Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33](O)=[O:34])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH2:40][C@@H:41]([OH:43])[CH3:42]>>[OH:43][C@@H:41]([CH3:42])[CH2:40][NH:39][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][CH:38]=[C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:29])=[O:28])[CH:31]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Reactant: C[C@H](O)CN
Product: C[C@H](O)CNC(=O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 57.9 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and (S)-1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 34 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 588 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C@H:12]([CH2:15][CH3:16])[CH2:13][OH:14].C(O[CH:20](O)[C:21]([F:24])([F:23])[F:22])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C@H:12]([CH2:15][CH3:16])[CH2:13][O:14][CH:20]1[C:21]([F:24])([F:23])[F:22]
Reactant: CC[C@H](CO)Nc1ccc([N+](=O)[O-])cc1F
Reactant: CCOC(O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC[C@@H]1COC(C(F)(F)F)N1c1ccc([N+](=O)[O-])cc1F
Yield: 17.2 %

Procedure:
This compound was prepared according to General Method 19 (EXAMPLE 45) from (2R)-2-(2-fluoro-4-nitrophenyl)amino-1-butanol (1.6 g, 70 mmol), trifluoroacetaldehyde ethyl hemiacetal (4.9 g, 34 mmol) and p-toluenesulfonic acid (0.13 g, 0.68 mmol) in 70 mL anhydrous benzene to afford 1.8 g (85%) of (4R)-3-(2-fluoro-4-nitrophenyl)-4-ethyl-2-trifluoromethyloxazolidine, after flash chromatography (gradient elution, hexanes:ethyl acetate 90:10 to 50:50). Data for (4R)-3-(2-fluoro-4-nitrophenyl)-4-ethyl-2-trifluoromethyloxazolidine: 1H NMR (500 MHz, CDCl3) δ 8.01 (m, 1H), 7.98 (m, 1H), 6.95 (dd, J=8.8, 8.8, 1H), 5.68 (m, 1H), 4.30 (m, 1H), 4.08 (m, 1H), 3.92 (m, 1H), 2.00 (m, 1H), 1.67 (m, 1H), 0.97 (t, J=7.8, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH:9]([C:16]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[O:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:17][C:16]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(C)cc1)C(=O)c1ccco1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccc(C)cc2)oc1-c1ccco1
Yield: 42.3 %

Procedure:
10 g of ethyl 3-(4-methylbenzoylamino)-3-(2-furylcarbonyl)propionate, 40 ml of chloroform and 23.3 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 4.0 g of ethyl 2-[2-(4-methylphenyl)-5-(2-furyl)-4-oxazolyl]acetate are thereby obtained. Yield: 42.3%
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3[NH:11][CH2:12][CH:13]=[CH:14][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:17]=1.[Na].[CH3:19][SH:20]>CN(C)C=O>[CH3:19][S:20][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3[NH:11][CH2:12][CH:13]=[CH:14][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:17]=1
Reactant: O=C1C2=C(C=CCN2)CCc2cc(Cl)ccc21
Reactant: CS
Agent: [Na]
Solvent: CN(C)C=O
Product: CSc1ccc2c(c1)CCC1=C(NCC=C1)C2=O
Yield: 97 %

Procedure:
8-Chloro-5,6-dihydro-1H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (3.5 g) was dissolved in 60 ml of dimethylformamide, followed by the addition of 13.4 g of a 15% aqueous solution of methyl mercaptan sodium salt. The resultant mixture was refluxed for 14 hours. The reaction mixture was cooled and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with methylene chloride. The resulting extract was washed with a brine, dried over anhydrous MgSO4 and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column and relevant chloroform eluate fractions were concentrated. The residue was recrystallized from toluene, whereby 3.57 g of 8-methylthio-5,6-dihydro-1H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one were obtained (yield: 97%). 2.50(3H,s), 3.16(4H,s), 7.00-7.52(3H,m), 7.66(1H,dd), 8.12(1H,d), 8 72(1H,dd).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:14]=1[CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=O)(C)(C)C.[H][H].[ClH:30]>C(OCC)(=O)C.O1CCOCC1.[Pd]>[ClH:30].[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:14]=1[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C=Cc1ccc(C#N)cc1OCCCNC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)CCc1ccc(C#N)cc1OCCCN
Reaction time: 8 h

Procedure:
3.8 g (10.2 mmol) of ethyl 3-[2-(3-(t-butoxycarbonylamino)propoxy)-4-cyanophenyl]acrylate was dissolved in 100 ml of ethyl acetate. 700 mg of 10% palladium/carbon (50% hydrous) was added to the obtained solution, and they were stirred in the presence of hydrogen for 3 hours. The reaction solution was filtered through Celite. The solvent was evaporated, and the obtained crude product was dissolved in 50 ml of 4 N solution of hydrogen chloride in dioxane. The obtained solution was stirred overnight. The solvent was evaporated to obtain hydrochloride of the crude title compound.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH2:19])[CH:13]=1.C>[OH-].[Na+]>[F:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:16][CH:17]=1)[NH:18][C:1](=[O:8])[C:2](=[O:4])[NH:19]2
Reactant: Nc1ccc(F)cc1N
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c2ccc(F)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound (Sarges, R. et al., J. Med. Chem. 33:2240 (1990)) was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (17.4 g, 0.100 mol) and 4-fluoro-1,2-diaminobenzene (1.00 g, 7.93 mmol) was heated to reflux with stirring under N2 for 2 h. The reaction was cooled to room temperature and the solid was collected by vacuum filtration and rinsed with EtOH (50 mL) to give a gray-brown solid which was further dried under vacuum (0.1 torr, 25° C.) to yield 1.06 g (74.4%) which was >98% pure by NMR. An analytically pure sample was prepared by dissolution of 60 mg of the solid in 1.0N NaOH and treatment of this solution with activated charcoal. Filtration of this mixture through a pad of Celite and acidification with 1N HCl gave fine white needles which were collected by vacuum filtration, rinsed with H2O and further dried under vacuum (0.1 torr, 25° C.) to give 25.5 mg of white needles, mp 375°-380° C. (dec) (lit.>300° C. (Sarges, R., et al., J. Med. Chem. 33:2240 (1990)). 1H NMR (d6 -DMSO) δ6.90 (m, 2H, ArH), 7.09 (dd, J=9, J=5.4), 11.9 (s, 1H, NH), 11.96 (s, 1H, NH). EIMS m/z180(100,M+), 152(44), 124(63), 97(43), 28(53). EIHRMS calc. for C8H5FN2N2O2 180.0334, found 180.0337.
Reaction SMILES: Cl.Cl[C:3]1C=CC=CC=1C(OC1CNC1)C1C=CC=CC=1Cl.[N-]=C=O.[Cl:25][C:26]1[CH:51]=[CH:50][CH:49]=[CH:48][C:27]=1[CH:28]([O:36][CH:37]1[CH2:40][N:39]([C:41]([NH:43][C:44]([CH3:47])([CH3:46])C)=[O:42])[CH2:38]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35]>>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH:28]([O:36][CH:37]1[CH2:38][N:39]([C:41]([NH:43][CH:44]([CH2:46][CH3:3])[CH3:47])=[O:42])[CH2:40]1)[C:27]1[CH:48]=[CH:49][CH:50]=[CH:51][C:26]=1[Cl:25]
Reactant: Clc1ccccc1C(OC1CNC1)c1ccccc1Cl
Reactant: CC(C)(C)NC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1
Agent: Cl
Agent: [N-]=C=O
Product: CCC(C)NC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1

Procedure:
This material was prepared from 3-(2,2′-dichlorobenzhydryloxy)azetidine hydrochloride (68) and the corresponding commercially available isocyanate using the procedure described for compound (69).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[N:13]=[C:14]2[C:19](=[O:20])[NH:18][NH:17][CH:16]=[C:15]2[N:21]=1.[OH:22]O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:11])(=[O:22])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[N:13]=[C:14]2[C:19](=[O:20])[NH:18][NH:17][CH:16]=[C:15]2[N:21]=1
Reactant: OO
Reactant: COc1cc(S(C)=O)ccc1-c1nc2c[nH][nH]c(=O)c-2n1
Solvent: CC(=O)O
Product: COc1cc(S(C)(=O)=O)ccc1-c1nc2c[nH][nH]c(=O)c-2n1
Temperature: 25 °C
Reaction time: 0.92 h

Procedure:
A quantity of 0.07 gm of 2-(2-methoxy-4-methylsulfinyl-phenyl)-5H-imidazo[4,5-d]pyridazin-4-one is dissolved in 5 ml of glacial acetic acid, mixed with 0.05 ml of 30% hydrogen peroxide, and stirred first for 55 minutes at ambient temperature then for two hours at 40°-50° C., Then, a further 0.05 ml of hydrogen peroxide are added, and the mixture is heated for another hour. The product precipitated is subjected to suction filtration and washed with ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[NH:7][CH:8]1[C:26](=[O:27])[N:25]2[CH:21]([CH2:22][CH:23]([O:28][Si](C(C)(C)C)(C)C)[CH2:24]2)[C:20](=[O:36])[NH:19][C:18]2([C:37]([NH:39][S:40]([CH:43]3[CH2:45][CH2:44]3)(=[O:42])=[O:41])=[O:38])[CH:16]([CH2:17]2)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:5][C:6](=[O:46])[NH:7][CH:8]1[C:26](=[O:27])[N:25]2[CH:21]([CH2:22][CH:23]([OH:28])[CH2:24]2)[C:20](=[O:36])[NH:19][C:18]2([C:37]([NH:39][S:40]([CH:43]3[CH2:45][CH2:44]3)(=[O:41])=[O:42])=[O:38])[CH:16]([CH2:17]2)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O[Si](C)(C)C(C)(C)C)CN2C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.8 %

Procedure:
To a mixture of [18-(tert-butyl-dimethylsilanyloxy)-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]-carbamic acid tert-butyl ester (330 mg, 0.48 mmoL) in 25 mL of THF was added tetrabutylammonium floride (150 mg, 0.54 mmoL). The reaction mixture was stirred at rt for 18 h, and then the THF was removed by rotary evaporation. The residue was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and concentrated in vacuo to give the crude product. It was then purified by triturating with hexane to yield 200 mg (73%) of (4-cyclopropanesulfonylaminocarbonyl-18-hydroxy-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl)-carbamic acid tert-butyl ester, Example 19, as a white solid. 1H NMR (500 MHz, CD3Cl) δ 1.87-1.64 (m, 21 H), 1.70-1.98 (m, 3 H), 2.15-2.56 (m, 5 H), 2.85-2.94 (m, 1 H), 3.71 (d, J=13.91 Hz, 1 H), 4.10-4.26 (m, 2 H), 4.51 (t, J=7.87 Hz, 1 H), 4.62 (s, 1 H), 4.98 (m, 1 H), 5.06 (d, J=8.78 Hz, 1 H), 5.64-5.71 (m, 1 H), 6.72 (s, 1 H), 10.24 (s, 1 H); MS m/z 569 (M++1). The following macrocyclic alcohol intermediates were prepared employing the procedures described in examples 29 and 30:
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9](=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:10](=[O:12])[N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:27][CH2:28][C@H:29]([OH:39])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1>>[OH:39][C@H:29]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH2:28][NH:27][CH:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:13]=[C:9]3[S:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[N:11][C:10]3=[O:12])=[CH:15][CH:16]=2)[CH2:21][CH2:22]1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCOCC4)=NC3=O)cc2)CC1
Product: O=C1N=C(N2CCOCC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)cc3)CC2)cc1

Procedure:
The title compound was prepared from 1-[4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one(which was obtained in Intermediate 28) and (2S)-1-amino-3-(4-hydroxy-phenoxy)-propan-2-ol (which was obtained in Intermediate 5) according to the procedure of Example 1 as a yellowish solid; mp>100° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.80-1.95 (m, 2 H), 2.50-3.00 (m, 7H), 3.60-4.00 (m, 11 H), 6.66(d, J=9.2 Hz, 2 H), 6.74 (d, J=8.9 Hz, 2 H), 7.02(d, J=9.2 Hz, 2 H), 7.45(d, J=8.9 Hz, 2 H), 7.54 (s, 1 H); MS (ES) m/z: 270.0 ((M+2 H)2+, 100%); 539.1(MH+, 40%); HRMS Calcd. for C28H35N4O5S (MH+): 539.2328. Found: 539.2322.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.C(N(CC)CC)C.[C:19]1([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH2:31][NH:30][CH2:29][CH2:28]3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH3:10][C:7]1[N:6]=[C:5]([NH2:11])[C:4]([CH2:3][N:30]2[CH2:29][CH2:28][C:27]3[C:32](=[CH:33][CH:34]=[C:25]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:26]=3)[CH2:31]2)=[CH:9][N:8]=1
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: c1ccc(-c2ccc3c(c2)CCNC3)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CCc3cc(-c4ccccc4)ccc3C2)c(N)n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 60.5 %

Procedure:
A suspension of 0.20 g (0.00080 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 10 ml of dimethylformamide was treated with 0.34 ml (0.0024 mol) of triethylamine and 0.19 g (0.00097 mol) of 6-phenyl-1,2,3,4-tetrahydro-isoquinoline and the mixture was stirred at room temperature under argon for 60 hours The mixture was completely freed from the solvents. The residue was partitioned between dichloromethane and water, extracted, chromatographed over silica gel with acetonitrile/methanol 5:1 as the eluent and digested in diethyl ether. 0.16 g (61%) of 2-methyl-5-(6-phenyl-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-pyrimidin-4-ylamine was obtained as white crystals; m.p. 186°-188°. A further 0.03 g of pale yellow crystals was recovered from the mother liquor.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[N:8]([CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([F:35])[CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[C:9]2[C:14]([C:15]=1[CH2:16][N:17](S(C)(=O)=O)C)=[CH:13][C:12]([F:23])=[CH:11][CH:10]=2)=[O:6])[CH3:3]>>[CH2:2]([O:4][C:5]([C:7]1[N:8]([CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([F:35])[CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[C:9]2[C:14]([C:15]=1[CH2:16][NH2:17])=[CH:13][C:12]([F:23])=[CH:11][CH:10]=2)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1c(CN(C)S(C)(=O)=O)c2cc(F)ccc2n1Cc1cccc2ccc(F)cc12
Agent: Cl
Product: CCOC(=O)c1c(CN)c2cc(F)ccc2n1Cc1cccc2ccc(F)cc12

Procedure:
salt with HCl (prepared according to Example 104.2.) was converted to 5-fluoro-1-(7-fluoro-naphthalen-1-ylmethyl)-3-[(methanesulfonyl-methyl-amino)-methyl]-1H-indole-2-carboxylic acid ethyl ester as described in Example 77.1. which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 457.4 ([M−H]−).
Reaction SMILES: S[C:2]1[N:3]([CH:11]2[CH2:24][CH:23]3[CH:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[N+]([O-])(O)=O.[OH-].[Na+]>O>[CH2:22]1[CH:23]2[CH:18]([C:17]3[C:12]([CH:11]([N:3]4[C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=[CH:2]4)[CH2:24]2)=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)c1cnc(S)n1C1CC2CCCCC2c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=[N+]([O-])O
Product: COC(=O)c1cncn1C1CC2CCCCC2c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.1 %

Procedure:
A mixture of 19.0 parts of methyl 2-mercapto-1-(1,2,3,4,4a,9,10,10a-octahydro-9-phenanthrenyl)-1H-imidazole-5-carboxylate, 75 parts of nitric acid and 150 parts of water was stirred for 1 hour at room temperature. The reaction mixture was diluted with crushed ice and treated with a sodium hydroxide solution. The product was extracted with 1,1'-oxybisethane. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.9 parts (11.1%) of methyl 1-(1,2,3,4,4a,9,10,10a-octahydro-9-phenanthrenyl)-1H-imidazole-5-carboxylate; mp. 139.9° C. (compound 3.2).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:12][CH:13]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CN(C)C=O.CCOCC>[CH2:19]([N:17]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])[S:14]([C:11]1[CH:10]=[CH:9][C:8]([CH3:7])=[CH:13][CH:12]=1)(=[O:16])=[O:15])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCCCCCCCCCN(CCCCCCCCCCCCCC)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.3 %

Procedure:
Potassium carbonate (20.18 g; 146.00 mmol) is added to a solution of p-toluenesulfonamide (5.00 g; 29.20 mmol) and 1-bromotetradecane (21.70 ml; 73.00 mmol) in dimethylformamide (75 ml). The suspension is stirred for 20 h at reflux; the reaction medium is then cooled to room temperature, diluted with ether (100 ml) and filtered. The filtrate is washed with water (50 ml) and the aqueous phase is extracted with ether (100 ml). The combined organic phases are dried over sodium sulfate, filtered and concentrated under reduced pressure to give a white solid which is purified by chromatography on a column of silica gel (eluent: 40/60 dichloromethane/hexane) to give N,N-ditetradecyl-p-toluenesulfonamide (15.86 g; 96%) in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[Cl-].[Li+].[CH2:12]1[O:15][CH:13]1[CH3:14]>CN(C)C=O>[OH:15][CH:13]([CH3:12])[CH2:14][N:6]1[C:2]([CH3:9])([CH3:1])[C:3](=[O:8])[N:4]([CH2:12][CH:13]([OH:15])[CH3:14])[C:5]1=[O:7]
Reactant: CC1CO1
Reactant: CC1(C)NC(=O)NC1=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(O)CN1C(=O)N(CC(C)O)C(C)(C)C1=O
Temperature: 50 °C

Procedure:
A mixture of 217 g of 5,5-dimethylhydantoin (1.695 mols) 3.61 g of lithium chloride (5 mol per cent) and 560 ml of dimethylformamide is stirred at 50° C. 230 g. of propene oxide (propylene oxide) (3.955 mols) are added dropwise to the clear solution over the course of 4 hours, at 50°-55° C. The reaction is slightly exothermic. After the dropwise addition, the temperature is slowly raised to 90° C. After 5 hours at 90° C. the dimethylformamide is distilled off in a waterpump vacuum and thereafter the product is dried to constant weight at 100° C. and 0.1 mm Hg. 415 g of a pale yellow highly viscous oil (100 % of theory) are obtained. The crude product is distilled at 0.1 to 0.2 mm Hg and 170°-172° C.: 386.0 yield of pure material (93.5 % of theory). On cooling the 1,3-di(β -hydroxy-n-propyl)-5,5-dimethylhydantoin solidifies to give white crystals of melting point 65°-67° C. The elementary analysis shows 11.81 % N (calculated, 11.47 % N), and the molecular weight was determined by vapour pressure osmometry to be 247 (theory 244). The infrared spectrum shows the absence of N--H-- amide frequencies at 3.1 to 3.2 μ and the presence of C--OH frequencies at 2.90 μ.
Reaction SMILES: Cl[C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:13]2[CH:12]=[CH:11][S:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>C(#N)C>[N:21]1([C:2]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[C:13]3[CH:12]=[CH:11][S:10][C:9]=3[C:8]3[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: Cc1ccccc1C1(Cl)c2ccccc2-c2sccc21
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: Cc1ccccc1C1(n2ccnc2)c2ccccc2-c2sccc21
Yield: 62.4 %

Procedure:
6.1 g (20 mmoles) of crude 4-chloro-4-(2-methyl-phenyl)-4H-indeno[1,2-b]thiophene were taken up in 30 ml of acetonitrile, 4.1 g (60 mmoles) of imidazole were added and the mixture was heated under reflux for 5 hours. The crude product was then precipitated as a syrup by adding 70 ml of water. The supernatant solution was decanted off and the crude product was taken up in ether. The ether solution was dried and evaporated. The residue was taken up in 100 ml of 2 N hydrochloric acid, the insoluble material was separated off and, after cooling, the base was liberated again with sodium hydroxide solution and extracted with ether. The organic phase was dried over sodium sulphate and concentrated. 4.1 g (62.1% of theory) of 4-(imidazol-1-yl)-4-(2-methyl-phenyl)-4H-indeno[1,2-b]thiophene of melting point 75° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([NH:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[N:33][CH:34]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:34]=[N:33][C:32]([NH:35][CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]2)=[CH:31][CH:30]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc(NC2CCCCC2)nc1
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(NC4CCCCC4)nc3)c2CC1)C(F)(F)F
Yield: 56.9 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (800 mg, 1.9 mmol) with 5-aminomethyl-2-cyclohexylamino-pyridine (910 mg, 4.4 mmol) in anhydrous toluene (15 mL). Purify the residue by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 3:2 gradient) to obtain 7-chloro-6-(6-cyclohexylamino-pyridin-3-ylmethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (520 mg, 58%). MS (ES+) m/z: 481.0 (M+H)+.
Reaction SMILES: C([O:8][C:9](=[O:37])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[N:18]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])C1C=CC=CC=1>C(Cl)Cl.CCCCCC>[CH2:30]([N:18]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:11]1[C:12]([O:16][CH3:17])=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([OH:37])=[O:8])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(OC)cccc2C(=O)OCc2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(OC)cccc2C(=O)O)cc1
Yield: 90.3 %

Procedure:
In the same manner as described in Example 19, 1.86 g (3.6 mmol) of the product of Example 97 provided 1.39 g (90%) of the desired carboxylic acid as a white solid after trituration with CH2Cl2 :hexane (1:4). CI Mass Spec 428.1 (M+H).