Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[C:4]=1[OH:10].Br[CH2:12]Cl.O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]2[O:10][CH2:12][O:9][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(O)c1O
Reactant: ClCBr
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c1OCO2
Reaction time: 4 h

Procedure:
A mixture of 3-methoxy-benzene-1,2-diol (1.161 g, 8.28 mmol) in DMF (10 mL) was added to bromo-chloro-methane (611 ul, 1.1 equivalents) and stirred at 90 degrees Celsius for 4 hours. The mixture was poured into water and extracted with dichloromethane. The organic layer was poured thru a phase separator cartridge and concentrated to dryness. The crude product is a yellow liquid. The liquid was purified by column chromatography yielding 1.21 g, (96%). 1H-NMR (DMSO, 500 MHz) 6.7 (t, 1H), 6.63 (d, 1H), 6.58 (d, 1H), 5.97 (s, 2H), 3.83 (s, 3H)HPLC (method A) 2.86 min.
Reaction SMILES: [NH2:1][C:2]1[CH:38]=[CH:37][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:36]=[CH:35][C:19]([CH2:20][N:21]([CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34])[C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:39])[CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:50](Cl)([O:52]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:61][C:62]1[CH:66]=[C:65]([CH3:67])[O:64][N:63]=1>O1CCCC1>[F:39][C:4]1[CH:3]=[C:2]([NH:1][C:50]([NH:61][C:62]2[CH:66]=[C:65]([CH3:67])[O:64][N:63]=2)=[O:52])[CH:38]=[CH:37][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([CH2:20][N:21]([CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34])[C:22](=[O:24])[CH3:23])=[CH:35][CH:36]=3)[S:15][C:8]=12
Reactant: COCCOCCOCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1)C(C)=O
Reactant: Cc1cc(N)no1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCCOCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5cc(C)on5)cc4F)c3s2)cc1)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a solution of 370 (0.14 g, 0.25 mmol) and DIPEA (0.11 mL, 0.080 g, 0.61 mmol) in tetrahydrofuran (50 mL) at 0° C. was added triphosgene (0.030 g, 0.10 mmol) and the resulting solution was stirred for 0.5 h at 0° C. 3-Amino-5-methylisoxazole (0.074 g, 0.76 mmol) was added and the mixture was warmed to room temperature and stirred for 3 h, then quenched with 1 mL of water and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water; the organic phase was collected, washed with brine, dried over MgSO4, filtered and concentrated. The product was purified by silica gel chromatography (10% MeOH in EtOAc), followed by Gilson reverse phase HPLC (35-65% acetonitrile/H2O, Aquasil C18, 30 min) and lyophilized. The residue (containing some formic acid from the HPLC) was partitioned between dichloromethane and 1M NaOH. The organic phase was dried (MgSO4), filtered and concentrated to give 371 (65 mg, 38% yield) as a 2:1 mixture of rotamers by 1H NMR. 1H NMR (DMSO-d6) δ (ppm) 1H: 9.64 (s, 1H); 9.19 (s, 1H); 8.50-8.48 (m, 1H); 8.04 (s, 0.4H); 8.01 (s, 0.6H); 7.89 (d, J=8.2, 0.4H); 7.82 (d, J=8.2, 0.6H); 7.72 (dd, J=12.9, 2.5, 1H); 7.45 (t, J=9.2, 1H); 7.33 (d, J=8.4, 2H); 7.27-7.24 (m, 1H); 6.61-6.59 (m, 1H); 6.54 (d, J=0.8, 1H); 4.68 (s, 0.4H); 4.59 (s, 0.6H); 3.52-3.38 (m, 12H); 3.21 (s, 1.8H); 3.20 (s, 1.2H); 2.35 (d, J=0.4, 3H); 2.12 (s, 1.8H); 2.00 (1.2H). LRMS (M+H): 678.8
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C@H:10]3[C@@:12]4([C:20]5[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=5)[NH:14][C:13]4=[O:22])[CH2:11]3)[CH:8]=2)[CH:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].[I:29]I>CN(C=O)C>[I:29][C:3]1[C:4]2[C:9](=[CH:8][C:7]([C@H:10]3[C@@:12]4([C:20]5[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=5)[NH:14][C:13]4=[O:22])[CH2:11]3)=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: Cc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3cn[nH]c3c1)C(=O)N2
Reactant: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(I)n[nH]c3c1)C(=O)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
To a solution of (1R,2S)-2-(1H-indazol-6-yl)-5′-methylspiro[cyclopropane-1,3′-indolin]-2′-one (680 mg, 2.35 mmol) in DMF (16 mL) was added K2CO3 (544 mg, 4 mmol), followed by iodine (851 mg, 3.2 mmol). The resulting mixture was stirred for 3 h at rt, cooled to 0° C., quenched with sat. Na2S2O3, diluted with H2O, extracted with EtOAc (50 mL×3) and dried (Na2SO4). Evaporation of solvents and purification by Biotage Isolera (EtOAc/hexane gradient: 10-90%) gave the title compound as a light yellow solid (794 mg, 81%; >98% e.e.). The major (1R,2S)-enantiomer eluted at 9.6 min (Phenomenex Lux 5u Cellulose-2 (150×4.6 mm); isocratic 10% EtOH in n-hexane 1.75 L/min; ambient temperature; Detection: 254, 214 nm). From the racemic reference standard, the retention time of the (1S,2R)-enantiomer was 7.7 min using this method. 1H NMR (400 MHz, DMSO-d6) δ 13.46 (s, 1H), 10.51 (s, 1H), 7.47 (s, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.81 (d, J=7.6 Hz, 1H), 6.73 (d, J=7.6 Hz, 1H), 5.86 (s, 1H), 3.16 (t, overlapping with trace MeOH residue), 2.32-2.25 (m, 1H), 2.00-1.93 (m, 1H), 1.85 (s, 3H); MS ESI 416.0 [M+H]+, calcd for [C18H14IN3O+H]+ 416.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[CH:10]([C@@H:12]1[N:16]([CH3:17])[C:15](=[O:18])[CH2:14][C@@H:13]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:11]>CCOC(C)=O.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C@H:10]([C@@H:12]2[N:16]([CH3:17])[C:15](=[O:18])[CH2:14][C@@H:13]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[OH:11])=[CH:4][CH:3]=1.[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@H:10]([C@@H:12]2[N:16]([CH3:17])[C:15](=[O:18])[CH2:14][C@@H:13]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[OH:11])=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)C#Cc1ccc(F)cc1
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)CCc1ccc(F)cc1
Reaction time: 8 h
Yield: 100 %

Procedure:
(±)-(4R*,5R*)-5-[(1R*)3-(4-Fluorophenyl) 1-hydroxyprop-2-ynyl]-1-methyl-4-phenylpyrrolidin-2-one was prepared from 4-fluorophenyl acetylene and Intermediate Z using a method analogous to that described for Examples 8. A solution of this compound (52 mg, 0.16 mmol) in EtOAc (5 mL) was added to a catalyst slurry prepared by addition of EtOAc (10 mL) to 10% Palladium on carbon (20 mg) under an Ar atmosphere. The reaction mixture was stirred under a H2 atmosphere (1 Atm) overnight. The resulting mixture was filtered through a pad of Celite® and the filtrate was concentrated under reduced pressure to give (±)-5-[(1R*)-3-(4-fluorophenyl)-1-hydroxypropyl](4R*,5R*)-1-methyl-4-phenylpyrrolidin-2-one (67 mg, 100%) as a white solid: mp 122-124° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:23]=O)=[C:4]([CH3:22])[N:5]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CO.[CH3:27][NH2:28].[BH4-].[Na+]>>[ClH:1].[Cl:1][C:2]1[C:3]([CH2:23][NH:28][CH3:27])=[C:4]([CH3:22])[N:5]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1c(C=O)c(Cl)c(-c2ccccc2)n1S(=O)(=O)c1ccccc1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1c(Cl)c(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1C
Product: Cl
Yield: 84.9 %

Procedure:
Using 4-chloro-2-methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (301 mg), 40% methylamine methanol solution (195 mg) and sodium borohydride (106 mg), a procedure as in Example 9 was performed. Recrystallization from a mixed solvent of ethyl acetate and ethanol gave the title compound as colorless crystals (yield 146 mg, 42%).
Reaction SMILES: F[C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([OH:6])=[O:5].[CH:13]1([NH2:16])[CH2:15][CH2:14]1>N1C=CC=CC=1>[CH:13]1([NH:16][C:2]2[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=2[C:4]([OH:6])=[O:5])[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: O=C(O)c1c(F)cc(F)cc1F
Solvent: c1ccncc1
Product: O=C(O)c1c(F)cc(F)cc1NC1CC1
Yield: 70.2 %

Procedure:
2,4,6-Trifluorobenzoic acid (9.0 g, 34.1 mmol) and cyclopropylamine (14.65 g, 256 mmol) were stirred in pyridine (300 mL) at 120° C. in a sealed tube for 22 h. The solution was concentrated in vacuo. The residue was taken up in water (30 mL) and the solution was acidified to pH 2-3 with 1N HCl. The resulting precipitate was collected by filtration to yield 5.1 g (47%) of clean desired product as a beige solid. 1H NMR (400 MHz, DMSO-d6): δ 8.05 (s, 1H), 6.65 (d, 1H, J=8.0 Hz), 6.42 (t, 1H, J=10.8 Hz), 2.42-2.48 (m, 1H), 0.76-0.83 (m, 2H), 0.45-0.51 (m, 2H). MS (ES) [m+H] calc'd for C10H9F2NO2, 213; found 213.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([CH2:9]O)=[CH:7][N:6]=[CH:5]1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]1[N:23]=[C:22]([SH:24])[N:21]=[C:20]([OH:25])[CH:19]=1.CC(C)=O>O=S(Cl)Cl.C(OCC)C>[CH3:17][C:18]1[N:23]=[C:22]([S:24][CH2:9][C:8]2[N:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=[N:6][CH:7]=2)[N:21]=[C:20]([OH:25])[CH:19]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: CC(C)n1cncc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: O=S(Cl)Cl
Product: Cc1cc(O)nc(SCc2cncn2C(C)C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.5 %

Procedure:
[1-(propan-2-yl)-1H-imidazol-5-yl]methanol (255 mg, 1.8 mmol) was dissolved in SOCl2 (2 mL) and diethyl ether (10 mL). After 3 hours, the solvents were evaporated. To the solid was added potassium carbonate (414 mg, 3 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (200 mg, 1.4 mmol), and acetone (20 mL). The resulting mixture was stirred at room temperature overnight. Acetone was evaporated, and the crude solid was purified by column chromatography to provide the title compound as a white solid (150 mg, 32% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.51 (m, 6H), 2.27 (s, 3H), 4.53 (m, 1H), 4.92 (s, 2H), 6.01 (br, 1H), 6.99 (s, 1H), 7.83 (s, 1H); M+ 265.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:9]=2[CH:8]=1)=[O:6])[CH3:3].C(=O)(O)[O-].[Na+].I[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:33].O>CN(C)C=O>[ClH:1].[CH2:2]([O:4][C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH2:28][CH2:29][CH2:30][CH2:31][C:32](=[O:33])[NH:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:20][CH2:21]3)[C:9]=2[CH:8]=1)=[O:6])[CH3:3]
Reactant: O=C(CCCCI)Nc1ccccc1
Reactant: CCOC(=O)c1cc2c(N3CCNCC3)cccc2s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(N3CCN(CCCCC(=O)Nc4ccccc4)CC3)cccc2s1
Temperature: 80 °C
Yield: 6.2 %

Procedure:
To a solution of ethyl-4-(1-piperazinyl)-benzo[b]thiophene-2-carboxylate monohydrochloride prepared in Example 5 (2.00 g, 6.12 mmol) in dry N,N-dimethylformamide (31 mL) was added sodium bicarbonate (1.03 g, 12.2 mmol) and 5-iodo-N-phenylpentanamide (1.86 g, 6.12 mmol). The mixture was heated at 80° C. under nitrogen for 24 h, cooled to 20° C., treated with saturated aqueous sodium bicarbonate (50 mL) and water (100 mL), and extracted with 2:1 ether:dichloromethane (4×75 mL). The combined extracts were diluted with ethanol (50 mL) washed with water (50 mL), brine (50 mL) dried over magnesium sulfate/sodium sulfate, filtered, and concentrated in vacuo. The crude product was chromatographed using 20:80 ethanol:ethyl acetate isolating the component with an Rf of ca. 0.5 (2.20 g). A solution of the product (0.20 g) in 5:2 ethanol:dichloromethane was treated with an equivalent of 1.0M hydrochloric acid and concentrated in vacuo. Recrystallization from 3:2 methanol:acetonitrile (10 mL) gave the title compound as a white solid (0.19 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]#[CH:11])[C:5]([I:12])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:28])(=[N:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:21])=[CH:16][CH:15]=1.Cl>C(#N)C.O1CCOCC1.O>[CH2:26]([O:25][C:23]([N:22]=[S:20]([C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:2]2[N:7]=[C:6]([NH:8][CH2:9][C:10]#[CH:11])[C:5]([I:12])=[CH:4][N:3]=2)=[CH:19][CH:18]=1)([CH3:28])=[O:21])=[O:24])[CH3:27]
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(N)cc1
Reactant: C#CCNc1nc(Cl)ncc1I
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O
Product: C#CCNc1nc(Nc2ccc(S(C)(=O)=NC(=O)OCC)cc2)ncc1I
Temperature: 50 °C
Reaction time: 24 h

Procedure:
400 mg (1.65 mmol) of (2-chloro-5-iodopyrimidin-4-yl)-prop-2-in-1-yl-amine and 630 mg (2.15 mmol) of (RS)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-methyl sulfoximide in 7 ml of acetonitrile are mixed with 0.6 ml of a 4N solution of HCl in dioxane and 1 ml of water. The batch is stirred for 24 hours at 50° C. The solvent is drawn off, and the remaining residue is purified by chromatography (DCM/EtOH 9:1). 279 mg (0.56 mmol, corresponding to 54% of theory) of the product is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[CH3:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[CH3:24].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[CH3:17][C:18]1[CH:19]=[C:20]([C:2]2[CH:3]=[C:4]([NH:8][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:16])[CH:5]=[N:6][CH:7]=2)[CH:21]=[CH:22][C:23]=1[CH3:24]
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: O=C(Nc1cncc(Br)c1)c1ccccc1
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: [K+]
Solvent: COCCOC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cncc(NC(=O)c3ccccc3)c2)cc1C
Temperature: 85 °C
Reaction time: 12 h

Procedure:
At 50° C., 4.5 g (16.2 mmol) of N-(5-bromopyridin-3-yl)benzamide, 3.0 g (19.5 mmol) of (3,4-dimethylphenyl)boronic acid and 4.5 g (32.5 mmol) of potassium carbonate were dissolved in 59 ml of 1,2-dimethoxyethane, 19 ml of water and 117 ml of DMF. The mixture was flushed with argon, 0.1 g (0.08 mmol) of tetrakis(triphenylphosphine)palladium(0) was added and the mixture was stirred at 85° C. for 12 h. The reaction mixture was concentrated slightly on a rotary evaporator, diluted with water and extracted with dichloromethane. The organic phase was concentrated and purified by column chromatography on silica gel (dichloromethane/methanol 100:1→100:4).
Reaction SMILES: C([O:5][C@@H:6]([C@@H:8]1[CH2:12][O:11][C:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[S:34][CH:35]=[CH:36][N:37]=3)=[C:27]([Cl:38])[CH:26]=2)=[N:9]1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:38][C:27]1[CH:26]=[C:25]([NH:24][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:10]4[O:11][CH2:12][C@@H:8]([C@H:6]([OH:5])[CH3:7])[N:9]=4)[CH:15]=3)[N:20]=[CH:19][N:18]=2)[CH:30]=[CH:29][C:28]=1[O:31][CH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1
Reactant: C[C@@H](OC(C)(C)C)[C@@H]1COC(Nc2ccc3ncnc(Nc4ccc(OCc5nccs5)c(Cl)c4)c3c2)=N1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](O)[C@@H]1COC(Nc2ccc3ncnc(Nc4ccc(OCc5nccs5)c(Cl)c4)c3c2)=N1

Procedure:
(R)-1-((S)-2-(4-(3-chloro-4-(thiazol-2-ylmethoxy)phenylamino)quinazolin-6-ylamino)-4,5-dihydrooxazol-4-yl)ethanol is prepared from (1R, 4S)-N6-[4-(1-tert-butoxyethyl)-4,5-dihydrooxazol-2-yl]-N4-[3-chloro-4-(thiazol-2-ylmethoxy)-phenyl]-quinazoline-4,6-diamine by standard deprotection methods using TFA in methylene chloride. MS ESI (+) m/z 497, 499 (M+1, Cl pattern) detected; 1H NMR (400 mHz, DMSO-D6) δ 9.53 (s, 1H), 8.47 (s, 1H), 8.08 (d, 1H), 7.87 (d, 1H), 7.80 (d, 1H), 7.76 (dd, 1H), 7.66 (m, 2H), 7.33 (d, 1H), 5.55 (s, 2H), 4.81 (m, 1H), 4.37 (m, 1H), 4.20 (m, 1H), 3.83 (m, 1H), 3.63 (m, 1H), 1.06 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]4[CH:17]([C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:15][CH2:14]4.[H-].[Na+].[CH3:20][C:21]1([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:23][O:22]1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:20][C:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)([OH:22])[CH3:23])[C:6]3[CH2:11][CH2:12][N:13]4[CH:17]([C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:15][CH2:14]4
Reactant: Clc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: CC1(c2cccnc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(O)(Cn1c2c(c3cc(Cl)ccc31)C1CCCN1CC2)c1cccnc1
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
To a stirred solution of 10-chloro-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (1.0 g, 4.06 mmol) in DMF (50 mL) was added sodium hydride (60%, 406 mg, 10.15 mmol). After stirring for 10 min., 3-(2-methyloxiran-2-yl)pyridine (823 mg, 6.09 mmol) was added to the reaction mixture, which was stirred at RT for 16 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice-water and extracted with EtOAc (2×100 mL). The organic layer was washed with water (5×100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the residue that was crystallized with ethanol-hexane to yield the 1.2 g of 1-(10-chloro-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)-2-(pyridin-3-yl)propan-2-ol. 1H NMR (CDCl3,freebase) δ (ppm): 8.70 (s, 1H), 8.49 (d, 1H), 7.62 (d, 1H), 7.36 (s, 1H), 7.12 (m, 2H), 7.02 (d, 1H), 4.17 (q, 2H), 3.86 (t, 1H), 3.19 (m, 1H), 2.86 (m, 1H), 2.74 (m, 3H), 2.41 (m, 2H), 1.85 (m, 3H), 1.7 (s, 3H). Separation by chiral HPLC provides diastereomers II-130a-d.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][OH:8].[Cl:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].C(#N)C>COC(C)(C)C>[Cl-:9].[C:13]1([C:11](=[O:12])[CH2:10][N+:3]2[C:2]([CH3:1])=[C:6]([CH2:7][OH:8])[S:5][CH:4]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CCl)c1ccccc1
Reactant: Cc1ncsc1CO
Solvent: COC(C)(C)C
Solvent: CC#N
Product: Cc1c(CO)sc[n+]1CC(=O)c1ccccc1
Product: [Cl-]
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
The neat reaction of 4-methyl-5-(hydroxymethyl)-thiazole (590 mg, 4.57 mmoL) and 2-chloroacetophenone (710 mg, 4.59 mmoL) was heated at 110° C. The mixture solidified within 15 minutes. Acetonitrile (10 mL) was added and the mixture refluxed for another 3 hrs. It was cooled to room temperature and tert-butyl methyl ether (5 mL) was added and the reaction mixture was left overnight at room temperature. The product crystallized was filtered and washed well with a mixture of hexanes:EtOAc (1:1, v/v) and dried. It was recrystallized from a mixture of actonitrile/ethanol/tert-butyl methyl ether; yield 130 mg (10%); mp. 240-242° C. (dec.).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3([CH3:16])[O:15][CH2:14][CH2:13][O:12]3)=[N:7][C:6]=2[C:5]([O:17][CH3:18])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C]=[O:56].[O:57]1[CH2:61]CCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:18][O:17][C:5]1[C:6]2[N:7]=[C:8]([C:11]3([CH3:16])[O:15][CH2:14][CH2:13][O:12]3)[O:9][C:10]=2[C:2]([C:61]([OH:57])=[O:56])=[CH:3][CH:4]=1
Reactant: C1CCOC1
Reactant: COc1ccc(Br)c2oc(C3(C)OCCO3)nc12
Reactant: [C]=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)O)c2oc(C3(C)OCCO3)nc12
Temperature: 25 °C

Procedure:
7-Bromo-4-methoxy-2-(2-methyl-[1,3]-dioxolan-2-yl)benzoxazole (480 mg), palladium acetate (34 mg), 1,3-bis(diphenylphosphino)propane (126 mg), triethylamine (0.21 ml), water (15 ml) and tetrahydrofuran (30 ml) were combined and heated to 90° C. in a Parr apparatus under 1035 kPa (150 psi) of carbon monoxide for 3 days. After cooling to room temperature, the tetrahydrofuran was evaporated in vacuo. The residue was partitioned between ethyl acetate (50 ml) and water (50 ml). The aqueous layer was extracted with ethyl acetate (50 ml). The combined organic extracts were dried over magnesium sulphate, evaporated in vacuo and purified by flash chromatography eluting with ethyl acetate to yield the title compound as a white solid (190 mg).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15]([O:17]C(C)(C)C)=O)[C@H:12]([C:22]([OH:24])=O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=C=O.[N:34]1[S:35][N:36]=[C:37]2[C:42]([NH2:43])=[CH:41][CH:40]=[CH:39][C:38]=12>>[N:34]1[S:35][N:36]=[C:37]2[C:42]([NH:43][C:22]([C@@H:12]3[CH2:11][C:10](=[N:9][O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:14][N:13]3[C:15]([NH:25][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:17])=[O:24])=[CH:41][CH:40]=[CH:39][C:38]=12
Reactant: O=C=Nc1ccccc1
Reactant: Nc1cccc2nsnc12
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccccc2)C[C@H]1C(=O)O
Product: O=C(Nc1cccc2nsnc12)[C@@H]1CC(=NOCc2ccccc2)CN1C(=O)Nc1ccccc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, isocyanatobenzene, and 2,1,3-benzothiadiazol-4-amine the title compound was obtained in 57% purity by LC/MS. MS(ESI+): m/z=487.4.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:7][CH:6]=1)#[N:4].CN(C)C=O.Br[CH2:27][CH2:28][CH2:29][Cl:30]>O1CCCC1>[Cl:30][CH2:29][CH2:28][CH2:27][N:13]([CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([C:3]#[N:4])=[CH:10][CH:9]=1)[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18]
Reactant: ClCCCBr
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCCCl)CCc1ccc(C#N)cc1
Reaction time: 0.25 h

Procedure:
At room temperature, 0.23 g (9.03 mmol) of sodium hydride (95%) was added to a solution of 1.482 g (6.02 mmol) of tert.-butyl [2-(4-cyanophenyl)ethyl]carbamate in 25 ml of tetrahydrofuran/25 ml of dimethylformamide. The mixture was stirred for a further 15 minutes. 1.49 ml (15.04 mmol) of 1-bromo-3-chloropropane were then added, and the reaction mixture was stirred at room temperature overnight. With ice bath cooling, the mixture was then quenched with water, and extracted with ethyl acetate. The organic extracts were washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated to dryness. The crude product obtained in this manner was purified by column chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate 4:1).