18-3.38 (m, 4H), 2.28 (s, 3H). MS (ES) M+H expected 317.37, found 318.1
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[S:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:10]([CH2:19][C:20](O)=[O:21])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH:25][N:26]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1.ON.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[S:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:10]([CH2:19][C:20]([NH:26][OH:25])=[O:21])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1cc(C(=O)c2ccc(Cl)cc2)sc1-c1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(Cc1cc(C(=O)c2ccc(Cl)cc2)sc1-c1ccccc1)NO
Reaction time: 8 h
Yield: 20.2 %

Procedure:
To a stirred mixture of 30 mg (0.08 mmol) of 1, 11 mg (0.08 mmol) of N-hydroxybenzotriazole (HOBt), 21 mg (0.11 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl), and 28 mL (0.25 mmol) of 4-methylmorpholine in 5 mL dry CH2Cl2 was added 6 mg (0.08 mmol) of HONH2.HCl at room temperature. The resulting mixture was stirred overnight and washed with 5 mL of H2O. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc) to give 6 mg (20%) of 2 as a white viscous residue that solidified slowly at room temperature: 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.90 (brs, 1H), 7.86 (d, J=8.6 Hz, 2H), 7.72 (s, 1H), 7.68-7.50 (m, 7H), 3.39 (s, 2H); 13C NMR (100 MHz, DMSO-d6) 185.9, 166.3, 148.8, 139.7, 138.6, 137.4, 136.0, 133.0, 132.3, 130.6, 129.2, 129.2, 129.1, 128.9; IR (KBr) cm−1 3305, 3223, 3060, 2921, 1746, 1631, 1436; LREIMS C19H14ClNO3S requires 371.04. Found: 371 ([M+], 9%), 355 (100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([NH:11][C@H:12]([C:31]([OH:33])=[O:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:16][CH:15]=1)=[O:10].C(=O)(O)[O-].[Na+].[C:39]([O:42][CH:43](Cl)[CH3:44])(=[O:41])[CH3:40].O>CN(C=O)C>[C:39]([O:42][CH:43]([O:32][C:31](=[O:33])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:18][CH:19]=1)[NH:11][C:9]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])=[O:10])[CH3:44])(=[O:41])[CH3:40]
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cccc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Reactant: CC(=O)OC(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OC(C)OC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.6 %

Procedure:
To a suspension of N-[(2,6-difluorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine (0.743 mmol, 340 mg) and sodium bicarbonate (5.94 mmol, 499 mg) in DMF (3.0 mL) was added 1-chloroethyl acetate (5.94 mmol, 0.73 g) at room temperature. The mixture was stirred for 48 h at room temperature. Then, the reaction mixture was poured into water (50 mL) and was extracted with ethyl acetate (3×25 mL). The combined extracts were washed with brine solution (80 mL) and were dried over anhydrous sodium sulfate. Filtration of the drying agent and concentration of the filtrate gave the crude product which was purified by silica gel chromatography using a Biotage (40m) column to obtain 265 mg (66% yield) of N-[(2,6-difluorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 1-(acetoxy)ethyl ester as an amorphous white solid. ES-HRMS m/e calcd for C27H27F2N3O7 (M+Na) 566.1709, found 566.1710.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].Cl[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11].Cl>CCC(C)C>[CH2:13]([O:12][C:10]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:11])[CH2:14][CH2:15][CH3:16]
Reactant: NCCC(=O)O
Reactant: CCCCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)C
Product: CCCCOC(=O)NCCC(=O)O
Temperature: 23 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
A solution containing β-alanine (8.9 g; 0.1 mol) and 100 ml of a 1N solution of sodium hydroxide is cooled down to 10° C. n-butyl chloroformate (13.66 g; 0.1 mol) and 50 ml of a 2N solution of sodium hydroxide are added simultaneously. After stirring for 16 hours at 23° C., approximately 10 ml of a solution of concentrated hydrochloric acid (approximately 11 N) is added in order to adjust the pH to 4-5. The oil obtained is extracted with ethyl acetate (2×50 ml), washed with water then dried over magnesium sulphate. The product crystallizes from isopentane in the form of a white powder (yield of 68%). Melting point: 50.5° C.
Reaction SMILES: OCCN(C)[C:5](=[O:11])[O:6][C:7]([CH3:10])(C)C.[N:13]1C=CC=C[CH:14]=1.[CH:19]1(C([Cl:27])=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[ClH:27].[CH:19]1([C:5]([O:6][CH2:7][CH2:10][NH:13][CH3:14])=[O:11])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: O=C(Cl)C1CCCCC1
Reactant: c1ccncc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CNCCOC(=O)C1CCCCC1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Synthetic Example 1 and ethyl acetate (20 mL) were added pyridine (0.97 mL) and 4-dimethylaminopyridine (catalytic amount), and cyclohexanecarbonyl chloride (1.60 mL) was added thereto. After stirring at room temperature for 2 hrs, pyridine (0.65 mL) and cyclohexanecarbonyl chloride (0.58 mL) was further added, and stirred overnight at room temperature. To the reaction solution was added ethyl acetate (50 mL), and washed sequentially with water (50 mL), 5% aqueous solution of citric acid (50 mL) and saturated saline (50 mL), and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and to the residue was added 4N hydrogen chloride-ethyl acetate solution (10 mL). After stirring at room temperature for 2 hrs, diethyl ether (10 mL) was added thereto, and the depositting solid was collected by filtration. The solid was dried under reduced pressure to give title compound as white solid (1.88 g).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][C:7]1[N:8]=[C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]2[CH:18]=1.[C:19](=O)([O-])[OH:20].[Na+]>CN(C)C=O>[CH:19]([C:18]1[N:10]2[CH:11]=[CH:12][CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:9]2=[N:8][C:7]=1[CH3:6])=[O:20]
Reactant: Cc1cn2cccc([N+](=O)[O-])c2n1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2c([N+](=O)[O-])cccn2c1C=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
20 ml phosphoroxychloride is added dropwise within 5 minutes to a solution of 7.6 g 2-methyl-8-nitro-imidazo[1,2-a]pyridine in 100 ml dimethylformamide at 0° C. After stirring for 1 hour at 0° C. and for 2 hours at 70° C. the mixture is cooled again to 0° C. 10 ml phosphoroxychloride is added dropwise and the same procedure is carried out as before. When the reaction is finished the mixture is poured over 200 ml icewater, neutralized with saturated sodium hydrogen carbonate solution and extracted 3×with 50 ml ethyl acetate each time. The solvent is stripped off in vacuo and the residue is washed with ether and recrystallized from acetronitrile, giving the title compound of m.p. 188°-189° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([N:6]([C:9]1[C:10]([Cl:20])=[N:11][N:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:13]=1)[CH2:7][CH3:8])=[O:5].[F:21][C:22]1([F:29])[CH2:24][C:23]1([CH3:28])[C:25](O)=[O:26].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:20][C:10]1[C:9]([N:6]([CH2:7][CH3:8])[C:4](=[O:5])[CH2:3][CH2:2][NH:1][C:25]([C:23]2([CH3:28])[CH2:24][C:22]2([F:29])[F:21])=[O:26])=[CH:13][N:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:11]=1
Reactant: CC1(C(=O)O)CC1(F)F
Reactant: CCN(C(=O)CCN)c1cn(-c2cccnc2)nc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCN(C(=O)CCNC(=O)C1(C)CC1(F)F)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-amino-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylpropanamide (0.074 mg, 0.25 mmol), DMAP (0.047 mg, 0.38 mmol), 2,2-difluoro-1-methylcyclopropanecarboxylic acid (0.052 mg, 0.38 mmol) in dry CH2Cl2 (1.69 mL) was cooled to a temperature of about 0° C. under N2. DCC (0.13 g, 0.61 mmol) was added, and the reaction was slowly warmed up to room temperature under N2, then stirred at room temperature overnight. The reaction mixture was filtered using additional CH2Cl2 (0.5 mL) to remove solids and concentrated under reduced pressure. The product was purified by silica gel chromatography eluting with 0%-10% MeOH/CH2Cl2 to afford the title compound F113 as a yellow viscous oil (0.029 g, 26% over 2 steps from compound C2).
Reaction SMILES: [CH3:1][CH:2]([OH:5])[C:3]#[CH:4].[C:6](Cl)(Cl)=[O:7].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]([CH3:24])[CH2:19][C:20](=[O:23])[NH:21][N:22]=2)=[CH:13][CH:12]=1>CCOCC>[CH3:24][CH:18]1[C:17]([C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:6]([O:5][CH:2]([CH3:1])[C:3]#[CH:4])=[O:7])=[CH:12][CH:13]=2)=[N:22][NH:21][C:20](=[O:23])[CH2:19]1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: C#CC(C)O
Reactant: O=C(Cl)Cl
Solvent: CCOCC
Product: C#CC(C)OC(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
3.5 g (49.9 millimoles) of 1-methylprop-2-ynol are added dropwise to a stirred solution of 9.9 g (100 millimoles) of phosgene in 100 ml of absolute ether at -10° C. The reaction solution is then stirred for 1 hour at -10° C. followed by one hour at room temperature, and the excess phosgene is removed by means of a dry stream of nitrogen, after which the ether is removed under reduced pressure at room temperature. The 1-methylprop-2-ynyl chloroformate which is left (5.9 g) is reacted with 5.0 g (24.6 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone by the method described in Example 31. The reaction mixture is also worked up as described in Example 31. After recrystallizing the product first from ethanol/water, then from ethyl acetate/petroleum ether and finally from dimethylformamide/water, 1.7 g (23% of theory) of 4,5-dihydro-5-methyl-6-[p-(1-methylprop-2-ynyloxycarbonylamino)-phenyl]-3( 2H)-pyridazinone are obtained as colorless crystals of melting point 206°-207° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3[O:14][CH:8]3[C:7]=2[CH:15]=1)#[N:2].[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[NH:17][NH2:18]>C(O)C>[C:21]([O:20][C:16]([NH:17][NH:18][C@@H:8]1[C:7]2[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11][C:10]([CH3:13])([CH3:12])[C@H:9]1[OH:14])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Solvent: CCO
Product: CC(C)(C)OC(=O)NN[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Yield: 65.6 %

Procedure:
6-Cyano-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (8.0 g) and tert-butyl carbazate (6.3 g) were dissolved in 40 ml of ethanol and the solution was heated under reflux for 28 hours. The resulting ethanol was distilled off and the residue was recrystallized from 80 ml of hexane and 8 ml of ethanol to yield 8.7 g of trans 4-(2-tert-butoxycarbonylhydrazino)-6-cyano-3,4-dihydro 2,2-dimethyl-2H-1-benzopyran- 3-ol as white crystals, m.p. 136°-138° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][N:26]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:23])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=2)[CH:13]=1)=[O:6].[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:23][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:24]=[CH:25][N:26]=[C:2]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:3]=2)=[CH:13][C:12]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)O)cc1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(C(=O)O)cc1
Yield: 83 %

Procedure:
5′-[(2-Chloroisonicotinoyl)amino]-2′-methyl-1,1′-biphenyl-4-carboxylic acid (600 mg, 1.64 mmol) and pyrrolidine (0.6 ml) were heated in a sealed tube at 90° C. for 5 h. The excess pyrrolidine was evaporated under vacuum and the residue purified by flash chromatography (silica) eluting with DCM/ethanol/ammonia (20:8:1). The solvents were evaportated under vacuum to give 2′-methyl-5′-[(2-pyrrolidin-1-ylisonicotinoyl)amino]-1,1′-biphenyl-4-carboxylic acid (546 mg, 83%).