Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[O:25][C:26]([CH2:29][CH2:30][NH2:31])=[CH:27][CH:28]=4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:9][C:8]=1[Cl:32].[CH3:36][S:37]([CH2:40][C:41](O)=[O:42])(=[O:39])=[O:38].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[O:25][C:26]([CH2:29][CH2:30][NH:31][C:41](=[O:42])[CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:27][CH:28]=4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:9][C:8]=1[Cl:32]
Reactant: CS(=O)(=O)CC(=O)O
Reactant: NCCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CC(=O)NCCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1

Procedure:
Preparation according to Procedure (I) utilizing (4-(3-fluorobenzyloxy)-3-chlorophenyl)-(6-(5-(2-aminoethyl)-furan-2-yl)-quinazolin-4-yl)-amine (26 mg, 0.0537 mmol), methanesulfonylacetic acid (22.2 mg, 0.161 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.0 mg, 0.161 mmol) and N,N-diisopropylethylamine (0.028 mL, 0.161 mmol). 1H (DMSO) 9.84 (s, 1 H), 8.65 (s, 1 H), 8.49 (s, 1 H), 8.10 (d, 1 H), 7.96 (d, 1 H), 7.73 (d, 1 H), 7.69 (m, 1 H), 7.41 (m, 1 H), 7.22-7.29 (m, 3 H), 7.13 (m, 1 H), 6.98 (d, 1 H), 6.35 (d, 1 H), (5.21 (s, 2 H), 4.02 (s, 2 H), 3.07 (t, 2 H), 3.05 (s, 3 H), 2.87 (t, 2 H). Electrospray m/z 609 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[CH:15])[CH:8]=2)[S:3]1.I[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:16])[CH2:11][C:10]([CH3:12])([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[C:15][C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=3)[CH:8]=2)[S:3]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CC(C)(C)S2
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)(C)S3)cc1
Reaction time: 40 h

Procedure:
A solution of 110.7 mg (o.481 mmol) of 2,2,4,4-tetramethyl-6-ethynylthiochroman (Compound 35) and 142.3 mg (0.516 mmol) of ethyl 4-iodobenzoate (Compound 29) in 2 ml of triethylamine was placed in a heavy walled glass tube and degassed under argon. The mixture was then treated with a finely ground mixture of 42 mg (0.221 mmol) of cuprous iodide and 63 mg (0.09 mmol) of bis (triphenylphosphine) palladium (II) chloride. The reaction mixture was degassed under argon again and the tube was sealed. The mixture was stirred at room temperatures for 40 hours. The triethylamine was removed under vacuum and the residue purified by flash chromatography (silica, 3% ethyl acetate in hexanes) to give the title compound as a pale yellow solid. PMR (CDCl3) : & 1.37-1.42 (15 H, m), 1.96 (2 H, s), 4.38 (2 H, q, J~7.0 Hz), 7.25 (1 H, dd, J~8.2 Hz, 1.8 Hz), 7.33 (1 H, d, J~1.8 Hz), 7.37 (1 H, d, J~8.2 Hz), 7.65 (2 H, d, J~8.6 Hz), 8.01 (2 H, d, J~8.6 Hz). MS exact mass, m/e 378.1636 (calcd. for C24H26O2S, 378.165.3).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[O:15])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.BrN1C(=O)CC[C:20]1=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[O:15])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1)[CH3:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(c1)CCc1ccccc1C2=O
Solvent: ClC(Cl)(Cl)Cl
Product: CCc1ccc2c(c1)CCc1ccccc1C2=O
Temperature: 80 °C

Procedure:
60.5 Gm. of 2-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one is refluxed in 500 ml. of carbon tetrachloride with 58.2 gm. of N-bromosuccinimide for 8 hours. The solution is cooled and filtered and the solvent removed under vacuum. The residue is dissolved in 200 ml. of dimethylformamide and 44 gm. of 1,5-diazabicyclo[3.4.0]nonene-5 is added. The mixture is heated to 80° C. for 20 minutes, then cooled and added to water. The solution is extracted with ether and the extract washed, dried and evaporated. The residue is recrystallized from acetone/hexane to afford 39.7 gm., 69%, of 2-methyl-5H-dibenzo[a,d]cyclohepten-5-one,m.p. 78°-80° C. Use of 2-ethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one gives a similar yield of 2-ethyl-5H-dibenzo[a,d]cyclohepten-5-one,m.p. 62°-64° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]([CH2:9][CH2:10][C:11](Cl)=[O:12])([O:7][CH3:8])=[O:6].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.Cl>ClCCCl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:25][C:24]([C:11](=[O:12])[CH2:10][CH2:9][C:5]([O:7][CH3:8])=[O:6])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1
Reactant: Clc1ccc(-c2ccco2)cc1
Reactant: COC(=O)CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(Cl)cc2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring mixture of 62 g (0.50 mole) of AlCl3 in 375 ml of 1,2-dichlorethane was added portionwise 75 g (0.5 mole) of 3-carbomethoxypropionyl chloride while keeping the temperature below 25° by means of an ice bath. The reaction mixture was cooled to 15° and a solution of 89 g (0.5 mole) of 5-(4-chlorphenyl)furan in 250 ml of 1,2-dichloroethane was added dropwise with large volumes of HCl gas being evolved and the temperature rising to 30°. The reaction mixture was stirred at ambient temperature for one hour and then added to 1000 ml of ice water. The organic layer was separated and the aqueous layer extracted with dichlormethane. The combined organic layers were washed with 1000 ml of 6% sodium carbonate solution, with 1000 ml of water and dried over MgSO4. The solvent was removed on the Calab evaporator yielding a residual oil which was extracted several times with refluxing hexane. The hexane extracts were cooled to yield a solid which was filtered, washed twice with 6% sodium carbonate solution, recrystallized from hexane and air dried to yield 7 g (5%). An analytical sample was prepared by drying a sample in a vacuum pistol at room temperature, m.p. 99°-100°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C:8]1[C:9]([CH3:22])=[N:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=2)[C:12]=1[CH3:13])([CH3:4])([CH3:3])[CH3:2].[CH:24](N(C(C)C)CC)(C)[CH3:25].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6](=[O:23])[CH2:7][C:8]1[C:9]([CH3:22])=[N:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:24]#[CH:25])=[CH:17][CH:16]=2)[C:12]=1[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nn(Cc2ccc(I)cc2)c(C)c1CC(=O)OC(C)(C)C
Reactant: CCN(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(Cn2nc(C)c(CC(=O)OC(C)(C)C)c2C)cc1
Reaction time: 15 h

Procedure:
To a stirred solution of 1-(4-iodobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl-acetic acid tert.-butyl ester (12.2 g) in tetrahydrofuran (100 ml) at room temperature is added diisopropylethylamine (12.3 ml). The solution is degassed and put under argon. Ethynyltrimethylsilane (4.5 ml), copper(I)iodide (543 mg) and bis-(triphenylphosphine)-palladiumdichloride (1.0 g) are added. After 15 h of stirring, the reaction is absorbed onto Extrelute and purified by flash chromatography (4:1 isocratic-cyclohexane:ethyl acetate) to yield a solid (10.7 g; [M+H]=397; HPLC retention time 1.71 min (Method J)). The solid is dissolved in tetrahydrofuran (200 ml) and is stirred together with tetrabutylammonium fluoride (1 M in THF, 28 ml). After 15 h at room temperature, the reaction mixture is concentrated in vacuo. The residue is purified by flash chromatography (4:1 isocratic-cyclohexane:ethyl acetate) to yield 1-(4-ethynylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl-acetic acid tert.-butyl ester (6.8 g; [M+H]=325; HPLC retention time 1.47 min (Method J)).
Reaction SMILES: [NH:1]1[C:4](=[O:5])[CH:3]2[CH2:6][CH2:7][C:8]3[C:13]([CH:2]12)=[CH:12][CH:11]=[CH:10][CH:9]=3.[ClH:14].[CH3:15][OH:16]>>[ClH:14].[NH2:1][CH:2]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH:3]1[C:4]([O:16][CH3:15])=[O:5]
Reactant: O=C1NC2c3ccccc3CCC12
Reactant: CO
Agent: Cl
Product: COC(=O)C1CCc2ccccc2C1N
Temperature: 90 °C
Reaction time: 6 h

Procedure:
To 2.36 g of 2a,3,4,8b-tetrahydronaphtho[1,2-b]azet-2(1H)-one was added 50 ml of a 10% hydrogen chloride/methanol solution, followed by stirring at 90° C. for 6 hours. After leaving to be cooled, the solvent was evaporated under reduced pressure. To the obtained residue were added methanol and diethyl ether, and the insoluble material was collected by filtration and dried to obtain 3.08 g of methyl rac-(1S,2S)-1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylate hydrochloride.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH:4]=[C:3]1[CH2:13]O.P(Br)(Br)[Br:16].C(Cl)Cl>CN(C=O)C>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH:4]=[C:3]1[CH2:13][Br:16]
Reactant: Cn1c(CO)cc(=O)c2ccccc21
Reactant: BrP(Br)Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1c(CBr)cc(=O)c2ccccc21

Procedure:
A solution of 1-methyl-4-oxo-1,4-dihydroquinolin-2-ylmethanol (112 mg, 0.592 mmoles, Coppola, G. M. J. Heterocyclic Chem., 1986, 23, 1717) and phosphorous tribromide (56.2 uL, 0.592 mmoles) in 3:1 CH2Cl2: DMF (20 mL) is stirred 18 hours and another portion (20 mL) of phosphorous tribromide is added. After 24 hours distilled water (10 mL) is added and extracted with EtOAc. The organic layer is concentrated and the resulting residue purified by column chromatography (silica, 20:1 CH2Cl2:MeOH) to yield the title compound as a white solid. MS (ESI) 252, 254 (M+H)+, Br pattern.
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][C:8]=1[CH2:17][CH:18]=[CH2:19])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:1]([Si:5]([CH3:21])([CH3:20])[O:6][C:7]1[CH:16]=[CH:15][C:10]([CH2:11][OH:12])=[CH:9][C:8]=1[CH2:17][CH:18]=[CH2:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCc1cc(C(=O)OC)ccc1O[Si](C)(C)C(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCc1cc(CO)ccc1O[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a magnetically stirred solution of 8.523 g (28.0 mmol) of the product from Step C in 35 mL of anhydrous THF was added 15.0 mL of a 1.0M solution of lithium aluminum hydride in THF, and the reaction mixture was stirred under a nitrogen atmosphere for 2 hours. At this point, the reaction was quenched by cautious addition of 10 mL water, the resulting precipitate was dissolved by addition of 1.0N is hydrochloric acid and the product was extracted into ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and evaporated in vacuo to afford 7.258 g (93%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.B(Cl)(Cl)Cl.[CH2:18]1[CH2:29][O:28][C:27]2[C:20](=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH:22]=[O:23])[O:19]1.C(N(CC)CC)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH:22]([C:21]2[CH:24]=[CH:25][CH:26]=[C:27]3[O:28][CH2:29][CH2:18][O:19][C:20]=23)[OH:23])[CH:3]=1
Reactant: CC(C)(C)CNc1ccc(Cl)cc1
Reactant: O=Cc1cccc2c1OCCO2
Agent: ClB(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)CNc1ccc(Cl)cc1C(O)c1cccc2c1OCCO2
Reaction time: 3.5 h
Yield: 88.5 %

Procedure:
A solution of (4-chloro-phenyl)-(neopentyl)-amine (2.24 g, 11.3 mmol) in benzene (6 mL) was added to a solution of boron trichloride (1.0 M in xylenes; 12.5 mL, 12.5 mmol) in benzene (13 mL) at 0° C. under a nitrogen atmosphere. Once the addition was complete, the resulting mixture was heated at reflux for 3 hours, under a steady stream of nitrogen exiting into an aqueous 5N sodium hydroxide trap, and then recooled to 0° C. A solution of 2,3-ethylenedioxybenzaldehyde (1.86 g, 11.3 mmol), triethylamine (2.29 g, 22.7 mmol, 3.2 mL) and benzene (6 mL) was then added and the resulting mixture stirred 3.5 hours before quenching with aqueous 1N hydrochloric acid. After 1 hour, ethyl acetate was added and the resulting mixture was shaken vigorously. The aqueous layer was alkalized with aqueous 5N sodium hydroxide and the layers separated. The aqueous layer was extracted with ethyl acetate (2×). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography (4:1 hexanes/ethyl acetate) to produce 3.62 g (88%) of the title compound as an off-white foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([CH:9]([CH3:31])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]3=[N:21][C:20]=2[CH3:28])=[C:15]([C:29]#[CH:30])[N:14]=1)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Br[C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[N:40]([CH3:44])[C:39](=[O:45])[CH:38]=[CH:37]2.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.[Cu]I.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>[C:1]([O:5][C:6](=[O:32])[N:7]([CH3:8])[CH:9]([CH3:31])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]3=[N:21][C:20]=2[CH3:28])=[C:15]([C:29]#[C:30][C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[N:40]([CH3:44])[C:39](=[O:45])[CH:38]=[CH:37]3)[N:14]=1)=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1nc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)ccc1-c1c(C)nc2ccccn12
Reactant: Cn1c(=O)ccc2cc(Br)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1nc2ccccn2c1-c1ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc1C#Cc1ccc2c(ccc(=O)n2C)c1

Procedure:
A mixture of tert-butyl-N-[1-[[6-ethynyl-5-(2-methylimidazo[1,2-a]pyridin-3-yl)pyridin-2-yl]amino]-1-oxopropan-2-yl]-N-methylcarbamate F1a (60 mg, 0.14 mmol), 6-bromo-1-methylquinolin-2-one (82 mg, 0.35 mmol), copper(I) iodide (2.6 mg, 0.01 mmol), Dichlorobis(triphenylphosphine)palladium(II) (8.1 mg, 0.01 mmol) and DIPEA (94 μl, 0.55 mmol) is stirred under argon atmosphere in NMP (0.5 ml) for 2 h at 50° C. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 17 mg (21%). HPLC-MS: M+H=591; tR=1.79 min (*Method—4).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([NH:29][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[N:3]=1
Reactant: NC1CCCCC1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Product: N#Cc1c(NC2CCCCC2)nc(N)nc1-c1ccc2c(c1)OCO2

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and cyclohexylamine in !)ME. ES-MS m/e (%): 338 (M+H+, 100).
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccccc2C)ccn1
Reactant: NO
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccccc1-c1ccnc(N(CCCCCCC(=O)NO)c2ccccn2)c1
Reaction time: 22 h
Yield: 55 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to II (37 mg, 0.09 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 22 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 to 100:8) to furnish III as a yellow oil (20 mg, 55%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/C1(c2ccc(F)cc2)CCCCC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCC1(c2ccc(F)cc2)CCCCC1
Reaction time: 16 h
Yield: 99.2 %

Procedure:
To a solution of (E)-ethyl 3-(1-(4-fluorophenyl)cyclohexyl)acrylate (Intermediate I-7B, 1 g, 3.62 mmol) in methanol (25 mL) was added 10% Pd/C (˜0.5 g, wet 50%) under argon, and the mixture was stirred under hydrogen atmosphere (50 psi) for 16 hrs. The reaction mixture was filtered through CELITE® and evaporated to give the desired ethyl 3-(1-(4-fluorophenyl)cyclohexyl)propanoate (1 g, 99% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.25 (2H, dd, J=9.02, 5.28 Hz), 7.00 (2H, t, J=8.80 Hz), 4.02 (2H, q, J=7.26 Hz), 2.00-2.08 (2H, m), 1.89-1.96 (2H, m), 1.81-1.87 (2H, m), 1.34-1.61 (8H, m), 1.18 (3H, t, J=7.15 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8](O)[CH3:9].CCN(CC)CC.CS(Cl)(=O)=O.Cl.[NH:24]1[C:30]2[CH:31]=[CH:32][S:33][C:29]=2[C:28](=[O:34])[NH:27][CH2:26][CH2:25]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:24]1[C:30]2[CH:31]=[CH:32][S:33][C:29]=2[C:28](=[O:34])[NH:27][CH2:26][CH2:25]1)[CH3:9]
Reactant: O=C1NCCNc2ccsc21
Reactant: CC(O)c1ccccc1Cl
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(c1ccccc1Cl)N1CCNC(=O)c2sccc21
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 3.4 %

Procedure:
1-(2-Chloro-phenyl)-ethanol (1.0 g, 6.39 mmol, 3.6 Eq) and Et3N (1.16 mL, 8.30 mmol, 4.7 Eq) were dissolved in anhydrous DCM (20 mL) and cooled to 0° C. under nitrogen. MsCl (645 μL, 8.30 mmol, 4.7 Eq) was added portionwise. After 3.5 hours, the reaction was poured into 1M HCl (20 mL) and the layers separated. The aqueous layer was extracted with EtOAc (2×30 mL) and the combined organic extracts washed with brine (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in dioxane (6 mL) and 1,2,3,4-tetrahydro-thieno[3,2-e][1,4]diazepin-5-one (300 mg, 1.78 mmol, 1.0 Eq) was added and the reaction heated at reflux overnight. The reaction was cooled to ambient temperature and the solvent removed in vacuo. The residue was purified by column chromatography (ISCO™ Companion©, 40 g column, 0 to 10% MeOH/DCM) to give the title compound as an off-white solid (178 mg, 0.06 mmol, 33%); 1H NMR (DMSO D6) 1.50 (3H, d), 2.92-2.99 (1H, m), 3.13 (1H, m), 3.20-3.25 (2H, m), 5.32 (1H, dd), 6.91 (1H, d), 7.25-7.35 (2H, m), 7.36-7.41 (2H, m), 7.58 (1H, d), 7.61-7.63 (1H, m); LC/MS M+1 (obs.) 307.0.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Li]CCCC.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O>CCOCC>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22]([OH:25])([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1nccs1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)(c2nccs2)CC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 94.1 %

Procedure:
2-Bromo-thiazole (0.27 mL, 2.99 mmol) was dissolved in Et2O (8 mL) and cooled down to −78° C. BuLi (1.3 mL, 2.5 M) was added dropwise. The resulting yellow solution was stirred at −78° C. for 45 min. 4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (720 mg, 3.61 mmol) in Et2O (5 mL) was then added dropwise. The reaction temperature rose to rt naturally overnight. H2O (10 mL) was added to quench the reaction and extracted with ethyl acetate. The combined organic layer was dried (MgSO4), filtered and concentrated. The residue was purified on silica gel column eluting with 33% to 50% ethyl acetate/hexanes to give 4-Hydroxy-4-thiazol-2-yl-piperidine-1-carboxylic acid tert-butyl ester (800 mg) as a colorless oil.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:33][CH2:34]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)NC1CCNCC1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ccnc23)CC1

Procedure:
Starting from 7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-N-piperidin-4-yl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f1) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6]>C1(C)C(C)=CC=CC=1>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([NH:6][C:8](=[O:10])[CH2:9][C:3](=[O:2])[CH2:4][CH2:5][CH3:7])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: COc1cc(N)cc(OC)c1
Solvent: Cc1ccccc1C
Product: CCCC(=O)CC(=O)Nc1cc(OC)cc(OC)c1
Yield: 153.2 %

Procedure:
3,5-Dimethoxy aniline 1(14.5 g, 92.5 mmol) in xylene (50 mL) was treated with 2,2-dimethyl-6-propyl-4H-1,3-dioxinone (17.3 g, 101.7 mmol) worked up and purified as described for 9 to afford e N-(3, 5-dimethoxyphenyl)-3-oxo-hexanamide (10, 18.8 g) in 77% yield as an oily liquid.
Reaction SMILES: C([N:4]1[C:12]2[CH:11]=[C:10]3[C:13]4([CH2:20][S:21][C:9]3=[CH:8][C:7]=2[CH2:6][CH2:5]1)[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]4)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.Cl.O>[CH3:19][N:16]1[CH2:15][CH2:14][C:13]2([C:10]3[C:9](=[CH:8][C:7]4[CH2:6][CH2:5][NH:4][C:12]=4[CH:11]=3)[S:21][CH2:20]2)[CH2:18][CH2:17]1
Reactant: CC(=O)N1CCc2cc3c(cc21)C1(CCN(C)CC1)CS3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CN1CCC2(CC1)CSc1cc3c(cc12)NCC3
Reaction time: 3 h

Procedure:
5-Acetyl-1'-methyl-2,3,6,7-tetrahydrospiro[thiopheno[2,3-f]indole-3,4'-piperidine] (D52) (0.047 g, 0.156 mmol) was dissolved in a mixture of ethanol (2 ml) and 5M HCl (4 ml) and was heated to reflux with stirring under argon. After 3 h, the reaction mixture was allowed to cool, was diluted with water (10 ml) and was basified using solid potassium carbonate. The resulting suspension (pH 9 ) was then extracted with dichloromethane (3×10 ml) and the combined extracts were dried (Na2SO4) and evaporated under reduced pressure to give the title compound as an off white solid, which was dried in vacuo (0.029 g, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][C:17]([F:20])([F:19])[F:18])[C:6]([O:8]C)=[O:7].[Li+].[OH-]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][C:17]([F:18])([F:19])[F:20])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(OCCOC(F)(F)F)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)ccc1OCCOC(F)(F)F
Temperature: 60 °C
Yield: 82 %

Procedure:
Methyl 3-methoxy-4-(2-(trifluoromethoxy)ethoxy)benzoate (crude from Step 1) was dissolved in THF (5 mL) and a suspension of LiOH (550 mg, 23 mmol) in water (5 mL) was added. The mixture was stirred vigorously and heated at 60° C. for 6 h before it was concentrated to half volume. Water (5 mL) was added and the mixture was extracted with diethyl ether (1×10 mL). The aqueous layer was acidified with 4N HCl to pH 2. The resulting mixture was extracted with ethyl acetate (3×10 mL) and the combined organics were washed (1×10 mL H2O, 1×10 mL brine), dried over MgSO4 and evaporated to give 3-methoxy-4-(2-(trifluoromethoxy)ethoxy)benzoic acid (1.0 g, 82%) as a white solid. ESI-MS m/z calc. 280.1. found 281.3 (M+1)+; Retention time: 1.34 minutes (3 min run).