Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:7])[C:4](O)=[O:5].[OH-].[Na+].[CH3:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=O)=[CH:14][CH:13]=1.Cl>O1CCCC1>[CH3:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][NH:1][CH2:2][CH:3]([CH3:7])[CH2:4][OH:5])=[CH:14][CH:13]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(CN)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(CNCC(C)CO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
To a solution of 3-amino-2-methyl-propionic acid (5.00 g, 48.4 mmol) in tetrahydrofuran (107 ml) and 1N sodium hydroxide (107 ml, 107 mmol) was added 4-methoxybenzoyl chloride (8.69 g, 50.9 mmol) at 0° C. The mixture was stirred at room temperature for 3 hours and partitioned between water and ethyl acetate. The water phase was washed with ethyl acetate and acidified with 1N hydrochloric acid. The product was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, and concentrated in vacuo. To the residue dissolved into tetrahydrofuran (20 ml) was added 1M borane-tetrahydrofuran complex (6.40 ml, 6.40 mmol) at 0° C. The mixture was stirred at room temperature. After 30 minutes, the mixture was refluxed for 5 hours and acidified with 3N hydrochloric acid. The acidic aqueous solution was stirred at 60° C. for 2 hours. The organic solvent was evaporated under reduced pressure, then the residue was partitioned between water and ethyl acetate. The water phase was washed with ethyl acetate and basified with 3N sodium hydroxide. The product was extracted with chloroform. The organic phase was dried over sodium sulfate, and concentrated in vacuo to afford 3-(4-methoxy-benzylamino)-2-methyl-propan-1-ol as colorless oil (8.28 g, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.[C:10]([CH:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1)#[CH:11].CCN(CC)CC>[Cu]I.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.C(#N)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[C:11]#[C:10][CH:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1
Reactant: Nc1ccc(Br)cc1I
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(Br)ccc2N)C1
Temperature: 70 °C
Yield: 94.7 %

Procedure:
4-Bromo-2-iodoaniline (3.88 g, 19.88 mmol), tert-butyl 3-ethynylpyrrolidine-1-carboxylate (4.90 g, 16.45 mmol), CuI (65 mg, 0.34 mmol, 2 mol %) and Pd(PPh3)2Cl2 (115 mg, 0.16 mmol, 1 mol %) were mixed together under argon in a heat-gun dried flask. Acetonitrile (17 mL) and NEt3 (4.60 mL, 33.00 mmol) were added to the mixture and reaction was heated at 70° C. for 1.5 h. TLC showed complete consumption of the alkyne. Acetonitrile was concentrated under reduced pressure and EtOAc (100 mL) was added to the residue. Triethylamine salt was filtered off and washed with EtOAc. Mother liquor was concentrated and residue was purified by column chromatography using EtOAc/hexanes (gradient 0-40%) to afford tert-butyl 3-((2-amino-5-bromophenyl)ethynyl)pyrrolidine-1-carboxylate (5.69 g) in 95% yield.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[C:14](OC)=[N:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-:17].[NH4+:18]>CO>[ClH:17].[CH:1]1([CH2:7][CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]2=[NH:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: COC1=NCCCCC1CC1CCCCC1
Solvent: CO
Product: Cl
Product: N=C1NCCCCC1CC1CCCCC1

Procedure:
The title product of Example 11 in MeOH is reacted with ammonium chloride by the method of Example 5 to generate the title material.
Reaction SMILES: [CH2:1]([C:8](O)=O)[C:2]([CH2:4][C:5]([OH:7])=O)=[O:3].C(O[C:16](=O)[CH2:17][CH3:18])(=O)CC.S(=O)(=O)(O)O.[C:25](=O)=O>C(O)(=O)C.O>[CH2:16]([C:17]1[O:3][C:2]([CH2:1][CH3:8])=[CH:4][C:5](=[O:7])[CH:18]=1)[CH3:25]
Reactant: O=C(O)CC(=O)CC(=O)O
Reactant: O=C=O
Reactant: CCC(=O)OC(=O)CC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc(=O)cc(CC)o1
Temperature: 100 °C

Procedure:
Acetonedicarboxylic acid (Aldrich, 165115) (60 g, 0.41 mol) was added rapidly to propionic anhydride (Aldrich, 240311) (170 mL, 1.3 mol) containing concentrated sulfuric acid (2 mL), and the reaction mixture was heated at 100° C. for 30 minutes with stirring. The solution was cooled rapidly in an ice-salt mixture, and just when a white solid mass was forming, the reaction was added to cold water (500 mL), stirred and filtered immediately. The product was air-dried and placed in a 3 L flask and treated with aqueous 10% sodium carbonate (600 mL). The resulting paste was stirred with a stirrer and heated at 100° C. for 30 min. Carbon dioxide evolved and a light yellow solution was obtained which was heated at 85–90° C. for further 80 min. The solution was cooled and acidified with aqueous 30% acetic acid until no more carbon dioxide was evolved. The white precipitate was filtered, washed with water, air-dried and then added to concentrate hydrochloric acid (120 mL) in a 2 L round-bottomed flask, and the mixture was heated under reflux for 4 hours. The solution was cooled in ice and neutralized by adding it to a stirred solution of sodium carbonate (about 115 g) in water (about 500 mL). The neutral solution was extracted thoroughly with EtOAc. The extract was dried and stripped of solvent to give product 2,6-Diethyl-4-pyrone as a brown oil. (Yates et al, JOC, vol. 34, No, 12, 1969, p4046–4052)
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:5][O:4]1.C(=O)(O)[O-].[Na+].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C.O>[CH2:11]([N:18]1[CH2:5][CH:3]([OH:4])[CH2:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCC1CO1
Reactant: NCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: OC1CN(Cc2ccccc2)C1

Procedure:
reacting (±)-2-(chloromethyl)oxirane, sodium bicarbonate and benzylamine in acetonitrile and water to provide 1-benzyl-3-azetidinol, reacting the 1-benzyl-3-azetidinol and (2E/Z)-2-butenedioic acid at about 35° C. to about 45° C., and isolating 1-benzyl-3-azetidinol (2E/Z)-2-butenedioate;
Reaction SMILES: CC1C2C(S([Cl:15])(=O)=O)=CC=CC=2C=NC=1.BrC1C2C(S(Cl)(=O)=O)=CC=CC=2C=NC=1.C(OC(NC1CCNC1)=O)(C)(C)C.C(OC([NH:51][CH:52]1[CH2:56][CH2:55][N:54]([S:57]([C:60]2[C:61]3[C:62]([CH3:70])=[CH:63][N:64]=[CH:65][C:66]=3[CH:67]=[CH:68][CH:69]=2)(=[O:59])=[O:58])[CH2:53]1)=O)(C)(C)C>>[NH2:51][CH:52]1[CH2:56][CH2:55][N:54]([S:57]([C:60]2[C:61]3[C:62]([CH3:70])=[CH:63][N:64]=[CH:65][C:66]=3[CH:67]=[CH:68][CH:69]=2)(=[O:59])=[O:58])[CH2:53]1.[ClH:15]
Reactant: Cc1cncc2cccc(S(=O)(=O)Cl)c12
Reactant: Cc1cncc2cccc(S(=O)(=O)N3CCC(NC(=O)OC(C)(C)C)C3)c12
Agent: CC(C)(C)OC(=O)NC1CCNC1
Agent: O=S(=O)(Cl)c1cccc2cncc(Br)c12
Product: Cc1cncc2cccc(S(=O)(=O)N3CCC(N)C3)c12
Product: Cl

Procedure:
By using 4-methyl-5-isoquinolinesulfonyl chloride obtained according to the method described in WO09728130 instead of 4-bromo-5-isoquinolinesulfonyl chloride, and 3-(tert-butoxycarbonylamino)pyrrolidine instead of (S)-3-(tert-butoxycarbonylamino)pyrrolidine in the method of Example 1-1, (R/S)-3-(tert-butoxycarbonylamino)-1-(4-methyl-5 isoquinoline sulfonyl)pyrrolidine (Intermediate 5) can be prepared, and then the protective group of Intermediate 5 can be removed according to the method described in Example 1-1, Step B to obtain the title compound as hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=4)[CH:35]=O)[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:41][OH:42].C(O)(=O)C>CO.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=4)[CH:35]=[N:41][OH:42])[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCC[C@@H](Nc2nccc(-c3c(-c4cccc(C=NO)c4)nc4sccn34)n2)C1
Temperature: 50 °C
Yield: 61.3 %

Procedure:
To a mixture 3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}benzaldehyde (0.81 g, 0.14 mmol) and hydroxylamine hydrochloride (0.0107 g, 0.154 mmoL) in methanol (2.0 mL) was added 0.2 mL of acetic acid. The mixture was heated at 50° C. for 2 hours. After cooled to room temperature, the mixture was diluted with dichloromethane (10 mL), washed with saturated aqueous sodium bicarbonate (5 mL×3), water (5 mL), dried over sodium sulfate and concentrated. Product was purified by flash chromatography on silica gel (methanol:dichloromethane:ethylacetate=0.5:7:2) to afford 0.051 g (61%) of the title compound as an off-white solid. M.p.=238-240° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 11.14 (s, 1H), 8.70 (bs, 1H), 8.17 (s, 1H), 8.11 (d, J=5.6 Hz, 1H), 7.8 (s, 1H), 7.77-7.74 (m, 2H), 7.68-7.64 (m, 3H), 7.60-7.57 (m, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.41 (d, J=4.4 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.40 (d, J=5.2 Hz, 1H), 3.93 (br. s, 1H), 3.74-3.71 (m, 1H), 3.48-3.45 (m, 1H), 2.5-2.4 (m, 1H), 2.33 (t, J=10.4 Hz, 1H), 1.89-1.82 (m, 2H), 1.59-1.56 (m, 1H), 1.40-1.32 (m, 1H). LCMS: 594 [M+H].
Reaction SMILES: Cl.[CH3:2][C:3]([NH2:12])([CH3:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[C:16]([NH2:21])[N:15]=1.CCN(C(C)C)C(C)C>CC#N>[Cl:13][C:14]1[N:15]=[C:16]([NH2:21])[N:17]=[C:18]([NH:12][C:3]([CH3:2])([CH3:11])[CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:19]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC(C)(N)Cc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(Cc1ccccc1)Nc1cc(Cl)nc(N)n1
Temperature: 160 °C
Yield: 50.5 %

Procedure:
A mixture of 2-methyl-1-phenyl-2-propanamine hydrochloride (742 mg, 4 mmol), 4,6-dichloro-2-pyrimidinamine (438 mg, 2.67 mmol) and Hunig's base (1.55 g, 12 mmol) in CH3CN (8 mL) was stirred and heated for 6 hours at 160° C. in a Biotage Initiator microwave synthesizer. The mixture was cooled to room temperature and concentrated to dryness. The resulting solids were partitioned between EtOAc and water, and the organic layer was dried over Na2SO4, filtered and concentrated to dryness. Purification by reverse phase chromatography using CH3CN in water from 45% to 65% (0.08% ammonium hydrogen carbonate) in 18 min, afforded the title compound (373 mg) as a white solid. LC-MS (ES) m/z=277.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=[C:8]2[C:7]([CH2:18]SC2C=CC=CC=2)=[CH:6]1.[CH3:31][O:32][CH:33](O)[CH3:34].CCN(C(C)C)C(C)C.CN(C=[O:49])C>>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=[C:8]2[C:7]([CH2:18][O:49][CH2:34][CH2:33][O:32][CH3:31])=[CH:6]1
Reactant: COC(=O)c1cc2c(CSc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Reactant: COC(C)O
Reactant: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)OC)cc12
Temperature: 40 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
To a solution of methyl 3-(chloromethyl)-1-(2,4-difluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (3 mL, 0.197M in CH2Cl2, 0.591 mmol) [prepared as described in step 2 of example 40] in anhydrous DMF (5 mL) was added methoxyethanol (0.25 g, 3.29 mmol, 0.26 mL, 5.5 eq.) followed by i-Pr2NEt (0.407 g, 3.14 mmol, 0.55 mL, 4 eq.). The mixture, under nitrogen, was placed in an oil bath and the bath was warmed to 40° C. After stirring for 24 hours (40° C.) the reaction was judged to by complete by HPLC-MS analysis and the volatiles were removed in vacuo (ca. 2 torr) to give a golden yellow oil. The crude material was purified by chromatography on a column of silica gel (40 mm OD, 100 g, 230-400 mesh, packed with CH2Cl2, eluted with CH2Cl2-EtOAc 70:30 v/v, 1.0 L, and CH2Cl2-EtOAc-MeOH 68:30:2, 1.0 L, 25 mL fractions) using the flash technique. Fractions 55-64 were combined to afford 0.148 g (77%) of methyl 1-(2,4-difluorobenzyl)-3-[(2-methoxyethoxy)methyl]-1H-pyrrolo[2,3-c]pyridine-5-carboxylate as a white, crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12](=[S:14])=[S:13]>C(O)C>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12](=[S:13])[SH:14]
Reactant: Cc1[nH]cnc1CSCCN
Reactant: S=C=S
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNC(=S)S
Reaction time: 8 h

Procedure:
A solution of 2-((5-methyl-4-imidazolyl)methylthio)ethylamine (10.2 g) in ethanol (75 ml) was added slowly, with stirring, to carbon disulphide (200 ml). The mixture was set aside overnight at room temperature and the solid formed was collected and recrystallised from aqueous isopropyl alcohol to afford N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]dithiocarbamic acid (9.8 g), m.p. 127°-129°. This was treated with dicyclohexylcarbodiimide in dry pyridine at -10°, and the mixture was filtered. The filtrate was evaporated to dryness and the residue was treated sith ethanolic hydrogen chloride to give 5-methyl-4-(2-isothiocyanatoethylthiomethyl)imidazole hydrochloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[F:14][C:15]1[CH:29]=[CH:28][C:18]([CH:19]=[N:20][CH:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][OH:23])=[CH:17][CH:16]=1.O>CCOCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C@H:19]([NH:20][C@@H:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][OH:23])[C:18]2[CH:17]=[CH:16][C:15]([F:14])=[CH:29][CH:28]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CC(C)CC(CO)N=Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC(C)C[C@@H](CO)N[C@H](c1ccc(F)cc1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1,4-dibromobenzene (11.4 g, 48.35 mmol) in ether (120 mL) at −30° C. was added n-butyllithium (24.2 mL, 2.0M cyclohexane solution) over 10 minutes. The reaction mixture was stirred for 45 minutes, whereupon a solution of (S) 2-[(4-fluorobenzylidene)-amino]-4-methylpentan-1-ol (maximum 2.16 g, 9.67 mmol from the previous step) in ether (30 mL) was added dropwise. After 2 hours, during which the reaction mixture was allowed to warm to 0° C., water (200 mL) was added. The product was extracted with ethyl acetate (150 mL), washed with brine (100 mL), dried over MgSO4, filtered, concentrated in vacuo, and purified on a short plug of silica gel (20% ethyl acetate/hexane elution) to give (2S)-2-{(R)-[(4-bromophenyl)-(4-fluorophenyl)-methyl]-amino}-4-methylpentan-1-ol.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[C:13]1(=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[NH:14]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]#[C:5][CH2:4][CH2:3][CH2:2][N:14]1[C:15](=[O:22])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]1=[O:23]
Reactant: BrCCCC#Cc1ccccn1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCC#Cc1ccccn1
Temperature: 150 °C
Yield: 20.7 %

Procedure:
2-(5-bromopent-1-ynyl)pyridine (118 mg, 0.525 mmol), isoindoline-1,3-dione (74 mg, 0.5 mmol) and potassium carbonate (140 mg, 1 mmol) were dissolved in acetone (1 mL). The resulting mixture was heated with microwave at 150° C. for 15 min. The reaction was quenched with water, then acetone was evaporated under reduced pressure. The aqueous layer was extracted with DCM, and the organic layer was washed one time with saturated brine, dried over MgSO4, filtrated and concentrated. Purification by flash chromatography pack 15 g silice 40-60, Cyclohexane/AcOEt: 50/50 to afford 30 mg of 2-(5-(pyridin-2-yl)pent-4-ynyl)isoindoline-1,3-dione (Yield: 20%) as a beige powder (Mp=127-129° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]2Cl.CCOC(C)=O.CC(O)=O.[H][H]>CO.[Pt]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6]2
Reactant: [H][H]
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1Cl
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C1CNc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6-methoxy-4-chloro-3-ethoxycarbonyl-quinoline (Step B, 20 g, 0.075 mol) in 1/1 EtOAc/AcOH (560 mL) in a Parr hydrogenation apparatus bottle kept under inert atmosphere was added Pt/C 10% (2 g). The mixture was hydrogenated under 60 psi hydrogen at RT for 2 h using a Parr hydrogenation apparatus. The resulting mixture was diluted with MeOH and filtered. The solid was washed several times with a 1/1 MeOH/CH2Cl2 mixture and the solvents were removed under vacuum. The resulting solid was suspended into CH2Cl2 and 2N NaOH was added. The mixture was stirred at RT for 30 min. The organic layer was recovered and washed once with 2 N NaOH and twice with water to give crude 6-methoxy-3-ethoxycarbonyl-1,2,3,4-tetrahydroquinoline, which was directly used in the next step.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]([C:16]([F:19])([F:18])[F:17])[O:13]2)=[CH:8][CH:7]=1)([CH3:5])[CH:3]=O.[CH2:25]([NH2:28])[CH2:26][CH3:27].C([BH3-])#N.[Na+]>CO.CC(O)=O.C1COCC1>[CH3:5][C:2]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]([C:16]([F:18])([F:17])[F:19])[O:13]2)=[CH:8][CH:7]=1)([CH3:1])[CH2:3][NH:28][CH2:25][CH2:26][CH3:27]
Reactant: CCOC(=O)C1=Cc2ccc(C(C)(C)C=O)cc2OC1C(F)(F)F
Reactant: CCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCCNCC(C)(C)c1ccc2c(c1)OC(C(F)(F)F)C(C(=O)OCC)=C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the title product of Example 113 Step 3 (198 mg, 0.579 mmole) in 8 mL of MeOH and 1 mL of HOAc was added n-propylamine (68 mg, 1.2 mmoles), 0.9 mL of 1 M sodium cyanoborohydride in THF, and 1 g of activated 4 Å molecular sieves. The resulting mixture was stirred overnight at room temperature. The mixture was diluted with MeOH, filtered through Celite, concentrated, azeotropically distilled with toluene. Chromatography of the residue over silica gel using 10% MeOH—DCM gave the title compound, 220 mg, as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:17][NH2:18]>C1(C)C=CC=CC=1>[CH3:17][NH:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CNc1ncccc1[N+](=O)[O-]

Procedure:
A procedure similar to that described in Preparation 66 was repeated, except that 24.9 g of 2-chloro-3-nitropyridine, 41.7 g of sodium carbonate, 22.7 ml of a 30% ethanolic solution of methylamine were reacted in 250 ml of toluene. After working up the product as described in Preparation 66, the resulting crude product was crystallized by trituration with isopropanol, to give 24.0 g of the title compound, melting at 52-53° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([SH:18])[N:3]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[S:24][CH:25]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[S:24][CH:25]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccccc1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 g (7.927 mmol) of 2-amino-4-phenyl-6-sulphanylpyridine-3,5-dicarbonitrile are initially charged in 15 ml of DMF, 2.13 g (8.720 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 1.99 g (23.781 mmol) of sodium bicarbonate are added and the mixture is stirred at room temperature overnight. Water is added to the reaction mixture, and the precipitated solid is filtered off, washed with MTBE and dried under high vacuum. This gives 3.87 g (100% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10](O)([CH3:12])[CH3:11].[CH2:14]([O:16][C:17](=[O:25])[C:18]([O:20][Si](C)(C)C)=[CH2:19])[CH3:15].[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:14]([O:16][C:17](=[O:25])[C:18](=[O:19])[CH2:20][C:10]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([CH3:9])[C:3]=1[O:2][CH3:1])([CH3:12])[CH3:11])[CH3:15]
Reactant: C=C(O[Si](C)(C)C)C(=O)OCC
Reactant: COc1c(C)cccc1C(C)(C)O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C(=O)CC(C)(C)c1cccc(C)c1OC
Reaction time: 3 h
Yield: 41.6 %

Procedure:
71.37 g (395.96 mmol) of 2-(2-methoxy-3-methylphenyl)-propan-2-ol and 149 g (791.92 mmol) of 2-trimethylsilanyloxyacrylic acid ethyl ester are introduced into 1.1 l of dichloromethane. At −78° C., 44.8 ml (379.91 mmol) of tin tetrachloride is added in drops, and the batch is then stirred for three hours at this low temperature. 1.4 1 of semiconcentrated potassium carbonate solution is carefully added in drops, and the reaction mixture is thus brought to room temperature. The batch is filtered, and the filtrate is extracted three times with ethyl acetate. The combined organic extracts are washed with brine, dried on sodium sulfate, and the solvent is spun off. The residue is chromatographed several times on silica gel (mobile solvent ethyl acetate/hexane). 45.81 g (41.6%) of the desired compound is isolated.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C:9]1=[S:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C:9]1=[S:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(=S)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: S=C1CNCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To a solution of 1-benzyl-4-(tert-butyloxycarbonyl)piperazin-2-thione (925 mg, 3.02 mmol) in CH2Cl2 (25 mL) was added trifluoroacetic acid (2.5 mL). The mixture was stirred at room temperature, under nitrogen, for 2 h. The solvent was evaporated and the residue azeotroped with toluene (2×10 mL). The residue was partitioned between CH2Cl2 (2×50 mL) and Na2CO3 solution (10% (w/v), 40 mL). The combined organic layers were dried Na2SO4) and evaporated. The residue was chromatographed on silica, eluting with CH2Cl2 :MeOH (95:5) to afford the title compound (539 mg, 87%) as a pale orange solid. mp. 70-73° C. 1H NMR (250 MHz, CDCl3) δ3.11-3.16 (2H, m), 3.29-3.33 (2H, m), 4.10 (2H, s), 5.31 (2H, s), 7.30-7.37 (5H, m). MS (ES+) (207, M+1).