Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]1=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>C(O)CCC>[C:2]1([C:1]2[C:9]3[S:13][C:12]4[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=4[C:10]=3[NH:20][N:21]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccccc1)C1Sc2ccccc2C1=O
Solvent: O
Solvent: CCCCO
Product: c1ccc(-c2n[nH]c3c2sc2ccccc23)cc1

Procedure:
A mixture of 2-benzoylbenzo[b]thiophen-3(2H)-one (1.50 g, supplied by the Maybridge Chemical Company, Tintagel, England) hydrazine hydrate (0.3 ml) and butan-1-ol (50 ml) was boiled under reflux under nitrogen for 7.5 hours. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate, washed with water, dried, filtered and evaporated to give a solid which was purified by flash column chromatography on silica using toluene/ethyl acetate (7.5:1) as the mobile phase. Appropriate fractions were collected, combined and evaporated to give a solid which was triturated with ether, and filtered to give 3-phenyl-1H-[1]benzothieno[3,2-c]pyrazole, m.p. 236-238° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[C:3]([O:5][C@H:6]([O:10][C:11](ON1C(=O)[C@@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C2C=CC=CC=2)C1=O)=[O:12])[CH:7]([CH3:9])[CH3:8])=[O:4].[NH2:40][CH2:41][CH2:42][CH2:43][P:44]([CH2:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1)(=[O:46])[OH:45].C1COCC1>O>[C:3]([O:5][C@H:6]([O:10][C:11]([NH:40][CH2:41][CH2:42][CH2:43][P:44]([CH2:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1)(=[O:45])[OH:46])=[O:12])[CH:7]([CH3:8])[CH3:9])(=[O:4])[CH:2]([CH3:39])[CH3:1]
Reactant: CC(C)C(=O)O[C@H](OC(=O)ON1C(=O)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)C1=O)C(C)C
Reactant: NCCCP(=O)(O)CC1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(=O)O[C@H](OC(=O)NCCCP(=O)(O)CC1CCCCC1)C(C)C
Temperature: 19 °C
Reaction time: 4 h

Procedure:
To a 3 L three necked round bottom flask fitted with a mechanical stirrer, temperature probe, and nitrogen inlet is added compound (25) (100 mmol), 3-aminopropyl(cyclohexylmethyl)phosphinic acid (100 mmol), THF (1 L), and water (100 mL). The suspension is stirred under a nitrogen atmosphere at 18-20° C. for 4 h during which time the reaction mixture becomes homogeneous. The THF is removed in vacuo and the reaction mixture is diluted with methyl tert-butyl ether (250 mL) and washed with 1N HCl (1×500 mL) and water (2×200 mL). The organic phase is separated and concentrated in vacuo to leave a white solid. The solid is purified by flash chromatography to afford the product (99) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.[CH3:27][O:28][C:29]([CH:31]1[CH2:36][CH2:35][CH:34]([CH2:37]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:33][CH2:32]1)=[O:30]>>[CH3:27][O:28][C:29]([CH:31]1[CH2:36][CH2:35][CH:34]([CH2:37][O:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)[CH2:33][CH2:32]1)=[O:30]
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Reactant: COC(=O)C1CCC(COS(=O)(=O)c2ccc(C)cc2)CC1
Product: COC(=O)C1CCC(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)CC1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) and 4-(toluene-4-sulfonyloxymethyl)-cyclohexane carboxylic acid methyl ester (CAS Reg. No. 1003013-11-3). Brown solid (51%). MS (Turbo Spray): m/z=531.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:25]1([CH:31]=[CH:32][S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1CCN2C(=NCCC2)CC1>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:36][S:33]([CH:32]=[CH:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:34])=[O:35])=[O:8])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: NS(=O)(=O)C=Cc1ccccc1
Reactant: COc1cc(Cl)ccc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1cc(Cl)ccc1C(=O)NS(=O)(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A mixture of 4-chloro-2-methoxybenzoic acid (509 mg, 2.7 mmol) and CDI (443 mg, 2.7 mmol) in dichloromethane (25 ml) was heated to reflux for 30 minutes. After cooling down to room temperature 2-phenyl-ethenesulfonic acid amide (for preparation see example 1-1, steps i) and ii)) (500 mg, 2.7 mmol) and DBU (416 mg, 2.7 mmol) were added and the mixture was stirred at room temperature overnight. After washing twice with 1N HCl (50 ml each) and water (50 ml) the mixture was dried over Na2SO4 and concentrated in vacuo. Preparative HPLC (RP18, methanol-water-gradient) returned the title compound (570 mg, 60% yield) as a white solid.
Reaction SMILES: C(OC(=O)[NH:10][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)([CH3:13])[CH3:12])C1C=CC=CC=1>[Pd].C(O)C>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([C:11]([NH2:10])([CH3:12])[CH3:13])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(C(C)(C)NC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(C(C)(C)N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a round bottom flask, [1-(3-methoxy-phenyl)-1-methyl-ethyl]-carbamic acid benzyl ester (10.0 g, 33.4 mmol), ethanol (200 mL), and 10% Pd/C (1.20 g) were added. The mixture was evacuated under vacuum and charged with hydrogen via balloon (3 times). The reaction was stirred at room temperature overnight under a hydrogen atmosphere via a balloon. The solid was filtered and washed with Ethanol. The solvent was removed under vacuum to give 1-(3-Methoxy-phenyl)-1-methyl-ethylamine as a viscous oil 1-(3-methoxy-phenyl)-1-methyl-ethylamine (4.80 g, 0.0290 mol;)was treated with DMF and N,N-diisopropylethylamine (7.59 mL, 0.0436 mol) acetic acid, bromo-, 1,1-dimethylethyl ester (6.23 g, 0.0320 mol), respectively. The reaction mixture was stirred at 50° C. for 24 hours. The solvent was removed under vacuum. The reaction was partitioned with water and DCM. The organic was separated, washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The product was isolate via column chromatography with hexane and EtOAc as eluant (0 to 50%) to afford [1-(3-methoxy-phenyl)-1-methyl-ethylamino]-acetic acid tert-butyl ester as a white solid (5.86 g, 63%). 1H-NMR (CDCl3, 400 MHz): δ 7.22-7.28 (m, 1H), 6.97-7.02 (m, 2H), 6.75-6.80 (m, 1H), 3.80 (s, 3H), 3.06 (s, 2H), 1.44 (s, 6H), 1.42 (s, 9H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][C:27]([F:30])([F:29])[F:28])[N:11]=2)[CH2:4][CH2:3]1.[BH-](OC(C)=O)(OC(C)=O)O[C:33]([CH3:35])=O.[Na+].C(=O)C.C([O-])(O)=O.[Na+]>CC(O)=O.CO>[CH2:33]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][C:27]([F:29])([F:30])[F:28])[N:11]=2)[CH2:6][CH2:7]1)[CH3:35]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: N#Cc1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](N)CC1
Agent: CC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCN[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2C#N)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
4-{[(trans-4-Aminocyclohexyl)methyl]amino}-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidine-5-carbonitrile (150 mg, 0.36 mmol) was dissolved in a solution of 1% AcOH in MeOH. The solution was cooled to 0° C. and to this cold solution were added NaBH(OAc)3 and acetaldehyde. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then treated with saturated NaHCO3 and extracted with EtOAc. The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using 9:1:0.1 CH2Cl2:MeOH:NH4OH as an eluent to afford 24 mg (15%) of the title compound, m/z 449.4 (M+1)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]OS(C)(=O)=O)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:26])[C:12]=2[C@H:27]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[I-:39].[Na+]>CC(C)=O.CCOC(C)=O>[CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][I:39])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:26])[C:12]=2[C@H:27]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COS(C)(=O)=O)nn23)CC1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84.1 %

Procedure:
To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methyl-2-(((methylsulfonyl)oxy)methyl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.62 g, 1.122 mmol) in acetone (6 ml) was added sodium iodide (0.673 g, 4.49 mmol) and the mixture was stirred at rt for 45 min. The reaction was diluted with EtOAc and washed with water. The organic phase was dried (Na2SO4), filtered and concentrated. The crude oil was purified by flash chromatography (Biotage; 0%-50% EtOAc/hexane; 20 CV) to give (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.5519 g, 0.944 mmol, 84% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.53 (s, 1H), 6.16-5.99 (m, 1H), 5.99-5.77 (m, 1H), 5.64-5.39 (m, 1H), 5.32-5.14 (m, 1H), 4.56 (s, 2H), 4.35-4.17 (m, 2H), 4.03 (d, J=4.9 Hz, 2H), 2.59 (s, 3H), 1.93 (br. s., 4H), 1.36 (s, 3H), 1.31-1.18 (m, 12H). 4 piperidine protons not seen. LCMS (M+H) calcd for C25H38IN4O4: 585.19. found: 585.5.
Reaction SMILES: [C:1]([CH:5]1[C:11](=[O:12])[CH2:10][C@H:9]2[N:13]([CH3:14])[CH:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2].[BH4-].[Na+].[ClH:17]>CO.C(O)C>[ClH:17].[C:1]([CH:5]1[CH:11]([OH:12])[CH2:10][C@H:9]2[N:13]([CH3:14])[CH:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1C(=O)C[C@@H]2CCC1N2C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: COC(=O)C1C(O)C[C@@H]2CCC1N2C
Reaction time: 4 h

Procedure:
To a solution of (1RS,2RS)-2-carbomethoxy-3-tropanone (17 g, 85 mmol) in 750 ml methanol cooled to -35° C. was added sodium borohydride (17 g, 450 mmol) and the mixture was stirred for 4 hours. The cooled solution was quenched by slow addition of concentrated hydrochloric acid (40 ml) and the mixture was concentrated in vacuo. Water (400 ml) was added and the pH was adjusted to 3 by addition of concentrated hydrochloric acid. After having washed the water phase three times with diethyl ether pH was adjusted to 11 by addition of concentrated ammonium hydroxide and the water phase was extracted three times with methylene chloride. Concentration in vacuo yields an oil which was dissolved in ethanol and added cocncentrated hydrochloric acid followed by concentration in vacuo. Freeze drying the residue yielded the title compound as an amorphous product.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.C[O:46]C(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[C:5]([C:4]4[CH:3]=[CH:2][C:43]([OH:46])=[CH:42][CH:41]=4)=[CH:6][CH:7]=[C:8]([O:39][CH3:40])[CH:9]=2)[CH:20]=[CH:19]3)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Product: COc1ccc(-c2ccc(O)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 8 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 4-phenolboronic acid (36 mg, 0.2625 mmol) to produce the title compound (10 mg, 8% yield).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[O:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[C:34]1[NH:38][C:37]2[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=2[N:35]=1>>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:35]1[C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[N:38]=[C:34]1[C@@H:30]1[CH2:31][CH2:32][CH2:33][O:29]1)=[N:3][C:4]=2[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: c1ccc2[nH]c(C3CCCO3)nc2c1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c([C@@H]4CCCO4)nc4ccccc43)nc21

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and racemic 2-(tetrahydrofuran-2-yl)-1H-benzimidazole were reacted to give a racemic mixture. The enantiomers were separated by SFC to give 253. LCMS m/z: 561.3 (MH+)
Reaction SMILES: Cl.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:6][CH2:5][C:4]1=[O:19].[O:20]=[C:21]1[NH:30][C:29]2[N:28]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][CH:35]=O)[CH:26]=[CH:25][C:24]=2[CH2:23][CH2:22]1>>[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]2[CH2:18][CH2:17][N:16]([CH2:35][CH2:34][CH2:33][CH2:32][O:31][C:27]3[N:28]=[C:29]4[C:24]([CH2:23][CH2:22][C:21](=[O:20])[NH:30]4)=[CH:25][CH:26]=3)[CH2:15][CH2:14]2)[CH2:6][CH2:5][C:4]1=[O:19]
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Reactant: CN1C(=O)CCc2cccc(N3CCNCC3)c21
Agent: Cl
Product: CN1C(=O)CCc2cccc(N3CCN(CCCCOc4ccc5c(n4)NC(=O)CC5)CC3)c21

Procedure:
In a manner similar to that of other examples above, 1-methyl-8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one hydrochloride was coupled by reductive amination to 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 464.6 (Exact Mass: 463.26).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:17]>>[OH:10][C:3]1[C:2]([CH3:1])=[C:7]([CH3:8])[CH:6]=[C:5]([CH3:9])[C:4]=1[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:17]
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: CCOC(=O)CCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)CCCCCC(=O)c1c(C)cc(C)c(C)c1O

Procedure:
2,3,5-Trimethylphenol (formula VII wherein R=H3C, X=H, Y=OH)(0.9 part,) aluminum chloride (2.1 parts) and ethyl 6-chloroformylhexanoate (1.3 part) were treated as in Example 1 (1). The procedure provided colorless needles of ethyl 6-(2'-hydroxy-3', 4', 6'-trimethylbenzoyl)hexanoate (formula II-1 wherein R=H3C, X=H, Y=OH, n=5, in the form of ethyl ester) (1.5 part) melting at 47°-48° C.
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:8]Cl)[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:10][C:11]1[C:16]([CH3:17])=[C:15]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:13][C:12]=1[N:21]=[C:22]=[S:23]>>[CH3:10][C:11]1[C:16]([CH3:17])=[C:15]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:13][C:12]=1[N:21]=[C:22]1[S:23][CH2:8][C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[NH:2]1
Reactant: Cc1c(N=C=S)ccc([N+](=O)[O-])c1C
Reactant: NC1(CCl)CCCC1
Agent: Cl
Product: Cc1c(N=C2NC3(CCCC3)CS2)ccc([N+](=O)[O-])c1C

Procedure:
2,3-Dimethyl-4-nitroaniline was synthesized as described in Method A4a. The aniline was converted into 2,3-dimethyl-4-nitrophenyl isothiocyanate as described in method A2d. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7e to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2,3-dimethyl-4-nitrophenyl isothiocyanate according to Method C1c to give 2-(2,3-dimethyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(2-isopropyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [CH3:1]OC1C=CC(C)=CC=1C.[F:11][C:12]([F:29])([F:28])[C:13](=[O:27])[CH2:14][C:15]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[O:25][CH3:26])([CH3:17])[CH3:16]>>[F:11][C:12]([F:28])([F:29])[C:13](=[O:27])[CH2:14][C:15]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:1])[C:19]=1[O:25][CH3:26])([CH3:17])[CH3:16]
Reactant: COc1ccc(C)cc1C
Reactant: COc1ccc(C)cc1C(C)(C)CC(=O)C(F)(F)F
Product: COc1c(C)cc(C)cc1C(C)(C)CC(=O)C(F)(F)F

Procedure:
The title product was prepared from 1-methoxy-2,4-dimethylbenzene according to the same procedure described in the synthesis of 1,1,1-trifluoro-4-(2-methoxy-5-methylphenyl)-4-methylpentan-2-one.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[CH2:16][CH2:17][C:18]([O:20]C)=[O:19])[N+:12]([O-])=[C:11]1[C:6](=[CH:7][C:8](=[O:23])[CH:9]=[CH:10]1)[O:5]2.S(S([O-])=O)([O-])=O.[Na+].[Na+]>[OH-].[Na+]>[OH:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[N:12]=[C:11]1[C:6](=[CH:7][C:8](=[O:23])[CH:9]=[CH:10]1)[O:5]2
Reactant: COC(=O)CCc1cc2c(cc1O)oc1cc(=O)ccc-1[n+]2[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCc1cc2nc3ccc(=O)cc-3oc2cc1O
Reaction time: 1 h
Yield: 68.4 %

Procedure:
Methyl ester (10a) (22.83 g, 72.4 mmol) was dissolved in 400 ml of 0.5 M aqueous sodium hydroxide and the solution was stirred for 1 h. A solution of sodium dithionite solution (200 ml, 100 mmol) was added and reaction mixture was stirred for additional 15 minutes. To precipitate the product 3 M hydrochloric acid (80 ml) was carefully added and resultant suspension was stirred for 10 min and centrifuged. The supernatant was decanted and the residue was re-suspended in ˜800 ml of water and centrifuged again. This operation was repeated one more time. Final supernatant had pH of 3-4. The centrifuged material was dried under vacuum overnight at 40° C. to afford 14.12 g (68%) of desired product (11a) as a brown solid. 1H NMR (CD3OD, +40° C.): δ 7.64 (d, J=9.0 Hz, 1H), 7.39 (s, 1H), 6.89 (d, J=9.0 Hz, 1H), 6.74 (s, 1H), 6.34 (s, 1H), 2.63 (m, 2H), 2.51 (m, 2H).
Reaction SMILES: I.[CH3:2][NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1.[C:16](#[N:20])[C:17]([CH3:19])=[CH2:18].C(N(CC)CC)C>ClCCl>[CH3:2][N:3]([CH2:18][CH:17]([CH3:19])[C:16]#[N:20])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: C=C(C)C#N
Reactant: CNCCc1ccc(OC)c(OC)c1
Agent: I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCN(C)CC(C)C#N)cc1OC
Temperature: 70 °C
Yield: 39.8 %

Procedure:
A mixture comprising 6.5 g of N-methyl-2-(3,4-dimethoxyphenyl)ethylamine hydroiodide, 1.6 g of methacrylonitrile and 2.4 g of triethylamine was heated at about 70° C. for 2.5 hours and cooled, followed by the addition of dichloromethane. The obtained mixture was washed with water, dried over magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography (solvent: dichloromethane/ethanol (100:1)) to obtain 2.1 g of 3-[N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)amino]-2-methylpropionitrile.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:14]=1[NH2:15]>>[CH3:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Cc1cccc(C)c1N
Product: Cc1cccc(C)c1Nc1ccccc1CC(=O)O

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid was condensed with 2,6-dimethylaniline to yield 2-[(2,6-dimethylphenyl] amino] phenylacetic acid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH2:10])=[O:9])[C:3]1=[O:11].[C:12](Cl)(=[O:14])[CH3:13]>C(Cl)(Cl)Cl>[C:12]([O:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH2:10])=[O:9])[C:3]1=[O:11])(=[O:14])[CH3:13]
Reactant: NC(=O)CN1CCC(O)C1=O
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)OC1CCN(CC(N)=O)C1=O

Procedure:
1.5 g of (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide are heated to reflux for 20 minutes with 13.5 ml of acetyl chloride and 25 ml of chloroform. The mixture is evaporated. The residue is treated four times with toluene and in each case again evaporated. There is obtained (R/S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetamide which melts at 116°-117° after crystallization from diethyl ether.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][N:6]1[C:14]2[C:13](=[O:15])[NH:12][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])=[N:10][C:9]=2[C:8]([CH2:26][CH2:27][CH3:28])=[N:7]1.[Br:29][CH2:30][C:31](Cl)=[O:32].O>ClCCl>[Br:29][CH2:30][C:31]([C:20]1[CH:19]=[CH:18][C:17]([O:22][CH2:23][CH2:24][CH3:25])=[C:16]([C:11]2[NH:12][C:13](=[O:15])[C:14]3[N:6]([CH3:5])[N:7]=[C:8]([CH2:26][CH2:27][CH3:28])[C:9]=3[N:10]=2)[CH:21]=1)=[O:32]
Reactant: CCCOc1ccccc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Reactant: O=C(Cl)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCOc1ccc(C(=O)CBr)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.9 %

Procedure:
Aluminum trichloride (6.0 g, 0.045 mol) was added portionwise to a stirred solution of -1-methyl-5-(2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (5.0 g, 0.0153 mol) and 2-bromoacetyl chloride (2.5 ml, 0.0303 mol) in dichloromethane (100 ml) at 0° C. The reaction mixture was allowed to warm to room temperature, stirred for 18 hours, heated under reflux for 3 hours and then added cautiously to ice and water (100 g). The resulting mixture was stirred for 1 hour and extracted with dichloromethane (2×50 ml). The combined organic extracts were washed with brine (2×50 ml), dried (Na2SO4), then evaporated under vacuum to give an off-white solid, which was triturated with ether to give the title compound as a white solid (4.1 g, 60%). A small sample was crystallised from ethyl acetate-hexane to give the pure product, m.p. 136°-137° C. Found: C,53.82; H,5.24; N,12.57. C20H23BrN4O3 requires C,53.70;H,5.18; N,12.52%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[O:17][CH3:18])[C:6]([CH2:8][C:9]([O:11]CC)=O)=O.[C:22]1([NH:28][NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[CH2:8][C:9](=[O:11])[N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:29]=2)[CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[O:17][CH3:18]
Reactant: CCOC(=O)CC(=O)c1cc(OC)c(OC)c([N+](=O)[O-])c1
Reactant: NNc1ccccc1
Product: COc1cc(C2=NN(c3ccccc3)C(=O)C2)cc([N+](=O)[O-])c1OC

Procedure:
10.0 g of ethyl (3,4-dimethoxy-5-nitrobenzoyl)acetate are reacted with 4.0 g of phenylhydrazine in analogy to Example 53a. After recrystallization from methylene chloride/ethanol, there is obtained 3-(3,4-dimethoxy-5-nitrophenyl)-1-phenyl-2-pyrazolin-5-one in the form of yellow crystals of m.p. 190°-192°.