Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][C:16](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:15]3[C:31](=[O:38])[C:32]4[CH:33]=[CH:34][N:35]=[CH:36][C:37]=4[C:13]([C:14]=23)=[N:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]([O:43][C:44]([NH:46][CH2:47][CH2:48][NH2:49])=[O:45])([CH3:42])([CH3:41])[CH3:40]>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][C:16]([NH:49][CH2:48][CH2:47][NH:46][C:44]([O:43][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:45])=[C:15]3[C:31](=[O:38])[C:32]4[CH:33]=[CH:34][N:35]=[CH:36][C:37]=4[C:13]([C:14]=23)=[N:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc3c4c(nn3CCNC(=O)OC(C)(C)C)-c3cnccc3C(=O)c24)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCNc1ccc2c3c(nn2CCNC(=O)OC(C)(C)C)-c2cnccc2C(=O)c13
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A suspension of 2-[2-(N-tert-butoxycarbonylamino)ethyl]-5-(p-toluenesulfonyl oxy)isoquino[8,7,6cd]indazole-6(2H)-one Example 3 (0.535 g) and N-(tert-butoxycarbonyl)ethylenediamine (1.12 g) in dry pyridine (5.35 mL) is heated at 80° C. The dark solution obtained is held at this temperature for 5 hours, then it is concentrated to dryness and partitioned between brine (30 mL) and ethyl acetate (2×25 mL). The orange-red solid insoluble in the biphasic mixture is separated by suction filtration and dried at 40° C. under vacuum (0.43 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([O:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1OCCN1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(Cl)cc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-chloro-2-fluoro-benzonitrile (869 mg, 5.58 mmol) and 2-pyrrolidin-1-yl-ethanol (0.80 mL, 6.70 mmol) in THF (30 mL) is treated with a 0.5 M toluene solution of KHMDS (13.4 mL, 6.7 mmol) at 0° C. After completion of the reaction at RT, the reaction mixture is quenched by H2O. EtOAc is added and the organic layer is washed with brine, dried over MgSO4. Concentration in vacuo affords the corresponding 4-chloro-2-(2-pyrrolidin-1-ylethoxy)-benzonitrile. A THF (7 mL) solution of 4-chloro-2-(2-pyrrolidin-1-yl-ethoxy)-benzonitrile is added to a suspension of LAH (293 mg, 7.71 mmol) in THF (50 mL) at 0° C. The reaction is allowed to stir for 2 h at ambient temperature and then quenched by Na2SO4.10H2O, and the product is isolated by filtration with Celite and washed with THF and dried under reduced pressure to give the title compound as oil; ES-MS: M+=255.2; HPLC: AtRet=1.22 min.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH3:13])[C:6]3[CH2:20][CH2:21][NH:22][CH2:23][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:31][C:32](=[O:34])[CH3:33]>C(#N)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH3:13])[C:6]3[CH2:20][CH2:21][N:22]([CH2:31][C:32](=[O:34])[CH3:33])[CH2:23][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(=Cn1c2c(c3cc(C)ccc31)CNCC2)c1ccncc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)CN1CCc2c(c3cc(C)ccc3n2C=C(C)c2ccncc2)C1
Temperature: 70 °C
Yield: 32 %

Procedure:
8-Methyl-5-(2-pyridin-4-yl-propenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (50 mg, 0.165 mmol) was dissolved in 1 mL acetonitrile. Potassium carbonate (70 mg, 0.50 mmol) and chloroacetone (30 mg, 0.33 mmol) were added to the reaction mixture under nitrogen and the contents heated to 70° C. for 2 h. The reaction was monitored by TLC and LCMS. Acetonitrile was evaporated under vacuum and the reaction mixture diluted with water (10 mL). The desired compound was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to obtain crude compound which was purified by column chromatography (Eluent: 3% MeOH in DCM) to obtain 19 mg of 1-[8-methyl-5-(2-pyridin-4-yl-propenyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl]-propan-2-one. 1H NMR (CD3OD, oxalate salt) δ (ppm): 8.60 (d, 2H), 7.78 (d, 2H), 7.40 (s, 1H), 7.30 (s, 1H), 7.15 (m, 2H), 4.59 (s, 2H), 4.50 (s, 2H), 3.70 (m, 2H), 3.20 (m, 2H), 3.44 (s, 3H), 3.30 (s, 3H), 2.06 (s, 3H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH:10]([O:11][C:12](=[O:14])[CH3:13])[CH:9]([O:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH:8]([N:22]2[C:26]3[N:27]=[C:28]([NH:31]C=O)[N:29]=[CH:30][C:25]=3[S:24][C:23]2=[O:34])[O:7]1)(=[O:3])[CH3:2].CC(O)=O>CO>[C:1]([O:4][CH2:5][CH:6]1[CH:10]([O:11][C:12](=[O:14])[CH3:13])[CH:9]([O:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH:8]([N:22]2[C:26]3[N:27]=[C:28]([NH2:31])[N:29]=[CH:30][C:25]=3[S:24][C:23]2=[O:34])[O:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1OC(n2c(=O)sc3cnc(NC=O)nc32)C(OC(=O)OC(C)C)C1OC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)OCC1OC(n2c(=O)sc3cnc(N)nc32)C(OC(=O)OC(C)C)C1OC(C)=O
Yield: 78.4 %

Procedure:
Acetic acid 3-acetoxy-5-(5-formylamino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-isopropoxycarbonyloxy-tetrahydro-furan-2-ylmethyl ester (58) (420 mg, 0.84 mmol) was dissolved in MeOH (8.4 mL), cat. HOAc, and heated to 85° C. for 2 days. The reaction mixture was reduced to an oil in vacuo then subjected to flash chromatography (10-80% EtOAc-hexanes) yielding 310 mg (78%) of 59 as a pure white solid: 1HNMR (400 MHz, DMSO-d6) δ 8.37 (1H, s), 6.88 (2H, bs), 5.91-5.98 (2H, m), 5.47 (1H, dd, J1=5.2 Hz, J2=8.3 Hz), 4.65 (1H, septet, J=6.2 Hz), 4.46-4.51 (1H, m), 4.28 (1H, dd, J1=4.2 Hz, J2=11.9 Hz), 4.18 (1H, dd, J1=7.8 Hz, J2=11.6 Hz), 2.11 (3H, s),2.00 (3H, s), 1.16 (3H, d, J=6.3 Hz), 1.12 (3H, d, J=6.2 Hz).
Reaction SMILES: C([S@@]([N:7]=[CH:8][CH2:9][CH2:10][C:11]([CH3:23])([CH3:22])[C:12](OCC1C=CC=CC=1)=[O:13])=O)(C)(C)C.[F:24][C:25]1[CH:26]=[C:27]([Mg]Br)[CH:28]=[CH:29][C:30]=1[CH3:31]>C1(C)C=CC=CC=1.C1COCC1>[F:24][C:25]1[CH:26]=[C:27]([C@H:8]2[NH:7][C:12](=[O:13])[C:11]([CH3:23])([CH3:22])[CH2:10][CH2:9]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: CC(C)(CCC=N[S@@](=O)C(C)(C)C)C(=O)OCc1ccccc1
Reactant: Cc1ccc([Mg]Br)cc1F
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc([C@@H]2CCC(C)(C)C(=O)N2)cc1F
Temperature: 25 °C

Procedure:
To a stirred solution of benzyl (Ss)-5-[(tert-butylsulfinyl)imino]-2,2-dimethylpentanoate (1.00 g, 2.96 mmol, described in Intermediate 3) in toluene (28 mL) at −78° C. was added 3-fluoro-4-methylphenylmagnesium bromide (11.9 mL of a 0.5 M solution in THF, 5.93 mmol). The reaction mixture was warmed to ambient temperature for 2 h, and then heated at reflux for 2 h. The solvent was removed in vacuo and the crude solid dissolved in DMSO (5 mL). The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=236 (M+1).
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:30]2[C:31]([C:36](O)=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:27]=[CH:28][CH:29]=1>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:30]2[C:31]([C:36]([N:3]3[CH2:4][C@H:5]4[C@H:1]([CH2:8][CH2:7][CH2:6]4)[C@H:2]3[CH2:9][NH:10][C:11]([C:13]3[N:20]4[C:16]([S:17][CH:18]=[CH:19]4)=[N:15][C:14]=3[CH3:21])=[O:12])=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Reactant: COc1cccc(-c2ccccc2C(=O)O)c1
Product: COc1cccc(-c2ccccc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with commercially available 3′-methoxy-biphenyl-2-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][O:6][B:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]CC(O)=O)=[CH:10][CH:9]=2)[O:4][CH2:3]1.BrC1C=CC(CC[O:30][C:31](=[O:41])[NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=2)=CC=1>>[CH3:20][C:2]1([CH3:1])[CH2:3][O:4][B:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][O:41][C:31](=[O:30])[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=3)=[CH:12][CH:13]=2)[O:6][CH2:7]1
Reactant: CC1(C)COB(c2ccc(CCCC(=O)O)cc2)OC1
Reactant: N#Cc1cccc(NC(=O)OCCc2ccc(Br)cc2)c1
Product: CC1(C)COB(c2ccc(CCOC(=O)Nc3cccc(C#N)c3)cc2)OC1
Yield: 76 %

Procedure:
Using a procedure analogous to that used to prepare 2A, 11A (516 mg, 1.50 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 11B (434 mg, 76%). This crude material was taken on to the next step.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[NH:22][C:23]1[NH:24][CH2:25][CH2:26][N:27]=1>O1CCCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([N:27]1[CH2:26][CH2:25][N:24]=[C:23]1[NH:22][C:16]1[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=1[Cl:14])=[O:13]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: Clc1cccc(Cl)c1NC1=NCCN1
Solvent: C1CCOC1
Product: O=C(c1ccc2ccccc2n1)N1CCN=C1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 51.9 %

Procedure:
2.85 g (16.5 millimoles) of quinoline-2-carboxylic acid are dissolved in 200 ml of absolute tetrahydrofuran, 2.7 g (16.5 millimoles) of N,N'-carbonyl-diimidazole are added and the mixture is stirred for 45 minutes at room temperature. A solution of 3.75 g (16.5 millimoles) of 2-(2',6'-dichlorophenylamino)-2-imidazoline in 75 ml of absolute tetrahydrofuran is then added dropwise and the batch is stirred overnight. Thereafter, the reaction solution is freed from solvent on a rotary evaporator and the oily residue is introduced into 200 ml of an 0.5% strength sodium bicarbonate solution. The crystalline crude product (5.2 g) is filtered off and recrystallized from N,N-dimethylacetamide/isopropanol, and the crystals are washed with cold isopropanol. 3.3 g of 1-(quinolin-2-oyl)-2-(2',6'-dichlorophenylamino)-2-imidazoline are obtained, melting point 197°-198° C.
Reaction SMILES: C([O-])C.Cl.Cl.[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1.[CH3:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=[O:26]>>[CH3:23][C:24]([CH3:29])([CH3:28])[C:25]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)=[O:26]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CC(C)(C)C(=O)Cl
Agent: CC[O-]
Agent: Cl
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C(C)(C)C)cc23)CC1
Yield: 34.6 %

Procedure:
Beginning with 2.00 gm (5.74 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole dihydrochloride ethanolate and 1.78 gm (14.4 mMol) trimethylacetyl chloride, 0.623 gm (34.6%) of the title compound were recovered as an off-white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.9 %

Procedure:
The compound (17.6 g) obtained in Example 23-2 was dissolved in chloroform (400 ml) and then added with manganese dioxide (chemically processed product) (88.2 g) and the whole was stirred overnight at room temperature. After completion of the reaction, the resultant was filtrated through Celite. The solvent was distilled off, thereby obtaining the subject compound (20.4 g) as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:24]=[C:23]([CH3:25])[O:22][N:21]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][N:12]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:15][CH2:16][C@H:17]([C:20]2[CH:24]=[C:23]([CH3:25])[O:22][N:21]=2)[CH2:18][CH2:19]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)no1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CN(S(C)(=O)=O)C4)CC2)no1
Reaction time: 0.75 h

Procedure:
To a solution of trans-8-chloro-1-[4-(5-methyl-isoxazol-3-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50 mg, 0.13 mmol) and triethylamine (0.036 ml, 0.26 mmol) in dichloromethane (1.3 ml) was added methanesulfonyl chloride (0.020 ml, 0.26 mmol) at room temperature. Stirring for 45 minutes was followed by quenching with methanol (0.5 ml). The mixture was concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (37 mg, 62%) as white solid. MS m/e: 462 ([M+H]+).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][SH:5].[Na].Br[CH2:8][C:9]1[CH:13]=[CH:12][S:11][N:10]=1>C(O)C>[ClH:1].[NH2:2][CH2:3][CH2:4][S:5][CH2:8][C:9]1[CH:13]=[CH:12][S:11][N:10]=1
Reactant: BrCc1ccsn1
Reactant: NCCS
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: NCCSCc1ccsn1
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A solution was prepared by the gradual addition of cysteamine hydrochloride (2.03 g) to sodium (0.83 g) dissolved in ethanol (50 ml) with stirring at 0° under a nitrogen atmosphere. After stirring for 2 hours at 0° 3-bromomethylisothiazole (3.2 g) was added dropwise over 15 minutes at 0°, the reaction mixture subsequently being set aside overnight at room temperature. Following acidification to pH 3.5 with hydrochloric acid, concentration and re-evaporation with ethanol, the residue was dissolved in ethanol, filtered and concentrated to yield 3-[(2-aminoethyl)thiomethyl]isothiazole hydrochloride (3.5 g). This was converted directly to the free base by treatment with aqueous potassium carbonate and extraction with ether. The extracts were dried over magnesium sulphate, dried and concentrated to yield the amine base as an oil (1.56 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][CH3:10])[CH:7]=1.[B:11](OC(C)C)([O:16]C(C)C)[O:12]C(C)C.[Li]CCCC.Cl>C1(C)C=CC=CC=1>[C:8]([C:6]1[CH:7]=[C:2]([B:11]([OH:16])[OH:12])[CH:3]=[N:4][CH:5]=1)#[C:9][CH3:10]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC#Cc1cncc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC#Cc1cncc(B(O)O)c1
Temperature: -50 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
3-Bromo-5-(prop-1-ynyl)pyridine (Intermediate 24, 25 g, 117 mmol), 2-Me THF (60 mL), toluene (200 mL) and triisopropyl borate (33.2 mL, 140.78 mmol) were mixed. The mixture was cooled to −50° C. To the cold mixture was added n-BuLi (59.8 mL, 149.5 mmol) dropwise during 30 min. The mixture was stirred for 60 min. at −50° C. 2M HCl aq. (100 mL) was added. The mixture was then allowed to reach r.t. and stirred for 20 min. The organic and water phase were separated. The organic phase was extracted with NaOH (2M aq.) (2×100 mL). The water phases were combined and the pH was adjusted to pH 5. The product was extracted with 2-methyl-THF (2×100 mL). The organic phase was dried with Na2SO4, filtered and concentrated to give the title compound (16.47 g, 87% yield): 1H NMR (500 MHz, CD3OD) δ ppm 2.11 (s, 3 H) 8.21 (br. s., 1 H) 8.53 (m, 2 H); MS (APCI+) m/z 162.2 [M+H]+.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C=O)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([O:5][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1

Procedure:
While cooling on ice, Boc-D-Pro-OH (17.2 g, 80 mmol) and benzyl bromide (14.3 ml, 120 mmol) were reacted in DMF (160 ml) in the presence of triethylamine (16.8 ml, 120 mmol) to obtain Boc-D-Pro-OBzl as an oily product. This product was reacted with 2 N HCl/dioxane (5 eq.) for 3 hours to obtain H-D-Pro-OBzl-HCl.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)=[N:12][CH:13]=1>C1COCC1.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.[Cu]I>[CH3:1][Si:2]([C:5]#[C:6][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:16][N:15]=2)=[N:12][CH:13]=1)([CH3:4])[CH3:3]
Reactant: Brc1ccc(-c2ccc(Br)cn2)nc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(-c2ccc(C#C[Si](C)(C)C)cn2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under dry nitrogen atmosphere, successively trimethylsilyl-acetylene (619 mg, 6.30 mmol), [Pd(PPh3)2Cl2] (112 mg, 159 mol), CuI (54.5 mg, 286 mol) and DIPA (4 ml) were added to a stirred suspension of 3 (500 mg, 1.59 mmol) in 30 ml THF. While the mixture was stirred for 24 hours at room temperature, its color turned black. It was stirred together with activated carbon for 20 minutes and filtered over celite. Then the solvent was removed under reduced pressure, the residue was resuspended in hexane, sonicated for 15 minutes and filtered over celite again yielding an orange solution. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica (eluent: CH2Cl2) to yield 430 mg (1.23 mmol, 78%) of pure 4 as an off-white solid. 1H NMR (CDCl3, 250 MHz): δ=8.71 (s, 2H, bpy-H), 8.33 (d, 2H, JHH=8.3 Hz, bpy-H), 7.85 (d, 2H, JHH=7.8 Hz, bpy-H), 0.27 (s, 18H, Si(CH3)3).
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C@@H:25]([C:39](O)=[O:40])[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=3)=[O:23])[CH2:18][CH2:17]2)[CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[NH:10]1.[CH2:46]([O:48][C:49](=[O:64])[CH2:50][N:51]1[CH2:56][CH2:55][N:54]([C:57]2([CH3:63])[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:53][CH2:52]1)[CH3:47].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[O:8]=[C:9]1[N:15]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C@H:25]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=3)[C:39]([N:60]3[CH2:61][CH2:62][C:57]([N:54]4[CH2:53][CH2:52][N:51]([CH2:50][C:49]([O:48][CH2:46][CH3:47])=[O:64])[CH2:56][CH2:55]4)([CH3:63])[CH2:58][CH2:59]3)=[O:40])=[O:23])[CH2:20][CH2:21]2)[CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[NH:10]1
Reactant: CCOC(=O)CN1CCN(C2(C)CCNCC2)CC1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(C2(C)CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.10 mL (0.72 mmol) triethylamine were added to a mixture of 250 mg (0.45 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f), 140 mg (0.49 mmol) ethyl[4-(4-methyl-piperidin-4-yl)-piperazin-1-yl]-acetate (Example A8b) and 160 mg (0.50 mmol) TBTU in 2 mL DMF and the reaction mixture was stirred for 18 h at RT. It was evaporated down i. vac. and the residue was purified by chromatography (Alox, gradient DCM/MeOH 40:1 nach 30:1). The fractions containing the product were combined, evaporated down i. vac. and purified by HPLC; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([NH:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([NH:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[S:35])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNC(=S)c1ccc(OCc2ccccc2)cc1
Reaction time: 48 h

Procedure:
Di-t-butyl dicarbonate (10.8 g, 49.5 mmol) was added to a solution of 4-(benzyloxy)benzohydrazide (10 g, 41.3 mmol) in dichloromethane (206 mL) at 0° C. The resulting mixture was stirred for 2 d at room temperature, then concentrated and the residue was triturated with diethyl ether to yield tert-butyl 2-(4-(benzyloxy)benzoyl)hydrazinecarboxylate. A mixture of tert-butyl 2-(4-(benzyloxy)benzoyl)hydrazinecarboxylate (13.7 g, 40 mmol) and Lawesson's reagent (8.1 g, 20.0 mmol) in THF (200 mL) THF was stirred for 2 d. Solvent was removed under vacuum and the residue was chromatographed (silica gel, heptane-ethyl acetate) to yield tert-butyl 2-(4-(benzyloxy)phenylcarbonothioyl)hydrazinecarboxylate. A solution of tert-butyl 2-(4-(benzyloxy)phenylcarbonothioyl)hydrazinecarboxylate(12 g) in 1,4-dioxane (34 mL) and 4.0 N HCl (34 mL) in 1,4-dioxane was stirred for 5 h. The resulting solid was collected and washed with diethyl ether to yield 4-(benzyloxy)benzothiohydrazide.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C=O)C.O>[N+:13]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-:15])=[O:14]
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: C1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Temperature: 50 °C

Procedure:
A mixture of ethyl 4-fluoro-3-nitrobenzoate (Clontech 01072, 500 mg; 2.35 mmol; 1 eq.) and piperidine (599.2 mg; 7.04 mmol; 3 eq.) in DMF (2 mL) was heated to 50° C. for 3 hours. The reaction was then allowed to return to RT and diluted with water. It was extracted with EtOAc and the organic phase was dried over sodium sulfate and concentrated in vacuo, affording ethyl 3-nitro-4-piperidin-1-ylbenzoate as a yellow oil. The residue was taken up in THF (15 mL) and lithium hydroxide (280.86 mg; 11.73 mmol; 5 eq.) was added, followed by water (15 mL). The reaction mixture was then stirred at RT for 5 hours. It was concentrated and the residue was diluted with water. The aqueous phase was washed with Et2O and acidified to pH 5 with acetic acid. It was extracted with Et2O and the organic phase was dried over magnesium sulfate and concentrated, affording the title compound as a yellow solid (562 mg, 96%). 1H NMR: (DMSO-d6, 300 MHz) δ 13.07 (s, 1H), 8.29-8.28 (d, J=2.11 Hz, 1H), 8.03-8 (dd, J=8.91 Hz, J=2.20 Hz, 1H), 7.35-7.33 (d, J=8.91 Hz, 1H), 3.15-3.13 (m, 4H), 1.64-1.60 (m, 6H). LC/MS (Method A): 252.9 (M+H)+; 250.9 (M−H)−. HPLC (Method A) Rt 3.69 min (Purity: 99.7%).