Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[CH:12]12[NH:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][CH2:14][CH2:13]2.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH:16]12[N:19]([C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=3)[CH:12]([CH2:18][CH2:17]1)[CH2:13][CH2:14][CH2:15]2
Reactant: C1CC2CCC(C1)N2
Reactant: N#Cc1ccc(F)cc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1ccc(N2C3CCCC2CC3)cc1Cl
Temperature: 120 °C

Procedure:
2-Chloro-4-fluorobenzonitrile (0.97 g, 6.2 mmol), 8-aza-bicyclo[3.2.1]octane hydrochloride (0.92 g, 6.2 mmol), and N,N-diisopropylethylamine (1.6 g, 12 mmol) were combined in DMSO (15 mL) and heated at 120° C. for 16 hours. The mixture was allowed to cool to ambient temperature and partitioned between diethyl ether and saturated NaHCO3 solution. The aqueous phase was separated and extracted with diethyl ether. The organic layers were combined, washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)NC1CCNCC1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f1) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[C:3]([NH2:22])=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:28]#[C:29][C:30]([F:33])([F:32])[F:31])CCC>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:11]1([CH3:14])[CH:12]=[CH:13][C:8]([C:6]2[N:7]=[C:2]([C:28]#[C:29][C:30]([F:33])([F:32])[F:31])[C:3]([NH2:22])=[N:4][C:5]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:9][CH:10]=1
Reactant: CCCC[Sn](C#CC(F)(F)F)(CCCC)CCCC
Reactant: Cc1ccc(-c2nc(N)c(Br)nc2-c2ccc(C)cc2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(-c2nc(N)c(C#CC(F)(F)F)nc2-c2ccc(C)cc2)cc1
Temperature: 140 °C

Procedure:
A solution of 3-bromo-5,6-di-p-tolylpyrazin-2-amine (Ex 1, step 3) (200 mg, 0.565 mmol) in dioxane (4 ml) bubbled with nitrogen was treated with tributyl(3,3,3-trifluoroprop-1-ynyl)stannane (238 mg, 0.621 mmol) and PdCl2(dppf)-CH2Cl2-Adduct (46.1 mg, 0.056 mmol). The resulting mixture was heated at 140° C. for 1 hour using microwave radiation. After cooling to RT, the mixture was concentrated under reduced pressure. The crude residue was dissolved in DCM and loaded onto a 25 g Silica column. Purification by chromatography on silica eluting with 0-5% EtOAc in iso-hexane afford the title compound;
Reaction SMILES: Cl[C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[NH2:7][CH2:8][CH2:9][CH2:10][NH2:11].[O-]CC.[Na+]>C(O)C>[NH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:2]1[N:6]=[CH:5][NH:4][N:3]=1
Reactant: Clc1nc[nH]n1
Reactant: NCCCN
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NCCCNc1nc[nH]n1
Reaction time: 8 h

Procedure:
A mixture of 3-chloro-1,2,4-triazole (10.3 g., 0.1 m.) and 1,3-diaminopropane (7.4 g., 0.1 m.) in ethanol containing sodium ethoxide is allowed to stand overnight. The solvent is removed to give 3-(3-aminopropylamino)-1,2,4-triazole. This intermediate is reacted with methyl isothiocyanate give N-methyl-N'-[3-(3-(1,2,4-triazolyl)amino)propyl]thiourea.
Reaction SMILES: [C:1]1([C@@:7]2([CH3:29])[C:11](=[O:12])[N:10]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([O-])=[O:15])[C:9](=[O:21])[N:8]2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:30][C@H:31]([C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=1[O:48][CH3:49])[CH2:32][C:33]([O:35]C(C)(C)C)=[O:34].FC(F)(F)C(O)=O>>[C:1]1([C@@:7]2([CH3:29])[C:11](=[O:12])[N:10]([C@@H:13]([CH2:17][CH:18]([CH3:19])[CH3:20])[C:14]([NH:30][C@H:31]([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=3[O:48][CH3:49])[CH2:32][C:33]([OH:35])=[O:34])=[O:15])[C:9](=[O:21])[N:8]2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc([C@@H](N)CC(=O)OC(C)(C)C)c(OC)c1
Reactant: CC(C)C[C@@H](C(=O)[O-])N1C(=O)N(Cc2ccccc2)[C@@](C)(c2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc([C@H](CC(=O)O)NC(=O)[C@H](CC(C)C)N2C(=O)N(Cc3ccccc3)[C@@](C)(c3ccccc3)C2=O)c(OC)c1

Procedure:
(by reaction of 169.5 with tert-butyl (S)-3-amino-3-(2,4-dimethoxyphenyl)propionate and subsequent cleavage of the tert-butyl ester with trifluoroacetic acid)
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15].C1(NC2CCCCC2)CCCCC1.C(#N)C>[Cu]I.CCOCC>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[C:15]#[C:14][CH2:13][CH2:12][OH:16]
Reactant: C#CCCO
Reactant: Brc1ccc2ccccc2n1
Agent: [Cu]I
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CC#N
Solvent: CCOCC
Product: OCCC#Cc1ccc2ccccc2n1
Reaction time: 5 h

Procedure:
A mixture of 2-bromoquinoline (0.44 g), 3-butynol (0.2 ml), N,N-dicyclohexylamine (0.46 ml), BTPC (30 mg), copper (I) iodide (5 mg) and acetonitrile (10 ml) was stirred at 22° for 5 h. Ether (50 ml) was added, and the mixture filtered and evaporated in vacuo. The residue was purified by FCC eluting with ether followed by ether-methanol (19:1), to afford the title compound as a colourless solid (0.41 g). A small sample recrystallised from ethyl acetate-hexane had m.p. 89°-91°.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C:7](=[CH:9][CH:10]=O)[CH3:8])[CH3:3].[CH3:12][C:13]([CH3:15])=[O:14]>[Cu]=O.[O-2].[Zn+2]>[CH3:3][C:2]([CH3:1])=[CH:4][CH2:5][CH2:6]/[C:7](/[CH3:8])=[CH:9]/[CH:10]=[CH:12]/[C:13]([CH3:15])=[O:14]
Reactant: CC(C)=CCCC(C)=CC=O
Reactant: CC(C)=O
Agent: O=[Cu]
Agent: [O-2]
Agent: [Zn+2]
Product: CC(=O)/C=C/C=C(\C)CCC=C(C)C

Procedure:
50 Parts of citral and 100 parts of acetone are reacted for 45 minutes at 200° C and a pressure of 80 atmospheres in the presence of 12 parts of a catalyst consisting of 12% by weight of copper(II) oxide and 88% by weight of zinc oxide. 45.6 parts of pseudoionone having a boiling point of 90° C at 0.01 mm is obtained analogously to Example 1. The conversion is 82% of theory and the yield based on citral is 88% of theory.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH3:23])([CH3:22])[C:19]([NH2:21])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:30][C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1>>[CH3:22][C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:3][C:2]([N:32]4[C:33]5[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=5[N:35]=[C:31]4[CH3:30])=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)([CH3:23])[C:19]([NH2:21])=[O:20]
Reactant: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: Cc1nc2ccccc2[nH]1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1

Procedure:
2-(4-((2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide (0.15 g) was reacted with 2-methylbenzimidazole via General Procedure I for Buchwald coupling to give 29.3 mg 192 following reverse phase purification. MS (Q1) 535.2 (M)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:4]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][NH:31][C:32](=[O:34])[CH3:33].[H-].[Na+]>O1CCCC1>[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][N:31]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:4]=1)[C:32](=[O:34])[CH3:33]
Reactant: CC(=O)NCc1ccccn1
Reactant: CCCCCCCCCCCCCCOc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1cccc(CN(Cc2ccccn2)C(C)=O)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
The title compound is prepared by the procedure of Example 27 using 2.25 g of product from Example 25, 0.881 g of product from Example 12, 0.282 g of 50% sodium hydride and 30 ml of tetrahydrofuran. The reaction is stirred at 0° C. for I hour, room temperature for 18 hours and at reflux temperature for 6 hours. The residue is purified by column chromatography (silica gel: 90% ethyl acetate/hexane) to give 1.57 g of product as pale yellow crystals. Spectral data shows the product as 2 rotomers.
Reaction SMILES: CS(C)=O.[OH-:5].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[C:15]([F:18])([F:17])[F:16]>C(O)(C)(C)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([OH:5])=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:10]=1
Reactant: FC(F)(F)c1cc(Cl)ccc1Cl
Reactant: [OH-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Product: Oc1ccc(Cl)cc1C(F)(F)F
Reaction time: 24 h

Procedure:
To a 300 ml, 3-necked flask fitted with a stirrer, condenser, thermometer and drying tube is added dimethylsulfoxide (100 ml), tert-butanol (20 ml), powdered potassium hydroxide (KOH) pellets (85%, 30 g) and 2,5-dichlorobenzotrifluoride (21.5 g, 0.10 mole). The reaction mixture is warmed to 71°-73° C. for 60 hours, then additional KOH (10 g) is added and heating is continued at 73°-75° C. for 24 hours. The reaction mixture is cooled and the solvent partially removed by distillation at 0.9 mm, bp 55° C.). The cooled pot residue is then poured into ice water (1000 g) which had been preacidified to pH 1 with conc. HCl (50 ml). The aqueous mixture is extracted with carbon tetrachloride (CCl4), the CCl4 layer decanted and dried and the solvent removed under vacuum to afford 10.8 g of 4-chloro-2-trifluoromethylphenol, which is sublimed to afford pure product, mp 81°-81.5° C. Elemental Anal. Calcd for C7H4ClF3O: C, 42.75; H, 2.06; Cl, 18.04: Found: C, 42.54; H, 2.36; Cl, 18.16. ##STR14##
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:30][OH:31])=[C:19]([N:23]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:34])C.O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:30][OH:31])=[C:19]([N:23]3[CH:27]=[CH:26][C:25]([C:28]([NH2:29])=[O:34])=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4ccc(C#N)n4)c3CO)ncc2c1
Reactant: CCO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4ccc(C(N)=O)n4)c3CO)ncc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
In a 10 mL round-bottomed flask, 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-1H-pyrazole-3-carbonitrile (16 mg, 38.3 μmol, Eq: 1.00) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (1 mg, 2.33 μmol, Eq: 0.0608) were combined with ethanol (821 μl) and water (410 μl) to give a colorless solution. The reaction mixture was heated to 80° C. and stirred for 2 h. The reaction mixture was diluted with DCM. The reaction mixture was filtered through glass fiber paper. The crude material was purified by preparative HPLC to give 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrazole-3-carboxylic acid amide (11 mg, 66%, [M+H]+ 436) of lyophilized white solid.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:8][CH2:9][N:10]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]1([N:42]=[C:43]=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[C:30]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9][N:10]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[CH:15]=2)=[O:12])[CH:24]2[CH2:25][CH2:26][N:27]([C:43]([NH:42][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:44])[CH2:28][CH2:29]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)N(CCC(c1ccccc1)c1ccccc1)C1CCNCC1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N1CCC(N(CCC(c2ccccc2)c2ccccc2)C(=O)Nc2cccc(C(F)(F)F)c2)CC1
Reaction time: 2.5 h
Yield: 40 %

Procedure:
N-(3,3-diphenylpropyl)-N-(4-piperidinyl)-N′-[3-(trifluoromethyl)phenyl]urea (24 mg, 0.05 mmol) is dissolved in dichloromethane. Phenylisocyanate (9 mg, 0.075 mmol, 1.5 eq.) is added and the mixture is agitated for 2.5 hours. The aminomethyl resin (0.02 mmol) is added and the reaction is again agitated overnight. The resin is filtered, rinsed with dichloromethane and the filtrate is concentrated. The oil obtained is passed through a silica gel cartridge eluting with an equimolar mixture of heptane and ethyl acetate in order to obtain 12 mg (yield=40%) of a yellow oil after concentration.
Reaction SMILES: [I-].[CH3:2][O:3]/[N:4]=[C:5](\[C:10]1[CH:11]=[N+:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1)/[C:6]([F:9])([F:8])[F:7].CO.[BH4-].[Na+].O.CO>O>[CH3:2][O:3][N:4]=[C:5]([C:10]1[CH:15]=[CH:14][CH2:13][N:12]([CH3:16])[CH:11]=1)[C:6]([F:9])([F:7])[F:8]
Reactant: CO/N=C(\c1ccc[n+](C)c1)C(F)(F)F
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CON=C(C1=CN(C)CC=C1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
1-Methyl-3-(α,α,α-trifluoroacetyl)pyridinium-O-methyl oxime iodide (D10) (10.4 g, 0.030 mol) in a 1:1 mixture of water and methanol (20 ml) was added dropwise to a suspension of sodium borohydride (2.17 g, 0.057 mol) in 1:1 water/methanol (40 ml) at 0° C. The reaction mixture was maintained at 0° C. for 0.5 h then warmed to room temperature and stirred at this temperature for 1 h. The mixture was diluted with water (40 ml) and extracted with chloroform (3×100 ml). The combined organic extracts were dried (Na2SO4) and evaporated to give a gum which was chromatographed on silica using ethyl acetate as eluant to afford in order of elution 1-methyl-3-(α,α,α-trifluoroacetyl)-1,6-dihydropyridine-O-methyl oxime (3.65 g, 55%) as a mobile oil which rapidly became highly coloured and 1-methyl-3-(α,α,α-trifluoroacetyl)-1,2,5,6-tetrahydropyridine-O-methyl oxime (1.52 g, 23%) as a pale yellow mobile oil which consisted of a 14:1 mixture of E and Z isomers. A portion of this material (0.5 g, 0.0023 mol) was taken-up in benzene and irradiated (254 A) for 4 days. The benzene was removed in vacuo and the residue was filtered through silica using ethyl acetate as eluant to give a 3:1 mixture of E and Z isomers (0.25 g). Addition of oxalic acid gave a solid which was recrystallised twice from methanol/acetone to give the E isomer (0.12 g) m.p. 140°-143° C. The combined mother liquors were evaporated to give a solid which was a 1:1 mixture of E and Z isomers (E4) m.p. 103°-110° C.
Reaction SMILES: N1C=N[C:3]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=N1.[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1>C(#N)C.C(Cl)(Cl)Cl>[CH:13]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]([CH:6]([N:15]2[N:16]=[CH:17][N:18]=[CH:19]2)[C:3]2[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=2)[CH:14]=1
Reactant: N#Cc1ccc(Cc2nc[nH]n2)cc1
Reactant: c1nc[nH]n1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(C(c2ccc(C#N)cc2)n2cncn2)cc1

Procedure:
U.S. Pat. No. 5,473,078 (“the '078 patent”) describes a method for preparing 4-[1-(1,2,4-triazolyl)methyl]benzonitrile by refluxing a solution of c-bromo-4-tolunitrile with 1,2,4-triazole for 15 hours in a mixture of acetonitrile and chloroform. The intermediate is purified by chromatography on silica gel, eluting with chloroform and isopropanol, and then reacted with 4-fluorobenzonitrile and potassium tert-butoxide in DMF, to obtain letrozole. An exemplary process described in the '078 patent is generally depicted in Scheme 1.
Reaction SMILES: [C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(O[C@@H:45]1[O:57][C@H:56]([CH2:58][O:59][C:60](=[O:62])[CH3:61])[C@@H:51]([O:52][C:53](=[O:55])[CH3:54])[C@H:46]1[O:47][C:48](=[O:50])[CH3:49])(=O)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>ClC(Cl)(Cl)C.C(OCC)(=O)C>[C:48]([O:47][C@@H:46]1[C@H:51]([O:52][C:53](=[O:55])[CH3:54])[C@@H:56]([CH2:58][O:59][C:60](=[O:62])[CH3:61])[O:57][C@H:45]1[N:14]1[CH:13]=[N:12][C:11]2[C:15]1=[N:16][C:17]([C:19]([O:21][CH3:22])=[O:20])=[N:18][C:10]=2[NH:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:50])[CH3:49]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A suspension of methyl 6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (Preparation 16) (1.5 g, 4.02 mmol) in 1,1,1-trichloroethane (40 ml) was treated with N,O-bis(trimethylsilyl)acetamide (4.8 ml, 19.6 mmol). The mixture was heated under reflux for two hours. The solution was allowed to cool to room temperature and the solvent removed under reduced pressure. The residue was taken up in anhydrous toluene (40 ml) and 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose (1.65 g, 5.19 mmol) and trimethylsilyl trifluoromethanesulfonate (0.98 ml, 5.43 mmol) added. The resulting solution was heated under reflux under a nitrogen atmosphere for 3 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (200 ml) and washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was separated, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel using gradient elution with ethyl acetate:pentane (70:30, by volume) then ethyl acetate:pentane (80:20, by volume) then ethyl acetate to afford the title compound as a foam (2.05 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].CN(C1C=CC=CN=1)C.[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:24][S:25][C:26]1[N:30]=[CH:29][NH:28][N:27]=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:3]([CH2:7][CH3:8])[C:4]([N:28]1[CH:29]=[N:30][C:26]([S:25][CH2:24][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][O:18]2)=[N:27]1)=[O:5])[CH3:2]
Reactant: c1nc(SCC2CCCCO2)n[nH]1
Reactant: CCN(CC)C(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)n1cnc(SCC2CCCCO2)n1

Procedure:
11.6 g (85 mmol) of diethylcarbamoyl chloride and a spatula-tipful of dimethylaminopyridine were added to a solution of 200 ml of absolute tetrahydrofuran and 17.0 g (85 mmol) of 3-(tetrahydropyran-2-yl)methylthio-1,2,4-triazole (step b). 9.5 g (94 mmol) of triethylamine were then added dropwise and the mixture was heated under reflux for 2 hours. The solvent was distilled off and the residue was purified by chromatography over silica gel. 11.2 g (44% of theory) of a viscous clear oil were obtained. (1H-NMR (CDCl3; δ in ppm): 8.75 (s,1H); 4.00 (d,1H); 3.70-3.50 (bm,5H); 3.40 (dt,1H); 3.25 (d,2H); 1.85 (d,1H); 1.80 (d,1H); 1.65-1.45 (m,4H); 1.30 (t,6H))
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([C:16]#[N:17])=[C:5]2[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.[C:25]([O:28][CH2:29][CH2:30]Br)(=[O:27])[CH3:26].CN(C)C=O>O>[C:25]([O:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([C:16]#[N:17])=[C:5]2[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:27])[CH3:26]
Reactant: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(O)cc23)cc1
Reactant: CC(=O)OCCBr
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCOc1ccc2nc(CC(C)C)c(C#N)c(-c3ccc(C)cc3)c2c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 78.6 %

Procedure:
A mixture of 6-hydroxy-2-isobutyl-4-(4-methylphenyl)quinoline-3-carbonitrile (5.0 g, 15.8 mmol), 2-bromoethyl acetate (3.2 g, 19 mmol) and N,N-dimethylformamide (20 ml) was stirred at 50° C. for 15 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous-magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diethyl ether and filtered to give 2-{[3-cyano-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}ethyl acetate (5.0 g, yield 79%) as crystals.
Reaction SMILES: [Br-].[O:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:44][O:45][C:46]1[CH:53]=[CH:52][C:49]([CH:50]=O)=[CH:48][CH:47]=1>C1COCC1>[CH3:44][O:45][C:46]1[CH:53]=[CH:52][C:49]([CH:50]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:48][CH:47]=1
Reactant: COc1ccc(C=O)cc1
Reactant: c1ccc(OCCCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C=CCCCCCOc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92 %

Procedure:
To a suspension of 6-phenoxyhexyltriphenylphosphonium bromide (6.1) (4.60 g, 8.86 mmol) in dry THF (80 mL) at 0° C., under an argon atmosphere was added potassium bis(trimethylsilyl)amide (1.76 g, 8.86 mmol). The resulting slurry was stirred for 5 min at the same temperature and then a solution of 4-methoxybenzaldehyde (0.61 g, 4.46 mmol) in dry THF (10 mL) was added. The reaction mixture was stirred for an additional 10 min and quenched with saturated aqueous NH4Cl (20 mL). The resulting mixture was warmed to room temperature, diluted with Et2O (100 mL), the organic phase was separated and the aqueous phase extracted with Et2O. The combined organic layer was washed with brine, dried over MgSO4 and the solvent evaporated under reduced pressure. The residue obtained was purified through a short column of silica gel, eluting with 5% Et2O-hexane, to give the product 7.1 (1.21 g, 92% yield, predominantly cis, cis:trans=96:4) as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:8](Cl)Cl)=[N:4][N:5]([CH3:7])[CH:6]=1.[FH:11].[FH:12].F.C(N(CC)CC)C.[OH-].[Na+]>>[Br:1][C:2]1[C:3]([CH:8]([F:12])[F:11])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Br)c(C(Cl)Cl)n1
Reactant: F
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: Cn1cc(Br)c(C(F)F)n1
Temperature: 0 °C

Procedure:
At 160° C., 4-bromo-3-dichloromethyl-1-methylpyrazole (3.0 g; 0.01 mol; 90% pure according to GC analysis) was stirred with triethylamine trishydrofluoride (25 g, 0.16 mol) under autogenous pressure (<1 bar) for 1 h. After venting, the reaction mixture is added to ice (200 g), made alkaline with aqueous sodium hydroxide solution and extracted three times with methyl tert-butyl ether (100 ml). The combined organic phases were washed successively with dilute hydrochloric acid (100 ml) and a saturated aqueous NaCl solution (100 ml) and dried over magnesium sulfate, and the solvent was removed under reduced pressure. 4-Bromo-3-difluoromethyl-1-methylpyrazole was isolated in a purity of 81.3% (GC analysis) with a yield of 2.0 g (70%).