Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[O:22][CH:23]=2)[N:3]=1.Cl.[NH:32]1[CH2:35][CH:34]([OH:36])[CH2:33]1.C(N(C(C)C)C(C)C)C>C1COCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2[O:22][CH:23]=[C:19]([CH2:18][S:17][C:4]3[C:5]([C:15]#[N:16])=[C:6]([C:10]4[S:14][CH:13]=[N:12][CH:11]=4)[C:7]([C:8]#[N:9])=[C:2]([N:32]4[CH2:35][CH:34]([OH:36])[CH2:33]4)[N:3]=3)[N:20]=2)=[CH:25][CH:26]=1
Reactant: N#Cc1c(Cl)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1
Reactant: OC1CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1c(SCc2coc(-c3ccc(Cl)cc3)n2)nc(N2CC(O)C2)c(C#N)c1-c1cncs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
80 mg (0.170 mmol) of 2-chloro-6-({[2-(4-chlorophenyl)-1,3-oxazol-4-yl]methyl}sulfanyl)-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile, together with 37 mg (0.340 mmol) of azetidin-3-ol hydrochloride and 44 mg (0.340 mmol) of N-ethyl-N-(1-methylethyl)propan-2-amine, were dissolved in 1 ml of THF. The mixture was stirred at room temperature for two hours, and the product was then purified by preparative HPLC (acetonitrile/water: 10:90→95:5, 0.1% TFA added). This gave 40 mg (46% of theory) of the target compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[N:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:29]([CH:37]=O)[NH:28][C:27]=2[CH3:39])=[O:25])=[CH:19][CH:18]=1>>[N:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:30]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:29]([CH:37]=[C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[CH:15][C:7]=4[CH:4]4[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]4)[NH:11][C:10]3=[O:16])[NH:28][C:27]=2[CH3:39])=[O:25])=[CH:19][CH:18]=1
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: Cc1[nH]c(C=O)c(-c2ccccc2)c1C(=O)Nc1ccncc1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)c(-c2ccccc2)c1C(=O)Nc1ccncc1

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid pyridin-4-ylamide (67 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:11][C@@H:10]([NH:12][C:13](=[O:29])[NH:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[C:18]([NH:25]C(=O)C)[N:19]=[CH:20]3)[C:9]2[C:4](=[CH:5][C:6]([C:30]([F:33])([F:32])[F:31])=[CH:7][CH:8]=2)[O:3]1.[OH-].[Na+]>CO.O>[NH2:25][C:18]1[N:19]=[CH:20][C:21]2[C:16]([CH:17]=1)=[C:15]([NH:14][C:13]([NH:12][C@H:10]1[C:9]3[C:4](=[CH:5][C:6]([C:30]([F:33])([F:31])[F:32])=[CH:7][CH:8]=3)[O:3][C:2]([CH3:34])([CH3:1])[CH2:11]1)=[O:29])[CH:24]=[CH:23][CH:22]=2
Reactant: CC(=O)Nc1cc2c(NC(=O)N[C@@H]3CC(C)(C)Oc4cc(C(F)(F)F)ccc43)cccc2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)C[C@@H](NC(=O)Nc2cccc3cnc(N)cc23)c2ccc(C(F)(F)F)cc2O1
Temperature: 25 °C
Yield: 51.7 %

Procedure:
A mixture of Example 90D (505 mg, 1.07 mmol) and NaOH (428 mg, 10.7 mmol) in MeOH (10 mL) and H2O (3.5 mL) was heated to 85° C. After 24 h the reaction mixture was cooled to ambient temperature. The precipitate was collected by vacuum filtration, washed with minimal MeOH and then water, and dried in the vacuum oven at 50° C. for 4 h to provide the title compound (238 mg, 0.553 mmol, 52% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.35 (s, 1H), 7.89 (d, J=7.4 Hz, 1H), 7.52 (t, J=7.5 Hz, 2H), 7.26 (d, J=8.2 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 7.06 (s, 1H), 6.95 (d, J=8.5 Hz, 1H), 6.71 (s, 1H), 5.99 (s, 2H), 5.14-5.00 (m, 1H), 2.21 (dd, J=13.3, 6.2 Hz, 1H), 1.82 (dd, J=13.1, 11.6 Hz, 1H), 1.44 (s, 3H), 1.32 (s, 3H); MS (ESI+) m/z 431 (M+H)+; [α]23D +35.7° (c 0.61, CH3OH).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=O)=[CH:17][C:16]=1[NH2:24]>>[NH2:24][C:16]1[CH:17]=[C:18]([C:19]2[O:12][C:3]3[CH:4]=[C:5]4[C:10]([CH:9]=[CH:8][CH:7]=[CH:6]4)=[CH:11][C:2]=3[N:1]=2)[CH:22]=[CH:23][C:15]=1[O:14][CH3:13]
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: Nc1cc2ccccc2cc1O
Product: COc1ccc(-c2nc3cc4ccccc4cc3o2)cc1N

Procedure:
Prepared by the method of Example 1a), from 3-amino-2-naphthol (476 mg, 2.9 mmol) and 4-methoxy-3-aminobenzoic acid (500 mg, 2.9 mmol) the subtitle compound was obtained, 120 mg (14%). 1H NMR (CDCl3) δ 8.06(s, 1H), 7.92–7.83(m, 3H), 7.67(dd, J=1.9, 8.2 Hz, 1H), 7.60(d, J=1.9 Hz, 1H), 7.38(m, 2H), 6.85(d, J=8.3 Hz, 1H), 3.88(s, 3H). MS 291 m/z (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:47][CH2:48][C:49]1[CH:59]=[CH:58][C:52]([O:53][CH2:54][CH:55]([OH:57])[CH3:56])=[CH:51][C:50]=1[O:60][CH3:61]>CN(C=O)C>[OH:57][CH:55]([CH3:56])[CH2:54][O:53][C:52]1[CH:58]=[CH:59][C:49]([CH2:48][NH:47][C:12]([C:7]2[S:8][C:9]([CH3:11])=[C:10]3[C:6]=2[CH2:5][C@H:4]2[C:2]([CH3:1])([CH3:15])[C@H:3]23)=[O:14])=[C:50]([O:60][CH3:61])[CH:51]=1
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Reactant: COc1cc(OCC(C)O)ccc1CN
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: COc1cc(OCC(C)O)ccc1CNC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
A solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (9.6 mg, 0.043 mmol), TBTU (13.8 mg, 0.043 mmol) and ethyl-diisopropylamine (22 μL, 0.129 mmol) in DMF (1 mL) is allowed to stand at rt for 30 min. The solution is added to (rac)-1-(4-aminomethyl-3-methoxy-phenoxy)-propan-2-ol (9.1 mg, 0.043 mmol) and the mixture is allowed to stand at rt for 1 h. The mixture is separated by prep. HPLC to afford (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-((R/S)-2-hydroxy-propoxy)-2-methoxy-benzylamide (7.6 mg) as a colourless oil. LC-MS: tR=0.98 min, [M+1]+=402.16; 1H NMR (CDCl3): δ 7.20 (d, J=8.2 Hz, 1H), 6.50 (d, J=2.3 Hz, 1H), 6.44 (d, J=8.2 Hz, 1H), 6.16 (t br, J=5.3 Hz, 1H), 4.47 (d, J=5.9 Hz, 2H), 3.93 (dd, J=2.9, 11.1 Hz, 1H), 3.87 (s, 3H), 3.82-3.72 (m, 1H), 2.90 (dd, J=5.3, 17.6 Hz, 1H), 2.69 (d, J=18.1 Hz, 1H), 2.35 (s, 3H), 1.92-1.85 (m, 2H), 1.30 (d, J=6.4 Hz, 3H), 1.11 (s, 3H), 0.72 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH2:13])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[OH-].[Na+].[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:13][N:12]([C:9]1[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=1)[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1ccc(N(N)C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1ccc(N(NC(C)=O)C(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
tert-Butyl 1-[4-(ethoxycarbonyl)phenyl]hydrazinecarboxylate (5.60 g) and acetic anhydride (10 ml) were mixed, and the mixture was stirred at 90° C. for 1 hr. The reaction mixture was neutralized with 1N aqueous sodium hydroxide solution, and washed with water and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 (volume ratio)→1:1 (volume ratio)), and further recrystallized from ethyl acetate-hexane to give the title compound (4.42 g) as colorless crystals.
Reaction SMILES: C(N(C[CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]#[N:17])[CH2:10]1)CCC)CC.[NH3:18]>ClCCl.CO>[N:18]1([CH2:9][CH:14]2[CH2:13][CH2:12][N:11]([CH2:15][C:16]#[N:17])[CH2:10]2)[CH2:10][CH2:9][CH2:14][CH2:13][CH2:12]1
Reactant: N
Reactant: CCCN(CCC)CC1CCCN(CC#N)C1
Solvent: CO
Solvent: ClCCl
Product: N#CCN1CCC(CN2CCCCC2)C1

Procedure:
2-[3-[(dipropylamino)methyl]-piperidin-1-yl]acetonitrile in a yield of 76% of theory, RF 0.545 (Macherey-Nagel, PolygramRSIL G/UV254, pre-coated plastic sheets for TLC, eluant: dichloromethane/methanol/conc. ammonia 89/10/1 v/v);
Reaction SMILES: C([NH:5][C:6]([NH:8][C@H:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10]O)=[S:7])(C)(C)C.[ClH:18]>>[ClH:18].[C:12]1([C@@H:9]2[CH2:10][S:7][C:6]([NH2:5])=[N:8]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)NC(=S)N[C@@H](CO)c1ccccc1
Agent: Cl
Product: NC1=N[C@H](c2ccccc2)CS1
Temperature: 0 °C

Procedure:
The process is performed under the conditions of Example 1, starting with 2.4 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-phenylethyl]thiourea in 24 cm3 of aqueous 6N hydrochloric acid for 1 hour 30 minutes at a temperature in the region of 100° C. After cooling the medium to a temperature in the region of 0° C., the precipitate formed is filtered off and the filter cake is then washed with 7 cm3 of aqueous 6N hydrochloric acid and twice 15 cm3 of diethyl ether. The solid obtained is dried in an oven under reduced pressure (10 Pa) at a temperature in the region of 60° C. 1.6 g of (−)-(4R)-4-phenyl-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride are obtained in the form of a white solid melting at 260° C. (αd20=−109.6±1.3 at a concentration of 1% in methanol).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C@@:8]2([CH3:23])[CH2:9][CH2:10][C@@H:11]3[C@:21]4([CH3:22])[C:15](=[CH:16][C:17]([CH2:19][CH2:20]4)=[O:18])[CH2:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH:5]=1)=[O:3].ClCCCl.C([OH:31])(C)C>>[CH3:1][C:2]([C@:4]1([OH:31])[C@@:8]2([CH3:23])[CH2:9][CH2:10][C@@H:11]3[C@:21]4([CH3:22])[C:15](=[CH:16][C:17]([CH2:19][CH2:20]4)=[O:18])[CH2:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3]
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)O
Solvent: ClCCCl
Product: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a stirred solution of 16-dehydroprogesterone 3 (0.041 g, 0.131 mmol, 1.0 equ) and Mn(dpm)3 (0.002 g, 0.003 mmol, 0.02 eq) in a mixture of isopropanol (1.5 mL) and enough 1,2-dichloroethane (0.6 mL) to completely dissolve the starting material at 0° C. for 20 min. then at room temperature for 2 h under O2. The solvents were removed by distillation under reduced pressure, affording a cream solid. Purification by flash column chromatography over silica, eluting with 30% EtOAc-hexanes afforded the 17 α-hydroxyprogesterone 4 as a white crystalline solid (0.037 g, 85%) which was identical in all respects with an authentic sample.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>O1CCCC1>[F:11][C:2]([F:1])([F:10])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:4]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(C(F)(F)F)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(F)(F)F)ncn1)Oc1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
According to the procedure described in Example 113B, 6-(trifluoromethyl)pyrimidin-4-amine (480 mg, 2.94 mmoles) was dissolved in 20 mL of tetrahydrofuran. To this solution was added potassium carbonate (528 mg, 3.82 mmoles), followed by phenyl chloroformate (598 mg, 3.82 mmoles). An additional equivalent of phenyl chloroformate was added after stirring overnight and the reaction heated to 60° C. for 2 days. The crude product was purified to afford phenyl 6-(trifluoromethyl)pyrimidin-4-ylcarbamate as a white solid. 1H NMR (300 MHz, CDCl3) δ 10.12 (s, 1H), 9.13 (s, 1H), 8.46 (s, 1H), 7.7-7.2 (m, 5H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](OCC)=[O:12])=[CH:5]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][OH:12])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2cc(F)ccc2[nH]1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 89.4 %

Procedure:
To ethyl 5-fluoro-1H-indole-2-carboxylate 45 (3.1 g, 14.96 mmol) in THF at 0° C. was added lithium aluminum hydride solution (1 M, in THF 0.625 g, 16.44 mmol) dropwise and the reaction mixture was stirred for 3.5 hours at 0° C. The reaction mixture was quenched with H2O, 15% NaOH, and H2O before it was filtered and rinsed with THF. Reaction mixture was dried (anhydrous Na2SO4) and evaporation of the solvent gave 2.21 g (90% yield) of the crude (5-fluoro-1H-indol-2-yl)methanol 46 which was used directly in the next step.
Reaction SMILES: Cl[CH:2]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)[C:3]1[CH:15]=[CH:14][C:6]([C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1.[I:24][C:25]1[C:26]([CH3:31])=[N:27][NH:28][C:29]=1[CH3:30]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC#N>[CH2:10]([N:9]([CH2:12][CH3:13])[C:7](=[O:8])[C:6]1[CH:14]=[CH:15][C:3]([CH:2]([N:27]2[C:26]([CH3:31])=[C:25]([I:24])[C:29]([CH3:30])=[N:28]2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[CH:4][CH:5]=1)[CH3:11]
Reactant: CCN(CC)C(=O)c1ccc(C(Cl)c2cccc(OC)c2)cc1
Reactant: Cc1n[nH]c(C)c1I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CC#N
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(OC)c2)n2nc(C)c(I)c2C)cc1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To a stirring solution of 4-[Chloro-(3-methoxy-phenyl)-methyl]-N,N-diethyl-benzamide (1.11 g, 3.32 mmol) in 20 Ml CH3CN was added 4-iodo-3,5-dimethyl pyrazole (1.64 g, 7.40 mmol) and tetra-n-butyl ammonium iodide (619 mg, 1.68 mmol). The mixture was heated to reflux for 24 h, cooled to room temperature and concentrated under reduce pressure. The crude oil was purified by flash chromatography on a 3×20 cm column, eluting with 30% ethyl acetate/hexanes, collecting 8 mL fractions. The product containing fractions were collected and concentrated under reduce pressure to give the desired product (1.65 g, 96%) as a clear yellow oil. 400 MHz 1H NMR (CDCl3) δ 7.31 (d, J=8.1 Hz, 2H), 7.19-7.24 (m, 1H), 7.13 (d, J=8.3 Hz, 2H), 6.79-6.82 (m, 1H), 6.68-6.70 (m, 2H), 6.54 (s, 1H), 3.71 (s, 3H), 3.50 (br s, 2H), 3.23 (br s, 2H), 2.21 (s, 3H), 2.18 (s, 3H), 1.21 (br s, 3H), 1.08 (br s, 3H); 75 MHz 13C NMR (CDCl3), δ 170.8, 159.7, 149.8, 141.2, 140.3, 140.1, 136.7, 129.6, 128.5, 126.6, 120.8, 114.4, 113.2, 66.5, 55.3, 43.3, 39.3, 14.4, 12.6; MS (M+1) 518.0.
Reaction SMILES: [NH2:1][C@H:2]([C:9]([NH:11][C@H:12]([C:20]([NH2:22])=[O:21])[CH2:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl.Cl.[NH:25]([C:39]([CH3:41])=[O:40])[C@H:26]([C:36](O)=[O:37])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C.[N-]=[N+]=[N-]>CN(C)C=O>[NH:25]([C:39]([CH3:41])=[O:40])[C@H:26]([C:36]([NH:1][C@H:2]([C:9]([NH:11][C@H:12]([C:20]([NH2:22])=[O:21])[CH2:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:37])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1
Reactant: CC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)O
Reactant: NC(=O)[C@H](Cc1cccnc1)NC(=O)[C@@H](N)C1CCCCC1
Agent: Cl
Agent: [N-]=[N+]=[N-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)N[C@H](C(=O)N[C@@H](Cc1cccnc1)C(N)=O)C1CCCCC1
Yield: 82.4 %

Procedure:
Stir overnight H-(L)-Chg-(L)-Pal-NH2.2HCl (1.13 g, 3 mmol), Ac-(L)Phe(4-CN)-OH (0.84 g, 3.6 mmol), diisopropylethylamine (10 mmol). and diphenylphoshoryl azide (803 μl 3.6 mmol) dimethyl formamide (30 mL) overnight. Evaporate dimethyl formamide, precipitate by ether, filter and wash by ether to give Ac-(L)-Phe(4-CN)-(L)-Chg-(L)-Pal-NH2 (1.282 g, 82%). ##STR21##
Reaction SMILES: [CH2:1]([O:5][C@@H:6]1[C@@H:14]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:13]([CH3:20])[O:12][C:11](=[O:21])[C@@H:10]([NH:22][C:23](=[O:33])[C:24]2[C:29]([OH:30])=[C:28]([O:31][CH3:32])[CH:27]=[CH:26][N:25]=2)[CH2:9][O:8][CH2:7]1)[CH:2]([CH3:4])[CH3:3].[CH3:34][O:35][CH2:36][CH2:37][C:38](Cl)=[O:39]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:34][O:35][CH2:36][CH2:37][C:38]([O:30][C:29]1[C:24]([C:23](=[O:33])[NH:22][C@H:10]2[CH2:9][O:8][CH2:7][C@H:6]([O:5][CH2:1][CH:2]([CH3:3])[CH3:4])[C@@H:14]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:13]([CH3:20])[O:12][C:11]2=[O:21])=[N:25][CH:26]=[CH:27][C:28]=1[O:31][CH3:32])=[O:39]
Reactant: COc1ccnc(C(=O)N[C@H]2COC[C@H](OCC(C)C)[C@@H](OCC(C)C)[C@H](C)OC2=O)c1O
Reactant: COCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCCC(=O)Oc1c(OC)ccnc1C(=O)N[C@H]1COC[C@H](OCC(C)C)[C@@H](OCC(C)C)[C@H](C)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
A reaction flask was charged with N-((3S,7S,8S,9S)-7,8-diisobutoxy-9-methyl-2-oxo-1,5-dioxonan-3-yl)-3-hydroxy-4-methoxypicolinamide (97 mg, 0.207 mmol), DMAP (40.1 mg, 0.328 mmol), and DCM. 3-Methoxypropanoyl chloride (22.5 μl, 0.207 mmol) was added and the colorless solution was stirred at room temperature under N2 overnight. The reaction mixture was concentrated and purified by column chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound (108.5 mg, 94% yield) as a sticky orange oil: IR (thin film) 3375, 2955, 2873, 1753, 1677, 1507, 1088 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J=8.2 Hz, 1H), 8.38-8.30 (m, 1H), 7.00 (dd, J=5.7, 1.8 Hz, 1H), 5.08-4.98 (m, 1H), 4.93 (ddt, J=12.2, 8.4, 4.1 Hz, 1H), 4.00 (tt, J=7.2, 3.4 Hz, 1H), 3.93-3.84 (m, 3H), 3.85-3.64 (m, 5H), 3.64-3.55 (m, 1H), 3.41 (d, J=1.5 Hz, 3H), 3.33-3.12 (m, 5H), 2.97 (t, J=6.6 Hz, 2H), 1.82 (tt, J=12.9, 6.0 Hz, 2H), 1.43 (dd, J=6.3, 1.7 Hz, 3H), 0.97-0.85 (m, 12H); 13C NMR (101 MHz, CDCl3) δ 170.85, 169.37, 162.67, 159.42, 146.81, 141.19, 137.38, 109.88, 84.82, 83.75, 80.56, 77.70, 74.88, 74.07, 72.99, 67.58, 58.80, 56.32, 52.13, 34.61, 29.11, 28.87, 19.58, 19.46, 19.37, 18.63; ESIMS m/z 555 ([M+H]+).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[CH3:15]O>Cl>[NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[CH2:3][C:4]([O:6][CH3:15])=[O:5]
Reactant: COc1cccc(C(N)CC(=O)O)c1
Reactant: CO
Agent: Cl
Product: COC(=O)CC(N)c1cccc(OC)c1

Procedure:
A solution of β-amino-3-methoxy-benzenepropanoic acid (WO 0041469) (9.38 g, 52 mmol) in concentrated hydrochloric acid (10 ml) and methanol (115 ml), was heated under reflux for 7 hours, then cooled. The reaction was evaporated under reduced pressure, and the residue partitioned between ethyl acetate (300 ml) and 1N sodium hydroxide solution (300 ml). The layers were separated, and the organic phase evaporated under reduced pressure to afford the title compound as a colourless oil, 8.8 g.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[N:6]=[C:5]([F:11])[C:4]=1[Cl:12].[C:13]([O-:21])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+]>CN(C=O)C.CCOCC>[Cl:12][C:4]1[C:5]([F:11])=[N:6][C:7]([F:10])=[C:8]([F:9])[C:3]=1[CH2:2][O:21][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Fc1nc(F)c(Cl)c(CBr)c1F
Reactant: O=C([O-])c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(OCc1c(F)c(F)nc(F)c1Cl)c1ccccc1
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of the 4-bromomethyl-3-chloro-2,5,6-trifluoro-pyridine (15.6 g, 59.9 mmol) in DMF (90 ml) cooled in an ice bath, sodium benzoate (12.9 g, 89.8 mmol) was added. After 1 hr., the mixture was stirred in a water bath for ca. 20 hr. The mixture was then diluted with ether, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a light brown oil. The crude product was purified by silica gel column chromatography (eluent, ether:hexane (1:15) to afford 11.9 g (66%) of benzoic acid 3-chloro-2,5,6-trifluoro-pyridin-4-ylmethyl ester as a white solid. m.p. 60° C.; 1H NMR (200 MHz, CDCl3) δ 5.54 (2H, d, J=1.6 Hz), 7.41-7.64 (3H, m), 8.00-8.05 (2H, m).
Reaction SMILES: C([O:5][C:6]([CH:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:9]1[C:13]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=2[N:11](C(OC(C)(C)C)=O)[C:10]1=[O:27])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:18]([C:15]1[CH:16]=[CH:17][C:12]2[NH:11][C:10](=[O:27])[N:9]([CH:8]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:6]([OH:7])=[O:5])[C:13]=2[CH:14]=1)#[N:19]
Reactant: CC(C)(C)OC(=O)C(c1ccccc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(C#N)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2[nH]c(=O)n(C(C(=O)O)c3ccccc3)c2c1
Temperature: 25 °C

Procedure:
tert-Butyl 3-(tert-butoxycarbonylphenylmethyl)-5-cyano-2-oxo-2,3-dihydrobenzimidazole-1-carboxylate 695 mg (1.55 mmol) of tert-butyl 3-(tert-butoxycarbonylphenylmethyl)-5-cyano-2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (VIIc) were dissolved in dichloromethane (30 ml) and, while stirring at room temperature, trifluoroacetic acid (20 ml) was added. The reaction solution was stirred for 2 h and then the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was taken up again in toluene, concentrated in vacuo and then dried in vacuo. Yield: 449 mg (99%) of white solid
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[N:12]3[C:21]([CH3:24])=[N:22][N:23]=[C:11]3[C@H:10]([CH2:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])[N:9]=2)=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[N:39]=[N:40][NH:41][N:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:21]([CH3:24])=[N:22][N:23]=[C:11]3[C@H:10]([CH2:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(C#N)ccc2-n2c(C)nnc21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3nn[nH]n3)ccc2-n2c(C)nnc21
Temperature: 100 °C

Procedure:
(S)-2-(6-(4-Chlorophenyl)-8-cyano-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (for a preparation see Intermediate 7) (68.4 mg) was dissolved in DMF (5 ml). Triethylamine hydrochloride (45.0 mg) and sodium azide (21.23 mg) were added and the reaction mixture was heated at 100° C., under nitrogen, overnight. The temperature was raised to 120° C. and the reaction mixture was heated overnight. The reaction mixture was allowed to cool to room temperature, partitioned between ethyl acetate and water. The organic phase was washed with water (2×10 ml) and brine (10 ml). The aqueous layer was passed through a pre equilibrated Biotage 103 column. The organic content was eluted with methanol, the methanolic solution was evaporated and the residue was chromatographed (10-20% methanol:DCM). Trituration with diethyl ether gave (S)-2-(6-(4-chlorophenyl)-1-methyl-8-(2H-tetrazol-5-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (25.6 mg) as a yellow solid. LCMS (formate): MH+ 462/464, RT 0.75 min
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:2]=1.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)#[CH:23]>CCCCCCC.CCOC(C)=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:23]#[C:22][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cnc3ccccc3c2)cc1
Reactant: C#Cc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Nc1ccc(C#Cc2cnc3ccccc3c2)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid quinolin-3-yl ester and 4-ethynyl-phenylamine following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 6:4; yield (120 mg, 98%); 1H NMR δ (CDCl3): 8.98 (s, 1H), 8.34 (s, 1H), 8.21 (d, J=8.60 Hz, 1H), 7.87-7.71 (d m, 2H), 7.68-7.57 (m, 1H), 7.40 (d, J=8.36 Hz, 2H), 6.67 (d, J=8.38 Hz, 2H), 4.46 (br s, 2H); LCMS m/z: 244.