Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=2[Cl:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]([Br:21])=[CH:4][N:3]=1.[C:22]([N:30]=[C:31]=[S:32])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:22]([NH:30][C:31](=[S:32])[NH:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=2[Cl:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]([Br:21])=[CH:4][N:3]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCOC(=O)c1ccc(Cl)c(Oc2cc(Br)cnc2N)c1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(Cl)c(Oc2cc(Br)cnc2NC(=S)NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
Ethyl 3-(2-amino-5-bromopyridin-3-yloxy)-4-chlorobenzoate (9.645 g, 25.95 mmol) and benzoyl isothiocyanate (4.659 g, 28.55 mmol) were placed in THF (250 mL) and the reaction mixture was stirred at room temperature for 18 hours, then heated at 55° C. for two days. THF was removed and the residue was purified by silica gel chromatography (5-25% EtOAc in hexane) to provide ethyl 3-(2-(3-benzoylthioureido)-5-bromopyridin-3-yloxy)-4-chlorobenzoate (7.08 g, 51.0%) as a yellow solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[Cu][C:21]#[N:22].CCOC(C)=O>CN(C=O)C>[CH3:19][N:16]1[CH2:17][CH2:18][N:13]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([C:5]3[S:6][C:2]([C:21]#[N:22])=[CH:3][CH:4]=3)[CH:12]=2)[CH2:14][CH2:15]1
Reactant: CN1CCN(c2ccnc(-c3ccc(Br)s3)c2)CC1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccnc(-c3ccc(C#N)s3)c2)CC1

Procedure:
A mixture of 1-[2-(5-bromo-thiophen-2-yl)-pyridin-4-yl]-4-methyl-piperazine (41 mg, 0.13 mmol) and copper(I) cyanide (55 mg, 0.62 mmol) was heated in DMF at 180° C. by microwave for 30 minutes. After cooling, EtOAc was added and the resulting mixture was passed through Celite®. The filtrate was washed with water and the organic layer was concentrated. The resulting residue was purified by preparative TLC to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].Cl.[Al+3].[Cl-].[Cl-].[Cl-]>N1C=CC=CC=1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([OH:8])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)c1ccc(Br)cc1O
Reaction time: 2 h

Procedure:
3-Bromo-phenol (10.0 g, 57.8 mmol) was dissolved in 10 ml of pyridine and 10 ml of acetic anhydride and stirred overnight at RT. The mixture was then poured into water, and 1 M HCl was added until reaching a neutral pH value. Extraction with AcOEt furnished a crude product, which was treated with AlCl3 (13.25 g, 100 mmol) at 140° C. After 2 h, the mixture was poured into water and extracted with diethyl ether. The crude residue was purified by column chromatography (eluent:hexane/AcOEt 70:30) to give 1-(4-bromo-2-hydroxy-phenyl)-ethanone (10.1 g) as a red solid.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([O:8][CH2:9][CH3:10])(=[O:7])/[CH:4]=[CH:5]/[CH3:6]>>[CH3:1][NH:2][CH:5]([CH3:6])[CH2:4][C:3]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: C/C=C/C(=O)OCC
Reactant: CN
Product: CCOC(=O)CC(C)NC
Yield: 72.1 %

Procedure:
A solution of 479.2 mL (0.958 mole) methylamine (2M in tetrahydrofuran) was added dropwise to 99.44 gm ethyl crotonate with stirring. After stirring 5 days at room temperature the reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. The residue was distilled to provide 91.25 gm (72%) of the desired product in 2 fractions. MS(FD): m/e=145 (M+); EA: Calculated for: C7H15NO2: Theory: C, 57.90; H, 10.41; N, 9.65. Found: C, 57.61; H, 10.66; N, 9.88.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[NH:10][CH:11]([CH2:14][O:15][CH3:16])[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]I.[H-].[Na+]>C1COCC1.CN(C=O)C>[CH2:1]([O:8][C:9](=[O:17])[N:10]([CH:11]([CH2:14][O:15][CH3:16])[CH2:12][CH3:13])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(COC)NC(=O)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCC(COC)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
To a solution of (1-methoxymethyl-propyl)-carbamic acid benzyl ester (4.4 g, 18.5 mmol, 1.0 eq.) and MeI (6.9 mL, 111 mmol, 6 eq.) in THF/DMF (4:1, 50 mL) at 0° C. was slowly added NaH (1.35 g, 55.5 mmol, 3 eq.). The resulting mixture was warmed to room temperature and stirred over night. The reaction was quenched carefully by slow addition of water until no bubbling (H2) was observed. The reaction mixture was poured over ice water and extracted with 3×EtOAc. The combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (30% to 50% EtOAc-hexanes) to give (1-methoxymethyl-propyl)-methyl-carbamic acid benzyl ester (4.4 g, 94%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[C:9]2=[O:16])=[CH:4][CH:3]=1.C(OC1C=[CH:29][C:28]([NH:31][C:32]2[N:37]=CN=[C:34]([O:38][C:39]3[CH:44]=[CH:43][C:42]([NH:45]C(=O)CC(NC4C=CC(F)=CC=4)=O)=[CH:41][C:40]=3[F:59])[CH:33]=2)=CC=1)C1C=CC=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:37][C:32]1[CH:33]=[C:34]([O:38][C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:13]([CH:10]3[CH2:11][CH2:12][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:9]3=[O:16])=[O:15])=[CH:41][C:40]=2[F:59])[CH:29]=[CH:28][N:31]=1
Reactant: O=C(O)C1CCN(c2ccc(F)cc2)C1=O
Reactant: O=C(CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1)Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(Oc2ccc(NC(=O)C3CCN(c4ccc(F)cc4)C3=O)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.3 mol), 4-(4-amino-2-fluorophenoxy)pyridin-2-amine (Compound B of Example 24, 21.9 mg, 0.1 mmol) in DMF (0.5 ml), was added HATU (76 mg, 0.2 mmol) and followed by diisopropylethylamine (0.1 mL, 0.57 mmol). The reaction mixture was stirred at room temperature overnight and was then quenched with 2 mL of methanol. The reaction mixture was purified by prep HPLC. The desired fractions were combined, neutralized with sat. aq. NaHCO3 solution, and concentrated in vacuo to afford the title compound (18 mg, 43%) as a white solid. 1H NMR (DMSO-d6) δ 10.76 (br s, 1H), 7.95 (d, 1H, J=7.2 Hz), 7.91 (m, 1H), 7.68 (m, 2H), 7.50 (m, 1H), 7.44 (t, 1H, J=10.0 Hz), 7.24 (m, 2H), 6.70 (m, 1H), 6.11 (d, 1H, J=2.8 Hz), 3.91 (m, 2H), 3.78 (t, 1H, J=5.0 Hz), 2.41 (m, 2H); MS(ESI+) m/z 425.15 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:4][CH:3]=1.CC([O-])(C)C.[K+].Cl>C(O)(C)(C)C>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([CH:2]=[CH:3][CH:4]=[C:5]2[CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:10][CH:9]=1
Reactant: COc1ccc2c(c1)C(CCNC(C)=O)CC=C2Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: COc1ccc2cccc(CCNC(C)=O)c2c1
Reaction time: 3 h
Yield: 68 %

Procedure:
To a solution of the compound obtained in Step C (125 mg, 0.45 mmol) in tert-butanol (1 mL) at reflux there is added potassium tert-butylate (200 mg, 1.8 mmol). The mixture is stirred for 3 hours under reflux and then hydrochloric acid (1N) is added. The aqueous phase is extracted with dichloromethane and the organic phases are washed with saturated NaCl solution, dried over magnesium sulphate, filtered and evaporated. The title compound is obtained after purification by flash column chromatography (ethyl acetate-petroleum ether: 90-10, then ethyl acetate-methanol: 90-10) in the form of a solid in a yield of 68%.
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH2:3][CH3:4].C([N-]C(C)C)(C)C.[Li+].[CH2:14]([O:21][CH2:22][C:23]([O:25]C)=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:15]1([CH2:14][O:21][CH2:22][C:23](=[O:25])[CH2:1][C:2](=[O:5])[CH2:3][CH3:4])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCC(C)=O
Reactant: COC(=O)COCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(=O)CC(=O)COCc1ccccc1
Temperature: 25 °C

Procedure:
2-Butanone (32.7 ml) in dry THF (120 ml) was added to lithium diisopropylamide (1.5M in THF; 250 ml) at -78° C. Methyl benzyloxyacetate (30,0 g) was added with stirring and the mixture allowed to warm to room temperature and was then heated at 45° overnight. After cooling the reaction was quenched with saturated ammonium chloride solution, acidified and extracted with ether (3×100 ml). After drying and evaporation, the title compound was obtained as a brown oil (45.6 g).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:21][CH2:22]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[NH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1>CCCCCCC>[C:15]1([S:12]([N:9]2[CH2:10][CH2:11][C:6]3([C:4](=[O:3])[N:29]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)[CH2:22][CH2:21]3)[CH2:7][CH2:8]2)(=[O:13])=[O:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cccnc1
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Product: O=C1N(c2cccnc2)CCC12CCN(S(=O)(=O)c1ccccc1)CC2
Yield: 26.3 %

Procedure:
This material was prepared in analogy to example 1 step D) from 1-benzenesulfonyl-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.2 g), dimethylaluminium chloride in heptane (0.9 molar, 1.88 ml) and 3-amino-pyridine (0.069 g) to give the desired 8-benzenesulfonyl-2-pyridin-3-yl-2,8-diaza-spiro[4.5]decan-1-one (0.055 g) as a white solid. MS (ESI): 372.13 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]2([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:18]3[C:13](=[C:14]([F:19])[CH:15]=[CH:16][CH:17]=3)[C:12]([NH2:20])=[N:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[N:40][CH:39]=[CH:38][N:37]=1)CCC>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.CN(C=O)C>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[C:12]([NH2:20])=[N:11][C:10]2([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([C:36]2[CH:41]=[N:40][CH:39]=[CH:38][N:37]=2)[CH:3]=1)[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: COc1ccc(C2(c3ccnc(C(F)(F)F)c3)N=C(N)c3c(F)cccc32)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(C2(c3ccnc(C(F)(F)F)c3)N=C(N)c3c(F)cccc32)cc1-c1cnccn1
Yield: 54.8 %

Procedure:
1-(3-Bromo-4-methoxyphenyl)-4-fluoro-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine (1.5 g, 3.12 mmol), 2-tributylstannylpyrazine (1.268 g, 3.44 mmol), tetrakis(triphenylphosphine)palladium(0) (0.361 g, 0.31 mmol) and DMF (10 mL) were heated in a microwave oven for 20 min at 150° C. The reaction mixture was filtered and concentrated under reduced pressure. The residue was diluted with DCM (40 ml) and silica powder was added and the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (0-10% 0.1M NH3 in Methanol in DCM) to afford the title compound (0.82 g, 54.8%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:14])[CH2:7][C:8](=[S:13])[O:9][CH:10]([CH3:12])[CH3:11].[C:15](=O)([O-])[O-].[K+].[K+].CC(C)=O.CI>C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:14])/[CH:7]=[C:8](/[O:9][CH:10]([CH3:11])[CH3:12])\[S:13][CH3:15]
Reactant: O=C([O-])[O-]
Reactant: CC(C)OC(=S)CC(=O)c1ccco1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CS/C(=C\C(=O)c1ccco1)OC(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
A mixture of isopropyl 3-(2-furyl)-3-oxopropanethioate (3.7 g, 17.5 mmol), potassium carbonate (7.3 g, 52.4 mmol) and acetone (15 mL) was heated under reflux for 1 hour. After cooling the mixture to 0° C., methyl iodide (2.17 mL, 34.9 mmol) was added thereto, followed by stirring at room temperature for 2 hours. After diluting the reaction solution with ethyl acetate, the insoluble matters were filtered off. The filtrate was concentrated, and then the residue was purified by silica gel column chromatography (elution solvent; ethyl acetate/hexane=1:1), to give the title compound (3.2 g, 81%).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[C:13]1([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+]>C1(C)C(C)=CC=CC=1.CO>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:21]1[CH2:20][C:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:24][CH2:23][CH2:22]1
Reactant: c1ccc(-c2cccnc2)cc1
Reactant: BrCC1COc2ccccc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CO
Product: C1=C(c2ccccc2)CN(CC2COc3ccccc3O2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (500 mg, 2.18 mmol) and 3-phenyl-pyridine (339 mg, 2.18 mmol) in xylene (2 ml) was refluxed for 4 h. After cooling, the solvent was decanted to give the crude oily pyridinium salt, which was dissolved in MeOH (5 ml). NaBH4 (330 mg, 4 eq) was added in small portions to the cooled mixture. After stirring for 2 h at RT, MeOH was evaporated, water was added and the mixture extracted with EtOAc. Drying (Na2SO4) and evaporation gave the crude product, which was purified by flash chromatography (heptane/EtOAc).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[C:49]([F:51])[C:48]([F:52])=[CH:47][C:46]=1[Cl:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:50]=[C:49]([F:51])[C:48]([F:52])=[CH:47][C:46]=3[Cl:53])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1cc(Cl)c(CBr)cc1F
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cc(F)c(F)cc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-chloro-4,5-difluorobenzene and isolated as colorless gum (8.3 mg, 45%). MS(m/e): 443.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>CO.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH:25]([OH:27])[CH3:26])=[CH:22][CH:23]=3)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.6 %

Procedure:
To a solution of 1-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)propan-2-one (0.072 g, 0.19 mmol) in methanol (5 mL) was added sodium borohydride (0.014 g, 0.38 mmol). The mixture stirred at rt for 10 min. After this time, the mixture was diluted with a saturated solution of NaHCO3 and extracted with ethyl acetate. The organic layer were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.069 g, 95%) as a white solid. MW=379.88. 1H NMR (DMSO-d6, 500 MHz) δ 8.27 (s, 1H), 8.29-8.16 (m, 2H), 7.69 (d, J=8.5 Hz, 2H), 7.54-7.49 (m, 2H), 7.20 (d, J=8.5 Hz, 2H), 4.54 (d, J=5.0 Hz, 1H), 3.87-3.80 (m, 1H), 2.93-2.84 (m, 4H), 2.72-2.66 (m, 1H), 2.58-2.53 (m, 1H), 2.10 (quin, J=7.5 Hz, 2H), 1.06 (d, J=6.0 Hz, 3H); APCI MS m/z 380 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][C:15](F)(F)F)=[CH:7][CH:6]=1)=[O:4].[F:21][C:22]([F:36])([F:35])[CH2:23]CCOC1C=CC(C=O)=CC=1.FC(F)(F)CCCCCOC1C=CC(C=O)=CC=1>>[F:1][C:2]([F:20])([F:19])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:23][C:22]([F:36])([F:35])[F:21])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=Cc1ccc(OCCCC(F)(F)F)cc1
Reactant: O=C(c1ccc(OCCCC(F)(F)F)cc1)C(F)(F)F
Agent: O=Cc1ccc(OCCCCCC(F)(F)F)cc1
Product: O=C(c1ccc(OCCCCCC(F)(F)F)cc1)C(F)(F)F

Procedure:
Intermediate 8B was prepared using a procedure analogous to Intermediate 2C except that Intermediate 2A was replaced with Intermediate 8A. 1H NMR (500 MHz, CDCl3) δ 8.06-8.02 (m, 2H), 6.99-6.97 (m, 1H), 4.08 (t, J=6.2 Hz, 2H), 2.19-2.06 (m, 2H), 1.92-1.82 (m, 2H), 1.71-1.55 (m, 4H).
Reaction SMILES: CC([N:6]1CCCC1)(C)CO.C(N(CC)CC)C.C1(C)C(S(Cl)(=O)=O)=CC=CC=1.C[C:30]1[NH:31][C:32]2[C:37]([C:38]=1C(OCC1C=CC=CC=1)=O)=[CH:36][C:35](O)=[CH:34][CH:33]=2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C.CO.C(N(CC)CC)C>[NH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:38]=[C:30]1[NH2:6]
Reactant: Cc1[nH]c2ccc(O)cc2c1C(=O)OCc1ccccc1
Reactant: CC(C)(CO)N1CCCC1
Agent: Cc1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.5 %

Procedure:
Crude 2-methyl-2-pyrrolidin-1-yl-propan-1-ol (0.849 g, 5.94 mmol, 1 eq) was suspended in dry acetonitrile (30 mL) under Ar. Triethylamine (1.4 mL, 10 mmol, 1.7 eq) was added followed by the addition of toluenesulfonyl chloride (1.05 g, 5.50 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 1 hour. After 4 hours, the reaction was treated with 2-methyl-3-benzyloxycarbonyl-5-hydroxyindole (1.5 g; 5.5 mmol, 1 eq) and potassium carbonate (1.38 g, 10 mmol, 1.7 eq.). The reaction was heated to reflux and followed by TLC (ethyl acetate/methanol/triethylamine 87/10/3). After 23 hours, the reaction was loaded directly on silica gel and chromatographed (ethyl acetate/methanol/triethylamine 87/10/3). Impure product was further purified by reverse-phase prep-HPLC 10-100% Acetonitrile/water, 0.1% TFA. 0.040 g (5% yield) of the indole-amine was obtained as a brown semisolid: LC/MS (ESI+) 407 (M+1), Anal. (C24H30N2O2.TFA.1.0H2O) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.C[O:15][C:16](=[O:37])[CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].[OH-]>C1(C)C=CC=CC=1.CCOC(C)=O.O.C1COCC1>[CH3:1][C:2]1[C:7]([CH:8]=[CH:17][C:16]([OH:37])=[O:15])=[CH:6][CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1nc(C(F)(F)F)ccc1C=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(C(F)(F)F)ccc1C=CC(=O)O
Temperature: 110 °C
Reaction time: 1 h
Yield: 37.3 %

Procedure:
To a solution of 2-methyl-6-trifluoromethyl-3-pyridinecarboxaldehyde (440 mg, 2.32 mmol) in toluene (10 mL) was added methyl(triphenylphosphoranylidene)acetate (855 mg, 2.56 mmol). The mixture was heated at 110° C. for overnight, cooled to room temperature, and diluted with EtOAc and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (EtOAc/hexanes=1/4) to 3-(2-methyl-6-trifluoromethylpyridin-3-yl)acrylic acid methyl ester (376 mg, 65.9%) as a mixture of cis- and trans-isomers (cis-/trans-=1/10). To a solution of the ester (376 mg, 1.53 mmol) in THF (5 mL) was added 1 N LiOH (2.5 mL). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was diluted with EtOAc and water. The aqueous layer was then separated, acidified to pH 4 with 3 N HCl, and extracted with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was purified by recrystallization from EtOAc/hexanes to give 3-(2-methyl-6-trifluoromethylpyridin-3-yl)acrylic acid (trans-isomer, 200 mg, 56.4%) as solid.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C@@:6]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)([CH:8]([CH3:10])[CH3:9])[O:5][C:4](=[O:20])[CH:3]=1.[NH2:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([S:29]S(C2C=CC(C)=CC=2)(=O)=O)=[C:24]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([S:29][C:3]2[C:4](=[O:20])[O:5][C:6]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH:8]([CH3:10])[CH3:9])[CH2:7][C:2]=2[OH:1])=[C:24]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(N)cc2C(C)(C)C)cc1
Reactant: CC(C)[C@]1(CCc2ccc(O)cc2)CC(O)=CC(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(O)cc3)(C(C)C)OC2=O)c(C(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared as described in General Method 9 using 3.0 g (10.86 mmol) of (S)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one (prepared in Example WWWW), 3.98 g (11.40 mmol) of toluene-4-thiosulfonic acid S-(4-amino-2-tert-butyl-5-methyl-phenyl) ester (prepared in Example HHHH), 4.50 g of anhydrous K2CO3 and 54 mL DMF. The reaction was stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl solution and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated. The crude material was purified by flash silica gel chromatography, eluting with EtOAc, to give the title compound, m.p. 147°-149° C. (dec.). 1H-NMR (DMSO-d6) δ 0.89 (d, 3 H), 0.93 (d, 3 H), 1.42 (s, 9 H), 1.71 (s. 3 H), 1.85-1.93 (m, 2 H), 2.15 (m, 1 H), 2.41-2.50 (m, 2 H, partially obscured by DMSO), 2.67 (d of ABX q, 1 H), 2.89 (d of ABX q, 1 H), 6.55 (s, 1 H), 6.60 (s, 1 H), 6.64 (d, 2H), 6.93 (d, 2H), 9.13 (br s, 1 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O:15]=[C:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][C:19]2[CH:27]=[CH:28][C:29]([CH:31]=[O:32])=[CH:30][C:18]=2[NH:17]1>C(#N)C.C(OCC)(=O)C>[CH2:7]([N:17]1[C:16](=[O:15])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][C:19]2[CH:27]=[CH:28][C:29]([CH:31]=[O:32])=[CH:30][C:18]1=2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccc2c(c1)NC(=O)c1ccccc1O2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1ccc2c(c1)N(Cc1ccccc1)C(=O)c1ccccc1O2
Temperature: 25 °C
Yield: 63 %

Procedure:
Potassium carbonate anhydrous (0.207 g, 1.5 mmole) and benzyl bromide (0.205 g, 1.2 mmole) were added to a solution of the 11-oxo-10,11 dihydrodibenzo[b,f][1,4]oxazepine-8-carbaldehyde (0.240 g, 1 mmole) in acetonitrile under N2 at room temperature. The reaction mixture then was refluxed for 4 hours, and cooled to room temperature. Diluted the reaction mixture with ethyl acetate and filtered through a magnesol pad and concentrated. Purified with silica gel column and 50% ethyl acetate in hexane. Obtained the desired compound (light yellow oil) in 63% yield.