Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[C:2]([C:5]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][NH+:14]([CH3:16])[CH3:15])[CH:8]=[CH:7][C:6]=1[Cl:17])([OH:4])=O.[NH2:18][C:19]1[CH:41]=[CH:40][C:22]2[CH2:23][CH2:24][C:25]3[C:26]([C:37]([NH2:39])=[O:38])=[N:27][N:28]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[C:29]=3[C:21]=2[CH:20]=1>>[Cl:17][C:6]1[C:5]([C:2]([NH:18][C:19]2[CH:41]=[CH:40][C:22]3[CH2:23][CH2:24][C:25]4[C:26]([C:37]([NH2:39])=[O:38])=[N:27][N:28]([C:30]5[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=5)[C:29]=4[C:21]=3[CH:20]=2)=[O:4])=[N:10][C:9]([S:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])=[CH:8][CH:7]=1
Reactant: C[NH+](C)CCSc1ccc(Cl)c(C(=O)O)n1
Reactant: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(N)cc1-2
Agent: [Cl-]
Product: CN(C)CCSc1ccc(Cl)c(C(=O)Nc2ccc3c(c2)-c2c(c(C(N)=O)nn2-c2ccc(F)cc2)CC3)n1

Procedure:
The title compound was synthesized from 0.355 g of the title compound of Step 1 and the title compound of Example 244 (0.32 g) by the same procedure used in Example 255. The title compound is a white solid (0.49 g, 87%). Its structure was confirmed by 1H NMR and LC/MS: 1H NMR (CD3CN): δ 2.18 (s, 6H), 2.57 (m, 2H), 2.85 (m, 4H), 3.00 (m, 4H), 3.26 (m, 2H), 5.88 (s, 1H), 6.94 (d, 1H), 7.27–7.38 (m, 5H), 7.47–7.62 (m, 3H), 7.69 (d, 1H, J=9 Hz), 9.40 (s, 1H). ESI mass spectrum for C28H27ClFN6O2S+: 565 (M+1).
Reaction SMILES: CN1CCCC1=O.Cl[C:9]1[N:10]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:11]2[C:16]([N:17]=1)=[C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:14]=[C:13]([C:24]1[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=1)[N:12]=2.[CH3:36][C@H:37]1[CH2:42][NH:41][CH2:40][CH2:39][NH:38]1>C(Cl)Cl.CO>[CH3:36][C@@H:37]1[NH:38][CH2:39][CH2:40][N:41]([C:9]2[N:10]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:11]3[C:16]([N:17]=2)=[C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:14]=[C:13]([C:24]2[CH:29]=[N:28][C:27]([NH2:30])=[N:26][CH:25]=2)[N:12]=3)[CH2:42]1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC(F)(F)F)c3n2)cn1
Reactant: C[C@H]1CNCCN1
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: ClCCl
Product: C[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Temperature: 100 °C
Reaction time: 5 h
Yield: 30.8 %

Procedure:
An N-methyl-2-pyrrolidone suspension (10 ml) of 5-[8-chloro-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (1.02 g, 2.46 mmol) and (2S)-2-methylpiperazine (1.23 g, 12.3 mmol) was heated at 120° C. to dissolve and then the resulting mixture was stirred at 100° C. for 5 hours. The resulting mixture was left standing to cool, poured into methylene chloride-methanol (10:1), and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting solid was washed with a small amount of methylene chloride and collected by filtration to give the title compound (362.9 mg). The filtrate was concentrated under reduced pressure and the resulting residue was purified by medium pressure silica gel column chromatography (methylene chloride:methanol=32:1 to 7:1) to give the title compound (623.8 mg). These lots were combined to give the title compound (986.7 mg, 84%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>C(#N)C>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([S:17]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[C:4](=[O:9])[N:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1nc(O)ncc1F
Solvent: CC#N
Product: Nc1nc(=O)n(S(=O)(=O)c2ccc(Cl)cc2)cc1F
Temperature: 70 °C
Reaction time: 24 h
Yield: 41 %

Procedure:
To 4-amino-5-fluoro-pyrimidin-2-ol* (1.0 g, 7.75 mmol) in acetonitrile (CH3CN; 40 mL) was added bis-N,O-trimethylsilylacetamide (BSA; 5.7 mL, 23.3 mmol) and the mixture was heated to 70° C. for 1 h resulting in a clear solution. After cooling to room temperature, 4-chlorobenzene sulfonyl chloride (1.8 g, 8.5 mmol) was added, and the mixture was stirred for 24 h. The solvent was evaporated and the residue was partitioned between EtOAc and brine. The organic phase was dried over MgSO4, filtered, and evaporated to yield the crude product as a white solid (1.3 g). Recrystallization from EtOAc and heptane furnished the title product as a white solid (0.96 g, 41%): mp 174-178° C.; 1H NMR (300 MHz, CDCl3) δ 8.5 (br s, 1H), 8.08 (d, J=5.9 Hz, 1H), 8.04-7.98 (m, 2H), 7.55-7.49 (m, 2H), 5.9 (br s, 1H); ESIMS m/z 304 ([M+H]+).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:7])[C:5]#[CH:6].Br[CH2:9][C:10]([O:12][CH3:13])=[O:11].[CH2:14]1COCC1>>[CH3:13][O:12][C:10](=[O:11])[CH2:9][O:7][C:4]([CH3:14])([CH3:3])[C:5]#[CH:6]
Reactant: C#CC(C)O
Reactant: C1CCOC1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: C#CC(C)(C)OCC(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mechanically stirred suspension of sodium hydride (60% dispersion in mineral oil, 10.0 g, 0.25 mol) in THF (170 mL) at 0° C. under N2 gas was treated with 2-methyl)-3-butyn-2-ol (29.1 mL, 0.30 mol) in THF (70 mL) dropwise. After stirring at 0° C. for 1 hour, the reaction mixture was treated with methyl bromoacetate (35.5 mL, 0.38 mol) in THF (100 mL). After stirring at ambient temperature overnight, the mixture was quenched into 1 M HCl (300 mL) and extracted with ethyl acetate (3×300 mL). The organic layers were combined, dried over Na2SO4, and concentrated to half the volume. The residue was distilled by vacuum distillation (bp. 118-120° C./20 mmHg) to provide the tittle compound (10.0 g). 1H NMR (CDCl3) δ 1.52 (s, 6H), 2.47 (s, 1H), 3.77 (s, 3H), 4.25 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[CH:3]=1.C(O[CH:11]=[C:12]([C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])C>C(O)(=O)C>[CH3:7][C:4]1[C:3]2[C:2](=[N:1][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[O:6][N:5]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(=O)OCC
Reactant: Cc1cc(N)on1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(C)noc2nc1C(=O)OCC
Temperature: 25 °C
Reaction time: 65 h
Yield: 40.8 %

Procedure:
5-Amino-3-methylisoxazole (12.25 g, 0.125 mol) and diethyl (ethoxymethylene)oxalacetate (33.55 g, 0.138 mol) are dissolved in 200 mL glacial acetic acid under an N2 atmosphere. The solution is heated to reflux for hours, then stirred at room temperature for 65 hours. The solution is poured into ice water, causing the precipitation of a red solid. The solid is collected by filtration, redissolved in 175 mL glacial acetic acid and reprecipitated with the addition of ice. The resulting yellow sol is collected by filtration and air dried, giving 14.20 g of product, yield 40.8%, having melting point 95°-99° C. A small amount is recrystallized from hexanes/ethyl acetate, melting point 100°-101° C.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[CH:5][C:3]=1[OH:4].C(O)(=O)C.C(C(C)=O)C.[CH2:21]=[CH:22][C:23](=[CH2:25])[CH3:24]>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH3:25][C:23]1([CH3:24])[CH2:22][CH2:21][C:5]2[C:3](=[C:2]([CH3:1])[C:8]([CH3:9])=[C:7]([OH:10])[C:6]=2[CH3:11])[O:4]1
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=CC(=C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Solvent: CCC(C)=O
Solvent: Cc1ccccc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C)O2
Temperature: 25 °C

Procedure:
In a 50 ml four-necked flask were charged 2,3,5-trimethylhydroquinone (5.0 g), zinc chloride (0.8 g), acetic acid (0.35 ml), methyl ethyl ketone (4 ml) and toluene (15 ml) and the mixture was heated. At 100° C., a solution of isoprene (2.5 g) in toluene (5 ml) was added dropwise under reflux over 2 hr. After the dropwise addition, the mixture was refluxed for 4 more hours and cooled to room temperature. The reaction mixture was transferred to a partition funnel, and, after washing 3 times with 50 ml of water, the solvent was evaporated to give 6.5 g of an oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=O.[C:12](#[N:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH2:15].C(=O)([O-])[O-:22].[K+].[K+].O>C(OCC)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]1[N:20]=[C:12]([OH:22])[C:13]2[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:15]=1
Reactant: N#Cc1ccccc1N
Reactant: COc1ccccc1C(=O)Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: COc1ccccc1-c1nc(O)c2ccccc2n1
Yield: 31 %

Procedure:
2-Methoxybenzoyl chloride (10.2 mL, 75.81 mmol) was added to a mixture of anthranilonitrile (7.46 g, 63.18 mmol) and potassium carbonate (43.76 g, 315.90 mmol) in diethyl ether (400 mL) at reflux. After 24 hours the solution was cooled and water (60 mL) was added. The resulting white solid was collected and washed with water (20 mL) and diethyl ether (50 mL). The solid was suspended in a mixture of 16% w/v aqueous sodium hydroxide (200 mL) and hydrogen peroxide (50 mL of a 30% v/v aqueous solution) and refluxed for 20 hours. The resulting pale yellow solution was cooled and acidified with acetic acid. The resulting precipitate was collected and washed with water to give the title compound as a white solid (4.94 g, 33%).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].C(N1C=CN=C1)(N1[CH:28]=[CH:27]N=C1)=O.NCCN1CCCC1.FC1C=CC(N2CCNCC2)=CC=1>O1CCCC1>[F:20][C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([NH:5][CH2:4][CH2:3][N:2]3[CH2:21][CH2:28][CH2:27][CH2:1]3)=[O:7])[CH2:9][CH2:10]2)=[CH:19][CH:18]=1
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Fc1ccc(N2CCNCC2)cc1
Agent: NCCN1CCCC1
Solvent: C1CCOC1
Product: O=C(NCCN1CCCC1)N1CCN(c2ccc(F)cc2)CC1

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 10.4 g (0.064 mole) of 1,1'-carbonyldiimidazole, 7.3 g (0.064 mole) of N-(2-aminoethyl)pyrrolidine and 11.5 g (0.064 mole) of 1-(4-fluorophenyl)piperazine in a total volume of 500 ml of tetrahydrofuran gave an oil that solidified when triturated with petroleum ether. The collected solid was recrystallized from benzene to give 2.8 g of the title compound as a white solid, m.p. 100°-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][S:10]([C:13]1[N:23]=[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[C:20](Cl)[N:15]2[N:14]=1)(=[O:12])=[O:11].C[O-].[Na+].[C:27](O)(=[O:29])C.CCOCC>CO.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][S:10]([C:13]1[N:23]=[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[C:20]([O:29][CH3:27])[N:15]2[N:14]=1)(=[O:12])=[O:11]
Reactant: CC(=O)O
Reactant: Cc1cc(Cl)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C)cc2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nn12
Reaction time: 2 h

Procedure:
N-(2,6-Dichlorophenyl)-5-chloro-7-methyl[1,2,4]triazolo[1,5-a]pyridine-2-sulfonamide (3.0 g, 0.0077 mol) and 25 percent sodium methoxide in methanol (12 mL, 2.8 g, 0.050 mol) were combined in methanol (100 mL) and heated to reflux with stirring for 2 hours. The reaction mixture was cooled and acidified with acetic acid and the volatiles were removed by evaporation under reduced pressure. The residue obtained was diluted with dichloromethane and the mixture was washed with water. The organic solution phase was filtered and the filtrate was concentrated by evaporation under reduced pressure. The residue obtained was mixed with ether and filtered to recover the solids. The solids were dried to obtain 2.6 g (87 percent of theory) of the title compound as a white powder melting at 269°-270° C.(d).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[N:8]=[CH:9][S:10][C:4]=2[CH2:3]1.[C:11](=[O:13])=[O:12].C([Li:18])CCC>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[N:8]=[C:9]([C:11]([O-:13])=[O:12])[S:10][C:4]=2[CH2:3]1.[Li+:18]
Reactant: O=C=O
Reactant: CN1CCc2ncsc2C1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCc2nc(C(=O)[O-])sc2C1
Product: [Li+]
Temperature: 25 °C

Procedure:
5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (6.43 g) was dissolved in absolute tetrahydrofuran (200 ml), to the solution n-butyllithium (1.47N hexane solution, 34.0 ml) was added dropwise at −78° C., and the resultant mixture was stirred for 40 minutes. After carbon dioxide gas was blown into the reaction mixture at −78° C. for 1 hour, the reaction mixture was warmed to room temperature and then concentrated under reduced pressure to obtain the title compound (9.42 g) as pale brown foamy solids.
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][C:5](=[O:26])[C@@H:6]1[C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C@H:20]([CH2:21][CH2:22]2)[C@:18]2([CH3:19])[C@H:13]([CH2:14][C:15](=[O:25])[CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1>C1COCC1>[CH3:4][C:5]([C@@H:6]1[C@@:23]2([CH3:24])[CH2:22][CH2:21][C@@H:20]3[C@@:18]4([CH3:19])[CH2:17][CH2:16][C@:15]([OH:25])([CH3:1])[CH2:14][C@@H:13]4[CH2:12][CH2:11][C@H:10]3[C@@H:9]2[CH2:8][CH2:7]1)=[O:26]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -25 °C
Reaction time: 4 h

Procedure:
Ferrous chloride (4 g) is reacted with MeMgCl (3 equiv based on FeCl2) in THF (anhydrous, 200 mL) at −25° C. under nitrogen. To this mixture is then added 5α-Pregnane 3,20-dione (10 g). The mixture is stirred at −25° C. for 4 h and is quenched by adding acetic acid (32 mL). The mixture is concentrated in vacuo and the residue is stirred in 3N HCl (200 mL) for 6 h. The solid is collected by filtration, washed with water and dried. The crude product is dissolved in THF (33 mL) at reflux and filtered hot. The filtrate is mixed with water (45 mL) and the solid is collected by filtration, washed with water and dried. The solid is further slurried in ethyl acetate (50 mL) at 70° C. for 19 h. It is cooled to 5° C. and filtered, washed with cold ethyl acetate and dried to obtain ganaxolone.
Reaction SMILES: COP([CH2:7][C:8]1[S:16][C:15]2[C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:13][C:12]([Cl:23])=[N:11][C:10]=2[CH:9]=1)(=O)OC.C([N-]C(C)C)(C)C.[Li+].[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][C:42](=O)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>C1COCC1.C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][C:42](=[CH:7][C:8]2[S:16][C:15]3[C:14]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[N:13][C:12]([Cl:23])=[N:11][C:10]=3[CH:9]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: COP(=O)(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)OC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a suspension of (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-phosphonic acid dimethyl ester (0.80 gm) in THF (10 mL) at −78° C. was added dropwise lithium diisopropylamide (1.17 mL of a 2.0 M solution in THF/heptane/ethylbenzene). The mixture was warmed to room temperature and a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.48 g) in THF (10 mL) was added via cannula. The mixture was then stirred at room temperature for 2 h, quenched with brine (20 mL) and extracted into dichloromethane (2×20 mL). The combined organics were dried (MgSO4), reduced in vacuo and purified by column chromatography to give 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethylene)-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil (0.862 g).
Reaction SMILES: Cl.Cl[C:3]1[N:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]2=[O:17])=[C:13]([F:18])[CH:12]=[CH:11][CH:10]=3)[C:6]2[CH:19]=[CH:20][N:21](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]=2[N:4]=1.[CH3:32][N:33]([CH3:50])[C@H:34]([CH3:49])[C:35]([N:37]1[C:45]2[C:40](=[CH:41][C:42]([O:47][CH3:48])=[C:43]([NH2:46])[CH:44]=2)[CH2:39][CH2:38]1)=[O:36].[CH3:51][NH2:52].[OH-].[K+]>C1COCC1.C(OCC)(=O)C>[CH3:32][N:33]([CH3:50])[C@@H:34]([C:35]([N:37]1[C:45]2[C:40](=[CH:41][C:42]([O:47][CH3:48])=[C:43]([NH:46][C:3]3[NH:4][C:5]4=[N:21][CH:20]=[CH:19][C:6]4=[C:7]([NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:18])[C:14]=4[C:15]([NH:52][CH3:51])=[O:17])[N:16]=3)[CH:44]=2)[CH2:39][CH2:38]1)=[O:36])[CH3:49]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2nc(Cl)n2c(=O)c4c(F)cccc4nc32)cc1
Reactant: COc1cc2c(cc1N)N(C(=O)[C@@H](C)N(C)C)CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)[C@@H](C)N(C)C)[nH]c2nccc1-2
Temperature: 65 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
A suspension of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride (500 mg, 1.043 mmol) and 1-[(2R)-2-(dimethylamino)propanoyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine (302 mg, 1.147 mmol) in THF (50 ml) was heated at 65° C. for 4 hrs. The reaction was diluted with ethyl acetate (200 ml) and washed with saturated NaHCO3 (300 ml). Organic layer was removed, concentrated by rotary evaporation, solids triturated from ethyl acetate/hexanes, and dried under house vacuum prior to next step. ESIMS (M+H)+=670. The solids were then added to THF (50 ml)mmol) followed by methylamine 2.0M/THF (26.1 ml, 52.3 mmol) and the resulting mixture was stirred at rt overnight. Next, the crude reaction was adsorbed onto silica gel and purified by silica gel chromatography (DCM to 10% MeOH/DCM over 30 min). ESIMS (M+H)+=701. The isolated pure amide was redissolved in 1,4-dioxane (10 ml), potassium hydroxide (2.497 ml, 12.49 mmol) added and the reaction was heated in the microwave at 120° C. for 20 min. The resulting solution was adsorbed onto silica gel and purified by silica gel chromatography (DCM to 10% MeOH/DCM) to afford the title compound (0.1 g, 17% over three steps). ESIMS (M+H)+=547. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 (d, J=6.62 Hz, 3 H) 2.20 (s, 6 H) 2.80 (d, J=4.41 Hz, 3 H) 3.08-3.16 (m, 2 H) 3.56-3.64 (m, 1 H) 3.77 (s, 3 H) 4.12-4.23 (m, 1 H) 4.36-4.45 (m, 1 H) 6.26-6.28 (m, 1 H) 6.85-6.94 (m, 1 H) 6.94-7.00 (m, 2 H) 7.27-7.37 (m, 1 H) 7.57 (s, 1 H) 8.36 (d, J=8.43 Hz, 1 H) 8.52-8.60 (m, 1 H) 8.62 (s, 1 H) 10.16 (s, 1 H) 11.26 (s, 1 H)
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][NH:17][C:16](=S)[C@H:15]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:14][CH2:13]1>CO>[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][NH:17][C:16](=[N:2][NH2:3])[C@H:15]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:14][CH2:13]1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=NN
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
Hydrazine monohydrate (2.23 mL, 46.0 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-thioxoazepan-3-ylcarbamate (546 mg, 1.53 mmol) in methanol (25 mL). After 30 min, the mixture was concentrated. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to give the title compound (548 mg). MS 355.2 (M+1).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1.C(N(CC)CC)C>C(Cl)Cl.O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C:8]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Oc2ccccc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 76.4 %

Procedure:
A solution of 3-cyclopentyl-2-(4-phenoxy-phenyl)-propionic acid (50 mg, 0.16 mmol),benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (106 mg, 0.24 mmol), and 2-aminothiazole (21 mg, 0.24 mmol) in methylene chloride (10 mL) at 25° C. was treated with triethylamine (0.067 mL, 0.48 mmol). The reaction mixture was then stirred at 25° C. for 14 h. After this time, the reaction mixture was diluted with water (10 mL) and then extracted with methylene chloride (3×10 mL). The combined organic extracts were then washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), and a 1N aqueous hydrochloric acid solution (1×10 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-phenoxy-phenyl)-N-thiazol-2-yl-propionamide (48 mg, 76%) as an off-white solid: mp 154.9-155.1° C.; EI-HRMS m/e calcd for C23H24O2N2S (M+) 392.1558, found 392.1546.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23](Br)[O:22][C:18]=2[N:19]=[CH:20][N:21]=1.[CH2:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O)[CH3:36]>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[CH2:35][CH3:36])[O:22][C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(Br)c(-c3ccc(OC)cc3)c12
Reactant: CCc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1ccccc1-c1oc2ncnc(NCCCCCC(=O)OC)c2c1-c1ccc(OC)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
Add 0.50 ml of 2 M aqueous sodium carbonate solution to a mixture of 224 mg (0.50 mmol) 6-{[6-bromo-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester and 18 mg (0.03 mmol) bis(triphenylphosphine)palladium(II) chloride in 11.2 ml DMSO. Next, add 187 mg (1.25 mmol) (2-ethylphenyl)boronic acid and stir the mixture for 15 h at 80° C. Filter the reaction mixture and purify directly by preparative RP-HPLC (gradient: water/acetonitrile). 69 mg (29% of theor.) of the desired product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:16]=[C:15](I)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][C:20]1=[O:24].C(N)CN.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.ClCCl.[Cu]I>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:16]=[C:15]([N:19]2[CH2:23][CH2:22][CH2:21][C:20]2=[O:24])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: O=C1CCCN1
Reactant: CCCN(C)C(=O)c1cc(I)cc(C(=O)OC)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: NCCN
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(C(=O)OC)cc(N2CCCC2=O)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
Mix 5-iodo-N-methyl-N-propyl-isophthalamic acid methyl ester (220 mg, 0.61 mmol), 2-pyrrolidone (56 μL, 0.73 mmol), ethane-1,2-diamine (4 μL, 0.061 mmol), cesium carbonate (398 mg, 1.22) and copper (I) iodide (12 mg, 0.061 mmol) in 1,4-dioxane (4 mL). Heat the mixture to 110° C. for 1 h then stir at room temperature overnight. Dilute with dichloromethane and filter through a filtering agent. Concentrate and purify (silica gel chromatography, eluting with ethyl acetate and hexanes) to give the title compound (100 mg, 52%).