Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[CH2:19]([S:23](Cl)(=[O:25])=[O:24])[CH2:20][CH2:21][CH3:22]>>[CH2:19]([S:23]([NH:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1)(=[O:25])=[O:24])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCS(=O)(=O)Cl
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Product: CCCCS(=O)(=O)NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
Following the procedure described in example 1 but using 3-amino-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and butanesulfonylchloride, the title compound was obtained in a similar yield as a solid foam: 1H NMR (80 MHz, CDCl3)δ(TMS) 8.00 (s, 1H, CH=N), 7.83 (s, 1H, CH=N), 7.62 (d, J=8.5 Hz, 1H, arom), 7.4-7.1 (m, 2H, arom), 5.00 (AB system, Δv=0.56, J=14.5 Hz, 2H, CH2 -Tr), 4.88 (t, J=6.4 Hz, 1H, NH), 4.1-3.5 (m, 2H, CH2NH), 3.1-2.8 (m, 2H, NCH2CH2), 1.8-1.1 (m, 4H, NCH2CH2CH2), 1.1-0.7 (m, 3H, CH3). Anal calcd. for C15H20Cl2N4O3S: C 44.23%; H 4.95%; N 13.76%. Found: C 44.80%; H 5.37%; N 13.16%.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17]([OH:19])=[O:18])=[C:12]([C:15]#[CH:16])[CH2:13][S:14][C@H:9]12)=[O:6].C([O-])(=O)C.[Na+:32]>O1CCCC1.CO>[CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17]([O-:19])=[O:18])=[C:12]([C:15]#[CH:16])[CH2:13][S:14][C@H:9]12)=[O:6].[Na+:32]
Reactant: C#CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C#CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Yield: 100.1 %

Procedure:
To a solution of 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-ethynyl-3-cephem-4-carboxylic acid (syn isomer) (1.1 g) in tetrahydrofuran (22 ml) was added a solution of sodium acetate (0.234 g) in methanol (2.3 ml) at ambient temperature. After the mixture was stirred under ice-cooling for 30 minutes, the precipitates were collected by filtration to give sodium 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-ethynyl-3-cephem-4-carboxylate (syn isomer) (1.16 g).
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:35])[CH:14]([C:18]2[C:19]([CH3:34])=[N:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[CH:22][CH:23]=2)[CH2:15][CH2:16][CH3:17])=[CH:9][C:8]=1[CH2:36][CH2:37][CH2:38][O:39][CH3:40])C.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:40][O:39][CH2:38][CH2:37][CH2:36][C:8]1[CH:9]=[C:10]([N:13]([CH3:35])[CH:14]([C:18]2[C:19]([CH3:34])=[N:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[CH:22][CH:23]=2)[CH2:15][CH2:16][CH3:17])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:41])=[O:3]
Reactant: CCCC(c1ccc(-c2cccc(C(F)(F)F)c2)nc1C)N(C)c1ccc(OCC(=O)OCC)c(CCCOC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCC(c1ccc(-c2cccc(C(F)(F)F)c2)nc1C)N(C)c1ccc(OCC(=O)O)c(CCCOC)c1
Reaction time: 2 h

Procedure:
0.082 g (0.143 mmol) of the above prepared [rac]-[2-(3-methoxy-propyl)-4-(methyl-{1-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-butyl}-amino)-phenoxy]-acetic acid ethyl ester was dissolved in 1.64 ml of THF/EtOH=1/1, treated at 0° C. with 0.43 ml (3 eq.) of 1N NaOH, and kept at ambient temperature for 2 h. The reaction mixture was then neutralized with HCl dil. to pH 7, extracted with AcOEt, the organic layer was washed with water, dried over sodium sulfate, and evaporated to dryness to leave 0.070 g of the title compound as light brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][NH:16][C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.C(N(CC)C(C)C)(C)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[C:34]([N:16]1[C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[CH2:19][N:20]2[C:11]([C:9]([NH:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:10])=[CH:12][CH:13]=[C:14]2[CH2:15]1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1NC2
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 21 h
Yield: 80.2 %

Procedure:
To a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Step C (300 mg, 0.942 mmol) in dry tetrahydrofuran (15 mL) at room temperature under nitrogen was added N,N-diisopropylethylamine (0.26 mL, 1.508 mmol) followed by benzoyl chloride (0.165 mL, 1.41 mmol) and the reaction mixture stirred at room temperature for 21 hours. The reaction was quenched by the addition of 2 M sodium hydroxide (5 mL) and then the mixture partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The organic phase was washed with 2 M sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to afford a yellow syrup. Purification by flash chromatography using a solvent gradient of 0 to 4% methanol in dichloromethane gave a white foam that was crystallized from diethyl ether/hexane to give the title compound (0.319 g, 80%) as a white crystalline solid, m.p. 197° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4](Cl)[N:3]=1.[F:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]2[NH:40][CH:41]=[CH:42][C:35]=12)[NH2:29].Cl.C(=O)(O)[O-].[Na+]>O.C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([NH:29][C:28]2[CH:30]=[CH:31][C:32]([O:33][C:34]3[CH:39]=[CH:38][N:37]=[C:36]4[NH:40][CH:41]=[CH:42][C:35]=34)=[C:26]([F:25])[CH:27]=2)[N:3]=1
Reactant: Nc1nc(Cl)cc(C2CCCN(C(=O)OCc3ccccc3)C2)n1
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1nc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)cc(C2CCCN(C(=O)OCc3ccccc3)C2)n1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
1.05 g (2.89 mmol) of benzyl 3-(2-amino-6-chloropyrimidin-4-yl)piperidine-1-carboxylate (from example LXXII) and 0.75 g (2.89 mmol) of [3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]amine (from example XIX) are suspended in 35 ml of water and 4 ml of ethanol. 0.29 ml (3.47 mmol) of 37% strength hydrochloric acid is added. The mixture is stirred at 100° C. for 18 hours. After cooling, the mixture is neutralized using a saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate (in each case 30 ml). The organic phase is dried over anhydrous magnesium sulfate and concentrated. The residue is purified on a silica gel column using dichloromethane/methanol 20:1. This gives 1.38 g (86% of theory) of product.
Reaction SMILES: Cl.C([O:9][CH2:10][C@H:11]([NH:26]C(=O)OC(C)(C)C)[CH2:12][O:13][CH2:14][C:15](=O)[C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18]([F:24])[CH:17]=1)C1C=CC=CC=1>C(OCC)(=O)C>[F:24][C:18]1[CH:17]=[C:16]([C@H:15]2[NH:26][C@@H:11]([CH2:10][OH:9])[CH2:12][O:13][CH2:14]2)[CH:21]=[C:20]([F:22])[C:19]=1[F:23]
Reactant: CC(C)(C)OC(=O)N[C@H](COCC(=O)c1cc(F)c(F)c(F)c1)COCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: OC[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
A solution of 4 N hydrochloric acid in ethyl acetate (30 mL) was added to a solution of tert-butyl {(S)-1-benzyloxymethyl-2-[2-oxo-2-(3,4,5-trifluorophenyl)ethoxy]ethyl}carbamate (3.55 g) in ethyl acetate (30 mL) at room temperature. The reaction solution was stirred at room temperature for one hour and then concentrated under reduced pressure. 10% palladium-carbon (containing 50% water, 167 mg) was added to a solution of the resulting residue in methanol (50 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for 18 hours. Palladium-carbon in the reaction solution was removed by filtration, and then the filtrate was concentrated under reduced pressure. A saturated sodium bicarbonate solution and ethyl acetate were added to the resulting residue, and the organic layer was separated. The organic layer was washed with brine. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.52 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[N:9]([CH2:27][CH3:28])[C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])[CH:13]=[C:12]([CH3:26])[N:11]=1.[CH3:29][S-:30].[Na+]>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([S:30][CH3:29])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:27][CH3:28])[C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])[CH:13]=[C:12]([CH3:26])[N:11]=1
Reactant: CCN(c1nc(C)cc(-c2ccccc2C(F)(F)F)n1)c1ccc(Br)cc1Br
Reactant: C[S-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCN(c1nc(C)cc(-c2ccccc2C(F)(F)F)n1)c1ccc(SC)cc1Br

Procedure:
The product from Example 15 (450 mg), dimethylsulfoxide (12 mL), tetrakis(triphenylphosphine)Pd(0) (40 mg), and sodium thiomethoxide (61 mg) were heated at reflux 18 hours. The reaction was cooled, taken up and partitioned between ethyl acetate (100 mL) and water (100 mL). The ethyl acetate was washed with brine, dried over MgSO4, and concentrated to dryness. The crude product was chromatographed on silica gel giving the title compound (90 mg). CI-HRMS calcd. for C21H20N3F3SBr (M+H)+ : 482.051340. Found: 482.051434.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C@H:11]1[CH2:15][CH2:14][C@H:13]([OH:16])[C@@H:12]1[OH:17].[CH3:18][C:19]1([CH3:44])[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[C:25]2[CH:24]=[C:23]([C:31]3[N:36]=[C:35]([N:37]4[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]4)[CH:34]=[CH:33][CH:32]=3)[CH:22]=[CH:21][C:20]1=2.Cl>>[CH3:18][C:19]1([CH3:44])[CH2:28][CH2:27][C:26]([CH3:29])([CH3:30])[C:25]2[CH:24]=[C:23]([C:31]3[N:36]=[C:35]([N:37]4[CH2:42][CH2:41][CH:40]([NH:10][C@H:11]5[CH2:15][CH2:14][C@H:13]([OH:16])[C@@H:12]5[OH:17])[CH2:39][CH2:38]4)[CH:34]=[CH:33][CH:32]=3)[CH:22]=[CH:21][C:20]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(=O)CC4)n3)ccc21
Reactant: N[C@H]1CC[C@H](O)[C@@H]1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(N[C@H]5CC[C@H](O)[C@@H]5O)CC4)n3)ccc21

Procedure:
The preparation is carried out analogously to FS1007 without addition of DIPEA starting from 23 mg (0.199 mmol) of (1S,2R,3S)-3-aminocyclopentane-1,2-diol and 80 mg (0.199 mmol) of 6′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2,3,5,6-tetrahydro-1,2′-bipyridinyl-4-one. The product is in the form of the hydrochloride.
Reaction SMILES: I[C@@H:2]1[C@@H:8]2[CH2:9][C@@H:5]([C:6](=[O:10])[O:7]2)[CH2:4][CH2:3]1.[OH-].[Na+].[CH2:13]([OH:15])[CH3:14]>>[C@@H:3]12[O:15][C@@H:13]1[CH2:14][CH2:9][C@H:5]([C:6]([O:7][CH2:8][CH3:2])=[O:10])[CH2:4]2
Reactant: O=C1O[C@H]2C[C@@H]1CC[C@@H]2I
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)[C@H]1CC[C@H]2O[C@H]2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(1S,4S,5S)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-one (J. Org. Chem., 1996, Vol. 61, p. 8687) (89.3 g) was suspended in ethanol (810 ml), a 2N aqueous solution (213 ml) of sodium hydroxide was added, and the mixture was then stirred at room temperature for 3 hours. After the solvent was distilled off under reduced pressure, and water was added to the residue to conduct extraction with methylene chloride, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=17:3) to obtain the title compound (41.3 g).
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20](OCC)(=[O:24])[C:21]([NH2:23])=[O:22]>C(O)C>[CH2:1]([NH:19][C:20]([C:21]([NH2:23])=[O:22])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: CCOC(=O)C(N)=O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCNC(=O)C(N)=O
Temperature: 25 °C

Procedure:
13.5 Grams of octadecylamine, 6.4 g of ethyl oxamate and 200 ml of ethanol were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and refluxed with heating for 1 hour. The reaction mixture was cooled to room temperature and the precipitated crystal was filtered off under reduced pressure and was recrystallized from ethanol to obtain 12.8 g of the desired product. m.p. 169° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][N:5]([CH2:7]O)[CH:6]=1.S(Cl)([Cl:15])=O>ClCCl>[Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][N:5]([CH2:7][Cl:15])[CH:6]=1
Reactant: OCn1cc(Br)c(C(F)(F)F)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1nn(CCl)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.28 g of 4-bromo-3-(trifluoromethyl)-1H-pyrazole-1-ylmethanol was dissolved to 40 ml of dichloromethane. 2.9 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure. The obtained solid was washed with the mixture of hexane and chloroform to obtain 3.33 g of 4-bromo-1-(chloromethyl)-3-(trifluoromethyl)-1H-pyrazole.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30].C(N(CC)CC)C>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:27]=4[O:26][CH3:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc(Cl)ccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Cl)ccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
As described for Example 9, a mixture of 0.377 g (1 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.295 g of 2-methoxy-4-chlorobenzoyl chloride, and 0.15 g of triethylamine in 10 ml of dichloromethane is stirred at room temperature for 3 hours. An additional 0.148 g of 2-methoxy-4-chlorobenzoyl chloride and 75 mg of triethylamine is added and the mixture stirred overnight. The solution is worked-up as for Example 9 to give 0.38 g of product (crystallized from dichloromethane-hexane) m.p. 237°-239° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([NH:20][C:21]2[S:22][C:23]([CH:26]=O)=[CH:24][N:25]=2)[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1.O1CCCC1>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:26][C:23]1[S:22][C:21]([NH:20][C:10]2[CH:11]=[CH:12][C:13]([N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]3)=[C:8]([O:7][CH3:6])[CH:9]=2)=[N:25][CH:24]=1
Reactant: COCCN
Reactant: COc1cc(Nc2ncc(C=O)s2)ccc1-n1cnc(C)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCCNCc1cnc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)s1

Procedure:
The title compound was prepared in analogy to example 57 from 14 mg (0.19 mmol) 2-methoxyethylamine and 65 mg (0.21 mmol) 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazole-5-carbaldehyde using a solvent mixture of tetrahydrofurane (2 ml), and methylene chloride (1 ml). The reaction was not complete and the same amount of reagent was added like in example 57. The crude product was purified on silica gel with methylene chloride/methanol 9/1 yielding 47 mg (54%) {5-[(2-methoxy-ethylamino)-methyl]-thiazol-2-yl}-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a yellow oil. MS ISP (m/e): 374.2 (100) (M+H)+. 1H NMR (CDCl3, 250 MHz): δ (ppm)=7.64 (s, 1H), 7.26 (s, 1H), 7.18 (d, 1H), 7.12 (s, 1H), 6.95 (d, 1H), 6.87 (s, 1H), 3.93 (s, 2H), 3.85 (s, 3H), 3.51 (t, 2H), 3.36 (s, 3H), 2.83 (t, 2H), 2.30 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[S:6]1(=[O:24])=[O:23].[CH3:25][NH2:26].Cl>>[ClH:1].[CH3:22][O:21][C:17]1[CH:16]=[C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:26][CH3:25])[S:6]2(=[O:24])=[O:23])[CH:20]=[CH:19][CH:18]=1
Reactant: CN
Reactant: COc1cccc(N2c3ccccc3CN(CCCCl)S2(=O)=O)c1
Agent: Cl
Product: CNCCCN1Cc2ccccc2N(c2cccc(OC)c2)S1(=O)=O

Procedure:
In an analogous manner to Example 1, step 8, 3-(3-chloropropyl)-1-(3-methoxyphenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (33 mg) was reacted with methylamine and then treated with HCl to provide 3-[1-(3-methoxyphenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine hydrochloride (21 mg):
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[CH2:11][C@H:10]([N:22]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:23]([C:25]2[N:29]([CH2:30][CH2:31][C:32]([OH:34])=O)[C:28]3[CH:35]=[CH:36][CH:37]=[CH:38][C:27]=3[N:26]=2)=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[N:44]1(O)C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[NH2:44][C:32](=[O:34])[CH2:31][CH2:30][N:29]1[C:28]2[CH:35]=[CH:36][CH:37]=[CH:38][C:27]=2[N:26]=[C:25]1[C:23]([N:22]([CH2:39][CH:40]([CH3:41])[CH3:42])[C@H:10]1[CH2:11][C@@H:12]([C:14]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[O:15])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:24]
Reactant: CC(C)CN(C(=O)c1nc2ccccc2n1CCC(=O)O)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCC(N)=O)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.7 %

Procedure:
3-(2-{[(3S,5R)-1-(tert-Butoxycarbonyl)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl](2-methylpropyl) carbamoyl}-1H-benzimidazol-1-yl)propanoic acid (215 mg) and 1H-1,2,3-benzotriazol-1-ol ammonium salt (84 mg) were dissolved in DMF (5 ml), WSC.HCl (142 mg) was added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (199 mg).
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([CH2:18][CH:19]([F:21])[F:20])[C:16]#[N:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([Li])CCC.IC>C1COCC1>[C:1]1([C:7](=[N:14][C:15]([CH3:22])([CH2:18][CH:19]([F:20])[F:21])[C:16]#[N:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: N#CC(CC(F)F)N=C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CI
Product: CC(C#N)(CC(F)F)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
13.07 g (38.62 mmol) of rac-2-[(diphenylmethylene)amino]-4,4-difluorobutanonitrile from Example 67A were initially charged in 255 ml of abs. THF, and 15.6 ml (39.0 mmol) of n-butyllithium (2.5 N in hexane) were added at −78° C. under argon, and the mixture was stirred at −78° C. for a further 10 min. Subsequently, 22.6 g (154.46 mmol) of iodomethane were added to the reaction solution at −78° C. The reaction mixture was gradually brought to 0° C. over 3.5 h. After complete depletion of the starting material, the reaction solution was quenched with water at 0° C., ethyl acetate was added and the mixture was washed twice with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate=15/1). 11.4 g of the target compound were obtained (91% of theory, 92% purity).
Reaction SMILES: [C:1]([CH2:5][N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]([NH:17][C:18]([C:20]2[NH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([Cl:29])=[CH:24][CH:23]=3)=[O:19])[C:7]1=[O:8])([O:3]C)=O.[NH3:30]>O1CCCC1.CO>[NH2:30][C:1]([CH2:5][N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]([NH:17][C:18]([C:20]2[NH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([Cl:29])=[CH:24][CH:23]=3)=[O:19])[C:7]1=[O:8])=[O:3]
Reactant: N
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)CN1C(=O)[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-1-carbomethoxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril (Example 8) (5 mg) was dissolved in a mixture of tetrahydrofuran (1 mL) and 2 M ammonia in methanol solution (2 mL). After stirring for 16 h at room temperature, the solvent was evaporated and the residue was coevaporated with methanol (3 mL twice) under vacuum. Purification by reverse phase preparative HPLC provided the title compound (2.2 mg). HPLC/MS [M+H]+, 397.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[CH:7][N:6]=1>O1CCOCC1.O>[Br:4][C:5]1[N:6]=[CH:7][C:8]([CH2:11][C:1]#[N:2])=[CH:9][CH:10]=1
Reactant: BrCc1ccc(Br)nc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#CCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 44 %

Procedure:
To a stirred solution of NaCN (117 g, 2.38 mol) in dioxane (1 L) and water (1 L), was added the above crude 2-bromo-5-bromomethylpyridine (275 g) and the mixture was stirred at rt for 15 h. The reaction mixture was quenched with cold water (15 L) and extracted with EtOAc (3×1 L). The organic layer was washed with water (3×1 L), brine (2×1 L), dried with Na2SO4 and concentrated under reduced pressure to give crude title compound. The crude residue was purified by column chromatography over silica gel (pet. ether/ethylacetate, 7:3) to give 95 g (6-bromopyridin-3-yl)acetonitrile as a pale yellow solid (49%). [TLC, Rf=0.5, pet. ether/ethylacetate 7:3]