Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:23])[O:5][C:6]1[C:7]([NH:19][C:20]([NH2:22])=[S:21])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1.Cl[CH2:25][CH:26]=O>CN(C=O)C>[CH3:1][O:2][CH2:3][CH:4]([CH3:23])[O:5][C:6]1[C:7]([NH:19][C:20]2[S:21][CH:25]=[CH:26][N:22]=2)=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COCC(C)Oc1cc(Oc2ccccc2)cnc1NC(N)=S
Reactant: O=CCCl
Solvent: CN(C)C=O
Product: COCC(C)Oc1cc(Oc2ccccc2)cnc1Nc1nccs1
Temperature: 100 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
[3-(2-Methoxy-1-methyl-ethoxy)-5-phenoxy-pyridin-2-yl]-thiourea (0.2 mmol) is dissolved in DMF (1 ml) and chloro-acetaldehyde (1.0 eq., 55% in water) is added and stirred three hours at 100° C. After cooling to room temperature the suspension is pored into ice-water and extracted with methyl-tert.-butyl ether. The combined organic phases are washed with brine and dried over MgSO4. The solvent is removed in vacuo. [3-(2-Methoxy-1-methyl-ethoxy)-5-phenoxy-pyridine-2-yl]-thiazole-2-yl-amine (“A28”) is obtained after reversed phase column chromatography (acetonitrile/water+0.1% TFA) as yellow solid in a yield of 46%. HPLC (method C): 1.80 min; LC-MS (method A): 1.72 min, 358.15 (MH+); 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] 7.739 (d, 1H, J=2.3 Hz), 7.477 (d, 1H, J=3.9 Hz), 7.421-7.369 (m, 3H), 7.142-7.087 (m, 2H), 7.025 (d, 2H, J=8 Hz), 5.408 (br, 1H), 4.737-4.696 (m, 1H), 3.639 (dd, 1H, J=6.5 Hz, J=10.6 Hz), 3.505 (dd, 1H, J=3.6 Hz, J=10.6 Hz), 3.3 (S, 3H), 1.268 (D, 3H, J=6.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11]C1C2C(=CC=CC=2)NC=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: Cc1c[nH]c2ccccc12
Product: Cn1ccc2ccc(Cl)cc21
Yield: 100 %

Procedure:
According to the procedure of Preparation 13 (a), except substituting 6-chloroindole for the 3-methylindole, the title compound (2.2 g, 100%) was obtained as a white solid: MS (ES) m/e 166.2.0 (M+H)+.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[O:11]=C[C@@H]([C@H]([C@H](CO)O)O)O.OP([O-])([O-])=O.[K+:26].[K+].OP([O-])(O)=O.[K+]>>[O:1]=[C:2]([O-:11])[C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[K+:26]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: [K+]
Product: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)CO
Temperature: 30 °C
Reaction time: 12 h

Procedure:
For microbial oxidation of D-xylose or L-arabinose, fermentation medium (1 L) contains K2HPO4 (2 g), KH2PO4 (1 g), (NH4)2SO4 (5 g) and yeast extract (5 g). Solutions of D-xylose (100 g) or L-arabinose (100 g) and MgSO4 (0.24 g) are autoclaved separately and added immediately prior to initiation of the fermentation. Inoculants are started by introduction of a Pseudomonas fragi single colony picked from a nutrient agar plate into 5 mL of fermentation medium. Cultures are grown at 30° C. with agitation at 250 rpm until they are turbid (˜24 h) and subsequently transferred to 100 mL of fermentation medium. Cultures are grown at 30° C. and 250 rpm for an additional 12 h. The inoculant (OD600=1.0-3.0) is then transferred into the fermentation vessel and the batch fermentation is initiated (t=0 h). The fermentation control settings are: 30° C., stirring speed at 650 rpm, and airflow at 0.5 L/L/min. The culture medium is maintained at pH 6.4 by addition of 2 N H2SO4 and a base solution, which is 30% CaCO3 for oxidation of D-xylose or concentrated NH4OH for oxidation of L-arabinose. A standard curve is determined for each metabolite using solutions of authentic, chemically synthesized samples. (Moore, S.; Link, K. P. J. Biol. Chem. 1940, 133, 293.) Compounds are quantified by 1H NMR using the following resonances: D-xylonic acid (δ4.08, d, 1H); L-arabinonic acid (δ4.24, d, 1H); and L-arabino-1,4-lactone (δ4.64, d, 1H). A modified procedure by Buchert is employed for the purification of D-xylonate. Following treatment with activated carbon and concentration (1-1.1 L to 250 mL) of D-xylonate containing fermentation broth, EtOH (3:1, v/v) is added. After 12 h at 4° C., the precipitated calcium xylonate is filtered and dried under vacuum (95% recovery based on D-xylonate in the crude fermentation broth). Potassium D-xylonate is obtained by passing an aqueous solution of calcium xylonate through a Dowex 50 (K+ form) column (Applied Membranes, Vista, Calif., USA).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]2[CH:15]=1.Cl.Cl.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][C:3]3[N:4]=[C:5]4[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]4[CH:15]=3)[CH2:27][CH2:26]2)=[CH:23][CH:24]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: FC(F)(F)c1ccc2nc(CCl)cn2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc2nc(CN3CCN(c4ccc(Cl)cc4)CC3)cn2c1
Yield: 41 %

Procedure:
Following the same general procedure as for Example 49, Step 2, and making non-critical variations, 2-(chloromethyl)-6-trifluoromethylimidazo[1,2-a]pyridine (Example 49, Step 1; 0.435 g), 1-(4-chlorophenyl)piperazine dihydrochloride (Aldrich; 0.550 g), diisopropylethylamine (Aldrich; 0.815 g), and THF (6 mL) give 0.30 g of 2-[[4-(4-chlorophenyl)-1-piperazinyl]methyl]-6-(trifluoromethyl)imidazo[1,2-a]pyridine after crystallization from ethyl acetate/hexane; mp 128-135° C.; MS m/z 394; IR (mineral oil) 1331, 1141, 1127, 1055, 1500, 830 cm-1. 1H NMR (CDCl3) δ 2.74, 3.20, 3.80, 6.83, 7.19, 7.31, 7.66, 7.68, 8.47.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([N+:18]([O-])=O)[CH:9]=2)[CH2:4][CH2:3]1.C(O)C.[H][H]>[Pd].C(O)(=O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[C:10]([NH2:18])[CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: CN1CCN(c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CN1CCN(c2cc(N)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Into a 100 mL round bottom flask under inert atmosphere was placed 1-methyl-4-(3-nitro-5-(trifluoromethyl)phenyl)piperazine (0.736 g, 2.54 mmol), 10% palladium on carbon (90 mg), ethanol (40 mL), and acetic acid (20 mL). The atmosphere was exchanged with hydrogen gas via balloon. The reaction was allowed to stir 3 days at room temperature, then filtered through celite and concentrated under reduced pressure to afford the crude as an orange oil. The crude mixture was purified via silica column chromatography with a solvent solution of 90%/10%/1% ratio of CH2Cl2/CH3OH/NH4OH, to afford the title compound. MS m/z=260 [M+H]+; Calc'd for C12H16F3N3: 259.3.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:21]3[C:25](/[CH:26]=[CH:27]\[S:28]([CH3:30])=[O:29])=[CH:24][N:23]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:22]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1.ClC1C=CC=C(C(OO)=[O:48])C=1.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:21]3[C:25](/[CH:26]=[CH:27]\[S:28]([CH3:30])(=[O:48])=[O:29])=[CH:24][N:23]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:22]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C\S(C)=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C\S(C)(=O)=O)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a mixture of 2-(2-furyl)-4-({2-methoxy-4-[({4-[(Z)-2-(methylsulfinyl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole (0.20 g) and tetrahydrofuran (20 mL) was added m-chloroperbenzoic acid (0.08 g) at room temperature, and the mixture was stirred at the same temperature for 1 hr. Saturated aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was stirred at room temperature for 10 min, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to give 2-(2-furyl)-4-({2-methoxy-4-[({4-[(Z)-2-(methylsulfonyl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole as colorless crystals (0.15 g, yield 71%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 158-159° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=O.C1(C)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=C(O)[CH:27]=[CH:28][CH:29]=1.S(=O)(=O)(O)O>CO>[OH:1][C:2]1[CH:3]=[C:4]([C:5]2[C:27]3[C:11](=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=3)[O:10][C:8](=[O:9])[CH:7]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)CC(=O)c1cccc(O)c1
Reactant: COc1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc2c(-c3cccc(O)c3)cc(=O)oc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
The solution of methyl 3-hydroxybenzoylacetate (about 4.0 kg) and toluene (total weight of solution 5.6 kg) from the step above was charged to a reaction vessel along with 3-methoxyphenol (2.55 kg). The mixture was stirred vigorously at 0° C. while 27 M sulfuric acid (5.55 L) was added over 5 minutes. The resulting dark solution was warmed to 25° C. When the reaction began to thicken (40 minutes), methanol (21.8 L) was added. The addition was exothermic. Continued stirring (15 minutes) yielded a smooth, brown slurry which was cooled to 5° C. over 25 minutes, stirred for one hour, then filtered. The filter cake was washed with methanol (5.50 L) and dried under vacuum at 45-50° C. to give 3.70 kg (13.8 mol, 70% yield for two steps) of 4-[3′-(hydroxy)phenyl]-7-methoxycoumarin (a compound of Formula (b)).
Reaction SMILES: [CH2:1]([C:3]12[CH2:23][CH2:22][C:17]3([O:21][CH2:20][CH2:19][O:18]3)[CH2:16][CH:4]1[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([CH3:15])=[CH:10][C:9]=12)[CH3:2].[C:24]([O-])(=[O:26])[CH3:25].[K+].C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([C@:3]12[CH2:23][CH2:22][C:17]3([O:18][CH2:19][CH2:20][O:21]3)[CH2:16][C@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([NH:14][C:24](=[O:26])[CH3:25])[C:11]([CH3:15])=[CH:10][C:9]=12)[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCC12CCC3(CC1CCCc1cc(N)c(C)cc12)OCCO3
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC[C@]12CCC3(C[C@H]1CCCc1cc(NC(C)=O)c(C)cc12)OCCO3
Yield: 62.1 %

Procedure:
rac-(4aR,11bS)-11b-ethyl-10-methyl-1,2,4,4a,5,6,7,11b-octahydrospiro[dibenzo[a,c][7]annulene-3,2′-[1,3]dioxolan]-9-amine (24, R2=Ethyl) (0.178 g, 0.563 mmol) was dissolved in DCM (4 mL) then potassium acetate (0.138 g, 1.408 mmol) and acetic anhydride (0.115 g, 1.126 mmol) were added. After about 10 min sat. aq. NaHCO3 (3 mL) was added and the mixture was diluted with DCM (15 mL). The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (12 g) using a gradient of 0-50% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to yield rac-N-((4aR,11bS)-11b-ethyl-10-methyl-1,2,4,4a,5,6,7,11b-octahydrospiro[dibenzo[a,c][7]annulene-3,2′-[1,3]dioxolan]-9-yl)acetamide (25, R2=Ethyl) (0.125 g, 62%); LC/MS, method 3, Rt=2.36 min, MS m/z 358 (M+H)+. 1H NMR (400 MHz, DMSO) δ 9.12 (s, 1H), 7.13 (s, 1H), 6.99 (s, 1H), 3.89-3.73 (m, 4H), 2.87-2.81 (m, 1H), 2.67-2.59 (m, 1H), 2.39-2.32 (m, 1H), 2.22-2.06 (m, 1H), 2.15 (s, 3H) 2.02 (s, 3H), 2.01-1.91 (m, 2H), 1.69-161 (m, 3H), 1.58-1.51 (m, 1H), 1.49-1.20 (m, 5H), 0.61 (t, J=7.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([CH3:37])([CH3:36])[C:34]#[N:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:39]1[CH:40]=[CH:41][C:42](=[O:46])[N:43]([CH3:45])[CH:44]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][C:33]([CH3:36])([CH3:37])[C:34]#[N:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:39]4[CH:40]=[CH:41][C:42](=[O:46])[N:43]([CH3:45])[CH:44]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cn1cc(Br)ccc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from 3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile and 5-bromo-1-methylpyridin-2(1H)-one following a procedure analogous to that described in Example 3 Step 2. LC-MS Method 1 tR=1.45 min, m/z=488; 1H NMR (CDCl3) 7.68(dd, 1H), 7.52(d, 1H), 7.32(q, 2H), 7.17(d, 2H), 7.06(t, 2H), 6.97(d, 2H), 6.91(d, 1H), 5.66(q, 1H), 3.72(s, 3H), 2.99(dt, 1H), 2.48(dd, 2H), 2.27(m, 1H), 2.11(s, 2H), 1.55(d, 3H), 1.44(s, 3H), 1.34(s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[S:20][C:21](Br)=[CH:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[S:20][C:21]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([C:26]([F:37])([F:36])[F:25])[CH:32]=3)=[CH:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1ccc(Br)s1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: CC(NC(=O)c1ccc(-c2cccc(C(F)(F)F)c2)s1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 69.4 %

Procedure:
5-Bromo-thiophene-2-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.12 mmol) was reacted with 3-trifluoromethyl phenyl boronic acid (42 mg, 0.23 mmol) as described in example 60 to give the title compound (42 mg, 77%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>C1COCC1.C(OCC)C>[C:11]([NH:15][S:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccc(Cl)s1
Temperature: 23 °C
Yield: 91.7 %

Procedure:
A solution of 5.5 g (27.5 mmol) of 5-chlorothiophenesulfonyl chloride in dry THF at 0° C. was treated with a solution of 5.7 mL (75.5 mmol) of t-butylamine. After warming to 23° C., the reaction mixture was diluted with 125 mL of diethyl ether, filtered, and washed with 1 N HCl, brine, and dried (MgSO4). Concentration in vacuo affords 6.4 g (98%) of the named compound as an oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[S:24]([O:15][CH2:14][CH2:13][CH2:12][O:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1)(=[O:26])(=[O:25])[CH3:23]
Reactant: OCCCOc1ccnc2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCOc1ccnc2ccccc12
Yield: 53 %

Procedure:
A solution of the 3-(quinolin-4-yloxy)propan-1-ol obtained in step a) (0.5298 g, 2.6 mmol) was treated with triethylamine (0.60 mL) and methanesulfonyl chloride (0.55 g, 4.8 mmol) in dichloromethane (5 mL). After the starting material was consumed, the reaction was diluted with dichloromethane, washed with water, aq NaHCO3 and evaporated. The residue was purified by column chromatography on SiO2 and eluted with ethyl acetate. The product was obtained as a light yellow solid (0.3868 g, 53%). 1H NMR (400 MHz, CDCl3): 2.43 (2H, m), 3.00 (3H, s), 4.38 (2H, t, J=5.8 Hz), 4.55 (2H, t, J=5.8 Hz), 6.80 (1H, d, J=5.5 Hz), 7.55 (1H, t, J=8.0 Hz), 7.75 (1H, ddd, J=1.2, 7.0, 8.2 Hz), 8.20 (1H, d, J=8.4 Hz), 8.13 (1H, d, J=8.4 Hz), 8.77 (1H, d, J=5.3 Hz).
Reaction SMILES: I[Si](C)(C)C.[C:6]([NH:14][C:15]1[S:16][CH2:17][C@@H:18]2[CH2:23][N:22](C(OCC3C=CC=CC=3)=O)[CH2:21][C@:19]2([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:20]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(#N)C>[C:34]1([C@:19]23[CH2:21][NH:22][CH2:23][C@H:18]2[CH2:17][S:16][C:15]([NH:14][C:6](=[O:13])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:20]3)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(NC1=N[C@@]2(c3ccccc3)CN(C(=O)OCc3ccccc3)C[C@H]2CS1)c1ccccc1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: O=C(NC1=N[C@@]2(c3ccccc3)CNC[C@H]2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 399.4 %

Procedure:
Iodotrimethylsilane (10 mL, 70 mmol) is added to a solution of benzyl(4aR,7aS)-2-benzamido-7a-phenyl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (11 g, 23 mmol) in acetonitrile (165 mL), stirred at room temperature for 2 hours and concentrated. The mixture is diluted with water (100 mL) and ethyl acetate (150 mL) and the pH adjusted to 4 with 1 M hydrochloric acid. The aqueous layer is collected. The pH of this aqueous layer is then adjusted to 10 with 2 M sodium hydroxide. The resulting solution is then extracted with ethyl acetate (100 mL), dried over magnesium sulfate and concentrated to give the title compound (31 g, 63%). ES/MS (m/e): 338 (M+H).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:16]=2)[C:13](=[O:27])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:28])[N:6]=1)[CH2:3][CH3:4].Cl[C:30]1[C:31]2[CH:38]=[CH:37][NH:36][C:32]=2[N:33]=[CH:34][N:35]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:33]1[C:32]2[NH:36][CH:37]=[CH:38][C:31]=2[C:30]([NH:1][C@H:2]([C:5]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([F:26])([F:24])[F:25])[CH:16]=3)[C:13](=[O:27])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[F:28])[N:6]=2)[CH2:3][CH3:4])=[N:35][CH:34]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC[C@H](Nc1ncnc2[nH]ccc12)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 14 h
Yield: 17.4 %

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-(3-(2,2,2-trifluoroethoxy)phenyl)quinazolin-4(3H)-one (22 mg, 0.056 mmol, 1.0 equiv) in t-BuOH (0.11 mL) at 23° C. was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (10 mg, 0.067 mmol, 1.2 equiv) and diisopropylethylamine (19 μL, 0.11 mmol, 2.0 equiv). After stirring for 14 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 5.0 mg of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12]3([CH2:23][C:22](=[O:24])[C:21]4[C:16](=[CH:17][CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27](O)=[O:28])[CH:20]=4)[O:15]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:30][O:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12]3([CH2:23][C:22](=[O:24])[C:21]4[C:16](=[CH:17][CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:30][O:31][CH:32]5[CH2:37][CH2:36][CH2:35][CH2:34][O:33]5)=[O:28])[CH:20]=4)[O:15]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccccc3)CC1)O2
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccccc3)CC1)O2)NOC1CCCCO1

Procedure:
(E)-3-{1′-(2-Phenyl-ethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (1.71 g, 4.00 mmol) obtained in Step B was suspended in DCM (50 ml). TEA (0.84 ml, 6.0 mmol) was added and the clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-(2-phenyl-ethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (1.62 g) as a light yellow solid.
Reaction SMILES: O[CH2:2][C:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:12])([CH3:11])[CH3:10])[CH2:5][CH:4]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[OH:12][C:9]([CH:6]1[CH2:7][CH2:8][C:3]([CH2:2][N:17]2[C:13](=[O:23])[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16]2=[O:18])=[CH:4][CH2:5]1)([CH3:11])[CH3:10]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(O)C1CC=C(CO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: CC(C)(O)C1CC=C(CN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
To a stirred solution of 2-(4-Hydroxymethyl-cyclohex-3-enyl)-propan-2-ol (5.765 grams, 34.270 mmole), Phthalimide (6.50 grams, 44.208 mmole), and triphenyl phosphene (11.60 grams, 44.208 mmole) in tetrahydrofuran (200 ml) at room temperature was added DIAD (9.010 grams, 44.552 mmole) dropwise, and the peach mixture was stirred at room temperature over night. The mixture was quenched with 150 ml water and extracted with 2×100 ml ethyl acetate. It was then concentrated to a yellow residue. This was taken up in diethyl ether, diluted with hexane, chilled and filtered. The crude product was purified via flash chromatography on silica using 50% ethyl acetate/hexane as eluent to give a yellow gum (5.73 g). MW 299.373; MS (m/e) 279 (M+−18).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Br-].[CH3:7][O:8][C:9](=[O:28])[CH2:10][C:11]1([CH3:27])[C:16]2=[CH:17][CH:18]=[CH:19][N:15]2[C:14]2[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:13]=2[O:12]1>>[CH3:7][O:8][C:9](=[O:28])[CH2:10][C:11]1([CH3:27])[C:16]2=[CH:17][CH:18]=[C:19]([Cl:4])[N:15]2[C:14]2[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:13]=2[O:12]1
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)CC1(C)Oc2ccc([N+](=O)[O-])cc2-n2cccc21
Agent: [Br-]
Product: COC(=O)CC1(C)Oc2ccc([N+](=O)[O-])cc2-n2c(Cl)ccc21

Procedure:
By following the procedure of Example 75 but using as a starting material the appropriate starting material of formula 3, for example those described in Examples 2 to 41 or the appropriate starting material of formula 1, for example, those described in Examples 42 to 69, together with the appropriate nucleophilic reagent, for instance, sulfuryl chloride or bromide, respective compounds of formulae 3 and 1 in which R2 is halogen are obtained. More specifically exemplified, the use of 4-methyl-8-nitro-4H-pyrrolo-[2,1-c][1,4]benzoxazine-4-acetic acid methyl ester, described in Example 2 gives 1-chloro-4-methyl-8-nitro-4H-pyrrolo[2,1-c][1,4]-benzoxazine-4-acetic acid methyl ester, m.p. 124° - 125° C.