Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:7][CH:6]([CH2:8][NH2:9])[CH2:5][O:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2.[S:14](N)([NH2:17])(=[O:16])=[O:15].C(Cl)(Cl)Cl>O1CCOCC1>[O:1]1[CH2:7][CH:6]([CH2:8][NH:9][S:14]([NH2:17])(=[O:16])=[O:15])[CH2:5][O:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2
Reactant: NS(N)(=O)=O
Reactant: NCC1COc2ccccc2OC1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: NS(=O)(=O)NCC1COc2ccccc2OC1

Procedure:
((3,4-Dihydro-2H-benzo[b][1,4]dioxepin-3-yl)methyl)amine (2.90 g, 16.2 mmol) and sulfamide (3.11 g, 32.4 mmol) were combined in dry dioxane (60 ml) and heated to reflux overnight. Chloroform was added and the precipitate was removed by filtration. The filtrate was concentrated under vacuum and purified by chromatography (2% to 8% acetone in dichloromethane) to yield the title compound as an off-white solid.
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([I:21])=[C:17]([CH:20]=1)[CH2:18][OH:19].N1C=CN=C1>CN(C=O)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([I:21])=[C:17]([CH:20]=1)[CH2:18][O:19][Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2]
Reactant: OCc1cc(Cl)ccc1I
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](OCc1cc(Cl)ccc1I)(C(C)C)C(C)C
Yield: 8345.5 %

Procedure:
Triisopropylsilylchloride (14.59 mL, 68.16 mmol) was added to a stiffed solution of 5-chloro-2-iodobenzyl alcohol (12.2 g, 45.44 mmol) and imidazole (4.64 g, 68.16 mmol) in DMF (45 mL). After 1 h the mixture was partitioned between hexanes and water. The organic layer was dried (Na2SO4) and evaporated in vacuo to an oil which was purified by flash column chromatography on silica (eluting with 5% methylene chloride/hexanes) to give [(5-chloro-2-iodobenzyl)oxy](triisopropyl)silane as an oil (1611 g): 1H NMR (CDCl3, 400 MHz) δ 1.11 (d, J=6.8 Hz, 18H), 1.20 (septet, J=6.8 Hz, 3H), 4.65 (s, 2H), 6.96 (dd, J=2.6, 8.4 Hz, 1H), 7.56 (d, J=2.8 Hz, 1H), 7.66 (d, J=8.2 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[CH2:21]([CH:23]([CH2:26][CH3:27])[CH:24]=[O:25])[CH3:22]>C1COCC1>[CH2:21]([CH:23]([CH2:26][CH3:27])[CH:24]([C:15]1[N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[N:12]=[CH:13][CH:14]=1)[OH:25])[CH3:22]
Reactant: CCC(C=O)CC
Reactant: Cc1ccc(S(=O)(=O)n2cccn2)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCC(CC)C(O)c1ccnn1S(=O)(=O)c1ccc(C)cc1
Yield: 74.9 %

Procedure:
To 1-[(4-methylphenyl)sulfonyl]-1H-pyrazole (0.50 g, 2.26 mmol) [J. Chem. Res., Synopses, 10, 327 (1979)] in THF (23 mL) at −78° C. was added a solution of t-butyllithium (1.7 M in pentane, 1.5 mL, 2.49 mmol) dropwise. After 10 min 2-ethylbutyraldehyde (0.31 mL, 2.49 mmol) was added. After 10 min the reaction mixture was quenched with saturated aqueous ammonium chloride (5 mL) and then diluted with H2O (30 mL) and extracted with EtOAc (3×30 mL). The organic extract was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (EtOAc/hexane, 3:7) to give 0.546 g (75%) of 2-ethyl-1-{1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-5-yl}butan-1-ol.
Reaction SMILES: ClC1C=CC([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=CC=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=O)COC>CC(C)=O>[CH3:19][S:16]([C:13]1[CH:12]=[CH:11][C:10]([N:9]2[CH2:28][CH2:27][N:20]=[CH:8]2)=[CH:15][CH:14]=1)(=[O:17])=[O:18]
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Reactant: COCC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CS(=O)(=O)c1ccc(N2C=NCC2)cc1

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (1 mmol) and sodium bicarbonate (2 mmol) in acetone (20 mL), 1-bromo-3-methoxy-2-propanone from Step 1 (1.5 mmol) is added. After heating to reflux for 24 hours, the reaction mixture is filtered, washed with acetone and concentrated in vacuo. The crude product is chromatographed (silica gel, toluene/ethyl acetate) to give 2-(4-chlorophenyl)-4-hydroxy-4-[methoxy)methyl]-1-[4-(methylsulfonyl)phenyl]-4,5-dihydro-1H-imidazole.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][C:10](=[O:69])[NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26](=[O:68])[NH:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:67]=[CH:66][C:35]([C:36]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][CH2:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][CH2:57][NH:58]C(=O)OC(C)(C)C)=[CH:40][CH:39]=2)=[O:37])=[CH:34][CH:33]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:58][CH2:57][CH2:56][CH2:55][O:54][CH2:53][CH2:52][O:51][CH2:50][CH2:49][O:48][CH2:47][CH2:46][CH2:45][NH:44][C:41]1[CH:40]=[CH:39][C:38]([C:36]([C:35]2[CH:66]=[CH:67][C:32]([O:31][CH2:30][CH2:29][CH2:28][NH:27][C:26](=[O:68])[CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][NH:11][C:10](=[O:69])[CH2:9][CH2:8][N:3]3[C:4](=[O:7])[CH:5]=[CH:6][C:2]3=[O:1])=[CH:33][CH:34]=2)=[O:37])=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)NCCCOCCOCCOCCCNc1ccc(C(=O)c2ccc(OCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCN3C(=O)C=CC3=O)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCOCCOCCOCCCNc1ccc(C(=O)c2ccc(OCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCN3C(=O)C=CC3=O)cc2)cc1
Reaction time: 1 h
Yield: 108.5 %

Procedure:
tert-butyl (3-(2-(2-(3-((4-(4-((1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,19-dioxo-7,10,13,16-tetraoxa-4,20-diazatricosan-23-yl)oxy)benzoyl)phenyl)amino)propoxy)ethoxy)ethoxy)propyl)carbamate (6.31 g, 6.50 mmol) was dissolved in a solution of DCM:TFA (2:1, 60 ml) and stirred ca. 1 h. Upon completion, reaction was then concentrated under reduced pressure, co-evaporated with toluene, and dried on oil pump for 2 hs to yield 6.15 g of crude N-(3-(4-(4-((3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)-amino)benzoyl)phenoxy)propyl)-1-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-3,6,9,12-tetraoxapentadecan-15-amide as yellow oil. The crude product was used without any further purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[O:7][C:8]1[N:9]([CH2:23][CH2:24][CH3:25])[C:10](=[O:22])[C:11]2[NH:12][C:13]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:14][C:15]=2[N:16]=1)(=[O:3])[CH3:2].[CH3:29][Mg]Br>C1COCC1>[CH:17]1([C:13]2[NH:12][C:11]3[C:10](=[O:22])[N:9]([CH2:23][CH2:24][CH3:25])[C:8]([O:7][C:6]4[CH:26]=[CH:27][CH:28]=[C:4]([C:1]([OH:3])([CH3:29])[CH3:2])[CH:5]=4)=[N:16][C:15]=3[N:14]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C[Mg]Br
Reactant: CCCn1c(Oc2cccc(C(C)=O)c2)nc2nc(C3CCCC3)[nH]c2c1=O
Solvent: C1CCOC1
Product: CCCn1c(Oc2cccc(C(C)(C)O)c2)nc2nc(C3CCCC3)[nH]c2c1=O
Reaction time: 2 h
Yield: 32.4 %

Procedure:
2-(3-Acetyl-phenoxy)-8-cyclopentyl-1-propyl-1,7-dihydro-purin-6-one (0.08 g, 0.21 mmol), was taken in THF. To this was added methyl magnesium bromide (30 μl, 0.25 mmol) drop wise at −70° C. and stirred for 2 hours. Another lot of methyl magnesium bromide (30 μl, 0.25 mmol) was added and stirred further for 2 hours. Reaction was quenched with saturated NH4Cl solution and concentrated to evaporate THF and residue was dissolved in ethyl acetate, washed with water followed by brine and dried over anhydrous Na2SO4. The crude product was purified by preparative TLC to give the product (0.027 g) as an off white solid in 32% yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH3:36][N:37]([CH3:41])[C:38](Cl)=[O:39]>>[CH3:35][O:34][C:33]1[CH:32]=[CH:31][C:4]([CH2:5][CH:6]2[C:15]3[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=3)[CH2:9][CH2:8][N:7]2[CH2:20][C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[CH:3][C:2]=1[O:1][C:38](=[O:39])[N:37]([CH3:41])[CH3:36]
Reactant: CN(C)C(=O)Cl
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1O
Product: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OC(=O)N(C)C)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with N,N-dimethyl-carbamoyl chloride
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C([O:22][N:23]1[CH2:27][C@H:26]([CH2:28][CH3:29])[C@H:25]([NH:30]CC2C=CC(OC)=CC=2)[C:24]1=[O:40])C1C=CC=CC=1>ClCCl.O>[NH2:30][C@H:25]1[C@@H:26]([CH2:28][CH3:29])[CH2:27][N:23]([OH:22])[C:24]1=[O:40]
Reactant: CC[C@H]1CN(OCc2ccccc2)C(=O)[C@H]1NCc1ccc(OC)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: CC[C@H]1CN(O)C(=O)[C@H]1N
Reaction time: 2 h
Yield: 44.1 %

Procedure:
Dichlorodicyanobenzoquinone (125 mg, 550 μmol) was added to a stirred solution of cis-1-benzyloxy-4-ethyl-3-(4-methoxybenzylamino) pyrrolidin-2-one (190 mg, 458 μmol) in dichloromethane (20 ml) and water (1 ml). After 90 min the mixture was evaporated, dissolved in dilute hydrochloric acid, and applied to a column containing DOWEX 50W-X8 (100-200 mesh, 2×2 cm, H+ form). After washing the column with water (100 ml), the product was eluted with dilute aqueous ammonia. Fractions containing the product were evaporated in vacuo, then purified by flash chromatography, eluting with dichloromethane: methanol (95:5 v/v). The resulting oil (62 mg) was hydrogenated on palladium black (30 mg) in ethanol (20 ml) and acetic acid (200 μl) at 50 p.s.i. for 2 h. After filtration and evaporation, the residue was dissolved in water and applied to a column containing DOWEX 50W-X8 (100-200 mesh, 2× 2 cm, H+ form) After washing the column with water (50 ml), the product was eluted with dilute aqueous ammonia. Fractions containing the desired product were freeze dried to give cis-3-amino-1-hydroxy-4-ethylpyrrolidin- 2-one (29.1 mg, 45%) as a white powder. 1H NMR (360 MHZ, D2O) δ3.82 (1 H, d, J=8.0 Hz, CHN), 3.69 (1 H, dd, J=7.3 and 10.0 Hz, NCHAHB), 3.38 (1 H , dd, J=4.8 and 10 0 Hz, NCHAHB), 2.45-2.55 (1 H, m, CHCH2), 1.5-1.6 and 1.3-1.4 (2 H, m, CH2CH3), 0.96 (3 H, t, J=7.3 Hz, CH3), m/z (CI, NH3) 145 (M+ +H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH2:9]([OH:14])[C:10]([F:13])([F:12])[F:11].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:11][C:10]([F:13])([F:12])[CH2:9][O:14][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1
Reactant: OCC(F)(F)F
Reactant: O=Cc1ccc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCC(F)(F)F)s1
Temperature: 100 °C
Reaction time: 20 h
Yield: 66.4 %

Procedure:
To a solution of 5-bromothiophene-2-carbaldehyde (909 mg, 4.76 mmol) and trifluoroethanol (0.69 mL, 9.52 mmol) in 10 mL dimethylformamide was added potassium carbonate (1.38 g, 10.00 mmol). The resulting suspension was stirred at 100° C. for 20 h before being cooled to room temperature and poured into 50 mL water. Organics were extracted with ether (3×50 mL), washed with water and brine (50 mL each), dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (10-20% ethyl acetate in hexanes) to give 5-(2,2,2-trifluoroethoxyl)thiophene-2-carbaldehyde (664 mg, 66%) as an off-white solid. Used without further characterization.
Reaction SMILES: [C:1](=[NH:21])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([Cl:20])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:22]([CH:24]([CH2:29][C:30]1[CH:31]=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=1)[C:25](OC)=O)=[O:23].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:20][C:15]1[CH:14]=[C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:25]=[C:24]([CH2:29][C:30]4[CH:31]=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=4)[C:22](=[O:23])[N:21]=3)=[CH:11][CH:10]=2)[CH:18]=[CH:17][C:16]=1[CH3:19]
Reactant: Cc1ccc(Oc2ccc(CCOC(=N)N)cc2)cc1Cl
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(C)c(Cl)c4)cc3)nc2=O)cn1
Temperature: 130 °C
Yield: 2.3 %

Procedure:
To the solution of 2-{4-[(3-chloro-4-methylphenyl)oxy]phenyl}ethyl imidocarbamate (150 mg, 0.359 mmol) and methyl 2-formyl-3-[2-(methyloxy)-5-pyrimidinyl]propanoate (89 mg, 0.395 mmol) in NMP (2 mL), was added K2CO3 (198 mg, 1.436 mmol). The mixture was heated with a microwave reactor at 130° C. for 1 h. Purification via MDAP then afforded the title compound (4 mg, 2.33% yield). LCMS: rt=3.54 min, [M+H+]=479
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[CH3:31]>>[CH3:31][C:22]1[CH:23]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[CH:29]=[CH:30][C:21]=1[O:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14][CH2:13][C:12]=2[CH:15]=1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2CC1
Product: COC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c(C)c1

Procedure:
The title compound was prepared from 7-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (PCT Int. Appl. (2002), WO 02/40471) and methyl 4-bromo-3-methylbenzoate using the method outlined in Example 128 (211 mg, 29%); NMR (CDCl3) δ 1.49 (9H, s), 2.32 (3H, m), 2.86 (4H, m), 3.55 (4H, m), 3.89 (3H, s), 6.71-6.81 (3H, m), 7.08 (H, m), 7.80 (H. m), 7.94 (H, s)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:3]=1.[C:33]([O:37][C:38]([N:40]1[CH:44]=[CH:43][CH:42]=[C:41]1B(O)O)=[O:39])([CH3:36])([CH3:35])[CH3:34]>CCCCCCC.CCOC(C)=O>[C:33]([O:37][C:38]([N:40]1[CH:44]=[CH:43][CH:42]=[C:41]1[C:2]1[CH:3]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[C:5]([N:8]([C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[C:12]([C:20]([F:22])([F:23])[F:21])[CH:11]=2)[CH3:25])=[CH:6][N:7]=1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1cc(-c2cccn2C(=O)OC(C)(C)C)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 72, from N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 12) and 1-(tert-butoxycarbonyl)pyrrole-2-boronic acid (CAS RN 135884-31-0) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light yellow oil (18%). MS (ESI): m/z=604.202 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([NH2:24])=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:25]1(O)OC2OC(O)C(O)OC2O[CH:26]1O>O.C(O)C.C(=O)([O-])O.[Na+]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3=[C:19]4[C:20](=[CH:21][CH:22]=[C:16]3[O:15][CH2:14]2)[N:23]=[CH:26][CH:25]=[N:24]4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(N)c3O2)cc1
Reactant: OC1OC2OC(O)C(O)OC2OC1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4nccnc4c3O2)cc1
Temperature: 60 °C

Procedure:
To a solution of [(2R)-7,8-diamino-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (2.226 g, 5.258 mmole) in water (50 mL) was added a solution of glyoxal trimeric dihydrate (1.104 g, 5.258 mmole) in ethyl alcohol (50 mL) and the reaction mixture was heated at 60° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and was diluted with aqueous sodium hydrogen carbonate (250 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 7:3) gave 1.135 g (58%) of the (R)-enantiomer of the title compound as a brown crystalline solid. Rf=0.27 (silica, ethyl acetate:hexanes 3:2); mp 124-127° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH2:11][Cl:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: ClCc1ccc(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
2,4-Dibenzyloxybenzyl alcohol (19.8 g) was dissolved in anhydrous benzene (150 ml) and then thereto was added thionyl chloride (40 g), followed by reflux under heating for 1 hour. This was concentrated to dryness under reduced pressure to obtain crude 2,4-dibenzyloxybenzyl chloride. This product was used for the subsequent reaction without purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([OH:12])[CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:28]([CH3:30])[CH3:29]>CN(C)C=O>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([O:12][CH:28]([CH3:30])[CH3:29])[CH:5]=1)[CH3:14]
Reactant: CC(C)I
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(C=O)c(OC(C)C)c1
Reaction time: 7 h
Yield: 91.3 %

Procedure:
To a suspension of 4-diethylamino-2-hydroxybenzaldehyde (300 mg, 1.55 mmol), potassium carbonate (428 mg, 3.10 mmol), and cesium carbonate (50 mg, 0.15 mmol) in 1.6 mL of dry N,N-dimethylformamide was added 2-iodopropane (0.47 mL, 4.7 mmol) at room temperature. After being stirred at the same temperature for 7 h, the reaction mixture was filtered to remove inorganic salts. The filtrate was diluted with diethyl ether, and the solution was washed with water, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 75/25) to obtain the title compound as a colorless oil (333 mg, 91%).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH:11]1([C:14](=[O:21])[CH2:15][C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])[CH2:13][CH2:12]1>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:15]([C:14]([CH:11]2[CH2:13][CH2:12]2)=[O:21])[C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C(CC(=O)C1CC1)C1CC1
Reactant: N#Cc1ccc(C=O)cc1
Product: N#Cc1ccc(C=C(C(=O)C2CC2)C(=O)C2CC2)cc1

Procedure:
The procedure described in Example 19 was repeated by using 3.78 g 4-cyanobenzaldehyde and 2.23 g 1,3-dicyclopropyl-1,3-propanedione. Yield 1.5 g, mp 100°-102° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][S:6]1(=[O:16])=[O:15].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([F:17])[CH:23]=2)[S:6]1(=[O:16])=[O:15]
Reactant: OB(O)c1cccc(F)c1
Reactant: O=S1(=O)Nc2ccccc2CN1CCCCl
Product: O=S1(=O)N(CCCCl)Cc2ccccc2N1c1cccc(F)c1

Procedure:
In an analogous manner to Example 1 step 7, 3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (400 mg) was coupled to m-fluorophenylboronic acid to provide 3-(3-chloropropyl)-1-(3-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (78 mg):
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:22])=[C:10]([N:14]3[CH2:19][CH2:18][NH:17][CH:16]([CH2:20][F:21])[CH2:15]3)[C:11]=2[F:13])[C:6](=[O:23])[C:5]([C:24]([OH:26])=[O:25])=[CH:4]1)[CH3:2].[C:27]([O-])(=O)C.[Na+].C=O>C(O)=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:22])=[C:10]([N:14]3[CH2:19][CH2:18][N:17]([CH3:27])[CH:16]([CH2:20][F:21])[CH2:15]3)[C:11]=2[F:13])[C:6](=[O:23])[C:5]([C:24]([OH:26])=[O:25])=[CH:4]1)[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(CF)C3)c(F)c21
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)C(CF)C3)c(F)c21

Procedure:
A 715 mg portion of (+)-1-ethyl-6,8-difluoro-7-[3-(fluoromethyl)-1-piperazinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (Ex. 65) was reacted as described previously with 400 mg of sodium acetate, 3 ml of formic acid and 3 ml of formaldehyde, giving 125 mg of the desired product, mp 208°-210° C. (dec.).
Reaction SMILES: O[C@H:2]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][N:11]=1)[C:7]#[N:8])[CH3:3].C1C(=O)N([Cl:19])C(=O)C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[Cl:19][C@@H:2]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][N:11]=1)[C:7]#[N:8])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@H](O)c1cc(C#N)ccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@@H](Cl)c1cc(C#N)ccn1
Temperature: 30 °C
Yield: 7 %

Procedure:
The title compound was prepared from 2-((S)-1-hydroxy-ethyl)-isonicotinonitrile (620 mg, 4.18 mmol) according to General Method C, except that 1.0 equiv. NCS and 1.0 equiv. PPh3 were used. After 24 hrs reaction time another 0.2 equiv. each of NCS and PPh3 were added and the temperature was increased to 30° C. for 12 h. Workup and purification by flash column chromatography yielded the title compound (46 mg, 7% yield) with 82% ee. 1H NMR (CDCl3) δ 8.74 (d, 1H), 7.76 (s, 1H), 7.46 (dd, 1H), 5.16 (q, 1H), 1.88 (d, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:10]=[C:11]([N:19]2[C@H:24]([CH3:25])[CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:21]([CH3:33])[CH2:20]2)[C:12]2[CH2:18][NH:17][CH2:16][CH2:15][C:13]=2[N:14]=1.FC(F)(F)S(O[C:40]1[CH:45]=[C:44]([CH:46]([CH3:48])[CH3:47])[CH:43]=[CH:42][C:41]=1[CH3:49])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:10]=[C:11]([N:19]2[C@H:24]([CH3:25])[CH2:23][N:22]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[C@@H:21]([CH3:33])[CH2:20]2)[C:12]2[CH2:18][N:17]([C:40]3[CH:45]=[C:44]([CH:46]([CH3:48])[CH3:47])[CH:43]=[CH:42][C:41]=3[CH3:49])[CH2:16][CH2:15][C:13]=2[N:14]=1
Reactant: Cc1ccc(C(C)C)cc1OS(=O)(=O)C(F)(F)F
Reactant: Cc1cccc(C)c1-c1nc2c(c(N3C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]3C)n1)CNCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cc1ccc(C(C)C)cc1N1CCc2nc(-c3c(C)cccc3C)nc(N3C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]3C)c2C1
Temperature: 130 °C

Procedure:
To a solution of racemic tert-butyl 4-(2-(2,6-dimethylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-(trans)-2,5-dimethylpiperazine-1-carboxylate (0.187 g, 0.414 mmol) in THF (4 mL) was added 5-isopropyl-2-methylphenyl trifluoromethanesulfonate (0.175 g, 0.620 mmol) prepared as described in Example 15, Cs2CO3 (0.404 g, 1.24 mmol) and chloro(2-dicyclohexylphosphino-2′-4′-6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)-methyl-t-butylether adduct (0.046 mg, 0.062 mmol). The reaction was purged with argon and was heated at 130° C. for 3 h in a microwave reactor. The mixture was then concentrated and the residue was purified via FCC (10-35% EtOAc/heptane) to give racemic tert-butyl 4-(2-(2,6-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-(trans)-2,5-dimethylpiperazine-1-carboxylate. MS (ESI+) m/z 584.4 (M+H)+.