Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].Cl.C([CH:24]([NH2:76])[C@H:25]1[O:29][C:28](=[O:30])[N:27]([C:31]2[CH:74]=[CH:73][C:34]([O:35][CH2:36][C:37]3([O:43][C:44](=[O:72])[CH:45]([NH:61][C:62]([O:64][CH2:65][C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)=[O:63])[CH2:46][CH2:47][CH2:48][CH2:49][NH:50][C:51]([O:53][CH2:54][C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)=[O:52])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[C:33]([F:75])[CH:32]=2)[CH2:26]1)(=O)C.C(N(CC)CC)C.C[Si](C)(C)Cl.CN1CC[CH2:92][C:91]1=[O:95]>>[C:91]([NH:76][CH2:24][C@@H:25]1[O:29][C:28](=[O:30])[N:27]([C:31]2[CH:74]=[CH:73][C:34]([O:35][CH2:36][C:37]3([O:43][C:44](=[O:72])[CH:45]([NH:61][C:62]([O:64][CH2:65][C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)=[O:63])[CH2:46][CH2:47][CH2:48][CH2:49][NH:50][C:51]([O:53][CH2:54][C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)=[O:52])[CH2:42][CH2:41][N:40]([C:2]4[N:11]=[C:10]5[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]5[CH:12]5[CH2:14][CH2:13]5)=[CH:4][C:3]=4[F:19])[CH2:39][CH2:38]3)=[C:33]([F:75])[CH:32]=2)[CH2:26]1)(=[O:95])[CH3:92]
Reactant: CC(=O)C(N)[C@@H]1CN(c2ccc(OCC3(OC(=O)C(CCCCNC(=O)OCc4ccccc4)NC(=O)OCc4ccccc4)CCNCC3)c(F)c2)C(=O)O1
Reactant: CN1CCCC1=O
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)C(CCCCNC(=O)OCc4ccccc4)NC(=O)OCc4ccccc4)CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1

Procedure:
In analogy to example 1 step 7, with 62 mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[1,8]naphthyridine-3-carboxylic acid (MW: 282.66, 0.25 mmol), 178 mg 2,6-bis-benzyloxycarbonylamino-hexanoic acid 4-{4-[5-(55)-(acetyl-amino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxy-methyl}-piperidin-4-yl ester hydrochloride (MW: 814.31, 0.22 mmol), 90 mg triethylamine (MW: 101.19, 0.88 mmol) and 48 mg trimethylchlorsilan (MW: 108.64, 0.44 mmol) in 1 ml N-methyl-pyrrolidin-2-one. Yield: 94 mg, 42%. MS: 1025.3 (M+H)+, Method ESI+.
Reaction SMILES: [OH:1][C:2]([OH:23])([OH:22])[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][CH2:18][C:19]([OH:21])=[O:20].Cl.[CH2:25](O)[CH3:26]>>[CH2:25]([O:20][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([OH:1])([OH:22])[OH:23])[CH3:26]
Reactant: CCO
Reactant: O=C(O)CCCCCCCCCCCCCCCCC(O)(O)O
Agent: Cl
Product: CCOC(=O)CCCCCCCCCCCCCCCCC(O)(O)O

Procedure:
3 kg of trihydroxystearic acid are suspended in 10 l of absolute ethanol. Hydrogen chloride gas is slowly introduced at room temperature whilst stirring, until the acid has almost completely dissolved. The alcoholic ester solutionh is freed of a slight residue by filtration; thereafter the ester is precipitated by pouring the alcoholic solution into a 10-fold volume of water. The ester is filtered off and dried. The excess ethanol is recovered from the filtrate by distillation.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[C:5]([C:19]([O:21][CH3:22])=[O:20])=[N:6][C:7]=1[NH:8][C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@@H:10]1[OH:18].[CH3:31][O-:32].[Na+].[CH3:34]O>CCOC(C)=O>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:4]1[C:5]([C:19]([O:21][CH2:22][CH3:34])=[O:20])=[N:6][C:7]([NH:8][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[OH:18])=[C:2]([O:32][CH3:31])[N:3]=1
Reactant: C[O-]
Reactant: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(Br)nc1-c1ccc(Cl)cc1Cl
Reactant: CO
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(OC)nc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 73 %

Procedure:
To a solution of methyl 5-bromo-3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate (0.19 g, 0.37 mmol) in MeOH (3.7 mL) was added NaOMe (60 mg, 1.1 mmol). The mixture was heated at reflux for 3 hr. Cool to rt, and dilute with EtOAc. Wash with sat. aq. NaHCO3. Dry organic extract over MgSO4, filter and concentrate. Purify by biotage MPLC (90 g column, 25% ethyl acetate/hexanes) to afford 0.15 g (73%) of ethyl 3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-5-methoxypyrazine-2-carboxylate as a solid: 1H NMR (CDCl3) δ 3.07–3.12, 3.25–3.31, 3.76, 4.04, 4.85–4.89, 5.68–5.76, 7.28–7.49; MS (ESI+) for C22H19Cl2N3O4 m/z 460 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8](O)[CH2:9][C:10]#[CH:11])[CH:2]=1.[H][H].C[OH:16]>[Pd].C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:16])[CH:2]=1
Reactant: CO
Reactant: C#CCC(O)Cc1cccnc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: OCCCCCc1cccnc1
Yield: 97 %

Procedure:
5-(3-Pyridyl)-1-pentyn-4-ol (0.776 g, 4.82 mmol) was added to a stirred suspension of 10% palladium on charcoal (0.2 g) in methanol (30 ml). The reaction was stirred at room temperature under a hydrogen atmosphere for 48 h, by which time hydrogen uptake had ceased. The mixture was filtered through celite and evaporated to provide a yellow oil. Column chromatography (flash silica gel, 5% methanol in ethyl acetate) gave 5-(3-pyridyl)-1-pentanol (0.769 g, 97%) as a colourless oil.
Reaction SMILES: [OH:1][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][C:17]([OH:19])=[O:18].[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1.Cl>CO.C(OCC)C.O1CCCC1>[Si:20]([O:1][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][C:17]([OH:19])=[O:18])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Agent: Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.6 %

Procedure:
50 ml of a dry tetrahydrofuran solution containing 1 g of 16-hydroxyhexadecanoic acid, 1.1 g of tert-butyldimethylsilyl chloride and 0.75 g of imidazole, was stirred at room temperature for 12 hours under an inert atmosphere of nitrogen gas. The solvent was distilled off under reduced pressure, and then 200 ml of ethyl acetate was added. The mixture was washed three times with 200 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a syrup product. Then, 40 ml of diethyl ether, 30 ml of methanol and 30 ml of 1N hydrochloric acid were added thereto, and the mixture was stirred at room temperature for 15 minutes. The solvent was distilled off under reduced pressure, and then 200 ml of ethyl acetate was added. The mixture was washed once with 200 ml of a saturated sodium hydrogencarbonate aqueous solution and then washed twice with 200 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a syrup product. This product was purified by silica gel column chromatography (ethyl acetate: hexane =1:1) to obtain 1.4 g of 16-tert-butyldimethylsilyloxyhexadecanoic acid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24]>ClCC(Cl)(Cl)Cl>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:9]
Reactant: Cc1cccc(C(=O)Cl)n1
Reactant: COc1ccccc1OC
Agent: ClCC(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2cccc(C)n2)cc1OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled, stirred suspension of 6-methylpicolinic acid chloride and 2 equivalents of aluminum chloride in tetrachloroethane is added slowly an equivalent amount of 1,2-dimethoxybenzene. The reaction mixture is allowed to come to room temperature overnight, then decomposed over cracked ice. Extractive workup followed by chromatography of the organic residue gives the desired ketone.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[O:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[C:20]([C:27](OC)=[O:28])=[CH:19]1>O1CCCC1>[OH:28][CH2:27][C:20]1[C:21]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[O:18][CH:19]=1
Reactant: COC(=O)c1coc2ncccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1coc2ncccc12
Temperature: -75 °C
Reaction time: 0.67 h
Yield: 92.6 %

Procedure:
Diisobutylaluminium hydride in toluene (1.5M; 2.4 ml, 3.6 mmol) was added dropwise to a solution of methyl furo[2,3-b]pyridine-3-carboxylate (0.28 g, 1.58 mmol) in tetrahydrofuran (10 ml) at -75° C. The resulting solution was stirred at -75° C. for 40 minutes, the cooling bath removed and the mixture allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 15 minutes, recooled to -40° C. and quenched by sequential addition of methanol (0.5 ml), water (0.25 ml) and 2M sodium hydroxide (0.25 ml). The mixture was allowed to warm up to produce a gel (exotherm observed), which was filtered off and washed with dichloromethane (8×10 ml). The filtrate was evaporated, the residue redissolved in dichloromethane and the solution dried (MgSO4). The solution was concentrated in vacuo to afford the title compound (0.2182 g, 93%) as a colourless solid; δH (CDCl3) 1.94 (1H, br s, CH2OH), 4.85 (2H, s, CH2OH), 7.26 (1H, dd, J 7.6, 4.9 Hz, 5-H), 7.69 (1H, s, 2-H), 8.05 (1H, dd, J 7.6, 1.7 Hz, 4-H), 8.34 (1H, dd, J 4.9, 1.7 Hz, 6-H).
Reaction SMILES: [OH-:1].[Na+].C([C:5]1[CH:31]=[C:30]([F:32])[C:8]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:19]=[N:20][N:21]([CH2:23]C(NC(C)C)=O)[CH:22]=3)[N:12]=2)=[C:7]([F:33])[CH:6]=1)#N.Cl.C1[CH2:39][O:38]CC1.CO>>[F:32][C:30]1[CH:31]=[C:5]([CH:6]=[C:7]([F:33])[C:8]=1[CH2:9][NH:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]2[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=2)[N:12]=1)[C:39]([OH:38])=[O:1]
Reactant: C1CCOC1
Reactant: [OH-]
Reactant: CC(C)NC(=O)Cn1cc(Nc2nccc(NCc3c(F)cc(C#N)cc3F)n2)cn1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cn1cc(Nc2nccc(NCc3c(F)cc(C(=O)O)cc3F)n2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2M NaOH(aq) (2 mL, 4 mmol) was added to a stirred mixture of methyl 3,5-difluoro-4-(((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)methyl)benzoate (370 mg, 1 mmol, prepared by Procedure A) in 3:1 v/v THF/MeOH (40 mL) and the reaction was stirred at room temperature overnight. The mixture was neutralized with 1M hydrochloric acid and concentrated in vacuo to afford 3,5-difluoro-4-(((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)methyl)benzoic acid (theoretically 360 mg) which was used in the next step without purification.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([C:17]1[N:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)C>C1(C)C=CC=CC=1>[C:1]1([N:7]2[C:19](=[O:20])[C:18]3[CH:22]=[CH:23][CH:24]=[N:25][C:17]=3[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: O=C(O)c1cccnc1C(=O)c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=c1c2cccnc2c(-c2ccccc2)nn1-c1ccccc1
Reaction time: 7 h

Procedure:
A mixture of phenylhydrazine (5.0 g) and 2-benzoylnicotinic acid (3.25 g) in toluene was stirred at the reflux temperature for 7 hours. The solvent was then evaporated and the residue was purified by chromatography to give the crude product which, on trituration with diethyl ether, yielded the title compound as a yellow solid, 0.41 g, m.p. 173.5°-176.5° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[ClH:1].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]2([CH2:16][CH3:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:30][CH2:31]1
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Reactant: Clc1ccc(N2CCNCC2)c(Cl)c1
Product: CCC1(CCCCN2CCN(c3ccc(Cl)cc3Cl)CC2)C(=O)Nc2ccccc21
Product: Cl

Procedure:
The title compound is prepared according to process H by applying processing method 2 starting from 3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(2,4-dichloro-phenyl)-piperazine.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH2:60])[S:57][C:47]=2[C:48]([CH:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[N:49][CH:50]=1>C1COCC1>[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH:60][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][N:11]=[C:3]([CH3:2])[CH:4]=3)[S:57][C:47]=2[C:48]([CH:51]2[CH2:52][CH2:53][O:54][CH2:55][CH2:56]2)=[N:49][CH:50]=1
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: COc1cnc(C2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(C2CCOCC2)c2sc(NC(=O)c3ccnc(C)c3)nc12

Procedure:
From 2-methyl-isonicotinic acid hydrochloride, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-(tetrahydro-pyran-4-yl)-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 385 (M+H+, 100).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)C.CC(C)=O.S(=O)(=O)(O)O>O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH:4]=[O:3])=[CH:8][CH:9]=1
Reactant: CCOC(COc1ccc(F)cc1)OCC
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: O=CCOc1ccc(F)cc1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
A mixture of 4-fluorophenoxyacetaldehyde diethyl acetal (30.0 g., 0.131 mole) acetone (150 ml.), water (150 ml.), and concentrated sulfuric acid (0.8 ml.) is refluxed overnight (ca. 16 hours). The mixture is allowed to cool to room temperature, and is then extracted with methylenechloride four times. The combined extracts are washed with aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent is stripped off on a rotary evaporator and the oil residue is subsequently distilled in vacuo at 70°/0.05 mm to give the title compound (19.0 g., 0.123 mole, 94%). ir (neat) 3.23, 3.50, 3.63, 5.71, 6.62, 7.00, 8.00, 8.24, 9.07, 9.38, 12.03, 12.51, 13.12δ; pmr (CCl4) δ 4.37 (2H, d, J=1Hz), 6.6-7.1 (4H, m), 9.68 (1H, t, J=1Hz).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:7]=[C:8]([CH:17]2[NH:21][CH2:20][CH2:19][S:18]2)[CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31]>O1CCCC1>[C:13]([C:10]1[CH:9]=[C:8]([CH:17]2[N:21]([C:29](=[O:32])[CH:30]=[CH2:31])[CH2:20][CH2:19][S:18]2)[CH:7]=[C:6]([C:2]([CH3:3])([CH3:4])[CH3:5])[C:11]=1[OH:12])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1cc(C2NCCS2)cc(C(C)(C)C)c1O
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCSC1c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 53.5 %

Procedure:
To a suspension of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazolidine hydrochloride (1.65 g) obtained in Reference Example 61 in tetrahydrofuran (20 ml) was added triethylamine (1.52 g), and acryloyl chloride (0.63 g) was added thereto at 0° C. The mixture was stirred at that temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into ice-water; and the product was extracted with chloroform. The organic layer was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate, and brine, then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform-methanol, 98:2) to afford 0.93 g (54%) of the title compound as colorless crystals. mp 147-149° C. NMR (CDCl3) (200 MHz) δ: 1.40 (18H, s), 3.0-3.2 (2H, m), 3.8-4.0 (1H, m), 4.2-4.5 (1H, m), 5.20 (1H, brs), 5.5-5.8 (1H, m), 5.9-6.6 (3H, m), 6.98 (2H, brs)
Reaction SMILES: FC(F)(F)C([O-])=O.[NH2:8][C:9]1[C:10]([C:17]([NH:19][C@H:20]2[CH2:25][CH2:24][CH2:23][N+:22]([CH2:41][CH2:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH2:51][C:52]([O:54]C)=[O:53])[CH:45]=3)([CH2:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][C:37]([O:39]C)=[O:38])[CH:30]=3)[CH2:21]2)=[O:18])=[N:11][C:12]([Cl:16])=[C:13]([NH2:15])[N:14]=1.Cl>O1CCOCC1>[Cl-:16].[C:52]([CH2:51][O:50][C:46]1[CH:45]=[C:44]([CH2:43][CH2:42][CH2:41][N+:22]2([CH2:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][C:37]([OH:39])=[O:38])[CH:30]=3)[CH2:23][CH2:24][CH2:25][C@H:20]([NH:19][C:17]([C:10]3[C:9]([NH2:8])=[N:14][C:13]([NH2:15])=[C:12]([Cl:16])[N:11]=3)=[O:18])[CH2:21]2)[CH:49]=[CH:48][CH:47]=1)([OH:54])=[O:53]
Reactant: COC(=O)COc1cccc(CCC[N+]2(CCCc3cccc(OCC(=O)OC)c3)CCC[C@H](NC(=O)c3nc(Cl)c(N)nc3N)C2)c1
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: C1COCCO1
Product: Nc1nc(N)c(C(=O)N[C@H]2CCC[N+](CCCc3cccc(OCC(=O)O)c3)(CCCc3cccc(OCC(=O)O)c3)C2)nc1Cl
Product: [Cl-]

Procedure:
(S)3-[(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-amino]-1,1-bis-[3-(3-methoxycarbonylmethoxy-phenyl)-propyl]-piperidinium trifluoroacetate (2.67 g, 3.8 mmol)) is dissolved in dioxane (20 ml) and 6N HCl (20 ml, 120 mmol) and stirred at room temperature for 3 days and solvent is removed in vacuo. LC (method L)): tR=1.06 min; Mass spectrum (ESI+): m/z=655 [M]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].F[C:14]1[CH:19]=[CH:18][C:17]([S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:16]([N+:27]([O-:29])=[O:28])[CH:15]=1.O>C(#N)C.C(Cl)Cl>[N+:27]([C:16]1[CH:15]=[C:14]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:19]=[CH:18][C:17]=1[S:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1cc(F)ccc1Sc1ccccc1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1cc(N2CCNCC2)ccc1Sc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a mixture of piperazine (1.0 g, 12 mmol) and potassium carbonate (2.0 g, 14 mmol) in 80 mL of dry acetonitrile is added 4-fluoro-2-nitro-1-(phenylsulfanyl) benzene (2, EXAMPLE 1, step 1, 2.7 g, 9.5 mmol). The mixture is allowed to stir overnight at rt. Water and CH2Cl2 (80 mL each) are added and the layers separated. The aqueous layer is extracted with CH2Cl2 (3×50 mL). The combined organic layers are dried over MgSO4, filtered, and concentrated. Purification via column chromatography (50% EtOAc/hexane) gives 1.6 g (47%) of the title compound as a red oil.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([Cl:15])(=O)C>>[Cl-:15].[CH:4](=[N+:2]([CH3:3])[CH3:1])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CNC
Reactant: O=Cc1ccccc1
Reactant: CC(=O)Cl
Product: C[N+](C)=Cc1ccccc1
Product: [Cl-]

Procedure:
The reaction of 32.0 ml (0.213 mol) dimethylamine solution and 8.0 ml (0.079 mol) benzaldehyde in accordance with general synthesis instructions 1 and subsequent reaction with 4.7 ml (0.079 mol) acetyl chloride in accordance with general synthesis instructions 3 gave 9.5 g (corresponding to 70.7% of the yield calculated by theory) benzylidene-dimethyl-ammonium chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([N:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35]([NH2:37])=[O:36])(OC(C)(C)C)=O.[ClH:41].O1CCOCC1.C(OCC)C>ClCCl>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[ClH:41].[NH:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35]([NH2:37])=[O:36]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(N)=O
Agent: COc1ccc(/C=C(/C#N)c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)[C@@H]1CCCN1

Procedure:
(E)-3-(3-Amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-enenitrile-Boc-L-prolineamide (1,250 mg, 2.33 mmols) was dissolved in 10 ml of dichloromethane, and 5 ml of a solution of 4-M hydrochloric acid and dioxane were added thereto. The mixture was reacted at room temperature for 1 hour. One-hundred milliliters of diethyl ether were added thereto, and the mixture was filtered. The resulting powder was purified through medium-pressure liquid chromatography (ODS, mixture of water and acetonitrile at a ratio of 70:30). The product was recrystallized three times with a mixture of chloroform and ethyl acetate at a ratio by volume of 1:10 to produce 465 mg (0.980 mmols) of the final product in a yield of 42%.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]#[N:18])[C:10]([C:19]3[N:23]=[C:22]([CH2:24][OH:25])[S:21][N:20]=3)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[C:17]([C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[N:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:9]=[C:10]2[C:19]1[N:23]=[C:22]([CH2:24][O:25][S:27]([CH3:26])(=[O:29])=[O:28])[S:21][N:20]=1)#[N:18]
Reactant: N#Cc1cccc2c(-c3nsc(CO)n3)cn(CC3CCCCC3)c12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1nc(-c2cn(CC3CCCCC3)c3c(C#N)cccc23)ns1
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of 1-cyclohexylmethyl-3-(5-hydroxymethyl-[1,2,4]thiadiazol-3-yl)-1H-indole-7-carbonitrile (416 mg, 1.18 mmol) in dichloromethane (40 ml) was added methanesulfonyl chloride (0.110 ml, 1.42 mmol) and triethylamine (0.214 ml, 1.53 mmol) sequentially. The reaction was allowed to stir for 1 h and then poured into a separating funnel. The organics were washed with 2M aqueous sodium carbonate solution (20 ml), brine (20 ml), dried over magnesium sulfate, filtered, and the solvent removed in vacuo to afford methanesulfonic acid 3-(7-cyano-1-cyclohexylmethyl-1H-indol-3-yl)-[1,2,4]thiadiazol-5-ylmethyl ester (503 mg, 1.17 mmol) which was used without further purification.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=S)[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][CH:19]([O:22][CH3:23])[CH2:20][NH2:21]>>[CH3:17][O:18][CH:19]([O:22][CH3:23])[CH2:20][NH:21][C:10]1[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[NH:7][C:6]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[N:11]=1
Reactant: COC(CN)OC
Reactant: S=C1Nc2cccnc2Nc2ccccc21
Product: COC(CNC1=Nc2cccnc2Nc2ccccc21)OC
Temperature: 95 °C

Procedure:
A mixture of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-thione (3.21 g, 14 mmol) and 2,2-dimethoxyethylamine (7.6 mL, 70 mmol) was heated to 95° C. for 1 hour. After cooling to room temperature the solvent was evaporated in vacuo. The crude product was used in the next step without further purification.