Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([Cl:20])=[C:15]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:14]=[CH:13]2.[C:28](Cl)(=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Cl:20][C:16]1[C:17]2[C:12](=[CH:11][C:10]([C:2]3[O:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]=3[C:28](=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32])=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]=1[O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)COc1ccc2cc(-c3cc4ccccc4o3)ccc2c1Cl
Reactant: CCCCC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCC(=O)c1c(-c2ccc3c(Cl)c(OCC(=O)OCC)ccc3c2)oc2ccccc12
Yield: 23 %

Procedure:
Following the procedure described in Step 3 of Example 23, ethyl 2-{[6-(1-benzofuran-2-yl)-1-chloro-2-naphthyl]oxy}acetate (1.90 g, 4.99 mmol) was acylated by valeryl chloride (0.61 mL, 5.1 mmol) in presence of tin (IV) chloride (0.60 mL, 5.1 mmol) in methylene chloride (20 mL). ethyl 2-{[1-chloro-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy} acetate was prepared. Purification by HPLC using 10% tert-butyl methyl ether in hexane as the mobile phase yielded the title compound as a light yellow solid (0.533 g), mp 95-97° C. Mass spectrum (+ESI, [M+H]+) m/z 465. 1HNMR (500 MHz, DMSO-d6): δ8.5 (s, 1H), 8.25 (d, 1H, J=8.9 Hz), 8.15 (d, 1H, J=9.0 Hz), 8.05 (t, 2H, J=8.6 Hz), 7.75 (d, 1H, J=7.8 Hz), 7.55 (d, 1H, J=9.2 Hz), 7.4-7.45 (m, 2H), 5.13 (s, 2H), 4.2 (q, 2H, J=7.0 Hz), 2.75 (t, 2H, J=7.3 Hz), 1.5-1.6 (m, 2H), 1.1-1.3 (m, 5H), and 0.7 ppm (t, 3H, J=7.3 Hz). Elemental Analysis for C27H25ClO5: Calculated: C, 69.75; H, 5.42; N, 0.00. Found: C, 69.64; H, 5.20; N, 0.01.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[S:9][C:10]2[CH:17]=[CH:16][C:15]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=3)=[CH:14][C:11]=2[C:12]=1[CH3:13])(=[O:7])=[O:6].[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].N1C=CN=C1>CN(C=O)C.CCOCC>[Si:28]([O:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[S:9][C:10]2[CH:17]=[CH:16][C:15]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=3)=[CH:14][C:11]=2[C:12]=1[CH3:13])(=[O:7])=[O:6])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1ccc(-c2ccc3sc(S(=O)(=O)NCCO)c(C)c3c2)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1ccc(-c2ccc3sc(S(=O)(=O)NCCO[Si](C)(C)C(C)(C)C)c(C)c3c2)cc1

Procedure:
A solution of Example 398B (200 mg, 0.5 mmol), tert-butyldimethylsilyl chloride (85 mg, 0.55 mmol) and imidazole (36 mg, 0.6 mmol) in DMF (5 mL) at room temperature was stirred for 24 hours, diluted with ether, filtered through a pad of silica gel, and concentrated to provide the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:9][C:10]([NH:12][CH3:13])=O)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-]>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH2:9][CH2:10][NH:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CNC(=O)CC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: CNCCC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Reaction time: 16 h
Yield: 62 %

Procedure:
Under a nitrogen atmosphere, the crude 3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-N-methyl-propionamide was cooled to 0° C., lithium aluminum hydride (0.075 g, 1.97 mmol) and diethyl ether (3 ml) were added. With cooling, aluminum chloride (0.23 g, 1.69 mmol) was dissolved in diethyl ether (2 ml) and added. The reaction mixture was stirred for 16 hours, quenched with addition of water, basified (2N NaOH) and extracted with ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated, the crude product was purified over Phenomenex_Strata_SCX column chromatography eluting with methanol followed by 2N ammonia in methanol to afford the desired product (0.254 g, 62% yield for steps 1D and 1E combined). LC/MS: (PS-B3) Rt 3.20 [M+H]+ 339.85.
Reaction SMILES: C1N=C[N:3](C(N2C=NC=C2)=O)[CH:2]=1.[NH2:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].CN>C1COCC1>[NH2:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16]([NH:3][CH3:2])=[O:17]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(Cl)cc1N
Reaction time: 3 h
Yield: 74.3 %

Procedure:
Carbonyl-1,1′-diimidazole (1.70 g) was added to 2-amino-4-chlorobenzoic acid (1.50 g) in THF (22.2 mL). After stirring overnight a solution of methylamine in THF (2M, 6.6 mL) was added and the reaction stirred for 3 hours. The reaction was concentrated in vacuo and the residue dissolved in EtOAc (100 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The organics were then washed with saturated aqueous sodium bicarbonate solution (50 mL) and then water (2×100 mL). The organics were extracted with 1 M HCl (4×25 mL, then 2×100 mL then 50 mL), the aqueous phase basified with potassium carbonate (˜50 g) and the organics discarded. The aqueous was then extracted with EtOAc (2×50 mL). The combined organics were dried (MgSO4, 10 g) and concentrated to give 2-amino-4-chloro-N-methylbenzamide (1.2 g, 74%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]2)[CH2:3][CH2:2]1.O.C=O.[CH:34](O)=O>C1COCC1>[CH3:34][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]2)[CH2:3][CH2:2]1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCNCC2)cn1
Reactant: O=CO
Agent: C=O
Solvent: C1CCOC1
Solvent: O
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCN(C)CC2)cn1
Temperature: 80 °C

Procedure:
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (1-piperidin-4-yl-1H-imidazol-4-yl)-amide (200 mg, 4.8 mmol) was dissolved in 5 mL of THF and 0.5 mL of water and 0.04 mL of 38% formaldehyde and 0.06 mL of formic acid was added. The reaction was heated for 12 h at 80° C. The solution was extracted with methylene chloride and sodium bicarbonate. The resultant organics were concentrated and purified by silica gel chromatography to afford the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 18.9, 33.3, 36.0, 43.1, 46.1, 53.0, 54.7, 55.3, 102.6, 102.9, 103.1, 105.9, 112.3, 112.6, 131.5, 137.7, 138.7, 162.0, 164.5, 169.2; MS 432.2 m/z (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[NH:8][C:9]2[C:10]([N:15]=1)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:5][CH3:6].[C:16]1([C:22]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:23]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=3)=[N:26][N:25]=[N:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:3]([CH:7]1[N:15]([CH2:40][C:37]2[CH:36]=[CH:35][C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[C:27]3[N:23]([C:22]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:24]=[N:25][N:26]=3)=[CH:39][CH:38]=2)[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[NH:8]1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc2ncccc2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC1Nc2cccnc2N1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 23.6 %

Procedure:
To a stirred suspension of NaH (102 mg of an 80% dispersion, 3.39 mmol) in dry dimethylformamide (6 mL) at rt was added 2-butylimidazo[4,5-b]pyridine (495 mg, 2.83 mmol) in one portion. After 20 minutes, the mixture was cooled to 0° C. and N-triphenylmethyl-5-(4'-bromomethylbiphenyl-2-yl)tetrazole (1.50 g, 2.70 mmol) was added in one portion. The resulting dark colored mixture was warmed to rt and stirred for 15 hours. The excess NaH was quenched with water (1 mL) and the bulk of the DMF was removed in vacuo at 40°-50° C. Extraction with EtOAc (4×20 mL) from brine (60 mL), drying (K2CO3), and concentration gave a thick dark oil. Purification by flash chromatography (SiO2, solvent gradient: 80% EtOAc/hexanes, 100% EtOAc) gave 417 mg (23%) of 2-butyl-3-(2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl)methyl-1H-imidazo[ 4,5-b]pyridine as a thick oil: Rf=0.75 (SiO2, 100% EtOAc), 1H NMR (300 MHz, CDCl3) δ8.35 (1H, dd, J=6, 1 Hz), 8.05 (1H, dd, J=9, 1 Hz), 7.92 (1H, dd, J=9, 1.5 Hz), 7.51-7.42 (3H, m), 7.36-7.20 (11H, M), 7.07 (2H, d, 7 Hz), 6.96-6.89 (7H, m), 5.40 (2H, s), 2.73 (2H, t, J=7.5 Hz), 1.84-1.70 (2H, m), 1.41-1.30 (2H, m), 0.88 (3H, t, J=7.5 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C:9]#[N:10])[CH:2]=1.C([O-])([O-])=[O:12].[K+].[K+].CS(C)=O.OO>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C:9]([NH2:10])=[O:12])[CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: N#CCOc1cccnc1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)COc1cccnc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.5 %

Procedure:
To a mixture of 2-(pyridin-3-yloxy)acetonitrile (100 mg, 0.75 mmol), K2CO3 (103 mg, 0.75 mmol) and DMSO (0.1 mL) in H2O (2 mL) was added H2O2 (0.1 mL, 30%) dropwise in an ice bath and the mixture was stirred at rt for 5 min. It was then concentrated in vacuo and the residue was purified by a silica gel column chromatography (EtOAc) to give the title compound as a white solid (62.2 mg, 55%).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([Cl:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: OB(O)c1ccc(Br)cc1
Product: Clc1nc2c(-c3ccc(Br)cc3)cccn2n1

Procedure:
198 a) 8-(4-Bromo-phenyl)-2-chloro-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (1.0 g, 4.5 mmol) and 4-bromobenzeneboronic acid (1.0 g, 5.0 mmol) in a manner analogous to Example 2c. Product isolated as an off-white solid (1.0 g, 72%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.5 Hz, 1H), 7.88 (d, J=7.1 Hz, 2H), 7.70 (d, J=7.0 Hz, 1H), 7.65 (d, J=7.1 Hz, 2H), 7.16 (t, J=7.5 Hz, 1H). MS=310, 312 (MH)+. 198 b) To an oven dried tube was added 8-(4-bromo-phenyl)-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.90 g, 2.9 mmol), methylphosphinoylmethane (0.24 g, 3.1 mmol)(prepared as described in WO2005/009348), palladium acetate (13.5 mg, 0.0601 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (36.0 mg, 0.0622 mmol), cesium carbonate (1422.0 mg, 4.3644 mmol) and 1,4-dioxane (9 mL). The tube was evacuated, carefully, and backflushed with nitrogen. The tube was sealed and heated at 90° C. for 24 hours then cooled to room temperature, diluted with dichloromethane (30 mL), filtered through a plug of diatomaceous earth and evaporated. The residue was purified via chromatography using an ISCO automated purification apparatus (silica gel column 40 g and 0%→7% dichloromethane:methanol). 2-Chloro-8-[4-(dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine was isolated as a white solid (0.303 g, 34%). MP=220-223° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.55 (d, J=6.9 Hz, 1H), 8.11 (d, J=7.7 Hz, 2H), 7.94-7.86 (m, 2H), 7.77 (t, J=7.4 Hz, 1H), 7.21 (t, J=6.9 Hz, 1H), 1.80 (s, 3H), 1.77 (s, 3H). MS=306, 308 (MH)+. 198 c) {8-[4-(Dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 2-chloro-8-[4-(dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3271 mmol) and 3-(4-methylpiperazin-1-yl)aniline (70.0 mg, 0.366 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (28.0 mg, 0.0512 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan solid (0.097 g, 64%). MP=243-246° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.46 (d, J=6.2 Hz, 1H), 8.15 (d, J=8.0 Hz, 2H), 7.92-7.84 (m, 2H), 7.63-7.50 (m, 1H), 7.34 (s, 1H), 7.23 (t, J=8.2 Hz, 1H), 7.02-6.96 (m, 2H), 6.84 (s, 1H), 6.59 (d, J=7.8 Hz, 1H), 3.30-3.25 (m, 4H), 2.63-2.58 (m, 4H), 2.37 (s, 3H), 1.80 (s, 3H), 1.77 (s, 3H). MS=461 (MH)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([NH:16][C@H:17]([C:25]([O:27]CC)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH:8]=[CH:7]2)([O-])=O.[C:30]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[C:30]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:35]=[CH:34][C:33]([S:36]([NH:1][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH2:13][C:14]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:15])[CH:8]=[CH:7]3)(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)Cn1ccc2cc([N+](=O)[O-])ccc21
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: O=C(Cn1ccc2cc(NS(=O)(=O)c3ccc(-c4ccccc4)cc3)ccc21)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
The title compound was prepared from ethyl N-[(5-nitro-1H-indol-1-yl)acetyl]-L-phenylalaninate and biphenyl-4-sulfonyl chloride following the procedures of Example 10 Step 4 & Step 5: MS (ESI) m/z 554; MS (ESI) m/z 552
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N2CCN(C(C3C=C4C(=CC=3)NC(C(N3CCS(=O)(=O)CC3)=O)=C4)=O)CC2)CCCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:80][C:81]1[CH:87]=[CH:86][CH:85]=[C:84]([CH3:88])[C:82]=1[NH2:83].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:80][C:81]1[CH:87]=[CH:86][CH:85]=[C:84]([CH3:88])[C:82]=1[NH:83][C:23]([C:18]1[NH:19][C:20]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:12]([N:9]1[CH2:8][CH2:7][N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:11][CH2:10]1)=[O:13])=[CH:22][CH:21]=2)=[O:25]
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: Cc1cccc(C)c1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1NC(=O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Yield: 22 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride (example 34, intermediate b), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 2,6-dimethylaniline (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a yellow solid (22%).
Reaction SMILES: C(O[C:4](=[O:30])[CH:5]([F:29])[C:6]([C:8]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:11]2=[N:12][CH:13]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:15]=[C:10]2[CH:9]=1)=O)C.C(O)(=O)C.[CH:35]([NH2:37])=[NH:36].CO.C[O-].[Na+]>C(OCC)(=O)C.C(O)(=O)C>[F:29][C:5]1[C:4](=[O:30])[NH:37][CH:35]=[N:36][C:6]=1[C:8]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:11]2=[N:12][CH:13]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:15]=[C:10]2[CH:9]=1
Reactant: CCOC(=O)C(F)C(=O)c1cc2cc(S(C)(=O)=O)cnc2n1Cc1ccc(F)cc1
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1cnc2c(c1)cc(-c1nc[nH]c(=O)c1F)n2Cc1ccc(F)cc1
Reaction time: 18 h
Yield: 27.4 %

Procedure:
To a mixture of 2-fluoro-3-(1-(4-fluorobenzyl)-5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-oxopropionic acid ethyl ester obtained in Example 36 (3) (88 mg), formamidine acetate (42 mg) and methanol (1.2 ml), sodium methoxide (0.6 ml, 1 mol/l solution in methanol) was added at 15 to 30° C. and the mixture was stirred at the same temperature for 18 hours. The mixture was neutralized with acetic acid and diluted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (methanol:dichloromethane=5:95) to obtain the desired product (23 mg) in a white amorphous form.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:22]=[C:21]([CH2:23][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[C:20](=[O:30])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([OH:19])=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.S(Cl)(Cl)=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:22]=[C:21]([CH2:23][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[C:20](=[O:30])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([O:19][CH2:13][CH2:14][CH2:2][CH2:3][CH3:4])=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=C(O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCOC(=O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Reaction time: 0.33 h
Yield: 115.8 %

Procedure:
10-bromo-2-carboxymethyloxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (300 mg) obtained in Example 6 was suspended in anhydrous benzene (10 ml), and to the suspension was added thionyl chloride (0.95 ml) at room temperature. The mixture was heated under reflux in an argon atmosphere for 3 hours and allowed to cool. The solvent was evaporated under reduced pressure, and after adding anhydrous benzene (5 ml), the solvent was evaporated again. The resulting residue was dissolved in anhydrous methylene chloride (3 ml), and the solution was added dropwise to a solution of 1-pentanol (0.065 ml) and triethylamine (0.18 ml) dissolved in methylene chloride (30 ml) in an ice bath, and the solution was stirred for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The methylene chloride layer was repeatedly washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The residual crude crystals were washed with ether, and recovered by filtration to obtain the title compound (200 mg, 58%).
Reaction SMILES: [CH2:1]([CH:10]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[N:11]1[CH:14]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:17])[CH:13]([CH:28]([OH:30])[CH3:29])[C:12]1=[O:31])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.Cl[C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([N+:52]([O-:54])=[O:53])=[CH:48][CH:47]=1)=[O:43].O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:32]([CH:10]([CH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1)[N:11]1[CH:14]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:17])[CH:13]([CH:28]([O:30][C:42]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][C:49]([N+:52]([O-:54])=[O:53])=[CH:50][CH:51]=2)=[O:43])[CH3:29])[C:12]1=[O:31])[C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1
Reactant: COc1ccc(COC(=O)CC2C(C(C)O)C(=O)N2C(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)cc1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(COC(=O)CC2C(C(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)N2C(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
2.6 g of 1-(di-p-anisylmethyl)-3-(1hydroxyethyl)-4-p-methoxybenzyloxycarbonylmethyl-2-azetidinone was dissolved in 15 ml of dried methylene chloride, and 1.22 g of 4-dimethylaminopyridine was added thereto. Under ice-cooling, a solution of 1.3 g of p-nitrobenzyl chloroformate in 7 ml of dried methylene chloride was added dropwise to the mixture, followed by stirring at room temperature for 1 hours. To the reaction mixture were added methylene chloride and water, and the methylene chloride layer was washed successively with a 1N hydrochloric acid aqueous solution, water, a 5% aqueous solution of sodium bicarbonate and water, and dried over sodium sulfate. The solvent was removed by distillation, and the residue was purified by silica gel chromatography to obtain 2.2 g of 1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-p-methoxybenzyloxycarbonylmethyl-2-azetidinone.
Reaction SMILES: ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O.[CH:13]([O:16][CH2:17][CH2:18]O)([CH3:15])[CH3:14].Cl.[NH2:21][C:22]1[N:23]=[CH:24][NH:25][C:26]=1[C:27]([NH2:29])=[O:28]>C(Cl)Cl.CO.CC1(C)N([O])C(C)(C)CCC1>[CH:13]([O:16][CH2:17][CH2:18][NH:21][C:22]1[N:23]=[CH:24][NH:25][C:26]=1[C:27]([NH2:29])=[O:28])([CH3:14])[CH3:15]
Reactant: CC(C)OCCO
Reactant: NC(=O)c1[nH]cnc1N
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: Cl
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Solvent: CO
Product: CC(C)OCCNc1nc[nH]c1C(N)=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 38.3 %

Procedure:
Trichlorocyanuric acid (1.23 g, 5.29 mmol) was added to a solution of 2-isopropoxyethanol (0.50 g, 4.80 mmol) in CH2Cl2 (3 mL). The reaction mixture was cooled to 0° C. and TEMPO (0.015 g, 0.09 mmol) was carefully added in small portions. The mixture was stirred at r.t. for 20 minutes and then filtrated through Celite and washed with CH2Cl2. The filtrate was kept cold, 0° C., during the filtration. The obtained aldehyde solution was added to a stirred mixture of 4-amino-1H-imidazole-5-carboxamide hydrochloride (0.78 g, 4.80 mmol), which was obtained from Example 3(b), at 0° C. in MeOH (5 mL). The mixture was stirred for 20 minutes, then NaCNBH4 (0.30 g, 4.80 mmol) was added. After stirring at r.t for 5 h the mixture was concentrated and purified by flash chromatography (CH2Cl2/methanol gradient; 0 to 5% methanol), to yield the title compound (0.39 g, 38%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([OH:20])=O)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[NH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([OH:31])[CH2:26]1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([OH:31])[CH2:26]2)=[O:20])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: OC1CCCNC1
Reactant: O=C(O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCC(=O)N1CCCC(O)C1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 2-(5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxamido)acetic acid (200 mg, 0.49 mmol) from example 210 and piperidin-3-ol (59.0 mg, 0.59 mmol). The title compound was obtained as a solid (25.0 mg, 11% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (1H, m), 8.51 (1H, s), 4.87 (1H, m), 4.08 (2H, m), 3.58 (1H, m), 3.48 (1H, m), 3.38 (1H, m), 3.15 (1H, m), 2.60 (1H, m), 1.85 (1H, m), 1.75 (1H, m), 1.47 (1H, m), 1.33 (1H, m). MS m/z: 491.23, 493.26 [M+H]+.
Reaction SMILES: O=S(Cl)[Cl:3].O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:25])[CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:11][CH:10]=1>N1C=CC=CC=1.C1C=CC=CC=1>[Cl:3][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:25])[CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:11][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: CC(CCCC1CCCCC1)c1ccc(CCCO)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(CCCC1CCCCC1)c1ccc(CCCCl)cc1

Procedure:
Next, 0.82 g of Li[AlH4 ] was added to 50 ml of dried (C2H5)2O, and the resulting mixture was stirred. Thereto was gradually added 5 g of 4-[p-(2-hydroxycarbonylethyl)phenyl]pentylcyclohexane. Thereafter, the thus obtained mixture was stirred for 5 hours, and filtered. The (C2H5)2O was distilled off from the filtrate, and the residue was recrystallized from n--C6H14 to obtain 4-[p-(3-hydroxypropyl)phenyl]pentylcyclohexane. The melting point of this compound was 70.7° to 72.5° C. To a mixture of 3.6 g of SOCl2, one drop of pyridine and 50 ml of benzene was added 4.3 of the 4-[p-(3-hydroxypropyl)phenyl]pentylcyclohexane obtained above, and the resulting mixture was refluxed for 5 hours. Thereafter, the surplus SOCl2 was distilled off to obtain 4-[p-(3-chloropropyl)phenyl]pentylcyclohexane. The melting point of this compound was 70.7° to 72.5° C.