Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](Cl)=[N:15][N:14]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][C:6]=2[CH3:11])=[N:15][N:14]=1
Reactant: Cc1cc2cc(Cl)ccc2[nH]1
Reactant: Clc1nnc(Cl)c2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1[nH]c2ccc(Cl)cc2c1-c1nnc(Cl)c2ccccc12
Temperature: 65 °C
Yield: 87.6 %

Procedure:
5-Chloro-2-methylindole (0.74 g, 2.26 mmol) and 1,4-dichloro-phthalazine (0.45 g, 2.26 mmol) were treated with 30 mL of 1,2-dichloroethane and 3.2 mmol of AlCl3 (427 mg). The resulting suspension was heated to 65° C. overnight. The reaction was cooled and quenched with 3 mL water. The resultant precipitate was filtered and dried under vacuum to give 0.65 g of the sub-title compound. MS: ESI (negative): 326, 328 (M−H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[Cl:11][C:12]([NH2:14])=[NH:13].C1COCC1>C1C=CC=CC=1>[ClH:11].[N:1]1[N:2]([C:12]([NH2:14])=[NH:13])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: N=C(N)Cl
Reactant: c1ccc2[nH]ncc2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: N=C(N)n1cc2ccccc2n1
Yield: 52.8 %

Procedure:
940 mg of indazole and 920 mg of chloroformamidine hydrochloride were heated under reflux in 30 ml of benzene of THF for 5 hours, and the crystals formed were removed by filtration. These were recrystallized from ethanol ether to obtain 826 mg of 2H-indazole-2-carboxamidine hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[N:6][O:7][CH2:8][CH2:9][N:10]([CH3:30])[CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21]([NH2:22])[C:20]=3[N:19]=[C:18]2C)[C@H:14]([OH:28])[C@@H:13]1[OH:29])[CH3:5])[CH3:2].[CH3:31][NH:32]C[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2NC)[C@H](O)[C@@H]1O.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[N:6][O:7][CH2:8][CH2:9][N:10]([CH3:30])[CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21]([NH2:22])[C:20]=3[N:19]=[C:18]2[NH:32][CH3:31])[C@H:14]([OH:28])[C@@H:13]1[OH:29])[CH3:5])[CH3:2]
Reactant: CNC[C@H]1O[C@@H](n2c(NC)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reactant: CCOC(C)=NOCCN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(C)=NOCCN(C)C[C@H]1O[C@@H](n2c(NC)nc3c(N)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Compound 6b was prepared by the same procedure as reported for 6a using 4c (500 mg, 1.61 mmol), ethyl N-(2-bromoethoxy)ethanamidate48 (407 mg, 1.93 mmol), DIEA (104 mg, 0.14 mL, 0.80 mmol), and DMF (5 mL). After column chromatography (elution with 7:1:0.3 chloroform:methanol:NH4OH), a yellow glassy sticky solid was obtained: yield 209 mg (30%), MS: m/z 439 (M+H)+; 1HNMR (DMSO-d6) δ 7.89 (s, 1H, H-2), 6.85 (q, 1H, 8CH3—NH), 6.47 (bs, 2H, 6-NH2), 5.69 (d, 1H, H-1′, J1′,2′=5.0 Hz), 5.27 (d, 1H, 2′-OH, J2′-2′OH=5.5 Hz), 5.06 (d, 1H, 3′-OH, J3′-3′OH=5.0 Hz), 4.88 (ddd, 1H, H-2′, J1′,2′=5.0 Hz, J2′,3′=5.8 Hz, J2′-2′OH=5.5 Hz), 4.17 (ddd, 1H, H-3′, J2′,3′=5.8 Hz, J3′,4′=4.7 Hz, J3′-3′OH=5.0 Hz), 3.86-3.95 (m, 3H, H-4′, NO—CH2), 3.92 (q, 2H, CH2CH3), 2.88 (d, 3H, 8NH—CH3, J=4.6 Hz), 2.71-2.77 (m, 1H, 5′-CH2), 2.56-2.67 (m, 3H, 5′-CH2, N(CH3)—CH2), 2.24 (s, 3H, N—CH3), 1.83 (s, 3H, C—CH3), 1.19 (t, 3H, OCH2CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH2:12]O)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(P([N:28]=[N+:29]=[N-:30])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>O1CCCC1>[N:28]([CH2:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([Cl:1])[CH:11]=1)=[N+:29]=[N-:30]
Reactant: COC(=O)c1ccc(CO)cc1Cl
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc(CN=[N+]=[N-])cc1Cl
Yield: 97.5 %

Procedure:
A solution of 2-chloro-4-(hydroxymethyl)benzoic acid, methyl ester (11.09 g, 55.3 mmol), diphenylphosphoryl azide (22.58 g, 82.0 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (8.57 g, 56.3 mmol) in tetrahydrofuran was stirred overnight at room temperature. Silica gel was added and the solvent was evaporated. The residue was chromatographed (10% ethyl acetate/hexanes) to give 4-(azidomethyl)-2-chlorobenzoic acid, methyl ester (12.17 g, 98%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[CH3:13][N:14]1[CH:18]=[CH:17][C:16]([NH2:19])=[N:15]1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([NH:19][C:16]3[CH:17]=[CH:18][N:14]([CH3:13])[N:15]=3)[N:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cc1ccc2ccnc(Cl)c2n1
Reactant: Cn1ccc(N)n1
Product: Cc1ccc2ccnc(Nc3ccn(C)n3)c2n1

Procedure:
The title compound, MS: m/e=240.3 (M+H+), was prepared in accordance with the general method of example 1 from 8-chloro-2-methyl-[1,7]naphthyridine (Example E) and 1-methyl-1H-pyrazol-3-ylamine.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]([CH3:8])[C:6]=1[CH3:7].[Cl:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.N>O.CC(O)C.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[Cl:16][C:17]1/[C:22](=[N:1]/[C:2]2[C:3](=[O:15])[N:4]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:5]([CH3:8])[C:6]=2[CH3:7])/[CH:21]=[CH:20][C:19](=[O:23])[CH:18]=1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Reactant: Oc1cccc(Cl)c1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: N
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: Cc1c(/N=C2\C=CC(=O)C=C2Cl)c(=O)n(-c2ccccc2)n1C

Procedure:
10 mmol of 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one was dissolved in 30 ml of water. This solution was admixed with 10 mmol of 3-chlorophenol in solution in 30 ml of 2-propanol, 3 ml of 20% aqueous ammonia and 22 mmol of potassium ferricyanide at a temperature ranging from 5 to 10° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2.O[Li].O>C1COCC1.O>[CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccccn2)=CCC3(C)C)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC=C(c2ccccn2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
A solution of 80.0 mg (0.196 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(2-pyridyl)-2-naphthalenyl)ethynyl]benzoate (Compound 10) and 20.6 mg (0.491 mmol) of LiOH—H2O in 3 ml of THF/water (3:1, v/v), was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. 1H NMR (d6-DMSO): δ 8.64 (1H, m), 7.94 (2H, d, J=8.3 Hz), 7.87 (1H, dt, J=1.7, 7.8 Hz), 7.58 (2H, d, J=8.3 Hz), 7.50 (1H, d, J=8.2 Hz), 7.47 (2H, s), 7.37 (1H, m), 7.25 (1H, s), 6.30 (1H, t, J=4.6 Hz), 2.39 (2H, d, J=4.6 Hz), 1.31 (6H, s).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[F:10])=[N+:2]=[N-:3].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[C:12]#[CH:13]>C1(C)C=CC=CC=1>[F:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N:1]1[CH:13]=[C:12]([C:11]([O:15][CH2:16][CH3:17])=[O:14])[N:3]=[N:2]1
Reactant: C#CC(=O)OCC
Reactant: [N-]=[N+]=Nc1ccccc1F
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2ccccc2F)nn1
Temperature: 100 °C
Reaction time: 13 h
Yield: 6.5 %

Procedure:
1-Azido-2-fluorobenzene (1.0 g) and ethyl propiolate (2.2 g) were dissolved in toluene (12 ml) and the mixture was stirred at 100° C. for 13 hr. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-80:20) was concentrated under reduced pressure to give the object product (111 mg).
Reaction SMILES: Br.Br.[CH3:3][C@H:4]1[CH2:9][NH:8][C@@H:7]([CH3:10])[CH2:6][NH:5]1.[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](Cl)=[N:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>C(OCC)(=O)C>[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([N:5]2[CH2:6][C@H:7]([CH3:10])[NH:8][CH2:9][C@@H:4]2[CH3:3])=[N:14][N:13]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: C[C@H]1CN[C@@H](C)CN1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C[C@H]1CN(c2nnc(Cl)c3ccccc23)[C@@H](C)CN1

Procedure:
(2S,5S)-2,5-dimethylpiperazine dihydrobromide (1.16 g, 4.20 mmol), 1,4-dichlorophthalazine (700 mg, 3.52 mmol), potassium carbonate (973 mg, 7.04 mmol), and N-methylpyrrolidinone (7 mL) were heated at 120° C. for 22 hours. The reaction was taken up in ethyl acetate (80 mL) and washed with aqueous K2CO3 (10%), water, and saturated sodium chloride. The organics were dried (MgSO4) and evaporated to give an orange oil. Chromatography over silica gel with a gradient of hexanes+2.5% triethylamine/0-100% ethyl acetate+2.5% triethylamine gave a pale yellow semi-solid. MS (M+H)+=277.8.
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]([N:12]1[C:20]2[C:15](=[C:16]([CH2:21]O)[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C([O-])(O)=O.[Na+]>CCOCC.C(Cl)Cl>[Br:2][CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][N:12]2[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: BrP(Br)Br
Reactant: CC(C)(C)OC(=O)n1ccc2c(CO)cccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)n1ccc2c(CBr)cccc21
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
PBr3 (2.4 mL. 25.8 mmol) was added dropwise at 0° C. under nitrogen to a stirred solution of tert-butyl 4-(hydroxymethyl) 1H-1-indolecarboxylate 6 (6.0 g, 24.3 mmol) in ether (80 mL) and CH2Cl2 (20 mL) under nitrogen. The reaction was completed 30 minutes after the addition. The mixture was poured into a cold aqueous NaHCO3 solution (100 mL) and extracted with ethyl acetate (3×80 mL). The combined extract was washed sequentially with water (80 mL), and brine (80 mL), then dried (MgSO4), filtered, and finally concentrated to provide tert-butyl 4-(bromomethyl)-1H-1-indolecarboxylate 7 (6.3 g, 84%) as an oil which was immediately taken to the next step.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])[C:13]([NH:15][C:16]2[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=2[Cl:24])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][S:40]([CH3:39])(=[O:42])=[O:41])[C:13]([NH:15][C:16]2[C:17]([Cl:24])=[CH:18][C:19]([Cl:23])=[CH:20][C:21]=2[Cl:22])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(CN(CCCCCCO)C(=O)Nc2c(Cl)cc(Cl)cc2Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1ccc(CN(CCCCCCOS(C)(=O)=O)C(=O)Nc2c(Cl)cc(Cl)cc2Cl)cc1
Reaction time: 16 h
Yield: 97 %

Procedure:
To a cooled solution (0°-5° C.) of 4.0 g of 1-[(4-butylphenyl)methyl]-1-(6-hydroxyhexyl)-3-(2,4,6-trichlorophenyl)urea and 2.6 ml of triethylamine in 90 ml of dichloromethane was added dropwise a solution of 0.8 ml of methanesulfonyl chloride in 10 ml of dichloromethane. The resulting solution was allowed to come to room temperature and was stirred for 16 hours. The procedure of Example 515 was continued and gave 4.5 g of the desired product as a light yellow oil in 97% yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C:16]3[C@H:15]4[CH2:17][C@H:14]4[CH2:13][C:12]=3[C:11]([C:18](O)=[O:19])=[N:10]2)[CH:4]=1)#[N:2].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:53][C@@H:54]([CH2:57][C:58]([F:61])([F:60])[F:59])[CH2:55][OH:56]>CN(C=O)C>[F:59][C:58]([F:61])([F:60])[CH2:57][C@H:54]([NH:53][C:18]([C:11]1[C:12]2[CH2:13][C@@H:14]3[CH2:17][C@@H:15]3[C:16]=2[N:9]([C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][N:6]=2)[N:10]=1)=[O:19])[CH2:55][OH:56]
Reactant: N[C@H](CO)CC(F)(F)F
Reactant: N#Cc1ccnc(-n2nc(C(=O)O)c3c2[C@H]2C[C@H]2C3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccnc(-n2nc(C(=O)N[C@H](CO)CC(F)(F)F)c3c2[C@H]2C[C@H]2C3)c1
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 77.9 %

Procedure:
To a solution of (1aS,5aS)-2-(4-cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (75 mg, 0.282 mmol) and triethylamine (0.118 mL, 0.845 mmol) in DMF (1 mL) was added HATU (118 mg, 0.310 mmol). The reaction was stirred at 23° C., for 5 min, then was added (S)-2-amino-4,4,4-trifluorobutan-1-ol hydrochloride (55.6 mg, 0.310 mmol). The reaction was stirred at 23° C. for 30 min, then concentrated. The residue was purified by silica gel flash chromatography to give the title compound (86 mg) as a white solid. LCMS m/z=392.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.47 (td, J=4.7, 3.2 Hz, 1H), 1.27 (td, J=8.1, 4.8 Hz, 1H), 2.26-2.32 (m, 1H), 2.54-2.69 (m, 3H), 2.77-2.82 (m, 1H), 2.93 (d, J=16.8 Hz, 1H), 3.01 (dd, J=16.6, 6.1 Hz, 1H), 3.88 (d, J=2.9 Hz, 2H), 4.33-4.41 (m, 1H), 7.23 (d, J=8.2 Hz, 1H), 7.41 (dd, J=5.1, 1.4 Hz, 1H), 8.17 (t, J=0.8 Hz, 1H), 8.62 (dd, J=5.1, 0.6 Hz, 1H).
Reaction SMILES: [CH2:1]([O:9][C:10]1[C:11]([F:25])=[C:12](C2C(O)=CC=CC=2F)[C:13](O)=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C(OC1C=CC(Br)=CC=1F)C1C=CC=CC=1.BrCCCCCCCC.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:29]2[CH:30]=[CH:31][C:32]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[C:27]([F:26])[CH:28]=2)=[CH:12][C:11]=1[F:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(B(O)O)cc1F
Reactant: CCCCCCCCOc1ccc(O)c(-c2c(O)cccc2F)c1F
Agent: Fc1cc(Br)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCCCCCCCBr
Product: CCCCCCCCOc1ccc(-c2ccc(OCCCCCCCC)c(F)c2)cc1F
Reaction time: 20 h

Procedure:
A mixture of 4'-octyloxy-3,3'-difluorobiphenol (0.1 mol, obtained by coupling 3-fluoro-4-octyloxyphenyl boronic acid with 4-benzyloxy-3-fluoro-brombenzene followed by hydrogenolytic cleavage of the benzylic ether), 1-bromooctane (0.12 mol), potassium carbonate (30 g) and butanone (125 ml) is heated under reflux and stirred for 20 hrs. After cooling the reaction mixture is filtered and the filtrate evaporated off, distillation under reduced pressure affords the required product, m.p. 84°.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]CC3C=CC=CC=3)=[O:12])=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:21]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:21]
Reactant: CN1C(=O)Cc2cc(C(=O)OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1C(=O)Cc2cc(C(=O)O)ccc21
Reaction time: 18 h
Yield: 56.3 %

Procedure:
A solution of Example 59A (1.2 g, 4.27 mmol) in ethyl acetate (30 mL) and methanol (20 mL) was treated with 10% Pd/C (200 mg), stirred under hydrogen (balloon) for 18 hours, filtered through diatomaceous earth (Celite®) with 9:1 dichloromethane/methanol solution rinses, and concentrated to provide 460 mg of the desired product.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][O:7][CH:8]([F:10])[F:9])[C:3]([OH:5])=[O:4].C(=O)(O)[O-].[Na+].[C:16](OC(=O)C)(=[O:18])[CH3:17].Cl>O.O1CCOCC1>[C:16]([NH:1][C@H:2]([CH2:6][O:7][CH:8]([F:10])[F:9])[C:3]([OH:5])=[O:4])(=[O:18])[CH3:17]
Reactant: N[C@H](COC(F)F)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N[C@H](COC(F)F)C(=O)O
Yield: 67 %

Procedure:
(2R)-2-Amino-3-(difluoromethoxy)propanoic acid (680 mg, 4.39 mmol) was mixed with sodium bicarbonate (738 mg. 8.78 mmol) and acetic anhydride (491 mg, 4.82 mmol) in water (10 mL) and dioxane (10 mL) at 0° C. to room temperature overnight. The reaction mixture was acidified with 1N HCl to pH 2, concentrated and extracted with ethyl acetate, and concentrated again to give (2R)-2-(Acetylamino)-3-(difluoromethoxy)propanoic acid (580 mg, 82.3%) as a colorless sticky oil. 1H NMR (300 MHz, CDCl3): (ppm) 6.40 (d, 1H), 6.24 (wt, 1H), 4.88 (m, 1H), 4.36 (dd, 1H), 4.22 (dd, 1H), 2.12 (s, 3H).
Reaction SMILES: ClC1C=NC=C(Cl)C=1[NH:8][C:9]([C:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([NH2:24])[CH:21]=3)[N:16]([CH3:25])[C:15]=2[C:14]([O:26][CH3:27])=[CH:13][CH:12]=1)=[O:10].N1C=CC=CC=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C1COCC1>[CH3:27][O:26][C:14]1[C:15]2[N:16]([CH3:25])[C:17]3[C:22](=[CH:21][C:20]([NH:24][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:19][CH:18]=3)[C:23]=2[C:11]([C:9]([NH2:8])=[O:10])=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3cc(N)ccc3n(C)c12
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(C(N)=O)c2c3cc(NS(C)(=O)=O)ccc3n(C)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-amino-9H-4-carbazolecarboxamide (75 mg, 0.00018 mol) was suspended in THF (5 ml) and added with pyridine (28 mg, 0.00036 mol) and stirred at room temperature for 10 minutes. The solution obtained, was added with a solution of methane sulphonyl chloride (30 mg, 0.00027 mol) in dry THF (5 ml). The reaction mixture was stirred for 1 hr. THF was evaporated and the solid was washed with water to get crude solid which was column chromatographed using 10% methanol in chloroform to give N-3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-methanesulphon-amido-9H-4-carbazolecarboxamide(20 mg),mp>250° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[S:12][CH:11]=[C:10]([CH3:13])[N:6]2[C:7](=[O:9])[CH:8]=1.ClCC1N(C)N=C(C)N=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:35][CH2:36][C:37]2([CH:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)[O:42][C:41](=[O:43])[CH2:40][C:39](=[O:44])[CH2:38]2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH:32]1[CH2:34][CH2:33]1>O>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:35][CH2:36][C:37]2([CH:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)[O:42][C:41](=[O:43])[C:40]([CH2:2][C:3]3[N:4]=[C:5]4[S:12][CH:11]=[C:10]([CH3:13])[N:6]4[C:7](=[O:9])[CH:8]=3)=[C:39]([OH:44])[CH2:38]2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH:32]1[CH2:34][CH2:33]1
Reactant: Cc1csc2nc(CCl)cc(=O)n12
Reactant: O=C1CC(=O)OC(CCc2ccc(OCC3CC3)c(Cl)c2)(C2CCCC2)C1
Agent: Cc1nc(CCl)n(C)n1
Solvent: O
Product: Cc1csc2nc(CC3=C(O)CC(CCc4ccc(OCC5CC5)c(Cl)c4)(C4CCCC4)OC3=O)cc(=O)n12
Yield: 1 %

Procedure:
The title compound was prepared as described in Example B(53), using 7-(chloromethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (prepared according to a reported procedure: Doria, G.; Passarotti, C.; Sala, R.; Magrini, R.; Sberze, P.; Tibolla, M.; Cesarani, R.; Arcari, G.; Castello, R.; Toti, D. Farmaco Ed. Sci. 1985, 40, 885) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole and using 6-{-[3-chloro-4-(cyclopropylmethoxy)phenyl]ethyl}-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione (from Step 4, below) in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 1%. 1H NMR (300 MHz, DMSO-d6) □ 0.31 (m, 2H), 0.56 (m, 2H), 1.22 (m, 1H), 1.23-1.65 (m, 8H), 1.92 (m, 2H), 2.33 (m, 1H), 2.48-2.75 (s, m, 7H, overlap with DMSO-d5), 3.45 (m, 2H, overlap with H2O peak), 3.84 (d, J=7.8 Hz, 2H), 4.87 (s, 2H), 5.20 (s, 1H), 6.16 (s, 1H), 6.93 (d, J=9 Hz, 1H), 7.01 (dd, J=9, 1.5 Hz, 1H), 7.18 (d, J=1.5 Hz, 1H). LC-MS (APCI) calcd for C30H33ClN2O5S: 568.18; found (M+H+) 569.0 m/z.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH2:18]([CH:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][NH2:22])[CH3:19].C([O-])([O-])=O.[K+].[K+]>O>[CH2:18]([CH:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][NH:22][C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:3]=1[N:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=2)[CH3:19]
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: CCCCC(CC)CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCC(CC)CNc1nc(C)[nH]c2cc(-c3ccccc3)nc1-2
Yield: 62.5 %

Procedure:
This compound was prepared according to the method described in Example 2 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (70.0 mg, 0.29 mmol), 2-ethylhexylamine (Aldrich Chemical Company) (0.24 mL, 1.44 mmol) and K2CO3 (0.40 g, 2.87 mmol) in H2O (2 mL) to give 61 mg (63%) of the title compound as a white solid. An analytical sample was obtained by recrystallization from i-PrOH. Mp: 288-289° C. (dec.).1H NMR (CDCl3; 500 MHz): δ 0.72-0.78 (m, 6), 1.15-1.34 (m, 9), 2.62 (s, 3), 3.56 (dd, 2, J=5.3, 7.6), 6.71 (s, 2), 7.17-7.24 (m, 3), 7.59 (d, 2, J=7.6), 12.78 (br s, 1). MS m/z: 337 (M+1), 335 (M−1). HRMS: Calcd for M+H: 337.2392. Found: 337.2397.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[N:11]([CH2:26][CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[CH:10]=1)=[O:8]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccccn2)cc1
Reactant: O=C(Nc1nccs1)c1c[nH]c2cc(F)ccc12
Product: O=C(Nc1nccs1)c1cn(CCc2ccccn2)c2cc(F)ccc12

Procedure:
The title compound was prepared using 6-Fluoro-1H-indole-3-carboxylic acid thiazol-2-ylamide and toluene-4-sulfonic acid 2-pyridin-2-yl-ethyl ester as R5X.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([CH3:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([OH:22])=[O:21]>>[Cl:1][C:2]1[C:10]2[S:9][C:8]([S:11]([NH:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])(=[O:13])=[O:12])=[C:7]([CH3:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: Cc1c(S(=O)(=O)Cl)sc2c(Cl)cccc12
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2c(Cl)cccc12
Yield: 62.9 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 7-chloro-3-methylbenzothiophene-2-sulfonyl chloride (Intermediate 6) (30 mg, 0.10 mmol) and 3-amino-benzoic acid (29 mg, 0.21 mmol) to afford 24 mg (63%) of the title compound. MS (ESI+) calcd for C16H12ClNO4S2 380.989627, found 380.989977.
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:10][CH:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([NH2:24])[CH:18]=2)=[N:15][NH:14][C:13](=[O:25])[CH2:12]1.ClC1C=CC=CC=1>C(O)(=O)C>[CH3:10][CH:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]3[N:23]=[C:1]([C:2]4[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=4)[NH:24][C:19]=3[CH:18]=2)=[N:15][NH:14][C:13](=[O:25])[CH2:12]1
Reactant: CC1CC(=O)NN=C1c1ccc(N)c(N)c1
Reactant: O=C(Cl)c1ccncc1
Solvent: Clc1ccccc1
Solvent: CC(=O)O
Product: CC1CC(=O)NN=C1c1ccc2nc(-c3ccncc3)[nH]c2c1
Reaction time: 2 h

Procedure:
A mixture of 17 g of isonicotinoyl chloride, 21.8 g of 5-methyl-6-(3,4-diaminophenyl)-4,5-dihydropyridazin-3-one ("IIa"; m.p. 195°-196°) and 400 ml of chlorobenzene is boiled for 2 hours. After having been cooled, the usual working up is carried out and, initially, an oily mixture of 5-methyl-6-(3-amino-4-isonicotinamidophenyl)- and 5-methyl-6-(3-isonicotinamido-4-aminophenyl)-4,5-dihydropyridazin-3-one is obtained, which is dissolved in 400 ml of acetic acid and boiled for 3 hours. After having been cooled, 5-methyl-6-[2-(4-pyridyl)-5-benzimidazolyl]-4,5-dihydropyridazin-3-one ("M"), dihydrate, m.p.195°-198° (decomposition) is obtained. Dihydrochloride-dihydrate, m.p. 224°-227°. Methanesulphonate, m.p. 282°-285°.