Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N-:15][S:16](N1C=CC(=[N+](C)C)C=C1)(=[O:18])=[O:17])=[O:14])([CH3:11])([CH3:10])[CH3:9].[NH2:28][C:29]1[CH:30]=[C:31]([CH:53]=[CH:54][CH:55]=1)[CH2:32][C:33]1[C:34](=[O:52])[O:35][C:36]2[CH:44]=[C:43]([O:45][C:46](=[O:50])[N:47]([CH3:49])[CH3:48])[C:42]([Cl:51])=[CH:41][C:37]=2[C:38]=1[CH2:39][F:40].O>ClCCl>[C:8]([O:12][C:13]([NH:15][S:16]([NH:28][C:29]1[CH:30]=[C:31]([CH:53]=[CH:54][CH:55]=1)[CH2:32][C:33]1[C:34](=[O:52])[O:35][C:36]2[CH:44]=[C:43]([O:45][C:46](=[O:50])[N:47]([CH3:49])[CH3:48])[C:42]([Cl:51])=[CH:41][C:37]=2[C:38]=1[CH2:39][F:40])(=[O:18])=[O:17])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Reactant: CN(C)C(=O)Oc1cc2oc(=O)c(Cc3cccc(N)c3)c(CF)c2cc1Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Oc1cc2oc(=O)c(Cc3cccc(NS(=O)(=O)NC(=O)OC(C)(C)C)c3)c(CF)c2cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
Triethylamine (34 μL, 0.25 mmol) and N-(tert-butoxycarbonyl)-N-{4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl}azanide (49 mg, 0.16 mmol) were added in series to a solution of dimethylcarbamic acid 3-(3-aminobenzyl)-6-chloro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester (compound 1h-1-3F) (33 mg, 0.082 mmol) in anhydrous dichloromethane (1.0 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic extract was washed with saturated saline and dried over magnesium sulfate. A crude solid was then obtained by vacuum concentration, and purified by preparative TLC (ethyl acetate:hexane=1:2) to yield the title compound (30 mg, 63%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:17])=[CH:4][CH:3]=1.[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.C(Cl)CCl>C(#N)C.O>[CH3:17][C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[O:25])=[CH:3][CH:4]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: Cc1cc2ccccc2n1-c1ccc(N)cc1
Reactant: O=C(O)c1cccnc1
Solvent: O
Solvent: CC#N
Solvent: ClCCCl
Product: Cc1cc2ccccc2n1-c1ccc(NC(=O)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
A mixture of the above amine (0.08 g, 0.36 mmol), nicotinic acid (114 mg, 0.59 mmol) and EDC (66 mg, 0.54 mmol) was dissolved in 2 mL acetonitrile and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, extracted with EtOAc, washed with water and dried (MgSO4). The residue obtained on concentration was flash chromatographed on silica gel, eluting with a gradient of 2% MeOH in dichloromethane to give the title compound (40 mg).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[NH4+:18].[OH-]>>[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])(=[O:3])[NH2:18]
Reactant: O=C(O)c1cc(C(F)(F)F)cc(S(=O)(=O)Cl)c1
Reactant: [NH4+]
Agent: [OH-]
Product: NS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a 3-chlorosulfonyl-5-(trifluoromethyl)benzoic acid (0.4 g) was added 28% ammonia aqueous solution (5.0 ml) at 0° C. The mixture was stirred at 0° C., and then allowed to stand at room temperature overnight. The mixture was concentrated to dryness, and then 1N hydrochloric acid (5 ml) was added to the mixture, and stirred at 0° C. for 30 minutes. The resulted powder was collected by filtration and dried under reduced pressure to give 3-sulfamoyl-5-(trifluoromethyl)benzoic acid (299.4 mg) as a pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.CO.[NH2:29][CH:30]1[CH2:33][O:32][CH2:31]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1.CN1CCCC1=O>[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:29][CH:30]4[CH2:33][O:32][CH2:31]4)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: NC1COC1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Solvent: CO
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NC4COC4)c(Cl)c32)c(F)cc1F
Temperature: 70 °C
Reaction time: 18 h

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg) was dissolved in a mixed liquid of pyridine (0.5 ml) and N-methylpyrrolidone (0.5 ml). A methanol solution (45%; 1.5 ml) of 3-aminooxetane was added to the resultant solution. The mixture was stirred at 70° C. for 18 hours. The reaction mixture was acidified with a 3% aqueous solution (20 ml) of citric acid, and solids formed were collected by filtration. The solids were subjected to azeotropic distillation with ethanol. Ether (5 ml) was added to the residue to conduct filtration, thereby obtaining the title compound (48 mg) as a pale yellow powder.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[N:8]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:11]2[CH2:10][CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1cccnc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccnc2)CC1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
7.07 g (44.74 mmol) of 3-bromopyridine, 10 g (53.69 mmol) of 1,1-dimethylethyl 1-piperazinecarboxylate, 6.02 g (62.64 mmol) of sodium tert-butoxide and 0.836 g (1.34 mmol) of (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) (BINAP) suspended in 100 ml of toluene are introduced under an inert atmosphere. 0.41 g (0.45 mmol) of [tris(dibenzylideneacetone)dipalladium] (Pd2(dba)3) is then added. The reaction mixture is then refluxed for 22 hours. The mixture is allowed to cool to room temperature, the salts are separated out by filtration through glass fiber and the filtrate is then concentrated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate and 100 ml of water, the aqueous phase is separated out and extracted several times with ethyl acetate, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by chromatography on silica gel, eluting with a 98/2 and then 95/5 mixture of dichloromethane and methanol. 9.80 g of product are obtained in the form of an oil that crystallizes at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([C:14]([OH:16])=O)=[CH:12][S:11][N:10]=2)[CH:5]=[C:6]([SH:8])[CH:7]=1.S(Cl)([Cl:19])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([C:14]([Cl:19])=[O:16])=[CH:12][S:11][N:10]=2)[CH:5]=[C:6]([SH:8])[CH:7]=1
Reactant: O=C(O)c1csnc1-c1cc(S)cc(Cl)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1csnc1-c1cc(S)cc(Cl)c1
Reaction time: 20 h

Procedure:
50 g of the product of step (b) are dissolved in 500 ml of thionyl chloride and the mixture is held at 50° for 20 hours. The thionyl chloride is removed at 12 mm to obtain the heading compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][C@@H:18]1[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][C@H:18]2[CH2:23][CH2:22][C@@H:21]([OH:24])[CH2:20][CH2:19]2)[N:3]=1
Reactant: N[C@H]1CC[C@@H](O)CC1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: O[C@H]1CC[C@@H](Nc2nc(Cl)nc3c2ncn3C2CCCC2)CC1

Procedure:
Cis-2-chloro-6-[(4-hydroxy)cyclohexylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, cis-4-(amino)cyclohexanol, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:12][O:11][CH2:10][CH2:9][NH:8]1)=[O:6])[CH3:3].[CH2:13](Br)[C:14]#[CH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:12][O:11][CH2:10][CH2:9][N:8]1[CH2:15][C:14]#[CH:13])=[O:6])[CH3:3]
Reactant: C#CCBr
Reactant: CCOC(=O)[C@@H]1COCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCN1CCOC[C@H]1C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (3S)-3-ethoxycarbonylmorpholine hydrochloride (0.3 g), propargyl bromide (0.34 ml) and potassium carbonate (0.91 g) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 1 hour and then the solvent was removed under reduced pressure. Ethyl acetate and sodium hydrogen carbonate solution were added to the residue and the organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (3:7) as an eluent to give (3S)-3-ethoxycarbonyl-4-(2-propynyl)morpholine (0.22 g) as an oil.
Reaction SMILES: C[O:2][C:3](=O)[NH:4][N:5]=[CH:6][C:7]([C:15]#[N:16])=[C:8]([Cl:14])[N:9]=[CH:10][N:11]([CH3:13])[CH3:12].Cl[C:19](N=CN(C)C)=[C:20](C=NNC=O)C#N>>[Cl:14][C:8]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[C:7]([CH:6]=[N:5][NH:4][C:3]([CH2:19][CH3:20])=[O:2])[C:15]#[N:16]
Reactant: CN(C)C=NC(Cl)=C(C#N)C=NNC=O
Reactant: COC(=O)NN=CC(C#N)=C(Cl)N=CN(C)C
Product: CCC(=O)NN=CC(C#N)=C(Cl)N=CN(C)C

Procedure:
Following the same procedure and replacing the methyl-3-(3-chloro-2-cyano-5-dimethylamino-4-aza-2,4-pentadienylidene)carbazate by an equivalent of 3-chloro-5-dimethylamino-2-formylhydrazonomethyl-4-aza-2,4-pentadienenitrile or of 3-chloro-5-dimethylamino-2-ethylcarbonylhydrazonomethyl-4-aza-2,4-pentadienenitrile results in the similar preparation of the corresponding compound of formula I.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[C:24]([F:25])=[CH:23][C:12]2[C:13](=O)[CH2:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[S:17][C:11]=2[CH:10]=1>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:8][C:9]1[C:24]([F:25])=[CH:23][C:12]2[C:13]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[S:17][C:11]=2[CH:10]=1
Reactant: CN1CCNCC1
Reactant: O=C1Cc2ccccc2Sc2cc(Cl)c(F)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CN1CCN(C2=Cc3ccccc3Sc3cc(Cl)c(F)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
1-Methylpiperazine (18.2 ml) was added to a solution of 7-chloro-8-fluorodibenzo(b,f)thiepine-10(11H)-one (see Example 24) (10.16 g) in benzene (90 ml). To this mixture a solution of titanium tetrachloride (3.7 g) in benzene (30 ml) was added dropwise during 5 minutes. The mixture was refluxed for 24 hours, cooled and decomposed by addition of ice-cold water (150 ml). After 30 minutes' standing, the precipitated solid was filtered and washed with benzene. The aqueous layer of the filtrate was extracted with the same solvent, the benzene layers combined, washed with water, dried and taken down, leaving 12.1 g (91%) of the oily base which slowly crystallizes from ethanol. When pure, it melts at 158°-160° C. Neutralization with maleic acid in ethanol yielded the crystalline maleate, m.p. 228°-230° C. (aqueous ethanol).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[NH:13]([C:20]([C:23]1[N:24]([CH3:35])[C:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[N:26][N:27]=1)([CH3:22])[CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH2:8]([NH:10][C:11](=[O:12])[O:34][C:31]1[CH:32]=[CH:33][C:28]([C:25]2[N:24]([CH3:35])[C:23]([C:20]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([CH3:22])[CH3:21])=[N:27][N:26]=2)=[CH:29][CH:30]=1)[CH3:9]
Reactant: CCN=C=O
Reactant: Cn1c(-c2ccc(O)cc2)nnc1C(C)(C)Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCNC(=O)Oc1ccc(-c2nnc(C(C)(C)Nc3ccccc3)n2C)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Triethylamine and ethyl isocyanate were added to a chloroform solution (3 ml) of 4-[5-(1-anilino-1-methylethyl)-4-methyl-4H-1,2,4-triazol-3-yl}phenol (20 mg), followed by stirring at 60° C. for 3 hours. After concentration, a small amount of ethyl acetate was added to the residue and the resulting crystalline powder was filtered to obtain 4-[5-(1-anilino-1-methylethyl)-4-methyl-4H-1,2,4-triazol-3-yl}phenyl ethylcarbamate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH:13]([CH3:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].[CH2:16]([O:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1)[CH3:17]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:13]([O:12][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:23]3[CH:24]=[CH:25][C:20]([C:19]([O:18][CH2:16][CH3:17])=[O:27])=[CH:21][CH:22]=3)=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C2(OC(C)C)CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-isopropoxycyclopropyl)-benzene (Intermediate 66, 114.0 mg, 0.57 mmol) and ethyl-4-iodo benzoate (Reagent A, 731.0 mg, 0.63 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (36.0 mg, 0.19 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (133 mg, 0.19 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 151.0 mg (76%) of the title compound as an orange solid.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:30][C:29]=2[CH2:41][CH2:42][CH3:43])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:4].[OH-].[Na+].O1CCCC1>CO>[O:34]([C:31]1[CH:32]=[CH:33][C:28]([O:27][CH2:26][CH2:25][CH2:24][O:23][C:20]2[CH:21]=[CH:22][C:17]([S:14]([N:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH2:13][C@@H:5]3[C:3]([OH:4])=[O:2])(=[O:16])=[O:15])=[CH:18][CH:19]=2)=[C:29]([CH2:41][CH2:42][CH3:43])[CH:30]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc(S(=O)(=O)N2c3ccccc3C[C@@H]2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc(S(=O)(=O)N2c3ccccc3C[C@@H]2C(=O)O)cc1
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a mixture of the title D compound, (R)-1-{4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylic acid methyl ester (1.47 g, 2.44 mmol) in methanol (50 mL) under nitrogen at room temperature is added 1N aqueous sodium hydroxide (4.9 mL, 4.9 mmol) dropwise. Upon complete addition, the mixture is stirred at room temperature for 45 minutes, at which time 5 mL of tetrahydrofuran is added to facilitate the dissolution of the starting material. The mixture is stirred overnight. The reaction mixture is concentrated in vacuo, the residue is partitioned between water (50 mL) and ether (50 mL). The aqueous layer is separated and acidified with 1N aqueous hydrochloric acid. The product is extracted into dichloromethane. The extract is washed with brine, dried over anhydrous sodium sulfate (Na2SO4), filtered and concentrated to give 1.02 g of (R)-1-{4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylic acid as a white foamy solid. The solid is treated with ethanol (1 mL) which results in dissolution of the solid and upon standing crystals start to form. The crystals are separated and dried at high vacuum at 40° C. to give 0.85 g of pure (R)-1-{4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylic acid: [M+1]+=588.46, [M−1]−=586.41.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[CH:12]1[O:17][CH2:16][C:15]([CH3:19])([CH3:18])[CH2:14][O:13]1.[CH:20](=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH3:18][C:15]1([CH3:19])[CH2:16][O:17][CH:12](/[CH:11]=[CH:10]/[C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[OH:30])[O:13][CH2:14]1
Reactant: CCCCCCCCCC=O
Reactant: Cc1cc(C)c(/C=C/C2OCC(C)(C)CO2)c(Br)c1
Product: CCCCCCCCCC(O)c1cc(C)cc(C)c1/C=C/C1OCC(C)(C)CO1
Yield: 38 %

Procedure:
In the manner described in Example 1, (E)-2-[2-(2-bromo-4,6-dimethylphenyl)ethenyl]-5,5-dimethyl-1,3-dioxane was reacted with n-decanal to obtain (E)-2-[2-(5,5-dimethyl-1,3-dioxan-2-yl)ethenyl]3,5-dimethyl-α-nonylbenzenemethanol as a white solid (955.4 mg, 38%): 59°-61° C.; IR (KBr) 3320, 2900, 2820, 1460 and 1375 cm-1 ; NMR (DMSO-d6) δ 0.72 (3H, s), 0.86 (3H, t, J=8 Hz), 1.14 (3H, s), 1.22 (14H, broad singlet), 1.40-1.56 (2H, m), 2.18 (3H, s), 2.26 (3H, s), 3.54 (2H, d, J=12 Hz), 3.64 (2H, d, J=12 Hz), 4.66-4.76 (1H, m), 4.90 (1H, d, J=5 Hz, exchangeable), 5.06 (1H, d, J=6 Hz), 5.58 (1H, dd, J=5, 15 Hz), 6.72 (1H, d, J=15 Hz), 6.92 (1H, s), 7.18 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([O:24][CH3:25])[C:18]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[C:17]3[Cl:37])[OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Al]>[O-2].[O-2].[Mn+4].O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([O:24][CH3:25])[C:18]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[C:17]3[Cl:37])=[O:13])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1nc2ccc(C(O)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Mn+4]
Agent: [Al]
Agent: [O-2]
Solvent: C1COCCO1
Product: COc1nc2ccc(C(=O)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a flask containing tert-butyl-3-((4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(hydroxy)methyl)azetidine-1-carboxylate (525 mg, 0.98 mmol, Intermediate 61: step a) was added 1,4-dioxane (40 mL) to give a homogeneous solution at room temperature. Manganese dioxide (715 mg, 8.23 mmol) was then added and the mixture was heated to 85° C. in an aluminum heating mantle under nitrogen. After 60 minutes, the contents were filtered through a Celite® pad while the solution was still warm, rinsing with THF. The effluent was concentrated and purified by passing through a short column of silica gel (10% acetone-hexane increasing to 25% acetone) to provide the title compound as a white amorphous solid.
Reaction SMILES: [C:1]([C@:3]1([CH3:17])[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])#[N:2].Cl.C(N(CC)CC)C.[N-:26]=[N+:27]=[N-:28].[Na+]>C1(C)C=CC=CC=1>[CH3:8][C:5]1([CH3:9])[N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@:3]([CH3:17])([C:1]2[N:26]=[N:27][NH:28][N:2]=2)[CH2:7][O:6]1
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@@]1(C)C#N
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C(C)(C)OC[C@@]1(C)c1nn[nH]n1
Temperature: 103 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
To a mixture of 6.96 g of tert-butyl (4R)-4-cyano-2,2,4-trimethyl-1,3-oxazolidine-3-carboxylate, 12.5 g of triethylamine hydrochloride, and 105 ml of toluene was added 5.84 g of sodium azide, followed by stirring at 103° C. for 3 hours. The insoluble materials were separated by filtration and the filtrate was concentrated. The obtained residue was purified twice by silica gel column chromatography to obtain 7.65 g of tert-butyl (4R)-2,2,4-trimethyl-4-(2H-tetrazol-5-yl)-1,3-oxazolidine-3-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[I:9]N1C(=O)CCC1=O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([I:9])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ccc(F)cn1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: Nc1ncc(F)cc1I
Yield: 57.5 %

Procedure:
But using 5 g of 5-fluoropyridin-2-ylamine and 11.04 g of N-iodosuccinimide in 250 ml of glacial acetic acid. 6.1 g of 5-fluoro-3-iodopyridin-2-ylamine are thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:20]([CH:17]3[CH2:19][CH2:18]3)=[O:21])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Reactant: O=C(Cl)C1CC1
Product: CCC(NC(=O)C1CC1)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 80 mg (0.74 mmol) cyclopropylcarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:7]2[S:18][C:10]3[N:11]=[C:12]([CH3:17])[N:13]=[C:14]([CH2:15]O)[C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)[Cl:20].S(Cl)(Cl)=O>CN(C=O)C>[Cl:20][CH2:15][C:14]1[C:9]2[CH:8]=[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[S:18][C:10]=2[N:11]=[C:12]([CH3:17])[N:13]=1
Reactant: ClCCl
Reactant: Cc1nc(CO)c2cc(C3CCCCC3)sc2n1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nc(CCl)c2cc(C3CCCCC3)sc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methanol (1.28 g) and DCM (20 mL) were added thionyl chloride (1 mL) and DMF (50 μL), followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and dried. To the residue was added EtOAc. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by silica gel column (chloroform/EtOAc) to obtain 4-(chloromethyl)-6-cyclohexyl-2-methylthieno[2,3-d]pyrimidine (663 mg).