Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)[CH3:2].[NH2:20]C(N)=S>CN(C)C=O>[CH3:2][C:1]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:20]=1
Reactant: CC(=O)OC(C(=O)c1ccccc1)c1ccccc1
Reactant: NC(N)=S
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 160 °C

Procedure:
0.2 g of the above 2-oxo-1,2-diphenylethyl acetate is dissolved in 10 ml of dimethylformamide in a reactor. 0.12 g of thiourea (2 eq.) is subsequently added and the reaction mixture is left to react at reflux (160° C.) for 10 hours. The reaction mixture is extracted using dichloromethane and then washed with water 3 times. The organic phase is recovered after separating by settling, dried over sodium sulphate, filtered and then concentrated to dryness under vacuum. The oil obtained is subsequently purified on a column of silica gel (elutent: dichloromethane).
Reaction SMILES: [NH:1](C(OC(C1C=C(OC)C=C(OC)C=1)(C)C)=O)[C@H:2]([C:24]([NH:26][C@H:27]([C:49]([NH:51][C@H:52]([C:60]([NH:62][C@H:63]([C:70]([OH:72])=[O:71])[CH2:64][O:65]C(C)(C)C)=[O:61])[C@@H:53]([CH3:59])[O:54]C(C)(C)C)=[O:50])[CH2:28][S:29]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:25])[CH2:3][S:4]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.[F:90][C:91]([F:96])([F:95])[C:92]([OH:94])=[O:93]>C(S)C>[NH2:1][C@H:2]([C:24]([NH:26][C@H:27]([C:49]([NH:51][C@H:52]([C:60]([NH:62][C@H:63]([C:70]([OH:72])=[O:71])[CH2:64][OH:65])=[O:61])[C@@H:53]([CH3:59])[OH:54])=[O:50])[CH2:28][SH:29])=[O:25])[CH2:3][SH:4].[F:90][C:91]([C:92]([OH:94])=[O:93])([F:96])[F:95]
Reactant: COc1cc(OC)cc(C(C)(C)OC(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@H](C(=O)N[C@@H](COC(C)(C)C)C(=O)O)[C@@H](C)OC(C)(C)C)c1
Solvent: CCS
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](O)[C@H](NC(=O)[C@H](CS)NC(=O)[C@@H](N)CS)C(=O)N[C@@H](CO)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
615.8 mg (0.5 mmole) of Ddz-Cys(Trt)-Cys(Trt)-Thr(But)-Ser(But)-OH are dissolved in a mixture of 2.5 ml of ethylmercaptan and 2.5 ml of trifluoroacetic acid. The reaction mixture is stirred for 4 hours at room temperature and is then poured into 50 ml of water. The aqueous phase is extracted three times with ether and is then freeze-dried.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:12][C:13]1[C:14]([O:21][C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])=[C:15]([Cl:20])[C:16]([NH2:19])=[N:17][CH:18]=1>ClCCl>[Br:12][C:13]1[C:14]([O:21][C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])=[C:15]([Cl:20])[C:16]([NH:19][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])=[N:17][CH:18]=1
Reactant: Nc1ncc(Br)c(Oc2c(F)cccc2F)c1Cl
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: O=C(NC(=S)Nc1ncc(Br)c(Oc2c(F)cccc2F)c1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzoyl isothiocyanate (163 mg, 1.0 mmol) is added to a solution of 5-bromo-3-chloro-4-(2,6-difluorophenoxy)pyridin-2-amine (336 mg, 1.0 mmol) in dichloromethane (20 mL) at 0° C. The reaction mixture is warmed to room temperature and stirred for one hour. The reaction mixture is diluted with hexanes and filtered to afford N-(5-bromo-3-chloro-4-(2,6-difluorophenoxy)pyridin-2-ylcarbamothioyl)benzamide.
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([CH3:25])[CH:18]=2)=[CH2:16])[CH:10]=1)(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]([C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=2)=[CH2:16])=[CH:18][C:19]=1[CH3:25]
Reactant: C=C(c1cccc(O[Si](C)(C)C(C)(C)C)c1)c1ccc(OC)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=C(c1cccc(O)c1)c1ccc(OC)c(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyl-{3-[1-(4-methoxy-3-methyl-phenyl)-vinyl]-phenoxy}-dimethyl-silane (7.1 g, 19.8 mmol, 1.0 eq) was dissolved in 50 mL of dry tetrahydrofuran, the solution was cooled to 0° C. 21.8 mL of a tetrabutylammonium fluoride solution (1 M tetrahydrofuran, 21.8 mmol, 1.1 eq) was added and the mixture was allowed to warm up to room temperature. After 1 hour LCMS which showed complete conversion to the desired product. Water was added to the reaction mixture which was then extracted with ethyl acetate. The organic fraction was collected and dried with over sodium sulfate The crude product was purified by flash chromatography eluting with cyclohexane/ethylacetate (100:0 to 90:10). 5.3 g of clean product was obtained as colorless liquid (yield: 95%)
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4](F)[CH:3]=1.OC1C=CC(C(O)=O)=CC=1Cl>>[C:6]([OH:8])(=[O:7])[C:5]1[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccc(O)cc1F
Agent: O=C(O)c1ccc(O)c(Cl)c1
Product: O=C(O)c1ccccc1

Procedure:
Using 4-hydroxyfluorobenzoic acid and 4-hydroxy-3-chlorobenzoic acid, reactions and treatments were carried out in the same manner as in Reference Example 80, thereby giving various benzoic acid derivatives.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]([C:10]2([CH3:13])[CH2:12][CH2:11]2)[NH:7][C:8]=1[Br:9].[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16]>C1COCC1>[Br:9][C:8]1[N:7]=[C:6]([C:10]2([CH3:13])[CH2:12][CH2:11]2)[N:5]([CH2:21][O:20][CH2:19][CH2:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[C:4]=1[Br:3]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC1(c2nc(Br)c(Br)[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(c2nc(Br)c(Br)n2COCC[Si](C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
A 250 mL round-bottom flask was purged with N2 and charged with NaH (95%, 0.33 g, 13.1 mmol). THF (15 mL) added, and the mixture cooled to 0° C. After 5 minutes, a solution of 4,5-dibromo-2-(1-methylcyclopropyl)-1H-imidazole (3.0 g, 10.7 mmol) in THF (20 mL) was added dropwise from an addition funnel over 5 minutes. The light tan solution was stirred at 0° C. for 25 minutes and SEMCl (2.1 mL, 11.8 mmol) was then added dropwise over 2 minutes. After 5 minutes, ice bath was removed, and the reaction stirred at room temperature. After stirring 2 hours, LCMS indicated 90% conversion. Another 0.3 mL of SEMCl (0.3 mL, 1.7 mmol) was added. LCMS indicates that the reaction has not proceeded; additional NaH (95%, 51 mg, 2.0 mmol) was added with concomitant gas evolution. After 15 minutes, LCMS indicated complete reaction. The reaction was quenched with water (1 mL). Heptane (250 mL) was added and organic layer was washed with water (200 mL). The aqueous layer was extracted with heptane (100 mL), and the combined organic layers were washed with water and brine, dried (Na2SO4), and concentrated to give 4.46 g of crude material. The crude material was purified by flash chromatography (SiO2; 0-25% EtOAc in heptane) to give the product (3.45 g) as a light yellow oil: LCMS (m/z) 409.0 (MH+), tR=1.27 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:22][CH3:23])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:24][C:25]1[C:26]([O:41][CH3:42])=[N:27][C:28]([O:39][CH3:40])=[C:29]([Cl:38])[C:30]=1[C:31](=O)[C:32]([O:34]CC)=O.CC(O)=O>COCCO.CCOC(C)=O>[Cl:38][C:29]1[C:28]([O:39][CH3:40])=[N:27][C:26]([O:41][CH3:42])=[C:25]([Cl:24])[C:30]=1[C:31]1[C:32](=[O:34])[N:22]([CH3:23])[C:3]2[N:4]=[C:5]([NH:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]([N:17]([CH2:18][CH3:19])[CH2:20][CH3:21])=[O:16])=[CH:13][CH:14]=3)[N:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CCN(CC)C(=O)c1ccc(Nc2ncc(N)c(NC)n2)cc1
Reactant: CCOC(=O)C(=O)c1c(Cl)c(OC)nc(OC)c1Cl
Solvent: CC(=O)O
Solvent: COCCO
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)c1ccc(Nc2ncc3nc(-c4c(Cl)c(OC)nc(OC)c4Cl)c(=O)n(C)c3n2)cc1
Yield: 50.1 %

Procedure:
A mixture of 0.47 g (1.5 mmol) of 5-amino-2-[[4-(diethylaminocarbonyl)-phenyl]amino]-4-(methylamino)pyrimidine, 0.62 g (2 mmol) of ethyl 2-(3,5-dichloro-2,6-dimethoxypyridin-4-yl)-2-oxoacetate and 1.0 mL of HOAc in 20 mL of 2-methoxyethanol is heated under reflux for 16 hours. Workup in EtOAc, followed by chromatography on silica, eluting with hexane/EtOAc (1:1), gives 0.42 g (56%) of the title compound (Compound 22): mp (EtOH) 274–276° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[N+:10]([O-])=O)=[C:4]([O:13][CH3:14])[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: COc1cc(Cl)ccc1/C=C/[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1CCN
Temperature: 0 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
(E)-4-chloro-2-methoxy-1-(2-nitrovinyl)benzene (245 mg, 1.15 mmol) was diluted with THF (1 mL), placed under nitrogen and cooled to 0° C. LAH (4588 μL, 4.59 mmol) was added dropwise and the reaction was stirred for 5 hours warming to ambient temperature. The reaction was cooled to 0° C. and quenched with 174 μL of water, 174 μL of 15% NaOH and 522 μL water. After stirring for 1 hour, ethyl acetate and MgSO4 was added. The reaction mixture was filtered and concentrated to yield 2-(4-chloro-2-methoxyphenyl)ethanamine (160 mg, 0.862 mmol, 75.1% yield).
Reaction SMILES: [CH2:1]([N:3]([CH3:15])[C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([CH3:14])[N:13]=1)[C:7]([NH:9][OH:10])=[NH:8])[CH3:2].[CH2:16](N(CC)C1C=C(C=C(C)N=1)C(O)=O)C>>[CH2:1]([N:3]([CH2:15][CH3:16])[C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([CH3:14])[N:13]=1)[C:7]([NH:9][OH:10])=[NH:8])[CH3:2]
Reactant: CCN(C)c1cc(C(=N)NO)cc(C)n1
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Product: CCN(CC)c1cc(C(=N)NO)cc(C)n1

Procedure:
The title compound is prepared in analogy to 2-(ethyl-methyl-amino)-N-hydroxy-6-methyl-isonicotinamidine from 2-(diethylamino)-6-methyl-isonicotinic acid; LC-MS: tR=0.50 min, [M+1]+=223.12.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1C(=O)N([Br:24])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:24][CH2:12][C:11]1[C:2]([CH3:1])=[C:3]([CH:8]=[CH:9][C:10]=1[S:13]([CH3:16])(=[O:14])=[O:15])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1C
Yield: 143.8 %

Procedure:
29.69 g of methyl 2,3-dimethyl-4-methylsulfonylbenzoate was dissolved in 260 ml of carbon tetrachloride, and 22.93 g of NBS and 1.0 g of benzoyl peroxide were added to heat at reflux for 2.5 hours. The reaction solution was cooled down, and insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure to give 56.58 g of viscous oil. The obtained oil was purified by column chromatography on silica gel with n-hexane/ethyl acetate=5/1 to give 18.98 g of the title compound as white crystals.
Reaction SMILES: C(OC([NH:8][N:9]1[CH2:14][C:13](/[CH:15]=[N:16]/[O:17][CH3:18])=[N:12][N:11](C(OC(C)(C)C)=O)[C:10]1=[O:26])=O)(C)(C)C.C(Cl)(=O)C.C([O-])(O)=O.[Na+]>CO>[NH2:8][N:9]1[CH2:14][C:13](/[CH:15]=[N:16]/[O:17][CH3:18])=[N:12][NH:11][C:10]1=[O:26]
Reactant: CO/N=C/C1=NN(C(=O)OC(C)(C)C)C(=O)N(NC(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)Cl
Product: CO/N=C/C1=NNC(=O)N(N)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-(tert-butoxycarbonylamino)-6-[(E)-methoxyiminomethyl]-3-oxo-5H-1,2,4-triazine-2-carboxylate (12.4 g, 30.0 mmol) in MeOH (120 mL) at 0° C. was slowly added acetyl chloride (10.7 mL, 150 mmol). After completion of the addition, the reaction mixture was stirred at this temperature for another 30 min before it was allowed to warm to room temperature. After additional 20 h stirring at room temperature, the reaction mixture was carefully neutralized with sat. NaHCO3. The volatiles were removed in vacuo and the residual was repeatedly diluted with acetonitrile and evaporated. The remaining material were stirred for 10 min with hot acetonitrile and filtered. Concentration of the filtrate furnished the desired product as an off-white solid. LCMS (Method K) RT 0.42 min. [M+H]+ 172.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:36]([N:38]([C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[CH3:39])=[O:37])[CH2:10][C:11]1[CH:12]=[C:13]([CH:33]=[CH:34][CH:35]=1)[CH:14]=[CH:15][C:16]1[NH:24][C:23]2[C:18](=[N:19][C:20]([O:25][CH3:26])=[CH:21][CH:22]=2)[C:17]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:36]([N:38]([C:40]1[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=1)[CH3:39])=[O:37])[CH2:10][C:11]1[CH:12]=[C:13]([CH:33]=[CH:34][CH:35]=1)[CH2:14][CH2:15][C:16]1[NH:24][C:23]2[C:18](=[N:19][C:20]([O:25][CH3:26])=[CH:21][CH:22]=2)[C:17]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)Cc1c(C=Cc2cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)c3ccc(Cl)cc3)c2)[nH]c2ccc(OC)nc12
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1c(CCc2cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)c3ccc(Cl)cc3)c2)[nH]c2ccc(OC)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-ethyl 2-(2-(3-(2-(tert-butoxycarbonylamino)-3-((4-chlorophenyl)(methyl)amino)-3-oxopropyl)styryl)-5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetate (170 mg, 0.26 mmol) was dissolved in 50 mL of ethyl acetate and purged with nitrogen. Rhodium (5 wt. % on alumina powder, 60 mg) was added. The reaction mixture was purged with hydrogen and stirred at ambient temperature overnight under a hydrogen balloon. After completion of the reaction, the mixture was filtered, rinsing with ethyl acetate. The filtrate was concentrated to afford (S)-ethyl 2-(2-(3-(2-(tert-butoxycarbonylamino)-3-((4-chlorophenyl)(methyl)amino)-3-oxopropyl)phenethyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetate which was dissolved in 5 mL of THF/MeOH/H2O (3/2/1), and to it was added LiOH.H2O (55 mg). The reaction mixture was allowed to stir at ambient temperature for two hours and then purified by RP HPLC eluting with acetonitrile/water (with 0.1% TFA) to afford (S)-2-(2-(3-(2-(tert-butoxycarbonylamino)-3-((4-chlorophenyl)(methyl)amino)-3-oxopropyl)phenethyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetic acid. The compound was dissolved in 3 mL of 10% TFA/CH2Cl2 and stirred at ambient temperature for two hours. The reaction was cooled down to 0° C. and quenched with 0.3 mL of pyridine. The solvent was removed and the residue was purified by RP HPLC eluting with acetonitrile and water to afford 106 mg of (S)-2-(2-(3-(2-amino-3-((4-chlorophenyl)(methyl)amino)-3-oxopropyl)phenethyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetic acid. MS (m/z): 521.3 [M+H]+; HPLC retention time 2.05 min (5-99% acetonitrile:water with 0.05% formic acid).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH:11][S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][N:29]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC.O.CCO>[OH:26][CH2:27][C:28]1[N:29]=[CH:30][C:31]([C:2]2[N:7]=[N:6][C:5]([C:8]([NH:11][S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])([CH3:10])[CH3:9])=[CH:4][CH:3]=2)=[CH:32][CH:33]=1
Reactant: CC(C)(NS(=O)C(C)(C)C)c1ccc(Cl)nn1
Reactant: OCc1ccc(B(O)O)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CC(C)(NS(=O)C(C)(C)C)c1ccc(-c2ccc(CO)nc2)nn1
Temperature: 140 °C
Yield: 21.3 %

Procedure:
Impure 2-methyl-propane-2-sulfinic acid[1-(6-chloro-pyridazin-3-yl)-1-methyl-ethyl]-amide (15 mg, 0.054 mmol) was combined with Pd(dppf)Cl2.dichloromethane complex (4.7 mg, 0.006 mmol), 1M K3PO4 (0.07 mL, 0.07 mmol) and 2-(hydroxymethyl)pyridine-5-boronic acid (18 mg, 0.12 mmol) in a microwave vial. A 7:3:2 mixture of DME/H2O/EtOH (1 mL) was added. The vial was flushed with argon and sealed. This vial was then heated in the microwave reactor for 15 min at 140° C. The reaction mixture was diluted with 2 mL of water and extracted 4×4 mL with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated. Purification via normal phase flash chromatography on silica gel (0→4% MeOH/CH2Cl2) yielded 4 mg of 2-methyl-propane-2-sulfinic acid{1-[6-(6-hydroxymethyl-pyridin-3-yl)-pyridazin-3-yl]-1-methyl-ethyl}-amide as a brown solid.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]1([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][S:26][C:27]3[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=3[CH2:29][OH:30])[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl.O>[C:11]1([N:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][S:26][C:27]3[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=3[CH:29]=[O:30])[CH2:21][CH2:22]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OCc1ccccc1SCCCN1CCN(c2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=Cc1ccccc1SCCCN1CCN(c2ccccc2)CC1
Reaction time: 0.25 h
Yield: 90.5 %

Procedure:
A solution of 1.1 g of dimethylsulfoxide in 5 ml of methylene chloride is added to a solution of 0.894 g of oxalyl chloride in 20 ml of methylene chloride at -50° C. A solution of 2.19 g of 2-[3-(4-phenylpiperazin-1-yl)propylthio]benzylalcohol in 10 ml of methylene chloride is added to the mixture at -50° C., and the mixture is stirred at the same temperature for 15 minutes. 3.24 g of triethylamine are added to the mixture, and the mixture is stirred at -50° C. for 5 minutes and further stirred at room temperature for one hour. The mixture is poured into water, and the aqueous mixture is extracted with methylene chloride. The extract is washed with water, dried and concentrated under reduced pressure to remove solvent. The residue is purified by silica gel chromatography (solvent, ethyl acetate:chloroform=1:6). 1.97 g of 2-[3-(4-phenylpiperazin-1-yl)propylthio]benzaldehyde are obtained as an oil. Yield: 90.5%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[C:21]([CH:25]=1)=[N:22][O:23][N:24]=2>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[C:21]([CH:25]=2)=[N:22][O:23][N:24]=3)[N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Nn2cncn2)cc1
Reactant: BrCc1ccc2nonc2c1
Product: N#Cc1ccc(N(Cc2ccc3nonc3c2)n2cncn2)cc1

Procedure:
Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 5-bromomethylbenzofurazan
Reaction SMILES: O.[CH3:2][N:3]([CH3:23])[C@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[N+:20]([O-])=O)[CH2:5]1>CO.[Pd]>[NH2:20][C:11]1[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=1[N:6]1[CH2:7][CH2:8][CH2:9][C@H:4]([N:3]([CH3:23])[CH3:2])[CH2:5]1
Reactant: CN(C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CN(C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2N)C1
Reaction time: 8 h

Procedure:
A 500 mL parr pressure bottle was charged with palladium, 10 wt. % on activated carbon, 50% water wet (9.1 g, 8.6 mmol) under nitrogen. (S)-N,N-dimethyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-amine (13.6 g, 43 mmol) was added as a solution in methanol via syringe, rinsing in with multiple methanol washes until the final volume was approximately 100 mL. The vessel was placed in a parr shaker, and treated with 2 atm H2 and shaken overnight. The reaction was flushed with nitrogen, and filtered through a pad of celite rinsing with 1.3 L of methanol and concentrated in vacuo. The oil was taken up in CH2Cl2, dried over Na2SO4, filtered, and concentrated in vacuo to give (S)-1-(2-amino-4-(trifluoromethyl)phenyl)-N,N-dimethylpiperidin-3-amine as a red oil. MS m/z=288 [M+H]+. Calc'd for C14H20F3N3: 287.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH:10]=1.[CH:11]1(B(O)O)[CH2:13][CH2:12]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[H+].[B-](F)(F)(F)F>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:11]1([C:2]2[CH:3]=[CH:4][C:5]3[S:9][CH:8]=[N:7][C:6]=3[CH:10]=2)[CH2:13][CH2:12]1
Reactant: OB(O)C1CC1
Reactant: Brc1ccc2scnc2c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: c1nc2cc(C3CC3)ccc2s1

Procedure:
Following the same procedure in step 1 of Example 344 using 5-bromo-1,3-benzothiazole (500 mg, 2.34 mmol, 1.00 equiv), cyclopropylboronic acid (300 mg, 3.49 mmol, 1.50 equiv), potassium phosphate (2.2 g, 10.36 mmol, 4.50 equiv), palladium acetate (51.6 mg, 0.10 equiv), and PCy3.HBF4 (0.17 g, 0.20 equiv) in a mixture of toluene (12 mL) and water (1.2 mL). The crude product was purified by flash chromatography on silica gel, eluting with petroleum ether/ethyl acetate (10:1-5:1) to provide the title compound as a purple oil. MS m/z [M+H]+ (ESI): 176.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=4)=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[NH:3]1.[N-:38]=[N+:39]=[N-:40].[Na+].O>[Zn+2].[Br-].[Br-].O>[C:28]1([C:27]2[C:20]([C:17]3[CH:16]=[CH:15][C:14]([CH2:13][N:10]4[CH2:9][CH2:8][CH:7]([N:6]5[C:5]6[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=6[NH:3][C:2]5=[O:1])[CH2:12][CH2:11]4)=[CH:19][CH:18]=3)=[N:21][CH:22]=[C:23]([C:24]3[NH:40][N:39]=[N:38][N:25]=3)[CH:26]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: N#Cc1cnc(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)c(-c2ccccc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Product: O=c1[nH]c2ccccc2n1C1CCN(Cc2ccc(-c3ncc(-c4nnn[nH]4)cc3-c3ccccc3)cc2)CC1

Procedure:
A mixture of 6-(4-{[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-5-phenylnicotinonitrile (1-5; TFA salt) (71 mg, 0.1 mmol), 2M of NaN3 water solution (0.75 mL, 1.5 mmol), 2M of ZnBr2 water solution (0.5 mL, 1.0 mmol) was microwaved (Smith-Synthesizer) at 165° C. for 15 min. After this time, the solution was concentrated. The residue was re-dissolved in DMSO (1 mL) and purified by LCMS to afford the pure desired product (1-6; TFA salt) as a slightly yellow solid. Analytical LCMS: single peak (214 nm), 2.248 min. 1H NMR (500 MHz, DMSO-d6): δ 10.94 (s, 1H), 9.74-9.90 (s, 1H), 9.33 (d, J=2.1 Hz, 1H), 8.44 (d, J=2.1 Hz, 1H), 7.47-7.50 (s, 4H), 7.36-7.40 (m, 3H), 7.26-7.30 (m, 3H), 6.98-7.02 m, 3H), 4.45-4.54 (m, 1H), 4.33-4.38 (s, 2H), 3.49 (d, J=12.7 Hz, 2H), 3.13-3.23 (m, 2H), 2.58-2.69 (m, 2H), 1.95 (d, J=12.8 Hz, 2H); HRMS, calc'd for C31H29N8O (M+1), 529.2459; found 529.2449.