Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][N:8]([CH3:12])[CH2:9][C:10]=2[CH:11]=1.[Cl:13]N1C(=O)CCC1=O.CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C.O.ClCCl>[NH2:1][C:2]1[C:3]([Cl:13])=[N:4][C:5]2[CH2:6][CH2:7][N:8]([CH3:12])[CH2:9][C:10]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1CCc2ncc(N)cc2C1
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CN1CCc2nc(Cl)c(N)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Amino-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridine D4 (900 mg, 5.52 mmol) was dissolved in acetic acid (50 ml) before being treated portionwise with N-chlorosuccinimide (1.11 g, 8.28 mmol) 20 min. The reaction mixture was stirred overnight at room temperature under argon. The reaction mixture was diluted with water (125 ml), basified to pH10 with solid K2CO3 and extracted with dichloromethane (×2). The combined organic extracts were washed with sodium bicarbonate, dried (MgSO4) and evaporation in vacuo gave a crude black solid. Flash chromatography using dichloromethane (10% MeOH) gave thetitle compound as a pale orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][N:11]=[C:12]([Cl:16])[C:13](O)=[O:14].S(Cl)([Cl:19])=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][N:11]=[C:12]([Cl:16])[C:13]([Cl:19])=[O:14]
Reactant: O=C(O)C(Cl)=NNc1c(Cl)cc(Cl)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Cl)C(Cl)=NNc1c(Cl)cc(Cl)cc1Cl

Procedure:
A mixture consisting of 61 g. (0.20 mole) chloroglyoxylic acid (2,4,6-trichlorophenyl)hydrazone, 200 ml. carbon tetrachloride, and 100 ml. thionyl chloride was heated at the reflux temperature for 6 1/2 hrs. The carbon tetrachloride and thionyl chloride were removed by evaporation under reduced pressure and 50° C. to give 64 g. of an oil. The oil was extracted with technical hexane and the insoluble starting material was removed by filtration. The technical hexane was removed by evaporation under reduced pressure to give chloroglyoxyloyl chloride (2,4,6-trichlorophenyl) hydrazone.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[Si:23]([O:30][CH2:31][CH2:32][CH2:33]O)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].C(O)(=O)C.C(=O)(O)[O-].[Na+]>CO>[Si:23]([O:30][CH2:31][CH2:32][CH2:33][NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:20])[F:21])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1)([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Reactant: Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OCCCNc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
The 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (300 mg, 0.986 mmol) obtained in step C of Example 1-1 was dissolved in methanol (10 ml). Thereafter, 3-[(tert-butyldimethylsilyl)oxy]-1-propanol (186 mg, 0.986 mmol), acetic acid (0.339 ml), and a 1 M sodium cyanoborohydride THF solution (2.96 ml, 2.96 mmol) were added at 0° C. to the obtained solution, and the obtained mixture was stirred at a room temperature for 1 hour. Thereafter, a saturated sodium bicarbonate solution was added to the reaction mixture, and the obtained mixture was then extracted with methylene chloride. The extract was dried over magnesium sulfate, and was then concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:3), so as to obtain 7-[3-(tert-butyldimethylsilyloxy)propylamino]-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (376 mg, 80%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:11]1([C:17]2[S:18][C:19]3[C:24](=[O:25])[N:23]=[CH:22][NH:21][C:20]=3[N:26]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:38])([F:37])[F:36]>O1CCCC1>[N:11]1([C:17]2[S:18][C:19]3[C:24](=[O:25])[N:23]=[CH:22][N:21]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:36])([F:37])[F:38])[C:20]=3[N:26]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=c1nc[nH]c2nc(N3CCOCC3)sc12
Reactant: FC(F)(F)c1ccccc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1ncn(Cc2ccccc2C(F)(F)F)c2nc(N3CCOCC3)sc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
Lithium bis(trimethylsilyl)amide (0.755 mL, 0.755 mmol) was added to a suspension of 2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (90 mg, 0.378 mmol) in tetrahydrofuran (THF) (3 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 30 min before the addition of 1-(bromomethyl)-2-(trifluoromethyl)benzene (0.069 mL, 0.453 mmol). The mixture was warmed up to RT and stirred overnight. The solvent was removed and the residue was partitioned between DCM and brine. The organic layer was concentrated and the residue was purified on a biotage column (5% MeOH/DCM) to give 80 mg (55%) of the product (the undesired regioisomer (24 mg, 17%) was less polar on silica gel). LCMS (ES) m/z=397.0 (M+H)+, 1H NMR (400 MHz, CDCl3-d1) δppm 8.05 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.45˜7.55 (m, 2H), 7.05 (d, J=7.6 Hz, 1H), 5.54 (s, 2H), 3.80 (m, 4H), 3.58 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>O.C1(C)C(C)=CC=CC=1>[CH:17]1[CH:18]=[CH:19][C:14]([NH:13][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: O=CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Temperature: 205 °C
Reaction time: 4 h

Procedure:
To a charge of 157 grams of p-nitrochlorobenzene (1 mole), 169 grams of formanilide (1.4 moles) and 50 grams of xylene at 180° C. is fed over a period of about 4 hours a solution of 58 grams of potassium carbonate (0.42 mole) and 22.5 grams of sodium hydroxide (0.56 mole) in 120 grams of water. Water is removed concurrently from the reaction mixture with the addition of the aforesaid solution. The temperature of the reaction mixture is then raised to 205° C. and heated at such temperature for 11/2 hours. The amounts of 4-nitrodiphenylamine formed and p-nitrochlorobenzene remaining unreacted are then determined, as described in Example 1. The yield of 4-nitrodiphenylamine is 69.3%, and the conversion of the p-nitrochlorobenzene charged is 78.4 or 88.4%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(=O)CC.C(OCC)(=O)C>[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])=[CH:25][CH:24]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: O=C1N(Cc2ccc(Br)cc2)c2ccccc2C12COc1cc3c(cc12)OCO3
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
A mixture of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.05 g, 3.73 mmol), 4-bromobenzyl bromide (1.21 g, 4.84 mmol) and cesium carbonate (1.84 g, 5.65 mmol) in 2-butanone (25 mL) was stirred at ambient temperature for 16 h. The mixture was diluted with ethyl acetate and filtered through Celite. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography and eluted with hexanes/ethyl acetate (9:1, increased to 1:1) to afford 1′-(4-bromobenzyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.42 g, 84%) as a colorless solid: mp 148-150° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ 7.48 (d, J=8.4 Hz, 2H), 7.25-7.17 (m, 4H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.12 (s, 1H), 5.89 (s, 1H), 5.88 (s, 1H), 5.02 (d, J=15.6 Hz, 1H), 4.97 (d, J=9.0 Hz, 1H), 4.78 (d, J=15.6 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 177.8, 156.1, 149.1, 142.5, 141.9, 134.9, 132.3, 132.2, 129.3, 129.1, 124.2, 123.8, 122.0, 119.4, 109.3, 103.1, 101.7, 93.8, 80.6, 58.4, 43.7; MS (ES+) m/z 452.0 (M+1), 450.0 (M+1).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH:8]([OH:10])[C:7]2[S:11][CH:12]=[CH:13][C:6]=2[CH2:5]1.[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1F>>[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[O:10][CH:8]1[CH2:9][N:4]([CH2:3][CH2:2][F:1])[CH2:5][C:6]2[CH:13]=[CH:12][S:11][C:7]1=2
Reactant: OC1CN(CCF)Cc2ccsc21
Reactant: Fc1cccc(Cl)c1Cl
Product: FCCN1Cc2ccsc2C(Oc2cccc(Cl)c2Cl)C1

Procedure:
The same method as in Example 1 was conducted using 5-(2-fluoroethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 17) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,3-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25](Br)[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH3:42][S-:43].[Na+]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[S:43][CH3:42])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(Br)C2CCCCC2)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
To a solution of (3,5-bis-trifluoromethyl-benzyl)-[2-(bromo-cyclohexyl-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine (26 mg; 0.039 mmol) in THF (1 mL) was added sodium thiomethoxide (8 mg; 0.114 mmol). Reaction stirred at room temperature for 16 hours. Reaction was diluted with ethyl acetate and washed twice with water. The organic layer was dried sodium sulfate and concentrated to give 23 mg (93% yield) of the title compound as a gum. MS (ES+): Calc: 625.6, Found: 626.0 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 7.79 (s, 1H), 7.67 (s, 2H), 7.57 (d, J=7.88 Hz, 1H), 7.75-7.56 (bs, 1H), 7.27 (s, 1H), 4.79 (t, J=15.35 Hz, 2H), 4.69 (t, J=15.77 Hz, 2H), 4.23 (s, 3H), 3.81 (bs, 1H), 2.21 (d, J=12.86 Hz, 1H), 1.76 (s, 3H), 1.76-1.57 (m, 4H), 1.36 (d, J=12.45 Hz, 1H), 1.25-1.03 (m, 3H), 1.0-0.76 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH3:24][C:25]([OH:29])([C:27]#[CH:28])[CH3:26]>>[OH:29][C:25]([CH3:26])([CH3:24])[C:27]#[C:28][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)O
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)CCc1ccc(Br)cc1
Product: CC(C)(O)C#Cc1ccc(CCS(=O)(=O)Nc2ccccc2S(N)(=O)=O)cc1
Yield: 42 %

Procedure:
The title compound was synthesized as described for Example 179 a) in 42% yield, starting from 2-[2-(4-bromophenyl)ethylsulfonylamino]benzenesulfonamide and 2-methyl-3-butyn-2-ol.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[O:13]=[C:11]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)/[CH:10]=[CH:9]/[C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2]
Reactant: C1CCN(C[C@@H]2CCCN2)CC1
Reactant: N#Cc1cccc(/C=C/C(=O)O)c1
Product: N#Cc1cccc(/C=C/C(=O)N2CCC[C@H]2CN2CCCCC2)c1

Procedure:
370 mg of the title compound were synthesized as described for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(3-cyanophenyl)acrylic acid instead of (E)-4-bromocinnamic acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][N:6]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:5]=1>CCO>[Cl:3][C:4]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:5]=1
Reactant: CCOC(=O)c1cn(-c2ncccn2)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn(-c2ncccn2)nc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1 N aqueous sodium hydroxide solution (5.0 mL) is added to a suspension of ethyl 3-chloro-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylate (850 mg, 3.36 mmol) in 10.0 mL of EtOH. The reaction mixture is stirred at RT for 1 h. Most of the EtOH is removed in vacuo, and the aqueous solution is diluted with water, extracted with EtOAc (3×), cooled to 0° C., and acidified to pH=2-3 with conc. HCl. The precipitated solid is collected by vacuum filtration and dried in vacuo to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[C:12]#[N:13].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CN(C)C=O>[C:12]([C:3]1[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[N:7]([CH3:8])[C:2]=1[N:1]=[CH:16][N:17]([CH3:19])[CH3:18])#[N:13]
Reactant: Cn1c(N)c(C#N)c(=O)n(C)c1=O
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Nc1c(C#N)c(=O)n(C)c(=O)n1C
Yield: 99.5 %

Procedure:
3.6 g (20 mmol) of 6-amino-5-cyano-1,3-dimethyluracil and 9.36 g (80 mmol) of dimethylformamide dimethyl acetal were added to 36 ml of dimethylformamide, and the reaction mixture was refluxed for 30 minutes. The solvent was removed by distillation under reduced pressure. The crude product was crystallized from ether, filtered off, and recrystallized from ethyl acetate to give 4.68 g of 5-cyano-6-dimethylaminomethyleneamino-1,3-dimethyluracil (compound 15) in a 99% yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][O:28]CC4C=CC=CC=4)=[CH:22][CH:23]=3)[N:18]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:17]=2[CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[C:44]=2[CH3:50])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)C.[Pd]>[F:49][C:45]1[C:44]([CH3:50])=[C:43]([CH:48]=[CH:47][CH:46]=1)[CH2:42][C:17]1[N:18]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:19]2[C:24]([C:16]=1[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15])=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][OH:28])[CH:20]=2
Reactant: Cc1c(F)cccc1Cc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(OCCOCc3ccccc3)cc2n1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Cc1c(F)cccc1Cc1c(C(=O)N2CCNCC2)c2ccc(OCCO)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.3 %

Procedure:
The compound of step 1 (20 mg, 30 μmol) was dissolved in ethanol (5 ml), palladium on carbon (4 mg) was added, and the mixture was stirred under an atmosphere of hydrogen at a pressure of 1.5 bar at room temperature for 3 h. The mixture was filtered over a pad of celite and evaporated under reduced pressure. The residue was dissolved in DCM (20 ml), TFA (5 ml) was added, and the mixture was stirred at room temperature for 1 h. The solvents were evaporated and the obtained solid was purified by preparative HPLC. The eluate was lyophilized overnight, the residue dissolved in a small quantity of MOH, mixed with hydrochloric acid (0.1 M) and lyophilized overnight. 4 mg of the title compound were obtained in the form of the [2-(3-fluoro-2-methyl-benzyl)-6-(2-hydroxy-ethoxy)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone hydrochloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[PH:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28].CCN(CC)CC>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:27]([O:26][P:25]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)([O:29][CH2:30][CH3:31])=[O:32])[CH3:28]
Reactant: CCO[PH](=O)OCC
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2ccc(Br)cc2)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1ccc(-c2ccc(C(C)(C)NC(=O)OC(C)(C)C)cn2)cc1
Yield: 92.4 %

Procedure:
To a solution of tert-butyl 2-(6-(4-bromophenyl)pyridin-3-yl)propan-2-ylcarbamate, 33-f, (850 mg, 2.17 mmol) in toluene (15 ml) was added diethyl phosphonate (900 mg, 6.52 mmol) and Et3N (660 mg, 6.52 mmol) and PdCl2(dppf) (85 mg) under N2, and the reaction mixture was refluxed for 8 hours. The reaction solution was then evaporated and diluted with EtOAc. The organic phase was washed with brine, dried and concentrated. Purified by silica gel (DCM-DCM:MeOH=50:1) to give tert-butyl 2-(6-(4-(diethoxyphosphoryl)phenyl)pyridin-3-yl)propan-2-ylcarbamate (900 mg, 92.4%).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C:10]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([C:17]2([OH:24])[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO>CC(C)=O>[CH2:3]([C:10]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([C:17]2([OH:24])[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[N:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCC(O)(c2ccc(O)c(Cc3ccccc3)n2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: Oc1ccc(C2(O)CCC(O)CC2)nc1Cc1ccccc1
Reaction time: 1 h
Yield: 54.3 %

Procedure:
67.4 mg of sodium borohydride was added to a mixture of 353 mg of 2-benzyl-3-hydroxy-6-(4-oxo-1-hydroxycyclohexyl)pyridine and 4 ml of methanol under ice-cooling, followed by stirring at the same temperature for one hour. Acetone was added thereto, and the solvent was removed. Then, the residue was subjected to silica gel column chromatography using 20% hexane/ethyl acetate, to give 193 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=1.Cl.C(OCC)C>CC(O)C>[ClH:1].[C:30]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]([NH:13][CH3:14])=[O:12])[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][N:3]=2)=[CH:24][CH:25]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc(NC(C)=O)cc2)ncc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 71.2 %

Procedure:
To a mixture of 2-[(2-chloro-5-nitropyrimidin-4-yl)amino]-N-methylbenzamide (54 mg, 0.178 mmol) and N-(4-aminophenyl)acetamide (28 mg, 0.185 mmol) in 2-propanol (2 mL) was added 1N HCl in diethyl ether (50 uL, 0.05 mmol). The reaction mixture was heated at 90° C. for 30 hours. After the reaction was cooled to room temperature the mixture was filtered, and the solid was washed with 2-propanol, hexane, and ethyl acetate. The solid was then dried under vacuum to give 2-[(2-{[4-(acetylamino)phenyl]amino}-5-nitropyrimidin-4-yl)amino]-N-methylbenzamide hydrochloride (58 mg, 71%) as a yellow tan solid. 1H NMR (DMSO-d6/D2O): δ 9.05 (s, 1H), 8.20 (m, 1H), 7.59 (d, 1 H), 7.40-7.50 (m, 5 H), 7.24 (t, 1 H), 2.76 (s, 3 H), 2.02 (s, 3H). MS m/z 421 (M+1).
Reaction SMILES: N[C:2]1[C:3]([CH3:12])=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.Cl.N([O-])=O.[Na+].[I-:18].[K+].[OH-].[Na+]>O>[I:18][C:2]1[C:3]([CH3:12])=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1
Reactant: [I-]
Reactant: Cc1c(N)cccc1C(F)(F)F
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: Cc1c(I)cccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
3-Amino-2-methylbenzotrifluoride (Aldrich Co., 5.25 g) was added to a mixture of concentrated hydrochloric acid (20 ml) and water (20 ml) and, under ice-cooling, sodium nitrite (3.31 g) dissolved in water (10 ml) was added dropwise thereto. The mixture was stirred at 0° C. for 1 hr. Potassium iodide (9.95 g) dissolved in water (20 ml) was added to the reaction mixture. The mixture was stirred at −4° C. for 2 hr. The mixture was adjusted to pH 11 or above with a 6N aqueous sodium hydroxide solution, and an aqueous thiosodium sulfate solution was added thereto. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure to give a brown oil. The oil was purified by silica gel column chromatography (elution solvent: hexane) to give 3-iodo-2-methylbenzotrifluoride (6.28 g, yield 73%).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C(N(CC)C(C)C)(C)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([NH:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1coc(N)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1coc(NS(C)(=O)=O)n1
Reaction time: 14 h

Procedure:
To a 20 ml screw cap vial was added (1 g, 5.8069 mmoles) ethyl 2-amino-1,3-oxazole-4-carboxylate, (10 ml) dichloromethane and (1.39 ml, 7.9797 mmoles, 1.25 eq.) N,N-diisopropylethylamine. To the reaction was then added (0.545 ml, 7.0415 mmoles, 1.1 eq.) methanesulfonyl chloride, and the reaction was agitated for 14 hours. The reaction was then evaporated to dryness and purified using a Biotage silica gel column, resulting in (272 mg) of ethyl 2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2F)=O)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH3:20][NH:21][NH2:22]>C(O)C>[CH3:20][N:21]1[C:11]2[C:10](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:17]([O-:19])=[O:18])[CH:4]=2)=[N:22]1
Reactant: CNN
Reactant: Nc1ccc(C(=O)c2ccccc2F)cc1[N+](=O)[O-]
Solvent: CCO
Product: Cn1nc(-c2ccc(N)c([N+](=O)[O-])c2)c2ccccc21
Reaction time: 40 h
Yield: 51.3 %

Procedure:
A mixture of 10.4 parts of (4-amino-3-nitrophenyl) (2-fluorophenyl)methanone, 14.03 parts of methylhydrazine and 79 parts of ethanol was stirred for 40 hours at reflux temperature. After cooling, the precipitated product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 5.5 parts (51.3%) of 4-(1-methyl-1H-indazol-3-yl)-2-nitrobenzenamine; mp. 230.6° C. (interm. 7). In a similar manner there was also prepared: 4-(1H-indazol-3-yl)-2-nitrobenzenamine (interm. 8).