Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2CCN)[N:5]=[N:4][N:3]=1.[OH:16][C@H:17]1[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]2[C:29]([C:30]#[N:31])=[CH:28][N:27]=[C:26](S(C)(=O)=O)[N:25]=2)[CH2:19][C:18]1([CH3:37])[CH3:36].O[C@H]1CC[C@@H:42]([NH:45]C2C(C#N)=CN=C(S(C)=O)N=2)[CH2:41]C1(C)C.CCN(C(C)C)C(C)C>>[OH:16][C@H:17]1[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]2[C:29]([C:30]#[N:31])=[CH:28][N:27]=[C:26]([NH:45][CH2:42][CH2:41][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([N:6]4[C:2]([CH3:1])=[N:3][N:4]=[N:5]4)[CH:12]=3)[N:25]=2)[CH2:19][C:18]1([CH3:37])[CH3:36]
Reactant: CS(=O)c1ncc(C#N)c(N[C@@H]2CC[C@H](O)C(C)(C)C2)n1
Reactant: Cc1nnnn1-c1ccccc1CCN
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnnn1-c1cccc(CCNc2ncc(C#N)c(N[C@@H]3CC[C@H](O)C(C)(C)C3)n2)c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 21 %

Procedure:
A mixture of 2-(2-(5-methyl-1H-tetrazol-1-yl)phenyl)ethanamine (85 mg, 0.42 mmol), 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile and 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfinyl)pyrimidine-5-carbonitrile (90 mg, 0.27 mmol) and DIEA (105 mg, 0.81 mmol) was stirred at 100° C. under microwave irradiation for 1.5 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by standard methods to give the title compound (44.3 mg, 0.073 mmol, 21% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 7.92 (m, 1H), 7.50-7.40 (m, 2H), 7.34-7.25 (m, 2H), 4.25-4.15 (m, 1H), 3.68-3.49 (m, 2H), 3.25-3.22 (m, 1H), 3.00-2.87 (m, 2H), 2.46 (s, 3H), 1.79-1.22 (m, 6H), 0.88-0.83 (m, 6H). MS (ESI) m/z 448.2 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[C@H:17]([NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH3:18])[C:11](O)=[O:12])=[N+:6]=[N-:7]>CN(C)C=O.ClCCl>[N:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[C@H:17]([NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH3:18])[C:11]([Cl:3])=[O:12])=[N+:6]=[N-:7]
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1N=[N+]=[N-]
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1N=[N+]=[N-]

Procedure:
Thionyl chloride (4 ml) and dimethylformamide (1 drop) were added to a solution of (R)-3-azido-4-(1-benzyloxycarbonylaminoethyl)benzoic acid in dichloromethane (20 ml), and the mixture was refluxed under heating for 2 hours. After the reaction, the solvent was evaporated under reduced pressure. The obtained residue was boiled with benzene to give 1.65 g of (R)-3-azido-4-(1-benzyloxycarbonylaminoethyl)benzoyl chloride as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[C:4]([OH:11])[CH:3]=1.[CH2:12]([O:14][C:15](=[O:21])[C:16](OCC)=O)[CH3:13].[O-]CC.[Na+]>C(O)C.CCOCC>[C:15]([C:16]1[O:11][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=2[C:8](=[O:9])[CH:10]=1)([O:14][CH2:12][CH3:13])=[O:21]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(C)cc1O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cc(=O)c2ccc(C)cc2o1
Temperature: 0 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
A solution of 10.7 g (71.25 mmoles) of 2-hydroxy-4-methylacetophenone and 31.24 g (214 mmoles) of diethyloxalate in 25 ml of ethanol is added dropwise to a solution of sodium ethoxide (formed by adding 6.55 g of sodium metal to 120 ml of ethanol). The mixture is refluxed for 4 hours, cooled to 0° C. and diluted with 500 ml of ether. The precipitate which forms on standing overnight is filtered off and redissolved in water and the solution acidified (pH approximately 1) with 1 N hydrochloric acid. The mixture is extracted with ethyl acetate which is dried and concentrated in vacuo. The residue is dissolved in 100 ml of ethanol and 3 ml of concentrated hydrochloric acid. This solution is refluxed for 1.5 hours, then concentrated in vacuo. The residue is poured into ice water and the precipitate which formed on standing overnight is filtered off and dissolved in ethyl acetate. The ethyl acetate solution is dried and concentrated in vacuo. The residue is purified by flash column chromatography through silica gel and recrystallization from ether/hexanes to give 8.75 g of 2-carboethoxy-7-methyl-4-oxo-4H-1-benzopyran as a white crystalline solid having an m.p. of 62°-4° C.
Reaction SMILES: [Cl-].C(O[CH:6]1[C@H:11]([NH3+:12])[C@@H:10]([O:13][C:14](=[O:16])[CH3:15])[C@H:9]([O:17][C:18](=[O:20])[CH3:19])[C@@H:8]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:7]1)(=O)C.[CH3:26][N:27]=[C:28]=[S:29].C(N(CC)CC)C.C(O)(C(F)(F)F)=O>CC#N>[C:18]([O:17][C@@H:9]1[C@@H:8]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:7][C@H:6]2[C@H:11]([N:12]=[C:28]([NH:27][CH3:26])[S:29]2)[C@H:10]1[O:13][C:14](=[O:16])[CH3:15])(=[O:20])[CH3:19]
Reactant: CN=C=S
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H]([NH3+])[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNC1=N[C@@H]2[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H]2S1
Temperature: 60 °C
Reaction time: 12 h
Yield: 159.5 %

Procedure:
To a solution of (3R,4R,5S,6R)-2,4,5-triacetoxy-6-(acetoxymethyl)-tetrahydro-2H-pyran-3-aminium chloride (100 g, 261 mmol) in CH3CN (1 L) was added methyl isothiocyanate (21 g, 287 mmol), triethylamine (29 g, 287 mmol). After stirred for 12 h at 60° C., the resulting solution was treated with TFA (110 g, 0.96 mol) at room temperature overnight, and then washed with saturated sodium bicarbonate (1 L). The organic layer was dried over magnesium sulfate and concentrated under vacuum to provide a residue, which was purified by silica gel column, eluted with 1% MeOH in dichloromethane to give compound 23 as a yellow oil (150 g, 87%). (ES, tri/z): [M+H]+ 360.9; 1H NMR (300 MHz, CDCl3) δ 6.31-6.33 (d, J=6.6 Hz, 1H), 5.41-5.48 (t, J=8.4 Hz, 1H), 4.97-5.00 (m, 1H), 4.31-4.37 (t, J=5.7 Hz, 1H), 4.21 (m, 2H), 3.97 (m, 1H), 2.99 (s, 3H), 2.00-2.20 (m, 9H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[N:19]1[CH:24]=[CH:23][C:22]([S:25]([C:28]2[S:32][C:31]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[N:30][CH:29]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:36]1[CH2:35][CH2:34][N:33]([C:31]2[S:32][C:28]([S:25]([C:22]3[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=3)(=[O:26])=[O:27])=[CH:29][N:30]=2)[CH2:38][CH2:37]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: O=S(=O)(c1ccncc1)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(=O)(=O)c3ccncc3)s2)CC1
Yield: 32 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[5-(pyridine-4-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a light red crystalline solid (yield 32%). MS (m/e): 551.2 (M+H+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)N.C(ON=O)CC(C)C.[S:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccsc1
Reactant: Nc1cccc(Br)c1
Agent: CC(C)CCON=O
Solvent: CCOCC
Product: Brc1cccc(-c2cccs2)c1
Temperature: 25 °C
Yield: 34 %

Procedure:
To stirred solution of m-bromoaniline (34.4 g; 0.2M) in thiophene (200 mL) was added isoamylnitrite (46.86 g; 0.4M) dropwise over a period of 30 mins. at 0° C. The resulting mixture was cautiously warmed to R.T. and heated to reflux for 16 hours. The reaction mixture was cooled, diluted with 400 mL of ether, washed with 3×100 mL of satd. sodium chloride solution, and dried over anhydrous magnesium sulfate. Solvent and excess thiophene were removed. A solution of the residue in 200 mL of ether was filtered through 50 G silica gel bed. Solvent was removed, and the residue was distilled to give 34% of 2-(3'-bromophenyl)thiophene as a yellow liquid boiling at 130°-2°/~0.2 mm. This liquid solidified on standing in the refrigerator.
Reaction SMILES: [C:1]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:30]=[C:10]3[N:11]=[C:12]([CH3:29])[C:13]([C:23](=[O:28])[C:24]([O:26][CH3:27])=[O:25])=[C:14]([N:15]4[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][CH2:16]4)[N:9]3[N:8]=2)[CH:2]=1.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1.C1COCC1>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[C:1]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:30]=[C:10]3[N:11]=[C:12]([CH3:29])[C:13]([C@H:23]([OH:28])[C:24]([O:26][CH3:27])=[O:25])=[C:14]([N:15]4[CH2:16][CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][CH2:20]4)[N:9]3[N:8]=2)[CH:2]=1
Reactant: COC(=O)C(=O)c1c(C)nc2nc(-c3cccc(-c4ccccc4)c3)nn2c1N1CCC(C)(C)CC1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](O)c1c(C)nc2nc(-c3cccc(-c4ccccc4)c3)nn2c1N1CCC(C)(C)CC1
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
To a stirred yellow solution of methyl 2-(2-([1,1′-biphenyl]-3-yl)-7-(4,4-dimethylpiperidin-1-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (61 mg, 0.126 mmol) in anhydrous Toluene (6 mL) was added 1.1M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole/toluene (0.046 mL, 0.050 mmol). The mixture was cooled to −35° C. and a solution of 1M catechoborane/THF (0.177 mL, 0.177 mmol) was added over 10 min. After 30 min, the reaction mixture was slowly warmed to −15° C. and stirred for additional 2 h. and diluted with EtOAc (100 mL) and sat. Na2CO3 (50 mL). The mixture was stirred vigorously for 30 min, and the organic phase washed with sat Na2CO3 (2×50 mL), dried (Na2SO4), filtered, concentrated and the residue was purified by Biotage (5-70% EtOAc/hexane) to afford desired (S)-methyl 2-(2-([1,1′-biphenyl]-3-yl)-7-(4,4-dimethylpiperidin-1-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (59 mg, 0.115 mmol, 92% yield).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([OH:19])=O)=[O:7])(C)(C)C.[O:20]=[C:21]1[C:26](C(Cl)=O)=[CH:25][CH:24]=[C:23]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[O:22]1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[CH2:40][NH2:41]>>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[CH2:40][NH:41][C:17]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:12][N:8]1[C:6]([C:26]1[C:21](=[O:20])[O:22][C:23]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:24][CH:25]=1)=[O:7])=[O:19]
Reactant: COc1ccc(CN)cc1OC
Reactant: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Product: CCCCCc1ccc(C(=O)N2CC(=NOCC)C[C@H]2C(=O)NCc2ccc(OC)c(OC)c2)c(=O)o1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 3,4-dimethoxybenzylamine the title compound was obtained in 41% purity by LC/MS. MS(ESI+): m/z=514.2.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[O:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]3[S:1][CH:2]=[CH:3][C:4](=[O:14])[C:5]2=3)[CH2:19][CH2:20]1
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Reactant: ClCCN1CCOCC1
Product: O=c1ccsc2c3ccccc3n(CCN3CCOCC3)c12
Yield: 68 %

Procedure:
4.8 g of thiopyrano [3,2-b]indol-4-one and 15 g of chloroethylmorpholine, are reacted in the same manner as described in Example 14, except that the crude free base crystallized. This is filtered and recrystallized from methylenechloride-hexane to give 5.1 g of product, mp 136°-137° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH:18]([CH2:20]O)[CH2:17][C:16]2=[O:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH:18]([CH2:20][Cl:25])[CH2:17][C:16]2=[O:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1CC(CO)CN1c1ccc(OCc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C1CC(CCl)CN1c1ccc(OCc2ccccc2)cc1
Yield: 15.6 %

Procedure:
740 mg (2.49 mmol) (RS)-1-(4-benzyloxy-phenyl)-4-hydroxymethyl-pyrrolidin-2-one is dissolved in 20 ml toluene. 1.08 ml (14.9 mmol) thionyl chloride is added and the mixture refluxed for 6 hours. Evaporation and chromatography (silica gel, n-hexane/ethyl acetate 1:1) yields 123 mg (16%) of a brownish semisolid. MS: m/e=315.2 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH2:10]2)=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].Br[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([F:26])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:26][C:18]1[CH:17]=[C:16]([CH2:15][O:13][C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:10][CH2:9][CH2:8]3)[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: O=[N+]([O-])c1cc2c(cc1O)CCC2
Reactant: COC(=O)c1ccc(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2cc3c(cc2[N+](=O)[O-])CCC3)cc1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
7.17 g of 6-nitroindan-5-ol was dissolved in 80.0 mL of DMF, and 10.9 g of methyl 4-(bromomethyl)-2-fluorobenzoate and 6.63 g of potassium carbonate were added thereto, followed by stirring at 50° C. overnight. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:1) to obtain 11.1 g of methyl 2-fluoro-4-{[(6-nitro-2,3-dihydro-1H-inden-5-yl)oxy]methyl}benzoate.
Reaction SMILES: [C:1]1([CH2:7][C:8](O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([NH2:13])[CH3:12].N.[CH2:15]1[CH:24]2[CH:19]([CH2:20][CH2:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=32)[NH:18][C:17](=[O:29])[CH2:16]1>C(O)CO>[CH2:11]([N:18]1[C:19]2[C:7]([CH3:8])([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=3[CH2:23][CH:24]=2)[CH2:15][CH2:16][C:17]1=[O:29])[CH3:12].[CH2:11]([N:13]1[C@@H:19]2[C@:24]([CH3:1])([C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[CH2:21][CH2:20]2)[CH2:15][CH2:16][C:17]1=[O:29])[CH3:12]
Reactant: O=C(O)Cc1ccccc1
Reactant: O=C1CCC2c3ccccc3CCC2N1
Reactant: CCN
Agent: N
Solvent: OCCO
Product: CCN1C(=O)CCC2(C)C1=CCc1ccccc12
Product: CCN1C(=O)CC[C@@]2(C)c3ccccc3CC[C@H]12
Reaction time: 7 h

Procedure:
By following the procedures described in Example 40, Steps A, B, C, D, E and F using phenylacetic acid as the starting material and using ethylamine rather than ammonia, and digylme rather ethylene glycol in Step F, the compound 4-ethyl-10b-methyl-1,2,3,4,6,10b-hexahydrobenzo[f]quinolin-3-one was prepared. This hexahydrobenzo[f]quinolin-3-one was hydrogenated by following the procedures described Example 22 except that the reaction was carried out at 70° C. over 7 hours to afford a crude reaction mixture. The reaction mixture was filtered and the solvents evaporated under vacuum to afford a glassy solid residue. The crude product was purified by chromatography on SiO2 (gradient elution from 100% hexanes to 100% CHCl3) to afford 92 mg of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[C:14](Cl)(=O)C(Cl)=O.C(OCC)(=O)CC(OCC)=O.[H-].[Na+]>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:8])[CH3:14])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(=O)CC(=O)OCC
Product: CC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 23.7 %

Procedure:
To a solution of 4-chloro-2-nitrobenzoic acid (30.0 g, 0.15 mol) in THF (400 mL) was added oxalyl chloride (26 mL, 0.3 mol) at 0° C., followed by DMF (2 drops). After stirring for 10 min at 0° C., the ice bath was removed and the reaction mixture was heated at reflux for 3 h. The resulting mixture was then cooled and evaporated under reduced pressure. A second 1 L round bottom flask was loaded with diethyl malonate (22.8 mL, 0.15 mol) and THF (150 mL): sodium hydride (60% dispersion in mineral oil, 7.2 g, 0.18 mol) was then added at 0° C., portionwise over a period of 30 minutes. The ice bath was then removed, and the mixture was heated at reflux for 3 h. The acyl chloride, dissolved in 2 portions of THF, was added and the resulting mixture was heated at reflux for 3 h and then stirred at room temperature overnight. The reaction mixture was partitioned between water and EtOAc; the organic layer was separated and the aqueous layer was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. A mixture of glacial AcOH (50 mL) and sulfuric acid (20% in water, 50 mL) was added to the residue, and the resulting mixture was heated at reflux for 6 h and then stirred at 80° C. overnight. The reaction mixture was basified to pH 10 by adding NaOH (aq) and then was extracted 3 times with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane) to give 7.1 g of 1-(4-chloro-2-nitro-phenyl)-ethanone.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[Cl:8][C:9]1[C:23]([Cl:24])=[CH:22][CH:21]=[C:20]([Cl:25])[C:10]=1[C:11]([NH:13][O:14][CH2:15][C:16]([O:18]C)=[O:17])=[O:12]>O1CCCC1>[Cl:8][C:9]1[C:23]([Cl:24])=[CH:22][CH:21]=[C:20]([Cl:25])[C:10]=1[C:11]([NH:13][O:14][CH2:15][C:16]([OH:18])=[O:17])=[O:12]
Reactant: COC(=O)CONC(=O)c1c(Cl)ccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CONC(=O)c1c(Cl)ccc(Cl)c1Cl

Procedure:
To 1.25 g. of potassium carbonate in 15 ml. of water and 35 ml. of tetrahydrofuran was added 2.0 g. of methyl [(2,3,6-trichlorobenzoyl)aminooxy]acetate and the resulting mixture was stirred at 50° C., for 2 days. The solvents were evaporated in vacuo and residue dissolved in dilute aqueous sodium hydroxide, washed with ethyl acetate and the aqueous layer acidified with concentrated hydrochloric acid. The resulting aqueous layer was extracted with two portions of ethylacetate, the combined ethyl acetate layers were dried over MoSO4 and concentrated in vacuo to obtain [2,3,6-trichlorobenzoyl)aminooxy]acetic acid, m.p. 145°-147° C.
Reaction SMILES: C1(C(C2[C:14]([CH2:15][O:16][CH2:17][C:18]3[C:23](C4C(=CC=C(O)C=4)O)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=[CH:11][CH:10]=2)=CC(=CC=1)O)O.Br[CH2:33][CH2:34][O:35][CH2:36][CH2:37][CH3:38].[OH-:39].[Na+]>>[CH2:17]([O:16][C:15]1[CH:10]=[CH:11][C:12]([O:39][CH2:33][CH2:34][O:35][CH2:36][CH2:37][CH3:38])=[CH:13][CH:14]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: [OH-]
Reactant: CCCOCCBr
Reactant: Oc1ccc(O)c(-c2ccccc2COCc2ccccc2-c2cc(O)ccc2O)c1
Agent: [Na+]
Product: CCCOCCOc1ccc(OCc2ccccc2)cc1

Procedure:
Hydroquinone monobenzyl ether is reacted with 2-bromoethyl-n-propyl ether in aqueous sodium hydroxide and then purified over silica gel with toluene as eluent. The middle fraction gives 1-benzyloxy-4-(2-propoxy-ethoxy)benzene (used without further purification).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][NH:14][C:15]3=[O:18])=[CH:10][CH:9]=2)[N:6]=[C:5]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:4]=1.N1C=CC=CC=1.Cl[C:30]([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31]>C(Cl)Cl>[C:19]([C:5]1[CH:4]=[C:3]([NH:2][C:30](=[O:31])[O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])[N:7]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][NH:14][C:15]3=[O:18])=[CH:10][CH:9]=2)[N:6]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2ccc3c(c2)C(=O)NCC3)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc3c(c2)C(=O)NCC3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of 7-(5-amino-3-t-butyl-pyrazol-1-yl)-3,4-dihydro-2H-isoquinolin-1-one hydrochloride (0.5 g, 1.76 mmol) in CH2Cl2 (25 mL) were added pyridine (0.22 mL) and trichloroethyl chloroformate (0.27 mL) at 0° C. and the mixture was stirred overnight at RT. LCMS showed the reaction was incomplete. Pyridine (0.25 mL) and TROC-Cl (0.25 mL) were added and then the mixture stirred at RT for 2 hours. The reaction mixture was diluted with CH2Cl2, the organic layer was washed with 3M HCl and brine, dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in EtOAc and hexane was added. The solid was filtered to obtain 2,2,2-trichloroethyl 3-tert-butyl-1-(1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-ylcarbamate (0.46 g, 57% yield). MS (ESI) m/z: 458.0 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:14]O>>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([O:9][CH3:14])=[O:8]
Reactant: CO
Reactant: O=C(O)[C@H]1CCCCN1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CCCCN1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To (R)-Piperidine-2-carboxylic acid (5.00 g, 38.73) in 150 ml of dry methanol at 0° C. was added thionyl chloride (5.2 ml, 71.28 mmol) under Ar. The mixture was stirred at 0° C. for 30 min, then at RT overnight, evaporated and crystallized with EtOH/hexane to afford 4.96 g (92%) of the title product. 1H NMR (CD3OD) 3.67 (s, 3H), 3.57 (m, 1H), 2.79 (m, 1H), 2.69 (m, 1H), 2.01 (m, 1H), 1.98 (m, 1H), 1.73 (m, 1H), 1.55-1.45 (m, 4H); 13C NMR 171.22, 62.50, 51.35, 45.35, 29.52, 28.41, 23.82; MS m/z+ 144.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[S:8])[O:5][C:6]=1[CH3:7].C(N1C(=O)C2=CC=C[CH:21]=[C:14]2[C:13]1=[S:22])CC>>[CH3:1][C:2]1[N:3]=[C:4]([S:8][S:22][CH2:13][CH2:14][CH3:21])[O:5][C:6]=1[CH3:7]
Reactant: Cc1[nH]c(=S)oc1C
Reactant: CCCN1C(=O)c2ccccc2C1=S
Product: CCCSSc1nc(C)c(C)o1

Procedure:
Starting from 4,5-dimethyl-2-thiono-4-oxazoline and N-propylthiophthalimide there is obtained (4,5-dimethyl-2-oxazolyl)propyl-disulphide.