Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12](O)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)[Cl:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([Cl:28])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2O)cc1
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2Cl)cc1
Temperature: 25 °C
Yield: 29 %

Procedure:
A solution of 2-(3-chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 332, in POCl3 was heated to reflux for 3 hours while stirring under nitrogen. The mixture was cooled to room temperature and poured into ice with constant swirling. The resulting white solid was extracted with ethyl acetate. The combined organics were washed with H2O, dried over MgSO4, and concentrated to a solid. The crude product was purified using flash chromatography (SiO2, eluting with 1:1 ethyl acetate/hexanes) to provide the desired product (yield: 0.151 g, 29%). mp 203-204° C. 1H NMR (300 MHz, DMSO d6) δ 3.29-3.36 (3H, obstructed by H2O), 7.60 (m, 3H), 7.76 (m, 1H), 7.92 (m, 2H), 8.14 (m, 2H), 8.25 (s, 1H). MS (DCI/NH3) m/z 395 (M+H)+, 412 (M+NH4)+. Anal. calc. for C17H12Cl2N2O3S: C, 51.66; H, 3.06; N, 7.09. Found: C, 51.67; H, 3.03; N, 6.93.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2.C(N(CC)CC)C.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C)C=O.CS(C)=O>[C:27]1([NH:33][C:34](=[O:35])[NH:2][CH:3]2[C:15]3[N:14]4[CH:16]=[CH:17][N:18]=[C:13]4[C:12](=[O:19])[NH:11][C:10]=3[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]2=3)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccccc1
Reactant: NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: 20 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
To a suspension of 0.92 g of 10-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride in 20 ml of anhydrous dimethylformamide, maintained under a nitrogen atmosphere at a temperature in the region of 20° C., are added 1.1 g of triethylamine followed, dropwise over 10 minutes, by a solution of 1.25 g of phenyl isocyanate in 2 ml of anhydrous dimethylformamide and the mixture is stirred for 2 hours at the same temperature. The insoluble material formed is separated out by filtration, washed twice with 2 ml in total of dimethylformamide and dried under reduced pressure (5 mmHg; 0.65 kPa) at 100° C. The product obtained (0.9 g) is dissolved in 15 ml of dimethyl sulphoxide and, after addition of 15 ml of distilled water, the solution is stirred for 2 hours at a temperature in the region of 20° C. The insoluble material formed is separated out by filtration, washed twice with 2 ml in total of distilled water and dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 0.53 g of 10-(3-phenylureido)-5H,10H-imidazo[1,2-a]-indeno[1,2-e]pyrazin-4-one is thus obtained, decomposing without melting above 260° C. [N.M.R. spectrum: [200 MHz; (CD3)2SO d6 ; δ in ppm]: 6.10 (d, J=8.5 Hz, 1H: --CH-- 10); 6.91 (d, J=8.5 Hz, 1H: --NHCO-- at 10); 7.00 (t, J=7.5 Hz, 1H: --H at 4 of the phenylcarbamoyl); 7.31 (t, J=7.5 Hz, 2H: --H at 3 and --H at 5 of the phenylcarbamoyl); 7.38 and 7.48 (2t broad, J=8 Hz, 1H each: --H7 and --H8); 7.52 (d, J=7.5 Hz, 2H: --H at 2 and --H at 6 of the phenylcarbamoyl); 7.60 and 7.85 (2s, 1H each: --H of the imidazole); 7.62 and 7.88 (2d broad, J=8 Hz, 1H each: --H6 and --H9); 8.68 (s, 1H: Ar--NO--CO); 12.50 (broad s, 1H: --CONH-- of the ring)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]#[N:38])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:34][CH3:35])[C:17]([NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24]([C:29]([O:31]CC)=[O:30])=[CH:23]4)=[O:18])[C:10](=[O:36])[CH:9]=2)[CH:7]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]#[N:38])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:34][CH3:35])[C:17]([NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24]([C:29]([OH:31])=[O:30])=[CH:23]4)=[O:18])[C:10](=[O:36])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1cc2cc(NC(=O)C(CC)n3cc(OC)c(-c4cc(Cl)ccc4C#N)cc3=O)ccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Product: CCC(C(=O)Nc1ccc2[nH]c(C(=O)O)cc2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
94 mg (0.18 mmol) of ethyl 5-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-1H-indole-2-carboxylate (racemate) were hydrolysed with lithium hydroxide according to General Method 3. Yield: 39 mg (43% of theory)
Reaction SMILES: [C:1]1([C:7]2[N:12]=[N:11][C:10](Cl)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][NH:15][NH2:16]>C(O)CCC>[C:1]1([C:7]2[N:12]=[N:11][C:10]([N:15]([CH3:14])[NH2:16])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNN
Reactant: Clc1ccc(-c2ccccc2)nn1
Solvent: CCCCO
Product: CN(N)c1ccc(-c2ccccc2)nn1

Procedure:
A mixture of 10.0 g. of 6-phenyl-3-chloropyridazine 7.8 g. of methylhydrazine and 75 ml. of n-butanol is refluxed 6 hours. The mixture is cooled and filtered to give product and the filtrate is concentrated and filtered to give additional product. The two crops of product are recrystallized from ethanol to give crystals, m.p. 145°-147° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:15]=[CH:14][N:13]=3)[CH:9]=[C:8]([C:25]([OH:27])=O)[C:5]2=[N:6][CH:7]=1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl.[F:54][CH2:55][CH2:56][NH2:57]>ClCCl>[F:54][CH2:55][CH2:56][NH:57][C:25]([C:8]1[C:5]2=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]2[N:10]([CH2:11][C:12]2[C:17]([CH3:18])=[C:16]([O:19][CH2:20][C:21]([F:22])([F:24])[F:23])[CH:15]=[CH:14][N:13]=2)[CH:9]=1)=[O:27]
Reactant: Cc1cnc2c(C(=O)O)cn(Cc3nccc(OCC(F)(F)F)c3C)c2c1
Reactant: NCCF
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnc2c(C(=O)NCCF)cn(Cc3nccc(OCC(F)(F)F)c3C)c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44.3 %

Procedure:
See FIG. 21(a). 6-methyl-1-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (111 mg, 0.29 mmol) was taken dichloromethane (10 mL). Triethyl amine (0.204 mL, 1.46 mmol) was added to get a clear solution. 1-Propanephosphonic acid cyclic anhydride (0.348 mL, 0.59 mmol) was added and stirred at RT for 5 minutes. Added 2-Fluoroethylamine hydrochloride (87 mg, 0.88 mmol) and stirred at RT for overnight. After the completion of the reaction, diluted the reaction mass with dichloromethane, washed with water, brine solution. The organic layer was separated, dried over sodium sulphate, evaporated to get the crude compound. The compound was purified by silica gel chromatography using methanol and dichloromethane as eluent. Yield-44.3%. ES+MS m/z: 425.2 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.24 (s, 3 H ) 2.39 (s, 3 H ) 3.66 (q, J=5.21 Hz, 1 H ) 3.75 (q, J=5.15 Hz, 1 H ) 4.49 (t, J=4.99 Hz, 1 H ) 4.65 (t, J=4.99 Hz, 1 H ) 4.90 (q, J=8.85 Hz, 2 H ) 5.63 (s, 2 H ) 7.07 (d, J=5.65 Hz, 1 H ) 7.76 (s, 1 H ) 8.11 (s, 1 H ) 8.17 (d, J=5.65 Hz, 1 H ) 8.34 (s, 1 H ) 8.88 (t, J=5.84 Hz, 1 H ).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][C@@H:27]([CH3:52])[CH2:28][O:29][NH:30][C:31]([C:33]1[N:41]([CH3:42])[C:40]2[CH:39]=[CH:38][N:37]=[CH:36][C:35]=2[C:34]=1[NH:43][C:44]1[CH:49]=[CH:48][C:47]([I:50])=[CH:46][C:45]=1[F:51])=[O:32])(C(C)(C)C)(C)C>C1COCC1>[OH:26][C@@H:27]([CH3:52])[CH2:28][O:29][NH:30][C:31]([C:33]1[N:41]([CH3:42])[C:40]2[CH:39]=[CH:38][N:37]=[CH:36][C:35]=2[C:34]=1[NH:43][C:44]1[CH:49]=[CH:48][C:47]([I:50])=[CH:46][C:45]=1[F:51])=[O:32]
Reactant: C[C@@H](CONC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](O)CONC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C
Temperature: 45 °C
Yield: 24.9 %

Procedure:
TBAF (1.71 ml, 1N solution in THF, 1.71 mmol) was added to a solution of 3-(2-fluoro-4-iodo-phenylamino)-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid [(S)-2-(tert-butyldimethylsilanyloxy)-propoxy]-amide (171 mg, 0.29 mmol) in THF (3 ml) and the reaction heated at 45° C. for 4.5 hours. The reaction was concentrated in vacuo and the resultant residue purified by flash chromatography (SiO2, gradient 0-10% methanol in dichloromethane) to yield the title compound as a yellow solid (35 mg, 25%). 1H NMR (DMSO-D6, 400 MHz) 8.54 (1H, s), 8.27 (1H, d, J=5.7 Hz), 7.56-7.50 (2H, m), 7.48 (1H, dd, J=11.0, 2.1 Hz), 7.16-7.13 (1H, m), 6.18 (1H, t, J=8.9 Hz), 3.81 (3H, s), 3.74-3.67 (1H, m), 3.57-3.55 (2H, m), 0.95 (3H, d, J=5.99 Hz). LCMS (method A): RT=5.82 min, M+H+=485.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:34])[C@@H:16]([NH:23][C:24]([C@H:26]3[O:28][C@@H:27]3[C:29]([O:31]CC)=[O:30])=[O:25])[CH2:17][C:18]3[N:19]=[CH:20][S:21][CH:22]=3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[CH:2].[Li+].[OH-]>C1COCC1.CO.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:34])[C@@H:16]([NH:23][C:24]([C@H:26]3[O:28][C@@H:27]3[C:29]([OH:31])=[O:30])=[O:25])[CH2:17][C:18]3[N:19]=[CH:20][S:21][CH:22]=3)[S:12][CH:13]=2)=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1ccc(-c2csc(NC(=O)[C@H](Cc3cscn3)NC(=O)[C@H]3O[C@@H]3C(=O)OCC)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1ccc(-c2csc(NC(=O)[C@H](Cc3cscn3)NC(=O)[C@H]3O[C@@H]3C(=O)O)n2)cc1
Yield: 44.5 %

Procedure:
Synthesized following general saponification procedure using the following quantities: 19c (115 mg, 0.23 mmol); LiOH (6.7 mg, 0.28 mmol); THF/MeOH/H2O (4.5 ml: 1.5 ml: 1.5 ml); yielded 34 as a white solid (48 mg, 44.2%). 1H NMR (DMSO-d6, 400 MHz): δ 12.57 (s, 1H); 9.06-9.05 (d, 1H, J=1.92 Hz); 8.81-8.79 (d, 1H, J=7.8 Hz); 7.93-7.91 (d, 2H, J=8.4 Hz); 7.76 (s, 1H); 7.55-7.53 (d, 2H, J=8.4 Hz); 7.45-7.44 (d, 1H, 1.8 Hz); 4.98-4.93 (q, 1H); 4.25 (s, 1H): 3.66-3.65 (d, 1H, J=1.8 Hz); 3.42-3.41 (d, 1H, J=1.8 Hz): 3.35-3.22 (m, 2H). 13C NMR (DMSO-d6, 100 MHz): 170.08, 169.03, 165.98, 158.25, 154.33, 152.54, 148.47, 134.95, 132.61, 126.26, 121.32, 116.75, 110.20, 83.87, 81.99, 53.15, 53.08, 51.88, 33.05. ESI-HRMS (m/z): [M+H+] calcd. for C21H16N4O5S2: 469.0635; observed, 469.0627; HPLC method 1: Rt=12.5 min, Purity=95.7%.
Reaction SMILES: [NH:1]1[CH:7]([CH2:8][C:9]([OH:11])=[O:10])[C:5](=[O:6])[NH:4][C:2]1=[O:3].OS(O)(=O)=O.[CH3:17]O>O>[CH3:17][O:10][C:9](=[O:11])[CH2:8][CH:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1]1
Reactant: O=C(O)CC1NC(=O)NC1=O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)CC1NC(=O)NC1=O
Yield: 88 %

Procedure:
5-Hydantoin acetic acid (20.57 g, 0.130 mol) in MeOH (210 mL) was treated with conc. H2SO4 (7 mL) and heated to reflux under N2 for 2.5 h. The resultant clear solution was cooled and the solvent removed in vacuo to give an oil which was diluted with water (65 mL) and extracted 4 times with EtOAc. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford 19.81 g (88%) of (2,5-dioxo-imidazolidin-4-yl)-acetic acid methyl ester. MS (ES+) Calc'd for C6H9N2O4 (M+1) 173. Found m/z 173 (100%). 1H NMR.
Reaction SMILES: [NH2:1][C:2](=[N:13][NH:14][C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5]>C(O)C>[C:7]1([S:4]([CH2:3][C:2]2[N:1]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[NH:14][N:13]=2)(=[O:6])=[O:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(CS(=O)(=O)c1ccccc1)=NNC(=O)c1ccccc1F
Solvent: CCO
Product: O=S(=O)(Cc1n[nH]c(-c2ccccc2F)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
14 g (0.042 mol) 2-fluoro-benzoic acid (1-amino-2-benzenesulfonyl-ethylidene)-hydrazide were heated at 210° C. for 20 minutes. The molten mass was then cooled, dissolved in 40 ml hot ethanol and stirred overnight at room temperature. The precipitated crystals were filtered off and dried to yield 11.4 g (86%) 3-benzenesulfonylmethyl-5-(2-fluoro-phenyl)-1H-[1,2,4]triazole as beige solid, MS m/e (%): 317 (M+, 2), 253(68), 176(100), 122(61).
Reaction SMILES: P(=O)(O)O.C([CH:7](CC)[C:8]([N:10]([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])=[O:9])C.[H-].[Na+].[F:21][C:22]([F:38])([F:37])[C:23]1[CH:36]=[CH:35][CH:34]=[CH:33][C:24]=1[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O.C(OCC)C>C1COCC1.O>[CH:11]([N:10]([CH:14]([CH3:16])[CH3:15])[C:8](=[O:9])[CH:7]=[C:25]([C:24]1[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=1[C:22]([F:38])([F:37])[F:21])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:13])[CH3:12]
Reactant: CCC(CC)C(=O)N(C(C)C)C(C)C
Reactant: O=C(c1ccccc1)c1ccccc1C(F)(F)F
Agent: O=[PH](O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)N(C(=O)C=C(c1ccccc1)c1ccccc1C(F)(F)F)C(C)C
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A solution of diethyl N,N-diisopropylacetamide phosphonate (8.4 g, 30 mmol) in THF (20 mL) was added dropwise to sodium hydride (80%, 0.85 g, 29 mmol) during 30 min, keeping the temperature below 30° C. A solution of 2-trifluoromethyl-benzophenone (5.0 g, 20 mmol) in THF (20 mL) was added and the reaction mixture was heated to 50° C. and kept at that temperature for 16 h. A second portion of the phosphorous ylide (15 mmol), prepared as above, was added. After another 24 h at 50° C. the mixture was partioned between diethyl ether and water. The etheral layer was evaporated and the residue chromatographed on silica (toluene-ethyl acetate 9:1) yielding 3.0 g (41%) as a mixture of the E- and Z-isomers. Labels a and b refer to the different isomers. 1H NMR (CDCl3-d) δ0.80 (d, 6Ha), 1.08 (d, 3Hb), 1.24 (t, 6Hb), 1.31 (d, 3Hb), 1.44 (d, 6Ha), 3.32 (m, 1Ha), 3.34 (m, 1Hb), 4.19 (m, 1Hb), 4.32 (m, 1Ha), 6.04 (s, 1Ha), 6.65 (s, 1Hb) and 7.18-7.75 (m, 9Ha, 9Hb).
Reaction SMILES: [CH:1]1([NH:7][CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:13]=2[Cl:22])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]=O>C(O)C.O>[CH:1]1([N:7]2[CH2:8][C:9](=[O:10])[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:13]=3[Cl:22])[CH2:23]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=O
Reactant: NS(=O)(=O)c1ccc(NC(=O)CNC2CCCCC2)c(Cl)c1
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)c1ccc(N2CN(C3CCCCC3)CC2=O)c(Cl)c1

Procedure:
2-Cyclohexylamino-N-(2-chloro-4-sulphamoylphenyl)-acetamide (17.2g) was dissolved in ethanol (150 ml) and paraformaldehyde (3g) in water (300 ml) added. The mixture was refluxed 2 hrs, cooled and filtered. The residue was crystallised from ethanol/petroleum ether. Yield 13.5 g, m.p. 188°-190° .
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:38]([CH3:39])[C:37]4[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=4[N:35]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[ClH:44].O>C(O)(=O)C>[CH3:3][CH2:2][CH2:1][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([OH:24])=[O:23])=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:38]([CH3:39])[C:37]4[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=4[N:35]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1.[ClH:44]
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 0.17 h

Procedure:
411 g of tert-butyl 4′-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazol-1-yl]methyl]biphenyl-2-carboxylate is suspended in 822 mL of glacial acetic acid and combined with 213 g of concentrated aqueous hydrochloric acid (37%). The mixture is refluxed and about 640 mL of solvent is distilled off. The residue remaining is slowly combined with about 620 mL of water at 50° C. to 60° C. To this mixture is added 20 g of activated charcoal (e.g., Norit SX 2 Ultra) and the resulting mixture is stirred for about 10 minutes at constant temperature. After filtering, the residue is washed three times with 25 mL of glacial acetic acid and about 620 mL of water. The filtrate obtained is again heated to about 50° C. to 60° C. and about 2 L of water are added. After stirring for about 12 hours at about 23° C., the crystals formed are suction filtered and washed twice with about 500 mL of water, once with about 900 mL of acetone, and then dried at about 60° C. Yield: 367 g (92.5%) colorless crystals, melting point: 278° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH2:9][CH:8]([CH2:10][CH:11]([CH3:13])[CH3:12])[S:7][C:6]=2[C:14]=1[Cl:15].C(O)(=O)C.B(F)(F)F.CCOCC.[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH:11]([CH3:13])[CH3:12])[S:7][C:6]=2[C:14]=1[Cl:15]
Reactant: COc1cc2c(c(Cl)c1Cl)SC(CC(C)C)C2
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc2cc(CC(C)C)sc2c(Cl)c1Cl
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
A mixture of 18 g of 6,7-dichloro-2,3-dihydro-2-isobutyl-5-methoxybenzo[b]thiophene, 90 ml of glacial acetic acid and 25 ml of boron trifluoride etherate is heated on a steam bath until dissolution occurs and for an additional 30 mins, with stirring. The reaction mixture is poured onto ice and the mixture is basified with 25% sodium hydroxide solution and extracted with ether. The ether extracts are washed with water, sodium bicarbonate solution, water, dried and filtered. Evaporation of the filtrate affords an oil which crystallies on cooling in a dry ice-acetone bath. Chromatography of the crystalline material on alumina using dichloromethane as the eluent affords 14.5 g of 6,7-dichloro-5-methoxy-2-isobutylbenzo[b]thiophene, mp 40°-41°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH3:28])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pt]=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH3:28])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)(=[O:11])=[O:12])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CCCOc1ccc(N2CCN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)CC2)cc1
Agent: O=[Pt]
Product: CCCOc1ccc(N2CCN(S(=O)(=O)c3ccc(N)cc3)CC2)cc1

Procedure:
In the manner given in Example 1B, 1[(p-nitrophenyl)sulfonyl] -4-(p-propoxyphenyl)piperazine is reduced with hydrogen over platinum oxide catalyst (PtO2) to give 1-[(p-aminophenyl)sulfonyl]-4-(p-propoxyphenyl)piperazine.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:20][CH2:19][CH2:18][C@H:17]([N:21](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH2:16]2)[N:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(NC1C=CC=C(N2CCC[C@H](NC(OC(C)(C)C)=O)C2)N=1)(OC(C)(C)C)=O.[ClH:64]>>[ClH:64].[NH2:21][C@H:17]1[CH2:18][CH2:19][CH2:20][N:15]([C:11]2[N:10]=[C:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:6])([CH3:5])[CH3:7])[CH:14]=[CH:13][CH:12]=2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N2CCC[C@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C2)n1
Agent: CC(C)(C)OC(=O)Nc1cccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)n1
Agent: Cl
Product: CC(C)(C)OC(=O)Nc1cccc(N2CCC[C@H](N)C2)n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 90 %

Procedure:
A mixture of 114a and 114b (2.3 g, 4.69 mmol) in HCl (10 mL, 4 M in 1,4-dioxane, 40 mmol) was stirred at rt for 7 h. The reaction mixture was concentrated to give (S)-tert-butyl 6-(3-aminopiperidin-1-yl)pyridin-2-ylcarbamate hydrochloride 114c (1.39 g, 90%) as yellow solid which was used for the next step directly.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH2:25])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[C:35]2[C:30](=[CH:31][C:32]([C:36](O)=[O:37])=[CH:33][CH:34]=2)[NH:29][CH:28]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH:25][C:36]([C:32]2[CH:31]=[C:30]3[C:35]([C:27]([Cl:26])=[CH:28][NH:29]3)=[CH:34][CH:33]=2)=[O:37])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(COCC(N)c2ccc(F)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccc(F)cc2)CC1
Yield: 100.6 %

Procedure:
Using coupling method A, 4-[2-amino-2-(4-fluorophenyl)-ethoxymethyl]piperidine-1-carboxylic acid tert-butyl ester (1.1 g, 3.0 mmol) and 3-chloroindole-6-carboxylic acid (653 mg, 3.3 mmol) afforded 1.6 g (100%) of the title compound as a crude residue, which was used without further purification.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:6]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=2[CH3:32])[C:26]([OH:28])=O)[C:7](=[O:22])[C:8]([Cl:21])=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[N:10]=1)[CH:2]=[CH2:3].ClC(OCC(C)C)=O.CN1CCOCC1.[CH2:48]([NH2:51])[CH:49]=[CH2:50]>CN(C)C(=O)C>[CH2:48]([NH:51][C:26](=[O:28])[C:25]1[CH:29]=[CH:30][C:31]([CH3:32])=[C:23]([N:6]2[C:7](=[O:22])[C:8]([Cl:21])=[C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:10]=[C:5]2[NH:4][CH2:1][CH:2]=[CH2:3])[CH:24]=1)[CH:49]=[CH2:50]
Reactant: C=CCNc1nc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(C(=O)O)ccc1C
Reactant: C=CCN
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Product: C=CCNC(=O)c1ccc(C)c(-n2c(NCC=C)nc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a cooled (0° C.) solution of 3-[2-(allylamino)-5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (from Step 3) (0.37 g, 0.80 mmol) in N,N-dimethylacetamide (2 mL) was added isobutyl chloroformate (0.12 mL, 0.96 mmol) and 4-methylmorpholine (0.11 mL, 1.04 mmol). Stirred at 0° C. for 5 min, ambient temperature for 30 min. Added allyl amine (0.09 mL, 1.20 mmol). Stirred at ambient temperature for 2 h. Purified by preparatory HPLC using a 10-90% CH3CN/H2O (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z=494) were combined, freeze-dried, and lyophilized. Washed with 5% NaHCO3 (20 mL) and extracted with DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as a white solid (0.24 g, 60%). 1H NMR (CD3OD/400 MHz) δ7.93 (m, 1H), 7.67 (s, 1H), 7.55 (q, 2H, J=8.0 Hz), 7.00 (t, 2H, J=8.8 Hz), 5.90 (m, 1H), 5.80 (m, 1H), 5.51 (m, 2H), 5.21 (m, 1H), 5.09 (m, 3H), 3.95 (m, 4H), 2.14 (s, 3H). ESHRMS m/z 501.1520 (M+H calculated for C25H24ClF2N4O3 requires 501.1500).