Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=3)=[O:21])[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.ClC1C=CC=C(C(OO)=[O:40])C=1>C(Cl)Cl>[CH3:1][C:2]1([CH2:13][N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([S:30]([CH3:31])=[O:40])=[CH:28][CH:29]=3)=[O:21])[CH2:18][CH2:19]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(COC(=O)N2CCN(CC3(C)Cn4cc([N+](=O)[O-])nc4O3)CC2)cc1
Solvent: ClCCl
Product: CS(=O)c1ccc(COC(=O)N2CCN(CC3(C)Cn4cc([N+](=O)[O-])nc4O3)CC2)cc1
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To a mixture of 4-methylsulfanylbenzyl 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate prepared in Example 345 (300 mg, 0.67 mmol) and methylene chloride (10 ml), m-chloroperbenzoic acid (210 mg, 0.85 mmol) was added followed by stirring for 2 hours with cooling on ice-bath. The reaction mixture was washed with a saturated sodium sulfite solution, a saturated sodium hydrogencarbonate solution, and a saturated saline solution in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from isopropyl alcohol-ether to afford 4-methanesulfinylbenzyl 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (203 mg, yield 65%) as a white powder.
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[CH:4][CH:3]=1.C([O-])(=O)C1C=CC(C([O-])=O)=CC=1.[NH4+:25].[NH4+:26]>[Ti].O>[C:1](#[N:26])[C:2]1[CH:10]=[CH:9][C:5]([C:6]#[N:25])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: [NH4+]
Agent: [Ti]
Agent: O=C([O-])c1ccc(C(=O)[O-])cc1
Solvent: O
Product: N#Cc1ccc(C#N)cc1
Temperature: 280 °C
Reaction time: 1 h

Procedure:
To a two-liter all-titanium stirred autoclave is added 146.19 g. (0.88 moles) of terephthalic acid, 24.02 g. (0.12 moles) of diammonium terephthalate and 1000 ml. of water. This mixture is heated with stirring to 280° C and held at this temperature for approximately one hour. The resultant equilibrated mixture represents the hydrolyzate obtained by the non-catalytic hydrolysis of terephthalonitrile which would result from the removal, as ammonia, of 88 percent of the total available nitrogen from a one molal solution of terephthalonitrile. That this is so is clearly evident from the hydrolysis equilibria of a terephthalonitrile hydrolysis system which are discussed above. The reactor is then rapidly cooled to ambient temperature and sufficient NaOH is added to the contents of the reactor to effect complete solution at room temperature. An excess of H2SO4 is then added to effect precipitation of the terephthalic acid product. After filtration, thorough washing and drying, a sample of the acid is submitted for determination of parts per million (by weight) of nitrogen. The value of 2400 ppm corresponds to 2.84 mole percent terephthalamic acid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:15][NH:16][C:17]([C:19]3[NH:28][C:22]4=[CH:23][N:24]=[C:25]([Cl:27])[CH:26]=[C:21]4[CH:20]=3)=[O:18])OCC[O:11]2)=[CH:6][CH:5]=1>CC(C)=O>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:11])[CH2:15][NH:16][C:17]([C:19]2[NH:28][C:22]3=[CH:23][N:24]=[C:25]([Cl:27])[CH:26]=[C:21]3[CH:20]=2)=[O:18])=[CH:8][CH:9]=1
Reactant: COc1ccc(C2(CNC(=O)c3cc4cc(Cl)ncc4[nH]3)OCCO2)cc1
Agent: Cl
Solvent: CC(C)=O
Product: COc1ccc(C(=O)CNC(=O)c2cc3cc(Cl)ncc3[nH]2)cc1
Temperature: 25 °C

Procedure:
Aqueous hydrochloric acid (2.1 mL, 2M) was added to a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid [2-(4-methoxyphenyl)[1,3]dioxolan-2-ylmethyl]amide (Preparation 49, 160 mg, 0.41 mmol) in acetone (20 mL). The mixture was heated under reflux for 90 min then allowed to cool to rt. The suspension was filtered then washed with acetone and air dried, to give the title compound as a pale yellow solid. δH (d6 DMSO): 3.86 (3H, s), 4.79 (2H, d), 7.08 (2H, d), 7.23 (1H, s), 7.77 (1H, s), 8.03 (2H, d), 8.58 (1H, s), 9.14 (1H, t), 12.31 (1H, br s). m/z (ES+)=344 [M+H]+; RT=3.34 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[CH3:20][S:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:20][S:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:8]([CH2:7][C:6]2[CH:18]=[CH:19][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:9]2[CH:17]=[CH:16][C:12]3[NH:13][CH:14]=[N:15][C:11]=3[CH:10]=2)=[CH:24][CH:23]=1
Reactant: CCc1ccc(CNc2ccc3nc[nH]c3c2)cc1
Reactant: CSc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(CN(Cc2ccc(SC)cc2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from N-(4-ethylbenzyl)benzimidazol-5-amine (251 mg; 1 mmol; 1 eq.), 4-methylthiobenzylbromide (239 mg; 1.1 mmol; 1.1 eq.) and K2CO3 (152 mg; 1.1 mmol; 1.1 eq.) according to method 6; Yield: 0.166 g (42.9%); MS m/z: 388.4
Reaction SMILES: [NH2:1][C:2]1[C:26]([Cl:27])=[CH:25][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:18]([O:20]C(C)(C)C)=O)[CH2:12]2)=[O:7])=[C:4]([O:28][CH3:29])[CH:3]=1.[NH2:30][C:31]1[C:39]([Cl:40])=[CH:38][C:34](C(O)=O)=[C:33]([O:41][CH3:42])[CH:32]=1>>[NH2:30][C:31]1[C:39]([Cl:40])=[CH:38][C:34]([C:18]([NH:17][CH2:16][CH:13]2[CH2:14][CH2:15][N:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:25]=[C:26]([Cl:27])[C:2]([NH2:1])=[CH:3][C:4]=3[O:28][CH3:29])[CH2:12]2)=[O:20])=[C:33]([O:41][CH3:42])[CH:32]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCCN1CCC(CNC(=O)OC(C)(C)C)C1
Product: COc1cc(N)c(Cl)cc1C(=O)NCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)C1

Procedure:
4-Amino-N-(2-(3-tert-butoxycarbonylaminomethylpyrrolidin-1-yl)-ethyl)-5-chloro-2-methoxybenzamide (0.97 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.50 g) to give 4-amino-N-(1-(2-(4-amino-5-chloro-2-methoxybenzoylamino)ethyl)pyrrolidin-3-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.Cl.[Cl:28][C:29]1[CH:30]=[C:31]([CH2:36][C:37]([N:39]2[CH2:44][CH2:43][C:42](=[O:45])[CH2:41][CH:40]2[CH2:46][N:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)=[O:38])[CH:32]=[CH:33][C:34]=1[Cl:35].Cl>CCCCCC.C1(C)C=CC=CC=1>[ClH:28].[Cl:28][C:29]1[CH:30]=[C:31]([CH2:36][C:37]([N:39]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41][C@@H:40]2[CH2:46][N:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)=[O:38])[CH:32]=[CH:33][C:34]=1[Cl:35]
Reactant: O=C1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C(CN2CCCC2)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CC[C@H](O)C[C@@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 153.1 %

Procedure:
Diisobutyl aluminium hydride (142 ml of a 1M solution in hexane) was added dropwise to a stirred solution of 2,6-di-tert-butyl-4-methylphenol (62.24 g) in dry toluene (590 ml) at 4° under nitrogen. After stirring for 45 min the mixture was cooled to -60° and a solution of the free base of the product of Example 8, (5.2 g) in dry toluene (95 ml) was added over 5 min. The reaction mixture was stirred at -60° for 2 h and allowed to warm to room temperature and stirred at room temperature for a further 1 h. Dilute hydrochloric acid (1M, 500 ml) was added and the resulting mixture was stirred vigorously for 1 h. The layers were separated and the aqueous layer was washed with ether (500 ml), basified with aqueous sodium hydroxide (2M, 500 ml) and extracted with dichloromethane (3×500 ml). The dichloromethane extracts were combined, dried and evaporated to give the free base of the title compound as a foam (4 g) which was shown by g.l.c. to have a cis:trans ratio of 98.6:1.4. A portion of the foam (1 g) was dissolved in a mixture of ether (40 ml)/ethyl acetate (10 ml) and an ethereal solution of hydrogen chloride was added to give a solid (1.07 g). This solid was crystallised from a mixture of ethanol (20 ml)-ethyl acetate (20 ml) to give the title compound (669 mg) as a solid, m.p. 202°-203°.
Reaction SMILES: [CH2:1]1[CH2:6][C:5](=[C:7]2[C:17](=[C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]3[CH:12]([OH:16])[C:13](=[O:15])[O:14][C:10]=3[C:9]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8]2)[CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.N(C1CCN(C)C(C)(C)C1C)C(C)=O>ClCCl>[CH2:3]1[CH2:4][C:5](=[C:7]2[C:17](=[C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]3[C:12](=[O:16])[C:13](=[O:15])[O:14][C:10]=3[C:9]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8]2)[CH2:6][CH2:1][CH2:2]1
Reactant: CC(C)(C)c1cc(=C2CCCCC2)c(=C2CCCCC2)c2c1OC(=O)C2O
Agent: CC(=O)NC1CCN(C)C(C)(C)C1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(=C2CCCCC2)c(=C2CCCCC2)c2c1OC(=O)C2=O
Yield: 136.4 %

Procedure:
5.1 g (0.01 mol) of bis(5-cyclo-hexylidene)-7-tert-butyl-3-hydroxy-benzofuranone (U.S. Pat. No. 5,614,572, compound 107, Table 1), 8.75 g (0.046 mol) of p-toluenesulfonic acid and 9.8 g (0.046 mol) of 4-acetamino-tetramethylpiperidine (TEMPO) are stirred in 60 ml of dichloromethane at room temperature for 48 hours. The yellow solution is then washed with 50 ml of 5% hydrochloric acid and 4×50 ml of water, dried over magnesium sulfate and concentrated to dryness by evaporation. The residue is dissolved in 100 ml of toluene, and the solution is heated under reflux for 1 hour and then concentrated by evaporation again, yielding 5 g of the abovementioned compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[S:16])[NH:5][C:6]=1[C:7](=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:18]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4](=[S:16])[NH:5][C:6]=1[C:7](=[S:18])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1[nH]c(=S)[nH]c1C(=O)Cc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1[nH]c(=S)[nH]c1C(=S)Cc1ccccc1

Procedure:
In 100 ml toluene is placed 15 g 1,3-dihydro-4-methyl-5-(2-phenylacetyl)-2H-imidazol-2-thione and 15 g phosphorus pentasulfide. The mixture is refluxed 5 hours and the solvent is evaporated to give the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:40])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([NH:33]CC(O)=O)=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.C(OC(NCCCC[C@H](C(OC(C)(C)C)=O)N)=O)(C)(C)C.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.O1C2C=CC(C(O)CS[C@H]3C(=O)N(C4C=CC(F)=CC=4)[C@@H]3C3C=CC(OCC(N[CH2:125][C:126]([NH:128][C@@H:129]([C:142]([O:144]C(C)(C)C)=[O:143])[CH2:130][CH2:131][CH2:132][CH2:133][NH:134]C(OC(C)(C)C)=O)=[O:127])=O)=CC=3)=CC=2OC1>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:40])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:125][C:126]([NH:128][C@@H:129]([C:142]([OH:144])=[O:143])[CH2:130][CH2:131][CH2:132][CH2:133][NH2:134])=[O:127])=[O:32])=[CH:38][CH:39]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(F)cc2)cc1)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)NCCCC[C@@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: NCCCC[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N-({4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycine (11.3 mg, 0.020 mmol) in DCM (2 ml) were added tert-butyl N6-(tert-butoxycarbonyl)-D-lysinate hydrochloride (9.5 mg, 0.028 mmol), N-methylmorpholine (15 μl, 0.091 mmol) and TBTU (11.0 mg, 0.034 mmol). The reaction mixture was stirred at ambient temperature for 3 hours. The formation of the intermediate tert-butyl N-({4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-N6-(tert-butoxycarbonyl)-D-lysinate was confirmed. M/z: 852.23 (M−1). The solvent was removed under reduced pressure and the residue was dissolved in formic acid (2 ml). The mixture was stirred at ambient temperature for 48 hours. The solvent was co-evaporated with toluene and the residue was purified with preparative HPLC on a C8 column, UV 240/260 nm. A gradient from 20 to 45% MeCN in 0.1M NH4OAc buffer was used as eluent. The MeCN was removed under reduced pressure and the residue was lyophilised to give the title. H-NMR (400 MHz, DMSO-d6): 1.08-1.32 (m, 2H), 1.37-65 (m, 4H), 2.63 (t, 2H), 2.77-2.92 (m, 2H), 3.70 (d, 2H), 3.76-3.82 (m, 1H), 4.25 (d, 0.5H), 4.28 (d, 0.5H), 4.50 (s, 2H), 4.57-4.64 (m, 1H), 5.00 (d, 0.5H), 5.02 (d, 0.5H), 5.90-5.94 (m, 2H), 6.70-6.81 (m, 2H), 6.83 (s, 1H), 6.96 (d, 2H), 7.08-7.16 (m, 2H), 7.17-7.24 (m, 2H), 7.34 (d, 2H), 7.45-7.55 (m, 1H), 8.37-8.43 (m, 1H). M/z: 697.32 (M+1) and 695.39 (M−1).
Reaction SMILES: [C:1]([C:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29]([OH:31])=[O:30])=[CH:26][CH:27]=2)[NH:22][CH:21]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl(O)(=O)(=O)=O>C(O)(=O)C.[Pd]>[CH2:1]([CH:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29]([OH:31])=[O:30])=[CH:26][CH:27]=2)[NH:22][CH2:21]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][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)c1c[nH]c2cc(C(=O)O)ccc12
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCC1CNc2cc(C(=O)O)ccc21
Yield: 42.7 %

Procedure:
3-(n-Octadecanoyl)indole-6-carboxylic acid (20.5 g) in glacial acetic acid (300 ml), containing perchloric acid (13 ml, of strength 70% w/v), was hydrogenated over palladium on charcoal (3 g of 5% w/w) at atmospheric pressure and at a temperature of 80°-90° C. The mixture was then hot filtered through diatomaceous earth and was poured into water (1500 ml) to give an off-white solid. The solid was collected, washed with water (2×100 ml) and was dissolved in ethyl acetate (100 ml). The ethyl acetate solution was washed with an aqueous solution of sodium carbonate (of strength 2N, 150 ml) and the organic layer was separated and was dried over magnesium sulphate. The organic solvent was removed in vacuo to give (RS)-3-(n-octadecyl)indoline-6-carboxylic acid (8.5 g), in the form of an off-white solid, m.p. 112°-114° C.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[OH:31][C:32]1([C:39]2[S:43][C:42]([CH:44]([CH3:46])[CH3:45])=[N:41][CH:40]=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>>[OH:31][C:32]1([C:39]2[S:43][C:42]([CH:44]([CH3:46])[CH3:45])=[N:41][CH:40]=2)[CH2:33][CH2:34][CH:35]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:36][CH2:37]1
Reactant: CC(C)c1ncc(C2(O)CCC(=O)CC2)s1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ncc(C2(O)CCC(N3CC(NC(=O)CNc4nn(C)c5ccc(C(F)(F)F)cc45)C3)CC2)s1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-hydroxy-4-(2-isopropyl-thiazol-5-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[CH:19](N(C)C)[N:20]([CH3:22])[CH3:21])(C)(C)C>>[CH3:19][N:20]([CH3:22])/[CH:21]=[C:9]1/[C:8](=[O:13])[CH:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:12][CH2:11][CH2:10]/1
Reactant: O=C1CCCCC1C1CCCCC1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)/C=C1\CCCC(C2CCCCC2)C1=O

Procedure:
2-Cyclohexylcyclohexanone (99 mg, 0.55 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (116 mg) as a brown solid which was used directly in the next step. MS ISP (m/e): 236.2 (100) [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=[S:6].[C:14](O)(=[O:16])[CH3:15].C(OC(=O)C)(=O)C>O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12][C:14]([CH3:15])=[O:16])[C:9]([CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=[S:6]
Reactant: COc1cc(N)c(C)cc1C(O)=S
Reactant: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1cc(NC(C)=O)c(C)cc1C(O)=S
Temperature: 85 °C

Procedure:
260 g of 2-methoxy-4-amino-5-methyl-thio-benzoic acid and 520 ml of acetic acid are placed in a 2 liter flask fitted with an agitator, a thermometer, a condenser and a dropping funnel. 123 ml of acetic anhydride (density 1.082) is poured in slowly. The temperature rises to reach 40° C. The reaction mixture is heated for 1 hour 30 at 85° C., cooled and poured over 1,000 g of ice and 1,000 ml of water. The precipitate which forms is filtered, washed with water and dried in an oven at 50° C.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].O.C(N(CC[Cl:20])CC)C>C(C(C)=O)C>[ClH:20].[C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCN(CC)CCCl
Agent: CCCC(=O)c1ccccc1
Solvent: CCC(C)=O
Solvent: O
Product: Cl

Procedure:
Five grams of the butyrophenone are dissolved in 100 mls of methyl ethyl ketone; 4.2 grams of water-free potash are added to this. The reaction medium is well stirred while adding dropwise 5.2 grams of diethylaminoethylchloride. This mixture is boiled under reflux for 3 days. The inorganic salts are sucked off, the methyl ethyl ketone is evaporated in vacuo, and, after taking up the residue in ether, it is washed several times with water. After drying the ethereal phase with sodium sulfate, the hydrochloride is precipitated by adding ethereal hydrochloric acid. 4-[2-N,N-diethylamino)-ethoxy]-3,5-dimethyl-γ-[4'-chloro-3'-methyl)-phenoxy]-butyrophenone hydrochloride (Melting point of 156° C.), is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[N:18]([C:21]([CH3:27])([CH3:26])[CH2:22][C:23](Cl)=[O:24])=[N+:19]=[N-:20].Cl>ClCCCl>[N:18]([C:21]([CH3:27])([CH3:26])[CH2:22][C:23]([N:5]1[CH2:6][CH2:7][C:2]([CH3:8])([CH3:1])[CH2:3][CH2:4]1)=[O:24])=[N+:19]=[N-:20]
Reactant: CC1(C)CCNCC1
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCN(C(=O)CC(C)(C)N=[N+]=[N-])CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a stirred ice cold solution of 4,4-dimethylpiperidine (4.21 g, 1 equiv, 37.2 mmol) and DIEA (9.73 mL, 1.5 equiv, 55.9 mmol) in anhydrous DCE (65 mL) was added 3-azido-3-methylbutanoyl chloride (6.02 g, 37.2 mmol) in small portions. The reaction was stirred and left at 0° C. for 1 h. Aqueous 1 M HCl (100 mL) was added to the reaction mixture and the contents poured into a separatory funnel. The organic layer was separated and washed with 1 M HCl (100 mL). It was dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a crude oil (7.72 g, 87.1%). The crude oil was purified on an ISCO purification system with gradient elution from 20-50% ethyl acetate in hexanes. The desired fractions were collected and concentrated to give a colorless oil (6.00 g, yield: 67.7%). 1H NMR (CDCl3, 400 MHz): δ 0.98 (s, 6H), 1.32-1.39 (m, 4H), 1.45 (s, 6H), 2.52 (s, 2H), 3.42-3.47 (m, 2H), 3.55-3.60 (m, 2H). LRMS (ESI+) for C12H22N4O (238.2); Found: 239 (M+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:26]=[CH:25][C:13]([O:14][CH:15]([CH3:24])[CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36]>C(Cl)Cl>[CH3:36][CH:35]([CH3:37])[C:34]([NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:26]=[CH:25][C:13]([O:14][CH:15]([CH3:24])[CH2:16][NH:17][S:18]([CH:21]([CH3:22])[CH3:23])(=[O:20])=[O:19])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=[O:38]
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CN)cc2)cc1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CNC(=O)C(C)C)cc2)cc1
Yield: 19 %

Procedure:
The final title compound (59 mg, 19%) was prepared from (2-{4-[4-(aminomethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]amine hydrochloride (250 mg, 0.717 mmol, prepared in example 32) methylene chloride (4.6 mL, absolute) triethylamine (0.07 mL, 0.8621 mmol), aind isobutyryl chloride (0.06 mL, 1.0345 mmol), in a manner analogous to Example 29.
Reaction SMILES: OO.O[Li].O.C([C@@H]1COC(=O)N1[C:19](=[O:43])[C@H:20]([C@H:29]1[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:32]([CH3:42])([CH3:41])[CH2:31][CH2:30]1)[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([F:28])[CH:22]=1)C1C=CC=CC=1.[O-:44]S([O-])=O.[Na+:48].[Na+]>C1COCC1.O>[Na+:48].[C:37]([O:36][C:34]([N:33]1[C:32]([CH3:42])([CH3:41])[CH2:31][CH2:30][C@H:29]1[C@H:20]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([F:28])[CH:22]=1)[C:19]([O-:43])=[O:44])=[O:35])([CH3:38])([CH3:39])[CH3:40]
Reactant: O=S([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccc(Cl)c(F)c2)CCC1(C)C
Agent: OO
Agent: [Li]O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)[O-])c2ccc(Cl)c(F)c2)CCC1(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
30% H2O2 (0.159 mL, 1.65 mmol) was added to a solution of LiOH—H2O (0.055 g, 1.32 mmol) in 2:1 THF:H2O (40 mL). The mixture was stirred for 20 minutes and then cooled to 0° C. A solution of (S)-tert-butyl 5-((S)-2-((R)-4-benzyl-2-oxooxazolidin-3-yl)-1-(4-chloro-3-fluorophenyl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.360 g, 0.660 mmol) in THF (3 mL) was next added slowly. Upon completion of the addition, the reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was then recooled to 0° C., and 1M Na2SO3 (4 mL) was added. The reaction was stirred for 10 minutes at 0° C. and then warmed to room temperature and stirred for an additional 10 minutes. The reaction was then concentrated in vacuo to remove THF, and the resulting mixture was washed with EtOAc. The organic fraction was then dried over sodium sulfate, filtered and concentrated to give (S)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)-2-(4-chloro-3-fluorophenyl)acetic acid sodium salt (0.24 g, 94%) as a powder. MS ESI (+) m/z 386 detected.