Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[O:11][CH:10](CC([O-])=O)[C@H:9]([N:16]=[C:17]=[S:18])[C@H:8](CC([O-])=O)[C@@H:7]1CC([O-])=O)(=[O:3])[CH3:2].[CH2:27]([NH2:30])[CH2:28][CH3:29].F[C:32](F)(F)[C:33]([OH:35])=[O:34]>ClCCl>[C:33]([O:35][C@@H:7]1[C@@H:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:11][C@H:10]2[C@H:9]([N:16]=[C:17]([NH:30][CH2:27][CH2:28][CH3:29])[S:18]2)[C@H:8]1[O:4][C:1](=[O:3])[CH3:2])(=[O:34])[CH3:32]
Reactant: CCCN
Reactant: CC(=O)OC[C@@H]1OC(CC(=O)[O-])[C@H](N=C=S)[C@H](CC(=O)[O-])[C@@H]1CC(=O)[O-]
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCNC1=N[C@@H]2[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H]2S1
Temperature: 0 °C
Yield: 170.5 %

Procedure:
To a solution of (3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyltriacetate (59 g, 151 mmol) in dichloromethane (500 mL) was added propan-1-amine (9.4 g, 159 mmol) dropwise with stirring at 0° C. After stirred for 1 h, the reaction solution was treated with trifluoroacetic acid (130 g, 1.34 mol) overnight at room temperature. The reaction mixture was washed with saturated sodium bicarbonate (300 mL), dried over anhydrous magnesium sulfate, and concentrated under vacuum to provide a residue, which was purified by silica gel column, eluted with 1% MeOH in dichloromethane to give compound 14 as a yellow oil (50 g, 84%). (ES, m/z): [M+H]+ 388.9; 1H NMR (300 MHz, CDCl3) δ 6.14-6.16 (d, J=6.6 Hz, 1H), 5.33-5.35 (m, 1H), 5.05-5.19 (m, 1H), 4.85-4.89 (m, 1H), 4.27-4.30 (m, 1H), 4.08 (s, 2H), 3.75-3.81 (m, 1H), 3.06-3.28 (m, 2H), 1.97-2.04 (m, 9H), 1.49-1.58 (m, 2H), 0.82-0.91 (m, 3H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[C:30]([NH2:44])=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1>>[NH2:44][C:30]1[N:31]=[CH:32][C:33]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)=[CH:34][C:29]=1[F:28]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2cnc(N)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)cc1F

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 169 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine to afford a white amorphous powder. HPLC (Condition 4) tR=4.37 min, UPLC-MS (Condition 3) tR=0.91 min, m/z=478.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.89 (m, 2H) 2.94 (d, J=11.34 Hz, 1H) 3.18-3.28 (m, 2H) 3.34-3.47 (m, 1H) 4.19 (br. s, 1H) 4.83 (d, J=3.13 Hz, 1H) 6.32 (s, 2H) 7.32 (d, J=8.99 Hz, 2H) 7.40 (d, J=11.73 Hz, 1H) 7.77 (s, 1H) 7.83 (d, J=8.99 Hz, 2H) 7.93 (m, J=2.30, 1.20 Hz, 1H) 8.64-8.72 (m, 1H) 10.11 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.[O:23]=[C:24](Cl)OC(Cl)(Cl)Cl.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH2:39][CH3:40])=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]([CH2:39][CH3:40])[C:24]([N:17]2[CH2:16][CH2:15][C:12]3([C:11](=[O:20])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:19][CH2:18]2)=[O:23])=[CH:34][CH:33]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCNc1ccc(Cl)cc1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: CCN(C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and (4-chloro-phenyl)-ethyl-amine. The reaction mixture was stirred for 1 h at room temperature, 2 h at 50° C. and 1 h at 80° C. before subjecting to work-up and purification. MS (ESI): 496.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=4)[CH:18]=3)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[Cl:35][CH2:36][C:37]1[C:38]([C:43]2[CH:48]=[C:47]([O:49][CH3:50])[C:46]([O:51][CH3:52])=[C:45]([O:53][CH3:54])[CH:44]=2)=[N:39][CH:40]=[CH:41][CH:42]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[ClH:35].[ClH:35].[ClH:35].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=4)[CH:18]=3)[CH2:14][CH2:15]2)[CH2:36][C:37]2[C:38]([C:43]3[CH:48]=[C:47]([O:49][CH3:50])[C:46]([O:51][CH3:52])=[C:45]([O:53][CH3:54])[CH:44]=3)=[N:39][CH:40]=[CH:41][CH:42]=2)=[CH:5][CH:4]=1
Reactant: COc1cc(-c2ncccc2CCl)cc(OC)c1OC
Reactant: COc1ccc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(N(Cc2cccnc2-c2cc(OC)c(OC)c(OC)c2)C2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1
Product: Cl
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(p-anisidino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (139 mg) and 3-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) in acetonitrile (5 ml) was added potassium carbonate (83 mg) and potassium iodide (63 mg). The mixture was stirred at 70° C. overnight and evaporated. The residue was dissolved in chloroform, washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residual oil was applied to a column of silica gel using diethylether-metanol (20:1) as an eluent. A free base obtained was converted to a trihydrochloride to give the title compound as yellow powder.
Reaction SMILES: CO[CH:3]([O:11]C)[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[Mg].II.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:7]1[CH:6]=[CH:5][C:4]([CH:3]=[O:11])=[CH:9][CH:8]=1
Reactant: Brc1ccccn1
Reactant: COC(OC)c1ccc(Br)cc1
Agent: II
Agent: [Mg]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(-c2ccccn2)cc1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
6.93 g (29.9 mmol) of 4-bromobenzaldehyde dimethyl acetal in 40 ml of THF are added dropwise to a warm (from 40° C. to 50° C.) suspension of 0.8 g (31.6 mmol) of magnesium turnings and a small amount of iodine in 10 ml of THF. The reaction mixture is heated to 65° C. and stirred at that temperature for about 30 min. The mixture is allowed to cool to room temperature and the Grignard reagent is added dropwise to a solution of 4.46 g (28.2 mmol) of 2-bromopyridine (Fluka, Buchs, Switzerland) and 0.4 g (0.74 mmol) of DPPP (Fluka, Buchs, Switzerland) in 100 ml of THF (slightly exothermic reaction). After the dropwise addition is complete, the reaction mixture is boiled under reflux for 4 hours and is then allowed to cool; 100 ml of water are added. The mixture is concentrated to about 50 ml using a rotary evaporator, diluted with ethyl acetate and extracted with 0.1N hydrochloric acid (3×). The combined HCl extracts are stirred at room temperature for 20 min, rendered basic with concentrated ammonia solution and extracted with methylene chloride. After removal of the solvent, the residue is chromatographed on silica gel (hexane/ethyl acetate 2:1). The product-containing fractions are concentrated, with the desired title compound crystallising out spontaneously. TLC: Rf =0.22 (hexane/ethyl acetate 2:1). HPLC20-100 : tRet =6.08. 1H-NMR (CDCl3 ; 200 MHz): 8.73/d, J=5 (2H); 8.16 and 7.97/each d (2×2H); 7.80/d, J=4 (2H); 7.3/m (1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[O:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([CH:20]=[C:21](B3OC(C)(C)C(C)(C)O3)[CH:22]=2)[C:18]#[N:19])[CH2:11][CH2:10]1.BrC1C=C(C=C(N2CCOCC2)C=1)C#N.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1>>[Cl:1][C:2]1[N:7]=[C:6]([C:21]2[CH:20]=[C:17]([CH:16]=[C:15]([N:12]3[CH2:11][CH2:10][O:9][CH2:14][CH2:13]3)[CH:22]=2)[C:18]#[N:19])[CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cc(C#N)cc(N3CCOCC3)c2)OC1(C)C
Reactant: Clc1ccnc(Cl)n1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: N#Cc1cc(Br)cc(N2CCOCC2)c1
Product: N#Cc1cc(-c2ccnc(Cl)n2)cc(N2CCOCC2)c1

Procedure:
3-(2-Chloropyrimidin-4-yl)-5-morpholinobenzonitrile was prepared according procedure B from 2,4-dichloropyrimidine and 3-morpholino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile which was synthesized by following procedure A using 3-bromo-5-morpholinobenzonitrile and bis(pinacolato)diboron.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([O:20][CH3:21])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:21][O:20][C:13]1[CH:12]=[C:11]([N:3]2[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]2)[CH:16]=[CH:15][C:14]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C1CCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 20 h
Yield: 61.9 %

Procedure:
To a solution of 4-piperidone hydrochloride monohydrate (10.0 g, 0.065 mol) in DMF (80 mL) are added 4-Fluoro-2-methoxy-1-nitro-benzene (10.0 g, 0.058 mol) and potassium carbonate (20.2 g), and the mixture is stirred at 70° C. for 20 h. After a filtration, the filtrate is poured into H2O (ca. 300 mL), and the resulting precipitates are collected by a filtration followed by washing with H2O for several times to give title compound (8.98 g) in 61% yield. Orange solid.
Reaction SMILES: ClC1C=C2C(C(N[CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][NH:25][C:26]4[C:35]5[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=5)[N:29]=[CH:28][CH:27]=4)[CH2:18][CH2:17]3)=CC=N2)=CC=1.Br[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]Br.C([O-])([O-])=O.[K+].[K+].C[N:51](C=O)C>>[Cl:36][C:32]1[CH:31]=[C:30]2[C:35]([C:26]([NH:25][CH2:24][CH2:23][CH2:22][N:19]3[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][CH2:13][N:51]4[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]4)[CH2:21][CH2:20]3)=[CH:27][CH:28]=[N:29]2)=[CH:34][CH:33]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc2c(NCCCN3CCN(CCCNc4ccnc5cc(Cl)ccc45)CC3)ccnc2c1
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc2c(NCCCN3CCN(CCCN4CCCCC4)CC3)ccnc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1,4-bis{3-[N-(7-chloroquinolin-4-yl)amino]propyl}piperazine described in example 1 (0.15 g, 0.41 mmol), 1,5-dibromopentane (0.068 mL, 0.5 mmol) in DMF (5 mL), K2CO3 (287 mg, 2.07 mmol) is added. After stirring the mixture at room temperature for 48 h, the solvent was removed under reduced pressure. The residue was solubilized in CH2Cl2, washed with NaHCO3 1M and dried over MgSO4. Crude compound is purified by thick-layer chromatography (CH2Cl2/MeOH/NH4OH: 80/20/2.7).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[S:17]([C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18]>C(Cl)Cl>[CH2:1]([NH:8][S:17]([C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1S(=O)(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 12.6 %

Procedure:
To a solution of benzylamine 42 (0.140 mL, 1.278 mmol) in DCM (2.557 mL) was added triethylamine (0.535 mL, 3.84 mmol) and methyl 2-(chlorosulfonyl)benzoate 41 (300 mg, 1.278 mmol) and the resulting colorless solution was stirred at rt for 20 h. The reaction mixture was partitioned between DCM and H2O. The organic layer was washed with 1M HCl, saturated NaHCO3, and brine, dried over MgSO4, filtered and concentrated. The crude mixture was purified by Biotage using EtOAc/Hex ((20:80 to 40:60); 25+S column) to afford compound 43 (49 mgs, 13% yield) as a colorless oil. LRMS (ESI): (calc.) 305.07 (found) 306.2 (MH)+
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[C:7]([Cl:9])[C:6]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=2)=[N:5]1.[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:20]([C:23]1[CH:27]=[C:26]([C:28]([NH:1][C@@H:2]([CH3:19])[CH2:3][N:4]2[CH:8]=[C:7]([Cl:9])[C:6]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=3)=[N:5]2)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]
Reactant: C[C@H](N)Cn1cc(Cl)c(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2cc(Cl)c(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Yield: 50.6 %

Procedure:
The title compound was synthesized from (S)-4-(1-(2-aminopropyl)-4-chloro-1H-pyrazol-3-yl)-2-chlorobenzonitrile (518 mg, 1.75 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (270 mg, 1.75 mmol), HOBt (285 mg, 2.1 mmol), DIPEA (0.367 mL, 2.1 mmol) and EDCI (404 mg, 2.1 mmol) using DCM as solvent using the method of Example 34(d) to afford 382 mg of the title compound. 1H NMR (400 MHz; d6-DMSO): δ 1.15 (d, 3H), 2.42 (s, 3H), 4.30 (m, 2H), 4.44 (m, 1H), 6.86 (s, 1H), 8.01 (m, 3H), 8.12 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3C=[CH:32][CH:31]=[CH:30][N:29]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.C([N:36](CC)CC)C.[C:41](Cl)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]([C:28]3[N:29]=[CH:30][CH:31]=[CH:32][N:36]=3)[C:41](=[O:48])[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccccc1
Reactant: Fc1ccc(Cn2c(CC3CCN(CCNc4ccccn4)CC3)nc3ccccc32)cc1
Solvent: C1CCOC1
Product: O=C(c1ccccc1)N(CCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)c1ncccn1
Reaction time: 2 h
Yield: 69 %

Procedure:
To a stirred and cooled mixture of 6.2 parts of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-2-pyridinamine, 2 parts of N,N-diethylethanamine and 90 parts of tetrahydrofuran was added dropwise slowly a solution of 1.9 parts of benzoyl chloride in 45 parts of tetrahydrofuran. Upon completion, stirring was continued for 2 hours. The reaction mixture was evaporated. Water was added to the residue. The solution was treated with ammonium hydroxide. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 5.3 parts (69%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-N-(2-pyrimidinyl)benzamide; mp. 108.1° C. (508).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:13]=[C:12]([C:14]2[N:18]([CH3:19])[N:17]=[N:16][C:15]=2[CH3:20])[C:11]([Cl:21])=[C:10]2[C:5]=1[CH2:6][CH2:7][NH:8][C:9]2=[O:22].[CH2:23]([O:30][C:31]1[C:36]([CH2:37]Cl)=[C:35]([CH3:39])[CH:34]=[C:33]([CH3:40])[N:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH2:23]([O:30][C:31]1[C:36]([CH2:37][N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[C:11]([Cl:21])[C:12]([C:14]4[N:18]([CH3:19])[N:17]=[N:16][C:15]=4[CH3:20])=[CH:13][C:4]=3[Br:3])[C:9]2=[O:22])=[C:35]([CH3:39])[CH:34]=[C:33]([CH3:40])[N:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Reactant: Cc1nnn(C)c1-c1cc(Br)c2c(c1Cl)C(=O)NCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CN2CCc3c(Br)cc(-c4c(C)nnn4C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 18 mg, 0.45 mmol) was added to an icebath chilled solution of 5-bromo-8-chloro-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (293h, 80 mg, 0.225 mmol) in anhydrous N,N-dimethylformamide (15 mL), and the resulting mixture stirred at 0° C. for 30 minutes. Solid 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (compound Z, 59 mg, 0.225 mmol) was added and stirring continued at 0° C. for one hour. While still cold, the reaction was quenched with water (20 mL). The resulting solution was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (5×50 mL), dried over sodium sulfate, concentrated, and purified by silica gel chromatography (eluting with 1:1 petroleum ether/ethyl acetate) to give 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5-bromo-8-chloro-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (293i, 76 mg, 58% yield) as a light yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([CH2:19]C)([N:7]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:18])C)[CH3:2].[C:22]([O:26][C:27]([N:29]1[CH2:32][CH:31](OS(C)(=O)=O)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:32][CH:31]([O:17][C:14]2[CH:15]=[CH:16][C:11]3[O:10][CH2:9][C:8](=[O:18])[N:7]([CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:21])[CH3:19])[C:12]=3[CH:13]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(=O)C(C)(CC)N1C(=O)COc2ccc(O)cc21
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)N1C(=O)COc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 90 °C
Reaction time: 3 h
Yield: 40.9 %

Procedure:
A mixture of ethyl 2-(6-hydroxy-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (1.08 g, 4.07 mmol), 3-methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester (1.12 g, 4.48 mmol) and Cs2CO3 (2.65 g, 8.12 mmol) in DMF (20 mL) was stirred at 90° C. for 3 h. The reaction mixture was cooled to ambient temperature and poured into water (150 mL). The aqueous mixture was extracted with EtOAc (3×20 mL) and the combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether) to give 3-[4-(1-ethoxycarbonyl-ethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-azetidine-1-carboxylic acid tert-butyl ester as a white solid (0.7 g, 41%). 1H NMR (CDCl3, 400 MHz): δ 6.94 (d, J=8.4 Hz, 1H), 6.30 (m, 2H), 5.30 (q, J=7.2 Hz, 1H), 4.78 (m, 1H), 4.59 (d, J=15.2 Hz, 2H), 4.27 (m, 4H), 3.95 (m, 2H), 1.62 (d, J=7.2 Hz, 3H), 1.45 (s, 9H), 1.21 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:4][N:3]=1.[OH-:17].[Na+].OO>C(O)C.O>[Cl:1][C:2]1[C:6]([C:7]([NH2:8])=[O:17])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:4][N:3]=1
Reactant: COc1ccc(-c2snc(Cl)c2C#N)cc1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2snc(Cl)c2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-chloro-5-(4-methoxyphenyl)-1,2-thiazole-4-carbonitrile (3.4 g, 13.56 mmol, 1.00 equiv) in ethanol/H2O (20/10 mL), sodium hydroxide (1 g, 25.00 mmol, 1.84 equiv), H2O2 (10 g). The resulting solution was stirred overnight at 25° C. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3×80 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 680 mg (crude) of 3-chloro-5-(4-methoxyphenyl)-1,2-thiazole-4-carboxamide as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C11H9ClN2O2S, 269.0 (M+H). found 269.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15](=[CH:25][N:26](C)C)[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=O)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC([NH:36]C1C=C(C(=CN(C)C)C(C2C=CC(F)=CC=2)=O)C=CN=1)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[N:36][NH:26][CH:25]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=C(C(=O)c1cccc(F)c1)c1ccnc(NC(=O)OC(C)(C)C)c1
Reactant: CN(C)C=C(C(=O)c1ccc(F)cc1)c1ccnc(NC(=O)OC(C)(C)C)c1
Product: CC(C)(C)OC(=O)Nc1cc(-c2c[nH]nc2-c2cccc(F)c2)ccn1

Procedure:
The reaction was carried out in the same manner as in Example 2-2) except for using 13.5 g (35.0 mmol) of 2-(2-t-butoxycarbonylaminopyridin-4-yl)-3-dimethylamino-1-(3-fluorophenyl)-2-propen-1-one obtained in Example 22-1) in place of 2-(2-t-butoxycarbonylaminopyridin-4-yl)-3-dimethylamino-1-(4-fluorophenyl)-2-propen-1-one to obtain 12.4 g of the title compound as a yellowish white powder. (Yield: quantitative)
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=O.[C:11]1([NH:17]N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>[Cl-].[Zn+2].[Cl-]>[OH:10][C:7]1[CH:6]=[CH:5][C:4]([C:2]2[NH:17][C:11]3[C:16]([CH:1]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=1
Reactant: NNc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: Oc1ccc(-c2cc3ccccc3[nH]2)cc1
Reaction time: 1 h
Yield: 42.2 %

Procedure:
4-Hydroxyacetophenone phenylhydrazine (47 g.) was fused with 250 g. zinc chloride (10 min. at 180° C.), poured into 3 l. 0.3 HCl, heated and stirred for 1 hour on the steam bath, cooled to 0° and filtered. The precipitate was extracted with pet. ether and allowed to stand. 2-(p-hydroxyphenyl)indole (17 g., m. 224°-229°) was isolated. A well stirred mixture of 2-(p-hydroxyphenyl)indole (0.1 mole), iodoethane (0.1 mole) and sodium bicarbonate (0.12 mole) in 200 ml. of acetone was refluxed overnight, filtered and the acetone removed on the steambath. The isolated 2-(p-hydroxyphenyl)-1-ethylindole was reacted with 4-(2-bromoethoxy)-2,2,6,6-tetramethylpiperidine as in Example 1 to produce 4-{2-[4-(1-ethyl-2-indolyl)phenoxy]ethoxy}-2,2,6,6-tetramethylpiperidine.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH:13]=[CH:12]2)C1C=CC=CC=1>CCOC(C)=O.CCO.CCCCCC.CCOC(C)=O.[Pd]>[C:18]1([N:14]2[C:15]3[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=3)[CH:12]=[CH:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Brc1ccc(-n2ccc3cc(OCc4ccccc4)ccc32)cc1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: Oc1ccc2c(ccn2-c2ccccc2)c1
Yield: 62.1 %

Procedure:
3.8 g (10 mmol) 5-Benzyloxy-1-(4-bromo-phenyl)-1H-indole in 30 ml EtOAc and 10 ml EtOH were hydrogenated in the presence of 5% Pd/C. Column chromatography on silica gel in hexane/EtOAc 5:1 yielded 1.3 g (62%) 1-Phenyl-1H-indol-5-ol as colorless viscous oil, MS: 209 (M).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[C:9]([O:13][C:14](=[O:35])[NH:15][CH:16]([C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]1)=[O:27])[CH2:17][CH2:18]C1C=CC=CC=1Cl)([CH3:12])([CH3:11])[CH3:10]>>[C:9]([O:13][C:14](=[O:35])[NH:15][CH:16]([C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]1)=[O:27])[CH2:17][CH2:18][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8])([CH3:10])([CH3:11])[CH3:12]
Reactant: CC1CCN(C(=O)C(CCc2ccccc2Cl)NC(=O)OC(C)(C)C)CC1
Reactant: Brc1ccccc1I
Product: CC1CCN(C(=O)C(CCc2ccccc2Br)NC(=O)OC(C)(C)C)CC1

Procedure:
tert-Butyl{3-(2-bromophenyl)-1-[(4-methylpiperidin-1-yl)carbonyl]propyl}carbamate is prepared from 2-iodobromobenzene in the same manner that tert-butyl{3-(2-chlorophenyl)-1-[(4-methylpiperidin-1-yl)carbonyl]propyl}carbamate is synthesized.