Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([CH3:24])[CH2:11][N:12]1[C:17]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:23])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][C@@H:10]([CH3:24])[CH2:11][N:12]1[C:17]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:23]
Reactant: Cc1ccc2c(c1)N(C[C@H](C)CO[Si](C)(C)C(C)(C)C)C(=O)CO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)N(C[C@H](C)CO)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (S)-4-[3-(tert-butyldimethylsilanyloxy)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one (101IS60-1) (1.0 g, 2.9 mmol) was dissolved in dry THF (12 mL) and TBAF (1.2 g, 3.8 mmol) was added. The reaction was stirred at rt overnight and the solution was concentrated under reduced pressure, the remaining oil was diluted with EtOAc (60 mL) and washed with brine (3×30 mL), dried (Na2SO4) filtered and concentrated under reduced pressure. The remaining oil was purified by flash chromatography (SiO2; Heptane/EtOAc 30:70) to yield an oil which crystallized upon standing (0.69 g, 76%). 1H NMR (CDCl3) δ 6.88 (d, J=8.4 Hz, 1H), 6.83-6.78 (m, 2H), 4.59 (brs 2H), 4.22 (dd J=10.0, 14.4 Hz), 3.57-3.38 (m, 3H), 2.9 (vbrs, 1H), 2.33 (s, 3H), 2.04 (m, 1H), 1.08 (d, J=7.2 Hz); 13C NMR (CDCl3) δ 165.7, 143.4, 132.3, 124.9, 117.1, 115.9, 67.6, 63.7, 43.5, 34.2, 21.3, 15.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[C:22]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:22][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[O:8][CH:7]([C:13]([F:16])([F:14])[F:15])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1=Cc2cc(O)cc(C)c2OC1C(F)(F)F
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1=Cc2cc(OC)cc(C)c2OC1C(F)(F)F
Temperature: 55 °C
Yield: 105.4 %

Procedure:
The ethyl 6-hydroxy-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.2 g, 0.66 mmole) and K2CO3 (0.48 g, 3.44 mmole) was suspended in acetone (7.5 mL). lodomethane (0.93 g, 6.60 mmole) was added and heated to 55° C. for 3 hrs. The contents were filtered through a plug of celite and washed with acetone. The solution was concentrated in vacuo to give a yellow solid (0.22 g, 98%). GCMS m/z 316.0 (M+). LCMS m/z 317.0 (M+H). 1H NMR (CDCl3/400 MHz) 7.64 (s, 1H), 6.72 (s, 1H), 6.55 (s, 1H), 5.65 (q, 1H, J=7.0 Hz), 4.28 (m, 2H), 3.73 (s, 3H), 2.20 (s, 3H), 1.32 (m, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:20][CH3:21])=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]3[CH2:16][CH2:17][CH2:18][C:11]=3[C:10]=2[CH:19]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1.C(O)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O.C(O)(C)C>[CH3:21][O:20][C:7]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:35][CH2:34]2)=[CH:19][C:10]2[C:11]3[CH2:18][CH2:17][CH2:16][C:12]=3[C:13](=[O:15])[O:14][C:9]=2[CH:8]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCl)CCC3
Reactant: COc1cccc(N2CCNCC2)c1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)O
Solvent: CC(C)=O
Solvent: CCO
Product: COc1cccc(N2CCN(CCCOc3cc4c5c(c(=O)oc4cc3OC)CCC5)CC2)c1
Yield: 58 %

Procedure:
Method B (60 h at 50° C.); starting materials: 8-(3-chloropropoxy)-2,3-dihydro-7-methoxy-cyclopenta[c][1]benzopyran-4(1H)-one (example 83) and 1-(3-methoxyphenyl)piperazine; yield 58%; fusion point 130°-132° C. (from ethanol and isopropanol). Fumarate: method E; yield 80%; fusion point 174°-175° C. (from acetone).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][N:12]1[C@@H:28]2[CH2:29][C:17]3[CH:18]=[CH:19][C:20]([O:31][CH3:32])=[C:21]4[O:22][C@H:23]5[C@@H:24]([OH:30])[CH:25]=[CH:26][C@@H:27]2[C@:15]5([C:16]=34)[CH2:14][CH2:13]1.CCN(CC)CC>C(Cl)Cl>[CH3:11][N:12]1[C@@H:28]2[CH2:29][C:17]3[CH:18]=[CH:19][C:20]([O:31][CH3:32])=[C:21]4[O:22][C@H:23]5[C:24]([CH:25]=[CH:26][C@@H:27]2[C@:15]5([C:16]=34)[CH2:14][CH2:13]1)=[O:30]
Reactant: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c3c1O[C@H]1C(=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@]314
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 126.5 %

Procedure:
To a solution of dimethylsulfoxide (16.53 g, 0.21 mole) in CH2Cl2 (80 ml) at -78° C. was added dropwise a solution of oxalyl chloride (13.01 g, 0.10 mole) in CH2Cl2 (50 ml) over a period of 40 min. After stirring for 10 min., a solution of codeine (20.33 g, 0.068 mole) in CH2Cl2 (100 ml) was added over 50 min. while keeping the reaction mixture at -78°C. After stirring at -78° C. for 2 hr., Et3N (50 ml) was added, followed by CH2Cl2 (100 ml). The reaction mixture was allowed to warm-up to room temperature, washed with water (6×150 ml), dried over anhydrous Na2SO4 and evaporated to dryness in vacuo to give codeinone (25.57 g). IR (KBr)(v, cm-1): 1668 (s, sharp, --C=C--C=O); NMR (δH)(CDCl3): 6.67 (1, d, J, 8.2, 2-H), 6.62 (1, d, J, 10.2, 8-H), 6.59 (1, d, J, 8.2, 1-H), 6.07 (1, dd, J, 10.2 & 2.9, 7-H), 4.68 (1, s, 5-H), 3.85 (3, s, OCH3), 3.45-3.35 (1, m, 9-H), 3.25-3.17 (1, m, 14-H), 3.10 (1, d, J, 18.5, 10-Hβ), 2.61 (1, dm, J, 11.9, 16-He), 2.45 (3, s, NCH3), 2.30 (1, dd, J, 18.5 & 5.5, 10-Hα), 2.30 (1, td, J, 11.9 & 3.7, 16-Ha), 2.06 (1, td, J, 12.0 & 4.8, 15-Ha), 1.85 (1, dm, J, 12.5, 15-He).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH:25]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH2:26].CCN(CC)CC>CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH2:26][CH2:25][S:27]([CH3:30])(=[O:29])=[O:28])[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: C=CS(C)(=O)=O
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Solvent: CCN(CC)CC
Solvent: CO
Product: CS(=O)(=O)CCn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Temperature: 130 °C
Yield: 57.7 %

Procedure:
A mixture of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 210 mg; 0.62 mmol), methyl vinyl sulfone (654 mg; 6.16 mmol) and Et3N (0.26 mL; 1.85 mmol) in methanol (15 mL) was heated at 130° C. for 0.5 h in a microwave reactor. The reaction mixture was cooled to r.t., concentrated to give a residue which was triturated with MeOH (2 mL) to afford 160 mg (58%) of the title product as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: NCCCCCC(=O)O
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Product: O=C(O)CCCCCN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 98 %

Procedure:
4-nitrophthalic anhydride (0.25 g, 0.0013 mol) and 6-aminohexanoic acid (0.177 g, 0.0013 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.39 g (97%) 144 as very pale dull orange crystals: mp=140° C.; Rf 0.86 (A): Rf 0.85 (B): Rf 0.75 (D): IR (cm−1): 2875–3125 (OH), 3064 (C═CH), 1775 (C═O), 1706 (bs, C═O), 1624 (C═C), 1544 (N═O), 1437 (C═C), 1398 (C—O), 1348 (N═O), 1069 (C—O), 722 (C═CH); MS m/z (rel intensity) 277 (100), 251 (11), 191 (124).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].S([CH2:21][N+:22]#[C-:23])(C1C=CC(C)=CC=1)(=O)=O.[C:24]([O:34][CH2:35][CH3:36])(=[O:33])/[CH:25]=[CH:26]/[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.C(OCC)(=O)C>[C:24]([C:25]1[C:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:23][NH:22][CH:21]=1)([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)/C=C/c1ccccc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c[nH]cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 38.5 %

Procedure:
To a 1.0 M solution of lithium hexamethyldisilazide in THF (41 mL, 41 mmol) at −78° C. was added dropwise over 45 min. a solution of tosylmethyl isocyanide (8.1 g, 41 mmol) in THF. After the reaction was stirred for an additional 45 min. a solution of trans-ethyl cinnamate (7.3 g, 41 mmol) in THF (40 mL) was added over 40 min. The reaction was warmed to 25° C. and stirred for 5 h. The reaction was diluted with ethyl acetate and washed with sat. aqueous NaHCO3. The aqueous layer was extracted three times with ethyl acetate, dried (Na2SO4), concentrated and purified by chromatography on silica gel eluting with a gradient of 20-30% ethyl acetate in hexanes to provide 3.4 g (41%) of 3-carboethoxy-4-phenylpyrrole as an off-white solid. 1H NMR (CDCl3): δ 8.62 (br s, 1H), 7.57-7.12 (m, 6H), 6.73 (s, 1H), 4.19 (q, J=7.1 Hz, 2H), 1.23 (t, J=7.1 Hz, 3H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[N:10]([O-])=O.[Na+].[Sn](Cl)Cl>Cl.O>[F:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:10])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: O=N[O-]
Reactant: Nc1ccc(F)c(F)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(F)c(F)c1
Temperature: 10 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
A stirred mixture of 3,4-difluoroaniline (12.9 g, 0.1 mol) in concentrated hydrochloric acid (60 mL) was chilled to 10° C. with an ice/methanol bath. A solution of sodium nitrite (6.9 g, 0.1 mol) in water (30 mL) was added at a rate which maintained the temperature of the reaction mixture below 10° C. After stirring for 2 hours, the reaction mixture was cooled to 0° C. and a solution of tin(II) chloride. (56.88 g, 0.3 mol) in concentrated hydrochloric acid (50 mL) was added dropwise with vigorous stirring. Additional concentrated hydrochloric acid (150 mL) was added to the reaction mixture and stirring was continued for 2 hours. The reaction mixture was filtered to collect the precipitated hydrochloride salt of the title compound. This precipitate was dissolved in water (75 mL) and the resulting solution was basified with 50% aqueous sodium hydroxide and extracted with ethyl acetate. The organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to provide the title intermediate as a brown oil (8.11 g, 57.4%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:9]1([NH2:12])[CH2:11][CH2:10]1>C1(C)C=CC=CC=1>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][CH2:2][NH:12][CH:9]1[CH2:11][CH2:10]1)[CH3:8]
Reactant: NC1CC1
Reactant: CCOC(=O)CCBr
Solvent: Cc1ccccc1
Product: CCOC(=O)CCNC1CC1

Procedure:
B)a) 14.0 ml of ethyl 3-bromopropionate are added to a solution of 15.4 ml of cyclopropylamine in 100 ml of toluene and the reaction mixture is heated to 90° for 3 hours. Subsequently, the precipitated salt is filtered and the filtrate is distilled. There are obtained 9.5 g of N-cyclopropyl-β-alanine ethyl ester, Fab-MS: 157 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][C:37]1[C:38]([N:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]2)=[CH:39][C:40]([O:44][CH2:45][CH3:46])=[C:41]([NH2:43])[CH:42]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C(F)(F)F>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:41]3[CH:42]=[C:37]([CH3:36])[C:38]([N:47]4[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]4)=[CH:39][C:40]=3[O:44][CH2:45][CH3:46])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCC(F)(F)F
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 80 °C
Yield: 30.7 %

Procedure:
To 5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (200 mg, 0.407 mmol) and (5-methyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}phenyl)amine (200 mg, 0.586 mmol) (Example 248, Step B) in trifluoroethanol (10 mL) was added p-toluene sulfonic acid (200 mg, 1.05 mmol), and the vial was sealed and heated to 80° C. overnight. The reaction was then cooled to rt and silica was added. The solvent was removed on a rotovap and the product purified on a 12 g ISCO column. Desired fractions were combined and rotovaped down. The resulting foam was dissolved in DCM and ether was added to provide the title compound (100 mg, 0.125 mmol, 31%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.74 (s, 1H), 9.33 (d, J=7.1 Hz, 1H), 8.32 (s, 1H), 8.23 (d, J=5.3 Hz, 1H), 8.08 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.53 (s, 1H), 7.43-7.33 (m, 2H), 7.25 (d, J=8.4 Hz, 1H), 7.15 (t, J=8.0 Hz, 2H), 6.92 (t, J=6.9 Hz, 1H), 6.71 (s, 1H), 6.56 (d, J=5.3 Hz, 1H), 4.03 (q, J=6.8 Hz, 2H), 3.95 (s, 3H), 3.36-3.25 (m, 2H), 3.03 (s, 3H), 2.86-2.78 (m, 4H), 2.74 (t, J=6.7 Hz, 2H), 2.63-2.50 (m, 4H), 2.11 (s, 3H), 1.22 (t, J=7.0 Hz, 3H). MS (ESI) m/z=398 [M+2H]+2.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[Cs+].[Cs+].F[C:8]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=1)=[O:11].[F:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:30]=1OC>CN(C=O)C>[F:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][C:8]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:9]=2[C:10]([NH:12][C:13]2[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=2)=[O:11])=[C:31]([O:4][CH3:1])[CH:30]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(O)ccc1F
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1cc(C(F)(F)F)ccc1F
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1Oc1ccc(C(F)(F)F)cc1C(=O)Nc1cc[nH]c(=O)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
Cs2CO3 (651.6 mg, 2.0 mmol) was added to a solution of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide (60.0 mg, 0.2 mmol) and 4-fluoro-3-methoxyphenol (228 μl, 2.0 mmol) in DMF (1 mL) and the reaction was stirred at 100° C. for 1 hour. The reaction was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as a modifier to yield 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide (30) (67.9 mg, 80%). ESI-MS m/z calc. 422.09. found 423.2 (M+1)+; Retention time: 1.56 minutes (3 minutes run).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]1[O:8][CH2:7]1.C1OC1.[N-:12]=[N+:13]=[N-:14].[Na+].C1C(N)=NC(=O)N(CCOCCP(O)(O)=O)C=1.[OH-].[Na+]>CC(N(C)C)=O>[CH2:1]([N:12]=[N+:13]=[N-:14])[CH:3]1[O:5][CH2:4]1.[CH2:7]1[O:8][CH2:6]1
Reactant: [N-]=[N+]=[N-]
Reactant: ClCC1CO1
Agent: Nc1ccn(CCOCCP(=O)(O)O)c(=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: C1CO1
Product: [N-]=[N+]=NCC1CO1

Procedure:
Elastomeric GEC is prepared according to the same previous procedure as in Example 1, except that commercial rubbery Epichlorohydrin-Ethylene Oxide Copolymer (PEEC) is used instead of PECH as the starting material. The copolymer contains about 70% PECH and 30% Ethylene Oxide. For this reason, a weight ratio NaN3 :PEEC of 0.55 is used in this case. Specifically, the reaction for 5 h at 120° C. of 10 g PEEC (MW~9×105) in 50 g DMA and 5 g EG with 5.5 g NaN3 and 0.9 g NaOH will yield 9.0 g (90%) of GEC azido product. This copolymer containing about 70% GAP and 30% Ethylene Oxide has a MW of about 10,000, a Tg of about -55° C. and a functionality (f) of about 3.5.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][C:10]([CH3:20])([CH3:19])[C:9]=2[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:21][C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH2:1]([N:6]([C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][C:10]([CH3:19])([CH3:20])[C:9]=2[CH:8]=1)[C:22]([Cl:21])=[O:24])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCN(C(=O)Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Yield: 292.9 %

Procedure:
A solution of pentyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amine (33) (1.0 g, 3.6 mmole) in 20 mL of THF was treated with 380 mg of triphosgene (0.35 eq.). The reaction mixture was stirred at reflux for three hours, poured onto 30 mL ice-water and extracted with three portions of 30 mL of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give 1.26 g of pentyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-carbamoyl chloride (35) as a white solid, which was used without purification.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([C:19]([NH:21][NH2:22])=[O:20])[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[C:25]([O:28][C:29]([CH3:34])([CH3:33])[C:30](Cl)=[O:31])(=[O:27])[CH3:26]>>[C:25]([O:28][C:29]([CH3:34])([CH3:33])[C:30](=[O:31])[NH:22][NH:21][C:19]([C:16]1[CH:17]=[CH:18][C:13]2[N:12]=[CH:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:23])[F:24])=[CH:9][CH:8]=3)[C:14]=2[CH:15]=1)=[O:20])(=[O:27])[CH3:26]
Reactant: NNC(=O)c1ccc2ncn(-c3ccc(OC(F)(F)F)cc3)c2c1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Product: CC(=O)OC(C)(C)C(=O)NNC(=O)c1ccc2ncn(-c3ccc(OC(F)(F)F)cc3)c2c1
Yield: 66 %

Procedure:
In the same manner as in Reference Example 129 and using 1-[4-(trifluoromethoxy)phenyl]-1H-benzimidazole-6-carbohydrazide instead of 3-bromo-1-benzofuran-5-carbohydrazide and 2-chloro-1,1-dimethyl-2-oxoethyl acetate instead of (1S)-2-chloro-1-methyl-2-oxoethyl acetate, the title compound (yield 66%) was obtained as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH:23][C@H:24]1[CH2:27][C@H:26](N)[CH2:25]1.CC(C)([O-:32])C.[Na+]>[Pd](Cl)Cl>[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH:23][C@H:24]1[CH2:27][C@H:26]([N:13]2[C:2]3=[N:3][CH:4]=[CH:5][CH:6]=[C:7]3[C:8]3([CH2:11][CH2:10][CH2:9]3)[C:12]2=[O:32])[CH2:25]1
Reactant: N#CC1(c2cccnc2Cl)CCC1
Reactant: CC(C)(C)[O-]
Reactant: N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Agent: Cl[Pd]Cl
Agent: [Na+]
Product: O=C1N([C@H]2C[C@H](Nc3nc4ccccc4s3)C2)c2ncccc2C12CCC2
Temperature: 90 °C
Reaction time: 5 h

Procedure:
1-(2-Chloropyridin-3-yl)cyclobutanecarbonitrile (intermediate 19, 0.070 g, 0.363 mmol), (trans)-N1-(benzo[d]thiazol-2-yl)cyclobutane-1,3-diamine (intermediate 11, 0.080 g, 0.363 mmol), [dicyclohexyl(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine]2-(2-aminoethyl)phenyl)palladium(II) chloride (0.015 g, 0.018 mmol), and sodium t-butoxide (0.096 ml, 0.780 mmol) were combined under argon in a ROUND BOTTOMED FLASK. Dry, sparged dioxane (0.8 mL) was added and the reaction heated at 90° C. After 25 minutes water (150 mL), saturated ammonium chloride (20 mL) and ethyl acetate (200 mL) were added and the phases mixed and separated. The organic phase was dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude intermediate was dissolved in a mixture of water (5 mL) and concentrated sulfuric acid (5 mL) and heated at 100° C. After 5 hours the reaction was allowed to cool to room temperature. Water (100 mL) and ethyl acetate (100 mL) were added and the phases mixed and separated. The organic phase was discarded. Ice (100 mL) was added to the aqueous along with additional ethyl acetate (200 mL). The pH was adjusted to about 9 using 10 N sodium hydroxide and the phases mixed and separated. The aqueous was extracted with an additional portion of ethyl acetate (100 mL) then the combined organics were dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (dichloromethane to ethyl acetate gradient) gave the desired 1′-(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)spiro[cyclobutane-1,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (0.041 g, 0.109 mmol, 30.0% yield). M+1: 377.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.17-2.55 (m, 6 H) 2.61-2.78 (m, 2 H) 3.42-3.58 (m, 2 H) 4.53-4.67 (m, 1 H) 5.29 (quin, J=8.46 Hz, 1 H) 6.38 (br. s., 1 H) 6.99 (dd, J=7.24, 5.28 Hz, 1 H) 7.08 (td, J=7.58, 1.08 Hz, 1 H) 7.24-7.33 (m, 1 H) 7.54-7.64 (m, 2 H) 7.70 (dd, 1=7.24, 1.56 Hz, 1 H) 8.17 (dd, J=5.28, 1.56 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([NH2:31])[C:27]([CH3:33])([CH3:32])[CH2:26]2)=[CH:21][C:20]=1[O:34][CH3:35]>>[NH2:31][CH:28]1[CH2:29][CH2:30][N:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:2]3[N:7]=[C:6]([C:8]4[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[NH:10][CH:9]=4)[C:5]([Cl:17])=[CH:4][N:3]=3)=[C:20]([O:34][CH3:35])[CH:21]=2)[CH2:26][C:27]1([CH3:33])[CH3:32]
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: COc1cc(N2CCC(N)C(C)(C)C2)ccc1N
Product: COc1cc(N2CCC(N)C(C)(C)C2)ccc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (Intermediate 2) and 1-(4-amino-3-methoxyphenyl)-3,3-dimethylpiperidin-4-amine (180 mg, 0.72 mmol) (Intermediate 43).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11]([C:21]2[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=3)[CH:22]=2)=[CH:10][CH:9]=1.[CH3:35][N:36]([CH3:46])[C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1>N1C=CC=CC=1>[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11]([C:21]2[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([NH:34][C:41](=[O:42])[C:40]4[CH:39]=[CH:38][C:37]([N:36]([CH3:35])[CH3:46])=[CH:45][CH:44]=4)=[CH:32][CH:33]=3)[CH:22]=2)=[CH:10][CH:9]=1
Reactant: Nc1ccc(Nc2cc(-c3cccc4c3oc3ccccc34)ncn2)cc1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ccc(C(=O)Nc2ccc(Nc3cc(-c4cccc5c4oc4ccccc45)ncn3)cc2)cc1

Procedure:
To a solution of N-(6-dibenzofuran-4-yl-pyrimidin-4-yl)-benzene-1,4-diamine trifluoroacetate (compound A1) (500 mg, 1.1 mmol) in pyridine (10 mL) is added at 10° C. 4-dimethylaminobenzoyl chloride (288 mg, 1.21 mmol) portion wise. After 14 h at ambient temperature the mixture is evaporated and the crude product is purified by crystallization.
Reaction SMILES: CCN(CC)CC.Cl.[S:9]1[C:13]([NH2:14])=[CH:12][N:11]=[CH:10]1.[CH3:15][C:16](OC(C)=O)=[O:17]>C(Cl)Cl>[S:9]1[C:13]([NH:14][C:16](=[O:17])[CH3:15])=[CH:12][N:11]=[CH:10]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cncs1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cncs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.1 %

Procedure:
To a solution of Et3N (0.31 mL, 2.20 mmol) and thiazol-5-amine hydrochloride (0.2 g, 1.46 mmol) from example 1.2 in DCM (10 mL) was added Ac2O (0.21 mL, 2.20 mmol). The mixture was stirred at room temperature for 3 h and then concentrated. The resulting mixture was deposited onto silica gel and loaded onto a silica gel column and eluted with EA to give the title compound (0.14 g, 0.98 mmol, 70%).