Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9](C23CC4CC(CC(C5C=CC(O[CH2:29][CH:30]6[O:32][CH2:31]6)=CC=5)(C4)C2)C3)=[CH:8][CH:7]=1)C1OC1.CC(CC(C)=[O:38])C>[Br-].C([N+](CC)(CC)CC)C>[C:31]([OH:32])(=[O:38])[CH:30]=[CH2:29].[CH3:1][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:38])=[CH:8][CH:7]=1
Reactant: CC(=O)CC(C)C
Reactant: c1cc(C23CC4CC(C2)CC(c2ccc(OCC5CO5)cc2)(C4)C3)ccc1OCC1CO1
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Product: C=CC(=O)O
Product: COc1ccc(O)cc1

Procedure:
In a separable flask having an inner volume of 300 ml, equipped with a reflux condenser, a stirrer, a thermometer, and an air inlet were charged 22.4 g of 1,3-bis(4-glycidyloxyphenyl)adamantane obtained by the Synthesis Example 1, 7.6 g of acrylic acid, 20 mL of MIBK, 0.76 g of tetraethylammonium bromide, and 7.6 mg of p-methoxyphenol, and the mixture was heated to 120° C. with flowing a small amount of an air, and stirred for 20 hours. Thereafter, 80 mL of MIBK was added, and the reaction solution was cooled to room temperature. The MIBK solution was washed by 5% by mass of aqueous sodium chloride solution twice, and by pure water once, and then the organic layer was concentrated to obtain 26.8 g of the adamantyl group containing epoxy-modified acrylate having the following formula (purity of 91% by LC).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:39][CH3:40].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH3:12][N:11]1[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:6]2[N:21]=[C:2]([NH:22][C:23]3[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]4[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]4)=[O:28])=[CH:25][C:24]=3[O:39][CH3:40])[N:3]=[CH:4][C:5]1=2
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CC1CN(C2CCOCC2)c2nc(Cl)ncc2N(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCOCC1)CC(C)C(=O)N2C
Yield: 56.1 %

Procedure:
A solution of 0.050 g (0.00016 mole) of (rac)-2-chloro-5,7-dimethyl-9-(tetrahydropyran-4-yl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-45), 0.042 g (0.00016 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.047 g (0.00024 mole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 180 degrees for 2 hours in a microwave reactor. The reaction mixture was concentrated and the residue diluted with dichloromethane, washed twice with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane, and the combined organic phases were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane-methanol (100:0-75:25) to give 0.0483 g of (rac)-4-(5,7-dimethyl-6-oxo-9-(tetrahydro-pyran-4-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-45) as a white powder. HRMS (ES+) m/z Calcd for C28H39N7O4+H [(M+H)+]: 538.3137. Found: 538.3136.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]3[O:20][C:19]([CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[N:18][C:17]=3[CH:34]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][N:10]=[N:9]1.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>C(Cl)Cl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]3[O:20][C:19]([CH:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]4)=[N:18][C:17]=3[CH:34]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][N:10]=[N:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(-n5cnnn5)c(F)c4)ccc3o2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cc(-c2ccc3oc(C4CCNCC4)nc3c2)ccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tert-butyl 4-{5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate (120 mg, 0.26 mmol) dissolved in DCM (15 ml) and added Trifluoroacetic acid (0.5 ml). This mixture was stirred at rt for 2 h. DCM removed from the reaction mixture to obtain 5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (120 mg). 5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (120 mg, 0.25 mmol) was dissolved in DCM (15 ml) and added TEA (0.27 ml, 2 mmol). This mixture stirred at rt for 30 mins and added isopropyl chloroformate in toluene (61 mg, 0.34 mmol). After 1 h, reaction mass diluted with water and extracted with DCM. Removal of DCM afforded crude. Crude was purified by combiflash using a mixture of EtOAc and Petether (35:65) as eluent to afford the titled compound (20 mg) as an off-white solid. M.P.: 187-191° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 9.14 (d, J 2.6, 1H), 8.02 (t, J 8.2, 1H), 7.90 (d, J 1.4, 1H), 7.63-7.55 (m, 4H), 4.95 (septet, J 6.2, 1H), 4.20 (d, J 11.2, 2H), 3.22-3.14 (m, 1H), 3.04 (t, J 11.4, 2H), 2.18 (d, J 10.8, 2H), 2.00-1.88 (m, 2H), 1.26 (d, J 6.2, 6H).
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[CH:13]1[C:23]2[CH2:22][CH2:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[CH:18]([C:28]#[N:29])[C:17]=2[CH:16]=[CH:15][CH:14]=1.C(Br)C=C.Cl>C1COCC1.CCCCCC>[CH2:3]([C:18]1([C:28]#[N:29])[C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[CH2:21][CH2:22][C:23]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]1=2)[CH:1]=[CH2:2]
Reactant: N#CC1c2ccccc2CCc2ccccc21
Reactant: CC(C)NC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C=CCBr
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCC1(C#N)c2ccccc2CCc2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
Dissolved diisopropylamine (11.07 g, 0.109 mol) in 150 mL of dry THF and cooled to 0° C. under a nitrogen atmosphere. Added 40.1 mL (0.100 mol) of 2.5M n-butyl lithium in hexane dropwise via addition funnel. Stirred at 0° C. for 10 mins then cooled to -78° C. Added 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-nitrile (20.00 g, 0.0912 mol) dissolved in 100 mL of dry THF dropwise via addition funnel. Stirred at -78° C. for 45 mins. Added allyl bromide (14.34 g, 0.119 mol) via syringe, and allowed reaction mixture to warm slowly to room temperature. Stirred at room temperature for 90 mins. Added 250 mL of 0.5N HCl, and separated layers. Extracted aqueous solution with ethyl acetate. Washed combined organic extracts with saturated NaCl, dried with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 5% ethyl acetate-hexane then 10% ethyl acetate-hexane. Combined appropriate fractions and evaporated to give 23.65 g (100% yield) of 10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-nitrile.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[CH:15][C:16](=[O:32])[NH:17][C:18]2[CH:19]=[C:20]3[C:30](=[O:31])[NH:29][N:28]=[CH:27][C:22]4=[CH:23][NH:24][C:25]([CH:26]=2)=[C:21]34)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(C=[CH:47][C:48]([OH:50])=[O:49])CC1)=O)(C)(C)C.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[C:48]([OH:50])(=[O:49])[CH3:47].[O:31]=[C:30]1[C:20]2[C:21]3[C:22](=[CH:23][NH:24][C:25]=3[CH:26]=[C:18]([NH:17][C:16](=[O:32])[CH:15]=[CH:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=2)[CH:27]=[N:28][NH:29]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=CC(=O)O)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(C=CC(=O)Nc2cc3c4c(c[nH]c4c2)C=NNC3=O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)O
Product: O=C(C=CC1CCNCC1)Nc1cc2c3c(c[nH]c3c1)C=NNC2=O
Yield: 55 %

Procedure:
Preparation of intermediate 146(a) from the title compound of Example 2 (freebase) (49 mg, 0.245 mmol), 4-(2-carboxy-vinyl)-piperidine-1-carboxylic acid tert-butyl ester (99 mg, 0.39 mmol), triethylamine (0.069 mL, 0.49 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (148 mg, 0.39 mmol) in N,N-dimethylformamide (3 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 10% methanol in CH2Cl2), also in an analogous manner, afforded Intermediate 146(a) (58 mg, 0.13 mmol) as a yellow powder in 55% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.C(N(CC)CC)C.CN([CH:23]=[O:24])C.[CH3:25][OH:26]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:25][O:26][C:23]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2)=[O:24]
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Reactant: CO
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(=O)[nH]ccc2c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
To a mixture of 6-bromo-2H-isoquinolin-1-one (4.00 g, 17.9 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (750 mg, 0.92 mmol), triethylamine (9.0 mL, 65 mmol) in a Parr bomb add a 1:1 mixture (v/v) of DMF and MeOH. Seal the apparatus and flush with 100 psi of carbon monoxide (3×). Heat the reaction mixture at 70° C. with stifling for 15 h. Remove the solvent in vacuo and wash the residue with MeOH then crystallize from dichloromethane to give 3.11 g of the desired product 1-oxo-1,2-dihydro-isoquinoline-6-carboxylic acid methyl ester as an off white solid in 86% yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][CH:21]=3)([OH:17])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1)#[N:2].[BH4-].[Na+].O>C(O)C.O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=3)([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(CCN2CCC(O)(COc3ccc(C=O)cc3)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(CCN2CCC(O)(COc3ccc(CO)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
The compound (0.20 g) obtained in Step 1 was dissolved in a mixture of ethanol (3 mL) and tetrahydrofuran (2.75 mL) and to this solution was added sodium borohydride (0.016 g) under cooling with ice-water and the mixture was stirred at the same temperature for two hours under nitrogen atmosphere. After adding water (15 mL) and stirring, to the mixture was added salt until it was saturated, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (Chromatorex NH™) (eluent; ethyl acetate:methanol=99:1 to 9:1) to obtain the titled compound (0.16 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1([CH3:16])[CH2:15][CH2:14]1)[N:8]([CH:17]1[CH2:19][CH2:18]1)[C:7]2=[O:20].Br[C:23]1C(F)=CC=C2C=1N=C(Cl)N(C1CC1)C2=O.Cl.CC1(N)CCC1>>[Br:1][C:2]1[C:3]([F:21])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1([CH3:16])[CH2:14][CH2:15][CH2:23]1)[N:8]([CH:17]1[CH2:18][CH2:19]1)[C:7]2=[O:20]
Reactant: CC1(Nc2nc3c(Br)c(F)ccc3c(=O)n2C2CC2)CC1
Reactant: O=c1c2ccc(F)c(Br)c2nc(Cl)n1C1CC1
Agent: CC1(N)CCC1
Agent: Cl
Product: CC1(Nc2nc3c(Br)c(F)ccc3c(=O)n2C2CC2)CCC1

Procedure:
8-Bromo-3-cyclopropyl-7-fluoro-2-((1-methylcyclobutyl)amino)quinazolin-4(3H)-one (498a) was prepared according to the procedures described for Intermediate 495a, using 8-bromo-2-chloro-3-cyclopropyl-7-fluoroquinazolin-4(3H)-one (721) and 1-methylcyclobutanamine hydrochloride (Oakwood Chemical) as the starting materials. MS (ESI, pos. ion) m/z: 366.0/368.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([NH2:12])=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:34]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([NH2:12])=[S:34]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: NC(=S)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 1 h
Yield: 128.8 %

Procedure:
A suspension of 5-[2'-chloro-4'-(trifluoromethyl)phenoxy]-2-nitrobenzamide (54.1 g; 0.15 mol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (LAWESSON's reagent) (28 g; 0.075 mol) in toluene (250 cc) is prepared. It is heated to 100° C., with stirring, and the heating is continued for 1 hour at this temperature. The toluene is removed by evaporation and the residue is purified by chromatography. This gives a yellow solid of 5-[2'-chloro-4'-(trifluoromethyl)phenoxy]-2-nitrothiobenzamide (36.4 g; yield 65%) melting at 152° C. and having the formula: ##STR21##
Reaction SMILES: C([O:8][C:9](=[O:42])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:41])[NH:29][C:30]4[CH:38]=[C:37]5[C:33]([CH:34]=[CH:35][N:36]5[CH2:39][CH3:40])=[CH:32][CH:31]=4)=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.CCO.[H][H]>[Pd].CCOC(C)=O>[CH2:39]([N:36]1[C:37]2[C:33](=[CH:32][CH:31]=[C:30]([NH:29][C:28]([C:25]3[CH:26]=[CH:27][C:22]([N:19]4[CH2:18][CH2:17][N:16]([C:13]5[CH:12]=[CH:11][C:10]([C:9]([OH:42])=[O:8])=[CH:15][CH:14]=5)[CH2:21][CH2:20]4)=[N:23][CH:24]=3)=[O:41])[CH:38]=2)[CH:34]=[CH:35]1)[CH3:40]
Reactant: [H][H]
Reactant: CCn1ccc2ccc(NC(=O)c3ccc(N4CCN(c5ccc(C(=O)OCc6ccccc6)cc5)CC4)nc3)cc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCn1ccc2ccc(NC(=O)c3ccc(N4CCN(c5ccc(C(=O)O)cc5)CC4)nc3)cc21
Yield: 96 %

Procedure:
A mixture of 4-{4-[5-(1-ethyl-1H-indol-6-ylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid benzyl ester (100 mg, 0.18 mmol), 10% Pd/C (50 mg) in a 1:1 mixture of EtOH and EtOAc (50 mL) was hydrogenated under 1 atm of hydrogen for 2 h. The mixture was then filtered. The solids were washed with a 1:1 mixture of THF and DMF and the combined organic layer was concentrated. The residue was passed through a silica gel plug with DMF to afford the product (85 mg; Yield: 96%). HRMS m/z calcd for C27H27N5O3I [M+H]+: 470.2187. Found: 470.2184.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:23][CH2:24][C@H:25]2[CH2:30][CH2:29][C@H:28]([N:31]3[CH2:34][CH:33]([OH:35])[CH2:32]3)[CH2:27][CH2:26]2)=[N:6][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]([F:22])([F:21])[F:20])=[N:8][CH:9]=1)([O-:3])=[O:2].N1C=CC=CC=1.[C:42](OC(=O)C)(=[O:44])[CH3:43]>>[C:42]([O:35][CH:33]1[CH2:34][N:31]([C@H:28]2[CH2:27][CH2:26][C@H:25]([CH2:24][NH:23][C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]([NH:10][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[O:18][C:19]([F:21])([F:22])[F:20])[N:6]=3)[CH2:30][CH2:29]2)[CH2:32]1)(=[O:44])[CH3:43]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](N2CC(O)C2)CC1
Solvent: c1ccncc1
Product: CC(=O)OC1CN([C@H]2CC[C@H](CNc3nc(NCc4ccccc4OC(F)(F)F)ncc3[N+](=O)[O-])CC2)C1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
1-(trans-4-{[(5-Nitro-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidin-4-yl)amino]methyl}cyclohexyl)azetidin-3-ol (25 mg, 0.05 mmol) was dissolved in pyridine (12 μL, 0.15 mmol) and acetic anhydride (14 μL, 0.15 mmol) was added to the solution. The reaction was allowed to stir at 20° C. for 18 h. The volatiles were removed in vacuo and the crude product was purified by flash chromatography on a 12 g SiO2 column, eluting with 90:9:1 CH2Cl2:MeOH:NH4OH as an eluent to afford 5 mg of the title compound, m/z 539.6 [M+1]+
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[NH:5][CH:6]=1.[OH-].[K+].Br[CH2:23][CH2:24][O:25]C1CCCCO1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CS(C)=O.C(OCC)(=O)C>[Br:1][C:2]1[N:3]=[C:4]([CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)[N:5]([CH2:23][CH2:24][OH:25])[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)c[nH]2)CC1
Reactant: BrCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCO)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.6 %

Procedure:
A suspension of tert-butyl 4-(4-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate (36.0 g, 109.02 mmol) in dry DMSO (400 mL) was treated with KOH (36.0 g, 641.60 mmol, 4.5 eq), and the contents became a clear-yellow solution after 20-30 min. After 90 min, the solution was treated with 2-(2-bromoethoxy)terahydropyran (36.0 g, 172.18 mmol, 1.2 eq). The reaction was deemed complete after 4 h by LCMS data, so the contents were diluted with ethyl acetate (800 mL) and washed with brine (3×800 mL). The organics were dried over sodium sulfate and concentrated to an oil with an approximate 8:1 ratio of regioisomers and the major isomer is the desired one. The oil was redissolved in methanol (400 mL) and treated with p-toluenesulfonic acid monohydrate (32.11 g, 168.80 mmol, 1.5 eq). The contents were stirred at room temp for 20 min, poured into ethyl acetate (500 mL) and washed with aqueous potassium carbonate (400 mL), followed by brine (2×400 mL). The organics were dried over sodium sulfate and concentrated to a colorless oil that was further dried under vacuum for 60 min. The resultant, thick oil was suspended in diethyl ether (200 mL) and rolled in an ice-water-salt bath for 90 min. A white solid precipitated, which was filtered and dried under vacuum for 30 min to give the title compound (25.15 g, 67.20 mmol, 62%, >96% by NMR and LCMS data).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][O:14][CH3:15])[C:8](=O)[CH2:7][CH2:6]2.CC1C=CC(N=[CH:25][C:26]2[C:27]([NH2:35])=[CH:28][C:29]3[O:33][CH2:32][O:31][C:30]=3[CH:34]=2)=CC=1>>[CH3:1][O:2][C:3]1[C:11]([O:12][CH2:13][O:14][CH3:15])=[CH:10][C:9]2[CH2:8][C:7]3[C:6]([C:5]=2[CH:4]=1)=[N:35][C:27]1[CH:28]=[C:29]2[O:33][CH2:32][O:31][C:30]2=[CH:34][C:26]=1[CH:25]=3
Reactant: Cc1ccc(N=Cc2cc3c(cc2N)OCO3)cc1
Reactant: COCOc1cc2c(cc1OC)CCC2=O
Product: COCOc1cc2c(cc1OC)-c1nc3cc4c(cc3cc1C2)OCO4
Yield: 25.3 %

Procedure:
Using the procedure of Example 1, 5-methoxy-6-methoxymethoxyindan-1-one (1000 mg, 4.5 mmol) is reacted with 6[[(4-methylphenyl)imino]methyl]-1,3-benzodioxol-5-amine (1144 mg, 4.5 mmol) to yields 7-Methoxy-8-methoxymethoxy-10H-1,3-dioxolo[4,5-g]indeno[1,2-b]quinoline (400 mg, 25% of theory).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([N:9]([CH2:12][C:13]([OH:15])=O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[O:28]=[C:29]1[N:35]2[CH2:36][CH2:37][CH2:38][C@H:34]2[C:33]2=[C:39]([C:42]([NH:44][NH2:45])=[O:43])[N:40]=[CH:41][N:32]2[C:31]2[CH:46]=[CH:47][S:48][C:30]1=2>CN(C)C=O>[O:11]=[C:10]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7](=[O:8])[N:9]1[CH2:12][C:13]([NH:45][NH:44][C:42]([C:39]1[N:40]=[CH:41][N:32]2[C:31]3[CH:46]=[CH:47][S:48][C:30]=3[C:29](=[O:28])[N:35]3[CH2:36][CH2:37][CH2:38][C@H:34]3[C:33]=12)=[O:43])=[O:15]
Reactant: NNC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1sccc1-2
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)NNC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1sccc1-2
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.5 %

Procedure:
A solution of 1.0 g (4.9 mmol) of N-phthaloylglycine in 8 ml of dimethylformamide was treated at room temperature with 0.83 g is (5.11 mmol) of 1,1'-carbonyldiimidazole and the mixture was subsequently heated to 50°. After 30 minutes the mixture was cooled to room temperature, 1.5 g (5 mmol) of (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carboxylic acid hydrazide were added thereto and the mixture was stirred at room temperature for 12 hours. The suspension obtained was filtered and the colourless powder obtained was washed with ethanol and diethyl ether. There were obtained 2.2 g (100%) of (S)-N'-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-ylacetyl)-8-oxo-10,11,12,12a-tetrahydro-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carboxylic acid hydrazide of m.p. >260°.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[C:23]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:22][CH:21]=[CH:20][N:19]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1.CCN(C(C)C)C(C)C>CN(C)C=O.O>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[C:23]([N:24]3[CH2:29][CH2:28][N:27]([CH2:32][C:33]4[CH:42]=[CH:41][C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:34]=4)[CH2:26][CH2:25]3)=[N:22][CH:21]=[CH:20][N:19]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=S(=O)(Nc1nccnc1N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(Nc1nccnc1N1CCN(Cc2ccc3ccccc3n2)CC1)c1ccc(Oc2ccccc2)cc1
Yield: 76 %

Procedure:
To a solution of 4-phenoxy-N-(3-piperazin-1-ylpyrazin-2-yl)benzenesulfonamide (411 mg, 1.0 mmol, 1 eq) in dimethylformamide (10 mL) was added 2-(chloromethyl)quinoline hydrochloride (214 mg, 1 mmol, 1 eq) and DIPEA (322 mg, 2.5 mmol, 2.5 eq). The reaction mixture was heated to 50 degrees over 1 hour. The reaction was cooled, diluted with 30 mL of water and extracted with diethyl ether. The organic layer was dried over MgSO4, evaporated and purified by flash chromatography on silica gel eluting with AcOEt and cyclohexane to give pure 4-phenoxy-N-{3-[4-(quinolin-2-ylmethyl)piperazin-1-yl]pyrazin-2-yl}benzenesulfonamide as a yellow solid (419 mg, 0.76 mmol, yield: 76%, 97% HPLC purity).
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=[O:12].[CH3:13][S-:14].[Na+]>C(O)C>[Cl:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3](=[O:12])[CH:2]([S:14][CH3:13])[CH2:10]2
Reactant: C[S-]
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Agent: [Na+]
Solvent: CCO
Product: CSC1Cc2cc(Cl)ccc2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
0.98 g (4 mmol) of 2-bromo-5-chloroindan-1-one and 0.42 g (6 mmol) of sodium thiomethoxide are suspended in 5 ml of ethanol, treated in an ultrasonic bath for 30 minutes and then stirred at room temperature for 90 minutes. The reaction mixture is concentrated under reduced pressure and chromatographed on silica gel using toluene/ethyl acetate 10/1. The eluates are concentrated under reduced pressure, giving 0.63 g of 5-chloro-2-methylsulfanylindan-1-one of melting point 90° C.