Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[S:10][CH:11]=[C:12]([Br:14])[N:13]=2)[CH:5]=[C:4]([CH3:15])[C:3]=1[N:16]=[C:17]=[S:18].[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[S:10][CH:11]=[C:12]([Br:14])[N:13]=2)[CH:5]=[C:4]([CH3:15])[C:3]=1[NH:16][C:17]([NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[S:18]
Reactant: CC(C)(C)N
Reactant: Cc1cc(Oc2nc(Br)cs2)cc(C)c1N=C=S
Solvent: C1CCOC1
Product: Cc1cc(Oc2nc(Br)cs2)cc(C)c1NC(=S)NC(C)(C)C
Temperature: 0 °C

Procedure:
2.1 g of 2,6-dimethyl-4-(4-bromothiazol-2-yloxy)-phenylisothiocyanate and 0.7 g of tert-butylamine in 20 ml tetrahydrofuran are heated for 6 hours to 40° C. The batch is poured into 200 ml of ice-water and the precipitate is isolated by filtration. Recrystallisation of the precipitate from methanol affords the title compound of formula ##STR24## in crystalline form with a melting point of 143°-144° C. (compound 3.01).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[C:4]([C:18]([F:21])=[CH:19][CH:20]=1)[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=2)[NH:9][CH:8]=1)=[O:6].[N:23]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1.Cl>O1CCCC1.N1C=CC=CC=1>[C:16]([C:13]1[CH:14]=[C:15]2[C:7]([C:5]([C:4]3[C:3]([F:22])=[C:2]([NH:1][S:28]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)(=[O:30])=[O:29])[CH:20]=[CH:19][C:18]=3[F:21])=[O:6])=[CH:8][NH:9][C:10]2=[N:11][CH:12]=1)#[N:17]
Reactant: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(N)c3F)c2c1
Reactant: O=S(=O)(Cl)N1CCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(NS(=O)(=O)N4CCCC4)c3F)c2c1
Temperature: 60 °C
Reaction time: 48 h
Yield: 24.7 %

Procedure:
To 3-(3-amino-2,6-difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (28, 354 mg, 1.19 mmol) in 9.5 mL of tetrahydrofuran, 0.84 mL of pyridine was added. Pyrrolidine-1-sulfonyl chloride (31, 403 mg, 2.37 mmol) was added and the solution was stirred at 60° C. for 48 hours. The reaction mixture was poured into 1 M aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions were combined and the solvent removed under reduced pressure to provide the desired compound (P-0006, 127 mg). MS(ESI)[M+H+]+=432.1.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]([S:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:5]3[CH:14]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:12][N:6]3[C:7]=2[CH:8]=[C:9]([F:11])[CH:10]=1.C[Mg+].[Br-].[Li]CCCC.CCCCCC.[CH:41](=[O:44])[CH2:42][CH3:43]>C1COCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([S:19][C:4]2[C:3]3[C:2]([CH:41]([OH:44])[CH2:42][CH3:43])=[CH:10][C:9]([F:11])=[CH:8][C:7]=3[N:6]3[CH2:12][CH2:13][CH:14]([CH2:15][C:16]([OH:18])=[O:17])[C:5]=23)=[CH:21][CH:22]=1
Reactant: CCC=O
Reactant: O=C(O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Agent: C[Mg+]
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(O)c1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
To a solution of (+)-[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetic acid (Example 7A, 700 mg, 1.5 mmol) in THF (15 mL) at −78° C. was added 3M MeMgBr in THF (1.9 mmol) followed by the addition of 1.6M nBuLi in hexane (3.1 mmol). The reaction mixture was stirred at −78° C. for 2 minutes and an excess of propionaldehyde was added. The reaction mixture was stirred at −78° C. for 15 minutes, warmed to r.t and quenched with saturated aqueous NH4Cl The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with EtOAc/hexanes/AcOH (20:30:1) to provide the title compound as a white solid.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14]([O:16][C:17](=[O:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[CH3:15].[Br:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([C:39]2[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][CH:40]=2)=[CH:36][CH2:37]O)=[CH:31][CH:30]=1>C1COCC1>[CH2:14]([O:16][C:17](=[O:27])[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:37][CH:36]=[C:35]([C:32]2[CH:31]=[CH:30][C:29]([Br:28])=[CH:34][CH:33]=2)[C:39]2[CH:40]=[CH:41][C:42]([Br:45])=[CH:43][CH:44]=2)=[CH:24][CH:25]=1)[CH3:15]
Reactant: CCOC(=O)CCc1ccc(O)cc1
Reactant: OCC=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(OCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.9 %

Procedure:
Under a atmosphere of nitrogen, azodicarboxylic dipiperidide (504 mg, 2.0 mmol) was added at 0-5° C. to a stirred solution of tributylphosphine (404 mg, 2.0 mmol), 3-(4-hydroxy-phenyl)-propionic acid ethyl ester (388 mg, 2.0 mmol) and 3,3-bis-(4-bromophenyl)prop-2-en-1-ol (736 mg, 2.0 mmol) in dry THF (50 ml), the mixture warmed to room temperature, and stirred for 4 h. The reaction mixture was concentrated in vacuo, and added water and ethyl acetate (75 ml each). The aqueous layer was collected and further extracted with ethyl acetate (2×75 ml). The organic layers were combined, washed with water, dried (MgSO4) and evaporated. The crude product was then purified by column chromatography on silica (25% ethylacetane in heptane eluent) to give 1.0 g (92%) of the title compound.
Reaction SMILES: Cl.C([O:4][C:5](=[O:18])[CH2:6][CH2:7][NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)C.C([NH:29][C@H:30]([C:32](O)=[O:33])[CH3:31])(OCC1C=CC=CC=1)=O>>[NH2:29][C@H:30]([C:32]([N:8]([CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17]1)[CH2:7][CH2:6][C:5]([OH:4])=[O:18])=[O:33])[CH3:31]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)CCNC1Cc2ccccc2C1
Agent: Cl
Product: C[C@H](N)C(=O)N(CCC(=O)O)C1Cc2ccccc2C1
Yield: 69.7 %

Procedure:
By reacting 7 g of N-(indan-2-yl)-β-alanine ethyl ester hydrochloride with 7 g of N-carbobenzoxy-L-alanine and treating the reaction mixture as in Reference Example 4, there is obtained 5 g of L-alanyl-N-(indan-2-yl)-β-alanine. Melting point 205°-206° C.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:14][N:8]2[CH2:9][CH2:10][NH:11][C:12](=O)[C@@H:7]2[CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:2][CH2:3][C@@H:5]1[CH2:14][N:8]2[CH2:9][CH2:10][NH:11][CH2:12][C@@H:7]2[CH2:6]1
Reactant: COC(=O)[C@H]1C[C@H]2C(=O)NCCN2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@H]1C[C@H]2CNCCN2C1
Reaction time: 1 h
Yield: 101.4 %

Procedure:
A solution of 1.75 g (8.84 mmol) of (7S,8aS)-7-methoxycarbonyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazin-1-one (Preparation 11) in 100 mL of THF was added dropwise to a suspension of 0.67 g (18 mmol) of lithium aluminum hydride in 100 mL of refluxing tetrahydrofuran (THF). After stirring for 1 hour, the solution was cooled and carefully quenched with 0.67 mL of water, 0.67 mL of 15% sodium hydroxide, and 2.0 mL of water. The precipitate was filtered and the filtrate was concentrated to give 1.4 g of (7S,8aS)-7-hydroxymethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine of sufficient purity for use in subsequent reactions.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[NH:23][C:22](=[O:24])[C:21]4[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=4[O:25][CH3:26])[N:15]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CI.[CH3:31]CN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:26][O:25][C:20]1[CH:19]=[C:18]([O:27][CH3:28])[CH:17]=[C:16]2[C:21]=1[C:22](=[O:24])[NH:23][C:14]([C:11]1[CH:12]=[CH:13][C:8]([N:1]3[CH2:7][CH2:6][CH2:5][N:4]([CH3:31])[CH2:3][CH2:2]3)=[CH:9][CH:10]=1)=[N:15]2
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCCNCC4)cc3)nc2c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCCN(C)CC4)cc3)nc2c1
Temperature: 50 °C
Yield: 22.8 %

Procedure:
To a solution of 2-(4-(1,4-diazepan-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.150 g, 0.39 mmol) in DMF (20 mL) was added CH3I (0.067 g, 0.47 mmol) and Hünig's Base (0.138 mL, 0.79 mmol). The reaction mixture was heated at 50° C. for 1.5 hours, cooled to room temperature, diluted with ethyl acetate (150 mL), washed with brine (2×100 mL), dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 1:1 CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH, to afford the title compound (0.035 g, 23%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 11.66 (s, 1H), 8.06 (d, J=9.0 Hz, 2H), 6.78 (d, J=9.0 Hz, 2H), 6.65 (d, J=2.2 Hz, 1H), 6.44 (d, J=2.2 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.57-3.59 (m, 2H), 3.52 (t, J=6.1 Hz, 2H), 2.60-2.64 (m, 2H), 2.45-2.50 (m, 2H), 2.26 (s, 3H), 1.89-1.99 (m, 2H). ESI MS m/z 395 [M+H]+.
Reaction SMILES: [OH:1][C:2]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](OCCCC)=[O:16])[CH2:11][CH2:10]1)([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH3:3].C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CO>[OH:16][CH2:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([C:2]([C:4]2[S:5][CH:6]=[CH:7][N:8]=2)([OH:1])[CH3:3])[CH2:10][CH2:11]1
Reactant: CCCCOC(=O)[C@H]1CC[C@H](C(C)(O)c2nccs2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)(c1nccs1)[C@H]1CC[C@H](CO)CC1
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
Butyl trans-4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexanecarboxylate (150 mg, 0.482 mmol) was placed in a vial under an atmosphere of nitrogen and THF (2 mL) was added. Lithium aluminum hydride (3.5 M in THF, 0.270 mL, 0.945 mmol) was added. After 20 min of stirring at 23° C. the reaction was diluted carefully with methanol (5 mL) via dropwise addition. The resulting white suspension was filtered through CELITE, and the filtrate was concentrated to afford 1-[trans-4-(hydroxymethyl)cyclohexyl]-1-(1,3-thiazol-2-yl)ethanol, which was used in subsequent synthetic transformations without purification. MS ESI calc'd. for C12H19NO2S [M+H]+ 242. found 242.
Reaction SMILES: [SH:1][CH2:2][CH2:3][N:4]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:5](=[O:18])[NH:6][C@@H:7]([CH3:17])[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)=[O:9].C(N(CC)CC)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)(Cl)Cl>[C:34]([S:1][CH2:2][CH2:3][N:4]([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:5](=[O:18])[NH:6][C@@H:7]([CH3:17])[C:8]([N:10]1[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]1)=[O:9])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H](NC(=O)N(CCS)CCc1ccccc1)C(=O)N1CCN(C)CC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)N(CCSC(=O)c1ccccc1)CCc1ccccc1)C(=O)N1CCN(C)CC1

Procedure:
1-[(2S)-2-[3-(2-Mercaptoethyl)-3-phenethylureido]propionyl]-4-methylpiperazine (Compound No. 30-1, 32.9 g)is dissolved in chloroform (87 ml) under a nitrogen atmosphere, and the solution is stirred. To the solution are added triethylamine (13.3 ml) and then benzoyl chloride (10.1 ml )dropwise under ice cooling, and the mixture is stirred for 25 minutes. The reaction mixture is concentrated under reduced pressure, a 10% aqueous sodium hydrogencarbonate solution is added to the residue, and the whole is extracted with ethyl acetate. The organic layer is washed with a 10% aqueous sodium hydrogencarbonate solution, water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give the titled compound (Compound No. 32-1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl.[CH:10]([C:12]([CH3:14])=O)=[CH2:11]>C(O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[CH:11][CH:10]=[C:12]2[CH3:14]
Reactant: C=CC(C)=O
Reactant: Nc1ccccc1F
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c(F)cccc12
Temperature: 60 °C

Procedure:
To a solution of 2-fluoroaniline (25 ml) in ethanol (185 ml) was added concentrated hydrochloric acid (21 ml), iron (III) chloride hexahydrate (111 g) and zinc (II) chloride (4.1 g) and the resulting mixture was heated to 60° C. Methyl vinyl ketone (25 ml) was added dropwise over 45 min. then the mixture was refluxed for 2 hrs. The reaction mixture was allowed to cool then evaporated under reduced pressure. The resulting oil was basified to pH 12 with 2M sodium hydroxide solution, filtered through arbocel and then the aqueous was extracted with ethyl acetate (×2). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with i-hexane/diethyl ether (3:1) followed by i-hexane/diethyl ether (2:1) to give the sub-title compound as a solid (8.25 g).
Reaction SMILES: [CH3:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2=[C:10]3[C:15](=[N:16][C:17]4=[CH:18][CH:19]=[CH:20][C:4](=[C:5]24)[O:3]1)[CH2:14][CH2:13][CH2:12][CH2:11]3.CC(C)([O-])C.[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O.O>[CH2:27]([N:7]1[C:6]2=[C:10]3[C:15](=[N:16][C:17]4=[CH:18][CH:19]=[CH:20][C:4](=[C:5]24)[O:3][CH:2]([CH3:1])[C:8]1=[O:9])[CH2:14][CH2:13][CH2:12][CH2:11]3)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CC1Oc2cccc3nc4c(c(c23)NC1=O)CCCC4
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1Oc2cccc3nc4c(c(c23)N(Cc2ccccc2)C1=O)CCCC4
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To a suspension of 1,3,9,10,11,12-hexahydro-3-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (5.0 g) in dry dimethylformamide (60 ml) was added potassium t-butoxide (3.15 g), with stirring. After 15 mins, benzyl bromide (2.66 ml) was added, and the reaction mixture was stirred for two hrs. The reaction mixture was diluted with water (300 ml), extracted twice with 100 ml-portions of diethyl ether, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was adhered to silica and flash chromatographed (10-30% ethyl acetate/hexane). The mixed fractions were flash chromatographed (3% ethyl acetate/dichloromethane), and the appropriate fractions were combined, and concentrated. Trituration of the residue with (1/1-diethyl ether/pentane) gave 4.58 g (68%) of 1-benzyl-3-methyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10](Cl)(=[O:12])[CH3:11].[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:40][CH3:41])=[CH:30][C:31]=3[O:33][CH2:34][C@H:35]3[CH2:39][CH2:38][CH2:37][NH:36]3)[N:26]=[CH:25][N:24]=2)[CH:18]=[CH:19][C:20]=1[F:21]>C(Cl)Cl>[C:10]([N:36]1[CH2:37][CH2:38][CH2:39][C@@H:35]1[CH2:34][O:33][C:31]1[CH:30]=[C:29]([O:40][CH3:41])[CH:28]=[C:27]2[C:32]=1[C:23]([NH:22][C:17]1[CH:18]=[CH:19][C:20]([F:21])=[C:15]([Cl:14])[CH:16]=1)=[N:24][CH:25]=[N:26]2)(=[O:12])[CH3:11]
Reactant: COc1cc(OC[C@H]2CCCN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC[C@H]2CCCN2C(C)=O)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reaction time: 1 h
Yield: 83 %

Procedure:
N,N-Diisopropylethylamine (52 μl) and acetyl chloride (21 μl) were added sequentially, each in one portion, to a stirred mixture of N-(3-chloro-4-fluorophenyl)-7-methoxy-5-[(2R)-pyrrolidin-2-ylmethoxy]-quinazolin-4-amine (100 mg) in DCM (2 ml) at room temperature. The reaction mixture was stirred for 1 hour and then diluted with DCM (10 ml) and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried (MgSO4) and concentrated in vacuo to leave a yellow solid, which was purified by column chromatography using 24% methanol in DCM as eluent, followed by trituration with ether to give the title compound as a white solid (92 mg, 83%); NMR Spectrum (DMSO-d6) 9.90 (br s, 1H), 8.40 (s, 1H), 8.15 (m, 1H), 7.65 (m, 1H), 7.40 (m, 1H), 6.80 (m, 2H), 4.60 (m, 1H), 4.50 (m, 1H), 4.25 (m, 1H), 3.95 (s, 3H), 3.50 (m, 1H), 3.30 (s, 3H), 2.0-1.85 (m, 5H); Mass spectrum MH+ 445.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:25]2[CH2:30][CH2:29][N:28]([CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH2:27][CH2:26]2)=[C:21]([CH:24]=1)[C:22]#[N:23]>>[C:22]([C:21]1[CH:24]=[C:17]([NH:16][C:13]([C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:2]=2[CH3:1])=[O:15])[CH:18]=[CH:19][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH2:27][CH2:26]1)#[N:23]
Reactant: N#Cc1cc(N)ccc1N1CCN(C2CCOCC2)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccccc1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(C4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccccc1
Yield: 69.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 5-methyl-1-phenylpyrazole-4-carboxylic acid (0.5 g) and 5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile (0.7 g), the title compound (0.8 g) was obtained, melting point: 227° C.
Reaction SMILES: [Br:1]Br.[N+:3]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][CH:13]=[CH:14][C:7]=12)([O-:5])=[O:4].C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:14]1[C:7]2[C:8](=[N:9][CH:10]=[CH:11][C:6]=2[N+:3]([O-:5])=[O:4])[NH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccnc2[nH]ccc12
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccnc2[nH]cc(Br)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., 316 μl (6.13 mmol) of bromine are added dropwise to a solution of 1.00 g (6.13 mmol) of 4-nitro-1H-pyrrolo[2,3-b]pyridine (Antonini, Ippolito; Claudi, Francesco; Cristalli, Gloria; Franchetti, Palmarisa; Grifantini, Mario; Martelli, Sante; J. Med. Chem. 1982, 25, 1258-1261.) in 50 ml of dichloromethane. After 1 h of stirring at 0° C. and 1 h of stirring at room temperature, the solution is poured onto a mixture of ice and saturated sodium bicarbonate solution. The mixture is then extracted twice with dichloromethane. The combined organic phases are dried with sodium sulfate, and the solvent is removed under reduced pressure. The residue is taken up in a mixture of cyclohexane/ethyl acetate and the precipitate formed is filtered off.
Reaction SMILES: CCN(C1C=CC=CC=1)CC.Cl[C:13]([O:15][CH3:16])=[O:14].[CH3:17][C:18]([CH3:25])=[CH:19][CH:20]=[N:21][CH:22]([CH3:24])[CH3:23].Cl>C1(C)C=CC=CC=1.O>[CH3:16][O:15][C:13](=[O:14])[N:21]([CH:22]([CH3:24])[CH3:23])[CH:20]=[CH:19][C:18]([CH3:25])=[CH2:17]
Reactant: CC(C)=CC=NC(C)C
Reactant: COC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)c1ccccc1
Product: C=C(C)C=CN(C(=O)OC)C(C)C
Reaction time: 2 h

Procedure:
To a stirred solution of 657 g diethylaniline in 2 l toluene is added dropwise over ca. 5 minutes 416 g methyl chloroformate. 500 g N-(3-methyl-2-butenyliden)-isopropylamine in 500 ml toluene are then added dropwise with stirring over 2 hours, maintaining the temperature between 25° and 30° C. Stirring is continued for 1 hour and the reaction mixture is then treated with 400 ml of water and 90 ml conc. hydrochloric acid. The organic phase is washed with 600 ml of saturated aqueous sodium bicarbonate solution and with 600 ml water, dried and evaporated in vacuo to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[C:7]([C:14]#[N:15])([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([O:5][C:6](=[O:16])[C:7]([CH2:14][NH2:15])([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCC(C#N)(CCC)C(=O)OC(C)(C)C
Agent: [Ni]
Solvent: CO
Product: CCCC(CN)(CCC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
A mixture of 2-cyano-2-propyl-pentanoic acid tert-butyl ester (6.87 g) and Raney Ni (4 mL in water) in MeOH (200 mL) was stirred at rt under H2 atmosphere (balloon) overnight. Then the reaction mixture was filtered over Celite pad, filtrate was concentrated to give the desired product (4.92 g). 1H NMR in CDCl3, δ in ppm: 2.76 (s, 2H), 1.44 (s, 9H), 1.5-1.1 (m, 8H), 0.91 (t, 6H, J=7.0 Hz).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:6](=[O:8])[CH:7]=1.[CH:15]1[C:25]2[CH2:24][CH2:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[S:20][C:19]=2[C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].N#N>O1CCOCC1.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:15]1[C:25]2[CH2:24][CH2:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[S:20][C:19]=2[C:18]([C:2]2[O:3][C:4]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:5][C:6](=[O:8])[CH:7]=2)=[CH:17][CH:16]=1
Reactant: O=c1cc(Cl)oc(N2CCOCC2)c1
Reactant: CC1(C)OB(c2cccc3c2Sc2ccccc2CC3)OC1(C)C
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: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=c1cc(-c2cccc3c2Sc2ccccc2CC3)oc(N2CCOCC2)c1
Temperature: 90 °C
Yield: 4.9 %

Procedure:
2-Chloro-6-morpholin-4-yl-pyran-4-one (3)(1.12 g, 5.2 mmol), 2-(10,11-Dihydro-dibenzo[b,f]thiepin-4-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (880 mg, 2.6 mmol), and ground potassium carbonate (720 mg, 5.2 mmol) were suspended in 1,4-dioxane (10 ml) and degassed for 5 minutes. bis(tri-t-butylphosphine)palladium (66 mg, 0.13 mmol) was then added and the reaction mixture was then heated at 90° C. for 4 hours under a vigorous stirring and a N2 atmosphere. The solvent was removed in vaccuo and the residue was then suspended in water (100 ml). The organics were extracted with dichloromethane (3×100 ml), combined, washed with saturated brine and dried over sodium sulphate. The solvent was removed in vaccuo and the residue was purified by column chromatography (silica; ethyl acetate:ethanol; 9:1) to give a pale brown solid (50 mg, 5%). 1HNMR (300 MHz, DMSO-d6): δH=3.24–3.32 (6H, m), 3.44 (2H, t), 3.66 (4H, t), 5.50 (1H, d), 6.10 (1H, d), 7.08–7.51 (7H, m); m/z (LC-MS, ESP), RT=4.48 min, (M++1)=392.
Reaction SMILES: CC1(C)[NH:6][CH:5]([PH:7](=[O:9])[OH:8])[C:4]([CH3:11])([CH3:10])[S:3]1>O.C(O)(C)C>[NH2:6][CH:5]([PH:7](=[O:8])[OH:9])[C:4]([SH:3])([CH3:11])[CH3:10]
Reactant: CC1(C)NC([PH](=O)O)C(C)(C)S1
Solvent: CC(C)O
Solvent: O
Product: CC(C)(S)C(N)[PH](=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.5 g of DL-(2,2,5,5-tetramethyl-4-thiazolidinyl)-phosphinic acid were dissolved in 10 ml of boiling water and the volume was reduced by boiling for 0.25 hour. The mixture was cooled to room temperature and diluted with 25 ml of isopropanol. The resulting mixture was cooled at 0° C. overnight. The resulting solid was collected, washed with isopropanol and dried to give 0.85 g of DL-(1-amino-2-mercapto-2-methylpropyl)phosphinic acid of melting point 211° C. (decomposition).