Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[S:11][CH:10]=[CH:9][C:8]=2[C:7]([O:13][CH2:14][CH3:15])=[C:6]2[S:16][CH:17]=[CH:18][C:5]=12)[CH3:2].C([Li])CCC.CCCCCC.[CH3:30][Sn:31](Cl)([CH3:33])[CH3:32].CCOCC>C1COCC1.CCCCCC.O>[CH2:14]([O:13][C:7]1[C:6]2[S:16][C:17]([Sn:31]([CH3:33])([CH3:32])[CH3:30])=[CH:18][C:5]=2[C:4]([O:3][CH2:1][CH3:2])=[C:12]2[S:11][C:10]([Sn:31]([CH3:33])([CH3:32])[CH3:30])=[CH:9][C:8]=12)[CH3:15]
Reactant: CCOc1c2ccsc2c(OCC)c2ccsc12
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOc1c2cc([Sn](C)(C)C)sc2c(OCC)c2cc([Sn](C)(C)C)sc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 556 mg (2.0 mmol) of 4,8-diethoxythieno[2,3-f]benzothiophene (26) in 8 ml of dry THF are added dropwise 1.6 ml (4.1 mmol) of 2.5 M n-butyllithium/hexane solution at −78° C. After the mixture has been stirred at −78° C. for 1 h, the cooling bath is removed and the mixture is stirred at room temperature for a further hour. The mixture is cooled to −78° C. and a solution of 4.2 ml (4.2 mmol) of 1.0 M trimethylstannyl chloride in n-hexane is added. The reaction mixture is stirred at −78° C. for another 10 min and then at room temperature for 16 h. 20 ml of ether and 20 ml of water are added and the organic phase is separated. The aqueous phase is extracted with 20 ml of ether, and the organic phases are combined and dried over sodium sulfate. After the solvents have been distilled off, the residue is dried under reduced pressure. The crude product (1.13 g, 94%) is used in the next stage without further purification. 1H NMR (CDCl3): 7.51 ppm (s, 2H), 4.38 (qa, 4H), 1.50 (t, 6H), 0.45 (s. 18H).
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7]([CH3:10])[NH:6][C:5]=1[C:11]([OH:13])=O)(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:28]([O:32][C:33]([CH:35]1[CH2:43][CH:42]2[CH:37]([CH2:38][CH2:39][CH2:40][CH2:41]2)[N:36]1[C:44](=[O:61])[CH:45]([NH:50][C:51](=[O:60])[CH:52]([NH2:59])[CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1)[C:46]([CH3:49])([CH3:48])[CH3:47])=[O:34])([CH3:31])([CH3:30])[CH3:29]>CN(C=O)C>[C:28]([O:32][C:33]([CH:35]1[CH2:43][CH:42]2[CH:37]([CH2:38][CH2:39][CH2:40][CH2:41]2)[N:36]1[C:44](=[O:61])[CH:45]([NH:50][C:51](=[O:60])[CH:52]([NH:59][C:11]([C:5]1[NH:6][C:7]([CH3:10])=[C:8]([CH3:9])[C:4]=1[C:1](=[O:3])[CH3:2])=[O:13])[CH:53]1[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]1)[C:46]([CH3:49])([CH3:48])[CH3:47])=[O:34])([CH3:29])([CH3:30])[CH3:31]
Reactant: CC(=O)c1c(C(=O)O)[nH]c(C)c1C
Reactant: CC(C)(C)OC(=O)C1CC2CCCCC2N1C(=O)C(NC(=O)C(N)C1CCCCC1)C(C)(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(=O)c1c(C(=O)NC(C(=O)NC(C(=O)N2C(C(=O)OC(C)(C)C)CC3CCCCC32)C(C)(C)C)C2CCCCC2)[nH]c(C)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
3-acetyl-4,5-dimethyl-2-pyrrole carboxylic acid 10b (2.5 g, 13.7 mmol) in DMF (56 mL) was treated with EDC (2.75 g, 14.4 mmol) and HOBt (2.20 g, 14.4 mmol) and stirred at RT for 15 minutes. Amine 16b (6.23 g, 13.0 mmol) in DMF (10 mL) was added, the reaction mixture stirred at RT and monitored by HPLC. The mixture was concentrated in vacuo, then dissolved in EtOAc. 1.0N glycine sodium salt aqueous solution was added until all excess amino ester 16b was consumed (several hours). The mixture was washed with 1N HCl (3×), brine, bicarb (3×), and brine, then dried over sodium sulfate, filtered, and concentrated in vacuo. Purification through a short plug of silica gel (25%EA/Hex) afforded 7.08 g, (85%) of 1-(2-{2-[(3-acetyl-4,5-dimethyl-1H-pyrrole-2-carbonyl)-amino]-2-cyclohexyl-acetylamino}-3,3-dimethyl-butyryl)-octahydro-indole-2-carboxylic acid tert-butyl ester 17b.
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:7](OCCN2CCCC2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[CH3:18][N:19]1[CH2:24][CH2:23][N:22](C2C=CC(N)=CC=2)[CH2:21][CH2:20]1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)=[CH:16][CH:17]=1)=[C:2]=[S:3]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: S=C=Nc1ccc(OCCN2CCCC2)cc1
Product: CN1CCN(c2ccc(N=C=S)cc2)CC1

Procedure:
The title compound is prepared as described in Example 1 for 1-[2-(4-isothiocyanato-phenoxy)-ethyl]-pyrrolidine but using 4-(4-methyl-piperazin-1-yl)-phenylamine. Title compound: ES-MS: 234.0 [M+H]+; single peak at tR=6.60 min (System 1).
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[OH:4].[CH2:30]1[C@H:33]([C:34]([OH:36])=[O:35])[NH:32][CH2:31]1.C1CCN2C(=NCCC2)CC1>CS(C)=O>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][N:32]1[CH2:31][CH2:30][C@@H:33]1[C:34]([OH:36])=[O:35]
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Reactant: O=C(O)[C@H]1CCN1
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CC[C@@H]4C(=O)O)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C

Procedure:
To a mixture of 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol) and D-Azetidine-2-carboxylic acid (20.03 mg, 0.198 mmol) in DMSO (2 mL) was added DBU (0.030 mL, 0.198 mmol). The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 16 mg of (2R)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl) azetidine-2-carboxylic acid as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (2H, dd, J=8.57, 2.86 Hz), 7.82 (2H, dd, J=8.02, 1.65 Hz), 7.58-7.70 (5H, m), 5.16-5.29 (1H, m), 4.89-5.10 (1H, m), 3.84-4.05 (2H, m), 3.18-3.41 (2H, m), 2.96-3.03 (2H, m), 2.51-2.61 (1H, m), 1.63-1.76 (2H, m), 0.97 (3H, t, K=7.25 Hz). MS (m+1)=475. HPLC Peak RT=3.5 minutes (Analytical Method A). Purity=90%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:14][CH2:15][C:16]#[CH:17]>C(#N)C.O>[CH2:17]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:16][C:15]#[CH:14]
Reactant: C1CCNCC1
Reactant: C#CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C#CCCN1CCCCC1
Temperature: 80 °C
Yield: 40.5 %

Procedure:
A mixture of piperidine (T1, 2.90 g, 34.0 mmol), potassium carbonate (3.00 g, 21.7 mmol), and 4-bromobut-1-yne (5.00 g, 37.6 mmol) in anhydrous acetonitrile (60 mL) was heated to 80° C. under nitrogen for 20 h. After this time, the reaction mixture was cooled to room temperature and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford compound T2 as light brown oil (1.89 g, 40%): MS (M+H) 138.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:31])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH3:25])[C:20]4=[N:26][CH:27]=[C:28]([C:29]#[N:30])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][C@H:3]1[OH:32].CCN(C(C)C)C(C)C.[C:42](Cl)(=O)[O:43]C1C=CC([N+]([O-])=O)=CC=1>C(O)CO.C1COCC1.CCOC(C)=O>[Cl:31][C:9]1[C:8]([N:5]2[CH2:6][CH2:7][C@H:2]3[NH:1][C:42](=[O:43])[O:32][C@@H:3]3[CH2:4]2)=[CH:13][C:12]([C:14]#[N:15])=[CH:11][C:10]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][CH2:24][CH3:25])[C:20]2=[N:26][CH:27]=[C:28]([C:29]#[N:30])[N:19]2[N:18]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](N)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@H]4NC(=O)O[C@@H]4C3)c2Cl)nn2c(C#N)cnc12
Reaction time: 0.5 h
Yield: 19 %

Procedure:
A solution of 2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (30 mg, 0.066 mmol) and DIPEA (0.035 mL, 0.199 mmol) in ethane-1,2-diol 1 mL at 0° C. (ice bath) was treated with 4-nitrophenyl carbonochloridate (18 mg, 0.089 mmol). The reaction was stirred for 0.5 hour and the reaction is complete. The reaction mixture was diluted with THF 1 ml/EtOAc 30 ml, washed 2× brine (5 ml) and dried over Na2SO4. The solvents removed and the crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 35-80% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 2-((2-chloro-5-cyano-3-((3aR,7aR)-2-oxohexahydrooxazolo[5,4-c]pyridin-5(2H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (6.0 mg).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH:11]=[CH2:12].C12BC(CCC1)CCC2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:31]1[CH:40]=[C:39]2[C:34]([CH2:35][CH2:36][CH2:37][S:38]2(=[O:42])=[O:41])=[CH:33][CH:32]=1>O1CCCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:31]1[CH:40]=[C:39]2[C:34]([CH2:35][CH2:36][CH2:37][S:38]2(=[O:42])=[O:41])=[CH:33][CH:32]=1
Reactant: C=CCCOCCCCCCBr
Reactant: O=S1(=O)CCCc2ccc(Br)cc21
Agent: [Pd+2]
Agent: B1C2CCCC1CCC2
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCCc2ccc(CCCCOCCCCCCBr)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
To a solution of 4-[(6-bromohexyl)oxy]but-1-ene (180 mg) in tetrahydrofuran (0.6 ml) was added a 0.5M solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (1.8 ml). The solution was stirred at room temperature, under nitrogen for 2 h. Tripotassium phosphate (324 mg) in water (0.46 ml) was added, followed by 7-bromothiochromane 1,1-dioxide (200 mg), palladium (II) acetate (2 mg) and triphenylphosphine (4 mg). The resultant mixture was heated at 60° C. for 17 h. Water was added and the organic layer washed with brine, dried (Na2SO4) and evaporated. The residue was purified by chromatography on a Biotage cartridge (40 g) eluting with cyclohexane-ethyl acetate (1:1) to give the title compound (121 mg) LCMS RT=3.66 min
Reaction SMILES: FC(F)(F)C(O)=O.CC(C)C(OC(C1C=CC=CC=1)C1C=CC=CC=1)=O.C1(C)C=CC=CC=1.[NH2:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=[N:65][O:66][C:67]([CH3:85])([CH3:84])[C:68]([O:70]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:69])[C:41]([NH:43][C@H:44]2[CH2:47][N:46]([C:48]([NH:50][S:51]([NH:54][CH2:55][C:56]3[NH:57][CH:58]=[C:59]([OH:63])[C:60](=[O:62])[CH:61]=3)(=[O:53])=[O:52])=[O:49])[C:45]2=[O:64])=[O:42])[N:39]=1>ClCCl.C1(OC)C=CC=CC=1.CC#N.O>[NH2:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=[N:65][O:66][C:67]([CH3:85])([CH3:84])[C:68]([OH:70])=[O:69])[C:41]([NH:43][C@H:44]2[CH2:47][N:46]([C:48]([NH:50][S:51]([NH:54][CH2:55][C:56]3[NH:57][CH:58]=[C:59]([OH:63])[C:60](=[O:62])[CH:61]=3)(=[O:53])=[O:52])=[O:49])[C:45]2=[O:64])=[O:42])[N:39]=1
Reactant: CC(C)(ON=C(C(=O)N[C@H]1CN(C(=O)NS(=O)(=O)NCc2cc(=O)c(O)c[nH]2)C1=O)c1csc(N)n1)C(=O)OC(c1ccccc1)c1ccccc1
Agent: CC(C)C(=O)OC(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(ON=C(C(=O)N[C@H]1CN(C(=O)NS(=O)(=O)NCc2cc(=O)c(O)c[nH]2)C1=O)c1csc(N)n1)C(=O)O
Temperature: 5 °C
Reaction time: 0.75 h
Yield: 105.8 %

Procedure:
Trifluoroacetic acid (4.7 ml) was added dropwise to a stirred suspension of (3S)-2-[[1(2-amino-4-thiazolyl)-2-[[1-[[[[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)methyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, diphenylmethyl ester (131 mg, 0.113 mmole) in 3 ml of dichloromethane and 0.3 ml anisole at 0° C. After stirring 45 minutes at 5° C., 2 ml of toluene was added and the volatiles were removed in vacuo. The resulting oil was washed with hexane (3×4 ml) and triturated to a solid with 10 ml of ether. The solid was washed once with ether (10 ml) and dried in vacuo. The above reaction and work-up were repeated on 0.166 mmole of (3S)-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)methyl]amino]sulfonyl]amino]carbonyl] -2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, diphenylmethyl ester. The crude solids were combined, dissolved in 2 ml of acetonitrile-water (40-60) (pH 2.5) and chromatographed on a column (200 ml) of macroreticular styrene-divinylbenzene copolymer, using an acetonitrile-water gradient. The desired material eluted at acetonitrile-water (20-80). The relevant fractions were combined and lyophilized to afford 103 mg of the title compound as a white solid, melting point 180° C., dec.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH2:13][CH2:12]2.[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:24][CH2:25][CH3:26])[CH2:27][CH2:28][CH3:29])[CH2:13][CH2:12]2)[CH2:36][C:32]1[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=1
Reactant: CCCN(CCC)CCCCN1CCc2cc(CNCc3ncc[nH]3)ccc2C1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCN1CCc2cc(CN(Cc3ncc[nH]3)Cc3nccn3C)ccc2C1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 89.4 %

Procedure:
The compound (104 mg) obtained in Example 17-7 was dissolved in anhydrous methanol (4.0 ml) and added with 1-methyl-2-imidazole carboxaldehyde (42.9 mg) and sodium cyanoborohydride (49.0 mg). The solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 16.5 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution, subjected to extraction with chloroform, and dried with magnesium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (115 mg) of the subject compound as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=1[C:21]1[NH:26][C:25](=[O:27])[N:24]2[C:28]([CH3:34])=[N:29][C:30]([CH2:31][CH2:32][CH3:33])=[C:23]2[N:22]=1)[CH3:9]>ClCCl>[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)(=[O:19])=[O:18])=[CH:13][C:12]=1[C:21]1[NH:26][C:25](=[O:27])[N:24]2[C:28]([CH3:34])=[N:29][C:30]([CH2:31][CH2:32][CH3:33])=[C:23]2[N:22]=1)[CH3:9]
Reactant: OC1CCNCC1
Reactant: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nc12
Solvent: ClCCl
Product: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCC(O)CC4)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
74 mg (0.73 mmol) of 4-hydroxylpiperidine are added to a solution of 100 mg (0.24 mmol) of 4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzenesulfonyl chloride (example VI) in 5 ml of dichloromethane and the reaction mixture is stirred at room temperature for 2 hours. After chromatographic purification (dichloromethane/methanol=95:5), 100 mg (87%) of 2-[2-ethoxy-5-(4-hydroxyl-piperidine-1-sulfonyl)-phenyl]-6-methyl-8-propyl-3H-imidazo[1,5-a][1,3,5]triazin-4-one are obtained.
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](OCC)=[O:19].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCCC1.C1(C)C=CC=CC=1>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[O:19])[CH2:5][C:4]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]=[CH:2][CH:3]=1
Reactant: Cc1ccnc2ccccc12
Reactant: CCOC(=O)c1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccnc2ccccc12)c1ccccn1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 81.5 %

Procedure:
In a 3-neck 3-liter round bottom flask equipped with two addition funnels is dissolved lepidine (10.0 mL, 75.63 mmol) in tetrahydrofuran (200 mL). One addition funnel is charged with ethyl picolinate (20.43 mL, 151.26 mmol) and the other with 0.5 M potassium bis(trimethylsilyl)amide (166.4 mL, 83.19 mmol) in toluene. The solution is cooled to −78° C. and the base added to the reaction mixture dropwise over 40 min. The reaction mixture is stirred an additional 1.5 h and ethyl picolinate is added rapidly. The ice bath is removed and the reaction mixture stirred at ambient temperature for 3 h. The reaction is quenched with water (20 mL) and after 5 min formic acid added until the pH is slightly less than 7. The mixture is concentrated in vacuo and partitioned between ethyl acetate (300 mL) and brine-sodium bicarbonate (300 mL) mixture. The organic layer is washed with brine and sodium bicarbonate, dried over sodium sulfate, and concentrated. The product is chromatographed on SiO2 (27-30% acetone in hexane) to yield 15.31 g (82%) of a yellow-brown solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([OH:17])=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)[CH3:2].C(N(CC)CC)C.ClC(OC)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C=O)C.O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([N:30]=[N+:31]=[N-:32])=[O:17])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1ccc(-c2ccccc2C(=O)O)cc1
Agent: COC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1ccc(-c2ccccc2C(=O)N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 4'-ethylbiphenylcarboxylic acid (20 mmol) dissolved in 50 mL dry DMF was added 25 mmol of triethylamine and the mixture was cooled in an ice bath, added 38.5 mmol of methyl chloroformate dropwise at 0°-5° C., and then stirred at room temperature for 15 minutes. The mixture was cooled to 0° C. again, and a cold solution of 38.5 mmol of sodium azide dissolved in a minimum amount of water (<8 mL) was added as rapidly as possible (in one portion if possible) at <5° C. The reaction mixture was stirred at 0° C. for 1 hour and poured into 500 mL of ice-water. The resulting precipitate was filtered while still cold (<10 min), washed with cold water and dried under a stream of nitrogen to give the crude 4'-ethylbiphenylcarbonyl azide. The azide was used in place of 4'-ethylbiphenylisocyanate for the subsequent reactions according to the procedures exactly paralleling those described previously for Examples 1 through 3 to give the desired product as a colorless solid, mp 223°-224° C.
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O=O.[OH-].[K+].Br[CH:17](Br)[CH3:18]>O.C(O)C>[CH2:17]1[CH2:18][O:11][C:10]2[C:2](=[C:3]([CH:7]=[CH:8][CH:9]=2)[C:4]([OH:6])=[O:5])[O:1]1
Reactant: O=C(O)c1cccc(O)c1O
Reactant: CC(Br)Br
Agent: O=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc2c1OCCO2
Yield: 96.7 %

Procedure:
2,3-Dihydroxybenzoic acid (25 g, 0.16 mol) was heated under reflux in an oxygen-free atmosphere with potassium hydroxide (26.42 g, 0.47 mole) and dibromoethane (13.46 g, 0.07 mol) using 95% ethanol (60 ml) and water (142 ml as solvent as described in J. Org. Chem. (1948), 13, 489-95 to give 2,3-ethylenedioxybenzoic acid (12.2 g, 43%), m.pt. 195°-196° C.
Reaction SMILES: [Na+].[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O-:9])=O)=[CH:5][C:4]=1[O:12][C:13]1[C:14]([NH:28][C:29]2[S:30][CH:31]=[C:32]([CH3:34])[N:33]=2)=[N:15][CH:16]=[C:17]([S:19][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH3:21])[CH:18]=1.C(Cl)(=O)OCC.[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44][NH2:45].[OH-].[Na+].Cl>C(Cl)Cl.CCOCC>[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:45][CH2:44][CH2:43][N:42]([CH3:46])[CH3:41])=[O:9])=[CH:5][C:4]=1[O:12][C:13]1[C:14]([NH:28][C:29]2[S:30][CH:31]=[C:32]([CH3:34])[N:33]=2)=[N:15][CH:16]=[C:17]([S:19][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH3:21])[CH:18]=1
Reactant: Cc1csc(Nc2ncc(SC(C)c3ccccn3)cc2Oc2cc(C(=O)[O-])ccc2Cl)n1
Reactant: CN(C)CCN
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1csc(Nc2ncc(SC(C)c3ccccn3)cc2Oc2cc(C(=O)NCCN(C)C)ccc2Cl)n1
Reaction time: 3 h
Yield: 14.8 %

Procedure:
4-chloro-3-(2-(4-methylthiazol-2-ylamino)-5-(1-(pyridin-2-yl)ethylthio)pyridin-3-yloxy)benzoic acid (prepared according to Example 73; 0.131 g, 0.263 mmol), TEA (d. 0.726) (0.0732 mL, 0.525 mmol), ethyl carbonochloridate (0.057 g, 0.525 mmol), and N1,N1-dimethylethane-1,2-diamine (0.0231 g, 0.263 mmol) were reacted according the method of Example 72. 1N NaOH was added and the reaction mixture was stirred for 3 hours. The reaction mixture was extracted with CH2Cl2. The combined extracts were concentrated and purified by silica gel chromatography (4% MeOH in CH2Cl2, using 2% 7N ammonia in MeOH) and then purified by reverse phase chromatography to give the compound as the free base. The free base was dissolved in CH2Cl2 and HCl in ether was added. The mixture was concentrated to give 4-chloro-N-(2-(dimethylamino)ethyl)-3-(2-(4-methylthiazol-2-ylamino)-5-(1-(pyridin-2-yl)ethylthio)pyridin-3-yloxy)benzamide triihydrochloride (0.025 g, 14.8% yield). 1H NMR (d6-DMSO) δ 9.73 (s, 1H), 8.91 (m, 1H), 8.42 (m, 1H), 8.01 (d, 1H), 7.78 (m, 3H), 7.51 (s, 1H), 7.29 (m, 2H), 6.83 (s, 1H), 6.66 (m, 1H), 4.48 (q, 1H), 3.60 (m, 2H), 3.24 (m, 2H), 2.81 (d, 6H), 2.24 (s, 3H), 1.54 (d, 3H); Mass spectrum (esi) m/z=569.2 (100) (M+H-3HCl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9](O)[C:10]1[S:11][CH:12]=[CH:13][N:14]=1.CN(C)C=O.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>S(Cl)(Cl)=O.C(OCC)(=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:24][CH:23]=1
Reactant: OC(c1nccs1)c1cc(F)ccc1F
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2nccs2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 24 %

Procedure:
The 2-[(2,5-difluorophenyl)-hydroxymethyl]thiazole (348 mg, 1.53 mmol) obtained in Referential Example 15 was dissolved in thionyl chloride (1.5 ml). To the resulting solution was added a drop of dimethylformamide. The resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure. Dioxane was added to the residue, followed by further concentration under reduced pressure. The residue was dissolved in dimethylformamide (10.0 ml). To the resulting solution were added 4-chlorobenzenethiol (332 mg, 2.3 mmol) and potassium carbonate (845 mg, 6.12 mmol). The resulting mixture was stirred at 50° C. for 2 hours. After the reaction mixture was allowed to stand until it became room temperature, ethyl acetate (60 ml) was added thereto. The resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1 to 6:1) to give the title compound (130 mg, 24%) as a colorless oil.