Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CS(C)=O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:2]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)=[CH:17][CH:18]=1
Reactant: C1CNCCN1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCNCC3)nc2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (632 mg, 2.00 mmol) in DMSO (10 ml) was added DIEA (516 mg, 3.99 mmol) and piperazine (688 mg, 7.99 mmol). The resulting solution was stirred for 3 hours at 80° C. and then quenched by the addition of water (100 ml). The solids were collected by filtration to afford methyl 2-(4-fluorophenyl)-3-(piperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid (540 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:33])([CH3:32])[CH2:30][OH:31])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:39][S:40]([CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:42])=[O:41]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][CH2:43][S:40]([CH3:39])(=[O:41])=[O:42])[CH2:50][CH2:49]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:33])([CH3:32])[CH2:30][OH:31])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)CO)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)CO)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12g) and 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 701.4 [(M+H)+]
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH3:25][O:26][NH2:27]>O>[CH3:25][O:26][N:27]=[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(COCc1ccccc1)c1ccccc1
Reactant: CON
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CON=C(COCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To 50 ml of pyridine were added 0.0434 mole (9.77 g) of 2-benzyloxyacetophenone prepared in the first and second paragraphs in Referential Example 1 (Table 1, No. 1) and 4.35 g (0.0521 mole) of O-methylhydroxylamine hydrochloride. The mixture was stirred at room temperature for 2 hours and then at 100° C. for 1 hour. The reaction liquid was cooled down to room temperature, 300 ml of water was added thereto, and the oil layer was separated off. The aqueous layer was extracted with chloroform and the extract was combined with said oil layer, washed with water, dried and distilled under reduced pressure to obtain 10.77 g of 2-benzyloxyacetophenone O-methyloxime.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:17][N:18]([CH3:20])[CH:19]=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)=[O:9]
Reactant: O=C(Cc1ccccc1)c1cccs1
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C(=O)c1cccs1)c1ccccc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
2-Phenyl-1-(thiophen-2-yl)ethanone (1 g, 4.94 mmol) was treated with dimethylformamide dimethylacetal (5 mL) and heated to 100° C. while stirring. After 4 h, the reaction was allowed to cool down to room temperature. The solid that precipitated out of the reaction mixture was collected by filtration and washed with a 1:1 mixture of diethyl ether and hexanes to afford a yellow crystalline solid (1 g). MS (M+H)+ 258.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH3:3].S(Cl)([Cl:17])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:17])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH3:3]
Reactant: CCCOCc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCOCc1ccc(C(=O)Cl)cc1

Procedure:
4-(Propoxymethyl)benzoic acid (1.4 g, 7.2 mmol) was mixed with thionyl chloride (1.3 g, 10.9 mmol), pyridine (0.1 ml) and toluene (3 ml), followed by reacting them at 80° C. for 2 hours, and distilling off superfluous thionyl chloride and toluene under reduced pressure, to obtain raw 4-(propoxymethyl) benzoyl chloride.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][C@H:22]([CH2:24]O)[O:21][C:20]4=[O:26])=[CH:15][C:14]=3[F:27])=[CH:9][N:8]=2)=[N:3]1.C(N(S(F)(F)[F:34])CC)C.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][C@H:22]([CH2:24][F:34])[O:21][C:20]4=[O:26])=[CH:15][C:14]=3[F:27])=[CH:9][N:8]=2)=[N:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cn1nnc(-c2ccc(-c3ccc(N4C[C@H](CO)OC4=O)cc3F)cn2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nnc(-c2ccc(-c3ccc(N4C[C@H](CF)OC4=O)cc3F)cn2)n1
Reaction time: 24 h
Yield: 75.5 %

Procedure:
In 5 ml of methylenechloride was dissolved 100 mg of the compound 10. The solution was added with 43 mg of diethylaminosulfurtrifloride (DAST) and 0.078 ml of triethylamine and then stirred for 24 hours. After being concentrating, the reaction mixture was purified by column chromatography to obtain the title compound 75 mg. Yield 75%.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH3:12])[CH:6]=1)=O.O.[NH2:14][NH2:15]>C(O)C>[CH3:12][N:7]1[C:8](=[O:11])[CH:9]=[CH:10][C:5]([C:3]([NH:14][NH2:15])=[O:2])=[CH:6]1
Reactant: NN
Reactant: COC(=O)c1ccc(=O)n(C)c1
Solvent: O
Solvent: CCO
Product: Cn1cc(C(=O)NN)ccc1=O
Temperature: 78 °C
Reaction time: 8 h

Procedure:
The title compound of Example 27 (775 mg, 4.64 mmol) was dissolved in ethanol (10 mL) and heated to 78° C. Hydrazine hydrate (1.12 mL, 23.2 mmol) was added and the reaction was stirred at 78° C. overnight. The reaction was then cooled to room temperature and the product (white solid) was filtered off (590 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][C@@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH2:21])=[CH:17][CH:16]=1>C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:21][C@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:28][CH:27]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(OC)cc1)NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Yield: 92.4 %

Procedure:
5 g of 3,4-dichlorophenylsulphonyl chloride are introduced, with stirring, into a mixture of 3,8 g of ethyl O-methyltyrosinate in 35 ml of CH2Cl2 and 50 ml of a saturated aqueous potassium carbonate solution. After one night, the solid is removed, the organic phase separated and the aqueous phase reextracted with CH2Cl2. The dried organic phases are concentrated and the residue is chromatographed on a silica column, eluting with a mixture of CH2Cl2 and CH3OH (95/5-V/V). 6.8 g of racemic ethyl N-(3,4-dichlorophenylsulphonyl)-O-methyltyrosinate are obtained, which product melts at 99° C. This ester is hydrolysed in 100 ml of C2H5OH containing 9.5 ml of a 5N aqueous KOH solution to give, after acidification, 5.5 g of the corresponding acid which melts at 183° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])C3C([C:13]=2[CH:14]=1)=CC(Br)=CC=3.[CH3:22][N:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[Sn](CCCC)(CCCC)CCCC>>[CH3:22][N:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:2]1[CH:14]=[C:13]2[C:5](=[CH:4][CH:3]=1)[N:6]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]2=1
Reactant: CCCCCCn1c2ccc(Br)cc2c2cc(Br)ccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Product: CCCCCCn1c2ccc(Br)cc2c2cc(-c3cccn3C)ccc21

Procedure:
As shown in scheme 3, 3,6-dibromo-9-hexyl-9H-carbazole (31) is reacted with 1-methyl-2-(tributylstannyl)-1H-pyrrole by Stille coupling reaction to obtain N-methyl-2-(3-bromo-9-hexyl-9H-carbazol-6-yl)pyrrole (32). Then, in the presence of sodium tert-butoxide, Pd(dba)2, and tri-tert-butyl phosphine, N-methyl-2-(3-bromo-9-hexyl-9H-carbazol-6-yl)pyrrole (32) is reacted with diphenylamine to obtain N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)pyrrole (33). n-butyl lithium is reacted with N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)pyrrole (33), and then tributylstannylchloride is added thereto to obtain N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)-5-tributyl-stannylpyrrole (34). N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)-5-tributylstannylpyrrole (34) is reacted with 5-bromo-2-thiophene-carboxaldehyde by Stille coupling reaction to obtain 5-[N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)pyrrol-5-yl]thiophene-2-carbaldehyde (35). Finally, 5-[N-methyl-2-(3-diphenylamino-9-hexyl-9y-carbazol-6-yl)pyrrol-5-yl]thiophene-2-carbaldehyde (35) is reacted with cyanoacetic acid in acetic acid by using ammonium acetate as a catalyst, and (E)-2-cyano-3-[5-(N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)pyrrol-5-yl)thiophen-2-yl]acrylic acid (36) is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][C:37]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:36]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:45]([O:44][C:42]([C:37]1[NH:38][C:39]2[C:35]([CH:36]=1)=[CH:34][C:33]([NH:32][C:28]([C@H:9]1[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]1)=[O:30])=[CH:41][CH:40]=2)=[O:43])[CH3:46]
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
A mixture of chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (150 mg, 0.321 mmol), ethyl 5-amino-1H-indole-2-carboxylate (114 mg, 0.558 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 159 mg, 0.417 mmol) and iPr2NEt (0.4 mL, 2.29 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, then concentrated and purified by RP-HPLC chromatography (20-95% acetonitrile/water) to afford 5-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)pyrrolidine-2-carbonyl]-amino}-1H-indole-2-carboxylic acid ethyl ester (37 mg, 17.6%) as an off-white powder. LCMS (ES+) m/z Calcd for C34H32Cl2F2N4O3+H [(M+H)+]: 652.18. found: 6512.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([CH3:16])=[CH:8][C:9](=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:17]1([N:23]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[S:34][C:33]([CH:35]=O)=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1CCCCC1>C(O)C>[C:1]([C:5]1[O:6][C:7]([CH:16]=[CH:35][C:33]2[S:34][C:30]([C:27]3[CH:28]=[CH:29][C:24]([N:23]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:25][CH:26]=3)=[CH:31][CH:32]=2)=[CH:8][C:9](=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)s1
Reactant: CC1=CC(=C(C#N)C#N)C=C(C(C)(C)C)O1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)C1=CC(=C(C#N)C#N)C=C(C=Cc2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)s2)O1
Yield: 50 %

Procedure:
As shown in the following reaction 3, 0.72 g (3.37 mmol) of (2-(2-tert-butyl-6-methyl-pyran-4-ylidene)-malononitrile and 1 g (2.81 mmol) of 5-(4-diphenylamino-phenyl)-thiophene-2-carbaldehyde were added into 50 ml of ethanol, and 0.28 g (3.37 mmol) of piperidine was added thereto. The reaction solution was heated for 24 hours while refluxing. After cooling the reaction solution, the precipitated red solid was filtered, and recrystallized with ethanol to obtain 0.79 g of the target compound (Yield 50%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:34])[CH2:32][OH:33])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:35])[C@H:20]4[O:36][C:37](=[O:39])[CH3:38])=[O:17])[CH2:15][C@@:7]3([OH:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:41](N1C=CN=C1)([N:43]1[CH:47]=[CH:46][N:45]=[CH:44]1)=[O:42]>ClCCl.O>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:34])[CH2:32][O:33][C:41]([N:43]6[CH:47]=[CH:46][N:45]=[CH:44]6)=[O:42])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:35])[C@H:20]4[O:36][C:37](=[O:39])[CH3:38])=[O:17])[CH2:15][C@@:7]3([OH:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)CO)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)COC(=O)n3ccnc3)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Reaction time: 18 h
Yield: 45.7 %

Procedure:
To (1S,2R,4aS,5S,8R,8aR)-2-(acetyloxy)-8a-hydroxy-5-[2-hydroxy-1-methylethyl]-3,8-dimethyl-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate(Preparation 140, 0.30 g, 0.52 mmol) in dichloromethane was added 1,1′-carbonyldiimidazole (0.92 g, 0.57 mmol) and the reaction mixture was stirred for 18 h. The reaction mixture was diluted with water and extracted with dichloromethane. The organic extracts were washed with brine, dried and then concentrated in vacuo. The crude product was purified by flash chromatography eluting with ethyl acetate:hexane (2:1) to give the title compound (0.16 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([OH:21])([C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)[C:10]([F:13])([F:12])[F:11].Br[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=1[Cl:36].C(=O)([O-])[O-].[K+].[K+]>>[CH3:33][O:32][C:30](=[O:31])[C:29]1[CH:34]=[CH:35][C:26]([CH2:25][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([OH:21])([C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=3)[C:10]([F:13])([F:11])[F:12])=[C:2]([Cl:1])[CH:3]=2)=[C:27]([Cl:36])[CH:28]=1
Reactant: COC(=O)c1ccc(CBr)c(Cl)c1
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(COc2ccc(C(C)C(O)(c3cnc(C)cn3)C(F)(F)F)c(Cl)c2)c(Cl)c1

Procedure:
In analogy to Example 1, step 7, 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 1, step 6) was reacted with methyl 4-(bromomethyl)-3-chlorobenzoate and potassium carbonate to give the title compound as a colorless waxy solid. MS (m/e, ISP neg. ion)=526.9 [M−H+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][CH:18]1[CH2:23][CH2:22][CH:21]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:20][CH2:19]1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([O:45][CH3:46])[C:31]=1[OH:47]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][CH:18]2[CH2:23][CH2:22][CH:21]([N:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[CH2:20][CH2:19]2)[CH:33]=[C:32]([O:45][CH3:46])[C:31]=1[OH:47]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CCN(CC)C1CCC(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: CCN(CC)C1CCC(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(OC)c4)cc23)CC1
Yield: 53.1 %

Procedure:
Following general procedure F, {6-bromo-4-[4-(diethylamino)cyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (45 mg, 0.101 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (34 mg, 0.121 mmol) to afford the desired product (28 mg, 53%) as a yellow glass: 1H NMR (300 MHz, CD3OD) δ 9.39 (s, 0.5H), 9.28 (s, 0.5H), 8.44 (d, J=2.2 Hz, 1H), 8.30-8.21 (m, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.40-7.17 (m, 2H), 4.96 (s, 1H), 3.99 (d, J=2.5 Hz, 3H), 3.72-3.52 (m, 1H), 3.43-3.18 (m, 3H), 2.98-2.81 (m, 1H), 2.59-1.75 (m, 9H), 1.48-1.34 (m, 6H), 1.31-1.13 (m, 4H); ESI MS m/z 522 [C30H36ClN3O3+H]+; HPLC>99% (AUC), tR=7.67 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=O)[CH2:6][C:7](=O)[C:8]1[O:12][CH:11]=[N:10][C:9]=1[CH3:13])[CH3:2].O.[NH2:18][NH2:19]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:8]2[O:12][CH:11]=[N:10][C:9]=2[CH3:13])[NH:19][N:18]=1)=[O:16])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)c1ocnc1C
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ocnc2C)[nH]n1
Yield: 50.6 %

Procedure:
A mixture of 2,4-diketo4-(4-methyloxazol-5-yl)butyric acid ethyl ester (8.50 g), hydrazine hydrate (1.88 g), and ethanol (100 ml) was refluxed for 3 hours and concentrated. The residue was chromatographed (silica gel, Hex/EtOAc 1/1) to yield 4.20 g of 3-ethoxycarbonyl-5-(4-methyloxazol-5-yl)pyrazole as tan solids, mp 131°-133° C. (methanol/isopropyl ether). NMR: 1.42 (t, 3H), 2.48 (s, 3H), 4.44 (q, 2H), 7.05 (s, 1H, 4-pyrazolyl H), 7.85 (s, 1H, 2-oxazolyl H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)C(C)C)(C)C.C([O:23][C:24](=O)[CH:25]=[C:26]([O:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])[CH2:27]Br)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:27][C:26]([O:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[F:37])=[CH:25][C:24]1=[O:23])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CCOC(=O)C=C(CBr)Oc1cc(F)ccc1F
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2cc(F)ccc2F)=CC1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 17.4 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (1.28 g, 7.08 mmol) in acetonitrile (17.7 mL) was treated with N,N-diisopropylethylamine (1.15 mL, 6.95 mmol). After addition was complete, the mixture was stirred at 60° C. for 1 h. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (1.15 mL, 6.95 mmol) and acetonitrile (17.7 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(2,5-difluoro-phenoxy)-but-2-enoic acid ethyl ester (1.56 g, 6.44 mmol) in acetonitrile (16.1 mL). After the addition was complete, the reaction mixture was heated to 100° C. where it stirred overnight. At this time, the reaction mixture was cooled to 25° C. and was concentrated in vacuo. The residue was diluted with dichloromethane (75 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes) afforded (S)-2-[4-(2,5-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.38 g, 17%) as a yellow oil: HR-ES-MS m/z calculated for C17H19NO4F2 [M+H]+ 340.1355, observed 340.1355; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H), 1.35-1.53 (m, 1H), 1.53-1.69 (m, 1H), 1.72-1.89 (m, 1H), 3.66 (s, 3H), 4.13-4.33 (m, 2H), 4.73 (dd, J=11.5, 4.5 Hz, 1H), 5.07 (s, 1H), 7.13-7.35 (m, 1H), 7.42-7.64 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[C:5]2[CH:17]=[CH:18][CH:19]=[C:20]([NH:21][C:22](=[O:24])[CH3:23])[C:4]=2[N:3]=1.[C:25](OC)(=[O:28])[C:26]#[CH:27]>CO>[C:22]([NH:21][C:20]1[C:4]2[N:3]3[CH:27]=[CH:26][C:25](=[O:28])[N:1]=[C:2]3[CH2:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=3)[C:5]=2[CH:17]=[CH:18][CH:19]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Nc1cccc2c1N=C(N)CN=C2c1ccc(C#N)cc1
Reactant: C#CC(=O)OC
Solvent: CO
Product: CC(=O)Nc1cccc2c1-n1ccc(=O)nc1CN=C2c1ccc(C#N)cc1

Procedure:
In the manner given in Example 1, 2-amino-9-acetylamino-5-(p-cyanophenyl)-3H-1,4-benzodiazepine, methyl propiolate and methanol were refluxed. The mixture was chromatographed to give 11-acetylamino-7-(p-cyanophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[NH:12])SC.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(O)(=O)C(O)=O>C(O)C.C(O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[NH:12]
Reactant: C1CCNC1
Reactant: CSC(=N)Nc1ccccc1F
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CC(C)O
Product: N=C(Nc1ccccc1F)N1CCCC1

Procedure:
To stirred solution of 2.0 g (0.006 mol) of N-(2-fluorophenyl)-S-methylisothiourea in 50 ml of ethanol was added 2.0 g (0.028 mol) of pyrrolidine and the reaction refluxed for eight hours. The solvent was then evaporated and to the residue was added 100 ml of water and 20 ml of 2 N sodium hydroxide. The aqueous phase was then extracted with ethyl acetate (3×100 ml) and the organic phase dried over magnesium sulphate. Evaporation of the solvent gave a crude residue. This crude residue was then dissolved in 25 ml of hot isopropanol and oxalic acid was added in excess. Upon cooling a white solid crystallized and was collected by filtration and dried at 60° C. for 24 hours to give the oxalate salt of N-(2-fluorophenyl)-1-pyrrolidinecarboximidamide, M.P. 172-173° C.