Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][CH3:20])=[C:7]([CH:18]=1)[O:8][CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:17].[C-:21]#[N:22].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=1[CH2:9][O:8][C:7]1[CH:18]=[C:3]([CH2:2][C:21]#[N:22])[CH:4]=[CH:5][C:6]=1[O:19][CH3:20]
Reactant: [C-]#N
Reactant: COc1ccc(CBr)cc1OCc1c(C)cccc1C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CC#N)cc1OCc1c(C)cccc1C

Procedure:
The solution of 2-((5-(bromomethyl)-2-methoxyphenoxy)methyl)-1,3-dimethylbenzene (Step D, 3.28 g, 9.7 mmol) and NaCN (0.624 g, 12.7 mmol) in dry DMF (20 ml) was heated at 120° C. for 2.5 hours then cooled and diluted with EtOAc (50 ml). The organic layer was washed with water (30 ml), brine, dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 2:1) to give the title compound.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[C:12]([F:19])[CH:11]=1.CN([CH:23]=[O:24])C>C1COCC1>[Br:9][C:10]1[C:11]([CH:23]=[O:24])=[C:12]([F:19])[C:13]([CH2:16][CH2:17][CH3:18])=[CH:14][CH:15]=1
Reactant: CCCc1ccc(Br)cc1F
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCc1ccc(Br)c(C=O)c1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
Under a nitrogen atmosphere, LDA (50.7 mL, 56.25 mmol) was slowly added dropwise, at −70° C. or lower, to a THF (100 mL) solution of 4-bromo-2-fluoro-1-propylbenzene (50) (11.1 g, 51.13 mmol). The reaction mixture was agitated at −70° C. or lower for 1 hour, and then DMF (6.15 g, 76.70 mmol) was slowly added dropwise thereto. The reaction mixture was returned to room temperature, and then quenched with 100 mL of 1N hydrochloric acid aqueous solution, and extracted with 60 mL of toluene 3 times. Combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, dried over magnesium sulfate and a solvent was distilled off by evaporator. The residue was purified by silica gel column chromatography, and thus 6-bromo-2-fluoro-3-propylbenzaldehyde (51) (5.0 g, yield 36%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[CH:4][C:5](I)=[C:6]([O:8][CH3:9])[CH:7]=1.C([Mg]Cl)(C)C.CON(C)[C:20]([C:22]1[C:23]([NH2:31])=[N:24][C:25]([S:28][CH2:29][CH3:30])=[N:26][CH:27]=1)=[O:21]>O1CCCC1>[NH2:31][C:23]1[C:22]([C:20]([C:5]2[CH:4]=[C:3]([F:11])[C:2]([Cl:1])=[CH:7][C:6]=2[O:8][CH3:9])=[O:21])=[CH:27][N:26]=[C:25]([S:28][CH2:29][CH3:30])[N:24]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: COc1cc(Cl)c(F)cc1I
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCSc1ncc(C(=O)c2cc(F)c(Cl)cc2OC)c(N)n1

Procedure:
To a solution of 5-chloro-4-fluoro-2-iodoanisole (1.0 g, Example 375) was added isopropylmagnesium chloride (1.92 mL, 2M in tetrahydrofuran, Aldrich) and the reaction was stirred at −40 to −35° C. for 40 minutes before 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (170 mg, Example 1) in tetrahydrofuran (4 mL) was added. The resulting reaction was quenched with aqueous ammonium chloride. Work-up and purification as in Exam pie 47 gave (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(4-chloro-5-fluoro-2-methoxy-phenyl)-methanone. MS (M+H)+, 342.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:9](Cl)=[O:10])=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:32]=[C:31]([NH2:33])[CH:30]=[CH:29][C:20]=1[O:21][CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:18][C:19]1[CH:32]=[C:31]([NH:33][C:9](=[O:10])[C:8]#[C:7][C:4]2[CH:5]=[CH:6][C:1]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:2][CH:3]=2)[CH:30]=[CH:29][C:20]=1[O:21][CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26]
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Reactant: O=C(Cl)C#Cc1ccc(-c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCN(CC)CCOc1ccc(NC(=O)C#Cc2ccc(-c3ccccc3)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.48 g (2.0 mmol) of biphenyl-4-ylpropynoic acid chloride (for preparation method see Bioorg. Med. Chem. 1996, 4, 851) is dissolved in 15 mL of toluene and 0.58 g (2.4 mmol) of [2-(2-chloro-4-aminophenoxy)ethyl]diethylamine (educt IV.1) in 10 mL of toluene at ambient temperature is added dropwise. The mixture is stirred for 8 hours at ambient temperature, the solvent is eliminated, and the residue is taken up in ethyl acetate and washed with water. The organic phase is dried over sodium sulfate, the solvent is eliminated and the residue is purified through a silica gel column with dichloromethane/methanol/ammonia (9:1:0.01) as eluant. Yield: 0.28 g (31% of theory); m.p.: 105-108° C.; Rf value: 0.50 (silica gel, dichloromethane/methanol/ammonia=9:1:0.1); C27H27ClN2O2; EII mass spectrum: m/z=447/449 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[C:35]([O:37]C)[C:34]([Cl:39])=[C:33]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=3)[CH:32]=2)[O:11][C@@H:10]1[CH2:50][O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CN(C=O)C>[Cl:39][C:34]1[C:33]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=2)=[CH:32][C:31]([C@H:12]2[C@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:10]([CH2:50][O:51][CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[O:11]2)=[CH:36][C:35]=1[OH:37]
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cc(OC)c2Cl)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cc(O)c2Cl)cc1
Temperature: 90 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
A mixture of compound 76 (3.0 g, 3.82 mmol) in DMF (38 mL) was added NaSEt (1.1 g, 13.35 mmol) at 90° C. The mixture was stirred at 90° C. for 6 hours. To a mixture was added 1 N HCl (50 mL) and extracted EtOAc (200 mL). The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 77 (3.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[C:5]([C:7]1[CH:34]=[CH:33][C:10]2[N:11]([CH2:15][CH2:16][O:17][C:18]3[CH:32]=[CH:31][C:21]([O:22][C:23]([CH3:30])([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:19]=3)[C:12](=[O:14])[S:13][C:9]=2[CH:8]=1)=O.Cl.[CH3:39][O:40][NH2:41].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[N:41][O:40][CH3:39])[C:7]2[CH:34]=[CH:33][C:10]3[N:11]([CH2:15][CH2:16][O:17][C:18]4[CH:19]=[CH:20][C:21]([O:22][C:23]([CH3:29])([CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:31][CH:32]=4)[C:12](=[O:14])[S:13][C:9]=3[CH:8]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCn2c(=O)sc3cc(C(=O)c4cccc(Cl)c4)ccc32)cc1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCn2c(=O)sc3cc(C(=NOC)c4cccc(Cl)c4)ccc32)cc1
Temperature: 0 °C

Procedure:
A solution of the compound obtained in Step A (1.00 g) and O-methylhydroxylamine hydrochloride (309 mg) in 15 ml of pyridine is heated at reflux for 3 hours. The reaction mixture is hydrolysed using 100 ml of ice-cold water and acidified using 6N HCl. The precipitate obtained is filtered off, washed with water and then recrystallised from petroleum ether by cooling in a freezer to yield the title compound in the form of a white powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:13][C:12]([CH3:14])=[C:11]2[C:7]=1[CH2:8][C@H:9]1[C:15]([CH3:17])([CH3:16])[C@H:10]12)=[O:5])C.[Li+].[OH-]>CCO.O>[CH3:16][C:15]1([CH3:17])[C@@H:9]2[CH2:8][C:7]3[C:11]([C@H:10]12)=[C:12]([CH3:14])[S:13][C:6]=3[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Temperature: 70 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of crude (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (10.3 g, 41.2 mmol) in EtOH (200 mL) a solution of 2N aq. LiOH (300 mL) is added. The resulting mixture is stirred at 70° C. for 1 h, cooled to rt and diluted with water (250 mL). The aq. solution is extracted three times with DCM (125 mL) before it is acidified to pH 3 by adding citric acid. The acidified solution is extracted twice with DCM (2×250 mL), These second extracts are combined, dried over Na2SO4, filtered and evaporated to give (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (7.0 g) as a yellow solid. LC-MS: tR=0.95 min, [M+1]+=223.00. 1H NMR (CDCl3): δ 3.04-2.92 (m, 1H), 2.83 (d, J=19.3 Hz, 1 H), 2.39 (s, 3H), 1.91-1.87 (m, 2H), 1.13 (s, 3H), 0.73 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:18]([O:25][C:26](=[O:32])[C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:18]([O:25][C:26](=[O:32])[C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:14](=[O:16])[C@H:9]([C@H:10]([CH2:12][CH3:13])[CH3:11])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 93.1 %

Procedure:
N-t-butyloxycarbonyl-L-isoleucine 1/2 hydrate 36.05 g, 150 mmole), L-proline benzylester hydrochloride 36.26 g, 150 mmole) and HOBT (20.26 g, 150 mmole) were dissolved in methylene chloride (500 ml), and triethylamine 18 g, 150 mmole) and WSC hydrochloride (28.76 g, 150 mmole) were added thereto at -30° C. The mixture was stirred for 2 hours at less than 0° C. and then overnight at room temperature, and the solution was washed with 5% aqueous sodium bicarbonate (500 ml, twice), 5% aqueous citric acid (500 ml, twice) and water (508 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give N-t-butyloxycarbonyl-L-isoleucyl-L-proline benzylester(yield: 58.43 g, 93.1%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH2:17][C:16]([CH3:19])([CH3:18])[O:15][N:14]=1)(=[O:12])=[O:11].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>C1COCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH:9]([S:10]([C:13]1[CH2:17][C:16]([CH3:19])([CH3:18])[O:15][N:14]=1)(=[O:11])=[O:12])[CH2:25][C:24]1[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=1
Reactant: CC1(C)CC(S(=O)(=O)Cc2c(F)cccc2F)=NO1
Reactant: Fc1ccc(CBr)cc1
Solvent: C1CCOC1
Product: CC1(C)CC(S(=O)(=O)C(Cc2ccc(F)cc2)c2c(F)cccc2F)=NO1
Reaction time: 1 h
Yield: 98 %

Procedure:
Phosphazene base 1-ethyl-2,2,4,4,4-pentakis(dimethylamino)-2-lambda5-5,4-lambda5-5-catenadi(phosphazene) (P2-Et) (0.61 ml, 1.6 mmol) was added dropwise to a solution of 3-(2,6-difluoro-phenylmethanesulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole (0.3 g, 1.04 mmol) in THF (2 ml) at room temperature. After 10 minutes 4-fluorobenzyl bromide (0.16 ml, 1.3 mmol) was added dropwise at room temperature and the mixture was stirred for 1 hour. The reaction was quenched by addition of aqueous hydrochloric acid (2M). The mixture was diluted with ethyl acetate and the two phases were separated. The organic phase was washed several times with brine, dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product (Compound No. 1.05 of Table 27) as a white solid (405 mg, 98% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Mg].[CH3:10][C:11]1[O:16][C:15](=[O:17])[C:14]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:13]=2[N:12]=1.Cl>C(OCC)C.C1C=CC=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]([C:14]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:13]=2[NH:12][C:11](=[O:16])[CH3:10])=[O:17])=[CH:3][CH:4]=1
Reactant: Cc1ccc2nc(C)oc(=O)c2c1
Reactant: Fc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(=O)Nc1ccc(C)cc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A Grignard reagent prepared from 87.5 g (0.5 mole) of p-bromofluorobenzene and excess magnesium in 800 ml of diethyl ether was slowly added to a solution of 2,6-dimethyl-3,1-benzoxazine-4-one in 300 ml of dry benzene and 200 ml of dry diethyl ether at 0° C. The mixture was allowed to warm to room temperature and stirring was continued for 2 hr. The reaction mixture was cooled to -15° C. and 500 ml of 3N hydrochloric acid was added. After about 10 min additional stirring, the organic layer was separated and washed with dilute sodium hydroxide solution. The organic layer was concentrated and the residue was dissolved in a mixture of 600 ml of 95% ethanol and 300 ml of 6N hydrochloric acid. The precipitate (crude titled product) in the amount of 123 g (ca 91%) was recrystallized from cyclohexane to give tan crystals, m.p. 140°-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:20]([C:22]1[NH:23][C:24]([CH:32]([CH3:34])[CH3:33])=[CH:25][C:26]=1[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:20][C:22]4[NH:23][C:24]([CH:32]([CH3:34])[CH3:33])=[CH:25][C:26]=4[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)c1cc(CCC(=O)O)c(C=O)[nH]1
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)c1cc(CCC(=O)O)c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.7 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3-(2-formyl-5-isopropyl-1H-pyrrol-3-yl)-propionic acid (54.4 mg, 0.26 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 2 days. The precipitate was collected by vacuum filtration, washed with water, 1N HCl, water and finally ethanol, dried in vacuum oven to give 83 mg (71%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 13.44 (br s, 1H, NH), 12.15 (br s, 1H, COOH), 11.69 (br s, 1H, NH), 9.02 (br s, 1H), 8.29 (s, 1H), 7.77 (dd, J=2.5 & 6.4 Hz, 1H), 7.47 (s, 1H), 7.43 (m, 1H), 7.33 (t, J=8.9 Hz, 1H), 6.14 (d, J=2 Hz, 1H), 3.01 (m, 1H, CH(CH3)2), 2.83 (t, J=7.2 Hz, 2H, CH2), 2.48 (m, 2H, CH2), 1.21.27 (d, J=6.8 Hz, 6H, CH(CH3)2). MS 469 [M++1].
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[CH:9]=O)([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][C:19](=[O:25])[NH:20]2>>[CH:1]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[CH:9]=[C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[CH:24][C:16]=2[CH3:15])[NH:20][C:19]1=[O:25])([CH3:3])[CH3:2]
Reactant: COc1cc(C)c(C=O)cc1C(C)C
Reactant: Cc1cccc2c1CC(=O)N2
Product: COc1cc(C)c(C=C2C(=O)Nc3cccc(C)c32)cc1C(C)C

Procedure:
5-Isopropyl-4-methoxy-2-methylbenzaldehyde was condensed with 4-methyl-2-oxindole to give 0.3 g of 3-(5-isopropyl-4-methoxy-2-methylbenzylidene)-4-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([O:22][CH3:23])[C:16]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([O:22][CH3:23])[C:16]=1[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6]
Reactant: COc1ccc(F)c(F)c1B(O)O
Reactant: CON(C)C(=O)c1ccnc(Br)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(F)c(F)c1-c1cc(C(=O)N(C)OC)ccn1
Temperature: 90 °C
Yield: 22.8 %

Procedure:
A flask containing 2-bromo-N-methoxy-N-methyl-isonicotinamide (Example 25, using method 2) (3.0 g, 12.2 mmol) 2,3-difluoro-6-methoxyphenylboronic acid (4.6 g, 24.4 mmol)) and 2M aqueous K3PO4 (15 mL, 30.6 mmol) in 1,4-dioxane (40 mL) was successively evacuated and flushed with nitrogen. Pd(PtBu3)2 (268 mg, 0.48 mmol) was then added and the mixture heated at 90° C. for 2 hours. The mixture was cooled, concentrated in vacuo and then partitioned between EtOAc and sat. aqueous NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by SiO2 chromatography (eluting with 30-100% EtOAc/hexane) gave the title compound (0.856 g, 23%). MS(ESI) m/z 309 (M+H)+
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N+:10]([O-])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([C:18]#[N:19])(C)C.C(Cl)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:18]#[N:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [O-][n+]1ccc(-c2ccccc2)cc1
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: N#Cc1cc(-c2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-phenylpyridine N-oxide (5 g) in DCM (50 mL) was added at RT trimethylsilylcyanide (11 mL), followed by acetyl chloride (3.1 mL) over 10 min. The reaction mixture was stirred overnight at RT. A solution of aq. 10% Na2CO3 was added and the mixture was extracted with EA. The combined org. phases were washed with brine, dried (Na2SO4) and evaporated off. Filtration over a plug of silica gel (Hept/EA 1/1) gave the desired compound (450 mg).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)(=O)=O.[C-:35]#[N:36].[Na+]>CS(C)=O>[CH3:33][Si:31]([CH3:34])([CH3:32])[CH2:30][CH2:29][O:28][CH2:27][N:24]1[C:20]2[N:21]=[CH:22][N:23]=[C:18]([C:16]3[CH:15]=[N:14][N:13]([C@@H:10]4[CH2:11][CH2:12][C@H:7]([CH2:6][C:35]#[N:36])[CH2:8][CH2:9]4)[CH:17]=3)[C:19]=2[CH:26]=[CH:25]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](COS(C)(=O)=O)CC4)c3)ncnc21
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](CC#N)CC4)c3)ncnc21
Temperature: 60 °C
Reaction time: 24 h

Procedure:
cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl methanesulfonate (0.10 g, 0.00020 mol) and sodium cyanide (0.050 g, 0.0010 mol) and DMSO (1.0 mL) were mixed. The mixture was stirred at 60° C. for 24 hours, at which time LCMS analysis showed most of the starting material had been consumed. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using EtOAc as eluent to give the product. LC/MS (M+H)+: 437, 1H NMR (CDCl3): □δ 8.90 (s, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 7.45 (d, 1H), 6.87 (d, 1H), 5.73 (S, 2H), 4.43 (m, 1H), 3.60 (m, 2H), 2.45 (d, 2H, J=7.6 Hz), 2.37 (m, 2H), 2.10 (m, 4H), 1.70-1.93 (m, 3H), 0.98 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:32])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:29][CH3:30])[C:25]([O:27]C)=[O:26])[C:5]1=[O:31])[CH:2]=[CH2:3].[OH-].[Na+]>C1COCC1.O>[CH2:1]([C@@:4]1([CH3:32])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([CH:24]([CH2:29][CH3:30])[C:25]([OH:27])=[O:26])[C:5]1=[O:31])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OC)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)C(=O)O)C1=O
Temperature: 25 °C

Procedure:
To a stirred solution of methyl 2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate (200 mg, 0.42 mmol; Example 91, Step A) in THF (5 mL) was added sodium hydroxide (506 mg, 12.65 mmol) in water (5 mL) and the reaction was heated at reflux for about 12 h. After this time the reaction was cooled to rt and partitioned between EtOAc (80 mL) and 1.0 M HCl (20 mL). The separated aqueous layer was extracted with EtOAc (30 mL) and the combined organic layers were dried over MgSO4, filtered and the filtrate was evaporated in vacuo to give the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:27])[CH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])=[CH:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.Cl>C(O)C.[Fe]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:27])[CH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:17]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc([N+](=O)[O-])c(OC)c2)cc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc(N)c(OC)c2)cc1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
To a solution of methyl 4-(3′-methoxy-4′-nitro-1,1′-biphenyl-4-yl)-2,2-dimethyl -4-oxobutanoate (670 mg, 1.80 mmol) in 85% aqueous ethanol (27 mL) was added iron powder (1.01 g, 18.04 mmol) and 2 N aqueous HCl (0.9 mL, 1.8 mmol), and the resulting suspension was heated at reflux for 2.5 h. The mixture was then cooled to rt, and filtered through a pad of Celite®. Water was added, the mixture was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure and the residue was triturated with ethyl acetate/hexane to afford methyl 4-(4′-amino-3′-methoxy-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate (410 mg, 67%). LC-MS ret. time 2.58 min, m/z 342.1 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.31 (s, 6H), 3.28 (s, 2H), 3.66 (s, 3H), 3.90 (s, 3H), 6.75 (d, 1H), 7.02–7.09 (m, 2H), 7.59 (d, 2H), 7.94 (d, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:15][CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C>[Si:18]([O:17][CH2:16][CH2:15][N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCN1CCc2ccc([N+](=O)[O-])cc2C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
7-Nitro-tetrahydroisoquinoline (5.0 g; 28.0 mmol) was dissolved in DMF (150 ml). This solution was treated with (2-bromoethoxy)-tert-butyl-dimethylsilane (12.0 ml; 56.0 mmol), and stirred at 80° C. overnight. The mixture was cooled to room temperature and the solvent removed in vacuo. Purification by column chromatography through SiO2, eluting with 50% diethyl ether/petroleum ether gave the title compound (4.2 g, 44%).