Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25]OC(OC)OC.C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2([N:17]([CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:25]=[N:16][C:14]2=[O:15])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)C1(NCC2CCCCC2)CCN(Cc2ccccc2)CC1
Reactant: COC(OC)OC
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C1N=CN(CC2CCCCC2)C12CCN(Cc1ccccc1)CC2
Yield: 76.5 %

Procedure:
A stirred mixture of 1-benzyl-4-(cyclohexylmethylamino)piperidine-4-carboxamide (8 g, 24.32 mmol), 8 ml of trimethoxymethane, 2 ml of acetic acid and 65 ml of toluene was refluxed for 48 hours. The mixture was concentrated. The residue was dissolved in water, made alkaline with aqueous ammonia, and the mixture was extracted with chloroform. The extracts were dried (MgSO4) and concentrated. Recrystallization of the residue from ethyl acetate gave 6.3 g (76.5%) of crystals, mp 117°-118° C.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:8][N:9]=1)(=O)C.C(N)(=O)C.CC(NC1SC(S(N)(=O)=O)=NN=1)=O.Cl>CO>[NH2:4][C:5]1[S:6][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:8][N:9]=1
Reactant: CC(=O)Nc1nnc(S(N)(=O)=O)s1
Agent: CC(N)=O
Agent: Cl
Solvent: CO
Product: Nc1nnc(S(N)(=O)=O)s1
Reaction time: 6 h
Yield: 85 %

Procedure:
This is prepared by hydrolysis of the acetamide 2-acetylamino-1,3,4-thiadiazole-5-sulfonamide (acetazolamide). A slurry of 0.2 mol of acetazolamide in 600 mL of methanol is treated with 60 mL 12N HCl. This mixture is heated with stirring to reflux for 6 hours. Reaction progress is monitored using liquid chromatography. If reaction is not completed after 6 hours, another 30 mL of 12N HCl is added, and the mixture held at reflux for 2 hours. Methanol is then removed under reduced pressure. Product is recovered after raising the pH of the suspension to 7 by addition of NaOH at 0.4° , followed by filtration. Yield is between 85 and 98% of theoretical with 99% purity. KI =40 nM.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[CH3:21][O:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[S:30](Cl)(=[O:32])=[O:31]>>[CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:30]([C:24]1[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=1[O:22][CH3:21])(=[O:32])=[O:31])[CH:7]=[CH:6]2
Reactant: COc1cc(C)ccc1S(=O)(=O)Cl
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Solvent: CN(C)C=O
Product: COc1cc(C)ccc1S(=O)(=O)n1ccc2c(CN(C)C)c(OC)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 18.4 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 2-methoxy-4-methylbenzenesulfonyl chloride (24 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (5 mg, 17%) as a white solid. MS (ESI+) for C20H24N2O4S m/z 389 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH:19]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1.[Cl-].[NH4+]>C1COCC1.O.C(OCC)(=O)C>[CH2:27]([O:26][C:24]([C:19]1([CH2:35][C:34]2[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:25])[CH3:28]
Reactant: CCOC(=O)C1CCCC1
Reactant: COc1ccc(CBr)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccc(OC)cc2)CCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
A solution of diisopropylamine (58 mL. 0.44 mol) in THF 400 mL was cooled to below 0° C. and n-butyl lithium in hexane (170 mL, 2.5 N, 0.43 mol) was added dropwise maintaining the temperature below 0° C. Upon completion of the addition, ethyl cyclopentylcarboxylate (55 g, 0.39 mol) in THF (175 mL) was added dropwise maintaining the internal temperature between −60 and −70° C. Upon completion of the addition, the internal temperature was allowed to rise to −40° C. and was held there for 20 min and lowered back to −70° C. A solution of 4-methoxybenzyl bromide (75 g, 0.48 mol) in 175 mL of THF was added dropwise and the mixture was allowed to warm to room temperature overnight. A solution of 20% ammonium chloride in water (225 mL) was added followed by 450 mL of ethyl acetate, the layers were separated, the aqueous layer was extracted with ethyl acetate (450 mL) and the combined organic layers were washed with saturated brine (2×450 mL) and were dried (MgSO4). The crude product was chromatographed on silica gel, eluting with 1-5% ether in hexane to give 1-[(4-methoxyphenyl)methyl]cyclopentanecarboxylic acid ethyl ester (80.8 g, 79%) as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Si:5]([CH3:38])([CH3:37])[CH2:6][CH2:7][C:8]1[C:20]2[CH2:19][N:18]3[C:13](=[CH:14][C:15]4[C@@:25]([O:28][C:29](=[O:31])[CH3:30])([CH2:26][CH3:27])[C:24](=[O:32])[O:23][CH2:22][C:16]=4[C:17]3=[O:21])[C:12]=2[N:11]=[C:10]2[CH:33]=[CH:34][CH:35]=[CH:36][C:9]=12.[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C)C=O>[N:39]([CH2:2][CH2:3][CH2:4][Si:5]([CH3:38])([CH3:37])[CH2:6][CH2:7][C:8]1[C:20]2[CH2:19][N:18]3[C:13](=[CH:14][C:15]4[C@@:25]([O:28][C:29](=[O:31])[CH3:30])([CH2:26][CH3:27])[C:24](=[O:32])[O:23][CH2:22][C:16]=4[C:17]3=[O:21])[C:12]=2[N:11]=[C:10]2[CH:33]=[CH:34][CH:35]=[CH:36][C:9]=12)=[N+:40]=[N-:41]
Reactant: CC[C@@]1(OC(C)=O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@]1(OC(C)=O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCN=[N+]=[N-]
Yield: 95.3 %

Procedure:
A solution of Compound 19 (1.96 g) and sodium azide (725 mg) in N,N-dimethylformamide (15 mL) was heated at 80° C. for 3 hours. The N,N-dimethylformamide was concentrated under reduced pressure and the residue was partitioned between chloroform (25 mL) and 1 N HCl (10 mL). The organic layer was separated, dried and concentrated to obtain the crude product and was purified by eluting on a silica gel column using 1-2% ethanol in dichloromethane to yield 95% of the required product (1.75 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:11]([C:19](O)=[O:20])[C:10]2=[O:22])=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:26])=O.CN(C)C=O>ClCCl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:11]([C:19]([Cl:26])=[O:20])[C:10]2=[O:22])=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2c(=O)c(C(=O)O)cc3cccnc32)cn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(-n2c(=O)c(C(=O)Cl)cc3cccnc32)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.35 g (4.5 mmol) of 1-(6-methoxy-3-pyridinyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid was dissolved in dichloromethane (50 mL), and 2.5 mL (30 mmol) of oxalyl chloride was added thereto. One droplet of N,N-dimethylformamide was added to the above mixture, and the resulting mixture was stirred for 2 hours at room temperature. The reaction solution was concentrated under reduced pressure, and thus 1-(6-methoxy-3-pyridyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid chloride was obtained. The acid chloride thus obtained was dissolved in dichloromethane (50 mL), and 0.56 g (5.0 mmol) of 1,3-cyclohexanedione and 1.54 mL (10.8 mmol) of triethylamine were added to the above solution under ice cooling. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water, and the mixture was extracted with dichloromethane. The organic phase was dried and concentrated. The residue was washed with diisopropyl ether, and thus 1.78 g (yield: quantitative) of the title compound was obtained as a light yellow solid.
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[C:28]([F:48])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>CN(C)C=O>[F:48][C:28]1[CH:27]=[C:26]([O:25][C:23]2[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:8]([N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)=[O:7])[CH:24]=2)[CH:31]=[CH:30][C:29]=1[NH:32][C:33]([C:35]1([C:38]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)=[O:47])[CH2:37][CH2:36]1)=[O:34]
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1)N1CCOCC1
Reaction time: 8 h

Procedure:
To a solution of roughly purified [4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (150 mg) in N,N-dimethylformamide (1.5 ml) was added morpholine (0.100 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. To the resultant residue was added diethyl ether:heptane=1:2 to precipitate a solid. The solvent was concentrated under reduced pressure, and the residue was dried under reduced pressure to provide the titled compound as white powder (12.2 mg).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:13]2[C:14]([C:19]([OH:21])=O)=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:10]=[CH:11][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>ClCCl.O.CN(C)C=O>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]2[C:19](=[O:21])[C:14]3[C:13]([C:9]=2[CH:8]=1)=[CH:18][CH:17]=[CH:16][N:15]=3
Reactant: COc1cccc(-c2cccnc2C(=O)O)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)-c1cccnc1C2=O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (0.95 L) is added over 30 min to a solution of 3-(3-methoxy-phenyl)-pyridine-2-carboxylic acid (crude product; 2.0 kg) and N,N-dimethylformamide (34 mL) in dichloromethane (9 L) at 40° C. The addition vessel is rinsed with dichloromethane (1 L) and the solution is stirred at 40° C. for 2 h. The solution is diluted with toluene (10 L) and most of the solvent is evaporated (residual toluene ca. 2 L). Dichloromethane (10 L) is added to obtain a homogeneous solution. The solution is heated to 35° C. and added over 30 min to a vessel charged with aluminum chloride (1.75 kg) and dichloromethane (10 L) while keeping mild reflux. The mixture is stirred at 40° C. for 30 min and then cooled to 0° C. Water (4 L) is added at such a rate that the solution temperature maintained below 40° C. The aqueous layer is adjusted to pH value 2.5-3.5 using 2 M aqueous NaOH solution and the resulting mixture is stirred for 15 min. The organic layer is separated and the aqueous layer is extracted with dichloromethane (2×). The combined organic phase is concentrated (to ca. 10 L) and toluene (10 L) is added to the residue. The residual amount of dichloromethane is evaporated and the precipitate is separated and washed with toluene (2 L) and heptane (4 L) and dried under vacuum to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:19](Br)[CH:20]=[CH2:21]>CN(C=O)C.C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:21]([N:11]([C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:20]=[CH2:19]
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: C=CCBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCN(CCC(=O)O)C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 40 h

Procedure:
To a solution of 2.5 g (11.2 mmol) 3-benzyloxycarbonylamino-propionic acid in 30 ml DMF and 30 ml THF are added 1.34 g (33.6 mmol, 60% suspension in mineral oil) NaH and the mixture is heated at 60° C. for 3 h. After cooling down 1.42 ml (16.8 mmol) allyl bromide are added. After stirring for 40 h at rt the mixture is diluted with 10% citric acid and extracted three times with EtOAc. The combined organic layers are washed with water, dried with sodium sulfate and the volatiles are removed in vacuo. The residue is chromatographed on silica gel (hexane/EtOAc 3:1), yielding the title product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=O)[C@@H:18]([NH:28]C(=O)OC(C)(C)C)[CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)(=O)C>[CH2:21]([O:20][CH2:19][C@@H:18]([C:17]1[NH:16][C:3]2[CH:4]=[CH:5][C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)=[CH:7][C:2]=2[N:1]=1)[NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1N
Solvent: CC(=O)O
Product: N[C@@H](COCc1ccccc1)c1nc2cc(Oc3ccc(F)cc3)ccc2[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A mixture of (S)-tert-butyl 1-(2-amino-4-(4-fluorophenoxy)phenylamino)-3-(benzyloxy)-1-oxopropan-2-ylcarbamate (610 mg, 1.23 mmol) and acetic acid (6 mL) was stirred at 60° C. for 1 hour. The acetic acid was remove under vacuum and the residue was dissolve in hydrogen chloride (4 mL, 4N in dioxane). The resulting solution was stirred at ambient temperature for 30 minutes and then concentration. Product was purified from the residue by PrepLC to give (R)-2-(benzyloxy)-1-(5-(4-fluorophenoxy)-1H-benzo[d]imidazol-2-yl)ethanamine (250 mg, 54%) as a pale yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]1[N:15]=[C:14](F)[CH:13]=[C:12]([F:17])[N:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14]2[CH:13]=[C:12]([F:17])[N:11]=[C:10]([F:9])[N:15]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Fc1cc(F)nc(F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Fc1cc(Nc2ccc(Cl)cc2)nc(F)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Chloroaniline was added to a stirred solution of 2,4,6-trifluoropyrimidine (7.7 g), potassium carbonate (7.86 g) in ethanol (80 ml). The mixture was stirred at room temperature for 16 h, diluted with water, extracted with ethyl acetate, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/ethyl acetate (4:1). Yield 8.3 g cream solid
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]([CH3:3])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: CN(C)Cc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)Cc1ccccc1N1CCNCC1
Yield: 76 %

Procedure:
To tert-butyl 4-{2-[(dimethylamino)methyl]phenyl}-piperazinecarboxylate (Step 2) (0.68 g, 2.1 mmol) dissolved in CH2Cl2 (12 mL) was added TFA (6 mL). After stirring the reaction at RT for 1 h, the solvent was concentrated in vacuo and the residue was partitioned between CH2Cl2 and satd NaHCO3. The organic layer was washed with brine and the combined aqueous layer were extracted with a mixture of CH2Cl2 and 30% MeOH. The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give dimethyl[(2-piperazinylphenyl)methyl]amine as a yellow oil (0.35 g). MS m/z: 220 (M+H). Calc'd for C13H21N3: 219.33.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[C:10]([NH:13][CH:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1)(=[O:12])[CH3:11]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:16]2[CH2:17][CH2:18][CH2:19][CH:14]([NH:13][C:10](=[O:12])[CH3:11])[CH2:15]2)=[N:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(=O)NC1CCCNC1
Product: CC(=O)NC1CCCN(c2ccc(C#N)cn2)C1
Yield: 96 %

Procedure:
This compound was synthesized from 6-chloronicotinonitrile and 3-acetamidopiperidine as described for example 51 step 1 (850 mg, yield 96%) as white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.44 (d, J=2.2 Hz, 1H), 7.88 (d, J=7.5 Hz, 1H), 7.82-7.79 (dd, J=9.0 Hz, 2.4 Hz, 1H), 6.86 (d, J=9.2 Hz, 1H), 4.20-4.14 (dd, J=12.7 Hz, 3.1 Hz, 1H), 4.08-4.02 (dd, J=13.2 Hz, 3.9 Hz, 1H), 3.62 (m, 1H), 3.22-3.14 (m, 1H), 3.01-2.93 (dd, J=12.9 Hz, 9.2 Hz, 1H), 1.87-1.71 (m, 2H), 1.78 (s, 3H), 1.53-1.41 (m, 2H). MS (ESI) m/z: Calculated for C13H16N4O: 244.13. found: 245.2 (M+H)+
Reaction SMILES: [N:1]12[CH2:8][CH2:7]N([CH2:5][CH2:6]1)CC2.[C:9]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](NC2C=C(C)C(C)=CC=2I)[CH:16]=1)(=[O:12])C=C>CN(C=O)C>[CH3:14][C:15]1[CH:16]=[C:17]2[C:6](=[CH:5][C:20]=1[CH3:19])[NH:1][CH:8]=[C:7]2[C:9]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: C=CC(=O)OCc1cccc(Nc2cc(C)c(C)cc2I)c1
Reactant: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: Cc1cc2[nH]cc(C(=O)OCc3ccccc3)c2cc1C
Temperature: 120 °C
Yield: 140.6 %

Procedure:
8.60 g of 1,4-diazabicyclo[2.2.2]octane is added to a solution of 25.5 g of the compound obtained in step 1 in 120 ml of DMF. It is degassed with nitrogen, then 0.703 g of palladium acetate is added and the reaction mixture is heated at 120° C. for 7 hours. EtOAc is added, then it is washed with water and with brine, dried over Na2SO4 and evaporated. After trituration of the solid residue with iso ether, 12.3 g of the expected compound is obtained in the form of a beige powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=[O:12].Cl.[CH3:15]O>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH2:10][C:11]([O:13][CH3:15])=[O:12]
Reactant: CO
Reactant: Cc1cc(C)c(CC(=O)O)cc1C
Agent: Cl
Product: COC(=O)Cc1cc(C)c(C)cc1C
Temperature: 25 °C

Procedure:
100 g (0.56 mol) of 2,4,5-trimethylphenylacetic acid were dissolved in 230 ml of methanol, 6 ml of concentrated hydrochloric acid were added and the mixture was heated under reflux for 10 hours. It was then cooled to room temperature and the methanol was removed in vacuo. The residue was stirred into a solution of 53 g of sodium carbonate, dissolved in 260 ml of water, and the organic phase was taken up in 200 ml of toluene. The organic phase was separated off, dried and concentrated and the residue was distilled. 48.6 g of methyl 2,4,5-trimethylphenylacetate having a boiling point of 86° C. under 0.2 mbar were obtained.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5](Br)=[CH:4][CH:3]=1.[CH2:12]([C:18]1[CH:22]=[CH:21][S:20][C:19]=1B1OC(C)(C)C(C)(C)O1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:12]([C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([C:19]2[S:20][CH:21]=[CH:22][C:18]=2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Brc1ccc(Br)c2nsnc12
Reactant: CCCCCCc1ccsc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCCCc1ccsc1-c1ccc(-c2sccc2CCCCCC)c2nsnc12
Temperature: 100 °C
Reaction time: 12 h

Procedure:
4,7-Dibromobenzo[c]-1,2,5-thiadiazole (1.00 g, 3.41 mmol) and 3-hexylthiophene-2-boronic acid pinacol ester (2.10 g, 7.14 mmol) were placed in a 100 mL 3-neck round bottom flask which was flushed with N2 gas for 5 minutes. Dimethoxyethane (20 mL) and water (30 mL) were added and the mixture was purged with N2 gas for 30 minutes. Sodium carbonate (4.23 g, 34.1 mmol) and catalyst Pd(PPh3)4 (0.430 g, 0.372 mmol) were added and the mixture was heated to 100° C. and stirred for 12 hours. The mixture was extracted into hexanes and passed through a silica column, by eluting first with hexanes (200 mL) and then eluting the product with a solution of 5% EtOAc in hexanes (200 mL). The procedure afforded 1.59 g of vibrant orange, 4,7-bis(3-hexylthiophen-2-yl)benzo[c][1,2,5]thiadiazole (Formula 2) in 99% yield.
Reaction SMILES: C[O:2][C:3]1[CH2:8][CH:7]=[C:6]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH2:5][CH:4]=1>S(=O)(=O)(O)O>[OH:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH2:7][CH2:8][C:3](=[O:2])[CH2:4][CH:5]=1
Reactant: COC1=CCC(CCCCO)=CC1
Agent: O=S(=O)(O)O
Product: O=C1CC=C(CCCCO)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 4.76 g of 1-methoxy-4-(4-hydroxybutyl)-cyclohexa-1,4-diene in 75 ml 1N sulfuric acid is stirred at room temperature for 1.5 h and extracted with methylene chloride (2×40 ml). The combined organic extracts are washed with saturated sodium bicarbonate, dried (MgSO4), filtered and subjected to evaporation to obtain 4-(4-hydroxybutyl)-cyclohex-3-ene-1-one as an oil.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([NH:30][C@H:31]([CH2:34][CH3:35])[CH2:32][OH:33])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCCCCC>C(Cl)Cl.CCOCC>[C:11]([NH:30][C@H:31]([CH2:34][CH3:35])[CH:32]=[O:33])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCCCCC
Product: CC[C@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -45 °C
Reaction time: 1 h

Procedure:
To a stirred solution of DMSO (3.0 mL, 2.8 eq, 42.28 mmol) in DCM (30 mL) under an argon atmosphere at −45° C., was added oxalyl chloride (2 M in DCM, 10.56 mL, 1.40 eq, 21.12 mmol), dropwise. The reaction mixture was stirred at −45° C. for 1 h, after which time a solution of (R)-2-(trityl-amino)-butan-1-ol (5 g, 1 eq, 15.08 mmol) in DCM (30 mL) was added dropwise with stirring. The reaction mixture was stirred at this temperature for 3 h, when TLC (hexane:ether; 80:20) indicated that the reaction had gone to completion. To the reaction mixture was added a solution of TEA (10.5 mL, 5 eq, 75.33 mmol) in DCM (30 mL), and the solution allowed to warm to room temperature over 16 h. The reaction mixture was diluted with more DCM (200 mL) and washed with water (250 mL). The aqueous phase was extracted with DCM (3×50 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was dissolved in ether (30 mL), the solid precipitate removed by filtration and the filtrate was evaporated in vacuo. The residue was dissolved in hexane (50 mL), the solid precipitate removed by filtration and the filtrate was evaporated in vacuo to afford the title compound as a light yellow oil. Yield: 2.59 g (52%). 1H-NMR (d6-DMSO, 250 MHz): δ 0.77 (t, 3H, J=7.42 Hz, —NHCH(CH2CH3)CHO), 1.34-1.61 (m, 2H, —NHCH(CH2CH3)CHO), 2.92 (m, 1H, —NHCH(CH2CH3)CHO), 3.62 (d, 1H, J=8.21 Hz, —NHCH(CH2CH3)CHO), 7.16-7.46 (m, 15H, 3×Ph), 8.77 (d, 1H, J=3.00 Hz, —NHCH(CH2CH3)CHO).