Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[C:6]=2[N:7]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:3]=[C:4]([N:21]3[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4cccc(F)c4)ncnc23)CC1
Reactant: C1CNCCN1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(SCc4cccc(F)c4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(3-fluorobenzyl-thio)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 205°-207° C.) and piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])[CH2:16][CH2:15][CH:14]([CH2:17][S:18]([N:21]3[CH2:24][CH:23]([OH:25])[CH2:22]3)(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)(=O)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])[CH2:12][CH2:13][CH:14]([CH2:17][S:18]([N:21]3[CH2:24][C:23](=[O:25])[CH2:22]3)(=[O:19])=[O:20])[CH2:15][CH2:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1)N1CC(O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1CN(S(=O)(=O)CC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.6 %

Procedure:
To a stirred solution of 1-[4-(4-chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)-cyclohexylmethanesulfonyl]-azetidin-3-ol (Example 30) (143 mg, 0.28 mmol.) in dichloromethane (10 mL) was added Dess-Martin periodinane (230 mg, 0.56 mmol.) and the mixture stirred at ambient temperature for 18 hours. Ethyl acetate (20 mL) was added and the solution washed with 10% sodium thiosulfate solution (20 mL), water (20 mL) and brine (20 mL), dried (MgSO4) and evaporated to leave a residue which was purified by column chromatography on silica, eluting with ethyl acetate:dichloromethane:iso-hexane (1:1:2), to afford the desired product (98 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]2[O:20][CH3:21])=[C:4]([F:22])[CH:3]=1.[CH2:23](Br)[CH:24]=[CH2:25].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH2:25]([O:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:22])=[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]=[C:10]2[O:20][CH3:21])[CH:6]=1)[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CCOc1cc(-n2c(OC)nc(C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone and allyl bromide with sodium carbonate in acetone there is obtained 1-(5-allyloxy-4-chloro-2-fluorophenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 103°-104° C.;
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]COCC>>[NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Nc1cc(Br)ccc1C(=O)O
Reactant: CCOCC
Product: COC(=O)c1ccc(Br)cc1N
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A solution of 2-amino-4-bromobenzoic acid (500 mg, 2.3 mmol) in 20 mL of Et2O was cooled to 0° C. by ice water, and a solution of CH2N2 (145 mg, 3.5 mmol) was added. The reaction was warmed to r.t and stirred for 12 hours. The reaction mixture was concentrated to give methyl 2-amino-4-bromobenzoate 1H-NMR (400 MHz, CDCl3) δ 11.45 (s, 1H), 7.95-8.05 (in, 2H), 7.72 (d, J=8.0 Hz, 1H), 3.31 (s, 3H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].Br[C:32]1[CH:33]=[CH:34][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[N:36][CH:37]=1>>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:32]4[CH:37]=[N:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(Br)cn1
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3O2)CC1
Product: CC(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)nc4)ccc3O2)CC1
Yield: 66 %

Procedure:
The title compound is prepared from 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid isopropyl ester and 5-bromo-2-methanesulfonyl-pyridine following a procedure analogous to that described in Example 1.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCCCCC>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]([CH3:13])([CH3:12])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][Br:14])=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#CC(C)(C)C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: CC(C)(C)C#Cc1ccc(CBr)cc1

Procedure:
3.35 g of 4-(3,3-Dimethyl-1-butynyl)toluene, 3.47 g of N-bromosuccinimide and 100 mg of dibenzoylperoxide in 50 ml of carbon tetrachloride are refluxed for 8 hours. The mixture is filtered and the solvent removed under vacuum. The pure product is obtained as an oil following chromatography over silica gel using hexane as an eluant.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH3:17])[C:13](SC)=[N:12]3)[CH2:10][C:9]([CH3:26])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:27].[I-]>N.CCO>[NH2:27][C:13]1[N:14]([CH3:17])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][C:9]([CH3:26])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10]2)[N:12]=1
Reactant: CSC1=NC2(CC(C)(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1C
Reactant: [NH4+]
Agent: N
Agent: [I-]
Solvent: CCO
Product: CN1C(=O)C2(CC(C)(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Yield: 16.9 %

Procedure:
A solution of 6-bromo-1′,2-dimethyl-2′-(methylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (292 mg, 0.667 mmol), NH4I (245.7 mg, 1.668 mmol) in a solution of NH3/EtOH (30 mL, 5 N) was heated at 110° C. in a CEM tube in a microwave reactor for 4 h. After cooling, the mixture was concentrated in vacuum to give the residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-1′,2-dimethyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (45 mg, 18%). 1H-NMR (MeOD): 1.63 (s, 3H), 1.77 (s, 3H), 2.74 (d, 2H), 6.75 (d, 1H), 7.06 (d, 1H), 7.22 (m, 1H), 7.31 (m, 3H), 7.45 (m, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:6]([O:8][C:9](=[O:30])[N:10]([C:19]1[CH:24]=[C:23](Br)[N:22]=[C:21]([NH2:26])[C:20]=1[N+:27]([O-:29])=[O:28])[CH2:11][C:12]1[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[CH3:7]>>[CH2:6]([O:8][C:9](=[O:30])[N:10]([C:19]1[CH:24]=[C:23]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[N:22]=[C:21]([NH2:26])[C:20]=1[N+:27]([O-:29])=[O:28])[CH2:11][C:12]1[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[CH3:7]
Reactant: c1cscn1
Reactant: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Product: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(-c2nccs2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using thiazole (42 mg) and (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (100 mg), giving the product (79 mg) as a yellow gum.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:12]([O:14]CC)=[O:13])[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[NH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
A mixture of ethyl 4-phenyl-1H-pyrrole-2-carboxylate (700 mg, 3.25 mmol), aqueous sodium hydroxide (10% w/v, 10 mL) and ethanol (10 mL) were stirred at room temperature over night. The ethanol was evaporated in vacuo, then water (20 mL) was added and the organics were extracted with ethyl acetate (3×20 mL). The aqueous layer was acidified with 2N HCl (to pH 3) and extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with water, brine (20 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 4-phenyl-1H-pyrrole-2-carboxylic acid (400 mg, 66%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([C:12]([OH:14])=O)[CH3:11])=[CH:4][C:3]=1[N:15]1[C:23](=[O:24])[N:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C:17]2=[N:16]1.S(Cl)([Cl:27])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([C:12]([Cl:27])=[O:14])[CH3:11])=[CH:4][C:3]=1[N:15]1[C:23](=[O:24])[N:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C:17]2=[N:16]1
Reactant: O=S(Cl)Cl
Reactant: CC(Oc1cc(-n2nc3n(c2=O)CCCC3)c(Cl)cc1Cl)C(=O)O
Solvent: ClC(Cl)Cl
Product: CC(Oc1cc(-n2nc3n(c2=O)CCCC3)c(Cl)cc1Cl)C(=O)Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3.7 Parts of 2-[2,4-dichloro-5-(1-carboxy-ethoxy)phenyl]-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-A]pyridin-3(2H)-one, 15 parts of chloroform and 1.2 parts of thionyl chloride were combined and refluxed for 3 hours. The reaction was stirred for an additional 12 hours at room temperature. Solvent and excess thionyl chloride were removed from the product by evaporation on a rotary evaporator at reduced pressure. 4.0 Parts of crude product were obtained and used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:25]([F:28])([F:27])[F:26])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:13])[CH:11]=2)[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:5](=[O:23])[N:4]1[CH3:24].[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1.Cl.CN(C)CCCN=C=NCC.[H-].ON1C2C=CC=CC=2N=N1.N1C=CC=CC=1>CN(C=O)C.O.C(Cl)(Cl)Cl>[Br:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:5](=[O:23])[N:4]([CH3:24])[C:3]2([CH2:2][NH:1][C:34](=[O:35])[C:33]1[CH:37]=[CH:38][C:30]([F:29])=[CH:31][CH:32]=1)[C:25]([F:27])([F:28])[F:26]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COc1ccc(CN2C(=O)N(C)C(CN)(C(F)(F)F)c3cc(Br)ccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(CN2C(=O)N(C)C(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Aminomethyl)-6-bromo-1-(4-methoxybenzyl)-3-methyl-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (36.8 mg, 0.080 mmol) was dissolved in DMF (1.0 mL), and 4-fluorobenzoic acid (28.1 mg, 0.201 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (46.2 mg, 0.241 mmol), 1-hydroxybenzotriazole monohydride (36.9 mg, 0.241 mmol) and pyridine (0.032 mL, 0.402 mmol) were sequentially added to the reaction solution at room temperature. After the reaction solution was stirred overnight at room temperature, chloroform and water were added thereto and the mixture was stirred at room temperature. The organic layer was separated and washed with saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by thin-layer chromatography (chloroform/methanol=1/10), whereby the objective N-{[6-bromo-1-(4-methoxybenzyl)-3-methyl-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-4-yl]methyl}4-fluorobenzamide (33.9 mg, 73%) was obtained as a white solid.
Reaction SMILES: O[CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=2[N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[O:10])[C@@H:7]([CH3:23])[CH2:6][CH2:5][O:4]1.C(C=P(CCCC)(CCCC)CCCC)#N.[F:40][C:41]1[CH:42]=[CH:43][C:44]([C:47]2[CH:48]=[N:49][NH:50][CH:51]=2)=[N:45][CH:46]=1>C1(C)C=CC=CC=1>[F:40][C:41]1[CH:42]=[CH:43][C:44]([C:47]2[CH:51]=[N:50][N:49]([CH2:2][C@H:3]3[N:8]([C:9]([C:11]4[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=4[N:18]4[N:19]=[CH:20][CH:21]=[N:22]4)=[O:10])[C@@H:7]([CH3:23])[CH2:6][CH2:5][O:4]3)[CH:48]=2)=[N:45][CH:46]=1
Reactant: Fc1ccc(-c2cn[nH]c2)nc1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2[C@H](CO)OCC[C@@H]2C)c1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2[C@H](Cn3cc(-c4ccc(F)cn4)cn3)OCC[C@@H]2C)c1
Temperature: 100 °C

Procedure:
To a solution of [(2S,4S)-2-(hydroxymethyl)-4-methyl-1,3-oxazinan-3-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone obtained in Reference Example 17 (0.070 g, 0.22 mmol) in toluene (1 mL), 5-fluoro-2-(1H-pyrazol-4-yl)pyridine obtained in Reference Example 11 (0.040 g, 0.24 mmol) and cyanomethylene tributylphosphorane (0.087 mL, 0.33 mmol) were added, and the resulting mixture was stirred with heating for 3 hours at 100° C. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (KP-NH 12 g, hexane/EtOAc=80/20 to 0/100) (HP-Sil 10 g, hexane/EtOAc=80/20 to 0/100) to obtain the title compound (0.11 g) (colorless oil).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[C:7](=[O:12])[CH2:6][CH2:5]2.[C:13](=O)([O-])[O-].[K+].[K+].IC.CC(C)=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:13])[C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: O=C([O-])[O-]
Reactant: O=C1CCc2cc(Br)c(O)cc21
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1cc2c(cc1Br)CCC2=O
Yield: 72 %

Procedure:
A round bottom flask, fitted with a stir bar and condenser was charged with 5-bromo-6-hydroxy-1-indanone (0.50 g, 2.20 mmol), potassium carbonate (0.456 g, 3.30 mmol), iodomethane (0.341 g, 2.40 mmol), and acetone (10 mL). After heating at reflux for 24 hours the mixture was diluted with ethyl acetate, washed with water (3×10 mL), brine (1×10 mL) and dried with MgSO4. The mixture was filtered and concentrated to give 0.382 g (72%) of 5-bromo-6-methoxyindan-1-one as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1 H), 7.22 (s, 1 H), 3.95 (s, 3 H), 3.10 (m, 2 H), 2.73 (m, 2 H). MS (ESI+) for C10H9BrO2 m/z 239.9787 (M+H)+. Anal. Calcd. For C10H9BrO2: C, 49.82; H, 3.76. Found: C, 49.69; H, 3.72.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].N1C=CC=CC=1.[CH:16]([O:19][CH:20]([O:34][CH:35]([CH3:37])[CH3:36])[C:21]([CH3:33])([CH3:32])[C:22](=[O:31])[CH2:23][C@@H:24]([OH:30])[C@@H:25]([CH3:29])[CH2:26][CH:27]=[CH2:28])([CH3:18])[CH3:17].[Na+].[Cl-]>C(Cl)Cl>[CH:35]([O:34][CH:20]([O:19][CH:16]([CH3:18])[CH3:17])[C:21]([CH3:32])([CH3:33])[C:22](=[O:31])[CH2:23][C@@H:24]([O:30][C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3])[C@@H:25]([CH3:29])[CH2:26][CH:27]=[CH2:28])([CH3:37])[CH3:36]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: C=CC[C@H](C)[C@H](O)CC(=O)C(C)(C)C(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC[C@H](C)[C@@H](CC(=O)C(C)(C)C(OC(C)C)OC(C)C)OC(=O)OCC(Cl)(Cl)Cl
Reaction time: 5 h

Procedure:
Trichloroethyl chloroformate (2.5 mL) and pyridine (2.95 mL) are added to a solution of (5R,6S)-1,1-diisopropoxy-5-hydroxy-2,2,6-trimethyl-8-nonen-3-one (2.9 g) in 40 mL of CH2Cl2 at 0° C., and the mixture is stirred for 5 hours before pouring into sat. aq. NaCl and extracting with CH2Cl2. The extract is dried over Na2SO4, filtered, and evaporated. The product is purified by chromatography on SiO2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[CH:9]1[C:21]2[NH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>[Cu]I.C1(C)C=CC=CC=1.CN1C(=O)N(C)CCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:20]2[C:21]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:3][CH:4]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1ccc(Br)cc1
Agent: [Cu]I
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: CN1CCCN(C)C1=O
Solvent: Cc1ccccc1
Product: Brc1ccc(-n2c3ccccc3c3ccccc32)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
56 g (240 mmol) of p-dibromobenzene, 31 g (180 mmol) of 9H-carbazole, 4.6 g (24 mmol) of copper(I) iodide, 66 g (480 mmol) of potassium carbonate, and 2.1 g (8 mmol) of 18-crown-6-ether were put into a 300 mL three-neck flask. The mixture was heated at about 100° C., and then 8 mL of N,N′-dimethylpropyleneurea (DMPU) was added thereto. This mixture was stirred at 180° C. for 6 hours. After the stirring, the mixture was cooled to 100° C. To the mixture was added about 200 mL of toluene, and then the mixture was cooled to room temperature. After the cooling, this mixture was subjected to suction filtration so that the precipitate was removed. The obtained filtrate was washed with dilute hydrochloric acid, a saturated sodium hydrogen carbonate solution, and a saturated saline solution in this order. The organic layer was dried with magnesium sulfate. Then, the mixture was subjected to gravity filtration. The obtained filtrate was condensed to give an oily substance. This oily substance was purified by silica gel column chromatography (a developing solvent was a mixed solvent of hexane:ether acetate=9:1), and then recrystallized with chloroform/hexane to give 21 g of a light brown plate-like crystal, which was the object of the synthesis, at a yield of 35%. A synthesis scheme of Step 1 is shown in (f-1) given below.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([C@@H:15]1[N:19]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C:18](=[O:28])[C@@H:17]([CH3:29])[N:16]1[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])([CH3:14])([CH3:13])[CH3:12].[F:36][C:37]([F:48])([F:47])[O:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1>C1COCC1>[C:11]([C@@H:15]1[N:19]([C:20]2[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=2)[C:18](=[O:28])[C@@:17]([CH3:29])([CH2:43][C:42]2[CH:45]=[CH:46][C:39]([O:38][C:37]([F:48])([F:47])[F:36])=[CH:40][CH:41]=2)[N:16]1[C:30](=[O:35])[C:31]([F:33])([F:34])[F:32])([CH3:12])([CH3:13])[CH3:14]
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: C[C@@H]1C(=O)N(c2cc(Cl)cc(Cl)c2)[C@@H](C(C)(C)C)N1C(=O)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[C@@H]1N(c2cc(Cl)cc(Cl)c2)C(=O)[C@@](C)(Cc2ccc(OC(F)(F)F)cc2)N1C(=O)C(F)(F)F
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 86.9 %

Procedure:
Lithium bis(trimethylsilyl)amide (LiHMDS) (38.0 mL, 1 M in THF) was added slowly dropwise over 25 min to a solution of (2S,5R)-2-tert-butyl-3-(3,5-dichloro-phenyl)-5-methyl-1-(2,2,2-trifluoro-acetyl)-imidazolidin-4-one (10.0 g, 25.17 mmol) in 60 mL of THF at −20° C. After stirring at −20° C. for 20 min, a solution of 4-trifluoromethoxybenzyl bromide (6.04 mL, 37.76 mmol) in 30 mL of THF was added dropwise over 20 min. The mixture was stirred at −20° C. for 45 min, warmed to −5° C. over 1 h, and then poured over 50 mL of ice-cold saturated NH4Cl solution. The resulting mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was triturated with hexanes to afford 12.5 g (87%) of (2R,5R)-2-tert-butyl-3-(3,5-dichloro-phenyl)-5-methyl-1-(2,2,2-trifluoro-acetyl)-5-(4-trifluoromethoxy-benzyl)-imidazolidin-4-one as an off-white solid.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8](=[O:16])[NH:7][C:6]1=[O:17])([OH:3])=[O:2].S(=O)(=O)(O)O.[CH2:23](O)[CH3:24]>>[Cl:15][C:12]1[CH:13]=[C:14]2[C:9]([C:8](=[O:16])[NH:7][C:6](=[O:17])[N:5]2[CH2:4][C:1]([O:3][CH2:23][CH3:24])=[O:2])=[CH:10][CH:11]=1
Reactant: CCO
Reactant: O=C(O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Yield: 82 %

Procedure:
To a suspension of 1-carboxymethyl-7-chloro-2,4(1H, 3H)-quinazolinedione (I) (5 g) in ethanol (50 ml) was added concentrated sulfuric acid (0.96 g) at room temperature, and the reaction solution was refluxed for 19 hours. After the reaction solution was concentrated suitablely to half, water (25 ml) was added, 10% potassium bicarbonate solution (25 g) was further added to adjust to pH 8. The resulting crystal was collected by filtration, washed with water and dried under vacuum to give 4.55 g of the desired compound (yield, 82%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1COCC1.[Li+].[OH-]>CCOC(C)=O.OS([O-])(=O)=O.[K+]>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)c1ccc(OCCCC2CCCN(C(=O)OC(C)(C)C)C2)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(CCCOc2ccc(C(=O)O)cc2)C1
Yield: 101.8 %

Procedure:
A mixture of 16-5 (0.75 g, 2 mmol), THF (30 ml) and 1N LiOH (10 mL) was heated at reflux for 7 h. The cooled reaction mixture was diluted with EtOAc and 10% KHSO4. The organic portion was then washed with brine, dried (MgSO4) and concentrated to give 16-6 (740 mg) as a white solid. Rf 0.86 (silica, EtOAc).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C[Si](C)(C)N[Si](C)(C)C.[NH2-:20].[Na+].[F:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.[NH:31]1[CH:35]=[N:34][C:33]([CH2:36][C:37]2[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=2)=[N:32]1>O1CCCC1.CC(N(C)C)=O.CN(C)C=O>[NH:31]1[CH:35]=[N:34][C:33]([CH2:36][C:37]2[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=2)=[N:32]1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.[CH:25]1[C:26]([C:27]#[N:28])=[CH:29][CH:30]=[C:23]([CH:41]([N:42]2[N:32]=[CH:33][N:34]=[CH:35]2)[C:40]2[CH:43]=[CH:44][C:37]([C:36]#[N:20])=[CH:38][CH:39]=2)[CH:24]=1
Reactant: [NH2-]
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N#Cc1ccc(Cc2nc[nH]n2)cc1
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(c2ccc(C#N)cc2)n2cncn2)cc1

Procedure:
Most preferably, the base is sodium bis(trimethylsilyl)amide, which may be prepared from hexamethyldisilazane and sodium amide, or purchased as a 40 percent solution in tetrahydrofuran. To avoid reaction between the 4-fluorobenzonitrile V and the sodium bis(trimethylsilyl)amide, the base is preferably added gradually to the mixture of synthons (all known procedures first generate the anion of intermediate III prior to bringing it into contact with 4-fluorobenzonitrile V). Approximately equimolar amounts of the intermediate III and 4-fluorobenzonitrile V in dimethylacetamide, dimethylformamide, or tetrahydrofuran provide a yield of about 85 percent by weight of pure letrozole after isolation and purification. As no stoichiometric excess of 4-fluorobenzonitrile V is required, any side-reactions with the base are believed to be negligible.