Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:36])[CH2:33][C:34]#[N:35])[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12.N1[CH2:42][CH2:41][CH2:40][CH2:39]C1.C1(C=O)CC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32]([C:33](=[CH:39][CH:40]4[CH2:42][CH2:41]4)[C:34]#[N:35])=[O:36])[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cc(F)ccc4F)cc3)c3c(N)ncnc32)C1
Reactant: C1CCNCC1
Agent: O=CC1CC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cc(F)ccc4F)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 22.6 %

Procedure:
Into a 10 mL sealed tube, was placed a solution of 3-[(3R)-3-[4-amino-3-[4-(2,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (150 mg, 0.31 mmol, 1.00 equiv) in methanol (5 mL), piperidine (78 mg, 0.92 mmol, 3.0 equiv), and cyclopropanecarbaldehyde (64 mg, 0.91 mmol, 3.0 equiv). The resulting solution was stirred for 12 h at 25° C. and then concentrated under vacuum. The resulting solution was diluted with dichloromethane and washed with saturated aqueous ammonium chloride, water and brine. The organics were dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (20/1) to give 38 mg (23%) of 2-[[(3R)-3-[4-amino-3-[4-(2,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]carbonyl]-3-cyclopropylprop-2-enenitrile as a white solid. LC-MS (ES, m/z): 542 [M+H], H-NMR (CDCl3, ppm): δ8.51 (s, 1H); δ7.66 (d, 2H); δ7.12 (m, 3H); δ6.88 (m, 2H); δ6.51 (d, 1H); δ5.57 (s, 2H); δ4.95 (m, 1H); δ4.82 (m, 1H); δ4.23 (m, 1H); δ3.65 (m, 1H); δ3.28 (m, 1H); δ2.33 (m, 2H); δ2.01 (m, 2H); δ1.83 (m, 1H); δ1.20 (m, 2H); δ0.78 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:16][CH2:15][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:14])=[C:11]([CH3:13])[C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:19][C:20]1([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:22][O:21]1>CN(C=O)C>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:20]([OH:21])([CH3:22])[CH2:19][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:14])=[C:11]([CH3:13])[C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:16][CH2:15][C:5]2=3)[CH:24]=1
Reactant: Cc1ccc2[nH]c3c(c2c1C)CN(C)CC3
Reactant: CC1(c2cccnc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1C)c1c(n2CC(C)(O)c2cccnc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.5 %

Procedure:
2,8,9-Trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (400 mg, 1.86 mmol) 4 mL DMF, cooled to 0° C. and sodium hydride (224 mg, 5.60 mmol) was added portionwise at the same temperature. 3-(2-methyloxiran-2-yl)pyridine (504 mg, 3.73 mmol) in DMF (1 mL) was added to the reaction mixture and allowed to stir at RT for 12 h. After complete consumption of starting material, the reaction mixture was poured in to ice water and extracted with EtOAc (3×100 mL). The combined organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was crystallized with ether and hexane to obtain 400 mg of 2-(pyridin-3-yl)-1-(2,8,9-trimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propan-2-ol. 1H NMR (DMSO, freebase) δ (ppm): 8.59 (s, 1H), 8.42 (d, 1H), 7.73 (d, 1H), 7.31 (t, 1H), 7.1 (d, 1H), 6.73 (d, 1H), 4.11 (dd, 2H), 3.74 (s, 2H), 3.4 (m, 2H), 2.6 (m, 2H), 2.37 (s, 6H), 2.22 (s, 3H), 1.5 (s, 3H). Separation by chiral HPLC provides enantiomers II-145a-b.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([O:42][CH3:43])=[O:41])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:43][O:42][C:40](=[O:41])[CH2:39][C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]2)=[O:30])=[CH:34][CH:35]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)Cc1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
A mixture of chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (228 mg, 0.488 mmol), methyl 2-(4-aminophenyl)acetate (200 mg, 1.21 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 241 mg, 0.634 mmol) and iPr2NEt (0.4 mL, 2.29 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, then concentrated and purified by column chromatography (1-100% of EtOAc/heptane, 12 g Analogix column) to afford chiral (4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-acetic acid methyl ester (209 mg, 69.7%) as an white powder. LCMS (ES+) m/z Calcd for C32H31Cl2F2N3O3+H [M+H)+]: 613.17. found: 614.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.[Br:25]Br>C(Cl)Cl>[Br:25][C:16]1[CH:15]=[C:14]2[C:5]([CH:6]3[CH:11]([CH:12]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[CH2:13]2)[CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1ccc(C2Cc3ccc(OC)cc3C3CCCCC23)cc1
Solvent: ClCCl
Product: COc1ccc(C2Cc3cc(Br)c(OC)cc3C3CCCCC23)cc1
Reaction time: 1 h
Yield: 124.6 %

Procedure:
Combine 6-Methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthrene (chiral) (0.02 g, 0.32 mmol) and methylene chloride (10 ml) and add bromine (0.0162 ml, 0.32 mmol) at 0-5° C. over 15 minutes. Stir as such one hour. Remove volatiles in vacuo at 40° C. to yield the titled compound (0.16 g, 100%). 1H NMR (CDCl3): 7.38 (s, 1H), 7.25 (d, J=8.8 Hz, 2H), 6.9 (m, 3H), 3.93 (s, 3H), 3.85 (s, 3H), 3.2 (m, 3H), 2.85 (dd, J=4 and 11, 1H), 2.48 (d, J=14 Hz, 1H), 2.06 (m, 1H), 1.8-0.8 (m, 7H).
Reaction SMILES: [S:1]1[C:5]2[C:6]3[N:7]([CH:19]=[CH:20][N:21]=3)[CH2:8][C:9]3[N:10]([CH:11]=[N:12][C:13]=3[C:14]([O:16]CC)=[O:15])[C:4]=2[CH:3]=[CH:2]1.[OH-].[K+]>C(O)C.O>[S:1]1[C:5]2[C:6]3[N:7]([CH:19]=[CH:20][N:21]=3)[CH2:8][C:9]3[N:10]([CH:11]=[N:12][C:13]=3[C:14]([OH:16])=[O:15])[C:4]=2[CH:3]=[CH:2]1
Reactant: CCOC(=O)c1ncn2c1Cn1ccnc1-c1sccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ncn2c1Cn1ccnc1-c1sccc1-2

Procedure:
7. By hydrolyzing ethyl 8H-diimidazo[1,5-a:1',2'-d]thieno[2,3-f][1,4]diazepine-7-carboxylate with potassium hydroxide in ethanol/water in an analogous manner to that described in Example 5 there is obtained 8H-diimidazo[1,5-a:1',2'-d]thieno[2,3-f][1,4]diazepine-7-carboxylic acid of m.p. 225°-227° C.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][C:10]([CH3:23])([CH3:22])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O>[Ni].CN(C=O)C>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:10]([CH3:22])([CH3:23])[CH2:9][O:8][C:7]2[CH:24]=[CH:25][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:18][CH:17]=1
Reactant: CC(C)(COc1ccc([N+](=O)[O-])cc1)COc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CN(C)C=O
Product: CC(C)(COc1ccc(N)cc1)COc1ccc(N)cc1

Procedure:
1949 g 1,3-bis-(4-nitrophenoxy)-2,2-dimethylpropane were hydrogenated as in Example 10 in 10 1 DMF in the presence of 300 g Raney nickel. The crude product was recrystallized from ethanol/isopropanol (1:1).
Reaction SMILES: Br[C:2]1[C:15]([CH3:16])=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[CH3:17].[Li]CCCC.CN([CH:26]=[O:27])C>C1COCC1>[CH3:17][C:3]1[CH:4]=[C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:14]=[C:15]([CH3:16])[C:2]=1[CH:26]=[O:27]
Reactant: CN(C)C=O
Reactant: Cc1cc(OCCN2CCCC2)cc(C)c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCN2CCCC2)cc(C)c1C=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[2-(4-bromo-3,5-dimethyl-phenoxy)-ethyl]-pyrrolidine (176 mg) in THF (5 mL) was added n-BuLi (1.36 mL, 1.0 M solution in hexane) at −78° C. The mixture was stirred at −78° C. for 30 min, allowed to warm up to −40° C. for 5 min, and then cooled down to at −78° C. After 20 min. DMF (0.24 mL) was added. The mixture was stirred at −78° C. for 30 min and then allowed to warm up to room temperature for 1 h. The reaction was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give 2,6-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde: MS (m/z) 248 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(Cl)Cl>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][NH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: NCc1cccc2ccccc12
Solvent: ClCCl
Product: CCOC(=O)CNCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-aminomethylnaphthalene (2.15 g, 13.6 mmol) and TEA (1.65 g, 16.3 mmol) in CH2Cl2 (50 mL) is treated with ethyl bromoacetate (2.28 g, 13.6 mmol) dropwise over 90 min. The mixture is stirred at RT for 3 h and washed with water. The organic layer is dried over anhydrous MgSO4 and concentrated. The residue is flash chromatographed on silica gel using CH2Cl2→1% MeOH in CH2Cl2 as the eluent to afford N-(1-naphthyl-methyl)-glycine ethyl ester as a yellow oil: [M+1]+=244.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][O:27][C:21]=2[N:20]=[C:19]1[CH:28]([NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH2:29][CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][O:27][C:21]=2[N:20]=[C:19]1[CH:28]([N:31]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:29][CH3:30])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCC(NCCN(C)C)c1nc2occc2c(=O)n1Cc1ccccc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(c1nc2occc2c(=O)n1Cc1ccccc1)N(CCN(C)C)C(=O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A solution of 4-bromobenzoyl chloride (1 equiv) in dichloromethane is added to a solution of 3-benzyl-2-(1-{[2-(dimethylamino)ethyl]amino}-propyl)furo[2,3-d]pyrimidin-4(3H)-one (1-6, 1 equiv) and N,N-diisopropylethylamine (1 equiv) in dichloromethane, and the resulting mixture is stirred under ambient conditions for 1 h. The reaction mixture is washed with saturated aqueous NaHCO3 solution, and brine, then dried (MgSO4) and concentrated. The residue is purified by flash chromatography. Elution with CH2Cl2 to 5% NH3-EtOH/CH2Cl2 gives N-[1-(3-benzyl-4-oxo-3,4-dihydrofuro[2,3-d]pyrimidin-2-yl)propyl]4-bromo-N-[2-(dimethylamino)ethyl]benzamide (1-7).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@:8]2([CH3:21])[C@@H:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:12][O:11][C:10]([NH2:20])=[N:9]2)[CH:7]=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[NH2:20][C:10]1[O:11][CH2:12][C@H:13]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:27]3[CH:26]=[CH:25][C:24]([Cl:23])=[CH:29][N:28]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:22])([CH3:21])[N:9]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1OCC(F)(F)F
Product: C[C@]1(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)N=C(N)OC[C@@H]1OCC(F)(F)F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.4) and 5-chloro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=461.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:37]O)=[C:13]([CH:36]=1)[O:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH3:27])=[CH:20][C:19]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC.C[O-].[Na+]>C(#N)C.C(Cl)Cl>[CH2:29]([O:28][C:19]1[CH:20]=[C:21]([O:24][CH2:25][O:26][CH3:27])[CH:22]=[CH:23][C:18]=1[C:16]1[CH2:15][O:14][C:13]2[C:12]([CH:37]=1)=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:36]=2)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COCOc1ccc(C(=O)COc2cc(OCc3ccccc3)ccc2CO)c(OCc2ccccc2)c1
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Solvent: ClCCl
Product: COCOc1ccc(C2=Cc3ccc(OCc4ccccc4)cc3OC2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
To a solution of 2-(5-Benzyloxy-2-hydroxymethyl-phenoxy)-1-(2-benzyloxy-4-methoxymethyloxy-phenyl)-ethanone (0.514 g, 1 mmol) in 5 mL of acetonitrile was added triphenyl phosphine hydrobromide (0.343 g, 1 mmol) and the suspension stirred at RT for ca. 4 hours. After disappearance of starting material (TLC), organic solvent was evaporated at 20° C. to provide a yellowish solid. The solid was redissolved in 5 mL of DCM and anhydrous ether was added with constant stirring. The white Wittig's ylide precipitated. This product was used directly in the next step without further purification. The crude product (ca. 0.80 g) was dissolved in 10 mL of methanol followed by addition of sodium methoxide (0.108 g, 2 mmol). The suspension was refluxed for ca. 12 hours after which it was allowed to come to RT. A white solid precipitated. The precipitate was filtered and the filtrate was concentrated to ca. one-half the volume and again refluxed for 4 hours after which it provided additional product upon cooling to RT. The combined product was recrystallized from methanol (ca. 30 mL) to obtain 0.374 g (78%) of white solid: mp 132-134° C.; TLC Rf0.43, in hexanes:EtOAc (5:1); 1H NMR (600 MHz, acetone-d6) δ 7.51-7.31 (m, 10H, 2×C6H5), 7.28-7.27 (d, 1H, J=8.4 Hz, Ar—H5), 7.01-7.00 (d, 1H, J=7.8 Hz, Ar—H6′), 6.8 (d, 1H, J=2.4 Hz, Ar—H8), 6.69-6.67 (dd, 1H, 2J=8.4 Hz, 3J=2.4 Hz, Ar—H6), 6.60 (s, 1H, Ar—H4), 6.57-6.55 (dd, 1H, 2J=8.4 Hz, 3J=2.4 Hz, Ar—H5′), 6.46 (d, 1H, J=2.4 Hz, Ar—H3′), 5.2 (s, 2H, O—CH2—O), 5.13 (s, 2H, PhCH2), 5.09 (s, 2H, PhCH2), 4.92 (s, 2H, H2), 3.42 (s, 3H, OCH3); 13C NMR (100 MHz, acetone-d6) δ 161.1, 159.9, 158.9, 156.3, 138.9, 138.5, 130.6, 130.5, 130, 129.9, 129.4, 129.3, 129.2, 129, 128.9, 123.2, 122.6, 118.8, 109.6, 103.6, 103.2, 95.8, 71.8, 71.1, 69.6, 56.7; analysis calcd. for C31H28O5. C, 77.01; H, 5.80. found: C, 77.0; H, 5.80.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])=[C:11]([CH2:13][OH:14])[CH:12]=2)[N:5]=[C:4]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:3]=1.[OH-].[Na+].[Cl:32][C:33]([Cl:40])([Cl:39])[CH2:34][O:35][C:36](Cl)=[O:37]>CCOC(C)=O.O>[Cl:32][C:33]([Cl:40])([Cl:39])[CH2:34][O:35][C:36](=[O:37])[NH:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([O:15][Si:16]([CH:20]([CH3:21])[CH3:22])([CH:23]([CH3:25])[CH3:24])[CH:17]([CH3:18])[CH3:19])=[C:11]([CH2:13][OH:14])[CH:12]=2)[N:5]=[C:4]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:3]=1
Reactant: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2N)cc1CO)(C(C)C)C(C)C
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1CO)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a solution of Intermediate 61c (0.15 g, 0.36 mmol) in EtOAc (1.8 mL) was added 1N aqueous NaOH solution (0.6 mL, 0.60 mmol) followed by 2,2,2-trichloroethylchloroformate (54.0 μL, 0.40 mmol). The reaction was stirred at RT overnight then treated with another portion of 1N aqueous NaOH solution (0.3 mL, 0.30 mmol) followed by 2,2,2-trichloroethylchloroformate (27.0 μL, 0.20 mmol). After stirring for another 4 h, the mixture was diluted with EtOAc and water. The aqueous layer was then extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-25% EtOAc in cyclohexane, to give the title compound (176 mg, 84%). LCMS (Method 3): Rt 5.35 min, m/z 592, 594 [MH+].
Reaction SMILES: [C:1]1(=O)[CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH:15]([C:18](=[O:28])[CH2:19]P(OCC)(OCC)=O)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[OH-].[K+]>C(O)C>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH:15]([C:18](=[O:28])[CH:19]=[C:1]2[CH2:4][CH2:3][CH2:2]2)[CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CCOP(=O)(CC(=O)C1CCN(C(=O)OC(C)(C)C)C1)OCC
Reactant: O=C1CCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C(=O)C=C2CCC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.6 %

Procedure:
Add cyclobutanone (0.738 mL; 9.89 mmol) to a stirred mixture of 3-(2-(diethoxyphosphoryl)-acetyl)pyrrolidine-1-carboxylic acid tert butyl ester (3.14 g, 8.99 mmol) and potassium hydroxide (656 mg, 11.7 mmol) in ethanol (45 mL) kept under nitrogen at 5° C. Warm to room temperature and stir for 3 hours. Concentrate under reduced pressure and subject the residue to silica gel chromatography, eluting with 20% ethyl acetate in hexanes to afford 0.85 g (36%) of the crude desired compound, which is used in the next step without further purification.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[S:6][C:5]([S:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:12]=3)(=[O:9])=[O:8])=[CH:4][CH:3]=2)=[CH:25][CH:24]=1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2ccc(Cl)cc2)s1
Yield: 21.1 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, starting from 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.05 mmol) and 4-chlorophenylboronic acid (9 mg, 0.06 mmol) giving 4.4 mg (21%) of the title compound. MS (ESI+) calcd for C17H12ClN5O2S2 417.012094, found 417.013904.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN(C)CC1C=CC=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH:1](=[N:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C=O
Reactant: Nc1ccccc1
Agent: CN(C)Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)C=Nc1ccccc1
Yield: 105.3 %

Procedure:
144 g (2 mols) of isobutyraldehyde were added dropwise to a solution of 92 g (1 mol) of aniline, 250 ml of methylene chloride, 2 ml of dimethylbenzylamine and 150 g of anhydrous magnesium sulphate at 0° C. in the course of 1 hour, whilst stirring. The mixture was further stirred at from 0° to 10° C. for 5 hours and was filtered, and the residue was rinsed with 200 ml of methylene chloride. The combined organic phases were freed from solvent, in vacuo, at from 30° to 40° C. 155 g of crude N-isobutylideneaniline were obtained and were directly further reacted.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH3:12])=[N:4][C:5]([O:9][CH3:10])=[C:6]([Cl:8])[CH:7]=1.[Li+].CC([N-]C(C)C)C.[C:21](OCC)(=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].[Cl-].[NH4+]>C1COCC1>[Cl:8][C:6]1[C:5]([O:9][CH3:10])=[N:4][C:3]([O:11][CH3:12])=[C:2]([Cl:1])[C:7]=1[C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: COc1nc(OC)c(Cl)cc1Cl
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c(Cl)c(OC)nc(OC)c1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
A solution of 5.20 g (25 mmol) of 3,5-dichloro-2,6-dimethoxypyridine (J. Bratt, H. Suschitzky, J.C.S. Perkin I, 1983:1689–1693) in 40 mL THF is added dropwise over 30 minutes to a solution of 20 mL (30 mmol) of 1.5 M LDA in 20 mL THF at −78° C. The resulting solution is stirred at −78° C. for 1 hour, and 4.5 mL (33 mmol) of diethyl oxalate is then added. The temperature is allowed to rise slowly to room temperature and aqueous ammonium chloride solution is added, and the solvent is removed under vacuum. The residue is extracted into EtOAc and chromatographed on SiO2, eluting with hexane-EtOAc (9:1), to give 5.97 g (78%) of the title compound: mp (hexane) 195–196° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[CH:3]=1.[N:13]([O-])=[O:14].[Na+]>C(O)(=O)C>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[C:3]=1[N:13]=[O:14]
Reactant: O=N[O-]
Reactant: Oc1ccc2ccc(O)cc2c1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=Nc1c(O)ccc2ccc(O)cc12
Reaction time: 2 h

Procedure:
2,7-Dihydroxynaphthalene (BAYER) (250 g=1.56 mol) was dissolved in 875 ml of glacial acetic acid at 0°-90° C. and precipitated again by addition of 2.5 kg of crushed ice. A very finely disperse, light-beige, viscous suspension was formed and the temperature fell to -10° to -12° C. With good stirring and external cooling, 107.88 g (1.56 mol) of solid sodium nitrite were introduced in portions into this suspension, the mixture was stirred for another hour and a further 10.7 g (0.56 mol) of solid sodium nitrite were then added. Stirring was then continued for a further two hours at -8° to -5° C. The 2,7-dihydroxy-1-nitrosonaphthalene formed as dark-red crystals was filtered off with suction and well-pressed on the suction filter. The reaction product, still moist from the suction filter, was then stirred into 5 1 of water at 20°-25° C. for about one hour, again filtered off with suction, pressed down well and dried for 24 hours at 20°-25° C. in a circulating-air oven.