Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[NH:22][C:21](=[O:24])[CH2:20][CH2:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25]C(C)([O-])C.[K+].CI>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]([CH3:25])[C:21](=[O:24])[CH2:20][CH2:19]3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2NC(=O)CC3)CC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)CCc2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Reaction time: 0.25 h

Procedure:
A second intermediate compound, 1-Methyl-8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one hydrochloride, was produced as follows: To a solution of 4-(2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.5 g, 7.54 mmol) in THF (45 mL) cooled to −50° C. was added a solution of potassium t-butoxide, 1M in THF (8.3 mL, 8.30 mmol). After stirring for 15 minutes, methyl iodide (0.47 mL, 7.54 mmol) was added followed by stirring for 16 hours at 25° C. The mixture was evaporated and the residue was taken up into dichloromethane. The solution was washed consecutively with 1N citric acid, saturated sodium bicarbonate and brine. The organic phase was dried over sodium sulfate, filtered and evaporated to give a white foam, which was purified by chromatography on silica gel eluting with a gradient of dichloromethane and ethyl acetate. Evaporation of the appropriate fractions gave 4-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH2:13][F:14])[C:6](=[O:15])[CH2:5]2.[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][C@H:24]1[CH2:26][O:25]1)([CH3:19])([CH3:18])[CH3:17].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C.C(OCC)(=O)C>[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][C@H:24]([OH:25])[CH2:26][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH2:13][F:14])[C:6](=[O:15])[CH2:5]2)([CH3:18])([CH3:17])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CO1
Reactant: Nc1cc(F)c2c(c1)CC(=O)N2CCF
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC[C@H](O)CNc1cc(F)c2c(c1)CC(=O)N2CCF

Procedure:
5-Amino-7-fluoro-1-(2-fluoro-ethyl)-1,3-dihydro-indol-2-one (0.39 g, 1.84 mmol), (S)-oxiranylmethyl-carbamic acid tert-butyl ester (0.319 g, 1.84 mmol) and lithium trifluoromethanesulfonate (0.283 g, 1.84 mmol) in acetonitrile (4 ml) are heated at 90° C. for 6 hours. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated. Final purification by flash chromatography (70% Ethyl acetate/hexane) gives the title compound as a yellow-brown foamy solid. HPLC r.t. 3.92 min; MS for C18H25F2N3O4 m/z 386.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:14][C:15]([F:68])([F:67])[C:16]1[CH:17]=[C:18]([CH:60]=[C:61]([C:63]([F:66])([F:65])[F:64])[CH:62]=1)[C:19]([N:21]1[CH2:25][C@@:24]([CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][C:38]3([C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42][C@@H:41]3[O:49][CH2:50][C:51]([N:53]([CH3:59])[CH2:54][CH2:55][CH2:56][NH:57][CH3:58])=[O:52])[CH2:37][CH2:36]2)([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[O:23][CH2:22]1)=[O:20]>>[F:66][C:63]([F:64])([F:65])[C:61]1[CH:60]=[C:18]([CH:17]=[C:16]([C:15]([F:14])([F:68])[F:67])[CH:62]=1)[C:19]([N:21]1[CH2:25][C@@:24]([CH2:33][CH2:34][N:35]2[CH2:36][CH2:37][C:38]3([C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42][C@@H:41]3[O:49][CH2:50][C:51]([N:53]([CH3:59])[CH2:54][CH2:55][CH2:56][N:57]([CH3:58])[C:11](=[O:13])[CH2:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)=[O:52])[CH2:39][CH2:40]2)([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[O:23][CH2:22]1)=[O:20]
Reactant: CNCCCN(C)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Product: CN(CCCN(C)C(=O)Cc1ccc([N+](=O)[O-])cc1)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Yield: 94.2 %

Procedure:
(4-Nitrophenyl)acetic acid (52 mg, 0.287 mmol) and the compound (186 mg, 0.239 mmol) obtained in Example 1k were used to give the title compound (212 mg; yield, 94%) as a colorless oily substance according to the method described in Example 41a.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:22])([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16](Cl)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:29](B(CC)CC)[CH3:30].C1COCC1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:22])([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([CH2:29][CH3:30])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCB(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2nc(Cl)ccc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCc1ccc(Cl)c(C2(O)CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 150 °C

Procedure:
Tetrakis-triphenylphosphine (0.083 g, 0.072 mmol) was added to a solution of 3,6-dichloro-4′-hydroxy-3′,4′,5′,6′-tetrahydro-2′H[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.25 g, 0.72 mmol) and potassium carbonate (0.2 g, 1.44 mmol) in DMF (4 mL). Triethylborane in THF (1 M, 0.79 mL, 0.79 mmol) was added via syringe under a nitrogen atmosphere and the reaction heated by microwave at 150° C. for 20 minutes. The reaction mixture was then cooled, filtered through celite and partitioned between DCM and water. The organics were separated, washed with 15% lithium chloride, dried over sodium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 5-10% ethyl acetate/cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.086 g). LCMS m/z 241.3 [M+H]+. R.T.=5.20 min (Analytical Method 3).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([O:15][CH3:16])([O:13][CH3:14])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH3:14][O:13][C:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:21]3[CH:22]=[CH:23][C:18]([F:17])=[C:19]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:20]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([O:15][CH3:16])[CH3:12]
Reactant: COC(C)(OC)c1ccn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-c2cccnc2)c1
Product: COC(C)(OC)c1ccn2c(-c3ccc(F)c(-c4cccnc4)c3)cnc2n1

Procedure:
3-Bromo-7-(1,1-dimethoxyethyl)imidazo[1,2-α]pyrimidine was coupled with 4-fluoro-3-(pyridin-3-yl)benzeneboronic acid as described in Example 65 to give 7-(1,1-dimethoxyethyl)-3-[4-fluoro-3-(pyridin-3-yl)phenyl]imidazo[1,2-α]pyrimidine as an orange foam. This was dissolved in 2.5N hydrochloric acid and stirred at 50° C. for 15 h. After cooling to ambient temperature the reaction was neutralised by addition of solid sodium hydrogencarbonate and the resulting solid collected by filtration. The solid was dissolved in dichloromethane/methanol (1:1) and pre-adsorbed onto silica. Flash column chromatography on silica gel eluting with dichloromethane containing 1% ammonia and 5% methanol furnished 1-[3-(4-fluoro-3-(pyridin-3-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]ethanone as a yellow solid: δH (360 MHz, d6-DMSO) 2.71 (3H, s), 7.54-7.63 (3H, m), 7.84-7.88 (1H, m), 8.01 (1H, dd, J 8 and 2), 8.10-8.13 (1H, m), 8.34 (1H, s), 8.66 (1H, dd, J 5 and 2), 8.90 (1H, s), 9.24 (1H, d, J 7).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C@@H:14]3[CH2:18][NH:17][CH2:16][C@:15]3([CH2:20][OH:21])[CH3:19])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH2:31]([O:38][CH2:39][C:40](Cl)=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Li+].[OH-]>O>[CH2:31]([O:38][CH2:39][C:40]([N:17]1[CH2:18][C@@H:14]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:6]([O:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH:7]=2)[C@@:15]([CH2:20][OH:21])([CH3:19])[CH2:16]1)=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccc([C@@H]2CNC[C@@]2(C)CO)cc1OCC1CC1
Reactant: O=C(Cl)COCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([C@@H]2CN(C(=O)COCc3ccccc3)C[C@@]2(C)CO)cc1OCC1CC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]methanol (100 mg, 0.34 mmol) was dissolved in CH2C2 (1.7 mL), and the solution was cooled to 0° C. DIEA (144 μL, 0.82 mmol) was added, followed by benzyloxyacetyl chloride (114 μL, 0.72 mmol). The reaction was allowed to warm to room temperature slowly and stirred for 18 hours. Water was added (0.25 mL) and the reaction was stirred for 1.5 hours. CH2C2 was added and the mixture was washed once with water, twice with 1N HCl, once with water, twice with 6% NaHCO3, then dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in THF (1 mL) and cooled to 0° C. A solution of LiOH in water (1.36M, 1 mL, 1.36 mmol) was added and the hydrolysis was allowed to proceed at 0° C. for 4 hours. The reaction mixture was quenched with saturated NH4Cl, and the THF was removed by concentration in vacuo. The residue was resuspended in CH2C2, and washed twice with 6%. NaHCO3, dried over Na2SO4 and concentrated in vacuo.
Reaction SMILES: C(OCC)C.Br[C:7]1[C:11](OC)([CH3:12])[CH2:10][CH2:9][C:8]=1[CH3:15].C([Li])CCC.[CH:21](=[C:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1)[CH2:22][CH2:23][CH3:24]>O>[C:25]1([CH:21]([C:7]2[C:11]([CH3:12])=[CH:10][CH2:9][C:8]=2[CH3:15])[CH2:22][CH2:23][CH3:24])[CH:26]=[CH:27][CH2:28][CH:29]=1
Reactant: CCCC=C1C=CC=C1
Reactant: COC1(C)CCC(C)=C1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CCCC(C1=CCC=C1)C1=C(C)CC=C1C
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
15 ml of diethylether was added to 2-bromo-3-methoxy-1,3-dimethyl-cyclopentene (2 g, 9.75 mmol), and the result was cooled to −30° C. Then, n-butyllithium (2.7 g, 9.75 mmol) was added and the reactant solution was incubated at an elevated temperature for 15 minutes and again cooled to −30° C. Then, 1 eq. (1.3 g) of the 5-butylidene-cyclopenta-1,3-diene prepared in (1-1) was added, and the result was incubated for 3 hours. Then, 15 ml of diethylether and 15 ml of water were added, and the resultant solution was washed with 30 ml of 1 N HCl for 3 minutes and neutralized with 30 ml of an aqueous saturated sodium bicarbonate solution. An organic layer was separated, dried over magnesium sulfate to remove water and then subjected to solvent removal in a rotary evaporator. The resultant residue was purified through silica-based column chromatography (hexane) to give 2-(1-cyclopenta-1,4-dienylbutyl)-1,3-dimethylcyclopenta-1,3-diene (yield: 65%).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[Br-].[Cl:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[CH2:23][CH2:24][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[CH:20][C:19]([O:44][CH3:45])=[CH:18][CH:17]=2.[C:46]([O:50][C:51](=[O:61])[NH:52][C@H:53]1[CH2:58][CH2:57][C@H:56]([CH:59]=O)[CH2:55][CH2:54]1)([CH3:49])([CH3:48])[CH3:47].C(OCC)(=O)C>O1CCCC1>[C:46]([O:50][C:51](=[O:61])[NH:52][C@H:53]1[CH2:54][CH2:55][C@H:56]([CH:59]=[CH:24][CH2:23][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:44][CH3:45])[CH:20]=3)[N:15]=[CH:14][C:13]=2[Cl:12])[CH2:57][CH2:58]1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Reactant: COc1ccc2ncc(Cl)c(CC[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2ncc(Cl)c(CC=C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2c1
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
Sodium hexamethyldisilazide (1.0 M in tetrahydrofuran, 3.27 mL, 3.27 mmol, 2.3 eq) is added dropwise at −78° C. to a stirred solution of [2-(3-chloro-6-methoxy-quinolin-4-yl)-ethyl]-triphenyl-phosphonium bromide (800 g, 1.42 mmol, 1.0 eq) in tetrahydrofuran (25 mL). The reaction mixture is then stirred for 45 minutes at −10° C. before lowering down the temperature to −78° C. followed by the addition of (trans-4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (420 mg, 1.85 mmol, 1.3 eq). The reaction mixture is then stirred at 0° C. for 1 hour, extracted with ethyl acetate (3×30 mL) and a saturated ammonium chloride aqueous solution (30 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 8:1, v/v) to afford {trans-4-[3-(3-chloro-6-methoxy-quinolin-4-yl)-propenyl]-cyclohexyl}-carbamic acid tert-butyl ester as an off-white solid (374 mg, 61% yield).
Reaction SMILES: S(=O)(=O)(O)O.Cl.[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14]N)=[CH:10][CH:9]=1.[CH3:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=O>O1CCOCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]2[NH:14][C:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][C:19]=3[C:10]=2[CH:9]=1
Reactant: NNc1ccc(F)cc1
Reactant: CN1CCCCC1=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CN1CCc2[nH]c3ccc(F)cc3c2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sulfuric acid is added to a solution of 4-fluorophenyl hydrazine hydrochloride (1 equiv.) in dioxane and stirred for 5 min. at RT. N-Methyl piperidone (0.76-1.4 equiv.) is added and the mixture is heated at 80° C. for 2 h. After completion, as monitored by TLC, the reaction mixture is concentrated under reduced pressure and basified to pH 10 using 10% aqueous KOH solution. The reaction mixture is extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator to provide the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11](Cl)(=[O:15])[C:12]([Cl:14])=[O:13]>CCOCC>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:11](=[O:15])[C:12]([Cl:14])=[O:13])=[CH:5][NH:6]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: Fc1cccc2[nH]ccc12
Solvent: CCOCC
Product: O=C(Cl)C(=O)c1c[nH]c2cccc(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
To a stirred solution of 4-fluoroindole (2.00 g, 14.8 mmol) in ether (15 mL), at 0° C. under Ar, was added oxalyl chloride (1.55 mL, 17.8 mmol) dropwise. The resulting suspension was stirred at room temperature for 1 h and then it was filtered and the filtercake was washed with ether. The resulting solid was dried in vacuo to give the title compound (2.60 g, 78%) as a yellow powder:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[H-].[Na+].[C:13]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C>O1CCCC1>[NH2:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([NH:1][C:21]([C:20]2[CH:24]=[CH:25][C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:18][CH:19]=2)=[O:22])[CH:7]=1
Reactant: CSc1nc(N)cc(N)n1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(N)cc(NC(=O)c2ccc(C(C)(C)C)cc2)n1
Temperature: 50 °C

Procedure:
To a solution of 4,6-diamino-2-methylmercaptopyrimidine (50 mg, 0.032 mmol) in anhydrous tetrahydrofuran was added sodium hydride, followed by the addition of 4-t-butylbenzoyl chloride (0.084 mL, 0.32 mmol) and N, N-diisopropylethylamine. The mixture was heated at 50° C. for 16 hours after which it was subjected to aqueous work up. The product was extracted with ethyl acetate and purified by HPLC to give N-(6-amino-2-methylthiopyrimidin-4-yl)[4-(tert-butyl)phenyl]carboxamide. M+1=317.3.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:4][C@H:3]1[NH:5]C(=O)OCC1C=CC=CC=1.C(N(CC)CC)C.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl.[Pd]>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:5][C@@H:3]2[CH2:4][C@H:2]2[CH3:1])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: C[C@@H]1C[C@H]1NC(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1C[C@H]1NS(=O)(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution of benzyl ((1R,2R)-2-methylcyclopropyl)carbamate (1.68 g, 8.2 mmol) in DCM (55 mL) was charged with 10 wt % Pd/C, then degassed and charged with hydrogen (50 PSI). The reaction was complete after 30 min and so was filtered over celite, rinsing with DCM (15 mL). The liquor was cooled to 0° C., and treated with triethylamine (3.43 mL, 24.6 mmol) and 4-bromobenzene-1-sulfonyl chloride (2.20 g, 8.61 mmol). The cold bath was removed and the reaction was stirred for 1 h. At completion, the reaction was washed with 0.5 M aq. HCl (2×20 mL) and brine (20 mL), dried over MgSO4 and concentrated to provide 4-bromo-N-((1R,2R)-2-methylcyclopropyl)benzenesulfonamide (2.06 g, 87% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.74-7.80 (m, 1H), 7.66-7.72 (m, 1H), 4.90 (br. s., 1H), 1.94 (dt, J=3.5, 1.8 Hz, 1H), 1.41 (t, J=7.3 Hz, 1H), 0.89-1.01 (m, 3H), 0.70-0.81 (m, 1H), 0.35-0.45 (m, 1H).
Reaction SMILES: [C:1](OCC)(=[O:3])C.Cl.F[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][CH:17]=[C:18]([CH2:20][O:21][C@@H:22]3[CH2:27][CH2:26][CH2:25][C@H:24]([O:28][CH2:29][C:30]4[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:31]=4[C:32]([OH:34])=[O:33])[CH2:23]3)[N:19]=2)=[CH:11][CH:10]=1>C[O-].[Na+].CO>[CH3:1][O:3][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][CH:17]=[C:18]([CH2:20][O:21][C@@H:22]3[CH2:27][CH2:26][CH2:25][C@H:24]([O:28][CH2:29][C:30]4[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:31]=4[C:32]([OH:34])=[O:33])[CH2:23]3)[N:19]=2)=[CH:11][CH:10]=1
Reactant: CCOC(C)=O
Reactant: Cc1cccc(CO[C@H]2CCC[C@@H](OCc3coc(-c4ccc(F)cc4)n3)C2)c1C(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2nc(CO[C@@H]3CCC[C@H](OCc4cccc(C)c4C(=O)O)C3)co2)cc1

Procedure:
170 mg (0.39 mmol)of6b were heated in 4 ml of 5.6 M NaOMe/MeOH solution at an oil bath temperature of 120° C. for 20 hours. Ethyl acetate and 2 N HCl were added, and the mixture was then worked up analogously to the synthesis of 6b. This gave 7b as a colorless amorphous solid. TLC: (methylene chloride/-methanol/conc. ammonia, 30/5/1). Rf˜0.3. C26H29NO6 (451.52) MS(ESI): 452 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6](I)[CH:5]=1.O=[C:14]([CH3:18])[C:15]([OH:17])=[O:16].N12CCN(CC1)CC2>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][C:14]([C:15]([OH:17])=[O:16])=[CH:18]2)=[O:12]
Reactant: CC(=O)C(=O)O
Reactant: COC(=O)c1ccc(N)c(I)c1
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2[nH]c(C(=O)O)cc2c1

Procedure:
A solution of 25 g 4-Amino-3-Iodo-benzoic acid methyl ester, 19 ml 2-Oxo-propionic acid, 30.4 g 1,4-Diaza-bicyclo[2.2.2]octane and 1 g Pd(OAc)2 in 200 ml DMF was heated under argon to 100° C. After 5 h the reaction mixture was concentrated under reduced pressure and the residue was partitioned between 300 ml ethyl acetate and 200 ml 1 M hydrochloric acid. The organic layer was dried over MgSO4 and the solvent removed under reduced pressure to yield a yellow solid (6.4 g). From the aqueous layer additional product slowly precipitated as a white solid (7.9 g) which was collected by filtration. Both fractions were combined, dried in vacuo and used in the next reaction without further purification. Yield: 14.3 g. MS (ES+): m/e=220.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]([CH3:23])([CH3:22])[C:19](O)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]([CH3:23])([CH3:22])[CH2:19][OH:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(CO)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.4 %

Procedure:
To a solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid (2.0 mg, 5.15 mmol) in anhydrous THF (20 mL) was added 1.0M lithium aluminum hydride in diethyl ether (10.0 mL, 10.0 mmol) portionwise at RT under nitrogen. After stirring at RT for 24 hr, the mixture was carefully quenched with MeOH, poured into a 1N sodium hydroxide solution (100 mL), extracted with ethyl acetate (2×100 mL), dried (Na2SO4) and concentrated to give 1.3 g (67% yield) of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropan-1-ol, the NMR spectrum of which was consistent with the desired structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1.Br[CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29].N>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][N:23]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1
Reactant: Clc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(Cl)c1
Reactant: CC(C)=CCBr
Agent: N
Product: CC(C)=CCN1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (26 mg, 76%) from (7aS,11aR)-2-(2,4-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.083 mmol) and 4-bromo-2-methyl-2-butene (25 mg, 0.16 mmol). 1H NMR (CDCl3, 300 MHz) δ 1.68 (s, 3H), 1.81 (s, 3H), 2.12–2.23 (m, 3H), 2.26–2.42 (m, 1H), 2.55–2.70 (m, 2H), 2.78 (t, J=6.6 Hz, 2H), 3.10–3.45 (m, 6H), 3.63–3.77 (m, 2H), 5.42–5.55 (br, 1H), 6.99 (s, 1H), 7.03 (s, 1H), 7.24–7.217.29 (m, 2H), 7.47 (d, J=1.8 Hz, 1H) ppm. MS (CI, NH3): 427.1 (base, M+H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([C:14]([O:16]CC)=[O:15])=[CH:8][C:4]=2[CH:5]=[N:6][N:7]=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1B(O)O>O.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>[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[C:2]1[C:3]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([C:14]([OH:16])=[O:15])=[CH:8][C:4]=2[CH:5]=[N:6][N:7]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CCOC(=O)c1cc2cnnc(Cl)c2n(C)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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(=O)c(C(=O)O)cc2cnnc(-c3ccc(F)cc3F)c21
Temperature: 100 °C

Procedure:
To a suspension of ethyl 8-chloro-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylate (6) (1.40 g, 5.23 mmol) in 3:1 1,4-dioxane: 2 M aq Na2CO3 (16 mL) was added 2,4-difluorophenylboronic acid (1.03 g, 6.54 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.484 g, 0.418 mmol). The reaction mixture was heated in a microwave at 100° C. for 75 min, then more Na2CO3 solid (100 mg) was added and the reaction mixture was heated in the microwave at 100° C. for an additional 2 h. The mixture was diluted with water and washed with CH2Cl2. The aqueous layer was then acidified with 5 N HCl to pH ˜2 and extracted with CHCl3/iPrOH (4:1). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give 8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylic acid as a brown solid. MS (ESI, pos. ion) m/z: 318 (M+1).