Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].[CH:19]12[O:27][CH:23]([CH2:24][NH:25][CH2:26]1)[CH2:22][N:21]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=1)[CH2:20]2>CN(C=O)C>[C:36]([C:35]1[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][N:21]2[CH2:22][CH:23]3[O:27][CH:19]([CH2:26][N:25]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:24]3)[CH2:20]2)=[CH:39][CH:38]=1)#[N:37]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: N#Cc1ccc(CCCCN2CC3CNCC(C2)O3)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCN1CC2CN(CCCCc3ccc(C#N)cc3)CC(C1)O2
Temperature: 54 °C
Reaction time: 24 h

Procedure:
Triethylamine (2.2 mL, 0.016 mol) and tert-butyl 2-bromoethylcarbamate (see Preparation R above, 2.83 g, 0.013 mol) were added to a solution of 4-[4-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)butyl]benzonitrile (see Preparation G above, 3.0 g, 0.011 mol) in DMF (50 mL). The mixture was stirred for 24 h at 54° C., cooled to 25° C., and concentrated in vacuo. The residue was dissolved in chloroform and washed with saturated sodium chloride. The aqueous layer was separated and extracted with chloroform (2×150 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resulting material was chromatographed on silica gel, eluting first with chloroform:acetonitrile:conc. ammonium hydroxide (9:1:0.02) until the higher Rf impurities were removed. Then the eluent was switched to chloroform:methanol:conc. ammonium hydroxide (9:1:0.02). This afforded 2.76 g (61%) of the title compound.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]([O:16]CC)=[O:15])[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[C:14]([CH2:13][N:10]1[CH2:11][CH2:12][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:19])([OH:16])=[O:15]
Reactant: CCOC(=O)CN1CCC(Cc2ccccc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CN1CCC(Cc2ccccc2)C1=O

Procedure:
A mixture of 3-benzyl-1-(ethoxycarbonylmethyl)-2-pyrrolidinone (Method 5; 0.70 g, 2.68 mmol) and 2 M NaOH (4 ml) was stirred in ethanol (10 ml) for 24 hours. The mixture was evaporated in vacuo and the residue acidified. The product was collected by filtration and dried under high vacuum. NMR (90 MHz, CDCl3) 7.9 (s, 1H), 7.2 (in, 5H), 4.1 (d, 1H), 3.3 (m, 2H), 2.25 (m, 2H), 2.3-1.6 (m, 4H).
Reaction SMILES: [NH2:1][C:2]12[CH2:12][CH2:11][CH:8]([CH:9]=[CH:10]1)[CH:7]1[CH:3]2[C:4](=O)[NH:5][C:6]1=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCOCC1>[NH2:1][C:2]12[CH2:12][CH2:11][CH:8]([CH:9]=[CH:10]1)[CH:7]1[CH:3]2[CH2:4][NH:5][CH2:6]1
Reactant: NC12C=CC(CC1)C1C(=O)NC(=O)C12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: NC12C=CC(CC1)C1CNCC12

Procedure:
45 g (0.234 mol) of 1-amino-4-azatricyclo[5.2.2.02,6 ]undec-8-ene-3,5-dione are reduced with 24 g of LiAlH4 in 500 ml of absolute dioxane as under Z 1-B and the mixture is worked up accordingly.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].[F:9][C:10]([Si](C)(C)C)([F:12])[F:11].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.[OH-].[Na+]>[OH:8][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:10]([F:12])([F:11])[F:9]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccccn1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a stirred solution of 2-pyridine carboxaldehyde (2.09 g, 19.5 mmol) and (trifluoromethyl)trimethylsilane (3.33 g, 23.4 mmol) in THF (30 mL) at 0° C. add 1M tetrabutylammonium fluoride in THF (956 μl, 0.956 mmol). Continue stirring for 30 min at 0° C. and then at ambient temperature for 2 h. Add 1M aqueous HCl (20 mL) and stir 2 h at ambient temperature. Dilute with aqueous 1M aqueous NaOH to pH 8, extract the mixture three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography eluting with hexane/EtOAc (8:2) to give the desired intermediate as a yellow oil (3.22 g, 93%).
Reaction SMILES: [Cl:1][CH2:2][C@H:3]([OH:12])[CH2:4][C:5]#[C:6][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9]>N1C2C(=CC=CC=2)C=CC=1.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCO>[Cl:1][CH2:2][C@H:3]([OH:12])[CH2:4]/[CH:5]=[CH:6]\[CH2:7][Si:8]([CH3:9])([CH3:10])[CH3:11]
Reactant: C[Si](C)(C)CC#CC[C@@H](O)CCl
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: CCO
Product: C[Si](C)(C)C/C=C\C[C@@H](O)CCl
Yield: 98.5 %

Procedure:
13.04 g (63.7 mmol) of (R)-1-Chloro-6-trimethylsilanyl-hex-4-yn-2-ol was dissolved in 260 ml of abs. EtOH and hydrogenated, in the presence of 9 drops of quinoline, over 1.70 g of Lindlar catalyst at ambient temperature and 1 atm of H2. The progress of the reaction was followed by GC. After 2 h the reaction mixture was filtered and the solvent removed i.V. Short flash chromatography (SiO2, hexane/AcOEt=85/15) afforded 12.97 g of (Z)-(R)-1-chloro-6-trimethylsilanyl-hex-4-en-2-ol as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:33]([OH:35])=[O:34])[C:10]([S:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:38](=O)([O-])O.[K+]>CN(C)C=O>[CH3:38][O:34][C:33](=[O:35])[C@@H:9]([C:10]([S:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([CH3:12])[CH3:11])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C([O-])O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 14 h
Yield: 97.2 %

Procedure:
To the solution of N-t-butoxycarbonyl-S-trityl-D-penicillamine (A-2) (6.0 g) in dimethylformamide (40 ml), were added methyl iodide (1.5 ml) and potassium hydrogencarbonate (2.4 g), and the mixture was stirred for 14 hours. To the reaction mixture was added ice-water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated saline, and dried over magnesium sulfate. The solvent was evaporated off under reduced pressure, to give N-t-butoxycarbonyl-S-trityl-D-penicillamine methyl ester (6.0 g).
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:10]1[C:32]([CH3:33])=[CH:31][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH3:30])[CH:28]=4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)(=O)C(C)(C)C.[OH-].[Na+]>C1COCC1.CO>[C:42]([O:41][C@@H:9]([C:10]1[C:32]([CH3:33])=[CH:31][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH3:30])[CH:28]=4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[CH2:8][OH:7])([CH3:45])([CH3:43])[CH3:44]
Reactant: COc1cncc(-c2cc(-c3nc4cc(C)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(-c5ccc(Cl)cc5)c4s3)ccn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cncc(-c2cc(-c3nc4cc(C)c([C@@H](CO)OC(C)(C)C)c(-c5ccc(Cl)cc5)c4s3)ccn2)c1
Temperature: 40 °C

Procedure:
To a solution of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(5′-methoxy-2,3′-bipyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)ethyl pivalate (40.5 mg, 0.063 mmol) in THF (0.5 mL) and methanol (0.5 mL) was added NaOH (0.5 mL, 2N solution). The reaction mixture was heated at 40° C. for 4 h, cooled, diluted with satd. aqueous NH4Cl, and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product which was used without further purification. LCMS-ESI+: calc'd for C31H31ClN3O3S: 560.2 (M+H+); Found: 560.0 (M+H+).
Reaction SMILES: N#N.C([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=C.[C:14](OCC=C)(=O)[C:15](C)=C.C(O)(=O)C1C=CC=CC=1.C(OC(=O)C(C)=C)CCCCCCCCCCC>C(OC(=O)C)C.O1CCCC1>[CH:14]([C:7]1[CH:6]=[CH:5][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[CH2:15]
Reactant: C=CCOC(=O)C(=C)C
Reactant: C=Cc1ccc(C(=O)O)cc1
Agent: C=C(C)C(=O)OCCCCCCCCCCCC
Agent: N#N
Agent: O=C(O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=Cc1ccccc1C(=O)O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Into a 500 ml. 2-necked flask fitted with a thermometer, and a reflux condenser connected to a N2 source, was introduced a mixture of 3.5 g of 4-vinylbenzoic acid (Aldrich Chemical Co. , 3 g of allyl methacrylate, 150 ml tetrahydrofuran and 150 ml ethylacetate. The mixture was stirred to dissolve the benzoic acid compound. Next was added 93.5 g of laurylmethacrylate. The flask was purged with N2 and heated at 70° C. for 10 minutes. The flask was purged again with N2 and 1 g of 2,2-azobisisobutyronitrile (AIBN) was added all at once and heated at 70° C. under a N2 blanket. This was continued for a period of 8 hours. The resulting polymeric solution was cooled to room temperature and diluted with twice its volume with Isopar™ G and filtered to remove insoluble materials (About 125 mg of homopolymer of VBA acid remained on the filter paper). The clear filtered polymeric solution was further diluted with Isopar™ G to 4.1 liters and was subjected to distillation under reduced pressure until about 500 ml of the distillate was collected in the receiving flask. The distillate was mainly ethylacetate, tetrahydrofuran and Isopar™ G).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[CH3:20][C:21]1[CH:26]=[CH:25][NH:24][C:23](=[O:27])[N:22]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[C:4]=2[CH2:3][N:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[N:22][C:23]2=[O:27])=[CH:14][CH:15]=1
Reactant: Cc1cc[nH]c(=O)n1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Cc1ccnc(O)n1
Agent: Cl
Product: Cc1ccn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c(=O)n1

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 91 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and 4-methylpyrimidin-2(1H)-one or 4-methylpyrimidin-2-ol. m/e+ 351 for C19H16ClN40 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:17]([C:18]([OH:20])=[O:19])[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:29][C:30]([C:32]1[CH:33]=[CH:34][C:35]2[C:39]3[CH:40]=[CH:41][C:42]([Br:44])=[CH:43][C:38]=3[O:37][C:36]=2[CH:45]=1)=[O:31]>C(#N)C.CN(C=O)C>[Br:44][C:42]1[CH:41]=[CH:40][C:39]2[C:35]3[CH:34]=[CH:33][C:32]([C:30](=[O:31])[CH2:29][O:19][C:18]([CH:17]4[CH2:16][C:13]5([CH2:14][CH2:15]5)[CH2:12][N:11]4[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])=[O:20])=[CH:45][C:36]=3[O:37][C:38]=2[CH:43]=1
Reactant: O=C(O)C1CC2(CC2)CN1C(=O)OCc1ccccc1
Reactant: O=C(CBr)c1ccc2c(c1)oc1cc(Br)ccc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(COC(=O)C1CC2(CC2)CN1C(=O)OCc1ccccc1)c1ccc2c(c1)oc1cc(Br)ccc12
Reaction time: 12 h
Yield: 95.7 %

Procedure:
To the solution of (s) 5-aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester (138 mg, 0.5 mmol) and triethylamine (65 μl, 0.47 mmol) in acetonitrile (3 ml) was added slowly a solution of 2-bromo-1-(7-bromo-dibenzofuran-3-yl)-ethanone (143 mg, 0.39 mmol) in DMF (4 ml). The mixture was stirred for 12 hours, and the solvent was evaporated. The mixture was diluted with EtOAc, and washed with 1.0 N NaOH solution, water and brine, and was dried with sodium sulfate. Concentration gave 5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester 6-[2-(7-bromo-dibenzofuran-3-yl)-2-oxo-ethyl]ester (210 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]=[C:34]=[O:35])[C:28]=1[CH3:36].CCN(CC)CC>ClCCCl>[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:35])[C:28]=1[CH3:36]
Reactant: COC(=O)c1cccc(N=C=O)c1C
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c1C

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (example 9.1) was reacted with 3-isocyanato-2-methyl-benzoic acid methyl ester ([480-439-28-9]) in 1,2-dichloroethane in the presence of Et3N (1.4 eq.) for 3 days under reflux conditions to give the title compound as yellow oil. MS: m/e=517.2 [M+H+].
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:22])[CH2:15][CH2:16][C@H:17]([CH3:21])[CH2:18][CH2:19][CH3:20].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:33]([O:37][C:38](=[O:41])[CH2:39]Br)([CH3:36])([CH3:35])[CH3:34].[Cl-].[NH4+]>C1COCC1>[C:33]([O:37][C:38](=[O:41])[CH2:39][C@@H:15]([C:14]([N:3]1[C@H:2]([CH3:1])[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4]1=[O:13])=[O:22])[CH2:16][C@H:17]([CH3:21])[CH2:18][CH2:19][CH3:20])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCC[C@@H](C)CCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Temperature: -50 °C
Reaction time: 4 h
Yield: 71.8 %

Procedure:
To oxazolidinone 100 (12.1 g, 0.04 mol) in THF (200 ml) at −50° C. was added NaHMDS (48 mL of a 1 M solution in THF). After 30 t-butylbromoaceate (15.6 g, 0.08 mol) was added. The solution was stirred for 4 hours at −50° C. and then warmed to room temperature. After 16 hours a saturated aqueous solution of ammonium chloride was added and the two layers separated. The aqueous phase was extracted with ether and the combined organic phases dried (MgSO4) and concentrated. Flash chromatography (9:1 hexane/EtOAc) gave the product 101 as a white solid 12 g; 72%. [α]D=30.2 (c 1 in CHCl3). 13C NMR (100 MHz; CDCl3) 176.47, 171.24, 152.72, 133.63, 128.87, 125.86, 80.85, 78.88, 55.34, 39.98, 38.77, 38.15, 37.58, 30.60, 28.23, 20.38, 20.13, 14.50, 14.28.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[Cl:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[C:35]([C:40](O)=[O:41])[C:34]1=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[C:35]([C:40]([NH:1][C:2]2[CH:23]=[CH:22][C:5]([O:6][C:7]3[CH:8]=[CH:9][C:10]4[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]5[CH2:21][CH2:20]5)=[O:18])[N:15]=4)[CH:12]=3)=[C:4]([F:24])[CH:3]=2)=[O:41])[C:34]1=[O:43]
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1Cl
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.3 %

Procedure:
A mixture of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.459 mmol), 1-(2-chloro-4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (168 mg, 0.597 mmol), HATU (262 mg, 0.689 mmol), N,N-diisopropylethylamine (160 μL, 0.919 mmol) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 18 hr. After dilution with ethyl acetate, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, 30 g, ethyl acetate/hexane=2/98→100/0), silica gel column chromatography (30 g, ethyl acetate/hexane=0/100→100/0) and preparative HPLC (acetonitrile/water=40/60→50/50, containing 0.1% trifluoroacetic acid) to give the title compound (101 mg, 37%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:60][C:61]1[CH:62]=[C:63]([CH:65]=[CH:66][CH:67]=1)[NH2:64]>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:64][C:63]1[CH:65]=[CH:66][CH:67]=[C:61]([Cl:60])[CH:62]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Reactant: Nc1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Cl)c1)c1cc(Cl)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-4-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 67; 90 mg, 0.24 mmol) in N,N-dimethylformamide (3 ml) was added diisopropylethylamine (0.08 ml, 0.48 mmol), HATU (164 mg, 0.43 mmol) and 3-chloroaniline (0.03 ml, 0.29 mmol). The solution was stirred for 2 hours and the solvent removed in vacuo. The residue was purified by column chromatography (SiO2, (solute, 1:1 ethyl acetate/cyclohexane) to yield the title compound as a white solid. 55 mg.
Reaction SMILES: [Na].[CH3:2][N:3]([CH3:11])[C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Cl[CH2:13][CH2:14][CH2:15][OH:16]>>[CH3:2][N:3]([CH3:11])[C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:13][CH2:14][CH2:15][OH:16]
Reactant: CN(C)c1cccc(O)c1
Reactant: OCCCCl
Agent: [Na]
Product: CN(C)c1cccc(OCCCO)c1
Yield: 57 %

Procedure:
Preparation analogously to Example 70 by the reaction of 3-dimethylaminophenol sodium salt with 3-chloro-1-propanol to give 3-(3-dimethylaminophenoxy)-1-propanol (b.p.0.7 =150°-5°; yield 57%), which is converted quantitatively into 3-(3-dimethylaminophenoxy)-propyl 1-methanesulphonate (oil) and is reacted with excess 5-amino-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-nitrate in boiling ethanol. Isolation as hydrochloride. Yield, after recrystallisation from ethanol+active charcoal: 38.2%.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1.C(N(C(C)C)C(C)C)C.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].Cl>C(#N)C>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:2]2[O:3][C:4]3[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=3[N:6]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N#Cc1ccc2oc(Cl)nc2c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc3cc(C#N)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
To a solution of 2-chloro-benzooxazole-5-carbonitrile (5.0 g, 28.0 mmol, 1.0 equiv; prepared as described in A. Batista-Parra, S. Venkitachalam, W. D. Wilson, D. W. Boykin Heterocycles 2003, 60, 1367-1376) in acetonitrile (65 mL) was added N-ethyl diisopropylamine (36.0 mL, 27.1 g, 210.0 mmol, 7.5 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (5.61 g, 28.0 mmol, 1.0 equiv). The reaction mixture was stirred at rt for 18 h under Ar, poured on crashed ice and the pH adjusted by addition of a solution of 37% HCl to pH 3.0. The reaction mixture was extracted with ethyl acetate (3×100 mL), the combined organic phases washed with water and dried over MgSO4. The organic solvent was evaporated under reduced pressure and the crude reaction product purified with column chromatography on silica eluting with a gradient of dichloromethane/methanol (100:0→95:5) to give 7.31 g (76%) of the title compound. MS (ESI): 343.0 [M+H]+.
Reaction SMILES: [CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[N:25]=[CH:26][N:27]([CH3:29])[CH:28]=3)(=[O:23])=[O:22])[CH:15]=2)[CH2:10][CH:9]1[NH:30][CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>C(#N)C.ClCCl>[CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[N:25]=[CH:26][N:27]([CH3:29])[CH:28]=3)(=[O:23])=[O:22])[CH:15]=2)[CH2:10][CH:9]1[N:30]1[CH2:33][C:32]([CH3:36])([CH3:35])[CH2:31]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccccc2)C(NCC(C)(C)CCl)C3)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccccc2)C(N2CC(C)(C)C2)C3)c1
Reaction time: 2 h

Procedure:
Dissolved N-(2-(3-benzyl-2-(3-chloro-2,2-dimethylpropylamino)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide (17.7 mg, 0.033 mmol in dry acetonitrile (2.000 ml) and added sodium bicarbonate (5.60 mg, 0.067 mmol). Microwave at 70° C. for 2 h. Evaporated solvents and re-dissolved in dichloromethane, washed with water and brine, dried over magnesium sulfate, filtered and evaporated to obtain the crude product as clear white oil, that was purified by column chromatography on 1.5×2.5 cm SiO2 using 5% methanol in dichloromethane to afford N-(2-(3-benzyl-2-(3,3-dimethylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide as a white solid. m=1.7 mg (10%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.[F:13][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2.CO.O=P(Cl)(Cl)Cl>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[F:13]
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1[nH]cc(F)c2cc(Br)ccc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with 6-bromo-2h-isoquinolin-1-one (5.0 g, 22.32 mmol) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor®) (9.49 g, 26.8 mmol, Air Products, Allentown, Pa.). Methanol (55.8 ml) and acetonitrile (55.8 ml) were added and the reaction was heated to 50° C. and stirred for one hour. The reaction was concentrated, dissolved in DCE (110 mL), and POCl3 (4.16 ml, 44.6 mmol) was added. The reaction was stirred at 50° C. for one hour. The reaction was quenched into ice water and extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate, filtered, and concentrated to afford crude 6-bromo-4-fluoroisoquinolin-1(2H)-one as a light pink solid. (ESI) 242.1 (M+H)+.