Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:8]=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:10]=O.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:15]=[C:16]([C:20]#[CH:21])[CH:17]=[CH:18][CH:19]=1>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cu+2]>[F:12][C:13]([F:22])([F:23])[C:14]1[CH:15]=[C:16]([C:20]#[C:21][CH2:10][N:4]2[CH2:5][CH2:6][CH2:7][N:1]([CH:8]=[O:9])[CH2:2][CH2:3]2)[CH:17]=[CH:18][CH:19]=1
Reactant: O=CN1CCCNCC1
Reactant: C=O
Reactant: C#Cc1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=CN1CCCN(CC#Cc2cccc(C(F)(F)F)c2)CC1
Temperature: 80 °C
Yield: 86 %

Procedure:
A mixture of 1.28 g (10 mmol) of 1,4-diazepane-1-carbaldehyde and 0.33 g (11 mmol) of paraformaldehyde in 13 ml of dioxane is heated at 80° C. until a homogeneous solution is obtained. 1.70 g (10 mmol) of 3-trifluoromethylphenylacetylene in solution in 7 ml of dioxane and 1.81 g (10 mmol) of copper diacetate are added. The mixture is heated at 80° C. for 4 hours. It is cooled to ambient temperature and diluted with 75 ml of ethyl acetate. The organic phase is washed with 25 ml of 30% ammonia solution and with saturated aqueous sodium chloride solution. It is dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography on silica gel, eluting with a 98/2/0.2 then 96/4/0.4 and 94/6/0.6 mixture of dichloromethane, methanol and 30% ammonia, to give 2.67 g of product in the form of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccc(OCc2ccccn2)cc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
To a solution of 4-hydroxyphenylacetic acid methyl ester (8.4 g; 50 mmol) in DMF (100 ml)were added potassium carbonate (14.0g; 100 mmol) and 2-chloromethylpyridine hydrochloride (8.2 g; 50 mmol), and the resulting mixture was stirred at 50° C. for 24 h. The mixture was then poured into water, extracted with ethyl acetate, the acetate layer was washed with water, brine and concentrated in vacuo. The residue was purified on silica gel column (hexane-ethyl acetate 1:1) to provide 9.5 g of 4-(2-pyridylmethoxy)phenylacetic acid methyl ester.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=2)=[N:5][CH:4]=1)=O.Cl.[CH:24]1([CH2:30][CH2:31][NH2:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:30][CH2:31][NH:32][CH2:1][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=3)=[N:5][CH:4]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NCCC1CCCCC1
Reactant: NC(=O)c1ccc(Oc2ncc(C=O)c3ccccc23)cc1
Agent: Cl
Product: NC(=O)c1ccc(Oc2ncc(CNCCC3CCCCC3)c3ccccc23)cc1

Procedure:
Using the procedure outlined in Example 96, 4-(4-formylisoquinolin-1-yloxy)-benzamide (Preparation 16) and 2-cyclohexylethylamine hydrochloride were converted to the title compound: RT=2.70 min; m/z (ES+)=404.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=O.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[CH:12]1([NH:15][CH2:7][C:6]2[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][CH3:11])[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: COc1ccc(F)cc1C=O
Product: COc1ccc(F)cc1CNC1CC1

Procedure:
Synthesized according to typical procedure J from 5-fluoro-2-methoxybenzaldehyde and cyclopropylamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[N:14]([C:15]([O:17]C3C=CC([N+]([O-])=O)=CC=3)=O)[C:13](=[O:27])[NH:12][C:11]([CH2:28][O:29][CH3:30])=[C:10]2[C:31]([O:33][CH3:34])=[O:32])[CH:5]=[CH:6][C:7]=1[F:8].[N+:35]([C:38]1[CH:39]=[C:40]([C:44]2[CH2:45][CH2:46][N:47]([CH2:50][CH2:51][CH2:52][NH2:53])[CH2:48][CH:49]=2)[CH:41]=[CH:42][CH:43]=1)([O-])=O.C([O-])([O-])=O.[K+].[K+].CO>ClCCl>[NH2:35][C:38]1[CH:39]=[C:40]([CH:44]2[CH2:45][CH2:46][N:47]([CH2:50][CH2:51][CH2:52][NH:53][C:15]([N:14]3[C@@H:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)[C:10]([C:31]([O:33][CH3:34])=[O:32])=[C:11]([CH2:28][O:29][CH3:30])[NH:12][C:13]3=[O:27])=[O:17])[CH2:48][CH2:49]2)[CH:41]=[CH:42][CH:43]=1
Reactant: NCCCN1CC=C(c2cccc([N+](=O)[O-])c2)CC1
Reactant: COCC1=C(C(=O)OC)[C@H](c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: COCC1=C(C(=O)OC)[C@H](c2ccc(F)c(F)c2)N(C(=O)NCCCN2CCC(c3cccc(N)c3)CC2)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
A mixture of 3.02 g (6.33 mmol) 5-methyl 1-(4-nitrophenyl) (6S)-6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate, 1.50 g (5.80 mmol) of 3-(4-(3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinyl)-1-propanamine, 7.94 g (75.5 mmol) of K2CO3 and 1.00 mL of methanol in 200 mL dichloromethane (under argon) was stirred at room temperature for 1 hour. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in 100 mL of ethyl acetate and washed 3×50 mL of 5% aqueous NaOH solution, the organic layer was dried (MgSO4) and concentrated in vacuo. The residue was dissolved in 100 mL of anhydrous ethanol containing 0.50 g 10% Pd/C and the reaction mixture was stirred under a hydrogen balloon for 24 hours. The reaction mixture was passed through a column of Celite 545 filtering agent, washed with ethanol, the filtrate was dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica, 9.5:0.5, dichloromethane:methanol+1% isopropyl amine) to afford 1.65 g (52.0% yield) of the desired product.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:34])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([F:33])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]1([NH:41][C:42]([C:44]2([C:47](O)=[O:48])[CH2:46][CH2:45]2)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]1([O:7][C:8](=[O:34])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:47]([C:44]4([C:42](=[O:43])[NH:41][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH2:45][CH2:46]4)=[O:48])=[C:28]([F:33])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1(C(=O)Nc2ccccc2)CC1
Reactant: Nc1ccc(Oc2ccnc(N(C(=O)Oc3ccccc3)C(=O)Oc3ccccc3)c2)cc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccccc4)CC3)c(F)c2)ccn1
Reaction time: 8 h
Yield: 87.9 %

Procedure:
A crude product of [4-(4-amino-3-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (219 mg) was dissolved in N,N-dimethylformamide (5 ml). 1-(Phenylcarbamoyl)cyclopropanecarboxylic acid (196 mg), triethylamine (0.133 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (422 mg) were added under a nitrogen atmosphere at room temperature, followed by stirring overnight. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (3 times) and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed and the resultant residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=3:2) to provide the titled compound as white powder (271 mg).
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[C:9](C(O)=O)[S:10][C:6]=2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[F:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2cc(C(=O)O)sc12
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(F)c2ccsc12
Temperature: 200 °C
Yield: 69.5 %

Procedure:
4-Fluoro-7-methoxy-1-benzothiophene-2-carboxylic acid (2.00 g, 8.84 mmol) was added in one portion to DBU (8 mL) and dimethyl acetamide (10 mL). This was heated in the microwave with 300 W at 200° C. for 1 h. The reaction mixture was allowed to cool and poured onto water (100 mL). Product was extracted with hexane (2×100 mL), washed with aqueous hydrochloric acid (2 N, 50 mL), aqueous sodium hydroxide (2 N, 50 mL), and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with hexane:ethyl acetate [96:4] to give an oil (1.12 g, 70%); δH (300 MHz, CDCl3) 7.4 (2H, s, Ar), 6.9 (1H, t, Ar), 6.60 (1H, dd, Ar), 3.91 (3H, s, OCH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[CH:9]=[C:8]([C:16](O)=[O:17])[C:7]1=[O:19].C(Cl)(=O)C([Cl:27])=O.CN(C)C=O>ClCCl>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[CH:9]=[C:8]([C:16]([Cl:27])=[O:17])[C:7]1=[O:19]
Reactant: COc1ccccc1Cn1c(=O)c(C(=O)O)cc2cccnc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccccc1Cn1c(=O)c(C(=O)Cl)cc2cccnc21
Temperature: 40 °C
Reaction time: 1 h

Procedure:
3.83 g (12.3 mmol) of 1-(2-methoxybenzyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid was dissolved in dichloromethane (100 mL), and 7.5 mL (89 mmol) of oxalyl chloride was added thereto. One droplet of N,N-dimethylformamide was added to the above mixture, and the resulting mixture was stirred for one hour at 40° C. The reaction solution was concentrated under reduced pressure, and thus 1-(2-methoxybenzyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid chloride was obtained. The acid chloride thus obtained was dissolved in dichloromethane (100 mL), and this solution was added to a dichloromethane (100 mL) solution of 1.52 g (13.6 mmol) of 1,3-cyclohexanedione and 2.11 mL (14.8 mmol) of triethylamine under ice cooling. The mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into an aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with dichloromethane. The organic phase was dried and concentrated. The residue was washed with diisopropyl ether, and thus 4.82 g of the title compound was obtained as a light yellow solid (yield: 97%).
Reaction SMILES: [NH2:1][C:2]1[N:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20](=[O:26])(=[O:25])[NH:21][CH:22]3[CH2:24][CH2:23]3)[CH:15]=2)=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[C:27]([C:31]1[CH:36]=[CH:35][C:34]([Mg]Br)=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>C1COCC1.C(Cl)Cl>[NH2:1][C:2]1[N:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]([S:20]([NH:21][CH:22]3[CH2:23][CH2:24]3)(=[O:25])=[O:26])[CH:17]=[CH:18][CH:19]=2)=[CH:10][C:3]=1[C:4](=[O:5])[C:34]1[CH:35]=[CH:36][C:31]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:32][CH:33]=1
Reactant: CON(C)C(=O)c1cc(-c2cccc(S(=O)(=O)NC3CC3)c2)cnc1N
Reactant: CC(C)(C)c1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)c2cc(-c3cccc(S(=O)(=O)NC4CC4)c3)cnc2N)cc1
Temperature: 25 °C

Procedure:
A solution of 2-amino-5-(3-cyclopropylsulfamoyl-phenyl)-N-methoxy-N-methyl-nicotinamide (Intermediate GA) (0.08 g, 0.21 mmol) in THF (3 ml) is cooled to 0° C. 2M 4-tert Butyl phenyl magnesium bromide in THF (0.32 ml, 0.64 mmol) is added dropwise, and the resulting solution is stirred and allowed to warm to room temperature overnight. The reaction is quenched with 2M HCl (5 ml). The solvent is removed in vacuo and the residue purified by reverse phase column chromatography (Isolute™ C18, 0-100% MeCN in water −0.1% TFA). The solid obtained is dissolved in DCM, washed with 2M NaOH. The solvent is removed in vacuo and the resulting solid is dried in vacuo at 40° C. overnight to yield the title compound. 1H NMR (400 MHz, DMSO-6) δ 8.69 (1H, d), 8.01 (1H, d), 7.97-7.89 (3H, m), 7.78 (1H, d), 7.72-7.67 (5H, m), 7.64 (2H, d), 2.18-2.13 (1H, m), 1.38 (9H, s), 0.47-0.38 (4H, m); MS m/z 450 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH2:12]([N:20]=[C:21]=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C([N-]C(C)C)(C)C.[Li+]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH2:10][C:21]([NH:20][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:22]
Reactant: CC(=O)c1ccc(F)cc1F
Reactant: CCCCCCCCN=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCCCCCCNC(=O)CC(=O)c1ccc(F)cc1F
Yield: 40.6 %

Procedure:
The title compound was prepared from 2',4'-difluoroacetophenone (5.0 g, 0.032 mol), octyl isocyanate (4.97 g, 0.032 mol), and lithium diisopropylamide (0.032 mol) using the procedure described in Example 1. Purification by flash chromatography (silica gel, 20% EtoAc/hexane) yielded 4.25 g (0.013 mol, 42.6%) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:5]=[CH:4][C:3]=1[CH:17]([CH:27]([CH3:29])[CH3:28])[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].CI.[CH3:32][Si]([N-][Si](C)(C)C)(C)C.[Na+]>>[F:1][C:2]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:15])([CH3:16])[O:9]2)[CH:5]=[CH:4][C:3]=1[CH:17]([CH:27]([CH3:29])[CH3:28])[CH2:18][N:19]([CH3:32])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)C(CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Product: CC(C)C(CN(C)C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Yield: 96.4 %

Procedure:
Following the procedure described for Example 647, tert-butyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methylbutylcarbamate (650 mg, 1.6 mmol) was reacted with methyl iodide (1M solution in toluene, 3.2 mL, 3.2 mmol) and NaHMDS (1 M solution, 4.8 mL, 4.8 mmol) to afford the desired product (650 mg, 94%) as viscous mass. ESI MS m/z 421 [C23H38FBNO4+H]+
Reaction SMILES: C([O:5][C:6](=[O:16])[CH:7]([CH2:11][S:12](Cl)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[CH:18]=1.C(N(CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:10][CH:8]([CH3:9])[CH:7]([CH2:11][S:12]([N:32]1[CH2:33][CH2:34][N:29]([C:26]2[CH:25]=[CH:24][C:23]([C:19]3[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=3)=[CH:28][CH:27]=2)[CH2:30][CH2:31]1)(=[O:13])=[O:14])[C:6]([OH:5])=[O:16]
Reactant: CC(C)C(CS(=O)(=O)Cl)C(=O)OC(C)(C)C
Reactant: c1cncc(-c2ccc(N3CCNCC3)cc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(-c3cccnc3)cc2)CC1)C(=O)O
Reaction time: 2 h
Yield: 91.9 %

Procedure:
2-Chlorosulfonylmethyl-3-methylbutyric acid tert-butyl ester (0.072 g) [preparation described in WO-A-98/05635] was added as a solution in dichloromethane (2 ml) to a stirred mixture of 1-(4-pyridin-3-yl-phenyl)piperazine (0.053 g) and triethylamine (40 μl) and the resultant solution stirred at room temperature for 2 h. Trifluoroacetic acid (4 ml) was then added dropwise, and the mixture stirred for a further 2 h. The solvent were removed under reduced pressure and the residue azeotroped with 1:1 dichloromethane/hexane (2×10 ml). The residue was then diluted with diethyl ether (20 ml) and extracted with 1 M sodium hydroxide (10 ml) followed by 0.5 M sodium hydroxide (10 ml). The combined aqueous extracts were then washed with diethyl ether (20 ml), then cautiously acidified to pH 5 with acetic acid, forming a precipitate. The mixture was then extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with water (2×10 ml), saturated brine (10 ml), dried (Na2SO4) and reduced in vacuo to give the title compound as a pale green solid (0.085 g, 93%).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:15][CH:14]=2)=[N:10][CH:11]=1)([O-:5])=[O:4].I[CH3:28]>C1COCC1>[CH3:28][N:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:11][N:10]=2)=[CH:14][CH:15]=1)[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.8 %

Procedure:
To a THF (30 mL) suspension of NaH (60% in oil, 1.22 g) was added tert-butyl {4-[(5-nitropyridin-2-yl)oxy]phenyl}carbamate (7.77 g) at 0° C. After stirring at 0° C. for 10 min, iodomethane (4.33 g) was added and the mixture was stirred at room temperature for 3 hours. The mixture was poured into ice water and extracted with AcOEt. The organic layer was washed with water, saturated aqueous NaCl and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=2/1) to afford the title compound (6.30 g) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C@@H:26]([OH:28])[CH3:27])=[CH:21][CH:20]=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]3[CH2:15][CH2:16][CH2:17][C:3]3=[C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][C@@H:26]([OH:28])[CH3:27])=[CH:23][CH:24]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: C[C@H](O)Cc1ccc(N)cc1
Product: C[C@H](O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 26.4 %

Procedure:
Following general procedure B1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.089 g, 0.34 mmol) was reacted with (5)-1-(4-aminophenyl)propan-2-ol (0.061 g, 0.41 mmol) to afford the title compound (0.034 g, 26%) as a light yellow solid. MW=378.89. 1H NMR (DMSO-d6, 500 MHz) δ 8.06 (s, 1H), 7.91-7.88 (m, 1H), 7.76-7.72 (m, 1H), 7.46-7.38 (m, 2H), 7.23-7.14 (m, 5H), 4.53 (d, J=4.5 Hz, 1H), 3.86-3.78 (m, 1H), 2.90 (t, J=7.5 Hz, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.71-2.65 (m, 1H), 2.58-2.52 (m, 1H), 2.08 (quin, J=7.5 Hz, 2H), 1.05 (d, J=6.5 Hz, 3H); APCI MS m/z 379 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30](C)C)[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:34][C@@H:35]1[N:40]([CH3:41])[CH2:39][CH2:38][N:37]([CH2:42][CH2:43][OH:44])[CH2:36]1.[CH3:45][C@H]1N(C)[C@@H](C)CN(CCO)C1>>[CH3:34][C@@H:35]1[N:40]([CH3:41])[CH2:39][CH2:38][N:37]([CH2:42][CH2:43][O:44][C:2]2[CH:7]=[CH:6][N:5]3[C:8]([C:11]([NH:13][C:14]4[CH:22]=[CH:21][CH:20]=[C:19]5[C:15]=4[C:16]([CH3:33])=[N:17][N:18]5[CH2:23][C:24]4[CH:29]=[C:28]([CH3:45])[CH:27]=[C:26]([CH3:30])[N:25]=4)=[O:12])=[CH:9][N:10]=[C:4]3[CH:3]=2)[CH2:36]1
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(Cl)ccn34)c12
Reactant: C[C@H]1CN(CCO)CCN1C
Reactant: C[C@@H]1CN(CCO)C[C@H](C)N1C
Product: Cc1cc(C)nc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C)[C@@H](C)C6)ccn45)cccc32)c1
Yield: 42 %

Procedure:
Prepared according to Example 7, Step F, substituting 7-chloro-N-(1-((4,6-dimethylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide for 7-chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol for 2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)ethanol to give the title compound (42%). MS (APCI), positive scan, m/z=567.1 (M+H).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([O:11][CH:12]=[C:13]1[CH2:18][CH2:17]C[CH:15]=[CH:14]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CSC.B.Cl.[C:24]([O-:27])(O)=O.[Na+]>C(Cl)Cl>[CH2:4]([O:11][CH2:12][CH:13]([CH2:18][CH2:17][CH2:24][OH:27])[CH2:14][CH2:15][OH:1])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C1=CC(=COCc2ccccc2)CCC1
Reactant: O=C([O-])O
Reactant: O=[O+][O-]
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CSC
Product: OCCCC(CCO)COCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
Ozone was bubbled through a solution of (±)-3-benzyloxymethylene-1-cyclohexene (1.35 g, 6.70 mmol) in CH2Cl2 (65 mL) at -78° C. until the blue color of unreacted ozone persisted. The reaction mixture was allowed to warm to room temperature, while dry nitrogen was bubbled through the reaction. Borane-dimethyl sulfide complex (10.0M in THF, 2.7 mL, 27.8 mmol) was added via syringe over several minutes, and the reaction mixture was allowed to stand at room temperature for 24 hours. The reaction mixture was treated with 5 percent aqueous HCl (1 mL) and stirred vigorously for one hour. Solid NaHCO3 was added until the mixture tested basic to litmus paper. The mixture was dried over anhydrous MgSO4. The reaction mixture was filtered and concentrated to afford the crude (±)-3-(benzyloxy)methyl-1,6 hexanediol (1.49 g, ca. 100 percent) as an oil. This material, which showed essentially a single spot on TLC analysis, Rf=0.25, 25 percent EtOAc in hexane, was used directly in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13](C=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[NH2:18][N:19]1[C:23](=[O:24])[CH2:22][S:21][C:20]1=[S:25].[C:26]1(C)C=CC=CC=1>C(O)(=O)C>[OH:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][CH:13]=[C:16]([CH:17]=2)[CH:26]=[C:22]2[S:21][C:20](=[S:25])[N:19]([NH2:18])[C:23]2=[O:24])[CH2:8][CH2:9]1
Reactant: Cc1ccccc1
Reactant: O=Cc1ccc(N2CCN(CCO)CC2)cc1
Reactant: NN1C(=O)CSC1=S
Solvent: CC(=O)O
Product: NN1C(=O)C(=Cc2cccc(N3CCN(CCO)CC3)c2)SC1=S
Temperature: 25 °C

Procedure:
An admixture of 4.7 grams of 4-[4'-(2"-hydroxyethyl)piperazino]benzaldehyde (0.02 mol), 3.0 grams of 3-aminorhodanine (0.02 mol), toluene (30 mL), and glacial acetic acid (5 mL) was refluxed for 4 hours. The admixture was then cooled to room temperature and the solvent was decanted. The remaining paste was triturated with ethanol and then filtered off and dried.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Br)(Br)[Br:12]>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][Br:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCC1CCCCC1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: BrCCCC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.2 %

Procedure:
To the chilled (0° C.) 3-cyclohexyl-1-propanol (5 g, 35.15 mmol) was added slowly a solution of phosphorus tribromide (1.1 mL, 17.6 mmol) in dichloromethane (2 mL). Upon completion of the addition, the reaction mixture was allowed to warm up to room temperature and was stirred for 4 hours. The reaction was quenched by addition of saturated sodium bicarbonate aqueous solution (5 mL) and 10% NaOH (10 mL). The resulting mixture was extracted with diethyl ether (3×50 mL), the combined organic extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to provide an oil. Vacuum distillation yielded 3.4 g (47% yield) of the title compound.