Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12](N)[CH:11]=1)[C:3]([O:5]CC)=[O:4].Cl.N([O-])=[O:25].[Na+]>O>[OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12]([OH:25])[CH:11]=1)[C:3]([OH:5])=[O:4]
Reactant: O=N[O-]
Reactant: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)c(N)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)C(O)CCc1ccc(C2CCCCC2)c(O)c1
Reaction time: 0.17 h

Procedure:
To 4.9 g. of ethyl α-hydroxy-γ-(3-amino-4-cyclohexylphenyl)butyrate suspension in 125 ml. of 80% hydrochloric acid and cooled to 0°C is added dropwise a solution of 1.2 g. of sodium nitrite in 15 ml. of water. After about 10 min., 200 ml. of 50% hydrochloric acid is added portion wise and stirred for 15 hours. The reaction mixture is then poured onto ice water and extracted with chloroform, dried over sodium sulfate and concentrated in vacuo. The residue is crystallized to obtain α-hydroxy-γ-(3-hydroxy-4-cyclohexylphenyl)butyric acid.
Reaction SMILES: [Br-:1].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([C:11]#[C:12]/[C:13](/[CH3:35])=[CH:14]\[CH2:15][P+:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([CH3:36])[C:5]=1[CH3:37].O.[H][H]>CO>[Br-:1].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7](/[CH:11]=[CH:12]\[C:13](\[CH3:35])=[CH:14]/[CH2:15][P+:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:6]([CH3:36])[C:5]=1[CH3:37]
Reactant: COc1cc(C)c(C#C/C(C)=C\C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Reactant: [H][H]
Agent: [Br-]
Solvent: CO
Solvent: O
Product: COc1cc(C)c(/C=C\C(C)=C/C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Yield: 89 %

Procedure:
In a manner analogous to Example 2, a solution of 3.42 g of (Z)-[5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2-penten-4-ynyl]triphenylphosphonium bromide in 240 ml of methanol was hydrogenated in the presence of 1.8 g of water-moist Raney-nickel. 188 ml of hydrogen were taken up within 28 hours. The crude product (3.4 g), which contained 89.4% of (2Z,4Z)-[5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadienyl]triphenylphosphonium bromide (yield 89%), obtained after filtration and evaporation was dissolved in 20 ml of methylene chloride and crystallized by the dropwise addition of 50 ml of ethyl acetate while stirring. The suspension was left to stand at 0° C. overnight, filtered and the product, washed with a small amount of ethyl acetate/methylene chloride (volume ratio 5:1), was dried at 40°C./0.01 mbar. There were obtained 1.8 g of 99.6% (2Z,4Z)-[5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadienyl]triphenylphosphonium bromide as white crystals of melting point 202°-204° C.; yield 52.5%.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([C:16]([CH3:23])([CH3:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=[C:12]([CH2:24]Cl)[C:11]=2[OH:26])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:27]([OH:32])[CH2:28][CH:29]([CH3:31])[CH3:30].[H-].[Na+]>>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([C:16]([CH3:23])([CH3:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=[C:12]([CH2:24][O:32][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:11]=2[OH:26])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)CCO
Reactant: CC(C)(C)CC(C)(C)c1cc(CCl)c(O)c(-n2nc3ccccc3n2)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)CCOCc1cc(C(C)(C)CC(C)(C)C)cc(-n2nc3ccccc3n2)c1O
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 64.7 %

Procedure:
2-(2H-Benzotriazol-2-yl)-6-chloromethyl-4-(1,1,3,3-tetramethyl-butyl)-phenol (5.0 g, 13.5 mmol) is suspended in isoamyl alcohol (20.0 g, 227 mmol) and stirred at 80° C. for 15 minutes. Sodium hydride (0.2 g, 4.3 mmol, 60% in mineral oil) is added. The orange reaction mixture is stirred at 80° C. for 15 minutes and evaporated to dryness. The residue is dissolved in ethyl acetate and extracted with aqueous citric acid (5%) and brine. The organic layer is dried over sodium sulphate, filtered and evaporated to dryness. The crude product is purified by column chromatography (ethyl acetate/heptane 1:12) to yield 3.7 g of 2-(2H-Benzotriazol-2-yl)-6-(3-methyl-butoxymethyl)-4-(1,1,3,3-tetramethyl-butyl)-phenol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[N+:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][S:35](Cl)(=[O:37])=[O:36])([O-:27])=[O:26]>>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:35]([CH2:34][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N+:25]([O-:27])=[O:26])(=[O:36])=[O:37])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=[N+]([O-])c1ccccc1CS(=O)(=O)Cl
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)Cc3ccccc3[N+](=O)[O-])cc2)c2ccc3ccccc3c2N1
Yield: 41 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and (2-nitrophenyl)methanesulfonyl chloride, the title compound (yield 41%) was obtained in the same manner as that of Example 145.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][Cl:25]>CN(C)C=O>[Cl:25][CH2:24][CH2:23][CH2:22][O:14][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCCOc1ccc(Oc2ccccc2)cc1

Procedure:
Following the procedure described in example 1§E, but starting from 4-phenoxyphenol (950 mg), potassium carbonate (3.2 g) and 1-bromo-3-chloropropane (2.5 mL) in N,N-dimethylformamide (5 mL) affords 0.50 g of 4-(3-chloropropoxy)-O-phenylphenol used without any further purification.
Reaction SMILES: [Cl:1]/[C:2](/[CH3:7])=[CH:3]\[C:4](Cl)=[O:5].[NH2:8][C:9]1[CH:10]=[C:11]([C:15](=[O:19])[CH2:16][CH2:17][CH3:18])[CH:12]=[CH:13][CH:14]=1.C(N(CC)CC)C>O1CCCC1>[C:15]([C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[NH:8][C:4](=[O:5])/[CH:3]=[C:2](\[Cl:1])/[CH3:7])(=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: C/C(Cl)=C/C(=O)Cl
Reactant: CCCC(=O)c1cccc(N)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)c1cccc(NC(=O)/C=C(/C)Cl)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 49.5 %

Procedure:
29.2 g of β-chlorocrotonyl chloride were added over one hour at 0° C to a mixture of 31 g of m-amino-butyrophenone 21.2 g of triethylamine and 300 ml of tetrahydrofuran and after stirring for 16 hours at 20° C, the mixture was vacuum filtered. The filtrate was concentrated to dryness and the residue was chromatographed over silica gel to obtain 25 g of m-butyryl-3-chlorocrotonanilide melting at 106° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:17]=1[N:25]=[C:26]=[O:27])[CH3:15]>>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([C:26]([NH:25][C:17]1[C:16]([CH:14]([CH3:13])[CH3:15])=[CH:21][CH:20]=[CH:19][C:18]=1[CH:22]([CH3:24])[CH3:23])=[O:27])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:12]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCOC(=O)Cc1ccccc1
Product: CCOC(=O)C(C(=O)Nc1c(C(C)C)cccc1C(C)C)c1ccccc1

Procedure:
In a manner similar to Example 134, phenylacetic acid, ethyl ester was condensed with 2,6-bis(1-methylethyl)phenyl isocyanate to give the title compound, mp 168°-170° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=O.[NH:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1>C(O)(=O)CC>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[C:5]1[C:17]2[NH:13][C:14]([C:5]([C:4]3[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][C:3]=3[O:2][CH3:1])=[C:14]3[N:13]=[C:17]([C:5]([C:4]4[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][C:3]=4[O:2][CH3:1])=[C:14]4[NH:13][C:17](=[C:5]([C:4]5[C:3]([O:2][CH3:1])=[CH:10][CH:9]=[CH:8][C:7]=5[O:11][CH3:12])[C:14]5[CH:15]=[CH:16][C:17]=1[N:13]=5)[CH:16]=[CH:15]4)[CH:16]=[CH:15]3)=[CH:15][CH:16]=2
Reactant: c1cc[nH]c1
Reactant: COc1cccc(OC)c1C=O
Solvent: CCC(=O)O
Product: COc1cccc(OC)c1-c1c2nc(c(-c3c(OC)cccc3OC)c3ccc([nH]3)c(-c3c(OC)cccc3OC)c3nc(c(-c4c(OC)cccc4OC)c4ccc1[nH]4)C=C3)C=C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1500 ml of a solution of 20 g of 2,6-dimethoxybenzaldehyde in propionic acid was heated at 100° C. with stirring, 8.05 g of pyrrole was added and the mixture was continuously heated with stirring for 7 hours. After cooling to room temperature, the mixture solution was left overnight. The reaction solution was filtered through a glass filter, and the filtrate was washed with cooled methanol and purified with a silica gel column (dichloromethane) to obtain 5,10,15,20-tetra(2',6'-dimethoxyphenyl)porphyrin.
Reaction SMILES: [F:1][C:2]1([F:19])[C@H:6]([OH:7])[CH2:5][C@@H:4]([C@@:8]([OH:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([OH:11])=[O:10])[CH2:3]1.C(OC([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33]O)[CH2:29][CH2:28]1)=O)(C)(C)C>>[F:1][C:2]1([F:19])[C@H:6]([OH:7])[CH2:5][C@@H:4]([C@@:8]([OH:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([O:11][CH2:33][CH:30]2[CH2:31][CH2:32][NH:27][CH2:28][CH2:29]2)=[O:10])[CH2:3]1
Reactant: O=C(O)[C@](O)(c1ccccc1)[C@@H]1C[C@@H](O)C(F)(F)C1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Product: O=C(OCC1CCNCC1)[C@](O)(c1ccccc1)[C@@H]1C[C@@H](O)C(F)(F)C1

Procedure:
Using (2R)-2-((1R,4R)-3,3-difluoro-4-hydroxycyclopentyl)-2-hydroxy-2-phenylacetic acid and N-t-butoxycarbonyl-4-piperidine-methanol, the title compound was prepared by a method similar to steps 2 and 3 of Referential Example 12.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[CH:22]2.CN1CCOCC1>CN(C)C=O>[NH:24]1[C:25]2[C:21](=[CH:20][C:19]([NH:18][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][CH2:7][CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:27][CH:26]=2)[CH:22]=[N:23]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C(O)c1ccccc1NCC1CCOCC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Nc1ccc2[nH]ncc2c1)c1ccccc1NCC1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.4 %

Procedure:
235 mg (1 mmol) of 2-(tetrahydropyran-4-yl)methylaminobenzoic acid is mixed in 10 ml of dimethylformamide with 266 mg (2 mmol) of 5-aminoindazole. 253 mg (2.5 mmol) of N-methylmorpholine and 456 mg (1.2 mmol) of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetamethyluronium hexafluorophosphate are added to this solution under argon and in a moisture-free environment. This mixture is stirred for 3 hours at room temperature. It is concentrated by evaporation in a vacuum, taken up in dilute sodium bicarbonate solution and extracted three times with 30 ml of ethyl acetate each. The combined organic phase is washed with water, dried, filtered and concentrated by evaporation. The residue is absorptively precipitated in ethyl acetate and suctioned off. The filtrate is concentrated by evaporation, and the residue is chromatographed on silica gel with methylene chloride:ethanol=10:1 as an eluant. 124 mg (35% of theory) of N-(indazol-5-yl)-2-(tetrahydropyran-4-yl)methylaminobenzoic acid amide with a melting point of 173.6° C. is obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1>>[CH2:13]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:29]1[CH2:30][CH2:31][C:26]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([CH3:20])=[CH:34][CH:33]=2)([OH:32])[CH2:27][CH2:28]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCCCOc1ccccc1OCc1ccccc1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Product: Cc1ccc(CC2(O)CCN(CCCOc3ccccc3OCc3ccccc3)CC2)cc1

Procedure:
The title compound, MS: m/e=446.5(M+H+), was prepared from 1-(3-bromopropoxy)-2-(benzyloxy)-benzene and 4-(4-methyl-benzyl)-piperidin-4-ol.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>[Cl-].[NH4+]>[CH2:2]([C:3]([CH:4]=[CH2:5])=[CH2:2])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCBr
Agent: [Cl-]
Agent: [NH4+]
Product: C=CC(=C)CCCCC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a flask containing cuprous bromide (1.0 g) is added bromopentane (23 g) and tetrahydrofaran (154 mL). The solution is cooled to 0° C., and the Grignard reagent 1B is added. The reaction is stirred overnight, gradually warming to room temperature. To the solution is then added 30 mL saturated ammonium chloride. The reaction mixture is stirred for 10 minutes, during which time the aqueous layer turns blue. The reaction mixture is then extracted with hexanes, and the combined organic layers are dried over magnesium sulfate. The solvent is carefully removed by rotary evaporation to give 17 g of a colorless, malodorous liquid.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:71]/[O:72][C:73]([C:86]2[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=2)([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)/[C:27]([NH:29][CH:30]2[C:69](=[O:70])[N:32]3[C:33]([C:57]([O:59][CH2:60][C:61]4[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][CH:62]=4)=[O:58])=[C:34]([CH:37]=P(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:92]([O:99][CH2:100][CH:101]=O)([C:95]([CH3:98])([CH3:97])[CH3:96])([CH3:94])[CH3:93]>ClCCl>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:71]/[O:72][C:73]([C:80]2[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=2)([C:74]2[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=2)[C:86]2[CH:87]=[CH:88][CH:89]=[CH:90][CH:91]=2)/[C:27]([NH:29][CH:30]2[C:69](=[O:70])[N:32]3[C:33]([C:57]([O:59][CH2:60][C:61]4[CH:62]=[CH:63][C:64]([O:67][CH3:68])=[CH:65][CH:66]=4)=[O:58])=[C:34](/[CH:37]=[CH:101]\[CH2:100][O:99][Si:92]([C:95]([CH3:96])([CH3:97])[CH3:98])([CH3:93])[CH3:94])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: COc1ccc(COC(=O)C2=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@@H]3C(NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C(/C=C\CO[Si](C)(C)C(C)(C)C)CS[C@@H]3C(NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1

Procedure:
A solution of 4-methoxyphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(triphenylphosphoranylidene)methyl-3-cephem-4-carboxylate (9.07 g; 7.27 mmol) and t-butyldimethylsilyloxyacetaldehyde (1.8 g; 10.34 mmol) in dichloromethane (100 ml) was stirred at room temperature for 16 hours. After the solvent was distilled off under reduced pressure, the residue was purified by chromatography on a silica gel column (n-hexane:ethyl acetate=2.5:1) whereby the title compound (4.99 g; 4.36 mmol; 60% was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.S(Cl)([Cl:16])(=O)=O>C(O)(=O)C>[Cl:16][C:8]1[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]=1[NH2:7]
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc(Cl)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20.0 g (118.94 mmol) 4-methoxy-2-nitroaniline and 10.0 mL sulphuryl chloride were placed in 300.0 mL acetic acid and stirred for 3 h at RT. The reaction mixture was poured onto water and the precipitate formed was suction filtered, washed and dried. The substance obtained was purified by chromatography. The fractions containing product were combined and evaporated down i.vac.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH:14]1[CH2:18][CH2:17][CH:16]=[CH:15]1)[C:8](Cl)=[O:9])(=[O:4])=[O:3].[NH2:19][C:20]([NH2:22])=[NH:21]>>[NH2:21][C:20]([NH2:22])=[N:19][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:13]([CH:14]2[CH2:18][CH2:17][CH:16]=[CH:15]2)=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=1
Reactant: N=C(N)N
Reactant: CS(=O)(=O)c1cc(C(=O)Cl)ccc1C1C=CCC1
Product: CS(=O)(=O)c1cc(C(=O)N=C(N)N)ccc1C1C=CCC1

Procedure:
Analogously to Example 1, by reaction of 2.2 g of 3-methylsulfonyl-4-(1-cyclopenten-3-yl)-benzoyl chloride with guanidine, customary working up gives N-diaminomethylene-3-methylsulfonyl-4-(1-cyclopenten-3-yl)benzamide, which can be recrystallized from acetonitrile/diethylether, m.p. 188°-190°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[C:11](Cl)(=[O:15])[CH:12]([CH3:14])[CH3:13].O>COCCOC.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.[Zn]>[CH3:13][CH:12]([CH3:14])[C:11](=[O:15])[CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CC(C)C(=O)Cl
Reactant: COc1cccc(CBr)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Zn]
Solvent: COCCOC
Solvent: O
Product: COc1cccc(CC(=O)C(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of Pd(PPh3)2Cl2 (0.86 g, 1.22 mmol) and zinc powder (3.19 g, 48.8 mmol) in 1,2-dimethoxyethane (DME, 100 mL) at room temperature was slowly added a solution of 3-methoxybenzyl bromide (5.0 g, 24.4 mmol) and isobutyryl chloride in DME (25 mL). The mixture was stirred at room temperature for 1 h. Water was added, and the mixture was extracted with ether. The combined ether extract was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a brown oil. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (20:1) to give 3.03 g (64) of compound (§4 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.09 (d, J=7.0 Hz, 6H), 2.70-2.75 (m, 1H), 3.70 (s, 2H), 3.79 (s, 3H), 6.70-6.85 (m, 3H), 7.23 (t, J=8.0 Hz, 1H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][CH:6]([O:13][CH2:14][CH3:15])[CH2:7][C:8]([O:10]CC)=[O:9])[CH3:4].Cl>O>[CH2:14]([O:13][CH:6]([O:5][CH2:3][CH3:4])[CH2:7][C:8]([OH:10])=[O:9])[CH3:15]
Reactant: CCOC(=O)CC(OCC)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(CC(=O)O)OCC
Temperature: 110 °C
Yield: 93.2 %

Procedure:
Small pellets of solid NaOH (5.00 g, 125 mmol) were slowly added to a mixture of ethyl 3,3-diethoxypropionate (19.02 g, 100 mmol) and water (35 mL). As the NaOH dissolved the mixture became a homogeneous solution. The solution was heated to 110° C. for 30 min. The reaction was allowed to cool to ambient temperature and then chilled with an ice-water bath. The solution was acidified with drop-wise addition of concentrated aqueous HCl (9.37 mL, 113 mmol). The solution was allowed to warm to ambient temperature and then extracted with dichloromethane (4×15 mL). The combined organic extracts were washed with brine (15 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to yield 15.11 g of 3,3-diethoxypropionic acid as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][OH:8])[CH:3]=1.Br[C:10]1[C:11]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])=[N:12][CH:13]=[C:14]([CH3:16])[N:15]=1>>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:11]1[C:10]([O:8][CH2:7][C:4]2[CH:3]=[C:2]([CH3:1])[O:6][N:5]=2)=[N:15][C:14]([CH3:16])=[CH:13][N:12]=1)(=[O:19])=[O:20]
Reactant: Cc1cc(CO)no1
Reactant: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(Br)n1
Product: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OCc2cc(C)on2)n1

Procedure:
Prepared by the method of Example 20 using (5-methyl-3-isoxazolyl)methanol (0.05 g) and N-(3-bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (0.1 g). Yield 0.05 g.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[C:13]=3[CH2:12]2)=[CH:7][C:6]=1[C:27]([F:30])([F:29])[F:28].C(N(CC)CC)C.[I-].[C:39]([N:42]1[CH2:47][CH2:46][N:45]([C:48]([NH+]2C=CN(C)C2)=[O:49])[CH2:44][CH2:43]1)(=[O:41])[CH3:40]>C(Cl)Cl>[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C@H:20]4[CH2:24][CH2:23][N:22]([C:48]([N:45]5[CH2:46][CH2:47][N:42]([C:39](=[O:41])[CH3:40])[CH2:43][CH2:44]5)=[O:49])[CH2:21]4)[C:13]=3[CH2:12]2)=[CH:7][C:6]=1[C:27]([F:30])([F:28])[F:29]
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C(F)(F)F
Reactant: CC(=O)N1CCN(C(=O)[NH+]2C=CN(C)C2)CC1
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)N5CCN(C(C)=O)CC5)C4)c3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 26 %

Procedure:
To a solution of 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (prepared using step 1, example 91 from intermediate 13) (25 mg, 0.063 mmol) and triethylamine (0.013 mL, 0.095 mmol) in CH2Cl2 (2 mL) was added 3-(4-acetyl-piperazine-1-carbonyl)-1-methyl-3H-imidazol-3-ium iodide (Intermediate 6) (15 mg, 0.063 mmol) and the mixture stirred at room temperature under argon for 18 h. Partitioned between CH2Cl2 (10 mL) and sat. NaHCO3(aq) (2 mL) and the organic layer was filtered through a phase separation tube and evaporated in vacuo. Purification by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions by elution through an Isolute SCX-2 cartridge, eluting with methanol, then with 2M ammonia in methanol. Basic fractions were concentrated in vacuo to give 1-(4-{(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-piperazin-1-yl)-ethanone as a pale yellow powder (9 mg, 25% yield). 1H NMR (400 MHz, MeOH-d4, 298K) δ ppm 2.14 (s, 3H) 2.24-2.33 (m, 2H) 3.04 (t, 2H) 3.25-3.91 (m, 13H) 3.99 (s, 3H) 4.18 (s, 2H) 5.74-5.78 (m, 1H) 7.79 (d, 1H) 8.14 (d, 1H) 8.60 (s, 1H) LCMS: [M+H]+=550.2, Rt(1)=1.58 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9]COCCOC)[C:3]=1[CH2:16][CH2:17][CH:18]1[O:23][C:22](=[O:24])[CH2:21][CH:20]([OH:25])[CH2:19]1>C(Cl)Cl.[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([OH:9])[C:3]=1[CH2:16][CH2:17][CH:18]1[O:23][C:22](=[O:24])[CH2:21][CH:20]([OH:25])[CH2:19]1
Reactant: COCCOCOc1cc(Cl)cc(Cl)c1CCC1CC(O)CC(=O)O1
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: O=C1CC(O)CC(CCc2c(O)cc(Cl)cc2Cl)O1
Temperature: 20 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
Zinc bromide (2.4 g, 10 mmole) was added to a solution of 6-{2-[2,4-dichloro-6-(2-methoxyethoxymethoxy)phenyl]ethyl}-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (780 mg, 2 mmole) in methylene chloride (12 ml). The resulting mixture was stirred at 20° C. for 2 hours, then quenched with saturated sodium bicarbonate solution (50 ml) and diluted with ether (200 ml). The ethereal layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on a 50 mm low-pressure column with 6 inches of silica gel (230-400 mesh). The column was eluted with 470 ml of methylene chloride-acetone (4:1, v:v). The next 330 ml provided the title compound as a golden glass (100 mg., 16%): pmr (CDCl3) δ2.62 (2H, d), 4.29 (H, m), 4.78 (H, m), 6.87 (2H, s).