Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[Mg].Br[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[C:14]([CH:21]=[O:22])[CH:13]=1.Cl>O1CCCC1.O>[Br:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:19][CH:20]=1)[C:16](=[O:18])[O:22][CH:21]2[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Brc1ccccc1
Reactant: O=Cc1cc(Br)ccc1C(=O)O
Agent: Cl
Agent: N#N
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: O=C1OC(c2ccccc2)c2cc(Br)ccc21
Temperature: 30 °C
Reaction time: 0.75 h
Yield: 93.8 %

Procedure:
A tricol of 1 L with a condenser and an addition funnel is purged with N2 and magnesium turnings (5 g, 206 mmol) in tetrahydrofuran (80 mL) are added. Bromobenzene (32 g, 206 mmol) in tetrahydrofuran (80 mL) is added dropwise over 1¼ hour by maintaining the mixture temperature at 30° C. The resulting mixture is stirred for 45 min. at 30° C. 4-Bromo-2-formyl-benzoic acid (C3) (18.9 g, 83 mmol) in anhydrous tetrahydrofuran (200 mL) is added dropwise over 45 min. The mixture is stirred for 2 h at 30° C. The mixture is cooled in an ice-water bath and water (120 mL) and 5N HCl solution (80 mL) are added. The mixture is stirred overnight. THF is removed in vacuo and extracted with DCM (3×100 mL). The combined organics are washed with water (2×100 mL), dried over Na2SO4, filtered and the solvent is removed in vacuo to yield 5-bromo-3-phenyl-3H-isobenzofuran-1-one (22.5 g, 94%). Recrystallization: 5-bromo-3-phenyl-3H-isobenzofuran-1-one is dissolved in hot acetone (250 mL) and the mixture cooled in an ice-water bath over night. The resultant solid is filtered, rinsed with cold ACN (2×15 mL), and then vacuum dried over KOH to yield 5-bromo-3-phenyl-3H-isobenzofuran-1-one (D3) (14.4 g, 61%, mp: 189° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[CH3:18][C:19]1[S:23][CH:22]=[N:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CN(C=O)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:5]2[CH:6]=[CH:7][C:2]([C:22]3[S:23][C:19]([CH3:18])=[CH:20][N:21]=3)=[N:3][CH:4]=2)=[CH:11][CH:12]=1
Reactant: Cc1cncs1
Reactant: COc1ccc(COc2ccc(Br)nc2)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(-c3ncc(C)s3)nc2)cc1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture was prepared from 2-bromo-5-(4-methoxybenzyloxy)pyridine (2.0 g), 5-methylthiazole (614 mg), Pd(P(t-Bu)3)2 (253 mg), Cs2CO3 (2.02 g) and DMF (10 mL). The system was evacuated and refilled with nitrogen three times. The mixture was stirred at 150° C. under N2 atmosphere for 3 hours. After cooling, insoluble material was removed by filtration over Celite. The resulting solution was added water (100 mL). The precipitate obtained was filtered off and washed with MeOH three times to provide the subtitle compound. MS ESI+: m/z=313 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:14][C:15]1[N:19]([CH2:20][CH3:21])[N:18]=[CH:17][CH:16]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C>[CH2:20]([N:19]1[C:15]([NH:14][C:2]2[C:3](=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)[C:4]([OH:6])=[O:5])=[CH:16][CH:17]=[N:18]1)[CH3:21]
Reactant: CCn1nccc1N
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCn1nccc1Nc1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Yield: 68.8 %

Procedure:
A mixture of 2-chloro-5-nitrobenzoic acid (4.03 g, 0.02 mol), 5-amino-1-ethylpyrazole (2.22 g, 0.02 mol), DMF (25 ml), K2CO3 (2.76 g, 0.02 mol) and Cu(OAc)2H2O (0.5 g) is refluxed for 24 hours. The reaction mixture is cooled to room temperature, poured into ice waterl and acidified with acetic acid to a pH of 5. A solid forms which is collected by filtration and dried to afford 3.8 g (68%) of N-(1-ethylpyrazol-5-yl)-5-nitroanthranilic acid.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([N:13]1[CH2:25][CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH2:26]C4C=CC=C(O)C=4)[CH:21]=3)[NH:16][C:15]=2[CH2:14]1)=[O:12])=O)(C)(C)C.[ClH:34].[O:35]1[CH2:40][CH2:39]OCC1>>[NH2:8][CH2:9][CH2:10][C:11]([N:13]1[CH2:25][CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH3:26])[CH:21]=3)[NH:16][C:15]=2[CH:14]1[C:15]1[CH:14]=[C:40]([OH:35])[CH:39]=[CH:22][CH:23]=1)=[O:12].[ClH:34]
Reactant: CC(C)(C)OC(=O)NCCC(=O)N1CCc2c([nH]c3ccc(Cc4cccc(O)c4)cc23)C1
Reactant: C1COCCO1
Agent: Cl
Product: Cc1ccc2[nH]c3c(c2c1)CCN(C(=O)CCN)C3c1cccc(O)c1

Procedure:
(tert-Butoxy)-N-{3-[1-(3-hydroxyphenyl)-6-methyl-(1,2,3,4-tetrahydro-beta-carbolin-2-yl)]-3-oxopropyl}carboxamide was treated with HCl in dioxane (4 N, 10 equiv) for 30 min, and the solvent was removed to give 3-(2-beta-alanyl-6-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl)phenol 15 as its HCl salt.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[F:12])#[N:2].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[C:16]([NH2:21])[N:15]=1.C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[NH2:21][C:16]1[N:17]=[C:18]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:12])[CH:5]=2)[CH:19]=[C:14]([Cl:13])[N:15]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc(Cl)nc(N)n2)cc1F
Temperature: 95 °C
Reaction time: 16 h
Yield: 35.4 %

Procedure:
In a 25 mL sealable tube under argon were combined (4-cyano-3-fluorophenyl)boronic acid (0.50 g, 3.03 mmol), 4,6-dichloro-2-pyrimidinamine (0.497 g, 3.03 mmol), saturated aqueous NaHCO3 (4.04 mL), and 1,4-dioxane (16.2 mL), and the mixture was degassed with argon for 5 minutes. Pd(Ph3P)4 (0.175 g, 0.152 mmol) was added, the vial was sealed, and the reaction mixture was stirred for 16 hours at 95° C. The reaction was cooled to room temperature, filtered through a plug of celite503, and concentrated. The resulting orange tar was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. The resulting orange solid was sonicated in CHCl3 (50 mL) for 2 minutes. The mixture was filtrated, the solid was washed with CHCl3, and the filtrate was concentrated. Flash chromatography on SiO2 (40 g) of the resulting residue (gradient: 100% CHCl3 to 5% EtOAc/CHCl3) afforded the title compound (267 mg, 32%) as a yellow solid. LC-MS (ES) m/z=249 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]([OH:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1COCC1>[CH3:21][S:22]([O:13][CH:11]([C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1)[CH3:12])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C(C)O)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(C)OS(C)(=O)=O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
Into a THF solution (35 ml) of 1-(3-methyl-4-nitrophenyl)-ethanol (5.44 g) and triethylamine (3.95 g), a THF solution (10 ml) of methanesulfonyl chloride (3.48 g) was added dropwise at 5° C. over a period of 30 minutes. Further, the mixture was stirred at room temperature for 8 hours. After finishing the reaction, the solvent was distilled off and the residue was dissolved in ethyl acetate (100 ml). It was washed with 2N aqueous solution of hydrochloric acid and saturated aqueous solution of sodium bicarbonate and then dried with anhydrous magnesium sulfate. After distilling off the solvent, the aimed 1-(3-methyl-4-nitrophenyl)-ethyl methanesulfonate (5.80 g) was obtained.
Reaction SMILES: Br[CH2:2][CH:3]1[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=2)[CH:4]1[C:15]([O:17]CC)=O.C(=O)([O-])O.[Na+].[C:25]1([CH2:31][CH2:32][CH2:33][NH2:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O>[N+:12]([C:8]1[CH:7]=[C:6]([CH:5]2[CH:4]3[CH:3]2[CH2:2][N:34]([CH2:33][CH2:32][CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15]3=[O:17])[CH:11]=[CH:10][CH:9]=1)([O-:14])=[O:13]
Reactant: NCCCc1ccccc1
Reactant: CCOC(=O)C1C(CBr)C1c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C2C(CN1CCCc1ccccc1)C2c1cccc([N+](=O)[O-])c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
To a solution of ethyl 2-(bromomethyl)-3-(3-nitrophenyl)cyclopropane carboxylate (Preparation 23, 60 mg, 0.18 mmol) in N,N-dimethylformamide (2 ml) was added sodium hydrogen carbonate (30 mg, 0.36 mmol) and 3-phenylpropylamine (30 mg, 31 μl, 0.22 mmol). The mixture was heated to 150° C. for 1 hour, then cooled to room temperature and stirred for 16 hours. Water (30 ml) was added and the mixture was extracted with diethyl ether (2×50 ml). The combined extracts were concentrated in vacuo and the residue was purified by silica (5 g) column chromatography eluting with dichloromethane then 4:1 dichloromethane:ethyl acetate. Product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless glassy solid (55 mg, 90%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]([C:7]([OH:9])=[O:8])[C:2]=1[C:10]([OH:12])=[O:11].OS(O)(=O)=O.[CH3:18]O>>[CH3:18][O:11][C:10]([C:2]1[C:3]([C:7]([OH:9])=[O:8])=[N:4][CH:5]=[CH:6][N:1]=1)=[O:12]
Reactant: CO
Reactant: O=C(O)c1nccnc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1nccnc1C(=O)O
Temperature: 75 °C
Yield: 47 %

Procedure:
To a mixture of pyrazine-2,3-dicarboxylic acid (20 g, 119 mmol, 1 equiv.) was added MeOH (80 mL) followed by dropwise addition of concentrated H2SO4 (36 mL, 680 mmol, 5.7 equiv.) over 45 minutes. This method is similar to that that cited for a different substrate (J. Am. Chem. Soc., 73, 1951, 5614-5616). The reaction was heated at 75° C. for 16 hours and then cooled and quenched with water (200 mL). It was extracted with EtOAc (4×60 mL) and the organic layer washed several times with water (3×50 ml), saturated NaHCO3 (50 ml), brine solution (50 mL). It was dried over Na2SO4, filtered and concentrated in vacuo to yield pyrazine-2,3-dicarboxylic acid methyl ester 241 as a brown solid (47%, 10.97 g, 55.9 mmol). 1H NMR (300 MHz) CDCl3 δ 8.79 (d, J=2.7 Hz, 2 H), 4.05 (s, 3 H), 4.04 (s, 3 H). TLC Rf: 0.7 ethyl acetate/methanol (9/1)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32](O)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@@H:36]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][C@@H:36]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]4)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: COc1ccc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c5) and commercially available tert-butyl(R)-3-amino-pyrrolidine-1-carboxylate the title compound is obtained as colorless foam.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]([CH3:49])[CH2:43][C@@H:44]1[CH2:48][CH2:47][CH2:46][O:45]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]([CH3:49])[CH2:43][C@@H:44]2[CH2:48][CH2:47][CH2:46][O:45]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CN(C[C@@H]1CCCO1)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)C[C@@H]2CCCO2)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 79.8 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-methyl-N—[(S)-tetrahydrofuran-2-ylmethyl]acetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (13 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2N2CCNCC2)=[CH:5][CH:4]=1.FC1C=CC(CC(O)=[O:28])=CC=1.S(Cl)(Cl)=O>C(Cl)Cl>[OH:28][CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: COc1ccc2c(c1)C(N1CCNCC1)CCC2
Reactant: O=C(O)Cc1ccc(F)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)C(O)CCC2
Yield: 129 %

Procedure:
7-Methoxy-1-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (0.6 g) was reacted in methylene chloride for 2 hr with an acid chloride prepared from 4-fluorophenylacetic acid (0.44 g) and thionyl chloride (0.21 ml) Then the liquid reaction mixture was partitioned between methylene chloride and water, extracted with methylene chloride, dried and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (toluene/acetone system) to give the title compound (0.56 g) as an oil. (280-5) 1-{4-[2-(4-Fluorophenyl)ethyl]piperdin-1-yl}-7-methoxy-1,2,3,4-tetrahydronaphthalene
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11]([C:13]1[N:14]=[C:15]([CH3:25])[S:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:12].[OH-].[Na+]>CO.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[S:16][C:15]([CH3:25])=[N:14][C:13]=2[C:11]([N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]2[CH2:4][C:3]([OH:26])=[O:2])=[O:12])=[CH:19][CH:20]=1
Reactant: COC(=O)CC1CCCCN1C(=O)c1nc(C)sc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc(C(=O)N2CCCCC2CC(=O)O)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
A stirring solution of (1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-yl)-acetic acid methyl ester, D16 (4.00 g, 10.6 mmol) in methanol/water (75 ml/25 ml) was treated with sodium hydroxide (0.85 g, 21.3 mmol). The mixture was stirred for 16 h at room temperature. The methanol was removed in vacuo and the residue was diluted with water and extracted with diethyl ether (2×). The aqueous phase was acidified with 5N HCl and the product was extracted with ethyl acetate. The organic phase was dried (MgSO4) and the solvent removed in vacuo. The residue was triturated with pentane to afford the title compound as a white solid (3.10 g, 82%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[CH:11]=[CH:10][C:9]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]([CH3:35])[C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:28])[CH:21]=1)[CH2:4][CH2:5][CH3:6]>O1CCCC1.CO>[CH2:3]([O:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:11]=[CH:10][C:9]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]([CH3:35])[C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:28])[CH:21]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCCCC)c1
Yield: 46 %

Procedure:
In a manner similar to that of Example (25a), by reaction of 400 mg (10 mmol, 7.5 eq) of sodium hydroxide and methyl 3-[2-butoxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoate, obtained in the preceding step, in 6 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane, 220 mg of 3-[2-butoxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=78° C.). Yield=46% over the two steps.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][CH2:15]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[O:7])[CH:8]=[CH:9][CH:10]=1
Reactant: Fc1ccc2c(c1)CCN2
Reactant: O=C(O)c1cccc(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1cccc(Br)c1)N1CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.40 g (2.0 mmol) 3-bromobenzoic acid and 0.28 g (2.0 mmol) 5-fluoro-2,3-dihydro-1H-indole in 0.55 mL (4.0 mmol) TEA and 10 mL DCM were combined with 0.64 mg (2.0 mmol) TBTU and stirred overnight at RT. The reaction mixture was extracted with saturated sodium hydrogen carbonate solution and DCM. The combined organic phases were dried on sodium sulphate, filtered and evaporated down. The residue was suspended in MeOH, suction filtered and dried.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[C:6]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[C:5]([CH3:25])=[N:4]1)[CH3:2].[BH4-].[Na+].O>CO>[CH2:1]([N:3]1[C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[C:6]([CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[OH:18])[C:5]([CH3:25])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C)c(C(=O)c2ccccc2)c1Oc1ccc(OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCn1nc(C)c(C(O)c2ccccc2)c1Oc1ccc(OC)cc1
Yield: 69.7 %

Procedure:
A solution of 77 mg of [1-ethyl-5-(4-methoxyphenoxy)-3-methyl-1H-pyrazol-4-yl]-phenyl-methanone and 119 mg of sodium borohydride in 5 ml of methanol was stirred at room temperature for 24 h. 20 ml of water was added and the mixture was extracted three times with 15 ml of diethyl ether. The combined extracts were dried over magnesium sulphate, filtered and evaporated to give 54 mg of [1-ethyl-5-(4-methoxyphenoxy)-3-methyl-1H-pyrazol-4-yl]-phenyl-methanol as a colourless gum which was used without further purification. Mass spectrum (ES) m/z 339 [M+H]+, 380 [M+H+CH3CN]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]=[C:9]=[S:10])=[O:7].[CH2:11]([O:13][CH2:14][C:15]1[NH:16][C:17]2[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[C:18]=2[N:25]=1)[CH3:12]>>[NH2:24][C:19]1[C:18]2[N:25]=[C:15]([CH2:14][O:13][CH2:11][CH3:12])[N:16]([CH2:4][CH2:3][CH2:2][CH2:6][NH:8][C:9]([NH:8][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])=[S:10])[C:17]=2[CH:22]=[C:21]([CH3:23])[N:20]=1
Reactant: O=C(N=C=S)c1ccco1
Reactant: CCOCc1nc2c(N)nc(C)cc2[nH]1
Product: CCOCc1nc2c(N)nc(C)cc2n1CCCCNC(=S)NC(=O)c1ccco1

Procedure:
Using the method of Examples 36-45, 2-furoylisothiocyanate was reacted with 1-aminobutyl)-2-ethoxymethyl-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 431.887.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7].[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Cl.N12CCCN=C1CCCCC2>CCOC(C)=O>[CH3:1][CH:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=3[C:22]([F:21])([F:31])[F:32])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: FC(F)(F)c1ccccc1CCl
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(Cc3ccccc3C(F)(F)F)CC2)nn1
Temperature: 60 °C
Yield: 72 %

Procedure:
A mixture of 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide (0.255 mmol), 2-trifluoromethylbenzyl chloride (0.255 mmol), and 1,8-diazabicylco[5.4.0]undec-7-ene (0.77 mmol) was stirred and heated at 60° C. overnight. The reaction mixture was ten diluted with EtOAc (100 mL) and washed with aqueous saturated NaHCO3 (2×20 mL) and brine (2×20 mL). The organic layer was dried over anhydrous Na2SO4, concentrated, and purified by flash chromatography to give the title compound as a white solid (80 mg, 72% yield). 1H NMR (500 MHz, CDCl3) δ 8.00, 7.86, 7.82, 7.65, 7.55, 7.37, 6.95, 3.74-3.79, 3.73, 3.46-3.52, 2.62, 1.65-1.76, 1.52, 0.94. MS (ES+) m/z 436 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][N:8]=1)=[O:5].O1C=CN=C1[Cl:25]>CN(C)C=O.ClCCl>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:25])=[O:12])=[CH:9][N:8]=1)=[O:5]
Reactant: Clc1ncco1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)O)cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 6-(2-methylbenzoylamino)nicotinic acid (0.3 g) in dimethylformamide (0.5 ml) and dichloromethane (2.5 ml) is added dropwise oxazolyl chloride (0.2 ml), and the mixture is stirred at room temperature for 2 hours. The mixture is evaporated under reduced pressure to remove the solvent to give 6-(2-methylbenzoylamino)nicotinoyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:29])[CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:15]=1)[N:6]=[C:5]2[NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[N:35]=[CH:34]2.Br[CH2:48][CH2:49][Cl:50].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:50][CH2:49][CH2:48][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:29])[CH2:22][N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:15]=1)[N:6]=[C:5]2[NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[N:35]=[CH:34]2
Reactant: COc1cc2nc(-c3cccc(NC(=O)CN4CCOCC4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nc(-c3cccc(NC(=O)CN4CCOCC4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCCl
Temperature: 85 °C

Procedure:
A mixture of tert-butyl 5-(6-hydroxy-7-methoxy-2-(3-(2-morpholinoacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.330 g, 0.527 mmol), 1-bromo-2-chloroethane (0.287 g, 2.00 mmol) and K2CO3 (0.330 g, 2.39 mmol) in DMF (3 mL) was heated at 85° C. for 3 h. The mixture was allowed to cool to RT, upon which it was diluted with water (200 mL) and the resulting precipitate was collected via filtration. The solid was taken up in EtOAc (250 mL) and washed with water (1×100 mL) and brine (1×100 mL), dried (Na2SO4), filtered and concentrated in vacuo to give tert-butyl 5-(6-(2-chloroethoxy)-7-methoxy-2-(3-(2-morpholinoacetamido)-phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate which was used without further purification (0.300 g, 0.436 mmol, 83%). HPLC retention time 5.842 mins.