Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:8]1[O:10][CH:9]1[CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[O:10]1[CH2:8][CH:9]1[CH2:11][O:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: OCC1CO1
Reactant: Oc1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCC2CO2)ccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.1 %

Procedure:
To a round bottom flask was added 4-hydroxypyridine (250 mg, 2.63 mmol), glycidol (194.74 mg, 2.63 mmol) and triphenylphosphine (758.45 mg, 2.89 mmol) in 20 mL of dry THF, followed by the addition of diethyl azodicarboxylate (503.6 mg, 2.89 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo. The residue was diluted with CH2Cl2. The organic phase was washed with saturated NaHCO3 and brine. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was loaded to a flash chromatography column. The column was eluted with 0–5% MeOH/CH2Cl2. The product fractions were collected and concentrated to afford 80 mg (20.1%) of 4-oxiranylmethoxy-pyridine. (TLC: Rf=0.4, 5% MeOH/CH2Cl2, UV). MH+=152.31.
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[C:12](=[O:13])[NH:11][NH:10][C:9]2=[O:14])=[C:6]([F:15])[C:5]([F:16])=[C:4]([F:17])[C:3]=1[F:18].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)(=O)C>[F:15][C:6]1[C:7]([N:8]2[C:9](=[O:14])[N:10]=[N:11][C:12]2=[O:13])=[C:2]([F:1])[C:3]([F:18])=[C:4]([F:17])[C:5]=1[F:16]
Reactant: O=c1[nH][nH]c(=O)n1-c1c(F)c(F)c(F)c(F)c1F
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1N=NC(=O)N1c1c(F)c(F)c(F)c(F)c1F
Reaction time: 0.33 h

Procedure:
A 50 ml, three-necked flask is fitted with a gas-dispersion tube, a drying tube and a stirrer. 4-(Pentafluorophenyl)urazole, 0.5 g (1.8 mM) is dissolved in 25 ml of ethyl acetate. Anhydrous sodium sulfate, 3 g, is added to remove water present in NO2. The reaction mixture is cooled in an ice bath, and nitrogen dioxide added slowly for 20 minutes. The mixture is allowed to stir for 20 minutes. The Na2SO4 is removed by filtration and the ethyl acetate removed with the rotary evaporator to yield a red oil. The residual solvent is removed with a vacuum pump to yield a crystalline solid, 0.35 g, mp 88°-91° C. The product is further purified by sublimation, mp 94°-96° C.
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][C@H:4]1[C@H:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].C(Cl)(=O)C([Cl:16])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:12])=[CH:3][C@H:4]1[C@H:6]([C:7]([Cl:16])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Yield: 94.5 %

Procedure:
In a manner similar to Example 13A, the reaction of 25.0 g (0.12 mole) of (±)-trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid, 180 ml of toluene, and 30.4 g (0.24 mole) of oxalyl chloride gave 25.8 g of (±)-trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:8][C:9]1[C:17]([CH2:18][CH:19]([OH:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][CH2:13]2)C1C=CC=CC=1>C(O)C.[Pd]>[Si:22]([O:21][CH2:20][CH:19]([OH:29])[CH2:18][C:17]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][C:10]=2[C:9]=1[OH:8])([C:25]([CH3:27])([CH3:28])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OCC(O)Cc1ccc2c(c1OCc1ccccc1)CCC2
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCC(O)Cc1ccc2c(c1O)CCC2
Reaction time: 4 h
Yield: 94.3 %

Procedure:
To a solution of (±)-1-[4-(benzyloxy)-2,3-dihydro-1H-inden-5-yl]-3-{[tert-butyl(dimethyl)silyl]oxy}propan-2-ol (9.20 g, 22.29 mmol) in ethanol (200 mL) was added palladium on carbon (1.00 g, 10 wt. %) and the reaction mixture was shaken under an H2 atmosphere (50 psi) for 4 h. The reaction mixture was filtered (celite) and the solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:6) gave 6.78 g (94%) of (±)-5-(3-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxypropyl)indan-4-ol as a colorless oil. Rf=0.47 (silica, ethyl acetate:hexanes 1:3); Anal. calcd. for C18H30O3Si: C, 67.03; H, 9.38. Found: C, 66.01; H, 9.33.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH:13]([C:16]#[N:17])[CH2:12][CH2:11]1)[C:3](=[O:9])OC(C)(C)C.FC(F)(F)C(O)=O.[N:25]1[O:26][N:27]=[C:28]2[CH:33]=[C:32](C(Cl)=O)[CH:31]=[CH:30][C:29]=12>ClCCl>[C:16]([C@@H:13]1[CH2:12][CH2:11][C@H:10]([N:2]([CH3:1])[C:3]([C:32]2[CH:31]=[CH:30][C:29]3=[N:25][O:26][N:27]=[C:28]3[CH:33]=2)=[O:9])[CH2:15][CH2:14]1)#[N:17]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(C#N)CC1
Reactant: O=C(Cl)c1ccc2nonc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)c1ccc2nonc2c1)[C@H]1CC[C@@H](C#N)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
t-Butyl methyl-(4-cyanocyclohexyl)carbamate (710 mg, 3 mmol) was dissolved in dichloromethane (20 ml) and trifluoroacetic acid (3 ml) was added. The solvent was evaporated after 2 hours, the residue was re-dissolved in a 4N HCl (3 ml) solution in dioxane and the solvent evaporated. Dichloromethane (30 ml) and NEt3 (2 ml) were added to the residue followed by a solution of [2,1,3]-benzoxadiazole-5-carbonylchloride (548 mg, 3 mmol) in dichloromethane (10 ml). After stirring the mixture for 1 hour at room temperature, the organic phase was washed with 1N HCl and conc. NaHCO3 solution, dried over magnesium sulfate, and concentrated under vacuum. The material was purified on a silica gel column eluting with ethyl acetate/chloroform (1:1) to give 170 mg of N-(cis-4-cyanocyclohexyl)-N-methyl-[2,1,3]-benzoxadiazole-5-carboxamide as a white solid and as the less polar isomer. Mp=222-223° C., 1H NMR (300 MHz, CDCl3, rotamers) δ 7.93 (d, 1H, J=9.0 Hz); 7.85 (s, 1H), 7.42 (d, J=9.0 Hz, 1H); 4.65-4.50 and 3.55-3.40 and 3.15-2.80 (m, 5H) and 2.20-1.30 ppm (m, 8H).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)=[O:15])=[CH:6][CH:5]=1.O.Cl.C(O)(C(F)(F)F)=O>C1COCC1.CN1C(=O)CCC1>[CH:3]([C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][N:18]=2)=[O:15])=[CH:6][CH:5]=1)=[O:2]
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1ccc(C(F)(F)F)cn1)CCC2
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=Cc1ccc2c(n1)N(C(=O)Nc1ccc(C(F)(F)F)cn1)CCC2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 7-(dimethoxymethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 1, 64.5 mg, 0.163 mmol) in THF (0.4 ml) at room temperature was treated with water (0.6 ml) and conc. HCl (0.20 ml). After the addition, additional THF (0.2 ml) was added and the reaction mixture was stirred at room temperature for 2.5 h. Subsequently, NMP (0.1 ml) was added followed by TFA (0.10 ml, 1.3 mmol) and the resulting solution was stirred for 2 h. The reaction was then quenched by the addition of sat. aq. NaHCO3 (gas evolution) and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a white solid.
Reaction SMILES: [S:1]1[C:5]([C:6]([C:8]2[CH:13]=[C:12]([Br:14])[C:11]([F:15])=[CH:10][C:9]=2F)=O)=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.O.[NH2:22][NH2:23]>>[S:1]1[C:5]([C:6]2[C:8]3[C:9](=[CH:10][C:11]([F:15])=[C:12]([Br:14])[CH:13]=3)[NH:23][N:22]=2)=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: NN
Reactant: O=C(c1cc2ccccc2s1)c1cc(Br)c(F)cc1F
Solvent: O
Product: Fc1cc2[nH]nc(-c3cc4ccccc4s3)c2cc1Br

Procedure:
A total of 5.7 g of benzo[b]thiophen-2-yl-(5-bromo-2,4-difluorophenyl)methanone obtained in Production Example II-16-a was allowed to react with hydrazine monohydrate by the procedure of Production Example II-10-c and thereby yielded 0.6 g of the title compound as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[F:27][CH:28]([F:38])[CH2:29][O:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34].Cl>C(Cl)Cl.CN(C=O)C>[F:27][CH:28]([F:38])[CH2:29][O:30][C:31]1[CH:32]=[C:33]([NH:34][C:4](=[O:6])[C:3]2[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])[CH:35]=[CH:36][CH:37]=1
Reactant: O=C(O)c1c(F)cccc1[N+](=O)[O-]
Reactant: Nc1cccc(OCC(F)F)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(OCC(F)F)c1)c1c(F)cccc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
Under nitrogen, to 2-fluoro-6-nitrobenzoic acid (1.27 g, 6.28 mmol, 1.00 equiv) in CH2Cl2 (20 mL) at 23° C. was added oxalyl chloride (0.585 mL, 6.91 mmol, 1.10 equiv) and DMF (16 μL, 0.19 mmol, 3.0 mol %). After stirring for 1 hr at 23° C., the reaction mixture was cooled to 0° C. and triethylamine (2.63 mL, 18.8 mmol, 3.00 equiv) and 3-(2,2-difluoroethoxy)aniline (1.09 g, 6.28 mmol, 1.00 equiv) were added. After stirring for 15 min at 0° C., 3N HCl aq (50 mL) was added. The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×3.0 mL). The combined organic phases were washed with brine (3.0 mL) and dried (MgSO4). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc to afford 1.07 g of the title compound (50% yield).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:10]([CH3:23])[CH:9]=1)=[O:6].[NH3:25]>CO>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:25])=[O:2])=[CH:9][C:10]=1[CH3:23]
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)c(C)c1
Reactant: N
Solvent: CO
Product: Cc1cc(NC(=O)CC(N)=O)ccc1OCc1cccc(F)c1
Yield: 60 %

Procedure:
Prepared in analogy to example 3 from N-[4-(3-fluoro-benzyloxy)-3-methyl-phenyl]-malonamic acid methyl ester and 7M ammonia in methanol. Yield=60%. Colorless solid. MS: m/e=317.0 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:14][C@@H:15]([C:20]2[S:21][C:22]([C:25]3[C:33]4[C:28](=[N:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:16][C:17](O)=[O:18])=[O:13])[C:7]1=[O:34].[CH3:39][N:40](C)C=O.CN.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>O1CCCC1>[CH3:39][NH:40][C:17]([CH2:16][C@@H:15]([NH:14][C:12]([C:8]1[C:7](=[O:34])[N:6]([CH2:5][C:4]2[CH:35]=[CH:36][C:37]([F:38])=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:10][CH:9]=1)=[O:13])[C:20]1[S:21][C:22]([C:25]2[C:33]3[C:28](=[N:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)=[CH:23][CH:24]=1)=[O:18]
Reactant: O=C(O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2c[nH]c3ncccc23)s1
Reactant: CN(C)C=O
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CNC(=O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2c[nH]c3ncccc23)s1
Reaction time: 2 h

Procedure:
(R)-3-{[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-3-[5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiophen-2-yl]-propionic acid (0.026 g, 0.000049 mol;) was dissolved in N,N-Dimethylformamide (2 mL, 0.03 mol;) and 2.0 M of Methylamine in Tetrahydrofuran (0.2432 mL) and N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.024 g, 0.000063 mol;) were added. The reaction was checked after 2 hours and it showed that both product and starting material were present. The reaction was pushed by further addition of methylamine and HATU, but the reaction could not be pushed past 60-70 percent completion. The reaction was therefore worked up by concentration then dissolving in methylene chloride and washing 1× with saturated bicarbonate, and 1× with brine before drying with magnesium sulfate and concentration. The crude showed very little starting material left after workup, the acid was most likely removed by the bicarb wash. The crude was dissolved in DMSO and injected onto the Gilson for HPLC purification to give the pure product at 1.20 548.54. ES (+) MS m/e=548.54; NMR (400 MHz, DMSO-d6) δ ppm 2.55 (s, 3H), 2.78 (d, 2H, J=7 Hz), 5.22 (m, 2H), 6.66 (t, 1H, J=8 Hz), 6.97 (d, 1H, J=3 Hz), 7.14-7.21 (m, 3H), 7.38-7.49 (m, 2H), 7.79 (m, 1H), 8.2-8.25 (m, 2H), 8.29 (m, 1H), 8.4 (dd. 1H), 10.25 (d, 1H), 11.97 (s, 1H)
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)C.[CH3:19][NH:20][CH:21]([CH3:23])[CH3:22]>C(#N)C>[CH:21]([N:20]([CH3:19])[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)([CH3:23])[CH3:22]
Reactant: CNC(C)C
Reactant: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Solvent: CC#N
Product: COc1ccc(-c2c(N(C)C(C)C)c(=O)c2=O)cc1
Yield: 63.3 %

Procedure:
In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) and methyl-isopropylamine (0.07 mL, 0.670 mmol) in acetonitrile (3 mL) were converted to the title compound (0.10 g, 63%) m.p.: 109-115° C.; 1H NMR (DMSO-d6) δ 7.60(m,2H), 7.07(m,2H), 4.91(m,1H), 3.81(s,3H), 1.23(br d,6H); MS (m/z) 259 [M+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:34])[CH:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([O:30][CH3:31])[CH:26]=2)[CH2:21]1)=O.COC1C(OC)=CC=C2C=1CCC(NC)C2>C(O)C>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][CH2:13][NH:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:34])[CH:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([O:30][CH3:31])[CH:26]=2)[CH2:21]1
Reactant: COc1cc(N)c(CC(=O)NCCCN(C)C2CCc3cc(OC)c(OC)cc3C2)cc1OC
Agent: CNC1CCc2c(ccc(OC)c2OC)C1
Solvent: CCO
Product: COc1cc(N)c(CCNCCCN(C)C2CCc3cc(OC)c(OC)cc3C2)cc1OC

Procedure:
The title compound of this paragraph is prepared from 1-[2-(2-amino-4,5-dimethoxyphenyl)-1-oxo-ethylamino]-3-[N-methyl-N-(6,7-dimethoxy-1,2,3,4,-tetrahydronaphth-2-yl)-amino]-propane (7.8 g, 0.0165 mol) analogously to Example R(e). Yield: 2.7 g Rf value: 0.2 (alumina, eluant: 95 parts by volume of methylene chloride+5 parts by volume of ethanol).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH:15]([O:19][CH3:20])[CH2:16][CH2:17]Br.[H-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:17][CH2:16][CH:15]([O:19][CH3:20])[CH2:14][CH2:13]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: COC(CCBr)CCBr
Reactant: O=C1CCc2ccc(Br)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Reaction time: 3 h
Yield: 3.9 %

Procedure:
A mixture of 6-bromo-2,3-dihydro-1H-inden-1-one (1.037 g, 4.94 mmol) and 1,5-dibromo-3-methoxypentane (1.2 g, 4.94 mmol) in THF (16 mL) was added NaH (237.12 mg, 60%, 9.88 mmol) at room temperature. The mixture was refluxes for 3 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was dried and concentrated to give the residue, which was purified by column chromatography to give 6′-bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (60 mg, 4%).
Reaction SMILES: C1(S([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[CH:18][C:13]=3[C:12]([CH2:19][C:20]3[CH:21]=[N:22][C:23](S(C)(=O)=O)=[N:24][CH:25]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.CN1CCCC1=O.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][NH2:44].[OH-].[K+]>C(O)(=O)C>[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][NH:44][C:23]1[N:24]=[CH:25][C:20]([CH2:19][C:12]2[C:13]3[CH:18]=[N:17][CH:16]=[N:15][C:14]=3[NH:10][CH:11]=2)=[CH:21][N:22]=1
Reactant: CS(=O)(=O)c1ncc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncncc23)cn1
Reactant: NCc1ccccn1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: c1ccc(CNc2ncc(Cc3c[nH]c4ncncc34)cn2)nc1

Procedure:
In a microwave vial, 7-benzenesulfonyl-5-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (58, 12 mg, 0.028 mmol) was mixed with 600 μL of N-methylpyrrolidone and C-pyridin-2-yl-methylamine (59, 19.5 mg, 0.18 mmol). The reaction was irradiated at 160° C. for 40 minutes in microwave, then potassium hydroxide (500 μL, 4.00 M in water) was added and the reaction irradiated at 90° C. for 10 minutes in microwave. The reaction was neutralized with the addition of 120 μL of acetic acid, solvents were removed under vacuum, and the resulting material was dissolved in 400 μL of dimethylsulfoxide for purification by HPLC. Samples were purified on Phenomenex C18 column (50 mm×10 mm ID) with mobile phase A of 0.1% trifluoroacetic acid in water, mobile phase B of 0.1% trifluoroacetic acid in acetonitrile, 20-100% B over 16 minutes at a flow rate of 6 mL/min. Appropriate fractions were collected and solvents removed under vacuum to provide the desired compound. MS (ESI) [M+H+]+=317.9.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(CC)CC.[N:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:38]=[O:39].C(=O)([O-])O.[Na+]>C1COCC1>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:38]([NH:37][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[O:39])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: CCOC(=O)CN=C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the compound (35 mg) obtained in Example 1 and Et3N (22 μl) in THF (2.0 ml), ethyl isocyanatoacetate (11 mg) was added at 0° C., and the reaction mixture was stirred at room temperature for 3 hours. To the reaction mixture, an aqueous saturated sodium hydrogen carbonate solution was added, and then the product was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and then the solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]2[CH:10]=[CH:9][O:8][C:7]=12>CO>[O:8]1[C:7]2=[CH:2][N:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]2[CH2:10][CH2:9]1
Reactant: O=C(O)c1cc2ccoc2c(Cl)n1
Solvent: CO
Product: O=C(O)c1cc2c(cn1)OCC2
Reaction time: 24 h
Yield: 74 %

Procedure:
C7 (980 mg, 4.98 mmol) is dissolved in 75 mL MeOH containing 500 mg 20% palladium hydroxide on carbon in a 250 mL Parr shaker bottle. The reaction mixture is hydrogenated at 20 PSI for 24 h. The catalyst is removed by filtration and the filtrate is concentrated in vacuo to a white solid. The solid is dissolved in MeOH and is loaded onto 20 mL Dowex 50W-X2 ion exchange resin (hydrogen form) which had been prewashed with MeOH. The column is eluted with 50 mL MeOH followed by 150 mL 5% TEA in MeOH to afford 2,3-dihydrofuro[2,3-c]pyridine-5-carboxylic acid (C8) (74% yield). HRMS (FAB) calculated for C8H7NO3+H: 166.0504, found 166.0498 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12]C)=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]=[CH:7]2.[Cl-].[Al+3].[Cl-].[Cl-].C([O-])(O)=O.[Na+].[BH4-].[Na+].C(N(CC)CC)C.Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>ClC1C=CC=CC=1.CO.C(Cl)Cl>[CH2:36]([O:35][C:33]([N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[C:9]([OH:12])[CH:10]=[CH:11][C:2]=2[Br:1])[CH2:7]1)=[O:34])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc(Br)c2c1C=NCC2
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [BH4-]
Solvent: CO
Solvent: Clc1ccccc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCc2c(Br)ccc(O)c2C1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
A solution of 5-bromo-8-methoxy-3,4-dihydro-isoquinoline (312 mg, 1.3 mmol, 1.0 eq.) in chlorobenzene (18.4 mL) was treated with aluminium chloride (520 mg, 3.9 mmol, 3.0 eq.) and stirred at 130° C. for 1 hour. After cooling to r.t., sat. aq. NaHCO3 soln. was added and the mixture was extracted with AcOEt (2×). The combined org. layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was partially purified by flashmaster (column: 25 g, flow: 30 mL/min, 25 fractions of 30 mL, AcOEt+10% MeOH) to yield a yellow oil. To an ice-cooled solution of the residue in MeOH (13.1 mL), NaBH4 (98 mg, 2.6 mmol, 2.0 eq.) was added. The mixture was stirred at 0° C. for 30 min. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and AcOEt. The layers were separated and the aq. phase was extracted with AcOEt (2×). The comb. org. phases were dried over MgSO4, filtered, and concentrated in vacuo. To an ice-cooled solution of the residue and triethylamine (0.54 mL, 3.9 mmol, 3.0 eq.) in DCM (36 mL), benzyl chloroformate (0.21 mL, 1.43 mmol, 1.1 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the suspension was stirred at r.t. for 4 hours. The reaction was quenched with 1M aq. citric acid soln. (36 mL). The layers were separated. The aq. phase was extracted with DCM (3×). The comb. org. phases were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flashmaster (column: 25 g, flow: 30 mL/min, 27 fractions of 30 mL, Heptane 100% to Heptane+20% AcOEt). The residue was dissolved in THF (5 mL) and 1M aq. NaOH soln. (5 mL) was added. The mixture was stirred at r.t. for 18 hours. The org. solvent was removed in vacuo. The resulting aq. layer was acidified with 2N aq. HCl soln. and extracted with DCM (3×10 ml). The comb. org. phases were dried over MgSO4 and concentrated in vacuo to give the title compound as a beige solid.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:10]([C:13]1[O:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=O)[CH3:11].N1C=CC=CC=1.ClCCl>O1CCCC1.Cl[Ti](Cl)(Cl)Cl.O>[CH3:6][O:5][C:3](=[O:4])[C:2](=[C:10]([C:13]1[O:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[CH3:11])[C:1]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CC(=O)OC
Reactant: CC(=O)c1ccc(C)o1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(C(=O)OC)=C(C)c1ccc(C)o1
Reaction time: 18 h
Yield: 31.7 %

Procedure:
Step A To a solution of dimethyl malonate (6.5 g, 49 mmol), 2-acetyl-5-methylfuran (6.1 g, 49 mmol) and pyridine (16 g, 200 mmol) in anhydrous tetrahydrofuran (300 mL) at 0° C. was added a dichloromethane solution (1 M) of TiCl4 (100 mL, 100 mmol) during a period of 1 h. After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 18 h. Water was added to quench the reaction. The mixture was extracted with ethyl ether. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:10) to give 2-[1-(5-methyl-furan-2-yl)-ethylidene]-malonic acid dimethyl ester as a yellow oil (3.7 g, 32%).