Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].C([O:7][C:8](=[O:19])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][N:12]=1)(C)(C)C.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:29]=[C:30]([C:34](=[O:36])[CH3:35])[CH:31]=[CH:32][CH:33]=2)[CH2:23][CH2:22]1>CCO.O>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:29]=[C:30]([C:34](=[O:36])/[CH:35]=[CH:17]/[C:14]3[CH:15]=[CH:16][C:11](/[CH:10]=[CH:9]/[C:8]([OH:7])=[O:19])=[N:12][CH:13]=3)[CH:31]=[CH:32][CH:33]=2)[CH2:23][CH2:22]1
Reactant: CC(=O)c1cccc(CN2CCN(C)CC2)c1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C=O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1CCN(Cc2cccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)nc3)c2)CC1
Temperature: 0 °C
Reaction time: 7 h
Yield: 47.4 %

Procedure:
1.7 M KOH (0.634 ml) was added dropwise to a stirred mixture of (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid tert-butyl ester (see Example 11 STEP A-D, 250 mg, 1.078 mmol) and 1-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-ethanone (obtained as described in Preparation 14, 250 mg, 1.078 mmol) in EtOH (15 ml). The resulting solution was stirred at 0° C. for 7 h and then diluted with water and extracted with AcOEt. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by chromatographic column (eluent: DCM/MeOH/NH4OH from 97:3:0.1 to 95:5:0.2) and the desired intermediate was dissolved in DCM (4 ml) and TFA (1 ml). The mixture was stirred at room temperature for 6 h and then the solvent was removed in vacuo to give 200 mg of (E)-3-(5-{(E)-3-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-acrylic acid as its tris-trifluoroacetate salt. The crude mixture was used in the next step without further purifications.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[C:3]=1[NH2:18].[CH:19]1([CH2:24][C:25](Cl)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(#N)C.C(OCC)(=O)C>[CH:19]1([CH2:24][C:25]([NH:18][C:3]2[C:4]([C:14]([F:17])([F:16])[F:15])=[CH:5][C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:7][C:2]=2[CH3:1])=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: Cc1cc(N2CCOCC2)cc(C(F)(F)F)c1N
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCOCC2)cc(C(F)(F)F)c1NC(=O)CC1CCCC1
Temperature: 150 °C
Yield: 51.5 %

Procedure:
2-Methyl-4-morpholin-4-yl-6-trifluoromethyl-phenylamine (0.18 g) and cyclopentylacetyl chloride (112 mg) were dissolved in acetonitrile (4 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (2×20 mL) and brine (1×20 mL). The organic phase was dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography to furnish 132 mg (52%) of the title compound as a white solid. LC-MS (m/z) 371 (MH+); tR=2.87, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.20 (m, 2H), 1.51 (m, 2H), 1.60 (m, 2H), 1.76 (m, 2H), 2.11 (s, 3H), 2.24 (m, 1H), 2.26 (d, 2H), 3.16 (t, 4H), 3.73 (t, 4H), 7.00 (d, 1H), 7.12 (d, 1H), 9.16 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23]I)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[I-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1COCCN1
Reactant: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCI)CC1
Agent: [I-]
Agent: [Na+]
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCN2CCOCC2)CC1

Procedure:
In analogy to the procedure described in example 5D, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(3-iodo-propyl)-[1,4]diazepan-5-one and morpholine (with no additional sodium iodide) gave after flash silica gel column purification (CH2Cl2/EtOAc 99:1 to 96:4) the title compound as a light yellow viscous oil. MS: 440.2 (MH+, 2Cl).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH3:20][C:21]1[CH:22]=[C:23]([SH:27])[CH:24]=[CH:25][CH:26]=1>>[CH3:20][C:21]1[CH:22]=[C:23]([S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1cccc(S)c1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: Cc1cccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)c1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3-methyl-thiophenol.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[CH:8]=1.S(Cl)(Cl)=O>>[Cl:6][C:7]1[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1cc(Cl)n(C)n1
Solvent: O=S(Cl)Cl
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Into 150 xl of chlorosulfonic acid was added dropwise under cooling at 5° C. or lower, 30 g (0.23 ml) of 5-chloro-1,3-dimethylpyrazole. After the addition, the mixture was stirred at 100° C. for 8 hours. Then, the reaction mixture was cooled to 80° C., followed by dropwise addition of 36 g of thionyl chloride over 30 minutes After the addition, the mixture was stirred at 100° C. for an additional 2 hours. The reaction mixture was cooled on ice and poured carefully into ice-water, whereby crude 5-chloro-1,3-dimethylpyrazole-4-sulfonylchloride (50 g) was formed as crystals. Subsequently, into a solution of 40 g of dimethylamine in 250 ml of THF, the above compound was added under cooling and the reaction mixture was stirred at room temperature for 3 hours. After the reaction, THF was evaporated under reduced pressure and into the residue was added ether and washed with water. After drying and evaporating the etherial solution, there was obtained 47 g of the title compound m.p. 53 -55° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7]([C:12](O)=[O:13])=[CH:8][NH:9]2)=[CH:4][C:3]=1[O:16][CH3:17].[OH-].[NH4+:19]>CN(C)C=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7]([C:12]([NH2:19])=[O:13])=[CH:8][NH:9]2)=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: [NH4+]
Reactant: COc1cc2c(=O)c(C(=O)O)c[nH]c2cc1F
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc2c(=O)c(C(N)=O)c[nH]c2cc1F
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A mixture of 7-fluoro-6-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (1.0 g, 4.21 mmol) and N,N′-carbonyldiimidazole (1.51 g, 9.28 mmol) in 14 mL of N,N-dimethylformamide is heated at 65° C. for 2 hours then cooled to room temperature and poured into 200 mL of aqueous ammonium hydroxide in an ice water bath. The solution is allowed to stir at room temperature overnight and then concentrated to a small volume. Ice cold water is added followed by acidification with acetic acid. The resultant solid is collected by filtration washing with water to provide 821 mg of 7-fluoro-6-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxamide as a white solid, mp>300° C.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[OH:5][N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.ClCCl>[CH2:1]([O:5][N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)[C:2]#[CH:3]
Reactant: On1cccn1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: C#CCOn1cccn1
Reaction time: 12 h
Yield: 68.8 %

Procedure:
21.3 g of propargyl bromide are added to 15 g of 1-hydroxypyrazole and 15 g of sodium carbonate in 200 g of acetonitrile at 25° C., while stirring. Stirring is continued for 12 hours, after which the mixture is filtered under suction, the residue is washed with 100 g of acetonitrile, and the combined liquids are evaporated down in a rotary evaporator at 40° C. and under 20 mbar. The residue obtained in this procedure is dissolved in 200 g of dichloromethane, the solution is extracted 3 times with a total of 200 g of saturated aqueous sodium bicarbonate solution, and the organic phase is dried with magnesium sulfate and evaporated down. 15 g (70% of theory) of 1-pyrazolyl propargyl ether are obtained as an oil (H1 -NMR, δ in ppm: 2.6, t, 1H; 4.9, d, 2H; 6.2, m, 1H; 7.4, m, 2H). This substance is Example 10 in the Table below.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=[C:5]2[C:19]#[C:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C(O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:16])[CH3:17])[N:6]=[C:5]2[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C[Si](C)(C)CCOCn1nc(C#Cc2ccccc2)c2cc(N)ccc21
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1nc(CCc2ccccc2)c2cc(N)ccc21
Yield: 91.2 %

Procedure:
5-Amino-3-phenethyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole can be obtained in the following way: a solution of 0.9 g of 5-amino-3-phenylethynyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole in a mixture of 50 ml of absolute ethanol and of 2 ml of water containing 100 mg of 10% palladium-on-charcoal is hydrogenated under a pressure of 1000 kPa at a temperature in the region of 25° C. for 21.5 hours. After filtration of the catalyst through Celite® under argon and washing with ethanol, the filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.83 g of crude 5-amino-3-phenethyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole is thus obtained in the form of a brown-colored oil (Cl mass analysis: m/z 368 (M+H)+).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].CN(C)C=O.[F:12][C:13]([F:20])([F:19])[CH2:14]CC(O)=O>CCCCC>[F:12][C:13]([F:20])([F:19])[CH2:14][CH2:1][C:2]([Cl:4])=[O:3]
Reactant: O=C(O)CCC(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCCCC
Product: O=C(Cl)CCC(F)(F)F
Yield: 76 %

Procedure:
101 ml of oxalyl chloride and 0.1 ml of dimethylformamide was added to a solution of thus obtained 131 g of the 4,4,4-trifluorobutyric acid in 1 liter of pentane, and the resultant solution was refluxed for three hours. Then the reaction solution was distilled to yield 112 g of 4,4,4-trifluorobutyryl chloride in a yield of 76%. (b.p. 103° C./760 mmHg)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:19])=O)=[CH:14][CH:15]=3)[C:10]([C:20]([CH:22]3[C:24]([CH3:26])([CH3:25])[C:23]3([CH3:28])[CH3:27])=[O:21])=[CH:9]2)[CH2:3][CH2:2]1.[C:29](N1C=CN=C1)([N:31]1C=CN=[CH:32]1)=O.CNC>CCOC(C)=O.C1COCC1>[CH3:29][N:31]([CH3:32])[C:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[CH:9]=[C:10]2[C:20]([CH:22]1[C:24]([CH3:25])([CH3:26])[C:23]1([CH3:28])[CH3:27])=[O:21])=[O:19]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(C)C(C(=O)c2cn(CC3CCOCC3)c3ccc(C(=O)O)cc23)C1(C)C
Agent: CNC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc2c(c1)c(C(=O)C1C(C)(C)C1(C)C)cn2CC1CCOCC1
Yield: 35 %

Procedure:
A mixture 1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-5-carboxylic acid (0.10 g, 0.26 mmol, the minor product of Example 114B), 1,1′-carbonyldimidazole (55 mg, 0.34 mmol) and dimethylamine (2 M solution in THF, 0.17 mL, 0.34 mmol) in 4 mL of EtOAc and 3 mL of THF was processed as described in Example 93 to provide the title compound (38 mg, 0.093 mmol, 35% yield). 1H NMR (DMSO-d6, 300 MHz) δ ppm 1.25 (s, 6H), 1.27 (s, 6H), 1.29-1.48 (m, 4H), 2.03-2.18 (m, 1H), 2.20 (s, 1H), 2.97 (s, 6H), 3.23 (dt, J=11.3, 2.9 Hz, 2H), 3.78-3.89 (m, 2H), 4.17 (d, J=7.1 Hz, 2H), 7.27 (dd, J=8.5, 1.7 Hz, 1H), 7.66 (d, J=9.2 Hz, 1H), 8.27 (d, J=1.4 Hz, 1H), 8.37 (s, 1H); MS (DCI/NH3) m/z 411 (M+H)+; Anal. Calculated for C25H34N2O3.0.2H2O: C, 72.50; H, 8.37; N, 6.76. Found: C, 72.51; H, 8.29; N, 6.66.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:32][OH:33])[CH:28]=[CH:29][C:30]=1[CH3:31]>C(Cl)Cl.CCOCC>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][C:30]=1[CH3:31])[CH:32]=[O:33]
Reactant: COc1cc(CO)ccc1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc(C=O)ccc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Dess-Martin periodinane (3 gm, 7.07 mmol) was added to (3-methoxy-4-methylphenyl)methanol (1 gm, 6.57 mmol) in CH2Cl2 (35 ml) at 0° C. After stirring at 0° C. for 0.5 h, some of the CH2Cl2 was removed, reaction mixture was diluted with ether, washed with sodium bicarbonate solution, sodium thiosulfate solution and water. Organic layer was dried and evaporated to obtain 3-methoxy-4-methylbenzaldehyde in quantitative yield.
Reaction SMILES: Br[CH2:2][C:3](=[O:24])[CH:4]=[P:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:25]1([SH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Na].O>C(O)C>[O:24]=[C:3]([CH2:2][S:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:4]=[P:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)CBr
Reactant: Sc1ccccc1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)CSc1ccccc1
Yield: 74.1 %

Procedure:
3-Bromo-2-oxopropylidenetriphenylphosphorane (17.85 g) was added to a solution of thiophenol (5.22 g; 4.86 ml) in anhydrous ethanol (70 ml) containing sodium (1.09 g). The mixture was heated at reflux for 150 minutes and was then poured into a mixture of ice and water (250 ml). The mixture was then extracted with dichloromethane and the extract was washed with dilute aqueous sodium hydroxide solution (2 N) and then with water, and was dried over magnesium sulphate. Evaporation of the solvent gave a residual oil which was triturated with petroleum ether (b.p. 40°-60° C.), and the resulting crude solid was recrystallised from a mixture of toluene and petroleum ether (b.p. 60°-80° C.) to give 2-oxo-3-phenylthiopropylidenetriphenylphosphorane (14.2 g) in the form of cream prisms, m.p. 132°-134° C. [elemental analysis: C, 76.4; H, 5.3; P, 7.3; S, 7.7%. C27H23OPS requires C, 76.0; H, 5.4; P, 7.3; S, 7.5%. νmax 715, 740, 750, 1110, 1385, 1440, 1485 and 1550 cm-1 ].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:36][NH:37][O:38][CH3:39]>ClCCl>[CH3:39][O:38][N:37]([CH3:36])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)[CH:4]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(Cl)c(-n2cccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(Cl)c(-n2cccc2)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
5.0 g of 4-chloro-3-(1H-pyrrol-1-yl)benzoic acid in 200 ml of dichloromethane were treated in succession with 3.13 ml of triethylamine and 4.33 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC.HCl). The mixture was stirred at room temperature until it became clear and was then cooled to 0° C. and 2.21 g of N,O-dimethylhydroxylamine hydrochloride were added. The mixture was then left to come to room temperature and was stirred for a further 18 hours, washed with 1M aqueous hydrochloric acid and with brine and then dried over anhydrous magnesium sulphate. Evaporation under reduced pressure gave 5.73 g of N-methoxy-N-methyl-4-chloro-3-(1H-pyrrol-1-yl)benzamide as a viscous oil.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:29])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]4[CH:24]=[CH:25][C:26](Cl)=[CH:27][C:22]4=[N:21][CH:20]=3)=[CH:15][CH:14]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)[NH:36][CH2:37][CH2:38][S:39]([C:42]1[CH:47]=[CH:46][C:45](B2OC(C)(C)C(C)(C)O2)=[CH:44][CH:43]=1)(=[O:41])=[O:40])(C)(C)C>>[NH2:36][CH2:37][CH2:38][S:39]([C:42]1[CH:47]=[CH:46][C:45]([C:26]2[CH:25]=[CH:24][N:23]3[C:19]([C:16]4[CH:17]=[CH:18][C:13]([CH2:12][C:11]([NH:10][C:7]5[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[O:9][N:8]=5)=[O:29])=[CH:14][CH:15]=4)=[CH:20][N:21]=[C:22]3[CH:27]=2)=[CH:44][CH:43]=1)(=[O:41])=[O:40]
Reactant: CC(C)(C)c1cc(NC(=O)Cc2ccc(-c3cnc4cc(Cl)ccn34)cc2)no1
Reactant: CC(C)(C)OC(=O)NCCS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CC(C)(C)c1cc(NC(=O)Cc2ccc(-c3cnc4cc(-c5ccc(S(=O)(=O)CCN)cc5)ccn34)cc2)no1
Yield: 80.7 %

Procedure:
Couple N-(5-tert-Butyl-isoxazol-3-yl)-2-[4-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-acetamide (0.700 g, 1.71 mmol) to {2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonyl]-ethyl}-carbamic acid tert-butyl ester (0.775 g, 1.88 mmol) using procedure similar to Example 115. Treat the crude extracts to SCX ion exchange chromatography during which time some of the BOC-group is cleaved. Elute from the SCX column and treat with 2N HCl in dioxane (125 mL) and 10 mL of methanol for 2 hours. Evaporate in vacuo to provide the intermediate (0.87 g, 1.38 mmol). MS(ES), m/z 616 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[OH:11].[H-].[Na+].[CH3:18]I.CO>O1CCOCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[O:11][CH3:18]
Reactant: CI
Reactant: O[C@H]1CCC[C@H]1OCc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CO[C@H]1CCC[C@H]1OCc1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
6.3 g (0.03 mol) of cis-1-(2-fluorobenzyloxy)-cyclopentan-2-ol (Example 2) in 100 ml of absolute dioxan were added dropwise to a suspension of 0.72 g (0.03 mol) of sodium hydride (0.9 g of 80% pure sodium hydride in toluene) in 100 ml of absolute dioxan at 5° C. under nitrogen. After stirring the mixture at room temperature for 30 minutes, it was warmed to 70° C. for 45 minutes and cooled, 1.26 g (0.03 mol) of methyl iodide in dioxan were added dropwise and the mixture was then heated to the boil for 4 hours. After cooling the mixture to room temperature, 5 ml of methanol were added dropwise and the suspension was concentrated on a rotary evaporator. The residue was taken up in water and the mixture was extracted again with methylene chloride. The combined methylene chloride phases were dried over sodium sulphate and filtered and the solvent was stripped off from the filtrate on a rotary evaporator. The oily residue was distilled. 5 g (75% of theory) of cis-1-(2-fluorobenzyloxy)-2-methoxy-cyclopentane of boiling point 90° C./0.1 mm Hg were obtained.
Reaction SMILES: C[C:2]([C:4](=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[Cl:17])[C:5]([O:7][CH3:8])=[O:6])=O.C1(C)C=CC(S([CH2:27][N+:28]#[C-])(=O)=O)=CC=1.C[O-].[Na+].O>CO>[CH3:8][O:7][C:5]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[Cl:17])=[CH:27][NH:28][CH:2]=1)=[O:6]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)C(=Cc1cccc(Cl)c1Cl)C(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1c[nH]cc1-c1cccc(Cl)c1Cl
Yield: 58 %

Procedure:
With stirring, 20 g of methyl α-methylcarbonyl-2,3-dichlorocinnamate are added at 0° C. to a 22 % by weight solution of (p-tolylsulfonyl)methyl isocyanide prepared according to Example P1 (a). Then 26.3 g of a 30% solution of sodium methylate in methanol are added dropwise over 2 hours. The mixture is stirred for 2 hours and then 35 ml of water are added dropwise. The reaction mixture is concentrated at +50° C. under vacuum. After addition of 70 ml of water, the reaction mixture is concentrated once more under vacuum and then filtered. The filter residue is washed with toluene and recrystallised from ethanol, affording 10.8 g (58% of theory) of 4-methoxycarbonyl-3-(2,3-dichlorophenyl)-pyrrole which melts at 200°-201° C.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:30])[O:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([NH:17][C:18]2[N:23]=[C:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[N:21]=[C:20](Cl)[N:19]=2)[CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:31]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40])[CH2:32][CH2:33][CH3:34].O1CCCC1>O>[C:1]1([C:7]2[C:8](=[O:30])[O:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([NH:17][C:18]2[N:23]=[C:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[N:21]=[C:20]([N:35]([CH2:36][CH2:37][CH2:38][CH2:39][OH:40])[CH2:31][CH2:32][CH2:33][CH3:34])[N:19]=2)[CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)c1nc(Cl)nc(Nc2ccc3cc(-c4ccccc4)c(=O)oc3c2)n1
Reactant: CCCCNCCCCO
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(CCCCO)c1nc(Nc2ccc3cc(-c4ccccc4)c(=O)oc3c2)nc(N(CC)CC)n1

Procedure:
21.1 Parts of 3-phenyl-7-[(6-chloro-4-diethylamino-s-triazine-2-yl)amino]coumarin and 14.2 parts of N-butylamino-4-butanol were added to 20 parts of tetrahydrofuran and reacted for 6 hours under reflux. The reaction product was poured into water, and the crystals thus precipitated were collected by filtration. The product was recrystallized from a mixed solvent of chloroform:ethyl acetate (1:1 by volume) to obtain 20 parts of 3-phenyl-7-[[6-(4-hydroxybutylbutylamino)-4-diethylamino-s-triazine-2-yl]amino]coumarin. The resulting compound had a melting point of from 124° to 126° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH:29]1[O:31][CH2:30]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CO>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH:29]([OH:31])[CH2:30][S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Reactant: COc1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(SCC(O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reaction time: 1.5 h

Procedure:
4-Methoxythiophenol (1.0 ml) and triethylamine (1.0 ml) were added to (2S)-1-(t-butoxycarbonyl)-2-(1,2-epoxyethyl)-pyrrolidine (1.57 g) as obtained in Example 1-A) in methanol (50 ml), and the mixture was stirred for 1.5 hours under reflux. The reaction mixture was concentrated and the residue was poured into ice-water, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated. The residue was recrystallized from a mixted solution of hexane-ethyl acetate to give 2.16 g of the title compound as colorless needles.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][C:8](Cl)=[O:9].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1>>[Cl:5][CH2:6][CH2:7][C:8]([C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][C:14]=1[F:18])=[O:9]
Reactant: Fc1cccc(F)c1
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCl)c1ccc(F)cc1F
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a stirred mixture of aluminium (III) chloride (11.70 g, 88.0 mmol) in 1,3-difluorobenzene (21 mL) at RT was added 3-chloropropionyl chloride (4.0 mL, 41.9 mmol). The reaction mixture was stirred at 60° C. for 6 h. The mixture was cooled to RT and was poured into an ice/2M aqueous hydrochloric acid mixture (100 mL). After vigorous stirring, the mixture was extracted with DCM (2×75 ml). The combined organic extracts were dried over magnesium sulphate and concentrated in vacuo to give 8.68 g (quantitative yield) of crude title compound as an orange oil.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:20]#[CH:21])[CH:19]=1)[C:15]#[N:16].N>>[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:20]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[N:8][CH:7]=[CH:6][N:5]=3)[CH:21]=2)[CH:19]=1)[C:15]#[N:16]
Reactant: C#Cc1cc(Cl)cc(C#N)c1
Reactant: ON=C(Cl)c1cnccn1
Agent: N
Product: N#Cc1cc(Cl)cc(-c2cc(-c3cnccn3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and the product of Example 66A (82 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ7.66 (s, 1H), 7.97 (t, J=1.6 Hz, 1H), 8.30 (d, J=1.6 Hz, 2H), 8.71 (d, J=2.4 Hz, 1H), 8.77 (dd, J=2.8, 1.6 Hz, 1H), 9.31 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 283 (M+H)+, 285 (M+H)+.