Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.C(N(CC)C(C)C)(C)C.[F:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]=[C:46]=[O:47])=[CH:41][CH:40]=1>CN(C=O)C>[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][N:26]([C:46]([NH:45][C:42]6[CH:43]=[CH:44][C:39]([F:38])=[CH:40][CH:41]=6)=[O:47])[CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1
Reactant: C1=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CCNC1
Reactant: O=C=Nc1ccc(F)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)cc1)N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
To a suspension of benzothiazol-6-yl-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine trihydrochloride (50.0 mg, 0.11 mmol) in DMF (1.5 mL) was added N,N-diisopropylethylamine (0.04 mL, 0.20 mmol). The reaction mixture stirred at −20° C. for 5 min prior to the addition of 4-fluorophenyl isocyanate (9.5 mg, 0.07 mmol) in DMF (0.5 mL). The mixture was left to stir at rt for 1 h. The mixture was concentrated in vacuo and purified via MDP, which afforded the title compound as a white solid. MS (ES+): m/z: 485.88 (100) [MH+]. HPLC: tr=2.73 min (ZQ2000: polar—5 min). 1H NMR (400 MHz, CDCl3): δ=2.52-2.56 (m, 2H), 3.31 (s, 1H), 3.70 (t, 2H), 4.20 (s, 2H), 6.94 (m, 1H), 6.86 (d, J=0.8 Hz, 1H), 7.06-7.11 (m, 2H), 7.48-7.51 (m, 2H), 7.87 (dd, J=2.4, 8.8 Hz, 1H), 8.04 (d, J=8.8 Hz, 1H), 8.35 (s, 1H), 8.59 (s, 1H), 8.92 (d, J=2.0 Hz, 1H), 9.24 (s, 1H), 9.62 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[C:16]([N:19]3[CH2:23][CH:22]4[CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][CH:21]4[CH2:20]3)[S:17][CH:18]=2)[CH2:10]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[C:16]([N:19]3[CH2:20][CH:21]4[CH2:26][NH:25][CH2:24][CH:22]4[CH2:23]3)[S:17][CH:18]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC2CN(c3nc(C4=NOC(c5c(F)cccc5F)C4)cs3)CC2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cccc(F)c1C1CC(c2csc(N3CC4CNCC4C3)n2)=NO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1,1-dimethylethyl 5-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-carboxylate (i.e. the product of Step C) (0.6 g, 1.26 mmol) in dichloromethane (15 mL) cooled to 0° C. was added trifluoroacetic acid (2 mL, 26.93 mmol). The reaction mixture was allowed to warm to room temperature, stirred for 3 h, and then concentrated under reduced pressure. The resulting material was dissolved in water (50 ml) and basified by the addition of sodium hydroxide (10%) to pH 12, and then extracted with chloroform (3×50 mL). The combined organic extracts were concentrated under reduced pressure to provide the title product as a white-gummy solid (0.42 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[C:5]#[N:6].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:19][CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[C:8]([CH3:11])[C:9]=1[O:10][CH2:19][CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: CC(C)(C)OC(=O)CCCBr
Reactant: Cc1cc(C#N)cc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C#N)cc(Cl)c1OCCCC(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 72 h
Yield: 30.3 %

Procedure:
A mixture of 3-chloro-4-hydroxy-5-methyl-benzonitrile (1.15 g, 6.87 mmol) and Cs2CO3 (13.43 g, 41.2 mmol) in DMF (45 mL) is stirred at rt for 30 min before tert.-butyl 4-bromobutanoate (1.55 g, 6.95 mmol) is added. The orange suspension is stirred at 65° C. for 72 h. Another portion of tert.-butyl 4-bromobutanoate (1.55 g, 6.95 mmol) is added and stirring is continued at 65° C. for 24 h. The mixture is dilued with water (150 mL) and extracted three times with DCM (3×50 mL) and EA (3×50 mL). The org. extracts are combined, dried over MgSO4, filtered and concentrated. The crude product is purified by MPLC on silica gel eluting with heptane:EA:methanol to give tert-butyl 4-(2-chloro-4-cyano-6-methylphenoxy)butanoate (645 mg) as a colourless oil; LC-MS: tR=1.01 min, [M+H]+=no mass detectable; 1H NMR (D6-DMSO): δ 7.94 (d, J=1.7 Hz, 1H), 7.75 (d, J=1.3 Hz, 1H), 3.95 (t, J=6.3 Hz, 2H), 2.46 (t, J=7.2 Hz, 2H), 2.30 (s, 3H), 1.98 (quint, J=6.6 Hz, 2H), 1.41 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[O:6].[C-:11]#[N:12].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[C:11]#[N:12])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Product: N#CC(O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
25 g of 3,4-dichlorobenzaldehyde are added to a solution of 32.5 g of Na2S2O5 in 100 ml of water and the mixture is heated at 40°-45° C. for 1 hour. After one night at room temperature, the reaction mixture is cooled and a solution of 19.5 g of KCN in 40 ml of water is added slowly. After stirring for 30 minutes at RT, extraction is carried out with ether and the extract is washed with water, dried over MgSO4 and evaporated under vacuum to give 29 g of the expected product, which is used as such in the next step.
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([C@@H:7]1[N:12]2[C:13](=[O:26])[C@@H:14]([NH:15][C:16](=[O:25])[CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@H:11]2[S:10][CH:9]=[C:8]1[O:27][CH3:28])=[O:6].O.Cl>O1CCCC1.C(Cl)Cl>[O:18]([CH2:17][C:16]([NH:15][C@@H:14]1[C:13](=[O:26])[N:12]2[C@@H:7]([C:5]([OH:6])=[O:4])[C:8]([O:27][CH3:28])=[CH:9][S:10][C@H:11]12)=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@H]1C(OC)=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COC1=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)O
Reaction time: 0.08 h

Procedure:
15 ml of cooled 0.1 N aqueous potassium hydroxide solution are added, whilst stirring, to a solution, cooled in an ice bath, of 382 mg of 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid methyl ester in 30 ml of tetrahydrofurane. After 5 minutes, 100 ml of water and 70 ml of methylene chloride are added and the mixture is acidified by adding 10 ml of 1 N aqueous hydrochloric acid. The methylene chloride phase is separated off and the aqueous phase is extracted with 30 ml of methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is crystallised from chloroform/diethyl ether and gives 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid of melting point 142° C. (decomposition).
Reaction SMILES: [K].[CH3:2][C:3]1([CH3:14])[CH:5]([CH:6]=[C:7]2[CH2:10][CH2:9][CH2:8]2)[CH:4]1[C:11]([OH:13])=[O:12].[F:15][C:16]1[C:21]([CH2:22]Br)=[C:20]([F:24])[C:19]([F:25])=[C:18]([F:26])[C:17]=1[F:27].O>CN(C)C=O>[CH3:2][C:3]1([CH3:14])[CH:5]([CH:6]=[C:7]2[CH2:10][CH2:9][CH2:8]2)[CH:4]1[C:11]([O:13][CH2:22][C:21]1[C:20]([F:24])=[C:19]([F:25])[C:18]([F:26])=[C:17]([F:27])[C:16]=1[F:15])=[O:12]
Reactant: CC1(C)C(C=C2CCC2)C1C(=O)O
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C(C=C2CCC2)C1C(=O)OCc1c(F)c(F)c(F)c(F)c1F
Yield: 67.1 %

Procedure:
3.6 g (0.0165 mol) of the potassium salt of 2,2-dimethyl-3-cyclobutylidenemethylcyclopropanecarboxylic acid were dissolved in 50 ml of dimethylformamide and the solution was heated to 110° C., together with 4.3 g (0.0165 mol) of pentafluorobenzyl bromide, for 3 hours. After the reaction had ended, the reaction mixture was poured into 150 ml of water and extracted twice with 100 ml of methylene chloride each time. The organic phase was then extracted by shaking twice with 100 ml of water each time and then dried over sodium sulphate. The solvent was stripped off in vacuo and last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 4.0 g (67.1% of theory) of pentafluorobenzyl 2,2-dimethyl-3-cyclobutylidenemethylcyclopropanecaboxylate were obtained as a brown oil with the refractive index nD30 :1.4850.
Reaction SMILES: [NH:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[NH:3]1.Cl.Cl.N[CH:15]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:16]([NH:18][C:19]1([C:26]#[N:27])[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)=[O:17]>C1COCC1>[C:26]([C:19]1([NH:18][C:16](=[O:17])[CH:15]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]=2)[CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)#[N:27]
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Reactant: N=C1NC(=O)c2ccccc21
Agent: Cl
Solvent: C1CCOC1
Product: CN1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC2=NC(=O)c3ccccc32)CC1

Procedure:
The title compound was prepared starting from 3-imino-2, 3-dihydro-isoindol-1-one and 2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide bis hydrochloride salt according to the procedure from Example 10, except that refluxing THF was used as the solvent. The compound was further purified by HPLC using a 20×250 mm C18 reverse phase column with the method being 20% acetonitrile in water to acetonitrile. MS, m/z 422.5=M+1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][C:10]=1[NH2:11])=[O:5])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Br[CH:19]([CH3:28])[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].CCOC(C)=O.CCCCCC>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:19]([CH3:28])[C:20](=[O:21])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]=1[NH2:11])=[O:5])[CH3:2]
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: CCOC(=O)c1cn[nH]c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(C(C)C(=O)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 11.6 %

Procedure:
5-Amino-1H-pyrazole-4-carboxylic acid ethyl ester (7.35 g, 47.3 mmol) was dissolved in 160 mL of DMF. Na2CO3 (5.02 g, 47.3 mmol) was added followed by 2-bromopropiophenone (7.2 mL, 47.3 mmol). The reaction stirred at room temperature for 2 days. The solution was diluted with AcOEt and the organic layer was washed with sat. NaHCO3, brine, dried (MgSO4), and concentrated. Flash chromatography (20-45% AcOEt/hexane) gave the desired product (1.58 g, 12% yield). 1H NMR (400 MHz, CDCl3) δ 1.3 (t, J=7.0 Hz, 3H), 1.7 (d, J=7.4 Hz, 3H), 4.2 (q, J=7.0 Hz, 2H), 5.4 (bs, 2H), 5.9 (q, J=7.0 Hz, 1H), 7.41-7.59 (m, 3H), 7.60 (s, 1H), 8.0 (d, J=8.0 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:9])[CH3:8].[N+:17]([O-])([O-:19])=[O:18].[K+]>OS(O)(=O)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18])([CH3:9])[CH3:8]
Reactant: O=[N+]([O-])[O-]
Reactant: COCCOCC(C)(C)c1ccc(N)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COCCOCC(C)(C)c1ccc(N)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 71.7 %

Procedure:
To a solution of 4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenylamine (5.8 g, 26 mmol) in H2SO4 (20 mL) was added KNO3 (2.63 g, 26 mmol) at 0° C. After addition was complete, the mixture was stirred at this temperature for 20 min and then poured into ice-water. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (petroleum ether-EtOAc, 100:1) to give 4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-3-nitro-phenylamine (5 g, 71%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1([CH3:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][C:8]1[CH2:13][CH2:12][C@@H:11]([C:1]([CH3:6])=[CH2:2])[CH2:10][CH:9]=1
Reactant: Cc1ccccc1
Solvent: Oc1ccccc1
Product: C=C(C)[C@H]1CC=C(C)CC1
Temperature: 25 °C
Yield: 94 %

Procedure:
A 500 gram portion of phenol was dissolved in toluene and cooled to a temperature of less than 5° C. Gaseous nitrogen was bubbled through the phenol solution by means of a gas dispersion tube and a 30 cc. portion of redistilled BF3.(Et)2O was added. The solution changed color from light yellow to light red-brown. A 140 gram portion of d-limonene was slowly added by a dropping funnel while the solution was maintained at a temperature of less than 5° C. After maintaining this temperature overnight to allow completion of the reacion, the mixture was neutralized with 0.2N sodium hydroxide solution. The progress of the neutralization was followed by means of a color change (dark to light) of the reaction mixture. The reaction mixture was then steam distilled to remove the unreacted phenol. The mixture was cooled to room temperature, some of the water was removed by decantation and the remainder was removed by azetropic distillation using diethylether. The excess solvent was allowed to evaporate and the product was dried in an oven at 135° C. for 64 hours, yielding 236 grams of product (94% yield after correction for purity of the limonene).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH2:11])[C:5]2=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[N:3]=1.[S:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1.C(=O)([O-])[O-].[K+].[K+].COCCOC.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[O:18]([C:15]1[CH:16]=[CH:17][C:12]([C:4]2[N:3]=[C:2]([C:27]3[CH:28]=[CH:29][S:25][CH:26]=3)[N:6]3[CH:7]=[CH:8][N:9]=[C:10]([NH2:11])[C:5]=23)=[CH:13][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccsc1
Reactant: Nc1nccn2c(Br)nc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nccn2c(-c3ccsc3)nc(-c3ccc(Oc4ccccc4)cc3)c12

Procedure:
A mixture of 3-bromo-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazin-8-ylamine (20.0 mg, 0.0525 mmol), 3-thiophenylboronic acid (7.38 mg, 0.0577 mmol), Pd(PPh3)4 (10 mg, 0.01 mmol), potassium carbonate (21.8 mg, 0.157 mmol) and DME/Water (5:1) was microwaved at 300 watt, 100° C. for 30 min. The solution was transferred to a 20 mL vial, and 1 mL of DMF was added. The solution was concentrated in vacuo until only DMF remained. The mixture was passed through a syringe filter pad, and prepared for Gilson HPLC separation. The fractions containing the pure product were collected and concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=6.96 (d, J=5.3 Hz, 1H), 7.07-7.12 (m, 2H), 7.14-7.22 (m, 3H), 7.38-7.43 (m, 2H), 7.55-7.67 (m, 5H), 7.86 (dd, J=3.0, 1.3 Hz, 1H). MS (ES+): m/z 384.94 (100) [MH+]. HPLC: tR=2.58 min (polar—5 min).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[Cl:18][C:19]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][C:20]=1[CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>>[Cl:18][C:19]1[CH:34]=[C:33]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH:32]=[CH:31][C:20]=1[CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)c(Cl)c1
Yield: 56.3 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (3.0 g, 9.7 mmol) was reacted with tert-butyl 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethylcarbamate (5.53 g, 14.5 mmol) to afford the desired product (2.65 g, 57%) as a light brown solid. ESI MS m/z 485 [C25H25ClN2O4S+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.[Si:10]([O:17][CH2:18]/[CH:19]=[N:20]/[S@@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>>[Si:10]([O:17][CH2:18][C@@H:19]([NH:20][S@@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[S@@](=O)/N=C/CO[Si](C)(C)C(C)(C)C
Reactant: Fc1ccc(Br)cc1F
Product: CC(C)(C)[S@@](=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1ccc(F)c(F)c1
Yield: 65 %

Procedure:
(R)—N—((S)-2-(tert-butyldimethylsilyloxy)-1-(3,4-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (4.12 g, 65%) was prepared by the procedure described in Example 99, Step 1, using 4-bromo-1,2-difluorobenzene and (R,E)-N-(2-(tert-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:24])=[CH:9]/[S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:12])=[O:11])=[CH:4][CH:3]=1.ClC1C=CC(C(=C)CS(NC2C=CC=CC=2S(N)(=O)=O)(=O)=O)=CC=1>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:24])[CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:11])=[O:12])=[CH:4][CH:3]=1
Reactant: C/C(=C\S(=O)(=O)Nc1ccccc1S(N)(=O)=O)c1ccc(Cl)cc1
Agent: C=C(CS(=O)(=O)Nc1ccccc1S(N)(=O)=O)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: CC(CS(=O)(=O)Nc1ccccc1S(N)(=O)=O)c1ccc(Cl)cc1
Yield: 56 %

Procedure:
A mixture of (E)-2-(2-(4-chlorophenyl)prop-1-enylsulfonamido)benzenesulfonamide and 2-[2-(4-chlorophenyl)prop-2-enylsulfonylamino]benzenesulfonamide (100 mg, 0.26 mmol) was dissolved in EtOAc in a 5 mL syringe. The solution was filtered and injected into the H-cube (1 ml/min, full hydrogen. 10% Pd/C). The solvent was then removed under reduced pressure and the crude material was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (56 mg, 56%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH3:18])[CH:16]=[N:17][C:13]=2[CH:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>O>[CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH3:18])[CH:16]=[N:17][C:13]=2[CH:12]=[C:11]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[C:27]([O:28][CH3:29])[CH:26]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cnc2cc(Br)cc(OCc3ccccc3)c21
Reactant: COc1ccc(B(O)O)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cc(OCc3ccccc3)c3c(c2)ncn3C)cc1OC
Temperature: 110 °C

Procedure:
To a mixture 7-(benzyloxy)-5-bromo-1-methyl-1H-benzo[d]imidazole 2.51 (105 mg, 0.33 mmol), 3,4-dimethoxy phenyl boronic acid (72 mg, 0.39 mmol), Cs2CO3 (294 mg, 0.90 mmol) and PEPPSI″-IPr catalyst (10.2 mg, 0.015 mmol) was added DME and water (1:1, 3 mL) and the reaction was heated to 110° C. for 1 hr. The reaction mixture was concentrated and purified by flash chromatography (SiO2, 0% MeOH/EtOAc to 20% MeOHEtOAc/MeOH) to afford 7-(benzyloxy)-5-(3,4-dimethoxyphenyl)-1-methyl-1H-benzo[d]imidazole 2.52.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:20].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:21])=[C:7]([CH3:20])[CH:8]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Br)c2)cc1C
Reactant: Oc1ccc(Cl)cc1
Product: Cc1cc(Oc2cccc(Oc3ccc(Cl)cc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4-chlorophenol as in Example 18 to afford 0.019 g (9%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C22H19O4Cl 383.1050, found 383.1033 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:7][C:8](=[O:34])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22](=[O:25])[N:21]([CH3:26])[CH:20]=2)=O)=[CH:11][CH:10]=1)[CH:4]([CH3:6])[CH3:5].Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[OH:1][CH2:2][C@@H:3]([NH:7][C:8](=[O:34])[C:9]1[CH:10]=[CH:11][C:12]([CH:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH2:16]/[C:17](=[N:36]\[OH:37])/[C:19]2[CH:24]=[CH:23][C:22](=[O:25])[N:21]([CH3:26])[CH:20]=2)=[CH:13][CH:14]=1)[CH:4]([CH3:5])[CH3:6]
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N[C@H](CO)C(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N[C@H](CO)C(C)C)cc1

Procedure:
In analogy to example 151, step 3, N—((S)-1-hydroxy-3-methylbutan-2-yl)-4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as an off-white solid containing <10% of the corresponding Z isomer, MS (ESI+): m/z=476.2 [M+H]+.
Reaction SMILES: C1O[CH:4]([C:5]2[C:6]([C:10]3[O:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=3)=[N:7][NH:8][CH:9]=2)OC1.Cl.[NH2:20][OH:21].C([O-])(=O)C.[Na+]>>[N+:15]([C:12]1[O:11][C:10]([C:6]2[C:5]([CH:4]=[N:20][OH:21])=[CH:9][NH:8][N:7]=2)=[CH:14][CH:13]=1)([O-:17])=[O:16]
Reactant: NO
Reactant: O=[N+]([O-])c1ccc(-c2n[nH]cc2C2OCCO2)o1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(-c2n[nH]cc2C=NO)o1
Yield: 94 %

Procedure:
Following the same procedure, react 2.5 g of 3-(5-nitro-2-furyl)-1H-pyrazole-4-carboxaldehye ethyleneacetal in a similar manner with 0.9 g of hydroxylamine hydrochloride and 0.8 g of sodium acetate to obtain a 94% yield of 3-(5-nitro-2-furyl)-1H-pyrazole-4-carboxaldehydeoxime.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]([OH:27])=O)[CH:19]=3)[NH:14]2)[CH:5]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30]>CN(C)C1C=CN=CC=1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:13]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]([NH:32][S:29]([CH3:28])(=[O:31])=[O:30])=[O:27])[CH:19]=3)[NH:14]2)[CH:5]=[C:6]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(F)cc(N2CCCC2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cc(F)cc(N2CCCC2)c1
Temperature: 60 °C
Yield: 35.3 %

Procedure:
A mixture of 2-(3-fluoro-5-pyrrolidin-1-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (50 mg, 0.14 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (39 mg, 0.20 mmol), 4-dimethylaminopyridine (24.4 mg, 0.20 mmol), methane sulfonamide (40 mg, 0.42 mmol) in dichloromethane (3 mL) was heated for 12 hours at 60° C. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-[2-(3-fluoro-5-pyrrolidin-1-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (22 mg, 35%) as a light yellow solid: LC/MS m/e calcd for C23H28FN3O3S (M+H)+: 446.6, observed: 446.2.