Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=O)[C:3]([NH2:5])=[O:4].[NH2:15][C:16]([NH2:18])=[S:17]>C(O)C>[NH2:18][C:16]1[S:17][C:2]([C:3]([NH2:5])=[O:4])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:15]=1
Reactant: NC(=O)C(Br)C(=O)c1ccc(Cl)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: NC(=O)c1sc(N)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.5 %

Procedure:
To a mixture of 7.35 g (26.58 mmole) of 2-bromo-3-(4-chloro-phenyl)-3-oxo-propionamide and 300 mL of ethanol was added 2.02 g (26.58 mmole) of thiourea. The mixture was stirred at room temperature for 4 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-dichloromethane (1:3, then 3:1, then 1:0). Recrystallization of the residue gave 1.11 g of 2-amino-4-(4-chloro-phenyl)-thiazole-5-carboxylic acid amide (V.18) as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:21])[CH2:16][O:17][CH2:18][CH2:19][OH:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(OCC)C.Cl>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:21])[CH2:16][O:17][CH2:18][CH2:19][O:20][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCC(O)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCCOCC(O)c2ccc(OCc3ccccc3)cc2)cc1
Temperature: -20 °C
Reaction time: 15 h
Yield: 58.8 %

Procedure:
22.7 g of 1-(4-benzyloxyphenyl)-2-(2-hydroxyethoxy)ethanol was dissolved in 140 ml of pyridine. The solution was cooled to -20° C. To the solution was added 19 g of p-toluenesulfonyl chloride. The resulting mixture was heated to 0° C. and stirred for 15 hours at the same temperature. The reaction mixture was added to a mixture of 300 ml of ice water and 200 ml of diethyl ether. The resulting mixture was adjusted to pH 2 with 6N hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with 100 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layer was washed with 1N hydrochloric acid., water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=3/1) to obtain 20.5 g of oily 1-(4-benzyloxyphenyl)-2-[2-(p-toluenesulfonyl)oxyethoxy]ETHANOL.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C(N(CC)CC)C.[C:32](Cl)(Cl)=[S:33].[N:36]1([CH2:42][CH2:43][NH2:44])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:32]([NH:44][CH2:43][CH2:42][N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[S:33])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: NCCN1CCCCC1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=S)NCCN4CCCCC4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (51 mg) was dissolved in N,N-dimethylformamide (2 ml) and triethylamine (1 ml) to prepare a solution. Thiophosgene (51 mg) was then added to the solution, and the mixture was stirred at room temperature for 3 hr. Next, 2-piperidinylethylamine (50 mg) was added thereto, and the mixture was further stirred at room temperature for 16 hr. Ethyl acetate was added to the reaction solution, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (25 mg, yield 33%)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:5]([C:16]#[N:17])=[C:4]([SH:18])[N:3]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([NH2:26])[S:24][CH:25]=1.C(=O)(O)[O-].[Na+].NC1C(C#N)=C(C2CCCCO2)C(C#N)=C(SCC2N=C(C3C=CC(Cl)=CC=3)SC=2)N=1>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:20][C:21]2[N:22]=[C:23]([NH2:26])[S:24][CH:25]=2)[N:3]=1
Reactant: Nc1nc(CCl)cs1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1C1CCCCO1
Agent: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1C1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2csc(N)n2)c(C#N)c1C1CCCCO1

Procedure:
50 mg (0.14 mmol) of the compound from Example 31A, 39 mg (0.21 mmol) of 4-(chloromethyl)-1,3-thiazol-2-amine and 48 mg (0.58 mmol) of sodium bicarbonate in 2.0 ml of dry DMF are reacted analogously to the preparation of the compound of Example 14.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:5]=3[CH:17]=[CH:18][CH:19]=2.O.[OH-].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[C:22]([N:14]1[CH2:13][CH2:12][N:11]([C:6]2[C:5]3[CH:17]=[CH:18][CH:19]=[C:3]4[C:4]=3[C:8](=[CH:9][CH:10]=[C:2]4[Br:1])[N:7]=2)[CH2:16][CH2:15]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Brc1ccc2c3c(cccc13)C(N1CCNCC1)=N2
Reactant: O=C(Cl)c1ccccc1
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)N1CCN(C2=Nc3ccc(Br)c4cccc2c34)CC1
Reaction time: 0.5 h

Procedure:
A mixture consisting of 7.1 g. of 1-(6-bromobenz-[cd]indol-2-yl)piperazine, 75 ml. of water, and 75 ml. of chloroform is stirred vigorously as 10 ml. of 5 N soidum hydroxide is added, followed by 5 g. of benzoyl chloride, in six portions over a period of 10 minutes. The reaction mixture is stirred an additional 30 minutes after the completion of the benzoyl chloride addition. The chloroform layer is separated and dried over sodium sulrate. After separation from impurities by chromatography on an alumina column, the title compound is recrystallized from benzene-chloroform to yield orange flakes, melting at 237.5°-239° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Br[CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([O:9]CC)=O>C1COCC1.C(O)C>[C:13]1([CH2:12][CH:6]2[NH:4][CH2:1][CH2:2][NH:3][C:7]2=[O:9])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(Br)Cc1ccccc1
Reactant: NCCN
Solvent: CCO
Solvent: C1CCOC1
Product: O=C1NCCNC1Cc1ccccc1

Procedure:
Ethylenediamine (25 g.) is added to a stirred solution of ethyl 2-bromo-3-phenylpropionate (XXVII, Example 61, 4.0 g.) in THF (100 ml.) and ethanol (300 ml.). After 20 hours at 20°-25° the solvents are removed under reduced pressure and the residual oil is partitioned between ethyl acetate-1 N sodium hydroxide solution. The ethyl acetate extract is washed with water, saline, and concentrated. The residual oil is applied to a silica gel column which is eluted with chloroform-methanol (9/1). Fractions containing the product are pooled, concentrated to a residue and recrystallized from ethyl acetate-SSB to give 3-(phenylmethyl)piperazinone, m.p. 92°-93°.
Reaction SMILES: CN(C)[CH:3]=[O:4].[CH2:6]([N:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:7].P(Cl)(Cl)(Cl)=O.[C:27](=O)([O-])[O-:28].[Na+].[Na+]>[Cl-].[Zn+2].[Cl-].O.C1(C)C=CC=CC=1>[CH:27]([C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:6][CH3:7])[C:21]3[C:16]([S:15][C:14]=2[CH:13]=1)=[CH:17][C:18]([CH:3]=[O:4])=[CH:19][CH:20]=3)=[O:28]
Reactant: CCN1c2ccccc2Sc2ccccc21
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCN1c2ccc(C=O)cc2Sc2cc(C=O)ccc21
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a mixture of 6.5 g (47.7 mmol) of dehydrated zinc chloride and 150 ml of toluene were added 14 ml (180.1 mmol) of N,N-dimethylformamide (DMF) and 10.0 g (44.0 mmol) of 10-ethylphenothiazine (4a). Thereto was gradually added dropwise 27.0 g (176.1 mmol) of phosphorus oxychloride at room temperature to 35° C. The resultant mixture was reacted at 73 to 78° C. for 3 days and then poured into 200 ml of water. This mixture was neutralized with sodium carbonate, stirred at 80° C. for 3 hours, and then subjected to liquid separation. The aqueous layer was extracted with ethyl acetate three times, and the resultant organic layer collected was dried with magnesium sulfate and concentrated. The residue was recrystallized from an isopropanol/ethyl acetate mixed solvent to obtain 4.96 g of 3,7-diformyl-10-ethylphenothiazine (2a).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH3:19])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:25]([CH3:28])([O-:27])=[O:26]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:28]/[N+:25]([O-:27])=[O:26])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: CCOc1ccc(C=O)cc1OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOc1ccc(/C=C/[N+](=O)[O-])cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 2.5 h

Procedure:
3-(Benzyloxy)-4-ethoxy benzaldehyde described in Production Example 15-2 (14.5 g, 56.4 mmol) was dissolved in acetic acid (45 mL), then ammonium acetate (5.22 g, 67.7 mmol) and nitromethane (7.5 mL, 138 mmol) were added under nitrogen atmosphere at room temperature, and the mixture was heated and stirred at 130° C. for 2.5 hours. The mixture was cooled to room temperature and the precipitate was collected by filteration and washed with ethanol to quantitatively obtain the title compound.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].C([O-])([O-])=O.[K+].[K+].Cl[CH2:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])=[O:19]>>[N:1]1([CH2:17][C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][C:21]2=[O:26])=[O:19])[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: O=C(CCl)N1CCNCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cn(CC(=O)N2CCNCC2=O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 364.6 %

Procedure:
Thymine (630.6 mg, 5 mmol) and K2CO3 (1.38 g, 10 mmol) were combined in a 50 mL round bottom flask and azeotroped with benzene (3×10 mL). The mixture was suspended in anhydrous DMF (15 mL) under argon and allowed to stir at room temperature for 4 hours. Solid chloroacetyl piperazinone (1.37 mmol, 1.4 eq) as prepared was added, and the reaction mixture was stirred for an additional 3-4 hours. The crude reaction mixture was filtered, concentrated and precipitated by treatment with EtOAc (30 mL). The solid was washed extensively with EtOAc and dried in a dessicator under vacuum to afford 1.33g of N-(thymin-1-ylacetyl)-piperazinone (100% yield) as a white solid.
Reaction SMILES: CS(O[CH:6]([C:8]1[CH:21]=[C:20]2[C:11]([O:12][CH2:13][CH2:14][N:15]3[C:19]2=[N:18][C:17]([C:22]2[N:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[CH:24][N:23]=2)=[CH:16]3)=[CH:10][CH:9]=1)[CH3:7])(=O)=O.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.O1CCOC[CH2:38]1>>[CH:27]([N:26]1[C:22]([C:17]2[N:18]=[C:19]3[C:20]4[CH:21]=[C:8]([CH:6]([N:34]5[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]5)[CH2:7][CH3:38])[CH:9]=[CH:10][C:11]=4[O:12][CH2:13][CH2:14][N:15]3[CH:16]=2)=[N:23][CH:24]=[N:25]1)([CH3:29])[CH3:28]
Reactant: CC(OS(C)(=O)=O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Reactant: CN1CCNCC1
Reactant: C1COCCO1
Product: CCC(c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2)N1CCN(C)CC1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 1-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-13-yl}ethyl methanesulfonate from Example 146 (244 mg, 0.570 mmol) and 1-methylpiperazine (280 mg, 2.80 mmol) in 1,4-dioxane (4 mL) was stirred at 90° C. for 16 h under nitrogen atmosphere. After concentration, the residue was purified by reverse phase Combiflash eluting with a 0-50% gradient of CH3CN in 0.3% NH4HCO3 to give 170. The enantiomers were separated by chiral HPLC (OD-H column, 5% EtOH (0.1% DEA) in n-hexane isocratic) to give: 20 mg of one enantiomer and 16 mg of the other (15% total yield).
Reaction SMILES: [C:1]1(=[O:24])[N:5]([CH:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][P:8](=[O:11])([OH:10])O)[C:4](=[O:19])[C:3]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]12.P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:31](O)[CH3:32].C(N(CC)CC)C.[NH2:41][C@H:42]1[CH2:47][CH2:46][CH2:45][N:44]([CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:43]1=[O:54]>C1C=CC=CC=1.C(Cl)Cl>[C:4]1(=[O:19])[N:5]([CH:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][P:8]([NH:41][C@H:42]2[CH2:47][CH2:46][CH2:45][N:44]([CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:43]2=[O:54])([O:10][CH2:31][CH3:32])=[O:11])[C:1](=[O:24])[C:2]2=[CH:23][CH:22]=[CH:21][CH:20]=[C:3]12
Reactant: CCO
Reactant: CCOC(=O)CN1CCC[C@H](N)C1=O
Reactant: O=C1c2ccccc2C(=O)N1C(Cc1ccccc1)CP(=O)(O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCOC(=O)CN1CCC[C@H](NP(=O)(CC(Cc2ccccc2)N2C(=O)c3ccccc3C2=O)OCC)C1=O
Temperature: 25 °C

Procedure:
A suspension of (2-phthalimido-3-phenylpropyl)phosphonic acid in dry benzene is treated with phosphorus pentachloride and stirred at room temperature under argon for an hour. The mixture is then refluxed for 15 minutes, cooled and evaporated to dryness to room temperature (0.5 mm. of Hg). The residue is taken up in dry methylene chloride and reacted successively with a mixture of ethanol (1 eq.) and triethylamine (1 eq.) in methylene chloride and (S)-3-amino-2-oxopiperidineacetic acid, ethyl ester according to the procedure of Example 1(g). Work up of the reaction mixture according to the procedure of Example 1(g) yields (S)-3-[[[2-phthalimido-3-phenylpropyl]ethoxyphosphinyl]amino]-2-oxo-1-piperidineacetic acid, ethyl ester.
Reaction SMILES: [CH3:1][S:2]([N:5]([CH2:11][CH2:12][Cl:13])[NH:6][S:7]([CH3:10])(=[O:9])=[O:8])(=[O:4])=[O:3].[Cl:14][CH2:15][CH2:16][N:17]=[C:18]=[O:19].C(N(CC)CC)C.C(O)C>C(#N)C>[CH3:1][S:2]([N:5]([CH2:11][CH2:12][Cl:13])[N:6]([S:7]([CH3:10])(=[O:9])=[O:8])[C:18]([NH:17][CH2:16][CH2:15][Cl:14])=[O:19])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)NN(CCCl)S(C)(=O)=O
Reactant: O=C=NCCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCO
Product: CS(=O)(=O)N(CCCl)N(C(=O)NCCCl)S(C)(=O)=O
Reaction time: 0.17 h
Yield: 42.2 %

Procedure:
To a stirred solution of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (Shyam, et al.,J. Med. Chem., 1990, 33, 2259-2264) (2.5 g, 0.010 mol) and 2-chloroethyl isocyanate (1.2 g, 0.011 mol) in dry acetonitrile (100 mL) was added triethylamine (1.1 g, 0.011 mol) at room temperature. After an additional 10 min, the reaction mixture was evaporated to dryness in vacuo. The residue was triturated twice with 15 mL quantities of petroleum ether and the petroleum ether layer was discarded each time. The residue was then taken up in ethyl acetate (150 mL) and washed with dilute hydrochloric acid (3×15 mL). The ethyl acetate layer was dried over anhydrous magnesium sulfate and filtered. Upon evaporation of the solvent, a semi-solid residue was obtained which, upon trituration with absolute ethanol, gave a white solid. Recrystallization from ethanol afforded 1.5 g (42.2%) of the title compound: mp 96°-97.5° C.; 1H NMR (acetone-d6) δ 7.0 (br, 1 H, NH), 3.7-4.2 (m, 4 H, SO2NCH2CH2Cl ), 3.5-3.7 (m, 4H, CONHCH2CH2Cl), 3.5 and 3.3 (2s, 6 H, 2 CH3). Anal. (C7H15C12N3O5S2) C, H, N.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][CH3:9])([CH2:6][NH2:7])[CH2:4][NH2:5])[CH3:2].OO.[O-]Cl.[Na+]>O.CO>[CH2:1]([C:3]1([CH2:8][CH3:9])[CH2:6][N:7]=[N:5][CH2:4]1)[CH3:2]
Reactant: CCC(CC)(CN)CN
Agent: OO
Agent: [Na+]
Agent: [O-]Cl
Solvent: CO
Solvent: O
Product: CCC1(CC)CN=NC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
2,2-Diethyl-propane-1,3-diamine (5.0 g) was taken up in a mixture of H2O (40 mL) and MeOH (10 mL), and cooled in an ice bath. Simultaneously, H2O2 (24.2 mL of a 30% solution, 6 equiv.) and NaClO (54.9 mL of a 10% solution, 2.4 equiv.) were added dropwise, the ice bath was removed, and the mixture was stirred for 2 h. at room temperature. Extraction with DCM, drying over Na2SO4 and evaporation under reduced pressure yielded 3.51 g of a clear, yellow liquid containing 77% of the anticipated product and 23% of the diamine starting material. This material was used in subsequent steps without further purification. 1H NMR (400 MHz, CDCl3) δ 0.78 (t, J=7.5 Hz, 6H), 1.36 (q, J=7.5 Hz, 4H), 4.14 (s, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:14]([CH3:35])([CH3:34])[CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH:56]1[O:61][CH2:62][CH2:63]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O>[C:30]([Si:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:16][CH2:15][C:14]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:63][CH2:62][O:61][CH:56]3[CH2:57][CH2:58][CH2:59][CH2:60][O:55]3)[CH:8]=2)[N:5]=1)([CH3:35])[CH3:34])([CH3:33])([CH3:32])[CH3:31]
Reactant: OCCOC1CCCCO1
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(N)n(-c2cccc(O)c2)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(N)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Temperature: 0 °C
Reaction time: 20 h
Yield: 61.3 %

Procedure:
A mixture of Intermediate 153d (0.53 g, 1.09 mmol) in dry TI-IF (8 mL) was treated with triphenylphosphine (0.57 g, 2.18 mmol) and 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (0.22 mL, 1.64 mmol). The mixture was cooled to 0° C. then diisopropylazodicarboxylate (0.43 mL, 2.18 mmol) was added dropwise. After stirring at ambient temperature for 20 h the mixture was treated with water (0.1 mL) and concentrated in vacuo to a yellow oil. The oil was purified by FCC, using 0-30% EtOAc in cyclohexane, to give the title compound as an orange oil (0.41 g, 61%). LCMS (Method 3): Rt 5.25 min, ink 614.6 [MH+].
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])=[O:14].[CH3:25][C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[CH2:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1.[H-].[Na+].IC>>[F:11][C:4]1[CH:3]=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([S:13]([CH3:12])(=[O:15])=[O:14])=[CH:17][CH:18]=2)[CH:10]=[CH:9][C:5]=1[C:6]([N:33]1[CH2:34][CH2:35][CH2:36][C@H:32]1[CH2:31][N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[CH3:25])=[O:8]
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure A′, T′ and B′ starting from 4-bromo-2-fluoro-benzoic acid, 4-methanesulfonylphenyl boronic acid and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (M+H) 445.2. Alternatively, the title compound maybe prepared by methylation of 3′-fluoro-4-[(2-(R)-methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine-1-carbonyl]-biphenyl-4-sulfinic acid using NaH and iodomethane at 0° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>C(O)CCC>[ClH:1].[ClH:1].[F:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1cccnc1Cl
Reactant: C1CNCCN1
Solvent: CCCCO
Product: Cl
Product: Fc1cccnc1N1CCNCC1
Yield: 35 %

Procedure:
A solution of 2-chloro-3-fluoropyridine (500 mg, 4.25 mmol) and anhydrous piperazine (3.66 g, 42.5 mmol) in 40 ml of n-butanol is stirred at reflux for 18 hours. After concentrating to dryness in vacuo, the residue is partitioned between toluene and dilute sodium hydroxide solution (5% w/v). The toluene layer is washed with a saturated sodium chloride solution, dried over Na2SO4, filtered and concentrated to 0.65 g of oil. Upon treatment of the oil with ethanolic hydrogen chloride and crystallization by dissolving the crude material in a minimum of methanol:ethanol (1:1) mixture and addition of ethyl acetate to incipient cloudiness, there is obtained 0.38 g., (35% yield) of product, m.p. 203°-210° C.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([N:11]3[CH2:15][CH2:14][N:13]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][C:21]=4[CH3:22])[C:12]3=[O:23])=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.CO>C(O)(=O)C.C(Cl)Cl.[Zn]>[CH3:22][C:21]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N:13]1[CH2:14][CH2:15][N:11]([C:8]2[C:7]3[CH:2]=[N:3][CH:4]=[CH:5][C:6]=3[S:10][CH:9]=2)[C:12]1=[O:23]
Reactant: Cc1ccncc1N1CCN(c2csc3ccnc(Cl)c23)C1=O
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccncc1N1CCN(c2csc3ccncc23)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 40.4 %

Procedure:
Activated Zinc (417 mg, 6.380 mmol) was added to a stirred solution of 1-(4-chloro-thieno[3,2-c]pyridin-3-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-136a: 220 mg, 0.6380 mmol) in acetic acid (10 mL). The resulting mixture was stirred at room temperature for 2 days. The reaction was monitored by TLC (10% MeOH in DCM). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Aqueous NH3 solution was added to the concentrate and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (5% MeOH in DCM) afforded 80 mg of the product (40.6% yield).
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[CH:9][N:10]([C:12]3[C:13]4[N:14]([CH:25]=[CH:26][N:27]=4)[CH:15]=[C:16]([C:18]4[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=4)[N:17]=3)[CH:11]=2)=[CH:3][CH:2]=1.[N:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38])=[C:30]=[O:31].CN(C=O)C>ClCCl>[C:33]1([CH3:38])[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[NH:29][C:30]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:17]=[C:12]([N:10]3[CH:11]=[C:7]([C:4]4[CH:3]=[CH:2][C:1]([CH3:28])=[CH:6][CH:5]=4)[N:8]=[CH:9]3)[C:13]3[N:14]([CH:25]=[CH:26][N:27]=3)[CH:15]=2)[CH:19]=1)=[O:31]
Reactant: Cc1ccc(-c2cn(-c3nc(-c4cccc(N)c4)cn4ccnc34)cn2)cc1
Reactant: Cc1ccccc1N=C=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(-c2cn(-c3nc(-c4cccc(NC(=O)Nc5ccccc5C)c4)cn4ccnc34)cn2)cc1
Yield: 59.2 %

Procedure:
A solution of 3-[8-(4-p-tolyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenylamine (5) (50 mg), 1-isocyanato-2-methyl-benzene (18 mg), in dichloromethane (DCM) (3 ml) and DMF (0.5 ml) is stirred at room temperature for 16 hr. The mixture is concentrated in vacuo, the residue slurried with diethyl ether/methanol (20:1), and filtered to give 1-o-tolyl-3-{3-[8-(4-p-tolyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea (6) (40 mg) as a cream solid.