Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[Cl:7][C:8]1[C:16]2[N:15]=[C:14]3[N:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[CH2:18][CH2:19][CH2:20][N:13]3[C:12]=2[C:11]([CH2:29][C:30]#[N:31])=[CH:10][CH:9]=1.C(I)C>O1CCCC1.[Cl-].[NH4+]>[Cl:7][C:8]1[C:16]2[N:15]=[C:14]3[N:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[CH2:18][CH2:19][CH2:20][N:13]3[C:12]=2[C:11]([CH:29]([CH2:1][CH3:2])[C:30]#[N:31])=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: N#CCc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCC(C#N)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
Potassium t-butoxide (315 mg, 2.81 mmol) was added to a stirred solution of [9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]acetonitrile (500 mg, 1.28 mmol) and ethyl iodide (499 mg, 3.20 mmol) in tetrahydrofuran (13 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethanol/ethyl acetate to give the title compound as a colorless crystal (202 mg, 0.481 mmol, 38%).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:4]1.[C:19]1([C:25]2[O:29][N:28]=[C:27]([C:30](O)=[O:31])[CH:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=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>[CH3:1][N:2]([CH3:18])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([NH:17][C:30]([C:27]4[CH:26]=[C:25]([C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[O:29][N:28]=4)=[O:31])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:4]1
Reactant: O=C(O)c1cc(-c2ccccc2)on1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
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: CN(C)C1CCN(c2nc3ccc(NC(=O)c4cc(-c5ccccc5)on4)cc3s2)C1
Reaction time: 3 h

Procedure:
Combine 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (0.100 g, 0.381 mmol) (Example 1, step 3), dissolved in CH2Cl2 (5.0 mL), with 5-phenyl-isoxazole-3-carboxylic acid (0.079 g, 0.419 mmol), HATU (0.145 g, 0.381 mmol), and DIEA (0.20 mL, 1.14 mmol) in a 40 mL reaction vial and shake the mixture overnight at 40° C. Dilute the mixture with CH2Cl2 (25 mL) and wash with 1.0 M NaOH (25 mL) which results in emulsions forming. Wait 3 h for the emulsions to disappear, separate the layers and dry the organic portion over sodium sulfate. Filter and concentrate in vacuo to yield the compound as a yellow solid. Purify using silica gel chromatography (5% MeOH/CH2Cl2) to afford the title compound as a yellowish-white solid (117 mg, 71%). mass spectrum (m/e): 434.2 [M+1], 432.2 [M−1]. 1H NMR (400 MHz, DMSO-d6): δ10.76 (s, 1H), 8.27 (d, 1H, J=2 Hz), 7.98 (m, 2H), 7.56-7.63 (m, 4H), 7.49 (s, 1H), 7.45 (d, 1H, J=8.8 Hz), 3.73 (t, 1H, J=9.2 Hz), 3.64 (t, 1H, J=9.2 Hz), 3.49 (m, 1H), 3.29 (m, 1H), 2.90 (m, 1H), 2.21 (s, 6H), 2.19 (m, 1H), 1.91 (m, 1H).
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][C@H:7]([CH:13]=C)[CH2:8][CH2:9][C:10]#[C:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[CH2:17](Cl)Cl>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[C:1]([Si:5]([O:6][C@H:7]1[CH2:8][CH2:9][C:10]([C:11]([CH3:12])=[CH2:17])=[CH:13]1)([CH3:15])[CH3:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C[C@H](CCC#CC)O[Si](C)(C)C(C)(C)C
Reactant: ClCCl
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Product: C=C(C)C1=C[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
A solution of compound (5a) (263.8 mg, 1.106 mmol) and degassed DCM (37) was cooled to −78° C. The flask was flushed with ethylene gas over a period of 10 minutes before ethylene gas was bubbled through the solution itself for 3 additional minutes. Grubbs I catalyst (136.4 mg, 0.1657 mmol) was added and once again ethylene gas was bubbled through the resulting mixture for one minute. The icebath was removed and the mixture stirred for 24 hours. The flask was flushed with argon and the solvent was evaporated. Chromatography of the residue (pentane/ether 200/1) furnished 226.6 mg of compound of (6a) as clear colourless oil with 86% yield.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=2)[CH2:7][N:6]1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[CH2:26]([N:6]1[CH2:7][CH:8]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[C:14]([C:22]([F:25])([F:23])[F:24])[CH:13]=2)[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)C1CC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1ccccc1
Reaction time: 8 h

Procedure:
Benzyl-4-(3,5-bis-trifluoromethyl-benzylamino)-pyrrolidine-2-carboxylic acid methyl ester (124 mg, 0.269 mmol) and LiOH (53.9 mg, 1.5 mmol) were dissolved in THF/H2O (4 mL), and then stirred overnight. After removal of solvent, the residue was neutralized to PH=6-7, and then extracted by EA twice. The organic layer was washed with water and brine, dried, and concentrated to afford the title product 1-benzyl-4-(3,5-bis-trifluoromethyl-benzylamino)-pyrrolidine-2-carboxylic acid, 65 mg (54.2%) as a yellow solid. MS m/e=447.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=2)[CH:3]=1.[CH3:19][NH:20][CH3:21].C([BH3-])#N.[Na+].[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]>C(O)(=O)C.CO>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:20]([CH3:21])[CH3:19])[CH:12]=2)[CH:3]=1
Reactant: CNC
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)Cc1cccc(Oc2cc(Cl)ccc2C#N)c1
Yield: 57 %

Procedure:
4-Chloro-2-(3-formylphenoxy)benzonitrile (0.20 g, 0.78 mmol), dimethylamine (2M in methanol, 1.0 mL, 2.0 mmol) and sodium cyanoborohydride (60 mg, 0.96 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (20 mL) for 18 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.10 g, 0.86 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-[3-(dimethylaminomethyl)phenoxy]benzonitrile fumarate (179 mg, 58%) as a white solid.
Reaction SMILES: [S:1]([N:11]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[C:19]1([CH3:25])[CH:24]=CC=C[CH:20]=1.C(OC(OC(C)(C)C)N(C)C)(C)(C)C>O>[S:1]([N:11]1[CH:15]=[CH:14][C:13]([C:16]([O:18][C:19]([CH3:25])([CH3:24])[CH3:20])=[O:17])=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C(=O)O)c2)cc1
Agent: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc(C(=O)OC(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A 3-neck RBF was charged with 1-tosyl-1H-pyrrole-3-carboxylic acid (Astatech, Bristol, Pa.; 2.00 g, 7.54 mmol) and 20 mL anhydrous toluene, and was fitted with a water cooled reflux condenser and heated to reflux under N2. N,N-dimethylformamide di-tert-butyl acetal (Aldrich; 14.46 mL, 60.4 mmol) was added slowly dropwise via addition funnel. The reaction mixture was stirred for 1 h, then the oil bath was turned off, and the reaction mixture was cooled to RT over the weekend. It was partitioned between saturated aq. NaHCO3 and Et2O. The organic layer was washed with saturated aq. NaHCO3 once, saturated aq. NaCl once, and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (80 g column) using 0-20% EtOAc/hexanes. The product-containing fractions were concentrated to afford tert-butyl 1-tosyl-1H-pyrrole-3-carboxylate (287a; 2.22 g, 6.91 mmol, 92% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.80 (2H, d, J=8.4 Hz), 7.63-7.70 (1H, m), 7.33 (2H, d, J=8.2 Hz), 7.09 (1H, dd, J=3.3, 2.3 Hz), 6.61 (1H, dd, J=3.3, 1.6 Hz), 2.43 (3H, s), 1.53 (9H, s). m/z (ESI, +ve) 266.0 (M+H)+.
Reaction SMILES: C(OCCCCOC(OC1C=CC(C(O)=O)=CC=1)=O)(=[O:4])C=C.[CH:23]1([N:29]=[C:30]=[N:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C1C=CN=CC=1)C.ClCCl>[CH:32]1([NH:31][C:30]([NH:29][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:4])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C=CC(=O)OCCCCOC(=O)Oc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
A solution of 4-(acryloxybutyloxycarbonyloxy)benzoic acid (2 mmol), N,N′-dicyclohexylcarbodiimide (2.2 mmol), 2,4-O-benzylidene-D-threitol (1.1 mmol; cf. Example 1c) and the catalyst 4-DMAP (0.1 mmol) in dichloromethane (5 ml) is stirred at room temperature until the reaction is complete, the N,N′-dicyclohexylurea which has been formed is filtered off and the solvent is removed under reduced pressure. The residue is finally purified by column chromatography and recrystallized from ethanol.
Reaction SMILES: COC1C=CC(C[CH:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20](=[O:36])[C@H:21]([CH:33]([CH3:35])[CH3:34])[NH:22][C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:15]([O:37][C:38](=[O:54])[C@H:39]([CH:51]([CH3:53])[CH3:52])[NH:40][C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])[CH:14]=2)[C:9]([O-:11])=[O:10])=CC=1.C(O)(C(F)(F)F)=O>ClCCl>[C:41]([NH:40][C@H:39]([C:38]([O:37][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[O:19][C:20](=[O:36])[C@H:21]([CH:33]([CH3:35])[CH3:34])[NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH2:12][CH2:8][C:9]([OH:11])=[O:10])=[O:54])[CH:51]([CH3:52])[CH3:53])([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42]
Reactant: COc1ccc(CC(Cc2ccc(OC(=O)[C@@H](NC(=O)OCc3ccccc3)C(C)C)c(OC(=O)[C@@H](NC(=O)OCc3ccccc3)C(C)C)c2)C(=O)[O-])cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc(CCC(=O)O)cc1OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Yield: 79.4 %

Procedure:
4-Methoxybenzyl-3,4-di-(N-CBZ-L-valyloxy)hydrocinnamate (10 g, 13 mmol) was dissolved in dichloromethane and 1,1,1 trifluoroacetic acid (30 ml) and left at ambient temperature for 3.5 h. Evaporation under reduced pressure and purification by chromatography (chloroform-methanol, 10:1) yielded 6.7 g (80%) pure title product. The compound can be activated and esterified to a drug or further modified as described below.
Reaction SMILES: FC1C=CC=CC=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1.NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.[F:61][C:62]1[CH:67]=[CH:66][C:65](N=C=S)=[CH:64][CH:63]=1>>[F:61][C:62]1[CH:63]=[C:64]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:15][CH:16]=2)[CH:65]=[CH:66][CH:67]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Reactant: Fc1ccc(N=C=S)cc1
Agent: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4cccc(F)c4)cc3)ccc2C1=O

Procedure:
The compound of example 276 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 4-fluorophenyl isothiocyanate. The compound of example 276 was used directly without isolation, for the preparation of compound of example 277.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[CH:8][C:7]=1[OH:14])=[O:5].OS(O)(=O)=O>[OH-].[Na+]>[Cl:12][C:10]1[CH:11]=[C:6]2[C:7](=[CH:8][C:9]=1[OH:13])[O:14][CH2:2][CH2:3][C:4]2=[O:5]
Reactant: O=C(CCCl)c1cc(Cl)c(O)cc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCOc2cc(O)c(Cl)cc21
Temperature: 25 °C
Yield: 72.4 %

Procedure:
3-chloro-1-(5-chloro-2,4-dihydroxyphenyl)propan-1-one (140 g, 596 mmol) was dissolved in a 2M aqueous NaOH solution (2085 ml) at 0° C. then allowed to warm up to ambient temperature over the next 2 hours. The reaction was acidified by the addition of 6M H2SO4 to a pH of ˜2. The resulting solids were removed by filtration and dried under high vacuum. The resulting solid was dissolved in THF (600 ml) and washed with water. The organic layer and was dried over magnesium sulfate, filtered, and concentrated. The resulting solid was treated with a minimal amount of diethyl ether and sonicated until a homogeneous suspension resulted. The resulting solid was collected by filtration to give the desired compound (85.7 g, 73%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[NH:7][C:8]1[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([O-:3])=[O:2].[O:27]1CCC[CH2:28]1.[H-].[Na+].ClC1C=C(NC(N2C=CN=C2)=O)C=CC=1>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[C:8]3[C:9](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:10](=[O:11])[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:28]2=[O:27])[CH:24]=[CH:25][CH:26]=1)([O-:3])=[O:2]
Reactant: O=C(NCc1ccccc1)c1ccccc1Nc1cccc([N+](=O)[O-])c1
Reactant: C1CCOC1
Agent: O=C(Nc1cccc(Cl)c1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=c1c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c(=O)n1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 3.5 g of 2-(m-nitroanilino)-N-benzylbenzamide and 30 ml of dry tetrahydrofuran was added 1.0 g of about 55 % sodium hydride, and stirring was performed for 30 minutes at room temperature. To this was added dropwise a solution of 4.9 g of 1-[N-(m-chlorophenyl)carbamoyl]imidazole and 30 ml of dry tetrahydrofuran. The mixture was allowed to stand for 30 minutes at room temperature and then refluxed for 2 hours. After the reaction was complete, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure to leave a residue, to which was added water to precipitate a crude product. Recrystallization of this product from methanol gave 2.0 g of 1-(m-nitrophenyl)-3-benzylquinazoline-2,4(1H, 3H)-dione as colorless prisms, melting at 206°-207° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([N:34]3[CH2:39][CH2:38][C:37]([CH3:41])([CH3:40])[CH2:36][CH2:35]3)=[C:17]([C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]([CH3:22])=[N:19][C:20]=2[CH3:21])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[C:30]([O:29][C@@H:23]([C:17]1[C:18]([CH3:22])=[N:19][C:20]([CH3:21])=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[C:16]=1[N:34]1[CH2:35][CH2:36][C:37]([CH3:40])([CH3:41])[CH2:38][CH2:39]1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:31])([CH3:32])[CH3:33]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccccc3)cc2)c1N1CCC(C)(C)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Yield: 98.8 %

Procedure:
A mixture of (S)-ethyl 2-(5-(4-(benzyloxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.434 g, 0.777 mmol) and 10% Pd/C (0.083 g, 0.078 mmol) in EtOAc (25 mL) was evacuated and released to H2 three times and left under balloon H2 atmosphere for h. Then, filtered through a plug of celite and concentrated to afford (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (0.36 g, 0.768 mmol, 99% yield) as white solid which was used in subsequent reactions without purification. 1H NMR (500 MHz, CDCl3) δ 7.11 (dd, J=2.0, 8.6 Hz, 1H), 6.99-7.03 (m, 1H), 6.94 (tdd, J=2.2, 4.4, 6.4 Hz, 2H), 6.09 (s, 1H), 4.23-4.30 (m, 1H), 4.19 (qd, J=7.1, 10.8 Hz, 1H), 3.18 (d, J=11.4 Hz, 1H), 2.88 (t, J=12.1 Hz, 1H), 2.62 (s, 3H), 2.28 (d, J=10.9 Hz, 1H), 2.22 (s, 3H), 2.10 (t, J=11.7 Hz, 1H), 1.51-1.60 (m, 1H), 1.33-1.42 (m, 1H), 1.27 (t, J=7.1 Hz, 3H), 1.21 (s, 9H), 1.18-1.20 (m, 1H), 1.09 (d, J=9.9 Hz, 1H), 0.91 (br. s., 3H), 0.66 (br. s., 3H). LCMS (M+H)=469.3.
Reaction SMILES: [CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=1[C:12]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]#[N:24])[CH:17]=[C:18]([CH3:20])[CH:19]=1)=[O:13])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+].Br[CH2:34][CH:35]1[CH2:37][CH2:36]1>CN(C=O)C>[CH:35]1([CH2:34][N:6]2[C:5]([C:12]([C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][C:23]#[N:24])[CH:17]=[C:18]([CH3:20])[CH:19]=3)=[O:13])=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9](=[O:10])[NH:8][C:7]2=[O:11])[CH2:37][CH2:36]1
Reactant: Cc1cc(C=CC#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C=CC#N)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CC2CC2)c1
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a stirred solution of 3-[3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-phenyl]-acrylonitrile (Compound 55) (323 mg, 1 mmol), anhydrous powdered potassium carbonate (165 mg, 1.2 mmol), and lithium iodide (134 mg, 1 mmol) in DMF (5 mL) at room temperature, was added bromomethyl cyclopropane (97 μL, 1 mmol). After stirring overnight, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:2)) to give 320 mg (84%) of 3-[3-(3-cyclopropylmethyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-phenyl]-acrylonitrile (72) as a white solid. The product was recrystallized from chloroform-ether to afford a white solid. m.p. 225-226° C.; 1H-NMR (300 MHz, CDCl3) δ 0.22-0.44 (4H, m), 0.93 (1H, m), 1.12 (3H, d, J=6.9 Hz), 1.24 (3H, d, J=6.9 Hz), 2.28 (1H, m), 2.50 (3H, s), 3.28 (1H, dd, J=6.0 Hz, J=15.0 Hz), 3.59 (1H, dd, J=6.0 Hz, J=15.0 Hz), 6.01 (1H, d, J=16.8 Hz), 7.44 (1H, d, J=16.8 Hz), 7.61 (1H, s), 7.77 (1H, s), 7.88 (1H, s), 9.00 (1H, s); m/z (EI) 377 (M+).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=O.[N:9]1(N)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.B(F)(F)F.CCOCC.C(OCC)(=O)C>C(O)C>[CH2:7]([O:6][C:1]([C:2]1[N:9]2[CH2:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([CH:4]=1)[C:17]2=3)=[O:5])[CH3:8]
Reactant: NN1CCc2ccccc21
Reactant: CCOC(=O)C(C)=O
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cc2cccc3c2n1CC3
Yield: 16.5 %

Procedure:
Ethyl pyruvate (3.7 ml, 33.3 mmol) was added to a solution of 2,3-dihydro-indol-1-ylamine (4.216 g, 31.4 mmol) in absolute ethanol (40 ml). The mixture was heated to reflux for 1 hour before being evaporated to dryness. The residue was dissolved in acetic acid (40 ml) and boron trifluoride etherate (4.0 ml 31.4 mmol) added. The mixture was heated to reflux for 1 hour then poured into ethyl acetate (200 ml). The ethyl acetate was washed with water (1 L), saturated sodium hydrogen carbonate (2×300 ml) and brine (100 ml). After drying over anhydrous magnesium sulfate the mixture was evaporated to dryness and the residue purified by flash column chromatography (SiO2, 7% to 10% EtOAc in hexanes) to afford 4,5-dihydro-pyrrolo[3,2,1-hi]indole-2-carboxylic acid ethyl ester as a yellow solid (1.117 g). 400 MHz 1H NMR (DMSO-d6) δ: 7.35 (d, J=6.8 Hz, 1H), 7.12 (s, 1H), 7.04-6.99 (m, 2H), 4.73 (t, J=6.8 Hz, 2H), 4.37 (q, J=7.2 Hz, 2H), 3.77 (t, J=6.8 Hz, 2H), 1.41 (t, 6.8 Hz, 3H); LCMS: 216 [M+H].
Reaction SMILES: Cl.N[C@@H]1C(=O)N2CCCC[C@@H]2CCC1.[NH2:15][C@H:16]1[CH2:23][CH2:22][CH:21]=[CH:20][CH2:19][N:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:17]1=[O:30]>>[NH2:15][C@H:16]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][N:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:17]1=[O:30]
Reactant: N[C@H]1CCC=CCN(c2ccccc2)C1=O
Agent: Cl
Agent: N[C@H]1CC/C=C\CN(c2ccccc2)C1=O
Agent: N[C@H]1CCC[C@H]2CCCCN2C1=O
Product: N[C@H]1CCCCCN(c2ccccc2)C1=O

Procedure:
(S)-3-Amino-1-phenylazocan-2-one (87 mg, 0.34 mmol) was synthesized as described for the preparation of Intermediate 54 using (S,Z)-3-amino-1-phenyl-1,4,5,8-tetrahydroazocin-2(3H)-one. Anal. Calcd. for C13H18N2O m/z 218.2. found: 219.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>C(O)C.[Pd]>[NH2:11][C:8]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(N)cc1C(=O)O
Temperature: 25 °C

Procedure:
5.24 g of 2-methyl-5-nitrobenzoic acid are dissolved in 250 ml of ethanol, 0.5 g palladium on charcoal (5%) are added, and the reaction mixture is stirred under an atmosphere of hydrogen at RT over night, until the reaction is completed according to TLC analysis. The mixture is filtered over a plug of celite, and the solvent is removed under reduced pressure resulting in the crude 5-amino-2-methylbenzoic acid, which is used for the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:8]=1)[CH2:3][NH2:4].Br[C:21]1[S:25][C:24]([NH2:26])=[N:23][N:22]=1>>[CH3:1][CH:2]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:8]=1)[CH2:3][NH:4][C:21]1[S:25][C:24]([NH2:26])=[N:23][N:22]=1
Reactant: Nc1nnc(Br)s1
Reactant: CC(CN)COc1cccc(CN2CCCCC2)c1
Product: CC(CNc1nnc(N)s1)COc1cccc(CN2CCCCC2)c1

Procedure:
The compound is prepared by a method analogous to Example 51 from 2-methyl-3-[3-(1-piperidinylmethyl) phenoxy]-1-propanamine and 5-bromo-1,3,4-thiadiazole-2-amine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15].[C:16]([OH:24])(=[O:23])[C:17]([CH2:19][C:20](O)=[O:21])=[CH2:18]>>[F:15][C:3]1[CH:4]=[C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:6]=[CH:7][C:2]=1[N:1]1[C:20](=[O:21])[CH2:19][CH:17]([C:16]([OH:24])=[O:23])[CH2:18]1
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Reactant: C=C(CC(=O)O)C(=O)O
Product: O=C(O)C1CC(=O)N(c2ccc(-n3ccccc3=O)cc2F)C1

Procedure:
Prepared analogously to Example 1d from 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one by melting with itaconic acid. The crude product is purified by reversed-phase chromatography.