Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:29]=[CH:28][C:27]([CH2:30][C:31]([NH2:33])=[O:32])=[C:26]([NH:34][CH2:35][C:36]4[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([F:43])[CH:37]=4)[CH:25]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=O)(C)(C)C.Cl.C(OCC)(=O)C>C(Cl)(Cl)Cl>[NH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:29]=[CH:28][C:27]([CH2:30][C:31]([NH2:33])=[O:32])=[C:26]([NH:34][CH2:35][C:36]4[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([F:43])[CH:37]=4)[CH:25]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NCCN1CCN(c2ccc(Nc3cc(NCc4cc(F)cc(F)c4)c(CC(N)=O)cn3)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: NCCN1CCN(c2ccc(Nc3cc(NCc4cc(F)cc(F)c4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
18 mg of 6-[(4-{4-[2-(tert-butoxycarbonyl)aminoethyl]piperazin-1-yl}phenyl)amino]-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide (the compound of Example 247) was dissolved in 0.5 mL of chloroform, to which, under ice cooling, 0.5 mL of 4 mol/L hydrochloric acid-ethyl acetate was added, and stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified by silica gel thin layer chromatography (chloroform:ammonia methanol=10:1) to obtain 15 mg (95%) of the title compound as a slight yellow crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.ClC(Cl)C.[F:18][C:19]([F:34])([F:33])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]([CH:31]=O)[O:29][CH:30]=2)=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:34][C:19]([F:18])([F:33])[C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[C:28]([CH2:31][NH:1][C:2]3[CH:3]=[CH:4][C:5]([C@@H:8]4[CH2:10][C@H:9]4[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=3)[O:29][CH:30]=2)=[CH:24][CH:25]=1
Reactant: Nc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Reactant: O=Cc1cc(-c2ccc(C(F)(F)F)cc2)co1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2cc(-c3ccc(C(F)(F)F)cc3)co2)cc1
Reaction time: 7 h
Yield: 111 %

Procedure:
A mixture of racemic-(trans)-2-(4-aminophenyl)cyclopropanecarboxylic acid (I-1) (0.060 g, 0.339 mmols) and dichloroethane was heated slightly and allowed to cool before addition of 4-[4-(trifluoromethyl)phenyl]-2-furancarbaldehyde (0.075 g, 0.312 mmols). The mixture was stirred for 7 h, followed by addition of sodium triacetoxyborohydride (0.104 g, 0.491 mmols). After 12 h, the mixture was partitioned between water and CH2Cl2 (10 mL each). The aqueous phase was extracted with CH2Cl2 (1×10 mL). The combined organics were dried with MgSO4 and concentrated to give the title compound as a yellow solid (0.139 g, quant). 1H NMR (400 MHz, DMSO-d6): δ 12.01 (s, 1H), 8.23 (s, 1H), 7.75 (d, J=8.24 Hz, 2H), 7.68 (d, J=8.42 Hz, 2H), 6.85 (d, J=8.42 Hz, 2H), 6.81 (s, 1H), 6.56 (d, J=8.61 Hz, 2H), 6.05 (t, J=5.95 Hz, 1H), 4.22 (d, H=5.86 Hz, 2H), 2.18 (m, 1H), 1.58 (m, 1H), 1.27 (m, 1H), 1.16 (m, 1H). APCI m/z 399.93 (MH−).
Reaction SMILES: C(Cl)[Cl:2].O.[CH3:5][NH:6][C@@H:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C@H:10]([C:17]2[CH:18]=[CH:19][C:20]([Cl:24])=[C:21]([Cl:23])[CH:22]=2)[CH2:9][CH2:8]1.C([O-])(=O)C(C1C=CC=CC=1)O.[OH-].[Na+]>C(O)(C)C>[CH3:5][NH:6][C@@H:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C@H:10]([C:17]2[CH:18]=[CH:19][C:20]([Cl:24])=[C:21]([Cl:23])[CH:22]=2)[CH2:9][CH2:8]1.[ClH:2]
Reactant: ClCCl
Agent: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: O=C([O-])C(O)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cl
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a 12 liter, 3 neck round-bottom flask equipped with mechanical stirrer, 4287ml of methylene chloride, 2553ml water and 638.3gms sertraline mandelate were combined. A 10% sodium hydroxide solution, 383ml, was then added and the resulting two clear layers were separated. The aqueous layer was further extracted with 2×586ml of methylene chloride. The combined methylene chloride layers were washed with 2×1110ml water and separated. The methylene chloride solution was atmospherically distilled and displaced with isopropanol to a final volume of 4440ml. 53.7ml water were added to the resulting isopropanol solution. The solution was cooled to 50° C. and seeded with sertraline hydrochloride - Form I. Hydrogen chloride, 208.1ml of 6.37 molar, in aqueous isopropanol was added to the clear solution to give a thick white slurry. Additional isopropanol 1500ml was added and the material stirred for three hours at 50° C., then cooled to room temperature overnight. The solution was distilled at atmospheric pressure to remove 1,900ml. Isopropanol was then added (1000ml) to lower the water content. The mixture was then cooled and filtered to yield desired crystalline polymorph (Form I).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14]C)=[O:13])[CH:6]=[CH:5]2.C[O-].[Na+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33]Cl)[CH2:28][CH2:27]2)=[CH:22][CH:21]=1>CN(C=O)C.CO>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][O:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]4)[CH2:30][CH2:31]2)=[CH:24][CH:25]=1
Reactant: ClCCN1CCN(c2ccc(Cl)cc2)CC1
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(O)c1ccc2cc(OCCN3CCN(c4ccc(Cl)cc4)CC3)ccc2c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
2.11 g of methyl 6-hydroxy-2-naphthoate and 0.84 g of sodium methoxide are stirred under N2 at 40° C. for 30 min in 50 ml of DMF. 4.6 g of 4-(p-chlorophenyl)piperazinoethyl chloride are then added and the reaction mixture is stirred at 40° C. for 8 h. It is diluted with 350 ml of methanol and the precipitate which is deposited is filtered off with suction. It is dissolved in 80 ml of DMF and 10 ml of water, and the mixture is treated with 3.8 g of KOH and stirred at 100° C. for 10 h. The DMF is largely stripped off on a rotary evaporator, the residue is poured onto water and acidified, and the resulting precipitate is filtered off with suction. 2.5 g of 6-{2-[4-(4-chlorophenyl)-1-piperazinyl]ethoxy}-2-naphthoic acid are obtained; m.p. 197-199° C.
Reaction SMILES: [F:1][C:2]1[C:9](F)=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[NH:4][CH3:5].[C:14]1([CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(O)CCC>[C:22]1([CH:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:21][C:9]2[CH:8]=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[C:3]([NH:4][CH3:5])[C:2]=2[F:1])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CNc1c([N+](=O)[O-])ccc(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CNc1c([N+](=O)[O-])ccc(NC(c2ccccc2)c2ccccc2)c1F
Temperature: 200 °C
Yield: 29.6 %

Procedure:
A mixture of 2,3-difluoro-N-methyl-6-nitroaniline (2.66 g), 1,1-diphenylmethanamine (5.18 g), diisopropylethylamine (4.56 g) and butan-1-ol (26.6 mL) was heated at 200° C. for 2 hr using a microwave reactor. To the reaction mixture was added saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.47 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:26]#[N:27])=[C:11]([C:19]2[CH:24]=[CH:23][N:22]=[C:21](F)[CH:20]=2)[S:12][C:13]=1[C:14]1[NH:18][CH:17]=[N:16][N:15]=1.[CH3:28][NH2:29].CO>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:26]#[N:27])=[C:11]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:29][CH3:28])[CH:20]=2)[S:12][C:13]=1[C:14]1[NH:18][CH:17]=[N:16][N:15]=1
Reactant: CN
Reactant: N#Cc1c(-c2ccnc(F)c2)sc(-c2nnc[nH]2)c1-c1ccc(Cl)cc1Cl
Solvent: CO
Product: CNc1cc(-c2sc(-c3nnc[nH]3)c(-c3ccc(Cl)cc3Cl)c2C#N)ccn1
Yield: 44 %

Procedure:
A solution of 4-(2,4-dichlorophenyl)-2-(2-fluoropyridin-4-yl)-5-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile (0.100 g, 0.000240 mol) and 1M Methylamine in methanol (4 mL, 0.004 mol) 0.000163 mol) was heated at 80° C. for 5 hours. The solvent was removed and the residue was purified using a silica gel chromatography (12 g), elution DCM to 5% MeOH in DCM over 20 minutes to afford the title compound (0.045 g, 44%). LCMS: (FA) ES+, 427, 429. 1H NMR (400 MHz, d4-Methanol) 8.38 (s, 1H), 8.12-8.07 (m, 1H), 7.60 (dd, J=1.56, 0.77 Hz, 1H), 7.44-7.42 (m, 2H), 6.94 (dd, J=4.67, 1.66 Hz, 1H), 6.93 (s, 1H), 2.92 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:27][O:28][CH3:29])[N:21]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[C:17]=2[C:16]2[CH:15]=[CH:14][C:13]([CH:30]=[CH:31][C:32]#[N:33])=[CH:12][C:11]=2[N:10]=1>[Pd].CO>[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:27][O:28][CH3:29])[N:21]([CH2:22][C:23]([CH3:24])([OH:26])[CH3:25])[C:17]=2[C:16]2[CH:15]=[CH:14][C:13]([CH2:30][CH2:31][CH2:32][NH2:33])=[CH:12][C:11]=2[N:10]=1
Reactant: COCc1nc2c(N)nc3cc(C=CC#N)ccc3c2n1CC(C)(C)O
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COCc1nc2c(N)nc3cc(CCCN)ccc3c2n1CC(C)(C)O
Reaction time: 18 h
Yield: 90.7 %

Procedure:
A glass Parr vessel was charged with 10% palladium on carbon (1.0 g), methanol (200 mL), trifluoroacetic acid (5.4 mL, 72.5 mmol) and 3-[4-amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enenitrile (5.1 g, 14.5 mmol). The vessel was evacuated and charged with hydrogen gas (40 psi, 2.8×105 Pa). The mixture was shaken for approximately 18 hours and then filtered through a 0.2 micron PTFE membrane filter and concentrated under reduced pressure. The resulting yellow oil was dissolved in 10% aqueous hydrochloric acid (100 mL) and stirred for 30 minutes. The solution was made basic (pH 10) by the slow addition of potassium carbonate. Potassium hydroxide was added until pH equaled 13. The solution was then concentrated under reduced pressure. The resulting off-white solid was slurried in hot methanol (300 mL) and filtered. The hot methanol slurry procedure was repeated. The combined filtrates were concentrated and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient; 0-30% CMA) to provide 4.7 g of 1-[4-amino-7-(3-aminopropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as an off-white foam. MS (APCI) m/z 358 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[CH:13]([CH:19]([C:25]([O:27]CC)=[O:26])[C:20]([O:22]CC)=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>O.C(O)C>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[CH:13]([CH:19]([C:20]([OH:22])=[O:21])[C:25]([OH:27])=[O:26])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCC(c1ccc(OC)cc1OC)C(C(=O)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCC(c1ccc(OC)cc1OC)C(C(=O)O)C(=O)O
Temperature: 25 °C
Yield: 92.1 %

Procedure:
A solution of 4.40 g (110 mmol) of sodium hydroxide in 14 ml of water was added to a solution of 8.37 g (22.0 mmol) of diethyl 2-[1-(2,4-dimethoxy-phenyl)hexyl]malonate (prepared as described in Preparation 2) in 50ml of ethanol, and the resulting mixture was heated under reflux for 2.5 hours. At the end of this time, the reaction mixture was allowed to cool to room temperature, after which it was freed from ethanol by evaporation under reduced pressure. The resulting residue was acidified with concentrated hydrochloric acid and then extracted with ethyl acetate. The extract was washed with water and then with a. saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, to give 6.57 g of the title compound as a foam-like substance.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[C:8]([N+:16]([O-:18])=[O:17])[CH:7]=3)[CH:3]=1.C(N(CC)CC)C.O1CCCC1.[P:31]([S:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]#[N:46])=[CH:41][CH:40]=1)(=[O:37])(Cl)[S:32][CH2:33][CH2:34][CH3:35]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[P:31]([S:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]#[N:46])=[CH:41][CH:40]=1)(=[O:37])([S:32][CH2:33][CH2:34][CH3:35])[O:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[C:8]([N+:16]([O-:18])=[O:17])[CH:7]=3)[CH:3]=1
Reactant: CCCSP(=O)(Cl)Sc1ccc(C#N)cc1
Reactant: O=[N+]([O-])c1ccc2nc3ccc(O)cc3cc2c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCSP(=O)(Oc1ccc2nc3ccc([N+](=O)[O-])cc3cc2c1)Sc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Hydroxy-7-nitroacridine (0.01 mole), triethylamine (0.01 mole), tetrahydrofuran (25 ml) and toluene (25 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0° C. and S-(4-cyanophenyl) S-propyl phosphorochloridodithioate (0.01 mole) dissolved to toluene (25 ml) is added with stirring over a period of about 30 minutes. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 16 hours. After this time the reaction mixture is filtered to remove triethylamine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvents leaving a residue. This residue is subjected to flash chromatography using ethyl acetate as the eluant to yield the desired product S-(4-cyanophenyl) O-(7-nitroacridin-2-yl) S-propyl phosphorodithioate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=[CH:15][C:16]([OH:18])=[O:17])[CH:6]=[C:7]([Cl:11])[C:8]=1OC.[C:19](O)(=[O:21])C>Cl.[Pd]>[CH3:1][O:2][C:3]1[CH2:8][C:7]([O:21][CH3:19])([Cl:11])[CH:6]=[C:5]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:4]=1
Reactant: CC(=O)O
Reactant: COc1cc(C=CC=CC(=O)O)cc(Cl)c1OC
Agent: [Pd]
Agent: Cl
Product: COC1=CC(CCCCC(=O)O)=CC(Cl)(OC)C1

Procedure:
A solution containing 6.2 g of the above product obtained in Example 32 was dissolved in a mixture of 30 ml of acetic acid and 3 ml of conc. hydrochloric acid. Palladium on charcoal catalyst (10% Pd) was added and the mixture was hydrogenated at normal pressure and room temperature. After filteration the solvents were evaporated in vacuo. Yield 3.2 g (55%), a viscous oil.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([OH:19])=O)[N:6]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:33][CH3:34].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH2:36]([N:35]([CH2:32][CH2:33][CH3:34])[C:17](=[O:19])[CH2:16][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:5]([C:3](=[O:4])[C:2]([CH3:1])([CH3:21])[CH3:20])=[N:6]1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCNCCC
Reactant: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)O)c2c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(CCC)C(=O)Cn1nc(C(=O)C(C)(C)C)c2ccc(OC)cc21
Temperature: 45 °C
Reaction time: 2 h

Procedure:
Weigh 29.0 mg [3-(2,2-dimethylpropanoyl)-6-methoxy-1H-indazol-1-yl]acetic acid, 23.0 mg HOBt, and 38.3 mg EDC into a 13×100 mm screw cap tube. Add 17.3 mg N-propylbutylamine followed by 1 mL DMF and 45.2 mg DIEA in that order. The mixture was stirred at 45° C. for two hours and purified by RP-HPLC using 65-100% MeCN gradient. The pure product fractions were pooled and lyophilized to give the title compound as white solid. LC-MS: 4.20 min. (m/Z=388.3, 410.3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6](Br)[C:7](=O)[C:8]1[S:9][CH:10]=[CH:11][N:12]=1)[CH3:2].[CH:16]([NH2:18])=[S:17].C(N)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[S:17][CH:16]=[N:18][C:7]=1[C:8]1[S:9][CH:10]=[CH:11][N:12]=1)[CH3:2]
Reactant: NC=S
Reactant: CCOC(=O)CC(Br)C(=O)c1nccs1
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: NC=O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1scnc1-c1nccs1

Procedure:
To a solution of 3-bromo-4-oxo-4-thiazol-2-yl-butyric acid ethyl ester (2.2 g, 7.53 mmol) in 1,4-dioxane (40 mL) is added thioformamide (freshly made from formamide and P2S5 in 1,4-dioxane) (22.59 mmol). The mixture is refluxed overnight. The solvent is removed and NaHCO3 (aq.) (40 mL) and DCM (100 mL) are added to the residue. The organic layer is separated and the aqueous layer is extracted with DCM (2×40 mL). The combined organic layers are dried and solvent removed. The crude is purified by column (1% methanol n DCM) to give [2,4′]bithiazolyl-5′-yl-acetic acid ethyl ester.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)O>C1C=CC=CC=1>[C:3]1([CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CC(c1ccccc1)c1ccccc1
Yield: 25 %

Procedure:
1,1-Diphenylethane (DPE) is a valuable hydrocarbon for conversion to benzophenone, which, in turn, can be converted to the corresponding nitro and amine derivatives. Unfortunately, there are no simple methods known for its preparation in high yield. Thus, Baeyer, Ber., VI, 223 (1873) attempted to prepare 1,1-diphenylethane by reacting paraldehyde with benzene in the presence of sulfuric acid, but obtained only a resinous material. Later, in Ber. VII, 1190 (1874), he isolated some 1,1-diphenylethane from a tarry reaction product in disappointingly low yield. Spilker et al., Ber., 65B, 1686 (1932), condensed benzene with styrene in the presence of sulfuric acid and obtained a 25 percent yield of 1,1-diphenylethane. Higher yields of the same product, from 40 to 50 percent, were obtained by Reichert et al., J. Am. Chem. Soc., 45, 3090 (1923) in the mercury-catalyzed condensation of benzene with acetylene in sulfuric acid. More recently, Baeyer et al. in Ber., 94, 1717 (1961) and Ber., 95, 1989, ( 1962), reacted benzene with acetylene in the presence of phosphoric acid which has been saturated with boron trifluoride to obtain 1,1-diphenylethane in 65 percent yield, as well as some polymeric substances.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]([O:33]CC3C=CC=CC=3)=[O:32])[CH2:26][CH2:25]2)[CH:19]=1)[C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[O:8])([O-])=O.C([O-])=O.[NH4+]>O1CCCC1.CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:26][CH2:25]2)[CH:19]=1)[C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[O:8]
Reactant: COCCOC(=O)c1ccc(Nc2cccc(N3CCN(CC(=O)OCc4ccccc4)CC3)c2)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCOC(=O)c1ccc(Nc2cccc(N3CCN(CC(=O)O)CC3)c2)c(N)c1

Procedure:
To a solution of 2-methoxyethyl 3-nitro-4-(3-(4-(benzyloxy-carbonyl-methyl)-1-piperazinyl)-phenylamino)-benzoate (3d) (3.5 g; 6.4 mmol) in a mixture of tetrahydrofurane (50 ml) and DMF (5 ml) was added palladium catalyst (0.9 g; 5% Pd on activated carbon) and ammonium formiate (0.8 g; 12.6 mmol) and the mixture was heated to reflux for 2 hours. The cooled mixture was filtered through celite and the solvent was removed under reduced pressure to leave 2d, quantitatively.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[CH:8]=[C:9]([C:17]([OH:19])=[O:18])[CH:10]=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.[CH3:20]O>OS(O)(=O)=O.CN(C=O)C>[CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1
Reactant: CO
Reactant: Cc1ccc2[nH]c3cc(C(=O)O)ccc3c(=O)c2c1
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(=O)c3cc(C)ccc3[nH]c2c1

Procedure:
A mixture of compound 138B (50 mg), MeOH (12 mL), Conc. H2SO4 (2 drops), and DMF (2 drops) was heated to reflux over 18 h. LC/MS indicated the reaction was complete. The reaction mixture was concentrated in vacuo to give a brown oil (47.5 mg). HPLC retention time: 3.05 min., condition: A. M+: 268.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH3:48])[C:11]([CH2:13][O:14][C:15]3[CH:47]=[CH:46][C:18]([CH2:19][CH:20]4[S:24][C:23](=[O:25])[N:22](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:21]4=[O:45])=[CH:17][CH:16]=3)=[N:12][C:7]2=[CH:6][CH:5]=1)[CH3:2].C(O)(=O)C>O>[CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH3:48])[C:11]([CH2:13][O:14][C:15]3[CH:47]=[CH:46][C:18]([CH2:19][CH:20]4[S:24][C:23](=[O:25])[NH:22][C:21]4=[O:45])=[CH:17][CH:16]=3)=[N:12][C:7]2=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2nc(COc3ccc(CC4SC(=O)N(C(c5ccccc5)(c5ccccc5)c5ccccc5)C4=O)cc3)n(C)c2n1
Solvent: CC(=O)O
Solvent: O
Product: CCOc1ccc2nc(COc3ccc(CC4SC(=O)NC4=O)cc3)n(C)c2n1
Yield: 90.6 %

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 2.75 g of 5-{4-(5-ethoxy-3-methylimidazo [5,4-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 99) were treated with 24 ml of a 3:1 by volume mixture of acetic acid and water. After working up the product as described in Example 12, the resulting crude product was crystallized by trituration with ethyl acetate, to give 1.57 g of the title compound, melting at 245-246° C.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[N:11]([CH3:12])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[N:8]=2)=[CH:4][CH:3]=1.Cl[C:20](Cl)(Cl)[S:21]([SH-]C(=S)[S-])(=O)=O>O>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[N:11]([CH3:12])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[N:8]=2)=[CH:17][CH:18]=1)=[C:20]=[S:21]
Reactant: Cn1c(Oc2ccc(N)cc2)nc2ccccc21
Reactant: O=S(=O)([SH-]C(=S)[S-])C(Cl)(Cl)Cl
Solvent: O
Product: Cn1c(Oc2ccc(N=C=S)cc2)nc2ccccc21

Procedure:
An amount of 4.8 g of 2-(4'-aminophenoxy)-1-methylbenzimidazole is stirred with 2.3 g of bis-(trichloromethane-sulphonyl-trithiocarbonate in 25 ml of water for 24 hours at room temperature. The precipitate is separated, washed with sodium bicarbonate solution, and taken up in chloroform. After drying and distillation of the chloroform solution, the residue is boiled out with cyclohexane, filtered hot, and the filtrate diluted with petroleum ether. The 2-(4'-isothiocyanophenoxy)-1-methylbenzimidazole crystallising out melts at 59° to 61°C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH:12]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][CH:14]=2)[N:7]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC.[OH-].[Na+]>C1COCC1>[Cl:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:18]=1)[CH:12]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[N:8]1[C:9]([CH3:11])=[CH:10][C:6]([CH2:4][OH:3])=[N:7]1
Reactant: CCOC(=O)c1cc(C)n(C(OCc2ccc(Cl)cc2)c2cccc(Cl)c2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(CO)nn1C(OCc1ccc(Cl)cc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ester 3 (0.3 g, 0.72 mmol) in THF (6 mL) under N2 atmosphere was added 1M LiAlH4 in Et2O (2.2 mL, 2.20 mmol). The resulting mixture was stirred at RT for 2 h. 2 M NaOH (2 mL) was added dropwise and the precipitate was removed by filtration. The volatiles were removed in vacuo. The residue was dissolved in EtOAc (20 mL), washed with water (2×15 mL), brine (15 mL), dried (Na2SO4) and evaporated to dryness to give alcohol 4 as a white solid, 0.16 g (60%).