Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.NN.[C:4]([O:8][C:9](=[O:38])[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1)([CH3:7])([CH3:6])[CH3:5]>C(O)C>[C:4]([O:8][C:9](=[O:38])[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][NH2:27])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1)([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(CN)cc2)CC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 98.1 %

Procedure:
Hydrazine monohydrate (0.11 ml, 2.4 mmol) was added to a stirred solution of {1-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzenesulfonyl]-piperidin-4-yl}-carbamic acid tert-butyl ester (0.4 g, 0.8 mmol) in ethanol (10 ml), the mixture was heated to 70° C. and stirred at this temperature for 4 hours. After this time, the precipitate was removed by filtration and the filtrate was concentrated. The resulting residue was triturated with DCM and the resulting precipitate was collected by filtration and dried under vacuum to give the title compound (0.29 g, 98% yield) as a white solid. Tr=1.38 min, m/z (ES+) (M+Na)+ 392.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]([C:13]([F:16])([F:15])[F:14])[O:10]2)=[CH:5][CH:4]=1.II.[I:24](O)(=O)(=O)=O>C(O)C.O>[I:24][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[O:10][CH:9]([C:13]([F:14])([F:15])[F:16])[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:7]2
Reactant: CCOC(=O)C1=Cc2ccc(OC)cc2OC1C(F)(F)F
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1=Cc2cc(I)c(OC)cc2OC1C(F)(F)F
Temperature: 70 °C
Yield: 86.4 %

Procedure:
To a solution of 8 g (26.5 mmol) of ethyl 7-methoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 60 mL of ethanol was added 2.8 g (11.2 mmol) of iodine, followed by addition of a solution of 9.0 g (39.5 mmol) of periodic acid in 25 mL of water. The resulting solution was heated to 70° C. for five hrs. After cooling to room temperature, the volatiles were removed, the residue was dissolved in ethyl acetate, and the organic phase washed with saturated aqueous sodium sulfite and satr' brine. The resultant solution was dried over anhydrous magnesium sulfate and the volatiles were removed. The residue was purified by silica gel chromatography with hexane/ethyl acetate mixture to afford 9.8 g (70%) of a light yellow solid: 1H NMR (CDCl3/300 MHz) 7.62(s, 1H), 7.60(s, 1H), 6.49(s, 1H), 5.69(q, J=6.9 Hz, 1H), 4.30(m, 2H), 3.89(s, 3H), 1.34(t, J=7.2 Hz, 3H). MS (ESI+) 428.9(M+1, 100). HRMS (EI) m/z calcd for (C14H12F3O4) 427.9732, found 427.9741.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].C([CH:12]1[O:14][CH2:13]1)Cl>[OH-].[Na+]>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH:13]1[CH2:12][O:14]1)[CH3:2]
Reactant: ClCC1CO1
Reactant: CCc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Product: CCc1cccc(OC2CO2)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirred solution of 3-ethyl phenol (1.50 g, 12.28 mmol) in NaOH (1N) was added epichlorohydrin (2.07 g, 22.47 mmol). The reaction mixture was stirred at room temperature for 4 days. Excess epichlorohydrin was removed by concentration in vacuo and the two-phase mixture treated with NaOH (1N) (10 ml) after addition of THF (10 ml). The reaction mixture was heated to 55° C. for 15 minutes and then stirred at room temperature for 30 minutes. The THF was removed by concentration in vacuo and the product extracted with ethyl acetate (2×50 ml), concentrated in vacuo and purified by flash column chromatography on silica (150:10:1 dichloromethane:methanol:ammonia) to give the product as a yellow oil.
Reaction SMILES: C(N1CCCCC1)C.[C:9]([N:13]1[CH2:17][CH2:16][S:15][C:14]1=[S:18])(=[O:12])[CH2:10][CH3:11].C(O[C@H:23]1[NH:26][C:25](=[O:27])[C@@H:24]1[C@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH3:29])(=O)C.C(=O)(O)[O-].[Na+]>ClCCl>[Si:31]([O:30][C@@H:28]([C@@H:24]1[C@@H:23]([CH:10]([CH3:11])[C:9](=[O:12])[N:13]2[CH2:17][CH2:16][S:15][C:14]2=[S:18])[NH:26][C:25]1=[O:27])[CH3:29])([C:34]([CH3:35])([CH3:36])[CH3:37])([CH3:32])[CH3:33]
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: CCC(=O)N1CCSC1=S
Agent: CCN1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C(=O)N1CCSC1=S)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To a suspension of stannous trifluoromethanesulfonate (8.35 g) and N-ethylpiperidine (3.79 ml) in dichloromethane (60 ml) was added dropwise a solution of 3-propionyl-2-thioxothiazolidine (4.12 g) in dichloromethane (35 ml) at -78° C. under nitrogen atmosphere. After stirring at -78° C. for 30 minutes, a solution of (3R,4R)-4-acetoxy-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-azetidinone (2.25 g) in dichloromethane (8 ml) was added to the reaction mixture, and the reaction mixture was stirred at 0° C. for 30 minutes and then at room temperature for 20 minutes. The reaction mixture was poured into aqueous sodium bicarbonate solution (100 ml) and the precipitated white mass was removed by passing through a layer of celite. The organic layer was separated and washed with 10% aqueous sodium chloride solution (100 ml×2). The organic solution was dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (185 g) eluting with a mixture of acetone and dichloromethane (2:98, V/V) to give (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1RS)-1-methyl-2-oxo-2-(2-thioxothiazolidin-3-yl)ethyl]-2-azetidinone (2.39 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2.[C:17](OC(=O)C)(=[O:19])[CH3:18].CN(C)C=O>CN(C)C1C=CN=CC=1.C(O)C>[C:17]([O:1][CH2:2][CH2:3][CH2:4][O:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2)(=[O:19])[CH3:18]
Reactant: Nc1nc2c(ncn2OCCCO)c(=O)[nH]1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(=O)OCCCOn1cnc2c(=O)[nH]c(N)nc21
Temperature: 20 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
A mixture of 9-(3-hydroxyprop-1-oxy)guanine (150 mg, 0.67 mmol), 4-dimethylaminopyridine (15.6 mg, 0.13 mmol), acetic anhydride (0.25 ml, 2.65 mmol) and N,N-dimethylformamide (5 ml) was stirred at 20° C. for 3 hours and then ethanol was added. After a further 15 minutes the solvent was evaporated under reduced pressure and the residue was chromatographed on silica gel (eluted with chloroform-ethanol, 4:1), yielding the title compound (120 mg, 67%). Recrystallisation from methanol-water gave 9-(3-acetoxy-prop-1-oxy)guanine (82 mg, 46%). IR: υmax (KBr) 3330, 3168, 1736, 1696, 1648, 1602, 1589, 1391 cm-1. 1H NMR: δH [(CD3)2SO] 1.98 (2H, quintet, J=6.3, 6.6 Hz, CH2CH2CH2), 2.02 (3H, s, ##STR14## 4.17 (2H, t, J=6.6 Hz, CH2ON), 4.32 (2H, t, J=6.3 Hz, ##STR15## 6.60 (2H, br.s, D2O exchangeable NH2), 7.94 (1H, s, H-8), 10.69 (1H, br.s, D2O exchangeable, H-1). Found: C, 44.99; H, 4.93; N, 26.20% M+ 267.0964 C10H13N5O4 requires C, 44.93; H, 4.91; N, 26.21% M+ 267.0968.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH:8]([O:15][CH3:16])[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)([O:15][CH3:16])[O:7][CH3:6])=[CH:20][CH:19]=1
Reactant: COC(OC)c1ccncc1
Reactant: Fc1ccc(CCl)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(Cc1ccc(F)cc1)(OC)c1ccncc1
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
315 mL of n-butyllithium 1.6 M solution in hexane is added dropwise to a solution of 70.3 g (0.46 mole) of 4-dimethoxymethyl-pyridine in 1.4 L of tetrahydrofuran under nitrogen at −70° C. After 30 min. at −70° C., 73 g (0.505 mole) of 4-fluorobenzyl chloride in 280 mL of tetrahydrofuran is added dropwise. After 10 more min. at −70° C., the reaction mixture is allowed to reach room temperature and then stirred for 30 further min. The reaction mixture is poured into 2 L ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. After concentration the residue is purified by chromatography on silica gel (ethylacetate/hexane 1/1) to give 114 g of 4-[2-(4-Fluoro-phenyl)-1,1-dimethoxy-ethyl]-pyridine as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])[C:5]([NH2:8])=[N:6][CH:7]=1.Cl[CH:20]([C:26]([CH3:28])=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:12]([F:18])=[CH:13][CH:14]=[CH:15][C:16]=2[F:17])[C:5]2[N:6]([C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:26]([CH3:28])[N:8]=2)[CH:7]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1ncc(Cl)cc1OCc1c(F)cccc1F
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(Cl)cn12

Procedure:
40 g of 5-chloro-3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 14A; 147.8 mmol; 1 equivalent) were initially charged in 800 ml of ethanol, 30 g of powdered molecular sieve 3A and 128 g of ethyl 2-chloroacetoacetate (739 mmol, 5 equivalents) were added and the mixture was heated at reflux overnight. The reaction mixture was concentrated and the residue was taken up in ethyl acetate and filtered. The ethyl acetate phase was washed with water, dried, filtered and concentrated. This gave 44 g (78% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Li][CH2:12]CCC.CI>C1COCC1>[CH3:12][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Brc1cc2ccccc2[nH]1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The 2-bromoindole derivative 19-1 (1.009 g, 3.00 mmol, prepared as described in Example 12 of WO 03/010141) was dissolved in anhydrous THF (25 mL) under an argon atmosphere and the solution cooled to −78° C. n-BuLi (2.0 M in hexane, 1.60 mL, 3.20 mmol) was added dropwise and the mixture stirred for 15 min. MeI (0.37 mL, 2.00 mmol) was added and stirring was continued for an additional 30 min. The reaction mixture was then warmed up to RT and volatiles removed under reduced pressure. The residue was dissolved in TBME (100 mL) and the solution washed with brine (2×25 mL). The extract was dried (MgSO4), concentrated under reduced pressure and the residue purified by flash chromatography using 0-15% EtOAc in hexane as eluent. The desired 2-methylindole derivative 20-1 was obtained as a waxy solid (0.658 g, 80% yield): MS-ES m/z 272.1 (MH+). The methyl ester 20-1 was saponified in the usual way (NaOH/DMSO) to give the corresponding carboxylic acid 20-2 in 96% yield: MS-ES m/z 258.1 (MH+).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[Br:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C1COCC1.[Cl-].[Na+].O>[Br:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([N:3]2[CH:7]=[CH:6][CH:5]=[CH:4]2)(=[O:18])=[O:17])=[CH:14][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: c1cc[nH]c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(CBr)cc1)n1cccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 15 %

Procedure:
NaH (60% dispersion in mineral oil. 40 mg, 1.0 mmol) was added to a solution of pyrrole (67 mg, 1.0 mmol) in THF (2.0 mL) and the mixture was stirred at room temperature for 5 min. Then 4-(bromomethyl)benzenesulfonyl chloride (269 mg, 1.0 mmol) was added to the mixture. After stirring at room temperature for additional 10 min, brine (15 mL) was added and the mixture was extracted with AcOEt (40 mL×2). The combined extracts were dried over MgSO4. The solvent was removed under reduced pressure to afford an oil which was purified by column chromatography (SiO2, 10% AcOEt/hexane) to give 1-[4-(bromomethyl)benzenesulfonyl]pyrrole: 46 mg, 15% yield, colorless oil. The purity was determined by GC/MS (>95%), m/e 299 (M+, C11H10NO2BrS).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])[N:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:33][O:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[CH2:37][CH2:38]O>C1COCC1>[CH3:33][O:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[CH2:37][CH2:38][O:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])[N:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1
Reactant: COc1ccccc1CCO
Reactant: N#Cc1cccc(-n2nc(C(F)(F)F)cc2O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: COc1ccccc1CCOc1cc(C(F)(F)F)nn1-c1cccc(C#N)c1
Reaction time: 0.17 h
Yield: 28.1 %

Procedure:
A suspension of 130 (200 mg, 0.790 mmol) and PS-PPh2 (2.15 mmol/g, 0.522 g, 1.5 eq, polymer supported triphenylphosphine) in THF (7 mL) under a nitrogen atmosphere was stirred for 10 minutes. DIAD (0.154 mL, 0.790 mmol) was added and after 1 hour of stirring at room temperature 2-methoxy-phenethyl alcohol (0.112 mL, 0.790 mmol) was added and the suspension was stirred for 48 h. The reaction mixture was filtered and the resin washed with DCM, the filtrate was concentrated and the residue purified by silica gel chromatography (Biotage 25M, 5-20% ethyl acetate in hexanes) to give 131 (86 mg, 0.222 mmol, 28.1% yield) as white solid. LRMS(ESI): (calc.) 387.4 (found) 388.1 (MH)+, 410.0 (MNa)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([OH:16])=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:16])[N:11]([CH3:17])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ncc(Br)cc1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(Br)cc(OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a solution of 3-(benzyloxy)-5-bromopyridin-2-ol ((5.8 g, 20.7 mmol) in DMF (75 mL) was added Cs2CO3 (8.8 g, 26.9 mmol). A solution of MeI (1.62 mL, 25.9 mmol) in DMF (10 mL) was added dropwise to this mixture. After stirring at room temperature for 3 h, the reaction mixture was concentrated. The residue was taken up in H2O and the aqueous solution was extracted with CH2Cl2 (3×). Combined organic solutions washed with brine (1×), dried over Na2SO4 and concentrated. Purification by flash chromatography (250 g silica gel, 50% EtOAc in hexanes) afforded 4.02 g (66%) of 3-(benzyloxy)-5-bromo-1-methylpyridin-2(1H)-one as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.43-7.32 (m, 5H), 7.05 (s, 1H), 6.91 (s, 1H), 5.11 (s, 2H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[C:16]1([CH3:28])[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]1([CH3:28])[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1cc(C)c(OB(O)O)c(C)c1
Reactant: CC(C)(C)OC(=O)Nc1cnccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C)c(-c2ccncc2NC(=O)OC(C)(C)C)c(C)c1
Yield: 115.1 %

Procedure:
A solution of tert-butyl N-(4-iodo-3-pyridyl)carbamate (20.0 g, 62 mmol), mesitylboric acid (10.2 g, 62 mmol), Pd(PPh3)4 (3.6 g, 3.12 mmol), barium hydroxide octahydrate (49.3 g, 47.3 mmol) in 1,2-dimethoxyethane (400 mL) and water (67 mL) was heated under reflux for six hours. The mixture was filtered through Celite, and the filtrate was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and evaporated, to give the title compound (containing 22.3 g of impurities) as pale brown crystals.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.[Cl:19][C:20]1[C:25]2[CH:26]=[N:27][NH:28][C:24]=2[CH:23]=[C:22]([CH3:29])[N:21]=1>ClCCl>[Cl:19][C:20]1[C:25]2[CH:26]=[N:27][N:28]([CH:18]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:24]=2[CH:23]=[C:22]([CH3:29])[N:21]=1
Reactant: Cc1cc2[nH]ncc2c(Cl)n1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1cc2c(cnn2C2CCCCO2)c(Cl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
p-Toluenesulfonic acid monohydrate (29 mg, 0.15 mmol) and 3,4-dihydro-2H-pyran (99%, 205 μL, 2.39 mmol) were sequentially added to a suspension of C1 (250 mg, 1.49 mmol) and 4 Å molecular sieves in dichloromethane (10 mL). The reaction mixture was allowed to stir at room temperature for 4 hours, at which time it was filtered, concentrated in vacuo, and washed three times with heptane. Purification via silica gel chromatography (Gradient: 20% to 50% ethyl acetate in heptane) afforded the product as a colorless oil. Yield: 65 mg, 0.26 mmol, 17%. LCMS m/z 252.1 [M+H+]. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 8.08 (d, J=0.9 Hz, 1H), 7.26-7.27 (m, 1H), 5.67 (dd, J=9.1, 2.8 Hz, 1H), 3.99-4.05 (m, 1H), 3.71-3.79 (m, 1H), 2.65 (d, J=0.8 Hz, 3H), 2.06-2.2 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O)#[N:2].CN([C:17]([O:21][N:22]1N=NC2C=CC=N[C:23]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CONC>C(Cl)Cl.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([N:22]([O:21][CH3:17])[CH3:23])=[O:8])#[N:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccc(C(=O)O)cc1C#N
Agent: CNOC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)N(C)OC)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.4 %

Procedure:
To a stirred solution of 3-cyano-4-methoxybenzoic acid (1.0 g, 5.60 mmol) in DCM (30 mL) were added HATU (3.20 g, 8.01 mmol), N-methoxy,N-methylamine (0.82 g, 8.01 mmol) and TEA (2.3 mL, 17.01 mmol) at RT under a nitrogen atomosphere. The reaction mixture was then stirred at RT for 2 h, diluted with water and the aqueous layer was extracted with DCM (3×50 mL). The combined organic extracts were washed with water (50 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford 3-cyano-N,4-dimethoxy-N-methylbenzamide (1.3 g, 100%) as a white solid.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]2[C:16](=O)[C:15]3[C:10](=[CH:11][C:12]([C:18]([O:20]C)=[O:19])=[CH:13][CH:14]=3)[O:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH:23]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1)[NH2:24]>>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([N:23]2[CH:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]3[CH2:8][O:9][C:10]4[CH:11]=[C:12]([C:18]([OH:20])=[O:19])[CH:13]=[CH:14][C:15]=4[C:16]3=[N:24]2)=[CH:26][CH:27]=1)#[N:30]
Reactant: COC(=O)c1ccc2c(c1)OCC(=CC1CCCC1)C2=O
Reactant: N#Cc1ccc(NN)cc1
Agent: Cl
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4OCC3C2C2CCCC2)cc1

Procedure:
The title compound was prepared from methyl 3-(cyclopentylmethylene)-4-oxochroman-7-carboxylate; Preparation 31 (286 mg, 1.0 mmol) and 4-hydrazinylbenzonitrile hydrochloride (Aldrich; 254 mg, 1.5 mmol) according to Method B and Method C. 2-(4-Cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid was obtained (yellow solid, 142 mg, 0.367 mmol, 37% yield). The title compound was largely present as (±)-(3RS,3aSR)-2-(4-cyanophenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.16 (br. s., 1H), 7.93 (d, J=7.8 Hz, 1H), 7.53-7.66 (m, 3H), 7.46 (s, 1H), 7.27 (d, J=9.0 Hz, 2H), 4.90 (dd, J=9.4, 7.0 Hz, 1H), 4.77 (dd, J=10.4, 5.7 Hz, 1H), 4.30 (dd, J=12.7, 10.7 Hz, 1H), 3.98 (ddd, J=12.9, 9.8, 5.9 Hz, 1H), 2.02-2.16 (m, 1H), 1.56-1.67 (m, 1H), 1.43-1.55 (m, 3H), 1.29-1.43 (m, 2H), 1.13-1.29 (m, 2H). ES-MS m/z 388 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([NH:13][NH2:14])=[O:12])[O:8][C:7]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[CH:27]=1.[C:28](Cl)(Cl)=[O:29]>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]3[O:12][C:28](=[O:29])[NH:14][N:13]=3)[O:8][C:7]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[CH:27]=1
Reactant: NNC(=O)C1Oc2ccc(Cl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(C2Oc3ccc(Cl)cc3C(C3CCCCC3)(C3CCCCC3)O2)o1
Temperature: 25 °C

Procedure:
To a solution of 300 mg 6-chloro-4,4-dicyclohexyl-4H-benzo[1,3]dioxine-2-carboxylic acid hydrazide in 4.3 ml toluene was added 4 ml of a 1.9M solution of phosgene in toluene. The reaction mixture was heated to reflux for 4 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with water and brine and dried with MgSO4. Then the solvent was removed in vacuo and the crude product purified by preparative HPLC (C18 reverse phase column, elution with water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a solid. Yield: 180 mg.
Reaction SMILES: ClC(OCC(C)C)=O.[CH3:9][N:10]([CH3:17])[CH2:11][C:12]#[C:13][C:14](O)=[O:15].CN1CCOCC1.N#N.[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][C:32]([C:38]#[N:39])=[C:31]2[NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([Br:47])[CH:42]=1>N1C=CC=CC=1>[Br:47][C:43]1[CH:42]=[C:41]([NH:40][C:31]2[C:30]3[C:35](=[CH:36][CH:37]=[C:28]([NH:27][C:14](=[O:15])[C:13]#[C:12][CH2:11][N:10]([CH3:17])[CH3:9])[CH:29]=3)[N:34]=[CH:33][C:32]=2[C:38]#[N:39])[CH:46]=[CH:45][CH:44]=1
Reactant: CN(C)CC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Agent: CC(C)COC(=O)Cl
Agent: N#N
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: CN(C)CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16.9 %

Procedure:
Isobutyl chloroformate (0.342 g, 2.5 mmol) was dropwise added into an ice cold solution of 4-dimethylamino -2-butynoic acid (0.9 g, 3.8 mmol ) and N-methylmorpholine (0.384 g , 3.8 mmol ) in 50 mL of tetrahydrofuan under N2. After stirring for 30 min, a solution of 0.644 g (1.9 mmol ) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 10 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 2.5 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by thin-layer chromatography eluted with 15% methanol in ethyl acetate. The product was collected, and dried in vacuo to give 0.144 g (21%) of yellow solid; : mass spectrum (electrospray, m/e,): 447.9, 450.2 (M+H+); mp 180° C. (dec.).