Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[C@@H:13]3[N:14]([CH3:22])[C:15]4[C:20]([C@:12]3([CH3:23])[CH2:11][CH2:10]2)=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=4)C=CC=CC=1.COC1C=C2C(=CC=1)N(C)[C@H]1N(CC=C)CC[C@@]21C.B(Br)(Br)Br>C(Cl)(Cl)Cl>[CH2:8]([N:9]1[C@@H:13]2[N:14]([CH3:22])[C:15]3[C:20]([C@:12]2([CH3:23])[CH2:11][CH2:10]1)=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH:7]=[CH2:1]
Reactant: CN1c2ccc(O)cc2[C@]2(C)CCN(CCc3ccccc3)[C@H]12
Agent: BrB(Br)Br
Agent: C=CCN1CC[C@@]2(C)c3cc(OC)ccc3N(C)[C@@H]12
Solvent: ClC(Cl)Cl
Product: C=CCN1CC[C@@]2(C)c3cc(O)ccc3N(C)[C@@H]12

Procedure:
This compound is prepared in the same manner as the 1-(2-phenylethyl) derivative of Example 45 except that 2.58 g of (3aS-cis)-1,2,3,3a,8,8a-hexahydro-5-methoxy-1-(2-propenyl)-3a,8-dimethylpyrrolo[2,3-b]indole is reacted as a starting material with 10.1 g of boron tribromide in chloroform.
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.C([Li])(C)(C)C.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>O1CCCC1>[CH3:19][N:16]1[CH2:17][CH2:18][CH:13]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([B:25]([OH:30])[OH:26])[CH:5]=3)[NH:9][CH:8]=2)[CH2:14][CH2:15]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CN1CCC(c2c[nH]c3ccc(Br)cc23)CC1
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(B(O)O)cc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
To a slurry of potassium hydride (20% suspension in mineral oil, 0.72 g, 3.58 mmol) in 7 mL of anhydrous tetrahydrofuran at 0° C. was slowly added dropwise 5-bromo-3-(1-methylpiperidin-4-yl)-1H-indole (1.0 g, 3.41 mmol) in 7 mL of anhydrous tetrahydrofuran. After stirring at 0° C. for 30 minutes, the mixture was cooled to −78° C., and tert-butyl lithium (1.7M in pentane, 7.51 mmol, 4.42 mL) was added dropwise. After 15 minutes, a solution of triisopropyl borate (6.82 mmol, 2.0 eq, 1.57 mL) in 2 mL of anhydrous tetrahydrofuran was added dropwise. The stirred mixture was allowed to warm to room temperature, and was quenched with 5N aqueous hydrochloric acid. The aqueous phase was extracted with diethyl ether, and the ether extracts were separated, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a crude white solid which was treated with hexanes, sonicated for 30 minutes, filtered and dried to give 0.252 g (29%) of the title compound as an amorphous white material which was used without further purification.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[CH:20]=[CH:19][CH:18]=[C:17](F)[C:16]=5[C:15]5=[N:23][CH2:24][CH2:25][N:14]5[C:13]=34)[O:6][N:5]=2)[CH2:3][CH2:2]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CN(C=O)C>[CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[CH:20]=[CH:19][CH:18]=[C:17]([N:26]6[CH2:31][CH2:30][O:29][CH2:28][CH2:27]6)[C:16]=5[C:15]5=[N:23][CH2:24][CH2:25][N:14]5[C:13]=34)[O:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: Fc1cccc2c1C1=NCCN1c1c(-c3nc(C4CC4)no3)ncn1-2
Solvent: CN(C)C=O
Product: c1cc(N2CCOCC2)c2c(c1)-n1cnc(-c3nc(C4CC4)no3)c1N1CCN=C21
Temperature: 120 °C

Procedure:
A solution of 5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-12-fluoro-2,3-dihydrodiimidazo[1,5-a:1',2'-c]quinazoline (0.25 g, 0.7 mmol) in a mixture of morpholine (10 ml) and DMF (15 ml) was heated at 120° C. for 6 h. Then the solvent was evaporated and the solid residue was triturated with 10 ml of water, filtered off and dried to give the title compound as pale crystals, m.p. 217°-220° C. Yield 0.16 g (57%). (Compound 46).
Reaction SMILES: [N:1]1([CH:10]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:11]([OH:16])[C:12]([O:14][CH3:15])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[OH:16][CH:11]([CH:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(O)C(c1ccc(OC)cc1)N1CCc2ccccc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COC(=O)C(O)C(c1ccc(OC)cc1)n1ccc2ccccc21
Reaction time: 1.5 h
Yield: 96 %

Procedure:
To a solution of methyl (2SR,3SR)-3-(2,3-dihydro-1H-indol-1-yl)-2-hydroxy-3-(4-methoxyphenyl)propanoate (2.63 g, 8.0 mmol) in anhydrous toluene (50 mL) at 0° C. under nitrogen was added a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.87 g, 8.2 mmol) in anhydrous toluene (50 mL) over 5 minutes. The reaction mixture was stirred 0° C. to room temperature for 1.5 hours then quenched by the addition of 7% w/v aqueous sodium carbonate solution (100 mL). The resulting biphasic mixture was stirred vigorously for 5 minutes then partitioned between ethyl acetate (300 mL) and 7% w/v aqueous sodium carbonate (250 mL). The organic phase was separated, washed with 7% w/v aqueous sodium carbonate solution (3×250 mL), water (250 mL) and saturated brine (250 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a lilac solid. Purification by flash chromatography (silica, 20%, 30% ethyl acetate/hexane) afforded 2.5 g (96%) of methyl (2SR,3SR)-2-hydroxy-3-(1H-indol-1-yl)-3-(4-methoxyphenyl)propanoate as a cream solid. MS (ES) m/z 326.3 ([M+H]+); HRMS: calcd for C19H19NO4+H+, 326.13869; found (ESI, [M+H]+), 326.1378.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)[S:5][C:6]=1[C:7]#[N:8].[ClH:20]>O1CCOCC1>[ClH:20].[ClH:20].[NH2:1][C:2]1[N:3]=[C:4]([NH:9][CH2:10][CH2:11][NH2:12])[S:5][C:6]=1[C:7]#[N:8]
Reactant: CC(C)(C)OC(=O)NCCNc1nc(N)c(C#N)s1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1sc(NCCN)nc1N

Procedure:
2.18 g (7.7 mmol) of tert-butyl {2-[(4-amino-5-cyano-1,3-thiazol-2-yl)amino]ethyl}carbamate (Example 7A) in 100 ml of 4N hydrogen chloride in dioxane were stirred at RT for 30 min. The reaction mixture was concentrated. This gave 2 g (100% of theory) of the product as a solid.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[NH:7][CH2:6][C@:5]1([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)[CH3:15])[CH:2]=[CH2:3].Br[C:25]1[CH:42]=[C:41]2[C:28]([CH2:29][C@@:30]3([CH2:40]2)[C:38]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[NH:32][C:31]3=[O:39])=[CH:27][C:26]=1[C:43]#[N:44].C1(CNCC2CCCCC2)CCCCC1>CC(N(C)C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:22][C:20]1[CH:21]=[C:16]([C@@:5]2([CH3:15])[N:4]([CH2:1]/[CH:2]=[CH:3]/[C:25]3[CH:42]=[C:41]4[C:28]([CH2:29][C@@:30]5([CH2:40]4)[C:38]4[C:33](=[N:34][CH:35]=[CH:36][CH:37]=4)[NH:32][C:31]5=[O:39])=[CH:27][C:26]=3[C:43]#[N:44])[C:13](=[O:14])[C:8]3([CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7][CH2:6]2)[CH:17]=[C:18]([F:23])[CH:19]=1
Reactant: N#Cc1cc2c(cc1Br)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: C=CCN1C(=O)C2(CCCC2)NC[C@@]1(C)c1cc(F)cc(F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: C1CCC(CNCC2CCCCC2)CC1
Solvent: CC(=O)N(C)C
Product: C[C@@]1(c2cc(F)cc(F)c2)CNC2(CCCC2)C(=O)N1C/C=C/c1cc2c(cc1C#N)C[C@]1(C2)C(=O)Nc2ncccc21
Temperature: 120 °C

Procedure:
To a mixture of (8R)-9-allyl-8-(3,5-difluorophenyl)-8-methyl-6,9-diazaspiro[4.5]decan-10-one (84 mg, 0.262 mmol), (2R)-6-bromo-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-carbonitrile (98 mg, 0.288 mmol, described in Intermediate 26) and N,N-dicyclohexylmethylamine (0.0612 mL, 0.288 mmol) in degassed DMA (1.7 mL) at ambient temperature was added bis(tri-t-butylphosphine)palladium (44.2 mg, 0.087 mmol). The reaction mixture was heated at 120° C. for 18 h, cooled, and filtered through a plug of Celite, washing with EtOAc. The filtrate was concentrated in vacuo and the residue was first purified by HPLC using reverse phase C18 column, eluting with a gradient of H2O:CH3CN:CF3CO2H—65:35:0.1 to 45:55:0.1, then with preparative thin layer chromatography, eluting with a gradient of EtOAc:hexanes—50:50 to 70:30, to give the title compound. MS: m/z=580 (M+1). HRMS: m/z=580.2542 (M+1); calculated m/z=580.2519 (M+1) for C34H31F2N5O2.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][C:42](I)=[CH:41][CH:40]=3)=[C:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].CC1(C)C(C)(C)OB([C:62]2[CH:63]=[N:64][NH:65][CH:66]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.O>[NH:64]1[CH:63]=[C:62]([C:42]2[CH:43]=[CH:44][C:39]([O:38][CH2:37][CH2:36][CH2:35][C:25]3[S:24][C:23]([N:20]4[CH2:19][CH2:18][C:17]5[C:22](=[C:13]([C:11](=[O:12])[N:10]([C:2]6[S:1][C:5]7[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=7[N:3]=6)[CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:52])([CH3:51])[CH3:53])[CH:14]=[CH:15][CH:16]=5)[CH2:21]4)=[N:27][C:26]=3[C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])=[CH:40][CH:41]=2)[CH:66]=[N:65]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CCCOc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CCCOc1ccc(-c2cn[nH]c2)cc1
Reaction time: 0.5 h

Procedure:
A mixture of compound 41A (90 mg, 0.102 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (29.7 mg, 0.153 mmol), Na2CO3 (108 μl, 0.102 mmol) (1M) and (Ph3P)2Cl2Pd (7.15 mg, 10.19 μmol) in EtOH-DME-H2O (7:3:2, 4 ml) was in a Smith microwave synthesizer at 120° C. for 30 min and then concentrated. The residue was purified by flash chromatography to give the compound 73A. LCMS (APCI) m/e 824 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][S:12][CH:13]=2)=[C:5]([CH3:21])[CH:4]=1)#[N:2]>CCO.[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][S:12][CH:13]=2)=[C:5]([CH3:21])[CH:4]=1)#[N:2]
Reactant: CCOC(=O)/C=C/c1cscc1-c1ccc(C#N)cc1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cscc1-c1ccc(C#N)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a solution of (E)-ethyl 3-(4-(4-cyano-2-methylphenyl)thiophen-3-yl)acrylate (1 g, 3.4 mmol) in EtOH (20 mL) was added 10% Pd/C (w/w, 400 mg), and the mixture was stirred at room temperature under 1 atm of H2 overnight. The reaction mixture was filtered, and concentrated to give ethyl 3-(4-(4-cyano-2-methylphenyl)thiophen-3-yl)propanoate (Scheme III, 15, X1=4-cyano-2-methylphenyl) (0.9 g, yield 90%) as gray oil. 1H NMR (CD3OD 400 MHz): δ 7.69 (s, 1H), 7.60 (dd, J=8 Hz, J=1.2 Hz, 1H), 7.34 (d, J=8 Hz, 1H), 7.26-7.23 (m, 2H), 4.05 (q, J=7.2 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H), 2.45 (t, J=7.6 Hz, 2H), 2.19 (s, 3H), 1.19 (t, J=7.2 Hz, 3H).
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[CH2:13]([N:20]1[C:24](=O)[CH2:23][CH:22]([C:26](O)=[O:27])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.C1COCC1>[CH2:13]([N:20]1[CH2:24][CH2:23][CH:22]([CH2:26][OH:27])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCC1CCN(Cc2ccccc2)C1
Yield: 102.8 %

Procedure:
Red-Al (160 mL of a 3.5 M solution in toluene, 560 mmol) was added to a solution of 1-benzyl-5-oxo-pyrrolidine-3-carboxylic acid (20 g, 91 mmol) in dry THF (650 mL) under argon. The reaction mixture was refluxed for 2.5 h and then poured onto a mixture of crushed ice and NaOH (20%). The phases were separated, the aqueous phase was extracted with toluene and the combined organic phases were dried and concentrated under reduced pressure to give 17.9 g of the crude product as a yellow oil.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[N:17]=[C:16]([C:18]2[S:22][C:21]([NH:23][C:24](=[O:26])[CH3:25])=[N:20][C:19]=2[CH3:27])[CH:15]=[CH:14][CH:13]=1.CCCC(C)C>N1C=CC=CC=1>[CH3:27][C:19]1[N:20]=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[S:22][C:18]=1[C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:11][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[N:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(=O)Nc1nc(C)c(-c2cccc(N)n2)s1
Solvent: c1ccncc1
Solvent: CCCC(C)C
Product: CC(=O)Nc1nc(C)c(-c2cccc(NS(=O)(=O)c3ccccc3)n2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzenesulfonyl chloride (0.77 mL) was added to a stirred mixture of N-[5-(6-aminopyridin-2-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (249 mg) and pyridine (10 mL) and the reaction mixture was stirred at room temperature for 30 minutes. The resultant mixture was poured into isohexane (400 mL). The supernatant liquid was decanted from a residual gum. A 7M methanolic ammonia solution (20 mL) was added to the residual gum and the mixture was stirred at room temperature for 1 hour. The resultant mixture was evaporated and the residue was purified by preparative HPLC. There was thus obtained the title compound (296 mg); 1H NMR Spectrum: (DMSO-d6) 2.18 (s, 3H), 2.44 (s, 3H), 6.83 (d, 1H), 7.20 (d, 1H), 7.62 (m, 3H), 7.70 (t, 1H), 8.03 (d, 2H), 11.17 (br s, 1H), 12.12 (s, 1H); Mass Spectrum: M+H+ 389.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[F:13][C:14]1[CH:15]=[C:16]([CH:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH:35]=[CH:36][CH:37]=3)[CH2:28][CH2:27]2)[CH:17]=[CH:18][CH:19]=1>>[F:13][C:14]1[CH:15]=[C:16]([CH:20]([O:12][C:3]2[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:27][CH2:28][CH:29]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:41])[CH3:42])[CH:35]=[CH:36][CH:37]=3)[CH2:30][CH2:31]2)[CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3cccc(F)c3)CC2)c1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3cc(C(F)(F)F)ccc3F)c3cccc(F)c3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-(3-{1-[6-(3-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 603.3 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.C=O.[C:32]([O-])([O-])=[O:33].[Na+].[Na+]>CS(C)=O.CCOC(C)=O>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[N:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH2:32][OH:33])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=3)=[N:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C(CO)c1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1

Procedure:
Ethyl 2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)acetate 31 (1 mmol) and paraformaldehyde (5 mmol.) are dissolved in dry DMSO (0.2-0.5M) and heated at 70° C. in the presence of Na2CO3 (5 mmol.) for 2-6 h until greater than 50% conversion is achieved by LC/MS monitoring. The mixture is diluted with EtOAc and washed with water. After concentration, the residue is purified by silica gel chromatography to yield ethyl 2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxypropanoate 32. MS (m/z) (M+1)+: 432.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([S:11]C(OCC)=S)[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([SH:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=S)Sc1cccc(Cl)c1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c(S)cccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 106 %

Procedure:
To a stirred solution of 2.0 grams (0.007 mole) of 6-chloro-2-[ethoxy(thiocarbonyl)thio]benzoic acid in 50 mL of methanol was added 30 ml of aqueous 10% sodium hydroxide. The reaction mixture was warmed to reflux where it stirred for about 18 hours. After this time the reaction mixture was cooled to ambient temperature and was acidified with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to yield 1.4 grams of 6-chloro-2-mercaptobenzoic acid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][C:29]=1[Cl:30])[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=1>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][C:29]=1[Cl:30])[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:2]2[CH:12]=[C:6]3[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]3[C:4](=[O:13])[N:3]=2)=[CH:21][CH:20]=1
Reactant: OCc1ccc(Oc2ccc(Cl)c(Cl)c2)cc1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(Cl)c(Cl)c3)cc1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (4-(3,4-dichlorophenoxy)phenyl)methanol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:10]=3[C:9]=2[C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=2)=[O:19])=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[Si:44](Cl)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]>C1COCC1.CN(C=O)C>[Si:44]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:10]=3[C:9]=2[C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:22][CH:21]=2)=[O:19])=[CH:4][CH:3]=1)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2sc3cc(O)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A solution was prepared consisting of 10 g (21.1 mmol) of [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone and 6 g (49.1 mmol) of dimethylaminopyridine in 700 mL of THF-DMF (6:1)(v/v). This solution was stirred for one hour at ambient temperature and then cooled to 0° C. in an ice bath. To this solution was added 2.9 g (19.3 mmol) of tert-butyl-dimethylsilylchloride. The reaction mixture was stirred under a nitrogen atmosphere and allowed to warm to ambient temperature. After seventy-two hours, the reaction was quenched with the addition of a saturated solution of aqueous NH4Cl. The organic layer was separated and washed with water, brine, and finally dried by filtration through anhydrous Na2SO4 and evaporated to dryness. The crude product was triturated with CH2Cl2, allowed to stand for three hours, and filtered to remove unreacted starting material. This resulting product is a mixture of isomers, which are separated by chromatography on a silica gel column eluted with a linear gradient beginning with CHCl3 and ending with CHCl3 --MeOH (19:1)(v/v). The desired fractions were determined by tlc, combined, and evaporated to dryness. This yielded 5.1 g of the title compound, isolated as a yellow crystalline solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[C:21]([C:22](=[O:24])[NH2:23])=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:13]=2)[N:8]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[C:7]=1[CH2:36][C:37]([O:39]CC)=[O:38])=[O:5])[CH3:2].[OH-].[Na+].CCO>O>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[C:21]([C:22](=[O:24])[NH2:23])=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:13]=2)[N:8]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[C:7]=1[CH2:36][C:37]([OH:39])=[O:38])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ncccc3C(N)=O)ccc2n1-c1ccc(OC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(CC(=O)O)n(-c2ccc(OC(F)(F)F)cc2)c2ccc(Oc3ncccc3C(N)=O)cc12
Temperature: 55 °C
Reaction time: 3 h

Procedure:
A mixture of 5-(3-carbamoylpyridin-2-yl-oxy)-2-ethoxycarbonylmethyl-1-(4-trifluoromethoxy-phenyl)indole-3-carboxylic acid ethyl ester (86 mg, 0.15 mmol, see step (a) above), NaOH (aq, 1M, 0.45 mL), EtOH (1 mL) and H2O (1 mL) was stirred at 55° C. for 3 h, cooled, filtered through Celite® and acidified to pH 4 with HCl (aq, 2M). The solid was filtered off, washed with H2O and purified by chromatography and recrystallisation from EtOAc. Yield 36 mg (46%), mp 128-130° C.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:13]1([C:18]([OH:20])=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.Cl.[NH2:22][CH:23]([CH2:29][SH:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C>CN(C=O)C>[CH:13]1([C:18]([NH:22][CH:23]([CH2:29][SH:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=C(O)C1CCCC1
Reactant: CCOC(=O)C(N)CS
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CS)NC(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
CDI (8.5 g) was added to a solution of cyclopentanecarboxylic acid (5.2 mL) in DMF (40 mL). The resulting mixture was stirred for 1 h and cooled in an ice bath. Ethyl 2-amino-3-mercaptopropanoate hydrochloride (8.88 g) was added, followed by triethylamine (10 mL). The resulting mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with saturated sodium bicarbonate solution (50 mL) and the layers separated. The aqueous was extracted with DCM (2×100 mL). The combined organic solutions were washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated. The resulting solid was purified by silica gel chromatography eluting with 4:1 to 1:1 isohexane:ethyl acetate gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a white solid. Yield 7.7 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13][CH2:14]O)[CH2:10][C@@H:9]1[C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:39]N1C(=O)CCC1=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13][CH2:14][Br:39])[CH2:10][C@@H:9]1[C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)[C@H]1C[C@@H](CCO)CN1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@@H](CCBr)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of 0.58 g of cis methyl N-t-butoxycarbonyl-4-(2-hydroxyethyl)pyrrolidine-2-carboxylate in 6 ml methylene chloride is added at 0° 0.577 g triphenylphosphine followed by 0.388 g N-bromosuccinimide. After stirring 0.5 hour, the solvent is evaporated and the residue flash chromatographed using ethyl acetate/hexane (35:65) to afford cis methyl N-t-butoxycarbonyl-4-(2-bromoethyl)-pyrrolidine-2-carboxylate.