Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([N+:16]([O-])=O)=[CH:4][C:5]([N+:13]([O-])=O)=[C:6]([CH:8]=[CH:9]N(C)C)[CH:7]=1>CCO.[Ni]>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[NH2:16])[NH:13][CH:9]=[CH:8]2
Reactant: CN(C)C=Cc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Nc1cc2[nH]ccc2cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
A suspension of [2-(5-fluoro-2,4-dinitro-phenyl)-vinyl]-dimethyl-amine (8 g, 31.4 mmol) and Raney Ni (8 g) in EtOH (80 mL) was stirred under H2 (40 psi) at room temperature for 1 h. After filtration, the filtrate was concentrated and the residue was purified by chromatography (Pet.Ether/EtOAc=5/1) to give 5-fluoro-1H-indol-6-ylamine (B-20) as a brown solid (1 g, 16%) 1H NMR (DMSO-d6) δ 10.56 (br s, 1H), 7.07 (d, J=12 Hz, 1H), 7.02 (m, 1H), 6.71 (d, J=8 Hz, 1H), 6.17 (s, 1H), 3.91 (br s, 2H); ESI-MS 150.1 m/z (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[N:23][C:24]([CH3:28])=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:12][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([O:6][C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][C:4]=2[NH:17][C:18]2[C:27]3[C:22](=[N:23][C:24]([CH3:28])=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccc2c(Nc3cc(Cl)ccc3Oc3ccc(C#N)cc3)ccnc2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2c(Nc3cc(Cl)ccc3Oc3ccc(CN)cc3)ccnc2n1

Procedure:
The product of Example 167c (88 mg, 0.175 mmol) was reacted with lithium aluminum hydride (13.3 mg, 0.351 mmol) in THF (5 mL) at 60° C. for 15 h giving the crude title compound which was purified by HPLC with TFA providing the product as the trifluoroacetic acid (15 mg, 14%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 11.04 (s, 1H) 8.92 (d, J=8.82 Hz, 1H) 8.54 (d, J=6.99 Hz, 1H) 8.18 (s, 2H) 7.72-7.80 (m, 2H) 7.59 (dd, J=9.01, 2.76 Hz, 1H) 7.40 (d, J=8.82 Hz, 2H) 6.99-7.12 (m, 3H) 6.74 (d, J=6.99 Hz, 1H) 3.97 (q, J=5.52 Hz, 2H) 2.74 (s, 3H); MS (ESI+) m/z 391 (M+H)+.
Reaction SMILES: [OH:1][C:2]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3]1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:21]1[CH2:26][O:25][CH:24]=[CH:23][CH2:22]1>C(Cl)Cl>[O:25]1[CH2:26][CH2:21][CH2:22][CH2:23][CH:24]1[O:1][C:2]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1(O)CC1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCOC(=O)C1(OC2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.5 %

Procedure:
To a solution of ethyl 1-hydroxycyclopropanecarboxylate (1040 mg, 8.000 mmol) and PTSA (137 mg, 0.800 mmol) in DCM (20 mL) was added a solution of DHP (1344 mg, 16.00 mmol) in DCM (10 mL) dropwise at 0° C. The mixture was stirred for 20 h at room temperature. After concentration, the residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (10/1) to afford the title compound (1500 mg, 85%) as oil. LC-MS (ESI): m/z=215 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.O.OP([O-])(O)=O.[Na+].[OH-].[Na+].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OC(C)C)(=O)C.O>[OH:11][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:29])[CH:7]=1)[C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: O=C(Cl)c1ccccc1
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)C
Product: COC(=O)c1cc(O)cc(OC(=O)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a flask fitted with thermometer, condenser, overhead stirrer, pH probe and nitrogen line was added methyl-3,5-dihydroxybenzoate (1.0 eq), sodium phosphate mono-basic monohydrate (0.46 eq) and water (10.5 vols) under a nitrogen atmosphere. The temperature was adjusted to 20° C.±3° C. 10% w/w Sodium hydroxide was added to adjust the pH to pH 7.8±0.2. Benzoyl chloride (1.0 eq) was added drop-wise in small portions over 1-2 hours, and sodium hydroxide was added concurrently drop-wise in small portions over the same time period to maintain the reaction in a pH range of pH 7.8±0.2 and at a reaction temperature of 20° C.±3° C. The crude reaction mixture was agitated for a further 30 minutes, filtered, and then washed with 4 vols of a solution prepared from water (4 vols), sodium phosphate mono-basic monohydrate (0.05 eq), and adjusted to pH7.5 with 10% w/w sodium hydroxide. The crude solid was then washed with 4 vols of a solution prepared from water (4 vols), sodium phosphate mono-basic monohydrate (0.05 eq), and adjusted to pH6.5 with 10% w/w sodium hydroxide. The crude solid was then dissolved in iso-propyl acetate (8 vols) and water (2 vols) and the mixture agitated for at least 30 minutes to ensure the solid had dissolved. The mixture was filtered through a CUNO™ filter to remove a small amount of brown solid. The aqueous layer was separated off. Water (2 vols) was added to the organic layer and the batch agitated for at least 30 minutes. The aqueous layer was separated off and the organic layer was vacuum distilled, keeping the batch temperature below 40° C. to reduce the volume to 5-6 vols. Toluene was added then added (5 vols) and the mixture was vacuum distilled keeping the batch temperature below 40° C., reducing the volume to approximately 3.5 vols. The mixture was cooled to 15° C.±3° C. and agitated at this temperature for at least 30 minutes, then filtered, and the solid washed with toluene (1 vol). The product was dried at 20° C.-40° C. to give the desired product as a solid (corrected yield 40%-70%).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH2:7][OH:8])[CH2:3][CH2:4][OH:5].[H-].[Na+].Br[CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C)C=O>[C:19]([Si:16]([CH3:18])([CH3:17])[O:15][CH2:14][CH2:13][O:5][CH2:4][CH2:3][C:2]([CH3:9])([CH3:1])[CH2:6][CH2:7][OH:8])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)(CCO)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CCO)CCOCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9.4 %

Procedure:
Step A To the solution of 3,3-dimethyl-pentane-1,5-diol (1.5 g, 11 mmol) prepared in Example 116a Step A. in anhydrous dimethylformamide (15 mL) was added NaH (60%, 0.68 g, 17 mmol). The mixture was stirred at room temperature for 15 min, then (2-bromoethoxy)-tert-butyldimethylsilane (3.3 g, 14 mmol) was added. The mixture was stirred at room temperature for 1 h. Water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:3) to give 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pentan-1-ol as a yellow oil (0.3 g, 9%).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[CH3:29][CH:30]([CH3:33])[CH2:31][SH:32]>>[CH2:31]([S:32][CH2:27][C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:6]3([C:4]([OH:3])=[O:5])[CH2:8][CH2:7]3)=[CH:10][CH:11]=2)=[CH:16][CH:17]=1)[CH:30]([CH3:33])[CH3:29]
Reactant: CC(C)CS
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CSCC(C)C

Procedure:
Prepared according to the procedure described in Example 48, Step 2, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-methyl-propane-1-thiol.
Reaction SMILES: C([O:8][CH2:9][C:10]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12][CH2:11]1)C1C=CC=CC=1>[Pd].C(O)C>[OH:8][CH2:9][C:10]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C1(COCc2ccccc2)CCC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(CO)CCC1
Reaction time: 4 h

Procedure:
A mixture of ethyl 1-benzyloxymethylcyclobutanecarboxylate (6.57 g, 26.5 mmol), 10% palladium on carbon (0.4 g) and ethanol (100 ml) was hydrogenated on a Parr Shaker for 4 hours. The catalyst was removed by filtration. The filtrate was evaporated in vacuo to leave the desired product as a colorless oil: NMR (CDCl3) δ=1.26 (3H, t, J=7 Hz), 1.8~2.6 (6H, m), 2.61 (H, s), 3.78 (2H, s), 4.15 (2H, q, J=7 Hz).
Reaction SMILES: [OH:1][C:2]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[C:3]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][CH3:13])[CH2:8][CH2:7]1)=[O:4].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br.C(N(CC)CC)C>>[OH:1][C:2]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[C:3]([O:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([N:12]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][Br:24])[CH3:13])[CH2:10][CH2:11]1)=[O:4]
Reactant: BrCCCCCCCCCBr
Reactant: CN[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Solvent: CCN(CC)CC
Product: CN(CCCCCCCCCBr)[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Temperature: 70 °C
Reaction time: 94 h

Procedure:
Trans-4-(methylamino)cyclohexyl hydroxy(di-2-thienyl)acetate (intermediate 5, 0.5 g, 0.001 mol), 1,9-dibromononane (2.9 mL, 0.01 mol) and triethylamine (0.44 mL, 0.003 mol) were mixed together under nitrogen atmosphere and stirred at 70° C. for 94 hours. The reaction mixture was evaporated and purified by column chromatography with silica gel, eluting with chloroform/methanol (from 100 to 4:1) to give the title compound as a brown oil (55%).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=[O:8])[CH:3]([CH2:4]2)[CH2:2]1.[C:9]1([Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+].Cl>C1COCC1.CCOCC>[C:9]1([C:7]2([OH:8])[CH2:6][CH:5]3[CH2:4][CH:3]2[CH2:2][CH2:1]3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CC2CCC1C2
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1(c2ccccc2)CC2CCC1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of norcamphor (60.0 g, 0.54 mole) in THF (1 L) at −65° C. was added phenyl magnesium bromide (200 mL of a 3 M solution in ether, 0.60 mole). The temperature was kept between −65° C. and −20° C. during the addition. After completion of addition, the mixture was slowly warmed to room temperature and stirred overnight. The mixture was cooled to 0° C. and saturated aqueous ammonium chloride (200 mL) was added carefully. A solution of 1 N hydrochloric acid was added until the residual salts were dissolved. The mixture was then extracted twice with ether and the combined organic phases were washed successively with water and brine. The organic layer was dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/EtOAc 9:1) provided I-2a as a white solid (95.0 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C@H:18]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:21][CH2:20][S:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[NH2:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]1[OH:45]>>[C:29]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:30]=[CH:31][C:26]([S:23]([N:22]2[CH2:21][CH2:20][S:19][CH:18]2[C:16]([NH:15][CH:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:6][NH:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]2[OH:45])=[O:17])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)OCC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Reactant: NC1CCCCC1O
Product: O=C(NC(CCNC1CCCCC1O)c1ccccc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method B as outlined in Example 16, starting from 3-({[3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and 2-aminocyclohexanol, the title compound was obtained in 99% purity by HPLC.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][N:4]1[C@@H:21]2[CH2:22][C:9]3[CH:10]=[CH:11][C:12]([OH:24])=[C:13]4[O:14][C@H:15]5[C:16]([CH2:18][CH2:19][C@:20]2([OH:23])[C@:7]5([C:8]=34)[CH2:6][CH2:5]1)=O.Cl.Cl.[NH2:27][OH:28].[OH-].[Na+].O>CO>[N:27](=[C:16]1[CH2:18][CH2:19][C@:20]2([OH:23])[C@:7]34[CH2:6][CH2:5][N:4]([CH2:3][CH:2]=[CH2:1])[C@@H:21]2[CH2:22][C:9]2[CH:10]=[CH:11][C:12]([OH:24])=[C:13]([O:14][C@@H:15]13)[C:8]4=2)[OH:28]
Reactant: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=NO)CC[C@@]3(O)[C@H]1C5
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of naloxone hydrochloride (1.085 g, 3 mmol) and hydroxylamine hydrochloride (0.28 g, 4 mmol) was taken up in 30 mL of MeOH containing 2.8 mL of 10% aqueous NaOH. The mixture was stirred at room temperature for 24 h. Water was added (100 mL), and the oxime extracted into CHCl3 (3×50 mL). The extract was dried (MgSO4), and the solvent evaporated. The residue obtained was recrystallized from CH2Cl2 -petroleum ether. Yield: 840 mg (81.8%); mp: 119 C. IR: (KBr): No C=O absorption at 1717 cm-1. 1H NMR (CDCl3) δ 4.98 (s,C5H); Rf: silica gel 60 in EtOAc--EtOH--NH4OH (100:1:1) 0.13. Anal. Calcd for: C19H22N2O4C, 66.65; H, 6.48; N, 8.18. Found: C, 66.70; H, 6.52; N, 8.08.
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[O:4][C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=2[CH3:17])=[CH:6][C:7]=1[CH3:8].Cl.[NH2:20][OH:21].N1C=CN=C1>>[OH:21][N:20]1[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=2[CH3:17])=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[C:3]1=[O:4]
Reactant: NO
Reactant: Cc1ccc(Cc2cc(C)c(C)c(=O)o2)c(C)c1
Agent: Cl
Agent: c1c[nH]cn1
Product: Cc1ccc(Cc2cc(C)c(C)c(=O)n2O)c(C)c1
Yield: 59.3 %

Procedure:
1 g of 3,4-dimethyl-6-(2,4-dimethylbenzyl)-2-pyrone, 0.5 g of hydroxylamine hydrochloride and 3 g of imidazole were heated for 8 hours to 75° C and then worked up in the usual manner. There were obtained 0.63 g (59 %) of 1-hydroxy-3,4-dimethyl-6-(2,4-dimethylbenzyl)-2-pyridone melting at 141° C (Calc.: 5.4 % N; found: 5.6 % N). When using pyridine instead of imidazole under otherwise equal reaction conditions, the yield was 0.003 g (0.3 %).
Reaction SMILES: [O:1]=[C:2]1[N:6]=[C:5]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:4](=[O:15])[NH:3]1.C([O-])([O-])=O.[K+].[K+].I[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C=O)C.CCOCC>[CH2:23]([N:3]1[C:4](=[O:15])[C:5]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[N:6][C:2]1=[O:1])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCOP(=O)(OCC)C1=NC(=O)NC1=O
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCN1C(=O)N=C(P(=O)(OCC)OCC)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of diethyl 2,5-dioxo-4-imidazolylphosphonate (6.00 g, 0.025 moles) in DMF (15 mL), under N2, is added K2CO3 (17.5g, 0.127 moles) and 1-iodohexane (3.75 mL, 0.025 moles). This mixture is stirred at room temperature for 16 hours. The mixture is diluted with ether (300 mL) and washed with water and brine and then dried over MgSO4. Evaporation of solvents under high vacuum affords the required product as a viscous yellow oil. (Mass spectrometry also revealed a small amount of diethyl 1,3-dihexyl-2,5-dioxo-4-imidazolylphosphonate) MS (EI) 321
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][S:7][C:6](=[O:9])[C@@H:5]2[CH2:10][CH2:11][CH2:12][N:4]2[C:3]1=[O:13].CN(C)C=[O:17]>[OH-].[Na+]>[SH:7][CH2:8][CH:2]([CH3:1])[C:3]([N:4]1[CH2:12][CH2:11][CH2:10][C@H:5]1[C:6]([OH:17])=[O:9])=[O:13]
Reactant: CN(C)C=O
Reactant: CC1CSC(=O)[C@@H]2CCCN2C1=O
Agent: [Na+]
Agent: [OH-]
Product: CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (4RS-9aS)-hexahydro-4-methyl-1H,5H-pyrrolo[2,1-c][1,4]thiazepine-1,5-dione (2 g) in dimethylformamide (100 ml), normal sodium hydroxide (20 ml) is added. The mixture is stirred for four hours at room temperature under argon. The solvent is removed in vacuo, the residue is dissolved in ethyl acetate and washed with 10% potassium bisulfate and water. The organic layer is dried and concentrated to yield the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][N:28]=[CH:27]2>ClCCCl>[CH:2]([NH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][N:28]=[CH:27]2)([CH3:4])[CH3:1]
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)Nc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.1 %

Procedure:
Acetone (25 μl, 0.340 mmol), sodium triacetoxyborohydride (83 mg, 0.392 mmol) and acetic acid (18 μl, 0.314 mmol) were added in that order to a solution of 5-amino-1H-indazole (40 mg, 0.300 mmol) in 1,2-dichloroethane (1 ml), and the resulting mixture was stirred at room temperature for 20 hours. The reaction was terminated by the use of a saturated aqueous sodium hydrogencarbonate solution (4 ml), followed by extraction with ethyl acetate. The solvent was distilled off under reduced pressure to obtain a crude product. The crude product was purified by a silica gel column chromatography (eluent: chloroform/methanol=100/2) to obtain N-isopropyl-1H-indazol-5-amine (40 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].[Na+].[O:25]1[CH2:30][CH2:29][N:28]([C:31]2([C:34]([O-])=[O:35])[CH2:33][CH2:32]2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:34]([C:31]2([N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[CH2:33][CH2:32]2)=[O:35])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: O=C([O-])C1(N2CCOCC2)CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: [Na+]
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2(N3CCOCC3)CC2)CC1
Yield: 65 %

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H with 1-morpholinocyclopropanecarboxylic acid sodium salt 16J carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-morpholinocyclopropanecarbonyl)pyrrolidine-2-carboxamide as a yellow oil (65%). MS ISP (m/e): 507.2 (100) [(M+H)]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26]Br>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:11]2([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:26][CH2:25]2)=[O:17])=[CH:7][CH:8]=1)#[N:2]
Reactant: BrCCBr
Reactant: CCOC(=O)CC(=O)Nc1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)Nc2ccc(C#N)cc2)CC1
Yield: 46.5 %

Procedure:
In a manner similar to the procedure described in Example B except that a 100 milliliter three-necked Morton flask was used, 10.0 grams (43.0 mmol) of ethyl 3-[(4-cyanophenyl)amino]-3-oxopropanoate, 14.8 grams (108.0 mmol) of anhydrous potassium carbonate, 40 milliliters of anhydrous dimethylformamide and 3.7 milliliters (43.0 mmol) of 1,2-dibromoethane were reacted for a period of 8 days to give 5.19 grams (20.0 mmol) of ethyl 1-(4-cyanophenylaminocarbonyl)cyclopropanecarboxylate as a colorless solid having a melting point of 132.0° C.-133.5° C. The total yield was 47 percent. An analytical sample was prepared by recrystallization from hexane-ethyl acetate having a melting point of 133.0° C.-134.0° C. NMR analysis of the product indicated the following:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[C:22]([NH:25][C:26]1[CH:27]=[C:28](O)[CH:29]=[CH:30][CH:31]=1)(=[O:24])[CH3:23]>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[CH2:3][CH2:2][O:1][C:30]2[CH:31]=[C:26]([NH:25][C:22](=[O:24])[CH3:23])[CH:27]=[CH:28][CH:29]=2)=[CH:6][C:7]=1[C:13]([F:15])([F:16])[F:14])#[N:10]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Product: CC(=O)Nc1cccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)c1

Procedure:
Synthesized as described in Example 1C using 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 3-acetamidophenol: MS (APCI) m/z 446 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1>C(O)(=O)C.O.[Fe]>[NH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([O:11][C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[N:4][CH:5]=1
Reactant: O=[N+]([O-])c1cnc(Oc2c(Cl)cccc2Cl)c(Cl)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cnc(Oc2c(Cl)cccc2Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
6.39 g (20 mmol) of 3-chloro-2-(2,6-dichlorophenoxy)-5nitropyridine were suspended in 7 ml of glacial acetic acid and 40 ml of water, and 5.6 g (0.1 mol) of iron powder were added in portions at room temperature (temperature 50° C.). The mixture was stirred for 1 hour, complete conversion determined by means of TLC, the mixture was filtered through a glass filter frit under suction, and the filter cake was carefully washed with ethyl acetate. The organic phase was washed with water until neutral, dried using MgSO4 and concentrated by evaporation.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[Cr:9]([Cl:13])([O-:12])(=[O:11])=[O:10].[NH+:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCOCC>C(Cl)Cl>[Cr:9]([Cl:13])([O-:12])(=[O:11])=[O:10].[NH+:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:1][C:2]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1(CO)CCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(C=O)CCCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Pyridinium chlorochromate was prepared by following the procedure of E. J. Corey and J. W. Suggs, Tetrahedron Letters, 31, 2647 (1975). A solution of 11.8 g of 1-methylcyclopentanemethanol in 32 ml of anhydrous methylene chloride was added to a stirred suspension of 39.2 pyridinium chlorochromate in 312 ml of methylene chloride under argon. The resultant dark mixture was stirred for 1.5 hours at ambient temperature. A portion of ether was added to the resultant mixture and then the supernatant was decanted. The remaining dark residue was rinsed several times with ether. The combined ether solutions were filtered through a short pad of Florisil. The resultant solution was concentrated by distillation of ether and then the residue was distilled at 110 mm Hg to yield 6.41 g of 1-methylcyclopentanecarboxaldehyde as a colorless oil: bp 98°-100°; nmr (CDCl3) δ 1.12 (3H, s), 1.0-2.2 (8H, m) and 9.50 ppm (1H, s).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][NH:9][C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)C#N)=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3]1=[O:21].[F:22]C1C=C(Br)C=CC=1>>[F:22][C:13]1[CH:12]=[C:11]([C:10]2[NH:9][CH:8]=[C:7]3[C:6]=2[C:5](=[O:19])[N:4]([CH3:20])[C:3](=[O:21])[N:2]3[CH3:1])[CH:18]=[CH:17][CH:16]=1
Reactant: Fc1cccc(Br)c1
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)[nH]cc2n(C)c1=O
Product: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]cc2n(C)c1=O

Procedure:
The title compound was prepared analogously to 3-(1,3-Dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Example 9.0 Step 4) by replacing 3-bromobenzonitrile by 3-fluoro-1-bromobenzene in step 3;