Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:16]2[C:11](=[CH:12][CH:13]=[N:14][CH:15]=2)[N:10]2[C:17]3[C:7]([C:8]4[CH:21]=[C:20](B(O)O)[CH:19]=[CH:18][C:9]=42)=[CH:6][CH:5]=[CH:4][C:3]1=3.Br[C:27]1[CH:48]=[CH:47][C:30]2[N:31]3[C:44]4[C:43]([C:29]=2[CH:28]=1)=[CH:42][CH:41]=[CH:40][C:39]=4[C:38]([CH3:46])([CH3:45])[C:37]1[C:32]3=[CH:33][CH:34]=[N:35][CH:36]=1>>[CH3:1][C:2]1([CH3:25])[C:16]2[C:11](=[CH:12][CH:13]=[N:14][CH:15]=2)[N:10]2[C:17]3[C:7]([C:8]4[CH:21]=[C:20]([C:27]5[CH:48]=[CH:47][C:30]6[N:31]7[C:44]8[C:43]([C:29]=6[CH:28]=5)=[CH:42][CH:41]=[CH:40][C:39]=8[C:38]([CH3:45])([CH3:46])[C:37]5[C:32]7=[CH:33][CH:34]=[N:35][CH:36]=5)[CH:19]=[CH:18][C:9]=42)=[CH:6][CH:5]=[CH:4][C:3]1=3
Reactant: CC1(C)c2cnccc2-n2c3ccc(B(O)O)cc3c3cccc1c32
Reactant: CC1(C)c2cnccc2-n2c3ccc(Br)cc3c3cccc1c32
Product: CC1(C)c2cnccc2-n2c3ccc(-c4ccc5c(c4)c4cccc6c4n5-c4ccncc4C6(C)C)cc3c3cccc1c32

Procedure:
The compound is synthesised by the same procedure as Example 7 by reaction of 36 g (110 mmol) of 8,8-dimethyl-8H-10,12b-diazabenzo[a]aceanthrylene-3-boronic acid with (110 mmol) of 3-bromo-8,8-dimethyl-8H-10,12b-diazabenzo[a]aceanthrylene. The residue is recrystallised from toluene and from CH2Cl2/isopropanol and finally sublimed in a high vacuum. Yield: 50 g (88 mmol), 80% of theory, purity according to HPLC 99.9%.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][N:6]([C@@H:8]([CH2:12][CH3:13])[C:9]([NH2:11])=[O:10])[C:5](=[O:14])[CH2:4]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH:3]1[CH2:4][C:5](=[O:14])[N:6]([C@H:8]([C:9]([NH2:11])=[O:10])[CH2:12][CH3:13])[CH2:7]1)(=[O:25])=[O:24]
Reactant: CC[C@@H](C(N)=O)N1CC(CO)CC1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](C(N)=O)N1CC(COS(C)(=O)=O)CC1=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
In a 4 l three necked flask fitted with mechanical stirrer, dropping funnel and reflux condenser under inert atmosphere, 114 g (569 mmoles, 1 eq) of (2S)-2-[4-hydroxymethyl)-2-oxo-1-pyrrolidinyl]butanamide 6 are dissolved in 2 l of CH2Cl2 and cooled down to 0° C. 158.5 ml (115 g, 2 eq) of dry triethylamine are added in one portion, followed by dropwise addition of a solution of 66.3 ml (96.2 g, 1.5 eq) of methanesulfonyl chloride in 190 ml of CH2Cl2 over 1 hour, all the while maintaining the temperature below 4° C. After 4 hours, 7.5 ml of methanesulfonyl chloride and 15 ml of triethylamine are added and the mixture is kept overnight in the refrigerator. The mixture is filtered, the residue washed with CH2Cl2 and the combined organic phases concentrated to dryness to give 216 g of crude 37. It is purified by Prep LC in several batches (1 kg SiO2, CH2Cl2/EtOH, 100:0->96:4) to give 109 g of pure 37, 69%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH2:11]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][NH:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[ClH:1].[CH2:11]([CH:18]1[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][CH2:26][N:27]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:10])[CH2:22][CH2:23]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(CC2CCN(CCCNc3cccnc3)CC2)cc1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cl
Product: O=C(Nc1ccc(Cl)cc1)N(CCCN1CCC(Cc2ccccc2)CC1)c1cccnc1
Reaction time: 15 h
Yield: 114.9 %

Procedure:
4-Chlorophenyl isocyanate (297 mg) was added to a solution of N-[3-(4-benzyl-1-piperidinyl)propyl]-3-pyridineamine (400 mg) in tetrahydrofuran (5 ml) and the mixture was stirred for 15 hours. Ethyl acetate (15 ml) and saturated sodium bicarbonate (15 ml) were added to the reaction mixture. The organic phase was separated, washed with water (10 ml) and saturated brine (10 ml) and dried over sodium sulfate (anhydrous), and the solvent was removed. The residue was purified by silica gel column chromatography (20 g). The fraction eluted by ethyl acetate-methanol (10:1) was collected and concentrated under reduced pressure. A solution of 4N hydrogen chloride in ethyl acetate (1.0 ml) was added to the residue. The precipitate was filtered and collected, and dried under reduced pressure to give the title compound (555 mg, Yield 76.0%).
Reaction SMILES: Br[CH2:2][C:3]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12].N1C=[CH:20][N:19]=[N:18]1.[C:22](#[N:24])C>>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[CH:4]=[C:3]([CH2:2][N:19]1[CH:20]=[N:24][CH:22]=[N:18]1)[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC#N
Reactant: c1c[nH]nn1
Reactant: CC(C)(C)C(=Cc1ccc(Cl)cc1Cl)CBr
Product: CC(C)(C)C(=Cc1ccc(Cl)cc1Cl)Cn1cncn1
Temperature: 40 °C
Reaction time: 16 h
Yield: 24 %

Procedure:
A mixture of 20 g (0.062 mol) of 2-bromomethyl-1-(2,4-dichlorophenyl)-3,3-dimethylbut-1-ene and 8.6 g (0.125 mol) of triazole in 80 ml of absolute acetonitrile is stirred at 40° C. for 16 hours. For working up, the reaction mixture is filtered, the filtrate is concentrated in vacuo and the residue is taken up in methylene chloride. The mixture is washed twice with water, dried over sodium sulphate and concentrated in vacuo. The syrup which remains is purified by chromatography (silica gel) and crystallized from petroleum ether. 4.6 g (24% of theory) of 1-(2,4-dichlorophenyl)-3,3-dimethyl-2-(1,2,4-triazol-1-ylmethyl)-but-1-ene of melting point 78° C. are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=[C:5]2[CH:4]=[CH:3]1.[F:14][C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[C:17]([F:22])[N:16]=1.O>C(Cl)Cl.N1C=CC=CC=1>[F:14][C:15]1[C:20]([NH:21][C:11]([C:9]2[CH:10]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:6]3=[N:7][CH:8]=2)=[O:13])=[CH:19][CH:18]=[C:17]([F:22])[N:16]=1
Reactant: Cn1ccc2cc(C(=O)O)cnc21
Reactant: Nc1ccc(F)nc1F
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1ccc2cc(C(=O)Nc3ccc(F)nc3F)cnc21
Yield: 72.5 %

Procedure:
To a suspension of 1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (3.54 g, 20.1 mmol) in CH2Cl2 (400 mL) was added 1-chloro-N,N-2-trimethylpropenylamine (5.26 mL, 40.2 mmol). Following formation of the resulting acid chloride, the reaction mixture was concentrated affording a residue that was dissolved in pyridine (100 mL) before 2,6-difluoro-pyridin-3-ylamine (2.61 mg, 20.1 mmol) was added in one portion. After an additional 30 minutes the reaction mixture was concentrated to dryness affording a residue, to which was added water causing precipitation of analytically pure 1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (2,6-difluoro-pyridin-3-yl)-amide (4.2 g, 72.5% yield). ES MS (M+H+)=289.
Reaction SMILES: [Cl:1][CH2:2][O:3][C:4](Cl)=[O:5].[NH:7]1[CH2:17][CH2:16][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:8]1>>[Cl:1][CH2:2][O:3][C:4]([N:7]1[CH2:8][CH2:9][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:16][CH2:17]1)=[O:5]
Reactant: O=C(Cl)OCCl
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCN(C(=O)OCCl)CC1

Procedure:
Using chloroformic acid chloromethyl ester and ethyl isonipecotate as the raw materials, the same operation as the Example 101(1) gave the title compound as a crude product, and the crude product was used for the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].O1CCCC1.C([Li])CCC.C([O:22][B:23](OCCC)[O:24]CCC)CC>CCCCCC>[F:1][C:2]1[C:3]([F:8])=[CH:4][CH:5]=[CH:6][C:7]=1[B:23]([OH:24])[OH:22]
Reactant: Fc1ccccc1F
Reactant: CCCOB(OCCC)OCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1cccc(F)c1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
1,2-Difluorobenzene (40 g, 0.35 mol) and dry tetrahydrofurane (400 ml) were placed in 1 L flask equipped with mechanical stirrer, nitrogen inlet and outlet, pressure-equilibrated dropping funnel and thermometer. The reaction flask was flushed with nitrogen and minor flow was held during whole reaction time. The mixture was cooled down to −78° C. with dry ice/acetone bath and 2.5 mol/L hexane solution of n-butyllithium (140 ml; 0.35 mol) was added dropwise, keeping the reaction temperature below −70° C. After addition of all butyllithium solution the mixture was stirred at −78° C. for 2 h and then tripropylborate (66 g, 0.35 mol) was added dropwise keeping the reaction temperature below −70° C. After addition of tripropyl borate the cooling bath was removed and the reaction mixture continuously stirred to reach the room temperature then the solvents were evaporated. The thick liquid residue was acidified and then propanol was evaporated and the remaining solid was filtered off, washed out with hexane and recrystalized from water. The white crystalline product 47 g was obtained, with 85% of theor. yield.
Reaction SMILES: O=[C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1.[CH2:14]([Mg]Br)[CH2:15][CH3:16]>>[CH2:14]([CH:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1)[CH2:15][CH3:16]
Reactant: COC(=O)c1cc2c([nH]1)C(=O)CC2
Reactant: CCC[Mg]Br
Product: CCCC1CCc2cc(C(=O)OC)[nH]c21

Procedure:
The title compound was synthesized from methyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.5 g, 2.79 mmol) and n-propylmagnesium bromide (3.5 mL, 6.97 mmol, 2.0 M in ether, 2.5 equiv) according to General Procedure 3 to give the exocyclic olefin-containing compound (E)-methyl 6-propylidene-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, followed by hydrogenation according to General Procedure 6, and was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane to give the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.96 (t, J=7.1 Hz, 3H), 1.35-1.53 (m, 3H), 1.57-1.68 (m, 1H), 1.94-2.09 (m, 1H), 2.47-2.69 (m, 3H), 2.98-3.10 (m, 1H), 3.83 (s, 3H), 6.64 (d, J=1.61 Hz, 1H), 8.69 (br. s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:12][NH2:13]>O>[CH3:12][NH:13][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: ClCc1nc2ccccc2o1
Reactant: CN
Solvent: O
Product: CNCc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82 %

Procedure:
2-(Chloromethyl)benzoxazole (3.99 g, 23.8 mmol) was dissolved in aqueous methylamine (40 mL, 40 wt % in H2O) at 10° C. under a nitrogen atmosphere. After 20 minutes, the reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was diluted with water and extracted with dichloromethane. The organic phase was dried (MgSO4) and concentrated to afford crude product which was purified by flash column chromatography (5% methanol/dichloromethane) to afford 3.18 g (82%) of pure product as a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([N:24]1[C:30](=[O:31])[C:29]([CH3:33])([CH3:32])[C:28](=[O:34])[N:27]([CH3:35])[C:26]2[CH:36]=[C:37]([O:40][CH2:41][CH2:42][CH2:43]I)[CH:38]=[CH:39][C:25]1=2)[CH3:23].C(O)C.[ClH:48]>C(O)(C)C.CN(C=O)C>[ClH:48].[CH2:22]([N:24]1[C:30](=[O:31])[C:29]([CH3:32])([CH3:33])[C:28](=[O:34])[N:27]([CH3:35])[C:26]2[CH:36]=[C:37]([O:40][CH2:41][CH2:42][CH2:43][N:11]3[C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=4[N:8]=[C:7]3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:38]=[CH:39][C:25]1=2)[CH3:23]
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCI)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: CCO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(-c4ccccc4)nc4ccccc43)ccc21
Temperature: 60 °C
Reaction time: 7 h

Procedure:
2-Phenyl-1H-benzimidazole (0.2 g) and potassium carbonate (0.29 g) were added to a DMF solution (5 ml) of 1-ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.49 g). The mixture was stirred at 60° C. for 7 hours. The reaction mixture was poured to ice water (50 ml), and the generated insoluble matter was separated. The insoluble matter was dissolved in ethyl acetate. The liquid was dried over sodium sulfate and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:3). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride ethanol solution (1.0 ml) was added to an isopropyl alcohol solution of the residue. The mixture was condensed under reduced pressure. Ether was added to the residue. The generated insoluble matter was separated by filtration and dried to give the title compound (0.32 g) as a white powder.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(OC[C@@H:49]2[O:54][C:53]3[CH:55]=[C:56]([CH3:59])[CH:57]=[CH:58][C:52]=3[O:51][CH2:50]2)(=O)=O)=CC=1>ClCCl.C(#N)C>[NH2:8][C:9]1[C:14]([C:15]([NH:17][CH2:18][CH:19]2[CH2:20][CH2:21][N:22]([CH2:25][C@@H:49]3[O:54][C:53]4[CH:55]=[C:56]([CH3:59])[CH:57]=[CH:58][C:52]=4[O:51][CH2:50]3)[CH2:23][CH2:24]2)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2cccnc2N)CC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(C)cc3O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccc2c(c1)O[C@@H](CN1CCC(CNC(=O)c3cccnc3N)CC1)CO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (5 ml) was added to a solution of 2-amino-N-[(1-tert-butoxycarbonyl-4-piperidyl)methyl]pyridine-3-carboxamide (0.92 g; prepared in a similar manner to that described in Example 2) in dichloromethane (10 ml) then the mixture stirred at ambient temperature for 2 hours and the solvent removed in vacuo. The crude 2-amino-N-(4-piperidylmethyl)pyridine-3-carboxamide trifluoroacetate thus produced was dissolved in anhydrous acetonitrile (10 ml) and potassium carbonate (1.5 g) was added, followed by a solution of (R)-7-methyl-1,4-benzodioxan-2-ylmethyl 4-toluenesulphonate (0.9 g) in anhydrous acetonitrile (5 ml). The mixture was heated under reflux for 18 hours then poured onto water and extracted with ether (2×100 ml). The combined extracts were washed with water then extracted with hydrochloric acid (1M; 50 ml). The acid extracts were washed with ether (100 ml) then basified with sodium hydrogen carbonate and extracted with ether (2×100 ml). These extracts were combined, washed with water and dried over magnesium sulphate. The solvent was evaporated and the residue purified by flash chromatography on silica eluting with a 20:1 mixture of dichloromethane and methanol. Appropriate fractions were combined and evaporated to give (S)-2-amino-N-{[1-(7-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide as a colourless solid (0.36 g) m.p. 143-146° C., [α]D -46.23° (c=0.53, methanol).
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][CH:6]=1)=[O:4].[NH2:22][C@H:23]([CH2:25][OH:26])[CH3:24]>>[OH:26][CH2:25][C@@H:23]([NH:22][C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][CH:6]=1)=[O:4])[CH3:24]
Reactant: C[C@H](N)CO
Reactant: CCCCc1noc(C)c1CCc1ncc(C(=O)OC)s1
Product: CCCCc1noc(C)c1CCc1ncc(C(=O)N[C@@H](C)CO)s1
Yield: 81 %

Procedure:
As described for example 58, 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid methyl ester (90 mg, 0.29 mmol) was converted, using L-alaninol instead of rac-2-amino-1-propanol, to the title compound (50 mg, 81%) which was obtained as a colourless oil. MS: m/e=352.4 [M+H]+.
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(F)=CC=1)C.C=O.[C:22]1([CH2:28][CH2:29][NH2:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[F:31][C:32]1[CH:50]=[CH:49][C:35]([CH2:36][N:37]([CH3:48])[C:38]([C:40]2[CH2:41]N(C)[C:43](=[O:46])[C:44]=2[OH:45])=[O:39])=[CH:34][CH:33]=1>>[F:31][C:32]1[CH:50]=[CH:49][C:35]([CH2:36][N:37]([CH3:48])[C:38]([C:40]2[CH2:41][N:30]([CH2:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:43](=[O:46])[C:44]=2[OH:45])=[O:39])=[CH:34][CH:33]=1
Reactant: NCCc1ccccc1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(F)cc2)=C(O)C1=O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(F)cc1
Product: CN(Cc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(CCc2ccccc2)C1

Procedure:
3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 2-phenyl-ethylamine as described in the preparation of Compound 1. HRMS (M+H) calcd for C21H22FN2O3: 369.1615. found: 369.1625. 1H NMR (500 MHz, CDCl3) δ: 2.92 (overlapping m, 5), 3.74 (t, 2, J=7), 3.92 (s, 2), 4.56 (s, 2), 7.01–7.29 (overlapping m, 9). 13C NMR (125 MHz, CDCl3) δ: 34.45, 34.60, 44.70, 49.42, 51.46, 109.12, 115.66, 115.83, 126.75, 128.63, 128.72, 129.26, 129.33, 132.09, 132.11, 138.18, 153.11, 161.38, 163.34, 164.79, 166.18.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:31]([OH:33])=O)[CH2:19][C:20]3[CH:29]=[C:28]([CH3:30])[C:23]4[NH:24][C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[N:67]1([CH2:79][C:80]([O:82][CH2:83][CH3:84])=[O:81])[CH2:72][CH2:71][CH:70]([CH:73]2[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]2)[CH2:69][CH2:68]1>C1COCC1.CCOC(C)=O>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:29]=[C:28]([CH3:30])[C:23]4[NH:24][C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)[C:31]([N:76]3[CH2:75][CH2:74][CH:73]([CH:70]4[CH2:69][CH2:68][N:67]([CH2:79][C:80]([O:82][CH2:83][CH3:84])=[O:81])[CH2:72][CH2:71]4)[CH2:78][CH2:77]3)=[O:33])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2oc(=O)[nH]c12
Reactant: CCOC(=O)CN1CCC(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(C)c4[nH]c(=O)oc4c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 350 mg (0.69 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-dihydrobenz-oxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 244 mg (0.76 mmol) TBTU and 138 μL (1.04 mmol) triethylamine in 15 mL THF was stirred for 1 h at RT. Then 175 mg (0.69 mmol) ethyl [4,4′]bipiperidinyl-1-yl-acetate were added. The reaction mixture was stirred for 4 h at RT. The solvent was eliminated i.vac., the residue was taken up in 30 mL EtOAc, the organic phase was washed with 30 mL 5% NaHCO3 solution and dried on Na2SO4. After the desiccant and solvent had been eliminated the residue was purified by chromatography (silica gel, gradient DCM/EtOH 19:1 to DCM/EtOH 9:1). The fractions containing the product were combined and evaporated down i. vac.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:13][NH2:14])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:15]([N:22]=[C:23]=[S:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.C(N(CC)CC)C>[CH2:15]([NH:22][C:23]([NH:14][CH2:13][C:4]1[C:3]([Cl:2])=[CH:8][C:7]([C:9]([F:12])([F:10])[F:11])=[CH:6][N:5]=1)=[S:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: S=C=NCc1ccccc1
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cnc(CNC(=S)NCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of (3-chloro-5-trifluoromethyl-2-pyridyl)methylamine hydrochloride (0.12 g) and benzylisothiocyanate (0.11 g) in dry tetrahydrofuran (10 ml) was added triethylamine (10 drops) and the mixture stirred at room temperature for 12 hours. The solvent was evaporated and ethyl acetate added. The mixture was washed with 2M hydrochloric acid and then with saturated sodium bicarbonate solution. The organic layer was separated and the solvent removed to give the title product. 1H N.M.R. δ(ppm) 4.7 (2H, broad s), 4.95 (2H, d), 6.9 (1H, broad s), 7.3-7.55 (6H, m), 7.95 (1H, s) and 8.58 (1H, s).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:17]([NH:19][CH3:20])=[O:18].CCN(C(C)C)C(C)C>C1COCC1>[Cl:10][C:6]1[N:5]=[C:4]([S:11][CH3:12])[N:3]=[C:2]([NH:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:17]([NH:19][CH3:20])=[O:18])[C:7]=1[C:8]#[N:9]
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Reactant: CNC(=O)c1ccc(C)c(N)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(C)c(Nc2nc(SC)nc(Cl)c2C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbonitrile (2.19 g, 10 mmol), 3-amino-4,N-dimethyl-benzamide(1.64 g, 10 mmol), and DIEA(1.40 g, 18.8 mmol) were mixed in THF (20 mL). The resulting mixture was stirred at room temperature for overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was concentrated and the crude product was purified by flash chromatography to obtain 3-(6-chloro-5-cyano-2-methylsulfanyl-pyrimidin-4-ylamino)-4,N-dimethyl-benzamide (2.78 g, 80%). MS (m/z): 348 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:20](C)[CH2:21][CH2:22][CH2:23]N=C=NCC.C(N)C#C.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH:20][CH2:21][C:22]#[CH:23])=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: C#CCN
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCNC(=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(benzyloxy)phenylacetic acid (20.7 mmol), 1-hydroxybenzotrizole hydrate (37 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (37 mmol), propargylamine (20.7 mmol) and N-methylmorpholine (62 mmol) in DMF (60 mL) were stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (400 mL), washed with 1N HCl, water, saturated Na2CO3 solution, brine and dried over Na2SO4. After removing solvent under reduced pressure, the residue was triturated with dichloromethane. Compound 60.1 was obtained as a white solid after filtration and drying. LC-MS ESI (pos.) m/e: 280 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.COB([C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1)O.[C:23]([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:23][O:22][C:20](=[O:21])[C:17]1[CH:16]=[CH:15][C:14]([C:6]2[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)=[CH:19][CH:18]=1
Reactant: COB(O)c1ccc(C(=O)O)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2nc(Cl)ncc2F)cc1
Temperature: 85 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
To a solution of 2,4-dichloro-5-fluoropyrimidine (0.478 g, 2.86 mmol) and 4-carboxyphenyl boronic acid methyl ester (0.516 g, 2.86 mmol) in 5 mL of ethyleneglycol dimethyl ether was added Pd(PPh3)4 under argon, followed by 2N Na2CO3 and the resulting mixture purged with argon for 2 minutes. The resulting mixture was sealed and heated at 85° C. overnight. After 18 hours, the reaction was diluted with 20 mL of ethyl acetate and washed with H2O. The organic layer was concentrated and purified by chromatography (Silica, 10% ethyl acetate in hexanes) to afford 4-(2-chloro-5-fluoropyrimidin-4-yl)-benzoic acid methyl ester (0.35 g, 46%) as a white solid. LCMS: ES+=267.