Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:12]=[N:11][C:5]2[O:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(#N)C>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:2]2[CH:12]=[N:11][C:5]3[O:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=3[CH:3]=2)[CH:14]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C1COc2ncc(Br)cc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: O=C1COc2ncc(-c3cccnc3)cc2N1
Reaction time: 10 h
Yield: 110 %

Procedure:
To 1.6 ml of acetonitrile/0.4 ml of distilled water, 7-bromo-1H-pyrido[2,3-b][1,4]oxazin-2-one (100 mg, 0.436 mmol), 3-pyridine boronic acid (29.5 mg, 0.240 mmol), palladium acetate (4.9 mg, 0.0218 mmol), triphenylphosphine (11.4 mg, 0.0436 mmol) and potassium carbonate (45.2 mg, 0.327 mmol) were added and then stirred at 1000 for 10 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:methanol=50:1. The fractions containing the product were collected and evaporated to obtain 7-pyridin-3-yl-1H-pyrido[2,3-b][1,4]oxazin-2-one as brown oil (60 mg, 60%).
Reaction SMILES: [CH3:1][C:2]([N:7]=[C:8]=[N:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)([CH3:6])[CH2:3][CH2:4][CH3:5].C([N:20]=[C:21]=[N:22]C1C=NC=CC=1)(C)(C)C>>[C:21]([N:22]=[C:8]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[NH:7][C:2]([CH3:1])([CH3:6])[CH2:3][CH2:4][CH3:5])#[N:20]
Reactant: CCCC(C)(C)N=C=Nc1cccnc1
Reactant: CC(C)(C)N=C=Nc1cccnc1
Product: CCCC(C)(C)NC(=NC#N)Nc1cccnc1

Procedure:
By following the procedure of Example 1, but substituting N-(1,1-dimethylbutyl)-N'-3-pyridylcarbodiimide for the N-tert-butyl-N'-3-pyridylcarbodiimide, the N"-cyano-N-(1,1-dimethylbutyl)-N'-3-pyridylguanidine was obtained with a melting point of 188.0°-188.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23]Cl>COCCOC>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][O:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1ccc([N+](=O)[O-])cc1OCCN(C)C
Reaction time: 18 h
Yield: 86.2 %

Procedure:
A stirred solution of 2-methoxy-5-nitrophenol (10 g, 0.059 mole) in 1,2-dimethoxyethane (80 ml) was treated with saturated aqueous potassium carbonate solution (32 ml) followed by 2-dimethylaminoethyl chloride hydrochloride (8.2 g, 0.057 mole) and heated under reflux for 17 hours. A further quantity of 2-dimethylaminoethyl chloride hydrochloride (4.0 g, 0.029 mole) was added and reflux was continued for 18 hours. The mixture was then concentrated in vacuo and the residue treated with 10% Na2 CO3 solution (100 ml) and extracted with ethyl acetate (2×100 ml). The combined extract was dried (Na2SO4) and concentrated in vacuo to afford the title compound as a yellow solid (11.8 g, 83%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.Br[CH2:13][CH:14]1[CH2:17][CH2:16][CH2:15]1.Cl>CN(C)C=O.C(OCC)(=O)C>[CH:14]1([CH2:13][O:3][C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: BrCC1CCC1
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCC2CCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 0.328 g) in N,N-dimethylformamide (15.0 mL), a solution of 4-hydroxybenzaldehyde (1.00 g) in N,N-dimethylformamide (5.00 mL) was added at 0° C. and thereafter the mixture was stirred at room temperature for 30 minutes. After adding (bromomethyl)cyclobutane (1.22 g), the mixture was stirred at 70° C. for 24 hours. After cooling the reaction mixture to room temperature, 0.5 mol/L hydrochloric acid was added under cooling with ice and three extractions were conducted with ethyl acetate. The combined organic layers were passed through a phase separator and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-40:60) to give the titled compound as a colorless oil (1.19 g).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:3]=1[CH2:4][NH:5][S:6]([CH3:9])(=[O:8])=[O:7]>O1CCCC1.C(O)C.[Pd]>[NH2:14][C:12]1[CH:11]=[CH:10][C:3]([CH2:4][NH:5][S:6]([CH3:9])(=[O:8])=[O:7])=[C:2]([CH3:1])[CH:13]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1CNS(C)(=O)=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(N)ccc1CNS(C)(=O)=O
Reaction time: 24 h
Yield: 69.6 %

Procedure:
To a stirred solution of N-(2-methyl-4-nitrobenzyl)methanesulfonamide (100 mg, 0.409 mmol) in tetrahydrofuran and ethanol as co-solvent were added 10% Pd/C (40 mg). The mixture was charged with H2 (gas) balloon. The resulting mixture was stirred for 24 h, then filtered using celite. The filtrate removed in vacuo. The crude was purified by column chromatography. N-(4-Amino-2-methylbenzyl)methanesulfonamide (61 mg) was obtained as 70% yield.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([NH:11][NH2:12])[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH3:13][CH2:14][O:15][C:16]([CH:18]([C:22]([CH3:24])=O)[C:19]([CH3:21])=O)=[O:17]>CC(O)=O.O>[CH2:14]([O:15][C:16]([C:18]1[C:19]([CH3:21])=[N:12][N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=2)[C:22]=1[CH3:24])=[O:17])[CH3:13]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: NNc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nn(-c2cccc([N+](=O)[O-])c2)c1C
Reaction time: 20 h

Procedure:
Following the procedure described in Helvetica Chimica Acta (1952), 35, 478-85, 5.00 g (26.37 mmmol) of 3-nitrophenylhydrazine hydrochloride suspended in 46 ml of 55% aqueous AcOH were dissolved by careful heating and treated (without further heating) with 4.13 ml (26.37 mmol) of ethyl diacetoacetate. The reaction was immediately cooled and kept 20 h at 0° C. The precipitate was diluted with 28 ml of water and after 6 h filtered and washed with 2×5 ml of water to give after drying under reduced pressure 4.66 g (61%) of the title compound as a light yellow solid. MS: 289.9 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].N12CCCN=C1CCCCC2.[Cl-].[Na+]>ClCCl>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][N:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1)[CH3:14]
Reactant: O=Cc1cn[nH]c1
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)Cn1cc(C=O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a mixture of 1H-pyrazole-4-carbaldehyde (5.5 g) and ethyl bromoacetate (19.0 g) in dichloromethane (150 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (10 ml) at 0° C. The resulting mixture was stirred at room temperature for 30 minutes, and the reaction was stopped by addition of a saturated aqueous sodium chloride solution. The products were extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo, and the residue was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate (1:3) as the eluent to afford the title compound as a colourless oil (8.09 g, yield: 78%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[C:4]([Cl:17])[CH:3]=1.[C:18]1(=[O:29])[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]2[CH2:19]1>O1CCCC1>[Cl:17][C:4]1[CH:3]=[C:2]([NH:1][C:18]([CH2:19][C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])=[O:29])[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[CH2:11][O:10]1
Reactant: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: C1CCOC1
Product: CC1(C)CON(Cc2ccc(NC(=O)Cc3ccccc3C(=O)O)cc2Cl)C1=O
Yield: 58.5 %

Procedure:
This compound was prepared in a manner analogous to that of Example 1, Step C, using 4.0 grams (0.016 mole) of 2-[(4-amino-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone and 2.6 grams (0.016 mole) of homophthalic anhydride in 150 mL of tetrahydrofuran. The reaction mixture was concentrated under reduced pressure to a residual oil. The oil was dissolved in acetone, and petroleum ether was added. The resultant solid was collected by filtration and was recrystallized from acetone/water to yield 3.9 grams of 2-[[2-chloro-4-[(2-carboxyphenylmethyl)carbonylamino]phenyl]methyl]-4,4-dimethyl-3-isoxazolidinone; m.p. 194°-196° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[N:10]([CH2:31][CH:32]=[CH2:33])[C:11]1[C:16](=[O:17])[N:15]2[C@H:18]([C:22](=[O:30])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH:20]([CH3:21])[C:14]2=[N:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48]>C1COCC1>[C:50]([O:49][C:47](=[O:48])[CH2:46][C@@:20]1([CH3:21])[C:14]2=[N:13][CH:12]=[C:11]([N:10]([CH2:31][CH:32]=[CH2:33])[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:34])[C:16](=[O:17])[N:15]2[C@@H:18]([C:22](=[O:30])[NH:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:19]1)([CH3:53])([CH3:52])[CH3:51]
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)Nc1ccccc1)CC2C
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)Nc1ccccc1)C[C@@]2(C)CC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
To Intermediate 18c (495.7 mg, 1.08 mmol) in THF at −78° C. was added LiHMDS (2.268 mL, 2.268 mmol) dropwise. After 10 min, tert-butyl bromoacetate was added and the mixture was stirred at −78° C. for 20 min. It was allowed to warm to −40° C. over 20 min, then quenched with NH4Cl. The reaction mixture was diluted with EtOAc, then washed with H2O, brine, dried (Na2SO4) and concentrated. It was purified by SiO2 chromatography (50% EtOAc/hexanes) to afford 367.9 mg (59%) of intermediate 38a.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][CH2:27][O:28][C:21]=3[CH:20]=2)[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][CH2:27][O:28][C:21]=4[CH:20]=3)[C:10]3[CH:15]=[C:14]([Cl:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Clc1nc(NCc2ccc3c(c2)OCCO3)c2cc(Cl)sc2n1
Product: Clc1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2,6-dichloro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-chloro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.O>C(Cl)(Cl)Cl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH:7]([N:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:12][CH2:11]3)[CH2:6][CH2:5]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NCCN1CCC(N2CCc3ccccc32)CC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=S(=O)(NCCN1CCC(N2CCc3ccccc32)CC1)c1ccc(Cl)cc1
Yield: 69.4 %

Procedure:
1-[1-(2-Aminoethyl)piperidin-4-yl]indoline (113 mg) was dissolved in chloroform (3 ml). Under ice cooling, 4-chlorobenzenesulfonyl chloride (97 mg) was added thereto and the resultant mixture was stirred for 6 hr. After adding water, the reaction solution was extracted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. After evaporating the solvent, the resulting residue (205 mg) was purified by NH-silica gel column chromatography (methanol/methylene chloride system) to give the title compound (134 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[C:11]1([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[N:20]=[C:19](NC(NC3C=CC=C(C(F)(F)F)C=3)=O)[CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:8][CH2:5][CH2:4][CH2:3][C:19]2[CH:18]=[C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:21]([C:22]3[CH:23]=[CH:24][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:26][CH:27]=3)[N:20]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(-n2nc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2-c2ccccc2)cc1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CO
Product: NS(=O)(=O)c1ccc(-n2nc(CCCNC(=O)Nc3ccc(Cl)cc3)cc2-c2ccccc2)cc1
Yield: 92 %

Procedure:
The titled compound was prepared in 92% yield from 4-chlorophenyl isocyanate using the procedure detailed for compound 7. mp 103.2-110.4° C. 1H NMR (300 MHz, DMSO-d6): δ 8.60 (s, 1H), 7.79 (d, J=9 Hz, 2H), 7.47-7.35 (m, 9H), 7.29-7.21 (m, 4H), 6.57 (s, 1H), 6.29 (t, J=6 Hz, 1H), 3.26-3.13 (m, 2H), 2.68 (t, J=8 Hz, 2H), 1.92-1.77 (m, 2H). MS (ESI) m/z: 510.14 (M+H+). Anal. Calcd for C25H24ClN5O3S.MeOH: C, 58.22; H, 4.98; N, 13.31. Found: C, 58.18; H, 4.78; N, 13.25.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.[CH3:32][NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:33]([CH3:32])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: CNc1ccccc1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Product: CCOC(=O)c1c(CN(C)c2ccccc2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
According to the same manner as that described in Example 34, ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate was reacted with N-methylaniline to give ethyl 4-(3,4-dimethoxyphenyl)-2-(N-methyl-N-phenylaminomethyl)-6,7-dimethoxyquinoline-3-carboxylate. This compound was recrystallized from dichloromethane-hexane. Colorless prisms, mp. 194°-196° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:3]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].[CH3:69][NH2:70]>C1(C)C=CC=CC=1.CCCCCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O>[CH3:69][NH:70][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[C:5]([NH:8][CH3:9])=[CH:6][N:7]=1
Reactant: CN
Reactant: CNc1cnc(Cl)cc1-c1ccccc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CNc1cc(-c2ccccc2C)c(NC)cn1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
To a solution of 6-chloro-N-methyl-4-o-tolylpyridin-3-amine (74 mg, 0.318 mmol, prepared as described in WO2005/002577), palladium(II) acetate (7 mg, 0.031 mmol, CAS RN 3375-31-3) and (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (60 mg, 0.96 mmol, CAS RN 76189-55-4) in toluene (2.5 mL) was added sodium tert-butoxide (92 mg, 0.96 mmol). After stirring for 5 min, methylamine (2.0 M solution in THF, 400 μL, 0.80 mmol, CAS RN 74-89-5) was added and the reaction mixture was heated by microwave irradiation to 150° C. for 30 min. The reaction mixture was applied directly to a silica gel column. Flash chromatography (33-50% EtOAc in n-hexane) gave the product, as a light brown oil which was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:16]=[C:15](Cl)[CH:14]=[CH:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:16]=[C:15]([C:22]4[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=4)[CH:14]=[CH:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Clc1ccc2ncnc(N3CCOCC3)c2n1
Product: Clc1ccc(-c2ccc3ncnc(N4CCOCC4)c3n2)cc1
Yield: 92 %

Procedure:
The reaction of 4-morpholino-6-chloro-pyrido[3,2-d]pyrimidine and 4-chlorophenylboronic acid afforded the pure title compound (yield 92%) as a white solid solid which was characterized by its mass spectrum as follows: MS (m/z): 341.2 ([M+H]+, 100).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]([OH:22])=[C:9]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:12])[N:10]=1.Cl>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:13][C:11]([C:9]2[N:10]=[C:5]([CH2:4][CH:3]=[O:2])[N:6]([CH3:24])[C:7](=[O:23])[C:8]=2[OH:22])=[O:12])=[CH:20][CH:19]=1
Reactant: COC(Cc1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)n1C)OC
Agent: Cl
Product: Cn1c(CC=O)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O

Procedure:
The product of Step 1 was treated with a mixture HCl 1N/for 1 hour at 40° C. Organics were removed in vacuo and residue extracted in DCM, dried over Na2SO4 and concentrated to give the title compound as a foam which was immediately reacted in the following reductive amination.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C@@H:11](O)[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)=[O:4].C1C=CC(P([N:30]=[N+:31]=[N-:32])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:30]([C@@H:11]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:14]=[CH:13][C:12]1=2)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc2c(c1)CCC[C@@H]2O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc2c(c1)CCC[C@H]2N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a 500 mL three-neck round-bottomed flask equipped with argon inlet/outlet, thermometer, and magnetic stirring was added 5(S)-hydroxy-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester (29 g, 140 mmol) in 280 mL of toluene. The reaction mixture was cooled in a ice-salt bath, and DPPA (36 mL, 170 mmol, Aldrich) was added (internal temp.=−4° C.). DBU (25 mL, 170 mmol, Aldrich) was added over 10 min at such a rate that the internal temperature was kept below 1° C. The ice in the bath was allowed to melt, and the reaction continued for 12 h during which time the mixture stopped stirring because a precipitate had formed. Stirring was resumed, and the reaction mixture was stirred at RT for another 11 h. The reaction contents were poured into a 2 L sep funnel, and the lower dark-brown layer was removed. Water (250 mL) was added to the remaining top layer, and the mixture was extracted with Et2O (3×250 mL). The combined organic layers were washed with 1M H3PO4, water, satd NaHCO3, and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (330 g Isco Redisep® column, 1:1 hexane-CH2Cl2) of the crude material provided the title compound. MS (+ion ESI) m/z =232 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][Si](C(C)(C)C)(C)C)[C:25](Br)=[CH:24][C:23]=2[CH2:37][CH3:38])[C:12]=1[CH2:39][CH2:40][CH3:41].[O:43]1[CH:47]=[CH:46][CH:45]=[C:44]1B(O)O.C(=O)([O-])[O-].[Na+:55].[Na+]>O1CCCC1.O.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>[Na+:55].[CH2:37]([C:23]1[CH:24]=[C:25]([C:44]2[O:43][CH:47]=[CH:46][CH:45]=2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:39][CH2:40][CH3:41])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([O-:42])=[O:2])[CH3:38]
Reactant: OB(O)c1ccco1
Reactant: CCCc1c(OCCCOc2cc(O[Si](C)(C)C(C)(C)C)c(Br)cc2CC)cccc1Oc1ccccc1C(=O)OC
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: O
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2cc(O)c(-c3ccco3)cc2CC)cccc1Oc1ccccc1C(=O)[O-]
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of 2-(3-{3-[4-bromo-5-(tert-butyldimethylsilanyloxy)-2-ethylphenoxy]propoxy}-2-propylphenoxy)benzoic acid methyl ester (1.05 g, 1.60 mmol), furan-2-boronic acid (0.358 g, 3.20 mmol), tetrakis(triphenylphosphine)palladium(0) (0.185 g, 0.160 mmol), and 2 M aqueous sodium carbonate solution (8 mL) in tetrahydrofuran (20 mL) was heated at reflux for 18 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was separated, washed once with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate/90% hexane) of the residue provided 0.8 g (94%) of the title compound as a colorless oil. 1H NMR (CDCl3) δ 7.90 (d, J=9 Hz, 1H), 7.48 (s, 1H), 7.38 (t, J=8 Hz, 1H), 7.21 (s 1H), 7.13 (s, 1H), 7.10 (d, J=9 Hz, 1H), 7.07 (d, J=2 Hz, 1H), 6.81 (d, J=9 Hz, 1H), 6.69 (d, J=9 Hz, 1H), 6.52 (m, 3H), 6.44 (d, J=9 Hz, 1H), 4.20 (m, 4H), 3.83 (s, 3H), 2.67 (t, J=8 Hz, 2H), 2.59 (q, J=7 Hz, 2H), 2.32 (quintet, J=6 Hz, 2H), 1.55 (hextet, J=8 Hz, 2H), 1.18 (t, J=7 Hz, 3H), 0.91 (t, J=7 Hz, 3H); MS ES− m/z=589 (p+AcO−). Anal. Calcd for C32H34O7: C, 72.43; H, 6.46. Found: C, 72.21; H, 6.15.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([N:7]1[N:11]=[CH:10][C:9]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8]1)=[NH:6])[CH3:3].[C:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)(=[O:18])[CH3:17].C(N(CC)CC)C>ClCCl>[CH2:8]1[C:9]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:10]=[N:11][N:7]1[C:5](=[N:6][S:26]([C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:16](=[O:18])[CH3:17])=[CH:25][CH:24]=1)(=[O:28])=[O:27])[NH:4][CH2:2][CH3:3]
Reactant: CCNC(=N)N1CC2(C=N1)CCCC2
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=NS(=O)(=O)c1ccc(NC(C)=O)cc1)N1CC2(C=N1)CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
N-Ethyl-2,3-diaza-spiro[4.4]non-3-ene-2-carboxamidine hydrochloride (60 g, 260.08 mmol; isolated from reaction of N-ethyl-2,3-diaza-spiro[4.4]non-3-ene-2-carboxamidine, synthesized as described in WO 2009/115515, with HCl in isopropanol) was dissolved in 1000 mL dichloromethane, and 4-acetylamino-benzenesulfonyl chloride (60.7 g, 260.08 mmol) was added. Under mechanical stirring, triethylamine (131.6 g, 1300.4 mmol) was added over a period of 20 minutes, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water (250 mL) and the organic phase was concentrated under reduced pressure (40° C., 600 mbar). The oily residue was coevaporated twice with 96% ethanol (250 mL) and taken up in 500 mL dichloromethane. The organic phase was extracted with 1N aqueous HCl (75 mL) and subsequently twice with water (200 mL) and evaporated to dryness under reduced pressure to yield 78 g (199.2 mmol, 77%) of N-(4-{[(2,3-diaza-spiro[4.4]non-3-en-2-yl)-ethylamino-methylene]sulfamoyl}-phenyl)-acetamide. 1H NMR identical to spectrum obtained from material prepared via novel route (vide supra).