Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([F:12])[C:3]=1[C:13]1[S:17][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22](=[O:25])[NH:21][N:20]=2)=[C:15]([C:26]([NH2:28])=[O:27])[CH:14]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:36][C:37]([O:39][CH3:40])=[O:38].O>CN(C=O)C>[CH3:40][O:39][C:37](=[O:38])[CH2:36][N:21]1[C:22](=[O:25])[CH:23]=[CH:24][C:19]([NH:18][C:16]2[S:17][C:13]([C:3]3[C:2]([F:1])=[CH:7][C:6]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:5][C:4]=3[F:12])=[CH:14][C:15]=2[C:26]([NH2:28])=[O:27])=[N:20]1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(=O)[nH]n3)s2)c(F)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1=O
Temperature: 25 °C

Procedure:
5-[2,6-Difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-[(6-oxo-1,6-dihydropyridazin-3-yl)amino]thiophene-3-carboxamide (Example 578 Step 3) (50 mg, 0.12 mmol), K2CO3 (18.70 mg, 0.14 mmol) and methyl bromoacetate (0.012 mL, 0.13 mmol) were stirred in DMF (1 mL) at 80° C. overnight. The reaction mixture was cooled to room temperature, water was added and the reaction mixture was extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel column chromatography (0-15% MeOH—CHCl3) gave the title compound as a yellow solid after triturating in DCM.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.CO[CH:21]=[C:22]([C:27]([O:29][CH3:30])=[O:28])[C:23]([O:25][CH3:26])=[O:24].O>CN(C)C=O>[C:13]([NH:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:1][CH:21]=[C:22]([C:27]([O:29][CH3:30])=[O:28])[C:23]([O:25][CH3:26])=[O:24])=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1)(=[O:18])[C:14]([CH3:15])([CH3:17])[CH3:16]
Reactant: COC=C(C(=O)OC)C(=O)OC
Reactant: CC(C)(C)C(=O)Nc1ccc2c(N)ncnc2c1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(=CNc1ncnc2cc(NC(=O)C(C)(C)C)ccc12)C(=O)OC
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 82.5 %

Procedure:
A mixture of 4-amino-7-pivalamidoquinazoline (10.5 g) and dimethyl methoxymethylenepropanedioate (10.9 g) in N,N-dimethylformamide (32 ml) was stirred at 100° C. for 1 hour and 25 minutes. After the reaction mixture was cooled to ambient temperature, water was added. The resulting solid was separated by filtration, washed with water and dried. The crustals were recrystallized from a mixture of ethyl acetate and ethanol to give crystalline dimethyl [[7-pivalamido-4-quinazolinylamino]methylene]propanedioate (13.7 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])[CH3:11]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(=O)c1ccccc1
Product: O=C(C=Cc1ccc(Br)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-bromobenzaldehyde and acetophenone, 3-(4-bromophenyl)-1-phenylprop-2-en-1-one was obtained as yellow solid.
Reaction SMILES: N[C@@H:2]([CH2:23][C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)[C:3]([NH:5][C@@H](CC1CCCCC1)[C@@H](O)C[C@@H](C(C)C)C=C)=[O:4].CCN(C(C)C)C(C)C.O1CCN(NC(N[C@H](C(O)=O)CC2C=CC=CC=2)=O)CC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[NH:27]1[CH:28]=[C:24]([CH2:23][CH2:2][C:3]([NH2:5])=[O:4])[N:25]=[CH:26]1
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(N[C@@H](Cc1ccccc1)C(=O)O)NN1CCOCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CCc1c[nH]cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
100 mg (0.52 mmol) of (S)-α-amino- N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide and 0.052 ml of Hunig base in 2 ml of acetonitrile were treated at room temperature with 99 mg of N-(morpholinocarbamoyl)-3-phenyl-L-alanine and 113 mg of BOP in 2 ml of acetonitrile and stirred at room temperature for 12 hours. Thereafter, the reaction solution was poured onto 1N hydrochloric acid/ice, extracted with ethyl acetate, the organic extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was chromatoqraphed on silica gel with a 10:1 mixture of methylene chloride and methanol, to obtain 130 mg (67%) of (S)-N-[(1S,2S,4S)-1-(cyclohexyl-methyl)-2-hydroxy-4-isopropyl-5 hexenyl]-α-2-[N-(morpholinocarbamoyl)-3-phenyl-L-alanyl]amino]imidazole-4-propionamide as an amorphous solid. MS: 651 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]([F:23])[C:14](F)=[C:15]([F:21])[C:16]=2[F:20])[NH:11][C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.[CH2:30](I)[CH3:31].[H-].[Na+]>CC(N(C)C)=O.CN(C=O)C>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]([F:23])[C:14]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[C:15]([F:21])[C:16]=2[F:20])[N:11]([CH2:30][CH3:31])[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: C1CCNC1
Reactant: O=c1[nH]c2c(F)c(F)c(F)c(F)c2c(=O)n1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: CCn1c(=O)n(OCc2ccccc2)c(=O)c2c(F)c(F)c(N3CCCC3)c(F)c21
Temperature: 60 °C
Reaction time: 16 h
Yield: 22.1 %

Procedure:
A solution of 3-benzyloxy-5,6,7,8-tetrafluoro-1H-quinazoline-2,4-dione (Example W-3, 0.90 g, 2.7 mmol), in DMA (10 mL) was reacted with pyrrolidine (0.55 mL, 6.6 mmol) and heated to 60° C. for 3 hours. The mixture was then cooled and quenched with H2O and acidified with citric acid. The mixture was then extracted with ethyl acetate, dried with MgSO4, and concentrated. The residue was triturated with diethyl ether/hexanes and the solid filtered and dried (0.87 g). A portion of the solid (0.500 g, 1.28 mmol) was dissolved in DMF and reacted with ethyl iodide (1.0 mL, 12.77 mmol) and sodium hydride (0.060 g, 1.5 mmol). The mixture was stirred for 16 hours. The mixture was quenched with H2O and extracted with ethyl acetate. The organic layers were combined, dried with sodium sulfate. and concentrated. The residue was triturated with diethyl ether and filtered to yield 0.25 g of the title compound as a solid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[CH:59]=[CH:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[N:51]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[CH:28]1([CH2:34][CH:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36]([NH:49][C:50]2[CH:59]=[CH:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[N:51]=2)=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Nc1ccc2ccccc2n1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1ccc2ccccc2n1)C(CC1CCCCC1)N1Cc2ccccc2C1=O
Yield: 99 %

Procedure:
This compound was prepared via BOP coupling of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Step A of Example 1; 288 mg; 1.0 mmol) and 2-aminoquinoline (180 mg; 1.2 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as outlined in Example 1, Step B) to provide 3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-quinolin-2-yl-propionamide as a white solid in 99% yield: EI-HRMS m/e calcd for C26H27N3O2 (M+) 413.2103, found 413.2103.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:21])[C:8]3[C:13]([S:14](=[O:18])(=[O:17])[C:15]=2[CH:16]=1)=[CH:12][CH:11]=[C:10]([O:19][CH3:20])[CH:9]=3)#[N:2].[CH2:22](N)[CH2:23][NH2:24].C[O-].[Na+]>CO>[NH:2]1[CH2:22][CH2:23][N:24]=[C:1]1[C:3]1[CH:16]=[C:15]2[C:6](=[CH:5][CH:4]=1)[C:7](=[O:21])[C:8]1[CH:9]=[C:10]([O:19][CH3:20])[CH:11]=[CH:12][C:13]=1[S:14]2(=[O:18])=[O:17]
Reactant: NCCN
Reactant: COc1ccc2c(c1)C(=O)c1ccc(C#N)cc1S2(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)C(=O)c1ccc(C3=NCCN3)cc1S2(=O)=O
Temperature: 0 °C

Procedure:
To 5.0 g (0.017 mol) of 3-cyano-7-methoxythioxanthen-9-one 10,10-dioxide was added ethylenediamine, 10.8 g (0.18 mol), and sodium methoxide, (0.098 g, 0.002 mol), in methanol, 70 ml, and the mixture was refluxed for 70.5 hr. The mixture was then poured into ice water, 400 ml, and the precipitate was filtered and washed with water then was recrystallized from ethanol, DMSO and H2O to provide 1.1 g of 6-(2-imidazolin-2-yl)-2-methoxythioxanthen-9-one-10,10-dioxide with m.p. 220°-224° C.; TLC on silica gel (ethanol), Rf =0.44.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9](Cl)[N:8]=1)[CH3:5].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>CCO>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[N:8]=1)[CH3:5]
Reactant: COC(=O)[C@H](C)Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: COc1ccc(CN)cc1
Solvent: CCO
Product: COC(=O)[C@H](C)Nc1nc(NCc2ccc(OC)cc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
To a solution of (S)-2-(6-chloro-3-nitro-pyridin-2-ylamino)-propionic acid methyl ester (1.90 g, 7.3 mmol, 1.0 equiv) in EtOH (20 mL) was added 4-methoxy-benzylamine (1.4 mL, 11.0 mmol, 1.5 equiv) and the reaction mixture was stirred at ambient temperature for 16 h. The solvent was evaporated and the crude product was triturated with methanol to afford (S)-2-[6-(4-methoxy-benzylamino)-3-nitro-pyridin-2-ylamino]-propionic acid methyl ester (1.5 g) as a yellow solid. MS: [M+H]+=361.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: Cc1cc(-c2cc(C(=O)CC(=O)OC(C)(C)C)ccn2)on1
Product: COCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(-c3cc(C)no3)c2)cc1Cl

Procedure:
The title compound was prepared from {2-amino-4-chloro-5-[(2-methoxy-ethyl)-methyl-amino]-phenyl}-carbamic acid tert.-butyl ester (Example J4) (165 mg, 0.5 mmol) and 3-[2-(3-methyl-isoxazol-5-yl)-pyridin-4-yl]-3-oxo-propionic acid tert.-butyl ester (Example K6) (151 mg, 0.5 mmol) according to the general procedure M. Obtained as a yellow solid (190 mg).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([OH:6])=[O:5])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(O)c1ccccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(Nc2ccccc2C(=O)O)c([N+](=O)[O-])c1
Temperature: 200 °C

Procedure:
2-iodobenzoic acid (5 g, 20.16 mmol), 4-methyl-2-nitroaniline (6.12 g, 40.32 mmol), potassium carbonate (2.8 g, 20.3 mmol) and Cul (0.2 g) were thoroughly mixed and heated to 200° C. for 1 hour. After cooling the solid reaction mixture was partitioned between ethyl acetate and aqueous sodium hydroxide (1M). The product precipitated from the aqueous phase on acidification with hydrochloric acid (4M). Yield 3.69 g, mp 209°-213° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([N:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[CH:10]=[CH:9]2)[C@H:5]([OH:24])[C@@H:4]1[OH:25].CO[C:28](OC)([CH3:30])[CH3:29].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:29][C:28]1([CH3:30])[O:24][C@H:5]2[C@H:6]([N:8]3[C:12]4[N:13]=[CH:14][N:15]=[C:16]([S:17][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:11]=4[CH:10]=[CH:9]3)[CH2:7][C@@H:3]([CH2:2][OH:1])[C@H:4]2[O:25]1
Reactant: COC(C)(C)OC
Reactant: OC[C@@H]1C[C@@H](n2ccc3c(Sc4ccccc4)ncnc32)[C@H](O)[C@@H]1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)O[C@@H]2[C@H](CO)C[C@@H](n3ccc4c(Sc5ccccc5)ncnc43)[C@@H]2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
(1S,2R,3S,5R)-3-(Hydroxymethyl)-5-[4-(phenylsulfanyl)-7H-pyrrolo[2,3-d]-pyrimidin-7-yl]cyclopentane-1,2-diol (320 mg, 0.0895 mmol), 2,2-dimethoxypropane (0.0549 mL, 0.446 mmol), and p-toluenesulfonic acid monohydrate (17.0 mg, 0.0895 mmol) were dissolved in acetone (2.20 mL) and stirred at rt overnight. Then the reaction was quenched with saturated sodium bicarbonate solution and approximately half the solvent was removed in vacuo. The resulting residue was diluted with water and extracted with DCM (3×). Combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a white foam (35.5 mg, 99%), which was used without further purification. LC/MS: Rt=1.72 min, ES+ 389 (FA standard).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[C:23]([NH:27][C:28](=[O:31])[CH:29]=[CH2:30])([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH2:30][O:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: C=CC(=O)NC(C)(C)C
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)CCON(Cc1ccccc1)Cc1ccccc1

Procedure:
A solution of 21.33 g of dibenzylhydroxylamine in 100 ml of dry tetrahydrofuran is admixed with 1.12 g of potassium-tert-butoxide followed by 12.70 g of N-tert-butylacrylamide. The solution is heated under reflux for 24 hours under N2. The crude reaction mixture is concentrated under reduced pressure and the residue is partitioned between water and methylene chloride. The organic layer is washed with water, brine dried (MgSO4) and evaporated under reduced pressure. Purification by liquid chromatography affords the title compound as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.CCO>[Pd].CCN(CC)CC>[CH3:21][C:15]1[C:14]([CH:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=2)=[CH:2]3)[OH:13])=[CH:19][CH:18]=[C:17]([CH3:20])[N:16]=1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2cc1Cc1ccc(C(F)(F)F)cc1
Reaction time: 18 h

Procedure:
A 250 mL Parr flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanol (155 mg, 0.32 mmol, Example 14a) was added EtOH (25 mL) and Et3N (1 mL) followed by 5% palladium on carbon (75 mg). The flask was pressurized to 50 psi with H2 gas and shaken for 18 hours. HPLC analysis indicated the conversion was approximately 40%. The reaction mixture was filtered through Celite® and concentrated. The residue was dissolved in MeOH and run in the H-cube hydrogenation apparatus using a 10% Pd/C cartridge at 50° C., 70 psi H2 and 1.2 ml/minute (all with closed loop recycling). After the cycling was complete, the solution was concentrated to dryness and the residue was chromatographed on silica gel (10% EtOAc-DCM increasing to 5% MeOH-DCM) to provide the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.76 (d, J=8.5 Hz, 1H), 7.58-7.47 (m, 3H), 7.40-7.31 (m, 3H), 7.30-7.20 (m, 2H), 6.94 (d, J=7.7 Hz, 1H), 4.05 (overlapping s, 6H), 2.51 (s, 3H), 2.45 (s, 3H). MS (ESI): mass calcd. for C26H23F3N2O2, 452.2, m/z found 453.2 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:11])=[CH:5][CH:4]=1.[C:21]1([P:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1C=CC=CC=1>[Cl-:1].[C:17]([O:16][C:14]([NH:13][NH:12][C:10]([CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][P+:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:4][CH:5]=1)=[O:11])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NNC(=O)Cc1ccc(CCl)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)NNC(=O)Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Cl-]
Temperature: 25 °C
Yield: 78.5 %

Procedure:
A mixture of tert-butyl 2-{[4-(chloromethyl)phenyl]acetyl}hydrazinecarboxylate (5.9 g, 19.7 mmol), triphenylphosphine (5.18 g, 19.7 mmol) and benzene (15 ml) was heated under reflux for 21 hrs. After cooling to room temperature, the precipitate was collected by filtration, washed 3 times with benzene, and dried under reduced pressure to give {4-[2-(tert-butoxycarbonyl)hydrazinocarbonylmethyl]benzyl}(triphenyl)phosphonium chloride (8.68 g, yield 78%) as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=O)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:26]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:39][NH2:40].O>ClCCl>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([NH:39][NH2:40])=[O:22])[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:26]=1
Reactant: NN
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)O)c1)C2=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)NN)c1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
(S)-3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic acid (1.36 g, 3.68 mmol) obtained in Step 1 was dissolved in dichloromethane (18 mL), and the mixture was stirred at room temperature for 1 hour after adding 1,1′-carbonyldiimidazole (657 mg, 4.05 mmol). Thereafter, hydrazine.monohydrate (0.53 mL, 11.0 mmol) was added to the mixture, and the mixture was stirred at room temperature for 1 hour. Then, water was added to the mixture, stirred, and the precipitated solid was filtered off. After concentrating the filtrate under reduced pressure, the residue was recrystallized from dichloromethane and water to give (S)-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic hydrazide (1.21 g, 86%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH3:17])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:8]=2[CH:25]=1)([O-:3])=[O:2].[CH2:26]=[O:27]>C1(C)C(C)=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][CH2:26][OH:27])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:8]=2[CH:25]=1)([O-:3])=[O:2]
Reactant: Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2
Reactant: C=O
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCO)n1-2

Procedure:
In the manner given in Example 1, 8-nitro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepine in xylene was heated in an oil bath with repeated additions of portions of paraformaldehyde to give 8-nitro-1-(2-hydroxyethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:32](O)=[O:33])=[C:21]([CH3:31])[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]=23)[CH2:3][CH2:2]1.[NH2:35][C@H:36]1[C@H:40]([OH:41])[CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]1>>[C:45]([O:44][C:42]([N:38]1[CH2:39][C@@H:40]([OH:41])[C@H:36]([NH:35][C:32]([C:20]2[C:16]3=[N:17][CH:18]=[CH:19][C:14]([C:7]4[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)=[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[C:21]=2[CH3:31])=[O:33])[CH2:37]1)=[O:43])([CH3:48])([CH3:46])[CH3:47]
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](O)C1
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@@H]4CN(C(=O)OC(C)(C)C)C[C@H]4O)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c5) and commercially available tert-butyl (3R*,4R*)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[C:10](=[S:12])[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:19][CH:20]=O>C(O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:10]3[S:12][CH:19]=[CH:20][N:11]=3)[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CCCl
Reactant: COc1ccc(C(N)=S)cc1OC1CCCC1
Solvent: CCO
Product: COc1ccc(-c2nccs2)cc1OC1CCCC1
Yield: 63.2 %

Procedure:
A solution of 130 mg of 3-cyclopentyloxy-4-methoxybenzthioamide and 100 mg of chloroacetaldehyde in 15 ml of ethanol was heated at reflux for 6 hours. The volatiles were evaporated and the residue purified on silica gel with CH2Cl2 to give 90 mg of product. M.P.: 72°-75° C.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16](C(C)C)(=[O:18])=[O:17])=[C:12]([CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH3:24])[CH:11]=2)C=CC=CC=1.[Br:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42]C(NC2C=CC(SCC)=C(C=2)CN(C)C(=O)OC(C)(C)C)=O)=[CH:36][CH:35]=1.[CH:65]1C=C(Cl)C=C(C(OO)=O)[CH:66]=1>>[Br:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][C:8]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH2:65][CH3:66])(=[O:18])=[O:17])=[C:12]([CH:11]=2)[CH2:22][N:23]([CH3:24])[C:25](=[O:26])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:7])=[CH:36][CH:35]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1CN(C)C(=O)OC(C)(C)C
Reactant: CC(C)S(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1CN(C)C(=O)OC(C)(C)C
Product: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1CN(C)C(=O)OC(C)(C)C
Yield: 88 %

Procedure:
Using a procedure analogous to that used for preparation of 16G, 17B (0.460 g, 0.88 mmol) was reacted with mCPBA (0.500 g, 2.23 mmol) to give 17C (0.428 g, 88%) as a white foam. MS (ESI) m/z 555.0 (M+H)+.