Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:14](N)[CH2:15][NH2:16].Cl.C>C(=S)=S>[CH2:1]([C:12]1[NH:13][CH2:14][CH2:15][N:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: NCCN
Reactant: CCCCCCCCCCCC#N
Agent: Cl
Solvent: S=C=S
Product: CCCCCCCCCCCC1=NCCN1
Temperature: 125 °C

Procedure:
18.32g (100 mmoles) of undecyl cyanide, 8.5ml (127 mmole) of ethylenediamine and 0.5ml of carbon disulfide were mixed and heated in an oil bath at 125° C. for 24 hours. The reaction mixture was cooled, treated with dilute hydrochloric acid and treated with charcoal. The light yellow filtrate was extracted with ethyl acetate, the organic extracts dried over magnesium sulfate and concentrated. The residue was Kugelrohr distilled and then recrystallized from toluene. Yield 13.7 g (61.1), m.p. 82° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:12].[CH2:13]([O:15][C:16](=[O:28])[CH:17]([NH2:27])[CH:18]([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])[CH3:14].N1C=CC=CC=1>ClC(Cl)C>[CH2:13]([O:15][C:16](=[O:28])[CH:17]([NH:27][S:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:12])[CH:4]=1)(=[O:10])=[O:9])[CH:18]([C:19]([F:22])([F:20])[F:21])[C:23]([F:25])([F:26])[F:24])[CH3:14]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: CCOC(=O)C(N)C(C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CCOC(=O)C(NS(=O)(=O)c1ccc(F)c(C)c1)C(C(F)(F)F)C(F)(F)F
Reaction time: 18 h
Yield: 64.7 %

Procedure:
To a vial containing a solution of 4-fluoro-3-methylbenzenesulfonyl chloride (50 mg, 0.24 mmol) and 2-amino-4,4,4-trifluoro-3-trifluoromethyl-butyric acid ethyl ester (61 mg, 0.24 mmol) in anhydrous dichloroethane (1 mL) was added pyridine (58 μL, 0.719 mmol). The vial was capped and shaken for 18 h. The solvent was removed in vacuo and the residue transferred to a separatory funnel with EtOAc (100 mL) and washed with distilled water (100 mL×2). The organic layer was removed and the combined aqueous washings were extracted with EtOAc (100 mL×2). The organic extracts were combined, washed with brine (100 mL), dried (MgSO4), filtered, and evaporated to give a white solid (66 mg). This material was purified by Gilson RP-HPLC (column YMC Combiprep 50×20 mm, gradient 10-100% CH3CN: H2O) to afford a white solid (29 mg, 28%). Mass Spectrum (−ESI): 424 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:6][C:5]=1[OH:21].[CH3:23]OC(C1C(=O)NC(C2C=CC=C(C(F)(F)F)C=2)=CC=1C)=O.C(=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5](=[O:21])[N:6]([CH3:23])[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)=[CH:8][C:9]=1[CH3:10])=[O:22]
Reactant: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)[nH]c1=O
Reactant: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)nc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)n(C)c1=O
Temperature: 25 °C
Reaction time: 70 h
Yield: 32.3 %

Procedure:
A solution of 0.62 g (2.0 mmol) of 2-hydroxy-4-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid methyl ester/4-methyl-2-oxo-6-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid methyl ester in 20 ml of DMF was treated with 0.78 g (2.4 mmol) of cesium carbonate, followed by 0.62 ml=1.41 g (10.0 mmol) of iodomethane. This mixture was stirred for 70 hours at RT, then poured into crashed ice and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (heptane/EtOAc 4:1 to 0:1) to give 0.21 g (33%) of the title compound as light yellow solid; [MS: 326.1 (MH+)] and 0.42 g (65%) of 2-methoxy-4-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid methyl ester as light yellow oil. MS: 326.1 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([S:4]Cl)[CH3:3].[NH:7]1[C:11](=[O:12])[C:10](=[O:13])[NH:9][C:8]1=[O:14].[Na]>>[C:2]([S:4][N:7]1[C:11](=[O:12])[C:10](=[O:13])[NH:9][C:8]1=[O:14])([CH3:6])([CH3:3])[CH3:1]
Reactant: CC(C)(C)SCl
Reactant: O=C1NC(=O)C(=O)N1
Agent: [Na]
Product: CC(C)(C)SN1C(=O)NC(=O)C1=O

Procedure:
1-(t-Butylthio)imidazolidinetrione is prepared by adding a solution of 1,1-dimethylethane sulfenyl chloride (0.1 mole) to a stirred slurry of sodium imidazolidinetrione (0.1 mole). 1-(t-Butylthio)imidazolidinetrione, m.p. 150.5°-152° C. recrystallized from toluene, is recovered.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C:12](=[O:26])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:27])[N:5]=1)[CH3:3].Cl[C:29]1[C:30]2[CH:37]=[CH:36][NH:35][C:31]=2[N:32]=[CH:33][N:34]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:32]1[C:31]2[NH:35][CH:36]=[CH:37][C:30]=2[C:29]([NH:1][C@H:2]([C:4]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:23])([F:25])[F:24])[CH:15]=3)[C:12](=[O:26])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[F:27])[N:5]=2)[CH3:3])=[N:34][CH:33]=1
Reactant: C[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]ccc12)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 27.8 %

Procedure:
Under nitrogen, to (S)-2-(1-aminoethyl)-5-fluoro-3-(3-(2,2,2-trifluoroethoxy)phenyl)quinazolin-4(3H)-one (50 mg, 0.13 mmol, 1.0 equiv) in t-BuOH (0.13 mL) at 23° C. was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (24 mg, 0.16 mmol, 1.2 equiv) and diisopropylethylamine (46 μL, 0.26 mmol, 2.0 equiv). After stirring for 16 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 18 mg of the title compound (28% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:55])([CH3:54])[C:13]([NH:15][C@H:16]1[C:22](=[O:23])[NH:21][C:20]2[CH:24]=[CH:25][C:26]3[C:31]([C:19]=2[CH:18]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[CH2:45][NH:46]C(OC(C)(C)C)=O)=[CH:35][CH:34]=2)[CH2:17]1)=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:56]>CO>[ClH:56].[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:55])([CH3:54])[C:13]([NH:15][C@H:16]1[C:22](=[O:23])[NH:21][C:20]2[CH:24]=[CH:25][C:26]3[C:31]([C:19]=2[CH:18]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[CH2:45][NH2:46])=[CH:37][CH:38]=2)[CH2:17]1)=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CC2C[C@@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)C(=O)Nc3ccc4ccccc4c32)cc1
Agent: Cl
Solvent: CO
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CC(Cc2ccc(-c3ccccc3CN)cc2)c2c(ccc3ccccc23)NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of of 2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-4-oxo-1-[[2′-[(t-butoxycarbonylamino)methyl][1,1′-biphenyl]-4-yl]methyl]-1H-naphtho[2,1-b]azepin-3(R)-yl]propanamide (Step H) in methanol is added 9N aqueous hydrochloric acid. The reaction mixture is stirred overnight at room temperature then the solvent is removed under vacuum. The resulting oil is dissolved in methanol and the solvent is removed under vacuum to afford the title compound.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][C:5]1[N:10]=[C:9]([CH:11]=O)[CH:8]=[CH:7][CH:6]=1>>[CH2:1]([NH:3][CH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:4])[N:10]=1)[CH3:2]
Reactant: Cc1cccc(C=O)n1
Reactant: CCN
Product: CCNCc1cccc(C)n1

Procedure:
prepared by reaction of ethylamine with 6-methyl-pyridine-2-carbaldehyde
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4][C@H:3]2[CH2:6][NH:7][CH2:8][C@@H:2]12.Br[C:17]1[CH:18]=[C:19]([CH3:24])[C:20]([Cl:23])=[N:21][CH:22]=1>>[Cl:23][C:20]1[N:21]=[CH:22][C:17]([N:7]2[CH2:6][C@H:3]3[C@H:2]([N:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]3)[CH2:8]2)=[CH:18][C:19]=1[CH3:24]
Reactant: Cc1cc(Br)cnc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2CNC[C@H]21
Product: Cc1cc(N2C[C@@H]3CCN(C(=O)OC(C)(C)C)[C@@H]3C2)cnc1Cl
Yield: 41 %

Procedure:
The product from Example 15E and 5-bromo-2-chloro-3-methyl pyridine were processed as described in Example 1E to provide the title compound (41% yield). MS (DCI/NH3) m/z 338/340 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[O:20]1[C:24]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[O:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:20]1[C:24]2([CH2:29][CH2:28][N:27]([S:16]([C:14]3[S:15][C:11]([C:7]4[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=4[CH3:10])=[CH:12][CH:13]=3)(=[O:18])=[O:17])[CH2:26][CH2:25]2)[O:23][CH2:22][CH2:21]1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N3CCC4(CC3)OCCO4)s2)s1
Reaction time: 1 h
Yield: 37 %

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step 1 of example 9 (200 mg; 0.59 mmol; 1 eq.), is dissolved in DCM (10 ml). 1,4-Dioxa-8-azaspiro[4.5]decane (170.0 mg; 1.19 mmol; 2 eq.) and DIEA (460.4 mg; 3.56 mmol; 6 eq.) are added. After one hour, the solvents are evaporated. The crude product is purified by preparative HPLC, affording Compound (18) as yellow solid (96 mg; 37%). 1H NMR (DMSO-d6) δ 1.66-1.78 (m, 4H), 2.15 (s, 3H), 2.45 (s, 3H), 3-3.15 (m, 4H), 3.83 (s, 4H), 7.31 (d, J=3.8 Hz, 1H), 7.61 (d, J=3.8 Hz, 1H), 12.15 (br s, 1H). M−(ESI): 444.25; M+(ESI): 442.23. HPLC, Rt: 3.39 min (purity: 99.6%).
Reaction SMILES: [F:1][CH:2]([F:10])[CH:3]([CH:7]([F:9])[F:8])[CH:4]([F:6])[F:5].S(=O)(=O)(O)[OH:12]>O>[F:1][CH:2]([F:10])[C:3]([OH:12])([CH:7]([F:9])[F:8])[CH:4]([F:6])[F:5]
Reactant: O=S(=O)(O)O
Reactant: FC(F)C(C(F)F)C(F)F
Solvent: O
Product: OC(C(F)F)(C(F)F)C(F)F

Procedure:
As another example, the 2-difluoromethyl-1,1,3,3-tetrafluoro-2-propanol may be prepared by fluorinating commercially available 1,1,3-trichloro-2-propanone to form 1,1,3-trifluoro-2-propanone which may then be reacted with CF2 carbene to form 2-fluoromethyl-1,1,3,3-tetrafluoro-1-propene. The 2-fluoromethyl-1,1,3,3-tetrafluoro-1-propene may then be hydrogenated to form 2-fluoromethyl-1,1,3,3-tetrafluoropropane. The 2-fluoromethyl-1,1,3,3-tetrafluoropropane may then be dehydrogenated to form 2-difluoromethyl-1,3,3-trifluoro-1-propene which may then be reacted with hydrogen fluoride to form 2-difluoromethyl-1,1,3,3-tetrafluoropropane. The 2-difluoromethyl-1,1,3,3-tetrafluoropropane may then be dehydrogenated and then reacted with sulfuric acid and then water to form 2-difluoromethyl-1,1,3,3-tetrafluoro-2-propanol.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]=[CH2:13])[CH:7]=[CH:6][C:5]=1[OH:14].[OH-].[Na+].Cl>CO>[OH:14][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=1[C:3]([OH:15])=[O:2]
Reactant: C=CCOc1ccc(O)c(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOc1ccc(O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.2 %

Procedure:
5-allyloxy-2-hydroxy-benzoic acid methyl ester (6.10 g, 29.30 mmol) was dissolved in methanol (25.0 mL, 1.2 M) . This solution was treated with aq NaOH (75 mL, 1.33 M, 100 mmol) and stirred at room temperature for 48 h. The reaction is acidified to pH 1-2 with conc. HCl and extracted with ethyl acetate (4×). The combined organic extracts are washed with H2O(2×), aq saturated NaCl, dried with Na2SO4, filtered and concentrated to give 2-hydroxy-5-propoxy-benzoic acid (5.30 g, 91%) as a pale yellow solid: Anal. calcd for C10 H10O4: C, 61.85; H, 5.19. Found: C, 62.06; H, 5.27.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: CN1CCN(C)C1=O
Reactant: Nc1ccccc1N1CCOCC1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C)C1=Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 1,3-dimethyl-2-imidazolidinone (7 g) in benzene (45 ml), phosphorus oxychloride (6 ml) and 4-(2-aminophenyl)morpholine (8.5 g) in benzene (30 ml) was heated for 30 hours at 65°-70° C. The product was recrystallised from hexane to give 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)phenyl]morpholine (m.p. 133°-134° C.).
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@@H:7]([CH2:14]/[CH:15]=[C:16](/[CH3:20])\[CH2:17][CH:18]=[CH2:19])[C:8](N(OC)C)=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:23][Mg]Cl>C1COCC1>[C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@@H:7]([CH2:14]/[CH:15]=[C:16](/[CH3:20])\[CH2:17][CH:18]=[CH2:19])[C:8](=[O:9])[CH3:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Mg]Cl
Reactant: C=CC/C(C)=C\C[C@H](O[Si](C)(C)C(C)(C)C)C(=O)N(C)OC
Solvent: C1CCOC1
Product: C=CC/C(C)=C\C[C@H](O[Si](C)(C)C(C)(C)C)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To a THF (300 mL) solution of the starting material 5 (152.6 g, 465 mmol) was slowly added methylmagnesium chloride (200 mL, 3.0 M in THF, 600 mmol) in 30 min at 0° C. The reaction was stirred over 30 min at 0° C., and was carefully quenched with saturated ammonium chloride water solution (300 mL). Its pH was then adjusted to 7 with 1N hydrochloric acid. Volatiles were removed via a rotavap. The residue was extracted with diethyl ether (1 L). Ethereal extracts were washed with water and brine, dried over magnesium sulfate. Flash chromatography on silica gel (0-3% ethyl acetate in hexanes) afforded the desired product 6 as pale yellow oil (125 g, 95%).
Reaction SMILES: [F:1][C:2]([F:17])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][NH2:16])=[O:14].C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26]>C(OCC)C>[C:25]([NH:16][NH:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[C:2]([F:17])[F:1])(=[O:27])[CH3:26]
Reactant: NNC(=O)CCCCCCCCCC=C(F)F
Reactant: CC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)NNC(=O)CCCCCCCCCC=C(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
A solution of 0.5 gram (0.002 mole) of 12,12-difluoro-11-dodecenoic acid hydrazide and 0.3 gram (0.003 mole) of triethylamine in 20 ml of diethyl ether was stirred, and 0.2 gram (0.003 mole) of acetyl chloride was added. The reaction mixture was stirred at ambient temperature for 30 minutes and was filtered. The filtrate was in turn washed with aqueous 10% hydrochloric acid, aqueous 10% sodium hydroxide, and an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure yielding 0.4 gram of 12,12-difluoro-11-dodecenoic acid 2-acetylhydrazide. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH:5]=O.[CH3:12][C:13](=[O:18])[CH2:14][C:15](=[O:17])[CH3:16].N1CCCCC1>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH:5]=[C:14]([C:13](=[O:18])[CH3:12])[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1cc(F)c(F)c(F)c1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1cc(F)c(F)c(F)c1)C(C)=O

Procedure:
A stirring mixture of 3,4,5-trifluorobenzaldehyde (4.20 g, 26.2 mmol), 2,4-pentanedione (2.62 g, 26.2 mmol), piperidine (0.430 g, 5.00 mmol) in benzene (150 mL) was heated at reflux temperature in a Dean-Stark apparatus for 8 h. The benzene was evaporated and the yellow oily residue was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:18]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)=[O:8].[N:19]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22][C@H:21]2[CH2:24][NH:25][CH2:26][C@@H:20]12>>[F:17][C:12]1[CH:11]=[C:10]([NH:9][C:7]([C:6]2[CH:18]=[C:2]([N:25]3[CH2:24][C@@H:21]4[CH2:22][CH2:23][N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:20]4[CH2:26]3)[CH:3]=[N:4][CH:5]=2)=[O:8])[CH:15]=[C:14]([F:16])[CH:13]=1
Reactant: O=C(Nc1cc(F)cc(F)c1)c1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2CNC[C@H]21
Product: CC(C)(C)OC(=O)N1CC[C@H]2CN(c3cncc(C(=O)Nc4cc(F)cc(F)c4)c3)C[C@H]21

Procedure:
The product from Example 53A and (3aS,6aS)-tert-butyl hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate (prepared as described in WO2001081347) were processed as described in Example 53B to provide the title compound. MS (APCI) m/z=445 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[Br:9][C:10]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:13]([CH:14]=[O:15])=[C:12](F)[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CC(OC)(C)C>C(#N)C>[Br:9][C:10]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:13]([CH:14]=[O:15])=[C:12]([N:4]2[CH2:5][CH:6]([CH3:8])[O:7][CH:2]([CH3:1])[CH2:3]2)[CH:11]=1
Reactant: O=Cc1cc([N+](=O)[O-])c(Br)cc1F
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CC#N
Product: CC1CN(c2cc(Br)c([N+](=O)[O-])cc2C=O)CC(C)O1
Temperature: 25 °C
Reaction time: 63 h
Yield: 63.6 %

Procedure:
A solution of cis-2,6-dimethylmorpholine (1.06 g, 9.20 mmol) in acetonitrile (40 mL) is added to a flask containing 4-bromo-2-fluoro-5-nitrobenzaldehyde (from Step 1) (2.0 g, 8.06 mmol) and potassium carbonate (3.92 g, 28.4 mmol). The resulting slurry is stirred at room temperature for 63 hours. The mixture is poured into MTBE (100 mL) and is washed with water (100 mL) followed by brine (100 mL). The organics are filtered through silica gel and concentrated to give 1.76 g of bright yellow solid. 1H NMR (DMSO-d6) δ 9.93, 8.44, 7.53, 3.74–3.81, 3.48, 2.78, 1.12.
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([CH3:17])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:18]([NH2:20])=[O:19])[CH:8]=[N:7][N:6]2[CH:21]=1.Br[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([CH3:17])[CH2:15][N:14]([C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][N:24]=4)[CH2:13]3)=[C:9]([C:18]([NH2:20])=[O:19])[CH:8]=[N:7][N:6]2[CH:21]=1
Reactant: N#Cc1ccc(Br)nc1
Reactant: C[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2ccc(C#N)cn2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Yield: 96.6 %

Procedure:
A solution of 6-bromo-4-(((3S,4S)-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide (250 mg, 0.536 mmol), 6-bromonicotinonitrile (103 mg, 0.563 mmol) and potassium carbonate (222 mg, 1.609 mmol) in N,N-dimethylformamide (3 mL) was heated at 100° C. in a sealed tube for 90 min. The resulting mixture was cooled to room temperature, triturated with water and filtered. The filter cake was washed with water and dried under vacuum to give 6-bromo-4-(((3S,4S)-1-(5-cyanopyridin-2-yl)-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (0.228 g, 97% yield). 1H NMR (400 MHz, 1:1 mixture of chloroform-d/methanol-d4) δ ppm 8.39-8.27 (m, 1H), 8.08 (s, 1H), 7.69-7.57 (m, 2H), 6.95-6.82 (m, 1H), 6.48 (d, J=9.0 Hz, 1H), 4.83 (br. s., 1H), 4.01-3.69 (m, 3H), 3.39 (t, J=9.6 Hz, 1H), 2.81 (br. s., 1H), 1.27 (d, J=6.8 Hz, 3H); MS (ES+) m/z: 440.2 (M+H); LC retention time: 3.885 min (analytical HPLC Method H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].[OH-].[Na+]>ClCCl>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) in dichloromethane (1 ml) was added at room temperature triethylamine (89 mg, 123 μl, 880 μmol) and methanesulfonyl chloride (27.5 mg, 18.7 μl, 240 μmol). The mixture was allowed to stir at room temperature for 18 h, poured into ice/water (5 ml) and 1N sodium hydroxide solution (5 ml) and extracted with dichloromethane (2×15 ml). The combined organic layers were washed with brine (15 ml), dried (MgSO4) and evaporated. The crude material was further purified by flash chromatography on silica gel (dichloromethane/MeOH 9:1) and trituration with dichloromethane (1 ml) and heptane (5 mL) for 30 min to yield the title compound as an off-white solid (43 mg, 66%), MS (ISP) m/z=409.4 [(M+H)+], mp 220° C.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[S:8][C:9]([CH3:27])=[C:10]([CH3:26])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1.Cl[S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=1)(=[O:33])=[O:32]>>[Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[S:8][C:9]([CH3:27])=[C:10]([CH3:26])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][S:31]([C:34]3[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=3)(=[O:33])=[O:32])=[C:16]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1sc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Product: Cc1sc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Yield: 38.3 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using [2-(4-bromobenzyl)-4,5-dimethyl-thiophen-3-yl]-(3-cyclopentyl-4-hydroxy-phenyl)-methanone (1.01 g, 2.14 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (1.01 g, 4.29 mmol). Purification on 2% H3PO4 /MeOH treated silica gel, eluting with a 15 & 25% EtOAc/hexane step gradient followed by crystallization from ether/pet ether gave 0.549 g (38%) of the title compound as a tan solid, mp 165-170° C. 1H NMR (DMSO-d6) δ 1.22-1.32 (m, 2 H), 1.46-1.58 (m, 2 H), 1.61-1.76 (m, 4 H), 1.78 (s, 3 H), 2.26 (s, 3 H), 2.97 (quintet, 1 H), 3.84 (s, 2 H), 6.94 (d, 2 H), 7.23 (d, 1 H), 7.34-7.40 (m, 4 H), 7.50 (dd, 1 H), 7.53 (d, 1 H), 8.00 (d, 1 H). IR (KBr) 3400, 2950, 1680, 1480, 1390 and 1190 cm-1. mass spectrum (-ESI) m/z 667 (M-H). Anal. Calcd. for C32H29BrO7S2 : C, 57.40; H, 4.37; N, 0.00. Found: C, 57.47; H, 4.24; N, 0.08.