Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[CH:14]([Si:17]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])Cl)([CH3:16])[CH3:15]>O1CCCC1>[CH3:1][C:2]1[N:3]([Si:17]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:14]([CH3:16])[CH3:15])[CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc[nH]c1C
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccn([Si](C(C)C)(C(C)C)C(C)C)c1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of ethyl 2-methyl-1H-pyrrole-3-carboxylate (purchased from Beta Pharma Scientific, 9.91 g, 64.7 mmol) in tetrahydrofuran (200 mL) at 0° C. under N2 was treated portionwise with sodium hydride (dry, 95%) (2.06 g, 82 mmol). The resulting mixture was stirred for 20 minutes and treated with triisopropylchlorosilane (16.5 mL, 78 mmol). The mixture was stirred for 30 minutes, then the ice bath was removed. After warming to ambient temperature over 90 minutes, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous magnesium sulfate) filtered and concentrated. Purification by chromatography on a 330 g silica cartridge eluting with 0-20% ethyl acetate in hexane afforded the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][S:8]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O)(=[O:10])=[O:9].[Cl:20][C:21]1[CH:22]=[C:23]([CH:37]=[CH:38][C:39]=1[Cl:40])[O:24][CH:25]1[CH2:30][CH2:29][N:28]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:27][CH2:26]1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:37]=[CH:38][C:39]=1[Cl:40])[O:24][CH:25]1[CH2:26][CH2:27][N:28]([CH:31]2[CH2:32][CH2:33][N:34]([C:13]([C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[S:8]([CH3:7])(=[O:9])=[O:10])=[O:15])[CH2:35][CH2:36]2)[CH2:29][CH2:30]1
Reactant: CS(=O)(=O)c1ccccc1C(=O)O
Reactant: Clc1ccc(OC2CCN(C3CCNCC3)CC2)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccccc1C(=O)N1CCC(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
Oxalyl chloride (55 ml, 0.63 mol) was added dropwise over 10 minutes to a stirred suspension of 2-methanesulfonyl-benzoic acid (7.1 g, 0.036) in DCM (550 ml) containing DMF (0.5 ml). The solution was then stirred for 2 hours at room temperature. The solution was then evaporated to give a solid that was redissolved in dichloromethane and again evaporated to give a yellow solid. The solid acid chloride was dissolved in DCM (275 ml) and was added over 10 minutes to a stirred solution of the product of Step 3 (11.0 g, 0.033 mol) and triethylamine (15.4 ml, 0.11 mol) in dichloromethane (125 ml). The resultant solution was stirred at room temperature for 16 hours. The solution was then washed with water (500 ml), 1M aq NaOH (500 ml) and water (2×500 ml). The organic phase was dried (MgSO4), filterered and the solvent removed to give a pale yellow foam. The foam was triturated with diethyl ether to give the title compound (12.96 g, 76%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[H][H].Cl[C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)=[CH:16][N:15]=1>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)=[CH:16][N:15]=1
Reactant: [H][H]
Reactant: Oc1ccccc1Cl
Reactant: COc1ccc(C(=O)c2ccc(Cl)nc2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2ccc(Oc3ccccc3Cl)nc2)cc1OC
Temperature: 80 °C
Yield: 82.6 %

Procedure:
In dimethyl formamide (10 ml) was suspended 60% sodium hydride (dispersion in paraffin) (288 mg), to which was added dropwise a solution of 2-chlorophenol (926 mg) in dimethylformamide. When exothermic reaction and evolution of hydrogen gas ceased, 2-chloro-5-(3,4-dimethoxybenzoyl)pyridine (1 g) was added to the reaction mixture, followed by stirring for hours at 80° C. The reaction mixture was poured into ice-water, then precipitating substance was collected by filtration, and purified by means of a silica gel column chromatography [eluent: n-hexane+ethyl acetate (1:1)] to obtain 2-(2-chlorophenoxy)-5-(3,4-dimethoxybenzoyl)pyridine (1.1 g) as an oil.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36](O)=[O:37])[CH:27]=[CH:28][CH:29]=1>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:37])[CH:27]=[CH:28][CH:29]=1
Reactant: COc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Product: COc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(3-methoxy-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([N:9]1[C:17]2[C:12](=C[C:14](C#N)=[C:15](C)[C:16]=2[N+:18]([O-:20])=[O:19])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-:24].[Na+].[CH2:26]([OH:29])[CH2:27][CH3:28]>O>[CH2:1]([N:9]1[C:17]2[C:12](=[CH:28][C:27]([C:26]([OH:24])=[O:29])=[C:15]([CH3:14])[C:16]=2[N+:18]([O-:20])=[O:19])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: [OH-]
Reactant: CCCO
Reactant: CCCCCCCCN1CCc2cc(C#N)c(C)c([N+](=O)[O-])c21
Agent: [Na+]
Solvent: O
Product: CCCCCCCCN1CCc2cc(C(=O)O)c(C)c([N+](=O)[O-])c21

Procedure:
1-Octyl-5-cyano-6-methyl-7-nitroindoline (2.4 g) was dissolved in n-propanol and a solution of NaOH (3.0 g) in water (10 ml) was added, which was followed by refluxing for 20 hr. n-Propanol was evaporated under reduced pressure and ethyl acetate (100 ml) was added to the residue. The mixture was washed with water and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/benzenel1/5-1/1) to give 1.4 g of 1-octyl-5-carboxy-6-methyl-7-nitroindoline as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:5]2[C:10](=[C:11]([N+:13]([O-])=O)[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16].O.O(CCCC)CCCC>[Fe].CC(O)=O>[NH2:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16]
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCc1ccccc1
Agent: [Fe]
Solvent: CCCCOCCCC
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(N)c2nccc(C)c2c1OCCCCc1ccccc1
Yield: 65.4 %

Procedure:
A stirred mixture of 6-methoxy-4-methyl-8-nitro-5-(4-phenylbutoxy) quinoline (3.7 g, 0.01 mol), degreased 40 mesh Fe filings (10 g), H2O (40 ml), HOAc (8 ml) and Bu2O (8 ml) was heated at 80°-100° C. for 2.5 h, allowed to cool and filtered. The solid was thoroughly extracted with Et2O and the extract was dried (Na2SO4), treated with carbon and concentrated to an oil. Extraction of the latter with pet ether and cooling the extract gave 2.2 g (66%) of 8-amino-6-methoxy-4-methyl-5-(4-phenylbutoxy)quinoline as yellow-green crystals, mp 59°-59.5° C. Recrystallization from pet ether afforded the analytical sample as yellow crystals, mp 60°-61° C.
Reaction SMILES: C(O)=O.C1(C)C=CC=CC=1.C1CO[C:13]2([CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=3)[CH2:15][CH2:14]2)[O:12]1>O>[F:25][C:23]1[CH:24]=[C:19]([CH:16]2[CH2:15][CH2:14][C:13](=[O:12])[CH2:18][CH2:17]2)[CH:20]=[C:21]([F:27])[C:22]=1[F:26]
Reactant: Fc1cc(C2CCC3(CC2)OCCO3)cc(F)c1F
Solvent: O
Solvent: O=CO
Solvent: Cc1ccccc1
Product: O=C1CCC(c2cc(F)c(F)c(F)c2)CC1
Reaction time: 2 h
Yield: 79.2 %

Procedure:
Formic acid (82.7 g) and toluene (20 ml) were added to 1,1-ethylenedioxy-4-(3',4', 5'-trifluorophenyl)cyclohexane (95.02 g), followed by heating the mixture under reflux with stirring for 2 hours, adding the reaction solution to water (500 ml), extracting with ethyl acetate (1 l), drying the organic layer over anhydrous magnesium sulfate, distilling off the solvent under reduced pressure, and recrystallizing from ethanol, to obtain 4-(3',4',5'-trifluorophenyl)cyclohexanone (63.1 g). m.p. 123.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6](N)[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13].C(O)C.[BrH:18].N([O-])=O.[Na+]>O>[Br:18][C@H:6]1[C:7](=[O:8])[N:4]2[C:3]([C:12]([OH:14])=[O:13])=[C:2]([CH3:1])[CH2:11][S:10][C@H:5]12
Reactant: Br
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1=C(C(=O)O)N2C(=O)[C@H](Br)[C@H]2SC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 75.5 %

Procedure:
To an ice-cooled mixture of 7-ADCA (10.0 g, 0.4667 mol), ethanol (270 ml), water (83 ml) and hydrobromic acid (48%, 56.7 ml), sodium nitrite (4.67 g, 0.6769 mol) was added in small portions over 25 minutes and the mixture was stirred for 2.5 hours at ice-temperature. Ethanol was removed under reduced pressure and the residual mass was diluted with methylene chloride, washed with water. The aqueous washings were saturated with brine and re-extracted with methylene chloride. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give 9.8 g (75.5%) of 7α-bromo-3-methyl -3-cephem-4-carboxylic acid. This crude acid was directly used for the next step without further purification.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:14])[CH2:2][CH2:3][CH3:4].[N+:15]([C:18]1[CH:19]=[C:20]2[C:25](=[O:26])[O:24][C:22](=[O:23])[C:21]2=[CH:27][CH:28]=1)([O-:17])=[O:16]>C(OC(=O)C)C>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:22](=[O:23])[C:21]2[CH:27]=[CH:28][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][C:20]=2[C:25]([OH:26])=[O:24])=[C:6]1[CH3:14])[CH2:2][CH2:3][CH3:4].[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:25](=[O:26])[C:20]2[CH:19]=[C:18]([N+:15]([O-:17])=[O:16])[CH:28]=[CH:27][C:21]=2[C:22]([OH:24])=[O:23])=[C:6]1[CH3:14])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: CCCCn1c(C)cc2ccccc21
Solvent: CCOC(C)=O
Product: CCCCn1c(C)c(C(=O)c2cc([N+](=O)[O-])ccc2C(=O)O)c2ccccc21
Product: CCCCn1c(C)c(C(=O)c2ccc([N+](=O)[O-])cc2C(=O)O)c2ccccc21
Temperature: 80 °C

Procedure:
To a solution of 12.35 g of 1n-butyl-2-methylindole in 20 ml ethylacetate at 70° C, 11.6 g 4-nitrophthalic anhydride is added over 10 minutes. The reaction mixture is stirred under reflux at 80° C for C. hour and cooled to 20° C The crystalline solid thus obtained is filtered off, washed with a mixture of ethyl acetate and petroleum ether and dried in vacuo at 80° C to yield 19.6 g (86% of theory) of the two isomers 1-n-butyl-2-methyl-3-(2'-carboxy-4'-nitrobenzoyl) indole and 1-n-butyl-2-methyl-3-(2'-carboxy-5'-nitro-benzoyl)-indole having a melting point of 165°-167° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.I[CH2:23][CH2:24][OH:25]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][CH2:24][OH:25])[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Reactant: OCCI
Product: Cc1nc(-c2ccn(CCO)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 2-iodo-ethanol as described in Example 49 and isolated as a yellow oil (0.11 g, 55% yield). 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.54 (d, J=3 Hz, 1H), 7.71 (d, J=4 Hz, 1H), 7.50 (d, J=2 Hz, 1H), 7.27-7.31 (m, 1H), 6.82 (d, J=2 Hz, 1H), 6.24-6.28 (bm, 1H), 4.62 (d, J=8 Hz, 2H), 4.29 (t, J=4 Hz, 2H), 4.04 (t, J=4 Hz, 2H), 2.89-2.95 (bm, 1H), 2.74 (s, 3H); MS (M+H)+=344.1; Rt=0.85 min; HRMS (M+H)+=344.12.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[F:30][C:31]([F:40])([F:39])[C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:36][C:35]3[CH:37]=[CH:38][C:32]([C:31]([F:39])([F:40])[F:30])=[CH:33][CH:34]=3)=[O:18])=[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(-c3ccccc3)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)Nc3ccc(C(F)(F)F)cc3)c(-c3ccccc3)c2)=C(C)C1=O
Reaction time: 16 h
Yield: 36.5 %

Procedure:
4-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-phenylbenzoic acid (16 mg, 0.0408 mmol) was dissolved in methylene chloride (3 ml), then 4-trifluoromethylaniline (13 mg, 0.0807 mmol), triethylamine (8.2 mg, 0.0811 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (21 mg, 0.1242 mmol) were added thereto and the mixture was stirred for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (hexane:ethyl acetate=1:1) to give the title compound (8 mg, 0.0149 mmol, 37%).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C([O:13][C:14](=O)[C:15]([C:27]#[N:28])=[CH:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[CH:18]=1)C>>[C:27]([C:15]1[C:14](=[O:13])[O:9][C:5]2[C:6]([C:16]=1[C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[CH:18]=1)=[CH:7][CH:8]=[C:3]([N:2]([CH3:10])[CH3:1])[CH:4]=2)#[N:28]
Reactant: CN(C)c1cccc(O)c1
Reactant: CCOC(=O)C(C#N)=Cc1cc(OC)cc(OC)c1
Product: COc1cc(OC)cc(-c2c(C#N)c(=O)oc3cc(N(C)C)ccc23)c1
Yield: 0.4 %

Procedure:
The title compound was prepared from 3-dimethylaminophenol and 3-(3,5-dimethoxyphenyl)-2-cyano-acrylic acid ethyl ester by a procedure similar to that described for Example 16 in 0.4% yield. 1H NMR (DMSO-d6): 7.09 (d, J=8.7 Hz, 1H), 6.80 (d, J=7.5 Hz, 1H), 6.73-6.71 (m, 2H), 6.65 (d, J=2.1 Hz, 2H), 3.80 (s, 6H), 3.11 (s, 6H).
Reaction SMILES: C(#N)C.[N:4]1[NH:5][N:6]=[N:7][C:8]=1[CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][CH2:11]1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>C(N(CC)CC)C>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:6]2[N:5]=[N:4][C:8]([CH2:9][C@H:10]3[CH2:15][CH2:14][C@H:13]([O:16][C:17](=[O:24])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:12][CH2:11]3)=[N:7]2)=[CH:29][CH:28]=1
Reactant: O=C(O[C@H]1CC[C@H](Cc2nn[nH]n2)CC1)c1ccccc1
Reactant: COc1ccc(CCl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2nnc(C[C@H]3CC[C@H](OC(=O)c4ccccc4)CC3)n2)cc1
Temperature: 25 °C

Procedure:
To an acetonitrile (20 mL) suspension of trans-benzoic acid 4-(2H-tetrazol-5-ylmethyl)-cyclohexyl ester (1.34 g) obtained in Example (44b), triethylamine (0.68 mL) and 4-methoxybenzyl chloride (0.70 mL) were added at room temperature. The reaction mixture was heated to reflux for 2 hours, cooled to room temperature, concentrated, then diluted with ethyl acetate, and filtered. The filtrate was washed with 1 N hydrochloric acid, then dried over sodium sulfate, and then concentrated. The residue was purified by column chromatography (hexane/ethyl acetate) to obtain the title compound (610 mg, 32%) as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]Br.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:35])[C:19]=1[NH:20][C:21]1[C:30]2[C:25](=[C:26]([OH:33])[C:27]([O:31][CH3:32])=[CH:28][CH:29]=2)[O:24][C:23](=[O:34])[CH:22]=1>>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:35])[C:19]=1[NH:20][C:21]1[C:30]2[C:25](=[C:26]([O:33][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:2]([CH3:3])[CH3:1])[C:27]([O:31][CH3:32])=[CH:28][CH:29]=2)[O:24][C:23](=[O:34])[CH:22]=1
Reactant: CNC
Reactant: BrCCCCCCCBr
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCCCN(C)C

Procedure:
The title compound was prepared from dimethylamine, 1,7-dibromoheptane, and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedures outlined in Examples 25 & 27. 1H NMR (400 MHz, DMSO-d6): δ 9.38 (br s, 1H), 8.58 (s, 2H), 7.85 (d, 1H), 7.05 (d, 1H), 4.26 (br s, 1H), 3.96 (t, 2H), 3.87 (s, 3H), 2.51 (br, 2H), 2.35 (s, 6H), 1.67 (m, 2H), 1.46 (m, 4H), 1.30 (m, 4H); MS (ESI): 493.9.
Reaction SMILES: [NH2:1][CH:2]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:3][N:4]([CH2:10][CH:11]([NH2:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7].[C:27](=[O:45])([O:38][CH2:39][C:40]1[S:44][CH:43]=[N:42][CH:41]=1)OC1C=CC([N+]([O-])=O)=CC=1>C(OCC)(=O)C>[CH3:7][C:6]([CH3:9])([CH3:8])[CH2:5][N:4]([CH2:3][C@H:2]([NH:1][C:27]([O:38][CH2:39][C:40]1[S:44][CH:43]=[N:42][CH:41]=1)=[O:45])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:10][C@H:11]([NH:19][C:27]([O:38][CH2:39][C:40]1[S:44][CH:43]=[N:42][CH:41]=1)=[O:45])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)CN(CC(N)Cc1ccccc1)CC(N)Cc1ccccc1
Reactant: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Product: CC(C)(C)CN(C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
The product from Example 7C (0.34 g) was treated with 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate [prepared from 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate hydrochloride salt (0.63 g, 1.99 mmol) by extraction with aqueous NaHCO3] in ethyl acetate (10 mL). The mixture was stirred at 60° C. under a N2 atmosphere overnight. The mixture was diluted with ethyl acetate (50 mL), extracted with 10% aqueous K2CO3 (3×20 mL), washed with water (20 mL) and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (ethyl acetate:hexanes, 2:1) to provide the two title compounds combined and a third separated product. The mixture of (S,S) and (R,R) enantiomers were obtained as a colorless amorphous solid. Rf=0.32 (ethyl acetate); 1H NMR (CDCl3) δ 8.73 (s, 2H), 7.75 (s, 2H), 7.30-7.11 (m, 10H), 5.53 (br s, 2H), 5.23 (d, J=12.9 Hz, 2H), 5.16 (d, J=13.2 Hz, 2H), 3.91 (m, 2H), 2.90-2.79 (m, 2H), 2.68 (dd, J=7.5, 13.6 Hz, 2H), 2.42 (t, J=12 Hz, 2H), 2.26 (dd, J=1, 12 Hz, 2H), 1.99 (d, J=13.9 Hz, 1H), 1.87 (d, J=14.2 Hz, 1H), 0.71 (s, 9H); MS (ESI+) m/z 636 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([OH:17])[C:10]3[N:11]=[CH:12][CH:13]=[N:14][C:15]=3[CH:16]=2)[CH2:3][CH2:2]1.CS(O[C@H:23]1[CH2:28][CH2:27][C@H:26]([NH:29][C:30]2[N:35]=[CH:34][C:33]([Br:36])=[CH:32][N:31]=2)[CH2:25][CH2:24]1)(=O)=O>O1CCOCC1.CCOC(C)=O>[Br:36][C:33]1[CH:34]=[N:35][C:30]([NH:29][C@H:26]2[CH2:27][CH2:28][C@@H:23]([O:17][C:9]3[CH:8]=[C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH:16]=[C:15]4[C:10]=3[N:11]=[CH:12][CH:13]=[N:14]4)[CH2:24][CH2:25]2)=[N:31][CH:32]=1
Reactant: CS(=O)(=O)O[C@H]1CC[C@H](Nc2ncc(Br)cn2)CC1
Reactant: Oc1cc(N2CCOCC2)cc2nccnc12
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Brc1cnc(N[C@H]2CC[C@@H](Oc3cc(N4CCOCC4)cc4nccnc34)CC2)nc1
Yield: 52.5 %

Procedure:
As shown in step 6-viii of Scheme 6, a solution of 7-morpholinoquinoxalin-5-ol (100 mg, 0.432 mmol), (trans)-4-((5-bromopyrimidin-2-yl)amino)cyclohexyl methanesulfonate (compound 1014, 303 mg, 0.865 mmol), and CsCO3 (282 mg, 0.865 mmol) in dioxane (1.0 mL was stirred for 16 hours at 105° C. After cooling, the reaction mixture was diluted with EtOAc, filtered through diatomaceous earth, concentrated under reduced pressure, and purified by medium pressure silica gel chromatography (0 to 5% MeOH/DCM gradient) to produce 5-bromo-N-((cis)-4-((7-morpholinoquinoxalin-5-yl)oxy)cyclohexyl)pyrimidin-2-amine (compound 1020, 110 mg) as a yellow foam: 1H-NMR (400 MHz, CDCl3) δ 8.70 (d, J=2.0 Hz, 1H), 8.64 (d, J=1.9 Hz, 1H), 8.29 (s, 2H), 6.98 (d, J=2.5 Hz, 1H), 6.92 (d, J=2.5 Hz, 1H), 5.29 (d, J=8.3 Hz, 1H), 4.81 (s, 1H), 4.04-3.84 (m, 4H), 3.42-3.31 (m, 4H), 2.22 (s, 2H), 1.92 (d, J=4.9 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:15])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:7]=1.[CH2:16](OC(OCC)CBr)[CH3:17]>>[Br:1][C:2]1[C:3]2[N:4]([CH:16]=[CH:17][N:15]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Nc1ncc(-c2ccc(Cl)cc2)cc1Br
Reactant: CCOC(CBr)OCC
Product: Clc1ccc(-c2cc(Br)c3nccn3c2)cc1

Procedure:
Prepared from crude 3-bromo-5-(4-chloro-phenyl)-pyridin-2-ylamine (example C.27 step 2) (ca. 50 mmol) and bromoacetaldehyde diethyl acetal (90%, 17.2 mL, 100 mmol) as described in example C.20 step 1. Obtained the pure 8-bromo-6-(4-chloro-phenyl)-imidazo[1,2-a]pyridine after chromatography as a light brown solid (11.91 g, 77%). MS (ISP) 307.1 [(M+H)+], 309.1 [(M+2+H)+], 311.1 [(M+4+H)+].
Reaction SMILES: [C:1]1([C:7]2[C:18]3[CH:17]=[C:16]4[C:12]([CH2:13][CH2:14][CH:15]4[Li])=[CH:11][C:10]=3C[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:20]([CH3:24])([CH3:23])([Cl:22])Cl.[CH2:25]1COCC1>>[Cl:22][Si:20]([CH3:24])([CH3:25])[CH:23]1[C:10]2[C:18](=[CH:17][C:16]3[CH2:15][CH2:14][CH2:13][C:12]=3[CH:11]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8]1
Reactant: C1CCOC1
Reactant: [Li]C1CCc2cc3c(cc21)C(c1ccccc1)=CC3
Reactant: C[Si](C)(Cl)Cl
Product: C[Si](C)(Cl)C1C=C(c2ccccc2)c2cc3c(cc21)CCC3
Temperature: 22.5 °C
Reaction time: 16 h
Yield: 91.1 %

Procedure:
(7-phenyl-1,2,3,5-tetrahydro-s-indacenyl)lithium (12.2075 g, 0.05102 moles) in THF (50 mL) was added dropwise to a solution of Me2SiCl2 (19.5010 g, 0.1511 moles) in THF (100 mL) at 0° C. This mixture was then allowed to stir at 20-25° C. for 16 hours. After the reaction period the volatiles were removed and the residue extracted and filtered using hexane. The removal of the hexane resulted in the isolation of the desired product as a yellow oil (15.1492 g, 91.1 percent).