Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([NH2:31])(=[O:30])=[O:29]>ClCCl.N1C=CC=CC=1>[NH2:31][S:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:1](=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([NH2:31])(=[O:29])=[O:30])=[O:13])(=[O:29])=[O:30]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccccc1NC(=O)c1ccccc1SSc1ccccc1C(=O)Nc1ccccc1S(N)(=O)=O
Temperature: 23 °C
Reaction time: 144 h
Yield: 19.6 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 2-aminobenzenesulfonamide (2.00 g, 11.6 mmol) in 16 mL of pyridine. The reaction mixture was stirred for 6 days at 23° C. under nitrogen atmosphere. The crude product was. recrystallized from acetonitrile to yield 0.70 g of the title compound, mp 150-151° C. (dec.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16](Br)=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([N:25]1[CH:30]2[CH2:31][CH2:32][CH:26]1[CH:27]=[C:28](B1OC(C)(C)C(C)(C)O1)[CH2:29]2)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:18]([O:22][C:23]([N:25]1[CH:30]2[CH2:31][CH2:32][CH:26]1[CH:27]=[C:28]([C:16]1[CH:15]=[CH:14][CH:13]=[C:10]([C:11]#[N:12])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:29]2)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: N#Cc1cccc(Br)c1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C2C=C(B3OC(C)(C)C(C)(C)O3)CC1CC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2C=C(c3cccc(C#N)c3OCc3ccccc3)CC1CC2
Temperature: 25 °C
Yield: 64.5 %

Procedure:
To a flask was added 2-benzyloxy-3-bromobenzonitrile (1.29 g, 4.47 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester (1.50 g, 4.47 mmol), and THF (30 mL), 2.0 M sodium carbonate in water (8.95 mL), and bis(triphenylphosphine)palladium(II) chloride (78 mg, 0.11 mmol). The reaction mixture was purged with nitrogen, heated to reflux overnight, cooled to room temperature, and concentrated. The resulting solution was diluted with DCM (25 mL) and washed with water (25 mL) The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatraphy eluting with ethyl acetate in hexanes (0-50%) to give partially purified product (1.2 g). (m/z): [M+H]+ calcd for C26H28N2O3, 416.21; (-tert-butyl 361.2). found 361; (-Boc 317.2). found 317.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[N:16][C:7]=3[NH:6][C:5]=2[C:4]([CH3:17])=[N:3]1.[H-].[Na+].[CH3:20]I.O>CN(C)C=O>[CH3:1][N:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:20])[C:8]3[CH:13]=[CH:14][CH:15]=[N:16][C:7]=3[NH:6][C:5]=2[C:4]([CH3:17])=[N:3]1
Reactant: Cc1nn(C)c2c1Nc1ncccc1NC2=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(C)c2c1Nc1ncccc1N(C)C2=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
An amount of 5.25 gm (0.025 mol) of 1,3-dimethyl-1,4,9,10-tetrahydro-pyrazolo[4,3-e]pyrido[3,2-b][1,4]diazepin-10-one was dissolved in 25 ml of N,N-dimethylformamide and mixed with 1.2 gm of a 55% sodium hydride dispersion in mineral oil. After stirring for 2 hours at 60° C., the solution was cooled to 40° C., and 2.2 ml of methyl iodide were added dropwise. Subsequently the mixture was stirred for 3 hours at 40° C., and after addition of 50 ml of water and cooling in the ice-bath, the desired compound was obtained in crystals. The crystals were recovered by suction filtration, and the mineral oil was washed out by means of petroleum ether.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([O:6]CC)=[O:5].[NH:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[C:18](=[O:30])[C:19]4[C:24]([S:25](=[O:29])(=[O:28])[C:26]=3[CH:27]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:12][N:11]=[N:10]1.[OH-].[Na+]>CC(C)=O.O>[C:4]([CH2:3][CH2:2][N:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[C:18](=[O:30])[C:19]4[C:24]([S:25](=[O:28])(=[O:29])[C:26]=3[CH:27]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:12][N:11]=[N:10]1)([OH:6])=[O:5]
Reactant: O=C1c2ccccc2S(=O)(=O)c2cc(-c3nnn[nH]3)ccc21
Reactant: CCOC(=O)CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)CCn1nnnc1-c1ccc2c(c1)S(=O)(=O)c1ccccc1C2=O

Procedure:
Ethyl 3-bromopropionate (9.05 g) in acetone (70 ml) was added to 3-(5-tetrazolyl)thioxanthone-10,10-dioxide (15.6 g) and sodium hydroxide (2.0 g) in water (15 ml). The mixture was boiled under reflux for 8 hr. On cooling the ester product crystallised out and was filtered off, washed with dilute sodium bicarbonate solution, and recrystallised from ethanol, m.p. 143°-145° C. The ester (4.5 g) was boiled with a mixture of concentrated hydrochloric acid (40 ml) and acetic acid (120 ml) for 3 hr. On cooling, 3-((2-carboxyethyl)-5-tetrazolyl)thioxanthone-10,10-dioxide crystallised out and was filtered off and washed with water, m.p. 206°-207° C. Found: C, 53.10%; H, 3.22%; N, 14.59%. C17H12N4O5S requires C, 53.12%; H, 3.15%; N, 14.58%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[CH:19]([C:20]4[CH:24]=[CH:23][S:22][CH:21]=4)[CH2:18][NH:17][CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:32][C:33]1[N:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>C(Cl)Cl>[Cl:32][C:33]1[C:34]([C:35]([N:17]2[CH2:18][CH:19]([C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)[CH:15]([CH2:14][N:11]3[CH2:10][CH2:9][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:13][CH2:12]3)[CH2:16]2)=[O:36])=[CH:38][CH:39]=[CH:40][N:41]=1
Reactant: Fc1ccc(C2CCN(CC3CNCC3c3ccsc3)CC2)cc1
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccnc1Cl)N1CC(CN2CCC(c3ccc(F)cc3)CC2)C(c2ccsc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.6 %

Procedure:
A mixture of 0.105 g (0.3 mmol) of 3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-(3-thienyl)pyrrolidine, 0.082 mL (0.6 mmol) of triethylamine and 0.054 g (0.3 mmol) of 2-chloronicotinoyl chloride (Aldrich) in 6 mL of CH2Cl2 was stirred at rt for 4 h. The reaction mixture was concentrated and the residue was purified by chomatography (silica, hexanes: acetone=3:1) to afford 0.12 g of the title compound.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]2[C:7]([C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[NH:10][C:11]2=[O:17])=[CH:6][CH:5]=1>CC(O)=O>[NH2:3][C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]2[C:7]([C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[NH:10][C:11]2=[O:17])=[CH:6][C:5]=1[Br:1]
Reactant: BrBr
Reactant: CC1(C)C(=O)NC(=O)c2c1ccc(N)c2[N+](=O)[O-]
Solvent: CC(=O)O
Product: CC1(C)C(=O)NC(=O)c2c1cc(Br)c(N)c2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
Bromine (9.27 mL, 188.6 mmol) was added dropwise to a solution of 7-amino-4,4-dimethyl-8-nitroisoquinoline-1,3(2H,4H)-dione (4.70 g, 18.86 mmol) in AcOH (190 mL). The reaction mixture was stirred at 25° C. for 2 h then was concentrated under reduced pressure. The residue was diluted with EtOAc, and successively washed with water, aqueous saturated NaHCO3, aqueous saturated Na2S2O3, and brine, dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound (6.10 g, 99% yield).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:17]=1[O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH2:24])=[O:23]>C(O)C>[Cl:32][C:30]1[CH:29]=[CH:28][C:17]([O:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([NH2:24])=[O:23])=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:31]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: NC(=O)c1cccc(Oc2ccc(Cl)cc2N)c1
Solvent: CCO
Product: CCCc1ccc2c(Nc3cc(Cl)ccc3Oc3cccc(C(N)=O)c3)ccnc2n1

Procedure:
The product from Example 2g (140 mg, 0.68 mmol) was reacted with the product from Example 171b (178 mg, 0.68 mmol) in ethanol (5 mL) at 85° C. in a sealed tube for 18 h giving the crude title compound which was purified by HPLC with TFA providing the product as the trifluoroacetic acid (110 mg, 30%). 1H NMR (500 MHz, DMSO-d6) δ ppm: 8.81 (d, J=8.54 Hz, 1 H) 8.45 (d, J=7.32 Hz, 1 H) 6.76-6.79 (m, 2 H) 6.64 (d, J=8.54 Hz, 2 H) 6.44 (s, 1 H) 6.37 (t, J=7.93 Hz, 1 H) 6.31 (d, J=8.54 Hz, 1 H) 7.16 (dd, J=7.93, 2.44 Hz, 1 H) 6.84 (d, J=7.32 Hz, 1 H) 2.95 (t, J=7.32 Hz, 2 H) 1.80 (m, 2 H) 0.95 (t, J=7.32 Hz, 3 H); MS (ESI+) m/z 433 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH:5]=[CH:6][CH:7]=1.Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(Br)c2)C(OCc2ccc3ccccc3c2)C1
Agent: Cl
Solvent: CO
Product: Brc1cccc(C2CCNCC2OCc2ccc3ccccc3c2)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 90.8 %

Procedure:
A solution of 173 mg (0.35 mmol) of tert-butyl (3RS,4RS)-4-(3-bromophenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 6 ml of methanol was treated with 6 ml of a 2N solution of hydrogen chloride in MeOH and stirred at 50° C. for 4 hours. Subsequently, the mixture was partitioned between ethyl acetate and a 5% sodium hydrogen carbonate solution, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel with a 10:1:0.1 mixture of methylene chloride, MeOH and 25% ammonia and the eluent. There were obtained 126 mg (91% of theory) of (3RS,4RS)-4-(3-bromophenyl)-3-(naphthalen-2-ylmethoxy)-piperidine as a light yellow oil. MS: 396, 398 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH2:15])=[CH:5][C:4]=1[O:16][CH3:17].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](Cl)=[O:33])=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl.C(N(CC)CC)C>[CH3:17][O:16][C:4]1[CH:5]=[C:6]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:29]([C:27]([NH:26][C:23]3[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=3)=[O:28])[CH:30]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(NC(=O)c2cccc(C(=O)Cl)c2)cc1
Reactant: COc1ccc([C@@H]2CCCC[C@@H]2N)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2cccc(C(=O)N[C@@H]3CCCC[C@@H]3c3ccc(OC)c(OC)c3)c2)cc1
Reaction time: 8 h

Procedure:
4.0 g of (−)-cis-1,2-dimethoxy-4-(2-aminocyclohexyl)benzene (compound C2) are dissolved in 100 ml of methylene chloride and 5.0 ml of triethylamine. The solution is added dropwise at RT to 4.95 g of 3-(4-methoxyphenylcarbamoyl)benzoyl chloride in 50 ml of methylene chloride and the mixture is extracted with 100 ml each of water, 2N hydrochloric acid, satd. sodium hydrogencarbonate solution and water again after stirring overnight. The organic phase is dried using sodium sulfate and concentrated. The residue is taken up in petroleum ether (low)/ethyl acetate in the ratio 2/1, filtered off with suction and dried. 7.14 g of the title compound are obtained.
Reaction SMILES: CC1(C)[O:7][CH2:6][CH:5]([CH2:8][CH2:9][N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][C:13]([NH2:19])=[N:14][CH:15]=3)[CH2:4][O:3]1.[ClH:21]>O1CCCC1.CO>[ClH:21].[NH2:19][C:13]1[N:12]=[C:11]2[C:16]([N:17]=[CH:18][N:10]2[CH2:9][CH2:8][CH:5]([CH2:6][OH:7])[CH2:4][OH:3])=[CH:15][N:14]=1
Reactant: CC1(C)OCC(CCn2cnc3cnc(N)nc32)CO1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ncc2ncn(CCC(CO)CO)c2n1
Reaction time: 2 h

Procedure:
To a stirred solution of 2,2-dimethyl-5-[2-(2-aminopurin-9-yl)ethyl]-1,3-dioxane (1 g) in a mixture of tetrahydrofuran (20 ml) and methanol (6 ml) at room temperature was added concentrated hydrochloric acid (0.32 ml). The resulting mixture was stirred for 2 hours during which time a solid crystallised. The solid was collected by filtration, washed with tetrahydrofuran (2 ml) and dried under a flow of air to give the desired product as the hydrochloride salt (800 mg, 81% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[CH:16]=[C:17](/[CH:22]=[CH:23]/[S:24](Cl)(=[O:26])=[O:25])[CH:18]=[CH:19][C:20]=1[Cl:21]>>[Cl:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([NH:1][S:24](/[CH:23]=[CH:22]/[C:17]2[CH:18]=[CH:19][C:20]([Cl:21])=[C:15]([Cl:14])[CH:16]=2)(=[O:26])=[O:25])=[C:3]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:4]=1
Reactant: Nc1cc(F)c(Cl)cc1S(N)(=O)=O
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Cl)c(Cl)c1
Product: NS(=O)(=O)c1cc(Cl)c(F)cc1NS(=O)(=O)/C=C/c1ccc(Cl)c(Cl)c1
Yield: 40 %

Procedure:
The title compound was synthesized as described for Example 226 a) in 40% yield, starting from 2-amino-5-chloro-4-fluorobenzenesulfonamide and (E)-2-(3,4-dichlorophenyl)ethenesulfonyl chloride.
Reaction SMILES: CCCC.I[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.CCO.O1CCCC1.C1(C)C=CC=CC=1>[O:16]([C:9]1[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:28]3[CH:29]=[CH:30][C:25]([CH:23]=[O:24])=[CH:26][CH:27]=3)[CH:7]=2)[N:12]=[CH:11][N:10]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Ic1ccc2ncnc(Oc3ccccc3)c2c1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: N#Cc1ccccc1
Solvent: CCCC
Product: O=Cc1ccc(-c2ccc3ncnc(Oc4ccccc4)c3c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of toluene (211 mL) in a 1.0 L round-bottom flask equipped with a reflux condenser was added 1,4-bis(diphenyl)phosphino)-butane (1.22 g, 2.87 mmol) and bis(benzonitrile)dichloro-palladium (1.1 g, 2.87 mmol). The resulting solution was stirred at room temperature for 30 minutes followed by the addition of THF (tetrahydrofuran) (255 mL) and EtOH (115 mL). To the resulting mixture was added 6-iodo-4-phenoxy-quinazoline 14 (5.0 g, 14.4 mmol), 4-formylphenylboronic acid (4.3 g, 28.7 mmol) and aqueous 1M Na2CO3 (29 mL). The mixture was heated at reflux under an atmosphere of N2 for 18 hours. The reaction mixture was filtered hot and the solvent removed under reduced pressure. The residue was taken up in CHCl3 and washed with water, brine, and dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified using flash chromatography (silica gel, EtOAc/hexanes 4:6) to provide (4.42 g, 13.54 mmol) 4-(4-phenoxy-quinazolin-6-yl)benzaldehyde 15 in 94% yield. 1H NMR (CDCl3) δ 7.26 (m, 3H), 2.88 (m, 1H), 7.51 (M, 2H), 7.92 (d, 2H, J=8.4 Hz), 8.02 (d, 2H, J=8 Hz), 8.11 (d, 1H, J=8.8 Hz), 8.20 (dd, 1H, J=2.4 and 8.8 Hz), 8.63 (d, 1H, J=2.4 Hz), 8.79 (s, 1H); MS (Cl) m/e 326 (M++1, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)([CH2:12][CH3:13])[C:9](N)=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)([CH2:12][CH3:13])[C:9]([OH:21])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: CCC(Cn1cncn1)(C(N)=O)c1ccc(Cl)cc1
Product: CCC(Cn1cncn1)(C(=O)O)c1ccc(Cl)cc1
Temperature: 10 °C

Procedure:
To a 500 mL flask was charged 95 g (0.34 mole) of 2-(4-chlorophenyl)-2-[(1,2,4-triazol-1-yl)methyl]butyramide and 95 g (0.97 mole) of 95% sulfuric acid and 95 g of ice. The reaction was stirred at reflux for 55 hours, after which the reaction was cooled to 10° C. and partitioned between ethyl acetate and water. The mixture was treated with 200 g of 10% sodium hydroxide which resulted in a pH 10 aqueous phase. The organic phase was extracted with 200 ml of water, then 200 ml of 10% sodium hydroxide and again with 200 mL of water. The aqueous phases were combined and washed with ethyl ether then acidified to pH 5 at which point a solid formed. The solid was filtered, washed with water, dried and gave 73 g (77% yield) of a white solid, Example 1 of Table 1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][C@@:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23]([C:25]4[CH:30]=[N:29][C:28]([O:31][CH3:32])=[CH:27][N:26]=4)=[O:24])[CH:20]=3)[O:15][C:14]([CH3:34])([CH3:33])[C:13]32[CH2:36][CH2:35]3)[N:12]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:7][C:8]1[O:9][CH2:10][C@@:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23]([C:25]4[CH:30]=[N:29][C:28]([O:31][CH3:32])=[CH:27][N:26]=4)=[O:24])[CH:20]=3)[O:15][C:14]([CH3:33])([CH3:34])[C:13]32[CH2:35][CH2:36]3)[N:12]=1
Reactant: COc1cnc(C(=O)Nc2ccc3c(c2)[C@@]2(COC(NC(=O)OC(C)(C)C)=N2)C2(CC2)C(C)(C)O3)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1cnc(C(=O)Nc2ccc3c(c2)[C@@]2(COC(N)=N2)C2(CC2)C(C)(C)O3)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a solution of tert-butyl[(4′R)-6′-{[(5-methoxypyrazin-2-yl)carbonyl]amino}-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl]carbamate (392 mg, 0.769 mmol) in chloroform (3 ml) was added trifluoroacetic acid (1.8 ml), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (precolumn: NH-silica gel, main column: neutral silica gel, chloroform/methanol=10:0-10:1). To the purified product was added a mixture of hexane/ethyl acetate (4:1) and the mixture was stirred at room temperature over night. The precipitate was collected, washed with mixture of hexane/ethyl acetate (4:1), and dried in vacuo to afford N-[(4′R)-2″-amino-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-6′-yl]-5-me thoxypyrazine-2-carboxamide (246 mg).
Reaction SMILES: C(O[C@H:5]1[C@H:10]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[N:16][C:17]#[N:18])[C:9]2[CH:19]=[C:20]([C:23]#[N:24])[CH:21]=[CH:22][C:8]=2[O:7][C:6]1([CH3:26])[CH3:25])(=O)C.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[C:17]([N:16]=[C:12]1[NH:13][CH2:14][CH2:15][N:11]1[C:10]1[C:9]2[CH:19]=[C:20]([C:23]#[N:24])[CH:21]=[CH:22][C:8]=2[O:7][C:6]([CH3:26])([CH3:25])[CH:5]=1)#[N:18]
Reactant: CC(=O)O[C@H]1[C@H](N2CCNC2=NC#N)c2cc(C#N)ccc2OC1(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC1(C)C=C(N2CCNC2=NC#N)c2cc(C#N)ccc2O1
Yield: 58.5 %

Procedure:
To a suspension of trans-3-acetoxy-4-(2-cyanoiminoimidazolidin-1-yl)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.35 g) in toluene (7 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 ml) and the mixture was stirred under reflux for 2.5 hours. The solvent was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from ethanol to give 4-(2-cyanoiminoimidazolidin-1-yl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.17 g).
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]#[N:18])=[CH:9][CH:8]=2)[C:5]([S:19][CH2:20][C:21](O)=[O:22])=[N:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:31])[C@H:28]([CH3:30])[NH2:29])[CH3:25]>>[Br:1][C:2]1[N:6]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]#[N:18])=[CH:9][CH:8]=2)[C:5]([S:19][CH2:20][C:21]([NH:29][C@@H:28]([CH3:30])[C:27]([O:26][CH2:24][CH3:25])=[O:31])=[O:22])=[N:4][CH:3]=1
Reactant: CCOC(=O)[C@H](C)N
Reactant: N#Cc1ccc(-n2c(Br)cnc2SCC(=O)O)c2ccccc12
Product: CCOC(=O)[C@H](C)NC(=O)CSc1ncc(Br)n1-c1ccc(C#N)c2ccccc12

Procedure:
(2S)-ethyl 2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)propanoate was prepared by coupling 2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-acetic acid with alanine ethyl ester according to the procedure described in example 2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13](SC)=[NH:14])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.C(OC([N:24]1[CH2:29][CH2:28][CH2:27][C@H:26]([NH2:30])[CH2:25]1)=O)(C)(C)C.C(N(CC)CC)C>CN(C=O)C.C(O)(C)C>[NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13]([NH:30][CH:26]2[CH2:27][CH2:28][CH2:29][NH:24][CH2:25]2)=[NH:14])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: N=C(NC(=O)c1nc(Cl)c(N)nc1N)NC1CCCNC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
A mixture of 1.17 g (4.5 mmol) 4-Aminomethyl-4-phenethyl-piperidine-1-carbocylic acid tert-butyl ester (intermediate 3), 1 mg (4.9 mmol) (S)-3-amino-piperidine-1-carboxylic acid tert-butyl ester and 125 μl triethylamin in 50 ml DMF/iso-propanol (1:3) is stirred at 70° C. overnight. Then the reaction mixture is concentrated under reduced pressure. Then 50 ml 25% TFA in dicholoromethane is added and the mixture is stirred for 2 h at room temperature and evaporated. The residue is treated with excess HCl in methanol and evaporated again to yield 430 mg N-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-N′-piperidin-3-yl-guanidine. Step B: 100 mg N-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-N′-piperidin-3-yl-guanidine, 125 μl triethylamine and 62 mg 3-bromomethyl-benzoic acid methyl ester in 3 ml DMF were stirred at room temperature for 6 h. Then the reaction mixture is concentrated under reduced pressure and the residue is purified by preparative reverse phase HPLC (gradient of acetonitrile and water+0.2% trifluoroacetic acid, 25° C.). Fractions containing the title compound were concentrated under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9][CH2:10][C:11]2[NH:20][C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[N:12]=2)[N:3]=1.[CH2:21]([O:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[CH2:21]([O:28][C:29]1[CH:34]=[C:33]([C:17]2[CH:18]=[C:13]3[N:12]=[C:11]([CH2:10][CH2:9][C:4]4[N:3]=[C:2]([NH2:1])[CH:7]=[C:6]([CH3:8])[CH:5]=4)[NH:20][C:14]3=[N:15][CH:16]=2)[CH:32]=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Reactant: Cc1cc(N)nc(CCc2nc3cc(Br)cnc3[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(N)nc(CCc2nc3cc(-c4cccc(OCc5ccccc5)c4)cnc3[nH]2)c1
Yield: 61 %

Procedure:
The title compound is synthesized according to General Procedure A. 150 mg of 2-[2-(2-amino4-methylpyridin-6-yl)ethyl]-6-bromo-3H-imidazo[4,5-b]pyridine in 7.5 ml dioxane, 1.36 ml Na2CO3 solution, 116 mg of 3-benzyloxyphenylboronic acid, 20 mg of PdCl2(PCy3)2, 120° C. for 48 h, 20 ml of CH2Cl2/H2O, 220 mg of crude title compound is purified by re-crystallization from 6.0 ml isopropyl alcohol to yield 120 mg of the title compound. M.p. 181° C. ESI-MS: 436.3 (MH+). TLC: Rf=0.30 (dichloromethane/methanol 10:1).