Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[Cl:23][C:24]1[CH:29]=[C:28]([N:30]=[C:31]=[O:32])[CH:27]=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34]>>[Cl:23][C:24]1[CH:29]=[C:28]([NH:30][C:31]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)=[O:22])[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:32])[CH:27]=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34]
Reactant: C[C@@H]1NCCN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Reactant: O=C=Nc1ccc(C(F)(F)F)c(Cl)c1
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(C(F)(F)F)c(Cl)c1
Yield: 83 %

Procedure:
In analogy to the procedure described in Example 30, (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 13) and 2-chloro-4-isocyanato-1-trifluoromethyl-benzene (intermediate 16) gave the titled compound in 83% yield as white foam. MS: 531.20 (MH+, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:9](=[O:10])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:11][CH:12]=2)[CH:3]=1
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: O=C(O)c1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a solution of 4-chlorophthalic anhydride (25 g) in benzene (200 ml) was added aluminum chloride (36.5 g), and the mixture was stirred at room temperature for 1 hr. and subsequently refluxed for 30 min. After cooling the reaction mixture, it was diluted with ethyl acetate (200 ml) and poured into ice water. Conc. hydrochloric acid (20 ml) was added and the mixture was stirred at room temperature for 30 min. After separating the organic layer, the layer was washed successively with 4N hydrochloric acid, water and brine, dried over sodium sulfate and concentrated until the crystals precipitated. The crystals were collected by filtration and washed with isopropyl ether to give 4-chloro-2-benzoylbenzoic acid (16 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1([F:13])[CH2:6][C:5](F)([F:7])[C:4]([F:10])([F:9])[C:3]1([F:12])[F:11].[H][H]>[C].[Pd]>[F:1][C:2]1([F:13])[CH2:6][CH:5]([F:7])[C:4]([F:9])([F:10])[C:3]1([F:11])[F:12]
Reactant: FC1(F)CC(F)(F)C(F)(F)C1(F)F
Reactant: [H][H]
Agent: [Pd]
Product: FC1CC(F)(F)C(F)(F)C1(F)F
Temperature: 30 °C
Reaction time: 10 h

Procedure:
Octafluorocyclopentane (at a purity of 99.9%, 42.4 g, 200 mmol) and 5% palladium carbon (2.12 g) were charged in a 70 ml-autoclave fitted with an agitator, for hydrogenation a hydrogen pressure of 6 kg/cm2 at 50° C. Fifteen hours later when hydrogen consumption was completely ceased, heating was terminated to stop the reaction. After sufficient neutralization with saturated sodium bicarbonate solution, the organic layer was separated, followed by addition of 200 ml of an aqueous sodium carbonate solution at a concentration of 1 mol. The resulting mixture was agitated at 30° C. for 10 hours. The reaction solution was separated into two layers; the resulting organic layer was again charged, together with 5% palladium carbon (1.78 g) and 1 g of tridecane, in a 70 ml-autoclave, for hydrogenation at 50° C. under a hydrogen pressure of 6 kg/cm2. When hydrogen absorption was ceased 15 hours later, the reaction was terminated in the same manner as described above; then, the resulting solution was neutralized with saturated sodium bicarbonate solution, followed by distillation, to recover 1,1,2,2,3,3,3,4-heptafluorocyclopentane (at a purity of 99.0%; 34.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:28](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:28])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1[C@@H](CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cc1ccccc1[C@@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 161, step 1, 5-[(S)-3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a white solid, MS (ESI+): m/z=410.1 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=3)[CH2:3]1.[OH-].[Na+].Cl>CO.O>[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=3)[CH2:3]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CC[C@H](O)C3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CC[C@H](O)C3)nc2c1

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of (S)-methyl 3-(3-hydroxypyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate (170 mg, 0.49 mmol, 1.00 equiv) in methanol (20 mL). This was followed by the dropwise addition of a solution of sodium hydroxide (97.4 mg, 2.44 mmol, 5.00 equiv) in water (2.5 mL) with stirring. The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting solid was collected by filtration and washed with water and methanol. The solid was dried in an oven. This resulted in 40 mg (25%) of (S)-3-(3-hydroxypyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([CH3:8])([OH:7])[CH2:5][CH2:4][NH:3]1.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=1[C:18]([F:21])([F:20])[F:19].C(=O)([O-])[O-].[Li+].[Li+]>>[OH:7][C@@:6]1([CH3:8])[CH2:5][CH2:4][N:3]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=2[C:18]([F:19])([F:21])[F:20])[C@H:2]1[CH3:1]
Reactant: C[C@@H]1NCC[C@]1(C)O
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@@H]1N(c2ccc(C#N)cc2C(F)(F)F)CC[C@]1(C)O

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-dimethylpyrrolidin-3-ol 0.5 oxalate (228 mg), 4-fluoro-3-(trifluoromethyl)benzonitrile (397 mg) and lithium carbonate (206 mg), the title compound was obtained as a colorless oil (yield: 220 mg, yield: 55%).
Reaction SMILES: [CH2:1]([Sn:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:11]([OH:15])[CH2:12][CH2:13][CH3:14]>>[CH2:1]([Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([O:15][CH2:11][CH2:12][CH2:13][CH3:14])[O:10][Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:1][CH2:2][CH2:3][CH3:4])[O:15][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: CCCC[Sn](=O)CCCC
Product: CCCCO[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)OCCCC
Reaction time: 0.5 h
Yield: 99 %

Procedure:
692 g (2.78 mol) of dibutyltin oxide (made by Sankyo Organic Chemicals Co., Ltd., Japan) and 2000 g (27 mol) of 1-butanol (made by Wako, Japan) were put into a 3000 mL flask. The flask containing the mixture, which was a white slurry, was attached to an evaporator (R-144, made by Sibata, Japan) having a temperature regulator-equipped oil bath (OBH-24, made by Masuda Corporation, Japan), a vacuum pump (G-50A, made by Ulvac, Japan) and a vacuum controller (VC-10S, made by Okano Works Ltd., Japan) connected thereto. The outlet of a purge valve of the evaporator was connected to a line for nitrogen gas flowing at normal pressure. The purge valve of the evaporator was closed, and the pressure in the system was reduced, and then the purge valve was gradually opened, so as to pass nitrogen into the system, and thus return the system to normal pressure. The oil bath temperature was set to 126° C., and the flask was immersed in the oil bath and rotation of the evaporator was commenced. With the purge valve of the evaporator left open, rotational agitation and heating were carried out for approximately 30 minutes at normal pressure, whereupon the liquid mixture boiled, and hence distilling off of a low boiling component began. This state was maintained for 8 hours, and then the purge valve was closed, and the pressure in the system was gradually reduced, and residual low boiling component was distilled off with the pressure in the system at from 76 to 54 kPa. Once low boiling component stopped coming off, the flask was lifted out from the oil bath. The reaction liquid was a transparent liquid. After lifting the flask out from the oil bath, the purge valve was gradually opened, so as to return the pressure in the system to normal pressure. 952 g of reaction liquid was obtained in the flask. According to 119Sn-, 1H-, and 13C-NMR analysis results, the product 1,1,3,3-tetrabutyl-1,3-di(butyloxy)-distannoxane was obtained at a yield of 99% based on the dibutyltin oxide. The same procedure was repeated twelve times, thus obtaining a total of 11500 g of 1,1,3,3-tetrabutyl-1,3-di(butyloxy)-distannoxane.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=4)[CH:24]=O)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[O:32]1[CH2:33][CH2:34][N:29]([CH2:24][C:23]2[CH:22]=[C:21]([CH:13]3[NH:12][C:7]4[C:6]5[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=5[CH:10]=[CH:9][CH:8]=4)[CH:14]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:30][CH2:31]1
Reactant: O=Cc1cccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1cccc(CN3CCOCC3)c1)C2c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 64.3 %

Procedure:
A mixture of 3-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (40 mg, 0.11 mmol), morpholine (28 mg, 0.33 mmol) and acetic acid (33 mg, 0.55 mmol) in methanol (50 mL) was stirred at room temperature for 40 min. Then the mixture was cooled to 0° C. Sodium triacetoxyborohydride (35 mg, 0.16 mmol) was added. After the addition, the mixture was stirred at 0° C. for 2 hr. Methanol was removed under reduced pressure. The residue was resolved with 1N hydrochloric acid and washed with ethyl acetate. The mother liquor was adjusted to pH=8 and extracted with ethyl acetate. The solvent was removed to give 8-(3-(morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (31 mg, yield 66%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.23-2.24 (m, 4H), 3.32-3.43 (q, 2H), 4.30 (d, J=8.0 Hz, 1H), 4.74 (d, J=8.0 Hz, 1H), 7.08-7.10 (m, 2H), 7.13-7.19 (m, 6 H), 7.21-7.25 (m, 1H), 7.31-7.33 (m, 1H), 7.55-7.57 (d, J=8.0 Hz, 1H), 7.62-7.64 (m, 1H). LC-MS (ESI) m/z: 439 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[F:11].CCN=C=NCCCN(C)C.Cl.[CH3:24][NH:25][O:26][CH3:27]>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:25]([O:26][CH3:27])[CH3:24])=[O:7])=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.4 %

Procedure:
To a stirred solution of 4-bromo-3-fluorobenzoic acid (5.0 g, 22.83 mmol) in dichloromethane (100 ml) was added WSC (8.8 g, 45.66 mmol), N,O-dimethylhydroxylamine hydrochloride (4.5 g, 45.66 mmol) and stirred at room temperature for 5 h. The solvent was removed and the residue was diluted with ethyl acetate. The organic layer was washed with water, dried (MgSO4), and concentrated to afford 5.47 g of the titled compound as a yellow oil. The compound was used for the next reaction directly.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1.C([O:11][C:12](=O)[CH2:13][C:14]([CH2:16][Cl:17])=O)C>>[Cl:8][C:5]1[S:4][C:3]2=[N:2][C:14]([CH2:16][Cl:17])=[CH:13][C:12](=[O:11])[N:7]2[CH:6]=1
Reactant: Nc1ncc(Cl)s1
Reactant: CCOC(=O)CC(=O)CCl
Agent: Cl
Product: O=c1cc(CCl)nc2sc(Cl)cn12
Temperature: 110 °C
Reaction time: 1 h

Procedure:
2-amino-5-chloro-thiazole hydrochloride (8 g) was reacted with ethyl-4-chloroacetoacetate (15.8 g) in polyphosphoric acid (40 g) under stirring at 110° C. for 1 hour. After cooling, dilution with water and neutralization with 35% NaOH, the precipitate was filtered and washed with water. Crystallization from isopropyl ether gave 2-chloro-7-chloromethyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 123°-125° C. (7.45 g), which was reacted with triphenylphosphine (9.42 g) in acetonitrile (100 ml) under stirring at reflux temperature for 10 hours. After cooling the precipitate was filtered and washed with acetonitrile to give (2-chloro-5H-thiazolo[3,2-a]pyrimidine-5-one-7-yl)-methyl-triphenylphosphonium chloride, m.p. 300°-310° C. dec. (10 g) which was suspended in dimethylsulfoxide (40 ml) and treated with potassium tert-butoxide (2.48 g) dissolved in dimethylsulfoxide (40 ml) at room temperature under stirring for 10 minutes. To the solution of the ylide so obtained 5 -formyl-2-methyl-thiazole (3.1 g) dissolved in dimethylsulfoxide (20 ml) was added and the reaction mixture was kept under stirring at room temperature for 15 minutes: after dilution with ice water and neutralization with NaH2PO4 the precipitate was filtered and crystallized from CH2Cl2 -methanol to give 3.4 g of 2-chloro-7-trans-[2-(2-methyl-5-thiazolyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 224°-226° C., NMR (CDCl3) δ ppm: 2.97 (s) (3H, --CH3), 6.61 (s) (1H, C-6 proton), 6.78 (d) (1H, β-ethenyl proton), 7.82 (d) (1H, α-ethenyl proton), 7.88 (s) (1H, C-3 proton), 8.02 (s) (1H, C-4 thiazolyl proton); JHαHβ =16 Hz.
Reaction SMILES: Br[C:2]1[CH:43]=[CH:42][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[N:29]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:28](=[O:41])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[NH2:44][C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1>>[NH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:2]2[CH:43]=[CH:42][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[S:30](=[O:31])(=[O:32])[N:29]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:28](=[O:41])[CH2:27]5)=[CH:22][CH:21]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:4][CH:3]=2)=[CH:47][CH:46]=1
Reactant: Nc1ccc(B(O)O)cc1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S1(=O)=O
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N)cc4)cc3)cc2)S1(=O)=O

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (361 mg, 0.5 mmol) was treated as described in general procedure G using 4-aminophenylboronic acid (137 mg, 1 mmol) to give 5-{-4-[2-(4′-amino-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[C:5]([O:9][C:10]([N:12]1[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH2:19])[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>>[C:5]([O:9][C:10]([N:12]1[CH2:16][CH2:15][CH:14]([CH2:17][CH:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][S:3][C:1](=[O:4])[CH3:2])[CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: C=C(CC1CCN(C(=O)OC(C)(C)C)C1)C(=O)OCC
Reactant: CC(O)=S
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CSC(C)=O)CC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 23 h
Yield: 79 %

Procedure:
Thioacetic acid (5 mL), which had been cooled to 0° C., was added to a mixture of 3-(2-ethoxycarbonyl-allyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.72 g; 2.54 mmol) and triethyl amine (0.37 mL; 2.67 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes, at room temperature for 23 hours and then poured onto ice-water (400 mL). The aqueous layer was extracted with CH2Cl2. The combined organic phases were washed with saturated NaHCO3, dried and concentrated under reduced pressure. The crude product was purified by flash chromatography (CH2Cl2/EtOAc: 1/10→68/32) to yield 3-(3-acetylsulfanyl-2-ethoxycarbonyl-propyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.72 g, 79%) as an oil.
Reaction SMILES: CO[CH:3]1[S:7][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[N:5][CH2:4]1.Br>>[S:7]1[CH:3]=[CH:4][N:5]=[C:6]1[N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1
Reactant: COC1CN=C(N2CCN(c3ccc(O)cc3)CC2)S1
Agent: Br
Product: Oc1ccc(N2CCN(c3nccs3)CC2)cc1
Yield: 68 %

Procedure:
A mixture of 4 parts of 4-[4-(4,5-dihydro-5-methoxy-2-thiazolyl)-1-piperazinyl]phenol and 150 parts of a hydrobromic acid solution 48% is stirred and refluxed for 12 hours. The reaction mixture is evaporated and the residue is dissolved in water. The precipitated product is filtered off and crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 2.5 parts (68%) of 4-[4-(2-thiazolyl)-1-piperazinyl]phenol; mp 169.9° C.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O:7][C:8]1[C:13]2[O:14][CH2:15][CH2:16][O:17][C:12]=2[CH:11]=[C:10]([CH:18]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[C:19]([NH2:21])=[S:20])[CH:9]=1.[C:35](=O)([O-])O.[Na+].C(OCC)(=O)C>C(#N)C>[CH3:35][S:20][C:19](=[NH:21])[CH:18]([C:10]1[CH:9]=[C:8]([O:7][CH3:6])[C:13]2[O:14][CH2:15][CH2:16][O:17][C:12]=2[CH:11]=1)[NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:27][CH:28]=1
Reactant: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C(N)=S)cc2c1OCCO2
Reactant: O=C([O-])O
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C(=N)SC)cc2c1OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After adding 750 mg of Me3O+BF4− to a solution of 1.92 g of 2-(8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]thioacetamide in 20 ml of acetonitrile, the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give 2-(8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]thioacetimidic acid methyl ester.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][C:29]2=[O:35])[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:21][C:22]4[CH:23]=[C:24]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][C:29]5=[O:35])[CH:25]=[CH:26][CH:27]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CN1CCN(c2cccc(N)c2)C(=O)C1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)C(=O)C1

Procedure:
204 a) An oven dried tube was charged with 1-iodo-3-nitro-benzene (2.60 g, 10.4 mmol), 4-methyl-piperazin-2-one (1.00 g, 8.76 mmol), copper(I) iodide (85.0 mg, 0.446 mmol), (1R,2R)—N,N′-dimethyl-cyclohexane-1,2-diamine (0.14 mL, 0.89 mmol), potassium phosphate (3.75 g, 17.7 mmol) and 1,4-dioxane (10 mL). The tube was carefully evacuated and backflushed with nitrogen three times then sealed. The mixture was heated at 90° C. for 24 hours then cooled to room temperature and diluted with dichloromethane (20 mL). The mixture was filtered through a plug of diatomaceous earth and the filtrate was evaporated. The residue was purified via chromatography using an ISCO automated purification apparatus (silica gel column 40 g and 0%→4% methanol:dichloromethane). 4-Methyl-1-(3-nitro-phenyl)-piperazin-2-one was isolated as a red-brown waxy solid (1.13 g, 55%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.20 (s, 1H), 8.13 (d, J=7.5 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.57 (t, J=8.2 Hz, 1H), 3.79 (t, J=5.1 Hz, 2H), 3.31 (s, 2H), 2.83 (t, J=5.2 Hz, 2H), 2.42 (s, 3H). MS=236 (MH)+. 204 b) 1-(3-Amino-phenyl)-4-methyl-piperazin-2-one was prepared from 4-methyl-1-(3-nitro-phenyl)-piperazin-2-one (1.13 g, 4.80 mmol) in a manner analogous to Example 111a. Product isolated as an orange waxy solid (0.95 g, 96%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.17 (t, J=7.9 Hz, 1H), 6.66-6.57 (m, 3H), 3.71 (br s, 2H), 3.67 (t, J=4.7 Hz, 2H), 3.26 (s, 2H), 2.76 (t, J=4.7 Hz, 2H), 2.40 (s, 3H). MS=206 (MH)+. 204 c) 1-{3-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-4-methyl-piperazin-2-one was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3249 mmol) and 1-(3-amino-phenyl)-4-methyl-piperazin-2-one (75.0 mg, 0.365 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (27.0 mg, 0.0494 mmol) as the ligand in a manner analogous to Example 2d. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.91 (s, 1H), 8.89 (d, J=6.6 Hz, 1H), 8.44 (d, J=8.2 Hz, 2H), 8.08 (d, J=8.0 Hz, 2H), 7.99 (d, J=7.3 Hz, 1H), 7.86 (s, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.31 (t, J=7.9 Hz, 1H), 7.19 (t, J=7.0 Hz, 1H), 6.85 (d, J=7.7 Hz, 1H), 3.68-3.63 (m, 2H), 3.29 (s, 3H), 3.13 (s, 2H), 2.77-2.72 (m, 2H), 2.31 (s, 3H). MP=234-236° C. MS=477 (MH)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([N:15]1[CH2:20][CH2:19][C:18]2[C:21]3[C:22]([S:48][C:17]=2[CH2:16]1)=[N:23][C:24]([CH2:42][N:43]1[CH:47]=[N:46][CH:45]=[N:44]1)=[C:25]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:26]=3[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)(=O)C1C=CC=CC=1.O>O1CCCC1>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([C:26]2[C:25]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[C:24]([CH2:42][N:43]3[CH:47]=[N:46][CH:45]=[N:44]3)[N:23]=[C:22]3[S:48][C:17]4[CH2:16][NH:15][CH2:20][CH2:19][C:18]=4[C:21]=23)[CH:32]=[CH:31][C:30]=1[O:33][CH3:34]
Reactant: CCOC(=O)c1c(Cn2cncn2)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCN(C(=O)c1ccccc1)C3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cn2cncn2)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCNC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
Lithium aluminum hydride (0.164 g) was added to a solution of the compound (5.0 g) obtained in Example 20A in tetrahydrofuran (50 ml), the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (50:1, v/v) to yield ethyl 4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro-2-(1,2,4-triazol-1-ylmethyl)thieno[2,3-b:5,4-c']dipyridine-3-carboxylate (3.08 g, 75%), which was then recrystallized from ethyl acetate-hexane to yield colorless prismatic crystals having a melting point of 164 to 165° C.