Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.Br[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(O)CCC>[N:16]1[CH:17]=[CH:18][C:13]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:14][CH:15]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Brc1ccncc1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1cc(N2CCC3(CC2)OCCO3)ccn1
Yield: 58 %

Procedure:
1,4-Dioxa-8-azaspiro[4.5]decane (10.0 g, 69.9 mmol, 1 eq) and 4-bromopyridine hydrochloride (16.2 g, 83.7 mmol, 1.2 eq) were dissolved in n-butanol (120 ml) and DIPEA (23 ml, 139.8 mmol, 2 eq) and refluxed for 14 h. After monitoring by thin-layer chromatography, the reaction solution was concentrated under reduced pressure. After purification by column chromatography (silica gel, 3% MeOH in dichloromethane), the desired product was obtained in the form of a white solid. Yield: 58% (9.0 g, 40.9 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[C:10]([CH:11]([F:13])[F:12])=[CH:9][C:8]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[N:7][C:6]=12.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>>[F:12][CH:11]([F:13])[C:10]1[N:5]2[N:4]=[CH:3][C:2]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[C:6]2[N:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:9]=1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc2c(Br)cnn12
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Yield: 88.5 %

Procedure:
Prepared from 3-bromo-7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (18.6 g, 45 mmol) and commercially available trimethylsilylacetylene (11.1 mL, 80 mmol) as described in example C.1, step 3a to give 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-3-trimethylsilanylethynyl-pyrazolo[1,5-a]pyrimidine (16.3 g, 99%) as an orange-solid. MS (ISP) 410.1[(M+H)+].
Reaction SMILES: N#N.[OH:3][CH2:4][C:5]1[O:6][CH:7]=[C:8]([C:10](=[O:12])[CH3:11])[N:9]=1.CCN(CC)CC.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:10]([C:8]1[N:9]=[C:5]([CH2:4][O:3][S:20]([CH3:23])(=[O:22])=[O:21])[O:6][CH:7]=1)(=[O:12])[CH3:11]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1coc(CO)n1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1coc(COS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(2-hydroxymethyl-oxazol-4-yl)-ethanone (75 mg, 0.53 mmol) in dry CH2Cl2 (5.0 mL) was treated at 0° C. with Et3N (0.10 mL, 0.71 mmol) followed by DMAP (6 mg, 0.05 mmol) and Ms-Cl (0.05 mL, 0.66 mmol). After stirring at 0° C. for 30 min, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. TLC: rf (EA)=0.63. LC-MS-conditions 02: tR=0.64 min; [M+H]+=220.22.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[Br:12]Br>O1CCOCC1>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][C:3]=1[OH:11]
Reactant: BrBr
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: Nc1c(O)cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.8 %

Procedure:
As shown by scheme (CLX), to a solution of 2-amino-3-nitrophenol 44 (10 g, 65 mmol) in anhydrous 1,4-dioxane (1 L) was added bromine (12.5 g, 78 mmol). The mixture was stirred at room temperature overnight. The solid was collected by filtration, washed with dioxane and dried. 2-amino-5-bromo-3-nitrophenol 45 (18 g, 90%) was obtained as its HBr salt in a form of a yellow solid. 1H NMR (DMSO-d6): δ 6.28 (br, 2H); 6.99 (d, J=2.2 Hz, 1H); 7.57 (d, J=2.1 Hz, 1H). MS (ESI+): m/z=234. Compound 45 (6 g, 19.1 mmol) was converted into compound 46 by using a method that was analogous to that used to synthesize compound 27, as shown on scheme (CXLI). Hydrogenation of compound 46 affords compound 47 (3.1 g, 67%) as a red solid.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34](=[O:35])[C:33]5[CH:37]=[CH:38][C:30]([C:29]([F:28])([F:39])[F:40])=[CH:31][CH:32]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound, off-white solid (111 mg, 88%), MS (ISP) m/z=503.3 [(M+H)+], mp 227° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-trifluoromethyl-benzoic acid.
Reaction SMILES: [N+:1]([C:4]1[C:13]([Cl:14])=[C:12]([Cl:15])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:17])[C:8](=[O:16])[NH:9]2)([O-])=O.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[C:13]([Cl:14])=[C:12]([Cl:15])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:17])[C:8](=[O:16])[NH:9]2
Reactant: O=c1[nH]c2cc(Cl)c(Cl)c([N+](=O)[O-])c2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1c(Cl)c(Cl)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 90 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
To a stirred mixture of 5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (110 mg, 0.40 mMol) in ethanol (6 mL) was added SnCl2.2H2O (448 mg, 2.0 mMol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) with stirring for 1 h to form a clear solution and continually refluxed for another 3 h. The mixture was then cooled to room temperature and the yellow precipitate was collected by filtration and washed with cold ethanol (2×1 mL) to give 61 mg (62%) of crude title compound (contains minor impurities by NMR). Crystallization from DMSO/H2O gave 43 mg of pure title compound as bright yellow needles, mp >350° C. (dec.), changed color from 320° C. IR (KBr, cm-1): 3468; 3389; 3057; 1695; 1636; 1596; 1397. NMR (1H, DMSO-d6): δ 5.935 (s, 2H); 6.595 (s, 1H); 11.317 (s, 1H); 11.868 (s, 1H). Purity >98.95% by HPLC. HRMS: calcd for C8H5N3O2Br2 (M+) m/z: 244.9757; found 244.9740. Potency relative to DCK: 323%.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5])C.[Na:20]>C(O)C.[OH-].[Na+]>[C:4]([C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)([OH:5])=[O:3].[Na:20]
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(OCc2ccccc2)cc1
Reaction time: 18 h

Procedure:
To a solution of 4-ethoxycarbonylphenoxy phenyl methane (6.3g) in ethanol (30ml), sodium hydroxide solution (70ml.; 10N) was added and the mixture boiled under reflux with vigorous stirring for 18 hr. After cooling the sodium salt was filtered off and dried, m.p. >340°.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Br:23][C:24]1[C:25]([O:32][CH3:33])=[CH:26][C:27]([CH2:30][OH:31])=[N:28][CH:29]=1.[OH-].[Na+]>C(Cl)Cl>[Br:23][C:24]1[C:25]([O:32][CH3:33])=[CH:26][C:27]([CH:30]=[O:31])=[N:28][CH:29]=1
Reactant: COc1cc(CO)ncc1Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc(C=O)ncc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
Dess-Martin reagent (1.14 g) was added at 0° C. to a methylene chloride (5 mL) solution of (5-bromo-4-methoxypyridin-2-yl)methanol (450 mg) synthesized by the method described in organic Process Research & Development 2000 4,473. The reaction solution was agitated at 0° C. for 1 hour and further agitated at room temperature for 1 hour. 1N sodium hydroxide solution was added to the reaction solution, the organic layer was separated, and washed with a saturated sodium chloride solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent:heptane-ethyl acetate 1:1), and 300 mg (67%) 5-bromo-4-methoxypyridine-2-carbaldehyde was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.I[CH2:27][CH2:28][CH2:29][OH:30]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15](=[O:19])[N:16]3[CH2:27][CH2:28][CH2:29][OH:30])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: OCCCI
Solvent: C1CCOC1
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Yield: 94.1 %

Procedure:
In a similar manner to that described in example 316 step 1, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.0584 mmol), lithium (bis-trimethylsilyl)amide (0.18 mL of a 1 M tetrahydrofuran solution, 0.18 mmol), and 3-iodo-1-propanol (0.03 mL, 0.350 mmol) was prepared ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (22 mg, 95% yield) as a yellow oil. The product was carried on without further purification. MS m/z 423 (M+23).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7](F)=[CH:8][CH:9]=2)[N:4]([CH:12]2[CH2:14][CH2:13]2)[CH:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][OH:22].[H-].[Na+]>CS(C)=O.CO>[Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:22][CH2:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)=[CH:8][CH:9]=2)[N:4]([CH:12]2[CH2:14][CH2:13]2)[CH:3]=1
Reactant: Fc1ccc2c(Br)cn(C3CC3)c2n1
Reactant: OCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: Brc1cn(C2CC2)c2nc(OCc3ccccn3)ccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.6 %

Procedure:
To a solution of 3-bromo-1-cyclopropyl-6-fluoro-1H-pyrrolo[2,3-b]pyridine (0.249 g, 0.98 mmol) in dimethyl sulfoxide (5 mL) is added 2-pyridinemethanol (188 μL, 1.95 mmol), followed by portionwise addition of sodium hydride (97.6 mg, 2.44 mmol). The mixture is stirred at room temperature for 5 min., then poured onto brine and extracted with EtOAc. The organic layers are combined, dried (magnesium sulphate) and concentrated in vacuo to give a brown oil. This is taken up in methanol and poured onto a SCX-2 ion-exchange column. This is washed with 3 column volumes of MeOH, and then the product collected in the subsequent one column volume flush with 7 M methanolic ammonia. The solution is then concentrated in vacuo to give the title compound as a yellow oil (0.263 g, 0.76 mmol). MS (m/z): 344/346 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH3:20].[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: CC(C)C(=O)Cl
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)C(C)C
Yield: 44.6 %

Procedure:
Using the general method of Example 197, 1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.7 mmol) was reacted with isobutyryl chloride (0.43 mL, 4.1 mmol) to provide 0.56 g of N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-methylpropanamide as an off white solid, m.p. 159.7-160.7° C.
Reaction SMILES: [SiH3:1][SiH2:2][SiH2:3][SiH2:4][SiH2:5][SiH2:6][SiH2:7][SiH2:8][SiH2:9][SiH2:10][SiH3:11].[F:12][C:13]([F:19])([F:18])[S:14]([OH:17])(=[O:16])=[O:15]>ClCCl>[F:12][C:13]([F:19])([F:18])[S:14]([O:17][SiH2:11][SiH2:10][SiH2:9][SiH2:8][SiH2:7][SiH2:6][SiH2:5][SiH2:4][SiH2:3][SiH2:2][SiH3:1])(=[O:16])=[O:15]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: [SiH3][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH3]
Solvent: ClCCl
Product: O=S(=O)(O[SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH3])C(F)(F)F

Procedure:
In an argon atmosphere, to a tetrahydrofuran solution (1 ml) of 52 mg (0.15 mmol) of octaethylcyclotetrasilane was added 0.58 ml (0.15 mmol) of a tetrahydrofuran solution (0.27M) of phenyldimethylsilyllithium, and stirred at 0° C. for 15 minutes. Then, tetrahydrofuran was distilled out under vacuum, and hexane (1 ml) was added to give a hexane solution (Solution 1). A dichloromethane solution (1 ml) of 49 mg (0.05 mmol) of undecasilane (8) obtained in Example 8 was treated with 7.5 mg (0.05 mmol) of trifluoromethanesulfonic acid at room temperature for 30 minutes to afford 1-(trifluoromethanesulfonyloxy)undecasilane. Then, dichloromethane was distilled out under vacuum, and hexane (1 ml) was added to give a hexane solution (Solution 2). The Solution 1 was added to the Solution 2 at -78° C. and stirred for 15 minutes. Methanol (0.1 ml) and triethylamine (0.1 ml) were added, then saturated aqueous sodium bicarbonate solution (2 ml) was added, stirred, the hexane layer was separated, and dried with magnesium sulfate. The resulting crude product was purified by a silica gel column chromatography (hexane) to give 36 mg (41% yield) of hexadecasilane (9) as a colorless crystal.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:37][CH:38]([F:58])[O:39][C:40]1[N:41]=[CH:42][CH:43]=[C:44]2[C:49](=[O:50])[C:48](I)=[C:47]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:46][C:45]=12>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:48]3[C:49](=[O:50])[C:44]4[C:45]([O:46][C:47]=3[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[C:40]([O:39][CH:38]([F:58])[F:37])[N:41]=[CH:42][CH:43]=4)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=c1c(I)c(-c2ccccc2)oc2c(OC(F)F)nccc12
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(OC(F)F)nccc4c3=O)cc2)CCC1
Yield: 56 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 8-difluoromethoxy-3-iodo-2-phenyl-pyrano[2,3-c]pyridin-4-one was reacted to give the title compound as a colourless oil (24 mg, 56%). LCMS (Method A): RT=4.85 min, [M+H]+=535.
Reaction SMILES: [CH3:1][C:2]([NH:17]C(=O)C(F)(F)F)([CH3:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:16][C:2]([NH2:17])([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: Cc1nc(-c2ccc(CC(C)(C)NC(=O)C(F)(F)F)cc2)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(CC(C)(C)N)cc2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
In a round-bottomed flask, N-{1,1-dimethyl-2-[4-(2-methyl-thiazol-4-yl)-phenyl]-ethyl}-2,2,2-trifluoroacetamide (˜362 mg, 1.06 mmol) was suspended in 7.5 ml of 2:1 (v:v) methanol/tetrahydrofuran, and 5M sodium hydroxide (3.2 ml, 15 equiv.) was added dropwise. The solution turned from colorless to golden brown, and was then allowed to stir at room temperature overnight. The reaction mixture was then concentrated in vacuo to remove volatiles, and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqeuous layer was removed and was washed twice more with ethyl acetate. The combined organic extracts were then washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the product (242 mg, 93% yield for both steps), which was used directly without further purification. LRMS ([M+1]+)=247.3.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([NH:14][C:15](=[O:20])[O:16][CH:17]([CH3:19])[CH3:18])[CH:7]=[C:8]([CH2:11][CH2:12][CH3:13])[C:9]=1[OH:10].Cl[CH2:22][S:23][CH3:24]>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]([NH:14][C:15](=[O:20])[O:16][CH:17]([CH3:19])[CH3:18])[CH:7]=[C:8]([CH2:11][CH2:12][CH3:13])[C:9]=1[O:10][CH2:22][S:23][CH3:24]
Reactant: CCCc1cc(NC(=O)OC(C)C)cc(C)c1O
Reactant: CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cc(NC(=O)OC(C)C)cc(C)c1OCSC
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A mixture of 3-methyl-4-hydroxy-5-n-propylaniline (1.65 g) and ethyl acetate (20 ml) was added to an ethyl acetate solution containing 10 g of phosgene at 0° to 5° C. The resulting mixture was gradually heated and, after the solution became clear, cooled to room temperature. The solvent was removed by distillation under reduced pressure to give 3-methyl-4-hydroxy-5-n-propylphenyl isocyanate. the thus obtained crude substance was added to a toluene solution (50 ml) containing triethylamine (1.0 g) and isopropanol (1.0 g). The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-(3-methyl-4-hydroxy-5-n-propylphenyl)carbamate (1.70 g). Sodium hydride (0.28 g, 60% dispersion in mineral oil) was added to dimethylformamide (50 ml). To the resulting mixture was added isopropyl N-(3-methyl-4-hydroxy-5-n-propylphenyl)carbamate (1.70 g) under 5° C. The resulting solution was stirred at a temperature of 20° C. for 30 minutes, and (chloromethyl)methylsulfide (0.67 g) was added thereto in 5 minutes. The mixture was heated at 90° C. for 10 minutes, poured into ice-water and extracted with ethyl acetate. The extract was washed with aqueous potassium carbonate solution and water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-(3-methyl-4-methylthiomethyloxy-5-n-propylphenyl)carbamate (Compound No. 14) (1.90 g) in a yield of 61.0%. nD21.4
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].CCN(CC)CC.Cl[C:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24]([O:31][CH3:32])[N:23]=1>CCO>[CH3:32][O:31][C:24]1[N:23]=[C:22]([NH:1][C@@H:2]([CH2:5][O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3][OH:4])[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=1
Reactant: N[C@H](CO)COCc1ccccc1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c(N[C@H](CO)COCc2ccccc2)n1
Temperature: 78 °C
Yield: 115.5 %

Procedure:
To a solution of (R)-2-amino-3-benzyloxy-1-propanol (698.4 g, 3.931 mol) in EtOH (3.6 L) was added Et3N (1.27 L, 9.11 mol) in portions over 10 min. Then a solution of 2-chloro-6-methoxy-3-nitropyridine (672.7 g, 3.567 mol) in EtOH (0.6 L) was added in portions over 10 min. The mixture was heated at 78° C. for 2 h. The reaction mixture was cooled to room temperature and added to stirred ice/H2O (8.4 L). The mixture was extracted with EtOAc (9+6+3 L). The extracts were washed with brine (6 L), dried over MgSO4 (˜900 g), filtered and evaporated to give (2R)-2-{[6-(methyloxy)-3-nitro-2-pyridinyl]amino}-3-[(phenylmethyl)oxy]-1-propanol (1373.1 g, 115%) as an orange oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[CH2:30]=O>C(O)=O>[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[CH3:30])[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: C=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@H]1CCCN1
Agent: Cl
Solvent: O=CO
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@H]1CCCN1C
Temperature: 85 °C

Procedure:
A mixture of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2R)-pyrrolidin-2-ylmethoxy]quinazoline hydrochloride (250 mg) (Prepared as described in Example 32), formic acid (5 ml) and formaldehyde (37% w/v in water) (2.5 ml) was heated to 85° C. for one hour. The reaction mixture was then evaporated under vacuum, azeotroped with toluene and partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The residues were then purified by flash chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (saturated with ammonia) (98/2-94/6). The fractions containing the desired product were combined and evaporated to give a colourless gum, which was triturated with diethylether, filtered and dried under vacuum to give the title product as a white solid (0.15 g); 1H NMR Spectrum: (DMSO d6) 1.55-1.83 (m, 3H); 1.95-2.10 (m, 1H); 2.20-2.35 (m, 1H); 2.45 (s, 3H); 2.68-2.85 (m, 1H); 2.93-3.10 (m, 1H); 3.92 (s, 3H); 1924.15 (m, 2H); 7.19 (s, 1H); 7.20-7.30 (m, 1H); 7.40-7.55 (m, 2H); 7.81 (s, 1H); 8.36 (s, 1H); 9.57 (s, 1H); Mass Spectrum: (M+H)+ 417.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=2)[CH2:3]1.C[O:19][C:20]([CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[S:31](Cl)(=[O:33])=[O:32])[CH2:23]1)=[O:21]>>[CH3:1][C@H:2]1[CH2:3][N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][N:9]=2)[CH2:5][CH2:6][N:7]1[S:31]([C:28]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:29]=1[CH2:30][CH:22]([C:20]([OH:21])=[O:19])[CH2:23]2)(=[O:33])=[O:32]
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)Cl)c2C1
Reactant: C[C@H]1CN(c2ccc(C(F)(F)F)cn2)CCN1
Product: C[C@H]1CN(c2ccc(C(F)(F)F)cn2)CCN1S(=O)(=O)c1cccc2c1CC(C(=O)O)C2

Procedure:
The compound 4-[2-(S)-Methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid was prepared from 3-(S)-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine and 4-chlorosulfonyl-indan-2-carboxylic acid methyl ester following the procedure outlined in Example 79. 1H NMR (400 MHz, DMSO-d6): δ 8.3& (s, 1H), 7.82-7.76 (m, 1H), 7.65 (d, 1H), 7.52 (d, 1H), 7.37 (t, 1H), 6.93-6.88 (m, 1H), 4.35-4.18 (m, 2H), 4.18-4.02 (m, 1H), 3.60-3.46 (m, 1H), 3.45-3.10 (m, 7H), 2.97-2.80 (m, 1H), 1.06-1.01 (m, 3H); MS (ESI): 470.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[NH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>>[N:20]1[CH:21]=[CH:22][C:17]([NH:16][S:12]([C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[Cl:1])(=[O:14])=[O:13])=[CH:18][CH:19]=1
Reactant: Nc1ccncc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Nc2ccncc2)c1Cl
Yield: 74.5 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (500 mg, 1.72 mmol), 4-aminopyridine (165 mg,1.75 mmol) and triethylamine (0.36mL,2.58 mmol) were reacted to form the desired product (446 mg, 76%). EI-MS m/z 346(M-H)−.