Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.O[CH:14]1[CH2:19]SC(O)C[S:15]1.C(N(CC)CC)C>C(O)C>[NH2:10][C:9]1[S:15][CH:14]=[CH:19][C:8]=1[C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=1
Reactant: N#CCC(=O)c1ccc(F)cc1
Reactant: OC1CSC(O)CS1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1sccc1C(=O)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 116.6 %

Procedure:
A mixture of 4-fluorobenzoylacetonitrile (2.84 g), 2,5-dihydroxy-1,4-dithian (1.31 g), triethylamine (2.2 ml) and ethanol (15 ml) was stirred for 40 minutes at 50° C. The reaction mixture was cooled to give 2-amino-3-(4-fluorobenzoyl)thiophene as yellow crystals (2.22 g).
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[N:8]=[C:7](SC)[CH:6]=[N:5]1)[CH:2]=[CH2:3].Cl.C([OH:16])C>>[CH2:1]([N:4]1[C:9](=[O:10])[NH:8][C:7](=[O:16])[CH:6]=[N:5]1)[CH:2]=[CH2:3]
Reactant: CCO
Reactant: C=CCn1ncc(SC)nc1=O
Agent: Cl
Product: C=CCn1ncc(=O)[nH]c1=O
Temperature: 25 °C
Yield: 84.8 %

Procedure:
A mixture of 1.49 g 2-allyl-3-oxo-5-methylthio-2,3-dihydro-1,2,4-triazine, 6 ml conc. hydrochloric acid and 12 ml ethyl alcohol was heated under reflux for 1.5 hours. After cooling to room temperature, the solvent was removed under reduced pressure to obtain a yellow solid. This solid was recrystallized from ethyl alcohol to obtain 1.06 g of a white crystal.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21](=[O:36])[N:22]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][C:27]=2[Cl:35])[CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C1COCC1.[Pd]>[NH2:32][C:29]1[CH:30]=[CH:31][C:26]([N:22]2[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:21]2=[O:36])=[C:27]([Cl:35])[CH:28]=1
Reactant: CC(C)(C)[Si](OCc1cccn(-c2ccc([N+](=O)[O-])cc2Cl)c1=O)(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCc1cccn(-c2ccc(N)cc2Cl)c1=O)(c1ccccc1)c1ccccc1

Procedure:
800 mg (1.54 mmol) of the compound from Example 4A are dissolved in 48 ml of THF. 50 mg (0.05 mmol) of palladium on carbon are then added, and the mixture is hydrogenated at RT in a hydrogen atmosphere under atmospheric pressure. The mixture is then filtered, the filter cake is washed with THF and the filtrate is freed from the solvent. The reaction product (purity: 95%) is reacted further without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH2:9]Cl)=[CH:4][N:3]=1.ClC1C(C[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH:29]=[CH2:30])[C:20](=[O:22])[CH3:21])=CC(F)=C(Cl)N=1>>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=1[CH2:9][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=[CH2:30])[C:20](=[O:22])[CH3:21]
Reactant: C=Cc1ccccc1N(Cc1cc(F)c(Cl)nc1Cl)C(C)=O
Reactant: ClCc1cnc(Cl)cc1Cl
Product: C=Cc1ccccc1N(Cc1cnc(Cl)cc1Cl)C(C)=O
Yield: 82 %

Procedure:
Compound 41C (210 mg, 82%) was prepared from 41B (157 mg, 0.8 mmol) and bb (129 mg, 0.8 mmol) using a procedure similar to the synthesis of 1C.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[C:18]2[N:19]([CH:23]=[CH:24][N:25]=2)[CH:20]=[CH:21][CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(#N)C>[CH2:9]([O:16][C:17]1[C:18]2[N:19]([C:23]([I:1])=[CH:24][N:25]=2)[CH:20]=[CH:21][CH:22]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc(COc2cccn3ccnc23)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Ic1cnc2c(OCc3ccccc3)cccn12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
As shown in FIG. 6, N-iodosuccinimide (7.0 g, 31.2 mmol) was added to a solution of 8-benzyloxy-imidazo[1,2-α]pyridine (Example 19) 24 (7.0 g, 31.2 mmol) in dry acetonitrile (100 mL) at 0° C. The reaction was warmed to room temperature and then stirred for 12 hours. The mixture was filtered and the cake washed with acetonitrile and water and dried under high vacuum to afford 8-benzyloxy-3-iodo-imidazo[1,2-α]pyridine 31 as colorless solid. 9.0 g, 83%, yield.
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:14])[CH:5]=2)[CH2:3][CH2:2]1.[Br:15]Br.O>C(O)(=O)C>[Br:15][C:13]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][C:6]([OH:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: BrBr
Reactant: COC(=O)c1ccc(C2CC2)cc1O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(Br)c(C2CC2)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To a solution of methyl 4-cyclopropyl-2-hydroxybenzoate (1.80 g) in acetic acid (15.0 mL) was added dropwise bromine (1.57 g) under ice-cooling. The mixture was stirred at room temperature for 2 hr, to the reaction mixture was added water, and the resulting solid was collected by filtration. The obtained solid was dried under reduced pressure to give the title compound (2.28 g).
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.[N:26]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][CH2:29][CH2:28][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:34][CH2:33][CH2:32][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][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: NCCN1CCCCC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCN3CCCCC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 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 2-(piperidin-1-yl)ethanamine. MS obsd. (ESI+) [(M+H)+] 465, 1H NMR (400 MHz, CDCl3) δ ppm 8.04 (d, J=7.6 Hz, 1 H), 7.67 (d, J=7.6 Hz, 1 H), 7.51 (m, 2 H), 7.38 (t, J=7.6 Hz, 1 H), 7.30 (m, 2 H), 5.74 (m, 1 H), 5.12 (s, 2 H), 4.6 (brs, 2 H), 3.58 (s, 2 H), 3.28 (m, 2 H), 2.75 (t, J=8.4 Hz, 2 H), 2.46 (m, 7 H), 1.62 (m, 4 H), 1.52 (m, 2 H).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9](=[O:30])[CH2:10][C@@:11]1([C:24]2[S:25][C:26](Br)=[CH:27][CH:28]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:13][CH2:12]1.[CH3:31][NH:32][C:33]([NH:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)=[O:34]>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.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>[OH:7][NH:8][C:9](=[O:30])[CH2:10][C@@:11]1([C:24]2[S:25][C:26]([C:38]3[CH:39]=[CH:40][CH:41]=[C:36]([NH:35][C:33]([NH:32][CH3:31])=[O:34])[CH:37]=3)=[CH:27][CH:28]=2)[S:17](=[O:18])(=[O:19])[CH2:16][CH2:15][N:14]([S:20]([CH3:23])(=[O:21])=[O:22])[CH2:13][CH2:12]1
Reactant: CS(=O)(=O)N1CC[C@](CC(=O)NOC2CCCCO2)(c2ccc(Br)s2)S(=O)(=O)CC1
Reactant: CNC(=O)Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CNC(=O)Nc1cccc(-c2ccc([C@@]3(CC(=O)NO)CCN(S(C)(=O)=O)CCS3(=O)=O)s2)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 13.4 %

Procedure:
A mixture of N-(2-tetrahydropyranyloxy)-2-[(S)-7-(5-bromo-2-thienyl)-4-methanesulfonyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (230 mg), 3-(methylaminocarbonylamino)phenylboronic acid (123 mg) and tetrakis(triphenylphosphine)palladium(0) (24.4 mg) in a mixture of 1,2-dimethoxyethane (2 ml) and 2M aqueous sodium carbonate solution (0.85 ml) was stirred for 4 hours at 80° C. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo. The obtained residue was dissolved in methanol (2 ml) and 10% hydrogen chloride in methanol (0.5 ml) was added thereto. After being stirred for 30 minutes at room temperature, the solution was concentrated in vacuo. The residue was purified with silica gel column chromatography (eluent; 0.5-5% methanol in chloroform) to give N-hydroxy-2-[(S)-7-(5-(3-(methylaminocarbonylamino)-phenyl)-2-thienyl)-4-methanesulfonyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (30 mg).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:25](=[O:26])[N:5]2[C:6]([C:22]([O-:24])=[O:23])=[C:7]([CH:10]=[CH:11][CH2:12][N+:13]3[CH:18]=[CH:17][C:16]([C:19](=[O:21])[NH2:20])=[CH:15][CH:14]=3)[CH2:8][S:9][C@H:4]12.Cl.[CH2:28]([O:30][N:31]=[C:32]([C:36]1[N:40]=[C:39]([NH2:41])[S:38][N:37]=1)[C:33](Cl)=[O:34])[CH3:29].C([O-])([O-])=O.[Na+].[Na+].Cl>CC(C)=O>[NH2:41][C:39]1[S:38][N:37]=[C:36]([C:32](=[N:31][O:30][CH2:28][CH3:29])[C:33]([NH:2][CH:3]2[C:25](=[O:26])[N:5]3[C:6]([C:22]([O-:24])=[O:23])=[C:7]([CH:10]=[CH:11][CH2:12][N+:13]4[CH:14]=[CH:15][C:16]([C:19](=[O:21])[NH2:20])=[CH:17][CH:18]=4)[CH2:8][S:9][C@H:4]23)=[O:34])[N:40]=1
Reactant: CCON=C(C(=O)Cl)c1nsc(N)n1
Reactant: NC(=O)c1cc[n+](CC=CC2=C(C(=O)[O-])N3C(=O)C(N)[C@H]3SC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[n+]3ccc(C(N)=O)cc3)CS[C@H]12)c1nsc(N)n1
Temperature: 10 °C
Yield: 93.4 %

Procedure:
To a solution of 200 mg of 7-amino-3-[3-(4-carbamoylpyridinio)-1-propen-1-yl]-3-cephem-4-carboxylate hydrochloride (E isomer) in 5 ml of 50% aqueous acetone was added portionwise 190 mg of 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetyl chloride hydrochloride [prepared according to the procedure described in published Japan patent application (Kokai) No. 57-24389 (2/8/82)], and the mixture was adjusted to pH 6.5-7.0 with 2N Na2CO3 (about 1 ml). The reaction mixture was stirred at 10° C. for an hour, acidified to pH 2 with 1N HCl and evaporated in vacuo. The residue was filtered and the filtrate was chromatographed on a column of HP-20, which was eluted with 500 ml of water and 25% aqueous isopropanol, successively. Fractions containing the desired product were combined and evaporated under reduced pressure. The oily residue was treated with isopropanol (20 ml) to give 263 mg (93%) of the title compound (I-2H). M.p. 170° C. (dec.).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([NH2:17])[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[CH3:18][N:19]=[C:20]=[S:21].C(OCC)(=O)C>C(O)C>[C:1]([NH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([NH:17][C:20]([NH:19][CH3:18])=[S:21])[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1cccc(-c2csc(N)n2)n1
Reactant: CN=C=S
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNC(=S)Nc1nc(-c2cccc(CNC(C)=O)n2)cs1
Temperature: 25 °C
Yield: 20.7 %

Procedure:
A mixture of 4-(6-acetylaminomethylpyridin-2-yl)2-aminothiazole (7.0 g) and methyl isothiocyanate (6.2 g) in ethanol (140 ml) was heated under reflux for 40 minutes and then the mixture was cooling to ambient temperature. To the mixture was added ethyl acetate (140 ml) and isolated precipitate was collected by filtration to give 4-(6-acetylaminomethylpyridin-2-yl)-2-(3-methylthioureido)thiazole (1.88 g).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:15]2[C:14]([CH2:13][O:12][C:9]3[N:8]=[N:7][C:6]([C:4]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:5])=[CH:11][CH:10]=3)=[C:18]([CH3:19])[O:17][N:16]=2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C)nn1
Reactant: C1COCCN1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)N2CCOCC2)nn1
Yield: 83 %

Procedure:
As described for example 59, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (143 mg, 0.4 mmol) was converted, using morpholine instead of aminomethylcyclopropane, to the title compound (132 mg, 83%) which was obtained as a light yellow solid. MS: m/e=399.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:21]1[C:22](O)=[CH:23][C:24]3[O:28][CH2:27][CH2:26][C:25]=3[CH:29]=1)([CH2:19][OH:20])[C:5](=[O:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCOCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:19][O:20][C:22]3[CH:23]=[C:24]4[C:25](=[CH:29][C:21]1=3)[CH2:26][CH2:27][O:28]4)[C:5](=[O:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: O=C1N(Cc2ccccn2)c2cccc(Br)c2C1(CO)c1cc2c(cc1O)OCC2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C1N(Cc2ccccn2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Temperature: 25 °C
Yield: 36.7 %

Procedure:
A mixture of 4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-one (1.81 g, 3.88 mmol), triphenylphosphine (2.04 g, 7.77 mmol) and diisopropyl azodicarboxylate (1.57 g, 7.77 mmol) in anhydrous dioxane (60 mL) was heated at reflux for 16 h. After cooling down to ambient temperature, the solvent was removed in vacuo. The gummy residue was diluted with ethyl acetate (50.0 mL), washed with water (3×25.0 mL), brine (3×25.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate/hexane (80%) to give the title compound (0.64 g, 37%) as colorless solid: mp >200° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.47 (d, 1H), 7.77 (dt, 1H), 7.37 (d, 1H), 7.27 (dt, 1H), 7.19-7.13 (m, 2H), 6.94 (dd, 1H), 6.61 (s, 1H), 6.33 (s, 1H), 5.08 (d, 1H), 5.03 (d, 1H), 4.93 (d, 1H), 4.74 (d, 1H), 4.48 (t, J=8.6 Hz, 2H), 2.96 (t, 2H); 13C NMR (75 MHz, DMSO-d6) δ 177.4, 162.2, 161.8, 155.3, 149.8, 145.3, 137.6, 131.0, 130.5, 126.8, 123.3, 122.2, 119.9, 119.5, 119.0, 118.1, 109.3, 92.4, 77.5, 72.5, 58.8, 45.3, 28.8; MS (ES+) m/z 451.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>>[C:15]([C:7]1[C:8]([C:11]([F:12])([F:14])[F:13])=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])[C:2]([CH3:1])=[CH:10]2)#[N:16]
Reactant: COC(=O)C(C)Br
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)C(C)n1c(C)cc2c(C(F)(F)F)c(C#N)ccc21

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile, methyl 2-bromopropanoate (1.5 eq) and Cs2CO3 (1.5 eq): MS (ES) m/z 311 (M+1).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=3)[C:11]=2[CH2:12][S:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[O:6])[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:40])C=1>C1COCC1.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:26]=3)[C:11]=2[CH2:12][S:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:40])=[O:14])=[O:6])[CH2:2][CH2:3]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CS(=O)c2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CS(=O)(=O)c2ccccc2)cc1
Temperature: 0 °C
Yield: 100 %

Procedure:
N-Cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-[(phenylsulfinyl)methyl]-1H-1,2,3-triazole-4-carboxamide (107 mg, 0.24 mmol) obtained in Example 313 was dissolved in THF (2.0 ml), m-chloroperbenzoic acid (purity 65%, 64 mg, 0.24 mmol, 1.0 eq.) was added with stirring at 0° C., and the mixture was stirred for 1 hr and at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (25 ml), washed with 5% aqueous sodium sulfite solution, 2% aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated. Diethyl ether was added to the residue, and the precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (111 mg, 0.24 mmol, quant.).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.FC(F)(F)S(O[C:15]1[C:16]2[CH2:37][N:36]([CH3:38])[CH2:35][CH2:34][C:17]=2[N:18]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[CH:31][N:30]=[C:29]3[CH3:33])=[CH:24][CH:23]=2)[N:20]=1)(=O)=O>CS(C)=O>[CH:3]1([N:2]([CH3:1])[C:15]2[C:16]3[CH2:37][N:36]([CH3:38])[CH2:35][CH2:34][C:17]=3[N:18]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH3:33])=[CH:24][CH:23]=3)[N:20]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CNC1CCCCC1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C)CC3)cc1
Solvent: CS(C)=O
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(N(C)C4CCCCC4)n2)CN(C)CC3)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
N-Methylcyclohexanamine (9.67 mg, 0.09 mmol) was added to a solution of 6-methyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (40 mg, 0.09 mmol, Example 9a) in DMSO (1 mL) and the reaction was stirred at 80° C. for 2 h. Solvent was allowed to cool down, filtered and the product purified on preparative HPLC to give N4-cyclohexyl-N4,6-dimethyl-N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (22.00 mg, 59.7%). MS (ESI+)/(ESI−) m/z 432/430
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][C@H:4]1[CH3:16].[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]>C(Cl)Cl>[F:20][C:19]([F:22])([F:21])[C:17]([OH:23])=[O:18].[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][NH:6][CH2:5][C@H:4]1[CH3:16]
Reactant: CO[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@H]1CCNC[C@H]1C

Procedure:
A solution of racemic (cis)-tert-butyl 4-methoxy-3-methylpiperidine-1-carboxylate (230 mg, 1.0 mmol) in DCM (2 mL) with TFA (0.23 mL, 3.01 mmol) was stirred at room temperature overnight. The reaction mixture was then concentrated to give racemic (cis)-4-methoxy-3-methylpiperidine 2,2,2-trifluoroacetate. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.27 (s, 3 H), 3.01-3.09 (m, 1 H), 2.93-3.00 (m, 1 H), 2.81-2.93 (m, 1 H), 2.69-2.77 (m, 1 H), 1.90-2.08 (m, 2 H), 1.57-1.67 (m, 1 H), 0.90 (d, J=7.1 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:25]=[CH:26]/[C:27]([O:29]CC)=[O:28])[CH:5]=[N:6][C:7]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:16])[CH2:11][CH2:10]1.[OH-].[Na+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]([OH:29])=[O:28])[CH:5]=[N:6][C:7]=1[NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15](=[O:16])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:13][CH2:14]1
Reactant: CCOC(=O)/C=C/c1cnc(NC2CCN(C(=O)Nc3ccc(Cl)cc3)CC2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C=Cc1cnc(NC2CCN(C(=O)Nc3ccc(Cl)cc3)CC2)c(Cl)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl (2E)-3-{5-chloro-6-[(1-{[(4-chlorophenyl)amino]carbonyl}-4-piperidyl)amino]-3-pyridyl}acrylate (363 mg) in THF (3 ml) and MeOH (3 ml) was added 1N NaOH aq (2.35 ml), the mixture was stirred at 80° C. for 1 hour. The pH of the mixture was adjusted to ca.4.5 with 1N HCl aq. The solution was evaporated under reduced pressure to give crude 3-{5-Chloro-6-[1-(4-chlorophenylcarbamoyl)-piperidin-4-ylamino]-pyridin-3-yl}-acrylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH2:6][C:7]1[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)[CH:9]=[CH:10][CH:11]=1.[H][H]>C(O)(=O)C.[Rh]>[CH3:33][O:32][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[O:30][CH3:31])[CH2:23][CH:19]1[CH2:20][CH2:21][CH2:22][N:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][CH:7]1[CH2:6][C:5]1[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc(Cc2cccn2CCCCCCn2cccc2Cc2ccc(OC)c(OC)c2)cc1OC
Agent: [Rh]
Solvent: CC(=O)O
Product: COc1ccc(CC2CCCN2CCCCCCN2CCCC2Cc2ccc(OC)c(OC)c2)cc1OC
Yield: 92 %

Procedure:
A solution of 1,6-bis[2-(3,4-dimethoxybenzyl)pyrrol-1-yl]hexane (2.5 g) in glacial acetic acid (30 mL) containing suspended 5% rhodium on alumina catalyst (1.87 g) was reduced at room temperature and an initial hydrogen pressure of 45 p.s.i.g. (3 hour reaction, followed by TLC). The mixture was filtered through Celite. The filtrate was dried at reduced pressure, and the residue dissolved in dichloromethane, washed with ammonium hydroxide solution and dried over sodium sulfate. The solvent was removed in vacuo, and the residue subjected to column chromatographic purification on silica gel (100 g) using dichloromethane, to elute 1,6-bis[2-(3,4-dimethoxybenzyl)pyrrolidin-1-yl]hexane, 2.5 g (92% yield) as an oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:21]([O:23][CH2:24][CH2:25]Cl)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[C:28]1([CH:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:35][CH2:36][NH2:37])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OCC)C>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:21]([O:23][CH2:24][CH2:25][NH:37][CH2:36][CH2:35][CH:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCl)C1c1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCNCCC(c2ccccc2)c2ccccc2)C1c1cccc([N+](=O)[O-])c1
Reaction time: 1.75 h
Yield: 40.5 %

Procedure:
A solution comprising 5.92 g of methyl 2-chloroethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate and 9.50 g of 3,3-diphenylpropylamine in 20 ml of xylene was refluxed under stirring for 105 minutes. The mixture was then cooled. By dilution with diethyl ether a semisolid compound was obtained, and it was separated from the liquid by decantation. The residue was treated with diethyl ether at 0°-4° C. and the supernatant was decanted. This procedure was repeated until a solid was obtained, and this was collected by filtration. Mother liquors and washings from the decantation were collected and evaporated to dryness under vacuum. The residue was chromatographed on a silica gel column (270 g) using a mixture of chloroform and acetone as eluent. Pure fractions were combined and the solvent was evaporated off. The residue was dissolved in diethyl ether and hydrogen chloride in diethyl ether was added. The solid (3.92 g) was crystallized from ethyl acetate or isopropyl acetate and recrystallized from ethyl acetate to give 3.46 g of the title compound, m.p. 128°-132° C.