Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[S:14][C:15]([C:19]([O:21]CC)=O)=[C:16]([CH3:18])[N:17]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]>C(O)C>[CH3:18][C:16]1[N:17]=[C:13]([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH3:3])[CH:6]=2)[S:14][C:15]=1[C:19]([NH:2][CH3:1])=[O:21]
Reactant: CCOC(=O)c1sc(-c2ccc(OC)c(OC)c2)nc1C
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1sc(-c2ccc(OC)c(OC)c2)nc1C
Yield: 66 %

Procedure:
Into a mixed solvent of 80 ml of 40% methylamine and 600 ml of ethanol, 15.4 g of ethyl 2-(3,4-dimethoxyphenyl)-4-methylthiazole-5-carboxylate was dissolved, and then, in a similar manner as in Example 1, the object is obtained as colourless aciculate melting at 181.5° to 183° C. in an amount of 9.6 g corresponding to the yield of 66%.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.Cl[CH:11]([C:16](=O)[CH2:17][CH3:18])[C:12]([O:14][CH3:15])=[O:13]>>[CH3:15][O:14][C:12]([C:11]1[N:4]2[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([Br:1])[C:3]2=[N:9][C:16]=1[CH2:17][CH3:18])=[O:13]
Reactant: CCC(=O)C(Cl)C(=O)OC
Reactant: Cc1cnc(N)c(Br)n1
Product: CCc1nc2c(Br)nc(C)cn2c1C(=O)OC
Temperature: 130 °C
Reaction time: 1 h
Yield: 5.8 %

Procedure:
3-Bromo-5-methyl-2-pyrazineamine (3.5 g, 18.6 mmol) and methyl 2-chloro-3-oxopentanoate (6.7 mL, 48.6 mmol) were mixed, and the mixture was heated under stirring at 130° C. for 1 hour. After being allowed to cool, the unnecessary materials were filtered off and washed with ethyl acetate, and then the filtrates were combined and evaporated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give the title compound (0.32 g) as pale yellow crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[CH2:16]([O:23][C:24]1[CH:40]=[CH:39][CH:38]=[CH:37][C:25]=1[CH2:26][S:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([S:27][CH2:26][C:25]3[CH:37]=[CH:38][CH:39]=[CH:40][C:24]=3[O:23][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:36][CH:35]=2)[CH:4]=1
Reactant: NCc1cccnc1
Reactant: O=C(Cl)c1ccc(SCc2ccccc2OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1cccnc1)c1ccc(SCc2ccccc2OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a stirred mixture of 3-aminomethylpyridine (324 mg) and triethylamine (1.51 g) in dichloromethane (20 ml) at 0° C. was added 4-[2-benzyloxybenzylthio]benzoylchloride in CH2Cl2 (10 ml) (3 mmol). The mixture was allowed to warm to ambient temperature, washed with saturated aqueous NaHCO3 (3×20 ml), dried (MgSO4), filtered and evaporated. The residue was triturated with diethyl ether (20 ml) and crystallised from ethyl acetate to give N-(3-pyridylmethyl)-4-[2-benzyloxybenzylthio]benzamide (220 mg). (mpt. 108° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2.CN(C)CCN(C)CCN(C)C.C([Li])(CC)C.[I:39]I>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[C:10]=1[I:39])[N:7]([Si:12]([CH:16]([CH3:18])[CH3:17])([CH:19]([CH3:21])[CH3:20])[CH:13]([CH3:14])[CH3:15])[CH:6]=[CH:5]2
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(F)cc(F)c21
Reactant: II
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(F)c(I)c(F)c21
Temperature: -70 °C
Reaction time: 3 h

Procedure:
5,7-difluoro-1-(triisopropylsilyl)-1H-indole (1.4 g, 4.5 mmol) and pentamethyldiethylene-triamine (830 mg, 4.8 mmol) were combined in 10 mL dry THF, cooled to −70° C. and treated in portions with sec-butyl lithium (3.4 mL, 1.4 M, 4.8 mmol) and stirred for 3 h at this temperature. Iodine (1.3 g, 5.0 mmol) in 5 mL THF was added, the mixture was stirred for 50 min, quenched by addition of 3 mL sat. NH4Cl and partitioned between diethyl ether and water. The organic phase was washed with sat. NaCl, dried (Na2SO4), evaporated and purified by flash chromatography (SiO2; hexanes) the title compound as a clear oil which solidified on standing (1.9 g, 90%). 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=3.1 Hz, 1H), 7.14 (dd, J=7.7, 0.9 Hz, 1H), 6.60 (t, J=3.1 Hz, 1H), 1.67 (m, 3H), 1.13 (d, J=7.6 Hz, 18H). 19F NMR (376 MHz, CDCl3) δ −101.37, −105.33. MP: 74-76° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[N:15]=[C:14]([S:16]([CH3:18])=[O:17])[N:13]=[C:12]([NH2:19])[CH:11]=1>CN(C=O)C>[Br:1][C:11]1[C:12]([NH2:19])=[N:13][C:14]([S:16]([CH3:18])=[O:17])=[N:15][C:10]=1[Cl:9]
Reactant: CS(=O)c1nc(N)cc(Cl)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CS(=O)c1nc(N)c(Br)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 81 %

Procedure:
11.2 g (62.6 mmol) de N-bromosuccinimide were slowly added to a cooled suspension of 10 g (52.2 mmol) 6-chloro-2-(methylsulfinyl)pyrimidine-4-amine in 130 ml of DMF. After 50 minutes stirring at room temperature the precipitate was filtered washed with cool DMF, several times with cool water and dried in vacuum. There was obtained 11.4 g (81%) of a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:30]([CH3:31])=[CH:29][C:6]([O:7][CH2:8][CH2:9][N:10]2[CH2:28][CH2:27][C:13]3([O:18][CH2:17][CH2:16][N:15]([C:19]([C:21]4[N:22]=[C:23]([CH3:26])[S:24][CH:25]=4)=[O:20])[CH2:14]3)[CH2:12][CH2:11]2)=[C:5]([CH3:32])[CH:4]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:31][C:30]1[CH:29]=[C:6]([O:7][CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][C:13]3([O:18][CH2:17][CH2:16][N:15]([C:19]([C:21]4[N:22]=[C:23]([CH3:26])[S:24][CH:25]=4)=[O:20])[CH2:14]3)[CH2:27][CH2:28]2)[C:5]([CH3:32])=[CH:4][C:3]=1[CH:2]=[O:1]
Reactant: Cc1nc(C(=O)N2CCOC3(CCN(CCOc4cc(C)c(CO)cc4C)CC3)C2)cs1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCOc4cc(C)c(C=O)cc4C)CC3)C2)cs1

Procedure:
Manganese dioxide (0.32 g) was added to a solution of (9-(2-(4-(hydroxymethyl)-2,5-dimethylphenoxy)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-methylthiazol-4-yl)methanone (example 18, step e) (0.17 g) in DCM (10 mL). The resulting mixture was heated at reflux for 4 h. The reaction was filtered through Celite and the filter pad washed with DCM (2×50 mL). The mother liquors and the washings were combined and evaporated to give the subtitled compound as a yellow gum. Yield 0.17 g.
Reaction SMILES: [CH3:1][N:2]1[C:6](B(O)O)=[CH:5][C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.[NH2:14][C:15]1[S:16][C:17](Br)=[CH:18][N:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O1CCOCC1.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:1][N:2]1[C:6]([C:17]2[S:16][C:15]([NH2:14])=[N:19][CH:18]=2)=[CH:5][C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1
Reactant: Cn1nc(C(F)(F)F)cc1B(O)O
Reactant: Nc1ncc(Br)s1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc(C(F)(F)F)cc1-c1cnc(N)s1
Temperature: 70 °C
Yield: 1.9 %

Procedure:
A suspension of (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid (290 mg, 1.5 mmol), 2-amino-5-bromothiazole (1 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (A-Phos) (53 mg) and K3PO4 (212 mg, 1 mmol) in 2 ml ACN, 2 ml dioxane, 0.5 ml H2O was bubbled with argon before heated at 70° C. for 1 h. After cooling down to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine, dried over Na2SO4, concentrated to dryness. Prep HPLC purification furnished 4.6 mg 5-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl]-1,3-thiazole-2-ylamine (63) as light yellow solid (yield 1.9%; purity>95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:14][CH:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][C:11]2=[O:23])[CH:5]=[CH:6][C:7]=1[O:8]C>B(Br)(Br)Br.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:14][CH:13]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:12][C:11]2=[O:23])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(N2CC(COc3ccccc3)CC2=O)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1CC(COc2ccccc2)CN1c1ccc(O)c(F)c1

Procedure:
A solution of 1-(3-fluoro-4-methoxyphenyl)-4-(phenoxymethyl)pyrrolidin-2-one (Step 3, 1.0 g, 3.17 mmol) in 15.85 mL of 1 M BBr3/CH2Cl2 was stirred at RT for 10 h. The solution was concentrated in vacuo and the residue was diluted with 100 mL of EtOAc. The organic phase was washed with 40 mL of satd. NaHCO3 followed by 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (5% to 60% EtOAc/hexane) to give the title compound as a light yellow foam. MS (ESI pos. ion) m/z: 302.3 (M+H). Calc'd Exact Mass for C17H16FNO3: 301.31.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15]I)[O:11][CH:12]=2)=[CH:4][CH:3]=1.[C:17]1([O:24][CH3:25])[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][O:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:24][CH3:25])[O:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2coc(CCCI)n2)cc1
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1OCCCc1nc(-c2ccc(Cl)cc2)co1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A mixture of 4-(4-chlorophenyl)-2-(3-iodopropyl)oxazole (0.5 g), guaiacol (0.19 ml), potassium carbonate (0.24 g) and N,N-dimethylformamide (5 ml) was stirred for 30 minutes at 60° to 65° C. and poured into water. The precipitated crystals were collected by filtration to obtain 4-(4-chlorophenyl)-2-[3-(2-methoxyphenoxy) propyl]oxazole (0.445 g, 90%). Recrystallization from ether-hexane gave colorless prism crystals of mp 94°-95° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[C:27]([CH2:29][CH3:30])[CH:26]=[CH:25][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][O:20]C2=O)=[CH:14][C:13]=1[F:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Ba+2].[OH-]>CO.O>[CH2:1]([O:8][C:9]1[CH:28]=[C:27]([CH2:29][CH3:30])[CH:26]=[CH:25][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:22][CH2:21][OH:20])=[CH:14][C:13]=1[F:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(Oc2ccc(N3CCOC3=O)cc2F)c(OCc2ccccc2)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1ccc(Oc2ccc(NCCO)cc2F)c(OCc2ccccc2)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of 3-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]oxazolidin-2-one (350 mg, 0.85 mmol) in 5 ml of methanol was added barium hydroxide (245 mg, 1.28 mmol) taken in 5 ml of water. The reaction mixture was warmed to 65° C. and stirred overnight (reaction was complete on TLC). The reaction mixture concentrated in vacuo to remove methanol, diluted with water and the aqueous layer was extracted with ethyl acetate. The combined organic fraction was washed with brine, dried over anhydrous Na2SO4 and concentrated to get 300 mg, 91.57% of the title compound as a brown oil, used as such in the next step.
Reaction SMILES: [Cl:1][CH:2]1[CH:9]=[CH:8][CH:5]([C:6]#[N:7])[CH:4]([C:10]#[N:11])[CH2:3]1.BrBr>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7]
Reactant: N#CC1C=CC(Cl)CC1C#N
Agent: BrBr
Solvent: Clc1ccccc1
Product: N#Cc1ccc(Cl)cc1C#N
Temperature: 135 °C

Procedure:
To a 1--1 three-necked flask, equipped with a mechanical stirrer, a condenser with a gas outlet and an equa-pressured addition funnel, is charged 166.5 g (1 mole) of 4-chlorotetrahydrophthalonitrile and 75 g of chlorobenzene. The mixture is heated to 100°-110° C. with stirring. Bromine, 320 g (2 moles), is added dropwise into the mixture in a sub-surface manner. The red color of bromine dissipates quickly and a gas evolution starts. After about 240 g of bromine is added, the pot temperature is heated to 135° C. The addition of bromine continues until completion. The pot temperature is then raised to 165°-170° C. for 2-4 hours. During this period an additional amount of bromine, such as about 10 to 15 g, may be added to complete the conversion of 4-chlorotetrahydro-phthalonitrile. A good yield of 4-chlorophthalonitrile can be obtained by distilling out the chlorobenzene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([O:31]S(C)(=O)=O)=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C(O)(=O)C.O>C(O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Oc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1
Reaction time: 8 h

Procedure:
(+,-) cis Methanesulfonic acid 4-(7-benzyloxy-3-phenyl-chroman-4-yl)-phenyl ester (35 g, 71.9 mmol) was added to a solution of potassium hydroxide (350 g) in ethanol (2500 ml) and refluxed for 90 min. The reaction mixture was cooled, acetic acid (350 ml) was slowly added, and the resulting mixture was stirred overnight. Water (1.5 l) was added dropwise over 60 min, stirring was continued for 120 min, and the precipitated product was filtered. The precipitate was vacuum dried with sicapent (Merck) at 45° C. for 4 days.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@@H:13]1[CH2:17][CH2:16][C@:15]([CH3:21])([C:18]([OH:20])=O)[C:14]1([CH3:23])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH2:29]([NH2:32])[CH2:30][CH3:31]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:26])([CH3:27])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@@H:13]1[CH2:17][CH2:16][C@:15]([CH3:21])([C:18]([NH:32][CH2:29][CH2:30][CH3:31])=[O:20])[C:14]1([CH3:22])[CH3:23])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCN
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@@H]1CC[C@](C)(C(=O)O)C1(C)C
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@@H]1CC[C@](C)(C(=O)NCCC)C1(C)C

Procedure:
The product from Example 205 and propylamine hydrochloride (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.50 (s, 3H), 0.80 (t, J=7.3 Hz, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.14 (s, 3H), 1.24 (s, 3H), 1.28-1.43 (m, 5H), 1.57 (s, 9H), 1.57-1.67 (m, 2H), 1.72-1.82 (m, 1H), 2.25-2.47 (m, 2H), 2.61-2.67 (m, 2H), 2.96-3.03 (m, 3H), 7.25-7.29 (m, 1H), 8.50 (s, 1H). (ESI+) m/z 436 (M+H)+. Anal. calcd. for C24H41N3O2S: C, 66.16; H, 9.49; N, 9.65. Found: C, 65.94; H, 9.63; N, 9.44.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[O:14])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:28](Cl)(=[O:31])[O:29][CH3:30]>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[O:14])[C:28](=[O:31])[O:29][CH3:30])[CH3:9])=[CH:4][CH:3]=1
Reactant: COC(=O)Cl
Reactant: C[C@H](NCCC(=O)c1ccccc1F)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)N(CCC(=O)c1ccccc1F)[C@@H](C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
To a solution of (S)-3-(1-(4-bromophenyl)ethylamino)-1-(2-fluorophenyl)propan-1-one (500 mg, 1.43 mmol) in anhydrous CH3CN (15 mL) was added K2CO3 and methyl carbonochloridate (403 mg, 4.29 mmol), and the mixture was stirred at rt for 2 h. The solution was concentrate, and the residue was purified by preparative TLC to afford (S)-methyl 1-(4-bromophenyl)ethyl(3-(2-fluorophenyl)-3-oxopropyl)carbamate (400 mg, 70%). 1H NMR (CDCl3): δ=1.50 (m, 3H), 3.00 (m, 2H), 3.36 (m, 2H), 3.78 (m, 3H), 5.40 (m, 1H), 7.11 (m, 4H), 7.28-7.50 (m, 3H), 7.71 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][C@H:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19](Cl)[C:14]=3[C@H:13]([CH3:21])[CH2:12]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:24]([N:31]1[CH2:35][CH2:34][C:33]2([C:43]3[C:38](=[CH:39][CH:40]=[CH:41][C:42]=3[CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[NH:37][CH2:36]2)[CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][C@H:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([N:37]4[C:38]5[C:43](=[C:42]([CH2:44][NH:45][C:46]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:52])[CH:41]=[CH:40][CH:39]=5)[C:33]5([CH2:34][CH2:35][N:31]([CH2:24][C:25]6[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=6)[CH2:32]5)[CH2:36]4)[C:14]=3[C@H:13]([CH3:21])[CH2:12]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NCc1cccc2c1C1(CCN(Cc3ccccc3)C1)CN2
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(Cl)c21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(Cc5ccccc5)C4)c4c(CNC(=O)OC(C)(C)C)cccc43)c21
Temperature: 100 °C
Yield: 79090.9 %

Procedure:
A solution of (5R,7R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (0.110 g, 0.330 mmol), tert-butyl (1′-benzylspiro[indoline-3,3′-pyrrolidine]-4-yl)methylcarbamate (0.130 g, 0.330 mmol), Cs2CO3 (0.162 g, 0.496 mmol), and Xantphos (28.7 mg, 0.050 mmol) in toluene (2.00 mL) was degassed by bubbling a stream of nitrogen through the solution. Pd(OAc)2 (7.42 mg, 0.0330 mmol) was then added to this solution, and the resulting mixture was heated overnight at 100° C. The reaction mixture was concentrated and purified by Analogix chromatography (DCM/5% MeOH/1% NH4OH) to give (5R,7R)-4-(1′-benzyl-4-((tert-butoxycarbonylamino)methyl)spiro[indoline-3,3′-pyrrolidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (180 mg, 261 mmol, 79%). LCMS (APCI+) M+H+ 692 (100%); Rt=4.89 min.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:20][C:21]1[CH:26]=[C:25]([CH3:27])[O:24][C:23](=[O:28])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:29]([O:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH:40]=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+].Cl>O1CCCC1>[CH2:13]([O:20][C:21]1[CH:26]=[C:25]([CH2:27][CH:40]([C:39]2[CH:42]=[CH:43][C:44]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[C:37]([O:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:38]=2)[OH:41])[O:24][C:23](=[O:28])[CH:22]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cc(OCc2ccccc2)cc(=O)o1
Reactant: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=c1cc(OCc2ccccc2)cc(CC(O)c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)o1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 67.3 %

Procedure:
A solution of 10.1 g (14.0 ml, 100 mmol) diisopropylamine in 150 ml tetrahydrofuran was mixed under nitrogen at -78° C. with 41.0 ml (95 mmol) butyllithium (2.3M in n-hexane). It was allowed to reach 0° C. for a short time and immediately cooled again to -78° C. After a dropwise addition of a solution of 19.0 g (88 mmol) 4-benzyloxy-6-methyl-2H-pyran-2-one (V) in 100 ml anhydrous tetrahydrofuran it was stirred for a further 45 min. at -78° C. and subsequently a solution of 12.8 g (40 mmol) 3,4-dibenzyloxy-benzaldehyde (IV) in 150 ml anhydrous tetrahydro-furan was added dropwise. The internal temperature was gradually increased to -30° C. and it was admixed with an excess of saturated ammonium chloride solution. After acidifying with 6n HCl it was extracted with ethyl acetate, the combined organic phases were dried and evaporated. Purification of the residue by means of flash chromatography on silica gel (mobile solvent: ethyl acetate/heptane 1:2) yielded 14.4 g (68%) VI, melting point 109°-110° C. (ether).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([Cl:13])[C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:21][CH2:22][CH2:23][CH2:24]I>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([Cl:13])[C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:24][CH2:23][CH2:22][Cl:21])[C:6]=2[CH:12]=1
Reactant: Cc1c(Cl)cc2c(c1Cl)OCC(=O)N2
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cc2c(c1Cl)OCC(=O)N2CCCCl
Yield: 79.1 %

Procedure:
6,8-Dichloro-7-methyl-4H-benzo[1,4]oxazin-3-one (81MF2225a) (2.33 g, 10.0 mmol), Cs2CO3 (4.88 g, 15.0 mmol) and 3-chloro-1-iodopropane (2.25 g, 11.0 mmol) were mixed according to GP6. CC (SiO2; Heptane/EtOAc 10:1-5) gave the title compound (81MF2225b) (2.44 g, 79%). 1H NMR (CDCl3) δ 7.02 (s, 1H), 4.67 (s, 2H), 4.06 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.2, 2H), 2.43 (s, 3H), 2.18-2.10 (m, 2H); 13C NMR (CDCl3) δ 163.7, 140.5, 130.3, 128.3, 127.6, 124.1, 113.5, 67.9, 42.2, 39.3, 30.0, 17.2.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](O)=[O:13])=[C:5]2[O:15][CH3:16].[CH3:17][NH:18][CH3:19].O1CCCC1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:17][N:18]([CH3:19])[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[O:15][CH3:16])=[CH:3][C:2]([I:1])=[CH:11][CH:10]=2)=[O:13]
Reactant: COc1c(C(=O)O)cnc2ccc(I)cc12
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1c(C(=O)N(C)C)cnc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To the mixture of 6-iodo-4-methoxy-quinoline-3-carboxylic acid (example 1b) (1.5 g, 4.56 mmol), 2 M dimethylamine in THF (tetrahydrofuran) (9.11 mL, 18.2 mmol), HOBt (0.74 g, 5.5 mmol) and DIEA (diisopropylethylamine) (2.38 mL, 13.7 mmol) in DMF (N,N-dimethylformamide) (40 mL) was slowly added the solution of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (2.08 g, 5.47 mmol) in DMF (10 mL). After stirring at room temperature for 3 hours, the product was extracted with methylene chloride (2×100 mL). The combined organic layers were successively washed with a saturated aqueous sodium bicarbonate solution (3×50 mL) and water (3×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, using ethyl acetate as eluant) afforded 6-iodo-4-methoxy-quinoline-3-carboxylic acid dimethylamide (1.27 g, 78%) as a solid. LC-MS m/e 357 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][C:3]=1[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:17][CH:16]=1.[F-].[K+].C(O)(C(F)(F)[F:41])=O>C(#N)C.O>[F:41][CH2:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:3]2[O:4][C:5]3[C:10]([C:11](=[O:12])[C:2]=2[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCc2ccc(CNc3oc4ccccc4c(=O)c3C)cc2)cc1
Reactant: O=C(O)C(F)(F)F
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1c(NCc2ccc(CCCCF)cc2)oc2ccccc2c1=O
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 2 %

Procedure:
To a solution of toluene-4-sulfonic acid 4-{4-[(3-methyl-4-oxo-4H-chromen-2-ylamino)-methyl]-phenyl}-butyl ester (24 mg, 0.049 mmol) in ACN (1.1 mL) was added K222 (37 mg, 0.098 mmol) followed by KF (6 mg, 0.098 mmol). The reaction stirred in a 90° C. oil bath for 30 minutes under nitrogen atmosphere, monitored by LC-MS. The reaction was then cooled to room temperature and injected directly onto the preparative HPLC coloum chromatography (Luna, 10u, C18, 250×21.2 mm 10 micro, 60% of water in 90% acetonitrile in water with 0.1% TFA as the modifier in both mobile phases). The desired fractions were collected and neutralized to pH 7.6, then lyophilized. The material was re-purified by flash column chromatography (3:1 Hexane:ethyl acetate) to obtain the desired product as a solid (0.3 mg, <2% yield).