Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[O:23])=[CH:17][CH:16]=1)#[N:2].Br[CH2:33][CH2:34][Cl:35].C(=O)([O-])[O-].[K+].[K+].O1CCCC1>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:33][CH2:34][Cl:35])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[O:23])=[CH:19][CH:20]=1)#[N:2]
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1OCCCl
Temperature: 55 °C
Reaction time: 4 h
Yield: 75.7 %

Procedure:
N-(4-(6-Cyano-7-hydroxy-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea (400 mg, 0.9166 mmol) was dissolved in dimethylformamide (5.0 ml), and then 1-bromo-2-chloroethane (0.12 ml, 1.4479 mmol) and potassium carbonate (200 mg, 1.4479 mmol) were added and the mixture was heated and stirred at 55° C. for 4 hours. After cooling, tetrahydrofuran and ethyl acetate were added, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to NH silica gel column chromatography (ethyl acetate-methanol system). The obtained crystals were suspended in diethyl ether, the suspension was diluted with hexane, and the crystals were filtered out, washed with hexane and dried by aspiration to obtain the title compound (331 mg, 0.6941 mmol, 75.72%) as light yellow crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH2:25]([CH:27]1[NH:31][C:30](=[O:32])[N:29]([CH3:33])[C:28]1=[O:34])[CH3:26]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:31]4[CH:27]([CH2:25][CH3:26])[C:28](=[O:34])[N:29]([CH3:33])[C:30]4=[O:32])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CCC1NC(=O)N(C)C1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: CCC1C(=O)N(C)C(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(F)c1
Yield: 62.8 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (157 mg) described in Preparation Example 114 and 5-ethyl-3-methylimidazolidine-2,4-dione (63 mg) described in Preparation Example 215 and by the reaction and treatment in the same manner as in Example 536, the title compound (114 mg) was obtained.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.O.N[C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[C:15](NC2C=CC(N)=CC=2)=[CH:14][CH:13]=1.C1C(N)=CC=C(N)C=1>CC(C)=O>[CH:19]1[C:18]2[C:17](=[O:27])[C:16]3[C:25](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:24](=[O:26])[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(Nc2ccc(N)c3c2C(=O)c2ccccc2C3=O)cc1
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: Nc1ccc(N)cc1
Solvent: O
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)c2ccccc21
Reaction time: 0.55 h

Procedure:
1-18.4 g of cyanuric chloride was placed into a beaker. A small amount of crushed ice and water were added for pulping for 0.1-1 h; during which, 1-17.4 g of 1-amino-4-(p-aminoanilino) anthraquinone in 200 ml of acetone was added with the cyanuric chloride, and condensed for 4-5 h. The temperature was increased to 40° C. p-phenylene diamine was added and condensed for 4-5 h, to obtain an anthraquinone dye comprising triazinyl group and amino group.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C:34](=[O:36])[CH3:35])=[CH:29][CH:28]=2)O1>>[CH3:15][C:13]1([CH3:16])[CH2:14][CH:9]([NH:8][C:4]2[N:3]=[C:2]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C:34](=[O:36])[CH3:35])=[CH:29][CH:28]=3)[CH:7]=[CH:6][N:5]=2)[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12]1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: CC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CC(=O)Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1

Procedure:
The title compound was prepared from (4-chloro-pyrimidin-2-yl)(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propan-2-one according to Method C (Example 178). Yield: 160 mg (78%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH2:17][CH2:18][Cl:19])=[C:9]([O:12][CH2:13][CH2:14][Cl:15])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:20]([C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25])#[CH:21]>C(O)(C)C>[ClH:1].[Cl:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:16][CH2:17][CH2:18][Cl:19])[N:5]=[CH:4][N:3]=[C:2]2[NH:25][C:24]1[CH:26]=[CH:27][CH:28]=[C:22]([C:20]#[CH:21])[CH:23]=1
Reactant: C#Cc1cccc(N)c1
Reactant: ClCCOc1cc2ncnc(Cl)c2cc1OCCCl
Solvent: CC(C)O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCCl)c(OCCCl)cc23)c1
Product: Cl
Temperature: 20 °C

Procedure:
4-Chloro-6,7-bis-(2-chloro-ethoxy)-quinazoline (600 mg, 1.87 mmol) and 3-ethynyl-aniline (219 mg, 1.87 mmol) were reacted in refluxing isopropanol (15 mL) under an atmosphere of N2 for 2.5 hours. The mixture was cooled to 20° C. and the precipitated product was filtered, washed With isopropanol and ether and dried in vacuo. (707 mg; 86%; M.P. 230°-240° C. (dec); LC-MS: 402 (MH+); anal. RP18-HPLC RT: 5.35 min.).
Reaction SMILES: C(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)CCCC.I[C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1.[C:32](=[O:35])([O-])[O-].[Na+].[Na+].Cl>C(O)C.C1(C)C=CC=CC=1.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>[CH2:32]([O:35][C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:10]1[CH:9]=[CH:8][C:7]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)=[CH:12][CH:11]=1)[CH2:12][CH2:7][CH2:8][CH3:9]
Reactant: O=C(O)c1ccc(I)cc1
Reactant: O=C([O-])[O-]
Reactant: CCCCCOc1ccc(-c2ccc(B(O)O)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCOc1ccccc1-c1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 100 °C
Yield: 70.9 %

Procedure:
To a stirred mixture of 4-(4-n-pentoxyphenyl)phenyl-boronic acid (1.0 g, 3.52 mmol) and 4-iodobenzoic acid (874 mg, 3.52 mmol) in ethanol (11 ml) and toluene (30 ml) was added an aqueous solution of sodium carbonate (2M, 5.3 ml, 10.6 mmol) followed by tetrakis(triphenylphosphine)palladium (204 mg, 5 mol %). The reaction mixture was heated at 100° C. under a nitrogen atmosphere for a period of 18 h. The cooled mixture was acidified to pH 3 (1N HCl) and partitioned between ethyl acetate and water. The organic phase was washed with water (3×) and brine, dried with magnesium sulfate, and filtered through a bed of Celite. The solvent was removed in vacuo to give crude product which was purified by flash silica gel chromatography to provide 4-(n-pentoxyphenyl)-4'-carboxybiphenyl (450 mg): 1H NMR (400 MHz, DMSO-d6) δ0.89 (t, 3H), 1.37 (m, 4H), 1.72 (m, 2H), 3.98 (t, 2H), 7.01 (d, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)([NH2:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:26][C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[S:35])[CH:30]=[CH:31][CH:32]=1>O1CCOCC1>[Cl:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]([NH:15][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)[CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[S:35])[CH:30]=[CH:31][CH:32]=1
Reactant: NC(Cc1ccccc1)(c1cccc(C(F)(F)F)c1)c1ccccn1
Reactant: S=C=Nc1cccc(Cl)c1
Solvent: C1COCCO1
Product: FC(F)(F)c1cccc(C(Cc2ccccc2)(NC(=S)Nc2cccc(Cl)c2)c2ccccn2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(Pyridin-2-yl)-1-(3-(trifluoromethyl)phenyl)-2-phenylethanamine was dissolved in dioxane (40 uL, 0.5 M in dioxane, 20 umol) and 3-chlorophenylisothiocyanate was added (200 uL, 0.2 M in dioxane, 40 umol, 2.0 eq). The reaction mixture was agitated at room temperature for 18 h The solvent was evaporated and the residue was redissolved in 1 mL of MeOH and purified by reverse phase preparative HPLC using MeOH:water:TFA system. 1-(3-chlorophenyl)-3-(2-phenyl-1-(pyridin-2-yl)-1-(3-(trifluoromethyl)phenyl)ethyl)thiourea was obtained a colorless oil (13.9 umol, 69% yield). LCMS: M+calc=511.11; found=511.98.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:56][CH3:57])[C:44]([NH:49][C@H:50]2[CH2:54][O:53][CH2:52][C@H:51]2[OH:55])=[N:45][C:46]=1[CH2:47][CH3:48].Br[CH2:59][CH2:60][CH2:61][F:62]>>[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:56][CH3:57])[C:44]([NH:49][C@H:50]2[C@@H:51]([O:55][CH2:59][CH2:60][CH2:61][F:62])[CH2:52][O:53][CH2:54]2)=[N:45][C:46]=1[CH2:47][CH3:48]
Reactant: FCCCBr
Reactant: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@H]1COC[C@H]1O
Agent: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1COC[C@@H]1OCCCF

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting of cis-(+/−)-4-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}tetrahydrofuran-3-ol and 1-bromo-3-fluoropropane and making non-critical variations provided the title compound as a colorless semi-solid. IR (liq.) 2969, 2936, 2875, 1606, 1565, 1481, 1441, 1397, 1287, 1230, 1203, 1127, 1075, 1059, 1046 cm−1; OAMS supporting ions at: ESI+ 438.2; MS (EI) m/z 437 (M+); HRMS (FAB) calcd for C22H29CLFN3O3+H1 438.1960, found 438.1965. Anal. Calcd for C22H29ClFN3O3: C, 60.34; H, 6.67; N, 9.59. Found: C, 60.31; H, 6.78; N, 9.65.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-:6])O.[Na+].CS(C)=O.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[C:29](=[O:51])[N:30]([C@H:40]3[CH2:45][CH2:44][C@H:43]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:42][CH2:41]3)[C:31]3[N:32]([N:37]=[CH:38][N:39]=3)[C:33]=2[CH2:34][CH2:35][CH3:36])=[CH:23][CH:22]=1)#[N:14]>C(OCC)(=O)C>[O:51]=[C:29]1[C:28]([CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:13]3[NH:3][C:4](=[O:7])[O:6][N:14]=3)=[CH:22][CH:23]=2)=[C:33]([CH2:34][CH2:35][CH3:36])[N:32]2[N:37]=[CH:38][N:39]=[C:31]2[N:30]1[C@H:40]1[CH2:45][CH2:44][C@H:43]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:42][CH2:41]1
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(=O)OCC)CC2)c2ncnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](C(=O)OCC)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.16 g), sodium hydrogen carbonate (0.26 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, ethyl trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanoate (0.08 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.03 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.025 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.033 g, 37%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[C:3]=1[C:4](OC)=O.C(O)(=O)C.[CH:20](N)=[NH:21]>COCCO>[CH3:15][O:14][C:8]1[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:2]2[C:3]=1[CH2:4][NH:21][CH:20]=[N:1]2
Reactant: N=CN
Reactant: COC(=O)c1c(N)cc(OC)cc1OC
Solvent: CC(=O)O
Solvent: COCCO
Product: COc1cc2c(c(OC)c1)CNC=N2
Yield: 99.6 %

Procedure:
A mixture of methyl 2-amino-4,6-dimethoxybenzoate (16 g), formamidine acetate (24 g) and 2-methoxyethanol (330 ml) was stirred and heated to reflux until all of the starting material had reacted. The mixture was evaporated and the residue was triturated under water (100 ml). The resultant solid was isolated, washed with water and dried under vacuum to give 5,7-dimethoxy-3,4-dihydroquinazolin one (14.5 g); NMR Spectrum: (DMSOd6) 3.82 (s, 3H), 3.86 (s, 3H), 6.5 (s, 1H), 6.7 (s, 1H), 7.9 (s, 1H), 11.7 (br s, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13])(=[O:8])=[O:7].[C:18]1([O:24][CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[CH3:25][O:24][C:18]1[CH:23]=[CH:22][C:21]([C:12]([C:11]2[CH:10]=[C:9]([S:6]([Cl:5])(=[O:8])=[O:7])[CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cccc(S(=O)(=O)Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
Under a nitrogen atmosphere, aluminum chloride (7.5 g, 56.5 mmol) is slurried in dichloromethane (150 mL) then 3-chlorosulfonyl-benzoyl chloride (7.5 g, 31.4 mmol) is added and allowed to stir at ambient temperature for 10 minutes. Anisole (4.06 g, 37.65 mmol) is added. The reaction is allowed to stir at ambient temperature for 18 hours. The reaction mixture is poured over ice-cold 6 N HCl and extracted with dichloromethane to give a purple oil. Purification by silica gel chromatography (10% ethyl acetate in hexanes) yielded 4 g (41% yield) of the title compound as a yellow powder. 1H NMR (CDCl3): δ 8.5 (t, 1H, J=1.7 Hz), 8.25 (m, 1H), 8.1 (m, 1H), 7.7-7.9 (m, 3H), 7.0 (d, 2H, J=6.9 Hz), 3.9 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](=O)(O)[O-].[K+].CI>CN(C)C=O.O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1cc(OC)ccc1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 102.4 %

Procedure:
To a solution of 2-bromo-5-methoxybenzoic acid (15.0 g) in dimethylformamide (100 ml) were added potassium bicarbonate (7.83 g) and methyl iodide (8.12 ml) and the mixture was stirred for 20 hours at room temperature. The reaction mixture was diluted with water and was extracted with a mixture of ethyl acetate and hexane (1/1). The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=8:1) to give the title compound (16.3 g) having the following physical data.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[N:11]([CH3:16])[C:10]([CH3:18])([CH3:17])[CH2:9]1.[C:19]([C:21]1[N:26]=[CH:25][C:24]([C:27]2[C:39]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]([C:40]4[CH:52]=[CH:51][C:43]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[C:42](F)[CH:41]=4)[C:31]=3[CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)#[N:20]>CS(C)=O.O>[C:19]([C:21]1[N:26]=[CH:25][C:24]([C:27]2[C:39]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]([C:40]4[CH:41]=[CH:42][C:43]([C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])=[C:51]([NH:7][CH:8]5[CH2:9][C:10]([CH3:18])([CH3:17])[N:11]([CH3:16])[C:12]([CH3:14])([CH3:15])[CH2:13]5)[CH:52]=4)[C:31]=3[CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)#[N:20]
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1F
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN1C(C)(C)CC(Nc2cc(-n3c4ccccc4c4c(-c5ccc(C#N)nc5)cccc43)ccc2C(=O)OC(C)(C)C)CC1(C)C
Temperature: 90 °C

Procedure:
0.95 g of potassium carbonate and 7.8 ml of 4-amino-1,2,2,6,6-pentamethylpiperidine are successively added to a solution of 1.06 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-fluorobenzoate, obtained in stage 1 of Example 49, in 8 ml of dimethyl sulphoxide. The reaction mixture is heated at 90° C. for 2 hours and 15 minutes in a microwave, and then diluted with distilled water. The aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed with water and a saturated solution of sodium chloride and dried over magnesium sulphate. The residue is purified by silica gel chromatography, elution being carried out with a mixture of dichloromethane and methanol (97/3 by volume), so as to give 0.8 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]benzoate in the form of a yellow oil, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[CH3:11][NH2:12]>C1COCC1.CCO.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:12][CH3:11])=[O:9])[CH:3]=1
Reactant: CN
Reactant: O=C(Cl)c1cc(Cl)ccn1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)ccn1
Temperature: 3 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To a solution of 4-chloro-pyridine-2-carbonyl chloride (27.6 g, 0.16 mol) in anhydrous THF (100 mL) at 0° C. was added dropwise a solution of MeNH2 in EtOH. The resulting mixture was stirred at 3° C. for 4 h. The reaction mixture was concentrated under reduced pressure to yield a solid, which was suspended in EtOAc and filtered. The filtrate was washed with brine (2×100 mL), dried and concentrated to yield 4-chloro-N-methylpicolinamide (16.4 g, 60% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (br s, 1H), 8.55 (d, J=5.2 Hz, 1H), 7.97 (d, J=2.0 Hz, 1H), 7.66 (m, 1H), 2.82 (d, J=4.8 Hz, 3H); MS (ESI) m/z: 171.0 (M+H+).
Reaction SMILES: [OH-:1].[Na+].[OH:3][CH2:4][C:5]1([C:9]([O:11][CH2:12][CH3:13])=O)[CH2:8][CH2:7][CH2:6]1.[OH2:14]>C(O)C>[C:12]([O:11][CH2:9][C:5]1([C:4]([OH:14])=[O:3])[CH2:8][CH2:7][CH2:6]1)(=[O:1])[CH3:13]
Reactant: CCOC(=O)C1(CO)CCC1
Reactant: [OH-]
Reactant: O
Agent: [Na+]
Solvent: CCO
Product: CC(=O)OCC1(C(=O)O)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydroxide pellets (1.48 g, 37 mmol) was added to a stirred mixture of ethyl 1-hydroxymethylcyclobutanecarboxylate (4.14 g, 26.1 mmol), water (4 ml) and 95% ethanol (20 ml). The resulting mixture was stirred at room temperature overnight, then concentrated on a roatry evaporator. The residue was treated with toluene (100 ml). Evaporation of this mixture gave a flaky resiude which was further dried under high vacuum. The final residue was treated with pyridine (25 ml) and acetic anhydride (15 ml). The resulting mixture was stirred at room temperature for 18 hour, then heated on a steam bath for 20 minutes. It was cooled to room temperature, added crushed ice, then slowly treated with concentrated HCl (12N, 30 ml) with vigorous stirring. It was extracted with a mixture of diethyl ether (120 ml) and methylene chloride (40 ml). The extract was washed with water (4×100 ml), dried, filtered and evaporated to yield the desired product as a yellow oil: NMR (CDCl3) δ=1.82-2.7 (9H, m containing a singlet at 2.07δ), 4.40 (2H, s), 11.46 (H, bs).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN1C(=O)CCC1>[O:15]1[CH2:16][CH2:17][N:12]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=2)[NH2:7])[CH2:13][CH2:14]1
Reactant: C1COCCN1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Nc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 77 %

Procedure:
A solution of 5-chloro-2-nitroaniline (100 mg, 0.58 mmol) in NMP (4.5 mL) was treated with morpholine (75 mg, 0.86 mmol) in the presence of triethylamine (0.2 mL, 1.44 mmol). The reaction mixture was heated via microwave irradiation to 100° C. for 1 h and upon cooling, the solvent was removed by vacuum. Purification by flash column chromatography afforded the title compound in a 77% yield. 1H NMR: (400 MHz, DMSO-d6): δ 7.82 (d, 1H, J=9.6 Hz), 7.29 (bs, 2H), 6.39 (dd, 1H, J=2.8 and 9.6 Hz), 6.22 (d, 1H, J=2.4 Hz), 3.70 (m, 4H), 3.27 (m, 4H).
Reaction SMILES: C[O-].[Na+].C(O)(=O)C.[CH:8]([NH2:10])=[NH:9].[CH3:11][CH:12]([C:17](=O)[CH2:18][CH3:19])[C:13](OC)=[O:14].O>CO.C(O)(=O)C>[CH2:18]([C:17]1[N:10]=[CH:8][N:9]=[C:13]([OH:14])[C:12]=1[CH3:11])[CH3:19]
Reactant: N=CN
Reactant: CCC(=O)C(C)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCc1ncnc(O)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.5 %

Procedure:
A mixture of 25% sodium methoxide in methanol (24.16 ml, 100 mmol) in methanol was stirred during the addition of formamidine acetate (5.73 g, 55.0 mmol) and methyl 2-methyl-3-oxopentanoate (Intermediate 39, 7.21 g, 50 mmol) and the reaction mixture was stirred at room temperature for 3 hours. Water (20 ml) and acetic acid (20 ml) were then added and the solution was concentrated under reduced pressure removing most of the organic solvent from the reaction mixture which was then washed with brine and extracted with ethyl acetate (×3). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The resulting yellow residue was purified by trituration with ether, the resulting colourless solid was collected, washed with ether and dried to give the title compound as a clear solid (2.8 g);
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1.[N-:17]=[N+:18]=[N-:19].[Na+].CN(C=O)C>O>[N:17]([CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: NS(=O)(=O)c1cc2cc(CCBr)ccc2s1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCc1ccc2sc(S(N)(=O)=O)cc2c1
Reaction time: 18 h
Yield: 76.6 %

Procedure:
Under nitrogen, a solution of 5-(2-bromoethyl)-2-sulfamoylbenzo[b]thiophene (1.2 g, 0.0037 mol), NaN3 (0.6 g, 0.0092 mol) and DMF (25 ml) was heated at 100° C. After 18 hours, the solution was cooled, poured into H2O, and filtered to yield 0.8 g of product. The filtrate was extracted with ethyl acetate (2x). The organic layers were dried, filtered and concentrated to dryness to yield an additional 0.4 g of product (75%).