Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2(O)[C:14]3[CH:15]=[C:16]([Br:19])[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][N:10]3[CH:20]=[CH:21][CH:22]=[C:9]23)[CH2:4][CH2:3]1.Cl.C(#N)C>C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([Br:19])[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][N:10]3[CH:20]=[CH:21][CH:22]=[C:9]23)[CH2:6][CH2:7]1
Reactant: CN1CCC(C2(O)c3cc(Br)ccc3C=Cn3cccc32)CC1
Agent: Cl
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CN1CCC(=C2c3cc(Br)ccc3C=Cn3cccc32)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.5 %

Procedure:
1-Methyl-4-(9-bromo-11-hydroxy-11H-pyrrolo[2,1-b][3]benzazepin-11-yl)piperidine (8.8 g) is dissolved in 500 ml of chloroform and the solution stirred in an ice bath while dry hydrogen chloride gas is bubbled in until the solution is acidic. The flask is then stoppered and the mixture stirred at room temperature for six hours following which the mixture is carefully basified with dilute aqueous sodium carbonate. The layers are separated, the aqueous extracted twice with chloroform and the combined chloroform washed with dilute sodium bicarbonate and with water. After drying over magnesium sulfate the chloroform is removed on a film evaporator to give a dark brown oil. Trituration with acetonitrile gives slightly impure 1-methyl-4-(9-bromo-11H-pyrrolo[2,1-b][3]benzazepin-11-ylidene)piperidine (5.4 g, 64%), m.p. 138°-142° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2[N:15]([CH3:32])[C:16](=[O:31])[C:17]([CH3:30])=[C:18]([NH:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25][CH3:26])=[O:24])[C:13]=2[C:12](=[O:33])[N:11]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:10]1=[O:43].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:14]1[N:15]([CH3:32])[C:16](=[O:31])[C:17]([CH3:30])=[C:18]2[C:13]=1[C:12](=[O:33])[N:11]([CH2:34][C:35]1[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)[C:10](=[O:43])[N:19]2[C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1cccc(Nc2c(C)c(=O)n(C)c3c2c(=O)n(Cc2ccc(OC)cc2)c(=O)n3-c2ccc(I)cc2F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cccc(-n2c(=O)n(Cc3ccc(OC)cc3)c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c32)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.7 %

Procedure:
To a stirred solution of methyl 3-((1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)benzoate (3b) (3.20 g, 4.59 mmol) in THF (5 ml) and Methanol (10 ml), was added K2CO3 (2.54 g, 18.38 mmol) at RT. The reaction mixture was stirred at room temperature for 3 h under N2 atm. The solvents were evaporated in vacuo and the residue was suspended in water, the precipitated product was collected by filtration and dried under high vacuum to afford the titled compound (3c), (2.1 g). The crude product was carried forward for the next step without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([Cl:18])[CH:10]=2)=[N:5]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]2[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[N:27]2)[CH:21]=1.CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C>>[Cl:18][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:31]([C:28]3[CH:29]=[CH:30][N:26]([C:22]4[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=4)[N:27]=3)=[O:32])[CH3:19])[N:5]=2)[CH:16]=[C:15]([F:17])[C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1ccn(-c2cccnc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1ccn(-c2cccnc2)n1
Yield: 98.1 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.050 g, 0.179 mmol), 1-(pyridin-3-yl)-1H-pyrazole-3-carboxylic acid (0.034 g, 0.179 mmol), DIPEA (0.094 ml, 0.538 mmol 1), HOBt hydrate (0.041 g, 0.269 mmol) and EDCI (0.052 g, 0.269 mmol) using the method of Example 274 affording 0.079 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.19 (d, 3H), 4.38 (m, 2H), 4.49 (m, 1H), 6.89 (d, 1H), 7.01 (d, 1H), 7.59 (m, 1H), 7.88 (m, 3H), 8.30 (m, 1H), 8.35 (d, 1H), 8.59 (d, 1H), 8.65 (d, 1H), 9.18 (d, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[C:14]([O:22]CC2C=CC=CC=2)=[N:13][C:12]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].C(Cl)Cl>>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[NH2:7][CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[C:14](=[O:22])[NH:13][C:12]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1
Reactant: CC(C)(C)OC(=O)NCCOc1c(-c2ccc(Cl)c(Cl)c2)nc(OCc2ccccc2)c2cc(F)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCOc1c(-c2ccc(Cl)c(Cl)c2)[nH]c(=O)c2cc(F)ccc12
Temperature: 25 °C
Yield: 76 %

Procedure:
{2-[1-Benzyloxy-3-(3,4-dichloro-phenyl)-7-fluoro-isoquinolin-4-yloxy]-ethyl}-carbamic acid tert-butyl ester (85 mg, 0.15 mmol) was treated with trifluoroacetic acid/DCM=1:10 (4.5 mL) and stirred for 8 hs at RT. The reaction mixture was then concentrated under reduced pressure. The resulting crude was taken up with diethyl ether and filtered, thus affording 55 mg of the title compound (76% yield) as a white solid.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[N:13][N:12]([OH:15])[C:11]=3[CH:16]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1>CN(C)C=O>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[N:13][N:12]([O:15][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=4)[C:11]=3[CH:16]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1cccc(CCl)c1
Reactant: On1nnc2ccc(Cn3ccnc3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(COn2nnc3ccc(Cn4ccnc4)cc32)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
A mixture of 3.2 parts of 6-(1H-imidazol-1-ylmethyl)-1H-benzotriazol-1-ol, 1 part of potassium carbonate and 27 parts of N,N-dimethylformamide was stirred for 30 minutes at room temperature. 2.1 Parts of 1-(chloromethyl)-3-methylbenzene were added and stirring was continued for 3 hours at room temperature. The mixture was allowed to stand overnight at room temperature and was evaporated. The residue was diluted with water and the product was extracted with dichloromethane. The extract was dried, filtered and concentrated. The concentrate was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The solid residue was crystallized from a mixture of ethyl acetate and 2,2'-oxybispropane (10:20 by volume). The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 3.4 parts (70.9%) of 6-(1H-imidazol-1-ylmethyl)-1-[(3-methylphenyl)methoxy]-1H-benzotriazole; mp. 120.1° C. (compound 160). In a similar manner there were also prepared:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[NH:18][CH2:19][CH2:20][CH3:21])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Br[C:23]1[S:24][C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:26]([CH3:28])[N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:23]3[S:24][C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:26]([CH3:28])[N:27]=3)[CH2:14][C@H:13]2[NH:18][CH2:19][CH2:20][CH3:21])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: CCCN[C@@H]1CNCC[C@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCN[C@@H]1CN(c2nc(C)c(C(=O)OCC)s2)CC[C@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 84.1 %

Procedure:
The same operation as in Example (196c) was performed using trans(±)-4-chloro-5-ethyl-N-[3-(propylamino)piperidin-4-yl]-1H-imidazole-2-carboxamide obtained in Example (205a) (10.0 mg, 0.032 mmol), ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (9 mg, 0.035 mmol) and sodium carbonate (10 mg, 0.096 mmol), to obtain 13 mg of the title compound (85%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[CH3:8].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH:10]=[CH:14][N:15]([CH3:17])[CH3:16])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(=O)c1ccc(C)c(C)c1
Reactant: COC(OC)N(C)C
Product: Cc1ccc(C(=O)C=CN(C)C)cc1C

Procedure:
A mixture of 50 g. of 3',4'-dimethylacetophenone and 50 ml. of dimethylformamide dimethylacetal is refluxed for 16 hours. On cooling the desired compound crystallizes from the reaction mixture. After hexane is added, the desired compound is recovered by filtration, m.p. 108°-110° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][CH2:28][O:29][C:22]=3[CH:21]=2)[C:11]2[CH:16]=[C:15]([CH3:17])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][CH2:28][O:29][C:22]=4[CH:21]=3)[C:11]3[CH:16]=[C:15]([CH3:17])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Reactant: Cc1ncc[nH]1
Product: Cc1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[N:6][C:7]=1[O:8][C@H:9]([CH3:14])[C:10]([F:13])([F:12])[F:11].[Cl:16][C:17]1[C:18](F)=[CH:19][C:20]([F:33])=[C:21]([CH:32]=1)[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)=[O:23].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:16][C:17]1[C:18]([O:15][C:4]2[CH:5]=[N:6][C:7]([O:8][C@H:9]([CH3:14])[C:10]([F:11])([F:12])[F:13])=[C:2]([Cl:1])[CH:3]=2)=[CH:19][C:20]([F:33])=[C:21]([CH:32]=1)[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)=[O:23]
Reactant: Cc1ccc(OC(=O)c2cc(Cl)c(F)cc2F)cc1
Reactant: C[C@@H](Oc1ncc(O)cc1Cl)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(OC(=O)c2cc(Cl)c(Oc3cnc(O[C@H](C)C(F)(F)F)c(Cl)c3)cc2F)cc1
Reaction time: 5 h
Yield: 98.9 %

Procedure:
To a mixture of 5-chloro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]pyridin-3-ol (Preparation 235, 360 mg, 0.86 mmol) and 4-methylphenyl 5-chloro-2,4-difluorobenzoate (Preparation 12, 242 mg, 0.86 mmol) in DMSO (2 mL) was added K2CO3 (237 mg, 1.7 mmol) at room temperature under N2 and the resulting mixture was stirred for 5 hours. The reaction was quenched with water and extracted with DCM (3×5 mL). The mixture was filtered through a phase separation cartridge. The combined organic phases were washed with brine (3 mL) and filtered through another phase separation cartridge. The filtrate was dried by N2 blowing to give a crude product. The crude product was purified by silica gel column chromatography eluting with 0-40% EtOAc in heptane to give the title compound (429 mg, 99%) as colourless gum.
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH2:14])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2.[C:15]([OH:19])(=[O:18])[CH:16]=[CH2:17].C(N(CC)CC)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH:14][CH2:17][CH2:16][C:15]([OH:19])=[O:18])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: C=CC(=O)O
Reactant: COc1cc(N)c2ncccc2c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc(NCCC(=O)O)c2ncccc2c1
Reaction time: 16 h
Yield: 37 %

Procedure:
A mixture of 5.0 g (19.56 mmol) of 6-methoxy-8-aminoquinoline hydrobromide, 1.48 ml (21.51 mmol) of acrylic acid and 5.45 ml (39.12 mmol) of triethylamine is dissolved in 25 ml of toluene and brought to 110° C. for 16 h, with magnetic stirring. 10 ml of a 10% (w/v) aqueous sodium hydroxide solution are then added and the reaction medium is kept at 100° C. for 20 min, with stirring. After returning to ambient temperature, the phase containing the toluene is eliminated and the aqueous phase is extracted with 100 ml of chloroform. The aqueous phase is then acidified by adding acetic acid until a pH of 5-6 is obtained. The precipitate obtained is filtered off and then washed with water. After drying under vacuum, the compound 26 is obtained in the form of a green powder: 1.77 g (yield=37%).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:13]=[CH:14][C:15](=O)[NH:16][N:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].P(Br)(Br)([Br:21])=O>C1(C)C=CC=CC=1>[Br:21][C:15]1[N:16]=[N:17][C:12]([C@H:9]2[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]2)=[CH:13][CH:14]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(=O)[nH]n2)CC1
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](c2ccc(Br)nn2)CC1
Temperature: 68 °C
Reaction time: 2 h

Procedure:
24.8 g of 6-(trans-4-pentylcyclohexyl)-3(2H)-pyridazinone (prepared according to Example 2) and 150 ml of toluene were suspended in a sulphonation flask under nitrogen. Subsequently, there was added dropwise within 7 minutes a solution of 11.5 g of phosphorus oxybromide, the temperature rising from 17° C. to 30° C. and a viscous light brown mass resulting. The mixture was treated with 30 ml of toluene and then heated slowly to 68° C., whereby it became dark green in colour. After 2 hours, a solution of 5.7 g of phosphorus oxybromide was added dropwise at 68° C. within 10 minutes. The mixture was heated to reflux temperature and once more treated with a solution of 7.4 g of phosphorus oxybromide. After 6 hours, the mixture was poured into 400 ml of ice/water and extracted six times with 250 ml of methylene chloride each time. The organic phases were washed with 400 ml of 5% sodium hydrogen carbonate solution, subsequently combined, dried with sodium sulphate and concentrated at 40° C. on a rotary evaporator. Column chromatography on silica gel with ethyl acetate/hexane (1:1) as the eluant gave 24.81 g of crude product. Crystallization from 75 ml of ethyl acetate/hexane (2:1) and working-up of the mother liquor finally yielded a total of 21.7 g of 3-bromo-6-(trans-4-pentylcyclohexyl)pyridazine as white crystals of melting point 101°-103° C.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)C=C.CCOC(C)=O.[CH3:21][CH2:22][CH2:23]CCC>>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][C:14]=1[CH2:23][CH:22]=[CH2:21]
Reactant: CCCCCC
Reactant: C=CCOc1ccc(C(=O)OC)cc1
Solvent: CCOC(C)=O
Product: C=CCc1cc(C(=O)OC)ccc1O
Reaction time: 1.5 h

Procedure:
The neat allyl ether 22-2 from Step A (7.0 g, 38.6 mmol) was heated in an oil bath at 230 ° C. for 1 h. The reaction was followed by NMR and was found to be complete after 90 min. The resulting brown oil was cooled and subjected to column chromatography (1:1 EtOAc/Hexane) to afford 22-3 as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([CH3:12])[CH:6]=[C:7]([CH3:11])[CH:8]=2)[C:3]1=O.[BH4-].[Na+]>O1CCCC1.CO>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([CH:3]=1)=[C:5]([CH3:12])[CH:6]=[C:7]([CH3:11])[CH:8]=2
Reactant: Cc1cc(C)c2c(c1)CC(C)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1=Cc2c(C)cc(C)cc2C1
Yield: 95.6 %

Procedure:
20.4 g (117 mmol) of 2,5,7-trimethyl-l-indanone (1) were dissolved in 300 ml of a mixture of tetrahydrofuran/methanol (2:1), and 6.6 g (175 mmol) of NaBH4 were added at room temperature. The mixture was stirred for a further hour, 50 ml of half-concentrated HC1 were added and the mixture was extracted with ether. The combined organic phases were dried over sodium sulfate and freed from the solvent. The residue was transferred to a distillation apparatus, and 13 g of magnesium sulfate were added. A vacuum of about 10mbar was applied and the mixture was heated up until the product distilled over (130°-150° C). The distillation gave 17.7 g of the indene as a colorless oil. The yield was 96%. Mass spectrum: 158 M+, correct disintegration pattern.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17]([O:19]CC)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH:23][NH2:24].CO.[OH-].[K+].Cl>CO.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:23][N:24]=[C:17]([OH:19])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C#Cc1ccc(OCc2ccccc2)cc1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Oc1cc(-c2ccc(OCc3ccccc3)cc2)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-(4-(benzyloxy)phenyl)-2-propinoate (1.46 g) in methanol (30 ml), 1.45 g of hydroxyamine hydrochloride and 6.25 ml of 5M potassium hydroxide methanol were added, and the reaction solution was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, the residue obtained was suspended in water, and the suspension was adjusted to pH 2-3 with a 2N aqueous hydrochloric acid solution. The resultant solid was obtained by filtration to afford the title compound as a light brown solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH:9]1[CH2:14][CH:13]2[CH2:15][CH:10]1[CH:11]=[CH:12]2.[CH2:16]([O:18][P:19]([O:23]CC)[O:20][CH2:21][CH3:22])[CH3:17]>>[CH2:16]([O:18][P:19]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH:9]1[CH2:14][CH:13]2[CH2:15][CH:10]1[CH:11]=[CH:12]2)(=[O:23])[O:20][CH2:21][CH3:22])[CH3:17]
Reactant: CCOP(OCC)OCC
Reactant: BrCCCCCOCC1CC2C=CC1C2
Product: CCOP(=O)(CCCCCOCC1CC2C=CC1C2)OCC
Temperature: 160 °C

Procedure:
5-[[(5-bromopentyl)oxy]methyl]bicyclo[2.2.1]hept-2-ene 5 (10 g) was added to 50 mL of triethylphosphite and the solution was heated at 160° C. under nitrogen for 20 h. The solution was cooled to room temperature and excess triethylphosphite was removed under reduced pressure. The oily residue was distilled in vacuo to give 6 as a colorless oil, b.p. 145° C., 0.15 Torr. 1H NMR (500 MHz, 25° C., CDCl3): δ (endo isomer, 85%) 6.07-6.05 (m, 1H, olefinic), 5.87-5.85 (m, 1H, olefinic), 4.06-4.00 (m, 4H, POCH2CH3), 3.34-2.94 (m, 6H, CH2), 2.84 (br s, 1H, bridgehead CH), 2.73 (br s, 1H, bridgehead CH), 2.30-2.20 (m, 1H, exo CH), 1.70-1.49 (m, 9H, CH2), 1.27 (t, 6H, POCH2CH3), 0.44-0.41 (m, 1H, endo CH of CH2); (exo isomer, partial) 6.02-6.01 (m, 1H, olefinic), 2.70 (br s, 1H, bridgehead CH). 13C {1H} NMR (125 MHz, 25° C., CDCl3): δ (endo isomer) 137.0 (olefinic CH), 132.5 (olefinic CH), 74.6 (CH—CH2O), 61.4 (d, |2JC-P|=6 Hz, POCH2CH3), 49.4 (CH2 bridge), 44.0 (bridgehead CH), 42.2 (bridgehead CH), 38.9 (CH—CH2O), 29.3 (CH2), 27.4 (CH2), 27.3 (CH2), 25.7 (d, |1JC-P|=140 Hz, CH2P), 22.4 (CH2), 22.3 (CH2), 16.5 (d, |3JC-P|=5.4 Hz, POCH2CH3); (exo isomer, partial) 136.6 (olefinic CH), 75.6 (CH—CH2O), 45.0 (CH), 43.8 (CH), 41.6 (CH), 29.8 (CH2). 31P{1H} NMR (200 MHz, 25° C., CDCl3): δ 32.6
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([NH:15]C(=O)OC(C)(C)C)[CH:12]=[CH:13][CH:14]=2)[CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([OH:31])[CH:27]=[CH:28][C:29]=1[F:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][C:29]=1[F:30])[O:31][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=2)[CH:3]=1
Reactant: Oc1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Nc2cc(Cl)ncn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cccc(Nc2cc(Oc3ccc(F)c(Cl)c3)ncn2)c1
Yield: 45.4 %

Procedure:
A solution of tert-butyl 3-(6-chloropyrimidin-4-ylamino)phenylcarbamate (1.6 g, 5 mmol), 3-chloro-4-fluorophenol (1.4 g, 10 mmol) and potassium carbonate (1.4 g, 10 mmol) in 15 mL of DMF was heated to 120° C. for 16 h. The reaction mixture was mixed in 15 mL of water, the crude product was precipitated, filtered, purified by flash chromatography on silica gel with MeOH/DCM solvent system to afford 750 mg (45% yield) of N1-(6-(3-chloro-4-fluorophenoxy)pyrimidin-4-yl)benzene-1,3-diamine as an off-white solid. MS (m/z): MH+=331.
Reaction SMILES: [CH3:1][C:2](=[O:10])[CH2:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]C.I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:12]1([CH:3]([C:4](=[O:9])[CH2:5][CH2:6][CH3:7])[C:2](=[O:10])[CH3:1])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Ic1ccccc1
Reactant: CCCCC(=O)CC(C)=O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCC(=O)C(C(C)=O)c1ccccc1
Temperature: 120 °C
Yield: 48.7 %

Procedure:
To a stirred mixture of 2,4-octanedione (568 mg, 4.0 mmol) and iodobenzene (408 mg, 2.0 mmol) in dimethylsulfoxide (10 mL) were added copper(I) iodide (380 mg, 2.0 mg) and potassium carbonate (1.10 g, 8.0 mmol). The mixture was heated at 120° C. for 4 h. The mixture was filtered through a pad of Celite and the filtrate was partitioned between ether and water. Organic layer was dried (Na2SO4) and the solvent was removed. The crude product was purified by TLC with hexane/ethyl acetate (4:1) to afford 199 mg (46%) of the title compound as colorless oil: 1H-NMR (CDCl3) δ 7.42-7.33 (3H, m), 7.18-7.15 (2H, m), 2.11 (2H, t, J=8.3 Hz), 1.87 (3H, s), 1.58-1.44 (3H, m), 1.25-1.16 (2H, m), 0.79 (3H, t, J=7.2 Hz).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH:26]([C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].Cl>CC(N(C)C)=O.O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH:26]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NC(CC(=O)O)c1cccnc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1nc(C(=O)NC(CC(=O)O)c2cccnc2)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 41.3 %

Procedure:
To a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.16 mmol) and 3-amino-3-pyridin-3-yl-propionic acid (52 mg, 0.31 mmol) (commercially available from Combi-Blocks SS-4195) in DMA (2 mL) was added sodium methoxide (17 mg, 0.31 mmol). The resultant suspension mixture was heated in a 150° C. oil bath for 2 h. After cooled, reaction mixture was diluted with water (75 mL) and acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried in vacuo to provide the title compound 30 mg (0.066 mmol) in 42% yield. LC-MS ESI−: 453 (M−1)−.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[C:10]([C:18]2[CH2:23][CH2:22][O:21][CH2:20][CH:19]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[C].[Pd].C(O)C>[CH2:1]([C:8]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[C:10]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: COCOc1ccc(C2=CCOCC2)nc1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COCOc1ccc(C2CCOCC2)nc1Cc1ccccc1
Yield: 42.2 %

Procedure:
20 mg of 10% palladium carbon was added to a mixture of 197 mg of 2-benzyl-6-(5,6-dihydro-2H-pyran-4-yl)-3-methoxymethyloxypyridine and 3 ml of ethanol, followed by stirring at room temperature overnight in a hydrogen atmosphere. After the atmosphere in the reaction system was replaced by nitrogen, the reaction solution was filtered through Celite. The solvent was removed, and then the residue was subjected to silica gel column chromatography using 20% ethyl acetate/hexane, to give 83.7 mg of the target compound.