Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH2:32]([NH2:34])[CH3:33]>C1COCC1>[CH2:32]([NH:34][C:16]1[N:17]=[C:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[CH3:26])[C:13]2[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1)[CH3:33]
Reactant: CCN
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: C1CCOC1
Product: CCNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1

Procedure:
The product of Example 48 (200 mg, 0.45 mmol) was combined and stirred with 5 mL of a 2M solution of ethylamine in THF. After 5 min the solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography with 0-2% EtOAc/CH2Cl2 followed by recrystallization from CH2Cl2/hexane gave the product as a white-crystalline solid. mp 195-196°, LC MS m/z=411 (MH+) Retention time=2.4 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1.[NH4+]=[S:21]>N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([C:18](=[S:21])[NH2:19])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1
Reactant: N#Cc1cccc(-c2cnn(-c3cccnc3)c2)n1
Solvent: c1ccncc1
Product: NC(=S)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Reaction time: 1 h

Procedure:
With heating, 1 g (4 mmol) of 6-(1-pyridin-3-yl-1H-pyrazol-4-yl)pyridine-2-carbonitrile was dissolved in 30 ml of pyridine, and 1.5 ml of ammonium sulphide (40% strength aqueous solution, corresponds to 8.8 mmol) were added. After 1 h, the mixture was concentrated by evaporation. The residue was recrystallized from ethanol with filtration of the hot mixture, the filtrate was concentrated slightly and the precipitate formed was filtered off with suction, washed with MTBE and dried on a rotary evaporator.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[CH2:6][N:7]([C:13](=[O:39])[CH2:14][N:15]([C:17](=[O:38])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])=[O:27])=[C:21]([O:36][CH3:37])[CH:20]=1)[CH3:16])[CH2:8][CH2:9][C:10]([OH:12])=[O:11].[OH-].[Na+:46]>C(O)C>[Na+:46].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[CH2:6][N:7]([C:13](=[O:39])[CH2:14][N:15]([C:17](=[O:38])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])=[O:27])=[C:21]([O:36][CH3:37])[CH:20]=1)[CH3:16])[CH2:8][CH2:9][C:10]([O-:12])=[O:11]
Reactant: COc1cc(CC(=O)N(C)CC(=O)N(CCC(=O)O)Cc2ccc(OC)c(OC)c2)ccc1NC(=O)Nc1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(CC(=O)N(C)CC(=O)N(CCC(=O)[O-])Cc2ccc(OC)c(OC)c2)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-{(3,4-dimethoxy-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid [17 g, Example 5(a)] in ethanol (170 ml) was treated with sodium hydroxide solution (23.3 ml, 1N). After stirring at ambient temperature for 24 hours the reaction mixture was filtered through a short pad of diatomaceous earth and then evaporated. The residue was triturated with hot ethyl acetate (200 ml) and dried under vacuum. The resultant foam was dissolved in water (200 ml) and freeze dried for 40 hours to yield the title compound as a white solid (15.4 g), m.p. 225° C. (with decomposition). [Elemental analysis:- C,57.8; H,6.05; N,8.2; Na,3.5%. Calculated for C32H37N4NaO8.2H2O:- C,57.8; H,6.2; N,8.4; Na,3.5%].
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:24][C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].[Cl:33]CCl.Cl>C(O)C>[ClH:33].[CH:19]1[C:18]2[N:17]([CH2:16][CH2:15][O:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[S:24][C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCCN2c3ccccc3Sc3ccccc32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOCCN2c3ccccc3Sc3ccccc32)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The above ester (0.8 g, 1.8 mmol) was dissolved in ethanol (15 ml) and a 4 N sodium hydroxide solution (2 ml) was added. The mixture was stirred vigorously at room temperature for 4 h. The solvent was evaporated in vacuo to give an oily residue. Dichloromethane (100 ml) was added and the mixture was cooled on an ice-bath. A concentrated hydrochloric acid solution (1 ml) was added. The mixture was stirred vigorously for a few minutes and the phases were separated. The organic phase was dried over sodium sulphate and the solvent was evaporated in vacuo. The residue was re-evaporated with dichloromethane, dissolved in dichloromethane and left overnight at 4° C. The solid formed was isolated by filtration to give 0.6 g of the title compound as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)#[N:2].[NH2:9][C:10]1[S:11][C:12]([CH3:21])=[C:13]([CH3:20])[C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:15]1[C:14]2[C:13]([CH3:20])=[C:12]([CH3:21])[S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:8]=[N:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(N)sc(C)c1C
Reactant: N#Cc1cnccn1
Product: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1C

Procedure:
With the procedure of Example 477, the reaction of 2-cyanopyrazine and 2-amino-4,5-dimethyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyrazin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine
Reaction SMILES: [CH2:1]([NH:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][NH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:22](OC)(=[O:27])[CH2:23][C:24]([CH3:26])=O>>[CH2:1]([NH:15][CH2:16][CH2:17][N:18]1[C:22](=[O:27])[CH2:23][C:24]([CH3:26])=[N:21][CH2:20][CH2:19]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: COC(=O)CC(C)=O
Reactant: CCCCCCCCCCCCCCNCCNCCN
Product: CCCCCCCCCCCCCCNCCN1CCN=C(C)CC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 299.5 g (1 mole) of N-tetradecyldiethylenetriamine and 116.1 g (1 mole) of methyl acetoacetate. At 150° to 160° C., 18 g of water and 32 g of methanol were distilled off to obtain 4-tetradecylaminoethyl-7-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]=[C:39]=[O:40]>>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[Cl:31])[C:39]2=[O:40])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Reactant: O=C=Nc1ccccc1Cl
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccccc3Cl)CC2)c1

Procedure:
In analogy to example 2, (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 2, step 3) was reacted with sodium iodide and 2-chlorophenyl isocyanate to give the title compound as a colorless solid. MS: 553.3 ([M+H]+)
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].[Br-:6].[K+].S(=O)(=O)(O)O.[CH2:13]([O:17][CH2:18][CH2:19]O)[CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1.O>[Br:6][CH2:2][C:3]([O:5][CH2:19][CH2:18][O:17][CH2:13][CH2:14][CH2:15][CH3:16])=[O:4]
Reactant: O=C(O)CCl
Reactant: [Br-]
Reactant: CCCCOCCO
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOCCOC(=O)CBr

Procedure:
94.5g (1 mol) of chloroacetic acid, 142.8g (1.2 mol) of potassium bromide, 117.6g (1.2 mol) of sulfuric acid, 75 ml of water, 200g of toluene and 118.1g (1 mol) of ethylene glycol butyl ether were used and treated in a similar way as described in Example 3. 225.1g (94.1% of theory) of 2-n-butoxyethyl bromoacetate were obtained. Bp. = 123° ~ 124° C/3 mmHg, nD25 = 1.4572, D420 = 1.6450. 161.4g (98.9%) of potassium hydrogen sulfate was isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=O.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47]([S:50]([C:53]2[CH:58]=[CH:57][C:56]([NH:59][C:60]3[N:65]=[CH:64][C:63]([NH2:66])=[CH:62][N:61]=3)=[CH:55][CH:54]=2)(=[O:52])=[O:51])[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>C(Cl)Cl>[C:37]([O:41][C:42]([N:44]1[CH2:45][CH2:46][CH:47]([S:50]([C:53]2[CH:54]=[CH:55][C:56]([NH:59][C:60]3[N:65]=[CH:64][C:63]([NH:66][C:4](=[O:6])[C:3]4[CH:7]=[C:8]([NH:11][C:12]([C:14]5[S:15][CH:16]=[CH:17][CH:18]=5)=[O:13])[CH:9]=[CH:10][C:2]=4[Cl:1])=[CH:62][N:61]=3)=[CH:57][CH:58]=2)(=[O:51])=[O:52])[CH2:48][CH2:49]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(N)cn3)cc2)CC1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(NC(=O)c4cc(NC(=O)c5cccs5)ccc4Cl)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
Intermediate 15 (Example 23) (0.124 g, 0.439 mmol) was combined with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (0.093 g, 0.53 mmol) and diluted with DCM (4 mL). This was immediately treated with 4-methyl morpholine (0.10 mL, 0.88 mmol) and allowed to stir at ambient temperature for 1 h. Intermediate 13 (Example 20) (0.20 g, 0.462 mmol) was then added in one portion. Stirring was continued overnight. After 18 h, reaction solvents were removed and resulting crude solids purified via HPLC to afford the title compound as a white solid (0.1 g, 32%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([C:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=2)[CH:13]=1)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].[C:25]([C:27]1[N:28]=[C:29]([C:40](O)=[O:41])[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=1)#[N:26].[K+].C(C1N=C(C([O-])=O)N(COCC[Si](C)(C)C)C=1)#N>>[C:9]([O:8][CH2:7][CH:6]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:40]([C:29]2[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=[C:27]([C:25]#[N:26])[N:28]=2)=[O:41])=[C:14]([C:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=2)[CH:13]=1)[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: CC(=O)OCC(COC(C)=O)c1ccc(N)c(C2=CCCCC2)c1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)O
Agent: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Product: CC(=O)OCC(COC(C)=O)c1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1

Procedure:
Acetic acid 3-acetoxy-2-(4-amino-3-cyclohex-1-enyl-phenyl)-propyl ester (as prepared in the previous step) was coupled to 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid, potassium salt (as prepared in Example 1, step (d)) as described in Example 1, step (1) to obtain the title compound: Mass spectrum (ESI, m/z): Calcd. for C30H40N4O6Si, 581.2 (M+H). found 581.0.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH:10]([CH:28]([CH3:30])[CH3:29])[C:11]([O:13]CC1C=CC(CC2C=CC=CC=2)=CC=1)=[O:12].BrC(C(C)C)C(OC(C#N)C1C=CC=C(CC2C=CC=CC=2)C=1)=O>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C@H:10]([C:11]([OH:13])=[O:12])[CH:28]([CH3:30])[CH3:29])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)C(Br)C(=O)OCc1ccc(Cc2ccccc2)cc1
Agent: CC(C)C(Br)C(=O)OC(C#N)c1cccc(Cc2ccccc2)c1
Product: CC(C)[C@H](Nc1ccc(Cl)cc1)C(=O)O

Procedure:
Following the procedure of Example 6, 4-chloroaniline is reacted with each of p-benzylbenzyl α-bromoisovalerate and m-benzyl-α-cyanobenzyl α-bromoisovalerate to yield the p-benzylbenzyl ester of N-(4-chlorophenyl)valine, MS m/e 407 (M+), and the m-benzyl-α-cyanobenzyl ester of N-(4-chlorophenyl)valine, MS m/e 432 (M+).
Reaction SMILES: [C:1]1([C:12]([OH:14])=O)[CH:2]=[CH:3][CH:4]=[C:5]2[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7][C:6]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:38][CH:39]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]([F:62])([F:61])[C:57]([CH3:60])([CH3:59])[CH3:58])=[CH:52][CH:51]=1)[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[OH:41]>CN(C)C=O.C(OCC)(=O)C>[Cl:48][C:44]1[CH:43]=[C:42]([CH:40]([OH:41])[CH:39]([NH:38][C:12]([C:1]2[CH:2]=[CH:3][CH:4]=[C:5]3[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7][C:6]=23)=[O:14])[CH2:49][C:50]2[CH:55]=[CH:54][C:53]([C:56]([F:62])([F:61])[C:57]([CH3:60])([CH3:58])[CH3:59])=[CH:52][CH:51]=2)[CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)(C)C(F)(F)c1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C(F)(F)c1ccc(CC(NC(=O)c2cccc3c2C=CCCC3)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
To a solution of 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (216 mg, 1.15 mmol) in N,N-dimethylformamide (5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (220 mg, 1.15 mmol) and 1-hydroxybenzotriazole monohydrate (176 mg, 1.15 mmol), and (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(1,1-difluoro-2,2-dimethylpropyl)phenyl]-1-propanol (0.40 g, 1.09 mmol) was finally added. The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered using a glass filter filled with silica gel. The filtrate was washed with ethyl acetate, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give N-{(1RS,2SR)-2-(3-chlorophenyl)-1-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]-2-hydroxyethyl}-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide (316 mg, 54%) as colorless crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13](C)C)=[CH:9][CH:8]=1)=[O:6].[Br:16]N1C(=O)CCC1=O>C(Cl)Cl>[Br:16][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]([CH:4]2[CH2:3][CH2:2]2)=[O:6])=[CH:12][CH:11]=1
Reactant: CC(C)c1ccc(C(=O)CCCCl)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: O=C(c1ccc(CBr)cc1)C1CC1
Temperature: 5 °C
Reaction time: 7.5 h
Yield: 165.6 %

Procedure:
Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (20 g, 124 mmol) and 2,2′-Azolons (2-methylpropionitrile) (0.5 g) in methylene chloride (100 mL) and cool to 5° C. Add a suspension of N-bromosuccinimide (12 g) in methylene chloride (50 mL) and irradiate with light (150 Watt lamp), maintaining the temperature at 5° C. After 2, 3 and 7 hour time periods, add additional N-bromosuccinimide (6 g, 6 g, 2.8 g) and continue stirring. After 7.5 hours, wash with water (200 mL) and with 0.4M sodium hydrogen carbonate (2×200 mL). Dry (Na2SO4), evaporate the solvent in vacuo and recrystallize (hexane) to give the title compound as a crystalline solid (26.7 g).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]\[C:18]([OH:20])=O.[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH3:21]/[C:16](/[CH:15]=[CH:14]/[CH:13]=[C:12](\[CH3:22])/[CH:11]=[CH:10]/[C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1])=[CH:17]/[C:18]([NH:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)=[O:20]
Reactant: Nc1ccncc1
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C\C(=O)O)C(C)(C)CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C\C(=O)Nc2ccncc2)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.3 %

Procedure:
A suspension of 13-cis-retinoic acid (0.10 g, 0.33 mmol), CH2Cl2 (5 mL), 4-aminopyridine (0.03 g, 0.33 mmol), and DCC (0.07 g, 0.33 mmol) was stirred at room temperature for 24 h. The mixture was filtered, concentrated, and purified by silica gel flash column chromatography to give the product as a yellow solid (0.07 g, 57%). EIMS m/z: 377 ([M]+), 375 ([M]−).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=[O:12].[CH2:14](O)[CH3:15].OS(O)(=O)=O>C(Cl)Cl.O>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=C(O)C1CCc2ccccc2O1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1CCc2ccccc2O1

Procedure:
Chroman-2-carboxylic acid (35.6 g, 0.2 mol) prepared according to the method of Augstein et al., J. Med. Chem., v. 11, pp. 844-848, 1968) and absolute ethanol (24.3 g, 0.6 mol) were combined in 300 ml of CH2Cl2. H2SO4 (0.6 ml, 96%) was added and the mixture gently refluxed for 21 hours, then cooled and diluted with 500 ml H2O. The organic layer was separated, washed with saturated NaHCO3 and then H2O, dried (MgSO4) and stripped to yield present title product as an oil; 38.6 g (93%); 1H-NMR (CDCl3), 300 MHz) delta 7.12 (t, 1H), 7.02 (d, 1H), 6.92 (d, 1H), 6.85 (t, 1H), 4.71 (q, 1H), 4.25 (q. 2H), 2.80 (m, 2H), 2.22 (m, 2H), 1.29 (t, 3H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[CH2:11]([O:13][C:14]([CH:16]([C:22](OCC)=[O:23])[C:17](OCC)=[O:18])=[O:15])[CH3:12]>>[CH2:11]([O:13][C:14]([C:16]1[C:17](=[O:18])[N:4]2[CH2:3][CH2:2][O:1][C:6]3[C:5]2=[C:10]([CH:9]=[CH:8][CH:7]=3)[C:22]=1[OH:23])=[O:15])[CH3:12]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: c1ccc2c(c1)NCCO2
Product: CCOC(=O)c1c(O)c2cccc3c2n(c1=O)CCO3
Temperature: 200 °C
Reaction time: 1 h

Procedure:
A mixture of 3,4-dihydro-2H-1,4-benzoxazine (6 g) and tri(ethoxycarbonyl)methane (9.4 ml) was stirred at 150° C. for 1 hour and at 200° C. for 1 hour. The mixture was cooled and the solid was washed with ether to give pale brown crystals of 2,3-dihydro-6-ethoxycarbonyl-7-hydroxy-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (9.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[CH:5]=[C:6]([O:30][CH3:31])[C:7]=1[O:8][C@H:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:15]=1)[CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Na+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH:5]=[C:6]([O:30][CH3:31])[C:7]=1[O:8][C@H:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=2)[N:15]=1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCC[C@H](Oc1c(Cl)cc(CCC(=O)OCC)cc1OC)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC[C@H](Oc1c(Cl)cc(CCC(=O)O)cc1OC)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Reaction time: 2 h
Yield: 90 %

Procedure:
To a stirring solution of ethyl 3-{3-chloro-5-(methyloxy)-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoate (118 mg, 0.20 mmol) in THF (3 mL) and MeOH (3 mL) at ambient temperature was added NaOH (2N, 3 mL) and the mixture stirred for 2 h and then left to stand overnight. HCl (2N, 3 mL) was then added and the mixture reduced under vacuum. The residue was then purified by SPE (silica, 5 g cartridge) with a pad of celite on the top, eluting with cyclohexane:EtOAc (gradient 20:1 to 0:1) to give the title compound (94 mg).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:25]2)=CC=1>O1CCCC1>[F:1][C:2]1[C:10]([F:11])=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[S:25]
Reactant: NC(=O)c1ccc(C(F)(F)F)c(F)c1F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: NC(=S)c1ccc(C(F)(F)F)c(F)c1F
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 186.4 %

Procedure:
A suspension of 2,3-difluoro-4-trifluoromethyl-benzamide (1 g, 4.4 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent; 900 mg, 2.2 mmol) in tetrahydrofuran (2 ml) was stirred under microwave irradiation at 130° C. for 15 min. The solvent was removed under reduced pressure to give an orange oil which was purified by column chromatography (silica gel, heptane/AcOEt) to yield 1.0 g (4.1 mmol, 93%) of the title compound as yellow crystals.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:12]=1)=[O:7])[CH3:4].[OH-].[Na+]>C(O)(=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C:12]=1[Br:1])=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(-c2ccccc2Cl)n(-c2ccc(Cl)cc2)c1Br
Temperature: 0 °C
Reaction time: 17 h

Procedure:
Bromine (3.6 ml, 0.07 mol) was added to a solution of 1-(4-chloro-phenyl)-2-(2-chloro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester (I-5c, 3.6 g, 0.01 mol) in glacial acetic acid (50 ml) at room temperature. The reaction mixture was stirred for 17 hours, poured over ice-water, and treated with 25% aq. NaOH until the orange solution turned yellow. The aqueous solution was extracted with CH2Cl2 (3×) and the combined extracts were dried and concentrated in vacuo to give the desired compound I-5d as an oil (4.7 g): +APCI MS (M+1) 441.1; 1H NMR (CD3Cl) δ 1.41 (3H, t), 4.43 (2H, q), 7.08–7.12 (2H, m), 7.20–7.40 (7H, m).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]2([CH2:11][CH2:10][CH:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8]2)[O:4]1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1.CCOCC>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:1][CH2:2][CH:3]2[CH2:7][O:6][C:5]3([CH2:11][CH2:10][CH:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8]3)[O:4]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)CC1CCC2(C1)OCC(CO)O2
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)CC1CCC2(C1)OCC(COS(=O)(=O)c1ccc(C)cc1)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold (00) stirred solution of the alcohol of Example K (2.44 g, 10 mmol) in pyridine (30 ml) is added p-toluenesulfonyl chloride (1.91 g, 10 mmol) in portions over 15 minutes. When addition is completed, the reaction mixture is stirred at room temperature for 2 hrs. The reaction mixture is diluted with ether and washed successively with water, 0.5N aqueous sodium bisulfate solution, 5% aqueous sodium bicarbonate solution and water. The organic layer is dried over sodium sulfate, filtered, and the filtrate is concentrated on the rotary evaporator to give the titled compound.