Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CC(C)([O-])C.[K+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:22]3([N:25]4[CH:29]=[N:28][C:27]([Cl:30])=[N:26]4)[CH2:24][CH2:23]3)[CH2:21][O:20]2)=[CH:15][CH:14]=1>C(#N)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:22]2([N:25]3[CH:29]=[N:28][C:27]([Cl:30])=[N:26]3)[CH2:24][CH2:23]2)([OH:20])[CH2:21][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:15][CH:14]=1
Reactant: Clc1ccc(C2(C3(n4cnc(Cl)n4)CC3)CO2)cc1
Reactant: c1c[nH]cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Product: OC(Cn1ccnc1)(c1ccc(Cl)cc1)C1(n2cnc(Cl)n2)CC1

Procedure:
13 g (191 mmol) of imidazole and 1 g (9 mmol) of potassium tert. butoxide are initially introduced under a nitrogen atmosphere into 100 ml of acetonitrile under reflux and 18 g (61 mmol) of 2-(4-chlorophenyl)-2-[1-(3-chloro-1,2,4-triazol-1-yl)-cyclopropyl]-oxirane dissolved in 30 ml of acetonitrile are added dropwise. The mixture is allowed to react under reflux conditions for 10 hours and the solvent is then evaporated in vacuo. The residue is taken up in ethyl acetate and washed with water. The solution is dried over sodium sulphate and the solvent is removed in vacuo. Chromatographic purification on silica gel (solvent: dichloromethane/ethanol=90/10) gives 7.1 g (32% of theory) of the title compound of m.p. 231° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=O.S(Cl)([Cl:23])=O>>[CH3:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([Cl:23])=[O:20]
Reactant: Cc1c(CC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Product: Cc1c(CC(=O)Cl)cccc1C(=O)c1ccc(Cl)cc1

Procedure:
A solution of 5.8 g of 2-methyl-3-(p-chlorobenzoyl)-phenylacetic acid in 25 ml of thionyl chloride was refluxed for 11/2 hours and excess thionyl chloride was removed to obtain 2-methyl-3-(p-chlorobenzoyl)-phenylacetic acid chloride melting at 62°-63° C.
Reaction SMILES: Cl.Cl.[C:3]([O:7][C:8]([N:10]([C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[C:11]1[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[C:3]([O:7][C:8]([N:10]([C@@H:24]1[CH2:28][CH2:27][N:26]([CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:25]1)[C:11]1[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Reactant: BrCCOc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(CCOc3ccccc3)C2)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
To a mixture of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate dihydrochloride (500 mg), (2-bromoethoxy)benzene (347 mg), and DMF (5 mL) was added Na2CO3 (488 mg). After stirring for 3 hours at 100° C., the reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with H2O, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(2-phenoxyethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (516 mg).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].O>CC(C)=O>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:1][CH:2]=1
Reactant: Cc1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(C)cc1
Temperature: 25 °C

Procedure:
A stirred mixture of p-cresol (14.6 g, 0.135 mole) and anhydrous potassium carbonate (37.2 g, 0.27 mole) in dry acetone (200 ml) was heated under reflux for 30 minutes. The mixture was then cooled to room temperature and ethyl bromoacetate (16.6 ml, 0.15 mole) added. The mixture was heated upto reflux again and maintained at this temperature for 41/2 hours, then allowed to cool before pouring into water (1000 ml). The aqueous mixture was extracted with ether (2×250 ml) and the organic solution washed with dilute hydrochloric acid (1×200 ml) and water (1×200 ml), then dried (MgSO4) and evaporated to dryness to give a quantitative yield of the title compound as a yellow oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)(=[O:11])[CH3:10].C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:9](=[O:11])[CH3:10])[CH:17]=2)=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)c1cccc(-c2ccc(O)cc2)c1
Temperature: 55 °C
Yield: 95 %

Procedure:
4-Iodophenol (5.39 g, 24.5 mmol) and 3-acetylphenylboronic acid (4.42 g, 26.95 mmol) were mixed in N,N-dimethylformamide (15 mL) and treated with 1.0 M aqueous Na2CO3 (75 mL) and palladium (II) acetate (110 mg, 0.49 mmol). The suspension was heated at 55° C. for one hour and then brought to room temperature. CH2Cl2 (100 mL) was added to the mixture which was then filtered. The aqueous layer of the filtrate was extracted with CH2Cl2 and the combined organic phases were washed consecutively with pH 6 potassium phosphate buffer and brine, then dried (Na2SO4), concentrated, and chromatographed through silica with a 33 to 100% gradient of hexanes/CH2Cl2 followed by a gradient of 0 to 3% EtOAc/CH2Cl2. Impure fractions were combined, concentrated, and rechromatographed as before, twice, to provide the title compound as an oil which slowly crystallized to a white solid upon standing (˜95% yield). MS (ESI APCI negative ion detection) m/z 211 (M−H)−; 1HNMR (300 MHz, CDCl3) δ 2.65 (s, 3 H), 6.97 (d, 2 H), 7.47-7.53 (m, 3 H), 7.74 (ddd, 1 H), 7.88 (ddd, 1 H), 8.13 (dd, 1 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[C:8]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:20])=[O:19])[N:7]([CH3:27])[N:6]=1.[H-].[Na+].[Cl:30][C:31]1[CH:32]=[N:33][C:34](S(C)(=O)=O)=[N:35][CH:36]=1.O>O1CCCC1>[Cl:30][C:31]1[CH:32]=[N:33][C:34]([O:1][CH2:2][CH2:3][O:4][C:5]2[C:9]([C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[C:8]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)(=[O:19])=[O:20])[N:7]([CH3:27])[N:6]=2)=[N:35][CH:36]=1
Reactant: CS(=O)(=O)c1ncc(Cl)cn1
Reactant: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2c(OCCOc3ncc(Cl)cn3)nn(C)c2NS(=O)(=O)c2ccccn2)cc1
Reaction time: 0.17 h
Yield: 46.5 %

Procedure:
To N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-2-pyridine sulphonamide (Example 52) (200 mg) in dry tetrahydrofuran (2 ml) at room temperature was added sodium hydride (80% dispersion in oil, 35 mg) the mixture was stirred for 10 minutes. A solution of 5-chloro-2-methylsulphonylpyrimidine (134 mg) in dry tetrahydrofuran (2.5 ml) was then added and the mixture was stirred for a further 4 hours. The mixture was stirred for 4 hours. The reaction was treated with water (50 ml) and extracted with ethyl acetate (50 ml). The aqueous phase was neutralised to pH7 with 2N hydrochloric acid (aq.). The organic fraction was washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with a solvent gradient of pentane:ethyl acetate (1:1 to 0:1) to yield the tile compound as a colourless foam (120 mg).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][CH2:17][C:18]#[N:19])[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCOCC1.C(OCC)(=O)C>[NH2:19][CH2:18][CH2:17][CH2:16][C:13]12[CH2:15][CH:6]([C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=31)[C:7]1[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#CCCC12CC(c3ccccc31)c1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: NCCCC12CC(c3ccccc31)c1ccccc12
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A mixture of β-(9,10-dihydro-9,10-methano-9-anthryl)propionitrile (250 mg) and lithium aluminum hydride (100 mg) in dioxane (12 ml) was stirred at 60° C. for 5 hours. Excess lithium aluminum hydride was decomposed by addition of water. The reaction mixture was diluted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-γ-aminopropyl-9,10-dihydro-9,10-methanoanthracene, which was converted into its hydrochloride. M.P. 275° C. (decomp.).
Reaction SMILES: C(O)(C)C.[O:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11].[NH2:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[C:21](Cl)[N:20]=1>O>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:19]([NH2:18])=[N:20][C:21]([N:15]3[CH2:14][CH2:13][N:12]([C:10]([CH:6]4[O:5][CH2:9][CH2:8][CH2:7]4)=[O:11])[CH2:17][CH2:16]3)=[N:22][C:23]2=[CH:24][C:25]=1[O:31][CH3:32]
Reactant: O=C(C1CCCO1)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: O
Solvent: CC(C)O
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Yield: 108.1 %

Procedure:
To a solution of iso-propanol (290 ml), water (50 ml) and N-(2-tetrahydrofuroyl)piperazine (20 g) were added, while stirring, 4-amino-2-chloro-6,7-dimethoxyquinazoline (22.2 g). The reaction mixture was heated to reflux and the reflux was maintained for about 35 hours. Then the reaction mixture was cooled to room temperature and stirred at this temperature for about 12 hours. The crystals were collected by filtration, washed with iso-propanol and dried in vacuo at 40° C. to yield 38.8 g (94%) of Terazosin.HCl dihydrate. See Trial K in Table I. Trial L was performed using a 5% percent volume of water.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9]/[CH:10]=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][CH:13]=1.[NH2:23][CH2:24][CH:25]([C:27]1[CH:28]=[C:29]([OH:34])[CH:30]=[C:31]([OH:33])[CH:32]=1)[OH:26]>CN(C=O)C>[OH:33][C:31]1[CH:32]=[C:27]([CH:25]([OH:26])[CH2:24][NH:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9]/[CH:10]=[CH:11]\[C:12]2[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][CH:13]=2)[CH:28]=[C:29]([OH:34])[CH:30]=1
Reactant: CS(=O)(=O)Nc1ccc(/C=C\COCCCCCCBr)cc1
Reactant: NCC(O)c1cc(O)cc(O)c1
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(/C=C\COCCCCCCNCC(O)c2cc(O)cc(O)c2)cc1
Reaction time: 2 h

Procedure:
(Z)-N-[4-[3-[(6-Bromohexyl)oxy]-1-propenyl]phenyl]methanesulphonamide (1.56 g) was added portionwise over 10 min to a stirred solution of 5-(2-amino-1-hydroxyethyl)-1,3-benzenediol (1.01 g) and DEA (1.55 g) in dry DMF (20 ml) heated to 80° under nitrogen. When the addition was complete, the mixture was stirred at 80° for 2 h, cooled and evaporated onto `flash` silica. The impregnated material was purified by FCC eluting with System C (39:10:1) to give the title compound as a pale brown powder which was dried in vacuo at 50° for 6 h (0.75 g) m.p. 79°-82°.
Reaction SMILES: CO.[N+:3]([C:6]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])([O-])=O>[Fe].C(O)(=O)C>[NH2:3][C:6]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(-c2ccccc2)cc1N
Temperature: 25 °C

Procedure:
3.1 g of iron powder was added to a mixed solution of 24 mL of methanol and 24 mL of acetic acid containing 4.8 g of methyl 2-nitro-4-phenylbenzoate, and the resulting mixture was heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration and a saturated sodium hydrogen carbonate aqueous solution and ethyl acetate added to the filtrate. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure, Hexane was added to the obtained residue and a solid substance was separated by filtration to obtain 1.8 g of methyl 2-amino-4-phenylbenzoate as white solid.
Reaction SMILES: [P:1]([O-:13])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:14][CH2:15]I>C1C=CC=CC=1>[P:1]([O:13][CH2:15][Cl:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:2]
Reactant: ClCI
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Solvent: c1ccccc1
Product: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The tetrabutylammonium salt of bis-tert butyl phosphate (45.1 g, 0.1 mol) and chloroiodomethane (200 g, 1.14 mol) were combined in 100 ml of benzene and the mixture was stirred at room temperature for four hours and then the benzene was removed under vacuum. A portion of 500 ml of ethyl ether was added to the residue and insoluble solid was filtered away. Concentration of the filtrate in vacuo and removal of the volitiles on a vacuum pump provided di-tert-butyl chloromethyl phosphate, as a light yellow or light brown oil which was utilized in the next step without further purification.
Reaction SMILES: C(O)C(N)(CO)CO.Cl.[Mg+2].[Cl-].[Cl-].[Na+].[Cl-].[OH:15][P:16](=[O:43])([O:26][CH2:27][C@H:28]1[O:42][C@@H:32]([N:33]2[CH:39]=[C:37]([CH3:38])[C:36](=[O:40])[NH:35][C:34]2=[O:41])[CH2:31][C@@H:29]1[OH:30])[O:17]P(=O)(OP(=O)(O)O)O>>[CH3:38][C:37]1[C:36](=[O:40])[NH:35][C:34](=[O:41])[N:33]([C@@H:32]2[O:42][C@H:28]([CH2:27][O:26][P:16]([OH:17])([OH:43])=[O:15])[C@@H:29]([OH:30])[CH2:31]2)[CH:39]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: [Cl-]
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)O)O2)c(=O)[nH]c1=O
Reaction time: 6 h

Procedure:
To 300 μl of a solution comprising 10 mM Tris-HCl (pH 7.5), 6 mM MgCl2 and 10 mM NaCl, there was added 400 μg of pCDV1 [Okayama & Berg: Mol. Cell. Biol., 3, 280 (1983)] and, after further addition of 500 units of KpnI, the reaction was carried out at 37° C. for 6 hours, whereby the plasmid was cleaved at the KpnI site. The DNA recovered by phenol-chloroform extraction followed by ethanol precipitation. About 200 μg of the KpnI-cleaved DNA was added to 200 μl of a solution prepared by adding dTTP in a concentration of 0.25 mM to TdT buffer and, after further addition of 81 units of TdT (P-L Biochemicals), the reaction was carried out at 37° C. for 11 minutes, whereby a poly(dT) chain (about 67 dT residues) was added to each 3' end of the KpnI cleavage site of pCDV1. About 100 μg of the poly(dT) chain-tailed pCDV1 DNA was recovered from the solution by ethanol precipitation following phenol-chloroform extraction. The DNA was added to 150 μl of a solution comprising 10 mM Tris-HCl (pH 7.5), 6 mM MgCl2 and 100 mM NaCl and, after further addition of 360 units of EcoRI, the reaction was carried out at 37° C. for 2 hours. The reaction mixture was treated by the LGT method, and a DNA fragment of about 3.1 kb was recovered. About 60 μg of the poly(dT) chain-tailed pCDV1 was thus obtained. The DNA was dissolved in 500 μl of a solution comprising 10 mM Tris-HCl (pH 8.0) and 1 mM EDTA, the solution was incubated at 65° C. for 5 minutes and then cooled with ice, and 50 μl of 5M NaCl was added. The mixture was subjected to oligo(dA)-cellulose column (Collaborative Research) chromatography. Molecules having a sufficient poly(dT) chain length were adsorbed on the column and they were eluted with a solution comprising 10 mM Tris-HCl (pH 8.0) and 1 mM EDTA to give 27 μg of the poly(dT) chain-tailed pCDV1 therein-after referred to as vector primer).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2F)[N:6]=1.[CH3:21][N:22]([CH3:28])[C@H:23]1[CH2:27][CH2:26][NH:25][CH2:24]1.C(N(CC)CC)C.C(OCC)(=O)C>CS(C)=O.[Cl-].[Na+].O>[NH2:1][C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[N:25]2[CH2:26][CH2:27][C@H:23]([N:22]([CH3:28])[CH3:21])[CH2:24]2)[N:6]=1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N)nc2c1C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N)nc2c1C#N
Temperature: 150 °C
Yield: 29.9 %

Procedure:
2-Amino-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-172) (200 mg, 0.75 mmol), (3S)-3-(dimethylamino)pyrrolidine (190 μl, 1.50 mmol) and triethylamine (209 μl, 1.50 mmol) were dissolved in dimethyl sulfoxide (4 ml), and the mixture was heated in a sealed tube at 150° C. for 4 hours. After cooling to room temperature, the reaction liquid was fractionated with ethyl acetate and saturated brine. The aqueous layer was separated, and this was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, and the solvent was evaporated away under reduced pressure. The solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent; 7 N ammonia-containing methanol solution:chloroform=8:92) to obtain the entitled compound (81 mg, 30%) as a roughly-purified product. This was further recrystallized from ethyl acetate-hexane to obtain a brown solid (62 mg).
Reaction SMILES: Br[C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:18][CH:17]=1
Reactant: CCn1c(=O)c(Br)nc2ccccc21
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)c(-c2ccc(Cl)cc2)nc2ccccc21
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To 200 mg (0.79 mM) of 3-bromo-1-ethyl-quinoxalin-2(1H)-one and 27.7 mg (0.04 mM) of bis(triphenylphosphine)palladium (II) chloride in 1 ml of dimethylformamide were added under nitrogen 185.3 mg (1,185 mM) of 4-chlorophenylboronic acid and 0.8 ml (1.6 mM) of a 2M sodium carbonate aqueous solution. The reaction mixture was heated to 90° C. and stirred for 30 min under nitrogen atmosphere. Water was added and the mixture was extracted with ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. The compound was purified through a silica plug eluting with dichloromethane, which afforded after evaporation 132 mg of 3-(4-chlorophenyl)-1-ethyl-quinoxaline-2(1H)-one as a solid. Yield: 59%.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9][CH:8]=2)=[CH:4][CH:3]=1.[Li]C(C)(C)C.CCCCC.CN([CH:33]=[O:34])C.C(=O)=O>C1COCC1.CCOCC>[CH3:1][C:2]1[S:6][C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:33]=[O:34])[CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C2=CCC(C)(C)c3ccc(Br)cc32)s1
Reactant: CN(C)C=O
Agent: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C=O)cc32)s1
Reaction time: 0.25 h

Procedure:
To a cold (-78° C.) solution of 1-(5-methyl-thien-2-yl)-3,4-dihydro-4,4-dimethyl-7-bromo-naphthalene (Compound F, 1.35 g, 4.1 mmol), in THF (20 mL) was added t-BuLi in pentane (1.7M solution, 3.5 mL, 5.95 mmol). The reaction was stirred for 15 minutes and DMF (600 mg, 5.8 mmol) was added and dry-ice cooling was replaced with ice-water bath. The mixture was stirred at ambient temperature for 4 hours. The reaction mixture was diluted with ether (70 mL) and washed with water (5 mL), brine (5 mL) and dried with MgSO4. Solvent was removed by distillation. The product was purified by silicagel chromatography to afford the title compound as a colorless oil.
Reaction SMILES: [OH-].[NH4+:2].[F:3][C:4]1[C:12]([F:13])=[C:11](F)[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].Cl>O>[NH2:2][C:11]1[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:3])[C:12]=1[F:13]
Reactant: [NH4+]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)c(F)c1F
Agent: Cl
Agent: [OH-]
Solvent: O
Product: Nc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.7 %

Procedure:
Ammonium hydroxide solution (˜30% in water) (35 mL, 271 mmol) is added to a solution of 2,3,4-trifluoro-5-nitro-benzoic acid 2 (15 g, 67.8 mmol) in 30 mL water at 0° C. with stirring. Upon completion of ammonium hydroxide addition the reaction mixture is warmed to room temperature with stirring. After 2.5 hours, the reaction mixture is cooled to 0° C. and concentrated HCl is carefully added until pH of reaction mixture is near 0. The reaction mixture is diluted with water (30 mL) and extracted with diethyl ether (3×50 mL). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give 14 g (95%) of pure desired product: MS APCI (−) m/z 217 (M−1) detected.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([CH:8]1[O:12][CH2:11][CH2:10][O:9]1)([CH3:7])[CH3:6].[C-]#[N:14].[Na+]>CS(C)=O.O>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:5]([CH3:7])([CH3:6])[CH2:4][CH2:3][C:2]#[N:14]
Reactant: CC(C)(CCCCl)C1OCCO1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(CCC#N)C1OCCO1
Temperature: 25 °C
Yield: 107.3 %

Procedure:
0.74 g (3.8 mmol) of 2-(4-chloro-1,1-dimethylbutyl)-1,3-dioxolane) and 0.50 g (7.7 mmol) of sodium cyanide in 5 mL of DMSO was heated to 100° C. with stirring. After 18 hours the solution was cooled to RT, diluted with water, and the mixture extracted with ether (3×). The combined ether extracts were washed with water. (3×), dried over MgSO4, and concentrated in vacuo to afford 0.69 g (90%) of the desired compound as a light yellow liquid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]2[C:4]([NH:15][CH2:16][C:17]([OH:19])=O)=[N:3]1.[NH2:20][CH:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=[C:5]2[C:4]([NH:15][CH2:16][C:17]([NH:20][CH:21]2[CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24]2)=[O:19])=[N:3]1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: Cn1nc(NCC(=O)O)c2cc(C(F)(F)F)cnc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cn1nc(NCC(=O)NC2CN(C(=O)OC(C)(C)C)C2)c2cc(C(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed 2-((1-methyl-5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)amino)acetic acid (as prepared in the previous step, 134 mg, 0.49 mmol) followed by DCM (20 mL), tert-butyl 3-aminoazetidine-1-carboxylate (104 mg, 0.60 mmol), EDCI (104 mg, 0.54 mmol) and HOBt (75 mg, 0.49 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo. The resulting residue was purified by flash chromatography (silica gel, 0-20% MeOH/ethyl acetate) to afford the title compound in sufficient purity to conduct the next step.