Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH2:5][CH:4]=[CH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32](Cl)=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30].Cl.C(OCC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[ClH:23].[N:1]1([CH2:6][C:7]2([C:32](=[O:33])[CH2:31][C:26]3[CH:27]=[CH:28][C:29]([Cl:30])=[C:24]([Cl:23])[CH:25]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: C1=CCN(CC2NCCc3ccccc32)C1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(Cc1ccc(Cl)c(Cl)c1)C1(CN2CC=CC2)NCCc2ccccc21
Yield: 85.1 %

Procedure:
Prepared as Example No. 1 from 1.44 g (6.73 mmoles) of 1-(3-pyrrolin-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline, 1.8 g (13.05 mmoles) of anhydrous potassium carbonate and 1.8 g (8.05 mmoles) of 3,4-dichlorophenylacetyl chloride in 50 ml of dry chloroform. The work-up of the reaction mixture afforded 1.9 g of the crude product which was dissolved in 60 ml of ethyl acetate and the solution brought to acidic pH with HCl/diethyl ether. The precipitate was filtered, washed and dried, to yield 1.5 g of the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(F)(F)F.OP(O)(O)=O>ClCCl>[C:1]1([C:7]2([C:16]3[CH:17]=[CH:18][C:13]([OH:19])=[CH:14][CH:15]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=C(c2ccccc2)CCCC1
Reactant: Oc1ccccc1
Agent: FB(F)F
Agent: O=P(O)(O)O
Solvent: ClCCl
Product: Oc1ccc(C2(c3ccccc3)CCCCC2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1-Phenyl-1-cyclohexene (1 g, 6.3 mmol), phenol (1.5 g, 15.9 mmol) and BF3.H3PO4 (0.05 mL) were mixed and shaken at 80° C. overnight. Dichloromethane (30 mL) was added and the organic phase was washed with saturated NaHCO3 (aq.) (2×10 mL), dried (Na2SO4) and concentrated. The title compound was crystallised from a mixture of methanol and water. Yield: 1040 mg. 1H NMR (400 MHz, CDCl3): d 7.28-7.25 (m, 4H), 7.16-7.10 (m, 3H), 6.75-6.70 (m, 2H), 4.51 (br. s, 1H), 2.28-2.22 (m, 4H), 1.60-1.52 (m, 4H), 1.52-1.45 (m, 2H). 13C NMR (100 MHz, CDCl3): d 153.25, 149.15, 141.22, 128.63, 128.39, 127.29, 125.55, 115.21, 45.89, 37.50, 26.63, 23,14. LC-MS purity (UV/MS): 100/100%, R. 5.07 min, M−1: 251.62.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[O:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:24][O:23][C:22]1[C:17]2[O:16][CH:15]=[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)[C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc2c(C3=CCN(C(=O)OC(C)(C)C)CC3)coc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c(C3=CCNCC3)coc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a solution of 4-(7-methoxy-benzofuran-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.50 g, 1.5 mmol) in methylene chloride (10 mL), was added drop wise a solution of TFA (1 mL) in methylene chloride (5mL). The reaction was stirred at room temperature for one hour, then was diluted with 250 mL of methylene chloride, washed with 1N NaOH (100 mL) and with saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum to give 0.30 g of the title compound. 1H NMR (300 MHz, CDCl3); δ 2.5 (t, 2H), 3.19 (t, 2H), 3.64 (dd,2H), 4.01 (s, 3H), 6.30 (br s, 1H), 7.10 (d, 1H), 7.21 (t, 1H), 7.52 (d, 1H), 7.64 (s, 1H); MS (ES) m/z (relative intensity): 230 (M+H,100).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[Se:10][C:6]=2[N:5]=[CH:4][N:3]=1.[CH3:15][S:16][C:17]1[S:18][C:19]([N+:23]([O-:25])=[O:24])=[C:20]([NH2:22])[N:21]=1.[OH-].[Na+]>CN(C=O)C>[CH3:15][S:16][C:17]1[S:18][C:19]([N+:23]([O-:25])=[O:24])=[C:20]([NH:22][C:2]2[C:7]3[C:8]4[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=4[Se:10][C:6]=3[N:5]=[CH:4][N:3]=2)[N:21]=1
Reactant: Clc1ncnc2[se]c3c(c12)CCCC3
Reactant: CSc1nc(N)c([N+](=O)[O-])s1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CSc1nc(Nc2ncnc3[se]c4c(c23)CCCC4)c([N+](=O)[O-])s1

Procedure:
To a solution of 4-chloro-5,6,7,8-tetrahydrobenzo[1,2-b]pyrimidino[5,4-d]selenophene (420 mg, 1.57 mmol) in DMF (8 mL) was added sequentially 2-(methylthio)-5-nitrothiazol-4-amine (300 mg, 1.57 mmol) and powdered NaOH (180 mg, 4.71 mmol) at rt. Work-up as described in example 2, gave the product as a yellow color solid, mp 204-206° C. 1H NMR (400 MHz, CDCl3): δ 10.52 (1H, s, exchangeable with D2O, —NH), 8.73 (1H, s, H-2), 3.11 (2H, t, J=5.2 Hz, H-8), 2.98 (2H, t, J=5.0 Hz, H-5), 2.75 (3H, s, —SCH3), 1.92-1.98 (4H, m, H-6,7); 13C NMR (100 MHz, CDCl3): δ 176.9, 173.7, 152.2, 151.6, 151.1, 150.9, 142.7, 127.4, 124.1, 28.4, 28.0, 22.8, 22.5, 16.1; LC-MS (positive ion mode): m/z 426, 428 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([OH:16])[C:8]#[C:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.C(Cl)C1C=CC=NC=1.[O:32]1CCC[CH2:33]1>>[C:33]([O:16][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[C:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])(=[O:32])[C:19]1[CH:20]=[CH:21][CH:22]=[N:17][CH:18]=1
Reactant: CCN(CC)CC#CC(O)c1ccccc1
Reactant: c1ccncc1
Reactant: C1CCOC1
Agent: Cl
Agent: ClCc1cccnc1
Product: CCN(CC)CC#CC(OC(=O)c1cccnc1)c1ccccc1
Yield: 46.6 %

Procedure:
Dissolved in anhydrous tetrahydrofuran was 2.17 g of N-(4-phenyl-4-hydroxy-2-butynyl)-N,N-diethylamine, followed by an addition of 4 ml of pyridine. Then, 1.78 g of nicotinyl chloride hydrochloride was added at room temperature little by little. The resultant mixture was thereafter reacted at the same temperature for 4 hours. After the reaction, the solvent was distilled off under reduced pressure and the residue was taken up in chloroform. The resultant chloroform solution was washed with water and was then dried over anhydrous sodium sulfate. The chloroform was distilled off under reduced pressure and the residue was purified by column chromatography (silica gel) to obtain 1.5 g of the intended product as a light yellowish oily substance (yield: 46.6%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O.C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10](=[CH:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][C:25](=[O:27])[CH3:26])=[CH:18][CH:19]=2)[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)Oc1ccc(C=C(C(=O)O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 60 °C

Procedure:
p-Nitrophenylacetic acid (94.02 grams, 0.519 mole) and 1.038N sodium hydroxide solution (500 mL) are added to a 1,000 mL beaker and heated with stirring to 60° C. The resultant solution is rotary evaporated under vacuum until final conditions of 110° C. and 1 mm Hg are achieved and maintained for 30 minutes. A portion (101.6 grams, 0.50 mole) of the resultant dry white carboxylic acid sodium salt, p-hydroxybenzaldehyde (61.06 grams, 0.50 mole) and acetic anhydride (250 grams) are added to a reactor equipped with a reflux condenser and stirred under a nitrogen atmosphere at a 147° C. reflux. Refluxing continued over the next twenty hours at which time the temperature has increased to 159° C. At this time, the reactor is cooled to 100° C. and ethanol (300 mL) and water (50 mL) are added. The resultant slurry is boiled at 89° C. for one hour followed by cooling to 50° C. and filtration. The filtrate is added to deionized water (1500 mL) and the resultant precipitate recovered by filtration. The precipitate is exhaustively extracted with deionized water saturated with sodium carbonate. The combined extracts are filtered then neutralized with concentrated hydrochloric acid inducing formation of a precipitate. The precipitate is recovered by filtration then dried at 50° C. in a forced air convection type oven. The dry powder is added to a beaker along with carbon tetrachloride (200 mL) then stirred with heating to a boil. Acetic acid (40 mL) is added to the boiling slurry then heating back to a boil resumed. After boiling is achieved, the slurry is maintained at 4° C. for 15 hours. The precipitate is recovered by filtration and dried at 70° C. under a vacuum of 5 mm Hg to a constant weight of 38.55 grams of brilliant light yellow colored crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:11]=[C:4]2[N:3]=1.[NH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)CC)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:5]2[N:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:11]=[C:4]2[N:3]=1
Reactant: CCOC(=O)c1cc2nc(Cl)cc(Cl)n2n1
Reactant: NC1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2nc(Cl)cc(NC3CCOCC3)n2n1
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
To a solution of ethyl 5,7-dichloropyrazolo[1,5-a]pyrimidine-2-carboxylate (7.82 g, 30.1 mmol) in N,N-dimethylformamide (100 mL) was added 4-amino-tetrahydropyran (3.65 g, 36.1 mmol) and triethylamine (9.12 g, 90.2 mmol) at 0° C. The reaction mixture was stirred for 70 min at room temperature, and then pored into water. The resulting precipitate was collected to give ethyl 5-chloro-7-(tetrahydro-2H-pyran-4-ylamino)pyrazolo[1,5-a]pyrimidine-2-carboxylate. MS (APCI): m/z 325 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[NH2:8])([CH3:4])([CH3:3])[CH3:2].C([CH:17]([Cl:22])[CH2:18][N:19]=[C:20]=[O:21])C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:20]([NH:19][CH2:18][CH2:17][Cl:22])=[O:21])[CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(I)cc(N)cc1C(C)(C)C
Reactant: CCC(Cl)CN=C=O
Product: COc1c(I)cc(NC(=O)NCCCl)cc1C(C)(C)C

Procedure:
3-tert-Butyl-5-iodo-4-methoxyaniline (305 mg, 1 mmol) and ethyl 2-chloroethyl isocyanate (0.085 mL, 1.000 mmol) were reacted in the same manner as Example 15 Part A to give the title compound which was used without purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C@@H:27]([NH:32][C:33]([C:35]4[O:36][C:37]([C:40]5[CH:45]=[CH:44][C:43]([CH:46]([CH3:48])[CH3:47])=[CH:42][CH:41]=5)=[CH:38][CH:39]=4)=[O:34])[C:28]([O:30]C)=[O:29])=[CH:22][C:21]=3[F:49])[N:16]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.C(C1C=CC(C2C=COC=2C(O)=O)=CC=1)(C)C.C(Cl)(=O)C.C(OC(=O)C(N)CC1C=CC(C2N=C(C3C=CC(NC(OC(C)(C)C)=O)=CC=3)ON=2)=C(F)C=1)C>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C@@H:27]([NH:32][C:33]([C:35]4[O:36][C:37]([C:40]5[CH:45]=[CH:44][C:43]([CH:46]([CH3:47])[CH3:48])=[CH:42][CH:41]=5)=[CH:38][CH:39]=4)=[O:34])[C:28]([OH:30])=[O:29])=[CH:22][C:21]=3[F:49])[N:16]=2)=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](Cc1ccc(-c2noc(-c3ccc(NC(=O)OC(C)(C)C)cc3)n2)c(F)c1)NC(=O)c1ccc(-c2ccc(C(C)C)cc2)o1
Agent: CC(C)c1ccc(-c2ccoc2C(=O)O)cc1
Agent: CCOC(=O)C(N)Cc1ccc(-c2noc(-c3ccc(NC(=O)OC(C)(C)C)cc3)n2)c(F)c1
Solvent: O=S(Cl)Cl
Solvent: CC(=O)Cl
Product: CC(C)c1ccc(-c2ccc(C(=O)N[C@H](Cc3ccc(-c4noc(-c5ccc(NC(=O)OC(C)(C)C)cc5)n4)c(F)c3)C(=O)O)o2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)-methyl 3-(4-(5-(4-((tert-butoxycarbonyl)amino)phenyl)-1,2,4-oxadiazol-3-yl)-3-fluorophenyl)-2-(5-(4-isopropylphenyl)furan-2-carboxamido)propanoate. Thionyl chloride (5 mL) was added to p-isopropylphenyl-furan-2-carboxylic acid (1.7 g, 7.23 mmol) and the mixture was heated under reflux for 10 min. After removal of excess thionyl chloride under vacuum, the resulting acetyl chloride was added to the mixture of 2-amino-3-{4-[5-(4-tert-butoxycarbonylamino-phenyl)-[1,2,4]oxadiazol-3-yl]-3-fluorophenyl}-propionic acid ethyl ester (3 g, 6.58 mmol), disopropylethylamine (1.3 g, 9.87 mmol) and the mixture was stirred for 30 min at room temperature. The mixture was partitioned between EtOAc and water. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was chromatographed on silica gel to give the title compound as a yellow solid (2.94 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][C@@H:19]1[CH2:24][CH2:23][C@H:22]([CH2:25][OH:26])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Si:11]([O:18][C@@H:19]1[CH2:20][CH2:21][C@H:22]([CH:25]=[O:26])[CH2:23][CH2:24]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](CO)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](C=O)CC1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
16.4 g (129.47 mmol) oxalyl chloride are dissolved in 600 ml of dichloromethane and cooled to −78° C. 20.2 g (258.95 mmol) of dimethyl sulfoxide are then slowly added dropwise. The mixture is stirred for 5 min. After addition of a solution of 21.1 g (86.32 mmol) of the compound from Example 53A in 200 ml of dichloromethane the mixture is stirred at −78° C. for 1 h. 60 ml (431.58 mmol) of triethylamine are then slowly added dropwise. Over a period of one hour, the reaction mixture is then warmed to RT, and 500 ml of saturated aqueous sodium bicarbonate solution are then added. The phases are separated, the organic phase is dried over sodium sulfate and the solvent is removed on a rotary evaporator. The residue is purified chromatographically on silica gel 60 (mobile phase: gradient petroleum ether→petroleum ether/ethyl acetate 9:1).
Reaction SMILES: C(O[C:6](=[O:22])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[C:11]([CH:20]=[CH2:21])[CH:10]=1)(C)(C)C.C(N(CC)CC)C.[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>C(#N)C>[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:36][C:6](=[O:22])[NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[C:11]([CH:20]=[CH2:21])[CH:10]=2)=[CH:33][CH:32]=1
Reactant: C=Cc1cc(CNC(=O)OC(C)(C)C)ccc1NS(C)(=O)=O
Reactant: NCc1ccc(Cl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=Cc1cc(CNC(=O)NCc2ccc(Cl)cc2)ccc1NS(C)(=O)=O
Yield: 14.9 %

Procedure:
As described in scheme 12, (4-methanesulfonylamino-3-vinylbenzyl)carbamic acid t-butylester (50 mg, 0.153 mmol) and triethylamine (0.1 ml) and 4-chlorobenzylamine (26 mg) were stirred for one night in the presence of acetonitrile solvent. The solvent was removed from the reaction mixture and purified by column chromatography to yield the purposed compound (9 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH2:9][N:10]([C:11]([O:13]C(C)(C)C)=[O:12])[C:4]=2[CH:3]=1.[Li][CH2:25][CH2:26][CH2:27][CH3:28].[OH2:29]>C1COCC1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH:9]3[CH:28]([C:27]4[CH:23]=[CH:2][C:3]([CH2:4][C:5]([OH:6])=[O:29])=[CH:25][CH:26]=4)[O:13][C:11](=[O:12])[N:10]3[C:4]=2[CH:3]=1
Reactant: O
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(C2OC(=O)N3c4cc(Cl)ccc4Oc4ccccc4C23)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A stirring solution of 1 (2.0 g, 6.04 mmol) in 40 mL of THF was cooled to -78° C. followed by the addition of n-BuLi (1.6M, 4.32 mL, 6.91 mmol). The mixture was stirred at -78° C. for 30 minutes and treated with methyl 4-formyl benzoate (1.2 g, 7 mmol), and then slowly warmed to room temperature and let stir for 1.5 hours at room temperature, and then diluted with 16 mL of water. The mixture was then extracted with ethyl acetate (200 mL×2) and the combined extracts were washed with brine (saturated, 200 mL) and dried (Na2SO4). The extracts were concentrated to give the crude product (2.95g), which was purified by medium pressure chromatography with 1:4 EtOAc:Hexane, to yield 16 and 17 as follows:
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:12]C2C=CC=CC=2)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.O.Cl.[NH3:21]>C(Cl)Cl>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]2)=[C:4]([C:4]2[C:3]([NH2:12])=[C:2]([CH3:1])[CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][CH:8]=[CH:9]3)[C:3]=1[NH2:21]
Reactant: N
Reactant: Cc1cc2ccccc2cc1Nc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: Cc1cc2ccccc2c(-c2c(N)c(C)cc3ccccc23)c1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
At 50° C., 3.1 g (20 mmol) of 3-methyl-2-naphthylamline, 6.5 g (40 mmol) of FeCl3 and 80 mL of H2O were stirred for 2 hours. To the reaction mixture was added 2 mL of concentrated hydrochloric acid at room temperature. The mixture was stirred at room temperature for 10 minutes. To the reaction mixture were added 20 mL of methylene chloride and 20 mL of a saturated aqueous ammonia solution. After vigorous stirring at room temperature, the reaction mixture was filtered over Celite and the filtrate was washed with methylene chloride. The organic layer was concentrated by distilling off the solvent under reduced pressure. The residue was purified by Florisil (trade name) and then by chromatography on a silica gel column (hexane/ethyl acetate=4/1 to 3/1). By recrystallization from hexane-chloroform, 0.76 g (yield: 24%) of 3,3′-dimethyl-1,1′-binaphthyl-2,2′-diamine was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][NH:11][CH2:10][C@@:9]2([N:14]([CH3:25])[C:15](=[O:24])[O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH3:13])=[CH:4][CH:3]=1.[C:26]([N:31]1[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33][CH2:32]1)(=[O:30])[CH:27]([CH3:29])[CH3:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][C:15](=[O:24])[N:14]([C@:9]2([CH3:13])[C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:12][N:11]([C:37]([CH:34]3[CH2:33][CH2:32][N:31]([C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH2:36][CH2:35]3)=[O:38])[CH2:10]2)[CH3:25])=[CH:22][CH:21]=1
Reactant: CC(C)C(=O)N1CCC(C(=O)O)CC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@]1(C)CNC[C@@H]1c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)N1CCC(C(=O)N2C[C@H](c3ccc(Cl)cc3)[C@@](C)(N(C)C(=O)Oc3ccc(F)cc3)C2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 34 mg (0.093 mmol) rac-4-fluorophenyl (3R,4S)-4-(4-chlorophenyl)-3-methylpyrrolidin-3-yl(methyl)carbamate, 14.9 mg (0.075)mmol 1-isobutyrylpiperidine-4-carboxylic acid, 34.2 (0.09 mmol) HATU and 58 mg (0.45 mmol) DIPEA in 2 mL DMF was shaken for 3 h at room temperature. The mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield after evaporation of the product containing fractions 26.8 (66%) of the title compound as light yellow viscous oil. MS m/e: 544.2 [M+H]+.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C([N:14](CC)CC)C.[C:19](Cl)(=[O:28])[C:20]1[C:21]([O:26][CH3:27])=[CH:22][CH:23]=[CH:24][CH:25]=1.Cl.C(N(CC)CC)C>C1COCC1>[C:19]([C:2]1[C:10]([NH2:14])=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])(=[O:28])[C:20]1[C:21]([O:26][CH3:27])=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: CCN(CC)CC
Reactant: NC(=O)c1cc(Br)ccc1N
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)c1c(N)cc(Br)cc1C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.2 %

Procedure:
To a solution of 2-amino-5-bromo-benzamide (29.2 g, 136 mmol) and triethylamine (25.0 mL, 173 mmol) in THF (500 mL) was added dropwise o-anisoyl chloride (24.0 g, 140 mmol). Stirring at room temperature was continued for 3 h, after which the formed precipitate was filtered and washed once with THF and twice with dichloromethane yielding 2-(o-anisoyl)-amino-5-bromo-benzamide (51.4 g, 84%) with 1 equivalent of triethylamine hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O.[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH2:15][CH3:16])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(CC(=O)O)cc1O
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1ccc(OC)c(O)c1

Procedure:
The stirred solution of 2-(3-Hydroxy-4-methoxyphenyl)acetic acid (9.82 g, 53.90 mmol) and p-Toluenesulfonic acid monohydrate (1.15 g, 6.0 mmol) in abs ethanol (100 ml) was refluxed for 4 hours or until all the starting material is consumed. The reaction mixture was concentrated, diluted with ethyl acetate and washed with 1M HCl. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 2:1) to give the title compound.
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:14][CH2:15][CH3:16])[C:5]1=[O:6])[CH2:2][CH3:3].[OH:17][C:18]1[N:23]=[N:22][C:21]([C:24](O)=O)=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC.O>CO>[CH2:14]([N:7]1[C:8](=[O:9])[C:10]2[NH:13][C:24]([C:21]3[N:22]=[N:23][C:18]([OH:17])=[CH:19][CH:20]=3)=[N:12][C:11]=2[N:4]([CH2:1][CH2:2][CH3:3])[C:5]1=[O:6])[CH2:15][CH3:16]
Reactant: O=C(O)c1ccc(O)nn1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCn1c(=O)c2[nH]c(-c3ccc(O)nn3)nc2n(CCC)c1=O
Temperature: 25 °C

Procedure:
To a solution of 1,3-dipropyl-5,6-diaminouracil (2.2 mmol) in methanol was added an equimolar amount of 6-hydroxy-pyridazine-3-carboxylic acid, followed by a slight excess of DCl ((N-(3-(dimethylamino)propyl)-N′ethylcarbodiimide hydrochloride). The mixture was stirred at room temperature for 4–5 hours until complete by TLC. Water was then added and the precipitate removed by filtration. The solid was dissolved in 10% aqueous NaOH (20 mL), then heated at 70° C. for 30 minutes. After cooling to room temperature, the reaction mixture was acidified to pH=5 with 10% hydrochloric acid and the precipitated product collected by filtration.
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][NH:16][C:17](=[NH:20])SC)[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[N:21]#[C:22][NH2:23].O.C(OCC)(=O)C>CN(C)C=O>[N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][NH:16][C:17]([NH2:20])=[N:23][C:22]#[N:21])[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: CSC(=N)NCc1ccc2c(c1)Nc1nccnc1S2
Reactant: N#CN
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#CN=C(N)NCc1ccc2c(c1)Nc1nccnc1S2
Yield: 77.1 %

Procedure:
450 mg of N-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-S-methylisothiourea and 500 mg of cyanamide were heated in 30 ml of N,N-dimethylformamide to 70° C. for 12 hours. Then the reaction mixture was brought back to room temperature and distributed into water and ethyl acetate. The organic layer was extracted and washed with water. After adding 5 g of silica gel, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol/aqueous ammonia) to thereby give 340 mg of the title compound as yellow crystals.