Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Si:19]([O:26][C:27]1[CH:32]=[C:31]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:30]=[CH:29][C:28]=1[C@H:41]1[CH2:46][CH2:45][C@H:44]([OH:47])[CH2:43][CH2:42]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>ClCCl>[C:10]1([NH:16][C:17](=[O:18])[O:47][C@H:44]2[CH2:43][CH2:42][C@H:41]([C:28]3[CH:29]=[CH:30][C:31]([O:33][Si:34]([C:37]([CH3:38])([CH3:39])[CH3:40])([CH3:36])[CH3:35])=[CH:32][C:27]=3[O:26][Si:19]([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20])[CH2:46][CH2:45]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](OC(=O)Nc3ccccc3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 96 h

Procedure:
N,N-Diisopropylethylamine (100 μl) and phenylisocyanate (55 μl) were added to a stirred solution of trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (50 mg) in anhydrous dichloromethane (2 ml). After 96 hr at 40° C., the reaction mixture was partitioned between ethyl acetate (50 ml) and water (50 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with brine (50 ml); dried over magnesium sulfate and evaporated in vacuo. The residue was purified using flash column chromatography (SiO2, ethyl acetate/petrol, 1:2 v/v) to give the title compound (50 mg, 79%) as a pale yellow gum. δH(CDCl3) 0.00 (6H, s), 0.06 (6H, s), 0.80 (9H, s), 0.83 (9H, s), 1.30-1.40 (4H, m), 1.70-1.75 (2H, m), 2.00-2.05 (2H, m), 2.60-2.70 (1H, m), 4.55-4.65 (1H, m), 6.10 (1H, d), 6.23 (1H, dd), 6.40 (1H, s), 6.76-7.20 (5H, m).
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:29]([N:36]2[CH2:40][CH2:39][C:38](F)(F)[CH2:37]2)C2N=NNC=2N=1)(C)(C)C.Br.BrCCC1C=CN=CC=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][CH2:15][C:38]3[CH:37]=[CH:29][N:36]=[CH:40][CH:39]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: Br
Agent: BrCCc1ccncc1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CCc3ccncc3)nc2n1

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 4-(2-bromoethyl)pyridine hydrobromide and isolated as white solid. MS (m/e): 388.3 (MH+).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.Cl.[NH2:20][OH:21].C([O-])(=O)C.[Na+]>C(O)C>[OH:21][N:20]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1
Reactant: NO
Reactant: O=C(O)Cc1ccc(CC2CCCCC2=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)Cc1ccc(CC2CCCCC2=NO)cc1
Yield: 103.1 %

Procedure:
A solution of 0.64 g of 4-(2-oxocyclohexan-1-ylmethyl)phenylacetic acid, 0.19 g of hydroxylamine hydrochloride, and 0.45 g of anhydrous sodium acetate in 10 ml of 80% ethanol was heated under reflux for 2 hours. The solvent was removed by distillation, water and ethyl acetate were added to the residue, the mixture was acidified by addition of diluted hydrochloric acid, the ethyl acetate layer separated and the water layer was then extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, the solvent removed by distillation to give 0.7 g of the desired compound, which by recrystallization from ethyl acetate afforded colorless crystals, m.p. 180°-184° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:33])[CH:24]=[CH:23][C:22]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])=[CH:21][CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:22]3[CH:23]=[CH:24][C:19]([CH3:33])=[CH:20][CH:21]=3)=[O:31])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1ccc(-c2ocnc2C(=O)O)cc1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3ccc(C)cc3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-p-tolyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.04 min; [M+H]+=391.15.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]([O:39][C@H:40]1[C@@H:44]([O:45][C:46](=[O:48])[CH3:47])[C@@H:43](OC(=O)C)[O:42][C@@H:41]1[C:53]1[O:57][N:56]=[C:55]([CH2:58][CH3:59])[CH:54]=1)(=[O:38])[CH3:37].C(O[C@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)O[C@@H]1C1ON=C(CC)C=1)(=O)C>>[C:46]([O:45][C@@H:44]1[C@H:40]([O:39][C:36](=[O:38])[CH3:37])[C@@H:41]([C:53]2[O:57][N:56]=[C:55]([CH2:58][CH3:59])[CH:54]=2)[O:42][C@H:43]1[N:14]1[CH:13]=[N:12][C:11]2[C:15]1=[N:16][C:17]([C:19]([NH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:20])=[N:18][C:10]=2[NH:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:48])[CH3:47]
Reactant: O=C(NCCN1CCCCC1)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Reactant: CCc1cc([C@H]2O[C@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)on1
Agent: CCc1cc([C@H]2O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)on1
Product: CCc1cc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(C(=O)NCCN5CCCCC5)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)on1

Procedure:
Prepared by the same method as Preparation 27 from 6-[(2,2-diphenylethyl)amino]-N-[2-(1-piperidinyl)ethyl]-9H-purine-2-carboxamide (Preparation 11) and a mixture of (2S,3R,4R,5R)-4,5-bis(acetyloxy)-2-(3-ethyl-5-isoxazolyl)tetrahydro-3-furanyl acetate and (2S,3R,4R,5S)-4,5-bis(acetyloxy)-2-(3-ethyl-5-isoxazolyl)tetrahydro-3-furanyl acetate (WO-A-9967262).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[NH2:20][CH2:21][CH:22]1[CH2:27][O:26][CH2:25][CH2:24][NH:23]1>>[NH2:20][CH2:21][CH:22]1[N:23]([C:10]2[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:15])[CH2:24][CH2:25][O:26][CH2:27]1
Reactant: NCC1COCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOCC3CN)c(F)c21

Procedure:
By the use of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 3-(aminomethyl)morpholine, the reaction is similarly carried out as Example 1 to give 7-[3-(aminomethyl)morpholino]-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[S:11][CH:12]=2)=[CH:4][C:3]=1[F:19].Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C:14]([CH3:17])([CH3:18])[CH2:15][O:16][C:21]3=[O:23])[S:11][CH:12]=2)=[CH:4][C:3]=1[F:19]
Reactant: CC(C)(CO)Nc1nc(-c2ccc(Cl)c(F)c2)cs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(Cl)c(F)c2)cs1

Procedure:
In the same manner as described in step 7 of Example 78, using 2-[4-(4-chloro-3-fluoro-phenyl)-thiazol-2-ylamino]-2-methyl-propan-1-ol (810 mg, 2.66 mmol), prepared in the previous step, triphosgene (946 mg, 3.19 mmol) and diisopropylethyl amine (1.1 mL) in 20 mL of methylene chloride, the title compound was isolated (125 mg, 14%) after purification on silica gel using 6:1 hexane:ethyl acetate as the eluent. mp 140-142° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].Br[CH2:11][CH2:12][F:13].C(N(C(C)C)CC)(C)C>CCOCC>[CH2:5]([O:4][CH:3]([O:7][CH2:8][CH3:9])[CH2:2][NH:1][CH2:11][CH2:12][F:13])[CH3:6]
Reactant: FCCBr
Reactant: CCOC(CN)OCC
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CNCCF)OCC

Procedure:
A solution of 3.1 ml (21.5 mmol) of 1-amino-2,2-diethoxyethane, 3.0 g (23.6 mmol) of 1-bromo-2-fluoroethane and 5.56 g (43 mmol) of diisopropylethylamine was heated at 100° C. in a closed vessel for 6 hours. The reaction mixture was diluted with ether and washed with 1N NaOH and water. The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was distilled in vacuo. 1.3 g of substance were obtained as a clear liquid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[C:15]([F:23])=[C:16]([CH:20]=[CH:21][N:22]=1)[C:17](O)=[O:18].[BH4-].[Na+].Cl>C1COCC1.O>[Cl:13][C:14]1[C:15]([F:23])=[C:16]([CH2:17][OH:18])[CH:20]=[CH:21][N:22]=1
Reactant: O=C(O)c1ccnc(Cl)c1F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccnc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Carbonyldiimidazole (1.80 g, 11.1 mmol) was added to a solution of 2-chloro-3-fluoro-isonicotinic acid (1.3 g, 7.41 mmol) in THF (21.2 mL). The reaction mixture was stirred at RT overnight and was then added to a cold (0° C.) solution of NaBH4 (1.40 g, 37 mmol) in water (52.9 mL). The mixture was stirred for 10 min at 0° C., and 1M HCl was then added carefully to quench the reaction (caution: H2 evolving). Volatiles were removed via rotary evaporation and the residue was dissolved in saturated aqueous NaHCO3. The mixture was extracted repeatedly with CH2Cl2, the combined organics were dried (phase separator) and concentrated in vaccuo. Purification by flash column chromatography on silica gel (eluent gradient: c-hexane/EtOAc 4:1 to 2:1) afforded the title compound as a white solid. TLC, Rf (c-hexane/EtOAc 1:1)=0.37; MS (LC/MS): 162.0 [M+H]+; tR (HPLC conditions b): 1.60 min.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=[O:3])[CH3:2].[CH:24]([S:27]([NH:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)(=[O:29])=[O:28])([CH3:26])[CH3:25]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)/[C:6](=[C:13](/[NH:35][C:34]2[CH:36]=[CH:37][C:31]([NH:30][S:27]([CH:24]([CH3:26])[CH3:25])(=[O:29])=[O:28])=[CH:32][CH:33]=2)\[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)/[C:5]1=[O:23])(=[O:3])[CH3:2]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: CC(C)S(=O)(=O)Nc1ccc(N)cc1
Product: CC(=O)N1C(=O)/C(=C(\Nc2ccc(NS(=O)(=O)C(C)C)cc2)c2ccccc2)c2ccccc21

Procedure:
Prepared analogously to Example 1c from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-isopropylsulphonylamino-aniline.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:17]=[CH:18][N:19]3[C:24]=2[C:23]([NH:25][C:26]2[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=2)[N:31]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)[N:30]=[CH:29]4)=[N:22][CH:21]=[N:20]3)[CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+]>CO>[F:42][C:38]1[CH:37]=[C:36]([CH:41]=[CH:40][CH:39]=1)[CH2:35][N:31]1[C:32]2[C:28](=[CH:27][C:26]([NH:25][C:23]3[C:24]4=[C:16]([CH2:15][N:12]5[CH2:11][CH2:10][CH:9]([NH:8][C:5](=[O:7])[CH3:6])[CH2:14][CH2:13]5)[CH:17]=[CH:18][N:19]4[N:20]=[CH:21][N:22]=3)=[CH:34][CH:33]=2)[CH:29]=[N:30]1
Reactant: CC(=O)OC(C)=O
Reactant: NC1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)NC1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Acetic anhydride (25 uL, 2.3 equiv.) was added to a mixture of [5-(4-amino-piperidin-1-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (47 mg, 0.1 mmole) and K2CO3 (21 mg 0.15 mmole) in MeOH (3 mL) at 0° C. under nitrogen. After 1 h, the reaction was removed from the ice bath and the mixture was left stirred at RT overnight. The solvent was removed and the residue was taken up in DCM, washed with water and dried (Na2SO4). Removal of the solvent followed by radial chromatography (2 mm silica gel plate, gradient elution with DCM containing 0 to 3% MeOH) afforded the title compound as a solid (41 mg, 80%). MS: 513 (M+H)+; HPLC Ret Time: 1.12 min (Xterra 3.0×50 mm S7 C18 column, 2 min gradient, 5 mL/min).
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[CH:22][C:23]([OH:30])=[C:24]([CH:29]=1)[C:25]([NH:27][NH2:28])=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1.[CH2:37]([O:45][C:46](Cl)=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].O>CC(N(C)C)=O>[CH2:37]([O:45][C:46]([N:27]([C:25](=[O:26])[C:24]1[CH:29]=[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:21]=[CH:22][C:23]=1[OH:30])[NH2:28])=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCOC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(O)c(C(=O)NN)c1
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(O)c(C(=O)N(N)C(=O)OCCCCCCCC)c1
Temperature: 80 °C

Procedure:
42 g of 5-octadecoxy-2-hydroxybenzoic acid hydrazide are suspended in 200 ml of dimethylacetamide and 8 g of pyridine and 19.3 g of chloroformic acid n-octyl ester are added simultaneously over the course of 30 minutes. The reaction mixture is subsequently heated to 80° C for 5 hours whilst stirring, cooled and poured into 1 litre of water. This produces a white precipitate of the N-(5-octadecoxy-2-hydroxybenzoyl)-hydrazinecarboxylic acid n-octyl ester which has been formed (Stabiliser No. 9). The substance is isolated, washed with water, dried at 60° C and recrystallised from acetonitrile. Melting point 85° C.
Reaction SMILES: O=[C:2]([CH2:5][CH2:6][CH2:7][CH3:8])[CH:3]=O.O=C(C)C=O.CC1[N:16]=[C:17]([OH:24])[C:18]([C:21]([NH2:23])=[O:22])=[N:19]C=1.NC(C(N)=O)C(N)=O>>[CH2:5]([C:2]1[N:16]=[C:17]([OH:24])[C:18]([C:21]([NH2:23])=[O:22])=[N:19][CH:3]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCC(=O)C=O
Reactant: Cc1cnc(C(N)=O)c(O)n1
Agent: CC(=O)C=O
Agent: NC(=O)C(N)C(N)=O
Product: CCCCc1cnc(C(N)=O)c(O)n1

Procedure:
2-Oxohexanal (F. Ballistreri, et al., J. Organic Chem., 53, 830 (1988) is reacted (according to the method described by F. L. Muehlmann and A. R. Day in J. American Chem. Soc., 78, 242-4(1956) substituting 2-oxohexanal for the 2-oxopropanal used in the synthesis of 5-methyl-3-hydroxypyrazine-2-carboxamide) with aminomalonamide to give 5-n-butyl-3-hydroxypyrazine-2-carboxamide. The amide is hydrolyzed with sodium hydroxide in water at 95° C. to give 5-n-butyl-3-hydroxypyrazine-2-carboxylic acid. The acid is converted to the corresponding ester with methanol and hydrochloric acid and the ester is chlorinated with phosphorous oxychloride (according to the method described by G. Dick and H. Wood in J. Chem. Soc., 1955, 1379-82) to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([N:19]3[C:31]4[CH:30]=[C:29]5[C:32]([CH3:62])([CH3:61])[C:33]6[C:38]([C:28]5=[CH:27][C:26]=4[C:25]4[C:20]3=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:37][CH:36]=[CH:35][C:34]=6[C:39]3[CH:40]=[C:41]4[C:49](=[CH:50][CH:51]=3)[NH:48][C:47]3[CH:46]=[C:45]5[C:52]([CH3:60])([CH3:59])[C:53]6[C:58]([C:44]5=[CH:43][C:42]4=3)=[CH:57][CH:56]=[CH:55][CH:54]=6)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1.CC([O-])(C)C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>CC1C=CC(C)=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:13]1([C:11]2[N:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([N:19]3[C:31]4[CH:30]=[C:29]5[C:32]([CH3:62])([CH3:61])[C:33]6[C:38]([C:28]5=[CH:27][C:26]=4[C:25]4[C:20]3=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:37][CH:36]=[CH:35][C:34]=6[C:39]3[CH:40]=[C:41]4[C:49](=[CH:50][CH:51]=3)[N:48]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[C:47]3[CH:46]=[C:45]5[C:52]([CH3:60])([CH3:59])[C:53]6[C:58]([C:44]5=[CH:43][C:42]4=3)=[CH:57][CH:56]=[CH:55][CH:54]=6)[N:10]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccc(-c2cccc4c2C(C)(C)c2cc5c(cc2-4)c2ccccc2n5-c2nc(-c4ccccc4)nc(-c4ccccc4)n2)cc13
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccc(C)cc1
Product: CC1(C)c2ccccc2-c2cc3c4cc(-c5cccc6c5C(C)(C)c5cc7c(cc5-6)c5ccccc5n7-c5nc(-c6ccccc6)nc(-c6ccccc6)n5)ccc4n(-c4ccccc4)c3cc21

Procedure:
21.0 g (26 mmol) of 7-{10-(4,6-diphenyl-1,3,5-triazin-2-yl)-12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluorenyl}-12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluorene, 2.8 g (27 mmol) of bromobenzene and 6.8 g (71 mmol) of NaOtBu are suspended in 1000 ml of p-xylene. 0.11 g (0.5 mmol) of Pd(OAc)2 and 0.33 ml of a 1 M tri-tert-butylphosphine solution are added to this suspension. The reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, washed three times with 100 ml of water and subsequently evaporated to dryness. The residue is extracted with hot toluene, recrystallised from toluene and finally sublimed in a high vacuum. The yield is 15.3 g (18 mmol, 66.5%).
Reaction SMILES: C([C:4]1[C:12]2[CH:11]=[C:10]([B:13]([OH:15])[OH:14])[S:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(O)=O.S1C=CC2C=CC([C:25]([OH:27])=[O:26])=CC1=2>>[C:25]([C:6]1[CH:5]=[CH:4][C:12]2[CH:11]=[C:10]([B:13]([OH:14])[OH:15])[S:9][C:8]=2[CH:7]=1)([OH:27])=[O:26]
Reactant: O=C(O)c1ccc2ccsc2c1
Reactant: O=C(O)c1cccc2sc(B(O)O)cc12
Product: O=C(O)c1ccc2cc(B(O)O)sc2c1
Yield: 86 %

Procedure:
The title compound (120 g, 86%) is prepared essentially as described in the preparation of 4-carboxy-benzo[b]thiophen-2-boronic acid utilizing benzo[b]thiophene-6-carboxylic acid, ES/MS m/e 221 M−1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.[CH2:11]1[CH2:17][S:14](=[O:16])(=[O:15])[O:13][CH2:12]1.CC(=O)OCC>C(#N)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][CH2:12][CH2:11][CH2:17][S:14]([OH:16])(=[O:15])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCO1
Reactant: NCCc1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=S(=O)(O)CCCNCCc1ccc(Br)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of 4-Bromophenethylamine (4 g, 20 mmol) and 1,3-propane sultone (2.56 g, 21 mmol) in acetonitrile (30 mL) was heated at reflux for 2.5 hours. The mixture was cooled to room temperature. The solid was collected by filtration, rinsed with acetonitrile (2×5 mL) air-dried for 15 minutes (9.57 g), and further dried for 15 minutes in vacuo (8.02 g). The solid was suspended in ethanol (40 mL) and the suspension was heated at reflux for 1 hour. The mixture was then cooled to room temperature. The solid was collected by suction filtration, rinsed with ethanol (2×5 mL), air-dried for 15 minutes, and further dried in a vacuum oven at 60° C. for 18 hours. Compound EA was obtained as a white solid (6.04 g, 18.8 mmol, 94% yield). 1H NMR (500 MHz, DMSO) δ 1.95 (t, J=6.3 Hz, 3H), 2.63 (t, J=6.1 Hz, 2H), 2.88 (t, J=7.6 Hz, 2H), 3.09 (t, J=6.3 Hz, 2H), 3.15 (t, J=7.8 Hz, 2H), 7.25 (2, J=7.8 Hz, 2H), 7.53 (2, J=7.8 Hz, 2H), 8.63 (br s, 2H). 13C NMR (125 MHz, DMSO) δ 21.8, 31.0, 46.7, 47.2, 48.8, 119.9, 131.0, 131.4, 136.5. ES-MS 324 (M+1).
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1>>[N:7]1([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:8]2[CH:9]=[N:1][CH:2]=[N:3][C:4]=2[N:5]=[CH:6]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1ncc2[nH]cnc2n1
Product: O=[N+]([O-])c1ccc(-n2cnc3ncncc32)cc1

Procedure:
Prepared from purine and 1-fluoro-4-nitrobenzene as described for Example 1, Step 1. The product precipitated from the reaction mixture as a single isomer; δ (D6 -DMSO) 8.16 (2H, d, J=9.0Hz, Ar--H), 8.48 (2H, d, J=9.0Hz, Ar--H), 9.13 (1H, s, Ar--H), 9.28 (1H, s, Ar--H), 9.39 (1H, s, Ar--H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH2:9]([S:13]CCCC)[CH2:10][CH2:11][CH3:12]>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([S:13][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:3][CH:4]=1
Reactant: Cc1ccc(I)cc1
Reactant: CCCCSCCCC
Product: CCCCSc1ccc(C)cc1

Procedure:
The general procedure was used to convert 4-iodotoluene and n-butyl sulfide to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (331 mg, 94% yield). 1H NMR (300 MHz, CDCl3) δ 7.15–7.12 (d, J=8.2, 2H; Ha, Ha′), 6.98–6.96 (d, J=7.9, 2H; Hb, Hb′), 2.79–2.74 (t, J=7.1, 2H; Hc), 2.20 (Methyl Protons), 1.55–1.45 (m, 2H; Hd), 1.39–1.15 (m, 2H; He), 0.83–0.78 (t, J=7.1, 3H; Hf). 13C NMR (75 MHz, CDCl3) δ 135.6 (C4), 133 (C3), 129.6 (C1, C1′), 129.47 (C2, C2), 33.8 (methyl protons), 31.2 (C5), 21.8 (C6), 20.8 (C7), 13.54 (C8). Anal. Calcd. for C11H16S: C, 73.27; H, 8.94; S, 17.78; Found C, 73.21; H, 9.15; S, 17.57.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[NH:16][C:17]4[CH2:18][CH2:19][CH2:20][C:21](=[O:39])[C:22]=4[CH:23]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C@@H:35]([OH:38])[CH2:36][OH:37])=[CH:29][CH:28]=4)[C:24]=3[C:25]#[N:26])[N:12]=2)=[CH:4][CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:24]([C:25]#[N:26])=[C:23]([C:27]4[CH:28]=[CH:29][C:30]([O:33][CH2:34][C@@H:35]([OH:38])[CH2:36][OH:37])=[CH:31][CH:32]=4)[C:22]4[C:21](=[O:39])[CH2:20][CH2:19][CH2:18][C:17]=4[N:16]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: N#CC1=C(SCc2csc(-c3ccc(Cl)cc3)n2)NC2=C(C(=O)CCC2)C1c1ccc(OC[C@@H](O)CO)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc2c(c1-c1ccc(OC[C@@H](O)CO)cc1)C(=O)CCC2

Procedure:
At RT, 100 mg (0.172 mmol) of the compound from Example 5A and 40 mg (0.174 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone were stirred overnight in 6 ml of dichloromethane. The reaction solution was diluted with dichloromethane and water, and the two phases were separated. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were concentrated and purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% TFA).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:22][C:21](Cl)=[N:20][C:19]=4[CH:18]=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:33][O:34][C:35]1[N:40]=[C:39]([O:41][CH3:42])[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1>>[CH3:33][O:34][C:35]1[N:40]=[C:39]([O:41][CH3:42])[C:38]([C:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[C:24]3[S:25][C:17]([CH2:16][N:13]4[CH2:14][CH2:15][N:10]([S:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)(=[O:9])=[O:8])[CH2:11][CH2:12]4)=[CH:18][C:19]=3[N:20]=2)=[CH:37][N:36]=1
Reactant: O=S(=O)(c1ccccc1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Product: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(=O)(=O)c5ccccc5)CC4)cc3n2)c(OC)n1

Procedure:
6-(4-Benzenesulfonyl-piperazin-1-ylmethyl)-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (described above) was reacted with 2,4-dimethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine in General Procedure A. Purification on silica yielded 260. NMR (400 MHz, CDCl3): 2.56-2.58 (4H, m, CH2), 3.04 (4H, m, CH2), 3.74-3.77 (6H, m, CH2), 3.88-3.91 (4H, m, CH2), 3.98 (3H, s, CH3), 4.01 (3H, s, CH3), 7.21 (1H, s, ar), 7.47-7.51 (2H, m, ar), 7.54-7.58 (1H, m, ar), 7.71 (2H, d (J=7.13), ar), 8.84 (1H, s, ar). (M+H)+ 598.28