Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]#[N:10].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([O:35][C:36]2[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>CN(C=O)C>[C:9]([C:8]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([CH:7]=1)[O:5][CH2:4][CH2:3][NH:2][C:40](=[O:41])[C:39]1[CH:38]=[CH:37][C:36]([O:35][CH:32]2[CH2:31][CH2:30][N:29]([C:27]([O:26][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:28])[CH2:34][CH2:33]2)=[CH:44][CH:43]=1)#[N:10]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)O)cc2)CC1
Reactant: N#Cc1ccc(OCc2ccccc2)c(OCCN)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)NCCOc3cc(C#N)ccc3OCc3ccccc3)cc2)CC1
Reaction time: 8 h

Procedure:
1.06 g (3.50 mmol) of 3-(2-aminoethoxy)-4-benzyloxybenzonitrile hydrochloride was dissolved in 15 ml of DMF. 1.23 g (3.84 mmol) of 4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoic acid, 710 mg (4.2 mmol)) of 2-chloro-1,3-dimethylimidazonium chloride and 1.45 ml (5.19 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. After the treatment with dichloromethane as the extraction solvent in an ordinary manner, the solvent was evaporated, and the obtained residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [O-]Cl=O.[Na+].[OH2:5].[CH2:6]([C:13]1([CH2:19][CH:20]=[O:21])[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CS(C)=O.CCOCC>[CH2:6]([C:13]1([CH2:19][C:20]([OH:5])=[O:21])[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O
Reactant: O=CCC1(Cc2ccccc2)C=CCCC1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CS(C)=O
Solvent: CCOCC
Product: O=C(O)CC1(Cc2ccccc2)C=CCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of NaH2PO4 (55.3 g), NaClO2 (36.3 g), DMSO (200 mL) and water (375 mL) was added a solution of 3-benzyl-3-formylmethylcyclohexene (57 g) in DMSO (150 mL) during a 3 hour period. After addition, the mixture was stirred overnight and diluted with ether (200 mL). This was extracted with saturated NaHCO3 (3×100 mL). The combined aqueous layer was cooled to 0° C. and acidified to PH=1 with conc. HCl. This was extracted with CH2Cl2 (3×300 mL). The combined organic layer was dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel to give the title compound as thick oil (50 g). MS (MH+=231).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3](Cl)=[O:4].[NH2:17][C:18]1[C:19]([O:29][CH3:30])=[CH:20][CH:21]=[C:22]2[C:27]=1[O:26][CH2:25][CH2:24][C:23]2=[O:28].C(N(CC)CC)C.Cl>ClCCl>[CH3:30][O:29][C:19]1[C:18]([NH:17][C:3](=[O:4])[C:2]([CH3:16])([CH3:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:27]2[C:22]([C:23](=[O:28])[CH2:24][CH2:25][O:26]2)=[CH:21][CH:20]=1
Reactant: CCCCCCCCCCC(C)(C)C(=O)Cl
Reactant: COc1ccc2c(c1N)OCCC2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCC(C)(C)C(=O)Nc1c(OC)ccc2c1OCCC2=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.7 %

Procedure:
127 mg of 2,2-dimethyldodecanoyl chloride was added to a solution of 98 mg of 8-amino-7-methoxy-4-chromanone and 0.07 ml of triethylamine in 2 ml of dichloromethane, and the mixture was stirred at room temperature for 12 hr. 15 ml of 2N hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate (25 ml×2). The extract was washed with 25 ml of brine, dried over anhydrous magnesium sulfate, filtered, concentrated and purified by silica gel column chromatography (hexane/ethyl acetate=3:2) to give 198 mg of the intended title compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([C@H:8]2[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]2)[C:6]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:5]=2[N:4]=1.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][CH:24]([CH:29]=O)[CH2:23]2>>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][CH:24]([CH2:29][NH:13][C@H:10]1[CH2:11][CH2:12][C@H:8]([N:7]3[C:6]4[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:5]=4[N:4]=[C:3]3[CH3:2])[CH2:9]1)[CH2:23]2
Reactant: Cc1ccc2c(c1)nc(C)n2[C@H]1CC[C@H](N)C1
Reactant: O=CC1Cc2ccc(Cl)cc2C1
Agent: Cl
Product: Cc1ccc2c(c1)nc(C)n2[C@H]1CC[C@H](NCC2Cc3ccc(Cl)cc3C2)C1

Procedure:
This compound was prepared from trans-3-(2,5-dimethyl-benzoimidazol-1-yl)-cyclopentylamine hydrochloride and 5-chloro-indan-2-carbaldehyde using the same reductive amination method described in previous example. 1H-NMR is consistent with the assigned structure. LC-MS showed a single peak, C24H28ClN3 (m/e) calcd 393.1972, obsd 394.2 (M+H).
Reaction SMILES: [NH2:1][C:2]([CH3:11])([CH2:5][CH2:6][C:7]([F:10])([F:9])[F:8])[C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O1CCCC1.O>[C:3]([C:2]([NH:1][C:19](=[O:20])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH2:5][CH2:6][C:7]([F:8])([F:9])[F:10])[CH3:11])#[N:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(N)(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C#N)(CCC(F)(F)F)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
8.7 g (52.36 mmol) of rac-2-amino-5,5,5-trifluoro-2-methylpentanonitrile from Example 60A were initially charged in 128 ml of tetrahydrofuran/water=9/1, and 22.43 g (162.3 mmol) of potassium carbonate were added. At 0° C., 8.93 g (52.36 mmol) of benzyl chloroformate were added dropwise. Then the mixture was allowed to warm up gradually to room temperature and stirred at room temperature overnight. The supernatant solvent was decanted off, the residue was twice stirred with 100 ml each time of tetrahydrofuran, and then the supernatant solvent was decanted off each time. The combined organic phases were concentrated and the crude product was purified by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate gradient 9/1 to 4/1). 11.14 g of the title compound were obtained (68% of theory).
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43]([OH:45])=O)=[CH:31][CH:32]=2)[N:27]=1.C(N(CC)C(C)C)(C)C.[C:55]1([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:60]=[CH:59][C:58]([CH2:61][CH:62]([C:64]2[S:65][CH:66]=[CH:67][N:68]=2)[NH2:63])=[CH:57][CH:56]=1>CN(C)C=O>[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43]([NH:63][CH:62]([C:64]3[S:65][CH:66]=[CH:67][N:68]=3)[CH2:61][C:58]3[CH:57]=[CH:56][C:55]([C:69]4[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=4)=[CH:60][CH:59]=3)=[O:45])=[CH:31][CH:32]=2)[N:27]=1
Reactant: NC(Cc1ccc(-c2ccccc2)cc1)c1nccs1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2nc(N)nc3cc(C(=O)NC(Cc4ccc(-c5ccccc5)cc4)c4nccs4)ccc23)CC1
Reaction time: 0.17 h
Yield: 18.2 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (26 mg, 0.070 mmol) was added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (10 mg, 0.03 mmol) in N,N-Dimethylformamide (1 mL) and N,N-Diisopropylethylamine (12 uL, 0.070 mmol). The reaction was stirred for 10 min., and the 2-biphenyl-4-yl-1-(1,3-thiazol-2-yl)ethanamine (20 mg, 0.070 mmol) was added. The reaction was stirred for 1 h. at r.t. The final product was purified by prep RP-HPLC (pH=10) to afford the desired compound (0.003 g, 20%) as an amorphous white solid. Analytical LCMS (M+H)+: m/z=550.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH2:13][OH:14])[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[C:1]([O:5][C:6]([NH:7][C@@H:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[CH2:13][O:14][S:26]([CH3:25])(=[O:28])=[O:27])=[O:15])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of ((1S)-1-hydroxymethyl-3-methyl-butyl)-carbamic acid tert-butyl ester (25 g, 115 mmol) in dichloromethane (500 ml) cooled by an ice-water bath was successively added diisopropylethylamine (35.7 g, 276 mmol) and methanesulphonyl chloride (15.81 g, 138 mmol). The resulting solution was stirred over night during which time the mixture was allowed to gradually warm up to ambient temperature. The mixture was washed successively with water, 10% citric acid (aq), water and saturated NaHCO3 (aq), then dried with Na2SO4 and concentrated to a brown solid (32.6 g, 96%) which was used in the next reaction without further purification.
Reaction SMILES: [C:1]1([C:7]([C:9]2[O:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH:25][NH2:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C>CO>[CH2:18]([NH:25][N:26]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[O:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NNCc1ccccc1
Reactant: COC(=O)c1ccc(C(=O)c2ccccc2)o1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(=NNCc2ccccc2)c2ccccc2)o1

Procedure:
5-Methoxycarbonyl-2-furyl phenyl ketone (5.5 g, 0.024 mole) was dissolved in methanol (60 ml), added with benzylhydrazine (9 g, 0.07 mole) and acetic acid (0.5 ml) and then heated under reflux till the reaction was completed. After cooling, the solvent was evaporated. The resultant residue was extracted with chloroform and washed with dilute HCl solution, then water, and then dried over anhydrous magnesium sulfate and filtered. The solvent of the filtrate was removed to give 5-methoxycarbonylfuryl phenyl ketone benzylhydrazone.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:28][C:29](=[O:35])[CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C.[CH3:60][Si:61]([C:64]#[CH:65])([CH3:63])[CH3:62]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:23]([N:22]([CH2:25][CH3:26])[C:21]([CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([NH:28][C:29](=[O:35])[CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:3][C:2]=2[C:65]#[C:64][Si:61]([CH3:63])([CH3:62])[CH3:60])[CH2:9][CH2:10]1)=[O:27])[CH3:24]
Reactant: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)N(CC)CC)c3ccccc3)CC2)c(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)N(CC)CC)c3ccccc3)CC2)c(C#C[Si](C)(C)C)c1
Temperature: 120 °C
Yield: 15.6 %

Procedure:
To a solution of N-{3-bromo-4-[4-(diethylcarbamoyl-phenyl-methyl)-piperazin-1-yl]-phenyl}-2-ethyl-butyramide (66 mg, 0.12 mmol) in DMF (1.5 mL) was added CuI (1.3 mg, 0.01 mmol), triphenylphosphine (73 mg, 0.28 mmol), diethylamine (220 μL, 2.1 mmol), trimethylsilylacetylene (22 μL, 0.15 mmol) and dichlorobis(triphenylphosphine)palladium (II) (5.0 mg, 0.01 mmol). This solution was heated in a focused microwave reactor at 120° C. for 5 min, after which the solution was concentrated and purified by reverse phase HPLC to provide N-{4-[4-(diethylcarbamoyl-phenyl-methyl)-piperazin-1-yl]-3-trimethylsilanylethynyl-phenyl}-2-ethylbutyramide (10.5 mg, 16%). This compound (18 mg, 0.03 mmol) was dissolved in MeOH and treated with K2CO3 (9.0 mg, 0.06 mmol). After 1 h, the solids were filtered off, the filtrate concentrated, and the product purified by reverse phase HPLC to afford the title compound (10 mg, 63%). MS: 489.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:28][CH:27]=1>C(OCC)(=O)C>[C:35]([O:34][C:33](=[O:39])[NH:32][C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:13]2[N:12]=[C:11]3[C:16]([C:17](=[O:18])[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:9]4[N:10]3[CH:22]=[CH:23][N:24]=4)=[CH:15][N:14]=2)=[CH:31][CH:30]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2ncc3c(=O)n(-c4ccccc4Cl)c4nccn4c3n2)cc1

Procedure:
A mixture of Example 1E (330.0 mg, 0.917 mmol) and tert-butyl 4-aminophenylcarbamate (306 mg, 1.468 mmol) was heated in a capped vial at 100° C. for 1 hour. The residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, concentrated, and purified on a 40 g column using the ISCO Companion flash system eluting with hexane/ethyl acetate (5:5 to 4:6) to provide the title compound.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=O)[NH:11]3)[CH2:4][CH2:3][CH2:2]1.[NH2:19][CH:20]1[CH2:25][CH2:24][C:23]([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][C@H:32]([OH:35])[C@@H:31]([CH3:36])[CH2:30]2)([OH:26])[CH2:22][CH2:21]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:26][C:23]1([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][C@H:32]([OH:35])[C@@H:31]([CH3:36])[CH2:30]2)[CH2:24][CH2:25][CH:20]([NH:19][C:16]([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[C:7]([O:6][CH2:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH:15]=[CH:14][CH:13]=3)=[O:18])[CH2:21][CH2:22]1
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(CCC2(O)CCC(NC(=O)c3cc4c(OCC5CCC5)cccc4[nH]3)CC2)CC[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid (16a) (140 mg, 0.383 mmol), (3S,4S)-1-[2-(4-amino-1-hydroxy-cyclohexyl)-ethyl]-3-methyl-piperidin-4-ol (14) (103 mg, 0.421 mmol) and DIEA (0.263 ml, 1.532 mmol) in 5 ml of DMF is treated with solid TBTU (139 mg, 0.421 mmol). The mixture is stirred for 2 h at rt and then evaporated. The crude residue is dissolved in EtOAc and extracted with 1M-HCl. The aqueous layer is separated, its pH adjusted to 14 and extracted 3-times with DCM. The organic layers are dried over sodium sulphate and evaporated. The crude product is then purified by chromatography on silicagel using methanol and DCM (saturated with ammonia) from 1:99 to 5:95.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1.O>N1C=CC=CC=1>[CH:28]1([C:31]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[CH:11]=[CH:10][C:9]([C:12]([N:14]4[C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=5[CH2:18][N:17]5[CH:25]=[CH:26][CH:27]=[C:16]5[CH2:15]4)=[O:13])=[CH:8][CH:7]=3)=[N:2]2)=[O:32])[CH2:30][CH2:29]1
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(c1ccc(-c2ccn(C(=O)C3CC3)n2)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.8 %

Procedure:
To a solution of [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]-benzodiazepin-10-yl)-methanone (1.0 g) in dry pyridine (10 ml) was added cyclopropanecarbonyl chloride (0.44 g). After stirring at room temperature for 18 hours the reaction mixture was poured into water and the precipitate was collected by filtration. The crude product was dissolved in dichloromethane and dried over anhydrous sodium sulfate. This solution was filtered through a short column of hydrous sodium magnesium silicate, eluting with several additional volumes of dichloromethane. The eluant was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.88 g) was obtained as a crystalline solid, m.p. 197-199° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH:19]([OH:22])[CH:20]=[CH2:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH:19]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH2:21])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CC(O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Solvent: c1ccncc1
Product: C=CC(OC(=O)c1ccccc1)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 10.0 g of 1-(1-benzenesulfonyl-1H-indol-2-yl)-allyl alcohol (32 mmol) in 100 ml of pyridine were added dropwise 5,6 ml benzoyl chloride (48 mmol) at 10° C. The mixture was stirred for an additional 1 h at 20° C. Most of the pyridine was distilled off, the residue was given in portions to 300 ml of ice water. The pH was adjusted to 2-3 with conc. HCl. The water was distilled off and the residue was dissolved in 100 ml of diethyl ether. After about 1 h the product crystallized. The suspension was stirred in an ice bath for 2 h, the solid was filtered off. The crude material was recrystallized from 90 ml methanol and dried 12 h at 35° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[NH:27]([CH:23]1[CH2:22][CH2:21][N:20]([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[CH:18]=2)[CH2:25][CH2:24]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccccc1
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCC(Nc4ccccc4)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (1.1 g) and aniline (344 mg) were reacted in the same manner as described in Preparation Example 37 to give the title compound.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:38][CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1.CS(C)=O>C(#N)C>[CH3:35][O:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:38][CH2:39][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: NCc1cccnc1
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
A solution of 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step F (2 mmol), and 3-aminomethylpyridine (4.2 mmol), in dimethylsulfoxide (7 mmol) and acetonitrile (15 mL) was stirred at 80° C. for 18 hours. The solvents were evaporated and the residue was dissolved in dichloromethane, washed with water, dried over anhydrous sodium sulfate, and evaporated. The product crystallized from ethyl acetate and hexane (0.96g; 89%), m.p. 165-167° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[OH-].[Na+]>>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([NH:8][S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)(=[O:11])=[O:10])[CH:7]=2)[CH2:24][CH2:23]1
Reactant: O=[N+]([O-])c1ccc(F)cc1NS(=O)(=O)c1ccccc1
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(c2ccc([N+](=O)[O-])c(NS(=O)(=O)c3ccccc3)c2)CC1
Reaction time: 0.03 h
Yield: 78 %

Procedure:
N-(5-fluoro-2-nitrophenyl)benzenesulfonamide (2×0.50 g, 1.688 mmol) was treated with N-methyl-piperazine (2×4.65 g, 45.6 mmol) and put in two pyrex tubes and sealed. Each tube was put in a LabWell MW-10 microwave oven for 2 min at 50 W. The reaction mixtures were combined and poured into 0.5 M NaOH (aq) and extracted with CH2Cl2, dried (MgSO4) and concentrated to give 0.99 g, (2.63 mmol) in 78% yield as a yellow solid. Anal (C17H20O N4 O4 S)C, H, N, S; MS (posES-FIA) m/z=found: 377.4; Calcd: 376.12.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:16])[CH:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[NH2:7])[CH3:3].[CH:17](=O)[CH2:18][CH3:19].C([BH3-])#N.[Na+]>>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH:6]([NH:7][CH2:17][CH2:18][CH3:19])[C:5]([O:4][CH2:2][CH3:3])=[O:16])=[CH:14][CH:13]=1
Reactant: CCC=O
Reactant: CCOC(=O)C(N)Cc1ccc(O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCNC(Cc1ccc(O)cc1)C(=O)OCC

Procedure:
In a similar manner to that described in Reference example 59(a), a reaction is carried out using DL-tyrosine ethyl ester hydrochloride, propionaldehyde and sodium cyanoborohydride and the reaction mixture is treated to afford the desired compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.C([N:24]([CH:27]([CH3:29])[CH3:28])[CH2:25][CH3:26])(C)C.CS(C)=O>O>[C:9]1([CH3:10])[CH:8]=[CH:6][CH:5]=[CH:4][C:29]=1[CH:27]1[CH2:28][CH2:26][CH2:25][N:24]1[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Reactant: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)Nc1nc2ccc(-c3ccnc(N4CCCC4c4ccccc4C)n3)cc2s1
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 100.9 %

Procedure:
A mixture of N-(6-(2-chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.100 g, 0.3 mmol), 2-O— tolylpyrrolidine (0.053 g, 0.33 mmol) oxalate, diisopropylethylamine (0.20 ml, 1.2 mmol) in DMSO (1.0 g, 11 mmol) was heated under CEM microwave at 140° C., 130 W (Powermax® off) for 20 min. The resultant was diluted with 5 ml of water and filtered. The solid was dried to give a brown solid (0.065 g, 46%). MS (ESI pos. ion) Found m/z: 430, (M+H)+.