Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH:16][CH2:17][C:18]1[CH:29]=[CH:28][C:21]([C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])=[C:20]([OH:30])[CH:19]=1>>[OH:30][C:20]1[CH:19]=[C:18]([CH2:17][O:16][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:6]=2)[CH:29]=[CH:28][C:21]=1[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23]
Reactant: C=CCOC(=O)c1ccc(CO)cc1O
Reactant: COc1ccc(C(=O)Cl)cc1C(C)(C)C
Product: C=CCOC(=O)c1ccc(COC(=O)c2ccc(OC)c(C(C)(C)C)c2)cc1O

Procedure:
In a manner similar to Example 1(d), by reaction of 2.4 g (10.5 mmol) of 3-tert-butyl-4-methoxybenzoyl chloride with 2.2 g (10.5 mmol) of allyl 4-hydroxymethyl-2-hydroxybenzoate, 2.5 g (61%) of the expected allyl ester are obtained in the form of a slightly yellow oil.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH:4][CH3:5].[BrH:6].CC1(C)CNC(NN=C(C=CC2C=CC(Cl)=CC=2)C=CC2C=CC(Cl)=CC=2)=NC1.[N:36]1[CH:40]2CC[CH2:43][CH2:44][CH:39]2[NH:38][C:37]=1[NH:45][N:46]=[C:47]([CH:57]=[CH:58][C:59]1[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=1)[CH:48]=[CH:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=1>>[BrH:6].[NH:36]1[CH2:40][CH2:39][CH2:44][CH2:43][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][N:38]=[C:37]1[NH:45][N:46]=[C:47]([CH:48]=[CH:49][C:50]1[CH:51]=[CH:52][C:53]([Cl:56])=[CH:54][CH:55]=1)[CH:57]=[CH:58][C:59]1[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=1
Reactant: C=CC=CC
Reactant: Clc1ccc(C=CC(C=Cc2ccc(Cl)cc2)=NNC2=NC3CCCCC3N2)cc1
Agent: Br
Agent: CC1(C)CN=C(NN=C(C=Cc2ccc(Cl)cc2)C=Cc2ccc(Cl)cc2)NC1
Product: Clc1ccc(C=CC(C=Cc2ccc(Cl)cc2)=NNC2=NCCCCCCCCCN2)cc1

Procedure:
The pentadiene in accordance with claim 10, 1,5-bis(p-chlorophenyl)-1,4-pentadiene-3-one 5,5-dimethyl-1,4,5,6-tetrahydropyrimidin-2-ylhydrazone hydrobromide. 13. The pentadiene in accordance with claim 1, 1,5-bis(p-chlorophenyl)-1,4-pentadiene-3-one 3α ,4,5,6,7,7a-hexahydrobenzimidazol-2-yl-hydrazone hydrochloride. 14. The pentadiene in accordance with claim 1, 1,5-bis(p-chlorophenyl)-1,4-pentadien-3-one 3α ,4,5,6,7,7a-hexahydrobenzimidazol-2-yl-hydrazone hydrobromide. 15. The pentadiene in accordance with claim 1, 1,5-bis(p-chlorophenyl)-1,4-pentadiene-3-one 3a,4,5,6,7,7a-hexahydrobenzimidazol-2-yl-hydrazone.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5](N)=[CH:4][C:3]=1[Cl:10].S(=O)(=O)(O)[OH:12].N([O-])=O.[Na+]>O>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([OH:12])=[CH:4][C:3]=1[Cl:10]
Reactant: Nc1cc(Cl)c(Br)c(Cl)c1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1cc(Cl)c(Br)c(Cl)c1
Temperature: 160 °C
Reaction time: 0.25 h

Procedure:
100 g of 4-bromo-3,5-dichlorophenylamine are added with stirring at 5° C. to a mixture of 125 ml of water and 90 ml of concentrated sulphuric acid. 230 g of crushed ice are added to the reaction mixture, followed by 29 g of sodium nitrite in 70 ml of water, and the reaction mixture is left stirring for 15 minutes. The reaction mixture is added rapidly to a mixture composed of 280 ml of concentrated sulphuric acid and 200 ml of water raised to 160° C., and the reaction mixture is left stirring at 160° C. for 1 hour. The reaction mixture is poured onto a water/crushed ice mixture and extracted with dichloromethane. The organic phase is dried over magnesium sulphate and the solvents are evaporated off under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a 4/6 (v/v) cyclohexane/dichloromethane mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:7]([OH:8])[O:6][CH2:5][C:4]=2[CH:3]=1
Reactant: O=C1OCc2cc(Cl)ccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OC1OCc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-chlorophthalide (3.64 g, 21.6 mmol) in dichloromethane (100 mL) at −78° C. was added di-isobutylaluminium hydride (1M in toluene) (23.8 mL, 23.8 mmol) dropwise. After 1 h the reaction mixture was quenched with a saturated solution of sodium tartrate (250 mL), allowed to warm to room temperature and stirred for 1 h. The layers were separated and the aqueous layer extracted with dichloromethane. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to yield the title compound as a white solid.
Reaction SMILES: C([NH:8][C:9]1([C:12]([CH:14]2[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]2([CH3:22])[CH3:21])=[CH2:13])[CH2:11][CH2:10]1)(OC(C)(C)C)=O.O.[OH-].[K+]>FC(F)(F)C(O)=O>[NH2:8][C:9]1([C:12]([CH:14]2[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]2([CH3:22])[CH3:21])=[CH2:13])[CH2:11][CH2:10]1
Reactant: C=C(C1C(C)(C)CCC1(C)C)C1(NC(=O)OC(C)(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C=C(C1C(C)(C)CCC1(C)C)C1(N)CC1
Reaction time: 8 h

Procedure:
N-Boc-1-amino-1-(2,2,5,5-tetramethyl-1-cyclopentyl)ethenylcyclopropane is dissolved in trifluoroacetic acid and the solution is stirred overnight. Water is added and the mixture is made basic with 20% KOH. The mixture is extracted with ether, and the organic layer is dried over Na2SO4 and is evaporated to yield 1-amino-1-(2,2,5,5-tetramethyl-1-cyclopentyl)ethenylcyclopropane.
Reaction SMILES: [NH2:1][C:2](=[O:35])[C@H:3]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:4][C:5]1[N:6]=[N:7][N:8]([C@@H:10]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([C:20]([O:22]C)=[O:21])[CH:13]=[CH:12][C:11]2=3)[CH:9]=1.[Li+].[OH-]>C1COCC1>[NH2:1][C:2](=[O:35])[C@H:3]([NH:24][S:25]([C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)(=[O:27])=[O:26])[CH2:4][C:5]1[N:6]=[N:7][N:8]([C@@H:10]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([C:20]([OH:22])=[O:21])[CH:13]=[CH:12][C:11]2=3)[CH:9]=1
Reactant: COC(=O)c1ccc2c(c1)CCC[C@H]2n1cc(C[C@@H](NS(=O)(=O)c2ccc(C)cc2)C(N)=O)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn([C@@H]3CCCc4cc(C(=O)O)ccc43)nn2)C(N)=O)cc1

Procedure:
(R)-Methyl 5-(4-((R)-3-amino-2-(4-methylbenzenesulfonamido)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (0.2 g, 0.41 mmol) and 1N LiOH (1.9 mL, 1.9 mmol) in 5 mL THF was stirred for 16 h at RT. The reaction mixture was concentrated, taken up in H2O, and acidified with 10% HCl. A precipitate had formed, that was filtered and air-dried to afford the title compound. MS (m/z): 484.4 (m+H).
Reaction SMILES: [CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C([C@H]1CC[C@H](C(O)=O)CC1)CCC>>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([C:10]([OH:12])=[O:11])[CH2:13][CH2:14]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(C(=O)O)cc1
Agent: CCCC[C@H]1CC[C@H](C(=O)O)CC1
Product: CCCCC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
This compound was prepared from 4-n-pentylbenzoic acid (15, 53.8 g, 0.28 mol), in a manner similar to the procedure described for trans-4-n-butylcyclohexanecarboxylic acid (11) in Example I, Preparation 1 in an overall yield of 80% (43 g); m.p. 50-51° C. (pet. ether).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:20])=O>C1(C)C=CC=CC=1.C(Cl)(=O)C(Cl)=O>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cccc(C(=O)Cl)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
To a solution of 2,3-dimethylbenzoic acid (2.0 kg, 13.2 mol) in toluene (20 L) was added N,N-dimethylformamide (20 ml), followed by oxalyl chloride (2.0 kg, 15.6 mol) at room temperature. The reaction mixture was stirred at room temperature for 4 h and monitored by thin layer chromatography. If necessary, excess oxalyl chloride (25 g) was added until no starting material was observed. Excess toluene and oxalyl chloride were removed by distillation under vacuum at temperatures below 70° C. To the residue was added toluene (150 ml) and the mixture was again concentrated in vacuo to give 2,3-dimethylbenzoyl chloride (2.0 kg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:18]=1.[NH4+:33].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(Cl)Cl>ClCCCl>[NH2:33][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: COCCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCN(C)C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCCl
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN(C)C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
A solution of tert-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate (7.05 g, 15.9 mmol) in 100 mL of 1,2-dichloroethane was heated to 80° C. and treated with 5 mL of concentrated NH4OH solution. To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (3.33 g, 17.5 mmol) over a 10 min period. The reaction mixture was treated with an additional 5 mL concentrated NH4OH solution and then sealed in a pressure vessel and heating was continued for 4 h. The reaction mixture was then cooled and treated with 100 mL of CH2Cl2. The reaction mixture was then washed with H2O, 1% Na2CO3 solution (3×) and brine. The organic portion was dried over Na2SO4 and concentrated to give 6.50 g of tert-butyl 2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[C:18]1[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1)(=[O:32])[CH3:31].C(OC(N1C=C(C2N(C(OC(C)(C)C)=O)C3C=C(NC4C=CC(C(=O)N(C)C)=CC=4)N=CC=3C=2)C=N1)=O)(C)(C)C>>[C:30]([N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:45]=[CH:44][C:42]([NH:43][C:14]3[N:13]=[CH:12][C:11]4[CH:10]=[C:9]([C:18]5[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=5)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:16]=4[CH:15]=3)=[CH:41][CH:40]=2)[CH2:37][CH2:38]1)(=[O:32])[CH3:31]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Cl)cc3n2C(=O)OC(C)(C)C)cn1
Agent: CN(C)C(=O)c1ccc(Nc2cc3c(cn2)cc(-c2cnn(C(=O)OC(C)(C)C)c2)n3C(=O)OC(C)(C)C)cc1
Product: CC(=O)N1CCN(c2ccc(Nc3cc4c(cn3)cc(-c3cnn(C(=O)OC(C)(C)C)c3)n4C(=O)OC(C)(C)C)cc2)CC1
Yield: 27 %

Procedure:
The title compound was prepared in 27% yield from compound (17) and 4-(4-acetylpiperazin-1-yl)aniline using the method described for compound (49). 1H-NMR (500 MHz, CDCl3) 1.47 (s, 9H), 1.69 (s, 9H), 2.17 (s, 3H), 3.13 (t, J=5.0 Hz, 2H), 3.15 (t, J=5.3 Hz, 2H), 3.65 (t, J=5.8 Hz, 2H), 3.81 (t, J=5.2 Hz, 2H), 6.45 (br s, 1H), 6.56 (d, J=0.6 Hz, 1H), 6.96 (d, J=8.9 Hz, 2H), 7.29 (d, J=8.9 Hz, 2H), 7.42 (s, 1H), 7.81 (d, J=0.6 Hz, 1H), 8.20 (d, J=0.4 Hz, 1H), 8.41 (d, J=0.8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14]Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:18]([O-:21])([O-:20])=[O:19].[Na+:22].[Na+]>C(O)(C)(C)C.O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14][S:18]([O-:21])(=[O:20])=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:22]
Reactant: BrCCc1ccc(OCc2ccccc2)cc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=S(=O)([O-])CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-benzyloxyphenethyl bromide (11.8 g) and sodium sulfite (8.91 g) in tert-butyl alcohol (40 ml) and water (80 ml) is heated at reflux for 40 hours, cooled to room temperature, filtered and the solid washed with water and ether to give sodium 4-benzyloxyphenethyl sulfonate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][C:14]([C:22]3[CH2:26][CH:25]([O:27][CH2:28][CH3:29])[O:24][N:23]=3)=[C:13]([CH2:30][O:31][CH3:32])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([O:35]C=C)C>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][C:14]([C:22]3[C:26]([C:25]([O:27][CH2:28][CH3:29])=[O:24])=[CH:33][O:35][N:23]=3)=[C:13]([CH2:30][O:31][CH3:32])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=COCC
Reactant: CCOC1CC(c2ncc3[nH]c4ccc(OCc5ccccc5)cc4c3c2COC)=NO1
Product: CCOC(=O)c1conc1-c1ncc2[nH]c3ccc(OCc4ccccc4)cc3c2c1COC

Procedure:
6-benzyloxy-3-(5-ethoxy-4,5-dihydro-3-isoxazolyl)-4-methoxymethyl-β-carboline with vinyl ethyl ether; melting point: 149°-150° C.,
Reaction SMILES: O1CCOCC1.Cl.C([O:10][C:11]([C:13]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:16]=2[O:15][CH:14]=1)=[O:12])C>O>[C:11]([C:13]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:22]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][C:16]=2[O:15][CH:14]=1)([OH:12])=[O:10]
Reactant: CCOC(=O)c1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)Nc1cc2occ(C(=O)O)c(=O)c2cc1Oc1ccccc1
Yield: 90.9 %

Procedure:
80 ml of dioxane and 40 ml of 6N hydrochloric acid were added to 4.03 g of 3-ethoxycarbonyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. The mixture was refluxed for 30 minutes. The reaction mixture was cooled. 200 ml of water was added thereto. The resulting crystal was collected by filtration, washed with water and recrystallized from acetic acid to obtain 3.41 g (yield: 91%) of 3-carboxy-7-methylsulfonylamino-6-phenoxy4H-1-benzopyran-4-one having a melting point of >250° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][N:6]([C:11]([C:13]1[C:14]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:15][C:16]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:17]([CH:21]=1)[C:18](O)=[O:19])=[O:12])[CH2:7][CH2:8][CH2:9][CH3:10].[Br:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[CH2:44][NH:43][CH2:42]2.C(N(C(C)C)C(C)C)C>C1COCC1.ClCCl.C1(C)C=CC=CC=1>[CH2:31]([O:30][C:14]1[CH:15]=[C:16]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:17]([C:18]([N:43]2[CH2:42][C:41]3[C:45](=[CH:46][CH:47]=[C:39]([Br:38])[CH:40]=3)[CH2:44]2)=[O:19])=[CH:21][C:13]=1[C:11]([N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH3:5])=[O:12])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCCCN(C)C(=O)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: Brc1ccc2c(c1)CNC2
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(C)C(=O)c1cc(C(=O)N2Cc3ccc(Br)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 22 °C
Reaction time: 0.25 h
Yield: 41.6 %

Procedure:
652.9 μl (9 mmol) of thionyl chloride are added to a suspension of 2.06 g (4.6 mmol) of 2,4-bisbenzyloxy-5-[(N-methyl-N-butylamino)carbonyl]benzoic acid (5) in 20 ml of THF (dry), and the mixture is stirred for 15 min at 22° C. 10 ml of toluene are subsequently added, and the mixture is evaporated to dryness in vacuo at 40° C. The residue is dissolved in 20 ml of THF and added to a suspension of 923 mg (4.661 mmol) of 5-bromo-2,3-dihydro-1H-isoindole (13) in 30 ml of dichloromethane, 5 ml of THF and 1.7 ml (10 mmol) of N-ethyldiisopropylamine. After 2 h at 22° C., the mixture is evaporated and chromatographed over an RP18 column. Evaporation to dryness in vacuo gives 1.2 g (42%) of 2,4-bisbenzyloxy-N-butyl-5-(5-bromo-1,3-dihydroisoindole-2-carbonyl)-N-methylbenzamide (“A16a”), MW 627.6; Rt 2.478 min.
Reaction SMILES: Br[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Br:10])[C:3]=1[CH:4]=[O:5].[C:11]1(=[O:24])[C:16]2[S:17][C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[C:15]=2[CH2:14][CH2:13][NH:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:10][C:6]1[CH:7]=[N:8][CH:9]=[C:2]([N:12]2[C:11](=[O:24])[C:16]3[S:17][C:18]4[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=4[C:15]=3[CH2:14][CH2:13]2)[C:3]=1[CH:4]=[O:5]
Reactant: O=C1NCCc2c1sc1c2CCCC1
Reactant: O=Cc1c(Br)cncc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=Cc1c(Br)cncc1N1CCc2c(sc3c2CCCC3)C1=O
Temperature: 100 °C
Yield: 67.3 %

Procedure:
To a 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (15 mL), 3,5-dibromoisonicotin-aldehyde (400 mg, 1.5 mmol), 8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-6-one 105e (146 mg, 0.76 mmol), and cesium carbonate (176 mg, 1.5 mmol). Xantphos (40 mg, 0.08 mmol) and Pd2(dba)3 (70 mg, 0.08 mmol) were added, and the reaction mixture was heated at 100° C. for 5 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified on flash column eluting with DCM:MeOH (20:1) to afford 105f (200 mg, 70%). MS: [M+H]+ 377.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH2:11][OH:12]>ClCCl.[O-2].[Mn+2]>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH:11]=[O:12]
Reactant: OCc1sc2ncccc2c1Br
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1sc2ncccc2c1Br
Reaction time: 20 h

Procedure:
A mixture of {3-bromothieno[2,3-b]pyridin-2-yl}methanol (14c) (394 mg, 1.61 mmol) and manganese (II) oxide (1.4 g, 16.1 mmol) in dichloromethane (10 mL) was stirred for 20 hours, filtrated and evaporated to dryness to give the desired aldehyde (14d) without further purification (270 mg, 1.12 mmol, 70%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:20]([C:21]3[C:26]([F:27])=[CH:25][N:24]=[C:23]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=4)[N:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[F:78][C:79]1[CH:87]=[CH:86][CH:85]=[C:84]([F:88])[C:80]=1[C:81]([NH2:83])=[O:82].C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:78][C:79]1[CH:87]=[CH:86][CH:85]=[C:84]([F:88])[C:80]=1[C:81]([NH:83][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:20]([C:21]3[C:26]([F:27])=[CH:25][N:24]=[C:23]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=4)[N:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)[CH:3]=1)=[O:82]
Reactant: Fc1cccc(Nc2ncc(F)c(-c3c(-c4cccc(Br)c4)nn4cc(C(F)(F)F)ccc34)n2)c1
Reactant: NC(=O)c1c(F)cccc1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-c2nn3cc(C(F)(F)F)ccc3c2-c2nc(Nc3cccc(F)c3)ncc2F)c1)c1c(F)cccc1F
Temperature: 160 °C
Yield: 60.2 %

Procedure:
To an oven-dried flask under N2 was added 4-[2-(3-bromophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-5-fluoro-N-(3-fluorophenyl)-2-pyrimidinamine (40 mg, 0.08 mmol), anhydrous degassed 1,4-dioxane (10 mL), Pd2(dba)3 (13.4 mg, 0.01 mmol), Xantphos (12.7 mg, 0.02 mmol), 2,6-difluorobenzamide (34.5 mg, 0.2 mmol), and Cs2CO3 (83 mg, 0.26 mmol). The reaction was heated in the microwave at 160° C. for 15 min, adsorbed to silica gel, and purified by LC (DCM to 5% MeOH/DCM) to afford the desired product (30 mg, 66%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 6.63-6.67 (m, 1H), 7.10-7.25 (m, 4H), 7.29-7.34 (m, 2H), 7.39-7.47 (m, 1H), 7.53-7.59 (m, 1H), 7.68-7.70 (m, 2H), 8.04-8.10 (m, 2H), 8.60 (s, 1H), 9.57 (s, 1H), 9.97 (s, 1H), 10.87 (s, 1H); ESIMS (M+H)+=623.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:35]=[CH:36][C:37]([O:39]C)=[N:38][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([N:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[CH:20][N:21]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:35]=[CH:36][C:37]([OH:39])=[N:38][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc2c3cnc(Nc4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cn4)nc3n(C3CCCC3)c2n1
Agent: Cl
Product: Oc1ccc2c3cnc(Nc4ccc(N5CCNCC5)cn4)nc3n(C3CCCC3)c2n1
Temperature: 120 °C
Yield: 108.2 %

Procedure:
A 10 mL reaction tube vessel was charged with compound 269 (56.0 mg, 103 μmol) and concentrated hydrochloric acid (2.00 mL, 103 μmol). The reaction was heated with microwave energy (300 W) at 120° C. for 1 hour, then an additional 30 minutes at 140° C. The resulting solution was filtered through a 0.45 μM filter and washed with water. The solvent was removed in vacuo, and the residue coevaporated with water (10 mL) and then methanol (2×, 10 mL) to give compound 270 as a yellow solid (48 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.63-11.91 (m, 2 H) 9.40 (br. s., 4 H) 9.19 (s, 1 H) 8.50 (d, J=8.61 Hz, 1 H) 8.04 (d, J=2.74 Hz, 1 H) 7.99 (dd, J=9.39, 2.74 Hz, 1 H) 7.51 (d, J=9.39 Hz, 1 H) 6.69-6.78 (m, 1 H) 5.35 (quin, J=8.71 Hz, 1 H) 3.37-3.51 (m, 4 H) 3.20-3.34 (m, 4 H) 2.06-2.18 (m, 2 H) 1.93-2.06 (m, 2 H) 1.66-1.82 (m, 2 H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH3:15][N:16]=[C:17]=[O:18].C(N(CC)CC)C>C(Cl)Cl>[CH:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:13]=[CH:14][C:2]=1[O:1][C:17](=[O:18])[NH:16][CH3:15]
Reactant: CN=C=O
Reactant: Oc1ccc2oc3ccccc3c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1ccc2oc3ccccc3c2c1
Yield: 84 %

Procedure:
A solution of 2-hydroxydibenzofuran (5.0 g, 27 mmol), methyl isocyanate (1.9 mL, 32 mmol) and triethylamine (3.0 mL, 22 mmol) in 75 mL of methylene chloride was stirred under nitrogen at room temperature overnight. During this time a solid formed. Additional methylene chloride was added and the solid dissolved. The reaction was then extracted with 1N HCl, dried (MgSO4) and the solvent removed under reduced pressure to give 5.47 g of a yellow solid. Recrystallization from isopropyl ether gave 3.43 g (52%) of the title compound as a light brown crystalline solid, mp 155°-156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14]>C(Cl)CCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cccc(Cl)c1C(N)=O
Solvent: ClCCCl
Product: Cc1cccc(Cl)c1C(=O)N=C=O
Yield: 86.7 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 2-chloro-6-methylbenzamide (1.0 g, 5.9 mmol), oxalyl chloride (0.894 g, 7.1 mmol) and EDC (20 mL) to afford 1.00 g of the desired product.