Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2](C)[CH:3]=C.[CH2:6]([O:8][CH:9]([O:17][CH2:18][CH3:19])[CH2:10][CH2:11][O:12][CH2:13][C:14]([CH3:16])=[CH2:15])[CH3:7]>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[Br:1][CH2:2][CH2:3]/[CH:15]=[C:14](\[CH3:16])/[CH2:13][O:12][CH2:11][CH2:10][CH:9]([O:8][CH2:6][CH3:7])[O:17][CH2:18][CH3:19]
Reactant: C=CC(C)Br
Reactant: C=C(C)COCCC(OCC)OCC
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Product: CCOC(CCOC/C(C)=C/CCBr)OCC
Yield: 8.9 %

Procedure:
To previously nitrogen degassed DCM (18 mL) was added Second Generation Grubbs Catalyst (0.225 g, 0.30 mmol) followed by 3-bromobutene (2.03 g, 15.0 mmol) and 3-(3,3-diethoxypropoxy)-2-methylprop-1-ene (1.52 g, 7.52 mmol). The reaction mixture was further degassed for 5 minutes and then heated under reflux for 2 hours. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in iso-hexane to afford the title compound (0.208 g, 9%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[C:13](OC)(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([C:7]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[C:13](=[O:21])[N:8]=2)=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2ccc(C(F)(F)F)cc2)sc2ccccc12
Yield: 15.7 %

Procedure:
A mixture of 4-trifluoromethylbenzonitrile (2.00 g, 12 mmol), methyl thiosalicylate (3.93 g, 23 mmol), triethylamine (2.40 g, 24 mmol) and toluene (10 ml) was heated and refluxed for 25 hours under a nitrogen flow. The reaction solution was concentrated under reduced pressure and the residue was applied to column chromatography using silica gel (100 g). Fractions eluted with hexane-ethyl acetate (5:1, v/v) were concentrated under reduced pressure. The residue was recrystallized from isopropyl ether to give the title compound (0.58 g, 16%) as crystals.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH3:28]COCC.[Cl-].[NH4+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:27])([CH3:28])[CH3:26])=[CH:23][CH:24]=3)[N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc(C(C)=O)cc3)cc3ccccc23)CC1
Reactant: CCOCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN1CCN(c2nc(-c3ccc(C(C)(C)O)cc3)cc3ccccc23)CC1

Procedure:
The resulting 1-(4-ethylpiperazin-1-yl)-3-(4-acetylphenyl)isoquinoline (0.10 g) was dissolved in tetrahydrofuran (10 ml) and stirred under ice-cooling, to which was then added 3.0Methylmagnesiumbromide/ether solution (1.1 ml), and the mixture was further stirred for 1.5 hr. An aqueous solution of saturated ammonium chloride, a 10% aqueous solution of sodium carbonate and ethyl acetate were added to the resulting mixture, the mixture was stirred. The organic layer was separated, and then it was washed with brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.05 g of the free compound of the title compound as a pale brown amorphous.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[O:21])=[CH:13][CH:12]=2)=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].[C:33]1([CH2:39][CH2:40][CH2:41][C:42](O)=O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl.C(N=C=NCCCN(C)C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.ClCCl>[CH3:9][C:5]1[N:4]=[C:3]2[N:10]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]([NH:22][S:23]([C:26]4[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=4)(=[O:25])=[O:24])=[O:21])=[CH:13][CH:12]=3)[C:42]([CH2:41][CH2:40][CH2:39][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:1][C:2]2=[C:7]([CH3:8])[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(Nc3nc(C)cc(C)c3N)cc2)cc1
Reactant: O=C(O)CCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3c(CCCc4ccccc4)nc4c(C)cc(C)nc43)cc2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 29 %

Procedure:
A mixture of N-{[(2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (step 4 of Example 162, 86 mg, 0.19 mmol), 4-phenylbutyric acid (37 mg, 0.23 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (40 mg, 0.21 mmol) was stirred at room temperature for 5 days. The mixture was concentrated to give an orange syrup. This material was dissolved in toluene (8 ml), added p-toluenesulfonic acid mono-hydrate (3 mg, 0.02 mol), then stirred under reflux temperature for 5 h. The mixture was diluted with dichloromethane and washed with diluted hydrochloric acid. The organic layer was concentrated. Purification by TLC developing with hexane/ethyl acetate (1:3) gave 32 mg (29%) of the title compound as a colorless solid.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[CH2:21][NH:20][CH2:19][CH:18]([CH2:22][O:23]CC2C=CC=CC=2)[NH:17][CH2:16][CH2:15][S:14][CH2:13][CH2:12][NH:11]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[OH:23][CH2:22][CH:18]1[CH2:19][NH:20][CH2:21][CH:10]([CH2:9][OH:8])[NH:11][CH2:12][CH2:13][S:14][CH2:15][CH2:16][NH:17]1
Reactant: c1ccc(COCC2CNCC(COCc3ccccc3)NCCSCCN2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: OCC1CNCC(CO)NCCSCCN1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
5,9-Bis(benzyloxymethyl)-1-thia-4,7,10-triazacyclododecane (0.28 g, 0.65 mmol) was dissolved in methanol (10 ml). Ammonium formate (0.39 g) and 10% Palladium on carbon (1.3 g) were added under nitrogen and the mixture was stirred at 50° C. for 16 hours. The catalyst was filtered off and washed with methanol (5 ml). The filtrate was evaporated and 5,9-bis(hydroxymethyl) -1-thia-4,7,10-triazacyclododecane was isolated as a white solid. Mp. 210°-220° C. (subl.). Yield: 0.099 g (61%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][C:30]=2[C:38]([F:41])([F:40])[F:39])[CH2:24][CH2:23]1)[CH3:21].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH2:20]([N:22]1[CH2:23][CH2:24][N:25]([CH2:28][C:29]2[CH:37]=[CH:36][C:32]([C:33]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]4[CH:17]=[C:16]5[C:12]([CH2:13][C:14](=[O:18])[NH:15]5)=[CH:11][CH:10]=4)[CH:3]=3)=[O:34])=[CH:31][C:30]=2[C:38]([F:41])([F:39])[F:40])[CH2:26][CH2:27]1)[CH3:21]
Reactant: CCN1CCN(Cc2ccc(C(=O)O)cc2C(F)(F)F)CC1
Reactant: Nc1cccc(Nc2ccc3c(c2)NC(=O)C3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4ccc5c(c4)NC(=O)C5)c3)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(3-amino-phenylamino)-1,3-dihydro-indol-2-one (120 mg, 0.50 mmol, prepared as described in Example 1) and 4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzoic acid hydrochloride (213 mg, 0.60 mmol) in DMF (5 mL) is added N,N-diisopropylethylamine (437 μL, 2.5 mmol) followed by addition of HATU (191 mg, 0.50 mmol). The mixture is stirred at ambient temperature overnight. The mixture is diluted with EtOAc and washed with 10% Na2S2O3 aqueous solution and brine. The organic layer is separated, dried over MgSO4, and concentrated. The crude is purified by column chromatography (CH2Cl2/CH3OH=9:1) to give the desired compound. LC-MS: 538.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]([O:20]CC)=[O:19])=[C:5]2[C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1.[F:33][C:34]([F:47])([F:46])[O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:42]([C:39]3[CH:40]=[CH:41][C:36]([O:35][C:34]([F:47])([F:46])[F:33])=[CH:37][CH:38]=3)(=[O:44])=[O:43])=[CH:10][CH:9]=2)[C:5]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH3:31])([CH3:32])[CH3:30])=[CH:25][CH:24]=2)=[C:6]1[C:18]([OH:20])=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(N)ccc2n1Cc1ccccc1
Product: CC(C)(C)c1ccc(-c2c(C(=O)O)n(Cc3ccccc3)c3ccc(NS(=O)(=O)c4ccc(OC(F)(F)F)cc4)cc23)cc1

Procedure:
The title compound was prepared from ethyl 5-amino-1-benzyl-3-(4-tert-butylphenyl)-1H-indole-2-carboxylate and 4-trifluoromethoxy-benzenesulfonyl chloride followed the procedure of Example 1 Step 3 as a slight colored solid: 1H NMR (DMSO-d6) δ 1.34 (s, 9H, 5.76 (s, 2H, 7.00 (d, J=1.9 Hz, 1H, 7.07 (d, J=7.8 Hz, 4H, 7.15-7.35 (m, 5H), 7.42 (d, J=8.5 Hz, 2H, 7.54 (d, J=8.8 Hz, 2H, 7.75 (d, J=8.9 Hz, 2H, 9.95 (s, 1H, 12.50 (br s, 1H; MS (ESI) m/z 623 (MH+); MS (ESI) m/z 621 [M-H]−; HRMS calcd for C33H30F3N2O5S: 623.1825; found (ESI+): 623.1813; Anal. calcd for C33H29F3N2O5S.0.25H2O: C, 63.20; H, 4.74; N, 4.47. Found: C, 63.15; H, 4.58; N, 4.58.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:7]=[C:8]2[C@:15]3([C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16]3)[CH2:14][C@@H:13]([C:22]([OH:24])=O)[O:12][C:9]2=[CH:10][CH:11]=1>>[F:5][C:6]1[CH:7]=[C:8]2[C@:15]3([C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16]3)[CH2:14][C@@H:13]([C:22]([Cl:3])=[O:24])[O:12][C:9]2=[CH:10][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1NC(=O)[C@@]2(C[C@@H](C(=O)O)Oc3ccc(F)cc32)N1
Product: O=C1NC(=O)[C@@]2(C[C@@H](C(=O)Cl)Oc3ccc(F)cc32)N1

Procedure:
To thionyl chloride (24.9 ml, 3.57 mol) was added (2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxylic acid (20.0 g, 71.4 mmol). After refluxing the mixture under argon atmosphere for 22 hours, the excess thionyl chloride was evaporated in vacuo to dryness to give quantitatively crude crystals of (2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl chloride.
Reaction SMILES: C([O:3][C:4](=[O:11])[CH2:5][C:6]1[N:7]=[N:8][NH:9][N:10]=1)C.[C:12](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.[OH-].[K+]>C1COCC1.C(O)C>[C:12]([N:8]1[N:9]=[N:10][C:6]([CH2:5][C:4]([OH:3])=[O:11])=[N:7]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)Cc1nn[nH]n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)Cc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 18 h
Yield: 14.8 %

Procedure:
To a mixture of (2H-tetrazol-5-yl)-acetic acid ethyl ester (2.0 g, 12.81 mmol), trityl chloride (3.7 g, 13.45 mmol) in dry THF (75 ml) was added TEA (3.7 ml). The resulting mixture was stirred for 18 hrs. at room temperature. Water (10 ml) was added and the precipitate filtered off, redissolved in EtOAc (25 ml) and washed with saturated aqueous ammonium chloride (2×15 ml). The organic phase was dried (Na2SO4), filtered and evaporated in vacuo. The residue was suspended in ethanol (150 ml) and potassium hydroxide (0.8 g, 13.45 mmol) dissolved in ethanol (100 ml) was added. The resulting mixture was stirred for 18 hrs. at room temperature. The precipitate was filtered off and dissolved in water (150 ml) and acidified with conc. HCl (use diluted HCl). The precipitate was filtered off and washed with diethyl ether and dried in vacuo at 50° C. affording 0.7 g (15%) of (2-trityl-2H-tetrazol-5-yl)-acetic acid as a solid.
Reaction SMILES: [N:1]1([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[O:19]=[C:20]1[N:26]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C@@H:36]([C:54](O)=[O:55])[CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[C:40]([CH3:53])[CH:39]=3)=[O:34])[CH2:29][CH2:28]2)[CH2:25][CH2:24][C:23]2[CH:57]=[CH:58][CH:59]=[CH:60][C:22]=2[NH:21]1.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.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C>[O:19]=[C:20]1[N:26]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C@H:36]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[C:40]([CH3:53])[CH:39]=3)[C:54]([N:10]3[CH2:11][CH2:12][CH:7]([CH:4]4[CH2:5][CH2:6][N:1]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:2][CH2:3]4)[CH2:8][CH2:9]3)=[O:55])=[O:34])[CH2:29][CH2:28]2)[CH2:25][CH2:24][C:23]2[CH:57]=[CH:58][CH:59]=[CH:60][C:22]=2[NH:21]1
Reactant: CCOC(=O)CN1CCC(C2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(C)c(OCc4ccccc4)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Reaction time: 8 h

Procedure:
0.99 g (3.90 mmol) ethyl [4,4′]bipiperidinyl-1-yl-acetate were added at RT to a solution of 2.00 g (3.50 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1g), 1.25 g (3.90 mmol) TBTU and 0.67 mL (3.90 mmol) ethyldiisopropylamine in 20 mL THF and 5 mL DMF and the reaction mixture was stirred overnight. 15% K2CO3 solution was added, the mixture was extracted exhaustively with EtOAc, the combined organic phases were washed with saturated NaCl solution and dried on Na2SO4. After the elimination of the desiccant and solvent the product was obtained, which was reacted further without purification.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3I)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH:22][CH2:23][CH2:24][S:25][CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C1(C)C=CC=CC=1.[Cu](I)I>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:22][CH2:23][CH2:24][S:25][CH3:26])[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CSCCO
Reactant: Ic1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CSCCOc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Temperature: 110 °C
Reaction time: 48 h
Yield: 38 %

Procedure:
(R)-Indan-1-yl-(5-iodo-quinolin-2-yl)-amine (250 mg, 0.6 mmol) were dissolved in toluene (2 mL). 2-Hydroxyethyl-methylsulfide (0.17 □L, 1.8 mmol), copper iodide (12 mg), cesium carbonate (420 mg, 1.2 mmol) and phenantroline (23 mg) were added. The reaction mixture was stirred for 48 h at 110° C. The reaction mixture was extracted with water (2×10 mL). The organic phase was dried on sodium sulfate and evaporated. The residue was subjected to column chromatography (silica gel, heptane:ethyl acetate 10:0→3:2) to yield the title compound as brown oil (80 mg, 35%); MS: m/e=351.6 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2([CH2:12][OH:13])[CH2:11][CH2:10]2)[C:5]([O:14]C)=[C:4]([Cl:16])[N:3]=1.[Cl-].[Li+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:16])[C:5]([OH:14])=[C:6]([O:8][C:9]2([CH2:12][OH:13])[CH2:10][CH2:11]2)[N:7]=1
Reactant: COc1c(Cl)nc(Cl)nc1OC1(CO)CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: OCC1(Oc2nc(Cl)nc(Cl)c2O)CC1
Temperature: 140 °C
Yield: 39.6 %

Procedure:
A mixture of [1-(2,6-dichloro-5-methoxy-pyrimidin-4-yloxy)-cyclopropyl]-methanol (800 mg, 3.02 mmol) and lithium chloride (600 mg, 14.15 mmol) in anhydrous DMF (3 mL) was heated at 140° C. for 10 minutes using microwave irradiation, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0-5% methanol in DCM) affording 2,4-Dichloro-6-(1-hydroxymethyl-cyclopropoxy)-pyrimidin-5-ol (300 mg, 40%). LCMS: RT=2.52 min, [M−H]−=249/251/253.
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11]C)=[CH:7][CH:6]=1)=[O:4].[Br-].[Al+3].[Br-].[Br-]>C1(C)C=CC=CC=1>[CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4]
Reactant: CCCCCCC(C)C(=O)c1ccc(OC)cc1
Agent: [Al+3]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CCCCCCC(C)C(=O)c1ccc(O)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
Into a flask of 50 m were charged 1.84 g (7.4 mmol) of 4-(2-methyloctanoyl) anisole and 35 ml of dried toluene, to which was added 8.68 g of anhydrous aluminum bromide under ice cooling with stirring, and further the stirring was continued at room temperature over a night. Thereafter, the reaction mixture was stirred at 40° C. for 4 hours, cooled to room temperature and poured into 100 ml of ice water. After the extraction with 40 ml of toluene twice, the organic layer was washed with 80 ml of water, dried on magnesium sulfate, filtered, concentrated and distilled under a reduced pressure to obtain 1.70 g (7.3 mmol, yield 98%) of a redish brown and oily (+)-4-(2-methyloctanoyl) phenol.
Reaction SMILES: [N+:1]([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1)([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[NH2:1][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([OH:11])[CH2:6]1
Reactant: O=C1CCCC(C[N+](=O)[O-])C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCC1CCCC(O)C1
Yield: 24.5 %

Procedure:
37.2 g of 3-(nitromethyl)cyclohexanone are reduced with lithium aluminum hydride in analogy to the procedure for Example 2. In this way 7.5 g (24.5% of theory) of viscous oily 3-(aminomethyl)cyclohexanol are obtained.
Reaction SMILES: [N+:1]([C:4]1[C:5](O)=[N:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(-c2ccccn2)nc1O
Product: O=[N+]([O-])c1cnc(-c2ccccn2)nc1Cl
Temperature: 0 °C
Yield: 79242.8 %

Procedure:
A solution of 5-nitro-2-(pyridin-2-yl)pyrimidin-4-ol (1.74 g, 0.008 mmol, 1 equiv.) in POCl3 (6.12 g, 0.04 mmol, 5 equiv.) was refluxed for 3 h. Then, the mixture was poured into ice (200 g), extracted with EA (200 mL×2). The combined organic phases were evaporated to afford 4-chloro-5-nitro-2-(pyridin-2-yl)pyrimidine (1.5 g, 80%). LCMS: 237 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:11][CH2:12][CH3:13])(=[O:10])[O:6]C(C)C>Cl>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:11][CH2:12][CH3:13])(=[O:6])[OH:10]
Reactant: CCCP(=O)(CCCN)OC(C)C
Agent: Cl
Product: CCCP(=O)(O)CCCN

Procedure:
7.0 g of isopropyl 3-aminopropyl(n-propyl)phosphinate and 40 ml of 20% hydrochloric acid are stirred at reflux temperature overnight. The reaction mixture is evaporated to dryness, taken up in methanol and treated with propylene oxide. The white solid is filtered off and dried over phosphorous pentoxide to yield 3-aminopropyl(n-propyl)phosphinic acid ×0.1 H2O as white crystals, m.p. 210°-213°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH3:24][C:25]1[N:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>CN(C=O)C>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:28]5[CH:29]=[N:30][C:25]([CH3:24])=[CH:26][CH:27]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: Cc1ccc(B(O)O)cn1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)sc2CCO3)cn1
Yield: 23 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 6-methylpyridin-3-ylboronic acid were reacted. The crude material was diluted with DMF and the solids were collected by filtration to provide 135 (58 mg, 23%). 1H NMR (400 MHz, DMSO) δ 8.73 (dd, J=32.7, 2.1, 2H), 8.11 (s, 1H), 7.96 (dd, J=8.1, 2.4, 1H), 7.65 (dd, J=8.4, 2.3, 1H), 7.38 (d, J=8.1, 1H), 7.20 (d, J=8.4, 1H), 5.78 (dt, J=13.0, 6.5, 1H), 4.52-4.32 (m, 2H), 3.48 (t, J=4.9, 2H), 2.52 (s, 3H), 1.57 (d, J=6.6, 6H). MS (ESI(+)): m/z 404.1 (M+H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]([CH3:49])[C:18](=[O:48])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]2[C:36]3[N:35]=[C:34]([CH2:37][NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:33][C:32]=3[CH:31]=[CH:30][CH:29]=2)=[O:27])=[C:21]([O:46][CH3:47])[CH:20]=1)(O)=[O:2].[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)=[O:56])([CH3:53])([CH3:52])[CH3:51].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH3:47][O:46][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[NH:25][C:26]([C:28]1[C:36]2[N:35]=[C:34]([CH2:37][NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:33][C:32]=2[CH:31]=[CH:30][CH:29]=1)=[O:27])[C:18]([N:17]([CH3:49])[C:11]1[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=1[O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]([N:60]1[CH2:61][CH2:62][N:57]([C:55]([O:54][C:50]([CH3:53])([CH3:51])[CH3:52])=[O:56])[CH2:58][CH2:59]1)=[O:2])=[O:48]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)O)ccc1NC(=O)c1cccc2[nH]c(CNC(=O)OC(C)(C)C)nc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)ccc1NC(=O)c1cccc2[nH]c(CNC(=O)OC(C)(C)C)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of N-[2-(5-carboxypent-1-yloxy)-4-methylphenyl]-3-methoxy-N-methyl-4-[2-(tert-butoxycarbonylamino)methyl-1H-benzimidazol-4-yl]carbonylaminobenzamide (200 mg), 4-(tert-butoxycarbonyl)piperazine (66.3 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (68.3 mg) and 1-hydroxybenztriazol (48.1 mg) in N,N-dimethylformamide (5 ml) was stirred at ambient temperature overnight and the mixture was diluted with ethyl acetate. The solution was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and brine and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column (chloroform) to give 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-tert-butoxycarbonylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-[2-(tert-butoxycarbonyl)aminomethyl-1H-benzimidazol-4-yl]carbonylaminobenzamide (250 mg).