Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15]O>>[CH3:15][NH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CO
Reactant: NC1CCCCC1Cc1ccccc1
Product: CNC1CCCCC1Cc1ccccc1
Temperature: 25 °C
Yield: 14 %

Procedure:
To a solution of 1-amino-2-benzylcyclohexane (an intermediate in preparation I, 0.90 gm, 4.8 mmol) and methanol (25 mL) was added RhH(Ph3P)3 (275 mg, 0.24 mmol) and the reaction mixture heated to reflux for 12 h. After cooling to room temperature, the solvent was removed under vacuum and the residue chromatographed on neutral alumina with ether and then on silica gel with triethylamine/ethyl acetate/hexane to give the title compound isolated as an oil in 14% yield.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[NH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:31][C:32]1[CH:36]=[C:35]([C:37]2[S:38][C:39]([Cl:42])=[CH:40][CH:41]=2)[O:34][N:33]=1>CN(C=O)C>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([NH:10][C:11]([C:13]2[N:14]([CH2:31][C:32]3[CH:36]=[C:35]([C:37]4[S:38][C:39]([Cl:42])=[CH:40][CH:41]=4)[O:34][N:33]=3)[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:12])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: CC(C)N1CCC(NC(=O)c2ccc(-c3ccccc3)[nH]2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)N1CCC(NC(=O)c2ccc(-c3ccccc3)n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.4 %

Procedure:
To a solution of 5-phenyl-1H-pyrrole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide (50 mg) in DMF (2 mL) was added Cs2CO3 (105 mg). The mixture was stirred for 30 min at RT. 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole (45 mg) was added and stirring was continued for 3 h at RT. The mixture was filtered and directly subjected to preparative HPLC(CH3CN/H2O gradient+0.05% TFA) to give 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-phenyl-1H-pyrrole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide (15 mg) as its trifluoroacetate salt. MS (ESI+): m/e=509 [M+H]+, chloro pattern.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C)=[O:19])=[CH:13][C:12]=1[Cl:22].[OH-].[Na+]>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][C:12]=1[Cl:22]
Reactant: COC(=O)Cc1ccc(Nc2nc3ccccc3s2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(Nc2nc3ccccc3s2)c(Cl)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.7 %

Procedure:
In THF (5 ml) was dissolved methyl (4-(2-benzothiazolyl)amino-3-chlorophenyl)acetate (296 mg, 0.89 mmol). To the resulting solution was added 0.5N NaOH (5.0 ml, 2.50 mmol). The resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was poured in ice-1N HCl to acidify the mixture. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (4-(2-benzothiazolyl)amino-3-chlorophenyl)acetic acid (263 mg, 93%) as a white solid.
Reaction SMILES: [I-].C[N+:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:5]=2[CH:4]=1.C(CN)O>O>[CH:4]1[C:5]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][C:10]3[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=3[C:6]=2[CH:7]=[CH:8][N:3]=1
Reactant: C[n+]1ccc2c(c1)-c1ccccc1Cc1ccccc1-2
Agent: [I-]
Solvent: O
Solvent: NCCO
Product: c1ccc2c(c1)Cc1ccccc1-c1cnccc1-2
Temperature: 160 °C
Reaction time: 2 h

Procedure:
A mixture of 19.9 g 2-methyl-9H-dibenzo[1,2;5,6]cyclohepta[3,4-c]pyridinium iodide (formula IV) and 100 ml ethanolamine is heated with stirring in an oil bath at 160° C. for 2 hours. The reaction mixture is then poured out into H2O and extracted with ether. The organic phase is extracted with dilute HCl, after which the acid aqueous layer is made alkaline and extracted with ether. The ether layer is washed with H2O until neutral, dried over Na2SO4 and evaporated to dryness.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=[CH:18][C:13]=2[N:12]2[C:22]([CH3:25])=[N:23][N:24]=[C:11]2[CH2:10][CH:9]=1.[Sn](Cl)Cl.C(=O)([O-])O.[Na+]>Cl>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[N:12]3[C:22]([CH3:25])=[N:23][N:24]=[C:11]3[CH2:10][CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]=2[CH:15]=1
Reactant: Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=CC2
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Product: Cc1nnc2n1-c1ccc(N)cc1C(c1ccccc1Cl)=CC2
Temperature: 25 °C

Procedure:
A suspension of 195 mg of 6-(2-chlorophenyl)-1-methyl-8-nitro-4H-s-triazolo[4,3-a][1]benzazepine in 5 ml of concentrated hydrochloric acid is treated with 375 mg of tin (II) chloride, whereupon the mixture is heated to 50° for 40 hours while stirring. After cooling to room temperature, the mixture is neutralized with sodium hydrogen carbonate solution and extracted with chloroform. The chloroform extracts are dried and then evaporated. The residue is crystallized from ethyl acetate/ether, there being obtained 8-amino-6-(2-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1]benzazepine of melting point 271°-273°.
Reaction SMILES: Cl[CH:2]([C:4]1[C:5]([CH3:20])=[N:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)[CH3:3].[C:21]([O:25][C:26](=[O:40])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]C(=O)C)=[CH:31][C:30]=1[CH3:39])([CH3:24])([CH3:23])[CH3:22].C(OC(=O)COC1C=CC(S)=CC=1C)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.CO>[C:21]([O:25][C:26](=[O:40])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35][CH:2]([C:4]2[C:5]([CH3:20])=[N:6][C:7]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[CH:8][CH:9]=2)[CH3:3])=[CH:31][C:30]=1[CH3:39])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(=O)Sc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(C)Cl
Agent: Cc1cc(S)ccc1OCC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CC#N
Product: Cc1cc(SC(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)OC(C)(C)C
Yield: 54.1 %

Procedure:
0.224 g (0.75 mmol) of [rac]-3-(1-chloro-ethyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine and 0.222 g (0.75 mmol) of (4-acetylsulfanyl-2-methyl-phenoxy)-acetic acid tert-butyl ester (prepared by standard acetylation of (4-mercapto-2-methyl-phenoxy)-acetic acid tert-butyl ester, described below in example 28A)-C]) were dissolved in 3.9 ml of acetonitrile and 0.2 ml of MeOH and treated with 0.292 g (1.2 eq.) of Cs2CO3. The reaction was then allowed to proceed over night. Pouring onto crashed ice, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=9/1), afforded in the less polar fractions 0.210 g of pure title compound and in the more polar fractions 0.112 g of the corresponding methyl ester as waxy solid.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19].Cl>N1C=CC=CC=1>[C:18]([O:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(Cc2ccc(O)cc2)cn1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Cc2ccc(C(=O)O)nc2)cc1
Reaction time: 18 h

Procedure:
0.7 Gram of 5-(4-hydroxybenzyl)picolinic acid was dissolved in 6 ml. of pyridine. The resulting solution was then added with 2 ml. of acetic anhydride dropwise under ice-cooling and stirring. The whole was allowed to stand at room temperature for 18 hours. The reaction solution was acidified with hydrochloric acid and then subjected to extraction with ethyl acetate. After washing with water and drying, the solvent was distilled out and the residue was recrystallized from benzene to obtain 0.3 g of 5-(4-acetoxybenzyl)picolinic acid as colorless needle-like crystals of a melting point of 116°-119° C.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:14]1(B(O)O)[CH2:16][CH2:15]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:14]1([C:2]2[C:7]3[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH2:16][CH2:15]1
Reactant: CSc1ncc2ccnc(Cl)c2n1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CSc1ncc2ccnc(C3CC3)c2n1
Temperature: 95 °C
Yield: 63.6 %

Procedure:
A solution of 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine (Preparation 33, 20 mg, 0.094 mmol), cyclopropyl boronic acid (11 mg, 0.128 mmol), PCy3 (3 mg, 10.70 μmol), and Pd(OAc)2 (1 mg, 4.45 μmol) was dissolved in toluene/water 6:1 (1 mL) and heated to 95° C. for 18 hours. The mixture was diluted with EtOAc and quenched with brine. The aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 20% EtOAc in cyclohexane to give the title compound (13 mg, 62%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[CH2:21]Br>>[F:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Fc1ccc(CBr)c(F)c1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccc(F)cc1F

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2,4-difluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[O:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]=2[CH:4]=1.C[N+]1([O-])CCOCC1>C(#N)C.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[O:12]=[C:10]1[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[O:7][C:6]2[CH:17]=[CH:18][C:3]([CH:2]=[O:1])=[CH:4][C:5]=2[NH:11]1
Reactant: O=C1Nc2cc(CO)ccc2Oc2ccccc21
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1ccc2c(c1)NC(=O)c1ccccc1O2
Reaction time: 0.17 h
Yield: 83 %

Procedure:
8-(hydroxymethyl)dibenzo[b,f][1,4]oxazepin-11 (10H)-one (0.241 g, 1 mmole) in acetonitrile was added to the molecular sieves (1 g) under N2 at room temperature then 4-methylmorpholine N-oxide (0.175 g, 1.5 mmole) was also added into the reaction mixture. After stirring the mixture for 10 minutes, tetrapropylammonium perruthenate (0.0176 g, 0.05 mmole) was added and the reaction followed by t.l.c. until complete. Dilute the reaction mixture with 10 ml of ethyl acetate and flashed it through a small silica gel column. Collected all the ethyl acetate that contains desired material, extracted the organic layer with 1 N HCl and also washed it with brine. Dried the organic layer over sodium sulfate and filtered and concentrated. Obtained the desired-compound (white solid) in 83% yield.
Reaction SMILES: O[CH:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[C:10]=1[CH:19]([CH3:21])[CH3:20])[C:3]([CH3:8])=[CH:4][C:5]([OH:7])=[O:6].[H][H]>C(O)(=O)C.[Pd]>[CH3:18][O:17][C:11]1[C:10]([CH:19]([CH3:21])[CH3:20])=[C:9]([CH2:2][CH:3]([CH3:8])[CH2:4][C:5]([OH:7])=[O:6])[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: [H][H]
Reactant: COc1ccc(C(O)C(C)=CC(=O)O)c(C(C)C)c1OC
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(CC(C)CC(=O)O)c(C(C)C)c1OC
Yield: 89.1 %

Procedure:
Compound 9 (7.00 g, 23.8 mmol) in 100 mL of acetic acid was hydrogenated on a Parr hydrogenator with 0.4 g of 10% palladium on carbon and 60 psi hydrogen pressure at 60° C. for 20 h. The reaction mixture was vacuum filtered through celite and the celite was washed with ether. The solvent was evaporated in a fume hood and the residual oil was distilled bulb to bulb (170° C./1 torr) to give 5.95 g (21.2 mmol, 89%) of 10 as an amber oil which crystallized on standing to form nearly colorless microcrystals: mp 100°-101° C. (lit14 mp not reported); IR: 1710 (carbonyl) cm-1 ; 1H NMR δ 0.982 (d, J=6.1 Hz, 3 H), 1.33 (d, J=7.1 Hz, 6 H), 2.0-2.7 (m, 5 H), 3.14 (sept, J=7.1 Hz, 1 H), 3.82 (s, 3 H), 3.85 (s, 3 H), 6.62 (d, J=8.0 Hz, 1 H), 6.75 (d, J=8.0 Hz, 1 H). Anal. (C16H24O4) C,H.
Reaction SMILES: [F:1][C:2]([F:17])([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)[C:3](OCC)=[O:4].[NH3:18]>>[F:1][C:2]([F:17])([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)[C:3]([NH2:18])=[O:4]
Reactant: N
Reactant: CCOC(=O)C(F)(F)c1cccc([N+](=O)[O-])c1
Product: NC(=O)C(F)(F)c1cccc([N+](=O)[O-])c1
Temperature: 75 °C

Procedure:
A solution of ethyl 2,2-difluoro-2-(3-nitrophenyl)acetate (0.701 g, 2.86 mmol) in Methanolic ammonia (7M, 20.0 ml) was taken in sealed tube. Resulting mixture was heated at 75° C. for 3 hrs. The reaction mixture was concentrated under vacuum and cold water was added to obtain the precipitate. Solid was filtered to obtain 2,2-difluoro-2-(3-nitrophenyl)acetamide (0.515 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH2:26][CH2:27][C:28](O)=[O:29].C(Cl)(Cl)Cl.Cl>CO>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH3:22])[C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[C:3]3[C:2](=[CH:7][CH:6]=2)[NH:1][C:28](=[O:29])[CH2:27][CH2:26]3)[CH2:9][CH2:10]1)=[O:25]
Reactant: COc1ccc(C(=O)N2CCN(c3ccc(N)c(CCC(=O)O)c3)CC2)cc1OC
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
3-{2-Amino-5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]phenyl}propionic acid (1 g) was dissolved in a mixed solvent consisting of chloroform and methanol, and 1 ml of concentrated hydrochloric acid was added to the solution. The resulting mixture was stirred for 1 hour at room temperature. After distilling off the solvent, the residue was recrystallized from ethanol-chloroform to give 500 mg of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 238°-239.5° C., colorless granules.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH2:43][OH:44])[CH:37]=1)[CH2:10][NH:11][C@H:12]([CH3:35])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])=[O:24])=[CH:17]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:45]OC1C=C(C=CC=1)CCN>>[Si:1]([O:8][C@H:9]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH2:43][OH:44])[CH:37]=1)[CH2:10][NH:11][C@H:12]([CH3:35])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([NH:25][CH2:26][CH2:27][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([O:33][CH3:34])[CH:45]=1)=[O:24])=[CH:17]2)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: COc1ccccc1CNC(=O)c1cc2cc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)ccc2[nH]1
Reactant: COc1cccc(CCN)c1
Product: COc1cccc(CCNC(=O)c2cc3cc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c4ccc(O)c(CO)c4)ccc3[nH]2)c1

Procedure:
Prepared analogously to 5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-N-(2-methoxybenzyl)-1H-indole-2-carboxamide using 3-methoxyphenethylamine to give the title compound as a pale brown foam.
Reaction SMILES: [I:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[K+].IC.F[C:27](F)(F)C(O)=O.[OH-].[Na+]>COCCOC.C(OCC)(=O)C.C(Cl)Cl>[I:1][C:2]1[C:10]2[N:9]([CH3:27])[C:8]3[CH2:11][CH2:12][NH:13][CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(I)cccc3c2C1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: ClCCl
Product: Cn1c2c(c3cccc(I)c31)CNCC2
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
Tert-butyl 6-iodo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (6.8 g, 17 mmol) was dissolved in DME (50 mL), and potassium hydroxide (4.8 g, 85.4 mmol) and iodomethane (15.7 g, 110.5 mmol) were added and heated at 80° C. in a pressure vessel for 3 h. The reaction was cooled to rt and diluted with ethyl acetate (50 mL). The solids were removed by vacuum filtration. The filtrate was concentrated under reduced pressure to give a brown oil (5.5 g, 79% crude yield). The oil was dissolved in CH2Cl2 (30 mL). Trifluoroacetic acid (30 mL) was added in ten portions over 5 min and stirred for 30 min. The reaction was basified with 50% sodium hydroxide to pH 12. This mixture was extracted with CH2Cl2 (3×150 mL). The organics were collected, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to give 6-iodo-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (3.85 g, 73%). 1H NMR (CDCl3 300 MHz) δ 7.62 (d, 1H, J=7.6 Hz), 7.33 (d, 1H, J=7.7 Hz), 6.74 (t, 1H, J=7.5 Hz), 4.03 (s, 2H), 3.95 (s, 3H), 3.26 (t, 2H, J=5.6 Hz), 2.71 (t, 2H, J=5.6 Hz) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.[C:17]([OH:25])(=[O:24])[C:18]([CH2:20][C:21](O)=[O:22])=[CH2:19]>C1(C)C=CC=CC=1.C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:21](=[O:22])[CH2:20][CH:18]([C:17]([OH:25])=[O:24])[CH2:19]2)=[CH:9][CH:8]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C(O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 101 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
4-(3-Fluoro-benzyloxy)-phenylamine (31.2 g, 144 mmol) was dissolved in toluene (208 mL) and acetic acid (52 mL). Itaconic acid (18.96 g, 144 mmol) was added to the stirred mixture. The mixture was heated to reflux (101° C.) and kept at this temperature for 3 h. On cooling, the product started to crystallize. At 10° C., heptane (125 mL) was added to the suspension which was stirred 1 h at 0° C. and filtered. The crystals were washed with toluene/heptane 1:1 and with heptane and dried in vacuo to afford the crude product (43.2 g). The crude product was purified by treatment with hot isopropyl acetate to give rac-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid (40.5 g, 86%; HPLC: 99.2% area), m.p. 148-149° C. (uncorr.).
Reaction SMILES: C(N1CCN(C2C=CC(N)=CC=2C)CC1)(=O)C.[Cl:18][C:19]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[C:21]([Cl:28])[C:20]=1[N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[Cl:28][C:21]1[CH:22]=[C:23]([NH2:25])[CH:24]=[C:19]([Cl:18])[C:20]=1[N:29]1[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1
Reactant: O=[N+]([O-])c1cc(Cl)c(N2CCOCC2)c(Cl)c1
Agent: CC(=O)N1CCN(c2ccc(N)cc2C)CC1
Product: Nc1cc(Cl)c(N2CCOCC2)c(Cl)c1

Procedure:
Following the general procedure of Intermediate 36 using 4-(2,6-dichloro-4-nitrophenyl)morpholine (prepared as described in J. Med. Chem., 1980, 23(10), 1083) the title compound was obtained; 1H NMR δ 3.01 (4H, t), 3.64 (4H, t), 5.50 (1H, broad s), 6.57 (2H, s); MS m/e MH+ 247.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:9]([NH:12][C:13]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:14]=1[CH2:15]Br)(=[O:11])[CH3:10]>C(Cl)(Cl)(Cl)Cl>[C:9]([NH:12][C:13]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:14]=1[CH2:15][N:2]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:1])(=[O:11])[CH3:10]
Reactant: CNC1CCCCC1
Reactant: CC(=O)Nc1ccc(C(C)(C)C)cc1CBr
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Nc1ccc(C(C)(C)C)cc1CN(C)C1CCCCC1

Procedure:
24 gm of N-methyl-cyclohexylamine were added to 23 gm of 2-acetylamino-5-tert.butyl-benzylbromide in 1.6 liters of carbon tetrachloride, and the mixture was refluxed for 1 hour. After cooling, the precipitated N-methyl-cyclohexylamine hydrobromide was filtered off, the filtrate was evaporated, and the crude product was purified chromatographically on silicagel with ethyl acetate. The corresponding fractions were combined and evaporated, and the 2-acetylamino-5-tert.butyl-N-cyclohexyl-N-methyl-benzylamine thus obtained was recrystallized from petroleum ether, whereupon it had a melting point of 111°-112.5°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[N:14][O:15][C:16]=2/[CH:17]=C/C2C=CC=CC=2)=[N:6][CH:5]=1.I([O-])(=O)(=O)=[O:34].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[N:14][O:15][C:16]=2[CH:17]=[O:34])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2/C=C/c2ccccc2)nc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C=O)nc1
Temperature: 120 °C
Yield: 78.2 %

Procedure:
A mixture of 6-[3-(4-fluoro-phenyl)-5-((E)-styryl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (3.88 g, 9.01 mmol), osmium(VIII) oxide (57.3 mg, 0.23 mmol), sodium metaperiodate (7.71 g, 36.1 mmol), benzyltriethylammonium chloride (838 mg, 3.61 mmol) in dioxane (60 mL) and water (20 mL) was heated for 15 min at 120° C. in a microwave. Water was then added to the reaction mixture and the resulting mixture extracted with ethyl acetate. The organic extract was then evaporated and the residue purified by chromatography (silica, ethyl acetate:heptane=1:4 to 2:3) to afford the title compound (2.51 g, 78%) as off white oil. MS: m/e=357.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)(=[O:14])=[O:13])[N:4]=1.[C:24](O)(=[O:26])C.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C>CN(C=O)C.[Fe]>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([N:11]2[C:24](=[O:26])[NH:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:12]2(=[O:14])=[O:13])[N:4]=1
Reactant: CC(=O)O
Reactant: COc1cnc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])nc1OC
Agent: [Fe]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cnc(N2C(=O)Nc3ccccc3S2(=O)=O)nc1OC

Procedure:
The title compound was prepared in two steps from N-(4,5-dimethoxypyrimidin-2-yl)-2-nitrobenzenesulfonamide (231 mg, 0.68 mmol), Fe powder (380 mg, 6.8 mmol) and acetic acid (5 mL); followed by 1,1′-carbonyldiimidazole (396 mg, 2.44 mmol) and triethylamine (0.17 mL, 1.22 mmol) in DMF (4.0 mL) using the methods of (IntA17), step 2 and (IntA14), step 3. The residue from step 3 was triturated with Et2O to yield the title compound (104 mg, 0.31 mmol).