Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:13][CH:14]=[C:15]([C:21]([O:23]CC)=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]CC=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[OH:23][C:21]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:13]=[C:1]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]=12
Reactant: CCOC(=O)C(=CNC1=CCCCCCCCCCC1)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(c1O)CCCCCCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 46.0 g of diethyl N-(1-cyclododecenyl)aminomethylenemalonate in 40 ml of Dowtherm® is added to one liter of Dowtherm® at 250° under argon, and the distillate is collected in a Dean-Stark trap. After 0.5 hour the mixture is allowed to cool to room temperature and the solvent is distilled off. The residual solid is triturated with ether to give ethyl 4-hydroxy-5,6,7,8,9,10,11,12-octahydrocyclodeca[b]pyridine-3-carboxylate, m.p. 212°-30°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]>>[Cl:44][C:31]1[CH:32]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:18][CH:17]=2)[CH:34]=[C:29]([Cl:28])[C:30]=1[OH:45]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN2CCCC2)cc1
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(CN2CCCC2)cc1
Yield: 56.1 %

Procedure:
Following general procedure D, 1-(6-bromo-4-((4-(pyrrolidin-1-ylmethyl)phenyl)amino)quinolin-3-yl)ethanone (42.4 mg, 0.10 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (38.4 mg, 0.133 mmol) to afford the desired product (28.4 mg, 56%) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 9.17 (s, 1H), 8.02-7.94 (m, 2H), 7.77 (s, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H), 7.20 (s, 2H), 4.41 (s, 2H), 3.27 (br s, 4H), 2.78 (s, 3H), 2.07 (br s, 4H). ESI MS m/z 506 [C28H25Cl2N3O2+H]+; HPLC 95.1% (AUC), tR=10.81 min.
Reaction SMILES: [Br:1]C1C(C=O)=CC=CN=1.[CH2:10]([OH:13])[CH2:11][OH:12].ClC1C=C(S(NC2[C:35](OCC3C=CC4C(=CC=CC=4)C=3)=[N:34][C:33]3C(=[CH:29][CH:30]=[CH:31][CH:32]=3)N=2)(=O)=O)C=C(Cl)C=1.O>C1(C)C=CC=CC=1>[Br:1][C:33]1[CH:32]=[CH:31][C:30]([CH:29]2[O:13][CH2:10][CH2:11][O:12]2)=[CH:35][N:34]=1
Reactant: O=S(=O)(Nc1nc2ccccc2nc1OCc1ccc2ccccc2c1)c1cc(Cl)cc(Cl)c1
Reactant: O=Cc1cccnc1Br
Reactant: OCCO
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(C2OCCO2)cn1
Yield: 992.8 %

Procedure:
6 Bromo-3-pyridinecarboxaldehyde (1.03 g, 5.54 mmol), ethylene glycol (370 μL, 6.65 mol) and Amberlyst 15 (200 mg) were suspended in toluene (100 mL). The mixture was heated to reflux under a nitrogen atmosphere for 12 hours, during which produced water was removed by use of a Dean-Stark trap. The reaction mixture was filtered and the mother liquid was concentrated. The residue was purified by column chromatography (hexane/ethyl acetate=7/3) to give 2-bromo-5-(1,3-dioxolan-2-yl)pyridine (895 mg, yield: 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]3[CH2:13][CH2:14][CH2:15][CH:16]([C:18]([O:20]C)=[O:19])[CH2:17][C:11]3(N3CCCC3)[O:10][N:9]=2)=[CH:4][CH:3]=1.O>S(=O)(=O)(O)O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH2:15][CH:16]([C:18]([OH:20])=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCCC2C(c3ccc(Cl)cc3)=NOC2(N2CCCC2)C1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C1CCCc2c(-c3ccc(Cl)cc3)noc2C1

Procedure:
5 g of methyl 3-(4-chlorophenyl)-3a,5,6,7,8,8a-hexahydro-8a-pyrrolidino-4H-cyclohept[d]isoxazole-7-carboxylate in 5 ml of concentrated sulfuric acid, 5 ml of acetic acid and ml of water were heated at 120° C. for 5 hours. The separated product was filtered off, washed with water and dried in vacuo to give 3.1 of 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-cyclohept[d]isoxazole-7-carboxylic acid of melting point 215°-217° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:19]([Cl:20])=[CH:18][C:10]3[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[O:13][C:9]=3[CH:8]=2)[N:5]=[C:4]([C:21]#[N:22])[CH:3]=1.[F:23][C:24]([F:29])([F:28])[S:25]([O-])=O.[Na+].S(C1C=CC(C)=CC=1)(O)(=O)=O.CNC.S(Cl)(Cl)=O>C1(C)C=CC=CC=1.O>[NH2:1][C:2]1[N:6]([C:7]2[C:19]([Cl:20])=[CH:18][C:10]3[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[O:13][C:9]=3[CH:8]=2)[N:5]=[C:4]([C:21]#[N:22])[C:3]=1[S:25][C:24]([F:29])([F:28])[F:23]
Reactant: O=S([O-])C(F)(F)F
Reactant: N#Cc1cc(N)n(-c2cc3c(cc2Cl)C(F)(F)C(F)(F)O3)n1
Agent: CNC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: N#Cc1nn(-c2cc3c(cc2Cl)C(F)(F)C(F)(F)O3)c(N)c1SC(F)(F)F
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 23.1 %

Procedure:
To a suspension wherein 5-amino-1-(5-chloro-2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-6-yl)-3-cyanopyrazole (665 mg, 2.00 mmol), sodium trifluoromethanesulfinate (624 mg, 4.00 mmol) and dimethylamine tosylate (1.086 g, 5.00 mmol) are in toluene (5 ml), thionyl chloride (476 mg, 2.00 mmol) was added dropwise under ice cooling over a period of about 10 minutes and stirred at 50 to 60° C. for 10 minutes. After allowing time to cool, the reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to give 200 mg of 5-amino-1-(5-chloro-2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-6-yl)-3-cyano-4-trifluoromethylsulfenylpyrazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18](=[O:21])([O-])[O-].[Na+].[Na+].[CH2:24]1[CH2:28]O[CH2:26][CH2:25]1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:6][N:8]1[C@H:9]2[C@@:24]([CH3:28])([C:24]3[CH:28]=[CH:3][C:1]([C:13]4[CH:12]=[C:11]5[C:16](=[CH:15][CH:14]=4)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:9]=[CH:10]5)=[CH:2][C:25]=3[CH2:26][CH2:10]2)[CH2:25][CH2:26][C:18]1=[O:21]
Reactant: C1CCOC1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(Br)ccc21
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5c(ccn5C(=O)OC(C)(C)C)c4)cc3CC[C@@H]12
Yield: 39 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 1-(t-butoxycarbonyl)-5-bromoindole (193 mg, 0.65 mmol), 0.65 mL of 2M sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (5% methanol/ethyl acetate eluent) to give 113 mg (39%) of the title compound as an amorphous foam. FDMS: m/e=445. α[D]589 =+68.17 (c=0.47, chloroform).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1.[C:17]1(OB(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OCC)(=O)C.O1CCCC1>[C:11]1([C:9]2[NH:10][C:4]3[C:5]([N:8]=2)=[N:6][CH:7]=[C:2]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]=3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)Oc1ccccc1
Reactant: Brc1cnc2nc(-c3ccccc3)[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(-c2cnc3nc(-c4ccccc4)[nH]c3c2)cc1
Temperature: 85 °C
Reaction time: 24 h
Yield: 22.5 %

Procedure:
Under an argon stream, a mixture of 6-bromo-2-phenyl-1H-imidazo[4,5-b]pyridine (Compound of Reference Example 3) (90 mg), phenylboric acid (104 mg), tetrakis(triphenylphosphine)palladium(0) (38 mg), 2 M sodium carbonate (0.82 ml) and tetrahydrofuran (3.3 ml) was stirred at 85° C. for 24 hours. The mixture was distributed into ethyl acetate-tetrahydrofuran (3:1, v/v) and water. The organic layer was washed with water and dried over MgSO4, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-chloroform-hexane (1:1:4, v/v) was concentrated under reduced pressure. The resulting crystals were collected by filtration to obtain 2,6-diphenyl-1H-imidazo[4,5-b]pyridine (20 mg, 22%). The crystals were recrystallized from chloroform-methanol.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]1=[O:13])C.O.[NH2:16][NH2:17]>C(O)C>[CH3:12][C:8]1[C:7](=[O:13])[N:6]([CH2:5][C:4]([NH:16][NH2:17])=[O:3])[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)Cn1cccc(C)c1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cccn(CC(=O)NN)c1=O
Yield: 96 %

Procedure:
As described for example 112a, (3-methyl-2-oxo-2H-pyridin-1-yl)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 72 h. The mixture was concentrated and crystallized from ethanol/diisopropylether and the compound was obtained as a white solid (yield: 96%). MS: m/e=204.4 [M+Na]+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([CH2:11][S:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]2=3)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.Br[CH2:26][CH2:27][CH2:28][CH:29]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[CH2:30][N:31]([CH3:41])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33]>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:48][C:44]1[CH:43]=[C:42]([CH:29]([CH2:28][CH2:27][CH2:26][N:2]2[CH2:7][CH2:6][C:5]3([CH2:11][S:10][C:9]4[CH:12]=[CH:13][CH:14]=[CH:15][C:8]3=4)[CH2:4][CH2:3]2)[CH2:30][N:31]([CH3:41])[S:32]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH:47]=[CH:46][CH:45]=1
Reactant: c1ccc2c(c1)SCC21CCNCC1
Reactant: CN(CC(CCCBr)c1cccc(Cl)c1)S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(CC(CCCN1CCC2(CC1)CSc1ccccc12)c1cccc(Cl)c1)S(=O)(=O)c1ccccc1
Temperature: 52 °C
Reaction time: 48 h
Yield: 42.7 %

Procedure:
Spiro(benzo[b] thiophene-3(2H),4'-piperidine) hydrochloride (16.5 mg, 0.068 mmol) and N,N-diisopropylethylamine (0.036 mL, 27 mg, 0.21 mmol) were added to a solution of N-(5-bromo-2-(3-chlorophenyl)pentyl)-N-methylbenzenesulfonamide (24.6 mg, 0.057 mmol) in 0.30 mL of acetonitrile, and the mixture was heated in an oil bath at 52° C. After 2 days, tetrabutylammonium iodide (5.5 mg, 0.011 mmol) was added and the reaction was continued for an additional 24 h. Without work-up, the reaction mixture was purified by preparative TLC. Elution with 30% ethyl acetate in dichloromethane gave 13.5 mg the title compound. 1NMR (400 MHz, CD3OD): δ 7.74 (d, 2H, J=8 Hz), 7.64 (tt, 1H, J=8, 1 Hz), 7.57 (t, 2H, J=8 Hz), 7.33-7.22 (m, 3H), 7.18 (d, 1H, J=8 Hz), 7.13-7.01 (m, 4H), 3.32-3.25 (m, 3H), 3.11 (dd, 1H, J=13, 8 Hz), 3.00-2.84 (m, 3H), 2.61 (s, 3H), 2.48-2.35 (m, 2H), 2.21 (bq, 2H, J=12 Hz), 1.99 (tt, 2H, J=13, 4 Hz), 1.84-1.75 (m, 3H), 1.67-1.56 (m, 1H), 1.52-1.34 (m, 2H). Mass spectrum (ESI): m/z=555 (M+1).
Reaction SMILES: ClCCC1NC2C=CC=CC=2N=1.C(N)CN.[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][C:18]=1[CH2:26][CH2:27][NH:28][CH2:29][CH2:30][NH2:31].[C:32]([NH:34][C:35](=[N:38][CH3:39])SC)#[N:33]>>[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][C:18]=1[CH2:26][CH2:27][NH:28][CH2:29][CH2:30][NH:31][C:35]([NH:34][C:32]#[N:33])=[N:38][CH3:39]
Reactant: CN=C(NC#N)SC
Reactant: NCCNCCc1nc2ccccc2[nH]1
Agent: ClCCc1nc2ccccc2[nH]1
Solvent: NCCN
Product: CN=C(NC#N)NCCNCCc1nc2ccccc2[nH]1

Procedure:
Reacting 2-(2-chloroethyl)benzimidazole with ethylenediamine by the procedure of Example 34, then reacting the resulting N-[2-(2-benzimidazolyl)ethyl]-ethylenediamine with N-cyano N',S-dimethylisothiourea by the procedure of Example 3(a) give the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([CH:10]([CH2:14][CH3:15])[CH2:11][CH2:12][OH:13])[CH3:9].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl.C(OCC)C>[CH3:16][S:17]([O:13][CH2:12][CH2:11][CH:10]([CH2:14][CH3:15])[CH2:8][CH3:9])(=[O:19])=[O:18]
Reactant: CCC(CC)CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(CC)CCOS(C)(=O)=O
Reaction time: 2 h
Yield: 82.6 %

Procedure:
Triethylamine (2.4 ml, 17 mmol) was added dropwise to a solution of the 3-ethyl-1-pentanol (1.0 g, 8.6 mmol) and methanesulfonyl chloride (0.8 ml, 10 mmol) in dichloromethane (20 ml) while cooling on ice, and the mixture was stirred for 2 hours. After diluting the reaction mixture with diethyl ether, it was washed with water and brine, and the organic layer was dried over anhydrous sodium sulfate prior to distillation under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1.38 g) as a colorless oil.
Reaction SMILES: COC1C=CC(C[N:10]2[CH2:14][C:13]3([CH2:19][CH2:18][CH2:17][C:16]([CH2:29][N:30]4[C:34]5[CH:35]=[C:36]([C:39]#[N:40])[CH:37]=[CH:38][C:33]=5[N:32]=[CH:31]4)([CH2:20][O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:15]3)[O:12][C:11]2=[O:41])=CC=1.C(OCC)(=O)C.[OH-].[Na+]>C(#N)C>[O:41]=[C:11]1[NH:10][CH2:14][C:13]2([CH2:19][CH2:18][CH2:17][C:16]([CH2:29][N:30]3[C:34]4[CH:35]=[C:36]([C:39]#[N:40])[CH:37]=[CH:38][C:33]=4[N:32]=[CH:31]3)([CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:15]2)[O:12]1
Reactant: COc1ccc(CN2CC3(CCCC(COCc4ccccc4)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1ccc2ncn(CC3(COCc4ccccc4)CCCC4(CNC(=O)O4)C3)c2c1
Temperature: 25 °C
Yield: 54 %

Procedure:
To a colorless solution of 1-[(3-{[4-(methyloxy)phenyl]methyl}-2-oxo-7-{[(phenylmethyl)oxy]methyl}-1-oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1H-benzimidazole-6-carbonitrile (1.55 g, 2.81 mmol) in acetonitrile (28.1 mL) was added ceric ammonium nitrate (3.09 g, 5.63 mmol) and the mixture was stirred at room temperature. The reaction was then heated to 60° C. and stirred for 22 h. The reaction was then cooled to RT and the orange suspension was filtered using Buchner vacuum filtration. The solid was rinsed with MeCN (3×20 mL) and the filtrate concentrated to yield a glassy orange oil. Ethyl acetate (75 mL) and 2 N NaOH (50 mL) were then added. The mixture was filtered using Buchner vacuum filtration. The filtrate layers were separated and the aqueous layer was washed with EtOAc (50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The concentrated organic layer was loaded onto florisil and purified using silica gel chromatography CISCO): 1-4% methanol/dichloromethane (25 min), 40 g silica. The product eluted at 11 minutes to yield 1-[(2-oxo-7-{[(phenylmethyl)oxy]methyl}-1-oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1H-benzimidazole-6-carbonitrile as a orange foam (653 mg, 51% yield). MS (m/z) 431.0 (M+H+).
Reaction SMILES: [Mg].Br[C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>O1CCCC1>[O:7]1[C:6]2[CH:10]=[CH:11][C:3]([C:22]3([OH:25])[CH2:23][CH2:24][N:19]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:20][CH2:21]3)=[CH:4][C:5]=2[O:9][CH2:8]1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccc3c(c2)OCO3)CCN(Cc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To 1.46 g of magnesium shavings, which had previously been covered with tetrahydrofuran, was added dropwise a solution of 12.06 g (60 mmol) of 5-bromo-benzo[1,3]dioxol in 30 ml of absolute tetrahydrofuran, followed by 11.35 g (60 mmol) of 1-benzyl-4-piperidone. The reaction mixture was stirred at 50° C. for 1 hour, then poured on to ice and ammonium chloride solution. The 4-benzo[1,3]dioxol-5-yl-1-benzyl-piperidin-4-ol formed was extracted with ethyl acetate and crystallized upon concentration of the solution. There were obtained 10.85 g (58% of theory) of white crystals; m.p.: 144° C.
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][S:13]([C:16]2[N:17]=[CH:18][N:19]([CH3:21])[CH:20]=2)(=[O:15])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(OC([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=2[NH2:44])[CH2:31][CH2:30]1)=O)(C)(C)C.CCO.CC(O)=O>O>[CH3:43][O:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][CH:32]2[CH2:33][CH2:34][NH:29][CH2:30][CH2:31]2)=[C:37]([NH:44][C:2]2[C:3]([NH:12][S:13]([C:16]3[N:17]=[CH:18][N:19]([CH3:21])[CH:20]=3)(=[O:15])=[O:14])=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:38]=1
Reactant: Cn1cnc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)c1
Reactant: COc1ccc(CC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(CC2CCNCC2)c(Nc2nc3ccccc3nc2NS(=O)(=O)c2cn(C)cn2)c1
Temperature: 90 °C
Yield: 34.6 %

Procedure:
N-(3-chloroquinoxalin-2-yl)-1-methyl-1H-imidazole-4-sulfonamide (1 g; 3.1 mmol; 1 eq) and 4-(2-amino-4-methoxy-benzyl)-piperidine-1-carboxylic acid tert-butyl ester (1.1 g; 3.4 mmol; 1.1 eq) are suspended in water (12.5 mL) and EtOH (12.5 mL) then AcOH (2.5 mL) is added. The resulting suspension is heated up to 90° C. for 3 days. Boc deprotection occurs during the reaction. The solvents are evaporated under reduced pressure and the resulting oily brown residue is taken up in water. An excess triethylamine is added until pH=8 to trap the HCl formed during the reaction. The precipitate is filtered off then washed thoroughly with water until neutral. It is dried under vacuum at 40° C. for 2 days, affording 544 mg (35%) of the title compound as a grey solid. 1H NMR (DMSO-d6) δ 9.35 (s, 1H), 8.70 (d, J=2.4 Hz, 1H), 7.69 (s, 1H), 7.50-7.30 (m, 3H), 7.35-6.97 (m, 3H), 6.48 (dd, J=8.3, 2.7 Hz, 1H), 3.89 (s, 2H), 3.78 (s, 3H), 3.63 (s, 3H), 3.45-3.15 (m, 2H), 2.97-2.78 (m, 2H), 2.65-2.53 (m, 2H), 2.05-1.80 (m, 2H), 1.56-1.32 (m, 2H). HPLC (max plot) 89%; Rt 3.08 min. LC/MS: (ES+) 508.1, (ES−) 506.1.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH3:12])=[N:9][C:8]=2[CH:13]=1)([OH:3])=[O:2].[CH3:14][O:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>CC(C)=O>[C:22]1([CH3:25])[CH:21]=[CH:20][C:19]([S:16]([O-:18])(=[O:15])=[O:17])=[CH:24][CH:23]=1.[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH3:12])=[N+:9]([CH3:14])[C:8]=2[CH:13]=1)([OH:3])=[O:2]
Reactant: Cc1nc2cc(C(=O)O)ccc2o1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: Cc1oc2ccc(C(=O)O)cc2[n+]1C
Temperature: 200 °C
Reaction time: 0.17 h
Yield: 50.9 %

Procedure:
5-Carboxy-2-methylbenzoxazole (8.9 g) and methyl-p-toluenesulfonate (11.16 g) were combined and heated to 200° C. with stirring for 10 minutes. The mixture became a brown liquid and mild boiling occurred. The reaction was cooled to room temperature and the liquid solidified. Acetone (50 ml) was added, and with constant heating at reflux, the product was broken up with a spatula. The resulting slurry was heated at reflux for 15 minutes with rapid stirring and the off-white product was collected by filtration. This product was slurried again in refluxing acetone for 30 minutes, filtered, washed with ligroin P950, and dried to yield 9.3 g of 5-carboxy-2,3-dimethylbenzoxazolium p-toluene-sulfonate (Intermediate D).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[CH2:10](Br)[CH:11]=[CH2:12].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O.CCOC(C)=O>[CH2:10]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:11]=[CH2:12]
Reactant: C=CCBr
Reactant: CCNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCN(CC)c1ccccc1
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of ethyl-phenyl-amine (4.15 mL, 33 mmol), allyl bromide (4.3 mL, 1.5 eq.) and K2CO3 (9.1 g, 2.0 eq.) in acetone (50 mL) was heated at reflux for overnight. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and EtOAc (100 m). The separated organic phase was dried over Na2SO4, filtered and concentrated and the product was purified by chromatography (10% EtOAc/hexanes) to give allyl-ethyl-phenyl-amine (5.32 g, 100%).
Reaction SMILES: [C:1]([P:5](Cl)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].O1CC[CH2:13][CH2:12]1.C([Mg]Cl)C.S(=O)(=O)(O)O>[Cu]Br.C1(C)C=CC=CC=1>[C:1]([P:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Agent: [Cu]Br
Agent: CC[Mg]Cl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCP(C(C)(C)C)C(C)(C)C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
In a 300 ml four-necked flask thoroughly purged with nitrogen, 18.1 g (0.1 mol) of di-tert-butylphosphinous chloride, 0.28 g (0.002- mol (corresponding to 2% by mol)) of copper(I) bromide and 60 ml of tetrahydrofuran were placed. To the contents of the flask, 55 ml (0.11 mol) of a tetrahydrofuran solution of ethylmagnesium chloride having a concentration of 2 mol/liter was dropwise added over a period of 1 hour with maintaining the temperature at 25° C. to 30° C. After the dropwise addition was completed, stirring was conducted at the same temperature for 2 hours. After the temperature of the reaction solution was returned to room temperature, disappearance of di-tert-butylphosphinous chloride was confirmed by gas chromatography. Thereafter, 50 ml of toluene and 30 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, followed by further distillation. Then, fractions given by distillation at 92° C. to 95° C. under reduced pressure of 20 Torr were collected. As a result, 15.7 g (purity: 98.0%) of the aimed di-tert-butylethylphosphine was obtained as an oily substance. The yield was 88.2%.
Reaction SMILES: Cl.[NH:2]=[C:3]1[NH:7][C:6](=[NH:8])[CH2:5][S:4]1.[NH:9]=[C:10]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12](=N)[NH:11]1>CO>[NH:9]=[C:10]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12](=[C:5]2[S:4][C:3](=[NH:2])[NH:7][C:6]2=[NH:8])[NH:11]1
Reactant: N=C1CSC(=N)N1
Reactant: N=C1NC(=N)C2=C1CCCC2
Agent: Cl
Solvent: CO
Product: N=C1NC(=N)C(=C2NC(=N)C3=C2CCCC3)S1

Procedure:
A mixture of 6 parts of 2,4-diiminothiazolidine hydrochloride, 6 parts of 4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 100 arts of anhydrous methyl alcohol was stirred and heated at reflux under an atmosphere of nitrogen for approximately 16 hours. The reaction was then cooled and filtered. The solid product collected by filtration was converted to the free base by treatment with a slight excess of a methyl alcohol solution of triethylamine and the product thus obtained was recrystallized frm acetic acid. The resultant acetate salt was treated with dilute ammonium hydroxide and the product isolated to obtain in the free-base form 1-imino-4,5,6,7-tetrahydro-3-(2,4-diimino-5-thiazolidinylidene)isoindoline as a greenish-brown powder melting at 215°-223° C. (dec).