Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6](=[O:12])[N:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)[CH3:2].[CH3:14][S:15][C:16]1[N:21]=[C:20]([C:22](O)=[O:23])[CH:19]=[CH:18][N:17]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([N:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:22]([C:20]1[CH:19]=[CH:18][N:17]=[C:16]([S:15][CH3:14])[N:21]=1)=[O:23])=[O:12])[CH3:2]
Reactant: CCOC(=O)CC(=O)N1CCCN1
Reactant: CSc1nccc(C(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)N1CCCN1C(=O)c1ccnc(SC)n1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of the 3-oxo-3-pyrazolidin-1-yl propionic acid ethyl ester, 11, (8.8 g, 47.7 mmol) in DMF (165 mL) is added 2-methylsulfanyl-pyrimidine-4-carboxylic acid (8.5 g, 50.1 mmol), followed by 1-hydroxybenzotriazole (12.9 g, 95.5 mmol) and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.0 g, 57.3 mmol). The reaction mixture is stirred at room temperature for 22 hours then poured into aqueous saturated NaHCO3. The aqueous phase is extracted three times with EtOAc and the combined organic phases are dried (MgSO4), filtered and concentrated in vacuo to afford 10.5 g of the desired compound which is used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:14]([C:17](O)=[O:18])[N:15]([CH3:16])[C:9]=2[N:8]=[C:7]1[CH3:26].Cl.[NH2:31][CH:32]1[CH2:37][CH2:36][N:35]([C:38](=[O:41])[CH2:39][OH:40])[CH2:34][CH2:33]1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([O:20][CH2:21][C:22]([F:25])([F:23])[F:24])=[C:14]([C:17]([NH:31][CH:32]3[CH2:33][CH2:34][N:35]([C:38](=[O:41])[CH2:39][OH:40])[CH2:36][CH2:37]3)=[O:18])[N:15]([CH3:16])[C:9]=2[N:8]=[C:7]1[CH3:26]
Reactant: Cc1nc2c(c(OCC(F)(F)F)c(C(=O)O)n2C)c(=O)n1Cc1cccc(F)c1
Reactant: NC1CCN(C(=O)CO)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nc2c(c(OCC(F)(F)F)c(C(=O)NC3CCN(C(=O)CO)CC3)n2C)c(=O)n1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.8 %

Procedure:
A mixture of the compound of Reference Example 47 (84 mg, 0.19 mmol), 1N aqueous sodium hydroxide solution (2 mL), THF (2 mL) and ethanol (2 mL) was stirred at 60° C. for 3 hr. The reaction mixture was neutralized with 2N hydrochloric acid (1 mL), and concentrated under reduced pressure, and the precipitate was filtered and washed with water to give 3-(3-fluorobenzyl)-2,7-dimethyl-4-oxo-5-(2,2,2-trifluoroethoxy)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid as a powder (59 mg, 75%). A mixture of 3-(3-fluorobenzyl)-2,7-dimethyl-4-oxo-5-(2,2,2-trifluoroethoxy)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (59 mg, 0.14 mmol), 2-(4-aminopiperidin-1-yl)-2-oxoethanol hydrochloride (35 mg, 0.18 mmol), HOBt (28 mg, 0.18 mmol), WSCD (35 mg, 0.18 mmol) and triethylamine (18 mg, 0.18 mmol) in DMF (5 mL) was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, and dried over anhydrous sodium sulfate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluate, hexane:ethyl acetate=1:1→0:100), and recrystallized from ethyl acetate-hexane to give the title compound (13 mg, 17%) as a white powder.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[CH:17][N:18]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[B:30](OC(C)C)([O:35]C(C)C)[O:31]C(C)C.Cl>C1COCC1>[C:26]([O:25][C:23]([N:18]1[C:19]2[C:15](=[C:14]([F:13])[CH:22]=[CH:21][CH:20]=2)[CH:16]=[C:17]1[B:30]([OH:35])[OH:31])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)OC(=O)n1ccc2c(F)cccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(B(O)O)cc2c(F)cccc21
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 76.7 %

Procedure:
To a solution of diisopropylamine (7.5 mL, 0.11 mol) in THF (35 mL) at 0° C. was added n-BuLi (21 mL, 0.055 mol) dropwise. The mixture was stirred at 0° C. for 40 minutes. Then the mixture was cooled to −78° C. Tert-butyl 4-fluoro-1H-indole-1-carboxylate (5 g, 0.02 mol) in THF (13 mL) was added dropwise slowly. After addition, the mixture was stirred at −78° C. for 2 hours. Then triisopropyl borate (3.29 g, 0.03 mol) was added. The mixture was stirred at −78° C. for another 40 minutes. The reaction was monitored using TLC. When the reaction was completed, the mixture was adjusted to pH=6 with 1 N HCl. After extracted with EtOAc (25 mL×3), the combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The obtained solid was recrystallized with EtOAc and petroleum ether to provide (1-(tert-butoxycarbonyl)-4-fluoro-1H-indol-2-yl)boronic acid (4.5 g, yield: 76.7%, which might be unstable at high temp. work up, store in fridge). 1H-NMR (CDCl3, 400 MHz) δ 7.77 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.44 (s, 2H), 7.24 (m, 1H), 6.90 (m, 1H), 1.66 (s, 9H). MS (M+H)+: 280.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9](=[O:14])[NH:10][CH:11]=[CH:12][N:13]=2)[CH2:4][CH2:3]1.CC([O-])(C)C.[K+].CS(O[CH2:26][CH2:27][O:28][C:29]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=1[F:37])(=O)=O.O>C1COCC1>[F:37][C:30]1[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:29]=1[O:28][CH2:27][CH2:26][N:10]1[CH:11]=[CH:12][N:13]=[C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[C:9]1=[O:14]
Reactant: CN1CCN(c2ncc[nH]c2=O)CC1
Reactant: CS(=O)(=O)OCCOc1cc(F)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2nccn(CCOc3cc(F)c(F)cc3F)c2=O)CC1
Temperature: 60 °C

Procedure:
A mixture of 3-(4-methyl-1-piperazinyl)-2(1H)-pyrazinone (obtained in Step 2 above; 0.5 g, 2.6 mmol) and t-BuOK (440 mg, 3.90 mmol) in THF (40 mL) was stirred until the mixture became thick (about 10 min), and then a solution of 2-(2,4,5-trifluorophenoxy)ethyl methanesulfonate (0.90 g, 2.2 mmol; from Step 4) in THF (10 mL) was added. After being stirred for 5 days at ambient temp, HPLC showed only 50% conversion. The reaction solution was then heated to 60° C. overnight which gave almost full conversion. The reaction was worked up according to the following: water was added, THF was evaporated off and the aqueous mixture was extracted twice with EtOAc, dried (Na2SO4) and concentrated to yield 1.08 g of the crude product as a yellow oil. Purification by chromatography on silica gel [eluent: 2% MeOH in CHCl3+NH3 (g)] gave the title compound as a yellow oil, which solidified upon cooling. Yield: 304 mg (32%). HPLC purity: 100%. MS m/z 369 (M+H)+. HRMS m/z calcd for C17H19F3N4O2 (M)+ 368.1460, found 368.1462.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:4]=1[CH:5]=O.[NH2:17][C:18]1[CH:19]=[C:20]2[C:24]3=[C:25]([CH2:27][O:28][CH2:29][CH2:30][N:23]3[C@H:22]3[CH2:31][CH2:32][N:33](C(OC(C)(C)C)=O)[CH2:34][C@@H:21]23)[CH:26]=1>>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:4]=1[CH2:5][NH:17][C:18]1[CH:19]=[C:20]2[C:24]3=[C:25]([CH2:27][O:28][CH2:29][CH2:30][N:23]3[C@H:22]3[CH2:31][CH2:32][NH:33][CH2:34][C@@H:21]23)[CH:26]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Product: FC(F)(F)c1ccc(C(F)(F)F)c(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)c1

Procedure:
Using 2,5-bis(trifluoromethyl)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 130. 1H NMR (CDCl3) δ: 7.98 (s, 1H), 7.82 (d, 1H, J=8.1 Hz), 7.64 (d, 1H, J=8.1 Hz), 6.37 (d, 1H, J=2.5 Hz), 6.18 (d, 1H, J=2.5 Hz), 4.58 (ABq, 2H, JAB=14.1 Hz), 4.51 (s, 2H), 4.18 (app d, 1H, J=12.5 Hz), 3.90 (m, 1H), 3.74 (app t, 1H), 3.36-3.30 (m, 1H), 3.28-3.20 (m, 1H), 3.20-3.08 (m, 2H), 3.03 (dd, 1H), 2.93-2.85 (m, 2H), 2.64 (app t, 1H), 2.46 (dd, 1H, J=12.1, 10.6 Hz), 2.00-1.80 (m, 2H). LRMS (ES)+: 472.4 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[O:11][C:10]([CH2:23][F:24])([CH2:21][F:22])[CH:9]=1)=[O:7])#[N:2].[BH4-].[Na+].O1CCCC1>CO>[C:1]([CH2:3][CH2:4][NH:5][C:6]([CH:8]1[C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[O:11][C:10]([CH2:23][F:24])([CH2:21][F:22])[CH2:9]1)=[O:7])#[N:2]
Reactant: N#CCCNC(=O)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N#CCCNC(=O)C1CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
A mixture of 0.33 g of N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-nitro-2H-1-benzopyran-4-carboxamide, 0.20 g of sodium borohydride, 20 ml of tetrahydrofuran and 10 ml of methyl alcohol was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and 2N hydrochloric acid was added therein. The resultant mixture was extracted with ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing solution, ethyl acetate:hexane=1.1) to obtain 0.17 g of N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-3,4-dihydro-6-nitro-2H-1-benzopyran-4-carboxamide with a melting point of 137°-138° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([N+:15]([O-])=O)=[C:10]3[O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:8]([C:9]=23)=[N:7]1)[CH3:2].[H][H]>O1CCCC1.[Pd]>[NH2:15][C:11]1[CH:12]=[CH:13][C:14]2[N:6]([CH2:5][CH2:4][N:3]([CH2:25][CH3:26])[CH2:1][CH3:2])[N:7]=[C:8]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][C:10]=1[C:9]=23
Reactant: [H][H]
Reactant: CCN(CC)CCn1nc2c3c(c([N+](=O)[O-])ccc31)Oc1ccccc1-2
Agent: [Pd]
Solvent: C1CCOC1
Product: CCN(CC)CCn1nc2c3c(c(N)ccc31)Oc1ccccc1-2

Procedure:
A solution of 8.9 g (0.026 mole) of N,N-diethyl-5-nitro-2H-[1]benzopyrano[4,3,2-cd]indazole-2-ethanamine in 100 ml of tetrahydrofuran was hydrogenated over 1 g of 10% palladium on carbon at ambient temperature and a hydrogen pressure of 46.3-52.3 psi. The mixture was filtered and the solvent removed in vacuo. The oily residue was triturated with petroleum ether and recrystallized from n-hexane to give the product, mp 78°-80° C.
Reaction SMILES: [C:1]([S:5][NH:6][CH3:7])([CH3:4])([CH3:3])[CH3:2].[Cl:8][C:9]1[CH:10]=[C:11]([N:16]=[C:17]=[O:18])[CH:12]=[CH:13][C:14]=1[Cl:15]>C(N(CC)CC)C.O1CCCC1>[CH3:7][N:6]([S:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([NH:16][C:11]1[CH:12]=[CH:13][C:14]([Cl:15])=[C:9]([Cl:8])[CH:10]=1)=[O:18]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CNSC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(SC(C)(C)C)C(=O)Nc1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
12 g of tert.-butylmercapto monomethylamine, 20 g of 3,4-dichlorophenyl isocyanate and 3 drops of triethylamine were added to 120 ml of tetrahydrofuran and after stirring the mixture for 30 minutes, the solvent was distilled off under reduced pressure. The residue was crystallized from ethanol to obtain 25.6 g of N-methyl-N-tert.-butylthio-N'-(3,4-dichlorophenyl)-urea melting at 127° C.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[C:12]([O:16][CH2:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:13][N:14]=[CH:15][C:10]=3[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:35]=[C:34]([CH:36]=O)[O:33][N:32]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:35]=[C:34]([CH2:36][N:21]2[CH2:22][CH2:23][CH:18]([CH2:17][O:16][C:12]3[C:11]4[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[N:8][O:9][C:10]=4[CH:15]=[N:14][N:13]=3)[CH2:19][CH2:20]2)[O:33][N:32]=1
Reactant: O=Cc1cc(-c2ccccc2Cl)no1
Reactant: c1ccc(-c2noc3cnnc(OCC4CCNCC4)c23)cc1
Product: Clc1ccccc1-c1cc(CN2CCC(COc3nncc4onc(-c5ccccc5)c34)CC2)on1

Procedure:
According to the same procedure described in Example 35, using the compound obtained in Example 89 instead of the compound obtained in Example 11 and 3-(2-chlorophenyl)isoxazole-5-carbaldehyde instead of 4-phenylthiophene-2-carbaldehyde, the title compound having the following physical data was obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:39]>C(O)C>[ClH:39].[F:1][C:2]1[C:3]([CH2:23][NH:24][CH3:25])=[CH:4][N:5]([S:14]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)N2CCCCC2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cn(S(=O)(=O)N2CCCCC2)c(-c2cccnc2F)c1F
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
tert-Butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(piperidin-1-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (210 mg) was dissolved in ethanol (5 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added, and the mixture was stirred at 50° C. for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 145 mg, 80%).
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[C:7]([C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[NH2:14])([CH3:10])([CH3:9])[CH3:8].N1C=CC=CC=1>C(Cl)Cl>[C:7]([C:11]1[CH:12]=[C:13]([NH:14][C:1](=[O:5])[CH:2]=[CH:3][CH3:4])[CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])([CH3:10])([CH3:9])[CH3:8]
Reactant: C/C=C/C(=O)Cl
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC=CC(=O)Nc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 41.5 %

Procedure:
Crotonyl chloride (4.7 g, 45 mmol) in 10 ml of methylene chloride was added slowly to a stirred solution of 10 g (45 mmol) of 3,5-di-tert-butyl-4-hydroxyaniline in 50 ml of methylene chloride at 0° C. Ten minutes later 3.6 g (45 mmol) of pyridine was added and, after three hours, the mixture was filtered. The filtered solid was washed with water and triturated in ether to yield 5.4 g of N-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-butenamide having a melting point of 215°-218° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([NH:11][C:12](=[O:14])[CH3:13])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[N:32][NH:33]3)O1>>[NH:33]1[C:34]2[C:30](=[C:29]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[S:10][C:9]([NH:11][C:12](=[O:14])[CH3:13])=[CH:8][C:6]=4[N:7]=3)[CH:37]=[CH:36][CH:35]=2)[CH:31]=[N:32]1
Reactant: CC(=O)Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CC(=O)Nc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
The crude N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)acetamide (46 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 24.2 mg of 163. MS (Q1) 395 (M)+
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:16][CH2:15][CH2:14][O:13][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: COCCN
Product: COCCNc1ccc2ncc(Br)n2n1
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (844 mg, 3.77 mmol) and 2-methoxyethanamine (1.44 mL) was heated at 170° C. (microwave) for 30 min. The resulting mixture was cooled to room temperature and purified by preparative HPLC (neutral) to afford 3-bromo-N-(2-methoxyethyl)imidazo[1,2-b]pyridazin-6-amine (630 mg, 62% yield) as a off-white solid: 1H NMR (METHANOL-d4) δ: 7.56 (d, J=9.9 Hz, 1H), 7.41 (s, 1H), 6.74 (d, J=9.6 Hz, 1H), 3.62-3.76 (m, 2H), 3.50-3.62 (m, 2H), 3.42 (s, 3H); LRMS (ESI) m/e 271.1 [(M+H)+, calcd for C9H12BrN4O 271.0]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14](Cl)[N:13]=[C:12]([Cl:17])[N:11]=2)=[CH:5][CH:4]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:17][C:12]1[N:11]=[C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:15]=[C:14]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:13]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2nc(Cl)nc(Nc3ccccc3)n2)cc1
Reaction time: 24 h
Yield: 57 %

Procedure:
To a solution of 2-(4-methoxyphenyl)amino-4,6-dichloro-1,3,5-triazine (57 mg, 0.21 mmoles) in acetonitrile (0.5 ml) was added a solution of aniline (0.021 ml, 0.23 mmoles) and diisopropylethylamine (0.05 ml, 0.29 mmoles) in acetonitrile (0.5 ml). After stirring for 24 hours, the mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate (10 ml). The solution was washed with a solution composed of saturated aqueous sodium chloride solution and 1 M hydrochloric acid (1:1, 2×10 ml), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with 10% ethyl acetate-hexane to provide CT-31942 (38 mg, 57% yield). 1H NMR (d6-DMSO) δ 10.00-10.22 (m, 2H), 7.26-7.82 (m, 6H), 7.01-7.10 (m, 1H), 6.91 (d, J=9 Hz, 2H), 3.74 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH2:11][C@@H:12]([CH3:15])[CH2:13][OH:14].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[N:11]/[C@@H:12]([CH3:15])[CH2:13][OH:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: C[C@H](N)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(/C=N/[C@@H](C)CO)cc1

Procedure:
Into a 10000 mL 4-necked, round bottomed flask purged and maintained with an inert atmosphere of nitrogen was placed 4-methoxybenzaldehyde (500 g, 3.67 mol), (S)-2-aminopropan-1-ol (276 g, 3.68 mol), 4-methylbenzenesulfonic acid (31.7 g, 184.09 mmol) and toluene (5000 mL). The resulting solution was maintained at reflux overnight. The reaction mixture was cooled and concentrated under vacuum. The residue was washed with 3000 mL of hexane and filtered to afford the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH:14]=[CH:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:22][CH:9]1[C:10]2[C@:15]([CH3:16])([CH:14]=[CH:13][C:12](=[O:20])[CH:11]=2)[C@@H:17]2[C@H:7]([C@H:6]3[C@@:2]([CH2:19][CH2:18]2)([CH3:1])[C:3](=[O:21])[CH2:4][CH2:5]3)[CH2:8]1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: C[C@]12C=CC(=O)C=C1C(Br)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 76.7 %

Procedure:
A solution of 10 g of androsta-1,4-diene-3,17-dione in 95 ml of carbon tetrachloride is refluxed with 6.4 g of N-bromosuccinimide and 0.4 g of benzoyl peroxide for seventy five minutes. After filtration of succinimide, the filtrate was cooled in ice until crystallization is complete. The mixture is then filtered and dried so obtaining 9.8 g of crude 6-bromoandrosta-1,4-diene-3,17-dione satisfactory for the next step. The analytical sample is crystallized from diethyl ether/n-hexane, m.p. 188°-190° C., [α]D20° +116, U.V. (95% EtOH) λmax=250 nm.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([CH3:25])[C:5]([C:8]1[CH:9]=[C:10]([C:20]([CH3:24])([CH3:23])[C:21]#[N:22])[CH:11]=[C:12]([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:13]=1)([CH3:7])[CH3:6]>C(O)C.O>[OH:3][CH:4]([CH3:25])[C:5]([C:8]1[CH:9]=[C:10]([C:20]([CH3:24])([CH3:23])[C:21]#[N:22])[CH:11]=[C:12]([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:13]=1)([CH3:7])[CH3:6]
Reactant: CC(=O)C(C)(C)c1cc(Cn2cncn2)cc(C(C)(C)C#N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(O)C(C)(C)c1cc(Cn2cncn2)cc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium borohydride (20 mg) was added to a solution of 2-[3-(2-oxo-1,1-dimethylpropyl)-5-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-2-methylpropiononitrile (prepared as described in Example 2--40 mg) in ethanol (2 ml) and the mixture was stirred at room temperature for 18 h. The mixture was diluted with water and extracted with ethyl acetate, and the extract was dried and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography, using methanol (1% by volume) in ethyl acetate as eluant, to give 2-[3-(2-hydroxy-1,1-dimethylpropyl)-5-(1H-1,2,4-triazol-1-yl-methyl)phenyl]-2-methylpropiononitrile, mp 83°-84°.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH2:11]Br.[Li]CCCC>C1COCC1>[CH3:8][C:6]1[CH:7]=[CH:2][C:3]2[O:9][CH2:10][CH2:11][C:4]=2[CH:5]=1
Reactant: Cc1ccc(OCCBr)c(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)CCO2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-1-(2-bromoethoxy)-4-methylbenzene (1a) (1.0 g, 3.4 mmol) in THF (20 mL) at −78° C., under N2 was added n-BuLi (2.5 M, 11 mL, 27 mmol) and the resulting mixture was stirred at −78° C., for 1 h. The mixture was quenched with saturated NH4Cl (10 mL), extracted with EtOAc (150 mL), washed with brine, dried and concentrated to give the title compound (1b) as a colorless oil.
Reaction SMILES: [Br-].[C:2]([NH:10][C:11]1[CH:16]=[CH:15][N+:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+].O>CO>[CH2:17]([N:14]1[CH2:15][CH2:16][C:11]([NH:10][C:2](=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:12][CH2:13]1)[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Nc1cc[n+](CCc2ccccc2)cc1)c1ccccc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(NC1=CCN(CCc2ccccc2)CC1)c1ccccc1
Reaction time: 1 h
Yield: 89.6 %

Procedure:
4-Benzamido-1-phenethylpyridinium bromide (3.0 g.) in methanol (100 ml.) was treated with sodium borohydride (6.0 g.) in portions over 30 minutes. The solution was stirred during the addition and for 1 hour after. Water was then added to the warmed solution until crystallisation commenced to give the title compound (2.15 g.), m.p. 115°-7° C. (Found: C, 78.2; H, 7.3; N, 9.1 C20H22N2O requires C, 78.4; H, 7.2; N, 9.1%).