Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(CSC[C@H]1[O:11][C@@H:10]([N:12]2C3NC=NC(=O)C=3N=C2)[C@H](O)[C@@H]1O)C.[C:24]1([OH:34])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.C(N(CC)C(Cl)=O)C>N1C=CC=CC=1>[C:10](=[O:11])([O:34][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)[NH2:12]
Reactant: Oc1cccc2ccccc12
Reactant: CC(C)CSC[C@H]1O[C@@H](n2cnc3c(=O)nc[nH]c32)[C@H](O)[C@@H]1O
Agent: CCN(CC)C(=O)Cl
Solvent: c1ccncc1
Product: NC(=O)Oc1cccc2ccccc12

Procedure:
Sibi et al (J. Org. Chem., 48 (11), 1935-1937, 1983) disclose reaction of 1-naphthol with diethyl carbamyl chloride in pyridine to produce a 1-naphthyl carbamate. Treatment of 1-naphthyl carbamate under the standard conditions for methylation of tertiary amides (1.1 equiv. sec-BuLi/TMEDA/THF/-78° C./1 hour) followed by quenching with methyl iodide, warming to room temperature (8 to 12 hours) and NH4Cl work-up, afforded 2-methyl-1-naphthyl carbamate in a yield of 90%. Carbamate removal was effected in a yield of 90% by reduction (LAH/THF/reflux;H+) or hydrolysis (NaOH/aqueous CH3OH or HO(CH2)2OH/reflux) to yield 2-methyl-1-naphthol.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([OH:11])[CH:10]=1)#[N:4].Br[CH2:16][O:17][CH3:18]>C1COCC1>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([O:11][CH2:16][O:17][CH3:18])[CH:10]=1)#[N:4]
Reactant: COCBr
Reactant: N#Cc1ccc([N+](=O)[O-])c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1cc(C#N)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To sodium hydride (60% oil dispersion, 260 mg, 6.5 mmol), previously washed with hexanes, in THF (5 ml) was added dropwise at rt 5-cyano-2-nitro-phenol (978 mg, 5.96 mmol) in THF (10 ml). The solution turned bright orange and a large prepipitate formed. After stirring 15 min at rt bromomethylmethylether was added dropwise to this stirred slurry and the reaction was stirred for 18 h at rt. The yellow-colored mixture was then partitioned between t-butyl-O-methylether and water and the aqueous portion was extracted (×3) and washed with 5% sodium bicarbonate solution (×4) and brine. After drying (MgSO4), filtration and evaporation under reduced pressure afforded the title compound as a pale yellow solid (1.05 g, 85%).1H NMR(400 MHz, CDCl3) δ 7.84 (d, J=8.4 Hz, 1H), 7.66 (d, J=1.4 Hz 1H), 7.35 (dd, J=8.4 Hz J=1.5 Hz, 1H), 5.34 (s, 2H), 3.55 (s, 3H).
Reaction SMILES: [CH3:1][NH2:2].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]3[C:14]4[S:21][C:20]([C:22]5[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=5)=[CH:19][C:15]=4[N:16]=[CH:17][N:18]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Cl>>[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]3[C:14]4[S:21][C:20]([C:22]5[CH:29]=[CH:28][C:25]([CH2:26][NH:2][CH3:1])=[CH:24][CH:23]=5)=[CH:19][C:15]=4[N:16]=[CH:17][N:18]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: CN
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Agent: Cl
Product: CNCc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from methylamine and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. The product was converted to the mesylate salt analogous to example 17 being converted to the HCl salt. M.P. 140-147° C.; LC-MS: 386 (MH−); HPLC RT: 3.54 minutes.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][O:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][C@H:3]1[CH2:14][OH:15].C(N(CC)CC)C.CS(C)=O>ClCCl>[CH3:1][C:2]1([CH3:16])[CH2:7][O:6][CH:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:4][C@H:3]1[CH:14]=[O:15]
Reactant: CC1(C)COC(c2ccccc2)O[C@H]1CO
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC1(C)COC(c2ccccc2)O[C@H]1C=O
Yield: 74.6 %

Procedure:
Following the general procedure for oxidation reactions of Description 7, 40.2 g (181.9 mmol) of [(4R)-5,5-dimethyl-2-phenyl-1,3-dioxan-4-yl]methan-1-ol (7a) in 1,100 mL of dichloromethane (DCM) in the presence of 126.8 mL (92.1 g, 0.910 mol) of triethylamine and 103.3 mL (113.8 g, 1.456 mol) of dimethylsulfoxide (DMSO) was reacted with 86.9 g (0.55 mol) of sulfur trioxide pyridine complex to afford 38.3 g (96% yield) of the crude title compound (7b). Purification by silica gel column chromatography using mixtures of methyl tert-butyl ether (MTBE) and hexane (Hxn) as eluent (MTBE/Hxn=1:9→MTBE/Hxn=1:6) provided 29.9 g (75% yield) of the title compound (7b) as a colorless liquid. Rf=0.58 (MTBE/Hxn=1:2). 1H NMR (400 MHz, CHCl3): δ=1.04 (s, 3H), 1.27 (s, 3H), 3.69 (d, J=11.6 Hz, 1H), 3.75 (d, J=11.2 Hz, 1H), 3.97 (d, J=1.2 Hz, 1H), 5.56 (s, 1H), 7.35-7.44 (m, 3H), 7.54-7.58 (m, 2H), 9.66 (d, J=1.6 Hz, 1H) ppm. MS (ESI) m/z: 221.0 (M+H)+, 242.9 (M+Na)+. The analytical data for the compound was consistent with that given in the literature (Ito et al., Synthesis, 1993, 137-140).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(O)(C(F)(F)F)=O.[C:35]1([C:41](=[O:49])[CH2:42][C:43](=O)[CH2:44][CH2:45][CH2:46][CH3:47])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:44](/[C:43](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:42]/[C:41](=[O:49])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:45][CH2:46][CH3:47]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CCCCC(=O)CC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCC/C(=C/C(=O)c1ccccc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 1.0 g (2.05 mmol) of Intermediate 45 (as the TFA salt) and 0.86 g (4.2 mmol) of Intermediate 18 to yield 290 mg (25% yield) of Example 23 as a solid: TLC (EtOAc/MeOH , 7/3): Rf=0.55; 1H NMR (DMSO-d6, 400 MHz) δ11.59 (d, 1H, J=9.7), 7.86 (m, 2H), 7.76 (m, 2H), 7.48-7.34 (m, 6H), 7.10 (d, 2H, J=8.5), 7.10 (t, 2H, J=8.4), 6.8 (d, 2H, J=8.6), 5.52 (s, 1H), 4.12 (t, 2H, J=6.5), 4.02 (m, 1H), 3.16 (m, 1H), 2.86 (t, 2H, J=6.5), 2.75 (dd, 1H, J=13.5, 9.5), 2.31 (s, 3H), 1.9 (m, 2H), 1.3-1.1 (m, 4H), 0.73 (t, 3H, J=6.9); low resolution MS (ES+)m/e 553.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([C:15]3([CH:19]=[O:20])[CH2:18][CH2:17][CH2:16]3)[NH:8][CH2:7][CH2:6][C:5]2=1.Cl.[NH2:22][OH:23]>C(O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([C:15]3([C:19]([NH:22][OH:23])=[O:20])[CH2:18][CH2:17][CH2:16]3)[NH:8][CH2:7][CH2:6][C:5]2=1
Reactant: NO
Reactant: O=CC1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NO)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1

Procedure:
A solution of 1.2 g of the compound obtained in Step A in 120 ml of ethanol, 0.54 ml of triethylamine and 0.27 g of hydroxylarnine hydrochloride is stirred for 6 hours and then concentrated under reduced pressure. Chromatography on silica gel (dichloromethane/ethyl acetate: 98/2) enables the expected product to be isolated.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][C:13]=3[C:23]#[CH:24])[N:9]([CH3:25])[CH2:8]1)=[O:5])[CH3:2].[CH:28]([N-]C(C)C)([CH3:30])[CH3:29].[Li+].C(NC(C)C)(C)C.C([Li])CCC.C(I)CC>O1CCCC1>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[N:14]([CH2:29][CH2:28][CH3:30])[C:13]=3[C:23]#[CH:24])[N:9]([CH3:25])[CH2:8]1)=[O:5])[CH3:27]
Reactant: C#Cc1[nH]c2cccc3c2c1C[C@@H]1[C@@H]3C[C@H](NC(=O)N(CC)CC)CN1C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCI
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C#Cc1c2c3c(cccc3n1CCC)[C@H]1C[C@H](NC(=O)N(CC)CC)CN(C)[C@@H]1C2
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Under argon, 109 mg of 1,1-diethyl-3-(2-ethynyl-6-methyl-8α-ergolinyl)urea in 5 ml of absolute tetrahydrofuran is added dropwise at -30° C. to a solution of lithium diisopropylamide, prepared from 0.15 ml of diisopropylamine and 1.8 ml of 0.6-molar n-butyllithium solution (hexane) in 3 ml of absolute tetrahydrofuran at 0° C. within 15 minutes. After 30 minutes of agitation at -30° C., 0.07 ml of propyl iodide is added thereto. The mixture is stirred for one hour at -20° C. and overnight at room temperature. After evaporation, the mixture, after adding sodium bicarbonate solution and a small amount of ethanol, is extracted by shaking with ethyl acetate. The organic phase is concentrated and chromatographed over silica gel with toluene:glacial acetic acid:water=10:10:1, thus obtaining 30 mg of 1,1-diethyl-3-(2-ethynyl-1-propyl-6-methyl-8α-ergolinyl)urea as an oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[CH:11]([N:17]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:19]=[C:18]1[C:27]([O:29]CC)=O)[CH2:10]2)=[O:5])[CH3:2].C([O-])(=O)C.[NH4+:36]>C(O)(=O)C>[CH2:1]([NH:3][C:4]([CH2:6][C:7]1[CH:15]=[CH:14][C:13]2[C:12]3[NH:36][C:27](=[O:29])[C:18]4[N:17]([CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:19]=4)[C:11]=3[CH2:10][C:9]=2[CH:8]=1)=[O:5])[CH3:2]
Reactant: [NH4+]
Reactant: CCNC(=O)Cc1ccc2c(c1)CC(n1cc(C(=O)OCC)nc1C(=O)OCC)C2=O
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCNC(=O)Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nc(C(=O)OCC)cn12
Yield: 63.4 %

Procedure:
A mixture of 3.9 g of diethyl 1-[5-(N-ethylaminocarbonylmethyl)-1-oxoindan-2-yl]imidazole-2,4-dicarboxylate, 33.4 g of ammonium acetate and 200 ml of acetic acid is heated at reflux for 3 hours. The reaction mixture is evaporated on a rotary evaporator, 250 ml of distilled water are added to the evaporation residue and the residue is filtered. The solid obtained is washed with distilled water a number of times and dried in an oven. 2.2 g of ethyl 8-(N-ethylaminocarbonylmethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylate are obtained in the form of a light-brown solid melting above 300° C. (1H NMR spectrum in d6-DMSO, T=300 K, δ in ppm (300 MHz): 1.05 (3H, t, J=6 Hz, CH3), 1.40 (3H, t, J=6 Hz, CH3), 3.12 (2H, m, NCH2), 3.48 (2H, s, CH2CO), 4.05 (2H, s, CH2), 4.40 (2H, q, J=6 Hz, CH2 0), 7.32 (1H, d, J=8 Hz,-arom. CH), 7.42 (1H, 8, arom. CH), 7.83 (1H, d, J=8 Hz, arom. CH), 8.10 (1H, t, J=5 Hz, NH), 8.60 (1H, s, imidazole H)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12](CC=O)[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Mg]Br)C>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC=O)COC1(C)C
Agent: CC[Mg]Br
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCOC1(C)C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
To a stirred solution of (S)-2,2-dimethyl-4-(2-oxo-ethyl)-oxazolidine-3-carboxylic acid tert-butyl ester (15.5 g; CAS 147959-19-1) in dry diethyl ether (100 ml) under an argon atmosphere at room temperature was added dropwise a solution of ethylmagnesium bromide in diethyl ether (42.6 ml, 3 M solution) and stirring continued for 1 hour. The reaction mixture was then quenched by careful addition of water (10 ml) and the mixture was then filtered through decalite. The filtrate was washed sequentially with water and with saturated brine and then the organic phase was separated, dried over sodium sulphate, filtered and concentrated in vacuo. The reside was purified by column chromatography (SiO2; gradient: heptane/EtOAc 100:0→50:50) to give (S)-4-(R)-2-hydroxy-butyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (7.30 g) from fractions eluting first and (S)-4-(S)-2-hydroxy-butyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (6.44 g) from fractions eluting later, both compounds as colourless oils. (S)-4-(R)-2-Hydroxy-butyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester: 1H NMR δ (CDCl3, 300 MHz): 4.52 (1H, br. D, J=3.3 Hz), 4.23 (1H, m), 4.00 (1H, dd, J=8.7 & 5.4 Hz), 3.66 (1H, d, J=8.7 Hz), 3.40 (1H, m), 1.79 (1H, td, J=11.4 & 2.1 Hz), 1.60-1.44 (16H, m), 0.95 (3H, t, J=7.5 Hz). (S)-4-(S)-2-Hydroxy-butyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester: 1H NMR δ (CDCl3, 300 MHz): 4.12 (1H, m), 3.98 (1H, dd, J=9.0 & 5.7 Hz), 3.82 (1H, m), 3.55 (1H, m), 2.88 (1H, br. s), 1.79 (1H, m), 1.70-1.40 (16H, m), 0.95 (3H, t, J=7.5 Hz).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:47])[C@@H:5]([NH:15][C:16]([C:18]1[S:26][C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[O:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]3[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=3[F:45])=[O:36])=[C:30]([F:46])[CH:29]=2)[CH:19]=1)=[O:17])[CH2:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([NH:3][C:4](=[O:47])[C@@H:5]([NH:15][C:16]([C:18]1[S:26][C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[O:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]3[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=3[F:45])=[O:36])=[C:30]([F:46])[CH:29]=2)[CH:19]=1)=[O:17])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH3:2]
Reactant: CCNC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)[C@H](CCC(=O)O)NC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of tert-butyl (4S)-5-(ethylamino)-4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoate (70 mg, 0.10 mmol) in 5 ml of methylene chloride was added 2 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 2 hours and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5 ml) and poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give (4S)-5-(ethylamino)-4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoic acid as light yellow solid. Yield: 53 mg, 83%.
Reaction SMILES: [C:1]([C:4]1[C:13]2[O:12][CH2:11][C:10](=[O:14])[NH:9][C:8]=2[CH:7]=[C:6]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=1)(=[O:3])[CH3:2].C(O)(=O)C.O.S([O-])(O)=O.[Na+].[Cl:33]C(Cl)C>>[CH2:16]([O:15][C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH2:2][Cl:33])[C:13]2[O:12][CH2:11][C:10](=[O:14])[NH:9][C:8]=2[CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Reactant: CC(Cl)Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1COc2c(cc(OCc3ccccc3)cc2C(=O)CCl)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
13.8 g (46.0 mmol) 8-acetyl-6-benzyloxy-4H-benzo[1,4]oxazin-3-one and 35.3 g (101.5 mmol) benzyltrimethylammonium-dichloriodate are stirred in 250 mL dichloroethane, 84 mL glacial acetic acid and 14 mL water for 5 hours at 65° C. After cooling to ambient temperature the mixture is combined with 5% sodium hydrogen sulphite solution and stirred for 30 minutes. The precipitated solid is suction filtered, washed with water and diethyl ether and dried. Yield: 13.2 g (86%); mass spectroscopy [M+H]+=330/32.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH3:28][C:29]1[O:30][C:31]2[CH:46]=[CH:45][CH:44]=[CH:43][C:32]=2[C:33]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[CH3:28][C:29]1[O:30][C:31]2[CH:46]=[CH:45][CH:44]=[CH:43][C:32]=2[C:33]=1[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:13]3)[S:8][C:6]=2[N:7]=1
Reactant: Cc1oc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)sc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1oc2ccccc2c1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)sc2n1
Temperature: 140 °C
Yield: 47.7 %

Procedure:
A mixture of 5-chloro-7-morpholin-4-yl-2-(3-morpholin-4-ylazetidin-1-ylmethyl)thiazolo[5,4-d]pyrimidine (100 mg, 0.24 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzofuran (94 mg, 0.37 mmol), tetrakis(triphenylphosphine)palladium (28 mg, 0.02 mmol) and Cs2CO3 (159 mg, 0.48 mmol) in dioxane (6 mL) and H2O (3 mL) was purged with argon then heated at 140° C. for 30 min in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with DCM/MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-5%) to afford 212 as a cream solid (58 mg, 48%). LCMS (Method G): RT 9.83 min, [M+H]+ 507.3. 1H NMR (CDCl3, 400 MHz): δ 8.39-8.36 (m, 1 H); 7.45-7.42 (m, 1 H); 7.32-7.24 (m, 2 H); 4.40 (m, 4 H); 4.01 (s, 2 H); 3.89 (m, 4 H); 3.70 (m, 6 H); 3.18-3.08 (m, 3 H); 2.92 (s, 3H) and 2.36 (m, 4 H)
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][C@@H:5]2[CH2:4][O:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:4]1[C@H:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[C:2](=[O:1])[O:3]1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)OC[C@H]2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC[C@H]2CNCCN12
Yield: 134.2 %

Procedure:
To a cooled (0° C.) solution of (R)-tert-butyl 3-oxo-tetrahydro-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylate (3.01 g, 12 mmol) in 100 mL CH2Cl2 was added TFA (75 mL, 973 mmol) dropwise. After 2 h the reaction mixture was concentrated to dryness to give a brown semi-crystalline solid, which was purified through a plug of silica gel eluting successively with hexane, Et2O, CH2Cl2 and 10% 2M NH3 in MeOH/CH2Cl2 to give 2.29 g of an orange oil. MS m/z: 143.1 [M+1].
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C@@H:7]([N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6](=[O:20])[C@@H:7]([N:9]1[C:10](=[O:19])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]1[OH:18])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](C(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1O
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a solution of (2S)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionic acid tert-butyl ester (426 mg, 1.55 mmol) in a mixture of THF (10 mL) and MeOH (2 mL) was added sodium borohydride (181 mg, 4.8 mmol) in one portion. The reaction mixture was stirred for 30 minutes before solvents were evaporated at room temperature and the residue was columned on silica (Petrol/AcOEt, 8/2) to afford the sub-title compound as colorless oil (284 mg, 66%): 1H NMR (400 MHz CDCl3) δ 1.38-1.40 (9H, 2s), 1.57-1.60 (3H, 2d), 4.38-4.45 (1H, m), 4.65-4.76 (1H, m), 5.81-6.01 (1H, 2d), 7.33-7.64 (4H, d).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:8]=1)(=O)=O.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:21]1([CH2:6][C:7]2[N:8]=[C:9]([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:11][CH:12]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)Nc1cccc(COS(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cccc(CN2CCOCC2)n1
Reaction time: 16 h

Procedure:
To a solution of {6-[(tert-butoxycarbonyl)amino]pyridin-2-yl}methyl methanesulfonate (160 mg, 0.52 mmol) in acetonitrile (2.5 mL) was added morpholine (90 mg, 1.0 mmol) and potassium carbonate (214 mg, 1.55 mmol) at room temperature. After 16 hours, the reaction mixture was quenched with aqueous saturated sodium bicarbonate, partially concentrated under reduced pressure, and diluted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford tert-butyl [6-(morpholin-4-ylmethyl)pyridin-2-yl]carbamate that was used without further purification. MS ESI calc'd for C15H24N3O3 [M+H]+ 294. found 294.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([CH3:34])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:33]=[CH:32][C:23]([CH2:24][CH:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:22][CH:21]=1)([CH3:17])[CH:9]=[CH:8]2>[Pd].C(O)C>[OH:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([CH3:34])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:33]=[CH:32][C:23]([CH2:24][CH:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:22][CH:21]=1)([CH3:17])[CH2:9][CH2:8]2
Reactant: Cc1c(C)c2c(c(C)c1OCCO)C=CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: [Pd]
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1OCCO)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
Following the same procedure as described in Example 41, 0.35 g of 5-{4-[6-(2-hydroxyethoxy)-2,5,7,8-tetramethyl-2H-chromen-2-ylmethoxy]benzyl}-thiazolidine-2,4-dione (prepared as described in Example 40), 0.3 g of 10% w/w palladium on activated carbon and 10 ml of ethanol gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([OH:6])=O.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C.[Cl-].ClC1N(C)CC[NH+]1C>ClCCl.O>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([NH:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:6]
Reactant: NCc1ccccc1
Reactant: COc1cccc(N)c1C(=O)O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cccc(N)c1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.3 %

Procedure:
To a solution of 2-amino-6-methoxybenzoic acid (0.841 g, 5.0 mmol, 1.0 equiv), benzylamine (0.643 g, 6.0 mmol, 1.2 equiv), and diisopropylethylamine (1.935 g, 15.0 mmol, 3.0 equiv) in 50 mL of dichloromethane was added 2-chloro-1,3-dimethylimidazolinium chloride (1.099 g, 6.5 mmol, 1.3 equiv) at room temperature. The mixture was stirred at room temperature for 6 hours, poured into water, and extracted with dichloromethane. The organic solution was successively washed with aqueous saturated NaHCO3 and water. The organic layer was dried over MgSO4 and the solvent was removed by rotary evaporator. The residue was purified by column chromatography (silica gel, 2% 2.0 M ammonia MeOH solution in CH2Cl2) to give 2-Amino-N-benzyl-6-methoxybenzamide (0.593 g, 46%) as a solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 3.81 (s, 3H), 4.62 (s, 1H), 4.63 (s, 1H), 6.07 (vb.s, 2H), 6.19 (d, J=8.2 Hz, 1H), 6.32 (d, J=8.2 Hz, 1H), 7.07 (t, J=8.2 Hz, 1H), 7.14-7.54 (m, 5H), 8.05 (br. s., 1H); HPLC: tR=4.72 min, UV254=99%; HRMS (ESI): m/z calcd for C15H16N2O2 [M+1]+257.1296. found 257.1294.