Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:28][C:29]1[CH:30]=[C:31]([S:37](Cl)(=[O:39])=[O:38])[CH:32]=[C:33]([F:36])[C:34]=1[F:35]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:11][N:10]=[CH:9][N:8]=1)[S:37]([C:31]1[CH:30]=[C:29]([F:28])[C:34]([F:35])=[C:33]([F:36])[CH:32]=1)(=[O:39])=[O:38]
Reactant: O=S(=O)(Cl)c1cc(F)c(F)c(F)c1
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)c(F)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (2.8 g, 13 mmol) in tetrahydrofuran (50 mL) at −78° C. was added lithium bis(trimethylsilyl)amide (1 M solution in tetrahydrofuran, 15.6 mL, 15.6 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was then cooled to −78° C. and 3,4,5-trifluorobenzene-1-sulfonyl chloride (3.0 g, 13.0 mmol) was added. The mixture was stirred at −78° C. for 0.5 h, warmed to 0° C. and 4,5-trifluorobenzene-1-sulfonyl chloride (0.6 g, 2.6 mmol) was added. The mixture was allowed to warm to ambient temperature, stirred for 20 h, diluted with ethyl acetate (200 mL), washed with saturated aqueous ammonium chloride (200 mL) and brine (200 mL), dried over sodium sulphate, filtered and concentrated in vacuo. The residue was triturated with dichloromethane to afford N-(2,4-dimethoxybenzyl)-3,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a beige solid in 53% yield (3.1 g): 1H NMR (300 MHz, CDCl3) δ8.24-8.18 (m, 1H), 7.37-7.28 (m, 2H), 7.26-7.22 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 6.39-6.32 (m, 1H), 6.29-6.24 (m, 1H), 5.27 (s, 2H), 3.75 (s, 3H), 3.65 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].C(=O)([O-])[O-].[K+].[K+].[F-].[K+].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2/[C:32](=[CH:37]\[O:38][CH3:39])/[C:33]([O:35][CH3:36])=[O:34])[CH:20]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2/[C:32](=[CH:37]\[O:38][CH3:39])/[C:33]([O:35][CH3:36])=[O:34])[CH:20]=1)#[N:2]
Reactant: N#Cc1ccccc1O
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Cl)ncn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Oc2ccccc2C#N)ncn1
Temperature: 92.5 °C
Reaction time: 1 h

Procedure:
A mixture of 2-cyanophenol (41.0 g), potassium carbonate (62.1 g), potassium fluoride (12.3 g), tetrabutylammonium bromide (17.1 g), (E)-methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (98.9 g) and water (210 g) was heated at 90-95° C. for 22 hours. The reaction mixture was mixed with toluene and a further quantity of water. The organic layer was then separated. Toluene was removed from the organic phase by vacuum distillation (100° C., 20 mmHg). The melt was cooled to 85° C. after which methanol (120 ml) was added to help cooling to 70° C. The resulting mixture was cooled to 40° C. and kept at this temperature for 1 hour. It was then further cooled to 0-5° C. and held for another 1 hour period. The mixture was filtered to leave (E)-methyl 2-[2-(6-(2-cyanophenoxy)pyrimidin-4-yloxy)pheny]-3-methoxypropenoate as the residue (85.5% isolated yield).
Reaction SMILES: Br[C:2]1[C:3](=[O:16])[N:4]([CH3:15])[C:5]([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][C:26]=1[F:34])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[Li+]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:3](=[O:16])[N:4]([CH3:15])[C:5]([CH2:8][CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)=[N:6][CH:7]=2)=[CH:27][C:26]=1[F:34])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: Cn1c(CC2CCCCC2)ncc(Br)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: Cn1c(CC2CCCCC2)ncc(-c2ccc(OCc3ccccc3)c(F)c2)c1=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A suspension of 5-bromo-2-(cyclohexylmethyl)-3-methylpyrimidin-4(3H)-one (0.047 g, 0.165 mmol), 4-(benzyloxy)-3-fluorophenylboronic acid (0.049 g, 0.198 mmol), Pd(PPh3)4 (0.009 g, 0.008 mmol) and lithium chloride (0.028 g, 0.659 mmol) in dioxane (1 mL) and 2 M aqueous Na2CO3 (1 mL) was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature and then partitioned between EtOAc and H2O. The layers were separated and the aqueous layer was re-extracted with EtOAc (1×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography, eluting with 10:1 CH2Cl2/EtOAc. The product was obtained (0.048 g; 72%) as an off-white solid. LRMS (APCI pos) m/e 407 (M+1).
Reaction SMILES: C(OC([N:8]1[C:12]([C:13]2[C:14]([NH2:44])=[N:15][CH:16]=[N:17][C:18]=2[N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[N:26]([CH2:38][CH2:39][N:40]4[CH2:43][CH2:42][CH2:41]4)[CH:27]=[C:28]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[C:32]([CH3:37])[CH:31]=4)[N:29]=3)[CH2:21][CH2:20]2)=[CH:11][CH:10]=[N:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:40]1([CH2:39][CH2:38][N:26]2[CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([CH3:37])[CH:31]=3)[N:29]=[C:25]2[CH:22]2[CH2:21][CH2:20][N:19]([C:18]3[N:17]=[CH:16][N:15]=[C:14]([NH2:44])[C:13]=3[C:12]3[NH:8][N:9]=[CH:10][CH:11]=3)[CH2:24][CH2:23]2)[CH2:43][CH2:42][CH2:41]1
Reactant: Cc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4-c4ccnn4C(=O)OC(C)(C)C)CC3)n2)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4-c4ccn[nH]4)CC3)n2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(4-amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-yl)-pyrazole-1-carboxylic acid tert-butyl ester (1.00 eq.) in DCM (1 ml), was added trifluoro-acetic acid (0.5 ml). The reaction mixture was stirred at RT for 30 min. After removal of the solvent, the crude was purified by HPLC to yield the title compound. LC-MS (M+H=502, obsd=502).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]([C:13]([F:37])([F:36])[C@@:14]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])([C@@H:16]([CH:18]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[OH:19])[OH:17])[OH:15])=[O:12].[NH3:38]>C(O)C>[NH2:38][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]([C:13]([F:37])([F:36])[C@@:14]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])([C@@H:16]([CH:18]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[OH:19])[OH:17])[OH:15])=[O:12]
Reactant: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)n1cnc2c(Cl)ncnc21
Reactant: N
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)n1cnc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 0.5 g (0,936 mmol) of 1-(6-chloro-9H-purin-9-yl)-3,5-bis(t-butyldimethylsiloxy)-2-desoxy-2,2-difluororibose dissolved in 75 ml of absolute ethanol was saturated with anhydrous ammonia at about 0° C. The reaction flask was sealed, and the mixture was allowed to warm to room temperature. The mixture was stirred for about 72 hours at room temperature and the volatiles were evaporated under reduced pressure to provide 420 mg of 1-(6-amino-9H-purin-9-yl)-3,5-bis(t-butyldimethylsiloxy)-2-desoxy-2,2-difluororibose. Mass spec=458 [515-(t-butyl)]
Reaction SMILES: [C:1]([O:8]CC)(=[O:7])[C:2](OCC)=O.[O-]CC.[K+].[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1C)([O-:17])=[O:16]>CCOCC>[CH3:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([N+:15]([O-:17])=[O:16])[C:19]=1[CH2:2][C:1]([OH:8])=[O:7]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cccc([N+](=O)[O-])c1C
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Product: Cc1cccc([N+](=O)[O-])c1CC(=O)O
Yield: 45 %

Procedure:
Diethyl oxalate (30 mL) in 20 mL of dry ether was added with stirring to 19 g of potassium ethoxide suspended in 50 mL of dry ether. The mixture was cooled in an ice bath and 20 mL of 3-nitro-o-xylene in 20 mL of dry ether was slowly added. The thick dark red mixture was heated to reflux for 0.5 hr, concentrated to a dark red solid, and treated with 10% sodium hydroxide until almost all of the solid dissolved. The dark red mixture was treated with 30% hydrogen peroxide until the red color changed to yellow. The mixture was treated alternately with 10% sodium hydroxide and 30% hydrogen peroxide until the dark red color was no longer present. The solid was filtered off and the filtrate acidified with 6N hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with water, and dried under vacuum to give 9.8 g (45% yield) of 2-methyl-6-nitrophenylacetic acid as an off-white solid. The solid was hydrogenated in methanol over 10% palladium on carbon to give 9.04 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.B(O)(O)[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[N:11][CH:10]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[Br:15][C:12]1[N:11]=[CH:10][C:9]([NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)=[CH:14][CH:13]=1
Reactant: Cn1ccc(N)n1
Reactant: OB(O)c1ccc(Br)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1ccc(Nc2ccc(Br)nc2)n1
Reaction time: 8 h

Procedure:
To a solution of 1-methyl-1H-pyrazol-3-ylamine (0.23 g, 2.3 mmol, 1.0 equiv) and 2-bromopyridyl-5-boronic acid (0.70 g, 3.5 mmol, 1.5 equiv) in 10 Ml dichloromethane was added pyridine (0.43 Ml, 5.4 mmol, 2.4 equiv), copper (II) acetate (0.63 g, 3.5 mmol, 1.5 equiv) and 4 Å molecular sieves. The heterogeneous reaction mixture was allowed to stir vigorously open to air overnight. The reaction was then filtered through Celite, concentrated in vacuo, and purified by silica gel chromatography to afford the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.80 (s, 3H) 5.84 (s, 1H) 7.45 (d, J=8.59 Hz, 1H) 7.60 (d, J=2.02 Hz, 1H) 7.86 (dd, J=8.59, 3.03 Hz, 1H) 8.41 (d, J=2.78 Hz, 1H) 8.92 (s, 1H); (M+H)+255.1.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC(C)([O-])C.[K+].[F:18][C:19]1[CH:33]=[C:32]([N:34]2[CH2:37][C:36](=O)[CH2:35]2)[C:31]([F:39])=[CH:30][C:20]=1[C:21]([NH:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[O:22]>O1CCCC1>[C:1]([CH:3]=[C:36]1[CH2:37][N:34]([C:32]2[C:31]([F:39])=[CH:30][C:20]([C:21]([NH:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[O:22])=[C:19]([F:18])[CH:33]=2)[CH2:35]1)#[N:2]
Reactant: C[C@H](NC(=O)c1cc(F)c(N2CC(=O)C2)cc1F)C(F)(F)F
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1cc(F)c(N2CC(=CC#N)C2)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63.8 %

Procedure:
Diethyl cyanomethylphosphonate (1.95 mL, 11.8 mmol) was added drop-wise to a cooled (ice bath) solution of 1.0 M potassium tert-butoxide in THF (11.8 mL, 11.8 mmol) which was diluted with tetrahydrofuran (12 mL). The bath was removed and the reaction was warmed to room temperature, and stirred for 90 min. The reaction solution was cooled with an ice bath again. The above prepared solution was then added over 12 min to a cooled (ice-bath) solution of 2,5-difluoro-4-(3-oxoazetidin-1-yl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (4.00 g, 12.4 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred for 30 min. The ice bath was removed, and the reaction was stirred at room temperature overnight, then quenched by the addition of 20% brine (75 mL) and ethyl acetate (75 mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0% to 30%) to yield the desired product (2.6 g). 1H NMR (400 MHz, DMSO-d6) δ 8.59-8.37 (m, 1H), 7.33 (dd, J=12.5, 6.4 Hz, 1H), 6.59 (dd, J=12.0, 7.4 Hz, 1H), 5.88 (m, 1H), 4.94-4.75 (m, 4H), 4.76 (m, 1H), 1.31 (d, J=7.1 Hz, 3H) ppm. LCMS cacld. for C15H13F5N3O (M+1)+: m/z=346.1. Found: 346.1.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@H:4]([CH2:29][CH2:30][S:31][CH3:32])[NH:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][C:8]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27].[Li+].[OH-]>C1COCC1>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([OH:33])=[O:2])[CH2:29][CH2:30][S:31][CH3:32])=[O:28])=[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])[CH:9]=2)[CH:16]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CSCC[C@H](NC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
The [4-(3-pyridyloxymethyl)-2-(2-methylphenyl)benzoyl]methionine methyl ester prepared in Example 204F (72 mg, 0.15 mmol) was dissolved in 3 mL of THF and 1 mL of saturated aqueous LiOH was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction was thoroughly evaporated and formic acid was added until pH=3 was obtained at which time the reaction was evaporated to dryness and 10 mL of ethyl acetate was added followed by a minimum quantity of H2O (1 mL) to completely solubilize the free acid and the water soluble salts, respectively. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×5 mL). The ethyl acetate layers were combined, dried over Na2SO4, filtered and evaporated to give 58 mg (84%) of [4-(3-pyridyloxymethyl)-2-(2-methylphenyl)benzoyl]methionine as an amorphous solid. 1H NMR (300 mHz, CD3OD) δ 8.30 (d, 1H), 8.15 (dd, 1H), 7.68 (bd, 1H), 7.58-7.48 (m, 2H), 7.40-7.30 (m, 2H), 7.26-7.16 (m, 4H), 5.25 (s, 2H), 4.50-4.40 (m, 1H), 2.20-2.02 (m, 5H), 2.00 (s, 3H), 2.00-1.90 (m, 1H), 1.80-1.68 (m, 1H) CIMS MH+ 451.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7][S:8]([C:11]1[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[CH3:18][O:19][C:20]([C:22]1[C:30]2[O:29][C:28]([CH3:31])=[CH:27][C:26]=2[CH:25]=[C:24]([OH:32])[CH:23]=1)=[O:21]>CN(C=O)C>[CH3:18][O:19][C:20]([C:22]1[C:30]2[O:29][C:28]([CH3:31])=[CH:27][C:26]=2[CH:25]=[C:24]([O:32][C:14]2[CH:15]=[CH:16][C:11]([S:8]([CH3:7])(=[O:10])=[O:9])=[CH:12][CH:13]=2)[CH:23]=1)=[O:21]
Reactant: COC(=O)c1cc(O)cc2cc(C)oc12
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C)oc12
Temperature: 120 °C
Yield: 92 %

Procedure:
Cs2CO3 (2.36 g, 7.24 mmol) and 4-flurophenyl methyl sulfone (631 mg, 3.62 mmol) were added to a solution of 5-hydroxy-2-methyl-benzofuran-7-carboxylic acid methyl ester (4d) (746 mg, 3.62 mmol) in DMF (5 mL). The mixture was heated to 120° C. overnight and then cooled to RT. The mixture was then quenched with H2O (80 mL) and extracted with EtOAc 92×100 ml). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 4% CH3OH/CH2Cl2 to afford brown color oil (1.2 g, 92%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 2 H) 7.86-7.90 (m, 1 H) 7.58 (d, J=2.53 Hz, 1 H) 7.38 (d, J=2.53 Hz, 1 H) 7.05 (d, J=8.84 Hz, 1 H) 6.44 (s, 1H) 3.99 (s, 3 H) 3.05 (s, 3 H) 2.56 (s, 3 H); LCMS for C18H16O6S m/z 361.00 (M+H)+.
Reaction SMILES: C([O-])C.[Na+].Cl.[C:6]([NH2:9])(=[NH:8])[CH3:7].[CH2:10]([O:12][C:13](=[O:28])[C:14]([C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Br:26])=[CH:15]N(C)C)[CH3:11]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Br:26])=[N:8][C:6]([CH3:7])=[N:9][CH:15]=1)=[O:28])[CH3:11]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1Br
Reactant: CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(C)nc1-c1ccccc1Br
Yield: 84 %

Procedure:
To a fresh prepared solution of sodiumethanolate (prepared from 0.77 g (33.7 mmol) Na in 100 ml Ethanol) 3.18 g (33.7 mmol) acetamidinhydrochloride was added. After 10 Min. a solution of 10.0 g (30.6 mmol) 2-(2-bromo-benzoyl)-3-dimethylamino-acrylic acid ethyl ester in 120 ml ethanol was added and the reaction mixture heated for 16 hrs. at 80°. The solvent was evaporated, the residue distributed between 100 ml H2O and 100 ml CH2Cl2. The aqueous phase was extracted twice with 100 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtrated and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH 40:1) to give 8.3 g (84%) 4-(2-bromo-phenyl)-2-methyl-pyrimidine-5-carboxylic acid ethyl ester as a pale brown oil.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:42][CH:41]([C:43](O)=[O:44])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(N(CC)CC)C>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[CH2:31][CH2:30][N:29]([C:43]([CH:41]4[CH2:42][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:40]4)=[O:44])[CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(C(=O)N2CCC(c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)C2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
To a solution of (5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.244 mmol) in DMF (1.5 mL) was added 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (50.6 mg, 0.252 mmol), triethylamine (102 μl, 0.733 mmol), and (BOP) benzoltriazolyloxytris(dimethylamino)phosphomium-hexafluorophosphate (140 mg, 0.317 mmol). The reaction was stirred at rt overnight. The mixture was partitioned between ethyl acetate (25 mL) and H2O (25 mL). The layers were separated and the organic was washed with H2O (20 mL). The combined aqueous layers were extracted with ethyl acetate (20 mL). The combined organics were washed with water (5×20 mL) to remove DMF, dried (Na2SO4), and evaporated. The crude material was purified by trituration with ether to yield 50 mg (35%) of the desired product. 1H NMR (300 MHz, Methanol-d6) δ 8.36 (s, 1 H), 7.85-7.81 (m, 2 H), 7.65 (s, 1 H), 7.40-7.20 (m, 4 H), 7.23 (d, 1 H), 6.67 (d, 1 H), 5.85 (s, 2 H), 4.20-3.90 (m, 3 H), 3.80-3.40 (m, 2 H), 3.30-3.10 (m, 4 H), 2.60-2.10 (m, 2 H), 1.33 (d, 9H); ES-MS m/z 579.0 [M+H]+, HPLC RT (min) 2.46.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]3[CH2:20][CH2:19][CH:18]([OH:21])[C:14]=3[CH:15]=[N:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(N(CC)C(C)C)(C)C.[C:31](Cl)(=[O:34])[CH2:32][CH3:33].[OH-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]3[CH2:20][CH2:19][CH:18]([O:21][C:31](=[O:34])[CH2:32][CH3:33])[C:14]=3[CH:15]=[N:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: CCC(=O)Cl
Reactant: OC1CCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(=O)OC1CCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 11.2 %

Procedure:
A solution of (rac)-4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (example 82) (24 mg, 0.081 mmol) and N,N-diisopropylethylamine (0.028 mL, 0.162 mmol) in DMF (0.2 mL) was treated with propionyl chloride (0.021 mL, 0.243 mmol) and the reaction mixture stirred at room temperature. After 15 h, another aliquot of propionyl chloride (0.021 mL, 0.243 mmol) was added, the temperature increased to 50° C. and stirring continued for 2 h. The crude reaction mixture was poured into a 1 M solution of sodium hydroxide (10 mL) and extracted with ethyl acetate (2×15 mL). The combined organic extracts were washed with a sat. solution of sodium chloride (10 mL), dried (Na2SO4), and concentrated under reduced pressure. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 3.2 mg (11%) of the title compound as a light brown solid. MS: 354.5 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39](F)=[O:40])=[CH:35][CH:34]=2)=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.[NH2:42][C:43]([CH3:47])([CH3:46])[CH2:44][OH:45].CN1CCOCC1>O1CCCC1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39](=[O:40])[NH:42][C:43]([CH3:47])([CH3:46])[CH2:44][OH:45])=[CH:35][CH:34]=2)=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Br)ccc2Oc2ccc(C(=O)F)cc2)N1
Reactant: CC(C)(N)CO
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(CO)NC(=O)c1ccc(Oc2ccc(Br)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)cc1
Temperature: 100 °C
Yield: 41.5 %

Procedure:
To a solution of racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(4-fluorocarbonyl-phenoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.18 g, 0.28 mmol) in tetrahydrofuran (20 mL) was added 2-amino-2-methyl-propan-1-ol (0.2 g, 2.24 mmol), N-methylmorpholine (0.2 g, 2 mmol) and 4-dimethylaminopyridine (3 mg, 0.025 mmol). The reaction mixture was heated under nitrogen at 100° C. for 1 h, then cooled to room temperature. The mixture was diluted with ethyl acetate, washed with 1N HCl aqueous solution and H2O. The organic layer was separated, dried over Na2SO4 and concentrated. The residue was purified by chromatography (MeOH:EtOAc=1:19) to give racemic(2′R, 3R, 4′S)-2′-{5-Bromo-2-[4-(2-hydroxy-1,1-dimethyl-ethylcarbamoyl)-phenoxy]-phenyl}-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 84 mg, 42%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:25])[CH2:9][NH:10][C:11]2[S:15][N:14]=[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=3)[N:12]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:25])[CH2:9][NH:10][C:11]2[S:15][N:14]=[C:13]([CH2:16][C:17]3[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(Cc2nsc(NC[C@@H](C)c3ccc(F)cc3)n2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@H](CNc1nc(Cc2cccc(O)c2)ns1)c1ccc(F)cc1
Reaction time: 0.25 h
Yield: 31.8 %

Procedure:
To a solution of (S)—N-(2-(4-fluorophenyl)propyl)-3-(3-methoxybenzyl)-1,2,4-thiadiazol-5-amine (80.0 mg, 0.22 mmol, 1.0 equiv) in dry DCM (5 mL) was added BBr3 (2.0 mL, 21 mmol, 1.0 equiv) by syringe. After stirring for 15 min, the reaction mixture was quenched by the addition of MeOH and the resulting mixture was concentrated in vacuo. The residue was dissolved in EtOAc and washed with sat'd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel (25% EtOAc/Hexanes) provided the title compound (24 mg, 32%). m/z=344.2 [M+H]+.