Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.Br[CH2:19][CH2:20][CH2:21][Cl:22]>O1CCCC1>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:19][CH2:20][CH2:21][Cl:22])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: ClCCCBr
Reactant: CC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC1CCN(CCCCl)CC1

Procedure:
A mixture of 4-acetamidopiperidine (1.4 g; preparation 14), triethylamine (3.56 ml) and 1-bromo-3-chloropropane (1.45 ml) in 50 ml of tetrahydrofuran was refluxed overnight, then an additional 3.5 ml of triethylamine and 1.45 ml of 1-bromo-3-chloropropane were added. After a further 3 hours at reflux, the mixture was concentrated to a small volume, treated with chloroform and washed with aqueous saturated solution of potassium carbonate. The organic phase was dried over sodium sulfate, concentrated to dryness and the residue (2.3 g of a green oil) was purified by silica gel chromatography (eluent chloroform/methanol 9:1) to give 0.67 g of the product, m.p. 74-77° C.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.Cl.[NH2:11][CH2:12][CH2:13][C:14]1[N:15]=[CH:16][N:17]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)([CH3:25])[CH3:24])[CH:18]=1.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]([NH:22][CH2:21][CH2:20][CH2:19][N:17]2[CH:18]=[C:14]([CH2:13][CH2:12][NH:11][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:15]=[CH:16]2)([CH3:25])[CH3:24])=[CH:27][CH:28]=1
Reactant: CC(C)(NCCCn1cnc(CCN)c1)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NCCCn1cnc(CCNC(=O)c2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
Triethylamine (0.46 g) was added to a stirred suspension of 3-[4-(2-aminoethyl)imidazol-1-yl]-N-[1-(4-chlorophenyl)-1-methylethyl]propylamine trihydrochloride, (0.65 g) in dichloromethane (25 ml) and the resulting solution cooled to 0° C. A solution of benzoyl chloride (0.21 g) in dichloromethane (10 ml) was added over 20 minutes at 0-5° C. with stirring. The mixture was stirred at ambient temperature for 2.5 hours. The solution was washed with sodium bicarbonate solution, then water, then dried, filtered and evaporated to give N-[2-(1-{3-[1-(4-chlorophenyl)-1-methylethylamino]propyl}imidazol-4-yl)ethyl]benzamide as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](Cl)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]([O:16][C:17]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].COCCOC>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]([O:16][C:17]([C:19]1[CH:24]=[C:23]([C:9]2[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([Cl:1])[N:10]=2)[CH:22]=[CH:21][CH:20]=1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)c1cccc(B(O)O)c1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)c1cccc(-c2ccc(C(=O)O)c(Cl)n2)c1
Temperature: 90 °C
Yield: 67.1 %

Procedure:
2,6-Dichloronicotinic acid (1.20 g, 6.25 mmol), 3-(tert-butoxycarbonyl)benzene boronic acid (2.08 g, 9.10 mmol), potassium carbonate (2.60 g, 18.8 mmol), tetrakis(triphenylphosphine)palladium (0.72 g, 0.62 mmol), degassed 1,2-dimethoxyethane (30 mL) and water (0.5 mL) were combined under an argon atmosphere and the mixture heated at 90° C. overnight. The reaction mixture was then cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (2×150 mL). The aqueous layer was acidified to pH 3-4 using 2N HCl solution and extracted with ethyl acetate (2×200 mL). The combined organic portions were dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 20% methanol/dichloromethane) and the product containing fractions concentrated to give a solid, which was triturated with 2:1 heptane/ethyl acetate to give pure 6-(3-(tert-butoxycarbonyl)phenyl)-2-chloronicotinic acid (1.4 g, 67%) as an off-white foam. 1H NMR (400 MHz, CD3OD) δ ppm 8.64 (s, 1H), 8.34 (d, 1H), 8.29 (d, 1H), 8.04 (d, 1H), 7.95 (d, 1H), 7.59 (t, 1H), 1.60 (s, 9H); m/z 334 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:19][OH:20])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:33][C:34]([F:37])([F:36])[F:35])(=O)=O.O>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:9](=[N:19][O:20][CH2:33][C:34]([F:37])([F:36])[F:35])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCC(=NO)c1ncc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=NOCC(F)(F)F)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.4 %

Procedure:
To 5.0 g of tert-butyl N-[2-(3,5-dichloropyridin-2-yl)-2-(hydroxyimino)ethyl]carbamate in 16.0 ml of N,N-dimethylformamide, 4.3 g of potassium carbonate and 5.4 g of 2,2,2-trifluoroethyl trifluoromethanesulfonate were added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 100 ml of water and extracted with ethyl acetate (100 ml×2), the resulting organic layers were combined, washed with water (50 ml×2) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 0:10 to 3:7) as the eluent to obtain 4.8 g of the desired product as a pale yellow oil.
Reaction SMILES: [CH:1]1(F)[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]1O.C(C1C(C(C)(C)C)=NC=CC=1)(C)(C)C.CC[O:28]CC>Cl([O-])(=O)(=O)=O.[Ag+]>[O:9]1[C@H:8]([CH2:10][OH:28])[C@H:6]([OH:7])[C@H:4]([OH:5])[CH:2]=[CH:1]1
Reactant: CCOCC
Reactant: C[C@@H]1OC(F)[C@@H](O)[C@H](O)[C@@H]1O
Agent: [Ag+]
Agent: CC(C)(C)c1cccnc1C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: OC[C@H]1OC=C[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To 2.00 g (2.47 mmol) of lactal carbonate 8c was added 4.44 g (9.86 mmol) of fucosyl fluoride 9c. The mixture was azeotroped 5 times with benzene and placed under high vacuum for two hours. Under an argon atmosphere 2.77 mL (12.33 mmol) of di-tert-butyl pyridine and 16 mL of dry ether were added. 2.0 g of freshly activated 4 Å molecular sieves were added and the mixture stirred one hour at room temperature. In an argon glove bag, 2.34 g (12.33 mmol) of stannous chloride (SnCl2) and 2.56 g (12.33 mmol) of silver perchlorate (AgClO4) were added. The flask was equipped with a reflux condenser and the reaction brought to reflux for 72 hours. The reaction was quenched with 5 mL of saturated bicarbonate and filtered through a pad of celite. Diluted with 50 mL ethyl acetate and washed 2 times with saturated bicarbonate, 2 times with sat. copper sulfate and 2 times with sat. brine. The organics were dried over MgSO4 and concentrated. Flash chromatography in 20% ethyl acetate/hexanes afforded 2.10 g (51%) of a white foam 10 c:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@@H:5]1[N:10]2[C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([NH2:21])[C:12]=3[N:22]=[C:9]2[CH2:8][O:7][CH2:6]1.C(N(CC)CC)C.[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32]>C(Cl)Cl>[NH2:21][C:13]1[C:12]2[N:22]=[C:9]3[CH2:8][O:7][CH2:6][C@H:5]([CH2:4][CH2:3][CH2:2][NH:1][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[N:10]3[C:11]=2[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: NCCC[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)NCCC[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Temperature: 0 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
(11S)-11-(3-Aminopropyl)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (190 mg, 0.640 mmol) was dissolved in 8 mL of CH2Cl2 and the reaction mixture was cooled to 0° C. under N2. Triethylamine (356 μL, 2.56 mmol) was added followed by iso-butyryl chloride (67 μL, 0.643 mmol). After stirring overnight, the reaction mixture was diluted with 20 mL of CH2Cl2 and was washed successively with saturated NaHCO3 solution, H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 10% methanol/CHCl3) gave a white solid. Crystallization from ethyl acetate gave N-{3-[(11S)—6-amino-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propyl}-2-methylpropanamide (80 mg) as a white solid, mp 207-208° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[NH2:12]/[C:13](/[C:20]([F:23])([F:22])[F:21])=[CH:14]\[C:15](OCC)=[O:16].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:15](=[O:16])[CH:14]=[C:13]([C:20]([F:23])([F:22])[F:21])[NH:12][C:10]2=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)cc1
Reaction time: 1 h
Yield: 58.8 %

Procedure:
A stirred solution of 6.0 grams (0.0268 mole) of 4-methoxyphenyl isocyanate, 5.16 grams (0.028 mole) of ethyl 3-amino-4,4,4-trifluorocrotonate, and 4.45 grams (0.032 mole) of potassium carbonate in 40 mL of N,N-dimethylformamide was heated to 140° C. where it stirred for one hour. After this time, the reaction mixture was poured into 100 mL of 10% aqueous hydrochloric acid. The resulting mixture was stirred for ten minutes and then extracted with three 50 mL portions of ethyl acetate. The combined ethyl acetate extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield a black solid. This black solid was purified by flash chromatography, yielding 4.51 grams of 3-(4-methoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7](=[O:9])[CH3:8])([CH3:5])[CH3:4].N[C:11]1(CO)CCC[CH2:12]1.CC#N.O.CC#N>O>[OH:1][CH2:2][C:3]1([NH:6][C:7](=[O:9])[CH3:8])[CH2:5][CH2:12][CH2:11][CH2:4]1
Reactant: CC(=O)NC(C)(C)CO
Reactant: NC1(CO)CCCC1
Solvent: O
Solvent: CC#N
Product: CC(=O)NC1(CO)CCCC1

Procedure:
The title compound is prepared analogously as described for N-(2-hydroxy-1,1-dimethyl-ethyl)-acetamide from (1-amino-cyclopentyl)-methanol. MS (LC-MS): [M+H]+=158.2. tR (HPLC, Waters sun fire C18 column, 5-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.8 mL/min): 1.76 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1([CH3:41])[CH2:31][CH2:30][CH2:29][C:28]2[CH:27]=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=[CH:24][C:23]1=2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([C:26]3[CH:25]=[CH:24][C:23]4[C:22]([CH3:41])([CH3:21])[CH2:31][CH2:30][CH2:29][C:28]=4[CH:27]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)n2)CC1
Reactant: CC1(C)CCCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(-c3ccc4c(c3)CCCC4(C)C)n2)CC1

Procedure:
The preparation is carried out analogously to FS 102 starting from 4-(4-chloro-1,3,5-triazin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (US 2005/59668) and 2-(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:17][O:18][C:19](=[O:31])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29]Br)[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:17][O:18][C:19](=[O:31])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][NH:14][CH:11]2[CH2:12][CH2:13][N:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:16]=[CH:15][C:5]=4[N:6]=3)[CH2:10]2)[CH:22]=1
Reactant: NC1CCN(c2nc3ccc(Cl)cc3s2)C1
Reactant: COC(=O)Cc1cccc(OCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)Cc1cccc(OCCNC2CCN(c3nc4ccc(Cl)cc4s3)C2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
A mixture of 1-(6-chlorobenzothiazole-2-yl)pyrrolidine-3-ylamine (190 mg), [3-(2-bromoethoxy)phenyl]acetic acid methyl ester (205 mg) and potassium carbonate (114 mg) was stirred at 80° C. for 2 hours. To the reaction solution, was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (174 mg). Yield: 52%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[Cl:15][C:16]1[CH:17]=[C:18]([NH2:29])[CH:19]=[CH:20][C:21]=1[S:22][C:23]1[N:24]([CH3:28])[CH:25]=[CH:26][N:27]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:15][C:16]1[CH:17]=[C:18]([NH:29][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:13]#[N:14])[CH:19]=[CH:20][C:21]=1[S:22][C:23]1[N:24]([CH3:28])[CH:25]=[CH:26][N:27]=1
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Reactant: N#Cc1cnc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3cc(F)ccc23)cc1Cl

Procedure:
Following the procedure of Example 1, a mixture of 1.2 g (5.81 mmol) 4-chloro-7-fluoro-3-quinolinecarbonitrile, 1.53 g (6.39 mmol) of 3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)phenylamine and 0.671 g (5.81 mmol) of pyridine hydrochloride are refluxed in 2-ethoxyethanol (12 mL) at 120° C. for 45 minutes to yield 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-7-fluoroquinoline-3-carbonitrile as an off-white solid, mp 268-272° C.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH:13]([OH:23])[CH2:14][NH:15][CH:16]([CH3:22])[CH2:17][CH2:18][C:19](O)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:24]([NH:28][C:29](=[O:37])[CH2:30]CCCC(=O)C)[CH2:25][CH2:26][CH3:27].C([BH3-])#N.[Na+]>CO>[CH2:24]([NH:28][C:29](=[O:37])[CH2:30][CH2:19][CH2:18][CH2:17][CH:16]([NH:15][CH2:14][CH:13]([OH:23])[CH2:12][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:22])[CH2:25][CH2:26][CH3:27]
Reactant: CC(CCC(=O)O)NCC(O)COc1cccc2ccccc12
Reactant: CCCCNC(=O)CCCCC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCNC(=O)CCCCC(C)NCC(O)COc1cccc2ccccc12

Procedure:
The title compound was synthesized by the method given for Compound 7 using the following quantities: Compound V (R=1-naphthyl) (0.177 g, 0.5 mmol), 6-oxoheptanoic acid n-butylamide (0.100 g, 0.5 mmol), sodium cyanoborohydride (0.32 g, 0.5 mmol), methanol (2 ml). Purification of a portion of the product after extraction was achieved by semipreparative high pressure liquid chromatography using a C18 column, 1.3 ml/min flow rate with 64% methanol/0.01N hydrochloric acid as eluant. The appropriate fractions were combined, the solvent evaporated under reduced pressure and the residue lyophilized from methanol/water to give 13.8 mg of the hydrochloride salt of the desired compound. The purity of the product was verified by HPLC (1.2 ml/min, 64% methanol/0.01N hydrochloric acid, ret. time=20 min).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH:4]([N:16]1[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]1=[O:26])[CH2:5][CH2:6][C:7]2=[O:15].FC1C=CC([N+]([O-])=O)=C2C=1C(N1C(=O)C3C(=CC=CC=3)C1=O)CCC2=O>>[NH2:12][C:9]1[CH:10]=[CH:11][C:2]([CH3:1])=[C:3]2[C:8]=1[C:7](=[O:15])[CH2:6][CH2:5][CH:4]2[N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]
Reactant: Cc1ccc([N+](=O)[O-])c2c1C(N1C(=O)c3ccccc3C1=O)CCC2=O
Agent: O=C1CCC(N2C(=O)c3ccccc3C2=O)c2c(F)ccc([N+](=O)[O-])c21
Product: Cc1ccc(N)c2c1C(N1C(=O)c3ccccc3C1=O)CCC2=O

Procedure:
The reaction was carried out in the same manner as in Example 13-(10), except that 145 mg of the compound prepared in (2) above was used instead of 5-fluoro-8-nitro-4-(1,3-dioxoisoindoline-2-yl)-1-tetralone of Example 13-(10). The reaction product was post-treated to produce 753 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:11]1([C:17]#[C:18][C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[CH:9][CH:10]=3)[CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1cnc2ccnn2c1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C(#Cc1cnc2ccnn2c1)c1ccccc1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Bis-(triphenylphosphine)-palladium (II) dichloride (27 mg, 0.04 mmol) was dissolved in 1 ml of THF. 6-Bromo-pyrazolo[1,5-a]pyrimidine (150 mg, 0.76 mmol) and phenylacetylene (130 μl, 1.21 mmol) were added at room temperature. Triethylamine (310 μl, 2.3 mmol), triphenylphosphine (6 mg, 0.023 mmol) and copper (I) iodide (4 mg, 0.023 mmol) were added and the mixture was stirred for 2 hours at 65° C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with heptane:ethyl acetate 100:0->50:50. The desired compound was obtained as a yellow solid (150 mg, 90% yield), MS: m/e=220.3 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:16])[CH2:4][NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1.[CH2:17]([N:19]1[C:31]2[CH:30]=[CH:29][C:28]([C:32](O)=[O:33])=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([C:6]([NH:5][CH2:4][CH:3]([CH3:16])[CH2:2][NH:1][C:32]([C:28]2[CH:29]=[CH:30][C:31]3[N:19]([CH2:17][CH3:18])[C:20]4[C:25]([C:26]=3[CH:27]=2)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:33])=[O:15])=[CH:8][CH:9]=1)#[N:14]
Reactant: CC(CN)CNC(=O)c1ccc(C#N)cc1
Reactant: CCn1c2ccccc2c2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c2ccccc2c2cc(C(=O)NCC(C)CNC(=O)c3ccc(C#N)cc3)ccc21
Yield: 50.1 %

Procedure:
A solution of the compound obtained in Step 2 (198 mg, 0.91 mmol), 9-ethyl-9H-carbazole-3-carboxylic acid (218 mg, 0.91 mmol), HATU (450 mg, 1.18 mmol) and TEA (0.381 mL, 2.73 mmol) in DMF (4.5 mL) was stirred at room temperature for 16 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20 to 100% ethyl acetate/hexane) to give the title compound (200 mg, 0.456 mmol, 50.0%) as a white powder.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]4[CH2:23][N:22]([C:24](OC(C)(C)C)=O)[CH2:21][CH2:20][O:19][C:15]4=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)([C:33](F)(F)[F:34])=O.C(N(CC)CC)C.FCCI>C(Cl)Cl>[F:34][CH2:33][CH2:24][N:22]1[CH2:23][C:14]2=[C:13]3[C:18](=[CH:17][CH:16]=[C:15]2[O:19][CH2:20][CH2:21]1)[N:10]([S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])[CH:11]=[CH:12]3
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2C1
Agent: FCCI
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)n1ccc2c3c(ccc21)OCCN(CCF)C3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 8-(phenylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 17, 16 mg, 0.040 mmol) was dissolved in DCM (1 mL) and TFA (0.5 mL) was added. The reaction mixture was heated to reflux, and immediately allowed to cool to room temperature. The solution was evaporated and the residue was dissolved in DMF (0.5 mL). Triethylamine (0.011 mL, 0.080 mmol) was added and the reaction mixture was stirred for 5 minutes before 1-fluoro-2-iodoethane (0.063 mL, 0.080 mmol) was added. The solution was stirred at 60° C. overnight. The solution was evaporated and the crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (6.9 mg). MS m/z 375 [M+H]+.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([C:25](=[O:27])[CH3:26])[CH:17]2[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18]2)[CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([C:25](=[O:27])[CH3:26])[CH:17]2[CH2:22][CH2:21][C:20]([CH3:23])([CH3:24])[CH2:19][CH2:18]2)[CH2:13][C@H:9]1[C:10]([N:41]1[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]1)=[O:11])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(=O)N(C1CCC(C)(C)CC1)[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C1CCC(C)(C)CC1)[C@H]1C[C@@H](C(=O)N2CCN(C)CC2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
(4S)-1-BOC-4-[acetyl(4,4-dimethylcyclohexyl)amino]-L-proline (0.92 g, 2.41 mmol) obtained in Step C was dissolved in DMF (10 mL) and DIPEA (1.05 mL, 6.01 mmol) was added thereto. 1-methylpiperazine (0.32 mL, 2.89 mmol) and HBTU (0.91 g, 2.41 mmol) were also added thereto in order. After the reaction solution was stirred at room temperature for 2 hours, the solution was concentrated in vacuo. The residue was diluted with EtOAc and washed with saturated NaHCO3 aqueous solution. The extracted organic solution was dried over MgSO4, concentrated in vacuo and purified by column chromatography (eluent:MC/MeOH=10/1) to give the title compound (1.06 g, 95%).
Reaction SMILES: C[Si](C)(C)[C:3]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:5][N:4]=1.C(OCC=[N+]=[N-])(=O)C.C([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)#C>>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:3]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:5][N:4]=1
Reactant: C#Cc1ccccn1
Reactant: CCOC(=O)c1cc([Si](C)(C)C)n[nH]1
Agent: CC(=O)OCC=[N+]=[N-]
Product: CCOC(=O)c1cc(-c2ccccn2)n[nH]1

Procedure:
Was prepared in a similar way as ethyl 3-(trimethylsilyl)-1H-pyrazole-5-carboxylate using diazoethyl acetate (Purchased from Aldrich) and 2-ethynyl-pyridine (Purchased from Aldrich).