Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na:1].C([O:9][C@@H:10]1[C@@H:15]([O:16]CC2C=CC=CC=2)[C@H:14]([O:24]CC2C=CC=CC=2)[C@@H:13]([CH2:32][S:33]([OH:36])(=[O:35])=[O:34])[O:12][C@@H:11]1[O:37][CH2:38][CH2:39][CH2:40][O:41][C:42](=[O:60])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])C1C=CC=CC=1.[H][H]>C(O)C.ClCCl.[Pd]>[Na:1].[S:33]([CH2:32][C@H:13]1[O:12][C@H:11]([O:37][CH2:38][CH2:39][CH2:40][O:41][C:42](=[O:60])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C@H:10]([OH:9])[C@@H:15]([OH:16])[C@@H:14]1[OH:24])([OH:36])(=[O:34])=[O:35]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCCCO[C@H]1O[C@H](CS(=O)(=O)O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Pd]
Agent: [Na]
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)OCCCO[C@H]1O[C@H](CS(=O)(=O)O)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
To a solution of the compound (9) (28.7 g, 33.3 mmol) in ethanol (400 ml) and dichloromethane (150 ml) was added 10% palladium activated carbon (7.00 g), and the mixture was stirred at room temperature for 48 hours in a hydrogen gas atmosphere. After the sufficient progress of the reaction was confirmed, palladium activated carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified with silica gel chromatography (dichloromethane-methanol, 10:1→5:1→3:1→2:1→1:1), and precipitated from 98% heated ethanol to obtain the title compound (10) in the form of a colorless powder {15.6 g (26.4 mmol), 79.4%}.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])=[CH:10][CH:9]=2)[C:5]2[CH:22]=[C:23]([C:26]3[N:30]([CH3:31])[C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[N:27]=3)[CH:24]=[CH:25][C:4]=2[N:3]=1.[N-:36]=[N+:37]=[N-:38].[Na+]>CN(C)C=O>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[NH:38][N:37]=[N:36][N:21]=3)=[CH:12][CH:13]=2)[C:5]2[CH:22]=[C:23]([C:26]3[N:30]([CH3:31])[C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[N:27]=3)[CH:24]=[CH:25][C:4]=2[N:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nc2ccc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2ccc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 41 from 4'-[[2-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:9]=[C:10]([C:20]2[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=2)[CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CC(C)=O.O>[CH2:32]([O:31][C:29]([N:17]1[CH2:18][CH2:19][N:14]([C:13]2[CH:12]=[CH:11][C:10]([C:20]3[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=3)=[CH:9][C:8]=2[F:7])[CH2:15][CH2:16]1)=[O:30])[CH3:33]
Reactant: CC1CC(=O)NN=C1c1ccc(N2CCNCC2)c(F)c1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)N1CCN(c2ccc(C3=NNC(=O)CC3C)cc2F)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
1.2 g (8.6 mmol) of potassium carbonate are added to a solution of 1.0 g (3.4 mmol) of 6-[3-fluoro-4-(piperazin-1-yl)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone in 10 ml of acetone and 10 ml of water. When the suspension has cooled down to 0° C., 0.42 ml (4.4 mmol) of ethyl chloroformate are added and stirring is continued for 30 minutes. The precipitated solid is suction filtered, washed with 10 ml of acetone-water mixture and recrystallized from 40 ml of acetonitrile. 0.73 g (60%) of a colourless solid, m.p. 193°-194° C., are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:16]=1[C:17](O)=[O:18]>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:17](=[O:18])[C:16]2[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:15]=2[O:14][CH3:13])[CH2:7]1
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1ccc(OC)c(C(=O)O)c1
Product: COc1ccc(OC)c(C(=O)Nc2cccc3c2CCN(C)C3)c1

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 2,5-dimethoxybenzoic acid.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+].[ClH:37]>O.CN(C)C=O>[ClH:37].[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:17][CH2:18][N:19]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:20][CH2:21]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CCc1ccccc1C2=C1CCNCC1
Reactant: CCOC(=O)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN1CCC(=C2c3ccccc3CCc3ccccc32)CC1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 3.00 g of 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 2.34 g of ethyl 4-bromobutyrate, 1.51 g of potassium carbonate and 18 ml of N,N-dimethylformamide was stirred at 70° C. for 3 hrs. After cooling, water was added to the reaction mixture and then extracted with ether. The ether layer was washed with water, dried and concentrated to give pale brown solid, which was converted to the hydrochloride in the usual manner to give 3.88 g of colorless solid. The crude hydrochloride was recrystallized from a mixture of acetone and ether to give colorless crystals, mp 182°-184° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:12](OC(=O)C)(=[O:14])[CH3:13].O>C(O)(=O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:12](=[O:14])[CH3:13])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCc1ccc(N)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1ccc(NC(C)=O)cc1
Yield: 96 %

Procedure:
95.0 g (0.64 mol) of p-normalbutylaniline was dissolved in 170 ml of glacial acetic acid. 81.3 g (0.80 mol) of acetic anhydride was then added dropwise to the solution at a temperature of 30° C. After the completion of dropwise addition, the reaction mixture was then allowed to undergo reaction at a temperature of 40° C. for 1 hour. The reaction solution was then poured into 600 ml of water. The resulting crystal was filtered off, washed with water, and then dried. The crystal thus obtained was then recrystallized from a mixture of 120 ml of toluene and 1,000 ml of n-hexane to obtain 117.5 g (yield: 96.4%) of p-normalbutylacetanilide. The melting point of the crystal was from 105.5° C. to 106.0° C.
Reaction SMILES: CO[C:3]([C:5]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:15]2[C:7](=[CH:8][C:9]3[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=1[OH:27])=[O:4].[NH2:28][C@H:29]([C:31]([OH:33])=[O:32])[CH3:30].C[O-].[Na+]>COCCO>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:16]2[N:15]3[C:7](=[CH:8][C:9]4[C:14]3=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:6]([OH:27])=[C:5]([C:3]([NH:28][C@@H:29]([CH3:30])[C:31]([OH:33])=[O:32])=[O:4])[C:17]2=[O:18])=[CH:25][CH:24]=1
Reactant: COC(=O)c1c(O)c2cc3ccccc3n2n(Cc2ccc(F)cc2)c1=O
Reactant: C[C@H](N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: C[C@H](NC(=O)c1c(O)c2cc3ccccc3n2n(Cc2ccc(F)cc2)c1=O)C(=O)O
Yield: 61.4 %

Procedure:
A mixture of 4-(4-fluoro-benzyl)-1-hydroxy-3-oxo-3,4-dihydro-4,4a-diaza-fluorene-2-carboxylic acid methyl ester (110 mg), L-alanine (268 mg), NaOMe (146 mg) in 2-methoxyethanol (10 mL) was refluxed for 6 h; subsequently, the reaction was cooled and solvent was removed by rotovaping; the residue was dissolved in water and then acidified with 2 M HCl solution; the precipitates were collected via filtration, washed with water, dried, and then purified with column (eluent: DCM/EtOAc, 10/1 (v/v), with 0.5% acetic acid) to give the desired product (78 mg). ESI (m/z): 424 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=C[C:21](C#N)=[C:20](N=C(C3C=CC=CC=3)C3C=CC=CC=3)[CH:19]=2)[C:13](=[O:40])[C@@H:12]1[CH2:41][CH2:42][S:43][CH3:44])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:45]1[CH:50]=[N:49][CH:48]=[N:47][CH:46]=1.C(O)(=O)C>C(O)C>[NH2:45][C:50]1[C:21]2[C:46](=[CH:23][C:18]([CH2:17][N:14]3[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[C@@H:12]([CH2:41][CH2:42][S:43][CH3:44])[C:13]3=[O:40])=[CH:19][CH:20]=2)[N:47]=[CH:48][N:49]=1
Reactant: c1ncncn1
Reactant: CSCC[C@H]1C(=O)N(Cc2ccc(C#N)c(N=C(c3ccccc3)c3ccccc3)c2)CCN1C(=O)OCc1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: CSCC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)OCc1ccccc1
Yield: 39 %

Procedure:
To a solution of 4-benzyloxycarbonyl-1-[3-(benzhydrylidene-amino)-4-cyano-benzyl]-3-(S)-(2-methylsulfanyl-ethyl)-piperazin-2-one (1.17 g, 2.67 mmol) in 15 ml of ethanol is added 1,3,5-triazine and glacial acetic acid (3.1 ml, 53.4 mmol). The resulting solution is refluxed for 20 hours, concentrated under vacuum. The residue is dissolved in ethyle acetate, washed with 1N hydrochloric acid, a saturated aqueous NaHCO3 solution, water, brine. The solution is dried over MgSO4, concentrated. The resulting crude product is purified by column chromatography eluting with a gradient of 5% MeOH:CH2Cl2 to 10% MeOH:CH2Cl2. The title compound (489 mg, 39% yield) is obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[C:4]([C:6]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[H][H]>CO.O>[Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[CH:4]([OH:5])[C:6]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)C1(C(=O)c2ccc(Cl)cc2Cl)CCCC1
Reactant: [H][H]
Solvent: O
Solvent: CO
Product: CCOC(=O)C1(C(O)c2ccc(Cl)cc2Cl)CCCC1
Yield: 51.2 %

Procedure:
(S)-tBuBisP*-RuBr2 (16 mg) was placed in a reactor and deaerated. After substitution with argon, a mixture of ethyl 1-(2,4-dichlorobenzoyl)cyclopentanecarboxylate (2.8 g, 5.6 mmol) and methanol-water (101) (30 ml) was added. Under 70° C. and hydrogen pressure (6 kg/cm2), the mixture was stirred for 30 h and concentrated. This was diluted with ethyl acetate (50 ml), washed with water and concentrated to dryness. This was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (0.91 g, 41.3%) as a colorless oil. The enantiomer excess of this product was measured by high performance liquid chromatography (Condition F) and found to be 92%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:35]([F:37])[F:36])=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]([CH:16]([CH3:33])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:34])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:35]([F:37])[F:36])=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]([CH:16]([CH3:33])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:34])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C#N)c(-c2cc(Cl)ccc2C(F)F)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)Nc1ccc(C(=O)O)cc1)n1cc(C#N)c(-c2cc(Cl)ccc2C(F)F)cc1=O

Procedure:
48 mg (0.09 mmol) of tert-butyl 4-[(2-{4-[5-chloro-2-(difluoromethyl)phenyl]-5-cyano-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate (racemate) (Example 17.1D) were hydrolysed with TFA according to General Method 2. Yield: 30 mg (70% of theory)
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:24][C:25]([NH:27][C@@H:28]2[CH2:43][C:42]3=[CH:44][CH:45]=[C:39]([CH:40]=[CH:41]3)[O:38][CH2:37][CH2:36][CH2:35][CH2:34][O:33][CH2:32][C@H:31]([CH:46]([CH3:48])[CH3:47])[NH:30][C:29]2=[O:49])=[O:26])[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:24][C:25]([NH:27][C@@H:28]2[CH2:43][C:42]3=[CH:41][CH:40]=[C:39]([CH:45]=[CH:44]3)[O:38][CH2:37][CH2:36][CH2:35][CH2:34][O:33][CH2:32][C@H:31]([CH:46]([CH3:47])[CH3:48])[NH:30][C:29]2=[O:49])=[O:26])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1
Reactant: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(=O)OC(C)(C)C)C(=O)N1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](Cc2ccc(N)nc2)C(=O)O)C(=O)N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
160 mg (0.23 mmol) of tert-butyl(S)-3-(6-tert-butoxycarbonylaminopyridin-3-yl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)ureido]propionate were dissolved in 6 ml of dichloromethane and, after addition of the same volume of TFA, stirred at RT. After 5 h, the mixture was concentrated and purified by preparative HPLC. The required fractions were combined, freed of acetonitrile, mixed with 1N hydrochloric acid, concentrated further and finally freeze dried. 108 mg of the title compound were obtained as hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[O:10][CH:9]=[C:8]([C@H:11]3[C@:15]([CH3:17])([OH:16])[C@H:14]([OH:18])[C@@H:13]([CH2:19][OH:20])[O:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>C1COCC1.[Cl-].[Cl-].[Zn+2]>[NH2:1][C:2]1[C:3]2[O:10][CH:9]=[C:8]([C@H:11]3[C@:15]4([CH3:17])[O:16][CH:26]([C:25]5[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=5)[O:18][C@@H:14]4[C@@H:13]([CH2:19][OH:20])[O:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1c1coc2c(N)ncnc12
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: C[C@@]12OC(c3ccc(Cl)cc3)O[C@@H]1[C@@H](CO)O[C@H]2c1coc2c(N)ncnc12
Temperature: 60 °C
Reaction time: 14 h
Yield: 55.5 %

Procedure:
A suspension of (2S,3R,4R,5R)-2-(4-aminofuro[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)-3-methyl-tetrahydrofuran-3,4-diol (281 mg, 1.0 mmol) in THF (4 mL) was treated with ZnCl2 (695 mg, 98%, 5 0 mmol) and 4-chlorobenzaldehyde (1.43 g, 10.0 mmol) followed by stirring at 60° C. for 14 h. The reaction mixture was quenched with aqueous 2N NaOH (6.5 mL) followed by dilution with water (80 mL), and extraction with CHCl3 (2×100 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was purified on a silica gel column using chloroform/MeOH (1:0 to 20:1, Rf=0.31, CHCl3/MeOH=20:1) as eluent to give 224 mg (55%) of the desired product as a white solid. 1H NMR (MeOH-d4, a mixture of diastereoisomers): δ 8.23 (s, 1H), 8.22 (s, 1H), 7.72-7.50 (m, 4H), 7.44 (s, 2H), 6.16 (s, 1H), 5.47-5.41(m, 1H), 5.31 (s, 1H), 4.53 (d, J=3.1 Hz, 1H), 4.17-4.11 (m, 1H), 3.73-3.57 (m, 2H), 1.25 (s, 3H); MS (ES+): 404.3 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:24]=[C:23]([Cl:25])[C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([OH:22])=[C:12]([CH:21]=2)[C:13]([N:15]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[CH3:16])=[O:14])=[C:5]([Cl:26])[CH:4]=1.C[N+]1([O-])CC[O:31]CC1>C(#N)C>[CH:17]1([N:15]([CH3:16])[C:13](=[O:14])[C:12]2[CH:21]=[C:8]([O:7][C:6]3[C:23]([Cl:25])=[CH:24][C:3]([CH:2]=[O:31])=[CH:4][C:5]=3[Cl:26])[CH:9]=[CH:10][C:11]=2[OH:22])[CH2:20][CH2:19][CH2:18]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CN(C(=O)c1cc(Oc2c(Cl)cc(CBr)cc2Cl)ccc1O)C1CCC1
Solvent: CC#N
Product: CN(C(=O)c1cc(Oc2c(Cl)cc(C=O)cc2Cl)ccc1O)C1CCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
To a solution of the title compound of Step G (130 mg, 0.28 mmol) in dry acetonitrile (6 ml) at room temperature under nitrogen was added molecular serves (4 Å, 50 mg). After stirring for about 15 minutes at room temperature, N-methylmorpholine N-oxide (66 mg, 0.57 mmol) was added. The resulting mixture was stirred at room temperature for about 18 hours, then filtered through a short pad of silica gel with an acetonitrile wash. The filtrate was concentrated to afford the title compound (88 mg) as an off-white foam which was used in the next step without further purification. MS (APCI−) Calc: 393.1, found: 392.1 (M−1).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:13])[N:4]([CH2:10][CH2:11][CH3:12])[C:5](=[O:9])[NH:6][C:7]=1[NH2:8].[F:14][C:15]([F:32])([F:31])[C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][CH:30]=1)[CH2:19][N:20]1[CH:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[N:21]1.CCN=C=NCCCN(C)C.Cl>CO>[NH2:8][C:7]1[NH:6][C:5](=[O:9])[N:4]([CH2:10][CH2:11][CH3:12])[C:3](=[O:13])[C:2]=1[NH:1][C:25]([C:23]1[CH:22]=[N:21][N:20]([CH2:19][C:18]2[CH:28]=[CH:29][CH:30]=[C:16]([C:15]([F:32])([F:14])[F:31])[CH:17]=2)[CH:24]=1)=[O:26]
Reactant: CCCn1c(=O)[nH]c(N)c(N)c1=O
Reactant: O=C(O)c1cnn(Cc2cccc(C(F)(F)F)c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: CCCn1c(=O)[nH]c(N)c(NC(=O)c2cnn(Cc3cccc(C(F)(F)F)c3)c2)c1=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 71.7 %

Procedure:
A mixture of 5,6-diamino-3-propyl-1H-pyrimidine-2,4-dione (4.25 g, 0.023 mol), 1-(3-Trifluoromethyl-benzyl)-1H-pyrazole-4-carboxylic acid (6.23 g, 0.023 mol), prepared by conventional methods starting from pyrazole-4-carboxylic ester, in methanol (50 ml) were cooled to 0° C. and added EDCI.HCl (8.82 g, 0.046 mol). The reaction mixture was stirred at 25° C. for 6 h and the organic volatiles were evaporated. To this residue water (50 ml) was added and the precipitate was filtered off, and washed with cold water (50 ml) to obtain 1-(3-Trifluoromethyl-benzyl)-1H-pyrazole-4-carboxylic acid (6-amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide (7.2 g, 72%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[CH3:30][S:31]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)(=[O:33])=[O:32]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:37]3[CH:38]=[CH:39][C:34]([S:31]([CH3:30])(=[O:33])=[O:32])=[CH:35][CH:36]=3)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 84, Step 1, using the following starting materials: {3-[4-bromo-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and 4-(methanesulfonyl)phenylboronic acid.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[CH3:20][C:21]1[CH:22]=[C:23]([NH2:32])[N:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:25]=1>>[CH3:20][C:21]1[CH:22]=[C:23]([NH:32][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:25]=1
Reactant: Cc1cc(N)n(-c2ccccc2)n1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Product: Cc1cc(NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2)n(-c2ccccc2)n1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-methyl-2-phenyl-2H-pyrazol-3-ylamine. Title compound: ES-MS: 409.50 [M+H]+; tR=1.21 min (System 3).
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=O)[CH2:4][CH2:3]1.[F:8][C:9]([F:25])([F:24])[C:10]1[CH:23]=[CH:22][C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH:11]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>CCOCC.C1(C)C(C)=CC=CC=1>[CH3:1][CH:2]1[N:6]([C:5]2[CH2:4][CH2:3][CH:2]([CH3:1])[N:6]=2)[C:5]([N:13]2[C:12]3[CH:11]=[C:10]([C:9]([F:8])([F:24])[F:25])[CH:23]=[CH:22][C:21]=3[S:20][C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:4][CH2:3]1
Reactant: CC1CCC(=O)N1
Reactant: FC(F)(F)c1ccc2c(c1)Nc1ccccc1S2
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: CC1CCC(N2C(N3c4ccccc4Sc4ccc(C(F)(F)F)cc43)=CCC2C)=N1
Reaction time: 1.5 h

Procedure:
A solution of 5-methyl-2-pyrrolidinone (19.8 g., 0.2 mole) in 25 ml. of xylene is added drop-wise to a mixture of 2-trifluoromethylphenothiazine (26.7 g., 0.1 mole) and phosphorus oxychloride (15.3 g., 0.1 mole) in 125 ml. of refluxing xylene in a two hour period. When the addition is complete, refluxing is continued for an additional 1.5 hr., the reaction mixture poured into 75 ml. of 5 N sodium hydroxide and 75 g. of crushed ice, and, after mixing well, the xylene fraction is separated. The xylene fraction is seqentially extracted with 100 ml. of 1.5 HCl followed by 100 ml. of water and then made basic by stirring with 5 N sodium hydroxide solution. Separation of the basified xylene fraction which is dried over magnesium sulfate and concentrated under reduced pressure provides a residue which is taken up in 50 ml. of benzene and the solution then concentrated. An additional 100 ml. portion of benzene is added to the residue thus obtained and the solution partially concentrated until crystals begin to form. After cooling and standing, the mixture is filtered to remove recovered 2-trifluoromethylphenothiazine starting material. Concentration of the filtrate affords a residual material which is taken up in ether, extracted with 1.5 N hydrochloric acid and then with 50 ml. of water. The combined acid-aqueous extracts are made basic with sodium hydroxide and the mixture extracted with ether. The ethereal extract is dried over magnesium sulfate, filtered, anc concentrated. Distillation of the residual oil through a 6 cm. column provides 10-[5-methyl-1-(5-methyl-1-pyrrolin-2-yl)-2-pyrrolin-2-yl]-2-(trifluoromethyl)phenothiazine free base, b.p. 175°-185° C./0.15 mm. Hg. The bis-pyrrolinyl phenothiazine free base is taken up in ethanol and acidified with ethanolic hydrogen chloride. Addition of ether provides the hydrochloride salt which crystallized from ethanol affords analytically pure 10-[5-METHYL-1-(5-METHYL-1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]-2-(TRIFLUOROMETHYL)PHENOTHIAZINE HYDROCHLORIDE, m.p. 250°-253° C. (dec.)(corr.).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH2:6][CH2:7][O:8][C@@H:9]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=1)[CH2:10][CH2:11][N:12]([CH3:34])[C:13](=[O:33])[NH:14][C@@H:15]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:16][N:17](C)[C:18](=O)OC(C)(C)C)=[O:4]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:41][C:37]1[CH:36]=[C:35]([C@H:9]([O:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[O:2][CH3:1])[CH2:10][CH2:11][N:12]([CH3:34])[C:13](=[O:33])[NH:14][C@@H:15]([CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:16][NH:17][CH3:18])[CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)NCCO[C@H](CCN(C)C(=O)N[C@@H](CC1CCCCC1)CN(C)C(=O)OC(C)(C)C)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC[C@H](CC1CCCCC1)NC(=O)N(C)CC[C@@H](OCCNC(=O)OC)c1cccc(Cl)c1
Yield: 26.7 %

Procedure:
tert-butyl (S)-2-(3-((R)-3-(2-(methoxycarbonylamino)ethoxy)-3-(3-chlorophenyl)propyl)-3-methylureido)-3-cyclohexylpropyl(methyl)carbamate (40 mg) was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (5 mL). The reaction mixture was concentrated in vacuo. The residue was purified by Preparative HPLC to afford isomer 1 methyl (4S,10R)-10-(3-chlorophenyl)-4-(cyclohexylmethyl)-7-methyl-6-oxo-11-oxa-2,5,7-triazatridecan-13-ylcarbamate (8.88 mg, 27%) LC-MS (3 min) tR=2.195 m/z=497. 1H NMR (CD3OD) d 0.99 (m, 2H), 1.54 (m, 1H), 1.70 (m, 4H), 1.87 (m, 3H), 2.73 (s, 3H), 2.94 (s, 3H), 3.09 (m, 1H), 3.63 (s, 3H), 4.26 (m, 2H), 7.29 (m, 4H). isomer 1 methyl (4S,10R)-10-(3-chlorophenyl)-4-(cyclohexylmethyl)-7-methyl-6-oxo-11-oxa-2,5,7-triazatridecan-13-ylcarbamate and isomer 2 methyl (4S,10S)-10-(3-chlorophenyl)-4-(cyclohexylmethyl)-7-methyl-6-oxo-11-oxa-2,5,7-triazatridecan-13-ylcarbamate. LC-MS (3 min) tR=2.149 m/z=497. 1H NMR (CD3OD) d 0.96 (m, 2H), 1.25 (m, 5H), 1.54 (m, 1H), 1.69 (m, 4H), 1.89 (m, 3H), 2.71 (s, 3H), 2.93 (s, 3H), 3.06 (m, 1H0, 3.64 (s, 3H), 4.14 (m, 1H), 4.30 (m, 1H), 7.31 (m, 4H).