Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](Cl)=[N:13][CH:12]=1.[CH2:19]([NH2:23])[CH2:20][CH2:21][NH2:22]>>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([NH:22][CH2:21][CH2:20][CH2:19][NH2:23])=[N:13][CH:12]=1
Reactant: Nc1cc(F)ccc1NC(=O)c1ccc(Cl)nc1
Reactant: NCCCN
Product: NCCCNc1ccc(C(=O)Nc2ccc(F)cc2N)cn1
Yield: 52 %

Procedure:
N-(2-amino-4-fluorophenyl)-6-chloronicotinamide (266 mg, 1 mmol) and 6 ml of 1,3-propanediamine were heated to 80° C. for 3 hours. The excess 1,3-propanediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (158 mg, 52% yield) as a brown solid. LC-MS (m/z) 304 (M+1).
Reaction SMILES: C(OC(=O)[N:7]([CH2:25][C:26]1[CH:27]=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)[C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[C:24]3[CH:23]=[N:22][CH:21]=[N:20][C:19]=3[NH:18][CH:17]=2)=[O:15])=[CH:10][N:9]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:33][O:32][C:29]1[N:28]=[CH:27][C:26]([CH2:25][NH:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([C:16]3[C:24]4[CH:23]=[N:22][CH:21]=[N:20][C:19]=4[NH:18][CH:17]=3)=[O:15])=[CH:12][CH:13]=2)=[CH:31][CH:30]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(=O)c3c[nH]c4ncncc34)cn2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CNc2ccc(C(=O)c3c[nH]c4ncncc34)cn2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 9.5 %

Procedure:
To (6-methoxy-pyridin-3-ylmethyl)-[5-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (73, 66 mg, 0.14 mmol) in 5 mL of dichloromethane, trifluoroacetic acid (0.5 mL, 6.0 mmol) was added. The reaction was stirred at room temperature for 4 hours, then concentrated under vacuum, and combined with aqueous saturated sodium bicarbonate and ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate adsorbed onto silica. This was purified by silica gel column chromatography eluting with methanol and dichloromethane. Appropriate fractions were combined, the solvents removed under vacuum, and the resulting solid washed with hexanes and ethyl acetate, with sonicating. The solid was collected by filtration to provide the desired compound as a white solid (P-0008, 4.8 mg). MS (ESI) [M+H+]+=360.9.
Reaction SMILES: [Na].C[Si](C)(C)N[Si](C)(C)C.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=O)=[CH:15][CH:14]=1.[Cl:23][C:24]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:25]=1C(OC)=O>C1COCC1>[Cl:23][C:24]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:25]=1[C:20](=[O:22])[CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: COC(=O)c1ccc(Cl)cc1Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)c2ccc(Cl)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 31.2 %

Procedure:
413 ml of a 2M solution of the sodium salt of hexamethyldisilazane in THF are cooled to −65° C., under a nitrogen atmosphere, 300 ml of THF are added, followed dropwise by a solution of 55 g of 4-methoxyphenylacetic acid in 70 ml of THF and the mixture is kept stirred for 3 hours at a temperature of less than −45° C. 64.5 g of methyl 2,4-dichlorobenzoate are then added dropwise and the mixture is kept stirred while the temperature is allowed to rise to 0° C. The reaction mixture is poured over an ice/1 liter 2N HCl mixture, extracted with ether, the organic phase is washed with a saturated NaHCO3 solution, dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluted with heptane and then with the heptane/AcOEt mixture to (90/10; v/v). 29 g of the expected compound are obtained.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[C:12](O)(=O)/[C:13](=[C:15](\[CH:17]=[O:18])/[Br:16])/[Br:14].Cl>C(O)C.O>[Br:14][C:13]1[CH:12]=[N:2][N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[C:17](=[O:18])[C:15]=1[Br:16]
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(-n2ncc(Br)c(Br)c2=O)cc1
Yield: 93.1 %

Procedure:
4-Hydrazinobenzoic acid (2.00 g, 13.1 mmol) in ethanol-water (1:1, 20 mL) was stirred with mucobromic acid (2.26 g, 8.76 mmol) and concentrated hydrochloric acid (10 mL) at 70° C. for 2 days. After cooling, the resulting crystals were collected by filtration, washed with ethanol and water and dried under reduced pressure to give the desired product (3.05 g, 62% yield).
Reaction SMILES: [I:1][C:2]1[N:7]=[C:6](I)[C:5]([I:9])=[CH:4][N:3]=1.[S-:10][C:11]#[N:12].[K+]>C(O)=O>[I:1][C:2]1[N:7]=[C:6]([S:10][C:11]#[N:12])[C:5]([I:9])=[CH:4][N:3]=1
Reactant: Ic1ncc(I)c(I)n1
Reactant: N#C[S-]
Agent: [K+]
Solvent: O=CO
Product: N#CSc1nc(I)ncc1I
Yield: 84.7 %

Procedure:
In 150 ml of formic acid, a reaction of 19.0 g of 2,4,5-triiodopyrimidine and 5.0 g of potassium thiocyanate was conducted at room temperature (20° C.) for 3 hours in a similar manner as Synthesis Example 1. Then, the reaction mixture was treated in a similar procedure as Synthesis Example 1, there was obtained a 84.7% yield of 2,5-diiodo-4-thiocyanopyrimidine, m.p. 183°-185° C.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C([O-])([O-])=O.[Na+].[Na+].[CH3:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.COCCOC>C(Cl)(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2/[C:4](=[CH:12]/[C:13]2[NH:14][CH:15]=[CH:16][CH:17]=2)/[C:5](=[O:11])[NH:6]3)=[CH:27][CH:26]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)cc1
Temperature: 100 °C

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (30 mg, 0.089 mmol) (Starting Material 1) 2M aqueous Na2CO3 solution (89 μL, 0.178 mmol), (Ph3P)4Pd (5 mg, 0.004 mmol) (Aldrich), and 4-methylphenylboronic acid (15 mg, 0.110 mmol) (Aldrich) in 3 mL of a 2:1 mixture of 1,2-dimethoxyethane:distilled water was heated at 100° C. under a nitrogen atmosphere for 18 h. The reaction mixture was allowed to cool to room temperature and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 25% ethyl acetate-hexanes elution) to provide a crude yellow solid containing product. The solid was dissolved in chloroform and precipitation by the addition of hexanes provided pure (Z)-1,3-dihydro-4-(4-methylphenyl)-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (yield 19 mg, 71%) as a yellow solid (mp 217-218° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[CH3:9][O:10][C:11](=[O:27])[CH2:12]P(OCC(F)(F)F)(OCC(F)(F)F)=O>>[CH3:9][O:10][C:11](=[O:27])[CH:12]=[CH:7][C:4]1[S:5][CH:6]=[C:2]([Br:1])[CH:3]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Product: COC(=O)C=Cc1cc(Br)cs1
Yield: 78 %

Procedure:
4-Bromo-thiophene-2-carbaldehyde (44 g, 0.23 mol) and [Bis-(2,2,2-trifluoro-ethoxy)-phosphoryl]-acetic methyl ester (80.6 g, 0.253 mol) were treated by the method outlined in Example 34, step a) to afford the subtitle compound that was purified by column chromatography (SiO2) using a 0-60% ethylacetate-hexane gradient (46.22 g, yield: 78%). MS calculated for C8H7BrO2S +H: 247, observed: 247 249.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:22][O:23][CH3:24])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:25])=[CH:4][N:3]=1.[F:26][C:27]1[N:32]=[CH:31][C:30]([CH:33]=[O:34])=[CH:29][CH:28]=1>>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:33]([C:30]3[CH:31]=[N:32][C:27]([F:26])=[CH:28][CH:29]=3)=[O:34])=[N:3][CH:4]=[C:5]([Cl:25])[CH:6]=2)[CH2:22][O:23][CH3:24])(=[O:11])=[O:10])=[CH:13][CH:14]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: O=Cc1ccc(F)nc1
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccc(F)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Yield: 38 %

Procedure:
4-tert-Butyl-N-[5-chloro-2-(6-fluoro-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-benzenesulfonamide was prepared from N-(2-bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide and 6-fluoro-pyridine-3-carbaldehyde using the procedure described in examples 35 and 36.
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[N:9]=[CH:8]1.[Br:18]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:18][C:8]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:16])([CH3:17])[CH3:1])[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cn(COCC[Si](C)(C)C)cn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cn(COCC[Si](C)(C)C)c(Br)n1
Temperature: 60 °C
Yield: 43.6 %

Procedure:
To a stirred solution of methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (5.0 g, 19.5 mmol) in carbon tetrachloride (50 mL) was added N-bromosuccinimide (3.47 g, 19.5 mmol) and AIBN (160 mg, 5 mol %) at room temperature. The reaction mixture was heated at 60° C. for 3 h, cooled to room temperature, and filtered through a small pad of CELITE®. The filtrate was concentrated in vacuo to give light yellow colored residue which was dissolved in EtOAc and washed with 10% NaHCO3 solution. The organic layer was dried over Na2SO4 and concentrated to give crude compound. The crude material was purified by flash chromatography (gradient from 20 to 30% EtOAc/hexanes), to provide the title compound (2.85 g, 43%). 1H NMR (CDCl3) δ 7.76 (s, 1H), 5.30 (s, 2H), 3.90 (s, 3H), 3.55 (t, J=8.0 Hz, 2H), 0.92 (t, J=8.0 Hz, 2H), 0.01 (s, 9H); MS(ESI+) m/z 335.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:13]OC(C)(C)C>C(Cl)(Cl)Cl>[CH3:1][O:2][N:3]([Cl:13])[C:4](=[O:12])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CONC(=O)Cc1ccccc1
Reactant: CC(C)(C)OCl
Solvent: ClC(Cl)Cl
Product: CON(Cl)C(=O)Cc1ccccc1
Temperature: 0 °C

Procedure:
Dissolve 1.65 g (10 mmol) of N-(methoxy)-phenylacetamide in 30 cm3 of dry chloroform. Place in an ice-bath and maintain at a temperature of 0° C. Subsequently, pour in progressively, using a flask, 1.30 g (1.36 cm3, 12 mmol) of tert-butyl hypochlorite which has previously been dissolved in 20 cm3 of chloroform.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1O.C1OCCOCCOCCOCCOCCOC1.[CH2:40]([O:42][C:43](=[O:53])[NH:44][CH2:45][CH:46]([O:48]S(C)(=O)=O)[CH3:47])[CH3:41]>CS(C)=O>[CH2:40]([O:42][C:43](=[O:53])[NH:44][CH2:45][CH:46]([O:48][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:19]=[CH:20][CH:21]=[C:8]([Cl:7])[CH:9]=2)=[CH:13][CH:14]=1)[CH3:47])[CH3:41]
Reactant: Oc1ccccc1Oc1cccc(Cl)c1
Reactant: CCOC(=O)NCC(C)OS(C)(=O)=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)NCC(C)Oc1ccc(Oc2cccc(Cl)c2)cc1
Reaction time: 5 h

Procedure:
A solution of 15 g of potassium tert.-butoxide in 45 ml of dimethyl sulfoxide is added, with stirring and with slight external cooling, to a solution of 25.2 g of 3-chlorophenoxyphenol in 40 ml of dimethyl sulfoxide; 1.5 g of 18-Crown-6 are added, a solution of 28.3 g of 2-methylsulfonyloxypropylcarbamic acid ethyl ester in 30 ml of dimethyl sulfoxide is added dropwise at 15° C. within a period of one hour, and then the mixture is stirred firstly at 20° C.-22° C. for 5 hours and then at +55° C. for 19 hours. After cooling, the reaction mixture is poured onto ice-water and extracted repeatedly with ether, the combined ether phases are washed with water, and the solvent is distilled off. The crude product is purified further by chromatography over silica gel (eluant: diethyl ether/hexane, 1:9), yielding 2-[4-(3-chlorophenoxy)phenoxy]-propylcarbamic acid ethyl ester in the form of a pale yellow, viscous oil, n20D : 1.5500.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:28]([O:30][CH3:31])=[O:29])=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][CH2:6]/[CH:7]=[CH:8]/[C:9]1[CH:10]=[C:11]([C:15]2[O:19][N:18]=[C:17]([C:20]([O:22]CC)=[O:21])[CH:16]=2)[CH:12]=[CH:13][CH:14]=1.[OH-].[Na+]>C1COCC1.CO>[OH:1][C:2]1[C:3]([C:28]([O:30][CH3:31])=[O:29])=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][CH2:6]/[CH:7]=[CH:8]/[C:9]1[CH:10]=[C:11]([C:15]2[O:19][N:18]=[C:17]([C:20]([OH:22])=[O:21])[CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cc(-c2cccc(/C=C/COc3cccc(O)c3C(=O)OC)c2)on1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(O)cccc1OC/C=C/c1cccc(-c2cc(C(=O)O)no2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of Example 1E in THF/MeOH (1:1 10 mL), was added 2N NaOH (225 μL, 0.45 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes and quenched with 1N HCl and extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4), filtered and concentrated to provide the titled compound. MS (ESI(+)) m/e 413 (M+18)+; 1H NMR (300 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.06(s, 1H), 7.83(d, J=7.5 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.53 (t, J=7.5 Hz, 1H), 7.49(s, 1H), 7.19(t, J=8.4 Hz, 1H), 6.79 (d, J=15.9 Hz, 1H), 6.65 (dt, J1=15.9 Hz, J2=5.8 Hz, 1H), 6.61(d, J=8.4 Hz, 1H), 6.52(d, J=8.4 Hz, 1H), 4.75(d, J=5.0 Hz, 2H), 3.79 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[C:16][Si](C)(C)C)[CH:13]=2)[CH:8]=[N:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].C(O)(=O)C>CO>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[CH:16])[CH:13]=2)[CH:8]=[N:7][CH:6]=1
Reactant: COC(=O)Cc1cncc2ccc(C#C[Si](C)(C)C)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: C#Cc1ccc2cncc(CC(=O)OC)c2c1
Reaction time: 1 h

Procedure:
To a solution of (6-trimethylsilanylethynyl-isoquinolin-4-yl)-acetic acid methyl ester, as prepared for Intermediate 32 (0.19 g, 0.64 mmol), in anhydrous methanol (7 ml) is added K2CO3 (72 mg) and the resulting mixture stirred for 1 h. Additional K2CO3 (11 mg) is then added and stirring continued for 30 min. The mixture is then neutralized with glacial acetic acid and concentrated. Purification by flash silica column chromatography (ethylacetate/hexane 1:1) gives (6-ethynyl-isoquinolin4-yl)-acetic acid methyl ester M+ 225. This intermediate (79 mg, 0.35 mmol) is dissolved in methanol under an inert atmosphere and 10% Pd on carbon (79 mg) added. The resulting suspension is stirred vigorously under an atmosphere of gaseous hydrogen. After 90 mins, filtration, washing with methanol and concentration give (6-ethyl-isoquinolin-4-yl)-acetic acid methyl ester MW 229. To a solution of this intermediate (68 mg, 0.30 mmol) in THF/methanol/water (3:1:1, 3.5 ml) is added LiOH (12.5 mg) and the mixture stirred for 20 h at room temperature. Concentration under reduced pressure gives lithium (6-ethyl-isoquinolin4-yl)-acetate M+ 221.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]2[N:42]([CH:43]3[CH2:46][N:45]([CH:47]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[CH2:44]3)[N:41]=[CH:40][CH:39]=2)[CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:13]2[C:14]([F:16])=[CH:15][C:10]([S:7]([N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:3]=3[O:2][CH3:1])[C:19]3[S:23][N:22]=[CH:21][N:20]=3)(=[O:9])=[O:8])=[C:11]([F:18])[CH:12]=2)=[C:33]([C:38]2[N:42]([CH:43]3[CH2:46][N:45]([CH:47]([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[CH2:44]3)[N:41]=[CH:40][CH:39]=2)[CH:32]=1
Reactant: Oc1ccc(Cl)cc1-c1ccnn1C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccnn3C3CN(C(c4ccccc4)c4ccccc4)C3)cc2F)c(OC)c1

Procedure:
N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 647, 157 mg, 0.353 mmol), 4-chloro-2-{1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}phenol (Preparation 689, 147 mg, 0.353 mmol) and potassium carbonate (147 mg, 1.06 mmol) were stirred in dimethyl sulphoxide (1.0 ml) for 18 hours. The mixture was partitioned between methyl-t-butyl ether (40 ml) and water (20 ml), the organic layer was dried over anhydrous sodium sulphate, filtered and evaporated to give the title compound as a glass, 270 mg.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:10][C:8](=[O:9])[NH:7][C:5]=2[CH:6]=1.[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12]>>[OH:10][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[NH:7][C:8]([N:13]([CH2:14][CH3:15])[CH2:11][CH3:12])=[O:9]
Reactant: CCNCC
Reactant: O=c1[nH]c2ccccc2o1
Product: CCN(CC)C(=O)Nc1ccccc1O

Procedure:
Benzoxazolinone (1 mole) was stirred with 2 moles of diethylamine (dissolved in industrial alcohol) at 50° C. for 48 hours, then the alcohol and excess of diethylamine were distilled off under reduced pressure at below 60° C. The residue was taken up in acetone, the desired product was precipitated by adding water and then it was filtered off and dried under reduced pressure at 80° C.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:21]>C1C=CC=CC=1>[CH3:1][O:2][N:3]=[C:4]([Cl:21])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CONC(=O)c1ccccc1SCc1ccccc1
Solvent: c1ccccc1
Product: CON=C(Cl)c1ccccc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.7 %

Procedure:
To a suspension of 79 g of the product of Example 1 in 1500 ml of benzene under a N2 atmosphere, cooled at 20° to 30° C. with external cooling, was added, portionwise, 60.2 g of phosphorous pentachloride. After stirring at 25° C. for about 24 hours, the suspension was warmed at 40° C. for about four hours, then cooled to 25° C. and filtered. The filtrate was evaporated at less than 40° C. under vacuum, and residue was chromatographed on silica gel with methylene chloride at eluant to yield 47 g of the subject compound as a crude yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.[H-].[Na+].[CH:19]1[CH:24]=[C:23]([F:25])[C:22](F)=[CH:21][CH:20]=1.[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31]>CCOCC.CS(C)=O>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:22]3[CH:21]=[CH:20][CH:19]=[CH:24][C:23]=3[F:25])[CH2:9][C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: Fc1ccccc1F
Reactant: CN1CCC2(CC1)CNc1cc(Cl)ccc12
Agent: O=C(O)/C=C\C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CN1CCC2(CC1)CN(c1ccccc1F)c1cc(Cl)ccc12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6.3 g of 6-chloro-1'-methylspiro[indoline-3,4'-piperidine], Example 23b, 1.5 g of sodium hydride, 10 g of O-difluorobenzene and 50 ml of dimethylsulfoxide is stirred at 60° C. under nitrogen for 30 minutes. Thereafter, the mixture is permitted to cool before adding ice-water. The biphasic mixture is extracted thrice with ether. The combined ether extracts are extracted with a large excess of dilute hydrochloric acid. The acidic extract is basified with concentrated ammonium hydroxide effecting a heavy oil. The oil is purified by passing through an alumina column, ether eluant, to provide a yellowish oil. The oil, in ether, is converted to its maleic acid salt which is recrystallized from an acetone-ether mixture providing off-white crystals, mp 166°-168° C. of 6-chloro-1-(2-fluorophenyl)-1'-methylspiro[indoline-3,4'-piperidine] maleate.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:9][N:10]([C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([Cl:23])[N:15]=2)[CH:11]([CH3:13])[CH3:12])[CH2:8][CH2:7]1)=O)C>C(O)(=O)C.[Fe]>[Cl:23][C:16]1[N:17]=[CH:18][C:19]2[NH:20][C:4](=[O:3])[C:6]3([CH2:8][CH2:7]3)[CH2:9][N:10]([CH:11]([CH3:13])[CH3:12])[C:14]=2[N:15]=1
Reactant: CCOC(=O)C1(CN(c2nc(Cl)ncc2[N+](=O)[O-])C(C)C)CC1
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(C)N1CC2(CC2)C(=O)Nc2cnc(Cl)nc21
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Ethyl1-[[(2-chloro-5-nitro-pyrimidin-4-yl)-propan-2-yl-amino]methyl]cyclopropane-1-carboxylate (Intermediate 208; 10.26 g, 30 mmol) was dissolved in acetic acid (500 mL) and heated to 70° C. Iron powder (6 g) was added in portions over 10 minutes. The mixture was stirred at 70° C. for 3 hours. The reaction mixture was filtered hot through celite, and the pad washed with DCM. The filtrate was evaporated to dryness then sonicated in saturated aqueous sodium hydrogen carbonate solution to give a brown suspension. This was filtered, and the resulting solid washed with water. The solid was then sucked dry on a filter, and suspended in a small amount of methanol with sonication. The methanol suspension was then diluted with DCM (10× excess), and filtered to give a yellow solution, which was dried over sodium sulphate, then concentrated in vacuo to give a yellow/green solid. The solid was triturated under cold methanol to yield the title compound as a white powder. (5 g, 63%)
Reaction SMILES: [S:1]([Cl:5])(=O)(=[O:3])[OH:2].[CH2:6]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([S:27](=[O:30])(=[O:29])[NH2:28])[C:19]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH3:9]>>[CH2:6]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([S:27](=[O:30])(=[O:29])[NH2:28])[C:19]=1[O:20][C:21]1[CH:22]=[CH:23][C:24]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:25][CH:26]=1)[C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: O=S(=O)(O)Cl
Product: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C

Procedure:
To chlorosulphuric acid (5 ml), 3-butylamino-4-phenoxy-5-sulphamyl-benzoic acid (1 g) was added in portions, while stirring and keeping the temperature below 45° C. The reaction mixture was stirred to 10 minutes and then poured into ice water (10 g of ice and 20 ml of water). The precipitated 3-butylamino-4-(4-chlorosulphonylphenoxy)-5-sulphamyl-benzoic acid was isolated by filtration and without further purification added to aqueous ammonia (10 ml containing 2.5 g of ammonia). Excess of ammonia was removed by evaporation, and the resulting solution was adjusted to pH 2.5 by addition of 4N hydrochloric acid. The precipitated 3-butylamino-4-(4-sulphamylphenoxy)-5-sulphamyl-benzoic acid was isolated by filtration, recrystallized from aqueous ethanol, and dried. The obtained compound had a melting point of 265° C.