Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:15][C:16]#[N:17].C([O-])([O-])=O.[K+].[K+]>CC#N>[N:1]1([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][N:11]([CH2:15][C:16]#[N:17])[CH2:12][CH2:13]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: N#CCBr
Reactant: c1cn(CCN2CCNCC2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCN1CCN(CCn2ccnc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 1-(2-Imidazol-1-yl-ethyl)-piperazine (commercially available from CHESS GmbH) (1.0 g, 5.44 mmol), bromoacetonitrile (740 mg, 6.0 mmol) and K2CO3 (1.65 g, 12.0 mmol) in CH3CN (15 mL) is stirred at RT. After completion the product is isolated by filtration with Celite and washed with CH3CN and dried under reduced pressure to give the title compound as oil; ES-MS: M+H=220.2: CtRet=1.70.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])[CH:15]=[CH:14][C:13]=2[CH3:27])=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH3:27][C:13]1[CH:14]=[CH:15][C:16]([NH:18][C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])=[CH:17][C:12]=1[C:9]1[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(-c2cc(NC(=O)N3CCOCC3)ccc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(NC(=O)N2CCOCC2)cc1-c1ccc(C(=O)O)cc1
Yield: 76.8 %

Procedure:
2′-Methyl-5′-[(morpholine-4-carbonyl)-amino]-biphenyl-4-carboxylic acid ethyl ester (416 mg) was stirred in ethanol (15 ml) and 1M sodium hydroxide (4 ml) at 20 C for 18 h. The mixture was then acidified and extracted with dichloromethane. The dried extracts were then evaporated giving the title compound as a beige solid (295 mg).
Reaction SMILES: C(=O)(O)[O-].[Na+].[F:6][C:7]1[CH:8]=[CH:9][C:10]([OH:20])=[C:11]([C:13](=[O:19])/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])[CH:12]=1.Cl>O>[F:6][C:7]1[CH:8]=[CH:9][C:10]2[O:20][CH:15]([C:16]([OH:18])=[O:17])[CH2:14][C:13](=[O:19])[C:11]=2[CH:12]=1
Reactant: O=C(O)/C=C/C(=O)c1cc(F)ccc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C1CC(C(=O)O)Oc2ccc(F)cc21

Procedure:
Sodium bicarbonate (2.10 g, 25.0 mmol) was added to a suspension of (E)-4-(5-fluoro-2-hydroxyphenyl)-4-oxo-2-butenoic acid (5.00 g, 23.8 mmol) (obtained through the process as described in Example 22) in 200 ml of distilled water and the mixture was refluxed for 10 minutes. After cooling, the reaction mixture was acidified to pH 1.0 with concentrated hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give crude crystals which were recrystallized from the mixture of water and methanol to give 4.60 g (92.1%) of the subject desired compound as colorless crystals.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[C:10](Cl)=[N:11][CH:12]=[CH:13][C:8]=2[N:7]([CH3:15])[C:6]1=[O:16])[C:2]#[C:3][CH3:4].C(OC([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=O)(C)(C)C>>[CH2:1]([N:5]1[C:9]2[C:10]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:11][CH:12]=[CH:13][C:8]=2[N:7]([CH3:15])[C:6]1=[O:16])[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(=O)n(C)c2ccnc(Cl)c21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC#CCn1c(=O)n(C)c2ccnc(N3CCNCC3)c21
Temperature: 175 °C
Yield: 64.5 %

Procedure:
3-(2-butynyl)-4-chloro-1-methyl-1,3-dihydroimidazo[4.5-c]pyridin-2-one (0.041 g) and piperazine-1-carboxylic acid t-butyl ester (0.200 g) were heated at 175° C. for four hours under nitrogen atmosphere. Additional piperazine-1-carboxylic acid t-butyl ester (0.200 g) was then added, and this was heated at 175° C. for 16 hours. The residue was purified by reverse phase high performance liquid chromatography to give the title compound (0.032 g).
Reaction SMILES: P([O-])([O-])([O-])=[O:2].[OH:6][C@H:7]([CH2:59][CH2:60][C:61]1[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=1)[CH2:8][C:9](SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1OP(O)(O)=O)=[O:10]>>[OH:6][CH:7]([CH2:59][CH2:60][C:61]1[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=1)[CH2:8][C:9]([OH:10])=[O:2]
Reactant: O=P([O-])([O-])[O-]
Reactant: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@H](O)CCc1ccc(F)cc1
Product: O=C(O)CC(O)CCc1ccc(F)cc1

Procedure:
Ten parts of the above described immobilized enzyme was suspended in 480 parts of a 0.1M phosphate buffer (pH 7.0), then 10 parts of (R)-3-hydroxy-5-(4-fluorophenyl)valeryl CoA (prepared by a method described in Eur. J. Biochem., 250, 432–439 (1997) after obtaining 3-hydroxy-5-(4-fluorophenyl)valeric acid by hydrolyzing 3-hydroxyphenylvaleric acid ester obtained by a Reformatsky reaction) and one part of bovine serum albumin (Sigma) were added to the suspension and moderately shaken for one and a half hours at 30° C. After the reaction was completed, centrifugation was performed for 10 minutes at 10,000×g to recover the pellet.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[C:24]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1)([CH3:27])([CH3:26])[CH3:25].CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1.[Br-]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([N:31]5[CH2:32][CH2:33][CH2:34][C@H:30]5[C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:35])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCC[C@H]3C(=O)OC(C)(C)C)cc1OCC2
Temperature: 95 °C

Procedure:
A degassed mixture of 374 mg, (1.00 mmol) of 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 194, 342.5 mg, (2.000 mmol) of L-Proline tert-Butyl Ester, 26 mg, (0.050 mmol) of Bis(tri-t-butylphosphine)palladium and 192 mg, (2.00 mmol) of Sodium tert-butoxide in Toluene (10.0 mL, 93.9 mmol) was heated at 95° C. for 24 hours. The same quantity of L-Proline tert-Butyl Ester, Sodium tert-butoxide and the catalyst were added and the mixture was heated for 6 hours at 115° C. until no starting bromide remains in the reaction mixture. The mixture was concentrated in vacuum, the residue distributed between ethyl acetate and 5% aqueous citric acid. The organic extracts were washed with water, sat. NaHCO3, water, brine, dried over MgSO4 and purified on a silicagel 12 g column eluting with 4% Methanol in DCM to give (S)-tert-butyl 1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxylate. Yield 153 mg (55-60% purity, the product is contaminated with debromination byproduct). M/z 465.2, calc. 464.25
Reaction SMILES: N.C([S:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])(=O)C>CO>[SH:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12]
Reactant: CC(=O)SC1CCCC1C(=O)N1CCC[C@H]1C(=O)O
Agent: N
Solvent: CO
Product: O=C(O)[C@@H]1CCCN1C(=O)C1CCCC1S
Temperature: 0 °C

Procedure:
A mixture of 100 ml of anhydrous methanol and 100 ml of ammonia saturated anhydrous methanol, is added dropwise to a solution of 24.5 g (0.086 mole) of 1-[(2-acetylthiocyclopentyl)carbonyl]-L-proline in 50 ml of methanol cooled to 0° C. and maintained with stirring under nitrogen atmosphere. Once the addition is terminated the reaction mixture is stirred at room temperature under nitrogen for further four hours, then the solvent is evaporated and the residue is purified by column chromatography on Dowex 50® (a polystirene sulfonated resin) eluting with distilled water. Yield: 18.5 g (88%) of 1-[(2-mercaptocyclopentyl)carbonyl]-L-proline with the following characteristics: [α]D25 =-139.3° (C=1% in CHCl3).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:4]=1[O:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].[Br:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[N:23][C:24]=1[Cl:25]>N1C=CC=CC=1.C(OCC)(=O)C.Cl>[Br:18][C:19]1[CH:20]=[C:21]([S:26]([NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:3]=2[Cl:2])(=[O:28])=[O:27])[CH:22]=[N:23][C:24]=1[Cl:25]
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Br)c1
Reactant: Nc1ccccc1Oc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1ccccc1Oc1ccc(Cl)cc1Cl)c1cnc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(2,4-Dichlorophenoxy)aniline HCl (1.14 g, 3.94 mmol) and 5-bromo-6-chloropyridine-3-sulfonyl chloride (1.26 g, 4.33 mmol) were dissolved in pyridine (4 mL) and allowed to stir at ambient temperature for 1 hour. The reaction mixture was then diluted with 100 mL of ethyl acetate, 80 mL of 0.5 M HCl. The organic layer was washed successively with 100 mL of 0.5 M HCl, twice with 100 mL of water, 100 mL of half-saturated brine and finally 100 mL of brine. Drying of the organic layer over sodium sulfate was followed by filtration and solvent removal under reduced pressure. The resulting residue was purified by silica gel chromatography (linear gradient 60-100% DCM in hexanes) to yield 5-bromo-6-chloro-N-[2-(2,4-dichlorophenoxy)phenyl]pyridine-3-sulfonamide, giving proton NMR and mass spectral data consistent with theory.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([NH:17][CH3:18])[N:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>[Pd].C1(OC2C=CC=CC=2)C=CC=CC=1>[N:1]1([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([NH:17][CH3:18])[N:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CNc1nc(C)cc(N2CCc3ccccc32)n1
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CNc1nc(C)cc(-n2ccc3ccccc32)n1
Yield: 61.8 %

Procedure:
A mixture of 4-(1-indolinyl)-6-methyl-2-methylaminopyrimidine (2.4 g, 0.01M), 30% w/w palladium on charcoal (0.24 g) and diphenyl ether (10 ml) was heated under reflux in an argon atmosphere for 1 hour. The catalyst was then removed by filtration. The filtrate was then diluted with a large volume of hexane (100 ml). This gave a pale yellow solid which was recrystallised from 2-propanol to give 4-(1-indolyl)-6-methyl-2-methylaminopyrimidine (1.47 g, 62%), m.p. 160°-162° C.; microanalysis, found: C,70.5; H,5.9; N,23.6%; C14H14N4 requires C,70.6; H,5.9; N,23.5%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[C:43]([CH3:58])=[C:44]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([CH2:56][CH3:57])[CH2:52][CH2:51]2)=[O:49])[CH:45]=[CH:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[C:43]([CH3:58])=[C:44]([C:48]([N:50]6[CH2:51][CH2:52][N:53]([CH2:56][CH3:57])[CH2:54][CH2:55]6)=[O:49])[CH:45]=[CH:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CCN1CCN(C(=O)c2cccc(Br)c2C)CC1
Product: CCN1CCN(C(=O)c2cccc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)c2C)CC1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and (3-bromo-2-methyl-phenyl)-(4-ethyl-piperazin-1-yl)-methanone (156 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methyl-phenyl]-(4-ethyl-piperazin-1-yl)-methanone was obtained, and then the PMB groups were removed according to Deprotection method 3, to obtain the desired compound (D-158) as a pale yellow powder (53 mg, 54%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][CH2:13][C:14]1[C:15]([CH2:43][CH:44]([CH3:46])[CH3:45])=[N:16][C:17]2[C:22]([C:23]=1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)=[CH:21][C:20]([O:31][CH2:32][CH2:33][O:34][CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])=[CH:19][CH:18]=2>FC(F)(F)C(O)=O>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[NH2:12][CH2:13][C:14]1[C:15]([CH2:43][CH:44]([CH3:46])[CH3:45])=[N:16][C:17]2[C:22]([C:23]=1[C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1)=[CH:21][C:20]([O:31][CH2:32][CH2:33][O:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:19][CH:18]=2
Reactant: Cc1ccc(-c2c(CN)c(CC(C)C)nc3ccc(OCCOCC(=O)OC(C)(C)C)cc23)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2c(CN)c(CC(C)C)nc3ccc(OCCOCC(=O)O)cc23)cc1
Yield: 84.1 %

Procedure:
A solution of tert-butyl (2-{[3-(aminomethyl)-2-isobutyl-4-(4-methylphenyl)-6-quinolinyl]oxy}ethoxy)acetate p-toluenesulfonic acid salt (0.2 g, 0.3 mmol) in trifluoroacetic acid (5 ml) was stirred at room temperature for 4 hrs. The reaction mixture was concentrated under reduced pressure and the residue was solidified from diethyl ether. The obtained solid was dissolved in methanol and concentrated under reduced pressure. The residue was again solidified from diethyl ether to give the title compound (0.15 g, yield 83%) as an amorphous form.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[S:15][C:16]([NH:18][C:19]3[O:20][C@:21]4([CH2:29][N:30]=3)[CH:26]3[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]3)[CH2:22]4)=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>>[N:23]12[CH2:24][CH2:25][CH:26]([CH2:27][CH2:28]1)[C@@:21]1([O:20][C:19]([NH:18][C:16]3[S:15][C:13]4[NH:14][C:9](=[O:8])[CH:10]=[CH:11][C:12]=4[N:17]=3)=[N:30][CH2:29]1)[CH2:22]2.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]
Reactant: c1ccc(COc2ccc3nc(NC4=NC[C@@]5(CN6CCC5CC6)O4)sc3n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1ccc2nc(NC3=NC[C@@]4(CN5CCC4CC5)O3)sc2[nH]1

Procedure:
(R)—N-(5-(benzyloxy)thiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (390 mg, 0.925 mmol) was dissolved in TFA and allowed to react for 4 hours at ambient temperature, at which time LCMS and TLC showed the starting material to be mostly consumed. The TFA was removed in vacuo and the crude mixture was purified by preparative HPLC. The combined product fractions were concentrated in vacuo and triturated with ether to afford (R)-2-(4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)thiazolo[5,4-b]pyridin-5(4H)-one, TFA (164 mg, 0.368 mmol, 39.8% yield). M.P. 245 (dec). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.99 (br. s., 1 H) 9.05 (br. s., 1 H) 7.81 (d, J=8.53 Hz, 1 H) 6.65 (d, J=8.78 Hz, 1 H) 3.96 (d, J=10.29 Hz, 1 H) 3.82 (d, J=Hz, 1 H) 3.63-3.78 (m, 2 H) 3.36-3.47 (m, 1 H) 3.16-3.34 (m, 3 H) 2.43 (br. s., 1 H) 2.16 (br. s., 1 H) 1.76-2.07 (m, 3 H). MS (LC/MS) R.T.=0.50; [M+H]+=332.15.
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][O:10][C:11]([C:13]1[S:25][C:16]2[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([NH2:24])[C:22]=3[S:23][C:15]=2[C:14]=1[O:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:12]>>[CH3:9][O:10][C:11]([C:13]1[S:25][C:16]2[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([NH:24][CH2:7][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[C:22]=3[S:23][C:15]=2[C:14]=1[O:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:12]
Reactant: O=CC1CCCCC1
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1c(N)cccc12
Product: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1c(NCC3CCCCC3)cccc12
Yield: 63.9 %

Procedure:
Step A Reductive Amination: Addition of cyclohexane carboxaldehyde (0.063 mL, 0.61 mmol), to 7-Amino-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (250 mg, 0.61 mmol) was carried out following a procedure similar to that delineated in step A (“reductive amination,” Example 25) affording 180 mg of 7-(Cyclohexylmethyl-amino)-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester as a viscous yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:16][OH:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+].[Cl:24][C:25]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:26]=1[CH2:27]Cl.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:16][O:17][CH2:27][C:26]1[C:25]([Cl:24])=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:33])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: ClCc1c(Cl)cccc1Cl
Reactant: Cc1ccc(C(Cn2cncn2)=NO)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(Cn2cncn2)=NOCc2c(Cl)cccc2Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 21.4 %

Procedure:
2 g (0.008 mol) of 1-(2-chloro-4-methylphenyl)-1-oximino-2-(1,2,4-triazol-1-yl)-ethane and 1.2 g (0.008 mol) of potassium carbonate in 8 ml of dimethylformamide were heated to 45° C. and 1.7 g (0.008 mol) of 2,6-dichlorobenzylchloride were added dropwise at that temperature. It was stirred for 12 hours at 60° C., cooled and mixed with 50 ml of water. The mixture was twice extracted with 50 ml of methylene chloride, the combined organic phases were washed with water, dried over sodium sulphate and freed of solvent. The residue which crystallized after some time was recrystallized from ethyl ether/ethyl acetate (1:1). 0.7 g (21% of theory) of 1-(2-chloro 4-methylphenyl)-1-(2,6-dichlorobenzyloximino)-2-(1,2,4-triazol-1-yl)-ethane of melting point 97°-99° C. was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28].[OH-].[NH4+:39]>>[NH2:39][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:9][C:8]=2[C:7]2[C:2]([Cl:1])=[C:3]([NH:26][S:27]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][N:16]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1cc(F)ccc1F
Agent: [OH-]
Product: Nc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2Cl)n1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide (150 mg, 0.257 mmol) and ammonium hydroxide (3 mL, 77 mmol), the title compound was obtained as a tan solid (47 mg, 31% yield). MS (ESI): 565 [M+H]+.
Reaction SMILES: CC1C(/C(/C)=C/C2C=CC(C(O)=[O:23])=CC=2)=CC2C(C)(C)CCC(C)(C)C=2C=1.[CH3:28][C:29]1[C:30](/[C:43](/[CH3:55])=[CH:44]/[C:45]2S[CH:47]=[C:48]([C:50]([O:52]CC)=[O:51])[CH:49]=2)=[CH:31][C:32]2[C:33]([CH3:42])([CH3:41])[CH2:34][CH2:35][C:36]([CH3:40])([CH3:39])[C:37]=2[CH:38]=1.CC1C(/C(/C)=C/C2SC=C(C(O)=O)N=2)=CC2C(C)(C)CCC(C)(C)C=2C=1.CC1C(/C(/C)=C/C2NC(C(O)=O)=CN=2)=CC2C(C)(C)CCC(C)(C)C=2C=1>>[CH3:28][C:29]1[C:30](/[C:43](/[CH3:55])=[CH:44]/[C:45]2[O:23][CH:47]=[C:48]([C:50]([OH:52])=[O:51])[CH:49]=2)=[CH:31][C:32]2[C:33]([CH3:41])([CH3:42])[CH2:34][CH2:35][C:36]([CH3:39])([CH3:40])[C:37]=2[CH:38]=1
Reactant: C/C(=C\c1ccc(C(=O)O)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)c1csc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)c1
Agent: C/C(=C\c1nc(C(=O)O)cs1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: C/C(=C\c1ncc(C(=O)O)[nH]1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Product: C/C(=C\c1cc(C(=O)O)co1)c1cc2c(cc1C)C(C)(C)CCC2(C)C

Procedure:
4-[(E)-2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)propen-1-yl]benzoicacid; 2-[(E)-2-(4,4,7-trimethyl-6-thiochlomanyl)-propen-1-yl]-4-thiophenecarboxylic acid; ethyl 2[(E)-2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)propen-1-yl]-4-thiophenecarboxylate; 2-[(E)-2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)propen-1-yl]-4-thiazolecarboxylic acid and 2-[(E)-2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)propen-1-yl]-5-imidazolecarboxylic acid.
Reaction SMILES: B(Br)(Br)Br.[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+].CS[C:20]#[N:21]>ClCCCl>[C:20]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[OH:11])#[N:21]
Reactant: CSC#N
Reactant: Oc1ccccc1
Agent: BrB(Br)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: N#Cc1ccccc1O
Temperature: 25 °C
Yield: 79 %

Procedure:
To a solution of 1.13 ml of boron tribromide in 6 ml of 1,2-dichloroethane were added a solution of 941 mg of phenol in 10 ml of 1,2-dichloroethane, 0.82 ml of methyl thiocyanate and 1.33 g of aluminium chloride under ice-cooling. After dissolving aluminium chloride with stirring at room temperature, the mixture was heated at 80° C. on an oil bath for 3 hr. After cooling, the reaction solution was poured into 33 ml of 4N aqueous sodium hydroxide and stirred at 75°-80° C. for 30 min. on an oil bath. After washing with methylene chloride, the aqueous layer was acidified with 25 ml of 6N HCl and extracted with ether. The ether layer was extracted with 2N aqueous sodium carbonate, dried over anhydrous magnesium sulfate and concentrated to recover 147 mg of phenol. On the other hand, the sodium carbonate layer was acidified with 6N HCl, extracted with ether, and the ether layer was dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from methylene chloride-petroleum ether to give 943 mg of 2-cyanophenol as white crystals melting at 97°-98° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH:21]4[CH2:23][CH2:22]4)(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:37]#[C:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)O1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.C(O)CC>[CH:21]1([NH:20][S:17]([C:14]2[CH:15]=[CH:16][C:11]([C:8]3[N:6]4[CH:7]=[C:2]([C:37]#[C:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[N:3]=[C:4]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:5]4=[N:10][CH:9]=3)=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH2:23][CH2:22]1
Reactant: CC(C)CNc1nc(Br)cn2c(-c3ccc(S(=O)(=O)NC4CC4)cc3)cnc12
Reactant: CC1(C)OB(C#Cc2ccccc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCO
Product: CC(C)CNc1nc(C#Cc2ccccc2)cn2c(-c3ccc(S(=O)(=O)NC4CC4)cc3)cnc12
Temperature: 120 °C
Reaction time: 2 h
Yield: 14.6 %

Procedure:
A mixture of 30 mg (65 μmol) 4-[6-bromo-8-(isobutylamino)imidazo[1,2-a]pyrazin-3-yl]-N-cyclopropylbenzene sulfonamide which was prepared according to intermediate example 2a, 29.5 mg 4,4,5,5-tetramethyl-2-(phenylethynyl)-1,3,2-dioxaborolane, 1.0 mL n-propanol, 97 μL of an aqueous 2M potassium carbonate solution, 0.85 mg triphenylphosphine, and 4.55 mg bis(triphenylphosphine)palladium (II) chloride was stirred at 120° C. for 2 hours. The solution was cooled, water added and extracted with dichloromethane. The organic phase was dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 4.6 mg (14%) of the title compound.