Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[C:28]([CH2:29][CH2:30][CH3:31])=[CH:27][C:23]2[O:24][CH2:25][O:26][C:22]=2[CH:21]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[CH2:29]([C:28]1[C:20]([CH2:19][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH:21][C:22]2[O:26][CH2:25][O:24][C:23]=2[CH:27]=1)[CH2:30][CH3:31]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCc1cc2c(cc1CCl)OCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Product: CCCc1cc2c(cc1CC(C(=O)OCC)C(=O)OCC)OCO2

Procedure:
24.3 g of diethyl malonate, 42 g of potassium carbonate, 300 ml of acetone and a catalytic amount of tetrabutylammonium bromide were added to 16.1 g of crude 5-chloromethyl-6-propyl-1,3-benzodioxole and the mixture was heated under reflux for 25 h. The reaction mixture was filtered and the residue was washed with acetone. The washing was combined with the filtrate. The solvent was distilled off. 500 ml of ethyl acetate and 500 ml of water were added thereto and the layers thus formed were separated. The ethyl acetate layer was washed with water three times and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 16.5 g of the crude intended compound in the form of a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[NH:5][C:4](=[O:13])[CH:3]=1.[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31]Cl)[CH2:25][CH2:24]2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:31][CH2:30][CH2:29][N:26]3[CH2:25][CH2:24][N:23]([CH2:22][C:21]4[CH:20]=[CH:19][C:18]([C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)[CH:10]=2)[NH:5][C:4](=[O:13])[CH:3]=1
Reactant: CC(C)(C)c1ccc(CN2CCN(CCCCl)CC2)cc1
Reactant: Cc1cc(=O)[nH]c2ccc(O)cc12
Product: Cc1cc(=O)[nH]c2ccc(OCCCN3CCN(Cc4ccc(C(C)(C)C)cc4)CC3)cc12

Procedure:
In a manner analogous to that described in Example 5, by the reaction of 4-methyl-6-hydroxy-2-oxo-1,2-dihydroquinoline with 3-[4-(4-tert.-butylbenzyl)-piperazin-1-yl]-propyl chloride, there is obtained 4-methyl-6-{3-[4-(4-tert.-butylbenzyl)-piperazin-1-yl]-propoxy}-2-oxo-1,2-dihydroquinoline which, after recrystallization from ethyl acetate, melts at 171°-172° C.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([OH:24])=[C:19]([Cl:25])[CH:18]=1>>[Cl:23][C:21]1[CH:22]=[C:17]([NH2:16])[CH:18]=[C:19]([Cl:25])[C:20]=1[O:24][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: FC(F)(F)Oc1ccc2nc(Cl)sc2c1
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Product: Nc1cc(Cl)c(Oc2nc3ccc(OC(F)(F)F)cc3s2)c(Cl)c1

Procedure:
3,5-Dichloro-4-(6-trifluoromethoxy-benzothiazol-2-yloxy)-phenylamine was synthesized (76%) from 2-chloro-6-trifluoromethoxybenzotiazole (413) and 4-amino-2,6-dichlorophenol (Aldrich) in a similar manner as described in Example 417.
Reaction SMILES: [F:1][C:2]1[C:15]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]([OH:11])=O.[CH3:22][O:23][CH:24]([O:33][CH3:34])[CH2:25][NH:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([N:26]([CH2:25][CH:24]([O:33][CH3:34])[O:23][CH3:22])[C:9](=[O:11])[CH2:8][CH2:7][O:6][CH2:5][CH2:4][C:3]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[C:2]=2[F:1])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Cn1cc(-c2cccc(CCOCCC(=O)O)c2F)cn1
Reactant: COC(CNC1CCCCC1)OC
Product: COC(CN(C(=O)CCOCCc1cccc(-c2cnn(C)c2)c1F)C1CCCCC1)OC

Procedure:
The subtitled compound (1.6 g) was prepared form 3-(2-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 16, Step v)] and N-(2,2-dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 12, Step iii). MS [M+H-MeOH]+=430 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 7.97 (s, 1H), 7.84 (d, J=2.3 Hz, 1H), 7.46 (td, J=2.0 and 7.6 Hz, 1H), 7.15-7.02 (m, 2H), 4.53 and 4.37 (2×t, J=5.4 Hz, 1H), 4.04-3.94 and 3.70-3.60 (2×m, 1H), 3.92 (s, 3H), 3.76-3.64 (m, 4H), 3.35 and 3.33 (2×s, 6H), 3.36-3.26 (m, 2H), 2.95-2.88 (m, 2H), 2.65 and 2.63 (2×t, J=6.3 Hz, 2H), 1.81-1.00 (m, 10H); a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[CH:7]=1.C([Li])CCC.[F:28][C:29]1[CH:40]=[CH:39][C:32]([C:33](N(OC)C)=[O:34])=[CH:31][CH:30]=1>CCOCC>[F:28][C:29]1[CH:40]=[CH:39][C:32]([C:33]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([C@@H:8]3[CH2:12][CH2:11][CH2:10][N:9]3[C@@H:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH3:14])[CH:7]=2)=[O:34])=[CH:31][CH:30]=1
Reactant: CON(C)C(=O)c1ccc(F)cc1
Reactant: COc1ccc([C@@H](C)N2CCC[C@H]2c2cncc(Br)c2)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc([C@@H](C)N2CCC[C@H]2c2cncc(C(=O)c3ccc(F)cc3)c2)cc1
Temperature: -73 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
To a solution of 3-bromo-5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridine (3) (6.0 g, 16.6 mmole) in 100 mL of ether at −73° C., is added a solution of butyl lithium (7.3 mL, 18.3 mmole, 2.5 M in hexane) slowly (maintaining internal T<−70° C.). After stirring at −73° C. for 30 minutes, a solution of 4-fluoro-N-methoxy-N-methyl-benzamide (4a) (4.56 g, 24.9 mmole) in 15 mL of ether is added slowly (maintaining internal T<−70° C.). After stirring at −70° C. for 1.5 hours, the reaction is quenched by addition of 20 mL of water and warmed to room temperature with stirring. The resulting mixture is diluted with 100 mL of EtOAc and washed with 2×30 mL of water. The organic layer is concentrated and purified by flash column chromatography (CH2Cl2 95%, EtOAc 5%) to give (4-fluoro-phenyl)-(5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridin-3-yl)-methanone (4) (6.4 g, yield 86%) as a light brown viscose liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].CC[CH2:11][CH2:12][O:13]C=C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:12](=[O:13])[CH3:11]
Reactant: Cc1ccncc1Br
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cnccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
671 μl (5.81 mmol) of 3-bromo-4-methylpyridine in 15 mL of H2O/DMF (1/4: v/v), 1.93 mL (14.53 mmol) of N-butyl vinyl ether, 39.15 mg (0.17 mmol) of palladium(II) acetate, 163.14 mg (0.38 mmol) of 1,3-bis(diphenylphosphino)propane and 973.84 mg (6.98 mmol) of potassium carbonate are placed in a microwave tube. After irradiating with microwaves at 120° C. for 2 hours, 20 mL of 5% hydrochloric acid solution are added. The reaction mixture is stirred for 1 hour at room temperature and then basified with potassium carbonate and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 50/50 EtOAc/heptane) to give 320 mg of 1-(4-methylpyrid-3-yl)ethanone, the characteristics of which are as follows:
Reaction SMILES: [C:1](=[O:13])([S:11][CH3:12])[O:2][CH:3]([O:5][C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])C.ClC(OCCl)=O.[C:20](O)(=O)[C:21]1C=CC=C[CH:22]=1>>[C:1](=[O:13])([S:11][CH3:12])[O:2][CH2:3][O:5][C:6](=[O:10])[C:7]1[CH:9]=[CH:22][CH:21]=[CH:20][CH:8]=1
Reactant: CSC(=O)OC(C)OC(=O)C(C)C
Reactant: O=C(O)c1ccccc1
Agent: O=C(Cl)OCCl
Product: CSC(=O)OCOC(=O)c1ccccc1

Procedure:
Following the procedures for synthesizing O-(1-isobutanoyloxyethyl) S-methyl thiocarbonate (2) and replacing 1-chloroethyl chloroformate with chloromethyl chloroformate in Step A and replacing isobutyric acid with benzoic acid in Step B affords O-(benzoyloxymethyl) S-methyl thiocarbonate (213) as an oil.
Reaction SMILES: Cl[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.[CH2:38]([O:45][C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[C:33]([O:32][C:31](=[O:37])[NH:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[N:5]4[C:6]5[CH:18]=[CH:17][CH:16]=[N:15][C:7]=5[NH:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[C:4]4=[N:3][C:2]=3[C:49]3[CH:50]=[CH:51][C:46]([O:45][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:47][CH:48]=3)=[CH:21][CH:22]=2)[CH2:27][CH2:28][CH2:29]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Cl)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(OCc5ccccc5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Yield: 83.5 %

Procedure:
A mixture of tert-butyl {1-[4-(2-chloro-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (400 mg, 0.778 mmol), [4-(benzyloxy)phenyl]boronic acid (355 mg, 1.56 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (55 mg, 0.078 mmol), and 2M Na2CO3 aq. (0.780 mL, 1.56 mmol) in DMF (8 mL) was treated with microwave (160° C. for 1 hour). The mixture was diluted with AcOEt, washed with water(×3), brine, dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated and the residue was purified by column chromatography (n-hexane/AcOEt=3:2) to afford the mixture of the desired product (430 mg, 84%) as a pale yellow solid. 1HNMR (CDCl3) 400 MHz δ: 8.16 (dd, J=8.0, 1.1 Hz, 1H), 8.00 (d, J=4.0 Hz, 1H), 7.51 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 7.39-7.33 (m, 4H), 7.32-7.28 (m, 2H), 7.16-7.12 (m, 3H), 6.94 (d, J=8.0 Hz, 1H), 6.89 (d, J=8.6 Hz, 2H), 6.79 (d, J=7.4 Hz, 1H), 6.59 (dd, J=8.0, 4.6 Hz, 1H), 6.26 (s, 1H), 5.10 (br s, 1H), 5.05 (s, 2H), 2.56-2.46 (m, 4H), 2.18-2.09 (m, 1H), 1.93-1.84 (m, 1H), 1.39 (br s, 9H). LCMS: 662 [M+H].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37].O>C1COCC1>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([N:38]([CH2:39][CH3:40])[CH2:36][CH3:37])[N:3]=3)[N:25]=2)=[CH:34][CH:33]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CCNCC
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
At RT, 60 mg (0.11 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.023 ml (0.22 mmol) of diethylamine were stirred in 1.5 ml of THF for 30 min. About 15 ml of water were added to the reaction mixture, and the aqueous phase was extracted 3× with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, concentrated by evaporation and dried under high vacuum. This gave 67 mg (99% of theory, purity 95%) of the desired target compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:33]=[CH:32][C:31]3[C:30]4[C:25](=[CH:26][C:27]([C:34]5[CH:60]=[CH:59][C:37]6[N:38]=[C:39]([CH:41]7[CH:46]8[CH2:47][CH:43]([CH2:44][CH2:45]8)[N:42]7[C:48](=[O:58])[CH:49]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:50]([CH3:52])[CH3:51])[NH:40][C:36]=6[CH:35]=5)=[CH:28][CH:29]=4)[C:24]([F:62])([F:61])[C:23]=3[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[NH:64]1CCC[C@H:65]1C(O)=O.C(C1CN[C@H](C(O)=O)C1)#N>>[CH3:57][O:56][C:54](=[O:55])[NH:53][CH:49]([C:48]([N:42]1[CH:41]([C:39]2[NH:40][C:36]3[CH:35]=[C:34]([C:27]4[CH:28]=[CH:29][C:30]5[C:31]6[C:23](=[CH:22][C:21]([C:18]7[NH:17][C:16]([CH:12]8[CH2:13][CH:14]([C:65]#[N:64])[CH2:15][N:11]8[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:63])[CH:6]([CH3:7])[CH3:8])=[N:20][CH:19]=7)=[CH:33][CH:32]=6)[C:24]([F:62])([F:61])[C:25]=5[CH:26]=4)[CH:60]=[CH:59][C:37]=3[N:38]=2)[CH:46]2[CH2:47][CH:43]1[CH2:44][CH2:45]2)=[O:58])[CH:50]([CH3:52])[CH3:51]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)C)[nH]c5c4)ccc2-3)[nH]1)C(C)C
Reactant: O=C(O)[C@@H]1CCCN1
Agent: N#CC1CN[C@H](C(=O)O)C1
Product: COC(=O)NC(C(=O)N1CC(C#N)CC1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)C)[nH]c5c4)ccc2-3)[nH]1)C(C)C

Procedure:
(Example DV) was prepared in a similar fashion to (1-{2-[5-(9,9-Difluoro-7-{2-[2-(2-methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DK), replacing the proline derivative with the corresponding 4-cyano-proline derivative.
Reaction SMILES: [CH2:1]([Si:4]([CH:11]([CH3:13])[CH3:12])([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])[CH:2]=[CH2:3].[C:14]([OH:19])(=[O:18])[CH2:15]C=C>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C(Cl)Cl>[CH:11]([Si:4]([CH:5]([CH3:6])[CH3:7])([CH:8]([CH3:10])[CH3:9])[CH2:1][CH:2]=[CH:3][CH2:15][C:14]([OH:19])=[O:18])([CH3:13])[CH3:12]
Reactant: C=CC[Si](C(C)C)(C(C)C)C(C)C
Reactant: C=CCC(=O)O
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCl
Product: CC(C)[Si](CC=CCC(=O)O)(C(C)C)C(C)C
Temperature: 40 °C
Yield: 87 %

Procedure:
A flame dried round-bottomed flask was charged with allyltriisopropylsilane (0.722 mL, 3 mmol, 3 eq), 3-butenoic acid (0.084 mL, 1 mmol, 1 eq) and DCM (3 mL). Hoveyda-Grubbs' Catalyst (31 mg, 0.05 mmol, 0.05 eq) was subsequently added as a solid and the reaction was heated to reflux (40° C.) under an atmosphere of argon. After 3 days the reaction was concentrated under reduced pressure to give a dark brown oil. Column chromatography (hexane:ether, 85:15, to remove excess silane, then 50:50) gave 5-(triisopropylsilyl)-pent-3-enoic acid as a colourless oil (223 mg, 87% yield). For major isomer E: 1H NMR (400 MHz, CDCl3) δ 1.05-1.06 (m, 21H, Si(i−Pr)3), 1.61-1.63 (d, 2H, CH2Si(i−Pr)3, J=8.0 Hz), 3.04-3.06 (d, 2H, HOOCCH2, J=7 Hz), 5.37-5.45 (m, 1H, CH2CHCH), 5.62-5.70 (dt, CH2CHCH, J=15.1, 8.2 Hz), 11.41 (s, 1H, COOH); 13C NMR (50 MHz, CDCl3) δ 10.9 (Si(CH(CH3)2)3), 15.6 (CH2Si(i−Pr)3), 18.6 (Si(CH(CH3)2)3), 38.0 (HOOCCH2), 118.8 (CH2CHCH), 132.6 (CH2CHCH), 178.7 (HOOC). For minor isomer Z: 1H NMR (400 MHz, CDCl3) δ 1.05-1.06 (m, 21H, Si(i−Pr)3), 1.56-1.58 (d, 2H, CH2Si(i−Pr)3, J=8.6 Hz), 3.17-3.19 (d, 2H, HOOCCH2, J=7.8 Hz), 5.37-5.45 (m, 1H, CH2CHCH), 5.71-5.78 (m, CH2CHCH), 11.41 (s, 1H, COOH); 13C NMR (50 MHz, CDCl3) δ 11.0 (CH2Si(i−Pr)3), 11.1 (Si(CH(CH3)2)3), 18.6 (Si(CH(CH3)2)3), 32.5 (HOOCCH2), 117.5 (CH2CHCH), 130.7 (CH2CHCH), 178.6 (HOOC); IR (v, cm−1) 2867 (COO—H), 1713 (HOC═O), 660 (C—Si); HRMS required for C14H28O2Si: 256.1859, found 256.1866.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[N+:20]([O-:22])=[O:21])[N:5]=[CH:4][N:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]([NH2:33])[CH3:32])[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[N+:20]([C:9]1[CH:10]=[CH:11][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:13][C:8]=1[C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:33][CH:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=2)[CH3:32])[CH:7]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(Cl)ncn1
Reactant: CC(N)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(Nc1cc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])ncn1)c1cccc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 54.7 %

Procedure:
Into a 100 mL round bottom flask, was placed a solution of 4-chloro-6-(2-nitro-5-(piperidin-1-yl)phenyl)pyrimidine (100 mg, 0.31 mmol, 1.00 equiv) in toluene (10 mL), 1-(3-(trifluoromethyl)phenyl)ethanamine (71 mg, 0.38 mmol, 1.20 equiv), BINAP (9 mg, 0.01 mmol, 0.05 equiv), Cs2CO3 (144 mg, 0.44 mmol, 1.40 equiv), and Pd(dba)3 CHCl3 (6.5 mg, 0.01 mmol, 0.02 equiv). The resulting solution was stirred for 3 h at 120° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5). The product was obtained as 80 mg (54%) of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.N([O-])=O.[Na+].[N-:13]=[N+:14]=[N-].[Na+]>C(O)(C(F)(F)F)=O.O>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(Cl)nc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: [N-]=[N+]=Nc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
5-Amino-2-chloropyridine (2.28 g; 17.7 mmol; 1.0 eq.) was dissolved in TFA (7 mL). Sodium nitrite (1.35 g; 19.5 mmol; 1.1 eq.) was then added portion wise to this solution maintained at 0° C. Reaction mixture was stirred at 0° C. for 30 min before the addition of and ice-cold solution of sodium azide (1.15 g; 17.7 mmol; 1.0 eq.) in water (8 mL). It was stirred at 0° C. for 1 h. TFA was then removed and the residue was dissolved in EtOAc. Organic phase was washed with an aqueous saturated solution of NaHCO3, brine, dried over magnesium sulfate, filtered and concentrated. The crude obtained was purified by flash chromatography on silica (heptane:EtOAc, gradient from 95:5 to 80:20) to afford the title compound as a brown oil (1.89 g, 69%). 1H NMR (300 Mz, DMSO-d6) δ 8.23 (dd, J=0.6, 2.9 Hz, 1H), 7.68 (dd, J=2.9, 8.6 Hz, 1H), 7.54 (dd, J=0.6, 8.6 Hz, 1H).
Reaction SMILES: [C:1]1([C:11]2[O:12][C:13]3[CH:19]=[C:18]([CH2:20][C:21]([O:23]C)=[O:22])[CH:17]=[CH:16][C:14]=3[N:15]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[OH-].[Na+]>C1COCC1>[C:1]1([C:11]2[O:12][C:13]3[CH:19]=[C:18]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:16][C:14]=3[N:15]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: COC(=O)Cc1ccc2nc(-c3nccc4ccccc34)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc2nc(-c3nccc4ccccc34)oc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.2 %

Procedure:
To methyl (2-(1-isoquinolinyl)-6-benzoxazolyl)acetate (166 mg, 0.52 mmol) were added THF (3 ml) and 0.5N NaOH (3.0 ml, 1.50 mmol). The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was poured in ice-1N HCl to acidify therewith. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (2-(1-isoquinolinyl)-6-benzoxazolyl)acetic acid (138 mg, 87%) as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[CH2:9][C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[N:26][C:21]([NH:1][C:2]2[C:3]([O:18][CH3:19])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH:13]4[CH2:14][CH2:15]4)[CH2:9][C:8](=[O:16])[NH:7][C:6]=3[CH:17]=2)=[N:22][CH:23]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)NC(=O)CN(CC1CC1)C2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)NC(=O)CN(CC1CC1)C2
Yield: 38.4 %

Procedure:
In an analogous manner to procedure 1656g, 8-amino-4-cyclopropylmethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (150 mg, 0.57 mmol) and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (162 mg, 0.48 mmol) were coupled to provide N-(1R,2R)-{2-[5-chloro-2-(4-cyclopropylmethyl-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (104 mg, 38%) as a tan solid following preparative tlc on silica gel (10% MeOH-DCM); 1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 7.95 (s, 1H), 7.92 (s, 1H), 7.72 (s, 1H), 7.04 (d, J=8 Hz, 1H), 6.98 (s, 1H), 6.86 (d, J=8 Hz, 1H), 3.86 (s, 3H), 3.82 (m, 2H), 3.68 (s, 2H), 3.32 (s, 3H), 3.22 (s, 2H), 2.88 (m, 3H), 2.41 (m, 3H), 1.97 (m, 2H), 1.63 (m, 2H), 1.37 (m, 2H), 0.87 (m, 1H), 0.48 (m, 2H), 0.14 (m, 2H); MS (m/e) 564 (M+1); mp 97° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:3]=1[C:4](Cl)=[N:5][C:6]1[C:11]([F:12])=[CH:10][N:9]=[CH:8][C:7]=1F.NC(N)=[S:24].N1C=CC=CC=1.CCN(CC)CC>C(O)(C)C>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:3]=1[C:4]1[S:24][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([F:12])[C:6]=2[N:5]=1
Reactant: O=[N+]([O-])c1cccc(Cl)c1C(Cl)=Nc1c(F)cncc1F
Reactant: NC(N)=S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccc(Cl)c1-c1nc2c(F)cncc2s1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
A suspension of 2-chloro-N-(3,5-difluoropyridin-4-yl)-6-nitrobenzimidoyl chloride (5.53 g, 16.6 mmol), thiourea (5.05 g, 0.066 mol) and pyridine (6.7 mL, 83 mmol) in isopropanol (90 mL), under nitrogen, was heated under reflux for 6 hours. After this time, Et3N (14 mL, 100 mmol) was added over 5 minutes and the reaction mixture was heated under reflux for 18 hours. Upon cooling to room temperature, the volatiles were removed under reduced pressure and the resultant residue was partitioned between water and EtOAc. The aqueous phase was further extracted with EtOAc (×2) and the combined organic layers were dried (Na2SO4) and concentrated to dryness. The resultant residue was purified by column chromatography on silica gel eluting with 0-80% EtOAc in pentane followed by 0-50% EtOAc in DCM to afford the title compound as a yellow solid (2.55 g, 50% yield). LCMS (Method D): RT=3.29 min, m/z: 310 [M+H+].
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C(N(CC)CC)C.Cl[CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23].Cl>ClCCl>[CH:21]([S:22]([NH:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])(=[O:24])=[O:23])=[CH2:20]
Reactant: O=S(=O)(Cl)CCCl
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)NCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.9 %

Procedure:
2-Aminoacetophenone hydrochloride (1.00 g, 5.85 mmol) was dissolved in dichloromethane (50 mL). To the solution was added triethylamine (2.50 mL, 17.9 mmol), and the mixture was stirred at room temperature for 10 minutes. After the reaction mixture was cooled to 0° C., chloroethanesulfonyl chloride (0.92 mL, 8.80 mmol) was added to the mixture, and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added 2 mol/L hydrochloric acid and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added a mixed solvent of ethyl acetate and n-hexane for crystallization to obtain 2-(vinylsulfonylamino)acetophenone (0.42 g, 32%).