Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[Na+].CN(C)C(=O)C.[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]2[NH:30][C:29](=[O:31])[C:28]([CH3:33])([CH3:32])[C:27](=[O:34])[N:26]([CH3:35])[C:25]=2[CH:36]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(I)C>O>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]([CH2:1][CH3:2])[C:29](=[O:31])[C:28]([CH3:33])([CH3:32])[C:27](=[O:34])[N:26]([CH3:35])[C:25]=2[CH:36]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN1C(=O)C(C)(C)C(=O)Nc2ccc(OCc3ccccc3)cc21
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCI
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCc3ccccc3)ccc21
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Under ice cooling, sodium t-butoxide (1.96 g, 20.4 mmol) was added to a N,N-dimethylacetamide (30 mL) solution of 8-benzyloxy-1,3,3-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (6.0 g, 18.5 mmol), and the mixture was stirred for 30 minutes. 1.63 mL (20.4 mmol) of ethyl iodide was added dropwise. The reaction solution was stirred at 10-20° C. for 4 hours. Water (42 mL) was added to the reaction solution, and the mixture was stirred at 10° C. or less for 30 minutes. Thereafter, precipitated crystals were collected by filtration, and the crystals were added to methanol (60 mL). The resultant was heated under reflux, and stirred at 10° C. or less for 30 minutes. Crystals were collected by filtration, then washed with methanol, and dried at 60° C., thereby obtaining 5.90 g of a white, powdery target compound (yield: 91%).
Reaction SMILES: C(OC(=O)[N:7]([CH2:17][CH:18]([OH:41])[CH:19]([NH:29]C(=O)CNC(=O)CCCCBr)[CH2:20][C:21]1[CH:26]=[C:25]([OH:27])[CH:24]=[C:23]([F:28])[CH:22]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[CH:10]=1)(C)(C)C.[C:43]([O-:46])([O-])=O.[Cs+].[Cs+].[CH3:49][N:50]([CH:52]=[O:53])C>>[CH2:15]([C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH2:8][NH:7][CH2:17][CH:18]([CH:19]1[CH2:20][C:21]2=[CH:26][C:25](=[CH:24][C:23]([F:28])=[CH:22]2)[O:27][CH2:11][CH2:10][CH2:9][CH2:8][C:52](=[O:53])[NH:50][CH2:49][C:43](=[O:46])[NH:29]1)[OH:41])[CH3:16]
Reactant: CCc1cccc(CN(CC(O)C(Cc2cc(O)cc(F)c2)NC(=O)CNC(=O)CCCCBr)C(=O)OC(C)(C)C)c1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: [Cs+]
Product: CCc1cccc(CNCC(O)C2Cc3cc(F)cc(c3)OCCCCC(=O)NCC(=O)N2)c1
Reaction time: 8 h
Yield: 25 %

Procedure:
To a solution of the product from Step 6 (78 mg, 0.12 mmol, 1.00 eq.) and anhydrous DMF (1 mL) is added Cs2CO3 (flame-dried, 78 mg, 0.24 mmol, 2.00 eq.) under N2 with stirring overnight. The reaction mixture is filtered through Celite and then concentrated in vacuo. The crude product is then stirred with Dowex 50WX2-400 ion-exchange resin at 60° C. for 2 hours. The product is released from resin with 7N NH3/MeOH through a frit and the filtrate is concentrated in vacuo, yielding the final product as a white solid (14 mg, 25% yield). Calculate accurate mass for C26H34BrFN3O4+H1: 472.2611. Accurate Mass found for C26H34BrFN3O4+H1: 472.2592.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:13](=[O:14])[CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1)=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.CC(O)=O>COC(OC)OC>[O:14]=[C:13]1[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:4]=2)[CH2:10][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]1
Reactant: COC(=O)C1CC(=O)N(c2cccc(C=O)c2)C1
Reactant: Nc1ccccn1
Solvent: COC(OC)OC
Solvent: CC(=O)O
Product: COC(=O)C1CC(=O)N(c2cccc(CNc3ccccn3)c2)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of methyl (3-formylphenyl)-5-oxopyrrolidine-3-carboxylate, 2-aminopyridine, and AcOH in trimethylorthoformate was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was re-dissolved in methanol. The solution was then cooled to 0° C. AcOH was added followed by NaBH3CN solid in portions. The reaction was allowed to stirred at room temperature for 8 hours. The reaction solution was then concentrated in vacuo. The residue was dissolved in EtOAc and organic solution was washed with saturated NaHCO3 twice. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel chromatograph (10% meOH/EtOAc) to provide an orange oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[NH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1.CN(C=O)C>O>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: c1ccc2c(c1)CCCN2
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@](O)(CN1CCCc2ccccc21)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (100 mg, 0.46 mmol), 1,2,3,4-tetrahydroquinoline (122 mg, 0.92 mmol) and DMF (1 ml) was stirred at 80° C. for 8 hours. The reaction mixture was allowed to return to room temperature. To the solution, water was added, and the resulting solution was extracted with ethyl acetate twice. The organic phases were combined, washed with water twice and a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to afford (S)-1-(2-chloro-4-nitroimidazol-1-yl)-3-(3,4-dihydro-2H-quinolin-1-yl)-2-methylpropan-2-ol (134 mg, yield 83%) as an orange oil.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH2:3][CH3:4].[CH3:7][N:8]([CH3:31])[C:9]1(C#N)[CH2:14][CH2:13][CH:12]([CH:15]([O:23][CH:24]([O:26][CH2:27][CH3:28])[CH3:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10]1.O.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([C:9]1([N:8]([CH3:31])[CH3:7])[CH2:14][CH2:13][CH:12]([CH:15]([O:23][CH:24]([O:26][CH2:27][CH3:28])[CH3:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Mg]Cl
Reactant: CCOC(C)OC(Cc1ccccc1)C1CCC(C#N)(N(C)C)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC1(N(C)C)CCC(C(Cc2ccccc2)OC(C)OCC)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 2 M solution of n-butylmagnesium chloride in tetrahydrofuran (4.62 ml, 9.25 mmol) was added dropwise to a solution of 1-dimethylamino-4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclohexanecarbonitrile (1.06 g, 3.1 mmol) in tetrahydrofuran (15 ml), while cooling with ice and under an argon atmosphere. The mixture was stirred at room temperature for 48 h and thereafter water and saturated ammonium chloride solution (10 ml of each) were added. The phases were separated and the aqueous phase was extracted with diethyl ether (3×10 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH2:13][OH:14])[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl.O>[CH3:22][S:23]([O:14][CH2:13][C:10]1([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:11][CH2:12]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCC1(CO)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1(COS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of [1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methanol (Example 34c, 5.37 g) dissolved in DCM (20 mL) was treated with triethylamine (6.92 mL) at 0° C. before adding methanesulfonyl chloride (2.321 mL) under nitrogen. The resulting mixture was stirred at 0° C. for 30 min. The reaction mixture was diluted with water (100 mL), and extracted with DCM (250 mL). The organics were dried (MgSO4), filtered and evaporated. The crude product was purified (SiO2 chromatography, elution 50% isohexane in diethyl ether). Pure fractions were evaporated to dryness to afford the subtitle compound (5.37 g) as an oil.
Reaction SMILES: ClC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50]CC)=O)=[C:33]2[S:53](Cl)(=[O:55])=[O:54].Cl.CN.Cl.[CH3:61][S:62]([C:65]1[CH:72]=[CH:71][C:68]([CH2:69][NH2:70])=[CH:67][CH:66]=1)(=[O:64])=[O:63]>>[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:48]([NH2:7])=[O:50])=[C:33]2[S:53]([NH:70][CH2:69][C:68]1[CH:71]=[CH:72][C:65]([S:62]([CH3:61])(=[O:63])=[O:64])=[CH:66][CH:67]=1)(=[O:54])=[O:55]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: CN
Agent: Cl
Product: CS(=O)(=O)c1ccc(CNS(=O)(=O)c2c(C(N)=O)[nH]c3ccc(Br)cc23)cc1

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride with 4-(methylsulfonyl)benzylamine hydrochloride, the title compound was obtained. HRMS (ES) exact mass calculated for C17H17BrN3O5S2 (M+H+): 485.9788. Found 485.9784.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=1.O>C(N(CC)CC)C.[Cu]I.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>[CH3:16][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=1
Reactant: C#Cc1ccccc1
Reactant: Cc1ccnc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccnc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phenylacetylene (15.4 mL) is added to a mixture of 2-bromo-4-methyl-pyridine (20.0 g), CuI (2.2 g), and Pd(PPh3)2Cl2 (4.1 g) in triethylamine (600 mL) kept under argon atmosphere. The mixture is stirred at ambient temperature overnight. Then, water is added and the resulting mixture is extracted with diethyl ether. The combined organic extracts are washed with brine and dried (MgSO4). The solvent is removed under reduced pressure and the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 9:1→4:1) to give the product as an oil.
Reaction SMILES: [N:1]([CH:4]([CH3:16])[CH2:5][O:6][CH2:7][C:8](=O)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N+:2]=[N-:3].Cl[C:18]1C=CC=CC=1C=O.[NH2:26]/[C:27](/[CH3:33])=[CH:28]\[C:29]([O:31][CH3:32])=[O:30]>CO>[N:1]([CH:4]([CH3:16])[CH2:5][O:6][CH2:7][C:8]1[NH:26][C:27]([CH3:33])=[C:28]([C:29]([O:31][CH3:32])=[O:30])[CH2:18][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N+:2]=[N-:3]
Reactant: O=Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)COCC(C)N=[N+]=[N-]
Reactant: COC(=O)/C=C(/C)N
Solvent: CO
Product: CCOC(=O)C1=C(COCC(C)N=[N+]=[N-])NC(C)=C(C(=O)OC)C1
Yield: 20.8 %

Procedure:
A mixture of ethyl 4-(2-azidoprop-1-oxy)acetoacetate (13.05 g), 2-chlorobenzaldehyde (8.3 g) and methyl 3-aminocrotonate (6.8 g) in methanol (80 ml) was heated under reflux for 19 hours, reduced to half-volume, and then cooled overnight at -20°. The resulting precipitate was collected, washed with a little cold methanol, and dried to give 2-(2-azidoprop-1-oxymethyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (4.0 g) as a pale yellow solid, m.p. 115°, characterised spectroscopically.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:48][CH:49]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:50]1[CH:51]=[CH:52][C:53]([P:56](=[O:63])([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59])=[N:54][CH:55]=1>C(OCC)(=O)C>[OH:1][C:2]1[C:7]([C:8]([NH:48][CH:49]([C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=2)[C:50]2[CH:51]=[CH:52][C:53]([P:56](=[O:63])([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59])=[N:54][CH:55]=2)=[O:10])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1
Reactant: CCOP(=O)(OCC)c1ccc(C(N)c2ccccc2)cn1
Reactant: O=C(O)c1cnc(-c2ccccn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccc(C(NC(=O)c2cnc(-c3ccccn3)nc2O)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxylic acid, 1-1-h, (1 g, 4.6 mmol) in ethyl acetate (20 ml) was added HATU (1.75 g, 4.6 mmol), Et3N (465 mg, 4.6 mmol) and diethyl {5-[amino(phenyl)methyl]pyridin-2-yl}phosphonate (4-g) (1.47 g, 4.6 mmol). The resulting mixture was stirred at room temperature for 2 hour. Then it was filtered before diluted with saturated NH4Cl solution. The mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography to provide the product, 4-1, (360 mg, 15%). 1H NMR (CD3OD, 300 MHz,): δ 10.56 (m, 1H), 8.66 (m, 3H), 8.37 (m, 1H), 7.83 (m, 3H), 7.52 (m, 1H), 7.23 (m, 5H), 6.33 (m, 1H), 4.09 (m, 4H), 1.30 (m, 6H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([CH2:13][C:14]#[N:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19]OC(OC)OC.[CH3:26][NH:27][CH3:28]>C(O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([C:13](=[CH:26][N:27]([CH3:19])[CH3:28])[C:14]#[N:15])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCC(=O)c1cccc(Oc2ccccc2)c1
Reactant: COC(OC)OC
Reactant: CNC
Solvent: CCO
Product: CN(C)C=C(C#N)C(=O)c1cccc(Oc2ccccc2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
3-Phenoxybenzoylacetonitrile (4 g) and trimethylorthoformate (30 ml) was stirred and heated to 80° C. for 2 hours. After cooling to 0° C., an excess of dimethylamine in ethanol solution was added and the mixture stirred for 2 hours at room temperature. The volatiles were then removed in vacuo and the residue chromatographed on a silica gel column using 5% methanol-dichloromethane (v/v) as eluant to give the title compound (3.2 g, 65%) as a white solid of m.p. 80°-82° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:7]=1[Cl:8].[NH2:16][NH2:17]>>[Cl:8][C:7]1[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:5][N:4]=[N:3][C:2]=1[NH:16][NH2:17].[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:7]=1[NH:16][NH2:17]
Reactant: NN
Reactant: Clc1ccc(-c2cnnc(Cl)c2Cl)cc1
Product: NNc1c(-c2ccc(Cl)cc2)cnnc1Cl
Product: NNc1nncc(-c2ccc(Cl)cc2)c1Cl
Temperature: 60 °C
Reaction time: 5 h
Yield: 169.3 %

Procedure:
To a stirring suspension of 3,4-dichloro-5-(4-chlorophenyl)pyridazine (2.58 g, 10 mmol) in 2-BuOH (150 mL) at RT was added anhydrous hydrazine (4.80 g, 150 mmol). The reaction mixture was heated at 60° C. under argon. HPLC/MS analysis indicated that the reaction was complete after 5 h. The reaction mixture was cooled to 0° C., and the product was collected by filtration. The solid was then washed with ice-cold 2-propanol (10 mL×2). After drying the solid under vacuum at room temperature for 16 h, the title compound, 1-(4-chloro-5-(4-chlorophenyl)pyridazin-3-yl)hydrazine was obtained in a 1.6:1 ratio with undesired 1-(3-chloro-5-(4-chlorophenyl)pyridazin-4-yl)hydrazine (2.16 g gross). 1-(4-chloro-5-(4-chlorophenyl)pyridazin-3-yl)hydrazine MS [M+H]+ 255; HPLC retention time=1.63 min. 1-(3-chloro-5-(4-chlorophenyl)pyridazin-4-yl)hydrazine MS [M+H]+ 255; HPLC retention time=1.09 min.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1C.[NH2:8][C:9]1[N:18]=[C:17]([C:19]([N:21]2[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)=[O:20])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[S:36](Cl)(=[O:38])=[O:37])[CH:15]=2)[N:10]=1.[CH2:40]1COCC1>>[NH2:8][C:9]1[N:18]=[C:17]([C:19]([N:21]2[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)=[O:20])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[S:36]([N:3]3[CH:4]([CH3:40])[CH2:5][CH2:6][CH:2]3[CH3:1])(=[O:38])=[O:37])[CH:15]=2)[N:10]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3S(=O)(=O)Cl)ccc2n1
Reactant: CC1CCCN1C
Reactant: C1CCOC1
Product: CC1CCC(C)N1S(=O)(=O)c1ccccc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 22 °C
Reaction time: 1 h

Procedure:
A solution of 58 μl of dimethylpyrrolidine in 4 ml of THF is added dropwise to a solution of 400 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)-quinazolin-6-yl]benzenesulfonyl chloride in 4 ml of THF with ice-cooling. The mixture is subsequently stirred at 22° C. for a further 1 h, evaporated in vacuo and taken up in 4 ml of diethyl ether. The solution is washed 3 times against sodium hydroxide solution (2N) and finally purified by column chromatography.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](O)=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Li].[NH:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[CH2:26][OH:27]>>[OH:27][CH2:26][C@@H:22]1[CH2:23][CH2:24][CH2:25][N:21]1[C:15]([C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:18])([F:1])[F:19])=[CH:8][CH:7]=2)=[CH:14][CH:13]=1)=[O:16]
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [Li]
Product: O=C(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)N1CCC[C@H]1CO

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure B′ from 4′-trifluoromethyl-biphenyl-4-carboxylic acid, lithium salt using (S)-2-pyrrolidine methanol as the amine. MS (ES+) 350.2,
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[C@@H:13]([OH:14])[CH2:12][CH2:11][C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@H:9]1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[F:25][C:26]([F:47])([F:46])[C:27]1[CH:28]=[C:29]([C@@H:37](OC(=N)C(Cl)(Cl)Cl)[CH3:38])[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1>>[F:25][C:26]([F:46])([F:47])[C:27]1[CH:28]=[C:29]([C@H:37]([O:14][C@H:13]2[CH2:12][CH2:11][C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@@H:9]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C@@H:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH3:38])[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1
Reactant: C[C@H](OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)[C@H]1[C@H](c2ccccc2C)[C@@H](O)CC[C@@H]1C(=O)OCC
Product: CCOC(=O)[C@H]1[C@H](c2ccccc2C)[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC[C@@H]1C(=O)OCC

Procedure:
The title compound was prepared from the first eluting isomer diethyl (1S,2S,3R,4S)-3-(2-methylphenyl)-4-hydroxycyclohexane-1,2-dicarboxylate (step G) and (1S)-1-[3,5-bis(trifluoromethyl)-phenyl]ethyl-2,2,2-trichloroethanimidoate (Example 1, step H) according to the procedure of Example 1, step I. 1H-NMR (CDCl3): δ: 7.65 (1H, s), 7.15 (2H, s), 7.08-6.92 (4H, m), 4.25 (1H, q, J=6.0 Hz), 4.20-4.10 (2H, m), 3.85-3.66 (2H, m), 3.42 (1H, m), 3.21 (1H, t), 2.90-2.79 (2H, m), 2.35 (1H, m), 2.25 (1H in), 2.22 (3H, s), 1.69-1.56 (2H, m), 1.30 (3H, d, J=6.0 Hz), 1.23 (3H, t, J=7.2 Hz), 0.77 (3H, t, J=7.2 Hz). Unreacted starting alcohol could be recovered by flushing the column with EtOAc and reused in the above reaction.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[F:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.N1C=CC=CC=1>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[N:3]=[CH:4][N:5]([C:11]2[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=2)[CH:6]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1c[nH]cn1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Fc1ccc(-n2cnc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 44 h
Yield: 36.8 %

Procedure:
A mixture of 4-bromo-1H-imidazole (223 mg, 1.52 mmol), 4-fluorophenylboronic acid (425 mg, 3.03 mmol), copper(II) acetate (413 mg, 2.28 mmol), pyridine (0.25 mL) and powdered 4 Å molecular sieves (1 g) in 1,2-dichloroethane (7 mL) was stirred at room temperature under a slow stream of air for 44 hours. The reaction mixture was filtered through Celite®, washing with ethyl acetate. The filtrate was concentrated and the residue purified by flash column chromatography on silica eluting with 10 to 20% ethyl acetate/isohexane to give the product as a white solid (135 mg, 37%).
Reaction SMILES: [Li+].CCC[CH2-].Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.CN(C)[CH:25]=[O:26].O>CCCCCC.C1COCC1>[F:20][C:19]([F:22])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH:25]=[O:26])=[CH:8][CH:9]=2)=[CH:14][CH:15]=1
Reactant: FC(F)(F)c1ccc(-c2ccc(Br)cc2)cc1
Reactant: CN(C)C=O
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N-Butyllitium in hexane (95 ml, 1.55M) was added dropwise to 4-Bromo-4'-trifluoromethylbiphenyl (40 g) in 250 ml of THF under N2 at -70° C. After addition the mixture was stirred for a further 10 mins and then dry dimethylformamide (19.49) in a solution of dry tetrahydrofuran (100 ml) was added dropwise. The mixture was then allowed to warm to room temperature in the absence of coolant. After stirring for 1.5 hours water was added and the mixture extracted with ether. The water washed and dried extracts were evaporated to give p-(4-trifluoromethylphenyl)benzaldehyde (34.5 g) m.p. 70°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24])[CH3:8].[CH3:25][C:26]1[C:27]([CH:32]=O)=[N:28][CH:29]=[CH:30][CH:31]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:25][C:26]1[C:27]([CH2:32][N:9]([CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH3:8])[CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cccnc1C=O
Reactant: C[C@@H](NCCCCN1C(=O)c2ccccc2C1=O)c1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(CCCCN1C(=O)c2ccccc2C1=O)C(C)c1ccccn1

Procedure:
Using General Procedure B, reaction of (R)-2-[4-(1-pyridin-2-yl-ethylamino)-butyl]-isoindole-1,3-dion and 3-methyl-pyridine-2-carbaldehyde in CH2Cl2 with NaBH(OAc)3 gave 2-{4-[(3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amino]-butyl}-isoindole-1,3-dione. 1H NMR (CDCl3) δ 1.21-1.32 (m, 2H), 1.38-1.47 (m, 5H), 2.25 (s, 3H), 2.35-2.54 (m, 1H), 2.54-2.60 (m, 1H), 3.48 (t, 2H, J=7.5 Hz), 3.79 (s, 2H), 3.94-4.00 (m, 1H), 6.97-6.99 (m, 1H), 7.05-7.10 (m, 1H), 7.29-7.36 (m, 2H), 7.56-7.57 (m, 1H), 7.66-7.69 (m, 2H), 7.78-7.81 (m, 2H), 8.27 (d, 1H, J=3.5 Hz), 8.49 (d, 1H, J=3.5 Hz). Deprotection with H2NNH2.H2O following General Procedure E gave N1-(3-methyl-pyridin-2-ylmethyl)-N1-(1-pyridin-2-yl-ethyl)-butane-1,4-diamine as a beige oil. 1H NMR (CDCl3) δ 1.03 (s, 1H), 1.20-1.26 (m, 2H), 1.31-1.37 (m, 2H), 1.49 (d, 3H, J=6.0 Hz), 2.31 (s, 3H), 2.39-2.56 (m, 4H), 3.83 (s, 2H), 3.97-4.04 (m, 1H), 7.07-7.09 (m, 2H), 7.39 (d, 2H, J=9.0 Hz), 7.61-7.62 (m, 1H), 8.34-8.36 (m, 1H), 8.53-8.55 (m, 1H). Conversion to the HBr salt using General Procedure D gave COMPOUND 243 as a white solid. 1H NMR (D2O) 1.47-1.49 (m, 4H), 1.59 (d, 3H, 6.6 Hz), 2.45 (s, 3H), 2.60-2.66 (m, 1H), 2.70-2.77 (m, 1H), 2.85-2.86 (m, 2H), 4.30 (s, 2H), 4.57-4.60 (m, 2H), 7.81-7.85 (m, 1H), 7.99 (t, 1H, J=6.6 Hz), 8.13 (d, 1H, J=9.0 Hz), 8.32 (d, 1H, J=7.2 Hz), 8.56-8.58 (m, 2H), 8.77 (d, 1H, J=5.1 Hz). 13C NMR (D2O) δ 15.00, 17.00, 23.97, 25.01, 39.52, 51.06, 52.70, 59.88, 125.85, 126.82, 126.88, 137.10, 138.28, 142.11, 148.19, 148.25, 152.29, 156.10. ES-MS m/z 299 (M+H). Anal. Calcd. for C18H26N4.3.4HBr.0.3C4H10O.2.3H2O: C, 36.19; H, 5.85; N, 8.79; Br, 42.64. Found: C, 36.11; H, 5.54; N, 8.75; Br, 42.65.