Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1Cl.[C:13]1([S:19]([NH2:22])(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>CC(N(C)C)=O>[Cl:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[NH:22][S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: Clc1nc2ccncc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=S(=O)(Nc1nc2cnccc2nc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 4.5 %

Procedure:
2,3-dichloro-pyrido(3,4-b)pyrazine (300 mg, 1.5 mmol, 1 eq.), benzenesulfonamide (235.8 mg, 1.5 mmol, 1 eq.) and K2CO3 (207.3 mg, 1.5 mmol, 1 eq.) are taken up in anhydrous DMA (10 ml) under argon. The reaction mixture is stirred at room temperature for 3 days, then water (15 ml) is added. The aqueous phase is washed with EtOAc (4×10 ml) then lyophilized. The solid residue obtained is extracted with DCM and the solvent is evaporated to near dryness then purified by preparative HPLC using a gradient of H2O, TFA 0.1%/ACN, TFA 0.1%, to afford 21.7 mg (5%) of the title compound. 1H NMR (DMSO-d6) δ 9.13 (s, 1H), 8.42 (d. J=6.7 Hz, 1H), 8.03-7.97 (m, 2H), 7.56 (d, J=6.8 Hz, 1H), 7.51-7.45 (m, 3H). HPLC (max plot) 95%; Rt 1.71 min. LC/MS: (ES+): 321.0, (ES−): 319.0.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Si:13]([N:20]1[CH:23]([S:24][C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22][C:21]1=[O:44])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[CH:45]([C:47]1[S:51][N:50]=[CH:49][CH:48]=1)=[O:46].[Cl-].[NH4+].N1CCC1=O>O1CCCC1.C(OCC)(=O)C.C(Cl)(Cl)Cl.C(OCC)(=O)C.CCCCCC>[Si:13]([N:20]1[CH:23]([S:24][C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:22]([CH:45]([OH:46])[C:47]2[S:51][N:50]=[CH:49][CH:48]=2)[C:21]1=[O:44])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: O=Cc1ccns1
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C1CCN1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)N1C(=O)C(C(O)c2ccns2)C1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
A solution of n-butyl lithium (1.64M in hexane, 0.73 ml) was added to a solution of diisopropylamine (0.17 ml) in dry tetrahydrofuran (THF) (8 ml) at -30° C. under dry argon. After stirring at -30° C. for 10 minutes the mixture was cooled to -76° C. and treated with a solution of 1-t-butyldimethylsilyl-4-tritylthioazetidin-2-one (1) (459 mg) (Bristol-Myers Patent GB No. 2042515 A) in dry THF (4 ml). After a further 15 minutes at -76° C. the stirred mixture was treated with a solution of 5-formylisothiazole (135 mg) (M. P. L. Caton et. al., J. Chem. Soc., 1964, 446) in dry THF (1 ml). After 20 minutes at -76° C. the stirred mixture was treated with saturated ammonium chloride solution (5 ml) and allowed to attain 0° C. The mixture was diluted with ethyl acetate (25 ml) and washed with brine (5 ml), dilute scdium bisulphite solution (5 ml) and brine (3×5 ml). The dried (MgSO4) organic layer was evaporated and the residue chromatographed on silica gel eluting with ethyl acetate/hexane mixtures to give two fractions. The less polar fraction contained a 3:1 mixture of a trans (Isomer A) and a cis-isomer (Isomer B) of the title azetidinone (2) (112 mg), a solid, νmax (CHCl3) 3600-3100, 1745 cm-1 ; δppm (CDCl3) 0.91 and 0.99 (9H, each s, ratio 3:1), 1.60-2.10 (1H, broad signal, exch. D2O), 3.35-3.56 (1.25H, m), 4.06 (0.75H, d, J3 Hz), 4.57 (0.75H, d, J2 Hz), 4.88 (0.25H, d, J5 Hz), 7.00-7.60 (16H, m), 8.29 (1H, d, J2 Hz), both Me3Si signals were obscured by the TMS signal. The more polar fraction contained a trans-isomer (Isomer C) of the title azetidinone (2) (144 mg), a solid, mp 183°-184° C. (prisms ex ethyl acetate/hexane); νmax (CHCl3) 3600-3100, 1735 cm-1 ; δppm (CDCl3) 0.81 (9H, s), 2.70-3.10 (1H, broad signal, exch. D2O), 3.70 (1H, dd, J7 and 2 Hz), 4.10 (1H, d, J2 Hz), 4.30-4.50br (1H, m, collapses to d, J7 Hz on exch. D2O), 6.81br (1H, s), 7.20-7.50 (15H, m), 8.22 (1H, d, J2 Hz), both Me3Si signals were obscured by the TMS signal. (Found: C, 67.1; H, 6.3; N, 4.9; S, 11.2. C32H36N2O2S2Si requires C, 67.1; H, 6.3; N, 4.9; S, 11.2%).
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].O>CN(C=O)C>[O:3]=[C:2]1[NH:1][CH2:7][C:5](=[O:6])[N:4]1[CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C1CNC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)CNC1=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of hydantoin (10.0 g, 0.10 mol) in DMF (100 ml) at 60° C. were added potassium carbonate (20.7 g, 0.15 mol) and benzyl bromoacetate (18.9 ml, 0.12 mol). After stirring the mixture at 60° C. overnight, the reaction mixture was poured into water (250 ml) and the mixture was extracted with ethyl acetate. The organic phase was washed with 5% aqueous citric acid solution and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crystalline residue was washed with diethyl ether, and dried to give phenylmethyl 2-(2,5-dioxoimidazolidinyl)acetate (14.9 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.N#N.CCOC(C)=O>[C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([N:23]1[CH2:22][CH2:21][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:25][CH2:24]1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Acetylbenzoic acid (1.64 g, 10.0 mmol), 1-tert-butoxycarbonylpiperazine (2.23 g, 12.0 mmol), HATU (4.56 g, 12.0 mmol) and HOAT (1.63 g, 12.0 mmol) were dissolved in 20 mL anhydrous DMF in a 100 mL round-bottom flask under a positive pressure of N2 in an ice bath. DIPEA (3.8 mL, 22.0 mmol) was added and the mixture stirred at ambient temperature for 2 h. The solution was diluted with 100 mL of EtOAc and washed with 40 mL each: 0.2 N NaOH solution once and saturated NaCl solution twice. The organic layer was dried over Na2SO4, filtered, concentrated and purified by silica gel chromatography using EtOAc-hexanes (2:1 v/v) as the eluant to give tert-butyl 4-(3-acetylbenzoyl)piperazine-1-carboxylate as 2.97 g of white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.CS(O[CH:12]1[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)([O-])C.[K+]>CN(C=O)C.O>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH:12]2[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]2)[CH:6]=1
Reactant: Ic1cn[nH]c1
Reactant: CS(=O)(=O)OC1CCS(=O)(=O)CC1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S1(=O)CCC(n2cc(I)cn2)CC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
A suspension of 4-iodo-1H-pyrazole (1.00 g, 5.16 mmol), 1,1-dioxidotetrahydro-2H-thiopyran-4-yl methanesulfonate (1.77 g, 7.73 mmol) and cesium carbonate (2.52 g, 7.73 mmol) in DMF (10 mL) was heated to 80° C. for 2 h. The reaction was cooled to room temperature, and potassium tert-butoxide (0.578 g, 5.16 mmol) was added. The reaction mixture stirred at room temperature for 30 minutes and then water (30 mL) was added. The mixture stirred for 4 h and was then filtered. The filter cake was washed with water (10 mL) and dried in vacuo to afford 4-(4-iodo-1H-pyrazol-1-yl)tetrahydro-2H-thiopyran 1,1-dioxide (1.00 g, 60%) as an off-white solid. MS (ESI, pos. ion) m/z 327 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:5]=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36]C)=[O:35])=[CH:28][CH:27]=2)[CH:19]=1.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:5]=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:30][CH:31]=2)[CH:19]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3ccc(OCCCc4ccccn4)cc3C)c2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCCCc2ccccn2)ccc1-c1cccc(COc2ccc(CCC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 75 h
Yield: 47.7 %

Procedure:
A solution of methyl 3-(4-{[2′-methyl-4′-(3-(pyridin-2-yl)propoxy)biphenyl-3-yl]methoxy}phenyl)propanoate (0.401 g, 0.809 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) was added 2 M aqueous sodium hydroxide solution (1.5 mL) and the mixture was stirred at room temperature for 75 hrs. Water was added to the reaction mixture, and the mixture was neutralized with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane-ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (0.186 g, yield 48%) as colorless prism crystals.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[C:8]([CH3:16])[C:9]([F:15])=[C:10]2[C:14]=1[NH:13][CH:12]=[CH:11]2)=[O:5])C.[OH-].[K+].[C:19]([C:23]1[CH:39]=[CH:38][C:26]([CH2:27][NH:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[C:19]([C:23]1[CH:39]=[CH:38][C:26]([CH2:27][N:28]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:4]([C:6]2[CH:7]=[C:8]([CH3:16])[C:9]([F:15])=[C:10]3[C:14]=2[NH:13][CH:12]=[CH:11]3)=[O:5])=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)cc2)cc1
Reactant: CCOC(=O)c1cc(C)c(F)c2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)N(CCc2ccc(F)cc2)Cc2ccc(C(C)(C)C)cc2)c2[nH]ccc2c1F
Reaction time: 64 h
Yield: 67 %

Procedure:
A solution of 4-fluoro-5-methyl-1H-indole-7-carboxylic acid ethyl ester (50 mg, 0.23 mmol) in THF (0.7 mL) was treated with 2 M aq. potassium hydroxide solution (0.23 mL, 0.46 mmol), and the reaction mixture was heated under reflux. After 64 h, the solution was evaporated, the residue dissolved in DMF (3.2 mL) and treated with (4-tert-butyl-benzyl)-[2-(4-fluoro-phenyl)-ethyl]-amine (71 mg, 0.25 mmol), N-methylmorpholine (69 mg, 0.68 mmol), and HBTU (129 mg, 0.34 mmol). After 16 h, the reaction mixture was partitioned between water and EtOAc, the organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography of the residue (SiO2, heptane-EtOAc gradient) afforded the title compound (71 mg, 68%). Yellow oil, MS (EI) 176.1 (100), 351.2 (19), 460.2 (14, M+).
Reaction SMILES: [OH:1][CH:2]([CH3:31])[CH:3]([N:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH:7]=[N:6]1)[CH3:4].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:32][S:33]([O:1][CH:2]([CH3:31])[CH:3]([N:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)[CH2:21][CH2:22]3)=[CH:15][CH:16]=2)[CH:7]=[N:6]1)[CH3:4])(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(N2CCN(c3ccc(-n4cnn(C(C)C(C)O)c4=O)cc3)CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(N2CCN(c3ccc(-n4cnn(C(C)C(C)OS(C)(=O)=O)c4=O)cc3)CC2)cc1
Temperature: 25 °C

Procedure:
N,N-dimethyl-4-pyridinamine (0.01062 mol) and intermediate 5a (0.00708 mol) were suspended in CH2Cl2 (50 ml). A solution of methanesulfonylchloride (0.01062 mol) in CH2Cl2 (30 ml) was added dropwise at room temperature. The mixture was stirred at room temperature for the weekend. N,N-dimethyl-4-pyridinamine (0.00352 mol) and methanesulfonylchloride (0.00358 mol) were added again. The mixture was stirred overnight, washed with water (2×100 ml), dried, filtered over decalite and the solvent was evaporated. The residue was dissolved in MIK (150 ml). Activated charcoal (0.5 g) was added. The mixture was boiled, filtered warm and stirred for 2 hours. The precipitate was filtered off and dried, yielding 1.7 g (50%) of [S-(R*,S*)]-2,4-dihydro-2-(2-methanesulfonyloxy-1-methylpropyl)-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (interm. 5d).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1B1OC(C)(C)C(C)(C)O1)[C:5]#[N:6].Br[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH:26]([OH:28])[CH3:27].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH:26]([OH:28])[CH3:27])[C:5]#[N:6]
Reactant: CC(O)c1ccncc1Br
Reactant: CC1(C)OB(c2ccc(C#N)cc2F)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(O)c1ccncc1-c1ccc(C#N)cc1F
Temperature: 100 °C
Yield: 11.7 %

Procedure:
To the solution of 3-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (306 mg, 1.24 mmol), 1-(3-Bromo-pyridin-4-yl)-ethanol (250 mg, 1.24 mmol) and PdCl2(dppf). CH2Cl2 adduct (81 mg, 0.10 mmol) in DMF (6 mL) was added 2M Na2CO3 solution (1.55 ml, 3.09 mmol) under Nitrogen atmosphere. The mixture was stirred and heated at 100° C. for 4 hrs. After letting cool to room temperature, solvent was removed in vacuo. The resulting residue was dissolved in DCM and saturated NH4Cl solution. After extraction with DCM and separation, the combined extracts were concentrated and purified by ISCO 12 g (10% MeOH/DCM=0-25%) to give 3-Fluoro-4-[4-(1-hydroxy-ethyl)-pyridin-3-yl]-benzonitrile (35 mg, 11%) as colorless solid; ESI-MS m/z: 243 [M+1]+, Retention time 1.19 min. 1H-NMR (MeOD, 400 MHz) δ 1.26 (d, J=6.8 Hz, 3H), 4.71 (q, J=6.8 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.71 (dd, J=8.0, 1.6 Hz, 1H), 7.74 (d, J=9.6 Hz, 1H), 7.75 (d, J=5.2 Hz, 1H), 8.33 (s, 1H), 8.62 (d, J=5.2 Hz, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH2:5][CH2:4][N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[BH4-].[Na+].O.C(OCC)(=O)C>CO>[OH:8][CH:6]1[CH2:5][CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:2]([CH3:1])[CH2:7]1
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC1CC(O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (0.94 g, 4.41 mmol) in methanol (5 mL) was added sodium borohydride (0.22 g, 5.73 mmol) and the reaction was stirred at room temperature for 1 h. Water was added slowly, followed by ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to afford the desired product as a mixture of four stereoisomers, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:21][C:22]([N:24]([O:26][CH3:27])[CH3:25])=[O:23].N12CCCN=C1CCCCC2.Cl>O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:21]([C:22]([N:24]([O:26][CH3:27])[CH3:25])=[O:23])=[C:8]([CH3:9])[C:6]=2[CH:7]=1
Reactant: CON(C)C(=O)CCl
Reactant: CC(=O)c1cc(Cl)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CON(C)C(=O)c1oc2ccc(Cl)cc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.9 %

Procedure:
To a solution (50 mL) of 1-(5-chloro-2-hydroxyphenyl)ethanone (5.00 g) in tetrahydrofuran were added potassium carbonate (8.10 g), sodium iodide (8.78 g) and 2-chloro-N-methoxy-N-methylacetamide (4.43 g), and the mixture was stirred overnight with heating under reflux. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give a white solid. To a solution (50 mL) of the obtained solid in N,N-dimethylformamide was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.38 mL), and the mixture was stirred at 120° C. for 2 hr. The reaction mixture was cooled to room temperature, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane) to give the title object compound (2.15 g, 29%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.[F:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([NH:19][NH2:20])=O.Cl.C(N(CC)CC)C>CC1C=CC(C)=CC=1>[Cl:1][C:2]1[C:7]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:6][C:5]2[N:4]([C:17]([C:16]3[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=3[F:14])=[N:19][N:20]=2)[N:3]=1
Reactant: NNC(=O)c1ccccc1F
Reactant: Clc1cc(-c2cccs2)c(Cl)nn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccc(C)cc1
Product: Fc1ccccc1-c1nnc2cc(-c3cccs3)c(Cl)nn12
Yield: 26 %

Procedure:
A mixture of 3,6-dichloro-4-(thien-2-yl)pyridazine from above (0.5 g, 2.1 mmol), 2-fluorobenzhydrazide (0.66 g, 4,3 mmol) and triethylamine hydrochloride (0.59 g, 4,3 mmol) in p-xylene (10 ml) was stirred and heated at reflux under nitrogen for 30 hours. Upon cooling the volatiles were removed in vacuo. The residue was partly purified by chromatography on silica gel eluting with 50%→66%→100% ethyl acetate-hexane to give the title compound as a yellow solid (0.19 g, 26%). MS (ES+) m/e 331 [MH]+, 333 [MH]+. This material was used without further purification.
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][C:12]([CH:14]([CH3:16])[CH3:15])=[N:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:17]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18]1>C(Cl)Cl.[Pd]>[OH:1][C:2]1([C:9]2[S:13][C:12]([CH:14]([CH3:16])[CH3:15])=[N:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:17]2[CH2:21][CH2:20][C@@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:18]2)[CH2:4][CH2:3]1
Reactant: CC(C)c1ncc(C2(O)CCC(=O)CC2)s1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: [Pd]
Solvent: ClCCl
Product: CC(C)c1ncc(C2(O)CCC(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)CC2)s1
Reaction time: 24 h
Yield: 75.7 %

Procedure:
To a Parr hydrogenation bottle was added 4-hydroxy-4-(2-isopropyl-1,3-thiazol-5-yl)cyclohexanone (0.50 g, 2.09 mmol) and tert-butyl (3R)-pyrrolidin-3-ylcarbamate (0.373 g, 2.0 mmol), dissolved in CH2Cl2 (20 mL), followed by the addition of 10% Pd/C (0.12 g). This mixture was hydrogenated at 35 psi for 24 hour. After the catalyst was filtered and washed with methanol, the filtrate was concentrated in vacuo and chromatographed using MeOH/EtOAc/Et3N (1:9:0.1) to give 0.62 g of title compound in 76% yield. MS (EI) calcd: (M+1)+=409.2. Found: 410.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C@:8]2([CH3:26])[CH2:12]OS(=O)(=O)[N:9]2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[O:24][CH3:25])[CH:7]=1.CN(C)C(N(C)C)=N.[SH:36][CH2:37][C:38]#[N:39]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C@:8]([NH:9][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[O:24][CH3:25])([CH3:26])[CH2:12][S:36][CH2:37][C:38]#[N:39])[CH:7]=1
Reactant: N#CCS
Reactant: COc1ccc(CN2[C@](C)(c3cc(Br)ccc3F)COS2(=O)=O)c(OC)c1
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CN[C@@](C)(CSCC#N)c2cc(Br)ccc2F)c(OC)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 98.2 %

Procedure:
To a solution of (R)-4-(5-Bromo-2-fluoro-phenyl)-3-(2,4-dimethoxy-benzyl)-4-methyl-[1,2,3]oxathiazolidine 2,2-dioxide (5.1 g, 11.1 mmol, Eq: 1.00) and 1,1,3,3-tetramethylguanidine (1.91 g, 2.09 ml, 16.6 mmol, Eq: 1.5) in DMF (77.3 ml) was added at 23° C. 2-mercaptoacetonitrile (1.22 g, 16.6 mmol, Eq: 1.5) dropwise. The reaction mixture was stirred at 23° C. for 16 hours. All volatiles were was evaporated at high vacuum and the resulting residue was stirred vigorously between 60 ml of dichloromethane and 20% (v/v) sulfuric acid solution (60 ml) for 40 hours. Sat. NaHCO3 solution was slowly added (pH=8), then extracted twice with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography with 0-50% ethyl acetate in heptane to give (R)-2-(2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino)propylthio)acetonitrile (5.2 g, 10.9 mmol, 98.3% yield) as a light brown oil. MS (ISP): m/z=453.0 [M+H]+ and 455.2 [M+2+H]+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.ClC(N(C)C)=C(C)C.[NH2:26][CH2:27][C:28]([CH:31]1[CH2:33][CH2:32]1)([OH:30])[CH3:29].C(N(C(C)C)C(C)C)C>ClCCl>[CH:31]1([C:28]([OH:30])([CH3:29])[CH2:27][NH:26][C:15]([C:5]2[CH:4]=[N:3][C:2]([Br:1])=[C:7]([C:8]3[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=3)[N:6]=2)=[O:17])[CH2:33][CH2:32]1
Reactant: O=C(O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1
Reactant: CC(O)(CN)C1CC1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)(CNC(=O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1)C1CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 0.700 g (0.00223 mol) 5-bromo-6-(4-chloro-phenyl)-pyrazine-2-carboxylic acid in 7.0 ml dichloromethane was added a solution of 0.35 g (0.00262 mol) (1-chloro-2-methyl-propenyl)-dimethyl-amine and the mixture was stirred at room temperature for 45 min. To the resulting yellow solution was added dropwise during 15 minutes a solution of 0.296 g (0.00257 mol) 1-amino-2-cyclopropyl-propan-2-ol and 0.433 g ethyldiisopropylamine in 4.0 ml dichloromethane and the mixture was stirred at room temperature for 1 h. The resulting mixture was partitioned between 10% aqueous citric acid and ethyl acetate. The phases were separated and the organic phase was dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with heptane to ethyl acetate=7:3 to yield 0.748 g (81% Th) of the title compound as slightly yellow foam. MS (ISP) (M+H+)=410.1 and 412.0.