Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2Cl.[CH3:16][NH:17][CH2:18][CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH3:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:17]([CH2:18][CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH3:20])[CH3:16]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: CNCC(C)c1ccccn1
Product: COc1cc2ncnc(N(C)CC(C)c3ccccn3)c2cc1OC

Procedure:
Reaction of 6,7-dimethoxy-4-chloroquinazoline with 2-(1-[N-methylamino]prop-2-yl)pyridine, according to the procedure of Example I, afforded the title compound, isolated as its dihydrochloride trihydrate, m.p. 235°C.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].C(N(CC)CC)C.[C:17](ON1C(=O)CCC1=O)(=[O:41])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].CCCCCC.C(OCC)C.C(O)(=O)C>O.CC(C)=O>[C:17]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])(=[O:41])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CSCC[C@H](N)C(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)N[C@@H](CCSC)C(=O)O

Procedure:
To a stirred solution of L-methionine (5 mmol, 0.75 g) and triethylamine (15 mmol, 2.1 mL) in 15 mL of water-acetone (1:1), was added succinimidyl nervonate (5 mmol, 2.32 g, prepared according to Example 1A) in portions. The mixture was stirred for 4 hours until no ester remained according to TLC (hexane-diethyl ether-acetic acid, 80:18:2). The solvents were evaporated under reduced pressure. 10 mL of water was then added and the mixture was acidified with concentrated hydrochloric acid to pH 2. The precipitated product was separated by filtration, washed with water and crystallised from ethanol. Hexane was then used to remove traces of non-polar impurities from the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[NH:8][C:7]2=[O:13].C[Si](C)(C)N[Si](C)(C)C.S(=O)(=O)(O)O.Br[CH2:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=1)[C:33]([O:35][CH3:36])=[O:34]>C1(C)C=CC=CC=1.O1CCOCC1.CO.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH2:29][C:30]1[CH:39]=[CH:38][CH:37]=[C:32]([C:33]([O:35][CH3:36])=[O:34])[CH:31]=1)[C:7]2=[O:13]
Reactant: O=c1[nH]c(=O)c2cccc(Cl)c2[nH]1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(Cn2c(=O)[nH]c3c(Cl)cccc3c2=O)c1
Temperature: 160 °C
Reaction time: 3 h
Yield: 29.1 %

Procedure:
To a suspension of 8-chloroquinazoline-2,4(1H,3H)-dione (5.1 g, 25.9 mmol) in toluene (50 mL) and hexamethyldisilazane (HMDS, 10.4 g, 64.9 mmol) was added sulfuric acid (0.25 g, 2.6 mmol). The mixture was heated to reflux and refluxed for 8 h until a clear solution was obtained. The solvent and excessive HMDS was removed via vacuum evaporation, and methyl 3-(bromomethyl)benzoate (5.9 g, 25.9 mmol) and DMF (1 mL) was added to the residue. The reaction mixture was heated to 160° C. and was stirred at this temperature for 3 h. It was diluted with 1,4-dioxane (6 mL) at 100° C., and then methanol (10 mL) was added at 70° C. and it was stirred for 30 min. The mixture was cooled to 5° C. and the precipitates were collected. The solids was washed with methanol (10 mL) and water (20 mL), dried under vacuum for 12 h to give the title compound 8-chloro-3-(3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione (2.6 g, 29.1% yield) as gray solid. MS: m/z 477.1 [M+H]+. The filtrate was concentrated, and the residue was purified by preparative TLC (PE:EA=1:1) to give the other title compound 8-chloro-1-(3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione (0.2 g, 1.8%) as yellow solid. MS: m/z 477.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:10]2[C:9]3[CH2:11][NH:12][CH2:13][CH2:14][C:8]=3[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][CH:17]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[OH-].[K+]>C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:5]1[C:6]2[NH:7][C:8]3[CH2:14][CH2:13][NH:12][CH2:11][C:9]=3[C:10]=2[C:2]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)=[CH:3][CH:4]=1
Reactant: Clc1ccnc2[nH]c3c(c12)CNCC3
Reactant: Nc1ccc(NC(=O)c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)(C)O
Product: O=C(Nc1ccc(Nc2ccnc3[nH]c4c(c23)CNCC4)cc1)c1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
4-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (500 mg, 1.78 mmol), N-(4-Amino-phenyl)-benzamide (454 mg, 2.14 mmol), Pd(OAc)2 (20 mg, 0.09 mmol), X-Phos (85 mg, 0.18 mmol), and KOH (300 mg, 5.35 mmol) were dissolved in tert-butanol (9.0 mL), and stirred overnight at 100° C. The reaction mixture was concentrated, and then suspended in EtOAc/H2O. The resulting precipitate was filtered, washed with EtOAc/H2O, and dried under vacuum to provide 1 (255 mg, 37% yield) as a tan solid. LC-MS (M+H=384, obsd.=384).
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([OH:9])=O)[CH2:5][N:4]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[C:3]1=[O:16].C(N1CCOCC1)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:48][C:49]1[C:54]([C:55]([F:58])([F:57])[F:56])=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:59][NH2:60]>ClCCl>[Cl:48][C:49]1[C:54]([C:55]([F:57])([F:58])[F:56])=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:59][NH:60][C:7]([CH:6]1[CH2:5][N:4]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[C:3](=[O:16])[N:2]1[CH3:1])=[O:9]
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Reactant: CN1C(=O)N(c2cnccn2)CC1C(=O)O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CN1C(=O)N(c2cnccn2)CC1C(=O)NCc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19.4 %

Procedure:
To a solution of 3-methyl-2-oxo-1-(2-pyrazinyl)-4-imidazolidinecarboxylic acid (145 mg, 0.561 mmol) and N-ethylmorpholine (0.426 ml, 3.36 mmol) in dichloromethane (5 ml) was added 1-hydroxybenzotriazole hydrate (86 mg, 0.561 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (107 mg, 0.561 mmol) and the reaction mixture was stirred for 10 minutes at room temperature. 1-[2-Chloro-3-(trifluoromethyl)phenyl]methanamine (141 mg, 0.673 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with saturated sodium hydrogen carbonate solution, water and brine and separated by hydrophobic frit and the organic layer reduced under vacuum. The residue was purified by SP4 automated silica gel chromatography eluting with 10-100% ethyl acetate in isohexane to give N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-3-methyl-2-oxo-1-(2-pyrazinyl)-4-imidazolidinecarboxamide (45 mg, 19% yield). LC/MS [M+H]+=413, retention time=2.21 minutes.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[N:4]=1.[CH:23]([N:26](C(C)C)CC)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.CN>ClCCl>[CH3:23][NH:26][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:1])([F:22])[F:21])=[N:4]2)=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CNC(=O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
A solution of 4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid (87 mg, 0.28 mmol) and diisopropylethylamine (0.1 ml) in dichloromethane (3 ml) was treated with 1,1′-carbonyldiimidazole (46 mg, 0.28 mmol) in one portion and stirred at room temperature for 15 minutes. Then methylamine hydrochloride (22 mg, 0.33 mmol) was added and stirring continued for 1 hour. The reaction mix was added to a 5 g pre-packed silica column and eluted with 0-50% ethyl acetate in petroleum ether to give the title compound (28 mg, 31%).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].F[C:22]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>>[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH:17][C:22]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]
Reactant: Nc1cccc(F)c1
Reactant: O=C(O)c1cc(F)c(F)cc1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(F)c(F)cc1Nc1cccc(F)c1
Yield: 93.3 %

Procedure:
Using General Method 1, the reaction of 2.5 M solution of n-BuLi in hexanes (21 mL, 53 mmol), diisopropylamine (7.2 mL, 51 mmol), 3-fluoro-aniline (1.6 mL, 17 mmol), and 2,4,5-trifluorobenzoic acid (3.0 g, 17 mmol) provided 4.24 g of the crude title compound.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[CH2:8]([C@:15]1([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:22](=[O:23])[N:21]2[C@@H:17]([S:18][CH2:19][C@H:20]2[C:24]([OH:26])=[O:25])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCCCCC.CO>[CH2:8]([C@:15]1([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:22](=[O:23])[N:21]2[C@@H:17]([S:18][CH2:19][C@H:20]2[C:24]([O:26][CH3:1])=[O:25])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N[C@]1(Cc2ccccc2)C[C@@H]2SC[C@@H](C(=O)O)N2C1=O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)[C@@H]1CS[C@H]2C[C@@](Cc3ccccc3)(NC(=O)OC(C)(C)C)C(=O)N21
Temperature: 25 °C

Procedure:
A total of 1.5 ml of a 2 molar solution of trimethylsilyldiazomethane in hexane is added in portions to a solution of 250 mg of (3R,6R,7aS)-6-benzyl-6-tert-butoxycarbonylamino-5-oxohexahydropyrrolo[2,1-b]thiazole-3-carboxylic acid in 8 ml of methanol while stirring at room temperature. After the reaction is complete, the excess trimethylsilyldiazomethane is destroyed by dropwise addition of glacial acetic acid, and the volatile constituents are stripped off in a rotary evaporator at 40° C. The residue is purified on a column (silica gel, mobile phase:ethyl acetate:n-heptane=1:1.5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[CH3:23])[CH2:14][C:13](=[O:24])[NH:12][CH:11]3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C:5]2=[CH:4][CH:3]=1.COC([Si](C)(C)C)C.Br[CH2:42][C:43]([NH2:45])=[O:44].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.FC(F)(F)C(O)=O.ClCCl>[NH2:45][C:43]([CH2:42][N:12]1[C:13](=[O:24])[CH2:14][CH:15]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[CH3:23])[C:10]2([C:5]3[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:9]2=[O:32])[CH:11]1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)=[O:44]
Reactant: Cc1ccc(F)cc1C1CC(=O)NC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: NC(=O)CBr
Agent: COC(C)[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1C1CC(=O)N(CC(N)=O)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 19 %

Procedure:
In a manner similar to the method described in example 146d and 146e racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (50 mg g, 0.08 mmol) was reacted with 2-bromo-acetamide (35 mg, 0.25 mmol) and cesium carbonate (163 mg, 0.50 mmol) in DMF (2 ml). The resulting residue was dissolved in a mixture solution of trifluoroacetic acid (5 mL) and dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated. The residue was redissolved in methanol (10 mL). To the resulting solution was added N,N′-diisopropylethylamine and the crude was refluxed for 1 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and HCl aqueous solution (1N). The organic layer was separated, dried over MgSO4 and concentrated. The residue was triturated purified by Prep-HPLC to give racemic (2′S,3S,4′R)-1′-(aminocarbonyl-methyl)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (8 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:21][OH:22])[O:8][C:7]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:6]=2[N:5]2[C:16](=[O:20])[N:17]([CH3:19])[N:18]=[C:4]12.N1C=CC=CC=1.[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30].C(N(CC)CC)C>ClCCl>[CH3:36][C:35]1[CH:37]=[CH:38][C:32]([S:29]([O:1][CH2:2][C:3]2([CH2:21][OH:22])[O:8][C:7]3[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:6]=3[N:5]3[C:16](=[O:20])[N:17]([CH3:19])[N:18]=[C:4]23)(=[O:31])=[O:30])=[CH:33][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1nc2n(c1=O)-c1cc([N+](=O)[O-])ccc1OC2(CO)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2(CO)Oc3ccc([N+](=O)[O-])cc3-n3c2nn(C)c3=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4,4-Bis(hydroxymethyl)-2-methyl-8-nitro-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-1-one (1.6 g) and pyridine (0.84 mL, 2 eq.) were dissolved in anhydrous dichloromethane (100 mL). In an ice bath, tosyl chloride (1.2 g, 1.2 eq.) was added to the reaction solution in portions. The reaction was stirred in an ice bath to room temperature overnight. Then triethylamine (1.5 mL, 2 eq.) and more of tosyl chloride (500 mg, 0.5 eq.) were added and stirred at room temperature overnight. LCMS showed mixtures of starting material, mono-tosylated product and bis-tosylated product. The reaction solution was evaporated. The residue was purified by Combiflash chromatography (EtOAc in hexanes=20-100%) to give (4-(hydroxymethyl)-2-methyl-8-nitro-1-oxo-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-4-yl)methyl 4-methylbenzenesulfonate. m/z=462.83 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[CH2:17]([O:19][C:20](=[O:25])[CH2:21][C:22]([CH3:24])=[O:23])[CH3:18].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[O:23]=[C:22]([CH3:24])[C:21](=[CH:6][C:5]1[CH:4]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=1)[C:20]([O:19][CH2:17][CH3:18])=[O:25]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)=O

Procedure:
This compound is prepared in a manner analogous to that of Step A of Example 2, using 36.3 grams (0.15 mole) of 3,5-di(trifluoromethyl)benzaldehyde, 22.0 grams (0.17 mole) of ethylacetoacetate, 2 mL of piperidine, and 3 mL of glacial acetic acid in 250 mL of toluene, yielding ethyl 3-oxo-2-[3,5-di(trifluoromethyl)phenylmethylidene]butanoate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[NH:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]2[CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=3)[S:28][C:19]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[NH:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]2[CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:31][CH:30]=3)[S:28][C:19]=12
Reactant: C1CCNCC1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(C=O)cc4)sc23)c(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(CN5CCCCC5)cc4)sc23)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 17.8 %

Procedure:
Piperidine (50 mg, 0.59 mmol) is added to a suspension of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile (200 mg, 0.44 mmol) in 4 mL of dichloromethane and 1 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0° C. and sodium triacetoxyborohydride (500 mg, 2.4 mmol) is added. After stirring at 0° C. for 1.5 hours, a few drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred overnight. The reaction is quenched by the addition of water and then partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 1:1 hexane:ethyl acetate to 5% methanol in ethyl acetate to provide 41 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(piperidin-1-ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 218–220° C.; 1H NMR (DMSO-d6) δ 1.38 (m, 2H), 1.50 (m, 4H), 2.33 (m, 4H), 3.46 (m, 2H), 3.85 (s, 3H), 7.38 (s, 1H), 7.40 (d, J=8 Hz, 2H), 7.67 (d, J=8 Hz, 2H), 7.76 (s, 1H), 7.89 (s, 1H), 8.60 (s, 1H), 9.72 (s, 1H); MS 521.3 (M−H)−.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[C:23](OCCO)[N:22]=[CH:21][N:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl>C(O)(=O)C.O1CCOCC1.[C].[Pd]>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]2[C:19]([NH:18][S:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)(=[O:17])=[O:16])=[N:20][CH:21]=[N:22][CH:23]=2)=[CH:30][CH:29]=1
Reactant: O=S(=O)(Nc1ncnc(OCCO)c1-c1ccc(Cl)cc1)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=S(=O)(Nc1ncncc1-c1ccc(Cl)cc1)c1ccc(O)cc1

Procedure:
A solution of 512 mg of p-(benzyloxy)-N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl]benzene-sulfonamide in 30 ml of glacial acetic acid was treated with 2 ml of 4N HCl in dioxane and 100 mg of 10% palladium-carbon. The mixture was hydrogenated while stirring, thereafter the solution was suction filtered, evaporated under reduced pressure and the residue was recrystallized from isopropyl ether and again from CH3CN. There was obtained N-[5-(p-chlorophenyl)-4-pyrimidinyl]-p-hydroxybenzenesulfonamide, melting point 231°-232° C.
Reaction SMILES: [CH3:1][CH:2]([N:14]([CH3:16])[CH3:15])/[CH:3]=[CH:4]/[CH:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH:7]=[C:6]1[CH3:13].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1.C(O)C.[I-:30].[K+]>CO>[I-:30].[CH3:1][CH:2]([N+:14]([CH3:16])([CH3:15])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)/[CH:3]=[CH:4]/[CH:5]1[C:10]([CH3:11])([CH3:12])[CH2:9][CH2:8][CH:7]=[C:6]1[CH3:13]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CC1=CCCC(C)(C)C1/C=C/C(C)N(C)C
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: CCO
Product: CC1=CCCC(C)(C)C1/C=C/C(C)[N+](C)(C)Cc1ccc(Cl)c(Cl)c1
Yield: 58.1 %

Procedure:
A solution of [1-methyl-3-(2,6,6-trimethyl-2-cyclohexenyl)-2(trans)-propenyl]dimethylamine (3.0 g) and α,3,4-trichlorotoluene (4.0 g) in methanol (15 cc) was refluxed for 2 hours, and thereto were added ethanol (40 cc) and then an aqueous solution of potassium iodide (3.0 g). The solvent of the reaction mixture was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of methanol and ether to give colorless crystals (4.0 g) of [1-methyl-3-(2,6,6-trimethyl-2-cyclohexenyl)-2(trans)-propenyl]dimethyl(3,4-dichlorobenzyl)ammonium iodide, m.p. 160°-165° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][CH3:16]>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 88.4 %

Procedure:
To a solution of 4-bromobenzyl alcohol (10.0 g, 53.5 mmol) in N,N-dimethylformamide (200 mL) was added sodium hydride (3.08 g, 64.2 mmol, 50% in oil) at 0° C. This mixture was stirred for 5 minutes at 0° C., and 1-bromobutane (7.47 mL, 69.3 mmol) was added thereto at 0° C. This mixture was stirred for 40 minutes at room temperature and then stirred for 25 minutes at 70° C. The reaction solution was partitioned into water and ethyl acetate at 0° C. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=20:1) to obtain the title compound (11.5 g, 89%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[C:35]5[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][N:34]=5)[N:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH2:78]([Si:80]([C:85]#[CH:86])([CH2:83][CH3:84])[CH2:81][CH3:82])[CH3:79]>C(#N)C.C(#N)C.C(#N)C.Cl[Pd]Cl.O1CCOCC1>[CH3:37][O:36][C:32]1[CH:31]=[C:30]2[C:35]([C:26]([O:25][C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:11]4[C:12]5[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:8]([C:5]5[CH:6]=[CH:7][C:2]([C:86]#[C:85][Si:80]([CH2:83][CH3:84])([CH2:81][CH3:82])[CH2:78][CH3:79])=[CH:3][CH:4]=5)=[N:9][N:10]=4)=[CH:24][CH:23]=3)=[CH:27][CH:28]=[N:29]2)=[N:34][CH:33]=1
Reactant: COc1cnc2c(Oc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)ccnc2c1
Reactant: C#C[Si](CC)(CC)CC
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: C1COCCO1
Product: CC[Si](C#Cc1ccc(-c2nnc(Nc3ccc(Oc4ccnc5cc(OC)cnc45)cc3)c3ccccc23)cc1)(CC)CC
Temperature: 90 °C
Reaction time: 1 h

Procedure:
In an argon purged sealed pressure vessel was added 4-(4-chlorophenyl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine (0.120 g, 0.237 mmol), cesium carbonate (0.201 g, 0.617 mmol), X-phos (0.017 g, 0.0356 mmol), dichloropalladium bisacetonitrile (0.003 mg, 0.011 mmol), and acetonitrile (0.50 mL). Starting material was not soluble in acetonitrile, so added 0.5 mL 1.4 dioxane. Purged the reaction with argon, then added (triethylsilyl)acetylene (0.055 mL, 0.308 mmol), and agina purged with vessel with argon, sealed, heated it to 90° C. The reaction was stirred for 1 h. Reaction complete by LC/MS. The reaction was cooled to RT, passed through pad of silica, washed with 100% CH2Cl2:MeOH(90:10)/CH2Cl2 and the organics were concentrated. The crude material was purified by silica gel chromatography eluting with 0-100% CH2Cl2:MeOH(90:10)/CH2Cl2. The product fractions were concentrated to yield N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)-4-(4-(2-(triethylsilyl)ethynyl)phenyl)phthalazin-1-amine as light yellow solid. MS
Reaction SMILES: C(OP(CC(CC(C)C)C(O)=O)(C[N:7]1[C:11](=[O:12])[C:10]2=CC=[CH:15][CH:16]=[C:9]2C1=O)=O)C.N[CH:28]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C:30](=[O:41])[NH:29]1>>[O:41]=[C:30]1[CH:31]([CH:10]([CH2:9][CH2:16][CH3:15])[C:11]([NH2:7])=[O:12])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:28][NH:29]1
Reactant: NC1CCCCCCCCCCC(=O)N1
Reactant: CCOP(=O)(CC(CC(C)C)C(=O)O)CN1C(=O)c2ccccc2C1=O
Product: CCCC(C(N)=O)C1CCCCCCCCCCNC1=O

Procedure:
In a manner analogous to that describe in Example 1(A)(iv), from 1.9 g of 2(RS)-[[(RS)-(ethoxy)(phthalimidomethyl)phosphinyl]methyl]-4-methylvaleric acid and 1.0 g of (-)-3-amino-2-azacyclotridecanone, there were obtained 2.1 g of 2(RS)-[[(RS)-(ethoxy)(phthalimidomethyl)phosphinyl]methyl]-4-methyl-N(R or S)-(2-oxoazacyclotridecan-3-yl)valeramide in the form of a white solid.