Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:16].[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][CH:24]=2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[NH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([CH:20]2[CH2:21][CH2:22][N:17]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:7]4=[N:6][C:5]=3[CH3:16])[CH2:18][CH2:19]2)=[CH:24]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: Cc1nc2cccc(C)n2c(=O)c1CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Cc1nc2cccc(C)n2c(=O)c1CCN1CCC(c2c[nH]c3ccccc23)CC1
Yield: 31 %

Procedure:
A mixture of 4.8 parts of 3-(2-chloroethyl)-2,6-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one, 4 parts of 3-(4-piperidinyl)-1H-indole, 8.5 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone is stirred and refluxed overnight using a water-separator. The reaction mixture is cooled, water is added and the precipitated product is filtered off. It is dissolved in a mixture of trichloromethane and methanol (90:10 by volume). The solution is filtered over silica gel and the filtrate is evaporated. The residue is crystallized from 2-propanol, yielding 2.5 parts (31%) of 3-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2,6-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 224.9° C.
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[S:21][CH:22]=[CH:23][CH:24]=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[S:21][CH:22]=[CH:23][CH:24]=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: COCCCOc1cc(CCl)cc2c(OC)cccc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3cccs3)cc2)C(O)C1
Product: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3cccs3)cc2)cc2c(OC)cccc12

Procedure:
In an analogous manner to that described in Example 1g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(thiophen-2-ylmethoxy)-propoxy]-phenyl]-piperidine-1-carboxylate [Example 123b)] with 3-chloromethyl-5-methoxy-1-(3-methoxy-propoxy)-naphthalene there was obtained tert-butyl (3RS,4RS)-3-[8-methoxy-4-(3-methoxy-propoxy)-naphthalen-2-ylmethoxy]-4-{4-[3-(thiophen-2-ylmethoxy)-propoxy]-phenyl}-piperidine-1-carboxylate as a pale yellow, viscous oil; MS: 706 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]1[C:16]([O:18]CC)=O.CC(C)([O-])C.[K+].O>CS(C)=O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:16](=[O:18])[C:11]3=[CH:12][C:13]([CH3:15])=[CH:14][N:10]3[CH2:9][C:3]=2[CH:4]=1
Reactant: CCOC(=O)c1cc(C)cn1Cc1cc(Cl)ccc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc2n(c1)Cc1cc(Cl)ccc1NC2=O
Temperature: 77.5 °C
Reaction time: 1.5 h
Yield: 88.5 %

Procedure:
To a solution of ethyl 1-[(2-amino-5-chloro-phenyl)methyl]-4-methyl-pyrrole-2-carboxylate (20 g, 68.3 mmoles) in dimethyl sulfoxide (60 mL) add potassium t-butoxide (8.4 g, 74.9 mmoles) in DMSO (40 mL) and heat the reaction mixture to 75-80° C. for 1-2 hr. Add water (200 mL) slowly, cool to room temperature, and stir for 1-2 hr. Filter the solids, wash the filtercake with water (75 mL), and transfer the solids to a clean reaction vessel. Add THF (100 mL) and heat the reaction mixture to 30-35° C. until the solids dissolve. Add DCM (350 mL) and continue to stir at 30-35° C. for 1-2 hr. Add 1N hydrochloric acid (250 mL) and continue to stir at 30-35° C. for 1-2 hr. Separate the layers, wash the organic layer with 1N hydrochloric acid (250 mL) followed by a 25% aqueous solution of sodium chloride (50 mL), and concentrate the solution, at below 50° C., to arrive at a volume of approximately 25 mL. Add ethanol (50 mL), concentrate the solution, at below 50° C., to arrive at a volume of approximately 25 mL, and add additional ethanol (50 mL). Concentrate the solution, at below 50° C., to arrive at a volume of approximately 25 mL, heat the reaction mixture to 45-50° C., and stir for 1-2 hr. Cool the reaction mixture to 5-10° C. with stirring for 2-3 hr., and filter the resulting solids. Rinse the filtercake with ethanol (25 mL) and dry in an oven at less than 50° C. under reduced pressure to give 7-chloro-2-methyl-5,10-dihydro-11H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one as an off-white solid (14.9 g, 99.9% purity, 88.5% yield).
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].Cl.[NH2:11][CH2:12][CH2:13][SH:14]>Cl>[ClH:1].[ClH:1].[CH3:9][C:8]1[N:7]=[CH:6][NH:5][C:4]=1[CH2:3][S:14][CH2:13][CH2:12][NH2:11]
Reactant: Cc1[nH]cnc1CO
Reactant: NCCS
Agent: Cl
Product: Cc1nc[nH]c1CSCCN
Yield: 164.7 %

Procedure:
A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0 g.) and cysteamine hydrochloride (23.0 g.) in concentrated aqueous hydrochloric acid (450 ml.) was heated under reflux for 17 hours. Concentration followed by re-evaporation with water affored as residue which was dissolved in isopropyl alcohol, concentrated to low bulk and cooled to afford 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole dihydrochloride (40.6 g.), m.p. 185°-191°.
Reaction SMILES: [O:1]=[C:2]1[CH2:22][C:5]2[C:6]([C:19]([OH:21])=[O:20])=[N:7][N:8]([S:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)(=[O:11])=[O:10])[C:4]=2[CH2:3]1.O[N:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]1=[O:30].C(Cl)CCl>C(Cl)Cl>[O:30]=[C:25]1[CH2:26][CH2:27][C:28](=[O:29])[N:24]1[O:20][C:19]([C:6]1[C:5]2[CH2:22][C:2](=[O:1])[CH2:3][C:4]=2[N:8]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[N:7]=1)=[O:21]
Reactant: Cc1ccc(S(=O)(=O)n2nc(C(=O)O)c3c2CC(=O)C3)cc1
Reactant: O=C1CCC(=O)N1O
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2nc(C(=O)ON3C(=O)CCC3=O)c3c2CC(=O)C3)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the intermediate from step C above, (320 mg, 1.0 mmol) in CH2Cl2(20 mL) was added N-hydroxy succinimide (230 mg, 2.0 mmol) followed by EDC (384 mg, 2.0 mmol). After stirring at room temperature for 18 hours, the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (20 mL), washed with saturated NaHCO3, solution and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. A yellow solid was obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:11]([CH3:24])[CH2:12][C:13]1[C:21]2[C:16](=[C:17]([F:23])[CH:18]=[C:19]([F:22])[CH:20]=2)[NH:15][CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:33]>CN(C)C=O>[CH2:25]([N:10]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C@H:11]([CH3:24])[CH2:12][C:13]1[C:21]2[C:16](=[C:17]([F:23])[CH:18]=[C:19]([F:22])[CH:20]=2)[N:15]([CH3:33])[CH:14]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CI
Reactant: C[C@H](Cc1c[nH]c2c(F)cc(F)cc12)N(Cc1ccccc1)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](Cc1cn(C)c2c(F)cc(F)cc12)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
NaH (180 mg of 60% oil dispersion, 4.5 mmol) is added to a solution of dibenzyl-[2-(5,7-difluoro-1H-indol-3-yl)-1(R)-methyl-ethyl]-amine (1.4 g, 3.6 mmol) in 20 ml dimethylformamide under N2 at 0° C. The resulting mixture is stirred for 20 minutes, then is allowed to warm to room temperature over 20 minutes. A 5 ml solution of iodomethane in dimethylformamide (7.2 mmol) is added dropwise and the reaction mixture is stirred for 1 hour. The reaction is quenched with cold aqueous NaHCO3, extracted with ethyl acetate, washed with brine, dried (Na2SO4), filtered, concentrated and is purified by flash chromatography (SiO2, ethyl acetate/hexane gradient) to yield 1.3 g of dibenzyl-[2-(5,7-difluoro-1-methyl-1H-indol-3-yl)-1(R)-methyl-ethyl]-amine (89%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[CH2:10].C([Li])CCC.CN(C)[CH:18]=[O:19].O>C1COCC1>[F:8][C:4]1[C:3]([CH:9]=[CH2:10])=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: C=Cc1c(F)cccc1Br
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1c(F)cccc1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-bromo-3-fluoro-2-vinylbenzene (900 mg) in THF (40 ml) was added dropwise, at −78° C., n-butyllithium (3.4 ml 1.6 M/hexane). After 60 minutes, N,N-dimethylformamide (0.69 ml) was added dropwise at −78° C. After stirring at −78° C. for 60 minutes, the reaction mixture was admixed with water and then warmed to room temperature. Then the mixture was admixed with water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated. Purification by column chromatography gives 3-fluoro-2-vinylbenzaldehyde (160 mg).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:10]=[CH:9]2)C=CC=CC=1.Cl>C(O)C>[CH:19]1([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][NH:8][CH:12]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: C(#CCCC1CCCCC1)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: CCO
Product: c1nc(CCCCCCC2CCCCC2)c[nH]1
Temperature: 90 °C
Yield: 34.6 %

Procedure:
1-[1-Triphenylmethyl-1H-imidazol-4-yl]-6-cyclohexyl-3-hexyne (0.629 g, 1.33 mmol) was suspended in ethyl alcohol (3 ml). 2N HCl (25 ml) was added and the reaction mixture heated at 90° C. for 1 hr. The reaction mixture was cooled, filtered through a pad of celite and the filtrate evaporated in vacuo. The residue was dissolved in methanol (20 ml). 10% Pd(C) (0.139 g) and ammonium formate (1.5 g) were added, and the reaction mixture heated at 65° C. under N2 for 6.5 hours. The reaction mixture was cooled, filtered through a pad of celite and the methanol filtrate concentrated. The residue was partitioned between CH2Cl2 and 10% NaOH solution (100 ml, 1:1). The CH2Cl2 layer was separated, washed with water (50 ml), dried over MgSO4, filtered and evaporated in vacuo. Purification by flash chromatography using ethyl acetate as eluent gave 108 mgs of final product. ##STR72## 4-(6-Cyclohexylhexyl)imidazole (41) 1H-NMR (300 MHz, CD3OD): δ7.53 (s, 1H), 6.73 (s, 1H), 2.56 (t, J=7.5 Hz, 2H), 1.65 (m, 7H), 1.40-1.10 (m, 12H), 0.89 (m, 2H); Mass Spectrum: (DCl/NH3): 235 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3=[N:17][CH:18]=[CH:19][N:9]23)=[CH:4][CH:3]=1.Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>C1COCC1.C1CCCCC1>[C:25]([O:24][C:22](=[O:23])[CH2:21][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2=[N:17][CH:18]=[CH:19][N:9]12)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Brc1ccc(C2c3ccccc3-c3nccn32)cc1
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1(c2ccc(Br)cc2)c2ccccc2-c2nccn21
Temperature: 25 °C

Procedure:
To a solution of 5-(4-bromophenyl)-5H-imidazo[2,1-a]isoindole (3.17 g) in THF (60 mL) at −78° C. was added LAD solution (10.19 mL, 1.5 M in cyclohexane) drop wise. After stirring for 5 minutes tert-butyl bromoacetate was added, cooling bath was removed and the reaction mixture was stirred at room temperature. After 1.5 h the reaction was quenched with aqueous saturated NH4Cl and layers were separated. Aqueous layer was extracted with EtOAc (2×). Combined organic layers were dried over Na2SO4 and concentrated. Flash chromatography using a linear gradient of 1-50% EtOAc in hexanes afforded title compound as a white solid. Mass. found (M+H)+, 427.0.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:11]([OH:13])=O.O[N:24]=[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][C:34]([F:37])([F:36])[F:35])[NH2:26].CCN(C(C)C)C(C)C>>[CH3:7][C:8]1[CH:9]=[C:10]([C:11]2[O:13][N:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][C:34]([F:35])([F:36])[F:37])[N:24]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nc(-c3ccccc3OC(F)(F)F)no2)ccc1N1CCOCC1

Procedure:
Oxalyl chloride (1384; 1.63 mmol; 3 eq.), Intermediate 35 (120 mg; 0.54 mmol; 1 eq.), Intermediate 2 (119 mg; 0.54 mmol, 1 eq.) and DIEA (280 μL; 1.63 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 90/10) afforded the title compound as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:9](=[N:13][OH:14])[C:10]([NH2:12])=[O:11])#[N:8].[F:15][CH2:16]Br>CS(C)=O.CN(C)C=O>[C:7]([C:9](=[N:13][O:14][CH2:16][F:15])[C:10]([NH2:12])=[O:11])#[N:8]
Reactant: N#CC(=NO)C(N)=O
Reactant: FCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: N#CC(=NOCF)C(N)=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 72.9 %

Procedure:
Potassium carbonate (85.7 g, 0.62 mol) was added to 2-cyano-2-hydroxyiminoacetamide (35.0 g, 0.31 mol) in dimethylsulfoxide (150 ml) under ice-cooling, and the mixture was stirred for 20 mins. On the other hand, a solution of fluoromethyl bromide (27.8 g, 0.31 mol) in dimethylformamide (27 ml) was added dropwise to the reaction mixture under ice-cooling, and the resultant mixture was stirred at a room temperature for 1.5 hrs. The mixture was dispersed in ice water (1 kg), and it was extracted three times with ethyl acetate (500 ml, 400 ml, and 300 ml, respectively). The combined extracts were washed twice with saturated brine (150 ml) and dried over magnesium sulfate (100 g). The ethyl acetate was distilled off under reduced pressure until the residue weighed 65.5 g. The residue was cooled, filtered, and dried to give 2-cyano-2-fluoromethoxyimino-acetamide (32.8 g, yield: 72.6%).
Reaction SMILES: [CH3:1][C:2]([NH2:15])([CH3:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.ClC(Cl)(Cl)C1O[N:19]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C(Cl)Cl>[CH3:14][C:2]([NH:15][NH:19][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH3:1])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1OC1C(Cl)(Cl)Cl
Reactant: CC(C)(N)Cc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: CC(C)(Cc1ccc(C(F)(F)F)cc1)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.2 g of 2-methyl-1-(4-(trifluoromethyl)phenyl)propan-2-amine was dissolved in 30 mL of methylene chloride and mixed with 5.6 g (21 mmol) of separately prepared t-butyl 3-(trichloromethyl)-1,2-oxaziridine-2-carboxylate under cooling with ice. The reaction solution was stirred at room temperature for 30 minutes, washed with 10% aqueous citric acid, with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively and dried over anhydrous sodium sulfate, and methylene chloride was removed under reduced pressure. The resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel 100 g, ethyl acetate:hexane) to give 1.38 g of the desired product as a white solid.
Reaction SMILES: C[Sn](C)(C)[N:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[N:6][N:5]=[N:4]1.[C:23]1([C:29](Cl)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[C:23]1([C:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:3]2[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[N:6][N:5]=[N:4]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(-c2ccccc2-c2nnnn2[Sn](C)(C)C)cc1
Solvent: c1ccncc1
Product: Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of N-trimethylstannyl 5 (4'-methylbiphenyl-2-yl)tetrazole (Example 10, 0.4 g) and anhydrous pyridine (10 mL) was treated with triphenylmethyl chloride (0.3 g) and stirred at room temperature under a nitrogen atmosphere for 48 hours. The resulting solution was evaporated and the residue was partitioned between dichloromethane and saturated aqueous CuSO4. The organic layer was dried over MgSO4 and evaporated. The residual solid was triturated with diisopropyl ether and collected by filtration to give the title compound, mp 163°-165° C. (decomp., gas evol.).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:17]=1[CH:18]=[CH:19][CH:20]=O.C(O)=O.Cl>C(O)C>[ClH:1].[ClH:15].[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:20][CH:19]=[CH:18][C:17]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:16]=3[Cl:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: O=CC=Cc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Solvent: O=CO
Product: Clc1ccc(CN2CCN(CC=Cc3ccc(Cl)cc3Cl)CC2)cc1
Temperature: 130 °C
Yield: 81.4 %

Procedure:
N-(4-Chlorobenzyl)piperazine (4.2 g, 19.93 mmole) (which is prepared by the process as disclosed in Yoshiaki Ikeda et al., Yakugaku Zasshi, Vol. 89, 669-676, 1969) and 2,4-dichlorocinnamaldehyde (4.1 g, 20.39 mmole) (which is prepared by the process as disclosed in U.S. Pat. No. 3,094,561) are mixed and heated on an oil bath at 130° C. to melt them, and thereto is added dropwise formic acid (2.0 ml, 52.6 mmole), and the mixture is stirred under heating for 30 minutes. The reaction mixture is allowed to cool and is dissolved in ethanol (30 ml), and to the solution is added an ethanol solution (90 ml) of conc. hydrochloric acid (4.5 ml). The precipitated crystals are separated by filtration. The crystals are recrystallized from water-ethanol to give the title compound (3.8 g). The product shows the same physical properties as those of the compound prepared in Example 1-(1).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]#[C:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=4)[N:16]=[CH:15][CH:14]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>CCO.C(OCC)(=O)C.[Pt]=O>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([CH2:11][CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=4)[N:16]=[CH:15][CH:14]=3)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: COc1ccc2nccc(C#CC3CCC4(CC3)OCCO4)c2c1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc2nccc(CCC3CCC4(CC3)OCCO4)c2c1

Procedure:
Platinum oxide ((0.462 g) was added to a solution of 4-(1,4-dioxa-spiro[4.5]dec-8-yl-ethynyl)-6-methoxy-quinoline (0.83 g, 2.53 mmol) in EtOH (30 ml) and ethyl acetate (10 ml) and hydrogenation was carried out under a hydrogen atmosphere (1 bar). The catalyst was filtered off and the filtrate was concentrated to dryness by rotary evaporation. The residue was purified by column chromatography on silica gel (EtOAc and then EtOAc/-methanol 9/1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:18][C:17](=O)[C:16]2[C:11](=[CH:12][C:13]([CH3:20])=[CH:14][CH:15]=2)[N:10]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:32])=O>C1(C)C=CC=CC=1>[Cl:32][C:17]1[C:16]2[C:11](=[CH:12][C:13]([CH3:20])=[CH:14][CH:15]=2)[N:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccccc1-c1nc2cc(C)ccc2c(=O)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1nc(Cl)c2ccc(C)cc2n1
Temperature: 80 °C

Procedure:
To a mechanically stirred suspension of 2-(2-methoxyphenyl)-7-methyl-3H-quinazolin-4-one (100 g, 0.37 mol) in 1 L toluene was added diisopropyl ethylamine (100 mL), followed by phosphorus oxychloride (69 g, 0.45 mol). The reaction was then heated to 80° C. for 4 h. The reaction mixture was distilled under reduced pressure to remove toluene, and the resulting residue was dissolved in 2.2 L CH2Cl2. Ice water was added, and the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution while maintaining the temperature below 20° C. The resulting organic layer was separated and the aqueous solution extracted with CH2Cl2, then the combined the organic layers were dried over sodium sulfate and distilled under reduced pressure. The crude product was dissolved 2:1 CH2Cl2/hexane, and the solution was passed through silica gel (2.5 kg, 60-120 mesh), followed by washing the silica bed with 2:1 CH2Cl2/hexane until the product eluted. The pure fractions were collected and combined, and the solvent was removed under reduced pressure. Hexane (500 mL) was added, and the mixture was stirred and filtered to give 4-chloro-2-(2-methoxy-phenyl)-7-methyl-quinazoline as a white to off-white solid (77 g, 72%). mp 161-164° C. 1H NMR (CDCl3) δ 2.6 (s, 3H), 3.9 (s, 3H), 6.9-7.2 (m, 2H), 7.4-7.6 (m, 2H), 7.7-8 (d, 2H), 8.2 (d, 1H) ppm; M/z (obs., [m+H]+)=285.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[NH:12][CH:13]=2)=[CH:5][C:4]=1[C:20]([F:23])([F:22])[F:21].C(N(C(C)C)C(C)C)C.[CH2:33]([O:40][C:41](ON1C(=O)CCC1=O)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:41]([O:40][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:42])[CH2:16][CH2:15]3)[NH:12][CH:13]=2)=[CH:5][C:4]=1[C:20]([F:21])([F:22])[F:23]
Reactant: Fc1ccc(-c2c[nH]c(C3CCNCC3)n2)cc1C(F)(F)F
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Reaction time: 0.08 h
Yield: 74.9 %

Procedure:
To 4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine hydrochloride salt (1510.00 mg; 3.91 mmol; 1.00 eq.) in DCM was added Ethyldiisopropylamine (2.81 ml; 15.64 mmol; 4.00 eq.) and stirred for 5 mins. N-(Benzyloxycarbonyloxy) succinimide (1169.26 mg; 4.69 mmol; 1.20 eq.) was then added. The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with DCM, washed with water, 5% NaHCO3 aq and brine. The organic layer was dried and concentrated. The residue was subjected to SNAP column (100 g), eluted with 20-80% EA in hexane to afford the title compound (1310 mg, yield 74.9%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].Cl.[CH3:12][NH:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]([N:13]([OH:14])[CH3:12])=[NH:5]
Reactant: CNO
Reactant: N#Cc1c(F)cccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(O)C(=N)c1c(F)cccc1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
To a stirred solution of 2,6-difluorobenzonitrile (5.565 g, 40 mmol) and N-methylhydroxylamine hydrochloride (10 g, 120 mmol) in 4:1 water/ethanol (100 mL) was added sodium carbonate (8.5 g, 80 mmol) in small portions and the resulting mixture stirred at 100° C. for 2 h. The mixture was then cooled, concentrated and the resulting residue suspended in hot MeOH/CHCl3 (1:9, 200 mL). The insoluble solids were removed by filtration and concentration of the filtrate gave the desired product as an off-white solid (7.50 g, 100% yield). 1HNMR (500 MHz, DMSO-d6) δ: 7.69–7.63 (1H, m), 7.29 (2H, t, J=8.24 Hz), 6.90 (2H, s), 3.15 (3H, s). LCMS calcd for C8H9F2N2O (M+H): 187.07; found: 187.12.