Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:2].[Br:21]N1C(=O)CCC1=O.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>ClC(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[C:10]([CH2:11][Br:21])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:2]
Reactant: CCOC(=O)c1c(C)cccc1O[Si](C)(C)C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(CBr)cccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 60 h
Yield: 83.1 %

Procedure:
2-(tert-Butyl-dimethyl-silanyloxy)-6-methyl-benzoic acid ethyl ester (7.6 g, 25.8 mmol), N-bromosuccinimide (4.82 g, 27.1 mmol) and azobis(cyclohexanecarbonitrile) (0.32 g, 13 mmol) were dissolved in tetrachlormethane (130 ml). The solution was stirred at room temperature for 60 hours. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel column using a gradient of 1–2% ethyl acetate/hexane as eluent, which afforded 8.0 g (83%) of 6-bromomethyl-2-(tert-butyl-dimethyl-silanyloxy)-benzoic acid ethyl ester as an oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C(=S)=S>[C:19]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[CH2:7][CH2:6][CH:5]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C1CCc2ccccc21
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCOC(=O)C1CCc2c(C(=O)c3ccccc3)cccc21
Reaction time: 0.17 h

Procedure:
To 120 ml. of carbon disulfide is added 54 g. of anhydrous aluminum chloride powder on an ice bath, followed by the dropwise addition of a solution of 11.4 g. of ethyl indan-1-carboxylate in 60 ml. of carbon disulfide. The mixture is stirred for 10 minutes, after which a solution of 42 g. of benzoyl chloride in 60 ml. of carbon disulfide is added dropwise. After the dropwise addition has been completed, the temperature is gradually increased and the solution is stirred on reflux for 3 hours and thirty minutes to complete the reaction. Ice and hydrochloric acid are added to the reaction mixture followed by extraction with ether. The extract is washed with 1N hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in the order mentioned and, then, dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is column-chromatographed on silica gel (conditions: 2 Kg. of silica gel; eluant solvent-benzene containing 2.5 % of ethyl acetate). The first-emerging fractions rich in ethyl 4-benzoylindan-1-carboxylate are pooled separate from the ensuing fractions rich in ethyl 6-benzoylindan-1-carboxylate. The former fractions are further purified by rechromatography on a column of silica gel, whereby ethyl 4-benzoylindan-1-carboxylate is obtained as an oily product.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]#[N:22])[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]#[N:22])[CH2:17][CH2:16]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: N#CC1CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 92.6 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (5.56 g, 25 mmol), piperidine-4-carbonitrile (3.03 g, 27.50 mmol) and DIPEA (5.66 mL, 32.50 mmol) in DMF (50 mL) was heated at 70° C. for 1 hour. The solution was evaporated and partitioned between DCM and 1M aqueous K2CO3. The organic phase was washed with brine, dried over MgSO4, evaporated and the residue was triturated with ether. The solid was collected by filtration, washed with ether and dried under vacuum to afford 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidine-4-carbonitrile (6.86 g, 93%) as a cream crystalline solid.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@@H:15]([CH3:26])[C:16](=[O:25])[C:17]([CH3:24])([O:19][Si](C)(C)C)[CH3:18])[NH:13][C:12]1=[O:27])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.O.C(O)(=O)C(O)=O>CO>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@@H:15]([CH3:26])[C:16](=[O:25])[C:17]([OH:19])([CH3:24])[CH3:18])[NH:13][C:12]1=[O:27])[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(C)(C)O[Si](C)(C)C
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CO
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(C)(C)O
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-1,3-dimethyl-3-(trimethylsilyloxy)-2-oxobutyl]-2-azetidinone (132 mg) in methanol (6 ml) was added oxalic acid dihydrate (200 mg) at room temperature and the mixture was stirred for 1 hour. The reaction mixture was evaporated, and diethyl ether (30 ml) and saturated aqueous sodium bicarbonate (10 ml) were slowly added to the residue. The solution was extracted twice with diethyl ether, and the extracts were combined and washed in turn with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and evaporated to give (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-3-hydroxy-1,3-dimethyl-2-oxobutyl]-2-azetidinone (109 mg).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH2:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][NH:20]1)[CH3:18].CCN(C(C)C)C(C)C>CS(C)=O>[CH2:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)[CH3:18]
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: CCC1CCCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCC1CCCCN1c1nc2cc(C(=O)OC)ccc2[nH]c1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (500 mg, crude) in DMSO (5 mL) was added 2-ethylpiperidine (475 mg, 4.20 mmol) and DIEA (542 mg, 4.19 mmol). The resulting solution was stirred overnight at 80° C. in an oil bath and then quenched by the addition of water (50 mL), extracted with dichloromethane (5×20 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (1%-10% ethyl acetate in petroleum ether) to afford methyl 3-(2-ethylpiperidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as yellow oil (150 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C1COCC1.N(CC)CC.[Cu]I.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>[CH3:13][Si:14]([CH3:16])([CH3:15])[C:17]#[C:18][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1
Reactant: O=C1CCSc2ccc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc2c(c1)C(=O)CCS2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 1.00 g (4.11 mmol) 2,3-dihydro-6-bromo-(4H)-1-benzothiopyran-4-one and 78.3 mg (0.41 mmol) CuI in 15.0 ml THF and 6.0 ml Et2NH was sparged with argon for 5 minutes. To this solution was added 2.0 ml (1.39 g, 14.2 mmol) of (trimethylsilyl)acetylene followed by 288.5 mg (0.41 mmol) of bis(triphenylphosphine)palladium(II) chloride. The resulting dark solution was stirred at room temperature for 3 days and then filtered through a pad of Celite, which was washed with EtOAc. The filtrate was washed with H2O and saturated aqueous NaCl before being dried over MgSO4. The title compound was isolated as an orange oil by column chromatography (4% EtOAc-hexanes). 1H NMR (CDCl3): δ 8.13 (1H, d, J=1.9 Hz), 7.36 (1H, dd, J=2.1, 8.2 Hz), 7.14 (1H, d, J=8.2 Hz), 3.19 (2H, d, J=6.3 Hz), 2.91 (2H, d, J=6.3 Hz), 0.21 (9H, s).
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]([O:14]CC2C=CC=CC=2)[CH2:12][N:11]([CH2:22][C:23]([F:26])([F:25])[F:24])[C@@H:10]1[CH2:27][O:28]CC1C=CC=CC=1)C1C=CC=CC=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>C(O)C.[Pd]>[OH:8][C@H:9]1[C@H:13]([OH:14])[CH2:12][N:11]([CH2:22][C:23]([F:26])([F:24])[F:25])[C@@H:10]1[CH2:27][OH:28]
Reactant: FC(F)(F)CN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCO
Product: OC[C@@H]1[C@@H](O)[C@H](O)CN1CC(F)(F)F
Yield: 69.7 %

Procedure:
(2R,3R,4R)-3,4-Dibenzyloxy-2-benzyloxymethyl-1-(2,2,2-trifluoroethyl)pyrrolidine (Compound 6) (0.3 g, 0.6 mmol) was dissolved in 96% ethanol (30 ml), and 10% Pd/C (0.1 g) was added under N2. The compound was reduced in a Parr apparatus (40 Psi) for 16 hours. The reaction mixture was filtered and evaporated in vacuo giving (2R,3R,4R)-3,4-dihydroxy-2-hydroxymethyl-1-(2,2,2-trifluoroethyl)pyrrolidine (0.09 g) as an brown oil.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12](I)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].C([Sn](CCCC)(CCCC)[C:24]1[S:25][CH:26]=[CH:27][N:28]=1)CCC>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>[C:1]([C:3]1[CH:18]=[CH:17][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:24]4[S:25][CH:26]=[CH:27][N:28]=4)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: N#Cc1ccc2c(c1)ncn2-c1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: N#Cc1ccc2c(c1)ncn2-c1cccc(-c2nccs2)c1
Yield: 84.1 %

Procedure:
5-Cyano-1-(3-(2-thiazolyl)phenyl)benzimidazole (54) was synthesized as described in Example 18 but using 5-cyano-1-(3-iodophenyl)benzimidazole (2.0 g, 5.9 mmol) instead of (52), (PPh3)2PdCl2 (100 mg, 0.14 mmol) and (50) (3.6 g, 9.7 mmol). The reaction gave 5-cyano-1-(3-(2-thiazolyl)phenyl)benzimidazole (1.5 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C@:12]12[CH2:17][C@H:16]1[CH2:15][NH:14][CH2:13]2.Br[CH2:19][CH2:20][CH2:21][Cl:22]>O1CCCC1.C(N(C(C)C)CC)(C)C>[Cl:22][CH2:21][CH2:20][CH2:19][N:14]1[CH2:15][C@H:16]2[C@:12]([C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=3[F:1])([CH2:17]2)[CH2:13]1
Reactant: Fc1cc(C(F)(F)F)ccc1[C@@]12CNC[C@@H]1C2
Reactant: ClCCCBr
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc(C(F)(F)F)ccc1[C@]12C[C@H]1CN(CCCCl)C2

Procedure:
To a solution of (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (300 mg) in dry tetrahydrofuran (3 mL), diisopropylethylamine (0.65 mL) and 1-bromo-3-chloropropane (1.01 mL) were added and the resulting mixture was refluxed for 3 hours.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.[NH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
4-amino-5-chloro-2-methoxybenzoic acid (compound of formula 9) (16.6 g, 82.28 mmol) was dissolved in dimethylformamide (166 mL) and the solution was cooled to 0° C. Then, tertiary butyl 4-(aminomethyl)piperidine-1-carboxylate (21.16 g, 98.74 mmol), triethylamine (11.56 mL, 246.84 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC, 20.51 g, 106.96 mmol), and 1-hydroxybenzotriazole (HOBT, 16.68 g, 123.42 mmol) were added thereto. The reaction mixture was warmed to room temperature, stirred for 4 hours, and extracted with ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the title compound (31.4 g, 96%).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[Cu][C:11]#[N:12].O>CN(C=O)C>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([C:11]#[N:12])=[N:3][CH:4]=1
Reactant: Cc1cc(Br)cnc1Br
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)cnc1C#N
Temperature: 115 °C

Procedure:
A mixture of 2,5-dibromo-3-methylpyridine (20.17 g, 80.4 mmol) and copper(I) cyanide (7.24 g, 80.8 mmol) in 200 mL DMF was heated to 115° C. overnight. The reaction mixture was cooled to 25° C. and poured into 600 mL of H2O. The solid was filtered, washed with copious amounts of H2O. The filtrate was extracted with EtOAc (4×) and the combined organic layers were washed with H2O and dried over Na2SO4. The solution was filtered, evaporated onto silica gel and purified by flash chromatography eluting with EtOAc:hexane (0:1→1:9) to give the title compound as a white solid. MS m/z: 197.0 [M+1].
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[N:14]([CH2:25][C:26]3[CH:30]=[C:29]([C:31]4[S:32][C:33]([Cl:36])=[CH:34][CH:35]=4)[O:28][N:27]=3)[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([N+:22]([O-])=O)=[CH:17][CH:16]=3)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].O.O.[Sn](Cl)(Cl)(Cl)[Cl:40].Cl.[OH-].[Na+]>C(O)C>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[N:14]([CH2:25][C:26]3[CH:30]=[C:29]([C:31]4[S:32][C:33]([Cl:36])=[CH:34][CH:35]=4)[O:28][N:27]=3)[C:15]3[C:20]([CH:21]=2)=[C:19]([Cl:40])[C:18]([NH2:22])=[CH:17][CH:16]=3)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: Cl[Sn](Cl)(Cl)Cl
Reactant: CC(C)N1CCC(NC(=O)c2cc3cc([N+](=O)[O-])ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)N1CCC(NC(=O)c2cc3c(Cl)c(N)ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
24.4 mg 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-nitro-1H-indole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide were added to a solution of 58.5 mg tin chloride dihydrate in 1 ml ethanol. 0.5 ml 12 N aqueous hydrochloric acid was added and the mixture was stirred at room temperature for 16 hours. After cooling of the reaction mixture it was basified to pH 12 with saturated aqueous solution of sodium hydroxide and the product isolated by filtration. The product was obtained as a white solid which was dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]([OH:19])=O)=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.C(Cl)(=O)C([Cl:23])=O.ClCCl>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:17]([Cl:23])=[O:19])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1
Reactant: O=C(O)c1noc(-c2ccc(C(F)(F)F)cc2)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1noc(-c2ccc(C(F)(F)F)cc2)c1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.3 %

Procedure:
To a mixture of 4-chloro-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carboxylic acid (0.33 g, 1.13 mmol), oxalyl chloride (0.45 mL, 5.16 mmol) and dichloromethane (10 mL) was added a drop of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 6 hours. The volatiles were removed in vacuo to obtain 4-chloro-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carbonyl chloride (0.34 g, 1.1 mmol)
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:31](=[O:33])[CH3:32])(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:31](=[O:33])[CH3:32])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)NS(=O)(=O)c1ccc(N)cc1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CCCCN1C(=O)C(Nc2ccc(S(=O)(=O)NC(C)=O)cc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and N-[(4-aminophenyl)sulfonyl]acetamide in a similar manner as described for e.g. Examples 6-9, 22-25, 28 and 32-35. 1H NMR (500 MHz, CD3CN): δ 1.00 (t, 3H), 1.43-1.52 (m, 2H), 1.78-1.85 (m, 2H), 1.94 (s, 3H), 3.76 (t, 2H), 6.88-6.92 (m, 2H), 7.16-7.24 (m, 4H), 7.29-7.34 (m, 1H), 7.54-7.57 (m, 2H), 8.03 (bs, 1H), 9.26 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](Cl)=[O:5].[F:12][C:13]([F:40])([F:39])[C:14]([CH2:34][NH:35][CH2:36][CH2:37]C)([OH:33])[CH2:15][NH:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[N:20][N:21]2[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([N:35]([CH2:36][CH3:37])[CH2:34][C:14]([CH2:15][NH:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[N:20][N:21]2[C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)([OH:33])[C:13]([F:12])([F:40])[F:39])=[O:5]
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: Cc1cccc(Cl)c1C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1c(C)cccc1Cl

Procedure:
Prepared similarly to Example 48 by reaction of 2-chloro-6-methylbenzoylchloride and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol in chloroform over 42 hours. Purification by mass directed autopreparation (System B) resulted in separation of atropisomers of the title compound:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](Cl)(C)=O>CO.CC(=O)OCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C(O)c1cc(O)cc(Br)c1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(O)cc(Br)c1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
To a flask containing 3-bromo-5-hydroxybenzoic acid (2.0 g, 9.2 mmol) in anhydrous MeOH (10 mL) at 0° C. under N2 was added AcCl (912 μL, 12.9 mmol). The reaction mixture was allowed to warm to room temperature overnight. The mixture was diluted with EA and washed with NaHCO3. The organic layers were dried and concentrated to provide 2.1 g (97%) of methyl 3-bromo-5-hydroxybenzoate as a white solid. LCMS-ESI (m/z) calculated for C8H7BrO3: 231.04. found 232.9 [M+H]+, tR=3.06 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:12]([NH:14][O:15][CH3:16])=[O:13])[C:5]([F:21])=[CH:4][C:3]=1[C:22]#[N:23].[CH3:24][NH:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28].C(N(C(C)C)CC)(C)C.[F-].[K+]>CS(C)=O>[C:22]([C:3]1[CH:4]=[C:5]([F:21])[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:12]([NH:14][O:15][CH3:16])=[O:13])=[N:7][C:2]=1[N:25]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:24])#[N:23]
Reactant: CNCC(C)(C)C
Reactant: CONC(=O)c1ccc(C)c(Nc2nc(Cl)c(C#N)cc2F)c1
Agent: [F-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CONC(=O)c1ccc(C)c(Nc2nc(N(C)CC(C)(C)C)c(C#N)cc2F)c1
Temperature: 150 °C
Yield: 5.9 %

Procedure:
A mixture of 3-(6-chloro-5-cyano-3-fluoro-pyridin-2-ylamino)-N-methoxy-4-methyl-benzamide (55.6 mg, 0.166 mmol), N-methyl-neopentylamine (70 mg, 0.511 mmol), diisopropylethylamine (0.1 mL) and potassium fluoride (12 mg) in DMSO (1 mL) was heated to 150° C. overnight. The product (3.9 mg, 5.9%) was isolated after purification by HPLC. C21H26FN5O2 MS m/e=400 (M+H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.[Br:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Br:23])[C:15]=1OC.Cl>CN(C=O)C.O>[Br:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Br:23])[C:15]=1[CH:10]([C:7]1[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=1)[C:11]#[N:12]
Reactant: COc1c(Br)cc([N+](=O)[O-])cc1Br
Reactant: N#CCc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(c1ccc(Cl)cc1)c1c(Br)cc([N+](=O)[O-])cc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
NaH (0.0772 mol) was added portionwise at 0° C. under N2 flow to a mixture of 4-chloro-benzeneacetonitrile (0.0643 mol) in DMF (50 ml). The mixture was stirred at 0° C. under N2 flow for 1 hour. A mixture of 1,3-dibromo-2-methoxy-5-nitro-benzene (0.0643 mol) in DMF (50 ml) was added at 0° C. under N2 flow. The mixture was stirred at RT for 3 hours, hydrolized with H2O and HCl 3N and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/cyclohexane 60/40). The pure fractions were collected and the solvent was evaporated, yielding 12.8 g (46%) of (±)-2,6-dibromo-α-(4-chlorophenyl)-4-nitrobenzeneacetonitrile (interm. 76).
Reaction SMILES: [C:1]([CH2:3][CH:4]([OH:24])[CH2:5][CH:6]([OH:23])[CH2:7][C:8]([N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])#[N:2].CO[C:27](OC)([CH3:29])[CH3:28].CS(O)(=O)=O>CC(C)=O>[C:1]([CH2:3][C@H:4]1[O:24][C:27]([CH3:29])([CH3:28])[O:23][C@@H:6]([CH2:7][C:8]([N:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:9])[CH2:5]1)#[N:2]
Reactant: N#CCC(O)CC(O)CC(=O)N(c1ccccc1)c1ccccc1
Reactant: COC(C)(C)OC
Agent: CS(=O)(=O)O
Solvent: CC(C)=O
Product: CC1(C)O[C@H](CC#N)C[C@H](CC(=O)N(c2ccccc2)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Crude [R-(R*,R*)]-6-cyano-3,5-dihydroxy-N,N-diphenylhexanamide, approximately 0.18 mol, is dissolved in 2,2-dimethoxypropane (160 mL, 1.5 mol) and acetone (300 mL). Methanesulfonic acid (0.5 mL) is added, and the solution is stirred for 2 hours at room temperature. The reaction is quenched by the addition of aqueous sodium bicarbonate (800 mL) and ethyl acetate (500 mL). The ethyl acetate solution is concentrated by vacuum distillation to give 62.5 g of (4R -cis)-6-(cyanomethyl)-2,2-dimethyl-N,N-diphenyl-1,3-dioxane-4-acetamide as an off-white crystalline solid (mp 98°-100° C., uncorrected).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([C:21](OC)=[O:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Li+].C(OCC)(=O)C>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][OH:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Yield: 97.3 %

Procedure:
A solution of (2S,4R)-1-tert-butyl 2-methyl 4-(tert-butyldimethylsilyloxy)pyrrolidine-1,2-dicarboxylate (5.34 g, 14.8 mmol) in THF (20 mL) was cooled to 0° C. and lithium borohydride (0.485 g, 22.2 mmol) in THF (10 mL) was added dropwise. The mixture was stirred for about 16 hours while the ice-salt bath gradually melted. Ethyl acetate (30 mL) was added followed by the addition of ice. The organic portion was separated and quenched by a dropwise addition of 1N aqueous phosphoric acid. The organic portion was separated and washed with water (120 mL), saturated sodium bicarbonate solution (2×120 mL), and brine (100 mL) and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure to yield (2S,4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (4.8 g, 14.4 mmol) as a colorless oil. RP-HPLC (Table 1, Method f) Rt 6.25 min; m/z: (M−H)− 390.