Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][NH:3][C@@:4]12[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C@@H:9]1[CH2:8][CH2:7][CH2:6][CH2:5]2.C=O.[C:20]([BH3-])#N.[Na+]>CO>[CH3:2][N:3]([CH3:20])[C:4]12[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5]2
Reactant: CN[C@]12CCCC[C@H]1CCc1ccccc12
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)C12CCCCC1CCc1ccccc12
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a solution of the compound obtained in Example 4 (1.0 g) in methanol (15 ml) was added aqueous formaldehyde (5 ml, 35%) and in one batch sodium cyanoborohydride (1 g). The reaction was stirred overnight then the solvent removed in vacuo. The residue was taken up in ether and washed with dilute sodium hydroxide, water and finally 2N HCl. The aqueous acid solution was layered with fresh ether and basified with sodium hydroxide solution. The ether layer was washed with water and brine then dried (NaSO4). The ether layer was reduced in volume then to was added slowly a isopropanolic solution of HCl. The white solid obtained was dried in vacuo to give the title compound (0.81 g, 76%), mp 181°-182° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH2:13][CH2:14][OH:15])/[C:8]([OH:10])=O)[N:6]=1.[NH2:16][C@@H:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH2:24][O:25][C:26](=[O:31])[CH2:27][C:28](=[O:30])[CH3:29])[CH2:22][S:23][C@H:18]12>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH2:13][CH2:14][OH:15])/[C:8]([NH:16][C@@H:17]2[C:35](=[O:36])[N:19]3[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH2:24][O:25][C:26](=[O:31])[CH2:27][C:28](=[O:30])[CH3:29])[CH2:22][S:23][C@H:18]23)=[O:10])[N:6]=1
Reactant: Nc1nc(/C(=N/OCCO)C(=O)O)cs1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Product: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCCO)c3csc(N)n3)[C@H]2SC1

Procedure:
Starting from 2-(2-aminothiazol-4-yl)-2(Z)-(2-hydroxyethoxyimino)acetic acid and 7β-amino-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid, the titled compound is obtained by the procedure of Reference Example 3.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19].[OH-].[K+]>O.C(O)C>[F:1][C:2]([F:26])([F:27])[C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)/C=C/C=C/CCCCCCOCc1cccc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)/C=C/C=C/CCCCCCOCc1cccc(C(F)(F)F)c1
Yield: 62.4 %

Procedure:
The product of step (c) (1.74 g, 4.5 mmol) was hydrolysed with potassium hydroxide (0.88 g) in water (20 mL) and ethanol (60 mL) at room temperature over 18 hours to give 1.0 g (63% of theory) of 11-(3'trifluoromethylbenzyloxy)-(2E,4E)-undecadienoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[Br:16]Br.O>ClCCCl>[Br:16][C:6]1[C:5]([CH3:8])=[CH:4][C:3]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:2]([CH3:1])[CH:7]=1
Reactant: CCCCCCOc1cc(C)ccc1C
Reactant: BrBr
Solvent: ClCCCl
Solvent: O
Product: CCCCCCOc1cc(C)c(Br)cc1C
Yield: 97.6 %

Procedure:
In 250 g of ethanol were dissolved 250 g (2.05 mol) of 2,5-dimethylphenol (or p-xylenol), 90 g (2.25 mol) of sodium hydroxide and 371 g (2.25 mol) of n-hexyl bromide. The solution was heated for 2 hours in an oil bath at 80° C. Water, 500 g, was added to the reaction mixture, from which an oily matter was separated. Vacuum distillation of the oily matter yielded 384 g of 2,5-dimethyl-1-n-hexyloxy-benzene. Next, 129 g (0.625 mol) of 2,5-dimethyl-1-n-hexyloxybenzene was dissolved in 625 g of 1,2-dichloroethane. To the solution kept in an ice bath, 100 g (0.625 mol) of bromine was added dropwise at a temperature below 5C. At the end of dropwise addition, 500 g of water was added. The organic layer was separated therefrom and washed with 300 g of an aqueous solution of 5 wt % sodium hydrogen carbonate. The organic layer was concentrated to remove the solvent, leaving an oily matter. Vacuum distillation (boiling point 114-124° C./0.5 Torr) of the oily matter yielded 174 g of 4-bromo-2,5-dimethyl-n-hexyloxybenzene.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([OH:20])=O)[N:9]=2)=[CH:4][CH:3]=1.[CH2:21]([N:23](CC)[CH2:24][CH3:25])[CH3:22].ClC(OCC)=O.C(NCC)C>C(Cl)(Cl)Cl>[CH2:21]([N:23]([CH2:24][CH3:25])[C:18]([C:10]1[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:20])[CH3:22]
Reactant: Cc1ccc(-c2nc(C(=O)O)cc3ccccc23)cc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cc2ccccc2c(-c2ccc(C)cc2)n1
Yield: 53.7 %

Procedure:
Operations are carried out as for Example 7, starting from 5 g of 1-(4-methylphenyl) isoquinoline 3-carboxylic acid, 2.18 g of triethylamine, 2.39 g of ethyl chloroformate and 1.83 g of diethylamine in 190 ml of chloroform. 3.25 g of N,N-diethyl 1-(4-methylphenyl) isoquinoline 3-carboxamide melting at 113° C., are obtained.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:18]1(C)C=CC(S(O)(=O)=O)=CC=1.C=O>C1(C)C=CC=CC=1>[OH:1][N:2]1[C:3](=[O:17])[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:18]1
Reactant: O=C(NO)c1ccccc1Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2N(c2ccccc2)CN1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A mixture of N-hydroxy-2-(phenylamino)benzamide (1.4 g, 6.15 mmol), p-toluene sulfonic acid (400 ml), and paraformaldehyde (200 mg, 6.75 mmol) in toluene (50 ml) is stirred at room temperature for 30 minutes. The reaction mixture is heated for 10 minutes (in an oil bath preheated to 120°-130° C.) using a Dean-Stark trap to collect water. The reaction mixture is cooled and diluted with ethyl acetate (50 ml) and is extracted with saturated aqueous NaHCO3 (4×50 ml) and water (50 ml). The organic layer is dried (MgSO4) and evaporated. Recrystallization from EtOAc/hexane gives 0.6 g (40%) of 2,3-dihydro-3-hydroxy-1-phenyl-4(1H)-quinazolinone, mp 156°-160° C.
Reaction SMILES: [CH3:1][Li].[C:3]1([C:17]([OH:19])=O)[C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.N#N.Cl>O1CCCC1.O>[C:3]1([C:17](=[O:19])[CH3:1])[C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1cccc2c1Sc1ccccc1S2
Reactant: [Li]C
Agent: Cl
Agent: N#N
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cccc2c1Sc1ccccc1S2
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.6 %

Procedure:
Methyl lithium (1.6M in ether, 57 ml, 90 mmol) was added drop wise to a stirred solution of thianthrene-1-carboxylic acid (11.71 g, 45 mmol) in dry tetrahydrofuran (200 ml) at −78° C. over 30 minutes under an inert atmosphere (N2). The reaction mixture was allowed to warm to room temperature and (very thick white suspension present) was left stirring for 4 hours. Water (10 ml) was then added carefully to the solution and the pH was adjusted to 1 (pH paper) with 2N HCl. The solvent was removed in vacuo and the yellow solid formed was filtered and dried overnight in a vacuum desiccators. The solid was then purified by column chromatography (ethyl acetate/hexane; 1:9) and was recrystalised from ethanol to give the desired product (6.58 g, 57%). 1HNMR (300 MHz, CDCl3): δH=2.65 (3H, s); 7.26 (3H, m); 7.47 (2H, m); 7.62 (2H, d). m/z (LC-MS, ESP) RT=4.95 min; (M++1)=259
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:19][C:20]1[C:21]([C:26]2[N:30]([CH2:31][C:32]([F:35])([F:34])[F:33])[N:29]=[CH:28][CH:27]=2)=[N:22][CH:23]=[CH:24][CH:25]=1>CN(C=O)C>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:19][C:20]2[C:21]([C:26]3[N:30]([CH2:31][C:32]([F:35])([F:33])[F:34])[N:29]=[CH:28][CH:27]=3)=[N:22][CH:23]=[CH:24][CH:25]=2)[C:3]=1[CH:4]=[O:5]
Reactant: FC(F)(F)Cn1nccc1-c1ncccc1CCl
Reactant: O=Cc1c(O)cccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(O)cccc1OCc1cccnc1-c1ccnn1CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2,6-dihydroxybenzaldehyde (438 mg, 11.47 mmol, 2 eq.) and K2CO3 (2.4 g, 17.22 mmol, 3 eq.) in DMF (150 mL) was stirred at rt for 10 min. To this mixture was added 3-(chloromethyl)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridine hydrochloride (498 mg, 1.59 mmol, 1 eq.) at rt. The mixture was heated at 50° C. for 2 h, filtered, concentrated and purified on silica gel using a mixture of EtOAc and hexanes as eluent to 2-hydroxy-6-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (338.4 mg, 56%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.99 (s, 1H), 10.41 (s, 1H), 8.76 (dd, J=4.7, 1.6 Hz, 1H), 8.01 (dd, J=7.9, 1.4 Hz, 1H), 7.69 (d, J=1.9 Hz, 1H), 7.49-7.39 (m, 2H), 6.61 (d, J=8.5 Hz, 1H), 6.53 (d, J=1.9 Hz, 1H), 6.32 (d, J=8.3 Hz, 1H), 5.30 (q, J=8.6 Hz, 2H), 5.17 (s, 2H). LRMS (M+H+) m/z 378.1
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1.[CH3:11]OS(OC)(=O)=O.S(C)C.[OH-].[Na+]>CS(C)=O>[CH3:1][C:2]1[C:3]2([C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1)[O:10][CH2:11]2
Reactant: COS(=O)(=O)OC
Reactant: CC1=CCCC(C)(C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CSC
Product: CC1=CCCC(C)(C)C12CO2
Yield: 73 %

Procedure:
Prepared under the conditions described in a., starting from 25.0 g (181 mmol) of 2,6,6-trimethyl-2-cyclohexen-1-one, 31.9 g (253 mmol) of (CH3)2SO4, 17.0 g (274 mmol) of (CH3)2S and 43.0 g (1086 mmol) of NaOH in 60 ml of DMSO. 22.09 G of the desired product, 91% pure, were obtained.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[CH3:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:14]1[C:13]([CH3:12])=[CH:17][N:16]=[CH:15]1)[CH:6]=[O:7]
Reactant: Cc1c[nH]cn1
Reactant: COc1cc(C=O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1-n1cncc1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 1 %

Procedure:
To a DMF (50 mL) solution of 4-fluoro-3-methoxybenzaldehyde (3.00 g) and 4-methylimidazole (3.307 g), potassium carbonate (4.05 g) was added and the reaction mixture was agitated at 100° C. overnight. The obtained reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent:hexane-ethyl acetate system), and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (856 mg) and 3-methoxy-4-(5-methyl-1H-imidazol-1-yl)benzaldehyde (44 mg) were obtained.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:13])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:13][C:4]1[S:3][C:2]([N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]2)=[N:6][C:5]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1sc(Br)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1sc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1ccccc1
Yield: 18.1 %

Procedure:
A solution of 2-bromo-5-methyl-4-phenyl-1,3-thiazole (9.56 g, 37.6 mmol), tert-butyl piperazine-1-carboxylate (14.8 g, 75.2 mmol) and potassium carbonate (5.20 g, 37.6 mmol) in dimethylformamide (125 ml) was stirred at 120° C. for 4 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2.45 g (18.1%) of the desired product as a solid.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2.[N+]([O-])=[O:13]>[N+]([O-])(O)=O>[OH:13][C:7]12[CH2:9][CH:3]3[CH2:4][CH:5]([CH2:10][CH:1]([C:2]3=[O:11])[CH2:8]1)[CH2:6]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: O=[N+][O-]
Solvent: O=[N+]([O-])O
Product: O=C1C2CC3CC1CC(O)(C3)C2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Adamantanone (12 g, 80 mmol) was added under stirring to nitric acid (98%, 100 mL) at ice bath temperature over a period of 15 minutes. The reaction mixture was stirred at room temperature for 72 h and then heated to 60° C., for 2 h until most of the nitrogen dioxide evaporated. Excess nitric acid was distilled off under reduced pressure. The light yellow oil solidified upon cooling (NO3 adduct of the hydroxyketone). Water (40 mL) and conc. H2SO4 (98%, 15 mL) were added. The resulting clear yellow solution was heated on the steam bath in a hood (nitrous fumes) for 1 h. The solution was then cooled and extracted with a 2:1 mixture of n-hexane and diethylether to remove unreacted adamantanone (1.0 g). The acid layer was neutralized with 30% aq. NaOH solution, and while warm, extracted with chloroform. The extracts were combined, washed with brine solution, and concentrated in vacuum. The crude product was dissolved in CH2Cl2 (15 mL) and hexane was added until no more precipitate was formed. The solid material was isolated by filtration and dried to get 5-hydroxy-adamantan-2-one. Yield: 9.0 g (70%). Solid; M.R: 278.8-300° C. (decomposes) m/z (M+1) 167; 1H NMR (CDCl3) 300 MHz δ 2.70-2.55 (m, 2H), 2.36-2.32 (m, 1H), 2.11-1.93 (m, 10H). 13C NMR (CDCl3) 75 MHz δ 217.0, 66.7, 46.7, 46.6, 44.7 (2C), 43.8, 37.9 (2C), 29.5.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[Na].Cl.[CH2:8]([N:12]=[C:13]([NH2:22])[NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][Cl:21])[N:19]=1)[CH2:9][CH2:10][CH3:11].Cl>C(O)C.O>[ClH:21].[CH2:8]([N:12]=[C:13]([NH2:22])[NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][S:5][CH2:4][CH2:3][NH2:2])[N:19]=1)[CH2:9][CH2:10][CH3:11]
Reactant: NCCS
Reactant: CCCCN=C(N)Nc1nc(CCl)cs1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCCCN=C(N)Nc1nc(CSCCN)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2-aminoethanethiol hydrochloride (1.85 g.) in ethanol (30 ml.) was added to a stirred solution of sodium (0.90 g.) in ethanol (50 ml.) under a nitrogen atmosphere. A solution of 2-(2-n-butylguanidino)-4-chloromethylthiazole hydrochloride (2.20 g.) in ethanol (50 ml.) was added dropwise to the mixture, which was then stirred for 3 hours while warming to room temperature. A mixture of concentrated hydrochloric acid (5 ml.) and water (15 ml.) was then added, and the mixture evaporated to dryness. The residual gummy solid was extracted with boiling ethanol (3×20 ml.) and the residual white solid discarded. The combined ethanolic extracts were filtered and the filtrate evaporated to dryness to give 2-(2-n-butylguanidino)-4-(2-aminoethyl)thiomethylthiazole hydrochloride as a thick gum which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10](=O)[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[C:13]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH:12]=3)=[CH:4][C:3]=1[O:29][CH3:30].[NH2:31][CH2:32][C:33]([NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>>[C:36]([NH:35][C:33](=[O:34])[CH2:32][N:31]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:29][CH3:30])[CH:4]=2)=[CH:17][C:16]2[C:11](=[CH:12][C:13]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)=[CH:14][CH:15]=2)[C:10]1=[O:9])([CH3:39])([CH3:38])[CH3:37]
Reactant: COc1ccc(COc2ccc3cc(-c4ccc(F)c(OC)c4)oc(=O)c3c2)cc1
Reactant: CC(C)(C)NC(=O)CN
Product: COc1ccc(COc2ccc3cc(-c4ccc(F)c(OC)c4)n(CC(=O)NC(C)(C)C)c(=O)c3c2)cc1
Temperature: 120 °C
Yield: 92 %

Procedure:
A neat mixture of 3-(4-fluoro-3-methoxyphenyl)-7-(4-methoxybenzyloxy)isochromen-1-one (100 mg, 0.25 mmol) and 2-amino-N-tert-butyl acetamide (INTERMEDIATE I.2) (32 mg, 2.46 mmol) was heated at 120° C. for 3 h. The reaction mixture was cooled and partitioned between ethyl acetate and sat. NH4Cl (aq.). The organic layer was washed with brine (1×20 mL), dried (MgSO4) and concentrated in vacuo to afford N-tert-butyl-2-(3-(4-fluoro-3-methoxyphenyl)-7-(4-methoxybenzyloxy)-1-oxo-1H-isoquinolin-2-yl)acetamide (120 mg, 0.23 mmol, 94%) which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O.Cl>C1COCC1.O>[C:22]([O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([OH:12])=[O:11])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)[C@H](CCCCCC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 1.5 h

Procedure:
I2 was dissolved in a mixture of THF and H2O (4:1, 0.35M solution) at RT and LiOH.H2O (1.1 eq.) was added and the mixture was then stirred for 1.5 hr. 1M HCl was added until pH 4-5, then the THF was removed under reduced pressure. The aqueous phase was extracted with EtOAc (3×); the collected organic phases were washed with brine and then dried (Na2SO4). After removal of the solvent the title compound was obtained as a colorless oil which solidified upon standing, this was used in the next step without purification. 1H NMR (400 MHz, CDCl3) δ: 5.23 (1H, br. s), 4.13 (1H, br. s), 2.21 (2H, t, J=7.4 Hz), 1.75-1.90 (1H, m), 1.70-1.50 (3H, m), 1.45 (9H, s), 1.44 (9H, s), 1.50-1.25 (4H, m) MS (ES) C17H31NO6 requires: 345, found: 346 (M+H)+.
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][C:16]1[NH:20][C:19]2[CH:21]=[C:22]([CH3:26])[C:23]([CH3:25])=[CH:24][C:18]=2[N:17]=1)=[N+:13]=[N-:14]>>[ClH:1].[ClH:1].[CH3:25][C:23]1[C:22]([CH3:26])=[CH:21][C:19]2[NH:20][C:16]([CH2:15][N:12]3[CH:5]=[C:4]([CH2:3][CH2:2][C:6]4[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=4)[N:14]=[N:13]3)=[N:17][C:18]=2[CH:24]=1
Reactant: C#CCCc1c[nH]c(N)n1
Reactant: Cc1cc2nc(CN=[N+]=[N-])[nH]c2cc1C
Agent: Cl
Product: Cc1cc2nc(Cn3cc(CCc4c[nH]c(N)n4)nn3)[nH]c2cc1C
Yield: 117.6 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.0734 g, 0.432 mmol) was reacted with 2-azidomethyl-5,6-dimethyl-1H-benzimidazole (0.104 g, 0.518 mmol) following the general procedure for click reactions outlined above to produce 4-{2-[1-(5,6-Dimethyl-1Hbenzoimidazol-2-ylmethyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1H-imidazol-2-ylamine dihydrochloride (0.104 g, 59%) of a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.70 (s, 1H), δ 7.19 (s, 2H), δ 6.23 (s, 1H), δ 5.66 (s, 2H), δ 2.85 (t, 2H), δ 2.68 (t, 2H), □ 2.21 (s, 6H) ppm; 13C (75 MHz, CD3OD) δ 148.2, 147.0, 146.9, 132.3, 128.9, 122.8, 120.0, 115.1, 109.7, 100.4, 25.1, 24.4, 19.2 ppm; HRMS (ESI) calcd for C17H20N8(M+) 337.1883, found 337.1886.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[O:5][CH2:6][C:7]([OH:9])=O.[CH3:14][N:15]([CH3:31])[CH:16]1[CH2:20][CH2:19][N:18]([C:21]2[S:22][C:23]3[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:17]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[O:5][CH2:6][C:7]([NH:30][C:28]1[CH:27]=[CH:26][C:24]2[N:25]=[C:21]([N:18]3[CH2:19][CH2:20][CH:16]([N:15]([CH3:31])[CH3:14])[CH2:17]3)[S:22][C:23]=2[CH:29]=1)=[O:9]
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Reactant: O=C(O)COc1ccc(Cl)c(Cl)c1
Product: CN(C)C1CCN(c2nc3ccc(NC(=O)COc4ccc(Cl)c(Cl)c4)cc3s2)C1

Procedure:
Prepare according to the procedures described in Example 1, step 4, Method B, using 3,4-dichlorophenoxyacetic acid (135 mg, 0.611 mmol) and 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (162 mg, 0.618 mmol) to afford the title compound, mass spectrum (m/e): 465 [M+H], 463 [M−H].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([NH:15][NH:16][C:17](=O)[C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[CH3:25])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].P(Cl)(Cl)(Cl)=O>>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:14][C:17]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=3[CH3:25])=[N:16][N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:11])[CH3:12])#[N:2]
Reactant: Cc1cc(Br)ccc1C(=O)NNC(=O)c1ccc(OC(C)C)c(C#N)c1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(Br)ccc1-c1nnc(-c2ccc(OC(C)C)c(C#N)c2)o1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
In an oven-dried round bottom flask 145 mg (0.35 mmol) of N′-(3-cyano-4-isopropyloxyphenylcarbonyl)-4-bromo-2-methylbenzhydrazide (from EXAMPLE 87, Step A) was combined with 10 mL of anhydrous xylenes and 5 mL of phosphorus oxychloride and the heterogeneous reaction mixture was heated to reflux for 6 h. The resulting homogeneous mixture was cooled down to rt and combined with 200 mL of ice-water, neutralized to pH>10 and extracted with EtOAc (2×150 mL). The combined organic layers were dried with sodium sulfate and solvents were removed under reduced pressure. The crude compound was purified by flash chromatography using Biotage 40S (eluent: hexanes/EtOAc—4/1) to yield 121 mg of title compound: 1H NMR (500 MHZ, CDCl3) δ 1.50 (d, J=7.0, 6H), 2.78 (s, 3H), 4.80 (sep, J=7.0, 1H), 7.14 (d, J=9.0, 1H), 7.54 (dd, J=9.0, 2.0, 1H), 7.58 (d, J=2.0, 1H), 7.91 (d, J=8.5, 1H), 8.30 (d, J=2.0, 1H), 8.33 (dd, J=8.5, 2.0, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1([OH:17])[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1([OH:17])[CH2:15][CH2:14][CH:13]([N:18]2[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:24])[CH2:19]2)[CH2:12][CH2:11]1
Reactant: O=C1CCC(O)(c2nc3ccccc3o2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3nc4ccccc4o3)CC2)C1

Procedure:
The title compound was prepared as a white solid from reductive amination of 4-benzooxazol-2-yl-4-hydroxy-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.