Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH2:6]([C:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][C:10]=1[C:18]1[C:30]2[C:22](=[CH:23][C:24]3[NH:25][C:26](=[O:31])[O:27][C:28]=3[CH:29]=2)[CH:21]=[C:20]([CH3:32])[O+]=1)[CH2:7][CH3:8].C(C1C2C=CC=CC=2SC=1C=O)CC.O.[NH2:48][NH2:49]>CC(O)C>[CH3:32][C:20]1[CH2:21][C:22]2[CH:23]=[C:24]3[NH:25][C:26](=[O:31])[O:27][C:28]3=[CH:29][C:30]=2[C:18]([C:10]2[S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:9]=2[CH2:6][CH2:7][CH3:8])=[N:49][N:48]=1
Reactant: NN
Reactant: CCCc1c(-c2[o+]c(C)cc3cc4[nH]c(=O)oc4cc23)sc2ccccc12
Agent: CCCc1c(C=O)sc2ccccc12
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(C)O
Solvent: O
Product: CCCc1c(C2=NN=C(C)Cc3cc4[nH]c(=O)oc4cc32)sc2ccccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 5-(3-propyl-1-benzothien-2-yl)-7-methyl-2-oxo-1H,2H-isochromeno[6,7-d][1,3]oxazol-6-ium perchlorate (51 mmol) (obtained according to Steps A and B described in Example 1 using 3-propyl-1-benzothiophene-2-carbaldehyde instead of 2-naphthaldehyde) in 2-propanol (468 mL) there is added hydrazine hydrate (6.68 mL; 133 mmol), with vigorous stirring, at ambient temperature. The reaction mixture is stirred for 20 hours at ambient temperature. The crystals obtained are then filtered off and then stirred in warm water (1900 mL) for 30 minutes. After filtration and drying, the solid is purified by chromatography over a silica gel column (eluant: dichloromethane/ethyl acetate) to yield the title product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=1.[BH4-].[Na+]>CO.C(O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:15][C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=Cc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Oc1ccc(NCc2cccnc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Alternately, a solution of 4-aminophenol (1.0 equiv.) (Aldrich) in 2:1 methanol/ethanol was treated with 3-pyridinecarboxaldehyde (1.05 equiv.). The solution was allowed to stir for 1 hour. The reaction was cooled to 0° C. and treated with sodium borohydride (4.2 equiv.) in 5 portions. The cooling bath was removed and stirring continued for 20 hours. The reaction mixture was concentrated in vacuo. The residue was mixed with 1M HCl, warmed, and partitioned between ethyl acetate and 0.1M K2CO3. The pH of the aqueous phase was adjusted to pH=7 (using 1M HCl and 1M K2CO3) and the product extracted 4-6 times with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous MgSO4, and concentrated to afford N-(4-hydroxyphenyl)pyridin-3-ylmethylamine. 1H NMR(400 MHz, DMSO-d6): d 4.18(2H, s), 5.65(1H, s), 6.41-6.53(4H, m), 7.29-7.32(1H, m), 7.70-7.72(1H, m), 8.39-8.40(2H, m), 8.53-8.54(1H, m). MS Found 201.2 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.C([Li])CCC.B(F)(F)F.CCOCC.[N:24]1[O:25][CH2:26][C@@H:27]2[CH2:31][N:30]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:29][C:28]=12>O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]1[S:4][C:5]([C:28]23[CH2:29][N:30]([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH2:31][CH:27]2[CH2:26][O:25][NH:24]3)=[CH:6][N:7]=1
Reactant: O=C(OCc1ccccc1)N1CC2=NOC[C@@H]2C1
Reactant: C[Si](C)(C)c1nccs1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ncc(C23CN(C(=O)OCc4ccccc4)CC2CON3)s1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
A −78° C. solution of 2-trimethylsilylthiazole (383 mg, 2.44 mmol) in tetrahydrofuran (3 mL) is treated drop wise with a solution of n-butyl lithium (1.52 mL, 2.44 mmol, 1.6 M hexanes) and the reaction is stirred at −78° C. for 10 minutes to give a thick orange slurry. The slurry is treated with boron trifluoride etherate (205 μL, 1.62 mmol) to give a red mixture and then a solution of benzyl (3aR)-3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylate (200 mg, 812 μmol) is added immediately in toluene (2 mL) to this mixture. The resultant mixture is stirred at −78° C. for 20 minutes under nitrogen. The reaction is quenched with saturated ammonium chloride and warmed to room temperature. Water and saturated sodium bicarbonate is added and the mixture is extracted with ethyl acetate (3×). The combined organic layers are dried over sodium sulfate and the solvent is removed under vacuum. The crude product is purified over silica gel eluting with 5% to 100% ethyl acetate in hexanes gradient, to give the title compound (245 mg, 75%). ES/MS (m/e): 404(M+H).
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:24][CH:23]=1)([S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:6][CH2:7][CH2:8][CH3:9])C>CO.[OH-].[Na+]>[CH2:34]([N:31]([CH2:32][CH3:33])[CH2:30][CH2:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C:5]([S:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)(=[O:11])=[O:12])([CH2:6][CH2:7][CH2:8][CH3:9])[C:4]([OH:36])=[O:3])=[CH:27][CH:26]=1)[CH3:35]
Reactant: CCCCC(Cc1ccc(OCCN(CC)CC)cc1)(C(=O)OCC)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC(Cc1ccc(OCCN(CC)CC)cc1)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1

Procedure:
2-[4-(2-Diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoic acid was prepared starting from 2-[4-(2diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoic acid ethyl ester (8 g, 15.4 mmol) dissolved in methanol (200 ml) and 10 N NaOH (30 ml). The resulting mixture was worked up as outlined in example 1. Yield 3.88 g crude (51%); brown oil; MS: 492 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:13])[C:4]([C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:8])O[CH:7]=1.[CH3:14][C:15]1[CH:21]=[C:20]([CH3:22])[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:16]=1[NH2:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[N+:23]([C:19]1[CH:18]=[C:16]([N:17]2[CH:7]=[C:2]([Cl:1])[C:3](=[O:13])[C:4]([C:9]([O:11][CH3:12])=[O:10])=[C:5]2[CH3:8])[C:15]([CH3:14])=[CH:21][C:20]=1[CH3:22])([O-:25])=[O:24]
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1N
Reactant: COC(=O)c1c(C)occ(Cl)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(C)n(-c2cc([N+](=O)[O-])c(C)cc2C)cc(Cl)c1=O

Procedure:
A solution of 10.1 g (0.05 mol) 5-chloro-3-methoxycarbonyl-2-methyl-4-pyranone, 8.5 g 2,4-dimethyl-5-nitroaniline and 0.1 g p-toluenesulfonic acid monohydrate in 100 ml of toluene are refluxed for 8 h in a water separator apparatus. The mixture is allowed to cool and the precipitating product is filtered off, washed with a small amount of ethylacetate/petrolether and dried. Yield: 15.0 g (85.5%) 1-(3'-nitro-4',6'-dimethylphenyl)-5-chloro-3-methoxycarbonyl-2-methyl-4-pyridone, mp. 266° C.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])C.Cl.[CH2:21]([N:28]1[C:34](=[O:35])[C@H:33]2[CH2:36][CH2:37][CH2:38][C@H:32]2[NH:31][C:30]2[CH:39]=[CH:40][CH:41]=[CH:42][C:29]1=2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O.ClCCl>[CH2:21]([N:28]1[C:34](=[O:35])[C@H:33]2[CH2:36][CH2:37][CH2:38][C@H:32]2[N:31]([CH2:4][CH2:5][N:6]2[C:7](=[O:16])[C:8]3=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]3[C:10]2=[O:11])[C:30]2[CH:39]=[CH:40][CH:41]=[CH:42][C:29]1=2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(CN1C(=O)c2ccccc2C1=O)OCC
Reactant: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCN1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Temperature: 50 °C
Reaction time: 1.33 h
Yield: 57.3 %

Procedure:
To a solution of phthalimidoacetaldehyde diethyl acetal (790 mg, 3.0 mmol) in acetic acid (2.5 mL) was added conc.HCl (0.1 mL). The mixture was stirred for 80 minutes at 50° C. The reaction mixture was cooled to room temperature, to which was added (3aR*,10aS*)-9-benzyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta [e][1,4]diazepin-10(1H)-one (877 mg, 3.0 mmol), and the mixture was stirred for 25 minutes at room temperatures. To this solution was added, sodium triacetoxyborohydride (805 mg, 3.9 mmol) portionwise, and the mixture was stirred for 40 minutes at 45° C. The reaction mixture was cooled to room temperatures, to which were added dichloromethane (10 mL) and water (10 mL). The aqueous layer was separated, and the organic layer was washed with water and a saturated aqueous solution of sodium hydrogencarbonate, dried over magnesium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure. The concentrate was purified by silica-gel column chromatography (chloroform-methanol 20:1), followed by crystallization from ethanol-hexane to give 0.80 g (yield 57%) the titled compound. The sample for analytical experiment was prepared by recrystallization from dichloromethane-ethanol-hexane. m.p. 142.0°-142.6° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]#[C:9][C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][C:33]([C:39]#[N:40])=[C:32]2[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([C:48]#[CH:49])[CH:43]=1.C(=O)(O)[O-].[Na+]>C1COCC1.N1C=CC=CC=1>[C:39]([C:33]1[CH:34]=[N:35][C:36]2[C:31]([C:32]=1[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([C:48]#[CH:49])[CH:43]=1)=[CH:30][C:29]([NH:28][C:10](=[O:12])[C:9]#[C:8][CH2:7][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[CH:38][CH:37]=2)#[N:40]
Reactant: C#Cc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Reactant: O=C(O)C#CCN1CCCCC1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: C#Cc1cccc(Nc2c(C#N)cnc3ccc(NC(=O)C#CCN4CCCCC4)cc23)c1
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
Partially dissolved 1.03 g (6.16 mmol) 4-piperidino-2-butynoic acid in 70 ml THF and chilled to 0° under N2. Added 812 μl (7.38 mmol) N-methylmorpholine and 640 μl (4.92 mmol) isobutyl chloroformate. After 0.5 hour stirring, added a solution of 700 mg (2.46 mmol) 6-amino-4-[(3-ethynylphenyl)amino)-3-quinolinecarbonitrile dissolved in 5 ml pyridine. At 1 hours poured onto ice bath and made basic with a saturated solution of sodium bicarbonate. Extracted with ethyl acetate, dried organics with sodium sulfate, reduced to a small volume and loaded onto a column of silica gel. Eluted with 8% methanol in ethyl acetate. Stripped solvent of desired fractions and dried in vacuo, giving 641 mg of yellow-orange solid: mass spectrum (electrospray m/e): M+H=434.2.
Reaction SMILES: Cl.[CH:2]12[C:10](=[O:11])[CH:6]([CH2:7][NH:8][CH2:9]1)[CH2:5][O:4][CH2:3]2.C([O-])([O-])=O.[Na+].[Na+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>CCOC(C)=O>[CH2:22]([O:21][C:19]([N:8]1[CH2:7][CH:6]2[C:10](=[O:11])[CH:2]([CH2:3][O:4][CH2:5]2)[CH2:9]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1C2CNCC1COC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1C2COCC1CN(C(=O)OCc1ccccc1)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a stirred mixture of 3-oxa-7-aza-bicyclo[3.3.1]nonan-9-one hydrochloride [CAS #1228600-54-1] (4.80 g, 27 mmol), EtOAc (105 ml) and saturated aqueous Na2CO3 (105 ml) was added benzyl chloroformate (4.60 ml, 32.4 ml) at 0° C. The reaction mixture was stirred for 1 h at 0° C. and then extracted with EtOAc (2×). The organic phases were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. Purification of the residue by normal phase column chromatography, eluting with heptane-EtOAc 1:1, gave the title compound as a colorless oil (5.75 g, 20.68 mmol, 77%): 1H-NMR (400 MHz, DMSO-d6): δ 2.31-2.35 (d, 2H), 2.34 dd, 2H), 3.78 (d, 2H), 4.19 (t, 2H), 4.55 (q, 2H), 5.11 (m, 2H), 7.28-7.38 (m, 5H).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]([C:11]1[C:12](=[O:20])[NH:13][CH:14]=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:29]>CN(C)C=O.O>[CH2:21]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([C:11]1[C:12]([O:20][CH3:29])=[N:13][CH:14]=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=1)=[O:10])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CI
Reactant: O=C(O)c1c[nH]c(=O)c(C(=O)N(Cc2ccccc2)Cc2ccccc2)c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc(C(=O)O)cc1C(=O)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
To a solution of 0.5 g (1.4 mmol) 2-Oxo-1,2-dihydro-pyridine-3,5-dicarboxylic acid bis-benzylamide in 10 mL of N,N-dimethylformamide (DMF) was added 0.25 g (1.9 mmol) diisopropylethylamine amine followed by 0.19 g (1.4 mmol) iodomethane. The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with saturated aqueous NaCl solution, and dried over MgSO4. The product was crystallized from ethyl acetate, providing 0.24 g (46% yield) of the title compound. MS: m/z (APCI, AP+) 376.3 [M.]+. CHN Analysis: Calcd: C, 70.38; H, 5.64; N, 11.19. Found: C, 70.05; H, 5.49; N, 10.89.
Reaction SMILES: [Cl:1]Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[C:14]#[N:15]>>[NH2:3][C:4]1[C:5]([C:14]#[N:15])=[CH:6][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:8][C:9]=1[Cl:1]
Reactant: ClCl
Reactant: N#Cc1cc(C(F)(F)F)ccc1N
Product: N#Cc1cc(C(F)(F)F)cc(Cl)c1N

Procedure:
Chlorine gas was passed through a stirred solution of 4-amino-3-cyano-trifluoromethylbenzene (5g) in carbon tetachloride (75ml) until the absence of starting material was confirmed by gas liquid chromatography. Flow of the gas was then stopped and evaporation of the solvent under reduced pressure gave 4-amino-3-chloro-5-cyanotrifluoromethylbenzene as an orange solid (5.5g).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:9]([C:10]([CH3:15])=[C:11]([CH3:14])[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC.C1COCC1>[CH3:14][C:11]1[CH:12]=[C:13]2[N:9]([C:10]=1[CH3:15])[CH:8]=[CH:7][CH:6]=[C:5]2[CH2:3][OH:2]
Reactant: COC(=O)c1cccn2c(C)c(C)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc2c(CO)cccn2c1C
Reaction time: 0.5 h

Procedure:
A solution of the 2,3-dimethyl-indolizine-8-carboxylic acid methyl ester (265 mg, 1.3 mmol) in ether (10 ml) was cooled to 0° C. and treated with LAH (1.0M in THF, 1.6 ml, 1.6 mmol, dropwise addition). After 3.5 h the reaction was quenched with sodium sulfate decahydrate (added in small portions until gas evolution ceased). The resulting mixture was stirred for 0.5 h and the precipitated solids were removed via filtration and washed with EtOAc. The combined filtrates were concentrated to give the product which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[C:17]2[CH:16]=[N:15][C:14]([Cl:18])=[CH:13][C:12]=2[N:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:19]([S:21]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH3:20])[CH2:10]2.O.[Li+].[OH-].CC(O)=O>C1COCC1>[Cl:18][C:14]1[N:15]=[CH:16][C:17]2[C:5]([CH2:4][C:3]([OH:31])=[O:2])=[C:6]3[N:11]([C:12]=2[CH:13]=1)[CH2:10][CH:9]([N:19]([S:21]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH3:20])[CH2:8][CH2:7]3
Reactant: COC(=O)Cc1c2n(c3cc(Cl)ncc13)CC(N(C)S(=O)(=O)c1ccc(F)cc1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C1CCc2c(CC(=O)O)c3cnc(Cl)cc3n2C1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To a solution of 4 mg of (±)-{3-chloro-6-[(4-fluoro-benzenesulfonyl)-methyl-amino]-5,6,7,8-tetrahydro-2,4b-diaza-fluoren-9-yl}-acetic acid methyl ester in 0.2 mL of THF was added 0.1 mL of water, followed by 0.02 mL of 1 N aq. LiOH solution. After stirring for 1 h at room temperature, 0.05 mL of AcOH was added. The reaction mixture was the dried with a jet flow of nitrogen. The residue was suspended in 0.3 mL of EtOAc and filtered through silica gel. The filtrate was concentrated to give 2 mg of the title compound as a white solid. MS (ESI): 452.1 (M+1).
Reaction SMILES: [Mg].CI.[CH3:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12](=[O:14])[CH3:13])[C:6]=1[NH2:7].[CH2:15](Cl)Cl>C(OCC)C>[CH3:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([CH3:15])([OH:14])[CH3:13])[C:6]=1[NH2:7]
Reactant: ClCCl
Reactant: CC(=O)c1cccc(C)c1N
Agent: [Mg]
Solvent: CI
Solvent: CCOCC
Product: Cc1cccc(C(C)(C)O)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In this example 234.93 g (9.66 moles) of magnesium was placed under nitrogen and then mixed with 583 ml of ethyl ether at room temperature. A small amount of methyl iodide was then added with gentle stirring followed by the addition of another 468 ml of ethyl ether. A methyl iodide solution containing 1,371.72 g (9.66 moles) of methyl iodide in 468 ml of ethyl ether was slowly added at reflux over a 21/4-21/2-hour period. (During this period the mixture was diluted with another 583 ml of ethyl ether to reduce the reaction rate.) The mixture was cooled to room temperature and then a solution containing 433.9 g of 2-methyl-6-acetylaniline dissolved in 698 ml of ethyl ether was slowly added over 11/4-11/2 hours. During this addition the temperature of the mixture was maintained at about or below 25° C. The mixture was then stirred at room temperature for another hour. Three liters of methylene chloride was then added at about 25° C. and the reaction was then quenched by the addition of solid ammonium chloride and water. The mixture was then allowed to stand overnight (about 15 hours). The ether phase of the mixture was then separated and filtered. The water phase was mixed with three liters of methylene chloride filtered. The methylene chloride filtrate and the ethyl ether filtrate were each evaporated affording 2-methyl-6-(1-methyl-1-hydroxyethyl)-aniline.
Reaction SMILES: [CH3:1][C:2]([O:13][CH2:14][C@@H:15]1[CH2:17][O:16]1)([CH3:12])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[N:5]1.[CH3:18][NH:19][CH3:20]>C(O)(C)C>[CH3:18][N:19]([CH3:20])[CH2:17][C@H:15]([OH:16])[CH2:14][O:13][C:2]([CH3:12])([CH3:1])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[N:5]1
Reactant: CNC
Reactant: CC(C)(Cn1ccc([N+](=O)[O-])n1)OC[C@@H]1CO1
Solvent: CC(C)O
Product: CN(C)C[C@H](O)COC(C)(C)Cn1ccc([N+](=O)[O-])n1
Yield: 86.2 %

Procedure:
Compound (S)-1-dimethylamino-3-[1,1-dimethyl-2-(3-nitro-pyrazol-1-yl)-ethoxy]-propan-2-ol was prepared by reacting 1-[2-methyl-2-((S)-1-oxiranylmethoxy)-propyl]-3-nitro-1H-pyrazole (0.39 g, 1.62 mmol), isopropyl alcohol (6 mL), and dimethylamine (3 mL, 6 mmol, 2 M in dioxane) under microwave conditions at 130° C. for 15 min. The mixture was extracted with dichloromethane and water. The organic layer was separated and the solvent evaporated under reduced pressure to yield (S)-1-dimethylamino-3-[1,1-dimethyl-2-(3-nitro-pyrazol-1-yl)-ethoxy]-propan-2-ol (0.4 g, 87%). This compound was reduced under the following conditions. The mixture of (S)-1-dimethylamino-3-[1,1-dimethyl-2-(3-nitro-pyrazol-1-yl)-ethoxy]-propan-2-ol (0.39 g, 1.66 mmol), ethyl acetate (30 mL), ethanol (30 mL) was added to a Parr bottle with 10% Pd/C (0.22 g) and subjected hydrogen gas (20 psi) for 2 h under the Parr Shaker Apparatus conditions. Work up by filtration via a glass membrane filter paper, solvent was removed under reduced pressure to afford (S)-1-[2-(3-amino-pyrazol-1-yl)-1,1-dimethyl-ethoxy]-3-dimethylamino-propan-2-ol as an oil (0.37 g, 97.5%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:17][O:16][C:5]2=[C:6]([F:15])[CH:7]=[C:8]3[C:13]([C:12](=[O:14])[NH:11][CH2:10][CH2:9]3)=[C:4]2[CH2:3]1.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][CH:30]=O.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[F:15][C:6]1[CH:7]=[C:8]2[C:13](=[C:4]3[CH2:3][CH:2]([NH:1][CH2:30][CH2:29][CH2:28][C:22]4[C:21]5[C:25](=[CH:26][CH:27]=[C:19]([F:18])[CH:20]=5)[NH:24][CH:23]=4)[CH2:17][O:16][C:5]=13)[C:12](=[O:14])[NH:11][CH2:10][CH2:9]2
Reactant: NC1COc2c(F)cc3c(c2C1)C(=O)NCC3
Reactant: O=CCCc1c[nH]c2ccc(F)cc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1NCCc2cc(F)c3c(c21)CC(NCCCc1c[nH]c2ccc(F)cc12)CO3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 9-amino-6-fluoro-3,4,9,10-tetrahydro-2H-pyrano[2,3-h]isoquinolin-1(8H)-one (49) (110 mg, 0.47 mmol) in anhydrous methanol (7 ml) was added 3-(5-fluoro-1H-indol-3-yl) propanal (2) (89 mg, 0.47 mmol), acetic acid (0.060 ml), and NaBH3CN (59 mg, 0.930 mmol). Resulting reaction mixture was stirred at room temperature for 3 hr. The solvent was removed in vacuo and the residue was re-dissolved in CH2Cl2 (120 ml). The solution was washed with 1 N NaOH and H2O, saturated. NaCl. The organic solution was separated, dried over Na2SO4, then concentrated in vacuo. The crude compound was purified on silica gel eluting with 80% EtOAc/Hexane to yield the title compound. MS (ES) m/z 410.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19](F)=[CH:18][C:17]=1[F:24])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[N:26]1([C@@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]2[OH:37])[CH:30]=[CH:29][N:28]=[CH:27]1.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:25])[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:37][C@H:32]2[CH2:33][CH2:34][CH2:35][CH2:36][C@H:31]2[N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)=[CH:18][C:17]=1[F:24])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O[C@H]1CCCC[C@H]1n1ccnc1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(O[C@H]2CCCC[C@H]2n2ccnc2)cc1F
Yield: 64.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the tert-butyl[(5-chloro-2,4-difluorophenyl)sulfonyl](1,3-thiazol-4-yl)carbamic acid (WO 2010/079443; 390 mg, 0.949 mmol), (1S*,2R*)-2-(1H-imidazol-1-yl)cyclohexanol (Heterocycles, 31(3), 537-48, 1990; 160 mg, 0.963 mmol), sodium hydride (63%; 75.0 mg, 1.97 mmol) and DMF (4.0 mL), to yield the title compound (340 mg, 64%) as a colorless oil.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[CH3:13][C:14]1[NH:15][CH:16]=[C:17]([CH3:21])[C:18]=1[CH2:19][CH3:20].O>C(O)(=O)C.ClCCl>[CH2:19]([C:18]1[C:17]([CH3:21])=[C:16]([C:3]2[C:4](=[O:11])[C:5]3[C:10]([C:1](=[O:12])[CH:2]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[NH:15][C:14]=1[CH3:13])[CH3:20]
Reactant: CCc1c(C)c[nH]c1C
Reactant: O=C1C=CC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CCc1c(C)[nH]c(C2=CC(=O)c3ccccc3C2=O)c1C
Yield: 80 %

Procedure:
6.32 millimol of 1,4-naphthoquinone and 3.16 millimol of 2,4-dimethyl-3-ethylpyrrole were stirred in 20 ml of glacial acetic acid in a round-bottomed flask for 10 minutes at room temperature. The reaction mixture was diluted with 300 ml of dichloromethane and the resulting mixture was then poured into a large volume of water (300 ml). The organic phase was then separated out and washed four times with 100 ml of water and finally with saturated aqueous NaCl solution. The resulting organic phase was dried over Na2SO4 and then concentrated under vacuum. The product 2-(4-ethyl-3,5-dimethyl-1H-pyrrol-2-yl)-[1,4]-naphthoquinone was thus isolated in a yield of 80% after purification by chromatography on a column of silica.