Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:18])([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])=[CH:4][CH:3]=1.C([NH:29][CH2:30][C:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32])(OCC1C=CC=CC=1)=O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[NH2:29][CH2:30][C:31]([NH:33][CH2:34][C:35]([NH:18][C:9]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)([CH3:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:36])=[O:32]
Reactant: O=C(O)CNC(=O)CNC(=O)OCc1ccccc1
Reactant: CC(N)(Cc1ccc(F)cc1)c1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc(F)cc1)(NC(=O)CNC(=O)CN)c1ccc(F)cc1
Reaction time: 3 h
Yield: 29.6 %

Procedure:
To a stirred solution of 1,2-bis(4-fluorophenyl)-2-propylamine (8.47 g, 0.034 mol) in 200 ml of chloroform under nitrogen, was added N-CBZ-glycylglycine (9.13 g, 0.034 mol) and then a solution of dicyclohexylcarbodiimide (7.43 g, 0.036 mol) in 100 ml of chloroform and the mixture stirred for 72 hours. The precipitated solid was removed by filtration and the solvent evaporated. The residue was treated with ethylacetate (125 ml), filtered, an additional 250 ml of ethylacetate added and then washed with cold 1% HCl (150 ml), brine (200 ml), dried and the solvent evaporated. The residue was dissolved in 400 ml of methanol and 35 ml of 10% HCl and hydrogenated at 40 psi in a Parr apparatus over 3.0 g of 5% Pd/c catalyst for 3 hours. The catalyst was removed by filtration, solvent evaporated and the residue dissolved in water (300 ml) and chloroform (300 ml), basified to pH 11 with 50% NaOH, shaken and separated. The aqueous phase was extracted with chloroform (3×150 ml), and the combined organic phases were washed with water (2×200 ml), dried, and evaporated to a pale yellow oil. This oil was crystallized from cyclohexane (150 ml) and ethanol (5 ml); the solid obtained was recrystallized from hexane (150 ml) and ethanol (10 ml), and vacuum dried at 83° C. for 96 hours to give 3.64 g of 2-glycinamido-N-[1,2-bis(4-fluorophenyl)-1-methylethyl]acetamide, mp. 139°-140° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C(OCC)C>[Cl:8][C:7]1[C:2]([NH:11][C@H:12]2[CH2:13][CH2:14][C@@H:15]([C:18]([OH:24])([CH3:23])[C:19]([F:21])([F:22])[F:20])[CH2:16][CH2:17]2)=[N:3][CH:4]=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: CC(O)(C1CCC(N)CC1)C(F)(F)F
Reactant: CCc1ncnc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(O)C(F)(F)F)CC2)c1Cl
Yield: 39.5 %

Procedure:
1.3 g (7.2 mmol) of 4,5-dichloro-6-ethylpyrimidine, 2.7 g (7.2 mmol) of 1-amino-4(2-hydroxy-1,1,1-trifluoro-2-propyl)cyclohexane and 1.5 g (17.1 mmol) of potassium carbonate were stirred in 10 ml of dimethylformamide at from 80° to 90° C. for 6 hours. The solvent was stripped off and the residue was taken up in water/diethyl ether, and the organic phase was washed with water, dried and concentrated. For purification it was chromatographed on silica gel (ethyl acetate). 1.0 g of product was obtained as colorless crystals. m.p.: 119to 121° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])=[C:4]([NH:20][CH3:21])[N:3]=1.[CH3:22][NH:23][CH3:24]>>[F:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:23]([CH3:24])[CH3:22])=[N:3][C:4]=2[NH:20][CH3:21]
Reactant: CNc1nc(Cl)nc2c1ncn2Cc1c(F)cccc1F
Reactant: CNC
Product: CNc1nc(N(C)C)nc2c1ncn2Cc1c(F)cccc1F

Procedure:
In a manner analogous to that described in Example 2 it is possible, by reacting 2-chloro-9-(2,6-difluorobenzyl)-6-(N-methylamino)-9H-purine (Example 17) with N,N-dimethylamine, to obtain the 9-(2,6-difluorobenzyl)-2-(N,N-dimethylamino)-6-(N-methylamino)-9H-purine, which has a melting range of from 196° to 199° (methanol), the reaction mixture being heated at 140° for 24 hours.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][N:9](C(OC(C)(C)C)=O)[C:8](=[O:18])[CH2:7][C:6]1=[O:19])[CH:2]([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([CH:5]1[CH2:10][NH:9][C:8](=[O:18])[CH2:7][C:6]1=[O:19])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC1CN(C(=O)OC(C)(C)C)C(=O)CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC1CNC(=O)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
A mixture of rac-tert-butyl 5-isobutyl-2,4-dioxopiperidine-1-carboxylate (300 mg, 1.115 mmol), DCM (1 mL), and TFA (0.1 mL) was stirred at 25° C. for 2 h. The mixture was concentrated in vacuo and chromatographically purified (basic alumina, 40% EtOAc/petroleum ether) to afford rac-5-isobutylpiperidine-2,4-dione (85 mg, 45% yield) as a pale yellow solid: m/z (ESI, +ve) 170 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[F:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: Fc1ccccc1CBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1ccc(OCc2ccccc2F)cc1
Temperature: 80 °C
Yield: 79.2 %

Procedure:
A suspension of 1-(bromomethyl)-2-fluorobenzene (D91, 11.5 g, 60.8 mmol), 4-hydroxybenzaldehyde (5.3 g, 43.3 mmol) and K2CO3 (12.0 g, 86.8 mmol) in acetone was divided in three equal parts and heated in a microwave apparatus at 80° C. for 40 min. The mixtures were diluted with water and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and evaporated. The residue was purified via flash chromatography (cyclohexanes:ethyl acetate 95:5) to give the title compound (7.9 g, 79%). Rf (cyclohexanes:ethyl acetate 8:2): 0.38.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[N:19]=[C:6]2[CH:7]=[C:8]([NH:11]C(=O)OC(C)(C)C)[CH:9]=[CH:10][N:5]2[N:4]=1.Cl>ClCCl>[CH3:1][N:2]([CH3:20])[C:3]1[N:19]=[C:6]2[CH:7]=[C:8]([NH2:11])[CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: CN(C)c1nc2cc(NC(=O)OC(C)(C)C)ccn2n1
Agent: Cl
Solvent: ClCCl
Product: CN(C)c1nc2cc(N)ccn2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.2 %

Procedure:
A mixture of tert-butyl 2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamate (1.8 g, 6.49 mmol) in dichloromethane (15 ml) and hydrochloric acid (5N in diethyl ether, 50 ml, 250 mmol) is stirred for 18 hours at room temperature. The solvent is evaporated and the residue dissolved in water (100 ml), made basic with 32% aqueous sodium hydroxide and extracted twice with ethyl acetate. The combined organic layers are washed with water, dried with magnesium sulfate and the solvent is evaporated under reduced pressure affording N2,N2-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2,7-diamine (727 mg, 63.2%) as a yellow solid. Mp.: 236-8° C. MS: m/z=178.1 (M+H+).
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4C(=O)CCCC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:35][C:36]1([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[N:51]=[C:50]4[CH2:52][CH2:53][CH2:54][CH2:55][C:56](=[O:57])[C:49]4=[CH:48][C:47]=3[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37]1)(C)(C)C>>[NH2:35][C:36]1([C:40]2[CH:41]=[CH:42][C:43]([C:46]3[N:51]=[C:50]4[CH2:52][CH2:53][CH2:54][CH2:55][C:56](=[O:57])[C:49]4=[CH:48][C:47]=3[C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)=[CH:44][CH:45]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCCC4)cc2)CCC1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCC4)cc2)CCC1
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCCC4)cc2)CCC1
Yield: 122 %

Procedure:
Following the procedure for 2-(4-(1-aminocyclobutyl)phenyl)-3-phenyl-7,8-dihydroquinolin-5(6H)-one, tert-butyl(1-(4-(5-oxo-3-phenyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-2-yl)phenyl)cyclobutyl)carbamate (14 mg, 0.03 mmol) was reacted to afford the title compound as a white solid (14 mg, 100%). LCMS (Method A): RT=4.26 min, M-NH2=366. 1H NMR (500 MHz, MeOD): 8.06 (1H, s), 7.50 (2H, d), 7.42 (2H, d), 7.29-7.28 (3H, m), 7.20-7.18 (2H, m), 3.30 (2H, t), 2.89 (2H, t), 2.78-2.72 (2H, m), 2.59-2.54 (2H, m), 2.25-2.19 (1H, m), 2.06-2.01 (2H, m), 1.98-1.92 (3H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.OO.[CH3:15][NH:16][CH:17]=[O:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:17]([NH:16][CH3:15])=[O:18])[CH:3]=1
Reactant: CNC=O
Reactant: Clc1ccncc1
Agent: O=S(=O)(O)O
Agent: OO
Product: CNC(=O)c1cc(Cl)ccn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 5.3 %

Procedure:
Caution: this is a highly hazardous, potentially explosive reaction. To a stirring solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) at room temp. was added conc. H2SO4 (3.55 mL) to generate an exotherm. To this mixture was added H2O2 (30% wt in H2O, 17 mL) followed by FeSO4.7H2O (0.56 g) to generate another exotherm. The resulting mixture was stirred in the dark at room temp. for 1 h, then warmed slowly over 4 h to 45° C. When bubbling had subsided, the reaction was heated at 60° C. for 16 h. The resulting opaque brown solution was diluted with H2O (700 mL) followed by a 10% NaOH solution (250 mL). The resulting mixture was extracted with EtOAc (3×500 mL). The organic phases were washed separately with a saturated NaCl solution (3×150 mL), then they were combined, dried (MgSO4) and filtered through a pad of silica gel with the aid of EtOAc. The resulting brown oil was purified by column chromatography (gradient from 50% EtOAc/50% hexane to 80% EtOAc/20% hexane). The resulting yellow oil crystallized at 0° C. over 72 h to give 4-chloro-N-methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtOAc/50% hexane) Rf 0.50; 1H NMR (CDCl3) δ3.04 (d, J=5.1 Hz, 3H), 7.43 (dd, J=5.4, 2.4 Hz, 1H), 7.96 (br s, 1H), 8.21 (s, 1H), 8.44 (d, J=5.1 Hz, 1H); CI-MS m/z 171 ((M+H)+).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([S:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]C)=[O:30])=[C:12]([CH2:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)[S:13][C:7]=2[N:6]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:5]1=[O:37].Cl>CO.O1CCCC1.O>[CH3:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([S:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[C:12]([CH2:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)[S:13][C:7]=2[N:6]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:5]1=[O:37]
Reactant: COC(=O)CCCSc1c(Cc2cccc3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCC(=O)O)c(Cc3cccc4ccccc34)sc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.1 %

Procedure:
Aqueous sodium hydroxide solution (1M, 4 ml) was added to a solution of methyl 4-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]butanoate (0.382 g) in methanol (8 ml) and tetrahydrofuran (4 ml). The mixture was stirred at room temperature for 4 hours, diluted with water (50 ml), acidified with hydrochloric acid (2M) and extracted with an ether/ethyl acetate mixture (5:3, 80 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residual solid was recrystallised from ethyl acetate/hexane to give the title compound (0.19 g).
Reaction SMILES: [OH-].[Na+:2].[C:3](=[S:6])([SH:5])[NH2:4].[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C(=S)=S>[C:3](=[S:5])([S-:6])[NH2:4].[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[Na+:2]
Reactant: NC(=S)S
Agent: NCCCN1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: S=C=S
Product: NC(=S)[S-]
Reaction time: 1 h

Procedure:
When the reactor contents had reached 30° C., the carbon disulfide feed was started at a slow drop-wise rate. After five minutes the sodium hydroxide feed was also started at a slow drop-wise rate. The feeds were regulated such that the reaction temperature did not exceed 45° C., and both additions were complete after approximately forty-five minutes. The reaction was then allowed to cook for one hour at 40° C., after which the 4-(3-aminopropyl)morpholine dithiocarbamate solution was a clear orange solution. The pH was 12.0-14.0 and the activity was 28-30% by calculation.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]#[C:22][C:23]1[C:24]([O:33][CH3:34])=[CH:25][C:26]([O:31][CH3:32])=[C:27]([CH:30]=1)[CH:28]=O>>[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]#[C:22][C:23]1[C:24]([O:33][CH3:34])=[CH:25][C:26]([O:31][CH3:32])=[C:27](/[CH:28]=[CH:2]/[C:1]([C:4]2[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=2)=[O:3])[CH:30]=1
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: COc1cc(OC)c(C=O)cc1C#Cc1ccccc1N
Product: COc1cc(OC)c(/C=C/C(=O)c2ccc(S(N)(=O)=O)cc2)cc1C#Cc1ccccc1N
Yield: 82.6 %

Procedure:
Ex-35D: 4-{3E-[5-(2-Amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide was prepared in a similar manner as Ex-1 using 4-acetylbenzenesulfonamide (Ex-35A) and 5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C), 82.6% yield, yellow solid, mp 167–169° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.27 (d, J=8 Hz, 2H), 8.20(s, 1H), 8.01 (d, J=16Hz, 1H), 7.94 (d, J=8 Hz, 2H), 7.84 (d, J=16 Hz, 1H), 7.53 (s, 2H), 7.15–7.17 (m, 1H), 7.02–7.08 (m, 1H), 6.77 (s, 1H), 6.72 (d, J=8 Hz, 1H), 6.49–6.54 (m, 1H), 5.46 (br, 1H) 3.97 (s, 3H), 3.96 (s, 3H). MS m/z: 462 ([M+H]+, 100%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2.[NH:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=2[N:18]=[N:17]1.N1CCCCC1>CO>[NH:16]1[C:20]2[CH:21]=[CH:22][C:23](/[CH:25]=[C:7]3/[C:8](=[O:13])[NH:9][C:10]4[C:6]/3=[CH:5][C:4]([O:3][C:2]([F:1])([F:14])[F:15])=[CH:12][CH:11]=4)=[CH:24][C:19]=2[N:18]=[N:17]1
Reactant: O=Cc1ccc2[nH]nnc2c1
Reactant: O=C1Cc2cc(OC(F)(F)F)ccc2N1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2ccc(OC(F)(F)F)cc2/C1=C\c1ccc2[nH]nnc2c1
Temperature: 60 °C
Yield: 23.3 %

Procedure:
A scintillation vial was charged with 5-(trifluoromethoxy)indolin-2-one (27 mg, 0.124 mmol), 1H-benzo[d][1,2,3]triazole-5-carbaldehyde (20 mg, 0.136 mmol), piperidine (2 uL, 0.012 mmol) and MeOH (2 mL). The reaction was then heated to 60° C. for 2 hrs. The MeOH was removed in vacuo and the residue purified by column chromatography (silica gel, 95:4:1, CH2Cl2/MeOH/AcOH) to give the title compound as a yellow solid (10 mg, 23%). 1H NMR (400 MHz, CD3OD) δ 8.23 (s, 1H), 8.04 (d, J=4.5 Hz, 1H), 8.02 (s, 1H), 7.77 (d, J=9.3 Hz, 1H), 7.42 (s, 1H), 7.21-7.18 (m, 1H), 6.99 (s, 1H); MS ESI 347.0 [M+H]+, calcd for [C16H9F3N4O2+H]+ 347.08.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#N)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].CN(C)[CH:19]=[O:20].[BH4-].[Na+].COCCl>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][O:20][CH3:19])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(=O)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Agent: COCCl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COCSc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
2.37 G. of 1-acetamido-2-nitro-4-thiocyanatobenzene in 10 ml. dimethylformamide is treated at 20°-25° C under nitrogen, with 0.38 g. of sodium borohydride. After 1 hour 1.6 ml. of chloromethyl methyl ether is added, and the mixture kept at 20°-30° C for a further three hours. Water is then added and the product filtered off. Recrystallization from cyclohexane gives 1-acetamido-2-nitro-4-methoxymethylthiobenzene.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>C1COCC1>[N:39]1([C:36]2[CH:35]=[CH:34][C:33]([NH:32][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:38][CH:37]=2)[CH2:40][CH2:41][O:42][CH2:43][CH2:44]1
Reactant: CC(=O)c1ccc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)s1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCOCC4)cc3)c2)s1
Temperature: 65 °C
Reaction time: 24 h
Yield: 69.3 %

Procedure:
A small screw cap test tube was charged with 5-Acetyl-thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 54, 100 mg, 0.231 mmol) and THF (2 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (45.34 mg, 0.254 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes (5 mL) were added to the reaction mixture. The crude mixture was concentrated in vacuo and then dissolved into hot EtOAc. Hexanes (˜5 mL) were added causing a precipitate to crash out. The precipitate was filtered and washed with ˜1 mL of i-prOH yielding 69% (95 mg, 0.160 mmol) of the title compound.
Reaction SMILES: C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]2[N:26]=[CH:25][CH:24]=[C:23]([C@@H:27]([OH:38])[C@H:28]3[N:33]4[CH2:34][C@H:35]([CH:36]=[CH2:37])[C@@H:30]([CH2:31][CH2:32]4)[CH2:29]3)[C:21]=2[CH:22]=1.CC(C)([O-])C.[K+].Cl>C1(C)C=CC=CC=1>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]2[C:21](=[C:23]([C:27]([CH:28]3[N:33]4[CH2:34][CH:35]([CH:36]=[CH2:37])[CH:30]([CH2:31][CH2:32]4)[CH2:29]3)=[O:38])[CH:24]=[CH:25][N:26]=2)[CH:22]=1
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=CC1CN2CCC1CC2C(=O)c1ccnc2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.6 %

Procedure:
A solution of benzophenone (1.12 kg) in toluene (4 L) was treated with quinine (1.00 kg) and potassium t-butoxide (871 g). The resulting mixture was heated to reflux for six hours, then allowed to cool to room temperature. After about 18 hours, this mixture was cooled to a temperature of about 10° C. to about 15° C. This cold mixture was treated with 2N hydrochloric acid (4 L) at a rate such that the temperature of the mixture was less than 30° C. The resulting mixture was treated with additional 2N hydrochloric acid (3 L) and the phases separated. The organic phase was extracted with additional 2N hydrochloric acid (2×2.5 L). The combined aqueous phase was cooled to a temperature of about 5° C. to about 15° C., and the pH adjusted to pH 9-9.5 with the addition of 5N sodium hydroxide (ca. 2.6 L). The resulting mixture was stirred am about 5° C. to about 20° C. for one hour. The crystalline material was removed by filtration, rinsed with water (2×1L), and dried in vacuo at 50° C. to give 1.02 kg of quininone.
Reaction SMILES: [CH:1]1([CH2:7][S:8][C:9]2[N:14]=[C:13]([C:15]([O:17]C)=O)[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][C:20]#[N:21]>>[CH:1]1([CH2:7][S:8][C:9]2[N:14]=[C:13]([C:15](=[O:17])[CH2:19][C:20]#[N:21])[CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cccc(SCC2CCCCC2)n1
Reactant: CC#N
Product: N#CCC(=O)c1cccc(SCC2CCCCC2)n1

Procedure:
Addition of CH3CN to methyl 6-((cyclohexylmethyl)thio)picolinate following the method used in Example 6 gave 3-(6-((cyclohexylmethyl)thio)pyridin-2-yl)-3-oxopropanenitrile as a yellow oil which was used in the next step without further purification. Yield (0.63 g, quant.).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10](=[N:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:11]2[CH:16]3[CH:12]2[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15]3)[CH:6]=[CH:7][C:8]=1[Cl:9]>C(Cl)Cl>[ClH:2].[C:26]1([O:25][N:24]=[C:10]([CH:11]2[CH:16]3[CH:12]2[CH2:13][NH:14][CH2:15]3)[C:5]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CC2C(C1)C2C(=NOc1ccccc1)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: Clc1ccc(C(=NOc2ccccc2)C2C3CNCC32)cc1Cl

Procedure:
HCl (g) was bubbled through a solution of tert-butyl 6-((3,4-dichlorophenyl)(phenoxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (160 mg, 0.36 mmol) obtained in step-1 of example 2 in dry DCM (5 mL). After the completion of the reaction as confirmed by TLC, the reaction mixture was purged with excess of nitrogen. The solvent was removed in vacuo to afford hydrochloric acid salt of 3-azabicyclo[3.1.0]hexan-6-yl(3,4-dichlorophenyl)methanone O-phenyl oxime as a gummy solid which was titurated with hexane to afford (125 mg, 91%) as a white solid as a mixture of isomers.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]([CH:11]=O)[NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23]2>>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[C:23]2=[CH:11][C:9]1[NH:10][C:6]2[CH2:5][CH2:4][NH:3][C:2](=[O:1])[C:7]=2[C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: O=Cc1[nH]c2c(c1-c1ccccc1)C(=O)NCC2
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1[nH]c2c(c1-c1ccccc1)C(=O)NCC2
Yield: 31.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 41 with 4-oxo-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-chloro-1,3-dihydro-indol-2-one as starting materials to give 2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-phenyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (2.2 mg, 31.9%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:23]=[CH:22][C:11]([O:12][CH:13]([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:10]([F:24])[CH:9]=2)=[CH:4][N:3]=1.Cl[CH:26]([C:29]1([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[N:38]=[CH:37][CH:36]=[CH:35]3)[CH2:31][CH2:30]1)[CH:27]=O>C(O)(C)C>[F:24][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[N:7][C:2]3[N:3]([C:26]([C:29]4([C:32]5[CH:33]=[C:34]6[C:39](=[CH:40][CH:41]=5)[N:38]=[CH:37][CH:36]=[CH:35]6)[CH2:31][CH2:30]4)=[CH:27][N:1]=3)[CH:4]=2)[CH:23]=[CH:22][C:11]=1[O:12][CH:13]([CH3:21])[C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15]
Reactant: CC(Oc1ccc(-c2cnc(N)nc2)cc1F)C(=O)OC(C)(C)C
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Solvent: CC(C)O
Product: CC(Oc1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F)C(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 41.9 %

Procedure:
A mixture of tert-butyl 2-[4-(2-aminopyrimidin-5-yl)-2-fluorophenoxy]propanoate (0.33 g, 1.0 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.24 g, 1.0 mmol) in isopropanol was heated at 100° C. overnight. After cooling to RT, the mixture was purified by RP-HPLC (pH 2.0) to afford the desired product (0.22 g, 42%). LCMS: (M+H)=525.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:15](COCC[Si](C)(C)C)[C:14]([O:24][C@H:25]3[C@H:29]4[O:30][CH2:31][C@@H:32]([OH:33])[C@H:28]4[O:27][CH2:26]3)=[N:13][C:5]2=[N:6][C:7]=1[C:8]1[CH2:12][CH2:11][CH2:10][CH:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:15][C:14]([O:24][C@H:25]3[C@H:29]4[O:30][CH2:31][C@@H:32]([OH:33])[C@H:28]4[O:27][CH2:26]3)=[N:13][C:5]2=[N:6][C:7]=1[C:8]1[CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(C3=CCCC3)c(Cl)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(C3=CCCC3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 54 h

Procedure:
To (3R,3aR,6R,6aR)-6-((6-chloro-5-(cyclopent-1-en-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (15 mg, 0.030 mmol) in anhydrous DCM (0.55 mL) was added TFA (0.55 mL, 7.13 mmol). The solution stirred at RT for 54 h. The reaction solution was evaporated under reduced pressure. Flash chromatography utilizing a 4 g silica RediSep Rf® Gold column and employing a 0-20% (1% NH4OH in MeOH)/DCM gradient afforded the title compound. LC-MS: calculated for C17H18ClN3O4 363.10 observed m/e: 364.11 (M+H)+ (Rt 1.20/2.0 min).