Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(C)C)(C)C.[Br:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[OH:11]>>[Br:8][CH2:9][C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[OH:11]
Reactant: OC(CBr)c1cccc(Cl)c1
Solvent: CC(C)OC(C)C
Product: O[C@@H](CBr)c1cccc(Cl)c1

Procedure:
Diisopropyl ether was added to a mixture of 100 mg (0.4 mmol) of 2-bromo-1-(3-chlorophenyl)ethanol, 20 mg of TOYOCHIMU LIP (available from Toyobo Co., Ltd.) and 0.3 mmol of each of the various acid anhydrides shown in Table 3 was to make the total volume to 1 ml. These reaction mixtures were respectively allowed to undergo reaction at a temperature of 27° C. for 98 hours. The results are set forth in Table 3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH:9]1[CH:13]=[C:12]([CH:14]=[O:15])[N:11]=[CH:10]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[C:12]([CH:14]=[O:15])[N:11]=[CH:10]2)=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: O=Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cn(-c2ccc(Br)cn2)cn1
Temperature: 70 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
A mixture of 5-bromo-2-fluoropyridine (630 mg, 3.58 mmol), 4-imidazolecarboxaldehyde (355 mg, 3.70 mmol) and K2CO3 (1.00 g, 7.25 mmol) in DMF (10 mL) was stirred at 70° C. overnight. After being cooled down, H2O was added to induce precipitation. The precipitate was collected and dried on vacuum to give 1-(5-bromopyridin-2-yl)-1H-imidazole-4-carbaldehyde (738 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:12])=[CH:4][CH:3]=1.[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.C([Li])CCC>C1COCC1>[Cl:12][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([B:13]([OH:18])[OH:14])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Clc1nccc2ccc(Br)cc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2ccnc(Cl)c2c1
Temperature: -20 °C
Yield: 66.8 %

Procedure:
7-Bromo-1-chloroisoquinoline (1.38 g, 5.69 mmol) in THF (15 mL) under nitrogen, at −78° C. and triisopropyl borate (2.99 g, 15.93 mmol) added, followed by dropwise addition of n-butyllithium (7.11 mL of 1.6M in hexanes, 11.38 mmol). Allowed reaction mixture to warm to −20° C. over 30 minutes and quenched with 1N HCl (30 mL). Added triethylamine to give pH 7, presorbed solution directly onto silica and flash column chromatography on silica gel to give the product as pale yellow solid (0.78 g, 3.8 mmol). 1H NMR (DMSO) δ 8.73 (s, 1H), 8.48 (br s, 2H), 8.35-8.28 (m, 1H), 8.25-8.13 (m, 1H), 8.06-7.92 (m, 1H), 7.91-7.82 (m, 1H). ESI MS (M+1)+: 208, 210 (Cl).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=2[N+:24]([O-])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl.O>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=2[NH2:24])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc([N+](=O)[O-])c(N2CCN(C(=O)OCc3ccccc3)CC2)c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc(N)c(N2CCN(C(=O)OCc3ccccc3)CC2)c1
Yield: 92.4 %

Procedure:
4-(5-Methyl-2-nitro-phenyl)-piperazine-1-carboxylic acid benzyl ester (5.60 g; 15.7 mmol) and SnCl2.H2O (17.5 g; 77.6 mmol) were refluxed in 100 mL ethanol for 2½ hours. Ethanol was removed in vacuo. The residue was poured into 300 mL saturated NaHCO3. The mixture was extracted with ethyl acetate (2×250 mL). The organic phase was washed with brine (2×100 mL), dried with MgSO4, filtered through a pad of silica and concentrated in vacuo to give 4.71 g (14.5 mmol; 91.6%) 4-(2-amino-5-methyl-phenyl)-piperazine-1-carboxylic acid benzyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([NH2:14])=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:23][C:24](=O)[CH3:25]>C(OCC)(=O)C>[NH2:13][C:12]1[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH:23]=[C:24]([CH3:25])[N:14]=1
Reactant: CC(=O)CCl
Reactant: N=C(N)NC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cn(C(=O)OCc2ccccc2)c(N)n1
Temperature: 50 °C
Reaction time: 10 h
Yield: 21.6 %

Procedure:
A mixture of N-benzyloxycarbonylguanidine 1.93 g (10 mmol), triethylamine 1.39 ml (10 mmol), chloroacetone 2.40 ml (30 mmol) and ethyl acetate 40 ml was stirred at 50° C. for 10 hours. The reaction solution was washed with water and an aqueous sodium chloride solution and dried on magnesium sulfate. After evaporation of the solvent, the residue was purified by a column chromatography on silica gel and further recrystallized from n-hexane to give 500 mg of the title compound (yield: 22%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:15][N:16]2[C:24]3[CH:23]=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[C:18]3[CH2:26][N:27]([CH3:30])[CH2:28][CH2:29][C:17]2=3)=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H][H]>CCO.[Pd]>[CH3:30][N:27]1[CH2:28][CH2:29][C:17]2[N:16]([CH2:15][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:24]3[CH:23]=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[C:18]=2[CH2:26]1
Reactant: CCOC(=O)C=C(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl 3-(4-fluorophenyl)-4-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)but-2-enoate (112 mg, 0.275 mmol) in EtOH (5 mL) was added 20 mg of 10% Pd/C. The reaction mixture was stirred at RT under a hydrogen atmosphere at 60 psi for 24 h. The hydrogen pressure was released and the reaction mixture was filtered through Celite, the catalyst rinsed with EtOH and the filtrate evaporated under reduced pressure to obtain the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH2:19]([N:21]([CH2:35][CH3:36])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][CH:28]=1)=[O:26])[CH3:20]>C(O)C.N1CCCCC1>[CH2:35]([N:21]([CH2:19][CH3:20])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:13][C:12]2=[O:18])[NH:29][CH:28]=1)=[O:26])[CH3:36]
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Reactant: CCN(CC)CCNC(=O)c1c[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(OC)cc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.5 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (90.4 mg, 76.5%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[O:21])=[CH:14][C:13]=3[N+:35]([O-:37])=[O:36])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[C:38]([OH:44])([C:40](F)(F)F)=[O:39].BrCC(OC(C)(C)C)=O>C(Cl)Cl.C(#N)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][N:25]([CH2:40][C:38]([OH:44])=[O:39])[CH2:24][CH2:23]4)=[O:21])=[CH:14][C:13]=3[N+:35]([O-:37])=[O:36])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c([N+](=O)[O-])c2)CC1
Agent: CC(C)(C)OC(=O)CBr
Solvent: CC#N
Solvent: ClCCl
Product: O=C(O)CN1CCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c([N+](=O)[O-])c2)CC1

Procedure:
The title compound was prepared by deprotection of the compound of Example 205 with TFA in CH2Cl2. The resultant free amine was treated with tert-butyl bromoacetate and TEA in acetonitrile at room temperature, and followed by deprotection with TFA in CH2Cl2, giving a light solid, mp 120° C. (dec.). 1H NMR (DMSO-d6, 300 MHz) δ 3.20-3.45 (m, 4H), 4.20 (s, 2H), 3.50-3.80 (m, 4H), 4.28-4.46 (m, 4H), 6.86 (d, J=8.5 Hz, 1H), 7.04 (m, J=8.0 Hz, 1H), 7.09 (dd, J=2.0 8.0 Hz, 1H), 7.15 (d, J=2.0 Hz, 1H), 7.40 (d, J=15.5 Hz, 1H), 7.56 (d, J=15.0 Hz, 1H), 7.90 (dd, J=2.0, 8.5 Hz, 1H), 8.63 (m, 1H). MS (ESI) m/z 484 (M−H)+, 486 (M+H)+. Calcd. Anal for C23H21N3O7S.1.19CF3COOH.1.34H2O: 47.63; H, 4.11; N, 6.89. Found: C, 47.93; H, 4.51; N, 6.49.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:13])=[N:9][CH:10]=[CH:11][CH:12]=1)(=O)=O.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:13][C:8]1[C:7]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Cc1ncccc1OS(=O)(=O)C(F)(F)F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncccc1C#C[Si](C)(C)C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
First, 2-methylpyridin-3-yl trifluoromethanesulfonate (34.3 g, 142 mmol), trimethylsilylacetylene (30 ml, 212 mmol), bis(triphenylphosphine)palladium (II) chloride (10.0 g, 14.2 mmol), and copper (I) iodide (2.75 g, 14.4 mmol) were dissolved in N,N-dimethyl formamide (150 ml). Thereafter, triethylamine (43 ml, 309 mmol) was added in a nitrogen atmosphere at room temperature to the mixture. The mixture was then stirred for 3 hours (exothermic reaction took place). The reaction mixture was separated by ethyl acetate and a saturated aqueous ammonium chloride solution and insoluble substance was removed by filtration. The organic layer of the filtrate was washed twice with a saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtrated and concentrated to obtain the title compound (22.6 g, yield: 84.1%) as brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[F:11])[C:5](O)=[O:6].S(Cl)([Cl:15])=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[F:11])[C:5]([Cl:15])=[O:6]
Reactant: O=C(O)c1cc(Cl)c(F)c(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Cl)c(F)c(Cl)c1

Procedure:
3,5-dichloro-4-fluorobenzoic acid was refluxed with >1 equivalent of thionyl chloride and one drop of DMF neat or as a solution in CDCl3. The solvent and volatile by-products were removed in vacuo to provide 3,5-dichloro-4-fluorobenzoyl chloride.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:11]1([CH3:20])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O.[Pd].CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+]>[CH3:20][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: O=C(O)c1cccc(Cl)c1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: O
Product: Cc1ccccc1-c1cccc(C(=O)O)c1
Yield: 95.6 %

Procedure:
Using 0.1 mol % Pd. The general procedure described in Example 3 was used with 3-chlorobenzoic acid (157 mg, 1.00 mmol), o-tolylboronic acid (163 mg, 1.20 mmol), K2CO3 (345 mg, 2.50 mmol), water (1.5 mL), Pd/L solution (0.200 mL of a Pd(OAc)2 (1.1 mg, 0.005 mmol, 0.5 mol %), sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (5.0 mg, 0.010 mmol, 1 mol %) solution in 1.0 mL water), 6 h, 100° C. The product was isolated as a white solid (203 mg, 96%). Mp=127° C. 1H NMR (400 MHz, CDCl3) δ: 12.9 (br-s, 1H), 8.01 (m, 2H), 7.46 (d, 1H, J=7.6 Hz), 7.40 (t, 1H, J=7.6 Hz), 7.20-7.14 (m, 4H), 2.17 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 172.8, 142.5, 140.8, 135.5, 134.8, 131.1, 130.7, 129.9, 129.4, 128.8, 128.5, 127.9, 125.2, 20.6. IR (neat, cm−1): 2962, 1689, 1309, 1258, 747. Anal. Calcd for C14H12O2: C, 79.22; H, 5.70. Found: C, 79.12; H, 5.62.
Reaction SMILES: [OH:1][C:2]([C:15]([F:18])([F:17])[F:16])([CH2:5][C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[CH:3]=O.[NH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[N:23][NH:24]2.[Cl-].[Na+]>C1(C)C=CC=CC=1.[Ti]>[F:16][C:15]([F:18])([F:17])[C:2]([CH:3]=[N:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[N:23][NH:24]2)([OH:1])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:14])[CH3:7]
Reactant: Nc1cccc2[nH]ncc12
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1ccccc1
Agent: [Ti]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(CC(O)(C=Nc1cccc2[nH]ncc12)C(F)(F)F)c1ccccc1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 101.2 %

Procedure:
130 mg (0.50 mmol) of 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)-pentanal is dissolved in 15 ml of toluene and mixed with 73 mg (0.55 mmol) of 4-amino-indazole and with 0.22 ml of titanium tetraethylate and stirred at 100° C. for 2.5 hours under argon. For working-up, the reaction solution is mixed with 1 ml of saturated sodium chloride solution, and it is stirred for 30 minutes. The suspension is then suctioned off on Celite and washed with 200 ml of ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in a vacuum: 246 mg. Column chromatography on silica gel with pentane-ethyl acetate yields 190 mg of the product.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[CH3:59][O:60][C:61]1[CH:69]=[C:68]([O:70][CH3:71])[CH:67]=[CH:66][C:62]=1[C:63](Cl)=[O:64]>>[CH3:59][O:60][C:61]1[CH:69]=[C:68]([O:70][CH3:71])[CH:67]=[CH:66][C:62]=1[C:63]([NH:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:39][CH:40]=1)=[O:64]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(OC)cc4OC)cc3)cc2C1=O
Yield: 73 %

Procedure:
The compound of example 155 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 2,4-dimethoxy benzoyl chloride.
Reaction SMILES: C1C(C#N)=CC=[C:3]([CH:9](N2N=CN=C2)[C:10]2[CH:11]=[CH:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=2)C=1.BrCC1C=CC(C#N)=CC=1.[NH:33]1[CH:37]=[N:36]C=[N:34]1>>[NH:33]1[CH:37]=[N:36][C:3]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)=[N:34]1
Reactant: N#Cc1ccc(C(c2ccc(C#N)cc2)n2cncn2)cc1
Reactant: c1nc[nH]n1
Agent: N#Cc1ccc(CBr)cc1
Product: N#Cc1ccc(Cc2nc[nH]n2)cc1

Procedure:
U.S. Pat. No. 4,978,672 (“the '672 patent”) describes a process for preparing letrozole by reacting α-bromo-4-tolunitrile with 1,2,4-triazole to produce 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile, and reacting the product with 4-fluorobenzonitrile to obtain letrozole.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH2:20][C:21](O)=[O:22])([C:17](O)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][NH3+:26].[Cl-].C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2([C:17](=[O:18])[N:26]([O:25][CH3:24])[C:21](=[O:22])[CH2:20]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC1(C(=O)O)CCN(C(=O)OCc2ccccc2)CC1
Reactant: CO[NH3+]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON1C(=O)CC2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
To a solution of (1-benzyloxycarbonyl-4-carboxypiperidin-4-yl)acetic acid (3.64 g) in dimethylformamide (30 ml) dicyclohexylcarbodiimide (2.57 g) was added, and this was followed by stirring at room temperature for 30 minutes. o-Methylhydroxylamine hydrochloride (0.95 g) and triethylamine (1.56 ml) were then added, and this was followed by stirring at room temperature for 30 minutes. The resulting precipitates were removed, and the solvent was evaporated under reduced pressure. To the resulting residual oily compound acetic anhydride (20 ml) and anhydrous sodium acetate (0.39 g) were added, and this was followed by stirring at 100° C. for 30 minutes. After the completion of the reaction, the solvent was removed, and the residual oil was dissolved in 50 ml ethyl acetate. The resulting solution was sequentially washed with a saturated aqueous solution of sodium hydrogencarbonate, 1N hydrochloric acid and water, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure; the resulting residual solid was recrystallized from ethyl ether-petroleum ether to obtain 2.1 g of a colorless crystal having a melting point of 98° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:34][C:35]1[CH:36]=[C:37]([CH:40]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:42]=1)[C:38]#[N:39]>>[CH3:1][O:2][C:3](=[O:33])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=2)[CH:12]=[C:13]([C:41]2[CH:40]=[C:37]([C:38]#[N:39])[CH:36]=[C:35]([F:34])[CH:42]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CC1(C)OB(c2cc(F)cc(C#N)c2)OC1(C)C
Product: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cc(F)cc(C#N)c2)c1
Yield: 21 %

Procedure:
The title compound was prepared in 21% yield from 4-methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid methyl ester (prepared in Example 26, step (f)) and 3-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile under the conditions described in Example 26, step (d).
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[S:27][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:29][N:30]=4)=[O:25])=[CH:19]C=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5].[NH2:39]C1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=NC=1.C1(C2SC(C(OCC)=O)=NC=2)C=CC=CC=1>>[CH3:1][CH:2]([CH3:38])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[S:27][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:29][N:30]=4)=[O:25])=[CH:19][N:39]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cn3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cc3)cc2C1=O
Agent: CCOC(=O)c1ncc(-c2ccccc2)s1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cn3)cc2C1=O
Yield: 39 %

Procedure:
The compound of example 636 was prepared analogous to the compound of example 611 by reaction of compound of example 392 with ethyl 5-phenylthiazole-2-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]([OH:19])[C@H:9]([N:20]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:21][C:22]3[N:23]=[N:24][N:25]([CH3:27])[N:26]=3)[C:8]=2[CH:35]=1)([O-])=O.[BH4-].[Na+].C(OCC)(=O)C>CO.CC([O-])=O.CC([O-])=O.[Cu+2]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:14][CH3:15])[O:16][CH3:17])[C@@H:10]([OH:19])[C@H:9]([N:20]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[CH2:21][C:22]3[N:23]=[N:24][N:25]([CH3:27])[N:26]=3)[C:8]=2[CH:35]=1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H](N(Cc2nnn(C)n2)c2ccc(Cl)cc2)[C@@H]1O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(OC)[C@@]1(C)Oc2ccc(N)cc2[C@@H](N(Cc2nnn(C)n2)c2ccc(Cl)cc2)[C@@H]1O
Reaction time: 1 h
Yield: 67 %

Procedure:
(2S,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran obtained in the example 1 (100 mg, 0.2 mmol) was dissolved in methanol (2 ml), thereto Cu(OAc)2 aqueous solution (0.38 ml, 0.4 M aqueous solution, 0.15 mmol) was added. Sodium borohydride (NaBH4) (113 mg, 3.0 mmol) was slowly added to the solution for 30 min at room temperature, the reaction mixture was stirred for 1 hours, thereafter ethyl acetate (5 ml) was added to the reaction mixture. The resulting mixture was filtered to remove precipitated black solid. Saturated NaHCO3 aqueous solution (5 ml) was added to the filtrate, and extracted with ethyl acetate (30 ml). The organic layer was washed with saturated brine solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=1:3), to give desired compound, the compound that R1 is substituted to amino group (62 mg, yield: 67%).
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C.O>[CH2:23]([O:22][CH2:21][CH2:20][O:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:24][CH3:25]
Reactant: CCCOCCCl
Reactant: Oc1cccc2ccoc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOCCOc1cccc2ccoc12
Temperature: 95 °C
Reaction time: 72 h

Procedure:
To a solution of 7-hydroxybenzofuran (2.609) in DMF (70 ml) were added potassium carbonate (6.97 g) and sodium iodide (7.55 g) and then was added 2-chloroethylpropylether (4.76 g), and the mixture was stirred, under nitrogen atmosphere, at 95° C. for 3 days and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water (three times) and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography to give brown oil of 7-propoxyethoxybenzofuran (3.76 g).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:12]([Mg]Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Br)C1C=CC=CC=1.[Mg].[Cl-].[NH4+]>CC(P(C1C=CC=CC=1)C1C=CC=CC=1)C.C1C=CC(PC2C=CC=CC=2)=CC=1.[Cl-].[Ni].C(OCC)C.O1CCCC1>[CH2:12]([C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: COCOc1cccnc1Br
Agent: [Ni]
Agent: BrCc1ccccc1
Agent: CC(C)P(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCOc1cccnc1Cc1ccccc1

Procedure:
While stirring a mixture of 35 g of 2-bromo-3-methoxymethyloxypyridine, 5 g of 1,3-bis(diphenylphosphino)propanenickel (II) chloride and 200 ml of tetrahydrofuran under ice-cooling, a diethyl ether solution of benzylmagnesium bromide prepared from 38 ml of benzyl bromide, 8 g of magnesium and 250 ml of anhydrous diethyl ether was slowly added dropwise thereinto under nitrogen atmosphere. After stirring for 4.5 hours, a saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (8–20% ethyl acetate/hexane), to give 27 g of the title compound.