Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[N:9][C:10]([NH:13][C:14]2[CH:15]=[C:16]([NH2:29])[C:17]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)=[CH:18][C:19]=2[O:20][CH3:21])=[N:11][CH:12]=1.CCN(C(C)C)C(C)C>C1COCC1.O.C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)=[C:16]([NH:29][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3c[nH]c4ccccc34)n2)c(OC)cc1N1CCN(C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
Acryloyl chloride (0.621 mL, 1M in THF, 0.62 mmol) was added dropwise to N′-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (Intermediate 74, 288 mg, 0.62 mmol) and DIPEA (0.119 mL, 0.68 mmol) in THF (15 mL) at 0° C. under N2. The resulting suspension was stirred at 0° C. for 1 h, and then allowed to warm to r.t. The mixture was then diluted with water (15 mL) and concentrated in vacuo. The resulting residue was dissolved in a mixture of CH2Cl2 (20 mL) and CH3OH (5 mL) and the resulting solution was washed with water and sat. brine. The organic solution was dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-8% 7M methanolic ammonia in CH2Cl2 gave crude product as a pale brown dry film. This material was dissolved in CH2Cl2 and a beige solid precipitated from the solution. The solution was diluted with diethyl ether and then mixture filtered. The collected solid was washed with further diethyl ether and dried to give the title compound (134 mg, 42%) as a beige solid; 1H NMR: 2.27 (3H, s), 2.53-2.59 (4H, m), 2.87-2.94 (4H, m), 3.79 (3H, s), 5.70 (1H, d), 6.17 (1H, dd), 6.60 (1H, dd), 6.89 (1H, s), 7.01 (1H, t), 7.16 (1H, t), 7.45 (1H, d), 8.20 (1H, s), 8.27 (1H, d), 8.35 (1H, s), 8.43 (1H, s), 8.49 (1H, d), 8.96 (1H, s), 11.81 (1H, s); m/z: ES+ MH+ 518.51.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.S(Cl)([Cl:15])=O>>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([Cl:15])=[O:12]
Reactant: O=C(O)Cc1ccccc1CBr
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccccc1CBr

Procedure:
A solution of 0.18 g of o-bromomethylphenylacetic acid in excess thionyl chloride is stirred at room temperature for 18 hours after which the unreacted thionyl chloride is removed under high vacuum to give o-bromomethylphenylacetyl chloride as an oily residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[CH:20]=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[Cl:23]N1C(=O)CCC1=O.C(OCC)(=O)C.O>CN(C)C=O>[Cl:23][C:20]1[N:12]2[C:13]3[S:17][C:16]([CH2:18][CH3:19])=[CH:15][C:14]=3[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:9][CH2:10][C:11]2=[N:22][N:21]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1cc2c(s1)-n1cnnc1CN=C2c1ccccc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1cc2c(s1)-n1c(Cl)nnc1CN=C2c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
4-(2-Chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (10.0 g) and N-chlorosuccinimide (4.55 g) were dissolved in dimethylformamide (50 ml), and the mixture was stirred at room temperature overnight. Ethyl acetate and water were added thereto. The organic layer was washed with water and dried over magnesium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 1.8 g of 9-chloro-4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[CH3:13][C:14]([NH2:18])([CH3:17])[CH2:15][CH3:16]>C1COCC1>[CH2:9]([O:8][C:7]1[C:6](=[O:11])[C:5](=[O:12])[C:4]=1[NH:18][C:14]([CH3:17])([CH3:13])[CH2:15][CH3:16])[CH3:10]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CCC(C)(C)N
Solvent: C1CCOC1
Product: CCOc1c(NC(C)(C)CC)c(=O)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a room temperature solution of 4.9 g (29 mmol) of 3,4-diethoxy-3-cyclobutene-1,2-dione and 50 mL of THF was added 2.5 g (34 mmol) of 1,1-dimethyl-propylamine. After stirring at room temperature overnight, the reaction mixture was evaporated to a yellow oil. Trituration with Et2O and filtration gave 6.2 g (20 mmol, a 100% yield) of the title compound as a white solid: mp: 78-80° C.; 1H NMR: (300 MHz, DMSO-d6): δ 0.91 and 1.47 (t, J=7.5 Hz, 3H, rotamers), 1.36-1.97 (m, 6H), 4.70-4.92 (m, 2H), 5.41 and 5.99 (brs, 1H, rotamers); IR (KBr, cm-1H): 3252w, 3181w, 3067w, 2968m, 2887m, 1788m, 1695s, 1603s, 1578s, 1500-1434brs, 1343s; MS (CI) m/z (relative intensity): 212 (M+ +H, 100); Anal. Calcd. for C1OH15 NO3 : C 62.54; H 8.11; N 6.63. Found: C, 62.54; H, 8.12; N, 6.52.
Reaction SMILES: Cl.CS[C:4]1[NH:5][CH2:6][CH:7]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:8]=1.[NH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(O)C>[ClH:15].[O:23]1[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][NH:17][C:4]2[NH:5][CH2:6][CH:7]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[N:8]=2)[CH2:21][CH2:22]1
Reactant: CSC1=NC(c2c(Cl)cccc2Cl)CN1
Reactant: NCCN1CCOCC1
Agent: Cl
Solvent: CCO
Product: Clc1cccc(Cl)c1C1CNC(NCCN2CCOCC2)=N1
Temperature: 150 °C

Procedure:
A mixture consisting of 6.0 gm (0.0202 mol) of 2-methylmercapto-4-(2',6'-dichloro-phenyl)-2-imidazoline hydrochloride and 3.25 gm (0.025 mol) of N-(β-amino-ethyl)-morpholine was melted by heating it for 30 minutes at 150° C. Thereafter, while still hot, the molten mass was dissolved in ethanol and reprecipitated from solution by addition of ether. The precipitate, which solidified after some time, was collected and recrystallized from ethanol/acetone and, for further purification, briefly heated in boiling water in the presence of activated charcoal. The mixture was filtered, the filtrate was evaporated to dryness, and the residue was washed with acetone, yielding 3.0 gm (41.8% of theory) of the white crystalline compound of the formula ##STR11## which had a melting point of 225° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:35])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23](Br)[N:24]=3)[N:19](COCC[Si](C)(C)C)[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2].C(N(CC)CC)C.[C:43]([Si:45]([CH3:48])([CH3:47])[CH3:46])#[CH:44]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:1]([CH:3]1[CH2:4][CH2:5][N:6]([C:9](=[O:35])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:44]#[C:43][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:24]=3)[NH:19][CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:7][CH2:8]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cnc2[nH]cc(C(=O)N[C@@H](C(=O)N3CCC(C#N)CC3)C3CC3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (0.50 g, 0.89 mmol) (5:1 mix of 5-Br and 5-Cl) in DMF (3 mL) were added sequentially triethylamine (0.50 mL, 3.56 mmol), ethynyltrimethylsilane (0.15 mL, 1.07 mmol), Pd(PPh3)2Cl2 (31.2 mg, 0.045 mmol), and copper (I) iodide (8.5 mg, 0.045 mmol). Upon the addition of CuI all solids dissolved. The reaction mixture was stirred at room temperature for 30 min then heated at 50° C. for 1 h. The reaction mixture was cooled to room temperature, quenched with water and extracted with EtOAc (3×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (50% to 100% EtOAc/hexanes) to isolate 430 mg (83%) of 542-trimethylsilanyl-ethoxymethyl)-2-trimethylsilanylethynyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a brown foamy solid. NMR showed a trace of unreacted 5-Cl pyrrolopyrazine present.
Reaction SMILES: [C:1]1([C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([OH:14])=[O:13])O1)=[O:2].[NH3:15]>C(O)C>[C:1]1([C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([OH:14])=[O:13])[NH:15]1)=[O:2]
Reactant: O=C(O)c1cc2ccccc2c(=O)o1
Reactant: N
Solvent: CCO
Product: O=C(O)c1cc2ccccc2c(=O)[nH]1
Reaction time: 24 h

Procedure:
Isocoumarin-3-carboxylic acid (1.40g.) was added to a solution of ammonia (d. 0.88, 10ml.) in ethanol (40ml.) at 0° and allowed to stand for 24 hours. After removal of solvent in vacuo, 6N hydrochloric acid (70ml.) was added and allowed to stand for 1 hour at 0°. Filtration gave the product as a white solid, mp. 327°-330° (lit mp. 326°-8°), (Found: C, 62.91; H, 3.69; N, 7.46. C10H7NO3 requires C, 63.49; H, 3.73; N, 7.40).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:11][C@H:12]([NH2:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9]C.[BrH:15]>>[BrH:15].[OH:2][C:3]1[CH:4]=[C:5]([CH2:11][C@H:12]([NH2:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(C[C@@H](C)N)cc1OC
Agent: Br
Product: C[C@@H](N)Cc1ccc(O)c(O)c1

Procedure:
A solution of (R)-3-(3,4-dimethoxyphenyl)-2-propylamine hydrochloride1 (500 mg, 2.15 mMol) in hydrogen bromide (48%, 5 ml) was stirred at 100° C. under an argon atmosphere for 20 hours. After cooling, the solvent was evaporated and the residue was dried giving the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C(NC1SC=C(/C(=N/OC2CCNC2=O)/C(O)=O)N=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N[C@@H:45]1[C:62](=[O:63])[N:47]2[C:48]([C:59]([O-:61])=[O:60])=[C:49]([CH2:52][N+:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH2:50][S:51][C@H:46]12.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C>C(Cl)(Cl)Cl.O.C(N(CC)CC)C.CN(C)C=O>[N+:53]1([CH2:52][C:49]2[CH2:50][S:51][C@@H:46]3[CH2:45][C:62](=[O:63])[N:47]3[C:48]=2[C:59]([O-:61])=[O:60])[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C([O-])C1=C(C[n+]2ccccc2)CS[C@@H]2CC(=O)N12
Reaction time: 0.25 h

Procedure:
0.57 g of oxalyl chloride is added at -5° to 0° C. to 15 ml of chloroform containing 0.35 g of dimethylformamide, and the mixture is stirred at the same temperature for 15 minutes. A mixture of 1.54 g of (Z)-2-(2-tritylaminothiazol-4-yl)-2-[(2-pyrrolidon-3-yl)oxyimino]acetic acid, 0.3 g of triethylamine and 15 ml of chloroform is added to said mixture at -30° to -35° C., and the mixture is further stirred at the same temperature for 5 minutes. Then, a solution of 7β-amino-3-(1-pyridinio-methyl)-3-cephem-4-carboxylate in chloroform (said solution is prepared by suspending 1.82 g of the dihydrochloride of said cephem compound in 10 ml of chloroform and adding 4 ml of N,O-bis(trimethylsilyl)acetamide thereto to dissolve said salt therein) is added to said mixture at -35° to -30° C., and the mixture is stirred at the same temperature for 10 minutes and at -30° to -10° C. for one hour. The mixture is concentrated to dryness under reduced pressure. 60 ml of 80% aqueous formic acid are added to the residue, and the aqueous mixture is stirred at room temperature for one hour. 50 ml of water are added to said aqueous mixture. Then, insoluble materials are filtered off, and the filtrate is washed with ethyl acetate and concentrated to dryness under reduced pressure. The residue thus obtained is dissolved in water and chromatographed on a column of non-ionic polymer resin Diaion HP-20 (registered trade mark, manufactured by Mitsubishi Chemical Industries Ltd., Japan). The column is washed with water, followed by elution with 20% methanol. The fractions containing the cephalosporin compound are collected and concentrated to dryness under reduced pressure. Acetone is added to the residue thus obtained, and the resulting powder is collected by filtration. 0.84 g of 7β-{(Z)-2-(2-aminothiazol-4-yl)-2-(2-pyrrolidon-3-yl)oxyimino]acetamido}-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate is obtained.
Reaction SMILES: C(O[C:4](=[N:14][CH3:15])[CH2:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[F:13])C.[C:16]([NH2:22])(=[O:21])[C:17]([NH:19][NH2:20])=O.N>CN1CCOCC1.ClCCl>[F:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([F:13])[C:6]=1[CH2:5][C:4]1[N:14]([CH3:15])[C:17]([C:16]([NH2:22])=[O:21])=[N:19][N:20]=1
Reactant: CCOC(Cc1c(F)cccc1F)=NC
Reactant: NNC(=O)C(N)=O
Agent: N
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cn1c(Cc2c(F)cccc2F)nnc1C(N)=O

Procedure:
320 mg (1.5 mmol) of 1-ethoxy-2-(2,6-difluorophenyl)-1-(N-methylimino)-ethane and 155 mg (1.5 mmol) of oxalic acid monoamide monohydrazide are dissolved under a nitrogen atmosphere in 5 ml of N-methylmorpholine and the whole is heated under reflux for 41 hours. After cooling, the reaction mixture is diluted with 20 ml of dichloromethane and extracted by shaking in succession twice with water, twice with 2N hydrochloric acid and again with water The last three acidic aqueous phases obtained are combined, rendered alkaline with concentrated ammonia solution and extracted three times with dichloromethane. The combined organic phases are dried over magnesium sulphate and concentrated. Recrystallisation of the crude product from ethanol yields 102 mg (27% of the theoretical yield) of the desired 5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxamide which melts at 189°-190°.
Reaction SMILES: [CH2:1]=[N:2][N:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.N(N1CCC2C(=CC=CC=2)C1)=O>>[CH3:1][NH:2][N:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1
Reactant: C=NN1CCc2ccccc2C1
Agent: O=NN1CCc2ccccc2C1
Product: CNN1CCc2ccccc2C1
Yield: 95 %

Procedure:
Using N-methylene-3,4-dihydroisoquinolin-2 (1H)-amine and the compound (3.00 g, 18.5 mmol) obtained in step A, and according to the method of Reference Example 37, step B, the title compound (2.86 g, yield 95%) was obtained as a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C:8]2([NH:15][C:16]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[S:17])[CH:12]([CH2:13]O)[CH2:11][O:10][CH2:9]2)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C:8]23[CH2:9][O:10][CH2:11][CH:12]2[CH2:13][S:17][C:16]([NH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:15]3)[CH:7]=1
Reactant: O=C(NC(=S)NC1(c2cc(Br)ccc2F)COCC1CO)c1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NC1=NC2(c3cc(Br)ccc3F)COCC2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a 15° C. mixture of racemic N-((3SR,4RS)-3-(5-bromo-2-fluorophenyl)-4-(hydroxymethyl)tetrahydrofuran-3-ylcarbamothioyl)benzamide (110 g, 243 mmol) and triphenylphosphine (76.4 g, 291 mmol) in tetrahydrofuran (970 mL) is added di-tert-butyl azodicarboxylate (67.1 g, 291 mmol) in 3 portions over 10 minutes keeping internal temperature below 25° C. After the addition, the reaction mixture is stirred at 25° C. for 1 hour. The solvent is removed under reduced pressure and the residue is purified by silica gel chromatography using a linear gradient of 14% to 33% ethyl acetate in hexanes to give the title compound (80 g, 76%). ES/MS m/e (79Br/81Br) 435, 437 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[C:3]1=[O:18]>[Pd].C(O)C>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH:4]2[N:5]([CH3:8])[CH2:6][CH2:7][N:2]([CH3:1])[C:3]2=[O:18])=[CH:14][CH:13]=1
Reactant: CN1CCN(C)C(c2ccc([N+](=O)[O-])cc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(C)C(c2ccc(N)cc2)C1=O
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 3 (200 mg, 0.80 mmol), ethanol (5 mL) and 10% palladium on carbon (50% wet, 4 mg dry weight). The reaction flask was purged with hydrogen gas and the reaction mixture stirred under a balloon pressure of hydrogen for 2 h. After this time the flask was purged with nitrogen. The catalyst was removed by filtration through a pad of Celite 521 and the filter cake washed with ethanol (10 mL). The filtrate was concentrated under reduced pressure to afford a 94% yield of 4 (166 mg) as a colorless oil: 1H NMR (500 MHz, DMSO-d6) δ 6.89 (d, 2H, J=8.5 Hz), 6.47 (d, 2H, J=8.5 Hz), 4.94 (s, 2H), 3.53 (td, 1H, J=12.0, 4.0 Hz), 3.44 (m, 1H), 3.21 (dt, 1H, J=12.0, 4.0 Hz), 2.92 (dt, 1H, J=12.0, 4.0 Hz), 2.82 (s, 3H), 2.02 (s, 3H); MS (ESI+) m/z 220 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14](O)=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[Cl-].[NH4+:28]>>[NH2:28][C:14](=[O:15])[CH:13]([NH:12][C:10]([C:7]1[CH:6]=[C:5]([O:21][CH2:22][C:23]([F:25])([F:24])[F:26])[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:9][N:8]=1)=[O:11])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: [NH4+]
Reactant: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(=O)O
Agent: [Cl-]
Product: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoic acid (Example 194b) and ammonium chloride as starting materials and isolated (490 mg, 92%); MS (ESI, m/z): 374.5 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:3]([CH:24]([CH3:26])[CH3:25])=[N:4][C:5]([N:8]2[CH2:16][CH:15]3[C:10]([C:18]4[CH:23]=[N:22][CH:21]=[CH:20][N:19]=4)([N:11]=[C:12]([NH2:17])[S:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1.C(O)C>C(=O)=O>[F:1][C:2]1[C:3]([CH:24]([CH3:26])[CH3:25])=[N:4][C:5]([N:8]2[CH2:16][C@@H:15]3[C@@:10]([C:18]4[CH:23]=[N:22][CH:21]=[CH:20][N:19]=4)([N:11]=[C:12]([NH2:17])[S:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1
Reactant: CC(C)c1nc(N2CC3CSC(N)=NC3(c3cnccn3)C2)ncc1F
Agent: O=C=O
Solvent: CCO
Product: CC(C)c1nc(N2C[C@H]3CSC(N)=N[C@@]3(c3cnccn3)C2)ncc1F
Yield: 42.5 %

Procedure:
Racemic 6-(5-fluoro-4-isopropyl-pyrimidin-2-yl)-7a-pyrazin-2-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-amine (127 mg, 0.340 mmol) is separated into its constituent enantiomers by chiral SFC (Column: Chiralcel OD-H (5μ), 21.2×250 mm; eluent: 50% ethanol (0.2% diethylmethylamine) in CO2; flow: 70 mL/min at UV 260 nm). The first eluting isomer is the title compound (54 mg). ES/MS (m/e): 374 (M+1).
Reaction SMILES: C(C1SC(COC2C(C3CN(C)CCC=3)=NSN=2)=CC=1)CC.C([C:28]1[S:32][C:31]([CH2:33][CH2:34][CH2:35][O:36][C:37]2[C:41]([C:42]3[CH2:43][N:44]([CH3:48])[CH2:45][CH2:46][CH:47]=3)=[N:40][S:39][N:38]=2)=[CH:30][CH:29]=1)CCCC.S1C=CC=C1SCCCOC1C(C2CN(C)CCC=2)=NSN=1.S1C=CC=C1CCCSC1C(C2CN(C)CCC=2)=NSN=1.S1C=CC=C1CSC1C(C2CN(C)CCC=2)=NSN=1.O1CCN(CCCSC2C(C3CN(C)CCC=3)=NSN=2)C1=O.S1CCN(C2C(C3CN(C)CCC=3)=NS(SCCC)N=2)C1=O>>[CH3:48][N:44]1[CH2:45][CH2:46][CH:47]=[C:42]([C:41]2[C:37]([O:36][CH2:35][CH2:34][CH2:33][C:31]3[S:32][CH:28]=[CH:29][CH:30]=3)=[N:38][S:39][N:40]=2)[CH2:43]1
Reactant: CCCCCc1ccc(CCCOc2nsnc2C2=CCCN(C)C2)s1
Agent: CCCS[SH]1N=C(C2=CCCN(C)C2)C(N2CCSC2=O)=N1
Agent: CCCc1ccc(COc2nsnc2C2=CCCN(C)C2)s1
Agent: CN1CCC=C(c2nsnc2OCCCSc2cccs2)C1
Product: CN1CCC=C(c2nsnc2OCCCc2cccs2)C1

Procedure:
A compound according to claim 1, wherein the compound is: 3-(3-[2-(1-Pyrrolidinyl)ethoxy]-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1methylpyrid 3-(3-(3-(5-Methyl-2-thienyl)-1-propoxy)- 1,2,5-thiadiazol-4-yl)- 1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-( (5-Propyl-2-thienyl)methoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1methylpyridine; 3-(3-(3-(5-Pentyl-2-thienyl)-1-propoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-(3-(2-Thienylthio)-1-propoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; 3-(3-(3-(2-Thienyl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1methylpyridine; 3-(3-(2-Thienylmethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro- 1methylpyridine; 3-(3-(3-(2-Oxazolidinon-3-yl)-1-propylthio)-1,2,5-thiadiazol-4-yl )-1,2,5,6-tetrahydro- 1-methylpyridine; 3-(3-(3-(2-Thiazolidinon-3-yl)-1-propylthio- 1,2,5-thiadiazol-4yl)-1,2,5,6-tetrahydro- 1-methylpyridine; 3-(3-(5-Pentyl-2-thienyl)methylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyrid
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:24][CH2:25][O:26][CH3:27])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1[CH2:28][CH2:29][CH3:30])C1C=CC=CC=1>[C].[Pd].CO>[F:17][C:16]([F:18])([F:19])[C:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([CH2:28][CH2:29][CH3:30])[CH:11]=1)([O:24][CH2:25][O:26][CH3:27])[C:20]([F:21])([F:23])[F:22]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1O
Reaction time: 8 h
Yield: 104.7 %

Procedure:
A 10% palladium carbon catalyst (30 mg) was added to a mixed solution of 4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethyl)oxypropan-2-yl]-2-propylphenyl benzyl ether (264.9 mg, 0.61 mmol) in methanol (10 mL), followed by hydrogenation overnight. The catalyst was separated from the reaction solution by filtration, followed by concentration under reduced pressure to obtain 221.1 mg of the title compound (yield: 100%) as a pale yellow oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f6) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[O:16][CH2:17][CH2:18][CH3:19].[Li+].[OH-]>C1COCC1.CO>[CH2:17]([O:16][C:7]1[CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=[CH:11][C:6]=1[CH:5]=[CH:4][C:3]([OH:20])=[O:2])[CH2:18][CH3:19]
Reactant: CCCOc1cc(C(F)(F)F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOc1cc(C(F)(F)F)ccc1C=CC(=O)O
Yield: 72.2 %

Procedure:
3-(2-Propoxy-4-trifluoromethyl-phenyl)-acrylic acid methyl ester (198 mg) was reacted with 1N LiOH (5 ml) in THF (10 ml) and CH3OH (5 ml) for 1 hr. The reaction mixture was concentrated in vacuo. Water (30 ml) was added to the resulting residue, which was neutralized with 1N HCl solution. The mixture was extracted with ethyl acetate (30 ml×3). The combined organic layer was dried over MgSO4. The filterate was concentrated in vacuo to yield title compound (136 mg, 72%).