Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=O)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:21]=1.C1(C)C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.C(Cl)Cl.[NH:38]([C:40](OC)=[O:41])[NH2:39].C(=O)([O-])[O-].[K+].[K+]>C(=O)(O)[O-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:17]([CH:18]([CH3:20])[CH3:19])[C:40](=[O:41])[NH:38][N:39]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:21]=1
Reactant: CC(C)NC(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: COC(=O)NN
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)n1c(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)n[nH]c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 36.9 %

Procedure:
A solution of 8-bromo-N-isopropyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (200 mg, 0.5 mmol) in toluene (5 mL, 0.05 mol) under nitrogen atmosphere was treated with phosphorus pentachloride (0.182 g, 0.87 mmol) in one portion. The flask was sealed and heated at 80° C. for 2 h, cooled to room temperature and the solvent concentrated under reduced pressure with care to avoid atmospheric exposure. The crude residue was taken up in methylene chloride (8 mL, 0.1 mol) and treated with methyl hydrazinecarboxylate (0.123 g, 1.36 mmol). The resulting suspension was stirred at room temperature for 2 h. The reaction mixture was diluted with saturated sodium bicarbonate and extracted with methylene chloride. The combined organics were washed with brine, dried over sodium sulfate and concentrated. The crude residue was dissolved in ethanol (5 mL) and potassium carbonate (0.2264 g, 1.64 mmol) was added. The reaction mixture was stirred at 80° C. for 2 h. 0.5 mL water was added and the heating continued overnight. The mixture was concentrated, diluted with water and extracted with ethyl acetate. The organics were washed with brine, concentrated, and the resultant residue purified by flash column chromatography to give 265 (75 mg). 1H NMR (dmso-d6, 500 MHz) δ 11.9 (s, 1H), 7.60 (m, 1H), 7.30-7.23 (m, 3H), 4.44 (pentet, 1H), 4.32 (t, 2H), 3.22 (t, 2H), 1.46 (d, 6H). MS (ESI) 408.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].[CH3:19][S:20]([CH2:23][CH2:24][CH2:25]OS(C)(=O)=O)(=[O:22])=[O:21]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:12][CH2:25][CH2:24][CH2:23][S:20]([CH3:19])(=[O:22])=[O:21])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(O)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)CCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCCCS(C)(=O)=O)ccc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
Step B To a solution of 3-methoxy-4-nitrophenol (0.5 g, 3 mmol) prepared in Example 132 Step A in anhydrous DMF (25 mL) were added K2CO3 (0.8 g, 5.9 mmol) and methanesulfonic acid 3-methanesulfonyl-propyl ester (0.7 g, 3.2 mmol) sequentially. The reaction mixture was heated at 70° C. for 4 h. The mixture was cooled to room temperature, and diluted with water. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to give 2-methoxy-4-(3-(methylsulfonyl)propoxy)-1-nitrobenzene as a off white solid (0.58 g, 68%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C@@H:25]3[C@@H:20]([C:21]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:22]=4[CH2:23][CH2:24]3)[CH2:19][C:18]2=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C1COCC1.O.[OH-].[Na+]>C1COCC1.O>[CH:7]1([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C@@H:25]3[C@@H:20]([C:21]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:22]=4[CH2:23][CH2:24]3)[CH2:19][CH2:18]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCCCC1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCC1CCCCC1
Yield: 93 %

Procedure:
0.79 g (0.0208 mol) of lithium aluminum hydride was suspended in 20 ml of THF under argon. A solution of 5.60 g (0.01575 mol) of rac-cis-3-(4-cyclohexyl-butyl)-1,3,3a,4,5,9b-hexahydro-6-methoxy-2H-benzo[e]indol-2-one in 60 ml of THF was added dropwise thereto and the mixture was boiled under reflux for 1/2 hour. 10 ml of THF/water 4:1, 4 ml of 15% aqueous NaOH solution and 2 ml of water were cautiously added dropwise thereto in succession, whereupon the mixture was boiled under reflux for 15 minutes until a complete white precipitate had resulted. After filtration, concentration and chromatography of the residue over silica gel with n-hexane/ethyl acetate 1:1 there were obtained 5.0 g (93%) of oily rac-cis-3-(4-cyclohexyl-butyl)-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[SH:7].C(N(CC)CC)C.[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)#[N:16]>O1CCCC1>[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21](=[O:22])[S:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:19][CH:18]=1)#[N:16]
Reactant: Sc1ccccn1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccc(C(=O)Sc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 885.2 %

Procedure:
To a suspension of 2-pyridinethiol (17 g) in tetrahydrofuran (200 mL) was added triethylamine (15.5 g) in an ice-water bath under N2. To this was added a solution of 4-cyanobenzoyl chloride (25.3 g) in tetrahydrofuran (80 mL) below 10° C. over 30 minutes. After 15 minutes, the bath was removed and the mixture was stirred overnight at ambient temperature. The mixture was concentrated in vacuo. The residue was partitioned between chloroform and water. The organic layer was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue (38 g) was triturated with isopropyl ether to give S-(2-pyridinyl) 4-cyanobenzenecarbothioate (325 g) as a pale brown solid.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Cl[CH2:14][C:15]1[N:16]=[C:17]([NH2:20])[S:18][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C.O>[NH2:20][C:17]1[S:18][CH:19]=[C:15]([CH2:14][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[N:16]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Nc1nc(CCl)cs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CC#N
Product: Nc1nc(CON2C(=O)c3ccccc3C2=O)cs1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of N-hydroxyphthalimide (50.0 g, 306 mmol), 4-(chloromethyl)-1,3-thiazol-2-amine (50.1 g, 337 mmol), cesium carbonate (210 g, 0.64 mol) and potassium iodide (2.54 g, 15.3 mmol) in acetonitrile (440 mL) was stirred at room temperature for 18 h. Water (300 mL) was added, the precipitate was filtered off and washed with water until colourless, then dried in vacuo overnight to afford 2-[(2-amino-1,3-thiazol-4-yl)methoxy]-1H-isoindole-1,3(2H)-dione as a colourless solid [36.0 g; 43% of theory; HPLC/MS: m/z=276 (M+H); log P(HCOOH)=0.74].
Reaction SMILES: Cl[CH2:2][CH:3]=[O:4].[CH3:5][C:6]1[N:11]=[C:10]([NH:12][C:13](=[S:15])[S-:14])[CH:9]=[CH:8][CH:7]=1.C([NH+](CC)CC)C.C(O)C>O.C(Cl)(Cl)Cl.C(OCC)C>[OH:4][CH:3]1[CH2:2][S:15][C:13](=[S:14])[N:12]1[C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:5])[N:11]=1
Reactant: O=CCCl
Reactant: Cc1cccc(NC(=S)[S-])n1
Agent: CC[NH+](CC)CC
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: Cc1cccc(N2C(=S)SCC2O)n1
Temperature: 2 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
A 50% (by weight) aqueous solution of chloroacetaldehyde (28.4 g) is added, at a maximum temperature of 30° C., to a solution of triethylammonium (6-methylpyrid-2-yl)-dithiocarbamate (51.5 g) in distilled water (225 cc). The reaction is continued for 2 hours at 20°-30° C. The resulting crystals are separated by filtration, washed five times with distilled water (total 125 cc) and dried in air at 20° C. The product obtained (37.0 g; m.p. 127° C.) is dissolved in a mixture of chloroform (600 cc) and diethyl ether (300 cc); the organic solution is washed three times with distilled water (total 450 cc), dried over sodium sulphate, treated with decolorising charcoal (1 g) and evaporated. The crystals obtained (34.0 g; m.p. 128° C.) are dissolved in boiling ethanol (240 cc). After 2 hours cooling at 2° C., the resulting crystals are separated by filtration, washed twice with ice-cold ethanol (total 30 cc) and dried under reduced pressure (0.1 mm.Hg) at 50° C. 4-Hydroxy-3-(6-methylpyrid-2-yl)-thiazolidine-2-thione (28.8 g), melting at 128° C., is thus obtained.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]1(O)[C:23]2[CH:24]=[CH:25][C:26]([O:28][CH2:29][O:30][CH3:31])=[CH:27][C:22]=2[O:21][CH2:20][C:19]1([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:35][CH:34]=1)[CH3:32])(C(C)(C)C)(C)C>C(OCC)(=O)C.[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:23]2[CH:24]=[CH:25][C:26]([O:28][CH2:29][O:30][CH3:31])=[CH:27][C:22]=2[O:21][CH2:20][C:19]1([C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:37][CH:38]=1)[CH3:32]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2(O)C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCO)cc1
Reaction time: 15 h
Yield: 33 %

Procedure:
(3RS,4RS)-4-[9-(t-Butyldimethylsilyloxy)nonynyl]-4-hydroxy-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-2,3-dihydro-4H-benzopyran (340 mg, 0.56 mmol) was dissolved in ethyl acetate (10 ml) and then 10% Pd/C (180 mg) was added dropwise thereto. The reaction solution was stirred for 15 hours under hydrogen atmosphere, filtered and then concentrated. The residue was subjected to column chromatography (n-hexane:ethyl acetate=4:1→1:1) to obtain 90 mg (yield: 33%) of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1([N:7]2[C:11](=[O:12])[C:10]([NH:13][C:14]([C:16]3[C:20]([CH3:21])=[C:19]([C@H:22]4[CH2:27][CH:26]=[C:25]([CH3:28])[CH2:24][O:23]4)[O:18][N:17]=3)=[O:15])=[C:9]([CH3:29])[N:8]2[CH3:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N2C(=O)C(NC(C3C(C)=C([C@@H]4CC=C(C)CO4)ON=3)=O)=C(C)N2C)CCCCC1>CCO.[Pd]>[CH:1]1([N:7]2[C:11](=[O:12])[C:10]([NH:13][C:14]([C:16]3[C:20]([CH3:21])=[C:19]([C@H:22]4[CH2:27][CH2:26][C@@H:25]([CH3:28])[CH2:24][O:23]4)[O:18][N:17]=3)=[O:15])=[C:9]([CH3:29])[N:8]2[CH3:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1=CC[C@H](c2onc(C(=O)Nc3c(C)n(C)n(C4CCCCC4)c3=O)c2C)OC1
Agent: [Pd]
Agent: CC1=CC[C@@H](c2onc(C(=O)Nc3c(C)n(C)n(C4CCCCC4)c3=O)c2C)OC1
Solvent: CCO
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1[C@H]1CC[C@@H](C)CO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (R)—N-(2-cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-methyl-5-(5-methyl-3,6-dihydro-2H-pyran-2-yl)isoxazole-3-carboxamide compound and (S)—N-(2-cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-methyl-5-(5-methyl-3,6-dihydro-2H-pyran-2-yl)isoxazole-3-carboxamide (1:1) (Example 21.2) (35 mg, 0.084 mmol) in EtOH (15 mL) under a flow of nitrogen was added Pd—C (3.59 mg, 0.034 mmol). The reaction mixture was stirred at room temperature under an atmosphere of hydrogen at 0.35 bar for 2 hours. The resulting mixture was filtered through Celite®, washing with Ethanol. The filtrate was concentrated under reduced pressure and passed through a 1 g Biotage Silica-TMT cartridge under gravity. The cartridge was washed with ethanol and the eluent was concentrated under reduced pressure. The crude material was dissolved in DMSO and purified using UV-directed automated reverse phase chromatography over a 9.5 minute gradient of 30-70% MeCN in water (0.1% formic acid). The product fractions were added to EtOAc (30 mL) and washed with saturated aqueous NaHCO3 (30 mL). The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2([C:13]([O:15]CC)=O)[CH2:12][CH2:11][CH2:10]2)[CH:8]=1)([O-:3])=[O:2].[NH3:18]>CO>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2([C:13]([NH2:18])=[O:15])[CH2:10][CH2:11][CH2:12]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: N
Reactant: CCOC(=O)C1(n2cc([N+](=O)[O-])cn2)CCC1
Solvent: CO
Product: NC(=O)C1(n2cc([N+](=O)[O-])cn2)CCC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of ethyl 1-(4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxylate (300 mg) obtained in Step A of Example 127 and 8 M ammonia in methanol (15 mL) was stirred at room temperature for 10 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (260 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5][C:6]1[CH:7]=[C:8]([O:28][C:29]2[C:30]([CH3:35])=[N:31][CH:32]=[CH:33][CH:34]=2)[C:9]([NH:12][C:13]2[S:17][N:16]=[C:15]([C@H:18]3[CH2:22][O:21]C4(CCCCC4)[O:19]3)[N:14]=2)=[N:10][CH:11]=1.[ClH:36]>CCO>[ClH:36].[CH3:1][O:2][CH2:3][CH2:4][S:5][C:6]1[CH:7]=[C:8]([O:28][C:29]2[C:30]([CH3:35])=[N:31][CH:32]=[CH:33][CH:34]=2)[C:9]([NH:12][C:13]2[S:17][N:16]=[C:15]([C@H:18]([OH:19])[CH2:22][OH:21])[N:14]=2)=[N:10][CH:11]=1
Reactant: COCCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2cccnc2C)c1
Agent: Cl
Solvent: CCO
Product: COCCSc1cnc(Nc2nc([C@H](O)CO)ns2)c(Oc2cccnc2C)c1
Temperature: 60 °C
Yield: 65 %

Procedure:
(S)-N-(5-(2-methoxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decane-2-yl)-1,2,4-thiadiazol-5-amine (1.9 g, 3.68 mmol) was dissolved in EtOH (50 mL) and 6M HCl (3 mL) added and heated to 60° C. for 1.5 hours. The reaction was cooled to ambient temperature and partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate, extracted with CH2Cl2, dried, filtered and concentrated. The residue was purified over silica gel (0 to 10% methanol in EtOAc) to afford (S)-1-(5-(5-(2-methoxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol hydrochloride (1.13 g, 2.39 mmol, 65.0% yield) as a white solid after HCl salt formation. Mass Spectrum (apci) m/z=436.1 (M+H−HCl).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7][CH:8]([CH3:10])[CH3:9])=[N:4][CH:3]=1.[C:11]1([CH3:29])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18]2[N:19]([CH:26]=[CH:27][N:28]=2)[CH:20]=[C:21](B(O)O)[CH:22]=1>>[CH:8]([S:7][C:5]1[S:6][C:2]([C:21]2[CH:22]=[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH3:29])[C:18]3[N:19]([CH:26]=[CH:27][N:28]=3)[CH:20]=2)=[CH:3][N:4]=1)([CH3:10])[CH3:9]
Reactant: CC(C)Sc1ncc(Br)s1
Reactant: Cc1ccccc1-c1cc(B(O)O)cn2ccnc12
Product: Cc1ccccc1-c1cc(-c2cnc(SC(C)C)s2)cn2ccnc12

Procedure:
Prepared using the procedure describe for Example 34, step 4 from 5-bromo-2-(isopropylthio)thiazole and 8-o-tolylimidazo[1,2-a]pyridin-6-ylboronic acid. LCMS (Conditions C): Tr 2.96 min.; (M+H)+: 366.3.
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.[CH:12]1([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2B(O)O)[CH2:14][CH2:13]1>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:16][CH2:15][CH:12]3[CH2:13][CH2:14]3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: OB(O)c1ccccc1OCC1CC1
Reactant: Clc1nc2c(Br)cccn2n1
Product: Clc1nc2c(-c3ccccc3OCC3CC3)cccn2n1

Procedure:
2-Chloro-8-(2-cyclopropylmethoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 2-cyclopropylmethoxyphenylboronic acid in a manner analogous to Example 2c (0.47 g, 73%). MS=300 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]3[O:21][C:22]([NH:25][CH:26]([CH3:28])[CH3:27])=[N:23][N:24]=3)[CH:18]=2)[N:13](S(C2C=CC(C)=CC=2)(=O)=O)[CH:12]=1)[C:5]([NH2:7])=[O:6].[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]3[O:21][C:22]([NH:25][CH:26]([CH3:28])[CH3:27])=[N:23][N:24]=3)[CH:18]=2)[NH:13][CH:12]=1)[C:5]([NH2:7])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(C(N)=O)cc3F)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Nc1nnc(-c2ccc3[nH]cc(-c4ccc(C(N)=O)cc4F)c3c2)o1
Temperature: 90 °C
Yield: 45.7 %

Procedure:
To a solution of 3-fluoro-4-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)benzamide (200 mg, 0.375 mmol) in 1,4-dioxane (3.75 mL) was added aq. NaOH (7 M, 3.75 mL) and the reaction was heated at 90° C. for 1 h. The reaction was then quenched with water to get a precipitate. The precipitate was filtered and washed with water (2×100 mL) and dried. The crude product was purified with preparative HPLC (eluting with 20-80% ACN in water with 0.1% TFA in each solvent) to give 3-fluoro-4-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1H-indol-3-yl)benzamide (65 mg, 46%). MS (ESI, pos. ion) m/z: 380.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.07 (brs, 2H), 7.74-7.83 (m, 4H), 7.51-7.69 (m, 4H), 3.65-3.75 (m, 1H), 1.19 (d, 6H, J=6.6 Hz).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.O[CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH3:45])[CH:30]=1>CCOCC.CCCCCC.CCOCC.C(#N)C>[I:25][CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH3:45])[CH:30]=1
Reactant: COC(=O)c1ccc(CO)cc1-c1ccccc1C
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Solvent: CCCCCC
Product: COC(=O)c1ccc(CI)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
Triphenylphosphine (5.16 g), and imidazole (1.34 g) were dissolved in 3:1 ether:acetonitrile (80 mL), and the reaction was cooled to 0° C. Iodine (5.0 g) was added with vigorous stirring, and the reaction was warmed to ambient temperature. After 1 h, the reaction was recooled to 0° C. and 4-hydroxymethyl-2-(2-methylphenyl)benzoic acid, methyl ester (example 1178C, 4.6 g) was added as a solution in ether (20 mL). After 4 h at ambient temperature, the reaction was diluted with hexane/ether (1:1, 200 mL) and filtered. The filtrate was washed with a dilute solution of Na2SO3 until colorless, then with water (2×50 mL). The organic extracts were washed with brine (20 mL), dried (MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography eluting with 10% EtOAc/hexane to give a light yellow oil (4.7 g) which slowly crystalizes in the freezer.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][C:9](/[CH:11]=[CH:12]/[C:13]3[N:14]([CH3:18])[CH:15]=[CH:16][N:17]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]([NH:33][C:34]([NH:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[O:35])[CH:30]=[CH:31][CH:32]=2)O1>>[CH3:18][N:14]1[CH:15]=[CH:16][N:17]=[C:13]1/[CH:12]=[CH:11]/[C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:31]3[CH:30]=[C:29]([NH:33][C:34]([NH:36][CH2:37][C:38]([F:39])([F:40])[F:41])=[O:35])[CH:28]=[CH:27][CH:32]=3)=[CH:3][N:4]=[C:5]2[CH:10]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)NCC(F)(F)F)c2)OC1(C)C
Reactant: Cn1ccnc1/C=C/c1ccn2c(I)cnc2c1
Product: Cn1ccnc1/C=C/c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1

Procedure:
1-(3-{7-[(E)-2-(1-Methyl-1H-imidazol-2-yl)-vinyl]imidazo[1,2-a]pyridin-3-yl}-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea (86 mg) was prepared according to Procedure B3d using 3-Iodo-7-[(E)-2-(1-methyl-1H-imidazol-2-yl)-vinyl]imidazo[1,2-a]pyridine (170 mg, 0.49 mmol) and 1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea. 1H NMR (400 MHz, Me-d3-OD): 8.74 (1H, d), 8.01 (3H, d), 7.77-7.66 (2H, m), 7.64-7.50 (4H, m), 7.45-7.32 (2H, m), 4.04 (3H, s), 4.01-3.89 (2H, m). MS: [M+H]+441
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:8]=1[OH:20].[OH-].[Na+].S(=O)(=O)(O)O>[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC.O.C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:8]=1[O:20][CH2:2][CH2:3][CH2:4][OH:5]
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: OCCCBr
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 60 °C
Reaction time: 20 h
Yield: 91.5 %

Procedure:
To a mixture of 0.72 g of 3-bromopropanol, 1.0 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 5.0 g of toluene, 0.10 g of trioctylmethylammonium chloride and 5.0 g of water was added 0.77 g of a 27% aqueous sodium hydroxide solution. The mixture was heated to 60° C. and stirred for 20 hours. The reaction mixture was then cooled to 20° C. After 2.0 g of a 20% aqueous sulfuric acid solution was added thereto, the mixture was stirred and then separated. The obtained organic layer was washed with 5.0 g of water and concentrated under reduced pressure to give 1.1 g of 3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)-1-propyl alcohol (purity: 85%, yield: 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C([S:16][C:17]#[N:18])C.BrBr.[OH-].[Na+]>C(O)(=O)C>[NH2:18][C:17]1[S:16][C:7]2[CH:6]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CCSC#N
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc2nc(N)sc2c1
Temperature: 10 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
Ethyl 4-aminophenylacetate (18 g) was dissolved in acetic acid (120 ml) and ethyl thiocyanate (29.3 g) was added thereto. Under ice cooling, bromine (6.2 ml) was added dropwise thereinto over 45 minutes while maintaining the reaction temperature at about 10° C. After the completion of the addition, the resultant mixture was stirred at room temperature for 1.5 hr and then at 80° C. for about 2 hr until the reaction was completed. Then the reaction solution was poured into ice water, basified with an 8 N aqueous solution of sodium hydroxide, extracted with chloroform, washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (22.23 g) as orange crystals (yield: 93.66%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][CH:6]=1.[CH3:16]I.[NH4+].[Cl-]>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:9][CH:10]=1)[CH3:16]
Reactant: CI
Reactant: COC(=O)Cc1ccc(C(C)(C)C)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of methyl-2-(4-tert-butylphenyl)acetate (1 g, 4.85 mmol) in abs. THF (30 ml) was mixed with a 1 M solution of bis-(trimethylsilyl)lithium amide in THF (5.33 ml, 5.33 mmol) at a temperature of −70° C. within 15 min. The reaction was highly exothermic. The mixture was kept for 20 min at −70° C. and at this temperature methyliodide (0.452 ml, 1.03 g, 7.26 mmol) was added within 5 min. Within 16 h the mixture was heated to RT. For working up, the reaction mixture was mixed with sat. NH4Cl solution (30 ml). There were formed two phases and, as a solid, ammonium chloride which was separated off by filtration and washing with THF (2×8 ml). The filtrate was mixed with DCM (70 ml) and the phases were separated. The aqueous phase was extracted with DCM (2×20 ml). The organic phases were combined, dried and concentrated. There remained a colourless oil (1.08 g) which was purified by chromatography [silica gel 60 (50 g); cyclohexane (800 ml), EtOAc/cyclohexane 1:30 (600 ml)]. 2-(4-Tert-butylphenyl)propionic acid methyl ester was obtained as a colourless oil in a yield of 89% (946 mg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:6][CH2:7][C@@H:8]1[CH2:12][CH2:11]CN1CC.C(=O)C>>[N:1]1([CH2:11][CH2:12][CH2:8][CH2:7][NH2:6])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCN1CCC[C@H]1CN
Reactant: c1c[nH]cn1
Agent: CC=O
Product: NCCCCn1ccnc1

Procedure:
By using imidazole (2.00 g) as a starting material, the title compound (0.37 g) was obtained in the same manners as those of Reference Example 63, (1) and Reference Example 9, (2).