Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:7]=[CH:6]2.ClN1C(=[O:24])CCC1=O.P(=O)(O)(O)O>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:7](=[O:24])[CH2:6]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2c(ccn2-c2ccccc2)c1
Agent: O=P(O)(O)O
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(c1)CC(=O)N2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
The compound of step 1 (800 mg, 3.58 mmol) was dissolved in DCM (25 ml), and N-chlorosuccinimide (526 mg, 3.94 mmol) was added. The reaction mixture was stir at room temperature overnight. The solvent was removed, the resulting solid was dissolved in concentrated acetic acid (15 ml) and heated to 70° C. After the addition of phosphoric acid (3.04 ml, 44.6 mmol; 85%) the reaction mixture was heated to 130° C. for 2.5 h. The cooled mixture was diluted with water and extracted with EA. The extracts were dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (EA/HEP 1:3). 557 mg of the title compound were obtained.
Reaction SMILES: C([O:3][C:4](=O)[C:5](=[O:23])[CH:6]([C:21]#[N:22])[CH2:7][CH2:8][C:9]1[N:10]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[S:12][CH:13]=1)C.C([OH:27])C.O>CS(O)(=O)=O>[OH:23][C:5]1[C:4](=[O:3])[NH:22][C:21](=[O:27])[C:6]=1[CH2:7][CH2:8][C:9]1[N:10]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[S:12][CH:13]=1
Reactant: CCO
Reactant: CCOC(=O)C(=O)C(C#N)CCc1csc(-c2ccc(Br)cc2)n1
Agent: CS(=O)(=O)O
Solvent: O
Product: O=C1NC(=O)C(CCc2csc(-c3ccc(Br)cc3)n2)=C1O
Reaction time: 8 h

Procedure:
To 3-[2-(4-bromobiphenyl)thiazol-4-yl]butanenitrile (3.07 g., 0.01 mole) in dimethylformamide (30 ml.) is added diethyloxalate (1.74 g., 0.012 mole) and potassium t-butoxide (2.48 g., 0.022 mole). The mixture is stirred overnight. Following evaporation under vacuum to one-half volume, chloroform (300 ml.) is added, plus water (200 ml.), and the mixture acidified with conc. HCl to pH 2-3. The chloroform is separated and washed well with water. The combined aqueous fractions are extracted a second time with chloroform. The combined chloroform extracts on evaporation provide 2-oxo-3-cyano-5-[2-(4-bromophenyl)thiazol-4-yl]-pentanoic acid ethyl ester. The ester (1.97 g., 0.005 mole) is dissolved in methanesulfonic acid (70 ml.) and stirred overnight. To the mixture is added 80% ethanol-water (200 ml.). After standing for two hours the ethanol is partially removed by evaporation to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17]2[N:21]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:20]=[C:19]([CH3:28])[CH:18]=2)[C@H:14]([C:29]([NH:31][C:32]2([C:35]#[N:36])[CH2:34][CH2:33]2)=[O:30])[CH2:13]1)(=[O:11])=[O:10].Cl.[F:38][C:39]1([F:43])[CH2:42][NH:41][CH2:40]1>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:41]2[CH2:42][C:39]([F:43])([F:38])[CH2:40]2)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17]2[N:21]([CH:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:20]=[C:19]([CH3:28])[CH:18]=2)[C@H:14]([C:29]([NH:31][C:32]2([C:35]#[N:36])[CH2:34][CH2:33]2)=[O:30])[CH2:13]1)(=[O:10])=[O:11]
Reactant: FC1(F)CNC1
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1
Agent: Cl
Solvent: CC#N
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(N4CC(F)(F)C4)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1

Procedure:
In analogy to the procedure described in example 389, (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolidine-2-carboxamide was reacted with 3,3-difluoroazetidine hydrochloride (CAS Reg. No. 288315-03-7) in acetonitrile at 90° C. for 48 h to give the title compound as off-white foam. MS (ESI): m/z=609.2 [M+H]+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH2:13][C@@H:12]1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[CH3:29])=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C@H:12]2[CH2:13][C@H:14]([NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH2:15][CH2:16][NH:11]2)=[C:23]([CH3:29])[CH:24]=1
Reactant: CCC(=O)N[C@@H]1CCN(C(=O)OCc2ccccc2)[C@@H](c2ccc(F)cc2C)C1
Agent: [Pd]
Solvent: CCO
Product: CCC(=O)N[C@@H]1CCN[C@@H](c2ccc(F)cc2C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
In 17 ml of ethanol was dissolved 1.73 g of trans-1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-propanoylaminopiperidine, and added thereto was 280 mg of palladium-carbon (moisture content of 50.9%), and the mixture was stirred under hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered through Celite, and ethanol was removed by distillation. The residue was purified by NH silica gel column chromatography (chloroform:hexane:ethyl acetate=5:5:2), to give 772 mg of trans-2-(4-fluoro-2-methylphenyl)-4-propanoylaminopiperidine as shown in Table 129 below.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[CH3:13][C:14]([OH:18])([CH3:17])[C:15]#[CH:16]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:13][C:14]([OH:18])([CH3:17])[C:15]#[C:16][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)O
Reactant: CCCCCc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCc1ccc(C#CC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
1-Bromo-4-pentylbenzene (102 g), 3-methyl-1-butyne-3-ol (38 g), triphenylphosphine (2 g) and bis(triphenylphosphine)palladium(II) chloride (1 g) were dissolved in triethylamine (390 ml) under nitrogen atmosphere, and then copper(I) iodide (0.3 g) was added thereto. After stirring at room temperature for 1 hour, the reaction mixture was further stirred at 90° C. for 5 hours. The resulting precipitated crystals were filtered, and then triethylamine was distilled off therefrom, followed by extracting with chloroform. The resultant was washed twice with 10% hydrochloric acid, and further with water twice, and then chloroform was distilled off therefrom. The residue was purified using silica gel-chloroform column chromatography to give 3-methyl-1-(4'-pentylphenyl)-1-butyne-3-ol (82 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:17]12[CH2:22][CH:21]1[CH2:20][N:19]([CH2:23][C:24]1[S:25][CH:26]=[C:27](Br)[N:28]=1)[CH2:18]2.C(O)C>C1(C)C=CC=CC=1>[CH:17]12[CH2:22][CH:21]1[CH2:20][N:19]([CH2:23][C:24]1[S:25][CH:26]=[C:27]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:28]=1)[CH2:18]2
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Brc1csc(CN2CC3CC3C2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Clc1ccc(-c2csc(CN3CC4CC4C3)n2)cc1
Temperature: 97.5 °C
Yield: 79.8 %

Procedure:
(4-chlorophenyl) boronic acid (0.34 g, 2.17 mmol) and potassium carbonate (0.63 g, 4.53 mmol) were added to a solution of 2-(3-azabicyclo[3.1.0]hexan-3-ylmethyl)-4-bromothiazole (Step-1 of compound 102, 0.47 g, 1.81 mmol) in a mixture of toluene:ethanol (5:15 ml) in a tube at 25° C. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. Tetrakis(triphenylphosphine)(0)palladium (0.10 g, 0.09 mmol) was then added to the reaction mixture under nitrogen atmosphere and the tube was sealed. The reaction mixture was heated at 95-100° C. for 18 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was washed with ethanol (20 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography using 5% ethyl acetate in hexanes as an eluent to obtain the title compound (0.42 g, 79.0%). MS: m/z 291 (M+1).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][CH:12]=[O:13])[CH:6]=[CH:7][CH:8]=1.[CH3:14][S:15]C1C=C(CCN)C=CC=1.C(OC=O)C>>[CH3:14][S:15][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][CH:12]=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: CSc1cccc(CCN)c1
Reactant: COc1cccc(CCNC=O)c1
Solvent: CCOC=O
Product: CSc1cccc(CCNC=O)c1
Yield: 78 %

Procedure:
A procedure identical to that described for the preparation of N-[2-(3-methoxy-phenyl)-ethyl]-formamide in Example 1 was followed using 2-(3-methylsulfanyl-phenyl)-ethylamine (7.4 g, 44 mmol) and formic acid ethyl ester (3.6 g, 48 mmol) to give the desired product (6.7 g, 78%). MS: 168.9 (M+1+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][C@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[CH:11]=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>>[C:17]1([C@@H:15]([NH:14][C:12]2[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:26]([CH:23]4[CH2:25][CH2:24]4)=[O:27])=[CH:7][CH:6]=3)[CH:9]=[N:10][CH:11]=2)[CH3:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[C@H](Nc1cncc(-c2ccc(N)cc2)n1)c1ccccc1
Reactant: O=C(Cl)C1CC1
Product: C[C@H](Nc1cncc(-c2ccc(NC(=O)C3CC3)cc2)n1)c1ccccc1

Procedure:
In a method analogous to that reported in example 39, reaction of 6-(4-aminophenyl)-N-[(1S)-1-phenylethyl]pyrazin-2-amine (58 mg, 0.2 mmol) and cyclopropanecarbonyl chloride (25 mg, 0.24 mmol) furnished the pure product after chromatographic purification using ethyl acetate-hexane (3:2) (46 mg, 64%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@@H:25]3[CH2:29][C@@H:28]([F:30])[CH2:27][N:26]3[CH3:31])=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.O.CO.C(Cl)Cl>[F:30][C@H:28]1[CH2:27][N:26]([CH3:31])[C@H:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:29]1
Reactant: CN1C[C@H](F)C[C@H]1c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CN1C[C@H](F)C[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 51.5 %

Procedure:
To a solution of Intermediate A (161 mg, 0.99 mmol) in dry DMF (2.5 mL) at RT was added NaH (60% in mineral oil, 108 mg, 2.70 mmol) and the mixture stirred for 15 min. Intermediate 91c (214 mg, 0.89 mmol) in DMF (2.5 mL) was then added and the mixture heated at 60° C. for 1 h. After cooling, the resulting dark brown mixture was diluted with water and extracted with DCM. The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give crude product. FCC, using 0-10% (2M NH3 in MeOH) in DCM, gave the title compound as light brown foam (175 mg, 51%). LCMS (Method 3): Rt 0.43 min, m/z 382 [MH+].
Reaction SMILES: [C:1]([Si:5]([CH3:42])([CH3:41])[O:6][CH2:7][CH2:8][N:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38](O)=[O:39])=[CH:32]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl.[O:66]1[CH2:71][CH2:70][CH2:69][CH2:68][CH:67]1[O:72][NH2:73]>CN(C=O)C.C(N(CC)CC)C>[C:1]([Si:5]([CH3:42])([CH3:41])[O:6][CH2:7][CH2:8][N:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([NH:73][O:72][CH:67]3[CH2:68][CH2:69][CH2:70][CH2:71][O:66]3)=[O:39])=[CH:32]2)(=[O:29])=[O:30])=[CH:24][CH:23]=1)[CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: NOC1CCCCO1
Reactant: CC(C)(C)[Si](C)(C)OCCN(CCc1c[nH]c2ccccc12)Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)O)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCN(CCc1c[nH]c2ccccc12)Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NOC3CCCCO3)c2)cc1
Reaction time: 1.5 h

Procedure:
(E)-3-{1-[4-({[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylic acid (compound C15) (1.15 g, 1.16 mmol), HOBt.H2O (171 mg, 1.16 mmol) and triethylamine (2 ml) is dissolved in DMF (100 ml) at room temperature. After addition of EDC.HCl (786 mg, 3.48 mmol) the mixture is stirred for 1.5 hours. Then it is added O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (136 mg, 1.16 mmol) and stirred for 17 hours. After evaporation and addition of 200 ml water the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate. Then it is filtrated and evaporated. The crude product is purified by a silica gel flash chromatography using dichloromethane-methanol eluent.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[Mg].[Cl-].[Ce+3].[Cl-].[Cl-].[CH3:15][O:16][C:17]([C:19]12[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][CH2:25][C:24](=[O:34])[CH:23]1[CH2:22][N:21]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:20]2)=[O:18]>C(OCC)C>[CH3:15][O:16][C:17]([C:19]12[CH:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:26][CH2:25][C:24]([OH:34])([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=3)[CH:23]1[CH2:22][N:21]([CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:20]2)=[O:18]
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=O)CCC2c1ccccc1
Reactant: COc1cccc(Br)c1
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(O)(c1cccc(OC)c1)CCC2c1ccccc1
Yield: 48.5 %

Procedure:
By carrying out the reaction as in Stage A of Example 6, but from 1.56 cm3 (12.4 mmol) of 3-bromoanisole and from 302 mg (12.4 mmol) of magnesium turnings at reflux for one hour in 5 cm3 of dry diethyl ether, followed successively by 1.02 g (4.13 mmol) of anhydrous cerium chloride and by a solution of 1.5 g (4.13 mmol) of methyl(3aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate, obtained in Stage B of Example 1, in 8 cm3 of diethyl ether, 945 mg (48%) of methyl(3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-(3-methoxyphenyl)-4-phenyloctahydroisoindole-3a-carboxylate were obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with cyclohexane and then with a cyclohexane/ethyl acetate (80/20 by volume) mixture, in the form of a white solid, the characteristic of which was as follows:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][CH:12]=[C:13]([CH3:18])[C:14]([O:16]C)=O.C1(OC2C=CC=CC=2)C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]2[C:3]=1[NH:11][CH:12]=[C:13]([CH3:18])[C:14]2=[O:16]
Reactant: COC(=O)C(C)=CNc1cc([N+](=O)[O-])ccc1Br
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1c[nH]c2c(Br)ccc([N+](=O)[O-])c2c1=O
Temperature: 250 °C
Reaction time: 2 h
Yield: 309.1 %

Procedure:
A mixture of methyl 3-[(2-bromo-5-nitrophenyl)amino]-2-methylprop-2-enoate (Compound 304F, 10 g, 3.2 mmol) and PhOPh (6 mL) was stirred at 250° C. for 2 h. The reaction mixture was allowed to cool to room temperature. Petroleum ether (60 mL) was added to the reaction mixture and the precipitate was filtered. The material was purified by column chromatography to afford 2.8 g of the desired product (yield: 28%) as a solid. 1H NMR (DMSO-d6, 400 MHz): δ=1.95 (s, 3 H), 7.48 (d, J=8.0 Hz, 1 H), 7.91 (s, 1 H), 8.12 (d, J=8.0 Hz, 1 H), 11.46 (s, br, 1 H).
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:8]>CC(C)=O>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:7](=[O:8])[CH2:6][CH2:5][CH2:4][I:1])=[CH:10][CH:11]=1
Reactant: [I-]
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(CCCI)c1ccc(F)cc1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
Sodium iodide (7.47 g, 49.84 mmol, 2 equiv) was added to a solution of 4-chloro-1-(4-fluorophenyl)butan-1-one (5 g, 24.92 mmol, 1 equiv) in acetone. The reaction mixture was refluxed for 16 h. After cooling to ambient temperature, it was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and sodium bisulfite, followed by a wash with brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified using the Biotage flash chromatography system (SNAP 100 g cartridge, Rf=0.5, gradient—1%-10% ethyl acetate in hexanes) to afford the title compound as a clear oil (5.62 g, 77%). The bottle containing the compound was wrapped in aluminium foil and stored in the freezer to avoid further darkening of the mixture; MS for C10H10FIO m/z 291.98 (M+H)+.
Reaction SMILES: C([N:8]1[CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH:13]2[CH:9]1[CH2:10][N:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:12]2)C1C=CC=CC=1>C(O)C.[Pd]>[CH:9]12[CH2:10][N:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:12][CH:13]1[CH2:14][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:8]2
Reactant: CCOC(=O)C1CC2CN(C(=O)OCC)CC2N1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CC2CN(C(=O)OCC)CC2N1

Procedure:
96.5 g (0.279 mol) of diethyl 2-benzyl-2,7-diazabicyclo[3.3.0]octane-3,7-dicarboxylate in 1 l of ethanol are hydrogenated at 100° C. and 100 bar on 5 g of palladium-active carbon (10% Pd). The catalyst is filtered off with suction, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=[CH:26][C:27](Cl)=[O:28])[CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([NH:16][C:27](=[O:28])[CH:26]=[CH:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[CH:14][CH:13]=2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)c2ccc(N)cc2)cc1
Reactant: O=C(Cl)C=Cc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)c2ccc(NC(=O)C=Cc3cccnc3)cc2)cc1
Temperature: 50 °C
Yield: 57.7 %

Procedure:
To a solution of 4-((4-methoxyphenyl)sulfonyl)aniline (76 mg, 0.29 mmol) in DMF (3 mL) is added 3-(pyridin-3-yl)acryloyl chloride (62 mg, 0.30 mmol) and K2CO3 (138 mg, 1 mmol). The mixture is heated at 50° C. for 2 h and the solvent is evaporated. The residue is partitioned between EtOAc (15 mL) and brine (10 mL) and the layers are separated. The aqueous layer is extracted with EtOAc (10 mL) and the combined extracts are dried (Na2SO4) and evaporated. Purification of the residue by preparative TLC with 100:5:0.5 CH2Cl2/MeOH/NH4OH gives the titled compounds as a white solid (66 mg, 58%).
Reaction SMILES: O=[C:2]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)[CH2:3][C@H:4]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11].Cl.[NH2:38][OH:39].C(=O)([O-])O.[Na+]>>[OH:39]/[N:38]=[C:2](/[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]([F:35])([F:34])[F:36])[CH:28]=1)\[CH2:3][C@H:4]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([OH:26])=[O:25])=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11]
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccnc(C(F)(F)F)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1[C@H](C/C(=N\O)c1ccnc(C(F)(F)F)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
In analogy to example 132, step 6, from 4′-[(R)-3-oxo-1-o-tolyl-3-(2-trifluoromethyl-pyridin-4-yl)-propyl]-biphenyl-4-carboxylic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a light brown foam, MS (ESI−): m/z=503.0 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=4)[CH:12]=[C:11]([C:25]([NH2:27])=[O:26])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[CH3:28][N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1>CO>[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:14]=[C:13]([C:15]5[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=5)[CH:12]=[C:11]([C:25]([NH2:27])=[O:26])[C:7]=4[NH:8][C:9]=3[CH:10]=2)[CH2:31][CH2:30]1
Reactant: NC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc(N)ccc12
Reactant: CN1CCC(=O)CC1
Solvent: CO
Product: CN1CCC(Nc2ccc3c(c2)[nH]c2c(C(N)=O)cc(-c4cccc(C(F)(F)F)c4)nc23)CC1

Procedure:
This was similarly prepared 7-amino-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide and 1-methylpiperidin-4-one. MS (ESI) m/z 468.30 (M+H); HPLC retention time of 1.85 min with Xbridge S10 4.6×50 mm column, 3 min gradient, 0-100% B, 4 mL/min. Solvent A: 95% MeOH—5% H2O—0.1% TFA; Solvent B: 5% MeOH—95% H2O—0.1% TFA.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[S:8](Cl)(Cl)=[O:9].O>C(Cl)Cl>[CH3:1][C:2]1([CH3:7])[CH2:5][O:6][S:8](=[O:9])[O:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(CO)CO
Solvent: ClCCl
Solvent: O
Product: CC1(C)COS(=O)OC1
Temperature: 25 °C
Yield: 92 %

Procedure:
25.36 g (0.24 mol) of 2,2-dimethylpropane-1,3-diol was suspended at room temperature in 150 ml of methylene chloride in a 500 ml three-necked flask. 37.36 g (0.31 mol) of thionyl chloride was instilled over 30 minutes. After the end of the addition, the reaction solution was held at reflux for 1.5 hours and then cooled to room temperature. 100 ml of water was added to the reaction. The aqueous phase was discarded; the organic phase was extracted three times with saturated NaHCO3 solution (100 ml), then dried with Na2SO4 and concentrated by evaporation on a rotary evaporator. The residue was distilled at 24 mbars and 78° C. The product was a pure colorless liquid according to GC and weighed 23.4 g, which corresponded to a yield of 92 percent.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:25]([Zn]CC)[CH3:26].CC(C[AlH]CC(C)C)C>O1CCOCC1>[CH2:25]([C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccc2ncc(Br)n2n1
Reactant: CC[Zn]CC
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1COCCO1
Product: CCc1cnc2ccc(NC[C@@H]3CCCN3C(=O)OC(C)(C)C)nn12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of PdCl2dppf (25 mg, 0.03 mmol) and (S)-tert-butyl 2-(((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)methyl)pyrrolidine-1-carboxylate (100 mg, 0.2 mmol) in dioxane (2 mL) was added diethylzinc (0.24 ml, 1 M in hexane), DiBAL-H (0.008 mL, 1M in toluene) at room temperature. The reaction mixture was heated to 100° C. and stirred for 2 h. Filtered off celite, and concentrated the filtrate, purified by Prep HPLC (neutral) to give (S)-tert-butyl 2-(((3-ethylimidazo[1,2-b]pyridazin-6-yl)amino)methyl)pyrrolidine-1-carboxylate as oil. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.55 (d, J=9.60 Hz, 1H), 7.22 (s, 1H), 6.66 (d, J=9.60 Hz, 1H), 4.18 (br. s., 1H), 3.55 (br. s., 1H), 3.37-3.49 (m, 3H), 2.91 (q, J=7.49 Hz, 2H), 1.87-2.07 (m, 4H), 1.44 (br. s., 9H), 1.36 (t, J=7.45 Hz, 3H); LRMS (ESI) m/e 346.3 [(M+H)+, calcd for C18H28N6O2 346.4.