Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=[S:2].[C:13]([O:17][C:18]1C=C([CH:22]=[C:23]([F:25])[CH:24]=1)N)([CH3:16])([CH3:15])[CH3:14]>ClCCl.O>[C:13]([O:17][C:18]1[CH:11]=[C:12]([N:8]=[C:1]=[S:2])[CH:22]=[C:23]([F:25])[CH:24]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)Oc1cc(N)cc(F)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)Oc1cc(F)cc(N=C=S)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
1,1′-Thiocarbonyldiimidazole (423 g, 2.37 mol) was dissolved in dichloromethane (3200 ml). The mixture was stirred under N2 atmosphere while a solution of 3-tert-butoxy-5-fluoroaniline (435 g, 2.37 mol) in dichloromethane (800 ml) was added slowly within 2 h. Then the mixture was kept stirring at 20° C. for 16 h. The mixture was diluted with water (3000 ml). The separated dichloromethane phase was washed again with water (3000 ml) before dried with anhydrous Na2SO4 for 2 h. The mixture was filtered and the filtrate was concentrated under vacuum to remove solvent to give 1-tert-butoxy-3-fluoro-5-isothiocyanato-benzene (499 g). 1H-NMR (400 MHz, CDCl3): 6.63-6.68 (m, 3H), 1.37 (s, 9H).
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.Cl.[CH:18]1([C:21]2[C:22]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[N:23][CH:24]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[CH:26]=2)[CH2:20][CH2:19]1>>[CH:18]1([C:21]2[C:22]([N:30]3[CH2:31][CH2:32][N:33]([C:11]([C:10]4[CH:9]=[CH:8][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:16])=[CH:15][CH:14]=4)=[O:13])[CH2:34][CH2:35]3)=[N:23][CH:24]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[CH:26]=2)[CH2:19][CH2:20]1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Agent: Cl
Product: O=C(c1ccc(N2CCCS2(=O)=O)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 69.3 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (241 mg) described in Preparation Example 16 and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine hydrochloride (280 mg) described in Preparation Example 87 and by the reaction and treatment in the same manner as in Example 86, the title compound (323 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH:26](O)([CH3:28])[CH3:27]>ClCC(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:27]=[C:26]([CH3:28])[N:20]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Reactant: CC(C)O
Agent: CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cn(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(Cl)cc2)n1
Reaction time: 72 h
Yield: 67 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (240 mg, 0.78 mmol) and sodium bicarbonate (131 mg, 1.56 mmol) in isopropanol (20 mL), excess chloroacetone (1.5 mL) was added. After heating to reflux, the reaction mixture for 72 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (370 mg) was purified by chromatography (silica gel, hexane/ethyl acetate, 25/75) to give pure 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-methyl-1H-imidazole (160 mg, 67%): mp (DSC) 166° C. Anal Calc'd. for C17H15N2SO2Cl C, 58.87, H, 4.36, N, 8.08 Found: C, 58.78, H, 4.62, N, 7.99.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].Cl.Cl.[NH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]([CH3:50])[CH3:49])=[CH:44][CH:43]=1.C(N(CC)CC)C>>[CH3:49][N:48]([CH3:50])[C:45]1[CH:46]=[CH:47][C:42]([CH2:41][NH:40][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])=[CH:43][CH:44]=1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: CN(C)c1ccc(CN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4ccc(N(C)C)cc4)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and (4-aminomethylphenyl)-dimethylamine dihydrochloride in the presence of two equivalents of triethylamine. Purification was performed using HPLC with a normal phase column. Elution with a mixture of etoxynonafluorobutane and methanol gave the title compound in 37% yield, m.p. 148-150° C. MS [(+)ESI, m/z]: 585 [M+H]+
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[CH2:6][CH2:7][NH2:8].C(O[CH:16](OCC)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)C.Cl>C(O)CCC>[ClH:1].[ClH:1].[N:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH:16]2[C:9]3[C:5](=[CH:4][C:3]([OH:2])=[C:11]([OH:12])[CH:10]=3)[CH2:6][CH2:7][NH:8]2)=[CH:20][CH:21]=1
Reactant: NCCc1ccc(O)c(O)c1
Reactant: CCOC(COc1ccncc1)OCC
Agent: Cl
Solvent: CCCCO
Product: Oc1cc2c(cc1O)C(COc1ccncc1)NCC2
Yield: 215.2 %

Procedure:
A mixture of 3,4-dihydroxyphenethylamine hydrochloride (2.4 g), (4-pyridyl)oxyacetaldehyde diethyl acetal (3.7 g), n-butanol (40 ml) and 1N-hydrochloric acid (20 ml) was refluxed for 15 hours under stirring. After the reaction, n-butanol was distilled off from the reaction mixture under reduced pressure. The residue was dissolved in water, and the solution was washed twice with chloroform and once with ether. The aqueous layer was concentrated, and the oily residue was allowed to stand to give crystals of 1-(4-pyridyl)oxymethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline dihydrochloride (4.7 g). The product was recrystallized from aqueous methanol to give needles, mp 250° to 255°C (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][N:18]=3)=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:27]1[C:36]2[CH:35]=[C:34]3[O:37][CH2:38][O:39][C:33]3=[CH:32][C:31]=2[N:30]=[CH:29][N:28]=1>CN(C=O)C.CCOC(C)=O>[O:37]1[C:34]2=[CH:35][C:36]3[C:27]([O:23][C:20]4[CH:21]=[CH:22][C:17]([C:12]5[C:13](=[O:16])[N:14]([CH3:15])[C:9]([NH:8][C:5]6[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=6)=[N:10][CH:11]=5)=[N:18][CH:19]=4)=[N:28][CH:29]=[N:30][C:31]=3[CH:32]=[C:33]2[O:39][CH2:38]1
Reactant: Clc1ncnc2cc3c(cc12)OCO3
Reactant: Cn1c(Nc2ccc(F)cc2)ncc(-c2ccc(O)cn2)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(Nc2ccc(F)cc2)ncc(-c2ccc(Oc3ncnc4cc5c(cc34)OCO5)cn2)c1=O
Temperature: 25 °C
Yield: 113.4 %

Procedure:
2-(4-Fluoro-phenylamino)-5-(5-hydroxy-pyridin-2-yl)-3-methyl-3H-pyrimidin-4-one (2.18 g, 7 mmol) was dissolved in dry DMF (30 ml) to which was added 60% NaH (774 mg, 19.3 mmol). After the mixture was stirred at room temperature for several minutes, a suspension of 8-Chloro-[1,3]dioxolo[4,5-g]quinazoline (2.08 g, 6.7 mmol) in dry DMF (40 ml) was added. The reaction mixture was stirred at room temperature for 1-2 hrs, then diluted with EtOAc and washed with sat'd NaHCO3 (3×), H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo to give crude title compound and further purification to yield product (3.68 g, 90%). 1HNMR (400 MHz, DMSO): 9.18 (s, 1H), 8.60 (m, 3H), 8.45 (d, 1H), 7.84 (s, 1H), 7.82 (m, 1H), 7.55 (m, 3H), 7.21 (m, 2H), 4.15 (s, 2H). LC/MS Calcd for (M+H)+485.4. found 485.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1.C(N(CC)CC)C.FC(F)(F)S(O[Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])(=O)=O.[Cl-].[NH4+]>ClCCl>[CH:31]([Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[O:16][C:13]1[CH2:12][CH2:11][CH:10]([C:3]2[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH2:15][CH:14]=1)([CH3:33])[CH3:32]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: O=C1CCC(c2cc(F)c(F)cc2F)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](OC1=CCC(c2cc(F)c(F)cc2F)CC1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A three-neck flask (1 L) containing a stirred solution of 4-(2,4,5-trifluorophenyl)cyclohexanone (15.8 g) in dichloromethane (160 mL) under a nitrogen atmosphere was cooled to 0° C. and then treated with triethylamine (22 mL) followed by triisopropylsilyl trifluoromethanesulfonate (25.4 g) while maintaining the temperature below 5° C. The solution was stirred at 0° for 30 min and then allowed to rise to ambient temperature over a period of 0.5 h. It was then treated with saturated aqueous ammonium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate and evaporated. The crude product was chromatographed (silica gel, 3% ether in hexane) to yield the title compound.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH:1]([N:4]([CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])=[CH:10][CH:11]=1)([CH3:3])[CH3:2]
Reactant: CC(C)NCc1ccc(C(C)(C)C)cc1
Reactant: ClCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(Cc1ccc(C(C)(C)C)cc1)Cc1cccc2ccccc12
Temperature: 25 °C
Yield: 92 %

Procedure:
2.1 g (0.01 mole) of N-(isopropyl)-4-t-butylbenzylamine was dissolved in 50 ml of dry dimethylformamide, and 1.6 g (0.015 mole) of anhydrous sodium carbonate was added. While the mixture was stirred at room temperature, 1.94 g (0.011 mole) of 1-(chloromethyl)-naphthalene was added. The mixture was reacted at 30° to 40° C. for 6 hours. Ice water was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer was washed with water and then toluene was evaporated. The residue was chromatographed on a silica gel column and eluted with 5% ethyl acetate/n-hexane. The eluate was concentrated to give 3.17 g (yield 92%) of an oily substance.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:14][C:8]=2[C:7]=1[OH:19])=[O:5])C.[NH2:20][CH2:21][C:22]([OH:24])=[O:23]>C[O-].[Na+].CO>[C:15]([C:13]1[S:14][C:8]2[C:7]([OH:19])=[C:6]([C:4]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:5])[N:11]=[CH:10][C:9]=2[N:12]=1)([CH3:16])([CH3:17])[CH3:18]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2nc(C(C)(C)C)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1nc2cnc(C(=O)NCC(=O)O)c(O)c2s1
Temperature: 120 °C
Yield: 8.7 %

Procedure:
A suspension of 2-tert-butyl-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (103 mg, 0.37 mmol) and glycine (247 mg, 3.3 mmol) in 5.9 mL of 0.5 N NaOMe in methanol was heated to 120° C. for 15 min with microwave irradiation using a CEM Discovery microwave reactor. The resultant mixture was concentrated under reduced pressure and the residue was suspended in ethyl acetate and extracted three times with saturated aqueous sodium bicarbonate solution. The combined aqueous fractions were acidified with conc. HCl and extracted twice with ethyl acetate. The organic fractions were dried over anhydrous sodium sulfate and concentrated to a residue. The crude product was purified by reverse phase chromatography on a C-18 column, eluting the desired product with a gradient of 5-80% acetonitrile in water+0.1% formic acid. The lyophilized material fractions provided 10 mg of white solid. MS (ESI−): m/z 308.1 (M−1).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:52]=[CH:51][C:33]([O:34][CH2:35][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]3)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[N:15]2[N:16]=[C:11]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:52]=[CH:51][C:33]([O:34][CH2:35][CH2:36][CH2:37][N:38]5[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[CH2:42][CH2:43]5)=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)[CH:12]=[CH:13][C:14]2=[N:19][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C3CCNCC3)cc2)CC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
DIPEA (2.417 mL, 13.88 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Monatsh. Chem. 1972, 103, 1591) (2.059 g, 9.25 mmol) and tert-butyl 4-[3-[4-(piperidin-4-yl)phenoxy]propyl]piperazine-1-carboxylate (3.92 g, 9.71 mmol) in DMF (30 mL). The resulting solution was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and evaporated to dryness. The resulting solid was triturated with water, then collected by filtration, washed with ether and dried to afford tert-butyl 4-[3-[4-[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]propyl]piperazine-1-carboxylate (4.67 g, 86%) as a solid.
Reaction SMILES: [N:1]1[C:2](=[O:10])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O>N1CCCCC1.C(O)C>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: COc1ccc(C=O)cc1F
Reactant: O=C1C=c2ccccc2=N1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(C=C2C(=O)Nc3ccccc32)cc1F
Temperature: 25 °C

Procedure:
A mixture of 1.33 g of indole-2-one (10 mmol), 1.54 g of 3-fluoro-4-methoxybenzaldehyde (10 mmol) and 3 drops of piperidine are refluxed in 40 ml of ethanol for 5 hours. The desired product precipitates as a yellow crystalline solid during the reaction. After cooling to room temperature, the product is filtered off, washed with ethanol and dried in vacuo. Yield 2.2 g (82%).
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([SH:22])[CH2:20][CH3:21]>CN(C=O)C>[Cl:1][C:2]1[C:7]([S:22][CH2:19][CH2:20][CH3:21])=[CH:6][C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1cc(N)c([N+](=O)[O-])cc1Cl
Temperature: 90 °C
Yield: 98.1 %

Procedure:
To a mixture of 4,5-dichloro-2-nitro-phenylamine (3.50 g, 16.9 mmol), potassium carbonate (4.67 g, 33.8 mmol), and DMF (85 mL) was added 1-propanethiol (2.30 mL, 25.4 mmol). The reaction mixture was heated at 90° C. for 1.5 h, and allowed to cool to 23° C. The mixture was poured into ice/brine (600 mL) and the resulting precipitate was collected to yield the titled compound (4.09 g, 98%). 1H NMR (600 MHz, CDCl3): 8.11 (s, 1H), 6.46 (s, 1H), 6.10 (br s, 2H), 2.91 (t, J=7.3 Hz, 2H), 1.85-1.76 (m, 2H), 1.12 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:20]#[C:21][CH3:22])[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=1.C(=O)([O-])[O-].[K+].[K+].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:42][N+:43]1[CH:48]=[CH:47][C:46]([CH:49]([O:53][CH2:54][CH3:55])[O:50][CH2:51][CH3:52])=[CH:45][CH:44]=1>CN(C)C=O>[Br:1][C:2]1[N:3]=[C:4]([C:20]2[C:21]([CH3:22])=[N:42][N:43]3[CH:48]=[CH:47][C:46]([CH:49]([O:50][CH2:51][CH3:52])[O:53][CH2:54][CH3:55])=[CH:45][C:44]=23)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=1
Reactant: CCOC(OCC)c1cc[n+](N)cc1
Reactant: CC#Cc1nc(Br)c(-c2ncn(COCC[Si](C)(C)C)n2)s1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(OCC)c1ccn2nc(C)c(-c3nc(Br)c(-c4ncn(COCC[Si](C)(C)C)n4)s3)c2c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 70.5 %

Procedure:
To a mixture of 3-(4-bromo-2-prop-1-yn-1-yl-1,3-thiazol-5-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazole [Prepared as described in Example 14 (4.37 g, 10.9 mmol)] and potassium carbonate (3.00 g, 21.7 mmol) in dry N,N-dimethylformamide (20.0 mL) was added a solution of 1-amino-4-(diethoxymethyl)pyridinium 2,4,6-trimethylbenzenesulfonate (6.37 g, 15.6 mmol) in dry N,N-dimethylformamide (20.0 mL) over 10 min. The resulting dark brown solution was stirred at rt for 40 hours. The mixture was added to ˜250 mL of ice water with stirring, then was extracted with EtOAc (100 mL×5) until the aqueous layer turned into a clear solution. The combined EtOAc extracts were washed with water, brine, dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography on silica gel, using EtOAc/hexane (0/100 to 50/50) as an eluant to give a solid product (4.56 g, 70.2%). LCMS: (FA) ES+ 593, 595. 1H NMR (400 MHz, CDCl3) δ: 8.46 (d, J=2.01 Hz, 1H), 8.40-8.42 (d, J=7.28 Hz, 1H), 8.32 (s, 2H), 7.05-7.08 (dd, J=2.01, 7.03 Hz, 1H), 5.57 (s, 2H, 3.68-3.77 (m, 4H), 3.58-3.63 (m, 2H), 2.75 (s, 3H), 1.28-1.32 (m, 6H), 0.95-1.00 (m, 2H), 0.02 (s, 9H)
Reaction SMILES: [Cl:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20]([O:22]CC)=[O:21])[NH:8]2)=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1>CO>[Cl:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20]([OH:22])=[O:21])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccc(Cl)c(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2ccc(Cl)c(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
A mixture of ethyl 6-chloro-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (1.00 g), 4N aqueous sodium hydroxide solution (2.3 mL), tetrahydrofuran (5 mL) and methanol (5 mL) was stirred at 50° C. for 2 hr. The reaction mixture was concentrated and acidified with 10% aqueous citric acid solution. The resulting crystals were filtrated, washed with water, and dried to give the title compound (0.88 g, yield 95%) as colorless crystals. melting point>290° C. (decomposition).
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]3[CH2:23][CH2:22][NH:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3].Br[CH2:32][CH2:33][CH2:34][O:35][CH3:36]>>[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]3[CH2:23][CH2:22][N:21]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:20][C:18]=3[N:19]=2)=[CH:12][CH:13]=1)=[O:6])[CH3:3]
Reactant: COCCCBr
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Agent: Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(CCCOC)C3)cc1

Procedure:
The compound rx was prepared following the general procedure in Example 296, substituting 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride salt for (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride salt and substituting 1-bromo-2-methoxyethane for 1-bromo-3-methoxypropane: LC-MS m/z=469 (M+H).
Reaction SMILES: [C:1]([P:5](C(C)(C)C)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].C([Mg][Cl:19])(C)(C)C.[Mg].C(Cl)(C)(C)C.P(Cl)(Cl)Cl>>[C:1]([P:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[Cl:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Mg]Cl
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Mg]
Solvent: CC(C)(C)Cl
Solvent: ClP(Cl)Cl
Product: CC(C)(C)P(Cl)C(C)(C)C

Procedure:
By way of example, the preparation of tri-tert-butylphosphine is described in Chem. Ber., 100(2), 692-3 (1967). Tertiary butyl magnesium chloride is first prepared from magnesium metal and t-butyl chloride, then this is allowed to react with PCl3 to form di-tert-butylchlorophosphine. This product is then treated with tert-butyl lithium to yield tri-tert-butyl phosphine.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[C:12]2[CH2:13][NH:14][CH2:15][CH2:16][S:17][C:11]=2[CH:10]=[CH:9][CH:8]=1.Cl.C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[C:12]2[CH2:13][N:14]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][CH2:16][S:17][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Clc1cccc2c1CNCCS2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCSc2cccc(Cl)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methanesulphonyl chloride (3.43 g) in dichloromethane (30 ml) was added dropwise at room temperature to a stirred solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (5.2 g, prepared in a similar manner to its hydrochloride, Example 1 above) and triethylamine (3.03 g, 0.03 ml) in dichloromethane (100 ml). The reaction mixture was stirred at room temperature for one hour, washed with water, dried and the solvent was removed by evaporation. Purification of the residue by flash chromatography using dichloromethane as eluent gave 6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from hexane. Yield 6.06 g (m.p. 85°-86° C.).
Reaction SMILES: [N:1]([C:4]1[N:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[C:6]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[N:5]=1)=[C:2]=[O:3].[Br:22][C:23]1[CH:30]=[CH:29][C:26]([NH:27][CH3:28])=[CH:25][CH:24]=1>O1CCOCC1>[F:15][C:12]([F:13])([F:14])[CH2:11][O:10][C:8]1[CH:7]=[C:6]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[N:5]=[C:4]([NH:1][C:2](=[O:3])[N:27]([CH3:28])[C:26]2[CH:29]=[CH:30][C:23]([Br:22])=[CH:24][CH:25]=2)[N:9]=1
Reactant: CNc1ccc(Br)cc1
Reactant: O=C=Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Solvent: C1COCCO1
Product: CN(C(=O)Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
2-Isocyanato-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine (750 mg, 2.4 mmol) was dissolved in anhydrous dioxane (15 mL). To this solution was added 4-bromo-N-methylaniline (440 mg, 2.36 mmol) and the resulting solution was stirred under an N2 atmosphere at room temperature. After ca. 12 h an LCMS analysis of the reaction indicated mostly desired product (91%). The reaction was partitioned between EtOAc and water, the organics separated and the aqueous layer extracted with EtOAc (3×50 mL). Organic extracts were combined, washed with water (2×) and once with brine. The organic layer was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give a yellow oil. The oil was partially purified by column chromatography (silica, hexane/EtOAc) and then recrystallized (EtOAc/cyclohexane) to afford 41 as a white solid (346 mg, 29% yield): m.p. 110-111° C. Anal Calcd for C16H13BrF6N4O3: C, 38.19; H, 2.60; N, 11.13. Found: C, 38.42; H, 2.66; N, 11.20. 1H NMR (300 MHz, CDCl3) δ 9.42 (s, 1H), 7.55 (d, 2H, J=4.5 Hz), 7.26 (d, 2H, J=4.5 Hz), 6.14 (s, 1H), 4.99 (q, 4H, J=4.4 Hz), 3.28 (s, 3H).