Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][CH2:9][CH2:10][N:11]([CH3:21])[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][N:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]1([C:29]2[O:30][C:31]([C:37]([F:40])([F:39])[F:38])=[C:32]([C:34](O)=[O:35])[N:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][CH2:9][CH2:10][N:11]([CH3:21])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:34]([C:32]2[N:33]=[C:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:30][C:31]=2[C:37]([F:39])([F:40])[F:38])=[O:35])=[CH:14][N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCOCC(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CN(CCOCC(=O)OC(C)(C)C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1
Yield: 30.2 %

Procedure:
{2-[Methyl-(5-nitro-pyridin-2-yl)-amino]-ethoxy}-acetic acid tert-butyl ester (218 mg, 0.7 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (189 mg, 0.735 mmol), Et3N (394 uL, 2.8 mmol) and BOP (325 mg. 0.735 mmol). Following work-up as above, the crude material was purified by flash chromatography to yield [2-(methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-amino)-ethoxy]-acetic acid tert-butyl ester as a solid (110 mg). ES-MS calcd for C25H27F3N4O5 (m/e) 520.51, obsd 521.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[OH-].[Na+].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)Cl>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:20]
Reactant: COc1ccc(CN)cc1
Reactant: O=C(Cl)CCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(CNC(=O)CCCCCBr)cc1
Yield: 65 %

Procedure:
A cooled solution of (4-methoxyphenyl) methanamine (0.55 g, 4.0 mmol) in CH2Cl2 was stirred vigorously with 2% aqueous NaOH (9.6 mL, 4.8 mmol) while 6-bromohexanoyl chloride (4.8 mmol) in CH2Cl2 was added dropwise. The same NaOH solution was then used to maintain pH at 9, and at costant pH the layers were separated. The organic phase was washed with 3 N HCl, with H2O, and then dried over Na2SO4 and evaporated under reduced pressure. The crude residue was chromatographed (CHCl3/AcOEt, 1:1, as eluent) to afford pure compound in 65% yield. 1R NMR (CDCl3): δ 1.43-1.53 (m, 2H), 1.65-1.73 (m, 2H), 1.83-1.92 (m, 2H), 2.26 (app. t, 2H), 3.41 (t, 2H, J=6.6 Hz), 3.81 (s, 3H), 4.49 (d, 2H, J=6.05 Hz), 5.93 (br t, 1H, D2O exchanged), 7.37 (d, 2H, J=8.5 Hz), 7.59-7.63 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)#[N:2].Cl.[CH2:14](N)[CH2:15][NH2:16].[OH-].[Na+]>CCO>[NH:2]1[CH2:14][CH2:15][N:16]=[C:1]1[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1
Reactant: N#Cc1ccc(CC(=O)O)cc1
Reactant: NCCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccc(C2=NCCN2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-cyanophenyl)acetic acid (131 mg, 0.816 mmol) in EtOH (0.5 mL) at 0° C. was bubbled HCl(g) until saturation. Reaction mixture was allowed to warm to room temperature slowly. After overnight stirring, the crude reaction mixture was concentrated in vacuo. This residue was taken up in EtOH (4 mL) and ethylene diamine (0.1 mL, 1.49 mmol) was added. After stirring at room temperature for two hours, the crude reaction mixture was concentrated under reduced pressure and then re-dissolved in DMF (2 mL). To this solution was added 1M NaOH (2 mL, 2 mmol) and the reaction stirred at room temperature for three hours. Crude reaction mixture was neutralized with 1M HCl to a pH 6 and extracted with CHCl3 (4×15 mL). Product was found in the water layer, so combined all layers and concentrated in vacuo, re-dissolved in CHCl3/MeOH, and filtered to remove precipitate. Concentration of the filtrate gives [4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]acetic acid, which was used without further purification. LCMS (ES) 205.1 m/z (M+H)+
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([O:18][CH3:19])[C:9]([O:16][CH3:17])=[N:10]2)=[N+]=[N-]>O1CCCC1.[Ni]>[NH2:1][CH2:4][C:5]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([O:18][CH3:19])[C:9]([O:16][CH3:17])=[N:10]2
Reactant: COc1nc2cc(F)cc(CN=[N+]=[N-])c2nc1OC
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1nc2cc(F)cc(CN)c2nc1OC

Procedure:
3.5 g (13.3 mmol) of 5-azidomethyl-2,3-dimethoxy-7-fluoroquinoxaline in 35 ml of tetrahydrofuran are hydrogenated at room temperature for about 19 hours in the presence of 1.75 g of Raney nickel. The reaction mixture is filtered off and concentrated. The title compound is obtained as yellowish crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12](Cl)=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].C[O-].[Na+]>CN(C)C=O>[N:13]1[C:12]2[O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[NH:8][C:9](=[O:10])[C:11]=2[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Nc1ccccc1O)c1cccnc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2Oc2ncccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.1 %

Procedure:
A mixture of 13.0 g of N-(2-hydroxyphenyl)-2-chloro-3-pyridinecarboxamide and 2.82 g of sodium methoxide in 100 ml of N,N-dimethylformamide is refluxed under argon for 3 hours. Sodium methoxide (0.50 g) is added and the mixture refluxed 2 hours and then stirred at room temperature for 2 days. The solvent is removed under high vacuum and the red-brown residue triturated with cold methanol. The mixture is filtered and the solid washed with chilled methanol to give 5.0 g of white solid, m.p. 250°-253° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:12][O:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[I-].[Na+].C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[NH:5]([C:3]([CH2:2][N:19]1[CH2:20][CH2:21][CH:16]([O:15][CH2:14][O:13][CH3:12])[CH2:17][CH2:18]1)=[O:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(CCl)Nc1ccccc1
Reactant: COCOC1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCOC1CCN(CC(=O)Nc2ccccc2)CC1
Yield: 90.5 %

Procedure:
1.7 ml of chloroacetyl chloride was dropwise added to a solution of 3.0 g of aniline hydrochloride and 7 ml of triethylamine in 30 ml of dichloromethane. The mixture was stirred at room temperature for 3 hours, then washed with water and a saturated aqueous sodium hydrogencarbonate solution in this order, and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was crystallized from ethyl acetate-n-hexane to obtain 2.45 g of N-(2-chloroacetyl)aniline as a light brown solid. A suspension of 2.45 g of the N-(2-chloroacetyl)-aniline, 2.8 g of 4-methoxymethoxypiperidine, 2.45 g of sodium iodide and 2.3 ml of triethylamine dissolved in 30 ml of acetonitrile was refluxed for 1.5 hours. The reaction mixture was diluted with ethyl acetate. The dilution was washed with water and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was purified by a silica gel column chromatography (eluant: ethyl acetate: n-hexane=1:1) to obtain 3.64 g of 1-(anilinocarbonylmethyl)-4-methoxymethoxypiperidine as a light yellow oil.
Reaction SMILES: CN(C)[CH:3]=[O:4].[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22]([OH:23])=[C:21]([O:24][CH3:25])[C:20]([O:26][CH3:27])=[CH:19][C:18]=1C>N1C=CC=CC=1>[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22](=[O:23])[C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[C:3](=[O:4])[C:18]=1[CH3:19]
Reactant: COc1cc(C)c(CCCCCCCCCCO)c(O)c1OC
Reactant: CN(C)C=O
Solvent: c1ccncc1
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O
Reaction time: 72 h

Procedure:
To a dimethylformamide solution (30 ml) of 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methylphenol (1.6 g) are added bis(3-methoxysalicylidene)ethylenediiminocobalt(II) (0.06 g) and pyridine (10 mg), and the mixture is stirred in air streams at atmospheric temperature and pressure for 72 hours. After the reaction has been completed, the reaction product is isolated in the same manner as described in Example 7. The crude crystals thus obtained are recrystallized from ether-hexane (1:3). The above procedure yields 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (1.1 g) as orange-yellow needles melting at 51° C.-53° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:22]=[C:21](I)[C:19]([NH2:20])=[N:18][C:16]1=[O:17])(=[O:3])[CH3:2].O1C=C[CH:26]=[C:25]1P(C1OC=CC=1)C1OC=CC=1.C([Sn](CCCC)(CCCC)C=C)CCC>CN(C=O)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]>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:22]=[C:21]([CH:25]=[CH2:26])[C:19]([NH2:20])=[N:18][C:16]1=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cc(I)c(N)nc1=O
Reactant: c1coc(P(c2ccco2)c2ccco2)c1
Agent: [Pd]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: C=Cc1cn([C@@H]2O[C@H](C)[C@@H](OC(C)=O)[C@H]2OC(C)=O)c(=O)nc1N
Temperature: 40 °C
Reaction time: 19 h
Yield: 915.3 %

Procedure:
To a solution of 2',3'-di-O-acetyl-5'-deoxy-5-iodocytidine (1.6 g, 3.66 mmol) in 10 ml DMF were added Pd2 (dba)3 (67 mg, 0.073 mmol) and tri-2-furylphosphine (85 mg, 0.366 mmol) and tri-n-butyl(vinyl)stannane (2.1 ml, 7.318 mmol ) under Ar atmosphere at room temperature. After stirring for 19 hours, tri-n-butyl(vinyl)stannane (2.1 ml, 7.318 mmol ) was added to the reaction mixture, and then the reaction mixture was warmed up to 40° C. with stirring for 24 hours. The solvent was removed in vacuo, and the residue was purified on a column of silica gel (eluent: ethyl acetate ~CH2Cl2:MeOH=95: 5) to give 2',3'-di-O-acetyl-5'-deoxy-5-vinylcytidine (1.13 g, 92 %) as colorless solid:
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:22])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:23]1[CH2:29][C:27](=[O:28])[N:26]([CH2:30][C:31]([OH:33])=[O:32])[C:24]1=[S:25].[Cl-].[NH4+].N.Cl>C(O)C>[CH2:19]([O:18][C:16]([C:15](=[C:29]1[S:23][C:24](=[S:25])[N:26]([CH2:30][C:31]([OH:33])=[O:32])[C:27]1=[O:28])[C:13]1[N:14]=[C:10]([NH:9][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:22])[S:11][CH:12]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccccc2)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2ccccc2)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
A mixture comprising 1 g of ethyl 2-(3-phenylureido)thiazol-4-ylglyoxylate, 0.59 g of rhodanine-3-acetic acid 0.4 g of ammonium chloride, 0.4 ml of 28% v/v aqueous ammonia and 4 ml of ethanol was stirred at an external temperature of 80° C. for one hour. The reaction mixture was then acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography, using as eluent a 50:1:1:1 by volume mixture of benzene, ethyl acetate, ethanol and acetic acid. The product thus obtained was recrystallized from acetic acid, giving 0.74 g of the desired compound as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]1=2.C(N(CC)CC)C.[C:23](Cl)(=[O:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>ClCCl>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:23](=[O:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Reactant: CCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC(=O)Nc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (1) (0.5 g, 2.46 mmole) in 20 mL of dichloromethane was treated successively with 0.51 mL of triethylamine (1.5 eq.) and 0.35 mL of hexanoyl chloride (1 eq.). The reaction mixture was stirred at room temperature for two hours, diluted with an additional 20 mL of dichloromethane and washed with two 50 mL portions of water and one 50 mL portion of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo, giving 740 mg (100%) of hexanoic acid (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amide (15) as a pale yellow oil.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]1[CH2:24][CH2:23][C:22](=O)[N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH-](CC)CC)C.[Li+].CCN(C(C)C)C(C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[Si:1]([O:18][CH2:19][C@@H:20]1[CH2:24][CH:23]=[CH:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CC[BH-](CC)CC
Agent: CN(C)c1ccncc1
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C=CC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 0.58 h
Yield: 81.9 %

Procedure:
A three-necked flask equipped with a thermometer and a nitrogen inlet was charged with (S)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-5-oxopyrrolidine-1-carboxylate (10.05 g, 22.16 mmol) and toluene (36 mL) and lowered into −55° C. cooling bath. When the internal temperature of the mixture reached −50° C., lithium triethylborohydride (23 mL of 1.0 M/THF, 23 mmol) was added dropwise over 30 min and the mixture stirred for 35 min while maintaining the internal temperature between −50° C. and −45° C. Hunig's base (16.5 mL, 94 mmol) was added dropwise over 10 min. Then, DMAP (34 mg, 0.278 mmol) was added in one batch, followed by the addition of trifluoroacetic anhydride (3.6 mL, 25.5 mmol) over 15 min, while maintaining the internal temperature between −50° C. and −45° C. The bath was removed 10 min later and the reaction mixture was stirred for 14 h while allowing it to rise to ambient temperature. The reaction mixture was diluted with toluene (15 mL), cooled with an ice-water bath and treated slowly with water (55 mL) over 5 min. The phases were separated and the organic layer washed with water (50 mL, 2×) and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel; 5% EtOAc/hexanes) to afford (S)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (7.947 g, 82% yield) as a colorless viscous oil. LC/MS: [M+Na]+=460.19. Rt=2.41 min under the following HPLC conditions: Solvent gradient from 100% A:0% B to 0% A:100% B (A=0.1% TFA in 1:9 MeOH/water; B=0.1% TFA in 9:1 MeOH/water) over 2 min and hold for 1 min; detection at 220 nm; PHENOMENEX®Luna 3.0×50 mm S10 column. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.62-7.58 (m, 4H), 7.49-7.40 (m, 6H), 6.47 (br s, 1H), 5.07/5.01 (overlapping br d, 1H), 4.18 (br s, 1H), 3.89 (br s, 0.5H), 3.69 (br s, 1.5H), 2.90-2.58 (br m, 2H), 1.40/1.26 (overlapping br s, 9H), 0.98 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:18]2[C:13](=[CH:14][C:15]([C:20]([OH:22])=O)=[C:16]([CH3:19])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[I-].ClC1C=CC=C[N+]=1C>>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:18]2[C:13](=[CH:14][C:15]([C:20]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[O:22])=[C:16]([CH3:19])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc2c(cc1C(=O)O)SCCC2NC(=O)OC(C)(C)C
Reactant: Nc1ccncc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Product: Cc1cc2c(cc1C(=O)Nc1ccncc1)SCCC2NC(=O)OC(C)(C)C
Yield: 67.5 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 53 using 4-(tert-butoxycarbonylamino)-6-methylthiochromane-7-carboxylic acid (1.00 g), 4-aminopyridine (321 mg) and 2-chloro-1-methylpyridinium iodide (949 mg), the objective 4-(tert-butoxycarbonylamino)-6-methyl-N-(4-pyridyl)thiochromane-7-carboxamide (834 mg) was obtained as colorless crystals.
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][C@H:14]([N:18]2[C:24](=[O:25])[CH2:23][CH2:22][NH:21][C@H:20]([CH3:26])[CH2:19]2)[CH2:15][O:16][CH3:17])[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1>>[F:27][C:28]([F:38])([F:39])[C:29]1[CH:30]=[C:31]([NH:35][C:36]([N:21]2[CH2:22][CH2:23][C:24](=[O:25])[N:18]([C@H:14]([CH2:15][O:16][CH3:17])[CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:7][CH2:6]4)[C@H:4]([OH:3])[CH2:11]3)[CH2:19][C@H:20]2[CH3:26])=[O:37])[CH:32]=[CH:33][CH:34]=1
Reactant: COC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1C[C@@H](C)NCCC1=O
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: Cl
Product: COC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1C[C@@H](C)N(C(=O)Nc2cccc(C(F)(F)F)c2)CCC1=O
Yield: 39 %

Procedure:
In analogy to the procedure described for intermediate 58F, (R)-4-[(S)-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-methoxymethyl-propyl]-2-methyl-[1,4]diazepan-5-one dihydrochloride (example 65H) and 3-(trifluoromethyl)phenyl isocyanate gave the title compound in 39% yield as orange solid. MS: 527.3 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:11]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:41][CH:42]1[O:47][CH2:46][CH2:45][N:44]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:43]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:13]=[C:14]([O:16][CH2:41][CH:42]2[O:47][CH2:46][CH2:45][N:44]([C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:43]2)[CH:15]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cc2C#N)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(OCC2CN(C(=O)OC(C)(C)C)CCO2)cc(-c2ccc(C)cc2C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 2′-cyano-5-hydroxy-4′-methylbiphenyl-3-carboxylate (150 mg, 0.56 mmol), triphenylphosphine (220 mg, 0.84 mmol), tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (130 mg, 0.62 mmol) (Bioorg. Med. Chem. Lett. 2007, 17, 533) in CH2Cl2 (5 mL) at room temperature under nitrogen was slowly added a solution of diisopropyl azodicarboxylate (340 mg, 1.7 mmol) in CH2Cl2 (3 mL). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[N:13]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:12]=[N:11][C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][N:4]=1.Cl[CH2:27][C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.FC1C=CC(C2N=CN(C3CCN(CC4N=CC=CN=4)CC3)C=2C2C=CN=C(N)N=2)=CC=1.CCCCCCC>ClCCl.O>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[N:13]([CH:14]3[CH2:15][CH2:16][N:17]([CH2:27][C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:18][CH2:19]3)[CH:12]=[N:11][C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][N:4]=1
Reactant: ClCc1ncccn1
Reactant: CNc1nccc(-c2c(-c3ccccc3)ncn2C2CCNCC2)n1
Agent: Nc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCN(Cc3ncccn3)CC2)n1
Solvent: O
Solvent: CCCCCCC
Solvent: ClCCl
Product: CNc1nccc(-c2c(-c3ccccc3)ncn2C2CCN(Cc3ncccn3)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The title product was prepared by reaction of N-methyl-4-(4-phenyl-1-piperidin-4-yl-1H-imidazol-5-yl)pyrimidin-2-amine (C26) with 2-(chloromethyl)-pyrimidine according to the general procedure for the synthesis of 4-{4-(4-fluorophenyl)-1-[1-(pyrimidin-2-ylmethyl)piperidin-4-yl]-1H-imidazol-5-yl}pyrimidin-2-amine (3) in Example 3. In this case, after the reaction cooled to room temperature, it was diluted with dichloromethane (20 mL) and water (2 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to provide a light yellow solid, which was dissolved in a small volume of dichloromethane. Addition of heptane caused a solid to precipitate; this mixture was stirred for 30 minutes and then the solid was collected by filtration, washed with heptane and washed with diethyl ether to provide the product as a light yellow solid. Yield: 106 mg, 0.248 mmol, 34%. APCI m/z 427.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.12-2.17 (m, 4H), 2.29-2.36 (m, 2H), 2.97 (s, 3H), 3.11 (br d, J=12 Hz, 2H), 3.85 (s, 2H), 4.74 (br s, 1H), 6.34 (d, J=5.1 Hz, 1H), 7.29-7.35 (m, 3H), 7.38-7.43 (m, 3H), 8.06 (s, 1H), 8.09 (br d, J=5 Hz, 1H), 8.80 (d, J=4.9 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:28])([CH:16]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]([O:26]C)=O)[CH:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.O.[NH2:30][NH2:31]>C(O)(C)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:28])([CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[CH:16]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]([NH:30][NH2:31])=[O:26])[CH:19]=1)[CH3:17]
Reactant: NN
Reactant: COC(=O)c1cc(C(C)C(O)(Cn2cncn2)c2ccc(F)cc2F)ccn1
Solvent: O
Solvent: CC(C)O
Product: CC(c1ccnc(C(=O)NN)c1)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
A solution of the product of part (i) (3.80 g) and hydrazine hydrate (6.0 ml) in isopropanol (20 ml) was heated under reflux for 2.5 hours and then evaporated. Water was added to the residue and the mixture was extracted several times with dichloromethane. The combined extracts were washed with brine and dried (MgSO4). Evaporation of the solvent gave the title compound (3.30 g) as an amorphous foam which was used directly in the next stage.
Reaction SMILES: Cl[C:2]1[C:3]([OH:35])=[C:4]([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13]2=[O:34])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.F[C:37]1C=C(O)C(C2C3C(=CC=CC=3)N(CC3C=CC(OC)=CC=3)C2=O)=CC=1C#N>>[C:28]1([CH:21]([N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]3([C:4]4[C:5]5[O:10][CH2:9][CH2:8][O:7][C:6]=5[CH:11]=[CH:2][C:3]=4[O:35][CH2:37]3)[C:13]2=[O:34])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccc(CN2C(=O)C(c3cc(C#N)c(F)cc3O)c3ccccc32)cc1
Reactant: O=C1C(c2c(O)c(Cl)cc3c2OCCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1ccc3c(c12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2.40 and making non-critical variations using 3-(7-chloro-6-hydroxy-2,3-dihydro-1,4-benzodioxin-5-yl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one to replace 2-fluoro-4-hydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile, (diphenylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one was obtained (65%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.42-7.26 (m, 10H), 7.20-7.15 (m, 1H), 7.11 (s, 1H), 7.03-6.95 (m, 2H), 6.78 (s, 1H), 6.50-6.45 (m, 1H), 5.02 (d, J=8.7 Hz, 1H), 4.76 (d, J=8.7 Hz, 1H), 4.12-3.84 (m, 4H); MS (ES+) m/z 496.2 (M+1).