Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:46])([O:28][C:29]([F:45])([F:44])[C:30]([F:43])([F:42])[O:31][C:32]([F:41])([F:40])[CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38]Br)[C:24]([F:27])([F:26])[F:25].BrCCCCBr>>[CH2:1]([C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:38][CH2:37][CH2:36][CH2:35][O:34][CH2:33][C:32]([O:31][C:30]([F:42])([F:43])[C:29]([F:44])([F:45])[O:28][C:23]([F:22])([F:46])[C:24]([F:25])([F:27])[F:26])([F:41])[F:40])=[CH:17][CH:16]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: FC(F)(COCCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Solvent: BrCCCCBr
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-octyl-2-(4-hydroxyphenyl)pyrimidine (1,995 g, 7.01 mmol) and 4-(2-(2-(pentafluoroethoxy) tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromobutane (3.44 g, 7.36 mmol; prepared by combining 1,4-dibromobutane with 3-(2-(2-(pentafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethanol). The resulting crude product was isolated and further purified essentially as described in Example 3, eluting with 15 volume percent ethyl acetate/hexane, to yield 4.12 g of purified product.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:5]=1[NH:6][C@@H:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][C:9]([O:11][CH3:12])=[O:10])([O-])=O.C([O-])=O.[NH4+]>C(O)C.O.[Pd]>[NH2:1][C:4]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:5]=1[NH:6][C@@H:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C[C@@H](Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COC(=O)C[C@@H](Nc1ccc([N+](=O)[O-])cc1N)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl (3R)-3-(2,4-dinitroanilino)-3-phenylpropanoate (3.14 g, 9.1 mmol) in a mixture of ethanol (100 mL) and water (10 mL) was added ammonium formate (2.3 g, 36 mmol) and palladium on carbon (300 mg, 10% w/w Pd). The mixture was stirred at room temperature for 2 hours, then filtered through a pad of Celite®, evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (95:5), to afford the title compound, [LCMS (Method C, Mobile Phase I) RT=2.94 mins, MH+ 316].
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[CH:20][CH:19]=2)[CH2:9][CH2:8][CH2:7]1)=[O:4].Cl.[CH3:36][NH:37][CH3:38].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:36][N:37]([CH3:38])[CH2:2][C:3]([NH:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[CH:20][CH:19]=2)[CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(NC(=O)CCl)c3ccccc32)cc1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(NC(=O)CN(C)C)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.3 %

Procedure:
To a solution of 5-(2-chloroacetylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in dimethylformamide (20 ml) are added dimethylamine hydrochloride (0.21 g) and potassium carbonate (0.54 g), and the mixture is stirred at room temperature for 2 days. The reaction solution is concentrated and water is added to the resulting residue. The precipitated crystal is collected by filtration, and recrystallized from ethyl acetate to give 5-(2-dimethylaminoacetylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.24 g) as colorless prisms, m.p. 214°-216° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]([CH3:11])[S:6][C:7]=1[C:8]([OH:10])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[F:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([F:46])=[C:24]([NH:23][C:8]([C:7]5[S:6][C:5]([CH3:11])=[N:4][C:3]=5[O:2][CH3:1])=[O:10])[CH:25]=4)=[N:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: COc1nc(C)sc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: COc1nc(C)sc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 40.1 %

Procedure:
In the same manner as in Example 259 and using 4-methoxy-2-methyl-1,3-thiazole-5-carboxylic acid (100 mg, 0.60 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (61 μL, 0.72 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (89 mg, 40%) was obtained as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20](C(=O)C(F)(F)F)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[N:3][CH:2]=1.[OH-].[Na+].Cl>O>[NH:20]1[CH2:19][CH2:18][CH:17]([C:14]2[CH:13]=[CH:12][C:11]([S:8]([NH:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)(=[O:9])=[O:10])=[CH:16][CH:15]=2)[CH2:22][CH2:21]1
Reactant: O=C(N1CCC(c2ccc(S(=O)(=O)Nc3ccncn3)cc2)CC1)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(Nc1ccncn1)c1ccc(C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.2 %

Procedure:
Prepared using general procedure 16. A mixture of N-(pyrimidin-4-yl)-4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzenesulfonamide (850 mg, 2.1 mmol), NaOH (412 mg, 10.3 mmol), and H2O (3 mL) was stirred at RT for 30 minutes. A 1.0 N aqueous HCl solution was added (10.3 mL, 10.3 mmol), and the mixture was azeotroped with MeOH (3×50 mL). A 1:1 solution of CH2Cl2 and MeOH (10 mL) was added, and the mixture was filtered to remove NaCl. The filtrate was concentrated under reduced pressure to give 4-(piperidin-4-yl)-N-(pyrimidin-4-yl)benzenesulfonamide as a light yellow solid (710 mg). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=319.1; tR=0.43 min.
Reaction SMILES: O[CH:2]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:7]([O:8][C@@H:9]2[O:17][C@H:16]([CH2:18][OH:19])[C@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[C@H:5]([OH:6])[C@H:3]1[OH:4].[CH2:24]([NH2:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH3:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][NH:32][CH:2]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:7]([O:8][C@@H:9]2[O:17][C@H:16]([CH2:18][OH:19])[C@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CCCCCCCCN
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Product: CCCCCCCCNC1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O

Procedure:
The process was carried out in essentially the same manner as in Examples 5 and 6 above, using 21 g of lactose and 12.8 g of octylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH2:6][C:7]1[NH:8][C:9](=[O:12])[NH:10][CH:11]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH2:6][C:7]1[NH:8][C:9](=[O:12])[NH:10][CH:11]=1
Reactant: O=c1[nH]cc(Cc2ccccc2[N+](=O)[O-])[nH]1
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1Cc1c[nH]c(=O)[nH]1
Yield: 98.6 %

Procedure:
3b (82 mg, 0.37 mmol) in MeOH was hydrogenated over 10% Pd/C (10 mg) at 50 psi H2. The reaction mixture was filtered through a plug of Celite®, washed with MeOH and concentrated on a rotary evaporator to give 69 mg (98% yield) of 4-(2-aminobenzyl)-1,3-dihydroimidazol-2-one 3c. MS found: (M+H)+=190.
Reaction SMILES: [O:1]=[C:2]1[NH:9][CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:6]=[C:3]1C#N.O=C1NC=C(C2C=CN=CC=2)C=C1C(O)=O.S(=O)(=O)(O)O>>[N:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:6]=[CH:3][C:2](=[O:1])[NH:9][CH:8]=2)=[CH:11][CH:12]=1
Reactant: N#Cc1cc(-c2ccncc2)c[nH]c1=O
Agent: O=C(O)c1cc(-c2ccncc2)c[nH]c1=O
Agent: O=S(=O)(O)O
Product: O=c1ccc(-c2ccncc2)c[nH]1

Procedure:
The process according to claim 12 which comprises reacting 1,2-dihydro-2-oxo-5-(4-pyridinyl)-nicotinonitrile or 1,2-dihydro-2-oxo-5-(4-pyridinyl)-nicotinic acid with aqueous sulfuric acid to produce 5-(4-pyridinyl)-2(1H)-pyridinone.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=O)[CH3:11])=[C:5](I)[CH:4]=1)=[O:2].CN(C)C(N(C)C)=N.[CH2:22]([OH:25])C#C>CN(C=O)C.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.[Cu]I>[OH:25][CH2:22][C:10]1[NH:9][C:6]2[C:7]([CH:11]=1)=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2
Reactant: C#CCO
Reactant: CC(=O)Nc1ccc(C=O)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Product: O=Cc1ccc2[nH]c(CO)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a degassed solution of N-(4-formyl-2-iodo-phenyl)-acetamide (0.760 g, 2.63 mmol) in anhydrous DMF (20 mL) were added bis(triphenylphosphine)palladium(II) dichloride (90 mg, 0.13 mmol), copper (I) iodide (0.03 g, 0.13 mmol), 1,1,3,3-tetramethyl guanidine (1.51 g, 13.1 mmol), and propargyl alcohol (0.210 g, 3.68 mmol). The reaction mixture was stirred at room temperature for 2 hours and then at 80° C. for 24 hours under nitrogen. Solvent was evaporated under reduced pressure. Water (100 mL) was added and the mixture was extracted with ethyl acetate (200 mL). The organic phase was backwashed with water (2×100 mL), brine (100 mL), and dried over anhydrous Na2SO4. Solvent was evaporated and crude compound was purified by the Simpliflash system (60% ethyl acetate in hexanes as eluent) to give 2-hydroxymethyl-1H-indole-5-carbaldehyde as a pale yellow solid. Yield: 0.10 g (22%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)CCC.C([O-])([O-])=O.[K+].[K+].[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)=[O:31]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(O)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: O=C(c1ccc(O)cc1)c1ccccc1Cl
Reaction time: 2 h

Procedure:
4-Tributylstannanyl-phenol linked to Wang's resin from Step A (1 eq), Pd2(dba)3 (0.3 eq) and K2CO3 (70 mg) were suspended in THF/Diisopropilmethylamine. To this mixture 2-chloro-benzoyl chloride was added and stirred for 2 hours. The suspension was filtered and the resin washed with MeOH/CH2Cl2/DMF, then HCl diluted/dioxane and Na2CO3 5%(dioxane) and DMF/MeOH/CH2Cl2. Once the resin was dried TFA 95% and CH2Cl2 were added and the mixture stirred at room temperature for 30 min. The resin was filtered and washed with MeOH/CH2Cl2. The solvents were collected and concentrated to dryness to give the title product.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.CCCCCC.C([Li])CCC.[F:21][C:22]([F:30])([F:29])[C:23]([C:25]([F:28])([F:27])[F:26])=[O:24]>C(OCC)C>[F:21][C:22]([F:30])([F:29])[C:23]([C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1)([OH:24])[C:25]([F:28])([F:27])[F:26]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Brc1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OC(c1cc(Br)cc(Br)c1)(C(F)(F)F)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
Under a nitrogen atmosphere, 30.0 g (95.0 mmol) of 1,3,5-tribromobenzene and 400 mL of diethyl ether were placed in a 500-mL glass flask and cooled to −78° C. Further, 60 ml (96.0 mmol) of 1.6M n-butyl lithium hexane solution was dropped into the glass flask at −78° C. over 1 hour. The resulting solution was subjected to aging at −78° C. for 1 hour. The lithiation of the raw material was confirmed by gas chromatography. After that, 16.6 g (100.0 mmol) of hexafluoroacetone was charged into the solution at −78° C. and stirred for 1 hour. After the completion of the stirring, the reacted solution was separated into an organic layer and an aqueous layer by the addition of 400 mL of 2N hydrochloric acid. The aqueous layer was extracted with 100 mL of isopropyl ether. The extracted organic layers were combined, dried with anhydrous magnesium sulfate, concentrated by an evaporator, and then, subjected to distillation. With this, 23 g of 1-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-3,5-dibromobenzene was obtained. The yield was 60%.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[C:13]([C:16]([OH:18])=O)[CH:14]=[CH:15][C:9]=3[C:8]([N+:19]([O-:21])=[O:20])=[CH:7][C:6]=2[NH:5][CH2:4]1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26].C(P(=O)(OCC)OCC)#N.N.[Na+].[Cl-]>CN(C=O)C>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[C:13]([C:16]([NH:26][CH2:25][CH2:24][N:23]([CH3:27])[CH3:22])=[O:18])[CH:14]=[CH:15][C:9]=3[C:8]([N+:19]([O-:21])=[O:20])=[CH:7][C:6]=2[NH:5][CH2:4]1
Reactant: O=C(O)c1ccc2c([N+](=O)[O-])cc3c(c2c1)C(CCl)CN3
Reactant: CN(C)CCN
Agent: CCOP(=O)(C#N)OCC
Agent: N
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1ccc2c([N+](=O)[O-])cc3c(c2c1)C(CCl)CN3
Temperature: 25 °C
Yield: 59.9 %

Procedure:
A stirred solution of 187 (120 mg, 0.39 mmol) in dry DMF (1.5 mL) was treated at 0° C. with N,N-dimethyl-1,2-ethanediamine (107 μL, 0.97 mmol), followed by the dropwise addition of diethyl cyanophosphonate (128 μL, 93%, 0.78 mmol). The mixture was warmed to room temperature for 45 min, then poured into dilute aqueous NH3 saturated with NaCl. The resulting solid was collected, washed with water and recrystallised twice from CH2Cl2/i-Pr2O to give 1-(chloromethyl)-N-[2-(dimethylamino)ethyl]-5-nitro-1,2-dihydro-3H-benzo[e]indole-8-carboxamide (188) (88 mg, 60%) as a red solid: mp 178-180° C.; 1H NMR [(CD3)2SO] δ 8.68 (t, J=5.7 Hz, 1H), 8.22 (d, J=1.2 Hz, 1H), 8.16 (d, J=9.1 Hz, 1H), 7.77 (dd, J=9.1, 1.7 Hz, 1H), 7.72 (s, 1H), 6.41 (d, J=1.7 Hz, 1H), 4.28-4.18 (m, 1H), 3.98 (dd, J=10.9, 3.7 Hz, 1H), 3.84 (td, J=9.7, 2.4 Hz, 1H), 3.75 (dd, J=−11.0, 9.0 Hz, 2H), 3.49-3.37 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 2.21 (s, 6H). Anal. (C18H21ClN4O3) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](O)([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C2(O)C(=O)Nc3cc(Cl)ccc32)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1ccc(C2C(=O)Nc3cc(Cl)ccc32)cc1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
rac-6-Chloro-3-hydroxy-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (from Example 4a supra) was suspended in a mixture of triethylsilane (5 mL, 31.3 mmol) (Aldrich) and trifluoroacetic acid (12.5 mL) and heated in an 90° C. oil bath for 17 hours. After cooling to room temperature, mixture was diluted with ethyl acetate (100 mL) and treated with solid sodium carbonate (10.5 g). After stirring for 30 minutes, mixture was extracted with water (2×100 mL) and brine (100 mL). Aqueous layers were back washed with ethyl acetate (100 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40M, dichloromethane then 10% ethyl acetate in dichloromethane as solvent). Fractions containing product were combined, concentrated and recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as white needles. (Yield 2.26 g, 82.6% over two steps).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)=[N:24][CH:25]=1.O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH2:27][CH2:28][N:29]([C@H:11]([CH3:12])[C@:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])([OH:10])[CH2:13][N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)[CH2:30][CH:31]=2)=[N:24][CH:25]=1
Reactant: Clc1ccc(C2=CCNCC2)nc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: C[C@@H](N1CC=C(c2ccc(Cl)cn2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 63.8 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.76 g, 3.0 mmol) and 5-chloro-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine (1.31 g, 6.7 mmol) were dissolved in acetonitrile (20 ml), and lithium perchlorate trihydrate (1.50 g, 9.3 mmol) was added thereto and refluxed for 40 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 0.88 g of the intended substance (yield 63.8%).
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:9]([O:16][C:17]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+].Cl.[OH-].[Na+]>O.C(O)C>[CH2:1]([NH:8][CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH3:26])[C:17]=1[O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: COc1cccc(C=O)c1OCc1ccccc1
Reactant: CCCCCCCN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCNCc1cccc(OC)c1OCc1ccccc1
Temperature: 5 °C
Yield: 95.7 %

Procedure:
Ethyl alcohol (30 ml) and n-heptylamine (5.23 g, 45.4 mmol) were added to 2-benzyloxy-3-methoxybenzaldehyde (10 g, 41.3 mmol), and the mixture was heated with stirring under reflux for 2 hours. The reaction mixture was cooled to 5° C., added with sodium borohydride (2.34 g, 61.9 mmol), and then stirred at room temperature for 10 hours. The reaction mixture was added with water (10 ml) and aqueous 6N hydrochloric acid to decompose excess sodium borohydride, and then made alkaline with 25% aqueous sodium hydroxide and extracted with toluene. After the extract was washed with saturated brine and dried over anhydrous sodium sulfate, the solvent was evaporated to give N-heptyl-(2-benzyloxy-3-methoxyphenyl)methylamine (13.5 g) as oil.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([CH:15]=[O:16])=[N:10]2.O>C1COCC1>[Br:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([CH:15]([OH:16])[CH3:1])=[N:10]2
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2nc1C=O
Reactant: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1nc2cccc(Br)c2nc1NC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 92.2 %

Procedure:
Methylmagnesium bromide (Aldrich) (3.0M in Et2O; 2.23 mL, 6.70 mmol) was added to a solution of 5-bromo-3-(tert-butylamino)quinoxaline-2-carbaldehyde (306a) (983.0 mg, 3.19 mmol) in THF (15.0 mL) at 0° C., and the resulting solution was stirred at 0° C. for 5 min. Water (5 mL) was added, and the resulting mixture was partitioned between saturated aq. NaHCO3 (80 mL) and EtOAc (120 mL). The organic layer was separated and sequentially washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-40% EtOAc/hexanes) furnished 1-(5-bromo-3-(tert-butylamino)quinoxalin-2-yl)ethanol (952 mg, 2.94 mmol, 92% yield) as a light-yellow solid (following trituration with hexanes). 1H NMR (400 MHz, CDCl3) δ ppm 7.83 (1H, dd, J=7.6, 1.4 Hz), 7.75 (1H, dd, J=8.2, 1.4 Hz), 7.19 (1H, t, J=7.9 Hz), 5.74 (1H, br. s.), 5.01 (1H, q, J=6.7 Hz), 3.55 (1H, br. s.), 1.63 (9H, s), 1.59 (3H, d, J=6.7 Hz). m/z (EST, +ve) 324.1/326.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:21]2[N:28]=[CH:27][CH:26]=[CH:25][C:22]=2[CH:23]=O)(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[CH3:29][C:30]([S:33]([NH2:35])=[O:34])([CH3:32])[CH3:31].C(OCC)(=O)C>C1COCC1.[Cl-].[Na+].O.[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:21]2[C:22](/[CH:23]=[N:35]/[S:33]([C:30]([CH3:32])([CH3:31])[CH3:29])=[O:34])=[CH:25][CH:26]=[CH:27][N:28]=2)(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1
Reactant: CC(C)(C)S(N)=O
Reactant: O=Cc1cccnc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)S(=O)/N=C/c1cccnc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 44.6 %

Procedure:
To a solution of 2-{[6-(4-fluorophenyl)-2-naphthyl]sulfonyl}nicotinaldehyde (300 mg, 0.77 mmol) in THF (1.6 mL) was added 2-methylpropane-2-sulfinamide (102 mg, 0.84 mmol) and titanium tetraethoxide (0.32 mL, 1.54 mmol). The reaction was heated for 8 hours at 80° C. The reaction mixture was poured into brine, ethyl acetate was added and the mixture stirred for 10 minutes. The organic layer was separated and washed with water and brine, filtered through Hyflo and the volatiles evaporated in vacuo to give the title compound as solid (170 mg). 1H NMR (400 MHz, d6-DMSO): δ 9.60 (1H, s), 8.75 (1H, s), 8.72 (1H, d, J=4.6 Hz), 8.57 (1H, d, J=7.9 Hz), 8.40 (1H, s), 8.34 (1H, d, J=8.7 Hz), 8.24 (1H, d, J=8.7 Hz), 8.05 (1H, d, J=7.5 Hz), 7.93 (3H, dd, J=6.3, 8.5 Hz), 7.82 (1H, dd, J=4.6, 7.9 Hz), 7.39 (2H, t, J=8.8 Hz), 1.24 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[NH2:17][NH2:18]>C(Cl)Cl>[CH3:14][O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:15][CH3:16])[N:3]=[C:2]([Cl:1])[N:11]=[C:10]2[NH:17][NH2:18]
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Reactant: NN
Solvent: ClCCl
Product: COc1cc2nc(Cl)nc(NN)c2cc1OC
Reaction time: 0.75 h

Procedure:
To a solution of 20.8 g. of 2,4-dichloro-6,7-dimethoxyquinazoline in 400 ml. of methylene chloride is added dropwise 20 g. of hydrazine while maintaining the temperature below 30° C. with cooling. The resulting mixture was stirred for 45 minutes and then allowed to stand overnight at a temperature of 0° C. The mixture is then filtered and the solids washed first with water and then with methanol. The resulting solid material is then taken up in ice-water and stirred for 20 minutes. The mixture is then filtered and the resulting solid is recrystallized from methanol/methylene chloride to obtain 6,7-dimethoxy-2-chloro-4-hydrazino-quinazoline, m.p. 312°-315° C. (decomp.).