Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([NH:13][CH2:14][CH:15](OC)OC)[N:5]=[C:4]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[N:3]=1.FC(F)(F)C(O)=O.ClCCl.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O>[Cl:1][C:2]1[N:3]=[C:4]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[N:5]2[CH:15]=[CH:14][N:13]=[C:6]2[C:7]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc([N+](=O)[O-])cc2)nc1NCC(OC)OC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc([N+](=O)[O-])cc2)n2ccnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.1 %

Procedure:
Methyl [4-chloro-6-[(2,2-dimethoxyethyl)amino]-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (100 mg, 0.19 mmol) was treated with 50% trifluoroacetic acid/dichloromethane (5 mL) at room temperature overnight. The mixture was poured into water and extracted with dichloromethane. The extracts were washed with aq NaHCO3 and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was dissolved in dichloromethane (5 mL). To the solution was added trifluoroacetic anhydride (0.053 mL, 0.38 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was poured into water and extracted with dichloromethane. The extracts were washed with aq NaHCO3 and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (silica gel, chloroform:ethanol, 19/1) to give methyl [7-chloro-5-(4-nitrobenzyl)imidazo[1,2-c]pyrimidin-8-yl]acetate (22 mg, 25%) as a colorless film.
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:22])=[N:4][C:5]2[CH:6]=[C:7]([N+]([O-])=O)[C:8]3[CH:15]=[CH:14][CH:13]=[C:12]([N+]([O-])=O)[C:9]=3[C:10]=2[N:11]=1.Cl.O.O.C(O)(=O)C(O)=O>>[OH:1][C:2]1[C:3]([OH:22])=[N:4][C:5]2[CH:6]=[CH:7][C:8]3[CH2:15][CH2:14][CH2:13][CH2:12][C:9]=3[C:10]=2[N:11]=1
Reactant: O=[N+]([O-])c1cc2nc(O)c(O)nc2c2c([N+](=O)[O-])cccc12
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: O
Product: Oc1nc2ccc3c(c2nc1O)CCCC3

Procedure:
A suspension of 5,6-diamino-1 2 3,4-tetrahydronaphthalene (0.32 g, 2 mmol) in 5 ml of M hydrochloric acid was refluxed with oxalic acid dihydrate (0.38, 3 mmol) for 5 h. After cooling, the precipitate was isolated by filtration, washed with water, ethanol and ether giving 0.31 g (72%) of the title compound; m.p. >300° C.; IR (KBr): 1695 cm-1 (C=0),1H-NMR (DMSO-d6): 1.5-1.9 (m, 4H,2×CH2), 2.5-2.8 (m,4H,2×CH2), 6.63 (d,J=8Hz, 1H, ArH), 6.83 (d,J=8Hz, 1H, ArH), 10.94 (broad s, 1H, 0H), 11.77 (broad s, 1H, 0H)
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.C([Li])CCC.[OH:16][C:17]1[CH:30]=[CH:29][C:20]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=O)=[CH:19][CH:18]=1.Cl>O1CCCC1.CCCCCC.O>[S:4]1[CH2:5][CH2:6][CH2:7][S:8][C:3]1=[C:21]([C:20]1[CH:19]=[CH:18][C:17]([OH:16])=[CH:30][CH:29]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: C[Si](C)(C)C1SCCCS1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2SCCCS2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-trimethylsilyl-1,3-dithiane (29.1 g) in dry tetrahydrofuran (600 ml) is added at -65° a 1.4M solution of n-butyllithium in hexane (108 ml). The reaction mixture is progressively warmed to 0° during 4 hours and cooled to -65°. A further 1.4M solution of n-butyllithium in hexane (108 ml) and a solution of 4-hydroxybenzophenone (30.0 g) in dry tetrahydrofuran (180 ml) are added, the temperature being maintained under -60°. The reaction mixture is progressively warmed to room temperature overnight. The suspension is slowly poured into water (2 l) and acidified to pH 2 with hydrochloric acid (32%). The compound is immediately extracted with ethyl acetate (4×500 ml). The combined organic solutions are washed with water (3×250 ml) and dried over magnesium sulphate. The solvent is evaporated in vacuo. The residue is washed with hexane (3×50 ml) and then recrystallized from carbon teytrachloride. The product is dried in vacuo to constant weight to give (1,3-dithian-2-ylidene)-(4-hydroxyphenyl)-phenylmethane, m.p. 135°-137°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:18]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:18]=2)=[CH:4][C:3]=1[F:9]
Reactant: Nc1ccc(O)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Yield: 93.6 %

Procedure:
By analogy to Example A2, 4-amino-3-fluorophenol (0.12 g, 0.53 mmol), potassium tert-butoxide (0.080 g, 0.71 mmol) and tert-butyl 4-chloropicolinate (159 mg, 0.53 mmol) were combined to provide tert-butyl 4-(4-amino-3-fluorophenoxy)picolinate (151 mg, 67% yield). MS (ESI) m/z: 305.0 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[CH:37]=[CH:36][N:35]([CH2:38][CH3:39])[N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:38]([N:35]1[CH:36]=[CH:37][C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])=[N:34]1)[CH3:39]
Reactant: CCn1ccc(CCl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1ccc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (969 mg; compound B50) is reacted with 3-(chloromethyl)-1-ethyl-1H-pyrazole (454 mg) in the presence of potassium carbonate (630 mg; compound D17) in DMF (15 ml). Using WU2 the title compound is obtained after flash column chromatography [silica gel, eluent: cyclohexane/EtOAc, 15/1 (v/v)] as a solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:6]=1)=[O:4].[BH4-].[Na+]>C(O)C>[O:11]([C:7]1[N:6]=[C:5]([CH:3]([C:2]([F:19])([F:1])[F:18])[OH:4])[CH:10]=[CH:9][CH:8]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(c1cccc(Oc2ccccc2)n1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(c1cccc(Oc2ccccc2)n1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a solution of 10.0 g (0.0375 mol) of the 2,2,2-trifluoro-1-(6-phenoxy-2-pyridinyl)ethanone of Step B in 100 ml of ethanol at 0° C. was added 1.5 g (0.0395 mol) of sodium borohydride portionwise over 5 to 10 minutes. The reaction was then warmed to room temperature and stirred overnight. After this time, the reaction was quenched with 1N aqueous HCl, neutralized with aqueous NaHCO3 and extracted with chloroform. The chloroform extracts were dried over MgSO4, filtered and concentrated to afford a yellow oil which solidified on standing to a waxy solid. Recrystallization from 4:1 hexane-ether afforded 6.13 g (60%) of the title compound as a white powder: m.p. 75° to 77° C.; 1H NMR (CDCl3) δ 4.67 (d, 1H), 4.92 (dq, 1H), 6.9-7.5 (m, 7H), 7.78 (t, 1H); IR (Nujol) 1570, 1600, 3390 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[C:18]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)([CH2:23][C:24]([F:27])([F:26])[F:25])[C:19](OC)=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:18]([N:13]2[C:14]3[C:10](=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH:17]=[CH:16][CH:15]=3)[CH:11]=[N:12]2)([CH2:23][C:24]([F:26])([F:27])[F:25])[CH2:19][OH:20])=[CH:29][CH:30]=1
Reactant: COC(=O)C(CC(F)(F)F)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc2c1cnn2C(CO)(CC(F)(F)F)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of Step A (300 mg, 0.6 mmol) in THF (5 mL) was added LiAlH4 (38 mg, 0.96 mmol) at 0° C. The mixture was stirred at RT for 1 h and quenched with H2O (5 mL), extracted with ethyl acetate, and washed with brine (10 mL), dried over sodium sulfate, then filtered. After the solvent was removed, the residue was purified by silica gel chromatography (EA/PE=1:3) to afford the title compound. LC/MS m/z=470.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].I[CH2:12][CH3:13]>>[Cl:1][C:2]1[C:9]([CH2:12][CH3:13])=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CCI
Product: CCc1c(F)ccc(C#N)c1Cl
Yield: 28.2 %

Procedure:
The title compound is prepared by essentially following the procedure described in Preparation 1, using 2-chloro-4-fluoro-benzonitrile (12.2 g, 78.4 mmol), and iodoethane (18.4 g, 9.43 mL, 118 mmol). The crude product is purified on silica gel using 15-50% dichloromethane/hexanes to give the title compound as shiny white crystals (4.06 g, 28%). 1H-NMR (400 MHz, CDCl3) δ 7.54 (dd, J=5.6, 8.6 Hz, 1H), 7.07 (t, J=8.6 Hz, 1H), 2.85 (qd, J=7.5, 2.3 Hz, 2H), 1.19 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[N+:23]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(Cl)cc2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(Cl)cc2)cc1N
Yield: 72.7 %

Procedure:
Prepared from (4-(4-chloro-phenylethynyl)-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example F6) (606 mg, 1.63 mmol) by reduction with SnCl2.2H2O (1.83 g, 8.1 mmol) according to the general procedure G (method b). Obtained as a beige solid (406 mg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](=[NH:20])[NH2:19])[CH3:14]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)[C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:21])=[C:18]([NH2:19])[NH:20][C:18]=1[NH2:19])=[O:21])[CH3:14]
Reactant: CCOC(=O)CC(=N)N
Reactant: O=Cc1ccnc2ccccc12
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1ccnc2ccccc12
Yield: 58 %

Procedure:
Upon heating a solution of 7.8 g quinoline-4-aldehyde and 13.0 g amidinoacetic acid ethyl ester in 200 ml ethanol for two hours, 2,6-diamino-4-(quinol-4-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 145° (ethanol) is obtained.
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=[C:10]1[NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)=O)(C)(C)C>CCOC(C)=O>[ClH:1].[C:14]1([C@H:13]2[C@@H:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:11][C:10]([NH:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)=[N:9]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C(NCc2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(CNC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride is bubbled into a solution of 85 (0.69 g, 1.58 mmol) in EtOAc (40 mL) for 2 min, and the solution is stirred at RT overnight and then at 45° C. for 3 h. The solvent is removed by rotary evaporation, and the residue crystallized from dichloromethane and Et2O to give 0.52 g of the product 86. 1H NMR (DMSO-d6) δ 9.80-8.40 (m, 3 H), 7.60-7.45 (m, 2 H), 7.35-7.25 (m, 2 H), 7.15-6.95 (m, 6 H), 6.95-6.80 (m, 4 H), 5.50 (s, 2 H), 4.58 (d, 2 H); MS: m/z 346 (M++1).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:23]([F:26])([F:25])[F:24])=[CH:5][C:4]=2[N:3]=1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31]>O1CCOCC1.C(OCC)(=O)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:14]2[C:10]3[C:9]4[CH:8]=[CH:7][C:6]([C:23]([F:26])([F:25])[F:24])=[CH:5][C:4]=4[N:3]=[C:2]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[C:11]=3[N:12]=[CH:13]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(-n2cnc3c(Cl)nc4cc(C(F)(F)F)ccc4c32)cc1
Reactant: NCCCO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(-n2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4c32)cc1
Reaction time: 19 h
Yield: 85.4 %

Procedure:
To a solution of 4-chloro-1-(4-methoxy-phenyl)-7-trifluoromethyl-1H-imidazo[4,5-c]quinoline (153 mg; 0.41 mmol; 1 eq) in anhydrous 1,4-dioxane (18 mL), 3-aminopropanol (77 μL; 1.0 mmol; 2.5 eq) is added. The resulting solution is heated to reflux and allowed to stir for 19 hours after which period the reaction is still not complete on TLC. Thus, additional 3-aminopropanol (523 μL; 6.9 mmol; 17 eq) is added and the stirring is continued under reflux for 4 hours. The crude mixture is diluted with ethyl acetate (40 mL) and washed three times with a 1M aqueous solution of NaOH (3×40 mL). Aqueous layers are combined and re-extracted with ethyl acetate (75 mL). All organic layers are combined, dried over sodium sulfate and concentrated. The crude residue is purified on silica gel (cyclohexane/ethyl acetate 2:8) to afford the title compound as an off-white powder (145 mg; 0.35 mmol; 85%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][C:9]2[N:8]3[CH2:16][CH2:17][N:18]([C:23]4[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[C:26]([C:33](=[O:35])[CH3:34])=[CH:25][N:24]=4)[CH:19]([CH:20]([CH3:22])[CH3:21])[C:7]3=[CH:6][C:5]=2[CH:4]=1.N1C=CC=CC=1.[C:42](Cl)([CH3:44])=[O:43]>C(Cl)Cl>[C:42]([O:1][CH2:2][C:3]1[C:11]([S:12]([CH3:15])(=[O:13])=[O:14])=[CH:10][C:9]2[N:8]3[CH2:16][CH2:17][N:18]([C:23]4[N:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[C:26]([C:33](=[O:35])[CH3:34])=[CH:25][N:24]=4)[CH:19]([CH:20]([CH3:22])[CH3:21])[C:7]3=[CH:6][C:5]=2[CH:4]=1)(=[O:43])[CH3:44]
Reactant: CC(=O)c1cnc(N2CCn3c(cc4cc(CO)c(S(C)(=O)=O)cc43)C2C(C)C)nc1C(F)(F)F
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1cc2cc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(C)=O)c(C(F)(F)F)n1)C3C(C)C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (132 mg, 0.26 mmol) in CH2Cl2 (5 mL) was added pyridine (1 mL) and AcCl (130 μL, 1.3 mmol). The mixture was stirred at rt for 10 h. The reaction was quenched with water (5 mL). The aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with brine, and then dried over anhydrous Na2SO4. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (1/1) to give (2-(5-acetyl-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indol-8-yl)methyl acetate. LC-MS m/z 553 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[CH:12]=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[CH2:12][OH:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=Cc1c(Cl)ncc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1c(Cl)ncc2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
To 3-chloroisoquinoline-4-carbaldehyde (220 mg, crude) in THF (10 mL) was added NaBH4 (155 mg, 4.08 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, acidified to pH 3, and extracted with EtOAc. The combined organic layers were washed with saturated sodium bicarbonate solution and brine, dried over Na2SO4, filtered, and concentrated to give a crude solid. The crude was purified on silica gel using a mixture of EtOAc and hexanes as eluent to give (3-chloroisoquinolin-4-yl)methanol (92 mg, 24% for three steps). LRMS (M+H+) m/z 194.0.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:16])[CH:8]=[CH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:36]([N:43]1[C:47](=[O:48])[C:46](=[O:49])[NH:45][C:44]1=[O:50])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[CH2:36]([N:43]1[C:47](=[O:48])[C:46](=[O:49])[N:45]([CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:16])[CH:8]=[CH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:44]1=[O:50])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(C=Cc1cccnc1)NCCCCO
Reactant: O=C1NC(=O)N(Cc2ccccc2)C1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(C=Cc1cccnc1)NCCCCN1C(=O)C(=O)N(Cc2ccccc2)C1=O

Procedure:
Batch size: 4.4 g (20.0 mmol) N-(4-hydroxybutyl)-3-pyridin-3-yl-acrylamide, 5.2 g (19.8 mmol) triphenylphosphine, 4.1 g (20.1 mmol) 3-benzyl-2,4,5-trioxo-imidazolidine (production according to Ishii et al., J. Med. Chem. 39, 1924 (1996)) and 3.5 g (20.0 mmol) azodicarboxylic acid diethyl ester in 60 ml THF.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]1[CH:11]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:10]1[CH:11]=[C:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:13]=[CH:14][C:15]=1[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncccc1Br
Reactant: OB(O)c1ccc(-c2ccccc2)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncccc1-c1ccc(-c2ccccc2)cc1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 3-bromopyridin-2-amine (1.0 g) in 1,2-dimethoxyethane (50 mL) were added 3-fluorobiphenyl-4-ylboronic acid (1.623 g), sodium carbonate (1.225 g), tetrakis(triphenylphosphine)palladium(0) (0.334 g), and water (10 mL) at room temperature. The reaction mixture was stirred under a nitrogen atmosphere at 80° C. for 4 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by recrystallization (THF/diisopropyl ether) to give the title compound (1.528 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26].CO>>[ClH:26].[C:20]1([C:19]2[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncccc2-c2ccccc2)CC1
Agent: Cl
Solvent: CO
Product: c1ccc(-c2cccnc2C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A mixture of 3-phenyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (102) (202 mg, 0.60 mmol) in HCl/MeOH solution (5 mL) was stirred at RT. for 30 min. Then the solvent was evaporated at 40° C. to give 3-phenyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl hydrochloride (103) (162 mg, 0.60 mmol, 100% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.[CH3:11][C:12]1([CH3:19])[C:16](=[O:17])[CH:15]=[C:14]([CH3:18])[O:13]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:18][C:14]2[O:13][C:12]([CH3:19])([CH3:11])[C:16](=[O:17])[CH:15]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: CC1=CC(=O)C(C)(C)O1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2cc(Cl)cc(Cl)c2)=CC1=O
Temperature: 60 °C
Yield: 45.7 %

Procedure:
To a solution of 3,5-dichlorobenzaldehyde (2.3 g, 13.2 mM) and 2,2,5-trimethyl-3(2H)-furanone (2.0 gm, 15.9 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.6 mL, 1.6 mM). The reaction solution was heated at 60° C. for 4 hours. After the reaction solution was cooled, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a yellow solid. The crude product was purified by chromatography (silica gel, pet. ether/ethyl acetate) to afford a light yellow solid (1.7 g, 45% yield), m.p. 129°-131° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.F[C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][CH:21]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][CH:21]=2)[CH:17]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: Cn1nnc(-c2ccccc2F)c1-c1c[nH]cn1
Product: CC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4F)nnn3C)c2)cc1
Yield: 82 %

Procedure:
As described for example 8e, 4-(2-fluorophenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-1,2,3-triazole (70 mg, 0.29 mmol), was converted, using 4′-fluoro-acetophenone instead of 4-fluorobenzotrifluoride, to the title compound (85 mg, 82%) which was obtained as an off white solid. MS: m/e=362.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[NH2:12][CH2:13][C:14]1([N:20]([CH3:28])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:12][CH2:13][C:14]1([N:20]([CH3:28])[CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CN(Cc1ccccc1)C1(CN)CCCCC1
Solvent: c1ccccc1
Product: CN(Cc1ccccc1)C1(CNC(=O)c2ccc(Cl)c(Cl)c2)CCCCC1
Yield: 98.8 %

Procedure:
A solution of 3,4-dichlorobenzoyl chloride (2.095 g.) in benzene (50 ml) was added to a solution of 1-aminomethyl-N-methyl-N-benzylcyclohexylamine (2.32 g.) in benzene (50 ml) and the mixture heated under reflux for 1 hr. The solution was allowed to cool, washed with 2N sodium hydroxide solution (3 × 50 ml), water (4 × 100 ml), dried (Na2SO4) and evaporated to give a white crystalline solid (4.0 g). Recrystallization from cyclohexane afforded 1-[3,4-dichlorobenzoylaminomethyl]-N-methyl-N-benzylcyclohexylamine (110/39) as white prisms (3.589 g. 89%) m.p. 139°-145°.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.P(Cl)(Cl)(Cl)=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1
Reactant: C1=COCCC1
Reactant: OCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: BrCCCCOC1CCCCO1
Reaction time: 24 h

Procedure:
To a solution of commercially available 4-bromobutan-1-ol (16) (1 equi.) and 3,4-dihydropyran (17) (1.5 equi.) in dichloromethane (3 mL/mmole), phosphorus oxychloride (0.01 equi.) was added at room temperature. The reaction mixture was stirred at that temperature for 24 h. Then potassium carbonate (1 equi.) was added to the reaction mixture and the reaction mixture was stirred at room temperature for 1 h, quenched with water, extracted with dichloromethane, washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (5% EtOAc/hexanes) afforded 2-(4-bromobutoxy)-tetrahydropyran (18), as a colorless oil (88%).