Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[C:2]1([C:8]([PH3+])([C:15]2C=CC=CC=2)[C:9]2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CC(C1C=CC([Cl:36])=CC=1)=O>O1CCCC1.CCCCCC>[Cl:36][C:5]1[CH:6]=[CH:7][C:2]([C:8]([CH3:15])=[CH2:9])=[CH:3][CH:4]=1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(C)c1ccc(Cl)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a slurry of triphenylmethylphosphonium bromide (71.4 grams (g), 200 millimole (mmole)) in 500 milliliters (ml) dry tetrahydrofuran (THF) (distilled from sodium/benzophenone), were slowly added dropwise 129 ml (200 mmole) 1.55 molar (M) n-butyllithium in hexane. The reaction mixture was stirred for 30 minutes at -10° C. whereafter a solution of 30.92 g (200 mmol) 4-chloroacetophenone in 100 ml dry THF was slowly added dropwise. The reaction mixture was then stirred for one hour at -10° C., slowly warmed to ambient temperature (about 23° C.) and stirring continued overnight. The mixture was thereafter filtered and the solvent removed by distillation at atmospheric pressure. Distillation, using a water aspirator, yielded 16.5 g (54.2% yield) of p-chloro-α-methylstyrene, boiling point (bp) 82°-86° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:33][CH2:34][N:29]([C:23]3[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:22]=3[CH3:21])[CH2:30][CH2:31]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(F)cc1
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4ccc(F)cc4)n(C(C)(C)C)n3)CC2)c1C

Procedure:
133 mg (75%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg, 0.365 mmol), 1-(2,3-dimethylphenyl)piperazine (69 mg, 0.365 mmol), DIPEA (0.1 mL, 0.548 mmol) and NaBH(OAc)3 (232 mg, 1.095 mmol).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[NH2:15])[CH2:4]CC.[CH2:16]([N:18]([C:22]1[CH:27]=[CH:26][C:25]([N:28]=O)=[CH:24][CH:23]=1)[CH2:19][CH2:20][OH:21])[CH3:17]>[OH-].[Na+].O>[ClH:1].[NH2:14][C:11]1[C:12](=[N:28][C:25]2[CH:24]=[CH:23][C:22]([N:18]([CH2:16][CH3:17])[CH2:19][CH2:20][OH:21])=[CH:27][CH:26]=2)[CH:13]=[C:8]([O:7][CH2:3][CH3:4])[C:9](=[NH:15])[CH:10]=1
Reactant: CCN(CCO)c1ccc(N=O)cc1
Reactant: CCCCOc1ccc(N)cc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC1=CC(=Nc2ccc(N(CC)CCO)cc2)C(N)=CC1=N
Reaction time: 3 h

Procedure:
A solution of 4-butoxybenzene-1,3-diamine dihydrochloride in 4.2 ml of 0.25N sodium hydroxide is added to a solution of 2-[ethyl(4-nitrosophenyl)amino]ethanol in 4.2 ml of water at 50° C. After 3 hours at 50° C., the supernatant is removed and the residual gum is washed with water and then taken up in isopropyl ether. The solid formed is filtered off and dried. 360 mg of 2-{[4-(2-amino-5-ethoxy-4-imino cyclohexa-2,5-dienylideneamino)phenyl]-ethylamino}ethanol hydrochloride 65 are thus obtained in the form of a black powder.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].[OH-].[Na+]>ClCCl>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) in dichloromethane (1.6 ml) was added at room temperature triethylamine (139 mg, 192 μl, 1.38 mmol) and methanesulfonyl chloride (43.0 mg, 29.2 μl, 375 μmol). The mixture was allowed to stir at room temperature for 4 h, poured into ice/water (5 ml) and 1N sodium hydroxide solution (5 ml) and extracted with dichloromethane (2×20 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. The crude material (0.1 g) was triturated with dichloromethane (1 ml) and heptane (5 mL) for 30 min. The precipitate was collected by filtration, washed with heptane and dried to yield the title compound as a white solid (90 mg, 88%), MS (ISP) m/z=409.4 [(M+H)+], mp 220° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:19][C:14]3=[N:15][CH:16]=[CH:17][N:18]=[C:13]3[C:12]=2[CH2:20][CH2:21][CH2:22][NH2:23])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:24]([N:27]=[C:28]=[O:29])[CH2:25][CH3:26].O>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:19][C:14]3=[N:15][CH:16]=[CH:17][N:18]=[C:13]3[C:12]=2[CH2:20][CH2:21][CH2:22][NH:23][C:28]([NH:27][CH2:24][CH2:25][CH3:26])=[O:29])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2[nH]c3nccnc3c2CCCN)cc1
Reactant: CCCN=C=O
Solvent: O
Solvent: C1CCOC1
Product: CCCNC(=O)NCCCc1c(-c2ccc(C(C)(C)C)cc2)[nH]c2nccnc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-(6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)propylamine (0.0324 mmol). The [Example 24] in tetrahydrofuran (2 mL) was treated with n-propyl-isocyanate (0.0324 mmol). The solution was stirred at room temperature for 12 hours and then treated with water (3 mL). The resulting precipitate was filtered, then washed with water and then dried under vacuum at 50° C. to give the title compound as a beige solid. MS: 394 (MH+). HPLC (Method C): RT=3.25 minutes.
Reaction SMILES: [CH2:1](OC(=O)C(NC1C=CC(=O)C(O)=CC=1)=O)C.[CH2:18]([O:20][C:21](=[O:34])[C:22]([NH:24][C:25]1[C:26](=[O:33])[C:27]([OH:32])=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])C>>[CH3:18][O:20][C:21](=[O:34])[C:22]([NH:24][C:25]1[C:26](=[O:33])[C:27]([O:32][CH3:1])=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23]
Reactant: CCOC(=O)C(=O)Nc1ccccc(O)c1=O
Reactant: CCOC(=O)C(=O)Nc1ccc(O)c(=O)cc1
Product: COC(=O)C(=O)Nc1ccccc(OC)c1=O

Procedure:
In the same manner but replacing [(5-hydroxy-4-oxo-2.5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethyl ester with an equivalent amount of [(3-hydroxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethyl ester (described in Example 5), [(3-methoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid methyl ester is obtained.
Reaction SMILES: [O:1]=[C:2]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.[CH3:15][O:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([NH:23][C:24]2[C:25]([NH2:30])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:22])=[CH:19][CH:18]=1>C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:23][C:24]2[C:25]([NH:30][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: O=C(O)CCCC(=O)N1CCOCC1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)CCCC(=O)N2CCOCC2)cc1
Yield: 85 %

Procedure:
Using the procedure described in Example 161, 5-oxo-5-morpholinopentanoic acid (166 mg, 0.826 mmol) was reacted with N1-(4-methoxybenzoyl)-1,2-benzenediamine. The reaction mixture was diluted with additional methylene chloride and washed with 1 N aqueous sodium hydroxide. The organic phase was washed with 1 N aqueous hydrochloric acid, dried (sodium sulfate), filtered, and concentrated in vacuo to provide 300 mg (85%) of the title compound as an amorphous white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[NH4+].[N:13]#[C:14][S-:15].BrBr>C(O)(=O)C>[NH2:13][C:14]1[S:15][C:7]2[CH:6]=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:4]=[CH:3][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(CC(=O)O)cc2s1
Temperature: 15 °C
Reaction time: 4 h

Procedure:
(4-Amino-phenyl)-acetic acid (20 g, 132.5 mmol) and NH4SCN (20 g, 263.2 mmol) were dissolved in 300 ml of acetic acid and the mixture was cooled to 15° C., treated with Br2 (21.2 g, 6.8 ml) in acetic acid (10 ml) and the temperature did not exceed 15° C. Then the reaction was stirred at room temperature for 4 h. The mixture was filtered and the cake was re-dissolved in water, adjusted the pH=5. The precipitate was filtered and dried to obtain 2-amino-benzothiazol-6-yl)-acetic acid as light yellow powder (24 g, 87.1%).
Reaction SMILES: CN(C)/C=[CH:4]/[C:5](C1N(C(C)C)C(C)=NC=1)=[O:6].S([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:49]=[CH:48][C:30]([NH:31][C:32]3[N:37]=[C:36]([C:38]4[N:42]([CH:43]([CH3:45])[CH3:44])[C:41]([CH3:46])=[N:40][CH:39]=4)[C:35](Cl)=[CH:34][N:33]=3)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)(C)(=O)=O>COCCO>[C:5]([N:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:28]=[CH:29][C:30]([NH:31][C:32]3[N:37]=[C:36]([C:38]4[N:42]([CH:43]([CH3:45])[CH3:44])[C:41]([CH3:46])=[N:40][CH:39]=4)[CH:35]=[CH:34][N:33]=3)=[CH:48][CH:49]=2)[CH2:25][CH2:26]1)(=[O:6])[CH3:4]
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)ncc2Cl)n1C(C)C
Reactant: Cc1ncc(C(=O)/C=C/N(C)C)n1C(C)C
Solvent: COCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nccc(-c4cnc(C)n4C(C)C)n3)cc2)CC1

Procedure:
(2E)-3-(Dimethylamino)-1-(1-isopropyl-2-methyl-1H-imidazol-5-yl)prop-2-en-1-one (Method 24 of WO 03/076436; 140 mg 0.63 mmol) and N-[4-(4-acetylpiperazin-1-yl)phenyl]guanidine bicarbonate salt (Method 2; 240 mg 0.74 mmol) in 2-methoxyethanol (4 ml) were reacted under nitrogen under microwave conditions at 200° C. for 30 minutes. After evaporation under reduced pressure, chromatography on silica gel with MeOH:DCM (2:98 to 6:94) gave the title compound, after ether trituration, as a yellow solid. (85 mg 31.5%). NMR: 1.39 (d, 6H), 2.02 (s, 3H), 2.45 (s, 3H), 3.00 (b t, 2H), 3.06 (b t, 2H), 3.56 (b q, 4H), 5.70 (septuplet, 1H), 6.91 (d, 2H), 6.95 (d, 1H), 7.38 (s, 1H), 7.46 (d, 2H), 8.31 (d, 1H), 9.15 (s, 1H); m/z 420.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][NH:5][C:6](=[O:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]=[CH2:17])=[C:10]([Cl:18])[CH:9]=1.[H][H]>C(O)C.O=[Pt]=O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][NH:5][C:6](=[O:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH3:17])=[C:10]([Cl:18])[CH:9]=1
Reactant: C=CCOc1ccc(CC(=O)NCC(=O)OC)cc1Cl
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: CCCOc1ccc(CC(=O)NCC(=O)OC)cc1Cl
Reaction time: 5 h
Yield: 19.9 %

Procedure:
4-Allyloxy-3-chloro-phenylacetyl-glycine methyl ester (see Example 6; 3.0 g) was dissolved in absolute ethanol (100 ml) and Adams catalyst (20 mg) was added. Hydrogenation was carried out in an atmospheric pressure hydrogenator for 5 hrs. until hydrogen (310 ml) had been taken up. The catalyst was removed from the reaction mixture by filtration, the solvent was evaporated at reduced pressure, and light petroleum (b.p. 40°-60° C.) was added to the residue; a solid product (600 mg) of m.p. 76°-80° C. was obtained. After recrystallisation from chloroform/light petroleum (b.p. 40°-60° C.), the above-named product (200 mg), m.p. 79°-82° C., was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:31])([F:30])[CH:20]([OH:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].CN(C1C=CC=CN=1)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:29][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:19]([F:18])([F:30])[F:31])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCCCCC(O)C(F)(F)F
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCC(OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a solution of 4-benzyloxybenzoic acid chloride (1.23 g) in methylene chloride (10 ml) was added by little and little under ice-cooling a solution of optically active 1,1,1-trifluoro-2-decanol (0.96 g), dimethylaminopyridine (0.55 g) and triethylamine (0.48 g) in methylene chloride (20 ml). The mixture was left to stand overnight at room temperature in order to effect a reaction before the mixture obtained was poured in ice-water. Extraction was effected with methylene chloride and the extracted phase was washed with dilute aqueous hydrochloric acid solution, water, 1N aqueous sodium carbonate solution and water in due order before it was dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain a crude product which was purified by toluene/silica from ethanol to obtain the titled compound (1.84 g).
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[O:14][CH:15]1[CH2:32][CH:31]2[N:17]([C:18](=[O:44])[N:19]([CH3:43])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]3[C:28]([C:34]([NH:36][S:37]([CH:40]4[CH2:42][CH2:41]4)(=[O:39])=[O:38])=[O:35])([NH:29][C:30]2=[O:33])[CH2:27]3)[CH2:16]1.[CH3:45][O:46][C:47]1[CH:52]=[CH:51][C:50](B(O)O)=[CH:49][CH:48]=1.CC1C=CN=CC=1C1C(OC)=CC=C2C=1C=CN=C2OC1CC2N(C(=O)N(C)CCCCC=CC3C(C(NS(C4CC4)(=O)=O)=O)(NC2=O)C3)C1>>[CH3:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([C:2]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]=[C:7]3[O:14][CH:15]2[CH2:32][CH:31]3[N:17]([C:18](=[O:44])[N:19]([CH3:43])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([NH:36][S:37]([CH:40]5[CH2:42][CH2:41]5)(=[O:38])=[O:39])=[O:35])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)=[CH:49][CH:48]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nccc2c1Br
Reactant: COc1ccc(B(O)O)cc1
Agent: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nccc2c1-c1cnccc1C
Product: COc1ccc(-c2c(OC)ccc3c(OC4CC5C(=O)NC6(C(=O)NS(=O)(=O)C7CC7)CC6C=CCCCCN(C)C(=O)N5C4)nccc23)cc1

Procedure:
The title product was prepared from N-[17-(5-bromo-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl) sulfonamide (51, example 13) and 4-methoxybenzeneboronic acid following the procedure described for N-[17-[5-(4-methyl-3-pyridyl)-6-methoxyisoquinolin-1-yloxy]-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (52, Example 14): m/z=718 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:24])[CH2:4][CH2:3]1.[CH:25](=O)[C:26]1[O:30][CH:29]=[CH:28][CH:27]=1.C([BH3-])#N.[Na+]>CO>[O:30]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:25][N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:24])[CH2:6][CH2:7]1
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCNCC1
Reactant: O=Cc1ccco1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCN(Cc2ccco2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
To a solution of 344 mg (1.0 mmol) of 3-(piperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone HCl salt and 384 mg (4.0 mmol) of furfural in 40 mL of methanol was added 123 mg (2.0 mmol) of sodium cyano-borohydride under ice-cooling. After being stirred for 12 hours at ambient temperature, the reaction mixture was concentrated in vacuo. The residue was diluted with water, and the mixture was adjusted to pH 10 with aqueous ammonia, and then extracted with chloroform. The organic layer separated was dried on potassium carbonate and then concentrated in vacuo. The residue was purified by means of column chromatography (silica gel, 1:9 methanol:chloroform) to give 329 mg (0.85 mmol) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:31])[N:14]([CH2:16][CH2:17][O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[CH2:8]O.CS(Cl)(=O)=O.[N-:37]=[N+:38]=[N-:39].[Na+]>C(Cl)Cl.O>[N:37]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:31])[N:14]([CH2:16][CH2:17][O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)[N:15]=2)=[CH:3][C:2]=1[Cl:1])=[N+:38]=[N-:39]
Reactant: COc1ccc2c(OCCn3nc(-c4ccc(CO)c(Cl)c4)ccc3=O)ccnc2c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(OCCn3nc(-c4ccc(CN=[N+]=[N-])c(Cl)c4)ccc3=O)ccnc2c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a stirring solution of 6-(3-chloro-4-(hydroxymethyl)phenyl)-2-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridazin-3(2H)-one (1060 mg, 2421 μmol) and TEA (337 μL, 2421 μmol) in DCM (10 mL) at 0° C. under nitrogen was added methanesulfonyl chloride (187 μL, 2421 μmol) in DCM (1 mL). After 3 hours, the mixture was partitioned between DCM (25 mL) and 5% NaHCO3 (25 mL). The aqueous layer was further extracted with DCM (2×10 mL). The combined organics were dried over MgSO4, then concentrated to a solid. Solid was then dissolved in DMF (5 mL) and sodium azide (787 mg, 12104 μmol) in water (5 mL) was then added. The biphasic solution was then heated to 60° C. overnight. The reaction was then partitioned between DCM (25 mL) and 5% NaHCO3 (25 mL). The aqueous layer was then further extracted with DCM (2×10 mL). The combined organics were then dried over MgSO4, concentrated, and purified on silica (40 g) eluting with 1 to 4% of MeOH/DCM. MS (ESI pos. ion) m/z: 463 (MH+); calc'd for C23H19ClN6O3: 462.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C([Sn](CCCC)(CCCC)[C:43]1[O:44][C:45]2[CH:51]=[CH:50][CH:49]=[CH:48][C:46]=2[N:47]=1)CCC.[F-].[Cs+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[O:44]1[C:45]2[CH:51]=[CH:50][CH:49]=[CH:48][C:46]=2[N:47]=[C:43]1[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2o1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4nc5ccccc5o4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 130 °C
Yield: 21.2 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50.0 mg, 0.0895 mmol), 2-(tributylstannyl)-1,3-benzoxazole (81.2 mg, 0.179 mmol), bis (tri-tert-butylphosphine)palladium(0) (9.15 mg, 0.0179 mmol) and cesium fluoride (88.4 mg, 0.582 mmol) in 1,4-dioxane (1.00 mL) was heated at 130° C. under microwave irradiation for 2 hours under nitrogen. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (×3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by PTLC (EtOAc/hexane=1:1, DCM/EtOAc=1:1) to afford desired product (11.3 mg, 21.2%) as white solid. 1HNMR (CDCl3) 500 MHz δ: 8.27 (dd, J=7.7, 1.7 Hz, 1H), 8.08-8.02 (m, 1H), 7.75-7.68 (m, 1H), 7.52-7.38 (m, 5H), 7.37-7.25 (m, 3H), 7.20-7.14 (m, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.92-6.81 (m, 1H), 6.63 (dd, J=8.0, 4.6 Hz, 1H), 6.45 (s, 1H), 5.20 (s, 1H), 2.68-2.25 (m, 4H), 2.22-2.09 (m, 1H), 1.97-1.86 (m, 1H), 1.54-1.11 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:21]2[C:22](=[O:26])[NH:23][C:24](=[O:25])[C:20]=2[C:19]2[C:18]3[CH:17]=[C:16]([O:27][CH3:28])[CH:15]=[CH:14][C:13]=3[N:12]([CH2:29][CH2:30][C:31]([OH:33])=O)[C:11]=2[CH:10]=1.[NH3:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:21]2[C:22](=[O:26])[NH:23][C:24](=[O:25])[C:20]=2[C:19]2[C:18]3[CH:17]=[C:16]([O:27][CH3:28])[CH:15]=[CH:14][C:13]=3[N:12]([CH2:29][CH2:30][C:31]([NH2:34])=[O:33])[C:11]=2[CH:10]=1
Reactant: N
Reactant: COc1ccc2c(c1)c1c3c(c(-c4c(Cl)cccc4Cl)cc1n2CCC(=O)O)C(=O)NC3=O
Product: COc1ccc2c(c1)c1c3c(c(-c4c(Cl)cccc4Cl)cc1n2CCC(N)=O)C(=O)NC3=O
Yield: 73 %

Procedure:
Reaction of acid (244) (0.23 g, 0.48 mmol) prepared as described in example 204 according to the procedure described in example 207, except that concentrated ammonia (˜30%, 20 mL) was added as the amine, gave amide (250) (0.17 g, 73%) as a yellow powder, mp 261–264° C. 1H NMR δ [(CD3)2SO] 11.19 (br s, 1H), 8.50 (d, J=2.6 Hz, 1H), 7.87 (s, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.63 (m, 2H), 7.52 (dd, J=8.8, 7.3 Hz, 1H), 7.38 (br s, 1H), 7.33 (dd, J=9.0, 2.6 Hz, 1H), 6.87 (br s, 1H), 4.69 (t, J=6.7 Hz, 214), 3.91 (s, 3H), 2.57 (t, J=6.7 Hz, 2H). Found: C, 59.55; H, 3.79; N, 8.73. C14H17Cl2N3O4 requires: C, 59.75; H, 3.55; N, 8.71.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.CC1(C)[O:35][C@@H:34]([CH2:36][CH2:37][NH2:38])[CH2:33][O:32]1.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>[OH:35][C@H:34]([CH2:33][OH:32])[CH2:36][CH2:37][NH:38][C:27]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[NH:10]1)=[O:29]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: CC1(C)OC[C@H](CCN)O1
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: CC(C)(C)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (431.4 mg, 1.00 mmol) prepared in Example 1d, 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (217.5 mg, 1.5 mmol), HATU (570.30 mg, 1.50 mmol) and iPr2NEt (258.6 mg, 2.00 mmol) in CH2Cl2 (20 mL) was stirred at rt for 1 hour. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and the residue was treated with PPTS (cat) in MeOH (20 mL) at 120° C. for 5 min with CEM microwave reactor. The reaction mixture was concentrated and the residue was diluted with EtOAc and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by SiO2 flash column (5% of MeOH in EtOAc) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (450.0 mg, 86.7%) as a white amorphous.