Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:3]=1[CH2:4][N:5]([CH2:15][C:16](OCC)=[O:17])[C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[N:27]1([C:32]([C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)=[O:33])[CH2:31][CH:30]=[CH:29][CH2:28]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClCCl.[OH-].[Na+].C(O)C.C(OCC)(=O)C>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]([N:5]2[CH2:4][C:3]3[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:2]=3[N:1]([CH2:38][C:37]3[CH:36]=[CH:35][C:34]([C:32]([N:27]4[CH2:31][CH:30]=[CH:29][CH2:28]4)=[O:33])=[CH:41][CH:40]=3)[C:16](=[O:17])[CH2:15]2)=[O:14])=[CH:12][CH:11]=1
Reactant: CCOC(=O)CN(Cc1cc(OC)ccc1N)C(=O)c1ccc(Cl)cc1
Reactant: O=Cc1ccc(C(=O)N2CC=CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CN(C(=O)c1ccc(Cl)cc1)CC(=O)N2Cc1ccc(C(=O)N2CC=CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
320 mg (0.85 mmol) of ethyl [(2-amino-5-methoxybenzyl)-(4-chlorobenzoyl)amino]acetate was dissolved in 5 ml of dichloromethane. 205 mg (1.0 mmol) of 4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)benzaldehyde and 0.097 ml (1.7 mmol) of acetic acid were added to the obtained solution, and they were stirred at room temperature for 30 minutes. 440 mg (2.1 mmol) of sodium triacetoxyborohydride was added to the reaction mixture, and they were stirred at room temperature overnight. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was dissolved in a mixture of 5 ml of 1 N sodium hydroxide and 5 ml of ethanol, and the obtained solution was stirred at room temperature for 5 hours. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was dissolved in 5 ml of dichloromethane. 169 mg (1.0 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.24 ml (1.7 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28](Br)=[CH:27][N:26]=4)=[O:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[CH:27][N:26]=4)=[O:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(NC1CCC(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)CC1)c1ccc(Br)cn1
Product: O=C(NC1CCC(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)CC1)c1ccc(N2CCOCC2)cn1

Procedure:
The title compound, MS: m/e=523.2 (M+H+), was prepared in accordance with the general method of example 30A65, step 2 from 5-bromo-pyridine-2-carboxylic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide and morpholine.
Reaction SMILES: C([O:8][C:9](=[O:24])[CH2:10][C@@H:11]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:12][C:13]([NH2:15])=[O:14])C1C=CC=CC=1>C(OCC)(=O)C.[Pd].ClCCl.CCCCCC>[Si:17]([O:16][C@H:11]([CH2:10][C:9]([OH:24])=[O:8])[CH2:12][C:13]([NH2:15])=[O:14])([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CC(N)=O)CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H](CC(N)=O)CC(=O)O
Temperature: 5 °C

Procedure:
(S)-Benzyl-3-(tert-butyl dimethylsilyloxy)glutaramate (100 g) was dissolved in ethyl acetate and placed in pressure flask. To this Palladium on charcoal (5%, 1 g) was added and stirred under hydrogen atmosphere (˜2.8 Kg). Palladium was removed by filtration. The filtrate was mixed with water and adjusted pH to ˜9.0 by using Aq ammonia solution. The reaction mass was stirred and layers were separated. The aqueous phase was washed with dichloromethane and dichloromethane was added to aqueous phase. The reaction mass was cooled to 5° C. and pH was adjusted to 4.0 with Aq phosphoric acid. The reaction mass was stirred and layers were separated. The organic phase was washed with water and dried over sodium sulphate. The organic layer was evaporated under vacuum to yield residue. Residue was dissolved in dichloromethane and to this solution hexane was added, stirred, filtered and dried to yield (S)-3-(tert-butyl dimethylsilyloxy)glutaric acid monoamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[Br:18][C:19]1[C:20](Cl)=[C:21]([C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:22]([CH3:26])=[N:23][C:24]=1[CH3:25]>CC#N>[Br:18][C:19]1[C:20]([N:5]2[CH2:6][CH2:7][C:2]([CH3:8])([CH3:1])[CH2:3][CH2:4]2)=[C:21]([C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:22]([CH3:26])=[N:23][C:24]=1[CH3:25]
Reactant: CCOC(=O)C(=O)c1c(C)nc(C)c(Br)c1Cl
Reactant: CC1(C)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(=O)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Reaction time: 22 h
Yield: 71.6 %

Procedure:
To a solution of 4,4-dimethylpiperidine (1.245 g, 11.00 mmol) and DIEA (3.49 ml, 20.00 mmol) in anhydrous CH3CN (40 mL) was added ethyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (3.21 g, 10 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.). After 22 h, the reaction mixture was concentrated and the residue was purified by flash chromatography using 1-lit each 2.5, 5, 7.5 and 10% EtOAc/Hex to afford ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate (2.846 g, 7.16 mmol, 71.6% yield) as yellow solid. 1H NMR (500 MHz, CDCl3) δ 4.37 (q, J=7.1 Hz, 2H), 3.67-2.75 (br.s., 4H), 2.71 (s, 3H), 2.44 (s, 3H), 1.42 (t, J=7.1 Hz, 3H), 1.38 (t, J=5.6 Hz, 4H), 1.00 (s, 6H). LCMS (M+H)=399.4.
Reaction SMILES: C(CC[N:5]1[C:9]([C:10]2[CH:11]=[C:12]([CH:38]=[CH:39][CH:40]=2)[CH2:13][O:14][CH2:15][C@@H:16]([NH:19][C:20](=[O:37])[C@H:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=2)[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]#[N:18])=[N:8][N:7]=[N:6]1)#N.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[NH:8]1[C:9]([C:10]2[CH:11]=[C:12]([CH:38]=[CH:39][CH:40]=2)[CH2:13][O:14][CH2:15][C@@H:16]([NH:19][C:20](=[O:37])[C@H:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=2)[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]#[N:18])=[N:5][N:6]=[N:7]1
Reactant: Cc1cccc(C[C@H](Nc2ccccc2)C(=O)N[C@@H](C#N)COCc2cccc(-c3nnnn3CCC#N)c2)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cc1cccc(C[C@H](Nc2ccccc2)C(=O)N[C@@H](C#N)COCc2cccc(-c3nnn[nH]3)c2)c1
Reaction time: 2 h

Procedure:
To a solution of N-[2-[3-(1-(2-cyanoethyl)-5-tetrazolyl)-benzyloxy]-1(S)-cyanoethyl]-3-methyl-Nα-phenyl-L-phenylalaninamide (prepared according to examples 1(g) and 7 using intermediate of Example 1(e)), 160 mg, 0.30 mmol) in CH2Cl2 (10 mL) is added DBU (0.22 mL, 1.5 mmol) in one portion, and the solution is stirred at room temp. for 2 h., after which time the solution is washed with 1 N HCl (30 mL), brine (30 mL), dried (MgSO4), evaporated, and chromatographed (2% MeOH/CH2Cl2, 0 to 0.05% acetic acid) to yield N-[2-[3-(5-tetrazolyl)-benzyloxy]-1(S)-cyanoethyl]-3-methyl-Nα-phenyl-phenylalaninamide, as an off-white solid; m.p. 120-122° C.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:14][C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OC(F)F)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(OC(F)F)cc1
Temperature: 25 °C

Procedure:
A mixture of 10.0 g (7.68 ml, 58.1 mmol) 4-difluoromethoxy-benzaldehyde, 6.65 g (63.9 mmol) malonic acid, 0.21 g (2.50 mmol) piperidine and 50 ml pyridine was kept at reflux temperature until carbon dioxide development ceased (3 h). After cooling to room temperature the reaction mixture was poured onto 200 g ice and 100 ml 6N HCl. The precipitate was isolated, washed with water and dried. Yield: 8.8 g (71%) 3-(4-Difluoromethoxy-phenyl)-acrylic acid.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[CH:19]1([OH:26])[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1>>[C:13]1([C:12]#[C:11][C:8]2[CH:7]=[N:6][C:5]([O:25][CH:22]3[CH2:23][CH2:24][CH:19]([OH:26])[CH2:20][CH2:21]3)=[N:10][CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OC1CCC(O)CC1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Product: OC1CCC(Oc2ncc(C#Cc3ccccc3)cn2)CC1

Procedure:
The title compound, yellow solid, MS: m/e=295.3 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and cyclohexane-1,4-diol by using Cs2CO3 as base and dioxane as solvent for 16 hours at 100° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].C(OCC)(=O)C>CN(C=O)C>[CH3:1][C:2]1([CH3:21])[N:6]([CH2:25][C:26](=[O:27])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20]
Reactant: CC1(C)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Reactant: O=C(CBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.1 %

Procedure:
5,5-Dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione (35 mg) was dissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) was added. Then, 2-bromoacetophenone (25 mg) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 7 mg of white crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[O:26]1[CH2:29][CH:28]([NH2:30])[CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:30][CH:28]3[CH2:29][O:26][CH2:27]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NC1COC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC3COC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and oxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 410, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J=1.9 Hz, 1 H), 7.79 (d, J=1.9 Hz, 1 H), 7.72 (s, 1 H), 7.63 (t, J=3.8 Hz, 1 H), 7.44 (t, J=4.3 Hz, 2 H), 7.29 (d, J=2.1 Hz, 1 H), 5.72 (s, 1 H), 5.16 (t, J=3.3 Hz, 2 H), 5.12 (s, 2 H), 4.86 (m, 1 H), 4.72 (t, J=3.0 Hz, 2 H), 4.53 (brs, 2 H), 3.58 (t, J=2.3 Hz, 2 H), 2.43 (s, 3 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CC1C=CC(S(O[C@@H:31]2[CH2:35][CH2:34][O:33][CH2:32]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)CCC>[C:14]1([CH2:13][O:12][C:10]2[CH:9]=[C:4]([CH:3]=[C:2]([O:1][C@H:31]3[CH2:35][CH2:34][O:33][CH2:32]3)[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2)cc1
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCC#N
Product: COC(=O)c1cc(OCc2ccccc2)cc(O[C@H]2CCOC2)c1
Temperature: 130 °C
Yield: 84.1 %

Procedure:
A mixture of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (18.8 g, 72.75 mmol), (3R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (18.5 g, 76.4 mmol) and potassium carbonate (20.08 g, 145.5 mmol) in butyronitrile (250 mL) was heated to 130° C. for 3 hours. The solvent was removed in vacuo and ethyl acetate added. The organics were washed with water (40 mL), 0.5M sodium hydroxide solution (40 mL), brine (40 mL), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was chromatographed on silica, eluting with a gradient of 0-5% methanol in DCM, to give the desired compound as a colourless oil (20.1 g). 1H NMR δ (CDCl3): 2.08-2.26 (m, 2H), 3.78-4.01 (m, 4H), 3.90 (s, 3H), 4.92-4.96 (m, 1H), 5.08 (s, 2H), 6.69 (t, 1H), 7.15 (t, 1H), 7.29 (t, 1H), 7.34-7.44 (m, 5H); m/z 327 (M+H)+
Reaction SMILES: NC1N=C(N)C2C(=NC=C(CN(C3C=CC=CC=3)C3C=CC=CC=3)N=2)N=1.[CH:27]1[C:40]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][C:31]=2[CH:30]=[CH:29][CH:28]=1.[H-].[Na+].Br.[NH2:44][C:45]1[N:46]=[C:47]([NH2:57])[C:48]2[CH:54]=[C:53]([CH2:55]Br)[CH:52]=[N:51][C:49]=2[N:50]=1>>[NH2:44][C:45]1[N:46]=[C:47]([NH2:57])[C:48]2[CH:54]=[C:53]([CH2:55][N:32]3[C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:39][C:40]4[CH:27]=[CH:28][CH:29]=[CH:30][C:31]3=4)[CH:52]=[N:51][C:49]=2[N:50]=1
Reactant: c1ccc2c(c1)Cc1ccccc1N2
Reactant: Nc1nc(N)c2cc(CBr)cnc2n1
Agent: Br
Agent: Nc1nc(N)c2nc(CN(c3ccccc3)c3ccccc3)cnc2n1
Agent: [H-]
Product: Nc1nc(N)c2cc(CN3c4ccccc4Cc4ccccc43)cnc2n1

Procedure:
N-[(2,4-Diaminopyrido[2,3-d]pyrimidin-6-yl)methyl]-9,10-dihydroacridine (Formula I: Ar=2,4-diaminopyrido[2,3-d]pyrimidin-6-yl; W=CH2; X=N; Z=CH2; m=n=0) is prepared similarly to N-[(2,4-diaminopteridin-6-yl)methyl]-N,N-diphenylamine as disclosed above by using 9,10-dihydroacridine (134 mg, 0.8 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-6-bromomethylpyrido[2,3-d]pyrimidine hydrobromide (100 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20](C)[C:21](=O)C(F)(F)F)[CH:15]=2)=[O:12])=[CH:9][N:8]=[C:7]([NH:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[N:6]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>CO.O>[CH3:21][NH:20][C:16]1[CH:15]=[C:14]([NH:13][C:11]([C:10]2[C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[N:6][C:7]([NH:28][CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=3)=[N:8][CH:9]=2)=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)Nc1cccc(N(C)C(=O)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)Nc1cccc(NC)c1
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
To a solution of 4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)-N-(3-(2,2,2 -trifluoro-N-methylacetamido)phenyl)pyrimidine-5-carboxamide (A7, 186 mg) in methanol (4 mL) and water (2 mL), potassium carbonate (92 mg) was added at room temperature, and the mixture was stirred at the same temperature for 13 hours and 30 minutes. To the reaction mixture, water and chloroform were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain N-(3-(methylamino)phenyl)-4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxamide (A8, 141 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH:10]C(CC3C=CC=CC=3)=O)[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([O-:22])=[O:21].[K+].Cl>>[CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH2:10])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: Cl
Agent: [K+]
Product: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Reaction time: 8 h
Yield: 85 %

Procedure:
120 ml of the immobilized preparation of Escherichia coli ATCC 9637 are charged into a 2.1 cm × 34.8 cm column. 500 ml of an aqueous 1 % potassium Penicillin G solution (pH 9.0) are passed through the column at 40°C at the flow rate of 16 ml/hr. The effluent tus obtained is adjusted to pH 2.0 with 2N-hydrochloric acid and washed twice with 10 ml of methylisobutylketone to remove phenylacetic acid. The aqueous layer is again adjusted to pH 7.0 with 2N-sodium hydroxide. Then, the aqueous layer is concentrated at 50°C under reduced pressure to bring its total volume to 5 ml. After adjusting to pH 4.3 with 2N-hydrochloric acid, the concentrated solution is allowed to stand at 27°C overnight. The crystalline precipitate is collected by filtration and dried at 50°C under reduced pressure. 2.23 g of 6-APA are obtained. Yield: 85 % M.p. 204° - 207°C (decomp.)
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:3]#[CH:4].C[O:18][C:19]([CH3:21])=[CH2:20].CS(O)(=O)=O.CC([O-])=O.[Na+]>>[CH3:15][C@H:8]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][C@H:2]([CH2:3][CH2:4][CH2:20][C:19]([CH3:21])=[O:18])[CH3:1]
Reactant: C=C(C)OC
Reactant: C#CC(C)(O)CCCC(C)CCCC(C)C
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Product: CC(=O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Yield: 87 %

Procedure:
44.9 g 3,7,11-trimethyl-1-dodecin-3-ol and 50.5 g isopropenyl methyl ether were initially introduced into a 300 ml V4A steel autoclave with a temperature probe, sampler and pressure indicator. 19 mg methanesulfonic acid were added, while stirring. The autoclave was forced up to 2 bar with nitrogen. The mixture was stirred at 90 to 95° C. for 8 hours. After cooling, the reaction mixture was neutralized with 1.7 ml methanolic NaOAc solution (10 g/1). After evaporation, the crude product was hydrogenated in 2-propanol with 10% Pd/A-charcoal. Phytone was obtained in a yield of 87%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([N:23]([CH:33]2[CH2:35][CH2:34]2)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:20]2=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]2[N:18]=1.N12CCCN=C1CCCCC2.[O:52]1[CH2:55][C:54](=[CH:56][CH:57]=[O:58])[CH2:53]1.[BH4-].[Na+]>C1COCC1.CCOC(C)=O.CO>[Cl:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][N:11]([C:54]3([CH2:56][CH2:57][OH:58])[CH2:55][O:52][CH2:53]3)[CH2:10][CH2:9]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([N:23]([CH:33]2[CH2:35][CH2:34]2)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:20]2=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]2[N:18]=1
Reactant: O=CC=C1COC1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(C4CCNCC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(C4CCN(C5(CCO)COC5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: -15 °C
Reaction time: 2.5 h
Yield: 49.3 %

Procedure:
To a solution of 2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl (4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (375D) (50 mg, 0.090 mmol) in dry THF (0.3 mL) was added 1,8-Diazabicyclo[5.4.0]undec-7-ene (diluted with THF, 10V %) (0.013 mL, 9.02 μmol) at RT. The mixture was cooled in an ice/NaCl bath (−15° C.). To this was added 2-(oxetan-3-ylidene)acetaldehyde (36 mg, 0.367 mmol), and left stirring at −15° C. to 0° C. for 2.5 h, then the mixture was put in the freezer for 7 days. To the reaction mixture was added MeOH (1 mL), then sodium borohydride (10.30 mg, 0.271 mmol) at RT and stirred for 2 hrs. Diluted with EtOAc, washed with NaHCO3, water, brine, and dried over Na2SO4. Removal of the solvent. The crude material was purified by radial chromatography, eluting with DCM containing 0 to 1% MeOH to give 2-((2-chloro-5-cyano-3-(1-(3-(2-hydroxyethyl)oxetan-3-yl)piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (29 mg).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:23][C:24]4[CH:25]=[C:26]([C:30]5[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([OH:38])=O)[CH:31]=5)[CH:27]=[CH:28][CH:29]=4)[CH2:20][CH2:21][CH:22]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N:40]1CCOCC1.ClC(OCC(C)C)=O.N>C1COCC1.CCOC(C)=O>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:23][C:24]4[CH:25]=[C:26]([C:30]5[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([NH2:40])=[O:38])[CH:31]=5)[CH:27]=[CH:28][CH:29]=4)[CH2:20][CH2:21][CH:22]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc(-c2cccc(CC3CCC=C3c3nc(-c4ccccc4)c(-c4ccccc4)o3)c2)c1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc(-c2cccc(CC3CCC=C3c3nc(-c4ccccc4)c(-c4ccccc4)o3)c2)c1
Reaction time: 0.25 h

Procedure:
To a solution of 3′-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl]methyl}biphenyl-3-carboxylic acid (74 mg) and N-methylmorpholine (0.0197 ml) in THF (4 ml) was added isobutyl chloroformate (0.0232 ml) at 0° C. After stirring for 15 minutes, 28% ammonia solution (0.1 ml) was added thereto. The mixture was stirred at the same temperature for 15 minutes, then stirred at room temperature for 15 minutes. The reaction mixture was diluted with EtOAc, washed with water, 1N HCl, water, and brine, dried over magnesium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (CH2Cl2-MeOH 25:1) to give 3′-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl]methyl}-biphenyl-3-carboxamide (51.8 mg) as a solid.
Reaction SMILES: [N:1]1([CH2:6][C:7]#[C:8][C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2C(OC(C)(C)C)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.[ClH:24]>CO>[ClH:24].[ClH:24].[NH:10]1[CH2:11][CH2:12][CH2:13][C@@H:9]1[C:8]#[C:7][CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C#CCN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: C(#C[C@H]1CCCN1)CN1CCCC1
Temperature: 80 °C

Procedure:
A mixture of 7.0 g of (R)-2-[3-(1-pyrrolidinyl)-1-propynyl]-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester, 61 ml of ethanol and 61 ml of 2N hydrochloric acid is heated at 80° C. for one hour. The reaction is concentrated in vacuo and the residue is extracted with methylene chloride. The aqueous layer is concentrated in vacuo, made basic with 10N sodium hydroxide and extracted with methylene chloride. The methylene chloride solution is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is dissolved in methanol, treated with an excess of methanolic hydrogen chloride and precipitated with the addition of diethyl ether. The dihydrochloride is recrystallized from hot methanol to give pure product, mp 198°-200° C. with decomposition, [α]D26° =+21°±1 (C=1.012%, methanol).