Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH3:13][OH:14]>>[OH:14][CH2:13][CH2:4][CH2:3][CH2:2][C:1]([O:6][CH3:5])=[O:7]
Reactant: O=C1CCCCO1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCO

Procedure:
reaction of valerolactone with methyl alcohol in the presence of sulphuric acid to produce methyl 5-hydroxypentanoate;
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2/[C:11](=[CH:19]/[C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)/[C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[CH3:32][O:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C(Cl)(Cl)Cl>[O:18]=[C:12]1[NH:13][C:14]2[C:10](/[C:11]/1=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)=[C:9]([C:5]1[CH:4]=[C:3]([NH:2][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)[CH:8]=[CH:7][CH:6]=1)[CH:17]=[CH:16][CH:15]=2
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2cccc(-c3cccc4c3/C(=C/c3ccc[nH]3)C(=O)N4)c2)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one hydrochloride (30 mg, 0.089 mmol) (from Example 5 supra) and Et3N (24 μL , 0.172 mmol) in 3 mL of chloroform was cooled to −70° C. and then treated with 4-methoxybenzoyl chloride (17.4 mg, 0.102 mmol) (Fluka). The reaction mixture was stirred at −70° C. for 1 hr and then stirred at room temperature for 15 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50% ethyl acetate-hexanes elution) provided pure (Z)-N-[3-[2,3-dihydro-2-oxo3-[(1H-pyrrol-2-yl) methylene]-1H-indol-4-yl]-phenyl]-4-methoxybenzamide (31 mg, 80%) as a brown solid (mp 209-211° C.).
Reaction SMILES: CC1C[N@@]1S(C1C=CC=C(C(F)(F)F)C=1)(=O)=O.FC(F)(F)C1C=C(S(O[CH2:30][C@H:31]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)[NH:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)(=[O:35])=[O:34])(=O)=O)C=CC=1>>[F:52][C:49]1[CH:48]=[CH:47][C:46]([CH:31]2[CH2:30][N@@:32]2[S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:44])([F:43])[F:45])[CH:37]=2)(=[O:34])=[O:35])=[CH:51][CH:50]=1
Reactant: O=S(=O)(N[C@H](COS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1)c1cccc(C(F)(F)F)c1
Agent: CC1C[N@@]1S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: CC1C[N@]1S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: O=S(=O)(c1cccc(C(F)(F)F)c1)[N@@]1CC1c1ccc(F)cc1
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)[N@]1CC1c1ccc(F)cc1

Procedure:
Proceeding as described for (49), but using (S)-2-(4-fluorophenyl)-2-(3-(trifluoromethyl)-benzenesulfonamido)ethyl 3-(trifluoromethyl)benzenesulfonate afforded (S)-2-(4-Fluorophenyl)-1-(3-(trifluoromethyl)benzenesulfonyl)aziridine (50). MS (m/z): 355.2 (M+H) (Calc'd for C15H11F4NO2S: 354.31).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:16](Cl)([Cl:18])=[O:17]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]([Cl:18])=[O:17])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(C)cc(Nc2ccccc2)c1
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(N(C(=O)Cl)c2ccccc2)c1
Yield: 99 %

Procedure:
According to the procedure of Example 15, Step A, 5.5 g (27.9 mmole) of N-(3,5-dimethylphenyl)aniline, 27.9 mL of 1.93M phosgene in toluene and 15 mL of toluene gave 7.15 g (99%) of a red oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:7]2.[F:18][C:19]([F:27])([F:26])[C:20]([F:25])([F:24])C([O-])=O.[Na+].C1(C)C=CC=CC=1.N>[Cu]I.O.CN(C)C=O>[F:24][C:20]([F:25])([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:7]2)[C:19]([F:27])([F:26])[F:18]
Reactant: O=C(N1CCc2c(Br)cccc2C1)C(F)(F)F
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Agent: [Cu]I
Agent: N
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(N1CCc2c(cccc2C(F)(F)C(F)(F)F)C1)C(F)(F)F
Yield: 65.8 %

Procedure:
A mixture of 5-bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (4.0 g, 13 mmol), sodium pentafluoropropionate (4.85 g, 26 mmol), copper (I) iodide (5.22 g, 27.2 mmol), toluene (70 ml) and dimethylformamide (70 ml) was heated under argon with Dean-Stark distillation (70 ml distillate collected), then heated at reflux for 18 h. The mixture was cooled, then poured into a mixture of water (150 ml) and 0.880 ammonia (150 ml). Resulting solution was extracted with dichloromethane (4×100 ml) and the combined extracts dried (Na2SO4) and evaporated in vacuo to give a solid. Chromatography on silica with 10-50% ether-hexane gradient elution gave the title compound (2.97 g, 66%) as a colourless solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[OH:32])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br[CH2:35][C:36]1[CH:45]=[C:44]2[C:39]([CH:40]=[CH:41][CH:42]=[N:43]2)=[CH:38][CH:37]=1>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH:20]2[O:32][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH:40]=[CH:41][CH:42]=[N:43]3)=[CH:38][CH:37]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(O)C1
Reactant: BrCc1ccc2cccnc2c1
Agent: Br
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3cccnc3c2)C1

Procedure:
By alkylating tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxy-piperidine-1-carboxylate [Example 86 (n)] with 7-bromomethyl-quinoline hydrobromide [J.Am.Chem.Soc. 77, 1054(1955)] analogously to Example 1 (g) there was obtained tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(quinolin-7-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 583 (M+H)+.
Reaction SMILES: O1C=CCCC1.[N+:7]([C:10]1[S:24][C:13]2[S:14][C:15]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:16][C:17](=[O:18])[C:12]=2[CH:11]=1)([O-:9])=[O:8].[CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)=[CH2:26].O.O.O.C([O-])(=O)C.[Na+]>CO.O>[N+:7]([C:10]1[S:24][C:13]2[S:14][C:15]3([CH2:19][CH2:20][N:21]([CH2:26][CH2:25][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:22][CH2:23]3)[CH2:16][C:17](=[O:18])[C:12]=2[CH:11]=1)([O-:9])=[O:8]
Reactant: C=Cc1ccccn1
Reactant: O=C1CC2(CCNCC2)Sc2sc([N+](=O)[O-])cc21
Agent: C1=COCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1CC2(CCN(CCc3ccccn3)CC2)Sc2sc([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 60.4 %

Procedure:
A solution containing 660 mg (2.05 mmol) of 2'-Nitro-spiro(piperidine-4,6'-(6H)thieno[2,3-b]thiopyran)-4'(5'H)-one dihydropyran, 430 mg (4.1 mmol) of 2-vinylpyridine and 557 mg (4.1 mmol) of sodium acetate trihydrate in 10 ml of 1:1 methanol/water was heated at reflux for 4 hours. The reaction was cooled to room temperature and a solid separated. The solid was collected and dissolved in methanol and treated with excess ethanolic HCl. The dihydro chloride separated and was collected and dried over night in vacuo to give 482 mg of the product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[CH2:9]([C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]2[CH:21]=1)[CH2:10][C:11]#[CH:12]>C(N(CC)CC)C.[Cu](I)I.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>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]#[C:11][CH2:10][CH2:9][C:13]2[N:14]=[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]3[CH:21]=2)=[N:3][CH:4]=1
Reactant: Fc1ccc(Br)nc1
Reactant: C#CCCc1cn2ccccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Fc1ccc(C#CCCc2cn3ccccc3n2)nc1
Temperature: 25 °C
Yield: 8.3 %

Procedure:
In a dry reaction tube containing in suspension copper iodide (6.5 mg, 0.03 mmol) and triethylamine (2.3 mL), were added 2-bromo-5-fluoropyridine (120 mg, 0.68 mmol) and Pd(PPh3)2Cl2 (39 mg, 0.03 mmol) under N2. A yellow suspension was obtained after 5 min of stirring at room temperature. A solution of 2-(but-3-ynyl)-imidazo[1,2-a]pyridine (120 mg, 0.68 mmol) in triethylamine (0.5 mL) was then added under N2. Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 30 min and heated at 80° C. overnight. The reaction mixture was concentrated and the crude product was purified by Flash chromatography (prepacked 25 g silicagel column, DCM/MeOH from 100/0 to 97/3 as eluent) to afford 15 mg of 2-(4(5-fluoropyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 8%) as a brown semi-solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:15][CH3:16])[S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:17])=[CH:5][C:4]=2[N:3]=1.Cl[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:15][CH3:16])[S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:17][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCc1nc2c(N)nc3cc(O)ccc3c2s1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCc1nc2c(N)nc3cc(Oc4ccc(C(=O)OC)cn4)ccc3c2s1

Procedure:
A round bottom flask was charged with 4-amino-2-ethylthiazolo[4,5-c]quinolin-7-ol (1.0 eq., 2.0 mmol), methyl 6-chloronicotinate (1.0 eq., 2.0 mmol), cesium carbonate (3.0 eq. 6.0 mmol), and anhydrous 1,4-dioxane (45 mL). The mixture was heated to reflux for 24 hours. The reaction was monitored by HPLC. The reaction mixture was concentrated to dryness. The resulting solid was then dissolved in methanol and adsorbed onto silica gel (6 g) for purification by HPFC (0-15% CMA in chloroform, 1440 mL). Pure fractions were combined and concentrated; the resulting solid was recrystallized from acetonitrile to provide methyl 6-[(4-amino-2-ethyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]nicotinate as a light peach colored crystalline solid, mp 213-214° C. MS (APCI) m/z 381 (M+H)+. Anal. calcd for C19H16N4O3S: C, 59.99; H, 4.24; N, 14.73. Found: C, 59.76; H, 4.19; N, 14.71.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[N:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=3[CH:15]=[C:7]2[C:6]2[N:17]=[C:18]([C:21]3[C:22]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])=[CH:23][C:24]4[O:28][C:27]([C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=5)=[C:26]([C:36]([NH:38][CH3:39])=[O:37])[C:25]=4[CH:40]=3)[CH:19]=[CH:20][C:5]=2[O:4]1.[CH3:47][O:48][C:49]([N:51]1[CH2:55][CH2:54][CH2:53][C@H:52]1[C:56](O)=[O:57])=[O:50].CCN=C=NCCCN(C)C.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:16][C:13]1[C:14]2[CH:15]=[C:7]3[C:6]4[N:17]=[C:18]([C:21]5[C:22]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:43])=[O:44])=[CH:23][C:24]6[O:28][C:27]([C:29]7[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=7)=[C:26]([C:36](=[O:37])[NH:38][CH3:39])[C:25]=6[CH:40]=5)[CH:19]=[CH:20][C:5]=4[O:4][CH:3]([CH2:2][NH:1][C:56]([C@@H:52]4[CH2:53][CH2:54][CH2:55][N:51]4[C:49]([O:48][CH3:47])=[O:50])=[O:57])[N:8]3[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CN)O4)cc12
Reactant: COC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CNC(=O)[C@@H]3CCCN3C(=O)OC)O4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
A mixture of 5-(6-(aminomethyl)-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (70 mg, 0.11 mmol), (S)-1-(methoxycarbonyl)pyrrolidine-2-carboxylic acid (38 mg, 0.22 mmol), EDCI (12 mg, 0.27 mmol), DMAP (40 mg, 0.33 mmol) and triethylamine (33 mg, 0.33 mmol) in CH2Cl2 (2 mL) was stirred at room temperature overnight. The mixture was then purified using Prep-TLC(CH2Cl2:EtOAc=1:1) to provide (2S)-methyl 2-(((11-fluoro-2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate (60 mg, yield: 69.0%). 1H-NMR (CDCl3, 400 MHz) δ 7.86˜8.05 (m, 3H), 7.28˜7.69 (m, 4H), 7.16˜7.27 (m, 5H), 6.85 (d, J=9.2 Hz, 1H), 6.60 (dd, J=5.2, 7.2 Hz, 1H), 5.98˜6.25 (m, 1H), 4.31 (br. s, 1H), 3.65 (br. s, 5H), 3.39 (s, 5H), 2.97 (d, J=3.2 Hz, 3H), 2.72 (br. s, 3H), 1.90˜2.49 (m, 2H), 1.63˜1.79 (m, 2H). MS (M+H)+: 799.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:48]3[N:52](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:51]=[N:50][N:49]=3)=[CH:38][CH:37]=2)[C:7]([C:11]([O:13][CH:14]([O:16][C:17]([O:19][CH2:20][CH2:21][CH:22]([CH3:34])[C@@H:23]([O:30][N+:31]([O-:33])=[O:32])[C@H:24]([O:26][N+:27]([O-:29])=[O:28])[CH3:25])=[O:18])[CH3:15])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].CO>C(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:48]3[NH:52][N:51]=[N:50][N:49]=3)=[CH:38][CH:37]=2)[C:7]([C:11]([O:13][CH:14]([O:16][C:17]([O:19][CH2:20][CH2:21][CH:22]([CH3:34])[C@@H:23]([O:30][N+:31]([O-:33])=[O:32])[C@H:24]([O:26][N+:27]([O-:29])=[O:28])[CH3:25])=[O:18])[CH3:15])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(=O)OC(C)OC(=O)OCCC(C)[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(C(=O)OC(C)OC(=O)OCCC(C)[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 70 °C

Procedure:
1-[({[(4R,5R)-3-methyl-4,5-bis(nitrooxy)hexyl]oxy}carbonyl)oxy]ethyl 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate (1.08 g, 1.09 mmol) was dissolved in CH2Cl2 (3 mL) and MeOH was added (17 mL). The solution was heated in a microwave apparatus (70° C., 40 minutes). The solution was then concentrated and the residue was purified by flash chromatography (Biotage SP1, SNAP 100 g column, CH2Cl2/MeOH 98:2) affording the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[N+](C1C=C(S(O[CH2:31][C@H:32]2[O:34][CH2:33]2)(=O)=O)C=CC=1)([O-])=O>CN(C)C=O>[C:3]([O:7][C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:31][C@H:32]2[O:34][CH2:33]2)=[CH:15][CH:16]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(OC[C@@H]2CO2)cc1
Yield: 83 %

Procedure:
To an 8 ml dimethylformamide suspension of 60 mg of sodium hydride was added, under ice cooling, 300 mg of 4-(tert-butoxycarbonylamino)phenol. The resultant mixture was stirred at room temperature for 1 hour. Under ice cooling, 372 mg of (S)-glycidyl 3-nitrobenzenesulfonate was gradually added, then the resultant mixture was stirred at room temperature for 2 hours. The reaction was quenched with a 5 ml of saturated aqueous ammonium chloride solution, then the product was extracted with ether. The extract was washed with saturated saline, dried, filtered, then concentrated under reduced pressure to give a residue, which was then purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the above-referenced compound (9) in an amount of 315 mg (yield 83%).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].[Cl:8][CH:9]([CH3:13])[C:10]([OH:12])=O.[OH2:14]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:8][CH:9]([CH3:13])[C:10]([O:7][CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][C:10](=[O:12])[CH:9]([Cl:8])[CH3:13])=[O:14]
Reactant: O
Reactant: CC(Cl)C(=O)O
Reactant: OCCOCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(Cl)C(=O)OCCOCCOC(=O)C(C)Cl
Temperature: 25 °C

Procedure:
In a 20 L glass reactor equipped with a Dean-Stark apparatus was added a solution of diethylene glycol (1500 g), 2-chloropropionic acid (3200 g) and para-toluene sulphonic acid (50 g) in toluene (5 L). The reaction mixture was refluxed for 5 hours with azeotropic removal of water, and then cooled to room temperature. The toluene layer was washed with 5% sodium bicarbonate solution (4500 ml) and water (4 L). The toluene layer was dried over anhydrous anhydrous sodium sulphate, and distilled to obtain 2-chloropropionic acid 2-[2-(2-chloropropionyloxy)-ethoxy]-ethyl ester (3.3 Kg) as light yellow oil. The product was characterized by 1H NMR (CDCl3) δ 1.65 (d, 3H, CH3), 3.75 (t, 2H, CH2), 4.40 (t, 2H, CH2), 4.48 (q, 1H, CH)
Reaction SMILES: [C:1]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)(=O)[CH2:2][CH3:3].[CH:10]([NH2:12])=[O:11].C(O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH:10]([NH:12][CH:1]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][CH3:3])=[O:11]
Reactant: NC=O
Reactant: CCC(=O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Solvent: O
Product: CCC(NC=O)c1cccs1
Reaction time: 22 h
Yield: 79.9 %

Procedure:
A mixture of 100 g of 2-propionylthiophene, 161 g of formamide and 98 g of formic acid is stirred at 150°-160 ° C. for 22 hours. After cooling, the mixture is poured into a solution of 30 g of potassium carbonate in 200 ml of water and extracted with ethyl acetate. The extract is washed, dried and evaporated to remove solvent. The residue is distilled under reduced pressure to give 96.5 g of 2-(1-formylaminopropyl) thiophene as a colorless oil. b.p. 154°-156° C./4 mmHg
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Na].[NH2:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14]2[O:19][CH2:20][O:21][C:13]=12.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH2:36][CH2:37][CH2:38][Cl:39])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][N:24]=1>CN(C=O)C>[Cl:18][C:17]1[C:12]([NH:11][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:35][CH2:36][CH2:37][CH2:38][Cl:39])=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][N:24]=2)=[C:13]2[O:21][CH2:20][O:19][C:14]2=[N:15][CH:16]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCCl
Reactant: Nc1c(Cl)cnc2c1OCO2
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)cnc4c3OCO4)ncnc2cc1OCCCCl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.6 %

Procedure:
Sodium hexamethyldisilazane (1M solution in THF; 0.734 ml) was added to a solution of 4-amino-5-chloro-2,3-methylenedioxypyridine (0.12 g) in DMF (4 ml) that had been cooled to 0° C. and the mixture was stirred for 15 minutes. A portion (0.1 g) of 4-chloro-7-(3-chloropropoxy)-6-methoxyquinazoline was added and the resultant mixture was stirred and allowed to warm to ambient temperature. The mixture was stirred at ambient temperature for 16 hours. The reaction mixture was evaporated and the residue was partitioned between methylene chloride and a saturated aqueous ammonium chloride solution. The organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent followed by increasingly polar mixtures of methylene chloride and acetonitrile. There was thus obtained the title compound as a white foam (0.11 g); NMR Spectrum: (DMSOd6 and CD3CO2D) 2.3 (m, 2H), 3.8 (m, 2H), 4.05 (s, 3H), 4.4 (t, 2H), 6.3 (s, 2H), 7.4 (s, 1H), 7.9 (s, 1H), 8.15 (s, 1H), 8.95 (s, 1H); Mass Spectrum: M+H+ 423 and 425.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([NH2:13])[CH:10]=[C:9]([NH2:14])[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O.C([O-])(O)=O.[Na+].CO>O>[N:1]1([C:7]2[N:8]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:14]=[C:9]3[CH:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1cc(N)nc(N2CCOCC2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1cc2nc(-c3ccccc3)cn2c(N2CCOCC2)n1
Yield: 59.8 %

Procedure:
A mixture of 2-morpholin-4-yl-pyrimidine-4,6-diamine (1.0 g, 5.1 mmol), w-bromoacetophenone (1.02 g, 5.1 mmol), NaHCO3 (473 mg, 6 mmol) and methanol (15 ml) was heated under an atmosphere of argon to reflux (3 h). After cooling, water (10 ml) was added (the gummy precipitate could not be isolated). Methanol was evaporated, the residue was taken up in ethyl acetate, washed (water), and dried (Na2SO4). The solvent was evaporated and the title compound (900 mg, 50%) was isolated from the mixture by column chromatography (silica gel, heptane:ethyl acetate=80:20-60:40). MS (m/e)=296.3 [M+H+].
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH:7][C:8]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][C:9]=1[NH2:10].Cl.[C:25](=N)(OC)[CH3:26].O>CO>[O:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[C:12]1[CH:13]=[CH:14][C:8]2[N:7]([CH2:6][CH:2]3[CH2:3][CH2:4][CH2:5][O:1]3)[C:25]([CH3:26])=[N:10][C:9]=2[CH:11]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NCC1CCCO1
Reactant: COC(C)=N
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CC1CCCO1
Yield: 127.5 %

Procedure:
To a solution of 2-(tetrahydrofuran-2-yl)methylaminoanilin-5-yl)benzoxazole (see Working Example 95-1) (0.15 g, 0.4 mmol) in methanol (5 mL) was added methyl acetimidate hydrochloride (0.05 mg, 0.4 mmol), and this was heated to reflux for 3 hours. After the reaction solution was cooled, water was added, and the precipitated crystals were filtered, and after being washed with water were dried to yield the title compound (0.17 g, 79% yield) as white crystals.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18](Cl)[N:17]=[C:16]([CH:30]3[CH2:32][CH2:31]3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[NH2:33][CH2:34][CH2:35][OH:36]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:36][CH2:35][CH2:34][NH2:33])[N:17]=[C:16]([CH:30]3[CH2:32][CH2:31]3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: NCCO
Reactant: COc1ccccc1Oc1c(Cl)nc(C2CC2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(C2CC2)nc1OCCN

Procedure:
According to the procedure described in Example 4b) 5-i-propyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide was reacted with 2-aminoethanol to give 950 mg 5-i-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide. LC-MS: tR=3.66 min, [M−1]−=498.37.