Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:52])[C@@H:5]([O:49][CH2:50][CH3:51])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[CH:15]=[CH:16]/[C:17]#[C:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[C:26]/[CH:27]=[CH:28]/[CH2:29][O:30][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][C@H:38]([O:44][CH2:45][CH3:46])[C:39]([O:41]CC)=[O:40])=[CH:33][C:32]=3[Br:47])=[CH:21][CH:20]=2)=[C:9]([Br:48])[CH:8]=1)[CH3:2].[OH-].[Na+]>C1COCC1.C(O)C>[Br:47][C:32]1[CH:33]=[C:34]([CH2:37][C@H:38]([O:44][CH2:45][CH3:46])[C:39]([OH:41])=[O:40])[CH:35]=[CH:36][C:31]=1[O:30][CH2:29]/[CH:28]=[CH:27]/[C:26]#[C:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]#[C:17]/[CH:16]=[CH:15]/[CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C@H:5]([O:49][CH2:50][CH3:51])[C:4]([O:3][CH2:1][CH3:2])=[O:52])=[CH:8][C:9]=2[Br:48])=[CH:24][CH:23]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C/C#Cc2ccc(C#C/C=C/COc3ccc(C[C@H](OCC)C(=O)OCC)cc3Br)cc2)c(Br)c1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C/C#Cc2ccc(C#C/C=C/COc3ccc(C[C@H](OCC)C(=O)O)cc3Br)cc2)c(Br)c1)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a solution of (E)(E)(S)(S) 3-{3-bromo-4-[5-(4-{5-[2-bromo-4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-pent-3-en-1-ynyl}-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid ethyl ester (example 19) (250 mg 0.30 mmol) in THF (2 mL) and ethanol (3 mL) was added 1N sodium hydroxide (3 mL). After stirring at room temperature for 1 h, the reaction mixture was concentrated in vacuo, added water and 1N hydrochloride acid to pH 1. The product was extracted with ethyl acetate (×3) and the combined organic phases were washed with water, dried (MgSO4), filtered and concentrated in vacuo to give 230 mg of the title compound.
Reaction SMILES: [OH-].[Li+].[O:3]=[S:4]1(=[O:38])[C:10]2[CH:11]=[C:12]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])[C:13]([O:15][CH3:16])=[CH:14][C:9]=2[N:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:7][C:6]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:5]1.CC(O)=O>C1COCC1.O>[O:38]=[S:4]1(=[O:3])[C:10]2[CH:11]=[C:12]([O:17][CH2:18][C:19]([OH:21])=[O:20])[C:13]([O:15][CH3:16])=[CH:14][C:9]=2[N:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:7][C:6]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:5]1
Reactant: CCCCC1(CCCC)CN(c2ccccc2)c2cc(OC)c(OCC(=O)OCC)cc2S(=O)(=O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCC1(CCCC)CN(c2ccccc2)c2cc(OC)c(OCC(=O)O)cc2S(=O)(=O)C1
Yield: 96.3 %

Procedure:
Lithium hydroxide (0.062 g) was added to a solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 45; 0.448 g, 0.865 mmol) in THF/H2O (2/1, 6 ml). After 1 hour AcOH (0.5 ml) was added and most of the solvent was removed under reduced pressure. The crude product was purified by HPLC (MeCN) to give the title compound 0.408 g (96%) as a white solid. NMR (400 MHz, CD3OD): 0.75-0.85 (m, 6H), 1.00-1.30 (m, 8H), 1.35-1.55 (m, 4H), 3.20 (s, 2H), 3.65 (s, 3H), 3.70 (brs, 2H), 4.50 (s, 2H), 6.50 (s, 1H), 6.90-7.30 (m, 5H),
Reaction SMILES: [O:1]([C:6]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)=[O:7])[C:2]([CH3:5])([CH3:4])[CH3:3].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17]([CH:19]=[C:11]1[C:10](=[O:13])[CH2:9][N:8]([C:6]([O:1][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:7])[CH2:12]1)[CH3:18]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Product: CN(C)C=C1CN(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C

Procedure:
A solution of 1-(tert-butoxylcarbonyl)-3-pyrrolidone (4.10 g) and N,N-dimethylformamide dimethyl acetal (30.0 mL) was heated to 140° C. for 1 h. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was redissolved in a minimum amount of dichloromethane and triturated with hexane to yield the desired product as a yellow precipitate. LC-MS=241.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:11]([C:14]([CH3:21])([CH3:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].[F:30][C:31]([F:46])([F:45])[C:32]1[CH:33]=[C:34]([N:42]=[C:43]=[O:44])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1>N1C=CC=CC=1>[F:30][C:31]([F:45])([F:46])[C:32]1[CH:33]=[C:34]([NH:42][C:43](=[O:44])[NH:1][C:2]2[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:3]=2[O:4][C:5]2[CH:13]=[CH:12][C:11]([C:14]([CH3:21])([CH3:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][C:6]=2[C:7]([OH:9])=[O:8])[CH:35]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:37]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)CC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2N)c(C(=O)O)c1
Solvent: c1ccncc1
Product: CC(C)(C)CC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2NC(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(C(=O)O)c1

Procedure:
2-(2-amino-4-trifluoromethyphenoxy)-5-(1,1,3,3-tetramethylbutyl)benzoic acid (140 mg, 0.0003 mol) and 3,5-di(trifluoromethyl)phenyl isocyanate (86 μl, 0.0005 mol) were mixed in pyridine (8 ml) at room temperature 16 h. The solvent was evaporated and the residue flash chromatographed (silica gel, ethyl acetate/hexane/formic acid) to yield the title compound; mp 233° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][CH2:21][CH2:20]2>>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[CH2:22][CH2:21][CH2:20]3)[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: Clc1nc(Cl)nc(Nc2ccccc2)n1
Reactant: Nc1ccc2c(c1)CCC2
Product: Clc1nc(Nc2ccccc2)nc(Nc2ccc3c(c2)CCC3)n1
Yield: 37 %

Procedure:
The reaction of 4,6-dichloro-N-phenyl-[1,3,5]triazine-2-amine with 5-aminoindan using the method described for the synthesis of CT-32028 provided CT-32099 (36 mg, 37% yield). 1H NMR (d6-DMSO) δ 10.15–10.28 (m, 2 H), 7.56–7.72 (m, 3 H), 7.05–7.39 (m, 5 H), 2.75–90 (m, 4 H), 1.94–2.09 (m, 2 H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:20])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:5](Cl)=[O:6].[CH3:21][NH:22][CH3:23]>O1CCCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:20])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:5]([N:22]([CH3:23])[CH3:21])=[O:6]
Reactant: COc1ccc(Oc2c(I)cc(C(=O)Cl)cc2I)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: COc1ccc(Oc2c(I)cc(C(=O)N(C)C)cc2I)cc1

Procedure:
3,5-diiodo-4-(4'-methoxyphenoxy)-N,N-dimethyl benzamide (Compound 9) was prepared way of 3,5-diiodo-4-(4'-methoxyphenoxy)benzoyl chloride (see, Example 1.5). The acid chloride was reacted with excess dimethylamine in tetrahydrofuran at ambient temperature (1 hour), filtered to remove dimethylamine-hydrochloride precipitate, the solvent evaporated and the product crystallized from absolute ethanol.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[ClH:7].[F:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=O)[N:13]([NH:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[C:12]2=O.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[ClH:7].[F:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([NH:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[CH2:12]2
Reactant: O=C1c2ccc(F)cc2C(=O)N1Nc1ccncc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc2c(c1)CN(Nc1ccncc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
A mixture of 4-fluorophthalic anhydride (5.99 g), 4-pyridinylhydrazine hydrochloride (5.00 g), and glacial acetic (30 ml) acid was stirred under reflux, under nitrogen, for 4 hrs. The reaction mixture was evaporated, and the residue was azeotroped with heptane. The residue was dried in vacuo to give 4-fluoro-2-(4-pyridinylamino)-isoindol-1,3-dione. To a mixture of lithium aluminum hydride (3.91 g) and dry tetrahydrofuran (100 ml), 2,3-dihydro-5-fluoro-2-(4-pyridinylamino)isoindole-1,3-dione hydrochloride was added in portions with rapid stirring, under nitrogen, at ambient temperature. The reaction mixture was stirred under nitrogen, overnight, at ambient temperature, and sodium sulfate decahydrate was added in portions. The mixture was filtered through a bed of celite, the filter cake was washed with ethyl acetate and concentrated in vacuo. The residue was chromatographed over silica gel, eluting with 7% methanol-dichloromethane, followed by 185:14:1 dichloromethane:methanol:ammonium hydroxide. The appropriate fractions were collected and evaporated. The residue was dissolved in absolute ethanol, excess concentrated hydrochloric acid was added, and the mixture was evaporated. The residue was crystallized from absolute ethanol to give 550 mg (6%) of product, (dried under vacuum at 80° C. overnight), mp 235-240° C. (decomp).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][C:3]#[C:4][CH3:5].[H-].[Na+].Cl[C:10]1[C:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][S:13][N:14]=1.O>O1CCCC1>[CH2:1]([O:6][C:10]1[C:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][S:13][N:14]=1)[CH2:2][C:3]#[C:4][CH3:5]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CC#CCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC#CCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-pentyn-1-ol (750 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([N:7]([C:21](=[O:25])[CH2:22][O:23][CH3:24])[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([CH2:15][O:16]C(=O)C)[C:9]=1[CH3:20])[CH3:6])=[O:4].[OH-].[Na+].CC(C)=O>O>[CH3:1][O:2][C:3]([CH:5]([N:7]([C:21](=[O:25])[CH2:22][O:23][CH3:24])[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([CH2:15][OH:16])[C:9]=1[CH3:20])[CH3:6])=[O:4]
Reactant: COCC(=O)N(c1c(C)ccc(COC(C)=O)c1C)C(C)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COCC(=O)N(c1c(C)ccc(CO)c1C)C(C)C(=O)OC

Procedure:
23.0 g of N-(1'-methoxycarbonyl-ethyl)-N-methoxyacetyl-2,6-dimethyl-3-acetoxymethylaniline, 9.2 g of 30% sodium hydroxide solution and 100 ml of acetone were stirred for 3 hours at room temperature; 20 ml of water were then added, and the reaction mixture was extracted twice with 50 ml of diethyl ether each time. The combined ether extracts were dried over sodium sulfate, and the solvent was evaporated off. The oily crude product was chromatographed through a silica gel column by means of ether/chloroform (1:1) to thus obtain the product in the form of colourless oil: nD14 =1.5352.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[OH-].[Na+]>CO>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[CH:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: COc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C=CC(=O)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a well-stirred solution of 4-hydroxy acetophenone, 1 (10 g, 73.5 mmol) and 4-methoxy benzaldehyde, 4 (8.9 mL, 73.5 mmol) in methanol (140 mL) was added 50% w/v aqueous sodium hydroxide solution (70 mL). The reaction mixture was stirred at room temperature for 12 h and then evaporated in vacuo. Water was added and acidified with hydrochloric acid (1N) and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over sodium sulphate, filtered and evaporated in vacuo. The residue yielded pure 7 after purification by column chromatography. Yield 16.8 g (90%); mp 184-185° C. MS (EI) m/z 254 (M+, 100%), 253 (34.7%), 239 (32.3%), 161 (36.8%), 121 (79.5%); IR (KBr) 3371, 1654; 1H NMR (200 MHz, CDCl3) δ 7.99 (d, J=8.6 Hz, 2H), 7.78 (d, J=15.6 Hz, 1H), 7.60 (d, J=8.6 Hz, 2H), 7.41 (d, J=15.6 Hz, 1H), 6.93 (d, J=7.2 Hz, 4H), 5.85 (s, 1H), 3.86 (s, 3H).
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]([CH3:11])[CH2:9][F:10])(=O)=O.[CH3:14][C:15]1([CH3:41])[NH:27][CH:26]([C:28]2[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:30][C:29]=2[F:40])[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:40][C:29]1[CH:30]=[C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])[CH:32]=[CH:33][C:28]=1[CH:26]1[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16][C:15]([CH3:41])([CH3:14])[N:27]1[CH2:7][C@H:8]([CH3:11])[CH2:9][F:10])=[CH:24][CH:23]=[CH:22][CH:21]=3
Reactant: COC(=O)/C=C/c1ccc(C2NC(C)(C)Cc3c2[nH]c2ccccc32)c(F)c1
Reactant: C[C@H](CF)COS(=O)(=O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/c1ccc(C2c3[nH]c4ccccc4c3CC(C)(C)N2C[C@H](C)CF)c(F)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 58.9 %

Procedure:
(S)-3-Fluoro-2-methylpropyl trifluoromethanesulfonate (obtained as described in Example 3, preparation of starting materials) (1.259 g, 5.62 mmol) was added to a solution of (E)-methyl 3-(4-(3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3-fluorophenyl)acrylate (racemate) (850 mg, 2.25 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.467 ml, 8.42 mmol) in 1,4-dioxane (5 ml). The mixture was heated at 60° C. for 4 hours, then stirred at ambient temperature for 12 hours. The mixture was partitioned between ethyl acetate (25 ml) and water (25 ml). The aqueous layer was extracted with ethyl acetate (2×25 ml) and the extracts combined with the organic layer. The combined extracts were evaporated under vacuum. The residue was purified by flash silica chromatography, elution solvent 10% EtOAc in heptane. Pure fractions were evaporated to dryness to afford (E)-methyl 3-(3-fluoro-4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (mixture of diastereoisomers) (600 mg, 59.0%). m/z: ES+ [M+H]+ 453.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2.Cl.Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(O)C>[N:16]1([CH2:15][CH2:14][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:7](=[O:8])[O:6][CH2:5]3)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=C1OCc2cc(O)ccc21
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCO
Product: O=C1OCc2cc(OCCN3CCOCC3)ccc21
Temperature: 25 °C
Yield: 81.6 %

Procedure:
A mixture of 5-hydroxyphthalide (1.0 g, 6.66 mmol), 4-(2-chloroethyl)-morpholine hydrochloride (1.49 g, 8.01 mmol), potassium carbonate (2.3 g, 16.6 mmol) and sodium iodide (1.0 g, 6.67 mmol) in ethanol (40 ml) was stirred at reflux under nitrogen for 18 hours. The mixture was cooled to room temperature, and filtered through celite. The filtrate solution was evaporated to dryness. The residue was partitioned between EtOAc (75 ml) and 2M HCl solution (50 ml). The organic layer was extracted with 2M HCl (2×30 ml). The aqueous layers were combined, basified with NaOH aqueous solution, and extracted with CHCl3 (3×50 ml). The organic layers were combined, dried over anhydrous Na2SO4, and evaporated to a light brown solid, which was triturated with CHCl3/Hexanes to give 5-(2-morpholin-4-yl-ethoxy)-3H-isobenzofuran-1-one as white crystals (1.43 g, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:36])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:15][C@H:16]([CH2:24][N:25]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:14])[S:10][C:11]=1[Cl:12].NN>O1CCCC1.CO>[NH2:25][CH2:24][C@@H:16]([NH:15][C:13]([C:9]1[S:10][C:11]([Cl:12])=[C:7]([C:6]2[N:5]([CH3:36])[N:4]=[CH:3][C:2]=2[Br:1])[CH:8]=1)=[O:14])[CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Cn1ncc(Br)c1-c1cc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Cn1ncc(Br)c1-c1cc(C(=O)N[C@H](CN)CC2CCCCC2)sc1Cl
Reaction time: 12 h
Yield: 25 %

Procedure:
To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide (48 mg, 0.08 mmol) in tetrahydrofuran (0.41 ml) and methanol (0.41 ml) at 25° C. was added hydrazine (0.03 ml, 0.81 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH4OH)). The free base was then converted to the HCl salt by adding excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxamide (11 mg, 0.02 mmol, 24% yield) as a yellow solid: LCMS (ES) m/z=459, 461 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (br. s., 1H) 7.96 (br. s., 4H) 7.74 (s, 1H) 4.21-4.26 (m, 1H) 3.77 (s, 3H) 2.92-2.99 (m, 2H) 1.73-1.79 (m, 1H) 1.62-1.67 (m, 4H) 1.49-1.51 (m, 1H) 1.25 (br. s., 2H) 1.06-1.13 (m, 2H) 0.95 (d, J=6.82 Hz, 1H) 0.82-0.89 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:15])[N:9]([CH3:14])[CH2:10][C:11](=O)[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl-].C1(OP(=O)(O)OC2C=CC=CC=2)C=CC=CC=1.[N+:36]([CH2:38][C:39]1[S:40][CH:41]=[CH:42][CH:43]=1)#[C-:37]>CN(C)C=O.O.C(O)(=O)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:15])[N:9]([CH3:14])[CH2:10][C:11]3[N:12]([CH:37]=[N:36][C:38]=3[C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#[N+]Cc1cccs1
Reactant: CN1CC(=O)Nc2cccc(Cl)c2C1=O
Agent: O=P(O)(Oc1ccccc1)Oc1ccccc1
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: CN1Cc2c(-c3cccs3)ncn2-c2cccc(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 9.12 g (40.6 mmol) of 6-chloro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione in 35 ml of dry N,N-dimethylformamide is treated at -20° to -30° while stirring with 1.77 g (40.6 mmol) of sodium hydride (55 percent oil dispersion), the mixture is stirred at the above temperature for a further 30 minutes and there is subsequently added dropwise thereto at -70° a solution of 10.74 g (40.6 mmol) of phosphoric acid diphenyl ester chloride in 8 ml of dry N,N-dimethylformamide. After stirring in an acetone/dry-ice bath for 20 minutes there is added dropwise thereto at -70° to -55° a solution of 5 g (40.6 mmol) of 2-isocyanomethylthiophene in 5 ml of dry N,N-dimethylformamide and subsequently a solution of 4.56 g (40.6 mmol) of potassium tert.-butylate in 12 ml of dry N,N-dimethylformamide. The mixture is left to warm to room temperature, neutralized with 2.5 ml of glacial acetic acid, poured into 300 ml of water and extracted three times with methylene chloride. The organic extracts are washed four times with water, dried over magnesium sulphate and evaporated. The residue is chromatographed on silica gel while eluting with ethyl acetate. By recrystallization from acetonitrile there is obtained 7-chloro-4,5-dihydro-5-methyl-3-(2-thienyl)-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 222°-223°.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH:4]=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH3:13].[BH4-].[Na+]>CO.O>[Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH3:13]
Reactant: Cc1c(Cl)cccc1N=Cc1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c(Cl)cccc1NCc1ccccc1Cl
Reaction time: 0.25 h

Procedure:
A suspension of N-(o-chlorobenzylidene)-2-methyl-3-chloroaniline (0.038 mole) is brought to reflux in 100 cc of absolute methanol. An equivalent of sodium borohydride (1.5 g.) is added in portions and refluxing is continued for 15 mins. The reaction mixture is cooled and diluted with an equal volume of cold water to precipitate a solid. This material is collected, washed with H2O and air dried. Recrystallization from ethanol gives N-(o-Chlorobenzyl)-2-methyl-3-chloroaniline. m.p. 63°-66° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:16]=[C:17]([O:21]C)[C:18]=1[O:19]C)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]([SH:15])=[S:14])[CH2:9][CH2:8]1.C(Cl)Cl.B(Br)(Br)Br>O>[OH:21][C:17]1[CH:16]=[C:5]([CH:4]=[C:3]([OH:2])[C:18]=1[OH:19])[CH2:6][N:7]1[CH2:8][CH2:9][N:10]([C:13]([SH:15])=[S:14])[CH2:11][CH2:12]1
Reactant: COc1cc(CN2CCN(C(=S)S)CC2)cc(OC)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1cc(CN2CCN(C(=S)S)CC2)cc(O)c1O
Temperature: -78 °C
Reaction time: 120 h
Yield: 11.4 %

Procedure:
In a nitrogen atmosphere, 1,033 mg (3.02 mmol.) of 4-(3,4,5-trimethoxybenzyl)-1-piperazinecarbodithioic acid was suspended indry methylene chloride, and under chilling to -78° C. in a dry ice-acetone bath, to this was dropwise added 50 ml of methylene chloride solution containing 3 ml of boron tribromide. The mixture was left to slowly reach room temperature, and then stirred for 5 days at room temperatuere. To the reaction mixture was added water, and insolubles wereremoved by filtration. The insolubles were then washed with water, and thusobtained yellow solid was dissolved in methanol. The methanol solution was filtered to remove insoubles, and the solvent of the filtrate was distilled off. To the obtained yellow semi-oil was added ether, and insolubles were removed by filtration. The filtrate was dried and further purified by cellulose column chromatography (Avicel, trademark, eluent: butanol/acetic acid/water (10/1/1)). The eluate was treated to distill offthe solvent (eluent). To the residue was added ether, and insolubles were removed by filtration. The solvent of the filtrate was distilled off, leaving 103 mg of the desired compound, m.p. higher than 250° C., yield 11.4%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[NH:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:12][C:3]=12.[NH2:20][CH2:21][C:22]1[C:23]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])=[N:24][CH:25]=[CH:26][CH:27]=1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[C:8]([C:7]1[C:2]([NH:20][CH2:21][C:22]2[C:23]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:3]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[NH:10][C:4]2=[N:5][CH:6]=1)#[N:9]
Reactant: N#Cc1cnc2[nH]c(-c3ccc(F)cc3)cc2c1Cl
Reactant: CN(c1ncccc1CN)S(C)(=O)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ncccc1CNc1c(C#N)cnc2[nH]c(-c3ccc(F)cc3)cc12)S(C)(=O)=O
Temperature: 170 °C

Procedure:
4-Chloro-2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (30 mg, 0.11 mmol), N-(3-aminomethylpyridin-2-yl)-N-methylmethanesulfonamide (159 mg, 0.552 mmol) and N-ethyldiisopropylamine (0.282 ml, 1.656 mmol) are suspended in 0.4 ml of 1-methyl-2-pyrrolidone and heated in a microwave at 170° C. for 40 min. The reaction is still not complete even after a further 40 min, so that a further equivalent of N-(3-aminomethylpyridin-2-yl)-N-methylmethanesulfonamide (31.8 mg, 0.110 mmol) is added, and the batch is heated at 170° C. for a further 60 min. For work-up, the batch is partitioned between water and ethyl acetate, the organic phase is dried (Na2SO4) and evaporated, giving a brown oil, which is purified by chromatography; yield: 17 mg (34%); LC-MS: 451 [M+H]+; HPLC: 3.07 (RT/min).