Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[Cl:11][C:12]1[CH:39]=[CH:38][C:15]([C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH:22]=[C:21]3[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)=[O:17])=[CH:14][CH:13]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[Cl:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][CH2:29][C:21]1[C:20]2[C:25](=[CH:26][CH:27]=[C:18]([C:16]([C:15]3[CH:38]=[CH:39][C:12]([Cl:11])=[CH:13][CH:14]=3)([OH:17])[C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[CH:19]=2)[NH:24][C:23](=[O:28])[CH:22]=1
Reactant: c1cscn1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(CCc3cccc(Cl)c3)c2c1
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: O=c1cc(CCc2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3nccs3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of thiazole (201 mg, 2.368 mmol, 4.00 equip) in THF (10 mL) at −78° C. was added n-butyllithium (1.6 M in hexanes, 1.495 mL, 2.392 mmol, 4.04 equip) dropwise. After 30 minutes, a solution of 6-(4-chlorobenzoyl)-4-(3-chlorophenethyl)quinolin-2(1H)-one (250 mg, 0.592 mmol, 1 equip, prepared as described in ANGIBAUD, P. R., et al., PCT Publication WO2002/051835 A1, published 4 Jul. 2002) in HMPA (4 mL) was added dropwise and the reaction mixture was warmed to room temperature. The reaction was stirred overnight, then quenched with water and the resulting mixture extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated. The residue was purified by MPLC using methanol-dichloromethane as the eluent to yield 4-(3-chlorophenethyl)-6-((4-chlorophenyl)(hydroxy)(thiazol-2-yl)methyl)quinolin-2(1H)-one as a tan solid.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]1.Cl[CH2:33][C:34]1[CH:35]=[C:36]([O:46][CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:37]2[C:42]([CH:43]=1)=[C:41]([O:44][CH3:45])[CH:40]=[CH:39][CH:38]=2>>[CH3:45][O:44][C:41]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:42]=1[CH:43]=[C:34]([CH2:33][O:1][CH:2]1[CH:7]([C:8]3[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[CH:24]=[CH:23][S:22][CH:21]=4)=[CH:12][CH:13]=3)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]1)[CH:35]=[C:36]2[O:46][CH2:47][CH2:48][CH2:49][O:50][CH3:51]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccsc3)cc2)C(O)C1
Reactant: COCCCOc1cc(CCl)cc2c(OC)cccc12
Product: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccsc3)cc2)cc2c(OC)cccc12

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(thiophen-3-ylmethoxy)-propoxy]-phenyl]-piperidine-1-carboxylate with 3-chloromethyl-5-methoxy-1-(3-methoxy-propoxy)-naphthalene [Example 123(t)] there was obtained tert-butyl (3RS,4RS)-3-[8-methoxy-4-(3-methoxy-propoxy)-naphthalen-2-ylmethoxy]-4-{4-[3-(thiophen-3-ylmethoxy)-propoxy]-phenyl}-piperidine-1-carboxylate as a pale yellow, viscous oil; MS: 723 (M+NH4)+.
Reaction SMILES: [O:1]1[CH:3]([CH3:4])[CH:2]1[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:21]([CH3:22])[C:20](=[O:23])[C:19]3[C:14](=[CH:15][C:16]([O:26][CH3:27])=[C:17]([O:24][CH3:25])[CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1.[CH3:28][C:29]1[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=1[O:31][CH2:32][CH2:33][NH2:34]>>[OH:1][CH:3]([CH2:4][NH:34][CH2:33][CH2:32][O:31][C:30]1[CH:35]=[CH:36][CH:37]=[CH:38][C:29]=1[CH3:28])[CH2:2][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:21]([CH3:22])[C:20](=[O:23])[C:19]3[C:14](=[CH:15][C:16]([O:26][CH3:27])=[C:17]([O:24][CH3:25])[CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1
Reactant: COc1cc2nc(-c3ccc(OC4OC4C)cc3)n(C)c(=O)c2cc1OC
Reactant: Cc1ccccc1OCCN
Product: COc1cc2nc(-c3ccc(OCC(O)CNCCOc4ccccc4C)cc3)n(C)c(=O)c2cc1OC

Procedure:
This compound was prepared analogous to Example 2 from 2-[4-(1,2-epoxy-propoxy)-phenyl]-3-methyl-6,7-dimethoxy-3,4-dihydro-quinazolin-4-one and 2-(2-methyl-phenoxy)-ethylamine.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:4].C(=O)(O)[O-].[K+].[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH:26]1OS(C)(=O)=O.O>C(#N)C>[CH2:3]([O:5][C:6](=[O:19])[C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][N:16]([CH:26]3[CH2:25][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27]3)[CH2:17][CH2:18]2)=[CH:11][CH:12]=1)[CH3:4]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)OC1Cc2ccccc2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccc(N2CCN(C3Cc4ccccc4C3)CC2)cc1
Yield: 33.4 %

Procedure:
To a suspension of 4-piperazin-1-yl-benzoic acid ethyl ester dihydrochloride (1 g) and potassium bicarbonate (1.57 g) in acetonitrile (10 ml) was added methanesulfonic acid indane-2-yl ester (0.69 g) and the mixture was stirred under refluxing for 8 hours. The reaction mixture was pulverized with water. The precipitate was collected by filtration and dried over under reduced pressure. The powder was purified by column chromatography on silica gel using methanol/dichloromethane (50:1) as the eluent to give 4-(4-indan-2-yl-piperazin-1-yl)benzoic acid ethyl ester (0.38 g).
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C.O>CN(C)C=O.CO>[F:9][C:6]1[C:5]([CH3:10])=[CH:4][CH:3]=[CH:2][C:7]=1[NH2:8]
Reactant: Cc1ccc(Br)c(N)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: O
Product: Cc1cccc(N)c1F
Temperature: 85 °C
Reaction time: 2 h
Yield: 103.3 %

Procedure:
6-Bromo-2-fluoro-3-methylaniline (9.00 g, 44.1 mmol), which had been obtained in Reference example 4(4a), was dissolved in a 1:1 mixture (130 mL) of N,N-dimethyl formamide and methanol, and added with [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride-dichloromethane complex (10.8 g, 13.2 mmol) and N,N-diisopropylethylamine (23 mL, 132.3 mmol). The mixture was vigorously stirred at 85° C. for 2 hours under a carbon monoxide atmosphere. The reaction solution was cooled to room temperature, added with ethyl acetate and water, filtered using Millicup (registered trademark)-LH, and washed with ethyl acetate. The filtered solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a colorless solid (5.70 g, yield 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:5].Cl.[N:20]([O-])=O.[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[Br:18][C:15]1[CH:16]=[CH:17][C:2]2[N:1]=[N:20][N:6]([CH2:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[C:4](=[O:5])[C:3]=2[CH:14]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Br)cc1C(=O)NCc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=c1c2cc(Br)ccc2nnn1Cc1cccnc1
Yield: 84.1 %

Procedure:
To a mixture of 29.4 g of 2-amino-5-bromo-N-(3-pyridylmethyl)benzamide, 32 ml of conc. hydrochloric acid and 400 ml of water was dropwise added a solution of 6.83 g and 400 ml of water was dropwise added a solution of 6.83 g of sodium nitrite and 48 ml of water at 0° to 2° C. The resultant mixture was stirred at 0° to 2° C. for 45 minutes, neutralized with 1N aqueous sodium hydroxide and shaken with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 25.6 g of the titled compound.
Reaction SMILES: C[O:2][CH:3]=[C:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1>O1CCCC1.Cl>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([CH:7]2[CH2:8][CH2:9][CH:4]([CH:3]=[O:2])[CH2:5][CH2:6]2)=[CH:11][CH:12]=1)#[N:15]
Reactant: COC=C1CCC(c2ccc(C#N)cc2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(C2CCC(C=O)CC2)cc1
Temperature: 0 °C

Procedure:
The resulting oil (11.0 g) of p-[4-(methoxymethylidene)cyclohexyl]benzonitrile was heated to boiling for 1 hour in a mixture of 200 ml of tetrahydrofuran and 50 ml of 2N hydrochloric acid. The mixture was subsequently poured on to 500 ml of ice/water and extracted three times with 200 ml of diethyl ether each time. The organic phases were washed neutral with water, dried over sodium sulphate and concentrated, thereby obtaining 10.0 g of colourless and in part solid 4-(p-cyanophenyl)cyclohexanecarboxaldehyde (cis/trans ratio about 1:3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[C:12]([OH:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[C:10]#[N:11].ClC(Cl)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[C:12]([O:23][S:29]([CH3:28])(=[O:31])=[O:30])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:20])([F:21])[F:22])[C:10]#[N:11]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC(=C(O)c1ccccc1C(F)(F)F)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CS(=O)(=O)OC(=C(C#N)c1ccc(Cl)cc1Cl)c1ccccc1C(F)(F)F

Procedure:
93 mg of triethylamine was added to a mixture comprising 0.30 g of α-(2,4-dichlorophenyl)-β-hydroxy-β-(2-trifluoromethylphenyl)acrylonitrile and 7 ml of dichloroethane. Then, 96 mg of methanesulfonyl chloride was added thereto, and the mixture was reacted for 17 hours at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:18]#[C:19][CH:20]([OH:22])[CH3:21])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])=[N:7][C:6]=2[CH:17]=1>C(OCC)(=O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:18][CH2:19][CH:20]([OH:22])[CH3:21])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])=[N:7][C:6]=2[CH:17]=1
Reactant: CC(O)C#Cc1cc(Cl)cc2nc(-c3ccccc3Cl)oc12
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CC(O)CCc1cc(Cl)cc2nc(-c3ccccc3Cl)oc12
Reaction time: 2.5 h
Yield: 74.2 %

Procedure:
11.10 g (33.4 mmol) of 5-chloro-2-(2-chlorophenyl)-7-(3-hydroxy-1-butynyl)-benzoxazole was hydrogenated in 220 ml of ethyl acetate with 3.7 g of neutral Raney-nickel as catalyst. After 2.5 hours, H2 uptake had ceased and the nickel was filtered off. The solvent was removed in vacuo and the residue crystallized from di-isopropyl ether at 0° C. to give 8.33 g (74.2%) of title compound, mp 85-7° C. A second crop of 0.47 g (4.2%) was recovered.
Reaction SMILES: [Br:1][C:2]1[C:23]([O:24][CH3:25])=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15](S(C)=O)[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH2:26][C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]1[OH:33].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[Br:1][C:2]1[C:23]([O:24][CH3:25])=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15]([NH:26][C@@H:27]5[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]5[OH:33])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: COc1cc2c(cc1Br)ncn2Cc1ccc2nc(S(C)=O)sc2c1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1Br)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a suspension of 6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (502 mg, 1 mmol) from Step 1 of Example 49 and (1R,2R)-2-aminocyclohexanol in DMA (4 mL) was added DIEA (1 mL, 6 mmol). The mixture was heated in a sealed tube at 110° C. for 16 h. The mixture was cooled to rt and added dropwise with stirring to H2O (200 mL). After the mixture was stirred for 30 min, the solid was collected by filtration to afford (1R,2R)-2-((6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (443 mg, 80%) as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.86 (s, 1H), 7.66 (d, J=1.1 Hz, 1H), 7.37 (s, 1H), 7.30 (m, 1H), 7.22 (m, 1H), 5.46 (s, 2H), 4.76 (d, J=5.1 Hz, 1H), 3.86 (s, 3H), 3.53 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.88 (m, 1H), 1.55-1.69 (m, 2H), 1.11-1.33 (m, 4H). LCMS (ESI) m/z 486 and 488 (M+H)+.
Reaction SMILES: S(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]=1)(C)(=O)=O.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.[Na]>CN(C=O)C>[N:21]1([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)Nc1cccc(COS(C)(=O)=O)c1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(Cn2ccnc2)c1
Temperature: 70 °C
Yield: 68 %

Procedure:
The title compound from Step A above (14.54 g, 44.8 mmoles) was dissolved in anhydrous DMF (100 mL) and sodium imidazole (6.52 g, 72.4 mmoles) was added. The mixture was heated under argon at 70° C. for 2 h. The solution was evaporated to dryness and chromatographed on silica gel using 2% (10% conc. NH4OH in methanol)-dichloromethane as the eluant to give the title compound (8.92 g, 68%):
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[C:24]2[NH2:28])=[CH:18][CH:17]=1.C(O)C.[BH4-].[Na+]>O>[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:9][CH2:10]2)=[CH:20][CH:21]=1
Reactant: Nc1nccn1Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nccn2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
4-Oxo-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (0.053 mol), 1-[(4-fluorophenyl)methyl]-1H-imidazol-2-amine and titanium(IV)isopropoxyde (0.055 mol) were stirred at 50° C. for 2 hours. Ethanol (350 ml) and sodium borohydride (0.53 mol) were added. The mixture was stirred at RT overnight and water was added. The mixture was filtered over decalite, washed with ethanol/CH2Cl2 and the solvent was evaporated. The residue was taken up in CH2Cl2, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0, 99/1, 98/2, 97/3, 96/4 and 94/6). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE and the precipitate was filtered off and dried, yielding 11.3 g (57%) of 1,1-dimethylethyl 4-[[1-[(4-fluorophenyl)methyl]-1H-imidazol-2-yl]amino]-1-piperidinecarboxylate (intermediate 29).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[CH:17][CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[Br:20][C:21]1[C:29]2[C:28](Cl)=[N:27][CH:26]=[N:25][C:24]=2[N:23]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:22]=1.[F-].[Cs+].C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[Br:20][C:21]1[C:29]2[C:28]([NH:1][C@H:2]([C:4]3[N:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:8](=[O:16])[C:7]4=[CH:17][CH:18]=[CH:19][N:6]4[N:5]=3)[CH3:3])=[N:27][CH:26]=[N:25][C:24]=2[N:23]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:22]=1
Reactant: C[C@H](N)c1nn2cccc2c(=O)n1-c1ccccc1
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c(Cl)ncnc21
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: C[C@H](Nc1ncnc2c1c(Br)cn2COCC[Si](C)(C)C)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 72 %

Procedure:
(S)-2-(1-Aminoethyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (370 mg, 1.46 mmol) was treated with 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (793 mg, 2.19 mmol), cesium fluoride (120 mg, 0.79 mmol), N,N-diisopropylethylamine (2.3 ml, 13.20 mol) and tert-butanol (10 ml) as a solvent according to Preparation 13. The residue was purified using SP1® Purification System (0% to 35%, hexane-ethyl acetate) to give 0.61 g (72% yield) of the title compound. Purity 100%.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Na].Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:22][CH:21]=[C:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>C(O)C>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][O:11][C:8]3[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=3)[CH2:18][CH:19]=2)=[CH:24][CH:25]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: Fc1ccc(C2=CCN(CCCl)CC2)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CC(=O)Nc1ccc(OCCN2CC=C(c3ccc(F)cc3)CC2)cc1

Procedure:
0.3 g. of p-acetamidophenol are dissolved in a solution of 0.12 g. of sodium in 10 ml. of absolute ethanol and 0.55 g. of 1-(2-chloroethyl)-4 -(p-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride are added thereto all at once. The reaction mixture is heated under reflux conditions for 24 hours, filtered from the precipitated sodium chloride and the filtrate evaporated to dryness. The residue is absorbed on silica gel and eluted with methylene chloride-ether (1:1). The 4'-{2-[4-(p-fluorophenyl)-3,6-dihydro-1(2H)-pyridyl]-ethoxy}-acetanilide obtained from the eluate melts at 139°C. after recrystallization from acetic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][Cl:20])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CO.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][Cl:20])=[C:7]([NH2:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCCCCCl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1cnc2cc(Br)ccc2c1NCCCCCl
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A suspension of (7-bromo-3-nitroquinolin-4-yl)-(4-chlorobutyl)amine (8.05 g, 22.5 mmol) in methanol (250 mL) was cooled to 0° C.; a solution of sodium hydrosulfite (19.5 g, 112 mmol) in water (80 mL) was added dropwise over a period of 30 minutes. The reaction was stirred at ambient temperature for two hours and then concentrated under reduced pressure. The residue was partitioned between dichloromethane (300 mL) and aqueous sodium bicarbonate (150 mL of 50%). The aqueous layer was separated and extracted with dichloromethane (2×50 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 7.25 g of crude 7-bromo-N4-(4-chlorobutyl)quinoline-3,4-diamine as a light brown semi-solid.
Reaction SMILES: Cl[CH:2]([CH3:15])[CH2:3][NH:4][C:5]1[C:10]([CH2:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:13][CH3:14]>C(Cl)(Cl)Cl>[CH2:13]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH3:12])[C:5]=1[N:4]1[CH2:3][CH:2]([CH3:15])[N:4]([C:5]2[C:6]([CH2:13][CH3:14])=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:11][CH3:12])[CH2:3]1)[CH3:14]
Reactant: CCc1cccc(CC)c1NCC(C)Cl
Solvent: ClC(Cl)Cl
Product: CCc1cccc(CC)c1N1CC(C)N(c2c(CC)cccc2CC)C1

Procedure:
A mixture of 46.3 g (0.205 moles) of N-(β-chloropropyl)-2,6-diethyl-aniline, obtained as indicated in point (b) above, 61.2 g (0.41 moles) of 2,6-diethylaniline and 1.66 g (10 mmoles) of potassium iodide is stirred at 140° to 145° C. for 4 hours under nitrogen atmoshere. The mixture is allowed to cool, 150 ml of isopropanol are added, and the resulting mixture is stirred at 0° to +5° C. for 2 hours. The separated 2,6-diethyleniline hydrochloride (19.2 g, 25.2%) is filtered off, washed with cold isopropanol and dried. The filtrate is acidified with isopropanolic hydrochloric acid (acid content: about 15 g/100 ml), the separated precipitate is filtered off, washed with cold isopropanol and dried. The resulting crude substance, weighing 72 g, is recrystallized from methanol to obtain 29.4 g (34.8%) of 1,2-bis(2',6'-diethylphenyl-amino)-propane dihydrochloride as a uniform substance; m.p.: 161°-167° C. The base is liberated from this salt as described in point (c) of Example 16 and isolated from the reaction mixture by extraction with chloroform.
Reaction SMILES: [CH2:1](C1C=CC=C(CC)C=1N)C.[CH2:12]([C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([CH3:25])[C:23]=1[OH:24])[C:17]([NH:19][OH:20])=[NH:18])[CH3:13]>>[CH2:12]([C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([CH2:25][CH3:1])[C:23]=1[OH:24])[C:17]([NH:19][OH:20])=[NH:18])[CH3:13]
Reactant: CCc1cccc(CC)c1N
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Product: CCc1cc(C(=N)NO)cc(CC)c1O

Procedure:
The title compound is prepared from commercially available 2,6-diethylaniline following literature procedures (G. G. Ecke, J. P. Napolitano, A. H. Filbey, A. J. Kolka, J. Org. Chem. 22 (1957) 639-642; and literature cited for 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH3:23][NH2:24]>C(Cl)Cl>[CH3:23][NH:24][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN
Reactant: O=C(O)CCCCCCCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CNC(=O)CCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 8-phenyl octanoic acid (28.6 g, 129.8 mmol, 1 eq) in CH2Cl2 (100 mL) cooled to 0° C. was added oxalyl chloride (17 mL, 195 mmol, 1.5 eq) dropwise via an addition funnel over 30 minutes. Upon the completion of the addition, the ice bath was removed and the reaction was stirred at rt for 2 h. It was then heated at reflux for 30 minutes. The reaction was cooled to rt and concentrated in vacuo to afford a yellow oil. It was added as a solution in EtO (100 mL) to a solution of condensed methyl amine (-20 mL) in EtO (200 mL) at −78° C. Immediately, a white precipitate formed. The cold bath was removed and the reaction was allowed to stir overnight warming to rt under a stream of N2. The residue was washed with Et2O and concentrated to afford N-methyl-8-phenyloctanamide (25.2 g, 83%) as a yellow-white solid. 1H NMR (CDCl3) δ 7.68-7.10 (m, 5H); 5.42 (bs, 1H); 3.80 (m, 3H); 2.60 (m, 2H); 2.18 (m, 2H); 1.60 (m, 4H); 1.30 (m, 8H).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:36]1([CH2:42][S:43][C:44]2[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:36]1([CH2:42][S:43][C:44]2[CH:45]=[C:46]([C:2]3[CH:35]=[CH:34][C:5]([CH2:6][C:7]4[N:8]([C:20]5[CH:21]=[C:22]([N:26]6[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]6)[CH:23]=[CH:24][CH:25]=5)[CH:9]=[C:10]([C:12]5[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=5[Cl:19])[N:11]=4)=[CH:4][CH:3]=3)[CH:47]=[CH:48][CH:49]=2)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: OB(O)c1cccc(SCC2CCCCC2)c1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4cccc(SCC5CCCCC5)c4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (119 mg, 0.2 mmol) was treated as described in general procedure G using 3-(cyclohexylmethylsulfanyl)phenylboronic acid (100 mg, 0.4 mmol, prepared according to general procedure I) to give 5-{3-[2-(3′-cyclohexylmethylsulfanyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[O:9][CH2:8][CH:7]=[CH:6]1)(=[O:3])[CH3:2]>CO>[C:1]([O:4][C@@H:5]1[C@@H:10]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[O:9][CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OCC=C[C@@H]1OC(C)=O
Solvent: CO
Product: CC(=O)OC[C@H]1OCCC[C@@H]1OC(C)=O
Yield: 91.2 %

Procedure:
4,6-di-O-acetyl-1,5-anhydro-2,3-dideoxy-D-erythro-hex-2-enitol (5.17 g; 24.1 mmol) was hydrogenated on platinum/charcoal (10%) in dry methanol (20 ml) for 25 h. Filtration and evaporation yields 4.75 g of product (91%).