Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:30])[CH:6]([CH2:27][CH2:28][OH:29])[NH:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:31]1([C:37](Cl)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN1CCOCC1>CN(C=O)C.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.CO>[OH:29][CH2:28][CH2:27][CH:6]([C:5](=[O:30])[NH:4][CH2:3][CH2:2][NH:1][C:37]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[NH:7][C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NCCNC(=O)C(CCO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(NCCNC(c1ccccc1)(c1ccccc1)c1ccccc1)C(CCO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.5 %

Procedure:
6-Amino-2-(2-hydroxyethyl)-3-oxo-1-(triphenylmethyl)-1,4-diazahexane (15.0 g, 37.2 mmol) (Example 9(a)) was dissolved in 150 ml DMF and triphenylmethyl chloride (10.35 g, 37.2 mmol) and methylmorpholine (3.75 g, 37.2 mmol) was added. After being stirred for 24 hours at ambient temperature, the reaction mixture was filtered and poured into 200 ml of ice water. After 1 hour stirring, filtration and thoroughly washing the precipitate with water, the solid was dried in vacuo at 50° C. to yield 22 g of crude product. The product was dissolved in chloroform/toluene/methanol (80/16/14) and purified on silica to yield 6.6 g (27%) of 2-(2-hydroxyethyl)-3-oxo-1,7-bis(triphenylmethyl)-1,4,7-triazaheptane as white crystals, m.p. 71°-72° C., FAB MS: 646(M+1). The structure was confirmed by 13C NMR.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:23]([OH:25])=O)[S:5][C:6]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[N:12][N:11]=[CH:10]2.C([N:29]([CH:32]([CH3:34])[CH3:33])CC)(C)C.C1(N)CC1>S(Cl)(Cl)=O.CCOC(C)=O>[CH:32]1([NH:29][C:23]([C:4]2[S:5][C:6]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:12][N:11]=[CH:10]4)=[C:2]([CH3:1])[CH:3]=2)=[O:25])[CH2:34][CH2:33]1
Reactant: Cc1cc(C(=O)O)sc1-c1ccc2c(N3CCOCC3)nncc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: NC1CC1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)NC2CC2)sc1-c1ccc2c(N3CCOCC3)nncc2c1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
4-Methyl-5-(1-morpholinophthalazin-6-yl)thiophene-2-carboxylic acid (140 mg, 309 μmol) was suspended in thionyl chloride (3.1 mL) and heated to 65° C. for 1 h. The reaction mixture was concentrated in vacuo and azeotropically dried with toluene, before being dissolved/suspended in tetrahydrofuran 99.9% (3.1 mL), diisopropylethylamine (216 μl, 1238 μmol) and cyclopropylamine (71 μl, 1238 μmol). The reaction was stirred at RT for 2 h, diluted with 50 mL of EtOAc, added to an addition funnel and partitioned with sodium bicarbonate (saturated, aqueous). The organic layer was washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous), dried over sodium sulfate, and concentrated via rotovap to give a crude yellow product. The crude was purified by chromatography, to obtain the title compound. Found MS (ES+): 395(M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:16])=[O:5])C.ClC1C=C2C(=C(CC#N)C=1)NC(C(O)=O)=C2>>[CH3:15][C:14]1[C:13]2[C:8](=[C:9]([CH3:16])[CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1[nH]c2c(C)cccc2c1C
Agent: N#CCc1cc(Cl)cc2cc(C(=O)O)[nH]c12
Product: Cc1c(C(=O)O)[nH]c2c(C)cccc12

Procedure:
The title compound is prepared by saponification of 3,7-dimethyl-1H-indole-2-carboxylic acid ethyl ester (prepared by Fischer indole synthesis as described in Tetrahedron Lett. 2003, 44, 5665) using the procedure described above for the synthesis of 5-chloro-7-cyanomethyl-1H-indole-2-carboxylic acid (acid 1, step g)).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH2:13](Br)[CH:14]=[CH2:15]>CO.[OH-].[K+]>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2)[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: O=C1CCc2cc(O)ccc2N1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CCOc1ccc2c(c1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
32.6 Grams of 3,4-dihydro-6-hydroxy-2(1H)-quinolinone was dissolved in 500 ml of methanol containing 12.6 g of potassium hydroxide. Under stirring this solution, 20 ml of allyl bromide was added thereto at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and further stirred at 60° C. for 4 hours. After the reaction, the reaction mixture was concentrated to a half volume under reduced pressure, then 500 ml of water was added and stirred vigorously, the crystals precipitated were collected by filtration. The crystals were washed with water and small amount of diethyl ether in this order, and dried. Recrystallized from ethanol, 28 g (68.9%) of 6-allyloxy-3,4-dihydro-2(1H)-quinolinone was obtained. Colorless needle-like crystals (recrystallized from ethanol)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[N:10][C:9]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[Br:27]Br>C(Cl)(Cl)Cl>[Br:27][C:11]1[C:12]([NH2:14])=[N:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[C:9]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[N:10]=1
Reactant: Nc1cnc(-c2ccncc2)c(-c2cccc(F)c2)n1
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Nc1nc(-c2cccc(F)c2)c(-c2ccncc2)nc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.5 %

Procedure:
To a solution of 6-(3-fluorophenyl)-5-pyridin-4-ylpyrazin-2-ylamine (Example 1, 70 mg, 0.26 mmol) in chloroform (4 mL) at 0° C. was added pyridine (22 μL, 0.27 mmol) and bromine (14 μL, 0.27 mmol). The reaction mixture was stirred at room temperature for 24 h, chloroform (20 mL) was added, the organic layer was washed with water and brine, dried (MgSO4) and evaporated. The residue was purified by silica gel flash column chromatography (dichloromethane/methanol 95:5) to provide the title compound as a red solid (22 mg, 24%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[C:10]3[C@@H:9]3[CH2:22][CH2:23][CH2:24][N:8]3[C:7](=[O:25])[C:6]=2[C:26]=1[Cl:27].O[CH2:29][CH:30]1[CH2:32][CH2:31]1>CCO.CCO.CCO.CCO.[Ti]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[O:16])=[C:10]3[C@@H:9]3[CH2:22][CH2:23][CH2:24][N:8]3[C:7](=[O:25])[C:6]=2[C:26]=1[Cl:27]
Reactant: OCC1CC1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c-2ccc(Cl)c1Cl
Agent: [Ti]
Solvent: CCO
Product: O=C(OCC1CC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c-2ccc(Cl)c1Cl
Reaction time: 8 h

Procedure:
A mixture of 4.0 g (7.3 mmol) of tert.butyl (S)-7,8-dichloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 10 ml (126 mmol) of hydroxymethyl-cyclopropane and 1 g (3 mmol) of tetraethyl orthotitanate is stirred at 125° overnight, the mixture is evaporated and the residue is taken up in chloroform. The solution is stirred for 0.5 hour with 30 ml of a saturated potassium fluoride solution and the mixture is filtered through siliceous earth. The organic phase is separated, washed with water, dried over magnesium sulphate and evaporated. By crystallization from ethyl acetate there is obtained cyclopropylmethyl (S)-7,8-dichloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 185°-186°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH:24]=O)=[CH:19][C:18]=3[CH3:26])[CH:13]=[CH:12][C:11]=2[O:27][CH3:28])=[CH:5][N:4]=1.[C:29]([NH:32][CH2:33][C:34]([OH:36])=[O:35])(=O)[CH3:30].C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[CH3:30][C:29]1[O:36][C:34](=[O:35])[C:33](=[CH:24][C:20]2[CH:21]=[C:22]([CH3:23])[C:17]([O:16][C:14]3[CH:13]=[CH:12][C:11]([O:27][CH3:28])=[C:10]([CH2:9][C:6]4[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[CH:15]=3)=[C:18]([CH3:26])[CH:19]=2)[N:32]=1
Reactant: CC(=O)NCC(=O)O
Reactant: COc1ccc(Cc2cc(Oc3c(C)cc(C=O)cc3C)ccc2OC)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(Cc2cc(Oc3c(C)cc(C=C4N=C(C)OC4=O)cc3C)ccc2OC)cn1
Reaction time: 24 h
Yield: 62.8 %

Procedure:
2-Methoxy-5-(2-methoxy-5-(2,6-dimethyl-4-formylphenoxy)benzyl)-pyridine (10.84 g), N-acetylglycine (5.38 g), sodium acetate (3.77 g) and acetic anhydride (70 ml) were stirred at 100±5°, (oil bath temperature) for 24 hours. The solution was cooled and evaporated to leave a brown gum which was triturated with water, then with methanol to afford 2-methyl-4-(3,5-dimethyl-4-(4-methoxy-3-(6-methoxy-3-pyridylmethyl)-phenoxy)-benzal)-5-oxazolone as a yellow solid (8.27 g, 64%), m.p. 164°-165°.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Product: Clc1nc(NCc2ccccc2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[benzylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, benzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:14]2[N:15]=[C:16]([NH:19][CH:20]([CH3:22])[CH3:21])[S:17][CH:18]=2)[N:3]=1.ClC1N=C(O[CH:37]2[CH2:54][CH:53]3[N:39]([C:40](=[O:60])[N:41]([CH3:59])[CH2:42][CH2:43][CH2:44][CH2:45][CH:46]=[CH:47][CH:48]4[C:50]([C:56]([OH:58])=[O:57])([NH:51][C:52]3=[O:55])[CH2:49]4)[CH2:38]2)C2C(C=1)=CC(OC)=CC=2>>[CH:20]([NH:19][C:16]1[S:17][CH:18]=[C:14]([C:4]2[N:3]=[C:2]([O:1][CH:37]3[CH2:54][CH:53]4[N:39]([C:40](=[O:60])[N:41]([CH3:59])[CH2:42][CH2:43][CH2:44][CH2:45][CH:46]=[CH:47][CH:48]5[C:50]([C:56]([OH:58])=[O:57])([NH:51][C:52]4=[O:55])[CH2:49]5)[CH2:38]3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:15]=1)([CH3:22])[CH3:21]
Reactant: COc1ccc2c(O)nc(-c3csc(NC(C)C)n3)cc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(Cl)cc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3csc(NC(C)C)n3)cc2c1

Procedure:
The title product 71 was prepared from 1-hydroxy-3-(2-isopropylaminothiazol-4-yl)-6-methoxyisoquinoline following the same procedures described for the preparation of 17-(3-chloro-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (42, Example 10): m/z=649 (M+H)+.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:32][CH:31]=2)=[C:21]([CH:25]=1)[C:22](O)=[O:23])=[O:16])[CH3:13].C(N(CC)CC)C.Cl.[NH2:56][C@H:57]1[CH2:62][CH2:61][CH2:60][CH2:59][C@H:58]1[C:63]([O:65][CH2:66][CH3:67])=[O:64]>ClCCl.O>[CH2:66]([O:65][C:63]([C@H:58]1[CH2:59][CH2:60][CH2:61][CH2:62][C@H:57]1[NH:56][C:22]([C:21]1[CH:25]=[C:17]([CH:18]=[CH:19][C:20]=1[O:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[CH:32][CH:31]=1)[C:15]([O:14][CH2:12][CH3:13])=[O:16])=[O:23])=[O:64])[CH3:67]
Reactant: CCOC(=O)c1ccc(OCCCc2ccc(OCCCCOc3ccccc3)cc2)c(C(=O)O)c1
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(OCCCc2ccc(OCCCCOc3ccccc3)cc2)c(C(=O)N[C@@H]2CCCC[C@@H]2C(=O)OCC)c1
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
39 mg (0.20 mmol) of N-[(3-dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (EDC) and 27.4 mg (0.20 mmol) of 1-hydroxy-1H-benzotriazole hydrate (HOBT) are successively added to a suspension of 100 mg (0.20 mmol) of 5-(ethoxycarbonyl)-2-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}benzoic acid in 30 ml of dichloromethane at RT. After 30 min, 41 mg (0.41 mmol) of triethylamine and 38 mg (0.18 mmol) of ethyl cis-2-amino-1-cyclohexanecarboxylate hydrochloride are added, and the mixture is stirred overnight. 10 ml of water are then added, the phases are separated, and the aqueous phase is extracted with dichloromethane (three times 25 ml). The combined organic phases are washed with saturated sodium chloride solution, dried, (sodium sulphate) and concentrated in a rotary evaporator. The crude product is purified by column chromatography (silica gel 60, mobile phase gradient cyclohexane-->cyclohexane-ethyl acetate 5:1). 102 mg of product are obtained.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[NH:9][C:10](=O)[C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[CH:13]=1.[OH-].[Na+].O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:10]1[C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[CH:13]=[C:8]([CH3:7])[N:9]=1
Reactant: Cc1cn2ccnc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: Cc1cn2ccnc2c(Cl)n1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
Pyridine (0.4 mL, 4.9 mmol) was added to a solution of 6-methyl-7H-imidazo[1,2-a]pyrazin-8-one (0.97 g, 6.5 mmol) in POCl3 (19 mL) and the reaction is stirred at 120° C. under N2 atmosphere for 4 h 30 min. The reaction is cooled to 60° C. and poured into 60 g of ice and stirred for 1 h. The solution is neutralized with NaOH (10%), extracted with CHCl3/IPA 9/1, dried with MgSO4 anh., filtered and concentrated. The crude product is purified by column chromatography using a gradient of (DCM/MeOH:99/1 to 95/5) to give 8-chloro-6-methyl-imidazo[1,2-a]pyrazine as a pale yellow solid (0.383 g, 35%).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.Cl.[CH3:13][NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[CH3:21]>CN1C(=O)N(C)CC1.CCOC(C)=O.O>[F:8][C:7]1[CH:6]=[N:5][C:4]2[NH:9][CH:10]=[CH:11][C:3]=2[C:2]=1[N:14]([CH3:13])[C@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[CH3:21]
Reactant: CN[C@H]1CCCC[C@H]1C
Reactant: Fc1cnc2[nH]ccc2c1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: C[C@@H]1CCCC[C@@H]1N(C)c1c(F)cnc2[nH]ccc12
Temperature: 210 °C
Yield: 3.3 %

Procedure:
A mixture of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (100 mg) and (1S,2R)—N,2-dimethylcyclohexanamine hydrochloride (288 mg) in DMI (1 mL) was heated in the microwave reactor (210° C., 2 hours). The reaction mixture was allowed to cool to ambient temperature and diluted with EtOAc (10 mL) and water (10 mL). The aqueous phase was extracted with EtOAc (2×10 mL) and combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated. Purification of the crude product by preparative silica gel thin-layer chromatography (chloroform:methanol=10:1) gave 5-fluoro-N-methyl-N-[(1S,2R)-2-methylcyclohexyl]-1H-pyrrolo[2,3-b]pyridin-4-amine (5 mg) as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20]>O1CCCC1>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:3]1([CH2:4][N:5]2[CH:9]=[N:8][CH:7]=[N:6]2)[O:10][C:19](=[O:20])[NH:1][CH2:2]1
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1NCC(Cn2cncn2)(c2ccc(Cl)cc2Cl)O1

Procedure:
A solution of the amine (A) (0.1 g, 0.35 mmole) and 1,1'-carbonyldiimidazole (0.056 g, 0.35 mmole) in tetrahydrofuran (5 ml) was stirred at room temperature for five hours. The solvent was then evaporated and the residue was dissolved in ethyl acetate (20 ml). This solution was washed three times with water (300 ml, total), dried (MgSO4), evaporated and the residue triturated with a mixture of 60°-80° C. petrol:ether to give, as a white solid, the title compound, 0.074 g (68%), m.p. 223° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:9]2[C:10]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:15]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5([NH:34]C(=O)OC(C)(C)C)[CH2:33][CH2:32][CH2:31]5)=[CH:26][CH:25]=4)=[N:14][C:11]=3[O:12][CH2:13][C:8]2=[N:7][N:6]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:9]2[C:10]3[CH:17]=[C:16]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:15]([C:24]4[CH:25]=[CH:26][C:27]([C:30]5([NH2:34])[CH2:31][CH2:32][CH2:33]5)=[CH:28][CH:29]=4)=[N:14][C:11]=3[O:12][CH2:13][C:8]2=[N:7][N:6]=1
Reactant: COCCc1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc1OC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCc1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc1OC2
Reaction time: 0.01 h
Yield: 50.1 %

Procedure:
Tert-butyl (1-(4-(1-(2-methoxyethyl)-8-phenyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (12 mg, 0.022 mmol) was dissolved in dichloromethane (0.5 ml); TFA (0.5 ml) was added at room temperature and the resulting mixture was stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 ml) and concentrated to dryness under reduced pressure. This was repeated three times. The residue was then slurred in diethyl ether (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The residue was then slurred in n-hexane (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (5 mg, 50% yield). LCMS (Method D) RT=0.741 min, M+1=454. 1H-NMR (500 MHz, CD3OD) δ 8.40 (1H, s), 7.52-7.47 (2H, d), 7.46-7.41 (2H, d), 7.38-7.34 (3H, m), 7.32-7.26 (2H, dd), 5.65 (2H, s), 3.94 (2H, t), 3.49 (2H, t), 3.35 (3H, s), 2.82-2.74 (2H, m), 2.63-2.54 (2H, m), 2.30-2.19 (1H, m), 2.04-1.93 (1H, m).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[CH:10]([C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH2:28].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9](=[O:26])[CH:10]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:19]1[CH:24]=[CH:23][C:22](/[CH:28]=[CH:27]/[S:29]([CH3:32])(=[O:31])=[O:30])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)OCc1ccccc1)c1ccc(Br)cc1
Reactant: C=CS(C)(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC(C(=O)OCc1ccccc1)c1ccc(/C=C/S(C)(=O)=O)cc1
Yield: 74.8 %

Procedure:
(4-Bromo-phenyl)-tert-butoxycarbonylamino-acetic acid benzyl ester (1.5 g, 3.6 mmol), methyl vinyl sulfone (406 μL, 4.6 mmol), palladium(II) acetate (80 mg, 10 mol %), tri-o-tolylphosphine (217 mg, 20 mol %) and triethylamine (2.0 ml, 14.3 mmol) were combined in acetonitrile (18 mL), degassed and refluxed for 8 hours. Additional palladium(II) acetate (80 mg, 10 mol %) and tri-o-tolylphosphine (217 mg, 20 mol %) were added and refluxing continued overnight. The reaction was cooled, solvent removed in vacuo and the residue was purified by chromatography over silica gel gradient eluted from 20 to 90% v/v ethyl acetate in hexane to afford tert-butoxycarbonylamino-[4-((E)-2-methanesulfonyl-vinyl)-phenyl]-acetic acid benzyl ester (1.2 g, 75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([O:26][CH:27]([CH3:29])[CH3:28])=[CH:17][C:11]=3[C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:36][O:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH2:42][C:41]4[CH:44]=[CH:45][C:38]([O:37][CH3:36])=[CH:39][CH:40]=4)[S:22]([CH3:25])(=[O:23])=[O:24])[C:18]([O:26][CH:27]([CH3:29])[CH3:28])=[CH:17][C:11]=3[C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(OC(C)C)cc12
Reactant: COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(Cc3ccc(OC)cc3)S(C)(=O)=O)c(OC(C)C)cc12
Temperature: 70 °C

Procedure:
Methyl 2-(4-fluorophenyl)-5-isopropoxy-6-(methylsulfonamido)benzofuran-3-carboxylate (0.65 g, 1.5 mmol) was dissolved in 10 mL N,N-dimethylformamide and treated sequentially with potassium carbonate (0.26 g, 1.85 mmol) and 4-methoxybenzyl bromide (0.27 mL, 1.85 mmol). The slurry was stirred and heated at 70° C. for 3 hours. The reaction mixture was concentrated in vacuo to a pasty solid. The residue was dissolved in 100 mL ethyl acetate, washed with 1 N aqueous H3PO4 and 10% aqueous sodium chloride, dried over anhydrous sodium sulfate(s), filtered and the solvent was removed in vacuo leaving a yellow oil, 0.8 g.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al].Cl[CH:21](Cl)[CH2:22][Si:23]([Cl:26])([Cl:25])[Cl:24]>C(=S)=S.CCCCCC>[Cl:24][Si:23]([CH2:22][CH:21]1[C:8]2[CH:9]=[C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:11]=[CH:12][C:7]=2[C:1]2[C:2]1=[CH:3][CH:4]=[CH:5][CH:6]=2)([Cl:26])[Cl:25]
Reactant: c1ccc(-c2ccc(-c3ccccc3)cc2)cc1
Reactant: ClC(Cl)C[Si](Cl)(Cl)Cl
Agent: [Al]
Solvent: CCCCCC
Solvent: S=C=S
Product: Cl[Si](Cl)(Cl)CC1c2ccccc2-c2ccc(-c3ccccc3)cc21
Yield: 10 %

Procedure:
In the same apparatus and procedures as Example 1 above, 5.0 g (21.7 mmol) of para-terphenyl and 0.30 g (11.1 mmol) of aluminum were alkylated in CS2 (50 ml) solution with (2,2-dichloroethyl)trichlorosilane 6.68 g (21.7 mmol) under dry nitrogen atmospheric pressure for 24 hrs at reflux temperature. Freshly distilled hexane (100 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic solution. After hexane and CS2 were distilled, recrystallization from ether yielded 0.85 g of 9-(trichlorosilyl)methyl-2-phenylfluorene (yield; 10%).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C([Mg]C(C)C)(C)C.[CH:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.C(OC)(C)(C)C>[OH:27][CH:20]([C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: CC(C)[Mg]C(C)C
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A solution of 552 mg (2 mmol) of ethyl 4-iodobenzoate in 20 ml of THF was cooled to −40° C. and 1.06 mmol of diisopropylmagnesium in methyl tert-butyl ether were added. After 1 h at −40° C. 233 mg (2.2 mmol) of benzaldehyde were added. After 3 h, the reaction mixture was hydrolyzed and the org. phase was concentrated. Chromatography of the crude product with 4/1 pentane/ether afforded 460 mg (90%) of the alcohol.