Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][C:8]([CH3:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]4[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=4)[C:26]#[N:27])[CH:14]=3)[O:9][C:8]([CH3:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CN1C(=O)C2(CC(C)(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(C)(c3ccccc3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Yield: 35.6 %

Procedure:
Pd(PPh3)2Cl2 (14 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′,2-dimethyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (45 mg, 0.113 mmol) in 1,4-dioxane (2 mL), Cs2CO3 (2 N, 0.45 mL) and 4-cyanophenylboronic acid (33 mg, 0.226 mmol). The mixture was refluxed under Ar in a microwave reactor for 2 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative HPLC twice to give pure 3-(2′-amino-1′,2-dimethyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (17 mg, 36%). 1H-NMR (CDCl3): 1.78 (s, 3H), 1.97 (s, 3H), 2.60 (d, 1H), 2.85 (d, 1H), 6.84 & 6.93 (s, 1H), 7.23 (m, 2H), 7.31 (m, 4H), 7.48 (m, 2H), 7.52 (m, 2H), 7.62 (m, 1H), 7.67 (m, 1H), 11.51 (brs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].Cl.[CH2:38]([O:40][C:41](=[O:44])[CH2:42][NH2:43])[CH3:39]>>[CH2:38]([O:40][C:41](=[O:44])[CH2:42][NH:43][C:23](=[O:24])[CH:22]([N:8]1[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[CH:7]1[CH2:6][C:5]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:39]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: CCOC(=O)CN
Agent: Cl
Product: CCOC(=O)CNC(=O)C(c1ccccc1)N1CCCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with glycine ethyl ester hydrochloride.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[CH2:9]([O:16][N:17]1[C:23](=[O:24])[N:22]2[CH2:25][CH:18]1[CH2:19][CH2:20][CH:21]2[CH:26]=[N:27][OH:28])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl.N1C=CC=CC=1>[CH2:9]([O:16][N:17]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:18]1[CH2:19][CH2:20][C@H:21]2[C:26]([Cl:8])=[N:27][OH:28])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1N2CC(CCC2C=NO)N1OCc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1N2C[C@@H](CC[C@H]2C(Cl)=NO)N1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
NCS (295 mg, 2.2 mmol) was added to a solution of 6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbaldehyde oxime (560 mg, 2.0 mmol) in dry DCM (15 mL) at rt. Pyridine (one drop) was then added, and the reaction mixture was stirred at rt for 18 hrs. The solution was evaporated to afford (2S,5R)-6-(benzyloxy)-N-hydroxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbimidoyl chloride, which was directly used in the next step. ESI-MS (EI+, m/z): 274 [M-Cl]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[CH3:13][C:10]1[O:9][C:8]([C:7]2[C:2]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[N:12][N:11]=1
Reactant: Cc1nnc(-c2cccnc2Cl)o1
Reactant: C1CNCCN1
Product: Cc1nnc(-c2cccnc2N2CCNCC2)o1

Procedure:
This intermediate compound was synthesized from 2-chloro-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine (prepared according to J. Heterocyclic Chemistry, 17, 425 (1980)) and piperazine using the procedure of Example 6.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]\[CH:34]=O)=[CH:4][N:3]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][C:38]1=[O:43]>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([CH:32]=[CH:33][CH2:34][N:40]2[CH2:41][CH2:42][N:37]([CH3:36])[C:38](=[O:43])[CH2:39]2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C\C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CN1CCNCC1=O
Product: COc1cc(-c2csc3c(C=CCN4CCN(C)C(=O)C4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-(4-{4-amino-7-[(1Z)-3-oxoprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide, 1-methyl-piperazin-2-one (trifluoroacetic acid salt), and General Procedure B. 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (s, 1H), 7.99 (m, 1H), 7.97 (s, 1H), 7.70 (d, 1H), 7.60 (s, 1H), 7.58 (d, 1H), 7.33 (s, 1H), 7.31 (t, 1H), 7.19 (s, 1H), 7.11 (t, 1H), 7.07 (d, 1H), 6.71 (d, 1H), 6.22 (m, 1H), 5.65 (br, 2H), 4.02 (s, 3H), 3.89 (s, 3H); 3.30 (m, 4H), 3.03 (s, 2H), 2.81 (s, 3H), 2.72 (m, 2H); MS: (MH)+ 581.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13]>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]([CH:16]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C)c(Cc2ccc(-c3ccccc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.7 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-phenylbenzoate (349 mg, 0.8004 mmol) was dissolved in a mixed solution of a 1N aqueous solution of sodium hydroxide (10 ml) and 1,4-dioxane (20 ml) followed by stirring at room temperature for 16 hours. The reaction solution was diluted with water (100 ml), washed with ether, acidified with concentrated hydrochloric acid and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom to give the title compound (340 mg, 0.7819 mmol, 98%).
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]#[N:13])[N:9]=[CH:8]1.C1C(=O)N([Br:23])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:23][C:8]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:15])([CH3:14])[CH3:1])[CH:11]=[C:10]([C:12]#[N:13])[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[Si](C)(C)CCOCn1cnc(C#N)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1Br
Temperature: 60 °C
Yield: 77.9 %

Procedure:
To a solution of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile (0.70 g, 3.1 mmol) (as prepared in the previous step) in CCl4 (10 mL) was added NBS (0.61 g, 3.4 mmol) and AIBN (cat), and the mixture heated at 60° C. for 4 h. The reaction was diluted with EtOAc (30 mL) and washed with NaHCO3 (2×30 mL) and brine (30 mL) and the organic layer was dried over Na2SO4 and then concentrated. The title compound was eluted from a 20-g SPE cartridge (silica) with 30% EtOAc/hexane to give 0.73 g (77%) of a yellow solid. Mass spectrum (CI (CH4), m/z) Calcd. for C10H16BrN3OSi, 302.0/304.0 (M+H), found 302.1/304.1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC>C1(C)C=CC=CC=1.C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([CH:13]=[CH2:14])[N:11]=[C:10]([Cl:12])[CH:9]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=Cc1cc(C(=O)OC)cc(Cl)n1
Temperature: 25 °C
Yield: 70 %

Procedure:
Add methyl 2,6-dichloro-isonicotinate (3.8 g, 18.4 mmol), tetrakis(triphenylphosphine)palladium (0) (1.15 g, 0.99 mmol), triphenyhlphosphine (524 mg, 2 mmol) in toluene (40 mL) to a previously nitrogen-filled sealed vessel. Flush the reactants with nitrogen again. Add tributyl(vinyl)tin (6.98 mL, 24.0 mmol) and heat the sealed mixture at 95° C. overnight. Cool to room temperature, dilute with diethyl ether and filter through a filtering agent. Wash the organic filtrate with saturated ammonium chloride, saturated sodium bicarbonate and saturated aqueous sodium chloride. Dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 5:95 to 10:90 ethyl acetate:hexanes) to give the title compound (70%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[N:12]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)[S:13]([C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C([Sn](CCCC)(CCCC)[C:44]([O:46]CC)=[CH2:45])CCC.[F-].[K+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:44]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[N:12]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)[S:13]([C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14])(=[O:46])[CH3:45]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2ncc3ccccc3c2Br)cc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2ncc3ccccc3c2C(C)=O)cc1
Reaction time: 6 h
Yield: 46.6 %

Procedure:
A mixture of ethyl 4-({(4-bromoisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}-sulfonyl)benzoate (122.0 mg, 0.20 mmol) prepared in Example 153, tributyl(1-ethoxyvinyl)tin (94.0 mg, 0.26 mmol) and dichlorobis(triphenylphosphine)palladium (II) (14.0 mg, 0.02 mmol) in 1,4-dioxane (1 mL) was heated to reflux under argon atmosphere for 16 hours. After cooling, the reaction solution was diluted with ethyl acetate, and poured into aqueous potassium fluoride solution. The mixture was stirred for 6 hours. The insoluble was filtered off, and then the filtrate was extracted with ethyl acetate. The organic layer was washed with water. Then, thereto was added 2 mol/L hydrochloric acid, and the mixture was stirred for 3 days. Then, the organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→3:2) to give ethyl 4-({(4-acetylisoquinolin-3-yl) [4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate (53.4 mg, 47%) as a white powder.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:8])[N:5]([CH3:7])[CH:6]=1.[CH2:9]([N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:15]2=[N:14]1)[CH2:10][C:11]#[CH:12]>>[Cl:22][C:21]1[C:15]2[C:16](=[N:17][N:13]([CH2:9][CH2:10][C:11]#[C:12][C:2]3[N:3]=[C:4]([CH3:8])[N:5]([CH3:7])[CH:6]=3)[N:14]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: C#CCCn1nc2cccc(Cl)c2n1
Reactant: Cc1nc(Br)cn1C
Product: Cc1nc(C#CCCn2nc3cccc(Cl)c3n2)cn1C
Reaction time: 0.25 h
Yield: 5.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(C), from 4-bromo-1,2-dimethyl-1H-imidazole (85 mg, 0.49 mmol) and 2-but-3-ynyl-4-chloro-2H-benzo[d][1,2,3]triazole (100 mg, 0.49 mmol, Example 146(B)). Microwave conditions: 100° C. for 15 min. The crude residue was purified by C18 flash chromatography to yield 8.0 mg (27 μmol, 5%) of 4-chloro-2-(4-(1,2-dimethyl-1H-imidazol-4-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a brown semi-solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:31][N:30]([C:32]3[N:36]([CH3:37])[N:35]=[C:34]([CH:38]([CH3:40])[CH3:39])[CH:33]=3)[CH2:29][CH2:28][C:4]=2[N:5]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10]([CH3:27])=[CH:11][N:12]3[S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:7]=1.[Cl:41]N1C(=O)CCC1=O>CC#N.C(OCC)C.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[C:3]2[CH2:31][N:30]([C:32]3[N:36]([CH3:37])[N:35]=[C:34]([CH:38]([CH3:40])[CH3:39])[C:33]=3[Cl:41])[CH2:29][CH2:28][C:4]=2[N:5]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10]([CH3:27])=[CH:11][N:12]3[S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=2)(=[O:18])=[O:19])[N:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc(Cl)c5c(n4)CCN(c4cc(C(C)C)nn4C)C5)cccc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc(Cl)c5c(n4)CCN(c4c(Cl)c(C(C)C)nn4C)C5)cccc32)cc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of 4-chloro-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (90 mg, 0.156 mmol) in MeCN (2.0 mL) at 0° C. was added N-chlorosuccinimide (21 mg, 0.156 mmol). The reaction was permitted to stir for 2.5 h at 0° C., and then was diluted with diethyl ether and saturated aqueous sodium bicarbonate. The layers were separated and the organic layer was washed once with brine, dried over MgSO4, filtered and concentrated to furnish 4-chloro-6-(4-chloro-3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine without the need for further purification. MS (ESI+) m/z 609.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:18]([O-])=O)[C:5]([O:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[F:17])=[N:6][CH:7]=1>CC(O)=O.CCOC(C)=O.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([O:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[F:17])=[N:6][CH:7]=1
Reactant: COc1cccc(F)c1Oc1ncc(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cccc(F)c1Oc1ncc(Cl)cc1N
Temperature: 80 °C

Procedure:
AcOH (30 mL) and iron powder (5 g) were charged into a round bottom flask equipped with a magnetic stirring bar and warmed to 80° C. A solution of crude 5-chloro-2-(2-fluoro-6-methoxy-phenoxy)-3-nitro-pyridine in AcOH was added slowly into the mixture, keeping the temperature under 85° C. The reaction mixture was then cooled to room temperature, diluted with EtOAc, and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and the residue was partitioned between NaHCO3 and EtOAc. The organic portion was separated and the aqueous portion was extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide 5-chloro-2-(2-fluoro-6-methoxy-phenoxy)-pyridin-3-ylamine (3.56 g) as a colorless powder.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH2:16][CH3:17])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>CN(C)C=O>[CH2:18]([N:20]([CH2:21][CH3:22])[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH2:16][CH3:17])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:19]
Reactant: CCCc1nnc2c(Cl)nc3ccccc3n12
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCCc1nnc2c(N(CC)CC)nc3ccccc3n12
Yield: 78 %

Procedure:
4-Chloro-1-n-propyl-[1,2,4]-triazolo[4,3-a]quinoxaline (1.23 g., 0.005 mole), the product of Example 5, and 1.1 g. (0.015 mole) of diethylamine in N,N-dimethylformamide (15 ml.) were stirred at room temperature for 2 hours. The reaction mixture was then poured over ice. The precipitate was removed by filtration, washed with water and air dried. Recrystallization (twice) from ethanol/water afforded 1.1 g. (78% yield) of pure 4-diethylamino-1-n-propyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 92°-94° C. Mass spectrum: m/e, 283 (P).
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([OH:22])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:23][O:24][C:25]1[CH:44]=[CH:43][C:28]([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:27][CH:26]=1>N1C=CC=CC=1.O1CCCC1>[CH2:1]([O:17][CH2:18][CH:19]([OH:22])[CH2:20][O:21][C:29]([C:28]1[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCCCCCCCCCCCCOCC(O)CO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 13.4 %

Procedure:
To a mixture of 84.5 g of 3-(hexadecyloxy)-1,2-propanediol in 265 ml of dry pyridine, stirred in an ice bath under nitrogen, was added in a steady stream a solution of 115.5 g of 4-methoxytrityl chloride in 150 ml of dry tetrahydrofuran. This mixture was stirred in the ice bath for 30 minutes, then at room temperature for 2 hours, then refrigerated at 0° C. overnight. The mixture was concentrated to remove the volatile solvents. The residual solution was dissolved in 400 ml of chloroform, washed twice with 200 ml portions of 10% aqueous sodium bicarbonate and twice with 200 ml portions of water, dried and evaporated. The residue was evaporated twice from toluene, taken up in ether, chilled and filtered. The filtrate was taken to dryness, giving a syrup. A 30 g portion of this syrup was dissolved in petroleum ether and chromatographed on a silica gel column eluting with 20% ether in petroleum ether. The product fractions 6-20 (200 ml each) were combined and evaporated, giving 21 g of the desired compound.
Reaction SMILES: [C:1]1([CH:7]2[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][N:17]=[C:18]=[S:19]>O1CCOCC1>[C:1]1([CH:7]2[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH2:10][CH2:9][N:8]2[C:18](=[S:19])[NH:17][CH3:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2NCCc3[nH]cnc32)cc1
Reactant: CN=C=S
Solvent: C1COCCO1
Product: CNC(=S)N1CCc2[nH]cnc2C1c1ccccc1

Procedure:
A solution of 3.5 g of 4-phenyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (Farmaco, Ed. Sci., 1967, 22, 821) and 3.5 g of methyl isothiocyanate in 55 ml of dioxane is refluxed for 4 h. The solution is cooled and filtered: 3.6 g of 4-phenyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetrahydroimidazo-[4,5-c]-pyridine, m.p. 228°, are collected.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:2]12.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13]>C(#N)C>[CH2:1]1[N:6]([CH2:13][CH2:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])[CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:2]12
Reactant: C=CC(=O)OCC
Reactant: C1CCN2CCNCC2C1
Solvent: CC#N
Product: CCOC(=O)CCN1CCN2CCCCC2C1

Procedure:
A solution of 7 g of octahydro-2H-pyrido[1,2-a]pyrazine and 15 ml of ethyl acrylate in 100 ml of acetonitrile is refluxed for 24 hours and then concentrated to dryness in vacuo to yield the expected product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:5]=[C:6]([F:8])[CH:7]=1.[Li]CCCC.[S:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1>C1COCC1>[CH3:15][C:10]1[N:9]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([C:24]3([OH:27])[CH2:25][CH2:26][S:21][CH2:22][CH2:23]3)=[C:6]([F:8])[CH:5]=2)[C:13]([CH3:14])=[CH:12][CH:11]=1
Reactant: O=C1CCSCC1
Reactant: Cc1ccc(C)n1-c1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(F)c(C2(O)CCSCC2)c(F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To the solution of 1-(3,5-difluorophenyl)-2,5-dimethyl-1H-pyrrole (Step 1, 16.7 g, 80.6 mmol) in anhydrous THF (161 mL) at −78° C. under N2 is added n-BuLi (1.6 M in hexanes, 51.8 mL, 82.9 mmol) dropwise. After stirring at −78° C. for 1 h, the reaction mixture is treated with tetrahydrothiopyran-4-one (5.35 g, 46.1 mmol) in anhydrous THF (46 mL) dropwise and then stirred at −78° C. for 2 h and at 0° C. for 3 h. The reaction is then quenched by the slow addition of saturated aqueous ammonium chloride (50 mL), diluted with H2O (50 mL) and Et2O (50 mL) and the layers are separated. The organic phase is washed with H2O (50 mL) and saline (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the residue is purified by silica gel chromatography (650 mL, 10-20% EtOAc/Hexanes eluent) to give the title compound, mp 125-126° C.; MS (ESI+) for C17H19F2NOS m/z 324 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([CH2:14][C:15]2[O:16][CH:17]=[C:18]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:21])[N:19]=2)[CH2:8][C:9]([O:11]CC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-]>C1COCC1.O>[C:1]1([CH:7]([CH2:14][C:15]2[O:16][CH:17]=[C:18]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:21])[N:19]=2)[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(Cc1nc(C(=O)NCCCCNc2ccccn2)co1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC(Cc1nc(C(=O)NCCCCNc2ccccn2)co1)c1ccccc1
Reaction time: 24 h
Yield: 82.8 %

Procedure:
To a solution of ethyl (±)-3-phenyl-4-[4-[[[4-(pyridin-2-yl)amino-1-butyl]amino]carbonyl]-1,3-oxazol-2-yl]butanoate (197 mg, 0.44 mmole) in 1:1 THF/H2O (4 mL) was added 1.0 N LiOH (0.66 mL, 0.66 mmole). After 24 hr, the mixture was washed with Et2O (2×2 mL), and the pH of the aqueous layer was adjusted to 6 using 10% HCl. The solution was chromatographed on a C-18 Mega Bond Elut® column (50 mL H2O then 50 mL 20% CH3CN/H2O). Fractions containing the product were pooled and lyophilized to give the title compound (154 mg, 83%) as a white powder: MS (ES) m/e 423 (M+H)+. Anal. Calcd for C23H26N4O4.0.75 H2O: C, 63.36; H, 6.36; N, 12.85. Found: C, 63.55; H, 6.27; N, 12.50.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl[CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:9][CH2:8]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: FC(F)(F)c1ccc(-c2cccc(CCl)c2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(-c2cccc(CN3CCN(c4ncccn4)CC3)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1.6 g of 1-pyrimidin-2-ylpiperazine in 200 ml of THF is treated with 2.75 g of 3-chloromethyl-4′-trifluoromethylbiphenyl (“H”) [obtainable, for example, by radical chlorination of 3-methyl-4′-trifluoromethylbiphenyl], dissolved in 30 ml of THF, and the mixture is stirred for 4 hours at room temperature. After customary work-up, 1-pyrimidin-2-yl-4-[(4′-trifluoromethyl-3-biphenylyl)methyl]piperazine is obtained.