Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)[CH3:5].C(=O)([O-])[O-].[K+].[K+].[Cl:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29]>C1C=CC=CC=1>[ClH:25].[CH3:1][N:2]([CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)[CH3:5])[CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29]
Reactant: CNCC(C)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CC(C)=CCN(C)CC(C)c1cccc(Oc2ccccc2)c1
Product: Cl
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 23.9 g. of N-Methyl-2-(3-phenoxyphenyl)propylamine, prepared according to the method of Example 20, and 13.8 g. of potassium carbonate in benzene was treated with 20.8 g. of 1-chloro-3-methyl-2-butene. The reaction mixture was refluxed with mechanical stirring for about 60 hours. After cooling to room temperature, the reaction was washed with water and extracted with dilute hydrochloric acid. The acidic extract was basified with sodium hydroxide solution and extracted with ether. The ether extract was washed twice with water and dried over sodium sulfate. Dry hydrogen chloride gas was passed into the ethereal solution and the resulting precipitated hydrochloride salt was filtered and recrystallized from an alcohol-ether mixture to yield 11.5 g. of the titled product, m.p. 120°-122°C., pK'a 8.5.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].Cl.[NH2:18][OH:19]>CC(O)C.C(OCC)(=O)C>[OH:19]/[N:18]=[C:8](\[NH2:9])/[C:7]1[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][OH:1])=[CH:11][CH:10]=1
Reactant: N#Cc1ccc(CCO)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: N/C(=N\O)c1ccc(CCO)cc1
Temperature: 80 °C
Yield: 49 %

Procedure:
To a mixture of 4-(2-hydroxyethyl)benzonitrile (500mg, 3.40 mmol) and sodium bicarbonate (1427 mg, 16.99 mmol) in 2-propanol (50 mL) was added hydroxylamine hydrochloride (472 mg, 6.79 mmol). The reaction mixture was heated at 80° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried MgSO4, filtered, and concentrated to yield 300 mg of (Z)—N′-hydroxy-4-(2-hydroxyethyl)benzimidamide. MS (m+1)=181. HPLC Peak RT=0.13 minutes. (Analytical Method B).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]#[N:12])[CH:5]=1.CCN(CC)CC.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:23])=[O:21])=[C:6]([C:11]#[N:12])[CH:5]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
3-cyano-4-hydroxybenzoic acid methyl ester from example 51, step 1 (2 g, 11.3 mmol) was dissolved in CH2Cl2 (57 ml) and cooled to 0° C. in an ice bath. The mixture was treated with Et3N (3 ml, 22.6 mmol) followed by the addition of Tf2O (1.9 ml, 11.3 mmol). The reaction mixture was warmed to room temp. and stirred for 4 hours. Saturated NaHCO3 (10 mL) was added and the mixture was extracted with EtOAc (2×10 mL). The organic layers were combined and dried (MgSO4), filtered, and concentrated. The residue was then purified by flash chromatography (15% EtOAc/Hexane) to yield the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]2[N:15]=[C:16]([CH2:25][O:26][CH2:27][CH3:28])[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:4]2[N:3]=1.CCN(C(C)C)C(C)C.[NH:38]1[CH2:42][CH2:41][CH2:40][C@H:39]1[CH2:43][OH:44]>C(#N)C>[CH2:27]([O:26][CH2:25][C:16]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[C:4]2[N:3]=[C:2]([N:38]3[CH2:42][CH2:41][CH2:40][C@H:39]3[CH2:43][OH:44])[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[N:5]2[N:15]=1)[CH3:28]
Reactant: CCOCc1nn2c(-c3ccc(F)cc3)cc(Cl)nc2c1-c1ccc(C)cc1
Reactant: OC[C@@H]1CCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOCc1nn2c(-c3ccc(F)cc3)cc(N3CCC[C@H]3CO)nc2c1-c1ccc(C)cc1

Procedure:
5-Chloro-2-(ethoxymethyl)-7-(4-fluorophenyl)-3-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine (22 mg), DIPEA (0.1 mL) and (S)-2-pyrrolidinemethanol (0.1 mL) are stirred for 2 hours in an acetonitrile (7 mL) solvent at 84° C. The reaction solvent is removed by distillation under reduced pressure. The remainder is purified by column chromatography to yield the target compound (24 mg).
Reaction SMILES: [CH2:1]([C:3]1([OH:17])[CH2:8][CH2:7][CH:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5][CH2:4]1)[CH3:2].[ClH:18].O1CCOCC1>O1CCOCC1>[ClH:18].[NH2:9][CH:6]1[CH2:7][CH2:8][C:3]([CH2:1][CH3:2])([OH:17])[CH2:4][CH2:5]1
Reactant: CCC1(O)CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCC1(O)CCC(N)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of tert-butyl (4-ethyl-4-hydroxycyclohexyl)carbamate (Preparation Example 246) (0.202 g) and dioxane (2 mL), 26% hydrogen chloride-dioxane (1.1 mL) was added under ice cooling and stirred at room temperature for 12 hours. The solvent was distilled off to give 4-amino-1-ethylcyclohexanol hydrochloride (0.140 g) as a white viscous solid.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].C[Zn]C.[C:9]([O:12][C@@H:13]1[CH2:17][C:16](=[O:18])[CH:15]=[CH:14]1)(=[O:11])[CH3:10]>CCOCC.C1(C)C=CC=CC=1.C1COCC1>[C:9]([O:12][C@H:13]1[C@H:14]([CH2:1][CH2:2][CH3:3])[CH2:15][C:16](=[O:18])[CH2:17]1)(=[O:11])[CH3:10]
Reactant: CCC[Mg]Cl
Reactant: CC(=O)O[C@H]1C=CC(=O)C1
Agent: C[Zn]C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC[C@@H]1CC(=O)C[C@H]1OC(C)=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Propylmagnesium chloride (15.7 ml of a 2M solution in ether, 31.4 mmol) was added slowly to a stirred solution of dimethylzinc (15.7 ml of a 2M solution in toluene, 31.4 mmol) in THF (80 ml) under argon at 0° C. After 30 minutes, the mixture was cooled to −78° C. and (R)-4-acetoxycyclopent-2-enone (4.0 g, 28.5 mmol) in THF (45 ml) was added dropwise over 1 hour. The reaction mixture was stirred for a further 20 minutes and then quenched by the addition of saturated ammonium chloride solution (20 ml). The reaction mixture was allowed to warm to room temperature, diluted with 1N hydrochloric acid (100 ml) and extracted with ether (3×200 ml). The organic layer was washed with brine (200 ml), dried (MgSO4) and the solvent was removed under reduced pressure to yield the acetoxy cyclopentanone 1 as a solution in toluene which was used without further purification in the next step. νmax(film)/cm−1 1740 (C═O).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[C:53]([CH3:58])=[N:54][CH:55]=[CH:56][CH:57]=2)[C:47]1=[O:59])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[C:53]([CH3:58])=[N:54][CH:55]=[CH:56][CH:57]=2)[C:47]1=[O:59])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: Cc1ncccc1CN1CCN([C@H](C(=O)O)C(C)(C)C)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccnc2C)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.3 %

Procedure:
A solution containing the product from Example 2C (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 82A (0.025 g, 0.082 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.033 mL, 0.189 mmol) and the mixture was stirred at 25° C. for 16 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed brine, dried over MgSO4, filtered and concentrated to give the title compound (0.016 g, 52% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.83 (s, 9 H), 0.89 (s, 9 H), 1.26 (m, 2 H), 1.54 (m, 2 H), 2.32 (m, 1 H), 2.61 (m, 4 H), 2.81 (m, 2 H), 2.96 (q, J=8.95 Hz, 1 H), 3.21 (m, 1 H), 3.50 (s, 3 H), 3.66 (m, 1 H), 3.85 (d, J=9.93 Hz, 1 H), 4.08 (s, 1 H), 4.21 (m, 3 H), 4.42 (m, 1 H), 4.55 (d, J=7.72 Hz, 1 H), 6.65 (d, J=9.93 Hz, 1 H), 7.00 (m, 3 H), 7.10 (m, 2 H), 7.24 (m, 3 H), 7.31 (m, 1 H), 7.54 (m, 2 H), 7.87 (m, 5 H), 8.38 (dd, J=4.78, 1.47 Hz, 1 H), 8.64 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[F:7][C:8]1[C:9]([C:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CC(O)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(O)C#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (28.5 mg, 0.34 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.135 mmol) (Starting Material 3 supra) using (Ph3P)2PdCl2 (9.5 mg) and Cul (2.6 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give rac-(Z)-1,3-dihydro-5-fluoro-4-(3-hydroxy-1-pentynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 17 mg, 39%).
Reaction SMILES: C(O[C:4]([C:6]1[C:15](=S)[C:14]2[C:9](=[C:10]([Cl:17])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=2)[N:7]=1)=[O:5])C.N([C@H]1[C@H](O)CCOC1)N.[NH:39]([C@@H:41]1[CH2:46][CH2:45][O:44][CH2:43][C@H:42]1[OH:47])[NH2:40].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[Cl:17][C:10]1[C:9]2[N:8]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH:29]=[CH:28][CH:27]=[N:26]4)=[CH:23][CH:24]=3)[N:7]=[C:6]3[C:4](=[O:5])[N:39]([C@@H:41]4[CH2:46][CH2:45][O:44][CH2:43][C@H:42]4[OH:47])[N:40]=[C:15]3[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: NN[C@@H]1CCOC[C@H]1O
Reactant: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2c(Cl)cccc2c1=S
Agent: NN[C@@H]1COCC[C@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: O=c1c2nn(Cc3ccc(-n4cccn4)cc3)c3c(Cl)cccc3c-2nn1[C@@H]1CCOC[C@H]1O
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
Ethyl-8-chloro-1-[4-(1H-pyrazolo-1-yl)benzyl]-4-thioxo-1,4-dihydrocinnoline-3-carboxylate [(Example 60, Step 4) 188 mg, 0.442 mmol] was dissolved in 1,2-dimethoxyethane (1.5 mL) and treated with a mixture of (±)-trans-3-hydrazinotetrahydro-2H-pyran-4-ol and (±)-trans-4-hydrazinotetrahydro-2H-pyran-3-ol (117 mg, 0.885 mmol, 2 equiv) and potassium carbonate (183 mg, 1.327 mmol, 3 equiv). The mixture was placed into an oil bath preheated to 90° C. for 35 minutes, cooled to ambient temperature, diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed once with brine, dried with sodium sulfate; filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate), providing an inseparable mixture of regioisomers, which was further purified by chiral HPLC (Chiralcel OJ Column, 100% methanol) to produce a first-, second-, and third-eluting peak. The first-eluting peak was determined to the titled compound (enantiopure, relative trans stereochemical configuration), of which the absolute stereochemistry is unknown: 1H-NMR (400 MHz, CDCl3) δ 8.22 (1H, d, J=8.1 Hz), 7.87 (1H, s), 7.71-7.59 (4H, m), 7.46 (1H, t, J=8.1 Hz), 7.29-7.20 (2H, m), 6.44 (1H, s), 6.33 (2H, s), 4.52-4.43 (1H, m), 4.26-4.17 (2H, m), 4.11-4.04 (1H, m), 3.55 (1H, t, J=12.0 Hz), 3.32 (1H, t, J=10.3 Hz), 2.32-2.19 (1H, m), 2.14-2.06 (1H, br d J=12.4 Hz). ppm; low resolution mass spectrometry (ES+) m/z 477.3 [(M+H)+; calculated for C24H22ClN6O3: 477.5].
Reaction SMILES: [CH3:1][C:2]1[O:12][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Br:13][C:14]1[C:15]([Cl:21])=[C:16](F)[CH:17]=[CH:18][CH:19]=1>>[ClH:21].[Br:13][C:14]1[C:15]([Cl:21])=[C:16]([O:11][CH:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]3[O:12][C:2]([CH3:1])=[CH:3][C:4]2=3)[CH:17]=[CH:18][CH:19]=1
Reactant: Fc1cccc(Br)c1Cl
Reactant: Cc1cc2c(o1)CNCCC2O
Product: Cc1cc2c(o1)CNCCC2Oc1cccc(Br)c1Cl
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 2-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 44) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2-chloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: N1C=[CH:4][N:3]=[N:2]1.Br[CH:7]([C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1.[CH3:24][N:25](C=O)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:10]1[C:11]([C:14]#[N:15])=[CH:12][CH:13]=[C:8]([CH:7]([N:2]2[N:3]=[CH:4][N:25]=[CH:24]2)[C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[CH:9]=1
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(C(Br)c2ccc(C#N)cc2)cc1
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C(c2ccc(C#N)cc2)n2cncn2)cc1
Temperature: 60 °C
Yield: 65.7 %

Procedure:
A reactor was charged with triazole (104 g, 1.5 moles) and bromo-bis(4-cyanophenyl)methane (108 g, 0.6 mole) followed by addition of DMF (720 ml) and toluene (1080 ml), and the impeller speed was set at 800 RPM. The temperature was raised to 60° C. and potassium carbonate was added (83.5 g, 0.6 mole). Then, the temperature was raised to 80° C. and mixing was maintained at this temperature during about 1.5 hours. Then, air was bubbled at the same temperature for about 15 minutes at 3500 ml/minute air flow. An aliquot was withdrawn from the reaction mixture, diluted with a mixture of water and acetonitrile and injected to HPLC. The letrozole content was 73%, the isoletrozole content was 8.7% and the content of 4.4′-dicyano-benzophenone was 16.2%. After cooling to a temperature of 25° C., acetic acid (57.6 ml) was added. DMF (414 ml) and water (1760 ml) were added to the reaction mixture to form a suspension (two liquid phases and a solid inter-phase in between). After heating the suspension to 60° C. the resulting mixture was allowed to cool to 25° C. for one hour and then the mixture was cooled to 20° C. and mixed at that temperature for 2 hours. The precipitated crystals were washed with water (80 ml) and dried to obtain 112.3 g of crude letrozole in 65.7% yield, having a purity of 98.5% by HPLC, (containing 1.2% isoletrozole).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]([SH:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(C1C=CC(C)=CC=1)(O[CH2:27][CH2:28][O:29][CH3:30])(=O)=O>C1COCC1>[C:3]1([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[S:22][CH2:27][CH2:28][O:29][CH3:30])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
To sodium hydride (2.17 g, 0.09 mol) under nitrogen was added anhydrous THF (50 ml). The mixture was cooled to 0° C. and triphenylmethylmercaptan (24.88 g, 0.09 mol) in anhydrous THF (50 ml) added dropwise over 15 minutes. After a further 10 minutes at 0° C. the mixture was warmed to room temperature, at which it was stirred for 1 hour. The mixture was then recooled to 0° C. and ethylene glycol methyl ether tosylate (20.72 g, 0.09 mol) in dry THF (50 ml) added dropwise over 15 minutes. After warming to room temperature the mixture was left to stir for 16 hours. The mixture was filtered and the precipitate washed with dichloromethane. The combined filtrates were concentrated in vacuo. The residue was dissolved in dichloromethane, washed with water (3×50 ml), dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography (gradient from 100% petrol to 100% EtOAc) and recrystallisation (petrol) gave the title compound (12.39 g, 41%) as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][OH:8])=[NH:6].[C:12]1(=O)[O:17][C:15](=[O:16])[CH2:14][CH2:13]1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[O:8][N:7]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=C1CCC(=O)O1
Reactant: N=C(NO)c1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)CCc1nc(-c2cccc(Cl)c2)no1
Yield: 59.7 %

Procedure:
3-Chloro-N-hydroxy-benzamidine 4.52 g, 26.5 mmol) was heated with succinic anhydride (2.65 mg, 26.5 mmol) in DMF (5 ml) at 150° C. for an h. The reaction mixture was cooled down and diluted with ethyl acetate. The organic solution was washed with water and brine, concentrated by vacuum. The residue was triturated with 20% ethyl acetate in hexanes to give 4.0 g (60%) of 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid as white solid. ). 1H-NMR(CDCl3) d(ppm): 8.08 (s, 1H), 7.96 (d, 1H), 7.49 (d, 1H), 7.42 (t, 1H), 3.28 (t, 2H) and 3.04 (t, 2H). Step 2: 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid hydrazide: This acid was reacted with iodoethane (1.6 g, 10.5 mmol) and K2CO3 (1.46 10.5 mmol) in DMF (5 ml) for 5 min to form 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid ethyl ester. The ethyl ester was then treated with 37% hydrazine (2 ml) in ethanol (5 ml) at 80° C for2 h to give 595 mg (65% in 3 steps) of 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid hydrazide as off-white solid 1H-NMR (CDCl3) d(ppm): 8.07 (s, 1H), 7.96 (d, 1H), 7.49 (d, 1H), 7.43 (t, 1H), 7.00 (w, 1H), 3.95 (w, 2H), 3.34 (t, 2H) and 2.79 (t, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][NH:17]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:40][C:41](O)=[O:42])[CH:26]=[CH:27][C:28]=1[NH:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39])=[O:31]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:41](=[O:42])[CH2:40][C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])=[O:31])=[C:23]([O:22][CH3:21])[CH:24]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: CCOC(=O)c1ccc(OC[C@@H]2CCCN2)c(OC)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a stirred solution of ethyl (S)-3-methoxy-4-(2-pyrrolidinylmethoxy)benzoate (424 mg, 1.52 mmol) in DMF (8 mL) was added pentafluorphenyl ester of 3-methoxy-4-[N′-(2-methylphenyl) ureido]phenylacetic acid (728 mg, 1.52 mmol) and Et3 N (0.26 mL, 1.87 mmol). And the resulting mixture was stirred at room temp overnight. The mixture was diluted with EtOAc, washed with 1 N HCl, sat. NaHCO3, brine, and dried over MgSO4. The solvent was evaporated off in vacuo and the residue was purified by column chromatography on silica-gel with CHCl3-MeOH (50:1, v/v) as eluent to give 830 mg (95%) ethyl (S)-3-methoxy-4-[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenyl acetyl]-2-pyrrolidinyl methoxy]benzoate as an amorphous solid. 1H-NMR (CDCl3) δ 1.38 (t, 3 H, J=7.3 Hz), 1.88–2.20 (m, 4 H, m), 2.24 (m, 3 H), 3.44–3.50 (m, 1 H), 3.53–3.58 (m, 7 H), 3.82 (s, 3 H), 4.09–4.17 (m, 1 H), 4.22–4.25 (m, 1 H), 4.35 (q, 2 H, J=7.3 Hz), 4.38–4.49 (m, 1 H), 6.71–6.78 (m, 1 H), 6.99 (d, 1 H, J=8.3 Hz), 7.04–7.07 (m, 1H), 7.16–7.19 (m, 2 H), 7.49–7.66 (m, 3 H), 8.06 (d, 1 H, J=8.3 Hz).
Reaction SMILES: COC(=O)C.C[O:7][C:8](=O)[CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[C@@H:16]([CH3:30])[CH2:15][C@H:14]2[N:31]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:32](=[O:35])[CH2:33][CH3:34].[NH3:44]>CO>[C:8]([CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21](=[O:29])[C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[C@@H:16]([CH3:30])[CH2:15][C@H:14]2[N:31]([C:36]1[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=1)[C:32](=[O:35])[CH2:33][CH3:34])(=[O:7])[NH2:44]
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(OCC(=O)OC)cc21
Reactant: N
Solvent: COC(C)=O
Solvent: CO
Product: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(OCC(N)=O)cc21
Temperature: 25 °C

Procedure:
(±)-Cis-N-[6-carbamoylmethoxy-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-(4-chloro-phenyl)-propionamide was prepared from (±)-cis-4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yloxy]-acetic acid methyl ester. To solid (±)-cis-[4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yloxy]-acetic acid methyl ester (76 mg, 0.14 mmol) was added a solution of ammonia in methanol (2 M, 10 mL). The resulting solution was stirred over night at room temperature and concentrated. The resulting crude amide was purified by silica gel chromatography (100% hexanes—100% ethyl acetate gradient) to afford pure product (59 mg, 76%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[C:5]#[N:6].Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCO.CCOC(C)=O>[NH2:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(C#N)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(C#N)ccc1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
To a solution of 3-methyl-4-nitrobenzonitrile (2.0 g, 12.3 mmol) in 100 mL of EtOH is added SnCl2 (13.9 g, 61.7 mmol). The resulting solution is heated at reflux. After 2 h, the solution is cooled to ambient temperatures. The solution is poured into 150 mL of ice water. The pH of the solution is adjusted to >7 with a solution of saturated NaHCO3. The solution is diluted with EtOAc and the resulting mixture is filtered through Celite. The filtered solution is separated. The organic layer is dried over MgSO4, filtered and concentrated to give the title compound (1.57 g, 8.7 mmol) as an off-white solid.