Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[C:5]([CH3:25])=[CH:4][N:3]=1.[CH3:26][N:27]1[CH:31]=[C:30]([NH2:32])[CH:29]=[N:28]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:25][C:5]1[C:6]([NH:8][CH:9]2[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)=[N:7][C:2]([NH:32][C:30]2[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=2)=[N:3][CH:4]=1
Reactant: Cn1cc(N)cn1
Reactant: Cc1cnc(Cl)nc1NC1CN(C(=O)OC(C)(C)C)CC12CCCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CN(C(=O)OC(C)(C)C)CC12CCCC2
Temperature: 150 °C
Reaction time: 16 h
Yield: 110.8 %

Procedure:
To a solution of tert-butyl 4-((2-chloro-5-methylpyrimidin-4-yl)amino)-2-azaspiro[4.4]nonane-2-carboxylate (0.35 g, 0.95 mmol) and 1-methyl-1H-pyrazol-4-amine (0.14 g, 1.43 mmol) in n-BuOH (5 mL) was added DIPEA (0.25 g, 1.9 mmol). The reaction mixture was stirred at 150° C. for 16 h then concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the product as black oil (0.45 g, 86%).
Reaction SMILES: Cl.O1CCO[CH2:4][CH2:3]1.[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1>>[CH2:3]([O:16][C:15]([CH:12]1[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]1)=[O:17])[CH3:4]
Reactant: CN1CCC(C(=O)O)CC1
Reactant: C1COCCO1
Agent: Cl
Product: CCOC(=O)C1CCN(C)CC1
Yield: 499.5 %

Procedure:
A solution of 2N hydrochloric acid in dioxane (2.8 ml, 11.13 mmol) was added to 1-methyl-4-piperdine carboxylic acid (20 g, 111.33 mmol) and the mixture heated at reflux for 18 hours. The reaction was concentrated to dryness and the resultant solid dissolved in dichloromethane and washed with a saturated solution of sodium bicarbonate, dried (magnesium sulphate) and concentrated to afford 1-methyl-4-piperdine carboxylic acid ethyl ester as a white solid (9.52 g, 50% yield).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:15][CH2:14][C:13](=[C:16]=[N:17]O)[CH:12]([Cl:19])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>P(Cl)(Cl)(Cl)=O>[CH2:2]([N:9]1[CH2:15][CH2:14][C:13]([C:16]#[N:17])=[C:12]([Cl:19])[CH2:11][CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: ON=C=C1CCN(Cc2ccccc2)CCC1Cl
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC1=C(Cl)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
43.5 gm (0.144 mol) of 1-benzyl-4-chloro-2,3,6,7-tetrahydro-5-oximinomethylene-1H-azepine hydrochloride were added to 450 ml of phosphorus oxychloride while stirring at ambient temperature. The mixture was then stirred for 3 hours more, and the reaction mixture was then allowed to stand overnight. Then, the excess phosphorus oxychloride was distilled off in a rotary evaporator, and the residue was carefully mixed with water while cooling with ice. While cooling was continued, the mixture was made slightly alkaline by the addition of concentrated ammonia, and an oil separated out which crystallized when scratched. The crystal slurry thus obtained was suction-filtered, washed with water, dried and recrystallized from isopropyl alcohol.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH2:24][CH2:25][C:26]2([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[O:31][C:30](=[O:32])[CH2:29][C:28](=[O:33])[CH2:27]2)[CH:12]=[C:13]([CH2:22][CH3:23])[C:14]=1[O:15]COCCOC>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([CH2:24][CH2:25][C:26]2([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[O:31][C:30](=[O:32])[CH2:29][C:28](=[O:33])[CH2:27]2)[CH:12]=[C:13]([CH2:22][CH3:23])[C:14]=1[OH:15]
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1OCOCCOC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (0.07 mL, 0.88 mmol) was added to a solution of 6-{2-[3-Chloro-5-ethyl-4-(2-methoxy-ethoxymethoxy)-phenyl]-ethyl}-6-cyclopentyl-dihydro-pyran-2,4-dione (0.2 g, 0.44 mmol) dissolved in CH2Cl2 (4 mL). The reaction mixture was stirred for 2 hours at room temperature and then partitioned between H2O and EtOAc. The organic extracts were washed with brine, dried over Na2SO4 and concentrated to an oil. The oil was purified by flash column chromatography (0% to 30% EtOAc in hexanes) to give the title compound as a solid. (0.12 g, 75%). 1H NMR (400 MHz, CDCl3): δ 1.21 (t, J=7.6 Hz, 3H), 1.58-173 (br m, 8H), 1.92 (m, 2H), 2.26 (m, 1H), 2.57 (m, 2H), 2.65 (q, J=7.6 Hz, 2H), 2.76 (s, 2H), 3.43 (s, 2H), 5.47 (s, 1H), 6.81 (s, 1H), 6.95 (s, 1H). MS: C20H24O4Cl (M−H) 363.10.
Reaction SMILES: [CH3:1][C:2]1([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=2)[CH2:5][O:4][CH2:3]1.[OH-].[Na+].Cl>O>[CH3:1][C:2]1([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=2)[CH2:5][O:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(OCCCCCCOCC2(C)COC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(COCCCCCCOc2ccc(C(=O)O)cc2)COC1
Yield: 82.5 %

Procedure:
A mixture of ethyl 4-[6-(3-methyloxetane-3-yl-methoxy)hexyloxy]benzoate (83 g), sodium hydroxide (12 g), water (50 mL), and Solmix (registered trademark: 200 ml) was refluxed for 2 hours. The reaction mixture was rendered acidic with hydrochloric acid, extracted with ethyl acetate and an organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 4-[6-(3-methyloxetane-3-ylmethoxy)hexyloxy)benzoic acid (OX1: 63 g). Melting point: 58.5° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:17].C=O.[CH3:21]NC.O.Cl.[BH4-].[Na+]>CO>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:7]1([CH2:8][CH2:9][CH2:10]1)[CH:6]([CH3:21])[C:5]2=[O:17]
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CC1(CCC1)O2
Reactant: CNC
Agent: C=O
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)C(=O)C(C)C1(CCC1)O2

Procedure:
A solution of 6-hydroxy-5,7,8-trimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one (220 mg), formaldehyde (1 mL, 37% in water), dimethylamine solution (1 mL, 2.0 M in methanol), and concentrated HCl water solution (0.1, mL) was heated by microwave to 150° C. for 10 min. The allyl intermediate was treated with excessive NaBH4 in methanol at room temperature to give 6-hydroxy-3,5,7,8-tetramethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one, which was purified by chromatography (silica gel, hexane-ethyl acetate 3%).
Reaction SMILES: O.[NH2:2]N.FC(F)(F)C1C=C[C:9]2[N:15]3C(CON4C(=O)C5=CC=CC=C5C4=O)=NN=C3CN=[C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3Cl)[C:10]=2C=1>C(O)C>[NH:2]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:11]=[CH:10][CH:9]=[N:15]1
Reactant: NN
Reactant: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2
Solvent: O
Solvent: CCO
Product: C1=Cc2ccccc2NN=C1

Procedure:
In the manner given in Example 2, a solution of hydrazine hydrate in ethanol is reacted at 65° C. with 8-trifluoromethyl-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 1-[(aminooxy)methyl]-8-trifluoromethyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]1,4]benzodiazepine.
Reaction SMILES: CC1(C)OO1.[I:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7].IC1C=CC([C:22]2[S:23][C:24]3[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:25]=3[N:26]=2)=CC=1>ClCCl>[I:6]([C:9]1[CH:14]=[CH:13][C:12]([C:22]2[S:23][C:24]3[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:25]=3[N:26]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7]
Reactant: O=I(=O)c1ccccc1
Reactant: COc1ccc2nc(-c3ccc(I)cc3)sc2c1
Agent: CC1(C)OO1
Solvent: ClCCl
Product: COc1ccc2nc(-c3ccc(I(=O)=O)cc3)sc2c1
Yield: 84 %

Procedure:
A freshly prepared dimethyldioxirane solution (30 mL), as described above (para. [0035]) for the synthesis of simple iodylbenzene analogs, was added drop wise with stirring to an anhydrous dichloromethane (15 mL) solution of 4 (100 mg, 0.28 mmol) cooled in an ice bath. The resultant suspension was stirred at 0° C. for additional period of 2-3 hours and then at room temperature overnight. The yellow solid that was formed was collected by centrifugation and washed three times with dichloromethane. The residue was dried in vacuum to give 2-(4-iodylphenyl)-6-methoxy-1,3-benzothiazole (7) (95.4 mg, 84%) as a beige solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=O)[CH2:8][CH2:7]1)(=[O:3])[CH3:2].S(Cl)([Cl:17])=O>>[C:1]([NH:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([Cl:17])=[O:14])[CH2:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=S(Cl)Cl
Product: CC(=O)NC[C@H]1CC[C@H](C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
trans-4-[(Acetylamino)methyl]cyclohexanecarboxylic acid (12.1 g) was added by portions to thionyl chloride (25 ml) under ice-cooling. After stirred at room temperature for 30 minutes, thionyl chloride was evaporated under reduced pressure to give crude crystals of trans-4-[(acetylamino)methyl]cyclohexanecarbonyl chloride. Then, aluminum chloride (24.0 g) was added by portions to a solution of the crude crystals and 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (12.1 g) in dichloromethane (30 ml) under ice-cooling. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice (300 g), extracted with ethyl acetate, and washed 20 with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as colorless crystals (12.9 g) having a melting point of 178 to 180° C.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].Cl.[CH3:22][NH:23][CH3:24]>>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:20]=[CH:19][C:16]([CH2:17][N:23]([CH3:24])[CH3:22])=[CH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: CNC
Agent: Cl
Product: CCCCN1CCN(C(=O)c2ccc(CN(C)C)cc2)CC1

Procedure:
Prepared from the product of Example 13 and dimethylamine hydrochloride.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][C:8]2=[O:17])[CH2:3][CH2:2]1.Br[CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2[C:29]([O:33][CH3:34])=[CH:30][CH:31]=[CH:32][C:25]=2[S:24]1(=[O:36])=[O:35]>>[O:35]=[S:24]1(=[O:36])[C:25]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:26]=2[C:27](=[O:28])[N:23]1[CH2:22][CH2:21][CH2:20][CH2:19][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][C:8]2=[O:17])[CH2:3][CH2:2]1
Reactant: O=c1ccc2ccccc2n1C1CCNCC1
Reactant: COc1cccc2c1C(=O)N(CCCCBr)S2(=O)=O
Product: COc1cccc2c1C(=O)N(CCCCN1CCC(n3c(=O)ccc4ccccc43)CC1)S2(=O)=O

Procedure:
From the hydrochloride salt of 1-(4-piperidyl)-2(1H)-quinolinone prepared according to H. Ogawa et. al. J. Med. Chem. 1993, 36, 2011-2017, and 2-(4-bromobutyl)-4-methoxy-1,1-dioxido-1,2-benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: 1H NMR (300 MHz, CDCl3) 7.80 (t, J=8.1 Hz, 2H), 7.60 (d, J=9.33 Hz, 2H), 7.51 (m, 2H), 7.25 (m, 3H), 6.66 (d, J=9.27 Hz, 1H), 4.06 (s, 2H), 3.80 (t, J=6.9 Hz, 2H), 3.09 (dd, J=9.8, 1.8 Hz, 2H), 2.84 (m, 2H), 2.46 (t, J=7.2 Hz, 2H), 2.19 (t, J=11.6 Hz, 2H), 1.89 (br m, 2H), 1.69 (br m, 3H), 1.58 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]([OH:21])=[CH:4][C:5]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[CH2:10][N:9]([CH3:19])[CH2:8][CH2:7][C:6]=2[CH:20]=1.C([O-])(=O)C.[Na+].[H][H]>C(O)(=O)C.[Pd]>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:11]1[C:5]2[CH:4]=[C:3]([OH:21])[CH:2]=[CH:20][C:6]=2[CH2:7][CH2:8][N:9]([CH3:19])[CH2:10]1
Reactant: [H][H]
Reactant: CN1CCc2cc(Cl)c(O)cc2C(c2ccccc2F)C1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCc2ccc(O)cc2C(c2ccccc2F)C1
Temperature: 60 °C
Yield: 89 %

Procedure:
10.0 g 8-chloro-5-(2-fluorophenyl)-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was dissolved in 500 ml acetic acid containing sodium acetate. Palladium-on-carbon was added and the suspension was heated to 60° C. Under vigorous stirring hydrogen was led through the suspension giving after 48 h 7,9 g crystalline compound. Yield 72%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C@:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)([CH2:13][CH:14]=[CH2:15])[CH:10]=[N:11][CH3:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2].B.[Na].CC(C)=O.O>CO>[C:1]([O:5][C:6](=[O:24])[N:7]([C@:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)([CH2:13][CH:14]=[CH2:15])[CH2:10][NH:11][CH3:12])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CC[C@@](C=NC)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Agent: B
Agent: [Na]
Solvent: CO
Solvent: CC(C)=O
Solvent: O
Product: C=CC[C@@](CNC)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 100.8 %

Procedure:
tert-Butyl[2-(S)-(3,4-dichlorophenyl)-1-methylimino(4-penten-2-yl)]methylcarbamate (314.5 g) was dissolved in methanol (2 L). Under cooling with ice, sodium boron hydride (38.5 g) was added thereto, and the mixture was stirred for 3 hours. Acetone (177 g) was added to the reaction mixture and then stirred for 30 minutes. The reaction mixture was poured into water, and the resultant mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine and dried over sodium sulfate anhydrate. The solvent was concentrated under reduced pressure, and the residue was dissolved in methanol (2 L). Under cooling with ice, sodium boron hydride (16.0 g) was added thereto, and the mixture was stirred for 30 minutes. Acetone (49.2 g) was added to the reaction mixture, and the resultant mixture was stirred for 30 minutes. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine and dried over sodium sulfate anhydrate. The solvent was concentrated under reduced pressure, to thereby give the title compound (318.8 g). The compound was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][CH:14]=2)=[C:9]([CH3:22])[CH:8]=1)=[O:5])[CH3:2].[CH2:23]([N:25]1[CH2:30][CH2:29][C:28]2([C:41]3[C:33](=[CH:34][C:35]4[CH2:36][CH2:37][NH:38][C:39]=4[CH:40]=3)[O:32][CH2:31]2)[CH2:27][CH2:26]1)[CH3:24]>>[CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([N:38]3[C:39]4[CH:40]=[C:41]5[C:28]6([CH2:31][O:32][C:33]5=[CH:34][C:35]=4[CH2:36][CH2:37]3)[CH2:29][CH2:30][N:25]([CH2:23][CH3:24])[CH2:26][CH2:27]6)=[O:20])=[CH:15][CH:14]=2)=[C:9]([CH3:22])[CH:8]=1)=[O:5])[CH3:2]
Reactant: CCN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: CCOC(=O)Nc1ccc(-c2ccc(C(=O)O)cc2)c(C)c1
Product: CCOC(=O)Nc1ccc(-c2ccc(C(=O)N3CCc4cc5c(cc43)C3(CCN(CC)CC3)CO5)cc2)c(C)c1
Yield: 61 %

Procedure:
This compound was prepared from 4'-(ethoxycarbonylamino)-2'-methylbiphenyl-4-carboxylic acid (D61) and 1'-ethyl-2,3,6,7-tetrahydrosprio[furo[2,3-f]indole-3,4'-piperidine] (D109), following the procedure of Example 29. This gave the title compound (61%) as a straw coloured foam, which was converted to its hydrochloride salt.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.O.[C:15]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([C:7]2([C:10]([O:12][CH3:15])=[O:11])[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccc(C2(C(=O)O)CC2)cc1
Solvent: CO
Solvent: O
Product: COC(=O)C1(c2ccc(C)cc2)CC1
Temperature: 75 °C
Reaction time: 16 h
Yield: 969.3 %

Procedure:
To a stirred solution of 1-(p-tolyl)cyclopropanecarboxylic acid (6 g, 34.05 mmol) in methanol (48 mL), was added para-toluenesulphonic acid monohydrate (0.648 g, 3.405 mmol). The reaction was stirred at 75° C. for 16 hours. The mixture was concentrated under reduced pressure, and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium bicarbonate solution (×2), brine and dried (magnesium sulfate), filtered, and concentrated under reduced pressure to afford the title compound as an orange oil (6.279 g, 97%). The material was used directly in the next step with no further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1[C:24]2[C:23]3([CH2:26][N:27]4[CH2:32][CH2:31][C:30]([C:34]5[CH:35]=[N:36][CH:37]=[C:38]([CH2:40][OH:41])[CH:39]=5)([OH:33])[CH2:29][CH2:28]4)[CH2:25][CH:16]([C:17]4[C:22]3=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15]=2[CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:11]1[C:24]2[C:23]3([CH2:26][N:27]4[CH2:28][CH2:29][C:30]([C:34]5[CH:35]=[N:36][CH:37]=[C:38]([CH:40]=[O:41])[CH:39]=5)([OH:33])[CH2:31][CH2:32]4)[CH2:25][CH:16]([C:17]4[C:22]3=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: OCc1cncc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1cncc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a cooled solution (-78° C.) of oxalyl chloride (0.597 mL, 6.84 mmol, 2 eq) in methylene chloride (15 mL) under nitrogen was added freshly distilled dimethylsulfoxide (0.971 mL, 13.68 mmol, 4 eq). After 10 min 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(5-(hydroxymethyl)-3-pyridyl)piperidin-4-ol (described in example 70) (1.41 g, 3.42 mmol) was added as a dimethylsulfoxide solution (15 mL). The reaction was stirred at -78° C. for 1 h prior to the addition of triethylamine (3.81 mL, 27.4 mmol, 8 eq). The cooling bath was removed and the reaction warmed to room temperature over 2 h. Water (35 mL) was added to quench the reaction and the product extracted into methylene chloride (3×20 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to a white solid. The reaction product was purified by flash chromatography over silica gel (65 mL, eluent 10% hexane in ethyl acetate ramped to straight ethyl acetate) to yield 1.04 g (74%) of the title compound. TLC analysis (Rf 0.25, 10% hexane in ethyl acetate). MS (CI, CH4) m/z 411 (M+1,100), 439 (M+29,14), 393 (18), 260 (7), 219 (10), 206 (25), 169 (12)
Reaction SMILES: Cl.C(O)(=O)C.C([NH:10][C:11]1[N:16]=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=3[Cl:27])[C:20](=[O:30])[C:19]([C:31]([O:33]CC)=[O:32])=[CH:18]2)[C:14]([Cl:36])=[CH:13][C:12]=1[F:37])(C)(C)C>O>[NH2:10][C:11]1[N:16]=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=3[Cl:27])[C:20](=[O:30])[C:19]([C:31]([OH:33])=[O:32])=[CH:18]2)[C:14]([Cl:36])=[CH:13][C:12]=1[F:37]
Reactant: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2Cl)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(Cl)cc1F
Reaction time: 4.5 h
Yield: 92.2 %

Procedure:
To a mixed solution (1:1) of 2.5 ml of 4N hydrochloric acid and acetic acid was added 600 mg of ethyl 1-[6-(t-butylamino)-3-chloro-5-fluoropyridin-2-yl]-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 4.5 hours. After adding 2 ml of distilled water, the solution was allowed to cool and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 458 mg of the title compound as a pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[S:12]([CH2:22][N+:23]#[C-:24])([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[C-]#N.[Na+]>>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([C@H:5]2[O:6][CH:24]=[N:23][C@@H:22]2[S:12]([C:15]2[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:3][C:2]=1[CH3:1]
Reactant: COc1ccc(C=O)cc1C
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [C-]#N
Agent: [Na+]
Product: COc1ccc([C@H]2OC=N[C@@H]2S(=O)(=O)c2ccc(C)cc2)cc1C

Procedure:
In a manner analogous to Preparation 1, 3-methyl-p-anisaldehyde (0.73 mL, 5.25 mmol), tosylmethylisocyanide (0.98 g, 5.00 mmol) and NaCN (24.5 mg, 0.50 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 346.7 (M+H+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH:10]1[CH2:16][CH:15]2[N:17]([CH3:18])[CH:12]([CH2:13][CH2:14]2)[CH2:11]1)=O.O.[NH2:20][NH2:21]>C(O)C>[NH:20]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]([CH:10]2[CH2:16][CH:15]3[N:17]([CH3:18])[CH:12]([CH2:13][CH2:14]3)[CH2:11]2)=[N:21]1
Reactant: CN1C2CCC1CC(C(=O)c1ccccc1F)C2
Reactant: NN
Solvent: O
Solvent: CCO
Product: CN1C2CCC1CC(c1n[nH]c3ccccc13)C2
Temperature: 25 °C

Procedure:
A mixture of (2-fluorophenyl)(8-methyl-8-azabicyclo-[3.2.1]octan-3-yl) methanone (24.6 g), hydrazine hydrate (14.4 ml), and ethanol (250 ml) was heated to reflux for four hours. The reaction was cooled to room temperature and concentrated to an oil. This residue was dissolved in dimethylformamide (DMF) (250 ml). Potassium carbonate (28 g) was added to the mixture which was subsequently heated at reflux for 2 days. The reaction mixture was cooled and filtered and the DMF was removed in vacuo. The residue was dissolved in ethanol and 5.2 g of 3-(1H-indazol-3-yl)-8-methyl-8-azabicyclo[3.2.1]octane precipitated from solution, as a powder, m.p. 191°-192° C.
Reaction SMILES: [OH:1][C:2]([C:28]([F:31])([F:30])[F:29])([CH2:16][C:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:11](=[O:12])[O:10][CH2:9]2)=[O:4].[Cl:32]N1C(=O)CCC1=O>CO>[Cl:32][C:24]1[CH:25]=[C:20]([C:17]([CH3:18])([CH3:19])[CH2:16][C:2]([OH:1])([C:28]([F:31])([F:29])[F:30])[C:3]([NH:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:11](=[O:12])[O:10][CH2:9]3)=[O:4])[CH:21]=[CH:22][C:23]=1[O:26][CH3:27]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(C(C)(C)CC(O)(C(=O)Nc2ccc3c(c2)COC3=O)C(F)(F)F)cc1
Solvent: CO
Product: COc1ccc(C(C)(C)CC(O)(C(=O)Nc2ccc3c(c2)COC3=O)C(F)(F)F)cc1Cl
Temperature: 0 °C

Procedure:
22 mg of 5-[2-hydroxy-4-(4-methoxyphenyl)-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide is stirred in 1.5 ml of methanol with 20 mg of N-chlorosuccinimide for 5 hours. The mixture is then dispersed in ice water, sodium bicarbonate solution and ethyl acetate, the ethyl acetate phase is dried, and it is concentrated by evaporation. 20 mg of 5-[4-(3-bromo-4-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide, which melts after recrystallization from isopropyl ether at 189-191° C., is thus obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:17]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+].C(=O)(O)[O-].[Na+]>O1CCCC1.C(N1CCOCC1)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:17]=1
Reactant: O=C1Nc2ccc(O)cc2Sc2ccccc21
Agent: CCN1CCOCC1
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: C1CCOC1
Product: Oc1ccc2c(c1)Sc1ccccc1CN2

Procedure:
A mixture of 10,11-dihydro-7-hydroxy-11-oxodibenzo[b,f][1,4]thiazepin (4.5g,18.5 mmoles) and lithium aluminum hydride (3.5g,92.5 mmoles) in tetrahydrofuran (200 ml) and N-ethylmorpholine (100 ml) was refluxed for 18 hours. The reaction mixture was decomposed by the addition of 12 ml of a saturated solution of ammonium chloride and 33 ml of lM sodium bicarbonate. The mixture was filtered and the salts were washed with methanol. The filtrate was evaporated to dryness and the residue was extracted several times with ether. Chromatography of the residue on silica gel, eluting with 5% methanol in chloroform, afforded the title compound, m.p. 172°-174°.