Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[Cl:31])[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[Cl:31])=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: CCC(=O)C(Cc1ccc(F)cc1Cl)C(=O)OC
Reactant: COC(=O)COc1ccc(F)c(N)c1
Solvent: O
Solvent: C1COCCO1
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(F)cc1Cl
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (1.1 g), 2-(2-chloro-4-fluorobenzyl)-3-oxopentanoic acid methyl ester (2.4 g), polyphosphoric acid (5 g) and dioxane (10 mL) was heated at 130° C. for 17 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the solid washed with diethyl ether and dried to afford title compound, 1.5 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:27]([NH:29][C:30]2([C:33]#[N:34])[CH2:32][CH2:31]2)=[O:28])[CH2:12]1)(=[O:10])=[O:9].[CH:35](=O)[CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1.[OH-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([N:21]3[CH2:22][CH2:23][N:24]([CH2:35][CH3:36])[CH2:25][CH2:26]3)[CH2:19][CH2:20]2)=[O:17])[C@H:13]([C:27]([NH:29][C:30]2([C:33]#[N:34])[CH2:31][CH2:32]2)=[O:28])[CH2:12]1)(=[O:10])=[O:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2(N3CCNCC3)CC2)CC1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN1CCN(C2(C(=O)N3C[C@H](S(=O)(=O)c4ccccc4Cl)C[C@H]3C(=O)NC3(C#N)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 19.8 %

Procedure:
To a solution of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(piperazin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (35.4 mg, 70 μmol) in THF (1.05 mL) was added at room temperature acetaldehyde (4.35 μL, 77.0 μmol), sodium triacetoxyborohydride (44.5 mg, 210 μmol) and acetic acid (8.01 μL, 140 μmol). The reaction was stirred at room temperature for 2 days. It was diluted with 1N aqueous sodium hydroxid solution and water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC to yield the title compound as a white solid (7.4 mg, 20%). MS ISP (m/e): 534.2/536.3 (100/38) [(M+H)]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=O)[NH:7]2.P(Cl)(Cl)([Cl:21])=O>>[ClH:21].[Cl:21][C:6]1[N:5]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[CH3:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CN1Cc2c(C)cccc2NC1=O
Product: CCOC(=O)CN1Cc2c(C)cccc2N=C1Cl
Product: Cl
Reaction time: 3.5 h
Yield: 70 %

Procedure:
A mixture of 2.45 g (10 mmole) of 5-methyl-3-carbethoxymethyl- 1,2,3,4-tetrahydroquinazolin-2-one and 20 ml of phosphorus oxychloride was immersed in an oil bath (105°-110°) for 3.5 hr. The solution was cooled, the excess phosphorus oxychloride removed under aspirator pressure and the residue dissolved in chloroform (50 ml). Ice water was added, the mixture shaken and 40% sodium hydroxide was added dropwise to attain a pH=6. The above process was repeated until a pH=6 was maintained after shaking, the chloroform extract was separated, dried (Na2SO4) and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (100 ml), the solution saturated with hydrogen chloride gas and the mixture heated to gentle boiling for 10 mins. The mixture was filtered while hot and the precipitate dried yielding 2.11 g (70% yield) of a pale yellow powder. Purification was effected by crystallization from acetonitrile; mp 199-201.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].[CH3:10][N:11](C=O)C>C(OCC)(=O)C>[F:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[C:10]#[N:11]
Reactant: Cc1ccc(Br)c(F)c1
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C#N)c(F)c1
Yield: 70 %

Procedure:
A mixture of 4-bromo-3-fluorotoluene (2 g, 10.6 mmol) and cuprous cyanide (1.4 g, 15.9 mmol) in DMF (15 mL) was heated at reflux for 4 h. The reaction mixture was diluted with ethyl acetate, washed with aqueous ammonia, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc:n-hexane, 1:4) to give the title compound (1.0 g, 70%).
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[C:5]([C:10]([NH:13][C:14]2[N:15]=[N:16][C:17]([C:20]3[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=3)=[CH:18][N:19]=2)([CH3:12])[CH3:11])=[N:6][CH:7]=[CH:8][CH:9]=1.C([O-])([O-])=[O:29].[K+].[K+].CS(C)=O.OO>C(O)(=O)C>[F:27][CH:2]([F:1])[O:3][C:4]1[C:5]([C:10]([NH:13][C:14]2[N:15]=[N:16][C:17]([C:20]3[S:21][C:22]([C:25]([NH2:26])=[O:29])=[CH:23][N:24]=3)=[CH:18][N:19]=2)([CH3:12])[CH3:11])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(Nc1ncc(-c2ncc(C#N)s2)nn1)c1ncccc1OC(F)F
Agent: OO
Agent: [K+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CC(C)(Nc1ncc(-c2ncc(C(N)=O)s2)nn1)c1ncccc1OC(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 148.6 %

Procedure:
2-(3-(2-(3-(difluoromethoxy)pyridin-2-yl)propan-2-ylamino)-1,2,4-triazin-6-yl)thiazole-5-carbonitrile (15 mg, 38 μmol), K2CO3 (50 mg, 0.35 mmol), and DMSO (1 mL) were combined in a vial and cooled to 0° C. H2O2 (0.1 mL of 35% solution) was then added and the reaction was warmed to rt and stirred for 1 h. Acetic acid (0.1 mL) was added, and the reaction was filtered and then purified using reverse phase chromatography to afford 23 mg of 2-(3-(2-(3-(difluoromethoxy)pyridin-2-yl)propan-2-ylamino)-1,2,4-triazin-6-yl)thiazole-5-carboxamide as a white solid, m/z=408.3 [M+H].
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:14]2[C:15]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:16]=3[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][CH2:19][C:13]2=[N:12][N:11]=1)C1C=CC=CC=1.Br.[OH-].[Na+].O>C(O)(=O)C.C(Cl)Cl>[C:20]1([C:17]2[C:16]3[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:15]=3[N:14]3[C:10]([CH2:9][OH:8])=[N:11][N:12]=[C:13]3[CH2:19][N:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(COCc3ccccc3)n1-2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
An amount of 25 g of 1-(benzyloxymethyl)-6-phenyl- 8-chloro-4H-s-triazolo[4,3-a] [1,4]benzodiazepine is dissolved in 200 ml of glacial acetic acid; there is then added to the solution 170 ml of 48% aqueous hydrobromic acid. The mixture is heated for 90 minutes at 80° and then cooled to 5°; while stirring is maintained, the mixture is adjusted to pH 6 with concentrated sodium hydroxide solution, and water as well as methylene chloride subsequently added. The organic phase is separated, washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. The residue is dissolved in ethyl acetate/methanol (9:1); the solution is filtered through a column of 150 g of silica gel (Merck, particle size 0.05 - 0.2 mm), and the column eluted with ethyl acetate/methanol (9:1) to (7:3). The eluate is concentrated by evaporation and the residue crystallised from ethyl acetate/ether to obtain 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-methanol, M.P. 210°-211°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)/[C:3](=[CH:10]\[C:11]2[O:15][C:14]([CH:16]=O)=[CH:13][CH:12]=2)/[CH2:2]1.[C:18]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][C:22]1=[O:30])(=[O:20])[CH3:19].N1CCCCC1.C([OH:39])C>>[C:18]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)/[C:23](=[CH:16]\[C:14]2[O:15][C:11](/[CH:10]=[C:3]3/[C:2](=[O:39])[NH:1][C:9]4[C:4]/3=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:12][CH:13]=2)/[C:22]1=[O:30])(=[O:20])[CH3:19]
Reactant: O=Cc1ccc(/C=C2/CNc3ccccc32)o1
Reactant: CCO
Reactant: CC(=O)N1C(=O)Cc2ccccc21
Solvent: C1CCNCC1
Product: CC(=O)N1C(=O)/C(=C/c2ccc(/C=C3/C(=O)Nc4ccccc43)o2)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Diformylfuran (1 equivalent) was dissolved in ethanol, and a solution obtained by dissolving oxindole (0.5 equivalent) and piperidine (0.1 equivalent) in ethanol was gradually added thereto. After completion of the addition, the resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, the resulting precipitate was removed by filtration. To the filtrate, acetone was added and the resulting solution was acidified with a 1 N hydrochloric acid solution and evaporated to dryness under reduced pressure, whereby 5-((E)-(indolin-3-ylidene)methyl)furan-2-carbaldehyde was obtained (yield: 31%). Subsequently, the thus obtained 5-((E)-(indolin-3-ylidene)methyl)furan-2-carbaldehyde (1.2 equivalents), 1-acetyloxindole (1 equivalent) and piperidine (0.1 equivalent) were dissolved in ethanol and the resulting mixture was stirred at room temperature for 12 hours. After completion of the reaction, the resulting precipitate was collected by filtration, washed with cooled ethanol and dried, whereby a target compound was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Reactant: C#Cc1ccncc1
Product: CC(C)(C)c1cc2ncc(C#Cc3ccncc3)cn2n1

Procedure:
The title compound, white solid, MS: m/e=277.1 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 4-ethynylpyridine.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12](C=O)=[C:11]([C:27]3[CH2:28][CH2:29][O:30][CH2:31][CH:32]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:34]1[CH:35]=[CH:36][C:37]([C:42]([F:45])([F:44])[F:43])=[C:38]([CH:41]=1)[C:39]#[N:40].C([Mg]Cl)(C)C.[Cl-].[Li+].C([Mg]Cl)(C)C.[O:58]1CCC[CH2:59]1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:19][CH:20]([C@H:59]([OH:58])[C:34]3[CH:35]=[CH:36][C:37]([C:42]([F:45])([F:44])[F:43])=[C:38]([CH:41]=3)[C:39]#[N:40])[CH2:21]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:23])[CH3:24])[CH:12]=[C:11]([C:27]3[CH2:28][CH2:29][O:30][CH2:31][CH:32]=3)[C:10]1=2)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: N#Cc1cc(I)ccc1C(F)(F)F
Reactant: CC(C)c1nc2c(c(C3=CCOCC3)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2
Reactant: C1CCOC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Product: CC(C)c1cc(C2=CCOCC2)c2c(n1)CC1(CC([C@H](O)c3ccc(C(F)(F)F)c(C#N)c3)C1)C[C@@H]2O[Si](C)(C)C(C)(C)C

Procedure:
Obtained by starting from (S)-5′-(tert-butyldimethylsilyloxy)-4′-(3,6-dihydro-2H-pyran-4-yl)-2′-isopropyl-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-carbaldehyde and 5-iodo-2-(trifluoromethyl)benzonitrile. A 1.3 M solution of isopropylmagnesium chloride-lithium chloride-complex in tetrahydrofurane is used instead of a 2 M solution of isopropylmagnesium chloride in tetrahydrofurane.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C@H:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[C:31]1[CH:36]=[CH:35][C:34]([C:37](O)=[O:38])=[C:33]([F:40])[CH:32]=1)[CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:41][C:42]1([CH3:86])[O:47][C:46]2[N:48]=[CH:49][C:50](C(F)(F)F)=[CH:51][C:45]=2[N:44]([CH:56]2[CH2:61][CH2:60][N:59](C(C3C=CC(C4C=CC=CC=4OCC(C)(C)C(O)=O)=CC=3F)=O)[CH2:58][CH2:57]2)[C:43]1=[O:85].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl:120]CCl>>[Si:1]([O:18][CH2:19][CH2:20][C@H:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[C:31]1[CH:36]=[CH:35][C:34]([C:37]([N:59]2[CH2:60][CH2:61][CH:56]([N:44]3[C:43](=[O:85])[C:42]([CH3:86])([CH3:41])[O:47][C:46]4[N:48]=[CH:49][C:50]([Cl:120])=[CH:51][C:45]3=4)[CH2:57][CH2:58]2)=[O:38])=[C:33]([F:40])[CH:32]=1)[CH3:22])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(COc1ccccc1-c1ccc(C(=O)N2CCC(N3C(=O)C(C)(C)Oc4ncc(C(F)(F)F)cc43)CC2)c(F)c1)C(=O)O
Reactant: ClCCl
Reactant: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ccc(F)cc1-c1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ccc(F)cc1-c1ccc(C(=O)N2CCC(N3C(=O)C(C)(C)Oc4ncc(Cl)cc43)CC2)c(F)c1
Reaction time: 8 h

Procedure:
At room temperature, to a dichloromethane solution (10 ml) of 2′-{[(1R)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-methylpropyl]oxy}-3,5′-difluorobiphenyl-4-carboxylic acid (180 mg) were added 7-chloro-3,3-dimethyl-1-piperidin-4-yl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one trifluoroacetate (Reference Example 3) (132 mg), diisopropylethylamine (0.280 ml) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (183 mg), followed by stirring overnight. The reaction solution was diluted with dichloromethane, washed sequentially with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 1-{1-[(2′-{[(1R)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-methylpropyl]oxy}-3,5′-difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}-7-chloro-3,3-dimethyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (256 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C@@H:4]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([Cl:34])[CH:28]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[F:36][C:37]([F:48])([F:47])[C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH3:1][O:2][C:3](=[O:35])[C@@H:4]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([Cl:34])[CH:28]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:42]2[CH:41]=[CH:40][CH:39]=[C:38]([C:37]([F:48])([F:47])[F:36])[CH:43]=2)=[CH:8][CH:7]=1.[CH2:23]([O:22][C:21]1[CH:20]=[CH:19][C:18]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([Cl:34])[CH:28]=2)=[CH:17][C:16]=1[C:14]([NH:13][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:42]2[CH:41]=[CH:40][CH:39]=[C:38]([C:37]([F:48])([F:47])[F:36])[CH:43]=2)=[CH:8][CH:7]=1)[C:3]([OH:2])=[O:35])=[O:15])[CH2:24][CH2:25][CH3:26]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCCCOc1ccc(-c2ccc(F)c(Cl)c2)cc1C(=O)N[C@@H](Cc1ccc(Br)cc1)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCOc1ccc(-c2ccc(F)c(Cl)c2)cc1C(=O)N[C@@H](Cc1ccc(-c2cccc(C(F)(F)F)c2)cc1)C(=O)O
Product: CCCCOc1ccc(-c2ccc(F)c(Cl)c2)cc1C(=O)N[C@@H](Cc1ccc(-c2cccc(C(F)(F)F)c2)cc1)C(=O)OC
Temperature: 76 °C

Procedure:
2-(S)-[(4-Butoxy-3′-chloro-4′-fluoro-biphenyl-3-carbonyl)-amino]-3-(3′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester was prepared following General Procedure D using 3-(4-bromo-phenyl)-2-(S)-[(4-Butoxy-3′-chloro-4′-fluoro-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester ((0.677 g, 1.19 mmol), 3-trifluoromethyl-benzene boronic acid (0.349 g, 1.8 mmol), palladium tetrakis-triphenylphosphine (69 mg, 0.06 mmol), and Na2CO3(aq) (2.0 N, 5 mL, 10 mmol) in DME (10 mL). The mixture was heated at 76° C. for 19 h. Purification by flash chromatography (ethyl acetate/hexanes 1:5, 1:4) gave the methyl ester of the title compound (177 mg, 0.28 mmol).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH3:9].[F:10][C:11]1[C:16]([OH:17])=[CH:15][N:14]=[C:13]2[N:18]([Si](C(C)C)(C(C)C)C(C)C)[CH:19]=[CH:20][C:12]=12.O.C(#N)C>CN(C=O)C>[CH2:8]([O:17][C:16]1[C:11]([F:10])=[C:12]2[CH:20]=[CH:19][NH:18][C:13]2=[N:14][CH:15]=1)[CH3:9]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(O)cnc21
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: CCOc1cnc2[nH]ccc2c1F
Temperature: 60 °C
Yield: 23.7 %

Procedure:
Potassium carbonate (3.49 g, 25.3 mmol) and bromoethane (1.10 g, 10.1 mmol) were added to 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol (2.6 g, 8.43 mmol) in DMF (5 mL). The reaction was heated to 60° C. in a sealed tube for 24 hours and then filtered. After concentration, the filtrate was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, water/ACN, 90/10→10/90, 20CV) to yield 5-ethoxy-4-fluoro-1H-pyrrolo[2,3-b]pyridine (360 mg, 12% yield) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH:16]=O.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:16]/[C:15]3[CH:18]=[CH:19][C:20]([F:21])=[C:13]([Cl:12])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccc(F)c(Cl)c1
Temperature: 50 °C
Yield: 81.1 %

Procedure:
To the mixture of 6-chloro-2-oxindole (5.3 g, 32 mmol) (Crescent) and 3-chloro-4-fluorobenzaldehyde (5 g, 32 mmol) (Aldrich) in methanol (200 mL) was added piperidine (2.7 g, 32 mmol) (Aldrich) dropwise. The mixture was then heated at 50° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-4-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 8 g, 82%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O)([CH3:3])[CH3:2].[BH4-].[Na+].C([OH:15])C>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:15])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCO
Reactant: CC(C)N1CCCCC1=O
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a cold (0° C.) solution of 1-isopropylpiperidone (purchased at Chemie Brunschwig AG, 100 g, 1.0 eq.) in ethanol (500 mL) was added sodium borohydride (19.3 g, 0.7 eq.) in small portions. The reaction mixture was allowed to warm up to room temperature and was stirred overnight. After concentration in vacuo, ice water (1 kg), sodium hydroxide aqueous solution (28% in mass, 0.5 L) and dichloromethane (1 L) were added. The mixture was stirred vigorously for 4 h and the aqueous layer was extracted with dichloromethane. Combined organic layers were washed with brine, dried over sodium sulfate, filtered and purified by fractionated vacuum distillation (20 mBar). One fraction (95° C. at 20 mBar) was isolated to yield 61.3 g (60%) of the title product as colorless oil. MS (m/e): 144.5 (MH+, 100%).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.[CH:25]1(O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C>[CH:25]1([O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]2[N:2]([CH3:1])[C:3]3[CH:4]=[CH:5][C:6]([N:17]([CH2:18][CH2:19][Cl:20])[CH2:21][CH2:22][Cl:23])=[CH:7][C:8]=3[N:9]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: OC1CCCCC1
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: Cn1c(CCCC(=O)OC2CCCCC2)nc2cc(N(CCCl)CCCl)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 250 mL three neck round bottom flask was equipped with an overhead stirrer, thermocouple, temperature controller and nitrogen sweep then charged with 10 g (25.34 mmol) of bendamustine hydrochloride, 2.56 g (2.7 mL, 25.6 mmol, 1.01 eq) of cyclohexanol, 5.3 g (25.6 mmol, 1.01 eq) of dicyclohexylcarbodiimide (DCC), 100 mL of MDC and 0.31 g (2.54 mmol, 0.1 eq) of DMAP. The reaction slurry was stirred at RT for 18 h until an in process analysis indicated the reaction was complete. Two new major product peaks were observed. Solids were removed by vacuum filtration and washed with 5 mL of MDC. The filtrate was washed with 4% aqueous sodium bicarbonate solution (2×100 mL) before drying over sodium sulfate, filtering and concentrating to dryness in vacuo to yield a yellow oil with some solids present. 1H NMR analysis indicated residual DMAP and cyclohexanol was along with DCC by-products were present in addition to the desired product. The residue was slurried with 50 mL of MDC to remove residual cyclohexanol then concentrated in vacuo and chromatographed. The chromatography was carried out using 50 g of silica gel 60, 230-400 mesh, eluting with 1:1 heptane/EtOAc collecting 100 mL fractions. Product containing fractions were combined and concentrated to dryness in vacuo to yield 3.11 g (7.06 mmol, 27.9%) of the product as an off-white solid with an HPLC purity of 97.8A %. 1H NMR (400 MHz, DMSO-d6) δ 7.31 (d, J=8.76 Hz, 1H), 6.93 (d, J=2.28 Hz, 1H), 6.77 (dd, J=2.40, 8.80 Hz, 1H), 4.65 (m, 1H), 3.7 (s, 8H), 3.65 (s, 3H), 2.83 (t, J=7.4 Hz, 2H), 2.44 (t, J=7.36 Hz, 2H), 2.00 (m, 2H), 1.76 (m, 4H), 1.65 (m, 2H), 1.33 (m, b, 6H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([F:14])=[C:10]([CH:13]=1)[CH:11]=[O:12]>C(OCC)C.II>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([F:14])=[C:10]([CH:11]([OH:12])[CH2:1][CH2:2][CH3:3])[CH:13]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCCBr
Agent: II
Solvent: CCOCC
Product: CCCC(O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
To a suspension of Mg (0.236 g, 9.83 mmol) in diethyl ether (10 mL), I2 (1 spatula) was added n-propyl bromide (0.72 g, 0.53 mL, 5.9 mmol) at room temperature. When iodine color disappeared, the remaining n-propyl bromide in ether was added to the reaction mixture and stirred at room temperature for 10 minutes. To this Grignard reagent, 5-bromo-2-fluorobenzaldehyde (1.00 g, 4.92 mmol) in ether was added under cold conditions and stirred at room temperature for 1 hour. The reaction mixture was quenched with NH4Cl solution and extracted with ether. The ether layer was dried over anhydrous Na2SO4, filtered and concentrated to afford 1-(5-bromo-2-fluoro-phenyl)-butan-1-ol (1.14 g, 92.6%). 1H NMR (CDCl3): δ 7.6 (m, 1H), 7.3-7.4 (m, 1H), 6.9 (t, 1H), 5.0 (brs, 1H), 2.0 (brs, 1H), 1.6-1.7 (m, 2H), 1.3-1.5 (m, 2H), 1.0 (t, 3H).