Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=2)[N:3]=1.[CH3:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[CH:23]([NH2:25])[CH2:22][CH2:21]2>>[CH3:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[CH:23]([NH:25][C:2]1[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([NH2:12])[CH:8]=3)[N:3]=1)[CH2:22][CH2:21]2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: Cc1cccc2c1C(N)CC2
Product: Cc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method described in example 2 from 2-chloro-6-nitro-quinoline and rac-7-methyl-indan-1-ylamine (CAS no: 168902-78-1); MS: m/e=290.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[C:24](Cl)=[O:25]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:24](=[O:25])[C:23]3[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=[C:21]([O:20][CH3:19])[CH:22]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OC)c3)CC2)ccc1Cl
Yield: 56 %

Procedure:
The title compound (24 mg, 56%) was prepared analogously to example 7 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 3,5-dimethoxybenzoyl chloride. MS: 433.5 (MH+).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2C=CC=CC=2)C=CC=CC=1C1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[N:24]=[C:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[CH:22]=1>>[C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[CH:13][C:10]([C:11]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[N:24]=[C:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[CH:22]=2)=[CH:9][CH:8]=1
Reactant: c1ccc(-c2ccccc2-c2cc(-c3ccccn3)nc(-c3ccccn3)c2)cc1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Product: c1ccc(-c2ccc(-c3cc(-c4ccccn4)nc(-c4ccccn4)c3)cc2)cc1

Procedure:
This compound is prepared analogously to the procedure described above for the preparation of the ligand L12 in Example 12, but 4-phenyl benzaldehyde is used as carbonyl component. 4′-Biphenylyl-[2,2′;6′,2″]terpyridine, white solid. 13C-NMR (90 MHz, CDCl3): 156.6 (quart.); 156.3 (quart.); 150.0 (quart.); 149.5 (tert.); 142.2 (quart.); 140.8 (quart.); 137.6 (quart.); 136.9 (tert.); 129.3 (tert.); 128.1 (tert.); 128.0 (tert.); 127.9 (tert.); 126.3 (tert.); 124.2 (tert.); 121.8 (tert.); 119.1 (tert.).
Reaction SMILES: [F:1][C:2]1[C:3]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH:9][C:10]([C:12]2[N:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[O:11])[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[C:3]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH:9][C:10](=[O:11])[C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:16][N:17]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)NCc3cnc(-c4ccnc(C(F)(F)F)c4)c(F)c3)nc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1cnc(-c2ccnc(C(F)(F)F)c2)c(F)c1)c1ccc(N2CCNCC2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-(6-((3-fluoro-2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate 49-5 (106 mg, 0.21 mmol) in dichloromethane (2 mL) was added TFA (1 mL) dropwise. The mixture was stirred at room temperature for 2 hours, and the solvents were removed by rotary evaporation. The residue was dissolved in ethyl acetate (100 mL), washed with saturated aqueous NaHCO3 solution, H2O and brine, dried over Na2SO4 and concentrated to dryness by rotary evaporation to give N-((3-fluoro-2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methyl)-5-(piperazin-1-yl)picolinamide 49-6 as yellow solid. MS m/z 461.2 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.[NH2:17][C:18]1[C:26]([CH3:27])=[CH:25][C:24]([Cl:28])=[CH:23][C:19]=1[C:20](O)=[O:21]>>[Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:9][C:20](=[O:21])[C:19]3[CH:23]=[C:24]([Cl:28])[CH:25]=[C:26]([CH3:27])[C:18]=3[N:17]=2)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12

Procedure:
A procedure analogous to that of Example 1, Step E was used to convert 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the pyrazolecarboxylic acid product of Example 5, Step D) (1.5 g, 4.96 mmol) and 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product of Example 1 Step A) (0.92 g, 4.96 mmol) to the title product as a solid (1.21 g).
Reaction SMILES: O.[NH2:2][NH2:3].[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1>CO>[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[N:2][NH2:3])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: NN=Cc1ccc(-c2ccccn2)cc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a mixture of 80% hydrazine hydrate (1.64 g, 26.2 mmol) and methanol (5.0 ml) was dropwise added a solution of 4-(pyridin-2-yl)benzaldehyde (1.5 g, 8.2 mmol) in methanol (5.0 ml) at 25° C. over 10 minutes. After the dropwise addition, the mixture was stirred for 30 minutes. Methanol and excess hydrazine hydrate were evaporated under reduced pressure. The residue was crystallized and 4-(pyridin-2-yl)benzaldehyde hydrazone was obtained as crude crystals at a yield of 1.6 g (yield: 100%). The percentage of the area of 4-(pyridin-2-yl)benzaldehyde hydrazone in the crude crystals as determined by liquid chromatography was 94.3%. crude crystals melting point: 65.7-67.8° C. IR(KBr)cm−1: 3700-3000, 1636, 1590, 1468, 1432, 1394, 1150, 1114, 924, 840, 778, 742, 726. 1H-NMR(CDCl3) δ: 5.60(s,2H), 7.22(m,1H), 7.65(d,2H), 7.74(m,2H), 7.78(s,1H), 8.00(d,2H), 8.69(d,1H)
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6][CH:5]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[B-](F)(F)(F)[F:24].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C1COCC1.CN(C=O)C>[F:24][C:5]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:4](=[O:3])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1(F)CCN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
NaH (2.66 g, 105 mmol) was suspended in THF (300 mL) and cooled to 0° C., and 1-tert-butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate (30 g, 105 mmol) was added as THF solution (550 mL) using an addition funnel over 30 minutes. The mixture was stirred for 30 minutes and then diluted with DMF (200 mL). Selectfluor (41.0 g, 116 mmol) was added as a DMF solution (200 mL). The mixture was warmed to ambient temperature and stirred for 2 hours. The mixture was then concentrated to remove THF and diluted with 1N KHSO4 (300 mL), water (300 mL) and EtOAc (750 mL). The organic layer was washed with brine (2×250 mL). The combined aqueous layers were washed with EtOAc (200 mL) and this organic layer was washed with brine (200 mL). The combined organic layers were then dried over Na2SO4, filtered and concentrated. The crude product was passed through a silica gel plug (1 kg, 20 to 40% EtOAc/hexanes) to provide 23.6 g (74%) of the product as a colorless oil.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[F:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:25][CH2:24]1.O>CN(C)C=O>[F:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH2:25][CH2:24]1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(c3ccc([N+](=O)[O-])cc3F)CC2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCC1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
Potassium phthalimide (0.580 g, 4.68 mmol) was added to a solution of toluene-4-sulfonic acid 2-[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]ethyl ester (compound of Reference Example 65; 0.661 g, 1.56 mmol) in N,N-dimethylformamide (10 ml), and the mixture was stirred at 80° C. for 1 hour. Water was added to the reaction mixture, and the precipitated solid was collected by filtration and washed with water to give the title compound (0.577 g, 93%) as a yellow solid.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@H:12]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][CH:28]=[N:29][C:30]=3[NH2:34])[C@H:11]1O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(C(Cl)=S)C1C=CC=CC=1.[H-].C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C>C(#N)C.CN(C)C1C=CN=CC=1.O1CCOCC1>[C:1]([O:9][C@@H:10]1[C@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@H:12]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][CH:28]=[N:29][C:30]=3[NH2:34])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnc2c1ncn2[C@H]1O[C@@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1O
Agent: CN(C)c1ccncc1
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Agent: S=C(Cl)Oc1ccccc1
Solvent: CC#N
Solvent: C1COCCO1
Product: Nc1ncnc2c1ncn2[C@@H]1C[C@H](OC(=O)c2ccccc2)[C@H](COC(=O)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To a solution of compound 3 (1.00 g, 2.11 mmol) in dry acetonitrile (65 mL) were added 4-(dimethylamino)pyridine (0.77 g, 6.32 mmol) and phenoxythiocarbonyl chloride (0.44 mL, 3.16 mmol). The mixture was stirred at room temperature for 2 h. After concentration, the residue was dissolved in dichloromethane (50 mL) and washed successively with water (2×30 mL), aqueous solution of hydrochloric acid 0.5 N (30 mL) and water (3×30 mL). The organic layer was dried, filtered and concentrated to dryness. The crude thiocarbonylated intermediate was directly treated with tris-(trimethylsilyl)silane hydride (0.78 mL, 5.23 mmol) and α,α′-azoisobutyronitrile (AIBN, 0.112 g, 0.69 mmol) in dry dioxane (17 mL) at reflux for 2 h. The solvent was removed under vacuum and the residue was purified by silica gel column chromatography (0-5% MeOH in dichloromethane) to give pure 4 (0.93 g, 96%) as a foam: 1H NMR (DMSO-d6): δ2.9-3.1 (m, 2H, H-2′ and H-2″), 4.6-4.7 (m, 3H, H-4′, H-5′ and H-5″), 5.8 (br s, 1H, H-3′), 6.43 (dd, 1H, H-1′, J1′,2′32 3.1 Hz, J1′,2″=7.6 Hz), 7.3 (br s, 2H, NH2-6), 7.4-7.9 (m, 10H, 2 benzoyls), 8.05 and 8.33 (2s, 2H, H-2 and H-8); ms: matrix G/T, (FAB+) m/z 460 [M+H]+, 325 [S]+, 136 [BH2]+, (FAB−) m/z 458 [M−H]−, 134 [B]−; UV (95% ethanol): λmax 261 nm (ε14400), 231 nm (ε26300), λmin 249 nm (ε12000); [α]D20 =−38 (c 1.04, DMSO).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[NH:4][C@@H:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:24](O)(=O)C.C(N)=N>C(OCCO)C>[N:4]1([C@@H:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=2[N:1]=[CH:24]1
Reactant: CC(C)(C)OC(=O)C[C@@H](Nc1ccccc1N)c1ccccc1
Reactant: CC(=O)O
Agent: N=CN
Solvent: CCOCCO
Product: CC(C)(C)OC(=O)C[C@H](c1ccccc1)n1cnc2ccccc21
Temperature: 80 °C

Procedure:
To a solution of tert-butyl (3R)-3-(2-aminoanilino)-3-phenylpropanoate (78 mg, 250 μmol) in 2-ethoxyethanol (2 mL), was added formamidine acetate (41 mg, 394 μmol). The solution was heated at 80° C. for 1.75 hours, and was then evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (98:2) to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=6.30 min, MH+ 323].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1)#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:20](OC)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[C:1]([C:3]1[N:4]=[C:5]([CH2:9][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1cccc(CC(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.7 %

Procedure:
To a solution of 2-cyano-6-methylpyridine (9.7 g, 0.082 mol) in 400 ml of dry THF at -78° C. was added dropwise 90 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF. After stirring for 30 minutes a solution of methyl benzoate (30 ml, 0.245 mol) in 50 ml of THF was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred overnight. The mixture was cooled to 0° C., quenched with 1N HCl, made basic with 15% NaOH solution, and extracted with ethyl acetate (3×). The organic layer was separated, dried, and concentrated to give crude material which was purified by chromatography on silica gel to give 2.5 g of the subtitle compound.
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([N:15]1[CH2:19][C@@H:18]([C:20]([O:22]C(C)(C)C)=[O:21])[N:17]([C:27](=[O:50])[C@@H:28]([NH:30][C@H:31]([C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])[CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:29])[C:16]1=[O:51])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([N:15]1[CH2:19][C@@H:18]([C:20]([OH:22])=[O:21])[N:17]([C:27](=[O:50])[C@@H:28]([NH:30][C@H:31]([C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])[CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH3:29])[C:16]1=[O:51])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C[C@H](N[C@@H](CCc1ccccc1)C(=O)OCc1ccccc1)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N[C@@H](CCc1ccccc1)C(=O)OCc1ccccc1)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)O
Reaction time: 8 h
Yield: 91.9 %

Procedure:
20 ml of a 13% hydrogen chloride-dioxane solution are added to 1.2 g of tert.-butyl (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-benzyloxycarbonyl-3-phenylpropyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylate, and the mixture is allowed to stand at room temperature overnight. The mixture is concentrated under reduced pressure to remove solvent. Ethyl acetate and water are added to the residue and the mixture is adjusted to pH 5 to 6 with an aqueous sodium bicarbonate solution. The ethyl acetate layer is collected therefrom, washed with a saturated sodium chloride solution and dried. The resultant solution is concentrated under reduced pressure to remove solvent, whereby 1.0 g of (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-benzyloxycarbonyl-3-phenylpropyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid is obtained as colorless viscous oil. Yield: 91.9%
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[CH3:9][C:10]1([CH3:26])[C:14]([CH3:16])([CH3:15])[O:13][B:12]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH2:25])=[CH:19][CH:18]=2)[O:11]1.C1CCN2C(=NCCC2)CC1.Cl>ClCCl>[CH3:15][C:14]1([CH3:16])[C:10]([CH3:9])([CH3:26])[O:11][B:12]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH:25][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])=[CH:19][CH:18]=2)[O:13]1
Reactant: CC1(C)OB(c2ccc(CCN)cc2)OC1(C)C
Reactant: O=S(=O)(Cl)CCCCl
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OB(c2ccc(CCNS(=O)(=O)CCCCl)cc2)OC1(C)C
Temperature: 23 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
Add 3-chloropropanesulfonyl chloride (0.285 g, 1.6 mmol) to a suspension of 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethylamine (0.383 g, 1.3 mmol) in dichloromethane (10 mL) at 0° C. Then slowly add DBU (0.457 g, 3.0 mmol) and allow the mixture to warm up to 23° C. Stir 2 h at 23° C. and add more dichloromethane and 1M HCl. Separate layers and wash organic phase with more HCl (×2). Back-extract aqueous phase with dichloromethane (×2). Combine organic phases and wash them with brine, dry over sodium sulfate, concentrate over Celite® and purify by flash chromatography (silica gel), eluting with hexanes-ethyl acetate 3:1 to give 0.333 g of the desired compound as a thick oil. Mass spectrum ESI positive (m/z): 388 (M+1), 410 (M+23).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]#[N:9]
Reactant: CS(=O)(=O)c1ccc2c(Cl)c(C(N)=O)sc2c1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2c(Cl)c(C#N)sc2c1
Reaction time: 2 h
Yield: 79.7 %

Procedure:
A stirring 0° C. slurry of 3-chloro-6-methanesulfonyl-benzo[b]thiophene-2-carboxylic acid amide 7 (2.8 g, 9.7 mmol) in CH2Cl2 (50 mL) was treated by sequential addition of TFAA (4.0 mL, 5.9 g, 28 mmol) then pyridine (4.0 mL, 3.9 g, 49 mmol). After 2 h, the resulting solution was washed with 0.1 M HCl, dried (Na2SO4), filtered, and evaporated. Chromatography gave 2.1 g (81%) of 3-chloro-6-methanesulfonyl-benzo[b]thiophene-2-carbonitrile 8; 1H NMR δ 3.15 (s, 3H), 8.09 (dd, 1H, J=1.5, 8.6), 8.15 (dd, 1H, J=0.7, 8.6), 8.52 (dd, 1H, J=0.7, 1.5).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:16][CH3:17])[CH2:3][O:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][CH:6]=1.[OH-].[Na+].O.Cl>CCOCC.C(O)C>[CH3:1][C@@H:2]([CH2:16][CH3:17])[CH2:3][O:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(OC[C@@H](C)CC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CC[C@H](C)COc1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
A mixture of compound 8 (10.40 g, 0.04 mol), sodium hydroxide (11.67 g, 0.208 mol), water (23 ml) and ethanol (225 ml) was heated under reflux for 2 h. The solution was allowed to cool, to room temperature, and then acidified with dilute hydrochloric acid. The solvent was removed to leave a white solid which was dissolved in ether and washed successively with saturated sodium hydrogen carbonate solution (until no more effervescence was observed) and water. After drying the ether (MgSO4), the solvent was removed in vacuo and the white solid was recrystallised from ethanol to yield colourless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=[C:9]2SC)=[C:4]([F:21])[CH:3]=1.[CH2:22]([O:24][CH:25]([O:28][CH2:29]C)[CH2:26][NH2:27])C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=[C:9]2[NH:27][CH2:26][CH:25]([O:28][CH3:29])[O:24][CH3:22])=[C:4]([F:21])[CH:3]=1
Reactant: CCOC(CN)OCC
Reactant: CSc1nc(C(F)(F)F)cc(=O)n1-c1ccc(Br)cc1F
Product: COC(CNc1nc(C(F)(F)F)cc(=O)n1-c1ccc(Br)cc1F)OC

Procedure:
3-(4-Bromo-2-fluorophenyl)-3,4-dihydro-2-methylthio-6-trifluoromethylpyrimidin-4-one (21.5 g) and aminoacetaldehyde diethyl acetal (15 g) were stirred for 3 hours at 130° C. The excess aminoacetaldehyde diethyl acetal was distilled off under reduced pressure and the residue was used in the next reaction as it was.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][CH:3]=1.[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])[CH2:10][CH3:11].C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COC1C=CC=C(N(C)C2C=CC=CC=2)C=1P(C1CCCCC1)C1CCCCC1>[C:13]1([C:9](=[O:12])[CH:10]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=2)[CH3:11])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC(=O)c1ccccc1
Reactant: Cc1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Product: Cc1cccc(C(C)C(=O)c2ccccc2)c1
Yield: 84.7 %

Procedure:
This reaction is carried out in the same manner as the reaction in example 3. The difference is that, the reactants are p-methyphenyl chloride (126.6 mg, 1.0 mmol), propiophenone (161.1 mg, 1.2 mmol), palladium acetate (6.6 mg, 0.029 mmol), 2-Methoxy-6-(N-methyl-N-phenyl-amino)phenyl(dicyclohexyl)phosphine (18.4 mg, 0.045 mmol), t-BuONa (115.4 mg, 1.2 mmol) in 3 mL dry toluene at 110° C. for 16.5 h. 1-Phenyl-2-(m-tolyl)-1-propanone (190.0 mg) was obtained with a yield of 85% as liquid. 1H NMR (300 MHz, CDCl3) δ 8.10-7.94 (m, 2H, ArH), 7.52-7.44 (m, 1H, ArH), 7.44-7.35 (m, 2H, ArH), 7.25-7.18 (m, 1H, ArH), 7.17-7.10 (m, 2H, ArH), 7.07-7.02 (m, 1H, ArH), 4.69 (q, J=6.8 Hz, 1H, CH), 2.33 (s, 3H, ArCH3), 1.57 (d, J=6.8 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ 200.2, 141.3, 138.5, 136.4, 132.6, 128.73, 128.66, 128.3, 128.2, 127.6, 124.8, 47.7, 21.3, 19.4; IR (neat) v (cm−1) 3058, 3025, 2975, 2930, 2870, 1682, 1605, 1596, 1583, 1488, 1448, 1372, 1338, 1238, 1208, 1181, 1158, 1075, 1002; MS (70 eV, EI) m/z (%): 224 (M+, 4.20), 105 (100).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][C@@H:13]([NH2:16])C2)=[O:10])[CH2:4][CH2:3]1.[C:17](OC(N1CC[C@@H](N)C1)=O)(C)(C)C>>[NH2:1][CH:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([NH:11][C@@H:15]2[CH2:14][CH2:13][NH:16][CH2:17]2)=[O:10])[CH2:6][CH2:7]1
Reactant: NC1CCC(NC(=O)N2CC[C@@H](N)C2)CC1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Product: NC1CCC(NC(=O)N[C@@H]2CCNC2)CC1

Procedure:
1-(4-Amino-cyclohexyl)-3-(R)-pyrrolidin-3-yl-urea is prepared analogously to (R)-3-amino-pyrrolidine-1-carboxylic acid (4-amino-cyclohexyl)-amide (Intermediate IF) by replacing (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester with (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[NH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:26]([O:30][C:31](=[O:37])[NH:32][CH2:33][CH2:34][CH2:35]Br)([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:17])[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:35][CH2:34][CH2:33][NH:32][C:31]([O:30][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:37])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CCNCC1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCN1CCC(NC(=O)OCc2ccccc2)CC1
Temperature: 60 °C

Procedure:
To a solution of piperidin-4-yl-carbamic acid benzyl ester (15 g, 58.4 mmol, crude product from Boc-deprotection step) in dimethylformamide (60 mL) at 23° C. was added potassium carbonate (12.1 g, 87.6 mmol, 1.5 equiv), potassium iodide (4.85 g, 29.2 mmol, 0.5 equiv) and (3-bromo-propyl)-carbamic acid tert-butyl ester (13.9 g, 58.4 mmol, 1 equiv). The resulting mixture was warmed to 60° C. (oil bath). After 90 min at 60° C. the reaction mixture was cooled to 23° C. then partitioned between ethyl acetate and water (100 mL each). The organic layer was separated, washed with saturated brine solution (150 mL), dried (MgSO4), filtered and concentrated. The product was purified using an Isco CombiFlash automated chromatography system. The residue was loaded onto a 330 g silica gel column as a solution in dichloromethane (25 mL) then eluted with 2 M ammonia in methanol in dichloromethane (0-12.5% 2 M ammonia in methanol linear gradient over 12 column volumes at a flow rate of 100 mL/min) to give 16.9 g (43.2 mmol, 74% over 3 steps) of the title compound as a clear