Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][Si:10]([CH3:60])([CH3:59])[CH2:11][CH2:12][O:13][CH2:14][N:15]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[C:16]1[N:21]2[N:22]=[CH:23][C:24]([C:25]3[CH:26]=[N:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:29][CH:30]=3)=[C:20]2[N:19]=[C:18]([O:37][CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)[CH:17]=1>CC#N>[CH3:58][Si:55]([CH3:57])([CH3:56])[CH2:54][CH2:53][O:52][CH2:51][N:15]([CH2:14][O:13][CH2:12][CH2:11][Si:10]([CH3:9])([CH3:59])[CH3:60])[C:16]1[N:21]2[N:22]=[CH:23][C:24]([C:25]3[CH:26]=[N:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:29][CH:30]=3)=[C:20]2[N:19]=[C:18]([O:37][CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)[C:17]=1[Br:8]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Oc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NBS (246 mg, 1.38 mmoL) was added to a solution of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)piperidine-1-carboxylate (1022 mg, 1.38 mmoL) in CH3CN (15 mL). After stirring at room temperature for 30 min, the mixture was concentrated in vacuo. Purification by column chromatography afforded tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)piperidine-1-carboxylate: LCMS tR=3.59 Min (5 min run, UV254nm). Mass calculated for, M+ 824.3, observed LC/MS m/z 825.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[S:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:28]OC(OC)N(C)C.Cl.[CH3:37][O:38][NH2:39].[OH-].[Na+]>O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:27])[F:26])[S:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:20]/[CH:28]=[N:39]/[O:38][CH3:37])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NSC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Reactant: COC(OC)N(C)C
Reactant: CON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CO/N=C/NC(=O)c1ccc(C2=NSC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-2-methyl-benzamide (200 mg) and N,N-Dimethylformamide dimethylacetal (4 mL) was refluxed under argon for one hour then the solution was concentrated in vacuo. The residue was dissolved in 1,4-dioxane (2 mL) and a solution of O-methylhydroxylamine hydrochloride (2.8 eq.) and sodium hydroxide (6 eq.) in water (1.6 mL) and acetic acid (1.6 mL) was added. The solution was stirred at rt for 10 minutes. It was then quenched by addition of water and extracted with methyl tert-butyl ether. The combined organic extracts were washed with brine, dried over magnesium sulfate and evaporated. Flash Chromatography eluting with Cyclohexane:EtOAc afforded 243 mg of the title compound.
Reaction SMILES: N1CC[CH2:3][C:2]1=[O:6].[OH-:7].[K+].[CH2:9]([O:11][C:12](=[O:15])[CH2:13]Cl)[CH3:10].O>CS(C)=O>[C:12]([CH2:13][O:7][C:2](=[O:6])[CH3:3])([O:11][CH2:9][CH3:10])=[O:15]
Reactant: [OH-]
Reactant: O=C1CCCN1
Reactant: CCOC(=O)CCl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)COC(C)=O

Procedure:
Use is made of 25.5 g (0.3 mol) of 2-pyrrolidone, 50.4 g (0.9 mol) of potassium hydroxide in 200 ml of dimethylsulphoxide and 115 g (0.94 mol) of ethylchloroacetate. After keeping the reaction mass of room temperature, it is added with 600 ml of water and extracted 3 times with portions of 100 ml of dichoroethane. The combined extracts are evaporated, the residue is subjected to fractionation to give 46.9 g (68%) of 2-oxo-1-pyrrolidinyl)acetic acid carboethoxymethyl ester, b.p. 197°-200° C. (10 mm Hg), nD20 =1.4703.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=1.[NH:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[CH2:39][CH2:40][OH:41]>>[OH:41][CH2:40][CH2:39][C:31]1[N:30]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][CH2:17][N:16]([C:19]([CH3:22])([CH3:23])[CH2:20][OH:21])[CH2:15][CH2:14]4)[N:8]3[CH3:11])=[C:4]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:3]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=1
Reactant: Cn1c(CN2CCN(C(C)(C)CO)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: OCCc1nc2ccccc2[nH]1
Product: Cn1c(CN2CCN(C(C)(C)CO)CC2)nc2c(N3CCOCC3)nc(-n3c(CCO)nc4ccccc43)nc21

Procedure:
Following General Procedure I for Buchwald coupling, 2-(4-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-1-yl)-2-methylpropan-1-ol and 2-(1H-benzo[d]imidazol-2-yl)ethanol were reacted to give 427. LCMS m/z: 550.3 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](Cl)(=O)C(Cl)=O>CO>[CH3:14][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Product: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
Heat a solution of 4-fluoro-3-nitro-benzoic acid (5.00 g, 27.0 mmol, Sigma Chemical Co.) in methanol (135 mL, 0.2M) at reflux and slowly add oxalyl chloride (6.86 g, 54.0 mmol, Aldrich Chemical Co.) through reflux condenser. Stir for 2 h at reflux. Concentrate reaction mixture in vacuo. The title compound solidifies upon standing (5.30 g, 26.6 mmol, 99%): 19F NMR (acetone-d6, 400 MHz) δ-121.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.O.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([OH:29])(=[O:28])=O)=[CH:22][CH:21]=1.[CH2:31]=[C:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C(O)(C)C>[C:20]1([CH3:30])[CH:21]=[CH:22][C:23]([S:26]([O:10][C@@:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([C@H:11]([N:35]2[CH2:36][CH2:37][C:32](=[CH2:31])[CH2:33][CH2:34]2)[CH3:12])[CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)(=[O:28])=[O:29])=[CH:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: C=C1CCNCC1
Solvent: O
Solvent: CC(C)O
Product: C=C1CCN([C@H](C)[C@@](Cn2cncn2)(OS(=O)(=O)c2ccc(C)cc2)c2ccc(F)cc2F)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
There was dissolved 17-59 g (70 mmol) of (2R, 3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane in 113 g of an aqueous solution of 4-methylenepiperidine (content: 61%) and the obtained solution was refluxed with heating at 90° C. for 21 hours. After the reaction, an excess of 4-methylenepiperidine was removed under reduced pressure, and the residue was dissolved in 140 ml of isopropyl alcohol and thereto was added 13.32 g (70 mmol) of p-toluenesulfonic acid monohydrate dissolved in 50 ml of isopropyl alcohol. The obtained mixture was allowed to stand for 1 hour at room temperature and overnight in a refrigerator, and then the precipitated crystal was separated by filtration and washed with 50 ml of isopropyl alcohol and dried to obtain 32.20 g of (2R, 3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidino)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol p-toluenesulfonate in a form of a crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[NH2:33][CH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:33][CH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35]1)=[O:31]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3c2cc(OC)c(OC)c3OC)cc1OC
Reactant: NC1CCc2ccccc21
Product: COc1ccc(CC2c3cc(OC)c(OC)c(OC)c3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-indane
Reaction SMILES: C1(C2C=C(C3CC3)C=CC=2N2CCN(C(C3C=NC(F)=CC=3C)=O)CC2)CC1.COC1C=CC(CN)=CC=1.Cl[CH2:40][CH2:41][CH2:42][S:43](Cl)(=[O:45])=[O:44].[NH2:47][C:48]1[N:53]=[CH:52][C:51]([C:54]([N:56]2[CH2:61][CH2:60][N:59]([C:62]3[CH:67]=[CH:66][C:65]([CH:68]4[CH2:70][CH2:69]4)=[CH:64][C:63]=3[CH:71]3[CH2:73][CH2:72]3)[CH2:58][CH2:57]2)=[O:55])=[C:50]([CH3:74])[CH:49]=1>>[CH:71]1([C:63]2[CH:64]=[C:65]([CH:68]3[CH2:70][CH2:69]3)[CH:66]=[CH:67][C:62]=2[N:59]2[CH2:58][CH2:57][N:56]([C:54]([C:51]3[CH:52]=[N:53][C:48]([N:47]4[CH2:40][CH2:41][CH2:42][S:43]4(=[O:45])=[O:44])=[CH:49][C:50]=3[CH3:74])=[O:55])[CH2:61][CH2:60]2)[CH2:72][CH2:73]1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Cc1cc(N)ncc1C(=O)N1CCN(c2ccc(C3CC3)cc2C2CC2)CC1
Agent: COc1ccc(CN)cc1
Agent: Cc1cc(F)ncc1C(=O)N1CCN(c2ccc(C3CC3)cc2C2CC2)CC1
Product: Cc1cc(N2CCCS2(=O)=O)ncc1C(=O)N1CCN(c2ccc(C3CC3)cc2C2CC2)CC1

Procedure:
Using [4-(2,4-dicyclopropylphenyl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (480 mg) described in Preparation Example 179, 4-methoxybenzylamine (2 mL) and 3-chloropropane-1-sulfonyl chloride (0.31 mL) and by the reaction and treatment in the same manner as in Example 229, the title compound (450 mg) was obtained via (6-amino-4-methylpyridin-3-yl)[4-(2,4-dicyclopropylphenyl)piperazin-1-yl]methanone.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:7]([Li])CCC.[N+:12]([C:15]1C=[CH:19][CH:18]=[CH:17][C:16]=1C=CC(=O)C)([O-:14])=[O:13].O>[I-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C(OCC)C>[CH3:7][C:3](=[CH:2][CH3:1])[CH:4]=[CH:5][C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:12]([O-:14])=[O:13]
Reactant: [Li]CCCC
Reactant: CCCCCC
Reactant: CC(=O)C=Cc1ccccc1[N+](=O)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: CCOCC
Solvent: O
Product: CC=C(C)C=Cc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 42 %

Procedure:
20.3 g of ethyltriphenylphosphonium iodide was suspended in 160 ml of diethyl ether. Thereto was dropwise added 29.4 ml of 1.5 M n-butyllithium hexane solution, in 2 minutes with stirring at 0° C. Then, the mixture was stirred at 20° C. for 1 hour. To the resulting mixture being maintained at 10°-15° C. was dropwise added a solution of 8.4 g of 4-(2-nitrophenyl)-3-buten-2-one dissolved in 40 ml of diethyl ether, in 30 minutes. The resulting mixture was stirred at 20° C. for 3 hours. Thereto was added 100 ml of water. The organic layer was separated. The aqueous layer was extracted with 100 ml of diethyl ether, and the extract was combined with the previously separated organic layer. The combined solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: n-hexane/ethyl acetate=5/1) to obtain 3.8 g (yield: 42%) of 1-(3-methyl-1,3-pentadienyl)-2-nitrobenzene as a light yellow oily material.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:9][C:10]1[C:11]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])=[N:12][C:13]([Cl:17])=[N:14][C:15]=1[CH3:16]>CN(C)C=O>[ClH:17].[CH3:9][C:10]1[C:11]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])=[N:12][C:13]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[CH3:1])=[N:14][C:15]=1[CH3:16]
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Reactant: Cc1ccccc1N
Solvent: CN(C)C=O
Product: Cc1ccccc1Nc1nc(C)c(C)c(N2CCc3ccccc3C2C)n1
Product: Cl
Yield: 35.8 %

Procedure:
After 2-methylaniline(1.0 ml, 9.6 mmol) was added to a mixture solution of 5,6-Dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(1.34 g, 4.6 mmol) and dimethylformamide(5 ml), 0.65 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N:7]1([C:12]2[C:13]3[NH:20][CH:19]=C(C(O)=O)[C:14]=3[N:15]=[CH:16][N:17]=2)[CH:11]=[CH:10][CH:9]=[N:8]1>C(Cl)Cl.CN(C=O)C>[N:7]1([C:12]2[C:13]3[NH:20][CH:19]=[C:1]([C:2]([Cl:4])=[O:3])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH:11]=[CH:10][CH:9]=[N:8]1
Reactant: O=C(O)c1c[nH]c2c(-n3cccn3)ncnc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1c[nH]c2c(-n3cccn3)ncnc12
Reaction time: 14 h
Yield: 1042.6 %

Procedure:
Oxalyl chloride (4.5 mL, 51 mmol) was added to a solution of diazaindole carboxylic acid 50 (1.08 g, 4.7 mmol) in CH2Cl2 (8 mL) and the reaction mixture was stirred 14 h. Catalytic DMF (3 drops) was added to the reaction mixture and after 3 h the reaction was quenched with MeOH. The crude reaction mixture was concentrated to dryness to yield 51 (1.21 g, 49 mmol, 96%) as a tan solid with was used without further purification. 1H NMR: (500 MHz, DMSO-d6) δ 12.45 (br s, 1H), 8.87 (s, 1H), 8.87 (d, J=2.6 Hz, 1H), 8.32 (d, J=3.3 Hz, 1H), 8.14 (d, J=1.5 Hz, 1H), 6.77 (dd, J=2.6, 1.5 Hz, 1H); Methyl ester (obtained by stirring 51 in MeOH): LC/MS: (ES+) m/z (M+H)+=244; HPLC Rt=0.95 min., column 0, conditions B.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH3:15].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30](Cl)=[O:31].BrC1C=C(C=C(C(F)(F)F)C=1)C(O)=O>C1COCC1.S(Cl)(Cl)=O>[Br:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30]([N:14]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:15])=[O:31]
Reactant: O=C(Cl)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CN(C(=O)c1cc(Br)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine (300 mg, 1.37 mmol, prepared according to DE10008042) in THF (3 mL) was added dropwise lithium bis(trimethylsilyl)amide (1M solution in THF, 1.44 mL, 1.44 mmol) at −78° C. The reaction mixture was stirred for 10 minutes at −78° C. A solution of 3-bromo-5-trifluoromethyl-benzoyl chloride (prepared by stirring 3-bromo-5-(trifluoromethyl)benzoic acid (406 mg, 1.51 mmol, CAS RN 328-67-6) in thionylchloride (3 mL) at 100° C. for 1 hour. The reaction mixture was evaporated and the residue was dissolved in 5 mL toluene and concentrated under vacuum. This procedure was repeated three times to completely remove remainder of thionylchloride) in THF (3 mL) was added at −78° C. The reaction mixture was stirred for 1 hour at this temperature and then poured on 30 mL H2O and 30 mL EtOAc. The layers were separated and the aqueous layer extracted a second time with 30 mL EtOAc. The combined organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Yellow solid (265 mg, 41%). MS (TurboSpray): m/z=470.991 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH:12][C:19](=[O:22])[CH2:20][CH3:21])=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: Cc1nc(-c2sc(N)nc2-c2ccccc2)no1
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1nc(-c2ccccc2)c(-c2noc(C)n2)s1

Procedure:
Prepared from 5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-ylamine and propionyl chloride.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[C:23]([OH:25])=O)=O)(C)(C)C.C(N1CC[C@H](N)C1)C1C=CC=CC=1>>[NH3:8].[CH2:19]1[CH:18]2[C:23](=[O:25])[N:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[N:10]=[C:9]3[N:17]2[CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)n1c(N2CCCC[C@H]2C(=O)O)nc2ccccc21
Agent: N[C@H]1CCN(Cc2ccccc2)C1
Product: N
Product: O=C1C2CCCCN2c2nc3ccccc3n21

Procedure:
The title compound was prepared by a similar method to Example 1 from (2S)-1-[1-(tert-butoxycarbonyl)-1H-1,3-benzimidazol-2-yl]-2-piperidinecarboxylic acid [see Preparation 48] and (3S)-1-benzylpyrrolidin-3-ylamine. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 70:30 changing to 50:50, by volume, hexane:ethyl acetate followed by 90:10:1, dichloromethane:methanol:0.88 ammonia to afford 1,3,4,12a-tetrahydropyrido[1′,2′:3,4]imidazo[1,2-a][1,3]benzimidazol-12(2H)-one as a white solid.
Reaction SMILES: [CH:1]12[N:9]([C:10]3[N:15]=[C:14]([N:16]4[CH:21]5[CH2:22][O:23][CH2:24][CH:17]4[CH2:18][O:19][CH2:20]5)[N:13]=[C:12]([C:25]4[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=4)[N:11]=3)[CH:5]([CH2:6][O:7][CH2:8]1)[CH2:4][O:3][CH2:2]2.CCN(CC)CC.ClC(Cl)(O[C:43](=[O:49])OC(Cl)(Cl)Cl)Cl.[CH3:51][N:52]1[CH2:57][CH2:56][N:55]([C:58]2[CH:64]=[CH:63][C:61]([NH2:62])=[CH:60][CH:59]=2)[CH2:54][CH2:53]1>C(Cl)Cl>[CH:5]12[N:9]([C:10]3[N:15]=[C:14]([N:16]4[CH:17]5[CH2:24][O:23][CH2:22][CH:21]4[CH2:20][O:19][CH2:18]5)[N:13]=[C:12]([C:25]4[CH:31]=[CH:30][C:28]([NH:29][C:43]([NH:62][C:61]5[CH:60]=[CH:59][C:58]([N:55]6[CH2:54][CH2:53][N:52]([CH3:51])[CH2:57][CH2:56]6)=[CH:64][CH:63]=5)=[O:49])=[CH:27][CH:26]=4)[N:11]=3)[CH:1]([CH2:8][O:7][CH2:6]1)[CH2:2][O:3][CH2:4]2
Reactant: Nc1ccc(-c2nc(N3C4COCC3COC4)nc(N3C4COCC3COC4)n2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(NC(=O)Nc3ccc(-c4nc(N5C6COCC5COC6)nc(N5C6COCC5COC6)n4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-(4,6-di(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl)aniline (120 mg, 0.281 mmol) in CH2Cl2 was added Et3N (0.237 mL, 1.69 mmol) and triphosgene (42 mg, 0.14 mmol). The mixture was stirred at room temperature for 15 minutes and 4-(4-methylpiperazin-1-yl)aniline (107 mg, 0.56 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was removed, and the residue was subjected to HPLC separation to give the title compound (1TFA salt) MS (ESI) m/z 644.3306.
Reaction SMILES: [N:1]([C:4]1[CH:8]([O:9][CH2:10][CH3:11])[O:7][C:6](=[O:12])[CH:5]=1)=[N+]=[N-].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:26]1([P:19](=[N:1][C:4]2[CH:8]([O:9][CH2:10][CH3:11])[O:7][C:6](=[O:12])[CH:5]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC1OC(=O)C=C1N=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC1OC(=O)C=C1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 65 °C
Yield: 44.6 %

Procedure:
A solution of 4-azido-5-ethoxy-5H-furan-2-one (0.17 g, 1.0 mmol) and triphenylphosphine (0.26 g, 1.0 mmol) in toluene (5 mL) at room temperature under nitrogen was stirred for 1 h, then heated at 60-70° C. for 8 h. The reaction was cooled, was diluted with ethyl acetate, was washed with sodium bisulfate, sodium bicarbonate and brine, was dried over sodium sulfate and was evaporated. Purification by flash chromatography (SiO2) eluted with 1:1 ethyl acetate:hexanes afforded 4-[(triphenylphosphoranylidene)amino]-5-ethoxy-5H-furan-2-one (0.18 g, 45% yield) as an off-white solid. 1H-NMR (500 MHz, CDCl3) δ 7.73 (m, 6H), 7.65 (m, 3H), 7.55• (m, 6H), 5.58 (s, 1H), 4.33 (s, 1H), 3.81 (m, 1H), 3.64 (s, 1H), 1.27 (t, J=7.1 Hz, 3H) ppm. MS (ES+) m/e=404 (M+H).
Reaction SMILES: NC(CCS(OC1C=CC=CC=1)(=O)=O)C(NC1C=CC=CC=1)=O.[N+:24]([C:27]1[CH:28]=[C:29]([S:34](Cl)(=[O:36])=[O:35])[CH:30]=[CH:31][C:32]=1[Cl:33])([O-:26])=[O:25].[C:38]1([OH:44])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[N+:24]([C:27]1[CH:28]=[C:29]([S:34]([O:44][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:35])=[O:36])[CH:30]=[CH:31][C:32]=1[Cl:33])([O-:26])=[O:25]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: NC(CCS(=O)(=O)Oc1ccccc1)C(=O)Nc1ccccc1
Product: O=[N+]([O-])c1cc(S(=O)(=O)Oc2ccccc2)ccc1Cl

Procedure:
Thus, for example, 2-amino-4-phenoxysulfonyl-butyranilide can be obtained by reacting 3-nitro-4-chloro-benzene-sulfonic acid-chloride with phenol to yield 2-nitro-4-phenoxysulfonylchloro-benzene, reacting this product with ammonia to give 2-nitro-4-phenoxy-sulfonyl-aniline, acylating this compound with butyryl-chloride to form 2-nitro-4-phenoxysulfonyl-butyranilide, and by subsequently hydrogenating said product catalytically.
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:19][CH:20]1[CH2:25][N:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=2[O:21]1.O>CN(C)C=O>[C:1]1([N:7]2[C:11]3([CH2:12][CH2:13][N:14]([C:20]4([CH3:19])[CH2:25][N:24]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:23]5[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=5[O:21]4)[CH2:15][CH2:16]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCC1CN(c2ccccc2)c2ccccc2O1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Solvent: CN(C)C=O
Solvent: O
Product: CC1(N2CCC3(CC2)C(=O)NCN3c2ccccc2)CN(c2ccccc2)c2ccccc2O1
Temperature: 90 °C
Yield: 38.5 %

Procedure:
1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one (2.03 g; 8.8 mmol) is added to a stirred solution of 2-chloromethyl-4-phenyl-2,3-dihydro-4H-1,4-benzoxazine (1.29 g; 4 mmol) in dimethylformamide (20 ml). The reacting mixture is heated at 90° C. for 8 hours. After cooling, water (100 ml) is added and the product is extracted twice with ethyl acetate (80 ml). The organic layer is washed twice with water (30 ml) and dried over anhydrous sodium sulphate. The solid residue, obtained after evaporation of the solvent under reduced pressure, is purified by flash column chromatography on silica gel by using hexane/acetone=9/1 as eluant, thus obtaining 0.7 g of pure 2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-phenyl-2,3-dihydro-4H-1,4-benzoxazine, yield 37%; m.p. 191°-193° C.