Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N-:4][CH:5]([CH3:7])C)([CH3:3])C.[Li+].[O:9]1CCC[CH2:10]1.C(N(CC)C([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:21]=1[CH3:28])=O)C.C1(C)C=CC=CC=1>O>[CH2:5]([N:4]([CH2:1][CH3:3])[C:10](=[O:9])[CH2:28][C:21]1[C:22]([O:26][CH3:27])=[CH:23][CH:24]=[CH:25][C:20]=1[OH:19])[CH3:7]
Reactant: CCN(CC)C(=O)Oc1cccc(OC)c1C
Reactant: CC(C)[N-]C(C)C
Reactant: C1CCOC1
Agent: [Li+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)Cc1c(O)cccc1OC
Reaction time: 0.27 h

Procedure:
5.0 mL of lithium diisopropylamide (2M/tetrahydrofuran-ethylbenzene, 10 mmol) was stirred and cooled on dry ice-ethanol bath and 8.0 mL tetrahydrofuran solution containing 0.95 g (4.0 mmol) of 2-(N,N-diethylcarbamoyloxy)-6-methoxytoluene was added dropwise thereto over 16 minutes. After one minute, warming was started under room temperature and after the mixture was stirred for 47 minutes, it was allowed to stand overnight. 10 mL of toluene and 10 mL of water were added thereto and after the mixture was stirred for 4 minutes, it was transferred into a separatory funnel and settled. The aqueous layer was separated and collected and combined with aqueous layers extracted from the organic layer with 2 N potassium hydroxide aqueous solution twice (5.0 mL for each time). After this aqueous layer was washed with 10 mL of toluene, 10 mL of toluene was added therein and 20 mL of 2 N hydrochloric acid aqueous solution was added thereto while being stirred and the mixture was transferred into a separatory funnel and settled. The organic layer was separated and collected and combined with the organic layer extracted from the aqueous layer with 5 mL of toluene. This organic layer was washed with 5 mL of water twice and then concentrated in vacuo, and thereby 0.81 g of the title compound was obtained.
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]([CH3:13])[C:6](OC(C)(C)C)=O)#[N:4].Cl[C:15]1[N:16]=[N:17]C(Cl)=[CH:19][CH:20]=1.C(O)(=[O:24])C>O1CCCC1>[OH:24][C:15]1[N:16]=[N:17][C:6]([CH:5]([CH3:13])[C:3]#[N:4])=[CH:19][CH:20]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(=O)O
Reactant: CC(C#N)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C#N)c1ccc(O)nn1

Procedure:
60.4 g (2.02 mol) of 80% strength sodium hydride in white oil are suspended in 2 liters of tetrahydrofuran and 311.8 g (2.02 mol) of tert.-butyl 2-cyanopropionate are added dropwise at 20°-30° C. During the course of 45 minutes this clear solution is added dropwise to a solution of 298 g (2.0 mol) of 3,6-dichloropyridazine and the mixture is heated under reflux for 2 hours. 317 ml of acetic acid are then added and the solvent is removed in vacuo. The residue is taken up in a mixture of 6,400 ml of acetic acid, 250 ml of acetic anhydride and 32 g of p-toluenesulfonic acid monohydrate, heated under reflux for 3 hours and again brought to dryness in vacuo. The residue is suspended in a little water, adjusted to pH 5 with sodium hydroxide solution and the water removed by evaporation. The residue is extracted hot using ethyl acetate. 99.7 g (33% of theory) of crude product are thus obtained, which can be employed for the following reaction without further processing.
Reaction SMILES: [OH:1][C:2]1([CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:20]([C:21](OC)=[O:22])=[CH:19][CH:18]=2)[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[NH2:27][CH2:28][CH2:29][OH:30]>O>[OH:30][CH2:29][CH2:28][NH:27][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][C:2]2([OH:1])[CH2:3][CH2:4][N:5]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:6][CH2:7]2)=[CH:26][CH:25]=1
Reactant: NCCO
Reactant: COC(=O)c1ccc(OCC2(O)CCN(Cc3ccccc3)CC2)cc1
Solvent: O
Product: O=C(NCCO)c1ccc(OCC2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: 145 °C
Reaction time: 4 h
Yield: 69.3 %

Procedure:
A mixture of 10.7 parts of methyl 4-[[4-hydroxy-1-(phenylmethyl)-4-piperidinyl]-methoxy]benzoate and 8 parts of 2-aminoethanol was stirred for 4 hours in an oil bath at 145° C. After cooling, the reaction mixture was poured into water. The oil was decanted, washed twice with water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and 2-propanol. The product was filtered off and dried, yielding 8 parts (69.3%) of N-(2-hydroxyethyl)-4-[[4-hydroxy-1-(phenylmethyl)-4-piperidinyl]-methoxy]benzamide; mp. 161.1° C. (int. 80).
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][NH:25][C@@H:26]([CH3:35])[C@@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[OH:28]>>[OH:28][CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:26]([N:25]([CH3:24])[C:13]([C:12]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:10][CH:11]=1)=[O:15])[CH3:35]
Reactant: O=C(O)c1cnc(NCc2ccccn2)nc1-c1ccccc1
Reactant: CN[C@@H](C)[C@H](O)c1ccccc1
Product: CC(C(O)c1ccccc1)N(C)C(=O)c1cnc(NCc2ccccn2)nc1-c1ccccc1
Yield: 61.7 %

Procedure:
Starting from 4-phenyl-2-[(pyridin-2-ylmethyl)amino]pyrimidine-5-carboxylic acid (0.48 g, 1.5 mmol) and (1R,2S)-2-methylamino-1-phenyl-1-propanol [(−)-ephedrine] (0.25 g, 1.5 mmol) according to the method described in Example 17. the title amide 0.42 g (58%) is obtained as white crystalline material; m.p.: 82° C.; [M+H]+ 468.
Reaction SMILES: [Br:1][C:2]1[C:3]([Si](C)(C)C)=[C:4]([F:11])[C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[F-].[Cs+]>CN(C)C=O.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: C[Si](C)(C)c1c(Br)cc(C=O)c(F)c1F
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)cc(F)c1F
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a solution of 18.0 g of 5-bromo-2,3-difluoro-4-trimethylsilanyl benzaldehyde in 20 mL of N,N-dimethylformamide and 2 mL of water was added 1.63 g of cesium fluoride at room temperature, and stirred at this temperature for 1 hour. After diluting with ethyl acetate, the organic layer was washed successively with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated, to afford 10.26 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[Cl:22][S:23](O)(=[O:25])=[O:24]>CC(=O)CC.ClCCl>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:8][C:3]1[CH:4]=[CH:5][C:6]([S:23]([Cl:22])(=[O:25])=[O:24])=[CH:7][C:2]=1[Cl:1])[CH3:21]
Reactant: Oc1ccccc1Cl
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-chlorophenol (25.7 g, 200 mmol), potassium carbonate (41.4 g, 300 mmol) and ethyl bromoacetate (35.1 g, 210 mmol) in 2-butanone (240 ml) was stirred at 100° C. for 24 h. The reaction mixture was filtered and evaporated. The residue was dissolved in toluene (100 ml), washed with water (3×25 ml), dried and evaporated. The residue (37 g, 172 mmol) was dissolved in dichloromethane (50 ml) and chlorosulfonic acid (93 g, 800 mmol) was added slowly at −10° C. The reaction mixture was stirred at room temperature for 1 h. Ice water (25 ml) was added carefully and the mixture was extracted with dichloromethane (3×100 ml). The combined organic phases were washed with water, dried and evaporated to give crude (4-chlorosulfonyl-2-chloro-phenoxy)-acetic acid ethyl ester as an oil in 47.5 g yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[C:3]=1[CH3:21].[I:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([CH3:33])([CH3:32])[CH2:28][NH:29]2)=[CH:25][CH:24]=1.Cl.O1CCOCC1>CN1C(=O)CCC1>[F:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[C:4]1[C:3]([CH3:21])=[C:2]([N:29]2[C:30]3[C:26](=[CH:25][CH:24]=[C:23]([I:22])[CH:31]=3)[C:27]([CH3:33])([CH3:32])[CH2:28]2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1c(-c2cc(F)ccc2F)nc2cc(F)ccc2c1Cl
Reactant: CC1(C)CNc2cc(I)ccc21
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2cc(F)ccc2F)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(I)cc21
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 4-chloro-2-(2,5-difluorophenyl)-7-fluoro-3-methylquinoline (150 mg, 0.49 mmol) (described herein), 6-iodo-3,3-dimethylindoline (160 mg, 0.59 mmol) (described herein), and 4.0 hydrochloric acid in 1,4-dioxane (120 μL, 0.49 mmol) in NMP (810 μL). The reaction mixture was stirred and heated at 150° C. for 3 h. Purification afforded 2-(2,5-difluorophenyl)-7-fluoro-4-(6-iodo-3,3-dimethylindolin-1-yl)-3-methylquinoline as a yellow solid. Mass Spectrum (ESI) m/e=545 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7](CCS)=[N:6][S:5](=[O:11])[N:4]=1.COC1C(OC)=NS(=O)N=1.[NH2:22][CH2:23][CH2:24][SH:25].CN.[CH3:28][N:29]([CH2:31][C:32]1[S:33][CH:34]=[C:35]([CH2:37]O)[N:36]=1)[CH3:30]>>[CH3:28][N:29]([CH2:31][C:32]1[S:33][CH:34]=[C:35]([CH2:37][S:25][CH2:24][CH2:23][NH:22][C:7]2[C:3]([NH:2][CH3:1])=[N:4][S:5](=[O:11])[N:6]=2)[N:36]=1)[CH3:30]
Reactant: CN(C)Cc1nc(CO)cs1
Reactant: NCCS
Reactant: CNC1=NS(=O)N=C1CCS
Agent: CN
Agent: COC1=NS(=O)N=C1OC
Product: CNC1=NS(=O)N=C1NCCSCc1csc(CN(C)C)n1

Procedure:
Reaction of 3-methylamino-4-(2-mercaptoethyl)-1,2,5-thiadiazole 1-oxide [prepared by reacting 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide with 2-aminoethanethiol and methylamine according to the procedure described in Example 25, Step A] with about one equivalent of 2-dimethylaminomethyl-4-hydroxymethylthiazole [prepared in Example 34, Step D], produces the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]([NH2:8])[C:6](=[O:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[C:11](Cl)(=O)[CH2:12][CH3:13]>O1CCOCC1.CN(C)C=O>[OH:9][C:6]1[N:7]2[N:8]=[C:11]([CH2:12][CH3:13])[N:1]=[C:2]2[N:3]=[C:4]([CH3:10])[CH:5]=1
Reactant: CCC(=O)Cl
Reactant: Cc1cc(=O)n(N)c(N)n1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCc1nc2nc(C)cc(O)n2n1

Procedure:
Intermediate 1 (0.4 g, 2.85 mmol) was allowed to react with propionyl chloride (ALDRICH, 0.372 mL, 4.28 mmol) in a mixture of 1,4-dioxane (8 mL) and N,N-dimethylformamide (2 mL) overnight under refluxing conditions. The reaction was concentrated under vacuum and the residue was purified (silica gel column, eluting with DCM:MeOH mixtures from 100:0 to 90:10%) to obtain 7-hydroxy-2-ethyl-5-methyl[1,2,4]triazolo[1,5-a]pyrimidine (Intermediate 4) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([F:10])[CH:3]=1.[C-:11]#[N:12].[Na+]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[C:4]([F:10])[CH:3]=1
Reactant: [C-]#N
Reactant: Fc1cc(Br)ccc1CBr
Agent: [Na+]
Solvent: CCO
Product: N#CCc1ccc(Br)cc1F
Temperature: 60 °C
Reaction time: 12 h
Yield: 195246.5 %

Procedure:
To a solution of 4-bromo-1-(bromomethyl)-2-fluorobenzene (500 g, 1.87 mol) in EtOH (2.2 L) stirred under nitrogen at 20° C. was added NaCN (93 g, 1.90 mmol) in one charge. The reaction mixture was stirred at 60° C. for 12 h. Then the solution was concentrated and distributed between DCM (2000 mL) and saturated NaHCO3 solution (1800 mL). Another batch was repeated using the same procedure. Then the two batches were combined. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated to provide 2-(4-bromo-2-fluorophenyl)acetonitrile (794 g, 99% yield): 1H NMR (400 MHz, CDCl3) δ 7.38-7.27 (m, 3H), 3.72 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH2:30][C:31](=[O:37])[NH:32]3)=[C:24]([F:38])[CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[C:30](=[CH:19][C:3]2[NH:4][C:5]4[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]5[CH2:14][CH2:15][CH2:16][CH2:17]5)[C:7](=[O:18])[C:6]=4[C:2]=2[CH3:1])[C:31](=[O:37])[NH:32]3)=[C:24]([F:38])[CH:23]=1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2F)N1
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4F)c32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 51.6 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(4-chloro-2-fluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 2-[4-(4-chloro-2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (35 mg, 51.6%) as a yellow solid.
Reaction SMILES: [H][H].[NH3:3].[CH2:4](O)[CH2:5][O:6][CH2:7][CH2:8]O>>[O:6]1[CH2:5][CH2:4][N:3]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][N:3]2[CH2:4][CH2:5][O:6][CH2:7][CH2:8]2)[CH2:8][CH2:7]1
Reactant: [H][H]
Reactant: OCCOCCO
Reactant: N
Product: C1CN(CCOCCN2CCOCC2)CCO1

Procedure:
The pressure was set to a constant 16 bar absolute, the fresh gas flow was set to a constant 300 standard l/h of hydrogen and the circulating gas was set to a constant approx. 300 pressure liters/(lcat·h). Ammonia and diethylene glycol were vaporized separately and preheated diethylene glycol was then introduced into the hot circulating gas stream, after which hot ammonia was fed into the reactor via a pressurized gas pump. The laden circulating gas stream was reacted isothermally at 210° C. (+/−2° C.) and 16 bar over the catalyst in the tube reactor. The synthesis was carried out at a space velocity over the catalyst of 0.30 lalcohol/lcat·h, a molar ratio of ammonia/alcohol of 3:1 and an amount of fresh gas/H2 of 300 standard liters/lcat·h. 90% of the alcohol was reacted in the reaction end a selectivity of 50% based on the diol used was achieved. The product was condensed in a pressure gas separator and collected for purification by distillation.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:21][CH3:22])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[C:4]([F:23])[CH:3]=1.Cl.[NH2:25][OH:26].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:21][CH3:22])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:25]\[OH:26])=[C:4]([F:23])[CH:3]=1
Reactant: CCCC(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1F
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCC(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1F

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-2-fluoro-phenyl)-hexanoyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=395.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][C:13]1([CH3:21])[CH2:19][C:18](=[O:20])[O:17][C:15](=O)[CH2:14]1.N[C:23]1C=CC(C(OCC)=O)=CC=1>>[CH2:21]([C:13]1([CH3:12])[CH2:14][C:15](=[O:17])[N:1]([C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[C:18](=[O:20])[CH2:19]1)[CH3:23]
Reactant: CC1(C)CC(=O)OC(=O)C1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COC(=O)c1ccc(N)cc1
Product: CCC1(C)CC(=O)N(c2ccc(C(=O)OC)cc2)C(=O)C1

Procedure:
The desired product was prepared by substituting 3-ethyl-3-methylglutaric anhydride and methyl 4-aminobenzoate for 3,3-dimethylglutaric anhydride and ethyl 4-aminobenzoate, respectively, in Example 119A. MS (DCI(+)) m/e 290 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[OH-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14]>O>[C:13](=[O:14])([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Cl:1])[O:15][CH3:16]
Reactant: COC(=O)Cl
Reactant: Oc1ccc(F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Oc1ccc(F)cc1Cl
Reaction time: 0.25 h

Procedure:
To a stirred solution of 20.0 g (0.14 mole) of 2-chloro-4-fluorophenol and 6.64 g (0.17 mole) of sodium hydroxide in 100 mL of water at 15° C. was added 17.7 g (0.19 mole) of methyl chloroformate. After complete addition, the mixture was stirred for 15 minutes then extracted with ethyl acetate. The organic phase was washed with a 1N sodium hydroxide solution, then dried over anhydrous magnesium sulfate. The dried extract was filtered, and the filtrate evaporated under reduced pressure to provide methyl (2-chloro-4-fluorophenyl) carbonate as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[N:12]([O-])=O.[Na+].Cl.[OH2:17]>>[CH:7]([C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[NH:8][N:12]=1)=[O:17]
Reactant: O
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: N#Cc1ccc2[nH]nc(C=O)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 5-cyanoindole (3.93 g) and sodium nitrite (19.07 g) in water was added 6M hydrochloric acid slowly until the pH was less than 2. The suspension was then stirred for 3 hours at ambient temperature. The mixture was then extracted with ethyl acetate, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to give 3-formyl-1H-indazole-5-carbonitrile (4.5 g) as a pale brown solid. LC-MS (METHOD B): RT=2.47 minutes, 172.29 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:13]([NH2:38])[CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[C:27]2[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[CH:29][C:28]=2[O:36][CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.Cl[C:51](Cl)([O:53]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]([F:39])([F:40])[C:3]1[CH:4]=[C:5]([CH:13]2[CH2:14][N:15]([CH2:16][C:17]3[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:18]=3[C:27]3[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[CH:29][C:28]=3[O:36][CH3:37])[C:51](=[O:53])[NH:38]2)[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCC(N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1CC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)NC1=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of 1-[3,5-bis(trifluoromethyl)phenyl]-N2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}ethane-1,2-diamine (125.2 mg, 0.217 mmol) in CH2Cl2 (30 mL) was cooled to 0° C. and DIPEA (227 μL, 1.30 mmol) was added. Next, triphosgene (32.2 mg, 0.109 mmol) was added. The reaction was stirred at 0° C. for 45 minutes and then poured into saturated NaHCO3 (20 mL). The mixture was extracted with EtOAc (100 mL) and the organic layer was washed with brine (25 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography with 40% EtOAc/hexanes to afford 4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}imidazolidin-2-one. Rf=0.22 (40% EtOAc/hexane). LCMS=605.2 (M+1)+. 1H NMR (CDCl3, 500 MHz) (atropisomers present in 1:1 ratio; doubling of some peaks observed) δ 7.83 (s, 1H), 7.78 (s, 2H), 7.55-7.62 (m, 2H), 7.32 (d, J=7.8 Hz, 1H), 7.22 (m, 1H), 6.94 (s, 1H), 6.88 (d, J=8.3 Hz, 1H), 5.33 & 5.24 (2 singlets, 1H), 4.80-4.88 (m, 1H), 4.00-4.61 (m, 2H), 3.72 & 3.70 (2 singlets, 3H), 3.55-3.59 (m, 1H), 2.83-2.93 (m, 2H), 1.17-1.23 (m, 6H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH:5]1[CH:10]=[CH:9][C:8]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:7]=2[O:6]1)=[O:4].[BH4-].[Na+]>C(O)C.O.ClCCl>[Cl:1][CH2:2][CH:3]([CH:5]1[CH:10]=[CH:9][C:8]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:7]=2[O:6]1)[OH:4]
Reactant: O=C(CCl)C1C=Cc2cc(F)ccc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: OC(CCl)C1C=Cc2cc(F)ccc2O1
Reaction time: 2 h
Yield: 70 %

Procedure:
A stirred solution of 2-Chloro-1-(6-fluoro-1-benzopyran-2-yl)-ethanone (0.33 g, 1.28 mmol, 88.4% A) in ethanol (2.5 ml) was cooled to 0° C. under nitrogen. NaBH4 (60.1 mg, 1.59 mmol) was added to the solution and the reaction mixture stirred for 2 hours. After checking by GPC that the starting product had disappeared, the mixture was diluted with demineralized water (7 ml) and dichloromethane (7 ml) and the phases separated. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to give crude 2-Chloro-1-(6-fluoro-1-benzopyran-2-yl)-ethanol as a mixture of diastereoisomers 54:46 (0.30 g, 70% yield, 67.9% A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:16][NH2:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:16][NH:17][S:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=1)(=[O:29])=[O:28])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Product: COc1ccc(S(=O)(=O)NCC(O)(Cn2cncn2)c2ccc(Cl)cc2Cl)cc1

Procedure:
Following the procedure described in the preceeding examples but using 2-(2,4-dichlorophenyl)-3-amino-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and p-methoxybenzenesulfonylchloride, the title compound was obtained in a similar yield: mp 56°-66° C.; 1H NMR (80 MHz, CDCl3)δ(TMS) 8.0-7.5 (m, 4H, arom), 7.3-6.9 (m, 3H, arom.), 5.24 (br s, 1H, NH), 4.96 (AB system, Δv=0.52, J=14.5 Hz, 2H, CH2 -Tr), 3.85 (s, 3H, OMe), 3.55 (dq, Jd =5.2 Hz, Jq =J=14 Hz, 2H, CH2NH), 2.16 (s, 1H, N=CH), 2.03 (s, 1H, N=CH). Anal calcd. for C18H18Cl2N4O4S: C 47.27%; H 3.97%; N 12.25 %. Found: C 47.56%; H 4.08%; N 12.09%.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[C:6]([O:9][CH2:10][CH3:11])[N:5]=[C:4]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[O:13])[CH:3]=1.[C:26]([Si:28]([CH3:31])([CH3:30])[CH3:29])#[CH:27].C(N([CH2:37][CH3:38])CC)C>CN(C)C=O.[Cu]I>[CH3:25][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:4]2[CH:3]=[C:2]([NH2:1])[C:7]([C:37]([Si:28]([CH3:30])([CH3:29])[CH3:26])=[CH:38][C:27]#[C:26][Si:28]([CH3:31])([CH3:30])[CH3:29])=[C:6]([O:9][CH2:10][CH3:11])[N:5]=2)=[O:13])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: C#C[Si](C)(C)C
Reactant: CCOc1nc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cc(N)c1I
Reactant: CCN(CC)CC
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CCOc1nc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cc(N)c1C(=CC#C[Si](C)(C)C)[Si](C)(C)C
Temperature: 110 °C
Yield: 29.4 %

Procedure:
A mixture of Example 240B (95 mg, 0.2 mmol), ethynyltrimethylsilane (59 mg, 0.6 mmol), PdCl2 (Ph3P)2 (7 mg, 0.01 mmol), CuI (4 mg, 0.02 mmol) and triethylamine (40 mg, 0.4 mmol) in N,N-dimethylformamide (2 ml) was sealed in a tube and heated at 110° C. for 6 hours, checked with LC/MS until starting material disappeared. The mixture was filtered and the filtrate was partitioned between ethyl acetate and water (30 ml, 1:1). The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified on silica gel cartridge by Anal.ogix eluting with 100% ethyl acetate to give the titled compound (32 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ ppm 9.03 (t, J=6.44 Hz, 1H), 7.87 (d, J=8.48 Hz, 2H), 7.55 (d, J=8.14 Hz, 2H), 7.06 (s, 1H), 6.75 (s, 1H), 6.05 (s, 2H) 4.57 (d, J=6.44 Hz, 2H), 4.36 (q, J=6.95 Hz, 2H), 3.17 (s, 3H), 1.29 (t, J=6.95 Hz, 3H), 0.21 (s, 9H), 0.11 (s, 9H); MS (APCI) m/z 544 [M+H]+, 542 [M−H]−.