Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([C@:21]2([CH3:27])[CH2:25][O:24]C(=O)[NH:22]2)[CH:15]=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(O)C.O.[OH-].[Li+].O>>[NH2:22][C@@:21]([C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([O:10][CH:7]3[CH2:6][CH2:5][CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]3)[CH:12]=2)[CH:17]=1)([CH3:27])[CH2:25][OH:24]
Reactant: CC(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C1CCC(Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Yield: 32.8 %

Procedure:
The compound was prepared in a manner similar as to that described above using (R)-4-[6-(4-Isopropyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (200 mg, 0.0005 mol), ethanol (2.2 g, 0.049 mol), 4.2 M lithium hydroxide, monohydrate in water (2.1 mL, 0.0090 mol) to give 56 mg of the desired compound as a yellow brown solid (30%). ESI-MS: 325 (M-16)+. 1H NMR (400 MHz, CDCl3) δ=7.94-7.61 (m, 3 H), 7.50 (d, J=8.5 Hz, 1 H), 7.23-7.05 (m, 2 H), 4.67 (br. s., 1 H), 4.33-4.17 (m, 1 H), 3.84-3.51 (m, 2 H), 2.35-1.75 (m, 4 H), 1.68-1.08 (m, 10 H), 1.01-0.68 (m, 6 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1>C1C=CC=CC=1.C(NCC)C>[CH2:3]([N:4]([CH2:5][CH3:6])[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1)[CH3:2]
Reactant: O=C(Nc1nnn[nH]1)c1cncc(Cl)n1
Solvent: CCNCC
Solvent: c1ccccc1
Product: CCN(CC)c1cncc(C(=O)Nc2nnn[nH]2)n1

Procedure:
To a suspension of 1.13 g of 6-chloro-N-(1H-5-tetrazolyl)pyrazine-2-carboxamide in 20 ml of benzene, 20 ml of diethylamine was added, and the mixture was heated for 24 hours at 80°-90 ° C. in a sealed tube. The reaction mixture was evaporated. Water was added to the residue, and then the aqueous solutron was adjusted with dilute hydrochloric acid to pH 3. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 0.75 g of the desired compound as yellow plates, m.p. 217°-218 ° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[F:18].O>CN(C)C=O>[F:18][C:12]1[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: Fc1cccc(CBr)c1F
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCCN1Cc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
To a solution of pyrrolidin-2-one (9.38 mL, 121 mmol) in N,N-dimethylformamide (DMF) (200 mL) was added in portions sodium hydride (6.04 g, 151 mmol) (60%/mineral oil) in 10 min and the mixture was stirred under nitrogen atmosphere at ambient temperature for 2 h then 1-(bromomethyl)-2,3-difluorobenzene (15.37 mL, 121 mmol) was added dropwise over 15 min and the mixture was stirred at ambient temperature for 2.5 h. Water (600 mL) was added and the mixture was stirred at ambient temperature for 30 min then extracted with EtOAc. The organic phase was washed with water (3×), and brine, dried (Na2SO4), concentrated, dissolved in acetonitrile and washed with hexanes (2×). The acetonitrile phase was concentrated, dried in vacuo to provide 1-(2,3-difluorobenzyl)pyrrolidin-2-one (19.14 g, 86 mmol, 71.2% yield) as a yellowish oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.03 (quint, J=7.61 Hz, 2 H), 2.43 (t, J=8.10 Hz, 2 H), 3.34 (t, J=7.02 Hz, 2 H), 4.54 (s, 2 H), 6.99-7.17 (m, 3 H); LCMS (m/z) ES+=212 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6](Cl)[C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)=[CH:2]1.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20]/[CH:21]=[CH:22]\[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[CH2:16][CH2:15]1.OC1CCN(C/C=C/COC2C=CC=CC=2[N+]([O-])=O)CC1>>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[O:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:20]/[CH:21]=[CH:22]\[CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-:33])=[O:32])[CH2:18][CH2:19]2)=[CH:2]1
Reactant: ClC(c1ccsc1)c1ccsc1
Reactant: O=[N+]([O-])c1ccccc1OC/C=C\CN1CCC(O)CC1
Agent: O=[N+]([O-])c1ccccc1OC/C=C/CN1CCC(O)CC1
Product: O=[N+]([O-])c1ccccc1OC/C=C\CN1CCC(OC(c2ccsc2)c2ccsc2)CC1

Procedure:
The procedure of Example 39 (a) was repeated except for using di(3-thienyl)methyl chloride and 4-hydroxy-1-[4-(2-nitrophenoxy)-2(Z)-butenyl]piperidine instead of phenyl-2-thienylmethyl chloride and 4-hydroxy-1-[4-(2-nitrophenoxy)-2(E)-butenyl]piperidine to give oily 4-di(3-thienyl)methoxy-1-[4-(2-nitrophenoxy)-2(Z)-butenyl]piperidine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH:12]2[C:10]([CH2:15][NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:14][CH2:13][CH:12]2[C:10]([CH2:15][N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:32](=[O:35])[CH2:33][CH3:34])([CH2:11]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)Cl
Reactant: c1ccc(CN2CCC3CC3(CNc3ccccc3)C2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)N(CC12CC1CCN(Cc1ccccc1)C2)c1ccccc1
Reaction time: 2 h

Procedure:
To the a solution of 3-Benzyl-3-aza-bicyclo[4.1.0]hept-1-ylmethyl)-phenyl-amine (175) (250 mg, 0.86 mmol) in CH2Cl2 (2 ml) at 0° C. was added i-Pr2NEt (0.30 ml, 1.72 mmol)) and propionyl chloride (0.11 ml, 1.29 mmol). The mixture was stirred for 2 hrs. The mixture was diluted with CH2Cl2 (5 ml), washed with sat. NaHCO3 (2×5 ml), brine (5 ml) and water (5 ml) and dried with Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (0.5% to 2% MeOH in CH2Cl2) to give 176 as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 7.41-7.20 (m, 10H), 4.20 (d, 1H), 3.42 (AB, 2H), 3.21 (d, 1H), 2.65 (q, 2H), 2.20-2.00 (m, 4H), 1.80-1.60 (m, 2H), 1.30 (m, 1H), 1.05 (t, 3H), 0.80-0.20 (m, 2H) ppm; LRMS (calculated for C23H28N2O) 348, found 348; IR (film) 3308, 3105, 3064, 2978, 2937, 2874, 2811, 1689m 1666, 1598, 1540, 1499, 1445, 1314, 1246, 1196, 1074, 757 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][CH2:16][CH2:17][CH2:18]Br.C(COC)OC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][CH2:17][CH2:16][Br:15])=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: Fc1ccc(OCCCBr)cc1

Procedure:
A mixture of 11.2 g (0.1 mol) of 4-fluorophenol, 16.5 g (0.12 mol) of pulverized potassium carbonate, 20.2 g (0.1 mol) of 1,3-dibromopropane and 100 ml of anhydrous dimethoxyethane was refluxed under nitrogen for 6 hours and then cooled. The mixture was diluted with methylene chloride and washed with water. The resultant organic product solution was dried over Na2SO4 and evaporated in vacuo. The residue was chromatographed on silica gel using cyclohexane elution to give pure product.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:16](=[O:26])[C:17]([CH2:19][C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)=[CH:18][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:15])[CH:10]=3.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][CH2:36][OH:37]>CS(C)=O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:16](=[O:26])[C:17]([CH2:19][C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)=[CH:18][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH2:34][CH2:35][CH2:36][OH:37])[CH:10]=3
Reactant: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c3cc(O)cc1c32
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c3cc(OCCCO)cc1c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
9-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (400 mg) produced in Example 102 was suspended in dimethyl sulfoxide (40 ml). After adding potassium carbonate (540 mg), the mixture was stirred at room temperature for 30 minutes, and 3-bromo-1-propanol (0.3 ml) was added. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice water (100 ml) and the crystals precipitated were recovered by filtration. The thus obtained crude crystals were washed with water, ethanol and ether in succession and recovered by filtration to obtain the title compound (177 mg, 72%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(=O)([O-])O.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:22]([NH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: NCC1CN(Cc2ccccc2)CCO1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)NCC1CN(Cc2ccccc2)CCO1
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To a solution of crude 2-aminomethyl-4-benzylmorpholine (48 g) in toluene (400 ml) was added pyridine (24.5 ml, 0.303 mol) and then acetic anhydride (26.4 ml, 0.280 mol) was added dropwise under ice-cooling over 10 minutes and then allowed to rise to room temperature and the mixture was stirred for one hour. To the reaction mixture was added aqueous saturated sodium hydrogen carbonate (200 ml) under ice-cooling and then 10% aqueous sodium hydroxide was added until the mixture became strongly basic. The reaction mixture was extracted with ethyl acetate (200 ml×3) and the combined organic layer was washed with aqueous saturated sodium chloride (200 ml). The organic layer was dried over potassium carbonate and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (1/1) to give 2-(N-acetylaminomethyl)-4-benzylmorpholine (25.93 g). A total yield of 3 steps=56%.
Reaction SMILES: [NH:1]1C=CC=N1.ClC1C(C(NC2C=CC=CC=2[C:22]2[CH:27]=[C:26]([F:28])[C:25]([N:29]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[N:30]3)=[C:24]([F:38])[CH:23]=2)=O)=CC=CN=1.O.O.[Sn](Cl)Cl>C(O)C>[F:38][C:24]1[CH:23]=[C:22]([NH2:1])[CH:27]=[C:26]([F:28])[C:25]=1[N:29]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[N:30]1
Reactant: c1cn[nH]c1
Reactant: O=C(Nc1ccccc1-c1cc(F)c(-n2ccc(C(F)(F)F)n2)c(F)c1)c1cccnc1Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(F)c(-n2ccc(C(F)(F)F)n2)c(F)c1

Procedure:
A mixture of 1-(2,6-difluoro-4-nitrophenyl)-3-trifluoromethyl)-1H-pyrazole (i.e. the product of Step A; 2.39 g, 8.15 mmol) and tin(II) chloride dihydrate (9.33 g, 41.3 mmol) in ethanol (173 mL) was refluxed for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed successively with 1 N aqueous sodium hydroxide, and then water. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by medium pressure liquid chromatography on silica gel eluted with 0 to 100% ethyl acetate in hexanes to provide the title compound (2.00 g).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[C:7]([F:11])=[C:6]([I:12])[C:3]=1[C:4]#[N:5].CCN(CC)CC.[CH:20]1([C:23]2[NH:27][N:26]=[C:25]([NH2:28])[CH:24]=2)[CH2:22][CH2:21]1>C(#N)C>[Cl:1][C:2]1[N:9]=[C:8]([NH:28][C:25]2[CH:24]=[C:23]([CH:20]3[CH2:22][CH2:21]3)[NH:27][N:26]=2)[C:7]([F:11])=[C:6]([I:12])[C:3]=1[C:4]#[N:5]
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: N#Cc1c(Cl)nc(Cl)c(F)c1I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1c(Cl)nc(Nc2cc(C3CC3)[nH]n2)c(F)c1I
Temperature: 80 °C
Yield: 29.5 %

Procedure:
The crude 2,6-dichloro-5-fluoro-4-iodonicotinonitrile (8.0 g, 25.2 mmol), Et3N (3.3 g, 32.8 mmol) and 5-cyclopropyl-1H-pyrazol-3-amine (3.1 g, 25.2 mmol) were placed in ACN (50 ml) and the resulting solution was heated to 80° C. for 24 hours. The reaction was cooled to room temperature, filtered, and the resulting solid was washed with cold ACN, dried, and collected to give the title compound (3.0 g, 29%). MS: Calcd.: 403. Found: [M+H]+ 404.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:27]=[C:28]([OH:35])[CH:29]=[CH:30][C:31]=1[N+:32]([O-:34])=[O:33].C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:35][C:28]1[CH:29]=[CH:30][C:31]([N+:32]([O-:34])=[O:33])=[C:26]([F:25])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: COc1cc2nccc(Cl)c2cc1NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])c(F)c3)c2cc1NC(=O)OCc1ccccc1
Temperature: 130 °C
Reaction time: 6 h
Yield: 8.8 %

Procedure:
(4-Chloro-7-methoxyquinolin-6-yl)carbamic acid benzyl ester (1.58 g) was added to 1-methyl-2-pyrrolidone (5 ml), and then 3-fluoro-4-nitrophenol (0.87 g) and N,N-diisopropylethylamine (1.2 ml) were added and the mixture was heated and stirred at 130° C. for 6 hours. The reaction solution was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The organic layer was concentrated and the obtained residue was subjected to NH silica gel column chromatography for elution with a solvent (ethyl acetate) to obtain the title compound (188 mg) as a solid.
Reaction SMILES: [OH:1][C@H:2]([CH2:32][OH:33])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[C:26][Si](C)(C)C)=[CH:21][C:20]=3[F:31])=[C:12]([F:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(Cl)Cl>C1COCC1>[OH:1][C@H:2]([CH2:32][OH:33])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[CH:26])=[CH:21][C:20]=3[F:31])=[C:12]([F:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1
Reactant: Cn1c(=O)c(F)c(Nc2ccc(C#C[Si](C)(C)C)cc2F)c2c(=O)n(C[C@H](O)CO)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#Cc1ccc(Nc2c(F)c(=O)n(C)c3ncn(C[C@H](O)CO)c(=O)c23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a mixture of (S)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-((trimethylsilyl)ethynyl)phenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 21A in THF (3 mL) was added 1M solution of TBAF (0.14 mL, 0.14 mmol, 1.75 eq). The reaction mixture was stirred at ambient temperature for 1 hour. The solvent was removed under vacuum and the residue was purified by flash chromatography with 2:8 MeOH:DCM to yield the desired product (S)-3-(2,3-dihydroxypropyl)-5-(4-ethynyl-2-fluorophenylamino)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (example 21) as an off-white solid (10 mg, 30% yield). 1H NMR (400 MHz, MeOD) δ ppm 3.54 (s, 1H) 3.60 (d, J=5.05 Hz, 2H) 3.72 (s, 3H) 3.75-3.83 (m, 1H) 3.93-4.00 (m, 1H) 4.41 (dd, J=13.52, 2.91 Hz, 1H) 7.11 (td, J=8.15, 5.68 Hz, 1H) 7.21-7.29 (m, 2H) 8.40 (s, 1H). [M+H] calc'd for C19H16F2N4O4, 403; found, 403.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:18])([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])[CH3:7])=[O:5])[CH3:2].CN.Cl.[CH3:22][N:23](C)CCCN=C=NCC>C(Cl)Cl.C(O)C.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4](=[O:5])[C:6]([CH3:18])([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:11]([C:12](=[O:13])[NH:23][CH3:22])[CH:10]=1)[CH3:7])[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C(=O)O)c1
Agent: CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
1.0 g (4.0 mmol) of 3-(1-ethoxycarbonyl-1-methyl-ethoxy)-benzoic acid was dissolved in 50 ml of methylene chloride; then, 1.5 ml (4.0 mmol) of a methylamine-solution in ethanol was added. The reaction mixture was cooled down to 0° C. and 0.91 g (4.8 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 1.50 g (11.9 mmol) of 4-dimethylaminopyridine were added. After stirring for two hours at ambient temperature, it was poured into crashed ice/HCl (1N) and extracted twice with MeCl2. The combined organic phases were washed with water and brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography (SiO2, MeCl2/MeOH) to give 0.97 g of the title compound in form of colorless needles.
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[Br:10][CH2:1]/[C:2](/[CH3:9])=[CH:3]/[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C=C(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)/C=C(\C)CBr

Procedure:
A mixture of ethyl 3,3-dimethylacrylate (12.8g, 100 mmol), N-bromosuccinimide (11.8g, 66 mmol), dry benzene (50 ml) and benzoyl peroxide (20 mg) was heated under reflux for 0.5h. After cooling, filtration, concentration and distillation, ethyl 4-bromo-3-methylcrotonate was obtained. The latter (33.8 mmol) was added dropwise to triethylphosphite (47.17 mmol) at 100°. The mixture was warmed to 150o and the residue purified by distillation to give triethyl 4-phosphono-3-methylcrotonate (b.p. 120° at 0.5 mm.Hg) as a cis/trans mixture.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][O:8][CH2:7][CH:6]1[O:10][C:11]([CH2:13][O:14][C:15]1[C:16]([Cl:31])=[CH:17][C:18]([F:30])=[C:19]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]2)=[S:23])[CH:20]=1)=[O:12])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:38](Cl)(Cl)=[S:39]>ClCCl>[C:1]([O:4][CH:5]1[CH2:9][O:8][CH2:7][CH:6]1[O:10][C:11]([CH2:13][O:14][C:15]1[C:16]([Cl:31])=[CH:17][C:18]([F:30])=[C:19]([N:21]=[C:22]2[N:24]3[N:25]([CH2:26][CH2:27][CH2:28][CH2:29]3)[C:38](=[S:39])[S:23]2)[CH:20]=1)=[O:12])(=[O:3])[CH3:2]
Reactant: S=C(Cl)Cl
Reactant: CC(=O)OC1COCC1OC(=O)COc1cc(NC(=S)N2CCCCN2)c(F)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1COCC1OC(=O)COc1cc(N=c2sc(=S)n3n2CCCC3)c(F)cc1Cl
Yield: 72 %

Procedure:
In 15 ml of dichloromethane was dissolved 1.43 g of 1-(5-(4-acetoxytetrahydrofuran-3-yloxycarbonylmethoxy)-4-chloro-2-fluorophenylaminothiocarbonyl)hexahydropyridazine, followed by addition of 0.59 g of pyridine, which was then cooled in an ice-cold bath. Under stirring, a solution of 0.52 g of thiophosgene in dichloromethane was added dropwise, and after addition was completed, the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with water, subsequently with aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After distilling off the solvent the residue was purified by chromatography on a silica gel column (eluted with ethyl acetate/hexane=2/3), to obtain 1.12 g of a compound (No. 42) described in Table 1 (72%).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=CC=3)[N:11]=[C:10]([CH3:18])[C:9]=2[C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1.ClC1C=C(C)N=C(CC)C=1.BrC1C=CC(CN)=CC=1>>[Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]2[C:9]([C:19](=[O:21])[CH3:20])=[C:10]([CH3:18])[N:11]=[C:12]([CH2:13][CH3:14])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)cc1
Agent: CCc1cc(Cl)cc(C)n1
Agent: NCc1ccc(Br)cc1
Product: CCc1cc(NCc2ccc(Br)cc2)c(C(C)=O)c(C)n1

Procedure:
1-[4-(4-Bromobenzylamino)-2-ethyl-6-methylpyridin-5-yl]ethanone was prepared by the method described in Example 30 (Intermediate 2c) starting from 4-chloro-2-ethyl-6-methylpyridine and 4-bromobenzylamine. MS(ES+): 347/349.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:20]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH3:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(NS(=O)(=O)c2ccc(Br)cc2)c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(N(C)S(=O)(=O)c2ccc(Br)cc2)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-bromo-N-(3-methoxyphenyl)benzenesulphonamide (0.5 g 1.46 mmol) and K2CO3 (0.5 g) in anhydrous DMF (7 ml) MeI (1 ml) was added and this was stirred at 50° C. for 0.5 h. The mixture was diluted to 50 ml with H2O and extracted in EtOAc (50 ml). The organic layer was washed with H2O, dried over MgSO4, filtered and the filtrate was passed through silica gel bead. The filtrate was evaporated to dryness to give the product (0.5 g; 96%), as a pale solid. 1H-NMR (CDCl3) 3.14 (5, 3H); 3.75 (s, 3H); 6.58 (broad d, 1H), 6.69 (t, 1H, J=2.20 Hz); 6.80 (dd, 1H, J=2.5, 8.34, Hz); 7.18 (tr, 1H, J=8.15 Hz); 7.40 (d, 2H, J=8.67 Hz); 7.58 (d, 2H, J=8.64 Hz).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:14])[S:10](Cl)(=[O:12])=[O:11].[CH3:15][C:16]([CH3:27])([CH2:25][CH3:26])[CH2:17][C:18]1[N:19]=[C:20]([CH3:24])[N:21]([OH:23])[CH:22]=1>C(Cl)Cl>[CH3:15][C:16]([CH3:27])([CH2:25][CH3:26])[CH2:17][C:18]1[N:19]=[C:20]([CH3:24])[N:21]([O:23][S:10]([N:9]([CH3:14])[CH3:8])(=[O:12])=[O:11])[CH:22]=1
Reactant: CCC(C)(C)Cc1cn(O)c(C)n1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)(C)Cc1cn(OS(=O)(=O)N(C)C)c(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
Triethylamine (100 mL, 0.72 mol) followed by N,N-dimethylsulfamoyl chloride (42 mL, 0.38 mol) were added to a 0° C. solution of 4-(2,2-dimethylbutyl)-2-methyl-1H-imidazol-1-ol in methylene chloride (100 mL). After stirring at ambient temperature for 2 h, the reaction mixture was washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography over silica eluting with ethyl acetate/hexane followed by methanol afforded N-({[4-(2,2-dimethylbutyl)-2-methyl-1H-imidazol-1-yl]oxy}sulfonyl)-N-methylmethanamine (ca. 50% purity by HPLC) which was dissolved in 7:1 methanol/acetic acid (400 mL), and 10% Palladium (10% on activated carbon) (6 g) was added. After stirring under 40 psi hydrogen for 2 h, the reaction mixture was filtered through celite, rinsing with methanol and concentrated in vacuo. The residue was redissolved in ethyl acetate and washed with 1 N aqueous sodium hydroxide and brine, dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography over silica eluting with 5-20% methanol/methylene chloride afforded 4-(2,2-dimethylbutyl)-2-methyl-1H-imidazole.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)#[N:2].C([Mg]Br)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH2:22]([C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])[CH:10]=2)[NH:14][CH:13]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N#Cc1ccccc1-c1ccc2[nH]ccc2c1
Reactant: BrCc1ccccc1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccccc1-c1ccc2[nH]cc(Cc3ccccc3)c2c1
Temperature: 0 °C
Yield: 32.3 %

Procedure:
5-(2-Cyanophenyl)indole (2.3 mmole, 0.50 g) was dissolved in 3 ml THF, cooled to 0° C. Ethyl magnesium bromide (2.41 mmoles, 1.21 ml of 2.0M solution in ether) was added dropwise. Benzyl bromide (94.6 mole, 0.80 g) was added dropwise to the solution. The reaction was refluxed for 24 hours and poured into aqueous ammonium chloride and ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, and concentrated. The intermediate was chromatographed over silica gel eluted with 10% ethyl acetate in hexane to yield 229 mg of 3-benzyl-5-(2-cyanophenyl)indole. (MS)