Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20]N(C)C)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:32][C:33]1[CH2:38][CH2:37][CH2:36][C:35](=[O:39])[CH:34]=1>C(O)(=O)C>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][C:34]4[C:35](=[O:39])[CH2:36][CH2:37][CH2:38][C:33]=4[N:32]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=C(C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1)c1ccccc1
Reactant: NC1=CC(=O)CCC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCC4)cc2)CCC1
Temperature: 100 °C
Yield: 37.1 %

Procedure:
To acetic acid (120 mL) was added molecular sieves (5 Å, 1.50 g), tert-butyl(1-(4-(3-(dimethylamino)-2-phenylacryloyl)phenyl)cyclobutyl)carbamate (8.00 g, 19.0 mmol) and 3-amino-2-cyclohexene-1-one (3.20 g, 28.8 mmol). The reaction mixture was heated to 100° C. under a nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was partitioned between water (160 mL) and dichloromethane (160 mL) and decanted from the molecular sieves. The layers were separated and the aqueous phase extracted into dichloromethane (2×160 mL). The combined organic phases were washed with saturated NaHCO3 solution (2×160 mL), brine (160 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give a yellow/brown solid. This was purified by Biotage chromatography (silica, hexane:ethyl acetate, gradient elution from 90:10 to 20:80) to give the desired product as a yellow solid (3.30 g, 37% yield). 1H-NMR (500 MHz, CDCl3) δ 8.30 (1H, s), 7.37 (2H, d), 7.30 (2H, d), 7.24-7.27 (3H, m), 7.15-7.20 (2H, m), 5.01 (1H, br s), 3.26 (2H, t), 2.75 (2H, t), 2.42-2.55 (4H, m), 2.26 (2H, p), 2.00-2.10 (1H, m), 1.73-1.85 (1H, m), 1.12-1.44 (9H, br m). LCMS (Method A) RT=7.54 min, M+H+=469.15.
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([F:14])[CH:7]=1)=[CH:3][C:4]#[N:5].C(N)(=[S:17])C.Cl>O1CCOCC1>[NH2:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([F:14])[CH:7]=1)=[CH:3][C:4]([NH2:5])=[S:17]
Reactant: COc1ccc(C(N)=CC#N)cc1F
Reactant: CC(N)=S
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(C(N)=CC(N)=S)cc1F
Reaction time: 6 h
Yield: 98.5 %

Procedure:
Add dioxane (65 mL) to 3-amino-3-(3-fluoro-4-methoxyphenyl)acrylonitrile (25.0 g, 130 mmol) and thioacetamide (19.5 g, 260 mmol); then add 4 N HCl in dioxane (650 mL, 2,600 mmol) and allow the reaction to stir 4-8 h until complete by TLC. Evaporate the reaction mixture to dryness; then add dioxane (200 mL); add slowly TEA (dried with K2CO3, 1000 mL); and then add satd K2CO3 (1000 mL) and extract with EtOAc (2000 mL). Dry the organic phase (K2CO3) and evaporate to afford 3-amino-3-(3-fluoro-4-methoxyphenyl)thioacrylamide. Yield: 98.5%. ES-MS: m/e 227.0 (m+1).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:25])([CH3:24])[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[C:14]1[N:15]([CH3:23])[C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:4])([CH3:3])[CH3:2].ClS([N:30]=[C:31]=O)(=O)=O.CN(C=O)C>C(Cl)Cl>[C:1]([SiH2:5][O:6][C:7]([CH3:25])([CH3:24])[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[C:14]1[N:15]([CH3:23])[C:16]2[C:21]([C:22]=1[C:31]#[N:30])=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cn1c(-c2cnccc2C(C)(C)O[SiH2]C(C)(C)C)cc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1c(-c2cnccc2C(C)(C)O[SiH2]C(C)(C)C)c(C#N)c2ccccc21
Reaction time: 0.08 h

Procedure:
To a solution of 2-[4-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-3-yl]-1-methyl-1H-indole (0.263 g, 0.747 mmol) in DCM (5 mL) is added chlorosulfonyl isocyanate (0.162 mL, 1.867 mmol). After 5 min, DMF (1 mL) is added. After another 30 min, the reaction is concentrated under vacuo to afford 2-[4-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile as a light yellow solid, which is redissolved in DCM (3 mL). 4 M HCl in 1,4-dioxane (1 mL) is added, and the mixture is stirred at room temperature for 30 min. Purification by reverse phase HPLC with Xbridge Shield RP18 column and a 0.1% aqueous NH4OH in acetonitrile gradient affords 2-(4-hydroxymethyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile as a solid. 1H NMR (400 MHz, MeOD) δ ppm 3.67 (s, 3H), 4.44-4.67 (m, 2H), 7.39 (t, J=7.6 Hz, 1H), 7.47 (t, J=8.3 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.87 (d, J=5.3 Hz, 1H), 8.60 (s, 1H), 8.80 (d, J=5.3 Hz, 1H). HRMS (ESI) m/z 264.1142 [(M+H)+ Calcd for C16H14N3O: 264.11379].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][CH3:10])[C:3]=1[O:11][CH3:12].[Cl-].[Al+3].[Cl-].[Cl-].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24].O>C(Cl)Cl>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([C:7]1[CH:6]=[C:5]([CH3:8])[C:4]([O:9][CH3:10])=[C:3]([O:11][CH3:12])[C:2]=1[CH3:1])=[O:24]
Reactant: O=C(Cl)CCCCCBr
Reactant: COc1c(C)ccc(C)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1c(C)cc(C(=O)CCCCCBr)c(C)c1OC
Temperature: 0 °C
Reaction time: 19 h
Yield: 45.6 %

Procedure:
A solution of 0.227 g (1.5 mmol) of 3,6-dimethylveratrole in 1 mL of methylene chloride was added to an ice cooled mixture of 0.245 g (1.8 mmol) of aluminum chloride and 0.416 g (1.9 mmol) of 6-bromohexanoyl chloride in 3 mL of methylene chloride. The reaction mixture was kept at 0° for 19 hours. Water was added and the organic layer was separated and washed with sodium bicarbonate solution. The dried extract was concentrated to an oil which was chromatographed on 60 g of silica gel using 10% ethyl acetate-hexane to give 0.235 g of 6-bromo-1-(3,4-dimethoxy-2,5-dimethylphenyl)-1-hexanone as an oil. The nmr spectrum was consistent with the structure and the mass spectrum gave the molecular ion at m/z 342 (C16H23BrO3)
Reaction SMILES: [CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=1>CN(C=O)C>[CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=3)[CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccccc1)N(C1CCNCC1)C1CC1
Reactant: CC(C)c1ccc(CBr)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(CN2CCC(N(C3CC3)S(=O)(=O)c3ccccc3)CC2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 19.5 %

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-benzenesulfonamide (100 mg, 0.36 mmol) was dissolved in DMF (2.5 mL) and triethylamine (75 μL, 54 mg, 0.54 mmol) added, followed by 1-bromomethyl-4-isopropylbenzene (83.5 mg, 0.39 mmol). The reaction mixture was stirred for 12 hours at 80° C. and then the solvent was evaporated. The residue was purified by flash chromatography to give 29 mg of the title compound 17 as a yellow oil. 1H NMR (CDCl3): δ 7.88-7.83 (m, 2H), 7.59-7.47 (m, 3H), 7.21-7.14 (m, 4H), 3.89-3.78 (m, 1H), 3.45 (s, 2H), 2.95-2.88 (m, 3H), 2.03-1.84 (m, 5H), 1.51-1.44 (m, m, 2H), 1.23 (d, 6H, J=7.01 Hz), 1.01-0.93 (m, 2H), 0.79-0.69 (m, 2H). LC: 100%. MS (EI): m/z 413 (M+H+).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:27]=1[CH:28]=[CH:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:27]=1[CH:28]=[CH:29][C:30]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:31]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(O)C=Cc1c(F)cccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1c(F)cccc1F
Yield: 86.1 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 2,6-difluorocinnamic acid (2.6 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (3.9 g, 85%) as an oily product.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([CH:9]=1)[CH:7]=O.[C:14]([O:19][CH2:20][CH3:21])(=[O:18])[C:15]([CH3:17])=O.[Sn](Cl)Cl>C(O)C.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][C:3]=1[F:13])[N:10]=[C:15]([C:14]([O:19][CH2:20][CH3:21])=[O:18])[CH:17]=[CH:7]2
Reactant: CCOC(=O)C(C)=O
Reactant: O=Cc1cc(Br)c(F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Product: CCOC(=O)c1ccc2cc(Br)c(F)cc2n1
Temperature: 70 °C
Yield: 20.4 %

Procedure:
5-Bromo-4-fluoro-2-nitro-benzaldehyde (1.50 g, 6.05 mmol) and ethyl pyruvate (737.4 mg, 6.35 mmol) in ethanol (15 mL) was added via canula to zinc(II)chloride (4.12 g, 30.24 mmol), tin(II)chloride (5.73 g, 30.24 mmol), and activated 4 Å molecular sieve pellets (1.50 g) in ethanol (15 mL) under argon. The mixture was heated at 70° C. in an oil bath for four hours, then allowed to cool to room temperature, and carefully quenched with saturated sodium bicarbonate. Ethyl acetate was added and the mixture was filtered through Celite®. The filtrate was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 1:6 ethyl acetate:hexanes to give 368.5 mg (20%) of ethyl 6-bromo-7-fluoro-2-quinolinecarboxylate as a solid. 1H NMR (400 MHz, d6-DMSO): δ 8.63 (d, J=8 Hz, 1H), 8.58 (d, J=9 Hz, 1H), 8.15 (s, 1H), 8.13 (s, 1H), 4.42 (q, J=7 Hz, 2H), 1.37 (t, J=7 Hz, 3H). ESI-LCMS m/z 297 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[C:17]2[C:22]([F:23])=[CH:21][N:20]=[C:19]([O:24][CH3:25])[CH:18]=2)[C:10](OC)=[O:11])=[CH:5][CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1([CH3:26])[C:6]([C:7]2[CH:8]=[C:9]([CH2:10][OH:11])[CH:14]=[CH:15][C:16]=2[C:17]2[C:22]([F:23])=[CH:21][N:20]=[C:19]([O:24][CH3:25])[CH:18]=2)=[CH:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(-c2cc(OC)ncc2F)c(C2=CCCC2(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2ccc(CO)cc2C2=CCCC2(C)C)c(F)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To methyl 3-(5,5-dimethylcyclopent-1-enyl)-4-(5-fluoro-2-methoxypyridin-4-yl)benzoate L.2 (295 mg, 830 μmol) was added THF. The mixture was cooled to 0° C., and LAH (1660 μL, 1660 μmol) was added dropwise. The reaction was stirred at room temperature for 1 hour, and was quenched with water and a small amount of Rochelle's salt solution. Purification with silica gel chromatography afforded (3-(5,5-dimethylcyclopent-1-enyl)-4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)methanol L.3 (201 mg) as an oil (74%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:13]=[CH:12][N:11]([CH2:14][C:15]([OH:17])=O)[N:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:13]=[CH:12][N:11]([CH2:14][C:15]([N:30]3[CH2:29][CH2:28][N:27]([CH:24]4[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]4)[CH2:32][CH2:31]3)=[O:17])[N:10]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: O=C(O)Cn1ccc(NC(=O)c2ccc(Cl)cc2)n1
Reactant: CN1CCC(N2CCNCC2)CC1
Solvent: C1CCOC1
Product: CN1CCC(N2CCN(C(=O)Cn3ccc(NC(=O)c4ccc(Cl)cc4)n3)CC2)CC1

Procedure:
Using general method A, using THF instead of DMF as solvent, [3-(4-chloro-benzoylamino)-pyrazol-1-yl]-acetic acid (example 59.2) was reacted with 1-(N-methyl-4-piperidyl)-piperazine to give 4-chloro-N-(1-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazol-3-yl)-benzamide. Off-white solid. MS 445.4 ([M+H]+)
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:29])[C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:21])[CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].Cl[C:31](=[O:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>O1CCCC1>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:14][CH2:15][N:16]([C:19](=[O:29])[C:20]([NH:22][CH:23]2[CH2:24][CH2:25][N:26]([C:31](=[O:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:27][CH2:28]2)=[O:21])[CH2:17][CH2:18]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NC2CCNCC2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)N1CCC(NC(=O)C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 288 h
Yield: 88.4 %

Procedure:
A mixture of 2-[4-(2 tert-butylphenyl)piperazin-1-yl]-2-oxo-N-piperidin-4-ylacetamide dihydrochloride (Example 182-A, 0.35 g, 0.79 mmol), ethyl chloro(oxo)acetate (140 mg, 1.02 mmol) and triethylamine (439 3.15 mmol) in tetrahydrofuran (4 mL) was stirred at room temperature for 12 days. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 75:25 to 25:75) to give the title compound (0.33 g, 88%) as a white amorphous.
Reaction SMILES: [C:1](#N)[CH3:2].Br[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1.C(N(CC)CC)C>Cl[Pd]Cl.O>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH:1]=[CH2:2])[CH:14]=[CH:13]2
Reactant: CC#N
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: Cl[Pd]Cl
Solvent: O
Solvent: CCN(CC)CC
Product: C=Cc1ccc2cc(OC)ccc2c1
Reaction time: 0.5 h

Procedure:
A 20-gallon jacketed stainless steel reactor equipped with a mechanical agitator is charged with 19.45 kg of acetonitrile (ACN) and 12.45 kg of 2-bromo-6-methoxynaphthalene (BMN), and 4.8 g of PdCl2. The reactor is pressured and vented three times with 50 psig nitrogen. The reactor is then charged with 5.3 kg of ACN and 5.64 kg of triethylamine (TEA). The agitator is set at 158 rpm and the reactor is pressured and vented three times with 80 psig nitrogen. The reactor is then purged for ten minutes with nitrogen. Next a mixture of 48.6 g of neomenthyldiphenylphosphine (NMDP) dissolved in 0.35 kg of TEA is charged to the reactor. The agitator is set to 412 rpm and the reactor is heated with steam on the jacket. The reaction temperature is initially in the range of 91-109° C., while the pressure varies from 412-519 psig. The reaction produces a heat kick, and after 30 minutes the temperature rises to 109° C. with 26° C. cooling water on the jacket. The total reaction time is 1.75 hours with a BMN conversion of 100%. The reactor is cooled, vented, and the reactor contents are transferred to a 30-gallon glass lined reactor for workup.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([C:25]5[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cc(-c3cccnc3)ccc21
Product: CC1c2ccc(-c3cccnc3)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-pyridin-3-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][O:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(#N)C>[CH3:13][O:14][C:15]1[N:16]=[CH:17][N:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[O:11][CH3:12])[CH:19]=1
Reactant: COc1cc([N+](=O)[O-])ccc1F
Reactant: COc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1cn(-c2ccc([N+](=O)[O-])cc2OC)cn1
Temperature: 90 °C
Yield: 54.2 %

Procedure:
1-Fluoro-2-methoxy-4-nitrobenzene (0.785 g, 4.59 mmol), 4-methoxy-1H-imidazole (0.45 g, 4.59 mmol) and potassium carbonate (0.697 g, 5.05 mmol) were mixed in dry acetonitrile (10 mL) and heated at 90° C. for 4 days. DCM was added and the mixture was filtrated through a pad of silica eluting with 5% MeOH in DCM. The solvents were evaporated and mixture was purified by column chromatography in silica eluting with a gradient of MeOH and DCM to give the title compound as a gum 0.62 g (54%).
Reaction SMILES: Br[CH2:2][Mg].[CH3:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=[O:6].N>C(OCC)C>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([C:5]([OH:6])([CH3:2])[CH3:4])[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc(C(C)=O)c1
Reactant: [Mg]CBr
Agent: N
Solvent: CCOCC
Product: COc1cccc(C(C)(C)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
Bromomethylmagnesium (3 M diethyl ether solution) (24 ml, 72 mmols) was dropwise added to a diethyl ether (200 ml) solution of 3-methoxyacetophenone (10 g, 67 mmols) at room temperature. After the addition, the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonia was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with brine, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure to give an oil of 2-(3-methoxyphenyl)propan-2-ol (11 g, 98%).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:33]=[CH:32][C:31]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][C:23]=4[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.O>O1CCOCC1>[CH:22]1[C:23]2[CH2:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][C:21]=1[C:19]([N:10]1[C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13][N:14]2[C:5]([C:3]([NH:36][CH2:37][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)=[O:4])=[CH:6][CH:7]=[C:8]2[CH2:9]1)=[O:20]
Reactant: O=C(c1ccc2c(c1)Cc1ccccc1-2)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: NCc1cccnc1
Solvent: C1COCCO1
Solvent: O
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc3c(c1)Cc1ccccc1-3)C2
Temperature: 25 °C

Procedure:
A solution of 0.7 g (0.0014 mol) of 2,2,2-trichloro-1-[10-(9H-fluorene-2-carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]-ethanone of Step B and 0.30 g (0.0028 mol) of 3-aminomethylpyridine in 25 mL of 1,4-dioxane was heated under reflux for 1 hour. The reaction mixture was cooled to room temperature and poured into 75 mL of water with stirring. The precipitate was collected, washed with water, and recrystallized from ethanol to provide the title compound, m.p. 116-119° C.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:1]([CH:5]1[CH2:10][CH2:9][C:8]([C:16]2[CH:17]=[CH:18][C:13]([NH2:12])=[CH:14][CH:15]=2)=[CH:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: Nc1ccccc1
Product: CC(C)(C)C1CC=C(c2ccc(N)cc2)CC1

Procedure:
4-(4-tert-Butylcyclohex-1-enyl)aniline was prepared in analogy to procedure for preparation of building block 11 using 4-tert-butylcyclohexanone (0.59 mol) and aniline
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[H-].[Na+].[C:19](Cl)(=[O:21])[CH3:20]>C1C=CC=CC=1>[C:19]([N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(=O)N1C(=O)CC[C@H]1C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of 61.3 g (280 mmol) of benzyl (L)-pyroglutamate in 400 ml of benzene is added over 2 hours to a suspension of 13.4 g of NaH (280 mmol) in 50 ml of dry benzene. After stirring for one hour at ordinary temperature, a solution of 22.7 g (290 mmol) of acetyl chloride in 150 ml of benzene is run in and the mixture is heated at 55° for 5 hours and then stirred for 24 hours at ordinary temperature, washed with 2×150 ml of water, dried and evaporated. The product is distilled under reduced pressure; boiling point=150°-60° C. (0.25 mm Hg). This gives 60% of a pure product of Rf=0.63 (A).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1.C1(=O)O[CH2:21][CH2:20][O:19]1.C(=O)=O>[Cl-].C[N+](C)(C)C.O>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:21][CH2:20][OH:19])[CH:5]=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1
Reactant: O=C1OCCO1
Reactant: Oc1ccc(-n2nc3ccccc3n2)c(O)c1
Agent: C[N+](C)(C)C
Agent: O=C=O
Agent: [Cl-]
Solvent: O
Product: OCCOc1ccc(-n2nc3ccccc3n2)c(O)c1
Temperature: 155 °C

Procedure:
A mixture of 45.4 g (0.2 mole) of 2-(2',4'-dihydroxyphenyl)benzotriazole, 19.8 g (0.225 mole) of ethylene carbonate and 0.55 g (0.005 mole) of tetramethylammonium chloride was heated under argon while stirring in an oil bath. The mixture changed to a brown melt as the temperature rose to 140° C. The argon gas flow was stopped at this point and the temperature was raised to 155° C. After the evolution of carbon dioxide stopped (7-8 hours), the reaction mixture was cooled to about 100° C. and then within 5 minutes 150 mL of water was added while stirring. The mixture was cooled to room temperature while stirring, at which point the semi-solid looking product crystallized. After suctioning off the solid, washing with water, and drying; 2-[2'-hydroxy, 4'-(2"-hydroxyethoxy)phenyl]benzotriazole was obtained having purity of 98% (HPLC). Yield: 51.5 g (95% of the theoretical).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1Cl.[CH3:12][CH:13]([CH3:16])[CH2:14][SH:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1[S:15][CH2:14][CH:13]([CH3:16])[CH3:12]
Reactant: CC(C)CS
Reactant: O=C(O)c1ccc(Br)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)CSc1nc(C(=O)O)ccc1Br
Temperature: 150 °C
Reaction time: 24 h
Yield: 101.4 %

Procedure:
5-Bromo-6-chloropicolinic acid (2 g, 8.46 mmol; CAN 959958-25-9), 2-methylpropane-1-thiol (915 mg, 1.1 mL, 10.2 mmol) and cesium carbonate (6.89 g, 21.1 mmol) were suspended in DMSO (100 mL). The reaction mixture was heated to 150° C. and stirred for 1 d and was poured onto ice-water/1N HCl (100 mL). The aqueous layer was extracted with EtOAc (2×250 mL). The combined extracts were washed with ice-water/brine (100 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound (2.49 g, 51%) as an orange solid which was used in the next step without further purification. MS (EI): m/e=288.4 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14](=[O:15])[CH:13](C(OC)=O)[CH2:12][N:6]3[C:7]=2[CH:8]=[C:9]([F:11])[CH:10]=1.Cl.O>CCO>[Br:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14](=[O:15])[CH2:13][CH2:12][N:6]3[C:7]=2[CH:8]=[C:9]([F:11])[CH:10]=1
Reactant: COC(=O)C1Cn2c(cc3c(Br)cc(F)cc32)C1=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C1CCn2c1cc1c(Br)cc(F)cc12
Yield: 88.2 %

Procedure:
To a solution of the ketoester of Step 5 (4 g) in EtOH (150 mL) r.t. was added 40 mL of concentrated HCl. The reaction mixture was stirred at reflux for 1 hour and water was added. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were concentrated The residue was swished in EtOAc/Hexanes to provide 2.9 g of the title compound as a pale yellow solid.