Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9](I)[S:8][C:6]=2[N:7]=1.[CH3:18][S:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:20].O>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([S:19]([CH3:18])(=[O:21])=[O:20])[CH:27]=3)[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(I)sc2n1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)c1cccc(-c2nc3c(N4CCOCC4)nc(Cl)nc3s2)c1
Temperature: 100 °C
Yield: 97.3 %

Procedure:
A mixture of 4-(5-chloro-2-iodothiazolo[5,4-d]pyrimidin-7-yl)morpholine 18 (400 mg, 1 mmol), 3-methylsulfonylphenylboronic acid (230 mg, 1.1 mmol), bis (triphenylphosphine)palladium(II) dichloride (37 mg, 0.052 mmol) in 4 ml of acetonitrile and 4 mL of 1.0 M of sodium carbonate aqueous solution was heated to 100° C. in the microwave for 10 min. Water (5 mL) was added and the resulting solid was filtered and washed with water and ethyl acetate to yield crude 5-chloro-2-(3-methanesulfonyl-phenyl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine (400 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.CN(C=O)C.O=S(Cl)Cl.[CH2:20]([CH:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:27]O)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:27][CH:26]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:7])=[CH:4][N:3]=1
Reactant: CCCCCCCCC(CO)CCCCCC
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Solvent: O=S(Cl)Cl
Product: CCCCCCCCC(CCCCCC)COC(=O)c1ccc(Cl)nc1
Temperature: 80 °C

Procedure:
A suspension of 6-chloronicotinic acid (47.4 g, 0.3 mol) in xylene (150 ml) containing DMF (1.5 ml) was stirred and heated at 80° C. whilst SOCl2 (26.1 ml, 0.36 mol) was added during 20 minutes. Stirring and heating at 80° C. was continued for 11/2 hours, when all had passed into solution. Excess SOCl2, HCl, and a little xylene were then removed by distillation at 20 mm pressure. The residual solution was cooled to 40° C., and 2-hexyldecanol (72.9 g, 0.3 mol) was added during 20 minutes, the temperature rising to 55° C.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:19]=[CH:18][C:9]([O:10][CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:8][CH:7]=2)=[CH:4][C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]1=2.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.[Al].C(=O)(O)[O-].[Na+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl.O>[N:13]1([CH2:12][CH2:11][O:10][C:9]2[CH:18]=[CH:19][C:6]([C:5]3[S:1][C:2]4[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=4[C:4]=3[C:29]([C:28]3[CH:32]=[CH:33][C:25]([F:24])=[CH:26][CH:27]=3)=[O:30])=[CH:7][CH:8]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: c1ccc2sc(-c3ccc(OCCN4CCCC4)cc3)cc2c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Al]
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
In a flame-dried, argon-filled flask were combined 1-[2-[4-(benzo[b]thiophen-2-yl)phenoxy]ethyl]pyrrolidine (Example 4, Part A) (3.54 g; 11.0 mmol) and 2.6 g (16.4 mmol) of 4-fluorobenzoyl chloride in 130 mL of dichloromethane. The mixture was cooled in an ice-water bath and protected from light with aluminum foil. Titanium tetrachloride (8.3 g; 43.8 mmol) was added dropwise. The mixture was stirred overnight while allowed to warm to room temperature. The mixture was poured into a rapidly stirred solution of 300 mL of saturated aqueous sodium bicarbonate. After stirring for 1 h, the mixture was transferred to a separatory funnel with 200 mL of water and extracted with dichloromethane (2×150 mL). The combined organics were dried by passage through sodium sulfate. The title compound was isolated as a yellow oil (4.4 g; 90% yield) by preparation HPLC using PrepLC, eluting with hexanes/THF/Et3N (75:20:5).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:26])(=[O:25])[NH:23][CH3:24])[CH:17]=1.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:26])(=[O:25])[NH:23][CH3:24])[CH:17]=1
Reactant: CNS(=O)(=O)c1cccc(C2Nc3ccc(C(=O)OC)cc3CC2(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CNS(=O)(=O)c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Reaction time: 1.5 h
Yield: 79.7 %

Procedure:
To a stirred solution of methyl 3,3-dimethyl-2-(3-(N-methylsulfamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (75 mg, 0.19 mmol) in tetrahydrofuran/methanol (2.5 mL/2.5 mL) was added 1M sodium hydroxide aqueous solution (2.89 mL, 2.89 mmol). The mixture was heated to reflux and stirred for 1.5 h. LC-MS indicated that 2005467-012-01 was consumed. The mixture was concentrated and the residue was dissolved in water. The aqueous layer was basified to pH=4 by 1M hydrochloric acid solution. The precipitated solid was filtered, and dried to give 56.7 mg of 3,3-dimethyl-2-(3-(N-methylsulfamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid. Yield: 78.5%. MS (ESI+APCI) M+1=375.2.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:18])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[NH:3][N:2]=1)=[O:18])[CH3:5]
Reactant: CCOC(=O)C(=O)CC(=O)CCC(C)C
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(CCC(C)C)[nH]n1
Temperature: 25 °C
Yield: 707.9 %

Procedure:
Hydrazine hydrate (1.43 mL, 2.95 mmol) was added to a stirring room temperature solution of 46 (6.3112 g, 2.95 mmol) in EtOH (29.5 mL, 1 M) under N2. The reaction was then stirred at room temperature until judged complete by HPLC (35 min): The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 96:4 Hexanes:2N NH3 in EtOH): Only pure fractions were combined and concentrated to obtain 4.3911 g (70.9%) of 47. 1H (CDCl3, 400 MHz): δ 13.01 (1H, broad s), 6.52 (1H, s), 4.29 (2H, q, J=7.1 Hz), 2.64 (2H, t, J=7.8 Hz), 1.57-1.41 (3H, m), 1.26 (3H, t, J=7.1 Hz), 5.85 (6H, d, J=5.9 Hz) ppm. 13C (CDCl3, 100 MHz): δ 162.37, 146.26, 143.1, 105.73, 60.53, 37.88, 27.35, 23.42, 22.11, 14.06 ppm. HPLC: 10.006 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:31][CH3:32])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]3SC=CN=3)[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:31][CH3:32])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: Brc1ccncc1
Product: CCO[C@H]1CN(c2ccncc2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine but substituting 4-bromo pyridine provided the title compound as an amporphous solid: 1H NMR (400 MHz, CDCl3) δ) 8.23, 7.50, 7.35, 7.28, 6.50, 5.30, 4.90, 4.29, 3.95, 3.76, 3.65–3.58, 3.42, 2.73, 2.49, 1.35–1.27, 1.16; IR (diffuse reflectance) 2971 (s), 2497 (w), 2388 (w), 2350 (w), 2338 (w), 2328 (w), 1596 (s), 1569, 1550 (s), 1516, 1508, 1499 (s), 1467 (s), 1397 (s), 1393 (s) cm−1 HRMS (ESI) calcd for C25H29N5OCl2+H1 486.1827. found 486.1810.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CCO.O>[CH2:1]([O:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C(=O)OCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
(Scheme 1, Compound B) To a solution of ethyl 4-butoxybenzoate (2.0 g, 9.6 mmol) in EtOH (30 mL) was added NaOH (10 N, 6 mL, 60 mmol). The resulting mixture was stirred at room temperature for 3 hours, diluted with H2O (30 mL), acidified to about pH 1.0 using HCl (6N). The precipitates were filtered off by filter paper, washed by H2O and hexanes. This compound was obtained as a white solid. (1.63 g, 9.1 mmol, 94% yield). 1H NMR (DMSO-d6) δ 12.59 (br. s, 1H), 7.88 (d, 2H, J=9.5 Hz), 6.97 (d, 2H, J=9.5 Hz), 4.01 (t, 2H, J=6.5 Hz), 1.68 (m, 2H), 1.42 (m, 2H), 0.91 (t, 3H, J=6.5 Hz); 13C NMR (DMSO): 166.9, 162.2, 131.2, 122.7, 114.0, 67.3, 30.5, 18.6 and 13.5; Mass Spec.: 195.17 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[N:11]1([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CS(C)=O.Cl>[N:11]1([CH2:17][CH2:18][CH2:19][NH:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: NCCCN1CCOCC1
Agent: Cl
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(NCCCN2CCOCC2)nc1
Temperature: 50 °C

Procedure:
2-chloro-5-nitro-pyridine Compound 16a1 (6.06 g, 38.2 mmol) and 3-morpholin-4-yl-propylamine Compound 9a (6.27 mL, 42.1 mmol) were combined in DMSO (100 mL) and heated to 50° C. After 2.5 hours the reaction mixture was diluted with 0.5 M HCl and washed with ethyl ether. The aqueous layer was adjusted to pH 11 with NaOH and extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated to provide (3-morpholin-4-yl-propyl)-(5-nitro-pyridin-2-yl)-amine Compound 19a1. Using the procedure of Example 1, Compound 19a1 was used in place of Compound 1n3 with AcOH (30 mL) replacing EtOAc as solvent. 10% Pd/C (3.1 g) was added to the solution and the reaction was carried forward to provide N2-(3-morpholin-4-yl-propyl)-pyridine-2,5-diamine Compound 19a. 1H NMR (CDCl3) δ 7.67 (d, J=3.0 Hz, 1H); 6.95 (dd, J=8.6, 3.0 Hz, 1H); 6.31(d, J=8.6 Hz, 1H); 3.77-3.66 (m, 4H); 2.52-2.38 (m, 8H); 2.08.(p, J=6.8Hz, 2H). MS 267 (MH+).
Reaction SMILES: [CH2:1]1[C:6]2[C:7]3[C:13](=O)[NH:12][C:11]4[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=4[O:9][C:8]=3[S:19][C:5]=2[CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38].[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38].[CH3:42][N:43]1[CH2:48][CH2:47][N:46]([C:13]2[C:7]3[C:6]4[CH2:1][CH2:2][CH2:3][CH2:4][C:5]=4[S:19][C:8]=3[O:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[N:12]=2)[CH2:45][CH2:44]1
Reactant: CN1CCNCC1
Reactant: O=C1Nc2ccccc2Oc2sc3c(c21)CCCC3
Agent: O=C(O)/C=C/C(=O)O
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C2=Nc3ccccc3Oc3sc4c(c32)CCCC4)CC1

Procedure:
In the same manner as in Example 80 and using 1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one (0.6 g), phosphorus oxychloride (5 ml), N,N-dimethylaniline (0.14 ml), 1-methylpiperazine (10 ml) and fumaric acid (260 mg), 1,2,3,4-tetrahydro-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzoxazepine fumarate (575 mg) was obtained.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28]>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[C:6]([S:11][C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=3[N+:27]([O-:29])=[O:28])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Sc1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Sc2cccc3cnccc23)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
According to the method in Example 10, 5-isoquinolinethiol 1.00 g (6.2 mmol) was dissolved in DMF 14 ml, potassium carbonate 1.60 g (11.6 mmol) and 4-chloro-3-nitrobenzonitrile 1.00 g (5.5 mmol) were added and stirred at room temperature for 15 minutes, and 4-(5-isoquinolylsulfanyl)-3-nitrobenzonitrile 1.69 g (quantitative) was obtained.
Reaction SMILES: [Cl-].C([Al+]CC)C.Cl.[CH3:8][NH:9][O:10][CH3:11].[Br:12][C:13]1[S:17][C:16]2=[C:18]([C:21]([O:23]CC)=O)[N:19]=[CH:20][N:15]2[CH:14]=1.P([O-])([O-])([O-])=O>ClCCl>[CH3:11][O:10][N:9]([CH3:8])[C:21]([C:18]1[N:19]=[CH:20][N:15]2[CH:14]=[C:13]([Br:12])[S:17][C:16]=12)=[O:23]
Reactant: CNOC
Reactant: CCOC(=O)c1ncn2cc(Br)sc12
Agent: CC[Al+]CC
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: CON(C)C(=O)c1ncn2cc(Br)sc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Diethylaluminum chloride (0.9 M hexane solution; 2.3 ml, 2.11 mmol) was added to an ice cooled solution of N,O-dimethylhydroxylamine hydrochloride (206 mg, 2.11 mmol) in dichloromethane (8 ml), and, while gradually raising the temperature, the mixture was stirred for one hr. A solution of ethyl 2-bromoimidazo[5,1-b]thiazole-7-carboxylate (116 mg, 0.42 mmol) in dichloromethane (4 ml) was added and stirred at room temperature for 15 hr. A phosphate buffer solution (10 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 10 min and was filtered through Celite. The filtrate was washed with saturated brine and was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol=30:1→10:1) to give N-methoxy-N-methyl-2-bromoimidazo[5,1-b]thiazole-7-carboxamide (113 mg, 92%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:6]([CH:10]=1)[C:7]([N:21]([CH2:22][CH3:23])[CH2:19][CH3:20])=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1Oc1ccc(Cl)nc1
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cc(Br)ccc1Oc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
A mixture of 5-bromo-2-(6-chloropyridin-3-yloxy)benzoic acid (1.28 kg, 4.44 mol), diethylamine (461 mL, 4.44 mol), HOBT (600 g, 4.44 mol), DIPEA (1.547 L, 8.88 mol) in anhydrous DCM (8 L) was cooled to 0° C. EDCI (851.2 g, 4.44 mol) was added to the reaction mixture and it was stirred at 0° C. for 30 minutes and then at RT overnight. The reaction mixture was sequentially washed with aqueous NaHCO3, brine and water before being dried over MgSO4. Filtration and concentrated under reduced pressure provided a residue that was purified by silica gel chromatography (5-20% EtOAc in hexane) to provide 950 g of 5-bromo-2-(6-chloropyridin-3-yloxy)-N,N-diethylbenzamide.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([N:18]=O)=[C:13]([NH2:20])[N:12]=1.[C:21](OCC)(=[O:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:26]([O:25][C:23]([C:22]1[C:21](=[O:28])[NH:17][C:15]2[N:16]=[C:11]([S:10][CH2:9][C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[N:12]=[C:13]([NH2:20])[C:14]=2[N:18]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Nc1nc(SCc2cccc(F)c2F)nc(N)c1N=O
Product: CCOC(=O)c1nc2c(N)nc(SCc3cccc(F)c3F)nc2[nH]c1=O
Temperature: 120 °C

Procedure:
The product of Example 2, step (b) (5 g) was dissolved in diethyl malonate (100 ml) and heated to 120° C. for 10 hr, with stirring. The reaction mixture was allowed to cool and the solid that precipitated was filtered, washed with water and dried in the oven at 50° C. to yield the product as a yellow solid (3.2 g).
Reaction SMILES: [C:1]([CH:4]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:5][CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[CH3:2].[N+:23](/[CH:26]=[CH:27]/[CH:28]=[CH:29]/[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([O-:25])=[O:24]>C(OCC)C>[CH2:11]([O:10][C:8]([CH2:7][C@@H:6]1[CH2:5][C@@:4]([C:1](=[O:3])[CH3:2])([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C@@H:27]([CH:28]=[CH:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C@@H:26]1[N+:23]([O-:25])=[O:24])=[O:9])[CH3:12]
Reactant: CCOC(=O)C=CCC(C(C)=O)C(=O)OCc1ccccc1
Reactant: O=[N+]([O-])/C=C/C=C/c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C[C@@H]1C[C@@](C(C)=O)(C(=O)OCc2ccccc2)[C@@H](C=Cc2ccccc2)[C@@H]1[N+](=O)[O-]
Reaction time: 24 h
Yield: 83 %

Procedure:
To a solution of 6-benzyl 1-ethyl 5-acetylhex-2-enedioate (4b, 0.3 mmol, 1.0 eq) and 1-((1E,3E)-4-nitrobuta-1,3-dienyl)benzene (0.6 mmol, 2.0 eq) in diethyl ether (0.4 mL) was added catalyst VI (Q-NH2) (0.03 mmol, 0.2 eq) at room temperature (22° C.). The resulting mixture was stirred vigorously for 24 hours, and then the reaction was continued for about 6 hours after removal of the solvent. After the reaction was completed (monitored by TLC and crude NMR), the title product was afforded by flash chromatography over silica gel (Et2O:Hexane=1:10 to 1:4) in 83% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:15]3[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=3)=[N:9][N:10]3[CH:14]=[CH:13][S:12][C:11]=23)=[CH:3][CH:2]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C(Cl)Cl>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:8]([C:15]3[CH:16]=[C:17]([NH:21][C:31]([NH:30][C:27]4[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:29][CH:28]=4)=[O:32])[CH:18]=[CH:19][CH:20]=3)=[N:9][N:10]3[CH:14]=[CH:13][S:12][C:11]=23)=[CH:5][CH:6]=1
Reactant: Nc1cccc(-c2nn3ccsc3c2-c2ccncc2)c1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1cccc(-c2nn3ccsc3c2-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
3-(7-Pyridin-4-yl-pyrazolo[5,1-b]thiazol-6-yl)-phenylamine (50 mg, 0.171 mmol) was dissolved in dry DCM (1 mL) under nitrogen atmosphere. p-trifluoromethylphenylisocyanate (0.025 mL, 0.179 mmol, 1.05 eq) was added and the mixture was stirred at room temperature for 1 hour. The solution was evaporated to dryness and the crude product was purified by chromatography on silica gel (DCM/MeOH 96:4) to give 80 mg of an oil, which after trituration with ethylether gave 63 mg of 1-[3-(7-pyridin-4-yl-pyrazolo[5,1-b]thiazol-6-yl)-phenyl]-3-(4-trifluoro-methyl-phenyl)-urea white solid (77%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1>[Cu]>[CH3:8][C:9]1[CH:10]=[C:11]([N:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Ic1ccccc1
Reactant: Cc1cccc(Nc2ccccc2)c1
Agent: [Cu]
Product: Cc1cccc(N(c2ccccc2)c2ccccc2)c1
Yield: 75 %

Procedure:
The same equipment and conditions as in example I were employed with the following charge: 20.4 grams (0.1 mole) iodobenzene, 27.5 grams (0.15 mole) 3-methyldiphenylamine, 15.0 grams copper powder and 30.0 milliliters of Soltrol® 170. The above-identified intended product was obtained as colorless crystals having a melting point of 69°-70° C. Yield 75%.
Reaction SMILES: C[O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[OH:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7]
Reactant: COc1cccc(C=O)c1[N+](=O)[O-]
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cccc(O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
3.62 g of 3-methoxy-2-nitrobenzaldehyde was dissolved in 80 ml of methylene chloride and a boron tribromide-methylene chloride solution (15.03 g of, boron tribromide, 40 ml of methylene chloride) was added dropwise under ice cooling, followed by stirring at 0° C. for one hour. The reaction solution was poured into ice, extracted with chloroform, dried and then concentrated to obtain 3.32 g of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1.Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[CH2:11][CH2:12][N:13]([C:17]3[CH:18]=[CH:19][C:20]4[N:21]([C:23]([C:26]([F:27])([F:29])[F:28])=[N:24][N:25]=4)[N:22]=3)[CH2:14][CH2:15]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](c1ccc(F)cc1)N1CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: C[C@H](c1ccc(F)cc1)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 87 %

Procedure:
A mixture of (R)-1-[1-(4-fluorophenyl)ethyl]piperazine (obtained as described in J. Med. Chem. 2007, 50, 3528) and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by the method described in Example 306 to give 6-[4-[(1R)-1-(4-fluorophenyl)ethyl]piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine in 87% yield.
Reaction SMILES: [S:1]1CS[C:2]1=[C:5]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)=O.O.[NH2:24][NH2:25]>C(O)C>[N+:14]([C:10]1[CH:9]=[C:8]([C:6]2[C:5]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:2]([SH:1])[NH:24][N:25]=2)[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: O=C(C(=C1SCS1)c1ccncc1)c1cccc([N+](=O)[O-])c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cccc(-c2n[nH]c(S)c2-c2ccncc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
2-[1,3]-Dithietan-2-ylidene-1-(3-nitro-phenyl)-2-pyridin-4-yl-ethanone (5.2 g, 15.7 mmol) was suspended in absolute ethanol (60 mL) and heated to 60° C. Hydrazine monohydrate (3.05 mL, 63 mmol, 4 eq) was added dropwise and the mixture was stirred at 60° C. for 2 hours. The suspension was concentrated to about ¼ of the original volume, diluted with THF (30 mL) and stirred for 5 minutes. The solid was filtered, washed with THF and dried at 50° C. for 2 hours. 3.92 g of 5-(3-nitro-phenyl)-4-pyridin-4-yl-2H-pyrazole-3-thiol were obtained as an orange solid (84%).