Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.ClC[C:13]1[CH:14]=[CH:15][C:16]2[S:21][C:20]3[N:22]=[CH:23][CH:24]=[N:25][C:19]=3[NH:18][C:17]=2[CH:26]=1.C(OCC)C>CCCCCC>[CH2:9]([O:8][P:1]([C:13]1[CH:14]=[CH:15][C:16]2[S:21][C:20]3[N:22]=[CH:23][CH:24]=[N:25][C:19]=3[NH:18][C:17]=2[CH:26]=1)(=[O:2])[O:5][CH2:6][CH3:7])[CH3:10]
Reactant: ClCc1ccc2c(c1)Nc1nccnc1S2
Reactant: CCOP(OCC)OCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOP(=O)(OCC)c1ccc2c(c1)Nc1nccnc1S2
Temperature: 160 °C

Procedure:
To 2 ml of triethyl phosphite was added 0.374 g of 8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine and the resulting mixture was heated to 160° C. for 3 hours. Then the reaction mixture was brought back to room temperature and diethyl ether (10 ml) and n-hexane (20 ml) were added thereto. The precipitate was taken up by filtration and washed several times with n-hexane to thereby give 0.413 g of the title compound as a yellow powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH3:16]
Reactant: COc1ccccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2nccc(Oc3ccccc3OC)c2cc1OC
Temperature: 150 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (102 mg) and commercially available 2-methoxyphenol (0.5 ml) were mixed and stirred at 150° C. for 8 hours. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and then partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with brine and then dried with sodium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting first with hexane/ethyl acetate and then with chloroform/methanol to obtain 76 mg of the title compound (yield: 54%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][S-:16].[Na+]>CC(C)=O>[CH3:15][S:16][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: C[S-]
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(SC)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
A solution of methyl 4-chloro-3-nitrobenzoate (28 g) in acetone (250 mL) is treated portionwise with sodium thiomethoxide (10 g) and the mixture is stirred overnight at room temperature. After filtration, the solution is concentrated and water (300 mL) is added to the residue. The yellow solid is filtered off and subjected to flash chromatography eluting with a mixture of diethyl ether and pentane (1:4 v/v), to give methyl 4-methylthio-3-nitrobenzoate (18.5 g), in the form of a yellow solid, m.p. 118-120° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:17]([NH2:20])#[C:18][CH3:19].O>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:20][CH2:17][C:18]#[CH:19])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC#CN
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: C#CCNc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.1 g (66 mmol) of 2,4-dichloro-5-fluoropyrimidine is dissolved in 60 ml of acetonitrile, and 10.2 ml (73 mmol) of triethylamine and 6.0 ml (86 mmol) of propynylamine are added. The reaction mixture is stirred overnight at room temperature and then poured into water. The mixture is extracted by means of ethyl acetate, the combined organic phases are dried on MgSO2, and the solvent is evaporated by means of underpressure. After the remaining material is recrystallized with diisopropyl ether/hexane, the yield is 10.6 g (87% of theory) of the product.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:28][CH2:29][C:30]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:31]=1[C:32](=[O:49])[N:33]([CH:41]1[CH2:46][CH2:45][C:44](=[O:47])[NH:43][C:42]1=[O:48])[C:34]([CH3:40])=[N:35]2>CN(C=O)C>[O:48]=[C:42]1[CH:41]([N:33]2[C:32](=[O:49])[C:31]3[C:36](=[CH:37][CH:38]=[CH:39][C:30]=3[CH2:29][NH:28][C:10](=[O:12])[CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:13])=[CH:8][CH:7]=3)[N:35]=[C:34]2[CH3:40])[CH2:46][CH2:45][C:44](=[O:47])[NH:43]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc2cccc(CNC(=O)Cc3ccc(C(F)(F)F)cc3)c2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To a stirred solution of (4-trifluoromethyl-phenyl)-acetic acid (0.26 g, 1.3 mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1.1′ carbonyldiimidazole (0.22 g, 1.4 mmol) and stirred for one hour. To the mixture, 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.42 g, 1.3 mmol) was added, and the mixture was stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-2-(4-trifluoromethyl-phenyl)-acetamide as an off-white solid (450 mg, 74% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.36 min (99.1%); mp, 199-201° C.; 1HNMR (DMSO-d6) 2.14-2.19 (m, 1H, CHH), 2.57-2.87 (m, 6H, CHCH2, CH3), 3.66 (s, 2H, ArCH2), 4.75-4.86 (m, 2H, CH2NH), 5.24 (dd, J=6, 11 Hz, 1H, CH), 7.27-7.72 (m, 7H, Ar), 8.48 (t, J=6 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.74, 23.28, 30.58, 41.75, 41.93, 56.48, 117.69, 124.72, 125.01 (d, JC-F=4 Hz), 125.01 (d, JC-F=10 Hz), 125.61, 129.91, 133.82, 140.58, 141.19, 148.45, 154.81, 160.90, 169.50, 169.54, 172.59. LCMS MH=487; Anal Calcd For C24H21N4O4F3: C, 57.76; H, 4.52; N, 11.23; F, 11.42. Found: C, 57.38; H, 4.49; N, 11.07; F, 11.64.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:21]=[C:22]([CH:25]=[N:26][C:27]([O:29][Si](C)(C)C)=[CH2:28])[CH2:23][CH3:24].CO>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]2[NH:8][C:7](=[O:11])[C:6]3([CH:12]([C:13]4[CH:20]=[CH:19][CH:18]=[C:15]([C:16]#[N:17])[CH:14]=4)[CH2:28][C:27](=[O:29])[NH:26][CH:25]3[C:22](=[CH2:21])[CH2:23][CH3:24])[C:5]2=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(/C=C2\C(=O)Nc3cc(Cl)ccc32)c1
Reactant: C=C(C=NC(=C)O[Si](C)(C)C)CC
Solvent: CO
Solvent: Cc1ccccc1
Product: C=C(CC)C1NC(=O)CC(c2cccc(C#N)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Yield: 35 %

Procedure:
E/Z-3-(6-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-benzonitrile (280 mg, 1 mmol) prepared in example 134a was heated with 1-(1-methylene-propyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene freshly prepared in example 80a (2.06 g, 10.5 mmol) in toluene (20 mL) in a sealed tube at 135° C. for 1 h, then cooled to room temperature. Methanol (80 mL) was added, and the mixture was filtered through a short pad of celite. The filtrate was concentrated, the residue was purified by chromatography (EtOAc) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-cyano-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a solid (180 mg, 35%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=1)=[O:10].[CH3:18][O:19][C:20](=[O:33])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[CH3:18][O:19][C:20](=[O:33])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](=[O:30])(=[O:31])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=2)=[O:10])=[CH:25][CH:24]=1
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(C(=O)c2cc(Cl)ccc2N)ccn1
Product: COC(=O)CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccnc(C)c2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and 3-(4-chlorosulfonyl-phenyl)-propionic acid methyl ester and purified by HPLC. 1H NMR (CDCl3) δ 10.13 (s, 1H) 8.62 (d, J=4.8 Hz, 1H) 7.73 (d, J=8.8 Hz, 1H) 7.65 (d, J=8.8 Hz, 2H) 7.49 (dd, J=8.8 Hz, 2.4 Hz, 1H) 7.28 (d, J=2.4 Hz, 1H) 7.19 (d, J=12 Hz, 2H) 7.13 (s, 1H) 6.95 (d, J=4.8 Hz, 1H) 3.62 (s, 3H) 2.90 (t, J =8 Hz, 2H) 2.63 (s, 3H) 2.56 (t, J=8 Hz, 2H). MS: m/z=473.0 (M++1).
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[C@H:17]([NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH3:18])[C:11](O)=[O:12])=[N+:6]=[N-:7]>CN(C)C=O.ClCCl>[N:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[C@H:17]([NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH3:18])[C:11]([Cl:3])=[O:12])=[N+:6]=[N-:7]
Reactant: O=S(Cl)Cl
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1N=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1N=[N+]=[N-]

Procedure:
Thionyl chloride (4 ml) and dimethylformamide (1 drop) were added to a solution of (R)-3-azido-4-(1-benzyloxycarbonylaminoethyl)benzoic acid in dichloromethane (20 ml), and the mixture was refluxed under heating for 2 hours. After the reaction, the solvent was evaporated under reduced pressure. The obtained residue was boiled with benzene to give 1.65 g of (R)-3-azido-4-(1-benzyloxycarbonylaminoethyl)benzoyl chloride as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][CH2:11][CH3:12])[N:5]=[C:4]([NH2:13])[CH:3]=1.N1C=CC=CC=1.[O:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[CH2:30][C:31](Cl)=[O:32])[CH3:21]>C(Cl)Cl.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][CH2:11][CH3:12])[N:5]=[C:4]([NH:13][C:31](=[O:32])[CH2:30][C:23]2[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=2[O:20][CH3:21])[CH:3]=1
Reactant: CCCc1nc(N)cc(N)c1C#N
Reactant: COc1ccc(OC)c(CC(=O)Cl)c1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCc1nc(NC(=O)Cc2cc(OC)ccc2OC)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.6 %

Procedure:
To a solution of 23 mg (0.13 mmol) of 4,6-diamino-2-propyl-nicotinonitrile (Example 68B) and 50 mg (0.63 mmol) of pyridine in 1 mL of CH2Cl2 was added 35 mg (0.16 mmol) of (2,5-dimethoxyphenyl)acetyl chloride (Example 68A). The mixture was stirred at ambient temperature for 10 minutes then diluted with 3 mL of water. The mixture was extracted with ethyl acetate (3×3 mL), then the combined ethyl acetate layers were back extracted with saturated NaHCO3(aq.) (1×3 mL), and brine (1×3 mL), dried over MgSO4, filtered, and concentrated to an oil. This was suspended in 5 mL of toluene, then concentrated under reduced pressure to remove some pyridine. The product was purified via silica gel chromatography, eluting with 60:40 ethyl acetate:hexanes to provide 21 mg (46%) of a white solid. 1H NMR (300 MHz, d6-DMSO) δ 10.27 (s, 1H), 7.34 (s, 1H), 6.83 (m, 5H), 3.70 (m, 6H), 3.65 (s, 2H), 2.64 (m, 2H), 1.68 (m, 2H), 0.93 (t, 3H, J=7.3 Hz); MS (ESI) m/e 355 (M+H)+, 353 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([S:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[C:5]([CH3:15])[N:6]2[CH2:11][C:12]([OH:14])=[O:13].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C1(C)C=CC=CC=1>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([S:16][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[N:34]3[CH2:33][CH2:32][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:36][CH2:35]3)[N:6]([CH2:11][C:12]([OH:14])=[O:13])[C:5]=2[CH3:15])=[CH:18][CH:19]=1
Reactant: Cc1c(Sc2ccc(Cl)cc2)c2c(Br)cccc2n1CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1c(Sc2ccc(Cl)cc2)c2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2n1CC(=O)O
Temperature: 110 °C

Procedure:
To a dry flask was charged the product from example 22 part (ii) (1 g), N-tert-Butoxycarbonylpiperazine (0.48 g), Pd2(dba)3 (3 mg), 2,2′-bis(diphenylphosphino)-1,1′-binapthyl Binap (10 mg) and toluene (5 ml). The reaction was heated to 110° C. for 1 hour then allowed to cool. The mixture was diluted with EtOAc, washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified using Flash column chromatography (eluent 25% EtOAc/Hexane then 50% EtOAc/Hexane/1% Acetic acid). Further purification using reverse phase preparative HPLC (eluent MeCN/NH3 (aq)) gave titled compound (0.021 g).
Reaction SMILES: [Li][CH2:2]CCC.[CH2:6]([N:9]([CH2:23][CH2:24][CH3:25])[CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[C:20](=O)[CH3:21])[O:12][CH2:11]1)[CH2:7][CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[CH2:6]([N:9]([CH2:23][CH2:24][CH3:25])[CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[C:20]([CH3:2])=[CH2:21])[O:12][CH2:11]1)[CH2:7][CH3:8]
Reactant: [Li]CCCC
Reactant: CCCN(CCC)C1COc2cccc(C(C)=O)c2C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C=C(C)c1cccc2c1CC(N(CCC)CCC)CO2
Reaction time: 4 h

Procedure:
Methyltriphenylphosphoniumbromide (0.62 g, 1.74 mmol) was dissolved in dry ethyl ether (20 ml) under nitrogen at ambient temperature and n-BuLi (0.7 ml, 2.5M, 1.74 mmol) was added and the solution was stirred for 4 hours. 3-Dipropylamino-5-acetylchroman (Example 7; 0.40 g, 1.45 mmol) was dissolved in dry diethyl ether (2.0 ml) and this solution was added to the previously formed Wittig-reagent.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[CH:12][C:13]([OH:15])=O.[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[C:16]1([N:22]2[C:13](=[O:15])[CH:12]=[C:3]3[C:2]([C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[CH2:5][CH2:4]3)=[N:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)C=C1CCc2ccccc2C1=O
Reactant: NNc1ccccc1
Solvent: CCO
Product: O=c1cc2c(nn1-c1ccccc1)-c1ccccc1CC2
Yield: 20.6 %

Procedure:
A mixture of 5 g of 1,2,3,4-tetrahydro-1-oxo-2-naphthylideneacetic acid and 3 g of phenylhydrazine in 100 ml of ethanol is refluxed for 10 hours. The precipitated crystals are collected by filtration, washed with ethanol and dissolved in 50 ml of acetic acid. The solution is refluxed under heating for 8 hours and the acetic acid is distilled off. The residue is extracted with ethyl acetate and the extract is washed with an aqueous sodium hydrogencarbonate solution. After drying over magnesium sulfate anhydride, the solvent is distilled off and to the residue is added ethanol. The precipitated crystals are collected by filtration and recrystallized from ethanol to give 1.4 g of 2-phenyl-5,6-dihydrobenzo[h]cinnolin-3(2H)-one as pale yellow needles, melting at 155°-157° C.
Reaction SMILES: O1CCO[CH:2]1[C:6]1[O:10][C:9]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16]([NH:21][CH3:22])=[CH:17][N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=1.Cl.[CH3:24][NH:25][CH3:26].Cl.CNC.[BH4-].[Na+]>O.C(O)(=O)C>[CH3:24][N:25]([CH2:2][C:6]1[O:10][C:9]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16]([NH:21][CH3:22])=[CH:17][N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=1)[CH3:26]
Reactant: CNC(=C[N+](=O)[O-])NCCSCc1ccc(C2OCCO2)o1
Reactant: CNC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.3 %

Procedure:
To a solution of N-[2-[[5-(1,3-dioxolan-2-yl)-2-furanylmethyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine (2.21 g) and dimethylamine hydrochloride (20 g) in water (5 ml) was added 2 N hydrochloric acid (5 ml). After 10 min, dimethylamine (33% in ethanol) (2 ml) was added, the solution cooled to 18° and sodium borohydride (1 g) added portionwise. The suspension was acidified with acetic acid (2.5 ml) and after 15 mins was heated at 60° for 15 mins. The suspension was evaporated to low bulk and an excess of anhydrous sodium carbonate and tetrahydrofuran (100 ml) added. The suspension was refluxed for 2 hours and after 2 hours at room temperature was filtered and the filtrate evaporated in vacuo. The oily residue was chromatographed (silica/methanol) and the appropriate eluate evaporated in vacuo to give the title compound (0.45 g) which was crystallised from methyl isobutyl ketone, m.p. 64°-67° .
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[N:28][C:27]([C:30]([OH:38])([CH3:37])[CH2:31]OS(C)(=O)=O)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][NH:40][CH3:41].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[N:28][C:27]([C:30]([OH:38])([CH3:37])[CH2:31][N:40]([CH3:41])[CH3:39])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)(COS(C)(=O)=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)cn1
Reactant: CNC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(C)(O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)cn1
Yield: 23.1 %

Procedure:
Methanesulfonic acid 2-[4-(4-benzyl-phthalazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-2-hydroxy-propyl ester (64 mg, 0.120 mmol) is combined with dimethylamine (300 μL, 2M in THF, 0.600 mmol), diisoproylethylamine (63 μL, 0.360 mmol), and acetonitrile (1 mL). The mixture is heated to reflux for 16 h. Concentrate the crude mixture in vacuo. The residue is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (13.4 mg, 23%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25](O)=[O:26])=[N:10]2)=[CH:5][CH:4]=1.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32].O>CN(C)C=O>[CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])=[O:26])=[N:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)CCN
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)O)nc2n1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)NCCN(C)C)nc2n1
Reaction time: 2 h
Yield: 101.2 %

Procedure:
N,N'-Carbonyldiimidazole (1.8 g) is added at a temperature in the region of 25° C. to a solution of [2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]acetic acid (4 g) in anhydrous dimethylformamide (85 cc), and the mixture is stirred for 2 hours at this temperature. 2-Dimethylaminoethylamine (0.7 g) is then added and the mixture is stirred for 18 hours at this same temperature. The reaction mixture is then poured into water (200 cc) and extracted with methylene chloride (3×200 cc). The organic extracts are washed with water, dried and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue obtained is crystallized by stirring in ethyl ether. [2-(7-Methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]-N-(2-dimethylamino ethyl)acetamide (3.5 g), m.p. 146° C., is thereby obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[NH:18]C(=O)C)([O-:3])=[O:2].[OH-].[Na+]>CO>[N+:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[NH2:18])([O-:3])=[O:2]
Reactant: CC(=O)Nc1cc(N2CCC(O)CC2)c(F)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1cc(N2CCC(O)CC2)c(F)cc1[N+](=O)[O-]
Yield: 96.8 %

Procedure:
N-[2-Nitro-4-fluoro-5-(4-hydroxypiperidin-1-yl)phenyl]acetamide (10.0 g, 0.034 mol) (obtained in preparation 6, step 1) was deacetylated using 6 N NaOH solution (20 mL) and methanol (30 mL) using an analogous procedure to that described in preparation 4 (step 2) to afford 2-nitro-4-fluoro-5-(4-hydroxypiperidin-1-yl) aniline (8.4 g, 80%). mp 238-239 ° C.; IR (KBr) 3357, 3326, 1641 cm-1 ; 1H NMR (CDCl3) δd 1.70-1.80 (m, 2H, CH2), 1.99-2.08 (m, 2H, CH2), 2.99-3.12 (m, 2H, NCH2), 3.50-3.62 (m, 2H, NCH2), 3.94 (m, 1H, CH), 6.0 (d, J=7.4 Hz, 1H), 6.02 (brs, 2H, NH2), 7.80 (d, J=14.2 Hz, 1H); Mass (m/z) 255 (M+.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][OH:14])=[CH:5]2.[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C([O-])(=O)C.[K+]>CC#N.O>[Cl:12][C:7]1[C:6]([CH2:13][OH:14])=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH3:24])[CH:3]=2)[N:8]=1
Reactant: Cc1ccccc1B(O)O
Reactant: OCc1cc2cc(Br)ccc2nc1Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccccc1-c1ccc2nc(Cl)c(CO)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (6-bromo-2-chloroquinolin-3-yl)methanol (19.8 g, 72.5 mmol, prepared as in example 2, step 2), o-tolylboronic acid (10.4 g, 76.1 mmol), potassium acetate (21.3 g, 217.4 mmol) and dichlorobis(4-(di-tert-butylphosphino)-N,N-dimethylaniline)palladium (II) (0.51 g, 0.72 mmol) in CH3CN (300 ml) and water (100 ml) was heated in to reflux. After 2 h, the reaction was allowed to cool to RT and the aqueous phase was discarded. The organics were washed with 2×50% brine/water, and then 2× brine. The organics were concentrated to ˜100 mL, at which point the precipitate was filtered off to afford a pale yellow solid of (2-chloro-6-o-tolylquinolin-3-yl)methanol. Step 2: (2-chloro-6-o-tolylquinolin-3-yl)methanol (13.9 g, 49.0 mmol) was treated with DCM (100 ml) and thionyl chloride (106 ml, 1456 mmol) at ambient temperature. After 15 min, the solution was concentrated and azeotroped with 2×100 mL toluene, to afford a yellow solid of 2-chloro-3-(chloromethyl)-6-o-tolylquinoline.
Reaction SMILES: [OH:1][CH:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[CH:4]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[O:3]1.[BH4-].[Na+]>C(O)C.C(OCC)(=O)C>[OH:3][CH:4]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[CH2:2][OH:1])[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15]
Reactant: N#Cc1cccc(C2OC(O)c3cnccc32)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1cccc(C(O)c2ccncc2CO)c1
Reaction time: 1 h

Procedure:
3-(3-Hydroxy-1,3-dihydro-furo[3,4-c]pyridin-1-yl)-benzonitrile (110 mg) was dissolved in ethanol (5 mL) and then treated with sodium borohydride (51 mg). The reaction mixture was stirred for 1 hour, diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography to yield 3-[hydroxy-(3-hydroxymethyl-pyridin-4-yl)-methyl]-benzonitrile as a colorless foam.