Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[N:7][C:6]=2[N:20]=1.[CH3:29][N:30]([CH:32](OC)OC)[CH3:31]>CN(C=O)C>[Cl:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=1[C:3]1[C:2]([N:1]=[CH:29][N:30]([CH3:32])[CH3:31])=[N:20][C:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:9]=[CH:10][C:5]=2[CH:4]=1
Reactant: COC(OC)N(C)C
Reactant: CCN(CC)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N=CN(C)C)nc2n1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 68 %

Procedure:
To a suspension of 210 mg (1 mmol) of 7-amino-6-(2,6-dichlorophenyl)-2-[3-(diethylamino) propylamino]-pyrido[2,3-d]pyrimidine from Example 20 in 0.8 mL of DMF was added 0.8 mL of DMF dimethyl acetal. The mixture was stirred at room temperature for 5.5 hours, then concentrated in vacuo. The residual oil was distributed between dichloromethane and water. The organic phase was dried over magnesium sulfate, then concentrated to a glass that was crystallized from acetonitrile to give 160 mg (68%) of N'-[6-(2,6-dichlorophenyl)-2-{3-(diethylamino) propylamino}-pyrido[2,3-d]pyrimidin-7-yl]-N, N-dimethylformamidine, mp 100°-104° C.
Reaction SMILES: Br[CH:2]([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:18][C:19]([NH2:21])=[S:20]>C(O)C>[NH2:21][C:19]1[S:20][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=2)[N:18]=1
Reactant: CCOC(=O)C(Br)C(=O)c1cccc(C#N)c1
Reactant: NC(N)=S
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1-c1cccc(C#N)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of ethyl 2-bromo-3-(3-cyanophenyl)-3-oxopropionate (2.0 g, 6.75 mmol) in 100 mL of absolute ethanol was added thiourea (0.51 g, 6.75 mmol). The resulting mixture was stirred at 80° C. for 3 h. The reaction was allowed to cool and the solvent was evaporated in vacuo. The residue was taken up in ethyl acetate, washed with saturated aq NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to yield a solid. Trituration with hexanes/ethyl ether left the title compound as an off-white solid (1.55 g, 65%). 1H NMR (DMSO-d6) δ: 8.03 (s, 1H); 7.93 (s, 2H) ; 7.91 (d, 1H); 7.82 (d, 1H); 7.58 (t, 1H); 4.05 (q, 2H); 1.10 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].Cl[CH2:13][CH:14]=[C:15]([CH3:35])[CH2:16][CH2:17][CH2:18][C:19]([Cl:34])([CH3:33])[CH2:20][CH2:21][CH2:22][C:23]([Cl:32])([CH3:31])[CH2:24][CH2:25][CH2:26][C:27]([Cl:30])([CH3:29])[CH3:28].[Cl-].[NH4+]>O1CCOCC1>[CH3:35][C:15]1([CH2:16][CH2:17][CH2:18][C:19]([Cl:34])([CH3:33])[CH2:20][CH2:21][CH2:22][C:23]([Cl:32])([CH3:31])[CH2:24][CH2:25][CH2:26][C:27]([Cl:30])([CH3:29])[CH3:28])[CH2:14][CH2:13][C:8]2[C:6](=[C:5]([CH3:9])[C:4]([CH3:10])=[C:3]([OH:11])[C:2]=2[CH3:1])[O:7]1
Reactant: CC(=CCCl)CCCC(C)(Cl)CCCC(C)(Cl)CCCC(C)(C)Cl
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)(Cl)CCCC(C)(Cl)CCCC(C)(C)Cl)O2
Reaction time: 0.5 h
Yield: 43.5 %

Procedure:
Fused zinc chloride (0.22 g), trimethylhydroquinone (2.47 g) and anhydrous dioxane (10 cc) are introduced into a 250 cc reactor. The mixture is heated to 40°-45° C. and a solution of 1,7,11,15-tetrachloro-3,7,11,15-tetramethylhexadec-2-ene (6.8 g) in dioxane (7 cc) is then added over the course of 20 minutes. Stirring is continued for 1 hour 30 minutes. This reaction mixture is poured into an aqueous solution (50 cc) of ammonium chloride (100 g/liter). The mixture is extracted with ethyl acetate (twice 50 cc) and the organic phases are then dried over magnesium sulphate. After filtration and evaporation of the solvent, 2,5,7,8-tetramethyl-2-(4',8',12'-trichloro-4',8',12'-trimethyltridecyl)-chroman-6-ol is obtained in a yield of 43.5%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:31]CCl.CO.[ClH:36]>C(OCC)C>[ClH:31].[ClH:36].[ClH:31].[N:25]1([CH2:24][CH2:23][CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:16][CH:17]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1
Reactant: ClCCl
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: c1cc(OCCCN2CCCCC2)ccc1CN1CCNCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
To a solution of 4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine-1-carboxylic acid tert-butyl ester (D1) (1.576 g, 3.76 mmol) in a (1:1) mixture of dichloromethane and methanol (20 ml) was added a 1M solution of hydrogen chloride in diethyl ether (20 ml) and the reaction stirred for 5 hours at room temperature. The solvent was then evaporated in vacuo and the resulting residue triturated with diethyl ether to afford the title compound (1.5 g, 93%); MS (ES+), m/e 318 [M+H]+.
Reaction SMILES: [N+:1](=[CH:3][CH:4]([CH3:6])[CH3:5])=[N-:2].[N+:7]([C:10]1[CH:29]=[CH:28][C:13]([CH2:14][O:15][C:16](=[O:27])[C:17](=[CH2:26])[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:12][CH:11]=1)([O-:9])=[O:8]>C(Cl)Cl>[C:22]([O:21][C:19]([NH:18][C:17]1([C:16]([O:15][CH2:14][C:13]2[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:29][CH:28]=2)=[O:27])[CH2:26][CH:3]([CH:4]([CH3:6])[CH3:5])[NH:1][NH:2]1)=[O:20])([CH3:23])([CH3:24])[CH3:25]
Reactant: C=C(NC(=O)OC(C)(C)C)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)C=[N+]=[N-]
Solvent: ClCCl
Product: CC(C)C1CC(NC(=O)OC(C)(C)C)(C(=O)OCc2ccc([N+](=O)[O-])cc2)NN1
Yield: 98.4 %

Procedure:
The ethereal diazoisobutane (6) was gradually added to a solution of Boc-dehydroalanine-p-nitrobenzyl ester (2) (967 mg, 3 mmol) in CH2Cl2 (15 ml) at -10° C. to -15° C. with stirring. After stirring for 1 hr at the same temperature, the solvent was evaporated in vacuo and the resulting residue was triturated with hexane and filtered by suction to give 1.2 g of p-nitrobenzyl p-nitrobenzyl 3-t-butoxycarbonylamino-5-isopropylpyrazoline-3-carboxylate (7) (98.4%) mp 78°-79° C. (dec.). Recrystallization from AcOEt-n hexane gave colorless prisms having mp 87°-89° C. (dec.); IR (KBr) 3390(NH), 1745(C=O), 1690(C=O), 1605 (N=N).NMR (CDCl3)δ: 8.2 and 7.5 (d, d, 4H, ArH), 6.2 (br s, 1H, NH); 5.30 (s, 2H, OCH2), 4.8-5.2 (m, 1H, CH--N=N), 1.5-2.3 (m, 3H, (CH3)2CH and CH2), 1.35 (s, 9H, Boc), 1.00-1.30 (m, 3H, CH3), 0.8-1.10 (m, 3H, CH3).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[C:16]3[C:17]([OH:21])=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][CH:13]=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[C:22]([O:25][C@@H:26]1[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:37]([O:43][C:44](=[O:46])[CH3:45])[C@@H:36]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[O:35][C@@H:27]1OC(=N)C(Cl)(Cl)Cl)(=[O:24])[CH3:23].C(=O)([O-])O.[Na+]>ClCCl>[C:22]([O:25][C@@H:26]1[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:37]([O:43][C:44](=[O:46])[CH3:45])[C@@H:36]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[O:35][C@H:27]1[O:21][C:17]1[C:16]2[C:12]([CH2:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([C:1](=[O:3])[NH2:2])=[CH:9][CH:8]=3)=[CH:13][O:14][C:15]=2[CH:20]=[CH:19][CH:18]=1)(=[O:24])[CH3:23]
Reactant: NC(=O)c1ccc(CCc2coc3cccc(O)c23)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4ccc(C(N)=O)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a mixture of 3-[2-(4-carbamoylphenyl)ethyl]-4-hydroxybenzofuran (50 mg) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (96 mg) in dichloromethane (3 mL) was added borontrifluoride-diethyl ether complex (0.022 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethylacetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1) to give 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-[2-(4-carbamoylphenyl)ethyl]benzofuran (80 mg). This material was dissolved in methanol (3 mL). To the solution was added sodium methoxide (28% methanol solution, 0.02 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. To the residue was added a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was treated with dichloromethane. The precipitated crystals were collected by filtration and dried under reduced pressure to give the title compound (13 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH:36]1[CH2:40][CH2:39][CH2:38][N:37]1[CH2:41][CH3:42]>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:34][CH2:35][CH:36]3[CH2:40][CH2:39][CH2:38][N:37]3[CH2:41][CH3:42])=[O:22])(=[O:15])=[O:16])[CH2:12]2)=[CH:28][CH:29]=1
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 150 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (165 μM) and 0.0396 cm3 of 2-(aminomethyl)-N-ethylpyrrolidine. 58 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(1-ethylpyrrolidin-2-ylmethyl)benzamide are thus obtained in the form of an ochre-colored foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[F:26])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[F:26])=[C:6]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:15]3[NH:29][N:28]=[N:27][N:16]=3)[N:14]=2)[CH:7]=1
Reactant: N#Cc1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(Cl)ccc1COc1ccc(Cl)cc1Cc1cccc(-c2nnn[nH]2)n1
Reaction time: 11 h
Yield: 28.7 %

Procedure:
A mixture of 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)-methyl]-2-pyridinecarbonitrile (93 mg), sodium azide (51 mg), ammonium chloride (42 mg) and dimethylformamide (1 ml) was stirred at 120° for 11 hours. After cooling, water (5 ml) was added and the mixture extracted with ethyl acetate (2×5 ml). The combined extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by mass-directed autopreparation to afford the title compound (29.7 mg, 29%) as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[Br:24][C:25]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:26]=1[C:27](O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:27](=[O:28])[C:26]3[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:25]=3[Br:24])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: COc1ccc(Br)c(C(=O)O)c1
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: COc1ccc(Br)c(C(=O)Nc2ccc3c(c2)C(C)(c2ccccc2)CC(C)(C)N3C(C)=O)c1

Procedure:
Condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (25 mg) with 2-bromo-5-methoxybenzoic acid (21 mg) under the agency of HATU (68 mg) and N,N-diisopropylethylamine (32 l) in dichloromethane (4 ml) was performed according to the method described in example 11.,
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[C:12](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:12][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11]
Reactant: O=C([O-])[O-]
Reactant: O=C1CCc2c(O)cccc21
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccc2c1CCC2=O
Temperature: 50 °C
Reaction time: 72 h
Yield: 98.8 %

Procedure:
4-Hydroxy-1-indanone (5.0 g, 33.7 mmol) was dissolved in acetone (170 mL) and then potassium carbonate (9.0 g, 138.21 mmol) and MeI (9.6 g, 67.5 mmol) were added. The resulting suspension was heated to 50° C. and stirred for 3 days at which time the reaction mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and water. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (5.4 g, 98%) as a yellow solid. GC-MS m/z[M+H]+ 163.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH3:33])[CH2:16][CH2:17][N:18]([CH:20]2[CH2:25][CH2:24][N:23](CC3C=CC=CC=3)[CH2:22][CH2:21]2)[CH3:19])[CH2:11][CH2:10]1)C1C=CC=CC=1>[Pd].O.CO>[ClH:1].[ClH:1].[ClH:1].[ClH:1].[NH:9]1[CH2:10][CH2:11][CH:12]([N:15]([CH3:33])[CH2:16][CH2:17][N:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH3:19])[CH2:13][CH2:14]1
Reactant: CN(CCN(C)C1CCN(Cc2ccccc2)CC1)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CN(CCN(C)C1CCNCC1)C1CCNCC1
Reaction time: 6 h
Yield: 73 %

Procedure:
10% Palladium on carbon (125 mg) and concentrated hydrochloric acid (1.2 ml; 14 mmol) were added to a solution in water-methanol (4 ml-8 ml) of N,N′-bis(1-benzyl-4-piperidinyl)-N,N′-dimethylethylenediamine (757 mg; 1.7 mmol) synthesized by the above process, and the mixture was stirred for 6 hours in a bath controlled at 55° C. under hydrogen. The catalyst was removed from the reaction mixture by filtration, and the filtrate was concentrated under reduced pressure. The resultant crude crystals were washed with ethanol, thereby obtaining 497 mg (yield: 71%) of the title compound as a colorless crystalline powder [melting point: 275° C. (decomposition)].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9]I)=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9][NH:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[CH:4][N:3]=1
Reactant: COc1ccc(N)cc1
Reactant: Clc1ncc(CI)c(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(NCc2cnc(Cl)nc2Cl)cc1
Reaction time: 0.5 h

Procedure:
A 500-mL, three-necked flask equipped with a magnetic stirrer, thermometer, and nitrogen-inlet bubbler was charged with a solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (85 g, ca. 253.2 mmol) (from Example 1c supra) in toluene (13.7 mL) from the previous step and toluene (96.3 mL, thus, a total of ca. 110 mL of toluene). After cooling with an ice-water bath, p-anisidine (31.18 g, 253.2 mmol) (Aldrich) was added. After stirring for 30 minutes, a solution of sodium hydroxide (13.54 g, 331.7 mmol) in water (50 mL) was added dropwise over 8 minutes, while maintaining the temperature of the reaction mixture at 10–15° C. hexanes (55 mL) was added and the mixture was stirred at 10–15° C. for 45 minutes, then at room temperature for 22 hours to give a slurry. TLC analysis of the supernatant indicated complete reaction. The slurry was diluted with water (100 mL) and the solid was collected by filtration, washed with cold water and cold (−50° C.) methanol (100 mL), and dried by suction to give [(2,4-dichloropyrimidin-5-yl)methyl](4-methoxyphenyl)amine as an off-white solid, 97% pure by HPLC analysis. (Yield 59.87 g, 83.2%).
Reaction SMILES: CC(=[N:4][OH:5])C.CC(C)([O-])C.[K+].[C:12]([C:14]1[CH:15]=[C:16]([CH:37]=[CH:38][C:39]=1F)[C:17]([NH:19][C:20]1[C:21]([NH:26][C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:18])#[N:13]>CN(C=O)C.C1COCC1>[NH2:13][C:12]1[C:14]2[CH:15]=[C:16]([C:17]([NH:19][C:20]3[C:21]([NH:26][C:27](=[O:36])[C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:18])[CH:37]=[CH:38][C:39]=2[O:5][N:4]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(F)c(C#N)c2)cc1
Reactant: CC(C)=NO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc3onc(N)c3c2)cc1
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
To a stirring solution of acetone oxime (94 mg, 1.28 mmol) in DMF (2 mL) was added a 1 M solution of potassium t-butoxide (1.28 mL, 1.28 mmol) in THF. After 30 min, N1-(3-cyano-4-fluorobenzoyl)-N2-(4-methoxybenzoyl)-1,2-benzenediamine (100 mg, 0.26 mmol) was added and stirring continued for 72 h. The solvents were removed in vacuo and the residue was dissolved in methanol (20 mL). To this stirring solution was added water (15 mL) and conc HCl (3 mL), and the solution was heated to reflux. After 2 h, the solvents were removed in vacuo and the residue was dissolved in methanol. Silica gel was added and then the solvents were removed in vacuo. This dry pack was loaded onto a silica gel column and eluted with 1:1 ethyl acetate/dichloromethane. The product containing fractions were combined and concentrated to give 48 mg (46%) of white solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([O:13][CH3:14])=[O:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:1]([NH:9][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(N)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)C(NCc1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
to a mixture of benzaldehyde (3.06 ml, 30.3 mmol) and methyl 2-amino-2-phenylacetate 1a (4.552 g, 27.6 mmol) in 50 mL 1,2-dichloroethane was added sodium triacetoxyborohydride (14.6 g, 68.9 mmol) all at once. The reaction mixture was stirred at room temperature for several hours then poured into 100 mL saturated aqueous sodium bicarbonate solution. The biphase was vigorously stirred for 15 minutes then the organic separation dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a colorless oil. The product was purified by chromatography on silica gel eluting with 10-40% ethyl acetate in hexane. ESI+ m/z=256.1 [MH]+.
Reaction SMILES: [C:1]1([S:7]([N:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[N:20][O:21][CH2:22][CH2:23][OH:24])[CH3:19])=[CH:14][CH:13]=2)[CH3:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:26]1[CH:58]=[CH:57][C:29]([CH2:30][CH:31]2[S:35][C:34](=[O:36])[N:33]([C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]2=[O:56])=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([S:7]([N:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[N:20][O:21][CH2:22][CH2:23][O:24][C:26]3[CH:58]=[CH:57][C:29]([CH2:30][CH:31]4[S:35][C:34](=[O:36])[N:33]([C:37]([C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)[C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:32]4=[O:56])=[CH:28][CH:27]=3)[CH3:19])=[CH:14][CH:13]=2)[CH3:11])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=NOCCO)c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1
Yield: 36.4 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 667 mg of 2-(1-{4-[N-(phenylsulfonyl)-N-methylamino]phenyl}ethylideneaminooxy)-ethanol (prepared as described in Preparation 37), 1.02 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 577 mg of triphenylphosphine and 383 mg of diethyl azodicarboxylate, 554 mg of the title compound were obtained as a crystalline powder, melting at 143-145° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:30])[CH:10]2[NH:14][C:15](=[O:29])[CH2:16][C:17]2[N:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3O)[S:20][CH:21]=2)[C:7]=1[C:31]([OH:33])=[O:32])(=[O:3])[CH3:2].[SiH](CC)(CC)CC.FC(F)(F)C(O)=[O:44]>C(Cl)CCl>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:30])[CH:10]2[NH:14][C:15](=[O:29])[CH2:16][C:17]2[N:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:44])[CH:23]=3)[S:20][CH:21]=2)[C:7]=1[C:31]([OH:33])=[O:32])(=[O:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4ccccc4O)n3)C2SC1
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4cccc(O)c4)n3)C2SC1
Yield: 96 %

Procedure:
The procedure used for the preparation of 9a was repeated with 8m (157 mg, 0.240 mmol), Et3SiH (0.383 mL, 2.40 mmol), and trifluoroacetic acid (0.739 mL, 9.59 mmol) in dry ClCH2CH2Cl (6 mL) at 0° C. under nitrogen to give 9m (113 mg, 96%) as a white solid after crystallization from THF/CH2Cl2 /hexane. mp 140° C. (dec); IR (KBr) 3600-2650 (br), 3286, 1782, 1738, 1671, 1230 cm-1 ; 1H NMR (DMSO-d6) δ1.98 (3H, s, CH3), 3.44 (1H, d, J=18.1 Hz), 3.59 (1H, d, J=18.1 Hz), 3.72 (2H, s, CH2), 4.64 (1H, d, J=12.8 Hz), 4.96 (1H, d, J=12.8 Hz), 5.07 (1H, d, J=4.8 Hz), 5.69 (1H, dd, J=8.2 and 4.8 Hz), 6.82 (1H, d, J=7.8 Hz), 7.22 (1H, t, J=7.8 Hz), 7.28 (1H, d, J=7.8 Hz), 7.29 (1H, s), 7.39 (1H, s), 9.06 (1H, d, J=8.2 Hz, NH), 9.68 (1H, br s, OH), 13.62 (1H, br s, CO2H); FDMS m/z 490 (M+ +1); Anal. Calcd for C21H19N3O7S2.(C4H8O) 0.25: C, 52.06; H, 4.17; N, 8.28. Found: C, 51.95; H, 3.94; N, 8.04
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([CH:18]3[CH2:23][O:22][CH2:21][CH2:20][O:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7].[CH3:29][O-:30].[Na+].C(Cl)(Cl)Cl>CO>[O:19]1[CH2:20][CH2:21][O:22][CH2:23][CH:18]1[C:17]1[C:11]2[S:10][C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:26]=[CH:27][N:28]=[C:3]([CH2:2][O:30][CH3:29])[CH:4]=3)=[N:13][C:12]=2[C:14]([O:24][CH3:25])=[CH:15][CH:16]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(CCl)c3)nc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COCc1cc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)ccn1

Procedure:
From (+)-2-chloromethyl-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide with sodium methylate in methanol. [α]D20=+65.1° (c=0.55, CHCl3), ES-MS m/e (%): 416 (M+H+, 100).
Reaction SMILES: CO[C:3]([C:5]1[N:10]=[CH:9][C:8]2[N:11]=[CH:12][NH:13][C:7]=2[CH:6]=1)=[O:4].[CH3:14][O:15][CH2:16][CH2:17][NH2:18]>CO>[CH3:14][O:15][CH2:16][CH2:17][NH:18][C:3]([C:5]1[N:10]=[CH:9][C:8]2[N:11]=[CH:12][NH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: COCCN
Reactant: COC(=O)c1cc2[nH]cnc2cn1
Solvent: CO
Product: COCCNC(=O)c1cc2[nH]cnc2cn1

Procedure:
In a similar manner as described for example D5, 2.0 g of methyl-1H-imidazo[4,5-c]pyridine-6-carboxylate (example D2) and 8.5 g of 2-methoxyethanamine in 50 ml methanol yield the title compound.