Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:5]1=2)([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[NH2:16][C:13]1[CH:14]=[CH:15][C:5]2[N:4]([CH:1]([CH3:3])[CH3:2])[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:12]=1
Reactant: [H][H]
Reactant: CC(C)N1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)N1C(=O)CCCc2cc(N)ccc21
Yield: 83 %

Procedure:
1-Isopropyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (474 mg, 1.91 mmol) was charged to 10 ml ethanol and 100-200 mg 10% palladium on carbon was added. The suspension was hydrogenated at 30 psi hydrogen for 2.5 hours and followed by NMR. The reaction was filtered through a ¼″ pad of celite and the pad washed with 4×10 ml portions of methanol. The resulting solution was clarified through a 45 micron frit to yield 7-Amino-1-isopropyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (346 mg, 83% yield) as a clear oil. 1H-NMR (CDCl3) δ 6.96 (d, J=8.3 Hz, 1H), 6.56 (d, J=8.3 Hz, 1H), 6.51 (s, 1H), 4.80 (m, 1H), 3.67 (br s, 1H), 2.71 (m, 1H), 2.44 (m, 1H), 2.20 (m, 3H), 1.84 (m, 1H), 1.36 (d, J=6.8 Hz, 3H), 1.01 (d, J=6.8 Hz, 3H). LC/MS (ESI+)=219 (M+H).
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].O1CCCCC1[O:12][NH:13][C:14]([C@H:16]([C@@H:26]([CH2:42][CH:43]([CH3:45])[CH3:44])[C:27]([NH:29][N:30]([S:38]([CH3:41])(=[O:40])=[O:39])[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:28])[CH2:17]/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:15]>>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[OH:12][NH:13][C:14]([C@H:16]([C@@H:26]([CH2:42][CH:43]([CH3:45])[CH3:44])[C:27]([NH:29][N:30]([S:38]([CH3:41])(=[O:40])=[O:39])[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:28])[CH2:17]/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:15]
Reactant: CC(C)C[C@@H](C(=O)NN(Cc1cccnc1)S(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: CS(=O)(=O)O
Product: CC(C)C[C@@H](C(=O)NN(Cc1cccnc1)S(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NO

Procedure:
In a manner analogous to that described in the first paragraph of Example 2, but using methanesulphonic acid in place of p-toluenesulphonic acid, starting from 0.2 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methyl-2′-[(3-pyridyl)methyl]valerohydrazide there was obtained 0.177 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methyl-2′-[(3-pyridyl)methyl]valerohydrazide methanesulphonate in the form of an orange solid.
Reaction SMILES: Br[C:2]1[CH:39]=[CH:38][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[CH:16]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=2)[CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[F:40][C:41]([F:52])([F:51])[C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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:36]([C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][CH:16](/[CH:15]=[CH:14]/[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]2[CH:38]=[CH:39][C:2]([C:45]3[CH:46]=[CH:47][C:42]([C:41]([F:52])([F:51])[F:40])=[CH:43][CH:44]=3)=[CH:3][CH:4]=2)[CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)=[CH:31][CH:32]=1)#[N:37]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(Br)cc2)CCc2ccc(C#N)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CCc2ccc(C#N)cc2)cc1
Yield: 57.4 %

Procedure:
270 mg (0.47 mmol) of methyl E-4-{4-[2-(4-bromobenzyloxy)phenyl]-2-[2-(4-cyanophenyl)ethyl]but-3-enyl}benzoate from Example 18A are dissolved in 3 ml of 1,2-dimethoxyethane and, under argon, 106 mg (0.56 mmol) of 4-trifluoromethylphenylboronic acid, 3.3 mg of bis(triphenylphosphine)palladium(II) chloride and 0.51 ml of a 2 M solution of sodium carbonate in water are added. The reaction mixture is then stirred under reflux for 12 hours. The mixture is subsequently cooled, filtered through 1 g of Extrelut, washed with dichloromethane and concentrated. The resulting crude product is purified by preparative HPLC. 175 mg (0.27 mmol, 58% yield) of a colorless solid are obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:17][CH:16]2[NH:18][CH:13]([CH2:14][CH2:15]2)[CH:12]=1.Br[CH2:20][CH2:21][OH:22].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:12][CH:13]2[N:18]([CH2:20][CH2:21][OH:22])[CH:16]([CH2:15][CH2:14]2)[CH:17]=1
Reactant: OCCBr
Reactant: C1=C(c2ccc3ccccc3c2)CC2CCC1N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCN1C2C=C(c3ccc4ccccc4c3)CC1CC2
Yield: 91 %

Procedure:
3-Naphthalen-2-yl-8-aza-bicyclo[3.2.1]oct-2-ene (1.00 g, 4.25 mmol), 1.05 g (8.40 mmol) 2-bromoethanol, 1.70 g (12.6 mmol) K2CO3 and 57 mL of DMF are stirred at 80 C for 12 h. The reaction mixture is poured into 300 mL of cold H2O and extracted with 3×50 mL of EtOAc. The combined organics are washed with 3×100 mL of H2O, 1×100 mL of brine, dried over MgSO4, filtered, and the volatiles are evaporated to give 1.08 g (3.87 mmol, a 91% yield) of the title compound as a white solid. mp: 113-114° C.; MS (ES) m/z 280 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:15][C:14](=[O:16])[O:13][C:11](=[O:12])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][O:18][C:19]1[C:20]([NH2:25])=[CH:21][CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][C:11]([NH:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH3:17])=[O:12])[CH2:15][C:14]([OH:13])=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Reactant: COc1ccccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,4-Dichlorophenyl)glutaric anhydride (10 g, Example 1, Step C) in CH2Cl2 (150 mL) at 0° C. was treated sequentially with o-anisidine (6 mL), triethylamine (6.7 mL) and N,N-dimethylaminopyridine (440 mg). The mixture was stirred at 0° C. for two hours then allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was diluted with CH2Cl2 (500 mL) and washed with 1N HCl (1×200 mL) and water (1×200 mL). The organic layers were dried over MgSO4, filtered and concentrated to afford the title compound (14 g).
Reaction SMILES: [CH3:1][C:2]1[S:23][C:5]2[N:6]=[C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH:17]=[O:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)[NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.CO.[BH4-].[Na+]>C(Cl)Cl>[OH:18][CH2:17][C:15]1[C:14]([C:19]([F:20])([F:22])[F:21])=[N:13][N:12]([CH2:11][C:7]2[NH:8][C:9](=[O:10])[C:4]3[CH:3]=[C:2]([CH3:1])[S:23][C:5]=3[N:6]=2)[CH:16]=1
Reactant: Cc1cc2c(=O)[nH]c(Cn3cc(C=O)c(C(F)(F)F)n3)nc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc2c(=O)[nH]c(Cn3cc(CO)c(C(F)(F)F)n3)nc2s1
Yield: 27.7 %

Procedure:
1-((6-Methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (100 mg, 0.292 mmol) was dissolved in a 1:1 DCM:MeOH solution (2 mL) and sodium borohydride (33 mg, 0.876 mmol) added. After 30 min the mixture was quenched by addition of water (1 mL) then concentrated in vacuo. Purification by flash column chromatography-silica gel and elution with 3% MeOH:DCM resulted in a white solid which was recrystallised from isopropanol and freeze dried to give the title compound as a white solid (28 mg, 0.081 mmol, 28%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[NH:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30]>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:25]4[CH2:29][CH2:28][CH2:27][C:26]4=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: O=C1CCCN1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3)CC2)c(C)c1

Procedure:
Using [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (435 mg) described in Preparation Example 133 and pyrrolidin-2-one (115 μL) and by the reaction and treatment in the same manner as in Example 262, the title compound (234 mg) was obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.[CH2:15]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](Cl)=[O:38])=[CH:32][CH:31]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>O1CCCC1>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:37](=[O:38])[CH2:36][C:33]2[CH:34]=[CH:35][C:30]([O:29][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:31][CH:32]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1
Reactant: Nc1cccc(I)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(I)c2)cc1
Reaction time: 8 h

Procedure:
To a solution of 14.29 g of m-iodoaniline and 15.52 g of pyridine in 150 ml of tetrahydrofuran is added at room temperature over 20 minutes a solution of p-tetradecyloxyphenylacetyl chloride in 150 ml of tetrahydrofuran. The mixture is stirred overnight and the solvent removed. The residue is partitioned between dilute hydrochloric acid and warm chloroform. The separated organic layer is washed with dilute hydrochloric acid, dried and evaporated to a residue which is crystallized from carbon tetrachloride:hexane to give 25.0 g of the desired product as a pink solid, m.p. 108°-110° C.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)[NH2:2].[C:13]([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[C:24]([CH:27]=O)[CH:23]=[CH:22]2)([CH3:16])([CH3:15])[CH3:14]>C(O)C>[C:13]([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[C:24](/[CH:27]=[N:2]/[NH:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)[CH:23]=[CH:22]2)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cccc2ccc(C=O)nc12
Reactant: COC(=O)c1ccc(NN)nc1
Solvent: CCO
Product: COC(=O)c1ccc(N/N=C/c2ccc3cccc(C(C)(C)C)c3n2)nc1
Yield: 82.1 %

Procedure:
A solution of methyl 6-hydrazinylnicotinate (1.00 g, 5.98 mmol) and 8-tert-butylquinoline-2-carbaldehyde (1.28 g, 5.98 mmol) in absolute ethanol (20 mL) was stirred at ambient temperature for 4 hours. The solid that formed was collected by filtration, washed with ethanol (10 mL), ether (100 mL) and dried to give (E)-methyl 6-(2-((8-tert-butylquinolin-2-yl)methylene)hydrazinyl)nicotinate (1.78 g, 82.1%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([F:9])[C:3]=1[Cl:10].[Cl-].[Al+3].[Cl-].[Cl-].[C:15](Cl)(=[O:17])[CH3:16]>>[Cl:1][C:2]1[C:3]([Cl:10])=[C:4]([F:9])[C:5]([CH3:8])=[CH:6][C:7]=1[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(Cl)c(Cl)c1F
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc(C)c(F)c(Cl)c1Cl

Procedure:
Using 1,2-dichloro-3-fluoro-4-methylbenzene (12.0 g), anhydrous aluminum chloride (17.87 g) and acetyl chloride (5.26 g), the title compound was obtained as a pale-yellow oil (yield: 5.46 g) by an operation similar to that in Reference Example 9.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([C:16](=O)[C:17]#[C:18][CH2:19][CH3:20])=[CH:8]1.C(=O)(O)O.[NH2:26][C:27]([NH2:29])=[NH:28]>COCCO>[CH2:19]([C:18]1[CH:17]=[C:16]([C:9]2[C:10]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:7][CH:8]=2)[N:28]=[C:27]([NH2:29])[N:26]=1)[CH3:20]
Reactant: N=C(N)N
Reactant: CCC#CC(=O)c1c[nH]c2ncccc12
Agent: O=C(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCO
Product: CCc1cc(-c2c[nH]c3ncccc23)nc(N)n1

Procedure:
2.2 2.1 g (15.12 mmol) of potassium carbonate are added to a solution of 600 mg (3.03 mmol) of (1H-pyrrolo[2,3-b]pyridin-3-yl)pent-2-yn-1-one and 660 mg (3.66 mmol) of guanidine carbonate in 10 ml of ethylene glycol monomethyl ether, and the mixture is heated at the boil for 4 hours. After cooling, the mixture is partitioned between water and ethyl acetate. The organic phase is dried over sodium sulfate, evaporated, and the residue is chromatographed using preparative HPLC, giving 4-ethyl-6-(1H-pyrrolo-[2,3-b]pyridin-3-yl)pyrimidin-2-ylamine (“A5”) as colourless solid; ESI 240;
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:15])[CH2:13][CH2:14][C:5]=3[C:4]=2[CH:3]=1.N12CCCN=C1CCCCC2.[CH3:27][N:28]=[C:29]=[O:30]>C(Cl)Cl>[CH3:27][NH:28][C:29]([O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:15])[CH2:13][CH2:14][C:5]=3[C:4]=2[CH:3]=1)=[O:30]
Reactant: CN=C=O
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CNC(=O)Oc1ccc2c(c1)c1c(n2C)C(=O)CC1
Reaction time: 8 h

Procedure:
7-Chloroacetyloxy-1,4-dihydro-4-methylcyclopent[b]indol3(2H)-one (5.0 g) was suspended in EtOH (100 ml), and thereafter 10% NaOH solution (50 ml) was added and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo, CH2Cl2 (100 ml) was added followed by 10% HCl until the aqueous layer was neutralized. The layers were separated and the aqueous phase extracted with CH2Cl2 (2×100 ml). The organic portion was dried (Na2SO4) and concentrated and the residue was recrystallized from 95% EtOH to provide 1,4-dihydro-7-hydroxy-4-methylcyclopent[b]indol-3(2H)-one as an off-white solid. The phenol was dissolved in CH2Cl2 (100 ml), and thereafter 1,8-diazabicyclo[5.4.0]undec-7-ene (0.4 g) was added followed by methyl isocyanate (1.4 g) and the mixture was stirred overnight. The mixture was concentrated in vacuo to afford an oily solid which was crystallized from EtOH to provide 1,4-dihydro-7-methylaminocarbonyloxy-4-methylcyclopent[b] indol-3(2H)-one (1.1 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[NH:10][CH2:11][CH2:12][C:13]1[C:17]([CH2:18][CH:19]2OCCO2)=[C:16]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:15]([CH:31]([CH3:33])[CH3:32])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.O>[CH2:1]([O:8][C:9]([N:10]1[CH2:11][CH2:12][C:13]2[C:17](=[C:16]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[N:15]([CH:31]([CH3:32])[CH3:33])[N:14]=2)[CH:18]=[CH:19]1)=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)n1nc(CCNC(=O)OCc2ccccc2)c(CC2OCCO2)c1-c1ccc(F)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1nc2c(c1-c1ccc(F)cc1)C=CN(C(=O)OCc1ccccc1)CC2

Procedure:
A solution of {2-[4-[1,3]dioxolan-2-ylmethyl-5-(4-fluoro-phenyl)-1-isopropyl-1H-pyrazol-3-yl]-ethyl}-carbamic acid benzyl ester (0.5 g, 1.1 mmol) in TFA (10 mL) and water (2 mL) was heated at reflux for 2 h. The mixture was concentrated and the residue was purified by FCC to provide the title compound. HPLC: RT=11.00 min. MS (ESI): mass calcd. for C24H24FN3O2, 405.19; m/z found, 406.3 [M+H]+.
Reaction SMILES: OC[C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4]1.C(OC(N[C:29]1[CH:33]=[CH:32][O:31][N:30]=1)=O)(C)(C)C.C(P(CCCC)CCCC)CCC.[N:47]([C:57](N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[O:31]1[CH:32]=[CH:33][C:29]([CH:57]([NH2:47])[C@H:3]2[O:7][C:6](=[O:8])[N:5]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[CH:11][CH:10]=3)[CH2:4]2)=[N:30]1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(N2CCOCC2)cc1
Reactant: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Reactant: CC(C)(C)OC(=O)Nc1ccon1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: NC(c1ccon1)[C@@H]1CN(c2ccc(N3CCOCC3)cc2)C(=O)O1

Procedure:
5(R)-Hydroxymethyl-3-(4-morpholinophenyl)oxazolidin-2-one (prepared by analogy to the 3-fluoro compound—see WO95/07271; 0.50 g, 1.80 mmol), 3-t-butyloxycarbonylamino-isoxazole (0.50 g, 2.70 mmol), tri-n-butylphosphine (0.66 ml, 2.70 mmol), and 1,1′-(azodicarbonyl)-di-piperidine (0.68 g, 2.70 mmol) were reacted in anhydrous THF (30 ml) using the general method of Reference Example 15. The reaction was then purified by MPLC (Merck 9385 silica, 70% ethyl acetate in iso-hexane) and the solvent removed under reduced pressure to give a solid which was triturated with ether to give the title compound as an off-white solid. 1H-NMR (300 MHz, DMSO-d6): δ=1.50 (s, 9H), 3.08 (t, 4H), 3.70-3.80 (m, 5H), 3.93-4.01 (m, 1H), 4.14-4.30 (m, 2H), 4.95 (m, 1H), 6.88 (s, 1H), 6.99 (d, 2H), 7.40 (d, 2H), 8.81 (s, 1H). MS: ESP+ (M+H)+=445.
Reaction SMILES: [S:1](=O)(=O)(O)O.O[C@@H:7]1[C:16]2[CH:15]=[CH:14][N:13]3[C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=[C:12]3[C:11]=2[NH:10][C@H:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:8]1[OH:28].O.[OH-].[Na+].O1[CH2:37][CH2:36]OCC1>C(SCC)C>[CH3:20][C:18]1[N:19]=[C:12]2[C:11]3[NH:10][C@H:9]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:8]([OH:28])[C@H:7]([S:1][CH2:36][CH3:37])[C:16]=3[CH:15]=[CH:14][N:13]2[C:17]=1[CH3:21]
Reactant: O=S(=O)(O)O
Reactant: Cc1nc2c3c(ccn2c1C)[C@@H](O)[C@H](O)[C@@H](c1ccccc1)N3
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCSCC
Product: CCS[C@@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.9 g of concentrated sulphuric acid are added slowly at room temperature with stirring to 3 g of (7R,8R,9R)-7,8-dihydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetra-hydroimidazo[1,2-h][1,7]naphthyridine, dissolved in a mixture of 40 ml of dry dioxan and 4 ml of ethylsulfide: The temperature is brought to 50° C. by external heating and is then kept for 15 min. After cooling to room temperature, the mixture is poured into 300 g of a mixture of crushed ice and water. The pH is adjusted to neutral by adding aqueous 2N sodium hydroxide solution. The mixture is extracted three times (50 ml each) with ethyl acetate, the organic layers are collectively washed with water and dried over potassium carbonate. The solvent is stripped off under reduced pressure and the solid residue that remains is purified by chromatography on silica gel (mobile phase: diethyl ether). 700 mg of the title compound of m.p. 220-223° C. are obtained after crystallisation from 2-propanol.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[CH:15]=[N:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Na+]>CO>[CH3:25][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[CH2:15][NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(OCCCN(C)C)c(C=NCCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(OCCCN(C)C)c(CNCCc2ccccc2)c1
Yield: 74.7 %

Procedure:
N-[[2-[3-(Dimethylamino)propoxy]-5-methoxylphenyl]-methylene]benzeneethanamine (39.5 g) is reduced with 13.0 g of sodium borohydride in 200 ml of methanol following the procedure described in Example 1C yielding 29.7 g of the title compound, boiling point 205°-210° C. at 0.4-0.5 mm of Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1.[N:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[N:44][CH:43]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:48][C:45]4[CH:46]=[CH:47][N:42]=[CH:43][N:44]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1
Reactant: Nc1ccncn1
Reactant: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonate (INTERMEDIATE TTTT; 72.97 mg, 0.120 mmol) pyrimidin-4-amine (Alfa Aesar, Ward Hill, Mass., 12.52 mg, 0.132 mmol), and THF (598 μl) to give a clear, lightly-colored solution. The flask was cooled in an ice-bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (251 μl, 0.251 mmol) was added drop wise over 30 s to give a yellow suspension. After 30 min, the mixture was purified directly by chromatography on silica gel (12-g Redi-Sep Gold column, 3.5 MeOH/DCM, then 3.5-10% MeOH/DCM). A few mixed fractions were discarded, and the remainder of fractions containing product were combined and concentrated to give 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (40.83 mg, 0.078 mmol, 65.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=13.12 (br. s., 1H), 8.71 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 8.24 (d, J=6.6 Hz, 1H), 8.14 (d, J=5.8 Hz, 1H), 7.99 (dd, J=1.8, 8.9 Hz, 1H), 7.81 (d, J=8.9 Hz, 1H), 7.58 (dt, J=6.3, 8.0 Hz, 1H), 7.54 (s, 1H), 7.49-7.40 (m, 2H), 7.35-7.29 (m, 1H), 7.27 (s, 1H), 7.02 (d, J=6.6 Hz, 1H), 3.70 (s, 3H). m/z (ESI) 521.2 (M+H)+.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([S:18][C:19]([F:22])([F:21])[F:20])=[CH:14][C:12]=2[N:13]=1.[CH2:23]([SH:25])[CH3:24].O>CN1C(=O)CCC1>[CH2:23]([S:25][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([S:18][C:19]([F:22])([F:21])[F:20])=[CH:14][C:12]=2[N:13]=1)[CH3:24]
Reactant: FC(F)(F)Sc1ccc2oc(-c3sccc3Br)nc2c1
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCSc1ccsc1-c1nc2cc(SC(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.31 g of sodium hydride (60%) was added to 20 ml of a solution of 2.76 g of 2-(3-bromothiophen-2-yl)-5-(trifluoromethylthio)benzoxazole and 0.6 ml of ethanethiol in NMP at 0° C., and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous hydrochloric acid solution and a saturated aqueous salt solution and dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 2.65 g of 2-(3-ethylthiothiophen-2-yl)-5-(trifluoromethylthio)benzoxazole (Compound of Present Invention (30)).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].C([Li])CCC.[C:19](#[N:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:6][C:19](=[NH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:13])[CH3:12]
Reactant: N#Cc1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: [Li]CCCC
Product: CC(C)c1cccc(C(C)C)c1NC(=N)c1ccccc1
Yield: 50 %

Procedure:
Procedure as described for Amidine I using the following amounts: 8.50 mL of 2,6-diisopropylaniline (45.0 mmol); 23.5 mL of 2.0 M butyllithium (47.0 mmol); 4.70 mL of benzonitrile (46.0 mmol). Filtration of the final pentane solution yielded 6.31 g (50%) of white solid. 1H NMR (400 MHz, CDCl3): 7.92 (d, 2H), 7.48 (m, 3H), 7.17 (d, 2H), 7.09 (t, 1 H), 4.59 (s, 2H), 3.06 (septet, 2H), 1.20 (d, 12H).