Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH:18]([C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1)=[CH2:19]>CN1CCCC1=O.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:19][CH2:18][C:20]3[CH:21]=[N:22][CH:23]=[N:24][CH:25]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1cncnc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2cncnc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.3 %

Procedure:
To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.49 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.14 g, 2.5 mmol) and allowed to stir for 10 min at RT. 5-vinyl pyrimidine (0.132 g, 1.25 mmol) was added and stirred for further 5 h at 60 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200, mesh, Diameter of column—2.5 cm, Height of silica approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.050 g, 32.6% yield). 2,8-Dimethyl-5-(2-pyrimidin-5-yl-ethyl)-2,3,4,5-tetrahydro-1-pyrido[4,3-b]indole (0.040 g, 0.13 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.015 g, 0.119 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.046 g, 90% yield).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:4]=[C:5]([C:8]#[N:9])[S:6][CH:7]=1.CO[Na].[NH4+:15].[Cl-]>CO.C(Cl)Cl>[F:11][C:2]([F:1])([F:10])[C:3]1[N:4]=[C:5]([C:8]([NH2:15])=[NH:9])[S:6][CH:7]=1
Reactant: [NH4+]
Reactant: N#Cc1nc(C(F)(F)F)cs1
Agent: CO[Na]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: N=C(N)c1nc(C(F)(F)F)cs1
Temperature: 25 °C
Reaction time: 96 h
Yield: 32 %

Procedure:
To a solution of compound 285b (28.12 g, 1.0 eq.) in MeOH (13 mL) in an ice/water bath was added MeONa (853 mg, 0.1 eq.) portionwise. The reaction mixture was stirred in the ice/water bath for 15 min and at room temperature for 1 hr. NH4Cl (16.88 g, 2.0 eq.) was then added and the mixture was stirred at room temperature for 4 days. Solvent was removed in vacuo. The solid obtained was suspended in DCM (60 mL) and recovered by filtration. The solid was suspended in MeOH (50 mL) and filtered. The filtrate was concentrated under reduced pressure to yield compound 285 as a white solid in 32% yield. MS (ESI, EI+) m/z=196 (MH+).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][C@H:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[C@@H:6]([CH2:14][OH:15])[CH2:5]1)[CH:2]=[CH2:3].C(N(CC)C(C)C)(C)C.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>C(Cl)Cl>[CH2:1]([N:4]1[CH2:8][C@H:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[C@@H:6]([CH2:14][O:15][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCN1C[C@H](CO)[C@@H](c2ccsc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCN1C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c2ccsc2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.3 %

Procedure:
A solution of 1.06 g (4.75 mmol) of 1-(prop-2-enyl)-(3-(R)-(hydroxymethyl))-4-(S)-(3-thienyl)pyrrolidine (from Step A) in 12.0 mL of CH2Cl2 at 0° C. was treated with 0.99 mL (5.7 mmol) of N,N-diisopropylethylamine and 855 mg (5.6 mmol) of t-butyldimethylsilyl chloride. After warming to rt and stirring for 20 h, the solution was partitioned between 100 mL of ether and 100 mL of H2O. After separating the phases, the aqueous layer was extracted with 100 mL of ether. The combined organic phases were dried over MgSO4 and concentrated. The residue was purified by flash chromatography eluting with 3:1 v/v hexanes/EtOAc to yield 1.24 g (77%) of the title compound: RF: 0.54 (3:2 v/v hexanes/EtOAc); 1HNMR (300 Mhz) δ 0.0 (s, 6H), 0.86 (s, 9H), 2.35 (m, 1H), 2.52-2.71 (m, 3H), 2.97-3.20 (m, 4H), 3.54-3.66 (m, 2H), 5.06-5.21 (m, 2H), 5.89 (m, 1H). 6.98-7.02 (m, 2H), 7.22 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH2:7].[Br:17][C:18]1[CH:19]=[N:20][C:21](Cl)=[N:22][CH:23]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=1)[CH2:6][NH:7][C:21]1[N:22]=[CH:23][C:18]([Br:17])=[CH:19][N:20]=1
Reactant: Clc1ncc(Br)cn1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: FC(F)(F)c1cc(CNc2ncc(Br)cn2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 61.4 %

Procedure:
3,5-Bis-trifluoromethyl-benzylamine (10 g) and 5-bromo-2-chloro-pyrimidine (12 g) are dissolved in 1,4-dioxane (50 ml) and thereto is added N,N-diisopropylethylamine (10.7 ml) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amine (10.1 g). MS (m/z): 713 [M+H]+
Reaction SMILES: [CH3:1][Mg]Br.CON[C:7]([CH:9]1[CH2:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH3:16])[CH2:10]1)=[O:8].Cl>C(OCC)C.CC1CCCO1>[C:7]([CH:9]1[CH2:10][N:11]([C@H:15]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH3:16])[C:12](=[O:14])[CH2:13]1)(=[O:8])[CH3:1]
Reactant: C[Mg]Br
Reactant: CONC(=O)C1CC(=O)N([C@@H](C)c2ccc(OC)cc2)C1
Agent: Cl
Solvent: CC1CCCO1
Solvent: CCOCC
Product: COc1ccc([C@H](C)N2CC(C(C)=O)CC2=O)cc1
Temperature: 20 °C
Reaction time: 1.25 h

Procedure:
530 mL of a 3 M solution of methylmagnesium bromide in diethylether is added slowly to a cooled solution of 271 g of (R/S)—N-Methoxy-5-oxo-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-3-carboxamide (mixture of diastereoisomers) in 1.4 L of 2-methyltetrahydrofuran so that the temperature remains under 0° C. After complete addition the temperature is kept for 75 minutes at 0° C. and then warmed up to 20° C. The suspension is stirred 16 hours at 20° C. Under cooling 650 mL of a 4 M hydrochloric acid are added. The organic phase is separated and washed with 500 mL saturated sodium carbonate solution and with 500 mL saturated brine. The organic phase is dried over sodium sulfate. After filtration the solvent is evaporated under reduced pressure.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([NH:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1.[C:16]([Cu])#[N:17]>CN(C=O)C>[C:16]([C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([NH:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1)#[N:17]
Reactant: N#C[Cu]
Reactant: CC(=O)Nc1ccc(Br)c2c1CCCC2
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C#N)c2c1CCCC2
Temperature: 25 °C
Yield: 998.3 %

Procedure:
A suspension of compound 2B (1 g, 3.7 mmol) and CuCN (0.335 g, 0.374 mmol) in anhydrous DMF (8 mL) was refluxed for 5 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure to remove most of the DMF and the remaining residue triturated with EtOAc (5×). The combined EtOAc was washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure to dryness to yield compound 2C (0.8 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[Cl:8]>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[C:11](=[O:13])[CH2:10][CH2:9]2
Reactant: O=C(O)CCc1ccc(Cl)c(Cl)c1
Solvent: O=S(Cl)Cl
Product: O=C1CCc2cc(Cl)c(Cl)cc21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 20 g of 3-(3,4-dichlorophenyl)-propionic acid [J. Med. Chem., Vol. 16(2) (1973), p. 101-106] and 100 ml of thionyl chloride was refluxed for 30 minutes and the thionyl chloride was then evaporated. The residue was taken up in 20 ml of methylene chloride and the solution was poured into a suspension of 20 g of aluminum chloride in 150 ml of methylene chloride. The mixture was stirred for one hour at room temperature and 30 minutes at 50° C. The mixture was poured over ice and was stirred for 30 minutes and then was extracted with methylene chloride.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[S:14][C:15]3[N:16]=[C:17]([N:28]4[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[N:30]=[C:29]4[CH2:37][CH3:38])[N:18]=[C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:20]=3[N:21]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]([CH2:12][C:13]2[S:14][C:15]3[N:16]=[C:17]([N:28]4[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[N:30]=[C:29]4[CH2:37][CH3:38])[N:18]=[C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:20]=3[N:21]=2)[CH2:11]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)sc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)sc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl]azetidine-1-carboxylic acid tert-butyl ester in DCM (10 mL) was added TFA (3 mL) and the resulting mixture allowed to stir at r.t. for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 2-Azetidin-3-ylmethyl-5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine as a yellow oil (209 mg, 52% over two steps). 1H NMR (CDCl3, 400 MHz): δ 7.99-7.98 (1 H, m), 7.75-7.74 (1 H, m), 7.28-7.25 (2 H, m), 4.41 (4 H, brd s), 3.89-3.84 (5 H, m), 3.59 (2 H, t, J=7.25 Hz), 3.48 (2 H, s), 3.36-3.34 (5 H, m), 1.43 (3 H, t, J=7.47 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:24][C:21]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1)[CH:6]=[O:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C=O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
To a solution of 3-methoxy-4-hydroxy benzaldehyde (10.0 g; 64.9 mmol) in dry acetone (80 ml), potassium carbonate (17.9 gm, 129.8 mmol) and BnBr (11.5 ml, 97.30 mmol) were added and stirred in room temperature for 18 hours. Potassium carbonate was filtered, acetone concentrated and the residue purified on silica gel to give the title compound as a crystalline solid 14 gm, 88%). 1H NMR (CDCl3, 200 MHz): δ 3.9 (s, 3H), 5.2 (s, 2H), 6.95 (d, J=8.37 HZ, 1H), 7.4 (m, 7H), 9.8 (s, 1H); Mass (m/z): M+242, mp: 58° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[N:12]([C:15]([F:18])([F:17])[F:16])[C:11](=[O:19])[O:10]2)=[CH:5][CH:4]=1.[OH:20]O>CC(C)=O>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[N:12]([C:15]([F:18])([F:17])[F:16])[C:11](=[O:19])[O:10]2)=[CH:5][CH:4]=1)=[O:20]
Reactant: OO
Reactant: CSc1ccc(-n2oc(=O)n(C(F)(F)F)c2=O)cc1
Solvent: CC(C)=O
Product: CS(=O)c1ccc(-n2oc(=O)n(C(F)(F)F)c2=O)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 2-(4'-methylthiophenyl)-4-trifluoromethyl-1,2,4-oxadiazolidine-3,5-dione (29.2 grams; 0.10 mol) in acetone (200 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. Hydrogen peroxide (16 grams; 0.14 mol) is then slowly added, with stirring, at room temperature. Stirring is continued for a period of about 72 hours after the addition is completed. After this time the solvent is removed from the reaction mixture by evaporation resulting in a solid product. The product is washed, recrystallized, and dried to yield 2-(4'-methylsulfinylphenyl)-4-trifluoromethyl-1,2,4-oxadiazolidine-3,5-dione.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:5]=1[O:6][CH2:7][CH2:8][CH:9](O)[NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:3].C[OH:22]>N.[Ni]>[NH2:3][CH2:2][C:4]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:5]=1[O:6][CH2:7][CH:8]([OH:22])[CH2:9][NH:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CO
Reactant: CC(C)(C)NC(O)CCOc1ccc(Cl)cc1C#N
Agent: [Ni]
Agent: Cl
Agent: N
Product: CC(C)(C)NCC(O)COc1ccc(Cl)cc1CN

Procedure:
6.3 gm (0.02 mol) of 1-(2-cyano-4-chlorophenoxy)-3-hydroxy-3-tert.-butylamino propane hydrochloride were dissolved in 100 ml of methanol containing 10 ml of NH3 and the mixture was hydrogenated under normal pressure at 20° C. over Raney-nickel. After separation of the catalyst, the solvent was distilled off in vacuo, and the residue was admixed with ether and water. After an addition of a small amount of NaOH, the aqueous phase was separated and the organic phase was washed with water and dried over MgSO4. After distilling off the ether, a solid residue remained which was recrystallized from ethyl acetate with an addition of petroleum ether to obtain 1-(2-aminomethyl-4-chlorphenoxy)-2-hydroxy-3-tert.-butylamino propane. The base was dissolved in ethanol and ethereal HCl was added thereto. The precipitated crystals of the hydrochloride of the base were isolated to obtain 3.1 gm of the hydrochloride having a melting point of 118°-120° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Brc1cccc(-c2ccccc2)n1
Temperature: 100 °C

Procedure:
2,6-Dibromo-pyridine (1.2 g, 0.508 mmol), phenylboronic acid (0.620 g, 0.508 mmol) and sodium carbonate (2 M aq., 30 mL) were dissolved in MeOH (10 mL) and toluene (30 mL) and the solution was degassed with bubbling N2 (g). Tetrakis(triphenylphosphine)palladium(0) (0.172 g, 0.149 mmol) was added and the reaction was heated to 100° C. overnight. After cooling the reaction was submitted to standard aqueous workup and purified by silica gel chromatography to give the title compound
Reaction SMILES: Br[CH:2]([CH3:14])[C:3]([C:5]1[CH:6]=[N:7][C:8]([CH:11]([F:13])[F:12])=[CH:9][CH:10]=1)=O.[C:15]([NH:18][C:19]([NH2:21])=[NH:20])(=[O:17])[CH3:16].O>CN(C=O)C>[F:12][CH:11]([F:13])[C:8]1[N:7]=[CH:6][C:5]([C:3]2[NH:21][C:19]([NH:18][C:15](=[O:17])[CH3:16])=[N:20][C:2]=2[CH3:14])=[CH:10][CH:9]=1
Reactant: CC(=O)NC(=N)N
Reactant: CC(Br)C(=O)c1ccc(C(F)F)nc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(C)c(-c2ccc(C(F)F)nc2)[nH]1
Temperature: 50 °C
Reaction time: 16 h
Yield: 45.5 %

Procedure:
Dissolve 2-bromo-1-[6-(difluoromethyl)-3-pyridyl]propan-1-one (0.500 g, 1.89 mmol) and acetyl guanidine (0.514 g, 5.68 mmol) in DMF (12 mL). Heat the mixture to 50° C., and stir for 16 hours. Pour the mixture into water, and extract with EtOAc (3×20 mL). Dry the combined organic extracts over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure. Purify the resulting residue by flash chromatography (silca gel) eluting with a 40:1 ratio of DCM/MeOH to give the title compound as a white solid (0.229 g, 46% yield). LCMS (m/z) 267 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([C@@H:13]2[CH2:16][CH2:15][NH:14]2)=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[O:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([C@@H:13]2[CH2:16][CH2:15][N:14]2[CH:21]2[CH2:22][CH2:23][O:18][CH2:19][CH2:20]2)=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCOCC1
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCN2)on1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCN2C2CCOCC2)on1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of (S)-Azetidine-2-carboxylic acid (3-tert-butyl-isoxazol-5-yl)-amide; hydrochloride (78.6 mg; 0.303 mol) in DMF (1 mL) is added tetrahydro-4H-pyran-4-one (0.056 mL; 0.606 mmol) and acetic acid (0.069 mL; 1.212 mmol). The reaction is stirred at room temperature for 50 minutes before adding sodium cyanoborohydride (57 mg; 0.909 mmol). The reaction mixture is left stifling at room temperature for 18 hours. After this time, the reaction mixture is quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 308 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]2[C:13](=[O:14])[C:12]([C:15]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([O:25][Si](C(C)C)(C(C)C)C(C)C)=[CH:24][C:18]=4[S:17](=[O:37])(=[O:36])[N:16]=3)=[C:11]([OH:38])[C:10]3[S:39][CH:40]=[CH:41][C:9]2=3)=[CH:5][N:6]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1.O>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]2[C:13](=[O:14])[C:12]([C:15]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([OH:25])=[CH:24][C:18]=4[S:17](=[O:36])(=[O:37])[N:16]=3)=[C:11]([OH:38])[C:10]3[S:39][CH:40]=[CH:41][C:9]2=3)=[CH:5][N:6]=1
Reactant: CC(C)[Si](Oc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3sccc3n(Cc3cnc(Cl)s3)c1=O)N2)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=c1c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2sccc2n1Cc1cnc(Cl)s1
Yield: 84.2 %

Procedure:
The product of Example 307D (0.235 g 0.36 mmol.) in tetrahydrofuran (10 mL) was reacted with tetrabutylamonium fluoride in tetrahydrofuran (1M, 0.43 mL) at 25° C. for 2 hours. The reaction mixture was diluted with water (50 mL) and adjusted to pH 2 with 1 M HCl and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to give the title compound (0.15 g, 84%). MS (ESI−) m/z 493 (M−H)−. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6)δ ppm 5.63 (s, 2 H) 7.17 (s, 1 H) 7.20 (d, J=2.57 Hz, 1 H) 7.57 (d, J=8.82 Hz, 1 H) 7.85 (d, J=5.52 Hz, 1 H) 7.95 (s, 1 H) 8.42 (d, J=5.15 Hz, 1 H) 10.42 (s, 1 H) 13.95 (s, 1H) 15.10 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[N:10]=[N:11][C:12](Cl)=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=1.C([O-])(=[O:26])C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:26])[NH:11][N:10]=1
Reactant: CC(C)c1cc(Sc2c(Cl)cc(CC(=O)O)cc2Cl)nnc1Cl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1cc(Sc2c(Cl)cc(CC(=O)O)cc2Cl)n[nH]c1=O
Temperature: 100 °C
Yield: 47.8 %

Procedure:
A mixture of [3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-ylsulfanyl)-phenyl]-acetic acid (75) (90 mg, 0.23 mmol) and sodium acetate (66 mg, 0.80 mmol) in glacial acetic acid (2.5 mL) was heated to 100° C. for 7 h. At this time, the reaction was concentrated in vacuo. The residue was slurried three times in a 1:1 solution of methylene chloride:hexanes followed by concentration under vacuum. The resulting solid was diluted with water (100 mL) and was then treated with a 1N aqueous sodium hydroxide solution to adjust the pH between 10-11. This solution was extracted with ethyl acetate. The organics were discarded. The aqueous layer was then acidified to pH=2-3 with a 1N aqueous hydrochloric acid solution. This solution was then extracted with ethyl acetate (2×100 mL). The organics were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried with magnesium sulfate, filtered, and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70:30 hexanes/ethyl acetate with 2% glacial acetic acid) afforded [3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylsulfanyl)-phenyl]acetic acid (76) (41 mg, 17.5%) as a white solid; EI(+)-HRMS m/e calcd for C15H14Cl2N2O3S (M+H)+ 373.0175, found 373.0175. Exact Mass=372.0102; Molecular Weight=373.26
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.[CH3:12][C:13]([CH3:19])([C:16](=[O:18])[CH3:17])[CH2:14][OH:15].N1C=CC=CC=1.Cl>C(Cl)(Cl)Cl>[CH3:12][C:13]([CH3:19])([C:16](=[O:18])[CH3:17])[CH2:14][O:15][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: CC(=O)C(C)(C)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)C(C)(C)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71 %

Procedure:
47.6 g (0.25 mol) of 4-toluenesulphonyl chloride were dissolved in 100 ml of chloroform, 35 g (0.3 mol) of 2,2-dimethyl-1-hydroxy-butan-3-one were added, and 40 ml (0.5 mol) of pyridine were added dropwise at 0° to 5° C. The reaction mixture was subsequently stirred at room temperature for 15 hours and poured onto 200 g of ice and 70 ml of concentrated hydrochloric acid and the organic phase was separated off, washed three times with 200 ml of water each time, dried over sodium sulphate and concentrated. The residue was taken up in 100 ml of petroleum ether, whereupon the end product crystallized out. 48 g (71% of theory) of 2,2-dimethyl-1-tosyloxy-butan-3-one were obtained as colorless crystals of melting point 49°-52° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:17][OH:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1)(C)(C)C.Cl>CO.O1CCOCC1>[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1)[CH2:17][OH:18]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1cccc(Br)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@H](CO)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (S)-[2-(3-bromo-phenyl)-1-hydroxymethyl-ethyl]-carbamic acid tert-butyl ester (400 mg, 1.21 mmol) in methanol (30 mL) was added 4 M HCl in dioxane (2 mL, excess). The reaction mixture was stirred at room temperature for 14 h. After concentration in vacuo, the residue was used for the next step without purification. LCMS (M+H)+ m/z 230 (t=0.78 min.)
Reaction SMILES: N1CCCCC1.C(O)=O.CC1(C)[O:18][C:16](=[O:17])[CH2:15][C:13](=O)O1.C(=O)[C:21]1[CH:30]=[CH:29][C:26]([O:27][CH3:28])=[C:23]([O:24][CH3:25])[CH:22]=1>>[CH3:25][O:24][C:23]1[CH:22]=[C:21]([CH2:13][CH2:15][C:16]([OH:18])=[O:17])[CH:30]=[CH:29][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: C1CCNCC1
Solvent: O=CO
Product: COc1ccc(CCC(=O)O)cc1OC

Procedure:
After dropping 20.4 g (23.7 ml, 0.24 mol) of piperidine to 27.6 g (22.6 ml, 0.6 mol) of formic acid under stirring and cooling, 7.2 g (0.05 mol) of Meldrum's acid and 8.3 g (0.05 mol) of veratraldehyde were added to the above mixture, then the procedure of Example 35 was followed.