Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:13]#[N:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.[CH2:24]([S:27](Cl)(=[O:29])=[O:28])[CH2:25][CH3:26].[OH-].[Na+]>C(Cl)Cl>[CH2:24]([S:27]([N:10]1[CH2:9][CH2:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)([C:13]#[N:14])[CH2:12][CH2:11]1)(=[O:29])=[O:28])[CH2:25][CH3:26]
Reactant: N#CC1(c2ccccn2)CCNCC1
Reactant: CCCS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CCC(C#N)(c2ccccn2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-cyano-4-pyridin-2-ylpiperidine-1-carboxylate (5.45 g, 19 mmol) was dissolved in TFA/CH2Cl2 (1:1, 50 mL) at 0° C. After stirring 40 min, the reaction mixture was concentrated under reduced pressure. The residue was diluted with 2 N NaOH in saturated aqueous NaCl (1:1, 80 mL) and extracted with EtOAc (5×200 mL). The combined extracts were washed with saturated aqueous NaCl, dried (MgSO4), and concentrated under reduced pressure to afford 4-pyridin-2-ylpiperidine-4-carbonitrile (3.55 g, 19 mmol) which was used immediately in subsequent reactions. A solution of 4-pyridin-2-ylpiperidine-4-carbonitrile (3.55 g, 19 mmol) in CH2Cl2 (50 mL) at 0° C. was treated with i-Pr2NEt (10 mL) and n-PrSO2Cl (2.24 mL, 21 mmol). After stirring for 1 h at 0° C., the reaction mixture was treated with 2 N NaOH and stirred vigorously for an additional 1 h, before being extracted with EtOAc (4×200 mL). The combined organic extracts were washed with saturated aqueous NaCl, dried (MgSO4), and concentrated under reduced pressure to afford 1-(propylsulfonyl)-4-pyridin-2-ylpiperidine-4-carbonitrile. This material was used in subsequent reactions without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[NH:12][C:8]=2[CH:7]=1)([CH3:5])[CH3:4].C(N(CC)CC)C.ClCCl.[S:31](Cl)([CH3:34])(=[O:33])=[O:32]>O>[CH3:34][S:31]([NH:1][CH2:2][C:3]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[NH:12][C:8]=2[CH:7]=1)([CH3:4])[CH3:5])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CN)c1ccc2nc(-c3ccncc3)[nH]c2c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CNS(C)(=O)=O)c1ccc2nc(-c3ccncc3)[nH]c2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To 2.0 g. of the 5-(2-aminomethylprop-2-yl)-2-(4-pyridinyl)-benzimidazole (prepared in Example 1) and 830 mg. triethylamine in 50 ml. dry dichloromethane are added dropwise, while cooling with ice water, 953 mg. mesyl chloride. The reaction mixture is stirred for 10 minutes and then 20 ml. water are added thereto. After filtering off with suction, washing with water and dichloromethane and recrystallising from water/ethanol (2:1 v/v), there are obtained 2.0 g. (85% of theory) of the title compound as a hydrate in the form of yellowish crystals which sinter above 130° C., again crystalline above 150° C. and then melt at 215°-216° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:10](F)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].Cl.[CH3:15][NH:16][CH3:17].C(N(CC)C(C)C)(C)C>O1CCCC1.Cl>[C:1]([C:4]1[CH:5]=[C:6]([S:10]([N:16]([CH3:17])[CH3:15])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(S(=O)(=O)F)c1
Reactant: CNC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)c1cccc(S(=O)(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.6 %

Procedure:
To a solution of 40.44 g (0.20 mol) of 3-acetylbenzenesulfonyl fluoride in 200 ml of dry tetrahydrofuran is added 20.4 g (0.25 mol) of dimethylamine hydrochloride and 43.6 ml (0.25 mol) of N,N-diisopropylethylamine. The mixture is stirred at room temperature for 48 hours, diluted with 250 ml of 1N HCl and extracted with CH2Cl2. The extract is dried (MgSO4) and the solvent removed. The residue is chromatographed (silica gel column) with CH2Cl2 -hexane (1:1). The fractions containing product are combined, the solvent removed and the residue crystallized from CH2Cl2 -hexane to give 28 g (62%) of white crystals, m.p. 73°-76° C.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[C@@H:33]([CH3:38])[CH2:32]3)[N:27]=[C:26]([CH3:39])[N:25]=2)=[O:21])[CH2:8][N:9]([O:12]CC2C=CC=CC=2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO>[CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[C@@H:33]([CH3:38])[CH2:32]3)[N:27]=[C:26]([CH3:39])[N:25]=2)=[O:21])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CCN(C)[C@@H](C)C2)n1
Solvent: CO
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N2CCN(C)[C@@H](C)C2)n1
Yield: 95.2 %

Procedure:
A mixture of [(2R)-2-(cyclopentylmethyl)-3-(2-{6-[(3S)-3,4-dimethyl-1-piperazinyl]-5-fluoro-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.219 g, 0.40 mmol) and Pd(C) (0.042 g) in MeOH (10 mL) was run under standard hydrogenation conditions as in General Procedure A, Part C, to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{6-[(3S)-3,4-dimethyl-1-piperazinyl]-5-fluoro-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide as a white solid (0.172 g, 94%). LCMS: (M+H)+=452.3.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:1]1([C:7]#[C:8]/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: IC=Cc1ccccc1
Reactant: C#Cc1ccccc1
Product: C(#Cc1ccccc1)/C=C/c1ccccc1

Procedure:
The modified procedure was used to convert phenyl acetylene and β-iodostyrene to the title product. Purification by flash chromatography (20% CH2Cl2 in hexanes) gave the analytically pure product as a light yellow solid (399 mg, 98% yield). 1H NMR (400 MHz, CDCl3) δ 7.47 (m, 2H), 7.43 (d, J=7.22, 2H), 7.4-7.27 (m, 6H), 7.03 (d, J=16.24, 1H), 6.37 (d, J=16.24). 13C NMR (100 MHz, CDCl3) δ 141.24, 136.31, 131.50, 128.71, 128.60, 128.32, 128.16, 126.29, 123.42, 108.13, 91.75, 88.91. Anal. Calcd. for C16H12: C, 94.08; H, 5.92; Found C, 93.96; H, 6.10. m.p.: 97-98° C. (lit: 96-97° C.)
Reaction SMILES: ClC1C(O[C:9](=[O:26])[C@H:10]([CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=C(Cl)C(Cl)=C(Cl)C=1Cl.[CH2:31]([O:38][C:39](=[O:67])[C@H:40]([CH2:63][CH2:64][S:65][CH3:66])[NH:41]C(=O)[C@H](CC1C2C(=CC=CC=2)NC=1)NC(OC(C)(C)C)=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([O:38][C:39](=[O:67])[C@H:40]([CH2:63][CH2:64][S:65][CH3:66])[NH:41][C:9](=[O:26])[C@H:10]([CH2:19][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Product: CSCC[C@H](NC(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
When an equivalent quantity of N-t-butoxycarbonylhexahydro-L-phenylalanine pentachlorophenyl ester is substituted for the N-t-butoxycarbonyl-L-tryptophan 2,4,5-trichlorophenyl ester of Example 5 and the procedure detailed therein substantially repeated, there is obtained N-t-butoxycarbonylhexahydro-L-phenylalanyl-L-methionine benzyl ester.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[S:10][C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[N:8][C:5]2=[N:6][CH:7]=1.B([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)(O)O.C([O-])([O-])=O.[Na+].[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>O1CCOCC1>[CH:14]1([C:12]([NH:11][C:9]2[S:10][C:4]3[C:5]([N:8]=2)=[N:6][CH:7]=[C:2]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[N:3]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: O=C(Nc1nc2ncc(Br)nc2s1)C1CC1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2cnc3nc(NC(=O)C4CC4)sc3n2)cc1
Temperature: 120 °C
Reaction time: 10 h
Yield: 64.7 %

Procedure:
To a solution of N-(6-bromothiazolo[4,5-b]pyrazin-2-yl)cyclopropanecarboxamide (1.00 g, 3.36 mmol) in dioxane (16 mL) was added 4-boronobenzoic acid (557 mg, 3.36 mmol) and 1N Na2CO3 aqueous solution (13.2 mL, 13.2 mmol). The reaction mixture was degassed using Argon gas for 20 min followed by the addition of dichlorobis(triphenylphospine) palladium(II) (141 mg, 0.20 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (128 mg, 0.30 mmol). The reaction flask was put into the preheated oil-bath at 120° C. The reaction mixture was further stirred at 120° C. for a period of 10 h after which it was filtered. 2.0 N NaOH solution was added to the filtrate until pH 10 (monitored with pH paper) and then partitioned between ethyl acetate and water. A 6.0 N aqueous HCl solution was added to the water layer until pH 6 (monitored with pH paper). The resulting brown solid was collected by filtration and dried to give 740 mg (64% yield) of 4-(2-(cyclopropanecarboxamido)thiazolo[4,5-b]pyrazin-6-yl)benzoic acid.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([O:18][CH3:19])[C:12]=3[OH:20])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]12([C:11]3[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([O:18][CH3:19])[C:12]=3[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: BrCc1ccccc1
Reactant: COc1cc(Br)cc(C23CC4CC(CC(C4)C2)C3)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(Br)cc(C23CC4CC(CC(C4)C2)C3)c1OCc1ccccc1
Yield: 92.7 %

Procedure:
To a solution of 2-(1-adamantyl)-4-bromo-6-methoxyphenol (3.30 g, 79.78 mmol) in acetone (32 mL) was added benzyl bromide (1.72 g, 10.07 mmol) followed by K2CO3 (1.69 g, 12.2 mmol). This mixture was stirred and heated at reflux temperature for 20.75 h under argon. Acetone was removed at reduced pressure, and 2 N HCl (30 mL) was added. The mixture was extracted with EtOAc (150 mL), and the organic layer was washed with brine and dried. After removal of solvent at reduced pressure, the residue was crystallized (MeOH) to give 3.99 g (95%) of 3-(1-adamantyl)-4-benzyloxy-5-methoxyphenyl bromide as a white solid, mp 89-91° C. IR 2901, 2847, 1444, 1201 cm−1; 1H NMR (CDCl3) δ 1.67 (m, 6H, AdCH2), 2.00 (bs, 3H, AdCH), 2.05 (bs, 6H, AdCH2), 3.85 (s, 3H, OCH3), 5.07 (s, 2H, C6H5CH2), 6.96 (d, J=2.3 Hz, 1H, 6-ArH), 7.01 (d, J=2.3 Hz, 1H, 2-ArH), 7.30-7.52 ppm (m, 5H, C6H5).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N+:16]([O-])=O)=[CH:7][C:6]=2[N:5]([C:19]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][C:26]([O:30][CH3:31])=[C:25]([O:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH:24]=3)=[O:20])[CH2:4]1>C1COCC1.O=[Pt]=O>[NH2:16][C:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[C:11]2[CH:3]([CH2:2][Cl:1])[CH2:4][N:5]([C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[CH:27][C:26]([O:30][CH3:31])=[C:25]([O:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH:24]=4)=[O:20])[C:6]=2[CH:7]=1
Reactant: COc1cc2cc(C(=O)N3CC(CCl)c4c3cc([N+](=O)[O-])c3ccccc43)[nH]c2cc1OCCN(C)C
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: COc1cc2cc(C(=O)N3CC(CCl)c4c3cc(N)c3ccccc43)[nH]c2cc1OCCN(C)C

Procedure:
A solution of 14f (130 mg, 0.25 mmol) in THF (20 mL) was hydrogenated over PtO2 (30 mg) at 55 psi for 2 h. The catalyst was removed and the solution was concentrated under reduced pressure below 30° C. The residue was dissolved in a small volume of CH2Cl2, the solution was diluted with petroleum ether to precipitate impurities which were removed by filtration, and then further addition of petroleum ether precipitated 15f (87 mg, 71%), mp 130-133° C. 1H NMR [(CD3)2SO] δ 11.38 (d, J=1.6 Hz, 1 H, NH), 8.07 (d, J=8.5 Hz, 1 H, H-6), 7.75 (d, J=8.3 Hz, 1 H, H-9), 7.72 (s, 1 H, H-4), 7.45 (t, J=7.4 Hz, 1 H, H-8), 7.27 (t, J=7.7 hz, 1 H, H-7), 7.15 (s, 1 H, H-3'), 7.05 (s, 1 H, H-4' or 7'), 6.99 (s, 1 H, H-4' or 7'), 5.96, 5.94 (2×s, 2 H, NH2), 4.71 (dd, J=10.6, 9.1 Hz, 1 H, H-2), 4.50 (dd, J=10.9 Hz, 1.6 Hz, 1 H, H-2), 4.16-4.08 (m, 1 H, H-1), 4.05 (t, J=6.0 Hz, 2 H, OCH2), 3.98 (dd, J=11.0, 3.0 Hz, 1 H, CHHCl), 3.79 (s, 1 H, OCH3), 3.74 (dd, J=10.9, 8.2 Hz, 1 H, CHHCl), 2.68 (t, J=5.9 Hz, 2 H, OCH2CH2), 2.25 (s, 6 H, N(CH3)2).
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:6]2[S:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:9][C:7]=2[N:8]=1.[C:25]1([S:31]([N:34]2[C:38]3=[CH:39][N:40]=[CH:41][C:42]([Sn](CCCC)(CCCC)CCCC)=[C:37]3[CH:36]=[CH:35]2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]1([S:31]([N:34]2[C:38]3=[CH:39][N:40]=[CH:41][C:42]([C:3]4[N:4]=[C:5]([N:19]5[CH2:20][CH2:21][O:22][CH2:23][CH2:24]5)[C:6]5[S:11][C:10]([CH2:12][N:13]6[CH2:18][CH2:17][O:16][CH2:15][CH2:14]6)=[CH:9][C:7]=5[N:8]=4)=[C:37]3[CH:36]=[CH:35]2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CSc1nc(N2CCOCC2)c2sc(CN3CCOCC3)cc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc2c1ccn2S(=O)(=O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: O=S(=O)(c1ccccc1)n1ccc2c(-c3nc(N4CCOCC4)c4sc(CN5CCOCC5)cc4n3)cncc21
Temperature: 100 °C
Yield: 53.6 %

Procedure:
A solution of 2-methylsulfanyl-4-morpholin-4-yl-6-morpholin-4-ylmethyl-thieno[3,2-d]pyrimidine (40 mg, 0.11 mmol) and 1-benzenesulfonyl-4-(tributylstannanyl)-1H-pyrrolo[2,3-c]pyridine (129 mg, 0.24 mmol) in DME (2 mL) was treated with copper(I)bromide-dimethyl sulfide complex (50 mg, 2.43 mmol) in a sealed tube and the solution was degassed with argon for 5 min. Pd(PPh3)4 (19 mg, 0.016 mmol) was added and the reaction mixture heated at 100° C. for 3 hours. The mixture was filtered through celite, which was washed with DME and the combined filtrate was evaporated to give a yellow gum. The gum was purified by flash chromatography on silica, eluting with EtOAc to afford 2-(1-benzenesulfonyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-morpholin-4-yl-6-morpholin-4-ylmethyl-thieno[3,2-d]pyrimidine (34 mg, 54%). The sulfone intermediate was dissolved in IMS (1 mL) and 1,4-dioxane (1 mL) and the stirring solution was treated with NaOH solution (0.1 mL from 2.5 g NaOH in 5 mL H2O). After 10 min the reaction mixture was treated with HCl (10 N) until at pH 7. The reaction mixture was filtered to remove insoluble material. The solids were washed with 1,4-dioxane, and the filtrate was evaporated. The resulting residue was taken up in DCM and washed with brine; the isolated organic phase was dried (MgSO4), filtered and evaporated. The resultant crude residue was purified by flash chromatography, (Si—PPC) eluting with 2-8% MeOH in DCM to afford 103 as a white solid (14 mg, 29%). 1H NMR (MeOD, 400 MHz): δ 8.99 (s, 1 H); 8.75 (s, 1 H); 7.66 (d, J=3.95 Hz, 1 H); 7.40-7.36 (m, 2 H); 4.14-4.05 (m, 4 H); 3.94-3.85 (m, 6 H); 3.73 (t, J=4.6 Hz, 4 H); 2.59 (t, J=4.35 Hz, 4 H). LCMS (Method F): RT=4.59 min, [M+H]+ 437.2
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[F:24][C:25]1[CH:26]=[C:27]2[C:32](=[C:33]([F:35])[CH:34]=1)[CH2:31][C:30](=O)[CH2:29][CH2:28]2>>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:30]3[CH2:29][CH2:28][C:27]4[C:32](=[C:33]([F:35])[CH:34]=[C:25]([F:24])[CH:26]=4)[CH2:31]3)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]2)=[CH:8][CH:9]=1
Reactant: CCCC(N)C(=O)Nc1cn(-c2ccc(C(=O)OC)cc2)cn1
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(-c2ccc(C(=O)OC)cc2)cn1

Procedure:
4-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-benzoic acid methyl ester was reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: MS m/z 483.2 (M+1).
Reaction SMILES: [Si](OCC[CH:11]1[N:22]2[C:23]3[C:19]([CH:20]=[CH:21]2)=[C:18]([C:24]([F:27])([F:26])[F:25])[C:17]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:16][C:15]=3[CH2:14][NH:13][CH2:12]1)(C(C)(C)C)(C)C.Cl.C1C[O:40][CH2:39][CH2:38]1>>[CH2:28]([C:17]1[C:18]([C:24]([F:26])([F:25])[F:27])=[C:19]2[C:23]3=[C:15]([CH2:14][NH:13][CH:12]([CH2:38][CH2:39][OH:40])[CH2:11][N:22]3[CH:21]=[CH:20]2)[CH:16]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)[Si](C)(C)OCCC1CNCc2cc(CCc3ccccc3)c(C(F)(F)F)c3ccn1c23
Agent: Cl
Product: OCCC1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1
Reaction time: 1 h

Procedure:
To a mixture of 2-(2-((tert-butyldimethylsilyl)oxy)ethyl-6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (107 mg, 0.21 mmol) in THF was added conc. HCl (2 mL) at 0° C. and the resulting mixture stirred for 1 h. Purification by reverse-phase chromatography (25→90% CH3CN—H2O-TFA) yielded 2-(6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-2(1H)-yl)ethanol (50 mg).
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[S:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:27](O)(=[O:41])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH3:40].Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:3][C:2]1[CH2:4][S:5][C:6](=[O:7])[C:1]=1[C:27](=[O:41])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCC/C=C\CCCCCCCC(=O)O
Reactant: O=C1CSC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC/C=C\CCCCCCCC(=O)C1=C(O)CSC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
To a stirring solution of 855 mg (7.37 mmol) of thiotetronic acid in 10 mL of dimethylformamide is added 902 μL (6.47 mmol) of triethylamine and 240 mg (1.96 mmol) of 4-dimethylaminopyridine at 0° C. Next, 1.68 g (8.76 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 2.0 g (8.84 mmol) of myristoleic acid are added and the reaction mixture is stirred overnight at room temperature. The reaction is acidified with 1.0 N HCl and extracted three times with diethyl ether. The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue is subjected to HPLC chromatography (2 inch Dynamax silica gel column, 25 mL/min) eluting with 100% ethyl acetate to give 785 mg (33%) of 4-hydroxy-3-[(Z)-1-oxo-9-tetradecenyl]-2(5H)-thiophenone as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.7 %

Procedure:
A mixture containing 4-Chloro-2-methyl-benzoic acid (4 g, 23 mmol) and LiAlH4 (890 mg, 23.5 mmol) in 250 mL of THF under a nitrogen atmosphere was allowed to stir at room temperature for 2 hours. The reaction was quenched with sodium sulfate decahydrate. The mixture was filtered through a pad of Celite and the filter cake washed with THF. The filtrate was concentrated under reduced pressure. Purification of the residue via biotage eluting with 30% ethyl acetate/hexanes gave (4-Chloro-2-methyl-phenyl)-methanol (3.70 g, 100%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.30-7.25 (1H, m), 7.18-7.14 (2H, m), 4.66 (2H, d, J 5.8 Hz), 2.32 (3H, s.)
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].C(N(CC)CC)C.[Br:20][CH2:21][C:22](Br)=[O:23]>C(Cl)Cl>[Br:20][CH2:21][C:22]([O:3][C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([O:11][CH3:12])=[O:10])=[O:23]
Reactant: O=C(Br)CBr
Reactant: COC(=O)[C@H](O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](OC(=O)CBr)c1ccccc1
Temperature: -78 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
To a stirred solution of DCM, (R)-methyl mandelate (1.48 g, 8.92 mmol), and triethylamine (2.02 g, 20.0 mmol), in DCM (30 ml) under a nitrogen atmosphere at −78° C. was added dropwise bromoacetyl bromide (3.03 g, 15.0 mmol). After stirring at −78° C. for 5 h, the reaction mixture was allowed warm up to −20° C. and quenched by addition of water (20 mL). The organic phase was washed with distilled water (3×20 mL), saturated ammonium chloride (3×20 mL), saturated sodium bicarbonate (3×20 mL) and brine (2×20 mL). The organic phase was then dried over magnesium sulfate, filtered and solvents removed via rotary evaporation to yield a crude product in 84% yield (2.13 g, 7.42 mmol). Column chromatography was performed on the crude product (mobile phase: DCM:Hexane, 50:50) to give a pale yellow liquid at RT in 73% yield (1.85 g, 6.45 mmol).
Reaction SMILES: [Cl:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:16])[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[Br:17]Br.C[O-].[Na+]>CO>[Br:17][C:2]([Cl:1])([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:16])[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Cl)c1ccc([N+](=O)[O-])c(C)c1
Reactant: BrBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(Cl)(Br)c1ccc([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of methyl 2-chloro-2-(3-methyl-4-nitrophenyl)acetate (6 g) in methanol (20 cm3) was stirred at room temperature and the solutions of bromine and sodium methoxide were added dropwise and simultaneously. The methanol was removed from the reaction mixture under vacuum and the residue was dissolved in dichloromethane. The dichloromethane solution was washed with water, separated and evaporated to have a residue which was recrystallised from ethanol to give yellow methyl 2-bromo-2-chloro-2-(3-methyl-4-nitrophenyl)acetate (4.0 g, 50%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:25])=[C:20](B(O)O)[CH:21]=1>CCCCCCC.CCOC(C)=O>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:25])=[C:18]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:17]=1
Reactant: Cc1ccc(Cl)cc1B(O)O
Reactant: CC(C)(C)C(=O)Nc1cnccc1I
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccc(Cl)cc1-c1ccncc1NC(=O)C(C)(C)C

Procedure:
The title compound was prepared in analogy to example 72, from N-(4-iodo-pyridin-3-yl)-2,2-dimethyl-propionamide (CAS RN 113975-32-9) and 5-chloro-2-methylphenylboronic acid (CAS RN 148839-33-2) and using a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow solid (99%). MS (ESI): m/z=303.126 [M+H]+.