Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16]C)=O)=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]1[C:20]([O:22][CH3:23])=[O:21].[H-].[Na+].[N:26]1C=NC=N[CH:27]=1>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]2[C:14](=[O:16])[NH:26][CH:27]=[CH:18][C:12]=2[NH:11][C:10]([CH3:19])=[C:9]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: c1ncncn1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccccc1F
Temperature: 25 °C

Procedure:
A solution of 31.5 g (120 mMol) dimethyl 4-(2-fluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate in 260 ml dimethylformamide is added dropwise, under an atmosphere of nitrogen, to a suspension of 3.8 g (130 mMol) sodium hydride (80% in paraffin oil) in 60 ml dry dimethylformamide. Upon slowing down of the evolution of gas, the reaction mixture is further stirred for ten minutes at ambient temperature and subsequently 10.0 g (120 mMol) s-triazine in 260 ml dimethylformamide are added dropwise thereto. The reaction mixture is heated to 110° C. for 16 hours and, after cooling, evaporated in a vacuum. The dark residue is stirred with 600 ml acetone, filtered and the filtrate evaporated in a vacuum. The crude product is boiled with 300 ml methanol, the crystals formed after cooling are filtered off and, for further purification, are recrystallized from methanol. There is obtained methyl (±)-4-(2-fluorophenyl)-1,4,5,6-tetrahydro-2-methyl-5-oxo-1,6-naphthyridine-3-carboxylate in the form of pale beige crystals; mp 315°-316° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]1=[O:17].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.O>[CH2:18]([O:16][C:12]1[CH:13]=[C:14]([CH3:15])[N:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:10](=[O:17])[CH:11]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(O)cc(=O)n1-c1c(Cl)cccc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)cc(=O)n1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.125 g, 0.46 mmol) and benzylbromide (0.1 mL) in DMF (2.5 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with water (10.0 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water, dried (Na2SO4), filtered, concentrated under reduced pressure and the resulting material was purified by silica gel flash chromatography using 25% EtOAc in hexanes to afford the title compound (0.11 g) as a pale yellow syrup: 1H-NMR (CD3OD) δ: 7.61 (m, 2H), 7.55-7.3 (m, 6H), 6.23 (d, 1H, J=2.0 Hz), 6.01 (d, 1H, J=2.0 Hz), 5.12 (s, 2H), and 1.93 (s, 3H); ES-MS m/z=360 (MH+); HR-MS, m/z calc C19H16NO2Cl2, 360.0553, found 360.0569.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH2:11][N:12]1[C:20]2[CH:19]=[CH:18][C:17]([C:21]#[N:22])=[CH:16][C:15]=2[C:14]2[CH2:23][C@H:24]([NH:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:25][C:13]1=2)=[O:5])C.[Li+].[OH-].Cl>CCO.C1COCC1>[C:21]([C:17]1[CH:18]=[CH:19][C:20]2[N:12]([CH2:11][C:10]3[S:9][CH:8]=[N:7][C:6]=3[C:4]([OH:5])=[O:3])[C:13]3[CH2:25][C@@H:24]([NH:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:23][C:14]=3[C:15]=2[CH:16]=1)#[N:22]
Reactant: CCOC(=O)c1ncsc1Cn1c2c(c3cc(C#N)ccc31)C[C@H](NC(=O)OC(C)C)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3scnc3C(=O)O)c3ccc(C#N)cc23)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 109.8 %

Procedure:
Treat a mixture of 5-((S)-7-cyano-2-isopropoxycarbonylamino-2,3-dihydro-1H-cyclopenta[b]indol-4-ylmethyl)-thiazole-4-carboxylic acid ethyl ester (3.745 g, 8.28 mmol) in EtOH (100 mL) and THF (40 mL) with 5 M LiOH (8.3 mL, 41.4 mmol) and stir at room temperature for 18 h. Add 5 N HCl (9 mL) bringing pH to 2. Concentrate the reaction mixture by rotavap, extract into EtOAc (3×330 mL), dry organics (MgSO4), filter, and concentrate to give 3.86 g (>100%) of 5-((S)-7-cyano-2-isopropoxycarbonylamino-2,3-dihydro-1H-cyclopenta[b]indol-4-ylmethyl)-thiazole-4-carboxylic acid as a pale yellow solid. LC-ES/MS m/z 425 (M+1), 423 (M−H), TR=2.3 min.
Reaction SMILES: [C:1]([CH:5]([NH:13][NH:14][C:15]([C:17]1[CH:26]=[CH:25][C:20]2[O:21][CH2:22][CH2:23][O:24][C:19]=2[C:18]=1[CH2:27][CH3:28])=[O:16])[CH:6]=[C:7]([CH3:12])[C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([O:41][CH3:42])[C:39]=1[CH3:40])[C:34](Cl)=[O:35].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:1]([CH:5]([N:13]([C:34](=[O:35])[C:33]1[CH:37]=[C:38]([O:41][CH3:42])[C:39]([CH3:40])=[C:31]([O:30][CH3:29])[CH:32]=1)[NH:14][C:15]([C:17]1[CH:26]=[CH:25][C:20]2[O:21][CH2:22][CH2:23][O:24][C:19]=2[C:18]=1[CH2:27][CH3:28])=[O:16])[CH:6]=[C:7]([CH3:12])[C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1C
Reactant: CCc1c(C(=O)NNC(C=C(C)C(C)(C)C)C(C)(C)C)ccc2c1OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCc1c(C(=O)NN(C(=O)c2cc(OC)c(C)c(OC)c2)C(C=C(C)C(C)(C)C)C(C)(C)C)ccc2c1OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
5-Ethyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid N′-(1-tert-butyl-3,4,4-trimethyl-pent-2-enyl)-hydrazide (150 mg, 0.39 mmol) and 3,5-dimethoxy-4-methylbenzoyl chloride (83 mg, 0.39 mmol) were dissolved in 5 mL CH2Cl2. 5 mL of 25% K2CO3 were added, and the reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC. The phases were separated, adding additional CH2Cl2 and/or water as needed to aid manipulation. The CH2Cl2 layer was dried and solvent was removed in vacuo to provide 210 mg of crude product. This material was purified by silica gel column chromatography, eluting with a step gradient of 10-25% ethyl acetate in hexane to yield 3,5-dimethoxy-4-methyl-benzoic acid N-(1-tert-butyl-3,4,4-trimethyl-pent-2-enyl)-N′-(5-ethyl-2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-hydrazide RG115898 (83 mg, Rf=0.19 in 25% ethyl acetate in n-hexane, yield 38%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.19 (s, 1H), 6.75 (d, J=8.0 Hz, 1), 6.69 (s, 2H), 6.61 (d, J=8.0 Hz, 1H), 5.43 (d, J=10.0 Hz, 1H), 5.41 (d, 14.4 Hz, 1H), 4.30-4.20 (m, 4H), 3.80 (s, 6H), 2.21-2.15 (m, 1H), 2.01 (s, 3H), 1.81 (m, 1H), 1.76-1.64 (m, 1H), 1.06 (s, 9H), 1.00 (s, 9H), 0.70 (t, J=7.6 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH2:10]([O:17][C:18]([NH:20][C:21](=[NH:24])SC)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[CH2:10]([O:17][C:18]([NH:20][C:21]([N:7]1[CH2:8][CH2:9][CH:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1)=[NH:24])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCCC1CCNCC1
Reactant: CSC(=N)NC(=O)OCc1ccccc1
Solvent: CC#N
Product: N=C(NC(=O)OCc1ccccc1)N1CCC(CCO)CC1
Yield: 40.9 %

Procedure:
A mixture of 6.2 g (0.028 mol) of 4-hydroxyethyl piperidine and 3.6 g (0.028 mol) of N-benzyloxycarbonyl-S-methyl isothiourea in 50 ml of acetonitrile was refluxed overnight. Evaporation and flash chromatography on silica gel with ethyl acetate gave 3.5 g (41%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8](=[O:13])[CH2:9][CH2:10][CH2:11][Cl:12])=[C:4]([I:16])[CH:3]=1.[CH:17]([Mg]Br)=[CH2:18]>C1COCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([OH:13])([CH2:9][CH2:10][CH2:11][Cl:12])[CH:17]=[CH2:18])=[C:4]([I:16])[CH:3]=1
Reactant: C=C[Mg]Br
Reactant: O=C(CCCCl)COc1ccc(Br)cc1I
Solvent: C1CCOC1
Product: C=CC(O)(CCCCl)COc1ccc(Br)cc1I
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-bromo-2-iodophenoxy)-5-chloropentan-2-one (1.61 g, 3.86 mmol) in THF (35 mL) was added vinylmagnesium bromide (1M solution in THF, 4.3 mL) at −78° C. under an argon atmosphere. After stirring for 1 hour at −78° C., the mixture was gradually warmed up to −30° C. over 1 hour. The reaction was quenched by adding saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organic layer were washed with brine, dried over Na2SO4, filtered, and the filtrate was evaporated. The residue was purified by silicagel column chromatography (EtOAc-hexane, a linear gradient of EtOAc from 0 to 20%) afforded 3-[(4-bromo-2-iodophenoxy)methyl]-6-chlorohex-1-en-3-ol (1.35 g).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:32][CH2:31][C:30]3[C:29]4[CH2:28][C:27]([CH3:34])([CH3:33])[CH2:26][C:25]=4[S:24][C:23]=3[C:22]2=[O:35])=[N:8][CH:9]=[CH:10][C:11]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[N:47]=[N:48][N:49]([CH3:51])[CH:50]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1.C([O-])(=O)C.[K+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:32][CH2:31][C:30]3[C:29]4[CH2:28][C:27]([CH3:34])([CH3:33])[CH2:26][C:25]=4[S:24][C:23]=3[C:22]2=[O:35])=[N:8][CH:9]=[CH:10][C:11]=1[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[N:47]=[N:48][N:49]([CH3:51])[CH:50]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: Cn1cc(Nc2cc(Br)cn(C)c2=O)nn1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cn(C)nn3)c(=O)n(C)c2)ccnc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 70.7 %

Procedure:
A 50-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with (2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.02,6]dodeca-1(8),2(6)-dien-10-yl}-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl acetate 330c (180 mg, 0.37 mmol), 5-bromo-1-methyl-3-(1-methyl-1H-1,2,3-triazol-4-ylamino)pyridin-2(1H)-one 292c (125 mg, 0.43 mmol), Pd(dppf)Cl2 (20 mg, 0.025 mmol), potassium acetate (80 mg, 0.80 mmol), K3PO4 (165 mg, 0.80 mmol), and acetonitrile/water (10 mL/1 mL). After three cycles of vacuum/nitrogen flush, the mixture was heated at 100° C. for 1 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 20:1 dichloromethane/methanol to afford 333a (150 mg, 71%) as a brown solid. MS-ESI: [M+H]+ 574.1
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-])(=[O:3])=[O:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N:23]1C=CC=CC=1>>[S:1]([NH2:23])([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:3])=[O:2]
Reactant: c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(N)(=O)=O)cc1
Reaction time: 2 h
Yield: 95 %

Procedure:
The tosylate salt 3 (1.0 g; 0.0022 mol) was dissolved in pyridine (5.0 ml). p-Toluenesulfonyl chloride (476 mg; 0.0025 mol) was added and the reaction mixture stirred for 2 hours and concentrated. The residue was partitioned between THF/brine. The organic layer was washed with dilute HCl then with dilute K2CO3, and dried over MgSO4, and concentrated. The residue was placed on 50 g of silica and eluted with 50 mL of 50% EtOAc/heptane. The solution was concentrated to an oil which slowly crystallized to yield 913 mg (95%) of compound 4.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)OC(=O)[C:4]=1[C:20]([O:22][CH3:23])=[O:21].[C:24]1([N:30]2[CH:38]=[C:37]3[C:32]([CH2:33][CH2:34][CH2:35][C:36]3=O)=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH-].[K+].Cl>CN(C=O)C>[CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[C:35]2[CH2:34][CH2:33][C:32]3[C:37](=[CH:38][N:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:31]=3)[C:36]=2[C:4]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1c(SC)cc(-c2cccc3ccccc23)oc1=O
Reactant: O=C1CCCc2nn(-c3ccccc3)cc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1c(SC)cc(-c2cccc3ccccc23)c2c1-c1cn(-c3ccccc3)nc1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
A mixture of methyl 4-(methylthio)-6-(naphthalen-1-yl)-2-oxo-2H-pyran-3-carboxylate (326 mg, 1 mmol), 2-phenyl-6,7-dihydro-2H-indazol-4(5H)-one (212 mg, 1 mmol) and powdered KOH (84 mg, 1.5 mmol) in dry DMF (5 mL) was stirred at 25° C. for 8 hr. At the end the reaction mixture was poured into ice water with vigorous stifling and finally neutralized with dilute HCl. The solid thus obtained was filtered and purified on a neutral alumina column using 15% chloroform in hexane as eluent to yield 228 mg (48%) of methyl 8-(methylthio)-6-(naphthalen-1-yl)-2-phenyl-4,5-dihydro-2H-benzo[e]indazole-9-carboxylate.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][S:16]([CH3:19])(=[O:18])=[O:17].[CH2:20]([S:22][CH2:23][CH:24]([OH:27])[C:25]#[CH:26])[CH3:21]>>[CH2:20]([S:22][CH2:23][CH:24]([C:25]1[N:15]([S:16]([CH3:19])(=[O:18])=[O:17])[C:3]2[C:2]([CH:26]=1)=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=2)[OH:27])[CH3:21]
Reactant: CS(=O)(=O)Nc1cc(C(F)(F)F)c([N+](=O)[O-])cc1I
Reactant: C#CC(O)CSCC
Product: CCSCC(O)c1cc2cc([N+](=O)[O-])c(C(F)(F)F)cc2n1S(C)(=O)=O

Procedure:
This compound was prepared using the general Sonagashira procedure as described in General Procedures Example C, starting from N-(2-iodo-4-nitro-5-trifluoromethyl-phenyl)-methanesulfonamide (1.89 g, 4.6 mmol) and 1-ethylsulfanyl-but-3-yn-2-ol (0.6 g, 4.6 mmol), reacted to yield the title compound as a yellow solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:13]3[N:14]=[C:15]([CH2:18][O:19][C:20]4[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:22]([CH3:32])[CH:21]=4)[S:16][CH:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl.CCOC(C)=O>C1COCC1.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:13]3[N:14]=[C:15]([CH2:18][O:19][C:20]4[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:22]([CH3:32])[CH:21]=4)[S:16][CH:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)COc1ccc(OCc2nc(-c3cccc(OC4CCCC4)c3)cs2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCc2nc(-c3cccc(OC4CCCC4)c3)cs2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The methyl 2-(4-((4-(3-(cyclopentyloxy)phenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetate from Step A is dissolved in THF (1 mL), then a solution of 1 M LiOH in H2O (0.2 mL) is added and the mixture is stirred for 3 h at rt. The mixture is acidified with 1 M HCl (0.25 mL). EtOAc (10 mL) is added, and the organic layer is washed with brine (5 mL). The organic layer is dried (MgSO4), filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound C1 as a white solid: 1H-NMR (400 MHz, CDCl3) δ=7.46 (s, 1H), 7.33 (m, 3H), 6.89 (m, 2H), 6.76 (dd, J=2.8, 8.8 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 5.41 (s, 2H), 4.84 (m, 1H), 4.64 (s, 2H), 2.28 (s, 3H), 1.88 (m, 4H), 1.82 (m, 2H), 1.63 (m, 2H). MS calcd. for C24H26NO5S (M+H+) 440.2. found 440.1.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1.C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>ClCCl>[CH3:1][C:2]([CH3:12])=[CH:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Br:14])=[CH:6][CH:5]=1
Reactant: CC(C)=Cc1ccc(CO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)=Cc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 4-(2-methylprop-1-en-1-yl)benzyl alcohol (0.60 g) and carbon tetrabromide (1.2 g) in dichloromethane (12 mL) was added triphenylphosphine (0.97 g) at 0° C., and the mixture was stirred at room temperature for 3.5 hours. To the reaction mixture was added water, and the mixture was extracted with hexane. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane) to give 4-(2-methylprop-1-en-1-yl)benzyl bromide. To a solution of methyl acetoacetate (0.44 mL) in tetrahydrofuran (17 mL) was added sodium hydride (60%, 0.18 g) at 0° C., and the mixture was stirred for 10 minutes. To the reaction mixture was added a solution of 4-(2-methylprop-1-en-1-yl)benzyl bromide in tetrahydrofuran (3 mL), and the mixture was heated under reflux for 3.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in toluene (8 mL). To the solution was added hydrazine monohydrate (0.54 mL), and the mixture was stirred at 80° C. for 30 minutes. The reaction mixture was cooled to 0° C., and the resulting precipitates were collected by filtration, washed with water and hexane, and dried under reduced pressure to give 5-methyl-4-{[4-(2-methylprop-1-en-1-yl)phenyl]methyl}-1,2-dihydro-3H-pyrazol-3-one (0.31 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][N:8]1[CH2:13][C:12](=O)[NH:11][C:10]2[N:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:9]1=2>C1COCC1>[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:9]1=2
Reactant: Cc1ccc2c(n1)NC(=O)CN2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2c(n1)NCCN2C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
LiAlH4 (214 mg, 5.64 mmol) was slowly added to 10 mL anhydrous THF in a round-bottom flask fitted with a stir bar and a condenser. After stirring for 10 minutes, a solution of 1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazin-3(2H)-one (500 mg, 2.82 mmol) in 5 mL anhydrous THF was added drop wise. Upon completion of the addition, the reaction mixture was refluxed for 16 hours. The reaction was cooled to room temperature and quenched with 1 M NaOH solution until the mixture had become a milky yellow color. The precipitate was filtered off and washed 3 times with CH2Cl2. The filtrate and washings were combined, washed with brine, dried over MgSO4. Filtered and concentrated under reduced pressure to give the desired product as light yellow oil, which solidified on standing. (420 mg, 91% yield). H NMR (CDCl3) δ 2.27 (s, 3H), 2.80 (s, 3H), 3.17 (t, 2H), 3.58 (m, 2H), 6.36 (d, 1H), 6.56 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18]([O:20]CC)=O)=[CH:8][C:9]=1[NH:10]2.[CH2:23]([Mg]Cl)[CH3:24]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O>[Br:1][C:2]1[C:3]2[C:4]3[C:9](=[CH:8][C:7]([C:18]4([OH:20])[CH2:24][CH2:23]4)=[CH:6][CH:5]=3)[NH:10][C:11]=2[C:12]([C:15]([NH2:16])=[O:17])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Reactant: CC[Mg]Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Product: NC(=O)c1ccc(Br)c2c1[nH]c1cc(C3(O)CC3)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
Step 1 A solution of ethyl 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate (Intermediate 48-1, 0.275 g, 0.761 mmol) was treated with titanium (IV) isopropoxide (0.31 mL, 1.07 mmol), followed by ethylmagnesium chloride (2 M in THF, 3.81 mL, 7.61 mmol). The mixture was stirred at rt for 1 h, then was cooled on ice and treated with water (10 mL). After 30 min, the solid was removed by filtration and rinsed with ether (150 mL). The organic layer was dried and concentrated to give 4-bromo-7-(1-hydroxycyclopropyl)-9H-carbazole-1-carboxamide as a yellow solid (0.220 g, 79%). 1H NMR (400 MHz, DMSO-d6) δ 11.65 (1H, s), 8.52 (1H, d, J=8.4 Hz), 8.25 (1H, br. s.), 7.84-7.89 (2H, m), 7.61 (1H, br. s.), 7.45 (1H, d, J=8.1 Hz), 7.13 (1H, dd, J=8.5, 1.7 Hz), 6.11 (1H, s), 1.21-1.27 (2H, m), 1.06-1.11 (2H, m).
Reaction SMILES: [C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@@H:21]([NH2:26])[CH2:20]2.[C:27]([O:30][CH:31](C)C)(=[O:29])C.[OH-].[Na+].[Cl-].[Na+]>O>[CH3:31][O:30][C:27](=[O:29])[NH:26][C@H:21]1[CH2:20][C:19]2[C:23](=[CH:24][CH:25]=[C:17]([Br:16])[CH:18]=2)[CH2:22]1
Reactant: CC(=O)OC(C)C
Reactant: N[C@@H]1Cc2ccc(Br)cc2C1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)N[C@@H]1Cc2ccc(Br)cc2C1
Temperature: 22.5 °C

Procedure:
A suspension of 111.1 g of (R)-5-bromo-2-aminoindane (1S)-(+)-10-camphorsulfonate salt and 300 mL of isopropyl acetate is stirred at 20-25° C. and a solution of 15.0 g of sodium hydroxide and 75.0 g of sodium chloride in 300 mL of water is added over a period of 10 minutes while maintaining an internal temperature at 20 to 25° C. The suspension is stirred for 30 minutes or until all the solids dissolve. The organic layer is separated and the aqueous layer is extracted with 100 mL of isopropyl acetate. The organic layers containing (R)-5-bromo-2-aminoindane free base are combined. A solution of 60 g of sodium bicarbonate in 600 mL of water is added and the resulting white slurry is stirred under nitrogen and cooled to a temperature of 0-5° C. over a period of 15 minutes. A solution of 35.4 g of methyl chloroformate in 200 mL of isopropyl acetate is added over a period of 45 minutes while maintaining an internal temperature of 0-5° C. and the mixture is stirred at this temperature for an additional 1 hour. The organic layer is separated and washed with 150 mL of 1 N sulfuric acid is added, then with a solution of 10 g of sodium bicarbonate in 100 mL of deionized water and finally with 150 mL of deionized water. The organic layer is concentrated under vacuum (100-300 torr) at a temperature of 40-50° C. to ˜150 mL of a slurry. Heptane (500 mL) is added and the mixture is again concentrated under vacuum (100-200 torr) at a temperature of 40-50° C. to about 300 mL of a slurry. Heptane (500 mL) is again added and the mixture is cooled to an internal temperature of 0-5° C. The solid is collected and washed with 40 mL of heptane in two equal portions of 20 mL each. The solid is dried at 60-65° C. under vacuum (10-30 torr) to obtain (R)-(5-bromoindan 2-yl)-carbamic acid methyl ester as a crystalline white solid.
Reaction SMILES: [OH:1][CH:2]([C:23]1[N:24]=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:26][CH:27]=1)[CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])[CH:11]=1)[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>O1CCCC1CCO>[OH:1][CH:2]([C:23]1[N:24]=[C:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[S:26][CH:27]=1)[CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:21])([F:22])[CH:18]([F:19])[F:20])[CH:11]=1)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1csc(-c2ccccc2)n1
Agent: OCCC1CCCO1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1csc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a solution of ethyl 3-hydroxy-3-(2-phenyl-1,3-thiazol-4-yl)-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate (6.28 g, 13.0 mmol) in tetrahydrofuran-ethanol (20 ml—20 ml) was added 2N sodium hydroxide (17 ml, 34 mmol) at room temperature, and the mixture was stirred overnight at room temperature. After completion of the reaction, the organic solvent was evaporated under reduced pressure and diluted with water. The aqueous layer was washed with ether and acidified with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 3-hydroxy-3-(2-phenyl-1,3-thiazol-4-yl)-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionic acid (5.51 g, 93%) as a pale-yellow oil.