Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]32[CH2:17][CH2:16][CH2:15][N:14]2[CH:18]=[N:19][CH:20]=[C:13]32)=[CH:5][CH:4]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[C:10]12([CH2:17][CH2:16][CH2:15][N:14]3[CH:18]=[N:19][CH:20]=[C:13]13)[C:11]1[C:6](=[CH:5][CH:4]=[C:3]([OH:2])[CH:12]=1)[CH2:7][CH2:8][CH2:9]2
Reactant: COc1ccc2c(c1)C1(CCC2)CCCn2cncc21
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc2c(c1)C1(CCC2)CCCn2cncc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
7.450 mmol of 7′-methoxy-3′,4′,6,7-tetrahydro-2′H,5H-spiro[imidazo[1,5-a]pyridine-8,1′-naphthalene] (Example 1) are introduced at 0° C. into 50 ml of dichloromethane. 18.630 mmol of boron tribromide (1M in dichloromethane) are added dropwise over 20 minutes. The reaction mixture is subsequently stirred at 0° C. for 3 hours. It is admixed with 50 ml of saturated aqueous sodium bicarbonate solution and stirred thoroughly for 30 minutes. The organic phase is separated off and the aqueous phase is extracted with 30 ml of dichloromethane. The combined organic phases are dried with magnesium sulphate and evaporated. The title compound is obtained as a yellow foam. The crude title compound is reacted further without further purification. Rf=0.28 (dichlormethane-ethanol=95:5); Rt=5.22.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4](Cl)[N:3]=1.[C:10]1([P:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:17]C)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClC1C=CC=CC=1Cl>[C:10]1([P:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:2]2[N:7]=[C:6]([P:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:17])[CH:5]=[C:4]([P:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:17])[N:3]=2)=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COP(c1ccccc1)c1ccccc1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: Clc1ccccc1Cl
Product: O=P(c1ccccc1)(c1ccccc1)c1cc(P(=O)(c2ccccc2)c2ccccc2)nc(P(=O)(c2ccccc2)c2ccccc2)n1
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a stirred, refluxing mixture of 5.00 g of 2,4,6-trichloropyrimidine in 100 ml of o-dichlorobenzene under nitrogen was added dropwise 26.00 g of methyl diphenylphosphinite. After the addition was completed, the mixture was refluxed for 6.5 hours and then allowed to stand overnight at room temperature. The next day a small amount of the solvent was removed by boiling, and the solution was allowed to stand again overnight. The next day the resulting solid was separated by filtration, washed twice with benzene and three times with hexane, recrystallized from 650 ml of toluene, and dried at 100° C./0.1 mm (13 Pa) to give 11.35 g of 2,4,6-tris(diphenylphosphinyl)pyrimidine as a white solid, mp 235°-236° C. Anal. Calcd for C40H31N2O3P3 : C, 70.59; H, 4.59; N, 4.12; P, 13.65. Found: C, 70.72; H, 4.90; N, 3.92; P, 13.61.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].C[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1>C(OCC)C>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([C:10]1[NH:9][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: Cn1cccc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a well stirred solution of trichloroacetyl chloride (1 kg, 5.5 mole) in 1.5 liter ethyl ether in a 12 liter flask was added dropwise over a period of 3 h a solution of N-methylpyrrole (0.45 kg, 5.5 mole) in 1.5 liter anhydrous ethyl ether. The reaction was stirred for an additional 3 hours and quenched by the dropwise addition of a solution of 400 g potassium carbonate in 1.5 liters water. The layers were separated and the ether layer concentrated in vacuo to provide 2-(trichloroacetyl)pyrrole (1.2 kg, 5.1 mol) as a yellow crystalline solid sufficiently pure to be used without further purification. To a cooled (−40° C.) solution of 2-(trichloroacetyl) pyrrole (1.2 kg, 5.1 mol) in acetic anhydride (6 L) in a 12 L flask equipped with a mechanical stirrer was added 440 mL fuming nitric acid over a period of 1 hour while maintaining a temperature of (−40° C.). The reaction was carefully allowed to warm to room temperature and stir an additional 4 h. The mixture was cooled to −30 ° C., and isopropyl alcohol (6 L) added. The solution was stirred at −20° C. for 30 min during which time a white precipitate forms. The solution was allowed to stand for 15 min and the resulting precipitate collected by vacuum filtration to provide 4-nitro-2-trichloroacetyl-1-methylpyrrole, shown as compound B-1 in Scheme B (0.8 kg, 54% yield) TLC (7:2 benzene/ethyl acetate) Rf 0.7; 1H NMR (DMSO-d6) δ 8.55 (d, 1 H, J=1.7 Hz), 7.77 (d, 1 H, J=1.7 Hz), 3.98 (s, 3 H); 13C NMR (DMSO-d6) δ 173.3, 134.7, 133.2, 121.1, 116.9, 95.0, 51.5; IR(KBr) 1694, 1516, 1423, 1314, 1183, 1113, 998, 750. FABMS m/e 269.936 (M+H 269.937 calc. for C7H5N2O3Cl3).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:19]=[C:18]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)[CH:17]=[CH:16][C:13]=1[C:14]#N.C[OH:26].Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:11][C:12]1[CH:19]=[C:18]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)[CH:17]=[CH:16][C:13]=1[CH:14]=[O:26]
Reactant: N#Cc1ccc(-n2cccn2)cc1F
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-n2cccn2)cc1F
Reaction time: 1 h
Yield: 65 %

Procedure:
Diisobutylaluminum hydride (1.0 M in toluene, 11.00 mL, 11.00 mol) was added dropwise over 10 min to a vigorously stirred suspension of the compound from step A (1.88 g, 10.04 mmol) in toluene (100 mL) at −78° C. After 1 h at −78° C., MeOH (1 mL) was added, the mixture was stirred for 5 min, and then poured into a stirred, cold (0° C.) mixture of 1.2 N HCl (100 mL) and ethyl acetate (100 mL). After stirring for 30 min at RT, the layers were separated and the aqueous layer was extracted with additional ethyl acetate (100 mL). The combined organic layers were washed with sat. aq. NaHCO3 (100 mL) and brine (100 mL), dried (MgSO4), and concentrated. Recrystallization from IPA followed by chromatography (SiO2, dichloromethane) provided 1.25 g (65%) of the title compound as a colorless solid. MS 191 (M+H)+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C[O:10][C:11]([C:13]1[NH:14][C:15]([CH2:20][CH3:21])=[CH:16][C:17]=1[C:18]#[N:19])=[O:12].[OH-].[Na+]>C(Cl)Cl>[Br:1][C:16]1[C:17]([C:18]#[N:19])=[C:13]([C:11]([OH:10])=[O:12])[NH:14][C:15]=1[CH2:20][CH3:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1cc(C#N)c(C(=O)OC)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)O)c(C#N)c1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-Bromosuccinimide (289 mg, 1.63 mmol) was added to a cooled solution of 3-cyano-5-ethyl-1H-pyrrole-2-carboxylic acid methyl ester (Intermediate 27; 290 mg, 1.63 mmol) in anhydrous DCM at 0° C. The mixture was stirred at 0° C. for 30 minutes. The mixture was poured into a cold solution of 2 N sodium hydroxide (15 ml) and extracted with DCM. The combined extracts were washed with water (2×15 ml), dried over sodium sulphate and concentrated in vacuo to give small amounts of title compound. The aqueous phase was acidified, extracted with EtOAc, concentrated in vacuo to give the title compound as a creamy brown solid (240 mg).
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH2:21][CH2:22][OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br.[OH-].[Na+]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:23][CH2:22][CH2:21][CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOCCCO
Reactant: BrCCCCCCCCBr
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCCCOCCCOCCCCCCCCBr
Yield: 53.1 %

Procedure:
Using 3-(octadecyloxy)propanol (5 g), 1,8-dibromooctane (12.7 g), cetyltrimethylammonium chloride (0.96 g) and a 50% aqueous solution of sodium hydroxide (12 g), a reaction is conducted in the same manner as that in Reference Example 4 to give the above-titled compound as colorless solid (4.2 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:29][O:30][C:31](=[O:47])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]2[CH3:45])=[C:34]([NH2:46])[CH:33]=1>CN(C=O)C.O.C(Cl)CCl>[CH3:29][O:30][C:31](=[O:47])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]2[CH3:45])=[C:34]([NH:46][C:7](=[O:9])[CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:33]=1
Reactant: COC(=O)c1ccc(NC2CCCCC2C)c(N)c1
Reactant: O=C(O)Cc1cccs1
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COC(=O)c1ccc(NC2CCCCC2C)c(NC(=O)Cc2cccs2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.7 %

Procedure:
To a solution of 4.34 g of thiophen-2-yl-acetic acid in 40 ml of dry DMF 2.08 g of HOAT, 8.77 g of EDC and 13 ml of DIPEA were added at 0° C. After 30 min 8.00 g of 3-Amino-4-(2-methyl-cyclohexylamino)-benzoic acid methyl ester were added, followed by the addition of 6 ml of DIPEA and the reaction was stirred at rt for 48 h. The reaction was then poured into water and extracted with ethyl acetate three times. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and concentrated to obtain 11.75 g (100%) of 4-(2-Methyl-cyclohexylamino)-3-(2-thiophen-2-yl-acetylamino)-benzoic acid methyl ester, which was used without further purification.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(Cc4cccnc4)c4ccc(OC(F)F)cc34)nc12
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(Cc4cccnc4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
In a round-bottomed flask, 2-(5-difluoromethoxy-1-pyridin-3-ylmethyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (124 mg, 0.20 mmol) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (0.62 ml, 8.05 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (1 ml) and ethylenediamine (0.81 ml, 12.0 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was triturated with a small amount of diethyl ether containing a few drops of ethyl acetate to afford 83 mg (80%) of 2-(5-difluoromethoxy-1-pyridin-3-ylmethyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a light yellow powder. MS: (M+H)+=492; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.78 (br. s., 1H), 9.09 (s, 1H), 8.68 (d, J=1.9 Hz, 1H), 8.50 (dd, J=4.7, 1.3 Hz, 1H), 8.39 (s, 1H), 8.22 (d, J=2.3 Hz, 1H), 8.02 (d, J=9.4 Hz, 1H), 7.87 (s, 1H), 7.75 (d, J=7.9 Hz, 1H), 7.32-7.46 (m, 2H), 7.07 (t, J=74.0 Hz, 1H), 5.88 (s, 2H), 1.50 (s, 9H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1F)[NH:18][CH:17]=[N:16][C:15]2=[O:23].O>CN(C)C=O>[CH2:1]([O:8][C:21]1[CH:20]=[C:19]2[C:14]([C:15](=[O:23])[N:16]=[CH:17][NH:18]2)=[CH:13][C:12]=1[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=c1nc[nH]c2cc(F)c(F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1nc[nH]c2cc(OCc3ccccc3)c(F)cc12
Temperature: 60 °C
Yield: 83.2 %

Procedure:
Benzyl alcohol (4.27 g, 39.5 mmol) was added dropwise to a stirred suspension of sodium hydride (1.6 g of a 60% dispersion in mineral oil, 40.0 mmol) in dimethylformamide (50 ml) at 0° C. The reaction was stirred at 0° C. for 1 hour before addition of 6,7-difluoroquinazolin-4(1H)-one (3.60 g, 19.8 mmol) whereupon the reaction was heated to 60° C. for 2 hours. The reaction was cooled to ambient temperature, poured into water (200 ml) and the resultant solid collected by suction filtration. Drying of the solid in vacuo yielded 7-(benzyloxy)-6-fluoroquinazolin-4(1H)-one (4.45 g, 83% yield) as a pale brown solid:
Reaction SMILES: C(OC(=O)C(OC1C=C(O)C=CC=1CCCC)(C)C)C.CC1OC(C2C=CC=CC=2)=NC=1CCOS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C([O:54][C:55](=[O:85])[C:56]([O:59][C:60]1[CH:65]=[C:64]([O:66][CH2:67][CH2:68][C:69]2[N:70]=[C:71]([C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)[O:72][C:73]=2[CH3:74])[CH:63]=[CH:62][C:61]=1[CH2:81][CH2:82][CH2:83][CH3:84])([CH3:58])[CH3:57])C.[OH-].[Na+]>C(O)C>[CH2:81]([C:61]1[CH:62]=[CH:63][C:64]([O:66][CH2:67][CH2:68][C:69]2[N:70]=[C:71]([C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)[O:72][C:73]=2[CH3:74])=[CH:65][C:60]=1[O:59][C:56]([CH3:57])([CH3:58])[C:55]([OH:85])=[O:54])[CH2:82][CH2:83][CH3:84]
Reactant: CCCCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1OC(C)(C)C(=O)OCC
Agent: CCCCc1ccc(O)cc1OC(C)(C)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCCCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1OC(C)(C)C(=O)O
Temperature: 55 °C
Yield: 49 %

Procedure:
The following example exemplifies the general procedure for the parallel synthesis of analogs utilizing the DynaVac carousel. To a 50 mL glass tube with screw cap and nitrogen inlet were charged 2-(2-butyl-5-hydroxyphenoxy)-2-methylpropionic acid ethyl ester, (0.050 g, 0.178 mmol), toluene-4-sulfonic acid 2-(5-methyl-2-phenyloxazol-4-yl)ethyl ester (0.067 g, 0.187 mmol), and powdered potassium carbonate (0.050 g, 0.36 mmol) in 1 mL of absolute ethanol. The mixture was heated to reflux for 18 h. MS analysis of the reaction indicated that 2-{2-Butyl-5-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic acid ethyl ester, MS (ES) m/e 466 (M+1) had formed. Next 0.4 mL of 5N sodium hydoxide was added and the reaction was heated for 3 h at 55° C. The ethanol was removed in vacuo and the residue was treated with 1 mL of 5N hydrochloric acid and 1 mL of dichloromethane and poured into a 3 mL ChemElute column to remove the aqueous layer. The column was eluted with additional dichloromethane until nothing UV active remained on the column. The solvent was removed in vaco. The crude residue was purified by mass-directed reverse phase HPLC to provide 0.038 g (49%) of 2-{2-Butyl-5-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic acid, 1H NMR (400 MHz, CDCl3) δ 7.99 (dd, J=6.4, 2.4 Hz, 2H), 7.46 (dd, J=5.9, 2.4 Hz, 3H), 7.03 (d, J=8.3 Hz, 1H), 6.62 (d, J=2.4 Hz, 1H), 6.51 (dd, J=8.3, 2.4 Hz, 1H), 4.18 (t, J=7.3 Hz, 2H), 2.95 (t, J=7.3 Hz, 2H), 2.54 (t, J=7.6 Hz, 2H), 2.38 (s, 3H), 1.63 (s, 6H), 1.53 (quintet, J=7.6 Hz, 2H), 1.35 (sextet, J=7.3 Hz, 2H), 0.92 (t, J=7.1 Hz, 3H), MS (ES) m/e 438 (M+1). The following compounds were also prepared by this procedure: 2-{2-Butyl-5-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic acid ethyl ester, MS (ES) m/e 472 (M+1). Example 34A: 2-{2-Butyl-5-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic acid
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=3)[C:10]([C:18]([OH:20])=O)=[N:9]2)[CH:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.CN(C=O)C.[CH3:30][CH:31]1[O:36][CH:35]([CH3:37])[CH2:34][NH:33][CH2:32]1>C(Cl)Cl>[Br:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([C:18]([N:33]3[CH2:32][CH:31]([CH3:30])[O:36][CH:35]([CH3:37])[CH2:34]3)=[O:20])=[N:9][N:8]2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)=[CH:12][CH:13]=1
Reactant: CC1CNCC(C)O1
Reactant: Nc1nccc(-n2nc(C(=O)O)c3ccc(Br)cc32)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC1CN(C(=O)c2nn(-c3ccnc(N)n3)c3cc(Br)ccc23)CC(C)O1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-6-bromoindazole-3-carboxylic acid (0.38 g, 1.12 mmol)) in DCM (5 mL), was added thionyl chloride (0.49 ml, 6.74 mmol) followed by a drop of DMF. The mixture was stirred at 40° C. overnight. The reaction mixture was concentrated in vacuo and DCM added and the concentration repeated (×2). The acid chloride intermediate was suspended in DCM (10 ml), 2,6-dimethylmorpholine (0.55 ml, 4.49 mmol) added. The reaction was stirred at RT for 0.5 hr and then concentrated in vacuo. The residue was diluted with more DCM and water and the organics extracted (2×20 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Crude material purified by column chromatography, (9:1 DCM:methanol, Rf=0.6). Elution with DCM:methanol 98:2 to 90:10 gave the mixture of cis and trans 2,6-dimethylmorpholin-4-yl compound (200 mg): 1H NMR (500 MHz, CDCl3) delta 1.21 (3H, d, J=6.2 Hz), 1.30 (3H, d, J=6.1 Hz), 2.64 (1H, dd, J=13.1, 10.8 Hz), 2.99 (1H, dd, J=13.2, 10.6 Hz), 4.84-3.26 (6H, m), 5.23 (2H, s), 7.23-7.19 (1H, m), 7.50 (1H, dd, J=8.6, 1.6 Hz), 7.98 (1H, d, J=8.6 Hz), 8.37 (1H, dd, J=5.6, 2.2 Hz), 9.01 (1H, d, J=1.2 Hz); LC-MS: m/z=+430.95/432.85 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].N([O-])=O.[Na+].[N-:14]=[N+:15]=[N-].[Na+]>C(O)(C(F)(F)F)=O.O>[N:4]([C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[F:1])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(I)cc1F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=Nc1ccc(I)cc1F
Yield: 99 %

Procedure:
2-Fluoro-4-iodoaniline (1.1, 6.50 g, 27.4 mmol) was dissolved in 25 mL TFA and stirred in ice bath. Solid NaNO2 (2.07 g, 30.1 mmol) was added in small portions. The resulting mixture was stirred for 30 min in ice bath. Sodium azide (1.87 g, 28.8 mmol) was dissolved in 10 mL water and chilled in ice bath. This cold solution was then added to the TFA solution in three portions. The mixture was stirred in ice bath for 1 hr and concentrated in vacuo to remove TFA. The residue was taken into 600 mL DCM and washed with water three times. The organic phase was dried using MgSO4 and concentrated in vacuo to afford 1-azido-2-fluoro-4-iodobenzene 1.2 as a brownish waxy solid in >99% yield. In the mean time, 5-chlorothiophene-2-carboxylic acid (1.3, 9.13 g, 56 mmol) was dissolved in 200 mL dry DCM along with 0.5 mL dry DMF. To the vigorously stirred solution was carefully added oxalyl chlororide (14.7 mL, 169 mmol) dropwise. The resulting solution was stirred for 3 hrs at RT and concentrated in vacuo. The residue was pumped to dryness and then dissolved in 300 mL dry DCM. To this solution was added propargylamine (5.8 mL, 84 mmol) dropwise. The mixture was stirred at RT overnight during which time solid precipitated out. 600 mL hexane was added and the mixture was vigorously stirred for a few hours. The solid was collected by filtration and washed with hexane to give 5-chloro-N-(prop-2-ynyl)thiophene-2-carboxamide 1.4 (9.47 g, 85%) which was used directly without further purification. MS found for C8H6ClNOS as (M+H)+ 200.0, 202.0 (chlorine pattern).
Reaction SMILES: C[O:2][C:3]1[N:11]=[CH:10][C:9]2[NH:8][C:7]3[N:12]=[CH:13][C:14]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22][N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)=[CH:18][CH:17]=4)=[CH:15][C:6]=3[C:5]=2[CH:4]=1.Br>>[O:2]=[C:3]1[NH:11][CH:10]=[C:9]2[C:5]([C:6]3[CH:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([CH2:22][N:23]5[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]5)=[CH:20][CH:21]=4)[CH:13]=[N:12][C:7]=3[NH:8]2)=[CH:4]1
Reactant: COc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Agent: Br
Product: O=c1cc2c(c[nH]1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 100 °C
Yield: 27.9 %

Procedure:
To 6-methoxy-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (200 mg, 0.5 mmol) was added HBr (33% in acetic acid, 5 mL) and the reaction was heated at 100° C. for 16 h. The cooled reaction mixture was then evaporated in vacuo to afford a residue that was purified by preparative HPLC [0-30% MeCN in water (0.1% formic acid) over 30 min, 35 mL/min] to afford the title compound as a bright yellow solid (50 mg, 30%). 1H NMR (DMSO-D6, 400 MHz): 11.51 (s, 1H), 8.91-8.74 (m, 2H), 8.28 (s, 1H), 7.72 (d, J=8.2 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 7.29 (s, 1H), 6.68-6.44 (s, 1H), 3.48 (s, 2H), 2.36 (s, 4H), 1.51 (m, 4H), 1.40 (m, 2H). LCMS (Method D): RT=4.97 min, M+H+=359.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][CH:14]=2)=[C:6]([CH3:8])[CH:7]=1.[C:19]([NH:22][NH2:23])(=O)[CH3:20]>C(O)CCC>[CH3:20][C:19]1[N:3]2[N:4]=[C:5]([C:9]3[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][CH:14]=3)[C:6]([CH3:8])=[CH:7][C:2]2=[N:23][N:22]=1
Reactant: Cc1cc(Cl)nnc1-c1cccc(C(F)(F)F)c1
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1cc2nnc(C)n2nc1-c1cccc(C(F)(F)F)c1

Procedure:
As in Example 36, a mixture of 8.0 g of 3-chloro-5-methyl-6-(α,α,αtrifluoro-m-tolyl)pyridazine and 4.34 g. of acetylhydrazine in 125 ml. of n-butanol is refluxed for 48 hr. to give 6.2 g. of cream colored crystals, m.p. 185°-187° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3C(=O)C4=CC=CC=C4C3=O)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].O.NN>C(O)C>[NH2:20][CH2:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:18]=1
Reactant: COc1cc(-c2cc(CN3C(=O)c4ccccc4C3=O)ccn2)cc(OC)c1OC
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1cc(-c2cc(CN)ccn2)cc(OC)c1OC

Procedure:
To a suspension of N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]phthalimide (1.16 g) in ethanol (30 mL) was added hydrazine monohydrate (1 mL). The mixture was refluxed for 3 hours. After cooling, the precipitates were filtered off. The filtrate was evaporated and the residue was dissolved in chloroform. The solution was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and evaporated to give the title compound as pale yellow oil.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[C:13](C(OCC)=O)[C:12]2=[O:30])=[CH:2]1>CN(C)C=O.CC(O)CC>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:30])[CH:13]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[O:15]2)=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2ccccc2OC)OC(=Cc2c[nH]c3ncccc23)C1=O
Solvent: CCC(C)O
Solvent: CN(C)C=O
Product: COc1ccccc1NC1=CC(=O)C(=Cc2c[nH]c3ncccc23)O1
Temperature: 25 °C
Yield: 12.1 %

Procedure:
A solution of the compound (0.099 g, 0.24 mmol) of Example 7 in N,N-dimethylformamide (2.0 mL) was refluxed for 9 h. Cooled to ambient temperature, the reaction mixture was diluted with 2-butanol and washed with 4M sodium hydroxide solution. The organic layer was concentrated then purified by chromatography on silica gel(chloroform/methanol) to afford the titled compound as solid (0.0097 g, y. 12%).