Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:10]1.[N+:18]([O-])([OH:20])=[O:19].S(=O)(=O)(O)O.[OH-].[Na+]>[N+](C)([O-])=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:18]([O-:20])=[O:19])=[CH:5][C:4]=1[CH:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:10]1
Reactant: O=[N+]([O-])O
Reactant: CCC(=O)N1CCC(c2ccccc2OC)C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: CCC(=O)N1CCC(c2cc([N+](=O)[O-])ccc2OC)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.8 %

Procedure:
1-[3-(2-Methoxy-phenyl)-pyrrolidin-1-yl]-propan-1-one (0.7 g; 3 mmol) were dissolved in 10 ml of nitromethane. At −5° C. to −10° C., a mixture of 0.290 g nitric acid, 0.5 g water and 5.52 g sulphuric acid were added within 25 minutes, and the reaction mixture was stirred for another 1 h at low temperature and 16 h at room temperature. Ice was added, the reaction mixture was adjusted to alkaline pH with 50% aqueous NaOH, and the aqueous phase was extracted twice with diethylether. The organic layers were combined, dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure to yield 0.85 g of the desired product as a mixture of isomers and small amounts of the dinitro derivative which was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5](=[O:8])[CH2:6]Cl.[C:13]([OH:16])(=[O:15])[CH3:14]>>[C:13]([O:16][CH2:6][C:5]([C:4]1[CH:9]=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=1)=[O:8])(=[O:15])[CH3:14]
Reactant: O=C(CCl)c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)O
Product: CC(=O)OCC(=O)c1ccc(Cl)c(Cl)c1

Procedure:
Following the procedure of Example 1, 5 grams of 3,4-dichlorophenacyl chloride are reacted with 5 grams of acetic acid to obtain 3,4-dichlorophenacyl acetate, m.p. 68°-70° C.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[C:17]([O:19][CH3:20])=[O:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=1[CH3:21])=[CH:13][CH:12]=[CH:11][C:10]=2[C:17]([O:19][CH3:20])=[O:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(C(=O)OC)cccc2c1Cl
Reactant: Cc1ccccc1N
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(C(=O)OC)cccc2c1Nc1ccccc1C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
A solution of methyl 3-butyryl-4-chloroquinoline-8-carboxylate (3.8 g) and 2-methylaniline (1.6 ml, 15 mmol) in 1,4-dioxan (20 ml) was heated at reflux for 30 minutes, then left to stand overnight. The solid was filtered off and washed with ethyl acetate, then converted to free base and recrystallised from methanol to obtain methyl 3-butyryl-4-(2-methylphenylamino)quinoline-8- carboxylate (2.86 g, 56%), m.p. 113-115°.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[NH2:8][C:9]([NH2:11])=[NH2+:10].[CH3:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:32])[N:16]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH:17]2[CH2:22][C:23](OCC)=[O:24]>O>[CH2:28]([N:16]1[C:15](=[O:32])[C:14]2[C:18](=[CH:19][CH:20]=[CH:21][C:13]=2[CH3:12])[CH:17]1[CH2:22][C:23]([NH:10][C:9]([NH2:11])=[NH:8])=[O:24])[CH:29]([CH3:31])[CH3:30]
Reactant: NC(N)=[NH2+]
Reactant: CCOC(=O)CC1c2cccc(C)c2C(=O)N1CC(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: Cc1cccc2c1C(=O)N(CC(C)C)C2CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 20 h
Yield: 55.8 %

Procedure:
N-[2-(2-Isobutyl-4-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-acetyl]-guanidine is prepared as described in Example 1, starting with 0.68 g of potassium tert-butoxide, 0.58 g of guanidinium chloride and 0.36 g of ethyl (4-methyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours, followed by addition of 20 cm3 of water. The aqueous phase is extracted with 3 times 100 cm3 of ethyl acetate. The organic extracts are combined and then concentrated to dryness under reduced pressure (0.5 kPa) at a temperature in the region of 40° C. The residue is taken up in dichloromethane and then concentrated again under the same conditions. The residue is taken up in water, triturated and filtered, and then taken up in dichloromethane, triturated and filtered. The solid is then dried in a desiccator. 0.21 g of N-[2-(2-Isobutyl-4-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-acetyl]-guanidine is thus obtained in the form of a white powder melting at 270-272° C. (decomposition). 1H NMR (300 MHz, d6-(CD3)2SO, δ in ppm): 0.76 (d, J=7 Hz: 3H); 0.91 (d, J=7 Hz: 3H); 2.03 (mt: 1H); 2.42 (dd, J=15.5 and 6.5 Hz: 1H); 2.60 (dd, J=15.5 and 6.5 Hz: 1H); 2.62 (s: 3H); 3.00 (dd, J=14 and 5.5 Hz: 1H); 3.56 (dd, J=14 and 10 Hz: 1H); 4.98 (t, J=6.5 Hz: 1H); from 6.40 to 7.10 (broad multiplet: 2H); 7.21 (broad d, J=7.5 Hz: 1H); 7.36 (broad d, J=7.5 Hz: 1H); 7.42 (t, J=7.5 Hz: 1H); from 7.50 to 8.30 (broad multiplet: 2H).
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH2:13][S:14][C:15]2[N:20]3[CH:21]=[CH:22][N:23]=[C:19]3[CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([N:7]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH2:13][S:14][C:15]1[N:20]2[CH:21]=[CH:22][N:23]=[C:19]2[CH:18]=[CH:17][CH:16]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:34])=[O:33]
Reactant: c1ccc(NCCOCCCSc2cccc3nccn23)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(CCOCCCSc1cccc2nccn12)c1ccccc1
Yield: 1.2 %

Procedure:
To a solution of 5-[3-[2-(phenylamino)ethyloxy]propylthio]imidazo[1,2-a]pyridine (1.034 g, 3.158 mmoles) and triethylamine (0.88 ml, 6.3 mmoles) in methylene chloride (30 ml) was added methanesulfonyl chloride (0.37 ml, 4.7 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 10 minutes. The reaction mixture was washed with water and the aqueous layer was extracted with methylene chloride (30 ml×3). The methylene chloride layers were combined and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 16 mg of the desired product (brown oily product)
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26])=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=4)[C:25]#[N:26])[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: N#Cc1cccc(C=O)c1
Product: N#Cc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-formylbenzonitrile was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 3-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]benzonitrile.
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:28][O:29][C:30]([CH3:45])([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=2)=[O:33])[CH3:31])[C:12]([NH:14][C@H:15]2[C@@H:18]([C:19]([O:21][CH3:22])=[O:20])[N:17]([S:23]([O-:26])(=[O:25])=[O:24])[C:16]2=[O:27])=[O:13])[N:10]=1)=O.[Na+:46].CSC(=S)N.[Na]>O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:28][O:29][C:30]([CH3:45])([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=2)=[O:33])[CH3:31])[C:12]([NH:14][C@H:15]2[C@@H:18]([C:19]([O:21][CH3:22])=[O:20])[N:17]([S:23]([O-:26])(=[O:25])=[O:24])[C:16]2=[O:27])=[O:13])[N:10]=1.[Na+:46]
Reactant: COC(=O)[C@@H]1[C@H](NC(=O)C(=NOC(C)(C)C(=O)OCc2ccc([N+](=O)[O-])cc2)c2csc(NC(=O)CCl)n2)C(=O)N1S(=O)(=O)[O-]
Agent: CSC(N)=S
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: COC(=O)[C@@H]1[C@H](NC(=O)C(=NOC(C)(C)C(=O)OCc2ccc([N+](=O)[O-])cc2)c2csc(N)n2)C(=O)N1S(=O)(=O)[O-]

Procedure:
In 30 ml of water is dissolved 1.158 g of sodium cis-3-{2-(2-chloroacetamido-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido}-4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer), and under ice-cooling and stirring, 241 mg of sodium monomethyldithiocarbamate is added. The mixture is stirred at room temperature for one hour, after which a further 241 mg of sodium monomethyldithiocarbamate is added. The mixture is further stirred for one hour. The reaction mixture is then washed with ether and concentrated under reduced pressure. The residue is chromatographed on an Amberlite XAD-II column and lyophilized to give sodium cis-3-{2-(2-amino-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido}-4-methoxycarbonyl-2-oxoazetidine-1-sulfonate (syn-isomer) as a colorless powder.
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([O:1][CH:2]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C(O)c2ccccc2)ccn1
Solvent: c1ccncc1
Product: COc1cc(C(OC(C)=O)c2ccccc2)ccn1
Reaction time: 5 h

Procedure:
A mixture of 104 g of 4-(α-hydroxybenzyl)-2-methoxypyridine, 100 ml of acetic acid anhydride and 100 ml of pyridine was heated under stirring for 5 hours in an oil bath kept at 110° C. After the reaction solution was evaporated, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 5-20% ethyl acetate/hexane, to give 112 g of the target compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:14]4[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=4[Cl:22])[CH2:12][CH2:13][N:7]3[C:6]=2[C:5]([CH2:23][OH:24])=[CH:4][CH:3]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:23]=[O:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=3[Cl:22])[CH2:12][CH2:13][N:7]21
Reactant: Cc1cc(Cl)cc(Cl)c1N1CCn2c1nc1c(Cl)ccc(CO)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)cc(Cl)c1N1CCn2c1nc1c(Cl)ccc(C=O)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.9 %

Procedure:
To a solution of [8-chloro-1-(2,4-dichloro-6-methylphenyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-5-yl]methanol (163 mg, 0.426 mmol) and triethylamine (0.48 mL, 3.44 mmol) in dimethylsulfoxide (5.0 mL) was added sulfur trioxide-pyridine complex (0.44 g, 2.76 mmol) at room temperature. The mixture was stirred at room temperature for 24 hr. Aqueous sodium hydrogen carbonate was added dropwise to the reaction mixture at room temperature. The precipitated solid was collected by filtration. The solid was washed with water, 2-propanol and diisopropyl ether to give the title compound (140.8 mg, 0.37 mmol, 87%) as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]([O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=1.[H-].[Na+].Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][N:25]=1.O>O1CCCC1>[O:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[O:14][CH:3]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][CH:9]=1)[CH2:2][O:1][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][N:25]=1
Reactant: Clc1ncnc2ccccc12
Reactant: CC(C)(C)c1ccc(C(CO)OC2CCCCO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(COc2ncnc3ccccc23)OC2CCCCO2)cc1

Procedure:
1-Hydroxy-2-tetrahydropyranyloxy-2-(4-tert-butylphenyl)ethane (0.3 g, 1.07 mmol) is dissolved in dry tetrahydrofuran (7 ml) and to it is added sodium hydride (30.96 mg, 1.29 mmol). The resulting solution is stirred at room temperature for 30 minutes after which 4-chloroquinazoline (0.175 g, 1.07 mmol) is added to the above solution. The solution is then stirred for 6 hours after which water is added to the mixture. The solution is then extracted in dichloromethane. The organic layer is washed, dried and then concentrated to yield the crude product which is purified by flash chromatography (silica gel; ethyl acetate/hexanes) to give the product.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:24][O:25][C:26]1[C:27](=[O:50])[C:28]([CH3:49])=[C:29]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:45][C:46](=[O:48])[CH3:47])=[C:40]([CH:44]=2)[C:41](O)=[O:42])[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)Cl>[CH:1]1([NH:7][C:41](=[O:42])[C:40]2[CH:44]=[C:36]([CH2:35][C:29]3[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:50])[C:28]=3[CH3:49])[CH:37]=[CH:38][C:39]=2[O:45][C:46](=[O:48])[CH3:47])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)NC3CCCCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 55 %

Procedure:
Cyclohexylamine (0.159 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) and then recrystallized from ether to obtain the titled compound (0.134 g, 0.294 mmol, 55%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:16][C:17]2[CH:27]=[CH:26][C:20]3[NH:21][C:22](=[O:25])[CH2:23][S:24][C:19]=3[CH:18]=2)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:28]I>>[F:1][C:2]1[CH:3]=[C:4]([S:16][C:17]2[CH:27]=[CH:26][C:20]3[N:21]([CH3:28])[C:22](=[O:25])[CH2:23][S:24][C:19]=3[CH:18]=2)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:7]=1
Reactant: CI
Reactant: COC1(c2cc(F)cc(Sc3ccc4c(c3)SCC(=O)N4)c2)CCOCC1
Product: COC1(c2cc(F)cc(Sc3ccc4c(c3)SCC(=O)N4C)c2)CCOCC1
Yield: 41 %

Procedure:
Using the procedure described in Example 12, 4-[5-fluoro-3-(3-oxo-2,3-dihydro-4H-1,4-benzothiazin-7-ylthio)phenyl]-4-methoxytetrahydropyran was reacted with methyl iodide to give 4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-7-ylthio)phenyl]-4-methoxytetrahydropyran in 41% yield, m.p. 131°-133° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([O:8][CH3:9])[CH:7]=1.[H][H]>C1COCC1.[Pd]>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[NH2:10]
Reactant: COc1cc(C)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(C)ccc1N
Yield: 99.7 %

Procedure:
A mixture of 5-methyl-2-nitroanisol (265 g, 1.58 mol) and 10% Pd/C (39.75 g) in THF (1.32 L) was stirred overnight at rt under 1 atm of hydrogen. Filtration over kieselguhr and evaporation afforded 216.1 g of the crude product which was used in the next step without further purification.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH2:15]([C:11]1([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: OC1(Cc2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: OC1(Cc2ccccc2)CCNCC1

Procedure:
A mixture of N-benzyl-4-benzyl-4-piperidinol (2.0 g, 7.1 mmol) and 10% palladium on charcoal catalyst (0.5 g) in absolute ethanol (100 ml), was stirred vigorously at 40° C. under a balloon of hydrogen for 5 h. The reaction mixture was then filtered through a pad of Celite and the filtrate concentrated in vacuo to a grayish solid. This material was dissolved in methanol and filtered a second time through Celite and the filtrate concentrated in vacuo to the product, a white solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH3:10][C:11]1[C:12]([NH2:26])=[N:13][C:14]2([C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH2:25])[CH:23]=3)[O:18][CH2:17][CH2:16]2)[N:15]=1>>[NH2:26][C:12]1[C:11]([CH3:10])=[N:15][C:14]2([C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:25][C:7]([C:5]4[S:6][C:2]([CH3:1])=[CH:3][CH:4]=4)=[O:9])[CH:23]=3)[O:18][CH2:17][CH2:16]2)[N:13]=1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: CC1=NC2(CCOc3ccc(N)cc32)N=C1N
Product: CC1=NC2(CCOc3ccc(NC(=O)c4ccc(C)s4)cc32)N=C1N
Yield: 55.8 %

Procedure:
The title compound (45.5 mg, 57% yield) was prepared as described for Example 13a starting from 5-methylthiophene-2-carboxylic acid (32.1 mg, 0.23 mmol) and 5′-methylspiro[chroman-4,2′-imidazole]-4′,6-diamine (Intermediate 30, 52 mg, 0.23 mmol): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.91 (m, 2 H), 2.23 (s, 3 H), 2.47 (s, 3 H), 4.39 (m, 2 H), 6.55 (s, 2 H), 6.73 (d, 1 H), 6.78 (d, 1 H), 6.86 (dd, 1 H), 7.50 (dd, 1 H), 7.73 (d, 1 H), 9.86 (s, 1 H); MS (ES+) m/z 355 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[CH:12]=[C:11]([NH:14][C:15](=[O:21])OC(C)(C)C)[N:10]=[CH:9][C:8]=3[CH:7]=[CH:6]2)[CH2:3][CH2:2]1.N1C=CC=CC=1.ClC([C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1)=O>Cl.O1CCOCC1>[CH:1]1([CH2:4][N:5]2[C:13]3[CH:12]=[C:11]([NH:14][C:15]([C:31]4[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=4)=[O:21])[N:10]=[CH:9][C:8]=3[CH:7]=[CH:6]2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)Nc1cc2c(ccn2CC2CC2)cn1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C(=O)Nc2cc3c(ccn3CC3CC3)cn2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.6 %

Procedure:
A mixture of tert-butyl 1-(cyclopropylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamate (2C, 260 mg, 0.91 mmol) in 4M HCl in dioxane (3 ml) was stirred at room temperature for 15 h. The mixture was concentrated in vacuo and dissolved in pyridine (3 ml, 37 mmol). To the mixture, methyl 4-(chlorocarbonyl)benzoate (270 mg, 1.4 mmol) was added and stirred at room temperature for 3 hours. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude mixture was purified by chromatography (NH—SiO2, EtOAc) to give methyl 4-(1-(cyclopropylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamoyl)benzoate (2D, 270 mg, 0.77 mmol, 85% yield) as a white powder. 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.39-0.47 (m, 2 H) 0.50-0.59 (m, 2 H) 1.17-1.33 (m, 1 H) 3.89 (s, 3 H) 4.06 (d, J=7.07 Hz, 2 H) 6.57-6.59 (m, 1 H) 7.52 (d, J=3.28 Hz, 1 H) 8.03-8.09 (m, 2 H) 8.14-8.19 (m, 2 H) 8.34 (s, 1 H) 8.65 (s, 1 H) 10.86 (s, 1 H). ESI-MS: m/z 350.0 (M+H)+.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4]O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:28][O:29][C:30]1[CH:49]=[CH:48][C:33]2[N:34]=[C:35]3[N:40]=[C:39]([C:41]4[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=4)[CH:38]=[CH:37][N:36]3[C:32]=2[CH:31]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[F:1][CH2:2][CH2:3][CH2:4][NH:45][C:44]1[CH:46]=[CH:47][C:41]([C:39]2[CH:38]=[CH:37][N:36]3[C:32]4[CH:31]=[C:30]([O:29][CH3:28])[CH:49]=[CH:48][C:33]=4[N:34]=[C:35]3[N:40]=2)=[CH:42][CH:43]=1
Reactant: OCCCF
Reactant: COc1ccc2nc3nc(-c4ccc(N)cc4)ccn3c2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2nc3nc(-c4ccc(NCCCF)cc4)ccn3c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a stirred solution of 3-fluoropropan-1-ol (5 mg, 0.05 mmol) in 0.3 mL o DCM at rt was added Dess-Martin reagent (42 mg, 0.1 mmol). The mixture was stirred for 1 h at rt and 0.3 mL of DCE was added. It was filtered through a cotton pad into a stirred mixture of 4-(7-methoxybenzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)aniline (5 mg, 0.017 mmol, prepared following General Experiment Procedures Q and R) and NaBH(AcO)3 (42 mg, 0.2 mmol) in 0.3 mL of DCE. The reaction was vigorously stirred for 5 min and quenched by adding Na2CO3 (2 mL, saturated). The mixture was extracted with EtOAc (3×5 mL) and the combined organic phase was washed with water (2×10 mL) and dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by reversed phase HPLC (TFA buffered water/MeCN) to afford the title compound as an orange solid (5 mg, 53%, TFA salt). MS (ESI) m/z [M+H]+351.
Reaction SMILES: O[CH:2]=[C:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=O.Cl.[C:14]1([NH:20][NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>C(O)C>[C:14]1([N:20]2[C:4]3[C:5]4[C:10]([CH2:11][C:3]=3[CH:2]=[N:21]2)=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1C(=CO)Cc2ccccc21
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Product: c1ccc(-n2ncc3c2-c2ccccc2C3)cc1

Procedure:
2-Hydroxymethlene indan-1-one (Example 1(ii)(a) (6.0 g, 37.5 mmol), phenylhydrazine hydrochloride (Aldrich) (5.48 g, 37.9 mmol), 10 M hydrochloric acid (1 cm3) and ethanol (30 cm3) were stirred under reflux for 19 hours. After cooling, the solvent was evaporated under reduced pressure and the residue dissolved in dichloromethane, then washed with 2M sodium hydroxide. The organic layer was separated, dried (Na2SO4) filtered and concentrated in vacuo. Purification by Kugelrohr distillation afforded an off-white solid (150° C., 0.01 mmHg) m.p. 119-120° C.