Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9](=[O:21])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[C:7]1[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=1[S:5]2.[CH2:26]([O:28][CH2:29][CH2:30][O:31][C:32]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O)[CH3:27].[O-]CC.[Na+]>C(O)C>[CH2:26]([O:28][CH2:29][CH2:30][O:31][C:32]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[CH:36][C:33]=1/[CH:34]=[CH:1]/[C:2]1[N:3]=[C:4]2[S:5][C:6]3[CH:25]=[CH:24][CH:23]=[CH:22][C:7]=3[N:8]2[C:9](=[O:21])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=1)[CH3:27]
Reactant: CCOCCOc1c(C=O)cccc1OC
Reactant: Cc1nc2sc3ccccc3n2c(=O)c1-c1ccc(C(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOCCOc1c(/C=C/c2nc3sc4ccccc4n3c(=O)c2-c2ccc(C(F)(F)F)cc2)cccc1OC
Yield: 45.5 %

Procedure:
The title compound was synthesized by condensation of Intermediate 23 (250 mg, 0.690 mmol) with 2-(2-ethoxyethoxy)-3-methoxybenzaldehyde (204 mg, 0.970 mmol) in presence of sodium ethoxide (94 mg, 1.380 mmol) in ethanol (15 ml) according to the procedure outlined in Example 24 to give 178 mg of the desired product as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 1.91 (t, J=6.9 Hz, 3H), 3.48-3.55 (m, 4H), 3.78 (s, 3H), 4.06 (br s, 2H), 6.81 (d, J=15.6 Hz, 1H), 6.92-6.94 (m, 1H), 7.00-7.02 (m, 1H), 7.55-7.57 (m, 2H), 7.61-7.64 (m, 2H), 7.84-7.87 (m, 2H), 8.07-8.09 (m, 1H), 8.23 (d, J=15.6 Hz, 1H), 8.84-8.87 (m, 1H); ESI-MS (m/z) 567.21 (M+H)+.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][N:12]([CH3:33])[CH:13]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]3[NH:24][C:25]([CH2:27][C:28]([O:30]CC)=O)=[N:26][C:21]3=[CH:20][CH:19]=2)[CH2:14]1.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]#[N:42]>C1COCC1>[NH2:42][C:41]1[C:36]2[C:35](=[CH:40][CH:39]=[CH:38][CH:37]=2)[NH:34][C:28](=[O:30])[C:27]=1[C:25]1[NH:24][C:22]2=[N:23][C:18]([N:15]3[CH2:16][CH2:17][CH:13]([N:12]([CH3:11])[CH3:33])[CH2:14]3)=[CH:19][CH:20]=[C:21]2[N:26]=1
Reactant: CCOC(=O)Cc1nc2ccc(N3CCC(N(C)C)C3)nc2[nH]1
Reactant: N#Cc1ccccc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)C1CCN(c2ccc3nc(-c4c(N)c5ccccc5[nH]c4=O)[nH]c3n2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
LiHMDS (3.5 eq) was added to ethyl {5-[3-(dimethylamino)pyrrolidin-1-yl]-3H-imidazo[4,5-b]pyridin-2-yl}acetate (1.0 eq) in THF at −40° C. After 10 minutes, a solution of 2-aminobenzenecarbonitrile (1.1 eq) in THF was added. The resulting mixture was allowed to warm to room temperature, stirred for 1 h and then heated to 60° C. overnight. The mixture was cooled to room temperature and quenched with NH4Cl (aq, saturated). The aqueous phase was extracted with CH2Cl2 (5 times). The product crashes out of the organic solution during the extractions. Evaporation of the solvent under reduced pressure afforded a brown solid that was triturated repeatedly with MeOH and acetone to obtain a yellow greenish powder. LC/MS m/z 390.2 (MH+), Rf 1.48 minutes.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(C(C)=O)C>[C:1]1([S:7][CH2:8][CH2:9][CH2:10][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCSc1ccccc1
Reactant: C1CNCCN1
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: c1ccc(SCCCN2CCNCC2)cc1

Procedure:
To 1000 ml methyl ethyl ketone are added 3-phenylthio-1-chloro-propane (1 mole), sodium iodide (1 mole) and anhydrous piperazine (4 moles). The resulting mixture is refluxed during 24 hours, with stirring, after which the solvent is evaporated in vacuo, the residue is taken up into water and ether. The ether phase is washed with water, dried and concentrated. The residue is distilled in vacuo. B.p. = 140° C./0.05 mm Hg. N.M.R.: consistent.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.P(CCCC)(CCCC)CCCC.[CH2:28]([CH:30]1[CH:34]([C:35]2[N:39]3[C:40]4[CH:46]=[CH:45][N:44]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[C:41]=4[N:42]=[CH:43][C:38]3=[N:37][N:36]=2)[CH2:33][CH:32](O)[CH2:31]1)[CH3:29].[F:56][C:57]([F:61])([F:60])[CH2:58][SH:59]>C1COCC1>[CH2:28]([CH:30]1[CH2:31][CH:32]([S:59][CH2:58][C:57]([F:61])([F:60])[F:56])[CH2:33][CH:34]1[C:35]1[N:39]2[C:40]3[CH:46]=[CH:45][N:44]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:52])([CH3:54])[CH3:53])[C:41]=3[N:42]=[CH:43][C:38]2=[N:37][N:36]=1)[CH3:29]
Reactant: CCC1CC(O)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Reactant: FC(F)(F)CS
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCC1CC(SCC(F)(F)F)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.2 %

Procedure:
An oven-dried flask was charged with DIAD (0.177 mL, 0.896 mmol) and THF (3.74 mL). The reaction flask was cooled to 0° C. before the addition of P(n-Bu)3 (0.221 mL, 0.896 mmol), 3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol (0.300 g, 0.747 mmol, prepared from Preparation #20 using KK and SS), TEA (0.125 mL, 0.896 mmol) and 2,2,2-trifluoroethanthiol (0.080 mL, 0.896 mmol). The reaction was stirred at ambient temperature for about 16 h. The reaction mixture was partitioned between water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concd under reduced pressure to afford a crude oil. The crude material was purified by silica gel chromatography eluting with a gradient of 0-60% EtOAc in DCM to afford 1-(2-ethyl-4-(2,2,2-trifluoroethylthio)cyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.165 g, 44%) as an orange solid: LC/MS (Table 1, Method a) Rt=3.02 min; MS m/z: 500 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:12][C:11](=[O:13])[NH:10][C@@H:9]2[C:14]2[C:15]([O:28][CH3:29])=[N:16][CH:17]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=2)[CH:5]=[CH:6][CH:7]=1.[F:30]C1C=CC(F)=CC=1[C@H]1OC(=O)N[C@@H]1C1C(F)=NC=C(C#CC2C=CC=CC=2)C=1>>[F:30][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C@H:8]1[O:12][C:11](=[O:13])[NH:10][C@@H:9]1[C:14]1[C:15]([O:28][CH3:29])=[N:16][CH:17]=[C:18]([C:20]#[C:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=1
Reactant: O=C1N[C@H](c2cc(C#Cc3ccccc3)cnc2F)[C@@H](c2cc(F)ccc2F)O1
Reactant: COc1ncc(C#Cc2ccccc2)cc1[C@H]1NC(=O)O[C@@H]1c1cccc(F)c1
Product: COc1ncc(C#Cc2ccccc2)cc1[C@H]1NC(=O)O[C@@H]1c1cc(F)ccc1F

Procedure:
Prepared according to the same procedure as (4R,5R)-5-(3-fluorophenyl)-4-(2-methoxy-5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one, starting with ((4R,5R)-5-(2,5-difluorophenyl)-4-(2-fluoro-5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one. 1H NMR (CDCl3) δ: 8.33 (d, J=2.1 Hz, 1H), 7.83 (d, J=1.8 Hz, 1H), 7.50-7.54 (m, 2H), 7.33-7.38 (m, 3H), 7.20-7.25 (m, 1H), 7.03-7.10 (m, 2H), 6.06 (s, 1H), 5.54 (d, J=5.2 Hz, 1H), 4.98 (d, J=5.2 Hz, 1H), 3.88 (s, 3H). 19F NMR (CDCl3) δ: −119.97-115.26 (m, 1F), −123.84 (br. s., 1F). Mass spec.: 407.1 (MH)+.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][CH:15]=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5].[C:25](Cl)(=[O:27])[CH3:26]>CN(C=O)C>[C:25]([N:14]1[CH:15]=[CH:16][C:17]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:13]1[C:10]1[CH:9]=[CH:8][C:7]([S:4]([CH3:3])(=[O:5])=[O:6])=[CH:12][CH:11]=1)(=[O:27])[CH3:26]
Reactant: CS(=O)(=O)c1ccc(-c2[nH]ccc2-c2ccc(F)cc2)cc1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)n1ccc(-c2ccc(F)cc2)c1-c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
A suspension of sodium hydride (2.64 g, 0.11 mole) in 100 ml dry N,N'-dimethylformamide was heated dropwise with a solution of 2-(4-methylsulfonylphenyl)-3-(4-fluorophenyl)-1H-pyrrole (31.56 g, 0.1 mole) in 200 ml dry N,N'-dimethylformamide and stirred for one hour at room temperature. The mixture was then treated dropwise with acetyl chloride (7.9 g, 0.1 mole). The mixture was stirred for three hours and concentrated in vacuo. The residue was triturated with water, collected by filtration, dried, and column chromatographed on silica gel with toluene-ethyl acetate (3:2) as the mobile phase. The product was collected in 25% yield; m.p. 211°-214°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]3=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=[C:14]3[CH:13]([CH3:23])[C:12]2=[O:24])[CH:5]=1)([O-])=O>C(OCC)(=O)C.[Ni]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]3=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=[C:14]3[CH:13]([CH3:23])[C:12]2=[O:24])[CH:5]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1C(=O)c2cc(Cl)ccc2C(C)C1=O
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1N1C(=O)c2cc(Cl)ccc2C(C)C1=O

Procedure:
The solution of 0.5 g of N-(4-nitro-o-tolyl)-4-chloro-α-methylhomophthalimide in 120 ml of ethyl acetate is hydrogenated over 2.0 g of Raney nickel (washed with water and ethanol) at 2.5 atm. and room temperature for 5 hours. It is filtered and the filtrate evaporated, to yield the N-(4-amino-o-tolyl)-4-chloro-α-methylhomophthalimide of the formula ##STR8## showing in the I.R.-spectrum bands at 1665 and 1710cm-1 and in the mass-spectrum the ion of 314/316.
Reaction SMILES: [O:1]1[CH2:19][CH:2]1[CH2:3][O:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8].[CH:20]([NH2:23])([CH3:22])[CH3:21]>>[OH:1][CH:2]([CH2:19][NH:23][CH:20]([CH3:22])[CH3:21])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8]
Reactant: COC(=O)CCC(=O)c1ccccc1OCC1CO1
Reactant: CC(C)N
Product: COC(=O)CCC(=O)c1ccccc1OCC(O)CNC(C)C
Yield: 101.7 %

Procedure:
A stirred mixture of methyl 3-[2-(2,3-epoxypropoxy)benzoyl]propionate (8.3 g, 0.031 mole), and isopropylamine (16.4 ml, 0.19 mole) was heated under reflux for 90 minutes. Evaporation of the solution under reduced pressure gave methyl 3-[2-(2-hydroxy-3-isopropylaminopropoxy)benzoyl]-propionate (10.2 g, 100%) as a pale brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][NH:21][O:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][NH:21][O:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CONCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CONCc1nc2c(N)nc3cc(-c4cccnc4)cnc3c2n1CC(C)(C)O
Temperature: 25 °C
Yield: 28.5 %

Procedure:
A stream of nitrogen was bubbled through a stirring suspension of 1-{4-amino-7-bromo-2-[(methoxyamino)methyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl}-2-methylpropan-2-ol (0.590 g, 1.49 mmol),3-pyridineboronic acid (0.220 g, 1.79 mmol), and potassium carbonate (0.681 g, 4.93 mmol) in ethylene glycol dimethyl ether (10 mL) and water (5 mL) in a pressure vessel for 5 minutes. Dichlorobis(triphenylphosphine)palladium(III) (0.031 g, 0.045 mmol) was added and nitrogen was bubbled through for an additional 5 minutes. The pressure vessel was capped and placed in a 110° C. oil bath for 10 minutes. The resulting solution was cooled to ambient temperature and concentrated. The residue was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 5-25% 1M ammonia/methanol in dichloromethane). The resulting yellow solid was crystallized from acetonitrile and isolated by filtration to yield 167 mg of 1-{4-amino-2-[(methoxyamino)methyl]-7-(pyridin-3-yl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl}-2-methylpropan-2-ol as a light yellow solid, mp 195-197° C.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][C:7]1([CH3:24])[CH2:15][C:14]2[NH:13][CH:12]=[C:11]([CH2:16][CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[C:10]=2[CH2:9][CH2:8]1.CN([CH:28]=[O:29])C>>[CH2:20]([N:19]([CH2:22][CH3:23])[CH2:18][CH2:17][CH2:16][C:11]1[C:10]2[CH2:9][CH2:8][C:7]([CH3:6])([CH3:24])[CH2:15][C:14]=2[NH:13][C:12]=1[CH:28]=[O:29])[CH3:21]
Reactant: CCN(CC)CCCc1c[nH]c2c1CCC(C)(C)C2
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CC)CCCc1c(C=O)[nH]c2c1CCC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
POCl3 (0.35 mL, 3.74 mmol) was added dropwise to DMF (0.8 mL, 10.3 mmol) at −5° C. After stirring at room temperature for 30 min, the mixture was cooled to −5° C. A solution of [3-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-diethylamine (0.9 g, 3.4 mmol) in DMF (2 mL) was then added dropwise. The mixture was stirred at room temperature for 3 hours and then quenched with ice, followed by 10 N KOH to adjust pH to 10-11. After stirring at room temperature for 1 hour, the mixture was extracted with EtOAc, washed with brine, dried and concentrated to give 0.55 g 3-(3-diethylaminopropyl)-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde.
Reaction SMILES: C(O[C:9](=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([F:18])[CH:12]=1)C1C=CC=CC=1.[C:20]([O:25][CH2:26][C@H:27]1[O:29]C1)(=[O:24])CCC>>[F:18][C:13]1[CH:12]=[C:11]([N:10]2[CH2:9][C@@H:26]([CH2:27][OH:29])[O:25][C:20]2=[O:24])[CH:16]=[CH:15][C:14]=1[CH3:17]
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)cc1F
Reactant: CCCC(=O)OC[C@@H]1CO1
Product: Cc1ccc(N2C[C@@H](CO)OC2=O)cc1F

Procedure:
Starting from (3-fluoro-4-methyl-phenyl)-carbamic acid benzyl ester (prepared from 3-fluoro-4-methyl-aniline and CbzCl according to procedure C) and (S)-glycidyl butyrate and following the procedure described for the preparation of intermediate 1.iii)(procedure D), the title compound was obtained as a yellow solid (4.16 g, 65%).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1[N:4]([C:9](=[O:13])[CH2:10][O:11][CH3:12])[CH2:5][C:6]([CH3:8])=O.Cl.[CH3:20][O:21][NH2:22].C(N(CC)CC)C>C(O)C>[CH3:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1[N:4]([CH2:5][C:6](=[N:22][O:21][CH3:20])[CH3:8])[C:9](=[O:13])[CH2:10][O:11][CH3:12]
Reactant: CON
Reactant: COCC(=O)N(CC(C)=O)c1c(C)cccc1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COCC(=O)N(CC(C)=NOC)c1c(C)cccc1C
Yield: 94.3 %

Procedure:
20 g (0.08 mol) of 2,6-dimethyl-N-methoxyacetyl-N-acetonylaniline, 7.5 g (0.09 mol) of O-methyl-hydroxylamine hydrochloride and 9.1 g (0.09 mol) of triethylamine in 100 ml of ethanol were heated under reflux for 5 hours. After distilling off the solvent in vacuo, the residue was partitioned between water/methylene chloride. The organic phase was separated off, dried over sodium sulphate and concentrated. After adding petroleum ether, the residue crystallized. 21 g (94% of theory) of 2,6-dimethyl-N-(2-methoxyimino-prop-1-yl)-N-methoxyacetylaniline of melting point 56°-57° C. were obtained.
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH:6]1C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:4].[ClH:30]>C(O)C.C(OCC)(=O)C>[ClH:30].[ClH:30].[OH:1][CH2:2][CH:3]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH3:4]
Reactant: CC(CO)N1CCNCC1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(CO)N1CCNCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
1-(1-Hydroxy-2-propyl)-2-triphenylmethylpiperazine (1.69 g) obtained in step 2 was dissolved in ethanol (20 ml), and a 4 mol/l hydrogen chloride solution in ethyl acetate (10 ml) was dropwise added thereto. The mixture was stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure, the residue was suspended in ethyl ether, and the precipitated crystals were collected by filtration to give Compound L (840 mg, 89%).
Reaction SMILES: [Si]([O:8][C:9]1([C:12]2[CH:24]=[C:23]3[C:15]([C:16]4[C:17]([C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([N:34]6[CH2:42][C:41]7[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=7)[C:35]6=[O:43])[C:29]=5[CH3:44])=[CH:18][CH:19]=[C:20]([C:25]([NH2:27])=[O:26])[C:21]=4[NH:22]3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][C:9]1([C:12]2[CH:24]=[C:23]3[C:15]([C:16]4[C:17]([C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([N:34]6[CH2:42][C:41]7[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=7)[C:35]6=[O:43])[C:29]=5[CH3:44])=[CH:18][CH:19]=[C:20]([C:25]([NH2:27])=[O:26])[C:21]=4[NH:22]3)=[CH:14][CH:13]=2)[CH2:10][CH2:11]1
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(C5(O[Si](C)(C)C(C)(C)C)CC5)ccc4c23)cccc1N1Cc2ccccc2C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(C5(O)CC5)ccc4c23)cccc1N1Cc2ccccc2C1=O
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
Step 4 A solution of 7-(1-(tert-butyldimethylsilyloxy)cyclopropyl)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (0.039 g, 0.065 mmol) in THF (0.66 mL) was treated with tetra-n-butylammonium fluoride (1 M in THF, 0.098 mL, 0.098 mmol). After 10 min, the mixture was combined with an identical reaction mixture done on 22% of the scale described, and the mixture was concentrated. The residue was purified by preparative HPLC. The appropriate effluent fractions were treated with NaHCO3 (aq) and partially concentrated. The aqueous residue was extracted three times with DCM and the combined organic phases were dried and concentrated to give 7-(1-hydroxycyclopropyl)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide as a white solid (23.3 mg, 60%). 1H NMR (500 MHz, DMSO-d6) δ 11.42 (1H, s), 8.18 (1H, br. s.), 7.98 (1H, d, J=7.7 Hz), 7.80 (1H, d, J=7.7 Hz), 7.72 (1H, s), 7.68 (2H, d, J=3.8 Hz), 7.60 (1H, d, J=7.7 Hz), 7.56 (1H, ddd, J=7.8, 4.1, 4.0 Hz), 7.49 (2H, t, J=7.7 Hz), 7.33 (1H, d, J=7.1 Hz), 7.01 (1H, d, J=7.7 Hz), 6.95 (1H, d, J=8.2 Hz), 6.79 (1H, d, J=8.2 Hz), 5.95 (1H, s), 4.90-5.02 (2H, m), 1.84 (3H, s), 1.07-1.15 (2H, m), 0.91-1.00 (2H, m). Mass spectrum m/z 488.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Br[C:13]([CH3:16])([CH3:15])[CH3:14].CO.[OH-].[K+]>CS(O)(=O)=O>[C:13]([C:11]1[CH:10]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)Br
Reactant: COC(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc(O)c(C(C)(C)C)c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Methyl 4-hydroxybenzoate (3.00 g) was dissolved in methanesulfonic acid (15 mL), and 2-bromo-2-methylpropane (11.1 mL) was added to the solution, and then the mixture was stirred at 70° C. for 16 hours. To the reaction solution, methanol (20 mL) was added, and then the reaction mixture was stirred at 50° C. for 3 hours. 1N potassium hydroxide was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous 10% potassium carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain the title compound (1.83 g) as a pale yellow crystal.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:11])[O:10][C:5]2=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:20]=[N:21][C:22]([C:25]3[CH:26]=[C:27]([CH2:31]O)[CH:28]=[CH:29][CH:30]=3)=[N:23][CH:24]=2)[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:31][C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([C:22]4[N:23]=[CH:24][C:19]([N:16]5[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]5)=[CH:20][N:21]=4)[CH:26]=3)[C:9](=[O:11])[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc2oc(=O)[nH]c2n1
Reactant: CN1CCN(c2cnc(-c3cccc(CO)c3)nc2)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc2oc(=O)n(Cc3cccc(-c4ncc(N5CCN(C)CC5)cn4)c3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
67 mg (0.44 mmol) of 5-methyl-3H-oxazolo[4,5-b]pyridin-2-one and 125 mg (0.44 mmol) of {3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]phenyl}methanol are suspended in 5 ml of DMF with 222 mg (0.67 mmol) of polymer-bound triphenylphosphine (about 3 mmol of triphenylphosphine per g), and the mixture is shaken at room temperature for 30 min. 156 mg (0.67 mmol) of di-tert-butyl azodicarboxylate are added. The reaction mixture is shaken at room temperature for 15 h. The reaction mixture is filtered, the residue is evaporated, and the residue is purified by column chromatography on silica gel, giving 67 mg of “A125”; HPLC: Rt=2.26 min (method B); ESI: 418 (M+H);
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[C:24]3[CH2:23][CH2:22][N:21]([CH3:25])[CH2:20][C:19]=3[CH:18]=[N:17][CH:16]=2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]3[C:24]=2[CH2:23][CH2:22][N+:21]([O-:34])([CH3:25])[CH2:20]3)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: CN1CCc2c(cncc2NC(=O)c2c(N)nn3cc(F)cnc23)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[N+]1([O-])CCc2c(cncc2NC(=O)c2c(N)nn3cc(F)cnc23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-amino-6-fluoro-N-(7-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (12 mg, 0.03516 mmol) in DCM (2 mL) was added mCPBA (5.764 mg, 0.03340 mmol) and the mixture was stirred at RT for 2 h before the solvent was removed in vacuo. The residue was purified by FractionLynx to yield 5-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-2-methyl-1,2,3,4-tetrahydro-2,7-naphthyridine 2-oxide. MS (ES+) 358.2.
Reaction SMILES: FC1C=C(C=CC=1)[O:5]C1N=C(CO)C=CC=1.[CH:17]([CH:20]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:21](Cl)=[O:22])([CH3:19])[CH3:18].C(N(CC)CC)C>CCOCC>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH:20]([CH:17]([CH3:19])[CH3:18])[C:21]([OH:5])=[O:22])=[CH:25][CH:26]=1
Reactant: OCc1cccc(Oc2cccc(F)c2)n1
Reactant: CC(C)C(C(=O)Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)C(C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 1.8 grams (0.0078 mole) of cyano(6-(3-fluorophenoxy)-2-pyridine methanol and 2.4 grams (0.0098 mole) of 2-isopropyl-2-(4-chlorophenyl)-acetic acid chloride in 50 milliliters of anhydrous ether was added 3 milliliters of triethylamine. A white precipitate separated out immediately. The reaction mixture was stirred at room temperature for one-half (1/2) hour. The mixture was successively washed with water, dilute hydrochloric acid, dilute sodium hydroxide, dilute sodium bicarbonate, dilute hydrochloric acid and water and thereafter dried over anhydrous magnesium sulfate and concentrated under vacuo to give 3.6 grams of 4-chloro-α-(1-methylethyl)benzeneacetic acid:cyano(6-(3-fluorophenoxy)-2-pyridinyl)methyl ester product as a viscous yellow oil having a refractive index of nD25 =1.5560. The structure of the product was confirmed by its nuclear magnetic resonance spectrum (NMR). In addition, upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 65.52, 4.74 and 6.18 percent, respectively, as compared with theoretical contents of 65.66, 4.59 and 6.38 percent, respectively, as calculated for the above-named compound (Compound No. 3).