Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25]([OH:27])=O)(=[O:3])[NH2:2].[O:28]1[CH2:32][CH2:31][CH:30]([CH2:33][NH2:34])[CH2:29]1>>[F:17][C:15]1[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])=[CH:13][C:12]2[C:6]3[N:7]([C:24]([C:25]([NH:34][CH2:33][CH:30]4[CH2:31][CH2:32][O:28][CH2:29]4)=[O:27])=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: NCC1CCOC1
Reactant: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O
Product: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)NCC1CCOC1

Procedure:
2-Carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.05 g) was reacted with (tetrahydrofuran-3-yl)methanamine similar to as described in Example 2 to afford 6.2 mg of (±) 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-(tetrahydrofuran-3-ylmethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 457 (M)+. 1H NMR (400 MHz, DMSO) δ 11.33 (t, J=5.4 Hz, 1H), 8.61 (d, J=8.5 Hz, 1H), 8.38 (s, 1H), 7.89 (s, 1H), 7.01 (d, J=10.6 Hz, 1H), 5.47 (s, 1H), 5.06-4.94 (m, 2H), 4.60-4.44 (m, 2H), 3.81-3.71 (m, 2H), 3.63 (dd, J=15.2, 7.7 Hz, 1H), 3.44 (dd, J=8.6, 5.9 Hz, 1H), 2.48-2.37 (m, 1H), 2.04-1.92 (m, 1H), 1.68-1.54 (m, 1H), 1.49 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[CH2:11]([O:13][C:14]([C:16]1([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH2:20][CH2:19][NH:18][CH2:17]1)=[O:15])[CH3:12]>>[CH2:11]([O:13][C:14]([C:16]1([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[CH2:20][CH2:19][N:18]([C:9](=[O:10])[NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:17]1)=[O:15])[CH3:12]
Reactant: O=C=Nc1ccccc1F
Reactant: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCNC1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)Nc2ccccc2F)C1

Procedure:
The title compound was prepared according to the method described for Preparation 71 using 2-fluoro phenyl isocyanate and 3-(4′-fluoro-biphenyl-4-yloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 65) to afford the racemate as a colourless liquid (230 mg, 82%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=1F)=O.O.[NH2:25][NH2:26]>CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:13]2[C:14](=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=2)[NH:26][N:25]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2F)c(OC)c1
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)c(OC)c1
Yield: 37.2 %

Procedure:
Prepared according to Method D Step A from (2,4-dimethoxyphenyl)[2-fluoro-3-(trifluoromethyl)phenyl]methanone (1.50 g, 5.17 mmol), hydrazine hydrate (1.61 mL, 51.7 mmol) and DMAP (0.632 g, 5.17 mmol) to give the product (0.619 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:11]([CH3:16])[C:12]([SH:15])=[N:13][CH:14]=2)[OH:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>CC(C)=O.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]2[N:11]([CH3:16])[C:12]([S:15][CH2:24][CH2:25][CH2:26][Cl:27])=[N:13][CH:14]=2)[OH:9])=[CH:6][CH:7]=1
Reactant: Cn1c(C(O)c2ccc(Cl)cc2)cnc1S
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(C(O)c2ccc(Cl)cc2)cnc1SCCCCl
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
The product of Example I, Step A (0.09 g) in acetone (2 mL) and DMF (2 mL) was treated with K2CO3 (0.2 g) followed by 1-bromo-3-chloropropane (0.11 g). The mixture was allowed to stir at rt for 16 h and was then partitioned between EtOAc (50 mL) and brine (50 mL). The organic layer was separated and washed with brine (2×200 mL), dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by silica gel chromatography using 2-5% MeOH/CH2Cl2 as the eluent to provide (4-Chloro-phenyl)-[2-(3-chloro-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanol (0.08 g, 69%); M calc=330; M+H found=331.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[NH2:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][C@H:18]([OH:22])[CH2:17]1.CCN(C(C)C)C(C)C>C(O)C>[OH:22][C@H:18]1[CH2:19][CH2:20][CH2:21][C@@H:16]([NH:15][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=2)[CH2:17]1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: N[C@@H]1CCC[C@H](O)C1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(SC)nc1N[C@@H]1CCC[C@H](O)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (4.38 g, 18.82 mmol) and (1S,3R)-3-aminocyclohexanol (2.276 g, 19.76 mmol; prepared as described in Tetrahedron: Asymmetry 15:2051-2056 (2004)) were dissolved in ethanol (75 mL) before adding DIEA (4.93 ml, 28.2 mmol) and heating to 60° C. After 2 hrs, LCMS showed the desired product mass was the dominant peak formed. The reaction was removed from heat and concentrated. The crude material was purified on a 340G SNAP Biotage column (20-100% ethyl acetate in hexane) to give ethyl 4-((1R,3S)-3-hydroxy-cyclohexylamino)-2-(methylthio)pyrimidine-5-carboxylate (5 g, 16.06 mmol, 85% yield) as a white foam; MS (ESI) m/z 312.1 [M+1]+
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([C:16](=[O:26])[C:17]1[CH:22]=[C:21]([F:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=1)[CH2:13][CH2:14][CH3:15])=O)(C)(C)C>Cl>[Cl:25][C:19]1[CH:18]=[C:17]([C:16]([C:9]2([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:26])[CH:22]=[C:21]([F:23])[C:20]=1[Cl:24]
Reactant: CCCC1(C(=O)c2cc(F)c(Cl)c(Cl)c2)CCCN1C(=O)OC(C)(C)C
Agent: Cl
Product: CCCC1(C(=O)c2cc(F)c(Cl)c(Cl)c2)CCCN1
Yield: 112.9 %

Procedure:
A solution of 2-(3,4-dichloro-5-fluoro-benzoyl)-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.346 g, 0.856 mmol) in 1N methanolic HCl (8.6 mL) was stirred at ambient temperature under nitrogen for 15 hours. The reaction mixture was concentrated in vacuo then redissolved in DCM and re-concentrated in vacuo to remove excess HCl, furnishing (3,4-dichloro-5-fluoro-phenyl)-(2-propyl-pyrrolidin-2-yl)-methanone (0.294 g, quantitative yield) as a white powder, MS=304 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClC[C:45]1[N:49](C)[N:48]=[C:47]([CH3:51])[N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[N:49]([CH3:45])[N:48]=[C:47]([CH3:51])[N:46]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Cc1nc(CCl)n(C)n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cc1nc(Cn2nc3nc(C(C)(C)C)nc(N4CCC(F)(F)C4)c3n2)n(C)n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole and isolated as light yellow gum. MS (m/e): 392.3 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([F:28])[C:25]([CH3:29])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([F:28])[C:25]([CH3:29])=[CH:24][C:23]=2[C:2]2[C:3]3[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)c(OCC2CC2)cc1F
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C)c(F)cc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-(2-cyclopropylmethoxy-4-fluoro-5-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c11) the title compound is obtained as pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](OC(N1CCC(OS(C2C=CC(C)=CC=2)(=O)=O)CC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[CH3:18])[CH2:9][CH2:19]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: C[C@@H]1CCCN1[C@H]1CCN(C(=O)OC(C)(C)C)C1
Product: C[C@H]1CCCN1C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared in a manner substantially the same as intermediate (2R,3′S)-2-Methyl-[1,3′]bipyrrolidinyl-1′-carboxylic acid tert-butyl ester by condensing 4-(Toluene-4-sulfonyloxy)-piperidine-1-carboxylic acid tert-butyl ester with (S)-(−)-2-methylpiperindine to get 2.60 g (97% yield) of the product as a pale yellow oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([CH:18]([S:31][C:32]2[NH:36][N:35]=[N:34][N:33]=2)[N:19]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[S:20]2(=[O:22])=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)Cl>CCOCC>[C:12]1([CH:18]([S:31]([C:32]2[NH:36][N:35]=[N:34][N:33]=2)=[O:9])[N:19]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[S:20]2(=[O:22])=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1c2ccccc2S(=O)(=O)N1C(Sc1nnn[nH]1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1c2ccccc2S(=O)(=O)N1C(c1ccccc1)S(=O)c1nnn[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 199.3 %

Procedure:
A mixture of m-chloroperbenzoic acid (0.43 g, 9,.67 mmol) and 2-(1-phenyl-1H-tetrazol-5-ylthiomethyl) saccharin (1 g, 2.67 mmol) in MDC was stirred at room temperature for 24 hours. TLC (95:5 CH2Cl2 : ether) revealed the presence of starting sulfide. Additional peracid (0.2 g) was added and the mixture stirred for an additional 2 days. The reaction mixture was washed with sodium bicarbonate solution, dried (Na2SO4) and freed of solvent under vacuum. Chromatography (silica gel-95:5 CH2Cl2 :ether) afforded a foam that was crystallized from ether to afford 0.52 g of 2-(1-phenyl-1H-tetrazol-5-ylsulfinylmethyl) saccharin as a white solid, mp 161°-162° C. 1H nmr (90 MHz, CDCl3):5.5-6.0 (2H, q). FDMS: m/e 196 (M+ -PMT), 389 (M+).
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[CH3:10][C:11]1[NH:12][C:13](C)=[C:14]([C:29]([O:31][CH3:32])=[O:30])[CH:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[C:16]=1[C:17]([O:19][CH3:20])=[O:18].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:10][C:11]1[NH:12][C:13]2[CH2:32][O:31][C:29](=[O:30])[C:14]=2[CH:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1OC
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
In a manner similar to that described in the preceding examples, 1.45 grams of 80 percent pyridinium bromide perbromide was added to a cooled to 0° C. solution of 1.00 gram (3.02 millimoles) of dimethyl 2,6-dimethyl-4(2-methoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 0.40 milliliter of pyridine in 20 milliliters of chloroform. The mixture was then stirred at 0° C. for about 30 minutes and at reflux temperature for about 90 minutes. Thereafter the mixture was allowed to cool, diluted with chloroform, washed with 2N hydrochloric acid and brine, dried and the solvent evaporated to obtain a crude product residue. The latter was flash chromatographed on 35 grams of silica gel to obtain 510 milligrams (54 percent yield) of purified methyl 2-methyl-4-(2-methoxyphenyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate product. A portion of the product was recrystallized from ethyl acetate-hexane for elemental analyses which were as follows:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9](F)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[N:10]1[CH:2]=[C:3]2[C:7]([N:6]=[CH:5][NH:4]2)=[N:8][CH:9]=1
Reactant: Fc1nc(Cl)c2nc[nH]c2n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ncc2[nH]cnc2n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To the dried resin (0.29 mmol) was added a homogeneous suspension of 6-chloro-2-fluoro-9H-purine (0.50 g, 2.9 mmol) and triphenylphosphine (0.38 g, 1.44 mmol) in 1.75 mL of THF. The RV was cooled to 0° C. (Julabo chiller) and then added, under an atmosphere of N2, 2.0 mL (1.44 mmol) of a 0.72M solution of DEAD (diethyl azodicarboxylate) in THF. The resin mixture was warmed, while agitating, to ambient temperature over 1.5 h and then agitated for an additional 22 h, upon which the RV was drained and the resin washed successively with THF (5×5.0 mL), DMA (5×5.0 mL), CH2Cl2 (5×5.0 mL), Et2O (2×5.0 mL), CH2Cl2 (1×5.0 mL), Et2O (1×5.0 mL), and CH2Cl2 (2×5.0 mL). Excess solvent was removed via N2 flow overnight to provide the purine resin 1b. The following analytical data was obtained upon cleavage of 1b (3–5 mg) with 30% TFA/CH2Cl2 (˜5 min): 65% HPLC purity, ˜5:1 major/minor peaks (no apparent 3-hydroxyphenethyl alcohol HPLC peak).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10]([OH:12])=[O:11])=[C:4]([O:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[C:25]3C=C(C4OC(C(O)=O)=CN=4)O[C:24]3=[CH:23][C:22]=2[N:38]([CH2:43][C:44]([OH:46])=[O:45])[CH2:39][C:40]([OH:42])=[O:41])[CH:3]=1.[H][H]>C(O)(=O)C.[Pd]>[CH:7]1[CH:2]=[CH:3][C:4]([O:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:38]([CH2:43][C:44]([OH:46])=[O:45])[CH2:39][C:40]([OH:42])=[O:41])=[C:5]([N:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10]([OH:12])=[O:11])[CH:6]=1
Reactant: [H][H]
Reactant: Cc1ccc(N(CC(=O)O)CC(=O)O)c(OCCOc2cc3cc(-c4ncc(C(=O)O)o4)oc3cc2N(CC(=O)O)CC(=O)O)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)CN(CC(=O)O)c1ccccc1OCCOc1ccccc1N(CC(=O)O)CC(=O)O

Procedure:
Synthesis of a BAPTA tetramethyl ester that contains a phenolic reactive group (Compound XXV). A hydroxy derivative of BAPTA (4-hydroxy-BAPTA) is synthesized by hydrogenation of one of the key intermediate in the synthesis of the Ca2+ indicator fura-2 [U.S. Pat. No. 4,603,209]. For instance 9.8 g of 4-benzyloxy-5'-methyl BAPTA tetramethyl ester is hydrogenated in 50 mL glacial acetic acid in the presence of 0.3 g 10% palladium on charcoal at 40 psi hydrogen pressure for four hours. The reaction is filtered through a pad of Celite to remove the catalyst and the yellow filtrate is evaporated under reduced pressure to give a light brown oil. This is triturated with 50 mL methanol to yield 7.2 g of 4-hydroxy BAPTA tetramethyl ester as a colorless solid (Compound XXV).
Reaction SMILES: [CH2:1]([C:3]1[C:11]([N:12]([CH2:18][CH2:19][CH2:20][F:21])C(=O)COC)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C.CCCCCC>C1COCC1>[CH2:1]([C:3]1[C:11]([NH:12][CH2:18][CH2:19][CH2:20][F:21])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2ccccc2c1N(CCCF)C(=O)COC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1nn2ccccc2c1NCCCF
Temperature: 25 °C
Reaction time: 3.25 h

Procedure:
A solution of N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-(3-fluoropropyl)-2-methoxyacetamide (1.00 g, 3.39 mmol) in THF (12 mL) was added to a slurry of LAH (1.05 g, 27.7 mmol) in THF (6 mL) and the reaction was stirred at room temperature for 3.25 hours. The reaction was cooled to 0° C. and quenched with water (1 mL), 15% NaOH (3 mL) and water (3 mL). The mixture was filtered through diatomaceous earth and the filtrate was extracted with CH2Cl2, dried over MgSO4 and concentrated in vacuo to give a brown oil which was subjected to column chromatography (50% ethyl acetate/hexane) to give 0.568 g (75%) of yellow oil as the title compound: 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J=7.0 Hz, 1H), 7.49 (d, J=9.0 Hz, 1H), 6.98–6.94 (m, 1H), 6.63–6.60 (m, 1H), 4.52 (dt, J=47.5, 5.9 Hz, 2H), 4.10 (br, 1H), 3.04 (t, J=6.9 Hz, 2H), 2.70 (q, J=7.6 Hz, 2H), 1.89–1.76 (m, 2H), 1.24 (t, J=7.6 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ 148.8, 133.1, 128.1, 120.7, 118.5, 116.0, 110.1, 81.1 (d, J=160.6 Hz), 45.6 (d, J=5.2 Hz), 30.8 (d, J=19.2 Hz), 18.6, 13.4; 19F NMR (376 MHz, DMSO-d6) −219.0 (m); HRMS (FAB) calcd for C12H16FN3+H 222.1406. found 222.1403.
Reaction SMILES: C(C1C=CC=C(C(C)C)C=1N=[C:14]=[O:15])(C)C.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]2([C:29]([NH2:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:17]=1>C1(C)C=CC=CC=1>[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[C:23]3([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:29](=[O:30])[NH:31][C:14]2=[O:15])[CH:17]=1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: NC(=O)C1(Nc2cccnc2)CCCCC1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C2(CCCCC2)N1c1cccnc1
Temperature: 200 °C
Reaction time: 0.5 h

Procedure:
150 μl (0.71 mmol, 1.2 eq.) of 2,6-diisopropylphenylisocyanate are added to a solution of 130 mg (0.59 mmol, 1 eq.) of 1-(pyridin-3-ylamino)-cyclohexanecarboxylic acid amide in 5 ml of toluene. The reaction medium is stirred at 200° C. for 1 hour 30 minutes under microwave irradiation. The toluene is evaporated off and the residue is purified on silica gel (heptane and then with an increasing percentage of ethyl acetate). 1-Pyridin-3-yl-1,3-diaza-spiro[4.5]decane-2,4-dione is obtained in the form of a white solid. Melting point=264-266° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:19]=2)[NH:16][C:15]([C:27](O)=[O:28])=[CH:14]3)=[CH:6][CH:5]=1.O.O[N:32]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N>CN(C)C=O.O>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH:19]=2)[NH:16][C:15]([C:27]([NH2:32])=[O:28])=[CH:14]3)=[CH:6][CH:5]=1
Reactant: On1nnc2ccccc21
Reactant: COCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(=O)O)cc3c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: COCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=O)cc3c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 136.2 %

Procedure:
To a solution of 5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carboxylic acid (2.2 g) in N,N-dimethylformamide (20 mL) were added 1-hydroxybenzotriazole monohydrate (1.27 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.6 g) and 25% aqueous ammonia (10 mL) and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was crystallized from diethyl ether to give the title compound (2.99 g, yield 45%) as white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Mg].II.[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[Cl:23])[NH:19][C:18](=[O:24])[C:17]2=[O:25]>CCOCC.C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[Cl:23])[NH:19][C:18](=[O:24])[C:17]2([OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: COc1ccccc1Br
Reactant: O=C1Nc2cc(Cl)c(Cl)cc2C1=O
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccccc1C1(O)C(=O)Nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Yield: 74 %

Procedure:
5.57 g of 1-bromo-2-methoxybenzene are added dropwise to a suspension of 0.72 g of magnesium in 15 ml of ether containing a few crystals of iodine, the reflux being maintained once it has started. At the end of the addition, the mixture is refluxed for 2 hours. A suspension of 2.7 g of 5,6-dichloro-1H-indole-2,3-dione in 30 ml of THF is then added and the mixture is refluxed for 30 minutes. After cooling to RT, the reaction mixture is poured into a water/ice/-concentrated HCl mixture and extracted with EtOAc, the organic phase is dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is slurried in hot iso ether and the precipitate formed is spin-filtered off and washed with ether. 3 g of the expected product are obtained.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([OH:8])=O.C(Cl)Cl.[N:12]1([C:18]([C@H:20]2[CH2:25][CH2:24][C@H:23]([CH2:26][N:27]3[C:36](=[O:37])[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:38])[CH2:22][CH2:21]2)=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([N:15]1[CH2:16][CH2:17][N:12]([C:18]([CH:20]2[CH2:25][CH2:24][CH:23]([CH2:26][N:27]3[C:36](=[O:37])[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:38])[CH2:22][CH2:21]2)=[O:19])[CH2:13][CH2:14]1)=[O:8]
Reactant: O=c1[nH]c2ccccc2c(=O)n1C[C@H]1CC[C@H](C(=O)N2CCNCC2)CC1
Reactant: O=C(O)C1CCCO1
Solvent: ClCCl
Product: O=C(C1CCC(Cn2c(=O)[nH]c3ccccc3c2=O)CC1)N1CCN(C(=O)C2CCCO2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 55.3 %

Procedure:
To a suspension of tetrahydro-2-furoic acid (38 mg, 0.32 mmol) in DCM (3 mL) 1,1-carbonyldiimidazole (52 mg, 0.32 mmol) was added and the mixture was stirred for 6 hours at room temperature. Then 3-[trans-4-(piperazine-1-carbonyl)-cyclohexylmethyl]-1H-quinazoline-2,4-dione (100 mg, 0.27 mmol) was added and the reaction left stirring for 18 hours. The mixture was washed with 0.4 M Na2CO3 solution and the organic phase collected and concentrated under reduced pressure. The crude was purified by silica column eluting with DCM:MeOH (98:2). 70 mg of the titled compound were obtained (yield 55%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH:10]=[C:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>C(Cl)(Cl)Cl>[CH3:13][C:11]1([CH3:12])[C:4]2[C:5](=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[NH:8][C:9](=[O:14])[CH2:10]1
Reactant: CC(C)=CC(=O)Nc1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(=O)Nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
9.4 g (48.7 mmol) of 3-methyl-2-butenoic acid-(4-fluorophenyl)amide is heated to 130-140° C. and mixed in portions with 9.6 g (73.5 mmol) of aluminum trichloride. After the addition is completed, the temperature is kept at 80° C. for 30 more minutes. It is allowed to cool to room temperature and carefully treated with 60 ml of ice water. After 150 ml of chloroform is added, the batch is stirred for 15 minutes, acidified with dilute hydrochloric acid and extracted with chloroform (3×150 ml). The combined organic extracts are washed with saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with hexane-ethyl acetate yields 6.0 g.