Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:25])=[C:17]([CH:24]=1)[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C.O>CN(C1C=CN=CC=1)C.O1CCOCC1>[Cl:25][C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[CH:24][C:17]=1[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)OC(=O)c1cc(N)ccc1Cl
Reactant: COc1ccccc1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)Nc1ccc(Cl)c(C(=O)OC(C)C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.2 %

Procedure:
2-Methoxybenzoyl chloride (8.8 g, 0.05 mole) was added at room temperature under a dry nitrogen atmosphere to a stirred mixture of 1-methylethyl 5-amino-2-chlorobenzoate (10.7 g, 0.05 mole), triethylamine (5.6 g, 0.055 mole) and 4-(N,N,-dimethylamino)pyridine (catalyst, 0.2 g) dissolved in dry p-dioxane (100 ml). A solid precipitate formed. Following the initial exothermic reaction (temperature increased to about 45° C.), the reaction mixture was stirred under nitrogen at room temperature for 20 hours. Next, the reaction mixture was added to water (500 ml), resulting in the precipitation of a solid product, which was collected by vacuum filtration, washed with water (500 ml), and dried to yield 16.2 g of the title compound, m.p. 94°-96° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:20][CH3:21])=[C:13]2[C:17]=1[NH:16][C:15]([CH3:18])=[C:14]2[CH3:19])C1C=CC=CC=1.CC1NC2C(C=1C)=C(O)C=CC=2OC>>[CH3:18][C:15]1[NH:16][C:17]2[C:13]([C:14]=1[CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=[CH:10][C:9]=2[OH:8]
Reactant: COc1ccc(OCc2ccccc2)c2[nH]c(C)c(C)c12
Agent: COc1ccc(O)c2c(C)c(C)[nH]c12
Product: COc1ccc(O)c2[nH]c(C)c(C)c12

Procedure:
2,3-Dimethyl-7-hydroxy-4-methoxyindole is prepared from 7-benzyloxy-2,3-dimethyl-4-methoxyindole according to the operating method described for the preparation of 2,3-dimethyl-4-hydroxy-7-methoxyindole (Example 7c). It melts at 159° C.
Reaction SMILES: C1N2CCN(CC2)C1.[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[C:19](Cl)=[C:18]([S:27]([CH3:30])(=[O:29])=[O:28])[C:17]1=[O:31])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N:32]1([C:38]([C:40]2[S:41][CH:42]=[CH:43][CH:44]=2)=[O:39])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CN1CCCC1=O.O>[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[C:19]([N:35]2[CH2:36][CH2:37][N:32]([C:38]([C:40]3[S:41][CH:42]=[CH:43][CH:44]=3)=[O:39])[CH2:33][CH2:34]2)=[C:18]([S:27]([CH3:30])(=[O:29])=[O:28])[C:17]1=[O:31])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CS(=O)(=O)c1c(Cl)c2cccnc2n(Cc2ccccc2)c1=O
Reactant: O=C(c1cccs1)N1CCNCC1
Agent: C1CN2CCN1CC2
Solvent: CN1CCCC1=O
Solvent: O
Product: CS(=O)(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cccnc2n(Cc2ccccc2)c1=O
Temperature: 110 °C
Yield: 74.7 %

Procedure:
DABCO (0.57 g, 5.0 mmol) was added to a solution of 1-benzyl-4-chloro-3-(methylsulfonyl)-[1,8]-naphthyridin-2(1H)-one (115) (0.88 g, 2.5 mmol) and piperazine-1-yl-thiophene-2-yl-methanone (0.60 g, 3.08 mmol) in N-methylpyrrolidone at room temperature. The solution was heated at 110° C. for 15 min. The solution was cooled and poured into ice cold 10% ammonium chloride solution in water. The solids formed were filtered, washed by water, and dried to yield 0.95 g (74%) of 1-benzyl-3-methanesulfonyl-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1H-[1,8]-naphthyridin-2-one (116) as yellow solids MP: 223° C.; 1H-NMR (DMSO-d6): δ 3.37 (s, 3H), 3.59 (m, 4H), 3.93 (b, 4H), 5.59 (s, 2H), 7.2 (m, 6H), 7.38 (m, 1H), 7.47 (dd, J=1.2, 3.6 Hz, 1H), 7.81 (dd, J=1.2, 5.2 Hz, 1H), 8.46 (dd, J=1.6, 8.0 Hz, 1H), 8.70 (dd, J=1.6, 4.4 Hz, 1H); EIMS m/z 509 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:19]=[O:20])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:14]([CH:19]=[O:20])[CH:13]=1
Reactant: CCOC(=O)CCCCBr
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCOc1ccc(Br)cc1C=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Ethyl 5-bromopentanoate (28.6 g) was added to a suspension of 4-bromo-2-formylphenol (25.0 g) and potassium carbonate (18.9 g) in DMF (100 ml), and the resulting solution was stirred at 50° C. overnight under a nitrogen atmosphere. The solution was allowed to cool. Water was added and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain yellow oil of ethyl 5-(4-bromo-2-formylphenoxy)pentanoate (40.9 g).
Reaction SMILES: [CH2:1]([CH:3]([C:11](=O)[C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])[C:4](=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].Cl.Cl.[NH2:24][NH2:25]>CCO>[CH2:1]([C:3]1[C:11]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])=[N:24][NH:25][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)C(CC)C(=O)c1c(C)cc(C)cc1C
Reactant: NN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1[nH]nc(-c2c(C)cc(C)cc2C)c1CC
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of ethyl 3-ethyl-2,4-dioxo-4-(2,4,6-trimethylphenyl)butanoate (6.0 g, 20.7 mmol) and hydrazine dihydrochloride (2.17 g, 20.7 mmoL) in 100 mL of EtOH was stirred at 80° C. for 6 hours. The solvent was then removed from the mixture. 200 mL of water was added to the residue and mixture was neutralized by the addition of solid NaHCO3. The product was extracted into ether. The ether extract was dried over Na2SO4 and evaporated to give 5.8 g as an oil which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]2[N:18]=[C:17]([CH2:19][C:20]3([CH2:25][C:26]([OH:28])=[O:27])CCCC3)[O:16][N:15]=2)=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[N:3]=1.[C:29]1(C2CCC(=O)OC2=O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]2[N:18]=[C:17]([CH2:19][CH2:20][CH:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:26]([OH:28])=[O:27])[O:16][N:15]=2)=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[N:3]=1
Reactant: Cc1nc2c(cc1CCc1noc(CC3(CC(=O)O)CCCC3)n1)CCCN2
Reactant: O=C1CCC(c2ccccc2)C(=O)O1
Product: Cc1nc2c(cc1CCc1noc(CCC(C(=O)O)c3ccccc3)n1)CCCN2

Procedure:
The procedure for the preparation of the product of EXAMPLE 8 was repeated using 2-phenylglutaric anhydride (Aldrich) in the place of 3,3-tetramethyleneglutaric anhydride to provide a 55:45 mixture of the title products as a gum. 1H (CD3OD) δ1.90 (2H, m); 2.15–2.35 (2H, comp. band); 2.32/2.40 (3H, s); 2.42–2.53 (1H, comp. band); 2.69/2.76 (2H, t); 2.85 (1H, m); 2.92–3.04 (4H, comp. band); 3.45 (2H, t); 3.66/4.39, (1H, t); 7.23–7.40 (5H, comp. band), 7.44/7.52 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[C:12](C(F)(F)F)[CH:11]=2)[N:5]=[C:4]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=CC=CC=3)C2)[CH:3]=1.[Cl:30]C1C=C(C)N=C(C=CC2C=CC=C(Cl)C=2)N=1.N1CCCC1>C(Cl)Cl.CCOC(C)=O>[Cl:30][C:12]1[CH:11]=[C:10](/[CH:9]=[CH:8]/[C:6]2[N:7]=[C:2]([CH3:1])[CH:3]=[C:4]([N:20]3[CH2:29][CH2:28][CH2:27][CH2:22]3)[N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(N2CCc3ccccc3C2)nc(/C=C/c2cccc(C(F)(F)F)c2)n1
Reactant: Cc1cc(Cl)nc(C=Cc2cccc(Cl)c2)n1
Solvent: C1CCNC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(N2CCCC2)nc(/C=C/c2cccc(Cl)c2)n1
Temperature: 60 °C
Yield: 80 %

Procedure:
A mixture of 66 mg (0.25 mmol) of (E) 4-chloro-2-[2-(3-chloro-phenyl)-vinyl]-6-methyl-pyrimidine and 0.89 g (12.5 mmol) pyrrolidine was heated at 60° C. for 1.5 h after which time the reaction was completed according to TLC analysis (CH2Cl2/EtOAc: 4/1). The excess pyrrolidine was removed in vacuo and the residue was purified on a silica gel chromatography column (eluted with CH2Cl2/EtOAc: 4/1). The purified fractions were combined, evacuated in vacuo, the solid residue was triturated with ether and filtered off by suction to give (E)-2-[2-(3-Chloro-phenyl)-vinyl]-4-methyl-6-pyrrolidin-1-yl-pyrimidine (61 mg, 80%) as an off-white crystalline solid. ISP mass spectrum, m/e: 300.3 (M+1 calculated for C17H18ClN3: 300).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1.[C:9]1(/[CH:15]=[CH:16]/B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC1C=CC(CC2C=C(C=O)SC=2)=CC=1>CN(C=O)C>[CH:16](/[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1)=[CH:15]\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: O=Cc1cc(Br)co1
Agent: O=Cc1cc(Cc2ccc(Cl)cc2)cs1
Solvent: CN(C)C=O
Product: O=Cc1cc(/C=C/c2ccccc2)co1

Procedure:
The title compound was synthesized from 4-bromo-furan-2-carboxaldehyde (1.1 g, 6.3 mmol, 1 equiv) and trans-phenylvinyl-boronic acid (1.4 g, 9.4 mmol, 1.5 equiv) using the conditions used to synthesize 4-(4-chlorobenzyl)thiophene-2-carbaldehyde, with the exception that the reaction was run in DMF (25 mL). The resulting residue was purified via ISCO Companion (0-30% EtOAc/heptane) and preparative HPLC using the Chromeleon purification system (0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 40% methanol and increasing to 100% over 7 min)) afforded a clean product, retention time of product: 3.4-3.6 min. Amount of (E)-4-styrylfuran-2-carbaldehyde isolated: 89.1 mg (7% yield). 1H NMR (400 MHz, CD3CN) δ (ppm): 9.62 (d, J=0.59 Hz, 1H), 7.91 (s, 1H), 7.63 (d, J=0.63 Hz, 1H), 7.50-7.55 (m, 2H), 7.35-7.42 (m, 2H), 7.26-7.32 (m, 1H), 7.08 (s, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][C:14]=2[CH3:15])[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)[N:4]=1)[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:3]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][C:14]=2[CH3:15])[N:5]([C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(-c2ccc(OC)cc2)c(-c2occc2C)c1C#N
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1nn(-c2ccc(O)cc2)c(-c2occc2C)c1C#N
Temperature: 25 °C
Yield: 100 %

Procedure:
3-ethyl-1-(4-methoxyphenyl)-5-(3-methylfuran-2-yl)-1H-pyrazole-4-carbonitrile (5 mg, 0.02 mmol) was dissolved in CH2Cl2 (3 mL) and BBr3 (1 M solution on DCM, 0.3 mL, 0.3 mmol) was added and stirred at room temperature over night. The reaction was quenched using water and extracted with CH2Cl2. Concentration gave a crude 3-ethyl-1-(4-hydroxyphenyl)-5-(3-methylfuran-2-yl)-1H-pyrazole-4-carbonitrile (5 mg, 0.02 mmol, 100%) which was used as such in the next step.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][S:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][C@@H:18]23)[CH:23]=1>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][S:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][NH:30][CH2:31][C@@H:18]23)[CH:23]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCSC3
Product: FC(F)(F)c1ccccc1-c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2

Procedure:
Using 2-(trifluoromethyl)phenylboronic acid and following the procedures described in EXAMPLE 7, Parts B and C, tert-butyl (7bR,11aS)-6-bromo-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 7, Part A was converted into the title compound of EXAMPLE 147. 1H NMR(CDCl3) δ: 9.50 (broad s, 1H), 9.30 (broad s, 1H), 7.68 (d, 1H, J=8.1 Hz), 7.50 (t, 1H, J=7.3 Hz), 7.40 (t, 1H, J=7.3 Hz), 7.26 (d, 1H), 6.93 (s, 1H), 6.87 (s, 1H), 3.80 (ABq, 2H, JAB=15.8 Hz), 3.61-3.45 (m, 2H), 3.37-3.05 (m, 6H), 2.90-2.80 (m, 1H), 2.70-2.57 (m, 1H), 2.25-2.10 (m, 2H). LRMS (ES)+: 391.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.C(Cl)(=O)C([Cl:16])=O>CN(C=O)C.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([Cl:16])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccc(F)cc1F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2,4-difluorophenylacetic acid (206 mg), DMF (1 drop) and tetrahydrofuran (4 ml) was added oxalyl chloride (0.13 ml) dropwise. The resulting mixture was stirred at room temperature for 1 hour and the solvent was then distilled off to give 2,4-difluorophenylacetyl chloride. This chloride was dissolved in dichloromethane (5 ml) followed by addition of 3-amino-4-(2-chlorophenyl)-7,8-dihydro-6H-cyclopenta[g]quinoline (294 mg) and N,N-dimethylaniline (0.13 ml). The mixture was further stirred at room temperature for 3 hours, after which it was washed with water, saturated aqueous solution of NaHCO3 and water in the order mentioned and dried (over MgSO4). The solvent was then distilled off to give 4-(2-chlorophenyl)-3-(2,4-difluorophenylacetylamino)-7,8-dihydro-6H-cyclopenta(g)quinoline as oil. This oil was crystallized from isopropyl ether (yield 342 mg, 76.3%). Recrystallization from ethanol gave colorless prisms, mp. 179°-180° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C@@H:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Cl[CH2:39][C:40]([N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])=O>>[CH2:43]([N:42]([CH2:45][CH3:46])[CH2:40][CH2:39][O:37][C:36]1[CH:35]=[CH:34][C:4]([CH2:5][CH2:7][NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[C@@H:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=3[CH2:18]2)=[CH:3][C:2]=1[F:1])[CH3:44]
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Reactant: CCN(CC)C(=O)CCl
Product: CCN(CC)CCOc1ccc(CCNc2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)cc1F
Yield: 47.4 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N,N-diethylacetamide (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.5 mg) was obtained.
Reaction SMILES: C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]([NH:27][NH2:28])=[O:26].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([CH:39]([C:49]2[CH:54]=[C:53]([F:55])[CH:52]=[CH:51][C:50]=2[F:56])[C:40]2[N:45]=[CH:44][C:43]([C:46](O)=[O:47])=[CH:42][CH:41]=2)(=[O:38])=[O:37])=[CH:32][CH:31]=1>CN(C)C1C=CN=CC=1.ClCCl.ClCCl.CCCCCC>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]([NH:27][NH:28][C:46](=[O:47])[C:43]1[CH:42]=[CH:41][C:40]([CH:39]([S:36]([C:33]2[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=2)(=[O:37])=[O:38])[C:49]2[CH:54]=[C:53]([F:55])[CH:52]=[CH:51][C:50]=2[F:56])=[N:45][CH:44]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reactant: NNC(=O)c1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NNC(=O)c1ccco1)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 57.9 %

Procedure:
Triethylamine (32 μl, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0.095 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23 mmol) and 2-furancarboxylic acid hydrazide (29 mg, 0.23 mmol) were added to a solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (80 mg, 0.19 mmol), which had been obtained in Example 338, in dichloromethane (5 ml). The resulting mixture was stirred at room temperature for 7.5 hours. The reaction mixture was diluted with dichloromethane, followed by successive washing with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel colunm and a fraction obtained from the elution portion with dichloromethane:methanol=50:1 was concentrated under reduced pressure. The solid thus obtained was recrystallized from dichloromethane-hexane, whereby the title compound (58 mg, 0.11 mmol, 58%) was obtained as a white powder.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26](OC)=[O:27])=[C:20]([F:30])[CH:19]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[F:30][C:20]1[CH:19]=[C:18]([NH:17][C:15](=[O:16])[O:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:23]=[CH:22][C:21]=1/[CH:24]=[CH:25]/[CH2:26][OH:27]
Reactant: COC(=O)/C=C/c1ccc(NC(=O)OCc2ccccc2)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(/C=C/CO)c(F)c1)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A THF solution of LiAlH4 (10.2 mL of a 1.0 M solution, 10.2 mmol) was added to a cooled (−78° C.) solution of methyl (2E)-3-(4-{[(benzyloxy)carbonyl]amino}-2-fluorophenyl)acrylate (3.35 g, 10.2 mmol) in TBF (50 mL). The solution was allowed to warm slowly to −20° C. and maintained at that temperature for 2 hours. The reaction mixture was quenched by slow addition of saturated NH4Cl and then treated with 30 mL of dilute citric acid. The resulting solution was stirred for 15 minutes and then extracted with three portions of ethyl acetate. Combined organic phases were washed with H2O, brine and dried (MgSO4), filtered and concentrated to give a red oil. The crude product was purified by column chromatography (25-50% ethyl acetate-hexane) to provide the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][P:9]([CH2:19][CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:18])[O:10]CC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.O>[CH2:1]([O:8][P:9]([CH2:19][CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:10])[OH:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=P(CCOCc1ccccc1)(OCc1ccccc1)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=P(O)(CCOCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2-benzyloxy-ethyl)-phosphonic acid dibenzyl ester (0.200 g, 0.543 mmol) in THF was added a solution of NaOH (1.36 mL, 1M) in water. The reaction mixture was stirred at room temperature for 3 hours. Most of THF was removed in vacuo and the residue was dissolved in water. The aqueous solution was washed with ethylacetate three times then acidified with 1N HCl (to pH=1) then extracted with ethylacetate. The organic phase was dried (MgSO4), concentrated and co-evaporated with toluene in vacuo to afford the mono-acid, (2-benzyloxy-ethyl)-phosphonic acid monobenzyl ester, 173 (0.160 g. 100%) as an oil with no further purification: 1H NMR (CDCl3) δ 9.25 (bs, 1H), 7.4-7.1 (m, 10H), 4.5 (s, 2H), 3.8 (m, 2H), 2.25 (m, 2H); 31P NMR (CDCl3) δ 28.63.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.P(Br)(Br)[Br:11]>C(Cl)Cl>[I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][Br:11]
Reactant: OCc1ccccc1I
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: BrCc1ccccc1I
Temperature: 0 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a dry 100 mL 3-necked flask equipped with a nitrogen inlet and a magnetic stirrer were added 5.00 g of 2-iodobenzyl alcohol (Aldrich) and 20 mL of anhydrous CH2Cl2. The resulting suspension was cooled to 0° C. and treated with 0.71 mL of PBr3 (Aldrich) by dropwise addition over a 2 minute period. The solid slowly dissolved giving a light yellow solution which was stirred under nitrogen at 0° C. for 2 h and then allowed to warm to RT with continued stirring for 18 h. The solution was concentrated in vacuo to dryness and the residue was dissolved in 60 mL of ethyl ether. The ether solution was washed with ice cold 5% aqueous NaHCO3 (3×50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to afford 5.65 g (89%) of 2-iodobenzyl bromide as a white crystalline solid, m.p. 52-54° C.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[C:11](=O)[NH:12][N:13]=[C:6]2[C:5]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]#[N:29])=[CH:18][CH:17]=1)[CH2:2][CH3:3].C[Sn]([N:34]=[N+:35]=[N-:36])(C)C>C1(C)C=CC=CC=1>[CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[CH:11]=[N:12][N:13]=[C:6]2[C:5]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[NH:29][N:36]=[N:35][N:34]=2)=[CH:18][CH:17]=1)[CH2:2][CH3:3]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCc1nc(C)n2c(=O)[nH]nc2c1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: Cc1ccccc1
Product: CCCc1nc(C)n2cnnc2c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 8 h
Yield: 35 %

Procedure:
4 g of 7-n-propyl-5-methyl-8-[(2'-cyano-4-biphenylyl)methyl]-1,2,4-triazolo[4,3-c]pyrimidin-3(2H)-one, prepared in Example 15, are dissolved in 100 ml of toluene. 2.8 g of trimethyltin azide are added and the mixture is heated to reflux for 24 hours. The crystals formed are drained in the heated state and washed with ether, then suspended in 100 ml of tetrahydrofuran. Hydrogen chloride gas is bubbled into the mixture and, after the reactants have passed completely into solution, a precipitate appears. The mixture is left overnight at room temperature and the crystals formed are drained, washed with ether and dissolved in dilute sodium hydroxide solution. This solution is washed with ether, then acidified by bubbling in sulphur dioxide and extracted with chloroform. The organic phase is dried over magnesium sulphate and evaporated under vacuum, and the residue crystallises in an ether/acetone mixture to give 1.5 g of 7-n-propyl-5-methyl-8-{[2'-(5-tetrazolyl)-4-biphenylyl]methyl}-1,2,4-triazolo[4,3-c]pyrimidin-(3(2H)-one in the form of crystals of melting point 248°-249° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:16])[C:7]=1[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1.C(N(CC)CC)C>CO.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(Cl)Cl>[CH3:8][O:9][C:10](=[O:11])[C:2]1[C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[C:6]([Cl:16])[CH:5]=[N:4][CH:3]=1
Reactant: Clc1cncc(Cl)c1COC1CCCCO1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cncc(Cl)c1COC1CCCCO1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of 3,5-dichloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridine (400 mg, 1.533 mmol), triethylamine (278 μL, 1.993 mmol), (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II)•DCM (PdCl2(dppf)2•DCM, 63 mg, 0.077 mmol) and 4 Å molecular sieves (600 mg) in MeOH (10 mL) was stirred at 120° C. for 5 h under an atmosphere of carbon monoxide (15 bar). The reaction was filtered and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel (elution with mixtures of hexane/EA) to give the title compound. MS (m/z): 286.0 [M+H+].