Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:14][N:13]=1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[F:11].[OH-:27].[K+].[CH3:29]O>O>[F:11][C:5]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:4]=1[CH2:3][CH2:2][C:12]1[N:13]=[C:14]([O:27][CH3:29])[C:15]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:16][CH:17]=1
Reactant: [OH-]
Reactant: O=S(=O)(c1ccccc1)c1ccc(C(Cl)Cc2ccc(F)cc2F)nc1
Reactant: CO
Agent: [K+]
Solvent: O
Product: COc1nc(CCc2ccc(F)cc2F)ccc1S(=O)(=O)c1ccccc1
Yield: 72 %

Procedure:
2-Chloro-6-[2-(2,4-difluorophenyl)ethyl]-3-(phenylsulfonyl)pyridine (Example 43 Step 3, 0.21 g, 0.53 mmol) and potassium hydroxide (90 mg, 1.60 mmol) were stirred in refluxing methanol (10 ml) for 6 hours. The cooled reaction mixture was diluted with water and extracted with ethyl acetate (×2). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo while loading onto silica. Dry flash chromatography using 10-15% ethyl acetate/isohexane gave the title compound as a colourless gum (150 mg, 72%). δH (500 MHz, d6 DMSO): 8.25 (1H, d, J=7.7 Hz), 7.88 (2H, d, J=7.5 Hz), 7.69 (1H, t, J=7.4 Hz), 7.60 (2H, t, J=7.7 Hz), 7.27 (1H, q, J=8.0 Hz), 7.13-7.07 (2H, m), 6.94 (1H, td, J=2.1, 8.5 Hz), 3.78 (3H, s), 2.99-2.59 (4H, m); m/z (ES+) 390 [MH+].
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]2[N:7]([C@H:22]3[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]3)[C:8](=[O:21])[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]=[O:20])[CH:12]=3)[C:5]=2[CH:4]=1)#[N:2].[BH4-].[Na+]>C(O)C.O1CCCC1>[C:1]([C:3]1[CH:30]=[CH:29][C:6]2[N:7]([C@H:22]3[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]3)[C:8](=[O:21])[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH2:19][OH:20])[CH:12]=3)[C:5]=2[CH:4]=1)#[N:2]
Reactant: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](O)CC3)c3ccc(C#N)cc32)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](O)CC3)c3ccc(C#N)cc32)cc1CO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5-cyano-3-(3-formyl-4-methoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-1,3-dihydro-2H-benzimidazol-2-one (35.0 mg) in a mixture of ethanol (2 mL) and tetrahydrofuran (1 mL) was added sodium borohydride (3.27 mg) under ice cooling, and the mixture was stirred at 0° C. for 2 hours. The mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with 1N-hydrochloric acid, water, saturated sodium bicarbonate solution and brine, successively, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by a preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (10:1). The crude product was triturated with diisopropyl ether to give 5-cyano-1-(trans-4-hydroxycyclohexyl)-3-(3-hydroxymethyl-4-methoxybenzyl)-1,3-dihydro-2H-benzimidazol-2-one as a colorless powder (20.0 mg).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[C:14]([CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[N:13][CH:12]=1)C1C=CC=CC=1.C1COCC1.CCOCC>CCO.[Pd]>[C:30]([O:29][C:27](=[O:28])[NH:26][CH2:25][C:14]1[C:15]2[C:20](=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[C:11]([NH2:10])=[CH:12][N:13]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: COc1cc2c(NC(=O)OCc3ccccc3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Agent: [Pd]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc2c(N)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Yield: 89 %

Procedure:
A solution of [1-(tert-Butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinolin-4-yl]-carbamic acid benzyl ester, in 45 mL of EtOH and 20 mL THF was hydrogenated at 1 atm (balloon) over 60 mg of 10% Pd—C for 3 h. The catalyst was removed by filtration through a plug of celite and the filtrate was concentrated to give a white film. Trituration with ether gave 534 mg (89%) of the 4-aminoisoquinoline as a white granular solid. H1-NMR (CDCl3): δ 7.84 (s, 1H), 7.36 (s, 1H), 7.02 (s, 1H), 6.00 (s, 1H), 4.78 (d, J=5.1 Hz, 1H), 4.03 (s, 3H), 4.01 (s, 3H), (s, 1H), 3.89 (s, 2H), 1.48 (s, 9H). MS: APCI (M+H) calc' d for C18H24N2O4+H 334.4; found 334.0.
Reaction SMILES: C1(O[C:8](=[O:40])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[S:29]([CH3:32])(=[O:31])=[O:30])[N:19]=[C:18]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[NH2:41][CH2:42][CH:43]([OH:45])[CH3:44]>>[F:28][C:26]1[CH:25]=[CH:24][C:23]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:22]([C:20]2[N:19]=[C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]3[CH3:39])[N:17]=[C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:41][CH2:42][CH:43]([OH:45])[CH3:44])=[O:40])=[CH:15][CH:14]=3)[CH:21]=2)[CH:27]=1
Reactant: CC(O)CN
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Product: CC(O)CNC(=O)Nc1ccc(-c2cc(-c3cc(F)ccc3S(C)(=O)=O)nc(N3CCOC[C@@H]3C)n2)cc1

Procedure:
Method as described for example 58 using (S)-phenyl(4-(6-(5-fluoro-2-(methylsulfonyl)phenyl)-2-(3-methylmorpholino)pyrimidin-4-yl)phenyl)carbamate (intermediate 32) (100 mg, 0.18 mmol) and 1-aminopropan-2-ol (20 mg, 0.27 mmol). The reaction mixture was purified by prep HPLC at low pH to afford the title compound as a yellow solid. (46 mg, 48%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:19]1[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[S:19]1[CH:23]=[CH:22][C:21]([CH2:24][N:10]2[C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[N:14][C:13]=3[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[N:9]2)=[CH:20]1
Reactant: OCc1ccsc1
Reactant: O=c1[nH]nc(-c2cccc(Cl)c2)c2ncccc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1c2cccnc2c(-c2cccc(Cl)c2)nn1Cc1ccsc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.7 %

Procedure:
To a suspension of 8-(3-chlorophenyl) pyrido[2,3-d]pyridazin-5-one (0.21 g, 0.82 mmoles) in tetrahydrofuran (25 ml) was added 3-thiophenemethanol (0.085 ml, 0.9 moles) and triphenyl phosphine (0.32 g, 1.22 moles). To this mixture was added a solution of diisopropyl azodicarboxylate (0.24 ml, 1.22 moles) in tetrahydrofuran (5 ml) in a dropwise manner. The solution was stirred for 3 hours at room temperature. The solvent was removed and the residue chromatographed from hot methanol, yielding 0.15 g of 6-(3-thienylmethyl)-8-(3-chlorophenyl) pyrido[2,3-d]pyridazin-5-one, mp 165°-166° C.
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[CH:19](O)[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[CH2:16][S:15](=[O:26])(=[O:25])[C:14]=2[CH:27]=1)=[O:9].[H][H]>C(O)(=O)C.[Pd]>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[CH2:16][S:15](=[O:25])(=[O:26])[C:14]=2[CH:27]=1)=[O:9]
Reactant: [H][H]
Reactant: COC(=O)c1ccc2c(c1)S(=O)(=O)Cc1ccccc1C2O
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)S(=O)(=O)Cc1ccccc1C2
Temperature: 25 °C

Procedure:
Pd/C (0.015 g, 10% w/w) and catalytic amount of perchloric acid was added to a solution of compound of Example 40 (0.11 g, 0.3 mmol) in acetic acid (60 mL). The reaction mixture was subjected to hydrogenation at 100 psi of hydrogen at 65° C. for 6.5 h. The reaction mixture was cooled to 25° C. and filtered through high flow bed. The filtrate was concentrated, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water, brine, concentrated and purified using flash chromatography (silica gel, ethyl acetate and pet. ether 60-80° C.) to obtain the title compound. Yield: 0.05 g (47%); 1H NMR (CDCl3, 300 MHz): δ 3.90 (s, 3H, OCH3), 4.32 (s, 2H, CH2), 5.21 (s, 2H, CH2) 7.38 (m, 5H, Ar), 8.09 (d, 1H, Ar), 8.61 (s, 1H, Ar); MS: m/e (CI) 303 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1OC)[C:6]([C:8]1[NH:12][CH:11]=[C:10]([C:13]([O:15]C)=[O:14])[CH:9]=1)=[O:7].[OH-:22].[Na+].[CH3:24]O>>[CH3:24][O:22][C:18]1[CH:17]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:19]=1)[C:6]([C:8]1[NH:12][CH:11]=[C:10]([C:13]([OH:15])=[O:14])[CH:9]=1)=[O:7]
Reactant: COC(=O)c1c[nH]c(C(=O)c2ccc(OC)c(OC)c2)c1
Reactant: [OH-]
Reactant: CO
Agent: [Na+]
Product: COc1cc(OC)cc(C(=O)c2cc(C(=O)O)c[nH]2)c1

Procedure:
Methyl 5-(3,4-dimethoxybenzoyl)pyrrole-3-carboxylate (3.7 g.) was refluxed with 40 ml. of methanol and 40 ml. of 1 N sodium hydroxide for 2 hours and isolated by the procedure of Example 73. Recrystallization from methanol gave purified 5-(3,5-dimethoxybenzoyl)pyrrole-3-carboxylic acid (1.5 g., m.p. 267°-269° C.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([C:25]([CH3:41])([CH3:40])[CH2:26][NH:27][S:28]([CH2:31][CH2:32]N3CCN(C)CC3)(=[O:30])=[O:29])[NH:17][C:18]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:10][C:9]=1[OH:42]>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([C:25]([CH3:41])([CH3:40])[CH2:26][NH:27][S:28]([CH2:31][CH2:32][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)(=[O:30])=[O:29])[NH:17][C:18]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:10][C:9]=1[OH:42]
Reactant: C1COCCN1
Reactant: CN1CCN(CCS(=O)(=O)NCC(C)(C)c2nc(-c3ccc(Cl)c(O)c3)c(-c3ccncc3)[nH]2)CC1
Product: CC(C)(CNS(=O)(=O)CCN1CCOCC1)c1nc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)[nH]1

Procedure:
The title compound was prepared from morpholine and the product of Example 42 Step 1 using the method described in Example 42 Steps 2 and 2; MS(ES+) m/e 520/522 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[F:30][C:31]([F:48])([F:47])[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[C:43]([CH2:45][NH2:46])[CH:42]=[CH:41][N:40]=2)=[CH:35][CH:34]=1>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([NH:46][CH2:45][C:43]3[CH:42]=[CH:41][N:40]=[C:39]([C:36]4[CH:35]=[CH:34][C:33]([O:32][C:31]([F:48])([F:30])[F:47])=[CH:38][CH:37]=4)[CH:44]=3)=[O:16])[CH2:12][CH2:13]2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(Cl)s1
Reactant: NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: CCN(C1(C(=O)NCc2ccnc(-c3ccc(OC(F)(F)F)cc3)c2)CC1)S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Yield: 34.2 %

Procedure:
A solution of acid 18 (0.50 g, 1.62 mmol) in THF (25 mL) was added with DEPC (0.32 mL, 1.3 mol eq) and the mixture was stirred at room temperature for 10′. Then [2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (0.47 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, water (40 mL) was added to the residue that was extracted with EtOAc (3×25 mL) and washed with brine (1×40 mL). The separated organic phase was dried over Na2SO4, evaporated to dryness and the residue was purified by flash chromatography (1:1 EtOAc:Petroleum ether) to afford a pale yellow oil (0.31 g). Yield=35%, 1HNMR (DMSO, 200 MHz) δ 1.22 (t, 3H), 1.40 (bs, 2H), 1.61 (bs, 2H), 4.16 (q, 2H), 4.42 (d, 2H, J=6.1), 7.26 (m, 2H), 7.46 (d, 2H, J=8), 7.6 (dd, 1H), 7.87 (s, 1H), 8.21 (d, 2H, J=7.9), 8.25 (t, 1H), 8.60 (d, 1H, J=4); [M+1] 560.01 (C23H21ClF3N3O4S2 requires 559.06).
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)=[O:9].[C:21]1([C@H:31]([N:33]([CH2:41][C@@H:42]2[C@@H:46]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH2:45][NH:44][CH2:43]2)[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>C1COCC1>[C:36]([O:35][C:34]([N:33]([CH2:41][C@@H:42]1[C@@H:46]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:45][N:44]([C:8]([O:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[O:9])[CH2:43]1)[C@@H:31]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)[CH3:32])=[O:40])([CH3:37])([CH3:38])[CH3:39]
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(=O)N2C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)cc1

Procedure:
A 0.06 ml portion of pyridine and 103 mg of methyl 4-[(chlorocarbonyl)oxy]benzoate (mfd. by Fluka) were added in that order to a THF (5.0 ml) solution of 173 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate and stirred for 1 week. Thereafter, its work-up and purification were carried out in the standard method to obtain 4-(methoxycarbonyl)phenyl (3R,4S)-3-({(tert-butoxycarbonyl) [(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidine-1-carboxylate as a crude product. FP: 609.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:8]([CH2:20][CH3:21])[C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:19])[O:16]2)=[CH:11][CH:10]=1)[CH3:7].CN(C)[CH:24]=[O:25]>>[CH2:20]([N:8]([CH2:6][CH3:7])[C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([CH:24]=[O:25])[C:15](=[O:19])[O:16]2)=[CH:11][CH:10]=1)[CH3:21]
Reactant: CCN(CC)c1ccc2ccc(=O)oc2c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CC)c1ccc2cc(C=O)c(=O)oc2c1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 86.5 %

Procedure:
20 g of dimethylformamide are added dropwise to 40 g of phosphorus oxychloride at 20°-50° C. The mixture is stirred for 45 minutes at 50° C whilst excluding moisture. A suspension of 42 g of 7-diethylamino-coumarin in 50 g of dimethylformamide is then added, the mixture is warmed to 60° C for 2 hours and poured out onto 400 g of ice water, and the whole is stirred for 2 hours. The crystalline precipitate is filtered off, thoroughly washed with water and dried in vacuo at 70° C. 41 g of 7-diethylamino-coumarin-3-aldehyde are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](N)[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]2[C:17](=[O:18])[NH:16][NH:15][CH:14]=[C:13]2[N:19]=1.N([O-])=O.[Na+].[ClH:24]>O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([Cl:24])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]2[C:17](=[O:18])[NH:16][NH:15][CH:14]=[C:13]2[N:19]=1
Reactant: COc1cc(N)ccc1-c1nc2c[nH][nH]c(=O)c-2n1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(Cl)ccc1-c1nc2c[nH][nH]c(=O)c-2n1
Reaction time: 0.67 h

Procedure:
An amount of 1.05 gm of 2-(2-methoxy-4-amino-phenyl)-5H-imidazo[4,5-d]pyridazin-4-one is suspended in 20 ml of 6N hydrochloric acid. The suspension is cooled to 0° to -3° C., and 0.28 gm of sodium nitrite, dissolved in 2 ml of water, are added dropwise thereto. The mixture is stirred for a further 40 minutes and then heated to 80°-85° C. for one hour. The product precipitated on cooling is purified by chromatography on silica gel [eluant: first methylene chloride/ethanol (100:0 to 100:20, then 1.5 to 2.5% of glacial acetic aicd is added)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:17][C:18]([NH:20][N:21]=[C:22]([C:24]2[C:28]([OH:29])=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)[N:26]([CH3:40])[N:25]=2)[CH3:23])=[S:19])=[C:6]([CH:16]=1)[O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12].[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:17][C:18]([NH:20][N:21]=[C:22]([C:24]2[C:28]([OH:29])=[C:27]([C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:37])[F:39])=[CH:34][CH:35]=3)[N:26]([CH3:40])[N:25]=2)[CH3:23])=[S:19])=[C:6]([CH:16]=1)[O:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)CCCOc1cc(Cl)ccc1NC(=S)NN=C(C)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=NNC(=S)Nc1ccc(Cl)cc1OCCCC(=O)O)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Temperature: 25 °C
Reaction time: 19 h
Yield: 59 %

Procedure:
To a suspension of ethyl 4-(5-chloro-2-{[(2-{1-[4-hydroxy-1-methyl-5-(4-trifluoromethylphenyl)-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonothioyl]amino}-phenoxy)butyrate (74 mg, 0.12 mmol) in ethanol (3.0 mL) was added 1 M aqueous sodium hydroxide (370 μL, 0.37 mmol). After the reaction mixture was stirred at room temperature for 19 hours, 1 M hydrochloric acid (370 μL, 0.37 mmol) was added then the precipitated solid was collected by filtration, washed with chloroform and dried by means of a vacuum pump to give the desired product as a yellow solid (yield 59%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[N:34]1[C:43]2[C:38](=[CH:39][C:40]([NH2:44])=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:44][C:40]2[CH:39]=[C:38]3[C:43](=[CH:42][CH:41]=2)[N:34]=[CH:35][CH:36]=[CH:37]3)=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc2ncccc2c1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)Nc2ccc3ncccc3c2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and 6-quinolinamine the title compound was obtained in 79% purity by LC/MS. MS(ESI+): m/z=465.4.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH:11]C(=O)OC(C)(C)C)[C:6]1=[O:19].ClCCl.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[NH2:11][CH:7]1[CH2:8][CH2:9][CH2:10][N:5]([CH2:4][C:3]2[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:2]=2[F:1])[C:6]1=[O:19]
Reactant: COc1cccc(F)c1CN1CCCC(NC(=O)OC(C)(C)C)C1=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(F)c1CN1CCCC(N)C1=O
Reaction time: 1 h

Procedure:
The synthetic intermediate from Step 1 (329 mg, 0.934 mmol), dichloromethane (1 ml), and trifluoroacetic acid (1 ml) were combined in an open vial, and the mixture was allowed to stir for 1 hour. The mixture was then diluted with toluene (3 ml) and subsequently concentrated to dryness. Crude (3-amino-1-(2-fluoro-6-methoxybenzyl)piperidin-2-one so obtained was used in the next synthetic transformation without additional purification.
Reaction SMILES: N[CH:2]([CH2:6][CH2:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:3]([OH:5])=[O:4].[Br-:18].[K+].C(OC(CCC=O)C(O)=O)C1C=CC=CC=1>Br>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][CH2:6][CH:2]([Br:18])[C:3]([OH:5])=[O:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(CCC(=O)OCc1ccccc1)C(=O)O
Reactant: [Br-]
Agent: Br
Agent: O=CCCC(OCc1ccccc1)C(=O)O
Agent: [K+]
Product: O=C(CCC(Br)C(=O)O)OCc1ccccc1
Temperature: 0 °C

Procedure:
2-Amino-5-(benzyloxy)-5-oxopentanoic acid, 20.00 g (0.084 mole), and potassium bromide, 34.1 g (0.29 mole), were dissolved in 80 mL of ˜6N aqueous HBr, previously chilled to 0° C. A stream of nitrogen was bubbled through the solution and the mixture was chilled to −10° C. by means of a cold bath. Sodium nitrite, 6.98 g (0.10 mole) was added in portions over 30 min with stirring, while maintaining the temperature of the reaction from −13° C. to −10° C. After 6 hours stirring at −10° C., the mixture was extracted with ethyl ether, 4×100 mL and the resulting solution dried with magnesium sulfate. The mixture was filtered to remove the drying agent and evaporated to give an orange oil. The oil was purified by flash chromatography, chloroform-hexanes to give a clear and colorless oil. The yield was 11.5 g, i.e., 45%, based on starting 2-amino-{[(benzyl-oxy)-5-oxopentanoic acid. NMR is consistent with structure.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[N:4][C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[CH2:16]([N:4]1[C:3](=[O:9])[C:2]([Cl:1])=[C:7]([Cl:8])[CH:6]=[N:5]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1nncc(Cl)c1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(Cl)c(Cl)cnn1Cc1ccccc1
Yield: 96.4 %

Procedure:
To a stirring suspension of 4,5-dichloro-3-hydroxypyridazine (33 g, 200 mmol) in DMF (260 mL) at room temperature under argon was added K2CO3 (55 g, 400 mmol), followed by benzyl bromide (41 g, 505.8 mmol). After 16 h the reaction mixture was poured into a flask containing water (500 mL) with stirring. After 15 min stirring, the precipitated product was collected by filtration and washed thoroughly with water. The solid was dried in a vacuum oven at 50° C. for 16 h to obtain the title compound, 2-benzyl-4,5-dichloropyridazin-3(2H)-one, (49.2 g, 96%) as an off-white solid. MS [M+H]+ 255; HPLC retention time=3.02 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[C:18]([CH2:29][O:30][CH3:31])[CH:17]=3)[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:35])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[C:18]([CH2:29][O:30][CH3:31])[CH:17]=3)[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([Cl:35])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCc1cc(-c2nc(-c3ccc(C(=O)O)c(F)c3)no2)ccc1-c1ccccc1C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCc1cc(-c2nc(-c3ccc(C(=O)Cl)c(F)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
To a solution of example 35 (2 170 mg; 5.2 mmol) in dry DCM (40 mL), oxalyl chloride (1 316 μl; 15.6 mmol) was added followed by dry DMF (40 μl). The reaction mixture was stirred at RT for 2 h and concentrated to afford 2-fluoro-4-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride as a white powder (2300 mg, 100%). In dry THF (1 mL) with a catalytic amount of DMF was swelled morpholinomethyl polystyrene high loading resin (NovaBiochem; 35.77 mg; 0.14 mmol), 3.9 mmol/g). 2-Fluoro-4-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride (25 mg; 0.06 mmol) was added followed by sarcosine methyl ester hydrochloride (15.98 mg; 0.11 mmol). The mixture was stirred overnight at rt. Isocyanate resin Si—NCO (Argonaut, 97 mg; 1.5 eq; 1.7 mmol/g) was added and the mixture stirred for 2 h. It was filtered through a SAX column (2 g) to obtain the title compound as a colorless oil. LC/MS (Method B): 504.2 (M+H)+ HPLC (Method A) Rt: 5.39 min (purity: 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[O:30])[CH:24]=[CH:25][C:26]=1[CH3:27]>>[CH3:20][C:21]1[CH:22]=[C:23]([NH:28][C:29](=[O:30])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: Cc1ccc(N=C=O)cc1C
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Product: Cc1ccc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4ncccc34)cc2)cc1C

Procedure:
45.2 mg of solid white 3-{4-[3-(3,4-dimethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 3,4-dimethylphenyl isocyanate.