Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH:35]1([CH2:38]Br)[CH2:37][CH2:36]1>CN(C)C=O>[CH:35]1([CH2:38][N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:32])[CH2:3][CH2:4]2)=[O:9])[CH2:37][CH2:36]1
Reactant: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1)N1CCC(F)(F)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2n1CC1CC1)N1CCC(F)(F)CC1
Yield: 80 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (example 44), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a colorless foam (80%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:7]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:25][CH:26]=1
Reactant: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccnc(Cl)c1)C2
Reactant: C1CCNC1
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccnc(N3CCCC3)c1)C2

Procedure:
The title compound was prepared by the method of Preparation 4b using (R)-6-(2-chloropyridine-4-sulfonyl)-1-(4-fluorophenyl)-4a-methoxymethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene and pyrrolidine. 1H NMR (400 MHz, CHCl3-d): δ 8.30 (d, 1H), 7.44-7.36 (m, 3H), 7.15 (t, 2H), 6.76 (dd, 1H), 6.65 (s, 1H), 6.29 (d, 1H), 4.24-4.13 (m, 1H), 3.91 (dd, 1H), 3.49 (t, 4H), 3.36 (s, 4H), 3.16-3.07 (m, 2H), 2.78-2.68 (m, 1H), 2.59-2.51 (m, 1H), 2.38 (d, 1H), 2.28-2.20 (m, 2H), 2.05 (t, 4H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[CH:23]2>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH:24]=[CH:23]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1ccc2[nH]ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 103.7 %

Procedure:
p-Toluenesulfonyl chloride (2 g) and tetrabutyl ammonium hydrogen sulfate (250 mg) were added to a toluene (20 ml) solution containing 5-chloroindole (1.52 g), followed by stirring at room temperature for 11 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with water (×3) and saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=0:1 to 1:1), and a colorless solid of 5-chloro-1-tosyl-1H-indole (3.18 g) was thus obtained.
Reaction SMILES: ClC1C=CC(COC2C=CC(N)=CC=2)=CN=1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.[Br:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][OH:35])=[N:32][CH:33]=1>>[Br:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][O:35][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[N:32][CH:33]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCc1ccc(Br)cn1
Agent: Nc1ccc(OCc2ccc(Cl)nc2)cc1
Product: O=[N+]([O-])c1ccc(OCc2ccc(Br)cn2)cc1

Procedure:
The substituted aniline compounds of formula (I) wherein W is oxygen can be prepared by the reaction of nitrophenol with a substituted pyridylalkyl halide to obtain the corresponding substituted nitrobenzene which is reduced to the desired substituted aniline of formula (I). For example, the reaction of 4-nitrophenol and 6-chloro-3-pyridylmethyl bromide gives 4-(2-chloro-5-pyridylmethyloxy)nitrobenzene which is then reduced to 4-(2-chloro-5-pyridylmethyloxy)aniline of formula I. Alternatively, the compounds of formula I can be prepared by the reaction of a halo-nitrobenzene with a substituted pyridylalkyl alcohol or substituted pyridylalkyl thiol followed by reduction of the nitro group. For example, the reaction of 4-fluoronitrobenzene and 5-bromo-2-pyridine methanol gives 4-(5-bromo-2-pyridylmethyloxy)nitrobenzene which is then reduced using, for example, iron powder to give 4-(5-bromo-2-pyridylmethyloxy)aniline.
Reaction SMILES: [NH4+:1].[OH-:2].O[C@@H:4]1[C@@H:9](Br)[CH2:8][CH2:7][C@H:6]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:5]1>>[NH2:1][C@H:4]1[C@H:9]([OH:2])[CH2:8][CH2:7][C@H:6]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:5]1
Reactant: [NH4+]
Reactant: [OH-]
Reactant: CN(C)C(=O)[C@H]1CC[C@H](Br)[C@@H](O)C1
Product: CN(C)C(=O)[C@H]1CC[C@@H](O)[C@H](N)C1
Temperature: 40 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A 28% ammonia aqueous solution (125 mL) was added to an aqueous solution (50 mL) of (1S,3S,4S)-3-hydroxy-4-bromo-N,N-dimethylcyclohexanecarboxamide (21.84 g), and the obtained solution was then heated to 40° C., followed by stirring the reaction solution for 8 hours. Thereafter, the reaction solution was further stirred at room temperature for 6 hours. Thereafter, the reaction mixture was concentrated to 50 mL to obtain 14.33 g of the title compound (yield: 79%) in the form of an aqueous solution (49 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH2:11][CH2:12][N:13](C(OCC(Cl)(Cl)Cl)=O)[CH2:14][CH:15]=1>C(O)(=O)C.O.[Zn]>[NH:13]1[CH2:14][CH:15]=[C:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH2:11][CH2:12]1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CC=C(c2nc3ccccc3o2)CC1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: C1=C(c2nc3ccccc3o2)CCNC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 52.6 g of 4-(2-benzoxazolyl)-3,6-dihydro-1(2H)-pyridinecarboxylic acid, 2,2,2-trichloroethyl ester in 1250 ml of glacial acetic acid is gradually added 92.5 g of zinc dust and the reaction mixture stirred at room temperature under nitrogen for 6 hours. The reaction mixture is filtered and concentrated on the rotary evaporator to give a viscous gum. This material is suspended in 500 ml of water, the pH adjusted to 2-3, and the suspension extracted with 500 ml of ether in two portions. These are combined, dried and concentrated to give 11.32 g of unreacted starting material.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Br:20][C:21]1[CH:28]=[C:27]([F:29])[C:24]([CH:25]=O)=[C:23]([F:30])[CH:22]=1.OS([O-])(=O)=O.[Na+]>ClCCl.O>[Br:20][C:21]1[CH:28]=[C:27]([F:29])[C:24]([CH2:25][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:23]([F:30])[CH:22]=1
Reactant: C1CCNC1
Reactant: O=Cc1c(F)cc(Br)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Fc1cc(Br)cc(F)c1CN1CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.2 %

Procedure:
Pyrrolidine (25 mL, 0.30 mol) and sodium triacetoxyborohydride (64 g, 0.30 mol) were added in portions to a stirred solution of Intermediate 18a, 4-Bromo-2,6-difluorobenzaldehyde (53.5 g, 0.24 mol) in dichloromethane (500 mL) on ice bath. The reaction mixture was intensively stirred for 12 h at RT. Water (400 mL) was added followed by addition of 5M aq. NaHSO4 to attain pH˜2. The organic layer was separated. The aqueous one was extracted with CH2Cl2 (2×200 mL). The organic layers were discarded. The aqueous fraction was alkalized with K2CO3 to pH˜10, and extracted with CHCl3 (2×300 mL). The organic extract was washed with brine, dried over anhydrous Na2SO4 (100 g) and evaporated in vacuo to give the title compound (52.5 g, 79%, 0.19 mol). LC/MS data: 275.9 and 277.9 (M+H)+ (calculated for C11H12BrF2N, 276.13). 1H NMR data (DMSO-d6): 7.40-7.48 (m, 2H Ar—H), 3.66 (s, 2H, Ar—CH2), 2.38-2.46 (m, 4H pyrrolidine (CH2)2N), 1.61-1.71 (m, 4H, CH2CH2CH2CH2).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=O>>[N:34]1[CH:35]=[CH:36][CH:37]=[C:32]([C:30]2[N:26]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[S:27][CH:29]=2)[CH:33]=1
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: O=C(CBr)c1cccnc1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccnc3)cs2)C1

Procedure:
100 mg (0.224 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carbothioamide (Example 53A) and 54 mg (0.269 mmol) of 2-bromo-1-pyridin-3-ylethanone were reacted according to the General Method 3. Yield: 24 mg (21% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[NH:12][CH:11]=[C:10]([C:13]([O:15]CC)=[O:14])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[NH:12][CH:11]=[C:10]([C:13]([OH:15])=[O:14])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c[nH]c(C(=O)c2ccc(Cl)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(C(=O)c2ccc(Cl)cc2)c1
Yield: 87.4 %

Procedure:
Ethyl 5-(4-chlorobenzoyl)pyrrole-3-carboxylate (0.7 g.) was combined with 20 ml. of methanol and 15 ml. of 1N sodium hydroxide and boiled in an open flask for 1 hour. Most of the methanol evaporated. The mixture was diluted to 40 ml. with water, treated with activated charcoal, and acidified to yield 5-(4-chlorobenzoyl)pyrrole-3-carboxylic acid [550 mg., m.p. 278°-280° C. (dec)]. Recrystallization from 1:1 methanol-acetone gave two crops of purified product [385 mg., m.p. 280°-282° C. (dec)].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.[C:10]([OH:16])(=[O:15])[CH2:11]C(O)=O.C([O-])(=O)C.[NH4+:21]>C(O)C>[NH2:21][CH:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH2:11][C:10]([OH:16])=[O:15]
Reactant: [NH4+]
Reactant: O=Cc1cncc(Br)c1
Reactant: O=C(O)CC(=O)O
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC(CC(=O)O)c1cncc(Br)c1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
9.50 g (51.07 mmol) 5-bromopyridine-3-carbaldehyde were suspended in 22 ml ethanol. 5.31 g (51.07 mmol) propanedioic acid and 8.27 g (107.25 mmol) ammonium acetate were added. The mixture was refluxed for 4 hours and after cooling to room temperature filtrated. The residue was washed with cold ethanol and dried in vacuum at 45° C. to give 8.69 g (69%) 3-amino-3-(5-bromo-pyridin-3-yl)propionic acid.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7]Br)=[O:5].[C:10]([O:13][CH2:14][C:15]1[CH2:16][S:17][C@@H:18]2[C@H:25]([NH:26][C:27](=[O:37])/[C:28](/[C:32]3[O:33][CH:34]=[CH:35][CH:36]=3)=[N:29]\[O:30][CH3:31])[C:24](=[O:38])[N:19]2[C:20]=1[C:21]([OH:23])=[O:22])(=[O:12])[NH2:11].[K]>CN(C)C=O>[C:10]([O:13][CH2:14][C:15]1[CH2:16][S:17][C@@H:18]2[C@H:25]([NH:26][C:27](=[O:37])/[C:28](/[C:32]3[O:33][CH:34]=[CH:35][CH:36]=3)=[N:29]\[O:30][CH3:31])[C:24](=[O:38])[N:19]2[C:20]=1[C:21]([O:23][CH2:7][O:6][C:4](=[O:5])[CH2:3][CH:2]([CH3:9])[CH3:1])=[O:22])(=[O:12])[NH2:11]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reactant: CC(C)CC(=O)OCBr
Agent: [K]
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(=O)CC(C)C)=C(COC(N)=O)CS[C@H]12)c1ccco1

Procedure:
Bromomethyl 3-methylbutanoate (1.328 g, 6.7 mmole) was added to a solution of (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid, potassium salt (2.772 g, 6 mmole) in purified N,N dimethylformamide (18 ml). The mixture was allowed to react for 15 minutes and was then worked up as described in Example 4 to give the slightly impure title compound (2.809 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[N:7](C=O)[CH:8]=[CH2:9])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(OC)(C)(C)C.O>C1COCC1>[C:1]([O:5][C:6](=[O:12])[NH:7][CH:8]=[CH2:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CN(C=O)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: COC(C)(C)C
Product: C=CNC(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of N-formyl-N-vinyl-carbamic acid tert-butyl ester (103.6 g, crude 89% pure, 539 mmol) in THF (320 ml) was cooled to 0° C. and stirred rapidly. NaOH (2M, 323 ml, 6.46 mmol) was slowly added over ca 20 minutes. The internal temperature rose to 19° C., and began then to cool. After cooling to 5° C. the mixture was warmed to RT. After 1 hour the reaction was finished according to tlc and GC. The reaction mixture was shaken between tBuOMe (250 ml) and water (250 ml), washed with water (250 ml) and brine (250 ml), dried over MgSO4 and evaporated. The product was a yellow oil containing traces of THF (NMR). The crude product was dissolved in pentane (25 ml), seeded, and left overnight at −20° C. The colourless crystals were swirled in pentane, filtered off and washed 3× with pentane, then spread in the air to dry to yield 48.9 g (63%). The mother liquors were evaporated down, dissolved in a little pentane and seeded. A further 8.1 g (11%) was isolated. (The product can also be sublimed/distilled.) m.p. 67-68° C.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][SH:26])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.C(Cl)[Cl:28]>>[ClH:28].[ClH:28].[C:1]1([NH:7][C:8](=[SH:26][CH2:25][CH2:24][CH2:23][N:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=3)[CH2:18][CH2:19]2)[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Fc1ccc(N2CCN(CCCS)CC2)cc1
Reactant: ClCCl
Reactant: O=C=Nc1ccccc1
Product: Cl
Product: OC(Nc1ccccc1)=[SH]CCCN1CCN(c2ccc(F)cc2)CC1
Yield: 33 %

Procedure:
1.2 g of phenyl isocyanate was added to a solution of 2.5 g of 3-[4-(4-fluorophenyl)piperazin-1-yl]propanethiol in 75 ml of methylene chloride, and the mixture was refluxed for four hours. After the further addition of 100 ml of methylene chloride the solution was washed with water, dried (sodium sulfate) and concentrated. The salt was precipitated with ethereal hydrochloric acid and recrystallized from aqueous ethanol to give 1.35 g (33% of theory) of N-phenyl-S-{3-[4-(4-fluorophenyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 250°-252° C.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([OH:5])=[O:4].[CH3:13][CH2:14][CH2:15][N:16]([C@@H:24]1[CH2:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33]([OH:34])[C:27]=2[CH2:26][CH2:25]1)[CH2:17][CH2:18][C:19]1[S:23][CH:22]=[CH:21][CH:20]=1.Cl.FC(F)(F)C(O)=O>ClCCl>[NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH3:13][CH2:14][CH2:15][N:16]([C@@H:24]1[CH2:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33]([OH:34])[C:27]=2[CH2:26][CH2:25]1)[CH2:17][CH2:18][C:19]1[S:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCCN(CCc1cccs1)[C@H]1CCc2c(O)cccc2C1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The Boc-Gly-Rotigotine HCl was deprotected by first dissolving the product (1.258 g, 2.55 mmol) in dichloromethane (64 ml). After addition of trifluoroacetic acid (9.83 ml, 128 mmol), the reaction mixture was stirred for 1 hour at room temperature and then all the volatiles were removed using a rotary evaporator. The residue (dark yellow) was dissolved in methanol and precipitated by adding into diethyl ether (40 mL). The pale yellow precipitate was filtered using a glass frit and dried to give Gly-Rotigotine.2TFA (1.140 g, 79% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH2:19]S(C(F)(F)F)(=O)=O)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:30](#[N:33])[CH:31]=C>>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH:19]=[CH:31][C:30]#[N:33])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC#N
Reactant: CC(C)(Cc1c[nH]c2c(CS(=O)(=O)C(F)(F)F)cccc12)NC(=O)OC(C)(C)C
Product: CC(C)(Cc1c[nH]c2c(C=CC#N)cccc12)NC(=O)OC(C)(C)C

Procedure:
{2-[7-(2-Cyano-vinyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester is prepared from [1,1-dimethyl-2-(7-trifluoromethanesulfonylmethyl-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester and acrylonitrile as described for the preparation of Amine 23 (85%). FDMS m/e=339.2 (M++1).
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[C:18](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[CH2:4]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH2:3][C:2]#[CH:18]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC=O)CC1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#CCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate (0.874 g, 3.62 mmol) in methanol (15 mL) was added with potassium carbonate (1.00 g, 7.24 mmol), and the mixture was stirred at room temperature. The reaction mixture was added with dimethyl (1-diazo-2-oxopropyl)phosphonate (0.692 g, 3.62 mmol), and the mixture was stirred at room temperature for additional 3 hours. The reaction mixture was concentrated, and then added with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-(but-3-ynyl)piperidine-1-carboxylate (0.670 g, 78%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:13][O:14][CH2:15][C:16]2[N:21]=[C:20]([N:22]3C(=O)C4C(=CC=CC=4)C3=O)[CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)=[CH:5][N:4]=[CH:3]1.O.NN>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7](=[N:13][O:14][CH2:15][C:16]2[N:21]=[C:20]([NH2:22])[CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)=[CH:5][N:4]=[CH:3]1
Reactant: Cn1cncc1C(=NOCc1cccc(N2C(=O)c3ccccc3C2=O)n1)c1ccsc1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: Cn1cncc1C(=NOCc1cccc(N)n1)c1ccsc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 63 %

Procedure:
To a solution of 2-{6-[({[(1-methyl-1H-imidazol-5-yl)(3-thienyl)methylene]amino}oxy)-methyl]pyridin-2-yl}-1H-isoindole-1,3(2H)-dione (6.80 g, 15.3 mmol) in tetrahydrofuran (30 mL) was added dropwise hydrazine hydrate (3.72 mL, 76.7 mmol). After stirring at room temperature for 30 h, the reaction mixture was filtered, the insolubles washed with ethyl acetate, and the filtrate concentrated in vacuo. Purification on silica gel afforded 6-[({[(1-methyl-1H-imidazol-5-yl)(3-thienyl)methylene]amino}oxy)methyl]pyridin-2-amine [3.02 g, yield 60%; HPLC/MS: m/z=314 (M+H); log P(HCOOH)=0.39].
Reaction SMILES: [CH3:1][N:2]([CH3:14])[NH:3][CH:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]([O:11]CC)=O.[CH3:15][S:16]([NH:19][C:20]1[CH:35]=[CH:34][C:23]2[NH:24][C:25]([CH2:30][C:31](O)=[O:32])=[N:26][S:27](=[O:29])(=[O:28])[C:22]=2[CH:21]=1)(=[O:18])=[O:17].CN1CCOCC1.[ClH:43].CN(C)CCCN=C=NCC>CN(C)C=O>[ClH:43].[CH3:14][N:2]([CH3:1])[N:3]1[C@@H:4]2[C@@H:5]([CH2:6][CH2:7][CH2:8]2)[C:9]([OH:11])=[C:30]([C:25]2[NH:24][C:23]3[CH:34]=[CH:35][C:20]([NH:19][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:21][C:22]=3[S:27](=[O:28])(=[O:29])[N:26]=2)[C:31]1=[O:32]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C1CCCC1NN(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(C)N1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)[C@@H]2CCC[C@@H]21
Yield: 52.4 %

Procedure:
Ethyl 2-(2,2-dimethylhydrazinyl)cyclopentanecarboxylate (0.16 g, 0.82 mmol) was dissolved in anhydrous N,N-dimethylformamide (8 mL). (7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.27 g, 0.82 mmol) was added followed by N-methylmorpholine (0.19 mL, 1.72 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.16 g, 0.86 mmol) was added and the mixture was stirred at 25° C. for 16 h. The reaction was quenched via addition of saturated aqueous sodium bicarbonate solution (20 mL). The mixture was extracted with ethyl acetate (3×30 mL). The organic layers were combined and washed with saturated aqueous brine solution (20 mL). The resulting solution was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. The residue was triturated with ethyl acetate to afford the desired product, cis-N-[3-(1-dimethylamino-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl]-methanesulfonamide hydrochloride (0.22 g, 0.43 mmol, 52%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.48-1.73 (2H, m), 1.88-2.20 (4H, m), 2.82 (6H, s), 3.06 (3H, s), 4.01 (1H, s), 7.49-7.74 (3H, m), 10.18 (1H, s). LC-MS (ESI) calcd for C18H23N5O6S2 469.54, found 470.2 [M+H+].
Reaction SMILES: O.[C:2]1(C)C=CC(S(O)(=O)=O)=C[CH:3]=1.[CH:13]([SH:16])([SH:15])[CH3:14].[CH2:17]([N:24]1[CH2:29]CC(=O)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[C:18]1([CH2:17][N:24]2[CH2:25][CH2:26][C:13]3([S:16][CH2:3][CH2:2][S:15]3)[CH2:14][CH2:29]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(S)S
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(CN2CCC3(CC2)SCCS3)cc1
Yield: 42.9 %

Procedure:
31.5 g (0.165 mol) of p-toluenesulphonic acid monohydrate and 16.9 g (0.18 mol) of ethanedithiol are added to a solution of 28.35 g (0.150 mol) of 1-benzyl-4-piperidinone in 600 ml of toluene; the mixture is heated under reflux in a Dean-Stark system for 6 h, the solvent is evaporated off, 500 ml of ethyl acetate are added, the solution is washed successively with twice 100 ml of saturated sodium carbonate solution, with water and with brine; it is dried with sodium sulphate and then evaporated to dryness. The residue is purified by chromatography on silica gel with the aid of the 3/97 ethyl acetate/hexane eluent mixture. 17.1 g of 8-(phenylmethyl)-1,4-dithia-8-azaspiro[4.5]decane are obtained in the form of a white solid. Yield 42%. Melting point 51-53° C.