Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:10]([CH3:15])[CH2:11][CH2:12][CH:13]=[O:14])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].CN1C(C)C[CH2:19][C:18]1=[O:23].Cl.CNC(C)CCC(O)=O.CNC(C)CCC(OCC)=O.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>>[CH3:1][N:2]([CH:10]([CH3:15])[CH2:11][CH2:12][C:13]([O:23][CH2:18][CH3:19])=[O:14])[C:3]([O:5][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:4]
Reactant: CC1CCC(=O)N1C
Reactant: CC(CCC=O)N(C)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CCOC(=O)CCC(C)NC
Agent: CNC(C)CCC(=O)O
Product: CCOC(=O)CCC(C)N(C)C(=O)OC(C)(C)C

Procedure:
Alternatively, the aryl substituted olefinic amine compounds of the present invention can be prepared by coupling an N-protected aminoaldehyde, such as 4-(N-methyl-N-(tert-butoxycarbonyl)amino)pentanal with an aryllithium. The required aldehyde can be prepared according to methodology described by Otsuka et al., J. Am Chem. Soc. 112: 838-845 (1990), starting from commercially available 1,5-dimethyl-2-pyrrolidinone (Aldrich Chemical Company). Thus, heating 1,5-dimethyl-2-pyrrolidinone with 6N hydrochloric acid forms 4-(methylamino)pentanoic acid, which can be readily esterified to ethyl 4-(methylamino)pentanoate. The latter compound can be treated with one equivalent of di-tert-butyl dicarbonate to give ethyl 4-(N-methyl-N-(tert-butoxycarbonyl)amino)pentanoate which is then reduced with DIBAL-H to give 4-(N-methyl-N-(tert-butoxycarbonyl)amino)pentanal. Reaction of this aldehyde with an aryllithium generates an alcohol, which can subsequently be converted to the N-protected olefinic amine by conversion of the alcohol to the alkyl halide (with, for instance, carbon tetrachloride and triphenylphosphine) and subsequent dehydrohalogenation (with 1,8-diazabicyclo[5.4.0]undec-7-ene). Removal of the tert-butoxycarbonyl protecting group, with trifluoroacetic acid, affords the desired (E)-5-aryl-4-penten-2-amine. Thus, 3-lithio-5-isopropoxypyridine (from 3-bromo-5-isopropoxypyridine and n-butyllithium) can be condensed with 4-(N-methyl-N-(tert-butoxycarbonyl)amino)pentanal to give 1-(3-(5-isopropoxypyridin)yl)-4-(N-methyl-N-(tert-butoxycarbonyl)amino)-1-pentanol, which can subsequently be converted into (4E)-N-methyl-5-(3-(5-isopropoxypyridin)yl)-4-penten-2-amine.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.[O:13]1[C:23]23[C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22]2)[O:17][CH2:16][CH2:15][C@H:14]13.[OH-].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C@H:14]2[C@:23]3([OH:13])[C@H:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)[O:17][CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: C1CCC23O[C@H]2CCO[C@@H]3C1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O[C@]12CCCC[C@@H]1OCC[C@H]2Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-Fluoroaniline (0.173 g, 1.56 mmol) in CH2Cl2 (3 mL) at 0° C. was added trimethylaluminum (2M in toluene, 0.778 mL) dropwise. The mixture was warmed to rt and stirred for 30 min. Trans hexahydro-1aH,4aH-oxireno[d]chromene (0.200 g, 1.30 mmol) in CH2Cl2 (2 mL) was then added and the mixture was stirred at rt overnight. The reaction was cooled to 0° C. and treated with 50% NaOH (1 mL) then water (1 mL). The reaction mixture was extracted 3× with CH2Cl2. The combined organics were dried, filtered, and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 6.90 (t, 2H, J=8.8 Hz), 6.60 (dd, 2H, J=4.2 Hz, 8.8 Hz), 3.88 (dd, 1H, J=5.4 Hz, 12.0 Hz), 3.68-3.74 (m, 1H), 3.47 (dd, 1H, J=4.8 Hz, 11.5 Hz), 3.40 (t, 1H, J=3.2 Hz), 2.30-2.40 (m, 1H), 1.69-1.78 (m, 2H), 1.54-1.68 (m, 5H), 1.45-1.48 (m, 1H), 1.20-1.30 (m, 1H), HRMS (ES) m/z M+H calc'd.: 266.1551. found: 266.1556
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:14]1[S:15][C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]([CH2:19][CH2:20][CH3:21])[N:18]=1.C(N(C(C)C)CC)(C)C>>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][N:11]([C:14]2[S:15][C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]([CH2:19][CH2:20][CH3:21])[N:18]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: CCCc1nc(Br)sc1C(=O)OCC
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc(N2CC(NC(=O)OC(C)(C)C)C2)sc1C(=O)OCC
Yield: 70.8 %

Procedure:
The same operation as in Example (217a) was performed using 3-tert-butoxycarbonylaminoazetidine (161 mg, 0.94 mmol), ethyl 2-bromo-4-n-propyl-1,3-thiazole-5-carboxylate obtained in Example (219a) (217 mg, 0.78 mmol) and diisopropylethylamine (0.27 mL, 1.56 mmol), to obtain 204 mg of the title compound as a white solid (71%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]#[N:14])=[CH:11][C:10]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH:24]=O.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[C:13]([C:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH2:24][C:23]3[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:22]=3[Cl:21])=[CH:7][CH:6]=2)[N:9]=[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=1)#[N:14]
Reactant: N#Cc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Reactant: Cc1cccc(Cl)c1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cccc(Cl)c1CNc1ccc(-n2nc(-c3cccnc3)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a stirred solution of 1-(4-aminophenyl)-3-(3-pyridyl)-5-cyanopyrazole (130 mg, 0.5 mmol) and 2-chloro-6-methylbenzaldehyde (0.9 g) in acetic acid (4 mL) and MeOH (7 mL) at room temperature was added sodium cyanoborohydride (79 mg, 1.25 mmol). The reaction mixture was stirred at room temperature for 16 h and then concentrated under a stream of nitrogen, diluted with water, extracted into ethyl acetate, washed with sodium bicarbonate solution, water and dried (MgSO4). The residue obtained on concentration was chromatographed on silica gel (eluant, gradient of 15-25% EtOAc in CH2Cl2) to provide the title compound (152 mg, 76%). NMR (CDCl3, 400 MHz): 9.2 (s, 1H); 8.7(br, 1H); 8.4(br, 1H); 7.6-7.5 (overlapping m, 3H), 7.4-7.1(overlapping m, 5H), 6.8 (d, 2H), 4.5 (s, 2H), 2.5 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C@H:9]1[C@@H:13]2[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]2[C@@H:11]([C:19]([OH:21])=O)[O:10]1.[C:22]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:25])[NH:23][NH2:24].C(N(CC)CC)C>ClCCl.O.C(OCC)(=O)C>[CH3:7][O:8][C@H:9]1[C@@H:13]2[O:14][C:15]([CH3:17])([CH3:18])[O:16][C@@H:12]2[C@@H:11]([C:19]([NH:24][NH:23][C:22]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:21])[O:10]1
Reactant: CO[C@@H]1O[C@H](C(=O)O)[C@H]2OC(C)(C)O[C@@H]12
Reactant: NNC(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CO[C@@H]1O[C@H](C(=O)NNC(=O)OCc2ccccc2)[C@H]2OC(C)(C)O[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
Oxalyl chloride (3.5 ml, 40 mmol) was added to a solution of (3aS,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylic acid (Justus Liebigs Ann. Chem., 1974, 11, 1856) (3 g, 13.8 mmol) in dichloromethane (25 ml). The solution was stirred at room temperature for 3 hours and the solvent was then evaporated under reduced pressure. The acid chloride was re-dissolved in dichloromethane (25 ml) and treated with benzyl carbazate (2.3 g, 13.8 mmol) and triethylamine (5.7 ml, 41.4 mmol). After having been stirring at room temperature for 12 hours, the mixture was partioned between ethyl acetate (100 ml) and water (50 ml). The ethyl acetate layer was separated, washed with 1M aqueous citric acid solution (50 ml), saturated sodium hydrogencarbonate solution (50 ml) and brine (50 ml) and dried (anhydrous sodium sulphate). Evaporation of solvent under reduced pressure yielded the title compound as a yellow foam (4.87 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1.C([O-])(=O)C.C(=O)([O-])[O-].[K+].[K+]>>[F:27][C:26]([F:28])([F:29])[C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:21][CH:22]=1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC(F)(F)c1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 100 °C

Procedure:
A mixture of 0.511 g (2 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.746 ml (6 mmol) 4-aminobenzotrifluoride is heated for 2.5 h at 100° C. The reaction mixture is then distributed between acetate and 20% aqueous potassium carbonate solution. The title compound is obtained after further processing as described in Example 7; m.p. 205-206° C.; ESI-MS: (M+H)+=381.
Reaction SMILES: [C:1]1([CH:7]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:32][N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][CH:36](O)[CH2:37]2>CN(C=O)C>[C:1]1([CH:7]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([O:10][CH:36]2[CH2:37][CH:38]3[N:33]([CH3:32])[CH:34]([CH2:40][CH2:39]3)[CH2:35]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1C2CCC1CC(O)C2
Reactant: O=C(O)C(Nc1ccccc1)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1C2CCC1CC(OC(=O)C(Nc1ccccc1)c1ccccc1)C2
Temperature: 100 °C
Yield: 7 %

Procedure:
A mixture of 2-phenyl-2-(phenylamino)acetic acid I1 (250 mg, 0.90 mmol), EDC (255 mg, 1.35 mmol), HOBt (245 mg, 1.80 mmol) and 8-methyl-8-azabicyclo[3.2.1]octan-3-ol (380 mg, 2.71 mmol) in dry DMF (10 mL) is heated under microwave irradiation at 100° C. for 1 hour (LC-MS monitoring: complete conversion). The reaction is concentrated under reduced pressure and the residue is portioned between EtOAc and water. The organic phase is dried over Na2SO4, filtered and evaporated to dryness. The resulting crude is purified by preparative HPLC. The collected compound is partitioned between 1N NaHCO3 and DCM, the organic phase is separated dried over Na2SO4, filtered and evaporated under vacuum to give 20.1 mg of the title compound as a colorless oil (7% yield, mixture of diastereoisomers).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[CH3:10][C:11]1([CH3:17])[CH2:16][CH2:15]O[C:12]1=[O:13]>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH2:15][CH2:16][C:11]([CH3:17])([CH3:10])[C:12]2=[O:13])=[CH:4][C:3]=1[CH3:9]
Reactant: CC1(C)CCOC1=O
Reactant: Cc1cc(N)ccc1Br
Product: Cc1cc(N2CCC(C)(C)C2=O)ccc1Br

Procedure:
The title compound was prepared from 4-bromo-3-methylaniline and α,α-dimethyl-γ-butyrolactone following a similar procedure to Description 20, as a pink solid (53%).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:29][CH2:30][CH2:31][C:32]([NH2:34])=[O:33])[C:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:28]=1)[CH3:13]>C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:29][CH2:30][CH2:31][C:32]([NH2:34])=[O:33])[C:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N+:21]([O-:9])=[CH:20][C:19]=2[N:28]=1)[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOCc1nc2cnc3cccnc3c2n1CCCC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c[n+]([O-])c3cccnc3c2n1CCCC(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 136.6 %

Procedure:
mCPBA (1.80 g, 7.28 mmol) was added to a solution of 4-[2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]butanamide (1.63 g, 5.20 mmol) in chloroform (50 mL); the reaction was stirred for three hours at ambient temperature. An analysis by LC/MS indicated the reaction was incomplete; therefore, additional mCPBA (1.2 equivalents) was added. The reaction was stirred for two hours and then diluted with saturated aqueous sodium bicarbonate (75 mL) and chloroform (75 mL). The aqueous layer was extracted with dichloromethane (2×30 mL) and chloroform (12×20 mL), and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 2.34 g of 4-[2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c][ 1,5]naphthyridin-1-yl]butanamide as an orange solid.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:18][O:19][CH2:20][C:21]([O:23]CC)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[OH-].[Na+:29]>O1CCCC1>[C:1]1([C:7]#[C:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:18][O:19][CH2:20][C:21]([O-:23])=[O:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:29]
Reactant: CCOC(=O)COCc1nc2ccccn2c1C#Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C([O-])COCc1nc2ccccn2c1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 45 %

Procedure:
0.061 g (0.182 mmol) of ethyl 2-((3-(phenylethynyl)imidazo[1,2-a]pyridin-2-yl)methoxy)acetate were solubilised with magnetic stirring in 3 ml of a mixture consisting of methanol and tetrahydrofurane (1/1, v/v) and then 0.173 ml (0.173 mmol) of a 1N NaOH aqueous solution were added. The mixture was stirred at r.t. for 2 d before being concentrated in vacuo. The crude residue was triturated in 3 ml of diisopropyl ether, the obtained solid was isolated by filtration and dried under a vacuum bell jar in order to obtain 0.027 g (yield=45%) of sodium 2-((3-(phenyl ethynyl)imidazo[1,2-a]pyridin-2-yl)methoxy)acetate. LC-MS: m/z=307 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.62 (d, J=6.7 Hz, 1H), 7.79-7.58 (m, 3H), 7.45 (dd, J=8.8, 7.2 Hz, 4H), 7.13 (t, J=6.5 Hz, 1H), 4.74 (s, 2H), 3.70 (s, 2H)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:23]1[C:28]([C:29]2[N:34]=[C:33]([CH3:35])[N:32]=[C:31]([N:36]([CH2:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)[CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[N:30]=2)=[CH:27][C:26]([CH2:55][N:56]2[CH2:61][CH2:60][N:59]([S:62]([CH3:65])(=[O:64])=[O:63])[CH2:58][CH2:57]2)=[CH:25][N:24]=1>C1COCC1>[CH3:54][O:53][C:50]1[CH:49]=[CH:48][C:47]([CH2:46][N:36]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[C:31]2[N:32]=[C:33]([CH3:35])[N:34]=[C:29]([C:28]3[C:23]([NH:1][C:2]4[CH:3]=[CH:4][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[CH:10][CH:11]=4)=[N:24][CH:25]=[C:26]([CH2:55][N:56]4[CH2:61][CH2:60][N:59]([S:62]([CH3:65])(=[O:64])=[O:63])[CH2:58][CH2:57]4)[CH:27]=3)[N:30]=2)=[CH:52][CH:51]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Reactant: CC(=O)Nc1ccc(N)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(NC(C)=O)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.8 %

Procedure:
A solution of 4′-aminoacetanilide (0.097 g, 0.643 mmol) in THF (5 mL) was cooled to 0° C. under N2. Lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydrofuran (Aldrich) (0.313 mL, 1.608 mmol) was added and the mixture was stirred at 0° C. for 30 min before 4-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.200 g, 0.322 mmol) was added. The resulting mixture was stirred at 0° C. for 10 min, and then the ice bath was removed and stirring was continued for 2 h. The reaction was quenched with sat. NH4Cl. The resulting mixture was partitioned between pH 7 buffer (1 M TRIS-HCl) and CHCl3. The aqueous layer was extracted with CHCl3 (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, 3% MeOH and 12% EtOAc in DCM) to give the product as a yellow solid (0.140 g). m/z (ESI, +ve ion) 752.0 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 11.82 (s, 1H); 8.72 (s, 1H); 8.24 (s, 1H); 7.54 (d, J=8.48 Hz, 2H); 7.40 (d, J=8.62 Hz, 2H); 7.22 (d, J=7.75 Hz, 4H); 7.07 (br. s., 1H); 6.87 (dd, J=8.18, 4.09 Hz, 4H); 4.85 (d, J=4.68 Hz, 4H); 3.81 (d, J=3.95 Hz, 6H); 3.51 (s, 2H); 3.19 (br. s., 4H); 2.71 (s, 3H); 2.60 (s, 3H); 2.44-2.58 (m, 4H); 2.18 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:6][CH:7]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCCCc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCCCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-hydroxyphenyl)butanol (125 g, 0.75 mole) in acetone 0.85.8 g (1.25 mole) anhydrous potassium carbonate (285.8 g, 1.25 mole) was added, followed by 160.8 (0.94 mole) benzyl bromide. The reaction mixture was then heated at reflux for 25 hours. After cooling to room temperature, the reaction mixture was filtered and the filter cake washed with acetone. The filtrate was concentrated to dryness. The solid residue was washed twice with 500 ml hexane. After drying under high vacuum overnight, 161 g of the desired product were obtained, which was homogeneous on TLC. The 1H NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[Br:12]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][Br:12])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1cccc(CBr)c1
Temperature: 25 °C
Yield: 100.4 %

Procedure:
A suspension of m-tolyl acetate (583 mg), N-bromosuccinimide (691 mg) and α,α′-azobis(isobutyronitrile) (13 mg) in tetrachloromethane (10 mL) was refluxed for 1 hour. The reaction mixture was cooled to room temperature, and the insoluble material was removed by filtration. The filtrate was concentrated to give the title compound (893 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=2[C:5]([C:14]([O:16]C)=[O:15])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[C:10]2[N:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=2[C:5]([C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C)c2c1ccn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C(=O)O)c2ccn(C(C)C)c12
Yield: 80.9 %

Procedure:
To a solution of methyl 7-methyl-1-(1-methylethyl)-1H-indole-4-carboxylate (137 mg, 0.592 mmol) in ethanol (30 mL) was added 1N sodium hydroxide (2.369 mL, 2.369 mmol). The mixture was heated at reflux for 2 h, at which time it was concentrated. The residue was dissolved in water (20 mL) and acidified by addition of 1N HCl. The mixture was extracted with DCM (4×30 mL) and the combined extracts and washed with water and brine, dried over MgSO4, filtered and concentrated to give 104 mg of the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.55 (d, 6H), 2.82 (s, 3H), 5.11-5.28 (m, 1H), 7.00 (d, J=7.83 Hz, 1H), 7.31 (d, J=3.54 Hz, 1H), 7.44 (d, J=3.28 Hz, 1H), 7.89 (d, J=7.58 Hz, 1H). MS(ES) [M+H]+ 218.3.
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([NH:15][CH2:16][CH2:17][NH:18]C(=O)O)=[C:10]3[S:22][C:23]4[CH:28]=[C:27]([O:29]C)[CH:26]=[CH:25][C:24]=4[C:8]([C:9]=23)=[N:7]1)[CH3:2].B(Br)(Br)Br.CO>ClC(Cl)C.ClCCl>[NH2:18][CH2:17][CH2:16][NH:15][C:11]1[CH:12]=[CH:13][C:14]2[N:6]([CH2:5][CH2:4][N:3]([CH2:31][CH3:32])[CH2:1][CH3:2])[N:7]=[C:8]3[C:24]4[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:23]=4[S:22][C:10]=1[C:9]=23
Reactant: CCN(CC)CCn1nc2c3c(c(NCCNC(=O)O)ccc31)Sc1cc(OC)ccc1-2
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCN(CC)CCn1nc2c3c(c(NCCN)ccc31)Sc1cc(O)ccc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 154 %

Procedure:
A 25° C. solution of 0.25 g (0.49 mmol) of [2-[[2-[2-(diethylamino)ethyl]-8-methoxy-2H-[1]benzothiopyrano[4,3,2-cd]indazol-5-yl]amino]ethyl]-carbamic acid; 1,1-dimethylethyl ester (6) in 7.5 mL of dichloroethane was treated dropwise with 2.45 mL (2.45 mmol) of a 1M solution of boron tribromide in dichloromethane. The mixture was stirred at 25° C. for 18 hr, treated cautiously with 3 mL of methanol, then heated at reflux for 6 hr. After cooling to 25° C., the precipitated solids were collected by filtration, washed successively with methanol and dichloromethane, and dried at 200 mm/60° C./overnight to give 0.3 g of 4, 95.2% pure by HPLC. The solids were dissolved in 10.6 mL of ethanol:H2O (4:1) and the solution was treated portionwise with 1.6 mL of a 2.6M solution of hydrogen bromide in 2-propanol. After standing overnight at 0°-5° C., the precipitated solids were collected by filtration, washed, and dried as above to give 0.28 g (90%) of 4 as a salt with 2.9 equivalents of hydrogen bromide, mp 282° C. (dec), 96.1% pure by HPLC.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]=[CH2:12].[CH3:13][P:14]([CH3:23])([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)=[O:15].Cl.N1C=CC=CC=1>C(OCCO)C>[CH3:23][P:14]([C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:11]=[CH2:12])=[CH:18][CH:17]=1)([CH3:13])=[O:15]
Reactant: C=Cn1cnc2c(Cl)ncnc21
Reactant: CP(C)(=O)c1ccc(N)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: C=Cn1cnc2c(Nc3ccc(P(C)(C)=O)cc3)ncnc21
Temperature: 160 °C

Procedure:
A mixture of 6-chloro-9-vinylpurine (0.18 g, 1 mmol), 4-dimethylphosphinylaniline (0.17 g, 1 mmol), and pyridine hydrochloride (0.11 g, 1 mmol) was dissolved in 2-ethoxyethanol (2 mL). The resulting solution was heated at 160° C. for 10 minutes under microwave irradiation. The mixture was concentrated to dryness on a rotavap. EtOAc and aq. NaHCO3 were added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, concentrated on a rotavap, and then subjected to silica gel column chromatography (eluent: 10% methanol/methylene chloride) yielding the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]([C:16]2[CH:28]=[CH:27][C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)[N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH:34]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[CH2:25]([N:22]([CH2:23][CH3:24])[C:20]([C:19]1[CH:27]=[CH:28][C:16]([CH:9]([N:10]2[CH2:11][CH2:12][N:13]([CH2:34][C:30]3[O:29][CH:33]=[CH:32][CH:31]=3)[CH2:14][CH2:15]2)[C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])=[CH:17][CH:18]=1)=[O:21])[CH3:26]
Reactant: O=Cc1ccco1
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(C#N)c2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(C#N)c2)N2CCN(Cc3ccco3)CC2)cc1
Yield: 53 %

Procedure:
To a solution of INTERMEDIATE 3 (567 mg) in 1,2-dichloroethane (15 mL) was added 2-furaldehyde (160 μL, 1.3 eq) and sodium triacetoxyborohydride (450 mg, 1.4 eq). After 3 days the reaction was diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate. The aqueous layer was washed with dichloromethane (2×25 mL) and the combined organic extracts were dried (NgSO4), filtered and concentrated. The residue was purified by flash chromatography, eluting 5% methanol in dichloromethane to yield INTERMEDIATE 4b as a colorless foam (367 mg, 53%).