Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]2[N:9]=[C:10]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[S:11][C:5]2=[N:4][C:3]=1Cl.[F-:20].[K+].S1(CCCC1)(=O)=O.C1(C)C=CC=CC=1>O>[Cl:1][C:2]1[C:7](=[O:8])[N:6]2[N:9]=[C:10]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[S:11][C:5]2=[N:4][C:3]=1[F:20]
Reactant: CCCCCCSc1nn2c(=O)c(Cl)c(Cl)nc2s1
Reactant: [F-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCSc1nn2c(=O)c(Cl)c(F)nc2s1
Reaction time: 0.75 h
Yield: 71 %

Procedure:
A solution of 4.4 g of the thus obtained 6,7-dichloro-2-hexylthio-5H-1,3,4-thiadiazolo[3,2-a]-pyrimidin-5-one, 2.2 g of potassium fluoride and 20 ml of sulfolane was heated to 185°~200° C. and stirred for 45 minutes. After cooling, toluene and water were added to the reaction solution and extraction was carried out. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was separated by silica gel column chromatography using an ethyl acetate/toluene mixture as an eluent. Thus 3.0 g of 6-chloro-7-fluoro-2-hexylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 105°~111° C. Yield 71%.
Reaction SMILES: B.CSC.[CH:5]1([CH2:11][O:12][C:13]2[CH:14]=[C:15]([C:18](=[O:22])[CH2:19][C:20]#[N:21])[S:16][CH:17]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.N.CO.C(Cl)Cl>>[NH2:21][CH2:20][CH2:19][CH:18]([C:15]1[S:16][CH:17]=[C:13]([O:12][CH2:11][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:14]=1)[OH:22]
Reactant: N#CCC(=O)c1cc(OCC2CCCCC2)cs1
Agent: B
Agent: N
Solvent: ClCCl
Solvent: CSC
Solvent: CO
Product: NCCC(O)c1cc(OCC2CCCCC2)cs1

Procedure:
Borane-dimethylsulfide reduction of 3-(4-(cyclohexylmethoxy)thiophen-2-yl)-3-oxopropanenitrile following the method used in Example 2 gave after flash chromatography purification (2%-20% 7N NH3/MeOH—CH2Cl2 gradient) Example 18 as a colorless oil. Yield (0.037 g, 43%); 1H NMR (400 MHz, CD3OD) δ 6.62 (dm J=1 Hz, 1H), 6.22 (d, J=1.4 Hz, 1H), 4.85 (m, 1H), 3.71 (d, J=6.3 Hz, 2H), 2.71-2.78 (m, 2H), 1.64-1.97 (m, 8H), 1.15-1.37 (m, 3H), 1.05-1.15 (m, 2H); RP-HPLC tR=9.63 min; ESI-MS m/z 223.1 [C13H18OS2.+H]+ or [M−H2O—CH2NH2+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:35]=[CH:34][C:6]2[O:7][C:8]([CH3:33])([CH3:32])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][O:21]CC4C=CC(OC)=CC=4)=[CH:13][C:12]3=[O:31])[C:5]=2[CH:4]=1)#[N:2].O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(Cl)Cl>[C:1]([C:3]1[CH:35]=[CH:34][C:6]2[O:7][C:8]([CH3:32])([CH3:33])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:13][C:12]3=[O:31])[C:5]=2[CH:4]=1)#[N:2]
Reactant: COc1ccc(COCCCCc2ccn(C3=CC(C)(C)Oc4ccc(C#N)cc43)c(=O)c2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: CC1(C)C=C(n2ccc(CCCCO)cc2=O)c2cc(C#N)ccc2O1
Yield: 92.7 %

Procedure:
In 24 ml of methylene chloride, is dissolved 1.13 g of 6-cyano-2,2-dimethyl-4-{2-oxo-4-(4-p-methoxybenzyloxybutyl)-1-pyridinyl}-2H-benzo[b]pyran obtained in Example 46. Then, 1.33 ml of water is added. Then, 0.82 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone is added at room temperature and the resulting mixture is reacted at that temperature for 40 minutes. After stopping the reaction by adding water, the reaction mixture is extracted with methylene chloride. The organic layer is washed successively with 0.1M aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using 1/10 mixture of methanol/methylene chloride as a developing solvent. Thus, 0.78 g of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(4-hydroxybutyl)-1-pyridinyl}-2H-benzo[b]pyran is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]C(=O)N(C)C)=[CH:8][C:7]=1[CH3:18].C[O-].[Na+].Cl>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][C:7]=1[CH3:18]
Reactant: COC(=O)CCc1ccc(SC(=O)N(C)C)cc1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(S)cc1C
Temperature: 25 °C
Yield: 118.3 %

Procedure:
3-(4-Dimethylcarbamoylsulfanyl-2-methyl-phenyl)-propionic acid methyl ester (5.01 g, 17.8 mmol) is diluted with methanol (30 mL) and to this is added sodium methoxide (1.7 mL of 4M in methanol, 7.23 mmol). The reaction is heated to reflux under nitrogen and monitored by TLC. After complete conversion, 20 h., the reaction is allowed to cool to room temperature. The reaction is neutralized with 1N HCl (7.23 mL) and diluted with ethyl acetate (150 mL). The two phases are separated and the organic layer is washed with water (75 mL), then brine (75 mL). The organic layer is then dried over anhydrous sodium sulfate, then concentrated to yield 4.43 g crude product that is used without further purification.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH2:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[CH:6]=[CH:7][N:8]=1.[CH:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(#N)C>[CH:18]1([O:24][CH2:3][C:4]2[N:5]([CH2:9][C:10]3[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=3)[CH:6]=[CH:7][N:8]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: OC1CCCCC1
Reactant: ClCc1nccn1Cc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CC#N
Product: Clc1cc(Cl)cc(Cn2ccnc2COC2CCCCC2)c1
Temperature: 120 °C
Yield: 10.1 %

Procedure:
2-(Chloromethyl)-1-(3,5-dichlorobenzyl)-1H-imidazole hydrochloride (see Example 1) (100 mg, 0.32 mmol), cyclohexanol (160 mg, 1.6 mmol) and acetonitrile (1 mL) were combined in a Smith Process Vial. The reaction mixture was heated in a SmithSynthesizer™ (Personal Chemistry) microwave at 120° C. for 30 min. The heterogeneous solution was filtered and the solid was washed with acetonitrile. The filtrate was concentrated and the resulting semi-solid was partitioned between CH2Cl2 (10 mL) and 5% Na2CO3 (5 mL). The aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to afford the desired product (11 mg, 10%); MS m/z 339 [C17H20Cl2N2O+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([O:20][CH3:21])[C:14]([O:22][CH3:23])=[CH:13]2)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([O:20][CH3:21])[C:14]([O:22][CH3:23])=[CH:13]2
Reactant: COc1cc2ccc(-c3ccccc3[N+](=O)[O-])cc2cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc2ccc(-c3ccccc3N)cc2cc1OC
Yield: 93.4 %

Procedure:
6-(2-Nitrophenyl)-2,3-dimethoxynaphthalene (70 mg, 0.23 mmol) was hydrogenated overnight in ethyl acetate (45 mL) at 40-45 lb./sq. in. under catalysis of palladium (10 wt % on activated carbon, 20 mg). The solution was passeded through a celite bed and the catalyst was washed with ethyl acetate (3×10 mL). Concentration in vacuo gave compound 5 (60 mg) in 99% yield; 1H NMR (CDCl3) d 4.02(3H, s), 4.04(3H, s), 6.82(1H, d, J=8.0), 6.85˜6.93 (1H, m), 7.16(1H, s), 7.18(1H, s), 7.20˜7.26(2H m), 7.47(1H, dd, J=8.3, J=1.6), 7.78(1H, d, J=8.8), 7.80(1H, s); 13C NMR d 56.4, 106.6, 106.9, 116.1, 119.2, 126.1, 126.8, 127.3, 128.3, 128.7, 128.9, 129.9, 131.2, 135.8, 144.3, 150.2, 150.3.
Reaction SMILES: [CH2:1]([CH:7]1[CH:11]([C:12]#N)[CH2:10][CH2:9][C:8]1=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:27][OH:28]>>[CH2:1]([CH:7]1[C:8](=[O:14])[CH2:9][CH2:10][CH:11]1[C:12]([O:28][CH3:27])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC1C(=O)CCC1C#N
Reactant: O
Reactant: CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCC1C(=O)CCC1C(=O)OC
Temperature: 25 °C

Procedure:
In a 100 ml round bottomed flask fitted with a mechanical stirrer and a reflux condenser, are placed 19.3 g 2-n-hexyl-3-cyanocyclopentanone, 3.2 g of methanol and 19 g of 2-n-hexyl-3-cyanocyclopentanone, 3.2 g of methanol and 19 g of p-toluene-sulfonic acid monohydrate. The reaction mixture is stirred at reflux temperature for 6 hours. The reaction mixture is then cooled to room temperature and poured into 200 ml of ice cold water. The organic layer is separated and the water phase is extracted with pentane. The combined organic layer and pentane extract are washed with sodium carbonate solution and water and dried over anhydrous sodium sulphate. The solvent is distilled off at atmospheric pressure and the residue is distilled through a short Vigreux column.
Reaction SMILES: C=O.[CH3:3][N:4]([CH2:9][C:10]#[CH:11])[CH2:5][CH2:6][C:7]#[N:8].C([C:14]1[CH:23]=[CH:22][C:21]2[NH:20][C:19](=[O:24])[C:18]3[NH:25][CH:26]=[CH:27][C:17]=3[C:16]=2[CH:15]=1)#C.[CH2:28]([C:30]([O-:32])=[O:31])[CH3:29]>O1CCOCC1.[Cu](I)I>[C:7]([CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][C:10]#[C:11][C:14]1[CH:23]=[CH:22][C:21]2[NH:20][C:19](=[O:24])[C:18]3[NH:25][CH:26]=[CH:27][C:17]=3[C:16]=2[CH:15]=1)#[N:8].[CH2:28]([C:30]([O-:32])=[O:31])[CH3:29]
Reactant: C#Cc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: C#CCN(C)CCC#N
Agent: I[Cu]I
Agent: C=O
Agent: CCC(=O)[O-]
Solvent: C1COCCO1
Product: CN(CC#Cc1ccc2[nH]c(=O)c3[nH]ccc3c2c1)CCC#N
Temperature: 110 °C
Yield: 7.6 %

Procedure:
31 mg (0.35 mmol) of para-formaldehyde, 35 mg (0.42 mmol) of 3-(methyl-prop-2-ynyl-amino)-propionitrile and 7 mg (0.04 mmol) of copper iodide are added to a suspension of 98 mg (0.35 mmol) of 8-ethynyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 3 ml of anhydrous dioxan, then the mixture is heated at 110° C. for 6 hours. The raw reaction product is then filtered, and the filtrate is evaporated. The residue is triturated with methanol, then the new filtrate is evaporated. The product is recrystallized from methanol to give 10 mg (8%) of 8-{3-[(2-cyano-ethyl)-methyl-amino]-prop-1-ynyl}-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:15])[C:4](=[O:14])[CH2:5]P(OCC)(OCC)=O.[CH2:16]([Li])[CH2:17][CH2:18][CH3:19].C1(C=O)CC1>C1COCC1>[CH3:15][N:3]([O:2][CH3:1])[C:4](=[O:14])/[CH:5]=[CH:16]/[CH:17]1[CH2:19][CH2:18]1
Reactant: CCOP(=O)(CC(=O)N(C)OC)OCC
Reactant: [Li]CCCC
Agent: O=CC1CC1
Solvent: C1CCOC1
Product: CON(C)C(=O)/C=C/C1CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of N-methoxy-N-methyl diethylphosphonoacetamide (34.56 g, 144.5 mmol) in THF (200 mls) at -78° C., was added n-butyllithium (57.8 mls of a 2.5M solution in hexanes, 144.5 mmol) dropwise. Upon completion of addition, the mixture was stirred for 30 mins at -78° C. A solution of cyclopropanecarboxaldehyde (6.75 g, 96.3 mmol) in THF (50 mls) was then added dropwise. Upon completion of addition, the cooling bath was withdrawn and the reaction allowed to warm to r.t. It was then diluted with aqueous sat'd NH4Cl (200 mls) and the THF was stripped off in vacuo. The aqueous residue was extracted with ethylacetate (3×200 mls). The organics were combined, dried with MgSO4 and concentrated. The resulting residue was chromatographed (silica gel, ether:hexanes, 3:2) to afford 14.09 g (94%) of trans-N-methyl-N-methoxy-3-cyclopropylpropenamide as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH2:8][C:9]2[S:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[CH:7]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(COC)OC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([CH2:8][C:9]2[S:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Clc1ccc(Cc2cc(Br)ccc2I)s1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Clc1ccc(Cc2cc(Br)ccc2-c2ccccc2)s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a solution of the above 5-bromo-1-(5-chloro-2-thienylmethyl)-2-iodobenzene (1.0 g) in dimethoxyethane (10 ml) were added phenylboronic acid (310 mg), bis(triphenylphosphine)palladium (II)dichloride (85 mg) and 2M aqueous sodium carbonate solution (3.8 ml), and the mixture was stirred at 50° C. overnight. Added thereto was a saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give 5-bromo-1-(5-chloro-2-thienylmethyl)-2-phenylbenzene (683 mg) as oil.
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:24])[C@H:12]2[C@@H:15](OS(OCC)(=O)=O)[CH3:16])[C:9]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:3])[CH3:2].N12CCCCC1C=NCCC2>ClCCl>[C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:24])/[C:12]/2=[CH:15]/[CH3:16])[C:9]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:3])[CH3:2].[C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:24])/[C:12]/2=[CH:15]\[CH3:16])[C:9]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:3])[CH3:2]
Reactant: CCOS(=O)(=O)O[C@@H](C)[C@@H]1C(=O)N2C(C(=O)OC)=C(S/C=C/NC(C)=O)C[C@H]12
Agent: C1=NCCCN2CCCCC12
Solvent: ClCCl
Product: C/C=C1/C(=O)N2C(C(=O)OC)=C(S/C=C/NC(C)=O)C[C@H]12
Product: C/C=C1\C(=O)N2C(C(=O)OC)=C(S/C=C/NC(C)=O)C[C@H]12
Reaction time: 0.17 h

Procedure:
Methyl (5R,6R)-3-[(E)-2-acetamidoethenylthio]-6-[(S)-1-ethoxysulphonyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e22) (86 mg) was taken up in dichloromethane (3 ml) and treated with 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU) (33 mg) in dichloromethane (3.3 ml) added dropwise. After 15 minutes more DBU (3 mg) in dichloromethane (0.3 ml) was added and stirring was continued for 10 minutes. The solution was then washed with water (5 ml) and then chromatographed on silica gel to give methyl (5R,6E)-3-[(E)-2-acetamidoethenylthio]-6-ethylidene-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate and methyl (5R,6Z)-3-[(E)-2-acetamidoethenylthio]-6-ethylidene-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate as a mixture of isomers (e35 and e36) (21 mg), νmax (CH2Cl2) 1775 (broad), 1705, 1620 cm-1.
Reaction SMILES: O.O.[Cu:3](Cl)Cl.[NH2:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:11]=2[C:10]([NH2:23])=[CH:9][CH:8]=1>CN(C)C=O>[Cu+2:3].[NH2:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:11]=2[C:10]([NH2:23])=[CH:9][CH:8]=1
Reactant: Cl[Cu]Cl
Agent: Nc1ccc(N)c2c1C(=O)c1ccccc1C2=O
Solvent: CN(C)C=O
Solvent: O
Product: [Cu+2]

Procedure:
Copper (II) chloride dihydrate (0.71 g) is dissolved in dimethylformamide (30 ml) and 1,4-diamino anthraquinone (1.0 g) is added. The mixture quickly turns into a paste and is filtered and washed with methylene chloride before drying. The filtrate is then washed with water, acetone and finally methylene chloride and dried overnight in a vacuum oven. The yield is 0.86 g of a dark blue powder having a conductivity of 1.32×10-2S/cm. Analysis shows a composition of C--56.84 percent, H--3.86 percent, N--9.10 percent, Cu--5.7 percent and Cl--7.7 percent.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:25]1[NH:30][C:29](=[O:31])[NH:28][C:27](=[O:32])[CH:26]=1>O1CCOCC1>[O:1]([CH2:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][N:14]([C:25]2[NH:30][C:29](=[O:31])[NH:28][C:27](=[O:32])[CH:26]=2)[CH2:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(OCCCN2CCNCC2)cc1
Reactant: O=c1cc(Cl)[nH]c(=O)[nH]1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=c1cc(N2CCN(CCCOc3ccccc3)CC2)[nH]c(=O)[nH]1
Yield: 75.2 %

Procedure:
1.1 g of 1-(3-phenoxypropyl)piperazine, 0.8 ml of triethylamine and 0.59 g of 6-chloro-2,4(1H,3H)-pyrimidinedione were dissolved in 15 ml of dioxane, followed by heating under reflux for 1 hour. After cooling, the precipitated crystals were collected by filtration, and then washed with water and hot ethanol to obtain 1.0 g (yield 66% ) of 6-[4-(3-phenoxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:27])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[CH3:26][O:25][C:23]1[CH:22]=[CH:21][C:20]2[C:10]3([CH2:17][O:18][C:19]=2[CH:24]=1)[C:11]1[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:8][C:9]3=[O:27]
Reactant: COc1ccc2c(c1)OCC21C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: COc1ccc2c(c1)OCC21C(=O)Nc2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1′-(diphenylmethyl)-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (98%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.23-8.11 (br, 1H), 7.30-6.90 (m, 4 H), 6.69 (d, J=8.4 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 6.39 (dd, J=8.4, 1.8 Hz, 1H), 4.98 (d, J=9.0 Hz, 1H), 4.71 (d, J=9.0 Hz, 1H), 3.78 (s, 3H); MS (ES+) m/z 268.3 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].O1CCCCC1[N:33]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[N:34]1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:35]3[NH:34][N:33]=[CH:37][CH:36]=3)[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1Br
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1-c1ccn[nH]1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 26 using 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-((2-hydroxyethyl)(methyl)amino)nicotinamide (Stage 23.1) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to afford a yellow resin. UPLC-MS (Condition 3) tR=0.97 min, m/z=438.1 [M+H]+, m/z=436.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.77 (s, 3H) 3.37-3.49 (m, 2H) 3.49-3.65 (m, 2H) 4.62 (br. s, 1H) 6.47 (d, J=1.96 Hz, 1H) 7.33 (d, J=9.05 Hz, 2H) 7.72-7.85 (m, 1H) 7.85-7.96 (m, 2H) 8.14 (br. s, 1H) 8.71 (d, J=1.96 Hz, 1H) 10.26 (s, 1H) 12.58-13.18 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH2:12][CH2:13][O:14][CH2:15][CH:16]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.BrC1NC2N=CN=C([C:26]3[C:27]([CH3:45])=[C:28]([NH:32][C:33](=[O:44])[C:34]4[CH:39]=[CH:38][C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:36][CH:35]=4)[CH:29]=[CH:30][CH:31]=3)C=2C=1>>[C:40]([C:37]1[CH:38]=[CH:39][C:34]([C:33]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([C:2]3[C:3]4[CH:10]=[C:9]([C:11]5[CH2:12][CH2:13][O:14][CH2:15][CH:16]=5)[NH:8][C:4]=4[N:5]=[CH:6][N:7]=3)[C:27]=2[CH3:45])=[O:44])=[CH:35][CH:36]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: Clc1ncnc2[nH]c(C3=CCOCC3)cc12
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2[nH]c(Br)cc12
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2[nH]c(C3=CCOCC3)cc12

Procedure:
Example 64 was prepared analogue to Intermediate 11 by replacing 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine with Intermediate 54.
Reaction SMILES: [CH3:1][C:2]1([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:20]1(C2(C(Cl)=O)CCCCC2)[CH:25]=[CH:24]C=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[C:1]1([C:2]2([C:8]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:17]([O-:19])=[O:18])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Cl)C1(c2ccccc2)CCCCC1
Reactant: CC1(C(=O)Nc2ccccc2[N+](=O)[O-])CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1[N+](=O)[O-])C1(c2ccccc2)CCCCC1
Yield: 91 %

Procedure:
This compound was prepared following the procedure described for compound 39A in example 39, except that 1-phenylcyclohexanecarbonyl chloride (J. Am. Chem. Soc. 68, 2345-7 (1946)) was used in place of 1-methylcyclohexanecarbonyl chloride, toluene in place of CH2Cl2, DIPEA in place of triethylamine and reaction mixture was refluxed for 15 h. The crude was purified by flash chromatography (petroleum ether-EtOAc 98:2). Yield 91%.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:22])[CH2:4]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:49]>CO.CCOCC.C(Cl)Cl>[ClH:49].[ClH:49].[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH2:2][C@@H:3]3[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]4[C:20]5[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=5)[CH:14]=[CH:13][C:12]4=[O:22])[CH2:4]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: NC[C@H]1CN(CCn2c(=O)ccc3ccc(F)cc32)C[C@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: O=c1ccc2ccc(F)cc2n1CCN1C[C@H](CNCc2cc3c(cn2)OCCO3)[C@H](O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-{2-[(3S,4S)-3-(aminomethyl)-4-hydroxy-1-pyrrolidinyl]ethyl}-7-fluoro-2(1H)-quinolinone (60 mg; 0.2 mmol) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (32 mg, 0.2 mmol) in methanol (1 mL), DCM (3 mL) was stirred at room temperature overnight. Sodium triacetoxyborohydride (85 mg; 0.4 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was evaporated and chromatographed on silica gel, eluting with 0-10% methanol-DCM-1% NH4OH to give an oil. The oil was treated with 1M HCl in Et2O to give the title compound (50 mg) as a hydrochloride salt.
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)=[CH:18][CH:19]=2)[CH:14]=[CH:13]1>>[CH3:37][CH:36]([CH3:38])[C:35]([NH:34][C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]2[CH2:24][CH2:23][N:22]([CH2:21][C:17]3[CH:16]=[C:15]4[C:20](=[CH:19][CH:18]=3)[N:12]([C:2]3[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[CH:5]=[CH:4][CH:3]=3)[CH:13]=[CH:14]4)[CH2:27][CH2:26]2)[CH:29]=1)=[O:39]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Reactant: Ic1cccc2ccccc12
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(ccn4-c4cccc5ccccc45)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodonaphthalene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 502.2 (M+H)+.