Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:15](Cl)[CH:16]([C:18]([F:21])([F:20])[F:19])[CH3:17].[CH2:23]([NH:25][C:26]#[N:27])[CH3:24].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:26]([NH:25][CH2:23][CH3:24])=[N:27][C:15]([CH:16]([C:18]([F:21])([F:20])[F:19])[CH3:17])=[N:14]1
Reactant: CC(C(Cl)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl)C(F)(F)F
Reactant: CCNC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNc1nc(C(C)C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 3 h
Yield: 68.9 %

Procedure:
7.8 g (0.02 mol) of 2-trifluoromethylpropionyl chloride 2,6-dichloro-4-trifluoromethylphenylhydrazone and 1.5 g (0.022 mol) of ethyl cyanamide were dissolved in 50 ml of tetrahydrofuran, and 2.5 g (0.025 mol) of triethylamine was dropwise added thereto under stirring and cooling with ice. After completion of the dropwise addition, the stirring was continued at room temperature for 3 hours. The solvent was distilled off under reduced pressure. The residue was dissolved in hexane, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. Then, hexane was distilled off under reduced pressure. Further, the residue was subjected to distillation under reduced pressure. The fraction having a boiling point of 110°-120° C./0.1-0.2 mmHg was subjected to recrystallization from hexane to obtain 5.8 g (yield: 69%) of the desired compound having a melting point of from 82° to 83° C. as slightly yellow prismatic crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH2:23][N:24]([CH3:34])[CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:20]=[CH:19][C:18]=3[N+:35]([O-])=O)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.O1CCC[CH2:39]1.[Cl-].[NH4+].C(OCC)(OCC)OCC>[Zn].C(O)(=O)C>[OH-:14].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:17]4[CH:22]=[C:21]([CH2:23][N:24]([CH3:34])[CH2:25][CH2:26][CH2:27][N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH:20]=[CH:19][C:18]=4[N:35]=[CH:39]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(CCCN1CCOCC1)Cc1ccc([N+](=O)[O-])c(Nc2nc(-c3cccc(Cl)c3)c(C(N)=O)s2)c1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: CN(CCCN1CCOCC1)Cc1ccc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2c1
Product: [OH-]

Procedure:
To a mixture of 0.150 g (0.28 mmole) of 4-(3-chloro-phenyl)-2-(5-{[methyl-(3-morpholin-4-yl-propyl)-amino]-methyl}-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.50a), 20 mL of tetrahydrofuran, and 20 mL of saturated ammonium chloride solution was added 0.089 g (1.38 mg-atom) of zinc powder. After 5 minutes the mixture was filtered and the filtrate partitioned between 50 mL of saturated ammonium chloride and 50 mL of tetrahydrofuran. The tetrahydrofuran layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was stirred for 3 hours with 30 mL of acetic acid and 0.178 g (1.2 mmole) of triethyl orthoformate. The mixture was concentrated under reduced pressure, diluted with 100 mL of dichloromethane and washed with saturated sodium bicarbonate solution, then brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium:hydroxide (92:8:1) to give 0.075 g of 4-(3-chloro-phenyl)-2-(6-{[methyl-(3-morpholin-4-yl-propyl)-amino]-methyl}-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.50) as a light pink solid. MH+/Z=525.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:15]([C:22]#[N:23])[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl.ClCCl>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([C:22]#[N:23])[CH:16]=[C:17]([NH2:19])[CH:18]=3)[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: N#Cc1cc(-c2nc(-c3ccc(F)cn3)no2)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: N#Cc1cc(N)cc(-c2nc(-c3ccc(F)cn3)no2)c1
Yield: 23.3 %

Procedure:
3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-nitrophenyl)-1,2,4-oxadiazole (30 mg, 0.096 mmol) and tin(II) chloride dihydrate (109 mg, 0.48 mmol) in ethanol (1 mL) were sealed in a glass vial and then heated at 78 oC for 2 hours. The reaction was cooled and dichloromethane was added to the reaction mixture. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel chromatography of the residue using hexanes:ethyl acetate:dichloromethane 1:3:4 followed by recrystallization using methanol afforded 6.3 mg (23%) of 3-(5-fluoropyrid-2-yl)-5-(3-amino-5-cyanophenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.69 (d, 1H), 8.25 (m, 1H), 7.89 (s, 1H), 7.76 (s, 1H), 7.61 (m, 1H), 7.11 (s, 1H), 4.17 (bs, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1>CN(C=O)C.CO>[Cl:1][C:2]1[C:3]([C:8]([NH:62][C:55]2[CH:54]=[C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[C:52]4[C:47]=3[CH:46]=[CH:45][NH:44]4)[CH:61]=[C:60]3[C:56]=2[CH:57]=[N:58][NH:59]3)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1Cl
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27.7 %

Procedure:
To a solution of 3-chloropicolinic acid (380 mg, 2.42 mmol, available from Fluorochem Ltd.) in DMF (5 ml) was added HATU (920 mg, 2.42 mmol) and DIPEA (1.266 ml, 7.25 mmol). The mixture was stirred at room temperature for 20 mins then 6-(1H-indol-4-yl)-1H-indazol-4-amine (300 mg, 1.21 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give a volume of approx. 1 ml which was added to the top of a 20 g aminopropyl cartridge that had been preconditioned with MeOH. The reaction mixture remained on the cartridges for 2 h before being eluted with MeOH. The solvent was removed in vacuo to give a brown oil that was purified by chromatography using silica gel (70 g cartridge, FlashMaster II) eluting with 0-25% MeOH in DCM over 30 mins to afford the title compound (130 mg) as a brown solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:29]2[CH2:41][CH2:40][N:32]3[C:33]4[CH2:34][CH2:35][CH2:36][CH2:37][C:38]=4[CH:39]=[C:31]3[C:30]2=[O:42])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=C(C3CC3)N[N:20]=2)[C:15](=[O:27])[N:14]([CH3:28])[CH:13]=1)(=[O:3])[CH3:2].BrC1C=C(NC2C=[CH:57][C:56]([N:59]3[CH2:64][CH2:63][N:62]([CH2:65][C:66]([OH:69])([CH3:68])[CH3:67])[CH2:61][CH2:60]3)=[CH:55]N=2)C(=O)N(C)C=1.C(OCC1C(N2CCN3C4CCCCC=4C=C3C2=O)=NC=CC=1B1OC(C)(C)C(C)(C)O1)(=O)C>>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:29]2[CH2:41][CH2:40][N:32]3[C:33]4[CH2:34][CH2:35][CH2:36][CH2:37][C:38]=4[CH:39]=[C:31]3[C:30]2=[O:42])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=[CH:55][C:56]([N:59]3[CH2:64][CH2:63][N:62]([CH2:65][C:66]([OH:69])([CH3:67])[CH3:68])[CH2:61][CH2:60]3)=[CH:57][N:20]=2)[C:15](=[O:27])[N:14]([CH3:28])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(CC(C)(C)O)CC3)cn2)c1=O
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc(C4CC4)[nH]n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(CC(C)(C)O)CC4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 63 %

Procedure:
Following the procedures as described for preparation of 118c, reaction of 120a (435 mg, 1.0 mmol) and 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (383 mg, 1 mmol) gave 120b (437 mg, 63%). LCMS: [M+H]+ 696.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:23]=[CH:22][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[N-:30]=[N+:31]=[N-:32].[Na+].C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[C:24]1([C:4]2[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:8][C:9]3[CH:23]=[CH:22][C:12]([O:13][C:14]4[CH:19]=[CH:18][N:17]=[C:16]([C:20]5[NH:32][N:31]=[N:30][N:21]=5)[CH:15]=4)=[CH:11][CH:10]=3)[CH:5]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1nc(Nc2ccc(Oc3ccnc(-c4nnn[nH]4)c3)cc2)cc(-c2ccccc2)n1
Temperature: 100 °C

Procedure:
A mixture of 4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carbonitrile (0.20 g, 0.53 mmol, prepared in Example 8), sodium azide (0.051 g, 0.79 mmol), and triethylamine (0.11 g, 0.79 mmol) in toluene (15 in L) was heated at 100° C. for 2 days. The mixture was then treated with cold water. The solid was collected by filtration, washed with water and methanol to give pure product, 0.14 g (63%). 1H NMR (DMSO-d6) δ 9.51 (s, 1H), 8.62 (d, 1H), 7.94 (m, 4H), 7.55 (d, 1H), 7.48 (m, 3H), 7.19 (m, 3H), 6.48 (m, 3H); MS ES 424 (M+H)+calc 424.
Reaction SMILES: C(#N)C.[CH3:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6].OI(C1C=CC=CC=1)[O:19][S:20]([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C(OCC)(=O)C>[S:20]([O:22][CH2:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6])([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:21])=[O:19]
Reactant: CC(=O)c1ccc2ccccc2c1
Reactant: Cc1ccc(S(=O)(=O)OI(O)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OCC(=O)c2ccc3ccccc3c2)cc1
Yield: 68.5 %

Procedure:
Acetonitrile solution (40 mL) containing 2-acetonaphthone (1.70 g, 9.99 mmol) and [hydroxyl(tosyloxy)iodo]benzene (4.00 mg, 10.2 mmol) was heated under ref lux for 3 hours. The reaction mixture was cooled, and ethyl acetate was added thereto. The reaction solution was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to remove the solvent to obtain the title compound (2.33 g, 68.5%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][S:11]([CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[NH:18][C:17]1=[O:24])(=[O:13])=[O:12].C(O[Cl:30])(C)(C)C>CO>[Cl:30][N:18]1[C:19]([CH3:22])([CH3:23])[C:20](=[O:21])[N:16]([CH2:15][CH2:14][S:11]([CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:13])=[O:12])[C:17]1=[O:24]
Reactant: COCCOCCOCCS(=O)(=O)CCN1C(=O)NC(C)(C)C1=O
Reactant: CC(C)(C)OCl
Solvent: CO
Product: COCCOCCOCCS(=O)(=O)CCN1C(=O)N(Cl)C(C)(C)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 52.8 %

Procedure:
A solution of 3-(2-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)sulfonyl)ethyl)-5,5-dimethylimidazolidine-2,4-dione (1.9 g, 5.2 mmol) in methanol (10 ml) was cooled to 0° C. tert-Butylhypochlorite (613 ul, 5.45 mmol) was added. The resulting solution was stirred for 3 hours at 0° C., and then concentrated under reduced pressure. The crude material was purified by column chromatography, eluting from silica gel with a gradient of 5-12% methanol in dichloromethane to give 1.1 g of a clear oil. 1H NMR (D2O, 400 MHz) δ 1.39 (s, 6H), 3.28 (s, 3H), 3.43-3.47 (t, J=5.4 Hz, 2H), 3.51-3.61 (m, 10H) 3.85-3.88 (t, 5.2 Hz, 2H), 4.02-4.05 (m, 2H). LRMS (ESI/APCI) m/z 401 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[NH2:57][C@@H:58]([CH2:63][NH:64][C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[C:59]([O:61][CH3:62])=[O:60].CCN(C(C)C)C(C)C>CN(C=O)C>[C:68]([O:67][C:65]([NH:64][CH2:63][C@H:58]([NH:57][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:14]2[N:13]=[C:12]([NH:11][C:8]3([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH2:9][CH2:10]3)[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[N:15]=2)=[CH:33][CH:32]=1)[C:59]([O:61][CH3:62])=[O:60])=[O:66])([CH3:71])([CH3:70])[CH3:69]
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (50 mg) in DMF (2 mL) was added O-(benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (23.82 mg) and (S)-methyl 2-amino-3-(tert-butoxycarbonylamino)propanoate hydrochloride (18.90 mg) and iPr2NEt (0.052 ml). After stirring at rt for 4 h, the mixture was purified by preparative HPLC to give (S)-methyl 3-(tert-butoxycarbonylamino)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate.
Reaction SMILES: [N:1]12[CH2:6][CH:5]1[CH2:4][CH2:3][S:2]2(=[O:8])=[O:7].[OH2:9].[C:10]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:10][O:9][CH:5]1[CH2:4][CH2:3][S:2](=[O:8])(=[O:7])[NH:1][CH2:6]1
Reactant: O
Reactant: O=S1(=O)CCC2CN21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC1CCS(=O)(=O)NC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 677.9 %

Procedure:
A mixture of 2-thia-1-azabicyclo[3.1.0]hexane 2,2-dioxide (0.600 g, 4.5 mmol), p-toluenesulfonic acid hydrate (0.086 g, 0.5 mmol) and methanol (50 mL) was stirred at room temperature for 3 days. The reaction was concentrated and the residue purified by silica gel chromatography (0-100% ethyl acetate/hexanes) to afford the product as a white solid (0.56 g, 75%). 1H NMR (300 MHz, CDCl3) δ 4.43 (br s, 1H), 3.65-3.40 (m, 2H), 3.40 (s, 3H), 3.36-3.23 (m, 2H), 3.08 (dt, 1H, J=13.5, 3.9 Hz), 2.50-2.23 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@@H:4]([O:22][CH2:23][CH3:24])[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:8]=1[Cl:21])O.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([O:22][CH2:23][CH3:24])[CH2:5][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:8]=1[Cl:21]
Reactant: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(OCc2ccccc2)cc1Cl
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1Cl)C(=O)OC

Procedure:
In analogy to the procedure described in example 17 c], (2S,3R)-3-(4-benzyloxy-2-chloro-phenyl)-2-ethoxy-3-hydroxy-propionic acid methyl ester was treated with triethylsilane in trifluoroacetic acid to yield (2S)-3-(4-benzyloxy-2-chloro-phenyl)-2-ethoxy-propionic acid methyl ester as colorless liquid.
Reaction SMILES: C([Li])CCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20]([O:23][CH2:24][CH3:25])(=[O:22])C>O1CCCC1>[O:22]1[CH2:25][CH2:24][O:23][CH:20]1[C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(C)=O
Reactant: CCCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cccc(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
A stirred solution of the acetal (1.0 g, 4.37 mmol) of Description 1 in dry tetrahydrofuran (50 ml), under argon, was cooled to -80° and treated with a 1.6 M solution of n-butyllithium in hexane (2.73 ml, 4.37 mmol). The resulting yellow solution was stirred at -80° for 0.5 hours. A solution of redistilled benzaldehyde (0.44 ml, 4.37 mmol) in dry tetrahydofuran (5 ml) was added over 2 minutes and the solution left to stir for 1 hour. The reaction mixture was warmed to room temperature over the next hour and then diluted with ethyl acetate and washed with water. The organic layer was dried (MgSO4) and evaporated to afford an oil which was chromatographed on silica gel. Elution with ethyl acetate/hexane (1:2) gave the desired product as a colourless oil (0.57 g, 51%). δH (CDCl3) 2.23 (1H, d, J 3.5 Hz), 4.1 (4H, m), 5.80 (1H, s), 5.87 (1H, d, J 3.5 Hz), 7.2-7.6 (9H) ppm. EIMS M+ 256.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[H][H]>[Pt]=O.C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(/C=C/C1CCN(Cc2ccccc2)CC1)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc(C(=O)CCC2CCN(Cc3ccccc3)CC2)cc1
Yield: 37.5 %

Procedure:
2.00 g of (E)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]nitrobenzene was added to a mixed solvent of 30 ml of ethanol and 5 ml of acetic acid, and then 0.20 g of platinum oxide was added thereto. Thereafter, the mixture was stirred in a hydrogen stream at room temperature for 7.5 hours. After the reaction, the catalyst was removed by filtration, and the filtrate was condensed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 0.69 g of the title compound as pale yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:23]O)[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:23][N:29]3[C:25](=[O:35])[C:26]4[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:28]3=[O:30])[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)(c2ccc(Cl)c(Cl)c2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC(CN2C(=O)c3ccccc3C2=O)(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
To a solution of tert-butyl (7RS)-7-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (2 g), phthalimide (0.86 g) and triphenylphosphine (4.17 g) in THF (40 ml) was added dropwise a solution (2.2 M, 7.2 ml) of diethyl azodicarboxylate in toluene at 0° C., and the mixture was stirred at 0° C. for 30 min, and then for 6 hr while warming to room temperature. To the reaction mixture were added phthalimide (0.43 g) and a solution (2.2 M, 3.6 mL) of diethyl azodicarboxylate in toluene, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The obtained extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) and silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.49 g).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C.O1CCCCC1[O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH:32]([O:35][CH2:36][C:37]3[O:38][C:39]4[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][C:40]=4[CH:41]=3)[CH2:31][CH2:30]2)=[CH:25][CH:24]=1>O>[F:49][C:46]([F:47])([F:48])[C:43]1[CH:44]=[CH:45][C:39]2[O:38][C:37]([CH2:36][O:35][CH:32]3[CH2:33][CH2:34][N:29]([C:26]4[CH:27]=[CH:28][C:23]([OH:22])=[CH:24][CH:25]=4)[CH2:30][CH2:31]3)=[CH:41][C:40]=2[CH:42]=1
Reactant: FC(F)(F)c1ccc2oc(COC3CCN(c4ccc(OC5CCCCO5)cc4)CC3)cc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: Oc1ccc(N2CCC(OCc3cc4cc(C(F)(F)F)ccc4o3)CC2)cc1
Temperature: 25 °C
Yield: 81 %

Procedure:
p-Toluenesulfonic acid monohydrate (0.84 g) was added to an ethanol solution (40 ml) of 1-[4-(tetrahydropyran-2-yloxy)phenyl]-4-(5-trifluoromethylbenzofuran-2-ylmethoxy)piperidine (2.1 g) and the mixture was heated at reflux for 1 hour. After being cooled to room temperature, water was added to the reaction mixture and filtered through Celite, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was washed with ether and dried to afford the title compound as a white powder (1.4 g).
Reaction SMILES: [CH:1]1([NH:8][C:9]([NH2:11])=[S:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:13]1([C:17](OCC)=[O:18])[CH2:16][CH2:15][CH2:14]1>>[CH:1]1([NH:8][C:9]2[S:10][C:13]3([C:17](=[O:18])[N:11]=2)[CH2:16][CH2:15][CH2:14]3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=S)NC1CCCCCC1
Reactant: CCOC(=O)C1(Br)CCC1
Product: O=C1N=C(NC2CCCCCC2)SC12CCC2

Procedure:
Synthesis was performed from N-cycloheptylthiourea and ethyl 1-bromocyclobutanecarboxylate according to Method D.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([O:24][CH3:25])=[O:23])=[CH:12][CH:11]=2)=[C:4]([CH2:26][CH2:27][CH2:28][CH3:29])[N:3]=1.Cl[CH2:31][C:32](=O)[CH3:33]>CN(C=O)C>[CH2:26]([C:4]1[N:3]2[CH:32]([CH3:33])[CH:31]=[N:1][C:2]2=[N:7][C:6](=[O:8])[C:5]=1[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([O:24][CH3:25])=[O:23])=[CH:14][CH:15]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CC(=O)CCl
Reactant: CCCCc1nc(N)[nH]c(=O)c1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Solvent: CN(C)C=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3C(=O)OC)cc2)c(=O)nc2n1C(C)C=N2
Temperature: 100 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
A solution of 0.3 g of 2-amino-6-butyl-5-[(2'-methoxycarbonylbiphenyl-4-yl) methyl]pyrimidin-4-one in 6 ml of DMF is added under stirring with 61 μl of chloroacetone. After 18 h under stirring at 100° C., the solvent is evaporated under reduced pressure. The residue is taken up into water to separate a solid which is filtered and purified by FC (eluent CH2Cl2 --CH3OH 97:3), to obtain 90 mg of a spongy solid (27% yield).
Reaction SMILES: Br[C:2]1[CH:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[NH:6][CH:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.O>COCCOC.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.[Fe+2].Cl[Pd]Cl>[CH:9]1([O:8][C:7]2[C:2]([C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)=[CH:3][C:4]([C:14]([O:16][CH3:17])=[O:15])=[CH:5][N:6]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)C1=CNC(OC2CCCC2)C(Br)=C1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cnc(OC2CCCC2)c(-c2ccncc2)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 30.8 %

Procedure:
Methyl 5-bromo-6-(cyclopentyloxy)-1,6-dihydropyridine-3-carboxylate (2.50 g, 7.94 mmol) was dissolved in DME (10 mL) and pyridin-4-ylboronic acid (813 mg, 6.61 mmol), DPPF-PdCl2 (108 mg, 0.13 mmol, Strem) and water (0.5 mL, 28 mmol) were added. The mixture was stirred at 40° C. for 4 h. The reaction mixture was cooled to RT, diluted with H1O and extracted 3× with EtOAc. The combined organic extracts were washed 1× with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (40 g pre-packed column, elution 0-30% EtOAc:hexanes) to give the title compound (608 mg, 31%). MS m/z: 299 (M+1).