Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17]([CH3:19])/[CH:18]=[CH:10]/[C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=1)=[O:11]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Product: CN(C)/C=C/C(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
A solution of 4′-(trifluoromethyl)acetophenone (9.60 g, 50 mmol) in 25 ml of N,N-dimethylformamide dimethyl acetal (DMF-DMA) is stirred at 105 to 110° C. for 20 hrs. It is then cooled to room temperature, and diluted with hexanes. The resulting suspension is filtered, and the precipitate washed with hexanes to give 10.93 g of a yellow solid; mp 96.5-98° C.; MS (ESI) m/z 244.1 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][CH:17]=[O:18])[C:11]=1[OH:19].CN(C=O)C.Br[CH2:27][CH2:28][CH2:29]Cl>O.C(OCC)(=O)C>[CH3:7][O:8][C:9]([C:10]1[C:11]2[O:19][CH2:29][CH2:28][CH2:27][N:16]([CH:17]=[O:18])[C:12]=2[CH:13]=[CH:14][CH:15]=1)=[O:20]
Reactant: ClCCCBr
Reactant: COC(=O)c1cccc(NC=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1OCCCN2C=O
Temperature: 120 °C
Yield: 75.7 %

Procedure:
Potassium carbonate was ground and flame dried prior to each use. 3-formylamino-2-hydroxy-benzoic acid methyl ester compound (1.952 grams, 10 mmol) and potassium carbonate (2.764 grams, 20 mmol, 2 eq.) were placed in a flask together with 100 mL of anhydrous DMF. Heated to 120° C. for 1 hour. 1-bromo-3-chloropropane (1 mL, 10 mmol, 1 eq.) was added to the reaction mixture in several portions at 120° C. and the reaction heated for an additional 3 hours. The reaction was monitored on TLC (ethyl acetate). After cooling, the reaction mixture was stripped to a minimal volume, diluted with water and extracted three times with ethyl acetate. The combined organic portions were washed with water, brine and dried over magnesium sulfate. Filtration and solvent removal afforded crude product as a thick brown syrup (1.78 grams) which was chromatographed on silica gel using 30% ethyl acetate in hexane as eluent. The product was obtained in 67% yield as light yellow solid. M+236.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1.[CH:14]1(O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:14]1([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1n[nH]c2ccccc12
Reactant: OC1CCCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1nn(C2CCCCC2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a mixture of methyl 1H-indazole-3-carboxylate (5.00 g), cyclohexanol (9.00 mL), triphenylphosphine (14.9 g) and tetrahydrofuran (100 mL) was added 40% diethyl azodicarboxylate toluene solution (25.6 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, and the mixture was stirred at 0° C. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9, volume ratio) to give the title object compound (6.84 g, 93%) as a pale-red oil.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24]>N1C=CC=CC=1>[NH2:1][C:2]1[NH:3][C:4](=[S:24])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: COc1ccc(-c2ccc3nc(N)[nH]c(=O)c3n2)cc1OC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: COc1ccc(-c2ccc3nc(N)[nH]c(=S)c3n2)cc1OC

Procedure:
A suspension of 2-amino-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidin-4(3H)one (100 mg, 0.34 mmol) and phosphorus pentasulfide (163 mg, 0.37 mmol) in pyridine (10 ml) was refluxed for 4 hours. The solvents were evaporated in vacuo. The residue was re-suspended in a small amount of water and filtered off, yielding the title compound which was used without any further purification and which was characterised as follows: MS (m/z): 315 ([M+H]+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[O:16][C:17]([CH2:20]I)=[CH:18][N:19]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1.C(NC([C:31]1N=C[N:34]2[C:40]3[CH:41]=CC(F)=C[C:39]=3C(=O)N(C)[CH2:36][C:35]=12)=O)C#C.IN1C(=O)CCC1=O.C(NC(C)C)(C)C>C(O)(=O)C.C1COCC1>[CH:35]([N:34]([CH2:20][C:17]1[O:16][C:15]([C:14]2[N:13]=[CH:12][N:11]3[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:24][C:6]=4[C:7](=[O:23])[N:8]([CH3:22])[CH2:9][C:10]=23)=[N:19][CH:18]=1)[CH:40]([CH3:41])[CH3:39])([CH3:36])[CH3:31]
Reactant: CN1Cc2c(-c3ncc(CI)o3)ncn2-c2ccc(F)cc2C1=O
Reactant: C#CCNC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Agent: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)N(Cc1cnc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)o1)C(C)C
Temperature: 25 °C
Reaction time: 42 h
Yield: 16 %

Procedure:
125 ml of a crude THF solution of 8-fluoro-3-(5-iodomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one (prepared from 15.6 g (0.050 mol) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid prop-2-ynylamide and 16.9 g (0.075 mol) of N-iodosuccinimide in 300 ml of acetic acid, subsequently completely freed from the solvents, dried azeotropically several times with toluene and dissolved in 500 ml of THF) were treated with 15.4 ml (0.109 mol) of diisopropylamine and stirred at room temperature for 42 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated and the brownish product was chromatographed over silica gel with dichloromethane/methanol 39:1 as the eluent. There was obtained 0.83 g (16%) of 3-(5-diisopropylaminomethyl-oxazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as yellowish crystals; m.p. 176-178°.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([CH2:12][C:13]([OH:15])=O)[N:4]=1.Cl.[Br:19][C:20]1[C:21]([C@H:28]([NH2:38])[CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=2)=[N:22][C:23]([S:26][CH3:27])=[N:24][CH:25]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:19][C:20]1[C:21]([C@H:28]([NH:38][C:13](=[O:15])[CH2:12][N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:1])([F:17])[F:16])=[N:4]2)[CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=2)=[N:22][C:23]([S:26][CH3:27])=[N:24][CH:25]=1
Reactant: CSc1ncc(Br)c([C@H](N)Cc2cc(F)cc(F)c2)n1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1ncc(Br)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-(3-(Trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid (124 mg, 0.5 mmol) and 11F (200 mg, 0.5 mmol) were dissolved in 3 mL of DMF and cooled down to 0° C. To it were added N,N-diisopropylethylamine (435 μL, 2.5 mmol) and HATU (228 mg, 0.6 mmol). The reaction mixture was stirred at 0° C. for 5 minutes, and then partitioned between EtOAc and 5% LiCl aqueous solution. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in methylene chloride and to it added hexanes. The precipitate was collected by vacuum filtration and dried under high vacuum overnight to afford the title compound 11G. MS (m/z) 592.25 [M+H]+.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:13][CH3:14])([CH3:12])[CH3:11])=[CH:6][C:5]=1[CH3:15].S(=O)(=O)(O)O>CO>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:3]=[O:2])=[C:5]([CH3:15])[CH:6]=1)([CH2:13][CH3:14])([CH3:12])[CH3:11]
Reactant: CCC(C)(C)c1ccc(C(OC)OC)c(C)c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCC(C)(C)c1ccc(C=O)c(C)c1
Yield: 77.6 %

Procedure:
56 g of 4-tert-amyl-2-methylbenzaldehyde dimethyl acetal are boiled for 1 hour with 170 g of 1% strength sulfuric acid. The methanol formed is distilled off and the organic phase is separated off and dried over Na2SO4. 35 g (80%) of 4-tert-amyl-2-methylbenzaldehyde are obtained.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:20][CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].S(O)(C1C=CC(C)=CC=1)(=O)=O.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([NH:20][CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 47.7 %

Procedure:
Boc-Phe-OH (79.6 g, 0.3 mole), Gly-OBzl-TosOH (111 g, 1.1 eq), and HOBt (44.6 g, 1.1 eq) were dissolved in DMF (300 ml). WSCI (60.4 ml, 1.1 eq ) was added dropwise while cooling, and the solution was stirred overnight. DMF was distilled off. The residue was dissolved in CHCl3, and the solution was washed with 5% NaHCO3, 10% Na2CO3, water, 1HCl, and water, in order, and dried over MgSO4. The CHCl3 was distilled off, and to the residue, Et2O was added. The thus-produced powder was obtained by filtration and recrystalized two times with AcOEt/Et2O to obtain the object product (59 g).
Reaction SMILES: [C:1]([O:4][CH:5]1[S:9][C@H:8]([CH2:10][O:11][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(O)(=O)C.P([O-])(O)(O)=O.[K+].C(OCC)(=O)C>O1CCCC1>[C:1]([O:4][CH:5]1[S:9][C@@H:8]([CH2:10][OH:11])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)OC1CC[C@H](CO)S1
Reaction time: 5 h
Yield: 71.5 %

Procedure:
To a mixture of 0.54 g of 1-O-acetyl-5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-4-thioribofuranose (prepared by the procedure of J. A. Secrist et al., J. Meal. Chem.,1992, 35, 533) in 8 ml of tetrahydrofuran and 0.6 g of acetic acid is added 4 mmol of 1M n-tetrabutylammonium fluoride solution. The reaction is stirred for 5 hours and then another portion of 0.10 g of acetic acid and I mmol of n-tetrabutylammonium fluoride is added and the reaction is stirred for 1 hour. Cold potassium dihydrogen phosphate and ethyl acetate are added to the reaction mixture, followed by an aqueous workup. Purification by chromatography gives 0.164 g of the desired product.
Reaction SMILES: [F:1][C:2]1([F:60])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18]CC4C=CC(OC)=CC=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][O:43][CH2:44][CH:45]([CH3:47])[CH3:46])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:48]([F:59])[C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[CH2:4][CH2:3]1.FC1(F)CCC(C2C3C(OCC4C=CC(OC)=CC=4)CC(C)(C)CC=3N=C(C3CCN(C4N=CC(COCC)=CN=4)CC3)C=2C(F)C2C=CC(C(F)(F)F)=CC=2)CC1>>[F:60][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][O:43][CH2:44][CH:45]([CH3:46])[CH3:47])=[CH:38][N:37]=4)[CH2:34][CH2:35]3)[C:9]=2[CH:48]([F:59])[C:49]2[CH:50]=[CH:51][C:52]([C:55]([F:56])([F:58])[F:57])=[CH:53][CH:54]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(COCC(C)C)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: CCOCc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(OCc3ccc(OC)cc3)CC(C)(C)C4)CC2)nc1
Product: CC(C)COCc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1
Yield: 69.6 %

Procedure:
Reactions similar to those of Example 26 were performed except for using 59 mg (0.070 mmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(1-{5-[(2-methylpropoxy)methyl]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 24 instead of 4-(4,4-difluorocyclohexyl)-2-{1-[5-(ethoxymethyl)pyrimidin-2-yl]piperidin-4-yl}-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline to provide 35 mg of the title compound as a white solid (yield: 69%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]1([F:54])[CH2:29][N:28]([C:30]([C:32]2[N:33]=[C:34]([CH:37]([CH3:39])[CH3:38])[S:35][CH:36]=2)=[O:31])[CH2:27][C:26]2([CH2:44][CH2:43][N:42]([CH2:45][C:46]3[S:47][CH:48]=[C:49]([CH2:51][CH2:52][OH:53])[CH:50]=3)[CH2:41][CH2:40]2)[O:25]1.FC(F)(F)C(O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[F:54][C:24]1([F:23])[CH2:29][N:28]([C:30]([C:32]2[N:33]=[C:34]([CH:37]([CH3:38])[CH3:39])[S:35][CH:36]=2)=[O:31])[CH2:27][C:26]2([CH2:44][CH2:43][N:42]([CH2:45][C:46]3[S:47][CH:48]=[C:49]([CH2:51][CH:52]=[O:53])[CH:50]=3)[CH2:41][CH2:40]2)[O:25]1
Reactant: CC(C)c1nc(C(=O)N2CC(F)(F)OC3(CCN(Cc4cc(CCO)cs4)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CC(F)(F)OC3(CCN(Cc4cc(CC=O)cs4)CC3)C2)cs1
Reaction time: 0.67 h

Procedure:
Dess-Martin periodinane (0.20 g) was added to stirred solution of (2,2-difluoro-9-((4-(2-hydroxyethyl)thiophen-2-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 51, step b) (0.15 g) and trifluoroacetic acid (0.031 mL) in DCM (4 mL). After 40 min, the reaction mixture was treated with aqueous saturated sodium thiosulphate solution (5 mL), saturated sodium bicarbonate solution (5 mL) and ethyl acetate (30 mL). The mixture was extracted twice with ethyl acetate, the combined organics were washed with saturated sodium bicarbonate solution, acetic acid (0.08 mL) was added, then the solvent was dried over sodium sulphate, filtered, and evaporated in vacuo. Yield 0.19 g. Used directly.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:8]=1.O.O.C[N+]([O-:23])(C)C.O.C(Cl)(Cl)Cl>CS(C)=O.ClCCl>[CH:2]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:8]=1)=[O:23]
Reactant: C[N+](C)(C)[O-]
Reactant: CC(C)(C)OC(=O)Nc1cnc(CBr)cn1
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cnc(C=O)cn1
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a mixed solution of 0.17 g of tert-butyl (5-(bromomethyl)pyrazin-2-yl)carbamate in 4 mL of dimethyl sulfoxide and 2 mL of dichloromethane, 0.26 g of trimethylamine N-oxide dihydrate was added under cooling with ice, and the mixture was stirred for 2 hours. Thereto were added water and chloroform, the organic layer was separated, and washed with a saturated aqueous sodium hydrogen carbonate solution, water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.10 g of tert-butyl (5-formylpyrazin-2-yl)carbamate as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:17][C:18]1[C:19]([CH2:24]Br)=[CH:20][CH:21]=[CH:22][CH:23]=1.[OH-].[Na+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O1CCCC1>[C:1]1([C:7]2[C:8]3([CH2:24][C:19]4[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:17]3)[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1=C(c2ccccc2)Cc2ccccc21
Reactant: BrCc1ccccc1CBr
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C1=C(c2ccccc2)C2(Cc3ccccc3C2)c2ccccc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Benzyl trimethylammonium chloride (0.196 g, 1 mmol) was added to a solution of 2-phenylindene (0.200 g, 1.04 mmol) and α,α′-dibromoxylene (0.289 g, 1.09 mmol) in tetrahydrofuran (10 mL) then 50% aqueous sodium hydroxide (10 mL) was added. The resulting mixture was stirred at 50° C. overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed sequentially with water, 0.1 N hydrochloric acid, water, and saturated aqueous sodium chloride then dried (MgSO4), filtered, and evaporated to a yellow solid. The crude product was purified by preparative thin layer chromatography on silica gel eluted with 98:2 hexane:ethyl acetate to afford 2-phenyl-1′,3′-dihydro-spiro[1H-indene-1,2′-[2H]indene] as a white amorphous solid (0.048 g). NMR (CDCl3, 500 MHz) δ 7.56 (2H, d, J=7 Hz), 7.42 (1H, d, J=7 Hz), 7.24-7.38 (9H, m, ArH), 7.09 (1H, t, J=7 Hz, ArH), 7.02 (1H, d, J=7 Hz, ArH), 3.78 (2H, d, J=16.5 Hz, CH2), 3.19 (2H, d, J=16.5 Hz, CH2).
Reaction SMILES: [NH:1]1[CH2:3][C@H:2]1[C:4]([OH:6])=[O:5].[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17])([O-:9])=[O:8]>CC(C)=O>[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([N@:1]1[CH2:3][CH:2]1[C:4]([OH:6])=[O:5])(=[O:18])=[O:17])([O-:9])=[O:8]
Reactant: O=C(O)[C@@H]1CN1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CC(C)=O
Product: O=C(O)C1C[N@@]1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 2 °C
Yield: 94.8 %

Procedure:
The liquid reaction mixture containing 10.01 g (115 mmol) of (S)-aziridine-2-carboxylic acid obtained in Example 1 was cooled to 2° C. and 255 mL of acetone was added thereto at an internal temperature of 2 to 5° C. While maintaining this solution at an internal temperature of −5 to 0° C., a mixture of 26.9 g (121 mmol) of 2-nitrobenzenesulfonyl chloride with 67 mL of acetone was quickly added thereto. Then the reaction was continued as such for additional 2 hours. This liquid reaction mixture contained 29.7 g (109 mmol) of (S)-N-2-nitrobenzenesulfonyl-aziridine-2-carboxylic acid (yield: 95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:40])[N:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:27]([CH2:30][CH:31]([OH:33])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[CH3:41][N:42]([CH3:47])[CH2:43][C:44](O)=[O:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.C(Cl)Cl>[CH3:41][N:42]([CH3:47])[CH2:43][C:44]([O:33][C@H:31]([CH3:32])[CH2:30][N:27]1[C:28]([CH3:29])=[C:24]([C:22](=[O:23])[NH:21][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[C:2]([F:1])[CH:3]=2)[C:25](=[O:40])[N:26]1[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:45]
Reactant: CN(C)CC(=O)O
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(CC(C)O)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)CN(C)C)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a mixture of (R)—N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)-phenyl-1-(2-hydrox-ylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1.08 g, 2.0 mmol), N,N-dimethylglycine (0.516 g, 5 mmol Alfa Aesar), HATU (1.902 g. 5 mmol) and DMAP (62.5 mg, 0.5 mmol, Aladdin) was added TEA (1.012 g, 10 mmol) in DMF (12.5 mL) under nitrogen atmosphere at 0° C. The reaction was stirred at 0° C. for 2 hrs, and then warmed up to room temperature and continued to stir overnight. The reaction was diluted with 100 mL of CH2Cl2. The resulted solution was washed with 0.1 N HCl (10 mL×2), saturated NaHCO3 (20 mL×2) and followed by water (20 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/MeOH=2/1) to give the title compound as a yellow solid (1.1367 g, 84%).
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:18][CH:19]=[C:20]([C:22]([O:24]C)=[O:23])[N:21]=3)=[CH:13][CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1COCC1.[OH-].[Na+]>CO>[N:1]1([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:18][CH:19]=[C:20]([C:22]([OH:24])=[O:23])[N:21]=3)=[CH:15][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1coc(-c2ccc(Cn3ccc4ccccc43)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1coc(-c2ccc(Cn3ccc4ccccc43)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A solution of methyl 2-[4-(1H-indol-1-ylmethyl)phenyl]-1,3-oxazole-4-carboxylate (1.52 g; 4.57 mmol) in (1:1) MeOH:THF was treated with sodium hydroxide (4.57 g, 4.57 mmol) stirred at room temperature overnight and concentrated under reduced pressure. The resultant concentrate was diluted with 1N sodium hydroxide (50 mL), washed with EtOAc, acidified with concentrated HCl and extracted with EtOAc. The extracts were combined, dried over MgSO4 and concentrated to dryness to give the title product in 91% yield, identified by NMR and mass spectral analyses. LCMS (ESI−) 317 (MH−).