Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[CH:10][C:11]([CH2:17][O:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:29])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:29])=[CH:13][CH:12]=[C:11]([CH2:17][O:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1c[nH]c2cc(COC(=O)c3ccccc3)ccc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCCC(=O)c1cnc2cc(COC(=O)c3ccccc3)ccc2c1Cl

Procedure:
3-Butyryl-7-benzoyloxymethyl-4(1H)-quinolone (10.42 g, 29.8 mmol) and phosphoryl chloride (60 ml) were refluxed for 1 hour, then evaporated, and the residue poured onto ice (300 g) with stirring. After neutralising with concentrated ammonia, the product was extracted into chloroform and the solution dried (Na2SO4) and evaporated to a solid. Trituration with ether gave the title compound (9.76 g), m.p. 66°-8°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:20]2[C@@H:19]3[C@@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:21])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]([O:22][CH3:23])[CH:4]=1.[CH2:24]([OH:26])[CH3:25].C1COCC1.[BH4-].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:20]2[C@@H:19]3[C@@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([O:21][C:24](=[O:26])[CH3:25])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]([O:22][CH3:23])[CH:4]=1
Reactant: CCO
Reactant: COc1cc2c(c(OC)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@H]1CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc2c(c(OC)c1)[C@H]1CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]1CC2
Temperature: 80 °C

Procedure:
A solution of 60 mg. of rac.-1,3-dimethoxy-8α-estra-1,3,5(10)-trien-17-one in 3 ml. of ethanol and 1.0 ml. of THF is gradually combined at room temperature with 60 mg. of NaBH4 and agitated for 30 minutes under N2 and at room temperature. The reaction mixture is neutralized with glacial acetic acid, concentrated, taken up in ether, washed neutral with saturated NaCl solution, dried, and evaporated. The residue is dissolved in 1 ml. of pyridine, the solution is mixed with 0.5 ml. of acetic anhydride and maintained for 1 hour at 80° C. under N2. After cooling, the mixture is introduced into ice water; the precipitate is filtered off and taken up in ether. The ether solution is washed neutral with saturated NaCl solution, dried, and evaporated. Recrystallization from methanol over carbon yields 42 mg. of product, m.p. 131°-134° C.
Reaction SMILES: [C:1]([O:12][C@H:13]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:14][C:15]([OH:17])=O)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(Cl)CCl.CI.CC[CH2:37][CH2:38][N+:39](CCCC)(CCCC)CCCC.[F-].C1C[O:56]CC1>>[C:1]([O:12][C@H:13]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:14][C:15]([NH:39][CH2:38][CH2:37][OH:56])=[O:17])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C1CCOC1
Reactant: CCCCCCCCCCC[C@H](CC(=O)O)OC(=O)CCCCCCCCC
Agent: [F-]
Solvent: ClCCCl
Solvent: CI
Product: CCCCCCCCCCC[C@H](CC(=O)NCCO)OC(=O)CCCCCCCCC
Yield: 81 %

Procedure:
In the same manner as described in Example 20-(1), 2-amino-1-(t-butyldiphenylsilyloy)ethane (450 mg, 1.5 mmol) was acylated with (R)-3-decanoyloxytetradecanoic acid (600 mg, 1.5 mmol) in the presence of EDC MeI (594 mg, 2.0 mmol) and then deprotected with TBAF (1.0 M in THF, 2.5 mL, 2.5 mmol) in THF (10 mL) to afford 488 mg (81%) of 2-[(R)-3-decanoyloxytetradecanoylamino]ethanol as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][C:47]=1[F:48])[NH2:44]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:44][C:43]3[CH:45]=[CH:46][C:47]([F:48])=[C:41]([F:40])[CH:42]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Reactant: Nc1ccc(F)c(F)c1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)Nc4ccc(F)c(F)c4)C3)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.1 %

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (146 mg, 0.428 mmol), EDC (115 mg, 0.599 mmol), and HOBT (81 mg, 0.599 mmol) in DMF (8 mL was added 3,4-difluoroaniline (77 mg, 0.599 mmol), and the reaction mixture was stirred at room temperature for 4 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (95 mg) as a yellow solid. LC-MS (ES) m/z=453 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][NH2:19])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[N:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>O.C(N(CC)CC)C.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][NH:19][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([NH2:30])=[N:29][C:21]=2[NH2:20])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)O)c(N)n1
Reactant: NNC(=O)Cc1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)NNC(=O)Cc2ccc(OCc3ccccc3)cc2)c(N)n1
Reaction time: 8 h
Yield: 66.9 %

Procedure:
To a solution of DMF (1 mL) of (4-benzyloxy-phenyl)-acetic acid hydrazide (46 mg) described in Manufacturing Example 8-1 were added triethylamine (0.10 mL), 2,6-diamino-nicotinic acid (30 mg) described in Manufacturing Example 10-2-4, HOBt (27 mg), and WSC (41 mg), which was stirred overnight at the same temperature. Water was added to the reaction solution, and the precipitated solids were filtered off to obtain the titled compound (47 mg) as a crude form. This compound was used directly as a crude form in the subsequent reaction.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].[OH-].[Na+]>FC(F)(F)C(O)=O.O.O=[Pt]=O>[NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24]
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COCCc1nc2c(N)nc3c(c2n1CCOCCN)CCCC3
Reaction time: 96 h
Yield: 56.8 %

Procedure:
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (10.0 g, 27.3 mmol) was dissolved in 50 mL of trifluoroacetic acid and treated with PtO2 (1.0 g). The reaction mixture was shaken under H2 (3 Kg/cm2). After 4 d, an additional 0.5 g of PtO2 was added and hydrogenation was continued for an additional 3 d. The reaction was then filtered through Celite and concentrated under reduced pressure to give a brown oil. The oil was dissolved in 200 mL of H2O then made basic (pH˜11) by addition of 10% NaOH solution. This was then extracted with CHCl3 (5×75 mL) and the combined organic layers were dried over Na2SO4 and concentrated to give 5.17 g of 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as a tan solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([CH:9](O)[CH3:10])=[CH:7][N:6]=[C:5]([S:12][CH3:13])[N:4]=1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH:9]([C:8]1[C:3]([NH:2][CH3:1])=[N:4][C:5]([S:12][CH3:13])=[N:6][CH:7]=1)[CH3:10]
Reactant: CNc1nc(SC)ncc1C(C)O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CNc1nc(SC)ncc1C(C)Cl
Yield: 113.5 %

Procedure:
0.25 g of the product from Example 11a, supra, were dissolved in 10 mL chloroform and 0.30 g thionyl chloride were added drop-wise. The mixture was refluxed for 2 hrs and evaporated to yield 0.31 g of the title product as the hydrochloride salt.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22].[CH3:35][C:36]1[C:40]([S:41]([NH2:44])(=[O:43])=[O:42])=[C:39]([CH3:45])[O:38][N:37]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:44][S:41]([C:40]3[C:36]([CH3:35])=[N:37][O:38][C:39]=3[CH3:45])(=[O:42])=[O:43])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:27][CH2:28]1)=[O:22]
Reactant: Cc1ccccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Reactant: Cc1noc(C)c1S(N)(=O)=O
Product: Cc1ccccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)NS(=O)(=O)c3c(C)noc3C)cnn12
Yield: 63.4 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.08 g, 0.18 mmol) obtained in Example 39, step 2 and 3,5-dimethylisoxazole-4-sulfonamide (0.16 g, 0.88 mmol), the title compound (0.07 g, 66%) was obtained.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[Cl:7][C:8]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH3:19])=[C:13]2[C:9]=1[CH2:10][CH2:11][CH:12]2[NH:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([NH2:31])[CH:27]=2)[N:22]=1>>[Cl:7][C:8]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH3:19])=[C:13]2[C:9]=1[CH2:10][CH2:11][CH:12]2[NH:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([NH:31][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH:27]=2)[N:22]=1
Reactant: COc1c(Cl)cc(Cl)c2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Reactant: CC(C)N=C=O
Product: COc1c(Cl)cc(Cl)c2c1C(Nc1ccc3cc(NC(=O)NC(C)C)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method described in example 3 from isopropyl isocyanate and rac-N2-(4,6-dichloro-7-methoxy-indan-1-yl)-quinoline-2,6-diamine; MS: m/e=460.6 (M+H+).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1([CH:10]=[CH:11][CH:12]([CH3:16])[CH2:13][CH2:14][OH:15])[CH2:9][CH2:8][CH2:7][CH2:6]1.N1C=CC=CC=1.Cl>CN(C1C=CN=CC=1)C.C1CCCCC1.CC(OC)(C)C>[C:1]([O:15][CH2:14][CH2:13][CH:12]([CH3:16])[CH:11]=[CH:10][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C=CC1CCCC1)CCO
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: c1ccncc1
Solvent: C1CCCCC1
Product: CC(=O)OCCC(C)C=CC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
Acetyl chloride (1.7 g; 22 mmol) was added to a cooled solution of 5-cyclopentyl-3-methylpent-4-en-1-ol (obtained in example 1; 2.6 g; 15 mmol), pyridine (2.4 g; 30 mmol), and DMAP (0.13 g; 0.1 mmol) in cyclohexane (65 ml). After 3 hours stirring at room temperature, the reaction mixture was poured into 1N HCl (130 ml) and MTBE (65 ml). The organic layer was separated, washed successively with 1N HCl (130 ml), sodium bicarbonate solution (100 ml) and brine (2×100 ml) and treated as in example 1 (distillation at 120° C./0.8 torr) to give 3.05 g (94% yield) of 5-cyclopentyl-3-methylpent-4-en-1-yl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:26][OH:27])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:28](Cl)([CH3:31])(=[O:30])=[O:29]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:26][O:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCCCCCNC(=O)C(CO)NS(=O)(=O)c1ccc(Cl)cc1
Product: COC(=O)CCCCCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(6-methoxycarbonylhexyl)propanamide (502 mg) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(6-methoxycarbonylhexyl)propanamide (453.1 mg).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[C:34]([CH3:36])[N:35]=[C:9]23)[CH2:4][CH2:3]1.[N+](=[CH:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N-].O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([O:1][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:3][CH2:4]3)[C:9]3[N:10]([N:33]=[C:34]([CH3:36])[N:35]=3)[C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(C)nn12
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2nc(C)nn12
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4′-{[4-(trans-4-hydroxycyclohexyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.5 g), rhodium(II) acetate (dimer) (0.0070 g) and toluene (15 mL) was heated to 80° C. under an argon atmosphere, a solution of ethyl 2-diazoacetate (1.6 g) in toluene (15 mL) was added dropwise, and the mixture was stirred at 80° C. for 10 min. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.0 g, 56%).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH:6]=[CH2:7])(=[O:5])=[O:4].Br[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2.C(N(CC)CC)C>C(O)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][NH:2][S:3](/[CH:6]=[CH:7]/[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)(=[O:5])=[O:4]
Reactant: C=CS(=O)(=O)NC
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CNS(=O)(=O)/C=C/c1ccc2[nH]ccc2c1
Temperature: 25 °C
Yield: 221.2 %

Procedure:
A mixture of N-methylethenesulphonamide (45 g), 5-bromoindole (60 g), palladium acetate (0.9 g), triotolylphosphine (18.6 g) and triethylamine (90 mL) in isopropanol (300 mL) was heated at 85° under nitrogen for 18 h. The reaction mixture was cooled to ambient temperature, filtered and the filter cake washed with isopropanol (30 mL). The combined washings and filtrate were concentrated in vacuo to give a yellow-brown solid (160 g). This material was purified by column chromatography on silica gel. Eluting initially with ethyl acetate/cyclohexane (1:1) followed by ethyl acetate provided the product (26.4 g, 36% of theory) as a yellow powder.
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[NH:13])[NH:11][OH:12])[CH:5]=1.C(N(C(C)C)CC)(C)C.[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=O>C1COCC1>[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]1[O:12][N:11]=[C:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:2])=[O:14])[N:13]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: COC(=O)c1cccc(C(=N)NO)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of 3-(N-Hydroxycarbamimidoyl)-benzoic acid methyl ester (60 g, 310 mmol) in anhydrous THF (200 mL) was added diisopropylethylamine (75 mL, 434 mmol) at 5° C., and then to the mixture was added 2-fluorobenzoyl chloride (48.1 mL, 403 mmol) over 20 min. The reaction mixture was stirred for 1 h at room temperature. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethylacetate (400 mL) and then washed with water (200 mL×2). The solvent was removed under reduced pressure and the desired product was crystallized in 60% ethylacetate in hexane to yield the desired product (81 g, 83% yield) as a white solid. 1H-NMR (CDCl3) δ 8.18 (1H), 8.03 (2H), 7.48 (2H), 7.18 (2H), 5.61 (2H), 3.82 (3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].Cl>C(O)C.O.[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:12]([F:13])([F:14])[F:15]
Reactant: COc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(N)cc1C(F)(F)F

Procedure:
A suspension of 4-methoxy-3-trifluoromethyl-nitrobenzene (2.2 g) and iron powder (1.68 g) in ethanol (35 mL) and water (15 mL) is treated with a solution of concentrated hydrochloric acid (0.42 mL) in ethanol (6 mL) and water (3 mL) and the mixture is heated to reflux for approximately 1 hour. The mixture is then cooled, filtered, and concentrated under reduced pressure. The resulting oil is dissolved in ethyl acetate and extracted three times with 5% aqueous hydrochloric acid. The pooled acidic extracts are then cooled in an ice bath and basified with solid potassium carbonate, then extracted with ethyl acetate. These organic extracts are washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, then passed through a short column of silica gel (ethyl acetate is used as the eluant) to provide the desired compound as an amber oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:15])=[N:12][O:13][N:14]=1.[H-].[Na+].[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][O:22][CH2:23]Cl>O1CCCC1.C(OCC)(=O)C>[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][O:22][CH2:23][N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:11]([NH2:15])=[N:12][O:13][N:14]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Nc1nonc1-c1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c(-c2nonc2N)nc2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
To a stirred suspension of 0.5 g of 4-(1H-benzoimidazol-2-yl)-furazan-3-ylamine (CAS 332026-86-5) (2.49 mmol; 1.0 eq.) in 15 mL of dry tetrahydrofuran cooled to 0° C. are added portionwise 0.075 g of sodium hydride (2.98 mmol; 1.2 eq.). After stirring for 10 min at 0-5° C., the resulting clear solution is treated with 0.54 mL of 2-(trimethylsilyl)ethoxymethyl chloride (2.91 mmol; 1.17 eq.). The reaction solution is stirred for 0.5 h at 0-5° C. and then diluted with 30 mL of ethyl acetate. The solution is washed with water (20 mL) and brine (20 mL), dried over magnesium sulfate, filtered and concentrated to dryness. The oily residue is triturated in diisopropylether (10 mL) and the solvent is removed under reduced pressure to give 0.78 g of the desired product as an off-white solid.
Reaction SMILES: [CH:1]1[C:5]2=[C:6]([OH:15])[C:7]3[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:8]=3[CH:9]=[C:4]2[O:3][CH:2]=1.Cl[CH2:17][CH2:18][CH2:19][C:20]#[N:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[C:20]([CH2:19][CH2:18][CH2:17][O:15][C:6]1[C:7]2[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:8]=2[CH:9]=[C:4]2[O:3][CH:2]=[CH:1][C:5]=12)#[N:21]
Reactant: N#CCCCCl
Reactant: O=c1ccc2c(O)c3ccoc3cc2o1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#CCCCOc1c2ccoc2cc2oc(=O)ccc12
Reaction time: 0.29 h

Procedure:
800 mg (3.956 mmol) of 5-hydroxypsoralen and 0.7 ml (655.5 mg, 6.33 mmol) of 4-chlorobutyronitrile were refluxed in 50 ml of 2-butanone in the presence of an excess (2.6 g) of anhydrous potassium carbonate and catalytic amounts of potassium iodide for 48 hours. The progress of the reaction was monitored by thin layer chromatography. After 48 hours the reaction mixture was concentrated under reduced pressure. The residual oily layer was cooled, diluted with water and acidified with concentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20 min and then filtered. The solids were washed with water to neutral pH, dried bysuction and then further washed with petroleum ether. The dried solids were dissolved in refluxing methanol, treated with charcoal and recrystallized from methanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH2:14])=[N:10][CH:9]=2)=[CH:4][C:3]=1[F:15].Cl[CH:17]([CH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][CH:32]=[CH:31]2)[CH:18](N1C(=O)CCC1=O)O>C(O)(C)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:17]([CH2:27][C:28]4[CH:29]=[C:30]5[C:35](=[CH:36][CH:37]=4)[N:34]=[CH:33][CH:32]=[CH:31]5)=[CH:18][N:14]=3)[N:13]=2)=[CH:4][C:3]=1[F:15]
Reactant: O=C1CCC(=O)N1C(O)C(Cl)Cc1ccc2ncccc2c1
Reactant: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Solvent: O
Solvent: CC(C)O
Product: Fc1cc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)ccc1Br
Temperature: 105 °C
Yield: 55.8 %

Procedure:
A mixture of 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (Step 5, 200 mg, 0.743 mmol) and 1-(2-chloro-1-hydroxy-3-quinolin-6-ylpropyl)pyrrolidine-2,5-dione (Step 7, 284 mg, 0.892 mmol) in isopropyl alcohol (7.4 mL) and water (0.11 mL) in a sealed tube was heated at 105° C. for 5 d. After the reaction mixture was cooled to ambient temperature, the precipitate was collected by filtration, washed with isopropanyl alcohol, and dried in vacuum to give the desired product (180 mg, 55%) LCMS (M+H)+: m/z=433.9/436.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1.C(N(CC)CC)C.Cl>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc([N+](=O)[O-])cn2)CC1
Yield: 82.5 %

Procedure:
A mixture of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (440 mg; 2.2 mmol), 2-chloro-5-nitro-pyridine (316 mg; 2.0 mmol), and triethylamine (420 μL; 3.0 mL) is dissolved in tetrahydrofuran (6 mL) and the resulting mixture is irradiated in a mono-mode microwave oven for 6 hours at 120° C. The reaction mixture is then treated by water (10 mL) and the pH of the aqueous phase is set to 4-5 by the addition of aqueous 1N hydrochloric acid. The aqueous phase is then extracted with dichloromethane (2×20 mL), the combined organic layers are washed with brine (10 mL), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude residue is then purified by column chromatography on silica gel (dichloromethane:ethyl acetate 1:0 and then 5:1) to afford the desired product (533 mg; 1.65 mmol).