Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CC(C)([O-])C.[K+].[C:40]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]2)=[CH:44][CH:43]=1)#[N:41]>CCOCC>[O:4]1[CH2:5][CH2:6][CH2:7][O:2][CH:3]1[CH2:8][CH:9]=[C:51]1[CH2:50][CH2:49][CH:48]([C:45]2[CH:46]=[CH:47][C:42]([C:40]#[N:41])=[CH:43][CH:44]=2)[CH2:53][CH2:52]1
Reactant: N#Cc1ccc(C2CCC(=O)CC2)cc1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#Cc1ccc(C2CCC(=CCC3OCCCO3)CC2)cc1
Yield: 56 %

Procedure:
Into a three-necked flask equipped with a dropping funnel, a three-way cock and a thermometer, was placed 2-(1,3-dioxan-2-yl)ethyltriphenylphosphonium bromide (12.2 g, 27 mmols), followed by adding tetrahydrofuran (200 ml), suspending, stirring the suspension under ice cooling till the liquid temperature reached 10° C., adding to the reaction mixture, potassium t-butoxide (30 g, 27 mmols), elevating the temperaure up to room temperature under ice cooling for one hour, stirring the mixture for one hour, dropwise adding a tetrahydrofuran (50 ml) solution of 4-(4-cyanophenyl)cyclohexanone (5.0 g, 25 mmols) from the dropping funnel over 30 minutes. The reaction mixture was stirred for 5 hours after completion of the dropwise addition, followed by adding ether (100 ml), allowing the mixture to stand, filtering off deposited insoluble substance, concentrating the flitrate under reduced pressure, and isolating and purifying the resulting pale brown oil by means of silica gel column chromatography, to obtain 1-(2-(1,3-dioxan-2-yl)ethylidene)-4-(4-cyanophenyl)-cyclohexane (4.1 g, 14 mmols).
Reaction SMILES: [C:1]([C:4]1[C:19]([OH:20])=[CH:18][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#N)=[C:6]([CH2:21][CH3:22])[CH:5]=1)(=[O:3])[CH3:2].[OH-:23].[K+].C(O)C.Cl.[OH2:29]>C(OCC)(=O)C>[C:1]([C:4]1[C:19]([OH:20])=[CH:18][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]([OH:29])=[O:23])=[C:6]([CH2:21][CH3:22])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCc1cc(C(C)=O)c(O)cc1OCc1cccc(C#N)c1
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1cc(C(C)=O)c(O)cc1OCc1cccc(C(=O)O)c1

Procedure:
A mixture of 1.5 % of 3-[(4-acetyl-5-hydroxy-2-ethylphenoxy)methyl]benzonitrile, 1.14 g of potassium hydroxide, 75 ml of ethanol and 75 ml of water was heated at reflux overnight. The mixture was acidified with hydrochloric acid and ettracted with ethyl acetate. The organic layer was extracted with 1 N sodium hydroxide. The base layer was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo providing 1.06 g of the desired title product, m.p.=161°-164° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([NH2:15])([CH3:14])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3]([C:4]1([CH3:14])[CH2:5][N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:25](=[O:27])[NH:15]1)=[O:16]
Reactant: COC(=O)C(C)(N)CNc1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1(C)CN(c2ccc(F)cc2)C(=O)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 145.2 %

Procedure:
A solution of 2-amino-3-(4-fluoro-phenylamino)-2-methyl-propionic acid methyl ester (282 mg, 1.25 mmol) in THF (10 mL) was treated with triethylamine (2.00 mL, 14.3 mmol) and cooled to 0° C. under argon. A solution of triphosgene (211 mg, 0.71 mmol) was added to the reaction dropwise and the mixture allowed to reach room temperature. After 1 hour, the mixture was diluted with DCM, washed with 1N HCl and the organic layers concentrated in vacuo. The resulting residue was purified by flash chromatography to afford the product (260 mg, 82%).
Reaction SMILES: N1C=CC=C[C:2]=1[CH2:7][C:8](=[O:10])[CH3:9].[N+:11]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)C=O)([O-:13])=[O:12].C([O-])(=O)C.[NH2+:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C1C=CC=CC=1>[N+:11]([C:14]1[CH:21]=[C:20]([C:29]2[CH:30]=[CH:31][N:26]=[CH:27][C:28]=2[CH2:9][C:8](=[O:10])[CH:7]=[CH2:2])[CH:19]=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: C1CC[NH2+]CC1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)Cc1ccccn1
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: C=CC(=O)Cc1cnccc1-c1cccc([N+](=O)[O-])c1

Procedure:
2.76 g (20 mmol) of 1-pyridyl-2-propanone and 3.066 g (20 mmol) of 3-nitrobenzaldehyde were dissolved in benzene. To this solution, 0.29 g (2.0 mmol) of piperidinium acetate was added, and the mixture was refluxed with application of heat for 6 hours for dehydration. The reaction mixture was washed with water, and dried over anhydrous sodium sulfate. The benzene contained in the reaction mixture was distilled off under reduced pressure and the remaining reaction product was chromatographed on a silica gel column, whereby the captioned compound was obtained. The yield was 4.5 g (87.9%).
Reaction SMILES: C([N:8]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:10]=[C:9]1[CH2:23][O:24][CH2:25][CH3:26])C1C=CC=CC=1.Cl>>[CH2:25]([O:24][CH2:23][C:9]1[NH:10][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]=1)[CH3:26]
Reactant: CCOCc1nc(C(=O)OCC)c(C(=O)OCC)n1Cc1ccccc1
Agent: Cl
Product: CCOCc1nc(C(=O)OCC)c(C(=O)OCC)[nH]1

Procedure:
Following a procedure similar to that described in Preparation 42(iv), but using 4.37 g of diethyl benzyl-2-ethoxymethylimidazole-4,5-dicarboxylate [prepared as described in step (i) above], 3.49 g of the hydrochloride of the title compound were obtained as crystals, melting at 60°-61° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:47])[C:32]([C:45]#[N:46])=[CH:33][C:34]3([NH:37]C(=O)OC(C)(C)C)[CH2:36][CH2:35]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:33][C:34]3([NH2:37])[CH2:36][CH2:35]3)[C:45]#[N:46])=[O:47])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C)OC(=O)NC1(C=C(C#N)C(=O)N2CCC[C@@H]2Cn2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC(=CC1(N)CC1)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reaction time: 5 h
Yield: 12.4 %

Procedure:
To a solution of tert-butyl N-[1-[3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-2-cyano-3-oxo-prop-1-enyl]cyclopropyl]carbamate (27 mg, 0.04 mmol) in DCM (3 mL) was added TFA (1 mL). The solution was stirred for 5 hrs. and then concentrated. The residue was purified by prep-TLC (5% MeOH/DCM) to provide 2.68 mg (12%) of the title compound. MS (pos. ion) m/z: 539 (M+1).
Reaction SMILES: C(O)(=O)C.[NH:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C@H:14]1[CH2:19][C@H:18]([NH:20][C:21]([C:23]2[CH:32]=[CH:31][C:26]3[O:27][CH2:28][CH2:29][O:30][C:25]=3[CH:24]=2)=[O:22])[CH2:17][CH2:16][NH:15]1.C(O[C:36]1(O[Si](C)(C)C)[CH2:38][CH2:37]1)C.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[NH:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C@H:14]1[CH2:19][C@H:18]([NH:20][C:21]([C:23]2[CH:32]=[CH:31][C:26]3[O:27][CH2:28][CH2:29][O:30][C:25]=3[CH:24]=2)=[O:22])[CH2:17][CH2:16][N:15]1[CH:36]1[CH2:38][CH2:37]1
Reactant: O=C(N[C@@H]1CCN[C@@H](c2nc3ccccc3[nH]2)C1)c1ccc2c(c1)OCCO2
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(N[C@@H]1CCN(C2CC2)[C@@H](c2nc3ccccc3[nH]2)C1)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
Acetic acid (0.075 mL, 1.3 mmol) was added to a solution of N-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide (50 mg, 0.13 mmol) in methanol (2 mL) and the then (1-ethoxycyclopropoxy)trimethylsilane (138 mg, 1.79 mmol) was added to the reaction solution and reaction mixture was stirred at room temperature for 10 min, then sodium cyanoborohydride (37 mg, 0.59 mmol) was added carefully. The reaction mixture was stirred at 50° C. 24 hours. Saturated sodium bicarbonate solution (10 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, dried over MgSO4, and concentrated. Product was purified by Companion (ReadySep, 12 g, silica gel packed) with CH3OH/CH2Cl2 from 1%-5% to give the named compound as a white solid 46 mg (85%). LC-MS: 419.2, 417.3 (t=1.7 min).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]([OH:13])[C@H:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[OH-].[Na+].C=O.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:23](Cl)=[O:24].[C:33](=O)(O)[O-].[Na+]>CC(C)=O>[C:4]1([CH:7]2[O:13][CH2:33][N:12]([C:23](=[O:24])[C:22]3[CH:21]=[C:20]([O:19][CH3:18])[C:28]([O:29][CH3:30])=[C:27]([O:31][CH3:32])[CH:26]=3)[CH:8]2[C:9]([OH:11])=[O:10])[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: N[C@H](C(=O)O)[C@H](O)c1ccccc1
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1cc(C(=O)N2COC(c3ccccc3)C2C(=O)O)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 21 h

Procedure:
DL-threo-3-Phenylserine hydrate (5.00 g, 27.6 mmol) and 2N NaOH (13.8 mL, 27.6 mmol) are combined and cooled in an ice-bath. Formaldehyde (2.24 g of a 37% aqueous solution) is added and the reaction mixture is stirred at 0° C. for 21 hours. A solution of 3,4,5-trimethoxybenzoyl chloride (6.36 g, 27.6 mmol) in acetone (20 mL) is added slowly using solid sodium bicarbonate to maintain the pH>7. After stirring for 1 hour the reaction mixture is poured onto water and extracted with ethyl acetate (3×50 mL). The aqueous solution is cooled in an ice-bath, the pH is adjusted to 1 with 1N HCl and the mixture is extracted with methylene chloride (3×100 mL). The combined methylene chloride extracts are washed with water, dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford the desired product as a white solid. CIMS: MH+ 388
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[CH3:17][O:15][C:14]([CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Yield: 83.7 %

Procedure:
To a room temperature solution of piperidine-1,3-dicarboxylic acid-1-tert-butyl ester (5.00 g, 21.81 mmol) in 20% MeOH/toluene (100 ml) was added 14.18 ml of (trimethylsilyl)diazomethane (2.0 M, 28.35 mmol) dropwise and the reaction was monitored by TLC until completion and then concentrated under reduced pressure to yield 4.44 g (83.7%) of piperidine-1,3-dicarboxylic acid 1-tert-butyl ester-3-methyl ester (Intermediate 53). 1H NMR (400 MHz, CDCl3) δ ppm 1.4 (s, 9H), 1.6 (d, J=3.4 Hz, 1H), 1.6 (m, 1H), 1.7 (m, 1H), 2.0 (m, 1H), 2.4 (m, 1H), 2.8 (m, 1H), 3.0 (s, 1 H), 3.7 (s, 3H), 3.9 (d, J=13.2 Hz, 1H), 4.1 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1C=[CH:15][CH2:14][CH2:13]1.C([Mg]Cl)(C)C.P(=O)(O)(O)O>ClCCl.CS(O)(=O)=O.O1CCCC1>[CH3:13][CH:14]([CH3:15])[C:9](=[O:11])[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1=COCC1
Reactant: O=C(O)CCc1ccccc1
Agent: CC(C)[Mg]Cl
Agent: CS(=O)(=O)O
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C(=O)CCc1ccccc1
Temperature: -60 °C
Reaction time: 4 h
Yield: 39.1 %

Procedure:
A mixture of 3-phenylpropionic acid (13.0 g, 86.6 mmol), 2,3-dihydrofuran (6.67 g, 95.2 mmol) and dichloromethane (90 ml) was cooled to −60° C., followed by adding thereto a solution of methanesulfonic acid (0.012 g, 0.13 mmol) in dichloromethane (1 ml). The reaction mixture was heated to −5° C. and stirred at this temperature for 4 hours. The reaction mixture was re-cooled to −60° C., followed by adding dropwise thereto isopropylmagnesium chloride (a 2M tetrahydrofuran solution; 48 ml, 95.2 mmol), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into a cooled aqueous phosphoric acid solution and extracted with chloroform. The extract solution was washed successively with water, a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography to obtain 5.97 g of 4-methyl-1-phenylpentan-3-one.
Reaction SMILES: [CH3:1][C:2]1([OH:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:10][CH2:11][Cl:12]>>[Cl:12][CH2:11][CH2:10][N:5]1[CH2:6][CH2:7][C:2]([CH3:1])([OH:8])[CH2:3][CH2:4]1
Reactant: ClCCBr
Reactant: CC1(O)CCNCC1
Product: CC1(O)CCN(CCCl)CC1

Procedure:
4-methylpiperidin-4-ol (made via literature methods) and 1-bromo-2-chloroethane are reacted using the procedure for Example OO to afford 1-(2-chloroethyl)4-methylpiperidin-4-ol.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][C:19]=3[F:25])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:26](C#N)#[N:27].N1C=CC=CC=1.CN1CCCC1=O>Cl>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:26]#[N:27])=[CH:20][C:19]=3[F:25])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](CCc2ccc(-c3ccc(Br)cc3F)cc2)CC1
Reactant: N#CC#N
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: CCC[C@H]1CC[C@H](CCc2ccc(-c3ccc(C#N)cc3F)cc2)CC1

Procedure:
A mixture of 38.4 g of 1-(trans-4-n-propylcyclohexyl)-2-(4'-bromo-2'-fluorobiphenyl-4-yl)-ethane (M.p. 61.1°, C.p. 114.7°), 10 g of Cu2 (CN)2, 120 ml of pyridine and 60 ml of N-methylpyrrolidone is heated at 160° for 2 hours. The mixture is cooled, a solution of 120 g of FeCl3.6H2O in 600 ml of 20% hydrochloric acid is added and the mixture is warmed at 70° for 1.5 hours, with stirring, and worked up in the customary manner to give 1-(trans-4-n-propylcyclohexyl)-2-(4'-cyano-2'-fluorobiphenyl-4-yl)-ethane, M.p. 89.4°, C.p. 168.4°.
Reaction SMILES: [C:1]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][S:17]([C:20]3[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=2[N:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH:27]([N:30]([CH:34]([CH3:36])[CH3:35])[CH2:31][CH2:32][NH2:33])([CH3:29])[CH3:28].[ClH:37]>CN1CCCC1=O.C(OCC)(=O)C.O1CCOCC1>[ClH:37].[C:1]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([NH:33][CH2:32][CH2:31][N:30]([CH:34]([CH3:36])[CH3:35])[CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=2[N:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)N(CCN)C(C)C
Reactant: CCCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(NCCN(C(C)C)C(C)C)cc3)cc2s1
Temperature: 150 °C
Yield: 28 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-butyrylaminobenzothiazol-6-yl ester (intermediate 78) (100 mg, 0.2 mmol) and N,N-diisopropylethylene-diamine (185 μl, 1.01 mmol) in 3 ml of N-methylpyrrolidone in a 5 ml microwave vial, equipped with a magnetic bar, is heated for 10 minutes at 150° C. by microwave. The reaction medium is extracted with ethyl acetate and washed with water. The organic phase is dried over magnesium sulfate, filtered and then evaporated to dryness. The residue obtained is purified by chromatography on Merck silica (40-63 μm). After evaporating off the solvent, 41 mg of a colorless oil (crystallizes when dry) are obtained. The product is dissolved in a minimum amount of ethyl acetate, and 4 N hydrochloric acid as a solution in dioxane is then added. The medium precipitates, and is concentrated, taken up in water and then filtered through a Milex 45 μm filter. The solution precipitates, and 31 mg (28% yield) of 4-(2-diisopropylamino-ethylamino)benzenesulfonic acid 2-butyrylaminobenzothiazol-6-yl ester hydrochloride are obtained after vacuum filtration and then drying under vacuum at 40° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:14]([CH3:34])=[C:13]([CH3:35])[N:12]=1.[O-]C1C=CC=CC=1.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:35][C:13]1[C:14]([CH3:34])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1
Reactant: Oc1ccccc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOCCNC(=O)OC(C)(C)C)c1C
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCOCCNC(=O)OC(C)(C)C)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
Phenol (5.33 g, 56.63 mmol) was added in small portions over a period of 10 minutes to a chilled (0°) suspension of sodium hydride (2.39 g of 60%, 59.75 mmol) in anhydrous tetrahydrofuran (100 mL). After the addition was complete, the reaction was allowed to stir at 0° for 30 minutes. A solution tert-butyl 2-{2-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]ethoxy}ethylcarbamate (20.67 g, 53.16 mmol) in tetrahydrofuran (100 mL) was added over a period of 1 hour while maintaining the temperature at 0° C. The ice bath was removed and the reaction mixture was heated to reflux. At 46 and 52 hours additional fresh sodium phenoxide (11.3 mmol) was added. Refluxing was continued for 2 hours after the second addition. The reaction mixture was diluted with ethyl acetate (500 mL); washed sequentially with water (3×100 mL), 1N sodium hydroxide (2×100 mL), and brine; dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (450 g of silica gel eluting with 1/1 hexanes/ethyl acetate) to provide 19.85 g of tert-butyl 2-{2-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]ethoxy}ethylcarbamate.
Reaction SMILES: [I:1]I.[CH3:3][C:4]1([CH3:10])[CH2:8][C:7](=[O:9])[CH:6]=[CH:5]1>C(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.CCOCC>[CH3:3][C:4]1([CH3:10])[CH2:8][C:7](=[O:9])[C:6]([I:1])=[CH:5]1
Reactant: II
Reactant: CC1(C)C=CC(=O)C1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)C=C(I)C(=O)C1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a cold (4° C.) solution of iodine (4.5 g, 18 mmol) in carbon tetrachloride (15 mL) and pyridine (15 mL), was added over 1 min. a solution of 4,4-dimethyl-2-cyclopenten-1-one (930 mg, 8.4 mmol) in carbon tetrachloride (15 mL) and pyridine (15 mL). The resulting red-brown solution was stirred at r.t. for 22 h. The reaction was diluted with Et2O (200 mL), washed successively with water (50 mL), 1.0 N HCl (50 mL), water (50 mL), and aqueous Na2S2O5 20% w/v, then dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography eluting with 10% EtOAc/hexanes to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][N:17]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].CN(C1C=CC=CN=1)C.C(N(CC)C(C)C)(C)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1.C(OCC)(=O)C>[C:36]([NH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][N:17]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1)c1ccnc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 14 %

Procedure:
To a solution of 2-amino-N-benzylisonicotinamide (0.23 g, 0.43 mmol), dimethylaminopyridine (0.01 g, 0.08 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.7 mmol) in tetrahydrofuran (10 mL) at 0° C. was added benzoyl chloride (0.12 mL, 1.00 mmol). The resulting solution was warmed to ambient temperature and stirred for 18 hours, diluted with ethyl acetate (30 mL), washed with water (20 mL) and brine (20 mL). The organic solution was dried over anhydrous sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography to give 2-benzamido-N-benzylisonicotinamide (0.02 g, 15%): mp 174-176° C.; 1H NMR (300 MHz, CDCl3) δ 8.86 (br s, 1H), 8.72 (s, 1H), 8.38 (d, J=5.1 Hz, 1H), 7.91-7.82 (m, 2H), 7.60-7.32 (m, 9H), 6.73 (br s, 1H), 4.64 (d, J=5.7 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 165.9, 165.0, 151.9, 148.3, 144.4, 137.4, 133.5, 132.7, 129.0, 128.8, 128.0, 127.8, 127.2, 118.6, 110.5, 44.3; MS (ES+) m/z 332.5 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](OS(C(F)(F)F)(=O)=O)=[C:6]2[C:11]=1[O:10][CH2:9][C@H:8]([N:12]([CH:16]([CH3:18])[CH3:17])[CH2:13][CH2:14][CH3:15])[CH2:7]2.C(N(CC)CC)C.CN([CH:37]=[O:38])C.[CH3:39][OH:40]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]([O:38][CH3:37])=[O:40])=[C:6]2[C:11]=1[O:10][CH2:9][C@H:8]([N:12]([CH:16]([CH3:18])[CH3:17])[CH2:13][CH2:14][CH3:15])[CH2:7]2
Reactant: CCCN(C(C)C)[C@H]1COc2c(F)ccc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: CN(C)C=O
Reactant: CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCN(C(C)C)[C@H]1COc2c(F)ccc(C(=O)OC)c2C1
Temperature: 70 °C
Reaction time: 7.5 h
Yield: 71 %

Procedure:
(R)-8-Fluoro-3-(N-isopropyl,N-propylamino)-5-trifluoromethanesulfonyloxychroman (2.4 g, 6.0 mmol), triethylamine (1.3 g, 12.9 mmol), 1,3-bis(diphenylphosphino)propane (95 mg, catalytic amount), palladium(II)acetate (48 mg, catalytic amount) and DMF/MeOH (30 mL, 3:1) were mixed in a 50 mL three necked round bottom flask. The flask was evacuated followed by the inlet of CO (repeated two times). The reaction mixture was stirred at 70° C. for 7.5 hours. The solvent was removed in vacuo and the residue was dissolved in diethyl ether/sat=NaHCO3. The layers were separated and the water phase was extracted once with ether. The combined ether layers were dried (MgSO4) and the solvent was removed in vacuo to give a crude which was purified by flash chromatography (SiO2, hexane/EtOAC, 9:1) to give 1.3 g of the title compound (71% yield).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][NH2:19])=[O:17])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:20](O)(=O)C.C(N)=N.O>CN(C)C=O>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH:20]=[N:19][NH:18][C:16]2=[O:17])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(NC(=O)NN)cc1
Reactant: CC(=O)O
Agent: N=CN
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(-n2cn[nH]c2=O)cc1

Procedure:
N-(4-octylphenyl)-N'-aminourea, Formamidine acetate (12.76 g) and N-carbazoyl-4-octylaniline (6.458 g) in N,N-dimethylformamide (19.4 ml) were stirred at 150° C. for 6 hours. The reaction mixture was pulverized with water. The precipitate was collected by filtration and washed with water to give 4-(4-Octylphenyl)-2,3-dihydro-4H-1,2,4-triazol-3-one (4.27 g).