Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([OH:16])=O)[C:12]=2[C:20]([OH:22])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[NH2:24][CH:25]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:26]1=[O:27]>N1C=CC=CC=1>[O:27]=[C:26]1[CH:25]([N:24]2[C:20](=[O:22])[C:12]3[C:13](=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10][C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=3)[C:14]2=[O:16])[CH2:31][CH2:30][C:29](=[O:32])[NH:28]1
Reactant: NC1CCC(=O)NC1=O
Reactant: COc1ccc(Nc2cccc(C(=O)O)c2C(=O)O)cc1O
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1O
Yield: 56.9 %

Procedure:
A mixture of 3-(3-hydroxy-4-methoxyphenylamino)phthalic acid (0.60 g, 2.0 mmol) and rac-α-aminoglutarimide hydrochloride (0.33 g, 2.0 mmol) in pyridine (10 mL) was heated to reflux for 16 hours. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (150 mL), washed with dilute aqueous HCl (2×100 mL) and water (2×100 mL), was dried (MgSO4) and evaporated. The residue was triturated in 1:1 acetonitrile-water (15 mL) and filtered, and the resulting solid was washed with additional 1:1 acetonitrile-water and dried under high vacuum, providing 0.45 g of the product, in 58% yield: mp 225-227° C.; 1H NMR (DMSO-d6) δ 2.03-2.08 (m, 1H), 2.52-2.63 (m, 2H), 2.83-2.92 (m, 1H), 3.77 (s, 3H), 5.11 (dd, J=12.5 Hz, J=5.4 Hz, 1H), 6.69-6.76 (m, 2H), 6.94 (d, J=8.5 Hz, 1H), 7.14-7.23 (m, 2H), 7.56 (t, J=7.8 Hz, 1H), 8.15 (s, 1H), 9.21 (s, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 22.1, 31.0, 48.6, 55.9, 110.7, 111.5, 112.5, 113.0, 114.2, 118.8, 132.1, 132.3, 136.1, 144.2, 145.2, 147.2, 167.1, 168.4, 170.0, 172.8; Anal. calcd for C20H17N3O6: C, 60.76; H, 4.33; N, 10.63. Found: C, 60.76; H, 4.11; N, 10.42.
Reaction SMILES: [F:1][C:2]([F:20])([C:16]([F:19])([F:18])[F:17])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[CH:15]=1)=[O:4].Cl[C:22]1[C:27]([CH3:28])=[CH:26][C:25]([N+:29]([O-])=O)=[CH:24][N:23]=1>>[NH2:29][C:25]1[CH:26]=[C:27]([CH3:28])[C:22]([O:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=3[CH:15]=2)[C:2]([F:1])([F:20])[C:16]([F:18])([F:17])[F:19])=[N:23][CH:24]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: CC1(C)Cc2cc(C(=O)C(F)(F)C(F)(F)F)ccc2O1
Product: Cc1cc(N)cnc1OC(c1ccc2c(c1)CC(C)(C)O2)C(F)(F)C(F)(F)F

Procedure:
5-Amino-3-methyl-2-[1-(2,3-dihydro-2,2-dimethylbenzofuran-5-yl)-2,2,3,3,3-pentafluoropropoxy]pyridine was prepared from 2,2,3,3,3-pentafluoro-1-(2,3-dihydro-2,2-dimethylbenzofuran-5-yl)propan-1-one, by the method of Example 42. 2-Chloro-3-methyl-5-nitropyridine was used in place of 2-chloro-5-nitropyridine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.[Br:6][C:7]([C:29]([OH:31])=[O:30])=[CH:8][C:9]1[CH:10]=[C:11]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:27])[C:17]2=[O:28])[CH:12]=[CH:13][C:14]=1[Cl:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:6][C:7]([C:29]([O:31][CH2:4][CH2:3][O:2][CH3:1])=[O:30])=[CH:8][C:9]1[CH:10]=[C:11]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[N:18]([CH3:27])[C:17]2=[O:28])[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: COCCBr
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=C(Br)C(=O)O)c2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOC(=O)C(Br)=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Reaction time: 17 h

Procedure:
0.52 ml of methoxyethyl bromide was added to a solution of 2.27 g of 3-[3-(2-bromo-2-carboxyethenyl)-4-chlorophenyl]-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine and 0.76 g of potassium carbonate in dimethylformamide, and the resulting solution was stirred for 17 hours. Thereafter, 100 ml of water were added and the aqueous phase was extracted with twice 100 ml of dichloromethane. The combined organic phases were washed with three times 50 ml of water, dried over sodium sulfate and evaporated down. After flash chromatography (dichloromethane→9:1 dichloromethane/ethyl acetate), the title compound was obtained as an oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:8]([CH3:10])[CH3:9])[N:5]([CH3:7])[N:6]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13].C(N(CC)CC)C>C(OCC)(=O)C.[Cu]I>[NH2:13][CH2:12][CH2:11][NH:14][C:2]1[N:3]=[C:4]([N:8]([CH3:10])[CH3:9])[N:5]([CH3:7])[N:6]=1
Reactant: NCCN
Reactant: CN(C)c1nc(Br)nn1C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)c1nc(NCCN)nn1C
Temperature: 80 °C

Procedure:
5-Bromo-N,N,2-trimethyl-1,2,4-triazol-3-amine (103 mg, 0.5 mmol) and copper (I) iodide (4.8 mg, 0.025 mmol) were placed in a sealed microwave vial and flushed with argon. Then ethane-1,2-diamine (1.5 ml, 22 mmol) and triethylamine (140 μL, 1 mmol) were added via siringe. The reaction mixture was heated in a microwave oven at 80° C. for 1 h. The reaction mixture was diluted with ethyl acetate, filtered through kieselguhr and the filtrate was concentrated under reduced pressure to give 97 mg (quantitative) MS(ESI) m/z=185.1 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[O:16][C:15]=3[CH2:23][CH2:24][CH2:25][CH3:26])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:27].Br[CH2:29][C:30]([O:32]C)=[O:31]>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[O:16][C:15]=3[CH2:23][CH2:24][CH2:25][CH3:26])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH2:29][C:30]([OH:32])=[O:31]
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccc2c(Br)c(O)ccc2c1
Reactant: COC(=O)CBr
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc2c(Br)c(OCC(=O)O)ccc2c1

Procedure:
The title compound was prepared from 1-bromo-6-(2-butyl-benzofuran-3-carbonyl)-naphthalen-2-ol, and methyl bromoacetate, in substantially the same manner, as described in Example 4, and was obtained as a white solid, mp 163-165° C.; MS m/e 680 (M+);
Reaction SMILES: CN(C=O)C.Br[CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:26]=[CH:25][C:15]([CH2:16][NH:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:14][CH:13]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(Cl)Cl>[N:27]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:26]=[CH:25][C:15]([CH2:16][NH:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:14][CH:13]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C1CCNCC1
Reactant: BrCCCCOc1ccc(CNCCN2CCCC2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: c1cc(OCCCCN2CCCCC2)ccc1CNCCN1CCCC1

Procedure:
An 8 mL DMF solution of [4-(4-bromo-butoxy)-benzyl]-(2-pyrrolidin-1-yl-ethyl)-amine (307 mg, 0.86 mmol) and piperidine (0.22 mL, 2.2 mmol) is stirred at 90° C. for six hours under N2. The reaction mixture is cooled, diluted with CH2Cl2, filtered, washed with brine, dried (Na2SO4), and concentrated. The residue is purified by chromatography (SiO2; 0-6% MeOH/CH2Cl2/1% NH4OH gradient) to give the product (40 mg, 12% yld). MS(ES+)360.4(M+H)+ free base.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9](=[O:14])[N:8]([CH2:15][CH2:16][OH:17])[C@@H:7]3[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@H:6]3[C:5]=2[CH:4]=1)[CH3:2].[C:28]1(O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1.Cl>[CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9](=[O:14])[N:8]([CH2:15][CH2:16][O:17][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@@H:7]3[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:20][C@H:6]3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: Oc1ccccc1
Reactant: CCc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N(CCO)C2=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N(CCOc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
To a solution of (±)-trans tert-butyl 8-ethyl-4-(2-hydroxyethyl)-6-methyl-5-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, from Example 86, Part B, (24 mg, 0.064 mmol) in 1 mL of toluene was added phenol (9 mg, 0.096 mmol), triphenylphosphine (20 mg, 0.077 mmol) and diethylazodicarboxylate (0.035 mL, 0.077 mmol). The resulting mixture was allowed to stir at ambient temperature for 18 h. The reaction was diluted with 10 mL of 1 N HCl and extracted with ethyl acetate. The organics were washed with sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo. The residue was purified by flash chromatography (elution with 3:1 hexane/ethyl acetate) to afford 17 mg (59%) of the title compound as an oil. LRMS (ESI): 451.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([CH:11]([N:14]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]2)[CH2:12][NH2:13])=[CH:7][N:6]=1)([F:4])[CH3:3].[Cl:22][C:23]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].C1COCC1.CCN(C(C)C)C(C)C>>[Cl:22][C:23]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH:13][CH2:12][CH:11]([C:8]1[CH:7]=[N:6][C:5]([C:2]([F:1])([F:4])[CH3:3])=[N:10][CH:9]=1)[N:14]1[CH2:19][CH2:18][C:17]([F:20])([F:21])[CH2:16][CH2:15]1)=[O:26]
Reactant: CC(F)(F)c1ncc(C(CN)N2CCC(F)(F)CC2)cn1
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(F)(F)c1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCC(F)(F)CC2)cn1
Yield: 47.4 %

Procedure:
2-(2-(1,1-Difluoroethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethanamine (34 mg, 0.044 mmol, 40% pure) and 2,3-dichlorobenzoyl chloride (65 mg, 0.31 mmol), was dissolved in anhydrous THF (4400 mg, 5 ml, 61.0 mmol), DIPEA (111 mg, 0.15 ml, 0.859 mmol) was added and stirred over night. The solution was concentrated and purified by column chromatography on silica gel (petroleum ether: EtOAc=1:0 to 0:1) followed by HPLC, to afford 2,3-dichloro-N-(2-(2-(1,1-difluoroethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide (10 mg, 47% yield).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[C:9]([CH3:10])=[C:8]([OH:11])[CH:7]=[C:6]([O:12][CH3:13])[C:5]=1[Br:14]>[OH-].[Na+]>[Br:14][C:5]1[C:6]([O:12][CH3:13])=[CH:7][C:8]([OH:11])=[C:9]([CH3:10])[C:4]=1[C:3]([OH:15])=[O:2]
Reactant: COC(=O)c1c(C)c(O)cc(OC)c1Br
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(O)c(C)c(C(=O)O)c1Br
Temperature: 70 °C
Reaction time: 85 h
Yield: 96.2 %

Procedure:
A suspension of 23 g 2-bromo-5-hydroxy-3-methoxy-6-methyl-benzoic acid methyl ester in 200 ml of 3N sodium hydroxide was stirred at 70° C. for 85 h. The cooled solution was washed with diethyl ether and then acidified to pH 1 by the addition of 3N hydrochloric acid. The aqueous layer was extracted with diethyl ether and the organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was recrystallized from diethyl ether/pentane to yield 21 g of 2-bromo-5-hydroxy-3-methoxy-6-methyl-benzoic acid as white crystals, m.p.79°-80° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[C:17]([C:36]2[CH:48]=[C:47]([F:49])[C:39]3[N:40]=[C:41]([CH3:46])[N:42]([CH:43]([CH3:45])[CH3:44])[C:38]=3[CH:37]=2)=[N:18][C:19]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:25][N:24]=2)=[N:20][CH:21]=1.[CH3:50][C:51]([CH3:53])=O.ClCCCl>C(O)(=O)C>[F:15][C:16]1[C:17]([C:36]2[CH:48]=[C:47]([F:49])[C:39]3[N:40]=[C:41]([CH3:46])[N:42]([CH:43]([CH3:45])[CH3:44])[C:38]=3[CH:37]=2)=[N:18][C:19]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]3[CH2:31][CH2:32][N:33]([CH:51]([CH3:53])[CH3:50])[CH2:34][CH2:35]3)=[CH:25][N:24]=2)=[N:20][CH:21]=1
Reactant: CC(C)=O
Reactant: Cc1nc2c(F)cc(-c3nc(Nc4ccc(CN5CCNCC5)cn4)ncc3F)cc2n1C(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1nc2c(F)cc(-c3nc(Nc4ccc(CN5CCN(C(C)C)CC5)cn4)ncc3F)cc2n1C(C)C
Temperature: 60 °C

Procedure:
Add sodium triacetoxyborohydride (299.9 mg) to a mixture of [5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-(5-piperazin-1-ylmethyl-pyridin-2-yl)-amine (130 mg), acetone (31.6 μL), 1,2-dichloroethane (9 mL) and acetic acid (16.3 μL). Heat at 60° C. for 1 h. Remove the solvent under vacuum. Purify by strong cation exchange cartridge (SCX) eluting with methanol and then methanol-NH3 2 M followed by silica gel column chromatography eluting with DCM/methanol-NH3 2 M (3%) to afford 115 mg of the title compound. MS (ES+): m/z=521 (M+H)+.
Reaction SMILES: C(C1C=C2C(C3C=C(C=CC=3)CNC(C3C(=O)N(CC4C=CC(F)=C(F)C=4)C=CC=3)=O)=CNC2=NC=1)#N.CC1(C)C(C)(C)OB([C:46]2[S:50][C:49]([CH2:51][NH:52][C:53]([C:55]3[C:56](=[O:70])[N:57]([CH2:61][C:62]4[CH:67]=[CH:66][C:65]([F:68])=[C:64]([F:69])[CH:63]=4)[CH:58]=[CH:59][CH:60]=3)=[O:54])=[CH:48][CH:47]=2)O1.[B].[NH:73]1[C:77]2=[N:78][CH:79]=[C:80]([CH2:82][OH:83])[CH:81]=[C:76]2[CH:75]=[CH:74]1>>[OH:83][CH2:82][C:80]1[CH:81]=[C:76]2[C:75]([C:46]3[S:50][C:49]([CH2:51][NH:52][C:53]([C:55]4[C:56](=[O:70])[N:57]([CH2:61][C:62]5[CH:67]=[CH:66][C:65]([F:68])=[C:64]([F:69])[CH:63]=5)[CH:58]=[CH:59][CH:60]=4)=[O:54])=[CH:48][CH:47]=3)=[CH:74][NH:73][C:77]2=[N:78][CH:79]=1
Reactant: OCc1cnc2[nH]ccc2c1
Reactant: CC1(C)OB(c2ccc(CNC(=O)c3cccn(Cc4ccc(F)c(F)c4)c3=O)s2)OC1(C)C
Agent: N#Cc1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Agent: [B]
Product: O=C(NCc1ccc(-c2c[nH]c3ncc(CO)cc23)s1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
Except where indicated, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [5-(5-hydroxymethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiophen-2-ylmethyl]-amide was synthesized as per Example 68, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide using 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophen-2-ylmethyl]-amide as activated boron species and (1H-Pyrrolo[2,3-b]pyridin-5-yl)-methanol as substituted bicyclic heterocycle, to yield the title compound. 1H NMR (400 MHz, DMSO-d6) d ppm 11.888 (s, 1H) 10.052 (t, J=6.0 Hz, 1H) 8.401 (dd, J=7.3, 2.1 Hz, 1H) 8.255-8.211 (m, 2H) 8.171 (d, J=1.7 Hz, 1H) 7.782 (d, J=2.5 Hz, 1H) 7.472-7.350 (m, 2H) 7.181 (d, J=3.5 Hz, 1H) 7.192-7.131 (m, 1H) 7.017 (d, J=3.5 Hz, 1H) 6.594 (t, J=6.9 Hz, 1H) 5.193 (s, 2H) 4.672 (d, J=5.8 Hz, 2H) 4.616 (s, 2H); MS m/z=507.33 M+H.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:10]2[N:14]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[Cl:20])[O:12][N:11]=2)[CH:6]=[CH:7][C:8]=1[Cl:9].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.CCN(CC)CC>ClCCl>[Cl:9][C:8]1[CH:7]=[CH:6][C:5]([C:10]2[N:14]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[Cl:20])[O:12][N:11]=2)=[CH:4][C:3]=1[CH2:2][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNC1
Reactant: Clc1ccc(-c2noc(-c3sccc3Cl)n2)cc1CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1ccc(-c2noc(-c3sccc3Cl)n2)cc1CN1CCCC1
Yield: 95.6 %

Procedure:
A solution of 3-(3-bromomethyl-4-chloro-phenyl)-5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazol (0.030 g, 0.077 mmol), pyrrolidine (0.013 mL, 0.16 mmol), Et3N (0.054 mL, 0.39 mmol) and dichloromethane (8.0 mL) was stirred at room temperature for 20 h. The solution was diluted with dichloromethane (30 mL), washed with 10% Na2CO3 (25 mL), dried over Na2SO4, and concentrated. The product was azeotroped with dichloromethane (3×5 mL) and hexanes (2×5 mL) to give 0.028 g (96%) of the title compound as a white solid. 1H NMR (CDCl3): 8.27 (d, 1H, J=1.7 Hz), 7.98 (dd, 1H, J=8.2 and 1.9 Hz), 7.61 (d, 1H, J=5.2 Hz), 7.49 (d, 1H, J=8.5 Hz), 7.13 (d, 1H, J=5.2 Hz), 3.85 (s, 2H), 2.67 (br s, 4H), 1.84 (br s, 4H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[CH3:14][O:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27].O>O1CCCC1>[CH3:14][O:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH:7][C:5]([O:4][CH3:3])=[O:6])=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: COCOc1ccc(C=O)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(C=CC(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
Under a current of argon, a solution having 832 mg of sodium hydride suspended in 60 ml and a solution of 4.17 g of trimethyl phosphonoacetate in 15 ml of tetrahydrofuran added thereto as kept cooled with ice were stirred for 30 minutes and the resultant mixture and a solution of 4.39 g of 4-methoxymethoxy-3-nitrobenzaldehyde in 15 ml of tetrahydrofuran added thereto were stirred for eight hours with the temperature raised to room temperature in the meantime. The produced reaction mixture was combined with water and extracted from ethyl acetate. The consequently separated organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. The residue from drying was concentrated under a vacuum. The resultant concentrate was subjected to silica gel column chromatography. From the hexane-ethyl acetate (3:1 V/V) eluate, 4.52 g of methyl 4-methoxymethoxy-3-nitrocinnamate was obtained in the form of yellow crystals. The yield was 81%.
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH:11]2[CH2:14][N:13](C(C3C=CC=CC=3)C)[CH2:12]2)[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>[OH-].[OH-].[Pd+2].C(O)C>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[C:1]1([C:7]([CH:11]2[CH2:14][NH:13][CH2:12]2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(c1ccccc1)N1CC(C(C(N)=O)(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: O=C(O)/C=C/C(=O)O
Agent: [OH-]
Solvent: CCO
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CNC1
Reaction time: 18 h

Procedure:
To a suspension of 23 g. (0.062 mole) of α,α-diphenyl-α-[1-(1-phenylethyl)-3-azetidinyl]acetamide in 150 ml. of ethanol solution was added 1.5 g. of 10% palladium hydroxide on carbon. The mixture was hydrogenated at 70° C. and an initial pressure of 45 p.s.i. for 18 hours and filtered. The filtrate was concentrated and the residue dissolved in 150 ml. of isopropyl alcohol. To this was added 7.2 g. (0.062 mole) of fumaric acid. The resulting crystals were recrystallized three times from ethanol to give 3 g. (13%) of product melting at 171°-173° C.
Reaction SMILES: C1(C2CC(O)C3C(=CC=C(O)C=3)O2)C=CC=CC=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]1[CH2:35][C:34](=[O:36])[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=2)[O:27]1>>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]1[CH2:35][CH:34]([OH:36])[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=2)[O:27]1
Reactant: O=C1CC(c2ccccc2F)Oc2ccc(O)cc21
Agent: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Product: Oc1ccc2c(c1)C(O)CC(c1ccccc1F)O2

Procedure:
2-(2-Fluorophenyl)chroman-4,6-diol was prepared as described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 1.19 g of 2-(2-fluorophenyl)-6-hydroxychroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 8.85 (s, 1H), 7.56 (m, 1H), 7.40 (m, 1H), 7.28-7.21 (m, 2H), 6.89 (d, 1H, J 2.9 Hz), 6.60 (d, 1H, J 8.7 Hz), 6.54 (dd, 1H, J 8.7, 2.8 Hz), 5.46 (d, 1H, J 6.9 Hz), 5.35 (d, 1H, J 10.6 Hz), 4.89 (m, 1H), 2.26 (m, 1H), 1.98 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].[CH3:8][C:9]([CH3:29])([O:11][C:12]([NH:14][C@@H:15]([C:19](ON1C(=O)CCC1=O)=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:5][CH2:4][C:3]([CH3:7])([CH3:6])[CH2:2][NH:1][C:19]([C@@H:15]([NH:14][C:12](=[O:13])[O:11][C:9]([CH3:8])([CH3:29])[CH3:10])[CH:16]([CH3:18])[CH3:17])=[O:20]
Reactant: CC(C)(CN)CO
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(C)(C)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of commercial 3-amino-2,2-dimethyl-1-propanol (1.7 g, 16.5 mmol), N-[(1,1-dimethylethoxy)carbonyl]-D-Valine, 2,5-dioxo-1-pyrrolidinyl ester (Giuntini F. et al., J. Med. Chem. (2009), 52(13), 4026-4037, incorporated herein by reference) (4.7 g, 15.0 mmol) and 1M aqueous potassium carbonate (10 mL, 10.0 mmol) in acetonitrile (30 mL) was stirred at room temperature for 2 h. The mixture was concentrated to about one third of its volume, diluted with 1M hydrochloric acid and extracted three times with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered and the filtrate evaporated to a residue. The crude product was purified by silica gel chromatography using hexane/ethyl acetate (50:50) to isolate 4 g (88% yield) of tert-butyl N-[(1S)-1-[(3-hydroxy-2,2-dimethyl-propyl)carbamoyl]-2-methyl-propyl]carbamate.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([NH:14][C:15]1[S:16](=[O:39])[NH:17][C:18]2[CH:24]=[C:23]([O:25][S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:21][C:19]=2[N:20]=1)([O:12][CH3:13])=[O:11].C(OCC)(=O)C>N1C=CC=CC=1.O>[C:1]([N:17]1[C:18]2[CH:24]=[C:23]([O:25][S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:36])[F:38])[CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:21][C:19]=2[N:20]=[C:15]([NH:14][C:10]([O:12][CH3:13])=[O:11])[S:16]1=[O:39])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)NC1=Nc2ccc(OS(=O)(=O)c3cccc(C(F)(F)F)c3)cc2NS1=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)NC1=Nc2ccc(OS(=O)(=O)c3cccc(C(F)(F)F)c3)cc2N(C(=O)c2ccccc2)S1=O
Temperature: 0 °C

Procedure:
1 Milliliter of benzoyl chloride was added dropwise, while stirring and cooling with an ice mixture, to a solution of 1.4 g of 3-carbomethoxyamino-7-(3-trifluoromethyl-phenylsulfonyloxy)-1H-2,1,4-benzothiadiazine-S-oxide in 20 ml of pyridine. After the mixture has been stirred for 2 hours at 0° C, 1 ml of benzoyl chloride was added once more. After another hour of stirring at 0° C, the reaction mixture was diluted with water. It was then shaken with ethyl acetate, and the extract was washed with saturated sodium chloride solution. After evaporation of the solvent, the residue was isolated by trituration with methanol and filtration. 1-Benzoyl-3-carbomethoxyamino-7-(3-trifluoromethyl-phenylsulfonyloxy)-1H-2,1,4-benzothiadiazine-S-oxide was obtained in a yield of 1.1 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[C:15](Cl)[C:14]([N+:20]([O-:22])=[O:21])=[CH:13][CH:12]=3)=[O:5])[CH3:2].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(P(N(C)C)(N(C)C)=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[C:15]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:14]([N+:20]([O-:22])=[O:21])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc([N+](=O)[O-])c(Cl)c12
Reactant: C1CCNCC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc([N+](=O)[O-])c(N3CCCCC3)c12
Yield: 80.9 %

Procedure:
420 mg of 5-chloro-6-nitro-beta-carboline-3-carboxylic-acid-ethylester and 100 mg of piperidine in 10 ml of hexamethylphosphorotriamide are heated for 2 h to 80° C. After the solvent is distilled off, the residue is chromatographed on silica gel with methylene-chloride/ethanol. 350 mg of 5-piperidino-6-nitro-beta-carboline-3-carboxylic-acid-ethylester with a m.p. of 307° C. (decomposition) is obtained.