Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C@@:11]2([CH3:23])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)[C:3]=1[CH2:24][CH2:25]OS(C)(=O)=O.C1CCN2C(=NCCC2)CC1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[CH2:24][CH2:25][N:10]([C@@:11]3([CH3:23])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:12]3)[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1
Reactant: CSc1nc(Cl)c(CCOS(C)(=O)=O)c(N[C@@]2(C)CCN(C(=O)OC(C)(C)C)C2)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CSc1nc(Cl)c2c(n1)N([C@@]1(C)CCN(C(=O)OC(C)(C)C)C1)CC2
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 94.7 %

Procedure:
To a solution of tert-butyl(3S)-3-{[6-chloro-2-(methylsulfanyl)-5-{2-[(methylsulfonyl)oxy]ethyl}pyrimidin-4-yl]amino}-3-methylpyrrolidine-1-carboxylate (1635 mg, 3.4 mmol) in DMF (34 mL) was added DBU (1.1 mL, 6.8 mmol) and the mixture was stirred at 80° C. for 90 min. The reaction mixture was diluted with EtOAc (20 mL), washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and concentrated to give the title compound (1.24 g, 95%) as a light yellow-white solid. 1H NMR (400 MHz, DMSO-d6) δ 3.80-3.57 (m, 4 H), 3.40-3.35 (m, 1 H), 3.28-3.19 (m, 1 H), 2.91 (t, J=8.9 Hz, 2 H), 2.42 (s, 3 H), 2.39-2.24 (m, 1 H), 2.07-1.94 (m, 1 H), 1.39 (d, J=5.4 Hz, 9 H), 1.28 (s, 3 H). m/z (APCI+) for C17H25ClN4O2S 385.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Cl[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1>>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: Oc1cccc(F)c1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: [H-]
Agent: [Na+]
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Oc5cccc(F)c5)nc34)cc21
Temperature: 85 °C
Yield: 17.9 %

Procedure:
Prepared according to Example 103, using NaH as a 60% dispersion in mineral oil (47.0 mg, 1.176 mmol, Sigma Aldrich), 3-fluorophenol (108 μl, 1.176 mmol, Sigma Aldrich), and 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 50 mg, 0.168 mmol) and heating to 85° C. for 17 h. Purification by reverse-phase HPLC (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in ACN/H2O, gradient 5% to 90%) to provide 2-(2-(3-fluorophenoxy)-8-quinolinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (11.2 mg, 11%) as the free base following filtration through a Si-carbonate cartridge (Silicyle) with MeOH. 1H NMR (400 MHz, MeOH-d4) δ ppm 7.10 (1H, m) 7.10 (1H, d, J=1.00 Hz) 6.80-6.87 (1H, m) 6.82 (1H, d, J=1.00 Hz) 6.44-6.49 (1H, m) 6.31-6.38 (1H, m) 6.16-6.24 (1H, m) 6.01-6.07 (1H, m) 5.87-5.99 (2H, m) 5.73 (1H, s) 2.23 (2H, t, J=1.00 Hz) 1.26 (2H, t, J=1.00 Hz). m/z (ESI, +ve) 374.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[S:10](Cl)(=[O:12])=[O:11].Cl.[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]>O1CCOCC1.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[S:10]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:12])=[O:11]
Reactant: NCCCCC(=O)O
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCCCNS(=O)(=O)c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2,4,6-trichlorobenzenesulfonic acid chloride (3.00 g, 11 mmol) in 1,4-dioxane (50 ml) was added dropwise to a solution of 5-aminovaleric acid hydrochloride (1.50 g, 10 mmol) in 1 N sodium hydroxide solution (30 ml). The reaction mixture was stirred for 18 h at room temperature, and 1,4-dioxane was then distilled off in vacuo. The aqueous phase was extracted with ethyl acetate (3×50 ml) and then adjusted to pH 1 with concentrated hydrochloric acid. The acidic aqueous phase was extracted with ethyl acetate (3×60 ml). The combined organic phases were dried over sodium sulfate and concentrated in vacuo.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:28])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)[C:5]([F:29])=[CH:4][C:3]=1[C:30]#[N:31].C(=O)([O-])[O-].[Na+].[Na+].[CH3:38][O:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C(Cl)Cl>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.O1CCOCC1>[C:30]([C:3]1[CH:4]=[C:5]([F:29])[C:6]([N:8]([CH3:28])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)=[N:7][C:2]=1[C:43]1[CH:44]=[CH:45][C:40]([O:39][CH3:38])=[CH:41][CH:42]=1)#[N:31]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(Cl)c(C#N)cc3F)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(-c4ccc(OC)cc4)c(C#N)cc3F)ccc21
Temperature: 80 °C
Yield: 87.8 %

Procedure:
To a solution of ethyl ((1S)-5-{3-[(6-chloro-5-cyano-3-fluoro-2-pyridinyl)(methyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 312, 0.10 g, 0.22 mmol) in a mixture of toluene (1.5 mL), 1,4-dioxane (0.5 mL), and water (0.6 mL) were added sodium carbonate (0.24 g, 2.24 mmol), 4-methoxyphenyl boronic acid (0.14 g, 0.90 mmol) and PdCl2(dppf).CH2Cl2 (0.04 g, 0.04 mmol). The mixture was heated at 80° C. for 4 h, and then concentrated under reduced pressure. The product (0.10 g, 88%) was isolated after silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 7.87 (d, 2H), 7.37 (d, 1H), 7.04 (d, 1H), 6.98 (d, 2H), 6.72 (d, 1H), 6.65 (dd, 1H), 4.16 (q, 2H), 4.00 (t, 2H), 3.90-3.85 (m, 5H), 3.49 (qt, 1 H), 3.30 (d, 3H), 2.94-2.76 (m, 2H), 2.70 (dd, 1H), 2.45-2.32 (m, 2H), 2.16 (qt, 2H), 1.80-1.70 (m, 1H), 1.29 (t, 3H).
Reaction SMILES: C(OC([NH:8][C:9]([CH3:15])([CH2:13][OH:14])[C:10](O)=O)=O)(C)(C)C.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:31]([C:36]1[CH:37]=[C:38]([NH2:43])[C:39]([NH2:42])=[CH:40][CH:41]=1)[C:32]([CH3:35])([CH3:34])[CH3:33].C(O)(=O)C.FC(F)(F)C(O)=O>C(#N)C>[NH2:8][C:9]([C:10]1[NH:43][C:38]2[CH:37]=[C:36]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:41]=[CH:40][C:39]=2[N:42]=1)([CH3:15])[CH2:13][OH:14]
Reactant: CC(C)(C)OC(=O)NC(C)(CO)C(=O)O
Reactant: CC(C)(C)Cc1ccc(N)c(N)c1
Agent: CC(C)COC(=O)Cl
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)Cc1ccc2nc(C(C)(N)CO)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.1 %

Procedure:
To a solution of 2-((tert-butoxycarbonyl)amino)-3-hydroxy-2-methylpropanoic acid (Preparation 53, 186 mg, 0.85 mmol) acetonitrile (4.0 mL) and 4-methylmorpholine (0.15 mL, 1.4 mmol) cooled in an ice/brine bath was added isobutylchloroformate (0.050 mL, 0.38 mmol). The mixture was stirred for 30 minutes and then 4-neopentylbenzene-1,2-diamine (Preparation 83, 139 mg, 0.78 mmol) was added. The reaction mixture was allowed to warm to room temperature and stir for 4 days. The solvent was evaporated and the resulting oil was dissolved in acetic acid (3.0 mL, 50 mmol) and stirred at room temperature for 16 hours and then heated to 70° C. for 5 hours. After cooling, the solvent was removed in vacuo and the residue purified by silica gel column chromatography eluting with a 0-100% ethyl acetate/hexanes gradient. The resulting oil was dissolved in methylene chloride (5 mL) and treated with trifluoroacetic acid (0.5 mL, 6 mmol). After stirring for 2 hours, the reaction mixture was concentrated in vacuo and purified by silica gel column chromatography eluting with a 0-100% CMA80/methylene chloride gradient to provide the title compound (20.6 mg, 10%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12](SC)[N:13]=1.[NH2:26][CH2:27][CH2:28][OH:29]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12]([NH:26][CH2:27][CH2:28][OH:29])[N:13]=1
Reactant: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(SC)nc21
Reactant: NCCO
Product: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(NCCO)nc21

Procedure:
The product of Example 44, and 2-aminoethanol were reacted by the procedure of Example 60 to afford the title compound 4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-2-(2-hydroxy-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. LC MS (m/e)=387 (MH+). Rt=1.94 min
Reaction SMILES: [C:1]([C:3]1[S:4][CH:5]=[C:6]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][S:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][C:22]([O:28][CH3:29])=[CH:23][CH:24]=4)[CH:19]=3)(=[O:17])=[O:16])[C:10]2=[O:30])[CH:7]=1)#[N:2].Br[CH2:32][C:33]1[CH:37]=[CH:36][S:35][CH:34]=1>>[C:1]([C:3]1[S:4][CH:5]=[C:6]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([N:14]([CH2:32][C:33]3[CH:37]=[CH:36][S:35][CH:34]=3)[S:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][C:22]([O:28][CH3:29])=[CH:23][CH:24]=4)[CH:19]=3)(=[O:17])=[O:16])[C:10]2=[O:30])[CH:7]=1)#[N:2]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4csc(C#N)c4)C3=O)cc2c1
Reactant: BrCc1ccsc1
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3ccsc3)[C@H]3CCN(Cc4csc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared from 7-methoxynaphthalene-2-sulfonic acid [1-(2-cyanothiophen-4-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide (0.5 g, 1.16 mmol) as described in EXAMPLE 126, Part A, using 3-bromomethylthiophene in place of methyl iodide. The crude product is purified by column chromatography eluting with 60% EtOAc/hexanes to afford 7-methoxy-naphthalene-2-sulfonic acid-[1-(2-cyanothiophene-4-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]thiophene-3-ylmethylamide as a white solid (0.18 g, 0.33 mmol).
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:27])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:10][CH:11]=1.[C:28](O)(=O)C(C)O.C(O)(=O)CO>ClCCl>[CH:6]1[CH:11]=[CH:10][C:9]([C:12]([OH:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:8][CH:7]=1.[CH2:1]([S:2]([O-:5])(=[O:4])=[O:3])[CH3:28]
Reactant: CC(O)C(=O)O
Reactant: CS(=O)(=O)O
Agent: O=C(O)CO
Agent: OC(CCN1CCCCC1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCS(=O)(=O)[O-]

Procedure:
In 3.0 ml of 30% gelatin (dissolved by warming) is dissolved 50 mg of pridinol methanesulfonate and the solution is added to 10 ml of a 30% dichloromethane solution of lactic acid-glycolic acid copolymer (78.1/21.9, average mol. wt. 10,000). The mixture is then worked up in the same manner as Example 1 to give pridinol ethanesulfonate microcapsules for injection.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:19][O:20][C:5]=2[CH:4]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH:11][C:10]3=[O:18].CC1C2C=C3[C:33]4([C:41]5[C:36](=[CH:37]C=C[CH:40]=5)N[C:34]4=[O:42])COC3=CC=2ON=1.BrCC1CCOCC1.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:19][O:20][C:5]=2[CH:4]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:11]([CH2:40][CH:41]1[CH2:36][CH2:37][O:42][CH2:34][CH2:33]1)[C:10]3=[O:18]
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Reactant: COc1ccc2c(c1)OCC21C(=O)Nc2ccccc21
Agent: BrCC1CCOCC1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COc1ccc2c(c1)OCC21C(=O)N(CC2CCOCC2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 4-(bromomethyl)tetrahydro-2H-pyran to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 6-methoxy-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (84%) as a colorless foam; 1H NMR (300 MHz, CDCl3) δ 7.31 (dd, J=7.5, 1.2 Hz, 1H), 7.15 (dd, J=7.5, 1.2 Hz, 1H), 7.04 (dd, J=7.5 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 6.53 (d, J=2.4 Hz, 1H), 6.36 (dd, J=8.4, 2.4 Hz, 1H), 4.93 (d, J=9.0 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.03-3.94 (m, 2H), 3.77 (s, 3H), 3.80-3.30 (m, 4H), 2.21-2.05 (m, 1H), 1.74-1.38 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.8, 162.1, 161.5, 142.7, 132.6, 128.7, 123.9, 123.3, 123.2, 120.8, 108.5, 107.5, 96.6, 80.6, 67.4, 67.3, 57.5, 55.5, 46.0, 33.9, 30.8, 30.7; MS (ES+) m/z 366.4 (M+1).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([O-:10])=[O:9])[C:5]([N+:11]([O-:13])=[O:12])=[C:4]([OH:14])[N:3]=1.[K+].S(=O)(=O)(O)O.[CH3:21]O>>[OH:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:21])=[O:9])[C:5]([N+:11]([O-:13])=[O:12])=[C:4]([OH:14])[N:3]=1
Reactant: O=C([O-])c1nc(O)nc(O)c1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1nc(O)nc(O)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Potassium 2,6-dihydroxy-5-nitropyrimidine-4-carboxylate (25 gm, 105 mmol) was dissolved in MeOH (75 mL) and sulphuric acid (21 mL) was added dropwise. The reaction was heated at reflux overnight. After cooling to room temperature, the precipitate was collected by filtration, washed with water, and dried to give methyl 2,6-dihydroxy-5-nitropyrimidine-4-carboxylate (17.1 g) as a white solid. 1H NMR (DMSO-d6) δ ppm 12.04 (2H, br. s.), 3.90 (3H, s).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4](P(OCC)(=O)OCC)[NH:3]1.[N+:16]([C:19]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][CH2:30][CH:29]([C:33](=[O:42])[N:34]([CH3:41])[CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[CH2:28]2)=[CH:23][C:20]=1[CH:21]=O)([O-:18])=[O:17]>>[CH:35]1([N:34]([CH3:41])[C:33]([CH:29]2[CH2:30][CH2:31][CH2:32][N:27]([C:24]3[CH:25]=[CH:26][C:19]([N+:16]([O-:18])=[O:17])=[C:20]([CH:21]=[C:4]4[NH:3][C:2](=[O:1])[NH:6][C:5]4=[O:7])[CH:23]=3)[CH2:28]2)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CN(C(=O)C1CCCN(c2ccc([N+](=O)[O-])c(C=O)c2)C1)C1CCCCC1
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Product: CN(C(=O)C1CCCN(c2ccc([N+](=O)[O-])c(C=C3NC(=O)NC3=O)c2)C1)C1CCCCC1

Procedure:
Prepared from diethyl 2,4-dioxoimidazolidine-5-phosphonate and 2-nitro-5-[3-(N-methyl-N-cyclohexylcarbamoyl)-1-piperidinyl]benzaldehyde analogous to the procedure of Example (2-1), m.p. 153°-162° C., crystallized from MeOH-H2O.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH:13]=[O:14])[CH2:9][CH2:8]1)=[O:5].[CH3:23][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:14])[CH3:23])[CH2:9][CH2:8]1)=[O:5]
Reactant: C[Mg]Br
Reactant: O=C[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Solvent: C1CCOC1
Product: C[C@H](O)[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans-2-chloro-N-(4-formylcyclohexyl)-5-(trifluoromethyl)-benzamide (1.00 g, 3.00 mmol) in THF (50 mL) is added methylmagnesium bromide 2.5 mL of a 3M solution in THF, 7.49 mmol,) and the reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is quenched with water and partitioned between EtOAc and water. The organic phase is washed with water and brine, dried over MgSO4, filtered and the solvent is removed in vacuo. The mixture is used directly in step 2 without further purification.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CN(C1CCCCC1)C.Cl.[CH3:25][CH:26]([NH2:30])[CH:27]([CH3:29])[CH3:28].[Cl:31][C:32]1[CH:33]=[CH:34][C:35]2[S:40](=[O:42])(=[O:41])[NH:39][C:38](=O)[NH:37][C:36]=2[CH:44]=1>O>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]2[S:40](=[O:42])(=[O:41])[N:39]=[C:38]([NH:30][CH:26]([CH3:25])[CH:27]([CH3:29])[CH3:28])[NH:37][C:36]=2[CH:44]=1
Reactant: O=C1Nc2cc(Cl)ccc2S(=O)(=O)N1
Reactant: CC(C)C(C)N
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CN(C)C1CCCCC1
Product: CC(C)C(C)NC1=NS(=O)(=O)c2ccc(Cl)cc2N1
Temperature: 195 °C
Reaction time: 0.25 h
Yield: 37.4 %

Procedure:
Phosphorus pentoxide (7.55 g, 53.2 mmol), N,N-dimethylcyclohexylamine (17 ml, 113 mmol) and 1,2-dimethylpropylamine hydrochloride (12.4 g, 100.4 mmol) were carefully mixed and heated with mechanical stirring on an oil bath at 190-200° C. for about 15 min. To the homogeneous mass was added 6-chloro-3,4-dihydro-3-oxo-1,2,4-benzothiadiazine 1,1-dioxide (5.84 g, 25.1 mmol) and the mixture was stirred at 235° C. for 2 h. After cooling to about 100° C., water (200 ml) was added and the dark mixture was hydrolysed by stirring over night at room temperature. The precipitate was isolated by filtration and recrystallised from ethanol with decolorising charcoal to give 2,83 g (37%) of the pure title compound; m.p. (DSC) 264.7° C.; 1H-NMR (DMSO-d6): δ 0.90 (dd, 6H, CH(CH3)2), 1.09 (d, 3H, NCHCH3), 1.76 (m, 1H, CH(CH3)2), 3.70 (m, 1H, NHCH), 7.15 (br., 1H, NH), 7.28 (m, 2H, ArH), 7.68 (d, 1H, ArH), 10.3 (br.s, 1H, NH); (C12H16N3Cl1O2S1) calc. C, 47.76; H, 5.34; N 13.92; found C, 47.66; H, 5.47; N, 13.91.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH2:16])[CH:10]=2)=[C:4]([CH2:17][CH3:18])[N:3]=1.[C:19](Cl)(=[O:30])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>N1C=CC=CC=1.O1CCCC1.O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:30])[CH:10]=2)=[C:4]([CH2:17][CH3:18])[N:3]=1
Reactant: CCc1nc(N)nc(N)c1-c1ccc(Cl)c(N)c1
Reactant: CCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCC(=O)Nc1cc(-c2c(N)nc(N)nc2CC)ccc1Cl
Reaction time: 96 h
Yield: 648.1 %

Procedure:
Under a nitrogen atmosphere, a solution of 2.5 grams (0.001 mole) of 2,4-diamino-6-ethyl-5-(3-amino-4-chlorophenyl)pyrimidine (prepared in Step B of this Example) in 75 mL of pyridine and 25 mL of tetrahydrofuran was stirred and cooled in an ice bath. To this was added dropwise during a 10 minute period, a solution of 2.2 grams (0.001 mole) of undecanoyl chloride in 50 mL of tetrahydrofuran. The reaction mixture was maintained below about 10° C. throughout the addition. Upon completion of addition, the reaction mixture was stirred under a nitrogen atmosphere for about 4 days. After this time, the reaction mixture was taken up in 100 mL of water and poured into 500 mL of water. The mixture was then extracted with two 200 mL portions of ethyl acetate. The combined extracts were washed with 150 mL of aqueous 10% lithium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. In an effort to remove any excess pyridine, the residue was taken up in 50 mL of toluene, and the solution was concentrated under reduced pressure to a residue. This procedure was repeated two more times. The residue was subjected to column chromatography on silica gel. Elution was accomplished with 10:1 methylene chloride and methanol. The product-containing fractions were combined and concentrated under reduced pressure, yielding 2.8 grams of 2,4-diamino-6-ethyl-5-(4-chloro-3-decylcarbonylaminophenyl)pyrimidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](Cl)=[C:11]([C:16]#[N:17])[CH:12]=[N:13]2)=[CH:8][C:7]=1[O:19][CH3:20].C(=O)([O-])OC.[Cl:26][C:27]1[C:33]([OH:34])=[CH:32][C:30]([NH2:31])=[C:29]([F:35])[CH:28]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:26][C:27]1[C:33]([OH:34])=[CH:32][C:30]([NH:31][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[C:7]([O:19][CH3:20])[CH:8]=3)[N:13]=[CH:12][C:11]=2[C:16]#[N:17])=[C:29]([F:35])[CH:28]=1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCCl
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: COC(=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)c(C#N)cnc2cc1OCCCCl

Procedure:
By using the above method, starting with 3 g of 7-(3-chloro-propoxy)-4-chloro-6-methoxy-quinoline-3-carbonitrile, 2.35 g of the methyl carbonate of 4chloro-2-fluoro-5-hydroxy-aniline, and 1.1 g of pyridine hydrochloride in 30 ml of 2-ethoxyethanol, 1.7 g of the title compound was obtained as a crystalline solid: mass spectrum (electrospray, m/e) M+H 435.8, 437.8.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].C[C:24]1[C:28]2[CH:29]=[C:30]3[C:35]4([C:43]5[C:38](=[CH:39][CH:40]=[CH:41]C=5)NC4=O)[CH2:34][O:33][C:31]3=[CH:32][C:27]=2ON=1.C(OC1C=CC(CCl)=CC=1)C1C=CC=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[CH2:34]([O:33][C:31]1[CH:32]=[CH:27][C:28]([CH2:24][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C@@:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[CH:29][CH:30]=1)[C:35]1[CH:43]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: ClCc1ccc(OCc2ccccc2)cc1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2ccc(OCc3ccccc3)cc2)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure described in EXAMPLE 9 and making non-critical variations using (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1H)-one, and 4-benzyloxybenzyl chloride to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, (8S)-1′-[4-(benzyloxy)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (95%) as a colorless solid: mp 151-153° C.; 1H NMR (300 MHz, DMSO-d6) δ7.45-7.23 (m, 8H), 7.18-7.14 (m, 1H), 7.05-6.97 (m, 4H), 6.53 (s, 1H), 6.06 (s, 1H), 5.07 (s, 2H), 4.86 (ABq, J=27.9, 15.6 Hz, 2H), 4.73 (ABq, J=39.9, 9.3 Hz, 2H), 4.22-4.07 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.6, 157.7, 154.6, 144.1, 142.1, 137.8, 136.9, 131.7, 128.7, 128.6, 128.4, 128.3, 127.8, 127.6, 123.5, 122.9, 121.2, 114.9, 110.8, 109.4, 98.8, 79.4, 69.1, 64.1, 63.5, 57.2, 42.4; MS (ES+) m/z 491.8 (M+1).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[OH-].[Na+].[CH2:17]([NH2:19])[CH3:18].Cl>C1COCC1.C(#N)C>[CH2:17]([NH:19][S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])[CH3:18]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Reactant: CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1ccc(F)c(C(=O)O)c1

Procedure:
To a 5 ml Biotage microwave reaction tube was added 5-(chlorosulfonyl)-2-fluorobenzoic acid (0.4 g, 1.68 mmol) and a Teflon covered magnetic stir-bar followed by 2.5 ml of THF. To the resulting mixture was added 10N aqueous NaOH (0.369 ml, 3.38 mmol) with stirring. After formation of a cloudy suspension, ethylamine (0.838 ml, 1.68 mmol) was added as a 2M solution in THF. The reaction vessel was capped and heated to 110° C. for 1.1 min in a Biotage Initiator 8 microwave set at high absorbance. Reaction mixture was then diluted with 4 ml acetonitrile and acidified with 6M aqueous HCl (0.670 ml, 4.02 mmol). Water was removed from the mixture by adding excess anhydrous Na2SO4 and subsequent filtration. The filtered was washed with acetonitrile and DMF. The combined filtrates were concentrated with rotary evaporation, yielding the crude 5-[(ethylamino)sulfonyl]-2-fluorobenzoic acid.