Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[O:10][CH:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:2]1.[CH3:20][C:21]([CH3:29])([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[NH2:22]>>[CH3:20][C:21]([NH:22][C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH:11]([CH3:16])[C:12]([F:13])([F:14])[F:15])[N:8]=1)=[O:19])([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[CH3:29]
Reactant: Cc1nc(C(C)(C)N)no1
Reactant: CC(Oc1nc(C(=O)O)ccc1C1CC1)C(F)(F)F
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C3CC3)c(OC(C)C(F)(F)F)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(1,1,1-trifluoropropan-2-yloxy)picolinic acid (Example 372 b) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials. MS (EI): m/e=399.5 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.F[C:20]1[C:25]([C:26]2[N:31]=[C:30]([CH3:32])[N:29]=[C:28]([NH2:33])[N:27]=2)=[CH:24][CH:23]=[CH:22][N:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>CN(C=O)C>[NH2:33][C:28]1[N:29]=[C:30]([CH3:32])[N:31]=[C:26]([C:25]2[C:20]([NH:1][C:2]3[CH:3]=[C:4]([NH:9][S:10]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=3)=[N:21][CH:22]=[CH:23][CH:24]=2)[N:27]=1
Reactant: Cc1nc(N)nc(-c2cccnc2F)n1
Reactant: Nc1cnc(Cl)c(NS(=O)(=O)N2CCOCC2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2cccnc2Nc2cnc(Cl)c(NS(=O)(=O)N3CCOCC3)c2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39.6 %

Procedure:
To a 15 mL RB flask was added N-(5-amino-2-chloropyridin-3-yl)morpholine-4-sulfonamide (0.065 g, 0.222 mmol), 4-(2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.055 g, 0.266 mmol), and DMF (3.0 mL). The mixture was cooled to 0° C. under N2. sodium bis(trimethylsilyl)amide, 1.0 m in THF (Aldrich) (0.888 mL, 0.888 mmol) was added to the solution in one portion. The now dark brown mixture was stirred at 0° C. for 10 min then warmed up to rt and stirred for 1 h. The reaction mixture was quenched with sat. NH4Cl and extracted with CHCl3 (3×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (24 g, 3% MeOH in DCM) to afford the desired product as a yellow solid (42.0 mg). MS (ESI pos. ion) m/z: 478.0. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.45 (s, 3H) 3.15 (br. s., 4H) 3.61 (br. s., 4H) 7.03 (dd, J=7.53, 4.60 Hz, 1H) 7.79 (br. s., 1H) 7.91 (br. s., 1H) 8.38 (d, J=3.36 Hz, 1H) 8.51 (s, 1H) 8.82 (d, J=5.41 Hz, 2H) 9.78 (s, 1H) 12.26 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1(NS(C)(=O)=O)[CH:11]=[C:10]([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:24]=[N:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:18]=3[CH:19]=[N:20][CH:21]=2)=[O:15])[CH:9]=[CH:8][NH:7]1)(=[O:4])=[O:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][S:2]([NH:5][C:6]1[CH:11]=[C:10]([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:24]=[N:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:18]=3[CH:19]=[N:20][CH:21]=2)=[O:15])[CH:9]=[CH:8][N:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)NC1(NS(C)(=O)=O)C=C(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)C=CN1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reaction time: 1 h

Procedure:
A solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (2,2-bismethanesulfonylamino-pyridin-4-ylmethyl)-amide (36 mg, 0.069 mmol) in THF (1 mL) was added a 1 M solution of tetra-n-butylammonium fluoride (347 μL, 0.347 mmol) in THF and the mixture was warmed at reflux. After 1 hour, the mixture was quenched with saturated aqueous ammonium chloride (15 mL) and diluted with EtOAc (15 mL). The organic phase was separated and washed with NaHCO3 (10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-10% methanol in dichloromethane to afford the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH2:11]1[O:22][CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)[O:13][CH2:12]1>>[O:13]1[CH2:12][CH2:11][O:22][CH:14]1[C:15]1[CH:16]=[C:17]([NH:21][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: Nc1cccc(C2OCCO2)c1
Product: O=C(Nc1cccc(C2OCCO2)c1)c1ccc(Cl)cn1

Procedure:
The title compound is prepared according to the reaction sequence described above for L-7 starting from 5-chloropyridine-2-carboxylic acid and 3-aminobenzaldehyde ethylene acetal to yield 5-chloro-pyridine-2-carboxylic acid (3-[1,3]dioxolan-2-yl-phenyl)-amide; LC-MS A: tR=0.84 min; [M+H]+=305.13 which is treated with m-chloro-perbenzoic acid to deliver 5-chloro-1-oxy-pyridine-2-carboxylic acid (3-[1,3]dioxolan-2-yl-phenyl)-amide; LC-MS A: tR=0.77 min; [M+H]+=321.02, then deprotected with HCl 10% to yield 5-chloro-1-oxy-pyridine-2-carboxylic acid (3-formyl-phenyl)-amide LC-MS A: tR=0.72 min; [M+H]+=277.01.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18](O)=[O:19])=[O:15])[CH2:7][CH2:6]2.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C1(CC(C2SCN[C@@H]2C(O)=O)=O)C2C(=CC=CC=2)CC1.S1CCNC1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:19])=[O:15])[CH2:7][CH2:6]2
Reactant: C1CCNC1
Reactant: COc1ccc2c(c1)CCC(CC(=O)N1CCC[C@H]1C(=O)O)C2
Agent: C1CSCN1
Agent: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Product: COc1ccc2c(c1)CCC(CC(=O)N1CCC[C@H]1C(=O)N1CCCC1)C2
Yield: 24 %

Procedure:
A colorless oil of 1-[1-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-prolyl]pyrrolidine was prepared in the same manner as in Example 1, except that 1-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-proline prepared in Reference Example 21 and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 24%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:17][C:16]([NH:21][CH2:22][CH3:23])([C:18]([NH2:20])=[O:19])[CH2:15]3)[N:11]3[C:24](=[O:27])[NH:25][N:26]=[C:10]3[C:9]=2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.[F:35][C:36]([F:46])([F:45])[C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Br)=[CH:39][CH:38]=1.ClC1C=CC(C2N=C(N3CC(NCC)(C(N)=O)C3)N3C(=O)N(CC)N=C3C=2C2C=CC(Cl)=CC=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:17][C:16]([NH:21][CH2:22][CH3:23])([C:18]([NH2:20])=[O:19])[CH2:15]3)[N:11]3[C:24](=[O:27])[N:25]([CH2:41][C:40]4[CH:39]=[CH:38][C:37]([C:36]([F:35])([F:45])[F:46])=[CH:44][CH:43]=4)[N:26]=[C:10]3[C:9]=2[C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3n[nH]c(=O)n23)C1
Agent: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3nn(CC)c(=O)n23)C1
Product: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3nn(Cc4ccc(C(F)(F)F)cc4)c(=O)n23)C1

Procedure:
The title compound was prepared by coupling 1-(7,8-bis(4-chlorophenyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(ethylamino)azetidine-3-carboxamide with 4-trifluoromethylbenzyl bromide in a manner analogous to that in which 1-(7,8-bis(4-chlorophenyl)-2-ethyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(ethylamino)azetidine-3-carboxamide was prepared. HPLC/MS: retention time=3.866 min, [M+H]30 =656.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:21][C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][C:27]([F:40])=[CH:26][CH:25]=4)[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([F:17])[C:14]([O:18]C)=[C:13]([F:20])[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:21][C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][C:27]([F:40])=[CH:26][CH:25]=4)[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([F:20])[C:14]([OH:18])=[C:15]([F:17])[CH:16]=3)[C:3]=12
Reactant: COc1c(F)cc(-c2nn(Cc3oc4ccc(F)cc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1cc(F)c(O)c(F)c1)nn2Cc1oc2ccc(F)cc2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 22.9 %

Procedure:
To a solution of example 127 (0.099 g, 0.180 mmoles) in dichloromethane (10 ml), BBr3 (1M in dichloromethane, 0.99 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated to afford the title compound as brown solid (0.022 g, 23% yield). MP: 274-278° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 10.20 (s, 1H), δ 8.18 (s, 1H), 7.72-7.60 (m, 4H), 7.38 (m, 1H), 7.20 (d, J=8.7 Hz, 2H), 7.17-7.10 (m, 4H), 5.51 (s, 2H). Mass: 534.06 (M++1).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14](OCC)=[O:15])=[CH:12][N:11]=[C:10]3[N:19]([S:22]([C:25]4[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=4)(=[O:24])=[O:23])[CH:20]=[CH:21][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH:1]1([NH:7][C:8]2[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[C:10]3[N:19]([S:22]([C:25]4[CH:26]=[CH:27][C:28]([CH3:29])=[CH:30][CH:31]=4)(=[O:24])=[O:23])[CH:20]=[CH:21][C:9]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1NC1CCCCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCCC4)c(CO)cnc32)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of ethyl 4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.71 g, 3.88 mmol) in toluene (43.1 mL) at about −78° C. was added DIBAL-H (1 M in hexanes, 6.60 mL, 6.60 mmol) dropwise. The reaction was stirred for about 1 h at about −78° C. and the reaction mixture was warmed to ambient temperature and stirred for about 1 h. The reaction was quenched with saturated aqueous potassium sodium tartrate (15 mL) and the mixture was stirred for about 1 h. EtOAc (25 mL) was added and the layers were separated. The organic layer was dried over anhydrous Na2SO4, filtered through a pad of silica gel while washing with EtOAc (20 mL), and the filtrate was concd under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-50% EtOAc in DCM to give (4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol (1.24 g, 80%) as an off white solid: LC/MS (Table 1, Method b) Rt=2.51 min; MS m/z: 400 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:21][C:22]([C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[C:27]([O:29]C)=[O:28])=[O:23])[CH2:9][N:10]([CH3:20])[C:11]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[Li].O>C1COCC1.O>[CH:1]1([CH2:7][C@H:8]([NH:21][C:22]([C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[C:27]([OH:29])=[O:28])=[O:23])[CH2:9][N:10]([CH3:20])[C:11]([O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:18])[CH3:19])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CN(C[C@H](CC1CCCCC1)NC(=O)c1cccc(C(=O)O)c1)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A mixture of (S)-methyl 3-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-ylcarbamoyl)benzoate (1.397 g) and LiOH.H2O (0.430 g, 10 mmol, 5.7 equiv) in THF (50 mL) and H2O (10 mL) was vigorously stirred at rt for 23 h. The reaction mixture was quenched with 2 N HCl (6 mL). After the organic solvent was removed in vacuo, the aqueous phase was extracted with CH2Cl2 (3×) and the combined organic layers were dried over Na2SO4. The crude (S)-3-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamoyl)benzoic acid (0.923 g) was used in the next step without further purification. LC-MS (3 min) tR=2.06 min, m/z 485 (M+Na+), 435, 391. 13C NMR (100 MHz, CDCl3) δ 168.45, 166.95, 157.89, 135.27, 132.73, 132.34, 129.95, 128.47, 128.42, 64.25, 52.86, 45.49, 40.59, 34.58, 34.26, 33.77, 33.13, 26.46, 26.23, 26.11, 17.64, −1.61.
Reaction SMILES: C([BH3-])#N.[Na+].O=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH3:23])[CH:18]=[N:17][C:16]=2[N:15]([CH3:24])[C:13]1=[O:14].[CH2:25]([NH2:36])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].Cl.[Cl-].[NH4+].[OH-].[NH4+]>O1CCCC1.CO>[CH2:25]([NH:36][CH:7]([CH3:6])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH3:23])[CH:18]=[N:17][C:16]=2[N:15]([CH3:24])[C:13]1=[O:14])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: Cn1cnc2c1c(=O)n(CCCCCC=O)c(=O)n2C
Reactant: CCCCCCCCCCCN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCNC(C)CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 48 h
Yield: 87.6 %

Procedure:
Sodium cyanoborohydride (63 mg, 1.0 mmol) was added to a mixture of 1-(6-oxohexyl)-3,7-dimethylxanthine (150 mg, 0.5 mmol), undecylamine (0.43 mL, 2.5 mmol), 38% aqueous hydrochloric acid solution (0.2 mL, 2.5 mmol), methanol (5 mL), and tetrahydrofuran (5 mL). The resulting mixture was stirred for 48 hours. Saturated aqueous ammonium chloride solution (20 mL) was added to the stirred mixture, followed by an additional 20 minutes of stirring and addition of 30% aqueous ammonium hydroxide solution (30 mL). The mixture was extracted with 25% methanol-dichloromethane (3×35 mL) and the combined extracts dried over sodium sulfate. The solvents were evaporated under vacuum, resulting in 190 mg of 1-[5-(Undecylamino)hexyl]-3,7-dimethylxanthine (86% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:18]([CH3:24])([CH3:23])[C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl>[OH-].[Na+].CO.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:18]([CH3:24])([CH3:23])[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: CC(C)(C(=O)O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 98.6 %

Procedure:
Methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoate (16.2 g, 40.2 mmol) was heated to 100° C. overnight in a mixture of 2 M NaOH/MeOH/DMSO (1:1:1). The next day, the reaction was cooled, acidified to pH 5 with HCl and extracted 2× EtOAc. The organic layers were washed with water×2, dried over MgSO4, filtered, and concentrated in vacuo to give 15.4 g (99% yield) of acid 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid. MS found: (M+H)+=389.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]1([CH3:21])[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1>>[CH3:21][C:12]1[CH:13]=[C:14]([C:2]2[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: Cc1cccc(B(O)O)c1
Product: COC(=O)c1cccc(-c2cccc(C)c2)c1

Procedure:
Analogously to Example 1, by reaction of methyl 3-bromobenzoate with 3-tolylboronic acid, methyl 3′-methylbiphenyl-3-carboxylate is obtained. By bromination with NBS and reaction with methyl 3-hydroxybenzoate, methyl 3′-(3-methoxycarbonylphenoxymethyl)biphenyl-3-carboxylate is obtained therefrom. By reaction with guanidine hydrochloride in methanolic sodium methoxide solution, N-[3′-(3-guanidinocarbonylphenoxymethyl)biphenyl-3-carbonyl]-guanidine
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH3:12])[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[O-]S([O-])(=O)=O.[Mg+2].C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[CH3:12][C:11]1[NH:10][N:9]=[CH:8][C:7]=1[C:5]1[S:4][C:3]2[C:13](=[O:14])[NH:15][C:25]3([CH2:26][CH2:27][N:22]([C:17]4[N:16]=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:23][CH2:24]3)[NH:1][C:2]=2[CH:6]=1
Reactant: O=C1CCN(c2ncccn2)CC1
Reactant: Cc1[nH]ncc1-c1cc(N)c(C(N)=O)s1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)N(C)C
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC1(CCN(c3ncccn3)CC1)N2
Temperature: 100 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
A mixture of 3-amino-5-(5-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamide (111 mg, 0.50 mmol), 1-(2-pyrimidinyl)-piperidin-4-one (266 mg, 1.50 mmol), CSA (11.6 mg, 0.05 mmol), MgSO4 (120 mg, 1.00 mmol) and DMA (4 mL) was stirred at 100° C. for 1 h. The mixture was poured into saturated aqueous NaHCO3 and extracted with 3:1 EtOAc/THF, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, EtOAc to 80:20 EtOAc/MeOH). The obtained yellow solid was triturated with MeOH/EtOAc and collected by filtration to afford the title compound (141 mg, 74%) as a pale yellow solid:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([OH:26])=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: C1CCNC1
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21)N1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28.2 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (510 mg, 1.4 mmol) in CH2Cl2 (9 mL) were added pyrrolidine (174 μL, 2.1 mmol), diisopropylethylamine (DIPEA) (366 μL, 2.1 mmol) and 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (798 mg, 2.1 mmol). The solution obtained was stirred at room temperature for 90 min then diluted with CH2Cl2. The organic phase was washed with aqueous NaHCO3, passed over a phase separator and concentrated in vacuo. The resultant residue was purified using chromatography (silica gel, gradient 0 to 70% ethyl acetate/isohexane) followed by a second chromatography purification (silica gel, gradient 0 to 25% dichloromethane/ether) yielding Compound 45 as a solid (165 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([CH2:10][CH2:11][C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[N+]=[N-]>C(OCC)C>[CH3:15][Si:14]([CH3:17])([CH3:16])[C:13]#[C:12][CH2:11][CH2:10][NH2:7]
Reactant: C[Si](C)(C)C#CCCN=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C[Si](C)(C)C#CCCN
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
Lithium aluminium hydride (0.095 g; 2.51 mmol) was added to a mixture of (4-azidobut-1-ynyl)trimethylsilane (0.700 g; 4.18 mmol) in diethyl ether. The resulting mixture was stirred at room temperature for two hours and carefully quenched with water and sodium hydroxide (10% in water). The aqueous layer was extracted with diethyl ether dried over magnesium sulfate, and concentrated under reduced pressure to yield 0.349 g (60%) of 4-(trimethylsilyl)but-3-yn-1-amine.
Reaction SMILES: [CH:1]1[C:17]2[C:16]([C:18]([OH:20])=[O:19])=[C:15]3[C:7](=[C:8]4[C:13](=[N:14]3)[CH:12]=[CH:11][CH:10]=[CH:9]4)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O.[CH3:26]O>>[CH:1]1[C:17]2[C:16]([C:18]([O:20][CH3:26])=[O:19])=[C:15]3[C:7](=[C:8]4[C:13](=[N:14]3)[CH:12]=[CH:11][CH:10]=[CH:9]4)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1c2nc3ccccc3c-2[nH]c2ccccc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1c2nc3ccccc3c-2[nH]c2ccccc12

Procedure:
To a suspension of quindoline-11-carboxylic acid (2.3 g, 8.77 mmol) from Example 1 in MeOH (50 mL) was added concentrated H2SO4 (1.5 ml, 28 mmol). The resulting solution was refluxed for 8 hours, cooled, and partitioned between benzene (100 mL) and water (50 mL). After adjusting the pH to 9 with a saturated solution of K2CO3, the benzene layer was separated, washed with water, dried and concentrated. Purification by LPLC (EtOAc-hexane 1:3) gave 0.28 g of the title compound as greenish-yellow crystals (from hexane), mp 152°-153.5° C. [lit 152.5°-154° C. (Degutis, Y. A.; Ezyarskaite, A. B. Khim. Geterotsik. Soedin. 1986, 1375)]; 1H NMR (CDCl3) δ 9.75 (s, 1H), 9.09 (d, J=6.4, 1H), 8.51 (d, J=8.0, 1H), 8.38 (d, J=7.2, 1H), 7.72-7.62 (m, 3H), 7.49 (d, J=8.0, 1H), 7.38 (t, J=8.0, 1H); 13 C NMR (CDCl3) δ 168.19, 147.81, 144.43, 143.56, 133.91, 130.50, 130.27, 127.40, 126.18, 125.05, 123.66, 122.23, 121.65, 121.06, 111.19, 109.21, 52.54; MS (EI, m/z) 276 (M+) . Acidification of the water layer with HCl gave 1.8 g (78.3%) of recovered starting material.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]=2[CH:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:3]=1.C[Si](C)(C)[C:22]([F:25])([F:24])[F:23].C([O-])(=O)C.[Li+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+]>O1CCCC1.C(O)(=O)C.CN(C)C=O>[OH:15][C:7]1([C:22]([F:25])([F:24])[F:23])[C:6]2[CH:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:3]=[C:2]([CH3:1])[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COC(=O)c1cc(C)c2c(c1)C(=O)c1ccccc1-2
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)C(O)(C(F)(F)F)c1ccccc1-2
Temperature: 25 °C
Yield: 78 %

Procedure:
Under an argon atmosphere, methyl 4-methyl-9-oxo-9H-fluorene-2-carboxylate (1.009 g), trimethyl(trifluoromethyl)silane (0.89 ml) and dimethylformamide (50 ml) were mixed, lithium acetate (0.027 g) was added with stirring at room temperature, and the mixture was further stirred at room temperature for 30 min. Acetic acid (0.7 ml) and a 1M solution (6 ml) of tetrabutylammonium fluoride in tetrahydrofuran were added, and the mixture was further stirred at room temperature for 15 min. To the reaction mixture was added aqueous sodium hydrogen carbonate (300 ml), and the mixture was extracted twice with ethyl acetate (50 ml). The combined organic layer was washed once with saturated aqueous sodium hydrogen carbonate, 4 times with water and once with saturated brine, and concentrated under reduced pressure. To the obtained residue was added hexane/ethyl acetate (8:2, 10 ml) and the mixture was stirred for 10 min. This slurry was filtered, and the obtained solid was dried to give the title compound (1.000 g, 78%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:10]([NH2:13])[CH2:11][CH3:12]>>[CH2:10]([NH:13][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH2:11][CH3:12]
Reactant: N#Cc1ccccc1F
Reactant: CCCN
Product: CCCNc1ccccc1C#N

Procedure:
According to a similar manner to that in Reference Example 3, the title compound was synthesized from 2-fluorobenzonitrile and n-propylamine.