Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]4[CH:18]([CH3:24])[CH2:19][C:20](=[O:23])[NH:21][N:22]=4)=[CH:16][C:10]=3[N:9]=2)C(=O)C2=CC=CC=C12.O.NN>>[NH2:5][CH2:6][CH2:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][C:15]([C:17]3[CH:18]([CH3:24])[CH2:19][C:20](=[O:23])[NH:21][N:22]=3)=[CH:16][C:10]=2[N:9]=1
Reactant: CC1CC(=O)NN=C1c1ccc2[nH]c(CCN3C(=O)c4ccccc4C3=O)nc2c1
Agent: NN
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc2[nH]c(CCN)nc2c1

Procedure:
##STR68## Prepared by a method analogous to that of Example 1d) from 1.44 g (3.6 mmol) of 6-[2-(2-phthalimidoethyl)-1H-benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone and 0.9 ml (18 mmol) of hydrazine hydrate. The crude product is chromatographed on silica gel with methanol/conc. ammonia (99:1). After concentration of the main fraction by evaporation under vacuum and crystallization of the residue from ethanol, 0.55 g (51%) of a colourless solid melting at 178° C. are obtained.
Reaction SMILES: [NH2:1][C:2]([CH3:33])([CH3:32])[C:3]#[C:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH3:31])[C:11]([CH:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24])=[C:12]2[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1.Cl[C:35]([O:37][CH3:38])=[O:36]>>[C:27]([O:26][CH:22]([C:11]1[C:10]([CH3:31])=[CH:9][C:8]2[C:13](=[CH:14][C:5]([C:4]#[C:3][C:2]([NH:1][C:35]([O:37][CH3:38])=[O:36])([CH3:33])[CH3:32])=[CH:6][CH:7]=2)[C:12]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:23]([OH:25])=[O:24])([CH3:28])([CH3:30])[CH3:29]
Reactant: COC(=O)Cl
Reactant: Cc1cc2ccc(C#CC(C)(C)N)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O
Product: COC(=O)NC(C)(C)C#Cc1ccc2cc(C)c(C(OC(C)(C)C)C(=O)O)c(-c3ccc(Cl)cc3)c2c1

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(3-(methoxycarbonylamino)-3-methylbut-1-ynyl)-3-methylnaphthalen-2-yl)acetic acid (97) was prepared by the method of Example 94 from 2-(7-(3-amino-3-methylbut-1-ynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid using methyl chloroformate. 1H-NMR: 400 MHz, (CD3OD) δ: 7.72 (d, J=8 Hz, 1H), 7.67 (s, 1H), 7.57 (m, 3H), 7.40 (d, J=8 Hz, 1H), 7.31 (d, J=9 Hz, 1H), 7.26 (s, 1H), 5.16 (s, 1H), 3.60 (s, 3H), 2.60 (s, 3H), 1.58 (s, 6H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C30H33ClNO5: 522.2. found: 522.1.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][OH:13])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>C(OCC)(=O)C>[C:1]1([C:7]2[CH:11]=[C:10]([CH:12]=[O:13])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1cc(-c2ccccc2)no1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CCOC(C)=O
Product: O=Cc1cc(-c2ccccc2)no1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
A solution of (3-phenylisoxazol-5-yl) methanol (10.0 g) and 2-iodoxybenzoic acid (24.0 g) in ethyl acetate (350 mL) was refluxed overnight. The mixture was cooled to room temperature, filtered and concentrated. The resulting solids were triturated (hexane:diethyl ether=1:1) to obtain the title compound (8.22 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:53]>CO.O1CCOCC1.ClCCCl>[ClH:1].[ClH:53].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:25][CH:26]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: O=CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCNC2CCCNC2)ccc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Prepared according to the method described in Example 66c from 2-chloro-5-(2-oxoethyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.094 g, Example 66b), 3-amino-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (0.109 g), sodium triacetoxyborohydride (0.081 g) and 1,2-dichloroethane (2 ml). After work-up, the residue was purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane. The white powder obtained was dissolved in methanol (2 ml) and a solution of hydrochloric acid in dioxane (4N, 1 ml) was added. The mixture was stirred for 14 h at room temperature. Solvents were then removed under reduced pressure and the product obtained was triturated with diethyl ether to afford the title compound as a white powder (0.065 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH2:15][CH2:16][CH2:17][C:4]=2[N:3]=1.[CH3:18][O:19][C:20]([C:22]1([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23]1)=[O:21].CCOCC>C(O)CCC>[CH3:18][O:19][C:20]([C:22]1([C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:2]3[N:7]=[C:6]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:5]4[CH2:15][CH2:16][CH2:17][C:4]=4[N:3]=3)=[CH:30][CH:31]=2)[CH2:23][CH2:24][CH2:25]1)=[O:21]
Reactant: Clc1nc2c(c(Oc3ccccc3)n1)CCC2
Reactant: COC(=O)C1(c2ccc(N)cc2)CCC1
Solvent: CCOCC
Solvent: CCCCO
Product: COC(=O)C1(c2ccc(Nc3nc4c(c(Oc5ccccc5)n3)CCC4)cc2)CCC1
Temperature: 27.5 °C
Reaction time: 12 h
Yield: 83.1 %

Procedure:
A mixture of 2-chloro-4-phenoxy-6,7-dihydro-5H-cyclopentapyrimidine (0.28 g, 1.1 mmol) and 1-(4-amino-phenyl)cyclobutanecarboxylic acid methyl ester (0.23 g, 1.11 mmol) in 1-butanol (3.0 mL) was stirred at a temperature in the range of 20° C. to 100° C. for 8 to 16 hours. Thereafter, the reaction was cooled to about 20 to 35° C. Anhydrous ether was added and the mixture was stirred for 1 hour at about 20 to 35° C. The separated solid was filtered, washed with ether, and dried in vacuum to afford the title compound as a white solid (0.38 g, 81% yield).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:27][C:28]1[CH:29]=[C:30]([CH3:37])[C:31]2[O:35][CH:34]=[CH:33][C:32]=2[CH:36]=1>C(Cl)(Cl)(Cl)Cl>[Br:27][C:28]1[CH:29]=[C:30]([CH2:37][Br:1])[C:31]2[O:35][CH:34]=[CH:33][C:32]=2[CH:36]=1
Reactant: Cc1cc(Br)cc2ccoc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc(Br)cc2ccoc12
Temperature: 25 °C
Yield: 31.5 %

Procedure:
N-Bromosuccinimide (10.0 g) and di-benzoylperoxide (500 mg) were added in five equal portions to a solution of 5-bromo-7-methylbenzofuran (9.7 g) stirring at reflux in CCl4 (100 ml), whilst being irradiated with an 850 W lamp. After the final addition, the reaction was stirred at reflux for a further 2 hours, then cooled to room temperature. The solution was filtered and the filtrate washed with 2N NaOH--H2O (40 ml), brine (40 ml), dried over MgSO4, filtered and the solvent removed under reduced pressure. Purification by MPLC (1% ethyl acetateln-hexane) gave 5-bromo-7-bromomethyl benzofuran as a dlear oil (4.2 g). 1H NMR (360 MHz,CDCl3)δ4.86 (2H, s), 6.69 (1H, d, J=3.0 Hz), 7.54 (1H, s), 7.62 (1H, s), 7.86 (1H, d, J=3.0 Hz).
Reaction SMILES: Cl.[CH:2]1([CH2:5][N:6]2[CH2:23][CH2:22][C@@:13]34[C:14]5[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=5[CH2:20][C@@H:7]2[C@@H:8]3[CH2:9][C:10]([CH3:25])([CH3:24])[O:11][CH2:12]4)[CH2:4][CH2:3]1.[C:26](Cl)(=[O:28])[CH3:27].N1C=CC=CC=1>C(Cl)Cl>[C:26]([O:21][C:16]1[CH:17]=[CH:18][C:19]2[CH2:20][C@H:7]3[N:6]([CH2:5][CH:2]4[CH2:4][CH2:3]4)[CH2:23][CH2:22][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][C:10]([CH3:25])([CH3:24])[O:11][CH2:12]4)(=[O:28])[CH3:27]
Reactant: CC1(C)C[C@H]2[C@H]3Cc4ccc(O)cc4[C@@]2(CCN3CC2CC2)CO1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)[C@]13CCN(CC4CC4)[C@H](C2)[C@@H]1CC(C)(C)OC3

Procedure:
Equimolar amounts of 17-cyclopropylmethyl-7,7-dimethyl-3-hydroxy-6-oxamorphinan (XIV, prepared in Example 5), acetyl chloride and pyridine are mixed together in dry methylene chloride and heated at reflux temperature for 3 hours to produce the title compound.
Reaction SMILES: S([O-])([O-])=O.[Na+:5].[Na+].[S:7]([O:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1)([CH3:10])(=[O:9])=[O:8].[OH-].[Na+]>O>[S:7]([O:11][C:12]1[CH:13]=[C:14]([S:18]([O-:20])=[O:19])[CH:15]=[CH:16][CH:17]=1)([CH3:10])(=[O:9])=[O:8].[Na+:5]
Reactant: CS(=O)(=O)Oc1cccc(S(=O)(=O)Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)Oc1cccc(S(=O)[O-])c1
Reaction time: 2 h

Procedure:
To a solution of sodium sulfite (63 g; 0.5 mole) in water (400 ml) was added m-mesyloxybenzenesulfonyl chloride (67.7 g; 0.25 mole). The mixture was stirred vigorously, adding 50 percent sodium hydroxide solution as needed to maintain pH at 7 to 7.25, holding the temperature at 20° to 25° C. by means of a cold water bath. After 2 hours, a clear solution with a small amount of brown sludge was obtained. The mixture was filtered through Celite and the filtrate was poured into an evaporating dish and slowly allowed to evaporate. The first material to separate (32.5 g) was inorganic (by I. R. Spectrum). Further evaporation afforded three crops of crystalline material which was used without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]([O:18]CC)=[O:17])=[C:14]([CH3:21])[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C1COCC1.O.[Li+].[OH-]>C(OCC)(=O)C>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]([OH:18])=[O:17])=[C:14]([CH3:21])[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(-c2noc(C)c2C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(-c2noc(C)c2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
To the crude ethyl 3-(4-(allyloxy)phenyl)-5-methylisoxazole-4-carboxylate (Preparation D) (0.66 g) was added 10 ml of THF, 0.5 mL of water, and 0.240 g of LiOH. The resulted reaction mixture was stirred at room temperature overnight. Water (150 mL) and ethyl acetate (150 mL) were added to the reaction mixture. Layers were separated and the aqueous solution was acidified by addition of 20 mL of 1.4 N HCl. The product was then extracted from the acidic aqueous solution with ethyl acetate (2×150 mL). The combined extract was dried over anhydrous sodium sulfate. Solvent was evaporated to give 0.600 g of product. LCMS (method B) RT 3.00 min., MH+260. 1H NMR (500 MHz, CD3OD) δ 7.57 (d, J=8.5Hz, 2H), 6.99 (d, J=8.5Hz, 2H), 6.16-6.01 (m, 1H), 5.45-5.24 (m, 2H), 4.60 (d, J=4.9Hz, 2H), 2.70 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH2:24][CH3:25])[CH:17]=3)[CH2:11][CH2:10]2)=[O:7])=[CH:4][N:3]=1.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:12]2[CH2:13][CH2:14][CH:9]([NH:8][C:6](=[O:7])[C:5]3[CH:26]=[CH:27][C:2]([NH:1][C:31]([CH:28]4[CH2:30][CH2:29]4)=[O:32])=[N:3][CH:4]=3)[CH2:10][CH2:11]2)=[CH:17][C:18]=1[O:23][CH2:24][CH3:25]
Reactant: CCOc1cc(CN2CCC(NC(=O)c3ccc(N)nc3)CC2)ccc1Cl
Reactant: O=C(Cl)C1CC1
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(NC(=O)C4CC4)nc3)CC2)ccc1Cl
Yield: 26 %

Procedure:
The title compound (12 mg, 26%) was prepared analogously to example 7 by coupling of 6-amino-N-[1-(4-chloro-3-ethoxy-benzyl)piperidin-4-yl]-nicotinamide with cyclopropanecarbonyl chloride. MS: 457.4 (MH+).
Reaction SMILES: [CH:1]12[N:7]([CH2:8][CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=3[C:18]3[N:19]([CH3:24])[N:20]=[CH:21][C:22]=3[Br:23])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.C1C([N+]([O-])=O)=CC=C([Cl-][C:35]([O-])=[O:36])C=1.[F:38][C:39]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:40]=1[CH2:41][NH2:42].C(N(CC)C(C)C)(C)C>ClCCCl>[CH:4]12[N:7]([CH2:8][CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:35]([NH:42][CH2:41][C:40]4[CH:43]=[CH:44][C:45]([F:47])=[CH:46][C:39]=4[F:38])=[O:36])=[CH:13][C:12]=3[C:18]3[N:19]([CH3:24])[N:20]=[CH:21][C:22]=3[Br:23])[CH:1]([CH2:2][CH2:3]1)[CH2:6][CH2:5]2
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1C2CCC1CC2
Reactant: NCc1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)NCc2ccc(F)cc2F)ccc1OCCN1C2CCC1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenylamine (50.0 mg, 0.13 mmol) was added to a solution of 4-nitrophenylchloroformate (26.0 mg, 0.13 mmol) in 1,2-dichloroethane (4.0 mL) and the mixture stirred at room temperature for 1 hour. To the resulting precipitate mixture was added 2,4-difluorobenzylamine (0.030 mL, 0.25 mmol) and N,N-diisopropylethylamine (0.030 mL, 0.17 mmol), and the mixture stirred an additional 1 hour. The mixture was concentrated and purified by RP-HPLC. The collected fractions were concentrated and 12% sodium hydroxide (aq) (0.2 mL) was added to give pH 9. The solution was extracted into ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to give a white solid (62 mg, 87%). LCMS m/z (%)=560 (M+H 79Br, 100), 562 (M+H 81Br, 91). 1H NMR (400 MHz, DMSO-d6) δ: 8.59 (bs, 1H), 7.58 (bs, 1H), 7.48-7.38 (m, 2H), 7.29 (bs, 1H), 7.24-7.18 (m, 1H), 7.10-7.04 (ma, 2H), 6.60-5.59 (m, 1H), 4.29 (d, J=4.0 Hz, 2H), 4.06-3.96 (m, 2H), 3.64 (s, 3H), 3.11 (bs, 2H), 2.58-2.54 (m, 2H), 1.54-1.52 (m, 4H), 1.15-1.13 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.OS(O)(=O)=O.[N+:16]([O-])([OH:18])=[O:17]>>[Cl:1][C:2]1[C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: N#Cc1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: 1.5 °C
Reaction time: 2 h

Procedure:
A mixture of 4-chloro-2-fluorobenzonitrile (4.62 g; 29.7 mmol) in cone. H2SO4 (42 mL) was treated dropwise with cone. HNO3 (3.9 mL) at 1-2° C. After stirring at 1-2° C. for 2 h the mixture was poured into ice and filtered to give the sub-title compound. Yield: 5.18 g (87%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[O:16][C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:14][C:13]=2[CH3:29])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:31][OH:32].C(N(CC)CC)C>O1CCCC1.CO>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[O:16][C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][CH:20]=3)=[N:14][C:13]=2[CH3:29])[CH:7]=[CH:6][C:3]=1[C:4]([NH:31][OH:32])=[NH:5]
Reactant: NO
Reactant: Cc1nc(CCc2ccc(C(F)(F)F)cc2)oc1COc1ccc(C#N)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(CCc2ccc(C(F)(F)F)cc2)oc1COc1ccc(C(=N)NO)c(Cl)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 136 %

Procedure:
3.0 g 2-Chloro-4-{4-methyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-oxazol-5-ylmethoxy}-benzonitrile were dissolved in a mixture of 20 ml tetrahydrofuran and 20 ml methanol. 9.91 g hydroxylamine hydrochloride were added followed by the addition of 19.9 ml triethylamine. The reaction mixture was stirred at 65° C. overnight. The solvents were removed in vacuo and the resulting residue poured into water and extracted five times with ethylacetate. The combined organic extracts were washed with brine, dried over MgSO4 and the solvent was evaporated in vacuo to obtain 4.4 g crude 2-chloro-N-hydroxy-4-{4-methyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-oxazol-5-ylmethoxy}-benzamidine which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:10][CH2:9]2)[CH:3]=1.[Li]CCCC.C(OCC)C.[S:21](Cl)([Cl:24])(=[O:23])=[O:22]>C1COCC1.C(OCC)C.CCCCCC>[CH:8]1([C:4]2[CH:3]=[C:2]([S:21]([Cl:24])(=[O:23])=[O:22])[CH:7]=[CH:6][CH:5]=2)[CH2:10][CH2:9]1
Reactant: O=S(=O)(Cl)Cl
Reactant: Brc1cccc(C2CC2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: O=S(=O)(Cl)c1cccc(C2CC2)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Bromo-3-cyclopropyl-benzene (1.0 g, 5.1 mmol) [prep.: J. Org. Chem. vol. 41, 2262-6 (1976)] was dissolved in dry THF/diethyl ether (1:1, 30 ml) under an argon atmosphere and cooled to −78° C. BuLi (1.6 M in hexanes, 3.2 ml, 5.1 mmol) was added dropwise and the reaction mixture was further stirred at low temperature for 15 min. This reaction mixture was added via cannula to a SO2 gas saturated solution of diethyl ether (20 ml) precooled to −78° C. The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure. The crude intermediate was suspended in n-hexane (4A sieves dried, 20 ml) and chilled (ice-water). A solution of sulfuryl chloride (0.3 ml, 3.6 mmol) in dry hexane (8 ml) was added dropwise to the stirred suspension and then the cold bath was removed. After 90 min at room temperature the reaction mixture was filtered (Speedex pad) and the filtrate was concentrated under reduced pressure to yield a yellow oil: 0.6 g, (67%) GC-MS: M=216.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH:12]=[O:13].C(C(OC1C(OC(C(C)(C)C)=O)=C(I)C=CC=1)=O)(C)(C)C.[CH3:35][S:36]([NH2:39])(=[O:38])=[O:37]>C(OC(C)C)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[C:12]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:13]
Reactant: CS(N)(=O)=O
Reactant: O=Cc1c[nH]c2cc(Cl)c(Br)cc12
Agent: CC(C)(C)C(=O)Oc1cccc(I)c1OC(=O)C(C)(C)C
Solvent: CC(=O)OC(C)C
Product: CS(=O)(=O)NC(=O)c1c[nH]c2cc(Cl)c(Br)cc12
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 5-bromo-6-chloro-1H-indole-3-carbaldehyde (445 mg, 1.72 mmol), Bis(tert-butylcarbonyloxy)iodobenzene (961 mg, 2.30 mmol) in isopropyl acetate (2 mL) was added methanesulfonamide (111 mg, 1.15 mmol). After stirring 5 minutes, Bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)] (18.3 mg, 0.0230 mmol) was added and heated to 50° C. for 2 h. The reaction was filtered and the collected solid (245 mg) was identified as a mixture of the title compound and 5-bromo-6-chloro-1H-indole-3-carbaldehyde. The mixture was taken forward without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[NH2:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][S:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@@H:15]23)[CH:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][S:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][NH:27][CH2:28][C@@H:15]23)[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Product: Clc1ccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)cc1Cl

Procedure:
Using 3,4-dichlorobenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 158. LRMS (ES)+: 420.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:25]3[CH:30]=[CH:29][C:28]([O:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH:17]C(OC(C)(C)C)=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[NH2:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:25]2[CH:30]=[CH:29][C:28]([O:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=2)([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[N:9]=1
Reactant: CC(C)(C)OC(=O)NC1=NC(c2ccc(OS(C)(=O)=O)cc2)(c2cccc(Br)c2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)cc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To methanesulfonic acid 4-[1-(3-bromo-phenyl)-3-tert-butoxycarbonylamino-1H-isoindol-1-yl]-phenyl ester (Scheme #6, T) (730 mg, 1.31 mmol) was added 10% trifluoroacetic acid in dichloromethane (10 mL) and the reaction stirred 30 minutes. The solvents were removed under reduced pressure and the resulting oil put under high vacuum. Ether, 20 mL, was added to the gum and the solvent removed under reduced pressure giving the title compound (671 mg, 90%). 1H NMR (500 MHz, DMSO-d6) δ 8.32 (d, J=7.9 Hz, 1 H), 7.90-7.86 (m, 2 H), 7.76 (ddd, J=7.9, 6.1, 2.0 Hz, 1 H), 7.63 (d, J=8.0 Hz, 1 H), 7.46 (t, J=1.8 Hz, 1 H), 7.41-7.35 (m, 5 H), 7.31 (d, J=8.5 Hz, 1 H), 3.40 (d, J=4.0 Hz, 3 H); MS (ES+) m/z 457 [M+1]+; tR=1.84 min.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=1.[C:19](OCC)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.[OH-].[Na+]>C1COCC1>[F:11][C:12]1[CH:17]=[C:16]([CH2:18][C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:26])[CH:15]=[CH:14][N:13]=1
Reactant: CCOC(=O)c1ccccc1
Reactant: Cc1ccnc(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Cc1ccnc(F)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 72.3 %

Procedure:
A solution of sodium bis(trimethylsilyl)amide (36 mL, 1M) was diluted with THF (60 mL) and cooled to 0° C. 2-Fluoro-4-methylpyridine (2.0 g, 18 mmol) was then added and after 45 min. at 0° C. ethyl benzoate (3.24 g, 21 mmol) was added dropwise. Stirring was continued for 45 min. and the solution then poured into 2M HCl (100 mL) cooled to 0° C. After thorough mixing, the solution was basified to pH9 with 5M NaOH, and the product extracted into ether (3×30 mL). The ethereal layers were combined and washed with brine (1×30 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in a minimum of dichloromethane and precipitated by addition of pet. spirit. The solid was collected and washed with cold pet. spirit to afford the pure product as a pale brown solid (2.8 g, 72%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:35])[NH:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[C:18]([C:27]#[C:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:17]=2)[CH3:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:35])[NH:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[C:18]([CH:27]=[CH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:17]=2)[CH3:15])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(NC(=O)Nc1ccc(C(C)(C)C)cc1)c1ccc(NS(C)(=O)=O)c(C#Cc2ccccc2)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: CC(NC(=O)Nc1ccc(C(C)(C)C)cc1)c1ccc(NS(C)(=O)=O)c(C=Cc2ccccc2)c1
Reaction time: 12 h
Yield: 31.9 %

Procedure:
N-(4-{1-[3-(4-tert-Butyl-phenyl)-ureido]-ethyl}-2-phenylethynylphenyl)-methanesulfonamide (50 mg, 0.102 mmol, 1 eq.) and palladium on calcium carbonate, poisoned with lead (Lindlar catalyst) were added in methanol. The reaction mixture stirred 12 hrs under H2 atmosphere. The reaction mixture was filtered with celite pad. The filterate was concentrated in vacuo. The residue was purified with column chromatography (n-Hx:EA=2:1) to yield title compound (16 mg, 32%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]#[N:21])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:22])[CH:5]=1.Br[C:25]1[CH:26]=[N:27][N:28]([CH2:30][CH3:31])[CH:29]=1>>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]#[N:21])=[CH:17][CH:18]=3)[N:13]([C:25]3[CH:26]=[N:27][N:28]([CH2:30][CH3:31])[CH:29]=3)[C:12]=2[CH3:22])[CH:5]=1
Reactant: CCn1cc(Br)cn1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(C#N)ccc23)c1
Product: CCn1cc(-n2c(C)c(Sc3cccc(C(=O)OC)c3)c3ccc(C#N)cc32)cn1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-cyano-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 4-bromo-1-ethyl-1H-pyrazole.