Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:20])=[CH:7][C:8]3[N:9]2[CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[N:14]=3)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[OH2:16].[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:20])=[CH:7][C:8]3[N:9]2[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=3)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn2c(cc(Cl)c3ccc(Br)cc32)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O
Product: O=C(O)c1cn2c(cc(Cl)c3ccc(Br)cc32)n1

Procedure:
400 mg of ethyl 8-bromo-5-chloroimidazo-[1,2-a]-quinoline-2-carboxylate were suspended in 200 ml of 50% aqueous ethanol and 4 ml of N sodium hydroxide solution were added. The mixture was heated on a steam bath for 1 hour and the resulting solution was filtered, then acidified with 4.4 ml of N hydrochloric acid. The mixture was cooled in ice to obtain cream needles of 8-bromo-5-chloroimidazo-[1,2-a]-quinoline-2-carboxylic acid monohydrate melting at >300° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([S:20](=[O:29])(=[O:28])[NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][N:31]([CH3:35])[C:32](Cl)=[O:33].Cl[C:37](OCC)=O>>[CH3:30][N:31]([CH3:35])[C:32]([N:25]1[CH2:24][CH2:23][CH:22]([NH:21][S:20]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([C:8](=[O:9])[N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH3:37])=[CH:11][CH:12]=2)(=[O:29])=[O:28])[CH2:27][CH2:26]1)=[O:33]
Reactant: CCOC(=O)Cl
Reactant: CN(C)C(=O)Cl
Reactant: O=C(NC1CCCCC1)c1ccc(S(=O)(=O)NC2CCNCC2)c2ccccc12
Product: CN(C)C(=O)N1CCC(NS(=O)(=O)c2ccc(C(=O)N(C)C3CCCCC3)c3ccccc23)CC1

Procedure:
The title compound was prepared according to the general procedure in Scheme 11, substituting 4-(piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid cyclohexyl-methyl-amide for 4-(piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid cyclohexylamide, and dimethylcarbamyl chloride for ethyl chloroformate. 1H NMR (300 MHz, CDCl3) δ 8.63 (d, 1H), 8.28 (d, 1H), 7.87 (m, 1H), 7.62 (m, 2H), 7.21 (m, 1H), 5.35 (m, 1H), 5.27 (d, 1H), 4.74 (m, 1H), 3.48 (m, 1H), 3.35 (m, 1H), 3.27 (m, 1H), 3.05 (m, 1H), 2.72 (s, 6H), 2.60 (s, 3H), 1.83 (m, 4H), 1.50 (m, 8H), 0.82 (m, 2H); LC/MS m/z 501 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].Br[CH2:19][CH2:20][CH2:21][CH2:22][Cl:23]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:19][CH2:20][CH2:21][CH2:22][Cl:23]
Reactant: ClCCCCBr
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Product: ClCCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl

Procedure:
In a first step as depicted in Scheme 1, an appropriately substituted phenol, for example, the known compound 2,6-dichloro-4-phenylmethoxyphenol, was reacted under basic conditions with a haloalkane derivative of a desired carbon chain length, for example 1-bromo-4-chlorobutane, to attach the bridging group B, thereby affording the corresponding 1,3-dichloro-2-(4-chlorobutoxy)-5-(phenylmethoxy)benzene (A). Intermediate (A) was then reacted under basic conditions with, for example, the known compound 2,2-dimethyl-2,3-dihydrobenzo[b]furan-7-ol, to attach moiety D, as well as the benzo-fused ring, affording the corresponding 2-[4-(2,2-dimethyl-(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-1,3-dichloro-5-(phenylmethoxy)benzene (B). Intermediate (B), for example 2-[4-(2,2-dimethyl-(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-1,3-dichloro-5-(phenylmethoxy)benzene, as set forth above, was then reduced with hydrogen gas in the presence of a catalyst, for example 10% palladium on carbon, providing the corresponding 4-[4-(2,2-dimethyl(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-3,5-dichlorophenol (C). Intermediate (C) was then reacted under basic conditions with, for example, 1,1,1,3-tetrachloropropane, which simultaneously dehydrohalogenates, thereby introducing the moiety —E—G—C(R4)═C(R5)(R5) into the molecule to provide Compound 12, a novel compound of formula I. Example 1 set forth below, provides a detailed method to how Compound 12 shown in Scheme 1 was prepared.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32](O)=[O:33]>>[CH:21]1[C:22]2[C:9]3([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:32](=[O:33])[CH2:31][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=5)[CH2:3][CH2:4]4)[CH2:23][CH:16]([C:15]4[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Agent: Cl
Product: O=C(Cc1ccccn1)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1

Procedure:
Using a procedure similar to that described in Example 6 except starting with 4-amino-1-[9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]piperidine and 2-(2-pyridyl)acetic acid hydrochloride, the title compound was obtained as a white solid (72%), mp 176.0°-7.5° C.; MS(CI): 424 (M+H); NMR (300 MHz,DMSO-d6): 1.37(m, 2H), 1.69(m, 2H), 2.27(m, 2H), 2.45(s, 2H), 2.93(m, 2H), 3.34(m, 2H), 3.57 (m, 3H), 4.31(s, 1H), 6.92(m, 4H), 7.17-7.31(m, 6H), 7.71(t, 1H, J=7.7 Hz), 8.02(d, 1H, J=7.7 Hz), 8.45(m, 1H).
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[CH:6]1([P:12]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C(OCC)C>[S:1]([O-:5])([OH:4])(=[O:3])=[O:2].[CH:19]1([PH+:12]([CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Reactant: O=S(=O)(O)O
Solvent: CCOCC
Product: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Product: O=S(=O)([O-])O

Procedure:
1.2 g (12 mmol) concentrated sulfuric acid are added to 25 ml of a solution of 12 mmol tricyclohexyl phosphine in diethylether prepared as in comparative example 3. The initially formed smudgy mass crystallizes over time, and can then be filtered off. 4.5 g of a colorless hygroscopic solid is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][CH:5]=1.[CH2:13]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:16]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1
Reactant: CCCNCCC
Reactant: COC(=O)c1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Bromomethylbenzoic acid methyl ester (831 mg) was dissolved in DMF (12.5 ml) and added with dipropylamine (971 μl) and the whole was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, and subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off, thereby obtaining the subject compound (883 mg) as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([Si:26]([CH3:29])([CH3:28])[CH3:27])#[CH:25].C1CCN2C(=NCCC2)CC1>O1CCCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:25]#[C:24][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Yield: 70.6 %

Procedure:
A 20 ml microwave vial was charged with 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1, 3.06 mmol) and ethynyltrimethylsilane (902 mg, 9.18 mmol) in tetrahydrofuran (5 ml) to afford an orange solution. The reaction was purged with nitrogen before DBU (2.77 ml, 18.36 mmol), dichlorobis(triphenylphosphine)palladium(II) (107 mg, 0.153 mmol) and copper(I) iodide (58.3 mg, 0.306 mmol) were added and the whole was subjected to microwave radiation for 1 hour at 80° C. Upon cooling, the reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was purified by silica chromatography (eluting with 0-30% ethyl acetate in petrol) to yield 3,4-bis(benzyloxy)-6-((trimethylsilyl)ethynyl)pyridazine (838 mg, 2.16 mmol, 70% yield)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]([NH2:11])=[O:10])=[C:4]([F:13])[CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.Cl.[CH:27]1([N:30]2[CH2:35][C:34]3([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[O:33][CH2:32][C:31]2=[O:41])[CH2:29][CH2:28]1>C(#N)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:38]2[CH2:39][CH2:40][C:34]3([O:33][CH2:32][C:31](=[O:41])[N:30]([CH:27]4[CH2:28][CH2:29]4)[CH2:35]3)[CH2:36][CH2:37]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:13])[CH:3]=1
Reactant: NC(=O)C(O)c1ccc(Br)cc1F
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.9 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)-2-hydroxyacetamide (14.35 mmol) and triethylamine (43.1 mmol) in anhydrous acetonitrile (50.0 ml) was added neat methanesulfonyl chloride (20.81 mmol). The reaction stirred at room temperature for 18 hours then additional triethylamine (43.1 mmol) was added followed by solid 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (15.79 mmol) in one portion. The reaction was heated at 90° C. for 3 hours then cooled to room temperature, diluted with water (150 mL) and stirred for 1 hour. The solids were collected by filtration, rinsed with water, and then dried by air suction and then vacuum to afford the title compound (3.53 g, 55% yield) as a white solid. MS(ES)+ m/e 440.1, 442.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]3=[C:11]([C:22]([OH:24])=[O:23])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]3=[C:11]([C:22]([O:24][CH3:25])=[O:23])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccccc3c(C(=O)O)c2C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1c2c(nc3ccccc13)CCN(C(=O)OC(C)(C)C)C2
Yield: 93.4 %

Procedure:
2-t-Butoxycarbonyl-1,2,3,4-tetrahydro-benzo[b][1,6]-naphthyridine-10-carboxylic acid (500 mg, 1.523 mmol) was dissolved in N,N-dimethylformamide (3 ml), followed by adding thereto potassium carbonate (315.1 mg, 2.28 mmol) and methyl iodide (0.13 ml, 2.06 mmol), and the resulting mixture was stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the desired compound (487 mg, 93.4%) as a brown oil.
Reaction SMILES: BrCC[C:4]1[C:9]2[C:10]([O:16][CH3:17])=[C:11]([C:13]([NH2:15])=[O:14])[S:12][C:8]=2[CH:7]=[CH:6][CH:5]=1.[CH:18]12[CH2:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][CH:19]2[NH2:25].[CH2:26](N(CC)CC)[CH3:27].Cl>CN(C)C=O.O>[CH:18]12[CH2:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][CH:19]2[NH:25][CH2:26][CH2:27][NH:15][C:13]([C:11]1[S:12][C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:9]=2[C:10]=1[O:16][CH3:17])=[O:14]
Reactant: CCN(CC)CC
Reactant: NC1CC2CCC1C2
Reactant: COc1c(C(N)=O)sc2cccc(CCBr)c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C(=O)NCCNC2CC3CCC2C3)sc2ccccc12
Temperature: 80 °C

Procedure:
A solution of 2-bromoethyl-3-methoxy benzothiophene-2-carboxamide (1.05 g) and 2-norbornylamine(0.42 g) in dry dimethyl formamide containing triethylamine (0.38 g) was heated under a nitrogen atmosphere at 80° C. for 8 hours. The solution was poured into water and extracted with ethyl acetate (3×50 ml), organic extracts washed with water (3×100 ml), dried and the solvent removed to give an oil which was converted to its hydrochloride to give N-[2-(2-norbornylamino) ethyl ]-3 -methoxy benzothiophene-2-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9]C(=O)C(F)(F)F)=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)[N:17]=1>CO>[ClH:1].[NH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=3)[N:17]=2)[CH:4]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)cc1
Solvent: CO
Product: COC(=O)c1ccc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)cc1
Product: Cl
Yield: 231.1 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-30 by using methyl 4-(3-(2-chloro-5-((2,2,2-trifluoroacetamido)methyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzoate (1.00 g, 2.19 mmol), methanol (20 mL) and HO (10 mL) to afford 1.00 g of desired product.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:25]([NH2:27])=[O:26])[CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:29][NH:30]C.CC(O)=O.[BH3-]C#N.[Na+]>CS(C)=O.CO>[O:28]=[S:2]1(=[O:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:25]([NH2:27])=[O:26])[CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:30][CH3:29])[CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CNC
Reactant: NC(=O)c1cc(-c2cccc(C=O)c2)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: CO
Product: CNCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)c1
Reaction time: 1 h
Yield: 15 %

Procedure:
To 3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(3-formylphenyl)-1H-indole-7-carboxamide (0.160 g, 0.404 mmol) in DMSO (1.8 ml) and MeOH (1.8 ml) was added 2M dimethyl amine in methanol (1.0 ml, 2.0 mmol) and HOAc (0.46 ml, 8.1 mmol). The mixture was allowed to stir for 1 hour, and then NaCNBH3 (0.051 g, 0.808 mmol) was added. After 1 hour, the reaction mixture was concentrated and purified via RP-HPLC (0.1% NH4OH in water/acetonitrile). The fractions containing product were combined and concentrated, giving 0.027 g (15%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([OH:8])[C:4]([CH3:9])=[N:3]1.CN(C=O)C.O1CCOCC1.[H-].[Na+].[Br:23][C:24]1[CH:25]=[C:26]([N+]([O-])=O)[C:27]([C:30]#[N:31])=[N:28][CH:29]=1>O>[Br:23][C:24]1[CH:25]=[C:26]([O:8][C:5]2[C:4]([CH3:9])=[N:3][N:2]([CH3:1])[C:6]=2[CH3:7])[C:27]([C:30]#[N:31])=[N:28][CH:29]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: Cc1nn(C)c(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(C)c(C)c1Oc1cc(Br)cnc1C#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.7 %

Procedure:
A flask was charged with 1,3,5-trimethyl-1H-pyrazol-4-ol (10.46 g, 82.89 mmol), and added DMF:dioxane (9:1) (700 mL). The reaction mixture was cooled to 0° C. and 60% sodium hydride (3.315 g, 82.89 mmol) was added portionwise and the reaction was stirred for 15 minutes. 5-Bromo-3-nitropicolinonitrile (18 g, 78.95 mmol) was added and the reaction was stirred at ambient temperature for 3 hours. The reaction was poured slowly into 600 mL water and stirred for 10 minutes. The resultant solids were filtered and dried to afford 5-bromo-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinonitrile (23.70 g, 97.74% yield) as very lightly tan (white) solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[S:16][C:17]4[C:23]([O:24][CH3:25])=[CH:22][C:21]([CH3:26])=[CH:20][C:18]=4[CH:19]=3)[C:9]([CH2:13][OH:14])=[C:10]([C:11]#[N:12])[N:6]2[N:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH3:31]CN(C(C)C)C(C)C>ClCCl.CO>[NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[S:16][C:17]4[C:23]([O:24][CH3:25])=[CH:22][C:21]([CH3:26])=[CH:20][C:18]=4[CH:19]=3)[C:9]([CH2:13][O:14][CH3:31])=[C:10]([C:11]#[N:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(C)cc2cc(-c3c(CO)c(C#N)n4ncnc(N)c34)sc12
Solvent: ClCCl
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COCc1c(-c2cc3cc(C)cc(OC)c3s2)c2c(N)ncnn2c1C#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of Example 68 (60 mg, 164 μmol) in dichloromethane (5 ml) was treated with thionyl chloride (18 μl, 246 μmol). The mixture was stirred at rt for 15 min and then evaporated. The residue was dissolved in methanol (2 ml) and treated with DIPEA (57 μl, 328 μmol). The mixture was stirred first 2 h at 60° C., then refluxed overnight and finally heated to 150° C. for 30 min in a microwave device. After this, the mixture was evaporated, and the residue was purified by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. TFA). The product thus obtained was dissolved in methanol and filtered through an anion exchange cartridge (Stratospheres SPE, PL-HCO3 MP-resin). The cartridge was eluted with methanol, and the filtrate was evaporated affording 18 mg (28% of th.) of the title compound.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=1[N:6]=[C:7]2Cl.[CH:18]1([NH2:21])[CH2:20][CH2:19]1.Cl.C(=O)([O-])[OH:24].[Na+]>CC(N(C)C)=O.C1COCC1.C(OCC)(=O)C>[CH:18]1([NH:21][C:7]2[C:8]3[CH:9]=[CH:10][NH:11][C:2](=[O:24])[C:3]=3[C:4]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=3[N:6]=2)[CH2:20][CH2:19]1
Reactant: NC1CC1
Reactant: O=C([O-])O
Reactant: Fc1ccc2nc(Cl)c3ccnc(Cl)c3c2c1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]ccc2c(NC3CC3)nc3ccc(F)cc3c12
Temperature: 100 °C

Procedure:
To a solution of 1,5-dichloro-9-fluorobenzo[c]-2,6-naphthyridine (40 mg, 0.15 mmol) in DMA (1.5 mL) was added cyclopropylamine (42.2 μl, 0.60 mmol) and the solution was heated to 100° C. for 30 min. The reaction mixture was cooled to room temperature and added to ethyl acetate (50 mL). The organic layer was washed with aqueous sodium hydrogen carbonate (saturated, 50 mL) and brine (50 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to afford the crude mixture as a yellow oil. The oil was dissolved in THF followed by the addition of hydrochloric acid (2 mL, 12.0 mmol, 6.0 M). The mixture was then refluxed at 100° C. for 3 hr. After cooling to room temperature, the reaction mixture was added to aqueous sodium hydrogen carbonate (saturated, 50 mL). The aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in water and DMSO and purified by preparative HPLC Reverse phase (C-18; eluting with acetonitrile/water+0.05% TFA), which afforded the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13].C(NC(C)C)(C)C>O1CCCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:15][Si:14]([C:12]#[C:13][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1)([CH3:17])[CH3:16]
Reactant: C#C[Si](C)(C)C
Reactant: CCC(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: CCC(=O)c1ccc(C#C[Si](C)(C)C)cc1

Procedure:
A mixture of 1.74 g 4′-bromopropiophenone, 2.0 g ethynyltrimethylsilane, 260 mg bis(triphenylphosphine)palladium(II) dichloride, 260 mg copper(I) iodide and 15 ml diisopropylamine in 40 ml tetrahydrofuran is heated at reflux for 1 h. After cooling the reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic layer is washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue is purified by chromatography on silica gel, using a mixture of heptane/ethyl acetate 9:1 as eluent to obtain 1-(4-trimethylsilanylethynylphenyl)propan-1-one, m.p. 36-37° C.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][C:46]=1[CH3:47])[CH2:6][O:7][CH:8]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[CH2:12][CH2:11][N:10]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:9]1.[C:48]([O:52][CH3:53])(=[O:51])[CH:49]=[CH2:50]>C(O)C>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH:13]2[CH2:12][CH2:11][N:10]([C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[CH2:9][CH:8]2[O:7][CH2:6][C:5]2[CH:44]=[CH:45][C:46]([CH3:47])=[C:3]([O:2][CH2:50][CH2:49][C:48]([O:52][CH3:53])=[O:51])[CH:4]=2)=[CH:15][CH:16]=1
Reactant: C=CC(=O)OC
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc(C)c(O)c2)cc1
Agent: [Na]
Solvent: CCO
Product: COC(=O)CCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The solution of 5.1 mg of sodium in 0.5 ml of ethanol is admixed with 0.626 g of benzyl 3-(3-hydroxy-4-methylbenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 15 ml of methyl acrylate and stirred at room temperature over 18 hours. The reaction mixture is concentrated by evaporation, and the residue is admixed with 25 ml of 0.5M HCl (cold) and extracted with tert-butyl methyl ether (2×25 ml). The organic phases are washed with brine (25 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.42 (1:1 EtOAc-heptane); Rt=6.00.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[N:11][NH:12][CH:13]=1.[C:22](Cl)(=[O:24])[CH3:23].O>CN(C)C1C=CN=CC=1.C1COCC1>[C:22]([N:12]1[CH:13]=[C:9]([Cl:8])[C:10]([C:14]2[CH:15]=[C:16]([Cl:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[N:11]1)(=[O:24])[CH3:23]
Reactant: Clc1cc(Cl)cc(-c2n[nH]cc2Cl)c1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)n1cc(Cl)c(-c2cc(Cl)cc(Cl)c2)n1
Reaction time: 2 h
Yield: 96.7 %

Procedure:
0.35 g (0.003 mol) of 4-dimethylaminopyridine and 1.55 ml (0.011 mol) of triethylamine are added to 2.55 g (0.01 mol) of 4-chloro-3-(3,5-dichlorophenyl)-pyrazole dissolved in 30 ml of THF. A solution of 0.85 g (0.011 mol) of acetyl chloride in 10 ml of THF is run, dropwise and at 0° C., onto this solution. Stirring is continued for 2 h at room temperature. The reaction mixture is poured into 100 ml of water and extracted with ethyl acetate. After drying the organic phase and concentration under vacuum, the residue is triturated with 50 ml of heptane, filtered and dried. We obtain 2.80 g of 1-acetyl-4-chloro-3-(3,5-dichlorophenyl)pyrazole, melting at 125° C.