Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21][C:20]1=[O:29]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][NH:21][C:20]2=[O:29])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1C(=O)NCc2ccccc21
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NCc2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine and 4-amino-1,2,3,4-tetrahydroisoquinoline-3-one, the title compound was prepared as a solid having a melting point of 243–244° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[NH2:19][C:20]1[CH:30]=[CH:29][C:23]2[NH:24][C:25](=[O:28])[CH2:26][O:27][C:22]=2[CH:21]=1>C(O)C>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][NH:19][C:20]3[CH:30]=[CH:29][C:23]4[NH:24][C:25](=[O:28])[CH2:26][O:27][C:22]=4[CH:21]=3)[CH2:6][CH2:7]2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(CC2CCN(C(=O)CCl)CC2)cc1
Reactant: Nc1ccc2c(c1)OCC(=O)N2
Solvent: CCO
Product: Cc1ccc(CC2CCN(C(=O)CNc3ccc4c(c3)OCC(=O)N4)CC2)cc1

Procedure:
The title compound is prepared from 2-chloro-1-[4-(4-methyl-benzyl)-piperidin-1-yl]-ethanone (Example 227a) and 7-amino-4H-benzo[1,4]oxazine-3-one according to the method described in Example 206. Melting Point: 206-208° C. (ethanol)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7](Cl)[N:6]=1)=[O:4].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(C(C)C)C(C)C)C>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:25][CH:22]2[CH2:21][CH2:20][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:24][CH2:23]2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccnc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Reaction time: 0.67 h

Procedure:
A mixture of 2-chloro-pyrimidine-4-carboxylic acid methyl ester (0.62 g, 3.59 mmol, 1.0 equiv), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.86 g, 4.31 mmol, 1.2 equiv; commercially available) and N-ethyl diisopropylamine (0.73 mL, 0.56 g, 4.31 mmol, 1.2 equiv) in acetonitrile (60 mL) was heated by microwave irradiation to 110° C. After stirring for 40 min, the reaction mixture was concentrated under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 0.48 g (34%) of the title compound. MS (ISP): 337.5 [M+H]+.
Reaction SMILES: [CH:1]([O:3][CH:4]1[CH2:9][C:8]([CH3:12])([CH2:10]C)[NH:7][C:6]([CH3:15])([CH2:13]C)[CH:5]1C)=[CH2:2].C(O[CH:20]1[CH2:25][C:24](C)(C)N(CC=C)[C:22]([CH3:32])([CH3:31])[CH2:21]1)=C.C(OC1CC(C)(C)N(CCCC)C(C)(C)C1)=C.C(OC1CC(C)(C)NC(C)(C)C1)=C>>[CH:1]([O:3][CH:4]1[CH2:5][C:6]([CH3:13])([CH3:15])[N:7]([CH2:32][C:22]2[CH:21]=[CH:20][CH:25]=[CH:24][CH:31]=2)[C:8]([CH3:10])([CH3:12])[CH2:9]1)=[CH2:2]
Reactant: C=COC1CC(C)(CC)NC(C)(CC)C1C
Reactant: C=CCN1C(C)(C)CC(OC=C)CC1(C)C
Agent: C=COC1CC(C)(C)N(CCCC)C(C)(C)C1
Agent: C=COC1CC(C)(C)NC(C)(C)C1
Product: C=COC1CC(C)(C)N(Cc2ccccc2)C(C)(C)C1

Procedure:
The following compounds were obtained in a similar manner: 2,3,6-trimethyl-2,6-diethyl-4-piperidyl vinyl ether, boiling point 121°/18 mm Hg; 1-allyl-2,2,6,6-tetramethyl-4-piperidyl vinyl ether, boiling point 63°/0.1 mm Hg; 1-butyl-2,2,6,6-tetramethyl-4-piperidyl vinyl ether, boiling point 66°-67°/0.1 mm Hg and 2,2,6,6-tetramethyl-4-piperidyl vinyl ether, boiling point 78°/19 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.C(N(CC)CC)C.Cl[C:15]([O:17][CH3:18])=[O:16]>C(#N)C>[CH3:18][O:17][C:15](=[O:16])[NH:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1
Reactant: COC(=O)Cl
Reactant: Nc1nnn[nH]1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)Nc1nnn[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-Amino tetrazole (10.00 g, 117.56 mmol)/Triethyl amine (16.48 ml, 118.739 mmol) in acetonitrile was added Methyl chloroformate (9.1375 ml, 118.739 mmol) at 0° C. The reaction mixture was slowly brought to room temperature and stirred for about 30 minutes. After about 30 minutes the reaction warmed and was refluxed for about 2 hrs. The reaction was then cooled to room temperature and the solvent was removed under reduced pressure, leaving a residue. The residue was washed with dilyte HCl to yield a white-colored solid. The solid was then dried at 105 C for about 6 hrs, resulting in a 92% yield.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].C(OC([N:37]1[C:45]2[C:40](=[CH:41][C:42]([CH:46]=O)=[CH:43][CH:44]=2)[CH:39]=[C:38]1[C:48]1[C:49](=[O:58])[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][CH:52]=2)=O)(C)(C)C>C1COCC1>[CH3:2][O:3][CH:4]=[CH:46][C:42]1[CH:41]=[C:40]2[C:45](=[CH:44][CH:43]=1)[NH:37][C:38]([C:48]1[C:49](=[O:58])[NH:50][C:51]3[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][CH:52]=3)=[CH:39]2
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3[nH]c2=O)cc2cc(C=O)ccc21
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of (methoxymethyl)triphenylphosphonium chloride (3.6 g, 10.5 mmol, 2.1 equiv) and potassium t-butoxide (2.48 g, 22 mmol, 4.4 equiv) was stirred 1 hour at 25° C. before a suspension of t-butyl 5-formyl-2-(2-oxo-1,2-dihydroquinolin-3-yl)-1H-indole-1-carboxylate (5-8, 1.94 g, 5.0 mmol, 1 equiv) in THF (100 mL) was added via canula and the resulting mixture was stirred at 25° C. for 18 hours. The reaction was concentrated and the residue was stirred in saturated NH4Cl solution. The insoluble solid was collected by filtration and sonicated in EtOAc and then water to give 3-{5-[2-methoxyethenyl]-1H-indol-2-yl}quinolin-2(1H)-one (10-1) as a 1:1 mixture of E and Z isomers. MS(M+1)=317.1
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([F:14])[CH:13]=1)[C:10](=O)[O:9][CH:8]2OC)([CH3:4])([CH3:3])[CH3:2].O.[NH2:19][NH2:20].O>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([F:14])[CH:13]=1)[C:10](=[O:9])[NH:20][N:19]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: COC1OC(=O)c2c(F)cc(C(C)(C)C)cc21
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(F)c2c(=O)[nH]ncc2c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 37.6 %

Procedure:
To a solution of 101g (40 g, 168 mmol) in glacial acetic acid (360 mL) was added hydrazine monohydrate (240 mL) at 0-10° C. under N2 protection. The resulting slurry was stirred under nitrogen at 50° C. for 1.5 hours. The reaction mixture was poured into 300 mL of water with continuous stirring. The aqueous phase was extracted with DCM (2×500 mL), and the combined organic phase was dried over Na2SO4, filtered and concentrated to give a residue, which was purified by re-crystallization in DMC and Et2O to provide 101h (17 g, 37.6% over 2 steps) as an off-white solid. 1HNMR (300 MHz, CDCl3) δ 8.11 (d, J=2.7 Hz, 1H), 7.46 (m, 2H), 1.39 (s, 9H). LCMS (ESI) m/z 221 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:42]/[CH:43]=[CH:44]/[C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51])[CH2:46][CH3:47]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:42]/[CH:43]=[CH:44]/[C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:50][CH3:51])[CH2:52][CH3:53])[CH2:46][CH3:47])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCC(/C=C/CBr)(CC)O[Si](CC)(CC)CC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(/C=C/CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Yield: 72.9 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5(10 μl) and (E)-1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene (134 mg, 0.420 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (62.4 mg, 73%).
Reaction SMILES: [CH3:1][Si:2]([CH3:6])([CH3:5])[C:3]#[CH:4].N12CCN(CC1)CC2.Br[C:16]1[S:20][C:19]([C:21]2[N:22]=[C:23]3[N:27]([C:28]=2[NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:26]=[CH:25][S:24]3)=[CH:18][CH:17]=1.C(Cl)Cl>C(#N)C>[C:30]([NH:29][C:28]1[N:27]2[C:23]([S:24][CH:25]=[CH:26]2)=[N:22][C:21]=1[C:19]1[S:20][C:16]([C:4]#[C:3][Si:2]([CH3:6])([CH3:5])[CH3:1])=[CH:17][CH:18]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)Nc1c(-c2ccc(Br)s2)nc2sccn12
Reactant: C#C[Si](C)(C)C
Agent: C1CN2CCN1CC2
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)Nc1c(-c2ccc(C#C[Si](C)(C)C)s2)nc2sccn12
Yield: 22.5 %

Procedure:
4.1 g (3.5 mmol) tetrakis(triphenyl)phosphine-palladium(0), 17.2 g (175.4 mmol) trimethyl-silylacetylene and 7.9 g (70.2 mmol) 1,4-diazabicyclo[2.2.2]octane were consecutively added to a suspension of 12.5 g (35.1 mmol) 6-(5-bromothiophene-2-yl)-N-tert-butylimidazo[2,1-b]thiazole-5-amine in acetonitrile (150 ml). The reaction solution was heated for 72 h under reflux and subsequently concentrated in a vacuum. 3.0 g (7.9 mmol, 23%) N-tert-butyl-6-(5-((trimethylsilyl)ethynyl)thiophene-2-yl)imidazo[2,1-b]thiazole-5-amine ([MH+] 374.1) was obtained by CC (DCM/AE 95:5).
Reaction SMILES: CC(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:11]=[C:10]([S:33]([CH3:35])=[O:34])[CH:9]=1)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:35][S:33]([C:10]1[CH:9]=[C:8]([NH2:7])[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:11]=1)=[O:34]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(NC(=O)OC(C)(C)C)cc(S(C)=O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(S(C)=O)c1

Procedure:
A solution of 1.5 g (2.86 mmol) of 3-(methylsulfinyl)-5-(octadecyloxy)phenylcarbamic acid dimethylethyl ester and 1.1 ml (14.3 mmol) of trifluoroacetic acid in 50 ml of methylene chloride was kept at room temperature for 41 hours. The solvent was removed at reduced pressure, the residue was treated with NaHCO3 solution and the product was extracted with methylene chloride. The dried extract was concentrated at reduced pressure to a solid which was recrystallized from methylene chloride-hexane to give 1.13 g (94% yield), mp 104°-106°, of 3-(methylsufinyl)-5-(octadecyloxy)benzenamine.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[S:32]1[CH:36]=[C:35]([CH2:37][CH2:38][NH2:39])[N:34]=[CH:33]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:39][CH2:38][CH2:37][C:35]1[N:34]=[CH:33][S:32][CH:36]=1)=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCCc1cscn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCCc1cscn1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 41.3 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), 2-(thiazol-4-yl)ethanamine (8.92 mg, 0.070 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 40-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(2-(thiazol-4-yl)ethyl)acetamide (10.1 mg, 0.019 mmol, 40.2% yield): LCMS=542.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.82 (1 H, d, J=2.01 Hz), 8.13 (2 H, d, J=8.28 Hz), 7.49-7.72 (8 H, m), 7.08 (1 H, d, J=2.01 Hz), 5.08 (1 H, s), 3.53-3.69 (2 H, m), 3.03 (2 H, t, J=6.78 Hz); HPLC peak RT=2.6 min (Method E).
Reaction SMILES: C(=O)=O.[CH3:4][C:5](C)=[O:6].[CH:8]1[C:20]2[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1.[H-].[Na+].C1OC1>O1CCCC1>[OH:6][CH2:5][CH2:4][N:19]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:20]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CC(C)=O
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CO1
Solvent: C1CCOC1
Product: OCCn1c2ccccc2c2ccccc21
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A 1-liter three-necked round bottom flask was equipped with a mechanical stirrer, an addition funnel, Dry Ice/acetone reflux condenser and a means for providing nitrogen atmosphere. To the flask were added 67 g (0.4 mole) of carbazole, 11 g (0.44 mole) of sodium hydride and 0.5 liter of dry tetrahydrofuran. After stirring vigorously at 0° C. for about 2.5 hours, 18 g (0.4 mole) of ethylene oxide was added dropwise to the reaction mixture over a period of 1 hour at 0° C. After the addition, stirring was continued for additional 5 hours and the tetrahydrofuran was evaporated. The residue was fully washed with water and then recrystallized from ether to give 80 g of N-(2-hydroxyethyl)carbazole.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.CCN(CC)CC.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:21]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](OC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a solution of (3S)-pyrrolidin-3-ol (0.87 g, 10.0 mmol) in THF (20 mL) was slowly added a solution of di-tert-butyl dicarbonate (2.18 g, 10.0 mmol) in THF (10 mL) at room temperature. After addition was completed, the reaction mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (0-2.5% methanol in dichloromethane) to give intermediate tert-Butyl(3S)-3-hydroxypyrrolidine-1-carboxylate. To a solution of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (900 mg, 4.8 mmol) in CH2Cl2 (6 mL) was added Et3N (699 mg, 6.91 mmol) followed by benzoyl chloride (809 mg, 5.76 mmol) at 0° C. After addition was completed, the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between CH2Cl2 and H2O. The organic layer was successively washed with aqueous NaHCO3 and water, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-1% methanol in dichloromethane) to give the subtitled compound (642 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:36][C:37]1[O:38][CH:39]=[CH:40][N:41]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[O:38]1[CH:39]=[CH:40][N:41]=[C:37]1[CH2:36][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(O)c4)nc4ccccc34)ccc21
Reactant: ClCc1ncco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(OCc5ncco5)c4)nc4ccccc34)ccc21
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A suspension of tert-butyl 5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol), 2-(chloromethyl)oxazole (31 mg, 0.26 mmol), KI (44 mg, 0.27 mmol), and K2CO3 (122 mg, 0.88 mmol) in dry DMF (1.5 mL) was stirred at 70° C. for 1 h. The mixture was poured into water, filtered, dried under high vacuum for several hours to afford tert-butyl 5-(2-(3-(oxazol-2-ylmethoxy)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate.
Reaction SMILES: Cl.[C:2]1([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].C(C[P+](C)(C)C)#N.O[CH2:23][C:24]1[CH:33]=[N:32][C:31]2[N:30]3[CH2:34][CH2:35][CH2:36][C@H:29]3[C:28](=[O:37])[NH:27][C:26]=2[CH:25]=1.CCN(C(C)C)C(C)C>C(#N)CC>[C:2]1([N:8]2[CH2:13][CH2:12][N:11]([CH2:23][C:24]3[CH:33]=[N:32][C:31]4[N:30]5[CH2:34][CH2:35][CH2:36][C@H:29]5[C:28](=[O:37])[NH:27][C:26]=4[CH:25]=3)[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: c1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2cc(CN3CCN(c4ccccc4)CC3)cnc2N2CCC[C@@H]12
Temperature: 90 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
1-Phenylpiperazine hydrochloride (11.9 mg, 0.060 mmol), (cyanomethyl)trimethylphosphonium iodide (0.025 g, 0.102 mmoles), and (S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (0.014 g, 0.063 mmoles) were diluted with propionitrile (0.5 ml) and treated with DIPEA (0.017 ml, 0.100 mmol). The reaction mixture was stirred at 90° C. overnight. The reaction mixture was washed with water (1 mL) and concentrated. The residue was dissolved in DMSO (1 mL) and purified using HPLC (acetonitrile-water, NH4HCO3 buffered). The fractions were concentrated in vacuo, dissolved in dioxane-water (1:1:, 2 mL) and lyophilized to yield the title compound as a white solid (5.1 mg, 23%). [M+H] calc'd for C21H25N5O 364; found, 364.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:6]([CH2:16][OH:17])=[CH:5][C:4]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[C-:25]#[N:26].[Na+].O>CN(C=O)C>[CH2:19]([O:18][C:4]1[CH:5]=[C:6]([CH2:16][OH:17])[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:8][C:3]=1[CH2:2][C:25]#[N:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCOc1cc(CCl)c(OCCCCCC)cc1CO
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCOc1cc(CC#N)c(OCCCCCC)cc1CO
Yield: 88.5 %

Procedure:
A solution of the chloride (31) (1.52 g) and sodium cyanide (0.22 g) in DMF (50 ml) was stirred at 60° C. for 3 h. It was poured into water (100ml), and extracted with ether -hexane (1:1, 150 ml ). The organic fraction was washed with water, dried (MgSO4) and the solvent evaporated to give an oil, which was crystallised from hexane (80 ml) to give (32), (1.31 g, 88%), as needles, m.p 63°-66° C., Found C. 73.0, 9.7, N 3.8, C21H33NO3 requires C 72.6, 9.6, N 4.0%!; vmax (KBr)/cm-1 3334 m, 2250 m, 1511 s, 1425 s, 1395 s, 1216 s, 1192 s, 1034 s, 998 s, 871 m, 724 m; δH (250.1 MHZ; CDCl3) 0.9-1.9 (22H, m), 4.36 (4H, m), 2.42 (1H, t, J=5), 3.68 (2H, s), 4.66 (2H, d, J=5), 6.84 (1H, s), 6.89 (1H, s); δC (62.9 MHz; CDCl3) 14.1, 18.7, 22.7, 25.9, 29.4, 31.7, 62.0, 69.1, 112.4, 112.7, 118.3, 130.2, 150.2, 150.7, m/z (CI) 347 (M+, 43), 330 (100), 263 (5).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH2:13][C:14]2[N:15]=[C:16]([CH3:19])[S:17][CH:18]=2)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:32][CH:33]1[CH:38]2[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]2)[CH2:34]1>O1CCCC1>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:32][CH:33]2[CH:38]3[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]3)[CH2:34]2)=[O:8])=[C:4]([O:12][CH2:13][C:14]2[N:15]=[C:16]([CH3:19])[S:17][CH:18]=2)[CH:3]=1
Reactant: NC1CN2CCC1CC2
Reactant: Cc1nc(COc2cc(N)c(Cl)cc2C(=O)O)cs1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1nc(COc2cc(N)c(Cl)cc2C(=O)NC2CN3CCC2CC3)cs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.4 %

Procedure:
A suspension of 4-amino-5-chloro-2-[(2-methylthiazol-4-yl)methoxy]benzoic acid (1.54 g, 5 mmoles) in anhydrous tetrahydrofuran (5 ml) was treated with 1,1'-carbonyldiimidazole (0.89 g, 5.5 mmoles), stirred at room temperature for 90 minutes, then added to a cooled (0° C.) solution of 3-aminoquinuclidine (from 6 mmoles of dihydrochloride salt and 12 mmoles of 25% sodium methoxide/methanol) in anhydrous tetrahydrofuran (5 ml) under nitogen. After 3 hours at room temperature and one hour at 60° C., the solution was concentrated in vacuo and partitioned between methylene chloride (50 ml) and 1.5N sodium hydroxide (20 ml). The organic layer was washed with 1.5N sodium hydroxide (20 ml), saturated sodium bicarbonate (20 ml), and brine (20 ml), dried (Na2SO4), and concentrated in vacuo. Filtration through alumina (eluted with 10% methanol/methylene chloride) provided 1.35 g (66%) of a colorless foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16](Br)=[CH:17][CH:18]=3)[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[CH3:28])[CH:5]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])(O)=O.[Na+]>COCCOC.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>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:18]=3)[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[CH3:28])[CH:5]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccc3)c3cc(Br)ccc23)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccc3)c3cc(-c4ccccc4)ccc23)c1
Temperature: 90 °C

Procedure:
3-(1-Benzyl-6-bromo-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.080 g, 0.17 mmol), phenylboronic acid (0.042 g, 0.34 mmol), NaHCO3 (0.073 g, 0.85 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.012 g, 0.02 mmol) were suspended in DME:H2O (1:1, 3 mL) and the reaction vessel was purged with N2 (g). The reaction was heated to 90° C. and after two hours the mixture was submitted to aqueous workup then purified by silica gel chromatography (0-30% EtOAc in hexanes) to give the title compound.