Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.[C:18]1([N:24]2[C:28]3[CH:29]=[N:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]2[CH:33](O)[CH3:34])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C(Cl)Cl>[N:15]([CH:33]([C:25]1[N:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:28]2[CH:29]=[N:30][CH:31]=[CH:32][C:27]=2[N:26]=1)[CH3:34])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(O)c1nc2ccncc2n1-c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(N=[N+]=[N-])c1nc2ccncc2n1-c1ccccc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 165.2 %

Procedure:
Diphenylphosphoryl azide (1.12 g, 4.06 mmol) and then diisopropyl azadicarboxylate (1.37 g, 6.77 mmol) were added to a stirred solution of 1-(3-phenyl-3H-imidazo[4,5-c]pyridin-2-yl)ethanol (0.81 g, 3.39 mmol) and triphenylphosphine (1.78 g, 6.77 mmol) in dioxane (50 mL) at 0° C. under nitrogen. The reaction mixture was stirred at 20° C. for 16 h then diluted with DCM to dissolve all the material. This was loaded onto an Isolute® SCX-2 cartridge and washed with methanol and the product eluted with 2M NH3/MeOH then concentrated in vacuo. The residue was purified by chromatography (SiO2 0-4% (2M ammonia in methanol) in DCM) to give the title compound as a colourless oil (1.48 g, contaminated with triphenylphosphine oxide). LCMS (method H): Rt 1.79 min, [M+H]+ 265.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12](C#N)[CH:11]=2)[C:7]2[CH:24]=[C:25]([N:31]3[CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]3=[O:40])[CH:26]=[C:27]([CH:28]([CH3:30])[CH3:29])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:41]=[N+:42]=[N-:43].[Na+].[CH3:45][N:46](C)C=O>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:45]3[NH:46][N:43]=[N:42][N:41]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([N:31]3[CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]3=[O:40])[CH:26]=[C:27]([CH:28]([CH3:29])[CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C(C)C)cc(N3Cc4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2)c(C#N)c1
Reactant: CN(C)C=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CCCc1nc2c(C(C)C)cc(N3Cc4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4-[[2-n-propyl-4-isopropyl-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]2[N:46]=[CH:45][CH:44]=[N:43]2)[C:34]=1[C:35](O)=[O:36].S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[F:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]2[N:46]=[CH:45][CH:44]=[N:43]2)[C:34]=1[C:35]([N:13]1[CH2:12][CH2:11][C@@H:10]2[C@@H:15]([N:8]([C:5]3[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH2:9]2)[CH2:14]1)=[O:36]
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: Cc1cnc(N2C[C@@H]3CCNC[C@@H]32)cn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: Cc1cnc(N2C[C@@H]3CCN(C(=O)c4c(F)cccc4-n4nccn4)C[C@@H]32)cn1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(5-methylpyrazin-2-yl)-3,8-diazabicyclo[4.2.0]octane (Intermediate 29) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 15) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C20H20FN7O, 393.43; m/z found 394.1 [M+H]+. 1H NMR (CDCl3): 7.99-7.69 (m, 3H), 7.58-7.39 (m, 2H), 7.31 (s, 1H), 7.19-6.84 (m, 1H), 4.67-4.34 (m, 1H), 4.15-3.80 (m, 4H), 3.69-3.18 (m, 2H), 2.96 (br s, 1H), 2.45-2.05 (m, 5H).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:3]1=[O:24].C(N(CC)CC)C.Cl.[C:33]1([C:39]2[NH:40][C:41](=[O:50])[N:42]([CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[CH:43]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[O:51]1CCC[CH2:52]1>>[O:24]=[C:3]1[C@H:2]([NH:1][C:52]([N:47]2[CH2:46][CH2:45][CH:44]([N:42]3[CH:43]=[C:39]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[NH:40][C:41]3=[O:50])[CH2:49][CH2:48]2)=[O:51])[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]1[CH2:19][C:20]([F:21])([F:23])[F:22]
Reactant: O=c1[nH]c(-c2ccccc2)cn1C1CCNCC1
Reactant: C1CCOC1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O)N1CCC(n2cc(-c3ccccc3)[nH]c2=O)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Amino-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepine (20.0 mg, 0.06 mmol) (Y.-J. Shi et al., Tetrahedron, 1999, 55, 909-918) and p-nitrophenylchloroformate (12.1 mg, 0.06 mmol) were dissolved in tetrahydrofuran (0.5 mL) under argon, and cooled to 0° C. Triethylamine (19 uL, 0.14 mmol) was added and the reaction stirred for 1 h, followed by addition of more triethylamine (19 uL) and 4-phenyl-1-piperidin-4-yl-1,3-dihydro-2H-imidazol-2-one hydrochloride (16.8 mg, 0.06 mmol), prepared according to the procedure described in the patent U.S. Pat. No. 6,344,449 B1. The reaction was warmed to room temperature and stirred overnight. The crude product was purified by reverse phase HPLC (C-18, 5% to 95% 0.1% trifluoroacetic acid/acetonitrile in 0.1% aqueous trifluoroacetic acid gradient elution) to give she title compound (26.1 mg). MS 603 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH3:44][C:45]1[N:46]=[C:47]([CH:51]([NH2:53])[CH3:52])[S:48][C:49]=1[CH3:50]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:53][CH:51]([C:47]2[S:48][C:49]([CH3:50])=[C:45]([CH3:44])[N:46]=2)[CH3:52])=[O:42])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1nc(C(C)N)sc1C
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1NC(=O)NC(C)c1nc(C)c(C)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methoxyaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(4,5-dimethyl-1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (45 mg, yield 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:13][CH2:14][CH3:15])=[CH:10]/[CH:11]=O)=[CH:5][CH:4]=1.[C:16]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:18][CH3:19])=[O:17]>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:19][O:18][C:16](=[O:17])/[CH:20]=[CH:11]/[CH:10]=[C:9](/[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)\[CH2:13][CH2:14][CH3:15]
Reactant: CCC/C(=C\C=O)c1ccc(OC)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCC/C(=C\C=C\C(=O)OC)c1ccc(OC)cc1

Procedure:
As described in Example 99, (E)-3-(4-methoxyphenyl)-2-hexenal (6 g) was treated with (carbomethoxymethylene)triphenylphosphorane (11 g) in carbon tetrachloride (70 mL) and dichloromethane (15 mL) for 4 days at room temperature. The ester was isolated in the normal manner to give 6.7 g of (E,E)-5-(4-methoxyphenyl)-2,4-octadienoic acid methyl ester as an oil.
Reaction SMILES: [Br-].[Br:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[CH:39]=O>C1COCC1>[Br:2]/[CH:3]=[CH:39]\[C:30]1[CH:31]=[CH:32][C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:29]=1
Reactant: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc2ccccc2n1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: Br/C=C\c1ccc2ccccc2n1
Temperature: -70 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
A suspension of 24.97 g (57.3 mmol) of (bromomethyl)triphenylphosphonium bromide in 160 mL of THF was chilled to −70° C. under argon. Then, 6.43 g (57.3 mmol) of potassium tert-butoxide were added portionwise and the suspension was allowed to stir at this temperature for 1 h. A solution of 7.5 g of (47.7 mmol) quinoline-2-carbaldehyde in 40 mL of THF was slowly added dropwise. The mixture was allowed to stir at −75° C. for further 5 hours and then warmed to room temperature overnight. 160 mL of PE were added. The precipitate formed was sucked off. The mother liquid was evaporated and the residue was stirred with diisopropyl ether. The residue formed was sucked off. Purification by chromatography (heptane/EA 3/1) yielded 6.6 g (59.1%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:6][O:7][C:8]1[CH:9]=[C:10]([C@@H:14]([NH:20][C:21]([C@@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)[CH2:24]2)=[O:22])[CH2:15][C:16]([O:18]C)=[O:17])[CH:11]=[N:12][CH:13]=1)#[N:2].CO.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>C(O)(C)(C)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:6][O:7][C:8]1[CH:9]=[C:10]([C@H:14]([NH:20][C:21]([C@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]3[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]3)[CH2:24]2)=[O:22])[CH2:15][C:16]([OH:18])=[O:17])[CH:11]=[N:12][CH:13]=1)#[N:2]
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCc2ccc(F)c(C#N)c2)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(C)(C)O
Product: N#Cc1cc(COc2cncc([C@@H](CC(=O)O)NC(=O)[C@H]3CCCN(C(=O)CCC4CCNCC4)C3)c2)ccc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 14.1 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-{[(1S)-1-{5-[(3-cyano-4-fluorobenzyl)oxy]pyridin-3-yl}-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (3.2 mg, 10 μmol) as solved in tert.-butanol (0.15 mL) and methanol (0.13 mL) and barium hydroxide octahydrate (7.4 mg, 20 μmol) was added. After stirring for 45 minutes at room temperature the solvent was distilled off at 0° C. by high vacuum. The residue was solved in water (0.3 mL) and acidified by formic acid (0.9 mL). After 3 hours at room temperature the solvent was distilled off at 0° C. by high vacuum and the residue was purified by preparative HPLC to yield 0.8 mg of (3R)-3-{5-[(3-cyano-4-fluorobenzyl)oxy]pyridin-3-yl}-3-[({(3S)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:9][CH2:8][C:7]1=[O:17])[CH3:4].Br[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1>>[ClH:1].[CH3:4][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([O:12][CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:9][CH2:8][C:7]1([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)[OH:17])[CH3:2]
Reactant: COc1cccc(Br)c1
Reactant: CC(C)COC1CCC(=O)C(CN(C)C)C1
Agent: Cl
Product: COc1cccc(C2(O)CCC(OCC(C)C)CC2CN(C)C)c1
Yield: 38 %

Procedure:
The base of compound (22) was reacted with 1-bromo-3-methoxy-benzene corresponding to the conditions described in Example 1. The base obtained was purified with 1:1 ethyl acetate/methanol via a silica gel column, and was taken up in ether. After adding trimethylchlorosilane/water, compound (20) was obtained in a yield of 38% theoretical.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[SH:12].[CH2:13]([N:20]1[C:28]2[C:27](Cl)=[N:26][C:25]([NH2:30])=[N:24][C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN1C(=O)CCC1.O>[CH2:13]([N:20]1[C:28]2[C:27]([S:12][C:5]3[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=3[CH3:3])=[N:26][C:25]([NH2:30])=[N:24][C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1nc(Cl)c2c(ccn2Cc2ccccc2)n1
Reactant: Cc1cc(C)c(S)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(Sc2nc(N)nc3ccn(Cc4ccccc4)c23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a stirred suspension of NaH (48 mg, 2 mmol) in dry NMP (2 mL) was added 2,4,6-trimethyl-benzene-1-thiol (191 mg, 1.2 mmol) The mixture was and stirred at room temperature for 30 min under argon. The reaction mixture was then added to a solution of 5-benzyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine (103 mg, 0.4 mmol) in dry NMP (2.5 mL) and heated at 60° C. for 16 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, 2% NaOH, and brine; dried over Na2SO4; filtered; and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (2:1-1:3) to give the product as a light yellow solid (131 mg, 88%).
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]4[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:27]([CH3:30])=[N:28][N:29]=[C:11]3[C@H:10]([CH2:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[N:9]=2)=[CH:4][CH:3]=1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=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[CH:20]=[CH:21][C:22]([CH2:25][N:41]5[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]5)=[CH:23][CH:24]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:27]([CH3:30])=[N:28][N:29]=[C:11]3[C@H:10]([CH2:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccc(C=O)cc3)ccc2-n2c(C)nnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccc(CN4CCN(C)CC4)cc3)ccc2-n2c(C)nnc21
Reaction time: 0.08 h

Procedure:
(S)-2-(6-(4-Chlorophenyl)-8-(4-formylphenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (for a preparation see Intermediate 6) (90 mg) was dissolved in DCM (5 ml). 1-Methylpiperazine (30 μl) and acetic acid (10.35 μl) were added and the reaction mixture was stirred for 5 min. Sodium triacetoxyborohydride (192 mg) was added and the reaction mixture was stirred at room temperature, under nitrogen, over the weekend. Saturated sodium hydrogen carbonate solution (5 ml) was added and the reaction mixture was stirred for 10 min. The organic phase was separated and the saturated sodium hydrogen carbonate solution was extracted with DCM (10 ml). The DCM extracts were combined, dried and the solvent was evaporated. The residue was chromatographed (0-15% methanol:DCM), triturated with diethyl ether and dried in a vacuum dessicator at 40° C. overnight to give (S)-2-(6-(4-chlorophenyl)-1-methyl-8-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (66.5 mg) as a white solid. LCMS (formate): MH+ 582, RT 0.65 min
Reaction SMILES: [CH2:1]([O:8][C:9]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])[CH:10]([O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[N:17]=1)[C:11]([O:13]C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([O:8][C:9]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])[CH:10]([O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[N:17]=1)[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(OCc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(OC)nc(OC(C(=O)O)C(C)(OCc2ccccc2)c2ccccc2)n1
Reaction time: 12 h

Procedure:
1.4 g (3 mmol) of methyl 3-benzyloxy-3-phenyl-2-(4,6-dimethoxypyrimidin-2-yloxy)butyrate (Example 3) are dissolved in 20 ml of methanol and 20 ml of tetrahydrofuran, and 3.7 g of 10% strength NaOH solution are added. Stirring is carried out for 6 hours at 60° C. and for 12 hours at room temperature, the solvent is distilled off under reduced pressure and the residue is taken up in 100 ml of water. Extraction is now carried out with ethyl acetate to remove unconverted ester. The aqueous phase is then brought to pH 1-2 with dilute hydrochloric acid and is extracted with ethyl acetate. After drying has been carried out over magnesium sulfate and the solvent has been distilled off, a little acetone is added to the residue and the precipitate formed is filtered off with suction. After drying, 1.2 g of a white powder remain.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:12])=[N:4][C:5](S(C)=O)=[N:6][C:7]=1[Cl:8].[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[N:14]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[C:3]([NH2:12])=[N:4][C:5]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[N:14]2)=[N:6][C:7]=1[Cl:8]
Reactant: c1ccc2[nH]ncc2c1
Reactant: CS(=O)c1nc(N)c(Br)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1nc(-n2ncc3ccccc32)nc(Cl)c1Br
Temperature: 0 °C

Procedure:
To a vigorously stirring suspension of 2 g (7.4 mmol) of 5-bromo-6-chloro-2-(methylsulfinyl)pyrimidine-4-amine (intermediate 3) in 40 ml of DMF, 0.87 g (7.4 mmol) indazole and 1.4 g (4.4 mmol) of cesium carbonate were added. The reaction mixture was stirred at room temperature for 20 minutes. The solution was poured onto 200 ml of ice-water. The resulting precipitate was filtered, washed with cold water and dried. The desired product is obtained as a white solid 1.31 g (54.6%)
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:97][CH2:96][CH2:95][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:48][C@H:49]([C@H:54]([CH2:56][C:57]([NH:59][C@H:60]([C:65]([NH:67][C@H:68]([C:75]([NH:77][C@H:78]([C:91]([O:93][CH3:94])=[O:92])[CH2:79][CH2:80][CH2:81][CH2:82][NH:83]C(OC(C)(C)C)=O)=[O:76])[CH2:69][C:70]1[N:74]=[CH:73][NH:72][CH:71]=1)=[O:66])[C@H:61]([CH2:63][CH3:64])[CH3:62])=[O:58])[OH:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8]>C(O)(C(F)(F)F)=O>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:97][CH2:96][CH2:95][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:48][C@H:49]([C@H:54]([CH2:56][C:57]([NH:59][C@H:60]([C:65]([NH:67][C@H:68]([C:75]([NH:77][C@H:78]([C:91]([O:93][CH3:94])=[O:92])[CH2:79][CH2:80][CH2:81][CH2:82][NH2:83])=[O:76])[CH2:69][C:70]1[N:74]=[CH:73][NH:72][CH:71]=1)=[O:66])[C@H:61]([CH2:63][CH3:64])[CH3:62])=[O:58])[OH:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:20])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCN)C(=O)OC
Reaction time: 0.42 h

Procedure:
200 mg of H-Arg-Arg-Pro-Phe-His-Sta-Ile-His-Lys(Boc)-OMe (Example 6) are dissolved in 1 ml of 95% strength TFA, left to stand for 25 minutes and then precipitation is effected by the addition of 10 ml of diisopropyl ether. The precipitate is filtered off, dried, dissolved in 4 ml of H2O and, in order to be converted into the acetate, the solution is slowly filtered through a column (φ=1 cm, length=12 cm) of weakly basic ion exchanger in acetate form. The eluate is concentrated to a small volume and lyophilised, yielding H-Arg-Arg-Pro-Phe-His-Sta-Ile-His-Lys-OMe; Rf (D)=0.15; Rf (M)=0.12; Rf (N)=0.09.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([OH:18])([CH3:17])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](F)(=[O:15])=[O:14])=[CH:9][CH:8]=1)=[O:5].[CH2:21]([NH:24][CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23]>CN(C)C1C=CN=CC=1.C(#N)C.O>[CH2:21]([N:24]([CH2:25][CH2:26][CH3:27])[S:13]([C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]([OH:18])([CH3:17])[C:2]([F:20])([F:19])[F:1])=[CH:8][CH:9]=1)(=[O:15])=[O:14])[CH2:22][CH3:23]
Reactant: CC(O)(C(=O)Nc1ccc(S(=O)(=O)F)cc1)C(F)(F)F
Reactant: CCCNCCC
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: O
Product: CCCN(CCC)S(=O)(=O)c1ccc(NC(=O)C(C)(O)C(F)(F)F)cc1
Temperature: 22 °C
Yield: 34.8 %

Procedure:
A solution of 3,3,3-trifluoro-N-[4-(fluorosulfonyl)phenyl]-2-hydroxy-2-methylpropanamide (0.2 g), di-n-propylamine (0.25 g), and 4-dimethylaminopyridine (13.0 mg) in dry acetonitrile (3 ml) was heated at reflux for 4 days. The reaction mixture was cooled to 22° C., diluted with water (30 ml) and extracted with ethyl acetate (2×15 ml). The combined ethyl acetate extracts were washed with 1N HCl, brine, dried and evaporated to give an oil. The oil was purified by chromatography (12:1 CHCl3 : diethyl ether) to yield an oil which crystallized from hexane to produce the title compound as a colourless crystalline solid (87.5 mg); mp 132°-134° C.; MS: m/z=397(M+1); NMR (250M Hz): 0.77-0.83 (t,6), 1.41-1.49 (m,4), 1.58 (s,3), 2.96-3.02 (t,4), 7.54 (s,1), 7.72-7.75 (m,2), 7.96-7.98 (m,2), 10.36 (s,1). Analysis for C16H23 F3N2O4S: Calculated: C, 48.47; H, 5.85; N, 7.07; Found: C, 48.84; H, 5.90; N, 6.89.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[CH2:15]([O:17]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:16].Cl>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:13][C:6]1([CH3:14])[C:5]2[C:10](=[CH:11][C:2]([C:15](=[O:17])[CH3:16])=[CH:3][CH:4]=2)[C:9](=[O:12])[CH2:8][CH2:7]1
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)C(=O)CCC2(C)C
Reaction time: 0.17 h

Procedure:
A solution of 4,4-dimethyl-7-bromo-3,4-dihydronaphthalen-1(2H)one (Compound G) (1.78 g, 7 mmol), 1-ethoxyvinyltributyltin (EVTB) (3.3 g, 9.12 mmol), bis(triphenylphosphine)palladium(II)chloride (260 mg, 0.23 mmol) in THF (25 mL) was refluxed for 24 h under argon atmosphere. To the reaction, additional EVTB (1.5 g, 4.1 mmol) and bis(triphenylphosphine)palladium(II)chloride (200 mg, 0.2 mmol) were added and the mixture was and refluxed for an additional 24 h. The reaction mixture was cooled to room temeperature and 10% hydrochloric acid (10 ml) was added. After 10 min, the mixture was extracted with ether (3×50 mL), the combined organic layer was washed with water (10 mL), 10% sodiumbicarbonate (10 mL), brine (10 mL), dried with magnesium sulfate. Solvent was removed under reduced pressure, and after purification by flash chromatography the title compound was obtained as a white solid.