Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:15]3)=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:12][N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][O:21][C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH2:15]3)[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: O=C(N1CCCC(COc2ccc(F)cc2)C1)C1(c2ccc(Cl)cc2)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Fc1ccc(OCC2CCCN(CC3(c4ccc(Cl)cc4)CCC3)C2)cc1
Yield: 49.5 %

Procedure:
Compound 86 was synthesized from compound 84 (0.50 g, 1.25 mmol) and lithium aluminum hydride (0.10 g), using the method described for the synthesis of compound 83 to give 0.24 g of the desired product 86. C23H27ClFNO, LRMS (m/z)=388 (MH+).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:28][C:29]([N:33]([CH2:38][CH3:39])[CH2:34][CH2:35][O:36][CH3:37])([CH3:32])[C:30]#[CH:31]>>[CH3:32][C:29]([N:33]([CH2:38][CH3:39])[CH2:34][CH2:35][O:36][CH3:37])([CH3:28])[C:30]#[C:31][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:26])([F:27])[F:1])=[CH:8][CH:7]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Reactant: C#CC(C)(C)N(CC)CCOC
Product: CCN(CCOC)C(C)(C)C#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and (1,1-Dimethyl-prop-2-ynyl)-ethyl-(2-methoxy-ethyl)-amine were converted to yield {1,1-Dimethyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-ethyl-(2-methoxy-ethyl)-amine as brown oil, MS: 447 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[C@@H:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([Cl:30])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:7]1.CN1CC[O:39][CH2:38][CH2:37]1.C(Cl)(=O)C>C(Cl)Cl>[C:38]([NH:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[C@@H:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([Cl:30])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:7]1)(=[O:39])[CH3:37]
Reactant: CN1CCOCC1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(N)c3)n2)cc1Cl
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
N-[1-(3-Amino-benzyl)-1H-pyrazol-3-yl]-2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared in Example 58, 110 mg, 0.22 mmol) was dissolved in methylene chloride (2 mL) and N-methyl-morpholine (26 μL, 0.24 mmol) was added. Acetyl chloride (16 μL, 0.22 mmol) was added and the reaction stirred at 25° C. for 30 min. The reaction was concentrated in vacuo to give a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 20% ethyl acetate/methylene chloride) afforded N-[1-(3-acetylamino-benzyl)-1H-pyrazol-3-yl]-2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (68 mg, 57%) as a white powder: ESI-LRMS m/e calcd for C27H31ClN4O4S [M+] 542.18, found 543.17 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.03-1.23 (m, 2H, CH2), 1.41-2.00 (m, 8H, 4×CH2), 2.15 (s, 3H, NCH3), 2.16-2.27 (m, 1H, CH), 3.25 (s, 3H, SO2CH3), 3.55 (t, J=7.5 Hz, 1H, CH), 5.09 (s, 2H, NCH2), 6.69 (d, J=2.3 Hz, 1H, Ar), 6.87 (d, Jo=7.5 Hz, 1H, Ar), 7.21-7.28 (m, 2H, NH and Ar), 7.28-7.33 (m, 2H, Ar), 7.35-7.41 (m, 1H, Ar), 7.44 (dd, Jo=8.1, Jm=1.3 Hz. 1H, Ar), 7.58 (d, Jm=1.3 Hz, 1H, Ar), 7.90-8.20 (m, 2H, Ar and NH).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:8])=[CH:4][CH:3]=1.[Cl:17][CH:18]([Cl:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:29]=[CH:28][C:27]([Sn](C)(C)C)=[CH:26][CH:25]=1)=[O:20]>>[Cl:17][CH:18]([Cl:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@@H:23]([C:24]1[CH:25]=[CH:26][C:27]([C:2]2[S:6][C:5]([CH:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:8])=[CH:4][CH:3]=2)=[CH:28][CH:29]=1)[OH:34])=[O:20]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Br)s1
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Product: CC(NC(=O)OC(C)(C)C)c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Yield: 30.8 %

Procedure:
The compound is prepared from tert-butyl (1-(5-bromothiophen-2-yl)ethyl)-carbamate (138 mg, 0.45 mmol) and 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethylstannyl)phenyl)propan-2-yl)acetamide (200 mg, 0.45 mmol) in a manner analogous to Example 74, Step 2 to give the title compound (70 mg): 1H-NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 1.57 (d, J=6.8 Hz, 3H), 2.68 (bs, 1H), 4.25-4.38 (m, 1H), 4.42-4.48 (m, 0.5H), 4.53-4.60 (m, 1H), 4.65-4.72 (m, 0.5H), 4.77-4.89 (m, 1H), 4.98-5.09 (m, 1H) 5.11 (d, J=4.0 Hz, 1H), 5.87 (s, 1H), 6.90 (d, J=3.5 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 7.14 (d, J=3.8 Hz, 1H), 7.37 (d, J=8.1 Hz, 2H), 7.55 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[CH3:19][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI.S(=O)(=O)(O)O>COCCOCCOC>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:7](=[O:9])[N:8]([CH3:19])[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=c1[nH]c2cc(Br)ccc2n1-c1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: CI
Solvent: COCCOCCOC
Product: Cn1c(=O)n(-c2ccc(F)cc2)c2ccc(Br)cc21
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To a stirred room temperature suspension of 5-bromo-1-(4-fluorophenyl)-1,3-dihydro-benzimidazol-2-one (160 mg, 0.52 mmol) in anhydrous bis(2-methoxyethyl)ether (5 mL) was added lithium bis(trimethylsilyl)amide (0.55 mL of 1.06 M solution in THF, 0.58 mmol). After 30 minutes, methyl iodide (125 μL, 2 mmol) was added. After 2 hours, the mixture was poured into 1 N sulfuric acid containing ice. The resulting precipitate was filtered, washed with water, and dried to afford 160 mg of 5-bromo-1-(4-fluorophenyl)-3-methyl-1,3-dihydro-benzimidazol-2-one as an off-white solid. MS m/z 321/323 (MH+).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.OC[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[NH:44][C:43](=[O:45])[C:42]3[C:37](=[CH:38][C:39]([O:48][CH3:49])=[CH:40][C:41]=3[O:46][CH3:47])[N:36]=2)=[CH:31][CH:30]=1>CN(C=O)C>[Br:5][CH2:1][CH2:27][O:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[NH:44][C:43](=[O:45])[C:42]3[C:37](=[CH:38][C:39]([O:48][CH3:49])=[CH:40][C:41]=3[O:46][CH3:47])[N:36]=2)=[CH:33][CH:34]=1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCCO)cc3)nc2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCCBr)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Carbon tetrabromide (0.26 g, 0.77 mmol) was added to a solution of triphenylphosphine (0.24 g, 0.92 mmol) in anhydrous DMF (5 mL) at 0° C. A solution of 2-[4-(2-hydroxy-ethoxy)-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.21 g, 0.61 mmol) in DMF (2 mL) was then added dropwise and stirred at room temperature for 16 hours. Solvent was removed under reduced pressure and the residue was diluted with water (10 mL) and extracted with dichloromethane (4×10 mL). The combined organic phase was washed with brine and dried over anhydrous magnesium sulfate. Solvent was removed and the residual solid was triturated with ether. The resulting slurry was filtered and washed with ether several times (to remove the triphenylphosphine oxide) and finally with a solution of dichloromethane-ether (1:4) to obtain 2-[4-(2-bromo-ethoxy)-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one as an off-white solid. Yield: 0.25 g (quantitative).
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[C:13]([O:17][CH2:18]C)(=[O:16])[CH2:14][SH:15].C(=O)([O-])[O-].[K+].[K+].CCCCCC.CCOC(C)=O>CCO>[NH2:7][C:6]1[C:5]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:4]=2[S:15][C:14]=1[C:13]([O:17][CH3:18])=[O:16]
Reactant: N#Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: COC(=O)c1sc2cc(Cl)ccc2c1N
Yield: 31 %

Procedure:
2-nitro-4-chlorobenzonitrile (1.94 g, 10.6 mmol) was treated with 1 eq of ethyl thioglycolate and 1 eq potassium carbonate in EtOH as described in Example 41A to give after chromatography (4:1 hexane/EtOAc) the title compound in 31% yield. 1H NMR (300 MHz, CDCl3) d 1.38 (t, J=7 Hz, 3H), 4.36 (q, J=7 Hz, 2H), 5.85 (bs, 2H), 7.33 (dd, J=9,2 Hz, 1H), 7.54 (d, J=9 Hz; 1H), 7.1 (d, J=2 Hz, 1H). MS (DCI/NH3) m/e 256 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH:18][S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(Cl)cc21
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3ccccc3)c2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
3-(6-Chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.53 mmol) and benzenesulfonyl chloride (92 mg, 0.63 mmol) were dissolved in pyridine (5 mL). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified on column chromatography using petroleum ether/ethyl acetate=5:1 as eluent to afford N-[3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide (110 mg, yield: 44%) as yellow solid. MS (ESI+APCI) M+1=427.1.
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]=1)#N.OS(O)(=O)=O.[OH2:17].[OH2:18]>C(O)(=O)C>[O:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:3]([C:1]([OH:18])=[O:17])=[CH:4]1
Reactant: N#Cc1coc2ccccc12
Reactant: O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(O)c1coc2ccccc12

Procedure:
To a solution of benzofuran (75 g) in chloroform (600 ml) was added dropwise a solution of bromine (41 ml) in chloroform (150 ml) at -10° C. The temperature was slowly allowed to reach room temperature and chloroform was evaporated in vacuo, leaving the crude 2,3-dibromo-2,3-dihydrobenzofuran as a crystalline produce which was used without further purification. Yield: 171 g. To the dibromoderivative (147 g) in ethanol (600 ml) was added a solution of KOH (59 g) in ethanol (200 ml). The mixture was refluxed for 2.5 hours. After cooling to room temperature the mixture was poured onto water and extracted with ethyl acetate (2×300 ml). The combined organic phases were worked-up and the 3-bromobenzofuran was subsequently purified by elution through silica gel using n-heptane as the eluent. Yield 51 g of a semicrystalline product. A solution of all of the thus obtained 3-bromobenzofuran and CuCN (33 g) in N-methyl-2-pyrrolidinone (350 ml) was heated at 190° C. under N2. With 1 hour intervals was added further CuCN (3×4.5 g). The mixture was poured into a solution of FeCl3.6H2O in water (610 ml) and concentrated hydrochloric acid (156 ml) while still hot. The resulting mixture was stirred at 60° C. for 1 hour and subsequently poured onto ice/water (5 l). Extraction with diethyl ether (3×300 ml) and working-up of the combined organic phases afforded crude, crystalline 3-cyanobenzofuran melting at 76-82° C. Yield: 34 g. The 3-cyanobenzofuran was dissolved in a mixture of acetic acid:conc. H2SO4 :water 1:1:1 (660 ml) and refluxed for 3 hours. After cooling water was added and the 3-benzofurancarboxylic acid was finally extracted with diethyl ether (3×200 ml) and worked-up. Yield: 37 g. Mp: 152-156° C.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[K+].C(O)C.O>Cl>[C:30]([CH2:29][CH2:28][CH2:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:15][CH:16]=2)=[CH:21][CH:22]=1)([OH:32])=[O:31]
Reactant: CCCCCCCCCCCCOc1ccc(-c2ccc(CCCCC(=O)OCC)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(-c2ccc(CCCCC(=O)O)cc2)cc1
Yield: 90.5 %

Procedure:
19 mmol of the compound from Example 15, 66.7 mmol of KOH, 100 ml of ethanol and 50 ml of water are introduced into a 500 ml single-necked flask fitted with reflux condenser and magnetic stirrer, and the mixture is refluxed for 6 hours. After cooling, the reaction mixture is carefully acidified in concentrated HCl solution and subsequently washed with water until neutral. The solvent is stripped off, and the residue is recrystallized a number of times from glacial acetic acid. The residue is then boiled with methanol and subsequently with ether and filtered off with suction. Yield: 90.5%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH2:25][CH3:26])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:27]([N:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35])(=[O:29])[CH3:28]>>[C:27]([N:30]1[CH2:34][CH2:33][N:32]([C:2]2[CH:3]=[CH:4][C:5]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]4[C:23]([CH3:24])=[CH:22][C:21]([CH2:25][CH3:26])=[CH:20][N:19]=4)[CH2:14][CH2:13]3)=[O:11])=[C:6]([CH:9]=2)[C:7]#[N:8])[C:31]1=[O:35])(=[O:29])[CH3:28]
Reactant: CC(=O)N1CCNC1=O
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C(C)=O)C4=O)cc3C#N)CC2)c(C)c1
Yield: 64.8 %

Procedure:
Using 5-bromo-2-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (2.48 g) described in Preparation Example 246 and 1-acetylimidazolidin-2-one (923 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (1.79 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[CH:6][C:5]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[NH:20][C:19]2=O)=[C:4]([F:30])[CH:3]=1.P(Cl)(Cl)([Cl:33])=O.C(N(CC)CC)C.C1(C)C=CC=CC=1>O>[Cl:33][C:19]1[N:18]([C:5]2[CH:6]=[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:15]([O-:17])=[O:16])[C:2]([Cl:1])=[CH:3][C:4]=2[F:30])[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:27])([F:26])[F:28])[N:20]=1
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(Oc2ccccc2[N+](=O)[O-])c(Cl)cc1F
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1cc(C(F)(F)F)nc(Cl)n1-c1cc(Oc2ccccc2[N+](=O)[O-])c(Cl)cc1F
Yield: 75.4 %

Procedure:
A mixture of 3-[4-chloro-2-fluoro-5-(2-nitrophenoxy)phenyl]-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione(4.5 g, 0.01 mol), phosphorus oxychloride(1.5 g, 0.01 mol), triethylamine(2.0 g, 0.02 mol) and toluene(14 ml) was heated under reflux for 24 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate solution contained 3.5 g(yield 76%) of the above compound III-1(HPLC analysis). The ethyl acetate solution was concentrated and purified by column chromatography on silica gel(20% ethyl acetate/hexane) to give compound III-1 as a white solid, m.p.128-131° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6](Cl)=[O:7].C(N(CC)C(C)C)(C)C.Cl.[N+:22]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29])([O-:24])=[O:23]>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=2)=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccc(F)cc1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1cccc([N+](=O)[O-])c1)c1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.1 %

Procedure:
A solution of 4-fluoro salicylic acid chloride (12.3 g, 70.3 mmol) in dichloromethane (140 mL) was cooled to 0° C., and treated with N,N-diisopropylethylamine (31.0 mL, 175 mmol) and 3-nitrobenzylamine hydrochloride (16 g, 84.6 mmol). After stirring at room temperature for 24 h, the solution was concentrated in vacuo and diluted with ethyl acetate. The organic layer was washed successively with aq 2 N HCl and saturated aq NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (10–100% ethyl acetate in heptane, 23 mL/min, 75 min) provided 4-fluoro-2-hydroxy-N-(3-nitro-benzyl)-benzamide as a yellow solid (13.7 g, 67%): 1H NMR (DMSO-d6 300 MHz) δ 12.75 (s, 1 H), 9.43 (t, J=6.0 Hz, 1 H), 8.11 (ddd, J, =8.3, J2=2.1 Hz, J3=1.2 Hz, 1 H), 8.18 (t, J=1.5 Hz, 1 H), 7.94 (dd, J1=8.9 Hz, J2=6.5 Hz, 1 H), 7.78 (td, J1=7.8 Hz, J2=1.4 Hz, 1 H), 7.63 (t, J=8.0 Hz, 1 H), 6.81–6.72 (m, 2 H), 4.61 (d, J=5.7 Hz, 2 H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[CH:30]=[C:29]([CH3:31])[C:28](=[O:32])[N:27]([CH:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CO.C(Cl)(Cl)[Cl:41]>>[ClH:41].[CH:33]1([N:27]2[C:25]3[N:26]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:15][N:16]=4)[N:22]=[CH:23][C:24]=3[CH:30]=[C:29]([CH3:31])[C:28]2=[O:32])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: Cc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Reactant: ClC(Cl)Cl
Solvent: CO
Product: Cc1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[6-(8-Cyclopentyl-6-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.411 g, 0.813 mmol), prepared as in Example 19, was dissolved in a 1:1 mixture of methanol/chloroform, purged with anhydrous hydrogen chloride gas, stirred for 2 hours at room temperature and a solid precipitated by addition of diethyl ether. The suspension was filtered and the residue dried in vacuo yielding 8-cyclopentyl-6-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride as a yellow solid (0.393 g). (APCI); M++1: Calc'd, 406.50, Found, 406.2. Analyses for C22H27N7O.2.85 H2O.2.2HCl: Calc'd: C, 49.20; H, 6.55; N. 18.26, Cl (ionic), 14.52; H2O, 9.56 Found: C, 49.43; H, 6.32; N, 17.87; Cl (ionic), 14.38 ; H2O, 7.35
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([Cl:13])=O)=[CH:4][CH:3]=1.[CH:15]([C:18]1([O:24][CH3:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([CH3:17])[CH3:16]>C1C=CC=CC=1.C(N(CC)CC)C>[ClH:13].[CH:15]([C:18]1([O:24][CH3:25])[CH2:19][CH2:20][N:21]([CH2:11][CH2:10][CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:14])[CH2:22][CH2:23]1)([CH3:17])[CH3:16]
Reactant: O=C(Cl)CCC(=O)c1ccc(F)cc1
Reactant: COC1(C(C)C)CCNCC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC1(C(C)C)CCN(CCCC(=O)c2ccc(F)cc2)CC1
Product: Cl

Procedure:
To a mixture of 21.5 g (0.1 m) of gamma-(p-fluorophenyl)-gamma-oxo-butyric acid chloride and 15.7 (0.1 m) of 4-isopropyl-4-methoxy-piperidine in 200 ml of benzene, 15.5 ml (0.11 m) of triethylamine is added. The triethylamine hydrochloride formed is filtered off and the solvent removed by evaporation under vacuum on a steambath. The residue is dissolved in dry ether and added dropwise to a suspension of 15 g of lithium aluminum hydride in ether. The reaction mixture is refluxed for two hours and the obtained mixture decomposed with water. The precipitate is filtered off and the ether solution evaporated. The residue, which consists of the alcohol corresponding to the butyrophenone, is oxidized according to Oppenauer with 60 g of aluminum-isopropylate in 500 ml of dry acetone. The reaction mixture is refluxed for 12 hours, cooled, and decomposed with water. After centrifugation, the solution is evaporated to dryness, whereafter the residue dissolved in ether and the hydrochloride precipitated with alcoholic hydrochloric acid. After recrystallization, the hydrochloride melts at 190°-192° C. Yield 19 g. The tartrate is prepared using tartaric acid.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:12]=[C:13]([C:22](O)=[O:23])[CH:14]=[C:15]2[C:19]([CH3:20])=[C:18]([CH3:21])[NH:17][C:16]=12.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:12]=[C:13]([C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:23])[CH:14]=[C:15]2[C:19]([CH3:20])=[C:18]([CH3:21])[NH:17][C:16]=12
Reactant: C1COCCN1
Reactant: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(C(=O)O)cc2c1C
Product: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(C(=O)N3CCOCC3)cc2c1C
Yield: 69 %

Procedure:
In accordance with the same procedures as in Step 1 of Example 756, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Step 1 and morpholine, the titled compound was obtained as a white solid. (Yield: 69%)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: OCCCCCCCCCl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCCCCCCO)cc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 62.4 %

Procedure:
20.0 g (164 mmol) of 4-hydroxybenzaldehyde and 30.0 g (182 mmol) of 8-chlorooctan-1-ol are dissolved in 200 mL of N,N-dimethylformamide. 29.0 g (210 mmol) of potassium carbonate and 2.7 g (16 mmol) of potassium iodide are added and the suspension is heated to 100° C. After 48 h, the excess of potassium carbonate is filtered off and the resulting filtrate is poured to icy water. The aqueous layer is extracted twice with ethyl acetate. Combined organic layers are washed with brine and evaporated to dryness. The crude is purified twice on column chromatography (SiO2, Heptane/ethyl acetate: 7/3) and dried overnight at 40° C. 25.6 g of 4-[(8-hydroxyoctyl)oxy]benzaldehyde are obtained as a yellow solid (62% yield). This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH:12]=O)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2].[S:14]1[CH2:18][C:17](=[O:19])[NH:16][C:15]1=[O:20]>>[CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH:12]=[C:18]1[S:14][C:15](=[O:20])[NH:16][C:17]1=[O:19])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: O=C1CSC(=O)N1
Reactant: CCc1[nH]c2ccccc2c1C=O
Product: CCc1[nH]c2ccccc2c1C=C1SC(=O)NC1=O

Procedure:
2-Ethylindole-3-carbaldehyde (170 mg) was treated with thiazolidine-2,4-dione using the general procedure (C) to afford the title compound (50 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[CH3:23][NH:24][CH3:25]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]([CH3:25])[CH3:23])=[CH:22][C:11]=3[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: CNC
Reactant: Fc1ccc(-c2csc3cc(OCCCCBr)ccc23)cc1
Product: CN(C)CCCCOc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and dimethylamine were converted to yield {4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-dimethyl-amine as white semisolid, MS: 344 (MH+).