Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(C1CC(=O)[N:7](C2C=CC(O)=CC=2)[CH2:6]1)=O.[C:18](C1C=C(C=CC=1)CBr)#[N:19].CO[C:30]([CH:32]1[CH2:36][C:35](=[O:37])[N:34]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([C:52]#[N:53])[CH:47]=3)=[CH:40][CH:39]=2)[CH2:33]1)=[O:31]>C(O)C>[CH3:6][NH2:7].[CH3:18][NH:19][C:30]([CH:32]1[CH2:36][C:35](=[O:37])[N:34]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([C:52]#[N:53])[CH:47]=3)=[CH:40][CH:39]=2)[CH2:33]1)=[O:31]
Reactant: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Reactant: N#Cc1cccc(CBr)c1
Reactant: COC(=O)C1CC(=O)N(c2ccc(OCc3cccc(C#N)c3)cc2)C1
Solvent: CCO
Product: CN
Product: CNC(=O)C1CC(=O)N(c2ccc(OCc3cccc(C#N)c3)cc2)C1

Procedure:
The title compound is prepared by alkylation of the (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester with 3-cyanobenzyl bromide giving the (RS)-1-[4-(3-cyano-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylester as a light yellow solid [69% of theory, MS: m/e=351 (M+H)+] which, thereupon, by treatment with methylamine in ethanol at 80° C. yields the (RS)-1-[4-(3-cyano-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide. Yield: 79% of theory as a white powder. MS: m/e=350 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.Cl[C:14]([O:16][CH2:17][Cl:18])=[O:15]>ClCCl>[C:14](=[O:15])([O:5][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])[O:16][CH2:17][Cl:18]
Reactant: CC(C)CCO
Reactant: O=C(Cl)OCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CCOC(=O)OCCl

Procedure:
3-Methyl-1-butanol (4.4 g) was dissolved in dichloromethane (75 ml) and pyridine (4.0 g) was added to it. The reaction mixture was cooled in an ice bath and chloromethyl chloroformate (6.5 g) was added to it with stirring. The cooling bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The dichloromethane solution was washed with water thrice and once with brine. The organic layer was dried over sodium sulfate and evaporated to furnish a colorless oil of desired product weighing 10.7 g which was the pure chloromethyl isopentyl carbonate. NMR (CDCl3) δ 0.95 (6H, d, J=5 Hz, CH(CH3)2), 1.66 (3H, m, CH2 and CH), 4.28 (2H, t, J=7 Hz, OCH2CH2) and 5.73 (2H, s, OCH2Cl). IR (film) 2950, 1783, 1265 cm-1.
Reaction SMILES: C[O:2][C:3]1[C:12]([O:13]C)=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][C:8]2=[O:15].COC1C(OC)=CC=CC=1C=O.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][C:8]2=[O:15]
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)CC2=O
Agent: BrB(Br)Br
Agent: COc1cccc(C=O)c1OC
Solvent: ClCCl
Product: O=C1CC(c2ccccc2)Cc2c1ccc(O)c2O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To a solution of 6.5 g (23 mmol) of 5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydro-1-naphthalenone (prepared from 2,3-dimethoxybenzaldehyde by the procedures described in Example 1) in 80 mL of anhydrous methylene chloride at -78° C., under nitrogen atmosphere, was added dropwise 100 mL (100 mmol) of a 1 M solution of boron tribromide in methylene chloride. The reaction mixture was stirred at -78° C. for 0.5 h and then at ambient temperature for 1 h. TLC analysis of the reaction mixture on silica gel plates eluted with 20% ethyl acetate in hexane indicated that the reaction was complete. The reaction mixture was cooled to -78° C. and 500 mL of methanol was added dropwise. The mixture was allowed to warm to ambient temperature and then was stirred for 1 h at ambient temperature and concentrated under reduced pressure. The residue was dissolved in methanol and the methanol was evaporated in vacuo. The residue was then purified on a silica gel column eluted with ethyl acetate:hexane (1:5 v/v) to give 5.57 g (95% yield) of the title compound.
Reaction SMILES: C([Li])CCC.[O:6]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7]1.[C:19](=[O:21])=[O:20]>C1COCC1.C(OCC)C.O>[C:14]([O:13][C:12]([NH:11][C:8]1[CH:9]=[CH:10][O:6][C:7]=1[C:19]([OH:21])=[O:20])=[O:18])([CH3:15])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)Nc1ccoc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccoc1C(=O)O
Temperature: -40 °C
Reaction time: 4 h

Procedure:
Butyl lithium (as 1.6 M in hexanes, 45 mL) was added slowly to a solution of tert-butyl 3-furylcarbamate (Intermediate 80) (5.49 g) in THF (60 mL) at −40° C., keeping the internal reaction temperature less than −35° C. The reaction was stirred at −40° C. for 4 hours, then poured onto solid CO2 (100 mL) under a blanket of diethyl ether (300 mL). After warming to ambient temperature, the mixture was poured into water (300 mL) with stirring and an additional 100 mL diethyl ether added. The phases were separated and the organic phase was further extracted into water (2×100 mL). The combined organic phases were washed with ether, acidified by addition of aqueous HCl, and extracted into EtOAc (4×250 mL). The combined extracts were dried and evaporated to give a pale yellow solid (7.5 g). This was triturated with cyclohexane to afford the title compound as a white solid (4.80 g, 70%);
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:54]([C:57]1[CH:61]=[CH:60][O:59][C:58]=1[CH3:62])=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:55]([NH:54][C:57]2[CH:61]=[CH:60][O:59][C:58]=2[CH3:62])=[O:56])[CH2:51][CH2:52]1
Reactant: Cc1occc1N=C=O
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1occc1NC(=O)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 8 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 3-isocyanato-2-methylfuran as the starting materials in 8% yield. LCMS for C30H33ClN7O3 (M+H)+: m/z=574.1.
Reaction SMILES: Br[C:2]1[C:3]([O:16][CH2:17][CH2:18][CH3:19])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[BH:20]([OH:22])[OH:21]>>[CH2:17]([O:16][C:3]1[CH:2]=[CH:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[C:4]=1[B:20]([OH:22])[OH:21])[CH2:18][CH3:19]
Reactant: OBO
Reactant: CCCOc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Product: CCCOc1ccc2c(c1B(O)O)C(C)(C)CCC2(C)C

Procedure:
In a similar manner to Example 3(a), by reaction of 8 g (24.6 mmol) of 3-bromo-2-propyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene, 5.7 g (80%) of the expected boronic acid are obtained, with a melting point of 138-9° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[O:3].[C:14]1([CH:24]=O)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.[OH-:26].[Na+]>C(O)C>[C:14]1([CH2:24][C:1](=[O:26])[CH:2]([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][CH:5]=2)[OH:3])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)c1cccc2ccccc12
Reactant: [OH-]
Reactant: O=Cc1cccc2ccccc12
Agent: [Na+]
Solvent: CCO
Product: O=C(Cc1cccc2ccccc12)C(O)c1cccc2ccccc12

Procedure:
1-Acetonaphtone is reacted with 1-naphtoaldehyde and sodium hydroxide in ethanol to produce 1,3-dinaphthyl-3-hydroxypropanone. The resulting compound is reacted with KHSO4 to obtain 1,3-dinaphthyl-3-propene-1-on. The resulting compound is reacted with hydrazine and potassium hydroxide in triethylene glycol to produce 1,3-dinaphthylpropane. 1,3-Dinaphthylpropane is reacted with fuming nitric acid and acetic acid anhydride to produce 1,3-dinitronaphthylpropane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[CH:26]1([C:29]2[CH:33]=[C:32]([NH:34][C:35](=O)[O:36]C3C=CC=CC=3)[O:31][N:30]=2)[CH2:28][CH2:27]1.COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(NC(NC2ON=C(C(C)C)C=2)=O)C=CC=1>>[CH:26]1([C:29]2[CH:33]=[C:32]([NH:34][C:35]([NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[C:19]([O:18][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)[CH:20]=3)=[O:36])[O:31][N:30]=2)[CH2:28][CH2:27]1
Reactant: O=C(Nc1cc(C2CC2)no1)Oc1ccccc1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C5CC5)no4)c3)c2cc1OC
Yield: 52.4 %

Procedure:
Prepared from 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (90 mg, 0.264 mmol) and phenyl 3-cyclopropylisoxazol-5-ylcarbamate from Example 124A (78 mg, 0.317 mmol) according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B to afford 1-(3-cyclopropylisoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea as a colorless solid (68 mg, 52%). 1H NMR (300 MHz, DMSO-d6) δ 10.21 (brs, 1H), 9.08 (brs, 1H), 8.55 (s, 1H), 7.56 (s, 2H), 7.38-7.44 (m, 2H), 7.29 (m, 1H), 6.99 (m, 1H), 5.77 (s, 1H), 4.35 (m, 2H), 3.99 (s, 3H), 3.78 (m, 2H), 3.30 (s, 3H), 1.90 (m, 1H), 0.94-0.98 (m, 2H), 0.71-0.73 (m, 2H); LC-MS (ESI) m/z 492 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:42][C:43]([CH3:45])=O.C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:23][CH2:24][N:25]([CH:43]([CH3:45])[CH3:42])[CH2:26][CH2:27]2)=[CH:20][CH:21]=1
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)cc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CC(C)N1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
(4Z)-6-iodo-4-{[(4-piperazin-1-ylphenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (23.7 mg, 0.05 mmol) is dissolved in N-methylpyrrolidinone (0.5 mL) and methylene chloride (0.15 mL), followed by addition of sodium triacetoxyborohydride (122 mg, 0.575 mmol), acetone (0.095 mL, 1.29 mmol) and acetic acid (0.075 mL, 1.31 mmol). After stirring at room temperature for 1 h, methylene chloride and saturated sodium bicarbonate solution were added. The organic layer is separated and dried to give 18.8 mg (73%) of the title compound as a yellow solid. MS (ESI) m/z 517.0 (M+H)+1
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[C:15](Cl)(=[O:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH:6]=[C:7]([C:15](=[O:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:8]=[CH:9]2
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: COc1cc2ccccc2cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCCCCCCCC(=O)c1ccc2cc(OC)c(OC)cc2c1

Procedure:
The solution of 2,3-dimethoxynaphthalene (1.9 g), palmitoyl chloride (3.2 ml) and aluminium chloride (1.5 g) in methylene chloride (40 ml) was stirred at ambient temperature overnight. The reaction mixture was worked up as described in example 4(a). The crude product was recrystallized from ethyl acetate-heptane. Yield 2.0 g.
Reaction SMILES: C1(=O)N([CH:6]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:22](=[O:23])[CH:21]=[CH:20][C:19]3=[O:24])=[CH:14][CH:13]=2)[C:7]([O-:9])=[O:8])C(=O)CC1.[CH3:27][OH:28]>C(N(CC)CC)C>[CH2:21]1[C:22](=[O:23])[N:18]([O:9][C:7]([CH2:6][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([N:18]3[C:19](=[O:24])[CH:20]=[CH:21][C:22]3=[O:23])=[CH:16][CH:17]=2)=[O:8])[C:27](=[O:28])[CH2:20]1
Reactant: O=C([O-])C(CCc1ccc(N2C(=O)C=CC2=O)cc1)N1C(=O)CCC1=O
Reactant: CO
Solvent: CCN(CC)CC
Product: O=C(CCCc1ccc(N2C(=O)C=CC2=O)cc1)ON1C(=O)CCC1=O

Procedure:
The following protocol is used to conjugate PE via an SMPB intermediate: 100 micromoles of phosphatidyl ethanolamine (PE) is dissolved in 5 mL of argon-purged, anhydrous methanol containing 100 micromoles of triethylamine (TEA). The solution is maintained over an argon or nitrogen atmosphere. The reaction may also be done in dry chloroform50 mg of succinimidyl-4-(p-maleimidophenyl)butyrate (SMPB, Pierce) is the added to the PE solution, and the solution is mixed well to dissolve. The solution is allowed to react for 2 hours at room temperature, while maintaining it under an argon or nitrogen atmosphere. Methanol is removed from the reaction solution by rotary evaporation and the solids are redissolved in 5 mLchloroform. The water-soluble reaction by-products are extracted from the chloroform with an equal volume of 1% NaCl. Extraction is repeated once more. The MPB-PE derivative is purified by chromatography on a column of silicic acid (Martin F J et al., Immunospecific targeting of liposomes to cells: A novel and efficient method for covalent attachment of Fab′ fragments via disulfide bonds. Biochemistry, 1981; 20:4229-38). Chloroform is removed from the MBP-PE by rotary evaporation. The derivative is stored at −20° C. under a nitrogen atmosphere until use.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:38]([O:55][CH2:56][CH2:57][N:58]1[CH2:63][CH2:62][N:61]([CH2:64][CH2:65][C@@H:66]([NH:75][C:76]2[CH:81]=[CH:80][C:79]([S:82]([NH2:85])(=[O:84])=[O:83])=[CH:78][C:77]=2[S:86]([C:89]([F:92])([F:91])[F:90])(=[O:88])=[O:87])[CH2:67][S:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH2:60][CH2:59]1)([C:51]([CH3:54])([CH3:53])[CH3:52])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:85][S:82]([C:79]3[CH:80]=[CH:81][C:76]([NH:75][C@H:66]([CH2:65][CH2:64][N:61]4[CH2:62][CH2:63][N:58]([CH2:57][CH2:56][O:55][Si:38]([C:51]([CH3:52])([CH3:53])[CH3:54])([C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=5)[C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH2:59][CH2:60]4)[CH2:67][S:68][C:69]4[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=4)=[C:77]([S:86]([C:89]([F:90])([F:92])[F:91])(=[O:87])=[O:88])[CH:78]=3)(=[O:83])=[O:84])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](OCCN1CCN(CC[C@H](CSc2ccccc2)Nc2ccc(S(N)(=O)=O)cc2S(=O)(=O)C(F)(F)F)CC1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCN(CCO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.6 %

Procedure:
(R)-4-(4-((tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 56.5 mg, 0.11 mmol), (R)-4-(4-(4-(2-(tert-butyldiphenylsilyloxy)ethyl)piperazin-1-yl)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 22, 80 mg, 0.1 mmol), DMAP (35.1 mg, 0.29 mmol), and EDC (36.7 mg, 0.19 mmol) were placed in a 50 ml flask and flushed with nitrogen. DCM (0.96 ml) was added, and the solution was stirred at room temperature overnight. The reaction mixture was diluted with DCM (40 ml) and washed with 1N sodium bisulfate (35 ml) followed by a saturated aq. sodium bicarbonate (40 ml). The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure to give the title product (147 mg, yield: quantitative), that was used in the preparation of EXAMPLE 1 without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:44][Si:45]([C:48]#[CH:49])([CH3:47])[CH3:46]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([NH:16][CH:10]([C:4]2[CH:3]=[C:2]([C:49]#[C:48][Si:45]([CH3:47])([CH3:46])[CH3:44])[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:18][CH:19]=1)#[N:24]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(Br)cc(CO)c1
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(C#C[Si](C)(C)C)cc(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
403 mg of the ethyl (RS)-(3-bromo-5-hydroxymethyl-phenyl)-(4-cyano-phenylamino)-acetate described in Example 156.2 were suspended in 3.1 ml of triethylamine and 4 mg of triphenylphosphine were added. Argon was conducted through the reaction mixture for 30 min. Then, 7 mg of palladium(II) acetate and 0.22 ml of trimethylsilylacetylene were added and the mixture was heated for 26 hrs. to 80° C. Then, the mixture was left to cool to room temperature and the crude product was isolated by extraction and purified by column chromatography (n-hexane/ethyl acetate). There were obtained 398 mg of ethyl (RS)-(4-cyano-phenylamino)-(3-hydroxymethyl-5-trimethylsilanylethynyl-phenyl)-acetate as a brown oil; MS: 406 ([M]+).
Reaction SMILES: [Cl:1][C:2]1[C:7]2OCO[C:6]=2[CH:5]=[C:4]([C:11]2[C:15]([C:16]([F:19])([F:18])[F:17])=[N:14][N:13]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:12]=2[NH2:26])[CH:3]=1.CO[CH:29]1[CH2:33][CH2:32][CH:31](OC)O1>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[C:15]([C:16]([F:19])([F:18])[F:17])=[N:14][N:13]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:12]=2[N:26]2[CH:29]=[CH:33][CH:32]=[CH:31]2)[CH:5]=[C:6]([C:16]([F:19])([F:18])[F:17])[CH:7]=1
Reactant: COC1CCC(OC)O1
Reactant: Nc1c(-c2cc(Cl)c3c(c2)OCO3)c(C(F)(F)F)nn1-c1ncccn1
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(Cl)cc(-c2c(C(F)(F)F)nn(-c3ncccn3)c2-n2cccc2)c1
Yield: 114.5 %

Procedure:
A mixture of 4-(7-chloro-1,3-benzodioxol-5-yl)-2-pyrimidin-2-yl-5-(trifluoromethyl)pyrazol-3-amine (0.383 g, 1.00 mmol) and 2,5-dimethoxytetrahydrofuran (0.145 g, 1.10 mmol) in acetic acid was stirred under reflux for 1 hour. After cooling, the precipitate was filtered off and recrystallized from ethanol to give the title compound (0.262 g, 57%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:22]I.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][C:9](=[O:13])[N:10]2[CH3:22])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(-c3ccccc3)cc(=O)[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(-c3ccccc3)cc(=O)n(C)c2c1
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
A solution of 7-methoxy-4-phenyl-2-quinolinone from Example 1, Step 2 (1.62 g) in DMF (30 mL) was treated with NaH (60% in mineral oil; 310 mg). After stirring at 50° C. for 45 min., the mixture was cooled to r.t. and methyl iodide (0.6 mL) was added. After 30 min., H2O (100 mL) was added and the resulting solution extracted with EtOAc (3×). The organics were washed with H2O (2×), brine, dried (MgSO4) and the solvents evaporated. Flash chromatography of the residue (silica gel; CHCl3 /EtOAc (4:1)) provided the title compound as a foam.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)=[CH:13][CH:12]=[C:11]2[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[C:6]([CH3:32])[CH:5]=1)(=[O:3])[NH2:2].O.[OH-].[Li+]>C1COCC1.O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:17][CH:16]=3)=[CH:13][CH:12]=[C:11]2[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[C:6]([CH3:32])[CH:5]=1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(C(N)=O)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(N)=O)ccc1-n1c(CCC(=O)O)ccc1-c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of ethyl 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-2-yl)propanoate (28C) (100 mg, 0.22 mmol) in THF/H2O (v/v=1/1, 1 mL) was added lithium hydroxide monohydrate (18 mg, 0.44 mmol) and stirred overnight at room temperature. THF was evaporated in vacuum and the resulting aqueous solution was acidified with 10% hydrochloric acid to pH=4.0. The resulting precipitate was separated by centrifuge, rinsed with distilled water and purified by prep-HPLC to afford 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-2-yl)propanoic acid (28D) as a light green solid (30 mg, 32%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:7]=1)[CH2:8][Br:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)ccc1F
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Br)cc1CBr

Procedure:
To a solution of 5-bromo-2-fluorotoluene (15 g, 0.079 mole) in CCl4 (150 mL) was added NBS (14.2 g, 0.080 mole). The resulting reaction solution was heated under reflux with the starting material being completely consumed within 2 hr. CCl4 was removed under reduced pressure and the residue was diluted, dissolved in ether, washed with brine (3×), dried over MgSO4, and concentrated. Chromotography in hexane yielded 5-bromo-2-fluorobenzyl bromide. The product was immediately used for the reaction below.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)=[O:4].CC1N=C(N)C=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Br:36]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Br:36][CH2:12][C:8]1[N:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:13])[F:14])[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(NC(=O)C(F)(F)F)n1
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1cccc(N)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc(CBr)n1)C(F)(F)F

Procedure:
2,2,2-trifluoro-N-(6-methyl-pyridin-2-yl)-acetamide xxii can be prepared from 6-methyl-pyridin-2-ylamine and trifluoroacetic anhydride in DCM. Radical bromination of xxii with N-bromosuccinimide and benzoyl peroxide in refluxing carbon tetrachloride affords N-(6-bromomethyl-pyridin-2-yl)-2,2,2-trifluoro-acetamide xxiii.