Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH3:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)=[O:21]>C(O)CCC>[NH:22]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:25][CH:24]=1)[C:20]([CH3:19])=[O:21]
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: CC(=O)Nc1ccc(N)cc1
Solvent: CCCCO
Product: CC(=O)Nc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 110 °C

Procedure:
A mixture of 0.511 g (2 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine, 0.901 g (6 mmol) 4-aminoacetanilide and 5 ml 1-butanol is heated for 3 h at 110° C. The reaction mixture is then evaporated under vacuum, the crystalline residue is taken up in a mixture of 20 ml dichloromethane and 10 ml 20% aqueous potassium carbonate solution while stirring, then filtered and the filter residue washed with water and dichloromethane. After recrystallization from dichloromethane/methanol and drying under HV (8 h, 100° C.), title compound is obtained with a methanol content of 1.27%; m.p. >270° C.; 1H NMR (DMSO-d6) 9.91 (s, 1H), 9.13 (s, 1H), 8.59-8.64 (m, 1H), 8.48 (d, 2H), 8.08-8.13 (m, 1H), 7.91-8.01 (m, 2H), 7.85 (d, 2H), 7.58 (d, 2H), 7.32 (d, 2H), 4.58 (s, 2H), 2,05 (s, 3H), [methanol: 4.13 (q, 0.15H), 3.19 (d, 0.45H)]; ESI-MS: (M+H)+=370.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:14]2=[C:15]3[CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9][CH2:8][CH2:7][C:6]3=[CH:5][C:4]=1[NH:16][C:17]1[N:22]=[CH:21][C:20]([C:23]([O:25]CC)=[O:24])=[CH:19][N:18]=1.I[CH3:29].[Cl-].[NH4+]>CN(C)C=O>[CH3:29][N:16]([C:4]1[CH:3]=[C:14]2[C:15]3[CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9][CH2:8][CH2:7][C:6]=3[CH:5]=1)[C:17]1[N:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][N:18]=1
Reactant: CI
Reactant: CCOC(=O)c1cnc(Nc2cc3c4c(c2)CCCC4CCC3)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(c1cc2c3c(c1)CCCC3CCC2)c1ncc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
A suspension of sodium hydride (60%, 0.008 g) in N,N-dimethylformamide (2 ml) was added with ethyl 2-[(5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)amino]pyrimidine-5-carboxylate (0.032 g) dissolved in N,N-dimethylformamide (1 ml), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was added with iodomethane (0.015 ml), and the mixture was stirred overnight. The reaction mixture was added with saturated aqueous ammonium chloride, and the mixture was extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, the resulting residue was suspended in ethanol (5 ml), the suspension was added with 20% aqueous sodium hydroxide (1 ml), and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was left to cool and then made acidic with 2 N aqueous hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from ethanol to obtain the title compound (0.027 g, yield: 87%) as colorless needles (melting point: 255-256° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:10])[CH:6]=[C:4]([OH:5])[C:3]=1[OH:17].[O:18]1[C:20]([CH3:25])([CH2:21][CH2:22][CH:23]=[CH2:24])[CH2:19]1.N1CCCCC1>CCOCC>[OH:18][C:20]([CH3:25])([CH2:21][CH2:22][CH:23]=[CH2:24])[CH2:19][O:5][C:4]1[CH:6]=[C:7]([C:9]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:10])[CH:8]=[C:2]([CH3:1])[C:3]=1[OH:17]
Reactant: C=CCCC1(C)CO1
Reactant: Cc1cc(C(C)(C)CC(C)(C)C)cc(O)c1O
Solvent: CCOCC
Solvent: C1CCNCC1
Product: C=CCCC(C)(O)COc1cc(C(C)(C)CC(C)(C)C)cc(C)c1O
Temperature: 120 °C
Reaction time: 168 h
Yield: 25 %

Procedure:
A mixture of 10.5 g (44 mmole) of 3-methyl-5-t-octylcatechol, 11 g (90 mmole) of 1,2-epoxy-2-methyl-5-hexene and 0.75 ml of piperidine was heated at 120° C., with stirring, under nitrogen, for 7 days. The reaction mixture was cooled and dissolved in ether (300 ml), and the resulting solution was washed with water, followed by 1N hydrochloric acid, followed by saturated sodium chloride solution. The washed ethereal solution was dried (MgSO4) and evaporated in vacuo, and the residue was purified by column chromatography on silica gel, eluting with chloroform. This afforded a 25% yield of the title compound as an oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[CH:5]=[CH:4][CH:3]=1.[CH2:11]([N:15]1[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]2=[N:16]1)[CH2:12][C:13]#[CH:14]>>[N:16]1[N:15]([CH2:11][CH2:12][C:13]#[C:14][C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[CH:5]=[CH:4][CH:3]=2)[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=12
Reactant: CCNc1cccc(Br)n1
Reactant: C#CCCn1nc2ccccc2n1
Product: CCNc1cccc(C#CCCn2nc3ccccc3n2)n1
Yield: 24 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from (6-bromo-pyridin-2-yl)-ethyl-amine (100 mg, 0.50 mmol) and 2-but-3-ynyl-2H-benzo[d][1,2,3]triazole (0.13 g, 0.75 nm mmol, Example 109(D)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 35 mg (0.12 mmol, 24%) of 6-(4-(2H-benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)-N-ethylpyridin-2-amine as a brown solid (M.P.=73-78° C.).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=1>C1COCC1>[CH3:17][S:16][C:12]1[N:13]=[C:14]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=[CH:10][N:11]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CSc1nccc(Cl)n1
Solvent: C1CCOC1
Product: CSc1nccc(-c2ccccc2)n1
Reaction time: 0.83 h
Yield: 52.9 %

Procedure:
A solution of phenylmagnesium bromide (1M in THF, 4.2 mL, 4.2 mmol) is added to a solution of 4-chloro-2-methylthio-pyrimidine (296 mg, 1.84 mmol) and Fe(acac)3 (32 mg, 0.09 mmol) in THF (10 mL) at −30° C. After stirring for 50 min at that temperature, the reaction is quenched with brine, the aqueous layer is extracted with Et2O, the combined organic phases are dried over Na2SO4 and evaporated, and the residue is purified by flash chromatography (hexane/ethyl acetate, 10:1). After eluting a first fraction containing biphenyl (90 mg), one obtains 2-methylthio-4-phenyl-pyrimidine as a pale yellow solid (197 mg, 53%). 1H NMR (300 MHz, CD2Cl2) δ 8.53 (d, 1H), 8.09–8.13 (m, 2H), 7.53–7.48 (m, 3H), 7.39 (d, 2H), 2.63 (s, 3H); 13C NMR (75 MHz, CD2Cl2) δ 173.0, 164.0, 158.0, 136.7, 131.1, 131.0, 129.2, 127.5, 127.4, 112.2, 14.3.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][N:13]=[C:12]([O:18]C)[CH:11]=2)[CH:3]=1.Cl.[NH+]1C=CC=CC=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][NH:13][C:12](=[O:18])[CH:11]=2)[CH:3]=1
Reactant: COc1cc(-c2cc(Cl)ccc2C#N)c(OC)cn1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: COc1c[nH]c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
7.23 g (purity 92%, 24.21 mmol) of 4-chloro-2-(2,5-dimethoxypyridin-4-yl)benzonitrile and pyridinium hydrochloride were reacted according to General Method 3A. Yield: 6.66 g (purity 91%, 96% of theory)
Reaction SMILES: [SH:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B>C1COCC1>[OH:5][CH2:4][C:3]1[CH:7]=[CH:8][N:9]=[CH:10][C:2]=1[SH:1]
Reactant: O=C(O)c1ccncc1S
Agent: B
Solvent: C1CCOC1
Product: OCc1ccncc1S
Reaction time: 0.5 h

Procedure:
To a suspension of 3-mercaptoisonicotinic acid (1.80 g, 11.6 mmol) in dry THF (70 mL) was added slowly borane in THF (52 ml, 1M, 52 mmol) and the reaction mixture was stirred for 30 min. The solvent was evaporated under reduced pressure, methanol (40 mL) was added, and after gas evolution stopped, concentrated hydrochloric acid (3.6 mL) was added. The solution was filtered and the filtrate was evaporated to dryness. The residue was redissolved in a small volume of water, concentrated aqueous ammonia (3.6 ml) was added and the reaction mixture was evaporated to dryness. After overnight drying under vacuum, a quantitative yield of the title product was obtained, which was used for the next step without purification. 1H NMR (CD3OD) δ4.786 (s, 2H), 8.13 (d, 2H, J=6), 8.60 (d, 2H, J=6), 8.70 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:18]2[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:22]([CH3:29])[NH:21][C:20]([C:30]3[S:31][CH:32]=[CH:33][N:34]=3)=[N:19]2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.C1C(=O)N([Br:42])C(=O)C1>>[Br:42][CH2:29][C:22]1[NH:21][C:20]([C:30]2[S:31][CH:32]=[CH:33][N:34]=2)=[N:19][CH:18]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=2[C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=2)[C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C1=C(C)NC(c2nccs2)=NC1c1ccc(F)cc1-c1ccc(C(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1-c1ccc(C(F)(F)F)cc1
Yield: 60 %

Procedure:
Ethyl 4-(5-fluoro-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (5 g, 10.2 mmol) was reacted with NBS (2.2 g, 12.2 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (3.48 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[CH2:17]([CH2:19][NH2:20])[OH:18].CCN(C(C)C)C(C)C>Cl.CCCCO>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:20][CH2:19][CH2:17][OH:18])[CH:3]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: NCCO
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2cc(NCCO)ncn2)cc1
Temperature: 200 °C

Procedure:
250 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 62 mg of ethanolamine and 296 mg of DIPEA were dissolved in 2 mL of n-BuOH and the mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 45 minutes under microwave irradiation. Progress of the reaction was monitored by TLC. Upon termination of the reaction n-BuOH was evaporated. The evaporation residue was subjected to crystallization from an n-BuOH/EtOH solvent mixture.
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].C1N=CN(C(N2C=NC=C2)=O)C=1.O[NH:40][C:41](=[NH:43])[CH3:42]>CN(C=O)C.O>[CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:26]=[CH:25][CH:24]=[C:20]([C:21]4[O:23][N:43]=[C:41]([CH3:42])[N:40]=4)[CH:19]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:6])[CH3:7])(=[O:4])=[O:3]
Reactant: CC(C)(c1cc(-c2cccc(C(=O)O)c2)c2ncccc2c1)S(C)(=O)=O
Reactant: CC(=N)NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-benzoic acid from Step 2 (1.0 eq.) in DMF (0.1M) was added CDI (2.0 eq.) and N-hydroxy-acetamidine (2.0 eq.). The mixture was stirred for 1 h at rt then 12 h at 120° C. The mixture was cooled, poured in water and extracted with EtOAc. The organic extract was washed with water (2×), brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 9:1 to 1:9 in 20 min) afforded the title compound as a white solid. 1H NMR (500 MHz, acetone-d6): δ 8.91 (dd, 1H), 8.52 (m, 3H), 8.38 (d, 1H), 8.25 (d, 1H), 8.04 (d, 1H), 7.78 (t, 1H), 7.64 (dd, 1H), 2.77 (s, 3H), 2.43 (s, 3H), 2.05 (s, 6H).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][CH:6]=2)[CH3:2].[H-].[Na+].CCCCCC.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.O>[C:24]1([CH2:23][N:4]2[C:5]3[C:10](=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][CH:6]=3)[CH:11]=[C:3]2[CH2:1][CH3:2])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCc1cc2c([N+](=O)[O-])cccc2[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: CCc1cc2c([N+](=O)[O-])cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.8 %

Procedure:
2-Ethyl-4-nitro-1H-indole (4.75 g, 25 mmol) was added to a mixture of 1.0 g (25 mmol) of 60% NaH/mineral oil (washed with hexane before adding DMF) in 40 ml DMF. After 45 minutes, 3.0 ml (25 mol) of benzyl bromide was added. The mixture was stirred at room temperature for four hours, diluted with water, and extracted with EtOAc. The EtOAc solution was washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 20% EtOAc/Hexane to give 6.36 g (91%) of 1-Phenylmethyl-2-ethyl-4-nitro-1H-indole as an oil.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([OH:15])(=[O:14])[CH2:10][CH2:11][CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:15][C:9](=[O:14])[CH2:10][CH2:11][CH:12]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: C=CCCC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: C=CCCC(=O)OCc1ccccc1
Reaction time: 48 h

Procedure:
Benzyl bromide (7.19 g, 42.04 mmol) was added to a solution of 4-pentenoic acid (6) (5.05 g, 50.45 mmol, 1.2 eq.) in acetone (75 ml) at RT under N2. Anhydrous potassium carbonate (29.05 g, 210.19 mmol, 5.0 eq.) and tetrabutylammonium iodide (0.776 g, 2.102 mmol, 0.05 eq.) were added and the resulting suspension was stirred over 2 days. LCMS analysis showed mainly product.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>C1COCC1>[C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH2:1][C:33]([NH:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[F:25])=[O:34])=[CH:3][C:4](=[O:14])[O:5]2)=[CH:10][CH:9]=1)#[N:13]
Reactant: Cc1cc(=O)oc2cc(C#N)ccc12
Reactant: O=C=Nc1ccccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(CC(=O)Nc3ccccc3F)cc(=O)oc2c1
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-2-oxo-2H-chromene-7-carbonitrile (670 mg, 3.6 mmol) in dry THF (30 mL) at −20° C. was added drop wise 1.0 M LiHMDS solution in THF (5.4 mL). After 30 minutes 2-fluoro-1-isocyanato-benzene (189 mg) was added into the reaction mixture and the reaction mixture was stirred for 1 hour. The reaction mixture was then quenched with saturated aqueous ammonium chloride (25 mL) and extracted with ethyl acetate (50 mL). The organic layer was separated and dried over sodium sulfate, then concentrated and purified on silica gel eluted with 30%-100% ethyl acetate in hexanes to yield 2-(7-cyano-2-oxo-2H-chromen-4-yl)-N-(2-fluoro-phenyl)-acetamide as a solid.
Reaction SMILES: [CH3:1][C:2]1([C:19]([NH2:21])=[O:20])[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH3:18])=O)=[CH:11][CH:10]=2)[O:3]1.[OH:22][CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)[CH2:24][NH2:25]>>[CH3:1][C:2]1([C:19]([NH2:21])=[O:20])[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:25][CH2:24][CH:23]([OH:22])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[CH3:18])=[CH:11][CH:10]=2)[O:3]1
Reactant: CC(=O)Cc1ccc(OCC2CCC(C)(C(N)=O)O2)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Product: CC(Cc1ccc(OCC2CCC(C)(C(N)=O)O2)cc1)NCC(O)c1cccc(Cl)c1

Procedure:
Methyl 5-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino] propyl]phenoxymethyl]tetrahydrofuran-2-carboxamide was prepared from methyl 5-[4-acetonylphenoxymethyl]tetrahydrofuran-2-carboxamide and 2-hydroxy-2-(3-chlorophenyl)ethanamine in an analogous manner to the compound described in Example 50.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[NH:10][C:8]=2[N:9]=1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1)=[O:26].C(OCC)(=O)C>CN(C)C=O>[CH3:23][O:24][C:25](=[O:26])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:10]2[C:8]3[N:9]=[C:4]([NH2:3])[N:5]=[CH:6][C:7]=3[CH:13]=[C:12]([C:14]3[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:20])[C:11]2=[O:22])=[CH:29][CH:28]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2c(=O)c(-c3c(Cl)cccc3Cl)cc3cnc(N)nc32)cc1
Temperature: 0 °C
Yield: 70 %

Procedure:
To a suspension of NaH (60% in mineral oil, 36 mg) in 7 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (195 mg, 0.64 mmol). The mixture was heated at 40° C. to 50° C. for 20 minutes, resulting in a clear solution. Methyl 4-(bromomethyl) benzoate (206 mg, 0.90 mmol) was added, and the reaction mixture was heated at 40° C. to 50° C. for 15 minutes, then poured onto 30 mL of ice water. The resulting precipitate was removed by filtration and washed with water. The solid was purified by flash chromatography, eluting with a gradient of 1:1 hexane:ethyl acetate to 1:2 hexane: ethyl acetate, then dried in vacuo to provide 204 mg of 4-[2-amino-6-(2,6-dichlorophenyl)-7-oxo-7H-pyrido[2,3-d]pyrimidin-8-ylmethyl]-benzoic acid methyl ester containing 0.16 equivalents of ethyl acetate; mp 235°-237° C.
Reaction SMILES: [N+:1](=[C:3]([C:17]([CH3:19])=[O:18])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-:2].[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21].[I-].[Na+].C(N(CC)CC)C>C(#N)C>[N+:1](=[C:3]([C:17]([O:18][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25])=[CH2:19])[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)=[O:5])=[N-:2]
Reactant: CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(O[Si](C)(C)C(C)(C)C)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Into 5 ml of dry acetonitrile were suspended 263 mg (1 millimole) of p-nitrobenzyl 2-diazoacetoacetate, 226 mg (1.5 millimoles) of tertbutyldimethylsilyl chloride and 210 mg (1.4 millimoles) of sodium iodide. To the mixture was added 220 μl (1.6 millimoles) of triethylamine under an argon atmosphere at a room temperature. The resultant was heated up to 40° C. and agitated at the same temperature overnight, followed by concentration under a reduced pressure. To the residue was added 20 ml of ethyl acetate, and the resultant was washed twice with 10 ml portions of water. The organic layer was dried and then concentrated to dryness under a reduced pressure to give 340 mg (yield 90%) of the desired compound in a yellow solid. The physical properties of the product were in agreement with those of the product obtained in Example 2.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1>>[CH3:14][N:15]([C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=1)[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CNc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: CN(c1ccc(C(F)(F)F)cc1)S(=O)(=O)c1ccc(C(=O)O)cc1

Procedure:
4-(chlorosulfonyl)benzoic acid (0.5 g, 2.27 mmol) was treated with N-methyl-4-(trifluoromethyl)aniline (1191 mg, 6.80 mmol) using method A to give 4-(N-methyl-N-(4-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid as a white solid. Yield: 385 mg (47%). 1H-NMR: 8.11 (d, J=8.5 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H), 7.66 (d, J=8.5 Hz, 2H), 7.39 (d, J=8.5 Hz, 2H), 3.21 (s, 3H).
Reaction SMILES: CO[C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([F:11])[CH2:7]1.[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1.C[O-].[Mg+2].C[O-].CO>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH:8]([F:11])[CH2:7]2)[C:3]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:20])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: COC(=O)C(CC1CCC(F)C1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nccs1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCC(F)C1)c1ccc(Cl)c(Cl)c1
Temperature: 110 °C
Yield: 2.5 %

Procedure:
A mixture of 2-(3,4-dichloro-phenyl)-3-(3-fluoro-cyclopentyl)-propionic acid methyl ester (70 mg, 0.24 mmol) and 2-aminothiazole (26.3 mg, 0.26 mmol) in a solution of magnesium methoxide in methanol (7.4 wt. % , 0.63 mL, 0.43 mmol) was heated to 110° C. for 18 h. At this time, the reaction mixture was cooled to 25° C. and then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-(3-fluoro-cyclopentyl)-N-thiazol-2-yl-propionamide (2.3 mg, 2.7%) as a light yellow oil: EI-HRMS m/e calcd for C17H17Cl2N2OS (M+H)+ 387.0496. found 387.0499.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[C:15]([N:17]2[CH2:30][CH2:29][C:20]3[NH:21][C:22]4[C:23]([OH:28])=[CH:24][CH:25]=[CH:26][C:27]=4[C:19]=3[CH2:18]2)=[O:16])=[O:8])[CH2:5][CH2:4]1)#[N:2].Br[CH2:32][CH2:33][CH3:34].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[C:15]([N:17]2[CH2:30][CH2:29][C:20]3[NH:21][C:22]4[C:23]([O:28][CH2:32][CH2:33][CH3:34])=[CH:24][CH:25]=[CH:26][C:27]=4[C:19]=3[CH2:18]2)=[O:16])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: CCCBr
Reactant: N#CC1(NC(=O)[C@@H]2CCCC[C@H]2C(=O)N2CCc3[nH]c4c(O)cccc4c3C2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1cccc2c3c([nH]c12)CCN(C(=O)[C@@H]1CCCC[C@H]1C(=O)NC1(C#N)CC1)C3
Yield: 60 %

Procedure:
(1R,2R)-2-(6-Hydroxy-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carbonyl)-cyclohexanecarboxylic acid (1-cyano-cyclopropyl)-amide (102 mg, 0.25 mmol), 1-bromopropane (28.0 uL, 0.30 mmol) and potassium carbonate (35.0 mg, 0.25 mmol) in acetone (5 mL) were heated to reflux for 3 h. Added further 1-bromopropane (58.0 uL, 0.60 mmol) and potassium carbonate (70.0 mg, 0.50 mmol) and heated overnight. The reaction darkened significantly and LCMS indicated 60% required product and 40% SM. The reaction was filtered and the liquors evaporated to dryness before redissolving in acetonitrile and purifying by preparative HPLC (0.5% HCOOH, CH3CN/H2O gradient) to give a brown glass (21.3 mg, 18%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:13]([O:12][C:11]([NH:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([O:19][CH3:18])=[O:29])=[CH:7][CH:6]=1)=[O:17])([CH3:14])([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccccc1CBr
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccccc1COc1ccc(CCNC(=O)OC(C)(C)C)cc1
Yield: 94.5 %

Procedure:
tert-Butyl 2-(4-hydroxyphenyl)ethylcarbamate (3.534 g, 14.9 mmol), 2-bromomethyl-benzoic acid methyl ester (3.582 g, 15.6 mmol) and potassium carbonate, anhydrous (3.087 g, 22.3 mmol) were mixed in acetonitrile (50 ml). The mixture was heated to reflux overnight and then evaporated to dry. Water and ethyl acetate were added and the two phases were separated. The organic phase was dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 20 g/70 ml) using DCM and then MeOH/DCM (1:99) as eluant gave 5.427 g the desired product, yield 94.5%.